Spontaneous Occurrence of Various Types of Hepatocellular Adenoma in the Livers of Metabolic Syndrome-Associated Steatohepatitis Model TSOD Mice

Abstract

Male Tsumura-Suzuki Obese Diabetes (TSOD) mice, a spontaneous metabolic syndrome model, develop non-alcoholic steatohepatitis and liver tumors by feeding on a standard mouse diet. Nearly 70% of liver tumors express glutamine synthetase (GS), a marker of hepatocellular carcinoma. In contrast, approximately 30% are GS-negative without prominent nuclear or structural atypia. In this study, we examined the characteristics of the GS-negative tumors of TSOD mice. Twenty male TSOD mice were sacrificed at 40 weeks and a total of 21 tumors were analyzed by HE staining and immunostaining of GS, liver fatty acid-binding protein (L-FABP), serum amyloid A (SAA), and beta-catenin. With immunostaining for GS, six (29%) tumors were negative. Based on the histological and immunohistological characteristics, six GS-negative tumors were classified into several subtypes of human hepatocellular adenoma (HCA). One large tumor showed generally similar findings to inflammatory HCA, but contained small atypical foci with GS staining and partial nuclear beta-catenin expression suggesting malignant transformation. GS-negative tumors of TSOD mice contained features similar to various subtypes of HCA. Different HCA subtypes occurring in the same liver have been reported in humans; however, the diversity of patient backgrounds limits the ability to conduct a detailed, multifaceted analysis. TSOD mice may share similar mechanisms of HCA development as in humans. It is timely to review the pathogenesis of HCA from both genetic and environmental perspectives, and it is expected that TSOD mice will make further contributions in this regard.

Estrobolome and Hepatocellular Adenomas—Connecting the Dots of the Gut Microbial β-Glucuronidase Pathway as a Metabolic Link

“…The frequency ratio of HCA is 8:1 in females and males; this can be explained by the fact that exogenous estrogen therapy (OC) is usually prescribed for women [12]. Other circumstances linked with HCA development include glycogen storage disease type I and type III (GSD) [9,11,14], hepatocyte nuclear factor 1α maturity-onset diabetes in young people (HNF1α-MODY) [33], history of liver diseases (non-alcoholic steatohepatitis, vascular diseases, alcoholic cirrhosis) [33], galactosemia, tyrosinemia, familial polyposis coli, polycystic ovary syndrome [7], and β-thalassemia [12,34] (Table 1).…”

“…However, 75% of hepatocellular carcinoma cases occur in males [35]. Differential diagnoses between HCA, well-differentiated HCC, and focal nodular hyperplasia (FNH) can be difficult, especially in males [14,36].…”

“…Mutation in CTNNB1 gene exon [3]; High blood androgen exposure [14]; Liver vascular disease Often in males [10]; Younger individuals; Frequently isolated tumors; Highest chance of Hepatocellular carcinoma (HCC) [10]; Potential of bleeding [37]; β-catenin HCA exon 7-8 [33] 5-10% Over-exposure to exogenous estrogen [14] Often one tumor; Younger individuals; Inflammatory phenotype; Low risk of HCC; Greater possibility of bleeding Rare HCA subtypes [33] Pigmented If the lesion/lesions are <5 cm, a reassessment will be made after one year; if the nodule/nodules are greater than 5 cm in size and continue to grow, surgical removal is advised [36]. Regardless of HCA size, in males or in any instance of proven β-catenin mutation, HCA resection is recommended [36].…”

“…Hepatocellular adenoma (HCA) or hepatic adenoma is defined as a benign liver lesion, seen in patients with excessive exposure to estrogen [9,10] (the higher the dose of estrogen therapy, the higher the risk of HCA), genetic and metabolic syndromes or who have undergone anabolic androgen therapy [9,[11][12][13][14]. Very few cohort studies and no epidemiological studies have argued that reductions in estrogen doses can reduce the risk of HCA.…”