Mucosal serotonin signaling is altered in chronic constipation but not in opiate-induced constipation.

OBJECTIVES: Changes in mucosal serotonin (5-HT) signaling have been detected in a number of functional and inflammatory disorders of the gastrointestinal (GI) tract. This study was undertaken to determine whether chronic constipation (CC) is associated with disordered 5-HT signaling and to evaluate whether constipation caused by opiate use causes such changes. METHODS: Human rectal biopsy samples were obtained from healthy volunteers, individuals with idiopathic CC, and individuals taking opiate medication with or without occurrence of constipation. EC cells were identified by 5-HT immunohistochemistry. 5-HT content and release levels were determined by enzyme immunoassay, and mRNA levels for the synthetic enzyme tryptophan hydroxylase-1 (TpH-1) and serotonin-selective reuptake transporter (SERT) were assessed by quantitative real-time reverse transcription PCR. RESULTS: CC was associated with increases in TpH-1 transcript, 5-HT content, and 5-HT release under basal and stimulated conditions, whereas EC cell numbers and SERT transcript levels were not altered. No changes in these elements of 5-HT signaling were detected in opiate-induced constipation (OIC). CONCLUSIONS: These findings demonstrate that CC is associated with a pattern of altered 5-HT signaling that leads to increased 5-HT availability but does not involve a decrease in SERT expression. It is possible that increased 5-HT availability due to increased synthesis and release contributes to constipation due to receptor desensitization. Furthermore, the finding that elements of 5-HT signaling were not altered in the mucosa of individuals with OIC indicates that constipation as a condition does not lead to compensatory changes in 5-HT synthesis, release, or signal termination.

Coinfection with HIV and hepatitis C virus in injection drug users and minority populations.

Coinfection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) is common. In the United States, it has been estimated that 25% of persons infected with HIV are also infected with HCV. The prevalence of coinfection with HIV and HCV is highest among those infected via percutaneous routes. In fact, in urban areas in the United States, 50%-90% of persons infected with HIV via injection drug use are coinfected with HCV. In addition, limited data from drug treatment centers in these urban areas suggest that the prevalence of coinfection with HIV and HCV may be highest among African Americans and Hispanics. Little information is available with regard to the epidemiology of coinfection with HIV and HCV among injection drug users (IDUs) or minority populations. Likewise, although there is a growing body of data on the potential complexities of treating HCV among IDUs and the poor response to current anti-HCV treatment among African Americans, few data address the therapy of coinfection with HIV and HCV among IDUs and minority populations.

Prospective multicenter study of eligibility for antiviral therapy among 4,084 U.S. veterans with chronic hepatitis C virus infection.

BACKGROUND: Many veterans may not be candidates for hepatitis C virus (HCV) treatment due to contraindications to therapy. The aims of this study were to determine the proportion of HCV-infected veterans who were eligible for interferon alfa and ribavirin therapy and to evaluate barriers to HCV treatment. METHODS: We prospectively enrolled 4,084 veterans who were referred for HCV treatment over a 1-yr period at 24 Veterans Affairs (VA) Medical Centers. Treatment candidacy was assessed using standardized criteria and the opinion of the treating clinician. RESULTS: Overall, 32.2% (95% CI, 30.8-33.7%) were candidates for HCV treatment according to standardized criteria, whereas 40.7% (95% CI, 39.2-42.3%) were candidates in the opinion of the treating clinician. Multivariable analysis identified ongoing substance abuse (OR = 17.68; 95% CI, 12.24-25.53), comorbid medical disease (OR = 9.62; 95% CI, 6.85-13.50), psychiatric disease (OR = 9.45; 95% CI, 6.70-13.32), and advanced liver disease (OR = 8.43; 95% CI, 4.42-16.06) as the strongest predictors of not being a treatment candidate. Among patients who were considered treatment candidates, 76.2% (95% CI, 74.0-78.3%) agreed to be treated and multivariable analysis showed that persons >/=50 yr of age (OR = 1.37; 95% CI, 1.07-1.76) and those with >50 lifetime sexual partners (OR = 1.44; 95% CI, 1.08-1.93) were more likely to decline treatment. CONCLUSIONS: The majority of veteran patients are not suitable candidates for HCV treatment because of substance abuse, psychiatric disease, and comorbid medical disease, and many who are candidates decline therapy. Multidisciplinary collaboration is needed to overcome barriers to HCV therapy in this population.

More severe parenchymal injury in chronic hepatitis C acquired by recent injection drug use.

OBJECTIVE: Histologic liver injury is reported to be less severe in persons who acquire hepatitis C through injection drug use (IDU) than by blood transfusion. Because age correlates with histologic severity, it may be that differences between routes of acquisition reflect the younger age of most drug abusers. The early histopathologic changes of hepatitis C acquired through IDU are less defined, probably because of the lack of liver biopsy material from a cohort of patients not long after initial exposure. The availability of material from a cohort of patients who had liver biopsy for IDU-related hepatitis C in the 1970s enabled us to compare the histology with that of current patients. METHODS: Liver biopsies of a group of injection drug users (n=70, all males; mean age, 27.6 years, designated as Group 1) in the 1970s cohort were compared with biopsies of patients (n=63, all males; mean age, 48 years, designated as Group 2, 23 who admitted past IDU) entering a treatment trial in 1999. All patients were positive for anti-HCV at the time of biopsy. RESULTS: The histologic features of the 23 patients in Group 2 with a history of IDU did not differ significantly from the other 40 patients who denied past IDU. Using a modified Histologic Activity Index (HAI), there was no difference between Group 1 and Group 2 in portal inflammation or periportal injury. However, parenchymal (lobular) injury and inflammation was significantly (P<0.0001) greater in Group 1 than Group 2. Fibrosis was significantly (P=0.014) greater in Group 2. CONCLUSIONS: The degree of parenchymal injury was greater in Group 1 than Group 2, perhaps because they were closer to the time of exposure or possibly because of a stronger immunologic response in younger patients. The degree of hepatic fibrosis was greater in Group 2, suggesting that progression with age may be the natural history of chronic hepatitis C.

Light, but not heavy alcohol drinking, stimulates paraoxonase by upregulating liver mRNA in rats and humans.

Paraoxonase 1 (PON) may contribute to the cardioprotective action of high-density lipoprotein (HDL) because it inhibits low-density lipoprotein (LDL) oxidation, a prerequisite for the onset of atherosclerosis. Because light drinking and heavy drinking have diametrically opposite effects on cardioprotection, we have determined the effects of ethanol dosage on rat serum PON activity and its hepatic expression. Furthermore, we have investigated PON activity and polymorphism in human light and heavy drinkers. Our results confirm that HDL-PON inhibited LDL oxidation, destroyed oxidized LDL, and inhibited its uptake by macrophages. Light ethanol feeding caused a 20% to 25% (P <.05) increase in PON activity in both serum and liver and a 59% (P <.001) increase in the level of liver PON mRNA compared with pair-fed control rats. In contrast, heavy ethanol feeding caused a 25% (P <.05) decrease in serum and liver PON activities with a 51% (P <.01) decrease in liver PON mRNA level. Light drinkers had a 395% (P <.001) higher, whereas heavy drinkers had a 45% (P <.001) lower serum PON activity compared with nondrinkers. Significantly, the number of homozygotes versus heterozygotes with respect to high or low activity PON phenotype was similar in all the groups. Therefore, we conclude that light drinking upregulates, whereas heavy drinking downregulates PON activity and its expression, irrespective of its genetic polymorphism.

Low-positive anti-hepatitis C virus enzyme immunoassay results: an important predictor of low likelihood of hepatitis C infection.

BACKGROUND: Tests for hepatitis C antibodies (anti-HCV enzyme immunoassays) are usually described as positive or negative. Several studies, mainly in blood donors, have found that specimens with low signal/cutoff (S/C) ratios are commonly negative when tested with a recombinant immunoblot assay (RIBA) or for HCV RNA. METHODS: We retrospectively reviewed 17 418 consecutive anti-HCV results from a screening program for high-risk veterans; 2986 (17.1%) samples were anti-HCV-positive, and 490 (16.4%) had S/C ratios

Understudied populations with hepatitis C.

Managing patients with hepatitis C virus (HCV) infection consists primarily of antiviral treatment, currently with peginterferon and ribavirin. Unfortunately, treatment recommendations derive largely from trials that have focused on highly selected patient populations. As a consequence of the strict inclusion and exclusion criteria in these studies, more than half of all HCV-infected patients would be ineligible for enrollment. Even among the selected patients enrolled into studies, only 50% achieve a sustained virological response (SVR). Patients not eligible for current therapies include those with mild disease and normal alanine aminotransferase (ALT) levels, patients with advanced and decompensated liver disease, children, the elderly, patients with ongoing or recent alcohol and substance abuse, renal disease, human immunodeficiency virus (HIV) infection, severe psychiatric or neurologic illness, autoimmune disorders, solid organ transplant, and other significant comorbid conditions. Because these patients have been excluded from most clinical trials, little is known about the safety or efficacy of therapy in these populations. The expense and side effects of therapy are also an impediment to treatment of patients who are on public assistance, in prisons, and in institutions. Clearly, new efforts and new approaches are needed to expand the eligibility for antiviral therapy of hepatitis C and make treatment more available for understudied populations with this disease.

Use of complementary and alternative medicine in patients with liver disease.

OBJECTIVES: Complementary and alternative medicine (CAM) is used by 42% of the U.S. population. Its use among patients with chronic liver disease has not been well defined. Toward that end, we surveyed patients in six geographically diverse liver disease clinics in the United States for use of CAM. METHODS: Patients attending six liver disease clinics were polled via a common questionnaire regarding their use of CAM. Demographic information was obtained to identify predictors of CAM use. Statistical analysis included univariate and multivariate analysis using logistic regression. RESULTS: A total of 989 patients completed the questionnaire. Of these, 389 (39%) admitted to using some form of CAM at least once during the preceding month; 21% admitted to using herbal preparations, and 13% used herbs to treat their liver disease. Five variables were found to be predictive of alternative therapy use: female sex, young age, level of education, annual income, and geographic location. In all, 74% of patients reported using CAM in addition to the medications prescribed by their physician, but 26% did not inform their physician of their CAM use. CONCLUSIONS: CAM use is as common among patients visiting liver disease clinics in the United States as in the general population (39% vs 42%). Many patients are using herbs to treat their liver disease but are declining to discuss this use with their physician.