Diseases of Tetrapyrrole Metabolism - Refsum Disease and the Hepatic Porphyrias 

Updated: Jun 28, 2018
Author: Norman C Reynolds, Jr, MD; Chief Editor: Stephen A Berman, MD, PhD, MBA 

Overview

Practice Essentials

Refsum disease and the hepatic porphyrias are rare inherited neurodegenerative conditions with exacerbations and remissions due to abnormal metabolism of large tetrapyrrole molecules. Two common examples of large tetrapyrrole molecules are chlorophyll a, the photosynthetic pigment of green plants, and heme, the prosthetic group of hemoglobin (see the image below). Side groups on both species involve relatively small organic groups (methyl, vinyl, and free propionyl); one major exception is phytol, a large hydrocarbon alcoholic substituent on chlorophyll. Patients in both disease categories must avoid foods and drugs that lead to high levels of the relevant biological toxin, which can trigger or perpetuate an exacerbation.

Tetrapyrrole molecules are large-ringed structures Tetrapyrrole molecules are large-ringed structures developed from 4 pyrrole groups and used in energy metabolism in both plants and animals.

In acute disease, blood or urine tests are definitive, including increased phytanic acid in serum for Refsum disease; increased ALA and porphobilinogen (PBG) in the urine and serum  for porphyrias; and low uroporphyrinogen decarboxylase[1]  level in porphyria cutanea tarda. When porphyria is suspected in a patient without a family history, lead levels from blood or 24-hour urine collection should be obtained to exclude lead poisoning. 

No specific treatments are indicated in Refsum disease, other than dietary restrictions of beef and milk products. Avoiding direct sunlight is necessary in preventing photosensitive dermatitis, especially in PCT.

Schedule annual or 6-month visits for a general physical examination. Analyze the patient's progress in avoiding exacerbating triggers and order blood tests used to monitor adequate control (phytanic acid or ALA/PBG).

Gabapentin: This agent is useful as a long-term anticonvulsant in patients with hepatic porphyrias. It is the first drug of choice because it does not require hepatic metabolism; incidentally, it also is well tolerated by these patients in treatment of chronic pain, as an alternative to narcotics, which invoke liver metabolism.

Levetiracetam: This agent is a viable alternative to gabapentin if the side effect profile (most notably somnolence) makes gabapentin undesirable. It does not provide a pain-reducing action like gabapentin.

Triple bromide is an alternative to the more traditional anticonvulsant choices of gabapentin and levetiracetam for long-term anticonvulsant therapy. Before the discovery of safe traditional anticonvulsants, it was the only treatment option for seizures in patients with hepatic porphyria. No specific dosing requirement is known, but the therapeutic range is 60-90 mg/dL to avoid toxic encephalopathy. Bromide preparation requires the assistance of a skilled pharmacist with compounding experience.

Because of its renal clearance, diphenhydramine is safe for use as a sleeping aid or antianxiety medication.

Although a gastroenterologist or a physician with specific interest in porphyria may be helpful in planning disease management, a doctoral level clinical pharmacist or pharmacologist is especially helpful in making choices of safe drug combinations. Medical geneticists can help establish diagnostic histories and help to order the appropriate diagnostic tests as well as provide genetic counseling.

Pathophysiology

The neurotoxin in Refsum disease is phytanic acid, which in affected individuals is stored in neural and visceral parenchyma because of a deficiency in phytanic acid alpha-hydroxylase. The source of phytanic acid is either direct absorption or conversion of absorbed phytol from ruminant fat in meat or milk (only ruminants can release phytol from chlorophyll during digestion). Homozygosity is required for significant phytanic acid build-up.

The hepatic porphyrias also are associated with neurologic problems. The neurotoxins in these conditions are porphyrin precursors (delta-aminolevulinic acid [ALA], porphobilinogen [PBG]) and porphyrinogen substrates in heme synthesis, whose levels are elevated (see the image below). The actual porphyrins are oxidized products of the substrates, which are excreted in the feces and urine (the latter characterized by its reddish-brown, fluorescent color.)

Three characteristic substrate molecules of the he Three characteristic substrate molecules of the heme porphyrin pathway.

Whereas the enzyme deficiency in Refsum disease is inherited in an autosomal-recessive pattern, the enzyme deficiencies involved in the hepatic porphyrias typically are inherited in an autosomal-dominant mode. The hepatic porphyrias account for a varying spectrum of upstream accumulations of porphyrins and porphyrin precursors specific to each type of porphyria.[2] The following are common hepatic porphyrias:

  • Acute intermittent porphyria (AIP) - Uroporphyrinogen synthase (or "porphobilinogen deaminase") deficiency with high ALA or PBG in urine and serum

  • Variegate porphyria (VP) - Protoporphyrinogen oxidase deficiency[3] with high fecal levels of protoporphyrin and coproporphyrin[4]

  • Hereditary coproporphyria - Coproporphyrinogen oxidase deficiency with high urinary and/or fecal levels of coproporphyrins

  • Porphyria cutanea tarda (PCT) - Uroporphyrinogen decarboxylase deficiency with high urinary and red cell levels of uroporphyrin

  • ALA dehydratase deficient porphyria (rare)

  • Erythropoietic protoporphyria (EPP), "protoporphyria", or "erythrohepatic protoporphyria" (not a hepatic porphyria)[5, 6] 5 ​: ferrochelatase deficiency, whereby fecal and erythrocyte levels of protoporphyrins are increased without any urinary porphyrins; abnormal porphyrin metabolism originates in erythrocytes, not the liver, yet ironically, patients with EPP may develop chronic liver failure; EPP is not characterized by neurologic symptoms and does not respond to sugar or hemin (ie, hematin) treatment

Epidemiology

Refsum disease is rare, but heterozygote carriers may be at risk if they have diets highly selective for beef and dairy products.

The incidence of acute intermittent porphyria is 5-10 per 100,000 (underestimated because of positive cases not being induced and long periods of latency). AIP is widely believed to be latent in 90% of cases. Porphyria cutanea tarda is believed to be the most common type, but because of poor recording, no data have been published. Erythropoietic protoporphyria is also believed to be common but not clearly documented. Other forms of true hepatic porphyrias are rare except variegate porphyria in individuals with ancestry of Afrikaner lineage. Variegate porphyria is common in South Africa (about 3 cases per 1000 population).

Mortality/Morbidity

Both Refsum disease and hepatic porphyrias are characterized by remissions and exacerbations of neurologic dysfunction, which can resolve completely or manifest stepwise deterioration. Permanent residual deficits are not uncommon; residual defects during latent periods include polyneuropathy in both conditions, ataxia and retinitis pigmentosa with night blindness in Refsum disease,[7] and photosensitive dermatitis in porphyrias (rare in acute intermittent porphyria). Death in either disease is commonly caused by cardiac arrhythmias during exacerbations. Cardiomyopathy can occur in Refsum disease owing to phytanic acid storage and in acute porphyric crises owing to electrolyte disturbance (in as many as 25% of acute intermittent porphyria cases).

Race

Both Refsum disease and the porphyrias tend to occur more often in individuals of white hereditary lineage. The exception is porphyria cutanea tarda, which is noted among blacks of Bantu lineage (as well as whites).

Acute intermittent porphyria is most common among whites of English or Scandinavian heritage. Variegate porphyria is most common among Afrikaners, selectively concentrated in royal European lineage (eg, as documented in the popular film "The Madness Of King George"), and also present in certain large families of Great Britain, Holland, Sweden, and the United States.

Sex

Prevalence is expected to be equal between the sexes because of autosomal inheritance; however, clinical attacks may be more common in females with acute intermittent porphyria and in males with porphyria cutanea tarda. Consanguinity, causing the homozygous recessive condition, is not an uncommon cause of Refsum disease.

Age

Initial attacks in both disease categories can occur in early childhood, but in the hepatic porphyrias, the onset is usually postpubertal.[8] Erythropoietic protoporphyria is characterized by childhood onset of acute cutaneous photosensitivity to direct sunlight.

Childhood epilepsy is an exception to the postpuberty onset rule for initial porphyric attacks in the hepatic forms. Long-term drug use in idiopathic epilepsy with inactive or latent hepatic porphyria, even in prepubertal children, is a potent activator of cytochrome P450. Liver synthesis of heme groups is accelerated, leading to high levels of porphyrins and premature porphyric crises.

Earlier-onset Refsum disease is due to a pervasive dietary risk from consuming large quantities of beef and, to a greater degree, milk. For this same reason, persisting residual deficits are typical by age 20 years. Sporadic intake of provocative drugs in latent porphyria can induce exacerbations and eventually lead to persisting residual deficits.

Prognosis

Prognosis in Refsum disease and the hepatic porphyrias depends entirely on the proper dietary and drug restrictions.

The patient's ability to survive an acute exacerbation depends on the adequacy of acute care (especially the care available in an intensive care unit).

Survival in an acute porphyric attack depends on monitoring levels of porphyrins and the proper use of D10W and hemin infusions. Despite appropriate treatment measures, mortality rate in acute attacks of acute intermittent porphyria may be as high as 25%.

Patient Education

Both patients with Refsum disease and those with porphyria must become experts in understanding their disease. Both the Hereditary Disease Foundation and the American Porphyria Foundation can be a source of peer support and information for patients and physicians.

Monitoring of phytanic acid and ALA/PBG levels is a key element in providing outpatient treatment.

For patients with Refsum disease, specific review of safe dietary patterns must be a regular part of outpatient care.

Safety of specific drugs must be emphasized to the patient with porphyria (ie, avoiding drugs that induce cytochrome P450 activity). Encourage patients to seek advice by telephone if they have questions or concerns.

Genetic inheritance patterns must be understood, so that the patient can exercise responsibility in sexual relations or family planning.

Patients with porphyria have a 50% risk of passing along an autosomal-dominant trait with high expressivity.

Patients with Refsum disease should avoid marriage or sexual involvement with blood relatives (consanguinity), especially if distant relatives have diagnoses of neurodegenerative disease with childhood onset. Planning offspring is especially difficult, since no simple method is available to detect heterozygotes in this autosomal-recessive disease.

 

Presentation

History

Family history is critical in diagnosis. In Refsum disease, manifest cases are homozygous recessive. If the key symptoms of failing vision and cerebellar ataxia are present, consanguinity should be considered. On the other hand, sporadic cases might occur with heterozygotes who are on selective diets high in beef and dairy products.

The porphyrias express an autosomal-dominant pattern, and the typical family has a history of combinations of photodermatitis and abdominal crises, concomitant mental and neurologic symptoms, and urine of a reddish-brown, fluorescent color.

Patients typically have a history of remissions and exacerbations (exacerbations - several days to 2 weeks; memissions - months to years)

Patients may have a history of drug-induced exacerbations (partial or significant) in the hepatic porphyrias but not in erythropoietic protoporphyria, which has obvious cutaneous photosensitivity and normal urine color during exacerbations without neurologic sequelae.

Physical

 

Findings in Refsum disease include the following:

  • Ocular changes - Retinitis pigmentosa, cataracts

  • Sensorimotor polyneuropathy

  • Nonspecific ECG changes

  • Anosmia

  • CN VIII deafness

  • Ichthyosis (can be widespread or limited to the palms)

  • Signs of epiphyseal dysplasia (eg, syndactyly, pes cavus, hammer toes)

Findings in hepatic porphyrias include the following:

  • During remissions: Signs are limited to residual axonal polyneuropathy and skin sensitivity to mechanical trauma and photodermatitis; these are often disabling in porphyria cutanea tarda but rare in acute intermittent porphyria. In erythropoietic protoporphyria, scarred, thickened skin is due to multiple sun-exposure reactions.

  • During acute attacks: Eighty percent of patients initially present with an acute abdomen, 20% ushered in with agitated and hysterical behavior. Other manifestations are autonomic instability (tachycardia, labile blood pressure), generalized pain, segmental sensorimotor polyneuropathy, urinary frequency, and diarrhea. Occasionally, patients present with seizures or coma. Acute attacks in erythropoietic protoporphyria involve rapid-onset burning and edematous, blistering lesions.

  • In erythropoietic protoporphyria, exacerbations are characterized uniquely by acute cutaneous eruptions immediately after ultraviolet light exposure, including that from operating room lights. Ironically, chronic disease may lead to hepatic failure, which can be fatal.

  • In general, the hepatic porphyrias are not associated with hepatic failure but only liver-based aberrant porphyrin metabolism.

Causes

Both Refsum disease and the hepatic porphyrias can be exacerbated by nonspecific causes, particularly environmental stress and prolonged or severe illness.

Causes unique to Refsum disease include the following:

  • Dietary intake of phytol and phytanic acid (from beef and milk)

  • Paradox: Liberal intake of chlorophyll-containing foods is perfectly safe, because hydrolysis to free phytol occurs only in the ruminant gut, not in the human digestive tract.

Causes unique to hepatic porphyrias include the following:

  • Prolonged fasting, hypoglycemia

  • Long-term drug use that leads to increased cytochrome P450 activity: This increases delta-ALA synthase activity, the hepatic, rate-limiting enzyme for the heme/porphyrin pathway. Depending on the inherited enzyme deficiency, specific characteristic porphyrins may build up.

  • Other drugs with acute inducing capability: Experienced patients learn to avoid these.

  • Light (especially UV) can induce skin eruptions in porphyric patients with photocutaneous sensitivity.[9] This sensitivity can be seen in several hepatic porphyrias, particularly porphyria cutanea tarda, but it is the sine qua non of erythropoietic protoporphyria and is the dominant, often sole, clinical problem in this nonhepatic porphyria.

  • Endogenous hormones: Some women have catamenial patterns of exacerbation initiated during the luteal phase of normal menstrual periods or during pregnancy.

 

DDx

 

Workup

Laboratory Studies

In acute disease, blood or urine tests are definitive. Although DNA tests are being developed using polymerase chain reactions, the current state-of-the-art testing relies on the identification of abnormally high levels of key substrates. In the diseases of tetrapyrrole metabolism, the value of DNA analysis will not be first-order identification but rather the clarification of new mutations or assistance in differentiating between types of hepatic porphyria, which have only borderline elevations of metabolites or inconclusive differences in metabolite results.[10, 11]  Lab findings include the following:

  • Refsum disease - Increased phytanic acid in serum

  • Porphyrias - Increased ALA and porphobilinogen (PBG) in the urine and serum (A work-up algorithm is available online from the American Porphyria Foundation.)

  • In quiescent or latent periods, monitoring of characteristic metabolites in serum is recommended. Refsum disease: Monitor phytanic acid to check the adequacy of dietary restrictions. Porphyrias: Monitor erythrocyte enzymes and quantitative porphyrins in 24-hour collections of urine and stool.

  • Erythrocyte enzymes: Low values are confirmatory and in some cases diagnostic.

  • Acute intermittent porphyria: Watch for low levels of porphobilinogen deaminase and uroporphyrinogen decarboxylase (also low in porphyria cutanea tarda).[12]

  • Porphyria cutanea tarda: Uroporphyrinogen decarboxylase[1] level is low, but porphobilinogen deaminase level is normal.

  • Variegate porphyria and other porphyrias: levels of both enzymes are normal. Make this diagnosis only from quantitative porphyrins.

  • Quantitative porphyrins are measured from 24-hour collections of urine and stool.

  • Acute intermittent porphyria: Urinary ALA and PBG levels are increased. Stool porphyrin levels are either normal or only marginally elevated.

  • Variegate porphyria: Urinary ALA and PBG levels are increased. Fecal protoporphyrin and, to a lesser extent, coproporphyrin levels are excessive.

  • Hereditary coproporphyria: Excessive excretion of urinary and fecal coproporphyrins is noted.[13]

  • Protoporphyria: As distinguished from variegate porphyria, abnormal excretion levels typically are limited to the stool. Levels of protoporphyrins are very high and, occasionally, coproporphyrin levels are elevated somewhat.

  • Porphyria cutanea tarda: Elevation of urinary uroporphyrin levels is characteristic. While ALA and PBG usually are not present in the urine, other porphyrins may be present, and the porphyrin composition of the stool is highly variable and nonspecific.

  • Quantitative porphyrins from 24-hour collections of urine and stool: Note that no protoporphyrin is detected in urine in erythropoietic protoporphyria (not a hepatic porphyria) despite high serum and erythrocyte porphyrin levels.

  • If further clarification is needed to distinguish between acute intermittent porphyria, porphyria cutanea tarda, or variegate porphyria, the Porphyria DNA Testing Laboratory at Mt. Sinai School of Medicine (New York) can be asked to perform DNA testing from a single blood sample. Issues of insurance coverage need to be considered, however, and genetic testing should be reserved for patients where additional clarification is necessary. As with other genetic tests, special privacy and counseling requirements must be met (POC for testing, contact porphyria@mssm.edu).

  • If DNA confirmation has occurred, further DNA testing of family members can be done to determine whether precautions should be taken to avoid exacerbating attacks including the avoidance of potentially risky medications[14] and fasting.

  • Liver function tests (eg, SGOT):

    • Refsum disease: Results may be abnormal with advanced phytanic acid storage.

    • Porphyrias: Findings are usually normal except in porphyria cutanea tarda, especially when liver is enlarged clinically, or in advanced erythropoietic protoporphyria with chronic secondary hepatic failure (recall that erythropoietic protoporphyria is erythropoietic, not hepatic in etiology).

    • Differentials to Refsum disease: LFT results should be abnormal in Niemann-Pick disease and metachromatic leukodystrophy with hepatosplenomegaly.

  • CBC count with differential should be checked. Refsum disease: Results are normal. Porphyrias: Results are normal, but leukocytosis may be evidence of generalized systemic stress during acute attacks. Differential for porphyrias: Hypochromic normocytic anemia with basophilic stippling is seen in chronic lead poisoning.

  • When porphyria is suspected in a patient without a family history, lead levels from blood or 24-hour urine collection should be obtained to exclude lead poisoning. Erythropoietic protoporphyria, a nonhepatic porphyria, should be considered when no clear family history is elicited.

Imaging Studies

Plain radiography of the hands documents skeletal deformities in Refsum disease.

An MRI has 2 indications in the work-up of porphyria: (1) To exclude glioma when a patient with porphyria also has seizures in latent or acute periods; confluent cortical signal intensities may occur during acute attacks and then resolve completely when attacks are over; (2) To exclude multiple sclerosis (periventricular lesions are typical) within the differential diagnosis of the porphyrias.

Other Tests

Electromyogram should include selective needle exam and nerve conduction exam for polyneuropathy. Both Refsum disease and the hepatic porphyrias are associated with polyneuropathy with both segmental and axonal characteristics.

For electroencephalography (EEG), perform a routine awake study to search for epileptiform tendencies that suggest a process independent of acute porphyric attacks. Localized or generalized spike and after slow wave activity observed during latent periods defines the risk (but not the severity or frequency) of seizures. Treatment is solely a clinical decision. During stupor or coma, the EEG can be used to exclude status epilepticus as a cause of obtundation. Interictal epileptiform activity observed during acute attacks has no value in diagnosing idiopathic epilepsy, since seizures at that time are likely part of the acute attack and should respond to appropriate treatment (see Treatment).

For urinalysis for metachromatic leukodystrophy, urinary screening for decreased arylsulfatase A or increased metachromatic granules may help rule out metachromatic leukodystrophy in the differential diagnosis of Refsum disease. If it is not definitive, a sural nerve biopsy can be done (see Procedures).

ECG may feature nonspecific changes in Refsum disease.

Procedures

Sural nerve biopsy: If noninvasive urinary tests are not diagnostic, examination of the sural nerve for metachromatic granules and decreased arylsulfatase A activity can confirm metachromatic leukodystrophy in the differential diagnosis of Refsum disease

Lumbar puncture may be done to exclude multiple sclerosis and Guillain-Barré syndrome.

Elevated cerebrospinal fluid (CSF) protein: Although characteristic of Guillain-Barré syndrome, this finding may be present with prominent polyneuropathy in either porphyria or Refsum disease.

Multiple sclerosis panel: Positive oligoclonal banding, increased gamma globulin, and increased immunoglobulin G synthesis rate confirm the diagnosis of multiple sclerosis. Myelin basic protein also may be present and supports the diagnosis.

Histologic Findings

Refsum disease at autopsy reveals widespread abnormal lipid stores (specifically phytanic acid) in neural and visceral tissues (eg, liver, heart, kidney).

Hepatic porphyrias at autopsy reveal no abnormal storage; liver tissue by light and electron microscopy is normal except in erythropoietic protoporphyria, which may be associated with hepatic failure (ironically, hepatic porphyrias are not associated with hepatic failure). Special fluorescent techniques can be used to document fluorescing porphyrins.

 

Treatment

Medical Care

No specific treatments are indicated in Refsum disease, other than dietary restrictions of beef and milk products. On the other hand, judicious medication choices are key elements in managing the porphyrias.

Any drug used over the long term has the risk of inducing increased cytochrome P450 activity and increased production of the heme group. Increased production of heme groups accelerates delta-ALA synthase activity in the rate-limiting step for the porphyrin pathway.[15] This results in excessive porphyrins in response to inherited low enzyme activity at specific points in the heme biosynthetic pathway. Lists of safe and unsafe drugs can be found through the American Porphyria Foundation (or European Porphyria Network). A drug risk profile can be found by entering the generic or brand name for the drug of interest.

Long-term care of concomitant idiopathic epilepsy is especially challenging, leaving only bromide (which should be administered only in cooperation with an experienced pharmacist) and gabapentin[16] as reasonable treatment options. New anticonvulsants that are tolerated for several months are not a sign of safety since the induction of higher levels of delta-ALA synthase may occur gradually over time. Other more immediate toxic responses occur with medications that induce cytochrome P450.

Short-term care is not as risky as long-term care, especially if the medications used are excreted by the kidneys. Experience teaches patients with latent porphyria which medications to avoid. Special care should be exercised in planning general anesthesia so that the anesthesiologist is alerted to special medication requirements and is aware of the risks of inducing acute attacks that may occur postoperatively.

Phlebotomy for porphyria cutanea tarda

Therapeutic phlebotomy is the treatment of choice to control the photocutaneous manifestations of porphyria cutanea tarda. Effective blood loss is defined as reducing serum porphyrins to 20% of prephlebotomy levels over 2-3 months, which allows a period of remission lasting 6-12 months. In the treatment of erythropoietic protoporphyria, ultraviolet light avoidance, rather than effective blood loss,is recommended. Sunscreens and possibly oral use of beta-carotene can improve sunlight tolerance.

Surgical Care

Patients with acute porphyria are at risk for exploratory laparoscopy for an acute abdomen that is unique because of the absence of rebound tenderness.

A high preoperative urinary PBG level should reduce the pressure to explore the abdomen surgically; this finding is especially compelling if an abdominal CT scan is not conclusive.

For other surgical procedures, the risk of anesthesia exacerbating acute attacks in Refsum disease or in the porphyrias, either as a nonspecific stress or in porphyria as a metabolic challenge to cytochrome P450, should be considered. The anesthesiologist should be alerted to the risk of exacerbation due to fasting or general anesthesia in patients with porphyria and be prepared to use glucose loading postoperatively when acute attacks appear likely or in progress.

Diet

Dietary management is a major part of treating Refsum disease and hepatic porphyrias. Inappropriate dietary choices may result in exacerbations.

In Refsum disease, dietary intake of phytol and phytanic acid must be restricted. Monitor serum phytanic acid levels to ensure that levels remain low.

The rule of thumb in dietary control is that vegetables are unrestricted (only ruminants can hydrolyze phytol from chlorophyll in the gut).

Phytol is converted readily to phytanic acid in all mammals. Both phytol and phytanic acid are found among the other fatty acids, therefore both are absorbed from ruminant fat stores and fatty fractions (eg, fat, beef, dairy products).

Without dietary restrictions, the phytanic acid level may comprise as much as one third of the total fatty acids of the plasma; healthy individuals have only trace levels.

The "glucose effect" is a major modulator of metabolic control of extremes in porphyrin synthesis. Fasting or hypoglycemia is a well-known precipitant of acute attacks, whereas oral or intravenous (IV) 10% dextrose solution is useful in averting or reversing acute attacks.

 

Medication

Medication Summary

Two medical therapies are effective in aborting porphyric attacks: IV 10% dextrose in water (D10W) and IV hemin (ie, hematin). Experienced patients with porphyria consume foods high in sugar (eg, candy, ice cream) when they feel an impending attack. If anxious feelings are not episodic but chronic, low dose loxapine is helpful and safe on a regular basis. Injectable hemin (Panhematin) is now approved by the FDA for women with catamenial patterns of exacerbation.

Intravenous Nutritional Therapy

Class Summary

Glucose is used most commonly. The "glucose effect" reverses or aborts acute porphyric attacks by reducing the rate of porphyrin synthesis using normal endogenous energy metabolism. The "glucose effect" should be reserved for patients with mild pain and no paresis or as a stopgap measure while waiting for hematin.

Dextrose (D-Glucose)

Administered IV to hospitalized patients. Observe carefully for what can become a rapidly changing situation using the first of 2 inpatient drugs of choice. If therapeutic control lost, the patient is switched to IV hemin. Prior to admission, oral sugar loading can be tried. Standard solution is D10W.

Biologicals

Class Summary

Hemin[17, 18] (ie, hematin) infusion is designed specifically for use in reversing severe acute porphyric attacks. It is also indicated for women who experience recurring attacks associated with their menstrual cycles. After acute attacks are aborted, the hemin can be administered again, either weekly or monthly in the more refractory individuals, when pain complaints initiate a recurring attack.

Hemin (Panhematin)

Enzyme inhibitor derived from processed RBCs and iron-containing metalloporphyrin. Previously known as hematin, term used to describe chemical reaction product of hemin and sodium carbonate solution. Generally used as second DOC (to follow D10W unless prior use suggests that it is superior in a given patient, a patient is at risk for severe diabetic ketoacidosis, or initial D10W treatment fails to stabilize the acute porphyric episode within 2 d). Patients should be well hydrated to avoid (reversible) renal shutdown. "Glucose effect" should be tried initially if possible.

Anticonvulsants

Class Summary

These agents control idiopathic seizures in patients with manifest porphyrias or in whom porphyric carrier status is suspected.

Gabapentin (Neurontin)

Has properties in common with other anticonvulsants, but most importantly is not metabolized in liver, which makes it safe for use in hepatic porphyrias.

Exact mechanism of action not known. Structurally related to GABA but does not interact with GABA receptors.

Levetiracetam (Keppra)

Used as adjunct therapy for partial seizures and myoclonic seizures. Also indicated for primary generalized tonic-clonic seizures. Mechanism of action is unknown.

Antipsychotics

Class Summary

These agents are useful in treating hepatic porphyrias, which are recurring anxious feelings not necessarily associated with impending porphyric attack.

Loxapine succinate (Loxitane)

Safety of medication use in hepatic porphyrias is key to maintaining health and avoiding attacks. Loxapine is well tolerated and useful for recurring anxious feelings common in porphyrias. Should be used for recurrent anxious feelings not associated with impending porphyric crisis. Treatment for the latter is noted under IV dextrose use and is initiated by using high oral sugar intake followed by IV dextrose in a hospital setting for close observation. Treatment for the former can be either low-dose maintenance or as needed.