Clinical Pathological Conference Mack C. Mitchell, Jr., M.D. Johns Hopkins Bayview Medical Center February 2, 2010

Questions to address What is the most likely etiology of her liver disease? What is the most likely cause of death?

Process of Differential Diagnosis Collecting the facts Clinical history Physical examination Ancillary examinations (lab and imaging) Observation of the course of illness Analyzing the facts Critically evaluate data Select 2 or 3 central features List diseases in which the features are encountered Reach final diagnosis by selecting the best fit Review all the evidence with final diagnosis in mind

Chief complaint 54 y.o woman with 2-3 yr h/o cirrhosis and several days increased lethargy

History of present illness 2-3 yr h/o cirrhosis with diuretic refractory ascites requiring monthly large volume paracentesis 3 days before admission, large volume paracentesis Increased lethargy and confusion the following day; symptoms progressed despite increased doses of lactulose

Past medical/surgical history Cirrhosis diagnosed 3 yrs ago after development of ascites and easy bruising No viral or autoimmune markers Normal iron saturation No history of alcohol consumption, drug or toxin exposure Possible portopulmonary hypertension Obesity and type 2 diabetes > 20 yrs, insulin therapy > 15 yrs (? Compliance) Chronic kidney disease, baseline creat 1.4

Past history (cont) Monthly large vol paracentesis for 2 yrs No h/o variceal bleeding Few episodes of encephalopathy treated with protein restriction and lactulose Irrelevant data H/O neck abscess H/O C-section H/O ingrown toenail age 9

Social history Medically disabled due to liver disease Active member of Jehovah’s Witness church Lifetime non-smoker and non-drinker Divorced, 2 children

Family history Mother died of complications of diabetes in her late 50’s Otherwise non-contributory

Medications on admission Furosemide Spironolactone Lactulose Metronidazole Pantoprazole Propranolol Darbopoietin (erythropoietin) injection

Idiopathic or “cryptogenic” cirrhosis Cirrhosis of unknown etiology without history of alcohol consumption or viral hepatitis Includes numerous conditions

Differential diagnosis of cryptogenic cirrhosis NAFLD/NASH Hemochromatosis Alpha 1 anti-trypsin deficiency Wilson disease Type IV glycogen storage disease Chronic right heart failure Constrictive pericarditis Budd-Chiari syndrome Sarcoidosis Sclerosing cholangitis Autoimmune hepatitis Primary biliary cirrhosis

Questions for physical exam Evidence of right heart failure Evidence of chronic lung disease Evidence of vasculitis or other autoimmune features (CRST in PBC) Splenomegaly? Hepatomegaly? Ascites?

Physical examination BP 80/46; P 112; R 26; T 97.8; Wt 115 kg Difficult to arouse, oriented only to person; asterixis Scleral icterus Tense ascites, peripheral edema No hepatosplenomegaly 3/6 murmur left upper sternal border, no JVD

Analyzing the facts Long history of diabetes, obesity Recent deterioration with confusion, lethargy Physical findings of ascites, jaundice and III/VI systolic murmur in pulmonic/tricuspid valve area

Differential diagnosis of cryptogenic cirrhosis NAFLD/NASH Hemochromatosis Alpha 1 anti-trypsin deficiency Wilson disease Type IV glycogen storage disease Chronic right heart failure Constrictive pericarditis Budd-Chiari syndrome Sarcoidosis Sclerosing cholangitis Autoimmune hepatitis Primary biliary cirrhosis

Laboratory findings WBC 16,700; left shift 80% polys, 12% bands Hct 34% (baseline 28%) Platelets 71,000 T. bili 6.0; AST169; ALT 43; Alk phos 251, ammonia 39 pO (2 l FIO 2 ); pCO 2 30; pH 7.24

Imaging results Nodular liver Ascites No evidence of mass within liver Previous echocardiogram estimated RVSP of 56

Prevalence of Chronic Liver Disorders in the United States Percentage of population Nonalcoholic Fatty Liver Disorder Nonalcoholic steatohepatitis Chronic Hepatitis C Alcoholic Liver Disease Hemochromatosis Chronic Hepatitis B

Villanova et al. Hepatology % NASH Neither HTN DMBoth NASH is Likely in Those with More Components of MS Predictors of NASH

Angulo, et al. Hepatology 30:1356, 1999 Predictors of Fibrosis in NAFLD Liver biopsies performed in 144 pts with NAFLD Multivariate analysis indicated 4 variables which were significant: Age > 45 (Odds ratio 5.6) BMI > 30 (Odds ratio 4.3) Diabetes mellitus (Odds ratio 3.5) AST/ALT ratio > 1 (Odds ratio 4.3)

Pulmonary complications in cirrhosis Portopulmonary hypertension (POPH) is the elevation of pulmonary artery pressure due to increased resistance to pulmonary blood flow in the setting of portal hypertension. Hepatopulmonary syndrome is characterized by a defect in arterial oxygenation induced by pulmonary vascular dilatation in the setting of chronic liver disease.

What is the cause of cirrhosis? Based on history of obesity and diabetes and absence of other causes, NAFLD is most likely. A1AT phenotype could be checked. Elevated pulmonary pressures are most likely secondary rather than primary.

Chronic liver disease Compensated cirrhosis Decompensated cirrhosis Death Development of complications: Variceal hemorrhage Ascites Encephalopathy Jaundice Bleeding Infection Hepatorenal syndrome What is cause of death?

All patients with cirrhosis Decompensated cirrhosis Gines et. al., Hepatology 1987;7:122 Median survival ~ 9 years Median survival ~ 9 years Median survival ~ 1.6 years Median survival ~ 1.6 years Probability of survival Months % 80% Decompensation shortens survival

Causes of death in cirrhosis Infections: SBP, UTI, pneumonia, bacteremia related to procedures, spontaneous Bleeding: varices, other Hepatorenal syndrome: type I –oliguric renal failure in absence of hypovolemia Hepatocellular carcinoma “Liver failure”—metabolic failure often due to one of above

Hepatorenal syndrome Often develops as a “pre-terminal” event precipitated by infection or bleeding Pathophysiology related to “systemic” arterial vasodilatation leading to ineffective plasma volume with renal arterial vasoconstriction and avid sodium retention

Circulatory dysfunction induced by paracentesis Occurs after large volume paracentesis (usually > 5 liters) Worsening vasodilatation Hyponatremia Activation of renin/angio/aldo system Azotemia Prevented by administration of albumin

Careful re-review of labs Elevated WBC, 16,700 (usual WBC is only in cirrhosis) Elevated BUN/creat ratio (BUN is usually low in cirrhosis) Elevated Hct above baseline Metabolic acidosis (pH 7.24) Patient has volume depletion and evidence of infection, despite absence of fever

Additional diagnostic tests to consider Analysis of ascitic fluid, particularly cell count and differential Alpha fetoprotein

Approach to management of “acute on chronic” liver failure Plasma volume expansion with albumin, rather than crystalloid Vasopressor therapy—constricts peripheral arteries Antibiotics if evidence of infection, albumin improves survival in SBP Encephalopathy does not usually improve with increased doses of lactulose Volume replacement for hemorrhage

Cause of death? Infection, possibly peritonitis Volume depletion probably due to large volume paracentesis These two factors occurred in setting of advanced cirrhosis, with pre-existing abnormalities in vascular tone leading to hypotension and compromised hepatocellular function leading to encepthalopathy, acidosis and coagulopathy