Evaluation of Liver Injury

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Evaluation of Liver Injury

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

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Liver Function Tests

• Alanine aminotransferase (ALT)
• Aspartate aminotransferase (AST)
• Lactate dehydrogenase (LDH)
• Alkaline phosphatase
• Bilirubin
• Albumin

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Mechanisms of Liver Dysfunction

• Direct cellular injury
• Blockage in bile flow
• Impaired blood flow

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Direct Cellular Injury - HCV Infection
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Blockage in Bile Flow - Biliary Atresia
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Impaired Blood Flow - CHF
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Consequences of Liver Injury
liver cell injury
liver cell death
proliferation
matrix deposition
sufficient
inadequate
altered architecture
recovery
liver failure
cirrhosis
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Types of Liver Tests

• True tests of liver function
• Biochemical markers of liver injury
• Biochemical markers of specific liver diseases

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Testable Biochemical Liver Function

• Ability to transport organic anions
• Capacity to metabolize certain substances
• Capability to synthesize various proteins

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Steps in Organic Anion Transport

• Delivery and uptake
• Metabolic alteration
• Secretion and excretion

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Bilirubin

• Tetrapyrole
• Toxic in neonates - kernicterus
• Derived from
• Senescent RBC (70-80)
• Hemoproteins (20-30)
• Ineffective erythropoiesis

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Bilirubin Formation
heme
biliverdin
heme
biliverdin
bilirubin
oxygenase
reductase
Transport hydrophobic due to internal
H-bonding circulates bound to
albumin
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Bilirubin Metabolism
Bile
Plasma
Hepatocyte
Alb UCB
BMG BDG
UCB ligandin
BMG BDG
glucuronyl
transferase
BMG BDG
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Bilirubin Elimination

• Intestine
• BMG (20) BDG (80) UCB (trace)
• Deconjugated to urobilinogen
• Excreted or reab-sorbed (20)

• Urine
• BMG and BDG
• No UCB

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Measurement of Serum Bilirubin

• Normal concentration lt 1 mg/dl
• Conjugated lt 5
• Jaundice if gt 3 mg/dl
• Detected by diazo reaction - cleaved to
  colored azo-dipyrole
• Conjugated reacts rapidly (direct)
• Unconjugated reacts slowly (indirect)

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Differential Diagnosis I

• Prehepatic
• Intrahepatic
• Congenital
• Acquired
• Posthepatic

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Differential Diagnosis II

• Unconjugated hyperbilirubinemia
• Increased bilirubin production (hematological)
• Decreased uptake (drug)
• Decreased conjugation (congenital)
• Conjugated hyperbilirubinemia
• Congenital
• Drug
• Liver disease
• Biliary obstruction

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Inherited Disorders Causing Unconjugated
Hyperbilirubinemia

• Crigler-Najjar syndrome
• Type 1 absent GT
• Type 2 reduced GT activity
• Gilberts syndrome reduced GT activity due to
  genetic defect in TATAA element of GT promoter

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Inherited Disorders Causing Conjugated
Hyperbilirubinemia

• Dubin-Johnson syndrome mutations in multidrug
  resistance associated protein 2 (MRP2)
• Rotors syndrome genetic defect

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Hepatic Metabolic Capacity

• Clearance must depend on total functional mass
  or metabolic activity
• Hepatic drug metabolism - 14Camino-pyrine
  breath test
• Galactose elimination
• Not used clinically

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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

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Albumin

• 50 of all synthesized hepatic protein
• Determinant of plasma oncotic pressure
• Important transport protein

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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

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Non-hepatic Causes of Hypoalbuminemia

• Severe malnutrition
• Renal or GI loss
• Glomerulopathy, HIV enteropathy
• High catabolism
• Infections, burns

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Coagulation Factors

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

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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

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Non-hepatic Causes of Elevated PT

• Congenital coagulation factor deficiencies
• Consumptive coagulopathies
• Vitamin K deficiency (II, VII, IX, X)

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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

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Serum Immunoglobulins

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

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Biochemical Markers of Liver Injury
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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

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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

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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

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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

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AST/ALT in Alcoholic Hepatitis

• Transaminases rarely exceed 300
• ASTALT gt2

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Factors Affecting AST/ALT

• Depressed by pyridoxine (vit. B6) deficiency
• Decreased by uremia and renal dialysis

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AST/ALT Controversies

• Should lower normal limits be used in females?
• Females lt 30 vs. males lt 40
• Are the normal limits too high?
• Females lt 20 and males lt 30

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Lactate Dehydrogenase (LDH)

• Component of classic LFTs
• Highly non-specific

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Tests of Impaired Hepatic ExcretionIncreased In

• Cholestasis
• Intra-hepatic biliary tract obstruction
• Extra-hepatic biliary obstruction

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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

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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

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

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

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g-Glutamyl Transpeptidase(GGTP)

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

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Biochemical Markersof Specific Liver Diseases
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Etiology-specific Liver Tests

• Viral hepatitis serologies
• Serum ferritin level
• Ceruloplasmin level
• Alpha1-antitrypsin level
• Antimitochondrial antibody titer

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Viral Hepatitis Serology

• HAV anti-HAV IgM and IgG
• HBV HBsAg, anti-HBsAg, and anti-HBcAg
• HCV anti-HCV, HCV RNA

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Serum Ferritin

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

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Serum Ceruloplasmin

• Copper-binding protein
• Decreased in 95 of patients with Wilsons
  disease
• 20 of heterozygotes have decreased levels

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a1-Antitrypsin

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

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Antimitochondrial Antibody(AMA)

• Directed against mitochondrial enzyme pyruvate
  dehydrogenase complex
• Positive in 90 of patients with primary biliary
  cirrhosis

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Interpretation of Abnormal LFTs

• Examine multiple tests
• Consider non-hepatic causes
• Determine the most abnormal tests

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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
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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)

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Hepatocellular W/U
H P EtOH, medications, transfusions
Risk for viral hepatitis
Risk factors for NASH
Autoimmune features
Etiology-specific LFTs
USG and liver biopsy
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HBV Infection - HBcAg Staining
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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)

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Cholestatic W/U
H P medications, gallstones, weight loss
USG
dilated ducts
normal
AMA
ERCP
liver biopsy
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Pancreatic Carcinoma - ERCP