Evaluation of Abnormal Liver Function Tests


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  • Routine reasons to order: annual labs, insurance physical, blood bank, routine eval of non-hepatic disease
  • AST made in cytosol and mitochondria. ALT in cytosol only.
    AST (aspartate aminotransferase) = SGOT
    ALT (alanine aminotransferase) = SGPT
    ALT is present in other tissues but just in lower levels
  • HCV – necrosis + apoptosis (programmed cell death)
    Do not follow normal bell shaped curve- skewed distribution with long tail at high end
    Up to 15% higher in African Americans and Hispanics
    There is also diurnal variation and day-to-day variation in values
  • Vit B6 (pyridoxine) depleted in alcoholics. B6 is coenzyme used by both AST and ALT. ALT is more strongly inhibited by vit B6 def. Also, alcohol causes mitochondrial damage releasing more AST (AST made in mitochondria but ALT is not)
  • HCV is common and affects nearly 2% of population
    HBV prevalence is .1 -2.0%
    Steatosis/steatohepatitis- most common cause of elevated lfts- alcohol and nonalcoholic fatty liver disease but ALT predominant suggests no alcohol
    Hereditary hemochromatosis- one of most common genetic disease (1:200 – 1:400) and not uncommon cause of AST/ALT elevation- iron, ferritin, tibc
    Autoimmune hep- more common in females; 1:6000-7000; associated with thyroid disease & other autoimmune conditions- anti-nuclear antibodies, anti-smooth muscle ab
    Wilson’s Disease- 1:30,000-300,000; lower serum ceruloplasmin; kayser-fleischer rings on slit-lamp (brown-green ring of copper deposit around the cornea)
    Alpha1 antitrypsin def- 1:1500-7600; decreased serum alpha one antitrypsin
    Celiac disease- antiendomysial & antigliadin ab’s
  • Signs/Sx’s of liver disease: ascites, encephalopathy, coagulation problems, portal HTN, spider telangiectasias, testicular atrophy, gynecomastia, jaundice, hepatosplenomegaly
    Illegal drugs raise LFTs: anabolic steroids, PCP, ectasy, cocaine
    Serologies: HAV- HAV IgM; HBV- HBsAg, HBcIgM; HCV- HCV Ab or RNA
  • Other agents: dantrolene, etretinate, halothane, nicotinic acid, phenylbutazone
  • Serologies: HAV- HAV IgM; HBV- HBsAg, HBcIgM; HCV- HCV Ab or RNA
  • Biliary duct obstruction: Delayed elevation when acute stone disease
    Takes several days
    AST/ALT elevated initially (> 6X normal value)
  • GGT = gamma glutanyl transferase
    GGT elevated in isolation (normal LFTs) with alcohol use & anticonvulsant use (dilantin) without liver disease
    Persistent elevated in asymptomatic women- think primary biliary cirrhosis (check antimitochondrial ab)
    Most mild elevations (<1.5 X normal) will have no identifiable etiology and will normalize within 6 months
    5 NNT = 5 nucleotidase
    ERCP: endoscopic retrograde cholangiopancreatography
    MRCP: magnetic resonance cholangio-pancreatography
    AMA (antimitochondrial ab)- for primary biliary cirrhosis-
  • Obstruction = intra- or extrahepatic
    Conjugated bili not elevated until liver loses >50% excretory capacity
    Gilbert’s- Congenital enzyme def gluconyltransferase (decreased conjugation ability); bilis 2-3; up to 5% of population
    In liver disease conjugation ability usually remains intact and therefore see a predominance of conjugated bili and not unconjugated
  • 1st step: hx, physical and liver function tests
    Hemolysis studies: haptoglobin, cbc, peripheral smear, retic
    Unconjugated etiologies: hemolysis (ie hereditary spherocytosis), Gilbert syndrome- bili values usually 2-3
  • Albumin: isolated, low values = nonhepatic etiology; ½ life is 3 weeks and values change slowly in relation to synthesis capacity; 2/3 is extravascular and extracellular so values very dependent on distribution
    Ammonia: not useful if known liver disease and encephalopathy; only useful if mental status changes of unknown etiology; values much higher in brain than serum; more accurate if arterial and not venous
  • Evaluation of Abnormal Liver Function Tests

    1. 1. Evaluation of Abnormal Liver Function Tests Joshua A. Hodge, Maj, USAF, MC Staff Family Physician Andrews AFB, MD
    2. 2. Overview • Background • Transaminases • Alkaline phosphatase • Bilirubin • Other liver labs • Summary
    3. 3. Background • Liver function tests ordered routinely • 1-4% of asymptomatic patients have abnormal values • Components – Transaminases – Alkaline phosphatase – Bilirubin – Others: albumin, protein
    4. 4. Transaminases • Located in hepatocytes – Released after hepatocellular injury • 2 Forms – AST • Non-specific to liver: heart, skeletal muscle, blood – ALT • More specific: elevated in myopathies
    5. 5. Transaminases • May not be elevated in chronic liver disease – HCV- apoptosis – Cirrhosis • Minimal ALT elevations (<1.5 X normal) – Race/Gender – Obesity – Muscle injury
    6. 6. Transaminases • Mild elevations – more to come • Marked elevations – Acute toxic injury- ie tylenol, ischemia – Acute viral disease – Alcoholic hepatitis
    7. 7. Transaminases • AST:ALT ratio – Elevated in alcoholic disease • 2:1 • If AST > 500 consider other cause – No alcohol use suggests cirrhosis
    8. 8. Mild Transaminitis • AST/ALT < 5 times upper limit of normal • Etiologies – Hepatic: ALT-predominant • Chronic Hep C ▪Hemochromatosis • Chronic Hep B ▪Medications/Toxins • Acute viral hep ▪Autoimmune Hep • Steatosis ▪Alpha1 Antitrypsin Def • Wilson’s Disease ▪Celiac Disease
    9. 9. Mild Transaminitis –Hepatic: AST predominant • Alcohol • Steatosis • Cirrhosis –Non-hepatic • Hemolysis • Myopathy • Thyroid disease • Strenuous exercise
    10. 10. Elevated AST & ALT, <5X normal Hx & physical; stop hepatotoxic meds LFTs, PT, albumin, CBC, Hep A/B/C, Fe, TIBC, Ferritin Positive serologyNegative serology Negative serology, asymptomatic Serologies: HAV IgM HBsAg HBcIgM HCV Ab or RNA
    11. 11. Hepatotoxic Medications • Analgesics- acetaminophen, NSAIDS • Antimicrobials – Amox-clav, nitrofurantoin, sulfonamides – INH – Azoles – Protease Inhibitors • Anticonvulsants- carbamazepine, valproic acid, phenyton
    12. 12. Hepatotoxic Medications • Cardiovascular- alpha-methyldopa, amiodarone, labetalol • Hyperglycemics- glyburide, troglidazone • Psychiatric- trazadone, disulfiram • Heparin • Propylthiouracil • Statins • Zafirlukast
    13. 13. Hepatotoxic Herbals • Chaparral leaf • Ephedra • Gentian • Germander • Jin Bu Huan • Senna, Kavakava • Scutellaria (skullcap) • Shark cartilage • Vitamin A ☺
    14. 14. Stop EtOH & meds; wt loss; glucose control Repeat LFTs Observation Ultrasound, ANA, smooth muscle Ab, ceruloplasmin, antitrypsin, gliadin & endomysial Ab Negative Serology- Asymptomatic Liver biopsy Abnormal Normal 6 months ☺
    15. 15. Consider ultrasound, ANA, smooth muscle Ab, ceruloplasmin, antitrypsin Liver biopsy Negative Serology- Clinical Signs/Symptoms of Liver Disease Abnormal ☺
    16. 16. + Hep C/B infection Observation Positive Serologies Hep A IgM Follow clinically, serial LFTs Observation Persistent elevated LFTs > 6 mo’s Clinical improvement, LFTs normalize in <6 mo’s Liver biopsy
    17. 17. Serologic Tests for Viral Hepatitis • HAV – Hep A IgM- ↑ in acute infxn – Hep A IgG- ↑ in previous infxn or vaccination • HCV – HCV Ab- ↑ during or after infection – HCV-RNA- ↑ during infection • Detectable prior to HCV Ab turning positive
    18. 18. Serologic Tests for Viral Hepatitis • HBV – Hep B Surface Ag- ↑ in active infxn – Hep B Surface Ab- ↑ in prior infxn or vaccinated – Hep B Core Ab IgM- ↑ in active infxn – Hep B Core Ab IgG- ↑ in current or prior infxn – HBV-DNA- ↑ in active infxn – Hep B e Ag & Ab- markers of viral presence and potential infectivity
    19. 19. Symptoms HBeAg anti-HBe Total anti-HBc IgM anti-HBc anti-HBsHBsAg 0 4 8 12 16 20 24 28 32 36 52 100 Acute Hepatitis B Virus Infection with Recovery Typical Serologic Course Weeks after Exposure Titre
    20. 20. Alkaline Phosphatase • Produced by biliary epithelial cells – Non-specific to liver: bone, intestine, placenta • Elevations – Biliary duct obstruction – Primary biliary cirrhosis – Primary sclerosing cholangitis – Infiltrative liver disease- ie sarcoid, lymphoma – Hepatitis/cirrhosis – Medications
    21. 21. Medications • Hormones- anabolic steroids, estrogen, methyltestosterone • Antimicrobials- augmentin, erythromycin, flucloxacillin, TMP-SMX, HIV meds • Cardiovascular- captopril, diltiazem, quinidine • Hyperglycemics- chlorpropamide, tolbutamide • Psychiatric- fluphenazine, imipramine, iprindole • Others- allopurinol, carbamazepine
    22. 22. RUQ us, med review, AMA Abnormal LFTsNormal LFTs, bili RUQ u/s for ductal dilatationGGT or 5’-NNT ALT eval, liver bx, ERCP or MRCP Other source Observation Liver bx No dilatation - + ERCP AMA NoYes Neg AP > 6 mo Elevated Alk Phos
    23. 23. Bilirubin • Product of hemoglobin breakdown • 2 Forms – Unconjugated (indirect)- insoluble •↑ in hemolysis, Gilbert syndrome, meds – Conjugated (direct)- soluble •↑ in obstruction, cholestasis, cirrhosis, hepatitis, primary biliary cirrhosis, etc. • No elevation until loss of > 50% capacity
    24. 24. Conjugated bili; Abnormal alk phos, ALT, AST Unconjugated bili; Normal alk phos, ALT, AST RUQ u/s to assess ductal dilatation Hemolysis studies, review meds ALT eval, review meds, AMA, ERCP or MRCP, liver bx ERCP or MRCP Elevated Bilirubin + -
    25. 25. Other Liver Labs • Albumin – Poor marker of liver function- decreased by trauma, inflammatory conditions, malnutrition • Prothrombin time (PT) – Insensitive: no change until liver loses 80% capacity • Ammonia – No correlation between brain & serum values – Only one contributor to encephalopathy
    26. 26. Summary • Algorithms based on poor quality or absence of evidence • Most asymptomatic patients can safely be followed for a period of time to see if abnormalities resolve • If lab abnormalities persist be thoughtful with ordering
    27. 27. References • AGA Clinical Practice Committee. AGA medical position statement: evaluation of liver chemistry tests. Gastroenterology 2002;123:1364-66. • AGA technical review on the evaluation of liver chemistry tests. Gastroenterology 2002;123:1367-84. • Bayard M, et al. Nonalcoholic fatty liver disease 2006;73:1961-8. • Giboney PT. Mildly elevated liver transaminase levels in the asymptomatic patient. Am Fam Physician 2005;71:1105-10. • Johnston DE. Special considerations in interpreting liver function tests. Am Fam Physician 1999;59: