Porphyrias

Porphyrin is a component of heme molecules. Porphyrin precursors or porphyrinogens are oxidized to porphyrins on exposure to UV light, they become fluorescent and impart a red wine color to urine. On exposure to sunlight, porphyrins sensitize the skin leading to bullae and vesicle formation.

Porphyrin combines with iron to form heme. Heme synthesis occurs in the mitochondria and cytosol. The mitochondrial enzyme ALA synthase or delta amino-levulinic acid synthase is the rate-limiting enzyme of heme synthesis. It is subject to negative feedback inhibition by heme. Drugs like alcohol and barbiturates decrease heme levels and indirectly activate ALA synthase.

Following are the important genetic and acquired disorders of heme metabolism:

1. Lead poisoning: Lead inhibits two enzymes of heme metabolism - ferrochelatase and ALA dehydratase. It leads to accumulation of delta ALA in urine and protoporphyrin IX in RBCs and decreased heme. Ringed sideroblasts are seen in the bone marrow. Peripheral smear shows basophilic stippling. It presents with abdominal pain, constipation, pica, fatigue, headache, irritability, loss of appetite , memory loss, pain or tingling in the hands and/or feet. It may cause miscarriage, stillbirths and infertility. Children are more sensitive to the adverse effects of lead and may develop mental retardation and other neurological sequelae. Burton’s line is a blue-purplish line on the gums seen in lead poisoning. It is caused by a reaction between circulating lead with sulphur ions released by oral bacterial activity, which deposits lead sulphide at the junction of the teeth and gums. Prolonged lead exposure may cause high blood pressure, heart disease and kidney disease. Exposure to lead can happen in painters, pottery makers, construction workers, on exposure to ceramic glazing, ammunition, batteries, pipes and in lead miners. Treatment is by removing exposure and chelation therapy for those with increased lead levels and symptoms. Succimer is preferred chelation therapy for those with milder symptoms. Alternatively, D-penicillamine, dimercaprol or calcium-disodium EDTA can be used. Patients with encephalopathy are treated with a combination of dimercaprol and calcium-disodium EDTA.
2. Acute intermittent porphyria: It is an AD deficiency of uroporphyrinogen I synthase. It presents with episodes of abdominal pain which may be precipitated by alcohol, progesterone and fasting. Patients may give history of previous surgeries for acute abdomen. Urine turns a red wine color on exposure to sunlight, increased levels of porphobilinogen and delta ALA are seen in urine. Management is by decreasing levels of porphobilinogen by carbohydrate loading or heme infusion.
3. Congenital erythropoietic porphyria: It is an AR deficiency of uroporphyrinogen III cosynthase. It presents with hemolytic anemia, cutaneous bullae and blisters. Uroporphyrinogen I and uroporphyrin I are elevated, which imparts a red wine color to urine. Sunlight exposure should be avoided. Bone marrow transplant is curative.
4. Porphyria cutanea tarda: It is an AD or acquired deficiency of uroporphyrinogen decarboxylase. It presents with skin bullae and blisters on exposure to sunlight and liver disease which may lead to cirrhosis. It may be exacerbated by hepatitis C, iron, alcohol and estrogens. Uroporphyrinogen I and III and coproporphyrinogens accumulate. Levels of porphobilinogen are normal. Urine turns red wine color on exposure to sunlight. Treatment is by phlebotomy and chloroquine.