Hayato Baba

The liver in itai-itai disease (chronic cadmium poisoning): pathological features and metallothionein expression

Cadmium (Cd) is a highly hepatotoxic heavy metal, which is widely dispersed in the environment. Acute Cd hepatotoxicity has been well studied in experimental animals; however, effects of prolonged exposure to Cd doses on the liver remain unclear. In the present study, to evaluate chronic Cd hepatotoxicity, we examined specimens from cases of itai-itai disease, the most severe form of chronic Cd poisoning. We compared 89 cases of itai-itai disease with 27 control cases to assess Cd concentration in organs. We also examined 80 cases of itai-itai disease and 70 control cases for histopathological evaluation. In addition, we performed immunohistochemistry for metallothionein, which binds and detoxifies Cd. Hepatic Cd concentration was higher than Cd concentration in all other organs measured in the itai-itai disease group, whereas it was second highest following renal concentration in the control group. In the liver in the itai-itai disease group, fibrosis was observed at a significantly higher rate than that in the control group. Metallothionein expression was significantly higher in the itai-itai disease group than that in the control group. Prolonged exposure to low doses of Cd leads to high hepatic accumulation, which can then cause fibrosis; however, it also causes high expression of metallothionein, which is thought to reduce Cd hepatotoxicity.

Neutrophil-to-lymphocyte ratio predicts recurrence after radiofrequency ablation in hepatitis B virus infection

Radiofrequency ablation (RFA) is an established treatment for small hepatocellular carcinoma (HCC) wherein non‐recurrence is essential for long‐term survival. Recently, neutrophil‐to‐lymphocyte ratio (NLR), a marker of systemic inflammation that is associated with tumor‐associated macrophages (TAMs), was suggested to be a prognostic marker of HCC treated with RFA. Therefore, we evaluated predictive factors, including NLR, associated with recurrence after curative RFA.

Neonatal monosodium glutamate treatment causes obesity, diabetes, and macrovesicular steatohepatitis with liver nodules in DIAR mice

Non‐alcoholic steatohepatitis (NASH) is the hepatic manifestation of metabolic syndrome (MS). Monosodium glutamate (MSG)‐treated ICR mice is a useful model of MS and NASH, but it shows the different patterns of steatosis from human NASH. Because inbred aged DIAR (ddY, Institute for Animal Reproduction) mice spontaneously show the similar pattern of steatosis as NASH, we analyzed their liver pathology after administering MSG.

Primary Biliary Cholangitis: Its Pathological Characteristics and Immunopathological Mechanisms

Primary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis, is an organ-specific autoimmune disease that predominantly affects middle-aged women and is characterized by the chronic progressive destruction of small intrahepatic bile ducts with portal inflammation and, ultimately, fibrosis. The serological hallmark of PBC is the presence of anti-mitochondrial autoantibodies (AMA). Several mechanisms have been proposed for immune-mediated bile duct damage in PBC, including the roles of T cells, B cells, other cell phenotypes, and AMA. A sign of fragility of biliary epithelial cells caused by apoptosis, senescence, and autophagy has also been noted. Several complex steps and mechanisms appear to be involved in the induction and progression of cholangitis and biliary degeneration in patients with PBC. J. Med. Invest. 64: 7-13, February, 2017.

Histopathological characteristics of glutamine synthetase-positive hepatic tumor lesions in a mouse model of spontaneous metabolic syndrome (TSOD mouse)

We previously reported that Tsumura-Suzuki obese diabetic (TSOD) mice, a polygenic model of spontaneous type 2 diabetes, is a valuable model of hepatic carcinogenesis via non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). One of the characteristics of tumors in these mice is the diffuse expression of glutamine synthetase (GS), which is a diagnostic marker for hepatocellular carcinoma (HCC). In this study, we performed detailed histopathological examinations and found that GS expression was diffusely positive in >70% of the hepatic tumors from 15-month-old male TSOD mice. Translocation of β-catenin into nuclei with enhanced membranous expression also occurred in GS-positive tumors. Small lesions (<1 mm) in GS-positive cases exhibited dysplastic nodules, with severe nuclear atypia, whereas large lesions (>3 mm) bore the characteristics of human HCC, exhibiting nuclear and structural atypia with invasive growth. By contrast, the majority of GS-negative tumors were hepatocellular adenomas with advanced fatty change and low nuclear grade. In GS-negative tumors, loss of liver fatty acid-binding protein expression was observed. These results suggest that the histological characteristics of GS-positive hepatic tumors in TSOD mice resemble human HCC; thus, this model may be a useful tool in translational research targeting the NAFLD/NASH-HCC sequence.

Hyperbilirubinemia without Transaminitis during Combined Therapy with Daclatasvir and Asunaprevir

Daclatasvir (DCV) and asunaprevir (ASV) are direct-acting antivirals (DAAs) used in the treatment of chronic hepatitis C virus (HCV) infection. Combined therapy with DCV and ASV shows high efficacy and safety even in patients with cirrhosis. We encountered a patient exhibiting severe hyperbilirubinemia during combined therapy, which is an unreported side effect of DCV and ASV. A 78-year-old woman with cirrhosis developed hyperbilirubinemia >10 mg/dl without transaminitis 3 weeks after starting combined therapy. We suspected DAAs-induced liver disorder and discontinued treatment, which resulted in the improvement of hyperbilirubinemia. Caution is required in the use of DAAs for patients with advanced cirrhosis.

Immunopathology of Bile Duct Lesions of Primary Biliary Cirrhosis

Primary biliary cirrhosis (PBC) is an organ-specific autoimmune disease that predominantly affects women and is characterized by chronic progressive destruction of the small intrahepatic bile ducts with portal inflammation and ultimately fibrosis. The serologic hallmark of PBC is the presence of anti-mitochondrial autoantibodies (AMA). Several mechanisms may now be proposed regarding the immune-mediated bile duct damage in PBC, including the possible roles of T cells, B cells, AMA, and other cell phenotypes. Weakness of biliary epithelial cells in association with apoptosis, senescence, and autophagy has also been noted recently. In PBC, several complex steps and mechanisms may be involved in the induction and progression of cholangitis and biliary degeneration, followed by bile duct loss.

Peritumoral Hyperplasia in Hepatic Sclerosed Hemangioma

Peritumoral hyperplasia (PTH) is a hyperplastic lesion located around hypervascular tumors. Hepatic sclerosed hemangioma is a very rare form of hemangioma with sclerotic changes and is distinct from sclerosing hemangioma. We present a patient with non-alcoholic steatohepatitis-induced cirrhosis who presented with a hypervascular tumor. The tumor showed atypical findings of hemangioma and was treated with surgical resection because hepatic malignancy could not be ruled out. Histopathologic examination revealed the tumor was a sclerosed hemangioma with PTH. Lesions with carcinogenic potential were found in the PTH lesion. Sclerosed hemangioma should be observed and managed carefully.

Complete Resolution of Pseudomalignant Erosion in a Reflux Gastroesophageal Polyp with Proton Pump Inhibitor

Pseudomalignant erosion is a diagnostic pitfall for pathologists in the differential diagnosis of malignant neoplasms. Here, we present a challenging case of a biopsy specimen from the eroded head of a polyp at the esophagogastric junction. A malignant neoplasm could not be ruled out due to the presence of bizarre stromal cells. A second biopsy performed after the administration of a proton pump inhibitor (PPI) for 4 weeks revealed endoscopic resolution of the polyp along with the complete histological resolution of the bizarre stromal cells and led to the diagnosis of pseudomalignant erosion in a reflux gastroesophageal polyp. In conclusion, histological and endoscopic response to PPI therapy is an important clue for the correct diagnosis of reflux gastroesophageal polyps with pseudomalignant erosion.