Jaundice & Bilirubin

Lecture17 by Dr Mohammad Manzoor Mashwani BKMC Mardan

Metabolism

Jaune (French word)- means Yellow

ICTERUS

Hematoidin

Definition of Jaundice

Bilirubin pigment has high affinity for elastic tissue and hence jaundice isparticularly noticeable in tissues rich in elastin content.

A rise of serum bilirubin between the normal and 2 mg/dl is generally notaccompanied by visible jaundice and is called latent jaundice.

CategoryPre-hepatic/ hemolytic

Hepatic/ hepatocellular

Post-Hepatic/ cholestatic

UnconjugatedConjugated

(1) Production of bilirubin;

(2) Uptake; (3) Conjugation; (4) Excretion (5) Bile flow.

Jaundice Mechanisms:

Jaundice occurs when the equilibrium between bilirubin production and clearance is disturbed.

Hepatic bile serves two major functions:

• I. Bile constitutes the primary pathway for the elimination of bilirubin, excess cholesterol, and xenobiotics (foreign substance) that are insufficiently water soluble to be excreted in the urine.

• II. Secreted bile salts and phospholipid molecules promote emulsification of dietary fat in the lumen of the gut.

Jaundice results from the retention of bile.

Emulsification is the breakdown of large fat globules into smaller, uniformly distributed particles. It is accomplished mainly by bile acids in the small intestine. Emulsification is the first preparation of fat for chemical digestion by specific enzymes.

The metabolism of bilirubin by the liver consists of four events:

1. Uptake (by the Liver) from the circulation;

2. Intracellular storage (Cytosolic protein binding and delivery to the endoplasmic reticulum.);

3.Conjugation with glucoronic acid;

4.Biliary excretion.Hepatocellular processing of bilirubin involves the following sequence:1. Carrier-mediated uptake at the sinusoidal membrane (Hepatocellular uptake).2. Cytosolic protein binding and delivery to the endoplasmic reticulum.3. Conjugation with one or two molecules of glucuronic acid by bilirubin uridine diphosphate–glucuronosyl transferase.4. Excretion of the water-soluble, nontoxic bilirubin glucuronides into bile.

Normal metabolism of bilirubin can be conveniently described under 4 main headings—source, transport, hepatic phase and intestinal phase.

Bilirubin metabolism and elimination.

Bilirubin is the end product of heme degradation. • The majority of daily production (0.2 to 0.3 gm, 85%) is

derived from breakdown of senescent red cells by the mononuclear phagocytic system, especially in the spleen, liver, and bone marrow.

Most of the remainder (15%) of bilirubin is derived from the turnover of hepatic heme or hemoproteins (e.g., the P-450 cytochromes, muscle myoglobin) and from premature destruction of red cell precursors in the bone marrow (Ineffective erythropoises)

Excessive destruction of erythroid progenitors in the bone marrow due to intramedullaryapoptosis (ineffective erythropoiesis) is an important cause of jaundice in hematologic disorders.

Bilirubin metabolism and elimination.• Intracellular heme oxygenase oxidizes heme to biliverdin

(step1), which is immediately reduced to bilirubin by biliverdin reductase.

Bilirubin thus formed outside the liver is released and bound to serum albumin (step 2).

Albumin binding is necessary to transport bilirubin because bilirubin is virtually insoluble in aqueous solutions at physiologic pH.

Hepatic processing of bilirubin involves carrier-media uptake at the sinusoidal membrane (step

3),

Conjugation with one or two molecules of glucuronic acid by bilirubin uridine

diphosphate (UDP)–glucuronyltransferase (UGT1A1, step 4) in the endoplasmic reticulum, and excretion of the water-soluble, nontoxic bilirubin glucuronides into bile.

Most bilirubin glucuronides are deconjugated in the gut lumen by bacterial β-glucuronidases and degraded to colorless urobilinogens (step 5).

5 STEPS

Bilirubin metabolism and elimination.• The urobilinogens and the residue of intact pigment are largely excreted in

feces. Approximately 20% of the urobilinogens formed are reabsorbed in the ileum and colon, returned to the liver, and re-excreted into bile.

A small amount of reabsorbed urobilinogen is excreted in the urine.Conjugated and unconjugated bile acids also are reabsorbed in the ileum andreturned to the liver by the enterohepatic circulation.

Stercobilin= stool +Yellow color

Urobilin= Urine + Yellow color

C34H32O4N4Fe

Heme B

Spleen Macrophage

5 steps

Prehepatic

Hepatic

Posthepatic

Sinusoid- Tiny endothelium-lined passages for blood in the tissue of an organ .

The perisinusoidal space (or space of Disse) is a location in the liver between a hepatocyte and a sinusoid.

SpleenBilirubin (Hematoidin) is the potentially toxic catabolic product of heme metabolism.MPS/ RES

Mononuclear Phagocyte system/Reticuloendothelial system

Erythrocytes generated in the bone marrow are disposed of in the spleen when they get old or damaged. This releases hemoglobin, which is broken down to heme as the globin parts are turned into amino acids. The heme is then turned into unconjugated bilirubin in the reticuloendothelial cells of the spleen.

Bilirubin metabolism and elimination. (1) Normal bilirubin production from heme (0.2–0.3

gm/day) is derived primarily from the breakdown of senescent circulating erythrocytes.

(2) Extrahepatic bilirubin is bound to serum albumin and delivered to the liver.

(3) Hepatocellular uptake and (4) glucuronidation in the endoplasmic reticulum

generate bilirubin monoglucuronides and diglucuronides, which are water soluble and readily excreted into bile.

(5) Gut bacteria deconjugate the bilirubin and degrade it to colorless urobilinogens. The urobilinogens and the residue of intact pigments are excreted in the feces, with some reabsorption and excretion into urine.

Pathophysiology of Jaundice • Both unconjugated (Indirect, free) bilirubin and

conjugated bilirubin (Direct, bilirubin glucuronides, combine with glucoronic acid)

may accumulate systemically. • There are two important pathophysiologic

differences between the two forms of bilirubin:

• 1. Solubility in water &• 2. Binding with Albumin

Unconjugated/Indirect/Free bilirubin

• Unconjugated bilirubin is virtually (almost)

insoluble in water (due to intramolecular hydrogen bonding) at physiologic pH and exists in tight complexes with serum albumin. This form cannot be excreted in the urine even when blood levels are high.

Serum bilirubin estimation is based on van den Bergh diazo reaction by spectrophotometric method. Water-soluble conjugated bilirubin gives direct van den Bergh reaction with diazo reagent within one minute, whereas alcohol-solubleunconjugated bilirubin is determined by indirect van den Bergh reaction. The unconjugated bilirubin level is then estimated by subtracting direct bilirubin value from this total value. However, unconjugated bilirubin also reacts slowly with diazosulfanilic acid, so that the measured indirect bilirubin is an underestimate of the true unconjugated concentration.

Pathophysiology of Jaundice

Alcohol soluble & water insoluble

Pathophysiology of JaundiceUnconjugated bilirubin & Kernicterus

• Normally, a very small amount of unconjugated bilirubin is present as an albumin-free anion in plasma. This fraction of unbound bilirubin may

diffuse into tissues, particularly the brain in infants, and produce toxic injury.

Pathophysiology of JaundiceUnconjugated bilirubin

• The unbound plasma fraction may increase in severe hemolytic disease or when protein-binding drugs (sulfonamides, salicylates). displace bilirubin from albumin. Hence, hemolytic disease of the newborn (erythroblastosis fetalis) may lead to accumulation of unconjugated bilirubin in the brain, which can cause severe neurologic damage, referred to as kernicterus.

Pathophysiology of Jaundice

Conjugated Bilirubin (Direct Bilirubin)

• Conjugated bilirubin is water-soluble, nontoxic, and only loosely bound to albumin. Because of its solubility and weak association with albumin, excess conjugated bilirubin in plasma can be excreted in urine.

Pathophysiology of JaundiceConjugated Bilirubin

With prolonged conjugated hyperbilirubinemia, a portion of circulating pigment may become covalently bound to albumin; this is termed the bilirubin delta (biliprotein) fraction.

• Although the terms direct and indirect bilirubin are used equivalently with conjugated and unconjugated bilirubin, this is not quantitatively correct, because

• the direct fraction includes both conjugated bilirubin and δ bilirubin.

• Furthermore, direct bilirubin tends to overestimate conjugated bilirubin levels due to unconjugated bilirubin that has reacted with diazosulfanilic acid, leading to increased azobilirubin levels (and increased direct bilirubin).

Pathophysiology of Jaundice

• Serum bilirubin levels in the normal adult vary between 0.3 and 1.2 mg/dL, and

• the rate of systemic bilirubin production is equal to the rates of

• HEPATIC UPTAKE, • CONJUGATION, and

• BILIARY EXCRETION.

Pathogenesis

Pathophysiology of Jaundice• Jaundice becomes evident when the serum

bilirubin levels rise above 2.0 to 2.5 mg/dL; levels as high as 30 to 40 mg/dL can occur with severe disease.

Jaundice occurs when the equilibrium between bilirubin production and clearance is disturbed by one or more of the following mechanisms :

(1) Excessive extrahepatic production of bilirubin; (2) Reduced hepatocyte uptake; (3) Impaired conjugation; (4) Decreased hepatocellular excretion; and (5) Impaired bile flow.The first three mechanisms produce unconjugated hyperbilirubinemia, and the latter two produce predominantly conjugated hyperbilirubinemia.

3 types: pre-hepatic (haemolytic), hepatic, and post-hepatic cholestatic.

Neonatal JaundiceBecause the hepatic machinery for conjugating and

excreting bilirubin does not fully mature until about 2 weeks of age, almost every newborn develops transient and mild unconjugated hyperbilirubinemia, termed neonatal jaundice or physiologic jaundice of the newborn.

This may be exacerbated by breastfeeding, as a result of the presence of bilirubin-deconjugating enzymes in breast milk. Nevertheless, sustained jaundice in the newborn is abnormal.

Cholestasis• Cholestasis is defined as systemic

retention of not only bilirubin but also other solutes eliminated in bile (particularly bile salts and cholesterol).

Cholestasis denotes a pathologic condition of impaired bile formation and bile flow, leading to accumulation of bile pigment in the hepatic parenchyma.

It can be caused by extrahepatic or intrahepatic obstruction of bile channels, or by defects in hepatocyte bile secretion. Extrahepatic biliary obstruction frequently is amenable to surgical correction. By contrast, cholestasis caused by diseases of the intrahepatic biliary tree or hepatocellular secretory failure (collectively termed intrahepatic cholestasis) cannot be treated surgically, and the patient’s condition may be

worsened by an operative procedure. Thus, there is some urgency in identifying the cause of jaundice and cholestasis.

Clinical features• Jaundice, pruritus, skin xanthomas (focal accumulation of

cholesterol), or symptoms related to intestinal malabsorption, including nutritional deficiencies of the fat-soluble vitamins A, D, or K. A characteristic laboratory finding is elevated serum alkaline phosphatase and γ-glutamyl transpeptidase (GGT),

enzymes present on the apical membranes of hepatocytes and bile duct epithelial cells.

HCC