AUTHOR INFORMATION

Section 1 of 12

Authored by Norman C Reynolds Jr, MD, Professor, Department of Neurology, Medical College of Wisconsin

Norman C Reynolds Jr, MD, is a member of the following medical societies: American Academy of Neurology, American Chemical Society, American Clinical Neurophysiology Society, Association of Military Surgeons of the US, Movement Disorders Society, Sigma Xi, and Society for Neuroscience

Edited by Ann M Neumeyer, MD, Clinic Director, Instructor, Departments of Neurology and Pediatrics, Massachusetts General Hospital, Harvard Medical School; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Kenneth J Mack, MD, PhD, Visiting Associate Professor, Department of Neurology, University of Wisconsin at Madison; Associate Professor and Consultant, Department of Neurology, Division of Child and Adolescent Neurology, Mayo Medical School; Matthew J Baker, MD, Consulting Staff, Collier Neurologic Specialists, Naples Community Hospital; and Nicholas Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants

Author's Email:	Norman C Reynolds Jr, MD
Editor's Email:	Ann M Neumeyer, MD

eMedicine Journal, September 26 2006, VOLUME 7, Number 9

INTRODUCTION

Section 2 of 12

Background: Refsum disease (RD) 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 Image 1). Side groups on both species involve relatively small organic groups (methyl, vinyl, and free propionyl); 1 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.

Pathophysiology: The neurotoxin in RD 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 neurological 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 Image 2). 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.)

Whereas the enzyme deficiency in RD 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. 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 with high fecal levels of protoporphyrin and coproporphyrin

• 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)
  • Ferrochelatase deficiency: 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.

Frequency:

• In the US:
  
  
  • RD is rare, but heterozygote carriers may be at risk if they eat diets highly selective for beef and dairy products.

  • AIP incidence ranges from 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.

  • PCT is believed to be the most common type, but because of poor recording, no data have been published.

  • EPP also is believed to be common but not clearly documented.

  • Other forms of true hepatic porphyrias are rare except VP in individuals with ancestry of Afrikaner lineage.

• Internationally: It is the same as in the United States, but VP is common in South Africa (about 3 cases per 1000 population).

Mortality/Morbidity: Both RD 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 RD, and photosensitive dermatitis in porphyrias (rare in AIP). Death in either disease is commonly caused by cardiac arrhythmias during exacerbations. Cardiomyopathy can occur in RD owing to phytanic acid storage and in acute porphyric crises owing to electrolyte disturbance (in as many as 25% of AIP cases).

Race:

• Both RD and the porphyrias tend to occur more often in individuals of white hereditary lineage. The exception is PCT, which is noted among blacks of Bantu lineage (as well as whites).

• AIP is most common among whites of English or Scandinavian heritage. VP 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 AIP and in males with PCT. Consanguinity, causing the homozygous recessive condition, is not an uncommon cause of RD.

Age: Initial attacks in both disease categories can occur in early childhood, but in the hepatic porphyrias, the onset is usually postpubertal. EPP 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 RD 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.

CLINICAL

Section 3 of 12

History: Family history is critical in diagnosis.

• In RD, 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 neurological symptoms, and urine of a reddish brown, fluorescent color.



• Patients typically have a history of remissions and exacerbations.


• • Exacerbations - Several days to 2 weeks
  
  
  
  • Remissions - Months to years
  
  
  
• Patients may have a history of drug-induced exacerbations (partial or significant) in the hepatic porphyrias but not in EPP, which has obvious cutaneous photosensitivity and normal urine color during exacerbations without neurological sequelae.

Physical:

• Findings in RD


• • 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


• • During remissions: Signs are limited to residual axonal polyneuropathy and skin sensitivity to mechanical trauma and photodermatitis; these are often disabling in PCT but rare in AIP. In EPP, 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 EPP involve rapid-onset burning and edematous, blistering lesions.
  
  
  
  • In EPP, 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 RD and the hepatic porphyrias can be exacerbated by nonspecific causes, particularly environmental stress and prolonged or severe illness.

• Causes unique to RD


• • 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


• • 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. This sensitivity can be seen in several hepatic porphyrias, particularly porphyria cutanea tarda, but it is the sine qua non of EPP 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.
  
  
  

DIFFERENTIALS

Section 4 of 12

Friedreich Ataxia
Guillain-Barre Syndrome in Childhood
Multiple Sclerosis

Other Problems to be Considered:

Metachromatic leukodystrophy
Niemann-Pick disease
Erythropoietic protoporphyria (erythrohepatic protoporphyria)

WORKUP

Section 5 of 12

Lab 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.


• • RD - Increased phytanic acid in serum
  
  
  
  • Porphyrias - Increased ALA and PBG in the urine and serum
  
  
  
• In quiescent or latent periods, monitoring of characteristic metabolites in serum is recommended.


• • RD: 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.


• • AIP: Watch for low levels of porphobilinogen deaminase and uroporphyrinogen decarboxylase (also low in PCT).
  
  
  
  • PCT: Uroporphyrinogen decarboxylase level is low, but porphobilinogen deaminase level is normal.
  
  
  
  • VP 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.


• • AIP: Urinary ALA and PBG levels are increased. Stool porphyrin levels are either normal or only marginally elevated.
  
  
  
  • VP: 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.

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

  • PCT: 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 EPP (not a hepatic porphyria) despite high serum and erythrocyte porphyrin levels.
  
  
  
• Liver function tests (eg, SGOT)


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

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

  • Differentials to RD: LFT results should be abnormal in Niemann-Pick disease and metachromatic leukodystrophy with hepatosplenomegaly.
  
  
  
• CBC count with differential should be checked.


• • RD: 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. EPP, a nonhepatic porphyria, should be considered when no clear family history is elicited.

Imaging Studies:

• Plain radiography of the hands documents skeletal deformities in RD.



• An MRI has 2 indications in the work-up of porphyria.


• • 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
  
  
  
  • To exclude multiple sclerosis (periventricular lesions are typical) within the differential diagnosis of the porphyrias
  
  
  

Other Tests:

• Electromyogram: This should include selective needle exam and nerve conduction exam for polyneuropathy. Both RD and the hepatic porphyrias are associated with polyneuropathy with both segmental and axonal characteristics.



• Electroencephalogram (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).
  
  
  
• 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 RD. If it is not definitive, a sural nerve biopsy can be done (see Procedures).



• ECG may feature nonspecific changes in RD.

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 RD.



• 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 RD.
  
  
  
  • 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.
  
  
  

• RD 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 EPP, 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

Section 6 of 12

Medical Care: No specific treatments are indicated in RD, 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. 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.


• • 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 as reasonable treatment options.
  
  
  
  • 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.
  
  
  
• Phlebotomy for PCT


• • Therapeutic phlebotomy is the treatment of choice to control the photocutaneous manifestations of PCT.

  • 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 EPP, not blood loss but rather ultraviolet light avoidance 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 RD or in the porphyrias, either as a nonspecific stress or in porphyria as a metabolic challenge to cytochrome P450, should be considered.

Consultations: 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.

Diet: Dietary management is a major part of treating RD and hepatic porphyrias. Inappropriate dietary choices may result in exacerbations.

• In RD, 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.

Activity: Avoiding direct sunlight is necessary in preventing photosensitive dermatitis, especially in PCT.

MEDICATION

Section 7 of 12

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.

Drug Category: Intravenous nutritional therapy -- 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.

Drug Name	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.
Adult Dose	Intake needs to approximate 400 g of dextrose qd for 1-2 d; if patient worsens in this interval, switch to hemin; if patient continues to respond effectively, continue treatment until PBG and ALA levels fall to normal
Pediatric Dose	Administer as in adults, but correct for body surface area for small children and use simple weight adjustment for juveniles and adolescents; preference is still D10W since more dilute solutions are not likely to be effective
Contraindications	Diabetics at risk for ketosis are not good candidates for IV D10W therapy—immediate initiation of hemin therapy is a better choice; do not administer concentrated solutions if intraspinal or intracranial hemorrhage is present; avoid in dehydrated patients with delirium tremens, hepatic coma, or glucose-galactose malabsorption syndrome
Interactions	Changes in insulin requirements are the major consideration and the reason for contraindication; caution when administering dextrose solutions to patients receiving corticosteroids or corticotropin, especially if solution contains sodium ions
Pregnancy	A - Safe in pregnancy
Precautions	If patient is dehydrated, D10W should not be sole IV solution administered; concomitant use of isotonic saline with 30 mEq potassium is preferred, whereas Ringer lactate may confound a well-intended "glucose effect"; may result in dilution of serum electrolyte concentrations or cause overhydration with fluid overload; caution in patients suffering from congested states or pulmonary edema; hypertonic dextrose given peripherally may cause thrombosis (administer instead through central venous catheter); caution in subclinical diabetes mellitus or carbohydrate intolerance The risk of inducing significant hyperglycemia or hyperosmolar syndrome is increased if the solution is administered rapidly, especially in patients with chronic uremia or carbohydrate intolerance; concentrated solutions should not be administered SC or IM; rates of dextrose infusion higher than 0.5 g/kg/h may produce glycosuria; at infusion rates of 0.8 g/kg/h, incidence of glycosuria is 5%; monitor fluid balance, electrolyte concentrations, and acid-base balance closely; dextrose administration may induce thiamine deficiency in some patients with poor nutritional status

Drug Category: Biologicals -- Hemin (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.

Drug Name	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.
Adult Dose	1-4 mg/kg/d IV over 10-15 min after reconstituting powder in sterile water; frequency of infusions should not exceed 12-h intervals in most severe cases and not more than 6 mg/kg in any 24-h period; duration of treatment is from 3-14 d, depending on clinical response; terminal filtration through 0.45 micron or smaller filter recommended to remove unwanted particulates
Pediatric Dose	<16 years: Not established >16 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Occasional anticoagulant effects have occurred, therefore anticoagulation should be terminated before use and PT/aPTT followed
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Warn patients about risk of viral or other infectious agent transmission, including prions (eg, Creutzfeldt-Jakob disease), with this procedure because hemin is made from human blood; note that since attacks of porphyria may progress to irreversible neuronal damage, treatment is given to prevent neuronal degeneration only and is not effective in repairing neuronal damage; note risk of asymptomatic and reversible renal shutdown, oliguria, and increased nitrogen retention, which have occurred in some patients in whom doses used exceeded recommended amounts.

Drug Category: Anticonvulsants -- These agents control idiopathic seizures in patients with manifest porphyrias or in whom porphyric carrier status is suspected.

Drug Name	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.
Adult Dose	Day 1: 100 mg PO tid or 300 mg hs Day 2: Increase to 400 mg PO tid over 3-d interval and titrate dose prn; not to exceed 1200 mg PO qid Increases in daily dose are best tolerated when done slowly
Pediatric Dose	<12 years: Not established >12 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Antacids may reduce bioavailability significantly (administer at least 2 h following antacids); may increase norethindrone levels significantly
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in severe renal disease

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

Drug Name	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.
Adult Dose	10 mg PO hs in most cases or bid if necessary to cover day needs
Pediatric Dose	Children: Not established Adolescents: 5 mg PO hs for severe anxiety
Contraindications	Documented hypersensitivity; severe CNS depression; severe liver or cardiac disease; bone marrow suppression; narrow-angle glaucoma
Interactions	May inhibit activity of bromocriptine and levodopa; benztropine may inhibit therapeutic response to loxapine, causing excess anticholinergic effects; barbiturates and cigarette smoking may enhance hepatic metabolism of loxapine; loxapine may reverse pressor effects of epinephrine; lorazepam combined with loxapine can cause major respiratory suppression
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in patients with cardiovascular disease or seizures; watch for hypotension if administering IM; in patients taking benzodiazepines, loxapine should be preceded by stopping benzodiazepine therapy for 2 weeks to avoid drug interactions capable of respiratory depression

FOLLOW-UP

Section 8 of 12

Further Outpatient Care:

• 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).

In/Out Patient Meds:

• 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.



• Triple bromide


• • This is the second drug of choice for long-term anticonvulsant therapy (first choice is gabapentin).
  
  
  
  • 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.
  
  
  
• Diphenhydramine: Because of its renal clearance, this drug is safe for use as a sleeping aid or antianxiety medication.

Deterrence/Prevention:

• Both RD and the hepatic porphyrias have diet and drug restriction requirements, which are key elements in medical management (see Treatment).

Prognosis:

• Prognosis in RD and the hepatic porphyrias depends entirely on the proper dietary and drug restrictions (see Treatment).



• The patient's ability to survive an acute exacerbation depends upon 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 (see Treatment). Despite appropriate treatment measures, mortality rate in acute attacks of AIP may be as high as 25%.

Patient Education:

• Both patients with RD 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 RD, 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 RD 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.
  
  
  

MISCELLANEOUS

Section 9 of 12

Medical/Legal Pitfalls:

• Patients with porphyria should be aware of their drug-sensitivity issues and should specifically mention them to a new physician, who should take the issue seriously. Patients with porphyria typically relate physician reactions of incredulity to their stated issues of drug sensitivity.



• On the other hand, trying a new medication in a partnership effort, encouraging the patient to communicate any difficulties and testing blood or urine for ALA/PBG, is positive medicolegal behavior by the physician.

TEST QUESTIONS

Section 10 of 12

CME Question 1: A 21-year-old white man with a history of night blindness and anosmia developed acute-onset, multiple neurological complaints at the end of a 2-week period of influenza. Signs and symptoms included quadriparesis, decreased reflexes, ataxia, nystagmus, and retinitis pigmentosa with visual field constriction. Recovery occurred over several months, except for bilateral foot drop. Four months after the acute episode, a spinal fluid protein was 450 mg/100 mL. Which of the following would be the definitive diagnosis at 6 months?

A: Multiple sclerosis confirmed by magnetic resonance imaging (MRI)
B: Friedreich ataxia confirmed by positive family history of ataxia among some first and second cousins
C: Refsum disease confirmed by high serum phytanic acid
D: Guillain-Barré syndrome confirmed by the persistence of elevated spinal fluid protein
E: Hepatic porphyria confirmed by quantitative porphyrins in a 24-hour urine sample

The correct answer is C: Key elements of history and physical examination that are specific for Refsum disease include night blindness, anosmia, retinitis pigmentosa, ataxia, polyneuropathy, increased CSF protein with multiple limb weakness, hyporeflexia, and residual bilateral foot drop. A remitting course does not fit Friedreich ataxia. Serum phytanic acid level is the only way to confirm the diagnosis.

CME Question 2: A 10-year-old white girl developed a major skin eruption on her anterior chest and abdomen after spending the afternoon at the local outdoor swimming pool. Her father, a psychiatrist who recently came to the United States from South Africa to do a sleep disorders fellowship, told the neurologist that she was probably allergic to phenytoin, which was initiated 3 months earlier for idiopathic epilepsy. The neurologist switched the child to gabapentin. Which of the following tests is most appropriate?

A: Serum porphobilinogen deaminase to rule out acute intermittent porphyria
B: Skin biopsy to rule out bullous pemphigus
C: Antinuclear antibody and erythrocyte sedimentation rate to exclude a vasculitic cause for seizures
D: Twenty-four–hour urine and fecal porphyrins to exclude variegate porphyria
E: CBC count and serum porphobilinogen level in preparation for phlebotomy

The correct answer is D: Conventional drug therapy of childhood epilepsy is a major cause of prepubertal onset of symptomatic porphyria. Hepatic porphyrias otherwise begin after puberty. Phenytoin induces cytochrome P450 and increases heme and porphyrin production. Although photodermatitis can occur in porphyria cutanea tarda, necessitating phlebotomy, and in phenytoin allergy, it is rare in acute intermittent porphyria; variegate porphyria is common in people of Afrikaner lineage and may have photodermatitis. Bullous pemphigus and vasculitis are not central considerations. Phenytoin is unlikely to be effective in an undiagnosed vasculitis.

Pearl Question 1 (T/F): Cerebrospinal fluid protein elevation is specific for acute inflammatory demyelinating polyradiculoneuropathy (AIDP, Guillain-Barré syndrome) in the differential diagnosis of porphyria or Refsum disease.

The correct answer is False: A generalized polyneuropathy associated with porphyria or Refsum disease also may cause an increase in cerebrospinal fluid protein.

Pearl Question 2 (T/F): Hepatic porphyrias always have postpubertal onset.

The correct answer is False: Children with porphyria who develop idiopathic epilepsy and are being treated with conventional anticonvulsants that induce hepatic cytochrome P450 activity typically present before puberty.

Pearl Question 3 (T/F): A metabolic substrate can abort acute porphyric attacks.

The correct answer is True: Sugars, especially glucose (ie, the glucose effect), can abort an acute porphyria attack.

Pearl Question 4 (T/F): Biological feedback inhibition of porphyrin production in patients with porphyria can be achieved by medication.

The correct answer is True: Hemin (hematin) infusion can inhibit porphyria production.

PICTURES

Section 11 of 12

Caption: Picture 1. Tetrapyrrole molecules are large-ringed structures developed from 4 pyrrole groups and used in energy metabolism in both plants and animals.
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Caption: Picture 2. Three characteristic substrate molecules of the heme porphyrin pathway.
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BIBLIOGRAPHY

Section 12 of 12

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• Meyer UA, Schuurmans MM, Lindberg RL: Acute porphyrias: pathogenesis of neurological manifestations. Semin Liver Dis 1998; 18(1): 43-52[Medline].
• Redeker AG: Phlebotomy treatment of porphyria cutanea tarda: is it really effective?. Calif Med 1969 Nov; 111(5): 404-6[Medline].
• Reynolds NC Jr, Miska RM: Safety of anticonvulsants in hepatic porphyrias. Neurology 1981 Apr; 31(4): 480-4[Medline].
• Tenhunen R, Mustajoki P: Acute porphyria: treatment with heme. Semin Liver Dis 1998; 18(1): 53-5[Medline].
• Verhoeven NM, Wanders RJ, Poll-The BT, et al: The metabolism of phytanic acid and pristanic acid in man: a review. J Inherit Metab Dis 1998 Oct; 21(7): 697-728[Medline].
• Zadra M, Grandi R, Erli LC, et al: Treatment of seizures in acute intermittent porphyria: safety and efficacy of gabapentin. Seizure 1998 Oct; 7(5): 415-6[Medline].

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