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1.
Drug Saf ; 44(2): 133-165, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33141341

RESUMEN

With the widespread development of new drugs to treat chronic liver diseases (CLDs), including viral hepatitis and nonalcoholic steatohepatitis (NASH), more patients are entering trials with abnormal baseline liver tests and with advanced liver injury, including cirrhosis. The current regulatory guidelines addressing the monitoring, diagnosis, and management of suspected drug-induced liver injury (DILI) during clinical trials primarily address individuals entering with normal baseline liver tests. Using the same laboratory criteria cited as signals of potential DILI in studies involving patients with no underlying liver disease and normal baseline liver tests may result in premature and unnecessary cessation of a study drug in a clinical trial population whose abnormal and fluctuating liver tests are actually due to their underlying CLD. This position paper focuses on defining best practices for the detection, monitoring, diagnosis, and management of suspected acute DILI during clinical trials in patients with CLD, including hepatitis C virus (HCV) and hepatitis B virus (HBV), both with and without cirrhosis and NASH with cirrhosis. This is one of several position papers developed by the IQ DILI Initiative, comprising members from 16 pharmaceutical companies in collaboration with DILI experts from academia and regulatory agencies. It is based on an extensive literature review and discussions between industry members and experts from outside industry to achieve consensus regarding the recommendations. Key conclusions and recommendations include (1) the importance of establishing laboratory criteria that signal potential DILI events and that fit the disease indication being studied in the clinical trial based on knowledge of the natural history of test fluctuations in that disease; (2) establishing a pretreatment value that is based on more than one screening determination, and revising that baseline during the trial if a new nadir is achieved during treatment; (3) basing rules for increased monitoring and for stopping drug for potential DILI on multiples of baseline liver test values and/or a threshold value rather than multiples of the upper limit of normal (ULN) for that test; (4) making use of more sensitive tests of liver function, including direct bilirubin (DB) or combined parameters such as aspartate transaminase:alanine transaminase (AST:ALT) ratio or model for end-stage liver disease (MELD) to signal potential DILI, especially in studies of patients with cirrhosis; and (5) being aware of potential confounders related to complications of the disease being studied that may masquerade as DILI events.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas , Consenso , Guías de Práctica Clínica como Asunto , Adulto , Enfermedad Hepática Inducida por Sustancias y Drogas/diagnóstico , Enfermedad Hepática Inducida por Sustancias y Drogas/terapia , Ensayos Clínicos como Asunto , Hepatitis B/complicaciones , Hepatitis C/complicaciones , Hepatitis Crónica/epidemiología , Humanos , Cirrosis Hepática/etiología , Cirrosis Hepática/virología , Enfermedad del Hígado Graso no Alcohólico/complicaciones
2.
Inflamm Bowel Dis ; 26(4): 619-625, 2020 03 04.
Artículo en Inglés | MEDLINE | ID: mdl-31504515

RESUMEN

BACKGROUND: The latest estimate of the prevalence of inflammatory bowel disease (IBD) in the United States was based on 2009 data, which indicates a need for an up-to-date re-estimation. The objectives of this study were to investigate the prevalence of all forms of IBD including ulcerative colitis (UC), Crohn's disease (CD), and IBD unspecified (IBDU). METHODS: Pediatric (age 2-17) and adult (age ≥18) IBD patients were identified from 2 large claims databases. For each year between 2007 and 2016, prevalence was calculated per 100,000 population and standardized based on the 2016 national Census. A fixed-effects meta-analytical model was used for overall prevalence. RESULTS: The pediatric prevalence of IBD overall increased by 133%, from 33.0/100,000 in 2007 to 77.0/100,000 in 2016. Among children, CD was twice as prevalent as UC (45.9 vs 21.6). Prevalence was higher in boys than girls for all forms of IBD, in contrast to the adult population where the prevalence was higher in women than men. We also found that the 10-17 age subgroup was the major contributor to the rising pediatric IBD prevalence. For adults, the prevalence of IBD overall increased by 123%, from 214.9 in 2007 to 478.4 in 2016. The prevalence rates of UC and CD were similar (181.1 vs 197.7) in 2016. CONCLUSIONS: Inflammatory bowel disease continues to affect a substantial proportion of the US population. In 2016, 1 in 209 adults and 1 in 1299 children aged 2-17 were affected by IBD. Prevalence of IBD has been increasing compared with previously published 2009 data.


Asunto(s)
Colitis Ulcerosa/epidemiología , Enfermedad de Crohn/epidemiología , Enfermedades Inflamatorias del Intestino/epidemiología , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Estudios Transversales , Bases de Datos Factuales , Femenino , Predicción , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Estudios Retrospectivos , Estados Unidos/epidemiología , Adulto Joven
3.
Aliment Pharmacol Ther ; 49(6): 702-713, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30761572

RESUMEN

BACKGROUND: The last decade has seen a rapid growth in the number of clinical trials enrolling patients with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH). Due to the underlying chronic liver disease, patients with NASH often require different approaches to the assessment and management of suspected drug-induced liver injury (DILI) compared to patients with healthy livers. However, currently no regulatory guidelines or position papers systematically address best practices pertaining to DILI in NASH clinical trials. AIMS: This publication focuses on best practices concerning the detection, monitoring, diagnosis and management of suspected acute DILI during clinical trials in patients with NASH. METHODS: This is one of several papers developed by the IQ DILI Initiative, comprised of members from 15 pharmaceutical companies, in collaboration with DILI experts from academia and regulatory agencies. This paper is based on extensive literature review, and discussions between industry members with expertise in drug safety and DILI experts from outside industry to achieve consensus on common questions related to this topic. RESULTS: Recommended best practices are outlined pertaining to hepatic inclusion and exclusion criteria, monitoring of liver tests, DILI detection, approach to a suspected DILI signal, causality assessment and hepatic discontinuation rules. CONCLUSIONS: This paper provides a framework for the approach to assessment and management of suspected acute DILI during clinical trials in patients with NASH.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/terapia , Ensayos Clínicos como Asunto/normas , Manejo de la Enfermedad , Enfermedad del Hígado Graso no Alcohólico/terapia , Guías de Práctica Clínica como Asunto/normas , Enfermedad Hepática Inducida por Sustancias y Drogas/diagnóstico , Enfermedad Hepática Inducida por Sustancias y Drogas/epidemiología , Ensayos Clínicos como Asunto/métodos , Humanos , Pruebas de Función Hepática/métodos , Pruebas de Función Hepática/normas , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/epidemiología
4.
World J Clin Pediatr ; 5(4): 365-369, 2016 Nov 08.
Artículo en Inglés | MEDLINE | ID: mdl-27872824

RESUMEN

AIM: To determine if packed red blood cell transfusions contribute to the development of parenteral nutrition associated liver disease. METHODS: A retrospective chart review of 49 premature infants on parenteral nutrition for > 30 d who received packed red blood cell (PRBC) transfusions was performed. Parenteral nutrition associated liver disease was primarily defined by direct bilirubin (db) > 2.0 mg/dL. A high transfusion cohort was defined as receiving > 75 mL packed red blood cells (the median value). Kaplan-Meier plots estimated the median volume of packed red blood cells received in order to develop parenteral nutrition associated liver disease. RESULTS: Parenteral nutritional associated liver disease (PNALD) was noted in 21 (43%) infants based on db. Among the 27 high transfusion infants, PNALD was present in 17 (64%) based on elevated direct bilirubin which was significantly greater than the low transfusion recipients. About 50% of the infants, who were transfused 101-125 mL packed red blood cells, developed PNALD based on elevation of direct bilirubin. All infants who were transfused more than 200 mL of packed red blood cells developed PNALD. Similar results were seen when using elevation of aspartate transaminase or alanine transaminase to define PNALD. CONCLUSION: In this retrospective, pilot study there was a statistically significant correlation between the volume of PRBC transfusions received by premature infants and the development of PNALD.

5.
J Clin Pharmacol ; 55(5): 592-600, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25639255

RESUMEN

The proton pump inhibitor, rabeprazole, has been studied in children for the treatment of gastroesophageal reflux disease (GERD). In adults, rabeprazole is indicated for Helicobacter pylori eradication in combination with amoxicillin and clarithromycin. Nonlinear mixed effects modeling was conducted to estimate pharmacokinetic (PK) parameters for rabeprazole and its thioether metabolite from 336 subjects, 35% of whom were children 1-11 years with GERD from phase I and III studies. A 2-compartment disposition model with a transit absorption model provided the best fit for rabeprazole PK. The steady-state area under the concentration-time curves given several candidate doses were simulated to identify a dose per each body weight group that is comparable to a 20 mg twice-daily dose in adults, which is the recommended dose for treatment of H. pylori in adults. Simulations provided the following recommended twice-daily weight-based doses for children ≥1 year and <16 years: 10 mg for 6-10 kg, 15 mg for 10-30 kg, and 20 mg for ≥30 kg.


Asunto(s)
Infecciones por Helicobacter/tratamiento farmacológico , Inhibidores de la Bomba de Protones/administración & dosificación , Inhibidores de la Bomba de Protones/farmacocinética , Rabeprazol/administración & dosificación , Rabeprazol/farmacocinética , Adolescente , Amoxicilina/administración & dosificación , Área Bajo la Curva , Peso Corporal , Niño , Preescolar , Claritromicina/administración & dosificación , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase III como Asunto , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Femenino , Helicobacter pylori , Humanos , Lactante , Masculino , Inhibidores de la Bomba de Protones/uso terapéutico , Rabeprazol/uso terapéutico
6.
JPEN J Parenter Enteral Nutr ; 38(5): 608-16, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23757305

RESUMEN

OBJECTIVES: ω-3 Fatty acids (FAs), natural ligands for the peroxisome proliferator-activated receptor-α (PPAR-α), attenuate parenteral nutrition-associated liver disease (PNALD). However, the mechanisms underlying the protective role of ω-3 FAs are still unknown. The aim of this study was to determine the effects of ω-3 FAs on hepatic triglyceride (TG) accumulation in a murine model of PNALD and to investigate the role of PPAR-α and microsomal triglyceride transfer protein (MTP) in this experimental setting. METHODS: 129S1/SvImJ wild-type or 129S4/SvJaePparatm/Gonz/J PPAR-α knockout mice were fed chow and water (controls); oral, fat-free PN solution only (PN-O); PN-O plus intraperitoneal (IP) ω-6 FA-predominant supplements (PN-ω-6); or PN-O plus IP ω-3 FA (PN-ω-3). Control and PN-O groups received sham IP injections of 0.9% NaCl. Hepatic histology, TG and cholesterol, MTP activity, and PPAR-α messenger RNA were assessed after 19 days. RESULTS: In all experimental groups, PN feeding increased hepatic TG and MTP activity compared with controls. Both PN-O and PN-ω-6 groups accumulated significantly greater amounts of TG when compared with PN-ω-3 mice. Studies in PPAR-α null animals showed that PN feeding increases hepatic TG as in wild-type mice. PPAR-α null mice in the PN-O and PN-ω-6 groups demonstrated variable degrees of hepatic steatosis, whereas no evidence of hepatic fat accumulation was found after 19 days of oral PN plus IP ω-3 FAs. CONCLUSIONS: PN induces TG accumulation (steatosis) in wild-type and PPAR-α null mice. In PN-fed wild-type and PPAR-α null mice given IP ω-3 FAs, reduced hepatic TG accumulation and absent steatosis are found. Prevention of steatosis by ω-3 FAs results from PPAR-α-independent pathways.


Asunto(s)
Ácidos Grasos Omega-3/farmacología , Hígado Graso/dietoterapia , Hígado/metabolismo , PPAR alfa/deficiencia , Nutrición Parenteral , Animales , Proteínas Portadoras/metabolismo , Colesterol/metabolismo , Modelos Animales de Enfermedad , Ácidos Grasos Omega-3/administración & dosificación , Hígado Graso/metabolismo , Hígado/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos , Ratones Noqueados , PPAR alfa/genética , Resultado del Tratamiento , Triglicéridos/metabolismo
10.
J Pediatr Gastroenterol Nutr ; 52(2): 140-6, 2011 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21240009

RESUMEN

OBJECTIVES: CD40, a co-stimulatory molecule, plays a critical role in coordinating enteric inflammatory immune responses. In necrotizing enterocolitis (NEC), upregulation of IL-10, a CD40-modulated cytokine, has been described, but the role of the IL-10 receptor (IL-10Rß), CD40, and its ligand CD40L in disease pathogenesis is unknown. The study herein investigates ileal expression of CD40, CD40L, and IL-10R in a rat model of NEC. SUBJECTS AND METHODS: NEC was induced in newborn rats using established methods of formula feeding, asphyxia, and cold stress. Expression of CD40, CD40L, IL-10Rß, and other proinflammatory molecules, including Toll-like receptor-4 (TLR-4) and IL-18, was assessed by immunoblotting. Tissue infiltration by macrophages, monocytes, and T cells was examined by confocal immunohistochemistry. RESULTS: Ileum from rat pups with NEC showed increased expression of TLR-4, IL-18, and IL-10Rß. Sections from both NEC and control pups demonstrated preservation of ileal cells expressing CD40/CD40L. The distal ileum of controls expressed both CD40 and CD40L; conversely, neither molecule was detected in ileal tissue from NEC pups. Additional studies showed that treatment with epidermal growth factor (EGF), previously shown to ameliorate the severity of NEC in an animal model, did not restore CD40 expression. CONCLUSIONS: Ileal cytokine dysregulation, manifested by decreased CD40/CD40L and increased IL-10Rß expression, may be involved in the pathogenesis of NEC. Dampened CD40 signaling may be related to enhanced IL-10 expression and a suppressed T-cell response to injury. We speculate that augmenting CD40-CD40L interactions may achieve a protective effect in this NEC model.


Asunto(s)
Antígenos CD40/inmunología , Enterocolitis Necrotizante/inmunología , Íleon/inmunología , Inflamación/inmunología , Subunidad beta del Receptor de Interleucina-10/inmunología , Animales , Western Blotting , Antígenos CD40/efectos de los fármacos , Antígenos CD40/metabolismo , Ligando de CD40/metabolismo , Enterocolitis Necrotizante/etiología , Enterocolitis Necrotizante/metabolismo , Factor de Crecimiento Epidérmico/farmacología , Íleon/metabolismo , Íleon/patología , Subunidad beta del Receptor de Interleucina-10/efectos de los fármacos , Subunidad beta del Receptor de Interleucina-10/metabolismo , Interleucina-18/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Modelos Animales , Monocitos/inmunología , Monocitos/metabolismo , Ratas , Ratas Sprague-Dawley , Linfocitos T/inmunología , Linfocitos T/metabolismo , Receptor Toll-Like 4/metabolismo
11.
J Pediatr Gastroenterol Nutr ; 51(5): 556-62, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-20818264

RESUMEN

BACKGROUND: Barrett esophagus (BE) is a premalignant condition that develops due to prolonged gastroesophageal reflux disease (GERD). In some but not all cases, BE progresses to Barrett-associated adenocarcinoma. p27 is a tumor-suppressor protein that regulates the cell's division cycle and appears to be frequently inactivated in Barrett-associated adenocarcinoma due to increased degradation or cytoplasmic mislocalization. Reduced or mislocalized p27 would remove it from its nuclear targets and result in increased proliferation. Although bile acid and hydrochloric acid (HCl) are linked to the pathogenesis of BE, not every patient with BE has a history of GERD. Eosinophilic esophagitis mimics GERD, but eosinophil granule proteins, known to mediate inflammation, have not been linked to BE. It was unknown whether mediators of esophagitis affect p27 expression and/or localization in normal esophageal cells. We assessed the effects of bile acid, HCl, and eosinophil granule proteins on p27 protein expression, localization, and its ability to regulate cell proliferation. MATERIALS AND METHODS: Human esophageal epithelial (HET-1A) cells were incubated with chenodeoxycholic acid (CDC), HCl, and eosinophil granule proteins (major basic protein, MBP; and eosinophil peroxidase, EPO). Cell viability analysis, immunoblot, immunofluorescence microscopy, and flow cytometric analysis were performed. RESULTS: Exposure of HET-1A cells to CDC, HCl, MBP, and EPO did not affect total p27 levels. CDC, HCl, MBP, and EPO caused mislocalization of p27 from the nucleus to the cytoplasm. Flow cytometry showed that CDC exposure also increased HET-1A cell proliferation. CONCLUSIONS: Mislocalization of p27 caused by mediators of GERD or eosinophilic esophagitis may serve as an early marker of increased cell proliferation, which may contribute to the risk for esophageal dysplasia.


Asunto(s)
Esófago de Barrett/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Esofagitis Eosinofílica/metabolismo , Células Epiteliales/metabolismo , Neoplasias Esofágicas/metabolismo , Reflujo Gastroesofágico/metabolismo , Mediadores de Inflamación/metabolismo , Esófago de Barrett/patología , Transporte Biológico , Biomarcadores/metabolismo , Línea Celular , Núcleo Celular/metabolismo , Proliferación Celular , Ácido Quenodesoxicólico , Citoplasma/metabolismo , Proteínas en los Gránulos del Eosinófilo , Esofagitis Eosinofílica/etiología , Esofagitis Eosinofílica/patología , Eosinófilos/metabolismo , Células Epiteliales/patología , Neoplasias Esofágicas/patología , Citometría de Flujo , Reflujo Gastroesofágico/patología , Humanos , Ácido Clorhídrico
13.
Curr Gastroenterol Rep ; 9(3): 230-6, 2007 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-17511922

RESUMEN

Pediatric liver transplant patients are now routinely surviving 10 years or more. Beyond the first year after transplant, surgical biliary or vascular complications are rare, and the incidence of acute rejection episodes falls precipitously. Attention is turning to minimizing the toxicity of immunosuppressive regimens and their potential negative impact on growth, bone health, cognitive development, renal function, and quality of life. Innovative combinations of immunosuppressive medications are being used as initial management after transplantation to minimize acute rejection and allow rapid weaning of corticosteroids and reduction in maintenance levels of calcineurin inhibitors. The substitution of potentially less toxic immunosuppressive agents, such as mycophenolate mofetil and rapamycin, is being studied in patients who develop renal dysfunction. A major current emphasis is on defining the natural history of long-term graft injury and elucidating histopathologic changes that mimic autoimmune chronic active hepatitis but are likely a form of chronic rejection due to production by the recipient of antibodies to foreign graft antigens. As patients survive longer, we are seeing various forms of immune dysregulation engendered by the presence of the graft and chronic immunosuppression of the host. By defining the resulting patterns of graft injury and understanding their immunopathogenesis, we can devise rational adjustments in immunosuppression that will preserve graft function and maximize graft life.


Asunto(s)
Desarrollo Infantil/efectos de los fármacos , Inmunosupresores/efectos adversos , Trasplante de Hígado/efectos adversos , Sobrevivientes , Adolescente , Niño , Humanos , Inmunosupresores/uso terapéutico , Trasplante de Hígado/inmunología , Trasplante de Hígado/mortalidad , Calidad de Vida , Análisis de Supervivencia , Factores de Tiempo
15.
Hum Pathol ; 38(4): 570-80, 2007 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-17258790

RESUMEN

Enteroendocrine cell dysgenesis was observed in 3 patients with intestinal failure of unknown cause. Enteroendocrine cell dysgenesis is a congenitally acquired life-threatening malabsorptive condition with a unique clinical phenotype paired with a histologically identifiable disease pattern. Two cases were first presented at the Ninth International Small Bowel Transplantation Symposium, Brussels 2005, and were subsequently published (N Engl J Med 2006;355:270). We now present the histopathologic and immunohistochemical findings of the gastric antrum, small bowel, and colon in greater detail. The clinical phenotype of the patients was unusual in that the affected patients demonstrated profound malabsorption of all nutrients, except water, from birth. The small intestine in each patient demonstrated almost no abnormality, except a near absence of endocrine cells in the mucosa. The colon appeared similarly affected. Known causes of congenital malabsorption, inflammatory, and infectious causes of diarrhea were excluded. The defect is secondary to point mutations in NEUROG3, which result in an arrest of endocrine cell development in the small intestine and colon. This work describes the pathologic characterization of enteroendocrine cell dysgenesis using routine techniques. The pattern of injury is distinct from other histopathologically assessed congenital malabsorptive conditions such as microvillus inclusion disease, tufting enteropathy, and abetalipoproteinemia. It is also easily distinguished from inflammatory conditions such as food allergy, gluten-sensitive enteropathy, autoimmune enteropathy, IPEX (immune dysfunction, polyendocrinopathy, enteropathy, and X-linked inheritance), and inflammatory bowel disease. The histopathology of disease is similar to what has been found transiently in a single patient with autoimmune polyglandular syndrome type I.


Asunto(s)
Células Enteroendocrinas/patología , Enfermedades Intestinales/patología , Síndromes de Malabsorción/patología , Niño , Preescolar , Humanos , Inmunohistoquímica , Enfermedades Intestinales/cirugía , Intestino Delgado/patología , Síndromes de Malabsorción/cirugía , Masculino
16.
N Engl J Med ; 355(3): 270-80, 2006 Jul 20.
Artículo en Inglés | MEDLINE | ID: mdl-16855267

RESUMEN

BACKGROUND: Neurogenin-3 (NEUROG3) is expressed in endocrine progenitor cells and is required for endocrine-cell development in the pancreas and intestine. The NEUROG3 gene (NEUROG3) is therefore a candidate for the cause of a newly discovered autosomal recessive disorder characterized by generalized malabsorption and a paucity of enteroendocrine cells. METHODS: We screened genomic DNA from three unrelated patients with sparse enteroendocrine cells for mutations of NEUROG3. We then tested the ability of the observed mutations to alter NEUROG3 function, using in vitro and in vivo assays. RESULTS: The patients had few intestinal enteroendocrine cells positive for chromogranin A, but they had normal numbers of Paneth's, goblet, and absorptive cells. We identified two homozygous mutations in NEUROG3, both of which rendered the NEUROG3 protein unable to activate NEUROD1, a downstream target of NEUROG3, and compromised the ability of NEUROG3 to bind to an E-box element in the NEUROD1 promoter. The injection of wild-type but not mutant NEUROG3 messenger RNA into xenopus embryos induced NEUROD1 expression. CONCLUSIONS: A newly discovered disorder characterized by malabsorptive diarrhea and a lack of intestinal enteroendocrine cells is caused by loss-of-function mutations in NEUROG3.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Diarrea/congénito , Diarrea/genética , Intestino Delgado/patología , Síndromes de Malabsorción/genética , Mutación Missense , Proteínas del Tejido Nervioso/genética , Secuencia de Aminoácidos , Secuencia de Bases , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Enfermedad Crónica , Diarrea/patología , Células Enteroendocrinas/patología , Resultado Fatal , Humanos , Recién Nacido , Síndromes de Malabsorción/complicaciones , Síndromes de Malabsorción/patología , Masculino , Datos de Secuencia Molecular , Proteínas del Tejido Nervioso/metabolismo , Regiones Promotoras Genéticas
17.
Curr Gastroenterol Rep ; 8(3): 215-23, 2006 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-16764787

RESUMEN

Hepatic-based inborn errors of metabolism are targets for treatment with liver transplantation in children, in whom the metabolic defect causes irreversible damage to the liver. However, certain metabolic defects originate with enzyme deficiencies localized in the liver but then give rise to toxic intermediates that damage extrahepatic organs without any significant compromise of general liver function. Here, the rationale of using liver transplantation to replace an organ that is functioning normally except for a specific metabolic pathway raises difficult questions about indications for transplantation, timing, amount of replacement tissue needed to correct the defect, and whether heterozygote parents are suitable living donors for liver transplantation in their affected children. This review explores these questions and others, including the role of hepatocyte transplantation, in this select group of disorders. Until the promise of specific gene or enzyme replacement therapy is realized, liver and hepatocyte transplantation offers the best chance of achieving metabolic control in these challenging patients.


Asunto(s)
Hepatopatías/cirugía , Trasplante de Hígado , Errores Innatos del Metabolismo/complicaciones , Niño , Progresión de la Enfermedad , Humanos , Hepatopatías/etiología , Errores Innatos del Metabolismo/cirugía , Factores de Tiempo , Resultado del Tratamiento
18.
Pediatr Ann ; 35(4): 290-4, 297-9, 2006 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-16637558

RESUMEN

NAFLD likely is the most common liver disease in children and is responsible for significant progression to cirrhosis, portal hypertension, and the need for liver transplantation in adults and even in some adolescents. Early diagnosis and lifestyle interventions appear to be our best hope for controlling progression of disease. The pediatrician is responsible for screening all obese children with measurement of aminotransferases. Those with elevated enzymes (particularly ALT) for longer than 3 months, in the absence of markers of hepatitis B or C, autoimmune chronic active hepatitis, Wilson's disease, hemochromatosis, or alpha-1-antitrypsin deficiency, should follow up with an abdominal ultrasound. In patients with a BMI in the morbidly obese range, an ultrasound to search for a diffusely echogenic liver should be performed even if the liver enzymes are normal. Findings suggestive of NAFLD should prompt the institution of appropriate dietary and exercise regimens. If these are unsuccessful after a 3-month trial, the patient should be referred to a pediatric gastroenterologist and hepatologist for further work-up and treatment, preferably in the context of a controlled therapeutic trial. Only by aggressively engaging this current epidemic will we be able to decrease the mounting human cost of NAFLD.


Asunto(s)
Hígado Graso , Obesidad/complicaciones , Adolescente , Niño , Preescolar , Hígado Graso/diagnóstico , Hígado Graso/etiología , Hígado Graso/fisiopatología , Femenino , Hispánicos o Latinos , Humanos , Lactante , Masculino , Prevalencia , Transaminasas/sangre
19.
J Pediatr ; 145(3): 346-52, 2004 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-15343189

RESUMEN

OBJECTIVE: Transfusions prevent secondary stroke in children with sickle cell anemia (SCA) but also cause iron overload. Alternatives for stroke prophylaxis with effective therapy to reduce iron burden are needed. STUDY DESIGN: For 35 children with SCA and stroke, transfusions were prospectively discontinued. Hydroxyurea was prescribed for stroke prophylaxis, and phlebotomy removed excess iron. Initial patients discontinued transfusions before hydroxyurea therapy, but later patients overlapped transfusions with hydroxyurea until tolerating full-dose therapy. RESULTS: Children received hydroxyurea for 42 +/- 30 months (range, 3-104 months). Hydroxyurea (26.7 +/- 4.8 mg/kg per day) led to mild neutropenia (3.9 +/- 2.3 x 10(9)/L) with significant increases in hemoglobin concentration, mean corpuscular volume, and fetal hemoglobin. Stroke recurrence rate was 5.7 events per 100 patient-years, but children receiving overlapping hydroxyurea therapy had only 3.6 events per 100 patient-years. For 26 children with >6 months of phlebotomy, 14,311 +/- 12,459 mL blood (315 +/- 214 mL/kg) was removed, with serum ferritin decreasing from a median of 2722 to 298 ng/mL. Among patients completing phlebotomy, liver biopsy documented normal histology and no excess iron deposition. CONCLUSIONS: For children with SCA and stroke, hydroxyurea effectively prevents secondary stroke and serial phlebotomy leads to complete resolution of transfusional iron overload.


Asunto(s)
Anemia de Células Falciformes/tratamiento farmacológico , Antidrepanocíticos/uso terapéutico , Hidroxiurea/uso terapéutico , Accidente Cerebrovascular/prevención & control , Adolescente , Anemia de Células Falciformes/complicaciones , Niño , Preescolar , Femenino , Humanos , Lactante , Sobrecarga de Hierro/terapia , Masculino , Flebotomía , Estudios Prospectivos , Prevención Secundaria , Accidente Cerebrovascular/etiología
20.
Curr Opin Pediatr ; 16(5): 552-9, 2004 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-15367850

RESUMEN

PURPOSE OF REVIEW: There has been an explosion in knowledge about celiac disease (CD) in the last decade based on the availability of serologic screening tests and the elucidation of some of the important disease susceptibility genes. What has been discovered is that CD is among the most common inherited diseases with a worldwide prevalence of almost 1% of the population. Also, there has been a tremendous expansion of the possible clinical presentations in patients with CD, many of them predominantly or even exclusively extraintestinal. Over the last year, both the North American Society of Pediatric Gastroenterology and Nutrition, and the NIH, through the mechanism of a consensus development conference held in May 2004, have published guidelines outlining the current state of knowledge and the areas where more research is needed. RECENT FINDINGS: This review will stress the most recent findings in CD in the areas of genetics, pathogenesis, epidemiology, screening and diagnosis, and natural history. It will stress the importance of HLA DQ2 and DQ8 as disease susceptibility genes, and the interaction of the environmental triggers (gliadins and glutenins) with these gene products to trigger the immunologic response in the gut that is responsible for the pattern of injury. Recent reports that stress the importance of screening high-risk groups (i.e. siblings of index cases and first degree relatives, patients with Type I diabetes, patients with Downs syndrome, patients with IgA deficiency) will be highlighted. The identification of the most sensitive and specific screening tests will be summarized with an explanation of special situations that affect the interpretation of these tests. Finally, the long-term morbidities associated with CD will be characterized supporting the case for early diagnosis and treatment. SUMMARY: The implications of these recent findings are of tremendous importance for both pediatricians and internists. Screening of high-risk groups, and of patients with the common symptoms of irritable bowel syndrome, iron deficiency anemia, unexplained arthritis, and even chronic elevations of aminotransferases is becoming the accepted standard of practice. Much research remains to be done to further refine our understanding of CD, and to devise more effective strategies for treatment, compliance, and prevention of long-term complications.


Asunto(s)
Enfermedad Celíaca/genética , Adenocarcinoma/etiología , Enfermedades Autoinmunes/etiología , Enfermedad Celíaca/complicaciones , Enfermedad Celíaca/diagnóstico , Niño , Antígenos HLA-DQ/genética , Humanos , Inmunoglobulina A/metabolismo , Linfoma no Hodgkin/etiología , Osteoporosis/complicaciones , Factores de Riesgo
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