13 research outputs found
EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurrent Attacks
Abstract Acute hepatic porphyria comprises a group of rare, genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long-term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients. EXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months prior to the study, patients reported a median (range) of 6 (0-52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a healthcare facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0-37.0]). Elevated levels of hepatic δ-aminolevulinic acid synthase 1 messenger ribonucleic acid levels, δ-aminolevulinic acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased healthcare utilization. Conclusions: Patients experienced attacks often requiring treatment in a healthcare facility and/or with hemin, as well as chronic symptoms that adversely influence day-to-day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies. This article is protected by copyright. All rights reserved.Peer reviewe
EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurrent Attacks
BACKGROUND AND AIMS: Acute hepatic porphyria
comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can
experience acute neurovisceral attacks, debilitating chronic
symptoms, and long-term complications. There is a lack of
multinational, prospective data characterizing the disease and
current treatment practices in severely affected patients.
APPROACH AND RESULTS: EXPLORE is a prospective,
multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic
porphyria who experience recurrent attacks. Eligible patients
had a confirmed acute hepatic porphyria diagnosis and had
experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months
before the study, patients reported a median (range) of 6
(0-52) acute attacks, with 52 (46%) patients receiving hemin
prophylaxis. Chronic symptoms were reported by 73 (65%)
patients, with 52 (46%) patients experiencing these daily.
During the study, 98 (88%) patients experienced a total of
483 attacks, 77% of which required treatment at a health
care facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0-37.0]). Elevated levels of hepatic
δ-aminolevulinic acid synthase 1 messenger ribonucleic acid levels, δ-aminolevulinic acid, and porphobilinogen compared with
the upper limit of normal in healthy individuals were observed
at baseline and increased further during attacks. Patients had
impaired quality of life and increased health care utilization.
CONCLUSIONS: Patients experienced attacks often requiring treatment in a health care facility and/or with hemin, as
well as chronic symptoms that adversely influenced day-to-day
functioning. In this patient group, the high disease burden
and diminished quality of life highlight the need for novel
therapies. (Hepatology 2020;71:1546-1558)
EXPLORE: A prospective, multinational natural history study of patients with acute hepatic porphyria with recurrent attacks
BACKGROUND AND AIMS: Acute hepatic porphyria
comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can
experience acute neurovisceral attacks, debilitating chronic
symptoms, and long-term complications. There is a lack of
multinational, prospective data characterizing the disease and
current treatment practices in severely affected patients.
APPROACH AND RESULTS: EXPLORE is a prospective,
multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic
porphyria who experience recurrent attacks. Eligible patients
had a confirmed acute hepatic porphyria diagnosis and had
experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months
before the study, patients reported a median (range) of 6
(0-52) acute attacks, with 52 (46%) patients receiving hemin
prophylaxis. Chronic symptoms were reported by 73 (65%)
patients, with 52 (46%) patients experiencing these daily.
During the study, 98 (88%) patients experienced a total of
483 attacks, 77% of which required treatment at a health
care facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0-37.0]). Elevated levels of hepatic
δ-aminolevulinic acid synthase 1 messenger ribonucleic acid levels, δ-aminolevulinic acid, and porphobilinogen compared with
the upper limit of normal in healthy individuals were observed
at baseline and increased further during attacks. Patients had
impaired quality of life and increased health care utilization.
CONCLUSIONS: Patients experienced attacks often requiring treatment in a health care facility and/or with hemin, as
well as chronic symptoms that adversely influenced day-to-day
functioning. In this patient group, the high disease burden
and diminished quality of life highlight the need for novel
therapies. (Hepatology 2020;71:1546-1558)
EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurren
Background and Aims: Acute hepatic porphyria comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long-term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients. Approach and Results: EXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months before the study, patients reported a median (range) of 6 (0-52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a health care facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0-37.0]). Elevated levels of hepatic δ-aminolevulinic acid synthase 1 messenger ribonucleic acid levels, δ-aminolevulinic acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased health care utilization. Conclusions: Patients experienced attacks often requiring treatment in a health care facility and/or with hemin, as well as chronic symptoms that adversely influenced day-to-day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies
Quantification of urine and plasma porphyrin precursors using LC–MS in acute hepatic porphyrias: improvement in routine diagnosis and in the monitoring of kidney failure patients
International audienceBACKGROUND: The quantification of delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) in urine are the first-line tests for diagnosis and monitoring of acute hepatic porphyrias (AHP). Ion-exchange chromatography (IEC), which is time-and staff-consuming and limited to urine, is still the preferred method in many specialized laboratories, despite the development of mass spectrometry-based methods. METHODS: We describe a new LC-MS method that allows for rapid and simple quantification of ALA and PBG in urine and plasma with an affordable instrument that was used to analyze 2260 urine samples and 309 blood samples collected in 2 years of routine activity. The results were compared to those obtained with IEC, and urine reference ranges and concentrations in asymptomatic carriers were determined. Plasma concentrations were measured in healthy subjects and subgroups of symptomatic and asymptomatic AHP carriers. RESULTS: In urine, the clinical decision limits were not impacted by the change of method despite discrepancies in low absolute concentrations, leading to lower normal values. Two-thirds of asymptomatic AHP carriers (with the exception of coproporphyria carriers) showed an increased urine PBG concentration. Urine and plasma levels showed a good correlation except in patients with kidney disease in whom the urine/plasma ratio was relatively low. CONCLUSION: We described an LC-MS based method for the routine diagnosis and monitoring of AHP that allows for the detection of more asymptomatic carriers than the historical method. Blood analysis appears to be particularly relevant for patients with kidney disease, where urine measurement underestimates the increase in ALA and PBG levels
Hepcidin and Iron Deficiency in Women One Year after Sleeve Gastrectomy: A Prospective Cohort Study
International audienceIron deficiency with or without anemia, needing continuous iron supplementation, is very common in obese patients, particularly those requiring bariatric surgery. The aim of this study was to address the impact of weight loss on the rescue of iron balance in patients who underwent sleeve gastrectomy (SG), a procedure that preserves the duodenum, the main site of iron absorption. The cohort included 88 obese women; sampling of blood and duodenal biopsies of 35 patients were performed before and one year after SG. An analysis of the 35 patients consisted in evaluating iron homeostasis including hepcidin, markers of erythroid iron deficiency (soluble transferrin receptor (sTfR) and erythrocyte protoporphyrin (PPIX)), expression of duodenal iron transporters (DMT1 and ferroportin) and inflammatory markers. After surgery, sTfR and PPIX were decreased. Serum hepcidin levels were increased despite the significant reduction in inflammation. DMT1 abundance was negatively correlated with higher level of serum hepcidin. Ferroportin abundance was not modified. This study shed a new light in effective iron recovery pathways after SG involving suppression of inflammation, improvement of iron absorption, iron supply and efficiency of erythropoiesis, and finally beneficial control of iron homeostasis by hepcidin. Thus, recommendations for iron supplementation of patients after SG should take into account these new parameters of iron status assessment
Kidney transplantation improves the clinical outcomes of Acute Intermittent Porphyria
International audienceBackground - Acute Intermittent Porphyria (AIP) is a rare inherited autosomal dominant disorder of heme biosynthesis. Porphyria-associated kidney disease occurs in more than 50% of the patients with AIP, and end stage renal disease (ESRD) can be a devastating complication for AIP patients. The outcomes of AIP patients after kidney transplantation are poorly known. Methods - We examined the outcomes of 11 individuals with AIP, identified as kidney transplant recipients in the French Porphyria Center Registry. Results - AIP had been diagnosed on average 19 years before the diagnosis of ESRD except for one patient in whom the diagnosis of AIP had been made 5 years after the initiation of dialysis. Median follow-up after transplantation was 9 years. A patient died 2 months after transplantation from a cardiac arrest and a patient who received a donation after cardiac death experienced a primary non-function. No rejection episode and no noticeable adverse event occurred after transplantation. Serum creatinine was on average 117 μmol/l, and proteinuria <0.5 g/l in all patients at last follow up. All usually prescribed drugs after transplantation are authorized except for trimethoprim/sulfamethoxazole. Critically, acute porphyria attacks almost disappeared after kidney transplantation, and skin lesions resolved in all patients. Conclusion - Kidney transplantation is the treatment of choice for AIP patients with ESRD and dramatically reduces the disease activity
Urinary Metabolic Fingerprint of Acute Intermittent Porphyria Analyzed by <sup>1</sup>H NMR Spectroscopy
<sup>1</sup>H NMR is a nonbiased
technique for the quantification
of small molecules that could result in the identification and characterization
of potential biomarkers with prognostic value and contribute to better
understand pathophysiology of diseases. In this study, we used <sup>1</sup>H NMR spectroscopy to analyze the urinary metabolome of patients
with acute intermittent porphyria (AIP), an inherited metabolic disorder
of heme biosynthesis in which an accumulation of the heme precursors
5-aminolaevulinic acid (ALA) and porphobilinogen (PBG) promotes sudden
neurovisceral attacks, which can be life-threatening. Our objectives
were (1) to demonstrate the usefulness of <sup>1</sup>H NMR to identify
and quantify ALA and PBG in urines from AIP patients and (2) to identify
metabolites that would predict the response to AIP crisis treatment
and reflect differential metabolic reprogramming. Our results indicate
that <sup>1</sup>H NMR can help to diagnose AIP attacks based on the
identification of ALA and PBG. We also show that glycin concentration
increases in urines from patients with frequent recurrences at the
end of the treatment, after an initial decrease, whereas PBG concentration
remains low. Although the reasons for this altered are elusive, these
findings indicate that a glycin metabolic reprogramming occurs in
AIPr patients and is associated with recurrence. Our results validate
the proof of concept of the usefulness of <sup>1</sup>H NMR spectroscopy
in clinical chemistry for the diagnosis of acute attack of AIP and
identify urinary glycin as a potential marker of recurrence of AIP
acute attacks
Sideroblastic anemia: molecular analysis of the ALAS2 gene in a series of 29 probands and functional studies of 10 missense mutations.
X-linked Sideroblastic Anemia (XLSA) is the most common genetic form of sideroblastic anemia, a heterogeneous group of disorders characterized by iron deposits in the mitochondria of erythroid precursors. XLSA is due to mutations in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene. Thirteen different ALAS2 mutations were identified in 16 out of 29 probands with sideroblastic anemia. One third of the patients were females with a highly skewed X-chromosome inactivation. The identification of seven novel mutations in the ALAS2 gene, six missense mutations, and one deletion in the proximal promoter extends the allelic heterogeneity of XSLA. Most of the missense mutations were predicted to be deleterious, and 10 of them, without any published functional characterization, were expressed in Escherichia coli. ALAS2 activities were assayed in vitro. Five missense mutations resulted in decreased enzymatic activity under standard conditions, and two other mutated proteins had decreased activity when assayed in the absence of exogenous pyridoxal phosphate and increased thermosensitivity. Although most amino acid substitutions result in a clearly decreased enzymatic activity in vitro, a few mutations have a more subtle effect on the protein that is only revealed by in vitro tests under specific conditions