Points to consider

2. When are LFTs indicated? How are isolated borderline LFT results managed? Is LFT monitoring necessary for people on statins? What are the best tests of liver failure? Who is at risk of chronic hepatitis? How is acute hepatitis managed in primary care? Is non-alcoholic liver disease a benign condition? What is the role of GGT? Points to consider

3. Most liver problems are managed in primary care Testing and interpretation can be challenging Consider clinical findings, previous liver function tests and other test results Introduction

4. Liver function testing is not indicated for asymptomatic people without risk factors Requesting LFTs

5. Diabetes or metabolic syndrome (increased risk of NAFLD) Excessive alcohol intake Chronic hepatitis B Chronic hepatitis C Asymptomatic people at risk of abnormal LFTs

6. GGT, macrocytosis, triglycerides and uric acid are both non-sensitive and non-specific to EtOH Screening questionnaires give better results GGT has better predictive value when there is strong suspicion of alcohol excess Excessive alcohol intake

7. Diabetes, metabolic syndrome, insulin resistance and dyslipidaemia, increase the risk of NAFLD People with these conditions will benefit from occasional measurement of LFTs at diagnosis, start of antidiabetic therapy and any other time indicated by clinical judgment Diabetes or metabolic syndrome

8. 50 - 90% neonates and children infected with hepatitis will develop chronic hepatitis B infection, but < 5% of adults. Chronic hepatitis B carriers have ~ 25% risk of developing liver damage, cirrhosis, liver failure and liver cancer. LFTs should be tested at least 6 monthly. Screening for hepatitis B infection, using HBsAg, is recommended for all people of Maori, Pacific or Asian ethnicity over the age of 15years, who have not previously been immunised. Chronic hepatitis B

9. Most people will not be symptomatic during the acute infection but approximately 70% will remain infected. Chronic infections carry a substantial risk of liver damage, cirrhosis and liver cancer. Test people who had blood transfusions prior 1992, inject street drugs or share needles. Chronic hepatitis C

10. Liver disease is associated with a wide range of other illnesses: Haemochromatosis Autoimmune diseases, including coeliac disease Chronic inflammatory bowel disease Metastatic cancer Clinically significant thyroid disease Right heart failure People at risk of abnormal LFTs because of other illnesses

11. People at risk of abnormal LFTs because of drugs Drugs which LFT monitoring is recommended in primary care:

12. Risk of liver damage from statin use has been overstated. Liver failure occurs with statins is similar to liver failure rate in general population. Irreversible liver damage resulting from statin therapy is exceedingly rare. Routine monitoring is not necessary. Statins should not be withheld in patients with baseline abnormal LFTs. Routine monitoring of LFTs no longer considered necessary for statin use

13. In some situations LFTs may be indicated following abnormalities in apparently unrelated tests. Examples are: Abnormal iron studies/elevated ferritin Abnormalities on blood film Macrocytosis Neutropenia Thrombocytopenia People at risk of abnormal LFTs because of other abnormal blood tests

14. Liver function testing when there are clinical features of liver disease

15. Abnormal liver function tests must be interpreted with regard to clinical context and results of previous tests: History of symptoms Medication history Occupational exposure Family history Social history Physical examination Interpretation of liver function tests

16. Typical patterns of liver dysfunction

17. Most likely causes of hepatocyte injury are: Non-alcoholic fatty liver disease Viral hepatitis Alcohol, drugs, and herbal remedies Haemochromatosis Autoimmune disease Hepatocyte injury: usually results in ALT and/or AST elevation

18. Cascade of testing following abnormal LFTs • Tests are requested in a stepwise fashion guided by presence of risk factors and clinical features

19. < 3 X ULN recheck in 1-3 months Two results elevated 3 months apart, investigate further > 3 X ULN, Investigate further AST/ALT ratio < 1 in most hepatocellular injury >1 in alcholic liver diseae, drug induced, malignancy, cirrohosis Transaminases in general

20. This has limited use as primary liver test and there is no clear consensus on follow up. Suggestions are: Although non specfic, consider alcohol Review risk factors for non-alcoholic fatty liver disease. Mild rises < 3 X ULN, test three monthly and consider further investigation if elevation persists or rises. > 5 ULN or both GGT and alkaline phosphatase raised without explanation - consider ultrasound Isolated GGT elevation

21. Most likely causes of cholestasis include: Gall stones Abdominal masses Medications (erythromycin, phenytoin, flucloxacillin, amoxicillin-clavulanic acid, combined oral contraceptive pill, some antipsychotics) Pregnancy Primary biliary cirrhosis Paraneoplasia (especially lymphoma) Systemic sepsis Cholestasis

22. ALP and bilirubin usually both elevated Non-liver causes of ↑ ALP ALP is non-specific for liver. Other sources are bone, intestine, and placenta. Bony causes include: bony metastases, hyperparathyroidism, renal impairment, healing fractures and Paget’s disease. Other causes : CHF, hyperthyroidism, pregnancy, children during bone growth, perimenopausal years. A cholestatic pattern of LFT disturbance

23. ↑ ALP / ↑ GGT = most likely a liver cause ↑ ALP / normal GGT = bony cause is more likely Follow up of ↑ alkaline phosphatase Depends on the clinical context, other laboratory abnormalities, and clinical review Liver ultrasound if cholestasis is suspected Raised alkaline phosphatase plus raised GGT makes liver problem more likely

24. Response to ↑ ALP(when likelihood of disease is low)

25. Liver disease: usually along with other LFTs Isolated ↑ bilirubin: familial hyperbilirubinaemias, Haemolysis: ↑ unconjugated bilirubin. Causes of bilirubin elevation

26. Inherited haemolytic anaemias eg, spherocytosis, thalassaemia Immune reactions eg transfusion reaction or haemolytic disease of the newborn Auto-immune disorders eg SLE, RA Renal or liver failure Drugs and chemicals eg, arsenic, sulphasalazine Infections eg, malaria, Clostridium perfringes Mechanical eg, valve prosthesis, march haemoglobinuria Hypersplenism Burns Haemolysis may be due to:

27. Follow up of elevated bilirubin levels (when no clinical indications of cause)

28. Failure of the liver to perform its synthetic functions is most often related to loss of functioning liver mass. It is usually assessed by levels of serum albumin and coagulation factors, Failure of the liver to synthesise albumin results in  albumin.  albumin may be due to: cachexia, catabolic states, such as sepsis and cancer, nephrotic syndrome and protein-losing enteropathy. ↑ INR may be due to  synthesis of clotting factors Vitamin K malabsorption may ↑ INR Failure of liver synthetic function = severe liver disease Liver failure: reflected in serum albumin and INR

29. HBsAg positive, ALT > ULN for at least 6. AFP is >100 = should be seen urgently. Hepatitis C positive Evidence of acute or chronic failure of liver synthetic function. Haemochromatosis positive with abnormal LFTs, hepatomegaly or untreated ferritin > 1000 g/L. Anyone with persisting unexplained LFT abnormalities. People who require specialist referral for disturbed liver function

30. Common causes of acute hepatitis are: Hepatitis A: contaminated food, men who have sex with men <1% develop chronic autoimmune hepatitis Hepatitis B: adult infection – sexual, intra-venous drug use Acute hepatitis B is unlikely in adults of Maori, Pacific or Asian ethnicity (Likely to be immune or chronically infected due to infection at an early age) < 5% of adults develop chronic infection Hepatitis C: adult infection, intra-venous drug use >80% develop chronic hepatitis Epstein-Barr viral hepatitis: usually adolescent (infectious mononucleosis) None develop chronic hepatitis Management of acute hepatitis

31. Monitoring for acute hepatitis managed at home includes twice weekly testing of:ALT, AST, INR, bilirubin, creatinine, glucoseTesting frequency is decreased as the results return to normal. Monitoring in acute hepatitis

32. Liver function testing is rarely indicated in IM IM does not lead to chronic liver disease LFT results do not alter management Test LFTs only if patient becomes jaundice Liver function testing not indicated in infectious mononucleosis

33. Fatty liver is associated with alcoholic liver disease but non-alcoholic causes are becoming increasingly common. NAFLD often has ↑AST/ALT. 10-15% of people with NAFLD will develop long term scarring. NAFLD associated with metabolic syndrome, insulin resistance, diabetes, and hyperlipidaemia. LFTs especially indicated for people at risk of fibrosis or progression. Fatty liver (steatohepatitis)

34. Monitoring of LFTs is not routinely indicated for people with cancer as it is rare to get liver failure from liver metastases. Biliary obstruction may occur but leads rapidly to jaundice. Monitoring of LFTs is worthwhile for people on chemotherapy. Liver metastases

35. Gilbert’s syndrome is asymptomatic and it is not a serious disease. Occurs 2-10% of the population. Mostly unconjugated bilirubin and levels fluctuate, often higher at times of illness and fasting. No proven association between tiredness and Gilbert’s syndrome. No risk of kernicterus to the foetus. Gilbert’s syndrome

36. ALT AST GGT ALP Bilirubin Total protein Albumin INR Appendix 1 - Liver function tests

37. 1. The RAPS4 Alcohol Screening Test for dependent drinking Please answer these 4 questions: During the last year have you had a feeling of guilt or remorse after drinking? During the last year has a friend or a family member ever told you about things you said or did while you were drinking that you could not remember? During the last year have you failed to do what was normally expected from you because of drinking? Do you sometime take a drink when you first get up in the morning? Appendix 2 – Alcohol screening tests

38. 2. Alcohol Advisory Council of New Zealand ‘Drink Check’ The ALAC drinkcheck questionnaire, based on the AUDIT tool, is available online from ALAC: http://www.alac.org.nz/TestYourDrinking.aspx Appendix 2 – Alcohol screening tests …contd

39. HBsAg Negative Positive No evidence of Hepatitis B infection If positive for > 6 months, consistent with chronic Hepatitis B infection Appendix 3 -Screening for hepatitis B in people not previously immune

40. A previous vaccination with documented immune response, the patient can then be presumed to be protected long term unless they are immunosuppressed. If in doubt revaccinate and recheck anti-HBs in 3 weeks. A small number of patients may be positive for anti-HBc from a previous HBV infection in the absence of anti-HBs. If there is a strong suspicion of previous infection or high risk, then order an anti-HBc. Anti-HBs Negative Positive No evidence of previous infection or immunization See footnote(b) Compatible with previous infection or immunisation Appendix 3 -Investigation for Evidence of Previous Infection or Immunisation with Hepatitis B – See footnote (a)

41. A negative test does not exclude infection within the previous eight weeks. Positive anti-HCV is followed up by HCV RNA tests. Persistently normal LFTs and two negative HCV RNA tests 3 months apart indicate that active HCV is extremely unlikely. Anti-HCV Negative Positive No evidence of chronic Hepatitis C infection See footnote (a) Indicates possible current, previous or chronic Hepatitis C infection See footnote (b) Appendix 4: Investigation for Evidence of Chronic HCV Infection

42. Isoenzymes are different molecular forms of the same enzyme, which all react in a similar manner with a laboratory test. ALP isoenzymes may originate from liver, bone, placenta, intestinal or tumour cells. ALT is the most specific liver enzyme, but occasionally originates from sources other than the liver. AST may originate from liver, heart or red blood cells. GGT isoenzymes have been identified in kidney, heart and pancreas but these are not commonly encountered. Appendix 5 – Isoenzymes

43. Hepatitis C cannot reliably be diagnosed in the acute phase because of the prolonged period of sero-conversion. Testing may be done for people with known risk factors. However, if HCV is negative and other causes of viral hepatitis have been ruled out, a second sample should be specifically tested for HCV one to three months later. If HBsAg is positive for a period of greater than six months, it is consistent with chronic Hepatitis B infection. Appendix 6Investigation for Evidence of Acute Viral Hepatitis8 ALT Elevated > 5 x ULN Hepatitis A Hepatitis C See footnote (a) Hepatitis B Anti-HAV IgM Anti-HBc IgM HBsAg Negative Positive Positive Negative Positive No evidence of acute Hepatitis A infection Compatible with acute Hepatitis A infection Positive Compatible with acute or chronic hepatitis B infection See footnote (b) Compatible with acute Hepatitis B infection No evidence of acute Hepatitis B infection

44. BPAC, Laboratory Testing in Diabetes, 2006 Sleisenger and Fordtran’s Gastrointestinal and Liver Disease 8th ed, Chapter 83 pages 1807-1852 “Liver Disease Caused by Drugs” Law M, Rudnicka AR. Am J Cardiol. 2006;97:52C-60C Maddrey W. Drug-Induced Liver Disease: 2006 The risk profile of statins. Slide Show Presentation: AASLD 2006 Evaluation and Interpretation of Abnormal Liver Chemistry in Adults, BC Health services 2004 Giannini EG, Testa R, Savarino V. Liver enzyme alteration: a guide for clinicians. CMAJ 2005; 172:367-79. Smellie WS, Forth J, Ryder S. Best practice in primary care pathology: review 5. J Clin Path 2006;59:1229-37. OAML Guidelines for Clinical Laboratory Practice. CLP 012: Guidelines for Testing for Viral Hepatitis. Available from: http://www.oaml.ca/PDF/CLP012.pdf (accessed 21 June 2007) Alcohol Advisory Council of New Zealand, ‘Drink Check’ Is your drinking OK?, Available from: http://www.alac.org.nz/Documents/Campaigns/ALAC_DrinkCheck.pdf (accessed 21 June 2007) References