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 GENETICDISORDERS 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 GeneticDisorders 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 UnconjugatedBilirubin 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 UnconjugatedBilirubin 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 UnconjugatedBilirubin 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