The ongoing obesity epidemic and the increasing recognition of metabolic syndrome have contributed to the growing prevalence of nonalcoholic fatty liver disease (NAFLD), the most common form of liver ...disease worldwide. It is imperative to understand the incidence and prevalence of NAFLD as it is associated with a profound economic burden of hospitalizations, including the shifting trends in liver transplantation. The long-term cumulative healthcare cost of NAFLD patients has been shown to be 80% higher than that of non-NAFLD patients. We explore diagnostic challenges in identifying those with NAFLD who have a higher predilection to progress to end-stage liver disease. We aim to assess all-cause and cause-specific mortality as it relates to NAFLD.
Nonalcoholic fatty liver disease(NAFLD) is defined as the presence of hepatic fat accumulation after the exclusion of other causes of hepatic steatosis, including other causes of liver disease, ...excessive alcohol consumption, and other conditions that may lead to hepatic steatosis. NAFLD encompasses a broad clinical spectrum ranging from nonalcoholic fatty liver to nonalcoholic steatohepatitis(NASH), advanced fibrosis, cirrhosis, and finally hepatocellular carcinoma(HCC). NAFLD is the most common liver disease in the world and NASH may soon become the most common indication for liver transplantation. Ongoing persistence of obesity with increasing rate of diabetes will increase the prevalence of NAFLD, and as this population ages, many will develop cirrhosis and end-stage liver disease. There has been a general increase in the prevalence of NAFLD, with Asia leading the rise, yet the United States is following closely behind with a rising prevalence from 15% in 2005 to 25% within 5 years. NAFLD is commonly associated with metabolic comorbidities, including obesity, type Ⅱ diabetes, dyslipidemia, and metabolic syndrome. Our understanding of the pathophysiology of NAFLD is constantly evolving. Based on NAFLD subtypes, it has the potential to progress into advanced fibrosis, end-stage liver disease and HCC. The increasing prevalence of NAFLD with advanced fibrosis, is concerning because patients appear toexperience higher liver-related and non-liver-related mortality than the general population. The increased morbidity and mortality, healthcare costs and declining health related quality of life associated with NAFLD makes it a formidable disease, and one that requires more in-depth analysis.
A new efficient method for the direct alkenylation of chromones via a palladium(II)-catalyzed C–H functionalization reaction was developed. The use of pivalic acid with Cu(OAc)3/Ag2CO3 provided ...superior reactivity in the cross-coupling of chromones with alkene partners. This approach represents a significant advance over the existing two-step method and afforded various 3-vinylchromone derivatives, which are privileged structures in many biologically active compounds and versatile synthetic building blocks.
Background and Aims
In general, physical activity (PA) and nonalcoholic fatty liver disease (NAFLD) have an inverse association. However, studies assessing the impact of the widely accepted Physical ...Activity Guidelines for Americans (PA Guidelines) on NAFLD are lacking.
Approach and Results
We performed a serial, cross‐sectional analysis among adults by using the 2007‐2016 US National Health and Nutrition Examination Survey. NAFLD and advanced fibrosis were defined by using various noninvasive panels. A PA questionnaire assessed the leisure‐time PA, occupation‐related PA, transportation‐related PA, and total sitting time as sedentary behavior. PA was categorized according to the PA Guidelines. Of the 24,588 individuals (mean age, 47.4 years; 47.9% males), leisure‐time PA (≥150 minutes per week) demonstrated 40% lower odds of NAFLD, whereas transportation‐related PA was associated with a 33% risk reduction in NAFLD. Analysis of total PA and sitting times simultaneously showed a dose‐response association between sitting time and NAFLD (P for trend < 0.001). Compliance with the PA Guidelines was lower in individuals with NAFLD versus those without NAFLD. The trends in compliance with the PA Guidelines for any type of PA remained stable in individuals with NAFLD except for a downtrend in transportation‐related PA. In contrast, an improvement in compliance with the PA Guidelines for leisure time was noted in the cohort without NAFLD. Although PA demonstrated a 10% stronger association with risk reduction of NAFLD in women, women showed a lower tendency of meeting the PA Guidelines. Trends in total sitting time increased significantly regardless of NAFLD status.
Conclusions
Sedentary behavior emerged as an independent predictor of NAFLD. Overall compliance with the PA Guidelines was lower in the cohort with NAFLD, with sex‐ and ethnicity‐based differences. Implementation of these observations in clinical practice may improve our understanding as well as clinical outcomes.
With recent improvements in the treatment of end‐stage liver disease (ESLD), a better understanding of the burden of cirrhosis and hepatocellular carcinoma (HCC) is needed in the United States. A ...population‐based study using the US Census and national mortality database was performed. We identified the age‐standardized etiology‐specific mortality rates for cirrhosis and HCC among US adults ages 20 years or older from 2007 to 2016. We determined temporal mortality rate patterns by joinpoint analysis with estimates of annual percentage change (APC). Age‐standardized cirrhosis‐related mortality rates increased from 19.77/100,000 persons in 2007 to 23.67 in 2016 with an annual increase of 2.3% (95% confidence interval CI 2.0‐2.7). The APC in mortality rates for hepatitis C virus (HCV)‐cirrhosis shifted from a 2.9% increase per year during 2007 to 2014 to a 6.5% decline per year during 2014 to 2016. Meanwhile, mortality for cirrhosis from alcoholic liver disease (ALD, APC 4.5%) and NAFLD (APC 15.4%) increased over the same period, whereas mortality for hepatitis B virus (HBV)‐cirrhosis decreased with an average APC of −1.1%. HCC‐related mortality increased from 3.48/100,000 persons in 2007 to 4.41 in 2016 at an annual rate of 2.0% (95% CI 1.3‐2.6). Etiology‐specific mortality rates of HCC were largely consistent with cirrhosis‐related mortality. Minority populations had a higher burden of HCC‐related mortality. Conclusion: Cirrhosis‐related and HCC‐related mortality rates increased between 2007 and 2016 in the United States. However, mortality rates in HCV‐cirrhosis demonstrated a significant decline from 2014 to 2016, during the direct‐acting antiviral era. Mortality rates for ALD/NAFLD‐cirrhosis and HCC have continued to increase, whereas HBV‐cirrhosis‐related mortality declined during the 10‐year period. Importantly, minorities had a disproportionately higher burden of ESLD‐related mortality.
Key points
We studied the role of the large‐conductance Ca2+‐activated K+ channel (BK) and voltage‐dependent K+ channels (Kv) on Ca2+i responses to a wide range of hypoxia at different resting cell ...membrane potential (Em).
BK/Kv were mostly closed at rest in normoxia. BK/Kv became basally active when cells were depolarized by elevated KClo (>12 mm). Regardless of whether BK/Kv were closed or basally open, hypoxia‐induced elevation of Ca2+i was enhanced 2‐ to 3‐fold by inhibitors of BK/Kv.
Hypoxia‐induced elevation of Ca2+i was enhanced ∼2‐fold by an inhibitor of Kv2, a major Kv in rat glomus cells.
Hypoxia did not inhibit BK in inside‐out patches.
Our study supports a scheme in which activation of BK/Kv strongly limits the magnitude of hypoxia‐induced Ca2+i rise, with Kv having a much greater effect than BK.
Large‐conductance KCa (BK) and other voltage‐dependent K+ channels (Kv) are highly expressed in carotid body (CB) glomus cells, but their role in hypoxia‐induced excitation is still not well defined and remains controversial. We addressed this issue by studying the effects of inhibitors of BK (IBTX) and BK/Kv (TEA/4‐AP) on Ca2+i responses to a wide range of hypoxia at different levels of resting cell membrane potential (Em). IBTX and TEA/4‐AP did not affect the basal Ca2+i in isolated glomus cells bathed in 5 mm KClo, but elicited transient increases in Ca2+i in cells that were moderately depolarized (11–20 mV) by elevation of KClo (12–20 mm). Thus, BK and Kv were mostly closed at rest and activated by depolarization. Four different levels of hypoxia (mild, moderate, severe, anoxia) were used to produce a wide range of Ca2+i elevation (0–700 nm). IBTX did not affect the rise in Ca2+i, but TEA/4‐AP strongly (∼3‐fold) enhanced Ca2+i rise by moderate and severe levels of hypoxia. Guangxitoxin, a Kv2 blocker, inhibited the whole‐cell current by ∼50%, and enhanced 2‐fold the Ca2+i rise elicited by moderate and severe levels of hypoxia. Anoxia did not directly affect BK, but activated BK via depolarization. Our findings do not support the view that hypoxia inhibits BK/Kv to initiate or maintain the hypoxic response. Rather, our results show that BK/Kv are activated as glomus cells depolarize in response to hypoxia, which then limits the rise in Ca2+i. Inhibition of Kv may provide a mechanism to enhance the chemosensory activity of the CB and ventilation.
Key points
We studied the role of the large‐conductance Ca2+‐activated K+ channel (BK) and voltage‐dependent K+ channels (Kv) on Ca2+i responses to a wide range of hypoxia at different resting cell membrane potential (Em).
BK/Kv were mostly closed at rest in normoxia. BK/Kv became basally active when cells were depolarized by elevated KClo (>12 mm). Regardless of whether BK/Kv were closed or basally open, hypoxia‐induced elevation of Ca2+i was enhanced 2‐ to 3‐fold by inhibitors of BK/Kv.
Hypoxia‐induced elevation of Ca2+i was enhanced ∼2‐fold by an inhibitor of Kv2, a major Kv in rat glomus cells.
Hypoxia did not inhibit BK in inside‐out patches.
Our study supports a scheme in which activation of BK/Kv strongly limits the magnitude of hypoxia‐induced Ca2+i rise, with Kv having a much greater effect than BK.
Background & Aims
Testosterone plays a role in predisposing individuals to cardiovascular and metabolic diseases, but its effects differ between men and women. We investigated the association between ...serum total testosterone and non‐alcoholic fatty liver disease in adults in the US.
Methods
A cross‐sectional analysis of data from participants in the 2011‐2012 National Health and Nutrition Examination Survey was performed. Subjects with significant alcohol consumption and those with viral hepatitis were excluded. We used the highest sex‐specific quartiles of serum total testosterone as references. Suspected non‐alcoholic fatty liver disease was diagnosed when serum alanine aminotransferase was >30 IU/L for men and >19 IU/L for women.
Results
Of the 4758 subjects (49.4% men), the prevalence of suspected non‐alcoholic fatty liver disease was inversely correlated with the sex‐specific quartiles of testosterone in men and women. In a multivariate model, low total testosterone levels were associated with progressively higher odds of suspected non‐alcoholic fatty liver disease in men after adjusting for age, obesity and other metabolic risk factors (P values for trends <.01). When the women were divided into 2 groups according to menopausal status, a significant correlation was observed only in the post‐menopausal women (P values for trends <.01). The adjusted odds ratios for suspected non‐alcoholic fatty liver disease were 1.72‐1.99 in men and 2.15‐2.26 in post‐menopausal women (lowest quartile vs highest quartile).
Conclusions
In this nationally representative sample of adults in the US, low total testosterone levels were associated with suspected non‐alcoholic fatty liver disease in men and post‐menopausal women independent of known risk factors.
Background & Aims
Nonalcoholic fatty liver disease (NAFLD) has been associated with sarcopenia. However, mortality in the setting of NAFLD‐related sarcopenia remains undefined. We aim to determine ...the all‐cause and cause‐specific mortality from sarcopenia among adults with NAFLD in the USA.
Methods
11 065 individuals in the Third National Health and Nutrition Examination Survey were studied and linked mortality through 2015 was analysed. NAFLD was diagnosed based on presence of ultrasonographic hepatic steatosis without other known liver diseases. Sarcopenia was defined as skeletal muscle index determined by bioelectrical impedance analysis. The Cox proportional hazard model was used to assess all‐cause mortality and cause‐specific mortality, and hazard ratio (HR) adjusted for known risk factors.
Results
During a median follow‐up of 23 years or more, sarcopenia was associated with increased all‐cause mortality (HR 1.27, 95% confidence interval CI 1.11‐1.44). Only in individuals with NAFLD, sarcopenia was associated with a higher risk for all‐cause mortality, while this association was absent in those without NAFLD. Individuals with both sarcopenia and NAFLD had a higher risk for all‐cause mortality (HR 1.28 95% CI 1.06‐1.55) compared with those without sarcopenia and NAFLD. Furthermore, sarcopenia was associated with a higher risk for cancer‐ and diabetes‐related mortality among those with NAFLD. This association was not noted in those without NAFLD.
Conclusion
In this nationally representative sample of US adults, sarcopenia was associated with a higher risk for all‐cause, cancer‐ and diabetes‐related mortality in individuals with NAFLD.
Background and Aim
We investigated the effects of PNPLA3 rs738409, TM6SF2 rs58542926, and MBOAT7‐TMC4 rs641738 variants on metabolic phenotypes and their combined effects on the histological severity ...of non‐alcoholic fatty liver disease (NAFLD).
Methods
We genotyped rs738409, rs58542926, and rs641738 in biopsy‐proven NAFLD patients (n = 416) and healthy controls (n = 109). Homeostasis model assessment of insulin resistance and adipose tissue insulin resistance were calculated.
Results
The rs738409 and rs58542926 variants, but not rs641738, were associated not only with non‐alcoholic steatohepatitis (NASH) (odds ratio OR, 2.00; 95% confidence interval CI, 1.46–2.73 and OR, 1.91; 95% CI, 1.04–3.51) but also with significant fibrosis (≥ F2) (OR, 1.53; 95% CI, 1.11–2.11 and OR, 1.88; 95% CI, 1.02–3.46) in NAFLD, even after adjustment for metabolic risk factors. Of both variants, only rs738409 was associated with homeostasis model assessment of insulin resistance and adipose tissue insulin resistance even in healthy controls (P = 0.046 and 0.002, respectively) as well as in the entire study cohort (P = 0.016 and 0.048, respectively). PNPLA3 and TM6SF2 risk variants additively increased the risk of NASH and significant fibrosis (OR per risk allele, 2.03; 95% CI, 1.50–2.73 and 1.61; 95% CI, 1.19–2.17). Even in subjects with low insulin resistance, the risk of NASH or significant fibrosis increased as the number of risk alleles increased (P = 0.008 and 0.020, respectively).
Conclusions
PNPLA3 and TM6SF2 determine the risk of NASH and significant fibrosis, even after adjustment for insulin resistance, and exert an additive effect on NASH and significant fibrosis.
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