Pathology and Pathogenesis of Metabolic Dysfunction-Associated Steatotic Liver Disease-Associated Hepatic Tumors.

Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive fat accumulation in the livers of patients without a history of alcohol abuse. It is classified as either simple steatosis (nonalcoholic fatty liver) or nonalcoholic steatohepatitis (NASH), which can progress to liver cirrhosis and hepatocellular carcinoma (HCC). Recently, it was suggested that the terms "metabolic dysfunction-associated steatotic liver disease (MASLD)" and "metabolic dysfunction-associated steatohepatitis (MASH)" should replace the terms "nonalcoholic fatty liver disease (NAFLD)" and "nonalcoholic steatohepatitis (NASH)", respectively, with small changes in the definitions. MASLD, a hepatic manifestation of metabolic syndrome, is rapidly increasing in incidence globally, and is becoming an increasingly important cause of HCC. Steatohepatitic HCC, a histological variant of HCC, is characterized by its morphological features resembling non-neoplastic steatohepatitis and is closely associated with underlying steatohepatitis and metabolic syndrome. Variations in genes including patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily 2 (TM6SF2), and membrane-bound O-acyltransferase domain-containing protein 7 (MBOAT7) are associated with the natural history of MASLD, including HCC development. The mechanisms of HCC development in MASLD have not been fully elucidated; however, various factors, including lipotoxicity, inflammation, reactive oxygen species, insulin resistance, and alterations in the gut bacterial flora, are important in the pathogenesis of MASLD-associated HCC. Obesity and MASLD are also recognized as risk factors for hepatocellular adenomas, and recent meta-analyses have shown an association between MASLD and intrahepatic cholangiocarcinoma. In this review, we outline the pathology and pathogenesis of MASLD-associated liver tumors.

Artificial intelligence and deep learning: New tools for histopathological diagnosis of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) is associated with metabolic syndrome and is rapidly increasing globally with the increased prevalence of obesity. Although noninvasive diagnosis of NAFLD/NASH has progressed, pathological evaluation of liver biopsy specimens remains the gold standard for diagnosing NAFLD/NASH. However, the pathological diagnosis of NAFLD/NASH relies on the subjective judgment of the pathologist, resulting in non-negligible interobserver variations. Artificial intelligence (AI) is an emerging tool in pathology to assist diagnoses with high objectivity and accuracy. An increasing number of studies have reported the usefulness of AI in the pathological diagnosis of NAFLD/NASH, and our group has already used it in animal experiments. In this minireview, we first outline the histopathological characteristics of NAFLD/NASH and the basics of AI. Subsequently, we introduce previous research on AI-based pathological diagnosis of NAFLD/NASH.

Application of Immunohistochemistry in the Pathological Diagnosis of Liver Tumors.

Although radiological diagnostics have been progressing, pathological diagnosis remains the most reliable method for diagnosing liver tumors. In some cases, definite pathological diagnosis cannot be obtained by histological evaluation alone, especially when the sample is a small biopsy; in such cases, immunohistochemical staining is very useful. Immunohistochemistry is the most frequently used technique for molecular pathological diagnosis due to its broad application, ease of performance and evaluation, and reasonable cost. The results occasionally reflect specific genetic mutations. The immunohistochemical markers of hepatocellular carcinoma include those of hepatocellular differentiation-such as hepatocyte paraffin 1 and arginase-1-and those of malignant hepatocytes-such as glypican-3, heat shock protein 70, and glutamine synthetase (GS). To classify the subtypes of hepatocellular adenoma, examination of several immunohistochemical markers, such as liver fatty acid-binding protein, GS, and serum amyloid A, is indispensable. Immunohistochemical staining for GS is also important for the diagnosis of focal nodular hyperplasia. The representative immunohistochemical markers of intrahepatic cholangiocarcinoma include cytokeratin (CK) 7 and CK19. In this article, we provide an overview of the application of immunohistochemistry in the pathological diagnosis of liver tumors referring to the association with genetic alterations. Furthermore, we aimed to explain the practical points in the differential diagnosis of liver tumors by immunohistochemical staining.

Pathological Renal Findings of Chronic Renal Failure in a Patient with the E66Q Mutation in the α-galactosidase A Gene.

A 66-year-old Japanese man was diagnosed with interstitial nephritis on a renal biopsy at 45 years of age and began to receive hemodialysis at 65 years of age. He was suspected of having Fabry disease as a result of a screening study for Fabry disease performed in hemodialysis patients. He had an E66Q mutation in the α-galactosidase A gene. We conducted an electron microscopic examination of a renal biopsy specimen obtained when the patient was diagnosed with chronic renal failure at 45 years of age in order to elucidate the pathogenicity of the E66Q mutation. Interestingly, an electron microscopic examination of the renal biopsy specimen indicated no characteristic findings of Fabry disease.

Cholecystitis caused by a fish bone.

The accidental ingestion of a foreign body is not uncommon. However, the presence of a foreign body in the gallbladder is extremely rare. Here, we present a case of cholecystitis due to a fish bone that may have penetrated through the stomach wall and into the gallbladder without causing peritonitis. A laparoscopic cholecystectomy was performed; a fish bone, measuring 4.0 cm in length, was found in the gallbladder. To the best of our knowledge, this is the first such case to be reported.

Effect of chronic oral supplementation with vitamins on the endothelial function in chronic smokers.

Cigarette smoking has been associated with endothelial dysfunction including impaired endothelium-dependent flow-mediated dilation (FMD). In cigarette smokers, increased oxygen-derived free radicals have been suspected of being one of the major causes of endothelial dysfunction, owing possibly to the inactivation of nitric oxide by free radicals. Vitamins C and E are widely used antioxidant vitamins, which have also been reported to effectively improve the endothelial function in several conditions. To test the effect of moderate-term oral antioxidant vitamin supplementation on the endothelial function in smokers, the authors evaluated the combined effect of vitamins C and E, administered in normal dosages, on FMD in young male smokers. A prospective interventional study was performed. In 15 healthy male subjects (mean age, 24.4 +/-2.5 years old). They studied FMD in the brachial artery by using high-resolution ultrasound. The vascular effects of moderate-term oral supplementation with vitamin C (1.0 g/day) and vitamin E (500 mg/day) were determined during reactive hyperemia, which causes endothelium-dependent FMD. They performed a vascular function study 3 times including before vitamin supplement, after 25 days of vitamin supplement, and 4 weeks after the cessation of the vitamin supplement. The flow-mediated dilator response measurements were repeated twice a day before vitamin supplements, and the repeatability obtained from these measurements was found acceptable (variability of FMD <2%). The oral antioxidant vitamin supplement significantly restored FMD (3.8 +/-2.2% vs 5.9 +/-2.5%; p<0.05), however, this effect disappeared 4 weeks after the vitamin supplementations ended. The combined usual dosage of vitamins C and E supplements was found to improve the endothelial function in chronic smokers.

Sonodynamic therapy decreased neointimal hyperplasia after stenting in the rabbit iliac artery.

BACKGROUND: In-stent restenosis remains a pivotal problem after coronary and peripheral stenting. Sonodynamic therapy inhibits tumor growth by means of cytotoxicity after the activation of sonochemical sensitizers by ultrasound. PAD-S31 is known to be a water-soluble, chlorin-derivative sonochemical sensitizer. We assessed the efficacy of sonodynamic therapy using this sensitizer on neointimal hyperplasia in a rabbit stent model. METHODS AND RESULTS: Stents were implanted in the iliac arteries of 16 rabbits. A total of 32 stented arteries were randomized to sonodynamic therapy, control, ultrasound exposure, and PAD-S31 groups. One hour after the intravenous administration of PAD-S31 (25 mg/kg body weight), ultrasound energy (1 MHz, 0.3 W/cm(2)) was delivered transdermally to the sonodynamic therapy group. At 28 days, all stent sites were analyzed morphometrically. The size of the intimal cross-sectional area was smaller in the sonodynamic therapy group than in the control, ultrasound, and PAD-S31 groups (0.31+/-0.07 versus 1.38+/-0.47, 1.66+/-0.71, and 1.61+/-0.42 mm(2), respectively; P<0.05). The ratio of the intimal and medial cross-sectional area was smaller in the sonodynamic therapy group than in the control, ultrasound, and PAD-S31 groups (0.71+/-0.22 versus 2.53+/-1.39, 2.48+/-0.60, and 3.45+/-1.42 mm(2); P<0.05). CONCLUSIONS: Sonodynamic therapy with PAD-S31 is considered to be a feasible treatment modality for noninvasively inhibiting neointimal hyperplasia in a rabbit iliac stent model.