Keisuke Ojiro

Evaluation of liver fibrosis by transient elastography using acoustic radiation force impulse: comparison with Fibroscan ®

BackgroundAccurate evaluation of liver fibrosis in patients with chronic liver damage is required to determine the appropriate treatment. Various approaches, including laboratory tests and transient elastography, have been used to evaluate liver fibrosis. Recently, transient elastography with acoustic radiation force impulse (ARFI) has been developed and applied with conventional ultrasonography. The aim of this study was to evaluate the clinical utility of transient elastography with ARFI and to compare the results with this method and those of the Fibroscan® procedure.MethodsOne hundred and thirty-one patients with liver damage, who underwent liver biopsy at our department, were enrolled prospectively in this study. Elastography with ARFI (applied with ACUSON S2000®), and Fibroscan® was performed at the same time as liver biopsy. These measurements were compared with histological findings in liver biopsy specimens, and measurement accuracy was evaluated by receiver-operating characteristic analysis.ResultsElastography values with both procedures were significantly correlated with the stages of liver fibrosis and there was little difference in the results obtained using the 2 procedures. The accuracy of differential diagnosis between no fibrosis at F0 and more than F1 stage was insufficient with ARFI, but this procedure was sufficient for diagnosing advanced fibrosis. The accuracy of ARFI was almost equivalent to that of the Fibroscan® method. Moreover, both ARFI and Fibroscan® values increased in proportion to the severity of hepatic inflammation when fibrosis stage is low, but not in proportion to the severity of steatosis.ConclusionsTransient elastography with ARFI is simple, non-invasive and useful for diagnosing the stage of fibrosis in chronic liver disease. The utility of ARFI was almost equivalent to that of the Fibroscan® method.

Reactivation of hepatitis B in a patient with Crohn’s disease treated using infliximab

We encountered a case of reactivation of hepatitis B virus after administration of infliximab for Crohn’s disease. The use of infliximab was considered because the patient displayed abdominal symptoms and perianal lesions. Transaminases were normal, and hepatitis B virus (HBV) DNA was undetectable before treatment, so no antiviral treatment was used, and infliximab and low-dose 6-mercaptopurine were administered. This treatment was effective, but liver dysfunction and reactivation of HBV were observed after the fourth injection of infliximab. This is the first report of Crohn’s disease for which infliximab use was continued even after reactivation of HBV was observed. However, liver dysfunction was not improved by lamivudine. Antiviral treatment should be considered before administration of infliximab for patients with HBV.

CCR9 Macrophages Are Required for Acute Liver Inflammation in Mouse Models of Hepatitis

BACKGROUND & AIMS Antigen-presenting cells (APCs) are involved in the induction of liver inflammation. We investigated the roles of specific APCs in the pathogenesis of acute liver injury in mice. METHODS We used concanavalin A (con A) or carbon tetrachloride to induce acute liver inflammation in mice and studied the roles of macrophages that express CCR9. RESULTS After injection of con A, we detected CCR9(+)CD11b(+)CD11c(-) macrophages that express tumor necrosis factor (TNF)-α in livers of mice, whereas CCR9(+)Siglec-H(+)CD11b(-)CD11c(low) plasmacytoid DCs (pDCs), which are abundant in normal livers, disappeared. The CCR9(+) macrophages were also detected in the livers of RAG-2(-/-) mice, which lack lymphocytes and natural killer T cells, after injection of con A. Under inflammatory conditions, CCR9(+) macrophages induced naive CD4(+) T cells to become interferon gamma-producing Th1 cells in vivo and in vitro. CCR9(-/-) mice injected with con A did not develop hepatitis unless they also received CCR9(+) macrophages from mice that received con A; more CCR9(+) macrophages accumulated in their inflamed livers than CCR9(+) pDCs, CCR9(-) pDCs, or CCR9(-) macrophages isolated from mice that had received injections of con A. Levels of CCL25 messenger RNA increased in livers after injection of con A; neutralizing antibodies against CCL25 reduced the induction of hepatitis by con A by blocking the migration of CCR9(+) macrophages and their production of TNF-α. Peripheral blood samples from patients with acute hepatitis had greater numbers of TNF-α-producing CCR9(+)CD14(+)CD16(high) monocytes than controls. CONCLUSIONS CCR9(+) macrophages contribute to the induction of acute liver inflammation in mouse models of hepatitis.

Effect of Telmisartan or Losartan for Treatment of Nonalcoholic Fatty Liver Disease: Fatty Liver Protection Trial by Telmisartan or Losartan Study (FANTASY)

Aim. This study compared the effects of telmisartan and losartan on nonalcoholic fatty liver disease (NAFLD) and biochemical markers of insulin resistance in hypertensive NAFLD patients with type 2 diabetes mellitus. Methods. This was a randomized, open-label, parallel-group comparison of therapy with telmisartan or losartan. Nineteen hypertensive NAFLD patients with type 2 diabetes were randomly assigned to receive telmisartan at a dose of 20 mg once a day (n = 12) or losartan at a dose of 50 mg once a day (n = 7) for 12 months. Body fat area as determined by CT scanning and hepatic fat content based on the liver-to-spleen (L/S) ratio, as well as several parameters of glycemic and lipid metabolism, were compared before and after 12 months. Results. The telmisartan group showed a significant decline in serum free fatty acid (FFA) level (from 0.87 ± 0.26 to 0.59 ± 0.22 mEq/L (mean ± SD), P = 0.005) and a significant increase in L/S ratio (P = 0.049) evaluated by CT scan, while these parameters were not changed in the losartan group. Conclusion. Although there was no significant difference in improvement in liver enzymes with telmisartan and losartan treatment in hypertensive NAFLD patients with type 2 diabetes after 12 months, it is suggested that telmisartan may exert beneficial effects by improving fatty liver.

Treatment of hepatitis C virus with peg-interferon and ribavirin combination therapy significantly affects lipid metabolism.

Aim:  We investigated lipid metabolism in patients with chronic hepatitis C virus (HCV), serotype 1, undergoing combination therapy with PEG‐IFN α‐2b (PEG‐IFN) and ribavirin (RBV).

MyD88-dependent pathway accelerates the liver damage of Concanavalin A-induced hepatitis

We have explored the pathological role of the MyD88 signaling pathway via Toll-like receptors (TLRs) that mediate the recognition of pathogen-associated molecular patterns (PAMPs) in a murine model of autoimmune hepatitis induced by administering Concanavalin A (ConA). We first found that various TLRs and MyD88 molecules were expressed in liver of Con A-treated and untreated wild-type (WT) mice including liver macrophages. Flowcytometric analysis revealed that liver CD11b(+)CD11c(-) and CD11b(+)CD11c(+) antigen-presenting cells express TLR2, although NK and NKT cells did not. When WT and MyD88(-/-) mice were intravenously administered with Con A, the severity of hepatitis was significantly lower in Con A-injected MyD88(-/-) mice than in WT mice in terms of the histopathology, the levels of serum transaminase and pro-inflammatory cytokines (TNF-alpha, IFN-gamma, and IL-6), and upregulation of CD80/CD86 and TNF-alpha on/in liver macrophages. The results provide evidence of a possible contribution of the TLRs-MyD88 signaling pathway in activating TLR-expressing liver macrophages in the autoimmune hepatitis model, and thus indicate that the strategy of blockade of pathological pathogens via the intestinal lumen may be feasible for the treatment of the disease.

On-treatment decrease of NKG2D correlates to early emergence of clinically evident hepatocellular carcinoma after interferon-free therapy for chronic hepatitis C

Background and aims Interferon (IFN)- free direct antiviral agents (DAAs) with rapid HCV eradication might evoke immunological reconstitutions, and some early recurrences of HCC after IFN-free DAAs have been reported. This study aimed to investigate whether natural killer group 2, member D (NKG2D) predicts early emergence of HCC after IFN-free DAAs. Methods We conducted a clinical practice-based observational study of 101 patients infected with genotype 1 HCV who received IFN-free (DAAs), and stratified them into those who did or did not develop early (i.e., during the 6-month surveillance period following treatment.) recurrence or occurrence of clinically evident HCC. We also analyzed the peripheral blood mononuclear cells, both before treatment and at end of treatment (EOT), of 24 of the patients who received IFN-free DAAs, and 16 who received IFN-combined protease inhibitor. Results We found early emergence of clinically evident HCC after IFN-free DAAs in 12 (12%) patients. Higher pre-treatment NKG2D expression, higher FIB-4 score, previous HCC history and failure to achieve sustained viral response were significant factors correlating to early HCC emergence. After IFN-free DAAs, a rapid decrease of NKG2D at EOT correlated with early HCC emergence in the IFN-free DAA-treated patients, but not in patients treated with the IFN-combined regimen. The decrease of NKG2D until EOT was predictive of early HCC emergence at a cut-off of -52% (AUC = 0.92). Conclusions On-treatment decrease of NKG2D may be a useful predictor of early emerging HCC in patients treated with IFN-free DAAs.

A case of severe cholestatic jaundice with hyperthyroidism successfully treated with methimazole

Liver dysfunction is a common complication observed in patients with hyperthyroidism, however the dysfunction is always mild and obvious jaundice is rarely observed. We present the case of a 43-year-old man who suffered from hyperthyroidism complicated by severe jaundice. The jaundice likely occurred as a secondary consequence of cholestasis due to hyperthyroidism, since other causes such as drug-induced or autoimmune liver dysfunction were ruled out. Treatment with methimazole improved severe cholestatic jaundice in parallel with normalization of thyroid function. The mechanism of cholestasis as a secondary complication of hyperthyroidism has not been uncovered and there is no specific biochemical marker for cholestasis due to this hormonal disease at present. This case serves as a reminder that severe jaundice can be a manifestation of simple hyperthyroidism, and that administration of antithyroid drugs is an effective treatment for severe cholestatic jaundice in such cases.

Education and imaging. Gastrointestinal: capsule endoscopy assists in the complete deworming of parasites.

A 67-year-old man presented with the complaint of ribbon-like substances in the feces. In the beginning of August 2010, he was referred to our hospital for treatment of parasitic worm infection. The patient did not have symptoms such as diarrhea, anemia, or weight loss; the results of physical and hematological examinations and of thoracoabdominal radiography were normal. Although he did not have a history of parasitic worm infection and had never traveled abroad, he had eaten raw salmon 1 month ago. On the first day of the hospital visit, the patient was diagnosed with diphyllobothriasis after examination of the helminth eggs found in the feces. After diatrizoic acid swallow on the second day, the presence of the worm body was confirmed by colonoscopy, and the worm body was extirpated from the anus by using grasping forceps. Although approximately 1 m of the worm body together with most of the neck portion was successfully extirpated, removal of the scolex was not confirmed. On the fourth day, after obtaining the patient’s consent, we performed capsule endoscopy because of possible incomplete deworming. Capsule endoscopy confirmed parasitization by a cestode and detected the scolex attached to the jejunal mucosa (Figure 1). Parasite-specific drugs, i.e., praziquantel and magnesium citrate, were administered, and complete deworming was subsequently confirmed by microscopic identification of the scolex (Figure 2). The worm body was pathologically confirmed as Diphyllobothrium nihonkaiense by performing trichrome and carmine staining (Figure 3). For the successful treatment of diphyllobothriasis, it is essential to remove the scolex of the parasite. The use of capsule endoscopy now allows for (1) easy capture of images of parasites, such as that of the scolex of Diphyllobothrium nihonkaiense, in the small intestine, which was previously considered difficult; and (2) provides information critical for therapeutic decision making before administering anthelmintics.

Gastrointestinal: Capsule endoscopy assists in the complete deworming of parasites

A 67-year-old man presented with the complaint of ribbon-like substances in the feces. In the beginning of August 2010, he was referred to our hospital for treatment of parasitic worm infection. The patient did not have symptoms such as diarrhea, anemia, or weight loss; the results of physical and hematological examinations and of thoracoabdominal radiography were normal. Although he did not have a history of parasitic worm infection and had never traveled abroad, he had eaten raw salmon 1 month ago. On the first day of the hospital visit, the patient was diagnosed with diphyllobothriasis after examination of the helminth eggs found in the feces. After diatrizoic acid swallow on the second day, the presence of the worm body was confirmed by colonoscopy, and the worm body was extirpated from the anus by using grasping forceps. Although approximately 1 m of the worm body together with most of the neck portion was successfully extirpated, removal of the scolex was not confirmed. On the fourth day, after obtaining the patient’s consent, we performed capsule endoscopy because of possible incomplete deworming. Capsule endoscopy confirmed parasitization by a cestode and detected the scolex attached to the jejunal mucosa (Figure 1). Parasite-specific drugs, i.e., praziquantel and magnesium citrate, were administered, and complete deworming was subsequently confirmed by microscopic identification of the scolex (Figure 2). The worm body was pathologically confirmed as Diphyllobothrium nihonkaiense by performing trichrome and carmine staining (Figure 3). For the successful treatment of diphyllobothriasis, it is essential to remove the scolex of the parasite. The use of capsule endoscopy now allows for (1) easy capture of images of parasites, such as that of the scolex of Diphyllobothrium nihonkaiense, in the small intestine, which was previously considered difficult; and (2) provides information critical for therapeutic decision making before administering anthelmintics.