Acute intermittent porphyria presenting with a subarachnoid haemorrhage

This version was published on 1 November 2008

Ann Clin Biochem 2008;45:610-611
doi:10.1258/acb.2008.008084
© 2008 Association for Clinical Biochemistry

 

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Case Reports


Charles van Heyningen1 and
David M Simms2


1 Clinical Laboratories, University Hospital Aintree, Liverpool L9 7AL;
2 Chemical Pathology Department, Kingston Hospital, Kingston upon Thames KT2 7QB, UK


Corresponding author: Dr Charles van Heyningen. Email: charles.vanheyningen{at}aintree.nhs.uk




Abstract

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A 47-year-old man presented with abdominal pain, neck stiffness,severe transient hypertension and unusually dark urine. Cerebrospinalfluid investigations and angiography confirmed the diagnosisof a subarachnoid haemorrhage. Porphyrin studies on the patientand his family demonstrated that the family has acute intermittentporphyria. This is the second case report of an acute hepaticporphyria presenting with a subarachnoid haemorrhage. Acutetransient hypertension during the attack of porphyria causedthe rupture of an intracranial arterial aneurysm.





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Cardiovascular features of acute attacks of hepatic porphyriainclude tachycardia and hypertension and are a result of sympatheticoveractivity during the attack. No other cardiovascular diseaseevents or features have been associated with acute abnormalitiesof porphyrin metabolism. We report the case of a patient presentingwith a subarachnoid haemorrhage precipitated by transient hypertensionoccurring during an acute attack of hepatic porphyria.





Case report

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A previously well 47-year-old Caucasian man was admitted to hospital following a two-week illness that started with a mild upper respiratory tract infection and generalized myalgia. His symptoms progressed to abdominal pain, anorexia and vomiting and eventually constipation, oliguria and increasing headache. On admission he was confused, had abdominal tenderness, marked neck stiffness, a positive Kernig’s sign and a blood pressure of 200/140 mmHg. A lumbar puncture produced uniformly blood-stained CSF with a high red cell count of 1.2 x 109/mm3. His urine was noted to be unusually dark brown in colour becoming almost black on standing. Subsequent urine porphyrin and porphobilinogen screening tests were positive. Porphobilinogen was detected in fresh urine mixed with Ehrlich’s reagent to give a red colour. Porphyrins were detected in the same fresh urine using an extracting solvent and demonstrating red fluorescence under ultraviolet light. He developed a euvolaemic hyponatraemia with a serum sodium of 114 mmol/L, consistent with the inappropriate secretion of antidiuretic hormone. Determination of porphobilinogen in urine, by scanning the spectrum of the product formed with Ehrlich’s reagent, demonstrated a urine porphobilinogen of 97 µmol/24 hours (reference range 0–18 µmol/24 hours). Quantitative porphyrin determinations, determined by solvent partition methods,1 demonstrated a urine coproporphyrin of 1040 nmol/24 hours (reference range 0–245 nmol/24 hours), urine uroporphyrin of 2292 nmol/24 hours (reference range 6–43 nmol/24 hours) faecal coproporphyrin of 138 nmol/g dry weight (reference range 0–107 nmol/g dry weight) and faecal protoporphyrin of 352 nmol/g dry weight (reference range 0–135 nmol/g dry weight). Erythrocyte hydroxymethylbilane synthase (PBG deaminase) activity, measured as moles of uroporphyrin formed per millilitre of washed red cells per hour at 37°C, was within the reference range. These findings were consistent with a diagnosis of an acute hepatic porphyria.2

Carotid angiography demonstrated an aneurysm of the anteriorcommunicating artery. A frontal craniotomy was performed anda clip applied to the aneurysm. He made a complete physicalrecovery and his blood pressure fell to 130/80 mmHg over 20days without antihypertensive therapy. Six months before thisadmission he had remained normotensive before and after drainageof a perianal abscess under barbiturate-induced anaesthesia.

After discharge from the hospital he suffered major behaviouraland personality changes. He was disoriented in time and place,had poor concentration, marked short-term memory loss, lossof emotional inhibition, was sometimes jealous and bad-tempered,and suffered visual and aural hallucinations. He was unableto return to work and died after a further cerebrovascular accidentthree years later.

His large family was investigated extensively for porphyria (Figure 1). None of the other family members had symptoms suggesting porphyria. Enzyme studies and molecular genetic analysis demonstrated that the family has acute intermittent porphyria. In the next generation, the inheritance was traced by following the mutation in the hydroxymethylbilane synthase gene. Affected family members carry the R173W mutation in this enzyme gene. This mutation is a C-T substitution in nucleotide 517 in exon 10. A highly conserved arginine was converted to tryptophan in the mutant protein. The R173W mutation, one of the more common nucleotide substitution mutations affecting the hydroxymethylbilane synthase gene, is present in about 10% of patients with acute intermittent porphyria in the UK.3



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Figure 1 Pedigree showing autosomal dominant transmission of acute intermittent porphyria due to a R173W gene mutation. In the second generation, the deceased proband had five unaffected brothers, two unaffected sisters and one affected sister





Comment

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Although the final diagnosis is clear from the genetic analysis,the limitations and pitfalls in the original biochemical methodsare recognized and these methods have been superseded by reversed-phasehigh-performance liquid chromatography (HPLC), the current methodof choice for separating all porphyrins of clinical interest.Plasma scanning for porphyrins is now also regarded as a keyelement in performing a biochemical diagnosis.

An extensive review of the literature does not reveal any association between subarachnoid haemorrhage and acute porphyria2,46 except for one report of a 58-year-old female who was found to have acute intermittent porphyria, a recent subarachnoid haemorrhage and an intracranial aneurysm.7 The problems posedby the acute intermittent porphyria in the neurosurgical managementare discussed by the authors of this report.

A Swedish study of patients with porphyria cutanea tarda, a non-acute porphyria, found a high incidence of stroke on follow-up over a mean of ten years. This association may be due to common risk factors for both porphyria cutanea tarda and cardiovascular disease such as oestrogen therapy, alcohol abuse, diabetes and impaired glucose tolerance.8 They identified alcohol abuse in38% of male patients, oestrogen treatment in 55% of female patients,diabetes in 17% or impaired glucose tolerance in 45% of patientstested.

Hypertension is a well-recognized feature of acute porphyria, occurring in 64% of such attacks.2

The hypertension and tachycardia during the acute attack are thought to be secondary to sympathetic hyperactivity, stimulated by extreme pain, leading to increased production and release of catecholamines.9 Three-quarters of spontaneous subarachnoid bleeds are due to a ruptured aneurysm, 20% have no identifiable cause and the rest are caused by a variety of rare disorders such as arteriovenous malformations of the brain or spine, arterial dissection, sympathomimetic drugs, tumours or vasculitis.5 Porphyriahas not been recognized as a rare cause.

In our patient, it is probable that an acute attack of acuteintermittent porphyria, precipitated by a flu-like illness,produced transient severe hypertension which caused the ruptureof a congenital intracranial arterial aneurysm. Initial investigationsfor a patient presenting with subarachnoid haemorrhage neednot include a urine porphyrin screen unless other features suggestporphyria, such as the urine turning dark on standing in thelight, especially in populations with a high prevalence of inheritedacute porphyria.

Some further educational points illustrated by this case report are:

  1. The importance of investigating atypical findings (dark urine) and not assuming that all features are caused by the presenting disease (subarachnoid haemorrhage).
  2. The response to a porphyrinogenic drug, barbiturates in this patient, is unpredictable in a patient with acute porphyria. The initial uneventful exposure to barbiturates does not imply that a subsequent exposure to the same drug would have been safe. There is a great deal of current interest in trying to understand varying individual susceptibility to porphyrinogenic drugs.10

 

We conclude that an important message from this case is thevalue of investigating atypical findings in a disease presentationrather than assuming a single diagnosis.

 




ACKNOWLEDGEMENTS

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The authors thank Dr Gerald E. Levin at St George’s Hospital,London and the late Dr D. Nicholson at King’s College Hospital,London for initial biochemical investigations on the index patientand the Cardiff Porphyria Service for genetic mutation analyses.

(Accepted June 26, 2008)



REFERENCES

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  1. Practical Clinical Biochemistry. In: Varley H, Gowenlock AH, Bell M, eds. Porphyrins, Haemoglobin and Related Compounds. 5th edn. London: W. Heinemann Medical Books Ltd., 1980:960–4
  2. European Porphyria Initiative. Information for Healthcare Professionals. www.porphyria-europe.org (last accessed 3 June 2008)
  3. Puy H, Deybach JC, Lamoril J, et al. Molecular epidemiology and diagnosis of PBG deaminase gene defects in acute intermittent porphyria. Am J Hum Genet 1997;60:1373–83[Medline]
  4. Thadani H, Deacon A, Peters T. Diagnosis and management of porphyria (Review). Br Med J 2000;320:1647–51[Free Full Text]
  5. Al-Shahi R, White PM, Davenport RJ, Lindsay KW. Subarachnoid haemorrhage – clinical review. Br Med J 2006;333:235–40[Free Full Text]
  6. Gale EAM, Anderson JV. The porphyrias. In: Kumar P, Clark M, eds. Clinical Medicine. 6th edn. Amsterdam, The Netherlands: Elsevier, 2005:1149–51
  7. Gilsanz FJ, Vaquero J, Gómez-Arnau J, Bravo G, Avello F. Acute intermittent porphyria and intracranial aneurysm: therapeutic considerations. Acta Neurochir (Wien) 1981;57:33–6[Medline]
  8. Rossmann-Ringdahl I, Olsson R. Porphyria cutanea tarda in a Swedish population: risk factors and complications. Acta Derm Venereol 2005;85:337–41[Medline]
  9. Stewart MF, Croft J, Reed P, New JP. Acute intermittent porphyria and phaeochromocytoma: shared features. J Clin Pathol 2007;60:935–6[Free Full Text]
  10. Thunell S, Pomp E, Brun A. Guide to drug porphyrogenicity prediction and drug prescription in the acute porphyrias. Br J Clin Pharmacol 2007;64:668–79[Medline]


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