George H Elder, Richard J Hift, Peter N Meissner Public attention has been drawn to the acute porphyrias in the past few years by speculation that they affected thecharacter of George III and the creative genius of Vincent Acute intermittent porphyriaAutosomal dominant; acute attacks only; no cutaneous van Gogh. During the same period, there have been manifestations. Three families with homozygous/compound important advances in the understanding of the molecular basis of the acute porphyrias and in diagnosis and theclinical management of patients and their families. Four Hereditary coproporphyriaAutosomal dominant; acute attacks with skin lesions (blisters, types of porphyria are classified as acute because they fragility) in about one-third of patients; skin lesions without acute produce acute neurovisceral crises (panel).1 Here, we attacks are rare. Three families with homozygous/compound outline current knowledge of the three autosomal dominant types: acute intermittent porphyria, variegate porphyria, and hereditary coproporphyria.
Autosomal dominant. Of 61 UK patients, 45 (73%) presented withskin lesions (blisters, fragility) alone, seven (12%) with acute attacks alone, and nine (15%) with both together. 12 families with homozygous/compound heterozygous variant reported.
The inherited defect in each of the autosomal dominant 5-aminolaevulinic acid dehydratase deficiency porphyria acute porphyrias is the complete or near complete Autosomal recessive; presents at any age with severe acute inactivation of one of a pair of allelic genes that encodes attacks, neuropathy or both. Four families reported.
for an enzyme of the biosynthetic pathway for haem(table 1).1 The consequent 50% reduction in enzyme these mutations decrease enzyme activity in all tissues.
activity provokes a compensatory increase in substrate concentration, which is brought about through the deaminase has been solved at 0·176 nm resolution and negative feedback regulation by haem of the rate- provides a useful model for predicting the functional controlling initial enzyme of the pathway, 5- effects of human mutations (figure).6 Most mutations in aminolaevulinate synthase (ALA-S). Substrate acute intermittent porphyria are restricted to one or a few accumulation and increased ALA-S activity in response to families. However, one mutation (Trp198Stop), the enzyme deficiency are most prominent in the liver, in presumably inherited from a common founder, underlies which haem supply is finely regulated to adjust to internal the high prevalence of acute intermittent porphyria in and external stimuli—for example, drugs that induce northern Sweden (1 per 1500 people). There is no cytochrome P450s. The increase in synthesis andexcretion of porphobilinogen that characterises the acute evidence that any specific genotype determines either the attack reflects primary (acute intermittent porphyria) or pattern or severity of the acute attack, or major secondary (variegate porphyria and hereditary differences in clinical penetrance between families.4 coproporphyria) limitation of the rate of hepatic haem Preliminary data indicate that variegate porphyria may synthesis at porphobilinogen deaminase—the enzyme that be as heterogenous at the DNA level as other porphyrias has the lowest activity of those that convert in most countries, with the notable exception of South Africa. About 10 000 South Africans of Afrikaans descenthave variegate porphyria; genealogical evidence suggeststhat this acute porphyria was inherited from a single founder, a woman who emigrated from Holland in 1688.7 The porphyrias show extensive allelic heterogeneity.2 These families share the same mutation (Arg59Trp) in More than 90 mutations that cause acute intermittent the protoporphyrinogen oxidase gene.8 The existence of porphyria have been identified in the porphobilinogen such a large group with the same mutation provides a deaminase gene.3,4 Mutations in exon 1, which encodes unique opportunity to study the interaction of other the additional 17 aminoacids at the N-terminus that inherited and environmental factors in the acute distinguish the ubiquitous from the erythroid isoenzyme of this enzyme,3 are responsible for a rare variant of acute Homozygous forms of acute intermittent porphyria, intermittent porphyria in which only the ubiquitous variegate porphyria, and hereditary coporporphyria, which isoenzyme is defective.5 Other mutations are distributed are frequently associated with growth and psychomotor throughout the gene in exons common to both retardation, have been reported,1 as has more than one isoenzymes, with some clustering in exons 10 and 12; type of acute porphyria in the same individual or family.1,9 Department of Medical Biochemistry, University of Wales College of Medicine, Heath Park, Cardiff CF4 4XN, UK (Prof G H Elder MD);and MRC/UCT Liver Research Centre, Department of Medicine, Acute porphyria occurs in all races. In most European University of Cape Town, Cape Town, South Africa (R J Hift MD, countries, apart from Sweden, the estimated prevalence of clinically overt acute porphyria is 1–2 per 100 000 inhabitants.10,11 Most of these individuals have acute Urine: PBG and ALAFaeces: normal porphyrin ex cretion Urine: PBG, ALA, coproporphyrin III (acute phase)Faeces: coproporphyrin III Urine: PBG, ALA (acute phase); coproporphyrin III Faeces: protoporphyrin IX greater than coproporphyrin IIIPlasma: porphyrin-protein conjugate with fluorescence PBG=porphobilinogen; ALA=aminolaevulinate.
Table 1: Autosomal dominant acute porphyrias intermittent porphyria. Variegate porphyria is about one- opiates frequently lead to unwarranted suspicions of third as prevalent as acute intermittent porphyria in the histrionic behaviour or addiction. Yet as the attack remits, UK; it usually presents with skin lesions alone (panel) and the need for analgesia disappears, which confirms the is less often the cause of recurrent attacks. Even in South Africa, most acute attacks are now caused by acute Though tachycardia and hypertension are described as intermittent porphyria. Hereditary coproporphyria is the features of the acute attack, the pulse rate and blood pressure are often only moderately raised, and these signs Gene frequencies for these disorders are higher than the are of poor diagnostic value. Vomiting and constipation prevalence of overt cases. Biochemical studies of relatives are common; the latter is rarely a presenting symptom.
of patients with symptomatic acute porphyria suggest that These features of acute porphyria—pain, tachycardia, at least 90% of individuals with acute intermittent hypertension, and partial ileus—have been attributed to porphyria or variegate porphyria are clinically latent which an autonomic neuropathy. Dehydration is common and gives a frequency of 1–2 per 10 000 individuals for acute responds rapidly to fluid replacement. Hyponatraemia, intermittent porphyria. A study by Mustajoki and probably caused in some patients by inappropriate colleagues12 showed that screening blood donors for secretion of vasopressin,1 may also be present. The inherited porphobilinogen deaminase deficiency gives an sodium concentration may decline to dangerously low even higher rate of 1 per 500 donors.12 This prevalence is levels, which can lead to convulsions.
close to that reported by Tishler et al13 in a similar, but The severe attack may progress to a motor neuropathy uncontrolled, study of psychiatric inpatients, which is which may resemble a Guillain-Barré syndrome. In some often quoted as evidence of an increased frequency of patients, onset of the neuropathy may be preceded by acute intermittent porphyria among such patients. The disappearance of the abdominal pain, which may lead the occurrence of homozygous variants, sporadic presentation physician to erroneously assume that the patient is of acute intermittent porphyria in about 25% of cases,14 recovering. Mild sensory changes often accompany the and allelic heterogeneity combined with a low rate of new motor neuropathy, particularly, a “bathing trunk” mutations4,14 are all features consistent with a high distribution of hypoaesthesia over the trunk and thighs. In prevalence of latent acute porphyria in the population.
milder cases, particularly with repeated attacks of acuteintermittent porphyria, the features are of a distal Factors that may precipitate the acute attack neuropathy with foot drop and wrist drop. Occasionally, Drugs and the menstrual cycle are the most common sensory or sympathetic features such as dysaethesia or precipitants of the acute attack,1,10,15,16 and recurrent causalgia are prominent. Progression to neuropathy is attacks that occur in the late luteal phase are sometimes a seen less frequently than in the past (table 2).15 Abnormal major problem in acute intermittent porphyria. Factors behaiviour and confusion, with agitation and such as alcohol, fasting, stress, and infection have also hallucinations, are common in some patients during the been implicated. It is impossible to predict accurately acute attack. There is little evidence that porphyria whether specific drugs will provoke an acute attack produces chronic psychiatric illness, apart from in a particular individual.15 Drugs should be prescribed only after reference to a drug list,10,16 recommendations are not absolute and do not substitute for sound clinical judgment. The risk of an attack is Most difficulties in the diagnosis of an acute attack arise highest for drugs that are known to have repeatedly in patients who do not have a family history of porphyria, provoked acute attacks and for patients who have or have particularly if the combination of symptoms is atypical. A high index of clinical suspicion is important to avoiddelayed diagnosis, which may lead to inadvertent use of contraindicated drugs and a poorer prognosis.
Acute attacks are about five times more common in Increased urinary excretion of porphobilinogen women than in men; attacks are most frequent during the confirms the diagnosis of an acute attack (table 1).
second to fourth decades and are rare before puberty.
Excretion of aminolaevulinate is also increased but to a Abdominal pain is almost universal in acute porphyria lesser extent. Screening tests for porphobilinogen based (table 2). Pain is severe, constant, occurs in any quadrant on the insolubility of organic solvents of the red product and commonly in the back, buttocks, and thighs, and may of its reaction with p-dimethylaminobenzaldehyde in acid require large amounts of opiates for its control. Pain is (Ehrlich’s reagent) have been criticised because they lack sometimes accompanied by guarding, but not by true sensitivity and produce occasional false-positive results.18 peritonism. The incessant pleas of affected patients for A positive screening test is useful in an emergency, but especially in those few patients who become addictedto opiates. In variegate porphyria and hereditarycoporporhyria, porphobilinogen excretion will generallybe normal in the absence of symptoms. In acuteintermittent porphyria, concentratons are often raisedduring the symptomless phase and increase further duringan acute attack.
Pathogenesis of the acute attackIncreased ALA-S activity, overproduction ofaminolaevulinate, and relative haem deficiency in the liverare biochemical featues of all acute porphyrias and also ofthe identical syndrome that occurs in hereditarytyrosinaemia. How these changes are triggered and thepathogenesis of the neuronal dysfunction that producesthe symptoms are little understood.21 Some drugs andalcoholic beverages may increase the intrahepaticrequirement for haem by inducing the synthesis ofcytochrome P450. The mechanisms for other drugs andhormones and the explanation for differences betweenindividuals in their susceptibility to develop acute attacksare not known.15 Investigation of the pathogenesis of theneuropathy has been hampered by lack of an experimentalmodel. Current theories implicate aminolaevulinate as aneurotoxin (for which the evidence is controversial21),neurotransmitter disturbance secondary to deficiency of Model of human porphobilinogen deaminase with some of the haem and tryptophan dioxygenase in the liver, or mutations that cause acute intermittent porphyria The dipyrromethane cofactor at the active site is shown in yellow. We development of a transgenic porphobilinogen deaminase thank N Srinivasan and R Sowdhamini (Birkbeck College, London, UK)for the figure.
deficient mouse provides a system in which thesehypotheses can be tested.22 should always been confirmed by a specific, quantitative assay.19 A negative screening test does not exclude an acute attack. If clinical suspicion persists, quantification Most patients will require admission to hospital. Only of porphobilinogen and measurement of faecal and drugs clearly shown to be safe in porphyria should be plasma porphyrins are essential. Excretion of prescribed; all others should be withdrawn. Pain will porphobilinogen may fall below the detection limit of respond to opiates, though high doses may be required.
screening tests soon after the onset of symptoms, Sedation with chlorpromazine is often helpful. Vomiting particularly in variegate porphyria and hereditary may be suppressed with prochlorperazine or coporporphyria, and the diagnosis may be missed if this metaclopramide. Administration of dextrose or laevulose approach is not followed. The type of acute porphyria is in large amounts has been shown to suppress synthesis of established by measurement of faecal and plasma aminolaevulinate.23 However, intravenous dextrose may porphyrins (table 1);19 enzyme assays at this stage may aggravate hyponatraemia and must be used with caution.
mislead and should not be used in place of porphyrin Maintenance of an adequate calorie intake can be analysis. Fluorescence emission spectroscopy of plasma achieved more safely by nasogastric feeding. Intravenous simplifies the differentiation of variegate porphyria from haematin has largely replaced carbohydrate as the specific therapy of choice for the acute attack; it In patients who have latent porphyria or are in suppresses hepatic ALA-S by negative feedback and remission, differentiation of an attack of acute porphyria is highly effective in reducing aminolaevulinate and from other causes of abdominal pain may be difficult, porphobilinogen excretion.21 The only placebo-controlled Hypertension (diastolic blood pressure >85 mm Hg) Figures are percentages of number of acute attacks. *See further reading section. †Unpublished data.
Table 2: Symptoms and signs of acute porphyria study of this therapy suggested that the clinical benefit of intravenous haematin was modest.24 Uncontrolled data With improvements in management, severe neuropathy suggest that haem arginate (Normosang, Leiras Medica, and death are now less common than in the past.15 Finland) is highly efficacious, but it will not reverse an Recurrent attacks are more common in acute intermittent established neuropathy and must be given during the porphyria than in variegate porphyria. Patients may develop hypertension or chronic renal failure.28 Acute Administration of haematin may induce haem porphyrias may also be associated with an increased risk oxygenase, with consequent enhanced catabolism.21 We observed apparent clinical tolerance to haem arginate in afew patients who required repeated courses at short intervals; efficacy was restored by the coadministration of Success in caring for patients with the acute porphyrias tin protoporphyrin, an inhibitor of haem oxygenase.26 lies less in crisis intervention at the time of the acute However, tin protoporphyrin causes photosensitivity and attack than it does in enabling affected patients and their its long-term toxicity is unknown. Zinc mesoporphyrin families to keep to a minimum the risk of an attack.
may be a safer alternative but requires evaluation.21 Family studies are essential to identify individuals withclinically latent porphyria so that they can be counselled about the need to avoid drugs and other factors thatprovoke acute attacks.1,16,21 Frequent recurrences of the acute attack are usually porphyria in children and most adults requires specialised encountered in patients with acute intermittent porphyria enzymatic and other methods,19 such as DNA analysis,2–4,30 who have attacks induced by menstruation or who and is best undertaken in a referral centre. Most of those repeatedly take inducing agents. With menstrually related who inherit an acute porphyria will lead a normal life and attacks, attempts to regulate the menstrual cycle with sex many will be symptom-free; the lives of only a minority steroids may exacerbate the porphyria. Some patients are blighted by the disease. No specific diet is indicated have responded well to hormonal suppression with for porphyria, though sudden or prolonged calorie gonadotrophin-releasing hormone agonists.1,27 restriction may induce an acute attack and should be functional menopause is induced by these agonists which avoided, as should alcoholic beverages. Although early may be accompanied by symptoms of oestrogen reports suggest a high incidence of acute attacks in deficiency and accelerated osteoporosis. These effects pregnancy and the puerperium, pregnancy seems to pose may be reduced by cyclical adminstration or hormone little increased risk to patients who are known in advance replacement, but the safety and efficacy of different to have porphyria and need not be discouraged.18 regimens need further investigation. In one patient, we Similarly, general anaesthesia and surgical operations found that supplemental oestrogen arrested the carry little increased risk of an acute attack provided prior oestoporosis and was tolerated, whereas progesterone knowledge of the diagnosis enables agents that provoke intermittent acute porphyria in a psychiatric patient population. Am J
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