Chronic viral hepatitis.

Chronic liver disease is the tenth leading cause of death in the United States. The economic burden of liver disease is approximately 1% of the total national health care expenditure. Chronic hepatitis C is the most common cause of chronic liver disease in the United States, and chronic hepatitis B is the leading cause of liver disease worldwide. This article provides a brief overview of the evaluation and treatment of chronic hepatitis B and C infection.

Aging liver and hepatitis.

Chronic liver disease and cirrhosis are the tenth leading causes of death in the United States and results in approximately 25,000 deaths annually. As life expectancy in developed countries has increased, so has the number of elderly patients who have liver disease. With an aging population and chronic liver disease becoming an increasingly significant cause of morbidity and mortality, the various causes for hepatitis will need to be evaluated and available treatments considered, even in elderly population. Common causes for hepatitis in elderly individuals include viral, autoimmune, and drug-induced hepatitis, but evidence for treatment of this population is limited. This article reviews the likely causes of hepatitis in elderly individuals and discusses evidence for treating this population.

Imaging of pancreatic cancer: An overview.

Pancreatic cancer (PaCa) is the fourth leading cause of cancer-related death in the United States. The median size of pancreatic adenocarcinoma at the time of diagnosis is about 31 mm and has not changed significantly in last three decades despite major advances in imaging technology that can help diagnose increasingly smaller tumors. This is largely because patients are asymptomatic till late in course of pancreatic cancer or have nonspecific symptoms. Increased awareness of pancreatic cancer amongst the clinicians and knowledge of the available imaging modalities and their optimal use in evaluation of patients suspected to have pancreatic cancer can potentially help in diagnosing more early stage tumors. Another major challenge in the management of patients with pancreatic cancer involves reliable determination of resectability. Only about 10% of pancreatic adenocarcinomas are resectable at the time of diagnosis and would potentially benefit from a R0 surgical resection. The final determination of resectability cannot be made until late during surgical resection. Failure to identify unresectable tumor pre-operatively can result in considerable morbidity and mortality due to an unnecessary surgery. In this review, we review the relative advantages and shortcomings of imaging modalities available for evaluation of patients with suspected pancreatic cancer and for preoperative determination of resectability.

Novel fucosylated biomarkers for the early detection of hepatocellular carcinoma.

Changes in glycosylation, most notably fucosylation, have been associated with the development of hepatocellular carcinoma (HCC). In this report, the levels of fucosylated kininogen (Fc-Kin) and fucosylated alpha-1-antitrypsin were analyzed individually and in combination with the currently used marker, alpha-fetoprotein, and a previously identified biomarker, Golgi protein 73 (GP73), for the ability to distinguish between a diagnosis of cirrhosis and HCC. This analysis was done on serum from 113 patients with cirrhosis and 164 serum samples from patients with cirrhosis plus HCC. The levels of Fc-Kin and fucosylated alpha-1-antitrypsin were significantly higher in patients with HCC compared with those with cirrhosis (P < 0.0001). Greatest performance was achieved through the combination of Fc-Kin, alpha-fetoprotein, and GP73, giving an optimal sensitivity of 95%, a specificity of 70%, and an area under the receiver operating characteristic of 0.94. In conclusion, the altered glycosylation of serum glycoproteins can act as potential biomarkers of primary HCC when used independently or in combination with other markers of HCC.

Identification and development of fucosylated glycoproteins as biomarkers of primary hepatocellular carcinoma.

Changes in N-linked glycosylation are known to occur during the development of cancer. For example, we have previously reported changes in N-linked glycosylation that occur with the development of hepatocellular carcinoma (HCC) and, through the use of glycoproteomics, identified many of those proteins containing altered glycan structures. To advance these studies and further explore the glycoproteome, we performed N-linked glycan analysis from serum samples depleted of the major acute phase proteins, followed by targeted lectin extraction of those proteins containing changes in glycosylation. Using this method, changes in glycosylation, specifically increased amounts of core and outer arm fucosylation, were observed in the depleted samples. The identities of those proteins containing core and outer arm fucose were identified in the serum of patients with HCC. The usefulness of some of these proteins in the diagnosis of HCC was determined through the analysis of over 300 patient samples using a high-throughput plate based approach. Greatest performance was achieved with fucosylated hemopexin, which had an AUROC of 0.9515 with an optimal sensitivity of 92% and a specificity of 92%.

Decreased expression of peroxisome proliferator activated receptor gamma in cftr-/- mice.

Some of the pathological manifestations of cystic fibrosis are in accordance with an impaired expression and/or activity of PPARgamma. We hypothesized that PPARgamma expression is altered in tissues lacking the normal cystic fibrosis transmembrane regulator protein (CFTR). PPARgamma mRNA levels were measured in colonic mucosa, ileal mucosa, adipose tissue, lung, and liver from wild-type and cftr-/- mice by quantitative RT-PCR. PPARgamma expression was decreased twofold in CFTR-regulated tissues (colon, ileum, and lung) from cftr-/- mice compared to wild-type littermates. In contrast, no differences were found in fat and liver. Immunohistochemical analysis of PPARgamma in ileum and colon revealed a predominantly nuclear localization in wild-type mucosal epithelial cells while tissues from cftr-/- mice showed a more diffuse, lower intensity labeling. A significant decrease in PPARgamma expression was confirmed in nuclear extracts of colon mucosa by Western blot analysis. In addition, binding of the PPARgamma/RXR heterodimer to an oligonucletotide containing a peroxisome proliferator responsive element (PPRE) was also decreased in colonic mucosa extracts from cftr-/- mice. Treatment of cftr-/- mice with the PPARgamma ligand rosiglitazone restored both the nuclear localization and binding to DNA, but did not increase RNA levels. We conclude that PPARgamma expression in cftr-/- mice is downregulated at the RNA and protein levels and its function diminished. These changes may be related to the loss of function of CFTR and may be relevant to the pathogenesis of metabolic abnormalities associated with cystic fibrosis in humans.

Interleukin 8 secretion from monocytes of subjects heterozygous for the deltaF508 cystic fibrosis transmembrane conductance regulator gene mutation is altered.

Patients with cystic fibrosis (CF) exhibit an excessive host inflammatory response. The aim of this study was to determine (i) whether interleukin 8 (IL-8) secretion is increased from monocytes from subjects heterozygous as well as homozygous for cystic fibrosis transmembrane conductance regulator (CFTR) mutations and (ii) whether this is due to increased cell surface lipopolysaccharide (LPS) receptors or, alternatively, increased activation of mitogen-activated protein kinases (MAPK). The basal level of IL-8 secretion was higher from monocytes from CF patients than from monocytes from healthy controls (P = 0.02) and obligate heterozygotes (parents of the CF patients). The 50% effective concentrations for LPS-induced IL-8 production for monocytes from both CF patients and obligate heterozygotes were 100-fold lower than those for monocytes from healthy controls (P < 0.05). No differences in the levels of IL-1beta production were seen between these groups. Expression of the LPS surface receptors CD14 and Toll-like receptor 4 were not different between CF patients and healthy controls. In contrast, phosphorylation of the MAPKs p38 and ERK occurred at lower doses of LPS in monocytes from patients heterozygous and homozygous for CFTR mutations. These results indicate that a single allelic CFTR mutation is sufficient to augment IL-8 secretion in response to LPS. This is not a result of increased LPS receptor expression but, rather, is associated with alterations in MAPK signaling.

Induction of colitis in cftr-/- mice results in bile duct injury.

It is unknown why some patients with inflammatory bowel disease develop primary sclerosing cholangitis. We have recently shown that patients with primary sclerosing cholangitis have an increased prevalence of mutations in the gene responsible for cystic fibrosis (CFTR) compared with individuals with inflammatory bowel disease alone. Our aim was to examine whether induction of colitis by oral dextran leads to bile duct injury in mice heterozygous or homozygous for mutations in CFTR. The effect of oral administration of docosahexaenoic acid to correct a fatty acid imbalance associated with cystic fibrosis was also examined to determine whether this would prevent bile duct inflammation. Wild-type mice and mice heterozygous and homozygous for CFTR mutations were given dextran orally for 14 days to induce colitis. Bile duct injury was quantitated by blinded histological scoring and measurement of serum alkaline phosphatase activity. The effect of pretreatment with docosahexaenoic acid for 7 days was examined. Treatment of mice with 100 mg dextran/day for 9 days followed by 85 mg/day for 5 days resulted in a significant increase in bile duct injury as determined by histological scoring in homozygous cystic fibrosis mice compared with wild-type mice (P = 0.005). The bile duct injury seen in cystic fibrosis mice was reflected in a threefold increase in serum alkaline phosphatase (P = 0.0006). Pretreatment with oral docosahexaenoic acid decreased both histological evidence of bile duct injury and serum alkaline phosphatase levels. In the setting of colitis, loss of CFTR function leads to bile duct injury.