Leptin is an adipokine with roles in food intake and energy metabolism through its actions on neurons in the hypothalamus. The role of leptin in obesity and cardiovascular disorders is well ...documented. However, its influence on liver conditions such as cholestasis is poorly understood. The effects of exogenous leptin and leptin-neutralizing antibody on biliary hyperplasia, hepatic fibrosis, and inflammation in the multidrug resistance protein 2 knockout (Mdr2KO) mouse model of cholestasis were assessed by quantifying markers specific for cholangiocytes, activated hepatic stellate cells (HSCs), and cytokines. Serum and hepatic leptin were increased in Mdr2KO mice compared with FVB/NJ (FVBN) controls, and exogenous leptin enhanced biliary hyperplasia and liver fibrosis in Mdr2KO and FVBN mice. Leptin administration increased hepatic expression of C-C motif chemokine ligand 2 and IL-6 in Mdr2KO mice. In contrast, leptin-neutralizing antibody reduced intrahepatic bile duct mass and decreased HSC activation in Mdr2KO mice compared with FVBN controls. Sex-related differences were noted, with female Mdr2KO mice having more leptin than males. In cholangiocytes and LX2 cells in vitro, leptin increased phosphorylated Akt and stimulated cell proliferation. Leptin receptor siRNA and inhibitors of Akt phosphorylation impaired leptin-induced cell proliferation and proinflammatory cytokines. The current data suggest that leptin is abnormally increased in cholestatic mice, and excess leptin increases ductular reaction, hepatic fibrosis, and inflammation via leptin receptor–mediated phosphorylation of Akt in cholangiocytes and HSCs.
Secondary tumors of the ampulla of Vater are exceedingly rare and associated with relatively poor prognosis. Tumors of the ampulla are classified into four distinct subtypes based on the location and ...involvement of surrounding structures. Most reported cases are of renal cell or malignant skin melanoma primary with only five previously reported cases of breast primary found in a literature review. We present a 72-year-old woman with metastatic breast cancer to the ampulla of Vater as well as multiple bones. She had a history of breast cancer status post bilateral mastectomy and chemo 27 years prior. She presented to the hospital with altered mental status and was found to have an acute liver injury. Magnetic resonance cholangiopancreatography revealed a distended gallbladder and an indeterminate left retroperitoneal mass concerning for cystic or necrotic lymphadenopathy. Endoscopy then showed an edematous and erythematous periampullary region, which was biopsied and returned positive for carcinoma. Immunohistochemical staining of the retroperitoneal mass returned positive for keratin, estrogen receptor, GATA3, and MOC31 and negative for progesterone receptor, WT1, calretinin, and E-cadherin. The periampullary region's immunohistochemistry returned positive for pankeratin (AE1/AE3) and CD138 and negative for CD45 and S100, supporting a diagnosis of primary breast carcinoma. The average time from diagnosis of breast cancer to metastasis was found to be 2.5 years. Endoscopic visual presentation of metastatic cancer to the ampulla is indistinguishable from that of primary cancers. Thus, a biopsy with cytology and immunohistochemical analysis is necessary for diagnosis. Management of secondary ampullary tumors requires a multidisciplinary team, including gastroenterology, surgery, oncology, and often palliative care. Secondary tumors have been found to be treated by any combination of Whipple's resections, chemotherapy, drainage/stenting, and endoscopic ampullectomy.
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