Evaluation of Liver Injury
Mark J. Czaja
Liver Research Center
Albert Einstein College of Medicine
Bronx, N.Y.
Liver Function Tests
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•
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•
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Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Lactate dehydrogenase (LDH)
Alkaline phosphatase
Bilirubin
Albumin
Mechanisms of Liver Dysfunction
• Direct cellular injury
• Blockage in bile flow
• Impaired blood flow
Direct Cellular Injury - HCV Infection
Blockage in Bile Flow - Biliary
Atresia
Impaired Blood Flow - CHF
Consequences of Liver Injury
liver cell injury
liver cell death
proliferation
matrix deposition
sufficient
inadequate
recovery
liver failure
altered architecture
cirrhosis
Types of Liver Tests
• True tests of liver function
• Biochemical markers of liver injury
• Biochemical markers of specific
liver diseases
Testable Biochemical Liver
Function
• Ability to transport organic anions
• Capacity to metabolize certain
substances
• Capability to synthesize various
proteins
Steps in Organic Anion Transport
• Delivery and uptake
• Metabolic alteration
• Secretion and excretion
Bilirubin
• Tetrapyrole
• Toxic in neonates - kernicterus
• Derived from:



Senescent RBC (70-80%)
Hemoproteins (20-30%)
Ineffective erythropoiesis
Bilirubin Formation
heme
heme oxygenasebiliverdin
biliverdin
reductase
bilirubin
Transport: hydrophobic due to internal H-bonding
circulates bound to albumin
Bilirubin Metabolism
Plasma
Bile
Hepatocyte
Alb
UCB
BMG
BDG
UCB
ligandin
glucuronyl
BMG
BMG
transferase
BDG
BDG
Bilirubin Elimination
Intestine
• BMG (20%) +
BDG (80%)
+UCB (trace)
• Deconjugated to
urobilinogen
• Excreted or reabsorbed (20%)
Urine
• BMG and BDG
• No UCB
Measurement of Serum
Bilirubin
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•
•
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Normal concentration < 1 mg/dl
Conjugated < 5%
Jaundice if > 3 mg/dl
Detected by diazo reaction - cleaved
to colored azo-dipyrole
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Conjugated reacts rapidly (direct)
Unconjugated reacts slowly (indirect)
Differential Diagnosis I
• Prehepatic
• Intrahepatic
Congenital
 Acquired

• Posthepatic
Differential Diagnosis II
• Unconjugated hyperbilirubinemia
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Increased bilirubin production
(hematological)
Decreased uptake (drug)
Decreased conjugation (congenital)
• Conjugated hyperbilirubinemia
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
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Congenital
Drug
Liver disease
Biliary obstruction
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
Inherited Disorders Causing
Conjugated Hyperbilirubinemia
• Dubin-Johnson syndrome –
mutations in multidrug resistance
associated protein 2 (MRP2)
• Rotor’s syndrome – genetic
defect
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
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
Albumin
• 50% of all synthesized hepatic
protein
• Determinant of plasma oncotic
pressure
• Important transport protein
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
Non-hepatic Causes of
Hypoalbuminemia
• Severe malnutrition
• Renal or GI loss

Glomerulopathy, HIV enteropathy
• High catabolism
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Infections, burns
Coagulation Factors
• Half-lives of hours to days
• Liver synthesizes I, II, V, VII,
IX, and X
• Large synthetic reserve
Prothrombin Time (PT)
• PT detects abnormalities in I, II,
V, VII and X (extrinsic pathway)
• PT is increased in liver disease
• Best prognostic indicator
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Acute liver disease
Chronic liver disease
Non-hepatic Causes of
Elevated PT
• Congenital coagulation factor
deficiencies
• Consumptive coagulopathies
• Vitamin K deficiency (II, VII, IX, X)
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
Serum Immunoglobulins
• Not produced by hepatocytes
• Frequently elevated in liver disease
• Secondary to inflammatory process
• ? produced by antigen shunting
Biochemical
Markers of Liver
Injury
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
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
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
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
AST/ALT in Alcoholic
Hepatitis
• Transaminases rarely exceed 300
• AST:ALT >2
Factors Affecting AST/ALT
• Depressed by pyridoxine (vit. B6)
deficiency
• Decreased by uremia and renal dialysis
AST/ALT Controversies
• Should lower normal limits be
used in females?
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Females < 30 vs. males < 40
• Are the normal limits too high?
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Females < 20 and males < 30
Lactate Dehydrogenase
(LDH)
• Component of classic LFT’s
• Highly non-specific
Tests of Impaired Hepatic
Excretion
Increased In
• Cholestasis
• Intra-hepatic biliary tract obstruction
• Extra-hepatic biliary obstruction
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
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
Alkaline Phosphatase Isoenzymes
Source
Heat
Inactivation
5' NT
GGTP
Liver
Moderate
+
+
Bone
Rapid
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-
Placenta
Slow
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Intestine
Slow
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5'-Nucleotidase
• Hydrolyzes 5'- adenosine monophosphate
• Mainly present in liver
• Increases along with alkaline phosphatase
g-Glutamyl Transpeptidase
(GGTP)
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Transfers g-glutamyl groups
Widely distributed
Sensitive correlate to alkaline phosphatase
Non-specific (alcoholism, MI, DM,
pancreatic disease, renal failure)
Biochemical Markers
of Specific Liver
Diseases
Etiology-specific Liver Tests
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Viral hepatitis serologies
Serum ferritin level
Ceruloplasmin level
Alpha1-antitrypsin level
Antimitochondrial antibody titer
Viral Hepatitis Serology
• HAV – anti-HAV IgM and IgG
• HBV – HBsAg, anti-HBsAg,
and anti-HBcAg
• HCV – anti-HCV, HCV RNA
Serum Ferritin
• Widely distributed storage protein
• Levels reflect body iron stores
• Elevated in primary hemochromatosis
• Elevated in acute inflammation and
cirrhosis
Serum Ceruloplasmin
• Copper-binding protein
• Decreased in 95% of patients
with Wilson’s disease
• 20% of heterozygotes have
decreased levels
a1-Antitrypsin
• Inhibits serum trypsin
• Major component of a1-globulin
• Deficiency cause of neonatal
hepatitis
Antimitochondrial Antibody
(AMA)
• Directed against mitochondrial
enzyme pyruvate
dehydrogenase complex
• Positive in 90% of patients
with primary biliary cirrhosis
Interpretation of Abnormal
LFT’s
• Examine multiple tests
• Consider non-hepatic causes
• Determine the most abnormal tests
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
Case 1
25 yo IVDA c/o 1 week of nausea,
vomiting, and myalgias. Physical
exam revealed jaundice.
• 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)
Hepatocellular W/U
H&P
EtOH, medications, transfusions
Risk for viral
hepatitis
Risk factors
for NASH
Etiology-specific LFT’s
USG and liver biopsy
Autoimmune
features
HBV Infection - HBcAg Staining
Case 2
67 yo c/o several months of weight loss,
and 1 week of nausea, vomiting, and
myalgias. Physical exam revealed
cachexia and jaundice.
• 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)
Cholestatic W/U
H&P
medications, gallstones, weight loss
USG
normal
AMA
liver biopsy
dilated ducts
ERCP
Pancreatic Carcinoma - ERCP