Evaluation of Liver Injury

Mark J. Czaja

Liver Research Center

Albert Einstein College of Medicine
Bronx, N.Y.
 Liver Function Tests
• 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 altered architecture

recovery liver failure 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 biliverdin
heme oxygenasebiliverdin bilirubin
reductase

Transport: hydrophobic due to internal H-bonding

circulates bound to albumin
 Bilirubin Metabolism
Plasma Hepatocyte Bile

Alb
UCB BMG BMG
UCB glucuronyl
BMG transferase BDG BDG
ligandin
BDG
 Bilirubin Elimination
 Intestine  Urine
• BMG (20%) + • BMG and BDG
BDG (80%) • No UCB
+UCB (trace)
• Deconjugated to
urobilinogen
• Excreted or reab-
sorbed (20%)
 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)
Differential Diagnosis I
• Prehepatic
• Intrahepatic

Congenital
 Acquired

• Posthepatic
 Differential Diagnosis II
• Unconjugated hyperbilirubinemia

Increased bilirubin production (hematological)

Decreased uptake (drug)
 Decreased conjugation (congenital)
• Conjugated hyperbilirubinemia

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

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
 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 -amino group of aspartate
to -keto group of ketoglutaric acid
• Present in skeletal muscle, kidney, brain
 Alanine Aminotransferase
(ALT)
• Serum glutamic-pyruvic transaminase
(SGPT)
• Transfers an -amino group of alanine
to -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?

Females < 30 vs. males < 40
• Are the normal limits too high?

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
Heat
Source Inactivation 5' NT GGTP

Liver Moderate + +
Bone Rapid - -
Placenta Slow - -
Intestine Slow - -
 5'-Nucleotidase

• Hydrolyzes 5'- adenosine monophosphate

• Mainly present in liver
• Increases along with alkaline phosphatase
 -Glutamyl Transpeptidase
(GGTP)
• Transfers -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

• 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
 1-Antitrypsin

• Inhibits serum trypsin

• Major component of 1-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) • Bili 3.9 (0.1-1.0)
• AST 2300 (15-45) • Alb 4.2 (3.5-5.5)
• Alk Phos 273 • PT 11.5 (10-12)
(50-150)
 Hepatocellular W/U
H&P
EtOH, medications, transfusions

Risk for viral Risk factors Autoimmune

hepatitis for NASH features

Etiology-specific LFT’s

USG and liver biopsy

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) • Bili 10.2 (0.1-1.0)

• AST 115 (15-45) • Alb 4.2 (3.5-5.5)
• Alk Phos 650 • PT 11.0 (10-12)
(50-150)
 Cholestatic W/U
H&P
medications, gallstones, weight loss

USG
normal dilated ducts

AMA ERCP

liver biopsy
Pancreatic Carcinoma - ERCP