Heme Synthesis

Structure of Heme

Location

• Mitochondria: steps 1, 6, 7, 8 (first and last three steps)
• Cytoplasm: steps 2-5

The 8-Step Pathway

Regulation

1. Repression - elevated heme represses transcription of δ-ALA synthase (decreases enzyme synthesis)
2. Allosteric inhibition - heme directly inhibits δ-ALA synthase activity

Lead Poisoning and Heme Synthesis

• δ-ALA dehydratase (step 2, zinc-containing)
• Ferrochelatase (step 8)

Porphyrias - Enzyme Deficiencies

Heme Degradation (Brief Overview)

Clinical Mnemonics

• "Succinyl CoA + Glycine → ALA": the committed first step, needs B6
• Lead hits A and F: ALA dehydratase and Ferrochelatase - both inhibited by Pb
• AIP triad: abdominal pain, autonomic dysfunction, axonal neuropathy ("3 A's")
• PCT: most common porphyria; skin fragility and blistering on sun-exposed areas

Porphyrias

Overview

Classification

By Site of Accumulation

By Clinical Presentation

The Eight Porphyrias - Enzyme, Genetics, Clinic

Acute Porphyrias - Detailed

Acute Intermittent Porphyria (AIP)

• Abdominal pain - severe colic, most common initial symptom (up to 95%); no peritoneal signs but tenderness and distention present
• Autonomic dysfunction - tachycardia, hypertension, pupillary dilation, constipation/diarrhea, urinary retention
• Axonal neuropathy - predominantly motor; can progress to flaccid quadriplegia, respiratory paralysis, facial palsy, dysphagia
• Psychiatric - agitation, hallucinations, depression, seizures (10-20%)

• Drugs: anticonvulsants (especially phenytoin, carbamazepine), griseofulvin, rifampin, sulfonamides, barbiturates, progesterone-containing agents
• Hormonal: menstrual cycle (luteal phase), pregnancy
• Dietary: fasting / crash dieting
• Other: infections, surgery, smoking

• Acute attack: elevated urinary PBG and δ-ALA (urine may appear red/brown)
• Between attacks: urinary PBG elevated in 88% of cases
• Erythrocyte PBG deaminase activity decreased
• Fecal and erythrocyte porphyrins normal (distinguishes from VP and HCP)

1. Remove triggers - stop offending drugs immediately
2. Carbohydrate loading - IV glucose ≥300 g/day (downregulates ALAS1); for mild attacks
3. IV hemin (heme arginate / Panhematin) - 3-4 mg/kg/day × 4 days; first-line for moderate-severe attacks; suppresses ALAS1 by replacing heme
4. Givosiran (Givlaari) - siRNA targeting hepatic ALAS1 mRNA; 2.5 mg/kg SC monthly; FDA/EMA approved 2019 for recurrent acute hepatic porphyrias
5. Symptomatic: phenothiazines (nausea/pain), opiates (analgesia), benzodiazepines (seizures - safe in low doses; avoid barbiturates/phenytoin)
6. GnRH analogue for luteal-phase attacks
7. Liver transplant - last resort for intractable, disabling attacks

Hereditary Coproporphyria (HCP)

• Enzyme: coproporphyrinogen oxidase deficiency (AD)
• Presents with neurovisceral attacks plus cutaneous blistering (in ~30% of cases)
• Fecal coproporphyrins and protoporphyrins always elevated - key diagnostic marker
• Treatment: same as AIP (hemin, glucose, givosiran); GnRH analogue for premenstrual attacks

Variegate Porphyria (VP) - "Mixed Porphyria"

• Enzyme: protoporphyrinogen oxidase deficiency (AD)
• High prevalence in South Africa (founder effect)
• 40-70% have skin symptoms; 27% have acute attacks; 14% have both
• Skin: blistering vesicles/bullae, hypertrichosis, hyperpigmentation, scarring on sun-exposed areas - resembles PCT
• Neurologic: identical to AIP during attacks
• Pathognomonic: plasma fluorescence peak at 626 nm
• Fecal coproporphyrins + protoporphyrins always elevated; urinary coproporphyrins > uroporphyrins (distinguishes from PCT)
• Increased risk of HCC; liver imaging after age 50
• Treatment: hemin and glucose for acute attacks; antimalarials and phlebotomy not effective for skin in VP

Cutaneous Porphyrias - Detailed

Porphyria Cutanea Tarda (PCT) - Most Common Porphyria

• Excess iron / HFE hemochromatosis gene mutations
• Alcohol
• Smoking
• Chronic hepatitis C (very strongly associated)
• HIV
• Estrogens (oral contraceptives, HRT)

• Skin fragility and blistering on sun-exposed areas (dorsa of hands most common)
• Milia, erosions, scarring
• Hypertrichosis (especially facial)
• Hyperpigmentation

• Urine: massively elevated uroporphyrins (8-carboxyl porphyrins) - "port wine" urine
• Plasma: elevated highly carboxylated porphyrins
• Stool: elevated isocoproporphyrins (pathognomonic)
• Erythrocyte porphyrins normal (distinguishes from EPP)

1. Remove susceptibility factors - abstain from alcohol, estrogens, smoking
2. Phlebotomy (300-450 mL every 2-4 weeks) - depletes iron; most reliable therapy; follow serum ferritin to target 15-20 ng/mL
3. Low-dose hydroxychloroquine (100-200 mg twice weekly) - chelates porphyrins and promotes urinary excretion; used when phlebotomy is contraindicated (e.g., anemia)
4. Treat underlying HCV or HIV

Congenital Erythropoietic Porphyria (CEP) - Günther Disease

• Enzyme: uroporphyrinogen III cosynthase (AR - severe deficiency)
• Presents from birth/infancy with:
  • Dark urine (red-pink)
  • Severe photosensitivity → vesicles, scarring, mutilation
  • Red fluorescence of teeth under Wood's lamp (erythrodontia)
  • Hypertrichosis
  • Hemolytic anemia
• Treatment: sun protection, blood transfusions; bone marrow transplantation is curative

Hepatoerythropoietic Porphyria (HEP)

• Homozygous form of PCT (homozygous UROD deficiency, ~10% of normal activity)
• Clinical features similar to CEP but biochemistry like PCT
• Bone marrow transplantation may be required

Erythropoietic Protoporphyria (EPP)

• Enzyme: ferrochelatase deficiency (AD with low penetrance; requires second low-expression allele)
• Non-blistering photosensitivity - burning, stinging pain within minutes of sun exposure; edema and erythema
• Liver disease in ~5% (protoporphyrin deposits in bile ducts)
• Diagnosis: elevated free protoporphyrin in erythrocytes; fecal protoporphyrin elevated
• Treatment: sun protection, beta-carotene (some benefit), afamelanotide (MC1R agonist, increases skin melanin)

X-Linked Protoporphyria (XLP)

• ALAS2 gain-of-function mutation → overproduction of protoporphyrin
• Clinically identical to EPP
• X-linked; predominantly males

Biochemical Diagnostic Summary

Safe vs. Unsafe Drugs in Acute Porphyrias

Key Clinical Pearls

• AIP: neurovisceral only, no skin, PBG massively elevated in urine during attacks
• PCT: most common, skin only, blistering on sun-exposed areas, responds to phlebotomy
• VP: "South African porphyria," combination of AIP + PCT features, plasma 626 nm fluorescence is pathognomonic
• EPP/XLP: non-blistering painful photosensitivity, elevated erythrocyte free protoporphyrin
• CEP: rare, most severe, erythrodontia, bone marrow transplant is curative
• Givosiran (2019): first siRNA therapy approved for recurrent acute hepatic porphyria
• All acute porphyria patients need annual liver surveillance after age 50 for HCC