GGR Wk 2 Yr 2 - Jaundice/Abnormal Liver Functions

Identify medications that can lead to drug induced liver disease.

-Acetaminophen -37% → a form of intrinsic drug-induced liver injury (DILI) -Antibiotics, NSAIDs, antiepileptic - 13% -Two types of drug induced liver injury (DILI) -->Intrinsic >>>>Predictable >>>>Dose-related -->Idiosyncratic >>>>Occurs less frequently >>>>Less consistent dose-toxicity relationship >>>>Presentation is variable

Identify the main functions of the liver.

-Bile production: produced in the hepatocytes, liver produces 700-1200mL bile/day -Bilirubin conjugation -->RBCs broken down into heme and globin -->Unconjugated bilirubin (indirect) >>>>Bilirubin in plasma attaches to albumin >>>>Lipid soluble >>>>Absorbed into hepatocytes >>>>**Elevated with hemolysis (increased RBC destruction) or problems with conjugation process in liver -->Conjugated bilirubin (direct) >>>>Conjugated in the hepatocytes >>>>Is now water soluble, excreted in bile >>>>**Elevated with hepatobiliary conditions -->Once in the duodenum bile undergoes enterohepatic circulation >>>>Gut bacteria converts bile components into urobilinogen → excreted into stool/small amount in urine or gets transported back to liver (majority) -Lipid, protein, carbohydrate management -Plasma protein synthesis -Detoxification and drug metabolism -Vitamin and mineral storage -Immune function

Describe the pathophysiology of neonatal jaundice.

-Jaundice occurs when an infant is hyperbilirubinemia -Bilirubin is a byproduct of RBC breakdown -Bilirubin pigments are deposited in the skin and mucous membranes, causing the classic yellow or jaundiced appearance of the skin Statement of the problem -In utero, baby is relatively hypoxic -Hypoxia triggers production of erythropoietin, a hormone which stimulates red blood cell production. -Newborns have a higher mean hematocrit than adults. -Normal hematocrit in newborn is 45 - 60% (40-50 in an adult) -Jaundice occurs when this relatively large pool of RBCs are broken down, a process that can either be physiologic or pathologic in origin. Pathophysiology -Step One: RBCs are destroyed in the reticuloendothelial system. -->There, hemoglobin is separated into globin and a heme pyrrole ring. -Step Two: Heme is converted to unconjugated bilirubin -Step Three: Unconjugated bilirubin is released from the RES into the circulation where it is tightly but reversibly bound to albumin. -Step Four: The bilirubin-albumin complex is carried through the splenic vein to the portal vein to the liver. -Step Five: In the liver, the albumin-bilirubin complex is combined with glucuronic acid to make a bile salt or conjugated bilirubin. -Step Six: Conjugated bili is pumped out of hepatocyte into canalicular (bile duct) system -Step 7: Leaves liver through common bile duct -Step 8: Enters duodenum -Step 9: Leaves body in stool -Step 10: Or is deconjugated and reabsorbed back into enterohepatic circulation.

Justify the importance of ordering a viral hepatitis serology panel in a patient with abnormal LFTs.

-Many people with hepatitis have a subclinical form of the disease meaning many people will not show signs or symptoms of hepatitis. The only thing that will be abnormal might be LFTs, so further investigation needs to happen and such, viral hepatitis serology panels are appropriate to order

Describe the processes by which the liver is involved in drug metabolism.

-Metabolic reactions can either turn an active medication into an active metabolite or an inactive medication, called a prodrug, into an active metabolite Phase I -Primarily takes place in the liver but also to a lesser extent in the lungs, kidneys and small intestines -Carried out by a class of enzymes in the hepatocyte called cytochrome P450, which are found in cell compartments like the ER and mitochondria -->They convert non-polar, lipid-soluble medications into slightly more polar, water-soluble metabolites through oxidation, hydrolysis or reduction Phase II -Primarily takes place in the liver but also to a lesser extent in the lungs, kidneys and small intestines -These are conjugation reactions, meaning that the medications or metabolites are conjugates, or joined w/another compound - like a methyl, acetyl or sulfa group; glutathione or glucuronic acid. -->They include methylation, acetylation, sulfation, glutathionylation and glucuronidation -These reactions create highly polar, water-soluble metabolites that cannot diffuse through cell membranes very easily, so they are trapped in the urine and eliminated by the kidneys -Poor metabolizers vs ultra/rapid metabolizers

Identify and explain the red flag signs and symptoms of biliary conditions that require urgent referral.

-Reynolds pentad → pain + fever + jaundice + AMS + hypotension = emergent acute cholangitis -Evidence of sepsis -Evidence of jaundice

Describe how acetaminophen can lead to acute liver failure.

-The principal toxic metabolite of acetaminophen, N-acetyl-p-benzoquinone imine (NAPQI), is produced by the hepatic cytochrome P450 enzyme system; glutathione stores in the liver detoxify this metabolite -An acute overdose depletes glutathione stores in the liver and results in NAPQI accumulation, causing hepatocellular necrosis and possible damage to other organs (i.e. kidneys, pancreas). -To cause toxicity, an acute oral overdose must total > 150 mg/kg (about 7.5 g in adults) within 24 hours. -Likelihood and severity of hepatotoxicity caused by an acute ingestion can be predicted by the amount of ingested or by the serum acetaminophen level

Describe key risk factors for the development of cirrhosis.

-Viral: blood transfusion, tattoos, IV drug use, sexual hx -ETOH: long term heavy ETOH use -NASH: obesity, HLD, T2DM

Predict indications for a paracentesis and identify common risks of this procedure.

Ascites fluid -Diagnostic paracentesis: US guided aspiration/drainage -Appearance -->Normal - transparent, yellow tinge -->Pink or bloody - traumatic tap or malignancy -Cell count -->Normal <500 leukocytes/uL, <250 PMN/uL --> >500 leukocytes: any inflammatory condition --> >250 PMN: high suggestive of SBP -Indications -->Symptomatic -->Refractory ascites -Contraindications -->Platelets <20K - infuse platelets -->INR >2.0 - infuse FFP -->Pregnancy, distended bladder, abdominal wall cellulitis, distended bowel, intra-abdominal adhesions -Complications -->Infection, lyte imbalances, bleeding, bowel perforation, leakage -->Suspect bowel perforation if new fever +/- abdominal pain after paracentesis, hypotension -If >5L removed, then give albumin fluid replacement

Apply knowledge of the physiology of liver functions to interpretation of the following laboratory studies: albumin, prothrombin time, bilirubin, alkaline phosphatase, AST, ALT, gamma-glutamyl transferase (GGT), total protein and LDH.

Albumin -3.8 - 5.0 g/dL -Maintains oncotic pressure -Produced solely by liver; a transport protein -Critical for maintaining oncotic pressure; when levels are low can lead to third spacing and tissue edema -Important marker of hepatic function Bilirubin -Byproduct of RBC breakdown in reticuloendothelial system; conjugated in liver and excreted into bile -Total bilirubin = Measures direct + indirect bilirubin -Total bilirubin >2.5 mg/dL → Typically will see jaundice on exam -Bilirubin - direct (conjugated) = 0.00-0.02 mg/dL -Bilirubin - indirect (unconjugated) = 0.20-0.80 mg/dL Alkaline phosphatase -17-142 IU/L -Group of enzymes predominately made in liver cells and bone -*Increased production of enzyme is also mediated by bile acids within the biliary system -*NOT a specific marker for liver/biliary disease -Can also show bone disease; levels rise with osteoblastic activity -Levels much higher in persons < 20 years old and -Females>>Males after age 30 AST and ALT -Transaminases -Enzymes found in high concentrations in liver cells (among other organs/tissues) -Most sensitive markers for hepatocellular injury but are NOT specific -Increase in serum levels reflects either damage to cells rich in these enzymes or changes in cell membrane permeability that allow enzymes to leak into serum -Serum level is measuring the amount of enzyme in the blood at that moment in time -->Levels should be repeated at least once to trend prior to any major intervention -Degree of elevation does NOT correlate with the extent of liver injury -->Markers can sometimes be NORMAL in someone with end stage liver disease (cirrhosis) -May be noted as a direct lab value or "5X ULN" -ALT → alanine transaminase; 7-56 U/L -->Found in high concentrations in liver and kidney tissues -AST → aspartate transaminase; 5-40 U/L -->Less specific to liver function than ALT -->Found in liver, heart, skeletal muscle, kidney, brain, pancreas, spleen and lungs -->Following cell damage, AST rises within 12 hours and remains elevated for ~5 days Gamma-glutamyl transferase (GGT) -Females - 5-55 U/L and males - 5-85 U/L -Sensitive marker for liver disease but NOT specific -Found in liver, kidney, spleen and prostate -Men have higher levels due to prostate -Sensitive to amount of alcohol consumed + other meds -**Usefulness is to order after initial liver tests come back abnormal (esp alkaline phosphatase) Total protein -6.0 - 8.0 g/dL -Measurement of many different proteins found in the blood (including albumin) -Serum proteins are a source of nutrition, play a role in the buffer system, help to maintain oncotic pressure, act as immunoglobulins, carrier proteins, regulatory proteins and hormones -Levels affected by over or underproduction of 1 or more proteins OR hemoconcentration/hemodilution of the blood -Helpful to evaluate kidney disease, liver disease, immune dysfunction, and nutritional status LDH → lactate dehydrogenase -100-222 U/L -Enzyme present in all cells of the body with highest concentrations in heart, liver, muscle, kidney, lung, erythrocytes -High levels often indicate cell death/high cell turnover and leakage of enzyme into serum -A nonspecific test but sometimes helpful to confirm MI, pulmonary infarction or embolism, muscular dystrophy, tumors/malignancy, liver disease, kidney disease

Discriminate between physiologic jaundice and other diseases causing jaundice in a neonate when presented with a clinical scenario: infectious hepatitis, inborn errors of metabolism and biliary atresia.

Causes of conjugated hyperbilirubinemia: hepatitis, inborn errors of metabolism and biliary atresia Infectious hepatitis -Various infectious etiologies: Hep B, Rubella, CMV, Toxoplasmosis -Majority are "idiopathic", self-limited without permanent damage -Agents have a predilection for canalicular cells (cells of the ductal system) -CONJUGATED Galactosemia -Inborn error of galactose metabolism caused by congenital enzyme deficiency FTT, hepatosplenomegaly/cirrhosis, MR, cataracts -Clinically, disease looks like hepatitis -CONJUGATED -Note: other inborn errors of metabolism can also cause cholestatic jaundice -Cholestatic jaundice implies that conjugated bilirubin flow is obstructed Biliary atresia -Congenital absence of all or part of the biliary tree (ducts that drain bile from liver) -Etiology is uncertain, may be viral -Occurs in 1:15,-20,000 births -Presents weeks 2 to 8 after birth -->Light stools, dark urine, jaundice, weight loss and irritability are hallmarks -Initially treated with Kasai procedure- intestine attached to liver -Ultimately need liver transplant

Describe the clinical presentation of cirrhosis (including systemic manifestations of liver failure).

Compensated -Early stages are asymptomatic -->Nonspecific symptoms >>>>Anorexia, weight loss, weakness, fatigue >>>>Muscle cramps, easy bruising -->Chronic anovulation (women) >>>>Amenorrhea, oligomenorrhea, metrorrhagia -->Hypogonadism (men) >>>>Impotence, infertility, decreased libido, testicular atrophy Decompensated -Jaundice, pruritis, dark or "cola-colored urine" -Hematemesis, melena, hematochezia (UGI bleed) -Abdominal distension (Ascites) -Confusion or sleep disturbances (encephalopathy) -Lower extremity edema

Describe the stages of cirrhosis (including use of the MELD score) and how this relates to treatment and prognosis.

Compensated cirrhosis -No major complications -Median survival >12 years Decompensated cirrhosis -With major complicated - worse prognosis -Child-Pugh Score > 12 or MELD > 21 → medical survival < 6 months Predictive models -Child-Pugh Score -Model for end-stage liver disease (MELD) score Child-Pugh score -Stratifying operative risk MELD (model for end stage liver disease) score -30-day postoperative mortality rates -->MELD score of ≤7 = 5.7% mortality -->MELD score of 8-11 = 10.3% mortality -->MELD score of 12-15 = 25.4% mortality -->MELD score of 16-20 = 44% mortality -->MELD score of 21-25 = 53.8% mortality -->MELD score of ≥26 = 90% mortality Liver transplantation -For decompensated liver cirrhosis -MELD score - prioritizes patients -Patients should be referred to a transplant center at the first sign of cirrhosis -Contraindications -->Severe heart/lung disease -->Active drug or ETOH use -->Malignancy outside liver -->Sepsis -->Psychosocial issues that may affect compliance -->Living donor liver transplantation

Interpret laboratory values and recognize key signs/symptoms in a patient with drug induced liver disease when provided with a clinical scenario.

DILI Clinical Manifestations -Clinical symptoms: -->Fatigue, nausea, malaise, pruritus, jaundice, +/- abdominal pain -->Fever, rash, eosinophilia (systemic hypersensitivity) -->Prolonged jaundice, xanthomas, pruritus (chronic cholestasis)

Demonstrate the approach to work-up in a patient presenting with signs/symptoms concerning for an acute biliary process.

Diagnostic testing -CBC, LFTs, bilirubin, amylase -Lipase should be sent any time gallstone pathology is suspected due to high rates of concomitance w/gallstone pancreatitis -->Conditions that commonly present w/ jaundice and obstruct the common bile duct (choledocholithiasis and cholangitis) frequently have elevated bilirubin and alkaline phosphatase. Diagnostic imaging -US and CT are common modalities for initial workup of these entities -->US is the initial diagnostic study of choice for biliary tract diseases >>>>Gallstones outside of the gallbladder may be missed on US -->CT imaging is one of the most common initial modalities used for the evaluation of abdominal pain in the ER and plays an important role in the diagnosis of biliary disease >>>>CT is less sensitive for cholelithiasis since many gallstones are radiolucent >>>>It is sensitive for detection of acute cholecystitis and biliary obstruction -->Endoscopic retrograde cholangiopancreatography (ERCP), magnetic resonance cholangiopancreatography (MRCP), and hepatobiliary iminodiacetic acid (HIDA) scans serve to further confirm and in the case of ERCP, treat these conditions.

Discriminate between physiologic jaundice and other diseases causing jaundice in a neonate when presented with a clinical scenario: G6PD deficiency, prematurity, breastfeeding and defects in conjugation hyperbilirubinemia.

G6PD Deficiency -Glucose-6-phosphate dehydrogenase deficiency -Sex-linked disorder of cell membranes which makes them vulnerable to hemolysis -->More severe in males -->Variable presentation in females -Usually occurs upon exposure to oxidants, especially medications or infections -Protective against malaria -Occurs in Mediterranean region, China, Africa -Occurs in 10% of African Americans Prematurity -80% of premature infants become jaundiced -Premature infants conjugate more slowly -Higher risk for BIND at lower levels of bilirubin. -Leaky blood-brain barriers Associated with breastfeeding -A. Breastfeeding jaundice -->Caused by inadequate oral intake -->Increases enterohepatic circulation -->Essentially, dehydration -->Occurs on days 2 to 5 -->Baby's hydration is the urgent problem >>>>Mother needs breastfeeding support >>>>Consider supplementation with pumped milk or formula -->UNCONJUGATED -B. Breastmilk jaundice -->Begins day 4 -->Can peak weeks 2 to 4 -->Persists up to 3 months -->Not all breastfed babies get it -->Totally benign- don't interrupt nursing -->Etiology unclear -->UNCONJUGATED Defects in conjugation -A. Gilbert's -->Defect in glucuronyl transferase -->Typically, mild jaundice after puberty -->Possibly related to breastmilk jaundice -->Possibly related to increased jaundice in certain ethnic groups (Asian, Scots, N.A.) -->Autosomal dominant -->UNCONJUGATED -B. Crigler-Najjar Syndrome -->Severe, often lethal form of hyperbili. -->Clinically looks like kernicterus -->Autosomal recessive -->Occurs in one in one million live births -->Virtual absence of glucuronyl transferase enzyme -->Two Types (I, II). >>>>I: requires lifelong PTX to avoid BIND and liver transplantation >>>>II: treatable with Phenobarbital.

Describe the pathophysiology, risk factors, and spectrum of diseases for non-alcoholic fatty liver disease (NAFLD), including NASH.

Hepatic steatosis -Fatty changes of the liver that will be seen histologically Nonalcoholic fatty liver disease (NAFLD)/Metabolic associated fatty liver (MAFLD) (picture) -No significant alcohol hx -Hepatic steatosis associated with metabolic syndrome -Specifically has to do with peripheral insulin resistance causing increased insulin resistance in adipose tissue leading to increased lipolysis and circulating free fatty acids which get absorbed into the liver -Hepatic insulin resistance feeds back into this cycle -In metabolic syndrome it is a disease in which the body does not realize it has enough sugar circulating as it does that is called peripheral insulin resistance and we produce more insulin but it does not help us metabolize sugar like we should because the signaling pathways → more fat circulating in the blood and more sugar in the blood than is needed; the liver ends up storing that fat -Diagnosis of exclusion -Risk factors -->Obesity -->HTN -->Hyperlipidemia -->Hypertriglyceridemia -->Polycystic ovarian syndrome -->?Shift work Nonalcoholic steatohepatitis (NASH) -Histopathologic inflammation of the liver, due to fatty infiltration -Often manifested as elevated liver enzymes -Occasional , capsular RUQ pain -20-40% individuals with NASH will go on to develop NASH cirrhosis

Describe the key components of a focused history and physical exam for a patient presenting with signs and symptoms concerning for a biliary condition, when provided with a clinical case example.

History -Gallstones are common → 9% of women and 6% of men (U.S.), risk increases with age -Risk factors: obesity, rapid weight loss (bariatric surgery), diabetes -Native American, Hispanic, Black Americans at higher risk -Prevention → low carb diet, physical activity protects against gallstone formation. Physical exam -Vital signs! (Fever, HR, BP) -Observe patient → Does the patient appear sick? Uncomfortable? -Skin exam for jaundice, as well as volume (dehydration?) -Abdominal exam is the key! -->RUQ tenderness -->Murphy's sign → ask patient exhale and palpate RUQ, then ask patient to take deep breath in and during inspiration palpate RUQ - if pain increases with inspiration / while palpating = (+)

Describe the pathophysiology of ascites and explain why this can occur in patients with liver failure.

Pathophysiology -Build-up of fluid in the peritoneal cavity or the abdominal cavity -Increased portal HTN and fluid/electrolyte imbalances due to the underlying cause -Hepatic congestion, congestive heart failure, constrictive pericarditis, tricuspid insufficiency, Budd-Chiari syndrome -Liver disease, cirrhosis, alcoholic hepatitis, fulminant hepatic failure, massive hepatic metastases -One episode of ascites: 3 year mortality = 50% -Refractory ascites: 1 year survival <50% History -Stable cirrhosis with new ascites - c/f malignancy (HCC) -Usually painless SAAG - serum to ascites albumin gradient -Best single test for classifying cause of ascites -Correlates with portal pressure -Portal HTN if SAAG >1.1 g/dL -Non-portal HTN causes if SAAG <1.1 g/dL -High-albumin gradient or low-albumin gradient

Demonstrate an appropriate diagnostic work-up for a patient presenting with signs/symptoms concerning for cirrhosis: PE findings.

Signs/PE findings -Hepatomegaly -Splenomegaly -Spider angiomata/spider telangiectasias -Gynecomastia, loss of chest of axillary hair, testicular atrophy (men) -->Increased conversion of androgenic steroids into estrogens in skin, adipose tissue, muscle, and bone -Palmar erythema -Digit clubbing -Dupuytren's contracture -Muehrcke nails - double white horizontal lines -Terry Nails -White nails, no lunulae Signs/PE of advances disease -Caput medusae - congested abdominal wall varices -Jaundice -Ascites -Abdominal distension -Shifting dullness -Fluid wave -Asterixis - when patient extends their arm and dorsiflexes their wrist passively and when it is released the hand will flap -Fetor hepaticus - bad breath from high ammonia levels

Discriminate between physiologic jaundice and other diseases causing jaundice in a neonate when presented with a clinical scenario: physiologic, pathologic, ABO incompatibility and pooling of blood outside vascular system hyperbilirubinemia.

Unconjugated hyperbilirubinemia causes (picture) Physiologic hyperbilirubinemia -Normal hematocrit of term baby is 45- 60% -Begins to fall after delivery -Nadir occurs at 2 months, with hematocrit as low as 28-30% -Large # of RBCs destroyed in the process -Hemolysis begins in utero, jaundice occurs during the first 2 hours -Peaks at 3 to 5 days (timing of 1st visit) -UNCONJUGATED Pathologic hyperbilirubinemia -Occurs when a maternal antibody crosses the placenta to attack fetal RBCs -ABO most common, occurs in 20% of all births -Rh is more severe, decreased since rho-gam introduced in 1960's -Other hemolytic anemias, eg. Thalassemias -Begins in utero, therefore jaundice present during first few days of life -UNCONJUGATED ABO incompatibility -D antibody in ABO system -Works in the same way - if MOC is Rh- then she can make anti-D antibodies -Rho-gam is anti-D IgG given at 28 weeks after birth -Some studies report the incidence of fetomaternal hemorrhage to be 75% of all pregnancies -Most of these are small undetectable hemorrhages -Placental abruption, SAB, TAB, toxemia, C-sections, ectopic pregnancies, amniocentesis Pool of blood outside vascular system -Breakdown of extravascular blood i.e. bruising or cephalohematoma -->Blood trapped between periosteum and skull, caused by birth trauma -Unconjugated

Explain the key components of treatment for physiologic jaundice in the newborn.

When to treat -High risk zone: begin phototherapy -High intermediate: -->Recheck 6-12 hrs +/- phototherapy -Low intermediate: recheck based on clinical progress -Low risk: no need to follow up Phototherapy -Blue light with wavelengths between 440 and 470 causes the outer ring of bilirubin to be turned 180 degrees. In this form it is less tightly bound to albumin, is more water soluble and can be eliminated from the body via the kidneys without conjugation. -Phototherapy is only effective in unconjugated hyperbilirubinemia -Use of PTX in conjugated hyperbili results in "bronze baby", an unappealing discoloration of skin -Consider fractionated bili prior to starting light therapy if there is doubt -Is phototherapy harmful? -->Infant must protect eyes -->Disrupts bonding and breastfeeding -->Infant unswaddled and left open in bassinet

Predict when these tests might be ordered when provided with a clinical scenario.

ALT -Elevation mild-moderate levels (200's-500's): -->Viral hepatitis, non-alcoholic fatty liver disease, alcohol related liver disease, drug induced liver damage, cirrhosis, cholestatic diseases, genetic diseases of the liver, autoimmune diseases affecting the liver, certain infections such as mononucleosis, pancreatitis, trauma to skeletal muscle, polymyositis, kidney disease -Severely elevated levels (>500): -->Drug toxicity (such as acetaminophen overdose), Viral hepatitis (especially if acute presentation), acute bile duct obstruction, liver ischemia, some autoimmune diseases, some genetic diseases of liver, HELLP (complication of pregnancy) AST -Increased in: -->MI (nonspecific and not a typical marker) -->Pancreatitis, trauma to skeletal muscle including rhabdomyolysis, heat stroke/hyperthermia, TBI, muscular dystrophy, pulmonary emboli, gangrene, mushroom poisoning AST/ALT ratio can be useful in certain settings -AST/ALT ratio >2 may indicate alcohol associated liver disease (only when the AST level is <300) Alkaline phosphatase (AP or ALP) -Increased levels: -->Hepatobiliary disease including biliary obstruction, tumors, cirrhosis, hepatitis -->Bone disease including Paget's Dz, mets, osteogenic sarcoma -->Renal disease including renal failure -->Hyperparathyroidism -->Lung disease including infarction, cancer, sarcoidosis -->MI -->Sepsis -**Greater elevation of AP compared to elevation of AST/ALT suggests a cholestatic process Gamma-glutamyl transferase (GGT) -Elevated GGT + elevated ALP implies a pathologic hepatobiliary process -Normal GGT with elevated ALP is likely indicative of bone pathology Bilirubin -Evaluates liver function/disease, hemolytic anemia, newborn jaundice, hepatobiliary obstruction/disease Albumin -Increased levels: IV infusions, dehydration -Decreased levels (hypoalbuminemia): -->Decreased protein synthesis (including liver disease/failure) -->Increased albumin loss (often through kidney or gut) -->Poor nutrition -->Inadequate iron intake Total protein -Increased in: -->Dehydration from vomiting, diarrhea or poor kidney function (hemoconcentration of serum) -->Multiple myeloma -->Sarcoidosis -->Collagen vascular disease -->Chronic inflammation or infections -Decreased in: -->Starvation, malabsorption → decreased intake or unable to absorb -->Pregnancy (hemodilution of serum) -->Severe liver disease (cirrhosis) or alcoholism → decreased production -->Kidney disease including nephrotic syndrome → increased loss -->Severe skin diseases, burns, trauma, hemorrhage LDH -Increased in: -->Cardiovascular disease including MI, Heart failure -->Liver disease including cirrhosis and hepatitis -->Renal disease -->Pulmonary disease including infarction -->Megaloblastic and pernicious anemia -Decreased in: -->Good response to cancer chemotherapy (trend levels to normal)

Identify the common causes of biliary pain.

Biliary colic, which is also termed symptomatic cholelithiasis (gallstones), is the most classic hx finding in biliary pathology → due to intermittent obstruction of the gallbladder neck by gallstones -Gallstones remain in the gallbladder -This describe episodic RUQ or epigastric pain associated with N/V, which is caused by gallstones intermittently obstruction at the neck of the gallbladder -Symptomatic cholelithiasis occurs as a result of supersaturation of bile with cholesterol (70%), pigments such as bilirubin (20%) or both (10%) combined w/delayed emptying of the gallbladder (stasis) -Pts may often report previous episodes in association w/ fatty meals -In uncomplicated symptomatic cholelithiasis, this pain may last 4-6 hrs before spontaneously resolving Choledocholithiasis -The stone moved out of the gallbladder and is obstructing the common bile duct, which blocks the bile flow from the contributing ducts (cystic duct and hepatic duct) -Pain typically lasts >6 hours Cholecystitis -Acute cholecystitis is inflammation of the gallbladder and is related to the presence of gallstones in 90-95% of cases -The difference between cholecystitis and cholelithiasis include biliary colic >6 hours and constitutional sx's such as fever and malaise -Murphy sign Cholangitis -Inflammation of the bile ducts and is most often caused by a polymicrobial bacterial infection -->Unlike cholecystitis, >90% cultures in cholangitis will be (+) >>>>E. coli, klebsiella, enterobacter account for most gram-negative cultures -Biliary obstruction - such as from a stone or neoplasm - serves as a major factor in its pathogenesis -Charcot triad: fever, RUQ pain and jaundice -Reynold pentad (severe cases): fever, RUQ pain, jaundice, confusion and hypotension

Describe the management options for a patient with cholecystitis, cholelithiasis and cholangitis.

Cholecystitis management -All patients with cholecystitis should be hospitalized. -Acute cholecystitis will usually resolve with conservative management → antibiotics, pain medication and slow resumption of diet BUT because of the high risk of recurrent episodes patients (>30% have second case within 1 year), patients should be referred to a surgeon for consideration of cholecystectomy. -Poor surgical candidates may benefit from initial nonoperative management with antibiotics and a gallbladder drainage procedure Cholelithiasis management -Gallstones that are found incidentally (ie patient not having symptoms) do not need intervention -Gallstones causing symptoms (biliary colic) or measuring >3cm warrant intervention and patients should be referred for a laparoscopic cholecystectomy. -Acute cholecystitis develops in ~20% of patients with symptomatic gallstones Cholangitis management -Management depends where the obstruction is, cholecystectomy leaves behind the CBD and the hepatic ducts, so if stone is located in one of these ducts infection will not be managed. -The most frequent causes of biliary obstruction in patients with acute cholangitis are biliary calculi (28-70%), benign biliary stricture (5-28%), and malignancy (10-57%). -Biliary obstruction raises intra-biliary pressure and leads to increased permeability of bile ducts, permitting translocation of bacteria and toxins from the duodenum into the biliary tract. -Antibiotic selection should include coverage for GNR and anaerobes (gut flora) -Mortality rate for acute cholangitis ~20-30%

Be able to recognize the key signs/symptoms and laboratory values of this process.

Clinical Manifestations -Stage I - first 24 hours -->Signs/sx's: nausea, vomiting, malaise, lethargy, diaphoresis -->Labs: AST/ALT normal; may increase at 8-12 hours after massive overdose -Stage II (latent period) - 24-72 hours -->Signs/sx's: stage I sx's improve/resolve, nephrotoxicity occurs; in severe cases RUQ pain, tender hepatomegaly and jaundice will occur -->Labs: subclinical increase AST/ALT; increased Scr, oliguria, in severe cases there is a prolonged PT -Stage II (hepatic phase) - 72-96 hours -->Signs/sx's: stage I sx's reappear (n/v), jaundice, encephalopathy, AKI (10-25%; >50% if ALF), acute pancreatitis (0.3-5%), death - due to multiorgan system failure -->Labs: AST/ALT elevation (often >3000 IU/L), peak at 72-96 hours, prolonged PT, lactic acidosis -Stage IV (recovery phase) - 96 hrs - 2 weeks -->Signs/sx's: complete resolution in 1-2 weeks, may take longer in severe cases, complete functional recovery expected -Labs: histologic recovery occurs slower than clinical recovery Centri-lobular hepatocellular necrosis-->

Prepare a management plan for a patient presenting with acetaminophen toxicity.

Clinical evaluation: Careful history taking & physical examination -Intentional vs unintentional overdose -Precise time of ingestion -Type of product ingested amount of APAP intake -Pattern of ingestion - single dose vs repeated -Concomitant toxins: medications, drugs, herbs/complementary medicine Obtain APAP level Serum NAPQI-protein adducts -Useful diagnostic test -Detected in setting of negative APAP levels -Identify missed APAP overdoses -Limitation: not routinely available -**pts w/ clinical signs of acute liver failure (encephalopathy, coagulopathy, acidosis) should be transferred to an ICU and/or facility where liver transplant is available Rumack-Matthew Nomogram: predicts risk of hepatotoxicity in single acute overdose when presents w/in 24 hrs of ingestion -APAP levels > 20 ug/mL (or >10 ug/mL w/ risk factors) -Serum bilirubin levels >10 ug/mL, can cause false-positive or false elevations in serum APAP assay Gastric contamination -Consider gastric contamination: patient presents within 4 hours of potentially toxic APAP dose (> 7.5-10 g) -Activated charcoal 1 g/kg (maximum dose 5o g) by mouth -->Achieve greater reduction in APAP level compared to gastric lavage or eme-induced drug -->Dose within 1 hour of ingestion -->Shake well; can mix with flavored beverage to enhance palatability (i.e. cola, fruit juice, chocolate milk) -->IV antiemetics -Avoid -->AMS with unprotected airway -->GI obstruction -->Risk for GI hemorrhage or perforation N-acetylcysteine (NAC) -GSH precursor: restores GSH levels and protects from liver damage -Initiate before onset of liver injury; may also benefit if have established liver injury -Administer w/in 10 hrs → most effective -May be beneficial if given >/= 48 hrs after ingestion -->Monitor >>>>Baseline liver function tests (AST, ALT, bilirubin, INR), Scr >>>>Repeat at 24 hr intervals until at least 96 hrs have elapsed >>>>AST/ALT > 1000 IU/L - commonly associated with other signs of liver dysfunction -->Continue NAC until: >>>>APAP level < 10 g/mL and normal ALT OR >>>>Liver dysfunction reverses (AST/ALT have peaked & are improving, encephalopathy resolves, & INR < 1.5) Liver transplantation -Indicated in those who progress to acute liver failure -Pronostic models -->King's College Criteria (KCC) >>>>90% mortality if pH <7.3 >>>>81% mortality if met 2nd set of criteria >>>>Limited sensitivity 68-82% -->MELD -Evaluated psychiatric problems, identify family support, consider quality of life after transplants Other "theoretical" therapies (picture) Diagnosis and management of DILI -Proper diagnosis -Recognition of offending agent -Discontinuation of offending agent -Parameters of drug discontinuation -->ALT > 8x ULN -->ALT > 5x ULN x 3 weeks -->ALT > 3x ULN _ bilirubin > 2x ULN -->PT/INR ratio > 1.5 ULN or in presence of sx's suggesting liver injury

Demonstrate an appropriate diagnostic work-up for a patient presenting with signs/symptoms concerning for cirrhosis: diagnostic workup.

Diagnostic work up - labs -LFT --> ↑ AST/ALT (AST:ALT >1) --> ↑ AP (2-3x UNL) --> ↑ bilirubin --> ↓ albumin -Coags -->Prolonged PT --> ↑ INR -CBC: ↓ platelets -BMP: ↓ Na -Viral hep panel -Coagulopathy --> ↓ synthetic function of coagulation factors -->↓ vitamin K absorption >>>>↓ factors II, VII, and X -->Fibrinolysis -->Disseminated intravascular coagulation (DIC) -Thrombocytopenia -->2/2 splenomegaly --> ↓ production of thrombopoietin -Possible folate deficiency; anemia and leukopenia later in disease Diagnostic workup - imaging -US/CT/MRI -->Surface nodularity -->Increased echogenicity (US) -->Small, nodular liver -->Ascites -->Hepatocellular carcinoma -->Portal/splenic/SMV thrombosis -->Portosystemic collaterals -Fibroscan -->Fast, painless, noninvasive -->US probe, energy pulses -->Eval liver stiffness (fibrosis) and liver fat (steatosis) -->Liver stiffness >21 kPa = clinically significant portal HTN Diagnostic workup -Liver biopsy -->Gold standard -->Histologic hallmark - regenerative nodules surrounded by fibrotic tissue -->Establishes stage of liver fibrosis/cirrhosis -->Can confirm etiology of cirrhosis -->Ultrasound guided percutaneous or transjugular biopsy -->Coag goal PT >50 and Plt >50 -->Risks: bleeding, perforation of another organ -Measure portal venous pressure -->Hepatic venous pressure gradient (HVPG) -->Gradient between pressures in the portal vein and the intra-abdominal portion of the IVC -->HVPG > 10 mmHg predicts the likelihood of developing decompensation -->No absolute contra-indications -->Complications - transient cardiac arrhythmia, vagal response -Endoscopy -->Diagnose, stage, monitor, and treat varices

Demonstrate an appropriate diagnostic work-up (including labs and imaging) for a patient presenting with symptoms concerning for a biliary condition.

Diagnostic workup -Labs: CMP, Lipase, CBC and Blood cultures* -Imaging: Abdominal Ultrasound is the gold standard image -->Limited to RUQ - do not need complete or with doppler -->Cholecystitis → 90-95% sensitive and 80% specific -->Cholelithiasis → 98% sensitive and specific -->Looking for Gallbladder wall thickening/distention, stones, pericholecystic fluid and evaluating for (+) Murphy sign with US -->CT scans and Xrays are not sensitive for gallstones -->HIDA scan -> if abdominal US inconclusive. Works by injecting radioactive tracer selectively taken up by hepatocytes and excreted into bile, if there is an obstruction the tracer will not pass. 90-97% sensitive and 70-90% specific for cholecystitis. -->EUS (endoscopic ultrasound) or MRCP (MRI of biliary tree) may be needed to further evaluate if abdominal US inconclusive* -->Normal liver function tests and/or ultrasound without stones/thickening of gallbladder can occur if the patient is between symptoms. >>>>Recommend repeating when patient is having biliary pain for further evaluation -->EUS/MRCP/ERCP should not be ordered without discussion with specialist (GI therapeutics/surgeon) as they are expensive and EUS/ERCP are invasive and come with risk (sedation) Interpretation of liver function labs -Alk phos comes from several different sources (BLIP - bone, liver, intestine, placenta) -Checking a GGT can help confirm the source of the alk phos elevation -GGT should be high when alk phos etiology is liver

Develop a differential diagnosis and diagnostic work-up plan for a patient presenting with abnormal lab markers concerning for acute hepatitis.

Differential diagnosis for acute hepatitis -Viral** -Non-viral infections -Alcohol** -Drugs/toxins** -Ischemic/vascular -Autoimmune -Hepatobiliary/obstructive Diagnostic approach -Thorough H&P -->PMH (including recent surgeries, procedures) -->Medications (including OTC), Allergies -->Social history - diet, exposures, sick contacts, sexual history, drug use (including EtOH), travel -Basic labs - CBC, CMP -PT/INR, PTT, fibrinogen, prothrombin -+/- GGT (if indicated by abnormal ALP), LDH -Viral serologies -Urine Toxicology, serum acetaminophen level (if concerned about overdose) -Imaging (RUQ ultrasound +/- Doppler, CT scan, MRI) -Liver biopsy (*only after above tests have been done, other conditions ruled out)

Describe the main functions of the liver in regards to drug metabolism, including explanation of the first-pass effect and the role of cytochrome P450.

Drug metabolism in the liver -Facilitate clearing of endogenous +/or exogenous molecules from the body -->Convert lipophilic to hydrophilic -->Convert prodrug into pharmacologically active form (eg, MMF) -Major drug metabolizing/eliminating pathways -->Phase I, II, III >>>>Phase I: chemically modifies drugs into soluble water products to facilitate excretion by kidney and/or liver, mainly through oxidation, reducation, and hydrolysis -----Main reactions catalyzed by cytochrome P450 enzyme system >>>>Phase II: drugs & metabolites from phase I pathways are conjugated w/ a hydrophilic endogenous compound w/ help of transferase enzymes (UDP-glucuronosyltransferases) -----Glucuronidation: major phase II metabolism pathway -----Conjugates 40-70% of human endogenous/exogenous compounds to glucuronidated end products (more hydrophilic) >>>>Phase III: transmembrane proteins that facilitate transport of large and/or ionized molecules in and out of cells First pass effect -Process of drug elimination between the site of administration & site of sampling measurement -Liver is major site of first pass metabolism -Other sites: stomach, intestine -Essentially, the overall bioavailability is the product of the fractions of the drug entering the tissues that escapes metabolism in each successive tissue -->Foral = Fgut x Fintestine xFliver

Interpret viral hepatitis serology panels when provided with a clinical scenario.

Drug/toxin induced liver disease (top picture) Alcohol induced hepatitis (middle picture) Autoimmune hepatitis -Hepatocellular (ranges from mild-severe LFT elevation) -Presence of autoimmune antibodies (attacking hepatocytes) Ischemic/vascular causes -Severe LFT elevation -Diagnosed with US + doppler Acute hep B (bottom picture)

Discriminate among the common types of virally transmitted hepatitis (A, B and C) in terms of epidemiology, risk factors, serology, prevention, treatment and screening guidelines: Hepatitis A.

Hepatitis A -Symptoms -->Most infections are subclinical -->May experience GI sx's (N/V), RUQ pain, anorexia, fever, fatigue -->Symptoms last ~2-6 weeks -->No chronic form -Epidemiology -->A is for acute -->Picornavirus, related to enteroviruses -->Transmitted via fecal-oral route -->Major sources: contaminated water, food, person to person transmission -->Inactivated by cooking heat! -->Immunity is lifelong -Risk factors -->Higher risk: >>>>Travel to endemic region (like Mexico, Africa) >>>>Foodborne: chipotle outbreak from infected worker preparing food >>>>MSM >>>>Injection drug use >>>>Household contact -->Lower risk: daycare/school attendance in US and needlestick in US -Serology -->Elevated LFTs; +/- elevated bilirubin, AP -->Hep A IgM = acute infection -->Hep A IgG = past/cleared infection -Prevention -->Public health hygiene -->Vaccine >>>>All children >12 months >>>>Travelers >>>>Contacts of internationally adopted children >>>>Men having sex with men >>>>Drug users >>>>Pt with chronic liver disease -Treatment -->Post exposure >>>>Can be given within 2 weeks of exposure >>>>Hep A vaccine (single antigen vaccine): household or sexual contacts, illicit drug sharing, childcare centers >>>>Immune globulin: if age <12 months or >40 y/o, immunocompromised, chronic liver disease -Screening guidelines -->Screen any patient w/potential exposure/risk -->Consider testing in someone w/abnormal LFTs

Discriminate among the common types of virally transmitted hepatitis (A, B and C) in terms of epidemiology, risk factors, serology, prevention, treatment and screening guidelines: Hepatitis B.

Hepatitis B -Symptoms -->70% of cases are subclinical -->Incubation period is 4-26 weeks -->90% of cases will resolve spontaneously; remainder will go on to develop chronic hepatitis and potentially liver failure (1%) -Epidemiology -->B is for blood -->Hepadnaviridae family virus -->Double stranded DNA; enveloped -->Surface and intracellular proteins important for diagnosis -->Transmission via blood, semen, saliva, breast milk, cervical secretions -Risk factors -->Multiple sexual partners >>>>Unprotected sex >>>>MSM -->IV drug use: sharing needles, drug paraphernalia -->Tattoos, piercings: unsanitary practices -->Healthcare workers: needlesticks, body fluid exposures -->Household contacts -->Travel -->Blood transfusion before 1980 -->Maternal-fetal -Serology -->Elevated LFTs on labs; +/- elevated bilirubin, AP -->HBs Ag: early sign of active infection -->HBe Ag: early sign of active infection (while sx's occuring); also notes "infectivity" -->HBc Ab: first antibody to show up in an acute infection -->HBs Ab: late antibody = indicate immunity -->HB DNA >>>>PCR test >>>>Marker of viral activity >>>>Used to monitor patients w/chronic HBV -Prevention -->Vaccine -->Screening blood donors -->Safe sex practives -->Avoid needle sharing -->HBIG: if unvaccinated or nonresponder -Screening guidelines -->+ risk factor or exposure hx -->All blood donors -->Prenatal care -->Consider if any patient presenting abnormal LFTs, signs/sx's of hepatitis

Discriminate among the common types of virally transmitted hepatitis (A, B and C) in terms of epidemiology, risk factors, serology, prevention, treatment and screening guidelines: Hepatitis C.

Hepatitis C -Symptoms -->60-70% of cases are subclinical; >>>>25% will develop jaundice >>>>Chronic carriers: -----75-85% infected adults -----50-85% infected children >>>>10-20% develop liver failure >>>>1-6% develop hepatocellular -Epidemiology -->C is for chronic -->Single stranded RNA virus; enveloped -->Evades immune response -->Chronic infection occurs in 85% of cases -->Main indication for liver transplant -Risk factors -->Injection drug use -->Transfusions prior to 1992 -->HIV coinfection -->Born between 1945-1965 -->Tattoos, piercings (especially international) -->Hemodialysis -->Maternal-fetal transmission -Serology -->Anti-hepatitis C antibody detectable >>>>Average 7 wk after exposure (4-10 wk) >>>> >97% positive at 6 months -->99% sensitive -->May be negative if immunocompromised -->Antibody persists in majority -->Antibody titers may decline in some if no chronic viremia -Prevention -->Screen blood products for HCV Ab, HCV RNA -->Safe sex practices -->Using clean needles/avoid sharing needles -->Prenatal testing -->No evidence of efficacy of current preparations of immune globulin; no vaccine -Treatment -->Hepatitis C can be cured! Treatment managed by ID or hepatologist specialist (referral) -Screening guidelines -->Anyone with positive risk factors: including anyone born between 1945-1965 (test at least once) -->Abnormal LFT on workup -->Use HCV Ab test >>>>If reactive, proceed with HCV RNA test -->Always test for HIV as well -->Screening antibody test: anti-hep C antibody -->Confirmatory tests: >>>>Nucleic acid test (NAT) -----Qualitative RT-PCR for HCV RNA in plasma -----Positive by 2-3 weeks after acute infection -----In chronic infection, detection of RNA varies over time but should remain elevated

Discriminate between the clinical presentations and lab/imaging findings for non-alcoholic fatty liver disease (NAFLD), including NASH.

Histologically for NAFLD -5% of hepatocytes resemble adipocytes Radiographically for NAFLD -Typically visible on CT or US once >30% adipocytes -Ultrasound: enlarged liver with coarse echotexture or fatty infiltration -CT: enlarged liver with hyperattenuation NASH lab findings -Elevated AST and ALT, typically in the double digits to low hundreds

Develop an appropriate diagnostic work-up plan for a patient presenting with abnormal liver function concerning for NAFLD.

History -Alcohol intake -Medical hx (risk factors) -Family hx (Wilson's, A1AT, Hemochromatosis) -Medication review (MTX, amiodarone) Labs -Hepatic function panel (AST, ALT) -A1c -Lipid panel -If AST and ALT elevated: -->Hepatitis C antibody -->Hepatitis B surface antigen -->Ferritin + iron panel --> +/- A1AT --> +/- Ceruloplasmin -If AST/ALT >5x ULN: autoimmune hepatitis panel

Demonstrate an appropriate work-up for neonatal jaundice.

History and physical -Know MOC's blood type and Rh -Any family history of hemolytic disease? -Any maternal history of infections during pregnancy? Hepatitis B status? -Prematurity? -Medications? -Baby's diet history and stooling patterns -Physical findings consistent with intrauterine infections? -Hepato- or splenomegaly? -Hydration status Labs -Bilirubin level -->Generally, in the first week of life, if there is no cause to suspect hepatitis, obtain a transcutaneous bilirubin level. -->Indications for a bilirubin level: >>>>Baby appears jaundiced -----Very subjective -----Difficult to assess in dark skinned babies >>>>Compelling risk factors for hyperbilirubinemia -----ABO or rh "set-up;" ie. Risk for immune-mediated hemolysis -----Family history to suggest genetic causes -----History of, or signs which suggest viral infection -----Prematurity -----Asian -Total bili: Measures all bilirubin fractions in serum -Direct bili measures 90% of conjugated bili. -Ordering "fractionated" bili will get you total and direct values. -Indirect is a calculated value: -->Total - direct = indirect Interpreting lab values -Level of concern should take into account baby's age in hours -Concern lessens with time -Prematures are at greater risk for complications -Step 1 is to interpret and consider the transcutaneous bilirubin level. -->Is the level high enough to warrant a blood draw? -->In general - if the Tcb is in the HIRZ we will draw a serum bilirubin. -->Very important to keep the maternal and baby history in mind when making these decisions.

Explain the major etiologies of cirrhosis.

Inflammation -Viral -->Hep B (15%) -->Hep C (26%) -Schistosomiasis -Autoimmune -Sarcoidosis Toxic -ETOH (21%) -Methotrexate Genetic/congenital -Primary biliary cirrhosis -A1-antitrypsin deficiency -Hemochromatosis -NAFLD -Wilson disease CHF Veno-occlusive disease -Budd-chiari syndrome Unknown -Cryptogenic 18%* most cryptogenic actually NAFLD

Identify key signs and symptoms of neonatal jaundice.

Initial presentation -Jaundice in the newborn is a generally mild, transient physiologic increase in bilirubin occurring in a healthy, full term baby -Jaundice first becomes visible in the face and forehead and progresses caudally to the trunk and extremities

Prepare a management plan including appropriate referral, lifestyle modifications and patient education for a patient diagnosed with non-alcoholic fatty liver disease (NAFLD).

Management plan: in primary care office -The most important tx for NASH is weight loss through healthy diet and exercise → there are no medications with grade A recommendations for tx of NASH -About 10% weight loss (and maintenance) can reverse NASH, there is no single diet that has been shown to be better than another -->Limit consumption of fructose containing beverages -->1-2 cups of caffeinated coffee daily may be helpful -Counsel against alcohol intake (<1 drink/day women, <2 drinks/day men) -Treat diabetes -Treat hyperlipidemia -Control blood pressure Management plan: in the specialist's office -Who should be referred to hepatology/GI? -Depends on your institution and your comfort level. At CU, there is an integrated NASH clinic for any stage of disease. -Continue in primary care -->If low risk by surveillance scores -->If you are making progress with lifestyle change and risk modification -Refer for intermediate or high risk of fibrosis -->VCTE (vibration controlled transient elastography) -->Liver biopsy Preventing mortality -Liver (cirrhosis, liver failure) -Oncologic (hepatocellular carcinoma in those patients with cirrhosis) -->Screen all patients with NASH and cirrhosis q6m for HCC with US -Cardiovascular (ASCVD risk) NAFLD fibrosis score (NFS) -Use MD calc -->BMI, impaired glucose tolerance (y/n), AST, ALT, platelets and albumin

Describe how acetaminophen can lead to acute liver failure.

Maximum daily dose ≤ 4 g per 24 hour period -Therapeutic dose: -->Adults: 325-1000mg/dose q4-6h prn -->Children: 10-15mg/kg/dose q4-6h prn Metabolism of APAP -85-90% is metabolized through phase II pathways, then excreted in the urine - ~10% metabolized through phase I oxidation, specifically via CYP2E1, to N-acetyl-p-benzoquinoneimine (NAPQI) -->NAPQI is conjugated by glutathione -2% is excreted unchanged in urine Hepatotoxicity -42% of acute liver failure were attributed to APAP -Intentional overdose 44% vs unintentional overdose 48% Pathophysiology of hepatotoxicity -Hepatotoxicity occurs in dose-dependent manner -At toxic doses: -->Sulfation & glucuronidation pathways → readily saturated -->APAP is metabolized through CYP2E1 to NAPQI -->Increased NAPQI production → saturating/depleting GSH stores >>>> ~70-80% GSH depletion, NAPQI binds to hepatocytes (irreversible) → NAPQI-protein adducts → cellular injury >>>>Change in CA hemostasis >>>>Mitochondrial dysfunction with ATP depletion >>>>DNA damage >>>>Intracellular protein modification >>>> → these all lead to NECROTIC CELL DEATH -3 methods of toxicity -->Overdose -->Excessive CYP activation -->Depletion of GSH stores

Identify the risk factors for the development of pathologic jaundice in the newborn.

Nonpathologic causes of neonatal hyperbilirubinemia -Breastfeeding -->Early-onset breastfeeding jaundice is the most common cause of unconjugated hyperbilirubinemia -->Breastfeeding exaggerates physiologic jaundice in the first postnatal week because of caloric deprivation, leading to an increase in enterohepatic circulation -->Mild dehydration and delayed passage of meconium also play roles -Prematurity -->Hyperbilirubinemia is more common and more severe in preterm infants and lasts longer -->The outcome is related to the relative immaturity of RBCs, hepatic cells, and GI tract Risk factors for pathologic hyperbilirubinemia: -Increased bilirubin production -Deficiency of hepatic uptake -Impaired conjugation of bilirubin -Increased enterohepatic circulation

Describe the clinical presentations of cholecystitis, cholelithiasis and cholangitis.

Symptoms of biliary disease -Many patients with gallstones remain asymptomatic - NTD if seen on imaging without symptoms -Pain -> specifically RUQ and can radiate to back, often intermittent and following consumption of fatty meals -Nausea/Vomiting -Fever -Jaundice* → noticeable jaundice on exam usually occurs when bilirubin level > 3; will see jaundice in skin, sclera, and oral mucosa Cholecystitis clinical presentation -Inflammation/infection of gallbladder typically 2/2 obstruction from a gallstone -Acute cholecystitis is inflammation of the gallbladder and is related to the presence of gallstones in 90-95% of cases -The difference between cholecystitis and cholelithiasis include biliary colic >6 hours and constitutional sx's such as fever and malaise -Murphy sign Cholelithiasis clinical presentation -Gallstones within the gallbladder -Abdominal pain that can be going on for months due to the intermittent obstruction of the gallbladder neck by gallstones -Biliary colic, which is also termed symptomatic cholelithiasis (gallstones), is the most classic hx finding in biliary pathology → due to intermittent obstruction of the gallbladder neck by gallstones -->This describe episodic RUQ or epigastric pain associated with N/V, which is caused by gallstones intermittently obstruction at the neck of the gallbladder -->Symptomatic cholelithiasis occurs as a result of supersaturation of bile with cholesterol (70%), pigments such as bilirubin (20%) or both (10%) combined w/delayed emptying of the gallbladder (stasis) -->Pts may often report previous episodes in association w/ fatty meals -->In uncomplicated symptomatic cholelithiasis, this pain may last 4-6 hrs before spontaneously resolving Cholangitis clinical presentation -Infection of the biliary ducts causing systemic illness; life threatening -Inflammation of the bile ducts and is most often caused by a polymicrobial bacterial infection -->Unlike cholecystitis, >90% cultures in cholangitis will be (+): E. coli, klebsiella, enterobacter account for most gram-negative cultures -Biliary obstruction - such as from a stone or neoplasm - serves as a major factor in its pathogenesis -Charcot triad → pain + fever + jaundice = classic acute cholangitis -Reynolds pentad → pain + fever + jaundice + AMS + hypotension = emergent acute cholangitis