Beneficial effect of omarigliptin on diabetic patients with non-alcoholic fatty liver disease/non-alcoholic steatohepatitis.

BACKGROUND: Dipeptidyl peptidase 4 (DPP4) is a serine exopeptidase able to inactivate various oligopeptides, and also a hepatokine. Hepatocyte-specific overexpression of DPP4 is associated with hepatic insulin resistance and liver steatosis. METHOD: We examined whether weekly DPP4 inhibitor omarigliptin (OMG) can improve liver function as well as levels of inflammation and insulin resistance in type 2 diabetic patients with non-alcoholic fatty liver disease (NAFLD). Further, we investigated the effects of OMG in a diabetic patient with biopsy-confirmed nonalcoholic steatohepatitis (NASH). RESULTS: In NAFLD patients, OMG significantly decreased levels of aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, homeostatic model assessment of insulin resistance (HOMA-IR), and high-sensitivity C-reactive protein (hsCRP), while no significant change was seen in hemoglobin A1c or body mass index. In the NASH patient, liver function improved markedly, and levels of the hepatic fibrosis marker FIB-4 decreased in parallel with HOMA-IR and hsCRP. Slight but clear improvements in intrahepatic fat deposition and fibrosis appeared to be seen on diagnostic ultrasonography. CONCLUSION: Weekly administration of the DPP4 inhibitor OMG in ameliorating hepatic insulin resistance may cause beneficial effects in liver with NAFLD/NASH.

Gastric syphilis: The great imitator in the stomach.

Syphilis is resurging worldwide. Here, we present the case of a 33-year-old heterosexual man who presented with a 3-week history of epigastric pain, nausea, emesis, and 8 kg weight loss. He was subsequently diagnosed with gastric syphilis, based on reactive syphilis serological testing and Treponema pallidum found in gastric biopsy specimens. Gastric syphilis is a rare presentation observed in 1% of cases and usually develops in secondary syphilis. Given the nonspecific manifestation and findings, a high index of suspicion is required for diagnosis of gastric syphilis.

Endoscopic features of lymphoid follicles in Helicobacter pylori-associated chronic gastritis.

BACKGROUND AND AIM: Small, round, yellowish-white nodules (YWN) are frequently observed in Helicobacter pylori-associated gastritis. The aim of the present study was to investigate the clinical significance of these YWN. METHODS: Participants comprised 211 patients with H. pylori-associated gastritis, ranging in age from 23 to 86 years. RESULTS: YWN were detected in 23% of participants, more frequently in women (33%) than in men (12%; P < 0.01). YWN were observed on the antral mucosa in 4.7% of cases, lesser curvature of the corpus mucosa in 20%, greater curvature of the corpus mucosa in 0.9%, and fundic mucosa in 12%. Most YWN located on the antral mucosa showed nodular type, and most YWN located on the corpus mucosa and fundic mucosa showed flat type. On magnifying endoscopy with narrow-band imaging, YWN appeared as round whitish lesions with radial or branching microvessels on the surface and hypovascular globe structures just beneath the surface of the mucosa. Targeted biopsies of YWN revealed lymphoid follicles with lymphocyte infiltration or intense inflammatory cell infiltration. CONCLUSION: The endoscopic finding of YWN could be observed at any site of the gastric mucosa in H. pylori-associated gastritis, and represented histological lymphoid follicles.

Kinetics of peripheral hepatitis B virus-specific CD8+ T cells in patients with onset of viral reactivation.

BACKGROUND: Patients with resolved hepatitis B virus (HBV) infection undergoing chemotherapy or immunosuppressive therapy are potentially at risk of HBV reactivation. However, it remains unclear how liver disease develops after HBV reactivation. To compare the host immune response against HBV, we performed immunological analyses of six HBV reactivation patients. METHODS: The numbers of peripheral HBV-specific CD8+ T cells were investigated longitudinally in six HLA-A2- and/or A24-positive patients with HBV reactivation. In addition, 34 patients with resolved HBV, 17 patients with inactive chronic hepatitis B (ICHB), 17 patients with chronic hepatitis B (CHB) and 12 healthy controls were analyzed. The number and function of HBV-specific CD8+ T cells were assessed by flow cytometry using tetramer staining and intracellular IFN-γ production. Furthermore, the numbers of CD4+ CD25+ or CD4+ Foxp3+ T cells and serum inflammatory cytokine levels were analyzed. RESULTS: The frequency of HBV-specific CD8+ T cells was significantly increased in HBV reactivation patients compared with ICHB and CHB patients. In addition, the number of HBV-specific CD8+ T cells was increased in resolved HBV patients compared with ICHB patients. PD-1 expression was decreased in HBV reactivation patients compared with ICHB and CHB patients. The numbers of HBV-specific CD8+ T cells and CD4+ CD25+ or CD4+ Foxp3+ T cells were negatively correlated following onset of HBV reactivation. CONCLUSIONS: During HBV reactivation, the frequency of HBV-specific CD8+ T cells increased even though the administration of immunosuppressive drugs and interactions with CD4+ regulatory T cells may be important for the onset of liver disease.

A case of a large cholangiolocellular carcinoma.

Cholangiolocellular carcinoma (CoCC) is a rare malignant primary liver tumor that is considered to originate from the canals of Hering, where hepatic progenitor cells are located. CoCC has various clinicopathological findings, therefore it is difficult to describe a clear diagnostic criteria for CoCC. Reported is a case of a large CoCC in a 45-year-old Japanese woman, which could not be preoperatively diagnosed as CoCC. The final diagnosis of CoCC was determined by pathological observation. Since both the biological behavior and diagnostic criteria of CoCC remain unclear, it is necessary to accumulate more information on CoCCs in order to elucidate these characteristic findings.

Role of interleukin-18 in intrahepatic inflammatory cell recruitment in acute liver injury.

Although the innate immune system has been demonstrated to play important roles as the first line of defense against various infections, little is known about the interactions between intrahepatic inflammatory cells and the cytokine network in the liver. Here, we examined the role of IL-18 in IHL recruitment in acute liver injury. C57BL/6 mice were injected with an αCD40 mAb, and their serum IL-18 levels were observed to increase, with subsequent recruitment of IHLs into the liver. NKT cells were involved in this liver injury, as the serum ALT levels were reduced in NKT KO mice through the suppression of macrophage and monocyte migration and cytokine production. In contrast, depletion of neutrophils exacerbated the liver injury associated with high levels of TNF-α and IL-18 and increased numbers of macrophages and monocytes. Treatment with a neutralizing antibody against IL-18 reduced the serum ALT levels and inflammatory cell accumulation in the liver. Finally, additional administration of rIL-18 with αCD40 injection caused severe liver injury with increased IFN-γ production by NK cells. In conclusion, these findings demonstrate that IL-18 modulates liver inflammation by the recruitment of inflammatory cells, including NKT cells, macrophages, monocytes, and neutrophils.

Detection of hepatitis B and C viruses in almost all hepatocytes by modified PCR-based in situ hybridization.

Although PCR-based in situ hybridization (PCR-ISH) can be used to determine the distribution and localization of pathogens in tissues, this approach is hampered by its low specificity. Therefore, we used a highly specific and sensitive PCR-ISH method to reveal the lobular distribution and intracellular localization of hepatitis B virus (HBV) and HCV in chronic liver disease and to clarify the state of persistent HBV and HCV infection in the liver. HBV genomic DNA was detected in almost all hepatocytes, whereas HBV RNA or protein was differentially distributed only in a subset of the HBV DNA-positive region. Further, HCV genomic RNA was detected in almost all hepatocytes and was localized to the cytoplasm. HCV RNA was also detected in the epithelium of the large bile duct but not in endothelial cells, portal tracts, or sinusoidal lymphocytes. In patients with HBV and HCV coinfection, HCV RNA was localized to the noncancerous tissue, whereas HBV DNA was found only in the cancerous tissue. Using this novel PCR-ISH method, we could visualize the staining pattern of HBV and HCV in liver sections, and we obtained results consistent with those of real-time detection (RTD)-PCR analysis. In conclusion, almost all hepatocytes are infected with HBV or HCV in chronic liver disease; this finding implies that the viruses spreads throughout the liver in the chronic stage.

Roles of CD44 in chemical-induced liver injury.

CD44 has been identified as one of the adhesion molecules that regulate cell migration in inflamed tissue. The principal ligand of CD44 is hyaluronan, and CD44 is involved in the metabolism of this compound. Furthermore, an increasing quantity of evidence suggests that CD44 has various functions related to inflammatory disease. This review focuses on the potential roles of CD44 in the pathogenesis of chemical-induced liver injury and discusses some of the functions of this protein in pathological processes. The discovery that CD44 deficiency induces severe liver injury, (associated with an increase in hepatocyte apoptosis) rather than suppressing liver inflammation is summarized. These data suggest that targeted therapies against adhesion molecules should be monitored carefully to ensure that liver disease is not exacerbated by treatment.

A case of polymyositis in a chronic hepatitis C patient treated with peg-interferon-alpha 2b and ribavirin therapy.

Hepatitis C virus (HCV) infection may result in progression to chronic hepatitis, cirrhosis and hepatocellular carcinoma. Interferon-based treatment in patients with chronic hepatitis C may achieve viral clearance, and as a consequence improve liver histology and prevent progression to hepatocellular carcinoma. At present, the recommended therapy for chronic hepatitis C is peg-interferon-alpha (PEG-IFN-α) in conjunction with the oral nucleoside analog ribavirin. In the current study, we report a case of polymyositis associated with chronic hepatitis C following PEG-IFN-α and ribavirin therapy. The patient, a 64-year-old female who was treated with combination therapy, demonstrated elevated serum CPK, AST, ALT and LDH levels at 28 weeks after treatment onset. As there was an elevation of the serum HCV-RNA levels, combination treatment was ceased at 24 weeks. The patient had received IFN therapy twice previously (IFN-α 2a and IFN-α 2b with ribavirin therapy); however, no adverse side effects were observed. Further laboratory examination, muscle biopsy and imaging data suggested polymyositis, possibly triggered by the PEG-IFN-α treatment. The patient was subsequently administered prednisolone and the dose tapered over 7 months. As a result the polymyositis has remained in remission. Although many autoimmune diseases have been associated with IFN therapy, the development of polymyositis is extremely rare.