Impact of continuous positive airway pressure therapy for nonalcoholic fatty liver disease in patients with obstructive sleep apnea.

BACKGROUND: Obstructive sleep apnea (OSA) has been suggested as an independent risk factor for nonalcoholic fatty liver disease (NAFLD), and continuous positive airway pressure (CPAP) is the first-line therapy for OSA. AIM: To clarify the efficacy of effective CPAP therapy on NAFLD of OSA patients by serum markers and transient elastography (TE) using FibroScan® (Echosens, Paris, France). METHODS: We prospectively enrolled 123 consecutive patients with OSA who met the indications for CPAP. Liver fibrosis and steatosis were assessed using TE. Before and after 6 mo of CPAP therapy, serum markers and TE were assessed for all patients. The mean usage rate of CPAP therapy for 6 mo was arbitrarily calculated in each patient and expressed as "mean compliance index" (m-CI). RESULTS: In 50 OSA patients with NAFLD, both aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were significantly decreased after 6 mo of CPAP therapy. Univariate analysis showed that decreased body weight (BW), decreased body mass index (BMI), decreased AST level, decreased hemoglobin A1c, and high m-CI were significantly related with improved ALT level. In multivariate regression model adjusted for quantities of BW change during 6 mo of CPAP therapy, high m-CI tended to improve ALT level (P = 0.051). All 17 OSA patients with NAFLD, high m-CI and no BMI changes showed significant improvements in AST and ALT levels. Meanwhile, no significant changes in TE data or serum fibrosis markers were seen. CONCLUSION: Some NAFLD could be associated with chronic intermittent hypoxia due to OSA independent of BW changes. In those cases, adequate reoxygenation from effective CPAP therapy may improve NAFLD.

Practical Use of Transient Elastography in Screening for Nonalcoholic Steatohepatitis in a Japanese Population.

Background and Aims: Fatty infiltration of liver may induce insulin resistance (IR), and a proportion of patients with nonalcoholic fatty liver disease (NAFLD) is diagnosed with nonalcoholic steatohepatitis. Transient elastography is gaining popularity as a means of non-invasively determining both liver stiffness (fibrosis level) and degree of fatty infiltration, expressed as controlled attenuation parameter (CAP) value. Methods: The aims of this study were to investigate the association between IR and level of fatty liver, and to identify the group at a greater risk of nonalcoholic steatohepatitis using transient elastography and other noninvasive fibrosis markers. A total of 169 patients without chronic hepatitis B and C were analyzed. Results: The CAP value was significantly associated with IR (HOMA-IR ≥2.5; AUROC = 0.81), and the optimal cut-off to discriminate IR was 264 dB/m. The liver stiffness measurement and aspartate aminotransferase-to-platelet ratio index values were significantly higher for CAP ≥264 than in CAP <264. The 9 patients among the overall 169 patients (5.3%) and among the 102 NAFLD patients (8.8%) who showed ≥264 dB and ≥7.0 kPa in transient elastography could represent good candidates for liver biopsy. Conclusions: Evaluation of NAFLD based on CAP values was useful in diagnosing IR. About 9% of NAFLD patients in a Japanese outpatient clinic with a few metabolic complications might be considered good candidates for liver biopsy to confirm nonalcoholic steatohepatitis.

Dental pulp cell bank as a possible future source of individual hepatocytes.

Mesenchymal stem cells (MSCs) as a source for regenerative medicine are now the subject of much clinical attention. There are high expectations due to their safety, low tumorigenic risk, and low ethical concerns. MSC therapy has been approved for acute graft-versus host diseases since 2015. Tooth-derived MSCs are known to have a great potential in their proliferation and differentiation capacities, even when compared with bone-marrow-derived MSCs. In particular, stem cells from human exfoliated deciduous teeth (SHEDs) are the best candidates for personal cell banking (dental pulp cell bank), because they can be obtained less invasively in the natural process of individual growth. SHEDs are known to differentiate into hepatocytes. There have been several studies showing the effectiveness of SHEDs on the treatment of liver failure in animal models. They may exert their effects either by repopulation of cells in injured liver or by paracrine mechanisms due to their immune-regulatory functions. Moreover, it may be possible to use each individuals' dental pulp cells as a future source of tailor-made differentiated hepatocytes in the context of a bioartificial liver or liver-on-a-chip to screen for drug toxicity.

A Case of Right-Sided Ulcerative Colitis with Mesalamine-Induced Hypersensitivity Reactions.

BACKGROUND Ulcerative colitis (UC) is a chronic inflammatory bowel disease, affecting the colon continuously from the rectum proximally. However, a clinical type with right-sided colitis sparing the anal side of the colon is also known. Mesalamine, which is generally used to treat UC, can rarely aggravate the disease. CASE REPORT A 56-year-old woman with no history of colonic diseases visited our hospital because of a positive fecal occult blood test. The first colonoscopy showed inflamed and edematous mucosa extending from the ascending colon to the right-half of the transverse colon. Colonic biopsy specimens demonstrated infiltrations of chronic inflammatory cells in the mucosa and crypt abscesses, but no epithelioid granulomas, compatible with UC. She was highly positive for PR3-ANCA, confirming the diagnosis of UC. After starting mesalamine, she had hypersensitivity reactions and aggravations of UC, which were confirmed endoscopically. CONCLUSIONS Right-sided colitis may be a subgroup of UC, and this is the first report of this type of disease complicated by aggravation due to mesalamine hypersensitivity.

Regenerative medicine using dental pulp stem cells for liver diseases.

Acute liver failure is a refractory disease and its prognosis, if not treated using liver transplantation, is extremely poor. It is a good candidate for regenerative medicine, where stem cell-based therapies play a central role. Mesenchymal stem cells (MSCs) are known to differentiate into multiple cell lineages including hepatocytes. Autologous cell transplant without any foreign gene induction is feasible using MSCs, thereby avoiding possible risks of tumorigenesis and immune rejection. Dental pulp also contains an MSC population that differentiates into hepatocytes. A point worthy of special mention is that dental pulp can be obtained from deciduous teeth during childhood and can be subsequently harvested when necessary after deposition in a tooth bank. MSCs have not only a regenerative capacity but also act in an anti-inflammatory manner via paracrine mechanisms. Promising efficacies and difficulties with the use of MSC derived from teeth are summarized in this review.

Natural regression of fibrosis in chronic hepatitis B.

The fibrosis of liver cirrhosis was considered to be irreversible before the anti-viral drugs showed that it is reversible when they lead to continuous suppression of viral replication and inflammation. However, several reports previously showed that fibrosis of type B liver cirrhosis was almost completely absorbed after the natural remission of chronic inflammation. This phenomenon might not be limited to exceptional patients, but rather occur commonly, considering the dynamic clinical features of chronic hepatitis B (CHB), where inactive carrier stage normally follows aggravation of hepatitis and progression of fibrosis at the time of HBeAg seroconversion. Thus, fibrosis levels of CHB as a hepatocellular carcinoma (HCC)-surveillance marker, particularly those of the inactive stage, could be underestimated, because some of them might have been (pre)cirrhotic in the past and recovered with the natural regression of fibrosis. We argue that cirrhosis-induced HCC mechanisms, rather than direct action of viral genome, may be more common than generally considered in CHB patients. This may have some impact on reconsidering the surveillance rationale for HCC in CHB, from where advanced HCCs tended to be missed. In addition, a molecular marker to assess the cancer-prone characteristics of the liver will definitely be needed to resolve the issue.

Contributions of transgenic mouse studies on the research of hepatitis B virus and hepatitis C virus-induced hepatocarcinogenesis.

Transgenic mouse technology has enabled the investigation of the pathogenic effects, including those on development, immunological reactions and carcinogenesis, of viral genes directly in living organism in a real-time manner. Although viral hepatocarcinogenesis comprises multiple sequences of pathological events, that is, chronic necroinflammation and the subsequent regeneration of hepatocytes that induces the accumulation of genetic alterations and hepatocellular carcinoma (HCC), the direct action of viral proteins also play significant roles. The pathogenesis of hepatitis B virus X and hepatitis C virus (HCV) core genes has been extensively studied by virtue of their functions as a transactivator and a steatosis inducer, respectively. In particular, the mechanism of steatosis in HCV infection and its possible association with HCC has been well studied using HCV core gene transgenic mouse models. Although transgenic mouse models have remarkable advantages, they are intrinsically accompanied by some drawbacks when used to study human diseases. Therefore, the results obtained from transgenic mouse studies should be carefully interpreted in the context of whether or not they are well associated with human pathogenesis.

Direct antiviral agent treatment of decompensated hepatitis C virus-induced liver cirrhosis.

Recently, direct antiviral agents (DAAs) have been increasingly used for the treatment of chronic hepatitis C virus (HCV) infections, replacing interferon-based regimens that have severe adverse effects and low tolerability. The constant supply of new DAAs makes shorter treatment periods with enhanced safety possible. The efficacy of DAAs for treatment of compensated liver cirrhosis (LC) is not less than that for treatment of non-cirrhotic conditions. These clinical advantages have been useful in pre- and post-liver transplantation (LT) settings. Moreover, DAAs can be used to treat decompensated HCV-induced LC in elderly patients or those with severe complications otherwise having poor prognosis. Although encouraging clinical data are beginning to appear, the actual efficacy of DAAs for suppressing disease progression, allowing delisting for LT and, most importantly, improving prognosis of patients with decompensated HCV-LC remains unknown. Case-control studies to examine the short- or long-term effects of DAAs for treatment of decompensated HCV-LC are urgently need.

Literature review in cases with exacerbation of ulcerative colitis induced by treatment with interferon and/or ribavirin.

Ulcerative colitis (UC) is an immune disorder of the gastrointestinal tract which has been reported to be precipitated by interferon (IFN) therapy. We describe the results of a literature review of cases in which the development or exacerbation of UC was coincident with IFN and/or ribavirin (RIB) treatment for chronic hepatitis C. We summarized the studies on the effectiveness of IFN for UC or Crohn's disease, which were primarily carried out in Europe and the USA. In the nine reported cases of UC exacerbation by IFN therapy in Japan, seven involved IFN-α, one involved IFN-α2b plus RIB, and the other involved IFN-ß; thus cases induced by IFN-α were more common. The period between the initiation of IFN treatment and the development or exacerbation of UC varied widely among the reported cases (from 1 day to 4.5 years). The reports have all assumed a cause-and-effect correlation between IFN treatment and UC. However, although combination therapy of IFN and RIB has become widespread in Japan, UC development or exacerbation induced by IFN has not increased concurrently. Conversely, numerous studies reporting the effectiveness of IFN for treating UC and Crohn's disease have been published in Europe and the USA. One reason for this finding may be the difference in the balance of T helper cell 1 and T helper cell 2 between populations.

Successful treatment of mucosa-associated lymphoid tissue lymphoma in a patient with gastric and rectal lesions with metachronous and ectopic development.

A 75-year-old female, who had an abnormal stomach x-ray finding, was admitted to the hospital for further examination and therapy. Upper GI endoscopy showed reddish and swollen folds on the greater curvature of the gastric body and a biopsy was of this lesion revealed malignant lymphoma (small cell type or mucosa-associated lymphoid tissue (MALT) lymphoma suspected). The patient was infected with Helicobacter pylori (H. pylori), however, in response to the patient's wishes, a total gastrectomy, omentectomy and splenectomy were performed and the histological diagnosis was gastric MALT lymphoma. Two courses of CHOP therapy (cyclophosphamide (CPM) 750 mg/m(2)/day, day 1, adriamycin (ADM) 50 mg/m(2)/day, day 1, vincristine sulfate (VCR) 1.4 mg/m(2)/day, day 1, prednisolone 100 mg/body, day 1-5) were administered as adjuvant chemotherapy. A colonoscopic examination performed about 4.5 yr after the operation revealed rectal submucosal tumors and the biopsied specimens were diagnosed as malignant lymphoma. A transanal focal resection was performed and the histological diagnosis was metachronous and ectopic development of MALT lymphoma. The histological finding was similar to the gastric lesion. About 4 and 7 yr after the first development of rectal MALT lymphoma, MALT lymphomas developed repeatedly in the rectal lesion, however, these were resected repeatedly and no developmenthas occurred during the past two years. This report presents a very rare case of metachronous and ectopic MALT lymphoma development in the gastric and rectal lesions.

[A case of superior mesenteric artery occlusion associated with idiopathic chronic cold agglutinin disease].

A 64-year-old man who had been given a diagnosis of idiopathic chronic cold agglutinin disease in a medical clinic suffered from Raynaud's phenomenon and acrocyanosis in winter. He was admitted to our hospital with unbearable abdominal pain. Blood tests showed liver dysfunction with jaundice and severe acidosis. Abdominal angiogram and contrast-enhanced CT revealed superior mesenteric artery occlusion. These findings suggest that thrombosis due to cold agglutinin disease could be the cause of superior mesenteric artery occlusion.

Advanced gastric cancer patient with peritonitis carcinomatosa successfully treated with a combination therapy of paclitaxel and TS-1, but relapsed with multiple bone metastasis and died from rapidly progressive meningitis carcinomatosa--advanced gastric cancer with metachronous peritonitis carcinomatosa and meningitis carcinomatosa.

A 59-year-old man diagnosed as gastric cancer with peritonitis carcinomatosa was treated with paclitaxel and TS-1; 60 mg/m(2)/day of paclitaxel was given on days 1 and 8, and 60-80 mg/m(2)/day of TS-1 was given for 2 weeks. Six courses of combination therapy were administered, and the ascites disappeared completely. Because multiple bone metastases occurred, we attempted combination therapy with cisplatin and irinotecan hydrochloride; 50 or 30 mg/m(2)/day of cisplatin was given on day 1 or day 15, and 70 mg/m(2)/day of irinotecam hydrochloride was given on days 1 and 15. The patient achieved a remarkable response, however, intrameningeal dissemination occurred and he died from rapidly progressive meningitis carcinomatosa.

Features of hepatocellular carcinoma in cases with autoimmune hepatitis and primary biliary cirrhosis.

AIM: To characterize the clinical features of hepatocellular carcinoma (HCC) associated with autoimmune liver disease, we critically evaluated the literature on HCC associated with autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC). METHODS: A systematic review of the literature was conducted using the Japana Centra Revuo Medicina database which produced 38 cases of HCC with AIH (AIH-series) and 50 cases of HCC with PBC (PBC-series). We compared the clinical features of these two sets of patients with the general Japanese HCC population. RESULTS: On average, HCC was more common in men than in women with AIH or PBC. While many patients underwent chemolipiodolization (CL) or transcatheter arterial embolization (TAE) (AIH-series: P = 0.048 (vs operation), P = 0.018 (vs RFA, PEIT); PBC-series: P = 0.027 (vs RFA, PEIT), others refused therapeutic interventions [AIH-series: P = 0.038 (vs RFA, PEIT); PBC-series: P = 0.003 (vs RFA, PEIT)]. Liver failure was the primary cause of death among patients in this study, followed by tumor rupture. The survival interval between diagnosis and death was fairly short, averaging 14 +/- 12 mo in AIH patients and 8.4 +/- 14 mo in PBC patients. CONCLUSION: We demonstrated common clinical features among Japanese cases of HCC arising from AIH and PBC.

Synchronous development of HCC and CCC in the same subsegment of the liver in a patient with type C liver cirrhosis.

As a result of having undergone computed tomography (CT), a 75-year-old woman with type-C liver cirrhosiswas shown to have two tumors on the ventral and dorsal sides of subsegment 3 (S3). The tumor on the ventral side was diagnosed as a classic hepatocellular carcinoma (HCC), while that on the dorsal side was considered atypical for a HCC. Although the indocyanine green (ICG) findings indicated poor hepatic reserve, the prothrombin time (PT) was relatively good. An operation was performed in February 2007; however, this resulted in exploratory laparotomy. Dynamic CT performed 12 mo after the operation revealed that the tumor on the dorsal side of S3 had apparently increased. The marginal portion of the tumor was shown to be in the early and parenchymal phases, while the internal portion was found to have grown only slightly in the delayed phase. We diagnosed this tumor as a cholangiocellular carcinoma (CCC). S3 subsegmentectomy was performed in April 2008. The tumor on the ventral side was pathologically diagnosed as a moderately differentiated HCC, and that on the dorsal side was diagnosed as a CCC. We can therefore report a rare case of synchronous development of HCC and CCC in the same subsegment of the liver in a patient with type-C liver cirrhosis. We also add a literature review for all the reported cases published in Japan and around the world, and summarize the features of double cancer exhibiting both HCC and CCC.

Pelioid-type hepatocellular carcinoma with numerous eosinophilic infiltrations in a patient with primary biliary cirrhosis.

A 65-year-old woman with liver injury was referred to our hospital in 1992. She was diagnosed with primary biliary cirrhosis (PBC) of Scheuer's histological classification stage IV. She was treated with 600 mg/day of ursodeoxycholic acid. A 1-cm mass in S7 was detected in August 1995. The serum alpha-fetoprotein (AFP) level increased to 1288 ng/mL in January 1996. Angiography showed a cotton wool-like appearance in the delayed phase. Because the size of the tumor appeared to be increasing and the serum AFP levels increased with high levels of L3 fraction, a pelioid-type hepatocellular carcinoma (HCC) was strongly suspected. Hepatic artery infusion with SMANCS and partial resection of S7 and S8 of the liver were performed in March 1996. The pathological diagnosis for theresected liver tumor was pelioid-type HCC. The serum AFP level decreased to 50 ng/mL after the operation, but relapsed HCC was detected in S6 and S7. Angiography in September 1996 revealed multiple hypervascular lesions, and hepatic artery infusion with SMANCS was again performed; however, we were unable to suppress the progression of the relapsed HCC. The patient died due to an intra-abdominal rupture of relapsed HCC and subsequent liver failure in December 1996. We report a rare case of pelioid-type HCC with numerous eosinophilic infiltrations arising from PBC.

Bidirectional gastric differentiation in cellular mucin phenotype (foveolar and pyloric) in serrated adenoma and hyperplastic polyp of the colorectum.

This study examined whether gastric pyloric gland-type mucin is expressed in serrated adenoma (SA) and in hyperplastic polyp (HP) of the colorectum, and whether cellular position-based gastric differentiation is observed in these lesions as previously hypothesized. Immunostaining was performed for MUC6 and alpha-linked GlcNAc residue (pyloric gland-type mucin markers), human gastric mucin (HGM; foveolar-type mucin marker) and Ki-67 (proliferating cell marker) for 31 SA, 22 HP, 21 traditional tubular adenoma (TA) and 20 hyperplastic nodule (HN). MUC6 showed varying expression in SA, 22/31 (71.0%); HP, 15/22 (68.2%); TA, 2/21 (9.5%); and HN, 0/20 (0%) with significantly higher frequencies in SA and HP compared to those in TA and HN. The alpha-linked GlcNAc residue was found only in SA (3/31, 9.7%) and in HP (2/22, 9.1%). In SA and HP, HGM was typically expressed in the entire crypt length, but some reduction in expression was shown in the basal crypt portion below the proliferative zone. MUC6 and alpha-linked GlcNAc residues were expressed in the basal crypt portion below or below and including proliferative zone. These data demonstrate that SA and HP show bidirectional gastric (foveolar and pyloric gland) differentiation with respect to mucin cellular phenotype and the potential for cellular position-based differentiation, which mimics the gastric antral mucosa.

Bile duct involvement in a case of autoimmune pancreatitis successfully treated with an oral steroid.

In the case reported here, the characteristic features of AIP were evaluated by ultrasonography, computed tomography and endoscopic retrograde cholangiopancreatography, initially in the intrahepatic- and extrahepatic bile ducts, and later in the pancreas. In addition, histological examination revealed lymphocytic sclerosis around the intralobular bile ducts, as is reported in AIP, without chronic nonsuppurative destructive cholangitis or onion-skin-like appearance. Immunohistochemistry identified the infiltrating lymphocytes as T cells. Although hypergammaglobulinemia was observed with elevation of hepatobiliary and pancreatic enzymes, no other serological or physiological abnormalities suggestive of other systemic autoimmune diseases were detected. These findings progressed over a three-month period and were dramatically resolved within one month by steroid therapy. These observations support a novel clinical entity characterized by the presence of bile duct lesions similar to the pancreatic involvement seen in AIP that is distinct pathophysiologically, histologically, and therapeutically from the so-called autoimmune cholangitis or primary sclerosing cholangitis.