Approach to the patient with abnormal LFTs

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by Bushra Ibnauf as part of SAMA's Visiting Faculty Program in SMSB on July 4th 2011.

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Approach to the patient with abnormal LFTs

  1. 1. Approach to The Patient with Abnormal Liver Function Tests Bushra MI Sulieman, MD MS Consultant, Gastroenterology & Hepatology Department of Medicine King Faisal Specialist Hospital & Research Center - Jeddah
  2. 2. Definition  <ul><li>Enzymes: </li></ul><ul><li>- Serum Aminotransferases (AST & ALT) </li></ul><ul><li>- Alkaline Phosphatase (ALP) </li></ul><ul><li>- Gamma Glutamyl Transpeptidase (GGT) </li></ul><ul><li>Tests of synthetic function: </li></ul><ul><li>- Albumin </li></ul><ul><li>- PT/INR </li></ul><ul><li>Test of detoxifying/transport: </li></ul><ul><li>- Bilirubin </li></ul>
  3. 3. Epidemiology <ul><li>Abnormal ALT (55 IU/L) detected in 99 of 19,877 (0.5 %) blood donors . </li></ul><ul><li>- Cause was found in only 12/99 (Hep B/C, AIH, cholelithiasis). </li></ul><ul><li>- No specific diagnosis was established in the remaining 87 patients. </li></ul><ul><li>1124 patients referred for abnormal ALT </li></ul><ul><li>- 81 patients : diagnosis could not be inferred noninvasively </li></ul><ul><li>- A liver biopsy revealed steatosis or steatohepatitis in 84 % </li></ul><ul><li>354 patients underwent a liver biopsy to investigate abnormal LFTs </li></ul><ul><li>- Excluded patients with diagnostic clinical or serologic features. </li></ul><ul><li>- The most frequent finding NASH or fatty liver (66 %). </li></ul><ul><li>Population-based study to evaluate the impact of an  GGT & ALT on overall mortality </li></ul><ul><li>-  GGT associated with a modestly increased mortality from all causes (HR 1.5; 95% CI, 1.2-1.8), liver disease, cancer, and diabetes </li></ul><ul><li>-  ALT was associated only with an increase in liver-related mortality (HR, 8.2; 95% CI, 2.1-31.9). </li></ul>Kundrotas Dig Dis Sci. 1993;38(12):2145-50. Daniel Am J Gastroenterol. 1999;94(10):3010-4. Skelley J Hepatol. 2001;35(2):195-9. Ruhl Gastroenterology. 2009;136(2):477-85.e11.
  4. 4. Epidemiology Conclusions <ul><li>A diagnosis can be established noninvasively in the vast majority of patients with abnormal LFTs. </li></ul><ul><li>Appropriate testing can be guided by the pretest probability of specific forms of liver disease. </li></ul><ul><li>The majority of patients in whom the diagnosis remains unclear after obtaining a history and laboratory testing will have alcoholic liver disease, steatosis, or steatohepatitis. </li></ul><ul><li>On a population-level, abnormal liver biochemical tests may be a marker for worse health outcomes. </li></ul>
  5. 5. History <ul><li>Use/exposure to any chemical or medication (prescription/OTC/herbal) </li></ul><ul><li>Duration of LFT abnormalities </li></ul><ul><li>Accompanying symptoms: jaundice, arthralgias, myalgias, rash, anorexia, weight loss, abdominal pain, fever, pruritus, changes in the urine/stool </li></ul><ul><li>Parenteral exposures: transfusions, IV/ intranasal drug use, tattoos, and sexual activity. </li></ul><ul><li>Travel history, exposure to people with jaundice, exposure to possibly contaminated foods </li></ul><ul><li>Occupational exposure to hepatotoxins </li></ul><ul><li>Alcohol consumption. </li></ul>
  6. 6. Physical Examination <ul><li>Temporal and proximal muscle wasting suggest longstanding diseases </li></ul><ul><li>Stigmata of chronic liver disease </li></ul><ul><li>Enlarged LN (Virchow's/Sister Mary Joseph's) </li></ul><ul><li>JVD </li></ul><ul><li>Rt pleural effusion </li></ul><ul><li>Abdominal examination : </li></ul><ul><li>- size and consistency of the liver, ? tenderness </li></ul><ul><li>- size of the spleen </li></ul><ul><li>- ascites </li></ul><ul><li>- RUQ tenderness </li></ul>
  7. 7. Patterns <ul><li>Mild Chronic Elevation in AST/ALT </li></ul><ul><li>- ≥ 6 months </li></ul><ul><li>- ≤ 4x ULN </li></ul><ul><li>- AST ± ALT </li></ul><ul><li>Isolated Hyperbilirubinemia </li></ul><ul><li>Isolated Elevation in GGT ± ALP </li></ul><ul><li>Mixed </li></ul>
  8. 8. Laboratory Testing Patterns Pattern Cause  AST/ALT >  ALP  Bilirubin Hepatocellular Injury  ALP > AST/ALT  Bilirubin Cholestasis  Albumin Chronic process (cirrhosis / cancer)  Albumin Acute process (viral hepatitis / choledocholithiasis.  PT/INR Prolonged jaundice / Vit K malabsorption Hepatocellular dysfunction.
  9. 9. Mild Chronic AST/ALT Elevation <ul><li>Step 1 : </li></ul><ul><li>- Medications/ herbal therapies /recreational drugs </li></ul><ul><li>- Screen for alcohol abuse (screening instruments, AST/ALT ratio >2:1) </li></ul><ul><li>- Serology for HBV and HCV </li></ul><ul><li>- Screen for hemochromatosis </li></ul><ul><li>- Fatty liver </li></ul><ul><li>Step 2: confirm that source is hepatic </li></ul><ul><li>- Exclude muscle disorders (CK/ aldolase) </li></ul><ul><li>- celiac disease </li></ul><ul><li>Step 3: consider less common causes of liver disease </li></ul><ul><li>- Autoimmune hepatitis </li></ul><ul><li>- Wilson's disease </li></ul><ul><li>- Alpha-1-antitrypsin deficiency </li></ul><ul><li>Step 4: </li></ul><ul><li>- liver biopsy </li></ul><ul><li>- Observation </li></ul>
  10. 10. Mild Chronic AST/ALT Elevation Medications <ul><li>Timing !! </li></ul><ul><li>Antibiotics, antidepressants, lipid-lowering drugs, sulfonamides, salicylates, sulfonylureas, NSAIDs, antiepileptics, anti-TB drugs </li></ul><ul><li>OTC </li></ul><ul><li>- Healthy vounteers taking 4g/day for 14 days </li></ul><ul><li>- 20% 5xULN, </li></ul><ul><li>Risk-benefit analysis </li></ul>Watkins JAMA. 2006;296(1):87-93.
  11. 11. Mild Chronic AST/ALT Elevation Alcohol Abuse <ul><li>AST : ALT Ratio ≥ 2:1 </li></ul><ul><li>- 90% of biopsy proven liver damage </li></ul><ul><li>- also in Hep C cirrhosis and NASH </li></ul><ul><li>- ASt/ALT can be normal </li></ul><ul><li>History: can be difficult </li></ul><ul><li>- ?family, friends  be creative </li></ul>Cohen Dig Dis Sci. 1979;24(11):835-8.
  12. 12. Mild Chronic AST/ALT Elevation Viral Hepatitis <ul><li>History of exposure </li></ul><ul><li>Endemic areas </li></ul><ul><li>Serology </li></ul><ul><li>- Hepatitis B surface antigen </li></ul><ul><li>- Hepatitis B surface antibody </li></ul><ul><li>- Hepatitis B core antibody </li></ul><ul><li>- Hepatitis C antibody </li></ul>
  13. 13. Mild Chronic AST/ALT Elevation Hereditary Hemochromatosis <ul><li>Common disorder </li></ul><ul><li>- Heterozygotes 10 % of Caucasians </li></ul><ul><li>- Homozygous 0.5% </li></ul><ul><li>History/Family history </li></ul><ul><li>Screening </li></ul><ul><li>- Serum Fe and TIBC  Fe saturation </li></ul><ul><li>- Ferritin </li></ul><ul><li>- Diagnosis: Genetic testing/liver biopsy </li></ul>
  14. 14. Mild Chronic AST/ALT Elevation Fatty Liver/NASH <ul><li>History </li></ul><ul><li>- Age/sex </li></ul><ul><li>- Associated conditions </li></ul><ul><li>Diagnosis </li></ul><ul><li>- US </li></ul><ul><li>- ? Biopsy – no effective Rx </li></ul>
  15. 15. Mild Chronic AST/ALT Elevation <ul><li>Step 1 : </li></ul><ul><li>- Medications/ herbal therapies /recreational drugs </li></ul><ul><li>- Screen for alcohol abuse (screening instruments, AST/ALT ratio >2:1) </li></ul><ul><li>- Serology for HBV and HCV </li></ul><ul><li>- Screen for hemochromatosis </li></ul><ul><li>- Fatty liver </li></ul><ul><li>Step 2: confirm that source is hepatic </li></ul><ul><li>- Exclude muscle disorders (CK/ aldolase) </li></ul><ul><li>- celiac disease </li></ul><ul><li>Step 3: consider less common causes of liver disease </li></ul><ul><li>- Autoimmune hepatitis </li></ul><ul><li>- Wilson's disease </li></ul><ul><li>- Alpha-1-antitrypsin deficiency </li></ul><ul><li>Step 4: </li></ul><ul><li>- liver biopsy </li></ul><ul><li>- Observation </li></ul>
  16. 16. Mild Chronic AST/ALT Elevation <ul><li>Muscle injury </li></ul><ul><li>- Exercise, inflammatory </li></ul><ul><li>- AST/ALT Ratio 3:1 </li></ul><ul><li>- Peak values variable </li></ul><ul><li>Thyroid disorders </li></ul><ul><li>Celiac disease </li></ul><ul><li>Adrenal insufficiency </li></ul><ul><li>Anorexia Nervosa </li></ul>
  17. 17. Mild Chronic AST/ALT Elevation <ul><li>Step 1 : </li></ul><ul><li>- Medications/ herbal therapies /recreational drugs </li></ul><ul><li>- Screen for alcohol abuse (screening instruments, AST/ALT ratio >2:1) </li></ul><ul><li>- Serology for HBV and HCV </li></ul><ul><li>- Screen for hemochromatosis </li></ul><ul><li>- Fatty liver </li></ul><ul><li>Step 2: confirm that source is hepatic </li></ul><ul><li>- Exclude muscle disorders (CK/ aldolase) </li></ul><ul><li>- celiac disease </li></ul><ul><li>Step 3: consider less common causes of liver disease </li></ul><ul><li>- Autoimmune hepatitis </li></ul><ul><li>- Wilson's disease </li></ul><ul><li>- Alpha-1-antitrypsin deficiency </li></ul><ul><li>Step 4: </li></ul><ul><li>- liver biopsy </li></ul><ul><li>- Observation </li></ul>
  18. 18. Mild Chronic AST/ALT Elevation Autoimmune Hepatitis <ul><li>History </li></ul><ul><li>- family history </li></ul><ul><li>- associated conditions </li></ul><ul><li>Diagnosis </li></ul><ul><li>-  gammaglobulinemia </li></ul><ul><li>- Autoimmune serology </li></ul>
  19. 19. Mild Chronic AST/ALT Elevation Metabolic/other conditions <ul><li>Wilson Disease </li></ul><ul><li>Alpha-1-antitrypsin deficiency </li></ul>
  20. 20. Mild Chronic AST/ALT Elevation <ul><li>Step 1 : </li></ul><ul><li>- Medications/ herbal therapies /recreational drugs </li></ul><ul><li>- Screen for alcohol abuse (screening instruments, AST/ALT ratio >2:1) </li></ul><ul><li>- Serology for HBV and HCV </li></ul><ul><li>- Screen for hemochromatosis </li></ul><ul><li>- Fatty liver </li></ul><ul><li>Step 2: confirm that source is hepatic </li></ul><ul><li>- Exclude muscle disorders (CK/ aldolase) </li></ul><ul><li>- celiac disease </li></ul><ul><li>Step 3: consider less common causes of liver disease </li></ul><ul><li>- Autoimmune hepatitis </li></ul><ul><li>- Wilson's disease </li></ul><ul><li>- Alpha-1-antitrypsin deficiency </li></ul><ul><li>Step 4: </li></ul><ul><li>- liver biopsy </li></ul><ul><li>- Observation </li></ul>
  21. 21. Mild Chronic AST/ALT Elevation <ul><li>Whom to Observe ? </li></ul><ul><li>AST/ALT ≤ 2x ULN AND </li></ul><ul><li>No chronic liver condition </li></ul><ul><li>Most cost-effective approach </li></ul>Das, A, Post, AB. Should liver biopsy be done in asymptomatic patients with chronically elevated transaminases: A cost-utility analysis (abstract). Gastroenterology 1998; 114:A9. <ul><li>Whom to Biopsy ? </li></ul><ul><li>AST/ALT > 2x ULN </li></ul><ul><li>? chronic liver condition </li></ul>
  22. 22. Isolated Hyperbilirubinemia Unconjugated <ul><li>Increased bilirubin production </li></ul><ul><li>- Extravascular hemolysis </li></ul><ul><li>- Extravasation of blood into tissues </li></ul><ul><li>- Intravascular hemolysis </li></ul><ul><li>Impaired hepatic bilirubin uptake </li></ul><ul><li>- Heart failure </li></ul><ul><li>- Portosystemic shunts </li></ul><ul><li>- Drugs - rifampin, probenecid </li></ul><ul><li>Impaired bilirubin conjugation </li></ul><ul><li>- Gilbert's syndrome </li></ul><ul><li>- Hyperthyroidism </li></ul><ul><li>- Ethinyl estradiol </li></ul><ul><li>- Liver diseases - chronic persistent hepatitis, advanced cirrhosis, Wilson's disease </li></ul>
  23. 23. Isolated Hyperbilirubinemia Conjugated <ul><li>Extrahepatic cholestasis (biliary obstruction) </li></ul><ul><li>- Choledocholithiasis </li></ul><ul><li>- Intrinsic and extrinsic tumors - eg, cholangiocarcinoma </li></ul><ul><li>- PSC </li></ul><ul><li>- Acute and chronic pancreatitis </li></ul><ul><li>Intrahepatic cholestasis </li></ul><ul><li>- Viral hepatitis </li></ul><ul><li>- Alcoholic hepatitis </li></ul><ul><li>- NASH </li></ul><ul><li>- cirrhosis </li></ul><ul><li>- Drugs and toxins - eg, alkylated steroids, chlorpromazine, herbs </li></ul><ul><li>- Sepsis and hypoperfusion states </li></ul><ul><li>- Infiltrative diseases </li></ul><ul><li>- TPN </li></ul>
  24. 24. Isolated Elevation in GGT ± ALP
  25. 25. Laboratory Testing Patterns Pattern Cause  AST/ALT >  ALP  Bilirubin Hepatocellular Injury  ALP > AST/ALT  Bilirubin Cholestasis  Albumin Chronic process (cirrhosis / cancer)  Albumin Acute process (viral hepatitis / choledocholithiasis.  PT/INR Prolonged jaundice / Vit K malabsorption Hepatocellular dysfunction.
  26. 26. Imaging <ul><li>US </li></ul><ul><li>CT </li></ul><ul><li>MRI/MRCP </li></ul><ul><li>HIDA </li></ul>
  27. 30. Case One <ul><li>A 60-year-old man is brought to the ED by his wife, who comments that the patient has a drinking problem and has been complaining of back pain for several days. </li></ul><ul><li>PE: VSS, spider angiomas and enlarged firm liver. Spleen is palbabale. No ascites or edema </li></ul><ul><li>Labs: Hbg 119, WCC 12.1 Platelets 130. </li></ul><ul><li>BUN 50, Creatinine 230, AST 4,200, ALT 5,193 </li></ul><ul><li>T Bili 3.1, ALP 70, INR 1.6 </li></ul><ul><li>Which of the following is the MOST likely cause of this patient’s liver disease ? </li></ul><ul><li>- Pancreatic Cancer </li></ul><ul><li>- Acute hepatitis A </li></ul><ul><li>- Acetaminophen Toxicity </li></ul><ul><li>- Ischemic hepatitis </li></ul><ul><li>- Alcoholic hepatitis </li></ul>
  28. 31. Case One <ul><li>A 60-year-old man is brought to the ED by his wife, who comments that the patient has a drinking problem and has been complaining of back pain for several days. </li></ul><ul><li>PE: VSS, spider angiomas and enlarged firm liver. Spleen is palpable. No ascites or edema </li></ul><ul><li>Labs: Hgb 119, WCC 12.1 Platelets 130. </li></ul><ul><li>BUN 50, Creatinine 230, AST 4,200, ALT 5,193 </li></ul><ul><li>T Bili 3.1, ALP 70, INR 1.6 </li></ul><ul><li>Which of the following is the MOST likely cause of this patient’s liver disease ? </li></ul><ul><li>- Pancreatic Cancer </li></ul><ul><li>- Acute hepatitis A </li></ul><ul><li>- Acetaminophen Toxicity </li></ul><ul><li>- Ischemic hepatitis </li></ul><ul><li>- Alcoholic hepatitis </li></ul>
  29. 32. Case Two <ul><li>A 24-year-old man with a seizure disorder has a liver biopsy because he has increased AST/ALT for 6 months. The biopsy shows prominent microvascular steatosis. No inflammation or fibrosis is noted. Which of the following is most likely to contribute to this histologic finding? </li></ul><ul><li>- Excess copper accumulation in the liver </li></ul><ul><li>- Excess consumption of alcohol </li></ul><ul><li>- Obesity </li></ul><ul><li>- Diabetes </li></ul><ul><li>- Valproic acid </li></ul>
  30. 33. Case Two <ul><li>A 24-year-old man with a seizure disorder has a liver biopsy because he has increased AST/ALT for 6 months. The biopsy shows prominent microvascular steatosis. No inflammation or fibrosis is noted. Which of the following is most likely to contribute to this histologic finding? </li></ul><ul><li>- Excess copper accumulation in the liver </li></ul><ul><li>- Excess consumption of alcohol </li></ul><ul><li>- Obesity </li></ul><ul><li>- Diabetes </li></ul><ul><li>- Valproic acid </li></ul>
  31. 34. Case Three <ul><li>A 28 year-old man was rejected as a blood donor because his serum AST was 123. he has quiescent chronic UC and no risk factors for alcohol, viral, or drug induced liver injury. </li></ul><ul><li>PE shows a slender man and no icterus or hepatomegaly. </li></ul><ul><li>Labs: ALT 102, ALP 221, ANA titer 1:80. HepBsAg, antibodies to HAV, HCV, HIV all negative. </li></ul><ul><li>US Normal </li></ul><ul><li>Which diagnosis is most confidently excluded? </li></ul><ul><li>Autoimmune hepatitis </li></ul><ul><li>Chronic Hepatitis C </li></ul><ul><li>Wilson disease </li></ul><ul><li>NASH </li></ul><ul><li>PSC </li></ul>
  32. 35. Case Three <ul><li>A 28 year-old man was rejected as a blood donor because his serum AST was 123. he has quiescent chronic UC and no risk factors for alcohol, viral, or drug induced liver injury. </li></ul><ul><li>PE shows a slender man and no icterus or hepatomegaly. </li></ul><ul><li>Labs: ALT 102, ALP 221, ANA titer 1:80. HepBsAg, antibodies to HAV, HCV, HIV all negative. </li></ul><ul><li>US Normal </li></ul><ul><li>Which diagnosis is most confidently excluded? </li></ul><ul><li>Autoimmune hepatitis </li></ul><ul><li>Chronic Hepatitis C </li></ul><ul><li>Wilson disease </li></ul><ul><li>NASH </li></ul><ul><li>PSC </li></ul>
  33. 36. Case Four <ul><li>A 58 old asymptomatic diabetic woman is evaluated because of abnormal liver enzymes discovered 8 months ago. Her only medication is glyburide. She drinks one glass of wine monthly. </li></ul><ul><li>PE reveals moderate obesity. </li></ul><ul><li>Labs ALT 104, AST 95, anti-HCV and HBsAg both negative </li></ul><ul><li>US liver normal </li></ul><ul><li>Which of the following is true about the most likely diagnosis ? </li></ul><ul><li>Liver biopsy will exclude alcohol as a cause </li></ul><ul><li>Ursodiol is beneficial </li></ul><ul><li>Strong association with increased level of γ globulin </li></ul><ul><li>Progresses to cirrhosis in a small fraction of patients </li></ul><ul><li>Gluten free diet will improve transminases level </li></ul>
  34. 37. Case Four <ul><li>A 58 old asymptomatic diabetic woman is evaluated because of abnormal liver enzymes discovered 8 months ago. Her only medication is glyburide. She drinks one glass of wine monthly. </li></ul><ul><li>PE reveals moderate obesity. </li></ul><ul><li>Labs ALT 104, AST 95, anti-HCV and HBsAg both negative </li></ul><ul><li>US liver normal </li></ul><ul><li>Which of the following is true about the most likely diagnosis ? </li></ul><ul><li>Liver biopsy will exclude alcohol as a cause </li></ul><ul><li>Ursodiol is beneficial </li></ul><ul><li>Strong association with increased level of γ globulin </li></ul><ul><li>Progresses to cirrhosis in a small fraction of patients </li></ul><ul><li>Gluten free diet will improve transminases level </li></ul>
  35. 38. SAMA www.sama-sd.org

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