Liver Ann Parasram 8 th February 2010

1. Liver Ann Parasram 8th February 2010

2. Liver Physiology • What are LFT’s • Role of LFT’s in investigation of Liver Disease • Investigation of abnormal LFT • Case studies

3. Major functions of liver Carbohydrate Metabolism Fat Metabolism Protein Metabolism Hormone Metabolism Removal of endogenous and exogenous waste products Storage Metabolism and excretion of bilirubin

4. Liver Physiology 6 segments, each with own branch of hepatic artery, portal vein and bile duct Metabolic activity occurs within parenchymal cells.80% of organ mass Remarkable reserve and Ig functional reserve

5. Bilirubin Metabolism

6. What are LFT’s? No standard LFT profile Basildon use – -Total protein - Albumin - Total Bilirubin - Alkaline phosphatase (ALP) - Alanineaminotransferase (ALT) Do standard ‘LFT’ assess liver capacity to perform normal function

7. What are LFT’s? • Other biochemical LFT options • Total protein • Conjugated bilirubin • Gamma glutamyl transferase (GGT) • Aspartate aminotransferase (AST)

8. Normal Ranges • Total Protein 60 – 80g/l • Total Bilirubin <20µmol/l • ALT 5 – 40IU/l • ALP 30 – 130IU/l • Albumin 35 – 50g/l

9. Laboratory Investigations Diagnosis Prognosis Monitoring Screening No single lab test currently exists which: • Provides answers to the above • Provides a quantitative assessment of functioning liver capacity Use of combination of standard LFT’s and serial monitoring enhances clinical utility

10. Aminotransferase • ALT and AST • Intracellular enzymes • ↑ plasma enzymes activity due to leakage from damaged or necrotic hepatocytes • Not liver specific – wide tissue distribution, heart, muscle • Plasma activities of AST and ALT are sensitive indicators of hepatocyte damage due to toxins and viruses but are not specific for liver pathology

11. AST - 2 genetically distinct isoenzymes exist; mitochondrial AST (80%) and cystolic AST (20%) - Mild tissue injury results in predominately cystolic release • ALT - cystolic enzymes - shows greater liver specificity than AST - Majority of liver disease ALT elevated to a greater degree

12. Abnormal ALT in asymptomatic patients • Is it abnormal? • Alcohol abuse (GT useful) • Drugs • Antibiotics - penicillins, ciprofloxacin etc. • AED’s - phenytoin, carbamazepine • Statins • NSAID’s • Sulphonylureas - glipizide • Herbs, homeopathic Rx - ephedra, senna • Drugs of abuse - steroids, cocaine, MDMA, glues

13. Abnormal ALT in asymptomatic patients • Chronic hepatitis • hepatitis C, B • Autoimmune hepatitis • raised globulin (80%) on electrophoresis • auto-antibody tests (ANA) • Haemochromatosis • transferrin saturation (>45%) • Coeliac disease • Wilson’s disease (<40 yrs) • caeruloplasmin (85%), Kaiser-Fleischer rings • Alpha1-antitrypsin deficiency

14. Alkaline Phosphatase • Membrane bound enzyme • Family of isoenzymes and isoforms • Present in many tissues

15. Alkaline Phosphatase • Plasma ALP levels are increased further by the solubilisation of membrane bound enzyme due to the detergent action of bile acids • Plasma ALP is a sensitive indicator of Choleostasis but is non-specific for liver pathology

16. Alkaline Phosphatase • Produced by the biliary tract at all levels from the canalculi to the mucosa of the gall bladder • Involved in metabolic transport across cell membrane • Obstruction to bile flow or secretion results in enzyme induction with increased mucosal synthesis of ALP

17. Alkaline Phosphatase • Liver or bone? (pregnancy, adolescence) • GT useful to exclude liver • Age related changes • increase (particularly women) between 40 and 65 yrs • If persistent raised ALP of liver origin • Primary biliary cirrhosis • anti-mitochrondrial antibodies • Ultrasonography

18. GT – Gamma Glutamyl Transferase • Membrane bound, wide tissue distribution; liver, kidney and pancreas • Elevated plasma activity results from solubilisation of bound enzyme by bile salts, cell necrosis and altered membrane permeability • Slightly more sensitive than ALP in Obstructive Liver Disease

19. GT • Synthesis induced by drugs such as DPH, BARBS, Tricyclics and ETOH in absence of liver pathology • Sensitive indicator of liver disease but will differ hepatocellular from choleostatic disease • An increase GT activity can confirm an increase ALP activity as being liver in origin

20. GT • Very sensitive for hepatobiliary disease • Poor specificity • pancreatic disease, AMI, renal failure, diabetes, COPD, alcoholism • Alcohol abuse – poor marker • Reported sensitivity 52 - 94% • Best used to evaluate rises in other LFT’s

21. Albumin • Index of hepatic synthetic function • Low ALB often accompanies chronic liver disease • May not indicate reduced synthesis

22. Albumin • Plasma ALB also affected by nutritional stasis, leakage into ascites, renal losses and dilation due to fluid retention • Prothrombin better indicator as shorter ½ life • Normal ALB is good indicator of adequate synthetic function in chronic liver disease

23. Bilirubin • Specific for liver dysfunction • Assessment of hepatic anion transport • Insensitive due to large hepatic functional reserve • Normally 92% of bili unconjugated • Raised bili due to increased production, impaired metabolism or reduced excretion

24. Bilirubin • Plasma bilirubin levels >50µmol/l detected clinically as jaundiced • Bilirubinuria is always conjugated and is always pathological

25. Typical patterns of abnormalities of simple LFT in various liver diseases.

26. Miscellaneous tests of Liver Disease • Plasma Bile Acids – highly specific indicator of hepatic anion transport, technically demanding • Immunoglobulins – Generally increased in chronic disease. IgM greatly increased in Primary biliary cirrhosis. IgG in autoimmune chronic active hepatitis • α-fetoprotein – Increased in 70% of primary hepatocellular carcinomas

27. Role of LFT’s in the Investigation of Liver Disease A )Diagnosis • Poor diagnostic tool • Non-specific, cannot quantitate extent of liver damage • Imaging, Clinical history and histology better • Cheap, non-invasive, automated, can direct further investigation

28. Role of LFT’s in the Investigation of Liver Disease Surgical v’s non-surgical jaundice • Raised Bilirubin in range 20 – 100µmol/l with other LFT’s normal • Haemolytic jaundice or Gilberts rather than extrahepatic biliary dysfunction

29. Role of LFT’s in the Investigation of Liver Disease Hepatocellular v’s Choleostasis • Raised Bili, ALP and GT with normal or slightly raised ALT • Indicates Choleostasis (but cannot distinguish intra from extrahepatic)

30. Role of LFT’s in the Investigation of Liver DiseaseB) Monitoring – Main role of LFT Typical biochemical changes during acute hepatitis

31. Role of LFT’s in the Investigation of Liver Disease Causes of Acute Viral hepatitis • Pre icteric – ALT/AST raised; other LFT normal • Icteric – AST/ALT peak; 6 – 100 ULN • Normally ALT>AST • AST>ALT poor prognosis • ALP normal/slightly raised (unless choleostatic element).

32. Role of LFT’s in the Investigation of Liver Disease • Enzyme levels can be expected to return to normal in about 5 weeks • Persistently raised levels (3 x ULN) could indicate chronic persistent hepatitis • Sudden reduction in aminotransferase activity bad sign indicating fulminant liver function

33. Role of LFT’s in the Investigation of Liver Disease Neonatal raised Bilirubin • Need accurate measure of Bilirubin at critical levels (age, weight and ALB dependant) • Phototherapy > 200µmol/l • Exchange transfusion >3

34. Role of LFT’s in the Investigation of Liver Disease Autoimmune Chronic Hepatitis Therapy - Successful immunosuppressant indicated by reduced AST activity. Relapse indicated by raised ALP activity Post-op Obstructive Jaundice - Clearance of obstructive jaundiced followed by serial bilirubin measurement

35. Role of LFT’s in the Investigation of Liver Disease Cirrhosis - No reliable test for compensated cirrhosis - Procollagen Type III peptide. Non-invasive marker for fibrosis but it is non-specific

36. Role of LFT’s in the Investigation of Liver Disease Alcoholic Liver Disease • GT induced by ETOH • If raised as a result ETOH intake may never return to normal Liver Transplant • Std LFT used to monitor rejection • Raised Bilbirubin increased when rejection occurs

37. Role of LFT’s in the Investigation of Liver Disease C) Prognosis • Limited role • Pre-transplant assessment of end stage liver disease • Primary Biliary Cirrhosis - raised bili .....poor sign......<2yr survival bili >120µmol/l • Fulminant hepatic failure - bili >300µmol/l, poor prognostic sign

38. New Generation LFT • Need cheap, reliable, convenient test: • ‘accurately diagnose liver pathology’ • ‘provide a quantitative assessment of functional hepatic mass’

39. New Generation LFT • Quantitative LFT but are complex and limited to specific centres • Aminopyrine Breath Test, measures Cyto P450 (dependent demethylation of Carbon 14 labelled aminopyrine to Carbon Dioxide) • Indocyanine green clearance – asses hepatic blood flow and hepatocellular activity.

40. New Generation LFT • Hepatocellular damage – glutathione-5-transferase, molecule sensitive to AST/ALT. Evenly distributed throughout liver, half-life 90 minutes, early marker of liver injury • Choleostasis – CA19-9, Increased serum level due to biliary clearance

41. Investigation of abnormal LFTs • Causes of liver disease

42. Liver Pathology • Hepatitis – Inflammation and cell damage • Toxins, metabolites, infections, autoantibodies • Cirrhosis – fibrosis infiltration, shrinkage • Tumours (Carcinoma) • Primary or Secondary metastases • Obstruction (Choleostasis) - failure of secretion of bile e.g. Chronic hepatitis cirrhosis 30 years • Gold Std – Imaging and endoscopy

43. Hepatitis • Viral or toxic • Acute or chronic Viral Agents: Hep A B C (D + E) CMV, EBV Toxic Agents: Paracetamol, Alcohol Acute Disease: < 6 months duration Chronic Disease: > 6 months with non resolution of acute

44. Outcome of Hepatitis Majority of hepatitis cases result in complete resolution Minority will develop fulmanant hepatic failure All forms of acute hepatitis may develop into chronic disease except Hep A Chronic hepatitis may be classified by histology - Chronic persistent hepatitis (benign) Chronic acute hepatitis (histological distinct) Chronic disease can progress to Cirrhosis, can progress to Carcinoma

45. Case History 1 • A 20 year old student developed a flu-like illness with a loss of appetite, nausea and pain in the right hypochondrium. On examination, the liver was just palpable and was tender. Two weeks later he developed jaundice, his urine became darker in colour and his stool became pale.

46. Case History -1 Investigations on presentation one week later Serum: bilirubin 38µmol/l 230µmol/l albumin 40g/l 38g/l AST 450U/l 365U/l ALP 70IU/l 150IU/l GGT 60U/l 135U/l Urine: bilirubin positive positive urobilinogen positive negative

47. Cirrhosis • Aetiology – autoimmune, chronic viral, alcohol Inherited, metabolic disease or Primary cirrhosis • Diagnosed by demonstration of fibrous and architectural disruption in biopsy specimen • Irreversible • No symptoms whilst compensated due to functional reserve • Symptoms manifest after decompensation – haematemesis, ascites, portal hypertension, encephalopathy, coma

48. Case History 2 A middle aged female was admitted to hospital following a haematemesis. Endscopy revealed the presence of oesophageal varices. The only biochemical abnormality was an elevated GGT (245IU/L). The patient was told to abstain from alcohol. She was admitted one year later, jaundiced, drowsy and with clinical signs of liver disease.

49. Case History - 2 Investigations Serum: Albumin 25g/l Bilirubin 260µmol/l ALP 315U/l AST 134U/l GGT 360U/l

50. Hepatocellular Carcinoma (HCC) Only 2% of all Cancers in the UK Significant problem worldwide (Hep B, C; Haemachromatosis) 80% due to Cirrhosis 5yr Survival rate – 15% Imaging used to identify tumour, biopsy Inappropriate and surgical resection is only treatment