ABIM Hepatology Board Review

1. ABIM Hepatology Board Review 9 June 2010

2. General Recommendations • Go to ABIM website and look around • Do as many practice questions as you can • Get lots of sleep • Know where testing center is

3. 2010 ABIM exam

4. 2008 UNC ITE • Commonly missed Hepatology topics • Diagnose and Manage Gilbert’s Syndrome • Elevated indirect bilirubin, esp. during stress or other illness • Genetic test now avail, no treatment needed • Diagnose and treat AIP • Acute intermittent visceral pain and neurologic sx • Urine porphyrins (urine PBG – spot, followed by 24hr ALA, PBG, and porphyrin) • Rx: avoid stressors that exacerbate dz, IV Hemin products • Watch out for vampires • Red urine, phosphorescent teeth, photosensitive skin • 2009 UNC ITE • No specific pattern to missed Hepatology questions

5. Roadmap • Abnormal LFT’s • NAFLD/NASH • ETOH Liver Disease • Viral Hepatitis • AIH/PBC/PSC • Cirrhosis and its complications • ALF • Transplant • Liver disease in Pregnancy • Genetic Liver disease

6. Abnormal LFT’s • Asymptomatic patient • History! • Conceptualize if the pattern • Hepatocellular injury (elevated AST, ALT) • Cholestatic injury (elevated Tbili, AP, GGT) • Assess synthetic function (Tbili, INR +/- Cr) • Most common causes are NAFLD, chronic hepatitis and ETOH

8. NAFLD/NASH • NAFLD encompasses simple steatosis to NASH to cirrhosis • Highly prevalent ~30% • Not all steatosis progresses • NASH is high risk to progress • ~20% develop cirrhosis • Risk Factors • DM, HTN, Hyperlipidemia, Central obesity • Rx is to control risk factors

9. Steatohepatitis • Histologic findings include • Macrovesicular steatosis • Cytologic ballooning • Mallory bodies (eosinophilic concretions within ballooned hepatocytes) • Scattered lobular inflammation

10. ETOH Liver Disease • AST:ALT ratio 2:1 – 3:1 • AST rarely exceeds 300-400 unless another process is present • Elevated GGT, AP may be normal • AFLD • ETOH hepatitis carries 50% mortality rate • Rx Pentoxiphylline 400 TID or prednisilone 40 QD x 1 month

11. Viral Hepatitis • Acute Viral Hepatitis • Most commonly A & B, but all hepatotropic viruses can cause an acute illness • Tests • in general IgM for acute disease and IgG or total for chronic disease • A : HAV IgM • B : HBsAg, HBc IgM • C : HCV Ab*, HCV RNA • D : HBsAg*, HDV IgM • E : HEV IgM – RNA test now avail

13. Viral Hepatitis • Chronic Viral Hepatitis • A & E do not have a chronic form • D can only occur in setting of Chronic B • HBV • Only ~5% of adults get chronic HBV • 90% of neonates get chronic HBV • 20-30% progress to cirrhosis • Rx: INF vs. oral nucleoside analogues • Only treat those with active replication • Usually long term – few seroconvert

14. Viral Hepatitis • HCV • 70-80% exposed develop chronic infection • Current #1 indication for OLT in U.S. • Current therapy is Peg-INF and ribavirin • Genotype 1 most common in U.S. and most difficult to treat • 48 weeks of weekly sq injections and BID ribavirin • Monitor mental health (depression/suicide) • Cytopenias • Thyroid dysfunction • Flu-like symptoms • Fatigue

15. AIH/PBC/PSC • AIH • May present in asymptomatic patient or a life-threatening flare • 30-50 y.o. WF, AST/ALT 400-500 • +ANA, elevated IG levels. Biopsy required for Dx • Plasma cell infiltrate, “interface hepatitis” • Treat with prednisone and long term AZA • Recurs after OLT, but good survival

16. AIH/PBC/PSC • PBC • 90% cases are women • Pruritus and fatigue most common symptoms • Disease of mostly intrahepatic bile ducts • Elevated AP, GGT, +AMA, +ANA • Some patients have clinically identical dz but AMA(-) • “autoimmune cholangiopathy” or “seronegative PBC” • Rx ursodiol 12-15mg/Kg/day

17. AIH/PBC/PSC • PSC • Cholestatic LFT’s, +pANCA, +ASMA, ERCP required for dx (MRCP?) • Large duct disease • Usually widespread but patients may have a “dominant stricture” • “Beads on a string” found at ERCP • 70-80% also have IBD (UC) • 10-15% develop cholangiocarcinoma • Rx Urso (12-15mg/kg –higher doses have inc. mort.), treat dominant strictures, treat episodes of cholangitis, OLT

18. Viral Hepatitis B Hepatitis C Toxic Alcohol, MTX Metabolic Non Alcoholic Fatty Liver disease (NAFLD) Biliary PSC PBC Genetic/Hereditary Hemachromatosis Wilson’s Disease Alpha 1 Antitrypsin Inborn errors of metabolism Others Autoimmune Hepatitis Congestive hepatopathy (aka Cardiac Cirrhosis) Cystic Fibrosis Etiologies of Cirrhosis

19. The liver is unable to process bile resulting in jaundice and scleral icterus Bile pigments deposit in the skin causing pruritus The liver cannot produce clotting factors resulting in coagulopathy The liver cannot make albumin contributing to ascites and edema Capacity to metabolize drugs is reduced leading to longer half lives of active metabolites and accumulation of toxic byproducts Hypoglycemia may occur in end stage disease Scarring leads to increased resistance of blood flow through the liver and results in portal hypertension Pathophysiologic Changes in Cirrhosis

20. Assessing the Severity of Cirrhosis • Liver biopsy can give grade of inflammation and stage of fibrosis • Model for End-Stage Liver Disease (MELD) uses objective data to predict 3 month survival • Used in transplant selection • Bilirubin, INR, Creatinine • Evolving role of serum sodium for prognosis • Exception points for HCC, HPS, others • Child-Pugh score • Divides cirrhotics into class A,B,C to predict 1-2 year mortality • Bilirubin, INR, Albumin, Ascites, Encephalopathy

21. Complications of Cirrhosis • Once a patient develops complications of cirrhosis they have decompensated disease. • Variceal hemorrhage • Ascites • Spontaneous bacterial peritonitis • Hepatorenal syndrome • Hepatopulmonary syndrome • Portopulmonary hypertension • Hepatocellular carcinoma • Hepatic encephalopathy

22. Variceal Hemorrhage • Most devastating complication of cirrhosis and portal hypertension • Occurs in 25-40% of cirrhotics • Prior to current therapy, mortality 30% for a single episode and only 1/3 survived for one year afterwards • Mortality remains high

23. Variceal Hemorrhage • Therapy • Prevention! • All patients with cirrhosis need a screening EGD • Non selective beta-blockers reduce portal hypertension • Endoscopic variceal ligation now accepted as primary prophylaxis as well in new AASLD guidelines

24. Variceal Hemorrhage • Acute bleeding • Endoscopic variceal ligation “banding” • Sclerotherapy • Minnesota tube • Transjugular Intrahepatic Portosystemic Shunt “TIPS”

25. Ascites • Cirrhosis (75%) • Most common cause of ascites • Most common complication of cirrhosis • Other causes occur more frequently in cirrhotics • Malignancy (10%) • Cardiac (3%) • TB (2%) • Pancreatic Ascites(1%) • SAAG calculation

26. SAAG

27. Ascites • Low Sodium Diet (<2g/d) • Managed with Diuretics • Furosemide for volume • Spironolactone for renin-angitensin system and some diuresis • Must watch renal function and sodium closely • Diuretic dosing often limited by hyponatremia • Diuretic induced acute or chronic renal failure is common • Diuretic refractory/resistant ascites requires another intervention • TIPS, Denver shunt, routine LVP

28. Spontaneous Bacterial Peritonitis • Peritoneal fluid with >250 PMN • Typically due to bacterial translocation from gut • E. coli is the most common pathogen • Treat with 3rd gen. cephalosporin or quinolone • Secondary Prophalaxis • Norfloxacin 400mg qd • Ciprofloxacin 750mg q week • SMZ-TMP never has been tested in a trial with mortality but used frequently • Primary prophylaxis for selected patients • Childs C, low sodium, etc…

29. Hepatic Encephalopathy • Reversible decrease in neurologic function • May be subtle from sleep disturbance to outright coma with focal neurologic signs • Often a precipitating factor • Infection • Volume depletion/dehydration • Hyponatremia • Acidosis • Drugs

30. Pathophysiology of Hepatic Encephalopathy • Nitrogenous substances derived from the gut adversely affect brain function • Ammonia is the best known metabolite associated with HE • Compounds gain access to the systemic circulation via decreased metabolism in liver and/or portosystemic shunts • Experimental models describe derangements in glutamine, serotonin, GABA, and catecholamine metabolism.

31. Encephalopathy • First line therapy is lactulose/bowel catharsis • Theoretically lactulose acidifies bowel and prevents NH3 absorption • Non absorbable ABX • Rifaximin • Metronidazole • Neomycin • Misc • Zinc • Special diets (medium/branched chain AA)

32. Hepatorenal Syndrome • Development of acute renal failure in a patient with cirrhosis or fulminant hepatic failure • End stage of a sequence of events that reduces perfusion of kidneys • Clinical presentation • Oliguiria • Low urine sodium (often undetectable) • Bland urine sediment • Systemic hypotension • Absence of another cause of renal failure

33. Hepatorenal Syndrome • Type I • 50% reduction of plasma creatinine clearance to a level below 20ml/min or doubling of serum creatinine in less than 2 weeks. Rapidly fatal. • Type II • Less severe than type I, more indolent and primarily characterized by diuretic refractory ascites.

34. Hepatorenal Syndrome • Treatment options • Liver transplant. Renal dysfunction improves after transplant. • Midodrine (alpha-1 agonist) and Octreotide (somatostatin analog) • Midodrine promotes systemic vasoconstriction, octreotide inhibits vasodilitaion of splanchnic vasculature. End result is improved perfusion of kidneys. • Norepinephrine??? • Vasopressin analogs??? • TIPS??? • Dialysis (only as a bridge to transplant)

35. Hepatorenal Syndrome • Prevention is key in certain clinical situations • SBP – administration of albumin • Primary prophylaxis for SBP in patients with low albumin also reduces HRS • Alcoholic Hepatitis – use of steroids or pentoxiphylline

36. Hepatopulmonary Syndrome • HPS • Liver disease • Increased alveolar-arterial gradient on room air • Evidence of intrapulmonary vascular dilitations (intrapulmonary shunting) • Platypnea and orthodeoxia are the major symptom and sign • No consistent correlation with severity of liver disease (i.e. can be low MELD) • Presence of HPS independently worsens prognosis of liver disease • Spider angiomata and hyperdynamic circulation associated with HPS

37. Hepatopulmonary Syndrome • Etiology • Nitric oxide plays a central role in animal models • Diagnosis • Impaired DLCO on PFT’s, evidence of intrapulmonary shunt on contrast enhanced echocardiography, technetium labeled macro-aggregated albumin scan, and pulmonary angiography • Treatment • Minimal role for medical therapy • Supplemental oxygen • Liver transplant best treatment, reversal of shunting in most patients post transplant.

38. Portopulmonary Hypertension • 1998 WHO symposium defined pulmonary HTN as mean PAP >40mmHG (TR jet 3.0-3.5 m/s) and portopulmonary HTN as pulm HTN in association with portal HTN without other risk factors for secondary pulmonary HTN. • Etiology unknown • Presumed vasoactive substances like seratonin, IL-1, endothelin-1, glucagon, secretin, thromboxane B2 and VIP that are produced by splanchnic circulation and not metabolized by liver plus a genetic predisposition.

39. Portopulmonary Hypertension • Diagnosis via echocardiography or right heart catheterization • Treatment • Similar to idiopathic pulm HTN: anticoagulants, vasodilators, prostacyclins (Flolan), sildenafil. No good data, many contraindications.

40. Hepatocellular Carcinoma • 5th most common cancer worldwide • nearly 1,000,000 new cases annually as of 2007 • increasing incidence • HBV single most important etiologic factor worldwide • Risk increased without cirrhosis • HCV and ETOH main risk factors in West

41. Hepatocellular Carcinoma • Diagnosis possible without biopsy • AFP not sensitive or specific, levels over 200ng/dL highly suspicious for HCC • characteristic appearance with contrasted imaging • HCC has arterial blood supply that demonstrates uptake during early arterial phase and contrast washout in the delayed venous phase • biopsy is warranted in a liver mass larger than 2 cm without typical radiographic findings and no elevation in AFP

42. Hepatocellular Carcinoma • Early Arterial Phase CT • heterogeneously enhancing mass 4-5 cm • Portal Venous Phase CT • Decreased enhancement, iso-enhancing with liver

43. TIPS • Transjugular Intrahepatic Portosystemic Shunt • Shunt placed between hepatic vein and portal vein with goal of reducing portal hypertension • Utilized for varices and refractory ascites • Controversial for HRS and HPS • Lethal for PP-HTN • Complications include hepatic encephalopathy and hepatic failure

44. ALF • Encephalopathy that develops within 8 weeks of acute severe liver injury • Definition has transplant implications • Acetaminophen most common in U.S. • Know the difference between labs showing liver injury and synthetic dysfunction • e.g. decrease in transaminases after acute HBV infection, but INR drifting upwards… • Rapid referral to transplant center

45. Transplant • Status 1 : Acute liver failure • Status 2 : MELD scoring system • TB, Cr, INR. • Score 6-40. Eval @12, transplant over 15. • UNC transplants in 22-26 range • Status 7 : Inactive

46. Liver disease in Pregnancy • Don’t forget about routine liver disease in a patient who happens to be pregnant! • HBV is a sexually transmitted disease • HEV, VZV, HSV hepatitis may be more severe, but risk of acquisition unchanged • Cholestatsis of pregnancy • Puritus can be severe • Check fasting bile acids • Close monitoring (mom is ok, risk to fetus), ursodiol, deliver baby • HELLP • Hemolysis, elevated LFTs, low platelets • Deliver baby • Acute fatty liver of pregnancy • Large, acutely swollen liver on U/S • Deliver baby

47. Genetic Liver disease • Hemachromatosis • C282Y homozygote or C282Y / H63D heterozygote • Ferritin >1000, % sat >90% • Rx phlebotomy or chelation • Don’t be fooled by secondary iron overload • Wilson’s Disease • Ceruloplasm is LOW! • KF rings, 24 hr urine copper confirm dx • A1AT • Homozygous ZZ most common genetic liver disease in kids • Often emphysema develops later

48. Questions?