New onset of grave’s disease during anti-tnfα treatment in a case of fistulizing crohn’s disease

 New onset of grave’s disease during anti-tnfα treatment in a case of fistulizing crohn’s disease Presenting Author: NAWAF ZAKARY
Additional Authors: ALGUILI ELSHEIKH, NOOF HAMID, OMAR ABDULAAL, MOHAMMED ALGHAMDI, WALID FARAH
Corresponding Author: NAWAF ZAKARY
Affiliations: King Fahad Military Medical Complex
The association between inflammatory bowel disease in form of ulcerative colitis and autoimmune thyroid disease has been well documented. However, the association between crohn’s disease and autoimmune thyroid disease is not well established and there have only been a few reported cases in the literature.
Case presentation We present here a rare case of a 35-year-old Saudi female with simultaneous onset of Graves’ disease and fistulizing Crohn’s disease. Crohn’s disease was complicated with intra-abdominal fistulas. Despite intense medical treatment with regular Azathioprine, total parenteral nutrition, antibiotics, and corticosteroids the clinical course of the disease was suboptimal. Finally, the patient underwent laparotomy and right hemi-colectomy with ileo-transverse anastomosis, simultaneous drainage of the abdominal abscess and closure of the opening. Although the surgical approach cured the perforating complications of the disease (fistulas and abscess), the luminal disease in the colon remnant was still active. The subsequent successful treatment with infliximab, azathioprine and mesalazine resulted in the induction and maintenance of the disease remission. Later on, patient develop full blown picture of Graves’ disease after she started infliximab which was stopped later and the patient improved on antithyroid medication. Conclusion: We are not sure whether the association between Crohn’s disease and Gravés disease is infliximab dependent or independent and it needs more case studies and research.
 KeyWord(s): 1. Gravés disease; 2. Crohn’s disease; 3. ulcerative colitis; 4. infliximab; 5. azathioprine
 Poster 136 Journal of Gastroenterology and Hepatology 2014; 29 (Suppl. 3): 51–313 © 2014

Management of iatrogenic esophageal perforation with endoscopic stenting

Management of iatrogenic esophageal perforation with endoscopic stenting
Presenting Author: NAWAF ZAKARY
Additional Authors: ALGUILI ELSHEIKH, NOOF HAMID, HIND HAMID, MOHAMMED ALGHAMDI, WALID FARAH
Corresponding Author: NAWAF ZAKARY
Affiliations: King Fahad Military Medical Complex

Objective: Esophageal perforation is a challenging disease process with high morbidity and mortality. Despite the availability of diagnostic radiological tools, there is still a chance of delaying in diagnosis, because of non specific symptoms. In clinical practice 60% of cases are iatrogenic due to endoscopic procedures. The morbidity and mortality rate is directly related to the delay in diagnosis and initiation of optimum treatment. The reported mortality from treated esophageal perforation is 10% to 25%, when therapy is initiated within 24 hours of perforation, but it could rise up to 40% to 60% when the treatment is delayed beyond 48 hours.

Case Presentation: We like to present a 67 year old female patient of achalasia. She presented with weight loss and progressive dysphagia. Barium swallow and gastroscopy confirmed the diagnosis. She underwent successful first session of endoscopic pneumatic dilation but after the second session, she developed shortness of breath and abdominal pain. Gastrographin studies and computer tomography scan of the chest and abdomen confirmed the diagnosis of esophageal perforation. She was managed conservatively with endoscopic stenting, to which she recovered fully.

Conclusion: Esophageal perforation is a highly morbid condition with high mortality. More accurate diagnosis and less-invasive treatment are reducing morbidity and mortality to more acceptable levels. While surgery remains the gold standard treatment, less invasive and endoscopic methods are being explored, and their role is evolving. For optimum outcome for management of esophageal perforations, a multidisciplinary approach is needed.

Key Word(s): 1. achalasia; 2. esophageal perforation; 3. esophageal stenting

© 2014 The Authors. Journal of Gastroenterology and Hepatology

New onset of grave’s disease during anti-tnfα treatment in a case of fistulizing crohn’s disease

IBD P-254 New onset of grave’s disease during anti-tnfα treatment in a case of fistulizing crohn’s disease Presenting Author: NAWAF ZAKARY Additional Authors: ALGUILI ELSHEIKH, NOOF HAMID, OMAR ABDULAAL, MOHAMMED ALGHAMDI, WALID FARAH Corresponding Author: NAWAF ZAKARY Affiliations: King Fahad Military Medical Complex, King Fahad Military Medical Complex, King Fahad Military Medical Complex, King Fahad Military Medical Complex, King Fahad Military Medical Complex Objective: The association between inflammatory bowel disease in form of ulcerative colitis and autoimmune thyroid disease has been well documented. However, the association between crohn’s disease and autoimmune thyroid disease is not well established and there have only been a few reported cases in the literature. Case presentation We present here a rare case of a 35-year-old Saudi female with simultaneous onset of Graves’ disease and fistulizing Crohn’s disease. Crohn’s disease was complicated with intra-abdominal fistulas. Despite intense medical treatment with regular Azathioprine, total parenteral nutrition, antibiotics, and corticosteroids the clinical course of the disease was suboptimal. Finally, the patient underwent laparotomy and right hemi-colectomy with ileo-transverse anastomosis, simultaneous drainage of the abdominal abscess and closure of the opening. Although the surgical approach cured the perforating complications of the disease (fistulas and abscess), the luminal disease in the colon remnant was still active. The subsequent successful treatment with infliximab, azathioprine and mesalazine resulted in the induction and maintenance of the disease remission. Later on, patient develop full blown picture of Graves’ disease after she started infliximab which was stopped later and the patient improved on antithyroid medication. Conclusion: We are not sure whether the association between Crohn’s disease and Gravés disease is infliximab dependent or independent and it needs more case studies and research. KeyWord(s): 1. Gravés disease; 2. Crohn’s disease; 3. ulcerative colitis; 4. infliximab; 5. azathioprine Poster 136 Journal of Gastroenterology and Hepatology 2014; 29 (Suppl. 3): 51–313 © 2014

Link between early exposure to acetaminophen and childhood asthma found weak, overstated

FROM THE ARCHIVES OF DISEASE IN CHILDHOOD The reported link between early life exposure to acetaminophen and the development of asthma in children is “weak” and “overstated” based on currently available evidence, according to a report published by the Archives of Disease in Childhood. In a review of currently available data culled from Embase and PubMed databases, 1,192 relevant studies conducted between 1967 and 2013 were analyzed, of which 11 were included for analysis. Of these 11 studies, 5 found “increased odds” that exposure to acetaminophen during the first trimester of pregnancy could lead to development of asthma (pooled odds ratio, 1.39); however, there was a high degree of between-study heterogeneity among the trials (I= 64.2%, P = .03), reported Dr. M. Cheelo of the University of Melbourne, and associates. Of those five, only two studies examined the effects of acetaminophen exposure during the second trimester, but attained widely disparate results: Study one reported an OR of 1.06, while the other reported an OR of 2.15, with I= 80%. Two studies also tested acetaminophen exposure during the third trimester and found a “weak association,” with a pooled OR of 1.17. Three studies look at acetaminophen exposure through an entire pregnancy, but all had “significant heterogeneity” in their findings (OR = 1.65, 1.22, and 0.74; I= 89%). Only one study that was examined adjusted for respiratory tract infections during pregnancy, but according to the authors, “all studies that adjusted for early life respiratory tract infections found a reduction in the association between [acetaminophen] exposure and subsequent childhood asthma” (Arch. Dis. Child. 2014 [doi:10.1136/archdischild-2012-303043]). The other 6 of the 11 total studies examined acetaminophen exposure over the first 2 years of life. Three of these studies found a “weak positive association,” as did four studies directly comparing children with and without acetaminophen exposure. All but one study adjusted results for respiratory tract infections during pregnancy, which caused a “moderate attenuation of the association between frequency of [acetaminophen] intake and childhood asthma.” Consequently, investigators concluded that “evidence of an association between early life [acetaminophen] and asthma is often overstated, and there is currently insufficient evidence to support changing guidelines in the use of this medicine.”

PPI, steroid use raises risk of CDAD recurrence

AUSTIN, TEX. (FRONTLINE MEDICAL NEWS) – Use of proton pump inhibitors and steroids was independently associated with recurrences of Clostridium difficile–associated diarrhea among patients in an intensive care unit, based on a retrospective chart review reported at the annual meeting of the American College of Chest Physicians. Recurrences were noted in 268 of 2,019 patients who were admitted to a single intensive care unit during a 6-year period and were initially treated successfully for C. difficile–associated diarrhea (CDAD). In a univariate analysis, recurrence was correlated with use of proton pump inhibitors (PPIs) and steroids, but not with age, male gender, or length of hospital stay. After adjusting for age, sex, length of stay, and treatment used, the relationships between recurrence and PPI and steroid use remained statistically significant (P = .0331 and P = .0305, respectively), Dr. Ala Nijim of Akron (Ohio) General Medical Center. The study subjects comprised 798 men and 1,221 women with an average age of 68 years and an average hospital length of stay of 10 days. Severe disease was present in 233 patients, and 51 had cancer. CDAD in this study was defined as at least three episodes of loose stools in less than 24 hours with a positive C. difficile toxin assay. Recurrence was defined as a second positive stool test within 90 days following complete resolution of a previous episode of diarrhea episode and cessation of treatment comprising a 10-day period. Data suggest that the rate of CDAD recurrence is between 10% and 25% at a cost of between $3.2 and $4.8 billion, Dr. Nijim said. Glucocorticoids are known risk factors for acquiring CDAD, likely due to their immunosuppressive effects, and PPIs have also been suggested as risk factors for acquiring CDAD, although the findings have been mixed. Likewise, treatment with metronidazole for an initial episode has been linked with treatment failure and recurrence risk. In the current study, one of the largest to date to evaluate factors associated with CDAD recurrence, both PPIs and glucocorticoids were shown to be associated with recurrence risk, but no link was found between metronidazole or any CDAD treatment modality and recurrence, Dr. Nijim said. Though limited by the single-center, retrospective study design and its inherent information and selection biases, the study includes a large ICU patient sample, and the findings suggest that intensivists should watch carefully for recurrence in patients using PPIs and/or steroids. Also, clinicians should think carefully before starting patients on PPIs – and perhaps use histamine blockers instead – in patients with a history of CDAD, she said.

Topical steroid might improve mucosal integrity in eosinophilic esophagitis

FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Topical steroid therapy improved some indicators of mucosal integrity in patients with eosinophilic esophagitis, but proton pump inhibitor therapy did not, according to two studies reported in the November issue of Clinical Gastroenterology and Hepatology. The first study found that topical fluticasone therapy at a dose of 880 mcg twice daily for 2 months helped correct esophageal spongiosis, or dilated intercellular space, in patients with eosinophilic esophagitis (EoE). Spongiosis scores for treated patients were significantly lower than for untreated patients (0.4 vs. 1.3; P = .016), said Dr. David Katzka at the Mayo Clinic in Rochester, Minn. and his associates (Clin. Gastroenterol. Hepatol. 2014 [doi:10.1016/j.cgh.2014.02.039]). In the study, histologic analyses also showed that improved spongiosis scores in treated patients correlated with increased density of two tight junction proteins, filaggrin (P = .001) and zonula occludens-3 (P = .016), said the investigators. These proteins might help regulate antigenic penetration of the esophageal mucosa and also could permit migration of white blood cells, they said. “Loss of tight junction regulators and dilation of intercellular spaces appear to be involved in the pathophysiology of EoE and could be targets for treatment,” the researchers concluded. But they also noted that their study did not examine the same patients before and after steroid therapy and did not look at desmosomes, intercellular junctions that past research has suggested might be affected in EoE. For the second study, Dr. Bram van Rhijn and his associates at the Academic Medical Center in the Netherlands compared endoscopies of 16 patients with dysphagia and suspected (unconfirmed) EoE with 11 controls, both at baseline and after 8 weeks of high-dose esomeprazole treatment. Esophageal mucosal integrity was “severely impaired” in patients with confirmed EoE and in those with proton pump inhibitor–responsive eosinophilia (PPRE), the researchers said (Clin. Gasteroenterol. Hepatol. 2014 [doi:10.1016/j.cgh.2014.02.037]). In both forms of disease, molecules as large as 40,000 daltons were able to pass through the compromised esophageal mucosa, Dr. Bram van Rhijn and his associates reported. “This size is similar to the size of most plant and animal food allergens to which EoE patients are sensitized,” they added. Esophageal permeability might increase the rate of immune exposure to allergens, thereby mediating EoE and PPRE, they said. On mucosal functional tests, both EoE and PPRE were associated with reduced transepithelial electrical resistance and lower electrical tissue impedance, most notably in patients with EoE (P less than .001 for both, compared with controls), the investigators reported. Proton pump inhibitor treatment partially reversed these changes in patients with PPRE but showed no effect for patients with EoE, they said. This finding suggests that acid reflux might play a role in PPRE, but not in EOE, they concluded.

Adjustable Intragastric Balloons: A 12 Month Pilot Trial in Endoscopic Weight Loss Management

Objectives Intragastric balloons(IGBs) are associated with, 1) intolerances in the early period, 2) diminished weight loss after the third month, 3) risk of bowel obstruction mandating removal at six months, and 4) the need for a dedicated extraction tool.The introduction of an adjustable balloon could improve comfort and offer greater efficacy. A migration prevention function, safely enabling prolonged implantation, could improve efficacy and weight maintenance post extraction. Polypectomy snare extraction would also be beneficial. The first implantations of an adjustable balloon with attached migration-prevention anchor is reported.

Aims & Methods The SpatzTM Adjustable Balloon is mounted on a curled non-crushable catheter that straightens overa guidewire, and passed transorally, under conscious sedation. The non-crushability of the catheter loops is mediated by an internal chain. Post-implantation, an extractable inflation tube housed in the catheter can be snared endoscopically and pulled outside the mouth for volume adjustments. 18 patients (15 female, 3 male); mean BMI 39,4(range 29,4 to 53,2); and mean wt. 114,9kg (range 73,5 to 163kg) were implanted with mean balloon volume of 406,9 cc (range 350 to 600cc) of saline.

Results Mean weight loss at 24 weeks was 15.6 kg with a 26.4% EWL (% excess weight loss), and 35.5 kg with a 67.3 %EWL at 52 weeks. Sixteen adjustments were successfully performed. Six downward adjustments alleviated intolerance, yielding an additional mean weight loss of 4.6 kg. Ten upward adjustments for weight loss plateau yielded a mean additional weight loss of 8.1 kg. There were no major complications, however, seven of the 18 balloons were removed.

Conclusion The Spatz ABS has been successfully implanted in eighteen patients. 1) Upward adjustments yielded additional weight loss. 2) Downward adjustments alleviated intolerance, with continued weight loss. 3) Eight extractions were performed with a polypectomy snare. 4) Preliminary one year results are encouraging.



Jeffrey Brooks et al

Symptomatic bacterial contamination of an intragastric balloon

A 45-year-old woman had an intragastric balloon placed endoscopically for metabolic syndrome and obesity (body mass index = 37.42 kg/m2). She was being maintained on omeprazole daily. Under endoscopic view, the balloon was positioned in the stomach and inflated with 650 mL of 0.9% NaCl mixed with 20 mL of methylene blue solution. After 4 months, the patient had lost 22 kg but began to report intense nausea, vomiting, abdominal distention, and abdominal pain. An abdominal plain film showed a radiolucent and elongated structure in the upper abdomen (A). Endoscopy revealed an enlarged balloon, and the solution inside the balloon was collected during its removal by puncture. Inspection of the balloon after withdrawal showed its surface to be irregular with microbubbles and what appeared to be extensive fungal colonization (B). No samples were taken from the balloon surface, but culture and examination of the solution inside the balloon revealed Klebsiella pneumoniae (a gas-producing bacterium) and Candida spp. The patient was discharged without any symptoms and remained asymptomatic during the next 3 months. Disclosure All authors disclosed no financial relationships relevant to this publication. Commentary Patients with intragastric bezoars lose weight, an observation that prompted Mary and Lloyd Garren to develop the first intragastric balloon to function as an artificial bezoar, ostensibly by inducing a feeling of satiety and thereby helping to curb appetite. In 1985, the U.S. Food and Drug Administration approved the use of a 200-mL air-filled cylindrical, but sharp-edged, plastic bubble, ie, the Garren-Edwards Gastric Bubble, for use in morbidly obese patients, as an adjunct to dietary and behavior modification therapy. Other intragastric balloons have been developed and tried since then and have indeed resulted in weight loss, which sometimes was quite significant, although several randomized, controlled studies failed to show a significant advantage of the balloon over a sham procedure. Reported complications of intragastric balloons have included gastric ulceration, bubble intolerance, and, perhaps most important, spontaneous deflation of the bubble with resultant intestinal obstruction, the risk of which is significantly higher when balloons are left in place longer than 6 months. Here the authors report another adverse effect, namely, abdominal distention and pain, attributed to gas production by Klebsiella. The observation of Klebsiella in the balloon raises many questions: Why was the inner balloon not sterile? What happened to balloon permeability over the time that the balloon resided in the stomach? Was inner colonization a local phenomenon facilitated by the clumps of microorgansims on the external surface of the balloon? One would imagine that were gastric acid to have been normal, there probably would not have been a proliferation of “fungal-appearing” forms nor of bacteria other than Helicobacter pylori. How does the presence of an intragastric balloon affect gastric acid secretion? So many questions. Winnie the Pooh said, “No one can be uncheered with a balloon.” Although this balloon probably led to some cheering at first, it then, I am sure, lead to uncheering as reality set in: obesity is a major health problem that involves lifelong attention to diet, behavior modification, and perhaps the help of a skilled surgeon. I wish this patient good fortune.

Study finds no link between TNF-alpha blockers, cancer in inflammatory bowel disease

A large registry-based study has found no increased risk of cancer in inflammatory bowel disease patients treated with tumor necrosis factor alpha (TNF-alpha) antagonists. The findings, from the Danish National Patient Registry, are based on 56,146 inflammatory bowel disease (IBD) patients. "Given the upper limit of the conference intervals, this study could rule out a more than 36% relative increase in the risk of overall cancer over a median follow-up of 3.7 years among TNF-alpha antagonist-exposed patients, with 25% of these followed for 6 years or longer," Dr. Nynne Nyboe Andersen of Herlev University Hospital in Copenhagen told Reuters Health in an email. The findings are published in the June 18 issue of JAMA. Concerns had been raised that TNF-alpha antagonists might increase cancer risk through their immunosuppressive effects, Dr. Andersen and colleagues note in their report. Three studies of the issue have been done in IBD patients, with negative findings, but very short follow-up periods. In the current study, the researchers looked at IBD patients ages 15 years and older, including 4553 (8.1%) who had been treated with TNF-alpha antagonists. Their analysis included 489,433 person-years of follow-up, during which time 81 patients (1.8%) exposed to TNF-alpha antagonists developed cancer, and 3465 patients (6.7%) not exposed to the drugs were diagnosed with cancer. After Poisson regression analysis adjusting for age, calendar year, disease duration, propensity scores, and other IBD medication use, the relative risk associated with TNF-alpha antagonist use was 1.07, and not significant. The researchers also performed stratified analyses based on cumulative TNF-alpha antagonist dose and time since first TNF-alpha antagonist dose, but found no association with cancer risk. Their analysis also did not find an increased risk by cancer type. "Keeping in mind the often protracted progression of cancer, there is a need for future studies with an even longer follow-up time to evaluate the risk of cancer in patients exposed to TNF-alpha antagonists," Dr. Andersen said. "Further, it should be noted that due to the relatively small sample size and the small number of cancer cases in our study, statistical power was limited in subgroup analyses of site-specific cancer and there is a need for larger future studies to assess the risk in different types of cancer." Dr. William Sandborn, director of the IBD Center at the University of California, San Diego, reviewed the study for Reuters Health. He noted that the issue of TNF-alpha and cancer risk in IBD has not been a major concern. However, he added, the IBD drugs azathioprine and 6-mercaptopurine have clearly been linked to cancer. "They are unequivocally linked with a higher risk of non-melanoma skin cancer and a higher risk of non-Hodgkin lymphoma," Dr. Sandborn said. Studies have shown that combination therapy with azathioprine and TNF-alpha antagonists is more effective than either drug given as monotherapy, he added. The question that needs to be answered, he said, is how the benefit of combination therapy compares to the increased cancer risk seen with azathioprine. "I hope the authors will continue to mine their data to further explore the relationship of the whole range of drugs we use in IBD and cancer," he said.

Monitor elderly for bone loss after gastric bypass

CHICAGO (FRONTLINE MEDICAL NEWS) – Older adults who undergo Roux-en-Y gastric bypass are at risk for lessened bone mineral density for at least 2 years after their surgery and should be monitored appropriately for osteoporosis or fragility fractures, according to investigators from Massachusetts General Hospital in Boston. Two years postoperatively, vertebral bone mineral density (BMD) in 30 patients was about 7% lower on quantitative computed tomography (QCT) and 6% lower on dual-energy x-ray absorptiometry (DXA) – both methods were used to ensure accuracy – when compared with 20 well-matched, morbidly obese controls. Total hip BMD was 6% lower on QCT and 10% lower on DXA. Femoral neck BMD was about 6% lower by both measures. Biomarkers of bone turnover remained markedly elevated in surgery patients, as well, but unchanged in controls (C-telopeptide 0.65 ng/mL vs. 0.3 ng/mL; amino-terminal propeptide of type I collagen 65 ng/mL vs. 40 ng/mL). The findings were all statistically significant. The groups started to separate early on BMD, and there’s concern that bone loss will continue for more than 2 years after surgery. Preoperatively, most Roux-en-Y gastric bypass patients have a higher than normal BMD, “so even a loss of 10% over 2 years is not going to put most of them in the osteopenic or osteoporotic range. The caveat now is that we are [offering surgery] to older patients and adolescents. Elderly patients are starting with lower bone mass, so there are concerns about [post-op] skeletal fragility. The oldest patient in our study was 72. She became osteoporotic after surgery because her bone density was low to begin with,” said lead investigator Dr. Elaine W. Yu, an endocrinologist at Massachusetts General. “In adolescents, there are implications for achieving peak bone mass. Even if you have a normal bone density 2 years after surgery, what’s going to happen in 10 years, 20 years?” she asked. In short, “people should pay attention to bone density and bone loss and discuss this as one of the potential negative effects of bariatric surgery. For patients at risk, you should definitely consider serial bone density monitoring and osteoporosis therapy if needed,” she said at the joint meeting of the International Society of Endocrinology and the Endocrine Society. At baseline, both subjects and controls were about 47 years old and 270 pounds, with a mean a mean body mass index of 45 kg/m2. About 85% were women. The study excluded patients with histories of bone disorders or use of bone-affecting medications. Surgery patients lost a mean of about 85 pounds in the first 6 months; their weight loss then stabilized, but they continued to lose bone. Controls stayed about the same weight. The findings can’t be explained by post-op calcium or vitamin D depletion. “These subjects were aggressively supplemented with both,” and both groups maintained normal levels throughout the study. Also, there were no statistical differences in parathyroid hormone levels between the groups. “Our theory is that there are changes in gut hormones after gastric bypass that have direct effects on bone, like ghrelin,” Dr. Yu said. The National Institutes of Health funded the work. Dr. Yu is a consultant for Amgen.

Mesalazine didn’t help diarrhea-predominant IBS

CHICAGO (FRONTLINE MEDICAL NEWS) – Treating diarrhea-predominant irritable bowel syndrome with mesalazine for 12 weeks failed to improve stool frequency or other symptoms, compared with placebo, in a multicenter, randomized double-blind trial with 115 patients. Stool frequency decreased in both groups from a mean of four bowel movements per day to three per day by weeks 11 and 12. Mesalazine (also known as mesalamine or 5-aminosalicylic acid) also produced no significant differences, compared with placebo, in secondary outcomes, including abdominal pain scores, stool consistency, satisfactory relief of symptoms of irritable bowel syndrome (IBS), anxiety, depression, or Patient Health Questionnaire–12 Somatic Symptoms scores, Dr. Ching Lam reported at the annual Digestive Disease Week. Patients took 2 g/day of mesalazine or placebo for 1 week and then increased the dose to 2 g b.i.d. if they could tolerate it. All were adults with diarrhea-predominant IBD who had completed a prerandomization 2-week stool diary showing a stool frequency of at least three per day for more than 2 days per week and a stool consistency of at least 25% type 5-7 and less than 25% type 1-2 on the Bristol Stool Form Scale. All underwent a baseline colonoscopy/sigmoidoscopy before randomization to exclude patients with microscopic or inflammatory colitis. The study also excluded patients who were taking NSAIDs or other drugs that affect gut motility and patients with a history of abdominal surgery or renal or liver impairment. The study initially randomized 136 patients, but 11 in the mesalazine group and 10 on placebo were excluded from the intent-to-treat analysis of results because they withdrew consent, were lost to follow-up, or had an incomplete stool diary at weeks 11-12, or because results were not available due to adverse events, said Dr. Lam of Nottingham (England) University. Clinicians had been interested in mesalazine for diarrhea-predominant IBS because small randomized, controlled pilot studies and some open-label studies had suggested that the drug might improve IBS symptoms of abdominal pain and stool frequency and consistency, especially in patients with postinfectious IBS. The drug is approved to treat ulcerative colitis and some other bowel diseases. Those earlier studies also suggested that mesalazine might reduce the numbers of mast cells in unselected cohorts of patients with IBS. In the current study, a subgroup of patients did show elevations in “mast cell percent area stained,” and this correlated weakly with urgency and stool consistency, but mesalazine treatment did not reduce the mast cell percent area stained, Dr. Lam reported. An analysis of results for a small subgroup of patients with postinfectious IBS suggested that mesalazine may benefit them, “but this requires a larger, adequately powered study to confirm,” she said. Better phenotyping of the heterogeneous group of patients with IBS and diarrhea would help evaluate any new treatments, she added. British government agencies funded the trial. Several of Dr. Lam’s coinvestigators reported financial associations with multiple pharmaceutical companies.

Azathioprine, anti-TNF monotherapy safe in IBD pregnancy

CHICAGO (FRONTLINE MEDICAL NEWS) – Women with inflammatory bowel disease can safely continue monotherapy with azathioprine/6-mercaptopurine or antitumor necrosis–alpha agents during pregnancy to maintain remission, according to an analysis of 1,289 women and 1,039 live births. Infants exposed to azathioprine/6 MP and anti-TNF-alpha agents achieve developmental milestone scores at rates similar to unexposed infants and do not have higher rates of congenital anomalies, lead author Dr. Uma Mahadevan said at the annual Digestive Disease Week. Overall, there were 55 congenital anomalies, with 21 diagnosed at birth. Events were similar among infants with in utero exposure to azathioprine, anti-TNF agents, combination therapy, and those with no drug exposure (12 vs. 17 vs. 7 vs. 19 events). Exposure was defined as any use of azathioprine/6 MP or the anti-TNF-alpha agents infliximab (Remicade), adalimumab (Humira), or certolizumab pegol (Cimzia) at any time from 3 months prior to conception to the end of the pregnancy. Nine women had exposure to the recombinant monoclonal antibody natalizumab (Tysabri) and were included in the anti-TNF agents group. The analysis was based on the PIANO registry, a prospective cohort of pregnant women with IBD who were followed by telephone or in-person questionnaire at every trimester, at delivery, at 4, 9, and 12 months after delivery, and annually for the first 4 years of their child’s life. Seven women received their diagnosis of IBD during pregnancy, 59.4% had Crohn’s disease, 38.3% ulcerative colitis, and 2.3% were indeterminate. Two-thirds of women reported breastfeeding, with unexposed women significantly more likely to breastfeed than women with exposure to azathioprine, anti-TNF agents, or combination therapy (85% vs. 65% vs. 71% vs. 61%; P less than .0001). After controlling for drug exposure, breastfeeding was not associated with an increased risk of infant infection or reduced height or weight, reported Dr. Mahadevan, with the University of California San Francisco. Infants exposed to combination therapy, however, had higher rates of preterm birth, after adjustment for none/mild vs. moderate/severe IBD activity (odds ratio, 2.6; P less than .05). Infants exposed to combination therapy who were born to mothers with ulcerative colitis also had increased rates of preterm birth (odds ratio, 4.9), low birth weight (OR, 6.1), and NICU stay (OR, 3.9). One possible reason for this signal is that women with ulcerative colitis in the PIANO registry, as well as two other studies, have more disease activity during pregnancy, Dr. Mahadevan suggested. Another possibility is that mothers with ulcerative colitis may have low levels of untreated inflammation. With just 161 women available for analysis, the PIANO investigators previously reported a significant increase in infant infections at 12 months of age in those exposed to combination infliximab or adalimumab plus azathioprine. Most anti-TNF agents cross the placenta in the second and third trimester, which has raised concerns about immune system development and risk of subsequent infections. In the current analysis, there was no increase in infant infections when the investigators looked at all anti-TNF drugs. “But when we removed certolizumab from the analysis, it was significant just as it was 2 years ago,” Dr. Mahadevan said in an interview. “Certolizumab is not actively transported across the placenta. Fortunately, the majority of the infections were minor, including otitis media and upper respiratory infections.” Developmental milestones Overall, infants exposed to azathioprine or anti-TNF agents were found to achieve developmental milestones at rates similar to unexposed infants of mothers with IBD based on Denver Childhood Developmental Test and Ages and Stages Questionnaire scores, she said. After controlling for preterm birth, the mean developmental milestone score at 4 months was 0.92 for infants with no drug exposure, with a nonsignificant mean delta difference of 0.01, 0.01, 0.00 points for infants exposed to azathioprine, anti-TNF agents, and combination therapy, respectively. In a surprising twist, infants exposed to anti-TNF agents alone actually had significantly better scores at 12 months than unexposed infants, bettering the average score of 0.81 in the unexposed group by a mean delta of 0.02 points (P = .01), Dr. Mahadevan said. “I wouldn’t interpret this data [as indicating] that biologics make your baby smarter. I think the key thing is that it doesn’t make it worse,” she remarked. “When you see the deltas, they are pretty small.” On the Ages and Stages Questionnaire, the biologic group had significantly better mean scores than the unexposed group for gross motor skills at 36 months (55.94 vs. 47.53; P = .01), gross motor skills at 48 months (60 vs. 51.20; P = .02), fine motor skills at 48 months (53.50 vs. 42.11; P = .01), and personal/social interaction at 48 months (58 vs. 51.93; P = .04). The azathioprine-exposed group always had better scores than the unexposed group, Dr. Mahadevan said. Where it was statistically significant was for personal/social interaction at 24 months (50.75 vs. 47.34; P = .04), problem solving at 36 months (mean 52.04 vs. 48.66; P = .05), and problem solving at 48 months (mean 59.92 vs. 57.66; P = .02). Dr. Mahadevan observed that the data may change because not all infants have reached each time point and may not reflect outcomes in lower socioeconomic groups since more than 90% of women were of similar socioeconomic and educational status. Still, the findings are reassuring in the absence of any randomized controlled trials. A recent report found children born to mothers with IBD had higher rates of attention-deficit hyperactivity disorder and gross motor abnormalities (J. Crohns Colitis 2013;7:542-50), while a case series reported normal neuropsychological development in 25 consecutive children exposed in utero to TNF-alpha inhibitors (Inflamm. Bowel Dis. 2014;20:495-501), she noted. A recent systematic review of 58 articles or abstracts also found no association between TNF-alpha inhibitor use during pregnancy with IBD and adverse pregnancy outcomes, congenital abnormalities, or infections in the first year of life (BMC Medicine 2013;11:174). The study was supported by the Crohn’s and Colitis Foundation of America. Dr. Mahadevan reported serving as an advisor for Janssen-Cilag, AbbVie, Takeda, and UCB Pharma, and receiving research grants from Prometheus Laboratories and GlaxoSmithKline.

الارتداد المعدي المريئي - الدكتور / وليد يوسف فرح استشاري امراض الجهاز الهضمي والكبد

مقدمة

المريء هو أنبوب عضلي ضيق يبلغ طوله حوالي 40 سنتيمتر . ويبدأ بعد اللسان وينتهي في المعدة يتألف من ثلاث طبقات ليفية من الخارج وعضلية في الوسط وغشاء مخاطي من الداخل .
التعريف
الارتداد المريئي هو أعراض مزمنة أو تخريب لمخاطية المريء ينتج عن رجوع زائد وغير طبيعي لحامض المعدة إلى المريء وهذا ما يطلق عليه الارتداد ، ويحدث نتيجة قصور في الوظيفة العضلية للمريء أو فشل في وسائل الحماية الأخرى.

الوبائيات
يعتبر الارتداد المريئي مرض شائع جداً يصيب 20 -40 % من الناس . وقد زادت نسبة حدوثه خلال العقود الماضية ويحدث الارتداد بالتساوي في كلا الجنسين أما التهاب المريء ( الناتج عن الارتداد ) فيحدث في الذكور ضعف الإناث كما يحدث الارتداد في كافة الأعمار وتزداد نسبة حدوثه بعد سن الأربعين .
آلية حدوث الارتداد المريئي
في الواقع إن البنية الأهم في الحماية من حدوث الارتداد المريئي هي طبقة عضلية في أسفل المريء عند اتصاله بالمعدة تسمى مصرة المريء السفلي حيث تفتح بعد البلع ليتمكن الطعام من الدخول إلى المعدة وتنغلق مباشرة بعد ذلك لمنع حدوث أي ارتداد لمحتويات المعدة ( بما فيها الحامض ) إلى المريء وتحافظ على وضعية الإغلاق حتى يتم البلع مرة أخرى .

الأعراض السريرية
• الحرقة : إحساس بالحرقة خلف عظمة القص ويحدث هذا الإحساس بإرتداد الحامض المعدي الذي تزيد كميته بعد تناول الوجبات وفي وضعية الاستلقاء .
• عسر البلع
• البلع المؤلم
• التجشوء
• التظاهرات خارج المريء وهى الأعراض التي تحدث في مناطق خارج المريء وتلاحظ كثيراً في المرضى المحولين من عيادات أخرى للإشتباه بوجود الارتداد المريئي لديهم ، وأ÷م هذه الأعراض .
- ألم الصدر غير المفسر
حيث يحضر المرضى إلى عيادات أمراض القلب إثر معاناتهم من ألم في الصدر والاشتباه بوجود أمراض نقص التروية القلبية من ذبحة صدرية وأحتشاء قلبي ولكن بعد إجراء جميع الفحوصات يتبين عدم وجود أي علامات لذلك وهنا يتم الأشتباه بوجود الارتداد المعدي المريئي كمسبب لألم الصدر .
- تظاهرات رئوية
هناك العديد من الأمراض الرئوية قد تظهر بسبب وجود الارتداد المريئي وأهمها
• الربو القصبي
• التهاب القصبات المزمن
• ذات الرئة الإستنشاقية
• انقطاع التنفس أثناء النوم
• انخماص الرئة
• التليف الرئوي

- تظاهرات أذنية
قد يراجع المرضى اختصاصي الأنف والأذن والحنجرة إثر شكواهم من أحد الأعراض التالية :
• السعال
• ألم الحلق
• بحة الصوت
• التهاب الجيوب الأنفية المزمن
• التهاب البلعوم الخلفي
• إحساس بوجود جسم غريب في الحلق

التشخيص
القصة المرضية مهمة جداً في تشخيص الارتداد المعدي المريئي ، وهناك أسئلة ذات أهمية تشخيصية عالية يوجهها الطبيب لمريضة وهى:
1- هل تعاني من إحساس عدم الارتياح منتشر للأعلى خلف القص ؟
2- هل يصاحب هذا الإحساس حرقة بأعلى البطن ؟
3- هل استعمال مضادات الحموضة تخفف الأعراض ؟
4- هل حدثت الأعراض لمدة أكثر من 4 أيام خلال الأسبوع المنصرم ؟
وقد وجد أن 85% من المرضى يجيبون بنعم على جميع الأسئلة .
وقد يلجأ الطبيب لإجراء الفحوصات الشعاعية ونعني هنا الوجبة الباريتية وهي مفيدة في المرضى الذين يعانون من عسر البلع حيث يمكن أن توضح مكان وجود التضيق إن وجد كما يمكن الاستدلال على وجود وشكل الفتق الحجابي لإذا كان مصاحباً
وفي كثير من الأحيان يُّجرى للمريض التنظير الهضمي العلوي بالمنظار حيث يتم التأكد من وجود التهاب المريء وتحديد درجة الالتهاب وإمكانية وجود داء باريت وينفي وجود أمراض أخرى مشابهة من ناحية الأعراض مثل القرحة الهضمية . وفي أكثر من نصف المرضى يكون التنظير طبيعياً بالرغم من وجود الارتداد .
ومن الفحوصات التي قد يلجأ إليها الطبيب مراقبة إفراز الحامض المعدي لمدة 24 ساعة . ويستطب إجراء هذا الفحص في المرضى ذوي التنظير الطبيعي ويعانون من أعراض الارتداد ولا يستجيبو للعلاج أو الذين يشكون من ألم صدر غير نوعي ومظاهر خارج المريء ( ربو ، بحة ، سعال مزمن ) ، وكذلك في المرضى ذوي التنظير المرضي ولا يستجيبو للعلاج أو المرضى الذين سيخضعوا للعلاج الجراحي .

التشخيص التفريقي
يمكن أن يختلط تشخيص الارتداد المريئي بالكثير من الأمراض التي تتشابه معه في الصورة السريرية نذكر منها :
• التهاب المعدة
• التهاب المريء الميكروبي
• التهاب المريء بالأدوية
• القرحة الهضمية
• عسر الهضم
• أمراض القنوات الصفراوية
• أمراض الشرايين التاجية القلبية
• اضطرابات المريء الحركية

المضاعفات
قد يترافق الارتداد المريئي بالعديد من المضاعفات ومنها
• التضيق
• داء باريت
• السرطان الغدي للمريء

العلاج
يهدف العلاج إلى إراحة المريض من الأعراض وشفاء التهاب المريء بالإضافة إلى تجنب حدوث المضاعفات ؟
والخطوة الأولى والأهم في علاج التهاب المريء تقع على كاهل المريض ذاته وذلك بإتباع النصائح والإرشادات التالية :
رفع رأس السرير من جهة الرأس وإتباع حمية صارمة لإنقاص الوزن وتناول وجبات خفيفة بفترات متقاربة بدلاً من الوجبات العادية والأهم عدم تناول الطعام قبل الذهاب إلى النوم بساعتين على الأقل .
كما يتوجب على المريض الامتناع عن التدخين والكحول والنعناع والشوكولاته والأطعمة الدسمة .
أما العلاج الدوائي فالهدف الأساسي منه هو إراحة المريض من الأعراض التي يشكو منها والحفاظ على درجة حموضة المعدة بمستوى 4 أو أكثر .
وكانت مضادات الحموضة حجر الزاوية في العلاج حتى السبعينات من القرن الماضي حيث تم استحضار مضادات مستقبلات الهستامين حيث بدأ استعمال السيميتيدين وحالياً يتوفر علاجات أخرى ضمن هذه المجموعة تعطي وظيفة ألإضل ومضاعفات أقل .
وفي عام 1988 بدأ استعمال مضادات البروتون والعلاج الأقدم في هذه المجموعة هو الأميبرازول وتلا ذلك استحضار علاجات أخرى ضمن هذه المجموعة والاحدث عقار إيسوميبرازول في عام 2000 م .
وتعطى هذه الأدوية بمعدل مرة إلى مرتين يومياً وقد يحتاج المرضى للمواظبة على العلاج لفترات طويلة . وفي بعض الحالات قد يلجأ الطبيب للتدخل الجراحي بإجراء عمليات الهدف منها منع حدوث ارتداد حامض المعدة إلى المريء ولا يتسع المقام هنا لتفصيلها .

Early endoscopic follow-up nets dysplasia in 9.5% of Barrett’s

CHICAGO (FRONTLINE MEDICAL NEWS) – Early endoscopic follow-up within 24 months detected dysplasia in nearly one in 10 patients with nondysplastic or low-grade Barrett’s esophagus in a retrospective study at the Mayo Clinic. Initial endoscopy missed four cases of high-grade dysplasia or esophageal adenocarcinoma (1.9%) and 16 cases of low-grade dysplasia (7.6%) for an overall miss-rate of 9.5%. Patients on proton pump inhibitors were less likely to have dysplasia missed than were those off PPIs (20% vs. 52.6%, P = .008). Those with long- versus short-segment Barrett’s esophagus were more likely to have dysplasia overlooked (85% vs. 53.6%; P = .008; mean 6 mm vs. 4 mm; P = .006), Dr. Kavel Visrodia said at the annual Digestive Disease Week. Current American College of Gastroenterology (ACG) guidelines recommend early repeat esophagogastroduodenoscopy (EGD) to exclude the presence of missed dysplasia in newly diagnosed nondysplastic Barrett’s esophagus (BE), while the ACG and American Society for Gastrointestinal Endoscopy call for repeat EGD within 6 months for those with low-grade dysplasia. The yield for repeat EGD has not been established, and only one study exists in the literature, said Dr. Visrodia of the department of medicine, Mayo Clinic, Rochester, Minn. That study (Dis. Esophagus 2012 Sept. 28. [doi:10.1111/j.1442-2050.2012.01431.x]) showed a miss-rate of 8.2% among 146 patients with newly diagnosed nondysplastic BE. Long-segment BE was the only significant predictor of dysplasia on follow-up (odds ratio, 9.18; P = .008). The cohort was relatively small and had no long-term follow-up, and with an interval to follow-up of 36 months, “it’s possible that some of these were actually incident cases of dysplasia and not prevalent cases,” he said. To address these gaps, Dr. Visrodia and his colleagues identified 488 BE cases from 1977 to 2011 in the Rochester Epidemiology Project in Olmsted County, Minn. A total of 278 patients were excluded because of high-grade dysplasia (HGD) or esophageal cancer on index endoscopy or repeat endoscopy after 24 months, leaving 181 patients with nondysplastic BE and 29 with low-grade dysplasia (LGD). Repeat endoscopy within 24 months revealed 2 cases of HGD or cancer and 16 cases of LGD in the nondysplastic BE group, and 2 cases of HGD or cancer in the LGD group, Dr. Visrodia said. Three of the four HGD/cancer cases were in patients with long-segment BE, defined as at least 3 cm of columnar mucosa. Biopsies were insufficient in 63% of patients with missed dysplasia, compared with 55% in the group without missed dysplasia. Biopsies were considered adequate if the number of biopsies divided by the BE length was at least 2, indicating that samples were taken every 2 cm in accordance with guidelines. This risk factor is noteworthy, although the difference between groups was not statistically significant, possibly because of the small sample size, he said. Finally, after a median of 6.8 years of follow-up, 30 asymptomatic, prevalent HGDs or cancers were detected within 24 months, compared with 22 incident cases detected after 24 months. This suggests that “a greater number of high-grade dysplasias and cancers were detected up front rather than during long-term careful surveillance,” Dr. Visrodia said. During a discussion of the study, one attendee asked whether the results make a better case for aggressive ablation up front rather than for surveillance, while others expressed surprise at the high miss rate at an institution such as the Mayo Clinic. Dr. Visrodia replied that the results do give them pause, and suggested that tighter early endoscopic surveillance may be warranted, particularly in those with long-segment BE.

Infliximab monitoring during remission limits IBD flare-ups

Trough infliximab concentrations were measured in patients who were in clinical remission at about 1 year on maintenance therapy. When trough concentrations fell below 5 mcg/mL, patients got a dose increase. The goal was to prevent secondary loss of response due to recurrence of symptoms or antibody-mediated side effects, such as infusion reactions, Dr. Byron P. Vaughn explained at the annual Digestive Disease Week. In a retrospective, nonrandomized proof-of-concept study, 48 inflammatory bowel disease patients in remission on infliximab were proactively monitored, and 78 matched controls were conventionally managed. The infliximab discontinuation rate during up to 5 years of follow-up was 10% in the proactively monitored group and 31% in the controls. Nearly 90% of treatment discontinuations in the control group were caused by loss of response or development of acute infusion reactions; in contrast, no one in the proactively monitored group stopped infliximab for those reasons. “We think this is exciting information. We now recommend dose optimization to a trough level of at least 3 mcg/mL, and our current clinical practice is to target a range of 5-10 mcg/mL,” said Dr. Vaughn, of Beth Israel Deaconess Medical Center and Harvard University, Boston. Of course, the findings certainly need to be validated in a prospective study, he added. For about the first year of infliximab therapy, the treatment continuation curves were similar for the two groups. After 1 year, the curves separated and the benefit of proactive trough monitoring could be seen. The main reasons for stopping infliximab in the control group were a flare of symptoms (15 patients) and acute infusion reactions (6 patients). Neither of these events occurred in the proactively monitored patients. The reasons for treatment discontinuation in the proactively monitored group included drug-induced lupus (1 patient), psoriasis (1 patient), a delayed infusion reaction (1 patient), and a reason unrelated to the medication (1 patient). Three-quarters of study participants had Crohn’s disease, and the rest had ulcerative colitis. Other investigators have previously shown that an undetectable serum infliximab trough concentration in the setting of Crohn’s disease often heralds a loss of response. Dr. Vaughn emphasized that fully one in four patients had an undetectable trough level at the first measurement, and nearly two-thirds had levels below 5 mcg/mL. The infliximab dose was increased in those patients. Patients with a trough level of 5-10 mcg/mL received no change in their regimen, while those with a level of more than 10 mcg/mL on two occasions got either a dose reduction or an increase in the interval between doses if they were on 5 mg/kg. In gastroenterology, serum infliximab concentrations are typically measured when patients stop responding or have side effects. So the costs of proactive infliximab monitoring and dose escalation are going to be an impediment to widespread implementation of this strategy under many health plans, at least until there is confirmatory data, he said. Proactive trough concentration monitoring and dose titration are typical in recipients of solid organ transplants receiving cyclosporine, mycophenolate mofetil, and mTOR (mammalian target of rapamycin) inhibitors, and are often performed in sepsis patients receiving vancomycin and gentamicin. When asked how often he recommends proactive infliximab trough testing, Dr. Vaughn replied, “I think when people are in a steady state – they’re not ill and they’re not flaring – you could probably check once every 6 months or maybe once a year. After a few stable troughs, that could be enough unless there’s been a major change like a big weight change, a change in other medications, or an illness.”

Fecal transplant falls short in UC, but may not be the end

CHICAGO (FRONTLINE MEDICAL NEWS) – Results were negative from the first randomized placebo-controlled trial of fecal microbiota transplant in ulcerative colitis, but enthusiasm remains for this newly regulated and trendy therapy. “We need to get more data and we need to understand how better to use this approach, but I don’t think this study is telling us we should stop exploring. I still think it is an interesting avenue that we need to evaluate,” study author Dr. Paul Moayyedi said during a late-breaking abstract session at Digestive Disease Week. Part of the enthusiasm for what was described as “the new kid on the block for altering gut flora,” has been fueled by a roughly 90% success rate for fecal transplant in treating Clostridium difficile infection. Dr. Moayyedi also showcased a success story from the trial that “typifies a few patients in this study.” The patient had ulcerative colitis for almost 20 years that was unresponsive to steroids and 5-aminosalicylic acid for 2 years before the study and so severe it caused bloody diarrhea 10-20 times per day. No improvement was seen after 6 weeks of placebo therapy and his Mayo Clinic score was “about as bad as it can be” at 12. After crossing over to 6 weeks of open-label fecal microbiota transplantation (FMT), symptoms were much improved and his Mayo score dropped to 5. After 20 weeks, mucosa healed throughout the colon, his Mayo score reached 0, and he was “fine” on no medication. “What we’re finding is that 6 weeks is usually not enough and that if you continue longer, you can get remission in some patients,” said Dr. Moayyedi, the Richard Hunt-Astra Zeneca Chair in Gastroenterology, McMaster University, Hamilton, Ontario. He went on to say, “I’m a very big proponent of evidenced-based medicine, but cases like these make you think something must be going on in some patients, but we don’t have the funding to do the 500-patient trial you need to get that signal.” Dr. Moayyedi and his associates enrolled ambulatory patients with active ulcerative colitis, defined as a Mayo score of at least 4 and an endoscopic Mayo score of at least 1, who tested negative for the C. difficile gene. Patients could be on ulcerative colitis medications, if doses were stable for at least 12 weeks but had to be off antibiotics for 30 days. Patients were randomly assigned to receive a 50-mL retention enema containing fecal microbiota from an anonymous donor or water, once per week for 6 weeks. The primary outcome was remission of ulcerative colitis, defined as a Mayo score of 2 or less and an endoscopic Mayo score of 0 at week 7. Patients, clinicians, and investigators were blinded to therapy. The 31 FMT and 30 placebo patients were well matched at baseline, except for significantly more pancolitis in the FMT group (64% vs. 36%). Remission was achieved by seven FMT patients (23%) and two placebo patients (7%), which was not significantly different (P = .15), Dr. Moayyedi said. There also were no differences between the FMT and placebo groups in any of the secondary outcomes: 6-week Mayo score (6.36 vs. 6.30; P = .95), 6-week Inflammatory Bowel Disease Questionnaire (148.4 vs. 146.4; P = .85), and 6-week EQ-5D health questionnaire (61.0 vs. 66.2; P = .34). Based on these findings, the study is being stopped for futility, he said. There were no major adverse events, although the diagnosis changed to Crohn’s colitis for two patients given FMT and one on placebo. This was “much bigger than you’d expect,��� Dr. Moayyedi said. “We’re not sure why, and of course the worry is that FMT may change the phenotype, which would not be good.” If FMT is to succeed in ulcerative colitis, he suggested more data will be needed on the fecal microbiome and the best approach to administer FMT, including donor selection, timing, preparation, and duration of treatment. The group has not done an analysis of enema dwell time and response, and no signal was seen that FMT is more effective in left-sided disease. More detailed microbiome analyses of the patient highlighted during the talk, however, revealed the man had a “very diverse and unstable” microbiome at baseline that gradually became more stable, “with a loss of Ruminococcus that seems to be a feature of improvement and a movement toward the phenotype of the donor,” Dr. Moayyedi said. During a discussion of the results, some audience members expressed concern that FMT might change the phenotype, while others were more enthusiastic about the therapy. Dr. Scott Harris, a gastroenterologist and professor of medicine, Georgetown University Medical Center, Washington, said the trial was likely underpowered, and that by including patients with less severe disease, it may have been more difficult to see a treatment effect. Other trials have also shown that 6 weeks of therapy may not be enough for refractory patients. “I’m very optimistic, I wouldn’t stop at this point,” he said. Session cochair Dr. John M. Inadomi, professor of medicine and head of gastroenterology, University of Washington School of Medicine, Seattle, agreed that the length of treatment as well as the study’s use of anonymous donors could have affected results. One of the big questions is whether the donor feces actually grafted and thus affected the recipient. “If you use the wrong donor stool, if the stool didn’t graft, these kinds of things can obviously make a negative result, even if the concept is potentially fine,” he said in an interview. Last year, the Food and Drug Administration moved to require an investigational new drug permit to treat C. difficile with fecal microbiota, but changed course within weeks citing public pressure. While researchers are studying the potential to deliver feces via capsule, Dr. Moayyedi observed that some enthusiasts are offering Internet advice on how to mix your own FMT at home.

Gut microbiota may play a role in the development of alcoholic liver disease

London, UK, Saturday 12 April 2014: Exciting new data presented today at the International Liver Congress™ 2014 shows that the gut microbiota has a potential role in the development of alcoholic liver disease (ALD). Though an early stage animal model, the French study highlights the possibility of preventing ALD with faecal microbiota transplantation – the engrafting of new microbiota, usually through administering human faecal material from a healthy donor into the colon of a recipient. In the study, two groups of germ-free mice received gut microbiota transplants from human representatives; one set from a patient with severe alcoholic hepatitis, the other from a patient with a history of alcohol abuse but without alcoholic hepatitis. The two sets of germ-free mice were then fed a liquid alcoholic diet. The group that received microbiota from the patient with severe alcoholic hepatitis developed a more severe liver injury and a higher disruption of the intestinal mucosa in direct comparison to the group that received microbiota from the patient without severe alcoholic hepatitis. The study also identified two Clostridium bacteria that were able to produce ethanol in vitro and that were systematically associated with intestinal microbiota associated liver injury. EASL Scientific Committee Member Prof. Frank Lammert commented: “Among heavy drinkers, the severity of alcoholic liver disease does not strictly correlate with the amount of alcohol intake, meaning that other factors must be influencing its development.” “These findings provide first evidence for a causal role of gut microbiota in alcohol-induced inflammation, and open up new avenues for the treatment of alcoholic liver disease with potentially better patient outcomes.” At present, intestinal microbiota is considered to constitute a “microbial organ”: one that has pivotal roles in the body’s metabolism as well as immune function. Therefore transplantation aims to restore gut functionality and re-establish the homoestasis of intestinal flora. The study was developed by an INRA-Micalis and INSERM/Paris-South University/Antoine-Béclère hospital

New Chinese herbal medicine has significant potential in treating Hepatitis C

London, UK, Saturday 12 April 2014: Data from a late-breaking abstract presented at the International Liver CongressTM 2014 identifies a new compound, SBEL1, that has the ability to inhibit hepatitis C virus (HCV) activity in cells at several points in the virus’ lifecycle. SBEL1 is a compound isolated from Chinese herbal medicines that was found to inhibit HCV activity by approximately 90%. SBEL1 is extracted from a herb found in certain regions of Taiwan and Southern China. In Chinese medicine, it is used to treat sore throats and inflammations. The function of SBEL1 within the plant is unknown and its role and origins are currently being investigated. Scientists pre-treated human liver cells in vitro with SBEL1 prior to HCV infection and found that SBEL1 pre-treated cells contained 23 percent less HCV protein than the control, suggesting that SBEL1 blocks virus entry. The liver cells transfected with an HCV internal ribosome entry site (IRES)-driven luciferase reporter that were treated with SBEL1 reduced reporter activity by 50% compared to control. This suggests that that SBEL1 inhibits IRES-mediated translation, a critical process for viral protein production. In addition, the HCV ribonucleic acid (RNA) levels were significantly reduced by 78 percent in HCV infected cells treated with SBEL1 compared to the control group. This demonstrates that SBEL1 may also affect the viral RNA replication process. Prof. Markus Peck-Radosavljevic, Secretary-General of the European Association for the Study of the Liver and Associate Professor of Medicine, University of Vienna, Austria, commented: “People infected with hepatitis C are at risk of developing severe liver damage including liver cancer and cirrhosis. In the past, less than 20 percent of all HCV patients were treated because the available treatments were unsuitable due to poor efficacy and high toxicity. Recent advances means that we can now virtually cure HCV without unpleasant side effects. However, the different virus genotypes coupled with the complexity of the disease means there is still a major unmet need to improve options for all populations.” Professor Peck-Radosavljevic continued: “SBEL1 has demonstrated significant inhibition of HCV at multiple stages of the viral lifecycle, which is an exciting discovery because it allows us to gain a deeper understanding of the virus and its interactions with other compounds. Ultimately this adds to our library of knowledge that may bring us closer to improving future treatment outcomes.” HCV invades cells in the body by binding to specific receptors on the cell, enabling the virus to enter it.2 Once inside, HCV hijacks functions of the cell known as transcription, translation and replication, which enables HCV to make copies of its viral genome and proteins, allowing the virus to spread to other sites of the body.2 When HCV enters the host cell, it releases viral (+)RNA that is transcribed by viral RNA replicase into viral (-)RNA, which can be used as a template for viral genome replication to produce more (+) RNA or for viral protein synthesis. Once the viral RNA is transcribed, HCV initiates a process known as IRES-mediated translation, which allows the viral RNA to be translated into proteins by bypassing certain protein translation checkpoints that would normally be required by the host cell to start protein translation. Viral RNA is the genetic material that gives HCV its particular characteristics. This process enables the virus to take advantage of the host cell’s protein translation machinery for its own purposes. There are an estimated 150 million to 200 million people living with chronic HCV and more than 350,000 people die annually from HCV-related diseases. HCV is transmitted through blood contact between an infected individual and someone who is not infected. This can occur through needlestick injuries or sharing of equipment used to inject drugs. Disclaimer: the data referenced in this release is based on the submitted abstract. More recent data may be presented at the International Liver Congress™ 2014.

High rate of ED visits for insulin-related hypoglycemia

ST LOUIS - Insulin-related hypoglycemia and errors (IHEs) account for close to 100,000 emergency department (ED) visits per year in the United States, according to a study published online by JAMA Internal Medicine. The researchers sought to estimate the burden, rates, and characteristics of ED visits for IHEs, including identification of high-risk groups and precipitating factors. The analysis included National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance project data from 1997 through 2011, along with a national household survey of insulin use. The lead author was Dr Andrew I. Geller of the Centers for Disease Control and Prevention. Based on 8,100 cases identified from the adverse drug event surveillance database, the annual number of ED visits for IHEs was estimated at 97,648. Of these, 29.4% led to hospitalization and 60.6% were associated with severe neurologic sequelae. Blood glucose levels of 50 mg/dL or less were recorded in 53.4% of events. Patients aged 80 years older were at highest risk of ED visits for IHEs, rate ratio 2.5; and at highest risk for hospitalization, rate ratio 4.9 (compared to patients aged 45 to 64). The main precipitating factors were inadequate food intake and taking the wrong type of insulin. Recent reports have drawn attention to the potential for harmful effects of tight glycemic control with insulin in patients with type 2 diabetes. One important risk is insulin-related hypoglycemia, particularly in groups of patients who are less likely to benefit from tight control. This study identifies IHEs as an important cause of ED visits and hospitalizations, especially in diabetic patients aged 80 years and older. Of the nearly 100,000 annual ED visits for IHEs, 60,000 lead to severe neurologic sequelae and almost 30 000 to hospitalization. Efforts to reduce this risk should focus on the precipitating factors identified, such as "meal-related misadventures and insulin product mix-ups."

Distinct Presentation of Autoimmune Hepatitis in the Elderly

Distinct Presentation of Autoimmune Hepatitis in the Elderly

Dual-vaccine therapy prolonged survival in pancreatic cancer

SAN FRANCISCO (FRONTLINE MEDICAL NEWS) – Serial administration of two vaccines that stimulate the immune response to pancreatic cancer antigens prolonged survival of metastatic disease by about 2 months, according to Dr. Dung T. Le. A team led by Dr. Le of the Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center in Baltimore tested the vaccines – GVAX Pancreas and CRS-207 – in 90 patients. The interim results of the phase II trial showed that overall survival was about 4 months with GVAX alone but was 6 months with GVAX followed by CRS-207, Dr. Le reported in a press briefing held before the annual Gastrointestinal Cancers Symposium. The symposium was sponsored by the American Society of Clinical Oncology. In fact, the efficacy data met the criteria for an early halt to the trial, and patients in the single-vaccine arm are now receiving both vaccines. “This is the first randomized study of immunotherapy in metastatic pancreatic cancer demonstrating an improvement in survival,” commented press briefing moderator Dr. Smitha Krishnamurthi of Case Western Reserve University in Cleveland. “Patients who received at least one dose of the CRS-207 vaccine had a doubling of 1-year survival, and this was accomplished without the side effects of chemotherapy.” Safety results suggested that the vaccines were well tolerated. Local reactions of erythema, warmth, and swelling after intradermal administration of GVAX, as well as transient fevers and chills after infusion of CRS-207, were generally mild and transient. “Additional clinical study of the combination treatment is underway in a three-arm study testing the combination, CRS-207 alone, and chemotherapy alone,” Dr. Le noted. GVAX is an allogeneic whole-cell vaccine. Its genetically modified pancreatic cancer cells secrete granulocyte macrophage colony-stimulating factor, which attracts dendritic cells to the vaccine site, Dr. Le explained. It is given after low-dose cyclophosphamide to inhibit a regulatory T-cell response. CRS-207 consists of live-attenuated Listeria monocytogenes virus vaccine that expresses mesothelin. The vaccine stimulates innate and adaptive immunity to mesothelin, which is highly expressed in pancreatic cancer cells. The investigators tested the vaccines serially in part because GVAX induces a response to a wide variety of tumor-associated antigens, and CRS-207 then boosts the response to mesothelin. Patients in the trial, sponsored by Aduro BioTech, had declined or had experienced a failure of prior chemotherapy. They were randomized 2:1 to receive either two doses of GVAX followed by four doses of CRS-207 or to receive six doses of GVAX therapy alone, with all doses spaced 3 weeks apart. Repeated courses were allowed as long as patients were medically stable. With a median follow-up of 7.8 months, median overall survival among all patients who received at least one dose of vaccine was longer by nearly 2 months with dual-vaccine therapy compared with single-vaccine therapy (6.1 vs. 3.9 months; hazard ratio 0.59; P = .03). The 1-year probability of survival was doubled with dual versus single therapy (24% vs. 12%), according to Dr. Le. In a per-protocol analysis restricted to patients who received at least three doses of vaccine, dual therapy had a greater 5-month overall survival benefit (9.7 vs. 4.6 months; hazard ratio 0.53; P = .03).

Low hospital readmission rates apply across diagnoses

ST LOUIS (MD Consult) - Hospitals with lower 30-day readmission rates have a lower number of readmissions across a wide range of diagnoses and throughout the post-discharge period, reports a study in the January 11, 2014, British Medical Journal. The researchers analyzed data on Medicare beneficiaries aged 65 or older who were readmitted within 30 days after admission for heart failure, acute myocardial infarction, or pneumonia from 2007 to 2009. Readmission diagnoses were classified using a modified version of the Centers for Medicare and Medicaid Services' condition categories, and the timing of readmission was classified by day since discharge. Based on 30-day risk-standardized readmission rates over the 3 years studied, hospitals were classified as having high, average, or low readmission performance for each condition. The range of readmission diagnoses and median times to readmission were compared for high-, average-, and low-performing hospitals. The lead author was Kumar Dharmarajan of Columbia University Medical Center. The analysis included about 320,000 readmissions after 1.3 million admissions for heart failure at 4,041 hospitals, 103,000 readmissions after 516,000 admissions for acute myocardial infarction at 2,378 hospitals, and 208,000 readmissions after 1.1 million admissions for pneumonia at 4,328 hospitals. For all 3 index conditions, the range of readmission diagnoses was similar at hospitals with high, average, and low readmission rates. For heart failure and acute myocardial infarction, median time to readmission was similar across the 3 hospital performance groups. For pneumonia, median time to readmission was 1.4 days longer among high-performing hospitals, compared to low-performing hospitals. The patterns were similar after adjustment for additional hospital factors potentially affecting readmission rates. Thirty-day readmission rates vary substantially among U.S. hospitals. There are few data on how hospital readmission rates are related to the diagnoses and timing of readmissions. This information could have implications for identifying the effective strategies followed by the best-performing hospitals. For the 3 index diagnoses studied, hospitals with low 30-day readmission rates have proportionately fewer readmissions, with similar readmission diagnoses and timing. The results may help to explain why studies evaluating "broad based and longitudinal" interventions for lowering readmissions have higher reported higher success rates, compared to "disease specific or time limited interventions."

Never exceed dose of constipation drugs containing sodium phosphate, FDA warns

ST LOUIS (MD Consult) - On January 8, 2014, the US Food and Drug Administration (FDA) issued an alert concerning the use of over-the-counter (OTC) sodium phosphate drugs to treat constipation. The agency is warning that using more than 1 dose in 24 hours of such drugs can cause rare but serious harm to the kidneys and heart, and even death. These drug products include oral solutions and enemas. They are marketed under the brand-name Fleet, and as store brands and generic products. They are available as single-ingredient drug products, containing either sodium biphosphate or sodium phosphate, and as combination drug products containing both ingredients. The FDA reviewed the Adverse Event Reporting System database from 1969 through 2012 and the medical literature from 1957 through August 2013 for cases describing serious adverse events associated with the of over-the-counter (OTC) sodium phosphate drug products used to treat constipation. The agency identified 54 cases describing serious adverse events in 25 adults and in 29 children. These reports described severe dehydration and changes in serum electrolytes levels associated with taking more than the recommended dose of OTC sodium phosphate products, resulting in serious adverse effects on organs (eg, kidneys and heart) and in some cases resulting in death. These serum electrolytes include calcium, sodium, and phosphate. According to the reports, most cases of serious harm occurred with a single dose of sodium phosphate that was larger than recommended or with more than 1 dose in a day. Some persons may be at higher risk for potential adverse events when the recommended dose of OTC sodium phosphate is exceeded. This includes young children, persons older than 55 years, patients with dehydration, kidney disease, bowel obstruction, or bowel inflammation, and patients who receive medications that may affect kidney function. These medications include diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers used to treat hypertension, as well as nonsteroidal anti-inflammatory drugs such as aspirin, ibuprofen, and naproxen. Health care professionals should use caution when recommending an oral dose of these products for children 5 years and younger. The rectal form of these products should never be given to children younger than 2 years.

Resecting residual gastrointestinal stromal tumors improved survival

SAN FRANCISCO (IMNG)– Surgically removing residual gastrointestinal stromal tumors in patients who respond to imatinib therapy significantly increased time to tumor progression to 88 months, compared with 43 months using imatinib alone, based on findings from a retrospective study of 134 patients. After controlling for the effects of other risk factors, the surgery decreased threefold the likelihood of disease progression and decreased fivefold the risk of death, Dr. Seong Joon Park reported in a press briefing sponsored by the American Society of Clinical Oncology (ASCO). The press conference was held in advance of at a meeting on gastrointestinal cancers sponsored by ASCO and three other cancer organizations. The findings support the widely adopted practice of removing residual tumors in these patients, despite the retrospective and observational design of the study, Dr. Park said. A prospective European study of similar design to this one terminated early due to poor patient enrollment. “It’s really hard to conduct a prospective study of this design,” said Dr. Park of Asan Medical Center, Seoul, South Korea. He and his associates reviewed the records of patients who showed at least 6 months of disease stabilization or response to imatinib (Gleevec) treatment, 92 of whom got the drug treatment alone and 42 of whom underwent surgery to remove residual tumors after a median of 19 months of imatinib therapy. The imatinib therapy was restarted after surgery. Median follow-up for the cohort as a whole was 59 months. “This treatment strategy is worth trying as a clinical practice if the medical center is large enough to have an experienced multidisciplinary team and to have low morbidity and mortality associated with surgery,” he said. Each year, approximately 5,000 new cases of gastrointestinal stromal tumors are diagnosed in the United States, most often in the stomach and small intestine, though they can occur anywhere in or near the GI tract. Imatinib typically is first-line therapy, and 80%-85% of patients will respond to the treatment, he said. A majority of patients who respond to imatinib will have residual tumors, however, which are believed to contribute to the development of drug resistance, leading to the hypothesis that removing the residual tumors would improve survival. In general, one-third of patients are candidates for surgical removal of residual lesions, depending on the tumor size and other tumor and patient characteristics, Dr. Park said. The two patient groups in the study were similar except that the surgery group was significantly younger (51 vs. 58 years) and was less likely to have metastases in the peritoneum (41% in the surgery group vs. 61% in the control group). As it is an aggressive and difficult treatment, surgery is more likely to be considered and recommended to younger patients who have a good performance status and, thus, less likely to be recommended in patients with multiple peritoneal metastases. Factors associated with longer progression-free and overall survival included surgery and having an initial tumor size less than 150 mm, multivariate analyses showed. Female sex and having the KIT exon 11 mutation also were associated with longer progression-free survival. The researchers used propensity scores and inverse-probability-weighting adjustments to account for the effects of factors other than surgery.