Interpretation of Liver function test

Basic overview with case based scenario to interpret liver function test in children

1. Interpretation of liver function test - Dr. Kinisha Patel (M.D pediatrics , FISPGHAN)

2. Background Liver - to perform various kinds of biochemical synthetic, excretory functions No single test can detect globel liver function ‘Liver injury test’ – more appropriate terminology Clinical history, physical examination most important in interpretation of LFT

3. Use Screening Pattern of disease: differentiate acute viral hepatitis, various cholestatic & CLD Assess severity & to predict outcome Follow up - to evaluate response to therapy ( Eg . Autoimmune hepatitis)

4. Limitations Lack sensitivity : Normal in certain liver disease like congenital hepatic fibrosis, non cirrhotic portal fibrosis Lack specificity : Sr. albumin – decreased in chronic disease, malabsorption,nephrotic synd. Etc. Aminotransferase – may be raised in cardiac or muscular disease Except bile acid – other LFT changes for pathological process outside liver So important to keep clinical profile in mind

5. Classification of liver function test Test for transport & drug metabolism Test of biochemical activity - Test of liver cell injury - Test of cholestasis Test of liver synthetic capacity Test to detect substances cleared from plasma by liver Specific investigation of liver disease Other test – imaging studies , histologic studies

6. Test for transport & drug metabolism Serum bilirubin Urine bilirubin Urobilinogen

7. Serum bilirubin Endogenous anion derived from hemoglobin degradation from RBC. Confirms jaundice, indicates its depth , used to assess the progress

8. Types Total , direct (conjugated & delta), indirect (unconjugated) Conjugated hyperbilirubinemia is defined as a serum direct/conjugated bilirubin concentration greater than 1.0 mg/ dL if the total serum bilirubin (TSB) is <5.0 mg/ dL or > 20% of TSB if the TSB is >5.0 mg/ dL Unconjugated hyperbilirubinemia : over production or impaired uptake or conjugation of bilirubin Conjugated hyperbilirubinemia : decreased excretion or backward leakage of pigment

9. Total bilirubin : - not sensitive indicator for hepatic dysfunction - may not accurately reflect degree of liver damage Unconjugated hyperbilirubinemia Hemolytic Rhesus or ABO incompatibility Red cell membrane defect G6PD deficiency Internal hemorrhage Sepsis Polycythemia Cong. Hypothyroidism Criggler najjar syndrome Gilbert syndrome Galactosemia ( initially f/b conjugated)

10. Conjugated hyperbilirubinemia (hepatocellular, hepatobiliary ) Neonatal cholestasis Metabolic liver disease Inborn error of metabolism Infections (viral hepatitis – hepatotropic , non hepatotropic , bacterial, parasitic, fungal) Drug induced liver injury Ischemic causes Autoimmune liver disease

11. Urine bilirubin Conjugated bilirubin – water soluble – may be found in urine Early hepatobiliary disease like in acute viral hepatitis – positive, while patient may or may not be icteric

12. Urobilinogen Formed in terminal ileum & colon from conjugated bilirubin by anaerobic microbial flora 20% daily undergo enterohepatic circulation – small fraction excreted in urine In hepatocellular dysfunction – UBG escapes hepatic uptake thus appear in urine

13. Transaminase -Test of liver cell injury ALT/SGPT (Alanine aminotransferase) More sensitive & specific for liver disease Shorter half life so for acute liver disease Normal range: 10 -50 U/L AST/SGOT ( Aspartate aminotransferase) Rise – early indication for rejection post transplant Isolated rise – hemolysis, rhabdomyolysis , myopathy, cardiomyopathy Normal range : 10 – 40 U/L

14. Causes of deranged aminotransferase Mild elevation (1-3 times) Moderate elevation (3- 10 times) Marked elevation (>10 times) Neonatal hepatitis Wilson disease (CLD) Acute viral hepatitis Extra hepatic biliary atresia Autoimmune hepatitis (CLD) Ischemic hepatitis NASH Viral / parasitic hepatitis Drugs Drug toxicity Chronic hepatitis B & C Acute budd chiari syndrome Drugs Cholestatic liver disease

15. Points to remember Sudden decline in levels is a bad sign – indicates fulminant hepatitis Sr. bilirubin level gradual rise than aminotransferase in acute viral hepatitis. May be declining (steady fall) before sr. bilirubin in uncomplicated viral hepatitis Secondary elevation s/o chronic hepatitis AST:ALT >2 Wilson’s disease (few studies)

16. Test of cholestasis Alkaline phoshphatase Gamma glutamyl transferase (GGT)

17. Alkaline phosphatse Synthesized by canalicular membrane of hepatocyte – excreted in bile into intestine Found in liver, bone, intestine, kidney , placenta Sensitive but not specific for cholestasis Raised along with GGT – biliary damage Raised : biliary epithelial damage malignant infiltration cirrhosis osteopenia due to vit D deficiency graft rejection

18. Normal range : 45 -115 U/L High ALP Cholestatic disorder Acute viral hepatitis (normal or mod. increased) Infiltrative liver disease Abscess Drugs : antibiotics, tricyclic antidepressant, ACE inhibitor Bone metastasis Low ALP Wilson’s disease (ALP: Bili <4) Cong. hypophosphatemia Hypothyroidism Pernicious anemia

19. GGT Synthesized by epithelium of small bile ductule & hepatocytes Sensitive but not specific Present in biliary epithelium , kidney, pancreas, brain, spleen, small intestine In neonates higher value Normal value : 0 – 30 U/L

20. High GGT Biliary atresia Bile ducts paucity PFIC 3 Sclerosing cholangitis Acute viral hepatitis Acute pancreatitis Drugs : phenobarb ., phenytoin, paracetamol , TCA GBS Obesity Low GGT PFIC 1,2,4 Bile acid synthetic defect ARC syndrome ( arthrogyposis , renal abnormality, cholestasis syndrome) BRIC

21. Test of synthetic function Serum albumin Prothrombin time Lipid profile

22. Serum Albumin Principal form of protein – only synthesized in liver Half life 20 days In absence of other causes – low albumin s/o chronic liver disease In decompensated liver disease, an abrupt decrease in levels following acute illness ( viral infection) Normal range : 3.5 – 5.5 g/dl

23. Prothrombin time Time to convert prothrombin to thrombin Not specific for liver disease but high prognostic value Abnormal coagulation , (deranged after vit k deficiency is excluded) indicates significant hepatic dysfunction ( CLD, ALF, ACLF) Normal value : PT :10 -14 sec INR: > 3 sec ALF: Uncorrectable (6-8 hours after administration of one dose of parenteral vitamin K) coagulopathy with INR >1.5 in patients with hepatic encephalopathy, or INR > 2.0 in patients without encephalopathy

24. Lipids & lipoproteins Synthesized in liver except chylomicrones Marked increased in chronic cholestasis ( like in PFIC) – xanthoma >5times level GSD ( mainly type 1)

25. Test to detect substances cleared from plasma by liver Plasma ammonia Amino acids ( specifically tyrosin , phenylalanine, methionine) Raised in acute or chronic liver failure Non specific indication of liver dysfunction

26. Globulins Immunoglobulines : In autoimmune hepatitis/ chronic active hepatitis - raised IgG Primary biliary cirrhosis – raised IgM

27. Bile acids/ bile salts Primary bile acids – cholic acid chenodeoxycholic acid S econdary – deoxycholic acid T ertiary bile acids – Ursodeoxycholic acid In cholestasis – increased urine excretion Low levels – bile acid synthetic defect ( to differentiate PFIC from BASD)

28. Liver specific other Investigations (2 nd line) Septic screen Viral markers for hepatitis Metabolic screen – TMS, GCMS Alfa feto protein Sr. ceruloplasmin , urine copper Non organ specific antibody – ANA/SMA/LKM Thyroid function test Urine non glucose reducing substance, GALT Urine succinyl acetone Sweat chloride test

29. Radio imaging Bone marrow aspiration Liver biopsy Endoscopy Cholangiography

30. Case 1 2 month 12 days old FCH H/O Yellowish discoloration of skin & sclera from 5 th DOL Passing pale stool & high color urine O/E: icterus + S/E: hepatomegaly 3 cm below scm CBC –WNL Sr. bilirubin: 9.4 (T), 6.8(D) SGPT – 256 SGOT – 324 GGT – 340 ALP – 620 PT– 11.6/11.03 INR – 1.06 (After 1 dose vit K) Sr. protein -5.0 albumin – 3.6

31. Case 2 5 year old mch H/O fever, vomiting, decreased oral intake, yellowish discoloration of sclera, passing high color urine – 5 days h/o travel to village + No h/o loose stool, abdominal distension O/E : icterus + S/E: mild tenderness in right hypochodrium . L2 below scm Hb – 9.6, TLC – 11200, Platelet – 2 lac Sr . bilirubin: 4 .4 (T), 2 .5(D ) SGPT – 756 SGOT – 836 GGT – 56 ALP – 124 PT– 11.03/11.03 INR – 1.0 Sr. protein -6.8 albumin – 3.9

32. DAY 1 DAY 3 DAY 5 Sr. bilirubin (T/D) 4.4/2.5 12.5/9.6 18.2/16.5 SGPT 756 423 112 SGOT 836 376 104 GGT 56 34 36 Sr. protein / albumin 6.8/3.9 4.9/3.0 4.9/2.8 INR 1.0 1.40 1.74

33. CASE 3 8 Year old FCH h/o jaundice from 1.5 months, abdominal distension from 15 days, decreased oral intake + Outside admitted , ascitic tapping done. O/E : deep icterus + S/E : Hepatosplenomegaly + (L3,S3 below scm ) Hb –8.2, TLC–7800, platelet– 2.3 lac Outside viral markers – negative Sr. bilirubin : 18.8 (T), 14.6(D ) SGPT – 234 SGOT – 562 GGT – 46 ALP – 76 PT– 16.4/11.03 INR – 1.48 Sr. protein -5.0 albumin – 2.6

34. Case 4 3.5 year old MCH In PICU H/o fever, respiratory distress – 3 days. Increased irritability from 1 day Outside treated with antipyretic, antibiotics from 2 days. i /v/o deranged LFT shifted to KEM hospital O/E: HR – 128/min, RR -40/min S/E: P/A: mild hepatomegaly. L2 below SCM CNS :irritable CBC –WNL Sr. bilirubin: 8.6 (T), 6.4(D ) SGPT – 846 SGOT – 654 GGT – 84 ALP – 245 PT– 16/11.03 INR – 1.45 (After 1 dose vit K) Sr. protein -6.2 albumin – 3.5

35. Case 5 In PICU On mechanical ventilator H/o Fever, respiratory distress, 1 episode of convulsion CBC – 11.0, TLC – 23000, platelet – 4.5 lac Sr. bilirubin: 8.6 (T), 6.4(D) SGPT – 846 SGOT – 654 GGT – 64 ALP – 200 PT– 13/11.03 INR – 1.17 (After 1 dose vit K) Sr. protein -6.2 albumin – 3.5

36. Case 6 9 month old FCH H/o mild yellowish discoloration of sclera from 3months of life & itching over whole body from 4 months of life Outside taken treatment but symptoms persist so referred O/E – icterus present Scratch marks over whole body + S/E – mild hepatomegaly CBC –WNL Sr. bilirubin: 6.5(T ), 3.8(D ) SGPT – 220 SGOT – 236 GGT – 23 ALP – 100 PT– 11.6/11.03 INR – 1.06 (After 1 dose vit K) Sr. protein -5.0 albumin – 3.6

37. Thank you