Karl E. Anderson

Recommendations for the Diagnosis and Treatment of the Acute Porphyrias

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 panels 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

Defining translational research: Implications for training

Because translational research is not clearly defined, developers of translational research programs are struggling to articulate specific program objectives, delineate the knowledge and skills (competencies) that trainees are expected to develop, create an appropriate curriculum, and track outcomes to assess whether program objectives and competency requirements are being met. Members of the Evaluation Committee of the Association for Clinical Research Training (ACRT) reviewed current definitions of translational research and proposed an operational definition to use in the educational framework. In this article, the authors posit that translational research fosters the multidirectional and multidisciplinary integration of basic research, patient-oriented research, and population-based research, with the long-term aim of improving the health of the public. The authors argue that the approach to designing and evaluating the success of translational training programs must therefore be flexible enough to accommodate the needs of individual institutions and individual trainees within the institutions but that it must also be rigorous enough to document that the program is meeting its short-, intermediate-, and long-term objectives and that its trainees are meeting preestablished competency requirements. A logic model is proposed for the evaluation of translational research programs.

Diet-hormone interactions: Protein/carbohydrate ratio alters reciprocally the plasma levels of testosterone and cortisol and their respective binding globulins in man

The aim of this study was to determine if a change in protein/carbohydrate ratio influences plasma steroid hormone concentrations. There is little information about the effects of specific dietary components on steroid hormone metabolism in humans. Testosterone concentrations in seven normal men were consistently higher after ten days on a high carbohydrate diet (468 +/- 34 ng/dl, mean +/- S.E.) than during a high protein diet (371 +/- 23 ng/dl, p less than 0.05) and were accompanied by parallel changes in sex hormone binding globulin (32.5 +/- 2.8 nmol/l vs. 23.4 +/- 1.6 nmol/l respectively, p less than 0.01). By contrast, cortisol concentrations were consistently lower during the high carbohydrate diet than during the high protein diet (7.74 +/- 0.71 micrograms/dl vs. 10.6 +/- 0.4 micrograms/dl respectively, p less than 0.05), and there were parallel changes in corticosteroid binding globulin concentrations (635 +/- 60 nmol/l vs. 754 +/- 31 nmol/l respectively, p less than 0.05). The diets were equal in total calories and fat. These consistent and reciprocal changes suggest that the ratio of protein to carbohydrate in the human diet is an important regulatory factor for steroid hormone plasma levels and for liver-derived hormone binding proteins.

Enhanced phenacetin metabolism in human subjects fed charcoal‐broiled beef

There were marked individual differences in the plasma levels of phenacetin after oral administration of a 900‐mg dose to 9 normal volunteers eating their customary home diet. Feeding a diet that contained charcoal‐broiled beeffor 4 days prior to the administration of phenacetin markedly decreased the plasma levels of this drug without appreciably influencing the plasma concentrations of phenacetins metabolite, N‐acetyl‐p‐aminophenol (APAP), or the plasma half‐life of phenacetin. The average peak concentration of phenacetin in plasma, after a 900‐mg oral dose, fell from 1,628 ng/ml, when the subjects were fed a control diet for 7 days, to 352 ng/ml after they were fed the same diet which contained charcoal‐broiled beeffor 4 days. The average peak concentration of phenacetin rose to 1,885 ng Iml after the subjects were subsequently fed the control diet for 7 days. The ratios of the average concentrations of APAP in plasma to those of phenacetin markedly increased after the charcoal‐broiled beef diet. The results suggest that a diet containing charcoal‐broiled beef enhances the metabolism of phenacetin in the gastrointestinal tract and/or during its first pass through the liver. This effect greatly decreases the bioavailability of phenacetin.

Effect of charcoal‐broiled beef on antipyrine and theophylline metabolism

Eight healthy volunteers were sequentially fed a control diet, a charcoal‐broiled beef‐containing diet, and the control diet a second time. The mean plasma half‐lives (t½) of antipyrine and theophylline were each decreased by 22% after the subjects were fed the charcoal‐broiled beef‐containing diet. The mean plasma t½s for these drugs returned to control values when the subjects were fed the control diet for a second time. Considerable individuality occurred in the responsiveness of the subjects to the charcoal‐broiled beef‐containing diet. The decreases in antipyrine plasma t½s among the 8 subjects ranged from 5% to 39%, and the decreases in theophylline t½S ranged from 0% to 42%.

Sex and long-term soy diets affect the metabolism and excretion of soy isoflavones in humans.

Soybean consumption may be protective against hormone-dependent cancers, possibly in part because of the isoflavones daidzein and genistein, which are weakly estrogenic. This paper reviews our studies of the metabolism and disposition of these phytoestrogens in humans. During 1 mo of daily soy ingestion in a metabolic unit [1.065 L (36 oz) soymilk, providing 80-210 mg of each isoflavone daily], women initially excreted more isoflavone conjugates in urine than did men. Recoveries of conjugates of genistein, daidzein, and equol were 24%, 66%, and 28% of the amounts ingested in women, respectively, and 15%, 47%, and 15%, respectively, of those in men. A progressive decrease in urinary excretion of genistein and daidzein was observed in women but not in men during the study. At least 10% of ingested daidzin was excreted in urine as equol conjugate in one man and one woman after the first soy ingestion. Three more women but no more men developed the ability to produce and excrete large amounts of equol. Absorption rate constants (k(e)) of the isoflavones were estimated to be 0.24-0.50 h(-1). The elimination rates (k(e)) for genistein, daidzein, and equol were 0.1, 0.16, and 0.08 h(-1), respectively, in women and 0.19, 0.25, and 0.13 h(-1), respectively, in men. Thus, the excretion half-life values of genistein were longer in women (7, 4, and 9 h, respectively) than in men (4, 3, and 5 h, respectively) after the first soy ingestion. The excretion half-life shortened progressively in women but lengthened progressively in men over the study period. Thus, isoflavone metabolism and disposition were affected by the duration of soy ingestion and by sex.

Altered kinetics and extent of urinary daidzein and Genistein excretion in women during chronic Soya exposure

Soybean consumption may be protective for breast cancer, possibly due in part to the presence of the isoflavones daidzein and genistein, which are weakly estrogenic. The metabolism and disposition of these phytoestrogens during chronic soya exposure were studied on a metabolic unit. Six healthy 22- to 29-year-old women consumed an unrestricted hospital diet for most of the study and ingested 12 oz of soymilk with each meal for one month. At two-week intervals, excretion of isoflavones in urine was studied, during which time the subjects consumed a constant basal diet for three to four days, ingested the full daily 36-oz portion of soymilk within 30 minutes each day for one to two days, and collected urine continuously. Urinary recovery of genistein [initially 23.9 +/- 17.3% (SD) of ingested genistin + genistein], daidzein (initially 66.2 +/- 23.5% of ingested daidzin + daidzein), and equol (initially 28% of the ingested precursors daidzin + daidzein in 1 subject and < 1% in 5 subjects) decreased progressively over four weeks of daily soya ingestion by 42% for genistein (p < 0.05) and 31% for daidzein (p < 0.01) but increased by 3- to 100-fold for equol (4 subjects, p < 0.05). Total amounts excreted and peak levels were similarly affected. The absorption half-lives (t 1/2) for genistein and daidzein were initially 2.7 +/- 0.8 and 1.6 +/- 0.5 hours, respectively, and during four weeks of soymilk ingestion decreased to 2.0 +/- 0.6 (p = 0.04) and 1.4 +/- 0.2 hours (p = 0.06), respectively, suggesting more rapid absorption. The appearance t 1/2 of equol can be estimated for only one subject initially (2.9 hrs), but during four weeks of soya ingestion it could be estimated for three more subjects (4.7 +/- 2.3 hrs). The excretion t 1/2 values for genistein and daidzein were initially 6.7 +/- 0.8 and 4.4 +/- 0.7 hours, respectively, and during four weeks of soymilk ingestion decreased to 4.2 +/- 1.2 (p = 0.005) and 3.2 +/- 1.1 hours (p = 0.005), respectively, suggesting more rapid excretion. For equol, the excretion t 1/2 was initially 9.1 hours (1 subject), and after two and four weeks of soymilk ingestion it was 13.4 +/- 9.7 and 5.5 +/- 1.6 hours (4 subjects, p = 0.046, 2 wks vs. 4 wks), respectively. These results indicate that metabolism and disposition of ingested isoflavones are altered during chronic soya ingestion in women, perhaps from increased metabolic degradation to formation of nonisoflavone metabolites. Increased production of the longer- and stronger-acting estrogenic equol in some women during chronic soymilk ingestion may alter the estrogenic potency of dietary soya isoflavones.

Nutrition and oxidative drug metabolism in man: Relative influence of dietary lipids, carbohydrate, and protein

Effects of an increase in dietary lipid content relative to protein or carbohydrate, and consequences of an alteration in dietary fatty acid composition on oxidative metabolism of drugs in man were examined. Two studies were carried out in healthy subjects fed carefully controlled solid food diets. In the first, the isocaloric substitution of fat for carbohydrate produced little or no statistically significant change in the mean plasma half‐lifes (t½s), apparent volumes of distribution (aVD), or metabolic clearance rates (MCR) of antipyrine (t½, 12.3 ± 0.5 hr and 11.7 ± 0.6 hr on the high carbohydrate and high fat diets, respectively) or theophylline (t½, 7.9 ± 0.4 hr on both diets) after periods of 10 to 14 days on each diet; but when intake was changed to a high protein diet metabolism rates for both drugs were greater than on either the high fat or the high carbohydrate diet in that mean plasma antipyrine t½ decreased to 9.9 ± 0.5 hr and theophylline t½ to 5.8 ± 0.3 hr, with increases in MCR for both drugs. In the second study, which was carried out with 9 subjects on high fat and high carbohydrate diets, the isocaloric substitution of either saturated fat (butter) or polyunsaturated fat (corn oil) for carbohydrate (without changing total protein content) produced no significant changes in rates of metabolism of these drugs, whereas the alterations in dietary fatty acid composition produced expected changes in plasma concentrations of cholesterol and triglycerides. Our observations suggest that protein, when substituted for either dietary carbohydrate or lipid, has a clear inducing influence on oxidative drug metabolism in man, and the degree of fatty acid unsaturation has little or no effect on rates of metabolism of these drugs despite marked changes in plasma lipids.

Altered time course of urinary daidzein and genistein excretion during chronic soya diet in healthy male subjects

Soybean consumption is associated with reduced rates of prostate and other cancers, possibly due in part to the presence of isoflavones. The metabolism and disposition of these soya-derived phytoestrogens after chronic soya exposure were studied on a metabolic unit in six healthy males (21-35 yrs of age) who consumed an unrestricted hospital diet and a 12-oz portion of soymilk with each meal for one month. The daily isoflavone intake was about 100 mg of daidzein (mostly as diadzin) and about 100 of mg of genistein (mostly as genistin). At two-week intervals, excretion of isoflavones in urine was studied, during which time the subjects consumed a constant basal diet for three to four days, ingested the full daily 36-oz portion of soymilk within 30 minutes each day for one to two days, and collected urine continuously. The urinary recovery of ingested diadzin plus daidzein (46.9 +/- 15.2%, mean +/- SD) and genistin plus genistein (14.6 +/- 9.2%) did not change with prolonged soya ingestion. The absorption half-lives (t1/2) for daidzein and genistein and the appearance t1/2 for equol (1 subject) were initially 1.5 +/- 0.4, 1.9 +/- 0.6, and 2.2 hours, respectively, and 2.5 +/- 1.1 (p = 0.06 compared with baseline) 1.4 +/- 0.9 (p = 0.03) compared with baseline), and 4.2 hours, respectively, during one month of soymilk ingestion. The excretion t1/2 for daidzein, genistein, and equol were initially 2.9 +/- 0.5, 3.8 +/- 0.7, and 5.2 hours, respectively, and 3.9 +/- 1.2 (p - 0.03), 5.5 +/- 1.6 (p = 0.02), and 9.7 hours, respectively, during one month of soymilk ingestion. These results indicate that chronic soya exposure did not induce significant changes in the metabolic pathways of isoflavones but altered the time courses of daidzein and genistein excretion. Thus chronic exposure to soya might prolong the tissue exposure to the presumed biologically active free and unconjugated forms of these isoflavones and thereby enhance their oncoprotective effects.

Influences of diet and nutrition on clinical pharmacokinetics

SummaryThe human diet represents a complex and variable mixture of nutrients, many of which have the potential for altering the disposition of drugs. This review highlights progress from a number of laboratories illustrating nutrient influences on drug dispositions and actions. Emphasis is placed on nutritional effects on hepatic drug metabolism studied in humans. Data from animals have sometimes been difficult to extrapolate to humans, as illustrated by reports on the influences of starvation, dietary lipids, and ascorbic acid. From studies in healthy subjects it is now clear that a number of specific dietary factors can influence drug metabolism by the mixed function oxidase system and conjugating enzymes. These include dietary protein, cruciferous vegetables, charcoal-broiled beef containing polycyclic aromatic hydrocarbons, and methylxanthines. The effects of such dietary components have been demonstrated for only a limited number of drug substrates for these enzyme systems. Effects of food on bioavailability have been more widely studied, and depend greatly upon the type of drug.Malnutrition can be associated with variable but potentially important effects on the bioavailability, binding, hepatic metabolism, and renal clearance of drugs. In malnourished patients it is generally difficult to recognise the roles of individual nutrient deficiencies on drug disposition, and clinical predictors of altered pharmacokinetics for various drugs in such patients are not well defined.It is likely that many important interrelationships between nutrition and new or already marketed drugs remain to be recognised, and therefore warrant further research. Nutritional effects on drug metabolising enzymes also have implications for endogenous substances such as hormones and environmental toxins and carcinogens which are metabolised by the same or related enzyme systems, and for diseases likely to be related to the actions of such chemicals.