Variegate Porphyria Treatment & Management
- Author: Maureen B Poh-Fitzpatrick, MD; Chief Editor: Dirk M Elston, MD more...
Management of acute porphyric attacks is complex and has been the subject of several reviews,[3, 8, 23, 32, 33, 25, 34, 35] 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.
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:
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.
Intravenous infusion of hemin preparations acts to replete the hepatic free heme pool, thereby repressing aminolevulinic acid synthase. 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. In the United States, hemin is available as heme hydroxide (Panhematin; Recordati Rare Diseases; Kenilworth, NJ). In other parts of the world, hemin is available as heme arginate (Normosang; 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. Cyclic attacks are more characteristic of acute intermittent porphyria than variegate porphyria.
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.
Liver transplantation for alcoholic cirrhosis in a patient with concurrent variegate porphyria followed by recovery from the porphyria has been reported. 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.
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.
Carbohydrate restriction should be avoided. Meals should provide adequate sources of complex carbohydrates to maintain blood glucose levels in reference ranges.
Chronically uncontrolled hypertension from acute porphyria can lead to renal impairment.
Six cases of hepatocellular carcinoma (a known complication of acute intermittent porphyria in patients as young as 37 y) discovered at ages ranging from 54-81 years in patients with variegate porphyria were reviewed. One had no symptoms of porphyria prior to diagnosis of the cancer. Annual screening for hepatocellular carcinoma in patients with any acute porphyria, and of asymptomatic carriers of mutations for any acute porphyria, by hepatic ultrasound and serum α-fetoprotein studies beginning age 47 years is the practice of one porphyria specialist center. Additional variegate porphyria-hepatocellular carcinoma cases included one presenting at age 48 years. Liver imaging at 6-month intervals in patients with any acute porphyria aged 50 years or older with long-standing, unremitting elevations in porphobilinogen or porphyrins is another expert recommendation.
Gallstones, reported in a small number of patients, may be the presenting sign. High levels of protoporphyrin in bile may lead to gallstone formation. Surgical cholelithectomies or cholecystectomies must be performed with care to avoid anesthetics that can induce attacks.
Patients with acute porphyrias may be subject to attacks during pregnancy,[44, 45] but these are infrequent and most often brought on by inadvertent use of unsafe medications.[45, 46] When acute symptoms occur during pregnancy, management recommendations follow the same outlines as for nonpregnant women, including the use of an intravenous heme analogue if necessary. Several pregnant women manifesting acute porphyric attack symptoms have been treated with intravenous hemin (as the heme analogue heme arginate) without adverse fetal effects.
Patients must avoid use of hazardous drugs. Patients should also avoid carbohydrate-restricted diets and limit alcohol intake and smoking. 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) or sunless tanning creams or gels containing dihydroxyacetone that impart pigmentation to the stratum corneum may be of limited value, but these agents rarely provide complete relief. Tinting of window glass or application of plastic film filters to windows to exclude some of the offending light wavelengths can be helpful, but must conform with local motor vehicle safety regulations.
Avoidance of mechanical trauma to sun-exposed skin reduces the occurrence of blisters and erosions.
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, or even younger, 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.
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