Frequently abnormal serum gamma-glutamyl transferase activity is associated with future development of fatty liver: a retrospective cohort study

Fujii, Hideki; Doi, Haruna; Ko, Tetsuhisa; Fukuma, Taito; Kadono, Toru; Asaeda, Kohei; Kobayashi, Reo; Nakano, Takahiro; Doi, Takehiko; Nakatsugawa, Yoshikazu; Yamada, Shinya; Nishimura, Takeshi; Tomatsuri, Naoya; Sato, Hideki; Okuyama, Yûsuke; Kimura, Hiroyuki; Kishimoto, Etsuko; Nakabe, Nami; Shima, Takatomo

doi:10.1186/s12876-020-01369-x

Cited by 26 publications

(20 citation statements)

References 37 publications

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“…In addition, Ruhl and colleagues [ 28 ] reported that in the USA population, elevated GGT is associated with mortality from all causes, liver disease, cancer, and diabetes. A recent study has also found that individuals with repeated elevated GGT levels have an increased risk of developing fatty liver changes [ 29 ]. Nonetheless, serum GGT also contributes to several algorithms for the diagnosis of NAFLD and liver fibrosis such as the fatty liver index (FLI), SteatoTest, and Fibrotest.…”

Section: Discussionmentioning

confidence: 99%

Loss-of-function HSD17B13 variants, non-alcoholic steatohepatitis and adverse liver outcomes: Results from a multi-ethnic Asian cohort

et al. 2021

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Background/Aims: 17β-hydroxysteroid dehydrogenase 13 (HSD17B13) variants were recently reported to have significantly lower odds of non-alcoholic fatty liver disease (NAFLD). This is a two-part study that aimed to evaluate the association of HSD17B13 variants with NAFLD and its histological severity, and to identify the association of the variants with clinical outcomes in a cohort of biopsy-proven NAFLD patients.Methods: Consecutive biopsy-proven NAFLD patients and controls without fatty liver were recruited for this study between 2009 and 2014. Genotyping for HSD17B13 variants was performed using rhAmp assays. A total of 165 patients with NAFLD were monitored up until August 2019. Clinical outcomes were recorded.Results: HSD17B13 rs72613567 TA allele and rs6834314 G allele were associated with lower odds of non-alcoholic steatohepatitis (NASH) in the overall cohort and among ethnic Chinese, but not among ethnic Malays or Indians (P<0.05). During a mean follow-up of 89 months, 32 patients (19.4%) experienced at least one clinical outcome (cardiovascular events, n=22; liver-related complications, n=6; extra-hepatic malignancy, n=5; and mortality, n=6). The rs72613567 homozygous TA allele and the rs6834314 homozygous G allele were independently associated with a lower incidence of liver-related complications (hazard ratio [HR], 0.004; 95% confidence interval [CI], 0.00–0.64; P=0.033 and HR, 0.01; 95% CI, 0.00–0.97; P=0.048, respectively) and were associated with lower grade of hepatocyte ballooning among the ethnic Chinese.Conclusion: HSD17B13 rs72613567 and rs6834314 variants were inversely associated with NAFLD and NASH, and were associated with lower incidence of adverse liver outcomes in a cohort of multi-ethnic Asian patients with NAFLD.

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Section: Discussionmentioning

confidence: 99%

Loss-of-function HSD17B13 variants, non-alcoholic steatohepatitis and adverse liver outcomes: Results from a multi-ethnic Asian cohort

et al. 2021

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“…ALT and AST levels were also unaffected although GGT levels were reduced; this suggests the potential for a liver benefit given that GGT levels are frequently elevated (and may confer a higher risk of progression) in the context of NAFLD. 56 It should be noted that the aforementioned parameters were generally within normal reference ranges at baseline.…”

Section: Discussionmentioning

confidence: 77%

Pharmacodynamic effects of direct AMP kinase activation in humans with insulin resistance and non-alcoholic fatty liver disease: A phase 1b study

Fouqueray

Bolze

Dubourg

et al. 2021

Cell Reports Medicine

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Summary AMPK is an energy sensor modulating metabolism, inflammation, and a target for metabolic disorders. Metabolic dysfunction results in lower AMPK activity. PXL770 is a direct AMPK activator, inhibiting de novo lipogenesis (DNL) and producing efficacy in preclinical models. We aimed to assess pharmacokinetics, safety, and pharmacodynamics of PXL770 in humans with metabolic syndrome-associated fatty liver disease. In a randomized, double-blind four-week trial, 12 overweight/obese patients with non-alcoholic fatty liver disease (NAFLD) and insulin resistance received PXL770 500 mg QD; 4 subjects received matching placebo. Endpoints included pharmacokinetics, hepatic fractional DNL, oral glucose tolerance testing, additional pharmacodynamic parameters, and safety. PK parameters show adequate plasma exposure in NAFLD patients for daily oral dosing. PXL770 decreases DNL—both peak and AUC are reduced versus baseline—and improves glycemic parameters and indices of insulin sensitivity versus baseline. Assessment of specific lipids reveals decrease in diacyglycerols/triacylglycerols. Safety/tolerability are similar to placebo. These results unveil initial human translation of AMPK activation and support this therapeutic strategy for metabolic disorders.

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“…The remarkable aspects were as follows: (1) Our study had a lower incidence of fibrosis than the first cohort; (2) Among the noninvasive methods, the FIB-8 score and NFS included the BMI in their models, and our cohort had a lower mean BMI than previous reports (30.4 kg/m 2 vs 34.0 and 31.5 kg/m 2 ), which might have resulted in lower percentages of sensitivity and specificity in our cohort than those previously reported; and (3) GGT is a uniquely incorporated variable in the new FIB-8 scoring system. Some reported studies have demonstrated that a higher GGT level is a risk factor for advanced fibrosis in NAFLD[ 19 , 20 ]. Additionally, considering NAFLD patients with type 2 DM, a serum GGT level over 82 U/L was independently associated with advanced fibrosis using noninvasive methods in multivariate analysis ( P = 0.004)[ 21 ].…”

Section: Discussionmentioning

confidence: 99%

Validation model of fibrosis-8 index score to predict significant fibrosis among patients with nonalcoholic fatty liver disease

Prasoppokakorn¹,

Chan²,

Wong³

et al. 2022

WJG

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BACKGROUND Identifying hepatic fibrosis is crucial for nonalcoholic fatty liver disease (NAFLD) management. The fibrosis-8 (FIB-8) score, recently developed by incorporating four additional variables into the fibrosis-4 (FIB-4) score, showed better performance in predicting significant fibrosis in NAFLD. AIM To validate the FIB-8 score in a biopsy-proven NAFLD cohort and compare the diagnostic performance of the FIB-8 and FIB-4 scores and NAFLD fibrosis score (NFS) for predicting significant fibrosis. METHODS We collected the data of biopsy-proven NAFLD patients from three Asian centers in three countries. All the patients with available variables for the FIB-4 score (age, platelet count, and aspartate and alanine aminotransferase levels) and FIB-8 score (the FIB-4 variables plus 4 additional parameters: The body mass index (BMI), albumin to globulin ratio, gamma-glutamyl transferase level, and presence of diabetes mellitus) were included. The fibrosis stage was scored using nonalcoholic steatohepatitis CRN criteria, and significant fibrosis was defined as at least fibrosis stage 2. RESULTS A total of 511 patients with biopsy-proven NAFLD and complete data were included for validation. Of these 511 patients, 271 (53.0%) were female, with a median age of 51 (interquartile range: 41, 58) years. The median BMI was 29 (26.3, 32.6) kg/m 2 , and 268 (52.4%) had diabetes. Among the 511 NAFLD patients, 157 (30.7%) had significant fibrosis (≥ F2). The areas under the receiver operating characteristic curves of the FIB-8 and FIB-4 scores and NFS for predicting significant fibrosis were 0.774, 0.743, and 0.680, respectively. The FIB-8 score demonstrated significantly better performance for predicting significant fibrosis than the NFS ( P = 0.001) and was also clinically superior to FIB-4, although statistical significance was not reached ( P = 0.073). The low cutoff point of the FIB-8 score for predicting significant fibrosis of 0.88 showed 92.36% sensitivity, and the high cutoff point of the FIB-8 score for predicting significant fibrosis of 1.77 showed 67.51% specificity. CONCLUSION We demonstrated that the FIB-8 score had significantly better performance for predicting significant fibrosis in NAFLD patients than the NFS, as well as clinically superior performance vs the FIB-4 score in an Asian population. A novel simple fibrosis score comprising commonly accessible basic laboratories may be beneficial to use for an initial assessment in primary care units, excluding patients with significant liver fibrosis and aiding in patient selection for further hepatologist referral.

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Frequently abnormal serum gamma-glutamyl transferase activity is associated with future development of fatty liver: a retrospective cohort study

Cited by 26 publications

References 37 publications

Loss-of-function HSD17B13 variants, non-alcoholic steatohepatitis and adverse liver outcomes: Results from a multi-ethnic Asian cohort

Loss-of-function HSD17B13 variants, non-alcoholic steatohepatitis and adverse liver outcomes: Results from a multi-ethnic Asian cohort

Pharmacodynamic effects of direct AMP kinase activation in humans with insulin resistance and non-alcoholic fatty liver disease: A phase 1b study

Validation model of fibrosis-8 index score to predict significant fibrosis among patients with nonalcoholic fatty liver disease

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