TREATMENT OF THE ACUTE ATTACK
1. SUPPORTIVE TREATMENT
2. SPECIFIC TREATMENT
3. RECURRENT ATTACKS
4. LONG TERM MANAGEMENT
FURTHER INFORMATION
TREATMENT OF THE ACUTE ATTACK
The diagnosis of an acute attack of porphyria should be confirmed with a quantitative urine porphobilinogen (PBG) concentration before starting specific treatment (eg with human hemin). This is essential in patients without a previous diagnosis of acute porphyria. For patients who have had an unequivocally diagnosed porphyria attack in the past, it may be necessary to start specific treatment before the results of the laboratory investigation are available. Withdraw any drugs which are not safe in porphyria. Treat any infection.
1. Supportive treatment
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. In patients with sporadic attacks, pain is typically very severe but resolves completely within 7 days. In these patients, opiates can be used freely for the duration of the pain but should be stopped before discharge from hospital.
In some patients, particularly those with recurrent attacks, chronic 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 regular opiate use. Alternative medication should be considered, for example the gabapentinoids.
Fluid balance
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 associated with porphyria attacks is typically multifactorial resulting from renal and gastrointestinal losses as well as the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). The cause of any hyponatraemia should be evaluated including assessment of intravascular volume status. Fluid restriction is not usually appropriate, and treatment should be in compliance with local guidelines on hyponatraemia assessment and treatment. If correction with saline is indicated, this should should not exceed 8 mmol/L in any 24 hour period to reduce the risk of cerebral oedema and osmotic demyelination. Intensive care support should be considered if plasma sodium falls below 125 mmol/L and always if the patient is symptomatic (confusion, seizures, coma).
Carbohydrate support
Since impaired nutrition may aggravate acute porphyria, it is important to give adequate calories, preferably as carbohydrate-rich food supplements orally or via a nasogastric tube. When vomiting prevents enteral administration, carbohydrate may be provided as normal saline with 5-10% dextrose, two litres of which provide 100-200 g of glucose per day. Infusion of hypotonic dextrose may be harmful and should be avoided especially if the patient is hyponatraemic. As soon as patients are able to take food orally, they should be transferred to a normal diet in which carbohydrate provides 55-60% of the energy needed to maintain their normal weight.
Cardiovascular symptoms
Cardiovascular complications such as hypertension and tachycardia are rarely severe enough to require specific treatment. Very occasionally, the acute attack is accompanied by a severe cardiovascular crisis with dangerous hypertension, encephalopathy, seizures and ischaemic changes on CT brain scanning. Human hemin must be administered to abort the attack and symptomatic treatment given in compliance with local guidelines preferably within an intensive care unit.
Neuropathy
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. Human hemin must be administered as soon as possible to stop the attack and slow progression of the neuropathy. Artificial ventilation is necessary if vital capacity becomes severely reduced by paralysis of the intercostal muscles and may have to be continued for several months while neurological recovery takes place. Regular intensive physiotherapy is essential to achieve the best outcome.
2. Specific treatment
Mild attacks may resolve with supportive treatment. Severe attacks should be treated with intravenous hemin. Carbohydrate is obsolete in the treatment of an acute attack of porphyria except in situations where hemin is not readily available.Intravenous hemin
Preparations
- NormosangĀ® (human hemin, Recordati) 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 (1 g) and propylene glycol (4 g) made up to 10 ml with water. The recommended dose is 3 mg/kg body weight up to 250 mg given on each of four consecutive days. It is often convenient to use a dose of 250 mg for adults irrespective of their weight. The required volume of heme arginate solution should be mixed with 100 mL physiological saline immediately before infusion into a large peripheral vein or through a central venous line over 30-45 mins. Once diluted, the heme becomes unstable and may aggregate if there is delay. After infusion, the vein should be flushed thoroughly with saline, including positive pressure boluses. Repeated use of NormosangĀ® can lead to thrombophlebitis and disappearance of the superficial venous system with the consequent need for a central catheter. With time, these catheters may become obstructed by heme deposits. Diluting the human hemin in 100 ml of 20% human albumin instead of saline solution may reduce these problems and is the preferred practice in several countries although evidence is limited.
- Heme as a lyophilized powder (Panhematin; Abbot Laboratories) is available in the United States where human hemin (NormosangĀ®) does not have FDA approval.
TREATMENT WITH HUMAN HEMIN (NormosangĀ®)
NormosangĀ® should be given as soon after the onset of the attack as possible to any patient with severe symptoms (severe pain, vomiting), or with complications (such as seizures, hyponatraemia, or incipient neuropathy), and also to any patient with a history of a previous attack complicated by neuropathy. In a mild attack, it is acceptable to allow 24 hours for spontaneous settling of the attack while providing supportive measures and monitoring closely. Most patients improve within 5 days but, repeat courses of hemin may be needed in patients with severe attacks complicated by neuropathy.
Venous Access:
To reduce the risk of painful thrombophlebitis, hemin administration requires secure venous access, either via a large bore peripheral cannula or central line. Peripheral cannulas should be flushed thoroughly after hemin infusion and changed after each dose, preferably by alternating arms. During peripheral administration, the infusion should be continuously monitored for extravasation, which can cause a severe tissue injury.
Side-effects:
Few side effects have been reported for the short-term use of NormosangĀ®. The most common side effect is thrombophlebitis when the drug is administered through a peripheral cannula. Allergic reactions including anaphylaxis have been reported but are extremely rare. The coagulopathies reported with other heme preparations do not occur with NormosangĀ®. Each 250 mg dose of heme contains 22.7 mg of iron, about one tenth of the iron in one unit of blood. Iron overload is therefore a potential problem only in patients treated frequently for many years. Attacks during pregnancy and in breast feeding women have been treated without any apparent adverse effects on mother or child.
Carbohydrate loading (when hemin is not available)
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.
3. Recurrent attacks
Less than 10% of patients who have an acute attack will go on to have recurrent acute attacks. Advice on their management should be sought from a specialist porphyria centre. Most patients are managed with prophylactic human hemin, Long term treatment with hemin usually provides some benefit, but is only partially effective with many patients continuing to have attacks and hospital admissions, as well as debilitating symptoms such as pain, nausea, and fatigue, which have a profound negative impact on all aspects of their lives. Side effects, particularly difficulty maintaining central venous access, and liver iron overload mean that this treatment cannot continue indefinitely. Hemin is a potentially toxic molecule, which is taken up by the liver following infusion. Recent published evidence shows that regular hemin infusions can cause chronic hepatic inflammation, which may contribute to prolonged recurrence of attacks. Liver transplantation is a last resort option for the most severely affected patients with recurrent attacks when long term use of hemin is poorly effective or limited by loss of central venous access or other complications. Givlaari (givosiran) is a new treatment to prevent recurrent attacks which has shown high efficacy and an acceptable safety profile in clinical trials. Other management options may be available in some countries but not others, such as the use of gonadorelin analogues for women with repeated premenstrual attacks.4. Long term management
Patients with acute porphyria, especially those who are severely affected, are at risk of long term complications including hypertension, chronic kidney disease and in older patients, hepatocellular carcinoma. Recommendations for follow up care are being developed and will be published on this website when available. In the meantime, appropriate monitoring should include annual checks of blood pressure and renal function, and annual (at least) liver imaging in patients over the age of 50.Further information
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Early administration of heme arginate for acute porphyric attacks.
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Repression of the overproduction of porphyrin precursors in acute intermittent porphyria by intravenous infusions of hematin.
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Acute hepatic porphyrias: recommendations for evaluation and long-term management
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Recurrent attacks of acute hepatic porphyria: major role of the chronic inflammatory response in the liver.
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8. Balwani M, Sardh E, Ventura P, et al.
Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria.
N Engl J Med. 2020 Jun 11;382(24):2289-2301.
Date of last update: December 7th, 2020.