eMedicine Specialties > Dermatology > Metabolic Diseases

Variegate Porphyria

Maureen B Poh-Fitzpatrick, MD, Professor Emerita of Dermatology and Special Lecturer, Columbia University; Professor of Medicine (Dermatology), University of Tennessee

Updated: Feb 18, 2009

Introduction

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, systemic symptoms arising from neurologic dysfunction, or both.^3,5,6,7,8

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 These episodes are caused by dysfunctions of central, autonomic, and peripheral nervous systems that appear to be effects of deranged heme synthesis on neurons.¹⁰

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 protoporphyrinogen oxidase gene mutation traceable to Dutch immigrants who married there in 1680 has been widely disseminated.^11,12 In other parts of the world, variegate porphyria is considered uncommon to 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.^3,5,6,7,13

Race

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

Sex

Variegate porphyria occurs in both men and women.

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.^14,15

Clinical

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 approximately 60% of all individuals harboring a single protoporphyrinogen oxidase mutation remained silent carriers.^16,17  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.
• 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. 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.¹³

Physical

• Photocutaneous lesions are the most common presenting signs of variegate porphyria. 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 homozygous variegate porphyria experience photosensitivity of mutilating severity.^14,18
• Systemic signs occur less frequently and recur far less often in variegate porphyria than in acute intermittent porphyria (AIP).¹³
• Pain in variegate porphyria 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.
• 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 does occur in variegate porphyria crises and may contribute to some of these phenomena, as well as 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 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.

Causes

Variegate porphyria arises from autosomal dominant inheritance of a gene mutation encoding a defective protoporphyrinogen oxidase enzyme protein. Individuals with one such mutation have enzyme activity diminished to 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. Inheritance of 2 mutant protoporphyrin oxidase genes causes a more profound reduction in residual enzyme activity to 25% or less, with more severe disease manifestations presenting in childhood.^15,19

Differential Diagnoses

Other Problems to Be Considered

Hereditary coproporphyria
Acute intermittent porphyria

Workup

Laboratory Studies

• During active phases of variegate porphyria, urinary porphyrin levels are abnormally high, with the coproporphyrin faction larger than the uroporphyrin fraction.
• Urinary aminolevulinic acid and porphobilinogen levels are greatly elevated during attacks but often normalize during quiescent phases.²⁰
• Total fecal porphyrin excretion is often high, with protoporphyrin excretion greater than coproporphyrin excretion.²¹
• 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.^4,14,18
• 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 variegate porphyria and is a rapid means of confirming this specific diagnosis.²² 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.²¹
• Porphyrin abnormalities in urine, stool, and plasma may normalize during quiescent phases, or they may remain increased at variable levels.
• Increased biliary porphyrin levels may be the most sensitive biochemical indicator during quiescence.²³
• 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. Rapid qualitative porphobilinogen tests for screening random urine samples include modified Watson-Schwartz and Hoesch assays.²⁴ A commercial test kit with an anion-exchange minicolumn and a color chart for rapid, specific semiquantitative porphobilinogen estimation is available (Trace PBG Kit, Thermo Fisher Scientific; Waltham, Mass).
• Assays for protoporphyrinogen oxidase enzyme activity are technically difficult, but they are available in a few specialized porphyria  laboratories in several different countries.
• Mutation analysis of the protoporphyrinogen oxidase gene is performed in several centers with particular interest in porphyrias, and it is commercially available in the United States. Because variegate porphyria in most individuals carrying a mutated gene remains clinically silent and may 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.

Histologic Findings

Histologic findings resembling those of porphyria cutanea tarda are well described.^25,26 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

Medical Care

Management of acute porphyric attacks is complex and has been the subject of several reviews,^3,8,20,27,28 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 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" 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.²⁹
• Intravenous infusion of a heme-analogue acts to replete the hepatic free heme pool, thereby repressing aminolevulinic acid synthase.³⁰ 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.³¹ Cyclic attacks are more characteristic of acute intermittent porphyria than variegate porphyria.¹³
• 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.

Surgical Care

Liver transplantation for alcoholic cirrhosis in a patient with concurrent variegate porphyria followed by recovery of the porphyria has been reported.³² Whether variegate porphyria 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 variegate porphyria 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 variegate porphyria.

Diet

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

Medication

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

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.

Hemin (Panhematin)

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

Dosing

Adult

3-4 mg/kg/d IV for 4 d (up to 14 d prn);
1-4 mg/kg/d IV over 10-15 min for 3-14 d, based on clinical signs; in severe cases, may repeat no earlier than q12h, not to exceed 6 mg/kg/24h

Pediatric

Not established

Interactions

May further increase effect of anticoagulants

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Attacks of porphyria may progress to neuronal damage; prompt use may prevent attack from causing neuronal degeneration, but not effective in repairing existing neuronal damage; asymptomatic and reversible renal shutdown, oliguria, and increased nitrogen retention have occurred; no worsening of renal function has been seen with recommended dosages; monitor coagulation profile if patients have been on anticoagulation therapy; very large doses can cause hemolysis and transient renal failure

Heme arginate

Not currently available in the United States. Fewer adverse effects than hemin.

Dosing

Adult

3 mg/kg/d IV for 3-4 d or longer if needed; alternatively, 250 mg/d IV mixed with 100 mL human serum albumin infused over 20-30 min for 2-4 d

Pediatric

Not established

Interactions

May further increase effect of anticoagulants

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Luteinizing hormone-releasing hormone analogues

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)

Suppresses ovarian and testicular steroidogenesis by decreasing LH and FSH levels.

Dosing

Adult

1 mg SC qd; alternatively, Lupron Depot at 7.5 mg qmo

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity; undiagnosed vaginal bleeding; spinal cord compression; pregnancy

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Long-term use may cause osteoporosis and endometrial atrophy with vaginal bleeding; supplemental oral calcium (1500 mg/d) should be given with long-term use; reduction in bone density can be treated with bisphosphonates; supplemental estrogen therapy may be needed to relieve uterine bleeding; transdermal or oral estradiol is often tolerated and should be cautiously tried if therapy >6 mo; urinary tract obstruction, tumor flare, and bone pain may occur; monitor patients for weakness and paresthesia

Beta-adrenergic blocking agents

These agents reduce sympathetic hyperactivity.

Propranolol (Inderal)

Has membrane-stabilizing activity and decreases automaticity of contractions. Not suitable for emergency treatment of hypertension. Do not give IV in hypertensive emergencies.

Dosing

Adult

40-240 mg PO bid, up to 640 mg/d

Pediatric

2-4 mg/kg/d PO divided bid

Interactions

Coadministration with aluminum salts, barbiturates, NSAIDs, penicillins, calcium salts, cholestyramine, or rifampin may decrease effects; calcium channel blockers, cimetidine, loop diuretics, and MAOIs may increase toxicity; toxicity of hydralazine, haloperidol, benzodiazepines, and phenothiazines may increase

Contraindications

Documented hypersensitivity; uncompensated congestive heart failure; bradycardia; cardiogenic shock; A-V conduction abnormalities

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Beta-adrenergic blockade may decrease signs of acute hypoglycemia and hyperthyroidism; abrupt withdrawal may exacerbate symptoms of hyperthyroidism, including thyroid storm; withdraw drug slowly and monitor closely

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.

Morphine sulfate (Duramorph, Astramorph, MS Contin)

DOC for analgesia owing to reliable and predictable effects, safety profile, and ease of reversibility with naloxone. Various IV doses are used; commonly titrated until desired effect obtained.

Dosing

Adult

3-12 mg IV/IM repeat q3-4h prn

Pediatric

Infants and children: 0.1-0.2 mg/kg/dose IV/IM/SC q2-4h prn; not to exceed 15 mg/dose; may initiate at 0.05 mg/kg/dose

Interactions

Phenothiazines may antagonize analgesic effects of opiate agonists; TCAs, MAOIs, and other CNS depressants may potentiate adverse effects of morphine with coadministration

Contraindications

Documented hypersensitivity; hypotension; potentially compromised airway where establishing rapid airway control would be difficult

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in hypotension, respiratory depression, nausea, emesis, constipation, and urinary retention; caution in atrial flutter and other supraventricular tachycardias; has vagolytic action and may increase ventricular response rate

Meperidine (Demerol)

Analgesic with multiple actions similar to those of morphine; may produce less constipation, smooth muscle spasm, and depression of cough reflex than similar analgesic doses of morphine.

Dosing

Adult

50-200 mg IV/IM q3-4h prn

Pediatric

1-1.8 mg/kg (0.5-0.8 mg/lb) PO/IV/IM/SC q3-4h prn; not to exceed adult dose

Interactions

Monitor for increased respiratory and CNS depression with coadministration of cimetidine; hydantoins may decrease effects; avoid with protease inhibitors

Contraindications

Documented hypersensitivity; MAOIs; upper airway obstruction or significant respiratory depression; during labor when delivery of premature infant is anticipated

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in patients with head injuries because may increase respiratory depression and CSF pressure (use only if absolutely necessary); caution when using postoperatively and with history of pulmonary disease (suppresses cough reflex); because of tolerance, substantially increased dose levels may aggravate or cause seizures even if no prior history of convulsive disorders; monitor closely for morphine-induced seizure activity if prior history of seizures

Antiemetics/sedatives

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

Chlorpromazine (Thorazine)

Mechanisms responsible for relieving nausea and vomiting include blocking postsynaptic mesolimbic dopamine receptors, anticholinergic effects, and depression of RAS. Blocks alpha-adrenergic receptors and depresses release of hypophyseal and hypothalamic hormones. Slow IV infusion (patient lying flat) when symptoms persist; 25-50 mg with 500-1000 mL of NS; monitor blood pressure.

Dosing

Adult

10-50 mg IM q4-6h repeat prn

Pediatric

Not established

Interactions

Other CNS depressants, anticholinergics, or anticonvulsants; antihypertensives may cause additive effect; coadministration with epinephrine may cause hypotension

Contraindications

Documented hypersensitivity; bone marrow suppression; narrow-angle glaucoma; severe liver or cardiac disease

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May cause pseudoparkinsonism; akathisia is a common extrapyramidal reaction in elderly persons; lowers seizure threshold and increases risk of seizures in patients with history of seizures

Anticonvulsants

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

Magnesium sulfate

Corrects hypomagnesemia and helps control seizures. Nutritional supplement in hyperalimentation; cofactor in enzyme systems involved in neurochemical transmission and muscular excitability.

Dosing

Adult

3 g in 0.15 M sodium chloride IV infused over 1 h initially, followed by 1 g/h to achieve a serum magnesium level of 4-8 mEq/L

Pediatric

20-100 mg/kg/dose IV q4-6h prn; in severe cases, may use doses as high as 200 mg/kg/dose

Interactions

Concurrent use with nifedipine may cause hypotension and neuromuscular blockade; may increase neuromuscular blockade seen with aminoglycosides and potentiate neuromuscular blockade produced by tubocurarine, vecuronium, and succinylcholine; may increase CNS effects and toxicity of CNS depressants and betamethasone and cardiotoxicity of ritodrine

Contraindications

Documented hypersensitivity; heart block; Addison disease; myocardial damage; severe hepatitis

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Magnesium may alter cardiac conduction, leading to heart block in digitalized patients; monitor respiratory rate, deep tendon reflex, and renal function when electrolyte is administered parenterally; caution when administering because may produce significant hypertension or asystole; in overdose, calcium gluconate 10-20 mL IV of 10% solution can be given as antidote for clinically significant hypermagnesemia

Gabapentin (Neurontin)

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

Dosing

Adult

300-600 mg PO q8h

Pediatric

<12 years: Not established
>12 years: Administer as in adults

Interactions

Antacids may significantly reduce bioavailability (administer at least 2 h following antacids); may significantly increase norethindrone levels

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Administer 2 h after antacids

Diazepam (Valium)

For acute seizure control by intravenous infusion. Depresses all levels of CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA. Individualize dose and increase cautiously to avoid adverse effects.

Dosing

Adult

5-10 mg IV q10-15 min; not to exceed 30 mg

Pediatric

0.05-0.3 mg/kg/dose IV/IM over 2-3 min q15-30min; repeat in 2-4 h prn; not to exceed 10 mg

Interactions

Potentiates phenothiazines and narcotic analgesic agents; hepatic elimination of diazepam is reduced by many drugs, including cimetidine, oral contraceptives, disulfiram, fluoxetine, isoniazid, ketoconazole, metoprolol, propoxyphene, propranolol, and valproic acid

Contraindications

Documented hypersensitivity; narrow-angle glaucoma; open-angle glaucoma; coma; psychosis (requires clinical judgment); ketoconazole; itraconazole

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Increased risk of congenital malformations has been associated with use of minor tranquilizers during first trimester of pregnancy; caution with other CNS depressants, low albumin levels, or hepatic disease (may increase toxicity)

Clonazepam (Klonopin)

Long-acting benzodiazepine that increases presynaptic GABA inhibition and reduces monosynaptic and polysynaptic reflexes. Suppresses muscle contractions by facilitating inhibitory GABA neurotransmission and other inhibitory transmitters. Has multiple indications, including suppression of myoclonic, akinetic, or petit mal seizure activity and focal or generalized dystonias (eg, tardive dystonia). Reaches peak plasma concentration at 2-4 h after oral or rectal administration. Not often used IV in United States.

Dosing

Adult

1 mg IV for acute seizures
0.5 mg PO bid to prevent recurrent seizures
0.05-0.2 mg/kg/d PO for maintenance

Pediatric

Administer as in adults

Interactions

Phenytoin and barbiturates may reduce effects; coadministration of CNS depressants increase toxicity

Contraindications

Documented hypersensitivity; severe liver disease, and acute narrow-angle glaucoma

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in chronic respiratory tract disease or impaired renal function; withdrawal symptoms can result from abrupt discontinuation

Oral photoprotectants

These agents may reduce cutaneous photosensitivity.

Beta-carotene (Lumitene)

Effectiveness is uncertain in variegate porphyria, but a clinical trial may be warranted in view of its low-risk profile. Exact mechanism of action not completely elucidated. Patient must become carotenemic before effects are observed. More than an internal light screen may be responsible for effects. May provide a limited level of photoprotection. Causes yellowing of skin (carotenoderma). Any photoprotection afforded increases slowly after drug is commenced over a 4- to 6-wk period. When discontinued, skin color and benefit fade over several weeks.

Dosing

Adult

120-300 mg PO qd; divided doses may be better tolerated and better absorbed.

Pediatric

30-120 mg PO qd; divided doses may be better tolerated and better absorbed; for very small children, cap may be opened and beadlets inside mixed with applesauce or other easily swallowed foods

Interactions

Coadministration with vitamin A may result in additive toxic effects.

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in patients with renal or hepatic impairment; may increase risk for lung cancer in heavy smokers; may cause orange stools and diarrhea or loose stools at onset of therapy that tend to resolve with continued use.

Follow-up

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 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.

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 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. 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.  Application of plastic film filters that exclude some of the offending wavelengths to car windows can be helpful, but this practice 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 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.

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

Medicolegal Pitfalls

• 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.

References

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Keywords

VP, porphyria variegata, South African porphyria, protocoproporphyria, mixed porphyria, porphyria cutanea tarda hereditaria, royal malady, porphyrin-heme metabolism, protoporphyrinogen oxidase, protoporphyrinogen oxidase gene

Contributor Information and Disclosures

Author

Maureen B Poh-Fitzpatrick, MD, Professor Emerita of Dermatology and Special Lecturer, Columbia University; Professor of Medicine (Dermatology), University of Tennessee
Maureen B Poh-Fitzpatrick, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, and New York Academy of Medicine
Disclosure: Lundbeck, Inc. Honoraria Review panel membership

Medical Editor

David Woodley, MD, Co-Chair, Professor, Department of Medicine, Division of Dermatology, University of Southern California
David Woodley, MD is a member of the following medical societies: American Academy of Dermatology, American Association for the Advancement of Science, American College of Emergency Physicians, American College of Physicians, American Federation for Medical Research, American Society for Clinical Investigation, New York Academy of Medicine, Society for Investigative Dermatology, and Southern Medical Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University School of Medicine; Consulting Staff, Mountain View Dermatology, PA
Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Association of Military Dermatologists, Texas Dermatological Society, and Texas Medical Association
Disclosure: Nothing to disclose.

Managing Editor

Julia R Nunley, MD, Professor, Program Director, Dermatology Residency, Department of Dermatology, Virginia Commonwealth University Medical Center
Julia R Nunley, MD is a member of the following medical societies: American Academy of Dermatology, American College of Physicians, American Society of Nephrology, International Society of Nephrology, Medical Dermatology Society, Medical Society of Virginia, National Kidney Foundation, Phi Beta Kappa, and Women's Dermatologic Society
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CME Editor

Joel M Gelfand, MD, MSCE, Medical Director, Clinical Studies Unit, Assistant Professor, Department of Dermatology, Associate Scholar, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania
Joel M Gelfand, MD, MSCE is a member of the following medical societies: Society for Investigative Dermatology
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Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
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