Pharmacologic therapy for nonalcoholic steatohepatitis focusing on pathophysiology / 영남의대학술지

The paradigm of chronic liver diseases has been shifting. Although hepatitis B and C viral infections are still the main causes of liver cirrhosis and hepatocellular carcinoma (HCC), the introduction of effective antiviral drugs may control or cure them in the near future. In contrast, the burden of nonalcoholic fatty liver disease (NAFLD) has been increasing for decades, and 25 to 30% of the general population in Korea is estimated to have NAFLD. Over 10% of NAFLD patients may have nonalcoholic steatohepatitis (NASH), a severe form of NAFLD. NASH can progress to cirrhosis and HCC. NASH is currently the second leading cause to be placed on the liver transplantation list in the United States. NAFLD is associated with obesity, type 2 diabetes, dyslipidemia, and metabolic syndrome. The pathophysiology is complex and associated with lipotoxicity, inflammatory cytokines, apoptosis, and insulin resistance. The only proven effective treatment is weight reduction by diet and exercise. However, this may not be effective for advanced fibrosis or cirrhosis. Therefore, effective drugs are urgently needed for treating these conditions. Unfortunately, no drugs have been approved for the treatment of NASH. Many pharmaceutical companies are trying to develop new drugs for the treatment of NASH. Some of them are in phase 2 or 3 clinical trials. Here, pharmacologic therapies in clinical trials, as well as the basic principles of drug therapy, will be reviewed, focusing on pathophysiology.

Pharmacologic therapy for nonalcoholic steatohepatitis focusing on pathophysiology / 영남의대학술지

The paradigm of chronic liver diseases has been shifting. Although hepatitis B and C viral infections are still the main causes of liver cirrhosis and hepatocellular carcinoma (HCC), the introduction of effective antiviral drugs may control or cure them in the near future. In contrast, the burden of nonalcoholic fatty liver disease (NAFLD) has been increasing for decades, and 25 to 30% of the general population in Korea is estimated to have NAFLD. Over 10% of NAFLD patients may have nonalcoholic steatohepatitis (NASH), a severe form of NAFLD. NASH can progress to cirrhosis and HCC. NASH is currently the second leading cause to be placed on the liver transplantation list in the United States. NAFLD is associated with obesity, type 2 diabetes, dyslipidemia, and metabolic syndrome. The pathophysiology is complex and associated with lipotoxicity, inflammatory cytokines, apoptosis, and insulin resistance. The only proven effective treatment is weight reduction by diet and exercise. However, this may not be effective for advanced fibrosis or cirrhosis. Therefore, effective drugs are urgently needed for treating these conditions. Unfortunately, no drugs have been approved for the treatment of NASH. Many pharmaceutical companies are trying to develop new drugs for the treatment of NASH. Some of them are in phase 2 or 3 clinical trials. Here, pharmacologic therapies in clinical trials, as well as the basic principles of drug therapy, will be reviewed, focusing on pathophysiology.

Hepatic Arterial Infusion Chemotherapy Using the Port System in Advanced Gallbladder Cancer / 대한내과학회지

Gallbladder (GB) cancer is relatively rare and has a poor prognosis, with a median survival time of less than 3 months. It is resistant to chemotherapy. Therefore, the role of systemic chemotherapy is limited. However, administering the anticancer agent directly into the hepatic artery can result in a higher drug concentration in the cancer tissue. In this paper, we report a case of advanced GB cancer treated with hepatic arterial infusion chemotherapy (HAIC) using the port system. The patient received six cycles of HAIC with 5-fluorouracil (750 mg/m²) and cisplatin (25 mg/m²); each cycle lasted for 4 days every month. The tumor showed objective response during HAIC, and the patient survived for 15 months from the first therapy. HAIC using the port system might be a promising therapeutic modality for treating locally advanced GB cancer.

Hepatic Arterial Infusion Chemotherapy Using the Port System in Advanced Gallbladder Cancer / 대한내과학회지

Gallbladder (GB) cancer is relatively rare and has a poor prognosis, with a median survival time of less than 3 months. It is resistant to chemotherapy. Therefore, the role of systemic chemotherapy is limited. However, administering the anticancer agent directly into the hepatic artery can result in a higher drug concentration in the cancer tissue. In this paper, we report a case of advanced GB cancer treated with hepatic arterial infusion chemotherapy (HAIC) using the port system. The patient received six cycles of HAIC with 5-fluorouracil (750 mg/m²) and cisplatin (25 mg/m²); each cycle lasted for 4 days every month. The tumor showed objective response during HAIC, and the patient survived for 15 months from the first therapy. HAIC using the port system might be a promising therapeutic modality for treating locally advanced GB cancer.

Massive bleeding from a rectal Dieulafoy lesion in a patient with alcoholic cirrhosis / 영남의대학술지

Although Dieulafoy lesion can occur in any part of the gastrointestinal tract, its occurrence in the rectum is rare. Rectal Dieulafoy lesions have been associated with advanced age, renal failure, burns, liver transplantation and cirrhosis. Here, we report on a case of massive bleeding from a rectal Dieulafoy lesion after lung decortication surgery in a 57-year-old male patient with alcoholic cirrhosis. Although rare, a rectal Dieulafoy lesion should be included in the differential diagnosis of massive lower gastrointestinal bleeding in a patient with cirrhosis.

Massive bleeding from a rectal Dieulafoy lesion in a patient with alcoholic cirrhosis / 영남의대학술지

Although Dieulafoy lesion can occur in any part of the gastrointestinal tract, its occurrence in the rectum is rare. Rectal Dieulafoy lesions have been associated with advanced age, renal failure, burns, liver transplantation and cirrhosis. Here, we report on a case of massive bleeding from a rectal Dieulafoy lesion after lung decortication surgery in a 57-year-old male patient with alcoholic cirrhosis. Although rare, a rectal Dieulafoy lesion should be included in the differential diagnosis of massive lower gastrointestinal bleeding in a patient with cirrhosis.

Cellular origin of liver cancer stem cells / 영남의대학술지

Over several decades, a hierarchical cancer stem cell (CSC) model has been established in development of solid cancers, including hepatocellular carcinoma(HCC). In terms of this concept, HCCs originate from liver CSCs. Clinically HCCs show a wide range of manifestations from slow growth to very aggressive metastasis. One of the reasons may be that liver CSCs originate from different cells. This review describes the basic concept of CSCs and the cellular origin of liver CSCs.

Cilostazol Decreases Ethanol-Mediated TNFalpha Expression in RAW264.7 Murine Macrophage and in Liver from Binge Drinking Mice

Alcoholic hepatitis is a leading cause of liver failure in which the increased production of tumor necrosis factor alpha (TNFalpha) plays a critical role in progression of alcoholic liver disease. In the present study, we investigated the effects of cilostazol, a selective inhibitor of type III phosphodiesterase on ethanol-mediated TNFalpha production in vitro and in vivo, and the effect of cilostazol was compared with that of pentoxifylline, which is currently used in clinical trial. RAW264.7 murine macrophages were pretreated with ethanol in the presence or absence of cilostazol then, stimulated with lipopolysacchride (LPS). Cilostazol significantly suppressed the level of LPS-stimulated TNFalpha mRNA and protein with a similar degree to that by pentoxifylline. Cilostazol increased the basal AMP-activated protein kinase (AMPK) activity as well as normalized the decreased AMPK by LPS. AICAR, an AMPK activator and db-cAMP also significantly decreased TNFalpha production in RAW264.7 cells, but cilostazol did not affect the levels of intracellular cAMP and reactive oxygen species (ROS) production. The in vivo effect of cilostazol was examined using ethanol binge drinking (6 g/kg) mice model. TNFalpha mRNA and protein decreased in liver from ethanol gavaged mice compared to that from control mice. Pretreatment of mice with cilostazol or pentoxifylline further reduced the TNFalpha production in liver. These results demonstrated that cilostazol effectively decrease the ethanol-mediated TNFalpha production both in murine macrophage and in liver from binge drinking mice and AMPK may be responsible for the inhibition of TNFalpha production by cilostazol.