The cut‐off point of intrahepatic triglyceride (IHTG) content to define nonalcoholic fatty liver disease (NAFLD) by proton magnetic resonance spectroscopy (1H‐MRS) was established based on the 95th ...percentile in a group of healthy individuals (i.e., ≥5.56%). Whether this threshold correlates with metabolic and histological changes and whether a further accumulation of IHTG is associated with worsening of these parameters has not been properly assessed in a large cohort of patients. In this cross‐sectional study, 352 subjects were carefully characterized with the following studies: liver 1H‐MRS; euglycemic insulin clamp with measurement of glucose turnover; oral glucose tolerance test; and a liver biopsy. Hepatic insulin sensitivity (suppression of endogenous glucose production by insulin) was affected early on after IHTG content was ∼1.5% and remained uniformly impaired (∼40%‐45%), regardless of further IHTG accumulation. Skeletal muscle insulin sensitivity showed a gradual impairment at low degrees of IHTG accumulation, but remained unchanged after IHTG content reached the ∼6 ± 2% threshold. A similar pattern was observed for metabolic changes typically associated with NAFLD, such as hypertriglyceridemia and low high‐density lipoprotein cholesterol (HDL‐C). In contrast, adipose tissue insulin sensitivity (suppression of free fatty acids by insulin) showed a continuous worsening across the spectrum of IHTG accumulation in NAFLD (r = –0.38; P < 0.001). Histological severity of liver disease (inflammation, ballooning, and fibrosis) was not associated with the amount of IHTG content. Conclusion: IHTG accumulation is strongly associated with adipose tissue insulin resistance (IR), supporting the current theory of lipotoxicity as a driver of IHTG accumulation. Once IHTG accumulation reaches ∼6 ± 2%, skeletal muscle IR, hypertriglyceridemia, and low HDL‐C become fully established. Histological activity appears to have an early threshold and is not significantly influenced by increasing amounts of IHTG accumulation. (Hepatology 2017;65:1132‐1144).
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Hypogonadism is reported to occur in non-alcoholic fatty liver disease (NAFLD), but earlier studies used low-sensitivity diagnostic techniques (CT, ultrasound), for NAFLD diagnosis. We hypothesized ...that if hypogonadism was due to NAFLD, and not solely attributable to underlying obesity/diabetes, it would be more severe in the presence of steatohepatitis (NASH). To examine the influence of liver disease on testosterone in males with type 2 diabetes mellitus (T2DM), we used gold-standard liver imaging with MR-spectroscopy (1H-MRS), and performed liver biopsies to grade/stage the NAFLD.
In this cross-sectional study, we measured in 175 males with T2DM total and free testosterone, markers of insulin resistance, and intrahepatic triglyceride content (IHTG) by 1H-MRS. Those with NAFLD on imaging underwent a liver biopsy.
Total testosterone was higher in the group without NAFLD ("No-NAFLD"; n = 48) compared to isolated steatosis (IS; n = 62) or NASH (n = 65) (385 ± 116 vs. 339 ± 143 vs. 335 ± 127 ng/ml, ptrend 0.03). Testosterone was also lower in obese vs. non-obese subjects in both the No-NAFLD and IS groups (p = 0.06 and p = 0.11, respectively), but not in obese vs. non-obese patients with NASH (p = 0.81). IHTG was independently associated with total testosterone (ß = -4.8, p = 0.004). None of the liver histology characteristics were associated with lower testosterone.
NAFLD is linked to lower total testosterone in patients with T2DM, but likely given a common soil of insulin resistance/obesity and not from the severity of liver necroinflammation or fibrosis. Nevertheless, clinicians should consider screening patients with T2DM and NAFLD for hypogonadism.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Adiponectin, an adipocyte-secreted hormone that plays an important role in diabetes and cardiovascular disease, may also be of importance in the development and progression of several malignancies. ...Circulating adiponectin concentrations, which are determined mainly by genetic factors, nutrition, and adiposity, are lower in patients with breast, endometrial, prostate, and colon cancer. It has thus been proposed that adiponectin may be a biological link between obesity (especially central obesity) and increased cancer risk. Adiponectin may influence cancer risk through its well-recognized effects on insulin resistance, but it is also plausible that adiponectin acts on tumor cells directly. Several cancer cell types express adiponectin receptors that may mediate the effects of adiponectin on cellular proliferation. Herein, we review recent evidence supporting a role of serum adiponectin concentrations as a novel risk factor and possible diagnostic marker for obesity-related malignancies, including cancers of the breast, endometrium, colon, and prostate. Further studies are needed to fully elucidate the potential role of adiponectin in cancer diagnostics and therapeutics.
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CMK, GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Nonalcoholic fatty liver disease (NAFLD) affects one-third of the population and two-thirds of patients with obesity or T2DM. Its more aggressive form is known as nonalcoholic ...steatohepatitis (NASH) and is characterized by hepatocyte necrosis, inflammation and often fibrosis. The presence of fibrosis indicates a more aggressive course and may lead to cirrhosis. Premature mortality in NASH is related to both hepatic (cirrhosis and hepatocellular carcinoma) and extra-hepatic complications, largely cardiovascular disease (CVD). Many therapeutic agents have been tested, but still none approved specifically for NASH. Treatment of NAFLD includes aggressive management of diabetes and cardiovascular risk factors, although the role of controlling hyperglycemia per se in patients with T2DM and NASH remains unknown. Agents tested with some success in non-diabetic patients with NASH include pioglitazone, liraglutide, vitamin E and to a lesser degree, pentoxiphylline. In patients with T2DM and NASH only pioglitazone has shown to significantly improve liver histology, with only a handful of patients with diabetes having been studied with other modalities. This review focuses on available agents for NASH to assist clinicians in the management of these complex patients. Many novel compounds are being studied and will likely make combination therapy for NASH a reality in the future.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Little is known about the prevalence, clinical characteristics and impact of hypothyroidism in patients with sarcoidosis. We aimed to determine the prevalence and clinical features of hypothyroidism ...and its relation to organ involvement and other clinical manifestations in patients with sarcoidosis. We conducted a national registry-based study investigating 3835 respondents to the Sarcoidosis Advanced Registry for Cures Questionnaire between June 2014 and August 2019. This registry is based on a self-reported, web-based questionnaire that provides data related to demographics, diagnostics, sarcoidosis manifestations and treatment. We compared sarcoidosis patients with and without self-reported hypothyroidism. We used multivariable logistic regression and adjusted for potential confounders to determine the association of hypothyroidism with nonorgan-specific manifestations. 14% of the sarcoidosis patients self-reported hypothyroidism and were generally middle-aged white women. Hypothyroid patients had more comorbid conditions and were more likely to have multiorgan sarcoidosis involvement, especially with cutaneous, ocular, joints, liver and lacrimal gland involvement. Self-reported hypothyroidism was associated with depression (adjusted odds ratio (aOR) 1.3, 95% CI 1.01-1.6), antidepressant use (aOR 1.3, 95% CI 1.1-1.7), obesity (aOR 1.7, 95% CI 1.4-2.1), sleep apnoea (aOR 1.7, 95% CI 1.3-2.2), chronic fatigue syndrome (aOR 1.5, 95% CI 1.2-2) and was borderline associated with fibromyalgia (aOR 1.3, 95% CI 1-1.8). Physical impairment was more common in patients with hypothyroidism. Hypothyroidism is a frequent comorbidity in sarcoidosis patients that might be a potentially reversible contributor to fatigue, depression and physical impairment in this population. We recommend considering routine screening for hypothyroidism in sarcoidosis patients especially in those with multiorgan sarcoidosis, fatigue and depression.
Abstract
Context
The relationship between plasma fibroblast growth factor 21 (FGF21), insulin resistance, and steatohepatitis has not been systematically assessed.
Objective
To determine if higher ...plasma FGF21 is associated with worse steatohepatitis on liver biopsy in patients with nonalcoholic fatty liver disease (NAFLD).
Design and Setting
Cross-sectional study in a university hospital.
Patients Interventions and Main Outcome Measures
Patients with a body mass index >25 (n = 187) underwent: (i) euglycemic hyperinsulinemic clamp to assess tissue-specific insulin resistance (IR); (ii) liver magnetic resonance spectroscopy for intrahepatic triglyceride quantification, (iii) liver biopsy (if NAFLD present; n = 146); and (iv) fasting plasma FGF21 levels.
Methods and Results
Patients were divided into three groups: (i) No NAFLD (n = 41); (ii) No nonalcoholic steatohepatitis (NASH) (patients with isolated steatosis or borderline NASH; n = 52); and (iii) NASH (patients with definite NASH; n = 94). Groups were well-matched for age/sex, prevalence of type 2 diabetes mellitus, and hemoglobin A1c. During euglycemic hyperinsulinemic insulin clamp, insulin sensitivity in skeletal muscle and adipose tissue worsened from No NAFLD to NASH (both P < 0.001). Plasma FGF21 levels correlated inversely with insulin sensitivity in adipose tissue (r = −0.17, P = 0.006) and skeletal muscle (r = −0.23, P = 0.007), but not with liver insulin sensitivity. Plasma FGF21 was higher in patients with NASH (453 ± 262 pg/mL) when compared with the No NASH (341 ± 198 pg/mL, P = 0.03) or No NAFLD (325 ± 289 pg/mL, P = 0.02) groups. Plasma FGF21 increased with the severity of necroinflammation (P = 0.02), and most significantly with worse fibrosis (P < 0.001), but not with worsening steatosis (P = 0.60).
Conclusions
Plasma FGF21 correlates with severity of steatohepatitis, in particular of fibrosis, in patients with NASH. Measurement of FGF21 may help identify patients at the highest risk of disease progression.
We assessed the relationship between plasma FGF21 levels and steatohepatitis in patients with NAFLD. We found that higher FGF21 levels correlated with the severity of liver fibrosis.
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•Magnetic resonance-based images are frequently used in phase I-II studies for NASH.•It is assumed that changes in liver fat will predict histological changes.•We analyzed data from ...121 patients with paired biopsies and magnetic resonance imaging.•Changes in liver fat did not predict changes in inflammation, ballooning or fibrosis.•Quantification of liver fat after treatment may be misleading as a surrogate marker of treatment response.
Proof-of-concept studies frequently assess changes in intrahepatic triglyceride (IHTG) content by magnetic resonance-based techniques as a surrogate marker of histology. The aim of this study was to establish how reliable this strategy is to predict changes in liver histology in patients with non-alcoholic steatohepatitis (NASH).
Patients with NASH who had participated in our prior randomized controlled trials of pioglitazone with complete paired data for IHTG content by magnetic resonance spectroscopy and liver histology were included in the study.
A total of 121 patients were included. Changes in IHTG were assessed in several ways: as a continuous variable (correlations), as categorical groups (IHTG change ≥0%; or IHTG reduction of 1–30%; 31–50%; 51–70%; or >70%), and in a binomial way as steatosis resolution or not (defined as achieving IHTG <5.56%). Changes in IHTG correlated with steatosis on histology (r = 0.54; p <0.01). However, the magnitude of IHTG reduction was not associated with the rate of response of the primary histological outcome (2-point improvement in the NAFLD activity score from 2 different parameters, without worsening of fibrosis) or resolution of NASH without worsening of fibrosis, neither in patients receiving pioglitazone nor placebo. Changes in lobular inflammation, hepatocyte ballooning, or liver fibrosis were also independent of changes in IHTG, irrespective of treatment arm. Steatosis resolution was not associated with better histological outcomes either.
Changes in IHTG predict changes in steatosis but not of other liver histological parameters. This implies that IHTG response to treatment should be interpreted with caution, as it may not be as reliable as previously believed to predict a treatment’s overall clinical efficacy in patients with NASH.
Quantification of liver fat by magnetic resonance imaging (MRI) is currently used to assess treatment responses in patients with fatty liver, with the assumption that improvements in liver fat translate into less inflammation, necrosis, and fibrosis in the liver. However, in this article, we showed that changes in liver fat do not necessarily translate into changes in these parameters. This means that MRI may not be as useful to assess treatment response in patients with fatty liver as previously believed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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