Adipose tissue is a highly dynamic endocrine tissue and constitutes a central node in the interorgan crosstalk network through adipokines, which cause pleiotropic effects, including the modulation of ...angiogenesis, metabolism, and inflammation. Specifically, digestive cancers grow anatomically near adipose tissue. During their interaction with cancer cells, adipocytes are reprogrammed into cancer-associated adipocytes and secrete adipokines to affect tumor cells. Moreover, the liver is the central metabolic hub. Adipose tissue and the liver cooperatively regulate whole-body energy homeostasis via adipokines. Obesity, the excessive accumulation of adipose tissue due to hyperplasia and hypertrophy, is currently considered a global epidemic and is related to low-grade systemic inflammation characterized by altered adipokine regulation. Obesity-related digestive diseases, including gastroesophageal reflux disease, Barrett's esophagus, esophageal cancer, colon polyps and cancer, non-alcoholic fatty liver disease, viral hepatitis-related diseases, cholelithiasis, gallbladder cancer, cholangiocarcinoma, pancreatic cancer, and diabetes, might cause specific alterations in adipokine profiles. These patterns and associated bases potentially contribute to the identification of prognostic biomarkers and therapeutic approaches for the associated digestive diseases. This review highlights important findings about altered adipokine profiles relevant to digestive diseases, including hepatic, pancreatic, gastrointestinal, and biliary tract diseases, with a perspective on clinical implications and mechanistic explorations.
Aim
The response rate to pioglitazone and the predictive factors for its effects on improving liver biochemistry in patients with steatotic liver disease (SLD) remain elusive, so we aimed to ...investigate these issues.
Methods
A 3‐year prospective cohort study of 126 Taiwanese patients with SLD treated with pioglitazone (15‐30 mg/day) was conducted. Phospholipase domain‐containing protein 3 I148M rs738409, methylenetetrahydrofolate reductase rs1801133, aldehyde dehydrogenase 2 (ALDH2) rs671 and lipoprotein lipase rs10099160 single nucleotide polymorphisms were assessed in the patients.
Results
Of 126 patients, 78 (61.9%) were men, and the mean and median ages were 54.3 and 56.5 years, respectively. Pioglitazone responders were defined as those with decreased alanine aminotransferase (ALT) levels at 6 months post‐treatment, and 105 (83.3%) patients were responders. Compared with non‐responders, responders were more frequently women and had higher baseline ALT levels. The proportion of patients with the ALDH2 rs671 GG genotype was lower among responders (38.6% vs. 66.6%, p = .028). Female sex odds ratio (OR): 4.514, p = .023 and baseline ALT level (OR: 1.015, p = .046; cut‐off level: ≥82 U/L) were associated with pioglitazone response. Among responders, the liver biochemistry and homeostasis model assessment of insulin resistance improved from 6 to 24 months post‐treatment. The total cholesterol levels decreased within 6 months, while increases in high‐density lipoprotein cholesterol levels and decreases in triglyceride levels and fibrosis‐4 scores were noted only at 24 months post‐treatment. The 2‐year cumulative incidences of cardiovascular events, cancers and hepatic events were similar between responders and non‐responders.
Conclusions
Regarding liver biochemistry, over 80% of Taiwanese patients with SLD had a pioglitazone response, which was positively associated with female sex and baseline ALT levels. Insulin resistance improved as early as 6 months post‐treatment, while liver fibrosis improvement was not observed until 24 months post‐treatment. The link between the pioglitazone response and the ALDH2 genotype warrants further investigation.
The protective effect of statins in cirrhosis and its decompensation in chronic hepatitis B (CHB) patients remains unknown.
We conducted a population-based cohort study using data from the Taiwanese ...National Health Insurance Research Database from 1997 to 2009. A total of 298,761 CHB patients were identified. CHB patients using statins (n=6,543; defined as ≥28 cumulative defined daily doses (cDDD)) and a 1:1 ratio propensity score and inception point (the date of first use of statins)-matched non-statins (<28 cDDD) were followed up from the inception point until the development of cirrhosis or its decompensation or until withdrawal from insurance or December 2009.
After adjustment for competing mortality, CHB patients using statins had a significantly lower cumulative incidence of cirrhosis (relative risk)=0.433; 95% confidence interval (CI)=0.344-0.515; modified log-rank test, P<0.001) and decompensated cirrhosis (relative risk=0.468; 95% CI=0.344-0.637; P<0.001) compared with patients not using statins. After adjustment for age, gender, comorbidity index, hypertension, diabetes, hyperlipidemia, hepatocellular carcinoma, obesity, non-alcoholic fatty liver disease, aspirin use, diabetes medication, CHB treatment, non-statin lipid-lowering drugs, and triglyceride lipid-lowering drugs using the Cox proportional hazard model, statins were still an independent protector against cirrhosis (adjusted hazard ratio (AHR)=0.512; 95% CI=0.413-0.634; P<0.001) and its decompensation (AHR=0.534; 95% CI=0.433-0.659; P<0.001). The AHRs for cirrhosis were 0.467 and 0.200, and the AHRs for decompensated cirrhosis were 0.611 and 0.231 with 91-365 and >365 cDDD of statins, respectively.
CHB patients who receive statin therapy have a dose-dependent reduction in the risk of cirrhosis and its decompensation.
Nonalcoholic fatty liver disease (NAFLD) is a serious liver disorder associated with the accumulation of fat and inflammation. The objective of this study was to determine the gut microbiota ...composition that might influence the progression of NAFLD. Germ-free mice were inoculated with feces from patients with nonalcoholic steatohepatitis (NASH) or from healthy persons (HL) and then fed a standard diet (STD) or high-fat diet (HFD). We found that the epididymal fat weight, hepatic steatosis, multifocal necrosis, and inflammatory cell infiltration significantly increased in the NASH-HFD group. These findings were consistent with markedly elevated serum levels of alanine transaminase, aspartate transaminase, endotoxin, interleukin 6 (IL-6), monocyte chemotactic protein 1 (Mcp1), and hepatic triglycerides. In addition, the mRNA expression levels of Toll-like receptor 2
), Toll-like receptor 4
, tumor necrosis factor alpha (
),
, and peroxisome proliferator-activated receptor gamma (
) significantly increased. Only abundant lipid accumulation and a few inflammatory reactions were observed in group HL-HFD. Relative abundance of
and
shifted in the HFD-fed mice. Furthermore, the relative abundance of
was the highest in group NASH-HFD. Nevertheless, obesity-related
were significantly upregulated in HL-HFD mice. Our results revealed that the gut microbiota from NASH Patients aggravated hepatic steatosis and inflammation. These findings might partially explain the NAFLD progress distinctly was related to different compositions of gut microbiota.
The effect of diabetes on cirrhosis, its decompensation, and their time relationship in chronic hepatitis C (CHC) patients remains unclear. We conducted a nation‐wide cohort study by using the ...Taiwanese National Health Insurance Research Database, which is comprised of data from >99% of the entire population. Among having randomly sampled 1 million enrollees, 6,251 adult CHC patients were identified from 1997 to 2009. Diabetes was defined as new onset in CHC patients who were given the diagnosis in the years 1999‐2003, but not in 1997‐1998. The cohorts of CHC with new‐onset diabetes (n = 424) and nondiabetes (n = 1,708) were followed up from inception point in diabetes and from year 1999 in the nondiabetes cohort until development of cirrhosis or its decompensation, withdrawal from insurance, or December 2009. Kaplan‐Meier's survival analysis showed a significantly higher cumulative incidence of cirrhosis (relative risk RR = 1.53; 95% confidence interval CI = 1.11‐2.11; log‐rank test; P < 0.001) and decompensated cirrhosis (RR = 2.01; 95% CI = 1.07‐3.79; log‐rank test; P < 0.001) among patients with new‐onset diabetes, as compared to those without. After adjustment for age, gender, CHC treatment, diabetes treatment, hepatocellular carcinoma, comorbidity index, hypertension, hyperlipidemia, and obesity by Cox's proportional hazard model, diabetes was still an independent predictor for cirrhosis (hazard ratio HR = 2.505; 95% CI = 1.609‐3.897; P < 0.001) and its decompensation (HR = 3.560; 95% CI = 1.526‐8.307; P = 0.003). Conclusion: CHC patients who develop diabetes are at an increased risk of liver cirrhosis and its decompensation over time. (Hepatology 2014;60:807–814)
The impacts of patatin‐like phospholipase domain‐containing protein 3 (PNPLA3) I148M‐rs738409, methylenetetrahydrofolate reductase (MTHFR) Ala222Val‐rs1801133, and aldehyde dehydrogenase 2 (ALDH2) ...Glu504Lys‐rs671 on the outcomes of Taiwanese patients with steatotic liver disease (SLD) have remained elusive. An 8‐year prospective cohort study of patients with (n = 546) and without (n = 580) SLD (controls) was undertaken in a Taiwanese tertiary care center. The 546 SLD patients comprised 306 (56.0%) men and 240 (44.0%) women with mean ages of 53.3 and 56.4 years, respectively. Compared with the controls, SLD patients had an increased frequency of the PNPLA3 I148M‐rs738409 GG genotype (25.5 vs. 5.9%, p = 0.001). Among the SLD patients, 236 (43.1%) suffered cardiovascular events, 52 (9.5%) showed extrahepatic cancers, 13 (2.38%) experienced hepatic events, including hepatocellular carcinoma (n = 3, 0.5%) and liver cirrhosis (n = 8, 1.47%), and none died. The Fibrosis‐4 (FIB‐4) scores were associated with extrahepatic cancer (hazard ratio HR 1.325; 95% confidence interval CI, 1.038–1.691) and cirrhosis development (HR 1.532; 95% CI, 1.055–2.224), and the PNPLA3 I148M‐rs738409 G allele (β = 0.158, 95% CI, 0.054–0.325) was associated with the FIB‐4 score. Stratified analyses showed that the impact of the FIB‐4 score on extrahepatic cancer development was evident only in SLD patients with the PNPLA3 I148M‐rs738409 GG genotype (HR 1.543; 95% CI, 1.195–1.993) and not in patients with the GC or CC genotype. Moreover, the ALDH2 Glu504Lys‐rs671 G allele had a dose‐dependent effect on alcoholism, and the MTHFR and ALDH2 genotypes were not significantly associated with SLD patient outcomes. In conclusion, special vigilance should be exercised for emerging extrahepatic cancer in SLD patients with the PNPLA3 I148M‐rs738409 GG genotype and high FIB‐4 scores.
Hepatic fibrosis is a major cause of morbidity and mortality worldwide, as it ultimately leads to cirrhosis, which is estimated to affect up to 2% of the global population. Hepatic fibrosis is ...confirmed by liver biopsy, and the erroneous nature of this technique necessitates the search for noninvasive alternatives. However, current biomarker algorithms for hepatic fibrosis have many limitations. Given that the liver is the largest organ and a major metabolic hub in the body, probing the metabolic signature of hepatic fibrosis holds promise for the discovery of new markers and therapeutic targets. Regarding individual metabolic pathways, accumulating evidence shows that hepatic fibrosis leads to alterations in carbohydrate metabolism, as aerobic glycolysis is aggravated in activated hepatic stellate cells (HSCs) and the whole fibrotic liver; in amino acid metabolism, as Fischer's ratio (branched-chain amino acids/aromatic amino acids) decreases in patients with hepatic fibrosis; and in lipid metabolism, as HSCs lose vitamin A-containing lipid droplets during transdifferentiation, and cirrhotic patients have decreased serum lipids. The current review also summarizes recent findings of metabolic alterations relevant to hepatic fibrosis based on systems biology approaches, including transcriptomics, proteomics, and metabolomics in vitro, in animal models and in humans.
In real-world clinical practice, the acceptance of anticoagulation therapy in the management of portal vein thrombosis (PVT) in patients with cirrhosis is limited by the fear of an increased bleeding ...risk. Additionally, accumulating evidence indicates that spontaneous recanalization of PVT may occur in the absence of antithrombotic treatment. Therefore, risk stratification based on outcomes in such patients is crucial for determining a therapeutic strategy. In this paper, we draw attention to the distinct clinical entity, "transient PVT" by introducing two cases with PVT that spontaneously recanalized in the absence of antithrombotic treatment. We reviewed the available data regarding the probability of and predictors for spontaneous recanalization of PVT. Available data suggest singling out transient thrombosis in the natural history of PVT in patients with cirrhosis because of its prognostic and management implications.
Chronic viral hepatitis is a major global public health problem. The guidelines suggest the long-term performance of regular ongoing liver examinations to monitor liver inflammation and screen for ...hepatocellular carcinoma. However, the effects of regular liver examinations on health-related quality of life (HRQoL) have not been adequately evaluated. Therefore, this study evaluated the effects of regular ongoing examinations on the quality of life of patients with hepatitis. A cross-sectional study was conducted from October to December 2016 in four hospitals in northern Taiwan. A hepatitis pay-for-performance (P4P) program was launched in 2010 to ensure that hepatitis patients have regular ongoing liver examinations. The study group consisted of patients who joined and stayed in the program for more than one year. The study assessed HRQoL utilizing the five-level version of the EuroQol-5 Dimension (EQ-5D-5L) and the EuroQoL visual analog scale (EQ-VAS). The responses for the EQ-5D-5L in hepatitis patients were transformed into the EQ-5D index according to the Taiwanese population's value set. Sociodemographic and clinical characteristics were collected by questionnaire, and descriptive statistics were presented. A two-part model and generalized linear model with a Poisson distribution and a log link function, respectively, were used to examine the associations of the EQ-5D index and EQ-VAS score with participation in the hepatitis P4P program. We applied propensity score weighting with inverse probability weighting to control for selection bias. In all, 508 patients (aged 57.6 + or - 11.6 years; 60.8% male) were enrolled in this study. The mean (standard deviation, SD) reported EQ-5D index and EQ-VAS scores were 0.93 (0.12) and 75.1 (13.8), and the median (interquartile range, IQR) values were 1 (0.108) and 80 (15), respectively. The study group had a moderately significantly higher EQ-VAS score (mean ratio = 1.029, P < 0.001). However, the differences in the EQ-5D index scores between the study and control groups were not significant.
Variations at the six nucleotides −3279 (T > G), −53 (ATA6TAA > ATA7TAA), 211 (G > A), 686 (C > A), 1091 (C > T), and 1456 (T > G) in the UDP‐glucuronosyltransferase 1A1 (UGT1A1) gene were determined ...in 178 Taiwanese patients with Gilbert's syndrome and in 200 healthy adults. Every subject was classified as a genotype depending on variation status of the six nucleotides in the UGT1A1 gene. The UGT1A1 activity for each genotype was calculated and then those genotypes were divided into 10 subgroups (Q1~Q10) according to their UGT1A1 activities, by using 10% as an interval. There were 24 genotypes observed, with UGT1A1 activity ranged 9%~100% of normal. There were two and six subjects with Gilbert's syndrome and none of healthy controls carrying genotypes in the Q1 and Q2 subgroups, respectively. The odds of developing Gilbert's syndrome were significantly higher for subjects carrying genotypes in the Q3, Q4, and Q5 subgroups than for those with genotype in the Q10 subgroup (odds ratios: 240.22, 59.80, and 14.67, respectively, P < .001 for each). Among the 178 patients of Gilbert's syndrome, serum bilirubin value was inversely correlated with UGT1A1 activity (r = −.306, P < .001). The sensitivity was 72.0% and the specificity was 90.5% by using UGT1A1 activity ≦40% of normal as the cut‐off point to distinguish between healthy subjects and patients of Gilbert's syndrome. Our results demonstrate that UGT1A1 activity is certainly a determinate for serum bilirubin value and UGT1A1 activity ≦40% of normal is a proper risk factor for the development of Gilbert's syndrome.
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