Porphyrias

These are a group of inherited or acquired diseases, each characterized by a partial defect in one of the enzymes of haem synthesis (Chapter 2). Increased amounts of the intermediates of haem synthesis accumulate, the disorders being classified by whether the effects are predominantly in the liver or the erythron (Table 3.7). A full discussion of these disorders is beyond the scope of this chapter, but those with a particular haematological overlap will be mentioned briefly.

Congenital erythropoietic porphyria

This is a very rare autosomal recessive disorder that is due to reduced uroporphyrinogen III synthase activity. Most patients are heteroallelic for mutations in the uroporphyrinogen III synthase gene. Large amounts of porphyrinogens accumulate, and their conversion by spontaneous oxidation to photoactive porphyrins leads to severe, and disfiguring, cutaneous photo-sensitivity and dermatitis, as well as a haemolytic anaemia with splenomegaly. Increased amounts of uroporphyrin and copro-porphyrin, mainly type I, are found in bone marrow, red cells, plasma, urine and faeces. Ring sideroblasts have been found in the marrow in some cases but rarely in large numbers. The age of onset and clinical severity of the disease are highly variable, ranging from non-immune hydrops fetalis to a later onset in which there are only cutaneous lesions. Treatment, including avoidance of sunlight and splenectomy to improve red cell sur vival, is only partially effective. High-level blood transfusions to suppress erythropoiesis (combined with iron chelation therapy) have been used to reduce porphyrin production sufficiently to abolish the clinical symptoms. Allogeneic bone marrow transplantation has been successful.

Erythropoietic protoporphyria

This is the most common erythropoietic porphyria and is usually caused by an autosomal dominant inherited deficiency of ferrochelatase, which results in increased free (not Zn) pro-toporphyrin concentrations in bone marrow, red cells, plasma and bile. Bone marrow reticulocytes are the primary source of the excess protoporphyrin. This leaks from cells and is excreted in the bile and faeces. Molecular analysis of the ferrochelatase gene has revealed a variety of missense, nonsense and slicing mutations as well as deletions and insertions. The onset of the disease is usually in childhood. Expression of the gene is variable, and photosensitivity and dermatitis range from mild or absent to moderate in degree. There is little haemolysis, but a mild hypochromic anaemia may occur, and accumulation of protoporphyrins can occasionally lead to severe liver disease. Treatment is by the avoidance of sunlight; P-carotene may also diminish photosensitivity. Iron deficiency should be avoided as this may increase the amount of free protoporphyrin.

Porphyria cutanea tarda

This is the most common of the hepatic porphyrias and occurs worldwide. The incidence in the UK has been estimated at 2-5 per million. Type I or 'sporadic' porphyria cutanea tarda (PCT) accounts for 80% of cases of PCT. The underlying metabolic abnormality is decreased activity of uroporphyrinogen decar-boxylase (UROD) in the liver. Type II disease is an autosomal dominant disorder caused by mutations in the UROD gene. Type III disease is a rare familial form and appears to result from unknown inherited defects that affect hepatic UROD activity.

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