This heterogeneous group of rare inborn errors of metabolism is caused by abnormalities of enzymes involved in the biosynthesis of haem, resulting in overproduction of the intermediate compounds called porphyrins.
Structurally, porphyrins consist of four pyrrole rings. These pyrrole rings are formed from the precursors glycine and succinyl-CoA, which are converted to a-aminolaevulinic acid (a-ALA) in a reaction catalysed by the enzyme a-ALA synthetase. Two molecules of a-ALA condense to form a pyrrole ring.
Porphyrins can be divided into uroporphyrins, coproporphyrins or protoporphyrins depending on the structure of the side-chain. They are termed type I if the structure is symmetrical and type III if it is asymmetrical. Both uroporphyrins and coproporphyrins can be excreted in the urine.
The sequence of enzymatic changes in the production of haem. The chief rate-limiting step is the enzyme a-ALA synthetase, as an increase in this enzyme results in an overproduction of porphyrins. Haem provides a negative feedback mechanism on this enzyme.
In porphyria the excess production of porphyrins occurs either in the liver (hepatic porphyrias) or in the bone marrow (erythropoietic porphyria), but porphyrias can also be classified in terms of clinical presentation as acute or non-acute. Acute porphyrias usually produce neuropsychiatric problems and are associated with excess production and urinary excretion of a-ALA and porphobilinogen;
these metabolites are not increased in nonacute porphyrias. The second control mechanism is therefore porphobilinogen deaminase;
this is depressed or normal in the acute porphyrias and raised in non-acute cases.
3, porphyria cutanea tarda; 4, hereditary coproporphyria; 5, variegate porphyria; 6, erythropoietic protoporphyria.
Acute intermittent porphyria
This is an autosomal dominant disorder. Presentation is in early adult life, usually around the age of 30 years, and women are affected more than men. It may be precipitated by alcohol and drugs such as barbiturates and oral contraceptives, but a wide range of lipid-soluble drugs have also been incriminated. The abnormality lies at the level of porphobilinogen deaminase in the haem biosynthetic pathway.
Presentation is with:
• Abdominal pain, vomiting and constipation (90%)
• Polyneuropathy (motor, but occasionally sensory) (70%)
• Hypertension and tachycardia (70%)
• europsychiatric disorders (such as depression, anxiety and frank psychosis) (50%)
The diagnosis should be considered whenever there is a combination of these cardinal features or:
A FAMILY HISTORY of porphyria.
THE URINE TUR S RED-BROWN OR RED ON STANDING. A classic bedside test for excess porphobilinogen may be performed by adding one volume of urine to one volume of Ehrlich’s aldehyde, which produces a pink colour. If excess porphobilinogen is present, the pink colour persists when two volumes of chloroform are added.
Other investigations
NORMAL BLOOD COUNT; occasional neutrophil leucocytosis
ABNORMAL LIVER BIOCHEMICAL TESTs-elevated bilirubin and transferases
BLOOD UREA often raised
SCREENING. Family members should be screened to detect latent cases. Urinalysis is not adequate and measurement of erythrocyte porphobilinogen deaminase and ALA synthetase is extremely sensitive.
MANAGEMENT
Management of the acute episodes is largely supportive. A high carbohydrate intake is maintained (this has an indirect effect on porphyrin overproduction), and a narcotic may be given for pain. Intravenous haematin infusion also appears to be of benefit. Management in the remission period is by avoidance of possible precipitating factors, particularly drugs and alcohol.
Other acute porphyrias
Variegate porphyria
This combines many of the features of acute intermittent porphyria with those of a cutaneous porphyria. A bullous eruption develops on exposure to sunlight owing to the activation of porphyrins deposited in the skin. There is an increased production of protoporphyrinogens owing to an abnormality of protoporphyrinogen oxidase in the haem biosynthetic pathway.
Hereditary coproporphyria
This is extremely rare and broadly similar in presentation to variegate porphyria. The distinction is based on biochemical analysis.
Porphyria cutanea tarda (cutaneous hepatic porphyria) This condition, which has a genetic predisposition, presents with a bullous eruption on exposure to sunlight; the eruption heals with scarring. Alcohol is the most common aetiological agent. There is an abnormality in hepatic uroporphyrinogen decarboxylase. Evidence of biochemical or clinical liver disease may also be present. Polychlorinated hydrocarbons have been implicated and porphyria cutanea tarda has been seen in association with benign or malignant tumours of the liver.
The diagnosis depends on demonstration of increased levels of urinary uroporphyrin. Histology of the skin shows subepidermal blisters with perivascular deposition of periodic acid-Schiff-staining material. The serum iron and transferrin saturation are often raised. The liver biopsy shows mild iron overload as well as features of alcoholic liver disease.
Remission can be induced by venesection; this should be repeated if the urinary uroporphyrin rises in the remission phase. Chloroquine may also have a useful role in promoting urinary excretion of uroporphyrins.
Erythropoietic porphyrias
Congenital porphyria
This is extremely rare and is transmitted as an autosomal recessive trait. Its victims show extreme sensitivity to sunlight and develop disfiguring scars. Dystrophy of the nails, blindness due to lenticular scarring, and brownish discoloration of the teeth also occur.
Erythropoietic protoporphyria
This is commoner than congenital porphyria and is inherited as an autosomal dominant trait. It presents with irritation and burning pain in the skin on exposure to sunlight. Hepatic involvement may also occur. Diagnosis is made by fluorescence of the peripheral red blood cells and by increased protoporphyrin in the red cells and stools. Oral J3-carotene provides effective protection against solar sensitivity; the reason for this is not known.
Further reading
The Diabetes Control and Complications Trial Research Group (1993) The effect of intensive treatment of diabetes on the development and progression of longterm complications in insulin-dependent diabetes mellitus. New England Journal of Medicine 329: 977- 986.
Ferner RE, Alberti KGMM (1989) Sulphonylureas in the treatment of non-insulin dependent diabetes. Quarterly Journal of Medicine 73, 987-995.
Galton DJ, Krone W (1991) Hyperlipidaemia in Practice. London: Gower Medical Publishing. Kohner EM (1989) Diabetic retinopathy. British Medical Bulletin 45: 148-173.
Scriver CR, Beaudet AL, Sly WS & Valle D (1989) The Metabolic Basis of Inherited Disease, 6th edn. New York: McGraw-Hill. Tattersall RB, Gale EAM (eds) (1990) Diabetes Clinical Management. Edinburgh: Churchill Livingstone. Ward JD (1989) Diabetic neuropathy. British Medical Bulletin 45: 111-126.
