This Month in Gastroenterology

Article Outline

• Oral Budesonide for Maintenance Therapy of Collagenous Colitis
• Ursodeoxycholic Acid in Primary Biliary Cirrhosis
• Chemokine Regulation by MicroRNAs in Active Ulcerative Colitis
• Identity of the Cl/HCO3 Exchanger for Coupled Electroneutral NaCl Absorption in the Small Intestine
• Copyright

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Oral Budesonide for Maintenance Therapy of Collagenous Colitis 

Collagenous colitis is a relatively uncommon cause of chronic diarrhea, with an incidence that is highest in women and increases with age. Although macroscopically normal, microscopic examination of colonic biopsies shows microscopic colitis with a thickened subepithelial collagen band. The etiology of collagenous colitis is unknown, but placebo-controlled trials have established the efficacy of oral budesonide in the acute treatment of symptoms and histologic lesions of collagenous colitis. Although not all patients require long-term therapy to maintain symptomatic remission, relapses after cessation of budesonide therapy are not uncommon. It is unclear whether budesonide therapy is efficacious for prevention of relapses of collagenous colitis.

In this issue of Gastroenterology, Miehlke et al report on a multicenter study from Germany that assessed the efficacy of long-term treatment with oral budesonide on symptoms, histology, and quality of life in collagenous colitis patients. Patients with histologically proven collagenous colitis and >3 stools per day on most days were enrolled in the trial. All patients received initial open-label therapy with oral budesonide 9 mg/d for 6 weeks, to induce remission (no more than 3 stools per day). Subsequently, patients in remission were randomized to 6 months of therapy with budesonide 6 mg/d or matching placebo. Daily diaries were used to assess symptom control. The primary end point was the rate of relapse (defined as >3 stools per day on ≥4 consecutive days) at the end of the 6-month period. Secondary end points were the time to relapse, changes in histology (biopsies obtained after 6 months), and quality-of-life scores.

A total of 48 patients (mean age, 53 years) were enrolled into the study. Clinical remission was obtained in 46 (96%) after on average 6 days of open-label therapy with budesonide 9 mg/d, and these were randomized to active or placebo maintenance therapy. A significantly higher proportion of patients treated with budesonide maintained clinical remission at months 2, 4, and 6 versus placebo (Figure 1). The cumulative rate of relapse was significantly lower with budesonide maintenance therapy compared with placebo (6/23 vs 15/23; P = .02). Induction therapy with budesonide 9 mg once daily was associated with marked improvements in health-related quality of life, and this was maintained during maintenance therapy. Concomitant histologic improvement was seen in the majority of patients, although there was a discrepancy between symptomatic and histologic outcomes for a minor proportion of patients. No serious adverse events occurred during any of the treatment phases.

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• Figure 1. 

  Proportions of patients with clinical remission of collagenous colitis at months 2, 4, and 6 of maintenance therapy with oral budesonide 6 mg once daily or placebo.

The findings of this study therefore demonstrate that oral budesonide is efficacious and well tolerated for maintenance of clinical remission in patients with collagenous colitis. At present, no data are available for maintenance therapy beyond the first 6 months.

See page 1510.

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Ursodeoxycholic Acid in Primary Biliary Cirrhosis 

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease that slowly progresses over time to portal hypertension and cirrhosis. At present, ursodeoxycholic acid (UDCA) is the treatment of choice for PBC. Randomized controlled clinical trials with UDCA in PBC have shown sustained improvement in biochemical parameters, whereas effects on histologic progression, symptoms, need for liver transplantation, and survival have been less consistent. The effects of UDCA on the development or progression of portal hypertension in PBC patients have not been well assessed.

In this issue of Gastroenterology, Huet et al report the results of a long-term follow-up study evaluating the prevalence and prognostic value of portal hypertension in a large cohort of patients with PBC treated with UDCA. The study recruited a total of 132 PBC patients (118 women; mean age, 50 years) who were followed for up to 17 years. Patients were treated with 13–15 mg/kg body weight of UDCA per day. None of the patients had been treated with UDCA before inclusion in the study. Patients had clinical and biochemical follow-up visits at least once a year, and measurement of the portohepatic pressure gradient (PHG) at 2-year intervals. Measurement of free portal vein pressure and free hepatic vein pressure was performed with a thin needle through a percutaneous transhepatic approach under fluoroscopic guidance. The PHG was calculated as the difference between portal vein pressure and hepatic vein pressure.

The mean PHG at inclusion was 7.2 ± 5.8 mmHg. It was >6 mmHg (upper limit of normal) in 46 patients (34.9%) and >12 mmHg (the lower limit for risk of variceal bleeding) in 26 patients (19.7%). The PHG was significantly correlated with the Mayo risk score and liver biopsy stage, but a large variability precluded adequate prediction of portal hypertension from noninvasive parameters.

The first 30 patients were enrolled in a placebo-controlled treatment trial over 2 years, which was suggestive of a positive effect of UDCA treatment on the progression of portal hypertension. Patients were subdivided into 3 groups based on the PHG at inclusion (<6, 6–12, and >12mm Hg; respectively, no, moderate, and severe portal hypertension). With a mean follow-up period of 8.6 years, there was a significant difference between the 3 subgroups in the probability of survival free of liver transplantation (Figure 2). However, the Mayo score was the best predictor of survival.

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• Figure 2. 

  Probability of survival free of liver transplantation in the 3 subgroups of patients while treated with UDCA according to the severity of portal hypertension (PHG <6 [no portal hypertension], 6–12 [moderate portal hypertension], and >12 mmHg [severe portal hypertension]).

Patients were separated into 2 groups according to changes in PHG at the end of the 2nd year of UDCA treatment. The probability of survival free of liver transplantation was significantly higher among those with stable PHG values during the first 2 years of UDCA treatment compared with those with increasing PHG values. In addition, a decreased or stable PHG and normalization of aspartate aminotransferase (AST) levels were predictive of better long-term survival on multivariate analysis. Responders with a stable or decreased PHG and normalized AST levels had a 15-year survival which was similar to that of the age-matched control population.

The present study, therefore, is the first to report the incidence, severity, and prognostic impact of portal hypertension in a large series of patients with PBC. The severity of portal hypertension, which could not be predicted by noninvasive parameters, significantly correlated with long-term survival. In addition, it seemed that changes in the PHG observed while on UDCA treatment for 2 years could be used to identify responders and nonresponders in terms of portal hypertension, with different long-term survival.

See page 1552.

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Chemokine Regulation by MicroRNAs in Active Ulcerative Colitis 

Regulation of the inflammatory processes in inflammatory bowel disease has been intensively studied to find targets that can be manipulated to ameliorate this process for patients. Recently, microRNAs (miRNAs), small noncoding RNAs that cause degradation of mRNAs and inhibit protein translation, have been described that can affect a wide variety of cellular processes, including proliferation, apoptosis, and inflammation. There has been no prior evaluation of expression of miRNAs in human inflammatory bowel disease.

In the study by Wu et al, an miRNA microarray capable of measuring the expression of 553 known miRNAs was utilized to identify differential expression from sigmoid colon biopsies from histologically confirmed active ulcerative colitis (UC) and inactive UC, as well as those from normal healthy subjects and those with irritable bowel syndrome, microscopic colitis, infectious colitis, and chronic active colonic Crohn's disease. Six miRNAs were differentially expressed between active UC and inactive UC, which seemed to be distinct from the other colonic diseases and remained the focus of the study. A specific miRNA, miR-192, expressed predominantly in the epithelium of normal colon, was decreased by 47% in active UC tissues by microarray and reverse transcriptase polymerase chain reaction analysis. To identify potential targets of miR-192, cross-references of expressed colonic epithelial mRNAs at microarray analysis were made, identifying 12 potential epithelial-derived cytokines as potentially regulated by miR-192. Of these 12 chemokines, macrophage inflammatory pepetide-2a (MIP-2a) contained putative binding sites for miRNAs. MIP-2a, which is increased 32-fold relative to normal healthy colon tissue (but was not increased in the other colonic conditions evaluated including inactive UC), and was inversely related to miR-192 expression in 60 colonic biopsies. The authors tested this observation in a cell line in which MIP-2a expression and cytokine secretion was up-regulated by tumor necrosis factor (TNF)-α, a known stimulant for MIP-2a, which significantly decreased miR-192 expression. Using luciferase reporter constructs containing portions of MIP-2a that were predicted to bind miRNAs, endogenous miRNAs reduced luciferase activity that was partially restored by mutating the putative miRNA binding sites in the construct. In TNF-α–treated cells, transfection of miR-192 reduced MIP-2a expression by 53% at 4 hours and protein secretion by 28% by 24 hours after transfection (Figure 3).

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• Figure 3. 

  miR-192 inhibition of macrophage inflammatory peptide-2a (MIP-2a) mRNA and protein expression. TNF-α–induced MIP-2a mRNA expression (A) and protein secretion (B) were significantly reduced in HT29 cells transfected with miR-192 mimic. The control mimic had no effect (*P < .005; **P < .001).

The study indicates that MIP-2a and miR-192 can regulate each other's expression. In active UC, the abundance of MIP-2a presumably down-regulates miR-192, or there may be some dysregulation of miR-192 to allow increase in MIP-2a expression. The role of differentially expressed miRNAs could open other diagnostic and treatment avenues for UC.

See page 1624.

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Identity of the Cl/HCO₃ Exchanger for Coupled Electroneutral NaCl Absorption in the Small Intestine 

Transepithelial NaCl absorption in the small intestine is dependent on the coupling of Na/H and Cl/HCO₃ exchangers, and is a principal force for water absorption across the small intestine. Although electroneutral NaCl absorption and water absorption are major physiologic processes in the small intestine, only NHE3 has been identified as the Na/H exchanger component of this process, with the identity of the Cl/HCO₃ exchange speculated.

In the study by Walker et al, the jejunum was studied from mouse knockout models missing 1 of 2 different Cl/HCO₃ exchangers, the down-regulated in adenoma (Dra) Cl/HCO₃ exchanger, which causes congenital chloride-losing diarrhea from the colon, and the Pat-1 Cl/HCO₃ exchanger, which can also exchange sulfate, oxalate, and formate. Nhe3KO mice were also utilized. Steady-state intracellular pH measurements from the jejunum revealed that Pat-1KO mice epithelium were unchanged from wild-type (WT) mice, whereas DraKO epithelium was significantly alkaline and Nhe3KO epithelium was acidic. Pharmacologic inhibition of Dra or Nhe3 in WT jejunal epithelium did not affect pH, in contrast with genetic deletion, suggesting coincident inhibition of the 2 exchangers. Functional activities of WT, DraKO, and Nhe3KO jejunal cells revealed that DraKO epithelium had robust Na/H exchange, and as observed in Nhe3KO mice, most of the exchange is through Nhe3. Nhe3KO mice exhibited substantial Cl/HCO₃ exchange, and by observation in DraKO mice, most Cl/HCO₃ exchange represents Dra activity (Figure 4). Using a compound on the luminal surface that blocks apical Na/H exchange in Pat-1KO mice to isolate Dra Cl/HCO₃ exchange activity, Dra activity was reduced in half, indicating that half of activity is dependent on Nhe3 and half independent of Nhe3 for net HCO₃⁻ secretion, and suggests coupling of the Nhe3 and Dra exchangers. Utilizing ²²Na³⁶Cl isotopes for transepithelial flux studies, DraKO jejunal epithelium showed complete absence of Cl⁻ absorption compared with WT, indicating that Dra is the major pathway for Cl⁻ absorption. Dra immunostaining in murine jejunum was present, but modest when compared with the expression in colon. There were no compensatory up-regulation of Pat-1, Nhe3, or Cftr in DraKO mice.

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• Figure 4. 

  Functional activities of apical membrane Na⁺/H⁺ and Cl⁻/HCO₃⁻ in intact villous epithelium. (A) Na⁺/H⁺ exchange (Nhe) activity in wild type (WT), down-regulated in adenoma (Dra) knockout (KO), and Nhe3 KO jejunum as measured by removal and replacement of luminal Na⁺ (representative of 3 mice). (B) Cl⁻/HCO₃⁻ exchange activity in WT, Nhe3 KO, and Dra KO measured by removal and replacement of luminal Cl⁻ (representative of 3 mice).

This study indicates that Dra is the Cl/HCO₃ exchange that provides >80% of basal Cl⁻ absorption in the small intestine and is coupled to Nhe3 for electroneutral NaCl absorption. Manipulation of Dra activity could be considered in secretory diarrheas or cystic fibrosis.

See page 1645.