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Congenital erythropoietic porphyria, a disorder of haem synthesis, is caused by uroporphyrinogen III synthase deficiency in bone-marrow normoblasts. Uroporphyrins and coproporphyrins accumulate and cause oxidative damage to cells exposed to sunlight. Uroporphyrin overproduction was greatly reduced and skin changes reversed in a girl who received a bone-marrow graft from an HLA-identical sibling at 10 years of age. The patient died 11 months after transplantation because of severe progressive pneumonitis and encephalopathy associated with cytomegalovirus infection, but the encouraging response up to 8 months after engraftment indicates a possible benefit of bone-marrow transplantation in the treatment of this rare but usually fatal inherited disease.

Congenital erythropoietic porphyria (CEP) is a rare disorder of heme biosynthesis that results in the production of large quantities of photoactive porphyrins. The clinical syndrome is dominated by extreme photosensitivity with mutilation of light exposed extremities and hemolytic anemia. Bone disease has been occasionally noted, but is not well characterised. We describe a man with CEP who developed bone pain and spinal crush fractures at the age of 22. Skeletal radiographs revealed features typical of other severe hemolytic anemias, but in addition there was loss of the terminal phalanges of the hand as a result of photomutilation. Spinal bone density (assessed by DPA) was reduced and at the hip bone density was at the lower limit of normal. The metacarpal cortical bone density was 2.9 standard deviations below normal. Biochemical and histological studies accelerated bone turnover. Although the serum 250H vitamin D concentration was very low (because of light avoidance) there was no evidence that the bone disease was a consequence of this. Treatment for one year with clodronate and a high transfusion regime was associated with small reductions in serum alkaline phosphatase and urine hydroxyproline excretion, but there was no improvement in bone mineral density. We conclude that CEP has a distinctive osteodystrophy comprising osteolysis of light-exposed extremities and a high turnover type of osteoporosis. Privational vitamin D deficiency may also occur. The effect upon bone of the new therapies for CEP should be considered.

Heme is an important prosthetic group for proteins concerned with energy metabolism. All cells in the body probably make heme, but nucleated erythroid and hepatic cells have been studied the most. Feedback control of heme formation differs in the red cells and in the liver. About eight enzymes have a place in the formation of heme. Defects in the enzyme pathways may be the result of genetic abnormalities and phenotypically occur as hereditary porphyrias. If the major defect occurs in the red cell line, erythropoietic porphyrias occur; if the liver has the major defect, than hepatic porphyrias are present. There are probably three erythropoietic porphyrias and four hepatic porphyrias which are genetically determined. However, some are not clearly classified,--with erythropoietic protoporphyria involving hepatic and erythroid cells and porphyria cutanea tarda not being a clear cut genetic abnormality, at least some of the time. Elucidation of the genetic enzymatic defects introduces new diagnostic tools and also has led to at least one revolutionary new treatment for some hepatic porphyrias.

Recent research has elucidated several of the hitherto poorly understood steps in heme synthesis. This review describes this metabolic pathway and pinpoints the enzymatic blockages in the various porphyrias. Recent advances in the understanding of the etiology of porphyria cutanea tarda are discussed, as are the abnormalities of porphyrin metabolism seen in chronic renal failure and in lead poisoning. An outline is given of the clinical and biochemical abnormalities seen in the porphyrias. Included is an algorithm to aid in the differential diagnosis of these diseases, and a brief review of the new analytical techniques available for the identification and quantification of porphyrins and their precursors in body fluids.

Recent biochemical advances have contributed to clarification of certain skin diseases and metabolic disturbances with predominantly cutaneous symptoms. This is illustrated by the various forms of porphyria. Today we differentiate four hepatic forms: acute intermittent porphyria, variegate porphyria, hereditary coproporphyria and porphyria cutanea tarda, and two erythropoietic forms: congenital erythropoietic porphyria and erythropoietic protoporphyria, all of which are due to an inborn enzymatic deficiency of the heme biosynthesis. From the different forms of ichthyosis, the X-recessive ichthyosis has an underlying enzymatic deficiency of the steroid sulfatase, which seems of significance in the disturbance of keratinization. In epidermolysis bullosa dystrophica type Hallopeau-Siemens an increased collagenase activity was detected. Inhibition of this enzyme by phenytoin results in improvement of the blistering in this genodermatosis. The etiology and pathogenesis of psoriasis are unclear despite extensive efforts. The recently detected deficiency of the arylhydrocarbon-hydroxylase and its inducibility must be confirmed, additionally its significance in the pathogenesis of this disease is yet to be evaluated.

CURRENTLY, THE PORPHYRIAS ARE CLASSIFIED IN FOUR MAIN GROUPS: congenital porphyria, acute intermittent porphyria, porphyria cutanea tarda hereditaria, and porphyria cutanea tarda symptomatica. The acquired form of porphyria (porphyria cutanea tarda symptomatica) occurs in older males and is nearly always associated with chronic alcoholism and hepatic cirrhosis. The main clinical changes are dermatological, with excessive skin fragility and photosensitivity resulting in erosions and bullae. Biochemically, high levels of uroporphyrin are found in the urine and stools. Treatment to date has been symptomatic and usually unsuccessful.A case of porphyria cutanea tarda symptomatica is presented showing dramatic improvement of both the skin lesions and porphyrin levels in urine and blood following repeated phlebotomy.Possible mechanisms of action of phlebotomy on porphyria cutanea tarda symptomatica are discussed.