Manuela G. Neuman

The association between alcohol use, alcohol use disorders and tuberculosis (TB). A systematic review.

BackgroundIn 2004, tuberculosis (TB) was responsible for 2.5% of global mortality (among men 3.1%; among women 1.8%) and 2.2% of global burden of disease (men 2.7%; women 1.7%). The present work portrays accumulated evidence on the association between alcohol consumption and TB with the aim to clarify the nature of the relationship.MethodsA systematic review of existing scientific data on the association between alcohol consumption and TB, and on studies relevant for clarification of causality was undertaken.ResultsThere is a strong association between heavy alcohol use/alcohol use disorders (AUD) and TB. A meta-analysis on the risk of TB for these factors yielded a pooled relative risk of 2.94 (95% CI: 1.89-4.59). Numerous studies show pathogenic impact of alcohol on the immune system causing susceptibility to TB among heavy drinkers. In addition, there are potential social pathways linking AUD and TB. Heavy alcohol use strongly influences both the incidence and the outcome of the disease and was found to be linked to altered pharmacokinetics of medicines used in treatment of TB, social marginalization and drift, higher rate of re-infection, higher rate of treatment defaults and development of drug-resistant forms of TB. Based on the available data, about 10% of the TB cases globally were estimated to be attributable to alcohol.ConclusionThe epidemiological and other evidence presented indicates that heavy alcohol use/AUD constitute a risk factor for incidence and re-infection of TB. Consequences for prevention and clinical interventions are discussed.

Causal considerations on alcohol and HIV/AIDS--a systematic review.

AIM The study aimed to explore the possible causal nature of the association between alcohol consumption and HIV/AIDS. METHODS A review based on meta-analyses and reviews was conducted according to standard epidemiological criteria to distinguish causality from association, examining (i) the potential impact of alcohol on the incidence of HIV and (ii) alcohols impact on worsening the disease course. RESULTS In terms of incidence of HIV, although we found a consistent and strong association with consumption, there was not enough evidence for a causal connection. In particular, it is not clear whether personality traits such as sensation seeking or sexual compulsivity and psychiatric disorders such as antisocial personality disorder impact both alcohol consumption and risky sex, subsequently creating an association between both behaviors. In terms of worsening the disease course of HIV/AIDS, we found enough evidence for a causal impact of alcohol. Alcohol affects the immune system, thus contributing to a worsened course of HIV/AIDS. In addition, alcohol negatively impacts on behaviors that include support seeking and medication adherence. CONCLUSIONS A randomized controlled clinical trial targeted toward at-risk HIV-negative individuals who live in areas with high HIV prevalence is suggested to test the effects of proven effective alcohol interventions on HIV incidence.

Tumor necrosis factor-α and transforming growth factor-β reflect severity of liver damage in primary biliary cirrhosis

Background and Aims The pathogenesis of primary biliary cirrhosis (PBC) is unknown. The role of cytokines such as tumor necrosis factor‐α (TNF‐α) and transforming growth factor‐β (ΤGF‐β), and the effect of ursodeoxycholic acid (UDCA) in modifying the cytokine environment in patients with PBC has remained largely unstudied. Our aims were to determine: (i) the relationship between serum levels of TNF‐α and TGF‐β and the severity of PBC; and (ii) the effects of UDCA therapy on TNF‐α and TGF‐β levels in patients with PBC.

Adverse drug reactions induced by valproic acid

Valproic acid is a widely-used first-generation antiepileptic drug, prescribed predominantly in epilepsy and psychiatric disorders. VPA has good efficacy and pharmacoeconomic profiles, as well as a relatively favorable safety profile. However, adverse drug reactions have been reported in relation with valproic acid use, either as monotherapy or polytherapy with other antiepileptic drugs or antipsychotic drugs. This systematic review discusses valproic acid adverse drug reactions, in terms of hepatotoxicity, mitochondrial toxicity, hyperammonemic encephalopathy, hypersensitivity syndrome reactions, neurological toxicity, metabolic and endocrine adverse events, and teratogenicity.

Role of Cytokines in Ethanol-Induced Cytotoxicity In Vitro in Hep G2 Cells

BACKGROUND & AIMS As shown previously by us, ethanol (EtOH) causes time- and concentration-dependent reduction in cytoviability. Tauroursodeoxycholic acid (TUDCA) and ursodeoxycholic acid (UDCA) were shown to reduce cytotoxicity. Long-term EtOH exposure leads to immunoregulatory and detoxification impairment. This study aimed to determine the relationship between cytokine (interleukin [IL]-1 alpha and IL-6 and tumor necrosis factor [TNF]-alpha) production and expression, glutathione (GSH) status, and EtOH-induced cytotoxicity on Hep G2 cells. METHODS Cells were incubated with 80 mmol/L EtOH or alpha-minimal essential medium (control) in the presence or absence of 50 mumol/L TUDCA or UDCA. Cytokine release was quantitated by enzyme-linked immunosorbent assay. Cytokine expression was measured by reverse-transcription polymerase chain reaction. GSH content was determined in both the cytosolic and mitochondrial fractions. RESULTS After 24 hours of EtOH exposure, the release of IL-1 alpha doubled, that of IL-6 increased 10 times, and that of TNF-alpha increased 3.5 times. Cytokine expression was up-regulated compared with control for IL-1 alpha (42%), IL-6 (26%), and TNF-alpha (52%). Addition of 50 mumol/L TUDCA or UDCA reduced cytokine release and expression. TNF-alpha increased cytotoxicity by 18%. Anti-TNF-alpha antibody almost abolished it. EtOH depleted mGSH levels by 55% (P < 0.001). TUDCA replenished them by 88%. CONCLUSIONS EtOH up-regulated expression of cytokines in Hep G2 cells is down-regulated by bile acids. Increased amounts of TNF-alpha and depletion in both cytosolic and mitochondrial GSH contribute to EtOH cytotoxicity. Bile acids prevent toxicity.

Inflammatory bowel disease: role of diet, microbiota, life style

Inflammatory bowel disease (IBD) encompassed several chronic inflammatory disorders leading to damage of the gastrointestinal tract (GI). The 2 principal forms of these disorders are ulcerative colitis (UC) and Crohn disease (CD). Bacteria are involved in the etiology of IBD, and the genetic susceptibility, environmental factors, and lifestyle factors can affect the individuals predisposition to IBD. The review discusses the potential role of environmental factors such as diet and microbiota as well as genetics in the etiology of IBD. It is suggested that microbial ecosystem in the human bowel colonizing the gut in many different microhabitats can be influence by diet, leading to formation of metabolic processes that are essential form the bowel metabolism.

The toxicity of Callilepis laureola, a South African traditional herbal medicine

OBJECTIVES To review the literature on the toxicity of Callilepis laureola, and to assess the cytotoxicity of C. laureola in human hepatoblastoma Hep G2 cells in vitro. DESIGN AND METHODS Cells were incubated for up to 48 h in the presence of increasing concentrations of an aqueous extract of C. laureola (0.3-13.3 mg/mL). Cytotoxicity was quantitated spectrophotometrically by the metabolism of the tetrazolium dye MTT. Cytoviability of the control cells was considered to be 100%. RESULTS C. laureola produced cytotoxicity in a concentration-dependent manner. Cytotoxicity was significant at all concentrations tested (0.3-2.5 mg/mL, p < 0.05 vs. controls and 3.3-13.3 mg/mL, p < 0.0001 vs. controls). After 6 h, 100% toxicity was observed at a concentration of 6.7 mg/mL. CONCLUSION C. laureola causes significant cytotoxicity in Hep G2 cells in vitro. These findings are in accordance with the observed hepatotoxicity in clinical cases of C. laureola poisoning.

Immunopathogenesis of hepatitis C viral infection: Th1/Th2 responses and the role of cytokines

Hepatitis C virus is a common cause of hepatocellular injury that is associated with complex and vigorous immunologic mechanisms. Both humoral and cell-mediated immune responses participate in the host defense against hepatitis C viral infection, but there is increasing recognition of the roles played by the cell-mediated response, and in particular the cytokine system, in the immunopathogenesis of chronic hepatitis C. The cell-mediated response depends on cytotoxic and helper T-cell activity, and functions through the actions of cytokines to regulate macrophages, natural killer cells, and antiviral cellular proteins. Cytokines produced in the liver are essential in defending the host against hepatitis C invasion, but they have also been implicated in the hepatocellular injury seen in the majority of chronically infected patients. Cytokines are thought to be involved in the pathogenesis of hepatitis C under conditions where the virus can mutate effectively and evade T-cell immune defense mechanisms. Persistent infection upsets the balance between immunostimulatory and inhibitory cytokines which can prolong inflammation and lead to necrosis, fibrosis, and chronic liver disease.

Cytokines as predictors for sustained response and as markers for immunomodulation in patients with chronic hepatitis C.

OBJECTIVES (i) To characterize serum cytokine levels of tumor necrosis factor alpha (TNF alpha), interleukin 6 (IL 6), IL 8 and IL 12 in non-cirrhotic patients with chronic hepatitis C, (ii) to correlate the levels of these cytokines with the degree of the disease at the basal level, (iii) to correlate these levels with the response to therapy, (iv) to compare profiles of cytokines in monotherapy (MT) versus combination therapy (CT), and (v) to compare the immunomodulatory effects of MT versus CT. DESIGN AND METHODS 47 patients were enrolled in the study. The controls were 120 volunteers (recruited from students and staff) that did not present HCV RNA positive and were not known to suffer any other metabolic disease. Thirty patients formed the other group of controls, with alcoholic liver disease (ALD). Serum cytokine levels were assessed using enzyme-linked immunosorbent assay (ELISA). RESULTS The sustained responders (SRs) have basal values much lower than relapsed responders (RRs) and non-responders (NRs) regardless of the therapy. CONCLUSIONS Cytokines can be used as non-invasive markers for sustained response and as monitors for the outcome of therapy.

Kinetics of serum cytokines reflect changes in the severity of chronic hepatitis C presenting minimal fibrosis

Our aims were to measure the kinetics of serum tumour necrosis alpha (TNF‐α) and transforming growth factor beta (TGF‐β) levels as markers of progression of disease in nontreated chronic hepatitis C virus (HCV)‐infected patients with minimal or no fibrosis and minimal histology activity index (HAI) scores. Our study group consisted of 56 patients diagnosed with minimal (1) or no fibrosis (0) and minimal HAI (0–1) on their first biopsy as defined by Knodell and METAVIR scores. We compared their initial (entry of study) cytokine levels with a group of 103 HCV controls with minimal (0–1) to mild fibrosis (0–3) and mild HAI (5.5). Serum TNF‐α and TGF‐β levels were measured by enzyme‐linked‐immunosorbent‐assay. A significant difference was seen in TNF‐α levels at baseline in the study group vs. controls. Regardless of their HAI, there was a correlation between TGF‐β and degree of fibrosis. As shown by their biopsies, during the 3 years (from entry to follow up), many of the patients that initially had minimal fibrosis progressed to higher degree of fibrosis. This progression is paralleled by an increase in TGF‐β levels when comparing initial and follow‐up levels. In conclusion, serum TNF‐α reflects the progression of inflammation as seen in liver biopsies and TGF‐β reflects the degree of fibrosis in HCV patients.