STEPTRACKERBIOCHEMISTRY + HEMATOLOGY + TOXICOLOGY | AMINO ACID METABOLISM | HIGH-YIELD REVIEW

Heme Synthesis & Porphyrias

Glycine + succinyl-CoA becomes heme in a mitochondria → cytosol → mitochondria loop; block a step and porphyrins spill into urine, skin or nerves.

FOCUS ON

ALA synthase (mitochondria, B6) is rate-limiting; heme and glucose repress it. Lead inhibits ALA dehydratase and ferrochelatase → microcytic anemia, basophilic stippling. Acute intermittent porphyria (porphobilinogen deaminase): 5 Ps — Painful abdomen, Port-wine urine, Polyneuropathy, Psychological disturbance, Precipitated by drugs (CYP inducers), alcohol, starvation. Porphyria cutanea tarda (uroporphyrinogen decarboxylase): blistering photosensitive skin, most common.

STEP · DISORDER

ENZYME · LOCATION

BUILDUP · FEATURES

CLUE · TREATMENT

Step 1

rate-limiting

ALA synthase (B6) · mitochondria: glycine + succinyl-CoA → δ-ALA

X-linked mutation → sideroblastic anemia

Inhibited by heme, glucose; induced by CYP inducers

Step 2

ALA dehydratase · cytosol: 2 ALA → porphobilinogen

Inhibited by lead

↑ ALA in urine with lead

Step 3 — AIP

Porphobilinogen deaminase (HMBS) · cytosol

↑ ALA, ↑ PBG: abdominal pain, red/port-wine urine (darkens in light), neuropathy, psychosis, tachycardia, hyponatremia; no photosensitivity

Triggers: barbiturates, griseofulvin, rifampin, alcohol, fasting, OCPs · treat with hemin and glucose (↓ ALA synthase), givosiran

Step 5 — PCT

most common porphyria

Uroporphyrinogen decarboxylase · cytosol

↑ Uroporphyrin: blistering photosensitive skin on hands, fragility, hyperpigmentation, hypertrichosis; tea-colored urine

Triggers: HCV, alcohol, iron overload, estrogen, HIV · phlebotomy, low-dose hydroxychloroquine

Final step

Ferrochelatase · mitochondria: protoporphyrin + Fe²⁺ → heme

Inhibited by lead → ↑ protoporphyrin (zinc protoporphyrin)

Erythropoietic protoporphyria: painful photosensitivity, no blisters

Lead poisoning

Inhibits ALA dehydratase + ferrochelatase

Microcytic anemia with basophilic stippling, ringed sideroblasts, abdominal colic, neuropathy (wrist/foot drop), encephalopathy, Burton (gum) lines, lead lines on bone films

Old paint, batteries, pipes · chelate: succimer (kids, mild), dimercaprol + EDTA (severe)

Iron deficiency (contrast)

No iron for ferrochelatase

↑ Free protoporphyrin, microcytic anemia, no stippling

↓ Ferritin

Heme breakdown

Heme oxygenase → biliverdin (+ CO, Fe) → biliverdin reductase → unconjugated bilirubin → liver conjugation (UGT)

Bilirubin disorders: Gilbert, Crigler-Najjar, Dubin-Johnson, Rotor

Only endogenous source of CO

Picture it — heme synthesis and the porphyrias

Heme synthesisFirst and last steps in mitochondria, the middle in cytosol. Red labels mark the enzyme behind each disease: ALAS (sideroblastic anemia), ALA dehydratase and ferrochelatase (lead), PBG deaminase (AIP), UROD (PCT).

Schematic diagrams, not to scale.

Mechanism — heme synthesis loop

MitochondriaGlycine + succinyl-CoA → ALA (ALA synthase, B6)

→

CytosolALA → PBG (ALA dehydratase; lead) → HMB (PBG deaminase; AIP) → uroporphyrinogen → coproporphyrinogen (UROD; PCT)

→

Mitochondria→ protoporphyrin → heme (ferrochelatase; lead)

Heme feeds back to repress ALA synthase — that's why hemin and glucose abort AIP attacks.

AIP vs PCT vs lead

FEATURE

AIP

PCT

LEAD

Enzyme

PBG deaminase

UROD

ALA DH, ferrochelatase

Skin

Normal

Blisters

—

Neuro / abdomen

Yes

Urine

↑ PBG, ALA

↑ Uroporphyrin

↑ ALA

Anemia

Microcytic, stippled

How it's tested

COMMON CONFUSIONAIP gives neurovisceral attacks without skin findings; PCT gives skin findings without attacks. Porphyrins after the step that makes rings (uroporphyrinogen) cause photosensitivity.

THE TRAPGiving a barbiturate to a young woman with abdominal pain, psychosis and dark urine can precipitate a fatal AIP attack.

YOUR APPROACHSkin vs neurovisceral vs anemia → which porphyrin rises → enzyme → trigger and treatment.

If you see… think…

Rate-limiting enzyme of heme synthesis → ALA synthase (B6)

Abdominal pain, dark urine, psychosis after barbiturates → acute intermittent porphyria

Treatment of an AIP attack → hemin + glucose

Blistering on the back of the hands in a patient with hepatitis C → porphyria cutanea tarda

Child with microcytic anemia, basophilic stippling, abdominal colic → lead poisoning

Enzymes inhibited by lead → ALA dehydratase, ferrochelatase

Wrist drop and gum lines in a battery worker → lead neuropathy

Mild pediatric lead poisoning chelator → succimer

X-linked sideroblastic anemia → ALA synthase defect (B6-responsive)

Painful photosensitivity without blisters → erythropoietic protoporphyria