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Most Popular Gastroenterology and CGH Papers from 2013

Most Popular Gastroenterology and CGH Papers from 2013

As we begin 2014, we can’t help but look back at 2013 and all the incredible discoveries that were made by gastroenterology and hepatology researchers. Based on the year’s most-downloaded original research articles from Gastroenterology and CGH, exciting things are happening in research on inflammatory bowel diseases, gluten sensitivity, and other digestive disorders.

GI Tract

The most-downloaded article from Gastroenterology in 2013 came from Maria I. Vazquez–Roque et al. who reported that a gluten-free diet reduces the number of bowel movements/day and intestinal permeability, compared with a gluten-containing diet, in patients with diarrhea-predominant irritable bowel syndrome (IBS-D). The authors concluded that gluten alters bowel barrier functions in patients with IBS-D—particularly in those that are HLA-DQ2/8-positive.

However, gluten is not the culprit in all GI disorders. Jessica R. Biesiekierski et al. showed that rapidly fermented poorly absorbed short-chain carbohydrates (FODMAPs), rather than gluten or other wheat proteins, cause symptoms in people who do not have celiac disease but feel better on gluten-free diets.

In the third-most downloaded Gastroenterology article of 2013, Jacques Cosnes et al. reported that administration of azathioprine within 6 months of diagnosis of Crohn’s disease was no more effective than conventional management (giving azathioprine only to patients with corticosteroid dependency, chronic active disease with frequent flares, poor responses to corticosteroids, or those who developed severe perianal disease) in increasing time of clinical remission.

Although early administration of azathioprine does not appear to benefit patients with Crohn’s disease, cannabis does. In the most-downloaded CGH article of 2013, Timna Naftali et al. presented results from the first placebo-controlled study of cannabis for this disease. Their trial showed that 8 weeks of smoking THC-rich cannabis cigarettes significantly reduced disease activity scores and led to clinical responses in 90% of patients.

Almost as many readers downloaded the validation of the ulcerative colitis index of severity by Sunil Samuel et al., which correlated the index measurements of disease activity. Equally popular was a retrospective cohort study from Maryam Derogar et al. reporting that in patients with cardiovascular disease, discontinuation of low-dose aspirin therapy after peptic ulcer bleeding increases risk of death and acute cardiovascular events almost 7-fold.

Going into 2014, we anticipate more exciting insights into these disorders and others. As always, the AGA Journals Blog will keep you updated on the latest GI and hepatology research discoveries.

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Can We Treat Diarrhea by Stimulating Na+ Absorption?

Can We Treat Diarrhea by Stimulating Na+ Absorption?

Drugs designed to increase intestinal absorption of sodium might be the best approach for treatment of diarrheal diseases, according to the Advances in Translational Science article in the January issue of Clinical Gastroenterology and Hepatology.

Acute diarrheal diseases are the second leading cause of of death in children under 5 years old. Worldwide, there are an estimated 1.7 billion cases, and diarrhea is responsible for killing approximately 760, 000 children every year. In the US,  adults experience 99 million episodes of acute diarrhea or gastroenteritis, resulting in about 8 million physician visits and more than 250,000 hospital admissions each year (1.5% of adult hospitalizations).

There are some drugs for treatment of diarrhea, including opiates, which only moderately decrease stool output; racecadotril, which has inconsistent effects on acute diarrhea in children; and crofelemer—a CI– channel inhibitor approved by the FDA for treatment of HIV-associated diarrhea.

However, oral rehydration solutions still account for the greatest reductions in mortality among children in developing countries. These solutions rehydrate patients but don’t necessarily reduce stool output or length of illness. More effective drugs are needed.

Diarrheal diseases develop via altered intestinal transport of electrolytes and water. Epithelial cells in the villus of the small intestine or surface and upper crypt of the colon mostly absorb Na+, whereas those in the lower crypt primarily secrete Cl– and HCO3– . Infectious agents that cause diarrhea alter electrolyte transport and intestinal permeability by inhibiting Na+ absorption and stimulating anion and K+ secretion (see figure).

The plasma membrane of each cell is divided into the apical (brush border [BB]) and basolateral (serosal) membrane. Specific membrane transport proteins segregate to either the apical or basolateral side of these cells, and are required for transepithelial electrolyte transport (absorption and secretion). This transport processes contributes to intestinal Na+ absorption. Reagents are needed to either reverse the changes in transport that occur in diarrhea and/or stimulate other transport processes that can compensate for these changes.

The plasma membrane of each intestinal epitheial cell is divided into the apical (brush border) and basolateral membrane. Specific membrane transport proteins segregate to either side of these cells, and are required for electrolyte transport (absorption and secretion), which contributes to intestinal Na+ absorption. Reagents are needed to either reverse the changes in transport that occur in diarrhea and/or stimulate other transport processes to compensate for these changes.

Varsha Singh et al. review drugs that might be used to treat diarrhea by stimulating intestinal Na+ absorption. They describe the molecular mechanisms by which intestinal water and Na+ are absorbed in healthy people and how those processes change during development of diarrhea.

Singh et al. discuss the therapeutic potential of agents designed to stimulate intestinal absorption of Na+. These would alter activities of the brush border Na+/H+ exchanger (NHE3), the Cl–/HCO3– exchanger SLC26A3 (DRA), the Na+ D-glucose linked co-transporter 1 (SGLT1), or the epithelial Na+ channel (ENaC).

Another approach to increase intestinal absorption of Na+ involves addition of zinc to oral rehydration solutions—zinc inhibits stimulated Cl– secretion to reduce the duration of diarrhea. Furthermore, the intestinal calcium-sensing receptor (CaSR) regulates intestinal secretion and absorption. Stimulating the CaSR with either calcium or sensitizing (calcimimetic) compounds reverses changes in colonic Na+ absorption and Cl– secretion caused by bacterial toxins.

Singh et al. explain that drugs currently approved to stimulate NaCl absorption are restricted to analogues of physiologic regulators including mu agonist opiates, somatostatin, and clonidine (an alphaadrenergic receptor agonist). These agonists have all been used to treat diarrhea but are limited by side effects, high costs, requirement for parenteral administration, or limited potency. Although modifications of these classes of drugs might be developed, new ways to stimulate Na+ absorption are needed.

However, the authors conclude that drug development is a slow process, and no lead compounds that stimulate neutral NaCl absorption are likely to emerge as useful treatments of diarrhea any time soon.

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Mapping HCV Infection in the Liver

Mapping HCV Infection in the Liver

Using single-cell laser capture and high-resolution analysis, researchers show that hepatitis C virus (HCV) infects hepatocytes in the human liver in nonrandom clusters, whereas expression of anti-viral molecules is scattered among hepatocytes. The findings are presented in the December issue of Gastroenterology.

HCV predominantly infects hepatocytes, but most hepatocytes in the liver remain uninfected—HCV antigens have been observed to cluster. This suggests a localized mechanism of intra-hepatic propagation and control. Understanding this process could increase our understanding of infection and strategies for treatment.

Abraham J. Kandathil et al. analyzed liver samples from 4 patients with chronic HCV infection to estimate the proportion of infected hepatocytes and the amount of HCV RNA per cell using single-cell laser capture microdissection (LCM).

LCM unites light microscopy with a low-intensity ultraviolet laser, allowing researchers to ensnare enriched cellular material from tissue samples while preserving positional information, because the tissue is not homogenized. Kandathil et al. made improvements to the technique to increase its resolution, developing single-cell LCM, which allowed them to compare host and viral RNAs.

Studying viral replication in liver tissues from patients with chronic HCV infections, Kandathil et al. estimated the amount of HCV RNA per infected hepatocyte, to determine how the virus spreads in vivo and localize host cell expression of antiviral molecules.

The authors used their data to create a map of viral RNA in hepatocytes, which they called the viroscape. The viroscape shows hepatocytes containing narrow HCV replication peaks surrounded by broad regions with minimal or no HCV vRNA that resembled valleys (see video).

HCV viroscape with superimposed IFITM3 landscape. HCV RNA from 1 patient is represented as contoured gray peaks above the xy plane, and IFITM3 mRNA in the same hepatocytes is represented as contoured terrain below the xy plane.

HCV viroscape with superimposed IFITM3 landscape. HCV RNA from 1 patient is represented as contoured gray peaks above the xy plane, and IFITM3 mRNA in the same hepatocytes is represented as contoured terrain below the xy plane.

Kandathil et al. found that the proportion of HCV-infected hepatocytes per person ranged from 21% to 45%, and the level of viral RNA ranged from 1 to 50 IU/hepatocyte. However, infection was not random—the authors saw clusters of HCV-positive hepatocytes. These clusters in the hepatic viroscapes indicate cell-to-cell propagation of infection.

Kandathil et al. characterized the spatial association between intrahepatic HCV replication and innate immune signaling, and found that although expression of interferon-stimulated genes was sporadic, it was not specifically targeted toward or away from HCV-positive hepatocytes.

Clustering of HCV-infected hepatocytes did not appear to be caused by short-range immunologic control. IFITM3, an interferon-λ–induced protein that has direct antiviral effects against HCV in cell culture, did not appear to be directed specifically toward or away from infected hepatocytes (green in video).

In liver tissues from some subjects, the author found an association between the peak of viral RNA in a cluster and the number of cells in the cluster. This might suggest that infected hepatocytes depend on the robustness of viral replication in the hepatocyte most permissive to viral replication. Alternatively, the hepatocyte with the highest viral RNA copy number could have been the earliest infected cell of a cluster.

Cell-to-cell propagation of HCV could have important implications for vaccine design and drug development—strategies to inhibit entry of extracellular virions could be insufficient for HCV control if cell-to-cell spread of infection is rampant.

The authors hope for future studies with expanded viroscapes, so they can analyze expression of other host genes that control or support HCV replication.

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Chowing Down On Meat, Dairy Alters Gut Bacteria A Lot, And Quickly

American College of Gastroenterology » News
Chowing Down On Meat, Dairy Alters Gut Bacteria A Lot, And Quickly

Changing to a diet heavy in animal proteins rapidly changes the makeup of the gastrointestinal microbiome, according to new research, and the changes might contribute to inflammation and disease in the intestines. Nine participants in the research tried each of two diets, one loaded with animal proteins and fats, the other with plant-based foods and plenty of fiber. NPR (12/11)

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Does Thiopurine Therapy Increase Cancer Risk?

Does Thiopurine Therapy Increase Cancer Risk?

Patients with ulcerative colitis (UC) have a 4-fold increase in risk of lymphoma during treatment with thiopurines, compared to UC patients who have not been treated with these drugs, according to a nationwide cohort study in the November issue of Gastroenterology. The risk increases gradually with successive years of therapy, but decreases when patients stop taking the drugs.

UC is a chronic inflammatory disorder; it is commonly treated with corticosteroids, which cause a number of side effects (weight gain, mood disorders, and osteoporosis) and often lack long-term efficacy. Patients are therefore often treated with other drugs, such as thiopurines (azathioprine and 6-mercaptopurine)— purine anti-metabolites with immunosuppressive properties.

Although these drugs spare patients from the potential adverse effects of corticosteroids, they have their side effects, increasing the risk of lymphoma.

Thiopurines are also used to treat patients with lymphoproliferative disorders, including lymphoma, following organ transplantation. They are reported to increase the risk of lymphoproliferative diseases by up to 20- and 200-fold in kidney and heart transplant recipients, respectively. However, the level of risk for patients with inflammatory bowel disease (IBD) treated with thiopurines is not clear—studies have produced conflicting results.

The Veterans Affairs (VA) administration has the largest integrated health care system in the United States, serving approximately 8.3 million veterans each year. Nabeel Khan et al. used the VA population-based database to estimate the risk of lymphoma among 4734 patients with UC treated with thiopurines for a median time of 1 year.

They found that incidence rates of lymphoma were 0.60 per 1000 person-years among patients who had not been treated with thiopurines, 2.31 among patients who were treated with thiopurines, and 0.28 among patients who had discontinued treatment with thiopurines. Treatment with thiopurines was associated with an approximate 4-fold increase in the risk of lymphoma relative to patients with UC who were not treated with thiopurines (see below figure).

Incidence rate of lymphoma, stratified by age and use of thiopurines.

Incidence rate of lymphoma, stratified by age and use of thiopurines.

Khan et al. showed that risk increased with the duration of treatment—the incidence rates of lymphoma during the first year, second year, third year, fourth year, and >4 years of thiopurine therapy were 0.9, 1.6, 1.6, 5, and 8.9 per 1000 person-years, respectively. Furthermore, stopping thiopurine treatment reduced the risk of lymphoma during a median follow-up time of 3.5 years.

After adjusting for age, race, and use of thiopurines, men had a nonsignificant trend toward a higher incidence of lymphoma.

How might thiopurines contribute to development of this cancer? Decreased immune surveillance of Epstein–Barr virus (EBV)-infected B cells is one way (thiopurines been implicated in the development of EBV-positive lymphomas). They also destabilize DNA by incorporating thiopurine nucleotides during replication, which interferes with replication and repair mechanisms to cause mutations.

Khan et al. state that in the absence of a comparable therapy with a lower risk of malignancy, patients with corticosteroid-dependent IBD will still be treated with thiopurines. However, there are several approaches to reduce cancer risk. Candidates for thiopurine therapy should be selected with caution—especially older men. Patients should be assessed for thiopurine methyltransferase genotype or enzyme activity, and weight-based dose adjustments can be made. Finally, stopping thiopurine therapy after 3 years should be considered, especially for patients in long-term remission.

In an editorial that accompanies the article, Laurent Beaugerie reminds us that in patients with longstanding extensive colitis, the reduction of colorectal cancer risk may outweigh the excess risk of lymphoma from thiopurines.

Khan et al. warn that although the study is based on the largest integrated nationwide health care system in the US, it is not a population-based cohort, due to the differences between the demographics of the VA population and the general US population (specifically in age, race, and sex distribution). The VA population is predominantly composed of middle-age to older white men, which can limit the external validity of the study.

Beaugerie says that randomized, mid- or long-term strategy and benefit–risk studies on the prolonged use of thiopurines beyond 5 years, based on age, sex, and IBD phenotype, are needed.

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Fecal transplant needs careful, measured approach

American College of Gastroenterology » News
Fecal transplant needs careful, measured approach

“We need to be thinking as scientists as well as clinicians and to a phased approach to using this in the future,” David T. Rubin, MD, FACG, co-director, Inflammatory Bowel Disease Center, University of Chicago Medicine, said while delivering his portion of the American Journal of Gastroenterology Lecture during the American College of Gastroenterology Annual Scientific Meeting. Rubin was joined by Stephen M. Collins, MBBS, department of medicine, McMaster University in Hamilton, Ontario, in giving the lecture on the emerging role of the microbiome in the pathogenesis and management of inflammatory bowel disease.  Healio (10/16)

Exercise Could Protect You From Esophageal Cancer

Making sure to get that workout in could help lower your risk of developing esophageal cancer, according to a new study.

Mayo Clinic researchers found an association between physical activity and risk of the cancer, with physically active people having a 32 percent lower risk of developing one of the two forms of esophageal cancer, called esophageal adenocarcinoma. Huffington Post (10/14)

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What to do About Gastric Polyps

What to do About Gastric Polyps

When clinicians detect a gastric polyp during endoscopy, they are faced with many questions: does the polyp need to be excised, or can a biopsy sample be collected and analyzed? Which polyps should be biopsied? Should patients then be followed, and how? In the November issue of Clinical Gastroenterology and Hepatology, Yasser H. Shaib et al. attempt to provide some practical answers to these questions.

A gastric polyp is an abnormal growth from the gastric mucosal membrane. Detection of stomach polyps prompts concerns about histology, cause, progression, and possible treatment.

The overall incidence of gastric polyps has increased in North America, and there has been a shift in the proportions of types detected—clinically inconsequential fundic gland polyps have become the most prevalent, whereas those associated Helicobacter pylori-induced gastritis (hyperplastic and adenomatous polyps) have become less common. In contrast, in East Asia, Latin America, and possibly Africa, where H. pylori infection and chronic gastritis are still common, and larger proportions of gastric polyps are either hyperplastic or neoplastic.

In their Perspective article, Shaib et al. discuss the features, diagnostic criteria, and management strategies for different types of gastric polyps.

For example, fundic gland polyps (see below figure), which are usually multiple, small (less than 1 cm), and smooth, should be biopsied upon detection, but large polyps (>1 cm in diameter) should be removed.

Endoscopic view of multiple fundic gland polyps in a patient taking proton-pump inhibitors.

Endoscopic view of multiple fundic gland polyps in a patient taking proton-pump inhibitors.

Fundic gland polyps are often detected in patients who have taken proton pump inhibitors for prolonged time periods. Shaib et al. propose that when more than 20 polyps are present, or their size is larger than 1 cm, patients should be asked to stop taking these drugs, to see if the polyps regress.

The authors also provide advice for diagnosis and management of hyperplastic gastric polyps, gastric adenomas, gastrointestinal stromal tumors, inflammatory fibroid polyps, gastric neuroendocrine tumors.

Shaib et al. remind us that no polyp is an island unto itself—after polyps are removed or sampled, the non-affected gastric mucosa should be inspected and biopsy samples should be collected and examined.

Few data are available on short- or long-term outcomes of gastric polyps, so no evidence-based guidelines exist. Shaib et al. suggest that patients undergo surveillance endoscopy within 1 year of detection of non-fundic gland polyps, to check for recurrence. Patients with high-grade dysplasia or early-stage cancer should be followed for at least 2–3 years, at short intervals (6 months). Gastric carcinoids managed endoscopically (usually type 1) should be followed via endoscopy, every 1–2 years.

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Don’t Let GERD Go Unchecked

Get Yourself Checked Out

DallasReflux.com, acid reflux surgery in North Texas, help with acid reflux in DallasAcid reflux or GERD, if unchecked, can cause some serious health problems, so why risk it?  Here are two major medical conditions you may experience if you never get your symptoms looked at by a doctor.

Barrett’s Esophagus

A condition that occurs if the lining of the esophagus is changed to a state similar to the linings of small intestines. Although not everyone who is diagnosed with Barrett’s esophagus suffer from the acid reflux, those with acid reflux have a greater chance of getting this condition. Those suffering from this condition have high chances of getting terminal cancer. Men are more affected with this condition than women. The average age of the diagnosis of the esophagus condition is 60 years old.

Barrett’s esophagus is a difficult problem to diagnose. It cannot be diagnosed accurately since it has no symptoms and blood tests and physical examinations cannot accurately determine if this condition is present. The only proven way to diagnose it is a biopsy and upper gastrointestinal endoscopy.

Erosive Esophagitis

This is the other risk faced by those suffering from the acid reflux condition. It occurs if the acid from the stomach will back up into the esophagus and irritate it. It is very common in those who are suffering from acid reflux. Those suffering from this condition experience several symptoms such as trouble with swallowing, oral lesions, and a burning sensation in throat.

In order to detect it, the doctors perform a barium swallow or endoscopy. Barium is a chemical and it helps the x-ray to see inside of you. If untreated, it may cause intense discomfort and malnutrition as well as dehydration.

Contact us to get acid reflux help in Dallas today if you’re experiencing any discomfort. Now is always better than later.

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Vitamins vs. Acid Reflux

vitamins for acid reflux disease, DallasReflux.comGERD (Gastroesophageal Reflux Disease), also known as acid reflux, is a condition where the contents in the stomach normally end up chronically back in the oesophagus. This causes burping, heartburn, nausea, sore throat, coughing, chest pains and vomiting. 

But, you’re on this website so you already know all this. What you want to know is what can you do to make things better right now.

Below are some vitamins that can help to prevent acid reflux, or at least slow it down.

Vitamin U 

Also known as S-Methylmethionine but commonly referred to as vitamin u. Its use was uncovered when M.D. Garnett Cheney was experimenting with it in the form of fresh cabbage juice and found that it could be used to heal peptic ulcers. 

Vitamin B1

Insufficiency of Thiamine (Vitamin B1) normally causes beriberi that normally results in vomiting and weak muscles. Taking B1 vitamin aids the esophagus sphincter and also relives most of the stomach acid that had backed up. 

Vitamin B5

Also known as pantothenic acid, the vitamin is vital for healthy muscles and skin. It helps out with the condition as it works on the muscular valve which controls the esophagus sphincter and in turn it prevents the acid from going back to the throat. 

Vitamin B12

Vitamin B12 deficiency is one of the symptoms of acid reflux. Taking the vitamin is important as it helps the digestive system since it aids in the breaking down proteins. 

Vitamin B6

Also known as pyridoxine, this is a vitamin that helps in the metabolism of proteins, fats and carbohydrates. It is also vital for the growth of new cells. It is important for the replacement of the cells that are destroyed by the condition to ensure that they continue working the way they are supposed to without ant complications. 

Multi-vitamins 

Most doctors after studying the condition for a long time through treating several patients agree that acid reflux is one of the ways that the body states that there is something off with a person’s general health. This is because most patients with the reflux normally have a deficiency of various vitamins especially the B complex. For this reason, it is therefore recommended that the patients are put on a daily regimen of taking vitamins that will help people with their insufficiencies.

Ultimately, GERD surgery will stop your discomfort, but taking vitamins for acid reflux is still a smart option.

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