As the population that is infected with the hepatitis C virus (HCV) ages, the number of patients with decompensated cirrhosis is expected to increase.
We conducted a phase 3, open-label study ...involving both previously treated and previously untreated patients infected with HCV genotypes 1 through 6 who had decompensated cirrhosis (classified as Child-Pugh-Turcotte class B). Patients were randomly assigned in a 1:1:1 ratio to receive the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir once daily for 12 weeks, sofosbuvir-velpatasvir plus ribavirin for 12 weeks, or sofosbuvir-velpatasvir for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy.
Of the 267 patients who received treatment, 78% had HCV genotype 1, 4% genotype 2, 15% genotype 3, 3% genotype 4, and less than 1% genotype 6; no patients had genotype 5. Overall rates of sustained virologic response were 83% (95% confidence interval CI, 74 to 90) among patients who received 12 weeks of sofosbuvir-velpatasvir, 94% (95% CI, 87 to 98) among those who received 12 weeks of sofosbuvir-velpatasvir plus ribavirin, and 86% (95% CI, 77 to 92) among those who received 24 weeks of sofosbuvir-velpatasvir. Post hoc analysis did not detect any significant differences in rates of sustained virologic response among the three study groups. Serious adverse events occurred in 19% of patients who received 12 weeks of sofosbuvir-velpatasvir, 16% of those who received 12 weeks of sofosbuvir-velpatasvir plus ribavirin, and 18% of those who received 24 weeks of sofosbuvir-velpatasvir. The most common adverse events were fatigue (29%), nausea (23%), and headache (22%) in all patients and anemia (31%) in the patients receiving ribavirin.
Treatment with sofosbuvir-velpatasvir with or without ribavirin for 12 weeks and with sofosbuvir-velpatasvir for 24 weeks resulted in high rates of sustained virologic response in patients with HCV infection and decompensated cirrhosis. (Funded by Gilead Sciences; ASTRAL-4 ClinicalTrials.gov number, NCT02201901.).
Summary
Background
Butyrate, propionate and acetate are short chain fatty acids (SCFA), important for maintaining a healthy colon and are considered as protective in colorectal carcinogenesis. ...However, they may also regulate immune responses and the composition of the intestinal microbiota. Consequently, their importance in a variety of chronic inflammatory diseases is emerging.
Aims
To review the physiology and metabolism of SCFA in humans, cellular and molecular mechanisms by which SCFA may act in health and disease, and approaches for therapeutic delivery of SCFA.
Methods
A PubMed literature search was conducted for clinical and pre‐clinical studies using search terms: ‘dietary fibre’, short‐chain fatty acids’, ‘acetate’, ‘propionate’, ‘butyrate’, ‘inflammation’, ‘immune’, ‘gastrointestinal’, ‘metabolism’.
Results
A wide range of pre‐clinical evidence supports roles for SCFA as modulators of not only colonic function, but also multiple inflammatory and metabolic processes. SCFA are implicated in many autoimmune, allergic and metabolic diseases. However, translating effects of SCFA from animal studies to human disease is limited by physiological and dietary differences and by the challenge of delivering sufficient amounts of SCFA to the target sites that include the colon and the systemic circulation. Development of novel targeted approaches for colonic delivery, combined with postbiotic supplementation, may represent desirable strategies to achieve adequate targeted SCFA delivery.
Conclusions
There is a large array of potential disease‐modulating effects of SCFA. Adequate targeted delivery to the sites of action is the main limitation of such application. The ongoing development and evaluation of novel delivery techniques offer potential for translating promise to therapeutic benefit.
Summary
Background
Beneficial effects of carbohydrate fermentation on gastrointestinal health are well established. Conversely, protein fermentation generates harmful metabolites but their relevance ...to gastrointestinal health is poorly understood.
Aim
To review the effects of increased protein fermentation on biomarkers of colonic health, factors influencing fermentative activity and potential for dietary modulation to minimise detrimental effects.
Methods
A literature search was performed in PubMed, Medline, EMBASE and Google scholar for clinical and pre‐clinical studies using search terms – ‘dietary protein’, ‘fermentation’, ‘putrefaction’, ‘phenols’, ‘sulphide’, ‘branched‐chain fatty acid’, ‘carbohydrate fermentation’, ‘gastrointestinal’.
Results
High protein, reduced carbohydrate diets alter the colonic microbiome, favouring a potentially pathogenic and pro‐inflammatory microbiota profile, decreased short‐chain fatty acid production and increased ammonia, phenols and hydrogen sulphide concentrations. These metabolites largely compromise the colonic epithelium structure, causing mucosal inflammation but may also directly modulate the enteric nervous system and intestinal motility. Increased protein fermentation as a result of a high‐protein intake can be attenuated by addition of oligosaccharides, resistant starch and nonstarch polysaccharides and a reduction in total protein or specifically, aromatic and sulphur‐containing amino acids. These factors may have clinical importance as novel therapeutic approaches to problems, in which protein fermentation may be implicated, such as malodorous flatus, irritable bowel syndrome, ulcerative colitis and prevention of colorectal cancer.
Conclusions
The direct clinical relevance of excessive protein fermentation in the pathogenesis of irritable bowel syndrome, malodorous flatus and ulcerative colitis are underexplored. Manipulating dietary carbohydrate and protein intake have potential therapeutic applications in such settings and warrant further clinical studies.
Summary
Background Functional gut symptoms are induced by inclusion and reduced by dietary restriction of poorly absorbed short‐chain carbohydrates (FODMAPs), but the mechanisms of action remain ...untested.
Aims To determine the effect of dietary FODMAPs on the content of water and fermentable substrates of ileal effluent.
Methods Twelve ileostomates without evidence of small intestinal disease undertook two 4‐day dietary periods, comprising diets differing only in FODMAP content in a randomized, cross‐over, single‐blinded intervention study. Daytime (14 h) ileal effluent was collected on day four of each diet. Patients rated effluent volume and consistency on a 10‐cm visual analogue scale. The FODMAP content of the diet and effluent was measured.
Results Ingested FODMAPs of 32% (range 6–73%) was recovered in the high FODMAP diet effluent. Effluent collection weight increased by a mean of 22% (95% CI, 5–39), water content by 20% (2–38%) and dry weight by 24% (4–43%) with the high compared to low FODMAP diet arm. Output increased by 95 (28–161) mL. Volunteers perceived effluent consistency was thicker (95% CI, 0.6–1.9) with the low FODMAP diet than with the high FODMAP diet (3.5–6.1; P = 0.006).
Conclusions These data support the hypothetical mechanism; FODMAPs increase delivery of water and fermentable substrates to the proximal colon.
Wheat- and gluten-containing products are often blamed for triggering a wide range of gastrointestinal symptoms, and this has fueled demand for gluten-free products worldwide. The best studied ...‘gluten intolerance’ is coeliac disease, an auto-immune disease that affects the small intestine. Coeliac disease occurs in 1% of the population and requires strict, life-long avoidance of gluten-containing foods as the only medical treatment. There is a larger group of individuals (around 10–15% of the population) who report a wide-range of gastrointestinal symptoms that respond well to a ‘gluten-free diet’, but who do not have coeliac disease – so called ‘non-coeliac gluten sensitivity (NCGS)’. The team at Monash University has identified other factors in gluten-containing foods that may be responsible for symptoms in this group of individuals with so-called, NCGS. We have evidence that certain poorly absorbed short chain carbohydrates (called FODMAPs) present in many gluten-containing food products, induce symptoms of abdominal pain, bloating, wind and altered bowel habit (associated with irritable bowel syndrome, IBS). Our research has shown that FODMAPs, and not gluten, triggered symptoms in NCGS. Going forward, there are great opportunities for the food industry to develop low FODMAP products for this group, as choice of grain variety and type of food processing technique can greatly reduce the FODMAP levels in foods. The use of sourdough cultures in bread making has been shown to reduce the quantities of FODMAPs (mostly fructan), resulting in bread products that are well tolerated by patients with IBS. Greater interaction between biomedical- and food-scientists will improve understanding about the clinical problems many consumers face, and lead to the development of food products that are better tolerated by this group.
Embolic strokes of undetermined source represent 20% of ischemic strokes and are associated with a high rate of recurrence. Anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, may ...result in a lower risk of recurrent stroke than aspirin.
We compared the efficacy and safety of rivaroxaban (at a daily dose of 15 mg) with aspirin (at a daily dose of 100 mg) for the prevention of recurrent stroke in patients with recent ischemic stroke that was presumed to be from cerebral embolism but without arterial stenosis, lacune, or an identified cardioembolic source. The primary efficacy outcome was the first recurrence of ischemic or hemorrhagic stroke or systemic embolism in a time-to-event analysis; the primary safety outcome was the rate of major bleeding.
A total of 7213 participants were enrolled at 459 sites; 3609 patients were randomly assigned to receive rivaroxaban and 3604 to receive aspirin. Patients had been followed for a median of 11 months when the trial was terminated early because of a lack of benefit with regard to stroke risk and because of bleeding associated with rivaroxaban. The primary efficacy outcome occurred in 172 patients in the rivaroxaban group (annualized rate, 5.1%) and in 160 in the aspirin group (annualized rate, 4.8%) (hazard ratio, 1.07; 95% confidence interval CI, 0.87 to 1.33; P=0.52). Recurrent ischemic stroke occurred in 158 patients in the rivaroxaban group (annualized rate, 4.7%) and in 156 in the aspirin group (annualized rate, 4.7%). Major bleeding occurred in 62 patients in the rivaroxaban group (annualized rate, 1.8%) and in 23 in the aspirin group (annualized rate, 0.7%) (hazard ratio, 2.72; 95% CI, 1.68 to 4.39; P<0.001).
Rivaroxaban was not superior to aspirin with regard to the prevention of recurrent stroke after an initial embolic stroke of undetermined source and was associated with a higher risk of bleeding. (Funded by Bayer and Janssen Research and Development; NAVIGATE ESUS ClinicalTrials.gov number, NCT02313909 .).
Summary
Background
Gut‐directed hypnotherapy is being increasingly applied to patients with irritable bowel syndrome (IBS) and to a lesser extent, inflammatory bowel disease (IBD).
Aim
To review the ...technique, mechanisms of action and evidence for efficacy, and to identify gaps in the understanding of gut‐directed hypnotherapy as a treatment for IBS and IBD.
Methods
A review of published literature and a systematic review of clinical trials in its application to patients with IBS and IBD were performed.
Results
Gut‐directed hypnotherapy is a clearly described technique. Its potential mechanisms of action on the brain‐gut axis are multiple with evidence spanning psychological effects through to physiological gastrointestinal modifications. Six of seven randomised IBS studies reported a significant reduction (all P < 0.05) in overall gastrointestinal symptoms following treatment usually compared to supportive therapy only. Response rates amongst those who received gut‐directed hypnotherapy ranged between 24% and 73%. Efficacy was maintained long‐term in four of five studies. A therapeutic effect was also observed in the maintenance of clinical remission in patients with ulcerative colitis. Uncontrolled trials supported the efficacy and durability of gut‐directed hypnotherapy in IBS. Gaps in understanding included to whom and when it should be applied, the paucity of adequately trained hypnotherapists, and the difficulties in designing well controlled‐trials.
Conclusions
Gut‐directed hypnotherapy has durable efficacy in patients with IBS and possibly ulcerative colitis. Whether it sits in the therapeutic arsenal as a primary and/or adjunctive therapy cannot be ascertained on the current evidence base. Further research into efficacy, mechanisms of action and predictors of response is required.
Summary
Background Fructose malabsorption, lactose malabsorption and an early rise in breath hydrogen after lactulose (ERBHAL) may play roles in induction of symptoms in gastrointestinal conditions.
...Aim To compare prevalence and interactions of fructose malabsorption, lactose malabsorption and ERBHAL among healthy subjects and those with chronic intestinal disorders using consistent breath hydrogen testing methodologies.
Methods Consecutive series of Caucasian patients with Crohn’s disease (n = 91), ulcerative colitis (56), functional gastrointestinal disorders (FGID) (201), coeliac disease (136) and 71 healthy volunteers underwent breath hydrogen testing using lactulose, fructose and lactose.
Results Early rise in breath hydrogen after lactulose occurred more commonly in healthy controls (39%) than in Crohn’s disease (20%) and untreated coeliac disease (14%; P < 0.008), but not FGID (27%), ulcerative colitis (26%) or treated coeliac disease (29%). Fructose malabsorption was more frequent in Crohn’s disease (61%) than other groups (33–44%, P < 0.05). Lactose malabsorption was most common in Crohn’s disease (42%) and ulcerative colitis (40%) and uncommon (10%) in 79 patients with newly diagnosed coeliac disease. In Crohn’s disease, concurrent Fructose malabsorption and lactose malabsorption was most common (29%), and the association of fructose malabsorption with ERBHAL seen overall (62%) was not observed (36%, P < 0.0001).
Conclusions Carbohydrate malabsorption and ERBHAL are normal physiological phenomena. The abnormal patterns observed in Crohn’s disease may have pathogenic importance.
Summary
Background
Current evidence suggests that many patients with self‐reported non‐coeliac gluten sensitivity (NCGS) retain gastrointestinal symptoms on a gluten‐free diet (GFD) but continue to ...restrict gluten as they report ‘feeling better’.
Aim
To investigate the notion that a major effect of gluten in those with NCGS is on mental state and not necessarily on gastrointestinal symptoms.
Methods
Twenty‐two subjects (24–62 years, five male) with irritable bowel syndrome who had coeliac disease excluded but were symptomatically controlled on a GFD, undertook a double‐blind cross‐over study. Participants randomly received one of three dietary challenges for 3 days, followed by a minimum 3‐day washout before crossing over to the next diet. Challenge gluten‐free food was supplemented with gluten (16 g/day), whey (16 g/day) or not supplemented (placebo). End‐points included mental state as assessed by the Spielberger State Trait Personality Inventory (STPI), cortisol secretion and gastrointestinal symptoms.
Results
Gluten ingestion was associated with higher overall STPI state depression scores compared to placebo M = 2.03, 95% CI (0.55–3.51), P = 0.010 but not whey M = 1.48, 95% CI (−0.14 to 3.10), P = 0.07. No differences were found for other STPI state indices or for any STPI trait measures. No difference in cortisol secretion was identified between challenges. Gastrointestinal symptoms were induced similarly across all dietary challenges.
Conclusions
Short‐term exposure to gluten specifically induced current feelings of depression with no effect on other indices or on emotional disposition. Gluten‐specific induction of gastrointestinal symptoms was not identified. Such findings might explain why patients with non‐coeliac gluten sensitivity feel better on a gluten‐free diet despite the continuation of gastrointestinal symptoms.
Summary
Fructose is found widely in the diet as a free hexose, as the disaccharide, sucrose and in a polymerized form (fructans). Free fructose has limited absorption in the small intestine, with up ...to one half of the population unable to completely absorb a load of 25 g. Average daily intake of fructose varies from 11 to 54 g around the world. Fructans are not hydrolysed or absorbed in the small intestine.
The physiological consequences of their malabsorption include increasing osmotic load, providing substrate for rapid bacterial fermentation, changing gastrointestinal motility, promoting mucosal biofilm and altering the profile of bacteria. These effects are additive with other short‐chain poorly absorbed carbohydrates such as sorbitol.
The clinical significance of these events depends upon the response of the bowel to such changes; they have a higher chance of inducing symptoms in patients with functional gut disorders than asymptomatic subjects. Restricting dietary intake of free fructose and/or fructans may have durable symptomatic benefits in a high proportion of patients with functional gut disorders, but high quality evidence is lacking.
It is proposed that confusion over the clinical relevance of fructose malabsorption may be reduced by regarding it not as an abnormality but as a physiological process offering an opportunity to improve functional gastrointestinal symptoms by dietary change.
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