Animal models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease(NAFLD) is a condition in which excess fat accumulates in the liver of a patient without a history of alcohol abuse.Nonalcoholic steatohepatitis(NASH),a severe form of NAFLD,can progress to liver cirrhosis and hepatocellular carcinoma.NAFLD is regarded as a hepatic manifestation of metabolic syndrome and incidence has been increasing worldwide in line with the increased prevalence of obesity,type 2 diabetes,and hyperlipemia.Animal models of NAFLD/NASH give crucial information,not only in elucidating pathogenesis of NAFLD/NASH but also in examining therapeutic effects of various agents.An ideal model of NAFLD/NASH should correctly reflect both hepatic histopathology and pathophysiology of human NAFLD/NASH.Animal models of NAFLD/NASH are divided into genetic,dietary,and combination models.In this paper,we review commonly used animal models of NAFLD/NASH referring to their advantages and disadvantages.

Current pharmacological therapies for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease(NAFLD)/nonalcoholic steatohepatitis(NASH) is considered to be a hepatic manifestation of metabolic syndrome, and its incidence is rapidly increasing worldwide. It is currently the most common chronic liver disease. NASH can progress to liver cirrhosis and hepatocellular carcinoma, and may result in liver-related death. Currently, the principal treatment for NAFLD/NASH is lifestyle modification by diet and exercise. However, pharmacological therapy is indispensable because obese patients with NAFLD often have difficulty maintaining improved lifestyles. The pathogenesis of NAFLD/NASH has not been completely elucidated. However, insulin resistance, inflammatory cytokines, and oxidative stress are thought to be important in the development and/or progression of the disease. Currently, insulin sensitizers(thiazolidinediones) and antioxidants(vitamin E) seem to be the most promising therapeutic agents for NAFLD/NASH, and lipid-lowering drugs, pentoxifylline, angiotensin receptor blockers, and n-3 polyunsaturated fatty acids also have promise. However, there is a lack of consensus regarding the most effective and appropriate pharmacotherapy for NAFLD/NASH. Animal experiments suggest that herbal medicines and natural products may be promising therapeutic agents for NAFLD/NASH, but their efficacy and safety are yet to be investigated in human studies. In this paper, we review the existing and potential pharmacological therapies for NAFLD/NASH.

Histopathology of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease(NAFLD), a hepatic manifestation of metabolic syndrome, is the most common chronic liver disease, and the prevalence is rapidly increasing worldwide. Nonalcoholic steatohepatitis(NASH), the severe form of NAFLD, can progress to liver cirrhosis and hepatocellular carcinoma(HCC). Although noninvasive clinical scores and image-based diagnosis for NAFLD have improved, histopathological evaluation of biopsy specimens remains the gold standard for diagnosing NAFLD/NASH. Steatosis, lobular inflammation, and hepatocellular ballooning are all necessary components for the diagnosis of NASH; fibrosis is also typically observed. Other histopathological abnormalities commonly observed in NASH include hepatocellular glycogenated nuclei, lipogranulomas, and acidophil bodies. The characteristics of pediatric NAFLD/NASH differ from adult NAFLD/NASH. Specifically, steatosis and portal inflammation are more severe in pediatric NAFLD, while intralobular inflammation and perisinusoidal fibrosis are milder. Although interobserver agreement for evaluating the extent of steatosis and fibrosis is high, agreement is low for intralobular and portal inflammation. A recently reported histological variant of HCC, steatohepatitic HCC(SH-HCC), showsfeatures that resemble non-neoplastic steatohepatitis,and is thought to be strongly associated with underlying NASH.In this report,we review the histopathological features of NAFLD/NASH.

Plexiform angiomyxoid myofi broblastic tumor of the stomach

Plexiform angiomyxoid myofibroblastic tumor of the stomach is a unique mesenchymal tumor that we first described in 2007.The tumor is very rare,and to date,only 18 cases confirmed by immunohistochemistry have been reported in the literature.The patients' ages ranged from 7 to 75 years(mean,43 years),and the male-to-female ratio was approximately 1:1.Representative clinical symptoms are ulceration,associated upper gastrointestinal bleeding(hematemesis),and anemia.The tumors are located at the antrum in all cases,and grossly,the tumor is whitish to brownish or reddish,and forms a lobulated submucosal or transmural mass.Microscopically,the tumor is characterized by a plexiform growth pattern,the proliferation of cytologically bland spindle cells,and a myxoid stroma that is rich in small vessels and positive for Alcian blue stain.Immunohistochemically,the tumor cells are positive for α-smooth muscle actin and negative for KIT and CD34.Differential diagnoses include gastrointestinal stromal tumor and other mesenchymal tumors of the gastrointestinal tract.Some authors proposed that this tumor should be designated as "plexiform fibromyxoma",but this designation might cause confusion.The tumor is probably benign and thus far,neither recurrence nor metastasis has been reported.

Spontaneous regression of hepatic inflammatory pseudotumor with primary biliary cirrhosis:Case report and literature review

Hepatic inflammatory pseudotumor （IPT） is a rare benign non-neoplastic lesion characterized by proliferating fibrous tissue infiltrated by inflammatory cells. The exact etiology of IPT remains unclear. Although the association of IPT with systemic inflammatory disorders has been well established, a specific relationship with cholangitis is distinctly rare. We report a case of spontaneous regression of hepatic IPT with primary biliary cirrhosis （PBC）. To date, only two cases of IPT with PBC have been reported. In our case, however, IPT developed during the course of improvement of cholangitis of PBC induced by effective treatment, differing from two previously reported cases. Our case indicates that the development of IPT does not also relate to the activity of cholangitis and/or hyper gamma-globulinemia, since our case was confirmed radiologically to be free of IPT when biliary enzymes and immunoglobulins were much higher than the corresponding values on admission. Comparison of our case with the two previously reported cases suggests that IPT occurring with PBC does not represent the same disease entity or be a bystander for PBC.

Pediatric nonalcoholic fatty liver disease:Overview with emphasis on histology

Nonalcoholic fatty liver disease(NAFLD) is a disease in which excessive fat accumulates in the liver of a patient without a history of alcohol abuse.This disease includes simple steatosis and nonalcoholic steatohepatitis(NASH).NAFLD/NASH is recognized as a hepatic manifestation of metabolic syndrome.In recent years,pediatric NAFLD has increased in line with the increased prevalence of pediatric obesity.The estimated prevalence of pediatric NAFLD is 2.6%-9.6%,and it is associated with sex,age,and ethnicity.With regard to the pathogenesis of NAFLD,the "two-hit" hypothesis is widely accepted and oxidative stress is thought to play an important role in the second hit.Although clinical symptoms,laboratory data,and imaging findings are important,liver biopsy is regarded as the gold standard for the diagnosis of NAFLD/NASH.In addition,liver biopsy is essential for assessing the degree of necro-inflammatory change and fibrosis in NASH.Two different types of steatohepatitis(type 1 and type 2 NASH) have been reported,with type 2 NASH being present in as many as 51% of pediatric NAFLD patients.However,we and others have observed that type 1 and 2 patterns commonly overlap.Although pharmacotherapy has been studied in clinical trials,lifestyle modification by diet and exercise remains the mainstay of treatment for NAFLD/NASH.

Protein induced by vitamin K absence or antagonist Ⅱ-producing gastric cancer

Protein induced by vitamin K absence or antagonist Ⅱ(PIVKA-Ⅱ) is a putative specific marker of hepatocellular carcinoma(HCC),but it may also be produced by asmall number of gastric cancers.To date,16 cases of PIVKA-Ⅱ-producing gastric cancer have been reported,2 of which were reported by us and all of which were identified in Japan.There are no symptoms specific to PIVKA-Ⅱ-producing gastric cancer,and the representative clinical symptoms are general fatigue,appetite loss,and upper abdominal pain.Serum alpha-feto-protein(AFP)levels are also increased in almost allcases.Liver metastasis is observed in approximately 80% of cases and portal vein tumor thrombus is ob-served in approximately 20% of cases.Differential diagnosis between metastatic liver tumor and HCC is often difficult.Grossly,almost all cases appear as advanced gastric cancer.Histologically,a hepatoid pattern is observed in many cases,in addition to a moderately to poorly differentiated adenocarcinoma component.The production of PIVKA-Ⅱ and AFP is usually confirmed using immunohistochemical staining.Treatment and prognosis largely depends on the existence of liver meta-stasis,and the prognosis of patients with liver metas-tasis is very poor.PIVKA-Ⅱ may be produced during the hepatocellular metaplasia of the tumor cells.

Russell body duodenitis in a patient with retroperitoneal metastasis of ureteral cancer

Russell bodies are globular and eosinophilic inclusion bodies in the cytoplasm of mature plasma cells.Plasma cells whose cytoplasm is filled with Russell bodies are designated as Mott cells.Russell body duodenitis(RBD) is a unique form of chronic duodenitis that is characterized by infiltration of numerous Mott cells.RBD is very rare;only two cases have been reported to date.In this paper,we report a case of RBD in a patient with retroperitoneal metastasis of ureteral cancer.A 77-year-old man was admitted to our hospital complaining of appetite loss,vomiting,and upper abdominal distension.He had undergone left nephroureterectomy for ureteral cancer 4 years earlier.Upper digestive tract endoscopy revealed edema,stenosis,and punctate redness of the mucosa of the duodenum,and a biopsy was performed.Histological analysis showed that numerous Mott cells had infiltrated the lamina propria mucosae,and the condition was diagnosed as RBD.A mass lesion in the retroperitoneum adjacent to the duodenum was detected by abdominal computed tomography,and was diagnosed as metastatic urothelial carcinoma by biopsy.It is possible that chemokines produced by tumor cells caused RBD in this case.

Adenomyoma of the small intestine

Adenomyoma of the gastrointestinal tract is a rare benign tumor-like lesion.The small intestine is the second most frequent location,usually in the periampullary area,but the lesion also occurs in the jejunum and ileum.While adenomyoma of the Vaterian system is primarily diagnosed in adults,more than half of reported cases of jejunal and ileal adenomyoma have been diagnosed in pediatric patients.Adenomyoma of the periampullary area usually presents with biliary obstruction or abdominal pain,whereas jejunal and ileal adenomyoma usually presents with intussusception or is incidentally discovered during surgery or autopsy.Since endoscopic and radiological examination yields uncharacteristic findings,histopathological evaluation is important in adenomyoma diagnosis.Pathologically,adenomyoma consists of glandular structures of various sizes and interlacing smooth muscle bundles that surround the glandular elements.The pathogenesis of adenomyoma is generally considered to be either a form of hamartoma or a pancreatic heterotopia.Although limited resection is considered the most effective treatment,pancreaticoduodenectomy is often performed when the lesion occurs in the periampullary area due to preoperative misdiagnosis as a carcinoma.It is,therefore,important that clinicians and pathologists maintain current knowledge of the disease to avoid inaccurate diagnosis,which could lead to unnecessary surgery.