Unit 5- GI

Relate the development of megaloblastic anemia and metabolic acidosis with terminal ileitis.

- B12 deficiency due to terminal ileum damage and or surgical removal. - Loss of HCO3- (bicarb) leads to metabolic induced acidosis.

Type II Diabetes Genetic Factors

- Genetic factors ○ Susceptibility contributes to pathogenesis ○ First degree relative have 5-10 fold higher risk of developing type 2 DM than those without family hx ○ Genome wide studies performed over the last decade have identified at least 30 loci that individually confer a minimal to modest increase in lifetime risk for type 2 DM § Usually involved with insulin secretion

Ledipasavir MOA

- MOA: Inhibits HCV NS5A protein, which is required for viral replication; resistance selection in cell culture and cross-resistance studies indicate ledipasvir targets NS5A as its mode of action

Ceftriaxone MOA

- MOA: Inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins (PBPs) which in turn inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls, thus inhibiting cell wall biosynthesis. Bacteria eventually lyse due to ongoing activity of cell wall autolytic enzymes (autolysins and murein hydrolases) while cell wall assembly is arrested.

Albumin MOA

- MOA: Provides increase in intravascular oncotic pressure and causes mobilization of fluids from interstitial into intravascular space

Lactulose MOA

- MOA: The bacterial degradation of lactulose resulting in an acidic pH inhibits the diffusion of NH3 into the blood by causing the conversion of NH3 to NH4+; also enhances the diffusion of NH3 from the blood into the gut where conversion to NH4+ occurs; produces an osmotic effect in the colon with resultant distention promoting peristalsis; reduces blood ammonia concentration to reduce the degree of portal systemic encephalopathy

Sofobuvir MOA

-MOA: Sofosbuvir, a direct-acting antiviral agent against the hepatitis C virus, is a prodrug converted to its pharmacologically active form (GS-461203) via intracellular metabolism. It inhibits HCV NS5B RNA-dependent RNA polymerase, essential for viral replication, and acts as a chain terminator.

Describe specific complications from liver cirrhosis including spontaneous bacterial peritonitis, hepatic encephalopathy and ascite

-Spontaneous bacterial peritonitits UpToDate: Cirrhosis predisposes to the development of bacterial overgrowth, possibly because of altered small intestinal motility [5], and the presence of hypochlorhydria due to use of proton pump inhibitors [6]. In addition, patients with cirrhosis may have increased intestinal permeability Medscape: A variety of factors contributes to peritoneal inflammation and bacterial growth in ascitic fluid. A key predisposing factor may be the intestinal bacterial overgrowth found in people with cirrhosis, mainly attributed to delayed intestinal transit time. Intestinal bacterial overgrowth, along with impaired phagocytic function, low serum and ascites complement levels, and decreased activity of the reticuloendothelial system, contributes to an increased number of microorganisms and decreased capacity to clear them from the bloodstream, resulting in their migration into and eventual proliferation within ascites fluid. Patients with low protein levels in ascitic fluid (< 1 g/dL) have a 10-fold higher risk of developing spontaneous bacterial peritonitis than those with a protein level greater than 1 g/dL. -Hepatic Encephalopathy (Brain edema is caused by osmotic effects of glutamine accumulation within neurons) -Ascites From portal hypertension compounded with hypoalbuminemia (hypoalbuminemia creates a lower hydrostatic pressure within the blood vessels, so the plasma has less water-pulling power)

IBD: ileostomy, partial Small bowel resection, ileocolonic anastomoses

1) Ileostomy: a surgical operation in which a piece of the ileum is diverted to an artificial opening in the abdominal wall. 2) Ileocolonic anastomosis: joining of end of ileum to first part of colon, usually performed after a bowel resection 3) Partial small bowel resection: remove part of small bowel UC is surgically curable. However, surgical resection is not curative in CD, with recurrence being the norm. Consider early consultation with a surgeon in the setting of severe colitis or bowel obstruction and in cases of suspected toxic megacolon.

IBD: prognosis

1) The majority of studies indicate a small but significant increase in mortality associated with IBD. [39] A frequent cause of death in persons with IBD is the primary disease [40] ; infections and COPD/respiratory illness are other major causes of death. [41] IBD is not a risk factor for cardiovascular mortality 2) Patients with IBD are more prone to the development of malignancy. Persons with Crohn disease have a higher rate of small bowel malignancy. Patients with pancolitis, particularly ulcerative colitis, are at a higher risk of developing colonic malignancy after 8-10 years of disease. The current standard of practice is to screen patients with colonoscopy at 1-2 year intervals once they have had the disease for greater than 10 years.

Three function model of medical interview (Cole)

1. Build the relationship. 2. Assess and understand. 3. Collaborate for management.

Gastric Motilty patterns contributing to mixing, grinding, and sieving of gastric contents (LGS 5.2 #1)

1. Circumferential contraction A sweeps toward pylorus resulting in anterograde and retrograde propulsion of material 2. Contraction A subsides, a second contraction B, mixes contents further 3. Contraction B is sufficient to cause ransient and partial opening of the pylorus, allowing particles smaller than 1mm to exit the stomach. Larger particles are propelled back into the stomach to be further dispered by contraction C 4. Further cycles of contraction agasint a closed pylorus continue mixing and grinding until all of the meal is emptied from the stomach

Formation of cholesterol gallstones

1. During mixed micelle formation, cholesterol of phospholipids transfer to new forming micelles to form more mixed micelles 2. phospholipids are moved preferentially, leaving more cholesterol in micelles 3. when C concentration is higher than normal, more cholesterol is supersaturated in vesicles 4. this allows for crystallization, forming cholesterol gallstones

Pancreas has what 2 functions

1. Endocrine (hormonal-insulin) 2. Exocrine (enzyme secretion)

What are the essentials elements and order for an abdominal exam?

1. Inspection: Scars, Skin Color (Cullen, Gray turner) (surgical trivia) Veins (portal hypertension) Contour (distended, flat, scaphoid, symmetry, organomegaly) 2. Auscultation:Bowel sounds (Hyperactive, hypoactive, pitch, location) use diaphragm (higher pitch) Bruits (aorta, iliac, femoral arteries)- use bell, lower pitch Venous hum Friction rubs 3. Percussion Assess organ size (Hepatomegaly, Splenomegaly) Liver span Spleen 4. Palpation- light palpation first then moderate then deep. Start in the non tender quadrant first. Aorta Size. special tests: Assess Kidneys for tenderness (CVA tenderness) Murphy Sign (cholestatisis) Mcburneys (appendicitis) iliopsoas and obturator signs for appendicitis Fluid Wave (Ascites) Rebound Tenderness

Layers of the GI tract

1. Mucosa (basement membrane, lamina propria, and muscularis mucosa) 2. Submucosa 3. Muscularis propria (circular, myenteric plexus, and longitudinal muscle. 4. mesothelium/serosa.

Disease highlights- biliary colic

1. Occurs when a gallstone becomes lodged in the cystic duct and the gallbladder contracts against the obstruction. 2. Presents as one of the classic visceral obstructive syndromes with severe, constant, and crampy waves of pain that incapacitate the patient. 3. Characterized by episodes of pain with pain-free intervals of weeks to years. 4. Pain begins 1-4 hours after eating or may awaken the patient during the night. May be precipitated by fatty meals. 5. The pain is usually associated with nausea and vomiting. 6. The pain usually lasts < 2-4 hours. An episode that lasts longer than 4-6 hours and is accompanied by fever or marked tenderness suggests cholecystitis has developed. 7. Resolution occurs if the stone comes out of the gallbladder neck. The intense pain improves fairly rapidly, although mild discomfort may persist for 1 to 2 days. 8. Prognosis a. Biliary colic recurs in 50% of symptomatic patients. b. Acute cholecystitis develops if the stone remains lodged in the cystic duct. c. Complications (eg, pancreatitis, acute cholecystitis, or ascending cholangitis) occur in 25% of patients who have experienced biliary colic. 9. Colic occasionally develops in patients without stones secondary to sphincter of Oddi dysfunction or scarring leading to obstruction.

Disease highlights- asymptomatic cholelithiasis

1. Predisposing factors a. Increasing age is the predominant risk factor. The prevalence is 8% in patients older than 40 years and 20% in those older than 60 years (Figure 3-3). b. Obesity c. Gender: women are affected more than men (risk increases during pregnancy) d. Gallbladder stasis (due to rapid weight loss, which may occur in patients on very low calorie diets, on total parenteral nutrition, and after surgery) e. Other less common risk factors include family history, Crohn disease, and hemolytic anemias (eg, thalassemia, sickle cell disease) which can lead to increased bilirubin excretion and bilirubin stones. 2. Cholecystectomy not advised for patients with asymptomatic cholelithiasis. Make sure the gallstones are causing the pain before advising cholecystectomy. 3. Annual risk of biliary colic developing in patients with asymptomatic gallstones is 1-4%.

What are the four classes of pancreatic secretions?

1. Proteases 2. Amylolytic enzymes - only one is amylase. 3. Lipases 4. Nucleases.

Cell types of the pancreas

1. alpha cells secrete glucagon (stimulates glycogenolysis to increase blood glucose) 2. beta cells secrete insulin (helps to reduce blood glucose levels by facilitating glucose uptake) 3. delta cells secrete somatostatin (suppresses both insulin and glucagon release) 4. pancreatic polypeptide cells secrete pancreatic polypeptide (increased gastric enzyme secretion and inhibition go intestinal mobility) 5. D1 cells- VIP (vasoactive intestinal polypeptide- induces glycogenolysis and hyperglycemia) 6. enterchromaffin cells- synthesize serotonin.

bile salts as used in transport

1. are water soluble 2. are amphipathic= one side of molecule is hydrophilic and one side is hydrophobic 3. form micelles with an inner core to act as a solvent for hydrophobic lipids

Presence of chyme in the duodenum causes...

1. increased secretion of CCK 2. contraction of gallbladder 3. relaxation of sphincter of oddi by CCK-stimulated sago-vagal reflex leading to VIP and NO release

GI control

1. paracrine (local)-histamine, somatostatin 2. hormonal- gastrin, secretin, CCK 3. Neural- enteric nervous system AND ANS (sympathetic and parasympathetics) Myenteric plexus is between circular and longitudinal muscle and the submucosal plexus is between circular muscle and the muscular mucosa.

two processes enhance gallbladder storage of bile

1. receptive relaxation= stimulation of stretch receptors that activates enteric and vasovagal reflexes, leading to neural release of NO and VIP 2. gallbladder epithelial cells absorbing NaCl and H2O, leading to concentration of bile salts, PL's, Cholesterol, and bilirubin

cholesterol properties

1. slightly polar 2. virtually water insoluble

Diagnostic testing for Enterobacteriaceae

1. stool culture, use selective media for E.coli (MacConkey agar) 2. immunoassay to look for surface antigens 3. gram stain 4. serology (PCR) not common **most common culture, gram stain and immunoassay.

Fate of Bile Salts not reabsorbed in Small Intestine

1. unreabsorbed bile salts in terminal ileum continue to colon, are deconjugated and dehydroxylated into lithocolic acid and deoxycolic acid 2. these are nonionized, lipid soluble, and passively reabsorbed into portal blood 3. remainder of BS/BA are excreted in feces

ABC transporters...

1. utilize ATP for primary active transport 2. are export pumps with high affinity for their transported molecule 3. can be called, ABC/s, multi drug resistant proteins, and multi drug resistant pumps

GI motility and muscle contraction patterns

2 types of GI muscle- longitudinal and circular muscle. Peristalsis- forward propulsion of food. Occurs in the esophagus, stomach, small and large intestines. Contract behind the bolus, relax in front of bolus to push food forward. Segmentation- mixing of food. occurs in upper part of SI-- mix secretions with lumen contents and deliver contents to brush border. Also occurs in ascending and transverse colon to deliver contents to epithelial lining. Segmentation involves contractions of the circular muscles in the digestive tract, while peristalsis involves rhythmic contractions of the longitudinal muscles in the gastrointestinal tract.

Cholera- Clincial Features

24-48 hours after consumption of contaminated food or water Severe, profuse watery diarrhea, vomiting, crampy abdominal pain

Celiac Diseae- Histopathology

2nd portion of duodenum or proximal jejunum- exposed to highest concentrations of dietary gluten Characterized by increased intraepithelia CD8+ T cells, crypt hyperplasia, villous atrophy Loss of mucosal and brush border surface—> malabsorption Increased rates of epithelial turnover—> increased crypt mitotic activity Other features: increased plasma cells, mast cells and eosinophils in upper part of lamina propria

Differential diagnoses in ACUTE abdominal pain - first episode

AAA Acute mesenteric ischemia Appendicitis Biliary disease Diverticulitis DKA Ectopic pregnancy Gastroenteritis Ischemic colitis Myocardial infarction Ovarian torsion Nephrolithiasis Pancreatitis Peritonitis (from ruptured PUD, diverticulitis, etc) PID Small or large bowel obstruction Splenic rupture AAA Acute mesenteric ischemia Appendicitis Biliary disease Diverticulitis DKA Ectopic pregnancy Gastroenteritis Ischemic colitis Myocardial infarction Ovarian torsion Nephrolithiasis Pancreatitis Peritonitis (from ruptured PUD, diverticulitis, etc) PID Small or large bowel obstruction Splenic rupture

Cholera Toxin

AB Toxin Upregulate production of G-alpha s cAMP by binding and increasing activated adenylate cycles Gs pathway activated —> Active GC —> upregulate cAMP—> opens cystic fibrosis transmembrane conductance regulator CFTR—> releases. Chloride ions into lumen—> production of watery diarrhea Accumulation of chloride, bicarbonate, and sodium within the lume creates an osmotic driving force that draws water into lumen and causes diarrhea

PBC: relationship for AST, ATL, GGT, ALP with cholestatic liver injury to hepatocytes

AST, ALT, and GGT will be elevated if liver damage is present (although other issues can cause elevation of AST and ALT, like skeletal/cardiac muscle damage). If only ALP is elevated, indicative of bone disease. If both GGT and ALP are elevated, we know there is a bile duct issue. GGT is sensitive for bile duct issues, but non-specific for what the disease is. Drinking booze will cause in increase in GGT, but no increase in ALP

PBC: significance of AST to ALT ratio

AST:ALT ratio is usually <1, but will increase in w/ fibrosis. If it is >2, then indicative of acute alcoholic hepatitis

Abdominal pain with weight loss suggests?

Abdominal pain with weight loss may be due to inflammatory bowel disease, chronic mesenteric ischemia, or advanced GI malignant neoplasms

Type II Diabetes- Complications

Acute Complications -may develop hyperosmolar hyperosmotic syndrome (sever dehydration resulting from sustain osmotic dieresis) -hypoglycemia (dizziness, confusion, sweating, palpitations, tachycardia) Chronic Complications -diabetic macrovascular disease -diabetic microvascualr disease

Outline the clinical presentation of common causes of the acute abdomen. (LGS 5.6 a)

Acute abdominal pain History should determine the time course, character and location and radiation pattern of the pain Severe abdominal pain Begins suddenly during seconds to minutes indicates catastrophic event, § such as esophageal rupture § perforated peptic ulcer or viscus § ruptured ectopic pregnancy § ruptured aortic aneurysm § acute mesenteric ischemia § or myocardial infarction Pain that progresses within 1 to 2 hours is consistent with § a rapidly progressive inflammatory disorder (e.g., cholecystitis, appendicitis, pancreatitis) § acute obstruction of a viscus (small intestinal obstruction, ureteral colic), § organ ischemia caused by a strangulated blood supply (volvulus, strangulated hernia, ovarian torsion). Pain that is less severe develops during several hours medical rather then surgical condition § including upper GI disorders (dyspepsia) § intestinal disorders (gastroenteritis § inflammatory bowel disease) § liver disorders (hepatitis, abscess) § urinary disorders (cystitis, pyelonephritis) § gynecologic infections; however, the slow evolution of surgical disorders such as cholecystitis, appendicitis or diverticulitis, and intra-abdominal abscesses must not be overlooked.

Type II Diabetes Complications -Acute and Chronic

Acute complications: - May develop condition known as hyperosmolar hyperosmotic syndrome - Due to severe dehydration resulting from sustained osmotic diuresis - Less serious than DKA - not as many symptoms - Mostly just severe dehydration - Hyperglycemia is usually more severe than in DKA - Most common acute metabolic complication in either DM1 or DM2 is hypoglycemia - Usually as a result of having missed a meal, excessive physical exertion, excess of insulin admin or during the phase of dose finding for antidiabetic agents - Signs and symptoms include § Dizziness § Confusion § Sweating § Palpitations § Tachycardia - If it persists loss of consciousness may occur - Reversal of hypoglycemia through oral or IV glucose intake prevents the onset of permanent neuro damage Chronic complications - Morbidity associated with longstanding diabetes of either type is due to damage from chronic hyperglycemia - Diabetic macrovascular disease: damage induced in large and medium sized arteries § Causes accelerated atherosclerosis among diabetics § Results in increased risk of myocardial infarction, stroke, and lower extremity ischemia - Diabetic microvascular disease: damage induced in small vessels § Effects of microvascular disease are most profound in the retina, kidneys and peripheral nerves □ Results in diabetic retinopathy, nephropathy and neuropathy respectively

Discuss the metabolic changes that occur due to prolonged fasting (starvation).(LGS5.4c)

After 3 to 5 days of fasting • body enters the starved state • muscle decreases its use of ketone bodies and depends mainly on fatty acids for its fuel • The liver convert fatty acids to ketone bodies ○ The result is that the concentration of ketone bodies rises in the blood § The brain begins to take up these ketone bodies from the blood and to oxidize them for energy □ the brain needs less glucose than it did after an overnight fast Glucose is still required as an energy source for • red blood cells • brain continues to use a limited amount of glucose, ○ which it oxidizes for energy and uses as a source of carbon for the synthesis of neurotransmitters § Overall glucose is "spared" (conserved) □ Less glucose is used by the body ® the liver needs to produce less glucose per hour during prolonged fasting than during shorter periods of fasting. stores of glycogen in the liver are depleted by approximately 30 hours of fasting • gluconeogenesis is the only process by which the liver can supply glucose to the blood if fasting continues. • The amino acid pool, produced by the breakdown of protein, continues to serve as a major source of carbon for gluconeogenesis. • A fraction of this amino acid pool is also used for biosynthetic functions (e.g., synthesis of heme and neurotransmitters) and new protein synthesis, processes that must continue during fasting. • However, as a result of the decreased rate of gluconeogenesis during prolonged fasting, protein is "spared"; less protein is degraded to supply amino acids for gluconeogenesis. the liver also converts the nitrogen of these amino acids to urea. Consequently, because glucose production decreases during prolonged fasting compared with early fasting, urea production also decreases. Adipose adipose tissue continues to break down its triacylglycerol stores • providing fatty acids and glycerol to the blood ○ These fatty acids serve as the major source of fuel for the body ○ The glycerol is converted to glucose ○ whereas the fatty acids are oxidized to CO2 and H2O by tissues In the liver, fatty acids are converted to ketone bodies that are oxidized by many tissues, including the brain. Glucose is still used during prolonged fasting (starvation) but in significantly reduced amounts. we degrade protein to supply amino acids for gluconeogenesis at a slower rate during starvation than during the first days of a fast we are still losing protein that serves vital functions for our tissues. Protein can become so depleted that the heart, kidney, and other vital tissues stop functioning, or we can develop an infection and not have adequate reserves to mount an immune response In addition to fuel problems, we are also deprived of the vitamin and mineral precursors of coenzymes and other compounds necessary for tissue function. Because of either a lack of ATP or a decreased intake of electrolytes, the electrolyte composition of the blood or cells could become incompatible with life. Ultimately, we die of starvation.

Motility in the Fed State (LGS5.2 #1)

After meal ingested, motility in small intestion are more frequent, patterns to mix meal with secretions and maximize exposure to mucosa for absorption Peristalsis in esophagus stimulated by its distention Peristaltic wave processes: circular muscular contract to squeeze bolus along- at same time longitudinal muscles relax to allow bolus to glide through Mechanoreceptors on sensory afferents transmit impulses to dorsal vagus complex—> activates somatic and vagal efferent (terminated directly on striated muscle or onto nerves of enteric nervous system) Enteric nervous system capable of releasing ACh (inducing contraction) , NO (relaxation) Nature of bolus also influences intensity of motility pattern, larger or more viscous are propelled with greater force but move slowly, warm blouses are moved more rapidly than cold

Describe short bowel syndrome and correlate its development in patients who have undergone bowel resection surgery.

After multiple resections the body's ability to absorb has decreased and this leads to malabsorption and weight loss.

Hemosiderin

Another iron storage. Ferritin is the main storage form when tissue stores are low but hemosiderin predominates when iron stores are high.

Liver gallbladder and biliary duct system development

Arises as a ventral outgrowth - the hepatic diverticulum. • From the distal part of the foregut (early in the 4th week). • Wnt/B-catenin signaling plays a key role ○ In the differentiation and proliferation of the hepatic progenitor cells to form hepatocytes. • At sufficient levels FGFs secreted by the developing heart interact with the bipotential cells and induce the formation of the hepatic diverticulum. The diverticulum extends into the septum transversum. • This is a mass of splanchnic mesoderm separating the pericardial and peritoneal cavities. • The septum forms the ventral mesogastrium in this region. • The hepatic diverticulum enlarges rapidly and divides into two parts ○ As it grows between the layers of the ventral mesogastrium. The larger part of the hepatic diverticulum is the primordium of the liver. • The smaller, caudal part becomes the primordium of the gallbladder. The hepatic cords anastomose around endothelial-lined spaces - the primordia of the hepatic sinusoids. • Vascular endothelial growth factor - FLK-1 signaling appears to important for the early morphogenesis of the hepatic sinusoids. The liver grows rapidly from the 5th to the 10th weeks - filling a large part of the upper abdominal cavity • Quantity of oxygenated blood from the umbilical vein determines the development and functional segmentation of the liver Hematopoiesis • Begins in the liver during the 6th week; giving the liver a reddish appearance • By the 9th week Bile formation by the hepatic cells begins during the 12th week. The small caudal part of the hepatic diverticulum becomes the gallbladder, and the stalk of the diverticulum forms the cystic duct. Initially the extrahepatic biliary apparatus is occluded with epithelial cells. The bile entering the duodenum through te bile duct after the 13th week gives the meconium a dark green color

Define asterixis

Asterixis (also called the flapping tremor, or liver flap) is a tremor of the hand when the wrist is extended, sometimes said to resemble a bird flapping its wings.

Cholera- Screening/Diangosis

Bacterial antigens within still sample, most accurate is a stool culture Diagnosis approach: -Stool pH -presence of reducing substances in stool -Fecal leukocytes -Antilisteriolysin O (ALLO)

Describe the sphincters of the GI system

Bands of CIRCULAR muscle at junctions between compartments of the GI tract. **act as a barrier, control movement of contents** 1. UES 2. LES(esophagus and stomach) 3. Pyloric sphincter(stomach and small intestines) 4. Sphincter of Oddi (is a muscular valve that controls the flow of digestive juices (bile and pancreatic juice) through the ampulla of Vater into the second part of the duodenum. ) 5. ileocecal valve 6. internal anal sphincter 7. external anal sphincter Most sphincters are smooth muscle and thus are involuntary but the anal and UES are skeletal muscle and thus voluntary.

GERD- Complications

Barret's Esophagus: complication of chronic GERD that is characterized by intestinal metaplasia within esophageal squamous mucosa —> increased risk for esophageal adenocarcinoma Dysplasia: atypical mitosis, nuclear hyperchromimasia, irregularly clumped chromatin, increased nuclear to cytoplasmi ration, failure of epithelial cells to mature Gland Architecture: frequently abnormal and is characterized by budding, irregular shapes, cellular crowding Progression to esophageal carinoma : occurs over extended period with genetic and epigenetic changes -usually occurs in distal third of esophagus and may evade gastric cardia

Non-inflammatory vs inflammatory diarrhea

Big difference diagnostically, is that inflammatory diarrhea is characterized by presence of fecal leukocytes. Non-inflammatory---ETEC, vibrio cholerae. Inflammatory--salmonella (non-typhi), Shigella, campylobacteria, STEC, EIEC. Inflammatory is characterized by fever and bloody diarrhea whereas non-inflammatory is not, its usually watery.. Inflammatory is more likely to disrupt mucosal integrity leading to tissue invasion and destruction vs. non-inflammatory.

Pharmocologic guidelines for management of hypercholesterolemia

Bile acid sequestrants (ex. Cholestyramine)-adsorbs and combines with the bile acids in the intestine to form an insoluble complex which is excreted in the feces. This results in a partial removal of bile acids from the enterohepatic circulation by preventing their absorption.

Differential diagnosis in ACUTe abdominal pain- recurrent

Biliary disease DKA Diverticulitis Nephrolithiasis Pancreatitis PID Small or large bowel obstruction

Congenital hyperbilirubinemia

Bilirubin is elevated in blood due to inherited defects in bilirubin metabolic pathway Crigler-Najjar syndrome: -LOW ACTIVITY of glucoronyltransferase (conjugating enzyme) -rare inherited disease -severe hyperbilirubinemia in neonates (unconjugated bilirubin) -complicated kernicterus and early death Gilbert's Syndrome -decreased production(expression) of glucoronyltransferae -rare autosomal dominant trait -more common in men, 2-3% -usually asymptomatic hyperbilirubinemia -liver function tests normal Dublin Johnson syndrome -defect in transfer of conjugated bilirubin into biliary canalculi -conjugated hyperbilirubinemia

Cholera Species and Serotypes

Biotype: El Tor- asymptomatic , current pandemic Serotpye/Antigen: Ogawa/A,B Serotpye/Antigen:Inaba/A,C Serotpye/Antigen:Hikojima/ A,B, C Biotype: Classical- symptomatic and asymptomatic cases, first 6 pandemics, confined to Bangladesh Serotpye/Antigen: Ogawa/A,B Serotpye/Antigen:Inaba/A,C Serotpye/Antigen:Hikojima/ A,B, C Vibrio Cholera O1 can be classified into 3 serotypes (based on presence of somatic antigens) and 2 biotypes (based on specific phenotypic character is) O139 serogorup is composed of variety of genetically diverse stains, both to IgE is and nontoxigneic —> genetically closer to El Tor

Parietal cells are specific to which regions?

Body and fundus of stomach

NAFLD: association with pre-diabetes

Both DM and NAFLD are at increased risk of developing in the presence of metabolic syndromes

Alcohol Culture DOCs LG 5.2- Gather and record a social history with emphasis on alcohol use

CAGE interview: focuses on effects of drinking, can be helpful in eliciting information suggestive of alcohol abuse C: have the ever felt the need to Cut down on your drinking A: do you ever get Annoyed when people tell you to cut down on your drinking G: do you ever feel Guilty about drinking too much E: have you ever needed an Eye opener in the mornings Advantage: quick, easy- 2 yes= + screen Disadvantage: doesn't distinguish active vs. passive drinking, not sensitive for patients who are risky drinkers, less accurate in women AUDIT interview -how often do you have a drink containing alcohol -how many standard drinks containing alcohol do you have on a typical day -how often do you have 6+ drinks on 1 occasion? Advantage: more tailored questions, good for women

screening exams for alcohol use

CAGE, AUDIT, NIDA-1

Ivacaftor

CFTR activator potentiator of the CFTR protein, an ion channel involved in the transport of chloride and sodium ions across cell membranes of the lungs, pancreas, and other organs. Treats CF Common • Dermatologic: Rash (10% to 13% ) • Gastrointestinal: Abdominal pain (16% ), Diarrhea (13% ), Nausea (10% to 12% ) • Neurologic: Dizziness (5% to 9% ), Headache (17% to 24% ) • Respiratory: Nasal congestion (16% to 20% ), Nasopharyngitis (15% ), Pain in throat (22% ), Upper respiratory infection (16% to 22% ) Serious • Hepatic: AST/SGOT level raised (4% to 7% ), Increased liver enzymes (4% to 7% ) • Ophthalmic: Cataract >

Mechanism of Calcium Carbonate

Calcium carbonate (eg, Tums, Os-Cal) is less soluble and reacts more slowly than sodium bicarbonate with HCl to form carbon dioxide and calcium chloride (CaCl2). Side effect may cause belching or metabolic alkalosis. Calcium carbonate is used for a number of other indications apart from its antacid properties Excessive doses of either sodium bicarbonate or calcium carbonate with calcium-containing dairy products can lead to hypercalcemia, renal insufficiency, and metabolic alkalosis (milk-alkali syndrome).

How is iron taken into the cell?

Cells acquire transferrin-bound iron through a transferrin receptor. 1. The receptor binds iron loaded transferrin and is endocytosed. 2. The acidic environment of the endosome facilitates the release of iron from transferrin. 3. Ferrireductase STEAP 3 reduces iron to its ferrous state in the endosome. 4. DMT1 transfers the ferrous iron to the cytoplasm. 5. Transferrin is recycled in the blood. **cells adjust iron uptake by regulating their numbers of transferrin receptors. Iron response elements (IREs) bind IRPs in the iron depleted. When IRPs bind to IREs it prolongs the life span of the mRNA transferrin receptor by protecting it from nucleases. Allowing cells to make more transferrin receptors when it needs more iron.

What is CCK?

Cholecystokinin - 1. stimulates acinar secretion. 2. Reduces gastric emptying 3. Relaxes the sphincter of odi 4. Contracts the gall bladder.

Celiac Disease- Clincial Features

Chronic diarrhea , bloating, chronic fatigue, but can often be asymptomatic May present with anemia due to chronic iron and vitamin malabsorption In adults, detected 2x in women In pediatrics equal between male and female -manifests ~6-24 months: irritability, weight loss, abdominal distinction, anorexia, chronic diarrhea, muscle wasting — extraintestinal symptoms: arthritis/joint pain, aphthous stomatitis, iron deficiency anemia, delayed puberty, short statue Related: dermatitis herpetiformis: present in ~10% of patients

Differential diagnosis in subacute or CHRONIC abdominal pain

Chronic mesenteric ischemia IBD IBS Hepatitis PUD

Ranitidine

Class H2 Blocker Indication: Active duodenal or benign gastric ulcer. Maintenance of healing of duodenal or gastric ulcer. Pathological hypersecretory conditions (eg, Zollinger-Ellison syndrome and systemic mastocytosis). MOA: selectively antagonists H@ rectors Contraindication:Hypersensitivity, porphyria, caustic if hepatic impairment, caution if renal impairment

Mylanta

Class: Antacids Indication: reliever heartburn, upset stomach MOA: Aluminum hydroxide and magnesium hydroxide act as antacids by neutralizing stomach acid that result in an increasing pH in the stomach. Simethicone is anti-gas medication that works by lowering surface tension of gas bubbles, which gives relief from gas Contraindication: Hypersensitivity, colostomy or ileus tony, GI obstruction, intentional perforation

Esomoprazole

Class: Benzimidazole Indication: For the treatment of acid-reflux disorders (GERD), peptic ulcer disease, H. pylori eradication, and prevention of gastroinetestinal bleeds with NSAID use MOA: For the treatment of acid-reflux disorders (GERD), peptic ulcer disease, H. pylori eradication, and prevention of gastroinetestinal bleeds with NSAID use Contraindication: Hypersensitivity, caution if long term use, if high dose, in pt >50, caution f hepatic impairment

Omeprazole

Class: proton pump inhibitor Indication : Triple therapy (w. amoxicillin + clarithromycin) or dual therapy (w. clarithromycin) for H. pylori eradication in duodenal ulcer disease. Short-term treatment of active benign gastric ulcer, active duodenal ulcer, erosive esophagitis (EE), symptomatic GERD MOA: Triple therapy (w. amoxicillin + clarithromycin) or dual therapy (w. clarithromycin) for H. pylori eradication in duodenal ulcer disease. Short-term treatment of active benign gastric ulcer, active duodenal ulcer, erosive esophagitis (EE), symptomatic GERD Contraindication : Hypersensitivity, caution if long term use, caution if high dose, caution if hepatic impairment

Ductular cells

Classic columnar epithelial cells Transport bicarbonate into secretions to neutralize gastric acid.

Congenital Omphalocele

Congenital omphalocele • birth defect in which herniation of abdominal contents into the proximal part of the umbilical cord persists ○ Herniation of the intestine into the cord ~ 1 in 5000 births ○ herniation of the liver and intestine ~ 1 in 10,000 births. ○ Up to 50% of cases are associated with chromosomal abnormalities. • results from impaired growth of mesodermal (muscle) and ectodermal (skin) components of the abdominal wall. • formation of the abdominal compartment occurs during gastrulation... a critical failure of growth at this time is often associated with other birth defects of the CV and urogenital systems. • Surgical repair is required.

Conventional insulin verus basal/bolus insulin

Conventional insulin - Day and Night Basal/bolus insulin - when you eat a meal

Cystic Fibrosis- DIOS and acute pancreatitis presentation

DIOS A clinical spectrum from partial or complete obstruction of the bowel by abnormal intestinal contents occurs in DIOS: (1) abdominal pain caused by constipation or fecal impaction, (2) palpable cercal masses that may eventually pass spontaneously, and (3) complete obstruction of the bowel by firm, putty-like fecal material in the terminal ileum, right colon, or both. 215218220 Acute onset of vomiting of bilious material with progressive, colicky abdominal pain and/or fluid levels in the small intestine on abdominal radiography are signs of DIOS with complete intestinal obstruction. 212 Acute pancreatitis The cardinal symptom of acute pancreatitis is abdominal pain, which is characteristically dull, boring, and steady. Usually, the pain is sudden in onset and gradually intensifies in severity until reaching a constant ache. Most often, it is located in the upper abdomen, usually in the epigastric region, but it may be perceived more on the left or right side, depending on which portion of the pancreas is involved. The pain radiates directly through the abdomen to the back in approximately one half of cases. Nausea and vomiting are often present, along with accompanying anorexia. Diarrhea can also occur. Positioning can be important, because the discomfort frequently improves with the patient sitting up and bending forward. However, this improvement is usually temporary.

Type I Versus Type II diabetes

DM 1: autoimmune attack of 𝛃 cells DM 2: too much glucose --> too much insulin --> insulin resistance --> excess glucose in blood because cant get in Results in dysfunction of 𝛃 cells

Type II Diabetes- Compare to Type I

DM Type 1: autoimmune attack of Beta-Cells DM Type 2: excess glucose —> excess insulin —> insulin resistance —> excess glucose in blood—> dysfunction of beta cells

Indications for abdominal paracentesis

Diagnostic tap is used for the following: • New-onset ascites - Fluid evaluation helps to determine etiology, differentiate transudate versus exudate, detect the presence of cancerous cells, or address other considerations • Suspected spontaneous or secondary bacterial peritonitis • Refractory ascites

GERD- Behavioral/Lifestyle Modifications

Diet: avoid chocolate, alcohol, spicy foods Exercise: decrease obesity

Cystic Fibrosis: predisposition to bowel obstruction

Distal intestinal obstruction syndrome or meconium ileus equivalent is a well-known complication and is thought to be caused by pancreatic insufficiency, thickened intestinal secretions, undigested food remnants, poor motility, and fecal stasis with resultant impaction of mucofeculent material in the distal ileum and right colon

Summary of absorption and secretion of electrolytes and H2O

Electrolytes and H20 may cross intestinal epithelial cells by cellular or paracellular routes -Tight junctions attach epithelial cells to one another at luminal membrane —permeability of tight junctions Vader's with type of epithelium

Common Virulence Factors Associated with Enterobacteriaceae:

Endotoxin-The activity of this toxin depends on the lipid A component of LPS, which is released at cell lysis. Capsule-Encapsulated Enterobacteriaceae are protected from phagocytosis by the hydrophilic capsular antigens, which repel the hydrophobic phagocytic cell surface. Antigenic phase variation-The expression of the somatic O antigens, capsular K antigens, and flagellar H antigens is under the genetic control of the organism. Each of these antigens can be alternately expressed or not expressed (phase variation), a feature that protects the bacteria from antibody-mediated cell death. Type III secretion systems- A variety of bacteria (e.g., Yersinia, Salmonella, Shigella, enteropathogenic Escherichia, Pseudomonas, Chlamydia ) have a common effector system for delivering their virulence factors into targeted eukaryotic cells. Think of the type III secretion system as a molecular syringe consisting of approximately 20 proteins that facilitate transfer of bacterial virulence factors into the targeted host cells. Sequestration of growth factors- Iron is an important growth factor required by bacteria, but it is bound in heme proteins (e.g., hemoglobin, myoglobin) or in iron-chelating proteins (e.g., transferrin, lactoferrin). The bacteria counteract the binding by producing their own competitive siderophores or iron-chelating compounds (e.g., enterobactin, aerobactin ). Resistance to serum killing-The bacterial capsule can protect the organism from serum killing. Antimicrobial resistance- As rapidly as new antibiotics are introduced, organisms can develop resistance to them. This resistance can be encoded on transferable plasmids and exchanged among species, genera, and even families of bacteria.

Glycogen storage Disorder Type 1a: Von Gierke Disease

Enzyme affected: glucose 6-P Affected organ: liver Primary manifestation : hepatomegally, lactic acidosis, kidney failure, thrombocytes dysfunction

Glycogen storage disorder type VI: Her's

Enzyme affected: liver glycogen phosphorylase Affected organ: liver Primary manifestation

Glycogen storage disorder Type II: Pompe

Enzyme affected: lysosomal alpha glucosidase Affected organ: parietal and cardiac muscle Primary manifestation -infantile form: fatal by 2 years Juvenile form: myopathy Adult: muscular dystrophy like

Glycogen storage disorder type V: McArdles:

Enzyme affected: muscle glycogen phosphorylase Affected organ: liver and muscle Primary manifestation: exercise induced cramps and pain, myoglobinuria

Hepatits A

Epi- Acute, Fecal-oral Incubation: 15-50 days S/s: fever, malaise, loss of appetite, nausea, a Domain's pain, jaundice, increase in AST:ALT (children under 6 often have no symptoms) Serological Dx: Anti-HAV IgM Anti- HAV IgG Treatment: supportive PRevention: food/water hygiene, immunization Complications: full recovery within ~3 months, does NOT become chronic

Hepatits B

Epi- blood, perinatal, sexual, IV drug use Incubation: 30-180 days S/s: often aymptomatic, acute hepatitis, stigmata of cirrhosis in chronic cases Serological Dx: HBsAG, Anti-HBc, HBeAg, Anti HBe Treatment : auction- supportive, chronic- interferon alpha or tenofovir Prevention: safe sex HBV vaccination Complications: fulminanthepatits, chronic disease (cirrhosis, HCC)

Hepatits C:

Epi: parenteral (blood, IV drug) Incubation: 14-180 days S/S: often asymptomatic, acute hepatits, stigma mate of cirrhosis in chronic cases Serological Dx: Anti- HCV IgM, HCV RNA Treatment: acute- interferon alpha or peginterferon alpha Chronic- interferon alpha + ribavirin or D AA, liver transplant Prevention: sterile instruments, safe sex, NO vaccine available Complications: chronic disease)cirrhosis, HCC)

Conditions associated with Crohn's

Erythema nodosum - EN is considered a delayed-type hypersensitivity reaction resulting from exposure to various antigens; however, the pathogenesis is not fully understood. The pathogenic mechanism may involve immune complex deposition in the septal venules of the subcutaneous fat, neutrophil recruitment with resulting reactive oxygen species formation, tumor necrosis factor (TNF)-alpha production, and granuloma formation.

GERD Medications

Esomeprazole/Omeprazole Class: Proton Pump Inhibitor Clinical Uses: peptic ulcers, gastritis, esophageal reflux, Zollinger-Ellison Ellison Syndrome, part of therapy for H. Pylori, stress ulcer prophylaxis MOA: irreversibly inhibit H+/K+ ATPase in stomach parietal cells AES: increased risk of C. Difficile infection, pneumonia, lower serum Mg2+ long term use Ranitidine (Zantac) Class: H2 Blocker Clinical uses: peptic ulcer, mild gastritis, mild esophageal reflux MOA: reversible block of H2 receptors, lower H+ secretion of parietal cells AEs: Mild drowsiness ALuminum hydroxide/magnesium hydroxide (Mylanta) MOA: basic inorganic salt that acts by neutralizing hydrochloric acid in gastric secretions -slowly solubilized in the stomac and reacts with hydrochloric acid to form aluminum chloride and water -inhibit action of pepsin by increasing pH and via absorption -Cytoprotective effects may occur through increases in bicarbonate ion (HCO3-) Toxicity: unlikely Contraindications: concomitant use, may decrease absorption of some drugs, GI- may lead to diarrhea/dehydration (combined with magnesium should prevent diarrhea)

Discuss the process that regulate how undigestiable residues form a meal are eliminated from the body (LGS 5.2 #1) Function

Esophageal

Esophageal atresia

Esophageal Atresia (blockage): • Occurs 1 in 3000-4500 neonates. ○ ⅓ are associated with premature births. • 90% of cases are associated with tracheoesophageal fistula • Esophageal atresia results from deviation of the tracheoesophageal septum in the posterior direction. ○ And incomplete separation of the esophagus from the laryngotracheal tube • Isolated atresia (5-7% of cases) results from failure of recanalization of the esophagus during the 8th week of development. Presentation: • Fetus will be unable to swallow amniotic fluid. ○ Fluid will not pass to the intestine for absorption ○ And transfer through the placenta to the maternal blood for disposal ○ This results in polyhydramnios § The accumulation of excessive amount of amniotic fluid. • Neonate will appear healthy initially ○ Excessive drooling will be noted soon after birth ○ Consider atresia if baby rejects oral feeding - with immediate regurg and coughing Inability to pass catheter through the esophagus strongly suggest atresia. Radiographic exam will demonstrate the defect - arrested NG tube in the proximal esophageal pouch. Neonates > 2kg and without associated cardiac abnormalities = 100% survival (with surgical repair). With decreased birth weight and cardiac issues - survival decreases as low as 1%

Chapman's reflexes (anterior and posterior)

Esophagus-> ANT: Between ribs 1 and 2, near the sternum POST: Midline on the T2 transverse process (b/l) Pylorus-> ANT: Anywhere in the midline of the body of the sternum (b/l) POST:Costovertebral joint of T10 on the RIGHT Stomach acidity->(L) ANT:Between ribs 5 and 6 on LEFT, between sternum and mid clavicular line POST:Between the spinous and LEFT transverse processes of T5 and T6 Stomach peristalsis-> (L) ANT:Between ribs 6 and 7 on LEFT, between sternum and midclavicular line POST:Between the spinous and LEFT transverse processes of T6 and T7

IBD: Clincial manifestations

Examination in patients with IBD may include the following findings, which are directly related to the severity of the attack: • Fever • Tachycardia • Dehydration • Toxicity • Pallor, anemia • Toxic megacolon: Medical emergency; patients appear septic, have high fever, lethargy, chills, and tachycardia, as well as have increasing abdominal pain, tenderness, distention • Mass in the right lower abdominal quadrant: May be present in CD Perianal complications: May be observed in up to 90% of cases of CD b. Extraintestinal symptoms i. Ankylosis spondylitis ii. Uveitis iii. Pyoderm ganfrenosum iv. Erythema nodosum v. Calcium oxalate kidney stones (increased absorption of oxalate) vi. Gallstones with terminal ileum, decreased absorption of bile salts

Cholera- Hypovolemic Shock

Excess Cl- secretion from affected cells result in a secretory diarrhea —> pulling of fluids from intracellular to the lumen —> potential severe dehydration

Federally Qualified Health Centers/Sliding Source

FQHC: provide qualified care to underserved communities, receive federal funding , additionally funding comes from state and federal grants, local support, community funding Sliding scale: variable prices for products/services based on patient's ability to pay

Factors causing CCK release

Factors Causing CCK Release - Synthesized and stored by endocrine cells located predominantly in the duodenum § Labeled in some sources as I cells - Control of CCK release from these cells is carefully regulated to match the body's need for CCK bioactivity § Accomplished by activity of 2 luminally active CCK releasing factors □ CCK releasing peptide (CCK-RP) ® derived from cells in the duodenum ® Likely released into the lumen in response to specific nutrients including fatty acids and hydrophobic amino acids □ Monitor peptide ® Product of pancreatic acinar cells ® Release can be neurally mediated ◊ Including ACH and GRP in the vicinity of pancreatic acinar cells during cephalic phase ◊ Mediated by vago-vagal reflexes during the gastric and intestinal phases of the response to a meal ® Release of CCK stimulated by CCK RP can cause monitor peptide release

Dietary iron is mainly

Fe3+ which is reduced to Fe2+ by ferrireductase Dcytb on the surface of enterocytes in the DUODENUM. Only ferrous iron is transported across membranes. The reduction of ferric iron is favored by low pH. Therefore, iron absorption is IMPAIRED by LACK OF gastric acid.

Role of fiber supplementation

Fiber — Fiber supplementation can improve symptoms in patients with constipation. Fiber is available in a large variety of supplements and natural foods. Because fiber supplements are low cost, easy to use, and safe, they are frequently used first in the management of constipation. Cereal fibers generally possess cell walls that resist digestion and retain water within their cellular structures. Fiber found in citrus fruits and legumes stimulates the growth of colonic flora, thereby increasing fecal mass. Wheat bran is one of the more effective fiber laxatives, but may aggravate bloating and abdominal pain in irritable bowel syndrome. There is a dose response between fiber intake, water intake, and fecal output. Larger particle size of the fiber source, such as the large particle size of cereal products, enhances fecal bulking effects. In addition to fiber, sugar components (sorbitol and fructose) of foods such as apples, peaches, pears, cherries, raisins, grapes, and nuts are also beneficial. The recommended amount of dietary fiber is 20 to 35 g/day. In addition to consuming foods with high fiber, patients may add raw bran (two to six tablespoons with each meal) followed by a glass of water or another beverage to achieve the fiber intake goal. For some patients (and especially almost all those with slow transit constipation), fiber increases bloating and distention, leading to poor compliance (estimated to be as low as 50 percent). Patients should be warned that consuming large amounts of fiber can cause abdominal bloating or flatulence; this can be modulated by starting with small amounts and slowly increasing fiber intake according to tolerance and efficacy.

Understand the embryological development and adult derivatives of the GI system (STX LGS 5.6) Foregut

Foregut Derivatives: • Primordial pharynx & its derivatives • Lower respiratory system • Esophagus • Stomach • Duodenum, proximal to the opening of the bile duct • Liver, biliary apparatus (hepatic ducts, gallbladder, and bile duct) and pancreas • All of these derivatives (other than pharynx, lower respiratory tract & most of esophagus) as supplied by the celiac trunk - the artery of the foregut

Mechanism of Magnesium hydroxide/Aluminum Hydroxide

Formulations containing magnesium hydroxide or aluminum hydroxide react slowly with HCl to form magnesium chloride or aluminum chloride and water. Because unabsorbed magnesium salts may cause an osmotic diarrhea and aluminum salts may cause constipation, these agents are commonly administered together in proprietary formulations (eg, Gelusil, Maalox, Mylanta) to minimize the impact on bowel function. excreted by the kidneys Patients w/ renal insufficiency should not take these agents long-term. antacids should not be given within 2 hours of doses of tetracyclines, fluoroquinolones, itraconazole, and iron. effect on the pH in stomach Reducing absorption

Diffenrtiation DX of abdominal distention

Free air: appendicitis, Bowel infarction (SBO, AMI), diverticulitis, peptic ulcer disease with perforation Luminal air: large bowel obstruction, small bowel obstruction Ascities: pancreatitis, spontaneous bacterial peritonitis Hemorrhage: AAA< ruptured ectopic pregnancy, ruptured spleen

Discuss the process that regulate how undigestiable residues form a meal are eliminated from the body (LGS 5.2 #1) Anatomy

Functional anatomy: esophagus -2 layers innermost (circular)and outer (longitudinally) -muscle types: striated upper 1/3, striated and smooth middle 1/3, only smooth distal 1/3 -innervation —striated: somatic nerves that have motor end plates, terminate on striated fibers—> release ACh, act via nicotine receptors —smooth: vagus n—> synapses with myenteric neurons via ACh and directly via ACh Functional anatomy of gastric musculature 2 regions: proximal and distal Proximal: cardia and fundus- reservoir to move gastric contents to distal stomach (tonic contractions of proximal region are important in gastric emptying) Distal: distal body and antrum- grind and titurate meal Pyloric sphincter controls amount and size of food particles Muscle layers of stomach —circular layer of smooth muscle arranged circumfrentially and cluster to lumen —longitudinal layer oriented along length of organ, in distal stomach fibers are continuous with duodenum Innervation: mostly parasympathetic in nature —intrinsic innervation via enteric nervous system

Glucose transporters

GLUT 2- pancreas, liver, intestines, and kidney (cell membrane) GLUT 4- muscle and adipose tissue (stored in intracellular vesicles--insulin dependent for translocation to membrane)

Compare Gastric and Duodenal Ulcers

Gastric -occurs in stomach -epigastric pain -can cause hematoemeis, or melena -heartburn, chest discomfort, early saiety -can cause gastric carinoma, mostly in elderly -feel worse when eating Duodenal -occurs in duodenum -epigastric pain 2-5 hours after eating -can cause melena or hematochezia -heartburn, chest discomfort are less common but may be seen -pain may awaken patient during night -feel better when eating

Type II Diabetes - Risk Factors

Genetic: susceptibility, 1st degree relatives have 5-10x greater risk Environmental: obesity (central/visceral), sedentary lifestyle

Prednisone

Glucocorticoid that inhibits PLA2 (anti-inflammatory) Decrease inflammation Taken orally Metabolized in the liver Contra: immunosuppressed or kidney disease Renal damage, immunosupression, hyperglycemia

Celiac Disease- Treatment

Gluten Free Diet

Celiac Disease- Immune response

Gluten protein is deaminated to gliaden—> presented on APC to CD4+ T cell Th2 Response: —> activate B cells —> antibodies: anti-gliaden, anti- endymysial, transglutaminase —> autoimmunity—> intestinal and extraintestional symptoms Th1 Repsonse —> NK cells—> interferon gamma, TNF-alpha—> mucosal inflammation —> villous atrophy, intraepithelial lymphocytes http://cmr.asm.org/content/27/3/482.figures-only

Mechanism of H2 antagonists

H2 antagonists reduce acid secretion stimulated by histamine as well as by gastrin and cholinomimetic agents through two mechanisms. First, histamine released from ECL cells by gastrin or vagal stimulation is blocked from binding to the parietal cell H2receptor. Second, direct stimulation of the parietal cell by gastrin or acetylcholine has a diminished effect on acid secretion in the presence of H2-receptor blockade. When given in usual prescription doses, however, all inhibit 60-70% of total 24-hour acid secretion. H2 antagonists are especially effective at inhibiting nocturnal acid secretion (which depends largely on histamine), but they have a modest impact on meal-stimulated acid secretion (which is stimulated by gastrin and acetylcholine as well as histamine). Recommended prescription doses maintain greater than 50% acid inhibition for 10 hours; hence, these drugs are commonly given twice daily. At doses available in over-the-counter formulations, the duration of acid inhibition is 6-10 hours. Cimetidine interferes with several important hepatic cytochrome P450 drug metabolism pathways, including those catalyzed by CYP1A2, CYP2C9, CYP2D6, and CYP3A4 (see Chapter 4). Hence, the half-lives of drugs metabolized by these pathways may be prolonged. H2 antagonists compete with creatinine and certain drugs (eg, procainamide) for renal tubular secretion. All of these agents except famotidine inhibit gastric first-pass metabolism of ethanol, especially in women.

GERD - Clinical Features

Heartburn and acid regurgitation Extraesophageal manifestions: cough, laryngitis, asthma, dental erosions Atypical symptoms: chest pain, dysphasia, odynophagia

Hematemesis with upper abdominal pain suggests?

Hematemesis with upper abdominal pain suggests a Mallory-Weiss tear, alcoholic gastritis, or peptic ulcer disease. § commonly caused by medical conditions such as infectious gastroenteritis or inflammatory bowel disease, but it also may be caused by ischemic colitis or mesenteric ischemia Gross hematuria may be due to cystitis or a ureteral stone

GERD- Screening/Diagnosis

Hemoccult test: detect blood in stool

Hepatitis C- Pathogenesis

Hepatitis C results in hepatocytes damage--> CD8 cells release of IFN gamma-->which results in the activation of stellate cells via TGF-beta-->production of type 1 collagen--> the collagen build up results in narrowing of the portal venous system via sinusoids resulting in increase hepatic portal hypertension--> treatment involves management of portal hypertension and observing products that the liver is making.

PBC: rational for hepatitis serology studies in workout

Hepatitis can lead to liver damage, and thus elevated liver enzymes. Therefore, we want to rule in/out our differential dx's. Furthermore, autoimmune hepatitis is possible. Hepatitis has a tropism for the liver

Any bile salts lost through excretion must be made up through synthesis of new bile salts...

Hepatocytes synthesize new salts to make up for the loss, and rate of synthesis is determined by 7-alpha-hydroxylase activity. This activity is inversely related to rate of return of bile salts to the hepatocytes.

High birth defections of anorectal region

High Birth Defects of Anorectal Region • Anorectal agenesis ○ rectum ends superior to the puborectalis muscle. ○ most common type of anorectal birth defect. ○ usually a fistula to the bladder (rectovesical fistula) or urethra (rectourethral fistula) in males, or to the vagina (rectovaginal fistula) or the vestibule of the vagina (rectovestibular fistula) in females. § result of incomplete separation of the cloaca from the urogenital sinus by the urorectal septum. • Rectal atresia ○ anal canal and rectum are present but separated ○ Sometimes the two segments of intestine are connected by a fibrous cord, the remnant of an atretic portion of the rectum. Cause may be abnormal recanalization of the colon or, more likely, a defective blood supply

Pyloric Stneosis

Hypertrophic Pyloric Stenosis • Affects 1 in every 150 males (1 in 750 females). • In infants there is a marked muscular thickening of the pylorus. • The circular and (to a lesser degree) longitudinal muscle in the pyloric region are hypertrophied. ○ Results in severe stenosis of the pyloric canal § Blocking the passage of food. • Stomach becomes very distended ○ Infant expels stomach's contents with large force (projectile vomiting)

Rationalize the treatment options to those pathologic conditions of gastrointestinal motility (LGS 5.2 #1)

If elated gastric emptying, see if patient can do lower fat diet If Nausea and vomiting plus delayed emptying, consider metoclopramide (Reglan) which increase LES tone Other OTC options Bismuth subsalicylate (Pepto Bismol)- can cause black stool, do not give to kids Loperamide (Imodium) Bisacodyl (Ducolax)-increase contraction Sodium docusate (Colace) Sodium phosphate enema (Fleet) MOA: osmotic enzyme

Relationship between Bile Salt uptake by ileal epithelium/hepatocytes and bile salt synthesis

Ileal epithelium: 1. increased uptake of bile salts into ileal epithelium or hepatocytes 2. bile salts bind to nuclear farnesoid X receptor (FXR) in ileal epithelium or hepatocytes 3. stimulates gene expression of fibroblast growth factor 19 (FGF19) in ileal epithelium, which is secreted into portal blood. 4. FGF19 binds to FGF19 receptors in hepatocytes 5. inhibits gene expression of 7-alpha-hydroxylase 6. reduces synthesis of new primary bile salts from cholesterol Hepatocytes: Steps 1 and 2, skip to step 5-6

PBC: bilirubin and lipoprotein levels elevated

Impaired liver function will increase total serum bilirubin. Jaundice due to buildup of conjugated bilirubin in blood b/c it is water soluble. Unconjugated bilirubin is insoluble and transported w/ Albumin. Since bile ducts are obstructed in PBC, we get a buildup of bile, and thus a decrease of bilirubin excretion. Note: bilirubin is removed via renally (through urine) or hepatically (through bile and then feces)

Cystic Fibrosis: Neonatal Screening- False negative

In the Wisconsin CF newborn screening program, a floating cutoff value of IRT above the 96th percentile is used to trigger the second tier DNA analysis. Using this floating cutoff, we have had 2.6% of CF patients whose initial IRT level was below the cutoff. In the CF newborn screening program in France, there was a false negative rate of 3.4% due to infants' IRT values being less than the cutoff.22 Regardless of the choice of IRT cutoff value, there is always the possibility of a true biologic false negative. The experiences of many newborn screening programs and the publications available on this issue17,20,21 suggest that IRT levels below the cutoff values employed are the most common cause of false negatives, but as described in our conclusions, there are QI opportunities to alleviate this problem. Measurement of Immunoreactive trypsinogen (IRT) in blood of newborn babies is an assay in rapidly increasing use as a screening test for cystic fibrosis (CF).[1] In CF there is poor release from pancreatic ducts. Trypsinogen is a pancreatic enzyme precursor found in the blood that is raised in most of those with CF at birth, regardless of whether their mutation is pancreatic sufficient or insufficient. The concentration of IRT is elevated in babies with CF since pancreatic ducts are partially blocked leading to abnormal enzyme drainage. This occurs even if infants are pancreatic sufficient. Heterozygous carriers of cystic fibrosis can cause a raised IRT and it is therefore not diagnostic in isolation

Female considerations for abdominal pain

In women, a missed menstrual period, adnexal pain, spotting, or cramping § may suggest pregnancy, ectopic pregnancy, or spontaneous abortion. § Acute pain between cycles may be caused by ovarian follicles or ruptured corpus luteum cysts. § Pelvic pain with fever, chills, or cervical discharge suggests pelvic inflammatory disease.

Celiac Disease- Risk Factors

Inheritance Pattern: Class II HLA-DQ2/DQ8 Less than 1/2 of genetic component of celiac disease Remaining genetic factors may include polymorphism of genes involved i immune regulation and epithelial function Associated Diseases: Type 1 diabetes, thyroiditits, Sjogren's Syndrome, IgA nephrophathy, ataxia, austism, depression, epilepsy, Down Syndrome, Turner syndrome Individuals with celiac may have higher rate of malignancy -most common is enteropathy associated T cell lymphoma -Small intestinal adenocarcinoma

Type II Diabetes Pathophysiology

Insulin resistance - Is the failure of target tissues to respond normally to insulin ○ Liver, skeletal muscle and adipose tissue are the major tissues where insulin resistance manifests in abnormal glucose tolerance - Results in ○ Failure to inhibit endogenous glucose production (gluconeogenesis) in the liver § Which contributes to high fasting blood glucose levels ○ Failure of glucose uptake and glycogen synthesis to occur in skeletal muscle following a meal § Which contributes to high post prandial blood glucose level ○ Failure to inhibit lipoprotein lipase in adipose tissue, leading to excess circulating free fatty acids (FFAs) § In turn, amplify the state of insulin resistance - Variety of functional defects have been reported in the insulin signaling pathway in states of insulin resistance ○ Eg reduced tyrosine phosphorylation of the insulin receptor and IRS proteins is observed in peripheral tissues § Compromises insulin signaling § Reduces level of glucose transporter GLUT4 on the cell surface ○ One of the mechanisms by which exercise can improve insulin sensitivity is through increased translocation of GLUT4 on the surface of skeletal muscle cells 𝛃 cell dysfunction - While insulin resistance itself can lead to impaired glucose tolerance 𝛃 cell dysfunction is virtually a requirement for development of overt diabetes ○ Increases early in the disease process in most patients with sporadic type 2 DM § Mainly as a compensatory measure to counter insulin resistance and maintain euglycemia ○ Eventually 𝛃 cell seemingly exhaust capacity to adapt to long term demands of peripheral insulin resistance § Hyperinsulinemic state gives way to state of relative insulin deficiency - Several mechanisms have been implicated in promoting 𝛃 cell dysfunction § Excess FFAs that compromise 𝛃 cell function and attenuate insulin release § Lipotoxicity § Impact of chronic hyperglycemia § Glucotoxicity § Abnormal incretin effect § Leads to reduced secretion of GIP and GLP1 § Hormones that promote insulin release § Amyloid deposition within islets § Characteristic finding in individuals with long standing type 2 diabetes □ Present in more than 90% of diabetic islets examined □ Unclear whether it is cause or effect of 𝛃 cell burnout § Impact of genetics

Type II Diabetes- Pathophysiologcial mechanisms

Insulin resistance—> failure to inhibit endogenous glucose production (gluconeogenensis) in liver —> high fasting glucose Failure to inhibit lipoprotein lipase in adipose tissues —> excess circulation free fatty acids —> amplify insulin resisntacnt Functional defects in insulin signaling pathway - Eg reduced tyrosine phosphorylation Of INsulin receptor and IRS proteins—> compromises insulin signaling, reduced level of GLUT 4 on surface of cell Beta Cell dysfunction -Insulin increases early in the disease, compensatory measure to counter insulin resistance and maintain euglycemia -Evenutally beta cells exhaust capacity to adapt hyperinsulinemic —> insulin deficiency -mechanisms —lipotoxicity —glucotoxicity —abnormal incretin effect —> reduced secretion of GIP and GLP1 (hormones that promote insulin release) —amyloid deposition within islets —genetics

Basal Acid Secretion/Interdigestive Phase

Interdigestive phase Low level —> maintain sterility PH=3 surpass gastrin • Basal acid secretion: prior to any eating. Controlled by low acid levels ○ Fasted period, low levels of acid ○ Somatostatin: released from D cells inhibiting gastrin § Night time fasted state ○ Interdigestive phase

Transferrin

Iron transport protein in plasma. Binds ferric iron (Fe 3+) with extremely high affinity. Almost all iron in the plasma is bound to transferrin. Measured via TIBC. Total Iron Binding Capacity- maximal amount of iron that can be bound by circulating transferrin.

Genitourinary disorders

LOCATION: Bladder—suprapubic; renal colic—abrupt, excruciating LLQ or RLQ pain radiating to the groin; prostate—dull, suprapubic; kidney—CVA QUALITY: Constant or colicky; stone passage—restless, cannot find a comfortable position ONSET: min-days AGGRAVATING OR RELIEVING FACTORS: Better with antibiotics and pain medications (pyelonephritis or nephrolithiasis) ASSOCIATED SYMPTOMS OR SIGNS: Hematuria, dysuria, prostate tenderness, fever DIAGNOSTIC STUDIES: Urinalysis, urine culture, CT for stone disease

Herpes Zoster

LOCATION: Dermatomal distribution QUALITY: Burning, itching, neuropathic, constant ONSET: days AGGRAVATING OR RELIEVING FACTORS: Aggravated by touching the dermatome; better with pain or antiviral medications ASSOCIATED SYMPTOMS OR SIGNS: Recurrent; rash may or may not be present DIAGNOSTIC STUDIES: Skin culture or biopsy

Abdominal Abscess

LOCATION: Distention, anorexia, nausea, vomiting; no stool or flatus passage; small intestine—increased hyperperistaltic (rushes) bowel sounds (early) or quiet abdomen (late); large intestine—bowel sounds variable; associated factors (e.g., hernia, previous surgery) QUALITY: Insidious, intense, constant ONSET: days AGGRAVATING OR RELIEVING FACTORS: May be aggravated by movement; better with abscess drainage ASSOCIATED SYMPTOMS OR SIGNS: Fever, anorexia, nausea, abdominal mass DIAGNOSTIC STUDIES: Elevated WBC count, CT

Acute Appendicitis

LOCATION: Elevated WBC count, US or CT QUALITY: Vague initially; gradual, steady increase to intense, localized, pain ONSET: hours AGGRAVATING OR RELIEVING FACTORS: Vague initially; gradual, steady increase to intense, localized, pain ASSOCIATED SYMPTOMS OR SIGNS: Anorexia, nausea, obstipation; occasional vomiting, fever late DIAGNOSTIC STUDIES:Elevated WBC count, US or CT

Metabolic Disorders( ex DM)

LOCATION: Epigastric or generalized QUALITY: intense, constant ONSET: hours-days AGGRAVATING OR RELIEVING FACTORS: Worse with poor metabolic control (e.g., poor glucose control) ASSOCIATED SYMPTOMS OR SIGNS: Recurrent; nausea, vomiting, diabetic neuropathy DIAGNOSTIC STUDIES: Specific metabolic parameters abnormal (e.g., elevated glucose in DM)

Chronic Pancreatits

LOCATION: Epigastric or periumbilical, radiates to midback QUALITY: Intense, localized ONSET: days-years AGGRAVATING OR RELIEVING FACTORS: Aggravated by food; better with narcotics ASSOCIATED SYMPTOMS OR SIGNS: Anorexia, nausea, vomiting; associated factors (e.g., alcohol); DM (with advanced disease) DIAGNOSTIC STUDIES: Amylase and lipase may be normal; CT may show calcifications, dilated pancreatic duct, pseudocyst; increased fecal fat and decreased fecal elastase if pancreatic insufficiency

Abdominal Epilespy

LOCATION: Epigastric or umbilical QUALITY: constant ONSET: hours-days AGGRAVATING OR RELIEVING FACTORS: Unprovoked; better with antiseizure therapy ASSOCIATED SYMPTOMS OR SIGNS: Recurrent; may have associated seizure disorder DIAGNOSTIC STUDIES: EEG

Peptic ulcer Disease

LOCATION: Epigastric, occasionally RUQ, rarely LUQ QUALITY: Dyspepsia: mild to moderate aching discomfort, pain, burning, gnawing, postprandial fullness ONSET: days AGGRAVATING OR RELIEVING FACTORS: Variable relief with antacids; may be relieved by, worsened by, or unrelated to meals ASSOCIATED SYMPTOMS OR SIGNS: Recurrent; associated factors (e.g.,Helicobacter pylori, aspirin, NSAIDs) DIAGNOSTIC STUDIES: Anemia, upper endoscopy, H. pylori testing

Acute Pancreatisis

LOCATION: Epigastric, radiates to midback (occasionally RUQ or LUQ) QUALITY: Diffuse, steady, stabbing, penetrating ONSET: 1-2 hr AGGRAVATING OR RELIEVING FACTORS: Aggravated by food; better when lying still and with narcotics ASSOCIATED SYMPTOMS OR SIGNS: Severe nausea and vomiting; reduced or absent bowel sounds; associated factors (e.g., alcohol, gallstones) DIAGNOSTIC STUDIES: Elevated amylase and lipase, CT

Acute Cholecystitis

LOCATION: Epigastric, then moves to RUQ; may radiate to right scapula QUALITY: Gradual, steady increase, moderate to severe ONSET: hours AGGRAVATING OR RELIEVING FACTORS: May follow a fatty meal; better with narcotics and surgery ASSOCIATED SYMPTOMS OR SIGNS: Nausea, some vomiting, fever DIAGNOSTIC STUDIES: Elevated WBC count, US or CT

Ovarian Cysts or torsion

LOCATION: LLQ or RLQ QUALITY: constant, intense ONSET: min AGGRAVATING OR RELIEVING FACTORS: Better with NSAIDs or surgery (torsion) ASSOCIATED SYMPTOMS OR SIGNS: Nausea, vomiting; may be recurrent DIAGNOSTIC STUDIES: US

Ruptured Ectopic pregnancy

LOCATION: LLQ or RLQ QUALITY: Constant, intense, stabbing ONSET: min AGGRAVATING OR RELIEVING FACTORS: better with surgery ASSOCIATED SYMPTOMS OR SIGNS: Rebound and guarding present, abnormal menses or amenorrhea DIAGNOSTIC STUDIES: Acute anemia, elevated β-HCG, US

Diverticulitis

LOCATION: LLQ or suprapubic QUALITY: Moderate to severe, steady or cramping, sharp or aching, localized ONSET: hours-days AGGRAVATING OR RELIEVING FACTORS: Moderate to severe, steady or cramping, sharp or aching, localized ASSOCIATED SYMPTOMS OR SIGNS: Anorexia, nausea, distention, constipation or loose stools; partial relief with passage of flatus or BM; fever late DIAGNOSTIC STUDIES:Elevated WBC count, CT

Dissecting or leaking AAA

LOCATION: Over the aneurysm, radiates to the back or groin QUALITY: Severe, searing, constant ONSET: Minutes to hours to days AGGRAVATING OR RELIEVING FACTORS: History of HTN or CAD ASSOCIATED SYMPTOMS OR SIGNS: Shock, pulsatile mass; bruit notusually present DIAGNOSTIC STUDIES: Acute anemia, CT, angiography

Acute Hepatitis

LOCATION: RUQ QUALITYL Dull or intense; localized ONSET: days AGGRAVATING OR RELIEVING FACTORS: Worse with deep inspiration ASSOCIATED SYMPTOMS OR SIGNS: Jaundice, anorexia, nausea; liver enlarged and tender to palpation; associated factors (e.g., alcohol, infection) DIAGNOSTIC STUDIES: Abnormal liver test results

Angina and myocardial infarction

LOCATION: Retrosternal or epigastric QUALITY: Pressure, squeezing, heaviness, or intense ONSET: min AGGRAVATING OR RELIEVING FACTORS: Worse with exertion; relief with nitroglycerin ASSOCIATED SYMPTOMS OR SIGNS: Dyspnea, diaphoresis DIAGNOSTIC STUDIES: ECG, cardiac enzymes, stress testing

Inflammatory or infections enterocolitis

LOCATION: Small intestine—periumbilical; large intestine—right or left side of the abdomen over the colon; rectum—tenesmus QUALITY: crampy ONSET: hours-days AGGRAVATING OR RELIEVING FACTORS: Better with stool passage and treatment of underlying cause ASSOCIATED SYMPTOMS OR SIGNS: Nausea, vomiting, bloody diarrhea; associated factors (e.g., infectious—food transmission; IBD—prolonged duration, family history) DIAGNOSTIC STUDIES: Stool studies for culture, colonoscopy with biopsies

Intestinal ischemia

LOCATION: Small intestine—periumbilical; proximal (right) colon—periumbilical or RLQ; distal colon—LLQ QUALITY: Severe, stabbing pain out of proportion to physical findings ONSET: min AGGRAVATING OR RELIEVING FACTORS: Chronic ischemia—occurs after eating; acute ischemia—usually unprovoked; better with narcotics, thrombus dissolution, stenting, surgical resection ASSOCIATED SYMPTOMS OR SIGNS: Nausea, bloody diarrhea; associated factors (e.g., hypotension, cardiac arrhythmias) DIAGNOSTIC STUDIES: Elevated WBC count, CT or MR with angiography, or colonoscopy (colonic ischemia)

Musculoskeletal disorders

LOCATION: Specific muscle groups QUALITY: aching ONSET: days AGGRAVATING OR RELIEVING FACTORS: Better with heat or NSAIDs; aggravated by movement ASSOCIATED SYMPTOMS OR SIGNS: History of muscle injury or exertion DIAGNOSTIC STUDIES: Normal laboratory results

GERD

LOCATION: Substernal or epigastric QUALITY: Burning, gnawing ONSET: Days to years AGGRAVATING OR RELIEVING FACTORS: Provoked by large or fatty meals or recumbency; relief with antacids ASSOCIATED SYMPTOMS OR SIGNS: Recurrent; may have regurgitation, dysphagia, or extraesophageal manifestations (e.g., asthma, chronic cough, laryngitis) DIAGNOSTIC STUDIES: Upper endoscopy (usually normal), ambulatory pH/impedance probe

Pneumonia/pleurisy

LOCATION: Upper abdomen: epigastric, RUQ, or LUQ QUALITY: Localized; worse with deep breathing ONSET: hours to days AGGRAVATING OR RELIEVING FACTORS: Painful breathing; better with antibiotics ASSOCIATED SYMPTOMS OR SIGNS: Cough, fever, dyspnea DIAGNOSTIC STUDIES: CXR

Malignant dieases

LOCATION: Variable, depending on cancer location QUALITY: Variable; intense and crampy if bowel obstruction; steady and vague if local invasion ONSET: days AGGRAVATING OR RELIEVING FACTORS: Better with narcotics and cancer therapy ASSOCIATED SYMPTOMS OR SIGNS: Primary vs. metastatic disease DIAGNOSTIC STUDIESPrimary vs. metastatic disease

IBS

LOCATION: Variable; usually lower abdomen QUALITY: Vague, crampy, sense of urgency ONSET: years AGGRAVATING OR RELIEVING FACTORS: Pain may be precipitated by dietary factors or stress; associated with change in bowel characteristics (e.g., frequency, form, difficulty with passage); relieved with stool passage ASSOCIATED SYMPTOMS OR SIGNS: Bloating and abdominal distention DIAGNOSTIC STUDIES: Normal sigmoidoscopy, colonoscopy, and CT, but these are usually not necessary for diagnosis

Ruptured Viscus and peritonitis

LOCATION: diffuse QUALITY: intense ONSET: min-hours AGGRAVATING OR RELIEVING FACTORS: Worse with cough or movement; better when lying still or with narcotics or surgery ASSOCIATED SYMPTOMS OR SIGNS: Fever, anorexia, nausea, vomiting; lack of bowel sounds; tenderness with percussion, light touch, rebound; guarding and rigidity (late); loath to move DIAGNOSTIC STUDIES: Fever, anorexia, nausea, vomiting; lack of bowel sounds; tenderness with percussion, light touch, rebound; guarding and rigidity (late); loath to move

Nonucler (functionsal dyspepsia )

LOCATION: epigastric QUALITY: Mild to moderate discomfort, pain, burning, gnawing, postprandial fullness ONSET:years AGGRAVATING OR RELIEVING FACTORS: May be worsened by meals; cannot be reliably distinguished from ulcer disease by history alone ASSOCIATED SYMPTOMS OR SIGNS: Other symptoms of functional disorders (IBS, fibromyalgia, pelvic pain) DIAGNOSTIC STUDIES: normal EGD

Strangulated Hernia

LOCATION: localized QUALITY: Elevated WBC count, CT or MR with angiography, or colonoscopy (colonic ischemia) ONSET: min-hours AGGRAVATING OR RELIEVING FACTORS: Previous hernia history; unprovoked; better with narcotics and decompression, including surgery ASSOCIATED SYMPTOMS OR SIGNS: Anorexia, nausea, vomiting, no stool or flatus passage if obstruction; bowel sounds variable—hyperactive early if obstruction present, but absent bowel sounds late, especially with peritonitis DIAGNOSTIC STUDIES: Elevated WBC count, CT, US

Small or Large Bowel Obstruciton

LOCATIONSmall intestine—periumbilical; proximal (right) colon—periumbilical or right abdomen; distal (left) colon—LLQ QUALITY: Early—diffuse, colicky, crampy; late—steady and better localized ONSET: hours-days AGGRAVATING OR RELIEVING FACTORS: Aggravated by food; better with narcotics, NGT decompression, or surgery ASSOCIATED SYMPTOMS OR SIGNS: Distention, anorexia, nausea, vomiting; no stool or flatus passage; small intestine—increased hyperperistaltic (rushes) bowel sounds (early) or quiet abdomen (late); large intestine—bowel sounds variable; associated factors (e.g., hernia, previous surgery) DIAGNOSTIC STUDIES: CT

IBS: diagnosis

Laboratory testing — There is no definitive diagnostic laboratory test for IBS. The purpose of laboratory testing is primarily to exclude an alternative diagnosis. ○ In all patients with suspected IBS, we perform a complete blood count. ○ In patients with diarrhea, we perform the following: 1. C-reactive protein and/or fecal calprotectin □ Elevated levels of fecal calprotectin and fecal lactoferrin have been demonstrated to be very helpful in discriminating IBD from IBS □ CRP is an (nonspecific) inflammatory marker □ patients with IBS symptoms and a CRP level of ≤0.5 or calprotectin level of ≤40 μg/g, there was a ≤1 percent probability of IBD 2. Serologic testing for celiac disease Diagnosis/Evaluation — A clinical diagnosis of IBS requires the fulfillment of symptom based diagnostic criteria and a limited evaluation to exclude underlying organic disease. In the absence of a biologic disease marker, the most widely used diagnositic criteria is the Rome IV criteria. In patients with alarm features, we perform additional evaluation to exclude other causes of similar symptoms. In patients who meet diagnostic criteria for IBS and have no alarm features, we do not routinely perform any additional testing beyond the initial evaluation. Rome IV criteria for IBS — According to the Rome IV criteria, IBS is defined as recurrent abdominal pain, on average, at least one day per week in the last three months, associated with two or more of the following criteria [17,26]: § Related to defecation § Associated with a change in stool frequency § Associated with a change in stool form (appearance) Alarm features — Alarm features include: • Age of onset after age 50 years • Rectal bleeding or melena • Nocturnal diarrhea • Progressive abdominal pain • Unexplained weight loss • Laboratory abnormalities (iron deficiency anemia, elevated Creactive protein or fecal calprotectin) • Family history of IBD or colorectal cancer

Define probiotics

Live microorganisms that confer a health benefit on the host when administered in adequate amounts

Primary Biliary Cholangitis- ABnormal liver enzymes and association with liver disease

Liver enzymes are elevated due to hepatocyte damage and leakage of cellular contents (think how creatinine and LDH levels increase w/ skeletal muscle damage). Enzymes of note are AST, ALT, ALP, and GGT (if GGT and ALP are elevated as well, indicative of bile duct issues)

PBC: rational for ordering RUQ US

Liver is located in RUQ, thus using an ultrasound will allow us to visualize portal HTN, biliary obstruction, etc. A variation of U/S is the vibration-controlled transient liver elastography, which tests the elasticity of the liver and is a great, non-invasive way to see progression of fibrosis

M cells

Located in peyers patch and isolated lymphoid follicles. -Lack villi M cells are specialized epithelial cells of the mucosa-associated lymphoid tissues. A characteristic of M cells is that they transport antigens from the lumen to cells of the immune system, thereby initiating an immune response or tolerance. -constantly sampling gut environment and release sample into lamina propria where it is picked up by dendritic cells. d

Cystic Fibrosis: GI Complications

Loss of CFTR reduces fluid secretion and hydration of the intestinal contents. Loss of pancreatic digestive enzyme secretion with delayed or inadequate fat and nutrient digestion contributes to DIOS, possibly through slow intestinal transit induced by nutrient-mediated release of ileal break hormones such as peptide YY. 214Other risk factors for DIOS include a severe genotype, dehydration, history of meconium ileus or DIOS, organ transplantation, and CF-related diabetes mellitus. 212 The possible role of modifier genes causing meconium ileus has not been fully addressed in DIOS. 203 Intussusception and, less frequently, volvulus may complicate DIOS.

low birth defects of anorectal region

Low Birth Defects of Anorectal Region • Imperforate anus ○ 1 in 5000 neonates ○ more common in males than in females ○ The anal canal may end blindly or there may be an ectopic anus or an anoperineal fistula (abnormal passage) that opens into the perineum ○ Abnormal canal may open into the vagina in females or urethra in males ○ More than 90% of low anorectal defects are associated with a fistula (e.g., a passage connecting the rectum and urethra). • Anal stenosis ○ anus is in the normal position § anus and anal canal are narrow ○ defect is probably caused by a slight dorsal deviation of the urorectal septum as it grows caudally. • Membranous atresia ○ the anus is in the normal position § thin layer of tissue separates the anal canal from the exterior § The remnant of the epithelial anal plug is thin enough to bulge on straining and appears blue from the presence of meconium § results from failure of the epithelial plug to perforate at the end of the eighth week.

OMT for Cholecystitis

MFR: Thoracic, Thoracic Outlet VIS: Abdomen, Ganglion Inhibitory Pressure- Celiac Ganglion MFR: Anterior Thoracoabdominal Diaphragm: Single Direction, Direct Method LYM: Mesentery Pump VIS: Neurolymphatic Reflex Technique for Gallbladder, Liver VIS: Abdomen, Liver

Metformin

MOA: improves glucose tolerance Decreases blood glucose levels by decreasing hepatic glucose production, decrease uptake and utilization Effects are mediated by initial activation by metformin activated protein kinase (AMPK) Liver enzyme that plays an impt role in whole body energy balance Causees GLUT4 deploment to the plasma membrane Lactic acidosis could be due to decreased liver uptake of lactate = one of substrates of gluconeogenesis Toxicity: severe hepatic disease, acute decompensated heart failure, lactic acidosis Dosage: single dose once a day Metabolized: metformin is not metabolized, excreted in the urine unchanged

PBC: ursodiol

Mammalian bile acid that changes the composition of bile in humans—dissolves gallstones b/c it is anticholelithic and decreases hepatic synthesis of cholesterol, decreases hepatic secretion of cholesterol, and inhibits intestinal absorption of cholesterol. Less cholesterol in gallstones allows for dissolution Metabolized hepatically and excreted in feces. Only adverse effect is diarrhea as OD and toxicity is unlikely

Celiac Disease- Screening and Diagnosis

May be diagnosed without biopsy: symptoms consistent with celiac, anti-tissue transglutaminase IgA positive, EMA + (endomysial antibody), HLA-DQ2/DQ8 Biopsy of small bowel- positive for villuous atrophy

Differential diagnosis of patients with abdominal pain and unexplained hypotension

Mechanism of hypotension- differential. Dx Intra-abdominal hemorrhage- Abdominal aortic aneurysm, Ruptured ectopic pregnancy, Splenic rupture Sepsis: acute mesenteric ischemia, appendicitis, ascending cholangitis, bowel obstruction with infarction. Cholecycsitis, diverticulitis, IBD, ischemic colitis, nephrolithasis (with ascending infection), pancreatitis, PID, peptic ulcer disease with perforation , spontaneous bacterial peritonitis Other- adrenal insufficiency, DKA, MI

Enterobacteriaceae

Members of the family Enterobacteriaceae are moderate-sized , non-spore-forming, gram-negative rods that share a common antigen (enterobacterial common antigen). All members can grow rapidly, aerobically and anaerobically (facultative anaerobes), on a variety of nonselective (e.g., blood agar) and selective (e.g., MacConkey agar) media. are catalase positive and oxidase negative Most Enterobacteriaceae are motile, with the exception of some common genera (e.g., Klebsiella, Shigella, Yersinia ). cell wall- The heat-stable lipopolysaccharide (LPS) is the major cell wall antigen and consists of three components: the outermost somatic O polysaccharide, a core polysaccharide common to all Enterobacteriaceae (enterobacterial common antigen mentioned earlier), and lipid A. The core polysaccharide is important for classifying an organism as a member of the Enterobacteriaceae, the O polysaccharide is important for the epidemiologic classification of strains within a species, and the lipid A component of LPS is responsible for endotoxin activity, an important virulence factor. Serology can be done to identify and classify Enterobacteriaceae based on the cell surface antigens present.

Anorectal abnormalities

Most anorectal anomalies result from abnormal development of the urorectal septum • = incomplete separation of the cloaca into urogenital and anorectal parts • Shh and FGF-10, as well as disruption of β-catenin signaling, have been implicated in birth defects of the hindgut. • There is normally a temporary communication between the rectum and anal canal dorsally from the bladder and urethra ventrally. • Lesions are classified as low or high ○ depending on whether the rectum ends superior or inferior to the puborectalis muscle § Puborectalis m. maintains fecal continence and relaxes to allow defecation.

Type II Diabetes: Signs and Symptoms

Most of the time patient is asymptomatic until glucose levels and labs are done Some have fatigue, polydispsia, polyuria, and glucouria Clinical features: - Typically older than 40 years - Increased sedentary lifestyle + obesity = earlier ages - Frequently obese - Unexplained fatigue, dizziness or blurred vision - Usually made after routine blood testing in asymptomatic patients - Due to large number of asymptomatic patients with undiagnosed hyperglycemia in the US routine glucose testing is recommended for everyone older than 45

11. Explain the role of hepatoxicity and its impact on amino acid production and the urea cycle.

NH4+ is brought in by main guy alanine (aa) - Damaged hepatocytes --> buildup of ammonium --> no urea cycle

Characterize the pathophysiological mechanisms of those diesels or conditions that alter gastrointestinal motility (LGS 5.2 #1)

Need to find answer

Describe the transition from insulin therapy to oral therapy

Need to taper off because any extreme change can cause hypoglycemia (too much insulin) or hyper glycemia (not enough) - Get the body used to it having less and less insulin and transition to oral metformin

Normal esophageal development

Normal Esophageal Development: • Esophagus develops from the foregut immediately caudal to the pharynx. • The tracheoesophageal septum separates the trachea from the esophagus. • Esophagus is its final "relative" length by 7th week. • Esophageal epithelium and glands are derived from the endoderm ○ This endoderm proliferates - partly or completely § Obliterating the lumen of the esophagus. ○ Recanalization occurs by the end of the 8th week § Striated muscle will form the muscularis externa of the superior ⅓ of the esophagus § Smooth muscle (mainly in the lover ⅓) develops from the surrounding splanchnic mesenchyme □ Both muscular layers are innervated by branches of the vagus nerve

Cholera- Treatment

Oral of IV fluids Measure stool output to make sure patient is not over hydrates Antibiotic (doxycycline, tetracycline, cirpofloxacin)

Cholera- Management

Oral rehydration, IV rehydration, close monitoring for secondary complications, so bacterial gastroenteritis infections —> antimicrobial therapy Tetracycline TMP/SMX, erythromycin, doxycycline for resistant cases Dieatary: BRAT diet (bananas, rice, applesauce, toast) Introduce lean meats and clear fluids ASAP When giving lacrosse containing dairy products look for signs of malabsorption For infants- continue breast feeding

Define palmar erythema

Palmar erythema is a reddening of the skin on the palmar aspect of the hands, usually over the hypothenar eminence. It may also involve the thenar eminence and fingers. It can also be found on the soles of the feet, when it is termed plantar erythem UpToDate: Palmar erythema is an exaggeration of the normal speckled mottling of the palm and is believed to be caused by altered sex hormone metabolism. It is most frequently found on the thenar and hypothenar eminences, while sparing the central portions of the palm. Palmar erythema is not specific for liver disease and can be seen in association with pregnancy, rheumatoid arthritis, hyperthyroidism, and hematological malignancies. a.

Relate the tissue and cellular component structures of the pancreatic and salivary glands to the composition and functions of their exocrine secretions. (LGS 5.3a)

Pancreas is the source of majority of enzymes required for digestion of a mixed meal Enzymes fall below 10% of normal levels will result in impaired nutritional absorption Role of Secretin - Released from S cells in the duodenal mucosa § When meal enters the small intestine from the stomach the volume of pancreatic secretions increases rapidly § Shifts from low volume, protein rich fluid to a high volume secretion □ Enzymes are present at lower concentrations ® although greater absolute amount ◊ Reflects effect of CCK and neural effectors on acinar cell secretion § As secretory rate rises, pH and bicarb concentration in pancreatic juice rises □ Reciprocal fall in concentration of Cl ions § Secretin: mediates these effects on composition of pancreatic juice □ Postprandial bicarb secretory response can largely be reproduced by admin of secretin □ Particularly if given with low dose of CCK that potentiates ductular secretion

Cystic Fibrosis: pancreatic Enzymes

Pancreatic enzyme replacement ( Chapter 144 ) is the mainstay of treatment for exocrine pancreatic insufficiency. Because gastric acid decreases enzyme activity, H 2 -blockers (e.g., ranitidine 150mg twice daily in children weighing >30kg and in adults) or proton pump inhibitors (e.g., lansoprazole 30mg orally once daily in children weighing >30kg and in adults) are often used. Children and adolescents frequently use multiple nutritional supplements every day to maintain weight. Fat-soluble vitamin replacement therapy is necessary in most patients. Between 10% and 20% of patients may require gastrostomy feeding to aid growth or maintain weight. ○ Successful enzyme replacement therapy is generally defined as weight gain, absence of visible oil in the stool, and normalization of fat-soluble vitamin levels. Failure of enzyme therapy is most often caused by an inadequate dose. Increasing the dose up to the full 90,000 USP units with meals and encouraging compliance is appropriate as a first step. In patients using a non-enteric-coated preparation, the dose of the H2-blocker or proton pump inhibitor can be increased to reduce the acid destruction of enzymes. Some patients may not respond because a second disease, such as small intestinal bacterial overgrowth ( Chapter 140 ), is contributing to the malabsorption. ○ Amylase is an enzyme that helps digest carbohydrates. It is made in the pancreas and the glands that make saliva. When the pancreas is diseased or inflamed, amylase releases into the blood. ○ Lipase- Lipase is a protein (enzyme) released by the pancreas into the small intestine. It helps the body absorb fat. This test is used to measure the amount of the lipase in the blood.

Describe the procedure for abdominal paracentesis

Paracentesis is a procedure in which a needle or catheter is inserted into the peritoneal cavity to obtain ascitic fluid for diagnostic or therapeutic purposes. [1, 2]Ascitic fluid may be used to help determine the etiology of ascites, as well as to evaluate for infection or presence of cancer. With regard to differentiation of transudate from exudate, the preferred means for characterizing ascites is the serum-ascitic albumin gradient (SAAG). [3] The SAAG is calculated by subtracting the albumin concentration of the ascitic fluid from the albumin concentration of a serum specimen obtained on the same day. The SAAG correlates directly with portal pressure. Transudative ascites occurs when a patient's SAAG level is greater than or equal to 1.1 g/dL (portal hypertension). Exudative ascites occurs when patients have SAAG levels lower than 1.1 g/dL. (See the Ascites Albumin Gradient calculator.)

Giardia clinical features

Parasite with flagella SXS: cramping, gas, abdominal pain, relief with defecation, afebrile, diarrhea, weight problems Related to recent travel/outdoor activity. Infective Stage- cyst Incubation period- 5 days - 3 weeks. Life cycle: ingestion, excystation, stays in small bowel for incubation period, uses adhesive disc to attach to mucosal epithelial cells, non-invasive. Diagnosis: C&P, look for trophozoites (diagnostic stage) Treatment: metronidazole

Gastric Secretions (LGs 5.2 #2) understand th physiologic roles for gastric secretory products

Parietal cells: secrete acid and intrinsic factor -HCl: most characteristic secretory produc of the stomach, begins digestive process via simple hydrolysis, contributes to sterilization of meal Intrinsic factor: needed for absorption of cobalamin, secreted by parietal cells Chief cells: store pepsinogen in apical gnraules that can release contentment via exocytosis -proteases: pepsinogen inactive zymogen, secreted from both mucus and chief cells, activated into pepsin Mucus cells: secrete mucus and bicarbonate ADD more to this from notes

Celiac Disease - Pathophysiology

Pathophysiology: triggered by ingestion of gluten, disease producing components come from gliafin GLuten is digested by luminal brush border enzymes into AA and peptides, including gliaden Gliaden induces epithelial cells to produce IL-15 —> Activation of CD8+ lymphocytes —> express NKG2D , natural killer cell marker for MIC-A MIC-A expressed on enterocytes —> marked for destruction Gliaden interacts with HLA-DQ2/DQ* on APCs to stimulate CD4+ T cells —> contribute to tissue damage

NAFLD : pioglitazone

Pioglitazone improves hepatic histologic parameters such as ballooning degeneration, lobular inflammation, and steatosis as well as hepatic fibrosis. (MOA in #9) FDA use: Type 2 diabetes MOA: Improves target-cell response to insulin; decreases hepatic gluconeogenesis; depends on the presence of insulin for activity Pioglitazone hydrochloride, a thiazolidinedione antidiabetic agent and a potent peroxisome proliferator-activated receptor-gamma (PPAR(gamma)) agonist, is dependent on the presence of insulin for its mechanism of action. It increases insulin-dependent glucose disposal and decreases hepatic glucose output by decreasing insulin resistance in the periphery and in the liver Contraindications • Hypersensitivity to pioglitazone • Diabetic ketoacidosis • Moderate-severe hepatic impairment (ALT >2.5x ULN) • CHF (NYHA class III, IV) UpToDate: Thiazolidinediones, including pioglitazone, are insulin-sensitizing agents that improve liver biochemical and histologic parameters in patients with NASH. However, their use is associated with adverse events, including weight gain, painful swollen legs, and heart failure. In addition, it is likely that long-term treatment is required to achieve a clinically important benefit because the improvements seen with thiazolidinediones may reverse if the drugs are stopped. Our approach is to use thiazolidinediones for the treatment of NASH only in patients with type 2 diabetes who are otherwise candidates for treatment with a thiazolidinedione. The effect of thiazolidinediones on histologic parameters in NASH was examined in a meta-analysis of four randomized trials that compared thiazolidinediones with placebo in 334 patients with NASH. The analysis found that compared with placebo, thiazolidinediones were more likely to improve hepatic histologic parameters such as ballooning degeneration (odds ratio [OR] 2.1), lobular inflammation (OR 2.6), and steatosis (OR 3.4). Improvement in fibrosis was not seen when all thiazolidinediones were examined, but when the analysis was limited to three studies that used pioglitazone, there was a significant improvement in fibrosis among patients treated with pioglitazone compared with placebo (OR 1.7).

Type II Diabetes- Signs and Symptoms

Polydispia, polyuria, glucouria Clincial Features: typically over 40-> increased sedentary lifestyle + obesity= earlier onset Frequently obese Unexplained fatigue, dizziness or blurred vision

Celiac Disease- Nutritional Deficiencies

Poor fat absorption Poor absorption of fat soluable vitamins (A D E K) Folate and B12 deficiency Calcium absorption impaired ( can effect bone density)

pre- and post- digestion effects of bile salts and phospholipids

Predigestion: form a boundary around fat droplets for stabilization (sustaining emulsification) and increases available surface area for digestion by lipase. Postdigestion: mixed-micelle formation with lipid-soluble FFA and cholesterol inside, allows for diffusion through water layer to bring digested lipids up to apical membranes in intestines, greatly enhances rate of diffusional uptake

Define synbiotics

Products that contain both probiotics and prebiotics

Psyllium

Psyllium husk is a natural, therapeutic fiber that produces a laxative effect. Bulk-forming laxatives cause retention of fluid and an increase in fecal mass, resulting in stimulation of peristalsis • Constipation • Gastrointestinal symptom, Orlistat-induced • Hypercholesterolemia • Irritable bowel syndrome Common • Gastrointestinal: Borborygmi, Flatulence Serious • Gastrointestinal: Choking, Obstruction of esophagus • Immunologic: Allergic reaction, Anaphylaxis Specific contraindications have not been determined

Relationship of pulmonary embolisms and liver disease

Pulmonary embolism due to hypercoaguable state from liver dysfunction - can also have vascular wall injury of cholesterol dysfunction, fatty infiltrates, circulatory stasis from decreased hepatic function Virchow's triad: hypercoaguable sate, vascular wall injury, circulatory stasis

Rotavirus

RNA Virus, double stranded Diagnosis: immunoassay looking for antigens, RT-PCR Resistant to acidic pH, detergents and drying Has double layered capsid with RNA virus, virus gets inside cell and releases outer capsid and replicates inside inner capsid Transmission is fecal-oral, causes a secretary watery diarrhea. NSP4 toxin increases chloride permeability, increases water secretion Viral gastroenteritis in infants and young children, seasonal Treatment: oral vaccines- live attenuated or live reasserted with bovine vaccine

-malacia

RRRRRRRRRRRR Softening "Osteomalacia" softening of the bone

Shigella

Replicates: in the cytoplasm of the cell.

CCK

Role of CCK - CCK can be considered a master regulator of he duodenal cluster unit § Pancreas is an impt component of that - CCK is a potent stimulus of acinar secretion § Acts predominantly via CCK1 receptor dependent stimulation of vagal afferents close to site of release in the duodenum □ Evokes vago-vagal reflexes that stimulate acinar cell secretion via cholinergic (ACh) and noncholinergic NTs (GRP and VIP) □ Also CCK1 receptors on the basolatearl pole of acinar cells □ Seems likely that these are only activated if circulating concentrations of CCK rise to supraphysiologic levels § Coordinates activity of other GI segments and draining organs besides pancreas □ Includes ® contraction of gallbladder ® Relaxation of sphincter of Oddi ® Slowing gastric motility to slow gastric emptying ◊ Control rate of delivery of partially digested nutrients to more distal segments of the gut ◊ Serves to match luminal nutrient availability to the digestive and absorptive capacity of the small intestine § Modulates activity of other neurohormonal regulators in a synergistic fashion □ While CCK is a weak agonist of pancreatic ductular secretion of bicarb by itself - markedly potentiates effect of secretin on tranport mechanism □ During integrated response to a meal - likely that ability of secretin to evoke pancreatic bicarb secretion is amplified by occurring against the background of a CCK "tone" § Predominantly affects acinar cell secretion □ 5-HT and secretin also play a role ® Secretin effects mediated at the level of the ducts □ 5-HT release from intestinal enterochromaffin cells in response to nutrients activates a vago vagal reflex GPBAR1 that mirrors/augments that of CCK □ Enzyme secretion controle: 50% CCK, 50% 5-HT

Factors Causing Secretin Release

S cells in the duodenal mucosa can be considered to act functionally as pH meters - Sense acidity of luminal contents - As pH falls due to entry of gastric acid, secretin is released from S cells □ Travels through the bloodstream to bind to receptors on pancreatic duct cells ® Also bind on epithelial cells lining the bile ducts and duodenum itself □ Stimulated to secrete bicarb into the duodenal lumen ® Cause rise in pH that will eventually shut off secretin release - Threshold for secretin release appears to be luminal pH of less than 4.5 □ Mechanism by which S cells sense the change in luminal acidity is unclear ® Unsure if needs peptide releasing factor or sensory nerve endings - While other meal components like fatty acids have been shown to evoke secretin release response to acid appears to be more impt physiologically □ Subjects who fail to release secretin no matter what type of meal □ unable to secrete gastric acid (achlorhydric) secondary to disease or admin of PPI □ In whom gastric contents have been neutralized by oral admin of bicarb

Discuss the processes that regulate how indigestible residues from a meal are eliminated from the body (LGS 5.2 #1)

Segmental propulsion in the colon -propagate aborally , provide mass movement of feces -precede urge to defecate Contractions originate in cecum and sweep throughout colon to the rectum —> relaxation of internal anal sphincter -may be indicated by physiological stimuli (dissension) or by medications or disease (laxatives, inflammation) Propagation of contractions is mediated by cholinergic and neruokinin dependent pathways

Define prebiotics

Selectively fermented ingredients that result in specific changes in the composition and/or activity of the gastrointestinal microbiota thus conferring health benefit(s) upon host

Summarize the appropriate use of laboratory studies in the diagnosis of iron overload states.( STX LGD 5.5)

Serum Iron and transferrin saturdation Ratio of serum FE to TIBC provides an index of the fractional iron saturdaiton transferrin—> useful for assesment of iron status o. Serum Ferritin a. Small faction of intracellular ferritin is released from iron storage depots in macrophages and hepatocytes and enters the plasma, unattached to iron i. Useful measurement of iron stores in body ii. Interpretation may compounded in clincial setting 1) Inflammation regardless of cause increases ferritin synthesis by hepatocytes and liver disease may result in leakage of ferritin in plasma a) Patients with iron diffidence and concurrent inflammation or liver disease, serum ferritin levels may be normal or elevation p. Bone Marrow and Liver Iron Stores a. Most direct way to asses iron stores by staining macrophages in aspirated bone marrow smears with Prussian blue, stains iron q. Serum Transferrin receptor Small fraction transferrin receptor is released from maturing erythropoietin precursors and enters plasma where is can be measured

NAFLD: serum lipid abnormalities

Serum lipid abnormalities: -HDL/LDL/Total Cholesterol (LDL and total cholesterol elevated, HDL low) -VLDL (elevated) Other liver-related labs: • Serum ALT>AST ○ Elevated levels of aminotransferases, although common, are not required for the diagnosis of NAFLD. ○ In contrast to alcoholic liver disease, ALT levels are higher than AST levels, but they rarely exceed 250 IU/L. In general, AST and ALT levels do not have diagnostic or prognostic significance. • Mild hyperferritinemia is common and should not be confused with hereditary hemochromatosis . • Similarly, low-grade autoantibody (antinuclear antibody, anti-smooth muscle antibody) positivity is not uncommon and should not be confused with autoimmune liver disease. • Because steatosis is common in patients with Wilson disease , serum ceruloplasmin levels should be obtained as part of the diagnostic evaluation.

Cholera- Complications

Severe hypovolemia Hypokalemia Hypo/hypernatremia Renal Failure Acidosis Seizures Arrhythmias Death

Define shifting dullness

Shifting Dullness- feeling of the ascites fluid movement during abd exam

PBC: identifity signifiance Of assessing antibodies

Since PBC is autoimmune (T-cell mediated destruction of small bile duct epithelial cells), we want to test for the presence of self-antibodies. PBC is mostly AMA positive. There can also be PBC-autoimmune hepatitis overlap-syndrome if pt is positive for ASMA (will see symptoms of cholestasis and cytolysis) Anti-smooth muscle antibodies- autoimmune hepatitis Anti-liver/kidney microsomal-autoimmune hepatitis

GERD- Risk Factors

Smoking, obesity, pregnancy, ingestion of caffeine, chocolate, alcohol, fatty foods, hiatal hernia, incompetence of lower esophageal sphincter, scleroderma

Mechanism of Sodium Bicarbonate

Sodium bicarbonate (eg, baking soda, Alka Seltzer) reacts rapidly with hydrochloric acid (HCl) to produce carbon dioxide and sodium chloride. Formation of carbon dioxide results in gastric distention and belching Side effects Unreacted alkali is readily absorbed, potentially causing metabolic alkalosis when given in high doses or to patients with renal insufficiency. Sodium chloride absorption may exacerbate fluid retention in patients with heart failure, hypertension, and renal insufficiency Excessive doses of either sodium bicarbonate or calcium carbonate with calcium-containing dairy products can lead to hypercalcemia, renal insufficiency, and metabolic alkalosis (milk-alkali syndrome).

Ferritin

Storage iron found in cells

List the clinical indications for which there is moderate to strong evidence of benefit from probiotics. C

Strong • Prevention of necrotizing enterocolitis in preterm infants • Prevention of upper respiratory infections (URIs) in preschool-age children • Primary prevention of Clostridium difficile -associated diarrhea • Treatment of acute viral infectious diarrhea • Prevention of traveler's diarrhea • Prevention of antibiotic-associated diarrhea (children) • Irritable bowel syndrome (IBS) • Helicobacter pylori treatment enhancement

Crohn's Versus Ulcerative Colitis

Subtypes based on pattern of inflammation (firecracker) i. Crohn- transmural inflammation 1) Histo: Lymphoid aggregates with noncaseating ranulomas ii. Ulcerative colitis- mucosal inflammation (superficial mucosa may also be effected) 1) Histo: crypt abscesses with neutrophils but no granulomas 5. Subtypes differentiated based on affected location within GI i. Crohn: begins anywhere from mouth to anus with skip lesions 1) Terminal ileum is most common , rectum rarely ii. Ulcerative colitis: beings in rectum (always involved) and can extend to cecum with continuous involvement and sparing of remained of GI 6. Subtypes based on gross morphological appearance i. Crohn's: cobblestone mucosa, strictures and creeping fat ii. UC: pseudopolyps 7. Subtypes based on associations with certain extraintestinal disorders i. Crohns: calcium oxalate kidney stones and gallstones ii. UC: primary cleansing cholangitias (p-ANCA positive) iii. Both 1) Pyoderma ganfrenosum 2) Erythema nodosum 3) Ankylosis spondylitis 4) Uveitis 5) Aphthous lectures 6) Arthritis

Cephalic Phase

Summary: Vagal-vagal response Tases might smell thought ~30% acid production DVC—> vagus —> Ach and Grastrin Suppress somatostatin Detailed: □ Stomach gets ready even before meal is ingested □ Pancreas and galbladder begin to be regulated □ brain centers respond to the sight, smell, taste and even thought of food and relay info to the dorsal vagal complex (DVC) □ Vagal outflow intitiates both secretory and motor behavior in the stomach and distal segments ® Vagal outflow activates enteric nerves that release GRP and ACh ◊ GRP in the vicinity of antral G cells releases gastrin that then travels through the bloodstream to activate parietal and chief cells ◊ Ach supresses somatostatin release □ Pavlov's dogs experiment

Intestinal Phase

Summary: Digested peptides and AA in duodenum ~5-10% acid production Decreased buffering capacity Somatostain released —> potentiaton Detailed: □ Meal moves out of the stomach into the duodenum □ Buffering capacity of the lumen is reduced and pH falls □ At a pH of 3, CGRP triggers somatostatin release from D cells in gastric antrum, act on G cells to suppress gastrin release □ Somatostain from D cells in the oxyntic mucosa or from nerve endings also directly inhibit secretory function ® Acid sensing response ◊ Neural pathway that involves activation of chemoreceptors that react to change in pH and release CGRP via axon reflex □ Other signals limit gastric secretion ® Fat in the small intestine leads to inhibition via endocrine and paracrine factors GIP and CCK

Gastric Phase

Summary: Need vagus stimulation, histaminem Ach, gastrin Food entry into stomach ~50-60% acid production Mechanical and chemical stimuli Potentiaion of acid secretion Increased blood flow Detailed □ Most important □ Secretion amplified by mechanical and chemical stimuli due to presence of meal in lumen □ Luminal signals and stretch receptors ® Short and long reflexes to enhance secretory response ◊ Release of Ach close to parietal cells directly ◊ Ach activates ECL cells, or GRP that activates G cells to release gastrin indirectly □ Changes in motility happen in this phase □ Vago-vagal reflexes allow stomach to relax and distend in the process of receptive relaxation □ Reflexes also transmit info downstream to more distal segments of intestine to receive the meal □ Increase in gastric blood flow to supply metabolic requirements of the secreting cell types □ Secretory cells of the stomach are highly active □ Due to neurocrine and endocrine signals ® Histamine release from ECL cells ® pepsinogen released by chief cells is rapidly cleaved to pepsin in an autocatalytic reaction that occurs optimally at pH 2, and this pepsin then acts on ingested protein to release short peptides and amino acids that further enhance gastrin release. ® Moreover, many dietary substances, including proteins, are highly effective buffers. Thus, while acid secretory rates remain high, the effective pH in the bulk of the lumen may rise to pH 5. ◊ This ensures that the rate of acid secretion during the gastric phase is not attenuated by an inhibition of gastrin release that would otherwise be mediated by somatostatin.

NAFLD: clinical manifestations

Symptoms: ○ Typically asymptomatic ○ If symptomatic: fatigue, hepatosplenomegaly, RUQ abd pain, ascites, gynecomastia, red palms, icterus/jaundice Lab/Rad Findings ○ Persistent mild to moderate elevation of ALT, AST (mean range: 100-200 IU/L) is the most common biochemical abnormality • Not specific, but NAFLD is the most common cause of increased LFT ○ AST:ALT ratio is usually less than 1 ○ Liver biopsy is the gold standard and should be considered in atypical patients ○ Ultrasound detection rates for stenosis are 80-100%; diffuse increased echogenicity of the liver parenchyma with vascular blurring suggestive of fatty liver.

Pathophysiology IBD

The common end pathway of ulcerative colitis is inflammation of the mucosa of the intestinal tract, causing ulceration, edema, bleeding, and fluid and electrolyte loss. [6] In several studies, genetic factors appeared to influence the risk of inflammatory bowel disease (IBD) by causing a disruption of epithelial barrier integrity, deficits in autophagy,[7] deficiencies in innate pattern recognition receptors, and problems with lymphocyte differentiation, especially in Crohn disease. [8] Inflammatory mediators have been identified in IBD, and considerable evidence suggests that these mediators play an important role in the pathologic and clinical characteristics of these disorders. Cytokines, which are released by macrophages in response to various antigenic stimuli, bind to different receptors and produce autocrine, paracrine, and endocrine effects. Cytokines differentiate lymphocytes into different types of T cells. Helper T cells, type 1 (Th-1), are associated principally with Crohn disease, whereas Th-2 cells are associated principally with ulcerative colitis. The immune response disrupts the intestinal mucosa and leads to a chronic inflammatory process

IBD: treatment

The medical approach for patients with IBD is symptomatic care (ie, relief of symptoms) and mucosal healing following a stepwise approach to medication, with escalation of the medical regimen until a response is achieved ("step-up" or "stepwise" approach), such as the following: • Step I - Aminosalicylates (oral, enema, suppository formulations): For treating flares and maintaining remission; more effective in UC than in CD • Step IA - Antibiotics: Used sparingly in UC (limited efficacy, increased risk for antibiotic-associated pseudomembranous colitis); in CD, most commonly used for perianal disease, fistulas, intra-abdominal inflammatory masses • Step II - Corticosteroids (intravenous, oral, topical, rectal): For acute disease flares only • Step III - Immunomodulators: Effective for steroid-sparing action in refractory disease; primary treatment for fistulas and maintenance of remission in patients intolerant of or not responsive to aminosalicylates • Step IV - Clinical trial agents: Tend to be disease-specific (ie, an agent works for CD but not for UC, or vice versa) The following medications may be used in patients with IBD: • 5-Aminosalicylic acid derivatives (eg, sulfasalazine, mesalamine, balsalazide, olsalazine) • Antibiotics (eg, metronidazole, ciprofloxacin, rifaximin) • Corticosteroid agents (eg, hydrocortisone, prednisone, methylprednisolone, prednisolone, budesonide, dexamethasone) • Immunosuppressant agents (eg, azathioprine, 6-mercaptopurine, methotrexate, cyclosporine) • Tumor necrosis factor inhibitors (eg, infliximab, adalimumab, certolizumab pegol) • Monoclonal antibodies (eg, natalizumab) • H2-receptor antagonists (eg, cimetidine, ranitidine, famotidine, nizatidine) • Proton pump inhibitors (eg, omeprazole, lansoprazole, esomeprazole magnesium, rabeprazole sodium, pantoprazole) • Antidiarrheal agents (eg, diphenoxylate and atropine, loperamide, cholestyramine) • Anticholinergic antispasmodic agents (eg, dicyclomine, hyoscyamine)

HbA1c definition and clinical use

The most widely used clinical test to estimate blood glucose control is measurement of glycated hemoglobin (also called A1C, hemoglobin A1C, glycohemoglobin, or HbA1C). A1C reflects mean blood glucose over the entire 120-day lifespan of the red blood cell, but it correlates best with mean blood glucose over the previous 8 to 12 weeks. ○ Sources of error in A1C measurements: § A1C values are influenced by red cell survival. □ Thus, falsely high values in relation to a mean blood glucose values can be obtained when red cell turnover is low, resulting in a disproportionate number of older red cells. This problem can occur in patients with iron, vitamin B12, or folate deficiency anemia. □ On the other hand, rapid red cell turnover leads to a greater proportion of younger red cells and falsely low A1C values. Examples include patients with hemolysis or anemia and those treated for iron, vitamin B12, or folate deficiency, and patients treated with erythropoietin § A1C values may be falsely elevated or decreased in those with chronic kidney disease. False elevations may be due in part to analytical interference from carbamylated hemoglobin formed in the presence of elevated concentrations of urea, leading to false elevations in the A1C level with some assays. False decreases in measured A1C may occur with hemodialysis and altered red cell turnover, especially in the setting of erythropoietin treatment. ○ RECOMMENDATIONS IN TYPE 2 DIABETES — Although similar general considerations apply to patients with type 2 diabetes, there is less variability in blood glucose concentrations in this disorder. As a result, the fasting blood glucose concentration correlates fairly well with the A1C value and can be used with the A1C to estimate glycemic control

Differentiate physical exam findings in the setting of acute abdomen as evidence of visceral stimulation or parietal stimulation. (LGS 5.6 a)

The physical examination must identify life-threatening illnesses that require urgent surgical evaluation § must be orderly, careful, and complete. § First, the patient should be observed and the abdomen inspected. □ Patients who are writhing or restless may have pain due to visceral distention (e.g., renal colic, intestinal obstruction) □ patients who lie motionless may have peritonitis. ® Gentle shaking of the bed or having the patient cough may elicit sharp, well-localized pain in patients with parietal but not with visceral pain. □ Auscultation should be performed before percussion or palpation so that intestinal activity is undisturbed. ® An abdomen that is quiet except for infrequent squeaks or tinkles suggests peritonitis or ileus. ® Loud peristaltic rushes that occur in synchrony with abdominal pain suggest small bowel obstruction. □ Light percussion across the upper, middle, and lower abdomen can determine any site of focal tenderness suggestive of peritonitis. ® should be performed with one or two fingers ◊ beginning away from where the patient localizes the pain and gradually moving to the site of pain. □ gentle, deeper palpation of the entire abdomen is performed gradually, including the region of tenderness. ® palpate for an abdominal aortic aneurysm ® include the inguinal and femoral canals, umbilicus, and surgical scars for evidence of incarcerating hernias. □ focal tenderness indicates parietal peritoneal irritation □ gentle, steady compression of the abdomen with one hand, voluntary guarding usually subsides ◊ Persistent involuntary guarding indicates peritonitis with reflex muscle wall contraction □ Testing for "rebound tenderness" in patients with suspected peritonitis is not recommended because it causes significant pain and is usually not necessary to establish the diagnosis. § A digital rectal examination should be performed in most patients with acute abdominal pain to evaluate for tenderness or fluctuance that suggests a perirectal abscess and to assess the stool for signs of overt or occult blood. Women with lower abdominal pain should have a pelvic examination by a skilled examiner to evaluate for gynecologic disease.

Mesenteries of sotmach (embryo)

The stomach is suspended from the dorsal wall of the abdominal cavity by the dorsal mesentery. • Which is the primordial dorsal mesogastrium ○ Was originally in the media plane - & was carried to the left during stomach rotation ○ And during formation of the omental bursa (lesser sac of the peritoneum) • This mesentery contains the spleen and celiac artery. The primordial ventral mesogastrium attaches to the stomach • Also attaches the duodenum to the liver and the ventral abdominal wall. Omental Bursa • In the mesenchyme - isolated clefts develop and form the dorsal mesogastrium. ○ The will coalesce to form the omental bursa (lesser peritoneal sac) • Rotation pulls the mesogastrium to the left- enlarging the bursa ○ The bursa will expand transversely and cranially § Soon lying between the stomach and the posterior abdominal wall • The function of the bursa is to facilitate movements of the stomach. • The superior portion of the bursa is cut off by the diaphragm (as it develops) ○ Forming the infracardiac bursa. ○ It may or may not persist - If it does - it usually lies medial to the base of the right lung. ○ The inferior region of the superior part of the bursa will persists as the § Superior recess of the omental bursa. • As the stomach enlarges ○ The omental bursa expands and acquires an inferior recess of omental bursa. § Between the layers of the elongated dorsal mesogastrium □ The greater omentum. ® The greater omentum overhangs the developing intestines. ® The inferior recess disappears as layers of the greater omentum fuse. ○ The omental bursa communicates with the peritoneal cavity via the omental foramen.

ascaris lumbricoides

Third world countries more prevalent SXS: appetite change, vomiting worms, tympanic protuberant abdomens with mass (RLQ in some vignettes) Infective stage: embryonate egg Diagnostic stage: unembryonated egg or worm Has a pulmonary phase (lung infiltration) characterized by coughing, wheezing, bloody sputum TH2 response IgE mediated immune response Xray: show air fluid levels and abdominal mass (usually a build up of worms)

Role of tight junctions in maintaining intestinal barrier

Tight Junctions (zone occludens): attachment between epithelial cells, may be intracellular pathway for solutes- dependent on size, charge and characteristics -Tight: impermeable. Ex) renal distal tubule -Leaky: permable Ex) Rena proximal tubule, gallbladder

Acinar cells

Triangular in shape Apical pole is packed with zymogen granules.

OMT for GERD

VIS: Neurolymphatic Reflex Technique for esophagus, pylorus, stomach acidity, and stomach motility. Celiac Ganglion Inhibitory Pressure Gastroesophageal Junction (MFR: Single Direction, Direct Method) --SD: fascial tension of phrenoesophageal ligament (restricted GE junction) MFR: Abdomen, Thoracoabdominal Diaphragm (Single direction, Direct Method) a.k.a. Doming or Redoming the Diaphragm

PBC: identify reasons for evaluating vitamin levels and lipid panel

Want to evaluate fat-soluble vitamins and lipid panel b/c PBC pts have issues with their bile secretion, thus emulsification of lipids (and their absorption) Liver makes Thrombopoietin and is also responsible for putting iron back into circulation for heme synthesis (causing anemia of chronic inflammation) Decreased platelets will cause decrease in coagulation, thus increased PTT and INR (INR is ratio of pt's PTT to average PTT for comparison) Liver is responsible for metabolizing the thyroid hormones, while also being influenced by it. Liver damage can cause prolonged effects systemically to mimic hyperthyroidism

NAFLD: indication for liver biopsy

While liver biopsy is the gold standard for diagnosing NAFLD, in many cases a presumptive diagnosis can be made based upon the patient's history, laboratory tests, and imaging findings, provided other disorders have been excluded. However, some patients will continue to have an unclear diagnosis following a noninvasive evaluation. In such cases, a liver biopsy is indicated. In addition, imaging studies and laboratory tests do not reliably differentiate patients with NAFL from those with NASH, or predict the severity of liver disease. The only way to definitively confirm or exclude the diagnosis of NASH and to determine disease severity is with a liver biopsy . This information can be used to guide patient care and may motivate patients to enact lifestyle modifications. As examples, patients found to have cirrhosis will require screening for esophageal varices and hepatocellular carcinoma, whereas patients with early fibrosis may be motivated to lose weight to decrease the risk of progressing to cirrhosis. Although there is no definitive consensus, we typically obtain a biopsy if the patient: ●Has peripheral stigmata of chronic liver disease (suggestive of cirrhosis) ●Has splenomegaly (suggestive of cirrhosis) ●Has cytopenias (suggestive of cirrhosis) ●Has a serum ferritin >1.5 times the upper limit of normal (suggestive of NASH and advanced fibrosis) ●Is >45 years of age with associated obesity or diabetes (increased risk of advanced fibrosis)

Discuss why the requirements of lifelong monitoring for its development and the potential need for micronutrient supplementation is needed in patients who have undergone small bowel resection.

Without the small bowel or certain sections, the ability to absorb nutrients leave with it. This is a indication for lifelong supplementation of necessary vitamins and nutrients. Especially in Crohn's because it's lifelong, UC can be cured.

Acute appendicitis clincal features

a. Appendix is a normal diverticulum of the cecum that is prone to acute and chronic inflammation b. Acute appendicitis is most common in adolescents and young adults i. Males are slightly more affected than females c. Pathogenesis i. Initiated by progressive increases in intraluminal pressure that compromise venous outflow ii. Many cases are due to overt luminal obstruction which are usually caused by small stone-like mass of stool (fecalith) 1) Stasis of luminal contents favors bacterial proliferation which will trigger ischemia and inflammatory responses which results in tissue edema and neutrophilic infiltration of the lumen, muscular wall, and periappendiceal soft tissues d. Morphology i. Sub serosal vessels are congested ii. Modest perivascular neutrophilic infiltrate within all layers of the wall 1) Inflammatory reaction will cause the serosa to become dull, granular, erythematous iii. Diagnosis will require neutrophilic infiltration of the muscularis propria iv. As the process continues, focal abcesses may form within the wall 1) Further compromise of appendiceal vessels leads to large areas of hemorrhagic ulceration and gangrenous necrosis which extends to the series creating acute gangrenous appendicitis---> Rupture and supportive peritonitis e. Clinical Features i. Periumbilical pain that ultimately localizes to the RLQ followed by nausea, vomiting, low-grade fever, mildly elevated WBC ii. McBurney Sign iii. Sometimes, these signs may not be present Retrocecal appendix may present with right flank pain/pelvic pain

Diverticulosis and diverticulitis

a. Diverticular disease refers to acquired pseudoverticular outpouchings of colonic mucosa and submucosa i. Generally multiple b. Pathogenesis i. Result from the unique structure of the colonic muscularis propria and elevated intraluminal pressure in the sigmoid colon 1) Where nerves, arterial Casa recta, and their connective tissue sheaths penetrate the inner circular muscle coat, focal discontinuities in the muscle wall are created ii. Increased intraluminal pressure is probably due to exaggerated peristaltic contractions, with spasmodic sequestration of bowel segments, and may be enhanced by diets low in fiber, which reduce stool bulk c. Morphology i. Small, flask-like outpouchings that occur in regular distribution ii. Have a thin wall composed of a flattened/atrophic mucosa, compressed submucosa, and attenuated/totally absent muscularis propria iii. Hypertrophy of the circular layer of the muscularis propria in the affected bowel segment is common iv. Obstruction of diverticula leads to inflammatory changes which will result in diverticulitis d. Clinical Features i. Remain asymptomatic throughout their lives ii. Those that do have symptoms show intermittent cramping, continuous lower abdominal discomfort, constipation, distention, or sensation of never being able to completely empty the rectum 1) Sometimes there may be intermittent constipation and diarrhea which can mimic IBS iii. There may be minimal chronic/intermittent blood loss and, rarely, massive hemorrhage 1) Bleeding may be macroscopically seen

Apply knowledge of iron homeostasis to understand the etiology and clinical manifestations of iron overload. (5.5 STX LGS)

a. Hemochromatosis is caused by excessive iron absorption most of which is deposited in parenchymal organs such as liver and pancreas , followed by hear, joints and endocrine organs i. Results from inherited widowers: hereditary hemochromatosis ii. Accumulation results from parenteral administrations or iron (usually transfusions): secondary hemochromatosis b. Characteristic of severe iron overload in body i. Fully devleoped cases exhibit 1) micro nodular cirrhosis in all patients 2) DM in 75-80% 3) abnormal skin pigmentation ii. Iron accumulation in hereditary forms is lifelong but injury is slow and progressive 1) Symptoms usually 1st appear in 4th-5th decades in men and later in women, menstruated bleeding counterbalances the accumulation until menopause a) Affects men more than women iii. Manifests after 20 gym stored irons have accumulated 1) Excessive iron is toxic to tissues 2) Mechanisms on injury a) Lipid peroxidation via iron catlazyed free radical reactions b) Stimulation fo collagen formation by activation of hepatic stellate cells c) Interaction of ROS and iron with DNA —> lethal cell injury, predisposition to HCC

IBD

a. Idiopathic inflammatory disordered that can effect any portion of GI, relapsing and remitting episodes of abdominal pain and diarrhea Due to dysregulated pro-inflammatory response to bacterial lining the walls of GI —> release of inflammatory substances that cause direct mucosal injury

Phenylketonuria

a. Phenylketonuria (from accessmedicine) i. Autosomal recessive disease occurring in avg of 1 in 15,000 births ii. Caused by deficiency in phenylalanine hydroxylase enzyme 1) Converts phenylalanine to tyrosine when working properly a) Important in the production of neurotransmitters and skin pigment (melanin) iii. Disease results from decrease in tyrosine and increase in phenylalanine 1) Produces phenylketones, including phenylacetate, phenylpyruvate, and phenylethylamine a) Presence of phenylketones is normally screened for in the blood as part of standard neonatal testing and again at 2 weeks of age. iv. Symptoms 1) Traits of albinism a) Fair skin, white-blonde hair, pale blue eyes 2) Musty odor of phenylacetate in their sweat, urine, skin, and hair 3) Sometimes develop eczema v. Untreated PKU 1) Decreased brain development (microcephaly) 2) Hyperactivity 3) Brain damage 4) Seizures 5) Mental retardation and learning disabilities vi. Treatment 1) Diet low in phenylalanine 2) Decrease in phenylalanine levels

Shiga toxin-producing E. coli (STEC)

affects large intestine. Presentation: Initial watery diarrhea followed by grossly bloody diarrhea (hemorrhagic colitis) with abdominal cramps; little or no fever; may progress to hemolytic uremic syndrome Transmission: Most infections are attributed to the consumption of undercooked ground beef or other meat products, water, unpasteurized milk or fruit juices (e.g., cider made from apples contaminated with feces from cattle), uncooked vegetables such as spinach, and fruits. Ingestion of fewer than 100 bacteria can produce disease, and person-to-person spread occurs. Hemolytic uremic syndrome (HUS), a disorder characterized by acute renal failure, thrombocytopenia, and microangiopathic hemolytic anemia, is a complication in 5% to 10% of infected children younger than 10 years. **microthrombi cause hemolytic anemia** and large amounts of VWF produced cause the micro thrombi. (Stx1, Stx2) Both have one A subunit and five B subunits, with the B subunits binding to a specific glycolipid on the host cell (globotriaosylceramide [Gb3]). A high concentration of Gb3 receptors is found in the intestinal villi and renal endothelial cells. After the A subunit is internalized, it is cleaved into two molecules, and the A 1 fragment binds to 28S rRNA and causes a cessation of protein synthesis. STEC strains with both Shiga toxins and attaching and effacing activity are more pathogenic than strains producing only one Shiga toxin. A/E (Attachment/effacement) lesions with destruction of intestinal microvilli, resulting in decreased absorption.

Enterotoxigenic E. coli (ETEC)

affects the small intestine. transmission- fecally contaminated food or water. Secretory diarrhea caused by ETEC develops after a 1- to 2-day incubation period and persists for an average of 3 to 5 days. Presentation: Traveler's diarrhea; infant diarrhea in developing countries; watery diarrhea, vomiting, cramps, nausea, low-grade fever ETEC produce two classes of enterotoxins: heat-stable toxins (STa and STb) and heat-labile toxins (LT-I, LT-II). STa is a small monomeric peptide that binds to the transmembrane guanylate cyclase C receptor on the intestinal epithelium, leading to an increase in cyclic guanosine monophosphate (cGMP) and subsequent hypersecretion of fluids well as inhibition of fluid absorption. Of the heat-labile toxins, LT-I is more commonly associated with human disease. LT-I is functionally and structurally similar to cholera toxin (80% homology) and consists of one A subunit and five identical B subunits. The B subunits bind to the same receptor as cholera toxin (GM 1 gangliosides), as well as other surface glycoproteins on epithelial cells in the small intestine. After endocytosis, the A subunit moves across the membrane of the vacuole and interacts with a membrane protein (Gs) that regulates adenylate cyclase. The net effect of this interaction is an increase in cyclic adenosine monophosphate (cAMP) levels, resulting in enhanced secretion of chloride and decreased absorption of sodium and chloride. These changes are manifested in a watery diarrhea. Exposure to the toxin also stimulates prostaglandin secretion and production of inflammatory cytokines, resulting in further fluid loss.

Maple syrup urine disease

b. Maple syrup urine disease i. Autosomal recessive ii. Blocked degradation of branched amino acids (Isoleucine, Leucine, Valine) due to decreased branch chain alpha-ketoacid dehydrogenase (B1) 1) Increased alpha-ketoacids in the blood, especially those of leucine iii. Severe CNS defects, intellectual disability, and death iv. Treatment 1) Restriction of isoleucine, leucine, valine in diet, and thiamine supplementation v. Presentation 1) Vomitting, poor feeding, urine smells like maple syrup/burnt sugar vi. I Love Vermont maple syrup from maple trees (with B1 ranches)

Summary of apical secretion into Bile from hepatocyte

bile salts (conjugated), phospholipids, cholesterol, bilirubin (conjugated), xenobiotic metabolites are ALL actively transported into canaliculus by apical ABC transporters

Role of Hepcidin and relationship to hemochromatosis

c. Hepcidin is main regulator of iron absorption i. Encoded by HAMP gene, secreted by liver ii. Transcription of hepcidin is increased by inflammatory cytokines and iron 1) Decreased by iron deficiency, hypoxia, eneffective erythropoiesis d. Hepcidin binds to cellular iron efflux channel ferroportin —> internaliation and proteolytic of ferroportin—> inhibits release of iron from intestinal cells and macrophages i. Lowers plasma iron levels—> hepcidin defieinciny leads to iron overload e. Other proteins involved in iron metabolism do so by regulating hepcidin levels i. Hemojuvelin (HJV)- expressed in liver heart and skeletal muscle ii. Transferrin receptor 2 (TFR2)- expressed in hepatocytes, mediates uptake of transferrin bound iron iii. HFE- producer of hemochromatosis gene iv. Decrease hepcidin synthesis caused by mutations in hepcidin, HJV, TFR2, HFE has a central role in pathogenesis Of hemochromatosis

mixed micelles are made of

cholesterol-phospholipid vesicles and bile salt micelles

Type 2 diabetes

criteria: fasting plasma glucose >126 or HB AIC >6.5% prediabetes 100-125 and 5.7% and 6.4%. Multifactorial disease that is caused by a combination of insulin resistance and inadequate response by pancreatic B cells. considered a relative insulin deficiency rather than absolute (type 1). Native Americans, African Americans, and Hispanics are 1.5 to 2 times more likely to develop diabetes in their lifetime. c-peptide hormone and insulin are secreted in equimolar quantities--> c-peptide hormone serve as a surrogate for B cell function-- increasing with insulin resistance. The most important environmental risk factor is obesity-> visceral obesity.

HIsotlogical comparison crohns verus UC

d. Ulcerative Colitis i. Limited to the colon and rectum ii. Extends to only the mucosa and submucosa iii. More common in females iv. Extends proximally in a continuous fashion 1) If it includes the entire colon= Pancolitis v. Colonic mucosa may be slightly red/granular or have extensive, broad-based ulcers vi. Pseudopolyps are present 1) Isolated islands of regenerating mucosa often bulge into the lumen 2) Tips of these polyps may connect and create mucosal bridges vii. Mucosal atrophy may occur with chronic disease 1) Unlike Chron's disease, mural thickening is not present, serosal surface is normal, and strictures don't occur viii. Toxic Megacolon ix. Relapsed disorder that is characterized by attacks of bloody diarrhea with stringy mucoid material, lower abdominal pain/cramp that may be relieved by defecation e. Chron's Disease (Regional enteritis) i. Can involve any area of GI 1) Most common site is the terminal ileum 2) Skip lesions that result in a cobblestone appearance ii. Typically transmural iii. Strictures are common iv. The earliest lesion is the aphthous ulcer v. Fissures develop between mucosal folds and may extend deeply to become fistula tracts/sites of perforations vi. In places with extensive transmural disease, mesenteric fat will extend around the serosal surface= Creeping fat vii. Microscopic Features 2) Crypt Abcesses= Clusters of neutrophils within a crypt a) Associated with crypt destruction 3) Distortion of mucosal architecture 4) Paneth cell metaplasia may occur in the left colon a) Paneth cells are normally absent 5) Noncaseating Granulomas are a hallmark of Crohn's disease viii. Clinical Manifestations 1) Extremely variable 2) Approximately 20% present with RLQ pain, fever, and bloody diarrhea which may mimic acute appendicitis 3) Fibrosing Strictures 4) Fistulae 5) Perforations and peritoneal abcesses are common f. Similarities i. Occur in the teens and early 20s ii. Most common among Caucasians, more specifically in eastern Europeans and Ashkenazi Jews 1) Most common in North America, Northern Europe, and Australia iii. Combined effects of alterations in host interactions with intestinal microbiota, intestinal epithelial dysfunction, aberrant mucosal immune responses, and altered composition of the gut microbiome g. A possible complication is the development of neoplasia which is related to several factors i. Duration of disease ii. Extend of disease iii. Nature of the inflammatory response

Excess iron and liver injury in relationship to hemochromatosis

f. Excess iron results not only form transfusions but also from increased absorption i. Transfusions alone when given repeated all over a period of years can lead to systemic hemosiderin and parenchyma organ injury g. Cirrhosis caused y chronic liver diseases in which hepapatis is predominant form of injury i. Diminished dhepcidin production form loss of hepatocyte mass —> cirrhosis related increased iron uptake form gut ii. Other mechanisms (unknown ) suspected h. Neonatal hemochromatosis: disease of unknown origin a. Manifests as severe liver disease and extrahepatic hemosiderin depositor i. Not inherited ii. Liver injury leading to hemosiderin accusation, occurs in utero

Understand hormonal regulation of metabolic homeostasis (LGS 5.4a)

i. Achieved in 3 ways 1) The concentration of nutrients or metabolites in the blood effects the rate at which they are used or stored 2) Hormones carry messages to their individual tissues about the physiologic state of the body and the nutrient supply or demand 3) The CNS uses neural signals to control tissue metabolism

Clincial Features of hemochromatosis

i. Clinical Features : principal manifestations of classic hemochromatosis include hepatomegaly, abdominal pain, abnormal skin pigmentation (sun exposed areaS), deranged glucose homeostasis or diabetes mellitus due to destruction of pancreatic islets, cardiac dysfunction (arrhythmias, cardiomyopathy) atypical arthritis a. In some patients presenting complaint is hypogonadism b. More often disease of males and rarely evident before 40 c. Classic triad of cirrhosis, hepatomegaly, abnormal skin pigmentation, diabetes mellitus, cardiac dysfunction i. Death: from cirrhosis or caridac disease ii. Significant cause of death is hepatocellular carinoma d. Treatment for iron overload does not fully remove risk of cancer because DNA alternations that occur prior to time of diagnosis and treatment initiation i. Screening importan

Akaptonuria

i. Congenital deficiency of homogentisate oxidase in the degradative pathway of tyrosine to fumarate --> pigment forming homogetisic acid accumulates in tissue ii. Autosomal recessive iii. Usually benign iv. Findings 1) Bluish-black connective tissue, ear cartilage and sclerae spots, includes bones (ochronosis) 2) Urine turns black on prolonged exposure to air (~24H) 3) May have debilitating arthralgias (homogentisic acid toxic to cartilage) Femoral head with black discoloration, black spotting on Scarlatti

Homocystinuria

i. Types (all autosomal recessive) 1) Cystathionine synthase deficiency a) Treatment: decreased methionine, increased cysteine, increased B6, B12, and folate in diet 2) Decreased affinity of cystathionine synthase for pyridoxal phosphate a) Treatment: INCREASED B6 and moderate increase of cysteine in diet 3) Methionine synthase (homocysteine methyltransferase) deficiency a) Treatment: increased methionine in diet All forms result in excess homocysteine 1) HOMOCYstinuria a) Increased Homocysteine in urine b) Osteoporosis c) Marafanoid habitus d) Ocular changes (downward and inward subluxation) e) Cardiovascular effects i) Thrombosis, atherosclerosis One. Stroke and MI f) kYphosis g) Intellectual disability

Ischemic bowel Disease

ii. Pathogenesis 1) Damage occurs in 2 phases a) Hypoxic Injury- Occurs at the onset of vascular compromise i) Epithelial cells are resistant to transient hypoxia b) Reperfusion Injury- Initiated by restoration of blood i) Greatest damage occurs here ii) Causes leak of gut lumen bacterial products into the systemic circulation, free radical production, and release of inflammatory mediators 2) Following components make ischemic bowel disease have a variable progression a) Severity of vascular compromise b) Time frame that it develops c) Affected vessels 3) 2 aspects of vascular anatomy may contribute to this a) Intestinal segments at the end of their arterial supplies are more susceptible to ischemia= Watershed Zones i) Splenic flexure ii) Sigmoid colon iii) Rectum b) Intestinal capillaries are along glands, from crypt to surface, before making a hairpin turn to empty into the post-capillary venules which makes them susceptible iii. Morphology 1) Colon is the most common site of inflammation 2) May involve any part of the GI 3) Lesions can be continuous but are most often segmented and patchy 4) Mucosa is hemorrhagic and can be ulcerated 5) Bowel wall is thickened by edema or extend into the submucosa and muscularis propria 6) Microscopic examination a) Characteristic atrophy/sloughing of surface epithelium b) Crypts may be hyperproliferative c) Inflammatory infiltrates are initially absent in acute ischemia, but neutrophils are recruited within hours of reperfusion d) Chronic issues will result in fibrous scarring 7) Bacterial superinfection and enterotoxin release may induce pseudomembrane formation iv. Clinical Features 1) Most common in patients >70 years and have an increased incidence in women 2) May be due to anything that can lead to increased blood pressure or something that can cause endothelial damage 3) Acute colonic ischemia presents with sudden onset of cramping, LLQ pain, desire to defecate, and bloody diarrhea

Adult form hemochromatosis

j. Adult form of hemochromatosis is almost always caused by mutations of HFE a. Mutations i. Mutation of TFR2 is less common 1) HFE gene is located on short arm of chromosome 6 at 6p21.3 close to HLA gene locuse, encodes an HLA classI like molecule that governs intestinal absorption of dietary iron by regulating hepcidin synthesis ii. Most common HFE mutation is a cysteine to tyrosine substitute at amine acid 282 1) Causes inactivation of protein, a) Present in 70-100% of patients diagnosed with primary hemochromatosis iii. Other common mutation is H63D (histidine at postion 63 to aspartate) 1) H63D homozygous state and C282Y/H63D compound heterozygous mutations often cause only mild iron accumulation b. Adult is usually milder than juvenile

Juvenile and neonatal forms hemochromatosis s

k. Juvenile form a. Severe form caused by mutations of HAMP and HJV l. Neonatal hemochromatosis: disease of unknown origin a. Manifests as severe liver disease and extrahepatic hemosiderin depositor i. Not inherited ii. Liver injury leading to hemosiderin accusation, occurs in utero iii. Extrahepatic hemosiderin deposition detected by buccal biopsy needs to be document for the correct diagnosis iv. No specific treatment

EIEC (Enteroinvasive E. coli)

occurs in the large intestines. Rare in developing and developed countries; fever, cramping, *watery diarrhea*; may progress to dysentery with scant bloody stools. The bacteria are able to invade and destroy the colonic epithelium, producing a disease characterized initially by watery diarrhea. A minority of patients progress to the dysenteric form of disease, consisting of fever, abdominal cramps, and blood and leukocytes in stool specimens. A series of genes on a plasmid mediate bacterial invasion ( pInv genes) into the colonic epithelium. The bacteria then lyse the phagocytic vacuole and replicate in the cell cytoplasm. Movement within the cytoplasm and into adjacent epithelial cells is regulated by formation of actin tails (similar to that observed with Listeria ). This process of epithelial cell destruction with inflammatory infiltration can progress to colonic ulceration. Plasmid-mediated invasion and destruction of epithelial cells lining colon. diagnosis: Sereny (guinea pig keratoconjunctivitis) test; plaque assay in HeLa cells; probes and amplification assays for genes regulating invasion (cannot discriminate between EIEC and Shigella )

PMH and ROS for abdominal pain patients

past medical history and review of systems provide clues about systemic and extra-abdominal conditions that may be manifested with abdominal pain Acute coronary syndromes heart failure Pneumonia empyema may cause dyspepsia epigastric or right or left upper quadrant pain nausea, and vomiting Metabolic conditions uremia diabetes with hyperglycemia or ketoacidosis Hypercalcemia acute adrenocortical insufficiency may cause pain, nausea, vomiting, and diarrhea. Acute intermittent porphyria familial Mediterranean fever may cause recurrent episodes of severe pain and peritonitis that may be misdiagnosed, leading to unnecessary surgeries. Other causes of acute abdominal pain include narcotic withdrawal, insect or reptile bites, and lead or arsenic poisoning

Secondary: disorders associated with ineffective erythropoieses

severe thalassemia, myelodysplastic syndromes a. Excess iron results not only form transfusions but also from increased absorption i. Transfusions alone when given repeated all over a period of years can lead to systemic hemosiderin and parenchyma organ injury b. Cirrhosis caused y chronic liver diseases in which hepapatis is predominant form of injury i. Diminished dhepcidin production form loss of hepatocyte mass —> cirrhosis related increased iron uptake form gut Other mechanisms (unknown ) suspected

Salmonella

transmission: Most infections result from ingestion of contaminated food products and, in children, from direct fecal-oral spread. The most common sources of human infections are poultry, eggs, dairy products, and foods prepared on contaminated work surfaces (e.g., cutting boards where uncooked poultry was prepared). pathogenesis:After ingestion and passage through the stomach, salmonellae attach to the mucosa of the small intestine and invade into the M (microfold) cells located in Peyer patches, as well as into enterocytes. The bacteria remain in ENDOCYTIC VACUOLES, where they replicate. The bacteria can also be transported across the cytoplasm and released into the blood or lymphatic circulation. Regulation of attachment, engulfment, and replication is controlled primarily by two large clusters of genes (pathogenicity island I and II) on the bacterial chromosome. Pathogenicity island I encodes salmonella-secreted invasion proteins (Ssps) and a type III secretion system that injects the proteins into the host cell. Pathogenicity island II contains genes that allow the bacteria to evade the host's immune response and encodes a second type III secretion system for this function. The inflammatory response confines the infection to the GI tract, mediates the release of prostaglandins, and stimulates cAMP and active fluid secretion. Presentation:The following four forms of Salmonella infection exist: gastroenteritis, septicemia, enteric fever, and asymptomatic colonization. 1. Gastroenteritis is the most common form of salmonellosis in the United States. Symptoms generally appear 6 to 48 hours after the consumption of contaminated food or water, with the initial presentation consisting of nausea, vomiting, and nonbloody diarrhea. Fever, abdominal cramps, myalgias, and headache are also common. Colonic involvement can be demonstrated in the acute form of the disease. Symptoms can persist for 2 to 7 days before spontaneous resolution. 2. Salmonella Typhi produces a febrile illness called typhoid fever. he bacteria responsible for enteric fever pass through the cells lining the intestines and are engulfed by macrophages. They replicate after being transported to the liver, spleen, and bone marrow. Ten to 14 days after ingestion of the bacteria, patients experience gradually increasing fever, with nonspecific complaints of headache, myalgias, malaise, and anorexia. These symptoms persist for 1 week or longer and are followed by GI symptoms. This cycle corresponds to an initial bacteremic phase that is followed by colonization of the gallbladder and then reinfection of the intestines. Enteric fever is a serious clinical disease and must be suspected in febrile patients who have recently traveled to developing countries where disease is endemic.

Elongation of Fatty Acids

§ After synthesis on the fatty acid synthase complex, palmitate is activated, forming palmitoyl-CoA. Palmitoyl-CoA and other activated long-chain fatty acids can be elongated, two carbons at a time, by a series of reactions that occur in the endoplasmic reticulum

Enteric Reflexes

§ Enteric reflexes □ Short reflexes □ Involve neural transmission contained entirely within the enteric nervous system □ Example: stretch receptors that sense distention of the stomach wall, then activate reflexes that stimulate acid secretion at the level of the parietal cell □ Long reflexes □ Activation of primary afferents that travel through the vagus nerve, interperetd in the dorsal vagal complex and trigger vagal outflow via efferent nerves that travel back to the stomach and activate parietal cells or other componetns of the secretory machinery □ AKA vago-vagal reflexes

Cystis Fibrosis- Pathophysiology

§ F508 mutation --> misfolded CFTR protein --> chlorine can't exit cell and enter mucus --> sticky mucus --> sticky mucus clogs up pancreatic ducts --> clogged pancreatic ducts prevent excretion of pancreatic enzymes --> results in pancreatic cell damage and malabsorption of nutrients

Gastrin

§ Gastrin □ Primary endocrine regulator of gastric secretion □ Travels through the bloodstream from antral mucosa to stimulate parietal and ECL cells via their CCK2 receptors □ Regulation of gastric acid and pepsin secretion by soluble mediators and neural input. Gastrin is released from G cells in the antrum and travels through the circulation to influence the activity of ECL cells and parietal cells. The specific agonists of chief cells are not well understood. Gastrin release is negatively regulated by luminal acidity via the release of somatostatin from antral D cells. Fundic D cells may also exert a tonic negative influence on parietal as well as chief and ECL cells.

B3: Niacin:

§ In human body and dietary sources, is present as a constituent of NAD and NARP □ Dietary enzymes are hydrolyzed in GI tract, free nicotine acid and nicotinamide are absorbed in the small intestine —> transport to tissues —> vitamin forms are incorporated into the coenzymes □ Excess niacin is excreted by kidneys § NAD and NADP can be synthesized from dietary tryptophan, but pathway = inefficient □ Endogenous niacin synthesis requires riboflavin, thiamine and prydoxine, and is impaired in patients with vitamin deficiencies § Good sources: years, meat, liver, peanuts, other legume seeds, enriched cereals § Pellagra: niacin deficiency- people with low niacin and tryptophan, maize based diets □ S/S: weakness, lassitude, anorexia, indigestion, and glossitis ® 4Ds: Dermatitis, Diarrhea Dementia Death ® Dermatitis: dark discoloration of sun exposed skin ® Diarrhea: inflammation of mucosal surfaces ® Dementia: vague, can progress to profound encephalopathy with confusion, memory loss and overt organic psychosis

Zollinger Ellison

§ In patients affected by this disorder, a (usually extragastric) endocrine tumor develops whose cells secrete large amounts of gastrin in an unregulated fashion. Such individuals have extremely high rates of gastric acid secretion, both at rest and in response to a meal. Both values may be increased five to ten fold above their normal levels. Moreover, because the tumor cells are unaffected by the normal negative feedback mechanisms that reduce gastrin release from G cells as the luminal pH falls, serum gastrin levels increase yet further. § Patients with gastrinoma often present with symptoms of dyspepsia and even gastric or duodenal ulceration. Duodenal injury, in particular, results because the unremitting load of acid and pepsin from the stomach overwhelms the segment's defensive capacities. This allows pepsin to remain active for longer and to degrade the duodenal epithelial cells, which are not specialized to withstand acid-peptic damage. If the primary tumor can be found in these patients, surgery is usually curative. However, other patients must be managed symptomatically, most often with the use of PPI § Tumor that leads to a lot of gastrin produced ton of acid that can lead to gastric and duodenal ulcers

Define obstructive jaundice

§ It can result from an impacted gallstone, cancer in the head of the pancreas compressing the common bile duct, liver diseases that are severe enough to prevent the formation of bile, or autoimmune destruction of the bile canaliculi. § Bilirubin still becomes conjugated, but the conjugated bilirubin cannot reach the intestine. It "overflows" into the blood. Urobilinogen, normally formed from bilirubin by intestinal bacteria, disappears from blood, stool, and urine. In complete biliary obstruction, the stools lose their normal brown color and appear clay colored because the intestinal bacteria have no substrate for the synthesis of stercobilin. However, the urine is colored yellow-brown by bilirubin diglucuronide. Liver function is unimpaired in acute biliary obstruction, but long-standing cholestasis causes irreversible liver damage.

Azathioprine

§ MOA: Azathioprine is an imidazolyl derivative of mercaptopurine; metabolites are § incorporated into replicating DNA and halt replication; also block the pathway for purine synthesis. The 6-thioguanine nucleotide metabolites appear to mediate the majority of azathioprine's immunosuppressive and toxic effects. § Metabolism: Hepatic; metabolized to 6mercaptopurinevia glutathione Stransferase (GST) reduction. Further metabolized (in the liver and GI tract) via three major pathways: Hypoxanthine guanine phosphoribosyltransferase (to active metabolites: 6thioguaninenucleotides,or 6TGNs),xanthine oxidase (to inactive metabolite: 6thiouric acid), and thiopurine methyltransferase (TPMT) (to inactive metabolite: 6-methylmercaptopurine) □ TPMT genotyping or phenotyping: Consider testing in all patients with a lower threshold for testing in those with abnormally low CBC unresponsive to dose reduction. Patients with intermediate TPMT activity may be at an increased risk of bone marrow suppression; consider empirically reducing the dose § Toxicity/Warnings: myelosuppression (worse with people who habe low TPMT), increased risk for hepatocellular T cell lymphoma (or lymphomas in general), infections, progressive multifocal leukoencephalopathy Contraindications: pregnancy, patients who've been treated with alkylating agents for RA

Pernicious Anemia

§ Pernicious anemia is an autoimmune condition where patients develop antibodies to parietal cells and/or intrinsic factor. § The immune attack mediated by these antibodies leads to inflammation restricted to the corpus of the stomach, a reduction in parietal cell mass, and destruction of chief cells, likely via a bystander mechanism or secondary to the apparent ability of parietal cells to control the numbers of other cell types present in oxyntic glands. § Acid secretion by the stomach is markedly reduced both at baseline and after meals, and in advanced cases is completely absent. § Due to the loss of regulatory feedback, therefore, levels of gastrin in the bloodstream rise sharply, even approaching those seen in some gastrinoma patients in the most serious cases. § The loss of parietal and chief cell function in pernicious anemia significantly reduces the extent to which digestion of the meal can be initiated in the gastric lumen. □ However, under most circumstances this is not nutritionally significant, since the digestive capacity of the pancreatic enzymes is more than adequate to fully digest dietary macromolecules. □ On the other hand, the most clinically significant consequence of a reduction in parietal cell function is cobalamin deficiency, which manifests as pernicious anemia and also with neurological disturbances, such as numbness in the extremities and weakness. □ Some patients may develop iron-deficiency anemia, particularly if their diet is low in heme iron (e.g., in vegetarians). There is also some increased risk of infection via the oral route in patients with pernicious anemia, given the lost ability of the gastric juices to sterilize the ingested meal. § Pernicious anemia is thought to be a relatively rare condition, and often occurs in association with other autoimmune diseases such as Graves disease or thyroiditis. On the other hand, there is a normal decline in parietal cell mass with aging, which may result in cobalamin malabsorption and increased susceptibility to enteric infections in the elderly. The increased susceptibility to infections can also be seen in patients who take PPIs for long periods. However, in this latter group, cobalamin malabsorption does not occur unless present for other reasons, because of the fact that acid and intrinsic factor can be secreted independently by parietal cells.

Define neonatal jaundic

§ Physiological jaundice of the newborn is caused by immaturity of the bilirubin-metabolizing system of the liver. Uptake of unconjugated bilirubin, activity of UDP-glucuronosyl transferase 1A1, intracellular level of UDP-glucuronic acid, and biliary secretion of conjugated bilirubin all are low in the neonate. To make matters worse, bilirubin diglucuronide gets deconjugated by β-glucuronidase in the intestine and in breast milk, but no bacterial flora is present to convert bilirubin to urobilinogen. Some of the unconjugated bilirubin is absorbed and contributes to the hyperbilirubinemia.

Regulation of Covalent modification of HMG- Reductase

§ Reducatse is regulated by phosphorylation and dephosphorylation § Elevated glucagon = increased phosphorylation of enzyme, inactivating it § Elevate insulin = increased dephosphorylation, activates it § Increased amount of sterols = phosphorylation and reduces activity via feedback suppression § Thyroid hormone increases acitivity of enzyme § Glucocorticoids decrease enzyme acitivity § Phosphorylated by AMP-activated protein kinase

B. Explain the importance of, and the roles played by, the pancreatic and salivary secretions in digestion and absorption of a mixed meal

§ Salivary secretory products □ Serous acinar cells □ Supply proteinacous components ® Digestive enzymes ◊ Salivary amylase } Digestion of carbohydrates □ Mucus acinar cells □ Mucus LOL □ Host protection □ Lysozyme ® Limit colonization of oral cavity by microbes □ Lactoferrin ® Sequester iron to prevent bacteria growth □ Large amounts of secretory IgA □ Growth factors □ Growth and repair of epithelial and other distal cells in the GI tract ® Nerve growth factor and epidermal growth factor □ Mucin □ Lubrication and solubilizing functions □ Related to mucin produce by the stomach □ Large glycoproteins with viscoelastic properties □ Water □ Main component of saliva □ Lubrication and solubilizing functions □ Inorganic solutes □ Calcium and phosphate ® Tooth formation and maintenance • Acinar Cells ○ Specialized exocrine secretory cells that are the source of the majority of the proteinaceouse components of the pancreatic juice. • Ductular Cells Line the intercalated ducts of the pancreas also play an important role in modifying the composition of the pancreatic juice. Ductular cells • When stimulated cells transport bicarb (HCO3) ions into the pancreatic juice as it passes along the duct § Water follows paracellularly in response to the resulting transepithelial osmotic gradient • Effect of duct cells = dilute the pancreatic juice and render it alkaline

Somatostatin

§ Somatostatin □ Negative regulation of acid secretion □ Released from D cells in response to an axon reflex that releases CGRP in the antral mucosa when the luminal pH falls below 3 □ Inhibits the release of gastrin from G cells. □ Can also exert inhibitory influences on ECL, parietal and chief cells in the stomach SSTR2 somatostatin receptor is responsible for the inhibitory effects of the peptide in stomach

Review the vitamin B12 metabolism

§ Vitamin B12 aka cobalamin § Humans totally dependent on vit B12 § Microorganisms in food are main source of vit B12 § Absorption requires intrinsic factor that is secreted from parietal cells of fundic mucosa □ Vitamin B12 is freed from binding proteins through action of pepsin in stomach and then binds to haptocorrin, then associates with intrinsic factor ® Complex then goes to ileum and then endocytosed by ileal enterocytes using cubilin receptor for intrinsic factor ® B12 then associates with transcobalamin II protein in the ileum and secreted into the plasma ◊ Transcobalamin II delivers B12 to liver and other cells of the body

Jaundice as a symptom in a patient with abdominal pain

§ accompanying acute abdominal pain virtually always indicates a hepatobiliary disorder □ including obstruction of the biliary duct (choledocholithiasis, pancreatic carcinoma, cholangiocarcinoma) □ complications of acute cholecystitis □ acute hepatitis (viral, ischemic) □ hepatic malignant neoplasms § The possibility of cholangitis should be considered and excluded in all patients with acute abdominal pain and jaundice □ especially if the patient has fever, chills, hypotension, altered mental status, or leukocytosis.

Define hepatocellular jaundice

§ caused by parenchymal liver diseases. Viral hepatitis is the most common cause of acute hepatic jaundice, and liver cirrhosis can lead to chronic jaundice. Because both bilirubin conjugation and the energy-dependent secretion of conjugated bilirubin into bile are impaired, both forms of bilirubin are elevated to variable extents. As long as bile flow is uninterrupted, urobilinogen is elevated in blood and urine because the diseased liver loses its ability to scavenge urobilinogen from the portal circulation. However, if cholestasis occurs in the course of the illness, urobilinogen disappears

Define hemolytic jaundice

§ consequence of severe hemolytic conditions in which a large amount of bilirubin is formed from heme. The excess bilirubin is unconjugated bilirubin in transit from the spleen to the liver. Because an increased amount of bilirubin diglucuronide reaches the intestine, more urobilinogen is formed by intestinal bacteria, and levels of urobilinogen in blood and urine are increased. Most livers have a substantial spare capacity for the conjugation and excretion of bilirubin. Therefore the bilirubin level rarely exceeds 3 to 4 mg/dL.

define HbA1c and optimal levels

§ glycated hemoglobin = HbA1c □ Formed by nonenzymatic covalent addition of glucose moieties to hemoglobin in red cells □ Provides measure of glycemic control over the lifespan of a red cell (120 days) - Affected little by day to day variations - Should be maintained below 7% in diabetic patients - Above 6% is considered diabetic § 6.5%

Vitamin E

® Most patented alpha tocopherol ® Antioxidant and Scavenger of free radicals , protects membranes, fat deposits, and lipoproteins from lipid peroxidtion ® Deficiency is rare, can be seen in infants who have poor absorption □ Neurological abnormalities, fragility of RBCs ® Good sourcesL: vegetable oils, various seed oil, wheat germ

Vitamin K

® Naturally occurring forms of the vitamin are isoprenoids containing a wuinoid ring structure □ Most common form in plants: Phylloquinone ® Participates in enzymatic carboxylation of gutamyl residues during synthesis of prothrombin and other clotting factors in the liver □ Determination of disorder is prothrombin time ® Most common in newborns □ Hemorrhagic disease of newborns : most common nutritional deficiency ® Fat malabsorption is the most common cause of vitamin K deficiency in adults

Poly theme glycerol 3350

· Polyethylene glycol is an osmotic agent that causes retention of water in the stool resulting in a softer stool and more frequent bowel movements. It appears to have no effect on active absorption or secretion of glucose or electrolytes Constipation Common • Gastrointestinal: Diarrhea, Flatulence, Nausea, Stomach cramps, Swollen abdomen · Hypersensitivity to any component, such as polyethylene glycol § Bowel obstruction, known or suspected

How do mucin and HCO3- protect the mucosa from gastric secretions?

• Alkaline tide ○ Movement of bicarbonate into the bloodstream during gastric secretion ○ Secretion conducted from parietal cells challenges cell homeostasis ○ As protons are secreted apically, parietal cells also discharge bicarb ions across the basolateral membrane to maintain cytosolic pH § Some bicarb transport occurs in exchange for chloride ions that are needed for apical secretion via chloride-bicarbonate exchangers § Some bicarbonate is likely also lost secondary to pumping into intracellular vesicles (distinct from the tubulovesicles) that then move to the basolateral membrane and fuse with it, discharging their contents. § The bicarbonate effluxed from the cell by either mechanism is then picked up by the bloodstream, resulting in a measurable increase in circulating pH values when gastric secretory processes are active. § The arrangement of the microvasculature in the gastric mucosa also carries a portion of this bicarbonate up to the basolateral pole of surface epithelial cells, which secrete bicarbonates to defend themselves against the potentially injurious effects of acid and pepsin

Functions of vitamin A

• Animal origin food contain most vitamin A in form of esters between retinol and a long chain fatty acids ○ Esters are hydrolyzed by pancreatic enzyme in the small intesting and free retinol is absorbed with efficiency @ 60-90% • Beta carotene, major vitamin A precursor in plants ○ Cleaved to retinal by beta carotene dioxygenase in the cytoplasm of intestinal mucosal cell • Retinal is in equilibrium with reintol via reversible NADH dependent reaction ○ Small amount reversible to retinoic acid ○ Intestinal mucosal esterifies most of retinol with fatty acids and exports retinol esters as constituents of chylomicrons ® Remnentra bring the retinol esters to liver —> stores up to 100mg in stellate cells ○ From export from liver , retinol esters are hydrolyzed and retinol binds to retinol binding proteins RBP, released into blood ® Uptake into cells is mediated by an RBP receptor on cell sruface ○ Retinol is oxidized to active forms ® Retinal:prosthetic group of rhodopsin's, villa pigments of rods and cones ® Retinoic acid: gene regulator, matintentence of epithelial tissues ® Retinoic Acide receptor: similar to receptor for steroid hormones □ RAR-RXR heteodimer binds to retinoic acid repsonse elements RAREs in the enhancer region of regulated genes ○ Good sources: liver meat, eggs, dair, cod liver oil, yellow or orange fruits/veggies • Important during fetal development —> limb development ○ Deficiency and excess are teratogenic

Development of colon

• Ascending Colon ○ The ascending colon is the second part of the large intestine. It passes superiorly on the right side of the abdominal cavity from the cecum to the right lobe of the liver, where it turns to the left at the right colic flexure (hepatic flexure). This flexure lies deep to the 9th and 10th ribs and is over- lapped by the inferior part of the liver. ○ The ascending colon is narrower than the cecum and is secondarily retroperitoneal along the right side of the posterior abdominal wall. The ascending colon is usually covered by peritoneum anteriorly and on its sides; however, in approximately 25% of people, it has a short mesentery. The ascending colon is separated from the anterolateral abdominal wall by the greater omentum. A deep vertical groove lined with parietal peritoneum, the right paracolic gutter,lies between the lateral aspect of the ascending colon and the adjacent abdominal wall. • Transverse Colon ○ The transverse colon is the third, longest, and most mobile part of the large intestine. It crosses the abdomen from the right colic flexure to the left colic flexure,where it turns inferiorly to become the descending colon. The left colic flexure (splenic flexure) is usually more superior, more acute, and less mobile than the right colic flexure. It lies anterior to the inferior part of the left kidney and attaches to the diaphragm through the phrenicocolic ligament. The transverse colon and its mesentery, the transverse mesocolon, loops down, often inferior to the level of the iliac crests. The mesentery is adherent to or fused with the posterior wall of the omental bursa. The root of the transverse mesocolon lies along the inferior border of the pancreas and is continuous with the parietal peritoneum posteriorly. Being freely movable, the transverse colon is variable in position, usually hanging to the level of the umbilicus (L3 vertebral level). However, in tall thin people, the transverse colon may extend into the pelvis. • Descending Colon ○ The descending colon occupies a secondarily retroperitoneal position between the left colic flexure and the left iliac fossa, where it is continuous with the sigmoid colon. Thus, peritoneum covers the colon anteriorly and laterally and binds it to the posterior abdominal wall. Although retroperitoneal, the descending colon, especially in the iliac fossa, has a short mesentery in approximately 33% of people; however, it is usually not long enough to cause volvulus (twisting) of the colon. As it descends, the colon passes anterior to the lateral border of the left kidney. As with the ascending colon, the descending colon has a paracolic gutter(the left one) on its lateral aspect. • Sigmoid Colon ○ The sigmoid colon, characterized by its S-shaped loop of variable length, links the descending colon and the rectum. The sigmoid colon extends from the iliac fossa to the third sacral (S3) vertebra, where it joins the rectum. The termination of the teniae coli, approximately 15 cm from the anus, indicates the rectosigmoid junction. ○ The sigmoid colon usually has a long mesentery—the sigmoid mesocolon—and therefore has considerable freedom of movement, especially its middle part. (See the blue box "Volvulus of Sigmoid Colon," p. 261.) The root of the sigmoid mesocolon has an inverted V-shaped attachment, extending first medially and superiorly along the external iliac vessels and then medially and inferiorly from the bifurcation of the common iliac vessels to the anterior aspect of the sacrum. The left ureter and the division of the left common iliac artery lie retroperitoneally, posterior to the apex of the root of the sigmoid mesocolon. Theomental appendices of the sigmoid colon are long; they disappear when the sigmoid mesentery terminates. The teniae coli also disappear as the longitudinal muscle in the wall of the colon broadens to form a complete layer in the rectum

Lymphatic drainage of colon

• Ascending Colon ○ The lymphatic drainage passes first to the epic- olic and paracolic lymph nodes, next to the ileocolic and intermediate right colic lymph nodes, and from them to the superior mesenteric lymph nodes. • Descending Colon ○ The lymphatic drainage of the transverse colon is to the middle colic lymph nodes, which in turn drain to the superior mesenteric lymph nodes. • Transverse and Sigmoid Colon ○ Lymphatic drainage from the descending colon and sigmoid colon is conducted through vessels passing to the epico- lic and paracolic nodes, and then through the intermediate colic lymph nodes along the left colic artery. Lymph from these nodes passes to the inferior mesenteric lymph nodes that lie around the IMA. However, lymph from the left colic flexure may also drain to the superior mesenteric lymph nodes

Autoimmune Hepatits

• Autoimmune hepatitis is classified into types 1 and 2, based on the patterns of circulating antibodies. ○ Type 1, more common in middle-aged to older individuals, is characterized by the presence of antinuclear (ANA), anti-smooth muscle actin (SMA), anti-soluble liver antigen/liver-pancreas antigen (anti-SLA/LP) antibodies, and less commonly, anti-mitochondrial (AMA) antibodies. ○ type 2, usually seen in children and teenagers, the main serologic markers are anti-liver kidney microsome-1 (anti-LKM-1) antibodies, which are mostly directed against CYP2D6, and anti-liver cytosol-1 (ACL-1) antibodies. • An acute appearance of clinical illness is common (40%) and a fulminant presentation with hepatic encephalopathy within 8 weeks of disease onset may also occur • The mortality of patients with severe untreated autoimmune hepatitis is approximately 40% within 6 months of diagnosis and cirrhosis develops in at least 40% of survivors. • In general, prognosis is better in adults than in children, possibly due to delay in diagnosis in the pediatric population. Plasma cells are a prominent and characteristic component of the inflammatory infiltrate in biopsy specimens showing autoim• Autoimmune hepatitis is classified into types 1 and 2, based on the patterns of circulating antibodies. ○ Type 1, more common in middle-aged to older individuals, is characterized by the presence of antinuclear (ANA), anti-smooth muscle actin (SMA), anti-soluble liver antigen/liver-pancreas antigen (anti-SLA/LP) antibodies, and less commonly, anti-mitochondrial (AMA) antibodies. ○ type 2, usually seen in children and teenagers, the main serologic markers are anti-liver kidney microsome-1 (anti-LKM-1) antibodies, which are mostly directed against CYP2D6, and anti-liver cytosol-1 (ACL-1) antibodies. • An acute appearance of clinical illness is common (40%) and a fulminant presentation with hepatic encephalopathy within 8 weeks of disease onset may also occur • The mortality of patients with severe untreated autoimmune hepatitis is approximately 40% within 6 months of diagnosis and cirrhosis develops in at least 40% of survivors. • In general, prognosis is better in adults than in children, possibly due to delay in diagnosis in the pediatric population. Plasma cells are a prominent and characteristic component of the inflammatory infiltrate in biopsy specimens showing autoimMine hepatits

What mechanisms act on the basolateral membranes of parietal cells to control HCl secretion ?

• Basolateral membrane transporters § NHE-1 and NHE-4 □ Sodium-hydrogen exchangers □ Expel protons from the cell in exchange for sodium ions □ Driven secondarily by the low intracellular Na ion concentraion established by Na+, K+ ATPase § Basolateral potassium channel

Beriberi

• Beriberi: severe deficiency — nutritional □ Mild deficiency leads to GI complaints, weakness, and burning sensation of feet □ Moderate: peripheral neuropathy, mental abnormalities ataxia □ Severe: severe muscle weakness and muscle wasting, delirium, ophthalmoplegia, memory loss, peripheral vasodilation, increased venous return ® Myocardial contractlity is impair and death can result from high output cardiac failure ® Became problem in parts of Asia at end of 19th when milling and polishing of rice — removed outer layers where thiamine is present

A. Understand the hepatocyte mechanisms of bile constituent synthesis and secretion; the bile duct and gallbladder mechanisms of bile transport, concentration modifications, storage, and secretion; and the intestinal mechanisms of bile constituent action, recovery and excretion.( LGS 5.3b)

• Bile synthesis ○ Synthesized by the hepatcytes from cholesterol § Two primary bile acids □ Cholic acid □ Chenodeoxycholic acid § Rate limiting step: 7 alpha hydroxylase (CYP7A1) § Bile is insoluble in water • Bile secretion ○ Primary bile acids are congujated to amino Group of glycine or taurine § Lowers PKA (more dissoaciaqted at normal pH) § More water soluable ○ Hepatocyte secretion of bile salts § Only secreted conjugated bile salts through active transport □ Via ABC transporter • Bile duct and gallbladder mechanism of bile transport • Concentration of bile modifications • Bile storage • Intestinal mechanism of bile constitunts ○ Action ○ Rectory ○ Excretion ○ Absorption

Justify the use of fecal microbiota transplantation in the management of disease induced by colonic dysbiosis. (LGS 5.6b)

• C difficile colitis ○ Benefits § Successful treatment of recurrent CDI □ Restoration of normal colonic bacterial populations leads to competition for nutrients and inhibition of C difficile growth □ Regulation of the immune system and chagnes in bile acids that impair C difficle life cycle § Frozen oral FMT capsules □ Resolution of diarrhea ○ Risks § No serious adverse effects • Inflammatory Bowel Disease ○ Risks § Chronic inflammation § Leaky gut (impaired mucosal barrier) ○ Benefits § Microbiome reconstitution • Other diseases ○ Benefits § Improved insulin sensitivity § Increased diversity of gut microbiome ○ Risks ○ Increase in adiposity

Pellagra

• Case 2: B3 deficiency □ Pellagra: niacin deficiency- people with low niacin and tryptophan, maize based diets □ S/S: weakness, lassitude, anorexia, indigestion, and glossitis ® 4Ds: Dermatitis, Diarrhea Dementia Death ® Dermatitis: dark discoloration of sun exposed skin ® Diarrhea: inflammation of mucosal surfaces ® Dementia: vague, can progress to profound encephalopathy with confusion, memory loss and overt organic psychosis □ Other options? Hartnup diease —> body can synthesis niacin from tryptophan but not as efficient □ What form is niacin is in the body? NAD and NADP —> electron carriers Role of NADPH: reduces Gss —> Gsh (active glutathione )

A. Understand the role of different lipoproteins in the transport of dietary & endogenous lipids via blood; emphasize on lipoprotein related disorders (LGS 5.4b)

• Chylomicrons ○ Largest lipoprotein, least dense, a lot of triacylglycerol ○ Synthesized from dietary lipids (exogenous pathway) within epithelial cell of SI then secreted into the lymphatic system in the gut ○ Transport dietary fats to the liver and muscle ○ Enter bloodstream via L subclavian vein ○ Major apolipoproteins are apoB-48, apoCII, and apoE § ApoB-48 trunctuated version of apo-100 □ RNA editing, altering how many proteins are expressed ® Stop codon gets inserted in mRNA, stops translation ◊ Specific to the intestinal cells ® Liver makes apoB-100 § ApoCII activates LPL □ LPL in adipose tissue, cardiac muscle, skeletal muscle, and acinar cells of mammary tissue ® Hydrolyzes the triacylglycerol of chylomicrons, that releases FA ◊ Muscle cells use FA as fuel ◊ Adipose and mammary store them as fat or for milk formation ○ Remnants recyled in the liver • VLDL -Liver ○ Nascent VLDL components § TGs, free and esterified cholesterol, phospholipids, and apoB-100 □ These particles secreted from the liver (endogenous pathway of lipid metabolism) into bloodstream ® Then they accept apoCII and apoE from HDL, leads to mature VLDL ◊ Transported from liver to skeletal, cardiac muscle, and adipose, and mamary tissue where LPL is acitvated by apoCII in VLDL } Activated apoCII faciliates hydrolysis of TGs in VLDL - Leads to release of FA and glycerol from TG w VLDL remnants formed w Recycled in the liver using apoE and its receptor • LDL -Liver ○ Half of VLDL remnants become IDL which then becomes LDL § 60% of LDL transported back to liver □ Its apoB-100 binds to its receptors in liver cell plasma membrane that leads to endocytosis into hepatocyte § 40% transported to extrahepatic tissues ○ Some cholesterol of internalized LDL used for membrane synthesis and vit D synthesis ○ Excess LDL leads to saturation § More readily available for uptake by macrophages near the endothelial cells of arteries □ Leads to atherosclerosis • HDL -Liver- in the transport of dietary and endogenous fats via blood A ○ Synthesis § Synthesis in liver and intestines □ Nascent HDL components ® Phospholipids, free cholesterol, apolipoproteins (rich in apolipoproteins, helps chylomicrons mature, and VLDLs to mature) ◊ ApoA1, apoAII, apoCI, apoCII § Budding of apolipoproteins from chylomicrons and VLDL as they are digested by LPL § Free apoI accumulates and then acquires cholesterol and phospholipids ○ Maturation of nascent-HDL § Central hollow core fills with cholesterol esters and matures

Analyze the involvement of liver in the synthesis of endogenous fats (LGS 5.4b)

• Chylomicrons and VLDL deliver TAG to cells in the body. Two types of lipoproteins are triglyceride-rich: the chylomicrons and VLDL. Chylomicrons are synthesized by enterocytes from lipids absorbed in the small intestine. VLDL is synthesized in the liver. The function of these lipoproteins is to deliver energy-rich triacylglycerol (TAG) to cells in the body (pink pathway). TAG is stripped from chylomicrons and VLDL through the action of lipoprotein lipase, an enzyme that is found on the surface of endothelial cells. This enzyme digests the TAG to fatty acids and monoglycerides, which can then diffuse into the cell to be oxidized, or in the case of an adipose cell, to be re-synthesized into TAG and stored in the cell. • LDL delivers cholesterol to cells in the body. As VLDL particles are stripped of triacylglycerol, they become more dense. These particles are remodeled at the liver and transformed into LDL. The function of LDL is to deliver cholesterol to cells, where it is used in membranes, or for the synthesis of steroid hormones (blue pathway). Cells take up cholesterol by receptor-mediated endocytosis. LDL binds to a specific LDL receptor and is internalized in an endocytic vesicle. Receptors are recycled to the cell surface, while hydrolysis in an endolysosome releases cholesterol for use in the cell. • HDL is involved in reverse cholesterol transport. Excess cholesterol is eliminated from the body via the liver, which secretes cholesterol in bile or converts it to bile salts. The liver removes LDL and other lipoproteins from the circulation by receptor-mediated endocytosis. Additionally, excess cholesterol from cells is brought back to the liver by HDL in a process known as reverse cholesterol transport (green pathway). HDL (or really, the HDL precursor) is synthesized and secreted by the liver and small intestine. It travels in the circulation where it gathers cholesterol to form mature HDL, which then returns the cholesterol to the liver via various pathways. • • Synthesis § Synthesis in liver and intestines □ Nascent HDL components ® Phospholipids, free cholesterol, apolipoproteins (rich in apolipoproteins, helps chylomicrons mature, and VLDLs to mature) ◊ ApoA1, apoAII, apoCI, apoCII § Budding of apolipoproteins from chylomicrons and VLDL as they are digested by LPL § Free apoI accumulates and then acquires cholesterol and phospholipids • Maturation of nascent-HDL § Central hollow core fills with cholesterol esters and matures § LCAT matures HDL through esterification • Good cholesterol § Reverse transport of cholesterol □ Collects remnant cholesterol from adjacent tissues and has liver use it to make bile, etc.

Insulin - medicine

• Classes ○ Rapid acting § Lispro, aspart, glulisine ○ Short acting, § Regular ○ Intermediate acting § NPH ○ Long acting § Detemir, glargine • Clinical Uses ○ Rapid acting § Type 1 and type 2 DM, GDM (postprandial glucose control) ○ Short acting § Type 1 and type 2 DM, GDM, DKA (IV), hyperkalemia (+glucose), stress hyperglycemia ○ Intermediate acting § Type 1 DM, type 2 DM, GDM ○ Long acting § Type 1 and type 2 DM, GDM (basal glucose control) • MOA ○ Binds insulin receptor (tyrosine kinase activity) ○ Liver: Increased glucose stored as glycogen ○ Muscle: Increased glycogen, protein synthesis, increased K+ uptake ○ Fat: Increased TG storage • Adverse effects - Hypoglycemia, lipodystrophy, rare hypersensitivity reactions.

Probiotic effect- antimicrobial

• Compete for nutrients with pathogens • Compete for adhesion with pathogens • Inhibit translocation • Alter local environment (e.g., decrease pH) to inhibit pathogens • Produce bacteriocins to inhibit pathogens • Modify pathogen-derived toxins • Provide "decoy binding sites" for pathogens

Evaluate the role of the Cytochrome P450 system in Phase I metabolic reactions (LGS 5.5a)

• Cytochrome P450 ○ Serves as a terminal oxidase ○ In its reduced (ferrous) form, it binds CO to give a complex that absorbs light maximally at 450 nm § P450 heme reduction is rate limiting step in hepatic drug oxidations ○ Drug oxidations need P450, P450 reductase, NADPH, and molecular oxygen § Steps i. Briefly oxidized (Fe 3+) P450 combines with drug substrate to form binary complex ii. NADPH donates an electron to flavoprotein P450 reductase ® This reduces oxidized P450 drug complex iii. Second electron is introduced from NADPH via same P450 reductase ® Reduces molecular oxygen and forms "activated oxygen-P450 substrate complex iv. Complex transfers activated oxygen to the drug substrate to form the oxidized product • Inducer ○ Increases activity of CYP450 ○ Does not necessarily mean it's a substrate for CY450 ○ TURNS IT ON ○ ENHANCES ○ Decreases the activity of the drug • Inhibitor ○ Reducing CYP450 activity ○ Prolonging action of substrate for CYP450 ○ Increases activity of the drug • CYP450 ○ CYP = cytochrome P ○ 450 - wavelength where CO binds to the heme group

Development of pancreas

• Develops between the layers of the mesentery from dorsal and ventral pancreatic buds ○ Pancreatic buds - of endodermal cells § There arise from the caudal part of the foregut. • Most of the pancreas is derived from the larger dorsal pancreatic bud. • The smaller ventral pancreatic bud develops near the entry of the bile duct into the duodenum. • As the duodenum rotated to the right -and becomes C shaped ○ The bud is carried dorsally with the bile duct. ○ It soon lies posterior to the dorsal pancreatic bud - and later fuses with it. • The ventral pancreatic bud forms the uncinate process and part of the head. As the stomach, duodenum, and ventral mesentery rotate - the pancreas come sto lie along the dorsal abdominal wall (retroperitoneal). • The pancreatic duct forms from the duct of the ventral bud ○ And the distal part of teh dorsal bud. ○ The proximal part of the dorsal bud persists as the accessory pancreatic duct. § Which opens into minor duodenal papilla. Formation of the pancreas seems to develop from a bipotential cell population. • In the ventral region of the duodenum - where PDX1 is expressed. • Formation of the dorsal pancreatic bud depends on the notochord secreting activin and FGF-2 ○ Which block the expression of Shh in the associated endoderm. Histogenesis: • Parenchyma of the pancreas are derived from the endoderm of the pancreatic buds. ○ Which form a network of tubules. • Early in the fetal period ○ Pancreatic acini begin to develop from cell clusters around the ends of the tubules § → AKA the primordial pancreatic ducts. ○ Pancreatic islets develop from groups of cells that separate from the tubules and lie between acini. • Insulin secretion begins during the early fetal period (10 weeks). • Cells with glucagon & somatostatin develop before differentiation of B cells that secrete insulin.

Define clinical diarrhea

• Diarrhea is defined as the passage of loose or watery stools, typically at least three times in a 24-hour period. Acute diarrhea is defined as diarrhea of ≤14 days in duration, in contrast to persistent (>14 days and ≤30 days) or chronic (>30 days) diarrhea. Invasive diarrhea, or dysentery, is defined as diarrhea with visible blood, in contrast to watery diarrhea. Dysentery is commonly associated with fever and abdominal pain.

Dietary changes and hydration habitats for prevention/control of constitution

• Dietary changes — Increased intake of fruit and raw vegetables, bran, and whole-grain breads and cereals is commonly recommended, as is adequate intake of fluids other than milk. • Fiber — Increasing the intake of fiber, through dietary changes or fiber supplements, is often recommended for acute and chronic constipation • Fluid intake — To ensure adequate hydration, children with chronic constipation or fecal incontinence should be encouraged to consume at least 32 to 64 ounces (960 to 1920 mL) of water or other non-milk liquids per day, particularly if they are using fiber supplements.

Define direct bilirubin

• Direct bilirubin ○ Conjugated, or direct, bilirubin travels from the liver into the small intestine. A very small amount passes into your kidneys and is excreted in your urine. This bilirubin also gives urine its distinctive yellow color. ○ § Only conjugated bilirubin is excreted by the kidneys. Unconjugated bilirubin cannot be excreted because it is tightly bound to albumin, but conjugated bilirubin is water soluble and not protein bound. Therefore it is excreted in the urine, to which it imparts a yellow-brown coloration. This is called choluric jaundice.

Stomach development

• During the 4th week - a slight dilation indicates the site of the primordial stomach. • First appears as a fusiform enlargement at the caudal part of the foregut (distal) ○ Initially oriented in the median plane. ○ It soon enlarges and broadens ventrodorsally. ○ The dorsal border grows faster than the ventral border § Resulting in the greater curvature of the stomach. • Enlargement of mesentery and adjacent organs, and growth stomach walls contributes to the rotation of the stomach ○ It will rotate 90 degrees clockwise § With the dorsal border (greater curvature) moving to the left. § Ventral border is on the right § Original left side becomes the ventral surface § Original right side becomes the dorsal surface. ○ After rotation: § The left vagus nerve innervates the anterior wall § And the right vagus nerve innervates the posterior wall.

Analyze the metabolic pathways involved in cellular utilization of different types of dietary sugars (other than glucose) with a focus on clinical correlates (LGS5.4a) Galactose

• Excess galactose is channeled into pathways of glucose metabolism ○ Most dietary galactose metabolized in the liver and intestinal mucosa ○ Galactose phosphorylated to galactose-1-phosphate by galactokinase § Galactokinase reacts with UDP-glucose to form UDP-galactose § UDP-galactose is epimerized to UDP-glucose. This pathway amounts to the ATP-dependent conversion of galactose to glucose-1-phosphate. § Because of its reversibility, the epimerase reaction is also a source of UDP-galactose for the synthesis of glycolipids, glycoproteins, and proteoglycans. ○ Galactokinase deficiency is a relatively benign condition leading to elevated blood galactose levels after consumption of milk and milk products. § Cataracts (clouding of the lens) develop in those who consume milk despite their enzyme deficiency. Aldose reductase, the same enzyme that reduces glucose to sorbitol (see Fig. 24.24 ), reduces galactose to galactitol in the lens. The accumulating galactitol damages the lens, probably through its osmotic activity. The deficiency of galactose-1-phosphate-uridyl transferase is far more serious (see Clinical Example 24.7 ). ○ Galactosemia § Incidence at birth of 1 in 40,000 § Recessively inherited deficiency of galactose-1-phosphate-uridyl transferase § Symptoms appear after ingestion of milk or other galactose containing foods □ Accumulation of galactose in the blood and of galactose-1-phosphate in the cells ® Damages the liver by tying up inorganic phosphate and reducing ATP synthase □ Vomiting after feeding, weeks after birth § Untreated pts can develop liver cirrhosis, cataracts, and mental deficiency § Treatment □ Liver transplant

Explore the role of the microbiota in the mediation and causality of human disease considering the biota's diversity, functional capacity and age-associated dynamics. (LGS 5.6b)

• Factors ○ Anatomic site ○ Dietary changes ○ Season ○ Menses § Vaginal microbiota ○ Antibiotic exposure ○ Ethnicity ○ Influences during the Life Cycle • Factors ○ Anatomic site ○ Dietary changes ○ Season ○ Menses § Vaginal microbiota ○ Antibiotic exposure ○ Ethnicity ○ Influences during the Life Cycle

Hyperlipidemia- Risks factors of atherosclerosis

• Family history of coronary artery disease • Cigarette smoking • High LDL • Low HDL • Type 2 diabetes mellitus • Hypertension • Obesity

Define clinical constipation

• Functional constipation — Functional constipation describes persistently difficult, infrequent, or seemingly incomplete defecation, without evidence of a primary anatomic or biochemical cause. This definition is operationalized by the "Rome IV" diagnostic criteria, which require at least two of six symptoms describing stool frequency, hardness, size, fecal incontinence, or volitional stool retention (table 2), with the stipulation that organic causes of constipation are excluded by a thorough evaluation.

IBS: Symptoms

• Gastrointestinal motility - Although the symptoms of irritable bowel syndrome (IBS) have focused attention on colonic motility, no predominant pattern of motor activity has emerged as a marker for IBS, per UpToDate. Different motor abnormalities observed in some patients include: ○ Increased frequency and irregularity of luminal contractions ○ Prolonged transit time in constipation predominant IBS ○ An exaggerated motor response to cholecystokinin and meal ingestion in diarrheapredominant IBS • Hypersensitization of visceral afferent nerves in the gut - increased sensation in response to stimuli is a frequent finding in irritable bowel syndrome (IBS) patients. ○ Increased signal transduction via afferent neural pathways to the dorsal horn of the spinal cord and ultimately to the brain ○ Increased sensitivity resulting in sensation of bowel distention or bloating ○ FYI: It is unclear whether heightened sensitivity of the intestines to normal sensations is mediated by the local GI nervous system, by central modulation from the brain, or by some combination of the two. In addition, other factors may contribute to visceral hyperalgesia, such as specific gastrointestinal mediators (serotonin, kinins) or increases in spinal cord excitability due to activation of an NmethylDaspartate (NMDA) receptor • Symptoms of IBS include diarrhea, constipation, alternating diarrhea and constipation, or normal bowel habits alternating with either diarrhea and/or constipation.

Appreciate the relationship between the brain and gastrointestinal system and relate this to clinical scenarios involving food intake. (LGS5.4c)

• Ghrelin ○ From stomach ○ Acts on hypothalamus and vagal afferents to increase food intake • Leptin ○ During fed state ○ Suppresses ghrelin ○ From adipose tissue • CCK and PYY • Act directly on hypo and vagal afferents to reduce food intake

Integrate the hormonal regulation with mitochondrial ATP production from carbohydrate sources 2 (LGS 5.4a)

• Glucose enters B cell via GLUT2 ○ Phspohoylated via glucokinase to form glucose-6-phosphate (metabolized in TCA cycle and oxidative phosphorylation) ○ Result in increase in ATP within B cell § As B cell ATP/ADP rations increases, activated of membrane bound ATP dependent K+ channel is inhibited —> membrane depolkazation —> activates voltage gated Ca2+, Ca2+ enters cell—> fusion of insulin containing exocytoic vesibles —> insulin secretion • Binds to a receptor on cell surface —> activates both autophosphorylation of receptor and the phosphorylation of other enzymes by tyrosine kinase domain • Promotes deactivation of regulatory enzymes • Insulin receptor has 2 subunits- alpha (insulin binds) and beta ( span membrane into cytosol-tyrosine kinase activity) ○ On binding the tyrosine kinase phosphylates the tyrosine resides on beta subunit § Principle substrate: IRS-1 ○ Recognizes and binds to signal transduction proteins in SH2 dominates • Polypeptide synthesize as prohomornes in pancreatic alpha cells ○ Cleaved into mature glucagon within storage vesibles • Synthesis and Secretion ○ Synthesized by a-cells of pancreas by cleavage of preproglucagon § Preproglucagon is produced on the RER and converted to proglucagon as enters the lumen of the ER § Proteolytic cleavage at various sites -> glucagon • Regulated through changes in level of glucose and insulin bath in the alpha cells in pancreatic islets of langerhans ○ Many amino acids also stimulate glucagon release • Binds to a receptor on cell surface —> activates both autophosphorylation of receptor and the phosphorylation of other enzymes by tyrosine kinase domain • Promotes deactivation of regulatory enzymes • Insulin receptor has 2 subunits- alpha (insulin binds) and beta ( span membrane into cytosol-tyrosine kinase activity) ○ On binding the tyrosine kinase phosphylates the tyrosine resides on beta subunit § Principle substrate: IRS-1 ○ Recognizes and binds to signal transduction proteins in SH2 dominates • Binds to a receptor on plasma membrane of target cells ○ Stimulate synthesis of intracellular cAMP —> activates protein kinase A —> phosphorylates regulatory enzymes ○ G proteins, which couple glucagon receptor, bind GTP § In absence of glucagon Gs protein complex binds GDP, once glucagon binds to receptor, receptor also binds Gs complex, released GDP and binds to GTP § GI inhibits ○ cAMP is rapidly degraded to AMP by phosphodiesterase § Amount present at anytime reflective of hormone binding and activity of adenylte cycles ○ Cortisol ○ Glucocorticoid released from adrenal cortex in response to fasting and chronic stress ○ Oppose insulin ○ Signal Transduction ○ Effect on gen transcription is syngersitc to other hormones ○ Epinephrine ○ Fight or flight hormone, opposes insulin • Catecholamines: can acts as neurotransmitters or as hormones • Bind to andrenergic receptors ○ Concerned with B1,B2, B3, a1- those that work through adenylate cycles-cAMP system activating Gs protein § B1 is major adrenergic receptor in human heart • Signals increase use of blood glucose

Role of HCl in gastric digestion

• HCl ○ most characteristic secretory product of the stomach ○ Begins the digestive process via simple hydrolysis ○ Contributes to sterilization of meal

Apply knowledge of heme metabolism to laboratory testing and the clinical forms of jaundice. (LGS5.3b)

• Heme Metabolism and Biosynthesis of Heme ○ Compounds that contain heme § Hemoglobin § Myoglobin § Cytochromes Rate limiting steps: □ ALA synthase § Regulators: □ Ferrochelatase □ Heme □ Vitamin B6-> important for ALA synthatse • Conditions causes by biosynthesis dysfunction ○ Siderobalstic anemia caused by Vitamin B6 deficiency ○ Lead poisoning ○ Buildup heme synthesis intermediates are neurotoxic ○ Porphyria: Parietal deficiency of one or more of the enzymes other that ALA § Neruological symptoms □ Accumulation of intermediates § Cutaneous photosensitivity □ ROS □ Skin damage § Deficiency in heme

IBS- Treatment

• In patients with mild and intermittent symptoms that do not impair quality of life, we initially recommend lifestyle and dietary modification alone rather than specific pharmacologic agents. ○ Education and reassurance — It is important to establish a therapeutic clinicianpatient relationship to validate the patient's symptoms. ○ Dietary modification — A careful dietary history may reveal patterns of symptoms related to specific foods. Patients with IBS may benefit from exclusion of gas producing foods; a diet low in fermentable oligo, di, and monosaccharides and polyols (FODMAPs); and in select cases, lactose and gluten avoidance • Low FODMAP diet — We suggest a diet low in fermentable oligo, di, and monosaccharides and polyols (FODMAPs) in patients with IBS with abdominal bloating or pain despite exclusion of gasproducing foods (table 1). These shortchain carbohydrates are poorly absorbed and are osmotically active in the intestinal lumen where they are rapidly fermented, resulting in symptoms of abdominal bloating and pain. A low FODMAP diet involves elimination of a larger number of high FODMAP foods that would not be excluded in a diet that only required avoidance of gasproducing foods (eg, foods that contain fructose, including honey, highfructose corn syrup, apples, pears, mangoes, cherries, or oligosaccharides, including wheat). Low FODMAP dietary education should be provided by a trained dietician to avoid unnecessary dietary overrestriction and a nutritionally replete diet [13]. Low FODMAP education consists of initially eliminating FODMAPs from the diet for six to eight weeks and then, following symptom resolution, gradual reintroduction of foods high in fermentable carbohydrates to determine individual tolerance to specific fermentable carbohydrates • Exclusion of gas producing foods — Patients with IBS should be advised to exclude foods that increase flatulence (eg, beans, onions, celery, carrots, raisins, bananas, apricots, prunes, Brussels sprouts, wheat germ, pretzels, and bagels), alcohol, and caffeine [8]. Underlying visceral hypersensitivity may explain the exaggerated discomfort experienced by patients with IBS with the consumption of gas producing foods ○ Fiber — The role of fiber in patients with IBS is controversial, but given the absence of serious side effects and potential benefit, psyllium/ispaghula should be considered in patients with IBS whose predominant symptom is constipation. As some patients may experience increased bloating and gas, we suggest a starting dose of psyllium of one half to one tablespoon daily. The dose should then be slowly titrated up based on response to treatment. ○ Physical activity — Physical activity should be advised in patients with IBS given a potential benefit with regard to IBS symptoms and the general health benefits of exercise. ○ Probiotics - clinically important benefit might be achieved in certain subgroups of patients, particularly those with diarrhea-predominant symptoms due to alterations in the composition of commensal enteric bacterial species in patients with IBS

Define insulin (endogenous)

• Insulin ○ Released from Beta-cells of the pancreas in response to carbohydrate ingestion ○ Promotes glucose use as a fuel and glucose storage as fat and glycogen ○ Major anabolic hormone ○ Increases protein synthesis and cell growth ○ Blood insulin levels decrease as glucose is taken up by tissues and used ○ Synthesized as a prohormone from pancreatic Beta cells § Proinsulin cleaved to mature insulin and a C-peptide in storage vesicles and precipitated with Zn 2+ ○ Secretion regulated through changes in the level of blood glucose ○ Promotes dephosphorylation of key enzymes § Activation or deactivation of some of them

Describe Intrinsic Factor

• Intrinsic factor ○ Gastric location: fundus/body ○ Cell type: synthesized and released by parietal cells via exocytosis Used for B12 uptake

Describe dysfunction of intrinsic factor and cobalamin

• Intrinsic factor is known to considerably in excess of physiological requirements for the absorption of cobalamin. This is presumably to account for degradation of a portion of the secreted intrinsic factor by digestive enzymes, although the structure of the peptide is such that it is relatively resistant to degradation, and particularly to digestion by acid and pepsin.

Analyze the metabolic pathways involved in cellular utilization of different types of dietary sugars (other than glucose) with a focus on clinical correlates (LGS5.4a) Fructose

• Metabolism of fructose ○ Less rapidly absorbed from the intestine than glucose, once in blood more rapidly metabolized ○ Most of the dietary fructose is phosphorylated by fructokinase in live, kidneys, and intestines § Liver = half of fructose metabolism § Fructokinase produces fructose 1 phosphate § Fructose-1-phosphate is cleaved by aldolase B □ Aldolase B acts on fructose-1,6-bisphosphate and fructose-1-phosphate ® Produces dihdroxyacetone phophate and glyceraldehyde which are processed through glycolysis or gluconeogenesis ○ Excess fructose is problematic § Fructose bypasses rate limiting glucokinase and PFK-1 reactions of glycolysis § Pyruvate kinase is stimulated by fructose-1-phosphate as it is by fructose-1,6-bisphoste § Liver metabolizes fructose faster than glucose § Fructose kinase acitivity exceeds that of aldolase B, leads to accumulation of fructose-1-phosphate □ F1P stimulates glucokinase ® Channels dietary glucose into glycogen synthesis □ Leads to impairment of oxidative phosphorylation ® Ties up a lot of inorganic phosphate in the cell § High glycogen stores lead to conversion of consumed fructose and glucose into lactic acids and triglycerides instead of glycogen □ Risk factor for non-alcoholic fatty liver disease ○ Hereditary fructose intolerance § Caused by adolase B deficiency § Autosomal recessive condition that afflicts 1 in 20,000 people § Symptoms □ Nausea, vomiting after fructose containing meal, signs of hypoglycemi (weakness, trembling, sweating) □ Can lead to irreversible liver damage ○ Accumlation of F1P in the liver ties up phosphate § Shortage of inorganic P, impair ATP synthesis □ Damages cells, prevents gluconeogenesis □ Impairs glycogenolysis ○ Fructosuria □ a benign condition in which fructose appears in the urine after a fructose-containing meal. □ Urinalysis shows a positive test for "reducing sugar" (fructose, in this case), although enzymatic glucose tests are negative. □ Most of the fructose is metabolized slowly by hexokinase in muscle and adipose tissue.

Analyze the mechanisms underlying mobilization and deposition of fats at cellular levels (LGS 5.4b)

• Mobilization & deposition of fats ○ Mechanisms ○ At cellular level • Fatty acid synthesis ○ Majority occurs in the liver, some occurs in adipose tissue ○ Major source of carbon for the synthesis of FA = dietary carbohydrates § Alternative source = dietary protein □ Carbon source is AA that can be converted to acetyl-CoA or TCA cycle intermediates ○ Process summary § Excess dietary carbohydrate consume --> glucose converted to acetyl CoA --> fatty acid synthase complex produces palmitate --> palmitate converted to other FA types ○ Conversion of Glucose to Cytosolic Acetyl Coenzyme A § Begins with conversion of glucose to pyruvate in the cytosol via glycolysis § Pyruvate enters mito where it is converted to acetyl-CoA by pyruvate dehydrogenase and to OAA by pyruvate carboxylase □ Pathway dictated by acetyl-CoA levels in the mito ® High acetyl-CoA = PDH inhibited, pyruvate carboxylase stimulated ◊ Increase in OAA leads to condensation of OAA with acetyl-CoA to form citrate } Condenstation lowers acetyl-CoA levels, activates PDH and inhibits pyruvate carboxylase } Citrate transported across the inner mito membrane into cytosol - Cleaved by citrate lyase to form acetyl-CoA and OAA § Reduced NADPH is needed for fatty acid synthesis □ Generated by pentose phosphate pathway and recycling of OAA ® OAA conversion back to pyruvate ◊ Reduction of OAA to malate by NADP+ dependent malate dehydrogenase ◊ Oxidation and decarboxylation of malate to pyruvate by NADP+ dependent malate dehydrogenase (malic enzyme) ® Pyruvate then reconverted to citrate □ NADPH from malic enzyme and NADPH from PPP is used for reduction reactions in fatty acid synthase complex § Elevation of the insulin/glucagon ratio after a carb meal stimulates generation of cytosolic acetyl-CoA □ Insulin activates PDH ® Stimulates phosphatase § The synthesis of malic enzyme, glucose 6-phosphate dehydrogenase, and citrate lyase is induced by the high insulin/glucagon ratio. □ The ability of citrate to accumulate, and to leave the mitochondrial matrix for the synthesis of fatty acids, is attributable to the allosteric inhibition of isocitrate dehydrogenase by high energy levels within the matrix under these conditions. ○ Conversion of Acetyl-CoA to Malonyl CoA § Acetyl-coA carboxylase adds a carboxyl group to acetyl-CoA in a reaction that needs biotin and ATP § Acetyl-CoA carboxylase is the rate limiting enzyme of FA synthesis □ Regulated by phosphorylation, allosteric modification and induction/repression of its synthesis ® Citrate allosterically activates it through polymerization of four subunits ® Palmitoyl-CoA from palmitate inhbits it through negative feedback ® Phosphorylation of AMP inhibits it during fasted state ® Activated by dephosphorylation in the fed state High insulin/glucagon ratio activates it and fatty acid synthase

What mechanisms stimulate gastric mucin and HCO3-

• Mucus is released via exocytosis of granules containing high molecular weight mucins, which are molecules that resemble a bottlebrush with a protein core linked to many long chain oligosaccharides. • The oligosaccharide chains are responsible for the unusual physicochemical properties of the mucus. Thus, following the release of mucus, the oligosaccharides expand as they are hydrated, providing a highly viscoelastic substance. • The structure of the mucus layer is also stabilized by intramolecular disulfide bonds, as well as by interactions with trefoil peptides. The viscosity of the mucus may limit diffusion of acid through the plane of the gel via a mechanism known as viscous fingering. § Thus, acid secreted under hydrostatic pressure from the gastric glands may emerge as a discrete stream through the gel, restricting access of the acid to the gastric surface. Mucus-secreting cells also package phospholipids that are secreted concurrently with mucins, in a manner analogous to the secretion of surfactants in the lung. § These phospholipids are believed to confer a hydrophobic nature to the surface of the mucus gel and may thus limit the back-diffusion of apical solutes, such as protons, toward the epithelium, although this attractive hypothesis has yet to be proven. Nevertheless, secretion of the components of the mucus layer is increased by a variety of secretagogues, and is presumed to be under the control of both cholinergic and gastrin-dependent signaling pathways, as well as local reflexes that may involve CGRP and tachykinins.

Osteomalacia & Rickets

• Osteomalacia & rickets □ Rickets in children, ostoemalacia in adults □ Reduced intentional calcium absorption —> reduced plasma calcium concentrartion ® PTH released ® Bones drained of mineral contents • Vitamin D : prohormone ® Synthesized photochemically in the skin via action of UV radiation on minor membrane Steriod 7-dehydrocholesterol □ Product is cholecalciferol (no activity) to become active, must be hydroxylated to 25- hydroxycholecalciferol (storage form, in liver and fat) In liver —> hydroxylation to 1,25 dihydroxycholecalciferol (calcitriol) in kidney ® Catalyze by CYP450 ® In blood all forms of vitamin D bind tightly to D binding protein ® Hydroxycholecalciferol in liver is fast, calcitriol is major circulating form □ Hormone, it's receptor it's a TF the resembles steroids and retinoic acid □ Enhances and represses genes □ Thought to boost innate immunity when formed by immune cells □ Vitamin D levels and risks of CV and cancer, high doses not effective at prevention ® Calcitriol us used to treat osteoporosis □ Deficiency of Vitamin D leads to bone diseases □ Too much —> hypercalcemia, hypercalciuria, metastasis calcification ® Sources: liver, egg yolk, saltwater fish, fortified foods □ Synthesis effected by skin color • Vitamin D is not in breast milk, recommendation fo exclusively breast fed babies mom to supplement vitamin D • Non essential because you can make it

B. Use pattern recognition and analytic reasoning in the development of a prioritized differential diagnosis for upper gastrointestinal tract disorders. (DOCs 5.3)

• Other pivotal points include: ○ Time course of the pain § Subacute/ chronic over weeks to months/years □ Eg IBS § Acute within hours to days of onset □ Eg Appendicitis □ Severe acute abdominal pain - cant miss diagnoses ® Eg AAA, appendicitis, splenic rupture ® Either get treated or die of complications = don't recur □ Hx narrows down diagnoses ® Know if it's the first episode or if its recurrent/chronic • Peritoneal findings on exam ○ Peritoneal findings of rebound tenderness, rigidity, and guarding are pivotal features § suggest an intra-abdominal catastrophe. ○ Typical causes include § AAA, § bowel infarction (due to bowel obstruction or acute mesenteric ischemia), § bowel perforation (due to appendicitis, peptic ulcer disease [PUD], diverticulitis), § pancreatitis § pelvic inflammatory disease (PID). • Unexplained hypotension ○ Unexplained hypotension is yet another potential pivotal clue. ○ Many patients with abdominal pain experience hypotension due to dehydration from nausea, vomiting, or poor oral intake ○ some patients with abdominal pain present with unexplained hypotension. § Unexplained hypotension can suggest sepsis, retroperitoneal hemorrhage, or other diseases. ○ Orthostatic vital signs should be taken in patients with abdominal pain. They may provide invaluable diagnostic and therapeutic information.

Character of abdominal pain

• Patients with peritonitis may report sever localized pain or irritation with activities or maneuvers that stretch or move the parietal peritoneum ○ Such as walking, moving in bed, and coughing; as a result, they tend to lie quietly to avoid painful stimulation • Patients with viceral pain move or walk restlessly or attempt a bowel movement in a effort to relieve their symptoms

IBS: Risk Factors

• Recent diarrheal illness (loss of microbiodiome) • Family hx of IBS ○ Due to genetics ○ Also could be due to social learning • Psychosocial factors ○ more lifetime and daily stressful events than control groups ○ increased anxiety, depression, phobias, and somatization § In a prospective study, psychosocial factors (anxiety, sleep problems, somatic symptoms) were shown to be independent risk factors for the development of IBS in a population not previously diagnosed with the condition

Probiotic effect- immunological

• Reduce secretion of proinflammatory cytokines • Increase secretion of antiinflammatory cytokines • Activate local macrophages to increase antigen presentation to B lymphocytes and increase secretory IgA production • Induction of T regulatory lymphocytes • Promote hyporesponsiveness to food antigens

Regulation of HMG- Reductase

• Regulation of HMG-CoA Reductase ○ HMG-CoA reducatase is the rate-limiting step of cholesterol biosynthesis § Target of statins (cholesterol lowering drugs) ○ Transcriptional regulation § Sterol-regulatory element-binding proteins (SREBPs) control the rate of synthesis of HMG-CoA reductase mRNA ○ Proteolytic degradation of HMG-CoA Reductase § Rising levels of cholesterol and bile salts render the enzyme more susceptible to proteolysis □ Decreases activity

Regulation of Urea cycle

• Regulation of urea cycle ○ Regulated by substrate availability, higher rate of ammonia production = higher rate of urea formation □ Feed forward regulation ○ Two other types § Allosteric activation of CPSI by NAG □ NAG formed specifically to activate CPSI □ Synthesis of NAG from acteyl CoA and glutamate is stimulate by arginine ® As arginine levels rise, reactions are stimulate ◊ Synthesis of NAR (also increases rate at which carbamoyl phosphate is produced) ◊ Produce more orinthine § Induction and repression of synthesis of urea cycle enzymes □ Occurs in reposnse to conditions that require increase protein metabolism (high protein diet or prolonged fasting) □ AA carbon is converted to glucose, AA nitrogen converted to urea □ Induction occurs even though uninsured enzyme levels are far in excess of capacity required ® Feed forward regulation

Probiotic effects- other

• Scavenge superoxide radicals Produce short-chain fatty acids (SCFAs), which have multiple downstream effects

What is the Chemical Reaction that occurs in parietal cells that is needed for production of acid?

• Secretory capacity and energetic requirements of parietal cells ○ Acid secretion directly dependent on mass of parietal cells § Mass related to body weight, declines somewhat with age ○ Secrete acid against a concentration gradient § From cytoplasmic pH of 7.2 to a luminal pH of less than 1 when secretion is maximally activated ○ Parietal cell packed with mitochondria in order to sustain massive rates of secretion § Mitos make up 30%-40% of cell's volume ○ Resting parietal cell also has tubulovesicles and central canaliculus that invaginates apical membrane ○ Biochemical change § At rest: tubulovesicles are site of storage for majority of H+,K+,ATPase proton pump § After fusion of tubulovesicles and canaliculi, their membranes are brought into continuity with the apical membrane and the density of the proton pump increases § Protons are generated adjacent to apical membrane due to activity of carbonic anhydrase II □ Generates protons and bicarbonate ions from reaction of water and CO2 § Protons then pumped out of the cell across the apical membrane in exchange for K ions, using ATP as energy □ K ions come from cell cytosol and their levels are maintained due to Na,K ATPase transporter and sodium/potassium/chloride cotransporter NKCC1. ® Can exit across apical membrane using KCNE2/KCNQ1 channel § Chloride exits via chloride channels and CFTR

Probiotic effect- enhance mucosal barrier

• Stimulate epithelial mucin production • Strengthen epithelial barrier, e.g., via tight junction function and alteration of surface proteins

Distinguish IBS-C, IBS-D, IBS-mixed

• Subtypes of IBS are recognized based on the patient's reported predominant bowel habit on days with abnormal bowel movements (figure 1). The Bristol stool form scale (BSFS) should be used to record stool consistency (figure 2). Subtypes can only confidently be established when the patient is evaluated off medications used to treat bowel habit abnormalities. IBS subtypes are defined for clinical practice as follows: ○ IBS-C (IBS with predominant constipation): Patient reports that abnormal bowel movements are usually constipation (type 1 and 2 in the BSFS) ○ IBS-D (IBS with predominant diarrhea): Patient reports that abnormal bowel movements are usually diarrhea (type 6 and 7 in the BSFS) ○ IBS-mixed (IBS with mixed bowel habits): Patient reports that abnormal bowel movements are usually both constipation and diarrhea (more than onefourth of all the abnormal bowel movements were constipation and more than onefourth were diarrhea) ○ IBS unclassified: Patients who meet diagnostic criteria for IBS but cannot be accurately categorized into one of the other three subtypes.

Define Total Bilirubin

• Total bilirubin ○ Indirect and direct bilirubin make up your total bilirubin.

NAFLD: Pathophysiology with 2 hit model

• Two hit model: 1. Insulin resistance --> hepatic steatosis 2. Hepatocellular oxidative injury results in liver cell necrosis and inflammatory reactions. • Hepatic steatosis ○ Causes: overabundance of calorie rich food, diminished exercise, and genetic/epigenetic mechanisms ○ Individuals with established insulin resistance and metabolic syndrome § Increase in visceral adipose tissue which eventually becomes dysfunctional □ Reduced production of lipid hormone adiponectin □ Increased production of inflammatory cytokine TNF-a and IL-6 ® Both of the above changes promote hepatocyte apoptosis ○ Fat laden cells are highly sensitive to lipid peroxidation products generated from oxidative stress --> leads to damage of mito and plasma membranes --> apoptosis • Diminished autophagy --> mito injury and formation of Mallory-Denk bodies • Kupffer cells produce TNF-a and TGF-B --> activate stellate cells --> deposition of scar tissue • Stellate cell activation also occurs through the hedgehog signaling pathway in part through natural killer T-cell activation. The level of hedgehog pathway activity correlates with stage of fibrosis in NAFLD

Ulcers and H. Pylori Mechanisms

• Ulcers and H. pylori § two major exogenous causes of both gastric and duodenal ulcers; ingestion of nonsteroidal antiinflammatory drugs (NSAIDs) or gastric colonization with a gram-negative, spiral-shaped bacterium known as Helicobacter pylori. § Ulcer disease associated with the use of NSAIDs likely reflects a loss of protective factors, such as the prostaglandins that normally contribute to the gastric barrier by controlling blood flow, as discussed earlier. The full details of ulcer pathogenesis related to NSAID use are still being worked out, but it is clear that this condition is an increasing problem in developed countries, where aging populations are prescribed more and more NSAIDs to counter degenerative diseases, such as arthritis. NSAIDs thought to be less toxic to the stomach are being developed, but none thus far are completely without the risk of causing ulceration, especially when used chronically. § In the absence of NSAID use, the vast majority of all ulcer patients can be shown to be infected with H. pylori, which is specialized to colonize the gastric niche because it secretes large amounts of the enzyme, urease. □ This product converts urea to ammonium ions in the vicinity of the bacteria, thereby protecting them from the deleterious effects of gastric acidity. In genetically susceptible individuals, infection with H. pylori can have profound effects on both gastric and duodenal physiology, including both hyper- and hypo-secretion of acid, alterations in blood flow, and an inhibition of duodenal bicarbonate secretion. □ These changes may result indirectly from the inflammatory response mounted by the host in a futile attempt to expel the chronic bacterial colonization. § Nevertheless, it is clear that acid contributes to ulcer pathogenesis, even if secreted in normal amounts, due to its role in sustaining the activation of pepsin, and, in the case of duodenal ulcers, the direct injurious effects of protons on the epithelial cells at this site which are not designed to withstand prolonged exposure to low pH (contrast with the resilient epithelial cells in the stomach). In fact, a clinical adage: "no acid, no ulcer" also gives clues as to possible treatments.

Analyze the reactions involved in the urea cycle, the regulatory enzymes and disorders associated with malfunction of the cycle. (LGS 5.5a)

• Urea Cycle ○ Normally little ammonia is present in blood, ranges from 30-60 nM § Rapidly removed and converted to urea by liver § Travels in blood via AA, alanine and glutamine • Reactions of urea cycle ○ Nitrogen enters urea cycle as NH4+ and aspartate—> carbamoyl phosphate+ orinthine —> citrulline § Orinthine is initiates and regenerated by the cycle § Aspartame reacts with citrulline, donating N for urea formation § Arginine is formed in 2 successive steps □ Cleavage of arginine by arginase release urea and regenerates orinthine • Synthesis of carbamoyl phosphate ○ In 1st step: NH4+ +bicarbonate+ ATP —> carbamoyl phosphate § Cleavage of 2 ATP required § Catlazyed by CPSI (found in mitochondria of liver and intestine) § CPSII located in cytosol produces carbamoyl phosphate for pyrimidine biosynthesis, using nitrogen form glutamine • Production of arginine by urea cycle ○ Carbamoyl phosphate Reactions with orinthine to form citrulline § High energy bond of phosphate providers E required for RXN, occurs in mitochondria □ Catalyze by orinthine transcarbamoylase (OTC) ® Product: citrulline, transported across mitochondrial membranes in exchange for cytoplasmic orinthine and enters cytoso ® Carrier for transport RXN catalyze an electroneutral exchange ○ In cytosol, citrulline reactions with aspartarte (2nd source of N for urea synthesis) —> arininosuccinate § Catalyzed by arininosuccinate synthetase, Drive by hydrolysis of ATP to AMP and pyrophosphate § Aspartame produced by transamination of oxaloacetrate ○ Argininosuccinate is cleaved by argininosuccinate lyase to form fumarate and aringing § Fumarate is produced from carbon Of arininosuccinate provided by aspartate § Fumarate is converted to malate, used for synthesis of glucose but gluconeogeneic pathway or for regeneration of oxaloaxetate by cytoplasmis reactions § Oxaloacetate that is formed is transaminase to generate that aspartate that carries nitrogen into the urea cycle □ Carbons of fumarate can be recycled to aspartate • Cleavage of arginine to produce urea ○ Arginine is cleaved by aringase —> urea and regenerating orinthine § Urea is produced from guanidium Group on side chan of arginine § Portion of aringine originally derived from orinthine is reconverted to orinthine ○ Reactions by which citrulline is converted to arginine and arginine is cleaved toproduce urea occur in cytosol ○ Orinthine is transported to mitochondria in exchange for citrulline, can reaction with carbamoyl phosphate, initiating another round of cycle • Origin of Orinthine ○ AA, can be synthesized de Novo if needed, normally regenerated by urea cycle

Understand the unique cardiovascular anatomy of the GI system, the principles that govern GI system blood pressures, blood flows, and transcapillary fluxes, and the expressions of these cardiovascular principles in gastrointestinal system disease. (LGS 5.5c)

• Using Ohm's law we get: Q (flow rate) = P (pressure)/ R (resistance) OR P = QR ○ P needs to be pressure difference, while R is a sum of the resistances (b/c they are in series, meaning they are linear) ○ The two constant variables for P that we know are MAP (Mean Arterial Pressure, ~80-100 mmHg) and RAP (Right Atrial Pressure, ~2-3 mmHg) ▪ If we want to calculate the pressure or resistance at a specific point, we can use the above equation b/c Q will be constant (pre=post) ▪ Ex: Hepatic Pressure use the follow eq to estimate (we throughout some variables for mathematical simplicity) • P (pressure at Portal Vein) = (MAP * (R post/R pre)) + RAP • Normal P ~5-10 mmHg • Portal HTN >= 12 mmHg OR Hepatic Venous Pressure Gradient > 5mmHg

Locatin of abdominal pain

• Visceral pain arising from the foregut (esophagus, stomach, proximal duodenum, bile duct, gallbladder, pancreas) most often is manifested in the epigastrium • Pain derived from the midgut (small intestine, appendix, ascending colon, proximal transverse colon) occurs in a periumbilical location • Pain derived from the hindgut (distal transverse colon, left colon, rectum) localizes to the lower midline between the umbilicus and symphysis pubis • Paired intra-abdominal organs such as the kidneys, ureters, ovaries, and fallopian tubes have unilateral innervation that localizes pain to the side of the involved organ ○ As some surgical conditions progress, the character and location of the pain shift from a visceral to a parietal pain pattern Anorexia, vomiting, diarrhea, distention, and constipation are commonly seen with abdominal pain caused by both medical and surgical disorders. § absence of any of these symptoms is evidence against an emergent surgical or medical disorder because severe illness usually leads to reflex stimulation or inhibition of gastric and intestinal peristalsis. □ Vomiting is common in medical and surgical disorders involving the upper GI tract, including acute gastroenteritis, pancreatitis, gastric and small intestinal obstruction, and biliary tract disease. ® Pain that precedes the onset of vomiting is typical of surgical conditions, whereas the reverse is true of medical conditions (e.g., food poisoning, gastroenteritis). □ Abdominal pain with prominent diarrhea is most commonly caused by a medical condition (e.g., gastroenteritis, inflammatory bowel disease). ® Although constipation alone is a nonspecific complaint, the absence of stool passage and flatus is consistent with complete bowel obstruction or paralytic ileus.

Distinguish between marasmus and kwashiorkor.(LGS 5.4c)

• Weight related diseaes ○ Marasmus and Kwashiorkor • Kwashiorkor ○ Protein and calorie deficient ○ PE exam findings § Edema in the legs and hands § Muscle wasting □ Shoulders and butt § Skin lesions □ Hyperpigmentation □ Patchy □ Extremities □ Pellagra ® Niacin (B3) deficiency ◊ Seen in pts with diet heavily consisting of corn • Kwashiorkor, which occurs mostly in children 1-3 years of age, results from a deficiency of dietary protein and is usually associated with an infection. • Typically, there are skin lesions (pigmented or de-pigmented areas with or without ulceration), scanty lustre-less hair, loss of interest in the surroundings and loss of appetite • The edema is usually noticed in the feet, but can also occur in other parts of the body. β-lipoprotein is not produced in adequate amounts, resulting in impaired transport of fat and an enlarged fatty liver. A child with marasmic kwashiorkor has clinical findings of both marasmus and kwashiorkor. There may be mild hair and skin changes, and an enlarged, fatty liver. • Marasmus has been recognized for centuries. It is usually seen in infancy and is characterized by severe weight reduction, gross wasting of muscle and tissue beneath the skin, stunting and no edema. ○ Usually, the child is irritable. ○ Marasmus occurs as a result of severe deficiency of energy, protein, vitamins and minerals, although the primary cause is inadequate energy intake. § This deficiency often results when there is a decrease or absence of breastfeeding, feeding on diluted milk formula or a delay in introducing solid foods in the diet. § In marasmus, the body generally adapts itself to the deficiency of energy and protein. The muscles provide amino acids leading to the production of proteins including albumin and β-lipoprotein. Adequate amounts of albumin and β-lipoprotein prevent the development of edema and fatty enlargement of the liver in marasmus Marasmus is a condition primarily caused by a deficiency in calories and energy, whereas kwashiorkor indicates an associated protein deficiency, resulting in an edematous appearance. Marasmic kwashiorkor indicates that, in practice, separating these entities conclusively is difficult; this term indicates a condition that has features of both. [1, 2] These conditions are frequently associated with infections, mainly GI. The reasons for a progression of nutritional deficit into marasmus rather than kwashiorkor are unclear and cannot be solely explained by the composition of the deficient diet (ie, a diet deficient in energy for marasmus and a diet deficient in protein for kwashiorkor). The study of these phenomena is considerably limited by the lack of an appropriate animal model. Unfortunately, many authors combine these entities into one, thus precluding a better understanding of the differences between these clinical conditions.

Gastroschisis

• a birth defect of the abdominal wall (prevalence 1 in 2000) • results from a defect lateral to the median plane of the anterior abdominal wall. • permits extrusion of the abdominal viscera without involving the umbilical cord. • term gastroschisis means a "split or open stomach," is a misnomer because it is the anterior abdominal wall that is split, not the stomach. • usually occurs on the right side lateral to the umbilicus • more common in males than females. • exact cause is uncertain, ○ Suggestions: § ischemic injury to the anterior abdominal wall § absence of the right omphalomesenteric artery § rupture of the abdominal wall § weakness of the wall caused by abnormal involution of the right umbilical vein perhaps rupture of an omphalocele before the sides of the anterior abdominal wall have closed

Meckel Diverticulum

• congenital ileal diverticulum • occurs in 2% to 4% of people, • three to five times more prevalent in males than females. • of clinical significance because it may become inflamed and cause symptoms that mimic appendicitis. • Only a small percent of them actually cause symptoms. • The wall of the diverticulum contains all layers of the ileum and may contain small patches of gastric and pancreatic tissues. • remnant of the proximal part of the omphaloenteric duct • Typically appears as a finger-like pouch approximately 3 to 6 cm long that arises from the antimesenteric border of the ileum • may predispose the person to intestinal obstruction because the intestine may wrap around this cord or it may form an omphaloenteric fistula

What is the role of prostaglandins with gastric mucus and HCO3

• prostaglandins are potent mucus secretagogues, providing a partial explanation as to why non-steroidal anti-inflammatory drugs, which prevent prostaglandin synthesis, predispose the gastric mucosa to injury and ulceration. One drug that exploits the protective effect of prostaglandins is misoprostol, which is a synthetic prostaglandin that is often used to counteract the injurious effects of NSAIDs in patients that need to take these chronically.

Zinc Deficiency

□ Acrodermatitis enteropathica ® Rare rececessively inherited disease ® Deficiency in the import carrier ZIP4 ◊ ZIP4 absorbs zinc from the intestinal lumen into enterocytes ® Zinc malabsorption leads to signs of zinc deficiency with dermatitis, diarrhea, and alopecia ® High doses of zinc are curative suggesting there are other zinc carriers other than ZIP4 on the llumenal side

Wernicke Korsakoff

□ Combined effects of thiamine deficiency and alcohol toxicity □ Acute stage: Wernicke encephalopathy- mental derangement and delirium, ataxia, paralysis of eye muscles ® High carb or IV glucose can worsen condition because pyruvate dehydrogenase is thiamine depends ® Pyruvate that is formed in glycolysis diverted into lactate —> lactic acidosis □ Encephalopathy requires immediate treatment with thiamine injections to prevent chronic stage □ Chronic: Korsakoff psychosis- anterograde amnesia ® Most common form of amnesia, attributed to focal lesions in periventricular areas of thalamus and hypothalamus, periaquductal gray of midbrain, mammillary bodies □ Functionally connected to medial temporal lobe system for episodic memory ® Confabulation distinguishes Korsakoff psychosis from other forms of anteriogeade amnesia □ Concomitant damage frontal lobes Wernicke's area :language usage and development "women talk a lot but it doesnt make sense" Broca's area: comprehension "men have a lot of thoughts but don't know what they want to say"

Menke's Disease

□ Copper deficiency □ Menkes disease ® Rare X-linked disorder caused by deficiency of the ATP-dependent ATP7A transporter ◊ This transporter carries copper out of cells and distributes it to cell organelles ® Results in copper malabsorption ® Classical cases have disease present 2 months after birth with growth retardation, axial hypotonia, seizures, atrophy of gray matter in cerebral cortex and cerbellum, developmental delay or regression, coarse, lightly pigmented hair that is brittle and rubs off easily. ◊ Also have lax skin and joints, bone demineralization, jowly face ◊ If untreated kid will die at age 3 ® Low copper in plasma, liver and brain ◊ Deficient acitivtity of copper containing enzymes ® Hair pigmentation and light skin due to tyrosinase deficiency in melanocytes ® Connective tissue abnormalities due to ****ed up lysyl oxidase ® Neuro degeneration due to messed up up cytochrome c oxidase ® Treatment ◊ Parenteral admin of copper ® Its hard to transfer copper into the brain ◊ Residual activity of ATP7A transporter leads to substantial benefits Complete deficiency of transporter will still die, just a little later than those without treatment What the duck

Selenium

□ Found in 20 human proteins including antioxidant glutathione peroxidase ® These proteins contain AA selenocysteine ◊ AA is sythesized from tRNA bound serine before it is incorporated in the protein □ Keshan disease ® Endemic cardiomyopathy in China ® Caused by low selenium content of locally grown food

Role of iodine

□ Halogen needed for the synthesis of thyroid hormone

Acetylcholine

□ Mediator of both short and long reflexes of the stomach □ Participates in the stimulation of parietal, chief and ECL cells, suppression of D cells and the synapse between nerves within the enteric nervous system

Role of Copper

□ Participates in reactions of molecular oxygen □ Functions as a cofactor of enzymes that use either molecular oxygen or oxygen derivatives as one of their substrates. ® Ex: cytochrome oxidase, dopamamine Beta-hydroxylase, monoamine oxidase, tyrosinase etc. □ Dietary requirement: 1-3 mg/daily, 0.5 is absorbed ® Intake of more than 50 mg of zinc increases risk of copper deficiency since zinc leads to synthesis of metallothionein, that binds zinc and copper ◊ When this happens both minerals are retatined in the enterocyte instead of transferred to the blood and are returned to the intestinal lumen □ 60% of copper in serum is bound to ceruloplasmin, rest is loosely bound to albumin or complexed with histidine □ Major route of excretion is bile □ Copper deficiency ® Microcytic hypochromic anemia, leukopenia, hemorrhagic vascular changes, bone demineralization, hypercholesterolemia, and neurological problems ® Copper toxicity ◊ Could be linked to alzheimer's

Pernicious Anemia

□ Pernicious anemia and neurological symptoms □ Usually caused by malabsorption,autoimmune disease that destroys parietal cells in stomach, depletes IF —> no B12 can be absorbed ® Milder forms of B12 malabsorption are common in geriatric patients ® B12 supplements recommend □ Treated with large amounts of B12 orally or monthly injections of moderate dosage □ 2 types of abnormalities ® Megaloblastic anemia (similar to folate deficiency)- over 110 ◊ Methyl folate trap hypothesis ◊ During metabolism of 1 carbon units, small amount of methylene THF is irreversible reduced to methy THF —> useless for purine synthesis, must be converted back to other coenzyme forms ® Can only be done via b12 doesn't methylation of homocysteine to methionine, which regenerates free THF ® Methyl THF accumulates in B12 deficiency ◊ Secondary folate deficiency ® Neurological dysfunction with demyelination I the spinal cord brain and peripheral nerves

Histamine

□ Released from ECL cells under combined influence of gastrin and Ach □ Diffuses to parietal cells to activate acid secretion via histamine H2 receptors □ Histamine receptors linked to cAMP signaling pathway

Scurvy

□ Scurvy □ S/S: 2-3 months after sudden switch to VC free diet, total body pool reduced to 300 mg ® Cutaneous petechias, purpura, follicular hyperkeratosis, dry eyes mouth, decaying peeling gyms, loose teeth, disrupted wound healing, weakness, leathery, joint pain and aching legs □ Many iron and copper containined enzymes require absorbed acid to keep metal in reduced state □ Hydroxylatio Of prolly and Lysol resides in procollagen reuiqrws ascorbate - impairment in reaction —> prominent connective tissue abnormalies of scurvy □ Carnitine synthesis: require 2 Fe2+ containing ascorbate depends oxygenates ® Deficiency may continue to fatugyre and lassitude of scurvy □ Vitamin C does collage synthesis —> deficient cant synthesize and low collagen leads to weaker blood vessel—> boom □ Vitamin C: water soluable antioxidant ® Resembles monosaccharide, most animals can synthesis in minor pathway of carbohydrate metabolism ® Function: reducing agent and Schneider of free radicals □ Surpesses formation of carcinogenic nitrosamines from dietary nitrite and nitrate in the GI tract, protect lipoprotein from oxidative damage □ Strong reducing agent to donate electrons —> neutralize free radicals —> unstable outer orbit to stbialize —> decrease free radical levels ® Many iron and copper containined enzymes require absorbed acid to keep metal in reduced state □ Hydroxylatio Of prolly and Lysol resides in procollagen reuiqrws ascorbate - impairment in reaction —> prominent connective tissue abnormalies of scurvy □ Carnitine synthesis: require 2 Fe2+ containing ascorbate depends oxygenates ® Deficiency may continue to fatugyre and lassitude of scurvy □ Norepinephrine (noradrenaline ) requires ascorbate depends copped enzyme domaine beta hydroxylase □ Bile acid synthesis is regulated at the level of ascorbate dependent enzyme 7alpha-hydropylase ® Dietary can only be absorbed max 1-2 grams per day ® Good sources: fresh fruits and Vega tables □ Not very stable under neutral or alkaline controls, easily oxidized to inactive products by boiling in Porsche of oxygen and catalytic amounts of heavy metal ions • Vitamin C similar to Vitamin E (tocoferol) □ Vitamin E: prevents lipid oxidation ® Most patented alpha tocopherol ® Antioxidant and Scavenger of free radicals , protects membranes, fat deposits, and lipoproteins from lipid peroxidtion ® Fat forms dues to oxidation of LDL, Vitamin E is protective of oxidation of LDL —> CV protection ® Deficiency is rare, can be seen in infants who have poor absorption □ Neurological abnormalities, fragility of RBCs ® Good sourcesL: vegetable oils, various seed oil, wheat germ ® Alpha form is most stelae form — provides CV protection activity

Role of Zinc

□ Second most abundant trace mineral in the body after iron ® 60% found in skeletal muscle, 30% in the skeleton, the rest is in the liver and skin □ Does not change oxidation state under physiological conditions □ Does not participate in electron transfer reactions and formation of free radicals □ Fucntions as Lewis acid (electron pair acceptor) □ 10% of human proteins contain zinc ® Can be bound to oxygen, nitrogen, or sulfur □ Constituent of more than 300 zinc metalloenzymes ® Carbonic annhydrase, cytoplasmic superoxide dismutase, alcohol dehydrogenase, carboxypeptidase A and B, DNA and RNA polymerases and others □ Zinc finger proteins: major class of transcription factors □ Signaling functions both inside cells and in the extracellular compartment ® Released from neurons with glutamate and from pancreatic beta-cells together with insulin. ® GPCR for zinc is GPR39, believed to mediate antidepressant effects of zinc on the brain □ Most zinc in plasma is bound loosely to albumin, small amount bound to alpha-2 macroglobulin □ Some intracellular zinc bound to metallothioneins in tissue ® Reduce metal toxicity □ MTF-1 ® Metal response element binding factor ® Senses free unbound zinc ◊ Binds to metal response elements in promoters of metallothionein genes and induces their transcription ◊ Metal exporters also activated □ Recommended daily amount (RDA) = 11 mg/day for dudes, 8 mg/day for dudettes □ Zinc deficiency problems ® Anemia, growth retardation, hypogonadism in children ® Skin abnormalities, hair loss, immune dysfunction, poor wound healing, neuropsychiatric impairments, decreased taste acuity

Xerophthalmia

□ Vitamin A deficiency : Retinoids ® Animal origin food contain most vitamin A in form of esters between retinol and a long chain fatty acids ○ Esters are hydrolyzed by pancreatic enzyme in the small intesting and free retinol is absorbed with efficiency @ 60-90% ® Beta carotene, major vitamin A precursor in plants ○ Cleaved to retinal by beta carotene dioxygenase in the cytoplasm of intestinal mucosal cell ® Retinal is in equilibrium with reintol via reversible NADH dependent reaction ○ Small amount reversible to retinoic acid ○ Intestinal mucosal esterifies most of retinol with fatty acids and exports retinol esters as constituents of chylomicrons ® Remnentra bring the retinol esters to liver —> stores up to 100mg in stellate cells ○ From export from liver , retinol esters are hydrolyzed and retinol binds to retinol binding proteins RBP, released into blood ® Uptake into cells is mediated by an RBP receptor on cell sruface ○ Retinol is oxidized to active forms ® Retinal:prosthetic group of rhodopsin's, villa pigments of rods and cones ® Retinoic acid: gene regulator, matintentence of epithelial tissues ® Retinoic Acide receptor: similar to receptor for steroid hormones □ RAR-RXR heteodimer binds to retinoic acid repsonse elements RAREs in the enhancer region of regulated genes ○ Good sources: liver meat, eggs, dair, cod liver oil, yellow or orange fruits/veggies ® Important during fetal development —> limb development ○ Deficiency and excess are teratogenic ® □ Dry eyes, complicated by bacterial or chlamydial infection—> perforation of the cornea and blindness □ Microcytic anemia, susceptibility to infections, impairment of reproductive functions

Significance of having peptide factors that regulate CCK release lies in ability to match pancreatic secretion for proteolytic enzymes to the need of them in the small intestinal lumen

□ When meal proteins and oligopeptides are present in the lumen in large quantities- compete for action of trypsin and other proteases □ Means CCK-RP and monitor peptide are degraded only slowly ® CCK release sustained - causes further secretion of proteases and other components into the pancreatic juice □ Once meal has been fully digested and absorbed - CCK-RP and monitor peptide will be degraded by pancreatic proteases ® Leads to termination of CCK release and marked reduction in secretion of pancreatic enzymes □ Feedback mechanism for control of CCK release and in turn pancreatic secretion can be demonstrated in animals in which pancreatic juices have been diverted away from the intestinal lumen ® In such experiments CCK release in response to fatty acids or amino acids is potentiated and prolonged ® Presumably reflects persistance of CCK-RP

Wilson's Disease

□ Wilson Disease ® AKA hepatolenticular degeneration ® Rare autosomal recessive disease caused by deficient ATP7B copper transporter ◊ Carrier expressed mainly in the liver ® Excretion of copper inot the bile and transfer of copper to ceruloplasmin ® Inability to excrete copper leads to accumulation in the liver and then later in the brain where it has a predilection for the caudate-putamen ® Symptoms can appear at any age, most common in teens and young adults ◊ 50% have neuro symptoms, 20% with liver disease, most have combo of both ® Other symptoms, renal tubular dysfunction, hemolytic anemia, skeletal abnormalities ◊ Kayser-Fleischer rings are important diagnostic sign ® Golden to greenish brown deposits of copper in the periphery of the cornea ◊ Seen in 95% of pts with neuro signs and 65% of those with liver disease ® Neuro signs include ◊ Dysarthria, dystonia, rigidity, tremor, choreiform movements, abnormal gait, uncoordinated handwriting ◊ Often misdiagnosed as parkinson's ◊ Also can have personality changes ® Diagnostic chagnes in blood chem ◊ Low plasma levels of ceruloplasmin and copper ◊ Needs to be differentiated from aceruloplasminemia ◊ Increased urinary copper is important diagnostic test, along with percutaneous needle biopsy of the liver with measurement of hepatic liver copper concentration ® Treatment ◊ D-penicillamine ® Forms copper complex

Role of Fluorine

□ present in nature as the fluoride ion, which becomes incorporated in the inorganic substance of bones and teeth. □ Although not absolutely essential, it strengthens teeth and bones. □ may even have some protective effect in osteoporosis. □ excess fluoride is toxic. □ In some parts of the world, the drinking water contains excess fluoride from geological sources. In some Chinese provinces, for example, this is a major public health issue. Studies in these areas found not only dental fluorosis but also severe impairments of brain development as a result of fluoride exposure. The mechanisms of fluoride toxicity are not well known.

LGS 5.3c- Type of Pancreatic Neoplasms

► cystic pancreatic neoplasm --- refer to Sos at bottom of page ○ Pathogenesis ○ Morphology § Benign § Malignant ○ Histology ○ Clinical features ○ Lab/Rads ► pancreatic adenocarcinoma (CASE #1 FROM LECTURE) ○ Pathogenesis: developed from pancreatic intraepithelial neoplasm § Hyperplasia -> dysplasia -->(multi hit with gain of function of oncogene and loss of function of tumor suppressor gene) --> carcinoma ○ Morphology: hard, white mass with irregular borders, obstructing the distal common bile duct ○ Histology: irregular, ducts (with loss of nml architecture) invading the stroma --> stromal desmoplasia ○ Clinical features: abd pain, weight loss, jaundice, palpable gallbladder ○ Lab/Rads: IV Contrast CT abd is first choice; if allergic (aka anaphylactic allegy to contrast), then MRI; Pancreatic enzymes (amylase, lipase); LFTs (AST, ALT, AKP, GGT, Bilirubin, total + direct), CEA, CA19-9 § If suspect pulmonary embolus, DDimer & CXR --> CTA (aka CT chest with contrast)

LGS 5.3c- Types of hepatic neoplasms

► hepatocellular carcinoma (CASE #2 FROM LECTURE) ○ Pathogenesis: § If due to chronic hepatitis: IL-6 and Jak/Stat; chronic hepatitis causing multiple rounds of inflammation; cell-death and regeneration, increasing likelihood of mutations § If spontaneous HCC (not related to hepatitis), activation of beta catenin and inactivation of p53 ○ Morphology: well-circumcribed, yellow (possibly due to bile or hemosiderin pigmentation) nodular tumor § Sometimes one nodular present, but can also have infiltrates throughout ○ Histology: loss of nml architecture with nuclear atypia and cord-like (aka thick) trabeculae ○ Clinical features: fatigue, weightloss § Risk Factors □ Chronic Hep B or C; toxic injury due to aflatoxin or ETOH; Hereditary hemochromatosis w/cirrhosis; Alpha-1-anti-trypsin defiency w/cirrhosis; wilson dz; late stage primary biliary cirrhosis; metabolic assoiated w/obesity; DM; NAFLD ○ Lab/Rads: LFTs, Alpha-fetoprotein, Hepititis Panel (HBV: HBsAg, IgM anti-HcAb, anti-HCV, anti-HAV), CT abd with contrast - Multiphase/Triple phase ► Cholangiocarcinoma (vs hepatocellular carcinoma) -- refer to Sos at bottom of page ○ Pathogenesis ○ Morphology § Benign § Malignant ○ Histology ○ Clinical features ○ Lab/Rads

Glycogen depredation

○ 2 enzymes: glycogen phosphorylase and debranching enzyme ○ Phosphorolysis reaction § Starts at nonreducing end of a chain and successive cleaves glycosyl residues by adding phosphate to the anomeric carbon of the terminal glycosidic bond, releasing glucose 1P and producing a free 4` hydroxyl group on the gluvpose reside now at the end of the glycogen chain § glycogen phosphorylase cannot act on the glycosidic bonds of the four glucosyl residues closest to a branch point because the branching chain sterically hinders a proper fit into the catalytic site of the enzyme. § The debrancher enzyme, which catalyzes the removal of the four residues closest to the branch point, has two catalytic activities: □ It acts as a transferase and as an α-1,6-glucosidase. As a transferase, the debrancher first removes a unit containing three glucose residues and adds it to the end of a longer chain by an α-1,4-glycosidic bond. □ The one glucosyl residue remaining at the α-1,6-branch is hydrolyzed by the amylo-1,6-glucosidase activity of the debrancher, resulting in the release of free glucose. Thus, one glucose and approximately seven to nine glucose 1-P residues are released for every branchpoint. § Some degradation of glycogen also occurs within lysosomes when glycogen particles become surrounded by membranes that then fuse with the lysosomal membranes. A lysosomal α-glucosidase hydrolyzes this glycogen to glucose.

IBS- Applicable OMT

○ 2 types of Visceral OMT we can do (Mesenteries and Large Intestine) "Scoop the Poop" § Quick notes for performing them: □ If we start at a corner, pull to the opposite corner (Mesenteries and Ileocecum) □ If we start at a wall, pull to the opposite wall (Descending and Ascending Colon) □ Hold for 2 min, or until tissue texture change § Mesenteries—use ASIS as a landmark and draw a line to the pubic symphysis □ Along this line on the pubic bone is Sigmoid Mesocolon, pull to R shoulder □ A tad superior and medial to the ASIS we get Mesenteric Root, pull to R shoulder § Large Intestine—start from distal to proximal □ Use L anterior axillary line and scoop the Descending Colon and pull to the R side □ Use R anterior axillary line and scoop the Ascending Colon and pull to the L side □ Go towards your appendix (1/3 b/t ASIS and umbilicus) and move a little superior to get the Ileocecum (Cecum really) and pull to the L shoulder ○ We can do Neurolymphatics for this pt as well (see chapman point diagram) and apply a rotatory force § Neurolymphatics are a subtype of Viscero-Somatic reflexes □ Sympathetic tone causes a problem in circulation, creating palpable nodules along our lymphatic system ® Rotatory force is us improving circulation to relieve the viscero-somatic reflex ○ Last set of OMT we can do are the ganglia inhibition, where we apply a posteriorly directed force on the ganglia § Celiac ganglia (1 in below Xyphoid process), Superior Mesenteric ganglia (½ way b/t Xyphoid and Umbilicus), and Inferior Mesenteric ganglia (1 in above Umbilicus) • In patients with mild to moderate symptoms who fail to respond to initial management and in patients with moderate to severe symptoms that affect quality of life, we suggest pharmacologic therapy as adjunctive treatment.

Gut Microbiota and RA

○ Altered regulation of host responses secondary to dysbiosis within the gut lumen could affect distant anatomic sites. § This may be a mechanism in rheumatoid arthritis, another chronic idiopathic inflammatory condition. In mice, the presence of segmented filamentous bacteria in the gut microbiome causes local expansion of T h 17 cells that then migrate to peripheral immune compartments and activate B cells into antibody-producing plasma cells. § Antibody production leads to immune-mediated destruction of the joints that mirrors rheumatoid arthritis. Substantial alterations in the gut microbiota have been identified in patients in the early stages of rheumatoid arthritis, consistent with a pathogenic role.

B12: Cobalamin

○ B12 : Cobalamin ® Requires intrinsic factor for its absorption ® Corrin ring system with cobalt complexed in center, synthesized only by some microorganisms but not plants □ Small amount synthesized by colon bacteria, absorption negligible ® Metabolism tightly controlled by B12 binding proteins □ Two proteins bind dietary cobalamin with high affinity in the digestive tract : haptocorrin from salvia and bile with intrinsic factor from parietal cells ® Intrinsic factor binds. Only cobalamin with high affinity while haptocorrin also binds many other Corrine that cant be converted to B12 enzyme forms ® Complex of intrinsic factor and cobalamin is absorbed in the terminal ileum, binds to peripheral membrane protein cubilin on apical surface of enterocytes □ Endocytosis happens via interactions between complex and amnioless (integral membrane protein) ® Cubilin is multipurpose brining protein for endocytosos □ In kidneys megalin rather than amnionless is integral membrane protein required for endocytosis ® After uptake into enterocytes IF-B12 comples is directed to lysosomes where IF is degraded □ Vitamin is transferred to blood, binds 2 transport proteins ® 20% bound to transcobalamin II ◊ Only cells bound are taken up into cells by receptor mediated endocytosis of cobalamin-transcobalamin comples ® 80% to haptocorrin ◊ Also binds inactive Corrine's preventing tissue uptake to liver ® Reactions requiring cobalamin coenzymes □ Methionine synthase reaction— requires Methylcobalamin □ Mitochondrial methylmalonyl CoA mutase reaction required 5-deoxyadenoslycobalamine ® Conversion of cobalamin to active coenzyme requires set of proteins that function as enzymes, binding proteins or membrane carriers ® At risk: vegans, all dietary B12 derived from animal products □ Deficiency only at risk after > 10 years because 1-10 mg B12 stored in body, most I liver, 1-10microgram secreted in bile daily, intestinal absorption is efficient to compensate

B1: Thiamine

○ B1: Thiamine § Readily absorbed and transported to the tissues, phosphorylation to its coenzyme thiamine pyrophosphate (TPP) and in an ATP dependent reaction □ Aldehyde transfer □ Aldehyde is covalently to one of the carbon in the thiazole (sulfur and nitrogen) ring of the coenzyme § Oxidative decarboxylation of alpha ketoacids is catalyze by mitochondrial multienzyme complexes □ Pyruvate dehydrogenase, alpha ketoglutarate dehydrogenase, branched chain alpha KETO acid dehydrogenase, alpha ketobuyrate dehydrogenase all use thiamine dependent catalytic mechanism § Cytoplasmic transketolase reaction, TTP transverse a glycoaldehyde between monosaccrises □ Major catabolic energy producing pathways are most dependent on TTP § Good sources: yeast, meat, legume seeds § Deficiency: evaluated by determination of transketolast activity in whole blood or erythrocytes, before and after addition of TTP □ Plasma levels of lactate and pyruvate can be determined after oral glucose load, acids accumulate in persons with thiamine deficicnecy because pyruvate dehydrogenase requires TPP for its activity § Beriberi: severe deficiency □ Mild deficiency leads to GI complaints, weakness, and burning sensation of feet □ Moderate: peripheral neuropathy, mental abnormalities ataxia □ Severe: severe muscle weakness and muscle wasting, delirium, ophthalmoplegia, memory loss, peripheral vasodilation, increased venous return ® Myocardial contractlity is impair and death can result from high output cardiac failure ® Became problem in parts of Asia at end of 19th when milling and polishing of rice — removed outer layers where thiamine is present

B2: Riboflavin

○ B2: Ribofalvin- precursor of flavin mononucleotide and flavin adenine dinucleotide § Component of FAD and FMN § Consists of dimethylisoalloxzine ring convaneltny bound to sugar alcohol rib I told § Dietary riboflavin is absorbed in upper small intesting and transported to tissues, converted to FMN and FAD □ Excess is excreted in urine or metabolized by liver enzymes § Sources: liver, yeast, eggs, meat, enriched bread and cereal, and milk § Deficiency: common in alcoholics □ Symptoms: glossitits (magenta tongue) angular tomatitis, sore throat, seborrheic dermatisis of scrotum and nose, possibly normochromic or normocytic anemia § Heat stable but rapidly degraded to inactive produce on exposure to visible light □ Deficiency can occur in infants receiving photo therapy for hyperbilirubinemia § Status: assessed by flurometric or microbiological determination of urinary riboflavin □ Activity of erythrocytes gtathione reductase is deterred in freshly Kyser RBC before and after addition of FAD □ In deficiency apoenzyme is not completely saturated with its coenzyme, activity increased by added FAD

B5: constituent of Coenzyme A

○ B5: constituent of coenzyme A (CoA) and phosphopantetheine Group in fatty acid synthase complex § Deficiency has never been observed under ordinary conditions, isolated deficiency could be introduced under experimental conditions □ 5mg/day is safe and adequate □ Readily available in normal diet

B6

○ B6: plays role in AA metabolism § Generic name for dietary precursors of coenzyme pyrioxal phosphate PLP □ Pyridoxine, pyridoxal, pyridoxamine □ Phosphate is removed by intentional alkaline phosphates and dephosphoylated forms are absorbed § Total body content of PLP is only 25 my in adults, pyridoxal and PLP are major circulating forms § Synthesis of coenzyme form below § Several dozen AA metabolism contain PLP as a tightly bound prosthetic group □ Catalyze reactions where algehyde group of PLP forms an aldimide derivative with the amino group of the amino acid substrate □ Aldimide is stbialized by an intramolecular hydrogen bond with phenolic hydroxyl group § Good sources: liver, fish, whole grain, nuts, legumes, egg yolk, yeast § Deficiency: rare □ S/S: peripheral neuopathy, stomatitis, glosses it is, sideroblastic anemia, irritability, psychiatric symptoms, epileptic seizures in children □ Neuro manifestation may result from impaired activity of PLP dependent enzyme glutamate decarboxylase, forms GAGA □ Most common in alcohols —> sideroblastic anemia, peripheral neuropathy serizures § Drugs that induce synthesis of drug metabolizing enzymes in liver (phenobarbital, antiepileptic) can lead to deficiency □ Isoniazid and penicillamine can precipatite vitamin B6 deficiency by reacting noenzymatically with aldehyde Group of pyridoxal or PLP § Toxic in high doses >500 mg for several months leads to sensory neuropathy □ 100-150 mg per day treatment of carpal tunnel syndrome ® Unreleased to vitamin function, related to toxicity on sensory nerves

B7 Biotin

○ B7: Biotin, coenzyme in carboxylation Reactions § Prosthetic group of pyruvate carboxylase, acetyl-CoA carboxylase, proprionyl- CoA carboxylase and other ATP depends tcarboxylases □ Multisubunit enzymes contain biotin voalently bound to E-amino Group of lysine residue Biotin functions as carrier of bicarbonate derived carboxylase group § During catabolism of biotin containing proteins, biotin is released as lysine congujates biocytin □ Enzyme biotindase recycle biotin by cleaving biocytin into free biotin and lysine § Good sources: yeast, liver, eggs, peanuts, milk, chocolate, fish, intestinal bacteria § Only way to induce deficiency is to eat >20 raw egg whites per day—> contains avidin, binds biotin preventing intentional absorption § Biotinidase deficiency □ Present as constituent of carboxylase enzymes, during digestion and turnover of endogenous carboxylase, biotin is released as lysine conjugation biocytin ® Biotinidase deficiency causes nondietary biotin deficiency □ S/S: hypotonia, seizures, optic atrophy, dermatitis, conjunctivitis □ Cured with supplements ® Included in newborn screening exam □ Diagnosed by enzyme assay in fresh serum or in screening test on a strip of blood soaked filter paper

B9 Folic Acid

○ B9: Folic Acid § Deficiency causes megaloblastic anemia § Consists of pteroic acid and 1-7 gamma linked glutamate residues § Dietary forms for folic acid are hydrolyzed to petroglyphs monoglutmate in intentional lumen □ Monoglutamete is absorbed and reduced to active coenzyme tetrahydrofolate (THF) by dihydrofolate reductase in intestinal mucosa □ Circulation: monoglutamete conjugate of methyl-THF □ Intracellular: polyglutamate conjugated § THF is a carrier of 1 carbon units, bound covalently to one or both nitrogen atoms N-5 and N-10 □ THF acquires 1-carbon during catabolic reactions ® Major sources: serine in hydroxymethyl transferase reaction, glycine in glycine cleavage reaction and formiminoglutamate in pathway of histidine degradation □ THF bound 1 carbon unit is oxidized or reduced enzymatically ® Reversible, create 1 carbon units for use by bio synthetic enzymes □ THF transfers 1 carbon unit to an acceptor molecule ® THF dependent biosynthesis processes include synthesis of purine nucleotides, thymidylate synthase reaction, methylation of homocysteine to methionine § Deficiency: impaired DNA replication in dividing cells because of reduced synthesis of purine nucleotides and thymine □ In bone marrow hemoglobin is synthesized normally and cytoplasm frowns at normal rate, but cell division is delayed ® Production of mature cells slows, RBC precursors die, cells formed are oversized —> megaloblastic / macrocyclic anemia ◊ Megaloblastic: oversized erythrocytes precursors in bone marrow ◊ Macrocytes: oversized erythrocytes in blood □ Low serum levels of folate can be encouraged in late pregnancy and megaloblastic anemia can be precipitated by pregnancy □ Other causes: alcoholism and intestinal malabsorption syndromes § Good sources: yeast, liver, some fruits, green vegetables □ Heat labile § Measure: in serum and erythrocytes

Define indirect bilirubin

○ Bilirubin that is bound to a certain protein (albumin) in the blood is called unconjugated, or indirect, bilirubin. ○ Only unconjugated bilirubin, which is lipid soluble, can enter the brain. In infants this can lead to bilirubin encephalopathy, which rapidly progresses to irreversible brain damage. The latter is called kernicterus (from German kern meaning "nucleus"). § Survivors suffer permanent neurological impairments, including an athetoid movement disorder, oculomotor palsy, ataxia, spasticity, and mental deficiency. At a normal albumin concentration of 4 g/dL, up to 25 mg/dL of bilirubin is transported in tight, noncovalent association with a high-affinity binding site on this plasma protein. Kernicterus develops at bilirubin levels above this limit.

Parts of stomach (3 regions)

○ Cardia § 5% of gastric surface area § Transitional zone where stratified squamous epithelium of the esophagus gives way to columnar epithelium that lines the remainder of stomach and intestinal tract ○ Fundus/Body § 75% of gastric glands (oxyntic glands) □ Structure of a gastric gland from the fundus and body of the stomach. These acid- and pepsinogen-producing glands are referred to as "oxyntic" glands in some sources. ○ Antrum § Proximal to the pylorus § Contains glands that secrete gastrin □ Regulator of gastrin secretion Important motility functions

Function of Urea cycle during fasting

○ During fasting , liver maintains blood glucose levels § AA from muscle proteins are major carbon source □ Carbons converted to glucose, nitrogen converted to urea □ Urea excretion higher during fasting ○ The major AA substrate for gluconeogenesis is alanine, synthesized in peripheral tissues to act as nitrogen carrier ○ Glucagon release stimulates alanine transport into liver by activating trans tip of transport systems for alkaline § 2 alanine needed for 1 molecule of glucose □ Nitrogen from 2 alanine is converted into 1 urea

Microbiota effects brain and behavior

○ Early work suggests potential links between the gut microbiome and specific neurologic processes and disorders. Germ-free mice showed an exaggerated hypothalamic-pituitary response to stress that diminished after conventionalization with fecal matter. ○ Subsequent investigations showed that the microbiome could alter neurotransmitter levels, such as brain-derived neurotropic factor and serotonin. 9 ○ The rising incidence of autism in developed societies has led investigators to question whether shifts in gut microbes may play a causative role in these neurodevelopmental disorders. ○ However, causal associations are difficult to determine from existing studies because many affected children have concomitant gastrointestinal symptoms and were repeatedly treated with antibiotics. ○ Microbiome effects on multiple sclerosis and other neurologic diseases have been hypothesized.

Fatty Acid Synthase Complex

○ Fatty Acid Synthase Complex § Adds two carbon units from malonyl-CoA to growing FA chain to form palmitate □ After each addition, there are two reduction reactions using NADPH § In the initial step of fatty acid synthesis, an acetyl moiety is transferred from acetyl-CoA to the ACP phosphopantetheinyl sulfhydryl group of one subunit and then to the cysteinyl sulfhydryl group of the other subunit. □ The malonyl moiety from malonyl-CoA then attaches to the ACP phosphopantetheinyl sulfhydryl group of the first subunit. The acetyl and malonyl moieties condense, with the release of the malonyl carboxyl group as CO2. A four-carbon β-keto acyl chain is now attached to the ACP phosphopantetheinyl sulfhydryl group § A series of three reactions reduces the four-carbon keto group to an alcohol, then removes water to form a double bond, and lastly reduces the double bond (Fig. 31.9). NADPH provides the reducing equivalents for these reactions. The net result is that the original acetyl group is elongated by two carbons. § The four-carbon fatty acyl chain is then transferred to the cysteinyl sulfhydryl group and subsequently condenses with a malonyl group. This sequence of reactions is repeated until the chain is 16 carbons in length. At this point, hydrolysis occurs, and palmitate is released (Fig. 31.10). § Palmitate is elongated and desaturated to produce a series of fatty acids. In the liver, palmitate and other newly synthesized fatty acids are converted to triacylglycerols that are packaged into VLDL for secretion. § In the liver, the oxidation of newly synthesized fatty acids back to acetyl-CoA via the mitochondrial β-oxidation pathway is prevented by malonyl-CoA. Carnitine palmitoyltransferase I, the enzyme involved in the transport of long-chain fatty acids into mitochondria (see Chapter 30), is inhibited by malonyl-CoA (Fig. 31.11). Malonyl-CoA levels are elevated when acetyl-CoA carboxylase is activated, and thus, fatty acid oxidation is inhibited while fatty acid synthesis is proceeding. This inhibition prevents the occurrence of a futile cycle.

Define epinephrine role in metabolism

○ Fight or flight hormone ○ Insulin counterregulatory hormone ○ Epinepherine and cortisol bind to muscle cells in order to generate glucose through glycolysis (NOT GLUCAGON)

Gut Microbiota and Obesity

○ Genetically obese mice have decreased ratios of Bateroidetes to Fimicutes compared to lean siblings ○ Transplantation of gut microbiota from the obese (ob / ob ) to germ-free mice conferred an obese phenotype, which shows the transmissibility of metabolic phenotypes; the transferred microbiomes had increased capacity for energy harvest. Studies have shown that transplantation of human microbiota can achieve parallel effects. ○ Bacteroidetes proportions increase with weight loss ○ Antibiotic use in human infancy, before the age of 6 months, has been significantly associated with obesity development ○ perinatal administration of a Lactobacillus rhamnosus GG-based probiotic decreased excessive weight gain during childhood. These preliminary studies provide support for the concept that the early-life microbiota is modifiable, with alterations affecting risk of childhood-onset obesity. Studies are ongoing in adults to determine specific characteristics of the microbiome that may predict the risk of adiposity-related comorbidities. 8 ○ Interventions used to treat obesity, such as the Roux-en-Y gastric bypass, substantially alter the gut microbiome, which may contribute to the metabolic effects.

Define cortisol

○ Glucocorticoid released form the adrenal cortex in response to fasting and chronic stress ○ Insulin counterregulatory hormone ○ Epinepherine and cortisol bind to muscle cells in order to generate glucose through glycolysis (NOT GLUCAGON)

Gut micobiota and diseases of liver

○ Gut microbiota involved in NAFLD, alcoholic steatosis, and HCC ○ Liver is first solid organ exposed to metabolic processes generated from gut microbiome § Acetaldehyde, ammonia and phenols ○ Microbiome in mice led to suppression of intestinal epithelium angiopoietin-related protein 4 = inhibition of lipoprotein lipase § Lead to downstream accumulation of triglyceride in hepatic parenchyma and adipocytes ○ Chronic EtOh disturbs gut microbiome ○ Particular murine colonic commensals (e.g., Helicobacter hepaticus ) promote the development of hepatocellular carcinoma. ○ Patients with cirrhosis have a substantially altered microbiome, including community-wide changes at multiple taxonomic levels, with 1enrichment of Proteobacteria and Fusobacteria (phyla) and of Enterobacteriaceae, Veillonellaceae, and Streptococcaceae (family).

Colonic Micobiota and IBD

○ Host polymorphisms in bacterial sensor genes such as NOD2 and TLR4 ○ Exposure to antibiotics early in childhood has shown increased risk for Crohn's disease § Microbial diversity is diminished in Crohn's □ Decreased gut microbiome resilience □ adherent-invasive Escherichia coli as a candidate pathogen in ileal Crohn's disease, given its ability to adhere to and invade epithelial cells and to replicate within macrophages. ® Specific bacteria among the Enterobacteriaceae may synergize with a disordered microbiome to increase the risk of ulcerative colitis. ® Among twins discordant for ulcerative colitis, those affected had significantly reduced bacterial diversity but increased Actinobacteria and Proteobacteria. Patients with Crohn's disease have overrepresentation of Enterococcus faecium and several Proteobacteria compared with controls. ® The microbial patterns observed for the conditions described are preliminary, and their specificity and causal direction have not been established.

Summary of hormonal regulation with mitochondrial ATP production from carbohydrate sources

○ Increase in blood glucose levels ○ Signals pancreatic beta cells to release insulin § Insulin binds to its tyrosine kinase receptor □ Receptor autophosphorylation ® IRS phosphorylation ◊ Phosphorylation of PI3 kinase } PKB (Akt) phosphorylated - Activation or inhibition of certain TFs w End goal: transport of glucose into the cell using GLUT4 transporters then using glucose for ATP via cellular respiration and storage of glucose as glycogen in liver and skeletal muscle

Pivotal features of abdominal pain

○ Location: epigastrium § Common causes: PUD, biliary colic, and pancreatitis ○ Time course: multiple acute episodes § Many diseases do this but the only ones in the epigastrium are pancreatitis and biliary colic § PUD is also common in the epigastrium but pain is more chornic than acute ○ Type of pain § Crampy quality- "Colicky" § Suggets obstruction of hollow viscera (biliary, bowel or nephro)

Sironolactone MOA

○ MOA: Competes with aldosterone for receptor sites in the distal renal tubules, increasing sodium chloride and water excretion while conserving potassium and hydrogen ions; may block the effect of aldosterone on arteriolar smooth muscle as well

Furosemide MOA

○ MOA: inhibits reabsorption of sodium and chloride in the ascending loop of Henle and proximal and distal renal tubules, interfering with the chloride-binding cotransport system, thus causing increased excretion of water, sodium, chloride, magnesium, and calcium

Define glucagon

○ Major insulin counterregulatory hormone ○ Decreased in response to a carbohydrate meal and elevated during fasting ○ Concentration in blood increases as circulating levels of glucose fall § Promotes glucose production via glycogenolysis and gluconeogenesis § Increased levels of glucagon relative to insulin also stimulate mobilization of fatty acids from adipose tissue ○ Synthesized as prohormone and cleaved into mature glucagon in storage vesicles ○ Released and regulated through changes in the level of insulin and glucose on the alpha cells in the pancreatic islets of Langerhans ○ Binds to receptor located on plasma membrane of target cells § Stimulates cAMP □ Activates PKA ® Phosphorylates key regulatory enzymes, that acitvates some and inhibits others

Type II Diabetes Enviromental Factors

○ Most impt = obesity § Particularly central/visceral obesity § Greater than 80% of individuals with type 2 DM are obese □ Incidence of DM worldwide has risen in proportion with obesity § Contribues to cardinal metabolic abnormalities of diabetes and to insulin resitance early in disease □ Even modest weight loss through dietary modifications can reduce insulin resistance and improve glucose tolerance ○ Sedentary lifestyle § Typified by lack of exercise § Independent of obseity § Weight loss and exercise usually have additive effects on improving insulin sensitivity □ Often first non-pharm measures attempted in patients with milder type 2 diabetes

Cystic Fibrosis: Function of CFTR gene

○ Normal CFTR function § 148 AA polypeptide has two transmembrane domains, two cytoplasmic nucleotide binding domains (NBDs) and a regulatory domain that contains phosphorylation sites for protein kinase A and C. □ Two transmembrane sites form a channel for Cl- to pass through § Activated by agonist induced increases in cAMP which then leads to activation of protein kinase A that phosphorylates R domain § ATP binding and hydrolysis occurs at NBD ○ CFTR regulates multiple additional ion channels and cellular processes □ Primarily through NBDs □ Outward rectified Cl- channels, inwardly rectified K+ channels, epithelial sodium channel (ENaC), gap junction channels, cellular processes involved in ATP transport and mucus secretion ® ENaC interaction with CFTR is most pathologically relevant to CF ◊ ENaC is on the apical surface of exocrine epithelial cells, responsible for Na+ uptake from luminal fluid, makes luminal fluid hypotonic ◊ Inhibited by normally functioning CFTR ◊ In CF, ENaC activity increases, leading to increased Na+ uptake across the apical membrane } Exception: human sweat ducts have decrease in ENaC activity due to CFTR mutation. Results in hypertonic luminal fluid with a lot of sweat NaCl. Salty sweat

Cholesterol Synthesis

○ Occurs in the cytoplasm and utilizes NADPH for reduction reactions § NADPH is produced from hexomonophosphate (HMP) shunt pathway ○ All of it's 27 carbons derived from acetyl-CoA § Sources of acetyl-CoA = beta-oxidation of FA, oxidation of ketogenic AA, and PDH reaction ○ Four stages § Stage 1 □ Leads to production of mevalonate intermediate ® Mevalonate is rate limiting step ® Two acetyl-CoAs condense to from acetoacetyl-CoA --> HMG-CoA ® HMG-CoA reductase then reduces HMG-CoA to mevalonate

Gastric Cell Types

○ Oxyntic/parietal glands in the gastric fundus contain variety of cell types § Parietal cells □ Specialized to secrete acid and intrinsic factor § Chief cells □ Store pepsinogen in apical granules that can release their contents via exocytosis § Mucus cells □ Secrete mucous LOL ® No shit sherlock □ Turnover over 1-3 days § Endocrine cells □ Enterochromaffin-like (ECL) cells ® Synthesize histamine via the action of histidine decarboxylase and histidine § D cells □ Oppose parietal cells □ Contain inhibitory paracrine, somatostatin § Mucus neck cells □ Contain stem cells

Cystic Fibrosis: rational and purpose for pancreatic enzyme supplementation

○ Pancreatic enzyme replacement is the mainstay of treatment for exocrine pancreatic insufficiency. Because gastric acid decreases enzyme activity, H 2 -blockers (e.g., ranitidine 150 mg twice daily in children weighing >30 kg and in adults) or proton pump inhibitors (e.g., lansoprazole 30 mg orally once daily in children weighing >30 kg and in adults) are often used. Children and adolescents frequently use multiple nutritional supplements every day to maintain weight. Fat-soluble vitamin replacement therapy is necessary in most patients. Between 10% and 20% of patients may require gastrostomy feeding to aid growth or maintain weight.

Glycogen synthesis

○ Requires formation of alpha 1,4 glycosidic bonds link glucose resides in long chains and formation of alpha 1,6 branch ever 8-10 residues § Most synthesis occurs through lengthening of the polysaccrhide chains of a preexisting glycogen molecule in which the reducing end of the glycogen is attached to the protein glycogenin □ Glycosyl residues are added from UDP glucose to non reducing ends of the chain by glycogen synthase § When chain reaches 11 residue length, a 6-8 length piece is cleaved by amylo-4,6 transferase (branching enzyme) and reattached to a glycosyl until by an alpha 1,6 bond □ Both chains length until long enough to produce new branches ○ Branching of residues has 2 olds § Increased sites for synthesis and degradation § Enhancing solubility of molecule ○ Synthesis of new primer § Glycogenin glycosyl antes itself by attached the glycosyl resides of UDP glucose to the hydroxyl side chain of a serine residue in the protein □ Protein extends the carbohydrate chain until the glycosyl chain is long enough to serve as a substrae for glycogen synthase

3 forms of Vitamin A

○ Retinyl ester: storage form § Retinol- transport form, bound to protein (RBP, retinol binding protein in blood) ○ Retinal- rhodopsin and cone opsin, vision ○ Retinoic acid (COOH group)- maintain epithelium Beta-carotene- plant form of Vitamin A- carrots

Functions of saliva

○ Saliva § Primary function is to lubricate ingested food and form a bolus that can be swallowed § Solubilize molecules that can be diffused to taste buds on the tongue □ Importance: more gastric secretion when ingesting food a person actually likes § Host defense □ Contains antibacterial substances that protect oral cavity § Slightly alkaline □ Clears refluxed gastric acid from esophagus § Aids in speech as well Constituent- Functions Water- Facilitates taste and dissolution of nutrients; aids in swallowing and speech Bicarbonate- Neutralizes refluxed gastric acid Mucins- Lubrication Amylase- Starch digestion Lysozyme, lactoferrin, IgA- Innate and acquired immune protection Epidermal and nerve growth factors- Assumed to contribute to mucosal growth and protection

Colonic Microbiota and Colorectal cancer

○ Synthesis of short chain FA, in particular butyrate, may induce apoptosis, cell cycle arrest, and differentiation through Wnt signaling ○ Microbes may also be genotoxic to colonic epithelial cells, inducing polyploidy ○ May elicit host response § Th17 ○ antibiotic administration § altering the composition of the colonic microbiota, affecting expression of host genes involved in cell cycle regulation, and reducing epithelial proliferation ○ epigenetic phenomena § such as DNA hypermethylation, have been demonstrated to play an important role in the development of colorectal cancers through microsatellite instability and the sessile serrated adenoma pathway. § It is possible that interactions with the microbiome may affect epigenetic pathways for colonic carcinogenesis.

Neuro Vascular supply of colon

○ The arterial supply to the ascending colon and right colic flexure is from branches of the SMA, the ileocolic and right colic arteries (Figs. 2.54 and 2.55; Table 2.10). These arteries anastomose with each other and with the right branch of the middle colic artery, the first of a series of anastomotic arcades that is continued by the left colic and sigmoid arteries to form a continuous arterial channel, the marginal artery (juxtacolic artery). This artery parallels and extends the length of the colon close to its mesenteric border. ○ The nerve supply to the ascending colon is derived from the superior mesenteric nerve plexus. • Transverse Colon ○ The arterial supply of the transverse colon is mainly from the middle colic artery, a branch of the SMA. However, the transverse colon may also receive arterial blood from the right and left colic arteries via anastomoses, part of the series of anastomotic arcades that collectively form the marginal artery (juxtacolic artery). ○ The nerve supply of the transverse colon is from the superior mesenteric nerve plexus via the periarterial plexuses of the right and middle colic arteries (Fig. 2.56C). These nerves transmit sympathetic, parasympathetic (vagal), and visceral afferent nerve fibers. • Descending Colon and Sigmoid Colon ○ The arterial supply of the descending and sigmoid colonis from the left colic and sigmoid arteries, branches of the inferior mesenteric artery. Thus, at approximately the left colic flexure, a second transition occurs in the blood supply of the abdominal part of the alimentary canal: the SMA supplying blood to that part orad (proximal) to the flexure (derived from the embryonic midgut), and the IMA supplying blood to the part aborad (distal) to the flexure (derived from the embryonic hindgut). The sigmoid arteries descend obliquely to the left, where they divide into ascending and descending branches. The superior branch of the most superior sigmoid artery anastomoses with the descending branch of the left colic artery, thereby forming a part of themarginal artery. Venous drainage from the descending colon and sigmoid colon is provided by the inferior mesenteric vein,flowing usually into the splenic vein and then the hepatic portal vein on its way to the liver. ○ The sympathetic nerve supply of the descending and sigmoid colon is from the lumbar part of the sympathetic trunk via lumbar (abdominopelvic) splanchnic nerves, the superior mesenteric plexus, and the periarterial plexuses following the inferior mesenteric artery and its branches. ○ The parasympathetic nerve supply is from the pelvic splanchnic nerves via the inferior hypogastric (pelvic) plexus and nerves, which ascend retroperitoneally from the plexus, independent of the arterial supply to this part of the gastrointestinal tract. Orad to the middle of the sigmoid colon, visceral afferents conveying pain sensation pass retrogradely with sympathetic fibers to thoracolumbar spinal sensory ganglia, whereas those carrying reflex information travel with the parasympathetic fibers to vagal sensory ganglia. Aborad to the middle of the sigmoid colon, all visceral afferents follow the parasympathetic fibers retrogradely to the sensory ganglia of spinal nerves S2-S4

Vitamin C

○ Vitamin C: water soluable antioxidant ® Resembles monosaccharide, most animals can synthesis in minor pathway of carbohydrate metabolism ® Function: reducing agent and Schneider of free radicals □ Surpesses formation of carcinogenic nitrosamines from dietary nitrite and nitrate in the GI tract, protect lipoprotein from oxidative damage ® Many iron and copper containined enzymes require absorbed acid to keep metal in reduced state □ Hydroxylatio Of prolly and Lysol resides in procollagen reuiqrws ascorbate - impairment in reaction —> prominent connective tissue abnormalies of scurvy □ Carnitine synthesis: require 2 Fe2+ containing ascorbate depends oxygenates ® Deficiency may continue to fatugyre and lassitude of scurvy □ Norepinephrine (noradrenaline ) requires ascorbate depends copped enzyme domaine beta hydroxylase □ Bile acid synthesis is regulated at the level of ascorbate dependent enzyme 7alpha-hydropylase ® Dietary can only be absorbed max 1-2 grams per day ® Good sources: fresh fruits and Vega tables □ Not very stable under neutral or alkaline controls, easily oxidized to inactive products by boiling in Porsche of oxygen and catalytic amounts of heavy metal ions

Define Abdominal distention and its presentation

○ may develop from excess air or fluid in the abdomen ○ Excess air may occur with bowel obstruction or bowel perforation (free air). § Excess fluid may be seen in patients with ascites or hemorrhage. ○ Percussion and shifting dullness can usually distinguish excess air from fluid in such patients.