The porphyrias are inherited disturbances in heme biosynthesis. Each of the nine disorders causes a unique pattern of overproduction, accumulation, and excretion of intermediates of heme synthesis. These disorders are classified as either hepatic or erythropoietic, depending on the primary site of overproduction and accumulation of the porphyrin precursor or porphyrin. The major manifestations of the hepatic porphyrias are neurologic (neuropathic abdominal pain, neuropathy, and mental disturbances), whereas the erythropoietic porphyrias characteristically cause cutaneous photosensitivity. Laboratory testing is required to confirm or exclude the various types of porphyria. However, a definite diagnosis requires demonstration of the specific enzyme deficiency or gene defect. Only the three most common porphyrias are discussed here.
ACUTE INTERMITTENT PORPHYRIA
This is an autosomal dominant disorder with variable expressivity caused by partial (50%) deficiency in hydroxymethylbilane synthase. It has a prevalence of 1–3 in 100,000 but is much more common in certain parts of the world (Northern Sweden, Great Britain). Manifestations include colicky abdominal pain, vomiting, constipation, port wine–colored urine, and neurologic and psychiatric disturbances. Acute attacks rarely occur before puberty and may last from days to months. Photosensitivity does not occur. Clinical and biochemical manifestations may be precipitated by barbiturates, anticonvulsants, estrogens, oral contraceptives, the luteal phase of the menstrual cycle, alcohol, or low-calorie diets. Diagnosis is established by demonstrating elevation of urinary porphobilinogen (PBG) and γ-aminolevulinic acid (ALA) during an acute attack. Genetic testing, if available, should be used to confirm the diagnosis.
As soon as possible after the onset of an attack, 3–4 mg of heme, in the form of heme arginate, heme albumin, or hematin, should be infused daily for 4 days. Heme acts by inhibiting ALA synthase, thereby restraining ALA and PBG production. Administration of IV glucose at rates up to 20 g/h or parenteral nutrition, if oral feeding is not possible for long periods, can be effective in acute attacks. Narcotic analgesics may be required during acute attacks for abdominal pain, and phenothiazines are useful for nausea, vomiting, anxiety, and restlessness. Treatment between attacks involves adequate nutritional intake, avoidance of drugs known to exacerbate the disease, and prompt treatment of other intercurrent diseases or infections. Liver transplantation has been effective in selected patient and gene replacement trials are underway.
PORPHYRIA CUTANEA TARDA
This is the most common porphyria (2–4 in 100,000) and is characterized by cutaneous photosensitivity and, usually, hepatic disease. It is due to partial deficiency (familial, sporadic, or acquired) of hepatic uroporphyrinogen decarboxylase. Photosensitivity causes facial pigmentation, increased fragility of skin, erythema, and vesicular and ulcerative lesions, typically involving face, forehead, and forearms. Neurologic manifestations are not observed. Contributing factors include excess alcohol, iron, and estrogens. Pts with liver disease are at risk for cirrhosis and hepatocellular carcinoma. Plasma and urine uroporphyrin and 7-carboxylate porphyrin are increased.
Avoidance of precipitating factors, including abstinence from alcohol, estrogens, iron supplements, and other exacerbating drugs, is the first line of therapy. A complete response can almost always be achieved by repeated phlebotomy (every 1–2 weeks) until hepatic iron is reduced. Chloroquine or hydroxychloroquine may be used in low doses (e.g., 125-mg chloroquine phosphate twice weekly) to promote porphyrin excretion in pts unable to undergo or unresponsive to phlebotomy.
Erythropoietic protoporphyria is an autosomal dominant disorder due to partial deficiency of ferrochelatase, the last enzyme in the heme biosynthetic pathway. Its prevalence is 1 in 100,000. Porphyrins (primarily protoporphyrin IX) from bone marrow erythrocytes and plasma are deposited in the skin and lead to cutaneous photosensitivity. Skin photosensitivity usually begins in childhood. The skin manifestations differ from those of other porphyrias, in that vesicular lesions are uncommon. Redness, swelling, burning, and itching can develop within minutes of sun exposure and resemble angioedema. Symptoms may seem out of proportion to the visible skin lesions. Chronic skin changes may include lichenification, leathery pseudovesicles, labial grooving, and nail changes. Liver function is usually normal, but liver disease and gallstones may occur. Protoporphyrin levels are increased in bone marrow, circulating erythrocytes, plasma, bile, and feces; protoporphyrin in erythrocytes is free rather than zinc complexed as it is in other types of porphyria or hematologic disorders. Urinary porphyrin levels are normal. Diagnosis is confirmed by identifying a mutation in the ferrochelatase gene.
Avoidance of sun exposure is essential. Oral β-carotene (120–180 mg/d) improves tolerance to sunlight in many pts. The dosage may be adjusted to maintain serum carotene levels between 10 and 15 μmol/L (600–800 μg/dL). Cholestyramine or activated charcoal may promote fecal excretion of protoporphyrin. Plasmapheresis or IV heme therapy may be beneficial.
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