Interpretation of abnormal liver function tests. Dr Rania Bakry, MD

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1 Interpretation of abnormal liver function tests Dr Rania Bakry, MD

2 Liver function tests Noninvasive method of screening for the presence of liver dysfunction Pattern of lab test abnormality allows recognition of general type of disorder To assess the severity and occasionally allow prediction of outcome To follow the course of the disease, evaluate response to treatment, and adjust treatment when necessary

3 Limitations Lack of sensitivity (may be normal in cirrhosis or HCC) Lack of specificity (aminotransferase levels may be elevated in musculoskeletal or cardiac disease) Results suggest general category of liver disease, not a specific diagnosis Essential to use LFT as a battery of tests and repeat them over time Probability of liver disease is high when more than one test is abnormal or the findings are persistently abnormal on serial testing

4 General categories of tests Tests of the capacity of the liver to transport organic anions and metabolize drugs Eg. S bilirubin, s bile acids, BSP etc Measures ability of the liver to clear endogenous or exogenous substances from the circulation Tests to detect injury to hepatocytes All the enzyme tests Most commonly done and most useful are aminotransferases and alkaline phosphatase

5 Tests of the biosynthetic capacity of the liver Eg. S albumin, prothrombin time Tests to detect fibrosis in the liver Eg. Type 4 collagen, Fibrotest etc Tests for chronic inflammation or altered immunoregulation Immunoglobulins and specific antibodies Schiff s diseases of the liver, 2007

6 Common serum liver chemistry tests

7 Normal values

8 Initial approach to the evaluation of abnormal liver enzyme tests Asymtomatic or symptomatic History and physical Alcohol consumption Risk factors for viral hepatitis - IV drug abuse, sexual promiscuity, homosexual relations, tattoos, nonsterile body piercing, blood and blood products, medications, herbal or alternative med., occupational exposure to toxins Diabetes, obesity, hyperlipidemia Family history - Wilson s dis, hemochromatosis, autoimmune diseases

9 Evaluation of abnormalities of ALT (SGPT) and AST (SGOT) levels AST and ALT are markers of hepatocellular injury Participate in gluconeogenesis, transfer of amino groups from aspartate or alanine to ketoglutaric acid to form oxaloacetete or pyruvate. AST present in cytosol and mitochondria in liver, cardiac muscle, skeletal muscle, kidney, brain, pancreas, lungs, WBC and RBC. ALT a cytosolic enzyme, highest concentration in the liver ALT considered a liver specific enzyme

10 Useful paradigm to categorize increased levels of AST, ALT Mild AST, ALT elevation (less than 5 times ULN) - ALT predominant or AST predominant AST, ALT greater then 15 times normal Elevations in the intermediate range - less useful for limiting the DD, caused by diseases from both above categories AGA Technical review, Gastroenterology 2002

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12 Medications causing elevation of aminotransferases Acetaminophen Amoxicillin-clavulanic acid HMGCoA reductase inhbtrs INH NSAIDS Phenytoin Valproate Many others Herbs and toxins Herbs/alt. medicines Illicit drugs Toxins

13 ALD Reliable history Ratio of SGOT to SGPT is at least 2:1 Reflects low level of activity of SGPT SGOT rarely exceeds 300 IU Higher values - seek additional cause of liver injury A GGT (gammaglutamyl transferase) twice normal and AST/ALT ratio of 2:1 or more, highly suggestive of alcohol abuse

14 NAFLD Hepatic steatosis (fatty liver) and NASH Asymptomatic increase in transaminases Raised BMI, Type 2 DM and hyperlipidemia No evidence of clinically relevant alcohol use Probably commonest cause of mild transaminase increases AST/ALT ratio usually < 1:1 in the absence of cirrhosis Values < 250 IU usually

15 DD of moderately elevated aminotransferases (5 to 15 times ULN) Wide range of liver diseases ALT, AST less useful in determining cause Entire spectrum of liver diseases causing mild or severe aminotransferase elevation

16 DD of severe elevations of ALT, AST (> 15 times ULN) Relatively ltd Indicate marked hepatocellular injury or necrosis Drug induced - acetaminophen Occupational/environmental toxins - toluene, CCl 4 Ischemic hepatitis Viral hepatitis - A, B, D, E, Herpes

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18 Suggested algorithm for evaluating raised transaminases PMJ 2003

19 What is Normal? (Annals of Internal Medicine, 2002)

20 Other enzyme tests for hepatocellular necrosis Glutamate dehydrogenase Isocitrate dehydrogenase Lactate dehydrogenase More useful as marker for Hemolysis, Myocardial infarction Sorbitol dehydrogenase

21 Enzymes for the detection of cholestasis Alkaline phosphatase Present in nearly all tissues - isoenzymes Localised in the microvilli of the bile canalicus in the liver Also present in bone, intestine, placenta, kidney and wbc Elevation may be physiological or pathological Physiological In tissues undergoing metabolic stimulation Third trimester of pregnancy Adolescence

22 Normal adult serum AP is from liver and bone Intestine contributes about 15% Several procedures used to measure activity - differs in substrates used, end products measured, etc Isoenzymes differ in reactions in various assay systems Hence different units such as IU, KA, Bodansky

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24 Elevation of s. alkaline phosphatase Isolated Associated with hyperbilirubinemia (cholestatic disorders) May be sole abnormality in many cholestatic or infiltrative diseases To be interpreted in the clinical setting of history and physical examination if sole abnormality

25 When SAP elevation is detected Repeat the test Confirm the hepatic origin Serum gammaglutamyl transferase 5 -Nucleotidase AP isoenzymes If medications suspected, discontinue them and repeat test Persistently elevated SAP - evaluate for Cholestatic liver disease Infiltrative liver disease Biliary obstruction

26 AP elevation upto 3 times ULN > 3 times ULN Nonspecific Occurs in all types of liver disorders Viral hepatitis Cirrhosis Infiltrative diseases of the liver CHF etc Cholestatic disorders Extrahepatic Intrahepatic Infiltrative disorders Mets

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29 USS to assess hepatic parenchyma and biliary system should be part of initial evaluation Additional imaging of abdomen if indicated CT, MRI, MRCP If extrahepatic obstruction evident, ERCP or PTC If no obstruction, do AMA (anti-mitochondrial antibody) Continued presence of persistently elevated SAP ( > 6 months ) of unknown origin - further evaluation with imaging and/or biopsy Potentially treatable cholestatic and infiltrative diseases with long asymptomatic periods with mild elevations of AP being the only finding Eg PBC, PSC, Sarcoidosis etc

30 Suggested algorithm for evaluating a raised s.alkaline phosphatase PMJ 2003

31 Gammaglutamyl transferase (γ-glutamyl transpeptidase) Found in hepatocytes and biliary epithelial cells Sensitive for hepatobiliary disease but ltd by lack of specificity With other enzyme abnormalities, raised GGT would support a hepatobiliary cause Can confirm hepatic source for a raised AP Raised GGT and raised transaminases with ratio of AST to ALT 2:1 or more suggestive of ALD Medications can cause mild rise Normal range 0 to 30 IU/L

32 Causes of raised serum gammaglutamyl transferase (SGGT)

33 5 -Nucleotidase Normal 0.3 to 3.2 Bodansky units Spectrum of abnormality similar to that of SAP Specificity for hepatobiliary disease May be used to confirm hepatic origin of elevated SAP

34 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

35 Bilirubin UDP-glucoronyltransferase RE cell plasma hepatocyte HEME UCB UCB + albumin UCB+ligandin BMG BDG bile urobilinogen stercobilinogen

36 Isolated unconjugated hyperbilirubinemia IDB fraction > 85% of total bilirubin 1. Increased production hemolysis ineffective erythropoiesis : folate, IDA drugs : rifampicin resolution of hematoma 2. Defects in hepatic uptake/conjugation Gilbert s syndrome Crigler-Najjar syndrome

37 Gilbert s syndrome benign, unconjugated hyperbilirubinemia with otherwise normal liver chemistries up to 5% of normal population polymorphisms of gene encoding bilirubin UDP-GT impaired ability to conjugate bilirubin prominent in fasting state, systemic illnesses, hemolysis, some medications

38 Conjugated hyperbilirubinemia DB > 50% of total bilirubin can t differentiate obstruction and parenchymal disease Delta fraction CB tightly bound to albumin tendency of hyperbilirubinemia to resolve more slowly than other biochemical tests

39 Conjugated hyperbilirubinemia Bile duct obstruction Hepatitis Cirrhosis Medications/Toxins Primary biliary cirrhosis Primary sclerosing cholangitis Sepsis Total parenteral nutrition Intrahepatic cholestasis of pregnancy Benign recurrent cholestasis Vanishing bile duct syndromes Dubin-Johnson syndrome Rotor syndrome

40 Albumin depends on nutrition, hormonal factors, vascular integrity, catabolism, loss in stool and urine not specific for liver disease T1/2 = days Not a reliable indicator of acute liver disease Levels fall in progressive disease, reflects synthetic fn Correlates with prognosis in CLD

41 Prothrombin time The liver synthesizes coagulation factors except FVIII Most present in excess, clotting abnormality occurs only when substantial impairment in ability of liver to synthesise the CF PT : FI, II, V, VII, IX and X T1/2 FVII 6 hrs. (shortest) prognosis : acute, chronic hepatocellular disease

42 Prothrombin time prolonged : vitamin K deficiency (malnutrition, malabsorption, antibiotics) massive transfusion congenital disease liver disease warfarin DIC

43 Prothrombin time in vit K deficiency, vit K 10 mg SC decreases prolonged PT >30% within 24 hrs INR (international normalised ratio) More often tested now Standardising reports of PT Avoids interlab variability INR = [Patient PT/mean control PT] ISI ISI - international sensitivity index

44 Modified Child-Turcotte-Pugh score for grading severity of liver disease

45 Quantitative tests for liver function More sensitive Limitations of biochemical tests Expensive, ltd to research centers Trials needed before wider acceptance Indocyanine green clearance 14 C - aminopyrine breath test Antipyrine clearance Galactose elimination capacity 13 C - caffeine breath test

46 Take home message initial evaluation : assess in clinical context classified in 3 groups 1. synthetic function : albumin, clotting time 2. cholestasis : bilirubin, ALP, GGT 3. hepatocyte injury : AST, ALT

47 Liver Function Tests misnomer Does not effectively assess actual function not always specific for the liver limited information regarding presence or severity of complication Liver Chemistry Tests

48 When to refer for a specialist opinion? Unexplained liver abnormalities > 1.5 times normal on 2 occasions, a minimum of 6 months apart Unexplained liver disease with evidence of liver dysfunction (hypoalbuminemia, hyperbilirubinemia, prolonged PT or INR) Known liver disease where treatment beyond withdrawal of the implicating agent is required Limdi et al, Postgrad Med J 2003

49 What tests to do before referral? Consider the following; Screen for viral hepatitis IgM anti HAV HBsAg Anti HCV Antinuclear antibodies Ceruloplasmin in pts < 40 yrs Iron studies - S ferritin, transferrin saturation US of the hepatobiliary system PMJ 2003

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