WBR0345
| Author | [[PageAuthor::Yazan Daaboul, M.D. (Reviewed by Yazan Daaboul, M.D. and Alison Leibowitz [1])]] |
|---|---|
| Exam Type | ExamType::USMLE Step 1 |
| Main Category | MainCategory::Pathophysiology |
| Sub Category | SubCategory::Hematology |
| Prompt | [[Prompt::A 2-year-old boy is brought by his mother to the physician's office for delayed speech. The mother explains that the patient is irritable and unusually hyperactive unlike his siblings his age. Further questioning reveals that the patient's family lives in an old house with chipped paint. Physical examination is remarkable for pallor. Complete blood count (CBC) demonstrates hemoglobin levels of 9.2 g/dL and MCV: 68 fl. A peripheral smear of the patient's blood displays basophilic stippling. Based on the simplified diagram of heme synthesis demonstrated below, which of the following steps is most likely inhibited in this patient?
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| Answer A | AnswerA::A |
| Answer A Explanation | AnswerAExp::"A" corresponds to ALA-synthase. ALA-synthase is inhibited by B6 deficiency and in hereditary conditions (e.g. X-linked ALA-synthase deficiency). |
| Answer B | AnswerB::B |
| Answer B Explanation | AnswerBExp::"B" corresponds to ALA dehydratase. Lead inhibits ALA dehydratase and ferrochelatase of the heme synthesis pathway. |
| Answer C | AnswerC::C |
| Answer C Explanation | AnswerCExp::"C" corresponds to porphobilinogen deaminase. Deficiency of this enzyme typically causes acute intermittent porphyria. |
| Answer D | AnswerD::D |
| Answer D Explanation | [[AnswerDExp::"D" corresponds to uroporphyrinogen III synthase. Uroporphyrinogen III synthase deficiency is associated with Gunther disease (congenital erythropoietic porphyria)]] |
| Answer E | AnswerE::E |
| Answer E Explanation | AnswerEExp::"E" corresponds to uroporphyrinogen decarboxylase, which is typically deficient in porphyria cutanea tarda. |
| Right Answer | RightAnswer::B |
| Explanation | [[Explanation::Lead poisoning is a disease that occurs secondary to chronic exposure to lead-based paint flakes in old residencies. Other environmental or occupational sources of lead are chronic exposure to manufacturing or recycling of automobile batteries, lead smelting plant, lead-containing gasoline, and moonshine whiskey that is made in lead stills. Lead is readily absorbed through the respiratory tract and is incorporated into the bone. Lead competes with calcium and causes impaired remodeling of cartilage and trabecular bone in the epiphyses. It is detected as radiodense lead lines. Central nervous system disturbances that manifest as loss of short-term memory, delayed development, behavioral changes, or hearing impairment, are more common among children due to the relatively permeable blood-brain barrier, whereas demyelinating peripheral neuropathies (e.g. wrist or foot drop) predominate among adult patients. Additional findings of lead intoxication include abdominal pain and tubulointerstitial nephritis. Two important diagnostic clues for lead toxicity during work-up are the presence of microcytic hypochromic anemia (low hemoglobin count and low MCV) and basophilic stippling on peripheral blood smear, which represents precipitated ribosomes in reticulocytes. The diagnosis is confirmed with the detection of elevated serum concentration of lead (blood lead levels or BLL) and protoporphyrin.
In the heme biosynthesis pathway, lead inhibits the activity of 5-aminolevulinate (ALA) dehydratase, which converts ALA into porphobilinogen in the cytoplasm, and ferrochelatase, which incorporates the ferrous iron into protoporphyrin IX in the mitochondria. In addition, lead is associated with the inhibition of P5'N-1 interrupts the hydrolysis of uridine monophosphate (UMP) and cytidine monophosphate (CMP), resulting in the reduced availability of nucleosides, which in turn result in ineffective hematopoiesis and accelerated turnover. |
| Approved | Approved::Yes |
| Keyword | WBRKeyword::Lead poisoning, WBRKeyword::Lead toxicity, WBRKeyword::ALA dehydratase, WBRKeyword::Ferrochelatase, WBRKeyword::Anemia, WBRKeyword::Microcytic anemia, WBRKeyword::Basophilic stippling, WBRKeyword::MCV, WBRKeyword::Chipped paint, WBRKeyword::Heme synthesis pathway |
| Linked Question | Linked:: |
| Order in Linked Questions | LinkedOrder:: |
