Acute Intermittent Porphyria : Management Aspects

Transcription

1 POSTGRADUATE CLINIC JIACM 2002; 3(3): Acute Intermittent Porphyria : Management Aspects Rajashekar Reddi*, Nitin K Sethi**, Ish Anand***, PK Sethi**** Abstract Porphyrias are multifactorial genetic disorders in which environmental, genetic, and physiological factors interact to cause disease. Many of the symptoms are non-specific and diagnosis is often delayed. Laboratory testing is required to confirm or exclude the various types of porphyrias; however many of the tests are not available routinely. This article aims to create awareness regarding the common problems faced while managing this rare disorder. Key words Porphyria, Dyselectrolytaemia, Seizures, Abdominal pain. Introduction Acute intermittent porphyria (AIP) is a disorder due to an inherited defect of the haeme biosynthesis pathway and characterised by neurovisceral and neuropsychiatric manifestations, often precipitated by drugs and other exogenous factors 1. Porphyrias are classified as either hepatic or erythropoietic depending on the primary site of overproduction of the porphyrin precursor or porphyrin, although some have overlapping features. The major manifestations of the hepatic porphyrias are neurologic including neuropathic abdominal pain, neuropathy, and mental disturbances. The reason for neurologic involvement in hepatic porphyrias is poorly understood. The erythropoietic porphyrias cause cutaneous hypersensitivity. It has often been stated that a high index of suspicion needs to be maintained to detect this disorder as an early diagnosis is imperative for the treatment and prognosis of this rare but life threatening condition. We discuss the management of a patient who presented with the classical and well described clinical manifestations of hepatic porphyria, who, despite an early diagnosis had several difficulties due to various limitations. * Registrar, Department of Neurology ** Resident, Department of Medicine *** Consultant, Department of Neurology **** Chairman, Department of Neurology Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi Case report A 21 year old female was admitted to the emergency services of the hospital with complaints of severe colicky abdominal pain, vomiting, and constipation of 3 days duration. She had been treated by a surgeon with antibiotics, analgesics, and antiemetics after her X-ray abdomen and ultrasound abdomen had not revealed any abnormalities. Despite the above medications, her symptoms did not abate and she had developed urinary retention 1 day prior to admission. A Foley s catheter had been placed and attendants gave history of dark urine having been passed. This had been attributed to trivial trauma and to the fact that her menstrual periods had started 2 days earlier. After admission in the casualty ward the patient had 2 generalised tonic-clonic seizures for which 10 mg IV diazepam was given slowly and the neurologist was consulted. On examination the patient was found to have a pulse rate of 140/min, BP of 160/110 mm of Hg, and respiratory rate of 26/min. She was dehydrated, agitated, restless, and appeared in a great deal of distress. Examination of the abdomen revealed a soft abdomen with no tenderness and absent bowel sounds. Examination of the other systems was unremarkable. Questioning revealed history of episodic abdominal pain on 5 occasions in the past 3 years for which she had been treated similarly with analgesics, antibiotics, and antiemetics.

2 She had been hospitalised during 3 of those occasions and had improved after a period of days of hospitalisation. In between these attacks she was normal. There was no history of seizures in the past. With this history, a clinical diagnosis of AIP was made and the patient was investigated: Haematological parameters were normal. She was found to have hyponatraemia (Na meq/l) and hypokalaemia (K meq/l). Renal functions were within normal limits. Urine for porphobilinogen was positive in 3 out of 6 samples tested. X-ray abdomen revealed dilated bowel loops suggestive of paralytic ileus. A large bore central line was placed in the subclavian vein and 25% dextrose was administered, approximately 400g/day. Sodium correction was done initially with isotonic saline, and later with 3% saline containing 120 meq of potassium chloride given over 12 hours. Oral dextrose, salt, and potassium supplements could not be given because of paralytic ileus. Despite hypertonic saline therapy and potassium chloride supplementation, sodium and potassium levels were corrected to near normal (128 meq/l and 3.1 meq/l) only after 3-4 days. Paralytic ileus improved and once oral salt and potassium supplements were given, the sodium and potassium values became normal. Narcotic analgesics (pethidine 25 mg IV every 8 hours and morphine 2 mg IV when required) were given for abdominal pain. Prochlorperazine was given for vomiting. Abdominal pain and vomiting decreased and then subsided completely after 3 days of therapy. For restlessness, agitation, and anxiety, the patient was treated with low dose benzodiazepenes (Alprazolam 0.5 mg thrice a day) and injectable haloperidol when indicated, with which she improved. Despite the above therapy, the patient developed worsening symptoms in the form of dysphagia, followed by progressively increasing weakness of upper and lower limbs with universal areflexia 6 days after admission. Sensory examination was normal. Cranial nerve examination showed depressed gag reflex. Her single breath count and breath holding time, which were being monitored daily, decreased and respiratory rate increased. She was shifted to the ICU to be kept under close observation for ventilatory support, if required. She did not require ventilatory support and was shifted back to ward after 5 days with partial improvement in weakness. Electrophysiological studies revealed low amplitude compound motor action potential, borderline slow motor conduction velocities, and low amplitude sensory nerve action potential. She gradually improved over a period of 3-4 weeks but had developed significant muscle wasting. At the time of discharge, she was able to walk independently and take oral diet, though weakness in upper limbs persisted. Discussion What is the prevalence of AIP? AIP has been reported from many countries worldwide, but is especially common in Scandinavian countries and Great Britain. A study conducted to investigate the lifetime prevalence of seizures in a population with AIP in Sweden in 1996 included 294 patients; these were all the cases of known AIP in Sweden registered at the National Porphyria Centre 2. The reported prevalence of this disease in the Argentinean population is about 1:1,25, In a sample of Mexican psychiatric population, the prevalence of porphyria was found to be similar to controls 4. In India, AIP has been reported from various parts of the country 5,6 and some specific communities have been found to be especially susceptible. Fifteen patients of AIP were detected out of 2,500 persons of the Maheshwari community surveyed in Sri-Dungargarh municipal area of Bikaner 7. The fifteen patients belonged to 11 families and the female to male ratio was 9:6. Most of them were encountered in the age group years. Journal, Indian Academy of Clinical Medicine Vol. 3, No. 3 July-September

3 How is the diagnosis established? The clinical manifestations of AIP are given in the following table: Gastrointestinal Nausea Abdominal pain Vomiting Constipation Diarrhoea Neurological Autonomic Psychiatric Seizures Neuropathy Tachycardia Hypertension Sweating Pallor Urinary retention Agitation Mania Hallucinations Schizophrenia-like behaviour Depression AIP must be suspected if a patient presents with a combination of symptoms listed in the above table. A definitive diagnosis requires demonstration of specific enzyme deficiency or gene defect. This is possible in only a few advanced centres. To establish the diagnosis, the tests usually done are assay for the determination of porphyrin precursors and porphobilinogen in urine. This is based on a traditional colour reaction with Ehrlich s aldehyde reagent, an acidic solution of paradimethylaminobenzaldehyde 8. It is also known as the Watson Schwartz test 9 and the porphobilinogen and chromogen it forms always remain in the aqueous phase. The extraction with chloroform and butanol remove frequently occuring substances that interfere with the test. The most commonly interfering substance is urobilinogen which is chloroform soluble and produces a red color with Ehlrich s reagent. The reagent in the Hoesch test does not react with urobilinogen 10. In our patient, out of the six urinary samples sent for analysis, three tested positive for urobilinogen by the Watson Schwartz test. This was because the initial samples were sent from the urobag already exposed to light; also the excretion of porphyrins is intermittent and this possibly contributed to the false negative test 11. The Hoesch test was not being done in our laboratory. It is also known that substances such as phenothiazines 12 and methyldopa produce colours similar to porphobilinogen during analysis. Patients with AIP due to associated neuropsychiatric symptoms and hypertension may have been treated with these drugs and this makes the interpretation of urinalysis for porphyrins even more complicated. Our patient was not being treated with above mentioned drugs. What differential diagnosis should be considered? Lead intoxication and hereditary tyrosinaemia type 1 should be considered in the differential diagnosis of hepatic porphyrias 1,13. Lead poisoning which inhibits aminolevulinate dehydratase and increases urinary aminolevulinate excretion can present with seizures, delirium, mania, abdominal pain, vomiting, and constipation. Our patient did not have clinical features of lead poisoning, like blueish discoloration of gums due to lead sulphide deposition (Burton s line). Basophilic stippling was absent in the red blood cells. Urine and blood delta-aminolaevulinic levels could not be checked. Hereditary tyrosinaemia is caused by a deficiency of fumaryl-acetoacetate hydrolase which results in the accumalation of succinylacetone. This is structurally similar to aminolevulinate and causes symptomatology similar to porphyria including peripheral neuropathy 14. The presentation of these patients in early infancy and childhood and the presence of hepatic and renal dysfunction distinguishes this disorder from porphyrias. How should dyselectrolytaemia be managed? The patient had a low sodium value at the time of admission due to gastrointestinal losses as well 254 Journal, Indian Academy of Clinical Medicine Vol. 3, No. 3 July-September 2002

4 as possibly syndrome of inappropriate antidiuretic hormone secretion which occurs in patients of AIP. The ideal treatment would have been the restriction of free water and oral salt supplements. However, free water in the form of dextrose was essential for the treatment of AIP. Oral salt supplements could not be given because of paralytic ileus. Potassium supplementation was also administered exclusively intravenously because of the same reason. Patients of AIP who present with vomiting are likely to have dyselectrolytaemia and paralytic ileus (due to hypokalaemia) which causes difficulty in correction of these electrolytes and hence prolonged therapy for the same. How are seizures managed in patients of AIP? This patient was not started on any antiepileptic drugs. The seizures in this case were thought to be due to AIP itself as well as hyponatraemia. Seizures may be seen in 3-15% of patients with hepatic porphyria 2,15. During the seizure episode, our patient was given benzodiazapenes which in low doses are said to be safe in AIP. Despite the temptation to start antiepileptic drugs for prophylaxis because of two seizures as well possibility of recurrence of seizures due to hyponatraemia, we did not start antiepileptic drugs because no conventional antiepileptics are reported to be safe in porphyria 16. Bromides, which are reported to be safe 1, are not available. Other drugs like gabapentin 17,18 have been used but there is not enough evidence in literature to recommend their use routinely. Fortunately, our patient did not have further seizures. What is the management of acute abdomen of AIP? Abdominal pain is the most frequent presenting symptom and occurs in almost 95 percent of attacks of AIP 19. The origin of abdominal pain is obscure, but it is thought to be neurovisceral in origin. Antibiotics, often prescribed for abdominal pain and vomiting, may precipitate or worsen an attack in patients of AIP. Narcotic analgesics like morphine and pethidine are safe in AIP; other analgesics including pentazocine are not recommended. An exhaustive list of drugs safe and unsafe in AIP is available 19. However, the danger of addiction to narcotic analgesics remains, in view of the need for prolonged therapy. Phenothiazine derivatives like prochlorperazine (Stemetil) can be used as antiemetic, as phenothiazines are safe in AIP 19. However, interpretation of urinanalysis for porphyrins may be difficult once phenothiazines are used 12. What is the specific treatment of AIP? Acute attacks require a prompt diagnosis, withdrawal of the inciting agent, and treatment with analgesics, intravenous glucose, and haematin. Electrolyte imbalances requires careful monitoring and correction. Treatment with a high carbohydrate diet diminishes the number of attacks in some patients and is a reasonable empirical gesture considering its benignity. A minimum of 300 g/day of carbohydrate should be provided orally or intravenously. Despite the use of dextrose (400 g/day), our patient developed neuropathy. Haeme products like haeme arginate in a dose of 3 mg/kg/day for four days, is the recommended specific therapy for AIP 1,13,19,20 and should be started as early as possible. The administration of this end-product of the haeme biosynthesis pathway improves the underlying biochemical disturbance by reducing porphyrin precursor excretion. Adverse effects commonly seen are phlebitis and coagulapathy. This drug is not routinely available in our country. Though AIP is inherited in an autosomal dominant manner, it is more common in females 7,19 probably because hormonal fluctuations precipitate clinical attacks. Our patient too had presented in the perimenstrual period and related all her previous attacks to her menses, on direct questioning. These observations have led to various treatment strategies to modify the hormonal fluctuations in female patients. Gonadotropin releasing hormone analogues have been used to prevent cyclic attacks Journal, Indian Academy of Clinical Medicine Vol. 3, No. 3 July-September

5 of AIP 21. Nafarelin 22 is also reported to prevent menstrual exacerbations of AIP. Experience with these agents is limited. Conclusion AIP is a rare but often reported disorder and even rarer manifestations of this disease like posterior leucoencephalopathy 23,24 have been reported. Despite the abundance of articles in literature regarding this disease, there are many problems faced by treating physicians. The diagnosis of this disease can be made with the help of good laboratory support, but most of the recommended tests are not done by many hospital laboratories in India. Porphyrins in urine by colour chromatography costing Rs. 1,700 and lead poisoning/porphyria profile in urine costing Rs. 3,800 are being done by some private laboratories. Intravenous haeme is more effective than glucose in reducing porphyrin precursor excretion and probably leads to more rapid recovery. 3 to 4 mg of haeme/kg body weight in the form of haematin, haeme albumin, or haeme arginate may be infused daily for 4 days. The rate of recovery from acute attack depends on the degree of neuronal damage and may be rapid (1-2 days) with prompt therapy. The response to haeme therapy is unsatisfactory if treatment is delayed 1. Procuring haeme from Western countries is a long, arduous, and expensive procedure which makes the institution of early therapy of this drug almost impossible. Our patient developed an acute pure motor neuropathy involving, upper limbs more than lower limbs, classically described in porphyria 25,26, despite diagnosis and institution of available treatment. Management strategies for this condition and its various complications are clearly still in their infancy. References 1. Desnick RJ. The porphyrias. Braunwald E, Hauser SL, Fauci AS et al (eds). Harrisons Principles of Internal Medicine, 15th Edition. New York. McGraw Hill Inc, 2001; 2: Bylesjo I, Forsgren L, Lithner F, Boman K. Epidemiology and clinical characteristics of seizures in patients with acute intermittent porphyria. Epilepsia 1996; 37: De Siervi A, Rossetti MV, Parera VE et al. Acute Intermittent porphyria: biochemical and clinical analysis in Argentinean population. Clin Chim Acta 1999; 288: Jara-Prado A, Yescas P, Sanchez FJ et al. Prevalance of acute intermittent porphyria in a Mexican psychiatric population. Arch Med Res 2000; 31: Menawat AS, Gupta KD, Joshi CK. An epidemiologic approach to acute intermittent porphyria in Bikaner. J Assoc Physicians India 1979; 27: Singh H, Singh N. Acute intermittent porphyria as a diagnostic problem (A case report from Punjab). J Assoc Physicians India 1970; 18: Gauri LA, Chajjar KS, Saxena HC. An epidemiologic study of acute intermittent porphyria in Maheshwari community of Sri-Dungargarh municipal area. J Assoc Physicians India 1990; 38: Watson CJ, Taddeini L, Bossenmaier I. Present status of the Ehrlich aldehyde reaction for urinary porphobilinogen. J Am Med Assoc 1964; 190: Watson CJ, Schwartz S. A simple test for urinary porphobilinogen. Proc Soc Exp Biol Med 1941; 47: Lamon J, Torben TK, Realker AG. The Hoesch test: Bedside screening for urinary porphobilinogen in patients with suspected porphyria. Clin Chem 1974; 20: Schrieber WE, Jamani A, Pudek MR. Screening tests for porphobilinogen are insensitive. Am J Clin Pathol 1989; 92: Reio L, Wetterberg L. False porphobilinogen reaction in urine of mental patients. J Am Med Assoc 1969; 207: Anderson KE, Kappas A. Acute porphyria. Johnson RJ, Griffin JW eds. Current therapy in Neurologic disease. Missouri, Mosby-Year Book Inc, 1997; Grompe M, St Louis M, Demers SI et al. A single mutation of the fumarylacetoacetate hydroxylase gene in French- Canadians with hereditory tyrosinemia type 1. N Engl J Med 1994; 331: Bonkowsky HL, Schady W. Neurologic manifestations of acute porphyria. Semin Liver Dis 1982; 2: Reynolds Mc Jr, Miska RM. Safety of anticonvulsants in hepatic porphyria. Neurology 1981; 31: Tatum IVWO, Zachariah SB. Gabapentin treatment of seizures in acute intermittent porphyria. Neurology 1995; 45: Arora A, Mahajan V. Gabapentin in seizures due to acute intermittent porphyria. Neurol India 2000; 48: McColl KEL, Dover S, Fitzsimons E, Moore MR. Porphyrin metabolism and the porphyrias. Weatherall DJ, Ledingham JGG, Warell DA eds. Oxford Textbook of Medicine, 3rd Edition. New York, Oxford University Press Inc, 1996; 2: Journal, Indian Academy of Clinical Medicine Vol. 3, No. 3 July-September 2002

6 20. Elder GH, Hift RJ. Treatment of acute porphyrias. Hosp Med 2001; 62: Castelo Branco C, Vicente JJ, Vanrell JA. Use of gonadotropin releasing hormone along with tibolone to prevent cyclic attacks of acute intermittent porphyria. Metabolism 2001; 50: McNulty SJ, Hardy KJ. Two patients with acute intermittent porphyria treated with nafarelin to prevent menstrual exacerbation. J R Soc Med 2000; 93: Kupferscmidt H, Bont A, Schnorf H et al. Transient cortical blindness and bioccipital bran lesions in two patients with acute intermittent porphyria. Ann Intern Med 1995; 123: Garg RK. Acute intermittent porphyria: a new cause of posterior leucoencephalopathy syndrome. J Assoc Physicians India 2000; 48: Ridley A. The neuropathy of acute intermittent porphyria. Q J Med 1969; 38: Leger JM, Salachas F. Diagnosis of motor neuropathy. Eur J Neurol 2001; 8: Journal, Indian Academy of Clinical Medicine Vol. 3, No. 3 July-September