Porphyrias

Porphyrin is a component of heme molecules. Porphyrin precursors (porphyrinogens) are oxidized to porphyrins when exposed to UV light. Once oxidized, they become fluorescent and can give urine a red wine color. When porphyrins in the skin are exposed to sunlight, they act as photosensitizers and can cause bullae and vesicle formation.

Porphyrin combines with iron to form heme. Heme synthesis occurs in both the mitochondria and the cytosol. The mitochondrial enzyme ALA synthase (delta amino-levulinic acid synthase) is the rate-limiting enzyme in heme synthesis. It is regulated by negative feedback inhibition from heme. Drugs such as alcohol and barbiturates decrease heme levels and, as a result, 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. This causes accumulation of delta ALA in urine and protoporphyrin IX in RBCs, along with decreased heme. Ringed sideroblasts are seen in the bone marrow. The peripheral smear shows basophilic stippling. It presents with abdominal pain, constipation, pica, fatigue, headache, irritability, loss of appetite, memory loss, and 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 and 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 occur in painters, pottery makers, construction workers, with exposure to ceramic glazing, ammunition, batteries, pipes, and in lead miners. Treatment is removal from exposure and chelation therapy for those with increased lead levels and symptoms. Succimer is the 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: This is an AD deficiency of uroporphyrinogen I synthase. It presents with episodes of abdominal pain that may be precipitated by alcohol, progesterone, and fasting. Patients may report a history of previous surgeries for acute abdomen. Urine turns a red wine color on exposure to sunlight, and increased levels of porphobilinogen and delta ALA are seen in urine. Management is aimed at decreasing porphobilinogen levels using carbohydrate loading or heme infusion.
3. Congenital erythropoietic porphyria: This is an AR deficiency of uroporphyrinogen III cosynthase. It presents with hemolytic anemia and 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: This is an AD or acquired deficiency of uroporphyrinogen decarboxylase. It presents with skin bullae and blisters on exposure to sunlight and liver disease that may progress 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 a red wine color on exposure to sunlight. Treatment is phlebotomy and chloroquine.