RESUMO
The rise in food intolerances and celiac disease, along with advanced diagnostic techniques, has prompted health professionals to seek effective and economical testing methods. This study evaluates combining genetic tests with routine carbohydrate-absorption breath tests to classify patients with chronic gastrointestinal disorders into therapeutic groups, enhancing dietary management and improving gut health and quality of life. Forty-nine patients with suspected carbohydrate intolerance underwent genetic testing for lactase non-persistence, hereditary fructose intolerance, and celiac disease risk. Simultaneously, breath tests assessed lactose and fructose absorption. The lactase non-persistence genotype appeared in 36.7% of cases, with one hereditary fructose-intolerance case in a heterozygous condition. Celiac disease risk markers (HLA-DQ2/8 haplotypes) were found in 49.0% of the population. Secondary lactose and/or fructose malabsorption was present in 67.3% of patients, with 66.1% of lactase non-persistence individuals showing secondary lactose malabsorption. Fructose malabsorption was prevalent in 45.8% of patients at risk for celiac disease. Two main treatment groups were defined based on genetic results, indicating primary and irreversible gastrointestinal disorder causes, followed by a sub-classification using breath test results. Genetic testing is a valuable tool for designing dietary management plans, avoiding unnecessary diet restrictions, and reducing recovery times.
Assuntos
Testes Respiratórios , Doença Celíaca , Intolerância à Frutose , Gastroenteropatias , Testes Genéticos , Lactase , Intolerância à Lactose , Humanos , Feminino , Masculino , Adulto , Doença Celíaca/dietoterapia , Doença Celíaca/genética , Pessoa de Meia-Idade , Testes Respiratórios/métodos , Testes Genéticos/métodos , Intolerância à Frutose/genética , Intolerância à Frutose/dietoterapia , Intolerância à Frutose/diagnóstico , Gastroenteropatias/dietoterapia , Gastroenteropatias/genética , Gastroenteropatias/diagnóstico , Intolerância à Lactose/genética , Intolerância à Lactose/dietoterapia , Intolerância à Lactose/diagnóstico , Doença Crônica , Lactase/genética , Lactase/deficiência , Lactase/metabolismo , Idoso , Intolerância Alimentar/genética , Adulto Jovem , Adolescente , FrutoseRESUMO
Hereditary fructose intolerance (HFI) is a painful and potentially lethal genetic disease caused by a mutation in aldolase B resulting in accumulation of fructose-1-phosphate (F1P). No cure exists for HFI and treatment is limited to avoid exposure to fructose and sugar. Using aldolase B deficient mice, here we identify a yet unrecognized metabolic event activated in HFI and associated with the progression of the disease. Besides the accumulation of F1P, here we show that the activation of the purine degradation pathway is a common feature in aldolase B deficient mice exposed to fructose. The purine degradation pathway is a metabolic route initiated by adenosine monophosphate deaminase 2 (AMPD2) that regulates overall energy balance. We demonstrate that very low amounts of fructose are sufficient to activate AMPD2 in these mice via a phosphate trap. While blocking AMPD2 do not impact F1P accumulation and the risk of hypoglycemia, its deletion in hepatocytes markedly improves the metabolic dysregulation induced by fructose and corrects fat and glycogen storage while significantly increasing the voluntary tolerance of these mice to fructose. In summary, we provide evidence for a critical pathway activated in HFI that could be targeted to improve the metabolic consequences associated with fructose consumption.
Assuntos
AMP Desaminase , Intolerância à Frutose , Frutose-Bifosfato Aldolase , Frutose , Animais , Masculino , Camundongos , AMP Desaminase/genética , AMP Desaminase/metabolismo , Modelos Animais de Doenças , Metabolismo Energético/efeitos dos fármacos , Frutose/metabolismo , Intolerância à Frutose/metabolismo , Intolerância à Frutose/genética , Frutose-Bifosfato Aldolase/metabolismo , Frutose-Bifosfato Aldolase/genética , Frutosefosfatos/metabolismo , Hepatócitos/metabolismo , Hepatócitos/efeitos dos fármacos , Fígado/metabolismo , Hepatopatias/metabolismo , Hepatopatias/etiologia , Hepatopatias/genética , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
Excessive intake of sugar, and particularly fructose, is closely associated with the development and progression of metabolic syndrome in humans and animal models. However, genetic disorders in fructose metabolism have very different consequences. While the deficiency of fructokinase, the first enzyme involved in fructose metabolism, is benign and somewhat desirable, missense mutations in the second enzyme, aldolase B, causes a very dramatic and sometimes lethal condition known as hereditary fructose intolerance (HFI). To date, there is no cure for HFI, and treatment is limited to avoiding fructose and sugar. Because of this, for subjects with HFI, glucose is their sole source of carbohydrates in the diet. However, clinical symptoms still occur, suggesting that either low amounts of fructose are still being consumed or, alternatively, fructose is being produced endogenously in the body. Here, we demonstrate that as a consequence of consuming high glycemic foods, the polyol pathway, a metabolic route in which fructose is produced from glucose, is activated, triggering a deleterious mechanism whereby glucose, sorbitol and alcohol induce severe liver disease and growth retardation in aldolase B knockout mice. We show that generically and pharmacologically blocking this pathway significantly improves metabolic dysfunction and thriving and increases the tolerance of aldolase B knockout mice to dietary triggers of endogenous fructose production.
Assuntos
Doenças do Sistema Digestório , Intolerância à Frutose , Hepatopatias , Humanos , Animais , Camundongos , Intolerância à Frutose/genética , Intolerância à Frutose/diagnóstico , Frutose/metabolismo , Frutose-Bifosfato Aldolase/genética , Glucose/uso terapêutico , Camundongos KnockoutRESUMO
We report a patient with an extremely rare, combined diagnosis of PMM2-CDG and hereditary fructose intolerance (HFI). By comparing with other patients, under-galactosylation was identified as a feature of HFI. Fructose/sorbitol/sucrose restriction was initiated right afterwards. The patient is at the mild end of the PMM2-CDG spectrum, raising the question of sorbitol's role in the pathogenesis of PMM2-CDG and whether fructose/sorbitol/sucrose restriction could benefit other PMM2-CDG patients. Additionally, epalrestat, an emerging potential PMM2-CDG therapy, may benefit HFI patients.
Assuntos
Defeitos Congênitos da Glicosilação , Intolerância à Frutose , Fosfotransferases (Fosfomutases) , Humanos , Intolerância à Frutose/diagnóstico , Intolerância à Frutose/genética , Defeitos Congênitos da Glicosilação/diagnóstico , Defeitos Congênitos da Glicosilação/genética , Frutose/uso terapêutico , Sorbitol/uso terapêutico , Sacarose/uso terapêuticoRESUMO
OBJECTIVES: Hereditary fructose intolerance (HFI) is caused by aldolase B enzyme deficiency. There has been no report about HFI from Iran and the type of mutations has not been reported in the Iranian population so far. CASE PRESENTATION: Herein we report a 2 year old girl presented with failure to thrive, hepatomegaly, and liver dysfunction. The primary impression has been hepatic glycogen storage disease type 1 or 6. This diagnosis was not confirmed by laboratory data and liver biopsy. Therefore, targeted-gene sequencing (TGS) covering 450 genes involved in inborn errors in metabolic diseases was performed. The results of TGS showed a rare novel homozygous pathogenic variant c.944del (p.Gly315ValfsTer15) in the ALDOB gene. CONCLUSIONS: This report introduces a novel variant that expands the mutational spectrum of the ALDOB gene in patients with HFI.
Assuntos
Intolerância à Frutose , Feminino , Humanos , Pré-Escolar , Intolerância à Frutose/genética , Frutose-Bifosfato Aldolase/genética , Irã (Geográfico) , Mutação , Homozigoto , FrutoseRESUMO
Herein, we described the case of a newborn male, from consanguineous parents, who developed, at day 11 of life, an obstructive hydrocephalus resulting from bilateral cerebellar hemorrhage without evident cause. Then, at 1 month, he developed a fulminant hepatitis with hyperammonia, hyperlactatemia and metabolic acidosis. Infectious and first line metabolic explorations were normal. Screening for congenital disorder of glycosylation (CDG) was performed using capillary electrophoresis and western blot of serum transferrin. Abnormal results were evocative of mannose-phosphate isomerase deficiency (MPI-CDG or CDG-Ib) as it can be responsible for fulminant hepatitis, digestive disease, developmental delay, and coagulopathy. However, trio whole exome sequencing revealed a pathogenic variant at the homozygous state in ALDOB, responsible for hereditary fructose intolerance (HFI), an inherited metabolic disorder with excellent prognosis under a fructose-free diet. HFI had not been previously evoked in view of the absence of diet diversification, but meticulous inquiry revealed that parents systematically added white sugar to the bottle milk of their child, unintentionally triggering potentially fatal HFI decompensations. Early genetic analysis upsetted both diagnosis and prognosis for this infant who had excellent development after fructose removal. This full-of-surprises diagnostic approach illustrates the importance of an integrative collaboration between clinicians, biochemists, and geneticists.
Assuntos
Defeitos Congênitos da Glicosilação , Intolerância à Frutose , Necrose Hepática Massiva , Lactente , Criança , Recém-Nascido , Humanos , Masculino , Glicosilação , Intolerância à Frutose/diagnóstico , Intolerância à Frutose/genética , Intolerância à Frutose/metabolismo , Defeitos Congênitos da Glicosilação/diagnóstico , Defeitos Congênitos da Glicosilação/genética , Erros de DiagnósticoRESUMO
Chronic enteropathy associated with SLCO2A1 gene (CEAS) is a rare disorder characterized by multiple small intestine ulcers. Patients with CEAS typically present with chronic anemia and gastrointestinal bleeding. Besides CEAS, SLCO2A1 mutations cause primary hypertrophic osteoarthropathy (PHO) which is considered as an extraintestinal manifestation in CEAS patients. Since CEAS and Crohn's disease are clinically indistinguishable, patients are often misdiagnosed with Crohn's disease. Herein, we describe a 4-year-old Turkish girl with CEAS due to homozygous pathogenic variant (c.656C > T) in SLCO2A1 with concomitant hereditary fructose intolerance (HFI) caused by homozygous pathogenic variant (c.1005C > G) in ALDOB. Prompt restriction of fructose, sucrose and sorbitol resulted in hepatomegaly regression and mild amelioration of patient's symptoms. Despite budesonide and azathioprine treatments, patient's protein losing enteropathy and chronic anemia did not improve. Although previous CEAS cases were reported from East Asian countries, it is likely to occur in people from other geographic areas. CEAS seems to be underdiagnosed and high index of suspicion is required for the diagnosis of this rare entity. Patients with prior diagnosis of Crohn's disease with no response to immunosuppressive treatment or anti-TNF therapy should be re-evaluated for possible CEAS diagnosis.
Assuntos
Anemia , Doença de Crohn , Intolerância à Frutose , Transportadores de Ânions Orgânicos , Humanos , Pré-Escolar , Intolerância à Frutose/diagnóstico , Intolerância à Frutose/genética , Doença de Crohn/complicações , Doença de Crohn/diagnóstico , Doença de Crohn/genética , Doenças Raras , Inibidores do Fator de Necrose Tumoral , Transportadores de Ânions Orgânicos/genéticaRESUMO
BACKGROUND: While role of ALDOB-related gene variants for hereditary fructose intolerance is well established, contribution of gene variants for acquired fructose malabsorption (e.g. SLC2A5, GLUT5) is not well understood. METHODS: Patients referred to fructose breath test were further selected to identify those having acquired fructose malabsorption. Molecular analysis of genomic DNA included (I) exclusion of 3 main ALDOB gene variants causing hereditary fructose intolerance and (II) sequencing analysis of SLC2A5 gene comprising complete coding region, at least 20 bp of adjacent intronic regions and 700 bp of proximal promoter. RESULTS: Among 494 patients, 35 individuals with acquired fructose malabsorption were identified based on pathological fructose-breath test and normal lactose-breath test. Thirty four of them (97%) had negative tissue anti-transglutaminase and/or deamidated gliadin antibodies in their medical records. Molecular analysis of SLC2A5 gene of all 35 subjects identified 5 frequent and 5 singular gene variants mostly in noncoding regions (promoter and intron). Allele frequencies of gene variants were similar to those reported in public databases strongly implying that none of them was associated with acquired fructose malabsorption. CONCLUSIONS: Gene variants of coding exons, adjacent intronic regions and proximal promoter region of SLC2A5 gene are unlikely to contribute to genetic predisposition of acquired fructose malabsorption.
Assuntos
Intolerância à Frutose , Testes Respiratórios , Éxons , Frutose , Intolerância à Frutose/diagnóstico , Intolerância à Frutose/genética , Transportador de Glucose Tipo 5/genética , Humanos , Regiões Promotoras GenéticasRESUMO
Hereditary fructose intolerance (HFI) is an inborn error of fructose metabolism of autosomal recessive inheritance caused by pathogenic variants in the ALDOB gene that lead to aldolase B deficiency in the liver, kidneys, and intestine. Patients manifest symptoms, such as ketotic hypoglycemia, vomiting, nausea, in addition to hepatomegaly and other liver and kidney dysfunctions. The treatment consists of a fructose-restricted diet, which results in a good prognosis. To analyze the distribution of ALDOB variants described in patients and to estimate the prevalence of HFI based on carrier frequency in the gnomAD database, a systematic review was conducted to assess ALDOB gene variants among patients with HFI. The prevalence of HFI was estimated from the carrier frequency of variants described in patients, as well as rare variants predicted as pathogenic by in silico tools. The p.(Ala150Pro) and p.(Ala175Asp) variants are the most frequent and are distributed worldwide. However, these variants have particular distribution patterns in Europe. The analysis of the prevalence of HFI showed that the inclusion of rare alleles predicted as pathogenic is a more informative approach for populations with few patients. The data show that HFI has a wide distribution and an estimated prevalence of ~1:10,000.
Assuntos
Intolerância à Frutose , Alelos , Intolerância à Frutose/diagnóstico , Intolerância à Frutose/epidemiologia , Intolerância à Frutose/genética , Frutose-Bifosfato Aldolase/genética , Humanos , Fígado/patologia , MutaçãoRESUMO
OBJECTIVES: Hereditary fructose intolerance (HFI) is an autosomal recessive disorder caused by a deficiency in aldolase B that can result in hypoglycemia, nausea, vomiting, abdominal pain, liver and kidney dysfunction, coma, and even death. This study aims to represent the clinical features and molecular genetic analysis data of the patients diagnosed with HFI in our study population. METHODS: The medical records of the 26 patients with HFI were evaluated retrospectively. Age, gender, clinical findings, metabolic crises, and the results of molecular analyses were recorded. RESULTS: The patients with HFI had a good prognosis and the aversion to sugar-containing foods was the main complaint. Seven different variants were identified in the Aldolase B (ALDOB) gene in HFI patients. The most frequent mutations were p.Ala150Pro, p.Ala175Asp had a prevalence of 61 and 30%, respectively, in agreement with the literature and other known variants were found with minor frequencies c.360-363del4(3.8%), p.Asn335Lys(3.8%), and three novel mutations c.113-1_15del4 (3.8%), p.Ala338Val(7.6%), and p.Asp156His(3.8%) were identified at a heterozygous, homozygous, or compound heterozygous level. CONCLUSIONS: This study results revealed three novel mutations in patients with HFI. On the basis of age of presentation, clinical symptoms, and metabolic crisis, there was no clear-cut genotype-phenotype correlation. This article also demonstrates the importance of screening suspected infants in cases of acute liver failure for prompt diagnosis and treatment of HFI.
Assuntos
Intolerância à Frutose/epidemiologia , Frutose-Bifosfato Aldolase/genética , Predisposição Genética para Doença , Prontuários Médicos/estatística & dados numéricos , Mutação , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Intolerância à Frutose/genética , Intolerância à Frutose/patologia , Heterozigoto , Homozigoto , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Turquia/epidemiologia , Adulto JovemRESUMO
BACKGROUND & AIMS: Hyperuricemia is an independent risk factor for the metabolic syndrome and cardiovascular disease. We hypothesized that asymptomatic carriers for hereditary fructose intolerance (OMIM 22960) would have increased uric acid and altered component of the metabolic syndrome when exposed to fructose overfeeding. METHODS: Six heterozygotes for HFI (hHFI) and 6 controls (Ctrl) were studied in a randomized, controlled, crossover trial. Participants ingested two identical test meals containing 0.7 g kg-1 glucose and 0.7 g kg-1 fructose according to a cross-over design, once after a 7-day on a low fructose diet (LoFruD, <10 g/d) and on another occasion after 7 days on a high fructose diet (HiFruD, 1.4 g kg-1 day-1 fructose + 0.1 g kg-1 day-1 glucose). Uric acid, glucose, and insulin concentrations were monitored in fasting conditions and over 2 h postprandial, and insulin resistance indexes were calculated. RESULTS: HiFruD increased fasting uric acid (p < 0.05) and reduced fasting insulin sensitivity estimated by the homeostasis model assessment (HOMA) for insulin resistance (p < 0.05), in both groups. Postprandial glucose concentrations were not different between hHFI and Ctrl. However HiFruD increased postprandial plasma uric acid, insulin and hepatic insulin resistance index (HIRI) in hHFI only (all p < 0.05). CONCLUSIONS: Seven days of HiFruD increased fasting uric acid and slightly reduced fasting HOMA index in both groups. In contrast, HiFruD increased postprandial uric acid, insulin concentration and HIRI in hHFI only, suggesting that heterozygosity for pathogenic Aldolase B variants may confer an increased susceptibility to the effects of dietary fructose on uric acid and hepatic insulin sensitivity. This trial was registered at the U.S. Clinical Trials Registry as NCT03545581.
Assuntos
Dieta da Carga de Carboidratos/efeitos adversos , Intolerância à Frutose/sangue , Frutose/efeitos adversos , Hiperuricemia/genética , Ácido Úrico/sangue , Adulto , Glicemia/metabolismo , Estudos Cross-Over , Dieta da Carga de Carboidratos/métodos , Jejum/sangue , Feminino , Frutose/administração & dosagem , Intolerância à Frutose/genética , Frutose-Bifosfato Aldolase/genética , Glucose/administração & dosagem , Glucose/efeitos adversos , Heterozigoto , Humanos , Hiperuricemia/etiologia , Insulina/sangue , Resistência à Insulina/genética , Fígado/metabolismo , Masculino , Refeições/fisiologia , Síndrome Metabólica/sangue , Síndrome Metabólica/genética , Período Pós-PrandialRESUMO
Hereditary fructose intolerance (HFI) is an autosomal recessive disorder caused by a mutation in the aldolase B gene. HFI patients exhibit nausea, vomiting, abdominal pain, hypoglycemia, and elevated liver enzymes after dietary fructose exposure. Chronic exposure might lead to failure to thrive, liver failure, renal failure, and, eventually, death. HFI usually manifests in infants when they are being weaned off of breastmilk. Because HFI has an excellent prognosis when patients maintain a strict restrictive diet, some patients remain undiagnosed due to the voluntary avoidance of sweet foods. In the past, HFI was diagnosed using a fructose tolerance test, liver enzyme assays or intestinal biopsy specimens. Currently, HFI is diagnosed through the analysis of aldolase B mutations. Here, HFI was diagnosed in a 41-year-old woman who complained of sweating, nausea, and vomiting after consuming sweets. She had a compound heterozygous mutation in the aldolase B gene; gene analysis revealed pathogenic nonsense (c.178C>T, p.Arg60Ter) and frameshift (c.360_363delCAAA, p.Asn120LysfsTer32) variants. This is the first report of a Korean HFI patient diagnosed in adulthood.
Assuntos
Intolerância à Frutose , Adulto , Feminino , Frutose , Intolerância à Frutose/diagnóstico , Intolerância à Frutose/genética , Frutose-Bifosfato Aldolase/genética , Humanos , Fígado , MutaçãoRESUMO
Establishing the diagnosis of hereditary fructose intolerance (HFI) remains difficult despite the availability of specific molecular genetic testing of the ALDOB gene. This is attributable, at least in part, to the lack of a specific and practical biomarker. We report the incidental diagnosis of HFI as a consequence of nontargeted genetic testing ordered for alternative indications in 5 patients, including 3 children and 2 adults. Two of the children were diagnosed with HFI after extensive evaluations that ultimately involved clinical or research exome sequencing. The third child was diagnosed with HFI during subsequent genetic testing of at-risk family members. Both adults learned to avoid fructose and remained asymptomatic of HFI before diagnosis. One was diagnosed with HFI during preconception, nontargeted expanded carrier screening. For the other, concern for HFI was initially raised by indeterminate direct-to-consumer genetic testing results. None of these patients presented with infantile acute liver failure or other acute decompensation. Our findings suggest that the emphasis of classic teaching on infantile liver failure after first exposure to fructose may be inadvertently increasing the likelihood of missing cases of HFI characterized by other manifestations. HFI is likely underdiagnosed and should be considered for patients with nonspecific findings as well as for individuals with significant aversion to sweets.
Assuntos
Intolerância à Frutose/diagnóstico , Adulto , Idoso , Doenças Assintomáticas , Criança , Pré-Escolar , Deficiências do Desenvolvimento/genética , Triagem e Testes Direto ao Consumidor , Nanismo/genética , Insuficiência de Crescimento/genética , Feminino , Preferências Alimentares , Intolerância à Frutose/genética , Frutose-Bifosfato Aldolase/genética , Frutas/efeitos adversos , Testes Genéticos , Humanos , Achados Incidentais , Infertilidade Feminina , Masculino , Cuidado Pré-Concepcional , Verduras/efeitos adversos , Sequenciamento do ExomaRESUMO
INTRODUCTION: Hereditary fructose intolerance is a metabolic disease due to an aldolase B deficiency. Our objective was to ascertain the social and health care needs of those with this deficiency. MATERIAL AND METHODS: A prospective, observational study was performed. A survey of social and health care needs was conducted to hereditary fructose intolerance patients living in Spain. RESULTS: Most patients had been diagnosed, mainly by genetic analysis in children and based on fructose overload in adults. Population surveyed had no sequelae (72.34%) or disability (64%), and 83.33% of children and 52.38% of adults were taking drugs (p <.05) (2.06 drugs on average). Most patients had attended medical visits in the past two years, mainly in metabolic disease units (42.5%) and/or nutrition units (42.5%), but less than a half attended reference centers (mostly children [p <0.05]). Although 48% were satisfied with health care, they felt discriminated in recreational activities, school, health and/or daily activities. The most reliable sources of information were the specialized care physician (69.39%) and patients' association (59.18%). Fifty-five percent reported no problem in any quality of life dimension, although some had problems in daily activities, pain, and anxiety. CONCLUSIONS: Although hereditary fructose intolerance is less disabling than other rare diseases, it is important to know the needs of those who suffer from it. Although time to diagnosis has shortened, the poorer health care and satisfaction with it perceived in adults makes it necessary to emphasize the needs of this population, and the critical need of training and information of health care professionals.
Assuntos
Intolerância à Frutose/genética , Intolerância à Frutose/terapia , Necessidades e Demandas de Serviços de Saúde , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Estudos Prospectivos , Autorrelato , Fatores Sociais , Espanha , Adulto JovemRESUMO
BACKGROUND: Hereditary fructose intolerance (HFI) is a rare genetic disorder of fructose metabolism due to aldolase B enzyme deficiency. Treatment consists of fructose, sorbitol, and sucrose (FSS)-free diet. We explore possible correlations between daily fructose traces intake and liver injury biomarkers on a long-term period, in a cohort of young patients affected by HFI. METHODS: Patients' clinical data and fructose daily intake were retrospectively collected. Correlations among fructose intake, serum alanine aminotransferase (ALT) level, carbohydrate-deficient transferrin (CDT) percentage, liver ultrasonography, genotype were analyzed. RESULTS: We included 48 patients whose mean follow-up was 10.3 ± 5.6 years and fructose intake 169 ± 145.4 mg/day. Eighteen patients had persistently high ALT level, nine had abnormal CDT profile, 45 had signs of liver steatosis. Fructose intake did not correlate with ALT level nor with steatosis severity, whereas it correlated with disialotransferrin percentage (R2 0.7, p < 0.0001) and tetrasialotransferrin/disialotransferrin ratio (R2 0.5, p = 0.0001). p.A150P homozygous patients had lower ALT values at diagnosis than p.A175D variant homozygotes cases (58 ± 55 IU/L vs. 143 ± 90 IU/L, p = 0.01). CONCLUSION: A group of HFI patients on FSS-free diet presented persistent mild hypertransaminasemia which did not correlate with fructose intake. Genotypes may influence serum liver enzyme levels. CDT profile represents a good marker to assess FSS intake.
Assuntos
Dieta com Restrição de Carboidratos , Fígado Gorduroso/etiologia , Intolerância à Frutose/dietoterapia , Frutose/efeitos adversos , Adolescente , Alanina Transaminase/sangue , Biomarcadores/sangue , Criança , Fígado Gorduroso/sangue , Fígado Gorduroso/diagnóstico por imagem , Feminino , Frutose/metabolismo , Intolerância à Frutose/complicações , Intolerância à Frutose/diagnóstico , Intolerância à Frutose/genética , Frutose-Bifosfato Aldolase/genética , Predisposição Genética para Doença , Humanos , Masculino , Mutação , Fenótipo , Estudos Retrospectivos , Índice de Gravidade de Doença , Sialoglicoproteínas/sangue , Transferrina/análogos & derivados , Transferrina/metabolismoRESUMO
Hereditary fructose intolerance is an autosomal recessive disorder of fructose metabolism caused by catalytic deficiency of aldolase B enzyme [1]. The disease is typically expressed when fructose- and sucrose-containing foods are first introduced in the diet; acute manifestations include nausea, vomiting, abdominal distress, and symptomatic hypoglycemia [1,2]. Chronic fructose ingestion eventually leads to poor feeding, growth retardation and gradual liver and/or renal failure [3,4]. Some patients may remain undiagnosed until adulthood because of a self-protective avoidance of sweet tasting food that prevents the development of acute toxicity from fructose containing food; however, these subjects may suffer intermittent symptoms throughout life, leading to potentially serious misdiagnosis [4]. We report the case of a patient with unrecognized hereditary fructose intolerance in which chronic gastrointestinal complaints, low body weight, and unexplained food avoidance were addressed as manifestations of an eating disorder during adolescence.
Assuntos
Preferências Alimentares , Intolerância à Frutose/diagnóstico , Adulto , Erros de Diagnóstico , Transtornos da Alimentação e da Ingestão de Alimentos/diagnóstico , Feminino , Preferências Alimentares/psicologia , Intolerância à Frutose/genética , Intolerância à Frutose/psicologia , Gastroenteropatias/etiologia , HumanosRESUMO
Background: High fructose intake causes hepatic insulin resistance and increases postprandial blood glucose, lactate, triglyceride, and uric acid concentrations. Uric acid may contribute to insulin resistance and dyslipidemia in the general population. In patients with hereditary fructose intolerance, fructose consumption is associated with acute hypoglycemia, renal tubular acidosis, and hyperuricemia. Objective: We investigated whether asymptomatic carriers for hereditary fructose intolerance (HFI) would have a higher sensitivity to adverse effects of fructose than would the general population. Design: Eight subjects heterozygous for HFI (hHFI; 4 men, 4 women) and 8 control subjects received a low-fructose diet for 7 d and on the eighth day ingested a test meal, calculated to provide 25% of the basal energy requirement, containing 13C-labeled fructose (0.35 g/kg), glucose (0.35 g/kg), protein (0.21 g/kg), and lipid (0.22 g/kg). Glucose rate of appearance (GRa, calculated with [6,6-2H2]glucose), fructose, net carbohydrate, and lipid oxidation, and plasma triglyceride, uric acid, and lactate concentrations were monitored over 6 h postprandially. Results: Postprandial GRa, fructose, net carbohydrate, and lipid oxidation, and plasma lactate and triglyceride concentrations were not significantly different between the 2 groups. Postprandial plasma uric acid increased by 7.2% compared with fasting values in hHFI subjects (P < 0.01), but not in control subjects (-1.1%, ns). Conclusions: Heterozygous carriers of hereditary fructose intolerance had no significant alteration of postprandial fructose metabolism compared with control subjects. They did, however, show a postprandial increase in plasma uric acid concentration that was not observed in control subjects in responses to ingestion of a modest amount of fructose. This trial was registered at the US Clinical Trials Registry as NCT02979106.
Assuntos
Intolerância à Frutose/genética , Intolerância à Frutose/metabolismo , Frutose/administração & dosagem , Heterozigoto , Doenças Metabólicas/etiologia , Adulto , Metabolismo dos Carboidratos , Creatinina/sangue , Creatinina/urina , Feminino , Frutose/metabolismo , Humanos , Metabolismo dos Lipídeos , Masculino , Ácido Úrico/sangue , Ácido Úrico/urinaRESUMO
Increasing evidence suggests a role for excessive intake of fructose in the Western diet as a contributor to the current epidemics of metabolic syndrome and obesity. Hereditary fructose intolerance (HFI) is a difficult and potentially lethal orphan disease associated with impaired fructose metabolism. In HFI, the deficiency of aldolase B results in the accumulation of intracellular phosphorylated fructose, leading to phosphate sequestration and depletion, increased adenosine triphosphate (ATP) turnover, and a plethora of conditions that lead to clinical manifestations such as fatty liver, hyperuricemia, Fanconi syndrome, and severe hypoglycemia. Unfortunately, there is currently no treatment for HFI, and avoiding sugar and fructose has become challenging in our society. In this report, through use of genetically modified mice and pharmacological inhibitors, we demonstrate that the absence or inhibition of ketohexokinase (Khk), an enzyme upstream of aldolase B, is sufficient to prevent hypoglycemia and liver and intestinal injury associated with HFI. Herein we provide evidence for the first time to our knowledge of a potential therapeutic approach for HFI. Mechanistically, our studies suggest that it is the inhibition of the Khk C isoform, not the A isoform, that protects animals from HFI.
Assuntos
Frutoquinases/antagonistas & inibidores , Frutoquinases/metabolismo , Intolerância à Frutose/enzimologia , Animais , Frutoquinases/genética , Frutose/genética , Frutose/metabolismo , Intolerância à Frutose/tratamento farmacológico , Intolerância à Frutose/genética , Frutose-Bifosfato Aldolase/antagonistas & inibidores , Frutose-Bifosfato Aldolase/genética , Frutose-Bifosfato Aldolase/metabolismo , Isoenzimas/antagonistas & inibidores , Isoenzimas/genética , Camundongos , Camundongos KnockoutRESUMO
Increased sugar consumption is a risk factor for the metabolic syndrome including obesity, hypertriglyceridemia, insulin resistance, diabetes, and nonalcoholic fatty liver disease (NAFLD). Carbohydrate responsive element-binding protein (ChREBP) is a transcription factor that responds to sugar consumption to regulate adaptive metabolic programs. Hepatic ChREBP is particularly responsive to fructose and global ChREBP-KO mice are intolerant to diets containing fructose. It has recently been suggested that ChREBP protects the liver from hepatotoxicity following high-fructose diets (HFrDs). We directly tested this hypothesis using tissue-specific ChREBP deletion. HFrD increased adiposity and impaired glucose homeostasis in control mice, responses that were prevented in liver-specific ChREBP-KO (LiChKO) mice. Moreover, LiChKO mice tolerated chronic HFrD without marked weight loss or hepatotoxicity. In contrast, intestine-specific ChREBP-KO (IChKO) mice rapidly lost weight after transition to HFrD, and this was associated with dilation of the small intestine and cecum, suggestive of malabsorption. These findings were associated with downregulation of the intestinal fructose transporter, Slc2a5, which is essential for fructose tolerance. Altogether, these results establish an essential role for intestinal, but not hepatic, ChREBP in fructose tolerance.
Assuntos
Intolerância à Frutose/metabolismo , Frutose/toxicidade , Mucosa Intestinal/metabolismo , Fígado/metabolismo , Proteínas Nucleares/fisiologia , Fatores de Transcrição/fisiologia , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Colesterol/metabolismo , Regulação para Baixo/fisiologia , Feminino , Intolerância à Frutose/genética , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Transportador de Glucose Tipo 5 , Lipogênese/efeitos dos fármacos , Masculino , Camundongos Knockout , Proteínas Nucleares/deficiência , Proteínas Nucleares/genética , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética , Redução de Peso/fisiologiaRESUMO
Celiac disease (CD) has been associated with several genetic and immune disorders, but association between CD and hereditary fructose intolerance (HFI) is extremely rare. HFI is an autosomal recessive disease caused by catalytic deficiency of aldolase B (fructose-1,6-bisphosphate aldolase). We report the case of a 5-year-old boy suffering from CD, admitted with an initial diagnosis of Reye's-like syndrome. He presented with episodic unconsciousness, seizures, hypoglycemia, hepatomegaly and abnormal liver function. The patient has been on an exclusion diet for three years, but he still had symptoms: stunting, hepatomegaly, high transaminases, but tissue transglutaminase antibodies were negative. Liver biopsy showed hepatic steatosis and mitochondrial damage. The dietary history showed an aversion to fruits, vegetables and sweet-tasting foods. The fructose tolerance test was positive, revealing the diagnostic of hereditary fructose intolerance. Appropriate dietary management and precautions were recommended. The patient has been symptom-free and exhibited normal growth and development until 10 years of age.