Approach Considerations
Management of acute porphyric attacks is complex and has been the subject of several reviews, [3, 8, 33, 40, 51, 52, 53, 54] 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. Obtaining management advice from experts early in the course of a suspected acute porphyric attack is strongly recommended.
Medical Care
Extensive lists of 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:
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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.
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Porphyric patients appear to vary widely in tolerance of specific agents, even those well known to be porphyrinogenic.
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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.
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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. [55]
Intravenous infusion of hemin preparations acts to replete the hepatic free heme pool, thereby repressing aminolevulinic acid synthase and the build up of heme precursors. [56] Hemin should be given early in attacks, particularly those that are severe or are not responsive to symptomatic management, fluids, and carbohydrates within a day. It should be constituted in albumin and delivered at a rate of 3-4 mg/kg/day through a central vein. This decreases the risk of phlebitis, which can occur if administered via a peripheral vein. [46] In the United States, hemin is available as heme hydroxide (Panhematin; Recordati Rare Diseases; Lebanon, NJ). In other parts of the world, hemin is available as heme arginate (Normosang; Orphan Europe; Paris, France). Heme arginate is not currently available in the United States. It has fewer adverse effects than hemin. In general, adverse effects of heme in addition to phlebitis include endothelial toxicity, transient thrombocytopenia, prolonged prothrombin time, thrombosis, iron overload, and tachyphylaxis. [46, 57]
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. [58] Cyclic attacks are more characteristic of acute intermittent porphyria than variegate porphyria. [24]
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, levetiracetam, vigabatrin, gabapentin, or magnesium sulfate to control seizures; (2) with propranolol to effect beta-blockade to control severe tachycardia and hypertension; (3) with morphine for severe pain; and (4) with a phenothiazine or ondansetron or related agents 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 hemin (heme analogue) preparation 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.
Paralyses occurring during acute attacks that do not remit promptly with treatment may persist for long periods or improve incrementally over months. Lengthy rehabilitation therapy programs may be needed.
Attacks progressing to neuropathic phases are best handled in an intensive care setting until crises are stabilized and recovery ensured.
While intravenous hemin is the standard of care for variegate porphyria, additional treatments remain in development owing to the significant adverse effect profile of hemin and its slow therapeutic onset. [57] Givosiran, an RNA interference (RNAi) molecule directed against the gene that codes for delta aminolevulinic acid synthase 1 (ALAS1) in the liver, has emerged as a promising therapy. [59] Murine models of acute intermittent porphyria suggested that RNAi can both prevent and treat porphyric attacks. [57] Phase 1 clinical trials of givosiran showed similarly promising results in patients with acute intermittent porphyria. [59] Those treated with monthly injections of givosiran demonstrated decreased ALAS1 mRNA, aminolevulinic acid, and porphobilinogen levels, along with less frequent porphyric attacks. However, these results have yet to be extended to the other acute hepatic porphyrias, including variegate porphyria.
Surgical Care
Liver transplantation for alcoholic cirrhosis in a patient with concurrent variegate porphyria followed by recovery from the porphyria has been reported. [60] 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.
Anesthetic agents for any surgical procedure must be carefully selected to avoid several drugs well-known or suspected to induce or exacerbate acute porphyrias.
Consultations
Consultation with a porphyria expert is strongly recommended 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.
Diet
Carbohydrate restriction should be avoided. Meals should provide adequate sources of complex carbohydrates to maintain blood glucose levels in reference ranges.
Prevention
Patients must avoid use of hazardous drugs. Patients should also avoid carbohydrate-restricted diets and limit alcohol intake and smoking, including marijuana. [46] Although steroid hormonal fluctuations, infections, and other stressors may be less problematic in variegate porphyria than in acute intermittent porphyria, the possible association with porphyric attacks should be kept in mind.
Sun avoidance should be practiced by patients with photocutaneous symptoms of variegate porphyria. Lifestyle changes and protective clothing are required. Sunblock creams containing physical sunscreen agents (titanium dioxide, zinc oxide) are more effective than chemical sunscreens. [46] Tinting of window glass or application of plastic film filters to windows to exclude some of the offending light wavelengths can be helpful, but it must conform with local motor vehicle safety regulations.
Avoidance of mechanical trauma to sun-exposed skin reduces the occurrence of blisters and erosions.
Long-Term Monitoring
Individuals with a confirmed diagnosis of variegate porphyria should be instructed that if they sense an impending attack (usually onset of abdominal discomfort that continues over several hours), they should discontinue medication (especially any new drug), consume a source of glucose, and contact their physician immediately. Screening test results for urinary porphyrins and porphobilinogen should be obtained promptly, and the patient's condition should be monitored. Even if test results do confirm a porphyric attack, if symptoms do not worsen, fluids and carbohydrates can be taken orally; if vomiting does not ensue, conservative management may be continued in an outpatient setting. Otherwise, hospital admission is indicated.
Surveillance for hepatocellular carcinoma in patients with active variegate porphyria and silent carriers of protoporphyrinogen oxidase gene mutations by annual liver ultrasonography and serum α-fetoprotein testing starting at age 47 years, [31] or even younger, [32] has been recommended. Semiannual monitoring beginning at age 50 years has also been suggested, particularly when increased porphobilinogen or porphyrins have persisted over long periods. [33] Studies suggest an emerging role for the biomarker protein induced by vitamin K absence or antagonist-II (PIVKA-II) in surveillance for hepatocellular carcinoma; however, its utility remains a topic of investigation. [34]
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Variegate porphyria. Courtesy of DermNet New Zealand (http://www.dermnetnz.org/assets/Uploads/systemic/vp1.jpg0).
