Review Question - QID 108983

The most likely diagnosis for this patient is lead poisoning, which affects porphyrin synthesis by inhibiting aminolevulinic acid (ALA) dehydrogenase and ferrochelatase. Porphyria cunea tarda (PCT) is another disease affecting the porphyrin synthesis pathway.

In this scenario, a MCV of 65 μl makes this a microcytic anemia, which is usually caused by a deficiency in the components of hemoglobin (iron, the surrounding porphyrin ring, or globin). The recent renovation of a home combined with neurological symptoms (especially a wrist or foot drop) makes lead poisoning the most likely diagnosis. Lead interferes with the synthesis of the porphyrin ring in hemoglobin by inhibiting the enzyme ALA dehydrogenase and also inhibits ferrochelatase, the enzyme responsible for incorporating iron into the porphyrin ring to make heme. PCT is a genetic disease that affects uroporphyrinogen decarboxylase, another enzyme in the porphyrin ring synthesis pathway, that presents with skin lesions later in life due to the buildup of intermediate porphyrin compounds in the skin.

Figure A shows a peripheral blood smear containing basophilic stippling, which can be seen as the blue granules scattered throughout red blood cells. Basophilic stippling is not specific for lead poisoning as it can also occur in heavy metal poisoning, thalassemias, and alcohol abuse.

Incorrect Answers:
Answer 1: Xeroderma pigmentosum is caused by a defect in the nucleotide excision DNA repair mechanism resulting in an inability to correct thymine dimers caused by exposure to ultraviolet light. Patients usually present with numerous skin lesions though some patients may also present with neurological findings. Xeroderma pigmentosum does not affect porphyrin synthesis or cause anemia.

Answer 2: Lesch-Nyhan syndrome is caused by a defect in hypoxanthine-guanine phosphoribosyltransferase, an enzyme in the purine salvage pathway. This causes a buildup of uric acid leading to neurologic symptoms such as poor muscle control and intellectual disability. An almost pathognomonic symptom for this disease is self-mutilating behavior such as lip and finger biting found during childhood.

Answer 3: Von Gierke’s disease, also known as glycogen storage disease type 1, is caused by a deficiency in glucose-6-phosphatase, impairing the breakdown of glycogen into free glucose in the liver. Patients present between 3-6 months of age with seizures due to hypoglycemia, hepatomegaly, and failure to thrive. Von Gierke’s disease does not affect the porphyrin synthesis pathway

Answer 5: Hereditary hemochromatosis is caused by a defect in the HFE gene which codes for an iron transport protein in the intestines. As a result of this mutation, the iron transporters are constantly active leading to iron overload. Patients present with “bronze diabetes” (darkening of skin and diabetes mellitus due to iron deposition in the skin and pancreas respectively), and cirrhosis if left untreated.

Bullet Summary:
Lead inhibits the porphyrin synthesis pathway by interfering with the enzymes aminolevulinic acid dehydrogenase and ferrochelatase.