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Jorge Frank - One of the best experts on this subject based on the ideXlab platform.
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hepatocellular carcinoma in Variegate porphyria a serious complication
Acta Dermato-venereologica, 2010Co-Authors: Xiaoye Schneideryin, Annemoon Van Tuyll Van Serooskerken, Philip Went, Wojciech Tyblewski, Pamela Pobletegutierrez, Elisabeth I Minder, Jorge FrankAbstract:Variegate porphyria is an acute hepatic porphyria resulting from a partial deficiency of protoporphyrinogen oxidase, the penultimate enzyme in haem biosynthesis. Cutaneous symptoms and acute neurovisceral attacks are well-known clinical characteristics of the disease. Less studied, however, is the risk of developing hepatocellular carcinoma, an aggressive type of liver cancer. We describe here two Swiss patients with Variegate porphyria and this serious complication. Common risk factors, including alcohol over-consumption or chronic hepatitis, were absent in both patients. Interestingly, one patient carried mutation 1082-1083insC in the PPOX gene, a prevalent sequence deviation in the Swiss Variegate porphyria population, which was also found in a French patient with Variegate porphyria and hepatocellular carcinoma. Recent studies indicate that individuals with acute hepatic porphyria have a 36- to 61-fold increased risk of manifesting hepatocellular carcinoma. The incidence rate ratio in the Swiss population was estimated to be 34, comparable with those found in the French and Finnish populations. Because this tumour is associated with a rising mortality, we suggest regular screening for hepatocellular carcinoma in all patients with Variegate porphyria.
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identification of a recurrent mutation in the protoporphyrinogen oxidase gene in swiss patients with Variegate porphyria clinical and genetic implications
Cellular and Molecular Biology, 2009Co-Authors: A M Van Tuyll Van Serooskerke, Jorge Frank, Xiaoye Schneideryin, Pamela Pobletegutierrez, R J Schimmel, Reno S Bladergroen, J Barman, M Van Geel, Elisabeth I MinderAbstract:Variegate porphyria (VP), one of the acute hepatic porphyrias, results from an autosomal dominantly inherited deficiency of protoporphyrinogen oxidase (PPOX), the seventh enzyme in heme biosynthesis. Affected individuals can develop both cutaneous symptoms and potentially life-threatening neurovisceral attacks. Thirty unrelated VP index patients and families are currently known in the Swiss Porphyrin Reference Laboratory in Zurich. In 16 of a total of 24 genetically tested families, we detected a recurrent mutation in the PPOX gene, designated 1082-1083insC, reflecting a prevalence of 67%. Haplotype analysis revealed that 1082-1083insC arose on a common genetic background and, thus, represents a novel founder mutation in the Swiss population. Knowledge on the carrier status within a family does not only allow for adequate genetic counseling but also for prevention of the potentially life-threatening acute porphyric attacks. Hence, future molecular screening in Swiss VP patients might be facilitated by first seeking for mutation 1082-1083insC.
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a chilean boy with severe photosensitivity and finger shortening the first case of homozygous Variegate porphyria in south america
British Journal of Dermatology, 2006Co-Authors: Pamela Pobletegutierrez, Jorge Frank, C Wolff, R FariasAbstract:A 7-year-old Chilean boy presented with severe photosensitivity, blistering, erosions and scarring on sun-exposed areas of the body since the age of 6 months. Additionally, he showed a short stature and shortening of the fingers. Laboratory examination revealed greatly elevated protoporphyrin levels in the blood. Such biochemical findings can be observed in homozygous variants of usually autosomal dominantly inherited acute porphyrias such as Variegate porphyria (VP) and hereditary coproporphyria, which usually do not become manifest before the second or third decade of life in heterozygotes. Using polymerase chain reaction-based techniques we identified a missense mutation in exon 7 on the paternal allele and a frameshift mutation in exon 13 on the maternal allele of the protoporphyrinogen oxidase gene that harbours the mutations underlying VP. This is the first homozygous case of VP in South America. As VP represents the most frequent type of acute porphyria not only in Chile but also in South Africa, more such cases could be expected in the future, particularly because a founder mutation for this disease has already been described in the Chilean and South African population.
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Identification of a founder mutation in the protoporphyrinogen oxidase gene in Variegate porphyria patients from chile.
Human heredity, 2001Co-Authors: Jorge Frank, Vincent M. Aita, Wasim Ahmad, Hamut Lam, Wolff C, Angela M ChristianoAbstract:Variegate porphyria (VP; OMIM 176200) is characterized by a partial defect in the activity of protoporphyrinogen oxidase (PPO), the seventh enzyme of the porphyrin-heme biosynthetic pathway. The disea
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Mutations in the translation initiation codon of the protoporphyrinogen oxidase gene underlie Variegate porphyria.
Clinical and experimental dermatology, 1999Co-Authors: Jorge Frank, Maureen B. Poh-fitzpatrick, John A. Mcgrath, John L.m. Hawk, Angela M ChristianoAbstract:Variegate porphyria (VP), one of the acute hepatic porphyrias, is characterized by a reduced catalytic activity of protoporphyrinogen oxidase (PPO), the penultimate enzyme in the porphyrin-haem biosynthetic pathway. VP has been linked to the PPO gene on chromosome 1q22-23, and several mutations underlying this disorder have been described recently. In this study, we identified two different missense mutations in the translation initiation codon of the PPO gene in two unrelated patients with VP. Mutation analysis was carried out using PCR, heteroduplex analysis, automated sequencing, and restriction enzyme digestion. In the first patient, the results revealed an A-to-T transversion (ATG --> TTG), resulting in the substitution of methionine by leucine (M1L). The mutation detected in the second patient was a T-to-C transition (ATG --> ACG), leading to the conversion of methionine to threonine (M1T). These mutations abolish the initiation of translation at the normal site, and consequently, translation of an abnormal messenger RNA (mRNA) would result in the synthesis of a truncated PPO protein lacking the amino terminus.
P.n. Meissner - One of the best experts on this subject based on the ideXlab platform.
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PROPOFOL AS AN I.V. ANAESTHETIC INDUCTION AGENT IN Variegate porphyria
2016Co-Authors: P.n. Meissner, G. G. Harrison, R. J. HiftAbstract:The choice of an i. v. anaesthetic induction poses problems for the anaesthetist confronted with a patient with one of the acute porphyrias. We undertook a prospective clinical trial in 13 Variegate porphyric subjects using propofol as an anaesthetic induction agent. Urinary porphyrin precursors and porphyrins were measured before operation and 1-5 days after operation. Stool and plasma porphyrin concentrations were measured over the same period. Comparison of these data in the porphyric patients and in 21 control subjects over the trial period revealed no significant change in porphyrin or porphyrin precursor output after operation. Urinary por-phyrin precursor concentrations did not exceed the limits established for Variegate porphyric patients in remission, and there were no changes in the stool and plasma porphyrin profiles or any symptoms of an acute porphyric attack. We conclude that propofol did not appear to be porphyrinogenic when used for the induction of anaesthesia in 13 patients with Variegate porphyria
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a review of the clinical presentation natural history and inheritance of Variegate porphyria its implausibility as the source of the royal malady
Journal of Clinical Pathology, 2012Co-Authors: R. J. Hift, Timothy J Peters, P.n. MeissnerAbstract:It has been suggested that King George III of Great Britain suffered from the haem biosynthetic disorder, Variegate porphyria. This diagnosis is pervasive throughout the scientific and popular literature, and is often referred to as the 'Royal Malady.' The authors believe it inappropriate to view the case for porphyria purely in terms of symptoms, as has generally been the case in his presumptive acute porphyria diagnosis. Accordingly, this review provides a current description of the natural history and clinical presentation of the porphyrias, against which we measure the case for porphyria in George III and his relatives. The authors have critically assessed the prevalence of porphyria in a population, the expected patterns and frequency of inheritance, its penetrance and its expected natural history in affected individuals, and conclude that neither George nor his relatives had porphyria, based on four principal reasons. First, the rarity of the disease mandates a very low prior probability, and therefore implies a vanishingly low positive predictive value for any diagnostic indicator of low specificity, such as a historical reading of the symptoms. Second, penetrance of this autosomal dominant disorder is approximately 40%, and one may expect to have identified characteristic clinical features of porphyria in a large number of descendants without difficulty. Third, the symptoms of both George III and his relatives are highly atypical for porphyria and are more appropriately explained by other much commoner conditions. Finally, the natural history of the illnesses reported in this family is as atypical for Variegate porphyria as are their symptoms.
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an analysis of 112 acute porphyric attacks in cape town south africa evidence that acute intermittent porphyria and Variegate porphyria differ in susceptibility and severity
Medicine, 2005Co-Authors: R. J. Hift, P.n. MeissnerAbstract:Four forms of porphyria may present clinically with the acute attack, an episodic, severe, and potentially life-threatening manifestation characterized by abdominal and neurologic symptoms. We describe our experience with 112 consecutive attacks observed and treated in 25 patients with the 2 most common forms of acute porphyria in Cape Town, South Africa; 25 attacks in 10 patients with Variegate porphyria and 87 attacks in 14 patients with acute intermittent porphyria. The remaining patient experienced more than 100 sequential, severe, and poorly remitting attacks, which are not included in our analysis. In our population, the relative risk of an acute attack in acute intermittent porphyria compared with that in Variegate porphyria was 14.3 (confidence intervals, 6.3-32.7). Patients with Variegate porphyria were significantly older (median age at first attack, 30 yr) than those with acute intermittent porphyria (median age at first attack, 23.5 yr; p < 0.0001), and demonstrated an equal sex ratio, whereas the male:female ratio in acute intermittent porphyria was 2:12 (p < 0.0001). There was a significant difference in the incidence of factors precipitating the acute attack. Drug exposure was a frequent precipitant of the acute attack in Variegate porphyria, whereas hormonal factors were more important in acute intermittent porphyria (p < 0.00001). Patients with acute intermittent porphyria also showed a trend to earlier and more frequent recurrent acute attacks following the initial admission. Mean urine precursor levels, blood pressure, pulse rate, and heme arginate requirement were all significantly higher in patients with acute intermittent porphyria. No significant difference in the frequency of serious complications or in outcome could be shown. We describe our experience with treatment with heme arginate, and provide evidence that heme arginate results in a prompt and statistically significant improvement in symptoms. The incidence of serious complications and mortality in this series was low, confirming a trend to an increasingly good prognosis for patients with acute porphyria who receive expert treatment.
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a systematic study of the clinical and biochemical expression of Variegate porphyria in a large south african family
British Journal of Dermatology, 2004Co-Authors: R. J. Hift, Doreen M Meissner, P.n. MeissnerAbstract:Summary Background Variegate porphyria (VP) is an autosomal dominant disorder associated with deficient haem synthesis. Recent reports indicate that the clinical penetrance of VP may have been overestimated in studies which predated the availability of DNA-based testing for VP. Objectives To undertake a study specifically designed to assess the clinical and biochemical penetrance of VP in a kindred characterized by gene status. Methods We studied a large family carrying the South African founder mutation which is known to result in almost complete haplodeficiency. All informative members were tested for the R59W mutation. Biochemical evidence of porphyria was sought by porphyrin analysis and by plasma fluorescence scanning. The presence of clinically expressed porphyria was assessed using a structured questionnaire and telephone or personal interview. Results Of 62 informative subjects, 33 had inherited the mutation. Of 28 adults, one subject had experienced a single acute attack. She and a further 10 subjects had experienced photosensitivity. The frequency of acute attacks in this family is therefore 4% (95% confidence interval, CI 1–18%), and of photosensitivity is 39·3% (95% CI 24–58%). The sensitivity and specificity of porphyrin analysis in this family were 0·46 (95% CI 0·30–0·64) and 1·00 (95% CI 0·85–1·00), respectively, and for plasma scanning the values were 0·85 (95% CI 0·58–0·96) and 1·00 (95% CI 0·72–1·00), respectively. Conclusions The clinical penetrance of VP in our family is approximately 40%. Many more subjects with VP are diagnosed in an asymptomatic phase than previously, and the acute attack is now an uncommon manifestation of VP. Plasma scanning is more sensitive than faecal porphyrin analysis, but neither is sufficiently sensitive for the detection of carrier status.
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administration of oral activated charcoal in Variegate porphyria results in a paradoxical clinical and biochemical deterioration
British Journal of Dermatology, 2003Co-Authors: R. J. Hift, P.n. Meissner, Gail Todd, R. E. KirschAbstract:Summary Background Porphyrinogens are the obligate intracellular precursors of haem. These compounds are, however, unstable and are easily oxidized to the corresponding porphyrins, which are the form in which they are usually measured in the laboratory. A substantial enterohepatic cycling of porphyrins has been shown. Administration of oral activated charcoal, by interrupting this cycle, may reduce plasma and urine porphyrin levels in patients with some forms of porphyria. The effect of charcoal in subjects with Variegate porphyria (VP) has not been reported. Objectives To determine the clinical and biochemical effects of the administration of oral activated charcoal in patients with VP. Methods Oral activated charcoal was administered to eight subjects with VP. Clinical activity was assessed by skin lesion counts fortnightly for 6 weeks, 6 weeks after cessation of therapy, and during a subsequent 6-week control period during which no charcoal was taken. Urine and plasma porphyrins and urine precursors were measured by standard techniques. Results Treatment resulted in a significant increase in skin disease, urine and plasma porphyrins. Conclusions Oral charcoal administration results in a paradoxical aggravation of VP, suggesting a complex and as yet undefined interaction of hepatic porphyrin metabolism and bowel porphyrin reabsorption. Oral sorbents should not be prescribed to subjects with VP.
Angela M Christiano - One of the best experts on this subject based on the ideXlab platform.
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Identification of a founder mutation in the protoporphyrinogen oxidase gene in Variegate porphyria patients from chile.
Human heredity, 2001Co-Authors: Jorge Frank, Vincent M. Aita, Wasim Ahmad, Hamut Lam, Wolff C, Angela M ChristianoAbstract:Variegate porphyria (VP; OMIM 176200) is characterized by a partial defect in the activity of protoporphyrinogen oxidase (PPO), the seventh enzyme of the porphyrin-heme biosynthetic pathway. The disea
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Mutations in the translation initiation codon of the protoporphyrinogen oxidase gene underlie Variegate porphyria.
Clinical and experimental dermatology, 1999Co-Authors: Jorge Frank, Maureen B. Poh-fitzpatrick, John A. Mcgrath, John L.m. Hawk, Angela M ChristianoAbstract:Variegate porphyria (VP), one of the acute hepatic porphyrias, is characterized by a reduced catalytic activity of protoporphyrinogen oxidase (PPO), the penultimate enzyme in the porphyrin-haem biosynthetic pathway. VP has been linked to the PPO gene on chromosome 1q22-23, and several mutations underlying this disorder have been described recently. In this study, we identified two different missense mutations in the translation initiation codon of the PPO gene in two unrelated patients with VP. Mutation analysis was carried out using PCR, heteroduplex analysis, automated sequencing, and restriction enzyme digestion. In the first patient, the results revealed an A-to-T transversion (ATG --> TTG), resulting in the substitution of methionine by leucine (M1L). The mutation detected in the second patient was a T-to-C transition (ATG --> ACG), leading to the conversion of methionine to threonine (M1T). These mutations abolish the initiation of translation at the normal site, and consequently, translation of an abnormal messenger RNA (mRNA) would result in the synthesis of a truncated PPO protein lacking the amino terminus.
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Variegate porphyria past present and future
Skin Pharmacology and Applied Skin Physiology, 1998Co-Authors: Jorge Frank, Angela M ChristianoAbstract:Variegate porphyria, one of the acute hepatic porphyrias, is characterized by a partial reduction in protoporphyrinogen oxidase, the seventh enzyme of the heme biosynthetic pathway. For a long time, this disease has caused confusion among the porphyrias because it presents with clinical symptoms and biochemical findings that can be similar to those found in other types of porphyrias. Here, we provide an overview of historical, clinical, biochemical, genetical, and other aspects of Variegate porphyria that might be helpful in providing more insight into this rare disorder.
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recurrent missense mutation in the protoporphyrinogen oxidase gene underlies Variegate porphyria
American Journal of Medical Genetics, 1998Co-Authors: Jorge Frank, Frank K. Jugert, Günter Goerz, Hans F. Merk, Claudia Breitkopf, Angela M ChristianoAbstract:The porphyrias represent a heterogeneous group of disorders of porphyrin or porphyrin-precursor metabolism, resulting from the inherited or acquired dysregulation of one of the eight enzymes in the porphyrin-heme biosynthetic pathway. Variegate porphyria, one of the acute hepatic porphyrias, is characterized by a partial reduction in the activity of the penultimate enzyme in the heme biosynthetic pathway, protoporphyrinogen oxidase (PPO). Recently, VP has been linked to the PPO gene on chromosome 1q22-23, and several disease-causing mutations have been described. In this study, we identified the underlying genetic lesion in two unrelated patients with VP and investigated all available family members by polymerase chain reaction, heteroduplex analysis, automated sequencing, and restriction enzyme digestion. Mutation analyses in both families revealed a G-to-A transition in exon 6 of the PPO gene resulting in the substitution of arginine by histidine at position 168 of the protein (R168H). This arginine residue is evolutionarily conserved in human, mouse, and Bacillus subtilis, indicating the importance of this residue in PPO function. Our study establishes a recurrent missense mutation as the underlying genetic defect in two unrelated patients with VP and explains the occurrence of the phenotype in their families.
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the genetic basis of scarsdale gourmet diet Variegate porphyria a missense mutation in the protoporphyrinogen oxidase gene
Archives of Dermatological Research, 1998Co-Authors: Jorge Frank, Maureen B Pohfitzpatrick, Lloyd E King, Angela M ChristianoAbstract: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.
Pertti Mustajoki - One of the best experts on this subject based on the ideXlab platform.
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homozygous Variegate porphyria a severe skin disease of infancy
Clinical Genetics, 2008Co-Authors: Pertti Mustajoki, Raimo Tenhunen, Yves Nordmann, Kirsti Maria Niemi, Helena Kaariainen, Reijo NorioAbstract:A boy exhibited severe bullous skin disease a few days after birth, followed by increased fragility of the exposed skin in spring and summer. Examination at 2 1/2 years of age led to characteristic biochemical findings: increased excretion of fecal porphyrins (coproporphyrin 121 to 131 and protoporphyrin 467 to 576 nmol/g dry weight), and increased erythrocyte protoporphyrin concentration (3643 to 4840 nmol/l). Lymphocyte protoporphyrinogen oxidase activity was very low in the patient (0.4 nmol/mg protein/h) and half-normal (2.7 and 2.3 nmol/mg protein/h) in the parents, suggesting that the patient had homozygous Variegate porphyria. Severe skin symptoms and a high concentration of red cell protoporphyrin concentration in an infant should prompt suspicion of homozygous acute hepatic porphyria.
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clinical and biochemical characteristics and genotype phenotype correlation in finnish Variegate porphyria patients
European Journal of Human Genetics, 2002Co-Authors: M Von Und Zu Fraunberg, Pertti Mustajoki, Kaisa Timonen, Raili KauppinenAbstract:Variegate porphyria (VP) is an inherited metabolic disease resulting from the partial deficiency of protoporphyrinogen oxidase, the penultimate enzyme in the heme biosynthetic pathway. We have evaluated the clinical and biochemical outcome of 103 Finnish VP patients diagnosed between 1966 and 2001. Fifty-two per cent of patients had experienced clinical symptoms: 40% had photosensitivity, 27% acute attacks and 14% both manifestations. The proportion of patients with acute attacks has decreased dramatically from 38 to 14% in patients diagnosed before and after 1980, whereas the prevalence of skin symptoms had decreased only subtly from 45 to 34%. We have studied the correlation between PPOX genotype and clinical outcome of 90 patients with the three most common Finnish mutations I12T, R152C and 338G-->C. The patients with the I12T mutation experienced no photosensitivity and acute attacks were rare (8%). Therefore, the occurrence of photosensitivity was lower in the I12T group compared to the R152C group (P=0.001), whereas no significant differences between the R152C and 338G-->C groups could be observed. Biochemical abnormalities were significantly milder suggesting a milder form of the disease in patients with the I12T mutation. In all VP patients, normal excretion of protoporphyrin in faeces in adulthood predicted freedom from both skin symptoms and acute attacks. The most valuable test predicting an increased risk of symptoms was urinary coproporphyrin, but only a substantially increased excretion exceeding 1,000 nmol/day was associated with an increased risk of both skin symptoms and acute attacks. All patients with an excretion of more than 1,000 nmol/day experienced either skin symptoms, acute attacks, or both.
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homozygous Variegate porphyria 20 y follow up and characterization of molecular defect
Journal of Investigative Dermatology, 2001Co-Authors: Raili Kauppinen, Pertti Mustajoki, Raimo Tenhunen, Kaisa Timonen, Mikael Von, Und Zu Fraunberg, Helena Ahola, Eila Laitinen, Shigeru TaketaniAbstract:The long-term follow-up of a homozygous Variegate porphyria patient revealed severe photosensitivity accompanied by mild sensory neuropathy and IgA nephropathy. A 35T to C transition in exon 2 (I12T) and a 767C to G transversion in exon 7 (P256R) of the protoporphyrinogen oxidase gene were identified from both alleles of the patient's cDNA and genomic DNA samples. Both prokaryotic and eukaryotic expression studies showed that the first mutation in the evolutionary conserved region resulted in a decrease in the protoporphyrinogen oxidase activity in contrast to the polymorphic substitution in exon 7, which affected the function of the enzyme assayed in Escherichia coli but not COS-1 cells.
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effects of heme arginate on cytochrome p450 mediated metabolism of drugs in patients with Variegate porphyria and in healthy men
Clinical Pharmacology & Therapeutics, 1994Co-Authors: Sami Mustajoki, Pentti Arvela, Arja Rautio, Pertti Mustajoki, Olavi PelkonenAbstract:We investigated the effects of heme on metabolism of coumarin, debrisoquin, caffeine, and lidocaine in seven female patients with Variegate porphyria and in 10 healthy men. During baseline conditions metabolism of the drugs was identical in the two groups. Compared with the results without heme, a single infusion of heme arginate (3 mg/kg heme) significantly decreased the debrisoquin/4-hydroxy-debrisoquin metabolic ratio in subjects with porphyria (p = 0.016) and in the control subjects (p = 0.016) and increased formation of monoethylglycinexylidide from lidocaine (p = 0.016 and p = 0.004, respectively). Metabolism of coumarin and caffeine was not affected by heme. Our results show that, in patients with porphyria and in healthy subjects, exogenous heme is able to accelerate the reactions mediated by the cytochrome isozymes CYP2D6 (debrisoquin) and CYP3A4 (lidocaine) but not reactions mediated by CYP1A2 (caffeine) and CYP2A6 (coumarin). This suggests that influence of heme on drug metabolism is P450 isozyme-specific. Clinical Pharmacology and Therapeutics (1994) 56, 9–13; doi:10.1038/clpt.1994.94
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effects of heme arginate on cytochrome p450 mediated metabolism of drugs in patients with Variegate porphyria and in healthy men
Clinical Pharmacology & Therapeutics, 1994Co-Authors: Sami Mustajoki, Pentti Arvela, Arja Rautio, Pertti Mustajoki, Olavi PelkonenAbstract:We investigated the effects of heme on metabolism of coumarin, debrisoquin, caffeine, and lidocaine in seven female patients with Variegate porphyria and in 10 healthy men. During baseline conditions metabolism of the drugs was identical in the two groups. Compared with the results without heme, a single infusion of heme arginate (3 mg/kg heme) significantly decreased the debrisoquin/4-hydroxy-debrisoquin metabolic ratio in subjects with porphyria (p = 0.016) and in the control subjects (p = 0.016) and increased formation of monoethylglycinexylidide from lidocaine (p = 0.016 and p = 0.004, respectively). Metabolism of coumarin and caffeine was not affected by heme. Our results show that, in patients with porphyria and in healthy subjects, exogenous heme is able to accelerate the reactions mediated by the cytochrome isozymes CYP2D6 (debrisoquin) and CYP3A4 (lidocaine) but not reactions mediated by CYP1A2 (caffeine) and CYP2A6 (coumarin). This suggests that influence of heme on drug metabolism is P450 isozyme-specific.
R. J. Hift - One of the best experts on this subject based on the ideXlab platform.
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PROPOFOL AS AN I.V. ANAESTHETIC INDUCTION AGENT IN Variegate porphyria
2016Co-Authors: P.n. Meissner, G. G. Harrison, R. J. HiftAbstract:The choice of an i. v. anaesthetic induction poses problems for the anaesthetist confronted with a patient with one of the acute porphyrias. We undertook a prospective clinical trial in 13 Variegate porphyric subjects using propofol as an anaesthetic induction agent. Urinary porphyrin precursors and porphyrins were measured before operation and 1-5 days after operation. Stool and plasma porphyrin concentrations were measured over the same period. Comparison of these data in the porphyric patients and in 21 control subjects over the trial period revealed no significant change in porphyrin or porphyrin precursor output after operation. Urinary por-phyrin precursor concentrations did not exceed the limits established for Variegate porphyric patients in remission, and there were no changes in the stool and plasma porphyrin profiles or any symptoms of an acute porphyric attack. We conclude that propofol did not appear to be porphyrinogenic when used for the induction of anaesthesia in 13 patients with Variegate porphyria
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a review of the clinical presentation natural history and inheritance of Variegate porphyria its implausibility as the source of the royal malady
Journal of Clinical Pathology, 2012Co-Authors: R. J. Hift, Timothy J Peters, P.n. MeissnerAbstract:It has been suggested that King George III of Great Britain suffered from the haem biosynthetic disorder, Variegate porphyria. This diagnosis is pervasive throughout the scientific and popular literature, and is often referred to as the 'Royal Malady.' The authors believe it inappropriate to view the case for porphyria purely in terms of symptoms, as has generally been the case in his presumptive acute porphyria diagnosis. Accordingly, this review provides a current description of the natural history and clinical presentation of the porphyrias, against which we measure the case for porphyria in George III and his relatives. The authors have critically assessed the prevalence of porphyria in a population, the expected patterns and frequency of inheritance, its penetrance and its expected natural history in affected individuals, and conclude that neither George nor his relatives had porphyria, based on four principal reasons. First, the rarity of the disease mandates a very low prior probability, and therefore implies a vanishingly low positive predictive value for any diagnostic indicator of low specificity, such as a historical reading of the symptoms. Second, penetrance of this autosomal dominant disorder is approximately 40%, and one may expect to have identified characteristic clinical features of porphyria in a large number of descendants without difficulty. Third, the symptoms of both George III and his relatives are highly atypical for porphyria and are more appropriately explained by other much commoner conditions. Finally, the natural history of the illnesses reported in this family is as atypical for Variegate porphyria as are their symptoms.
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an analysis of 112 acute porphyric attacks in cape town south africa evidence that acute intermittent porphyria and Variegate porphyria differ in susceptibility and severity
Medicine, 2005Co-Authors: R. J. Hift, P.n. MeissnerAbstract:Four forms of porphyria may present clinically with the acute attack, an episodic, severe, and potentially life-threatening manifestation characterized by abdominal and neurologic symptoms. We describe our experience with 112 consecutive attacks observed and treated in 25 patients with the 2 most common forms of acute porphyria in Cape Town, South Africa; 25 attacks in 10 patients with Variegate porphyria and 87 attacks in 14 patients with acute intermittent porphyria. The remaining patient experienced more than 100 sequential, severe, and poorly remitting attacks, which are not included in our analysis. In our population, the relative risk of an acute attack in acute intermittent porphyria compared with that in Variegate porphyria was 14.3 (confidence intervals, 6.3-32.7). Patients with Variegate porphyria were significantly older (median age at first attack, 30 yr) than those with acute intermittent porphyria (median age at first attack, 23.5 yr; p < 0.0001), and demonstrated an equal sex ratio, whereas the male:female ratio in acute intermittent porphyria was 2:12 (p < 0.0001). There was a significant difference in the incidence of factors precipitating the acute attack. Drug exposure was a frequent precipitant of the acute attack in Variegate porphyria, whereas hormonal factors were more important in acute intermittent porphyria (p < 0.00001). Patients with acute intermittent porphyria also showed a trend to earlier and more frequent recurrent acute attacks following the initial admission. Mean urine precursor levels, blood pressure, pulse rate, and heme arginate requirement were all significantly higher in patients with acute intermittent porphyria. No significant difference in the frequency of serious complications or in outcome could be shown. We describe our experience with treatment with heme arginate, and provide evidence that heme arginate results in a prompt and statistically significant improvement in symptoms. The incidence of serious complications and mortality in this series was low, confirming a trend to an increasingly good prognosis for patients with acute porphyria who receive expert treatment.
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a systematic study of the clinical and biochemical expression of Variegate porphyria in a large south african family
British Journal of Dermatology, 2004Co-Authors: R. J. Hift, Doreen M Meissner, P.n. MeissnerAbstract:Summary Background Variegate porphyria (VP) is an autosomal dominant disorder associated with deficient haem synthesis. Recent reports indicate that the clinical penetrance of VP may have been overestimated in studies which predated the availability of DNA-based testing for VP. Objectives To undertake a study specifically designed to assess the clinical and biochemical penetrance of VP in a kindred characterized by gene status. Methods We studied a large family carrying the South African founder mutation which is known to result in almost complete haplodeficiency. All informative members were tested for the R59W mutation. Biochemical evidence of porphyria was sought by porphyrin analysis and by plasma fluorescence scanning. The presence of clinically expressed porphyria was assessed using a structured questionnaire and telephone or personal interview. Results Of 62 informative subjects, 33 had inherited the mutation. Of 28 adults, one subject had experienced a single acute attack. She and a further 10 subjects had experienced photosensitivity. The frequency of acute attacks in this family is therefore 4% (95% confidence interval, CI 1–18%), and of photosensitivity is 39·3% (95% CI 24–58%). The sensitivity and specificity of porphyrin analysis in this family were 0·46 (95% CI 0·30–0·64) and 1·00 (95% CI 0·85–1·00), respectively, and for plasma scanning the values were 0·85 (95% CI 0·58–0·96) and 1·00 (95% CI 0·72–1·00), respectively. Conclusions The clinical penetrance of VP in our family is approximately 40%. Many more subjects with VP are diagnosed in an asymptomatic phase than previously, and the acute attack is now an uncommon manifestation of VP. Plasma scanning is more sensitive than faecal porphyrin analysis, but neither is sufficiently sensitive for the detection of carrier status.
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administration of oral activated charcoal in Variegate porphyria results in a paradoxical clinical and biochemical deterioration
British Journal of Dermatology, 2003Co-Authors: R. J. Hift, P.n. Meissner, Gail Todd, R. E. KirschAbstract:Summary Background Porphyrinogens are the obligate intracellular precursors of haem. These compounds are, however, unstable and are easily oxidized to the corresponding porphyrins, which are the form in which they are usually measured in the laboratory. A substantial enterohepatic cycling of porphyrins has been shown. Administration of oral activated charcoal, by interrupting this cycle, may reduce plasma and urine porphyrin levels in patients with some forms of porphyria. The effect of charcoal in subjects with Variegate porphyria (VP) has not been reported. Objectives To determine the clinical and biochemical effects of the administration of oral activated charcoal in patients with VP. Methods Oral activated charcoal was administered to eight subjects with VP. Clinical activity was assessed by skin lesion counts fortnightly for 6 weeks, 6 weeks after cessation of therapy, and during a subsequent 6-week control period during which no charcoal was taken. Urine and plasma porphyrins and urine precursors were measured by standard techniques. Results Treatment resulted in a significant increase in skin disease, urine and plasma porphyrins. Conclusions Oral charcoal administration results in a paradoxical aggravation of VP, suggesting a complex and as yet undefined interaction of hepatic porphyrin metabolism and bowel porphyrin reabsorption. Oral sorbents should not be prescribed to subjects with VP.
