Mara Berrutti

Helicobacter pylori seroprevalence in hepatitis C virus positive patients with cirrhosis

BACKGROUND/AIMS Liver cirrhosis is a significant cause of death in Italy and one of the most frequent causes of hospitalization. Acute peptic ulcer and upper gastrointestinal bleeding reportedly occur in over one-third of cirrhotic patients. Since Helicobacter pylori (H. pylori) infection strongly correlates with peptic ulcer, we sought to ascertain the prevalence of H. pylori infection in cirrhotic patients. METHODS In a case-control study, we examined 254 consecutive patients (127 male and 127 female, age range 30-82 years) suffering from hepatitis C virus (HCV)-related cirrhosis and 463 sex- and age-matched patients admitted to the Department of Emergency Care of our hospital (254 male, 209 female, age range 30-79 years) resident in the same area. RESULTS Antibodies to H. pylori were present in 226/254 (89%) cirrhotic patients and in 275/463 (59%) controls (p<0.0001). The difference was significant both in males and in females. CONCLUSIONS The very high prevalence of H. pylori infection may explain the frequent occurrence of gastroduodenal ulcer in cirrhotic patients and may possibly determine the prognosis of those who are also infected with HCV.

Helicobacter pylori seroprevalence in cirrhotic patients with hepatitis B virus infection.

Liver cirrhosis is a significant cause of death in Italy and one of the most frequent causes of hospitalization. The burden of cirrhotic patients on the National Health System is extremely high due to the frequent need for medical care. Acute peptic ulcer and upper gastrointestinal bleeding reportedly occur in over one-third of cirrhotic patients. Since Helicobacter pylori (H. pylori) infection strongly correlates with peptic ulcer, we wished to ascertain the prevalence of H. pylori infection in cirrhotic patients. In a case-control study we looked for this infection in 45 consecutive male patients suffering from hepatitis B virus (HBV)-related cirrhosis and 310 sex and age matched blood donors resident in the same area. Antibodies against H. pylori were present in 40/45 (89%) patients and 183/310 (59%) blood donors (P<0.001). This very high prevalence of H. pylori may explain the frequent occurrence of gastroduodenal ulcer in cirrhotic patients. (See Editorial p. 203)

Prevalence of Non-Organ-Specific Autoantibodies in Patients Suffering from Duodenal Ulcer With and Without Helicobacter pylori Infection

Autoimmunity, a feature of chronic infection by Helicobacter pylori, is first directed against gastric cells but is also associated with extragastric diseases. The aim of the present work was to look for the influence of the infection on induction of non-organ-specific autoantibodies (NOSAs). We compared 49 patients (28 males and 21 females; age range, 36–72 years; mean, 61 ± 4.6 years) suffering from duodenal ulcer and H. pylori infection (Group A) to 38 subjects (20 male, 18 female; age range, 40–78 years; mean, 63 ± 3.8 years) affected by duodenal ulcer related to the assumption of nonsteroidal antiinflammatory drugs (Group B). H. pylori infection was diagnosed by histology, 13C-urea breath test, and serum IgG antibodies. Autoimmunitary pattern was demonstrated by the presence of NOSAs in serum. Antinuclear (ANA), anti-smooth muscle (SMA), and anti-liver/kidney microsomal-1 (LKM-1) antibodies were present in 5 of 49 (10.2%), 2 of 49 (4%), and 0 Group A patients, respectively. In Group B, ANA was present in 3 of 38 (7.9%), SMA in 3 of 38 (7.9%), and anti-LKM-1 in 0 patients. The difference was not statistically significant. In this population, H. pylori infection is not associated with an increased prevalence of NOSAs.

Helicobacter pylori seroprevalence in patients with autoimmune hepatitis.

Autoimmune hepatitis is characterized by a continuing hepatocyte necrosis that usually progresses to liver cirrhosis. Autoimmunity is also a feature of chronic infection by Helicobacter pylori, a gram-negative bacterium involved in the pathogenesis of peptic ulcer and upper gastrointestinal bleeding, with both events frequently occurring in patients with chronic liver disease. A newly described pathogenetic mechanism for chronic hepatitis and hepatocellular carcinoma in the mouse is linked to Helicobacter spp. infection. A high prevalence of H. pylori infection was demonstrated in patients with viral-related cirrhosis but never studied in cases of autoimmune hepatitis. In a case-control study, we examined 31 consecutive patients (25 women and 6 men, age range 20–66, mean age 46 ± 4.3 years) suffering from autoimmune hepatitis and 62 sex- and age-matched blood donors (50 women, 12 men, age range 20–65, mean age 46 ± 5.4 years) resident in the same area. Antibodies to H. pylori were present in 20 of 31 (64.5%) autoimmune patients compared to 33 of 62 (53.2%) controls (P = 0.3, odds ratio 1.60, 95% CI 0.60–4.28). The difference was not statistically significant either in female or male patients. In conclusion, the prevalence of H. pylori infection in patients and controls was similar in our study of patients with chronic autoimmune hepatitis.

New Pharmacologic Agents That Target Inflammation and Fibrosis in Nonalcoholic Steatohepatitis-Related Kidney Disease.

&NA; Epidemiologic data show an association between the prevalence and severity of nonalcoholic fatty liver disease and the incidence and stage of chronic kidney disease (CKD); furthermore, nonalcoholic steatohepatitis (NASH)‐related cirrhosis has a higher risk of renal failure, a greater necessity for simultaneous liver‐kidney transplantation, and a poorer renal outcome than cirrhosis of other etiologies even after simultaneous liver‐kidney transplantation. These data suggest that NASH and CKD share common proinflammatory and profibrotic mechanisms of progression, which are targeted incompletely by current treatments. We reviewed therapeutic approaches to late preclinical/early clinical stage of development in NASH and/or CKD, focusing on anti‐inflammatory and antifibrotic treatments, which could slow the progression of both disease conditions. Renin inhibitors and angiotensin‐converting enzyme‐2 activators are new renin‐angiotensin axis modulators that showed incremental advantages over angiotensin‐converting enzyme inhibitors/angiotensin‐receptor blockers in preclinical models. Novel, potent, and selective agonists of peroxisome proliferator‐activated receptors and of farnesoid X receptor, designed to overcome limitations of older compounds, showed promising results in clinical trials. Epigenetics, heat stress response, and common effectors of redox regulation also were subjected to intensive research, and the gut was targeted by several approaches, including synbiotics, antilipopolysaccharide antibodies, Toll‐like receptor‐4 antagonists, incretin mimetics, and fibroblast growth factor 19 analogs. Promising anti‐inflammatory therapies include inhibitors of NOD‐like receptor family, pyrin domain containing 3 inflammasome, of nuclear factor‐&kgr;B, and of vascular adhesion protein‐1, chemokine antagonists, and solithromycin, and approaches targeting common profibrogenic pathways operating in the liver and the kidney include galectin‐3 antagonists, and inhibitors of rho‐associated protein kinase and of epidermal growth factor activation. The evidence, merits, and limitations of each approach for the treatment of NASH and CKD are discussed.

Gut Microbiota, Hypertension and Chronic kidney Disease: recent advances

A large number of different microbial species populates intestine. Extensive research has studied the entire microbial population and their genes (microbiome) by using metagenomics, metatranscriptomics and metabolomic analysis. Studies suggest that the imbalances of the microbial community causes alterations in the intestinal homeostasis, leading to repercussions on other systems: metabolic, nervous, cardiovascular, immune. These studies have also shown that alterations in the structure and function of the gut microbiota play a key role in the pathogenesis and complications of Hypertension (HTN) and Chronic Kidney Disease (CKD). Increased blood pressure (BP) and CKD are two leading risk factors for cardiovascular disease and their treatment represents a challenge for the clinicians. In this Review, we discuss mechanisms whereby gut microbiota (GM) and its metabolites act on downstream cellular targets to contribute to the pathogenesis of HTN and CKD, and potential therapeutic implications.

TM6SF2 rs58542926 variant affects postprandial lipoprotein metabolism and glucose homeostasis in NAFLD

Mechanisms underlying the opposite effects of transmembrane 6 superfamily member 2 (TM6SF2) rs58542926 C>T polymorphism on liver injury and cardiometabolic risk in nonalcoholic fatty liver disease (NAFLD) are unclear. We assessed the impact of this polymorphism on postprandial lipoprotein metabolism, glucose homeostasis, and nutrient oxidation in NAFLD. Sixty nonobese nondiabetic normolipidemic biopsy-proven NAFLD patients and 60 matched controls genotyped for TM6SF2 C>T polymorphism underwent: indirect calorimetry; an oral fat tolerance test with measurement of plasma lipoprotein subfractions, adipokines, and incretin glucose-dependent insulinotropic polypeptide (GIP); and an oral glucose tolerance test with minimal model analysis of glucose homeostasis. The TM6SF2 T-allele was associated with higher hepatic and adipose insulin resistance, impaired pancreatic β-cell function and incretin effect, and higher muscle insulin sensitivity and whole-body fat oxidation rate. Compared with the TM6SF2 C-allele, the T-allele entailed lower postprandial lipemia and nefaemia, a less atherogenic lipoprotein profile, and a postprandial cholesterol (Chol) redistribution from smaller atherogenic lipoprotein subfractions to larger intestinal and hepatic VLDL1 subfractions. Postprandial plasma VLDL1-Chol response independently predicted the severity of liver histology. In conclusion, the TM6SF2 C>T polymorphism affects nutrient oxidation, glucose homeostasis, and postprandial lipoprotein, adipokine, and GIP responses to fat ingestion independently of fasting values. These differences may contribute to the dual and opposite effect of this polymorphism on liver injury and cardiometabolic risk in NAFLD.

MERTK rs4374383 variant predicts incident nonalcoholic fatty liver disease and diabetes: role of mononuclear cell activation and adipokine response to dietary fat

&NA; The loss‐of‐function rs4374383 G > A variant in Myeloid‐epithelial‐reproductive Tyrosine Kinase (MERTK) gene has been linked to hepatic fibrosis in chronic liver diseases. MERTK is expressed by immune and non‐immune cells involved in inflammation, metabolism and vascular homeostasis. We assessed the impact of MERTK rs4374383 G > A variant on nonalcoholic fatty liver disease (NAFLD) incidence and severity and on glucose and lipid metabolism. We followed‐up 305 healthy nonobese nondiabetic, metabolic syndrome‐free insulin sensitive participants in a population‐based study, characterized for MERTK G > A polymorphism, adipokine profile and inflammatory markers. An independent cohort of 69 biopsy‐proven nondiabetic NAFLD patients and 69 healthy controls underwent indirect calorimetry, an OGTT with Minimal Model analysis of glucose homeostasis, and an oral fat tolerance test with measurement of plasma lipoproteins, adipokines, MCP‐1, and of Nuclear Factor (NF)‐&kgr;B activation in circulating mononuclear cells (MNCs). In the longitudinal cohort, MERTK G > A polymorphism protected against 9‐year incident NAFLD (OR:0.48,95%CI:0.26‐0.79) and diabetes (OR: 0.47, 95% CI: 0.19‐0.87). In the cross‐sectional cohort, MERTK A‐allele carriers had higher fat oxidation rates and tissue insulin sensitivity. Despite comparable fastign and postprandial lipid profiles, MERTK A‐allele carriers showed lower resistin and MCP‐1 responses, milder MNC NF‐&kgr;B activation, and a higher postprandial adiponectin response to fat, which predicted tissue insulin resistance hepatocyte apoptosis and liver histology. MERTK G > A variant affects liver disease, nutrient oxidation and glucose metabolism in NAFLD. The modulation of adipokine, chemokine and pro‐inflammatory MNC activation in response to fat ingestion may contribute to the observed effects on liver and metabolic disease.

Altered Gut Microbiota in Type 2 Diabetes: Just a Coincidence?

Purpose of ReviewIn the last decade many studies have suggested an association between the altered gut microbiota and multiple systemic diseases including diabetes. In this review, we will discuss potential pathophysiological mechanisms, the latest findings regarding the mechanisms linking gut dysbiosis and type 2 diabetes (T2D), and the results obtained with experimental modulation of microbiota.Recent FindingsIn T2D, gut dysbiosis contributes to onset and maintenance of insulin resistance. Different strategies that reduce dysbiosis can improve glycemic control.SummaryEvidence in animals and humans reveals differences between the gut microbial composition in healthy individuals and those with T2D. Changes in the intestinal ecosystem could cause inflammation, alter intestinal permeability, and modulate metabolism of bile acids, short-chain fatty acids and metabolites that act synergistically on metabolic regulation systems contributing to insulin resistance. Interventions that restore equilibrium in the gut appear to have beneficial effects and improve glycemic control. Future research should examine in detail and in larger studies other possible pathophysiological mechanisms to identify specific pathways modulated by microbiota modulation and identify new potential therapeutic targets.