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.

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 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