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Acute intermittent porphyria (AIP) is rare in Europeans, with an estimated prevalence of 1–2 per 100000.1 Acute attacks of porphyria cause severe abdominal pain and a range of neurological and other features, including hypertension, tachycardia and excessive sweating. Some of the clinical features of AIP have been attributed to adrenergic hyperactivity.2
Phaeochromocytoma is a neuroendocrine tumour, with an incidence of approximately 0.15 cases per 100000 per year in the UK.3 The presenting symptoms are sustained or paroxysmal hypertension, sweating, palpitations and anxiety, secondary to excessive production of catecholamines and their metabolites. Diagnosis is based on raised urinary excretion of catecholamines or their metabolites, followed by localisation using CT and/or MRI and specific radio‐localisation, usually with meta‐iodobenzylguanidine (MIBG).
We present a patient with AIP and fluctuating hypertension in whom the finding of raised catecholamine excretion led to an incorrect diagnosis of co‐existent phaeochromocytoma.
A 34‐year‐old woman, diagnosed with AIP at age 29, developed intermittent labile hypertension which was difficult to control. Urinary catecholamine excretion was found to be abnormal ((tablestables 1 and 22).). Abdominal CT and MRI scans were normal but MIBG scintiscan was reported as showing increased tracer uptake in an area corresponding to the right adrenal gland, suggesting the possibility of a right‐sided phaeochromocytoma. A further CT scan showed no lesion in the right adrenal. Based on the positive MIBG scan, in the presence of raised catecholamines, an exploratory laparotomy was performed and the right adrenal removed. Histology of the adrenal gland was normal, showing no evidence of phaeochromocytoma. This finding was confirmed by an expert endocrine pathologist. Twelve weeks postoperatively, two further 24 h urine collections revealed abnormal norepinephrine and normetadrenaline levels and the question was raised whether she continued to harbour a phaeochromocytoma, not detected at the original operation.
Following referral to our centre, review of her history revealed that a number of the 24 h urine collections had been performed when she was an inpatient and acutely unwell with abdominal pain due to her porphyria. Further, she did not require the prescription of any antihypertensive drugs by her general practitioner while an outpatient.
Two subsequent 24 h catecholamine collections were taken when she was recovering from an acute attack. The first of these (21.05.02) showed only borderline raised norepinephrine levels which had returned to normal the following day (22.05.02). One month later, when she was completely well and normotensive on no antihypertensive medication, free catecholamines and metadrenalines were entirely normal on two consecutive days (25.06.02 and 26.06.02). It was concluded that there was no evidence of phaeochromocytoma and that the raised urinary catecholamine excretion observed prior to and following the removal of the right adrenal gland was due to sympathetic hyperactivity consequent to pain and AIP. Three years later she remains free of any evidence of phaeochromocytoma.
Acute intermittent porphyria and phaeochromocytoma are both rare conditions. Consequently few clinicians gain experience in recognising the spectrum of their clinical presentation. Lack of awareness of the features of an acute porphyria attack led, in this case, to another explanation being sought for a clinical sign (severe, labile hypertension) which was in fact compatible with the original diagnosis of AIP. This was compounded by “false positive” results of biochemical and radiological investigations. In retrospect this patient had an unnecessary major operation removing a normal adrenal gland.
Hypertension and tachycardia occur in approximately two‐thirds of patients presenting with acute attacks of porphyria.4 This is thought to be secondary to sympathetic hyperactivity, stimulated by extreme pain, leading to increased production and release of catecholamines. However, the evidence base is limited to reports on small numbers of patients, relying on assay methodology which is no longer in clinical use.5,6,7
More recently, there has been one report of diagnostic confusion between the clinical features of phaeochromocytoma and AIP,8 and a further single case report documenting markedly raised urinary free catecholamines, metadrenalines and vanillylmandelic acid during one of two acute attacks of AIP complicated by severe hypertension.9
Estimates of the performance of any diagnostic test are dependent on the patient population to which it is applied and the criteria chosen for positive or negative results. Published studies are therefore difficult to compare. Quantitation by HPLC of 24 h urinary free catecholamines (epinephrine and norepinephrine) was reported to be approximately 86% sensitive and 88% specific for phaeochromocytoma, with similar performance for urinary total metadrenalines.10 Others have reported considerably higher sensitivity (100%) and specificity (97–98%) for these urinary analytes.10 Known causes of “false positives” in modern HPLC methods include drugs (e.g. labetolol and linezolid) and unknown co‐eluting interferents. In a series of 400 cases, MIBG scanning was 88% sensitive and 99% specific.12 Causes of false positives include neuroendocrine tumours, adrenocortical carcinoma and adrenal metastases.
Morphological diagnosis of phaeochromocytoma is acknowledged to be difficult. Best practice was followed in that histological examination of the resected adrenal gland was confirmed to be normal by two pathologists, one an endocrine specialist. There was no clinical evidence of an extra‐adrenal lesion. The normal blood pressure and normal catecholamine excretion observed when the patient was well led us to conclude that her intermittent hypertension and raised catecholamines were a direct consequence of her AIP.
The biochemical investigations gave “false positive” results because of the activity of her underlying disease, i.e. AIP. When performing such tests it is essential to consider coexisting conditions which may produce abnormal results, rendering the investigation at best uninformative, and at worst dangerous. This patient illustrates the need for specialists in inherited metabolic disease who can advise at an early stage on the management of rare conditions such as acute porphyria and prevent inappropriate treatment.
Competing interests: None declared.