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Abnormal Liver Tests

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					Abnormal Liver Tests
     Harry Colt, MD
         9/4/07
              Goal

At the conclusion of this session,
participants will be able to initiate
appropriate evaluation and
management of abnormal liver tests.
              Objectives
Participants will be able to:
  1. recognize common patterns of
    abnormal liver tests
  2. list the common causes of
    hepatocellular injury
  3. list the common causes of
    cholestatic disease
  4. initiate further workup of abnormal
    liver tests.
      Why is this important?
 one of the common problems in everyday
 clinical practice
 sorting out the cause, can initially seem
 puzzling
 knowledge of the pathophysiology of the
 enzymes and patterns of abnormalities are
 helpful
Case # 1
    62 yo man with hypertension,
obesity and hyperlipidemia has a
CMP which is normal except for
AST194, ALT132.


What do you want to know and/or
do?
    Evaluation of Abnormal liver test
                includes
 history
 physical
 analysis of enzyme pattern
 1. hepatocellular or cholestatic
 2. magnitude of abnormality
 3. rate of change
 further testing
                 History

HPI
 anorexia, nausea, vomiting, fatigue
 jaundice, pruritus, clay colored stools,
dark urine
           History (cont’d)
PMH
 alcohol use
 medication list
 OTC meds, illicit meds, herbal remedies
 blood transfusions
 sexual history
 occupational history
 raw oysters, clams, etc.
Family history (Gilberts, Wilson’s, hemochromatosis,
alpha one antitrypsin deficiency
                  Physical
    jaundice, hepatomegaly, ascites, RUQ
    tenderness, palmar erythema, spider nevi,
    asterixis, encephalopathy
Pattern of Liver Enzyme Elevation
   Hepatocellular or cholestatic?
   Magnitude of change?
   Rate of change?
Hepatocellular (aminotransferases)
 not liver “function” tests
 sensitive indicators of liver cell injury
 released when liver cell membrane
 damaged
 AST found in liver, cardiac muscle,
 skeletal muscles, kidneys, brain, pancreas
 ALT found in liver, skeletal muscle
Degree of Elevation Important!
    Causes of Hepatocellular Pattern
   alcohol induced liver injury
   medications (prescriptions, OTC, drugs, herbs
   chronic Hepatitis B
   chronic Hepatitis C
   autoimmune
   hepatic steatosis (fatty liver)
   hemochromatosis
   Wilson’s disease
   alpha-one antitrypsin deficiency
   celiac disease
Non-Liver Causes of Hepatocellular
             Pattern
 inherited disorders of muscle metabolism
 Acquired muscle disease
 strenuous exercise
Case # 1
    62 yo man with hypertension,
obesity and hyperlipidemia has a
CMP which is normal except for
AST194, ALT132.

What tests do you want to order?
    Initial Tests (Hepatocellular)
   Hep C antibody
 Hep B Sag (Hep B SAb, Hep B Cab)
 Fe, TIBC
 SPEP
   *increased polyclonal immunoglobulins
   suggest autoimmune hepatitis
   *low alpha one globulin suggests alpha
   one antitrypsin deficiency
-----------------------------------------------------------
Ceruloplasmin (<40 yo)
Additional Tests (Hepatocellular)
 PCR for Hep C RNA
 alpha one antitrypsin phenotyping
 antiendomysial and antigliadin Ab
 ultrasound
 liver biopsy
      Alcoholic Liver Disease
 AST> ALT (at least 2:1)
 if AST twice ALT, 90% have alcoholic liver
 disease
 if AST 3x ALT, 96% have alcoholic liver
 disease
 only rarely in alcoholic liver disease is
 AST >8x normal or ALT >5x normal
                      Hepatitis C
    4 million Americans Hep C antibody positive
    3 million chronically infected (Hep C virus RNA
    present)
   risk factors: blood transfusions, IV drug use,
    tattoos/body piercing, high risk sexual activity, work
    duties
    initial test: Hep C Ab (92-97% sensitivity)
    if positive, confirm with PCR for Hep C virus RNA
    if positive for RNA, consider liver biopsy
    if Hep C and fibrosis, usually treat
                   Hep B
 tests: Hep B Sag, Hep B SAb, Hep B Cab
 Hep B Sag positive,
  Hep B Cab positive         Hep B
 Hep B SAb positive,
  Hep B Cab positive         immune to Hep B
 if Hep B Sag positive, do Hep B e antigen
  and Hep B virus DNA
 if Hep B virus DNA and Hep e antigen
  present, consider liver biopsy and treatment
      Autoimmune Hepatitis
 primarily young to middle aged women
 ♀:♂ = 4:1
 80% of those with autoimmune hepatitis
 have hypergammaglobulinemia on SPEP
 liver biopsy is necessary for diagnosis
 important: amenable to treatment
    Hepatic Steatosis and Nonalcoholic
              Steatohepatitis
 usually only mild elevation of
 aminotransferases
 AST:ALT usually less than 1:1
 ultrasound or CT can identify this
 diagnosis of nonalcoholic steatohepatitis
 requires liver biopsy
 steatosis has benign course
 nonalcoholic steatohepatitis can progress to
 cirrhosis
 weight loss is key to treatment
          Hemochromatosis
 common genetic disorder, autosomal
 recessive; homozygote frequency 1:300
 excessive GI absorption of iron, and
 subsequent iron deposition in heart, lung,
 skin
 screening test: Fe, TIBC
 if Fe/TIBC >45%, consider hemochromatosis
 if abnormal, liver biopsy
 important to diagnose for both individual and
 family
            Wilson’s Disease
 Rare genetic disorder (1:30,000-1:300,000) of
  biliary copper excretion
 Usually onset before age 25, but consider up
  to age 40
 Suspect if psych/neuro problems
 Screen with ceruloplasmin, reduced in 85%
 Also diagnosed by Kayser-Fleischer rings
 24 hour urine for copper excretion – excretion
  of >100g suggests Wilson’s
 Confirm by liver biopsy
  Alpha-one Antitrypsin Deficiency
 1:1600-1:2800, suspect if   pulmonary
  disease
 Screen by diminished alpha globulin on
  SPEP or direct measurement of alpha-one
  antitrypsin
 Confirm by phenotype determination
        Non-Hepatic Causes
 If other   causes ruled out, consider celiac
  sprue
 Test for antigliadin or antiendomysial
  antibodies
 Acquired and congenital muscle disorders
  and strenuous exercise can cause
  elevated hepatocellular enzymes
 if muscle disorder suspected, check CPK
  and aldolase which should be elevated
If ALT & AST elevated, but all other
        blood tests normal?
 If AST, ALT <2x normal, observe
 If AST, ALT >2x normal, biopsy
Case: 62 yo man with hypertension,
obesity, hyperlipidemia has CMP
notable for AST 194, ALT 132.


What would you do?
Answer: History (alcohol, meds, risk
factors for hepatitis, family history, etc.)
     Physical
     Analyze pattern: Hepatocellular
     Repeat enzymes (off ETOH)
     if remain elevated, further workup
Further eval includes:
    Hep C antibody
    Hep B SAg
    Fe, TIBC
    SPEP
Further eval includes:
    stop med(s)
    ultrasound
    etc.
Case #2        42 yo woman with
hypertension has CMP which is
notable for alkaline phosphatase of
320.


What do you do next?
History (abd pain, jaundice, pruritis,
etc.
Physical
Evaluate pattern of enzymes
    1. hepatocellular or cholestatic
    2. magnitude of abnormality
    3. rate of change
Further testing
  Causes of Elevated Alk Phos
 Alk phos  can come from liver, bone,
  placenta, intestine (rare)
 Alk phos higher in children, pregnant
  women
 First goal is to: identify the source (liver vs
  bone)
 Methods:
  1. Alk phos fractionation
  2. GGT
  Causes of Elevated Alk Phos
 If liver source established, suspect
  cholestasis or infiltrative liver disease
 Causes include: partial obstrction of bile
  ducts, primary biliary cirrhosis, sclerosing
  cholangitis, certain drugs (eg, steroids),
  sarcoidosis, granulomatous disease,
  metastatic cancer
 How to distinguish these entities?
 Next step
    ultrasound
    antimitochondrial antibodies
    (suggestive of primary biliary cirrhosis)
If antimitochondial antibodies positive,
consider liver biopsy for primary biliary
cirrhosis
If biliary dilatation or choledocholithiasis,
consider ERCP
If US and antimitochondrial antibodies
negative, and Alk phos significantly
elevated (>50%), consider liver biopsy
If US and antimochondrial antibodies
negative, and Alk phos <50% elevated,
observe
               Other Liver Tests

                          GGT
   Very sensitive for hepatobiliary disease, but low
    specificity
   Fallen out of favor except as confirmatory test
                    BILIRUBIN
   Unconjugated huperbilirubinemia caused by
    increased bilirubin production or decreased
    hepatic uptake
   Most common causes of unconjugated
    hyperbilirubinemia: Gilbert’s (5%), hemolysis
        Tests of Liver Function
1.Albumin – synthesized by liver
 Nonspecific. Decreased in advanced
  stage liver disease, malnutrition,
  nephrotic syndrome
 Albumin has 20 day half life, so if due to
  liver, it indicates at least several weeks of
  liver disease
Tests for Liver Function (cont’d)
2. INR
 Prolonged by end stage liver disease,
  warfarin, vitamin K deficiency
 INR dependant on clotting factors which
  have half life of one day
 More sensitive indicator of liver synthetic
  function
Questions?
Cases
Case #3
A 36 yo man seeks medical attention
because of anorexia, nausea, and
vomiting of 5 days duration. Has low
grade fever, and pain in RUQ of
abdomen.


What else do you want to know?
History: Pertinent history includes
longstanding alcohol abuse,
consumption of raw oysters during a
recent vacation, and taking 2 g
acetaminophen for back pain daily
Case #3: Liver tests show:
    bilrubin     4.8
    ALT          950 (18x normal)
    AST          700 (12x normal)
    Alk Phos     480 (2-3x normal)
What is the most likely cause?
What would you do next?
Questions?
Case #4:
A 72 yo man with alcoholic
cardiomyopathy is admitted for heart
failure. Medications include captopril and
furosemide which were started 2 weeks
earlier. On admission, bilirubin is 3.0, Alk
phos 600, AST 9,200, ALT 6,000.
What else do you want to know?
What is the most likely cause for his
elevated LFTs?
His captopril and furosemide are
discontinued, and 3 days later his liver
tests show: bilirubin 3.8, Alk Phos 320,
AST 400.


What is most likely?
Case #5:
A 48 yo man with arthritis and Hilar
adenopathy comes in for a low grade
fever. Liver tests are bilirubin 0.8, Alk
Phos 2,200, AST 88, ALT 72.


What would you do next?
What is the most likely cause?
Case #6:
72 yo woman with diabetes,HTN, CHF,
hyperlipidemia, obesity, and remote h/o
alcohol abuse. Meds include: metformin,
lovastatin, enalapril, propranolol, and
ASA.
LFTs on CMP show AST 340, ALT 100,
Alk phos 150, TB 0.8
What is your differential?
What is most likely?
              Resources

1.Giannini E, et al. Liver Enzyme Alteration:
  A Guide for Clinicians. CMAJ
  2005;172(3):367-79.
2. Pratt D, Kaplan M. Evaluation of
  Abnormal Liver-Enzyme Results in
  Asymptomatic Patients. NEJM
  2000;342(17):1266-71.

				
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