Chinese herbal medicine decreases incidence of hepatocellular carcinoma in diabetes mellitus patients with regular insulin management

BACKGROUND Type 2 diabetes mellitus(DM)is an independent risk factor for hepatocellular carcinoma(HCC),while insulin is a potent mitogen.Identifying a new therapeutic modality for preventing insulin users from developing HCC is a critical goal for researchers.AIM To investigate whether regular herbal medicine use can decrease HCC risk in DM patients with regular insulin control.METHODS We used data acquired from the Taiwan,Chinaese National Health Insurance research database between 2000 and 2017.We identified patients with DM who were prescribed insulin for>3 months.The herb user group was further defined as patients prescribed herbal medication for DM for>3 months per annum during RESULTS We initially enrolled 657144 DM patients with regular insulin use from 2000 to 2017.Among these,46849 patients had used a herbal treatment for DM,and 140547 patients were included as the matched control group.The baseline variables were similar between the herb users and nonusers.DM patients with regular herb use had a 12%decreased risk of HCC compared with the control group[adjusted hazard ratio(aHR)=0.88,95%CI=0.80–0.97].The cumulative incidence of HCC in the herb users was significantly lower than that of the nonusers.Patients with a herb use of>5 years cumulatively exhibited a protective effect against development of HCC(aHR=0.82,P<0.05).Of patients who developed HCC,herb users exhibited a longer survival time than nonusers(aHR=0.78,P=0.0001).Additionally,we report the top 10 herbs and formulas in prescriptions and summarize the potential pharmacological effects of the constituents.Our analysis indicated that Astragalus propinquus(Huang Qi)plus Salvia miltiorrhiza Bunge(Dan Shen),and Astragalus propinquus(Huang Qi)plus Trichosanthes kirilowii Maxim.(Tian Hua Fen)were the most frequent combination of single herbs.Meanwhile,Ji Sheng Shen Qi Wan plus Dan Shen was the most frequent combination of herbs and formulas.CONCLUSION This large-scale retrospective cohort study reveals that herbal medicine may decrease HCC risk by 12%in DM patients with regular insulin use.

Prognostic role of metformin in diabetes mellitus type 2 patients with hepatocellular carcinoma:A systematic review and meta-analysis

BACKGROUND Hepatocellular carcinoma(HCC)is among the commonest malignancies associated with significant cancer-related death.The identification of chemopreventive agents following HCC treatments with the potential to lower the risk of HCC adverse course is intriguing.Metformin,a first-line agent used in the treatment of type 2 diabetes mellitus(T2DM),has been associated with inhibition of HCC growth.AIM To determine whether metformin can prevent adverse events(i.e.,death,tumor progression,and recurrence)after any HCC treatment in T2DM patients.METHODS A systematic review of the published literature was undertaken focused on the role of metformin on outcomes in patients with T2DM and HCC receiving any tumor therapy.A search of the PubMed and Cochrane Central Register of Controlled Trials Databases was conducted.RESULTS A total of 13 studies(n=14886 patients)were included in this review.With regard to the risk of death,a decreased risk was reported in cases receiving metformin,although this decrease was not statistically significant[odds ratio(OR)=0.89,P=0.42].When only patients treated with curative strategies were considered,a more marked correlation between metformin and favorable cases was reported(OR=0.70,P=0.068).When analyzing palliative treatment,there was no statistical significance in terms of the correlation between metformin and favorable cases(OR=0.74,P=0.66).As for the risks of progressive disease and recurrence,no obvious correlation between metformin use and reduced risk was reported.When sub-analyses were performed for patients from different regions,the results for patients from Eastern countries showed a tendency for decreased risk of death in T2DM cases receiving metformin(OR=0.69,P=0.17),but the same was not seen in patients from Western countries(OR=1.19,P=0.31).CONCLUSION Metformin failed to show a marked impact in preventing adverse effects after HCC treatment.A trend was reported in T2DM cases receiving curative therapies in relation to the risk of death,especially in patients from Eastern regions.Great heterogeneity was reported among the different studies.Further large studies are required to definitively clarify the real impact of metformin as a chemopreventive agent for HCC.

Type 2 diabetes mellitus characteristics affect hepatocellular carcinoma development in chronic hepatitis B patients with cirrhosis

BACKGROUND Type 2 diabetes mellitus(T2DM)has been shown to be correlated with hepatocellular carcinoma(HCC)development.However,further investigation is needed to understand how T2DM characteristics affect the prognosis of chronic hepatitis B(CHB)patients.AIM To assess the effect of T2DM on CHB patients with cirrhosis and to determine the risk factors for HCC development.METHODS Among the 412 CHB patients with cirrhosis enrolled in this study,there were 196with T2DM.The patients in the T2DM group were compared to the remaining 216patients without T2DM(non-T2DM group).Clinical characteristics and outcomes of the two groups were reviewed and compared.RESULTS T2DM was significantly related to hepatocarcinogenesis in this study(P=0.002).The presence of T2DM,being male,alcohol abuse status,alpha-fetoprotein>20ng/mL,and hepatitis B surface antigen>2.0 log IU/mL were identified to be risk factors for HCC development in the multivariate analysis.T2DM duration of more than 5 years and treatment with diet control or insulin±sulfonylurea significantly increased the risk of hepatocarcinogenesis.CONCLUSION T2DM and its characteristics increase the risk of HCC in CHB patients with cirrhosis.The importance of diabetic control should be emphasized for these patients.

An Investigation into Disease Progression and the Correlation between Diabetes Mellitus and Hepatocellular Carcinoma

Diabetes mellitus has been associated with anincreased risk of hepatocellular carcinoma in recent studies ofpatients. At the same time, advanced hepatocellular carcinomaitself can cause glucose intolerance and can aggravate diabetes.Diabetes mellitus inducing hepatocellular carcinoma may resultin changes in the following aspects: dysfunction of organism,endocrine hormone balance and interactions, endothelins andso on. One way, diabetes mellitus may induce hepatocellularcarcinoma through the effects of chemotherapeutics and otheradjuvant drugs. This review outlines the relationship betweendiabetes mellitus and the risk of hepatocellular carcinoma as wellas treatments for hepatocellular carcinoma, which may be helpfulfor clinicians.

Diabetes mellitus and hepatocellular carcinoma:Comparison of Chinese patients with and without HBV-related cirrhosis

AIM:To determine the role of diabetes mellitus(DM) and other associated factors in Chinese hepatocellular carcinoma(HCC) patients with cirrhosis,compared with those HCC patients without cirrhosis,in the single setting of hepatitis B virus(HBV) infection,after other known concomitant diseases were excluded.METHODS:A total of 482 patients,treated at the China-Japan Friendship Hospital,Ministry of Health(Beijing,China),in the period January 2003 to June 2009,and with a hospital discharge diagnosis of HCC,were included.Demographic,clinical,laboratory,metabolic and instrumental features were analyzed.RESULTS:Of the total,310 patients were diagnosed with HBV infection and,following the inclusion and exclusion criteria,224 were analyzed,including 122 patients(54.5%) with cirrhosis(the case group) and 102 patients without cirrhosis(the control group).Twentyseven patients(12.1%) were diabetic,including 19 in the case group and 8 in the control group(19/122=15.6% vs 8/102=7.8%,P=0.077).Thirty-one possible relevant parameters were compared by univariate analysis,and 9 variables were selected for multivariable analysis,including DM(P=0.077),past history of HBV infection(P=0.005),total bilirubin(P<0.001),albumin level(P<0.001),international normalized ratio(INR)(P<0.001),alanine aminotransferase(P=0.050),platelet(P<0.001),total cholesterol(P= 0.047),and LDL cholesterol(P=0.002) levels.Diabetes showed a statistical difference by multivariable analysis [odds ratio(OR) 4.88,95% confidence interval(CI):1.08-21.99,P=0.039],although no significant difference was found in univariate analysis.In addition,three cirrhosis-related parameters remained statistically different,including INR(OR 117.14,95% CI:4.19-3272.28,P=0.005),albumin(OR 0.89,95% CI:0.80-0.99,P=0.027),and platelet count(OR 0.992,95% CI:0.987-0.999,P=0.002).CONCLUSION:Besides the three cirrhosis-related parameters,DM was found to be the sole independent factor associated with HCC in patients with HBV-related cirrhosis,compared with those without cirrhosis.

Diabetes mellitus: a “true” independent risk factor for hepatocellular carcinoma?

BACKGROUND:Diabetes mellitus(DM)is thought to be associated with an increased risk of hepatocellular carcinoma(HCC)in some published studies.However,can we draw the conclusion that DM is a'true'independent risk factor for HCC based on these references? DATA SOURCES:MEDLINE and PubMed searches were conducted for published studies(between January 1966 and June 2009)to identify relevant articles using the keywords 'diabetes','insulin resistance'and'hepatocellular carcinoma',including'primary liver cancer'.Because of the very limited number of relevant articles most were reviewed. RESULTS:This systematic review was conducted from 4 aspects:(1)the significant synergy between DM,hepatitis virus infection,and heavy alcohol consumption in HCC; (2)the role of DM independently in HCC cases while other identified risk factors were controlled or excluded; (3)obesity,DM,and nonalcoholic fatty liver disease in HCC patients;and(4)the impact of DM for the prognosis or surgical treatment in HCC patients with DM.No consensus has been reached among these studies and it is too early to draw the conclusion that DM is a'true' independent risk factor for HCC. CONCLUSIONS:DM can be regarded as a risk factor for HCC.However,whether DM itself directly predisposes to HCC or whether it is a'true'independent risk factor remains unclear.Related issues should be clarified by more research.

Prognostic role of diabetes mellitus in hepatocellular carcinoma patients after curative treatments:a meta-analysis

BACKGROUND:The prognostic role of diabetes mellitus (DM) coexisting with hepatocellular carcinoma (HCC) remains controversial.To clarify its impact on survival in HCC patients after curative treatments,a meta-analysis was performed.DATA SOURCES:Eligible studies were identified through multiple search strategies in the databases PubMed (MEDLINE),EMBASE,the Cochrane Library and ACP Journal Club between January 1950 and March 2010.Ten studies fulfilled the inclusion criteria,and data were aggregated comparing overall survival and recurrence-free survival in HCC patients according to DM status.RESULTS:The pooled hazard ratios (HRs) estimate for overall survival was 1.34 (95% CI,1.18-1.51;P<0.0001) and for recurrence-free survival was 1.48 (95% CI,1.00-2.18;P<0.0001),showing a worse survival for HCC with coexisting DM.However,the patients with DM had a shorter survival time in HCV-related HCC (HR=1.71;95% CI,1.10-2.66;P=0.016),while HBV-related cases were not significantly different (HR=1.29;95% CI,0.69-2.40;P=0.182).Meanwhile,the coexistence of DM impaired overall survival in HCC patients with a small tumor burden (HR=1.63;95% CI,1.25-2.12;P<0.0001).CONCLUSION:HCC patients with coexisting DM have a shorter survival time and a higher risk for tumor recurrence after curative treatments,while the precise value should be defined in more clinical trials with consistent methodology,especially prospective studies.

Potential role of diabetes mellitus in the progression of cirrhosis to hepatocellular carcinoma:a cross-sectional case-control study from Chinese patients with HBV infection

BACKGROUND: Diabetes mellitus (DM) is regarded as a new risk factor for hepatocellular carcinoma (HCC), but few studies have focused on the potential role of DM in the progression of cirrhosis to HCC as well as in patients with simple HBV infection. METHODS: A cohort of 1028 patients, treated at our hospital and with a hospital discharge diagnosis of HCC and/or cirrhosis, was screened. Among them, 558 were diagnosed with chronic HBV infection and 370 were analyzed statistically according to the diagnostic, inclusion and exclusion criteria. The demographic, clinical, metabolic, virological, biochemical, radiological and pathological features were analyzed and the multivariate logistic regression model was used to determine the potential role of DM. RESULTS: In 248 cirrhotic patients, 76 were diabetic and their mean duration of DM was 4.6 years. In 122 HCC patients with cirrhosis, 25 were diabetic and their mean duration of DM was 4.4 years. Univariate analysis showed that compared with cirrhotic patients, the HCC patients had a higher percentage in males (P=0.001), a lower percentage in DM patients (P=0.039), a higher percentage in cigarette smokers (P=0.005), a higher percentage in patients with AFP】400 ng/mL (P【0.001), higher values of white blood cells (P【0.001), hemoglobin (P【0.001) and platelet (P【0.001), increased levels of ALT (P【0.001) and GGT (P【0.001), higher total bilirubin (P=0.018) and albumin levels (P【0.001), and a lower international normalized ratio (P【0.001). Multivariate logistic regression analysis showed that DM was anindependent associated factor for HCC [odds ratio (OR)=0.376; 95% CI, 0.175-0.807; P=0.012]. Even after the HCC patients were restricted to those with decompensated cirrhosis and compared with decompensated cirrhotic patients, the similar result was observed (OR=0.192; 95% CI, 0.054-0.679; P=0.010). CONCLUSIONS: DM is an independent factor in the progression of cirrhosis to HCC, but the role may be contrary to our current viewpoint. To clarify the causal relationship of DM and HCC, prospective and experimental studies are required.

Diabetes mellitus and metformin in hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is the leading cause of cancer-related death worldwide. Diabetes mellitus, a risk factor for cancer, is also globally endemic. The clinical link between these two diseases has been the subject of investigation for a century, and diabetes mellitus has been established as a risk factor for HCC. Accordingly, metformin, a first-line oral anti-diabetic, was first proposed as a candidate anti-cancer agent in 2005 in a cohort study in Scotland. Several subsequent large cohort studies and randomized controlled trials have not demonstrated significant efficacy for metformin in suppressing HCC incidence and mortality in diabetic patients; however, two recent randomized controlled trials have reported positive data for the tumor-preventive potential of metformin in non-diabetic subjects. The search for biological links between cancer and diabetes has revealed intracellular pathways that are shared by cancer and diabetes. The signal transduction mechanisms by which metformin suppresses carcinogenesis in cell lines or xenograft tissues and improves chemoresistance in cancer stem cells have also been elucidated. This review addresses the clinical and biological links between HCC and diabetes mellitus and the anti-cancer activity of metformin in clinical studies and basic experiments.

Increased international normalized ratio level in hepatocellular carcinoma patients with diabetes mellitus

AIM: To determine the association of diabetes mellitus (DM) and international normalized ratio (INR) level in hepatocellular carcinoma (HCC) patients. METHODS: Our present study included 375 HCC patients who were treated at the China-Japan Friendship Hospital, Ministry of Health (Beijing, China), in the period from January 2003 to April 2012, and with a hospital discharge diagnosis of HCC. The demographic, clinical, laboratory, metabolic and instrumental features were analyzed. χ2 test, Student's t test and Mann-Whitney U test were used to compare the differences between HCC patients with and without DM. Unconditional multivariable logistic regression analysis was used to determine the association of DM and INR level in HCC patients. A sub-group analysis was performed to assess the effect of liver cirrhosis or hepatitis B virus (HBV) infection on the results. The Pearson correlation test was used to determine the relationship between INR level and fasting glucose. In addition, association between diabetes duration, and diabetes treatment and INR level was determined considering the potentially different effects. RESULTS: Of the total, 63 (16.8%) patients were diabetic (diabetic group) and 312 (83.2%) patients were diagnosed without diabetes (non-diabetic group). Their mean age was 56.4 ± 11.0 years and 312 (83.2%) patients were male. Compared with patients without DM, the HCC patients with diabetes were older (59.5 ± 10.3 vs 55.8 ± 11.1, P=0.015), had a lower incidence of HBV infection (79.4% vs 89.1%, P=0.033), had increased levels of systolic blood pressure (SBP) (133 ± 17 vs 129 ± 16 mmHg, P=0.048) and INR (1.31 ± 0.44 vs 1.18 ± 0.21, P=0.001), had lower values of hemoglobin (124.4 ± 23.9 vs 134.2 ± 23.4, P=0.003) and had a platelet count (median/interquartile-range: 113/64-157 vs 139/89-192, P=0.020). There was no statistically significant difference in the percentages of males, overweight or obesity, drinking, smoking, cirrhosis and Child classification. After controlling for the confounding effects of age, systolic blood pressure, hemoglobin, platelet count and HBV infection by logistic analyses, INR was shown as an independent variable [odds ratio (OR)=3.650; 95%CI: 1.372-9.714, P=0.010]. Considering the effect of liver cirrhosis on results, a sub-group analysis was performed and the study population was restricted to those patients with cirrhosis. Univariate analysis showed that diabetic patients had a higher INR than non-diabetic patients (1.43 ± 0.51 vs 1.25 ± 0.23, P=0.041). After controlling for confounding effect of age, SBP, hemoglobin, platelet count and HBV infection by logistic analyses, INR level remained as the sole independent variable (OR=5.161; 95%CI: 1.618-16.455, P=0.006). No significant difference in the relationship between INR level and fasting glucose was shown by Pearson test (r=0.070, P=0.184). Among the 63 diabetic patients, 35 (55.6%) patients had been diagnosed with DM for more than 5 years, 23 (36.5%) received oral anti-diabetic regimens, 11 (17.5%) received insulin, and 30 (47.6%) reported relying on diet alone to control serum glucose levels. No significant differences were found for the association between DM duration/treatment and INR level, except for the age at diabetes diagnosis. CONCLUSION: The INR level was increased in HCC patients with DM and these patients should be monitored for the coagulation function in clinical practice.

Molecular pathological epidemiology in diabetes mellitus and risk of hepatocellular carcinoma

Molecular pathological epidemiology(MPE) is a multidisciplinary and transdisciplinary study field,which has emerged as an integrated approach of molecular patho-logy and epidemiology,and investigates the relationship between exogenous and endogenous exposure factors,tumor molecular signatures,and tumor initiation,progression,and response to treatment.Molecular epidemiology broadly encompasses MPE and conventional-type molecular epidemiology.Hepatocellular carcinoma(HCC) is the third most common cause of cancer-associated death worldwide and remains as a major public health challenge.Over the past few decades,a number of epidemiological studies have demonstrated that diabetes mellitus(DM) is an established independent risk factor for HCC.However,how DM affects the occurrence and development of HCC remains as yet unclearly understood.MPE may be a promising approach to investigate the molecular mechanisms of carcinogenesis of DM in HCC,and provide some useful insights for this pathological process,although a few challenges must be overcome.This review highlights the recent advances in this field,including:(1) introduction of MPE;(2) HCC,risk factors,and DM as an established independent risk factor for HCC;(3) molecular pathology,molecular epidemiology,and MPE in DM and HCC;and(4) MPE studies in DM and risk of HCC.More MPE studies are expected to be performed in future and I believe that this field can provide some very important insights on the molecular mechanisms,diagnosis,personalized prevention and treatment for DM and risk of HCC.

Diabetes mellitus may affect the long-term survival of hepatitis B virus-related hepatocellular carcinoma patients after liver transplantation

AIM to determine whether diabetes mellitus(DM) affects prognosis/recurrence after liver transplantation(Lt) for hepatitis B virus(HBV)-related hepatocellular carcinoma(HCC). METHODS A retrospective study was conducted between January 2000 and August 2013 on 1631 patients with HBV-related HCC who underwent Lt with antiviral prophylaxis. Patient data were obtained from the China Liver transplant Registry(https://www.cltr.org/). to compare the outcomes and tumor recurrence in the HBV-related HCC patients with or without DM, statistical analyses were conducted using χ2 tests, Mann-Whitney tests, the Kaplan-Meier method, log-rank tests and multivariate step-wise Cox regression analysis. RESULTS Univariate analysis of 1631 patients who underwent Lt found overall 1-, 3- and 5-year survival rates of 79%, 73% and 71% respectively in the DM patients, and 84%, 78% and 76% in the non-DM patients respectively. Overall survival rate differences after Lt between the two groups were significant(P = 0.041), but recurrence-free survival rates were not(P = 0.096). By stratified analysis, the overall survival rates in DM patients for age > 50 years(P = 0.002), the presence of vascular invasion(P = 0.096), tumors ≤ 3 cm(P = 0.047), two to three tumor nodules(P = 0.007), Child-Pugh grade B(P = 0.018), and preLt alanine aminotransferase levels between 40 and 80 IU/L(P = 0.017) were significantly lower than in non-DM patients. Additionally, serum α-fetoprotein level > 2000 ng/m L(P = 0.052) was associated with a significant survival difference trend between DM and non-DM patients. Multivariate analysis showed that the presence of DM(P < 0.001, HR = 1.591; 95%CI: 1.239-2.041) was an independent predictor associated with poor survival after Lt. CONCLUSION HBV-related HCC patients with DM have decreased long-term overall survival and poor Lt outcomes. Prevention strategies for HCC patients with DM are recommended.

Glycated hemoglobin and antidiabetic strategies as risk factors for hepatocellular carcinoma

AIM: To evaluate the relationship between glycemic control [assessed by glycated hemoglobin (HbA1c)], antidiabetic therapies and the risk of hepatocellular carcinoma (HCC).METHODS: We recruited 465 patients with HCC, 618 cases with liver cirrhosis and 490 controls with no liver disease. Among subjects with type 2 diabetes mellitus (DM2), the associations between the antidiabetic strategies and HbA1c level with HCC were determined through 2 series of multivariate logistic regression models using cirrhotic patients and controls as comparison groups. RESULTS: DM2 prevalence was 31.2% in patients with HCC, 23.2% in cirrhotic patients and 12.6% in controls (P < 0.0001). In 86% of study subjects, DM2 had been diagnosed for more than 1 year before the HCC diagnosis. HCC patients with DM2 had a 1.52.5fold increased risk of liver cancer. The HbA1c mean levels were signif icantly higher in DM2 patients with HCC than in cirrhoticand control DM2 patients. Antidiabetic treatment with metformin was more common among cirrhotic and control DM2 subjects than among cases with HCC. In both series of multivariate analyses, treatment with metformin signif icantly reduced the risk of HCC by more than 80% compared with sulphonylureas and insulin therapy. No signif icant differences were seen between sulphonylureas and insulin treatment. Elevated HbA1c levels were positively related to the risk for HCC in diabetic patients, with a 26%50% increase in risk for each 1% increase in HbA1c values.CONCLUSION: In patients with preexisting DM2, the risk of HCC is positively associated with poor chronic glycemic control and significantly decreased by metformin therapy.

Clinical features of nonalcoholic fatty liver disease-associated hepatocellular carcinoma

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis, is a recognized risk factor for hepatocellular carcinoma (HCC). However, detailed analysis of the clinical features in patients with NAFLD and their association with HCC is lacking. This study aimed to update the clinical features of patients with NAFLD-associated HCC. DATA SOURCES: The clinical data of patients with NAFLD- associated HCC from 25 studies published between 1990 and 2010 in the Pubmed database were comprehensively reviewed. RESULTS: In a total of 169 patients with NAFLD-associated HCC, 72.8% were male. The median age at abnormal liver function tests and diagnosis of NAFLD and HCC was 60, 64 and 67 years, respectively. Most patients were obese (75%) and diabetic (59.8%), 32.3% had dyslipidemia, and 53% had hypertension. Nearly all patients (98.6%, 71/72) were complicated with at least one metabolic disorder. The majority (76%) of the HCC patients had a solitary tumor nodule, with the tumor size ranging from 0.8 to 20 cm in diameter (mean 3.4 cm). Most (61.1%) of the patients had moderately-differentiated HCC. In 40.2% of the patients, HCC occurred in the absence of cirrhosis. Among 130 patients, 57.7% underwent hepatectomy and 14.6% received liver transplantation. The mean follow-up of the treated patients for 25 months showed that 32.4% (24/74) died and 18.8% (9/48) had recurrence. CONCLUSIONS: Patients with NAFLD-associated HCC are usually accompanied with metabolic disorders. Regular surveillance in patients with NAFLD for HCC is necessary, especially for elderly men with metabolic syndrome.

Type 2 diabetes mellitus increases liver transplant-free mortality in patients with cirrhosis: A systematic review and meta-analysis

BACKGROUND The impact of type 2 diabetes mellitus(T2DM)on the prognosis and complications of liver cirrhosis is not fully clarified.AIM To clarify the mortality and related risk factors as well as complications in cirrhotic patients with T2DM.METHODS We searched PubMed,EMBASE,and the Cochrane Library from their inception to December 1,2020 for cohort studies comparing liver transplant-free mortality,hepatocellular carcinoma(HCC),ascites,spontaneous bacterial peritonitis(SBP),variceal bleeding,and hepatic encephalopathy(HE)in cirrhotic patients with vs without T2DM.Odds ratios(ORs)were combined by using fixed-effects or random-effects models with RevMan software.RESULTS The database search generated a total of 17 cohort studies that met the inclusion criteria.Among these studies,eight reported the risk of mortality,and eight reported the risk of HCC.Three studies provided SBP rates,and two documented ascites rates.Four articles focused on HE rates,and three focused on variceal bleeding rates.Meta-analysis indicated that T2DM was significantly associated with an increased risk of liver transplant-free mortality[OR:1.28,95%confidence intervals(CI):1.16-1.41,P<0.0001]and HCC incidence(OR:1.82,95%CI:1.32-2.51,P=0.003).The risk of SBP was not significantly increased(OR:1.1695%CI:0.86-1.57,P=0.34).Additionally,T2DM did not significantly increase HE(OR:1.3195%CI:0.97-1.77,P=0.08),ascites(OR:1.1195%CI:0.84-1.46,P=0.46),and variceal bleeding(OR:1.34,95%CI:0.99-1.82,P=0.06).CONCLUSION The findings suggest that cirrhotic patients with T2DM have a poor prognosis and high risk of HCC.T2DM may not be associated with an increased risk of SBP,variceal bleeding,ascites,or HE in cirrhotic patients with T2DM.

Nonalcoholic fatty liver disease, metabolic risk factors, and hepatocellular carcinoma: An open question

Non-alcoholic liver disease(NAFLD) defines liver abnormalities ranging from simple steatosis to nonalcoholic steatohepatitis with or without cirrhosis development, occurring in the absence of significant alcohol consumption, use of teratogenic medication, or hereditary disorders.The association between NAFLD and metabolic syndrome is well documented and widely recognized.Obesity, type 2 diabetes mellitus(T2DM), and dyslipidemia are the most common metabolic risk factors associated with NAFLD.Among the components of metabolic syndrome, current evidence strongly indicates obesity and diabetes as hepatocellular carcinoma(HCC) risk factors.There is also growing evidence that suggests an increased risk of HCC in NAFLD patients, even surpassing other etiologies in some high-income countries.Epidemiologic data demonstrate a parallel rise in prevalence of obesity, diabetes, NAFLD, and HCC.As obesity and its related diseases have steadily afflicted larger populations, HCC incidence is expected to increase in the future.Pathophysiologic mechanisms that underlie NAFLD development and subsequent progression to nonalcoholic steatohepatitis and cirrhosis(insulin resistance and hyperinsulinemia, oxidative stress, hepatic stellate cell activation, cytokine/adipocytokine signaling pathways, and genetic and environmental factors) appear to play a significant role in the development of NAFLD-related HCC.However, a comprehensive view of molecular mechanisms linking obesity, T2 DM, and NAFLD-related HCC, as well as the exact sequence of molecular events, is still not understood in its entirety.Good-quality data are still necessary, and efforts should continue towards better understanding the underlying carcinogenic mechanisms of NAFLD-related HCC.In this paper, we aimed to centralize the most important links supporting these relationships, focusing on obesity, T2 DM, and NAFLD-related HCC, as well as point out the major gaps in knowledge regarding the underlying molecular mechanisms behind them.

Alcohol,postprandial plasma glucose,and prognosis of hepatocellular carcinoma

AIM:To identify factors associated with prognosis of hepatocellular carcinoma(HCC) after initial therapy.METHODS:A total of 377 HCC patients who were newly treated at Katsushika Medical Center,Japan from January 2000 to December 2009 and followed up for > 2 years,or died during follow-up,were enrolled.The factors related to survival were first analyzed in 377 patients with HCC tumor stage T1-T4 using multivariate Cox proportional hazards regression analysis.A similar analysis was performed in 282 patients with tumor stage T1-T3.Additionally,factors associated with the period between initial and subsequent therapy were examined in 144 patients who did not show local recurrence.Finally,214 HCC stage T1-T3 patients who died during the observation period were classified into four groups according to their alcohol consumption and postprandial glucose levels,and differences in their causes of death were examined.RESULTS:On multivariate Cox proportional hazards regression analysis,the following were significantly associated with survival:underlying liver disease stage [non-cirrhosis/Child-Pugh A vs B/C,hazard ratio(HR):0.603,95% CI:0.417-0.874,P = 0.0079],HCC stage(T1/T2 vs T3/T4,HR:0.447,95% CI:0.347-0.576,P < 0.0001),and mean postprandial plasma glucose after initial therapy(< 200 vs ≥ 200 mg/dL,HR:0.181,95% CI:0.067-0.488,P = 0.0008).In T1-T3 patients,uninterrupted alcohol consumption after initial therapy(no vs yes,HR:0.641,95% CI:0.469-0.877,P = 0.0055) was significant in addition to underlying liver disease stage(non-cirrhosis/Child-Pugh A vs B/C,HR:0649,95% CI:0.476-0.885,P = 0.0068),HCC stage(T1 vs T2/T3,HR:0.788,95% CI:0.653-0.945,P = 0.0108),and mean postprandial plasma glucose after initial therapy(< 200 mg/dL vs ≥ 200 mg/dL,HR:0.502,95% CI:0.337-0.747,P = 0.0005).In patients without local recurrence,time from initial to subsequent therapy for newly emerging HCC was significantly longer in the "postprandial glucose within 200 mg/dL group" than the "postprandial glucose > 200 mg/dL group"(log-rank test,P < 0.05),whereas there was no difference in the period between the "non-alcohol group"(patients who did not drink regularly or those who could reduce their daily consumption to < 20 g) and the "continuation group"(drinkers who continued to drink > 20 g daily).Of 214 T1-T3 patients who died during the observation period,death caused by other than HCC progression was significantly more frequent in "group AL"(patients in the continuation and postprandial glucose within 200 mg/dL groups) than "group N"(patients in the non-alcohol and postprandial glucose within 200 mg/dL groups)(P = 0.0016).CONCLUSION:This study found that abstinence from habitual alcohol consumption and intensive care for diabetes mellitus were related to improved prognosis in HCC patients.

Antidiabetic therapy and increased risk of hepatocellular carcinoma in chronic liver disease

AIM:To explore the association between hepatocellular carcinoma(HCC) and type 2 diabetes mellitus, describe the temporal relations between the onset of diabetes and the development of HCC and evaluate the possible effects of antidiabetic therapy on HCC risk.METHODS:We recruited 465 HCC patients, 618 with cirrhosis and 490 control subjects.We evaluated the odds ratio(OR) for HCC by univariate and multivariate analysis.Moreover, OR for HCC in diabetic subjects treated with insulin or sulphanylureas and with metformin were calculated.RESULTS:The prevalence of diabetes mellitus was 31.2% in HCC, 23.3% in cirrhotic patients and 12.7% in the Control group.By univariate and multivariate analysis, the OR for HCC in diabetic patients were respectively 3.12(CI 2.2-4.4, P < 0.001) and 2.2(CI 1.2-4.4, P = 0.01).In 84.9% of cases, type 2 diabetes mellitus was present before the diagnosis of HCC.Moreover, we report an OR for HCC of 2.99(CI 1.34-6.65, P = 0.007) in diabetic patients treated with insulin or sulphanylureas, and an OR of 0.33(CI 0.1-0.7, P = 0.006) in diabetic patients treated with metformin.CONCLUSION:Our study confi rms that type 2 diabetes mellitus is an independent risk factor for HCC and pre-exists in the majority of HCC patients.Moreover, in male patients with type 2 diabetes mellitus, our data shows a direct association of HCC with insulin and sulphanylureas treatment and an inverse relationship with metformin therapy.

First multicenter study for risk factors for hepatocellular carcinoma development in North Africa

AIM:To assess the role of the major risk factors for hepatocellular carcinoma(HCC) development in the western part of North Africa.METHODS:A multicenter case control study was conducted in Tunisia,Morocco and Algeria in collaboration with Pasteur Institutes in these countries.A total of 164 patients with HCC and 250 control subjects without hepatic diseases were included.Prevalences of HBsAg,anti-hepatitis C virus(HCV)and diabetes were assessed.HCV and HBV genotyping were performed for anti-HCV and HBsAg positive patients.RESULTS:The mean age of patients was 62±10 years old for a 1.5 M:F sex ratio.Sixty percent of HCC patients were positive for anti-HCV and 17.9% for HBsAg.Diabetes was detected in 18% of cases.Odd ratio(OR)and 95% confidence intervals(CI) were 32.0(15.8-65.0),7.2(3.2-16.1) and 8.0(3.1 -20.0)for anti-HCV,HBsAg and diabetes respectively.Multivariate analysis indicated that the three studied factors were independent.1b HCV genotype and D HBV genotype were predominant in HCC patients.HCV was the only risk factor significantly associated with an excess of cirrhosis(90% vs 68% for all other risk factors collectively,P=0.00168).Excessive alcohol consumption was reliably established for 19(17.6%) cases among the 108 HCC patients for whom data is available.CONCLUSION:HCV and HBV infections and diabetes are the main determinants of HCC development in North Africa.An active surveillance and secondary prevention programs for patients with chronic hepatitis and nutrition-associated metabolic liver diseases are the most important steps to reduce the risk of HCC in the region.Salah Berkane,Department of Gastroenterology BologhineUniversity Hospital,Bologhine 16090,Algiers。

Hepatocellular carcinoma and type 2 diabetes mellitus: two cases highlighting changes in tumor glycogen content

This article reports two patients with hepatocellular carcinoma(HCC)and type 2 diabetes mellitus(T2DM),who showed marked changes in hepatocellular glycogen content.Periodic acid-Schiff(PAS)-positive and diastase-PAS-negative(glycogen-storing)hepatocytes were detected in both background liver parenchyma and in HCC tissues.In HCC tissues,the number of glycogen-storing cells resembling hepatocytes was considerably reduced and unevenly distributed as compared with hepatocytes in background liver.To be known,changes in hepatocellular glycogen content in T2DM patients have not been previously described.It is hypothesized that the reduction in glycogen content in both patients was likely associated with the emergence of Warburg type of glycolysis.