PORPHYRIA

PORPHYRIA - Jeremy Golding, MD
BASICS
DESCRIPTION
• Several heme synthesis pathway enzyme deficiencies with overproduction and accumulation of intermediate metabolic products and resultant neuropsychiatric-abdominal or dermatologic symptoms and syndromes
- Porphyria cutanea tarda: Dermatologic
- Acute intermittent porphyria: Pyrroloporphyria; neuropsychiatric-abdominal
- Protoporphyria: Erythropoietic or hepatoerythropoietic; mild dermatologic
- Variegate porphyria: South African porphyria, prevalence in South Africa is 1/400
- Hereditary coproporphyria: Neuropsychiatric, occasionally dermatologic
- Porphobilinogen synthetase deficiency: -Aminolevulinic aciduria; neuropsychiatric abdominal
- Congenital erythropoietic porphyria: Gunther disease; severe dermatologic
- Other rare genetic variants reported
• System(s) Affected: Gastrointestinal; Skin/Exocrine; Hematologic/Lymphatic/Immunologic; Nervous
• Synonym(s): -Aminolevulinic aciduria; Erythropoietic porphyria; Gunther disease; Hepatoerythropoietic porphyria; Pyrroloporphyria; South African porphyria
ALERT
Unpredictable disease activity
GENERAL PREVENTION
• Avoid precipitating drugs
- Alcohol
- Barbiturates
- Carbamazepine
- Chlorpropamide
- Danazol
- Ergots
- Estrogens and progestins
- Ethchlorvynol
- Glutethimide
- Griseofulvin
- Mephenytoin
- Meprobamate
- Methotrexate
- Methyprylon
- Metoclopramide
- Phenytoin
- Pyrazolones
- Succinimides
- Sulfonamide antibiotics
- Valproic acid
• Eat a diet with high-carbohydrate intake.
EPIDEMIOLOGY
• Predominant age
- Congenital erythropoietic porphyria: Early childhood
- Protoporphyria: Older childhood
- Acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, porphobilinogen synthetase deficiency: Young adult
- Porphyria cutanea tarda: Middle age
• Predominant sex
- Protoporphyria, congenital erythropoietic porphyria: Male = Female
- Porphyria cutanea tarda: Male > Female
- Acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, porphobilinogen synthetase deficiency: Female > Male
Incidence
• Porphyria cutanea tarda: 1/10,000; most common of the porphyrias in US and Europe
• Acute intermittent porphyria, protoporphyria, variegate porphyria: 1/10,000-100,000
• Hereditary coproporphyria: 1/100,000
• Porphobilinogen synthetase deficiency, congenital erythropoietic porphyriavery rare
Prevalence
All more common in whites than in African Americans or Asians
RISK FACTORS
• Multiple precipitating factors, especially acute intermittent porphyria, variegate porphyria, hereditary coproporphyria
• Drugs (e.g., barbiturates and sulfas in acute intermittent porphyria)
• Estrogens, especially oral contraceptives
• Steroids
• Liver disease
• Menstrual cycles
• Infection
• Fasting
• Heavy alcohol use
• Hexachlorobenzene exposure
Genetics
• Autosomal dominant: Porphyria cutanea tarda (20% of cases), acute intermittent porphyria, protoporphyria, variegate porphyria, hereditary coproporphyria
• Autosomal recessive: Porphobilinogen synthetase deficiency, congenital erythropoietic porphyria
• Latency common with variable expression, many asymptomatic or minimally symptomatic carriers
• Porphyria cutanea tarda also sporadic and acquired (>80% of cases)
• The pathogenesis of the inherited porphyrias has been defined at the molecular level. It is clear that a great deal of genetic heterogeneity is present in each porphyria.
ETIOLOGY
• Genetic enzyme deficiencies
- Porphyria cutanea tarda: Uroporphyrinogen decarboxylase
- Acute intermittent porphyria: Porphobilinogen deaminase
- Protoporphyria ferrochelatase
- Variegate porphyria: Protoporphyrinogen oxidase
- Hereditary coproporphyria: Coproporphyrinogen oxidase
- Porphobilinogen synthetase deficiency: Porphobilinogen synthetase
- Congenital erythropoietic porphyria: Uroporphyrinogen III synthetase (cosynthetase)
• Causes of acquired porphyria cutanea tarda:
- Hepatitis C virus (strong association)
- Heavy alcohol use
- Decreased enzyme associated with steroids and hormones
- Specific exposure to polyhalogenated hydrocarbons (e.g., hexachlorobenzene)
- Lead poisoning may alter pathways.
- HIV
- Possibly ascorbic acid deficiency

DIAGNOSIS
SIGNS AND SYMPTOMS
• All usually reversible, lasting days to weeks
• May be permanent
• Urine may turn dark red or brown on standing (porphyria is from the Greek porphyra, "purple").
• Abdominal
- Rather severe abdominal pain, occasionally in back and extremities
- Generalized more often than localized
- Often colicky
- Can mimic acute abdomen
- Fever not usually present
- Chronic constipation common
- Severity of symptoms often out of proportion to physical findings
• Neurologic
- Essentially any neurologic picture may be seen
- Includes sensory and motor systems
- Includes autonomic nervous system
- May include seizures
- May lead to quadriplegia and/or respiratory paralysis with death
• Psychiatric
- Essentially any psychiatric disorder may be mimicked
- Psychosis most common
- Visual hallucinations common
- Disorientation frequent
- Chronic depression frequent
• Dermatologic
- Photosensitivity (common)
- Scrapes, ulcerations, blisters with minimal trauma
- Hyperpigmentation, especially hands and face
- Scarring frequent
- Facial hypertrichosis
• Congenital erythropoietic porphyria (mutilating, with hemolysis, erythrodontia, splenomegaly)
• Protoporphyria (occasional hepatic disease, including hepatic failure)
TESTS
Genetic studies when applicable
Lab
• Urine for porphyrins during acute attack. Urine may be normal at other times.
• Individual enzyme activity in erythrocytes or other body cells/tissues
• Stool for porphyrins in protoporphyria, variegate porphyria, hereditary coproporphyria, congenital erythropoietic porphyria
• Bile for porphyrin in variegate porphyria
• Plasma for fluorescence emission spectroscopy in variegate porphyria
• Saliva for porphyria in porphyria cutanea tarda
• Erythrocyte uroporphyrin in congenital erythropoietic porphyria
• Protoporphyria exception urine unremarkable; test erythrocyte protoporphyrin.
• Ferritin typically elevated in porphyria cutanea tarda due to increased iron stores
• Drugs that may alter lab results: Unknown
• Disorders that may alter lab results:
- Numerous conditions may cause slight increase in porphyrinuria, but patients are asymptomatic
 Acute liver disease
 Hepatoma
 Hodgkin lymphoma
 Multiple neurologic diseases
DIFFERENTIAL DIAGNOSIS
• Vast and protean
• Pseudoporphyria is a rare syndrome, indistinguishable from porphyria cutanea tarda, owing to some NSAIDs (e.g., nabumetone and naproxen) and flutamide.
TREATMENT
Outpatient, except for crises
GENERAL MEASURES
• Neuropsychiatric-abdominal: Avoid drugs, alcohol, known toxins
• Dermatologic: Shade, protective clothing; avoid skin trauma; porphyria cutanea tarda phlebotomy weekly to monthly may help prevent.
• Congenital erythropoietic porphyria: Consider bone marrow transplantation.
Diet
Neuropsychiatric: Large quantities of carbohydrates have been reported to help.
Activity
Normal, except avoid sun exposure
MEDICATION (DRUGS)
First Line
• Neuropsychiatric-abdominal
- IV glucose 400 g/d for 1-2 days
- Hematin (ferriprotoporphyrin IX, hemin [Panhematin]) IV 1-4 mg/kg/d over 10-15 minutes for 3-14 days
- Seizures: Consider clonazepam or gabapentin.
- Depression: Consider selective serotonin reuptake inhibitors.
• Dermatologic: Oral carotenoids (e.g., -carotene [Solatene], 30 mg, 1-10 capsules per day)
• Contraindications: Known sensitivity to drug
• Precautions: Hematin phlebitis at IV site, reduced clotting ability
• Significant possible interactions: None
Second Line
• Porphyria cutanea tarda
- Chloroquine 125 mg twice weekly, or hydroxychloroquine 250 mg t.i.d., in conjunction with phlebotomy
- With hepatitis C virus: Interferon beneficial for both congenital erythropoietic porphyria and plumboporphyria.
- In vitro gene therapy has been successful.
• Acute intermittent porphyria
- Luteinizing hormone-releasing hormone (LHRH) analogs being studied
- Antioxidants ineffective
- Menstruating women: Hematin premenstrual; cycle suppressors (e.g., LHRH analogues)
- Autonomic manifestations: -Blockers
- Other symptoms: Treat symptomatically
FOLLOW-UP
PROGNOSIS
• In all porphyrias
- Patients who are asymptomatic or minimally symptomatic: Unaffected longevity
- Patients who are more symptomatic: Treatable and do well
- Neurologic complications (e.g., peripheral neuropathy, neurosis, or hemiplegia), at times permanent
• In acute intermittent porphyria
- Acute attacks have 25% mortality.
- Increased risk of hepatocellular carcinoma
• Acquired porphyria cutanea tarda
- HIV
- Hepatitis C virus
- Hepatic malignancies
REFERENCES
1. Dombeck TA. Emerg Med Clin North Am. 2005;23(3):885-899.
2. Goldman. Cecil Textbook of Medicine, 22nd ed. Philadelphia: WB Saunders, 2004.
3. Braunwald E, Fauci et al., eds. Harrison's Principles of Internal Medicine, 15th ed. New York: McGraw-Hill; 2001:2261-2267.
4. Kelly WN, Dupont HL, eds. Textbook of Internal Medicine, 3rd ed. New York: Lippincott-Raven; 1997:880-882.
MISCELLANEOUS
Some drugs considered safe
• Acetaminophen
• Amiodarone
• Aspirin
• Atropine
• Bromides
• Chlorpromazine
• Diazepam (in small doses)
• Dicumarol
• Digoxin
• Diphenhydramine
• Ether
• Glucocorticoids
• Guanethidine
• Heparin
• Insulin
• Lithium
• Magnesium
• Neostigmine
• Nitrous oxide
• Penicillin and derivatives
• Phenothiazines
• Promethazine
• Narcotic analgesics
• Propranolol
• Streptomycin
• Succinylcholine
• Thiazides