Epidemiological, clinical anf pathogenetic studies of acute intermittent porphyria

University dissertation from Department of Public Health and Clinical Medicine, Umeå University

Abstract: Porphyrias are inherited metabolic disorders characterised by an impairment of heme biosynthesis. Acute intermittent porphyria (AIP) is the most common of the acute porphyrias in Sweden. Acute attacks of AIP are characterised by neuro-psychiatric symptoms, including epileptic seizures. Environmental and acquired factors are related to the induction of symptoms. Acute attacks of AIP are treated with high doses of glucose and/or hematin infusions.The pathogenesis of the neuro-psychiatric symptoms is not known. Reversible white-matter lesions, probably due to vasospasm, have been seen on brain MRI. Similarities between multiple sclerosis (MS) and AIP have previously been described, but to our knowledge no study has investigated whether AIP-gene carriers have white-matter lesions seen on brain MRI or oligoclonal bands (OB) in cerebrospinal fluid (CSF).The percentage of AIP-gene carriers who have experienced epileptic seizures has been calculated at 10-20%, but previous investigations are derived from highly selected clinic-based studies. Studies were therefore undertaken to investigate the prevalence of epileptic seizures, the relationship of seizures to AIP, the type of seizures and the relationship of seizures to other factors such as melatonin.A case report described the disappearance of porphyric attacks after the onset of diabetes mellitus (DM). In our study, we investigated the rate of attacks after the onset of DM. For many years, clinical issues relating to AIP have not been a focal area. We therefore carried out a study to update our knowledge of the clinical course of AIP in order to improve prevention, control and treatment. In our studies of AIP-gene carriers and epileptic seizures, we found that epileptic seizures are less common than has previously been described (3.7%) and they are not very different from what is expected in the general population, but the prevalence of 5.1% of seizures with manifest AIP is higher than in the general population. The seizures may be generalised or partial and the seizure frequency was generally low. The AIP-gene carriers who had had epileptic seizures had a lower melatonin excretion level in their urine compared with gender- and aged-matched AIP-gene carriers’ relatives without epileptic seizures, which may indicate that melatonin plays a possible anti-convulsive role.In our study of AIP and DM, no subject had an attack of AIP after the onset of DM. White-matter lesions on brain MRI were seen in 25% of the AIP-gene carriers examined outside attacks. One carrier had elevated protein levels in the CSF, but no carrier had cells or OB in the CSF.In our population-based study, 356 DNA-confirmed AIP-gene carriers from northern Sweden participated. Manifest AIP (MAIP) was identified in 42%, 65% of whom were women. Eight mutations were found. Women were more severely stricken by AIP attacks in terms of number and duration, hospital admission and early onset. Men (30%) reported most attacks > 40 years of age. The most commonly reported symptoms during attacks were severe abdominal pain (86%), fatigue (42%), constipation (41%), vomiting (36%), muscle pain (30%), psychiatric symptoms (29%), pareses (20%) and sensory impairment (10%). Chronic AIP symptoms were reported by 18%. Precipitating factors were often reported: menstruation (31%), psychological strain (30%), certain drugs and fasting (20%), infection and alcohol (14%), physical strain (12%) and pregnancy (5%). Smoking was more frequent in MAIP and was associated with the number of AIP attacks. Some 30% of MAIP carriers used drugs that were not considered safe (in 1999), mainly diuretics, calcium antagonists and ACE inhibitors. Twenty per cent of MAIP carriers reported that they were receiving a disability pension due to AIP. Elevated levels of ASAT, bile acids, creatinine, creatinine clearance, U-ALA and U-PBG were often found in MAIP-gene carriers. Hypertension, renal impairment and pain in the legs were associated with MAIP. Hepatoma was strikingly over-represented.To summarise; epileptic seizures are less common than has previously been described, melatonin may have an anti-convulsive effect and DM may have a beneficial effect on MAIP-gene carriers. White-matter lesions are seen on brain MRI. The lesions are unspecific but may relate to the patients’ porphyria. AIP is not a harmless disease. A large percentage of the AIP-gene carriers had frequent attacks, severe symptoms, long-lasting fatigue and chronic AIP and women were more severely stricken. Effects on the kidneys, blood pressure and the liver, including HCC, were evident. Measures should be taken to improve the quality of life and prognosis for AIP-gene carriers.