Jihane N. Benhammou

Autoimmune atrophic gastritis: current perspectives

At present there is no universally accepted classification for gastritis. The first successful classification (The Sydney System) that is still commonly used by medical professionals was first introduced by Misiewicz et al in Sydney in 1990. In fact, it was the first detailed classification after the discovery of Helicobacter pylori by Warren and Marshall in 1982. In 1994, the Updated Sydney System was proposed during the International Workshop on the Histopathology of Gastritis followed by the publication in The American Journal of Surgical Pathology by Dixon et al. Using the new classification, distinction between atrophic and nonatrophic gastritis was revised, and the visual scale grading was incorporated. According to the Updated Sydney System Classification, atrophic gastritis is categorized into multifocal (H. pylori, environmental factors, specific diet) and corpus-predominant (autoimmune). Since metaplasia is a key histological characteristic in patients with atrophic gastritis, it has been recommended to use the word “metaplastic” in both variants of atrophic gastritis: autoimmune metaplastic atrophic gastritis (AMAG) and environmental metaplastic atrophic gastritis. Although there are many overlaps in the course of the disease and distinction between those two entities may be challenging, the aim of this review article was to describe the etiology, epidemiology, pathogenesis, diagnosis, clinical manifestations and treatment in patients with AMAG. However, it is important to mention that H. pylori is the most common etiologic factor for the development of gastritis in the world.

Gastric Hypersecretory States: Investigation and Management

Opinion statementHypersecretory conditions affecting the stomach account for significant morbidity and mortality manifested in some cases with peptic ulcer, gastrointestinal hemorrhage, and/or gastroesophageal reflux disease (GERD). The diagnosis of gastric acid hypersecretory states can be challenging and relies on the use of quantitative assays to measure gastric acid secretion and serum gastrin. The most common etiology for hypergastrinemia is the use of potent gastric acid inhibitors such as the proton pump inhibitors. The differential diagnosis of this condition is of critical importance, and will dictate management decisions. Conditions such as atrophic gastritis are relatively benign and can lead to hypergastrinemia without the presence of gastric acid hypersecretion. Zollinger-Ellison syndrome, on the other hand, causes hypergastrinemia with profound gastric acid hypersecretion [1]. More common causes of hypergastrinemia include gastric outlet obstruction, ileus, and chronic renal failure [2]. In most cases, proton pump inhibitors will be used to manage these conditions. In some instances, surgical therapy may be required. This chapter will review the important clinical causes of gastric acid hypersecretion and provide insights to the best medical management options to better care for patients with these disorders.

PACAP Regulation of Gastrointestinal Function and Obesity

Pituitary adenylate cyclase activating polypeptide (PACAP) is a 27- or 38-amino acid peptide that is widely distributed in both the peripheral and central nervous systems. PACAP has been found to be expressed within the enteric nervous system and gastric mucosa and has profound physiological effects in the gastrointestinal tract. We have previously shown that PACAP regulates gastric acid secretion by activating its high affinity PAC1 receptors expressed on gastric enterochromaffin-like cells (ECL). However, the peripheral mechanisms involved in PACAP regulation of appetite and feeding are unknown. Vasoactive intestinal peptide (VIP) is a 28-amino acid peptide abundantly expressed in the central nervous system as well as in the gastrointestinal tract, where it regulates different physiological functions. VIP inhibits gastric acid secretion via its VPAC1 receptors expressed on gastric D cells. VIP also regulates intestinal motility and VIP gene deletion results in the development of intestinal ileus. VIP is involved in the control of appetite/satiety, feeding behavior and in the secretion of some key regulatory metabolic hormones. VIP plays a very important role in the regulation of body weight and mass composition by significantly enhancing body weight and fat mass. Therefore, both PACAP and VIP neuropeptides could be crucial targets for the regulation of appetite/satiety, body phenotype and for the treatment of obesity.

Gastrointestinal Manifestations of Hereditary Hemorrhagic Telangiectasia (HHT): A Systematic Review of the Literature

Hereditary hemorrhagic telangiectasia (HHT), also called Osler–Weber–Rendu syndrome, is an autosomal dominant genetic disease that affects the vasculature of numerous organs. The prevalence of HHT is estimated to be between 1.5 and 2 persons per 10,000. While there is still much to learn about this condition, there is an increasing understanding its underlying pathophysiology, genetic basis, presentations, and management. Recognizing that the clinical manifestations of HHT can involve a number of organ systems will provide clinicians with a higher index of suspicion for the disease. This early diagnosis and genotyping can greatly reduce mortality for a patient with HHT through appropriate screening for complications. This review will focus on the gastrointestinal manifestations of HHT and how these can dictate treatment and prognosis.

Mo1881 Hypergastrinemia Associated With Gastrointestinal Dysmotility Is Mediated by Vasoactive Intestinal Polypeptide (VIP)

G A A b st ra ct s potencies (PLC activation) for BRS-3, GRPR and NMBR of human, rat or mouse on native and transfected cells. Results: GRP and NMB had very low affinity (IC50 >3000 nM) for r,m,hBRS-3 receptors, but high affinity and selectivity for their own receptors (GRPR, NMBR) in all species. Peptide #1 had high affinity for all three human BnRs, and r,mNMBR/GRPR. Because of a lack of a radioligand for r,mBRS-3, their affinities could not be assessed by binding studies, only by potency of cell activation. In human BRS-3 receptors, the relative affinities of the chiral diazepines was 9G (IC50: 70 nM) > 9D (IC50: 121 nM) > 9F (IC50: 495 nM) > 3F (IC50: 908 nM); each was selective for BRS-3, and each did not interact with hGRPR, hNMBR even at concentrations up to 3000 nM, nor did they interact with r,mGRPR, NMBR. For stimulating PLC activity, in hBRS-3 each of the four chiral diazepine analogs was fully efficacious and their relative potencies were: peptide #1 (EC50: 4 nM) > 9G (EC50: 9 nM) > 9D (EC50: 9.4 nM) > 9F (EC50: 39 nM) > 3F (EC50: 48 nM) >>GRP, NMB (EC50 >3000 nM). Comparison of affinities and potencies demonstrated the different diazepine analogs had variable receptor sparseness wirh IC50/EC50 ratios of: 7.7 (9G), 12.8 (9D), 12.6 (9F), 18.9 (3F). None of the four chiral diazepine analogs activated r,m,hGRPR, NMBR even at concentrations of 3000 nM. Conclusions: This study demonstrates the recently described chiral diazepines analogs (9G, 9D, 9F, 3F) are fully efficacious agonists for the BRS-3 receptor in human and rhodent cells. Furthermore, they are highly selective for this receptor, as well as having high potency, and should prove useful for exploring its role in GI physiological and pathological processes.

Metabolic syndrome does not affect sustained virologic response of direct-acting antivirals while hepatitis C clearance improves hemoglobin A1c

AIM To determine whether successful treatment with directacting antivirals (DAA) is associated with improvements in hemoglobin A1c (HbA1c) and if type 2 diabetes mellitus (T2DM) or metabolic syndrome affects sustained virologic response (SVR). METHODS We performed a retrospective analysis of all hepatitis C virus (HCV) patients at the VA Greater Los Angeles Healthcare System treated with varying DAA therapy between 2014-2016. Separate multivariable logistic regression was performed to determine predictors of HbA1c decrease ≥ 0.5 after DAA treatment and predictors of SVR 12-wk post treatment (SVR12). RESULTS A total of 1068 patients were treated with DAA therapy between 2014-2016. The presence of T2DM or metabolic syndrome did not adversely affect SVR12. 106 patients had both HCV and T2DM. Within that cohort, patients who achieved SVR12 had lower mean HbA1c pre treatment (7.35 vs 8.60, P = 0.02), and lower mean HbA1c post-treatment compared to non-responders (6.55 vs 8.61, P = 0.01). The mean reduction in HbA1c after treatment was greater for those who achieved SVR12 than for non-responders (0.79 vs 0.01, P = 0.03). In adjusted models, patients that achieved SVR12 were more likely to have a HbA1c decrease of ≥ 0.5 than those that did not achieve SVR12 (adjusted OR = 7.24, 95%CI: 1.22-42.94). CONCLUSION In HCV patients with T2DM, successful treatment with DAA was associated with a significant reduction in HbA1c suggesting that DAA may have a role in improving insulin sensitivity. Furthermore, the presence of T2DM or metabolic syndrome does not adversely affect SVR12 rates in patients treated with DAA.

Race affects SVR12 in a large and ethnically diverse hepatitis C‐infected patient population following treatment with direct‐acting antivirals: Analysis of a single‐center Department of Veterans Affairs cohort

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease. HCV cure has been linked to improved patient outcomes. In the era of direct‐acting antivirals (DAAs), HCV cure has become the goal, as defined by sustained virological response 12 weeks (SVR12) after completion of therapy. Historically, African‐Americans have had lower SVR12 rates compared to White people in the interferon era, which had been attributed to the high prevalence of non‐CC interleukin 28B (IL28B) type. Less is known about the association between race/ethnicity and SVR12 in DAA‐treated era. The aim of the study is to evaluate the predictors of SVR12 in a diverse, single‐center Veterans Affairs population. We conducted a retrospective study of patients undergoing HCV therapy with DAAs from 2014 to 2016 at the VA Greater Los Angeles Healthcare System. We performed a multivariable logistic regression analysis to determine predictors of SVR12, adjusting for age, HCV genotype, DAA regimen and duration, human immunodeficiency virus (HIV) status, fibrosis, nonalcoholic fatty liver disease (NAFLD) fibrosis score, homelessness, mental health, and adherence. Our cohort included 1068 patients, out of which 401 (37.5%) were White people and 400 (37.5%) were African‐American. Genotype 1 was the most common genotype (83.9%, N = 896). In the adjusted models, race/ethnicity and the presence of fibrosis were statistically significant predictors of non‐SVR. African‐Americans had 57% lower odds for reaching SVR12 (adj.OR = 0.43, 95% CI = 1.5‐4.1) compared to White people. Advanced fibrosis (adj.OR = 0.40, 95% CI = 0.26‐0.68) was also a significant predictor of non‐SVR. In a single‐center VA population on DAAs, African‐Americans were less likely than White people to reach SVR12 when adjusting for covariates.

Microbiome and bile acid profiles in duodenal aspirates from patients with liver cirrhosis: The Microbiome, Microbial Markers and Liver Disease Study: Microbiome, bile acids, and liver cirrhosis

Cirrhosis is a leading cause of death worldwide, yet there are no well‐established risk stratifying tools for lethal complications, including hepatocellular carcinoma (HCC). Patients with liver cirrhosis undergo routine endoscopic surveillance, providing ready access to duodenal aspirate samples that could be a source for identifying novel biomarkers. The aim of this study was to characterize the microbiome and bile acid profiles in duodenal aspirates from patients with liver cirrhosis to assess the feasibility of developing biomarkers for HCC risk stratification.

Impact of sustained virologic response on chronic kidney disease progression in hepatitis C

AIM To determine how sustained virological response at 12 wk (SVR12) with direct acting antivirals (DAAs) for the treatment of hepatitis C virus (HCV) infection affects chronic kidney disease (CKD) progression. METHODS A retrospective analysis was performed in patients aged ≥ 18 years treated for HCV with DAAs at the VA Greater Los Angeles Healthcare System from 2014-2016. The treatment group was compared to patients with HCV from 2011-2013 who did not undergo HCV treatment, prior to the introduction of DAAs; the control group was matched to the study group in terms of age, gender, and ethnicity. Analysis of variance and co-variance was performed to compare means between SVR12 subgroups adjusting for co-variates. RESULTS Five hundred and twenty-three patients were evaluated. When comparing the rate of change in estimated glomerular filtration rate (eGFR) one-year after HCV treatment to one-year before treatment, patients who achieved SVR12 had a decline in GFR of 3.1 mL/min ± 0.75 mL/min per 1.73 m2 compared to a decline in eGFR of 11.0 mL/min ± 2.81 mL/min per 1.73 m2 in patients who did not achieve SVR12 (P = 0.002). There were no significant clinical differences between patients who achieved SVR12 compared to those who did not in terms of cirrhosis, treatment course, treatment experience, CKD stage prior to treatment, diuretic use or other co-morbidities. The decline in eGFR in those with untreated HCV over 2 years was 2.8 mL/min ± 1.0 mL/min per 1.73 m2, which was not significantly different from the eGFR decline noted in HCV-treated patients who achieved SVR12 (P = 0.43). CONCLUSION Patients who achieve SVR12 have a lesser decline in renal function, but viral eradication in itself may not be associated improvement in renal disease progression.

A Sodium Channel Myotonia Presenting with Intermittent Dysphagia as a Manifestation of a Rare SCN4A Variant

The voltage gated sodium channel SCN4A mutations account for non-dystrophic myotonia and include a heterogeneous group of conditions that include hyperkalemic periodic paralysis, paramyotonica congenita, potassium-aggravated myotonia, and hypokalemic periodic paralysis type 2. This case report proposes that a rare variant p.Pro1629Leu in SCN4A can cause a skeletal muscle deficit with intermittent dysphagia.