Variegate Porphyria Treatment & Management

Management of acute porphyric attacks is complex and has been the subject of several reviews,^{[3, 8, 22, 29, 30]} which are the sources of most of the following guidelines.

Individuals with any acute porphyria must be informed of the risks of encountering the factors that can exacerbate the disease. Patients must avoid hazardous medications, and physicians must avoid administering them to those at risk. Most of these drugs are inducers of hepatic cytochrome P450, formation of which requires heme, thereby accelerating heme synthesis. Protoporphyrinogen oxidase deficiency then leads to accumulation of the porphyrins and porphyrin precursors that cause symptomatic variegate porphyria.

While most attacks of variegate porphyria appear to be drug induced, in some cases, the inducing factor is uncertain. Therefore, minimizing exposure to factors known to induce attacks in other acute porphyrias is prudent. Thus, avoidance of carbohydrate-restricted diets, moderation of alcohol intake, and smoking cessation is rational advice. Steroid hormonal fluctuations seem generally better tolerated by women with variegate porphyria than those with acute intermittent porphyria but cannot be considered negligible risks. Necessary hormone therapy should be initiated with caution. Prompt treatment of infections and other stressors is recommended. A bracelet or necklace tag identifying the wearer as having variegate porphyria can prevent inadvertent administration of hazardous drugs in emergency situations in which the patient cannot give a history. Medical management of an acute attack is complex; obtaining advice from experts early in its course is strongly recommended.

Extensive lists of the drugs and chemicals that are considered risky or believed safe can be obtained from several sources, including current textbooks and journal reviews. Online sources include the American Porphyria Foundation, the University of Cape Town Porphyria Service, and the European Porphyria Network (including the Nordic Acute Porphyria Drug Database). Note the following:

• These lists should only be considered general guides and can be confusing because some drugs appear on both "safe" and "unsafe" lists. Further, drugs on some unsafe lists are considered usable in patients with porphyrias by some authorities.
• Porphyric patients appear to vary widely in tolerance of specific agents, even those well known to be porphyrinogenic.
• Minimizing any drug usage is wise in porphyric individuals; however, when necessary, choose the safest possible agent after a careful review of lists and recommendations.
• Contentious agents should only be used in circumstances that allow for careful monitoring for adverse events.

Extreme carbohydrate-restricted dieting or fasting should be avoided. Individuals with variegate porphyria who sense an impending attack should immediately consume a source of glucose (eg, candy, soft drinks, fruit juices) and seek medical care. Intravenous infusions or high oral consumption (300-500 g/d) of glucose may abort attacks if given early. Glucose reduces the activity of hepatic aminolevulinic acid synthase, the rate-controlling enzyme of hepatic heme synthesis.^[31]

Intravenous infusion of a heme-analogue acts to replete the hepatic free heme pool, thereby repressing aminolevulinic acid synthase.^[32] Heme should be given early in attacks, particularly those that are severe or are not responsive to symptomatic management, fluids, and carbohydrates within a day. In the United States, the analogue hemin is available (Panhematin, Ovation Pharmaceuticals; Deerfield, Ill). In other parts of the world, heme arginate is available as Normosang from Orphan Europe (Paris, France).

Women with acute porphyrias who experience cyclic attacks in the week prior to menstruation may benefit from suppression of ovulation by exogenous luteinizing hormone–releasing hormone agonist therapy.^[33] Cyclic attacks are more characteristic of acute intermittent porphyria than variegate porphyria.^[15]

Management of fluid and electrolyte imbalances, particularly hyponatremia and hypomagnesemia, is critical during attacks. Intravenous fluid replacement should be with 5% dextrose in saline rather than in water. Experience in several porphyria centers with (1) clonazepam, diazepam, magnesium sulfate, or gabapentin to control seizures; (2) with propanolol to effect beta-blockade to control severe tachycardia and hypertension; (3) with morphine or meperidine for severe pain; and (4) with a phenothiazine to reduce nausea and vomiting, agitation, and anxiety supports the safety and efficacy of these agents.

Mild attacks (those in which pain levels can be adequately addressed by standard doses of acetaminophen, aspirin, or codeine and in which vomiting does not develop) may remit over 1-2 days with conservative management. Any porphyrinogenic drug must be eliminated, and adequate fluid and carbohydrate intake must be ensured. If improvement is not observed within this time frame, administration of a heme analogue is indicated. Obtaining this "orphan drug" may require delivery from a remote source; a supplier should be contacted as soon as an attack is recognized.

Liver transplantation for alcoholic cirrhosis in a patient with concurrent variegate porphyria followed by recovery of the porphyria has been reported.^[34] Whether variegate porphyria alone would constitute a sufficient indication for liver transplantation would require a stringent risk/benefit analysis on a case-by-case basis.

Consultation with a porphyria expert may be helpful in managing an acute attack. Lists of physicians with expertise in porphyrias and of laboratories for analysis of porphyrins and porphyrin precursors in the United States are available through the American Porphyria Foundation. A particularly comprehensive guide to diagnosis and therapy of variegate porphyria can be found through the University of Cape Town Porphyria Service. Several European centers with expertise and laboratory resources for evaluation and management of acute porphyrias may be found through the European Porphyria Network.

Consultation with a dermatologist is recommended for sun avoidance/protection measures and treatment of infected skin lesions.

Consultation with an anesthesiologist is required for the selection of safe anesthetic agents for any needed surgery.

Consultation with a neurologist for evaluation and treatment of neuropathy is indicated. Rehabilitation medicine services may be needed for recovery of neuromotor deficits over a several-month period.

Consultation with a gynecologist should be sought if hormonal therapies are considered.

A medical geneticist can assist in counseling patients and families about the heritability and penetrance of variegate porphyria.

Carbohydrate restriction should be avoided. Meals should provide adequate sources of complex carbohydrates to maintain blood glucose levels in reference ranges.