Describe the biosynthesis of haem and its regulation. Classify the porphyrias and add a note on lead poisoning.

Introduction

• Synthesised chiefly in the bone marrow (85%) and liver (15%)
• Begins and ends in the mitochondrion, with the middle steps in the cytosol

Pathway

Succinyl-CoA + Glycine (mitochondrion) → ala synthase — needs pyridoxal phosphate; rate-limiting → δ-Aminolaevulinic acid (ala) → moves to cytosol → ala dehydratase — inhibited by lead → Porphobilinogen → Uroporphyrinogen I synthase and III cosynthase → Uroporphyrinogen III → Coproporphyrinogen III → back to mitochondrion → Protoporphyrin IX → ferrochelatase — adds Fe2+; also inhibited by lead → haem

• All eight carbons and four nitrogens come from succinyl-CoA and glycine
• Haem inhibits ala synthase by feedback, and also represses its gene — the principal control

Regulation

Classification of Porphyrias

• The rule is simple: a block early in the pathway accumulates ala and porphobilinogen, which are neurotoxic; a block later accumulates porphyrins, which are photosensitising

Acute Intermittent Porphyria

• Autosomal dominant; attacks usually after puberty, commoner in women
• The five Ps — Pain in the abdomen, Polyneuropathy, Psychological disturbance, Port-wine urine, Precipitated by drugs
• Severe colicky abdominal pain with NO peritoneal signs — many patients undergo needless laparotomy
• Tachycardia, hypertension, vomiting, constipation; hyponatraemia from SIADH
• Urine darkens to port-wine colour on standing in light, as porphobilinogen polymerises
• Diagnosis — raised urinary ala and porphobilinogen; the Watson–Schwartz test
• Treatment — withdraw the precipitant, intravenous glucose, haem arginate, analgesia, and propranolol for the autonomic features

Lead Poisoning

Lead inhibits ala dehydratase and ferrochelatase → Two consequences → ala accumulates → neurotoxicity → Protoporphyrin accumulates (iron cannot be inserted) → Zinc is inserted instead → ↑ zinc protoporphyrin → Microcytic anaemia with basophilic stippling

• Features — abdominal colic, peripheral neuropathy with wrist drop, encephalopathy in children, blue lead line on the gums, anaemia
• Raised blood lead, raised urinary ala, raised zinc protoporphyrin; porphobilinogen is normal, which distinguishes it from acute porphyria
• Treated with chelation — EDTA, dimercaprol, penicillamine, succimer

Catabolism of Haem

Haem from senescent red cells → Haem oxygenase — releases iron (reused) and CO → Biliverdin → biliverdin reductase → bilirubin → albumin-bound to liver → Conjugated with glucuronic acid → excreted in bile

• Iron and globin are conserved; only the porphyrin ring is degraded
• Carbon monoxide from haem breakdown is the only endogenous source, and is measurable in exhaled breath as an index of haemolysis
• 250–350 mg of bilirubin is produced daily

Applied Aspects

• Porphyria is a great mimic — consider it in unexplained abdominal pain with neuropsychiatric features, especially if attacks recur and investigations are normal
• A long list of drugs is unsafe — barbiturates, sulphonamides, phenytoin, oestrogens, griseofulvin; safe alternatives must be checked before prescribing
• Sideroblastic anaemia — from pyridoxine deficiency, isoniazid or lead, all interfering with haem synthesis; ring sideroblasts on marrow
• Porphyria cutanea tarda responds to venesection and to low-dose chloroquine, and is strongly associated with alcohol, hepatitis C and iron overload
• Photosensitivity arises because porphyrins absorb light at 400 nm (the Soret band) and generate free radicals in the skin
• Haem is also the prosthetic group of cytochrome P450, which is why drugs that induce P450 consume haem and precipitate attacks
• Ala synthase requires pyridoxal phosphate, so B6 deficiency and isoniazid cause sideroblastic anaemia
• Erythropoietic protoporphyria causes burning pain on sun exposure without blistering, and may progress to liver failure from protoporphyrin deposition
• Givosiran, a small interfering RNA that silences ala synthase, is a recent treatment for recurrent acute attacks — derived directly from the regulation described above
• Urine porphobilinogen must be measured during an attack; it may be normal between attacks, so a negative result in a well patient does not exclude the diagnosis
• Family screening is essential, since asymptomatic carriers can be warned about unsafe drugs before their first attack
• The porphyrias are often described as the "little imitator", and delayed diagnosis by years is common