1. Evaluation of Abnormal Liver Function Tests Cengiz Pata Gastroenterology Department Yeditepe University

2. LFT’s Markers of hepatocellular damage Markers of hepatocellular damage Cholestasis Cholestasis Liver synthetic function Liver synthetic function

3. Markers of Hepatocellular damage (Transaminases) AST - liver, heart skeletal muscle, kidneys, brain, RBCs In liver 20% activity is cytosolic and 80% mitochondrial In liver 20% activity is cytosolic and 80% mitochondrial Clearance performed by sinusoidal cells, half-life 17hrs 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. In liver totally cytosolic. Half-life 47hrs Half-life 47hrs

4. Gamma-GT – hepatocytes and biliary epithelial cells, pancreas, renal tubules and intestine Very sensitive but Non-specific Very sensitive but Non-specific Raised in ANY liver discease hepatocellular or cholestatic Raised in ANY liver discease hepatocellular or cholestatic Usefulness limited ?, MRCP? Usefulness limited ?, MRCP? Confirm hepatic source for a raised ALP Confirm hepatic source for a raised ALP Alcohol Alcohol Isolated increase does not require any further evaluation, suggest watch and rpt 3/12 only if other LFT’s become abnormal then investigate Isolated increase does not require any further evaluation, suggest watch and rpt 3/12 only if other LFT’s become abnormal then investigate

5. Markers of Cholestasis ALP – liver and bone (placenta, kidneys, intestines or WCC) 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. 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 ALP isoenzymes, 5-NT or gamma GT may be necessary to evaluate the origin of ALP

6. Bilirubin, Albumin and Prothrombin time (INR) Useful indicators of liver synthetic function Useful indicators of liver synthetic function In primary care when associated with liver disease abnormalities should raise concern In primary care when associated with liver disease abnormalities should raise concern Thrombocytopaenia is a sensitive indicator of liver fibrosis Thrombocytopaenia is a sensitive indicator of liver fibrosis

7. Patterns of liver enzyme alteration Hepatic vs cholestatic Hepatic vs cholestatic Magnitude of enzyme alteration (ALT >10x vs minor abnormalities) Magnitude of enzyme alteration (ALT >10x vs minor abnormalities) Rate of change Rate of change Nature of the course of the abnormality (mild fluctuation vs progressive increase) Nature of the course of the abnormality (mild fluctuation vs progressive increase)

8. Patterns of liver enzyme alteration Acute hepatitis –transaminase > 10x ULN Acute hepatitis –transaminase > 10x ULN Cholestatic Cholestatic Mild rise in ALT Mild rise in ALT

9. Acute hepatitis (ALT>10xULN) Viral Viral Ischaemic Ischaemic Toxins Toxins Autoimmune Autoimmune Early phase of acute obstruction Early phase of acute obstruction

10. Acute hepatitis (ALT>10xULN) Viral – Hep A, B, C, E, CMV, EBV Viral – Hep A, B, C, E, CMV, EBV ALT levels usually peak before jaundice appears. ALT levels usually peak before jaundice appears. Jaundice occurs in 70% Hep A, 35% acute Hep B, 25% Hep C Jaundice occurs in 70% Hep A, 35% acute Hep B, 25% Hep C Check for exposure Check for exposure Check Hep A IgM, Hep B core IgM and HepBsAg, Hep C IgG or Hep C RNA Check Hep A IgM, Hep B core IgM and HepBsAg, Hep C IgG or Hep C RNA

11. Acute hepatitis (ALT>10xULN) Ischaemic- sepsis, hypotension Ischaemic- sepsis, hypotension ?most common cause in-patients ?most common cause in-patients Often extremely high >50x Often extremely high >50x Decrease rapidly Decrease rapidly LDH raised 80% LDH raised 80% Rarely jaundiced Rarely jaundiced

12. Acute hepatitis (ALT>10xULN) Toxins - paracetamol (up to 50% of all cases of Acute Liver Failure) Toxins - paracetamol (up to 50% of all cases of Acute Liver Failure) Ecstasy ( 2 nd most common cause in the young <35) Ecstasy ( 2 nd most common cause in the young <35) Any drug Any drug herbal remedies herbal remedies Alcohol – almost never, AST <7xULN in 98%, Alcohol – almost never, AST <7xULN in 98%, AST/ALT ratio > 1 in 92%, >2 in 70%

14. Acute hepatitis (ALT>10xULN) Autoimmune Rarely presents with acute hepatitis Rarely presents with acute hepatitis Usually jaundiced and progressive liver failure Usually jaundiced and progressive liver failure Raised IgG and autoantibodies (anti-SM, -LKM, -SLA) Raised IgG and autoantibodies (anti-SM, -LKM, -SLA)

15. Acute hepatitis (ALT>10xULN) Early phase- extrahepatic obstruction/cholangitis Early phase- extrahepatic obstruction/cholangitis Usually have history of pain Usually have history of pain USS – dilated CBD ? ERCP or lap chole USS – dilated CBD ? ERCP or lap chole

16. Cholestasis Isolated ALP 3 rd trimester, adolescents Isolated ALP 3 rd trimester, adolescents Bone – exclude by raised GGT, 5-NT or isoenzymes Bone – exclude by raised GGT, 5-NT or isoenzymes May suggest biliary obstruction, chronic liver disease or hepatic mass/tumour May suggest biliary obstruction, chronic liver disease or hepatic mass/tumour Liver USS/CT most important investigation-dilated ducts Liver USS/CT most important investigation-dilated ducts Ca pancreas, CBD stones, cholangioca or liver mets Ca pancreas, CBD stones, cholangioca or liver mets

17. Cholestasis – non-dilated ducts Cholestatic jaundice – Drugs- Antibiotics, Nsaids, Hormones, ACEI Cholestatic jaundice – Drugs- Antibiotics, Nsaids, Hormones, ACEI PBC – anti- mitochondrial Ab, M2 fraction, IgM PBC – anti- mitochondrial Ab, M2 fraction, IgM PSC – associated with IBD 70%, p-ANCA, MRCP and liver biopsy PSC – associated with IBD 70%, p-ANCA, MRCP and liver biopsy Chronic liver disease Chronic liver disease Cholangiocarcinoma – beware fluctuating levels Cholangiocarcinoma – beware fluctuating levels Primary or Metastatic cancer, lymphoma Primary or Metastatic cancer, lymphoma Infiltrative – sarcoid, inflammatory-PMR, IBD Infiltrative – sarcoid, inflammatory-PMR, IBD Liver biopsy often required Liver biopsy often required

18. “Dear Dr Hepaticus, I have just reviewed our patient data base and have identified 420 patients with persistently abnormal LFTs who are otherwise well and are not known to have liver disease. When can you see them? Yours, Dr G Practice”

19. COMMON CAUSES OF ABNORMAL LFTS IN THE UK Transient mild abnormalities which are simply impossible to explain Transient mild abnormalities which are simply impossible to explain Drugs – eg Statins Drugs – eg Statins Alcohol excess Alcohol excess Hepatitis C Hepatitis C Non-Alcoholic Fatty Liver Disease (NAFLD) Non-Alcoholic Fatty Liver Disease (NAFLD)

20. Investigation of Abnormal LFTs PRINCIPLES 2.5% of population have raised LFTs 2.5% of population have raised LFTs Normal LFTs do not exclude liver disease Normal LFTs do not exclude liver disease Interpret LFTs in clinical context Interpret LFTs in clinical context Take a careful history for risk factors, drugs (inc OTCs), alcohol, comorbidity, autoimmunity Take a careful history for risk factors, drugs (inc OTCs), alcohol, comorbidity, autoimmunity Physical examination for liver disease Physical examination for liver disease Chase likely diagnosis rather than follow algorithm unless there are no clues Chase likely diagnosis rather than follow algorithm unless there are no clues If mild abnormalities and no risk factors or suggestion of serious liver disease, repeat LFTs after an interval (with lifestyle modification) If mild abnormalities and no risk factors or suggestion of serious liver disease, repeat LFTs after an interval (with lifestyle modification)

21. Investigation of Abnormal LFTs - ALT/AST 2-5x normal (100-200) History and Examination History and Examination Discontinue hepatotoxic drugs Discontinue hepatotoxic drugs Continue statins but monitor LFTs monthly Continue statins but monitor LFTs monthly Lifestyle modification (lose wt, reduce alcohol, diabetic control) Lifestyle modification (lose wt, reduce alcohol, diabetic control) Repeat LFTs at 1 month and 6 months Repeat LFTs at 1 month and 6 months

22. Investigation of Abnormal LFTs - Raised ALT / AST If still abnormal at 6 months: If still abnormal at 6 months: Consider referral to secondary care Consider referral to secondary care Hepatitis serology (B, C) Hepatitis serology (B, C) Iron studies – transferrin saturation + ferritin Iron studies – transferrin saturation + ferritin Autoantibodies & immunoglobulins Autoantibodies & immunoglobulins Consider caeruloplasmin Consider caeruloplasmin Alpha-1- antitrypsin Alpha-1- antitrypsin Coeliac serology Coeliac serology TFTs, lipids/glucose TFTs, lipids/glucose Consider liver biopsy esp if ALT > 100) Consider liver biopsy esp if ALT > 100)

23. Liver biopsy Findings in Abnormal LFTs Skelly et al: 354 Asymptomatic patients 354 Asymptomatic patients Transaminases persistently 2X normal Transaminases persistently 2X normal No risk factors for liver disease No risk factors for liver disease Alcohol intake < 21 units/week Alcohol intake < 21 units/week Viral and autoimmune markers negative Viral and autoimmune markers negative Iron studies normal Iron studies normal Skelly et al. J Hepatol 2001; 35: 195-294

24. Liver biopsy Findings in Abnormal LFTs Skelly et al. J Hepatol 2001 6% Normal 6% Normal 26% Fibrosis 26% Fibrosis 6% Cirrhosis 6% Cirrhosis 34% NASH (11% of which had bridging fibrosis and 8% cirrhosis) 34% NASH (11% of which had bridging fibrosis and 8% cirrhosis) 32% Simple Fatty Liver 32% Simple Fatty Liver 18% Alteration in Management 18% Alteration in Management 3 Families entered into screening programmes 3 Families entered into screening programmes

25. Other Liver biopsy Findings in Abnormal LFTs Skelly et al. J Hepatol 2001 Cryptogenic hepatitis9% Cryptogenic hepatitis9% Drug induced7.6% Drug induced7.6% Alcoholic liver disease2.8% Alcoholic liver disease2.8% Autoimmune hepatitis1.9% Autoimmune hepatitis1.9% PBC1.4% PBC1.4% PSC1.1% PSC1.1% Granulomatous disease1.75% Granulomatous disease1.75% Haemochromatosis1% Haemochromatosis1% Amyloid 0.3% Amyloid 0.3% Glycogen storage disease0.31% Glycogen storage disease0.31%

26. What is the Value of Liver Biopsy in Abnormal LFTs? The most accurate way to grade the severity of liver disease The most accurate way to grade the severity of liver disease Aminotransferase levels correlate poorly with histological activity Aminotransferase levels correlate poorly with histological activity Narrows the diagnostic options, if not diagnostic Narrows the diagnostic options, if not diagnostic

27. LIVER BIOPSY FOR SERONEGATIVE ALT < 2X NORMAL N = 249, mean age 58, etoh 27 N = 249, mean age 58, etoh 27 ALT 51-99 (over 6 m) ALT 51-99 (over 6 m) 72% NAFLD 72% NAFLD 10% Normal histologically 10% Normal histologically Others: Granulomatous liver disease 4%, Autoimmune 2.7%, cryptogenic hepatitis 2.5%, ALD 1.4%, metobolic 2.1%, biliary 1.8% Others: Granulomatous liver disease 4%, Autoimmune 2.7%, cryptogenic hepatitis 2.5%, ALD 1.4%, metobolic 2.1%, biliary 1.8% Ryder et al BASL 2003

28. LIVER BIOPSY FOR SERONEGATIVE ALT < 2X NORMAL Of those with NAFLD: 56% had simple steatosis 56% had simple steatosis 44% inflammation and/or fibrosis 44% inflammation and/or fibrosis Risk of Severe Fibrotic Disease associated with: BMI >27 BMI >27 Gamma GT > 2x normal Gamma GT > 2x normal Ryder et al BASL 2003

29. Ultrasound in Liver Disease Detects Fatty Liver Detects Fatty Liver Increased echogenicity may not be specific for fat Increased echogenicity may not be specific for fat Unable to detect Inflammation or cirrhosis (unless advanced) Unable to detect Inflammation or cirrhosis (unless advanced) Therefore unable to discriminate between NASH and simple fatty liver or identify other types of liver disease (which may include fatty change) Therefore unable to discriminate between NASH and simple fatty liver or identify other types of liver disease (which may include fatty change) Liver biopsy is the only way to make an accurate diagnosis Liver biopsy is the only way to make an accurate diagnosis It may be worth treating fatty liver for 6 months before considering referral for biopsy It may be worth treating fatty liver for 6 months before considering referral for biopsy

30. Non-Alcoholic Fatty Liver Disease

31. Abnormal LFTs - Conclusions Many abnormal LFTs will return to normal spontaneously 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 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 Investigation requires clinical assessment and should be timely and pragmatic

34. GUIDANCE NOTES PREDICTIVE OF PATHOLOGY VS NORMAL: ALT > 2 x Normal AST: ALT >1 Age > 50 Low Platelet Count OTHER GROUPS WITH HIGH RISK PATHOLOGY: Raised Conjugated Bili with:  ALT  ALK P Consider: BX; MRCP; ERCP Any abnormality of ALK P in addition to abnormality ALT/AST Consider BX PREDICTORS OF NASH AND FIBROSIS IN PRESENCE OF NASH ALT > 2 x Normal AST > ALT Moderate Central Obesity BM1 > 28 NIDDM/Impaired GTT  BP  TGs. SUGGESTED ROUTINE SEROLOGICAL INVESTIGATIONS: Alpha 1 AT; HAV; HBV; HCV; AIP and Igs; Fe Studies and HFE genotype; Caeruloplasmin; USS – Fatty Change or Normal echo only; Bilirubin and haemolysis studies if appropriate - ANY ABNORMALITIES IN THESE PARAMETERS, RE-EVALUATE POTENTIAL DIAGNOSIS AND CONSIDER BIOPSY N.B. THESE NOTES/ALGORITHMS ARE FOR GUIDANCE ONLY. THIS IS A MOVING FIELD AND DESPITE IMPROVEMENTS IN SEROLOGICAL AND RADIOLOGICAL TECHNIQUES, THERE REMAIN SMALL NUMBERS OF PATIENTS WHO HAVE SIGNIFICANT LIVER DISEASE WITH ONLY MILDLY ABNORMAL LFTs. THE ALGORITHM IS NO SUBSTITUTE FOR CAREFUL AND REPEATED CLINICAL EVALUATION AND CLINICAL VIGILANCE.