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902 Part VI: The Erythrocyte Chapter 58: The Porphyrias 903

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TABLE 58–4. A Partial List of Drugs Known to Be Unsafe or of cases. It is usually severe, steady, and poorly localized, but may be
cramping, and is often accompanied by nausea, vomiting, constipa-
Safe in the Acute Porphyrias
tion, and abdominal distention because of ileus. Pain in the chest and
Unsafe Safe extremities are also common. Tachycardia is the most common phys-
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Alcohol Meprobamate * Acetaminophen ical sign, occurring in up to 80 percent of acute attacks, and often
*
Barbiturates * (also mebutamate , Aspirin accompanied by hypertension, sweating, tremors, and other effects of
*
Carbamazepine * tybamate ) Atropine sympathetic overactivity and excess catecholamine production. There is
little or no abdominal tenderness, fever, or leukocytosis because inflam-
Carisoprodol * Methyprylon * Bromides mation is not prominent. Bowel sounds are usually decreased, but are
Clonazepam (high Metoclopramide Cimetidine sometimes increased with diarrhea. The urine is often dark (because of
doses) Phenytoin * Erythropoietin *,† porphobilin, a degradation product of PBG) or reddish (because of por-
Danazol * Primidone * Gabapentin phyrins, including uroporphyrin formed nonenzymatically from PBG).
Diclofenac and pos- Progesterone Glucocorticoids Urinary hesitancy and dysuria may occur as a consequence of bladder
*
sibly other NSAIDs and synthetic Insulin dysfunction. Acute mental symptoms may include insomnia, anxiety,
*
Ergots progestins * Narcotic analgesics restlessness, disorientation, paranoia, and hallucinations.
Paresis because of peripheral motor neuropathy usually occurs
Estrogens *,‡ Pyrazinamide with prolonged, severe attacks, but is sometimes an early or even initial
Ethchlorvynol * Pyrazolones (amino- Penicillin and manifestation. 212,213 Porphyric neuropathy is primarily motor and results
derivatives
pyrine, antipyrine)
Glutethimide * Rifampin * Phenothiazines from axonal degeneration, which may be followed by demyelinization.
214
Griseofulvin * Succinimides Ranitidine *,† Muscle weakness may not be detected until it is quite advanced because
Mephenytoin (ethosuximide, Streptomycin it usually begins in the proximal muscles of the upper extremities. Pare-
methsuximide) Vigabatrin sis is usually symmetrical, but may be asymmetrical or focal. Course
Sulfonamide tremors, clonus and increased reflexes are sometimes prominent. Mag-
antibiotics * netic resonance imaging may demonstrate cortical densities resembling
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Valproic acid * the posterior reversible encephalopathy syndrome. Sensory loss may
develop, especially in the distal extremities. Cranial nerve involvement
NSAIDs, nonsteroidal antiinflammatory drugs. and cortical blindness have been described.
*Porphyria is listed as a contraindication, warning, precaution, or Motor neuropathy may progress to respiratory and bulbar paralysis
adverse effect in U.S. labeling for these drugs. and death especially if diagnosis and treatment are delayed and harm-
† Although porphyria is listed as a precaution in U.S. labeling, these ful drugs continued. Death may also result from respiratory arrest or
drugs are regarded as safe by other sources. cardiac arrhythmia. 214,215 Most attacks treated promptly resolve within
‡ Estrogens are unsafe for porphyria cutanea tarda, but can be can be days or even hours. Advanced neuropathy from a severe attack is poten-
used with caution in the acute porphyrias. tially completely reversible, with improvement continuing for up to 1 to
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2 years.
NOTE: More complete sources, such as the websites of the Ameri- Hyponatremia is common during severe attacks and is sometimes
can Porphyria Foundation (www.porphyriafoundation.com) and the a result of hypothalamic involvement and the syndrome of inappro-
European Porphyria Initiative (www.porphyria-europe.com) should
be consulted before using drugs not listed here, keeping in mind that priate antidiuretic hormone secretion. However, hyponatremia may
217
classifications may not be supported by high-quality evidence. be accompanied by reductions in blood volume, indicating that
increased antidiuretic hormone secretion in this setting is an appropri-
215
ate physiologic response. Hyponatremia may sometimes result from
acute porphyria, and these effects are reversed by administration of gastrointestinal loss, poor intake, and excess renal sodium loss. 215,218 A
carbohydrate. 30,206 Starvation, may also induce hepatic heme oxygenase, possible nephrotoxic effect of ALA may explain renal tubular sodium
207
218
which may deplete hepatic heme and contribute to ALAS1 induction. loss and impaired renal function in some patients. Other electrolyte
219
Stress Various forms of physical or psychological stress may exac- abnormalities may include hypomagnesemia and hypercalcemia. Sei-
erbate acute porphyrias, although the mechanisms are not well defined. zures may result from hyponatremia or represent a neurologic effect of
Medical illnesses, fever, infections, alcoholic excess, and surgery may acute porphyria.
decrease food intake and contribute to induction of hepatic ALAS1 and Chronic mental symptoms, such as depression, are difficult to
heme oxygenase. Psychological stress may also lead to decreased food attribute to AIP. But chronic pain accompanied by depression devel-
intake and have other metabolic effects. ops in some patients after frequent exacerbations, and risk for suicide is
increased. The disease also predisposes to chronic arterial hypertension
Clinical Features and impaired renal function. 203,220,221 The latter may progress and require
Symptoms are almost never seen before puberty, and most commonly renal transplantation. 222,223
develop in women in the third or fourth decade of life. Acute attacks Mild abnormalities in serum transaminases are common in AIP.
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are life-threatening but rarely fatal if promptly recognized and treated. More advanced liver disease may develop and the risk of hepatocellular
Frequently recurring attacks and chronic symptoms can develop and carcinoma is greatly increased (60- to 70-fold) in AIP, and is not related
be disabling. Although the most prominent symptoms are a result of to specific PBGD mutations. Serum α-fetoprotein was not increased and
effects on the nervous system, liver and kidney damage may be impor- the uninvolved liver was not cirrhotic in most acute porphyria cases
tant in the long-term. In very rare homozygous cases, severe neurologic with liver cancer reported as of this writing. Increased serum thyroxin
manifestations are seen early in childhood, and acute attacks are not levels because of increased thyroxin-binding globulin occurs in some
prominent. 207a,209 patients with AIP, and occasionally hyperthyroidism and porphyria
Symptoms and signs are nonspecific and highly variable. Abdom- occur together. Elevated low-density lipoprotein cholesterol is appar-
225
inal pain is the most common symptom, occurring in 85 to 95 percent ently less commonly observed in this disorder than in the past. 226

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