Pathophysiology of H. pylori

Helicobacter species were known for long as a causative agent of gastritis. H. pylori associated gastritis is characterized by the presence of acute and chronic inflammation. Previously, it was believed that in H. pylori gastritis, fundic inflammation was less important than that of the antral mucosa. However, H. pylori and gastroesophageal reflux disease create, or arise concurrently, may also be caused by the anatomical role of the inflammatory cell infiltrate. The source of H. pylori is mostly unknown. H. pylori has a small host range and is present in people and some non-human primates nearly exclusively. In rare cases, the presence of pets may be a concern for H. pylori infection; hence, pets should be isolated. There is also no definitive proof for zoonotic H. pylori transmission. The direct transmission from person to person, either oral or fecal-oral route or both, is expected to lead to new infections. H. pylori colonization is not an infection itself, but it impacts the relative likelihood that multiple pathological conditions of the upper gastrointestinal tract and even the hepatobiliary tract will grow. Therefore, H. pylori examination alone is not relevant but can be done in order to ascertain the cause of a basic disorder, such as peptic ulcer disease or to avoid disease, for example in subjects with family gastric carcinoma. A positive test result will validate the procedure, and a negative test result can suggest that other etiological causes or prevention steps needs to be examined. Gastritis is divided into acute and chronic. Several virulence factors play a role in the disease such as cag PAI (Pathogenicity Island) and VacA vacuolating cytotoxin. Different adhesins and their receptors aid in H. pylori colonization and invasion. Based on analogy with other mucosal infections, it was initially assumed that a protective immune response against H. pylori would predominantly be mediated by antibodies. Subsequent experiments have indicated that the relevance of the humoral system for protective immunity is only marginal. Antibodies can effectively prevent infection and reduce colonization in animal models.

Programmed knockout mutation of liver fluke granulin, Ov-grn-1, attenuates virulence and impedes malignant transformation during chronic opisthorchiasis

Infection with the food-borne liver fluke Opisthorchis viverrini is the principal risk factor for cholangiocarcinoma (CCA; bile duct cancer) in the Lower Mekong River Basin countries including Thailand, Lao PDR, Vietnam, Myanmar and Cambodia. Using gene edited liver flukes in a hamster model of CCA involving concurrent infection and administration of sub-carcinogenic levels of nitrosamine, we explored the role of the fluke granulin-like growth factor Ov-GRN-1 in malignancy. We produced programmed gene knockout flukes (ΔOv-grn-1) by delivery of a CRISPR/Cas9/gRNA system by square wave electroporation. Targeted genome sequencing confirmed Cas9-catalyzed mutations in target parasite genes, and the rapid depletion of transcripts and the targeted proteins. Hamsters were infected with gene edited larval parasites and exposed to sub-carcinogenic levels of dimethyl nitrosamine in drinking water. Whereas Ov-grn-1 gene-edited parasites colonized the biliary tract of hamsters and developed into adult flukes, less hepatobiliary tract disease manifested during chronic infection with ΔOv-grn-1 worms in comparison to hamsters infected with control parasites. Specifically, immunohistochemical analysis of thin sections of hamster livers revealed markedly less fibrosis surrounding flukes and less global liver fibrosis as a result of infection with ΔOv-grn-1 worms, minimal biliary epithelial cell proliferation, and markedly fewer mutations of TP53 in biliary epithelial cells. Moreover, fewer hamsters developed high grade CCA when infected with ΔOv-grn-1 flukes compared to controls. The clinically-relevant pathophysiological phenotype of the livers of the hamsters confirmed a role for this parasite secreted growth factor in morbidity and malignancy during opisthorchiasis.

Lynch Syndrome and MSI-H Cancers: From Mechanisms to “Off-The-Shelf” Cancer Vaccines

Defective DNA mismatch repair (dMMR) is associated with many cancer types including colon, gastric, endometrial, ovarian, hepatobiliary tract, urinary tract, brain and skin cancers. Lynch syndrome – a hereditary cause of dMMR – confers increased lifetime risk of malignancy in different organs and tissues. These Lynch syndrome pathogenic alleles are widely present in humans at a 1:320 population frequency of a single allele and associated with an up to 80% risk of developing microsatellite unstable cancer (microsatellite instability – high, or MSI-H). Advanced MSI-H tumors can be effectively treated with checkpoint inhibitors (CPI), however, that has led to response rates of only 30-60% despite their high tumor mutational burden and favorable immune gene signatures in the tumor microenvironment (TME). We and others have characterized a subset of MSI-H associated highly recurrent frameshift mutations that yield shared immunogenic neoantigens. These frameshifts might serve as targets for off-the-shelf cancer vaccine designs. In this review we discuss the current state of research around MSI-H cancer vaccine development, its application to MSI-H and Lynch syndrome cancer patients and the utility of MSI-H as a biomarker for CPI therapy. We also summarize the tumor intrinsic mechanisms underlying the high occurrence rates of certain frameshifts in MSI-H. Finally, we provide an overview of pivotal clinical trials investigating MSI-H as a biomarker for CPI therapy and MSI-H vaccines. Overall, this review aims to inform the development of novel research paradigms and therapeutics.

Prevention of structural changes in liver in patients with chronic acalculous cholecystitis

Chronic acalculous cholecystitis is the cause of violations of the functional state of the liver in the form of stagnation in the intrahepatic bile ducts and a decrease in the activity of hepatocytes and is considered within the framework of a single pathology of the hepatobiliary tract. Complex therapy with the inclusion of the drug ademetionine, which in addition to the hepatoprotective effect affects the outflow of intrahepatic bile, contributes to the restoration of the detected violations.

Massive biliary ascariasis: an unusual cause of acute cholangitis

Acute cholangitis is a condition of bacterial infection following hepatobiliary tract obstruction, which signifies poor prognosis unless adequately drained. The most common cause of bile duct obstruction is choledocholithiasis, in contrast to parasitic infestation, a rare entity causing acute cholangitis nowadays. Therefore, we reported the case of a 68-year-old Thai man who presented with acute fever, intense right upper quadrant abdominal pain and jaundice for 2 days. His medical history was normal except for the history of intermittent biliary colic for a year. Endoscopic retrograde cholangiography was performed and demonstrated multiple, creamy-coloured roundworms coming out from the ampulla of Vater as well as a tubular filling defect in dilated common bile duct from cholangiography. He was diagnosed with acute cholangitis by biliary ascariasis and underwent endoscopic parasitic removal, which subsequently improved symptoms.

Cystic and alveolar echinococcosis of the hepatobiliary tract – the role of new imaging techniques for improved diagnosis

Cystic echinococcosis (CE) or hydatidosis (hydatid cysts) is an infection with a wide spectrum of manifestations, from symptomatic infection to fatal disease. Ultrasound (US) allows screening, diagnosis, differential diagnosis, treatment guidance and follow-up of CE under many circumstances. Hydatid cysts are predominantly observed in the liver. Herewith we present a review to demonstrate established and innovative imaging features of CE of the hepatobiliary tract.

Non - alcoholic fatty liver disease and enteral insufficiency: comorbidity of their development

The article reflects current literature data on the epidemiology and risk factors of non - alcoholic fatty liver disease. An important aspect is the description of the modern views of combined lesions of the hepatobiliary tract and small intestine. Disorders of the intestinal microbiota play a special role in the development of non - alcoholic fatty liver disease. The value of enterohepatic circulation of bile acids in the development of intestinal and liver diseases was shown. It seems relevant to further study the comorbidity of the development of non - alcoholic fatty liver disease and enteropathy for the development of pathogenetically substantiated therapy.