Nutrients and Porphyria: An Intriguing Crosstalk.

Porphyria refers to a group of fascinating diseases from a metabolic and nutritional standpoint as it provides an example of how metabolic manipulation can be used for therapeutic purposes. It is characterized by defects in heme synthesis, particularly in the erythrocytes and liver. Specific enzymes involved in heme biosynthesis directly depend on adequate levels of vitamins and minerals in the tissues. Moreover, micronutrients that are required for producing succinyl CoA and other intermediates in the Krebs (TCA) cycle are indirectly necessary for heme metabolism. This review summarizes articles that describe the nutritional status, supplements intake, and dietary practices of patients affected by porphyria, paying special attention to the therapeutic use of nutrients that may help or hinder this group of diseases.

The genetic basis of "Scarsdale Gourmet Diet" variegate porphyria: a missense mutation in the protoporphyrinogen oxidase gene.

The porphyrias are disorders of porphyrin or porphyrin-precursor metabolism that result from inherited or acquired aberrations in the control of the porphyrin-heme biosynthetic pathway. Variegate porphyria (VP), one of the acute hepatic porphyrias, is characterized by a partial reduction in the activity of protoporphyrinogen oxidase (PPO), and recently, mutations in the PPO gene on chromosome 1q22-23 have been described. Our purpose was to identify the underlying genetic lesion in a severely affected patient with VP and to detect the silent mutation carriers in her family. The disease in this patient was precipitated by carbohydrate restriction as outlined in the "Scarsdale Gourmet Diet". Our mutation detection and confirmation strategy included PCR, automated sequencing, and restriction enzyme digestion. We identified a missense mutation in the patient and five family members. The mutation consisted of a previously unreported C-to-T transition in exon 5 of the PPO gene, resulting in the substitution of arginine by cysteine, designated R152C. This arginine residue is evolutionarily highly conserved in humans, mice, bacteria, yeast, and plants, indicating the importance of this residue in PPO. Our study established that a missense mutation in the PPO gene was the underlying mutation in this patient with VP and explained the occurrence of the phenotype in this family.

[Clinical and laboratory findings concerning at first dietary and afterwards cimetidine treatment of acute intermittent porphyria]. / Rilievi clinici-laboratoristici nel trattamento prima dietetico e dopo con cimetidina della porfiria acuta intermittente.

Clinical symptoms and laboratory findings were assessed in three women with acute intermittent porphyria. After 15 days of pharmacologic washout and free diet (time 0), the patients were give a well balanced normocaloric diet for 7 days (time 1), followed by 7 days of high carbohydrate normocaloric diet (time 2); on days 15 to 21 (time 3) well balanced normocaloric diet was given, and finally on days 22 to 28 (time 4) to the well balanced normocaloric diet cimetidine (0.4 g twice daily) was added. On days 3, 5, and 7 of times 1-4 the following porphyrin precursors were determined: ALA, PBG, total uroporphyrin, total coproporphyrin, and total porphyrin. At times 1 and 3, high values were found while levels dropped to normal during times 2 and 4. During times 1 and 3, patients complained of headache, insomnia and anxiety; during time 2, all patients complained of anxiety and only one suffered from insomnia. Finally, during time 4, all patients had only slight anxiety. Untoward effects of cimetidine were not observed in any of the patients.

Hereditary coproporphyria: an imitator of multiple sclerosis.

Hereditary coproporphyria can cause both peripheral neuropathy and central nervous system abnormalities. There are several similarities between multiple sclerosis and hereditary coproporphyria that are probably due to the central nervous system dysfunction present in both. This report describes a 62-year-old man with a five-year history of progressive paraparesis initially diagnosed as multiple sclerosis. Supporting evidence for the diagnosis of a demyelinating disease included three oligoclonal bands in the patient's cerebral spinal fluid, a prolonged visual evoked response bilaterally, abnormal sensory evoked potentials, and an area of increased signal in the posterior cervical cord suggestive of demyelination that was demonstrated on magnetic resonance imaging (MRI). Features atypical for multiple sclerosis were hypoactive deep-tendon reflexes, electromyographic evidence of peripheral neuropathy, and severe constipation. Elevated urine porphyrins and decreased levels of coproporphyrinogen oxidase confirmed the correct diagnosis of hereditary coproporphyria. The patient improved after being placed on a high-carbohydrate diet. Although central demyelination is known to occur in patients with porphyria, delayed evoked potentials and MRI abnormalities have not been previously reported.

Intravenous heme-albumin in acute intermittent porphyria: evidence for repletion of hepatic hemoproteins and regulatory heme pools.

The purpose of this study was to assess effects of heme administered intravenously, complexed to human serum albumin, on activities of the hepatic hemoproteins, cytochrome(s) P-450, and tryptophan pyrrolase, and on the size of the heme pool that regulates activity of 5-aminolevulinate synthase. Effects were compared in six normal women and four women with acute intermittent porphyria. All porphyric subjects over-excreted heme precursors and had histories of acute neurovisceral porphyric attacks. All subjects were placed on a constant daily diet that included at least 3 g carbohydrate/kg body weight and sufficient total intake to provide 1.4 times the estimated resting energy expenditure. Urinary excretions of 5-aminolevulinate, porphobilinogen, porphyrins, and metabolites of tryptophan were measured daily before, during, and after infusions of heme-albumin. In the porphyric subjects, intravenous heme [4 mg (6.1 mumol)/kg body weight (BWt) with equimolar albumin], given daily for 4 days, markedly reduced overexcretion of 5-aminolevulinate, porphobilinogen, and porphyrins, indicating repletion of the regulatory heme pool. The heme infusions also decreased mean urinary excretion of 5-hydroxyindoleacetic acid from 4.9 to 2.9 mg/g creatinine per day, suggesting increased activity of hepatic tryptophan pyrrolase, the rate-controlling enzyme for metabolism of tryptophan to products not in the serotonin-5-hydroxyindoleacetic acid pathway. Heme-albumin infusions were without detectable effects on excretions of heme precursors or tryptophan metabolites in normal subjects. In contrast, in both normals and porphyrics, heme-albumin infusions significantly increased rates of antipyrine metabolism (by 159% and 330%, respectively), suggesting increased activities of cytochrome(s) P-450 were produced by the infusions. The infusions were well tolerated; no subject developed thrombophlebitis or bleeding. We conclude that such infusions are safe and effective in repleting deficient heme pools and hemoproteins in patients with acute porphyria, and that activities of cytochrome(s) P-450 in normal subjects may also be increased by heme administration. The therapeutic effect of heme in acute porphyria probably relates to its ability to decrease overproduction of precursors of heme or serotonin, as the result of its increasing critical cellular heme pools.

Therapy of the acute porphyrias.

In the management of acute porphyria it is essential to be aware of the potential for many drugs to induce porphyrin synthesis and thus precipitate the acute porphyric crisis. In this review, lists of drugs unsafe and safe for use in the porphyrias are presented. In addition, therapeutic regimens are described which are appropriate to the porphyric subject. These include the use of high carbohydrate intake and the intravenous infusion of haem arginate.

Porfiria aguda intermitente: relato de um caso / Acute intermittent porphyria: report of a case

É relatado um caso de porfiria aguda intermitente. Descrevem-se os seus aspectos clínico-laboratoriais, ressaltando-se as medidas terapêuticas atuais que säo utilizadas. Infelizmente, na maioria dos casos, o prognóstico é reservado

Schizophrenia-like psychosis caused by a metabolic disorder.

Four patients with an intermittent psychosis closely resembling hallucinogenic drug-induced states were suspected of having a porphyric disease and were investigated for a possible relation between the metabolic dysfunctions of porphyria and the psychotic syndrome. Theoretically the link could be in a disturbance of serine and glycine metabolism. This theory was supported by disturbances in serine and glycine excretion found in all patients during psychotic episodes. In addition, loading with one low oral dose of serine produced psychotic symptoms 5 h later which lasted 3-6 h. One patient reacted to glycine in the same way. These findings suggest that disturbed serine-glycine metabolism may have a key role in certain schizophreniform psychotic syndromes.

[Hematin treatment of acute intermittent porphyria. A case report (author's transl)]. / Tratamento da porfiria aguda intermitente com hematina. Registro de caso.

A young woman with acute intermittent porphyria in profound relapse and severe nervous and respiratory involvement was treated by intravenous infusions of hematin, followed by improvement of symptoms. The diet with high carbohydrate and protein content and a B-adrenergic blocking agent, not showed any beneficial effect on acute attack. The infusion of hematin was followed by a lowering effect on urine porphybilinogen and delta-aminolevulinic acid and clinical improvement. The return to normal of porphyrin precursors in the urine was accompanied by almost complete clinical remission. The relationship of remission and repression of delta-aminolevulinic acid, decrease of urinary levels of porphyrin precursors, pulmonaries tests and electromyograms, were discussed.

[Treatment of porphyria cutanea tarda with and without phlebotomy (author's transl)]. / Behandlung der Porphyria cutanea tarda mit und ohne Aderlässe

Extensive investigations form 1962 to 1973 on 23 patients with porphyria cutanea tarda are reported. Two collectives of patients with different treatments are compared. One collective was treated conventionally with "liver therapy, abstinence from alcohol, and rest in bed", the other collective with "phlebotomy, abstinence from alcohol, and rest in bed". Both collectives showed a nearly equal decrease of uroporphyrin excretion. The unfavourable effect of alcohol in this disease was confirmed. In the post-observation period, minimal excretion of uroporphyrin was found to be more frequent and to persist longer in the collective treated by phlebotomy. In this collective, abstinence from alcohol was more consistently adhered to.

Grand mal seizures and acute intermittent porphyria. The problem of differential diagnosis and treatment.

A 36-year-old white man had both acute intermittent porphyria and long-standing idiopathic grand mal seizures. Diphenylhydantoin apparently adversely affected both the clinical and biochemical parameters of the acute intermittent porphyria. Comparison of urinary levels of the porphyrin precursors, delta aminolevulinic acid and porphobilinogen, under controlled diet conditions before and after withdrawal of diphenylhydantoin, showed that this drug accounted for approximately one-half of the porphyrin precursor excretion. Significant clinical improvement of the porphyria followed withdrawal of the diphenylhydantoin. Bromides appeared to be approximately as effective as diphenylhydantoin for seizure control in this patient.