Medium-chain triglycerides supplement therapy with a low-carbohydrate formula can supply energy and enhance ammonia detoxification in the hepatocytes of patients with adult-onset type II citrullinemia.

Citrin, encoded by SLC25A13, constitutes the malate-aspartate shuttle, the main NADH-shuttle in the liver. Citrin deficiency causes neonatal intrahepatic cholestasis (NICCD) and adult-onset type II citrullinemia (CTLN2). Citrin deficiency is predicted to impair hepatic glycolysis and de novo lipogenesis, resulting in hepatic energy deficit. Secondary decrease in hepatic argininosuccinate synthetase (ASS1) expression has been considered a cause of hyperammonemia in CTLN2. We previously reported that medium-chain triglyceride (MCT) supplement therapy with a low-carbohydrate formula was effective in CTLN2 to prevent a relapse of hyperammonemic encephalopathy. We present the therapy for six CTLN2 patients. All the patients' general condition steadily improved and five patients with hyperammonemic encephalopathy recovered from unconsciousness in a few days. Before the treatment, plasma glutamine levels did not increase over the normal range and rather decreased to lower than the normal range in some patients. The treatment promptly decreased the blood ammonia level, which was accompanied by a decrease in plasma citrulline levels and an increase in plasma glutamine levels. These findings indicated that hyperammonemia was not only caused by the impairment of ureagenesis at ASS1 step, but was also associated with an impairment of glutamine synthetase (GS) ammonia-detoxification system in the hepatocytes. There was no decrease in the GS expressing hepatocytes. MCT supplement with a low-carbohydrate formula can supply the energy and/or substrates for ASS1 and GS, and enhance ammonia detoxification in hepatocytes. Histological improvement in the hepatic steatosis and ASS1-expression was also observed in a patient after long-term treatment.

Interleukin-28B genotypes determine response to pegylated-interferon plus ribavirin therapy in patients with hepatitis C virus infection.

We recently reported that the interleukin (IL)-28B major genotype is a predictor of early suppression of the hepatitis C virus (HCV) at 12 weeks in response to pegylated interferon (PEG-IFN) plus ribavirin (RBV) therapy. The present study investigated the relationship between IL-28 genotypes and the virological response to PEG-IFN/RBV therapy at 24 and 48 weeks. Genotypes of the IL-28B rs8099917 T>G single nucleotide polymorphism were determined in 177 patients with HCV infection. Among them, 56 patients with HCV1 infection were treated with PEG-IFN/RBV. The frequency of the IL-28B major allele (TT) was 73.8% in patients with HCV serotype 1 and 86.3% in patients with HCV serotype 2. The rate of HCV-RNA positivity was significantly lower at 48 weeks in patients with the IL-28B major allele compared to patients with the IL-28B minor allele (TG or GG). The rate of HCV-RNA positivity at 24 weeks tended to be lower in patients with the IL-28B major allele, but there was no statistical significance (P=0.059). The sustained virological response (SVR) rate was 45.9% in patients with the IL-28B major allele, but 13.3% in patients with the IL-28B minor allele. The SVR correlated with the IL-28B major allele (OR=7.13, P=0.010), early virological response (OR=33.3, P=0.008), HCV-RNA ≤ 6.3 log IU/ml (OR=81.2, P=0.009) and γ-GTP ≤ 47 IU/l (OR=49.4, P=0.027). The IL-28B genotype is a significant pre-treatment predictor of the response to PEG-IFN/RBV therapy at 48 weeks in patients with HCV infection.

Interleukin-28B polymorphisms are associated with an early viral response in patients receiving hepatitis C therapy.

Prediction of the efficacy of pegylated interferon (PEG-IFN) plus ribavirin (RBV) therapy against hepatitis C (HCV) infection is valuable for determining its applications. This study investigated the relationship between the early response of HCV to PEG-IFN/RBV therapy and the inter-leukin (IL)-28B genetic polymorphism in patients with HCV infection. The genotypes of IL-28B rs8099917 T>G single nucleotide polymorphism were determined in 144 patients with HCV infection. Among them, 59 were treated with PEG-IFN/RBV. The frequency of IL-28B TT homozygosity was 75.2% in patients with HCV serotype 1 and 84.6% in patients with serotype 2. Multivariate analysis showed that IL-28B TT homozygosity (P=0.014) and the platelets number (P=0.030) was associated with the early suppression of HCV-RNA at 12 weeks after the start of PEG-IFN/RBV therapy. The IL-28B polymorphism was a significant pre-treatment predictor of the response to PEG-IFN/RBV therapy in patients with HCV infection.

Hepatic reactive lymphoid hyperplasia in a patient with primary biliary cirrhosis.

Reactive lymphoid hyperplasia (RLH) of the liver is an extremely rare lesion characterized by the proliferation of non-neoplastic lymphocytes forming follicles. Hepatic RLH is known to be associated with gastrointestinal carcinoma and autoimmune diseases including primary biliary cirrhosis (PBC). We report a case of hepatic RLH in a patient with PBC and gastric cancer. A 68 year old Japanese woman with a 10 year history of liver enzyme abnormality was admitted. Laboratory testing revealed that her anti-mitochondrial antibody was markedly elevated. Five mo after the diagnosis of PBC, she was found to have gastric cancer. Abdominal computed tomography disclosed a liver nodule in S8, suggesting metastatic gastric carcinoma. Histopathologically, the resected liver lesion comprised of a nodular proliferation of small lymphocytes with lymphoid follicles. This is the first reported case of hepatic RLH in a patient with both PBC and gastric cancer. Pre-operative diagnosis of hepatic RLH by clinical imaging is extremely difficult. Therefore, a needle biopsy could be useful to make a diagnosis of hepatic RLH, especially to differentiate from metastatic gastrointestinal carcinoma.

Hepatocellular carcinoma occurring in a Crohn's disease patient.

We report a case of hepatocellular carcinoma (HCC) occurring in a patient with Crohn's disease (CD) without chronic hepatitis or liver cirrhosis, and review the clinicopathological features of HCC in CD patients. A 37-year-old Japanese man with an 8-year history of CD and a medication history of azathioprine underwent resection of a liver tumor. The histopathology of the liver tumor was pseudoglandular type HCC. In the non-neoplastic liver, focal hepatocyte glycogenosis (FHG) was observed, however, there was no evidence of liver cirrhosis or primary sclerosing cholangitis. Only nine cases of HCC in CD patients have been reported previously in the English-language literature. Eight of 10 cases (including the present case) had received azathioprine treatment, and four of these cases also showed FHG, which is considered a preneoplastic liver lesion, within the non-neoplastic liver. Although the precise mechanism of the development of HCC in CD patients is controversial, these results suggest that azathioprine therapy and FHG in the non-neoplastic liver contribute to the development of HCC. These findings also indicate that it is important to survey CD patients treated with prolonged azathioprine therapy for potential liver tumors.

Factors affecting the efficacy of cyclosporin A therapy for refractory ulcerative colitis.

BACKGROUND AND AIMS: Cyclosporin A (CSA), an immunosuppressive agent, is highly efficacious in patients with refractory ulcerative colitis (UC). We retrospectively investigated patients with refractory UC treated with CSA therapy to elucidate the efficacy and the prognostic factors. METHODS: Forty-one patients (26 men and 15 women) were enrolled. The efficacy of CSA was assessed at three time points: short- and mid-term assessments took place 2 weeks and 1 year after CSA administration, respectively, and long-term assessments at the end of the observation period. RESULTS: The short-term response rate was 71%. Background analysis revealed risk factors for CSA unresponsiveness: (i) more than 10,000 mg of prednisolone used before CSA treatment; (ii) the presence of circulating (C7-HRP); and (iii) disease duration more than 4 years. The mid-term relapse-free survival rate was 51.0%. The addition of azathioprine (AZA) after CSA treatment significantly suppressed the incidence of relapse at 1 year (72.5% vs 26.7%, P = 0.0237). The overall colectomy-free survival rate was 46.4%, and the induction of AZA after CSA treatment significantly reduced the colectomy rate (66.7% vs 30.5%, P = 0.0419). Among CSA responders, AZA naïve patients had significant lower-probabilities for colectomies compared to patients with prior AZA treatment (22.5% vs 56.7%, P = 0.0309). The administration of CSA was discontinued in five cases. CONCLUSION: Our results revealed factors affecting the efficacy of CSA therapy for patients with refractory UC. AZA is an important agent that maintains disease quiescence once one responds to CSA. However, refractory patients despite AZA treatment are more likely to have consequent colectomies.

Alendronate improves low bone mineral density induced by steroid therapy in Crohn's disease.

AIM: We investigated whether steroid therapy for Crohn's disease (CD) patients influences bone mineral density (BMD), and whether alendronate is effective for improving this loss of BMD. METHODS: We recruited 16 outpatients with CD. The BMD of the whole body, the lumbar spine, and the proximal femoral neck was measured by dual-energy X-ray absorptimetry. The BMD was expressed as a T score. Some CD patients with low BMD values had been given vitamin K2 or alendronate for one year. RESULTS: In the steroid-dependent group, the mean dose of prednisolone was 968 mg per year and 2.7 mg per day. Although the duration of the disease was not related to the T score, the amount of total steroids was negatively correlated with the T score among patients taking no preventative drugs. The T score in the vitamin K2 group after one year did was not altered in the 3 areas examined. On the other hand, the T score in the alendronate group increased by 2.8% for the whole body, 4.5% in the lumbar spine, and 3.4% in the proximal femoral neck. CONCLUSION: The BMD of Japanese CD patients was decreased depending on the total amount of steroid administered, and oral alendronate improved the loss of BMD.

Usefulness of bispectral monitoring of conscious sedation during endoscopic mucosal dissection.

AIM: To assess the usefulness of bispectral index (BIS) monitoring in order to carry out endoscopic submucosal dissection (ESD) safely and with patients' satisfaction. METHODS: Three hundred sixty-six patients with an early-stage neoplasm of the digestive tract were enrolled. The BIS monitor (A-1050: Aspect medical systems/NIHON KOHDEN, Tokyo, Japan) was used. The appropriate sedative condition was set at 55 to 75 BIS levels (BIS value) during the endoscopic procedures. RESULTS: Among 366 cases, 13 were accompanied by adverse events during and/or after ESD. All episodes occurred in cases with BIS value between 56 and 65. Hypotension was observed in four cases, and bradycardia in six. Respiratory distress was observed in two cases with chronic pulmonary obstructive disease. All patients with adverse events were able to leave the hospital without extension of the hospitalization. CONCLUSION: BIS monitoring is useful to safely perform ESD. A BIS value of 70 to 75 is suitable for ESD.

Acute cytomegalovirus infection superimposed on corticosteroid-naïve ulcerative colitis.

Most cases of cytomegalovirus (CMV) colitis that develop in patients with inflammatory bowel disease (IBD) are caused by a reactivation of a latent virus; acute CMV infections are rare. Treatment with immunosuppressive agents further increases the infection risk. Here, we present a 32-year-old man with acute CMV-mononucleosis and colitis, superimposed on corticosteroid-naïve ulcerative colitis (UC). The diagnosis was confirmed by a viral-like prodrome, positive CMV antigenemia (C7-HRP), a positive CMV IgM titer, the presence of atypical lymphocytes, mild transaminase elevation, and immunohistological detection of CMV positive cells in his colonic mucosa. Gancyclovir was intravenously administered, and all symptoms were improved.

[Case report: periodical infliximab administration enabled closure of colostomy in fistulating perianal Crohn's disease].

A 29-year old woman with Crohn's disease was performed colostomy due to severe perianal abscess. Her disease had been easy to recur and she was admitted to hospital for intestinal bleeding caused by acute exacerbation in Crohn's disease on October 2006. The bleeding was stopped rapidly and clinical remission was maintained with bimonthly administration of infliximab. Finally, her colostomy was closed after 5 years 8 months. Periodical treatment of infliximab not only prevented recurrence but also enabled closure of colostomy in fistulating perianal Crohn's disease.

Chemoradiation therapy followed by endoscopic submucosal dissection for esophageal cancer.

We performed chemoradiation therapy (CRT) followed by an endoscopic submucosal dissection (ESD) for three patients with esophageal cancer. One patient refused surgery, and two patients were complicated with severe cardiopulmonary diseases. In all patients, CRT was effective in reducing tumor size, and the residual tumors were completely resected by ESD. All patients were recurrence-free for 6 months to 2.5 years. The combination of CRT plus subsequent ESD may be useful for treating patients with esophageal cancer who are not fit to undergo surgery.

Natriuretic peptides up-regulate aquaporin 3 in a human colonic epithelial cell line.

Several specialized channels termed aquaporins (AQPs) facilitate water transport in the gastrointestinal tract. AQP3 localizes to epithelial cells in the human small intestine and colon. However, the regulatory mechanisms responsible for AQP3 function in the gastrointestinal tract are not well understood. To characterize the regulation of AQP3 expression by atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), we studied mRNA expression by Northern blotting, protein expression by Western blotting and DNA binding activity by electrophoretic mobility shift assay (EMSA) in the human colonic epithelial cell line HT-29. We also used several inhibitors to investigate signal transduction. AQP3 mRNA was up-regulated in addition to ANP (>100 nM) and BNP (>10 nM). The expression of AQP3 protein was enhanced at 1 h after the addition of ANP and BNP. The combination of protein kinase-A (PK-A) and protein kinase-G (PK-G) inhibitors completely inhibited the expression of AQP3 mRNA enhanced by ANP or BNP to its basal level. The EMSA of the cyclic-AMP response element (CRE) in HT-29 cells revealed a single band. These results indicate that ANP and BNP up-regulated the expression of AQP3 mRNA and protein, and both PK-A and PK-G dependent pathways mediated this effect.

Extrapancreatic insulin-producing cells in multiple organs in diabetes.

Insulin-producing cells normally occur only in the pancreas and thymus. Surprisingly, we found widespread insulin mRNA and protein expression in different diabetic mouse and rat models, including streptozotocin-treated mice and rats, ob/ob mice, and mice fed high-fat diets. We detected in diabetic mice proinsulin- and insulin-positive cells in the liver, adipose tissue, spleen, bone marrow, and thymus; many cells also produced glucagon, somatostatin, and pancreatic polypeptide. By in situ nucleic acid hybridization, diabetic, but not nondiabetic, mouse liver exhibited insulin transcript-positive cells, indicating that insulin was synthesized by these cells. In transgenic mice that express GFP driven by the mouse insulin promoter, streptozotocin-induced diabetes led to the appearance of GFP-positive cells in liver, adipose tissue, and bone marrow; the fluorescent signals showed complete concordance with the presence of immunoreactive proinsulin. Hyperglycemia produced by glucose injections in nondiabetic mice led to the appearance of proinsulin- and insulin-positive cells within 3 days. Bone marrow transplantation experiments showed that most of the extrapancreatic proinsulin-producing cells originated from the bone marrow. Immunoreactive proinsulin- and insulin-positive cells were also detected in the liver, adipose tissue, and bone marrow of diabetic rats, indicating that extrapancreatic, extrathymic insulin production occurs in more than one species. These observations have implications for the regulation of insulin gene expression, modulation of self-tolerance by insulin gene expression, and strategies for the generation of insulin-producing cells for the treatment of diabetes.