Hepatobiliary Board review

1. HepatobiliaryBoard review Darrell Laudate 6-16-10 AM Report

2. Approach to Abnormal LFTs First important to attempt to sort out hepatitis vs cholestatic liver disease

3. Hepatitis • Hepatitis typically has elevations of AST/ALT • Present typically with fatigue, nausea, mild upper abdominal pain, and juandice • Recall the typical culprits of AST/ALT elevations of the thousands • Viral, toxins, shock/ischemia, occasionally AIH • However, an acute increase in biliary pressue (e.g. from choledocolithiasis can also cause transient AST elevations as high as 1000 but returns to normal after 48hrs • Serum Alk Phos may not be elevated

4. Cholestatic Diseases • Typically heralded by elevations of AlkPhos • Refers to injury of the microscopic ducts (e.g PBC), large bile ducts, (e.g pancreatic cancer with CBD obstruction) or both (PSC) • Infiltrative diseases can also cause elevated AlkPhos yet near normal serum bilirubin • Any systemic inflammatory process such as an infection or immune disorder may result in a mixed pattern

5. Serum Bilirubin • What is the fraction? • Overproduction of bilirubin (e.g. hemolysis or hematoma resorption) is associated with ≤ 20% conjugated bilirubin fraction • Hepatocyte dysfunction or impaired bile flow typically causes a hyperbilirubinemia with ≥ 50% conjugated bilirubin fraction • Direct hyperbilirubinemia more common than indirect in those with jaundice • Abdominal pain, fever, and/or palpable GB with direct hyperbilirubinemia suggests a large bile duct obstruction

6. Bilirubin (continued) • Viral hepatitis risk factors, a total bilirubin > 15mg/dL and persistent AST/ALT elevations suggest hepatocellular injury • In patients with acute hepatocellular dysfunction, improvement in serum bilirubin levels often lags behind improvement in ALT/AST

7. Synthetic Liver Function (PT and Alb) • Abnormal PT and Alb levels imply severe hepatocellular injury • Note that PT may also be elevated from Vit K deficiency (via Abx administration, prolonged fasting, samll-bowel mucosal disorders (celiac), or severe cholestasis leading to fat-soluble deficiencies) • Vitamin K will improve the INR within 2 days with Vitamin K but will have no effect if due to liver disease with poor synthetic dysfunction

8. MKSAP Questions

9. Question 24 • 30-year-old woman is evaluated because of an abnormal serum total bilirubin level detected when she had a life insurance examination. Medical history is unremarkable. Her only medication is an oral contraceptive agent. Physical examination is normal. • Labs: Hgb 13; MCV 90; Total bilirubin 2.4; Direct bilirubin 0.2; AST 23; ALT 25; Alkphos 90

10. Question 24 (continued) • Which of the following is the most appropriate management at this time? • Discontinue the oral contraceptive agent • Cholestasis due to an oral contraceptive agent will typically cause conjugated (direct) hyperbilirubinemia and an elevated serum alkaline phosphatase level • Repeat the liver chemistry tests in 3 months • Evaluate for the presence of hemolysis • Patients with hemolysis significant enough to cause unconjugated hyperbilirubinemia typically low Hgb and abnormal MCV • Schedule abdominal ultrasonography • Ultrasound may be a helpful study for direct hyperbilirubinemia as it is usually associated with liver disease • No additional diagnostic studies are indicated • An isolated indirect (unconjugated) hyperbilirubinemia in an asymptomatic patient with a normal Hgb level suggestive of Gilbert's syndrome, no further work-up indicated.

11. Gilbert’s Syndrome • Common, benign inherited disorder associated with indirect hyperbilirubinemia (with serum total bili > 3.0mg/dL but direct is 0.3mg/dL) • Recall that the Bilirubin will typically rise during illness or fasting periods • Presumptive diagnosis can be made in an otherwise healthy individual with an isolated indirect hyperbilirubinemia and a normal Hgb.

12. Question 32 • 37yo F with history of hypothyroidism (on Levothyroxine) presents with 1-week history of fatigue, jaundice, and slight fever. She traveled to Mexico 5 months ago and received one dose of hepatitis A vaccine before her trip. Physical examination significant for mild jaundice and hepatomegaly. • Labs: CBC normal; TSH normal; AST 310; ALT 450; Alkphos 180; total bili 2.3

13. Question 32 (continued) • Which will confirm the diagnosis? • Anti-mitochondrial antibody • Serologic marker for PBC, a cholestatic disease, thus will have a typically higher AlkPhos and T bili, lower AST/ALT • Antinuclear antibody and anti–smooth muscle antibody • Most likely AIH given concomitant autoimmune thyroid disease and abnormal liver test results. Antinuclear antibody and anti–smooth muscle antibody titers should therefore be obtained (titers >1:80 for both assays support the diagnosis) • IgM antibody to hepatitis A virus (IgM anti-HAV) • Does have travel risk factor but this was 5 months ago, incubation period for Hep A is typically 2-6 weeks of exposure. Furthermor she also received 1 dose of the Hep A vaccine before travel, which typically protects people for at least 4 weeks • Serum acetaminophen • Measurement of Acetaminophen level is appropriate for acute hepatitis of uncertain cause but is typically associated with more significantly elevated AST/ALT values and is typically not associated with the week-long prodrome noted prior to presentation • Endoscopic retrograde cholangiopancreatography • ERCP is indicated for evaluation of suspected biliary obstruction and could be considered given the fever, jaundice and acutely elevated ALT/AST values but the absence of pain makes obstruction very unlikely

14. Autoimmune Hepatitis • Typically develops in patients 20-40 years old • Females> Males (3.6:1) • 1/3rd to 1/2 have concomittant autoimmune disease • Most pts have features of chronic disease but up to 40% will have an acute or fulminant presentation • Fatigue present in 85%; jaundice (46%), anorexia (30%), myalgias (30%), diarrhea (28%) • Acne, hirsutism, menstrual irregularities, and fever are less common • Pruritis and weight loss are uncommon thus alternative etiologies should be considered

15. AIH (continued) • Some patients have features of both autoimmune hepatitis and a cholestatic liver disease • Referred to as an overlap syndrome • Exam often shows enlarged liver (78%) but otherwise typically normal despite presence of advanced disease • AST/ALT typically elevated (typically 150->1000 but often < 500) • Serum gamma globulin ≥ 1.5 of upper limit of normal • Mild hyperbilirubinemia (often < 3mg/dL) present in 83% • Elevated AlkP often present but values > 2x normal suggest another disorder • ANA, Anti-smooth muscle Ab, or antibody to liver/kidney microsome type 1 (anti-LKM1) is present in 87% • typically titers ≥1:80 support diagnosis • Biopsy shows Interface hepatitis with portal plasma cell infiltrate.

16. Treatment of AIH • Prednisone alone or Pred + Azathioprine associated with remission in 80% at 3 years • Relapse occurs in 50-86%, typically within 6 months of withdrawal of therapy & associated with an increase in AST/ALT • Relapse treatment is same as initial treatment • Liver transplant reserved for patients who do not respond to treatment alone • AIH can develop in the transplanted liver but is typically mild • Prognosis excellent for patients with treated AIH and is same for that of healthy persons matched for age, sex, and geographic location

17. Question 133 • 21yo F brought to ER by her roommate for slurred speech, tremor, and clumsy gait. Roommate last saw patient 2 days ago and does not know how long these changes have been present. Roommate believes the patient is health and does not take any prescription medications. However, a decline in her school performance over the last several months has been noted. PE shows she is jaundiced, tremulous, and delirious. • Labs: Hgb 8.2, WBC 6000/µL, plts 250,000/µL AST 250, ALT 275, AlkP 40, t bili 8.5 (direct 1.5)

18. Question 133 (continued) • Which of the following studies is most likely to suggest the diagnosis? • Measurement of serum acetaminophen • Should always be obtained for evaluation of her AST/ALT but does not explain all of her features, e.g. prolonged cognitive decline, hemolytic anemia • Measurement of serum ceruplasmin • Her chronic progressive decline along with her liver test abnormalities and evidence of hemolytic anemia (via a disproportionate elevation of the T bili) are highly suggestive of Wilson’s. A ceruplasmin level <20mg/dL will be supportive of this diagnosis. • Measurement of ANA and serum gamma-globulin • Helpful in diagnosis of AIH but this diagnosis would be hard to explain her cognitive deficits and hemolysis • Serologic studies for viral hepatitis • Should always be done with AST/ALT elevations but presentation and labs studies are lab studies are not strongly suggestive of viral hepatitis (more likely to have more significantly elevated AST/ALT; AlkP not likely • Urine Toxicology Screen • Would explain her overt psychosis and hepatitis but again would not explain her hemolytic anemia

19. Wilson’s Disease • A condition of aberrant biliary copper excretion that should be considered in a young patient with abnormal liver chemistry studies • A low ceruplasmin (esp. < 20mg/dL) is most likely to be strongly supportive of Wilsons • Hepatic Manifestations range from asymptomatic LFT elevations to fulminant hepatic failure • Copper deposition in the basal ganglia manifests as cognitive decline to overt pyschosis or delirium • 1/3rd will present with Parkinsonian features • Also associated with cardiomyopathy, endocrine dysfunction, and Fanconi’s syndrome

20. Wilson’s Disease (continued) • PE may show the Kayser-Fleischer rings (usually can only be seen on slit lamp examination) • Labs may show variable AST/ALT elevations but Alk Phos will typically be lower than normal • A ceruplasmin will typically be < 20mg/dL with Wilson’s but this test is neither confirmatory nor diagnostic

21. Wilson’s Disease (continued) • Wilson’s should be considered in a young patient with characteristic clinical features and a serum ceruplasmin • An elevated urine copper level (usually >250ug/24h is also characteristic • Biopsy will confirm the diagnosis via hepatic copper concentration

22. Treatment of Wilson’s • Pencillamine is in the initial therapy of choice, is lifelong • Side effects include neurologic deficits, hypersensitivity reactions, bone marrow suppression, and autoimmune disorders • Trientine and zinc acetate are alternative agents • Transplant indicated for those with fulminant disease or ESLD who do not respond to medical therapy • Significant improvement in neurologic function may occur s/p transplantation thus severe neurologic dysfunction should not be a contraindication to transplantation

23. Question 9 • 42yo F w/ history of dysmenorrhea (on estrogen/ progesterone) and hypothyroidism (on levothyroxine) has progressive fatigue without dyspnea, chest pain, or systemic symptoms. She sleeps well at night with no features of sleep apnea. Exam significant for slight but nontender thyromegaly and xanthomas on extensor surfaces. Labs: nml CBC & TSH; AST 25, ALT 32, t bili 1.1, AlkP 278

24. Question 9 (continued) • In addition to fasting serum lipid profile, which of the following studies would most likely be helpful in establishing the diagnosis? • Antimitochondrial antibody assay • 80% of PBC pts report fatigue but presence of xanthomas and elevated AlkP are characteristeic of PBC; Antimitochondrial Antibody titer ≥ 1:40 present in > 90% of PBC pts • Serum 25-OH Vitamin D • Although metabolic bone disease is associated with PBC, it vitamin D deficiency would not explain exam/lab findings • ERCP • Indicated for assessing cholestatic disease that affects large ducts (such as PSC) but would not be helpful in the diagnosis of PBC • Abdominal U/S • Helpful in detecting bile duct dilatation for those with an elevated AlkP but would be neither sensitive or specific for diagnosis PBC as U/S may be normal in PBC

25. PBC • Chronic, progressive, autoimmune cholestatic liver disease • Occurs predominantly in females (80-90%) between ages of 40-60 years old • 80% of PBC pts report fatigue but presence of xanthomas and elevated AlkP are characteristeic of PBC • Localized or generalized pruritis frequently develops; often in the perineal area, or the palmar/plantar surfaces and worsens at night or in a warm environement • Jaundice or abdominal pain may also develop • However many patients may be asymptomatic on presentation • Other autoimmune diseases are frequently present • Metabolic Bone disease, hypercholesterolemia, and fat-soluble Vitamin deficiencies are common

26. PBC (continued) • Exam typically include: • Skin thickening and hyperpigmentation from repeated excorations • Exanthomas, xanthelasma and • Hepatamegaly • Advanced disease may have clinical manifestations of portal hypertension

27. PBC (continued) • Diagnostic triad associated with PBC includes • Cholestatic liver profile • Positive Antimitochondrial antibody titers • >1:40 titers is serologic hallmark occurring in 90-95% of patients • Compatible histologic findings on liver biopsy • AlkP and GGT are usually elevated 10x or more above normal • Bilirubin increases with disease progression thus is a helpful prognostic factor • AMA titers do not correlate severity or prognosis • Biopsy characteristically shows nonsuppurativecholangitis plus findings ranging from bile duct lesions to cirrhosis

28. Question 105 • 42yo M is evaluated after an elevated Alk Phos is noted during a life insurance exam. Denies pruritis, abdominal pain, or jaundice. He has loos bowel movements for many years and occasionally has rectal bleeding, which he attributes to hemorrhoids. PE is unremarkable. Labs show a Hgb of 11.9, MCV 74, AST 45, ALT 52, Alk Phos 620, t bili 2.1 (1.6 direct)

29. Question 105 (continued) • Which of the following diagnostic studies is most appropriate at this time? • Abdominal U/S • May show bile duct dilatation but this is a non-specific finding • CT scan of the abdomen • May show bile duct dilatation but this is a non-specific finding • ERCP • PSC most likely diagnosis but this is confirmed with ERCP or MRCP showing a string of beads” pattern of the biliary tree. His chronic loose stools and rectal bleeding is likely to due to ulcerative colitis that often accompanies PSC in most patients. • HIDA scan • May be helpful for diagnosing acute cholecystitis, which is unlikely given lack of pain • CEA determination • Metastatic colorectal cancer should be considered in a patient with rectal bleeding and LFT elevations. However, the chronic nature of his altered bowel habits makes cancer unlikely. Furthermore, CEA is neither specific nor diagnostic for colorectal cancer

30. PSC • Chronic cholestatic liver disease characterized by progressive bile duct destruction and may lead to secondary biliary cirrhosis • 3M : 1F, typically occurs between 20-30y • 80% of PSC patients have IBD, typically UC • Conversely only 5% of UC develop PSC • Also associated with bacterial cholangitis, pigmented bile stones, steatorrhea, malabsoption and metabolic bone disease

31. PSC (continued) • Most commonly presents as pruritis, jaundice, abd pain, and fatigue • Almost 50% are asymptomatic at initial diagnosis • More advanced disease may have cirrhosis and its associated complications • Labs fit a cholestatic liver profile with Alk Phos 3-5x normal and mild hyperbilirubinemia • ERCP or MRCP confirms diagnosis with findings of multifocal strictures and dilatation of the intra- and extrahepatic bile ducts • Aka “beads on a string

33. PSC (continued) • Liver biopsy is usually done for staging rather than dianosis and may show findings ranging from portal hepatitis to biliary cirrhosis • Classic histologic lesion termed periductal (“onionskin”) fibrosis is only in 10% of biopsy specimens

34. PSC (continued) • PSC pts are at risk for developing cholangiocarcinoma with a lifetime prevalence of 10-30% • Detection at an early stage is difficult despite availability of CA12-9, CEA, cytologic sampling and advanced imaging techniques • Also have risk for HCC if cirrhosis is present • Pts with both PSC and UC have a higher risk of colorectal neoplasia compared to UC alone pts • Should have aggressive surveillance immediately after diagnosis for both diseases

35. Treatment of PSC • Management includes • Assessment of dominant strictures • Treatment of superimposed bacterial cholangitis • Symptomatic therapy • Median survival after diagnosis is ~12 years • Only transplant improves overall survival and quality of life

36. Question 54 • 23yo F w/ no PMH presents with an 8-month history of dyspnea and dry cough. Only medication is an OCP. PE significant for bilateral crackles on lung ausculation and mild hepatomegaly. Labs: CBC normal; AST 45; ALT 55; Alkphos 430 CXR shows shows mild diffuse pulmonary infiltrates but normal heart size. PPD is negative. Abdominal U/S shows mild hepatomegaly without bile duct dilatation.

37. Question 54 (continued) • What is the most likely diagnosis? • Amyloid • Causes HM and cholestasis but is usually accompanied by evidence of other organ involvement suchas nephrotic syndrome or neuropathy. Also is rare in young pts. • Sarcoid • High serum Alk Phos is commonly associated with infiltrative liver disease and with presence of pulmonary infiltrates and hepatomegaly. Liver biopsy showing noncaseating granulomas will confirm the diagnosis of sarcoidosis • Tuberculosis • Usually presents with a fever and + PPD • Primary biliary cirrhosis • Disease of middle aged women and generally does not cause pulmonary findings • OCP induced cholestasis • Can rarely cause cholestasis but again would not be associated with pulmonary findings

38. Question 96 • 63yo F w/ 3 month history gradually increasing abdominal distention and fatigue. She has no other symptoms and medical history is noncontributory. PE shows jaundice, mild muscle wasting, Xanthelasma spider angiomata, hepatosplenomegaly and moderate abdominal distension consistent with ascites. Labs shows Hgb 12.3, plts 102, AST 53, ALT 47, AlkP123, T bili 3.2, Alb 2.9, INR 1.3 U/S shows hepatomegaly, coarse echotexture of liver, patent hepatic/portal vessels, mild splenomegaly, moderate ascites, and no bile duct dilatation Paracentesissignficant for 80 PMNs, protein of 1.4g/dL, Albumin of 0.7g/dL

39. Question 96 (continued) • Which of the following is the most likely diagnosis? Key here is the SAAG (2.9-0.7 = 2.2) • Peritoneal carcinomatosis • Has a low-gradient-high protein ascitic fluid • Cirrhosis • SAAG > 1.1g/DL and fluid protein of < 2.5g/DL is consistent with siusoidal hypertension from chronic liver disease such as cirrhosis • Budd-Chiari syndrome • High-gradient, high protein ascitic fluid • Dilated Cardiomyopathy • High-gradient, high protein ascitic fluid

40. Serum-to-ascites albumin gradient (aka SAAG) • Accurately identifies the presence of portal hypertension • Patients with heart failure and ascites can narrow their gradient during diuresis, whereas the SAAG in the setting of cirrhosis remains stable unless blood pressure or portal pressure decreases significantly.

41. Question 7 • 38yo F w/ HTN presents with a 3 month history of intermittent, moderately severe epigastric pain that is sometimes associated with nausea and vomitting. The pain typically begins abruptly, lasts for 30-120 minutes before spontaneously abating, and sometimes awakens her at night. May be precipitated by eating. Current Meds include HCTZ. PE shows mild subjective epigastric tenderness only. Labs show Hgb 12.1, QBC 10.1, AST 312, ALT 468, AlkPhos 190, T bili 0.7, Amylase 182 Abd U/S shows several small gallstones but no GB wall thickening or pericholecystic fluid; negative U/S Murphy’s sign. CBD is 7mm (normal <6mm)

42. Question 7 (continued) • Which of the following is the most likely cause of her abdominal pain? • Acute Pancreatitis • Unlikely given episodic (vs constant) nature of her pain. Additionally will typically see an Amylase rise of 2-3 times the upper limit of normal • Acute Cholecystitis • U/S is not supportive of this diagnosis. • Choledocholithiasis • Typical presentation is with epigastric rather than RUQ pain that is intermittent, moderate-severe, not associated with N/V and can be nocturnal. LFTs particularly AST/ALT are almost always abnormal. CBD may be normal to slightly increased. Concomittant gallstones are present in 90%. • Peptic Ulcer Disease • Typically present with epigatric pain that is relieved with eating

43. Gallbladder Disease Overview Chole this, Chole that, Holy Moley

44. Cholelithiasis • Affects 20 million Americans but vast majority are asymptomatic • When symptoms do present, it is typically that of biliary pain or colic • Once symptoms are present, ~50% will have recurrent symptoms • Therefore Cholecystectomy is indicated for most symptomatic patients with laprascopic preferred over the open procedure • Patients with symptomatic gallstones have a 1-2% annual risk of developing complications • Including acute cholecystitis, choledocholithiasis, Mirizzi’s syndrome, and cholecystoenteric fistula

45. Acute Cholecystitis • Most common complication of cholelithiasis • Due to impaction of a stone within the cystic duct that subsequently becomes distended and GB may become inflamed • Secondary bacterial infection of bile/GB occurs in 50% of acute cholecystitis patients • These patients will have fever and biliary pain that persists for more than 6 hours • Murphy’s sign is relatively specific on PE

46. Acute Cholecystitis (continued) • Abd U/S may show the stone but also frequently shows a thickened gallbladder wall and pericholecystic fluid • If findings are uncertain, a HIDA scan may fail to visualize the GB and confirms the suspicion of cystic duct obstruction

47. Acute Cholecystitis (continued) • Treatment includes IVF and antibiotics followed by lap chole • Patients with repeated episodes of acute cholecystitis characterized by a shrunken gallbladder containing stones or sludge • Therefore paitents with more than one episode of acute cholecystitis require cholecystectomy (lap vs open)

48. Choledocholithiasis • ~5-19% of patients with cholelithiasis have concomittant CBD stones • These are stones that have migrated from the GB or formed de novo within the CBD • Also often asymptomatic but may cause epigastric/RUQ pain (that radiates to the back), biliary pancreatitis, or life-threatening cholangitis • Should be suspected in a patient with cholelithiasis, development of abnormal LFTs (typically AST/ALT that can mimic that of hepatitis) and dilatation of the CBD on imaging • Rarely the stone may be identified as well

49. Choledocholithiasis (continued) • U/S while very sensitive in detecting cholelithiasis is only 30-50% sensitive in detecting CBD stones but can be suggested by CBD dilatation • Helical CT scan is more sensitive (80%) • EUS very senstive (90%)’ • MRCP is less sensitive in detecting small CBD stones • ERCP is sensitive and allow for stone extraction at the same time. It is therefore the preferred test when cholethiasis is suspected • Also indicated for patients with acute cholangitis and prior to lap cholecystectomy when choledocholithiasis is highly suspected on imaging and liver chemistry studies.

50. Management of Choledocholithiasis • Dependent on comorbid conditions and availability of experts (laproscopic, endoscopic, and intervential radiology) • ERCP indication for those with cholangitis or for those with pancreatitis complicated by cholangitis • Contraindicated in patients with preveious enteric reconstruction (e.g Billroth II, Roux-en-Y), complex stones > 1cm in diameter, or a biliary stricture • Laproscopic transcystic bile duct exploration also effective in detection and removal of CBD in 90% if expertise is available • Laproscopic choledochotomy with stone extraction +/- T-tube placement should be consider if transcystic bile duct exploration is unsuccessful