Introduction:
Hepatic dysfunction refers to the impaired ability of the liver to perform its normal metabolic, synthetic, and excretory functions. Liver diseases can alter various biochemical pathways, affecting the metabolism of bilirubin, plasma proteins, and enzymes. Laboratory tests help in detecting and assessing the degree of such dysfunctions.
However, due to the liver’s large functional reserve and remarkable capacity for regeneration, the detection of early or minimal damage is challenging. Experimental studies have shown that up to 80–85% of liver tissue must be damaged before laboratory tests show significant abnormalities. Moreover, diffuse minor liver involvement may cause more striking test abnormalities than focal necrosis.
Purpose of Hepatic Function Tests
Given the complexity of liver functions, numerous biochemical tests have been developed to assess hepatic activity. No single test is completely specific or sensitive, so a panel of liver function tests is typically used. These tests serve three main purposes:
- Diagnosis: To determine if there is impairment of the hepatobiliary system.
- Differentiation: To identify whether the impairment is due to hepatocellular damage or biliary obstruction.
- Prognosis: To estimate the extent of liver damage and the likely outcome of treatment.
The ideal liver function test should be specific for hepatic disease, sensitive to early changes, and selective enough to detect specific types of disorders. Since no single test fulfills all these criteria, multiple parameters such as serum bilirubin, urine bilirubin, plasma proteins, and liver enzymes are evaluated together.
Bile Pigment Metabolism
Bilirubin:
Bilirubin is the principal bile pigment, derived primarily from the breakdown of hemoglobin in senescent red blood cells. The process takes place in cells of the reticuloendothelial (R-E) system — mainly in the spleen, liver, and bone marrow.
About 80% of daily bilirubin production comes from the breakdown of old erythrocytes, while the remaining 20% is from the degradation of immature red blood cells and other heme-containing proteins such as myoglobin, catalase, and cytochromes.
On average, an adult produces 250–300 mg of bilirubin daily, equivalent to the breakdown of approximately 6–6.5 g of hemoglobin. The following steps outline the metabolism of bilirubin from formation to excretion.
Step 1: Formation of Bilirubin
When red blood cells age (after ~120 days), they are engulfed by macrophages in the spleen and liver. Inside these cells:
- Globin (protein part of hemoglobin) is split off and hydrolyzed into amino acids for reuse.
- The heme portion (ferroprotoporphyrin) loses its iron atom, which binds to ferritin for storage.
- The porphyrin ring is opened, forming an open-chain tetrapyrrole structure — bilirubin, a reddish-yellow pigment.
Step 2: Transport in Blood
The unconjugated (free) bilirubin formed in macrophages is insoluble in water. It binds tightly to albumin in plasma for transport to the liver. This complex prevents bilirubin from diffusing into tissues or crossing the blood-brain barrier under normal conditions.
Step 3: Hepatic Uptake
When the bilirubin-albumin complex reaches the hepatic sinusoids, bilirubin is actively transported into the hepatocytes. Inside the liver cells, bilirubin detaches from albumin and moves to the endoplasmic reticulum for further processing.
Step 4: Conjugation (Esterification)
Within hepatocytes, bilirubin undergoes conjugation to make it water-soluble. This reaction is catalyzed by the enzyme UDP-glucuronyl transferase (UDPG-T). The enzyme transfers two glucuronic acid molecules to bilirubin, forming bilirubin diglucuronide (BDG), also known as conjugated or esterified bilirubin.
This process transforms bilirubin from a toxic, lipid-soluble form into a non-toxic, water-soluble form that can be excreted in bile.
Step 5: Excretion into Bile
The conjugated bilirubin (BDG) is secreted into bile canaliculi through active transport mechanisms. It then joins bile flow and moves through the bile ducts into the gallbladder or directly into the small intestine.
Bile is produced continuously by the liver, but between meals, it is stored in the gallbladder, where it becomes concentrated by water absorption.
Step 6: Intestinal Transformation
Upon entering the small intestine, bile pigments are acted upon by intestinal bacteria. In the colon, bilirubin diglucuronide is deconjugated and reduced by bacterial enzymes to form urobilinogen, a colorless compound.
Step 7: Enterohepatic Circulation of Urobilinogen
A portion of urobilinogen is reabsorbed from the intestine into the portal circulation and transported back to the liver, where it is re-excreted into bile. This recycling process is known as the enterohepatic circulation.
A small fraction (~1%) of urobilinogen escapes hepatic reuptake, enters systemic circulation, and is excreted in urine. In the colon, the remaining urobilinogen is oxidized to urobilin and other brown pigments, which are eliminated in feces, giving stool its characteristic color.
Summary of Bilirubin Metabolism
| Step | Process | Site | Product |
|---|---|---|---|
| 1 | Hemoglobin breakdown | Macrophages (R-E system) | Bilirubin (unconjugated) |
| 2 | Transport in plasma | Bound to albumin | Unconjugated bilirubin-albumin complex |
| 3 | Uptake by liver cells | Hepatocytes | Bilirubin inside hepatocytes |
| 4 | Conjugation | Endoplasmic reticulum | Bilirubin diglucuronide (conjugated bilirubin) |
| 5 | Excretion into bile | Bile canaliculi | Bile pigment (bilirubin diglucuronide) |
| 6 | Intestinal conversion | Colon (by bacteria) | Urobilinogen |
| 7 | Reabsorption & recycling | Portal circulation | Re-excreted urobilinogen |
| 8 | Excretion | Urine & feces | Urobilin (brown pigment) |
Clinical Importance
- Increased unconjugated bilirubin → Indicates hemolytic jaundice or impaired conjugation (e.g., neonatal jaundice).
- Increased conjugated bilirubin → Suggests hepatocellular damage or cholestasis.
- Elevated urinary urobilinogen → Seen in hepatitis and hemolytic conditions.
- Absent urinary urobilinogen → Indicates complete bile duct obstruction.
Detailed Notes:
For PDF style full-color notes, open the complete study material below: