Athanasios J. Archimandritis

The evolving role of leptin and adiponectin in chronic liver diseases.

Leptin and adiponectin, the main metabolic products of adipose tissue, have been implicated in a wide spectrum of human diseases. Given the frequent presence of hepatic steatosis in several chronic liver diseases, there is currently increasing interest in the role of these adipokines in the development of hepatic steatosis and also in necroinflammation and fibrosis, mostly in patients with nonalcoholic fatty liver disease or chronic hepatitis C. According to experimental data, reduced adiponectin levels and increased leptin levels associated with leptin resistance, which are usually observed in obese patients with or without metabolic syndrome, may result in fat accumulation in the liver and in the enhancement of liver inflammation and mostly fibrogenesis. Increased leptin and decreased adiponectin serum levels have been detected initially in patients with nonalcoholic steatohepatitis and more recently in patients with chronic hepatitis C compared to healthy controls in most but not all studies, while the data on the associations between these adipokine levels and the severity of hepatic steatosis or fibrosis are still rather conflicting. However, several potential confounding parameters were not evaluated in all studies. Therefore, the associations between adipokines and liver histological lesions and their effects on liver cells should be evaluated further in prospective, carefully designed studies, including larger cohorts of patients with detailed assessment of metabolic and other potential confounding factors.

Is there a meaningful serum hepatitis B virus DNA cutoff level for therapeutic decisions in hepatitis B e antigen–negative chronic hepatitis B virus infection?

The diagnosis of hepatitis B e antigen (HBeAg)‐negative chronic hepatitis B indicating therapeutic intervention currently requires serum hepatitis B virus (HBV) DNA ≥2,000 IU/mL. We evaluated the severity of liver histology and the presence of histological indication for treatment in patients with HBeAg‐negative chronic HBV infection focusing on those with low viremia and/or normal alanine aminotransferase (ALT). In total, 399 patients with increased ALT and detectable serum HBV DNA (chronic hepatitis B patients) and 35 cases with persistently normal ALT and HBV DNA >2,000 IU/mL (inactive carriers) were included. Histological indication for treatment (grading score ≥7 and/or stage ≥2 in Ishaks classification) was found in 91% (185/203), 82% (75/91), 75% (47/63), and 62% (26/42) of chronic hepatitis B patients with HBV DNA ≥200,000, 20,000‐199,999, 2,000‐19,999, and <2,000 IU/mL, respectively (P < 0.001). Histological indication for treatment was more frequent in chronic hepatitis B patients with persistently elevated ALT (86% or 275/321), but it was also found in 74% (58/78) of those with transiently normal ALT (P = 0.025). All inactive carriers had HBV DNA <20,000 IU/mL. Histological indication for treatment was present in 17% (6/35) of inactive carriers always due to moderate (stage 2) fibrosis without active necroinflammation. Conclusion: HBeAg‐negative chronic HBV patients with persistently or transiently increased ALT and HBV DNA ≥20,000 IU/mL almost always require therapeutic intervention, but histological indications for treatment are also present in the majority of such cases with HBV DNA <20,000 and even <2,000 IU/mL. In contrast, minimal histological lesions are observed in the majority of HBeAg‐negative patients with persistently normal ALT and HBV DNA >2,000 IU/mL, who may not require immediate liver biopsy and treatment but only close follow‐up. (HEPATOLOGY 2008.)

Adipokines in Nonalcoholic Steatohepatitis: From Pathogenesis to Implications in Diagnosis and Therapy

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and can vary from benign steatosis to end-stage liver disease. The pathogenesis of non-alcoholic steatohepatitis (NASH) is currently thought to involve a multiple-hit process with the first hit being the accumulation of liver fat which is followed by the development of necroinflammation and fibrosis. There is mounting evidence that cytokines secreted from adipose tissue, namely, adipokines, are implicated in the pathogenesis and progression of NAFLD. In the current review, we explore the role of these adipokines, particularly leptin, adiponectin, resistin, tumor necrosis factor-a, and interleukin-6 in NASH, as elucidated in experimental models and clinical practice. We also comment on their potential use as noninvasive markers for differentiating simple fatty liver from NASH as well as on their potential future therapeutic role in patients with NASH.

Increased arterial stiffness and impaired endothelial function in nonalcoholic Fatty liver disease: a pilot study.

BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease both in the general and pediatric population and has been associated with increased cardiovascular risk. Arterial function and early atherosclerotic changes are markers of cardiovascular disease and independent predictors of the corresponding risk. Through a global approach, we investigated the relationships between NAFLD and functional arterial changes and early atherosclerosis. METHODS A total of 23 consecutive patients (mean age 55 ± 14 years, 11 males) with biopsy evidence of NAFLD and 28 control subjects matched for age, gender, body mass index, and other cardiovascular risk factors participated in the study. RESULTS Compared to controls, NAFLD subjects had significantly higher carotid-femoral pulse wave velocity (PWV; 8.2 ± 1.3 m/s vs. 6.9 ± 1.3 m/s, P = 0.001), higher carotid intima-media thickness (IMT; 0.79 ± 0.18 mm vs. 0.67 ± 0.13 mm, P = 0.01), and reduced flow-mediated dilatation (FMD; 1.92 ± 2.11% vs. 4.8 ± 2.43%, P < 0.001). In multivariable analysis, presence of NAFLD was an independent determinant of both PWV and FMD, whereas leptin was an independent determinant of PWV (B = 0.036, P < 0.05), and adiponectin was independently associated with FMD (B = 0.104, P < 0.05). In addition, histological activity of liver disease expressed by the global Brunt Grade was associated independently with FMD (B = -1.054, P < 0.05). CONCLUSIONS NAFLD is associated with arterial stiffness and endothelial dysfunction. Given the important independent prognostic role of these arterial indexes, these findings have important implications for increased cardiovascular risk in patients with NAFLD.

Adverse drug reactions as a cause of hospital admissions: a 6-month experience in a single center in Greece.

BACKGROUND Adverse drug reactions (ADRs) are a significant cause of morbidity and mortality. METHODS A prospective study was conducted over a 6-month period. All patients consecutively admitted were enrolled in the study. Analysis included: (1) an evaluation of the frequency of ADR-related hospital admissions and their causality, severity, and preventability; (2) a description of the type of drugs involved; (3) a report of the most common clinical manifestations related to these ADRs; and (4) an assessment of the factors that were predictive of ADRs. RESULTS Seventy of the 548 admissions (12.8%) were related to an ADR. Hemorrhage represented the most common ADR (37.3%), followed by metabolic and renal events (10.8% each). The drugs most often involved were non-steroid anti-inflammatory drugs (NSAIDs), followed by diuretics, aspirin, oral anticoagulants, and oral hypoglycemic agents. A comparison between ADR and non-ADR-related admissions showed that mean number of medications and age were significantly higher for patients admitted for an ADR than for those who were not. Gender, chronic disease at admission, days of hospitalization, cognitive impairment, renal insufficiency, physical activity impairment, and use of psychoactive drugs did not differ between the two groups. In the multivariate analysis, number of drugs was the only independent predictor of ADR-related hospital admission (OR=1.064, 95% CI 1.019-1.109). In 13 of 70 (18.6%) ADR-related hospital admissions, ADRs were coded as severe. CONCLUSIONS ADRs are common causes of hospital admissions and may have important consequences. The most important determinant for ADR-related hospital admissions is the number of drugs taken.

Short‐course therapy with amoxycillin–clarithromycin triple therapy for 10 days (ACT‐10) eradicates Helicobacter pylori and heals duodenal ulcer

Whilst the role of Helicobacter pylori eradication in managing duodenal ulcers has been established, consensus regarding the ideal regimen has not been achieved.

Current management of hepatitis B virus infection before and after liver transplantation

The progress in treatment against hepatitis B virus (HBV) has substantially improved the outcome of all HBV‐infected patients. We systematically reviewed the existing data in the management of HBV transplant patients in order to assess the optimal regimen in the pretransplant setting, for post‐transplant prophylaxis and for therapy of HBV recurrent infection. All data suggest that an effective pretransplant anti‐HBV therapy prevents post‐transplant HBV recurrence. Pretransplant therapy has been based on lamivudine with addition of adefovir upon lamivudine resistance, but the use of newer, potent high‐genetic barrier agents is expected to improve long‐term efficacy. Moreover, it may lead to improvement of liver function, which sometimes removes the need for transplantation, although more objective criteria for removal from waiting lists are required. After liver transplantation, the combination of HBV immunoglobulin and one nucleos(t)ide analogue, mostly lamivudine, is currently the best approach, almost eliminating the probability of HBV recurrence. Treatment of post‐transplant HBV recurrence has been mainly studied with lamivudine, but it will be most effective with entecavir and tenofovir, which have a low risk of resistance. In conclusion, the newer anti‐HBV agents improve the treatment of HBV both pretransplant and post‐transplant. HBV immunoglobulin is still used in combination with an anti‐HBV agent for post‐transplant prophylaxis. Monoprophylaxis with one of the new anti‐HBV agents might be possible, particularly in patients preselected as having a low risk of HBV recurrence, but further data are needed and strategies to ensure compliance must be used.

Increasing frequency of Gram-positive bacteria in spontaneous bacterial peritonitis

Abstract: Aim: To evaluate the characteristics and possible recent changes of the microbial causes of spontaneous bacterial peritonitis (SBP) in cirrhotic patients.

Serum adipokine levels in chronic liver diseases: Association of resistin levels with fibrosis severity

Objective. Leptin and adiponectin have been implicated in the pathogenesis and progression of non-alcoholic steatohepatitis (NASH) and chronic hepatitis C (CHC), but little is known about the role of resistin in chronic liver diseases. The objective of this study was to investigate serum levels of the above three adipokines in relation to the etiology of liver disease and to determine their associations with histological severity. Material and methods. We prospectively evaluated 146 patients (HBeAg-negative chronic hepatitis B (CHB): 52, CHC: 70, NASH: 24) who consecutively underwent liver biopsy. Detailed epidemiological, anthropometric and laboratory data were recorded. Histological lesions were evaluated blindly according to the Ishak and the Brunt classifications for CHB/CHC and NASH, respectively. Results. Serum adipokine levels were similar between CHB and CHC patients, while CHB/CHC patients had significantly lower leptin levels compared with NASH patients (8.3±7.3 versus 17.6±16.6 ng/ml, p=0.012) and higher adiponectin (10.2±5.1 versus 7.5±4 µg/ml, p=0.018) and resistin levels (7.1±2.5 versus 5.7±2.8 ng/ml, p=0.016). In CHB/CHC, there was no significant association between steatosis or necroinflammation and levels of adipokines, while the presence of moderate/severe fibrosis (stages 4–6) was associated with higher leptin and adiponectin levels in male but not in female patients and with lower resistin levels irrespective of gender or other factors (adjusted odds ratio=0.788, p=0.035). Conclusions. Serum adipokine levels depend on the etiology of liver disease differing between chronic viral hepatitis and NASH, but not between CHB and CHC. In CHB/CHC, resistin levels are independently associated with fibrosis severity, whereas in the association of leptin and adiponectin levels with fibrosis, it seems to be a gender effect.

Insulin resistance and metabolic syndrome in chronic liver diseases: Old entities with new implications

Insulin resistance (IR) and metabolic syndrome have recently been implicated in the pathogenesis and progression of chronic liver diseases, especially chronic hepatitis C (CHC) and non-alcoholic fatty liver disease (NAFLD). In this review, we provide current information on their deleterious effect on the liver, with particular interest in those two entities. In NAFLD, IR causes both the accumulation of fat in hepatocytes and the progression to non-alcoholic steatohepatitis (NASH). Moreover, the presence of metabolic syndrome seems to be associated with severe fibrosis in NASH patients. In CHC, IR develops early in the course of the disease and precedes steatosis. It is also independently associated with histological severity and negatively affects treatment response, irrespective of genotype. Consequently, therapies targeting IR and metabolic syndrome could indirectly ameliorate the prognosis of both NAFLD and CHC. As specific therapies do not exist, patients with metabolic syndrome and CHC and NAFLD should be counseled to lose weight and ameliorate their glycemic control and lipid profile.