Variegate Porphyria 

Updated: Dec 20, 2019
Author: Carol E Cheng, MD; Chief Editor: Dirk M Elston, MD 

Overview

Background

Variegate porphyria (VP) is an inherited disorder of porphyrin-heme metabolism arising from mutations of the gene encoding the enzyme protoporphyrinogen oxidase.[1, 2, 3, 4] Manifestations of variegate porphyria in any given individual may include cutaneous photosensitivity (see image below), systemic symptoms arising from neurologic dysfunction, or both.[3, 5, 6, 7, 8]

Variegate porphyria. Courtesy of DermNet New Zeala Variegate porphyria. Courtesy of DermNet New Zealand (http://www.dermnetnz.org/assets/Uploads/systemic/vp1.jpg0).

Pathophysiology

Inherited as an autosomal dominant trait, variegate porphyria is biochemically characterized by accumulations of the photosensitizing porphyrins, protoporphyrin and coproporphyrin.[5] In addition, abnormally high levels of the porphyrin precursors, porphobilinogen and aminolevulinic acid, are found during episodic attacks of systemic symptoms.[5, 9] Acute attack symptoms are caused by dysfunctions of central, autonomic, and peripheral nervous systems that appear to be effects of deranged heme synthesis on neurons.[10]

Etiology

Variegate porphyria arises from autosomal dominant inheritance of a gene mutation encoding a defective protoporphyrinogen oxidase enzyme. To date, there have been 184 different mutations in the protoporphyrinogen oxidase gene that results in variegate porphyria.[11] Individuals with one such mutation have total enzyme activity diminished to as much as 50% of normal. Most individuals with one mutation remain asymptomatic, but they are at risk if exposed to environmental factors (most often drugs) that can induce overt phenotypical expression. Systemic stress, such as liver disease or cholelithiasis, has been noted to precipitate cutaneous symptoms in patients with underlying variegate porphyria.[12]

Inheritance of two mutant protoporphyrin oxidase genes causes a more profound reduction in residual enzyme activity to 25% or less, leading to more severe disease manifestations.[13, 14] Eleven such cases have been identified at this time. These homozygous patients present during early childhood with developmental delay, nystagmus, photosensitivity, and skeletal hand deformities.[11]

The founder gene mutation common among South Africans encodes an enzyme with little or no residual activity that may be lethal in homozygotes. Four South African children manifesting variegate porphyria were compound heterozygotes with the founder mutation on one allele, but a different mutation apparently encoding an enzyme with enough residual activity to enable survival, on the other.[15]

Epidemiology

Frequency

United States

A registry has been established to develop information about the prevalence of porphyrias in the United States (American Porphyria Foundation;http://www.rarediseasesnetwork.org/cms/porphyrias/registry). Unknown numbers of cases may be unrecognized or misdiagnosed as another porphyria.

International

Prevalence is estimated at 1 case in 300 persons in South Africa, where a protoporphyrinogen oxidase gene "founder" mutation traceable to Dutch immigrants who married there in 1680 has been widely disseminated.[15, 16] It is the most common acute porphyria in Chile,[17] where another founder mutation was identified in four apparently unrelated families.[18] A haplotype study of Argentinean patients with variegate porphyria suggested a founder mutation within its population as well.[19] Among the combined populations of 11 European countries, 70 new cases of variegate porphyria were identified over a 3-year period; assuming mean disease duration of 40 years, prevalence in Europe was calculated at 3.2 cases per million persons.[20] In Israel, its prevalence was estimated to be 6.3 cases per million people. This relatively high prevalence compared with Europe suggests a possible protoporphyrinogen oxidase gene mutation passed down through Jewish ancestry.[21]

Race

No well-established racial predilection is known, although the disease is common among South Africans of Dutch ancestry, many of whom inherit the founder gene propagated in that population. Most multiple case reports involve European populations or North or South American populations that include individuals with European heritage.

Sex

Variegate porphyria occurs in both men and women, but its distribution between the sexes remains unclear. A study exploring its prevalence in Europe suggested a female predominance[20] ; however, an Israeli cohort study found an equal distribution between the sexes.[21] In 2015, a publication by Ramanujam and Anderson stated that variegate porphyria is more often symptomatic in women.[22]

Age

Variegate porphyria usually presents after puberty. Very rare childhood cases have been ascribed to the presence of 2 mutant protoporphyrinogen oxidase genes in the same individual.[13, 23]

Prognosis

Mild attacks of variegate porphyria may resolve within a few to several days with conservative management. Those that progress to vomiting or early signs of neuropathy usually respond to the administration of a heme analogue for 4 days. Profound attacks that are either unrecognized or inadequately treated early enough in the course may progress to long-term debility or death.

Cutaneous photosensitivity may cause difficulty performing manual labor and may limit many daily activities. Neurovisceral disorders vary from relatively mild symptoms that can remit spontaneously to profound crises that can be fatal or incapacitating for months to years.[3, 5, 6, 7, 24]

Acute attacks of variegate porphyria can be life-threatening. However, with early diagnosis of active disease, identification of asymptomatic protoporphyrinogen oxidase gene mutation carriers, and avoidance of drugs and other factors known to induce or worsen clinical expression, symptomatology among those at risk can be minimized. Good medical management of overt episodes can reduce morbidity and mortality such that the long-term outlook for patients is positive.

Patient Education

Patients need careful instruction about the nature of the disease and its genetic implications for their family members. Current lists of safe and unsafe drugs should be provided to patients and their physicians. Dietary instructions for maintaining adequate carbohydrate intake and for consuming a rapidly absorbed form of glucose at the first signs of an attack should be given. Effective sun avoidance practices should be advised for those patients with cutaneous photosensitivity.

 

Presentation

History

A family history of variegate porphyria may or may not be present. Studies of the clinical penetrance of the variegate porphyria trait found that ~60% of all individuals harboring a single protoporphyrinogen oxidase mutation remained silent carriers.[25, 26] Among the 40% who did manifest symptoms, photosensitivity alone was the presenting complaint far more often than neurological disturbances alone, while only a small minority (4-8%) experienced both types of symptoms. Skin lesions were the presenting sign in approximately 80% of a group of 70 European patients identified.[20]

A porphyric attack is typically described as abdominal discomfort that may have progressed over several hours to severe pain extending into the back, chest, arms, and legs. Nausea with vomiting, constipation, hypertension, tachycardia, anxiety, and agitation may be reported. Pain and weakness developing in extremities indicates an accelerating attack that may progress to flaccid quadriparesis. Central nerve paralysis, respiratory distress, confusion and bizarre behavior, seizures, or coma may develop before the patient is assessed by medical personnel. Attack episodes of variegate porphyria can often be linked to history of a new medication. Factors historically associated with the onset of attacks in other acute porphyrias (eg, hormonal fluctuations due to menses, pregnancy or therapeutic hormones, infections, other stressors) appear to be less often responsible for attacks in variegate porphyria.[24]

Physical Examination

Photocutaneous lesions, the predominant presenting signs of variegate porphyria, include mechanical fragility, blistering, milia, furrowing, and scarring in sun-exposed skin. Hypertrichosis, dyspigmentation, sclerodermoid changes, and a weather-beaten or leathery skin texture may be present. Children with biallelic variegate porphyria experience photosensitivity of mutilating severity.[23, 27]

Neurovisceral dysfunctions occur less frequently and recur far less often in variegate porphyria than in acute intermittent porphyria (AIP).[24] Pain in variegate porphyria may become excruciating; uncontrolled vomiting can lead to dehydration. Deteriorating neurological function produces multiple sequelae, including peripheral neuropathy.[28] Initial limb weakness may progress to areflexic quadriparesis. Respiratory failure may occur. Heart rate and blood pressure can rise to critical levels. During such crises, dark-orange or reddish urine is excreted; bowel and bladder function may be disturbed. Ten to twenty percent of patients with acute porphyria experience seizures, which are most often characterized as tonic-clonic or focal with impaired awareness.[28] Coma may ensue.

Confusion, disorientation, agitation, mania, depression, and schizophrenialike behavior have all been reported. Psychiatric symptoms were noted in 80% of 18 Finnish patients during attacks, with 25% described as delirious and psychotic.[6] In the larger South African experience, however, neuropsychiatric disturbances are infrequent in variegate porphyria, especially in the absence of other signs and symptoms of an attack.[3] Metabolic encephalopathy may occur during variegate porphyria crises, contributing to some of these phenomena, as well as to seizures and coma. There has been one case study that reported posterior reversible encephalopathy syndrome (PRES) as a complication of variegate porphyria.[29]

Hypervolemia and hyponatremia noted in more severe attacks may involve renal salt wasting, inappropriate antidiuretic hormone secretion, or infusion of inappropriate replacement fluids. Hypomagnesemia may also be present.

Because variegate porphyria may variably manifest with only neurovisceral symptoms, with only cutaneous photosensitivity, or with both, other diagnoses to be considered include porphyrias that share either type or both types of symptoms and nonporphyric bullous disorders that occur in sun-exposed skin. Acute ascending polyneuropathy (Landry-Guillian-Barre syndrome) may resemble aspects of porphyric neuropathies in causing progressive paralyses that may affect respiratory muscles, in altering sensation or producing pain, and in disordering autonomic nervous system functions.

Complications

Complications can include renal disease[30] and hepatocellular carcinoma.[31, 32]

Chronically uncontrolled hypertension from acute porphyria can lead to renal impairment.[30]

Six cases of hepatocellular carcinoma (a known complication of acute intermittent porphyria in patients as young as 37 years) discovered at ages ranging from 54-81 years in patients with variegate porphyria were reviewed.[31] 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 at age 47 years is the practice of one porphyria specialist center.[31] Additional variegate porphyria-hepatocellular carcinoma cases included one presenting at age 48 years.[32] 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.[33] As of 2015, there have been 9 reported cases of hepatocellular carcinoma in patients with variegate porphyria, although the link between the two remains tenuous.[32, 34]

Gallstones, reported in a small number of patients, may be the presenting sign.[35] 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,[36, 37] but these are infrequent and most often brought on by inadvertent use of unsafe medications.[37, 38] 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.[38] Several pregnant women manifesting acute porphyric attack symptoms have been treated with intravenous hemin (as the heme analogue heme arginate) without adverse fetal effects.[39]

 

DDx

Diagnostic Considerations

Misdiagnosis of symptomatic variegate porphyria as porphyria cutanea tarda may lead to inappropriate treatment with phlebotomy or antimalarial therapies that are ineffective. This may also lead to failure to advise patients correctly about avoiding inducers of life-threatening attacks. Establishment of a complete profile of porphyrins and porphyrin precursors present in urine, feces, and blood should enable diagnostic distinction in most cases.

Other considerations include the following:

  • Hereditary coproporphyria

  • Acute intermittent porphyria

  • Landry-Guillain-Barré syndrome

Differential Diagnoses

 

Workup

Laboratory Studies

Urinary aminolevulinic acid and porphobilinogen levels are greatly elevated during attacks but often normalize during quiescent phases.[40] Older urinary porphobilinogen screening assays (eg, Watson-Schwartz and Hoesch methods)[41] had been supplanted for the last several years by a rapid semiquantitative test kit that is no longer commercially available. An alternative quantitative kit (PBG by Column Test #187-6001, BioRad; Hercules, Calif) remains available. Rapid determination of elevated urinary porphobilinogen allows early confirmation of an attack episode in variegate porphyria, acute intermittent porphyria, or hereditary coproporphyria porphyria.

Because medical management of an attack is the same for all three of these acute porphyrias, screening or rapid test kit evidence of elevated porphobilinogen is sufficient to justify initiating therapies in crisis situations, before other quantitative laboratory data for porphyrins and porphyrin precursors that establish a precise diagnosis can be obtained. Progressive motor weakness due to porphyric neuropathy, typically accompanied by high urinary porphobilinogen but normal cerebrospinal fluid protein levels, can be differentiated from acute ascending polyneuropathy (Landry-Guillain-Barré syndrome) by the normal urinary porphobilinogen but increased cerebrospinal fluid protein levels typical of the latter disorder.[33]

During symptomatic phases of variegate porphyria, urinary porphyrin levels are abnormally high, with coproporphyrin greater than uroporphyrin. Total fecal porphyrin excretion is also high; both protoporphyrin and coproporphyrin fractions are elevated,[42] with protoporphyrin greater than or equal to coproporphyrin. The isomer ratio of coproporphyrin III to coproporphyrin I is several-fold higher than normal.[43]

Erythrocyte porphyrin levels are typically normal in patients with one normal allele for the protoporphyrin oxidase gene and one with a deleterious mutation, but when 2 mutant alleles are present, zinc-protoporphyrin is elevated.[4, 23, 27]

Plasma porphyrin levels are increased in symptomatic patients. A fluorescence emission peak maximal at 625-627 nm detected by spectrofluorometry is unique to variegate porphyria, enabling rapid diagnostic confirmation.[44] Spectrofluorometry detects such plasma porphyrin peaks in many, but not all, asymptomatic adult carriers of protoporphyrin oxidase gene mutations, but only in some prepubertal carriers.[42]

Porphyrin abnormalities in urine, stool, and plasma may normalize during quiescent phases, or remain increased at variable levels. Increased biliary porphyrin levels may be the most sensitive biochemical indicator during quiescence.[45]

Assays for protoporphyrinogen oxidase enzyme activity are technically difficult, but are available in specialized porphyria laboratories in several countries.

Mutation analysis of the protoporphyrinogen oxidase (PPOX) gene is performed in several centers with particular interest in porphyrias and is commercially available in the United States. Genetic testing is often used to distinguish variegate porphyria from other acute hepatic porphyrias, in which clinical features may overlap significantly, and provides confirmation of the diagnosis.[46, 47] Because variegate porphyria in most individuals carrying a mutated gene remains clinically silent and may also be biochemically silent, family studies aimed at identifying all adults and children at risk for developing variegate porphyria require mutation analysis for absolute certainty of identifying all carriers. In order to accurately characterize the results of their mutational analysis, a genetic database of verified benign and pathological variants is necessary. To meet this need, the International Porphyria Molecular Diagnostic Collaborative was initiated in 2017 with the goal of establishing such a database.[48] Identifying asymptomatic patients with a pathologic mutation in their PPOX gene is important, as they should be counseled on avoiding triggers that may precipitate acute porphyric episodes.[47]

Imaging Studies

Ultrasonography screening for hepatocellular carcinoma is indicated at least annually for individuals with variegate porphyria aged 50 years or older, especially those who have had long-term elevations of porphyrins and porphobilinogen. Gallstones may also be detected by ultrasonography.

Bone mineral density scanning can be performed to detect significant bone loss in individuals who have avoided sunlight over long periods because of unremitting porphyric photosensitivity.

Other Tests

Serum vitamin D levels are recommended to assess insufficient or deficient levels resulting from long-term avoidance of sunlight exposure.

Periodic serum α-fetoprotein assessment is useful in surveillance for the development of hepatocellular carcinoma.

Periodic assessment of renal function is indicated in individuals with chronic arterial hypertension.

Histologic Findings

Histologic findings resembling those of porphyria cutanea tarda are well described.[49, 50] Bullae are subepidermal and cell poor; a mild perivascular lymphocytic inflammatory infiltrate may be present. Thickened, hyalinized superficial dermal blood vessel walls contain periodic acid-Schiff stain–positive, diastase-resistant glycoprotein deposits. Ultrastructural examination of the dermal vasculature and the dermoepidermal junction reveals replicated basement membranes believed to be elaborated by multiple episodes of damage and repair and fine fibrillar material in the surrounding dermis. Immunoglobulin and complement deposits that are present perivascularly and at the dermoepidermal junction are believed to be due to leakage of these proteins from damaged blood vessels rather than to immunologically mediated events.

 

Treatment

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:

  • 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.[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]

 

Medication

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Acute attack episodes often require use of many medications in intensive care settings, too numerous to list exhaustively here. Consultation with experts in the management of acute porphyrias is strongly recommended to obtain up-to-date guidance, especially in crisis situations. Judicious selection of agents, dosages, and routes of administration should take into account not only avoiding drugs known or suspected to be unsafe in acute porphyrias, but also best practices and continuously evolving guidelines for optimal use of agents generally considered safe.

Heme analogues

Class Summary

Infusion of hemelike agents rapidly restores the free-heme pool in hepatocytes, thereby exerting negative feedback repression on the rate-limiting enzyme of heme synthesis. Prompt use may prevent an attack from causing neuronal degeneration.

Hemin (Panhematin)

This agent is an enzyme inhibitor derived from processed red blood cells that is an iron-containing metalloporphyrin. It was previously known as hematin, a term used to describe the chemical reaction product of hemin and sodium carbonate solution. It has an anticoagulant effect and may cause thrombophlebitis at the infusion site. It must be reconstituted from lyophilized powder. Reconstitute it with human serum albumin 25% (132 mL of 25% human serum albumin to 1 vial of hemin [301 mg heme]) and infuse it into large vein to reduce the risk of thrombophlebitis.

Luteinizing hormone-releasing hormone analogues

Class Summary

These agents decrease endogenous estrogen and progesterone production. The infrequency of menses-related attacks in variegate porphyria would make this therapy infrequently considered.

Leuprolide (Lupron)

Leuprolide suppresses ovarian and testicular steroidogenesis by decreasing luteinizing hormone and follicle-stimulating hormone levels.

Beta-adrenergic blocking agents

Class Summary

These agents reduce sympathetic hyperactivity.

Propranolol (Inderal)

Propranolol has membrane-stabilizing activity and decreases the automaticity of contractions. It is not suitable for emergency treatment of hypertension. Do not give intravenously in hypertensive emergencies.

Opiate analgesics

Class Summary

These agents provide relief of severe abdominal and/or other pain. Very large doses may be required over the course of a day.

Morphine sulfate (Duramorph, Astramorph, MS Contin)

Morphine sulfate is the drug of choice for analgesia, owing to its reliable and predictable effects, safety profile, and ease of reversibility with naloxone. Various intravenous doses are used; it is commonly titrated until the desired effect is obtained.

Antiemetics/sedatives

Class Summary

These drugs reduce nausea and vomiting, control anxiety and agitation, and potentiate analgesia.

Chlorpromazine (Thorazine)

Chlorpromazine’s mechanisms responsible for relieving nausea and vomiting include blocking postsynaptic mesolimbic dopamine receptors, anticholinergic effects, and depression of RAS. It blocks alpha-adrenergic receptors and depresses the release of hypophyseal and hypothalamic hormones. Use a slow intravenous infusion (patient lying flat) when symptoms persist (25-50 mg with 500-1000 mL of normal saline); monitor blood pressure.

Ondansetron (Zofran, Zofran ODT, Zuplenz)

Ondansetron is one of a class of agents termed serotonin 5-HT3 receptor antagonists. It blocks the action of serotonin, a neurotransmitter manufactured in the brain that may cause nausea and vomiting.

Anticonvulsants

Class Summary

These agents prevent seizure recurrence and terminate clinical and electrical seizure activity.

Gabapentin (Neurontin)

Gabapentin is structurally related to GABA but does not interact with GABA receptors; it is not converted metabolically into GABA or a GABA agonist and is not an inhibitor of GABA uptake or degradation. Gabapentin does not exhibit an affinity for other common receptor sites.

Diazepam (Valium)

Diazepam is for acute seizure control by intravenous infusion. It depresses all levels of the CNS (eg, limbic and reticular formation), possibly by increasing the activity of GABA. Individualize the dose and increase cautiously to avoid adverse effects.

Clonazepam (Klonopin)

Clonazepam is a long-acting benzodiazepine that increases presynaptic GABA inhibition and reduces monosynaptic and polysynaptic reflexes. It suppresses muscle contractions by facilitating inhibitory GABA neurotransmission and other inhibitory transmitters. It has multiple indications, including suppression of myoclonic, akinetic, or petit mal seizure activity and focal or generalized dystonias (eg, tardive dystonia). It reaches peak plasma concentrations 2-4 hours after oral or rectal administration. It is not often used intravenously in the United States.

Levetiracetam (Keppra, Keppra XR, Spritam)

Levetiracetam is most often used in combination with other medications to treat partial (focal), myoclonic, and tonic-clonic seizures in people with epilepsy.

Magnesium sulfate

Magnesium sulphate corrects hypomagnesemia and helps control seizures. It is a nutritional supplement in hyperalimentation; it is a cofactor in enzyme systems involved in neurochemical transmission and muscular excitability.