Comprehensive Notes on Liver Function Tests

Liver Function Tests (LFTs)

Objectives

• Understand the major metabolic functions of the liver and causes of liver dysfunction.
• Discuss markers of liver function tests such as liver enzymes, bilirubin, albumin, and prothrombin time that can diagnose hepatic injury and assess hepatic function.

Major Metabolic Functions of the Liver

• Synthetic Function:
  • Plasma proteins (albumin, globulins)
  • Cholesterol, triglycerides, and lipoproteins
• Detoxification and Excretion:
  • Ammonia to urea (urea cycle)
  • Bilirubin, cholesterol, drug metabolites
• Storage Function:
  • Vitamins A, D, E, K, and B12
• Production of Bile Salts:
  • Helps in digestion

Examples of Liver Dysfunction

• Hepatocellular disease
• Cholestasis (obstruction of bile flow)
• Cirrhosis
• Hepatitis
• Jaundice
• Liver cancer
• Steatosis (fatty liver)
• Genetic Disorders:
  • Hemochromatosis (iron storage)

Liver Function Tests (LFTs)

• Noninvasive methods for screening of liver dysfunction.
• Help in identifying general types of disorder.
• Assess severity and allow prediction of outcome.
• Disease and treatment follow up

Classification of LFTs

• Broadly classified as:
  • Tests to detect hepatic injury:
    • Mild or severe; acute or chronic
    • Nature of liver injury (hepatocellular or cholestasis)
  • Tests to assess hepatic function

Group I: Markers of Liver Dysfunction

• Serum bilirubin: total and conjugated
• Urine: bile salts and urobilinogen
• Total protein, serum albumin, and albumin/globulin ratio
• Prothrombin Time

Group II: Markers of Hepatocellular Injury

• Alanine aminotransferase (ALT)
• Aspartate aminotransferase (AST)

Group III: Markers of Cholestasis

• Alkaline phosphatase (ALP)
• γ-glutamyltransferase (GGT)

Limitations of LFTs

• Normal LFT values do not always indicate the absence of liver disease; the liver has a very large reserve capacity.
• Asymptomatic people may have abnormal LFT results.
• Diagnosis should be based on clinical examination.

Common Serum Liver Chemistry Tests

Bilirubin

• A byproduct of red blood cell breakdown.
• It is the yellowish pigment observed in jaundice.
• High bilirubin levels are observed in: Gallstones, acute and chronic hepatitis.

Bilirubin Metabolism

1. Senescent red cells are a major source of hemeproteins.
2. Breakdown of heme to bilirubin occurs in macrophages of the reticulo-endothelial system (tissue macrophages, spleen, and liver).
3. Unconjugated bilirubin is transported through the blood (complexed to albumin) to the liver.
4. Bilirubin is taken up via facilitated diffusion by the liver and conjugated with glucuronic acid.
5. Conjugated bilirubin is actively secreted into bile and then the intestine.
6. In the intestine, glucuronic acid is removed by bacteria. The resulting bilirubin is converted to urobilinogen.
7. Some of the urobilinogen is reabsorbed from the gut and enters the portal blood.
8. A portion of this urobilinogen participates in the enterohepatic urobilinogen cycle.
9. The remainder of the urobilinogen is transported by the blood to the kidney, where it is converted to yellow urobilin and excreted, giving urine its characteristic color.
10. Urobilinogen is oxidized by intestinal bacteria to the brown stercobilin.

Serum Bilirubin Levels

• Normal: $0.2 – 0.8$ mg/dL
• Unconjugated (indirect): $0.2 – 0.7$ mg/dL
• Conjugated (direct): $0.1 – 0.4$ mg/dL
• Latent jaundice: Above $1$ mg/dL
• Jaundice: Above $2$ mg/dL

Bilirubin Levels and Jaundice

Urobilinogen (UBG) and Bile Salts

• Most UBG is metabolized in the large intestine, but a fraction is excreted in urine (less than $4$ mg/day).
• Normally, bile salts are NOT present in urine.
• Obstruction in the biliary passages causes:
  • Leakage of bile salts into circulation
  • Excretion in urine

Serum Albumin

• The most abundant protein synthesized by the liver.
• Normal serum levels: $3.5 – 5$ g/dL
• Synthesis depends on the extent of functioning liver cell mass.
• Longer half-life: $20$ days.
• Its levels decrease in all chronic liver diseases.

Serum Globulin

• Normal serum levels: $2.5 – 3.5$g/dL
• $α$ and $β$-globulins are mainly synthesized by the liver.
• They constitute immunoglobulins (antibodies).
• High serum $γ$-globulins are observed in chronic hepatitis and cirrhosis:
  • IgG in autoimmune hepatitis
  • IgA in alcoholic liver disease

Albumin to Globulin (A/G) Ratio

• Normal A/G ratio: $1.2/1 – 1.5/1$
• Globulin levels increase in hypoalbuminemia as a compensation.

Prothrombin Time (PT)

• Prothrombin: synthesized by the liver, a marker of liver function.
• Half-life: 6 hrs. (indicates the present function of the liver).
• PT is prolonged only when the liver loses more than 80% of its reserve capacity.
• Vitamin K deficiency also causes prolonged PT.
• Intake of vitamin K does not affect PT in liver disease.

Aspartate Aminotransferase (AST)

• Normal range: up to $40$ U/L
• A marker of hepatocellular damage.
• High serum levels are observed in: Chronic hepatitis, cirrhosis, and liver cancer.

Alanine Aminotransferase (ALT)

• More liver-specific than AST.
• Normal range (U/L):
  • up to $45$ U/L
• High serum levels in acute hepatitis ($300-1000$U/L).
• Moderate elevation in alcoholic hepatitis ($100-300$U/L).
• Minor elevation in cirrhosis, hepatitis C, and non-alcoholic steatohepatitis (NASH) ($50-100$U/L).

Alkaline Phosphatase (ALP)

• A non-specific marker of liver disease.
• Produced by bone osteoblasts (for bone calcification).
• Present on the hepatocyte membrane.
• Normal range: up to $250$ U/L.
• Moderate elevation observed in: Infective hepatitis, alcoholic hepatitis, and hepatocellular carcinoma.

Alkaline Phosphatase (ALP) cont.

• High levels are observed in:
  • Extrahepatic obstruction (obstructive jaundice)
  • Intrahepatic cholestasis
• Very high levels are observed in: Bone diseases.

γ-Glutamyltransferase (GGT)

• Used for glutathione synthesis.
• Normal range: up to $47$ U/L.
• Moderate elevation observed in: Infective hepatitis and prostate cancers.
• GGT is increased in alcoholics despite normal liver function tests.
• Highly sensitive to detecting alcohol abuse.