Role of muscarinic-3 receptor antibody in systemic sclerosis: correlation with disease duration and effects of IVIG.

Gastrointestinal dysmotility in systemic sclerosis (SSc) is associated with autoantibodies against muscarinic-3 receptor (M3-R). We investigated the temporal course of the site of action of these autoantibodies at the myenteric neurons (MN) vs. the smooth muscle (SM) M3-R in relation to disease duration, and determined the role of intravenous immunoglobulin (IVIG) in reversing these changes. Immunoglobulins purified from SSc patients (SScIgG) were used to assess their differential binding to MN and SM (from rat colon) employing immunohistochemistry (IHC). Effect of SScIgG on neural and direct muscle contraction was determined by cholinergic nerve stimulation and bethanechol-induced SM contraction. Effects of IVIG and its antigen-binding fragment F(ab')2 on SScIgG binding were studied by enzyme-linked immunosorbent assay (ELISA) of rat colonic longitudinal SM myenteric plexus (LSMMP) lysate and to second extracellular loop peptide of M3-R (M3-RL2). SScIgG from all patients demonstrated significantly higher binding to MN than to SM. With progression of SSc duration, binding at MN and SM increased in a linear fashion with a correlation coefficient of 0.696 and 0.726, respectively (P < 0.05). SScIgG-mediated attenuation of neural and direct SM contraction also increased with disease duration. ELISA analysis revealed that IVIG and F(ab')2 significantly reduced SScIgG binding to LSMMP lysate and M3-RL2. Dysmotility in SSc occurs sequentially, beginning with SScIgG-induced blockage of cholinergic neurotransmission (neuropathy), which progresses to inhibition of acetylcholine action at the SM cell (myopathy). IVIG reverses this cholinergic dysfunction at the neural and myogenic receptors by anti-idiotypic neutralization of SScIgG.

Effects of scleroderma antibodies and pooled human immunoglobulin on anal sphincter and colonic smooth muscle function.

BACKGROUND & AIMS: Patients with systemic sclerosis (SSc) have impairments in gastrointestinal smooth muscle function. The disorder has been associated with circulating antibodies to cholinergic muscarinic the type-3 receptor (M(3)-R). We investigated whether it is possible to neutralize these antibodies with pooled human IgGs (pooledhIgG). METHODS: We studied the effects of IgGs purified from patients with SSc (SScIgGs) on cholinergic nerve stimulation in rat colon tissues. We also examined the effects of SScIgGs on M(3)-R activation by bethanechol (BeCh), M(3)-R occupancy, and receptor binding using immunofluorescence, immunoblot, and enzyme-linked immunosorbent analyses of human internal anal sphincter (IAS) smooth muscle cells, before and after administration of pooledhIgG. Functional displacement of M(3)-R occupancy by the SScIgGs was compared with that of other IgGs during the sustained phase of BeCh-induced contraction of intact smooth muscles from rats. RESULTS: SScIgG significantly attenuated neurally mediated contraction and acetylcholine release in rat colon as well as BeCh-induced sustained contraction of the IAS smooth muscle. In immunofluorescence analysis, SScIgG co-localized with M(3)-R. In immunoblot and enzyme-linked immunosorbent analyses, M(3)-R loop-2 peptide and human IAS SMC membrane lysates bound significant amounts of SScIgG, compared with IgGs from healthy individuals and pooledhIgG. Binding was attenuated significantly by application of pooledhIgG, which by itself had no significant effect. Incubation of samples with pooledhIgG, or mixing pooledhIgG with SScIgG before administration to tissues, significantly reduced binding of SScIgG, indicating that pooledhIgG prevents SScIgG blockade of M(3)-R. CONCLUSIONS: In studies of rat and human tissues, pooled human IgG prevent and reverses the cholinergic dysfunction associated with the progressive gastrointestinal manifestations of SSc by neutralizing functional M(3)-R antibodies present in the circulation of patients with SSc.

Symptoms of gluten ingestion in patients with non-celiac gluten sensitivity: A randomized clinical trial.

OBJECTIVES: Non-celiac gluten sensitivity (NCGS) is the presence of symptoms induced by gluten and relieved by a gluten-free diet (GFD) in patients without celiac disease or wheat allergy. Studies are mixed as to whether gluten is the main symptom trigger in patients with NCGS. Gluten immunogenic peptides (GIPs) in stool and urine are novel methods to monitor GFD compliance. Few studies have investigated their use in patients with NCGS. The aim of this study was to assess whether patients with NCGS have increased symptoms with gluten ingestion and to assess compliance with the GFD using stool and urine GIPs. METHOD: This was a prospective, randomized, double-blinded crossover trial evaluating symptoms in patients with NCGS. Thirty patients with NCGS and 43 healthy controls were placed on a GFD. Patients received 0.5 or 2 g/d of gluten for 7 d each. The remaining weeks, they received placebo for a total of 4 wk. Symptoms were evaluated weekly using the Celiac Symptom Index (CSI). Urine and stool samples were collected weekly and measured for the detection of GIPs to detect exposure to gluten. RESULTS: There was no difference in symptom severity within the NCGS group whether receiving placebo or gluten (32.69 versus 31.54, P = 0.64). Patients with NCGS had significantly higher CSI scores at baseline than healthy controls. Patients with NCGS were less likely to have stool and urine GIPs than healthy patients. CONCLUSION: Patients with NCGS were more adherent to the GFD based on stool and urine GIP results. Patients with NCGS had increased symptom severity at baseline compared with healthy controls. Neither group had significantly increased symptoms after ingestion of gluten.

The impact of risk factors on gastroparesis at an urban medical center.

BACKGROUND: Gastroparesis is a complex and poorly understood disease. The literature is lacking with respect to the epidemiology of patient comorbidities and their effect on gastric emptying. We aimed to describe the most common comorbid conditions among patients with gastroparesis in an urban population and quantify the effect of these comorbidities on the severity of delayed gastric emptying (DGE). METHODS: We examined the medical records of all patients diagnosed with gastroparesis at a quaternary care center between 2014 and 2015. The severity of DGE was analyzed after patients were stratified for possible causative etiologies. Likelihood ratio tests were used to assess the significance of demographic and scintigraphic variation in this population. RESULTS: Of the 221 patients, 56.1% were Caucasian and 31.7% were African American. Among these patients, 29.4% had evidence of medication-associated gastroparesis, 29.0% had diabetes-associated gastroparesis, and 31.7% had idiopathic disease. African American patients with gastroparesis were more likely to have diabetic gastroparesis than patients of other races (P=0.01). There was a statistically significant relationship between the number of major risk factors and the severity of a patient's DGE (P=0.004). CONCLUSIONS: Among a diverse urban population, patients with DGE often carry multiple comorbid conditions that serve as risk factors for the development of gastroparesis, including prescriptions for narcotic medications. Greater numbers of these comorbid conditions are associated with more severe disease. Demographics are significantly associated with the etiology and severity of gastroparesis; in particular, African American patients are more likely to have diabetic gastroparesis than patients of other races.

Immunoglobulins from scleroderma patients inhibit the muscarinic receptor activation in internal anal sphincter smooth muscle cells.

Systemic sclerosis (SSc) IgGs affecting the M(3)-muscarinic receptor (M(3)-R) have been proposed to be responsible for the gastrointestinal (GI) dysmotility in this disease. However, the effect of SSc IgGs on smooth muscle cell (SMC) function has not been studied. We determined the effect of SSc IgGs on the muscarinic receptor activation by bethanechol (BeCh; methyl derivate of carbachol) in SMC and smooth muscle strips from rat internal anal sphincter. IgGs were purified from GI-symptomatic SSc patients and normal volunteers, with protein G-Sepharose columns. SMC lengths were determined via computerized digital micrometry. The presence of M(3)-R and IgG-M(3)-R complex was determined by Western blot. IgGs from SSc patients but not from normal volunteers caused significant and concentration-dependent inhibition of BeCh response (P < 0.05). The maximal shortening of 22.2 +/- 1.2% caused by 10(-4) M BeCh was significantly attenuated to 8.3 +/- 1.2% by 1 mg/ml of SSc IgGs (P < 0.05). Experiments performed in smooth muscle strips revealed a similar effect of SSc IgG that was fully reversible. In contrast to the effect on BeCh, the SSc IgGs caused no significant effect (P > 0.05) on K(+) depolarization and alpha(1)-adrenoceptor activation by phenylephrine. Western blot studies revealed the specific presence of SSc IgG-M(3)-R complex. SSc IgGs attenuated M(3)-R activation, which was reversible with antibody removal. These data suggest that SSc GI dysmotility may be caused by autoantibodies that inhibit the muscarinic neurotransmission. Future treatment of SSc patients may be directed at the removal or neutralization of these antibodies.

Effect of zolpidem on the sleep arousal response to nocturnal esophageal acid exposure.

BACKGROUND & AIMS: Nocturnal acid reflux is associated with complicated gastroesophageal reflux (GER) disease. Nocturnal GER initiates a protective arousal reflex, which induces a swallow to clear esophageal acid. The purpose of this study was to determine the effect of zolpidem on the sleep arousal mechanism and acid clearance in patients with documented GER, compared with control subjects with normal acid exposure. METHODS: Eight controls and 16 GER patients were enrolled in a randomized, double-blind, placebo-controlled study. Zolpidem or placebo was given on separate nights. Reflux events and reflux-associated arousals or awakenings were recorded using simultaneous esophageal pH recording and standard polysomnography. RESULTS: Nocturnal acid exposure resulted in a sleep arousal 89% of the time in participants (with and without GER) given placebo but only 40% in those given zolpidem (P < .01). In controls given placebo, acid reflux events lasted 1.15 +/- 0.28 seconds; in controls given zolpidem, they lasted 15.67 +/- 12.42 seconds (P < .01). In GER patients given placebo, the acid reflux events lasted 37.8 +/- 17.2 seconds compared with 363.3 +/- 139.3 seconds with zolpidem (P < .01). With zolpidem reflux events lasted 630.6 +/- 236.5 seconds when no arousal occurred and 49.2 +/- 19.11 seconds when an arousal was recorded (P < .001). CONCLUSIONS: Zolpidem reduced the arousal response to nocturnal acid exposure and increased the duration of each esophageal acid reflux event in healthy individuals and patients with GER. Because nocturnal acid exposure was prolonged, hypnotic use by patients with GER could lead to increased risk for complicated disease.

Clinical utility of selective esophageal manometry in a tertiary care setting.

PURPOSE: To evaluate the utility of selective esophageal manometry in clinical practice. RESULTS: Retrospective data from 200 subjects was reviewed. Manometry was considered to be (1) high clinical utility when specific abnormality was identified resulting in therapeutic intervention, (2) low clinical utility when specific abnormality was identified without alteration of therapy, (3) limited clinical utility when manometry was normal. High, low, and limited clinical utility was noted in 47, 40, and 13% of instances. Manometry was of high utility in patients with dysphagia or non-cardiac chest pain (P < 0.05), and low utility in gastroesophageal reflux (P < 0.05). CONCLUSIONS: (1) Esophageal manometry has high clinical utility in dysphagia after exclusion of structural disorders; and non-cardiac chest pain after careful exclusion of reflux. (2) Ineffective motility disorder has high association with gastroesophageal reflux disease but low clinical utility except in preoperative assessment for fundoplication. (3) Esophageal manometry is of high utility in clinical practice when used in conjunction with other diagnostic exclusions.

Presentation and prognosis of esophageal adenocarcinoma in patients below age 50.

Esophageal adenocarcinoma (EAC), one of the fastest growing cancers in the United States, is increasingly recognized in younger patients in whom the clinicopathologic features have been poorly described. We aim to compare clinical presentation between early (i.e.,

Persistent risk for new, subsequent new and recurrent hepatocellular carcinoma despite successful anti-hepatitis B virus therapy and tumor ablation: The need for hepatitis B virus cure.

Hepatitis B virus (HBV) is one of the most significant hepatocarcinogens. The ultimate goal of anti-HBV treatment is to prevent the development of hepatocellular carcinoma (HCC). During the last two decades, with the use of currently available anti-HBV therapies (lamivudine, entecavir and tenofovir disoproxil fumatate), there has been a decrease in the incidence of HBV-associated HCC (HBV-HCC). Furthermore, several studies have demonstrated a reduction in recurrent or new HCC development after initial HCC tumor ablation. However, during an observation period spanning 10 to 20 years, several case reports have demonstrated the development of new, subsequent new and recurrent HCC even in patients with undetectable serum HBV DNA. The persistent risk for HCC is attributed to the presence of covalently closed circular DNA (cccDNA) in the hepatocyte nucleus which continues to work as a template for HBV replication. While a functional cure (loss of hepatitis B surface antigen and undetectable viral DNA) can be attained with nucleos(t)ide analogues, these therapies do not eliminate cccDNA. Of utmost importance is successful eradication of the transcriptionally active HBV cccDNA from hepatocyte nuclei which would be considered a complete cure. The unpredictable nature of HCC development in patients with chronic HBV infection shows the need for a complete cure. Continued support and encouragement for research efforts aimed at developing curative therapies is imperative. The aims of this minireview are to highlight these observations and emphasize the need for a cure for HBV.

Update Treatment for HBV Infection and Persistent Risk for Hepatocellular Carcinoma: Prospect for an HBV Cure.

Since the discovery of the hepatitis B virus (HBV) by Blumberg et al. in 1965, its genome, sequence, epidemiology, and hepatocarcinogenesis have been elucidated. Globally, hepatitis B virus (HBV) is still responsible for the majority of hepatocellular carcinoma (HCC). HCC is the sixth-most common cancer in the world and the second-most common cancer death. The ultimate goal of treating HBV infection is the prevention of HCC. Fortunately, anti-HBV treatment with nucleos(t)ide analogues (NAs), which began with lamivudine in 1998, has resulted in remarkable improvements in the survival of patients with chronic hepatitis B and a reduced incidence of HCC. These results were documented with lamivudine, entecavir, and tenofovir. Nonetheless, as the duration of antiviral treatment increases, the risk for HCC still remains despite undetectable HBV DNA in serum, as reported by different investigators with observation up to 4⁻5 years. In our own experience, we are witnessing the development of HCC in patients who have received antiviral treatment. Some have enjoyed negative serum HBV DNA for over 12 years before developing HCC. Current treatment with NAs can effectively suppress the replication of the virus but cannot eradicate the covalently closed circular DNA (cccDNA) that is within the nucleus of hepatocytes. There still remains a great need for a cure for HBV. Fortunately, several compounds have been identified that have the potential to eradicate HBV, and there are ongoing clinical trials in progress in their early stages.

An audit of endoscopic complications in adult eosinophilic esophagitis.

BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) in adults, characterized by the triad of dysphagia, a ringed esophagus, and mucosal eosinophilic infiltration, has associated complications that include vertical mucosal lacerations, instrumental perforation, and emesis-induced rupture. The aim of this study was to determine whether clinical, endoscopic, and histologic features can be used to predict the risk for development of these complications. METHODS: A review was conducted of 36 patients with EoE. Complications were defined as mucosal lacerations or radiographic evidence of perforation. RESULTS: The mean age at presentation was 33.9 years. Twenty-eight (78%) patients were men. Complications occurred in 11 patients (31%). There were 7 mucosal lacerations, 3 perforations, and 1 emesis-induced rupture. Strictures were reported in 7 of 11 complicated cases compared with 2 of 25 of uncomplicated cases. Dilatation procedures had been performed in 6 of 7 complicated cases associated with stricture. Biopsy specimens obtained from 7 of 9 patients with complications showed 40 or more eosinophils/high-power field. There were no statistical differences between complicated and uncomplicated patients regarding demographics, clinical features, endoscopic characteristics, or histopathologic findings. CONCLUSIONS: EoE is a high-risk disorder with a range of complications. Although demographics, clinical presentation, and endoscopic features cannot distinguish risk, the presence of stricture, a longer duration of symptoms, and a greater density of eosinophilic infiltration suggest increased risk. The density of eosinophilic infiltration cannot be determined prospectively; therefore, the performance of endoscopy and subsequent dilatation should be deferred until biopsy specimens are reviewed or treatment is completed.

Impact of chronic conditions on quality of life in patients with inflammatory bowel disease.

BACKGROUND: Although studies suggest that inflammatory bowel disease (IBD) has a significant impact on an individual's health-related quality of life, the added weight of other health conditions and comorbidities has not been investigated. The purpose of this study was to expand on prior research by taking into account the impact of other chronic health conditions on the health-related quality of life of individuals with IBD, and to develop a model to help clinicians understand the relative impact of various predictors of their patients' physical and mental health-related quality of life. METHODS: 615 patients from the gastroenterology outpatient practice of a large, urban university hospital received a self-administered survey including questions about their health conditions, the severity of their bowel symptoms, and their health-related quality of life (measured using the SF-36 instrument). RESULTS: 314 completed surveys were returned, resulting in a response rate of 51.1%. Two regression analyses were conducted to identify the role of patient demographic variables and other chronic conditions on the 2 primary outcomes of interest: the SF-36 Physical Component and Mental Component Summary scores. Statistically significant predictors of physical quality of life included IBD disease severity, arthritis, heart disease, age, anemia, back/shoulder pain, and hypertension; statistically significant predictors of mental health-related quality of life were IBD disease severity, depression/anxiety, age, and headaches. CONCLUSIONS: IBD disease severity is the most important predictor of both physical and mental health-related quality of life in patients with this condition despite the presence of other chronic conditions.

Association between common variable immunodeficiency and collagenous infiltrative disorders of the gastrointestinal tract: A series of four patients.

Hypogammaglobulinemia/common variable immunodeficiency (CVID) may lead to disruption of the gut mucosal immune barrier. Collagenous infiltrative disorders of the intestinal tract (colitis, gastritis, sprue) constitute a relatively new spectrum of gastrointestinal disorders. Our aims were (1) to determine the association between immunoglobulin deficiency state like CVID and collagenous infiltrative disorders of the gut and (2) to study the clinic-pathologic characteristics and treatment outcomes in these patients. A retrospective search was conducted to identify cases with concurrence of these two conditions at an academic center from 2007 to 2013. Four such patients were identified from our database: three with collagenous colitis and one with collagenous gastritis. All patients with collagenous colitis had normal colonic mucosa while the patient with collagenous gastritis had nodular gastric mucosa. Only one patient out of four had decreased plasma cells in the submucosa as expected in low immunoglobulin states. All patients had improvement in their symptoms on immunoglobulin therapy with considerable remission on budesonide. Literature search revealed reporting of four similar patients. In conclusion, (1) the association between collagenous infiltrative disorders of the gut and CVID and its prompt response to immunoglobulins with effective maintenance with budesonide are novel findings. Our study also shows that the presence of plasma cells should not rule out the possibility of CVID. (2) In patients with chronic diarrhea, hypogammaglobulinemia and collagenous colitis/sprue should be considered for the available effective treatments such as immunoglobulins and budesonide.

Clinical relevance of esophageal and gastric pH measurements in patients with gastro-esophageal reflux disease (GERD).

BACKGROUND: Gastro-esophageal reflux disease (GERD) is a highly prevalent disease caused by the exposure of the esophagus to refluxed gastric contents. Proton pump inhibitors (PPIs) are the mainstay of current treatment. At present, the assessment of the efficacy of different PPIs in the treatment of GERD employs two measures: esophageal and gastric pH monitoring. Esophageal pH monitoring is the most accurate method of detecting reflux episodes and, therefore, its role as a diagnostic modality is well accepted. Gastric pH monitoring, on the other hand, is an accurate measure of gastric acid pH, but its relevance to patients with GERD is questionable, since recordings correlate poorly with esophageal acid exposure. OBJECTIVE: This paper reviews (based on a Medline literature search, 1980-2004) the clinical relevance of esophageal and gastric pH measurements in both the management of GERD and in the evaluation of the efficacy of PPI therapy. FINDINGS AND CONCLUSIONS: Evidence presented suggests that the assessment of esophageal pH yields data of greater relevance to patients with GERD than does data from gastric pH. This largely arises from the fact that esophageal pH monitoring assesses the pH of the refluxate and the frequency of reflux episodes at the mucosal site affected by the disease. The use of esophageal pH monitoring is recommended in patients who fail to present with endoscopic evidence of esophagitis, those with extra-esophageal symptoms, those who have failed traditional anti-reflux therapies, and those who are potential candidates for anti-reflux surgery. In recent years, the technique has benefited from the development of a wireless pH probe, and there is also an increasing body of evidence supporting its use in combination with other emerging technologies, such as Bilitec monitoring and multichannel intraluminal impedance. Such an approach is anticipated to aid both the diagnosis of GERD and the characterization of gastro-esophageal reflux (GER) in these patients.

Survey of anal sphincter dysfunction using anal manometry in patients with fecal incontinence: a possible guide to therapy.

BACKGROUND: Despite the surge of new medical and surgical approaches to treat fecal incontinence, the types of sphincter abnormalities in patients with incontinence have not been well characterized. We aimed to categorize anal sphincter dysfunction using anorectal manometry in patients with fecal incontinence as a potential guide for improved treatment. METHODS: A retrospective review of 162 consecutive patients with fecal incontinence referred for anorectal manometry was performed. Resting anal pressure and maximal squeeze pressure were considered as measures of internal anal sphincter and external anal sphincter function respectively. RESULTS: Mean age of the patients was 63 years (13-89); females (81.5%) and males (18.5%). 74% of the patients had sphincter dysfunction on anorectal manometry. Internal anal sphincter dysfunction was present in 62% patients vs. external anal sphincter dysfunction present in 44% patients. 80% females had abnormal manometry vs. 44% in males (P<0.0001). Internal anal sphincter dysfunction was present in 68% females vs. 37% in males (P=0.0026). CONCLUSIONS: Overall, abnormal anorectal manometry studies revealed that internal anal sphincter dysfunction is the most common finding, alone or in combination with external anal sphincter dysfunction. We suggest that anorectal manometry may be important to delineate anal sphincter function prior to using newer therapeutic mechanical devices. Future studies using pharmacological agents to increase internal anal sphincter tone may be of clinical importance. Finally, the classification of fecal incontinence based on the type of sphincter dysfunction may be an improved guide in the selection of newer agents in treating fecal incontinence.

Physicians Caring for Celiac Patients do not Routinely Recommend Screening of First-Degree Family Members.

AIM: Screening first-degree relatives of celiac disease (CD) patients offers an opportunity to diagnose CD in a high-risk population.This study aims to determine how frequently CD patients receive a physician-issued recommendation for first-degree relative screening. MATERIALS AND METHODS: A 12-question survey assessing whether CD patients receive a physician recommendation to screen first-degree relatives for CD, and the impact of such a recommendation, was validated with outpatients in a university gastroenterology practice ("University"). The 12-question survey was then distributed online to members of a celiac organization - the National Foundation for Celiac Awareness ("NFCA"). Results were collected over 3 months. Univariate analysis was used to compare cohort means and assess the association between demographic and diagnostic factors and first-degree relative screening recommendations. RESULTS: 87 University patients participated in the validation phase. Test-retest reliability of 4 key survey questions was high (Kappa coefficient > 0.80). The main analyses were based on data from 677 NFCA and 82 University respondents. Respondents were predominantly female, with a mean age of 45 years. Significantly more University patients received a recommendation for screening (78% vs 44%, p < 0.001). Ninety-eight percent receiving a screening recommendation (both groups) discussed this with family members, leading to CD screening (University 71%, NFCA 79%) and, ultimately, a CD diagnosis (University 18%, NFCA 27%). CONCLUSIONS: Physicians of CD patients often do not recommend screening first-degree family members. The high clinical impact of this recommendation suggests that greater physician compliance with screening may increase the diagnosis of CD in high risk individuals.

Increased rates of pregnancy complications in women with celiac disease.

BACKGROUND: Celiac disease is an immune-mediated small bowel disorder that develops in genetically susceptible individuals upon exposure to dietary gluten. Celiac disease could have extra-intestinal manifestations that affect women's reproductive health. The aim of this study was to investigate fertility and outcomes of pregnancy among women with celiac disease. METHODS: In a retrospective cohort study, we analyzed information collected from patients at a tertiary care celiac center and from members of 2 national celiac disease awareness organizations. Women without celiac disease were used as controls. Women completed an anonymous online survey, answering 43 questions about menstrual history, fertility, and outcomes of pregnancy (329 with small bowel biopsy-confirmed celiac disease and 641 controls). RESULTS: Of the 970 women included in the study, 733 (75.6%) reported that they had been pregnant at some point; there was no significant difference between women with celiac disease (n=245/329, 74.5%) and controls (488/641, 76.1%; P=0.57). However, fewer women with celiac disease than controls (79.6% vs. 84.8%) gave birth following 1 or more pregnancies (P=0.03). Women with celiac disease had higher percentages of spontaneous abortion than controls (50.6% vs. 40.6%; P=0.01), and of premature delivery (23.6% vs. 15.9% among controls; P=0.02). The mean age at menarche was higher in the celiac disease group (12.7 years) than controls (12.4 years; P=0.01). CONCLUSIONS: In a retrospective cohort analysis examining reproductive features of women with celiac disease, we associated celiac disease with significant increases in spontaneous abortion, premature delivery, and later age of menarche.

A long-term study of the effects of antiviral therapy on survival of patients with HBV-associated hepatocellular carcinoma (HCC) following local tumor ablation.

The ultimate goal of antiviral therapy for chronic hepatitis B (CHB) is prevention of hepatocellular carcinoma (HCC). Earlier we reported favorable effects of antiviral therapy on survival of HCC patients following curative tumor ablation (Int J Cancer online 14 April 2010; doi: 10.1002/ijc.25382). It was the first observation made in the United States. We now report 12 year follow-up of this patient group. CHB patients with no prior antiviral therapy with a single HCC (≤ 7 cm) were studied. All patients underwent local tumor ablation as their first option. Patients diagnosed before 1999 received no antiviral treatment while those diagnosed after 1999 received antiviral treatment. Survival between the treated and untreated groups was compared. Among 555 HCC patients seen at our clinic between 1991 and 2013, 25 subjects were eligible. Nine subjects (all male patients, median age 53 years [46-66]) did not receive antiviral therapy while 16 (14 male patients, median age 56 years [20-73]) received treatment. Between the two groups, there was no difference in their median tumor size and levels of alpha-fetoprotein and albumin. However, the survival was significantly different (P = 0.001): the median survival of the untreated was 16 months (3-36 months) while that of the treated was 80 months (15-152 months). Fourteen of 16 treated patients are alive to date with two longest survivors alive for ≥ 151 months. In conclusion, concomitant antiviral therapy for CHB patients with HCC reduces and prevents new/recurrent tumor and improves survival. This novel treatment strategy offers an alternative to liver transplantation in patients with HBV-associated HCC.

Association of achalasia and eosinophilic esophagitis.

Various esophageal motor disorders including achalasia have been sporadically reported in patients with eosinophilic esophagitis (EoE). The aim of this study was to determine the association between achalasia and EoE and to review the treatment outcomes in patients having both conditions. A retrospective search was conducted to identify the cases of achalasia having EoE over the last 10 years at a tertiary care hospital in the United States. Subsequently, a review of the literature was performed to search for cases of achalasia that have concurrent EoE. The retrospective study showed that 4 out of 512 patients of achalasia (<1 %) had concomitant EoE. The eosinophil counts were high (80-100/hpf) but the classic endoscopic features of EoE were present in only one patient. Long term outcome following treatment including botox, myotomy and corticosteroids was generally poor. Sixteen patients have been reported in the literature out of which five patients were reported in detail. Patients had good short term response to various therapies. The long term outcomes have not been reported. These studies suggest that a concurrence of these two conditions, although rare, may occur and may not be recognized by usual endoscopic features of EoE. Long term treatment outcomes, distinct from short term in the literature, may be poor.