Nonalcoholic fatty liver disease: Evolving paradigms

In the last years new evidence has accumulated on nonalcoholic fatty liver disease (NAFLD) challenging the paradigms that had been holding the scene over the previous 30 years. NAFLD has such an epidemic prevalence as to make it impossible to screen general population looking for NAFLD cases. Conversely, focusing on those cohorts of individuals exposed to the highest risk of NAFLD could be a more rational approach. NAFLD, which can be diagnosed with either non-invasive strategies or through liver biopsy, is a pathogenically complex and clinically heterogeneous disease. The existence of metabolic as opposed to genetic-associated disease, notably including "lean NAFLD" has recently been recognized. Moreover, NAFLD is a systemic condition, featuring metabolic, cardiovascular and (hepatic/extrahepatic) cancer risk. Among the clinico-laboratory features of NAFLD we discuss hyperuricemia, insulin resistance, atherosclerosis, gallstones, psoriasis and selected endocrine derangements. NAFLD is a precursor of type 2 diabetes (T2D) and metabolic syndrome and progressive liver disease develops in T2D patients in whom the course of disease is worsened by NAFLD. Finally, lifestyle changes and drug treatment options to be implemented in the individual patient are also critically discussed. In conclusion, this review emphasizes the new concepts on clinical and pathogenic heterogeneity of NAFLD, a systemic disorder with a multifactorial pathogenesis and protean clinical manifestations. It is highly prevalent in certain cohorts of individuals who are thus potentially amenable to selective screening strategies, intensive follow-up schedules for early identification of liver-related and extrahepatic complications and in whom earlier and more aggressive treatment schedules should be carried out whenever possible

Use of procalcitonin for the differential diagnosis of fever in cancer patients: an observational study

Fever often occurs in cancer patients and the possibility of having a reliable marker for the differential etiological diagnosis is desirable. The aim of this study was to investigate the eligibility of the use of procalcitonin (PCT) in hemato-oncological patients for the differential diagnosis of fever. We prospectively enrolled 98 cancer patients and divided them into two groups: those with active disease and those with non-active disease. Procalcitonin was dosed at Time 0 (recruitment) and at the onset of fever. On enrollment, PCT values were 0.1 ng/mL in 83% patients with active disease, and lower than 0.5 ng/mL in 23%, which is usually considered not suggestive of bacterial infection. Four percent of patients had values over 0.5 ng/mL and these were mainly patients with neuroendocrine tumors or affiliates. On enrollment, there were also no statistically significant differences in PCT values between the two groups of patients. This showed that active cancer is unable by itself to change PCT levels. In the active disease group, 21 episodes of fever due to bacterial infection were registered, and in all of them an increase in PCT values was observed. This demonstrates the ability of PCT to detect an infection-induced fever in cancer patients. Procalcitonin concentrations are not significantly altered by active neoplastic disease. On the contrary, in the course of fever due to a bacterial infection, PCT values increase and can, therefore, be considered a useful tool in the differential diagnosis between infection-induced fever and drug-related or tumor associated-fever. Procalcitonin may be a useful marker of bacterial infection even in cancer patients

A round trip from nonalcoholic fatty liver disease to diabetes: molecular targets to the rescue?

Evidence suggests a close relationship between nonalcoholic fatty liver disease (NAFLD) and type two diabetes (T2D). On the grounds of prevalence of disease, both conditions account for a significant financial cost for health care systems and individuals. Aim of this review article is to explore the epidemiological basis and the putative molecular mechanisms underlying the association of NAFLD with T2D. Epidemiological studies have shown that NAFLD is associated to the development of incident T2D and either reversal or improvement of NAFLD will result into decreased risk of developing incident T2D. On the other side of the coin data have shown that T2D will worsen the course of NAFLD doubling the risk of disease progression (i.e. evolution from simple steatosis to advanced fibrosis, cirrhosis, hepatocellular carcinoma, liver transplant and death). Conversely, NAFLD will contribute to metabolic decompensation of T2D. The pathogenesis of T2D in NAFLD patients may be mediated by several hepatokines impairing metabolic control. Among these, Fetuin-B, which causes glucose intolerance and is increased in patients with T2D and NAFLD with fibrosis is one of the most promising. T2D may affect the progression of NAFLD by acting at different levels of the pathogenic cascade involving gut microbiota and expanded, inflamed, dysfunctional adipose tissue. In conclusion, T2D and NAFLD are mutually, closely and bi-directionally associated. An improved understanding of molecular pathogenesis underlying this bi-directional association may allow us to be able to prevent the development of T2D by halting the progression of NAFLD

Classical and innovative insulin sensitizing drugs for the prevention and treatment of NAFLD

Background\ud \ud Nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disorder worldwide, comprises a spectrum of conditions ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. NASH is associated with an increased risk of hepatocellular carcinoma (HCC) and cardiometabolic disease. Insulin resistance (IR) is the underlying pathogenic mechanism for NAFLD, the presence of which in turn, is a strong predictor for the development of metabolic disorders. Hence, therapy of NAFLD with insulin-sensitizing drugs (ISDs) should ideally improve the key hepatic histological changes (steatosis, inflammation and fibrosis), but should also reduce cardiometabolic and cancer risk.\ud \ud \ud Objectives\ud \ud In this review, the rationale for the use of ISDs and the evidence for their efficacy are detailed. In particular, the mechanism of action, potential for use, limitations and untoward effects of metformin and thiazolidinediones are systematically reviewed. Further, we discuss novel ISDs that may have potential clinical utility in NAFLD.\ud \ud Results and conclusion\ud \ud Despite the theoretical prediction that ISDs might have beneficial effects on disease outcomes, evidence that ISDs are able to alter the natural history of NAFLD are presently not available. The exploration of novel strategies exploiting "nonconventional" ISDs is encouraged

Cholestatic icterus: is there still a role for the clinic?

Caso clinico. Ruolo della clinica e delle indagini strumentali nella diagnosi diferenziale della colestasi epatica

Liver Fibrosis Biomarkers Accurately Exclude Advanced Fibrosis and Are Associated with Higher Cardiovascular Risk Scores in Patients with NAFLD or Viral Chronic Liver Disease

Liver fibrosis predicts liver-related and cardiovascular outcomes in chronic liver disease patients. We compared the diagnostic performance of various liver fibrosis biomarkers for identifying histological significant/advanced fibrosis. Additionally, the correlations of such liver fibrosis biomarkers with cardiovascular risk (CVR) scores were evaluated. 173 patients with viral hepatitis (157 HCV and 16 HBV) and 107 with a non-alcoholic fatty liver disease (NAFLD) were consecutively enrolled. Various liver fibrosis biomarkers: aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio (ARR), AST to Platelet Ratio Index (APRI), Fibrosis-4 (FiB-4), Forns index, NAFLD fibrosis score (NFS), BARD (body mass index (BMI), AAR, Diabetes) score, and Hepamet fibrosis score (HFS), were used to identify significant/advanced fibrosis. CVR was assessed by using the SCORE, the Progetto CUORE, or the Framingham risk scoring systems. Liver fibrosis biomarkers performed better in predicting advanced rather than significant liver fibrosis in all patients, regardless of chronic liver disease aetiology. Forns index and HFS performed best in predicting advanced fibrosis in patients with viral chronic liver disease and NAFLD. Lower cut-offs of these liver fibrosis biomarkers had high negative predictive values for advanced fibrosis overall, as well as in patients with NAFLD or viral chronic liver disease. FIB-4, Forns index, NFS, and HFS were positively correlated with SCORE and Framingham risk scores. In conclusion, liver fibrosis biomarkers accurately exclude advanced fibrosis and positively correlate with CVR scores in patients with chronic liver disease

DIABETES AND CARDIOVASCULAR EVENTS: USEFULNESS AND LIMITS OF RISK FUNCTIONS

Cardiovascular diseases represent a leading cause of death and disability worldwide. Risk functions and algorithms have been constructed to estimate cardiovascular risk as the weighed sum of different variables, considered as risk factors. Basically all utilized functions consider age, gender, cigarette smoking status, some estimate of systemic blood pressure and of plasma lipid profile, and diabetes. The functions derived from the Framingham study are the most commonly utilized worldwide, even if their applicability to some geographical areas has been heavily questioned. Furthermore, almost all functions, including Framingham’s, consider diabetes only as a dichotomous (yes / no) variable, despite its heavy impact on cardiovascular risk. On the other hand, the risk engine developed by the United Kingdom Prevention of Diabetes Study (UKPDS) takes into account some variables which characterize diabetes and its severity.Evidence from an outpatient population of diabetic subjects in northern Italy has underlined the extreme variability of risk stratification when utilizing different risk functions; whereas anglo-american functions overestimate cardiovascular risk, Italian charts and functions tend to underestimate risk, particularly in women. Estimation of cardiovascular risk is largely dependent on the function adopted, and on the baseline risk of each cohort. Functions should be designed which are geographically homogeneous for a selected population, and which take into account variables that are specific for diabetes. This should hopefully allow appropriate identification of high risk subjects, and ultimately help to optimize the allocation of health care resources

TYPE 2 DIABETES AND CARDIOVASCULAR EVENTS : STUDY OF THE AMIN RISK FACTORS IN A LOCAL POPULATION OF PATIENTS

Background and aim. The aim of this study is to analyze the risk of cardiovascular events in a local cohort of patients with type 2 diabetes, and to evaluate the prognostic accuracy of four algorithms used to estimate cardiovascular risk: Framingham study, UKPDS study, Riskard study and Progetto Cuore. Method and results. We analyzed clinical charts of the Diabetes Clinics of Modena during the period 1991-1995. Patients aged 35-65 with type 2 diabetes and no previous cardiovascular disease were eligible. The incidence of new cardiovascular disease was compared with estimated rates deriving from the different functions. A stratification was obtained in subgroups at different cardiovascular risk, allowing comparison between the algorithms. The presence of heart failure and chronic obstructive pulmonary disease was also recorded. 1532 patients were eligible; women presented a worse cardiovascular risk profile. An absolute 10-yr rate of cardiovascular events of 14.9% was observed. Comparing patients with events with event-free subjects we found significant differences in systolic blood pressure, age at visit, smoke, HDL-cholesterol, duration of diabetes, HbA1c and comorbidities. Comparing the estimated risk rate according to the different functions, Italian algorithms were more consistent with observed data; however, Progetto Cuore shows underestimation of events, particularly when applied to females.Conclusions. Estimation of cardiovascular risk is dependent on the algorithm adopted and on the baseline risk of the reference cohort. Functions designed for a specific population, including risk variables peculiar for diabetes should be adopted to increase the performance of such functions which is presently clearly unsatisfactory

RISK FOR CARDIOVASCULAR EVENTS IN AN ITALIAN POPULATION OF PATIENTS WITH TYPE 2 DIABETES

Background and aim. The aim of this study is to analyze the risk of cardiovascular events in a local cohort of patients with type 2 diabetes, and to evaluate the prognostic accuracy of four algorithms used to estimate cardiovascular risk: Framingham study, UKPDS study, Riskard study and Progetto Cuore. Method and results. We analyzed clinical charts of the Diabetes Clinics of Modena during the period 1991-1995. Patients aged 35-65 with type 2 diabetes and no previous cardiovascular disease were eligible. The incidence of new cardiovascular disease was compared with estimated rates deriving from the different functions. A stratification was obtained in subgroups at different cardiovascular risk, allowing comparison between the algorithms. 1532 patients were eligible; women presented a worse cardiovascular risk profile. An absolute 10-yr rate of cardiovascular events of 14.9% was observed. Comparing patients with events with event-free subjects we found significant differences in systolic blood pressure, age at visit, smoke, HDL-cholesterol, duration of diabetes, HbA1c and comorbidities. Comparing the estimated risk rate according to the different functions, Italian algorithms were more consistent with observed data; however, Progetto Cuore shows underestimation of events, particularly when applied to females.Conclusions. Estimation of cardiovascular risk is dependent on the algorithm adopted and on the baseline risk of the reference cohort. Functions designed for a specific population, including risk peculiar for diabetes should be adopted to increase the performance of such functions which is presently clearly unsatisfactory