1. An Approach to Abnormal LFTs Robert C. Lowe, M.D. Boston Medical Center July 17, 2013

2. AST ALT ALP T. BIL ALB INR GGT

3. Chessboard

4. ALTAST T. BIL ALPALB GGT

5. Case 1 30 year old woman 4 days of malaise, fevers to 101, nausea 1 day of RUQ pain and jaundice Exam - T 100.5 Icteric sclerae and jaundice Tender hepatomegaly, no spleen tip

6. Case 1 AST 1535WBC 8.1 ALT 1602HCT 41 ALP 128PLT 353 T. Bil 7.3 Albumin 3.9

7. Transaminases AST - aspartate aminotransferase ALT - alanine aminotransferase Released when hepatocytes are injured - a sign of necrosis.

8. AST - less specific for liver disease Muscle (skeletal and cardiac) Kidney Erythrocytes ALT - very little outside of liver. A better marker of liver disease.

9. Differential Diagnosis Sky high transaminases > 15x normal

10. Differential Diagnosis Sky high transaminases > 15x normal Virus Drug Ischemia } >80% of cases

11. AST/ALT>1000 Virus Toxin Ischemia History and Exam Points

12. AST/ALT>1000 Virus Toxin Ischemia History and Exam Points IVDUArthralgias Sexual partnersUrticaria TravelHerpetic lesions Food exposuresStigmata of liver dz

14. AST/ALT>1000 Virus Toxin Ischemia History and Exam Points IVDUArthralgias Sexual partnersUrticaria TravelHerpetic lesions Food exposuresStigmata of liver dz

15. AST/ALT>1000 Virus Toxin Ischemia History and Exam Points IVDUArthralgias Sexual partnersUrticaria TravelHerpetic lesions Food exposuresStigmata of liver dz Meds OTC meds Herbs and supplements

16. AST/ALT>1000 Virus Toxin Ischemia History and Exam Points IVDUArthralgias Sexual partnersUrticaria TravelHerpetic lesions Food exposuresStigmata of liver dz Meds OTC meds Herbs and supplements Recent surgery Hypotension Cardiac arrest CMP

17. AST/ALT>1000

18. Autoimmune Wilson Disease Bile Duct Obstruction Budd-Chiari

19. AST/ALT>1000 Autoimmune Wilson Disease Bile Duct Obstruction Budd-Chiari Clinical Clues Female gender Personal or Family Hx of autoimmune dz

20. AST/ALT>1000 Autoimmune Wilson’s Disease Bile Duct Obstruction Budd-Chiari Clinical Clues Female gender Personal or Family Hx of autoimmune dz ANA ASMA Ig levels

21. AST/ALT>1000 Autoimmune Wilson’s Disease Bile Duct Obstruction Budd-Chiari

22. AST/ALT>1000 Autoimmune Wilson’s Disease Bile Duct Obstruction Budd-Chiari Clinical Clues Male gender < age 40 Neuropsychiatric syndrome Psychosis Movement disorder

23. AST/ALT>1000 Autoimmune Wilson’s Disease Bile Duct Obstruction Budd-Chiari Clinical Clues Male gender < age 40 Neuropsychiatric syndrome Psychosis Movement disorder Low ALP Hemolysis Ceruloplasmin less useful in acute disease

24. KF Rings

25. Head CT

26. AST/ALT>1000 Autoimmune Wilson Disease Bile Duct Obstruction Budd-Chiari

27. AST/ALT>1000 Autoimmune Wilson Disease Bile Duct Obstruction Budd-Chiari Clinical Clues H/O biliary colic or GS disease FH of gallstones RUQ pain N/V Transaminases fall rapidly - over 1-3 days U/S often diagnostic, but may need further imaging with MRCP/ERCP

29. AST/ALT>1000 Autoimmune Wilson Disease Bile Duct Obstruction Budd-Chiari

30. AST/ALT>1000 Autoimmune Wilson Disease Bile Duct Obstruction Budd-Chiari Clinical Clues OCP use Prior venous thrombosis Myeloproliferative disorder Malignancy Abdominal Pain Ascites

31. Laboratory Testing Hepatitis A - IgM and IgG Hepatitis B - sAg, cAb, eAg, HBV DNA Hepatitis C - RNA level ANA, ASMA, Ig levels RUQ U/S with Doppler Study Consider other viral serologies, ceruloplasmin, MRCP

32. Prognostic Features

33. Coagulopathy –INR elevation Encephalopathy –Mental Status –Asterixis –Apraxia

38. Case 2 Asymptomatic 45 year-old woman Cholesterol 245, Trig 266 No significant FH No meds Works as an accountant

39. Case 2 AST 84WBC 6.6 ALT 46HCT 37 ALP 121PLT 165 T. Bil 0.8 ALB 3.7

40. Alcoholic LFT Pattern AST/ALT > 2:1 Absolute AST and ALT < 300 GGT elevation is helpful, but nonspecific.

41. Alcoholic LFT Pattern WHY? ALT synthesis is decreased in EtOH hepatitis. Partially due to pyridoxine deficiency - may correct with B6 therapy.

42. Case 2 AST 84WBC 6.6 ALT 46HCT 37 ALP 121PLT 165 T. Bil 0.8 ALB 3.7

43. Case 2 AST 84WBC 6.6 ALT 89HCT 37 ALP 121PLT 165 T. Bil 0.8 ALB 3.7

44. Mildly Elevated Transaminases ABCDEFGHABCDEFGH

45. Alcohol / Autoimmune B Hepatitis C Hepatitis Drug Exotic Wilson Disease Alpha-1-antitrypsin deficiency Fatty liver Gluten sensitive enteropathy Hemochromatosis

46. Mildly Elevated Transaminases Alcohol / Autoimmune B Hepatitis C Hepatitis Drug Exotic Wilson Disease Alpha-1-antitrypsin deficiency Fatty liver Gluten sensitive enteropathy Hemochromatosis Thyroid disease, myopathies

47. Mildly Elevated Transaminases Alcohol / AutoimmuneAlcohol Hx B Hepatitis HBsAg, HBcAb, HBsAb C Hepatitis HCV Ab DrugDrug Hx Exotic Wilson Disease Alpha-1-antitrypsin deficiency Fatty liverRUQ U/S, TG Gluten sensitive enteropathy Hemochromatosis Thyroid disease, myopathies

48. Mildly Elevated Transaminases Alcohol / AutoimmuneANA, ASMA, Ig levels B Hepatitis HBsAg, HBcAb, HBsAb C Hepatitis HCV Ab DrugDrug Hx Exotic Wilson Disease Alpha-1-antitrypsin deficiency Fatty liverRUQ U/S, TG Gluten sensitive enteropathy HemochromatosisFe, TIBC, Ferritin Thyroid disease, myopathies

49. Mildly Elevated Transaminases Alcohol / AutoimmuneANA, ASMA, Ig levels B Hepatitis HBsAg, HBcAb, HBsAb C Hepatitis HCV Ab DrugDrug Hx Exotic Wilson DiseaseCeruloplasmin Alpha-1-antitrypsin deficiencyA-1-AT level Fatty liverRUQ U/S, TG Gluten sensitive enteropathy HemochromatosisFe, TIBC, Ferritin Thyroid disease, myopathies

50. Mildly Elevated Transaminases Alcohol / AutoimmuneANA, ASMA, Ig levels B Hepatitis HBsAg, HBcAb, HBsAb C Hepatitis HCV Ab DrugDrug Hx Exotic Wilson DiseaseCeruloplasmin Alpha-1-antitrypsin deficiencyA-1-AT level Fatty liverRUQ U/S, TG Gluten sensitive enteropathyAnti-TTG HemochromatosisFe, TIBC, Ferritin Thyroid disease, myopathiesTSH, CK, Aldolase

51. Liver Biopsy 1124 pts referred for elevated ALT --- 81 cases with negative serologic workup

52. Liver Biopsy 1124 pts referred for elevated ALT --- 81 cases with negative serologic workup Biopsies -- 41 pts with steatosis 26 pts with NASH 8% normal biopsies Daniel, et al. Am J Gastro, 1999

53. Liver Biopsy 354 patients with elevated ALT and negative workup Biopsies -- 32% with steatosis 34% with NASH 9% cryptogenic 7.6% Drug-induced 5.9% normal histology 2.8% ETOH Granulomatous dz, PBC, PSC, hemochromatosis, amyloidosis, glycogen storage disease = 6.3% In 18%, management was changed based on the pathology. Skelly, et al. J Hepatol, 2001 66% with NAFLD

56. PAS with Diastase digestion

57. An Approach to Abnormal LFTs Robert C. Lowe, M.D. Boston Medical Center July 17, 2013

59. An Approach to Abnormal LFTs Part 2 Robert C. Lowe, M.D. Boston Medical Center July 25, 2013

60. AST/ALT>1000 Virus Toxin Ischemia

61. AST/ALT>1000 Virus Toxin Ischemia Autoimmune Wilson’s Disease Bile Duct Obstruction Budd-Chiari

62. Alcohol / Autoimmune B Hepatitis C Hepatitis Drug Exotic Wilson’s Disease Alpha-1-antitrypsin deficiency Fatty liver Gluten sensitive enteropathy Hemochromatosis Thyroid disease, myopathies

64. Case 3 35 year old woman Mild fatigue No significant PMH No meds Exam - cervical LAN 0.5 cm, nontender Liver 3 cm below RCM

65. Case 3 AST 42 ALT 34 ALP 442 T. BIL 0.7 Albumin 3.9 INR 1.0

66. Case 3 AST 42 ALT 34 ALP 442 T. BIL 0.7 Albumin 3.9 INR 1.0 GGT = 650

67. Alkaline Phosphatase Produced in liver, bone, placenta, intestine. Blood group O and B may release intestinal ALP after a fatty meal. Elevations up to 2x normal are very nonspecific. Up to 1/3 have no disease.

68. Elevated ALP Bone disease -- Paget’s Metastases Myeloma Use GGT or 5’NT to distinguish bone from liver.

69. GGT and 5’ NT GGT - not found in bone, present in biliary epithelium. Problems - induced by EtOH, anticonvulsants, warfarin, so specificity is a problem. GGT/ALP > 2.5 suggests EtOH, but only 33% sensitive!

70. 5’ Nucleotidase More specific than GGT Rises over several days after bile duct obstruction, slower than GGT.

71. Elevated ALP

72. Biliary obstruction Tumor masses - primary or metastatic Drug Effect

73. Elevated ALP Special circumstances - Malignancy without liver involvement -- tumors produce Regan isoenzyme of ALP (gonadal and urologic) Hodgkin’s Disease and RCC - can cause nonspecific hepatitis with elevated ALP

74. Workup of ALP Elevation 1) Confirm liver origin with 5’-NT or GGT

75. Workup of ALP Elevation 1) Confirm liver origin with 5’-NT or GGT 2) U/S or CT to R/O mass and dilated ducts Mass -- biopsy Dilated ducts -- MRCP/ERCP

76. AST 42 ALT 34 ALP 442 T. BIL 0.7 Albumin 3.9 INR 1.0

77. AST 42 ALT 34 ALP 442 T. BIL 0.7 Albumin 3.9 INR 1.0 Pruritus for 4 months with no rash

78. AST 42 ALT 34 ALP 442 T. BIL 0.7 Albumin 3.9 INR 1.0 Pruritus for 4 months with no rash AMA = 1:2500

79. Primary Biliary Cirrhosis F:M = 8-9:1 Classic = fatigue, itching, elevated ALP Common = asyx elevated ALP NO jaundice until end-stage AMA is diagnostic (95% positive) Treat with ursodiol

82. AST 42 ALT 34 ALP 442 T. BIL 0.7 Albumin 3.9 INR 1.0

84. AST 42 ALT 34 ALP 442 T. BIL 0.7 Albumin 3.9 INR 1.0

85. AST 42 ALT 34 ALP 442 T. BIL 0.7 Albumin 3.9 INR 1.0 Patient reveals a 12 year history of ulcerative colitis

88. Primary Sclerosing Cholangitis IBD in > 70% (typically UC) MRCP makes diagnosis pANCA (+) in the majority Progression to cirrhosis – median survival 10-12 yrs after Dx Risk of cholangiocarcioma is 10-15%

89. AST 42 ALT 34 ALP 442 T. BIL 0.7 Albumin 3.9 INR 1.0

90. AST 42 ALT 34 ALP 442 T. BIL 0.7 Albumin 3.9 INR 1.0 Patient with Cr. 2.0 and significant proteinuria

91. Liver biopsy

93. AST 42 ALT 34 ALP 442 T. BIL 0.7 Albumin 3.9 INR 1.0

94. AST 42 ALT 34 ALP 442 T. BIL 0.7 Albumin 3.9 INR 1.0 41 M with advanced HIV – CD4 27

96. HIV Cholangiopathy Seen in advanced AIDS – CD4 <50 High ALP, mildly elevated bilirubin Significant RUQ pain Survival is 6-9 months – due to other infections, wasting…

97. Case 3 35 year old woman Mild fatigue No significant PMH No meds Exam - cervical LAN 0.5 cm, nontender Liver 3 cm below RCM

99. Elevated ALP Biliary obstruction Tumor masses - primary or metastatic Drug Effect

100. Elevated ALP Biliary obstruction Tumor masses - primary or metastatic Drug Effect PBC, PSC Infiltrative disease - amyloid Granulomatous diseases – sarcoid, TB, fungi Autoimmune variants

101. Workup of ALP Elevation 1)Confirm liver origin with 5’-NT or GGT 2) Take a thorough drug history 3) U/S or CT to R/O mass and dilated ducts Mass -- biopsy Dilated ducts -- MRCP/ERCP 4) Neither -- check AMA, then biopsy liver.

103. Final Case AST 175 ALT 112 ALP 163 T. Bili 12.3 INR 1.9 ALB 3.0

104. An Approach to Abnormal LFTs Part 2 Robert C. Lowe, M.D. Boston Medical Center July 25, 2013