ASSESEMENT OF ABNORMAL LIVER TESTS Prof. Eli Zuckerman, M.D. Liver Unit Haifa and Western Galilee District and Carmel Medical Center Clalit Health Services Liver tests ALT ALT (GPT) AST, LDH AST (GOT) LDH ALP (alkaline phosphatase) GGT bilirubin albumin P.T (prothrombin time) globulin CBC CLINICAL ASSESSMENT OF ABNORMAL LIVER TESTS Blood tests • Acute/recent vs. chronic liver disease • Hepatocellular vs. cholestatic injury • Etiology of liver disease (ALD, viral…) • Severity of liver disease (cirrhotic vs. noncirrhotic) Markers of Hepatocellular damage (Transaminases) AST- liver, heart skeletal muscle, kidneys, brain, RBCs In liver 20% activity is cytosolic and 80% mitochondrial Clearance performed by sinusoidal cells, half-life 17hrs ALT – more specific to liver, v.low concentrations in kidney and skeletal muscles. In liver totally cytosolic. Half-life 47hrs Gamma-GT – hepatocytes and biliary epithelial cells, pancreas, renal tubules and intestine Very sensitive but Non-specific Raised in ANY liver disease hepatocellular or cholestatic Usefulness limited Confirm hepatic source for a raised ALP Alcohol Isolated increase does not require any further evaluation, suggest watch and rpt 3/12 only if other LFT’s become abnormal then investigate Markers of Cholestasis ALP – liver and bone (placenta, kidneys, intestines) Hepatic ALP present on surface of bile duct epithelia and accumulating bile salts increase its release from cell surface. Takes time for induction of enzyme levels so may not be first enzyme to rise and half-life is 1 week. ALP isoenzymes, 5-NT or gamma GT may be necessary to evaluate the origin of ALP CLINICAL ASSESSMENT OF LIVER DISEASE SEVERITY Physical examination (I) Peripheral signs of CLD (“stigmata”): • spider angiomata • Dupuytren’s contracture • palmar erythema • testicular atrophy • gynecomastia Physical examination (II) Significant liver disease and/or portal HTN • Enlarged Lt. Lobe • Firm liver (fibrosis/cirrhosis) • Abdominal collaterals (portal HTN) • Splenomegaly (portal HTN) • Ascites (high SAAG, portal HTN) • Muscle wasting Bilirubin, Albumin and Prothrombin time (INR) Useful indicators of liver synthetic function In primary care when associated with liver disease abnormalities should raise concern Thrombocytopenia is a sensitive indicator of liver fibrosis Patterns of liver enzyme alteration Hepatic vs cholestatic Magnitude of enzyme alteration (ALT >10x vs minor abnormalities) Rate of change Nature of the course of the abnormality (mild fluctuation vs progressive increase) CLINICAL ASSESSMENT OF LIVER DISEASE SEVERITY Case 1. ALT (GPT) AST (GOT) LDH ALP GGT bilirubin albumin P.T globulin CBC 1890 1750 880 180 170 1.0 N 1.4 (60%) 4.3 N Admission? Differential diagnosis? Acute hepatitis (ALT>10xULN) Viral Ischaemic Toxins Autoimmune Acute Budd-Chiari Early phase of acute obstruction Metastatic liver-diffuse (extremely rare) Comments * Extremely high AST & LDH: ischemic, toxic (paracetamol, ecstasy) * “Hit and run” pattern: (AST 17h, ALT 47h): ischemic, toxic, CBD stone * Relatively preserved appetite: AIH, druginduced * Alcoholic hepatitis: AST/ALT >1 (92%) AST <300 (98%) “Hit and Run” pattern of liver enzymes AST ALT Diagnostic blood tests? Diagnostic tests: acute hepatitis * HAV-IgM, HBsAg, HBc-IgM, HCV (± HCV RNA) * Anti smooth muscle Ab, ANA, anti-LKM-1 * Ultrasound * CMV-IgM, EBV-IgM * Additional: toxic screen, Doppler US (hepatic veins) IgG 2430 mg/ml anti-smooth muscle +++ ANA 1:160 Liver biopsy? Interface hepatitis Lobular Hepatitis Plasma cell infiltration Case 2. 28 y/o male, asymptomatic, BMI 27.7, • ALT (GPT) 132 AST (GOT) 51 LDH 467 ALP 66 GGT 95 bilirubin 0.6 albumin 4.3 P.T 1.1 globulin N CBC N Cholesterol 277 (LDL-C 170) TG 304 Differential diagnosis? CLINICAL ASSESSMENT OF ABNORMAL LIVER TESTS Case 2. • D.D Fatty liver or NASH (non alcoholic steatohepatitis) (DM II, HLP, obesity, insulin resistance) Chronic viral hepatitis (HBV, HCV) Alcoholic liver disease (AST>ALT, MCV , GGT ) Autoimmune hepatitis (ANA, aSMA, LKM-1) Wison’s disease (age < 55) (hemochromatosis, A1AT) Drug induced liver injury Celiac disease, Addison. Diagnostic blood tests? Diagnostic tests case 2: asymptomatic abnormal LT (X2-5) * Viral serology: HBsAg, HCV (± HCV RNA) * Autoimmune screen: anti-smooth muscle Ab, ANA, anti-LKM-1, (anti mitochondrial) * Metabolic (age < 50): ceruloplasmin, ferritin, transferin, iron, α1 anti-trypsin * NAFLD: lipids, HbA1c, insulin resistance, glucose * US * Additional: celiac (anti-transglutaminase, endomysial) All diagnostic blood tests negative except anti-smooth muscle Ab ± Imaging features US sensitivity depends on hepatic fat content>30% fat, sensitivity 80% 10-19% fat, sensitivity 55% Morbid obesity – sensitivity 49%, specificity 75% MANAGEMENT OF NAFLD • • TO BIOPSY OR NOT TO BIOPSY ? WHOM TO BIOPSY ? NASH - RISK FACTORS FOR FIBROSIS AND CIRRHOSIS Independent risk factors in several studies: Age >45 ALT > 2x normal AST/ALT ratio > 1 Obesity, particularly truncal , BMI > 27 Type 2 diabetes Insulin Resistance Hyperlipdemia (trigycerides > X1.7) NB: Studies are in selected groups; may not apply to all patients Case 3. 48 y/o male, asymptomatic, BMI 36 • ALT (GPT) 100 AST (GOT) 125 LDH 467 ALP 66 GGT 95 bilirubin 0.6 albumin 3.7 P.T 1.1 globulin 4.0 PLT 138000 Cholesterol 277 (LDL-C 170) TG 304 HIT # 1 NAFLD-”simple” steatosis NASH Fibrosis NASH cirrhosis Management? Treatment of NAFLD Weight reduction Diet + exercise* Pharmacological: orlistat, Bariatric surgery * Insulin sensitizing agents thioglitazones * (pio-, rosi-) metformin * Anti-oxidants Vit E, betain Cytoprotective Ursodeoxicholic acid Lipid lowering agents HMG-CoA RI’s ? Fibrates ? Surgery Case 4. 61 y/o male, asymptomatic, BMI 27.7, IHD (PTCA + stent RCA), HTN, US: “fatty liver” • ALT (GPT) 87 AST (GOT) 51 ALP 66 GGT 95 bilirubin 0.6 albumin 4.3 P.T 1.1 globulin N CBC N Cholesterol 277 (LDL-C 170) TG 304 Statins? After 12 weeks of Rx with statins • ALT (GPT) 220 AST (GOT) 110 ALP 100 GGT 95 bilirubin 1.0 albumin 4.3 Cholesterol 210 (LDL-C 123) TG 220 FOR THE PHYSICIAN Continued treatment ALAT 3. Fulminant hepatitis 2. Chronic liver disease 5 ULN 1. Adaptation 1 ULN DRUG Black, Gastroenterology , 1975;69:289 CLINICAL 0.1% Death 1% Jaundice INFRACLINICAL ALT > 10 ULN Unfractionated heparin Isoniazid 30% Transaminases 15% Transaminases Monreal, Eur J Clin Pharmacol 1989;37:415 Huang, Hepatology 2002;35:883-889 Case 5. 28 y/o male, asymptomatic, BMI 27, • ALT (GPT) 132 AST (GOT) 51 LDH 467 ALP 66 GGT 95 bilirubin 0.6 albumin 4.3 P.T 1.1 globulin N CBC N Cholesterol 177 (LDL-C 108), TG 120 HCV + Case 6. 28 y/o male, asymptomatic, BMI 27, • ALT (GPT) AST (GOT) LDH ALP GGT bilirubin albumin P.T globulin CBC HBsAg + 98 51 467 66 95 0.6 4.3 1.1 N N Next step ? Case 6. 28 y/o male, asymptomatic,, HBsAg + HBeAg HBeAb + HBcAb + HDV HBV DNA (PCR) + HBV DNA 2.8 X 104 IU/ml New approaches to patient management strategy: HBV HBV TREATMENT HBV DNA (viral load) Elevated ALT HBeAg status Severity of liver disease Bהפטיטיס קריטריונים לטיפול עומס נגיפי מעל Iu/mL 2,000 רמת > ALTמULN - ביופסיה עם עדות לפיברוזיס או שינויים נקרו-אינפלמטוריים משמעותיים Liver biopsy Findings in Abnormal LFTs Skelly et al: 354 Asymptomatic patients Transaminases persistently 2X normal No risk factors for liver disease Alcohol intake < 21 units/week Viral and autoimmune markers negative Iron studies normal Skelly et al. J Hepatol 2001; 35: 195-294 Liver biopsy Findings in Abnormal LFTs Skelly et al. J Hepatol 2001 6% Normal 26% Fibrosis 6% Cirrhosis 34% NASH (11% of which had bridging fibrosis and 8% cirrhosis) 32% Simple Fatty Liver 18% Alteration in Management 3 Families entered into screening programmes Other Liver biopsy Findings in Abnormal LFTs Skelly et al. J Hepatol 2001 Cryptogenic hepatitis Drug induced Alcoholic liver disease Autoimmune hepatitis PBC PSC Granulomatous disease Haemochromatosis Amyloid Glycogen storage disease 9% 7.6% 2.8% 1.9% 1.4% 1.1% 1.75% 1% 0.3% 0.31% LIVER BIOPSY FOR SERONEGATIVE ALT < 2X NORMAL N = 249, mean age 58, etoh < 25 units per week, 9% diabetes, 24% BMI > 27 ALT 51-99 (over 6 m) 72% NAFLD 10% Normal histologically Others: Granulomatous liver disease 4%, Autoimmune 2.7%, cryptogenic hepatitis 2.5%, ALD 1.4%, metabolic 2.1%, biliary 1.8% Ryder et al BASL 2003 LIVER BIOPSY FOR SERONEGATIVE ALT < 2X NORMAL Of those with NAFLD: 56% had simple steatosis 44% inflammation and/or fibrosis Risk of Severe Fibrotic Disease associated with: BMI >27 Gamma GT > 2x normal Ryder et al BASL 2003 Abnormal LFTs - Conclusions Many abnormal LFTs will return to normal spontaneously An important minority of patients with abnormal LFTs will have important diagnoses, including communicable and potentially life threatening diseases Investigation requires clinical assessment and should be timely and pragmatic CLINICAL ASSESSMENT OF ABNORMAL LIVER TESTS Case 7. • ALT (GPT) AST (GOT) LDH ALP GGT bilirubin albumin globulin P.T CBC 48 52 214 348 488 1.0 N 3.2 0.8 N Case 7 • D.D ULTRASOUND (± CT): dilated vs. nondilated ducts PBC (anti-mitochondrial Ab, IgM) PSC (IBD-UC, ANCA, ERCP, MRCP) Infiltrative disease (neoplastic, amyloidosis ) Granulomatous disease (sarcoidosis, TB, Q fever) Granulomatous hepatitis Drug induced cholestatic liver injury (ACE-I, NSAIDs) Fatty liver (GGT-DM). Extra-hepatic obstruction (stones, neoplasm, stricture) Case 6 • anti-mitochondrial Ab +, IgM 330, IgG 1400 ANA +, anti-smooth muscle Ab - CLINICAL ASSESSMENT OF ABNORMAL LIVER TESTS Case 8 • ALT (GPT) AST (GOT) LDH ALP GGT bilirubin albumin globulin P.T CBC 24 37 214 100 112 1.0 N 3.2 0.8 N CLINICAL ASSESSMENT OF ABNORMAL LIVER TESTS Case 8. (ICU) (IDU, susp ABE, sepsis, renal failure) AST (GOT) ALT (GOT) LDH ALP GGT bilirubin albumin P.T globulin CBC 7800 2500 8900 125 69 5.2 3.4 1.7 (40%) N 18,000 CLINICAL ASSESSMENT OF ABNORMAL LIVER TESTS Case 8. (ICU) (IDU, susp ABE, sepsis, renal failure) AST (GOT) ALT (GOT) LDH ALP GGT bilirubin albumin P.T globulin CBC CPK 7800 2500 8900 125 69 5.2 3.4 1.7 (40%) N 18,000 23000 Liver tests