• DOI:10.7326/0003-4819-142-6-200503150-00010
• Corpus ID: 36122555

Recommendations for the Diagnosis and Treatment of the Acute Porphyrias

@article{Anderson2005RecommendationsFT,
  title={Recommendations for the Diagnosis and Treatment of the Acute Porphyrias},
  author={Karl E. Anderson and Joseph R. Bloomer and Herbert L. Bonkovsky and James P. Kushner and ClausA. Pierach and Neville Roy Pimstone and Robert J. Desnick},
  journal={Annals of Internal Medicine},
  year={2005},
  volume={142},
  pages={439-450}
}

• K. Anderson, J. Bloomer, +4 authors R. Desnick
• Published 15 March 2005
• Medicine
• Annals of Internal Medicine

Key Summary Points Early Diagnosis of Acute Porphyria Consider in all adults with unexplained symptoms seen in acute porphyrias (Table 2); certain clinical features are suggestive: women of reproductive age; abdominal pain; muscle weakness; hyponatremia; and dark or reddish urine. Establish diagnosis promptly by testing for increased porphobilinogen in a single-void urine (we recommend the Trace PBG Kit [Thermo Trace/DMA, Arlington, Texas]). If porphobilinogen is increased, begin treatment immediately. To establish the type of acute porphyria, save the same urine sample for measurement of ALA, porphobilinogen, and porphyrin levels, and measure plasma porphyrin levels, fecal porphyrin levels, and erythrocyte porphobilinogen deaminase levels (Table 5 and Figure). Treatment of the Acute Attack Hospitalize patient for control of acute symptoms and withdraw all unsafe medications (see Table 3) and other possible precipitating factors. Provide nutritional support and symptomatic and supportive treatment; consider seizure precautions, especially if patient is hyponatremic; use medications that are known to be safe in the acute porphyrias; and use intravenous fluids to correct dehydration and electrolyte imbalances, narcotic analgesics for pain, phenothiazine for nausea or vomiting, and -adrenergic blockers for hypertension and symptomatic tachycardia. Begin hemin (3 to 4 mg/kg daily for at least 4 days) as soon as possible. Intravenous glucose alone (10%, at least 300 g daily) may resolve mild attacks (mild pain, no paresis, or hyponatremia) or can be given while awaiting delivery of hemin. Monitor patient closely: Check vital capacity (if impaired, place patient in intensive care) and neurologic status, including muscle strength (especially proximal); check serum electrolytes, creatinine, and magnesium levels at least daily; and watch for bladder distention. Follow-up Educate patient and family about the disease, its inheritance, precipitating factors, and important preventive measures. Encourage patients to wear medical alert bracelets and keep records of diagnostic studies and recommended therapy. Treat chronic manifestations (such as pain and depression) and disability. Provide access to genetic testing for patient and family members. The acute porphyrias are well-defined genetic disorders of heme biosynthesis characterized by acute life-threatening attacks of nonspecific neurologic symptoms (1). Although the specific enzyme and gene defects have been identified, diagnosis and treatment of these 4 disorders still present formidable challenges because their symptoms and signs mimic other, more common conditions. Delaying diagnosis and treatment of acute porphyric attacks can be fatal or can cause long-term or permanent neurologic damage. Updated, consistent recommendations for timely diagnosis and treatment of these disorders have been lacking, despite the existence of rapid, sensitive, and specific biochemical tests (2) and the availability of an effective therapy, which was first described more than 30 years ago (3) and was approved by the U.S. Food and Drug Administration (FDA) more than 20 years ago. Formation of an Expert Panel and Basis of Recommendations Concerns about misdiagnosis, delayed diagnosis, and inappropriate therapy prompted the American Porphyria Foundation to assemble a panel of experts on the acute porphyrias who were selected on the basis of their clinical and research experience and their contributions to the medical literature. The panel, which represents specialties including internal medicine, pediatrics, genetics, gastroenterology, hepatology, and hematology, was charged with formulating updated recommendations for diagnosing and treating the acute porphyrias. With support from the American Porphyria Foundation, the panel members convened for a day-long meeting to formulate clinical recommendations. Two members, assisted by a medical writer funded by the Foundation, prepared a draft manuscript based on the panel's discussion and recommendations. All panel members participated in the review and revision of the manuscript and agreed to the final version. Recommendations are based on the clinical experience of the authors and their review of the literature. Because the acute porphyrias are rare, most of the literature consists of reviews, small series, and case studies. A detailed MEDLINE search on treatment of acute attacks, for example, revealed 71 papers (55 in English and 16 with English abstracts) published between 1966 and October 2004. Of these, 41 were single-case reports, 13 were case series of 10 or fewer patients, and 17 (11 in English) were studies with more than 10 patients (4-20). Altogether, 53 papers discuss more than 1000 patients who received hemin therapy with or without initial treatment with glucose. The American Porphyria Foundation partially funded this review. This nonprofit organization provides information and support to patients with porphyria and their physicians. It receives funding from private sources in addition to a nonrestricted grant from Ovation Pharmaceuticals, the manufacturer of hemin for injection (Panhematin), the only FDA-approved hemin therapy for the acute porphyrias. The Foundation and Ovation Pharmaceuticals had no role in the literature review, the formulation of recommendations, or the drafting and revising of the manuscript. Overview of the Acute Porphyrias Acute Porphyrias Are Inborn Errors of Heme Biosynthesis Each of the acute porphyrias results from the deficient activity of a distinct enzyme in the heme biosynthetic pathway (1). Porphyrias are classified as hepatic or erythroid, depending on whether most of the heme biosynthetic intermediates arise from, and accumulate in, the liver or in developing erythrocytes. They are also classified clinically as acute or cutaneous on the basis of their major clinical manifestations. Of the 5 hepatic porphyrias, 4 characteristically present with acute attacks of neurologic manifestationshence the designation acute porphyrias, a term that does not fully describe the clinical features, which can be prolonged and chronic. Table 1 shows the genetic and enzymatic features of the 4 acute hepatic porphyrias (21): acute intermittent porphyria, hereditary coproporphyria, variegate porphyria, and the very rare 5-aminolevulinic acid (ALA)dehydratase porphyria. The combined prevalence of these diseases is approximately 5 cases per 100000 persons (1). Numerous mutations have been identified for each disorder. The major manifestations of the acute porphyrias are neurologic, including neuropathic abdominal pain, peripheral neuropathy, and mental disturbances (Table 2) (1, 4, 22-25). These develop during adult life, are more common in women than in men, and are treated by methods to restore heme homeostasis. Variegate porphyria and, much less commonly, hereditary coproporphyria can also cause chronic, blistering lesions on sun-exposed skin that are identical to those in porphyria cutanea tarda, a much more common condition. Photocutaneous lesions may occur without neuropathic manifestations. Table 1. Characteristics of the 4 Acute Porphyrias Table 2. Common Presenting Symptoms and Signs of Acute Porphyria In addition to their highly variable neurologic signs and symptoms, the acute porphyrias are distinct from other porphyrias because of their common overproduction of the porphyrin precursors ALA (an amino acid), and porphobilinogen (a pyrrole). This striking biochemical feature is important for laboratory diagnosis and has implications for pathogenesis of the neurologic manifestations. While porphyrins (tetrapyrroles) are also increased, their measurement is of little value for initial diagnosis because they are also increased (in urine, feces, erythrocytes, or plasma) in other porphyrias and many other medical conditions. Pathogenesis of Acute Attacks The enzyme deficiency in each disorder is partial (approximately 50% of normal in the 3 most common acute porphyrias), and the remaining enzyme activity is usually sufficient for heme homeostasis. Because ALA dehydratase activity normally greatly exceeds that of the other enzymes in the pathway, a more severe deficiency of this enzyme (5% of normal) is required to cause manifestations of ALA-dehydratase porphyria. These enzymatic defects predispose the affected persons to the effects of precipitating factors, including many drugs (for example, barbiturates, anticonvulsants, rifampin, and progestins), endogenous steroid hormones (especially progesterone), fasting, dieting, smoking, and stress from illness, all of which can increase the demand for hepatic heme and induce synthesis of ALA synthase, the first enzyme in the heme biosynthetic pathway. Because hepatic ALA synthase is rate-controlling, production of heme pathway intermediates increases to the point at which the inherited partial enzyme deficiency becomes limiting, and intermediates accumulate in the liver. Porphobilinogen and ALA levels are increased in all patients with acute symptoms of these disorders and in some who are asymptomatic. The cause of hepatic overproduction of porphyrin precursors in the acute porphyrias is better understood than are the mechanisms for neurologic damage. Presumably, symptoms result primarily from the porphyrin precursors themselves rather than a deficiency of heme in nerve tissue (26, 27). Chronic symptoms and signs may reflect previous, unresolved neurologic damage. In the very rare cases of homozygous acute intermittent porphyria (26), variegate porphyria (28), and hereditary coproporphyria (29), severe neurologic manifestations begin in childhood. An allogeneic liver transplantation in a woman with heterozygous acute intermittent porphyria normalized her urinary ALA and porphobilinogen levels in 24 hours and completely eliminated her recurrent neurologic attacks, which supports the hepatic overproduction of porphyrin precursors in causing the neurologic symptoms (27). Si