Gamma glutamyl transferase – an underestimated marker for cardiovascular disease and the metabolic syndrome

Neuman, Manuela G.; Malnick, Stephen; Chertin, Lucy

doi:10.18433/jpps30923

Cited by 43 publications

(41 citation statements)

References 55 publications

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“…In the present study, the prevalence of simultaneous GGT and ALT abnormalities in Chinese patients with NAFLD was 46.4%, which was similar to another large-scale cross-sectional study conducted in China, in which over 50% of patients with NAFLD presented abnormal serum liver enzyme levels [ 31 ]. Although ALT, AST and GGT are considered markers of liver injury because they are released from disrupted hepatocytes in patients with NAFLD, the levels of GGT, a key enzyme involved in glutathione and cysteine metabolism, are increased in not only patients with NAFLD but also patients with many other conditions, including oxidative stress, cholestatic liver disease and ethanol exposure [ 32 ]. Increased bile pressure secondary to steatosis has been identified as an important pathogenic mechanism in patients with NAFLD and oxidative stress and may explain the higher specificity of this parameter for NAFLD than that of ALT [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

Normalization of γ-glutamyl transferase levels is associated with better metabolic control in individuals with nonalcoholic fatty liver disease

Liao

Shao

et al. 2021

BMC Gastroenterol

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Background The normalization of liver biochemical parameters usually reflects the histological response to treatment for nonalcoholic fatty liver disease (NAFLD). Researchers have not clearly determined whether different liver enzymes exhibit various metabolic changes during the follow-up period in patients with NAFLD. Methods We performed a retrospective analysis of patients with NAFLD who were receiving therapy from January 2011 to December 2019. Metabolism indexes, including glucose levels, lipid profiles, uric acid levels and liver biochemical parameters, were measured. Magnetic resonance imaging-based proton density fat fraction (MRI-PDFF) and liver ultrasound were used to evaluate steatosis. All patients received recommendations for lifestyle modifications and guideline-recommended pharmacological treatments with indications for drug therapy for metabolic abnormalities. Results Overall, 1048 patients with NAFLD were included and received lifestyle modification recommendations and pharmaceutical interventions, including 637 (60.7%) patients with abnormal GGT levels and 767 (73.2%) patients with abnormal ALT levels. Patients with concurrent ALT and GGT abnormalities presented higher levels of metabolism indexes and higher liver fat content than those in patients with single or no abnormalities. After 12 months of follow-up, the cumulative normalization rate of GGT was considerably lower than that of ALT (38% vs. 62%, P < 0.001). Greater weight loss resulted in higher cumulative normalization rates of GGT and ALT. Weight loss (OR = 1.21, 95% CI 1.11–1.32, P < 0.001), ALT normalization (OR = 2.75, 95% CI 1.41–5.36, P = 0.01) and lower TG and HOMA-IR values (OR = 2.03, 95% CI 1.11–3.71, P = 0.02; OR = 2.04, 95% CI 1.07–3.89, P = 0.03) were independent protective factors for GGT normalization. Elevated baseline GGT (OR = 0.99, 95% CI 0.98–0.99, P = 0.01) was a risk factor. Conclusions For NAFLD patients with concurrently increased ALT and GGT levels, a lower normalization rate of GGT was observed, rather than ALT. Good control of weight and insulin resistance was a reliable predictor of GGT normalization.

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Section: Discussionmentioning

confidence: 99%

Normalization of γ-glutamyl transferase levels is associated with better metabolic control in individuals with nonalcoholic fatty liver disease

Liao

Shao

et al. 2021

BMC Gastroenterol

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“…Since, CXCL12 is normally expressed at the basal surface of the NVU endothelium basal surface, we also used GGT1 (green) as canonical marker of NVU-endothelium apical surface, to accurately assess CXCL12 re-distribution. GGT1 is a glycosylated protein embedded in the apical of the plasma membrane responsible for transferring glutamyl groups and maintaining glutathione and cysteine homeostasis ( Neuman et al, 2020 ). HCMEC/D3 cells showed GGT1 and CXCL12 expression as anticipated ( Figure 7E ).…”

Section: Resultsmentioning

confidence: 99%

Expression of IL-20 Receptor Subunit β Is Linked to EAE Neuropathology and CNS Neuroinflammation

Dayton

Yuan

Pacumio

et al. 2021

Front. Cell. Neurosci.

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Considerable clinical evidence supports that increased blood–brain barrier (BBB) permeability is linked to immune extravasation of CNS parenchyma during neuroinflammation. Although BBB permeability and immune extravasation are known to be provoked by vascular endothelial growth factor-A (i.e., VEGF-A) and C-X-C motif chemokine ligand 12 (CXCL12), respectively, the mechanisms that link both processes are still elusive. The interleukin-20 (i.e., IL-20) cytokine signaling pathway was previously implicated in VEGF-mediated angiogenesis and is known to induce cellular response by way of signaling through IL-20 receptor subunit β (i.e., IL-20RB). Dysregulated IL-20 signaling is implicated in many inflammatory pathologies, but it’s contribution to neuroinflammation has yet to be reported. We hypothesize that the IL-20 cytokine, and the IL cytokine subfamily more broadly, play a key role in CNS neuroinflammation by signaling through IL-20RB, induce VEGF activity, and enhance both BBB-permeability and CXCL12-mediated immune extravasation. To address this hypothesis, we actively immunized IL-20RB–/– mice and wild-type mice to induce experimental autoimmune encephalomyelitis (EAE) and found that IL-20RB–/– mice showed amelioration of disease progression compared to wild-type mice. Similarly, we passively immunized IL-20RB–/– mice and wild-type mice with myelin-reactive Th1 cells from either IL-20RB–/– and wild-type genotype. Host IL-20RB–/– mice showed lesser disease progression than wild-type mice, regardless of the myelin-reactive Th1 cells genotype. Using multianalyte bead-based immunoassay and ELISA, we found distinctive changes in levels of pro-inflammatory cytokines between IL-20RB–/– mice and wild-type mice at peak of EAE. We also found detectable levels of all cytokines of the IL-20 subfamily within CNS tissues and specific alteration to IL-20 subfamily cytokines IL-19, IL-20, and IL-24, expression levels. Immunolabeling of CNS region-specific microvessels confirmed IL-20RB protein at the spinal cord microvasculature and upregulation during EAE. Microvessels isolated from macaques CNS tissues also expressed IL-20RB. Moreover, we identified the expression of all IL-20 receptor subunits: IL-22 receptor subunit α-1 (IL-22RA1), IL-20RB, and IL-20 receptor subunit α (IL-20RA) in human CNS microvessels. Notably, human cerebral microvasculature endothelial cells (HCMEC/D3) treated with IL-1β showed augmented expression of the IL-20 receptor. Lastly, IL-20-treated HCMEC/D3 showed alterations on CXCL12 apicobasal polarity consistent with a neuroinflammatory status. This evidence suggests that IL-20 subfamily cytokines may signal at the BBB via IL-20RB, triggering neuroinflammation.

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“…These ndings were similar to another large-scale cross-sectional study conducted in China, in which over 50% of patients with NAFLD presented abnormal serum liver enzyme levels [28]. Although both ALT, AST and GGT are considered markers of liver injury because they are released from disrupted hepatocytes in patients with NAFLD, the levels of GGT, a key enzyme involved in glutathione and cysteine metabolism, are increased not only in patients with NAFLD but also in patients with many other conditions, including oxidative stress, cholestatic liver disease and ethanol exposure [29]. In patients with NAFLD and oxidative stress, increased bile pressure secondary to steatosis (micro cholestasis) has been identi ed as an important pathogenic mechanism may help to explain its higher speci city for NAFLD than ALT.…”

Section: Discussionmentioning

confidence: 99%

Normalization of γ-glutamyl Transferase Levels is Associated with Better Metabolic Control in Individuals with Nonalcoholic Fatty Liver Disease

Liao

Shao

et al. 2020

Preprint

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Background: The normalization of liver biochemical parameters usually reflects the histological response to treatment for nonalcoholic fatty liver disease (NAFLD). Researchers have not clearly determined whether different liver enzymes exhibited various metabolic changes during the follow-up of patients with NAFLD.Methods: We conducted a retrospective analysis of patients with NAFLD who were receiving therapy from January 2011 to December 2019. Metabolism indexes, including glucose levels, lipid profiles, uric acid levels and liver biochemical parameters, were measured. Magnetic resonance imaging-based proton density fat fraction (MRI-PDFF) and liver ultrasound were used to evaluate steatosis.Results: Overall, 1048 patients with NAFLD were included and received lifestyle and pharmaceutical interventions, including 637 (60.7%) patients with abnormal GGT levels and 467 (44.6%) patients with abnormal ALT levels. Patients with concurrent ALT and GGT abnormalities presented higher levels of metabolism indexes and higher liver fat contents than patients with single or no abnormalities. After 12 months of follow-up, the cumulative normalization rate of GGT was much lower than that of ALT (33% vs. 52%, P < 0.001). Greater weight loss resulted in higher cumulative normalization rates of GGT and ALT. Weight loss (OR = 1.27, 95%CI: 1.15~1.41, P < 0.001), ALT normalization (OR = 4.32, 95%CI: 1.87~9.96, P = 0.01) and HOMA-IR decreased to normal levels (OR = 3.48, 95%CI: 1.60~7.57, P = 0.01) were independent protective factors for GGT normalization. Elevated baseline GGT (OR = 0.99, 95%CI: 0.98~0.99, P = 0.01), CHOL (OR = 0.47, 95%CI: 0.23~0.96, P = 0.04) and fasting insulin levels (OR = 0.91,95%CI: 0.86~0.96, P = 0.01) were risk factors.Conclusions: For NAFLD patients with concurrently increased ALT and GGT levels, a lower normalization rate of GGT was observed rather than ALT. Good control of weight and insulin resistance was reliable predictors of GGT normalization.

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Gamma glutamyl transferase – an underestimated marker for cardiovascular disease and the metabolic syndrome

Cited by 43 publications

References 55 publications

Normalization of γ-glutamyl transferase levels is associated with better metabolic control in individuals with nonalcoholic fatty liver disease

Normalization of γ-glutamyl transferase levels is associated with better metabolic control in individuals with nonalcoholic fatty liver disease

Expression of IL-20 Receptor Subunit β Is Linked to EAE Neuropathology and CNS Neuroinflammation

Normalization of γ-glutamyl Transferase Levels is Associated with Better Metabolic Control in Individuals with Nonalcoholic Fatty Liver Disease

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