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Porphyrins & Bile Pigments
Objectives
• After studying this chapter, you should be able to:
• Know the relationship between porphyrins and heme
• Be familiar with how heme is synthesized
• Understand the causes and general clinical pictures of
the various porphyrias
• Know how bilirubin is derived from heme and how it is
handled in the body
• Understand the nature of jaundice and appreciate how
to approach determining its cause in a patient.
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Hemoproteins
Heme
Porphyrias (Inherited)
Catabolism of the heme
Jaundice (causes of)
Some important hemoproteins
The porphyrins
• The porphin nucleus
– Methenyl bridges
– Pyrrole ring
• Side chains
The porphin molecule
• Arrangement of the substituents
– Side chains
• Asymmetric substitution
– Type III porphyrin
» More abundant
• Symmetric arrangement
– Type I porphyrin
Synthesis of Heme
• ALA Synthase Is the Key Regulatory Enzyme in
Hepatic Biosynthesis of Heme
– ALAS1
– ALAS2
• Heme
– Repression-derepression mechanism
– Translation of the enzyme
– Its transfer from the cytosol to the mitochondrion
• Drugs
– Cytochrome P450
• Utilization of heme
• Glucose
• Hematin
• (ALAS2)
– Not induced by the drugs
– Does not undergo feedback regulation by heme
Biosynthesis of porphobilinogen
Conversion of porphobilinogen to uroporphyrinogens
Decarboxylation of uroporphyrinogens
Addition of iron to protoporphyrin
Absorption spectrum of hematoporphyrin
The porphyrias
• 85% of heme synthesis occurs in erythroid
precursor cells in the bone marrow and the
majority of the remainder in hepatocytes
• Erythropoietic
or
• Hepatic
THE PORPHYRIAS ARE GENETIC
DISORDERS OF HEME METABOLISM
• Genetic or acquired
• Diagnosis
– Assay of the activity
• eg, red blood cells
– Use of appropriate gene probes
• Prenatal diagnosis
The Porphyrias are Genetic
Disorders of Heme Metabolism
• The signs and symptoms of porphyria result from
– Deficiency of metabolic products
• Deficiency of heme
– Accumulation of metabolites behind the block
• Prior to the formation of porphyrinogens
– ALA and PBG will accumulate
• Abdominal pain and neuropsychiatric symptoms
• Later in the pathway
– Accumulation of the porphyrinogens
Major findings in the porphyrias
Porphyrias
• Treatment
– Avoid drugs that cause induction of cytochrome
P450
– Repress ALAS1
• Glucose loading
• Hematin
– β-carotene
• Lessen production of free radicals
– Sunscreens
Catabolism of heme produces bilirubin
• Hemoglobin
– Globin
– Iron
– Porphyrin
• Hemoglobin
• Ineffective erythropoiesis
• other heme proteins
– Cytochrome P450
• Reticuloendothelial cells
Structure of bilirubin diglucuronide
Conjugation of bilirubin
• Hyperbilirubinemia
– Bilirubin in the blood exceeds 1 mg/dL
– Overproduction
– Failure of a damaged liver to excrete bilirubin
• Jaundice or icterus
– 2–2.5 mg/dL
• Direct reacting
– React without the addition of methanol
• Indirect-reacting
• Kernicterus
– Unconjugated bilirubin can cross the blood-brain
barrier
Elevated Unconjugated
Bilirubin in Blood
• HEMOLYTIC ANEMIAS
– Usually only slight (< 4 mg/dL)
• NEONATAL “PHYSIOLOGIC JAUNDICE”
– Accelerated hemolysis
– Immature hepatic system
• CRIGLER-NAJJAR SYNDROME
– TYPE I
• Serum bilirubin usually exceeds 20 mg/dL
• Mutations in the gene encoding bilirubin-UGT
Elevated Unconjugated
Bilirubin in Blood
• TYPE II
– Some activity of the enzyme is retained
– Usually do not exceed 20 mg/dL
• GILBERT SYNDROME
– Mutations in the gene encoding bilirubin-UGT
– 30% of the enzyme’s activity is preserved
– Harmless
Elevated Unconjugated
Bilirubin in Blood
• TOXIC HYPERBILIRUBINEMIA
– Acquired disorders
– Liver dysfunction
– Impairs conjugation
Conjugated Hyperbilirubinemia
• OBSTRUCTION OF THE BILIARY TREE
• DUBIN-JOHNSON SYNDROME
• ROTOR SYNDROME
OBSTRUCTION OF THE BILIARY
TREE
• Due to
– Gallstone
– Cancer of the head of the pancreas
• Cholestatic jaundice
– Include
• All cases of extrahepatic obstructive jaundice
• Micro-obstruction of intrahepatic biliary ductules
DUBIN-JOHNSON SYNDROME
• Benign autosomal recessive
• Mutations in the gene encoding MRP-2
– Secretion of conjugated bilirubin into bile
ROTOR SYNDROME
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Rare
Benign
A chronic conjugated hyperbilirubinemia
Normal liver histology
• Delta bilirubin
– Longer half-life
Laboratory results in normal patients and patients with
three different causes of jaundice.
• Hepatitis
– Damage to parenchymal cells
– Micro-obstruction to bile ductules
Causes of jaundice
• Prehepatic
• Hepatic
• Posthepatic
• Distinction
– Measurement of prothrombin time
– Electrophoresis of proteins
– Activities of the enzymes ALT,AST, and alkaline
phosphatase
Causes of jaundice
• Measurements of plasma
– Total and Nonconjugated bilirubin
• Urinary
– Urobilinogen and bilirubin