STEPTRACKERHEMATOLOGY | PATHOLOGY + BIOCHEMISTRY | HIGH-YIELD REVIEW

Sideroblastic Anemia & Lead Poisoning

Heme synthesis breaks down: iron arrives but can't be built into protoporphyrin — plus the porphyrias that share this pathway.

FOCUS ON
Ring sideroblasts are iron trapped in mitochondria around the nucleus, and the iron panel looks overloaded. Lead blocks ALA dehydratase and ferrochelatase and causes coarse basophilic stippling. Treat B6-related causes with pyridoxine. AIP vs PCT is the classic porphyria pair.
TOPIC
DETAIL
MECHANISM
CLUE · TREATMENT
Sideroblastic anemia
definition
Protoporphyrin can't be made → iron piles up in erythroblast mitochondria.
Ringed sideroblasts on Prussian blue marrow stain; usually microcytic
↑ ferritin, ↑ iron, ↑ % saturation, normal/↓ TIBC
Congenital form
ALAS2 defect (rate-limiting enzyme), X-linked.
Low ALA production
Boys; many respond to pyridoxine (B6)
Acquired forms
Alcohol (mitochondrial toxin), lead, B6 deficiency (isoniazid), copper deficiency, excess zinc.
Reversible once removed
Give B6 with isoniazid
MDS with ring sideroblasts
Clonal marrow disorder in older adults.
SF3B1 splicing mutation
Refractory anemia, may be macrocytic
Lead — mechanism
Inhibits ALA dehydratase and ferrochelatase; blocks rRNA degradation.
↑ ALA, ↑ zinc/free protoporphyrin; coarse basophilic stippling
Microcytic anemia
Lead — children
Old paint chips and dust (homes before 1978), pica.
Cognitive and developmental delay, abdominal colic, lead lines at metaphyses
Mild: succimer · severe/encephalopathy: dimercaprol + CaNa₂EDTA
Lead — adults
Batteries, smelting, ammunition, radiator repair, ceramics.
Headache, memory loss, wrist/foot drop (motor neuropathy), gingival lead (Burton) lines, nephropathy, hypertension, gout
Remove the source; chelate
Acute intermittent porphyria
hepatic, AD
Porphobilinogen deaminase (HMB synthase) deficiency → ALA and PBG build up.
Attacks: abdominal pain, neuropsychiatric symptoms, neuropathy, port-wine urine
Triggers: P450 inducers, alcohol, fasting · glucose and hemin (↓ ALAS)
Porphyria cutanea tarda
most common porphyria
Uroporphyrinogen decarboxylase deficiency → uroporphyrins in skin.
Blisters on sun-exposed skin, hypertrichosis, tea-colored urine
Associated with HCV, alcohol, iron · phlebotomy, hydroxychloroquine

Mechanism — the heme pathway and its blocks

Succinyl-CoA + glycineALAS (B6) — sideroblastic
→
ALAALA dehydratase — lead
→
PBGPBG deaminase — AIP
→
UroporphyrinogenUROD — PCT
→
Protoporphyrin + Fe²⁺Ferrochelatase — lead
→
HemeFeeds back on ALAS

First and last steps happen in mitochondria, which is why trapped iron rings the nucleus.

Telling them apart

CONDITION
BLOCKED ENZYME
KEY LAB
Lead poisoning
ALA dehydratase, ferrochelatase
↑ blood lead, ↑ ZPP, basophilic stippling
Sideroblastic anemia
ALAS (or downstream)
Ring sideroblasts, iron overload pattern
Acute intermittent porphyria
PBG deaminase
↑ urine PBG and ALA during attacks
Porphyria cutanea tarda
UROD
↑ urine uroporphyrin
Iron deficiency
None — no iron
↓ ferritin; ZPP also ↑

How it's tested

COMMON CONFUSIONSideroblastic anemia is microcytic like iron deficiency, but its iron studies show overload: ferritin and saturation are high.
THE TRAPEpisodic abdominal pain and confusion with a normal abdominal exam after starting a barbiturate is AIP. Surgery is the wrong answer; hemin and glucose are right.
YOUR APPROACHPlace the abnormality on the heme pathway. Exposure history (paint, batteries, isoniazid, alcohol) usually names the culprit.

If you see… think…

Child in an old house, pica, colic, coarse basophilic stippling → lead poisoning
Battery worker with wrist drop and gum lines → lead neuropathy
Ringed sideroblasts on Prussian blue stain → sideroblastic anemia
On isoniazid without B6, microcytic anemia → B6-deficient sideroblastic anemia
Heavy drinker, microcytic anemia, high ferritin → alcohol-induced sideroblastic anemia
Older adult with refractory anemia and SF3B1 → MDS with ring sideroblasts
Abdominal pain + psychosis + dark urine after a barbiturate → AIP — hemin, glucose
Blisters on hands, HCV, hypertrichosis → porphyria cutanea tarda
Very high lead level with encephalopathy → dimercaprol + EDTA