Carmel Medical Center Clalit Health Services 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 (GOT) LDH ALP (alkaline phosphatase) GGT bilirubin albumin P.T (prothrombin time) globulin CBC AST, LDH

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. non-cirrhotic)

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) 1890 AST (GOT) 1750 LDH 880 ALP 180 GGT 170 bilirubin 1.0 albumin N P.T 1.4 (60%) globulin 4.3 CBC 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)

* Extremely high AST & LDH: ischemic, toxic 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, drug- induced * 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 Interface hepatitis. Here you can see the limiting plate of the portal tract, demarcating the hepatocyte boundary, is disrupted by a lymphoplasmacytic infiltrate. This histologic pattern is the hallmark of autoimmune hepatitis, but it is not disease specific. Hematoxylin and eosin, *200. Extra notes: Acute onset AIH pattern: panancinar hepatitis that resembles an acute viral or drug-induced hepatitis. Centrilobular or pervenular (rappaprot zone 3) hepaitits that resembles an acute toxic injury.

Lobular Hepatitis Figure 75–2. Lobular hepatitis in which mononuclear inflammatory cells line the sinusoidal spaces. Typically, lobular hepatitis coexists with interface hepatitis, but it may be pronounced during acute onset or during relapse after treatment withdrawal. Hematoxylin and eosin, *200.

Plasma cell infiltration Plasma cells are identified by their eccentric, clock-face nucleus, and pale perinuclear cytoplasm. There are not pathognomonic of the disease nor required for diagnosis.

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% 30

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 ? 39

Surgery 40

41

Statins? Case 4. 61 y/o male, asymptomatic, BMI 27.7, • ALT (GPT) 87 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

Continued treatment FOR THE PHYSICIAN 3. Fulminant hepatitis ALAT 2. Chronic liver disease 5 ULN 1. Adaptation 1 ULN DRUG

Monreal, Eur J Clin Pharmacol Black, Gastroenterology , 1975;69:289 0.1% Death CLINICAL 1% Jaundice INFRA- CLINICAL 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) 98 AST (GOT) 51 LDH 467 ALP 66 GGT 95 bilirubin 0.6 albumin 4.3 P.T 1.1 globulin N CBC N HBsAg + 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

הפטיטיס B קריטריונים לטיפול עומס נגיפי מעל 2,000 Iu/mL רמת ALT > מ- ULN 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 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 Other Liver biopsy Findings in Abnormal LFTs Skelly et al. J Hepatol 2001 Cryptogenic hepatitis 9% Drug induced 7.6% Alcoholic liver disease 2.8% Autoimmune hepatitis 1.9% PBC 1.4% PSC 1.1% Granulomatous disease 1.75% Haemochromatosis 1% Amyloid 0.3% Glycogen storage disease 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) 48 AST (GOT) 52 LDH 214 ALP 348 GGT 488 bilirubin 1.0 albumin N globulin 3.2 P.T 0.8 CBC N

• D.D ULTRASOUND (± CT): dilated vs. non- dilated ducts Case 7 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)

• anti-mitochondrial Ab +, Case 6 • anti-mitochondrial Ab +, IgM 330, IgG 1400 ANA +, anti-smooth muscle Ab -

CLINICAL ASSESSMENT OF ABNORMAL LIVER TESTS Case 8 • ALT (GPT) 24 AST (GOT) 37 LDH 214 ALP 100 GGT 112 bilirubin 1.0 albumin N globulin 3.2 P.T 0.8 CBC N

CLINICAL ASSESSMENT OF ABNORMAL LIVER TESTS Case 8. (ICU) (IDU, susp ABE, sepsis, renal failure) AST (GOT) 7800 ALT (GOT) 2500 LDH 8900 ALP 125 GGT 69 bilirubin 5.2 albumin 3.4 P.T 1.7 (40%) globulin N CBC 18,000

CLINICAL ASSESSMENT OF ABNORMAL LIVER TESTS Case 8. (ICU) (IDU, susp ABE, sepsis, renal failure) AST (GOT) 7800 ALT (GOT) 2500 LDH 8900 ALP 125 GGT 69 bilirubin 5.2 albumin 3.4 P.T 1.7 (40%) globulin N CBC 18,000 CPK 23000

Thank you

THANK YOU Liver tests Slide 76. Predictability This section will discuss the ability to predict SVR or nonresponse early in the course of treatment with PEGASYS® (peginterferon alfa-2a [40KD]).