Digestion Exam 2

Regulation of Bile Secretion

-CCK: Contraction of the gall bladder, Relaxation of the sphincter of Oddi-> push bile out -SECRETIN: stimulates ion & water secretion by the bile ducts -Ach: Contraction of the gall bladder, Basically, a ParaNS response

Pancreatitis symptoms

-The most common initial symptom is severe epigastric and abdominal pain that radiates to the back -Abdominal distention accompanied by hypoactive bowel sounds is common -loss of a large volume of fluid into the abdominal cavity. -Tachycardia, hypotension, cool and clammy skin, and fever -Signs of hypocalcemia may develop, probably as a result of the precipitation of serum calcium in the areas of fat necrosis. -Mild jaundice may appear after the first 24 hours because of biliary obstruction.

Regulation of Bile Secretion -How to know to go to duodenum or be stored?

-When eating-> bile comes out-> goes to duodenum -Between meals-> sphincter of Oddi is closed-> bile gets stored During the "interdigestive" periods, the gall bladder can fill because it is relaxed (SNS-> β2) and the sphincter of Oddi is closed

amine groups cleaved from the amino acids are converted into ?

-the amine groups cleaved from the amino acids are converted into ammonia (NH3) or ammonium ions (NH4+), which are then converted into urea.

Liver functions

1. Lipid metapilism- forms lipoprotiens-> LDL and HDL -Made in the liver -Fatty liver- when liver cant process fats 2. Cholesterol Synthesis- An important enzyme in liver hepatocytes required for endogenous cholesterol synthesis is HMG-CoA reductase. -Inhibited by "statins"- lipitor, may take to lower cholesterol 3. Eliminates cholesterol-The only way the body can eliminate excess cholesterol is via the BILE 4. Ketogenesis (formation of ketones): Primarily occurs in fasting states or poorly controlled type I diabetes mellitus 5. Hormone Metabolism- The liver degrades all of the steroid hormones, as well as T3 and T4 6. Iron Metabolism & Storage- Iron stored in the liver as ferritin 7. Vitamin Storage- The liver stores large quantities of vitamins A, B12, and D 8. Drug Detoxification & Metabolism 9. Vitamin D activation 10. Plasma Protein Synthesis 11. Synthesis of Blood Clotting Factors- majority come from liver 12. Makes bile

PORTAL TRIAD -lobule diagram

1. Portal vein (branch of) 2. Hepatic artery (branch of) 3. Bile duct 4. ...... lymphatic vessel

Three factors appear to be involved in the formation of cholesterol stones:

1. bile stasis (sludge), as stones form in the bile that is sequestered in the gall bladder rather than the bile that is flowing in the bile ducts 2. supersaturation of bile with cholesterol -- cholesterol is very insoluble in bile, and it is maintained in solution in micelles only at certain concentrations of bile salts & lecithin 3. inflammation of the gallbladder (cholecystitis)

Acute cholecystitis

Acute cholecystitis refers to a syndrome of right upper quadrant pain, fever, and leukocytosis associated with gallbladder inflammation that is usually related to gallstone disease. The pain may radiate to the right shoulder or back. Characteristically, acute cholecystitis pain is steady and severe. Associated complaints may include nausea, vomiting, and anorexia.

Pancreatitis -acute -how to diagnose

Acute pancreatitis is a severe, life-threatening disorder associated with the escape of activated pancreatic enzymes into the pancreas and surrounding tissues. Small amounts of pancreatic digestive enzymes normally leak into the circulation, but in acute pancreatitis, the circulating levels of the digestive enzymes rise markedly. Measurement of the plasma pancreatic amylase or pancreatic lipase is therefore of value in diagnosing problems associated with inflammation and necrosis of pancreatic acinar cells.

Protein Metabolism -Amino acid degradation occurs where? -begins with?

Amino acid degradation occurs almost entirely in the liver, and it begins with a process known as deamination, which is the removal of amine (- NH2) groups from the amino acids.

As free bilirubin passes through the liver

As free bilirubin passes through the liver, it is released from albumin & moved into hepatocytes which perform the following functions: 1. Uptake of bilirubin from the circulation 2. Conjugation of bilirubin 3. Excretion of bilirubin into the bile

Lymphatics and the Liver - the liver is a prime site for the ?

Because of its portal blood supply and extensive lymphatic circulation, the liver is a prime site for the spread of cancerous cells (metastasis) from elsewhere in the body, especially from the GI tract, breast and lung.

Lymphatics and the Liver

Because substances in the plasma move freely into the spaces of Disse, the liver MUST have an extremely high lymph flow to prevent accumulation of interstitial fluid. If pressure rises in the portal veins & sinusoids, excessive amounts of fluid begin to transude into the lymph and to leak through the outer surface of the liver capsule directly into the abdominal cavity producing ASCITES.

Bile Functions

Bile has 2 important functions: 1. Bile provides the sole excretory route for many solutes that are not excreted by the kidneys 2. Secreted bile salts and lecithin are required for normal lipid digestion and absorption in the small intestine

Gall Bladder Plumbing

Bile is stored until stimulation of gall bladder contractions expels the bile back through the cystic duct into the common bile duct and, via the sphincter of Oddi, through Papilla of vater into the duodenum

Why prefer conjugated name

Bilirubin made by spleen is not very soluble (unconjugated)- Not free because attached to hemoglobin -once conjugated-> conjugated bilirubin

Chronic cholecystitis

Chronic cholecystitis is the term used by the pathologist to describe chronic inflammatory cell infiltration of the gallbladder seen on histopathology. It is almost invariably associated with the presence of gallstones and is thought to be the result of mechanical irritation or recurrent attacks of acute cholecystitis leading to fibrosis and thickening of the gallbladder.

CP450 Enzyme Types chart columns

CYP- liver enzyme Substrates- drug enzyme mtabolizes Inducer- increases enzyme activity (breaks down substrate quickly) Inhibitor- Drug drug interaction, inhibits the enzymes-> cant break down the substrate (build up of substrate- lower dose)-Results in decreased metabolic activity of CP450 enzymes leading to decreased metabolism of drugs

Cystic Fibrosis -Characteristics include -Clinical manifestations include: -How to diagnose

Characteristics include malfunction of exocrine glands, resulting in increased viscosity of mucus and increased chloride concentration in sweat and tears Clinical manifestations include: • Chronic pulmonary disease • Pancreatic insufficiency • Meconium ileus The sweat test is an important diagnostic procedure

Gallstones -Risks

Cholelithiasis (i.e. - the presence of gallstones) is a common condition. Its incidence increases with age, as 20% of women and 5% of men between the ages of 50 and 65 have gallstones. In the US and Europe, 90% of the stones are cholesterol stones.

Cholesterol

Cholesterol Hepatic synthesis of bile acids accounts for the majority of cholesterol breakdown in the body. In humans, roughly 500 mg of cholesterol are converted to bile acids and eliminated in bile every day. Some cholesterol is also eliminated in the bile as a waste product.

Conjugation reactions -Most important conjugation reaction. -Bilirubin

Conjugation reactions are designed to make metabolites more polar or hydrophilic, sometimes after they've been created by P450 enzymes. These reactions involve an endogenous substrate, such as glucuronic acid, glutathione, acetyl-CoA or an amino acid, being added to a metabolite. Glucuronidation is the most common and the most important conjugation reaction. Conjugation involves attaching glucuronic acid to bilirubin in a reaction catalyzed by the enzyme glucuronyl transferase. Conjugated bilirubin is much more water- soluble than free or unconjugated bilirubin

Deamination reactions require

Deamination reactions require a set of enzymes known as aminotransferases or transaminases: • SGOT (serum glutamate- oxaloacetate transaminase) also called aspartate transaminase or AST • SGPT (serum glutamate-pyruvate transaminase) also called alanine transaminase or ALT AST & ALT have a dual purpose, as they are also used to synthesize non-essential amino acids within liver hepatocytes. -High blood levels of ALT (SGPT) and AST (SGOT) can be indicative of liver disease.

Pancreas

Endocrine pancreas-> production of insulin & glucagon; plasma glucose regulation Exocrine pancreas-> production of pancreatic juice • source of HCO3- to neutralize gastric acid • source of many digestive enzymes

Pancreatic Juice -pH -how much is secreted?

HCO3- and the digestive enzymes are secreted by the pancreas as pancreatic juice (pH 7.6-8.2). Pancreatic juice travels from the pancreas to the duodenum via the main pancreatic duct. About 1500 ml of pancreatic juice is secreted per day. Bile and intestinal juices are also neutral or alkaline, and these three secretions neutralize the gastric acid, raising the duodenal contents to 6.0-7.0.

Types of Bile Acids -generated by

Hepatocytes synthesize two primary bile acids: cholic acid and chenodeoxycholic acid A portion of the primary bile acids is converted by intestinal bacteria into two secondary bile acids: deoxycholic acid and lithocholic acid All 4 are bile acids- first 2 made in liver, last 2 made by bacteria

Jaundice In neonates

In neonates, physiologic jaundice of the newborn is usually a harmless condition, lasting no longer than 2 weeks after delivery. The hepatic machinery excreting bilirubin does not fully mature until about two weeks of age; hence, it is common for newborns to develop transient and mild hyperbilirubinemia.

In pancreatitis, these enzymes cause -most cases result from

In pancreatitis, these enzymes cause fat necrosis, or autodigestion, of the pancreas and produce fatty deposits in the abdominal cavity with hemorrhage from the necrotic vessels. -Although a number of factors are associated with the development of acute pancreatitis, most cases result from gallstones (stones in the common bile duct) or alcohol abuse.

Jaundice -pre-hepatic (hemolytic) jaundice, -intrahepatic jaundice -post-hepatic (obstructive) jaundice,

In pre-hepatic (hemolytic) jaundice, the liver is not diseased, but RBCs are hemolyzed so quickly that hepatocytes cannot "keep pace" and excrete the bilirubin fast enough In intrahepatic jaundice, the liver (due to cirrhosis, hepatitis, etc.) is the reason why plasma bilirubin levels rise In post-hepatic (obstructive) jaundice, obstruction of the bile ducts (e.g. - by a gallstone) commonly occurs

In serious liver disease ? A build-up of urea ?

In serious liver disease (liver cant generate urea), ammonia can often accumulate in the blood and lead to a state called hepatic coma or hepatic encephalopathy. After its formation, urea diffuses from liver hepatocytes into the body fluids and is excreted by the kidneys. A build-up of urea in the blood can lead to a state of azotemia or uremia, in which high levels of urea become toxic to a variety of tissues. This is often a symptom of renal disease or failure. Why would someone in renal failure be put on a low-protein diet? -because urea is direct result of breaking down protein

Pancreatitis -biliary tract obstruction, pancreatic duct obstruction or biliary reflux does what? -Alcohol? -Acute pancreatitis also is associated with?

In the case of biliary tract obstruction due to gall stones, pancreatic duct obstruction or biliary reflux is believed to activate the enzymes in the pancreatic duct system. The precise mechanisms whereby alcohol exerts its action are largely unknown. Alcohol is known to be a potent stimulator of pancreatic secretions, and it is also is known to cause contraction of the sphincter of Oddi of the pancreatic duct. Acute pancreatitis also is associated with hyperlipidemia, hyperparathyroidism, infections (particularly viral), abdominal and surgical trauma, and drugs such as steroids and thiazide diuretics.

Inside some of the sinusoids are... -bile canaliculi

Inside some of the sinusoids are hepatic macrophages called Kupffer cells, which remove debris such as bacteria and worn-out blood cells Tiny ducts called bile canaliculi run parallel to the sinusoids and drain bile produced by the hepatocytes

Other Bile Constituents

Ions (e.g., Na+, K+, Ca+2, Cl-, HCO3-) and water are secreted into bile by epithelial cells lining the bile ducts. Other waste products-> lipophilic drugs and metabolites, antigen-antibody complexes, etc.

Microanatomy of the Liver

Lobules consists of rows upon rows of hepatocytes -- blood flows past hepatocytes via sinusoids from branches of the hepatic portal vein to the central vein of each lobule

The major types of plasma proteins are

Majority come from liver • albumin • globulin • fibrinogen Essentially all the albumin and fibrinogen, as well as 50-80% of the globulin are formed in the liver. The remainder of the globulins are formed almost entirely in the lymphoid tissues. They are mainly gamma globulins that constitute the antibodies used in the immune system. It's important to note that these are NOT the only proteins found in the blood. Other proteins such as hormones

gallstones symptoms.

Many persons with gallstones have no symptoms. Gallstones cause symptoms when they obstruct bile flow. Small stones (e.g. -- <8 mm in diameter) may pass into the common bile duct, producing symptoms of indigestion and biliary colic. Larger stones are more likely to obstruct flow and cause jaundice.

Cystic Fibrosis -Most common population -Results from

Most common lethal genetic diseases among whites Results from a defect in Cl- channels that is caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene

First Pass Effect

Most drugs absorbed from the GI tract enter the portal circulation and encounter the liver before they are distributed into the general circulation

Do We Need a Gall Bladder?

No The periodic discharge of bile from the gall bladder aids digestion but is not essential for it. Cholecystectomized patients maintain good health and nutrition with a constant slow discharge of bile into the duodenum, although eventually the common bile duct becomes somewhat dilated, and more bile tends to enter the duodenum after meals than at other times.

Laparoscopic Cholecystectomy

Performed as an outpatient procedure and done with general anesthesia, laparoscopic cholecystectomy requires just four small incisions for a cannula (narrow tube-like instrument) near the belly-button, laparoscope (telescope) and tiny camera and other cannulas used to separate the gallbladder from what it is attached to and remove it. Incisions are closed with stitches or surgical tape. This procedure generally has less pain than open surgery, faster recovery time and just four small incisions instead of one 5 to 7 inch incision in abdomen.

More Pancreatic Juice -Proteases of the pancreatic juice are secreted as? -Enterokinase difficienty

Proteases of the pancreatic juice are secreted as inactive "pro-enzymes". Trypsinogen is converted to the active enzyme trypsin by the brush border enzyme enterokinase (also known as enteropeptidase) when the pancreatic juice enters the duodenum. Trypsin converts chymotrypsinogen into active chymotrypsin, procarboxypeptidase into active carboxypeptidase and proelastase into active elastase. -Enterokinase deficiency can occur as a congenital abnormality, which leads to protein malnutrition. Cant activate protein. Need AA suppliments.

Hepatobiliary Plumbing

R/L hepatic ducts-> Common hepatic duct-> Common bile duct

Releasing trypsin in its active form in the pancreas can lead to

Releasing trypsin in its active form can lead to a chain reaction of producing several active enzymes capable of digesting the pancreas. Hence, pancreatic tissue normally contains trypsin inhibitors.

HORMONAL Regulation of Pancreatic Juice Secretion

Secretion of pancreatic juice is primarily under hormonal control. Secretin acts on the pancreas to cause copious secretion of a very alkaline pancreatic juice that is rich in HCO3- and low in enzymes. CCK, on the other hand, stimulates production of pancreatic juice rich in enzymes and low in HCO3-.

NEURAL Regulation of Pancreatic Juice Secretion

Stimulation of the parasympathetic fibers within the vagus nerves also causes secretion of a small amount of pancreatic juice rich in enzymes, but this influence is much less potent than CCK. There is some evidence for vagally-mediated conditioned reflex secretion of pancreatic juice in response to the sight or smell of food.

Biliary colic -caused by

Stone in gall blader and eat a meal- gall blader contracts response to CCK-> pain Biliary colic is usually caused by the gallbladder contracting in response to hormonal or neural stimulation, usually due to a fatty meal, forcing a stone (or possibly sludge or microlithiasis) against the gallbladder outlet or cystic duct opening, and leading to increased intra-gallbladder pressure and right upper quadrant pain.

Storage of glycogen allows -Liver cells can typically store how much glycogen? -muscles?

Storage of glycogen allows the liver to remove excess glucose from the blood, store it, and then return it to the blood when the blood glucose concentration falls Liver cells can typically store up to 8% of their weight as glycogen (100-120 g in an adult). In the muscles, glycogen is found in a much lower concentration (1-3% of the muscle mass), but the total amount exceeds that in liver.

Gall Bladder functions

Storage, NOT Production of Bile Stores and modifies bile Bile is secreted by hepatocytes into the bile canaliculi, from which it flows in the right & left hepatic ducts, common hepatic duct and then into the gallbladder via the cystic duct

curative treatment for exocrine pancreatic cancer

Surgical resection is the only potentially curative treatment for exocrine pancreatic cancer, but because of the late presentation of the disease, only 15-20% of patients are candidates for pancreatectomy. Furthermore, the prognosis of pancreatic cancer is poor even in those with potentially resectable disease. The five-year survival following pancreatico- duodenectomy is only about 25-30% for node-negative and 10% for node- positive tumors.

Blood Urea Nitrogen (BUN) -Normal BUN -Elevated BUN occurs with

Test to see how much urea levels there are Normal BUN has a range of 5-26 mg/dL in the adult Elevated BUN can occur with: • impaired renal function • increased protein intake or catabolism • GI bleeding (due to intestinal flora creating nitrogenous waste) • dehydration

The basic purpose of drug metabolism

The basic purpose of drug metabolism in the body is to make drugs less active and more water soluble and thus more readily excreted in the urine or bile.

Pancreatic Cancer usually refers to -Most common symptoms

The commonly used term "pancreatic cancer" usually refers to a ductal adenocarcinoma of the pancreas (including its subtypes). More than 95% of malignant neoplasms of the pancreas arise from the exocrine elements and are referred to as exocrine pancreatic cancers. The most common presenting symptoms in patients with exocrine pancreatic cancer are pain, jaundice, and weight loss. pancreatic head tumors more often present with jaundice, steatorrhea (fatty stool), and weight loss.

Bile Synthesis steps

The formation of bile occurs in 3 discrete steps: 1. The hepatocytes actively secrete bile into the bile canals (canaliculi) 2. Intrahepatic and extrahepatic ducts not only transport this bile, but the cells that line these ducts (cholangiocytes) also secrete a watery, HCO3-- rich fluid These first 2 steps may produce ~900 ml/day of so- called "hepatic bile" 3. Between meals, approx. 1⁄2 the hepatic bile is diverted to the gall bladder, which stores the bile and removes salts and water -> The result is that the gall bladder concentrates the key remaining solutes—bile salts, bilirubin, cholesterol and lecithin—by 10-20 fold. So, during meals, the bile that reaches the duodenum is a mixture of relatively "dilute" hepatic bile and "concentrated" gall bladder bile.

The initial presentation of pancreatic cancer depends on...?

The initial presentation of pancreatic cancer varies according to tumor location. Approximately 60-70% exocrine pancreatic cancers are localized to the head of the pancreas, while 20-25% are in the body/tail and the remainder involve the whole organ. Compared to tumors in the body and tail of the gland, pancreatic head tumors more often present with jaundice, steatorrhea (fatty stool), and weight loss.

Bile Acids vs. Bile Salts

The liver conjugates the bile acids with the amino acid glycine or taurine to form bile salts-> this helps make them AMPHIPATHIC at duodenal pH

The liver consists of

The liver consists of the right, left, quadrate and caudate lobes which in turn are composed of functional units called lobules

Drug Detoxification & Metabolism -Why occurs in the liver?

The liver is by far the most important organ involved in drug metabolism; most drug metabolism occurs in the liver because it has many enzyme systems (the cytochrome P450 system being the most important)

Recipe for Bile

The organic constituents of bile are: • bile salts (~50%) • phospholipids (~40%) • cholesterol (~4%) • bile pigments such as bilirubin (~2%) Bile also contains electrolytes and water, which are secreted by cells lining the bile ducts.

Liver Sinusoidal Blood Flow fenestrations

The sinusoids are lined by a fenestrated endothelium. This endothelium has NO underlying basement membrane. Therefore, the fenestrations permit blood plasma to wash freely over the exposed surfaces of the hepatocytes in the SPACE OF DISSE (perisinusoidal space). Sinusoidal blood flow is always TOWARDS the central vein.

Within each lobule

Within each lobule, HEPATOCYTES are arranged into HEPATIC CORDS separated by adjacent sinusoids

Ascites

The word ascites is of Greek origin (askos) and means bag or sac. Ascites describes the condition of pathologic fluid accumulation within the abdominal cavity. Healthy men have little or no intraperitoneal fluid, but women may normally have as much as 20 mL depending on the phase of the menstrual cycle.

Phospholipids -most common

There are a variety that can be find in bile-> most common is LECITHIN Recall that phospholipids are also amphipathic -Need bile salts and phospholipid to digest lipids

Cytochrome P450 Enzymes / Phase I Enzymes

These enzymes are most predominant in the liver but can also be found in the intestines, lungs and other organs. These cytochrome P450 enzymes are designated by the letters "CYP" followed by an Arabic numeral, a letter and another Arabic numeral (e.g., CYP2D6). Each enzyme is termed an isoform since each derives from a different gene.

cholecystitis -Complications

Wall of gall bladder is inflammed -Right upper quadrant -Complications — Left untreated, symptoms of cholecystitis may abate within 7 to 10 days. However, complications can occur at alarmingly high rates, so urgent plans for treatment must be entertained in patients with suspected acute cholecystitis. The most common complication is the development of gallbladder gangrene (up to 20% of cases) with subsequent perforation (2% of cases)

Bilirubin -Types

Waste product of hemoglobin degradation -comes from liver, spleen, bone marrow Free bilirubin OR unconjugated bilirubin (preferred) OR indirect bilirubin Free bilirubin is transported in the blood attached to albumin Conjugated bilirubin (preferred) OR direct bilirubin

Jaundice

When bilirubin accumulates in the blood (hyperbilirubinemia), the skin, sclera of the eyes and mucous membranes turn yellow. This yellowness is known as jaundice.

Islets of langerans

Where alpha and beta cells are (endocrine)-5% -Surrounded by pancreatic acini-> produce pancreatic juice (exocrine)- 95%

all urea formed in the human body is synthesized in ?

all urea formed in the human body is synthesized in the liver.

Worst place for stone

at the end of the main pancreatic duct- pancreas juice cant go anywhere- ducts can rupture -> pancreatitis

Are there other types of stones

yes others besides cholesterol (majority) -Black pigment stones- too much bili -Brown pigment stones- infections (rare)

Cholelithiasis Risk Factors

• Age • gender -- a higher prevalence of gallstones has been observed in women of all age groups • pregnancy - sex hormones may cause bile to become supersaturated with cholesterol • oral contraceptive use • family history/genetics (especially in Native Americans) • obesity -- a well-established risk factor for the development of cholesterol gallstones, • rapid weight loss -- the mechanism by which this occurs in incompletely understood • diabetes mellitus -- not well understood, but two possible contributing factors are hyperlipidemia and autonomic neuropathy leading to biliary stasis due to gall bladder hypomotility

The major risk factors for pancreatic cancer are:

• Cigarette smoking • High body mass and lack of physical activity • History of chronic pancreatitis A role for familial aggregation and/or genetic factors is suggested by the fact that 5- 10% of patients with pancreatic cancer have a first degree relative with the disease

The functions of the major classes of plasma proteins include:

• exertion of oncotic pressure across capillary walls, which in turn, prevents edema (albumin) • supplying approximately 15% of the buffering capacity of the blood (albumin) • transport of thyroid, adrenocortical, gonadal and other hormones (albumin & globulin) • acting as carriers for metals, ions, fatty acids, amino acids, bilirubin, enzymes and drugs (albumin & globulin) • participating in blood clotting (fibrinogen) • participating in immune responses (gamma-globulin)

Enzymes included in the pancreas juice:

• pancreatic amylase • pancreatic lipase • colipase • trypsinogen • chymotrypsinogen • procarboxypeptidase (A/B) • proelastase • ribonuclease • deoxyribonuclease