PORPHYRIAS

A group of rare disorders caused by deficiencies of enzymes of the heme biosynthetic pathway

Affected individuals have an accumulation of heme precursors (porphyrins), which are toxic at high concentrations

Attacks of the disease are triggered by certain drugs, chemicals, and foods, and also by exposure to sun

Treatment involves administration of hemin, which provides negative feedback for the heme biosynthetic pathway, and therefore, prevents accumulation of heme precursors

PORPHYRIAS

GLYCINE + SuccinylCoA

-aminolevulinic acid(ALA)

Porphobilinogen(PBG)

hydroxymethylbilane

uroporphyrinogen III

coprophyrinogene III

Protoporphyrinogene IX

protoporphyrin IX

Heme

ALA synthase

ALA dehydratase

PBG deaminase

Uroporphyrinogen IIIcosynthase

Uroporphyrinogendecarboxylase

Coproporphyrinogenoxidase

Protoporphyrinogenoxidase

Ferrochelatase

ALA-dehydrataseDeficiency porphyria

Acute intermittentporphyria

Congenital erythropoieticporphyria

Prophyria cutanea tarda

Herediatarycoproporphyria

Variegateporphyria

Erythropoieticprotoporphyria

Mitochondria

BLOOD CELLS

LIVER

Bilirubin diglucuronide(water-soluble)

2 UDP-glucuronic acid

via bile duct to intestines

Stercobilin excreted in feces

Urobilinogen formed by bacteria

KIDNEY

Urobilin excreted in urine

CO

Biliverdin IX

Heme oxygenase

O2

Bilirubin (water-insoluble)

NADP+

NADPH

Biliverdinreductase

HemeGlobin

Hemoglobin

reabsorbed into blood

Bilirubin (water-insoluble)via blood

to the liver

INTESTINE

Figure 2. Catabolism of hemoglobin

JaundiceNormal ranges: (bilirubin)

Total bilirubin = 0.2 - 1.2mg/dL

Direct bilirubin = less than 0.3mg/dL

Indirect bilirubin = less than 0.9mg/dL

Two forms

Direct bilirubin: Conjugated with glucoronic acid

Indirect bilirubin: unconjugated, insoluble in water.

Jaundice: the types

Stones in bile duct, tumor blocking bile flow, Dubin-Johnson and Rotor’s Syndromes

Parenchymal Liver disease e.g. hepatitis (viral and other), Wilson’s disease, Hemochromatosisetc.

Hemolysis

Congenital deficiency of enzyme Glucuronyl transferase e.g. in Criggler-Najjar and Gilbert Syndromes

Causes

Liver conjugates normally but outflow of conjugated bilirubin is impaired

Both Bilirubin uptake and conjugation impaired because of liver cell dysfunction

Unconjugated bilirubin levels exceed liver’s capacity to conjugate

Pathophysiology

Post-hepaticPredominantly conjugated conjugated HyperbilirubinemiaHyperbilirubinemia

HepatocellularMixedMixedHyperbilirubinemiaHyperbilirubinemia

Pre-hepaticIsolated unconjugated unconjugated HyperbilirubinemiaHyperbilirubinemia

A. Hemolytic anemia

excess hemolysis

unconjugated bilirubin

B. Hepatitis

unconjugated bilirubin conjugated bilirubin

C. Biliary duct stone

conjugated bilirubin (in blood)

Lab results of three different causes of Jaundice

Condition Serum Billirubin Urine Urobilinogen

Urine Biollirubin

Fecal Urobilinogen

Normal Direct:0.1-0.4mg/dlIndirect:0.2-0.7mg/dl

0-4mg/24h Absent 40-280mg/24h

Hemolytic anemia

Indirect (Increase) Increased Absent Increased

Hepatitis Direct &Indirect (Increased)

Decreased if micro-

obstruction present

Present if micro-

obstruction occurs

Decreased

Obstructive jaundice

Direct(Increased) Absent Present Trace to absent

Genetic Disorders of Bilirubin Metabolism

Condition Defect Bilirubin Clinical Findings

Crigler-Najjar syndrome-I

severely defective UDP-glucuronyltransferase

Unconjugated bilirubin

Profound jaundice

Dubin-Johnson syndrome

abnormal transport of conjugated bilirubin into the biliary system

Conjugated bilirubin

Jaundice

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