AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Variegate porphyria (VP) is an inherited disorder of porphyrin-heme metabolism arising from mutations of the gene encoding the enzyme protoporphyrinogen oxidase. Manifestations of VP in any given individual may include cutaneous photosensitivity, systemic symptoms arising from neurologic dysfunction, or both.

Pathophysiology

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

Frequency

United States

No porphyria registry exists in the United States; therefore, accurate figures are not available. Unknown numbers of cases may still be unrecognized or misdiagnosed as another porphyria.

International

Incidence is estimated at 1 case in 300 persons in South Africa, where a gene mutation traceable to Dutch immigrants who married there in 1680 has been widely disseminated. In other parts of the world, VP is considered very uncommon or rare.

Mortality/Morbidity

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.

Race

No well-established racial predilection is known, although the disease is common among South Africans of Dutch ancestry who inherit a founder gene propagated in that population.

Sex

VP occurs in both men and women.

Age

VP usually presents after puberty. Very rare childhood cases have been ascribed to the presence of 2 mutant protoporphyrinogen oxidase genes in the same individual.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• About 60% of individuals harboring a protoporphyrinogen oxidase gene mutation have never been symptomatic but may have a positive family history. In manifested cases, photosensitivity alone is the presenting complaint 3-5 times more often than neuropathic symptoms alone. Both may be present in a minority of cases. Attack episodes can often be linked to history of a new medication.
• A porphyric attack is typically described as abdominal discomfort that may have progressed over several hours to severe pain extending into the back and thighs. Nausea with vomiting, constipation, hypertension, tachycardia, anxiety, and agitation may be reported. Pain and weakness developing in the arms and legs indicates an accelerating attack that may progress to flaccid quadriparesis. Central nerve paralysis, respiratory distress, confusion and bizarre behavior, seizures, and coma may have developed before the patient is initially seen by medical personnel. Historical factors associated with the onset of attacks in other acute porphyrias (hormonal fluctuations due to menses, pregnancy or therapeutic hormones, infections, other stressors) are not clearly responsible for many attacks of VP.

Physical

• Photocutaneous lesions are the most common presenting signs of VP. Mechanical fragility, blistering, milia, furrowing, and scarring occur in sun-exposed skin. Hypertrichosis, dyspigmentation, sclerodermoid changes, and a weather-beaten or leathery texture may be present. Children with VP experience photosensitivity of mutilating severity.
• Systemic signs occur less frequently and recur far less often in VP than in acute intermittent porphyria (AIP).
• • Pain in VP may become excruciating; uncontrolled vomiting can lead to dehydration. Deteriorating neurological function produces multiple sequelae. Initial limb weakness may progress to areflexic quadriparesis. Respiratory distress may become profound. Heart rate and blood pressure can rise to critical levels. During such crises, dark-orange or reddish urine is excreted and bowel function is disturbed. Tonic-clonic seizures and coma may ensue.
  • Whether psychiatric disturbances observed in patients with VP are truly attributable to the disease is contentious. 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. The larger South African experience, however, suggests that neuropsychiatric disturbances should not be attributed to VP, especially in the absence of other signs and symptoms of an attack. Metabolic encephalopathy does occur in VP crises and may contribute to some of these phenomena, and to seizures and coma.
• 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 VP 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.

Causes

VP arises from autosomal dominant inheritance of a gene mutation encoding a defective protoporphyrinogen oxidase enzyme protein with resultant deficient activity at approximately 50% of normal. The disease in most individuals with such a mutation remains clinically silent, but these persons are at risk of becoming symptomatic if exposed to environmental factors (most often drugs) that can induce overt phenotypical expression.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Hereditary coproporphyria
Acute intermittent porphyria

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• During active phases of VP, urinary porphyrin levels are abnormally high, with the coproporphyrin faction larger than the uroporphyrin faction.
• • Urinary aminolevulinic acid and porphobilinogen levels are greatly elevated during attacks but often normalize during quiescent phases.
  • Total fecal porphyrin excretion is often high, with protoporphyrin excretion greater than coproporphyrin excretion.
  • Erythrocyte porphyrin levels are normal in patients with heterozygosity, but when 2 mutant alleles for the protoporphyrin oxidase gene are present, the zinc protoporphyrin level is elevated.
  • Plasma porphyrin levels are always increased in patients who are symptomatic. A fluorescence emission peak maximal at 625-627 nm detected by spectrofluorometry is unique to VP and is a rapid means of confirming this specific diagnosis. Spectrofluorometry identifies such plasma porphyrin peaks in many, but not all, asymptomatic adult carriers of a protoporphyrin oxidase gene mutation, but it detects only some carriers in childhood.
  • Porphyrin abnormalities in urine, stool, and plasma may normalize during quiescent phases, or it may remain increased at variable levels.
  • Increased biliary porphyrin levels may be the most sensitive biochemical indicator during quiescence.
• Because medical management of an attack is the same for all acute porphyrias, qualitative evidence of elevated porphobilinogen is sufficient to justify initiating therapies in crisis situations while quantitative assays to establish a precise diagnosis are still pending. Protocols for rapid urinary porphobilinogen tests that can be performed at the bedside (modified Watson-Schwartz and Hoesch tests) are discussed in the article by Zaider and Bickers. A test kit is available (Trace PBG Kit, Thermo Trace/DMA; Arlington, Tex) that uses an anion-exchange resin and color chart that permits rapid, specific semiquantitative estimation of porphobilinogen.
• Assays for protoporphyrinogen oxidase enzyme activity are technically difficult and not widely available.
• Analyses for mutations in the protoporphyrinogen oxidase gene are performed in several research centers around the world with particular interest in genetic studies of porphyrias. Because the disease in most individuals carrying a mutation causing VP remains clinically silent, and may also be biochemically silent, family studies aimed at identifying all adults and children at risk for developing VP require mutation analysis for absolute certainty of identifying all carriers.

Histologic Findings

Histologic findings resemble those of porphyria cutanea tarda. 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

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

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 VP.

While most attacks of VP 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 VP than those with AIP 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 VP 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 University of Queensland Porphyria Research Unit.
• • These lists should only be considered general guides and can be confusing because some drugs appear on both "safe" or "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; but, 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 VP 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 (300-400 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 a heme-analogue acts to replete the hepatic free heme pool, thereby repressing aminolevulinic acid synthase. 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 Leiras Medica, Helsinki, Finland.
• 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 AIP than VP.
• 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 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.

Surgical Care

Liver transplantation for alcoholic cirrhosis in a patient with concurrent VP followed by recovery of the porphyria has been reported. Whether VP alone would ever be sufficient indication for liver transplantation would require a stringent risk/benefit analysis.

Consultations

• 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 are available through the American Porphyria Foundation. A particularly comprehensive guide to diagnosis and therapy of VP can be found through the University of Cape Town Porphyria Service.
• 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 VP.

Diet

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

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Heme analogues

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

Drug Category: Luteinizing hormone releasing-hormone analogues

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

Drug Category: Beta-adrenergic blocking agents

These agents reduce sympathetic hyperactivity.

Drug Category: Opiate analgesics

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

Drug Category: Antiemetics/sedatives

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

Drug Category: Anticonvulsants

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

Drug Category: Oral photoprotectants

These agents may reduce cutaneous photosensitivity.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• 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.

Further Outpatient Care

• Individuals with a confirmed diagnosis of VP 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. Rapid test results for urinary porphyrins and porphobilinogen should be obtained promptly, and the patient's condition should be monitored. Even if test results confirm a porphyric attack and if symptoms do not worsen, fluids and carbohydrates can be taken orally; and if vomiting does not ensue, conservative management may be continued in an outpatient setting. Otherwise, hospital admission is indicated.

Deterrence/Prevention

• 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 VP than in AIP, the possible association with porphyric attacks should be kept in mind.
• Sun avoidance should be practiced by patients with photocutaneous symptoms of VP.
• 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 help, but these agents rarely provide complete relief.
• The application of plastic film filters that exclude some of the offending wavelengths to car windows can be helpful, but this must conform with local motor vehicle safety regulations.
• Avoidance of mechanical trauma to sun-exposed skin reduces the occurrence of blisters and erosions.

Complications

• High levels of protoporphyrin in bile can lead to gallstone formation.
• Surgical cholelithectomies or cholecystectomies must be performed with care to avoid anesthetics that can induce attacks.

Prognosis

• Mild attacks of VP 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.

Patient Education

• Patients need careful instruction about the nature of the disease and its genetic implications for their family members.
• • Up-to-date 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.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Misdiagnosis of symptomatic VP 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.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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• Anderson KE, Bloomer JR, Bonkovsky HL, et al. Recomendations For the Diagnosis and Treatment of the Acute Porphyrias. Ann Int Med. 2005;142:439-450. [Medline].
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Article Last Updated: Feb 7, 2007