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1.
Diabet Med ; 25(7): 782-7, 2008 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-18644064

RESUMEN

AIMS: Hepatocyte nuclear factor 1B (HNF1B) gene mutation carriers have a systemic disease characterized by congenital malformations in the urogenital tract, diabetes mellitus of maturity-onset diabetes of the young type and dysfunction of the liver and exocrine pancreas. We aimed to investigate pancreatic structure and exocrine function in carriers of HNF1B mutations. METHODS: We studied five subjects from two families with the previously reported mutation R137_K161del and the novel mutation F148L in HNF1B. All patients underwent computed tomography (CT) and magnetic resonance cholangiopancreatography (MRCP). We measured faecal elastase and serum vitamins D and E. RESULTS: One of the mutation carriers reported abdominal symptoms. All five subjects had faecal elastase deficiency, three had vitamin D deficiency and two had vitamin E deficiency. Neither CT nor MRCP depicted tissue corresponding to the pancreatic body and tail in the five mutation carriers, indicating agenesis of the dorsal pancreas. The head of the pancreas was slightly atrophic but had normal X-ray attenuation at CT in all patients. CONCLUSIONS: Agenesis of the pancreatic body and tail and pancreatic exocrine dysfunction are parts of the phenotype in HNF1B mutation carriers. This strengthens the evidence for a critical role of HNF1B in development and differentiation of at least the dorsal pancreas.


Asunto(s)
Diabetes Mellitus Tipo 2/genética , Factor Nuclear 1-beta del Hepatocito/genética , Mutación/genética , Páncreas/anomalías , Adolescente , Adulto , Niño , Femenino , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Páncreas Exocrino/patología , Linaje
2.
Aliment Pharmacol Ther ; 48(2): 179-189, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29851098

RESUMEN

BACKGROUND: Primary sclerosing cholangitis is a progressive liver disease with a remarkably variable course. Biomarkers of disease activity or prognostic models predicting outcome at an individual level are currently not established. AIM: To evaluate the prognostic utility of four biomarkers of basement membrane and interstitial extracellular matrix remodeling in patients with primary sclerosing cholangitis. METHODS: Serum samples were available from 138 large-duct primary sclerosing cholangitis patients (of which 102 [74%] with IBD) recruited 2008-2012 and 52 ulcerative colitis patients (controls). The median follow-up time was 2.2 (range 0-4.3) years. Specific biomarkers of type III and V collagen formation (PRO-C3 and PRO-C5, respectively) and type III and IV collagen degradation (C3M and C4M, respectively) were assessed. The Enhanced Liver Fibrosis test, including procollagen type III N-terminal peptide, tissue inhibitor of metalloproteinase-1 and hyaluronic acid was assessed for comparison. RESULTS: All markers were elevated in primary sclerosing cholangitis compared to ulcerative colitis patients (P < 0.001). PRO-C3 showed the largest difference between the two groups with a threefold increase in primary sclerosing cholangitis compared to ulcerative colitis patients. Patients with high baseline serum levels of all markers, except C3M, had shorter survival compared to patients with low baseline serum levels (P < 0.001). Combining PRO-C3 and PRO-C5 the odds ratio for predicting transplant-free survival was 47 compared to the Enhanced Liver Fibrosis test's odds ratio of 11. CONCLUSIONS: Extracellular matrix remodeling is elevated in primary sclerosing cholangitis patients compared to ulcerative colitis patients. Furthermore, the interstitial matrix marker PRO-C3 was identified as a potent prognostic marker and an independent predictor of transplant-free survival in primary sclerosing cholangitis.


Asunto(s)
Biomarcadores/sangre , Colangitis Esclerosante/diagnóstico , Colangitis Esclerosante/mortalidad , Matriz Extracelular/metabolismo , Adolescente , Adulto , Anciano , Colangitis Esclerosante/sangre , Colangitis Esclerosante/terapia , Colitis Ulcerosa/sangre , Colitis Ulcerosa/diagnóstico , Colitis Ulcerosa/mortalidad , Progresión de la Enfermedad , Matriz Extracelular/patología , Femenino , Humanos , Ácido Hialurónico/sangre , Cirrosis Hepática/sangre , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/mortalidad , Cirrosis Hepática/terapia , Trasplante de Hígado , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/sangre , Valor Predictivo de las Pruebas , Procolágeno/sangre , Pronóstico , Análisis de Supervivencia , Inhibidor Tisular de Metaloproteinasa-1/sangre , Adulto Joven
3.
Mucosal Immunol ; 9(6): 1455-1465, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-26982597

RESUMEN

Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency characterized by low immunoglobulin (Ig)G and IgA, and/or IgM. In addition to bacterial infections, a large subgroup has noninfectious inflammatory and autoimmune complications. We performed 16S ribosomal RNA-based profiling of stool samples in 44 CVID patients, 45 patients with inflammatory bowel disease (disease controls), and 263 healthy controls. We measured plasma lipopolysaccharide (LPS) and markers of immune cell activation (i.e., soluble (s) CD14 and sCD25) in an expanded cohort of 104 patients with CVID and in 30 healthy controls. We found a large shift in the microbiota of CVID patients characterized by a reduced within-individual bacterial diversity (alpha diversity, P<0.001) without obvious associations to antibiotics use. Plasma levels of both LPS (P=0.001) and sCD25 (P<0.0001) were elevated in CVID, correlating negatively with alpha diversity and positively with a dysbiosis index calculated from the taxonomic profile. Low alpha diversity and high dysbiosis index, LPS, and immune markers were most pronounced in the subgroup with inflammatory and autoimmune complications. Low level of IgA was associated with decreased alpha diversity, but not independently from sCD25 and LPS. Our findings suggest a link between immunodeficiency, systemic immune activation, LPS, and altered gut microbiota.


Asunto(s)
Inmunodeficiencia Variable Común/inmunología , Inmunodeficiencia Variable Común/microbiología , Disbiosis/inmunología , Microbioma Gastrointestinal/inmunología , Lipopolisacáridos/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biodiversidad , Biomarcadores , Estudios de Casos y Controles , Femenino , Humanos , Inmunoglobulina A/inmunología , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/microbiología , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Activación de Linfocitos/inmunología , Masculino , Persona de Mediana Edad , Linfocitos T/inmunología , Linfocitos T/metabolismo , Adulto Joven
4.
Aliment Pharmacol Ther ; 39(3): 282-301, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24372568

RESUMEN

BACKGROUND: Despite considerable advances over the last two decades in the molecular understanding of cholestasis and cholestatic liver disease, little improvement has been made in diagnostic tools and therapeutic strategies. AIMS: To critically review controversial aspects of the scientific basis for common clinical practice in primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) and to discuss key ongoing challenges to improve patient management. METHODS: We performed a literature search using PubMed and by examining the reference lists of relevant review articles related to the clinical management of PBC and PSC. Articles were considered on the background of the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD) practice guidelines and clinical experience of the authors. RESULTS: Ongoing challenges in PBC mainly pertain to the improvement of medical therapy, particularly for patients with a suboptimal response to ursodeoxycholic acid. In PSC, development of medical therapies and sensitive screening protocols for cholangiocarcinoma represent areas of intense research. To rationally improve patient management, a better understanding of pathogenesis, including complications like pruritis and fatigue, is needed and there is a need to identify biomarker end-points for treatment effect and prognosis. Timing of liver transplantation and determining optimal regimens of immunosuppression post-liver transplantation will also benefit from better appreciation of pre-transplant disease mechanisms. CONCLUSION: Controversies in the management of PBC and PSC relate to topics where evidence for current practice is weak and further research is needed.


Asunto(s)
Colangitis Esclerosante/terapia , Cirrosis Hepática Biliar/terapia , Trasplante de Hígado/métodos , Neoplasias de los Conductos Biliares/diagnóstico , Neoplasias de los Conductos Biliares/patología , Conductos Biliares Intrahepáticos/patología , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/patología , Colangitis Esclerosante/diagnóstico , Colangitis Esclerosante/fisiopatología , Humanos , Terapia de Inmunosupresión/métodos , Cirrosis Hepática Biliar/diagnóstico , Cirrosis Hepática Biliar/fisiopatología , Pronóstico , Factores de Tiempo , Ácido Ursodesoxicólico/uso terapéutico
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