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Background & Aims: Wilson disease (WD) is caused by accumulation of copper primarily in the liver and brain. During maintenance therapy of WD with D-penicillamine, current guidelines recommend on-treatment ranges of urinary copper excretion (UCE) of 200-500 µg/24 h and serum non-ceruloplasmin-bound copper (NCC) of 50-150 µg/L. We compared NCC (measured by two novel assays) and UCE from patients with clinically stable WD on D-penicillamine therapy with these recommendations. Methods: This is a secondary analysis of data from the Chelate trial (NCT03539952) that enrolled physician-selected patients with clinically stable WD on D-penicillamine maintenance therapy (at an unaltered dose for at least 4 months). We analyzed laboratory samples from the first screening visit, prior to interventions. NCC was measured by either protein speciation (NCC-Sp) using anion exchange high-performance liquid chromatography protein speciation followed by copper determination with inductively coupled plasma mass spectroscopy or as exchangeable copper (NCC-Ex). NCC-Sp was also analyzed in healthy controls (n = 75). Results: In 76 patients with WD with 21.3±14.3 average treatment-years, NCC-Sp (mean±SD: 56.6±26.2 µg/L) and NCC-Ex (mean±SD: 57.9±24.7 µg/L) were within the 50-150 µg/L target in 61% and 54% of patients, respectively. In addition, 36% and 31%, respectively, were even below the normal ranges (NCC-Sp: 46-213 µg/L, NCC-Ex: 41-71 µg/L). NCC-Ex positively correlated with NCC-Sp (r2 = 0.66, p <0.001) but with systematic deviation. UCE was outside the 200-500 µg/24 h target range in 58%. Only 14/69 (20%) fulfilled both the NCC-Sp and UCE targets. Clinical or biochemical signs of copper deficiency were not detected. Conclusion: Clinically stable patients with WD on maintenance D-penicillamine therapy frequently have lower NCC-Sp or higher UCE than current recommendations without signs of overtreatment. Further studies are warranted to identify appropriate target ranges of NCC-Sp, NCC-Ex and UCE in treated WD. Impact and implications: Chelator treatment of patients with Wilson disease (WD) is currently guided by measurements of non-ceruloplasmin-bound copper (NCC) and 24 h urinary copper excretion (UCE) but validation is limited. In 76 adults with ≈21 years history of treated WD and clinically stable disease on D-penicillamine therapy, NCC was commonly found to be below normal values and recommended target ranges whether measured by protein speciation (NCC-Sp) or as exchangeable copper (NCC-Ex), while UCE values were above the recommended target range in 49%. Common wisdom would suggest overtreatment in these cases, but no clinical or biochemical signs of copper deficiency were observed. Exploratory analysis of liver enzymes suggested that NCC below levels seen in controls may be beneficial, while the relation to UCE was less clear. The data calls for critical re-evaluation of target ranges for treatment of WD, specific for drug and laboratory methodology. Clinical trial number: (NCT03539952).
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OBJECTIVE: Stable isotope studies have shown that hepatic de novo lipogenesis (DNL) plays an important role in the pathogenesis of intrahepatic lipid (IHL) deposition. Furthermore, previous research has demonstrated that fructose 1-phosphate (F1P) not only serves as a substrate for DNL, but also acts as a signalling metabolite that stimulates DNL from glucose. The aim of this study was to elucidate the mediators of F1P-stimulated DNL, with special focus on two key regulators of intrahepatic glucose metabolism, i.e., glucokinase regulatory protein (GKRP) and carbohydrate response element binding protein (ChREBP). METHODS: Aldolase B deficient mice (Aldob-/-), characterized by hepatocellular F1P accumulation, enhanced DNL, and hepatic steatosis, were either crossed with GKRP deficient mice (Gckr-/-) or treated with short hairpin RNAs directed against hepatic ChREBP. RESULTS: Aldob-/- mice showed higher rates of de novo palmitate synthesis from glucose when compared to wildtype mice (p < 0.001). Gckr knockout reduced de novo palmitate synthesis in Aldob-/- mice (p = 0.017), without affecting the hepatic mRNA expression of enzymes involved in DNL. In contrast, hepatic ChREBP knockdown normalized the hepatic mRNA expression levels of enzymes involved in DNL and reduced fractional DNL in Aldob-/- mice (p < 0.05). Of interest, despite downregulation of DNL in response to Gckr and ChREBP attenuation, no reduction in intrahepatic triglyceride levels was observed. CONCLUSIONS: Both GKRP and ChREBP mediate F1P-stimulated DNL in aldolase B deficient mice. Further studies are needed to unravel the role of GKRP and hepatic ChREBP in regulating IHL accumulation in aldolase B deficiency.
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Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice , Fructosa-Bifosfato Aldolasa , Lipogénesis , Hígado , Ratones Noqueados , Triglicéridos , Animales , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Ratones , Hígado/metabolismo , Triglicéridos/metabolismo , Fructosa-Bifosfato Aldolasa/metabolismo , Fructosa-Bifosfato Aldolasa/genética , Masculino , Ratones Endogámicos C57BL , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Glucosa/metabolismo , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Proteínas PortadorasRESUMEN
BACKGROUND AND AIMS: Acute-on-chronic liver failure (ACLF) is a complication of cirrhosis characterized by multiple organ failure and high short-term mortality. The pathophysiology of ACLF involves elevated systemic inflammation leading to organ failure, along with immune dysfunction that heightens susceptibility to bacterial infections. However, it is unclear how these aspects are associated with recovery and nonrecovery in ACLF. APPROACH AND RESULTS: Here, we mapped the single-cell transcriptome of circulating immune cells from patients with ACLF and acute decompensated (AD) cirrhosis and healthy individuals. We further interrogate how these findings, as well as immunometabolic and functional profiles, associate with ACLF-recovery (ACLF-R) or nonrecovery (ACLF-NR). Our analysis unveiled 2 distinct states of classical monocytes (cMons). Hereto, ACLF-R cMons were characterized by transcripts associated with immune and stress tolerance, including anti-inflammatory genes such as RETN and LGALS1 . Additional metabolomic and functional validation experiments implicated an elevated oxidative phosphorylation metabolic program as well as an impaired ACLF-R cMon functionality. Interestingly, we observed a common stress-induced tolerant state, oxidative phosphorylation program, and blunted activation among lymphoid populations in patients with ACLF-R. Conversely, ACLF-NR cMon featured elevated expression of inflammatory and stress response genes such as VIM , LGALS2 , and TREM1 , along with blunted metabolic activity and increased functionality. CONCLUSIONS: This study identifies distinct immunometabolic cellular states that contribute to disease outcomes in patients with ACLF. Our findings provide valuable insights into the pathogenesis of ACLF, shedding light on factors driving either recovery or nonrecovery phenotypes, which may be harnessed as potential therapeutic targets in the future.
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Patients with classic galactosemia (CG), an inborn error of galactose metabolism, suffer from impairments in cognition, including language processing. Potential causes are atypical brain oscillations. Recent electroencephalogram (EEG) showed differences in the P300 event-related-potential (ERP) and alterations in the alpha/theta-range during speech planning. This study investigated whether transcranial alternating current stimulation (tACS) at theta-frequency compared to sham can cause a normalization of the ERP post stimulation and improves language performance. Eleven CG patients and fourteen healthy controls participated in two tACS-sessions (theta 6.5 Hz/sham). They were engaged in an active language task, describing animated scenes at three moments, that is, pre/during/post stimulation. Pre and post stimulation, behavior (naming accuracy, voice-onset-times; VOT) and mean-amplitudes of ERP were compared, by means of a P300 time-window analysis and cluster-based-permutation testing during speech planning. The results showed that theta stimulation, not sham, significantly reduced naming error-percentage in patients, not in controls. Theta did not systematically speed up naming beyond a general learning effect, which was larger for the patients. The EEG analysis revealed a significant pre-post stimulation effect (P300/late positivity), in patients and during theta stimulation only. In conclusion, theta-tACS improved accuracy in language performance in CG patients compared to controls and altered the P300 and late positive ERP-amplitude, suggesting a lasting effect on neural oscillation and behavior.
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Electroencefalografía , Galactosemias , Estimulación Transcraneal de Corriente Directa , Humanos , Femenino , Masculino , Adulto , Estimulación Transcraneal de Corriente Directa/métodos , Galactosemias/fisiopatología , Galactosemias/terapia , Adulto Joven , Ritmo Teta/fisiología , Lenguaje , Potenciales Relacionados con Evento P300/fisiología , Habla/fisiología , Persona de Mediana Edad , Estudios de Casos y ControlesRESUMEN
INTRODUCTION: The Baveno VI criteria have set the stage for noninvasive assessment of compensated advanced chronic liver disease (ACLD). The algorithm combining liver stiffness measurement (LSM, <20 kPa) and platelet count (>150,000/µL) safely avoids screening endoscopy for varices needing treatment (VNT) but identifies only a relatively low number of patients. We aimed to evaluate the value of spleen stiffness measurement (SSM) using spleen-dedicated elastography in ruling out VNT. METHODS: In this real-life multicenter retrospective derivation-validation cohort, all consecutive patients with ACLD (defined by LSM ≥10 kPa) with available upper endoscopy, laboratory results, spleen diameter, LSM, and SSM measured with spleen-dedicated transient elastography were included. VNT were defined as medium-to-large varices or small varices with red spots. RESULTS: In the derivation cohort (n = 201, 11.9% VNT), SSM demonstrated excellent capability at identifying VNT (area under the receiver operating characteristic curve [AUROC] 0.88), outperforming LSM (AUROC 0.77, P = 0.03) and platelets (AUROC 0.73, P = 0.002). In comparison with Baveno VI criteria (33.8% spared endoscopies), the sequential Baveno VI plus SSM and a novel spleen size and stiffness model were able to increase the number of patients avoiding endoscopy (66.2% and 71.1%, respectively) without missing more than 5% of VNT. These findings were confirmed in an external validation cohort of patients with more advanced liver disease (n = 176, 34.7% VNT) in which the number of spared endoscopies tripled (27.3% and 31.3% for SSM-based algorithms) compared with Baveno VI criteria (8.5%). DISCUSSION: Spleen stiffness-based algorithms are superior to Baveno VI criteria in ruling out VNT in patients with ACLD and double the number of patients avoiding screening endoscopy.
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Algoritmos , Diagnóstico por Imagen de Elasticidad , Várices Esofágicas y Gástricas , Bazo , Humanos , Bazo/diagnóstico por imagen , Bazo/patología , Femenino , Masculino , Persona de Mediana Edad , Várices Esofágicas y Gástricas/etiología , Várices Esofágicas y Gástricas/diagnóstico , Estudios Retrospectivos , Recuento de Plaquetas , Anciano , Cirrosis Hepática/complicaciones , Curva ROC , Hepatopatías/complicaciones , Hepatopatías/diagnóstico por imagenRESUMEN
De novo malignancy (DNM) is the primary cause of mortality after liver transplantation (LT) for alcohol-related liver disease (ALD). However, data on risk factors for DNM development after LT are limited, specifically in patients with ALD. Therefore, we retrospectively analyzed all patients transplanted for ALD at our center before October 2016. Patients with a post-LT follow-up of <12 months, DNM within 12 months after LT, patients not on tacrolimus in the 1st year post-LT, and unknown smoking habits were excluded. Tacrolimus drug exposure level (TDEL) was calculated by area under the curve of trough levels in the 1st year post-LT. 174 patients received tacrolimus of which 19 (10.9%) patients developed a DNM between 12 and 60 months post-LT. Multivariate cox regression analysis identified TDEL [HR: 1.710 (1.211-2.414); p = 0.002], age [1.158 (1.076-1.246); p < 0.001], number of pack years pre-LT [HR: 1.021 (1.004-1.038); p = 0.014] and active smoking at LT [HR: 3.056 (1.072-8.715); p = 0.037] as independent risk factors for DNM. Tacrolimus dose minimization in the 1st year after LT and smoking cessation before LT might lower DNM risk in patients transplanted for ALD.
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Hepatopatías , Trasplante de Hígado , Neoplasias , Humanos , Trasplante de Hígado/efectos adversos , Tacrolimus/efectos adversos , Estudios Retrospectivos , Fumar/efectos adversos , Factores de RiesgoAsunto(s)
Hígado Graso , Humanos , Diagnóstico Diferencial , Hígado Graso/genética , Hígado Graso/diagnósticoRESUMEN
Classic galactosemia (CG, OMIM #230400, ORPHA: 79,239) is a hereditary disorder of galactose metabolism that, despite treatment with galactose restriction, affects brain function in 85% of the patients. Problems with cognitive function, neuropsychological/social emotional difficulties, neurological symptoms, and abnormalities in neuroimaging and electrophysiological assessments are frequently reported in this group of patients, with an enormous individual variability. In this review, we describe the role of impaired galactose metabolism on brain dysfunction based on state of the art knowledge. Several proposed disease mechanisms are discussed, as well as the time of damage and potential treatment options. Furthermore, we combine data from longitudinal, cross-sectional and retrospective studies with the observations of specialist teams treating this disease to depict the brain disease course over time. Based on current data and insights, the majority of patients do not exhibit cognitive decline. A subset of patients, often with early onset cerebral and cerebellar volume loss, can nevertheless experience neurological worsening. While a large number of patients with CG suffer from anxiety and depression, the increased complaints about memory loss, anxiety and depression at an older age are likely multifactorial in origin.
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BACKGROUND: Although patients with hereditary fructose intolerance (HFI) generally have a good prognosis on a fructose-restricted diet, relatively little is known about their quality of life. The aim of this study was to investigate the quality of life in adult patients with HFI in comparison to patients with dietary-treated, classical phenylketonuria (PKU). METHODS: Patients with HFI and patients with classical PKU were recruited from the adult metabolic centers in The Netherlands and Belgium and via social media. Patients were asked to fill out the 36-item Short Form Health survey (SF-36) and a modified PKU Quality Of Life (PKU-QoL) questionnaire. RESULTS: Patients with HFI (n = 19) did not report any restrictions in their health-related quality of life, except for vitality and general mental health, which were scored more unfavorable compared to patients with PKU (n = 19) (p < 0.05, adjusted for level of education and country of origin). The results from the modified PKU-QoL demonstrated a statistically significantly greater impact of the disease in the social domain in HFI. A substantial proportion of both HFI and PKU patients (21%) reported a great to severe emotional impact of their disease. Finally, patients with HFI experienced statistically significantly less food temptations, less guilt if dietary restrictions not followed, and less overall difficulty following dietary restrictions. CONCLUSIONS: Although patients with HFI showed to have a generally good quality of life, they scored lower on vitality and general mental health, and reported a greater social impact of the disease. These aspects deserve further study and clinical attention.
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Intolerancia a la Fructosa , Fenilcetonurias , Humanos , Adulto , Intolerancia a la Fructosa/inducido químicamente , Calidad de Vida , Fenilcetonurias/metabolismo , Encuestas y Cuestionarios , Dieta , Fructosa/efectos adversosRESUMEN
Abnormal polyol metabolism is predominantly associated with diabetes, where excess glucose is converted to sorbitol by aldose reductase (AR). Recently, abnormal polyol metabolism has been implicated in phosphomannomutase 2 congenital disorder of glycosylation (PMM2-CDG) and an AR inhibitor, epalrestat, proposed as a potential therapy. Considering that the PMM2 enzyme is not directly involved in polyol metabolism, the increased polyol production and epalrestat's therapeutic mechanism in PMM2-CDG remained elusive. PMM2-CDG, caused by PMM2 deficiency, presents with depleted GDP-mannose and abnormal glycosylation. Here, we show that, apart from glycosylation abnormalities, PMM2 deficiency affects intracellular glucose flux, resulting in polyol increase. Targeting AR with epalrestat decreases polyols and increases GDP-mannose both in patient-derived fibroblasts and in pmm2 mutant zebrafish. Using tracer studies, we demonstrate that AR inhibition diverts glucose flux away from polyol production toward the synthesis of sugar nucleotides, and ultimately glycosylation. Finally, PMM2-CDG individuals treated with epalrestat show a clinical and biochemical improvement.
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Aldehído Reductasa , Pez Cebra , Animales , Pez Cebra/metabolismo , Glicosilación , Aldehído Reductasa/genética , Aldehído Reductasa/metabolismo , Manosa/metabolismo , MetabolómicaRESUMEN
The virome remains an understudied domain of the human microbiome. The role of commensal viruses on the outcome of infections with known pathogens is not well characterized. In this study we aimed to characterize the longitudinal plasma virome dynamics in chronic hepatitis B virus (HBV) infected patients. Eighty-five longitudinal plasma samples were collected from 12 chronic HBV infected individuals that were classified in the four stages of HBV infection. The virome was characterized with an optimized viral extraction protocol and deep-sequenced on a NextSeq 2500 platform. The plasma virome was primarily composed of members of the Anello- Flavi-, and Hepadnaviridae (HBV) families. The virome structure and dynamics did not correlate with the different stages of chronic HBV infection nor with the administration of antiviral therapy. We observed a higher intrapersonal similarity of viral contigs. Genomic analysis of viruses observed in multiple timepoint demonstrated the presence of a dynamic community. This study comprehensively assessed the blood virome structure in chronic HBV infected individuals and provided insights in the longitudinal development of this viral community.
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BACKGROUND: Recently, the term metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed to replace non-alcoholic fatty liver disease (NAFLD). This concept enables diagnosing liver disease associated with metabolic dysfunction in patients with alcohol-related liver disease (ALD), a main indication for liver transplantation (LTx). We assessed MAFLD prevalence in ALD patients undergoing LTx and its prognostic value on post-LTx outcomes. METHODS: We retrospectively analyzed all ALD patients transplanted at our center between 1990 and August 2020. MAFLD was diagnosed based on the presence or history of hepatic steatosis and a BMI > 25 or type II diabetes or ≥ 2 metabolic risk abnormalities at LTx. Overall survival and risk factors for recurrent liver and cardiovascular events were analyzed by Cox regression. RESULTS: Of the 371 included patients transplanted for ALD, 255 (68.7%) had concomitant MAFLD at LTx. Median follow-up post-LTx was 72 months (IQR: 34.50-122). Patients with ALD-MAFLD were older at LTx (p = .001), more often male (p < .001) and more frequently had hepatocellular carcinoma (p < .001). No differences in perioperative mortality and overall survival were found. ALD-MAFLD patients had an increased risk of recurrent hepatic steatosis, irrespective of alcohol relapse, but no superimposed risk of cardiovascular events. CONCLUSIONS: The co-presence of MAFLD at LTx for ALD is associated with a distinct patient profile and is an independent risk factor for recurrent hepatic steatosis. The use of MAFLD criteria in ALD patients might increase awareness and treatment of specific hepatic and systemic metabolic abnormalities before and after LTx.
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Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Neoplasias Hepáticas , Trasplante de Hígado , Enfermedad del Hígado Graso no Alcohólico , Humanos , Masculino , Pronóstico , Trasplante de Hígado/efectos adversos , Estudios Retrospectivos , Recurrencia Local de NeoplasiaRESUMEN
Peroxisome proliferator-activated receptor γ (PPARγ) is the master regulator of adipocyte differentiation, and mutations that interfere with its function cause lipodystrophy. PPARγ is a highly modular protein, and structural studies indicate that PPARγ domains engage in several intra- and inter-molecular interactions. How these interactions modulate PPARγ's ability to activate target genes in a cellular context is currently poorly understood. Here we take advantage of two previously uncharacterized lipodystrophy mutations, R212Q and E379K, that are predicted to interfere with the interaction of the hinge of PPARγ with DNA and with the interaction of PPARγ ligand binding domain (LBD) with the DNA-binding domain (DBD) of the retinoid X receptor, respectively. Using biochemical and genome-wide approaches we show that these mutations impair PPARγ function on an overlapping subset of target enhancers. The hinge region-DNA interaction appears mostly important for binding and remodelling of target enhancers in inaccessible chromatin, whereas the PPARγ-LBD:RXR-DBD interface stabilizes the PPARγ:RXR:DNA ternary complex. Our data demonstrate how in-depth analyses of lipodystrophy mutants can unravel molecular mechanisms of PPARγ function.
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Lipodistrofia , PPAR gamma , Humanos , PPAR gamma/genética , PPAR gamma/metabolismo , Adipocitos/metabolismo , Receptores X Retinoide/genética , Receptores X Retinoide/metabolismo , Lipodistrofia/metabolismo , Secuencias Reguladoras de Ácidos NucleicosRESUMEN
BACKGROUND: Wilson disease is an inherited disorder of copper transport. Whereas penicillamine is used therapeutically to re-establish copper balance, trientine is indicated for patients with penicillamine intolerance. We aimed to compare penicillamine with trientine tetrahydrochloride (TETA4) for maintenance therapy in patients with Wilson disease. METHODS: We conducted a randomised, open-label, non-inferiority, phase 3 trial at 15 health-care centres across nine countries (patients were recruited from 13 of these health-care centres across Brazil, Europe, and the USA). We enrolled patients aged 18-75 years with stable Wilson disease who were treated for at least 1 year with penicillamine. Patients entered a 12-week period to determine stability through clinical assessment by site investigators and predefined thresholds for serum non-caeruloplasmin-bound copper (NCC; by an exchangeable copper assay; 25-150 µg/L), 24 h urinary copper excretion (100-900 µg/24 h), and alanine aminotransferase (ALT; <2 × upper limit of normal). Stable patients were randomly assigned (1:1) to continue receiving the maintenance twice daily dose of oral penicillamine or switched mg-for-mg to oral TETA4 centrally with a web-based system using minimisation. The primary endpoint, assessed 24 weeks after randomisation, was NCC by speciation assay. The non-inferiority margin of mean difference in NCC by speciation assay was -50 µg/L, as estimated by a general linear model for repeated visits, adjusted for baseline values. Further data on safety and efficacy were collected during a 24-week extension period. Data were analysed using an intention-to-treat approach. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03539952 (active, not recruiting). FINDINGS: Between June 4, 2018, and March 10, 2020, 77 patients were screened. 53 patients were randomly assigned (27 to the penicillamine group and 26 to the TETA4 group). After 24 weeks, the mean difference in serum NCC by speciation assay between the penicillamine group and TETA4 group was -9·1 µg/L (95% CI -24·2 to 6·1), with the lower limit of the 95% CI within the defined non-inferiority margin. At 24 weeks, urinary copper excretion was lower with TETA4 than with penicillamine (mean difference 237·5 µg/24 h (99% CI 115·6 to 359·4). At 48 weeks, TETA4 remained non-inferior to penicillamine in terms of NCC by speciation assay (mean difference NCC -15·5 µg/L [95% CI -34·5 to 3·6]). Urinary copper excretion at 48 weeks remained in the expected range for well treated patients in both study groups, and the mean difference (124·8 µg/24 h [99% CI -37·6 to 287·1]) was not significantly different. At 24 weeks and 48 weeks, masked clinical adjudication of stability assessed by three independent clinicians confirmed clinical stability (100%) of all participants, in agreement with the stability seen with the NCC by speciation assay. There were no notable changes in either the Clinical Global Impression of Change or Unified Wilson Disease Rating Scale (neurological assessment) from baseline (pre-randomisation) at weeks 24 and 48. The mean change in serum total copper from baseline to 24 weeks was 17·6 µg/L (99% CI -9·5 to 44·7) with penicillamine and -6·3 µg/L (-34·7 to 22·1) with TETA4, and the mean change in serum total caeruloplasmin from baseline to 24 weeks was 1·8 mg/L (-19·2 to 22·8) with penicillamine and -2·2 mg/L (-6·1 to 1·7) with TETA4. All liver enzymes were similar at 24 weeks and 48 weeks, with the exception of elevated ALT concentration at 48 weeks for patients in the TETA4 group. Penicillamine was associated with three post-randomisation serious adverse events (leukopenia, cholangiocarcinoma, and hepatocellular cancer); none were reported for TETA4. The most common treatment-emergent adverse events were headache for penicillamine (five [19%] of 27 patients vs two [8%] of 26) and abdominal pain for TETA4 (one [4%] vs four [15%]); all treatment-emergent adverse events resolved and were mild to moderate. One patient developed a rash with TETA4 that resolved on discontinuation of therapy. INTERPRETATION: The efficacy of TETA4 as oral maintenance therapy was non-inferior to penicillamine and well tolerated in adults with Wilson disease. FUNDING: Orphalan.
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Degeneración Hepatolenticular , Adulto , Humanos , Quelantes/efectos adversos , Cobre , Degeneración Hepatolenticular/tratamiento farmacológico , Penicilamina/efectos adversos , Trientina/efectos adversosRESUMEN
Porphyrias are rare metabolic disorders of the haem synthesis. They can present with acute neurovisceral attacks, cutaneous symptoms, or a combination of both. As they present with a wide variety of clinical symptoms, diagnosis is often delayed and correct interpretation of porphyria-related tests remains a challenge for many physicians. We developed and validated two algorithms for the laboratory diagnosis of porphyrias based on presenting symptoms. Based on a literature search and clinical/laboratory expertise, we developed algorithms for acute and cutaneous porphyrias. We validated these algorithms using all porphyria related laboratory test requests between January 1st 2000 and September 30th 2020 in UZ Leuven. In addition, we also evaluated our algorithm using samples from the European porphyria network (EPNET) external quality assessment scheme (2010-2021). Sensitivity of the algorithm for acute porphyria was 100.0% [74.9%-100.0%] (13 acute intermittent porphyria (AIP) and 1 variegate porphyria [VP]) with a specificity of 98.5% [91.0%-100.0%] (65 patients). Sensitivity of the algorithm for cutaneous porphyria was 100% [95.1%-100.0%] (7 VP, 59 porphyria cutanea tarda (PCT), 23 erythropoietic protoporphyria (EPP), 2 X-linked erythropoietic protoporphyria [XLEPP]) with a specificity of 93.9% [82.9%-98.5%]. There were no diagnostic samples of other types of porphyria. The algorithms correctly identified 18 of the 19 EPNET porphyria cases. One of the two hereditary coproporphyria cases was missed. The algorithms for acute and cutaneous porphyria showed high sensitivity and specificity and can be used to aid the clinician in correctly interpreting the laboratory findings of porphyria-related tests.
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Porfiria Intermitente Aguda , Porfirias Hepáticas , Porfirias , Protoporfiria Eritropoyética , Humanos , Porfirias/diagnóstico , Técnicas de Laboratorio Clínico , AlgoritmosRESUMEN
One-year data from EXPLORE Part A showed high disease burden and impaired quality of life (QOL) in patients with acute hepatic porphyria (AHP) with recurrent attacks. We report baseline data of patients who enrolled in EXPLORE Part B for up to an additional 3 years of follow-up. EXPLORE B is a long-term, prospective study evaluating disease activity, pain intensity, and QOL in patients with AHP with ≥1 attack in the 12 months before enrollment or receiving hemin or gonadotropin-releasing hormone prophylaxis. Data were evaluated in patients with more (≥3 attacks or on prophylaxis treatment) or fewer (<3 attacks and no prophylaxis treatment) attacks. Patients in the total population (N = 136), and more (n = 110) and fewer (n = 26) attack subgroups, reported a median (range) of 3 (0-52), 4 (0-52), and 1 (0-2) acute attacks, respectively, in the 12 months prior to the baseline visit. Pain, mood/sleep, digestive/bladder, and nervous system symptoms were each experienced by ≥80% of patients; most received hemin during attacks. Almost three-quarters of patients reported chronic symptoms between attacks, including 85% of patients with fewer attacks. Pain intensity was comparable among both attack subgroups; most patients required pain medication. All groups had diminished QOL on the EuroQol visual analog scale and the European Organisation for Research and Treatment of Cancer Quality-of-life Questionnaire Core 30 versus population norms. Patients with AHP with recurrent attacks, even those having fewer attacks, experience a high disease burden, as evidenced by chronic symptoms between attacks and impaired QOL.
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Porfiria Intermitente Aguda , Porfirias Hepáticas , Humanos , Estudios Prospectivos , Calidad de Vida , Hemina/uso terapéutico , Porfirias Hepáticas/tratamiento farmacológico , Dolor , Porfiria Intermitente Aguda/complicaciones , Porfiria Intermitente Aguda/tratamiento farmacológicoRESUMEN
BACKGROUND: Acute hepatic porphyria (AHP) is a family of four rare genetic diseases, each involving deficiency in a hepatic heme biosynthetic enzyme. Resultant overproduction of the neurotoxic intermediates δ-aminolevulinic acid (ALA) and porphobilinogen (PBG) leads to disabling acute neurovisceral attacks and progressive neuropathy. We evaluated the AHP disease burden in patients aged ≥ 12 years in a post hoc analysis of the Phase 3, randomized, double-blind, placebo-controlled ENVISION trial of givosiran (NCT03338816), an RNA interference (RNAi) therapeutic that targets the enzyme ALAS1 to decrease ALA and PBG production. We analyzed baseline AHP severity via chronic symptoms between attacks, comorbidities, concomitant medications, hemin-associated complications, and quality of life (QOL) and evaluated givosiran (2.5 mg/kg monthly) in patients with and without prior hemin prophylaxis on number and severity of attacks and pain scores during and between attacks. RESULTS: Participants (placebo, n = 46; givosiran, n = 48) included patients with low and high annualized attack rates (AARs; range 0-46). At baseline, patients reported chronic symptoms (52%), including nausea, fatigue, and pain; comorbidities, including neuropathy (38%) and psychiatric disorders (47%); concomitant medications, including chronic opioids (29%); hemin-associated complications (eg, iron overload); and poor QOL (low SF-12 and EuroQol visual analog scale scores). A linear relationship between time since diagnosis and AAR with placebo suggested worsening of disease over time without effective treatment. Givosiran reduced the number and severity of attacks, days with worst pain scores above baseline, and opioid use versus placebo. CONCLUSIONS: Patients with AHP, regardless of annualized attack rates, have considerable disease burden that may partly be alleviated with givosiran.
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Porfiria Intermitente Aguda , Porfirias Hepáticas , Costo de Enfermedad , Hemina , Humanos , Dolor , Porfobilinógeno , Porfobilinógeno Sintasa/deficiencia , Calidad de VidaRESUMEN
INTRODUCTION: Primary mitochondrial diseases (PMD) are a large, heterogeneous group of genetic disorders affecting mitochondrial function, mostly by disrupting the oxidative phosphorylation (OXPHOS) system. Understanding the cellular metabolic re-wiring occurring in PMD is crucial for the development of novel diagnostic tools and treatments, as PMD are often complex to diagnose and most of them currently have no effective therapy. OBJECTIVES: To characterize the cellular metabolic consequences of OXPHOS dysfunction and based on the metabolic signature, to design new diagnostic and therapeutic strategies. METHODS: In vitro assays were performed in skin-derived fibroblasts obtained from patients with diverse PMD and validated in pharmacological models of OXPHOS dysfunction. Proliferation was assessed using the Incucyte technology. Steady-state glucose and glutamine tracing studies were performed with LC-MS quantification of cellular metabolites. The therapeutic potential of nutritional supplements was evaluated by assessing their effect on proliferation and on the metabolomics profile. Successful therapies were then tested in a in vivo lethal rotenone model in zebrafish. RESULTS: OXPHOS dysfunction has a unique metabolic signature linked to an NAD+/NADH imbalance including depletion of TCA intermediates and aspartate, and increased levels of glycerol-3-phosphate. Supplementation with pyruvate and uridine fully rescues this altered metabolic profile and the subsequent proliferation deficit. Additionally, in zebrafish, the same nutritional treatment increases the survival after rotenone exposure. CONCLUSIONS: Our findings reinforce the importance of the NAD+/NADH imbalance following OXPHOS dysfunction in PMD and open the door to new diagnostic and therapeutic tools for PMD.
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Enfermedades Mitocondriales , Fosforilación Oxidativa , Animales , Metaboloma , Enfermedades Mitocondriales/metabolismo , NAD/metabolismo , Ácido Pirúvico/metabolismo , Rotenona , Uridina/metabolismo , Uridina/farmacología , Pez Cebra/metabolismoRESUMEN
Early diagnosis and effective therapy are essential for improving the overall prognosis and quality of life of patients with nephropathic cystinosis. The severity of kidney dysfunction and the multi-organ involvement as a consequence of the increased intracellular concentration of cystine highlight the necessity of accurate monitoring of intracellular cystine to guarantee effective treatment of the disease. Cystine depletion is the only available treatment, which should begin immediately after diagnosis, and not discontinued, to significantly slow progression of renal and extra-renal organ damage. This review aims to discuss the importance of the close monitoring of intracellular cystine concentration to optimize cystine depletion therapy. In addition, the role of new biomarkers in the management of the disease, from timely diagnosis to implementing treatment during follow-up, is overviewed.
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Cistinosis , Síndrome de Fanconi , Biomarcadores , Cisteamina , Cistina , Cistinosis/diagnóstico , Humanos , Calidad de VidaRESUMEN
Tyrosinemia type 1 (TT1) and phenylketonuria (PKU) are both inborn errors of phenylalanine-tyrosine metabolism. Neurocognitive and behavioral outcomes have always featured in PKU research but received less attention in TT1 research. This study aimed to investigate and compare neurocognitive, behavioral, and social outcomes of treated TT1 and PKU patients. We included 33 TT1 patients (mean age 11.24 years; 16 male), 31 PKU patients (mean age 10.84; 14 male), and 58 age- and gender-matched healthy controls (mean age 10.82 years; 29 male). IQ (Wechsler-subtests), executive functioning (the Behavioral Rating Inventory of Executive Functioning), mental health (the Achenbach-scales), and social functioning (the Social Skills Rating System) were assessed. Results of TT1 patients, PKU patients, and healthy controls were compared using Kruskal-Wallis tests with post-hoc Mann-Whitney U tests. TT1 patients showed a lower IQ and poorer executive functioning, mental health, and social functioning compared to healthy controls and PKU patients. PKU patients did not differ from healthy controls regarding these outcome measures. Relatively poor outcomes for TT1 patients were particularly evident for verbal IQ, BRIEF dimensions "working memory", "plan and organize" and "monitor", ASEBA dimensions "social problems" and "attention problems", and for the SSRS "assertiveness" scale (all p values <0.001). To conclude, TT1 patients showed cognitive impairments on all domains studied, and appeared to be significantly more affected than PKU patients. More attention should be paid to investigating and monitoring neurocognitive outcome in TT1 and research should focus on explaining the underlying pathophysiological mechanism.