Liver disease accompanied by enteropathy in common variable immunodeficiency: Common pathophysiological mechanisms.

Common variable immunodeficiency (CVID) is one of the inborn errors of immunity that have the greatest clinical impact. Rates of morbidity and mortality are higher in patients with CVID who develop liver disease than in those who do not. The main liver disorder in CVID is nodular regenerative hyperplasia (NRH), the cause of which remains unclear and for which there is as yet no treatment. The etiology of liver disease in CVID is determined by analyzing the liver injury and the associated conditions. The objective of this study was to compare CVID patients with and without liver-spleen axis abnormalities in terms of clinical characteristics, as well as to analyze liver and duodenal biopsies from those with portal hypertension (PH), to elucidate the pathophysiology of liver injury. Patients were divided into three groups: Those with liver disease/PH, those with isolated splenomegaly, and those without liver-spleen axis abnormalities. Clinical and biochemical data were collected. Among 141 CVID patients, 46 (32.6%) had liver disease/PH; 27 (19.1%) had isolated splenomegaly; and 68 (48.2%) had no liver-spleen axis abnormalities. Among the liver disease/PH group, patients, even those with mild or no biochemical changes, had clinical manifestations of PH, mainly splenomegaly, thrombocytopenia, and esophageal varices. Duodenal celiac pattern was found to correlate with PH (p < 0.001). We identified NRH in the livers of all patients with PH (n = 11). Lymphocytic infiltration into the duodenal mucosa also correlated with PH. Electron microscopy of liver biopsy specimens showed varying degrees of lymphocytic infiltration and hepatocyte degeneration, which is a probable mechanism of lymphocyte-mediated cytotoxicity against hepatocytes and enterocytes. In comparison with the CVID patients without PH, those with PH were more likely to have lymphadenopathy (p < 0.001), elevated ß2-microglobulin (p < 0.001), low B-lymphocyte counts (p < 0.05), and low natural killer-lymphocyte counts (p < 0.05). In CVID patients, liver disease/PH is common and regular imaging follow-up is necessary. These patients have a distinct immunological phenotype that may predispose to liver and duodenal injury from lymphocyte-mediated cytotoxicity. Further studies could elucidate the cause of this immune-mediated mechanism and its treatment options.

Lactase persistence/non-persistence variants, C/T_13910 and G/A_22018, as a diagnostic tool for lactose intolerance in IBS patients.

BACKGROUND: Irritable bowel syndrome (IBS) is a symptom-based disorder characterized by abdominal pain related to altered bowel habit. We evaluated the predictive power of 2 genetic markers of hypolactasia, C/T_13910 and G/A_22018, in IBS patients with and without lactose intolerance in order to gain insight into the role of lactose intolerance in IBS. METHODS: Seventy five patients (59F/16M, mean age: 49.6+/-14.2 years) with an IBS diagnosis based on Rome II criteria and 272 healthy individuals, where 74 (58F/16M, 54.1+/-10.9 years) were matched-controls, were evaluated. IBS and healthy individuals were genotyped for the C/T_13910 and G/A_22018 polymorphisms nearby the lactase-phlorizin hydrolase gene. Hydrogen breath test (HBT) with gas chromatography was performed in IBS patients to assess for lactose intolerance. RESULTS: Of the 75 IBS patients, 28 (37%) were defined as lactose intolerants. The grade/severity of symptoms after an oral lactose load were positively correlated to the expiratory H2 excretion (P<0.001). Alleles and genotypes frequencies from C/T_13910 and G/A_22018 were not significantly different between IBS patients and control individuals (P>0.05;NS). Presence of the C and G allele were positively associated with a higher expiratory hydrogen excretion and more intense gastrointestinal symptoms (P<0.001). Considering these polymorphisms as a diagnostic test for lactose intolerance in IBS patients, presence of the CC and GG genotypes were estimated to have, a sensitivity of 100% and 96%, respectively; and a specificity of 83% and 79%, positive predictive value of 76% and 73%, and negative predictive value of 100% and 97%. CONCLUSIONS: In IBS patients, genotyping of C/T_13910 and G/A_22018 polymorphisms predicts gastrointestinal symptoms after lactose ingestion and are a diagnostic tool for lactose intolerance.

Ursodeoxycholic acid ameliorates experimental ileitis counteracting intestinal barrier dysfunction and oxidative stress.

The aim of this study was to evaluate the effect of ursodeoxycholic acid (UDCA) on intestinal permeability (IP) and reactive oxygen species (ROS) generation in indomethacin-induced enteropathy, a well-known experimental model of Crohn's disease. Seventy-eight male Wistar rats were randomly assigned to receive indomethacin, indomethacin + UDCA, or vehicles. Indomethacin induced a significant increase in the fraction of urinary excretion of 51Cr-EDTA following oral administration (7.9 +/- 1.3 vs 2.3 +/- 0.2%; P < 0.05) and lucigenin-amplified chemiluminescence in intestinal fragments ex vivo (10.1 +/- 1.9 vs 2.6 +/- 0.4 cpm x 10(3)/mg; P < 0.05) compared to controls. UDCA significantly reversed these effects (P < 0.05), without being incorporated in biliary bile acid composition (HPLC analysis). These findings support a local protective effect of UDCA in experimental ileitis by the modulation of intestinal barrier dysfunction and oxidative stress. In short, they provide insights into mechanisms of action of UDCA in intestinal inflammation and a new perspective on the treatment of Crohn's disease.