LFT sjh-1viral hepatitis and liver function tests.pptx

Liver function tests

1. LIVER FUNCTION TESTS AND VIRAL HEPATITIS SEROLOGY

2. Patterns of Liver Damage Hepatocellular damage Damage to hepatocytes themselves Inflammation, infection, ischemia, toxin, etc Cholestatic/Obstructive Blockage of bile ducts or impairment bile formation Determination of Liver Function Indicators of residual hepatocyte function and usually indicative of chronic or fulminant liver damage

3. Background Liver function tests ordered routinely 1-4% of asymptomatic patients have abnormal values Components Transaminases Alkaline phosphatase Bilirubin Others: albumin, protein

4. Investigation of Abnormal LFTs PRINCIPLES 2.5% of population have raised LFTs Normal LFTs do not exclude liver disease Interpret LFTs in clinical context Take a careful history for risk factors, drugs (inc OTCs), alcohol, comorbidity, autoimmunity Physical examination for liver disease 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)

5. Markers of Hepatocellular Injury Hepatocytes are damaged so they leak – so these enzymes are HIGH Aspartate aminotransferase (AST) Alanine aminotransferase (ALT) Lactate dehydrogenase (LDH)

6. Markers of Hepatocellular Injury Test ½ Life Locations found AST 10 hours Liver, Heart, Muscle, Kidney, Brain ALT 48 hours Liver , Kidney, Heart LDH 4 hours Liver, RBC, Heart, Muscle, kidney, tumor

7. Aminotransferase AST and ALT lack specificity to liver damage. Non-hepatic causes of elevation include: Myocardial – AST/ALT were once used as markers of myocardial ischemia Skeletal muscle disorders Normal distribution – particularly in obese patients, Hispanics, and males – longer “tail” region

8. Aminotransferase Typical ALT or AST Distribution Quinn PG, Johnston DE. Detection of chronic liver disease: costs and benefits. Gastroenterologist 1997;5:58-77

9. AST:ALT ratio Alcoholic hepatitis Ratio is >1 90% of the time – often 2:1 Mechanism thought to be related to B6 depletion in alcoholics which leads to disrupted ALT synthesis and therefore decreased levels. This is NOT SPECIFIC!! Viral Hepatitis Ration < 1 70% of the time Mechanism unclear

10. Transaminases Located in hepatocytes Released after hepatocellular injury 2 Forms AST Non-specific to liver: heart, skeletal muscle, blood ALT More specific: elevated in myopathies

11. Transaminases May not be elevated in chronic liver disease HCV- apoptosis Cirrhosis Minimal ALT elevations (<1.5 X normal) Race/Gender Obesity Muscle injury

12. Transaminases Mild elevations – more to come Marked elevations Acute toxic injury- ie tylenol, ischemia Acute viral disease Alcoholic hepatitis

13. Transaminases AST:ALT ratio Elevated in alcoholic disease 2:1 If AST > 500 consider other cause No alcohol use suggests cirrhosis

14. Mild Transaminitis AST/ALT < 5 times upper limit of normal Etiologies Hepatic: ALT-predominant Chronic Hep C ▪ Hemochromatosis Chronic Hep B ▪ Medications/Toxins Acute viral hep ▪ Autoimmune Hep Steatosis ▪ Alpha 1 Antitrypsin Def Wilson’s Disease ▪ Celiac Disease

15. Mild Transaminitis Hepatic: AST predominant Alcohol Steatosis Cirrhosis Non-hepatic Hemolysis Myopathy Thyroid disease Strenuous exercise

16. Elevated AST & ALT, <5X normal Hx & physical; stop hepatotoxic meds LFTs, PT, albumin, CBC, Hep A/B/C, Fe, TIBC, Ferritin Positive serolog y Negative serolog y Negative serology, asymptomati c Serologies : HAV IgM HBsAg HBcIgM HCV Ab or RNA

17. Causes of Hepatocellular Damage A Autoimmune hepatitis – ANA, Anti-smooth muscle ab (ASMA), Anti-Liver and Kidney Mitochondrial Ab. HEP A B Hepatitis B C Hepatitis C D Drugs or toxins E Ethanol / Hep E (Pregnancy) F Fatty liver G Growths (i.e., tumors) H Hemodynamic disorder (congestive heart failure or “shock liver”) I Inborn errors - iron (hemochromatosis), copper (Wilson's disease) or alpha1-antitrypsin deficiency

18. Level of Elevation Giannini, E. G. et al. CMAJ 2005;172:367-379

19. Key points AST and ALT elevations infer HEPATOCELLULAR DAMAGE NON-SPECIFIC TEST with other causes that can lead to elevation Levels in the 100’s ETOH, 1000’s viral, and 10,000’s toxin related. Ratio can SUGGEST but not diagnose alcoholic hepatitis

20. Markers of Cholestasis /Obstruction Cholestasis (lack of bile flow) results from the blockage of bile ducts or from a disease that impairs bile formation in the liver itself. Back leads to GRADUAL increase in enzymes over the course of days. Alkaline phosphatase (AP) Gamma-glutamyltransferase (GGT) Bilirubin

21. ALP Originates primarily in Bone and Liver Other sources include intestine, kidney, placenta . Isoenzymes can determine Bone vs Liver May lag behind symptoms in rising.

22. GGT Not found in bone. Used in conjunction with ALP to indicate hepatic source of elevation. May have mild rise (1.5-2.5x) with anti-epileptic medicines (particularly barbiturates and phenytoin) Also mild rise with chronic ETOH consumption (>3 drinks/day)

23. Causes of Cholestasis Obstruction Intrahepatic Primary Biliary Cirrhosis – young females. Test: Anti-Mitochondrial Ab (AMA) DRUGS – any number of medications, particularly antibiotics and anti-seizure Any Hepatocellular damage (CONFUSED? The hepatocellular can cause cholestatis, but the necrosis is greater) Critical illness Extraheptic Common duct obstruction (stone/Tumor) Primary Sclerosing Cholangitis – More often males with IBD Pancreatic head obstruction (Stone/Tumor) Differentiate – use U/S to look at common bile duct dilation. If non-diagnostic do ERCP then liver bx.

24. Causes of Biliary Obstruction

25. Jaundice

26. Bilirubin Bilirubin results from the enzymatic breakdown of heme. Unconjugated bilirubin is conjugated with glucuronic acid in hepatocytes to increase its water solubility and is then rapidly transported into bile. Indirect Bilirubin (Unconjugated) Direct Bilirubin (Conjugated)

27. Indirect Bilirubin Result of Heme breakdown Hemolysis from any cause is common source Check CBC, smear, and Retic count Can be mild-moderately elevated in some patients, particularly with stresses such as exercise and illness. Defect in uridine diphosphate-glucuronosyl transferase – the enzyme that conjugates bilirubin GILBERTS SYNDROME NOT renally excreted – so urine bilirubin neg

28. Direct Bilirubin Liver disease mainly impairs the secretion of conjugated bilirubin into bile Serum conjugated bilirubin level does not become elevated from liver disease until the liver has lost at least one half of its excretory capacity. Often implies Severe obstruction IS excreted by the kidneys – so Pos Urine bilirubin.

29. Hyperbilirubinemia Hyperbilirubinemia (Jaundice) Prehepatic (Hemolysis) Hepatic Genetic defects, primary liver disease Posthepatic Bile Duct Obstruction Pancreatic Head CA Unconjugated Bilirubin Mixed Conjugated Bilirubin

30. Key Points ALP and GGT combined are markers of cholestasis, but other things can make them rise. 2 types of Bilirubin, only conjugated excreted in urine Cholestasis can be extra or intrahepatic – remember how to differentiate

31. LIVER FUNCTION TESTS Protein production Albumin Clotting Factors Total protein production

32. Albumin 65% of serum protein ½ Life = 3 weeks Low levels can correlate with chronic liver dysfunction. Other reasons to be low? Decrease production Malnutrition Chronic Inflammation Increased Loss Kidney – Nephrotic Syndrome GI tract – Protein-losing enteropathy Skin – Severe burn

33. Clotting Factors Most clotting factors are synthesized in the liver ½ shorter than Albumin Prothrombin Time (PT) is a good functional test – but usually use INR to correct for lab variability PT/INR PROLONGED in liver disease

34. Clotting Factor Chronic cholestatic disease often have increased INR– Why? Vit K def Vit K Fat soluable Cholestatic/obustructive so not enough bile secretion so not enough Vit K absorption How to differentiate Vit K def from Decreased synthesis? Give Vit K (take 24-48 hours to correct) Factor V NOT Vit K dependent so can check directly

35. Key Points The only liver FUNCTION test are test of PROTEIN PRODUCTION Low albumin due to liver dysfunction implies CHRONIC (>3 week) liver damage Always differentiate Vit K Def from Decreased liver synthesis in pt with cholestatic disease

36. Further Testing Ultrasound Good to visualize large bile ducts and large masses. Cheap. Non-invasive Use: Obstruction ERCP Visualize smaller bile ducts, ampulla of Vater, and head of pancreas. Provides tissue. Expensive. Highly invasive Use: Obstruction Liver Biopsy See hepatic pathology, particularly of the hepatocytes. Gold Standart. Expensive. Invasive Use: Hepatocelluar

37. Hepatotoxic Medications Analgesics- acetaminophen, NSAIDS Antimicrobials Amox-clav, nitrofurantoin, sulfonamides INH Azoles Protease Inhibitors Anticonvulsants- carbamazepine, valproic acid, phenyton

38. Hepatotoxic Medications Cardiovascular - alpha-methyldopa, amiodarone, labetalol Hyperglycemics - glyburide, troglidazone Psychiatric - trazadone, disulfiram Heparin Propylthiouracil Statins Zafirlukast

39. Hepatotoxic Herbals Chaparral leaf Ephedra Gentian Germander Jin Bu Huan Senna, Kavakava Scutellaria (skullcap) Shark cartilage Vitamin A ☺

40. Stop EtOH & meds; wt loss; glucose control Repeat LFTs Observation Ultrasound, ANA, smooth muscle Ab, ceruloplasmin, antitrypsin, gliadin & endomysial Ab Negative Serology- Asymptomatic Liver biopsy Abnormal Normal 6 months ☺

41. Consider ultrasound, ANA, smooth muscle Ab, ceruloplasmin, antitrypsin Liver biopsy Negative Serology- Clinical Signs/Symptoms of Liver Disease Abnormal ☺

42. + Hep C/B infection Observation Positive Serologies  Hep A IgM Follow clinically, serial LFTs Observation Persistent elevated LFTs > 6 mo’s Clinical improvement, LFTs normalize in <6 mo’s Liver biopsy

43. Serologic Tests for Viral Hepatitis HAV Hep A IgM- ↑ in acute infxn Hep A IgG- ↑ in previous infxn or vaccination HCV HCV Ab- ↑ during or after infection HCV-RNA- ↑ during infection Detectable prior to HCV Ab turning positive

44. Serologic Tests for Viral Hepatitis HBV Hep B Surface Ag- ↑ in active infxn Hep B Surface Ab- ↑ in prior infxn or vaccinated Hep B Core Ab IgM- ↑ in active infxn Hep B Core Ab IgG- ↑ in current or prior infxn HBV-DNA- ↑ in active infxn Hep B e Ag & Ab- markers of viral presence and potential infectivity

45. Symptoms HBeAg anti-HBe Total anti-HBc IgM anti-HBc anti-HBs HBsAg 4 8 12 16 20 24 28 32 36 52 100 Acute Hepatitis B Virus Infection with Recovery Typical Serologic Course Weeks after Exposure Titre

46. Alkaline Phosphatase Produced by biliary epithelial cells Non-specific to liver: bone, intestine, placenta Elevations Biliary duct obstruction Primary biliary cirrhosis Primary sclerosing cholangitis Infiltrative liver disease- ie sarcoid, lymphoma Hepatitis/cirrhosis Medications

47. Medications Hormones - anabolic steroids, estrogen, methyltestosterone Antimicrobials - augmentin, erythromycin, flucloxacillin, TMP-SMX, HIV meds Cardiovascular - captopril, diltiazem, quinidine Hyperglycemics - chlorpropamide, tolbutamide Psychiatric - fluphenazine, imipramine, iprindole Others - allopurinol, carbamazepine

48. RUQ us, med review, AMA Abnormal LFTs Normal LFTs, bili RUQ u/s for ductal dilatation GGT or 5’-NNT  ALT eval, liver bx, ERCP or MRCP Other source Observation Liver bx No dilatation - + ERCP AMA No Yes Neg  AP > 6 mo Elevated Alk Phos

49. 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

50. Conjugated bili; Abnormal alk phos, ALT, AST Unconjugated bili; Normal alk phos, ALT, AST RUQ u/s to assess ductal dilatation Hemolysis studies, review meds  ALT eval, review meds, AMA, ERCP or MRCP, liver bx ERCP or MRCP Elevated Bilirubin + -

51. Other Liver Labs Albumin Poor marker of liver function- decreased by trauma, inflammatory conditions, malnutrition Prothrombin time (PT) Insensitive: no change until liver loses 80% capacity Ammonia No correlation between brain & serum values Only one contributor to encephalopathy

52. 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

53. Liver biopsy Findings in Abnormal LFTs Skelly et al. J Hepatol 2001 6% Normal 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

54. 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%

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

56. 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%, metobolic 2.1%, biliary 1.8% Ryder et al BASL 2003

57. 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

58. Ultrasound in Liver Disease Detects Fatty Liver Increased echogenicity may not be specific for fat 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) 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

59. Non-Alcoholic Fatty Liver Disease

60. 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

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