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The porphyrias 

The porphyrias

Chapter:
The porphyrias
Author(s):

T.M. Cox

DOI:
10.1093/med/9780199204854.003.1205_update_001

Update:

Expanded discussion of (1) role of sex-steroid metabolism in acute neurovisceral attacks; (2) incidence of inherited porphyrias; (3) long term sequelae of acute porphyrias; (4) treatment of congenital erythropoietic porphyria.

Updated on 28 Nov 2013. The previous version of this content can be found here.
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date: 27 March 2017

The porphyrias are metabolic disorders characterized by overproduction of haem precursors, principally in the liver and bone marrow. Most porphyrias are inborn errors that affect enzymatic steps in a tightly regulated biosynthetic pathway for haem; acquired forms also occur.

Hepatic synthesis of haem undergoes rapid and wide oscillations, but haem formation for erythropoiesis is generally constant; it increases many fold as the erythron expands to meet the demands of blood loss or destruction, or as a consequence of ineffective erythropoiesis.

Acute porphyrias

Clinical presentation—life-threatening neurovisceral attacks occur in four of the porphyrias: acute intermittent porphyria, variegate porphyria, hereditary coproporphyria and Doss porphyria (5-aminolaevulinate dehydratase deficiency). These present with abdominal pain, psychiatric symptoms, signs of sympathetic and hypothalamic autonomic overactivity, sometimes accompanied by convulsions and motor and sensory deficits. They typically develop on exposure to environmental or endogenous factors that place a demand for hepatic haem biosynthesis, the most frequent being changes in reproductive steroid hormones either due to natural hormone cycles or the administration of exogenous gonadal steroids (especially progestagens), starvation, intercurrent infection, alcohol and drugs. Surgical procedures, associated inevitably with fasting and often inapprorpriate exposure to injurious anaesthetic agents—as well as tissue injury and metabolic stress, typically induce acute porphyria in susceptible individuals. Acute porphyrias may also be associated with overproduction of photoactive metabolites and thus long-term photosensitivity, which is aggravated during acute attacks. Environmental, or occupational exposure to lead, induces an illness with neurovisceral manifestations and biochemical abnormlities in common with acute porphyria due to 5-aminiolaevulinate dehydratase deficiency—the very rare autosomal recessive disorder known as Doss porphyria. In this condition the heterozygous carriers show extreme sensitivity to lead exposure. In hereditary tyrosinaemia type 1, a rare inherited disorder tyrosine breakdown due to deficient activity of fumarylacetoacetase, raised plasma concentrations of succinylacetone (4,6 dioxoheptanoate) occur and are of diagnostic value in this disease. Succinylacetone is a powerful competitive inhibitor of 5-aminolaevulinate dehydratase and exacerbations of tyrosinaemia are accompanied by neurological crises and neuropathy with raised aminolaevulinic acid in the plasma and urine occurs also as a consequence of the metabolic disturbance with another secondary porphyria of an acute clinical variety.

Diagnosis—this is key to survival of an acute attack of porphyria, which can be suspected on the basis of the past history, in particular of photosensitivity or the intermittent discoloration of urine, and family history, and is confirmed by finding excess water-soluble haem precursors in urine. Enzymatic studies can later be used to verify the exact type of suspected porphyria, with molecular analysis of genes encoding relevant haem synthetic enzymes used to identify at-risk individuals in affected pedigrees.

Management—treatment of an acute porphyric attack mandates immediate withdrawal of inappropriate drugs and other precipitating factors; infusions of haem arginate (preferred but not available in the United States and some other countries) or other approved preparations of haem shorten life-threatening episodes and may be effective prophylaxis for recurrent porphyria in women with periodic attacks.

Nonacute porphyrias

The nonacute porphyrias are photosensitivity syndromes caused by excess photoactive macrocyclic porphyrins. The classic manifestations are of severe blistering lesions on sun-exposed skin, particularly of the hands and face, with the formation of vesicles and bullae that may become infected. Healing often leads to cutaneous deformities with loss of digits, scarring of the eyelids, nose, lips, scalp, and occasionally blindness due to corneal scarring. Protoporphyria characteristically causes burning pain and erythema with oedema; blistering is absent. Diagnosis is based on finding excess formed porphyrins in blood and excreta. Sunlight exposure should be avoided as much as possible until the porphyrin abnormality is corrected, e.g. by phlebotomy to cause iron depletion in porphyria cutanea tarda, or by liver or haematopoietic stem-cell transplantation in some (rare) cases.

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