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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
Recommended