Porphyrin Metabolism & Haem Synthesis

Haem is an iron–protoporphyrin IX complex that anchors haemoglobin, myoglobin, the cytochromes, catalase, peroxidase and nitric oxide synthase. This topic links a tightly regulated 8-step biosynthetic pathway to a clinically rich family of porphyrias and to bilirubin handling — a perennial NEET PG favourite where one enzyme defect predicts the entire clinical picture.

Definition & classification

A porphyrin is a cyclic tetrapyrrole — four pyrrole rings joined by methenyl (=CH–) bridges. When the central nitrogen atoms chelate a metal, you get a metalloporphyrin: iron gives haem, magnesium gives chlorophyll, cobalt gives the corrin ring of vitamin B12. The biologically relevant isomer in humans is type III (asymmetric substitution), produced because uroporphyrinogen III cosynthase flips ring D.

Porphyrias are classified two ways, and examiners love both axes:

Axis	Categories	Basis
Site of overproduction	Hepatic vs Erythropoietic	Where the enzyme block accumulates intermediates
Clinical presentation	Acute (neurovisceral) vs Cutaneous (photosensitive)	Whether porphyrin precursors (ALA, PBG) or porphyrins accumulate

High-yield: Accumulation of the colourless precursors ALA and porphobilinogen (PBG) → neurovisceral/acute attacks. Accumulation of the coloured porphyrins (uro-, copro-, proto-) → photosensitivity. This single rule lets you predict whether a porphyria presents with abdominal pain or with skin blisters.

The haem biosynthetic pathway — 8 steps

Haem synthesis is mitochondrial at both ends and cytosolic in the middle. The first and last three steps occur in mitochondria; steps 2–5 are cytosolic. About 85% occurs in erythroid precursors (bone marrow), the rest mainly in the liver.

Glycine + succinyl-CoA → δ-ALA → PBG → HMB → uroporphyrinogen III → coproporphyrinogen III → protoporphyrinogen IX → protoporphyrin IX → HAEM (+ Fe²⁺)

1. ALA synthase (ALAS) — mitochondria. Condenses glycine + succinyl-CoA → δ-aminolaevulinic acid (ALA). Rate-limiting / committed step. Requires pyridoxal phosphate (vitamin B6) as cofactor.
2. ALA dehydratase (PBG synthase / porphobilinogen synthase) — cytosol. 2 ALA → one porphobilinogen. A zinc-dependent enzyme, inhibited by lead.
3. PBG deaminase (hydroxymethylbilane synthase, HMB synthase / uroporphyrinogen I synthase) — cytosol. 4 PBG → linear hydroxymethylbilane. Deficient in Acute Intermittent Porphyria.
4. Uroporphyrinogen III cosynthase — cytosol. Cyclises HMB into the asymmetric uroporphyrinogen III. Deficient in Congenital Erythropoietic Porphyria.
5. Uroporphyrinogen decarboxylase (UROD) — cytosol. → Coproporphyrinogen III. Deficient in Porphyria Cutanea Tarda.
6. Coproporphyrinogen oxidase — mitochondria → protoporphyrinogen IX (Hereditary Coproporphyria).
7. Protoporphyrinogen oxidase — mitochondria → protoporphyrin IX (Variegate Porphyria).
8. Ferrochelatase (haem synthase) — mitochondria. Inserts Fe²⁺ into protoporphyrin IX → haem. Also inhibited by lead. Deficient in Erythropoietic Protoporphyria.

High-yield: The two enzymes inhibited by lead are ALA dehydratase and ferrochelatase — both involving the early and final steps. Lead poisoning therefore raises ALA, urinary coproporphyrin, and zinc protoporphyrin (ZPP), while ferrochelatase block causes basophilic stippling of RBCs.

Mnemonic (committed → final): "Glycine ALAs PBG, HMB Urges Copros to Protect Protoporphyrin's Haem" — Glycine, ALA, PBG, HMB, Uro'gen III, Copro'gen III, Proto'gen IX, Protoporphyrin IX, Haem.

Regulation of ALA synthase

ALAS exists as two isoforms — ALAS1 (hepatic, ubiquitous) and ALAS2 (erythroid-specific) — and their control is a classic exam discriminator.

Feature	Hepatic ALAS1	Erythroid ALAS2
Main regulator	Haem (negative feedback)	Iron availability (via IRE/IRP on mRNA)
Repressed by	Haem ↓ transcription, ↓ mitochondrial import, ↓ mRNA stability	Low iron represses translation
Induced by	Drugs that induce CYP450 (barbiturates, rifampicin, phenytoin, oestrogens, ethanol), fasting	Erythropoietin demand
Loss-of-function defect	—	X-linked sideroblastic anaemia (ALAS2 mutation)

High-yield: In acute hepatic porphyrias, CYP450-inducing drugs (barbiturates, sulfonamides, oestrogen, anticonvulsants), fasting, infection, and alcohol consume hepatic haem, de-repressing ALAS1, which floods the blocked pathway with ALA/PBG and precipitates an acute attack. Glucose/carbohydrate loading and intravenous haem (haem arginate) suppress ALAS1 and abort the attack.

The porphyrias — enzyme defects you must memorise

Porphyria	Deficient enzyme	Type	Acute?	Photosensitive?	Hallmark
ALA dehydratase deficiency (plumboporphyria)	ALA dehydratase	Hepatic	Yes	No	↑↑ ALA only; mimics lead poisoning
Acute Intermittent Porphyria (AIP)	PBG deaminase (HMB synthase)	Hepatic	Yes	No	Most common acute porphyria; ↑ALA, ↑PBG
Congenital Erythropoietic Porphyria (CEP / Günther disease)	Uroporphyrinogen III cosynthase	Erythropoietic	No	Severe	Red urine, red teeth (erythrodontia), haemolysis, hypertrichosis
Porphyria Cutanea Tarda (PCT)	Uroporphyrinogen decarboxylase (UROD)	Hepatic	No	Yes	Most common porphyria overall; chronic blistering
Hereditary Coproporphyria (HCP)	Coproporphyrinogen oxidase	Hepatic	Yes	Yes (mild)	Mixed picture
Variegate Porphyria (VP)	Protoporphyrinogen oxidase	Hepatic	Yes	Yes	"Mixed"; South African Dutch founder effect
Erythropoietic Protoporphyria (EPP)	Ferrochelatase	Erythropoietic	No	Yes (painful, non-blistering)	↑ protoporphyrin; risk of liver failure

Most porphyrias are autosomal dominant (AIP, PCT, HCP, VP, EPP). CEP and ALA-dehydratase deficiency are autosomal recessive.

High-yield: AIP = most common ACUTE porphyria; PCT = most common porphyria of ANY type. Do not confuse the two — AIP has no skin lesions, PCT has no acute attacks.

Acute Intermittent Porphyria (the most tested)

• Defect: PBG deaminase, autosomal dominant, low penetrance; precipitated by drugs/fasting/hormones.
• Classic "5 P's": Painful abdomen, Polyneuropathy, Psychiatric disturbance, Port-wine urine, Precipitated by drugs.
• The abdominal pain is severe, colicky, with NO peritoneal signs and a soft, non-tender abdomen — a clue against a surgical abdomen.
• Hyponatraemia (SIADH), tachycardia, hypertension, and motor-predominant neuropathy are common.
• Urine darkens on standing/light exposure as PBG polymerises to porphobilin (turns port-wine colour) — but no photosensitivity because precursors, not porphyrins, accumulate.

Porphyria Cutanea Tarda

• Defect: UROD; the most common, often sporadic (type I) and associated with hepatitis C, HIV, alcohol, oestrogens, and iron overload/haemochromatosis (HFE mutations).
• Photosensitive blistering, skin fragility, hyperpigmentation, hypertrichosis on sun-exposed areas; urine fluoresces coral-pink/red under Wood's lamp.
• Management: phlebotomy (to remove iron), low-dose hydroxychloroquine, sun avoidance, and treating hepatitis C.

Diagnosis & investigation of choice

Approach to a suspected acute attack:

Clinical suspicion (unexplained abdominal pain + neuro/psychiatric signs) → spot urine for PBG/ALA (screening) → quantitative urinary PBG (confirmatory) → fractionate porphyrins (urine, stool, plasma) to subtype → enzyme assay / genetic testing for definitive diagnosis.

1. Screening: Watson–Schwartz test (Ehrlich's aldehyde reagent → red colour with PBG, not extracted into chloroform/butanol). Largely superseded by quantitative assays.
2. Investigation of choice (acute attack): Quantitative urinary porphobilinogen (PBG) — markedly raised during an attack of AIP, HCP and VP.
3. Subtyping: Plasma fluorescence emission scan distinguishes VP (peak ~626 nm) from others; stool porphyrins are high in VP and HCP, normal in AIP.
4. PCT: elevated urinary uroporphyrin and 7-carboxylate porphyrin; the ratio of uro- to coproporphyrin differentiates from VP.
5. EPP: elevated free erythrocyte protoporphyrin (RBC protoporphyrin).

Disorder	Urine ALA/PBG	Urine porphyrins	Stool porphyrins	RBC porphyrin
AIP	↑↑ both	↑ (uro)	Normal	Normal
PCT	Normal	↑ uroporphyrin	Iso/coproporphyrin	Normal
VP	↑ during attack	↑ copro	↑↑ proto + copro	Normal
EPP	Normal	Normal	↑ proto	↑↑ protoporphyrin
Lead poisoning	↑ ALA	↑ coproporphyrin	Normal	↑ ZPP

High-yield: Quantitative urinary PBG is the single best test during an acute neurovisceral attack. A normal PBG during a symptomatic attack effectively excludes AIP, HCP and VP.

Management / drug of choice

Acute attack (AIP/HCP/VP):

• Stop all precipitating drugs; treat infection.
• Intravenous haem (haem arginate / haematin) is the definitive drug of choice — it replenishes the regulatory haem pool and switches off ALAS1.
• High-dose carbohydrate (IV 10% dextrose, ≥300 g glucose/day) for milder attacks ("glucose effect").
• Symptomatic: opioids for pain, beta-blockers for tachycardia/hypertension, phenothiazines for nausea/agitation; treat hyponatraemia carefully.
• Seizures are tricky — most anticonvulsants are porphyrinogenic; gabapentin and levetiracetam are considered safe.
• Givosiran (an siRNA that knocks down hepatic ALAS1) is a newer agent for recurrent attacks.

Safe vs unsafe drugs:

Generally UNSAFE (porphyrinogenic)	Generally SAFE
Barbiturates, sulfonamides, griseofulvin	Opioids (morphine, pethidine)
Phenytoin, carbamazepine, valproate	Gabapentin, levetiracetam
Oestrogens/progestogens, oral contraceptives	Paracetamol, aspirin
Rifampicin, ergot alkaloids, alcohol	Penicillins, propranolol, glucose

Bilirubin: catabolism, conjugation & excretion

Haem catabolism is the mirror image of synthesis and is tested alongside it.

RBC senescence (reticuloendothelial macrophages) → haem oxygenase opens the ring (releases CO + Fe²⁺) → biliverdin → biliverdin reductase → unconjugated bilirubin → albumin-bound transport to liver → UGT1A1 conjugation with glucuronic acid → conjugated bilirubin → bile → gut bacteria → urobilinogen → stercobilin (faeces) / urobilin (urine).

• Haem oxygenase is the rate-limiting catabolic enzyme; CO release makes this the body's main endogenous CO source. Biliverdin (green) → bilirubin (yellow-orange) explains bruise colour change.
• Unconjugated (indirect) bilirubin is lipid-soluble, albumin-bound, not excreted in urine, and neurotoxic (kernicterus) when it exceeds albumin binding in neonates.
• Conjugated (direct) bilirubin is water-soluble and appears in urine when raised.

Type of jaundice	Unconjugated	Conjugated	Urine bilirubin	Urine urobilinogen
Prehepatic (haemolytic)	↑↑	Normal	Absent	↑↑
Hepatic	↑	↑	Present	Variable
Posthepatic (obstructive)	Normal	↑↑	Present (dark urine)	↓/absent (pale stool)

Inherited hyperbilirubinaemias:

Disorder	Defect	Bilirubin type	Note
Gilbert syndrome	↓ UGT1A1 (mild)	Unconjugated	Common, benign; worse with fasting/stress
Crigler-Najjar type I	Absent UGT1A1	Unconjugated	Fatal kernicterus; needs liver transplant
Crigler-Najjar type II	↓↓ UGT1A1	Unconjugated	Responds to phenobarbitone
Dubin-Johnson	MRP2/ABCC2 (canalicular export)	Conjugated	Black liver; benign
Rotor syndrome	OATP1B1/1B3 reuptake	Conjugated	Normal-coloured liver

High-yield: Unconjugated > 25 mg/dL or rapidly rising risks kernicterus in neonates. Phototherapy converts bilirubin to water-soluble lumirubin (structural isomerisation) for excretion without conjugation.

Complications

• AIP: chronic neuropathy, recurrent attacks, hepatocellular carcinoma risk, chronic hypertension and renal impairment.
• CEP (Günther): transfusion-dependent haemolytic anaemia, mutilating photodermatitis, splenomegaly.
• PCT & EPP: EPP can cause protoporphyrin-induced cholestatic liver failure (a transplant indication); PCT carries hepatoma risk via associated liver disease.
• Lead poisoning: microcytic anaemia with basophilic stippling, encephalopathy, Burton's line on gums, peripheral (wrist/foot drop) neuropathy.

Key differentials

• Acute abdomen of AIP vs surgical abdomen, lead colic, and other causes of abdominal pain with neuropathy (e.g., arsenic, thallium). The soft non-tender abdomen + dark urine + hyponatraemia points to porphyria.
• Lead poisoning vs ALA-dehydratase porphyria — biochemically near-identical (↑ALA, ↑coproporphyrin, ↑ZPP); a blood lead level distinguishes them.
• Photosensitive blistering of PCT vs pseudoporphyria (drug-induced, normal porphyrins) and vs the painful non-blistering photosensitivity of EPP.

Recently asked / exam angle

• Rate-limiting enzyme of haem synthesis = ALA synthase; cofactor = pyridoxal phosphate (B6) — repeatedly asked single-best-answer.
• Enzyme deficient in AIP = PBG deaminase (HMB synthase) and in PCT = uroporphyrinogen decarboxylase — direct one-liners.
• Two enzymes inhibited by lead = ALA dehydratase + ferrochelatase.
• Which porphyria is both acute and photosensitive? → Variegate porphyria (and HCP).
• Investigation of choice in acute attack = urinary PBG; drug of choice = IV haem/haematin; newer drug = givosiran.
• Site of haem synthesis = mitochondria + cytosol (first & last 3 steps mitochondrial).
• Endogenous source of CO = haem oxygenase reaction.
• Bilirubin metabolism crossover: Crigler-Najjar II responds to phenobarbitone; type I needs transplant; Dubin-Johnson = black liver, conjugated.
• X-linked sideroblastic anaemia = ALAS2 mutation, B6-responsive.

Rapid revision

1. ALA synthase = rate-limiting, mitochondrial, needs vitamin B6; feedback-inhibited by haem.
2. Haem synthesis: first 3 + last 3 steps mitochondrial; middle steps cytosolic.
3. Precursors (ALA, PBG) accumulate → neurovisceral attacks; porphyrins accumulate → photosensitivity.
4. AIP = PBG deaminase deficiency = most common acute porphyria, no skin signs, autosomal dominant.
5. PCT = UROD deficiency = most common porphyria overall, linked to hepatitis C / iron / alcohol; treat with phlebotomy + hydroxychloroquine.
6. CEP (Günther) = uroporphyrinogen III cosynthase, autosomal recessive, erythrodontia + red urine.
7. EPP = ferrochelatase deficiency, painful non-blistering photosensitivity, ↑ RBC protoporphyrin, liver failure risk.
8. Variegate porphyria & HCP = both acute AND photosensitive ("mixed").
9. Lead inhibits ALA dehydratase + ferrochelatase → basophilic stippling, ↑ZPP, Burton's line.
10. Acute attack: stop offending drug, give IV dextrose then IV haem arginate; safe anticonvulsants = gabapentin, levetiracetam; givosiran for recurrent attacks.
11. Investigation of choice in acute attack = quantitative urinary PBG (Watson–Schwartz screen).
12. Bilirubin: unconjugated = indirect, albumin-bound, neurotoxic, not in urine; conjugated = direct, water-soluble, in urine; Crigler-Najjar II responds to phenobarbitone.