Haruka Hirono

CASE REPORT: 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.

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 α‐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 α‐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 α‐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.

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.

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.

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.

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.

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

Patient: Female, 56 Final Diagnosis: Right-sided ulcerative colitis • mesalamine-induced hypersensitivity Symptoms: High fever • vague discomfort of the upper abdomen Medication: Mesalamine Clinical Procedure: — Specialty: Gastroenterology and Hepatology Objective: Unusual clinical course 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.

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.