liver function test

1. Evaluation of Liver Injury
Mark J. Czaja
Liver Research Center
Albert Einstein College of Medicine
Bronx, N.Y.

2. Liver Function Tests
• Alanine aminotransferase (ALT)
• Aspartate aminotransferase (AST)
• Lactate dehydrogenase (LDH)
• Alkaline phosphatase
• Bilirubin
• Albumin

3. Mechanisms of Liver Dysfunction
• Direct cellular injury
• Blockage in bile flow
• Impaired blood flow

4. Direct Cellular Injury - HCV Infection

5. Blockage in Bile Flow - Biliary
Atresia

6. Impaired Blood Flow - CHF

7. Consequences of Liver Injury
liver cell injury
liver cell death
proliferation matrix deposition
sufficient inadequate altered architecture
recovery liver failure cirrhosis

8. Types of Liver Tests
• True tests of liver function
• Biochemical markers of liver injury
• Biochemical markers of specific
liver diseases

9. Testable Biochemical Liver
Function
• Ability to transport organic anions
• Capacity to metabolize certain
substances
• Capability to synthesize various
proteins

10. Steps in Organic Anion Transport
• Delivery and uptake
• Metabolic alteration
• Secretion and excretion

11. Bilirubin
• Tetrapyrole
• Toxic in neonates - kernicterus
• Derived from:
 Senescent RBC (70-80%)
 Hemoproteins (20-30%)
 Ineffective erythropoiesis

12. Bilirubin Formation
heme biliverdin bilirubin
heme
oxygenase
biliverdin
reductase
Transport: hydrophobic due to internal H-bonding
circulates bound to albumin

13. Bilirubin Metabolism
UCB
ligandin
glucuronyl
transferase
BMG
BDG
Alb
UCB
BMG
BDG
Plasma Hepatocyte Bile
BMG
BDG

14. Bilirubin Elimination
Intestine
• BMG (20%) +
BDG (80%)
+UCB (trace)
• Deconjugated to
urobilinogen
• Excreted or reab-
sorbed (20%)
Urine
• BMG and BDG
• No UCB

15. Measurement of Serum
Bilirubin
• Normal concentration < 1 mg/dl
• Conjugated < 5%
• Jaundice if > 3 mg/dl
• Detected by diazo reaction - cleaved
to colored azo-dipyrole
 Conjugated reacts rapidly (direct)
 Unconjugated reacts slowly (indirect)

16. Differential Diagnosis I
• Prehepatic
• Intrahepatic
 Congenital
 Acquired
• Posthepatic

17. Differential Diagnosis II
• Unconjugated hyperbilirubinemia
 Increased bilirubin production
(hematological)
 Decreased uptake (drug)
 Decreased conjugation (congenital)
• Conjugated hyperbilirubinemia
 Congenital
 Drug
 Liver disease
 Biliary obstruction

18. Inherited Disorders Causing
Unconjugated Hyperbilirubinemia
• Crigler-Najjar syndrome
 Type 1 – absent GT
 Type 2 – reduced GT activity
• Gilbert’s syndrome – reduced GT
activity due to genetic defect in
TATAA element of GT promoter

19. Inherited Disorders Causing
Conjugated Hyperbilirubinemia
• Dubin-Johnson syndrome –
mutations in multidrug resistance
associated protein 2 (MRP2)
• Rotor’s syndrome – genetic
defect

20. Hepatic Metabolic Capacity
• Clearance must depend on total
functional mass or metabolic activity
• Hepatic drug metabolism -
[14C]amino-pyrine breath test
• Galactose elimination
• Not used clinically

21. Hepatic Synthetic Capacity
• Most major plasma proteins are made
in the liver
• Decreased hepatocytes = decreased
protein synthesis and release
• Albumin and coagulation factors are
clinically important

22. Albumin
• 50% of all synthesized hepatic
protein
• Determinant of plasma oncotic
pressure
• Important transport protein

23. Serum Albumin Levels
• Long half-life of 20 days
• Large hepatic synthetic reserve
• Decreased with persistent, large injury
• Decreased in chronic liver disease
• Poor prognostic sign

24. Non-hepatic Causes of
Hypoalbuminemia
• Severe malnutrition
• Renal or GI loss
 Glomerulopathy, HIV enteropathy
• High catabolism
 Infections, burns

25. Coagulation Factors
• Half-lives of hours to days
• Liver synthesizes I, II, V, VII,
IX, and X
• Large synthetic reserve

26. Prothrombin Time (PT)
• PT detects abnormalities in I, II,
V, VII and X (extrinsic pathway)
• PT is increased in liver disease
• Best prognostic indicator
 Acute liver disease
 Chronic liver disease

27. Non-hepatic Causes of
Elevated PT
• Congenital coagulation factor
deficiencies
• Consumptive coagulopathies
• Vitamin K deficiency (II, VII, IX, X)

28. To Rule Out Vitamin K Deficiency
• Any patient with an elevated PT
• Parental vitamin K for 3 days
• Normalization of PT - vitamin K
deficiency
• Failure to normalize - hepatocellular
disease

29. Serum Immunoglobulins
• Not produced by hepatocytes
• Frequently elevated in liver disease
• Secondary to inflammatory process
• ? produced by antigen shunting

30. Biochemical
Markers of Liver
Injury

31. Liver Enzymes
• Low levels always present in serum
• Leak out from cell after injury
• Very sensitive
• Magnitude of abnormality does not
correlate well with degree of injury

32. Aspartate Aminotransferase
(AST)
• Serum glutamic-oxaloacetic
transaminase (SGOT)
• Transfers an a-amino group of aspartate
to a-keto group of ketoglutaric acid
• Present in skeletal muscle, kidney, brain

33. Alanine Aminotransferase
(ALT)
• Serum glutamic-pyruvic transaminase
(SGPT)
• Transfers an a-amino group of alanine
to a-keto group of ketoglutaric acid
• Present principally in liver

34. AST and ALT
• Elevated in most liver diseases
• Highest levels are in acute liver
diseases
• Only slight elevations in chronic
liver diseases
• Usually increase in parallel

35. AST/ALT in Alcoholic
Hepatitis
• Transaminases rarely exceed 300
• AST:ALT >2

36. Factors Affecting AST/ALT
• Depressed by pyridoxine (vit. B6)
deficiency
• Decreased by uremia and renal dialysis

37. AST/ALT Controversies
• Should lower normal limits be
used in females?
 Females < 30 vs. males < 40
• Are the normal limits too high?
 Females < 20 and males < 30

38. Lactate Dehydrogenase
(LDH)
• Component of classic LFT’s
• Highly non-specific

39. Tests of Impaired Hepatic
Excretion
Increased In
• Cholestasis
• Intra-hepatic biliary tract obstruction
• Extra-hepatic biliary obstruction

40. Alkaline Phosphatase
• Hydrolyzes phosphate esters at
alkaline pH
• Also present in bone, kidney, placenta,
intestine
• Mainly liver and bone in adults
• Increased in children from bone growth
• Placental form during pregnancy

41. Elevated Alkaline Phosphatase
• Can occur in any liver disease
• Highest with cholestasis or biliary tract
obstruction
• Elevated in infiltrative diseases
• Due to increase synthesis and secretion

42. Alkaline Phosphatase Isoenzymes
Source
Heat
Inactivation 5' NT GGTP
Liver Moderate + +
Bone Rapid - -
Placenta Slow - -
Intestine Slow - -

43. 5'-Nucleotidase
• Hydrolyzes 5'- adenosine monophosphate
• Mainly present in liver
• Increases along with alkaline phosphatase

44. g-Glutamyl Transpeptidase
(GGTP)
• Transfers g-glutamyl groups
• Widely distributed
• Sensitive correlate to alkaline phosphatase
• Non-specific (alcoholism, MI, DM,
pancreatic disease, renal failure)

45. Biochemical Markers
of Specific Liver
Diseases

46. Etiology-specific Liver Tests
• Viral hepatitis serologies
• Serum ferritin level
• Ceruloplasmin level
• Alpha1-antitrypsin level
• Antimitochondrial antibody titer

47. Viral Hepatitis Serology
• HAV – anti-HAV IgM and IgG
• HBV – HBsAg, anti-HBsAg,
and anti-HBcAg
• HCV – anti-HCV, HCV RNA

48. Serum Ferritin
• Widely distributed storage protein
• Levels reflect body iron stores
• Elevated in primary hemochromatosis
• Elevated in acute inflammation and
cirrhosis

49. Serum Ceruloplasmin
• Copper-binding protein
• Decreased in 95% of patients
with Wilson’s disease
• 20% of heterozygotes have
decreased levels

50. a1-Antitrypsin
• Inhibits serum trypsin
• Major component of a1-globulin
• Deficiency cause of neonatal
hepatitis

51. Antimitochondrial Antibody
(AMA)
• Directed against mitochondrial
enzyme pyruvate
dehydrogenase complex
• Positive in 90% of patients
with primary biliary cirrhosis

52. Interpretation of Abnormal
LFT’s
• Examine multiple tests
• Consider non-hepatic causes
• Determine the most abnormal tests

53. Hepatocellular vs. Cholestatic
Test Hepatocellular Cholestatic
ALT/AST 2-3 NL-1
Alk Phos NL-1 2-3
Bilirubin NL-3 NL-3
Albumin NL-3 NL
PT NL-3 NL

54. Case 1
• ALT 2045 (15-45)
• AST 2300 (15-45)
• Alk Phos 273
(50-150)
• Bili 3.9 (0.1-1.0)
• Alb 4.2 (3.5-5.5)
• PT 11.5 (10-12)
25 yo IVDA c/o 1 week of nausea,
vomiting, and myalgias. Physical
exam revealed jaundice.

55. Hepatocellular W/U
H & P
EtOH, medications, transfusions
Risk for viral
hepatitis
Risk factors
for NASH
Autoimmune
features
Etiology-specific LFT’s
USG and liver biopsy

56. HBV Infection - HBcAg Staining

57. Case 2
• ALT 75 (15-45)
• AST 115 (15-45)
• Alk Phos 650
(50-150)
• Bili 10.2 (0.1-1.0)
• Alb 4.2 (3.5-5.5)
• PT 11.0 (10-12)
67 yo c/o several months of weight loss,
and 1 week of nausea, vomiting, and
myalgias. Physical exam revealed
cachexia and jaundice.

58. Cholestatic W/U
H & P
medications, gallstones, weight loss
AMA
USG
ERCP
liver biopsy
dilated ducts
normal

59. Pancreatic Carcinoma - ERCP