Clinical Pathological Conference

Mack C. Mitchell, Jr., M.D.Johns Hopkins Bayview

Medical CenterFebruary 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 pO2 110 (2 l FIO2); pCO2 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

0.4

0.5

0.7

2

2.5

20

0 5 10 15 20 25

Percent of Population

Nonalcoholic Fatty Liver Disorder

Nonalcoholic steatohepatitis

Chronic Hepatitis C

Alcoholic Liver Disease

Hemochromatosis

Chronic Hepatitis B

Villanova et al. Hepatology 2005.

0

25

50

75

% N

AS

H

Neither HTN DM Both

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

Compensatedcirrhosis

Decompensatedcirrhosis

Death

Development of

complications:Variceal hemorrhage Ascites

Encephalopathy Jaundice

Bleeding

Infection

Hepatorenal syndrome

What is cause of death?

All patients with cirrhosisAll patients

with cirrhosis

Decompensated cirrhosis

Decompensated cirrhosis

Gines et. al., Hepatology 1987;7:122Gines 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

60

120 180

40%

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

3500-5000 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