Treatment of the acute attack
|The diagnosis of the acute attack should be made by measuring quantitative PBG before starting specific treatment for porphyria (eg with human hemin) (more about diagnosis). For patients who have previously had an unequivocally diagnosed attack of acute porphyria, it may be necessary to initiate specific treatment before the results of the laboratory investigation are available.|
|Withdraw any drugs or other potential provoking agents.|
Start appropriate supportive treatments using drugs that are safe in acute porphyria. Recommended drugs and procedures are listed below.
Opiates are the most effective analgesics for use in an acute attack. Since acute attacks are usually short lived and infrequent, opiates may be used in high doses without fear of addiction. Chlorpromazine or promazine may help to decrease the requirement for analgesics. In some patients, residual neuropathic pain continues once the acute attack has settled. It is important to recognise that this pain differs from that of the acute attack itself and, wherever possible, to avoid using addictive analgesics for its management.
Careful management of fluid balance, avoiding large volumes of hypotonic dextrose, is required to minimise the risk of severe hyponatraemia which may provoke convulsions. Hyponatraemia should be corrected slowly; patients with acute attacks seem particularly prone to cerebral oedema and osmotic demyelination. Restriction of water intake to around 500 mL per day may be sufficient alone but, if symptoms necessitate saline infusion, the rate of correction should not exceed 8 mmol/L in any 24 hour period.
Since impaired nutrition may aggravate acute porphyria, it is important to ensure that adequate calories are given. They are preferably given as carbohydrate-rich food supplements orally or, if necessary, via a nasogastric tube. When vomiting prevents enteral administration, carbohydrate may be provided as normal saline with 5% dextrose, two litres of which provide 100 g of glucose per day. Avoid infusing large volumes of hypotonic dextrose as this aggravates hyponatraemia. As soon as patients are able to take food orally, they should be transferred to a diet in which carbohydrate provides 55-60% of the energy needed to maintain their normal weight.
Cardiovascular complications such as hypertension and tachycardia are rarely sufficiently severe to require therapy in their own right. Very occasionally, the acute attack is accompanied by a severe adrenergic crisis with dangerous hypertension, encephalopathy, seizures and ischaemic changes on CT brain scanning. Intravenous infusion of magnesium sulphate may be effective in controlling the adrenergic symptoms; human hemin must be administered to abort the attack.
The onset of a motor neuropathy is often marked by severe pain and stiffness in the thighs and back followed by loss of tendon reflexes and motor paralysis. When vital capacity becomes severely reduced by paralysis of the intercostal muscles, artificial ventilation is necessary and may have to be continued for several months until the expected eventual recovery occurs.
Specific treatment should be started as soon as the diagnosis is established unless the attack is mild and clearly resolving. Two treatments are available: intravenous heme and carbohydrate loading. Intravenous heme is the more effective and should be used unless heme preparations are unavailable. Neither will reverse an established peripheral neuropathy, though heme may prevent its onset and may halt further progression of neuropathy if given sufficiently early.
Normosang® (human hemin, Orphan Europe) is a concentrated heme solution (250 mg heme per ampoule) in which heme is stabilised as a complex with arginine (267 mg) suspended in a mixture of ethanol (1g) and propyleneglycol (4g) made up to 10 ml with water. The recommended dose is 3mg/kg body weight up to 250mg given on each of four consecutive days. It is often convenient to use a dose of 250mg for adults irrespective of their weight. In the summary of the product characteristics, it is recommended that the concentrated heme arginate solution should be mixed with 100mL physiological saline in a glass container immediately before infusion into a large peripheral vein or through a central venous line over 15-20 mins. Once diluted, the heme becomes unstable and may aggregate if there is undue delay. After infusion, the vein should be washed with saline for 10-15 min. Repetitive use of Normosang® can lead to vein toxicity in the form of disappearance of the superficial venous system and the consequent need for a central catheter. With time, these catheters may become obstructed by heme deposits. Current experience suggests that diluting the human hemin in 100ml of human albumin (4-20% depending on country availability) instead of saline solution delays or suppresses these problems. For more details (more about porphyria specialist centres).
Heme as a lyophilized powder (Panhematin; Abbot Laboratories) is available in the United States where human hemin (Normosang®) does not have FDA approval.
TREATMENT WITH HUMAN HEMIN (Normosang®)
Normosang® should be given as soon after the onset of the attack as practicable. In a mild attack, it may be acceptable to allow 24 hours for spontaneous settling of the attack. Otherwise, it should be given promptly, if possible within 24 hours of admission, to any patient with severe symptoms (severe pain, vomiting), or who shows complications such as seizures, hyponatraemia, or incipient neuropathy, and also to any patient with a history of a previous attack complicated by neuropathy. If delay is unavoidable, carbohydrate loading may be carried out as described below. Measurement of urinary ALA or PBG excretion is useful to document the metabolic response to human hemin.
Most patients improve within 5 days but, if necessary, the course may be repeated after a day or two but the effectiveness of prolonged treatment has not been evaluated.
Few side effects have been reported for the short-term use of Normosang®. The coagulopathies reported with other heme preparations do not occur with Normosang®. Though thrombophlebitis at peripheral vein infusion sites has been reported in less than 1% of cases, our own experience is that it is much commoner. The most frequently observed phenomenon after several courses of Normosang® is the disappearance of the superficial venous system and the need for an indwelling venous access (Portacath®) Administration in 4-20% human serum albumin (see above) greatly reduces the incidence of phlebitis. Hypersensitivity reactions are very rare. Attacks during pregnancy have been treated without any apparent adverse effects on mother or child. Each 250mg dose of heme contains 22.7mg of iron; about one tenth of the iron in one unit of blood. Iron overload is therefore a potential problem only in patients treated on numerous occasions.
Two litres of normal saline with 10-20% glucose given in divided doses of 500 ml over 24 hours through a central venous catheter. Carbohydrate loading has now been replaced by heme preparations as the treatment of choice for an acute attack of porphyria.
Less than 10% of patients have frequently repeated acute attacks. Advice on their management should be sort from a specialist centre. Special measures include gonadorelin analogues for repeated premenstrual attacks and long-term treatment with human hemin.
1. Anderson KE, Spitz IM, Bardin CW, Kappas A.
A gonadotropin releasing hormone analogue prevents cyclical attacks of porphyria.
Arch Intern Med 1990; 150: 1469-74.
2. Bonkovsky HL, Tschudy DP, Collins A et al.
Repression of the overproduction of porphyrin precursors in acute intermittent porphyria by intravenous infusions of hematin. Proc Natl Acad Sci 1971; 68: 2725-9.
3. Bonkovsky HL.
Advances in understanding and treating 'The little imitator', acute porphyria.
Gastroenterology 1993; 105: 590-94.
4. Brodie MJ, Moore MR, Thompson GG, Goldberg A.
The treatment of acute intermittent porphyria with laevulose.
Clin Sci Mol Med 1977; 53: 365-71.
5. Dover SB, Moore MR, Fitzsimmons EJ, Graham A, McColl KEL.
Tin protoporphyrin prolongs the biochemical remission produced by heme arginate in acute hepatic porphyria. Gastroenterology 1993; 105: 500-506.
6. Elder GH, Hift RJ.
Treatment of acute porphyria.
Hospital Medicine 2001; 62: 422-25.
7. Gorchein A.
Drug treatment in acute porphyria.
Br J Clin Pharmacol 1997; 44: 427-34.
8. Herrick AL, McColl KEL, Moore MR, Cook A, Goldberg A.
Controlled trial of heme arginate in acute hepatic porphyria.
Lancet 1989; i: 1295-97.
9. Kalman DR, Bonkovsky HL.
Management of acute attacks in the porphyrias.
Clin Dermatol 1998; 16: 299-306.
10. Mustajoki P, Nordmann Y.
Early administration of heme arginate for acute porphyric attacks.
Arch Intern Med 1993; 153: 2004-08.
11. Robert TL, Varella L, Meguid MM.
Nutrition management of acute intermittent porphyria.
Nutrition 1994; 10: 551-55.
12. Tenhunen R, Mustajoki P. Acute porphyria: treatment with heme.
Seminars in Liver Disease 1998; 18: 53-56.