[Nephrologists and porphyrias].G Ital Nefrol. 2002 Jul-Aug; 19(4):393-412.GI
As usually occurs for rare diseases, the word "PORPHYRIA" often recalls a confused topic with shaded boundaries, presenting "bullous" skin lesions, rare opportunity of diagnosis in clinical practice, unknown pathogenesis, and almost absent therapeutic options. The goal of this review is to draw attention to this topic, as new diagnostic and therapeutic tools might change the natural history of this disease. Porphyrias are disorders resulting from abnormalities of porphyrin metabolism. Porphyrins are molecules made up of four pyrrol rings, which constitute haeme-proteins, including haemoglobin. Following the "trigger" enzyme delta-aminolevulinic acid (ALA) synthase, which is capable of condensing succynil CoA and glycine, seven additional enzymes are involved in the process that eventually leads to haeme biosynthesis. Porphyrias are the result of total or partial deficiencies in these seven enzymes involved in haeme synthesis. Usually, the final haeme product exerts a negative feed-back on its synthesis. The enzyme deficiency that occurs in porphyrias is responsible for reduced haeme production, which, in turn, allows the cascade to be stimulated by increased activity of the trigger enzyme, ALA-synthase (ALA-s). However, due to the subsequent enzyme defects, notwithstanding increased ALA-s activity, haeme synthesis is blunted and intermediate metabolites accumulate. Clinical manifestations depend on which step the enzymatic defect occurs: if enzymatic defects are in the initial steps of the metabolic cascade, early metabolic intermediates will accumulate [i.e. ALA and porphobilinogen (PBG)] responsible for attacks of neurological dysfunction; if the enzymatic defects are in the final steps, sunlight-induced cutaneous lesions (phtotosensitivity) due to porphyrin accumulation in the skin will develop. The seven major human porphyrias may be classified into "hepatic or erythropoietic porphyrias" depending on the organ/tissue where metabolic alterations are more evident, or "acute or chronic porphyrias" depending on the prevalence of clinical symptoms, if neurologic (acute) or cutaneous (chronic). Only a small number of people with inherited enzyme deficiency will develop overt clinical disease, mainly because of the role of acquired aggravating and precipitating factors, such as drugs, hormonal causes, infection, caloric restriction, alcohol. The biochemical diagnosis of porphyrias relies on the detection of the consequences of increased ALA-s activity in the liver: overproduction, accumulation and increased excretion of early (ALA, PBG) or late (porphyrins) intermediate compounds in plasma, faeces and urine. A major difficulty arises from the knowledge that such abnormalities may be completely absent during the remission phases of the disease. Only in very specialised Centres it is now possible to measure specific haeme synthesis enzyme defects, and to perform molecular diagnosis by DNA analysis. The true prevalence of the diseases is unknown, ranging from 1:500 to 1:50,000. Therapeutic strategies include withdrawal of all common precipitants (drug, alcohol, fasting, infection), use of opiates and chlorpromazine, carbohydrates (300-400 g/day) and infusion of human haemine. Genetic therapies are being studied for the future.