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Quick-Revision Summary Table

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How to Use These Notes for Exam

• Menkes = ATP7A, X-linked, Cu deficiency (kinky hair, neurodegeneration)
• Wilson's = ATP7B, AR, Cu accumulation (KF rings, liver disease)
• AIP = PBG deaminase deficiency → ↑ ALA+PBG → no photosensitivity
• PCT = Uroporphyrinogen decarboxylase → photosensitivity, most common porphyria
• Sickle cell = Glu→Val at β-6 → HbS polymerizes when deoxygenated
• β-thal major = ↑ HbA₂ (> 3.5%) on electrophoresis
• Homocystinuria = lens dislocation downward (Marfan's = upward)
• Hartnup = neutral AA transporter → pellagra + ataxia; treat with nicotinamide
• Carcinoid = ↑ urinary 5-HIAA; flushing + diarrhea + right heart valve disease
• Folate trap = B12 deficiency traps folate as 5-methyl-THF → megaloblastic anemia

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PORPHYRIAS — Complete Study Notes

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Definition

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Heme Synthesis Pathway — Full Sequence

Step 1: Glycine + Succinyl-CoA → δ-ALA              [ALAS; MIT; rate-limiting; PLP cofactor]
Step 2: 2× ALA → Porphobilinogen (PBG)               [ALA dehydratase = ALAD; CYT; inhibited by LEAD]
Step 3: 4× PBG → Hydroxymethylbilane (HMB)          [HMB synthase = PBG deaminase; CYT]
Step 4: HMB → Uroporphyrinogen III                   [URO synthase; CYT]
Step 5: Uroporphyrinogen III → Coproporphyrinogen III [URO decarboxylase = UROD; CYT]
Step 6: Coproporphyrinogen III → Protoporphyrinogen IX [COPRO oxidase; MIT]
Step 7: Protoporphyrinogen IX → Protoporphyrin IX    [PROTO oxidase = PPOX; MIT]
Step 8: Protoporphyrin IX + Fe²⁺ → HEME             [Ferrochelatase = FECH; MIT; inhibited by LEAD]

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Classification

Two main axes:

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Master Classification Table

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Lab Patterns (Urine/Stool/RBC Accumulations)

• AIP: ↑↑ urine PBG (Watson-Schwartz test turns red) — most important
• PCT: ↑ urine uroporphyrin + isocoproporphyrin in stool (pathognomonic)
• VP: ↑ stool protoporphyrin IX + plasma fluorescence at 624–628 nm (distinguishes from AIP)
• EPP: ↑ RBC free protoporphyrin (metal-free); NO urine changes

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Individual Porphyrias — Detailed

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1. Acute Intermittent Porphyria (AIP)

Pathogenesis:

• ALA synthase-1 (ALAS1) induced by triggers → ↑ flux through pathway
• HMB synthase deficiency → ALA and PBG accumulate
• ALA is neurotoxic (structural analog of GABA → neuronal damage)

Precipitants ("PABCD FASTING"):

• Physical stress (infection, surgery)
• Alcohol
• Barbiturates, anticonvulsants (phenytoin, carbamazepine)
• Carbamazepine, sulfonamides, rifampicin, griseofulvin, OCP
• Diet — fasting/low carbohydrate (↑ ALAS1)
• Hormones (progesterone — explains female predominance in reproductive age)

Clinical Features (Triad):

1. Abdominal pain — most common; severe, colicky; no peritoneal signs
2. Neuropsychiatric: anxiety, psychosis, depression, confusion, seizures
3. Peripheral neuropathy: motor > sensory; ascending weakness → may → respiratory paralysis

Diagnosis:

• Spot urine PBG (during attack) — elevated ↑↑ → most rapid and specific test
• Watson-Schwartz test: urine PBG + Ehrlich reagent (p-dimethylaminobenzaldehyde) → red colour (PBG doesn't extract into butanol — distinguishes from urobilinogen)
• ↑ ALA in urine
• HMBS mutation analysis for family screening

Treatment:

1. Remove/avoid precipitants
2. IV Hemin (heme arginate) — exogenous heme → feedback inhibits ALAS1 → ↓ ALA/PBG; mainstay of treatment
3. IV Glucose (300–500 g/day) — carbohydrate loading → inhibits ALAS1 via PGC-1α
4. Pain management (opioids safe); propranolol for tachycardia/hypertension
5. Seizures → benzodiazepines (safe); avoid phenytoin

• Avoid precipitants
• Givosiran (Alnylam, 2019) — siRNA targeting ALAS1 mRNA in hepatocytes → ↓ ALAS1 → ↓ ALA/PBG; monthly SC injection; major advance for recurrent AIP

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2. Porphyria Cutanea Tarda (PCT)

Pathogenesis:

• UROD inhibited (not mutated in Type I) → uroporphyrins accumulate in liver → skin → react with UV light → reactive oxygen species → skin damage

Risk factors/triggers:

• Alcohol (↑ iron + UROD inhibition)
• Hepatitis C (most important association)
• Iron overload (HFE mutations — C282Y common co-factor)
• Estrogens (OCP, HRT)
• HIV
• Chlorinated hydrocarbons (industrial exposure)

Clinical Features:

• Skin fragility and blistering on sun-exposed areas (dorsum of hands, face)
• Milia (small white cysts) at sites of healed blisters
• Hypertrichosis (excess facial hair — especially temples)
• Hyperpigmentation (brownish)
• No acute neurovisceral attacks
• Liver disease (associated hepatitis C/cirrhosis)

Diagnosis:

• ↑ Urine uroporphyrin (predominantly) and 7-carboxylate porphyrin
• ↑ Stool isocoproporphyrin (pathognomonic for PCT)
• Urine PBG/ALA: normal (distinguishes from acute porphyrias)
• Skin biopsy: subepidermal blistering; DIF: IgG + C3 at DEJ

Treatment:

1. Avoid triggers: Stop alcohol, iron supplementation, estrogens
2. Phlebotomy (weekly; remove 450 mL blood) — depletes iron, most effective long-term
3. Low-dose hydroxychloroquine/chloroquine — chelates uroporphyrin from liver; for those who can't tolerate phlebotomy
4. Treat Hepatitis C (antiviral therapy → remission of PCT)
5. Sun protection

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3. Hereditary Coproporphyria (HCP)

• Clinical picture similar to AIP but milder
• Skin lesions (blistering) appear during/after attacks
• Distinguishing lab: ↑ stool coproporphyrin III (copro-III/I ratio elevated)
• Treatment: same as AIP (hemin + glucose)

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4. Variegate Porphyria (VP)

• "Variegate" = variable — can present with neurovisceral, skin, or both
• Distinguishing feature: Plasma fluorescence emission peak at 624–628 nm (specific for VP; AIP peaks at 615–622 nm)
• ↑ Stool protoporphyrin IX + coproporphyrin III
• Treatment: same as AIP; avoid precipitants

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5. Congenital Erythropoietic Porphyria (CEP) — Günther's Disease

Clinical Features (severe, from infancy):

• Pink/red urine in diapers (first sign — uroporphyrin I)
• Severe photosensitivity: blistering, scarring, mutilation of face/hands
• Fluorescent teeth (erythrodontia) — pinkish-red under UV (Woods lamp)
• Hypertrichosis of face/extremities
• Hemolytic anemia with splenomegaly
• No neurovisceral attacks

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6. Erythropoietic Protoporphyria (EPP)

Clinical Features:

• Acute painful photosensitivity — burning, stinging, edema within minutes of sun exposure
• No blisters (distinguishes from other cutaneous porphyrias — immediate/acute type)
• Mild chronic skin changes over time
• Liver disease (protoporphyrin is insoluble → cholestasis → biliary cirrhosis in ~5%)
• Gallstones (protoporphyrin)
• Mild hemolytic anemia
• No neurovisceral attacks

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7. ALA Dehydratase Deficiency Porphyria (ADP)

• Rarest porphyria (< 10 cases worldwide)
• ALAD deficiency (same enzyme inhibited by lead)
• AR; severe neonatal/childhood onset
• Neurovisceral only (↑ ALA, coproporphyrin III in urine)

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Comparison: Acute vs Cutaneous — Key Exam Points

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Precipitants of Acute Porphyria — Must Know

• Carbohydrate low (fasting)
• Alcohol
• Stress (infection, surgery)
• Estrogens/progestogens
• Phenytoin, Phenobarbital
• Halothane, hydantoins
• Isoniazid
• Sulfonamides
• Progesterone (explains female preponderance)
• Sexual hormones, rifampicin

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Mnemonic: PORPHYRIA in AIP

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Quick Comparison Table — All 7 Porphyrias

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Watson-Schwartz Test

• PBG (AIP) → Red colour, does NOT extract into butanol or chloroform
• Urobilinogen → Red colour, DOES extract into butanol (moves to organic layer)
• This extraction step differentiates AIP from normal urobilinogen

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