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Nonalcoholic fatty liver disease (NAFLD) is currently the most common cause of chronic liver disease worldwide affecting a third of adults and 12% of children in Western countries. In around 50–60%% of cases, NAFLD and type 2 diabetes mellitus (T2DM) coexist and act synergistically to increase the risk of adverse hepatic and extra-hepatic outcomes. T2DM is a strong risk factor for rapid progression of NAFLD to nonalcoholic steatohepatitis (NASH), cirrhosis or hepatocellular carcinoma (HCC), which have become frequent indications of liver transplantation.The pathophysiology of NAFLD is complex and its relationship with T2DM is bidirectional, where lipotoxicity and insulin resistance (IR), act as the strongest pillars.To date, no pharmacological treatment has been approved for NAFLD. However, there is an intense research with numerous drugs focused on reversing inflammation and liver fibrosis through modulation of molecular targets without good results.It has been known for some time that weight reduction >10% is associated to histological improvement of NAFLD. Recently, glycemic control has been shown to induce similar results. Diet and physical exercise for weight reduction have limitations, so alternative methods (pharmacologic, endoscopic or surgical) may be required. Currently, new antidiabetic drugs inducing weight loss, have been recently approved for the treatment of obesity. Nevertheless, their therapeutic effects on NAFLD have not been extensively studied.We will review here, recently published data on the effects of weight loss and glycemic control on the histological and metabolic parameters of NAFLD and recent published data on therapeutic studies of NAFLD with new antidiabetic drugs.

Non-alcoholic fatty liver disease (NAFLD) affects one-third of the world's adult population and is linked to metabolic syndrome. It can progress to steatohepatitis, cirrhosis and hepatocellular carcinoma. During the last four decades, it has been the subject of exhaustive research in multiple aspects to define its epidemiology, pathophysiological mechanisms and therapy.In 2020, a group of international experts proposed the change of name to metabolic-associated fatty liver disease (MAFLD) with the main objective of making it an inclusive diagnosis prioritizing metabolic abnormalities. However, the change in terminology included the modification of the diagnostic criteria allowing the non-exclusion of other concomitant liver diseases such as alcohol liver disease, and chronic hepatitis B or C.The proposal precipitated a wave of debates among experts based on theoretical opinions on the desirability of the rapid adoption of the new terminology. But it also precipitated a wave of epidemiological and clinical studies which, two years later, have provided clinical evidence on the differences and similarities of the two entities, specially, those that could be considered for future refinements of the diagnostic criteria of MAFLD. Likewise, this evidence may contribute to deciding the time of adoption of this terminology.In this text, we discuss, in general terms, important aspects of the clinical evidence that has been generated to date in cross-sectional and longitudinal studies focusing on clinical characteristics and outcomes, mainly on all-cause and specific mortality of MAFLD.

Introduction: Cirrhosis and liver cancer are currently common causes of death worldwide. The global epidemic of obesity has increased the incidence of nonalcoholic fatty liver disease (NAFLD) and cirrhosis in recent years. Advanced fibrosis increases the morbimortality rate in NAFLD. The Mexican population has one of the highest prevalence of obesity and diabetes mellitus (DM) worldwide. Aim: To determine the prevalence of advanced liver fibrosis in Mexican general population. Methods: Adult individuals, without a history of liver disease nor heavy alcohol consumption were randomly sampled from 20,919 participants of a health and nutrition survey applied to the general population. Clinical and laboratory evaluations were performed to calculate the NAFLD fibrosis score (NFS) (an extensively validated non-invasive method). Two cut-off points were used. Advanced fibrosis was defined as a result >0.676. Results: In total 695 individuals were included. The mean age was 47.8 ± 16.4. The majority were between 20 and 50 years (59%), 70.2% were female, 35.5% showed obesity and 15.8% DM. The 93% had normal serum ALT. Based on the NFS results, 56 individuals (8.1%) had a high probability of fibrosis. Most patients from this subgroup showed normal serum ALT (92.9%), 89.3% were >45 yr. old, 52% were obese and 27% suffered from DM. Conclusions: Based on these results, 8.1% of Mexican general population without a history of liver disease is at high risk of having advanced liver fibrosis and complications and death derived from cardiovascular disease and cirrhosis. Most of them showed normal ALT serum levels.

Background & Aims. It is unclear whether portal vein thrombosis (PVT) unrelated to malignancy is associated with reduced survival or it is an epiphenomenon of advanced cirrhosis. The objective of this study was to assess clinical outcome in cirrhotic patients with PVT not associated with malignancy and determine its prevalence.Material and methods. Retrospective search in one center from June 2011 to December 2014.Results. 169 patients, 55 women and 114 men, median age 54 (19-90) years. Thirteen had PVT (7.6%). None of the patients received anticoagulant treatment. The PVT group was younger (49 [25-62] vs. 55 [19-90] years p = 0.025). Child A patients were more frequent in PVT and Child C in Non-PVT. Median Model for End Stage Liver Disease (MELD) score was lower in PVT (12 [8-21] vs. 19 [7-51] p ≤ 0.001) p ≤ 0.001). There was no difference between upper gastrointestinal bleeding and spontaneous bacterial peritonitis in the groups. Encephalopathy grade 3-4 (4 [30.8%] vs. 73 [46.8%] p = 0,007) and large volume ascites (5 [38.5%] vs. 89 [57.1%] p= 0,012) was more common in non-PVT. Survival was better for PVT (16.5 ± 27.9 vs. 4.13 ± 12.2 months p = 0.005). Conclusions: We found that PVT itself does not lead to a worse prognosis. The most reliable predictor for clinical outcome remains the MELD score. The presence of PVT could be just an epiphenomenon and not a marker of advanced cirrhosis.

About 80% of patients with liver cirrhosis may have glucose metabolism disorders, 30% show overt diabetes mellitus (DM). Prospective studies have demonstrated that DM is associated with an increased risk of hepatic complications and death in patients with liver cirrhosis. DM might contribute to liver damage by promoting inflammation and fibrosis through an increase in mitochondrial oxidative stress mediated by adipokines. Based on the above mentioned the effective control of hyperglycemia may have a favorable impact on the evolution of these patients. However, only few therapeutic studies have evaluated the effectiveness and safety of antidiabetic drugs and the impact of the treatment of DM on morbidity and mortality in patients with liver cirrhosis. In addition, oral hypoglycemic agents and insulin may produce hypoglycemia and lactic acidosis, as most of these agents are metabolized by the liver. This review discusses the clinical implications of DM in patients with chronic liver disease. In addition the effectiveness and safety of old, but particularly the new antidiabetic drugs will be described based on pharmacokinetic studies and chronic administration to patients. Recent reports regarding the use of the SGLT2 inhibitors as well as the new incretin-based therapies such as injectable glucagon-like peptide-1 (GLP-1) receptor agonists and oral inhibitors of dipeptidylpeptidase-4 (DPP-4) will be discussed. The establishment of clear guidelines for the management of diabetes in patients with CLD is strongly required.

Aims. To define if there is an imbalance in plasma levels of proinflammatory, fibrogenic and antifibrogenic cytokines in patients with liver cirrhosis (LC) and impaired glucose tolerance (IGT) or diabetes mellitus (DM).Material and methods. We randomly selected 54 out of 100 patients with LC who had normal fasting plasma glucose (FPG) levels. Three groups were formed based on an oral glucose tolerance test (OGTT) results: 18 patients were normal, 18 had IGT, and 18 had DM. Plasma levels of cytokines were measured: TNF-α, soluble tumor necrosis factor receptor 1 (sTNF-R1), leptin, TGF-β1, and hepatocyte growth factor (HGF). Also, fasting plasma insulin (FPI) levels were determined and HOMa2-IR was calculated. Results were compared with those of a control group of 18 patients without liver disease nor DM. Intergroup comparison was performed using non parametric tests.Results. Significantly higher sTNF-R1 and lower TGF-β1 were found in patients with IGT and DM compared to controls. Leptin, HGF, and TNF-α levels showed no significant differences. According to Child-Pugh classification all cytokines levels were impaired in groups B or C as compared to group A. Positive correlations between sTNF-R1 and HOMA2-IR and between leptin and HOMA2-IR were found.Conclusions. IGT and DM were associated with abnormalities of sTNF-R1 and TGF-β1 compared to non cirrhotic controls. Among cirrhotic patients impairment of all cytokines were more marked in advanced liver disease. Finally, sTNF-R1and leptin correlated with IR. These findings suggest that IGT and DM may be causally implicated with liver inflammation process.

Aims. To define the prevalence and clinical characteristics of glucose metabolism disorders (GMD) in patients with compensated liver cirrhosis (LC).Material and methods. Fasting plasma glucose (FPG) levels were measured to 130 patients with clinically stable LC. Oral glucose tolerance tests (OGTT) and fasting plasma insulin determinations were performed to patients with normal FPG. Insulin resistance (IR) was calculated with HOMA2-IR index. GMD were classified according to FPG and OGTT tests results and to the chronologic relation between diagnosis of diabetes mellitus (DM) and LC as follows: type-2 DM (T2DM), hepatogenous diabetes (HD) and impaired glucose tolerance. Patients from all groups were compared.Results. The prevalence of GMD were as follows: T2DM in 25 patients (19.2%, 95% CI 12.5-25.9), HD in 28 (21.5%, 95% CI 14.5-28.5) and IGT in 36 (38.5%, 95% CI 30.1-46.7). The total of patients with GMD was 79.2% (95% CI 72.3-86.1). In 41% of cases GMD were subclinical and 48.7% of patients had IR. Patients with T2DM had a higher number of variables with significant differences compared with the other groups (more marked compared to the patients without GMD). The only differences between the patients with T2DM and HD were hypercreatininemia: 1.14 ± 0.53 vs. 0.84 ± 0.22 mg/dL (p = 0.005) and family history of DM: 8 (32%) vs. 2 (7%) (p = 0.02).Conclusion. Almost 80% of patients with compensated LC had GMD. Half of them were subclinical. The patients with T2DM had marked clinical differences compared to patients from the other groups, particularly renal impairment.

Background. Clinical and endoscopic features of cirrhotic patients with nonvariceal upper gastrointestinal bleeding (NVUGIB) have been rarely reported and clinical outcomes and predictors of mortality have not been evaluated.Aims. 1) To describe the clinical features; 2) To define the clinical outcomes; and 3) To identify the predictors of in-hospital mortality of cirrhotic patients with NVUGIB.Methods. One hundred sixty cirrhotic patients with NVUGIB were prospectively studied. Clinical features, endoscopic findings, clinical outcomes and in-hospital mortality rate were studied. Predictors of death were identified by means of univariate and multiple logistic regression analysis.Results. The mean age was 56.5 ± 14.4, male gender prevailed. Alcohol was the most frequent etiology. Hemodynamic instability was reported in 29.4%. Mean serum hemoglobin was 9.5 ± 3.3 g/dL and blood transfusions were required in 59.4%. Gastroduodenal ulcers were the most frequent source of bleeding (50.6%). In endoscopy “high-risk” bleeding stigmata (HRBS) at the ulcer base were found in 53.1%. All patients with HRBS received endoscopic treatment. Rebleeding occurred in 3 patients (1.9%) and mortality was of 13.8%. By univariate analysis: Cryptogenic etiology, BUN, hypoalbuminemia, active bleeding at ulcer base, and endoscopic treatment were predictors of mortality. However, only cryptogenic etiology, hypoalbuminemia and active bleeding at ulcer base were independent predictors of death in multivariate analysis.Conclusions. Gastroduodenal ulcers as a source of NVUGIB are frequent in cirrhotic patients. They were severe; half of them had HRBS, and required frequently endos-copic treatment. In-hospital mortality of these patients seemed to be greater than that of non-cirrhotic patients, and it was significantly related to cryptogenic etiology of cirrhosis, renal dysfunction, severe hepatic failure, and active bleeding ulcers on admission to the hospital.

Background. It has been suggested that DM may reduce survival of patients with liver cirrhosis (LC). Nevertheless only few prospective studies assessing the impact of DM on mortality of cirrhotic patients have been published, none in compensated LC.Aims. (i) to study the impact of DM on mortality and (ii) to identify predictors of death.Methods. Patients with compensated LC with and without DM were studied. Survival was analyzed by the Kaplan-Meier Method. Univariate and multivariate analysis was performed to determine independent predictors of mortality.Results. 110 patients were included: 60 without DM and 50 with DM. Diabetic patients had significantly higher frequency of cryptogenic cirrhosis, anemia, hypoalbuminemia, and hypercreatininemia. They also had significantly higher BMI and Child-Pugh score. The 2.5-years cumulative survival was significantly lower in patients with DM (48 vs. 69%, p < 0.05). By univariate analysis: DM, female gender, serum creatinine > 1.5 mg/dL, Child-Pugh score class C and cryptogenic cirrhosis were significant. However, only serum creatinine > 1.5 mg/dL and Child-Pugh score class C were independent predictors of death.Conclusion: DM was associated with a significant increase in mortality in patients with compensated liver cirrhosis. Serum creatinine > 1.5 mg/dL and Child-Pugh score class C were independent predictors of death.

Diabetes developed as a complication of cirrhosis is known as «hepatogenous diabetes» (HD). Around 30% to 60% of cirrhotic patients suffer from this metabolic disorder. Insulin resistance in muscular, hepatic and adipose tissues as well as hyperinsulinemia, seem to be pathophysiologic bases for HD. An impaired response of the islet β-cells of the pancreas and the hepatic insulin resistance are also contributing factors. Diabetes develops when defective oxidative and nonoxidative muscle glucose metabolism develops. Non-alcoholic fatty liver disease (NAFLD), alcoholic cirrhosis, chronic hepatitis C (CHC), and hemochromatosis are more frequently associated with HD. HD in early cirrhosis stages may be sub clinical. Only insulin resistance and glucose intolerance may be observed. As liver disease advances, diabetes becomes clinically manifest, therefore HD may be considered as a marker for liver function deterioration. HD is clinically different from that of type 2 DM since it is less frequently associated with microangiopathy and patients suffer complications of cirrhosis more frequently as well as increased mortality. Insulin resistance and HD associate to a decrease in the sustained response to antiviral therapy and an increased progression of fibrosis in patients with CHC. Diabetes treatment is complex due to liver damage and hepatotoxicity of oral hypoglycemic drugs that are frequently prescribed to these patients. This paper will review current concepts in relation to the pathopysiolo-gy, the impact on the clinical outcome of cirrhosis, and the therapy of HD. Finally, the role of HD as a risk factor for the occurrence and exacerbation of hepatocel-lular carcinoma (HCC) will also be reviewed.

Aim: The Child Pugh and MELD are good methods for predicting mortality in patients with chronic liver disease. We investigated their performance as risk factors for failure to control bleeding, in-hospital overall mortality and death related to esophageal variceal bleeding episodes. Methods: From a previous collected database, 212 cirrhotic patients with variceal bleeding admitted to our hospital were studied. The predictive capability of Child Pugh and MELD scores were compared using c statistics. Results: The Child-Pugh and MELD scores showed marginal capability for predicting failure to control bleeding (the area under receiver operating characteristics curve (AUROC) values were < 0.70 for both). The AUROC values for predicting inhospital overall mortality of Child-Pugh and MELD score were similar: 0.809 (CI 95%, 0.710 - 0.907) and 0.88 (CI 95% 0.77-0.99,) respectively. There was no significant difference between them (p > 0.05). The AU-ROC value of MELD for predicting mortality related to variceal bleeding was higher than the Child-Pugh score: 0.905 (CI 95% 0.801-1.00) vs 0.794 (CI 95% 0.676 - 0.913) respectively (p < 0.05). Conclusions: MELD and Child-Pugh were not efficacious scores for predicting failure to control bleeding. The Child-Pugh and MELD scores had similar capability for predicting in-hospital overall mortality. Nevertheless, MELD was significantly better than Child-Pugh score for predicting in-hospital mortality related to variceal bleeding.

Transjugular liver biopsy was first reported in 1967. Since then, this technique has been broadly performed in many medical centers around the world. The number of its indications has increased, and by modifying the needles, the quality of the liver tissue sample has improved. The advantage of transjugular biopsy is that it can be performed in patients in whom the use of percutaneous biopsy is contraindicated Indications for transjugular liver biopsy are, precisely, most of the contraindications for percutaneous liver biopsy. This fact increases the number of patients that can benefit from this procedure.In most cases, the procedure is successfully performed. Minor complications may occur in 1% to 15% and major complications (perforation of the hepatic capsule, cholangitis, and intra-peritoneal bleeding) are observed in 1-3% of the cases. Mortality related to the procedure varies form 0.2 to 0.3%.It has been reported that diagnosis yielded by transjugular liver biopsy induced changes of treatment in 50% of patients with an acute hepatic illness, in 62% of the patients with a chronic hepatic illness, and in 87% of the patients with liver transplants. In conclusion, transjugular liver biopsy is a useful procedure in the diagnosis of hepatic diseases. Its success rate is high; it is a very safe procedure because complications and mortality are rare; and it is well tolerated by patients.

Intravenous albumin infusion prevents complications after large-volume paracentesis (LVP), particularly paracentesis-induced circulatory dysfunction (PCD), and improves patient survival. However, albumin is expensive. We compared a low-molecular weight dextran (Dextran-40) with albumin in treating LVP in cirrhotic patients with tense ascites. Sixty-nine cirrhotic patients were included and 96 LVPs were performed. Any repeat punctures on the same patient were at least three months apart. Patients were randomized to receive either i.v. Dextran-40 infusion (Group I, n = 48) or i.v. albumin infusion after LVP (Group II, n = 48). Clinical, biochemical, and hormonal evaluations were done before and after LVP. Patients were followed up for the detection of any recurrence of ascites or complications.The two groups were similar in age, sex, and etiology of cirrhosis, and in the volumes of ascites recovered. Significant decreases in mean arterial pressure were observed in both groups 24 and 48 h after LVP. Urine volumes increased significantly at 24 h in both groups (p < 0.05), but remained high only in Group I. Plasma renin activity and aldosterone concentrations increased in both groups 48 h after LVP, but they were more marked in Group I. Complications developed in 17 % of patients treated with Dextran-40 and in 23 % treated with albumin (p > 0.05). Ascites recurrence rates and survival were similar in the two groups. In conclusion, Dextran-40 was thus not as efficacious as albumin for preventing PCD.