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Buchanan RM, Reinson T, Bilson J, Woodland H, Nwoguh C, Cooper K, Harris S, Malone K, Byrne CD. Screening to identify people with type 2 diabetes at risk of liver cancer in primary care: a randomised controlled trial protocol. BMJ Open 2025; 15:e088043. [PMID: 40050060 PMCID: PMC11887308 DOI: 10.1136/bmjopen-2024-088043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Accepted: 02/07/2025] [Indexed: 03/09/2025] Open
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) is expected to become the third most common cause of cancer death worldwide by 2030. The increase in HCC is in large part due to the rising prevalence of risk factors such as type 2 diabetes mellitus (T2DM). Up to 1 in 20 people living with T2DM have liver cirrhosis, and they have a 1% to 2% incidence of HCC per year. Patients with cirrhosis enter surveillance for HCC to identify early-stage, curable tumours. A diagnosis of T2DM does not mandate testing to identify patients with cirrhosis, with testing restricted to those with additional risks. There has never been a trial and nested cost-effectiveness evaluation comparing screening all patients with T2DM for cirrhosis against usual care. METHODS AND ANALYSIS The study will use a multi-centre, unblinded individual randomised controlled trial design. The aim will be to determine the effectiveness and cost-effectiveness of screening all adults with T2DM to identify those at high risk of HCC. The recruitment strategy has been supported by patient and public involvement (PPI). Participants will be identified via an automated search of primary care records and invited to participate via text. 320 participants will be randomised for screening. The screening will include measurement of bio-markers for liver fibrosis (ELF and Fib-4) and vibration-controlled transient elastography. Another 320 participants will be randomised to standard care. Demographic and medical history data will be collected at baseline from all participants. Outcome data will be collected remotely from healthcare records. The primary outcome is the proportion of participants in each arm who are referred to HCC surveillance following testing for liver disease within 12 months of randomisation. The results will be used to calculate the incremental cost-effectiveness ratio of screening via a Markov model. ETHICS AND DISSEMINATION The results of this study will be presented directly to National Health Service England. Additional dissemination via conference proceedings and publication will be supported by our PPI team. Ethical approval was granted by the West of Scotland Research Ethics Service on 2 August 2023, REC reference 23/WS/0102. TRIAL REGISTRATION NUMBER ISRCTN17017677.
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Affiliation(s)
- Ryan M Buchanan
- University of Southampton Faculty of Medicine, Southampton, UK
- University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Tina Reinson
- Clinical and Experimental Sciences Division, University of Southampton Faculty of Medicine, Southampton, UK
| | - Josh Bilson
- University of Southampton Faculty of Medicine, Southampton, UK
| | - Hazel Woodland
- Salisbury District Hospital NHS Foundation Trust, Salisbury, UK
| | - Chinonso Nwoguh
- University of Southampton Faculty of Medicine, Southampton, UK
| | - Keith Cooper
- Southampton Health Technology Assessment Centre, University of Southampton, Southampton, UK
| | - Scott Harris
- University of Southampton Faculty of Medicine, Southampton, UK
| | | | - Christopher D Byrne
- University of Southampton Faculty of Medicine, Southampton, UK
- NIHR Southampton Biomedical Research Centre, Southampton, UK
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Li M, Yu H, Wan S, Hu F, Luo Q, Gong W. The fibrosis investigating navigator in diabetes (FIND): A tool to predict liver fibrosis risk in subjects with diabetes. Diabetes Obes Metab 2025; 27:1184-1197. [PMID: 39638772 PMCID: PMC11802394 DOI: 10.1111/dom.16109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 11/13/2024] [Accepted: 11/21/2024] [Indexed: 12/07/2024]
Abstract
BACKGROUND Type 2 diabetes increases the risk of cirrhosis and liver cancer. Noninvasive and early assessment of liver fibrosis is essential. We aimed to develop a score to aid in the initial assessment of liver fibrosis in the diabetic population. METHODS A fibrosis investigating navigator in diabetes (FIND) score was developed and validated in the NHANES dataset (2017-2020). Fibrosis was defined as a liver stiffness measurement (LSM) ≥8.0 kPa. The diagnostic accuracies of FIB-4, NFS, LiverRisk, steatosis-associated fibrosis estimator (SAFE) and metabolic dysfunction-associated fibrosis (MAF-5) were compared. FIND was also externally validated in various liver diseases via biopsy as a reference in an Asian centre between 2016 and 2020. Finally, we examined the prognostic implications of the FIND index utilizing data from the UK Biobank cohort (2006-2010). RESULTS The FIND score model yielded an AUROC of 0.781 for the prediction of an LSM ≥8 kPa in the validation set, which was consistently greater than that of other available models (all p < 0.05). In the whole NHANES dataset, the 85% sensitivity cut-off of 0.16 corresponded to a NPV of 91.9%, whereas the 85% specificity cut-off of 0.31 corresponded to a PPV of 50.6%. FIND displayed overall accuracies similar to those of the other models in staging fibrosis stages, with biopsy used as a reference. In the UK Biobank cohort, FIND >0.31 was associated with an increased risk of all-cause and liver-related mortality in the diabetic population in adjusted models (HR, 1.75; 95% CI, 1.62-1.89; HR, 23.59; 95% CI, 13.67-40.69). CONCLUSIONS In diabetes patients, the novel FIND score performs well in identifying subjects at risk of liver fibrosis and predicting all-cause and liver-related mortality.
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Affiliation(s)
- Mingkai Li
- Department of Gastroenterology, Shenzhen HospitalSouthern Medical UniversityShenzhenPeople's Republic of China
| | - Hongsheng Yu
- Department of GastroenterologyThe Third Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouPeople's Republic of China
| | - Sizhe Wan
- Department of Gastroenterology, Shenzhen HospitalSouthern Medical UniversityShenzhenPeople's Republic of China
| | - Fulan Hu
- Department of Biostatistics and Epidemiology, Public Health collegeShenzhen University Medical SchoolShenzhenPeople's Republic of China
| | - Qingtian Luo
- Department of Gastroenterology and Endoscopy CenterShenzhen Nanshan People’s Hospital, the 6th Affiliated Hospital of Shenzhen University Medical SchoolShenzhenPeople's Republic of China
| | - Wei Gong
- Department of Gastroenterology, Shenzhen HospitalSouthern Medical UniversityShenzhenPeople's Republic of China
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Bhattacharjee J, Beaton G, Ravula SB, Lee SJ, Bacon KB, Jenkinson CP, Warren M, Tucci FC, Kohli R. Lysophosphatidic acid receptor 1 antagonist (EPGN2154) causes regression of NASH in preclinical NASH models. Hepatol Commun 2023; 7:e0323. [PMID: 37994050 PMCID: PMC10666985 DOI: 10.1097/hc9.0000000000000323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 09/28/2023] [Indexed: 11/24/2023] Open
Abstract
BACKGROUND NASH causes a tremendous health care burden in the United States. A glucagon-like peptide-1 agonist, semaglutide (Sema), treatment resulted in hepatic steatosis reduction in clinical trials of NASH. Lysophosphatidic acid receptor 1 antagonists are known to have antifibrotic effects in several organs. We tested Sema and a novel lysophosphatidic acid receptor 1 antagonist, EPGN2154, individually and in combination to evaluate their efficacy for NASH remission in preclinical models. METHODS In the present study, we used (1) C57Bl6/J wild-type mice fed on a high-fat, high-carbohydrate (HFHC) diet for 16 weeks and (2) leptin-deficient mice (ob/ob) fed on an Amylin liver NASH diet for 16 weeks. After 16 weeks, the mice were randomly distributed in equal numbers in (1) no-drug, (2) EPGN2154, (3) Sema, and (4) EPGN2154+Sema treatment groups for 8 additional weeks at a dosage of 10 mg/kg body weight for EPGN2154 (oral gavage, 5 days a week) and 6.17 μg/kg body weight of Sema (subcutaneous injection every alternate day, 3 days a week). RESULTS In the wild-type-high-fat, high-carbohydrate model, we observed the most body weight loss in the EPGN2154+Sema combination group compared to the other treatment groups. All groups led to a significant reduction in alanine transaminase levels when compared to high-fat, high-carbohydrate-fed wild type. However, no significant difference in alanine transaminase levels was observed among the treatment groups. In the ob/ob mice study, Sema did not cause body weight loss. Moreover, the EPGN2154 and the combination groups had a lower NAFLD Activity Score and incidence of advanced-stage hepatic fibrosis than the Sema group. CONCLUSIONS EPGN2154 demonstrated a hepato-protective effect independent of body weight loss in preclinical NASH models.
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Affiliation(s)
- Jashdeep Bhattacharjee
- Department of Gastroenterology, Hepatology and Nutrition, Children’s Hospital Los Angeles, Los Angeles, California, USA
| | | | | | | | | | | | - Mikako Warren
- Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles, Los Angeles, California, USA
| | | | - Rohit Kohli
- Department of Gastroenterology, Hepatology and Nutrition, Children’s Hospital Los Angeles, Los Angeles, California, USA
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Nogueira ACC, Barreto J, Moura FA, Luchiari B, Abuhab A, Bonilha I, Nadruz W, Gaziano JM, Gaziano T, de Carvalho LSF, Sposito AC. Comparative effectiveness and cost-effectiveness of cardioprotective glucose-lowering therapies for type 2 diabetes in Brazil: a Bayesian network model. HEALTH ECONOMICS REVIEW 2023; 13:50. [PMID: 37878108 PMCID: PMC10599033 DOI: 10.1186/s13561-023-00466-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 10/16/2023] [Indexed: 10/26/2023]
Abstract
BACKGROUND The escalating prevalence of type 2 diabetes (T2DM) poses an unparalleled economic catastrophe to developing countries. Cardiovascular diseases remain the primary source of costs among individuals with T2DM, incurring expenses for medications, hospitalizations, and surgical interventions. Compelling evidence suggests that the risk of cardiovascular outcomes can be reduced by three classes of glucose-lowering therapies (GLT), including SGLT2i, GLP-1A, and pioglitazone. However, an evidence-based and cost-effective protocol is still unavailable for many countries. The objective of the current study is to compare the effectiveness and cost-effectiveness of GLT in individuals with T2DM in Brazil. METHODS We employed Bayesian Networks to calculate the incremental cost-effectiveness ratios (ICER), expressed in international dollars (Int$) per disease-adjusted life years [DALYs] averted. To determine the effectiveness of GLT, we conducted a systematic review with network meta-analysis (NMA) to provide insights for our model. Additionally, we obtained cardiovascular outcome incidence data from two real-world cohorts comprising 851 and 1337 patients in primary and secondary prevention, respectively. Our cost analysis took into account the perspective of the Brazilian public health system, and all values were converted to Int$. RESULTS In the NMA, SGLT2i [HR: 0.81 (95% CI 0.69-0.96)], GLP-1A [HR: 0.79 (95% CI 0.67-0.94)], and pioglitazone [HR: 0.73 (95% CI 0.59-0.91)] demonstrated reduced relative risks of non-fatal cardiovascular events. In the context of primary prevention, pioglitazone yielded 0.2339 DALYs averted, with an ICER of Int$7,082 (95% CI 4,521-10,770) per DALY averted when compared to standard care. SGLT2i and GLP-1A also increased effectiveness, resulting in 0.261 and 0.259 DALYs averted, respectively, but with higher ICERs of Int$12,061 (95% CI: 7,227-18,121) and Int$29,119 (95% CI: 23,811-35,367) per DALY averted. In the secondary prevention scenario, all three classes of treatments were deemed cost-effective at a maximum willingness-to-pay threshold of Int$26,700. Notably, pioglitazone consistently exhibited the highest probability of being cost-effective in both scenarios. CONCLUSIONS In Brazil, pioglitazone presented a higher probability of being cost-effective both in primary and secondary prevention, followed by SGLT2i and GLP-1A. Our findings support the use of cost-effectiveness models to build optimized and hierarchical therapeutic strategy in the management of T2DM. TRIAL REGISTRATION CRD42020194415.
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Affiliation(s)
- Ana Claudia Cavalcante Nogueira
- Cardiology Division, Unicamp Medical School, São Paulo, SP, Brazil
- Escola Superior de Ciências da Saúde (ESCS), Brasília, Distrito Federal, Brazil
| | - Joaquim Barreto
- Cardiology Division, Unicamp Medical School, São Paulo, SP, Brazil
| | - Filipe A Moura
- Cardiology Division, Unicamp Medical School, São Paulo, SP, Brazil
- TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Beatriz Luchiari
- Cardiology Division, Unicamp Medical School, São Paulo, SP, Brazil
| | - Abrão Abuhab
- Heart Institute (InCor), Do Hospital das Clínicas - FMUSP, Sao Paulo, Brazil
| | - Isabella Bonilha
- Cardiology Division, Unicamp Medical School, São Paulo, SP, Brazil
| | - Wilson Nadruz
- Cardiology Division, Unicamp Medical School, São Paulo, SP, Brazil
| | | | - Thomas Gaziano
- Department of Cardiovascular Medicine, Brigham & Women's Hospital, Boston, MA, USA
| | - Luiz Sergio F de Carvalho
- Cardiology Division, Unicamp Medical School, São Paulo, SP, Brazil
- Clarity Healthcare Intelligence, Jundiaí, SP, Brasil
| | - Andrei C Sposito
- Cardiology Division, Unicamp Medical School, São Paulo, SP, Brazil.
- Atherosclerosis and Vascular Biology Laboratory (Atherolab), State University of Campinas (Unicamp), Sao Paulo, Campinas, 13084-971, Brazil.
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Klaric KA, Parai JL, Kepron CA, Walker AE, Milroy CM. Postmortem survey of haemoglobin A1c, non-alcoholic steatohepatitis and liver fibrosis within a general population. J Clin Pathol 2023; 76:606-611. [PMID: 35534202 DOI: 10.1136/jclinpath-2021-207998] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Accepted: 04/14/2022] [Indexed: 11/04/2022]
Abstract
AIMS Non-alcoholic steatohepatitis (NASH), fatty liver disease and fibrosis are associated with diabetes mellitus and obesity. Previous autopsy series have reported prevalence of fatty liver disease to be 11%-24%. Recent studies, using imaging and serology, suggest a prevalence of 20%-35%, NASH of 5% and advanced fibrosis of 2%-3%. We examined the prevalence of NASH and liver fibrosis in a general autopsy population. METHODS A cross-sectional study of consecutive, adult, medicolegal autopsies over a 1-year period was conducted. Liver sections were scored for fibrosis, inflammation and steatosis using a modified NASH scoring system. Stepwise logistic regression was used to identify associations between NASH or moderate/severe fibrosis and several clinicopathological parameters, including postmortem haemoglobin A1c (HbA1c). RESULTS Of 376 cases, 86 (22.9%) were classified as NASH. Prevalence of diabetes mellitus, body mass index (BMI) and postmortem HbA1c were significantly higher in NASH cases (39.5%, 32.3 kg/m2 and 6.88%) than non-NASH cases (12.1%, 27.0 kg/m2 and 5.73%). Decedents with moderate/severe fibrosis (6.9%) had higher prevalence of diabetes, BMI and HbA1c (50%, 31.4 kg/m2 and 6.7%) compared with those with no/mild fibrosis (16%, 28 kg/m2 and 5.9%). HbA1c ≥7% was found to be an independent predictor of NASH (OR 5.11, 95% CI 2.61 to 9.98) and advanced fibrosis (OR 3.94, 95% CI 1.63 to 9.53). CONCLUSIONS NASH and advanced fibrosis were higher in our general adult autopsy population compared with previously published estimates. This is a large series with histological evaluation showing that HbA1c >7.0% is independently associated with NASH and advanced fibrosis.
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Affiliation(s)
- Kristina-Ana Klaric
- Department of Pathology and Laboratory Medicine, University of Ottawa Faculty of Medicine, Ottawa, Ontario, Canada
| | - Jacqueline Louise Parai
- Department of Pathology and Laboratory Medicine, University of Ottawa Faculty of Medicine, Ottawa, Ontario, Canada
- Pathology and Laboratory Medicine, Ottawa Hospital General Campus, Ottawa, Ontario, Canada
| | - Charis Anthea Kepron
- Department of Pathology and Laboratory Medicine, University of Ottawa Faculty of Medicine, Ottawa, Ontario, Canada
- Pathology and Laboratory Medicine, Ottawa Hospital General Campus, Ottawa, Ontario, Canada
| | - Alfredo Eugene Walker
- Department of Pathology and Laboratory Medicine, University of Ottawa Faculty of Medicine, Ottawa, Ontario, Canada
- Pathology and Laboratory Medicine, Ottawa Hospital General Campus, Ottawa, Ontario, Canada
| | - Christopher Mark Milroy
- Department of Pathology and Laboratory Medicine, University of Ottawa Faculty of Medicine, Ottawa, Ontario, Canada
- Pathology and Laboratory Medicine, Ottawa Hospital General Campus, Ottawa, Ontario, Canada
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He W, Huang C, Wang L, Su W, Wang S, Huang P, Zhang X, Huang Y, Zhao Y, Lin M, Shi X, Li X. The correlation between triiodothyronine and the severity of liver fibrosis. BMC Endocr Disord 2022; 22:313. [PMID: 36503486 PMCID: PMC9743744 DOI: 10.1186/s12902-022-01228-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 11/23/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The severity of liver fibrosis is an important predictor of death in patients with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM). However, there is still no definite conclusion on the relationship between triiodothyronine (T3) and the severity of liver fibrosis. Thus, the aim of this study was to analyze the correlation between T3 level and the severity of liver fibrosis. METHODS We performed a cross-sectional study of 2072 T2DM patients with normal thyroid function from January 2017 to January 2020. NAFLD fibrosis score (NFS), Fibrosis index based on the 4 factors (FIB-4) and BARD score (BARD) were used to assess the severity of fibrosis in T2DM patients, and linear regression analyses were used to determine the factors independently associated with liver fibrosis. Further experiments were performed to assess the impact of low T3 on fibrosis progression in mice model and explore possible mechanisms. RESULTS Free triiodothyronine (fT3) levels had significantly inverse correlations with NFS and FIB-4, and BARD in T2DM patients (P < 0.05). In multiple linear regression analyses, decreased fT3 level was an independent risk factor for the severity of liver fibrosis of T2DM patients (P < 0.01). Findings from in-vivo experiment using mice model proved that hypothyroidism mice had more severe of liver fibrosis than those mice with normal thyroid function. We also found that T3 could inhibit the profibrotic TREM2+CD9+ macrophage, which had been identified an important player in the progression of liver fibrosis. CONCLUSION The findings from this study proved an inverse correlation between T3 level and the severity of liver fibrosis, and lower fT3 level within the normal range was an independent risk factor for severe liver fibrosis.
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Affiliation(s)
- Weiwei He
- School of Medicine, Xiamen University, Xiamen, China
- Xiamen Diabetes Institute, The First Affiliated Hospital of Xiamen University, Xiamen, China
- Fujian Provincial Key Laboratory of Translational Medicine for Diabetes, Xiamen, Fujian, China
| | - Caoxin Huang
- Xiamen Diabetes Institute, The First Affiliated Hospital of Xiamen University, Xiamen, China
- Fujian Provincial Key Laboratory of Translational Medicine for Diabetes, Xiamen, Fujian, China
| | - Liying Wang
- Xiamen Diabetes Institute, The First Affiliated Hospital of Xiamen University, Xiamen, China
- Fujian Provincial Key Laboratory of Translational Medicine for Diabetes, Xiamen, Fujian, China
| | - Weijuan Su
- Xiamen Diabetes Institute, The First Affiliated Hospital of Xiamen University, Xiamen, China
- Fujian Provincial Key Laboratory of Translational Medicine for Diabetes, Xiamen, Fujian, China
| | - Shunhua Wang
- Xiamen Diabetes Institute, The First Affiliated Hospital of Xiamen University, Xiamen, China
- Fujian Provincial Key Laboratory of Translational Medicine for Diabetes, Xiamen, Fujian, China
| | - Peiying Huang
- Xiamen Diabetes Institute, The First Affiliated Hospital of Xiamen University, Xiamen, China
- Fujian Provincial Key Laboratory of Translational Medicine for Diabetes, Xiamen, Fujian, China
| | - Xiaofang Zhang
- Xiamen Diabetes Institute, The First Affiliated Hospital of Xiamen University, Xiamen, China
- Fujian Provincial Key Laboratory of Translational Medicine for Diabetes, Xiamen, Fujian, China
| | - Yinxiang Huang
- Xiamen Diabetes Institute, The First Affiliated Hospital of Xiamen University, Xiamen, China
- Fujian Provincial Key Laboratory of Translational Medicine for Diabetes, Xiamen, Fujian, China
| | - Yan Zhao
- Xiamen Diabetes Institute, The First Affiliated Hospital of Xiamen University, Xiamen, China
- Fujian Provincial Key Laboratory of Translational Medicine for Diabetes, Xiamen, Fujian, China
| | - Mingzhu Lin
- Xiamen Diabetes Institute, The First Affiliated Hospital of Xiamen University, Xiamen, China
- Fujian Provincial Key Laboratory of Translational Medicine for Diabetes, Xiamen, Fujian, China
| | - Xiulin Shi
- Xiamen Diabetes Institute, The First Affiliated Hospital of Xiamen University, Xiamen, China.
- Fujian Provincial Key Laboratory of Translational Medicine for Diabetes, Xiamen, Fujian, China.
- Department of Endocrinology and Diabetes, The First Affiliated Hospital, Xiamen University, No.55 Zhenhai Road, 361003, Xaimen, China.
| | - Xuejun Li
- Xiamen Diabetes Institute, The First Affiliated Hospital of Xiamen University, Xiamen, China.
- Fujian Provincial Key Laboratory of Translational Medicine for Diabetes, Xiamen, Fujian, China.
- Department of Endocrinology and Diabetes, The First Affiliated Hospital, Xiamen University, No.55 Zhenhai Road, 361003, Xaimen, China.
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Association between hepatic steatosis and fibrosis with measures of insulin sensitivity in patients with severe obesity and type 2 diabetes - a cross-sectional study. BMC Gastroenterol 2022; 22:448. [PMID: 36336684 PMCID: PMC9639281 DOI: 10.1186/s12876-022-02550-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 10/20/2022] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND Obesity, non-alcoholic fatty liver disease (NAFLD) and insulin resistance are three pathological conditions highly correlated, but this relationship is not fully elucidated. Hence, we aimed to assess the association of hepatic steatosis and fibrosis with different measures of insulin sensitivity in patients with severe obesity and type 2 diabetes mellitus (T2DM). METHODS A cross-sectional study (Oseberg trial) including patients with T2DM referred for bariatric surgery at Vestfold Hospital Trust, Norway. Magnetic resonance imaging (MRI) and the enhanced liver fibrosis (ELF) test was used for estimation of liver fat fraction (LFF) and degree of fibrosis, respectively. Oral and intravenous glucose tolerance tests were applied for estimation of insulin sensitivity (HOMA2S, Matsuda ISI and MinMod SI). RESULTS A total of 100 patients (mean [SD] age 47.5 [9.7] years, 65% women, BMI 42.0 [5.3] kg/m2 and 98% with metabolic syndrome) were included in the analyses. The mean (SD) LFF in the total population was 19.1 (11.5), and the mean (SD) ELF score was 8.46 (0.84), a value representing moderate fibrosis. LFF was inversely associated with HOMA2S and Matsuda ISI, and both measures were significantly higher in the no or low-grade steatosis group compared with the medium-to-high grade steatosis group (mean difference [95% CI] 5.9 [2.2-9.6]%, Cohen's d = 0.75), and (0.7 [0.3-1.1], Cohen's d = 0.80, respectively). There was no association between LFF, as a categorical or continuous variable, and MinMod SI. The proportions of patients with none to mild fibrosis, moderate fibrosis and severe fibrosis were 14, 78 and 6%, respectively, and there were no significant associations between level of fibrosis and measures of insulin sensitivity. CONCLUSIONS Patients with morbid obesity and T2DM demonstrated high levels of liver fat fraction, and we showed that hepatic steatosis, but not the degree of liver fibrosis, was associated with different measures of insulin sensitivity in patients with severe obesity and T2DM. Further, our results might indicate that the LFF is primarily associated with hepatic, and not peripheral insulin sensitivity. To improve the diagnosis of NAFLD and the prediction of its progression, more studies are needed to reveal the pathological mechanistic pathways involved in NAFLD and insulin sensitivity. TRIAL REGISTRATION ClinicalTrials.gov: NCT01778738.
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Phillips BE, Lantier L, Engman C, Garciafigueroa Y, Singhi A, Trucco M, Mantzoros C, Wasserman D, Giannoukakis N. Improvement in insulin sensitivity and prevention of high fat diet-induced liver pathology using a CXCR2 antagonist. Cardiovasc Diabetol 2022; 21:130. [PMID: 35831885 PMCID: PMC9277870 DOI: 10.1186/s12933-022-01564-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 05/28/2022] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Liver pathology (LP) characteristic of non-alcoholic fatty acid disease (NAFLD)/non-alcoholic steatohepatitis (NASH) is a prevalent co-morbidity of type 2 diabetes (T2D). Accumulating evidence indicates that neutrophils driving insulin resistance (IR), including hepatic IR, precipitate T2D-associated NAFLD/NASH. We hypothesized that targeting neutrophil accumulation into insulin-sensitive tissues in mice using a CXCR2 antagonist under T2D-precipitating high fat diet (HFD) could improve insulin sensitivity and prevent the progression towards liver pathology reminiscent of NAFLD/NASH. METHODS Mice were age-matched and on standard rodent chow prior to 1:1 randomization into control and HFD formulated with the CXCR2 antagonist AZD5069 or with biologically inactive substitute. They were monitored for metabolic changes including insulin sensitivity using the hyperinsulinemic-euglycemic clamp and hepatic histopathologic evaluation in H&E-stained sections as well as via immunofluorescence microscopy of liver sections for leukocyte markers, collagen 1A1 formation, α-smooth muscle actin (SMA), and galectin-3 expression, for 16 weeks. Statistical tests used to determine significant differences among study groups and outcomes include Student's t-test, one-way ANOVA, repeated measures two-way ANOVA, and Fisher's exact test, depending on the analytical question. RESULTS Compared to mice on HFD, mice in the AZD5069-formulated HFD exhibited improved insulin sensitivity, a modest reduction in weight gain, and a significant improvement in LP and markers related to NAFLD/NASH. Mice in the AZD5069-formulated HFD also exhibited reduced neutrophil accumulation into the liver at the end of the 16 week study period. CONCLUSIONS These results show, for the first time, the effectiveness of a selective CXCR2 antagonist to improve insulin sensitivity, concomitantly preventing the progression towards LP characteristic of NAFLD/NASH. This represents a novel approach to target IR and developing LP under T2D-susceptible conditions using a single agent. Furthermore, our data extend the growing evidence in support of neutrophils as a leukocyte population that imprints and maintains a chronic inflammatory state in the progression of dysregulated metabolism in liver-specific co-morbid conditions.
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Affiliation(s)
- Brett E. Phillips
- Institute of Cellular Therapeutics, Allegheny Health Network, 11th Floor South Tower, 320 East North Avenue, Pittsburgh, PA S15212 USA
| | - Louise Lantier
- Department of Molecular Physiology and Biophysics, Vanderbilt University., Nashville, TN 37232 USA
| | - Carl Engman
- Institute of Cellular Therapeutics, Allegheny Health Network, 11th Floor South Tower, 320 East North Avenue, Pittsburgh, PA S15212 USA
| | - Yesica Garciafigueroa
- Institute of Cellular Therapeutics, Allegheny Health Network, 11th Floor South Tower, 320 East North Avenue, Pittsburgh, PA S15212 USA
| | - Aatur Singhi
- Department of Pathology, School of Medicine, Room A616.2, UPMC Presbyterian, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15213 USA
| | - Massimo Trucco
- Institute of Cellular Therapeutics, Allegheny Health Network, 11th Floor South Tower, 320 East North Avenue, Pittsburgh, PA S15212 USA
| | - Christos Mantzoros
- Section of Endocrinology, VA Boston Healthcare System, Harvard Medical School, Boston, USA
- Department of Medicine Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA USA
| | - David Wasserman
- Department of Molecular Physiology and Biophysics, Vanderbilt University., Nashville, TN 37232 USA
| | - Nick Giannoukakis
- Institute of Cellular Therapeutics, Allegheny Health Network, 11th Floor South Tower, 320 East North Avenue, Pittsburgh, PA S15212 USA
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The Protective Effects of Securigera securidaca Seed Extract on Liver Injury Induced by Bile Duct Ligation in Rats. BIOMED RESEARCH INTERNATIONAL 2022; 2022:6989963. [PMID: 35155679 PMCID: PMC8837422 DOI: 10.1155/2022/6989963] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Accepted: 01/19/2022] [Indexed: 11/26/2022]
Abstract
This study is aimed at evaluating the effects of Securigera securidaca (SS) seed extract on cholestatic liver injury induced by bile duct ligation (BDL) in rats. Total polyphenols and flavonoids in SS seed extract were determined using a colorimetric assay, and their components were quantified using HPLC. Rats in four groups underwent BDL at the common bile duct and were treated for 21 days with either oral distilled water as vehicle, vitamin C, 100 mg/kg SS seed extract, or 200 mg/kg SS seed extract. Rats in the fifth group underwent abdominal incision without BDL and were treated with distilled water, and rats in the sixth group were healthy and received nothing. Finally, rats were sacrificed, blood samples were analyzed through biochemical methods, liver tissues were histologically assessed, and the expression of the TGFβ-1, iNOS, caspase-3, and α-SMA genes in the liver was assessed through real-time PCR. BDL significantly increased, and SS seed extract significantly decreased the serum levels of bilirubin and liver function enzymes. Moreover, SS seed extract suppressed the expression of the TGFβ-1, iNOS, caspase-3, and α-SMA genes, reduced the levels of nitric oxide, malondialdehyde, and protein carbonyl, and increased the levels of glutathione, total antioxidant capacity, and SOD and catalase enzyme activity in the serum and liver. Extract at a dose of 100 mg/kg had significant positive effects on liver morphology and parenchyma structure in a dose-dependent manner.
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10
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Ishiba H, Sumida Y, Seko Y, Tanaka S, Yoneda M, Hyogo H, Ono M, Fujii H, Eguchi Y, Suzuki Y, Yoneda M, Takahashi H, Nakahara T, Mori K, Kanemasa K, Shimada K, Imajo K, Yamaguchi K, Kawaguchi T, Nakajima A, Chayama K, Shima T, Fujimoto K, Okanoue T, Itoh Y. Type IV Collagen 7S Is the Most Accurate Test For Identifying Advanced Fibrosis in NAFLD With Type 2 Diabetes. Hepatol Commun 2021; 5:559-572. [PMID: 33860115 PMCID: PMC8034577 DOI: 10.1002/hep4.1637] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 10/06/2020] [Accepted: 10/16/2020] [Indexed: 12/17/2022] Open
Abstract
This study aimed to examine whether the diagnostic accuracy of four noninvasive tests (NITs) for detecting advanced fibrosis in nonalcoholic fatty liver disease (NAFLD) is maintained or is inferior to with or without the presence of type 2 diabetes. Overall, 874 patients with biopsy-proven NAFLD were enrolled. After propensity-score matching by age, sex, and the prevalence of dyslipidemia, 311 patients were enrolled in each group of with or without diabetes. To evaluate the effect of diabetes, we compared the diagnostic accuracy of the fibrosis-4 (FIB-4) index, the NAFLD fibrosis score (NFS), the aspartate aminotransferase to platelet ratio index (APRI), and type IV collagen 7S (COL4-7S) in patients with NAFLD with and without diabetes. The areas under the receiver operating characteristic curve (AUROC) for identifying advanced fibrosis in patients without diabetes were 0.879 for the FIB-4 index, 0.851 for the NFS, 0.862 for the APRI, and 0.883 for COL4-7S. The AUROCs in patients with diabetes were 0.790 for the FIB-4 index, 0.784 for the NFS, 0.771 for the APRI, and 0.872 for COL4-7S. The AUROC of COL4-7S was significantly larger than that of the other NITs in patients with NAFLD with diabetes than in those without diabetes. The optimal high and low cutoff points of COL4-7S were 5.9 ng/mL and 4.8 ng/mL, respectively. At the low cutoff point, the accuracy of COL4-7S was better than that of the other NITs, especially in patients with diabetes. Conclusion: COL4-7S measurement might be the best NIT for identifying advanced fibrosis in NAFLD, especially in NAFLD with diabetes.
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Affiliation(s)
- Hiroshi Ishiba
- Department of GastroenterologyJapanese Red Cross Society Kyoto Daiichi HospitalKyotoJapan.,Department of Gastroenterology and HepatologyKyoto Prefectural University of MedicineKyotoJapan
| | - Yoshio Sumida
- Division of Hepatology and PancreatologyDepartment of Internal MedicineAichi Medical UniversityAichiJapan
| | - Yuya Seko
- Department of Gastroenterology and HepatologyKyoto Prefectural University of MedicineKyotoJapan
| | - Saiyu Tanaka
- Center for Digestive and Liver DiseasesNara City HospitalNaraJapan
| | - Masato Yoneda
- Division of GastroenterologyYokohama City University Graduate School of MedicineYokohamaJapan
| | - Hideyuki Hyogo
- Department of GastroenterologyJA Hiroshima General HospitalHiroshimaJapan
| | - Masafumi Ono
- Division of Gastroenterology and HepatologyDepartment of Internal MedicineTokyo Women's Medical University Medical Center EastTokyoJapan
| | - Hideki Fujii
- Department of HepatologyGraduate School of MedicineOsaka City UniversityOsakaJapan
| | - Yuichiro Eguchi
- Department of Internal MedicineSaga Medical SchoolSaga UniversitySagaJapan
| | - Yasuaki Suzuki
- Department of GastroenterologyNayoro City General HospitalNayaroJapan
| | - Masashi Yoneda
- Division of Hepatology and PancreatologyDepartment of Internal MedicineAichi Medical UniversityAichiJapan
| | - Hirokazu Takahashi
- Department of Internal MedicineSaga Medical SchoolSaga UniversitySagaJapan
| | - Takashi Nakahara
- Department of Gastroenterology and MetabolismApplied Life SciencesInstitute of Biomedical & Health SciencesHiroshima UniversityHiroshimaJapan
| | - Kojiro Mori
- Center for Digestive and Liver DiseasesNara City HospitalNaraJapan
| | | | | | - Kento Imajo
- Division of GastroenterologyYokohama City University Graduate School of MedicineYokohamaJapan
| | - Kanji Yamaguchi
- Department of Gastroenterology and HepatologyKyoto Prefectural University of MedicineKyotoJapan
| | - Takumi Kawaguchi
- Division of GastroenterologyDepartment of MedicineKurume University School of MedicineKurumeJapan
| | - Atsushi Nakajima
- Division of GastroenterologyYokohama City University Graduate School of MedicineYokohamaJapan
| | - Kazuaki Chayama
- Department of Gastroenterology and MetabolismApplied Life SciencesInstitute of Biomedical & Health SciencesHiroshima UniversityHiroshimaJapan
| | | | - Kazuma Fujimoto
- Department of Internal MedicineSaga Medical SchoolSaga UniversitySagaJapan
| | | | - Yoshito Itoh
- Department of Gastroenterology and HepatologyKyoto Prefectural University of MedicineKyotoJapan
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Point-of-Care Ultrasound (POCUS) in the Field of Diabetology. Int J Chronic Dis 2021; 2021:8857016. [PMID: 33763467 PMCID: PMC7964119 DOI: 10.1155/2021/8857016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 02/16/2021] [Accepted: 02/23/2021] [Indexed: 11/17/2022] Open
Abstract
Ultrasound is increasingly used in daily clinical practice to improve the efficiency of the clinical examination. In this article, we reviewed its various possible uses in the field of diabetology. The ultrasonic evaluation of the carotid arteries (plaques and intima media thickness) allows improving the assessment of the cardiovascular risk. Steatosis can be detected relatively easily on liver ultrasound. Ultrasound also allows a more sensitive detection of lipohypertrophy resulting in glycemic fluctuations and thus increasing the risk of hypoglycemia than the clinical examination. Finally, muscle ultrasound appears to be a promising tool to assess the nutritional status and its consequences (e.g., falls).
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12
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Nah EH, Cho S, Kim S, Chu J, Kwon E, Cho HI. Prevalence of liver fibrosis and associated risk factors in the Korean general population: a retrospective cross-sectional study. BMJ Open 2021; 11:e046529. [PMID: 33762246 PMCID: PMC7993338 DOI: 10.1136/bmjopen-2020-046529] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES The health burden of chronic liver disease is increasing worldwide. Its main histological consequence is liver fibrosis, and eventually cirrhosis. This process is rarely diagnosed at the pre-cirrhotic stage due to it being asymptomatic. Little is known about the prevalence of liver fibrosis and associated risk factors in the general population. The aims of this study were to determine the prevalence and distribution of liver fibrosis using magnetic resonance elastography (MRE), as well as the risk factors associated with liver fibrosis in the asymptomatic general population. DESIGN, SETTING AND PARTICIPANTS This cross-sectional retrospective study consecutively selected subjects who underwent health check-ups including MRE at 13 health promotion centres in Korea between 2018 and 2020. Liver fibrosis was estimated using MRE with cut-off values for significant and advanced liver fibrosis of 2.90 and 3.60 kPa, respectively. PRIMARY AND SECONDARY OUTCOME MEASURES The Χ2 test was used to compare the prevalence of liver fibrosis according to sex and age groups. Multivariable logistic regression analyses were performed to identify the factors for significant and advanced liver fibrosis. RESULTS Among the 8183 subjects, 778 (9.5%) had ≥significant fibrosis (≥2.9 kPa), which included 214 (2.6%) subjects with ≥advanced fibrosis (≥3.6 kPa). Multivariable analysis revealed that liver fibrosis was associated with age (OR=1.34, 95% CI=1.18 to 1.51), male sex (OR=3.18, 95% CI=1.97 to 5.13), diabetes (OR=2.43, 95% CI=1.8 to 3.28), HBsAg positivity (OR=3.49, 95% CI=2.55 to 4.79), abnormal liver function test (OR=1.9, 95% CI=1.49 to 2.42) and obesity (OR=1.77, 95% CI=1.35 to 2.32) (all p<0.001), as well as metabolic syndrome (OR=1.4, 95% CI=1.05 to 1.87) (p=0.024). CONCLUSIONS The prevalence of significant or more liver fibrosis was high in the Korean general population and much higher among individuals with risk factors. This suggests that screening of liver fibrosis should be considered in general population, especially among high-risk groups.
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Affiliation(s)
- Eun-Hee Nah
- Health Promotion Research Institute, Korea Association of Health Promotion, Seoul, South Korea
| | - Seon Cho
- Health Promotion Research Institute, Korea Association of Health Promotion, Seoul, South Korea
| | - Suyoung Kim
- Health Promotion Research Institute, Korea Association of Health Promotion, Seoul, South Korea
| | - Jieun Chu
- Health Promotion Research Institute, Korea Association of Health Promotion, Seoul, South Korea
| | - Eunjoo Kwon
- Health Promotion Research Institute, Korea Association of Health Promotion, Seoul, South Korea
| | - Han-Ik Cho
- MEDIcheck LAB, Korea Association of Health Promotion, Seoul, South Korea
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Dufour JF, Caussy C, Loomba R. Combination therapy for non-alcoholic steatohepatitis: rationale, opportunities and challenges. Gut 2020; 69:1877-1884. [PMID: 32381514 PMCID: PMC7497577 DOI: 10.1136/gutjnl-2019-319104] [Citation(s) in RCA: 135] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 04/08/2020] [Accepted: 04/21/2020] [Indexed: 12/19/2022]
Abstract
Non-alcoholic steatohepatitis (NASH) is becoming a leading cause of cirrhosis with the burden of NASH-related complications projected to increase massively over the coming years. Several molecules with different mechanisms of action are currently in development to treat NASH, although reported efficacy to date has been limited. Given the complexity of the pathophysiology of NASH, it will take the engagement of several targets and pathways to improve the results of pharmacological intervention, which provides a rationale for combination therapies in the treatment of NASH. As the field is moving towards combination therapy, this article reviews the rationale for such combination therapies to treat NASH based on the current therapeutic landscape as well as the advantages and limitations of this approach.
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Affiliation(s)
- Jean-François Dufour
- Hepatology, Department of Clinical Research, University of Bern, Bern, Switzerland
- University Clinic for Visceral Surgery and Medicine, Inselspital, Bern, Switzerland
| | - Cyrielle Caussy
- Centre Hospitalier Lyon Sud, Endocrinologie Diabète et Nutrition, University Lyon 1, Hospices Civils de Lyon, Lyon, France
- NAFLD Research Center, University of California at San Diego, La Jolla, California, USA
| | - Rohit Loomba
- Division of Gastroenterology and Hepatology, Department of Medicine, NAFLD Research Center, University of California at San Diego, La Jolla, California, USA
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15
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Mansour A, Mohajeri-Tehrani MR, Samadi M, Gerami H, Qorbani M, Bellissimo N, Poustchi H, Hekmatdoost A. Risk factors for non-alcoholic fatty liver disease-associated hepatic fibrosis in type 2 diabetes patients. Acta Diabetol 2019; 56:1199-1207. [PMID: 31197470 DOI: 10.1007/s00592-019-01374-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Accepted: 05/30/2019] [Indexed: 02/07/2023]
Abstract
AIMS In patients with type 2 diabetes, non-alcoholic fatty liver disease (NAFLD) and liver fibrosis is frequent and presumably associated with increased cardiovascular disease risk and mortality. The objective was to investigate risk factors associated with hepatic fibrosis in patients with type 2 diabetes and NAFLD to provide a basis for the prevention and treatment. METHODS Liver stiffness measurements (LSM) expressed in kilopascals (kPa) and controlled attenuation parameter (CAP) expressed in dB/m were diagnosed by transient elastography. Hepatic steatosis and significant fibrosis were defined as having a CAP score ≥ 260 dB/m and an LSM score ≥ 8 kPa, respectively. Associations between fibrosis categories with anthropometric and metabolic variables were determined; then, variables with statistical significance in the univariate analysis were included in multivariate model. RESULTS A total of 108 participant with type 2 diabetes and NAFLD (mean age: 44.69 ± 5.57 years; mean duration of diabetes 4.68 ± 4.24 years) were recruited. In these patients, body mass index, obesity, fat mass, waist circumferences, resting energy expenditure, CAP score, fasting insulin, C-peptide, HbA1C, hs-CRP as well as liver enzymes and systolic blood pressure and diastolic blood pressure were positively associated with fibrosis (all p < 0.05). Using multivariate logistic regression, serum aspartate aminotransferase (OR 1.12; 95% CI 1.06-1.19), waist circumferences (odds ratio [OR] 1.15; 95% CI 1.05-1.25) and C-peptide (OR 3.81; 95% CI 1.5-9.7) remained as independently associated with liver fibrosis. CONCLUSION For participants with type 2 diabetes with coexisting NAFLD, stratification by independent risk factors for fibrosis could have important prognostic value.
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Affiliation(s)
- Asieh Mansour
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, 46, West Arghavan St., Farahzadi Blvd., Shahrak Gharb, Tehran, Iran
| | - Mohammad Reza Mohajeri-Tehrani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Majid Samadi
- Radiology Department, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Hadis Gerami
- Obesity and Eating Habits Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mostafa Qorbani
- Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
- Chronic Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Nick Bellissimo
- School of Nutrition, Faculty of Community Services, Ryerson University, Toronto, Canada
| | - Hossein Poustchi
- Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Azita Hekmatdoost
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, 46, West Arghavan St., Farahzadi Blvd., Shahrak Gharb, Tehran, Iran.
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16
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Uhanova J, Minuk G, Premji K, Chandok N. Serial liver transaminases have no prognostic value in non-alcoholic fatty liver disease. CANADIAN LIVER JOURNAL 2019; 2:19-22. [DOI: 10.3138/canlivj.2018-0006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Accepted: 04/07/2018] [Indexed: 11/20/2022]
Abstract
Background: Routine measurement of liver transaminases is common in the general monitoring of patients with non-alcoholic fatty liver disease (NAFLD), but there is little data to support the utility of this practice. The aims of this study were to determine how alanine aminotransferase (ALT) results vary over time in patients with NAFLD; and to determine if serial measurement of ALT is a useful clinical marker for progression of NAFLD. Methods: Consecutive adult patients with NAFLD were followed prospectively in a tertiary liver disease clinic over a 15-year period. Clinicodemographic characteristics and the change in liver enzymes, liver function, and histopathology were followed over time. Paired t test, chi-square test, analysis of variance (ANOVA), and logistic regression were performed to assess the relationship between ALT and severity of NAFLD, or development of cirrhosis or hepatocellular carcinoma (HCC). Results/Conclusion: A change in liver transaminases over time is not a useful metric in predicting outcomes in patients with NAFLD. Additionally, all stages of NAFLD are equally responsive to standard medical interventions of advocating for weight loss and correcting metabolic disturbances.
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Affiliation(s)
- Julia Uhanova
- Section of Hepatology, John Buhler Research Centre, University of Manitoba, Winnipeg, Manitoba
| | - Gerald Minuk
- Section of Hepatology, John Buhler Research Centre, University of Manitoba, Winnipeg, Manitoba
| | - Kamila Premji
- Division of Gastroenterology, Multi-Organ Transplant Program, University of Western Ontario, London, Ontario
| | - Natasha Chandok
- Section of Hepatology, John Buhler Research Centre, University of Manitoba, Winnipeg, Manitoba
- Division of Gastroenterology, Multi-Organ Transplant Program, University of Western Ontario, London, Ontario
- Department of Medicine, William Osler Health Centre, Brampton, Ontario
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Tabuchi H, Maegawa H, Tobe K, Nakamura I, Uno S. Effect of ipragliflozin on liver function in Japanese type 2 diabetes mellitus patients: a subgroup analysis of the STELLA-LONG TERM study (3-month interim results). Endocr J 2019; 66:31-41. [PMID: 30393249 DOI: 10.1507/endocrj.ej18-0217] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
This subgroup analysis of STELLA-LONG TERM, an ongoing 3-year post-marketing surveillance study on the long-term efficacy and safety of ipragliflozin, assessed the effect of ipragliflozin on liver function in type 2 diabetes mellitus (T2DM) patients. Patients were divided according to baseline liver function (normal [male: ALT ≤30, female: ALT ≤20], abnormal [male: ALT ≥31, female: ALT ≥21]). We evaluated changes in aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase (γ-GTP), alkaline phosphatase (ALP), and fatty liver index (FLI) at 3 months of treatment; the proportion of patients with abnormal liver function whose liver function normalized after 3 months of treatment; and correlations between changes in ALT levels and efficacy variables/laboratory values. Liver function was normal in 2,570 and abnormal in 3,239 patients. Only patients with abnormal liver function showed a statistically/clinically significant decrease in AST, ALT, γ-GTP, and ALP levels at 3 months (all p < 0.05 vs. baseline). The FLI significantly decreased from 63.2677 ± 26.4363 (baseline) to 56.7137 ± 27.6484 (3 months) (p < 0.05) in the overall patient population. Liver function normalized in 20.5% (543/2,648) of patients with abnormal liver function. There was no obvious correlation between changes in ALT and changes in efficacy/laboratory parameters. Liver function improved after 3-month treatment with ipragliflozin in T2DM patients with abnormal liver function.
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Affiliation(s)
| | - Hiroshi Maegawa
- Department of Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan
| | - Kazuyuki Tobe
- First Department of Internal Medicine, University of Toyama, Sugitani, Toyama 930-0194, Japan
| | | | - Satoshi Uno
- Astellas Pharma Inc., Chuo-ku, Tokyo 103-8411, Japan
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CB1 receptor blockade ameliorates hepatic fat infiltration and inflammation and increases Nrf2-AMPK pathway in a rat model of severely uncontrolled diabetes. PLoS One 2018; 13:e0206152. [PMID: 30365523 PMCID: PMC6203369 DOI: 10.1371/journal.pone.0206152] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 10/08/2018] [Indexed: 12/26/2022] Open
Abstract
Previous studies have shown that the CB1 receptor antagonist reverses steatohepatitis and its related features of metabolic syndrome, such as obesity and type 2 diabetes. However, the beneficial effects of CB1 receptor blockade on hepatic steatosis and inflammation have not been investigated independently of its effects on body weight and glycemic control. At 32 weeks of age, OLETF rats were administered with rimonabant (10 mg·kg−1·day−1) by oral gavage for 6 weeks. No significant changes in body weight, OGTT, and serum glucose were observed in spite of rimonabant-decreased food intake. Moreover, there was a significant difference between initial and final body weight, regardless of rimonabant administration, indicating that OLETF rats were severely diabetic rats. Rimonabant administration significantly decreased serum liver enzyme levels such as ALT and AST, hepatic fat accumulation, lipid peroxidation, and cell death as demonstrated by the number of TUNEL-positive cells in severely uncontrolled diabetic OLETF rats. Significant decreases in hepatic gene expression of proinflammatory cytokines (CD11b, F4/80, MCP1, and TNFα), negative inflammatory mediators (SOCS1 and SOCS3), and fibrosis-related proteins (TGFβ, collagen 1, and TIMP1) were found in rimonabant-treated OLETF rats. Six-week administration of rimonabant significantly upregulated mRNA levels of CPT1α and PPARα related to β-oxidation. Moreover, significant increases in Nrf2 gene expression and its downstream genes, NQO1, GSAT, HO-1, and TXNRD1 along with increased AMPK phosphorylation were noted in uncontrolled diabetic rats treated with rimonabant. The observed potent inhibitory effects of CB1 receptor blockade on hepatic fat infiltration and cellular death in severely uncontrolled diabetic rats indicate that CB1 receptor is a possible therapeutic target. Increased Nrf2 and AMPK phosphorylation may play a role in the mechanism of rimonabant action.
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Ultrasound Grade of Liver Steatosis Is Independently Associated with the Risk of Metabolic Syndrome. Can J Gastroenterol Hepatol 2018; 2018:8490242. [PMID: 30211140 PMCID: PMC6126110 DOI: 10.1155/2018/8490242] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Accepted: 07/30/2018] [Indexed: 12/12/2022] Open
Abstract
The aim of the study was to explore (a) prevalence and grade of nonalcoholic fatty liver (NAFL) among outpatients referred for abdominal ultrasound (US) examination and (b) relationship between the presence and severity of liver steatosis and metabolic syndrome (MS). This was a retrospective analysis of patients without history of liver disease examined by abdominal US in the University hospital setting. US was used to detect and semiquantitatively grade (0-3) liver steatosis. Data on patients' age, gender, body mass index (BMI), impaired glucose metabolism (IGM), atherogenic dyslipidaemia (AD), raised blood pressure (RBP), transaminases, and platelet counts were obtained from medical records. MS was defined as having at least 3 of the following components: obesity, IGM, AD, and RBP. Of the 631 patients (median age 60 years, median BMI 27.4 kg/m2, and 57.4% females) 71.5% were overweight and 48.5% had NAFL. In the subgroup of 159 patients with available data on the components of MS, patients with higher US grade of steatosis had significantly higher BMI and increased prevalence of obesity, IGM, AD, RBP, and accordingly more frequently had MS, whereas they did not differ in terms of age and gender. NAFL was independently associated with the risk of having MS in a multivariate model adjusted for age, gender, BMI, and IGM. The grade of liver steatosis did not correlate with the presence of liver fibrosis. We demonstrated worrisome prevalence of obesity and NAFL in the outpatient population from our geographic region. NAFL is independently associated with the risk of having MS implying worse prognosis.
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20
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Elcioglu ZC, Reeves HL. NAFLD-which patients should have hepatocellular carcinoma surveillance? Hepatobiliary Surg Nutr 2017; 6:353-355. [PMID: 29152488 DOI: 10.21037/hbsn.2017.06.04] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Affiliation(s)
- Zeynep C Elcioglu
- Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Helen L Reeves
- Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.,Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK
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21
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Cimini FA, Barchetta I, Carotti S, Bertoccini L, Baroni MG, Vespasiani-Gentilucci U, Cavallo MG, Morini S. Relationship between adipose tissue dysfunction, vitamin D deficiency and the pathogenesis of non-alcoholic fatty liver disease. World J Gastroenterol 2017; 23:3407-3417. [PMID: 28596677 PMCID: PMC5442077 DOI: 10.3748/wjg.v23.i19.3407] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2016] [Revised: 02/28/2017] [Accepted: 04/13/2017] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. Its pathogenesis is complex and not yet fully understood. Over the years many studies have proposed various pathophysiological hypotheses, among which the currently most widely accepted is the “multiple parallel hits” theory. According to this model, lipid accumulation in the hepatocytes and insulin resistance increase the vulnerability of the liver to many factors that act in a coordinated and cooperative manner to promote hepatic injury, inflammation and fibrosis. Among these factors, adipose tissue dysfunction and subsequent chronic low grade inflammation play a crucial role. Recent studies have shown that vitamin D exerts an immune-regulating action on adipose tissue, and the growing wealth of epidemiological data is demonstrating that hypovitaminosis D is associated with both obesity and NAFLD. Furthermore, given the strong association between these conditions, current findings suggest that vitamin D may be involved in the relationship between adipose tissue dysfunction and NAFLD. The purpose of this review is to provide an overview of recent advances in the pathogenesis of NAFLD in relation to adipose tissue dysfunction, and in the pathophysiology linking vitamin D deficiency with NAFLD and adiposity, together with an overview of the evidence available on the clinical utility of vitamin D supplementation in cases of NAFLD.
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22
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Prevalence of clinically significant liver disease within the general population, as defined by non-invasive markers of liver fibrosis: a systematic review. Lancet Gastroenterol Hepatol 2017; 2:288-297. [DOI: 10.1016/s2468-1253(16)30205-9] [Citation(s) in RCA: 105] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Revised: 11/24/2016] [Accepted: 11/24/2016] [Indexed: 02/06/2023]
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Rabiee B, Roozafzai F, Hemasi GR, Poustchi H, Keyvani H, Khonsari MR, Ajdarkosh H, Maadi M, Sima Saeedian F, Zamani F. The Prevalence of Non-alcoholic Fatty Liver Disease and Diabetes Mellitus in an Iranian Population. Middle East J Dig Dis 2017. [PMID: 28638584 PMCID: PMC5471107 DOI: 10.15171/mejdd.2017.56] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Type II diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD) are important causes of morbidity and mortality worldwide. We aimed to estimate the prevalence of DM in the context of NAFLD. METHODS In this cross-sectional study, we studied 5052 participants, aged 18 years and older, of a baseline population-based cohort in northern Iran (N=6143). The prevalence of DM was estimated in individuals with and without NAFLD. The association between NAFLD and T2DM was evaluated using logistic regression with the adjustment of confounding effects of age, sex, body mass index, lipid profiles, and fasting insulin. RESULTS In men, the prevalence (95% confidence interval) of T2DM was 5.34% (4.35%-6.34%) and 15.06% (13.12%-17.00%) in individuals without and with NAFLD, respectively (p <0.001). In women without NAFLD, the prevalence was 8.27% (6.83%-9.71%) while in the presence of NAFLD, the prevalence was 27.21% (24.59%-29.83%), (p <0.001). In univariate analysis, the chance of having T2DM was 3.700 (3.130-4.380) times more in patients with NAFLD compared with subjects without NAFLD (p<0.001). This chance was reduced (Odds Ratio=1.976, 95% CI: 1.593-2.451, p <0.001) after removing the effects of other variables. CONCLUSION The prevalence of T2DM is increased in the context of NAFLD. This condition may be considered as an independent predictor of T2DM.
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Affiliation(s)
- Behnam Rabiee
- Gastrointestinal and Liver Disease Research Center, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Farzin Roozafzai
- Gastrointestinal and Liver Disease Research Center, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Gholam Reza Hemasi
- Gastrointestinal and Liver Disease Research Center, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Hossein Poustchi
- Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Keyvani
- Department of Virology, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahmood Reza Khonsari
- Gastrointestinal and Liver Disease Research Center, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Hossein Ajdarkosh
- Gastrointestinal and Liver Disease Research Center, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Mansooreh Maadi
- Gastrointestinal and Liver Disease Research Center, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Sima Saeedian
- Gastrointestinal and Liver Disease Research Center, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Farhad Zamani
- Gastrointestinal and Liver Disease Research Center, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran
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The role of elevated alanine aminotransferase (ALT), FasL and atherogenic dyslipidemia in type II diabetes mellitus. J Taibah Univ Med Sci 2016; 12:8-13. [PMID: 31435207 PMCID: PMC6694928 DOI: 10.1016/j.jtumed.2016.10.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2016] [Revised: 09/28/2016] [Accepted: 10/02/2016] [Indexed: 01/09/2023] Open
Abstract
Objectives Many cross-sectional and prospective studies have shown that type 2 diabetes mellitus is a probable cause of non-alcoholic fatty liver disease (NAFLD) with fibrosis and cirrhosis. This research aimed to examine the plasma amino transaminase levels as biomarkers of NAFLD and their association with apoptosis markers (Fas and FasL) as well as the lipid profile in type II diabetic patients. Methods This cross-sectional comparative study included 120 type II diabetic and 100 non-diabetic patients, and their defined biomarkers were studied. Results The results showed that the mean ALT levels, FasL and triglyceride/high density lipoprotein (TG/HDL) ratio were significantly higher in patients with type II diabetics. According to the Atherogenic Index of Plasma (Log TG/HDL), approximately 45% of diabetic patients had a high risk and 11% had an intermediate risk of developing cardiovascular disease. Alanine aminotransferase (ALT) was significantly and positively correlated with FasL, TG, glucose levels and body mass index (BMI) in diabetic patients. Moreover, TG was positively correlated with blood glucose levels and BMI, whereas HDL was negatively correlated with FasL and ALT. Conclusion The results of this study showed that in diabetic patients, elevated ALT levels and FasL may play a role in the risk of developing liver disease and could be used as a distinct marker of NAFLD, indicating liver injury. Moreover, atherogenic dyslipidaemia is a prominent feature in type II diabetes mellitus. Low HDL-c is closely associated with hypertriglyceridemia with an increased risk of cardiovascular disease and NAFLD in diabetics.
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Hazlehurst JM, Woods C, Marjot T, Cobbold JF, Tomlinson JW. Non-alcoholic fatty liver disease and diabetes. Metabolism 2016; 65:1096-108. [PMID: 26856933 PMCID: PMC4943559 DOI: 10.1016/j.metabol.2016.01.001] [Citation(s) in RCA: 370] [Impact Index Per Article: 41.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Revised: 01/04/2016] [Accepted: 01/05/2016] [Indexed: 02/06/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2DM) are common conditions that regularly co-exist and can act synergistically to drive adverse outcomes. The presence of both NAFLD and T2DM increases the likelihood of the development of complications of diabetes (including both macro- and micro- vascular complications) as well as augmenting the risk of more severe NAFLD, including cirrhosis, hepatocellular carcinoma and death. The mainstay of NAFLD management is currently to reduce modifiable metabolic risk. Achieving good glycaemic control and optimising weight loss are pivotal to restricting disease progression. Once cirrhosis has developed, it is necessary to screen for complications and minimise the risk of hepatic decompensation. Therapeutic disease modifying options for patients with NAFLD are currently limited. When diabetes and NAFLD co-exist, there are published data that can help inform the clinician as to the most appropriate oral hypoglycaemic agent or injectable therapy that may improve NAFLD, however most of these data are drawn from observations in retrospective series and there is a paucity of well-designed randomised double blind placebo controlled studies with gold-standard end-points. Furthermore, given the heterogeneity of inclusion criteria and primary outcomes, as well as duration of follow-up, it is difficult to draw robust conclusions that are applicable across the entire spectrum of NAFLD and diabetes. In this review, we have summarised and critically evaluated the available data, with the aim of helping to inform the reader as to the most pertinent issues when managing patients with co-existent NAFLD and T2DM.
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Affiliation(s)
- Jonathan M Hazlehurst
- Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK, OX3 7LE
| | - Conor Woods
- Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK, OX3 7LE
| | - Thomas Marjot
- Department of Gastroenterology, Oxford University Hospitals NHS Trust, Oxford, UK, OX3 9DU
| | - Jeremy F Cobbold
- Department of Gastroenterology, Oxford University Hospitals NHS Trust, Oxford, UK, OX3 9DU
| | - Jeremy W Tomlinson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK, OX3 7LE.
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Hepatocellular Carcinoma in Obesity, Type 2 Diabetes, and NAFLD. Dig Dis Sci 2016; 61:1234-45. [PMID: 26921078 DOI: 10.1007/s10620-016-4085-6] [Citation(s) in RCA: 87] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2016] [Accepted: 02/09/2016] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is the second commonest cause of cancer death worldwide. Rather than falling as a result of prevention and treatments for viral hepatitis, an increase is evident in developed nations consequent to the rising prevalence of obesity and type 2 diabetes mellitus (T2DM)-the two major risk factors for nonalcoholic fatty liver disease (NAFLD). The majority of patients with HCC complicating these conditions present with advanced disease as the tools for surveillance are inadequate, and the "at-risk" population is not well characterized. This review will summarize the epidemiological evidence linking obesity, T2DM, and NAFLD with HCC, what is known about the pathogenic mechanisms involved, as well as their relevance for clinicians managing patients at risk. There will also be an overview of the "unmet needs" surrounding this topic, with suggestions for the direction translational research should take in order to prevent progression of NAFLD to HCC, to improve early detection of HCC in those with NAFLD, as well as to improve outcomes for those affected.
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27
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Doycheva I, Cui J, Nguyen P, Costa EA, Hooker J, Hofflich H, Bettencourt R, Brouha S, Sirlin CB, Loomba R. Non-invasive screening of diabetics in primary care for NAFLD and advanced fibrosis by MRI and MRE. Aliment Pharmacol Ther 2016; 43:83-95. [PMID: 26369383 PMCID: PMC4673036 DOI: 10.1111/apt.13405] [Citation(s) in RCA: 150] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Revised: 07/29/2015] [Accepted: 08/26/2015] [Indexed: 12/14/2022]
Abstract
BACKGROUND Current guidelines do not recommend screening for non-alcoholic fatty liver disease (NAFLD) or advanced fibrosis. Patients with type 2 diabetes mellitus (T2DM) are known to be at increased risk for NAFLD and advanced fibrosis. AIM To assess the feasibility in diabetics in a primary care setting of screening for NAFLD and advanced fibrosis, by using non-invasive magnetic resonance imaging (MRI) to estimate the hepatic proton density fat fraction (MRI-PDFF) and magnetic resonance elastography (MRE) to estimate hepatic stiffness. METHODS We performed a cross-sectional analysis of a prospective study that included 100 (53% men) consecutively enrolled diabetics who did not have any other aetiology of liver disease. All patients underwent a standardised research visit, laboratory tests, MRI-PDFF, and MRE. RESULTS Mean (±s.d.) age and body mass index (BMI) was 59.7 (±11.2) years and 30.8 (±6.5) kg/m(2) , respectively. The prevalence of NAFLD (defined as MRI-PDFF ≥5%) and advanced fibrosis (defined as MRE ≥3.6 kPa) was 65% and 7.1%, respectively. One patient with advanced fibrosis had definite hepatocellular carcinoma. When compared to those without NAFLD, patients with NAFLD were younger (P = 0.028) and had higher mean BMI (P = 0.0008), waist circumference (P < 0.0001) and prevalence of metabolic syndrome (84.6% vs. 40.0%, P < 0.0001). Only 26% of those with NAFLD had elevated alanine aminotransferase. CONCLUSIONS This proof-of-concept study demonstrates that T2DM has significant rates of both NAFLD and advanced fibrosis. Concomitant screening for NAFLD and advanced fibrosis by using MRI-proton density fat fraction and magnetic resonance elastography in T2DM is feasible and may be considered after validation in a larger cohort.
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Affiliation(s)
- Iliana Doycheva
- NAFLD Translational Research Unit, University of California, San Diego, La Jolla, CA
| | - Jeffrey Cui
- NAFLD Translational Research Unit, University of California, San Diego, La Jolla, CA
| | - Phirum Nguyen
- NAFLD Translational Research Unit, University of California, San Diego, La Jolla, CA,Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, CA
| | - Eduardo A. Costa
- Liver Imaging Group, Department of Radiology, University of California, San Diego, La Jolla, CA
| | - Jonathan Hooker
- Liver Imaging Group, Department of Radiology, University of California, San Diego, La Jolla, CA
| | - Heather Hofflich
- Division of General Internal Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA
| | - Ricki Bettencourt
- Division of Epidemiology, Department of Family and Preventive Medicine, University of California, San Diego, La Jolla, CA
| | - Sharon Brouha
- Department of Radiology, University of California, San Diego, La Jolla, CA
| | - Claude B. Sirlin
- Liver Imaging Group, Department of Radiology, University of California, San Diego, La Jolla, CA
| | - Rohit Loomba
- NAFLD Translational Research Unit, University of California, San Diego, La Jolla, CA,Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, CA,Division of Epidemiology, Department of Family and Preventive Medicine, University of California, San Diego, La Jolla, CA
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28
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Neuman MG, Cohen LB, Nanau RM. Hyaluronic acid as a non-invasive biomarker of liver fibrosis. Clin Biochem 2015; 49:302-15. [PMID: 26188920 DOI: 10.1016/j.clinbiochem.2015.07.019] [Citation(s) in RCA: 73] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Revised: 07/07/2015] [Accepted: 07/14/2015] [Indexed: 12/14/2022]
Abstract
UNLABELLED Chronic liver diseases may cause inflammation and progressive scarring, over time leading to irreversible hepatic damage (cirrhosis). As a result, the need to assess and closely monitor individuals for risk factors of components of matrix deposition and degradation, as well as the severity of the fibrosis using biomarkers, has been increasingly recognized. AIM Our aim is to review the use of biomarker for diagnosing and defining the severity of liver fibrosis. METHODS A systematic literature review was done using the terms "hyaluronic acid" and "liver fibrosis" as well as the name of each biomarker or algorithm known to be employed. PubMed and Google Scholar were searched, and English language articles indexed between January 2010 and October 2014 in which HA was used as a marker of liver fibrosis were retrieved, regardless of the underlying liver disease. Each author read the publications separately and the results were analyzed and discussed. RESULTS Biomarkers offer a potential prognostic or diagnostic indicator for disease manifestation, progression, or both. Serum biomarkers, including HA, have been used for many years. Emerging biomarkers such as metalloproteinases have been proposed as tools that provide valuable complementary information to that obtained from traditional biomarkers. Moreover, markers of extracellular matrix degradation provide powerful predictions of risk. In order for biomarkers to be clinically useful in accurately diagnosing and treating disorders, age-specific reference intervals that account for differences in gender and ethnic origin are a necessity. CONCLUSIONS This review attempts to provide a comprehensive analysis of the emerging risk biomarkers of liver fibrosis and to describe the clinical significance and analytical considerations of each biomarker pointing out sentinel features of disease progression.
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Affiliation(s)
- Manuela G Neuman
- Department of Pharmacology & Toxicology, University of Toronto, CEO In Vitro Drug Safety & BioTechnology, Banting Institute, 100 College Street, Lab 217, Toronto, Ontario M5G 0A3, Canada
| | - Lawrence B Cohen
- Department of Pharmacology & Toxicology, University of Toronto, CEO In Vitro Drug Safety & BioTechnology, Banting Institute, 100 College Street, Lab 217, Toronto, Ontario M5G 0A3, Canada; Sunnybrook HSC, Department of Medicine, University of Toronto, Toronto, Canada
| | - Radu M Nanau
- Department of Pharmacology & Toxicology, University of Toronto, CEO In Vitro Drug Safety & BioTechnology, Banting Institute, 100 College Street, Lab 217, Toronto, Ontario M5G 0A3, Canada
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Morling JR, Fallowfield JA, Williamson RM, Nee LD, Jackson AP, Glancy S, Reynolds RM, Hayes PC, Guha IN, Strachan MWJ, Price JF. Non-invasive hepatic biomarkers (ELF and CK18) in people with type 2 diabetes: the Edinburgh type 2 diabetes study. Liver Int 2014; 34:1267-77. [PMID: 24237940 DOI: 10.1111/liv.12385] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2013] [Accepted: 11/09/2013] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Type 2 diabetes is an established risk factor for the presence and progression of fatty liver. Little is known about the distributions and correlates of hepatic non-invasive biomarkers in community-based populations with diabetes, unselected for liver disease. We aimed to identify the distribution of, and metabolic risk factors associated with serum cytokeratin-18 (CK18) and the Enhanced Liver Fibrosis score (ELF), in a large, representative cohort of people with type 2 diabetes (the Edinburgh Type 2 Diabetes Study, ET2DS). METHODS Nine hundred and thirty-nine ET2DS participants, aged 60-74 years underwent physical examination including ultrasound for assessment of liver fat. Representative subgroups were assessed for markers of chronic liver disease (CK18 and ELF). RESULTS CK18 values ranged from 29-993 U/L (median 102, IQR 76-137 U/L) and ELF scores ranged from 6.9-11.6 (mean 8.9, SD 0.8). Statistically significant associations were found between both biomarkers and a number of metabolic risk factors. Neither CK18 nor ELF was consistently or strongly associated with established hepatic risk factors (alcohol excess, hepatotoxic medication use and positive immunology titres). CONCLUSIONS We identified the distribution of CK18 and ELF in a large cohort of older people with type 2 diabetes and showed that these markers are associated with an adverse metabolic risk factor profile, although much of the variation in biomarkers remained unexplained. Prospective studies are required to determine the extent to which CK18 and/or ELF predict the development of symptomatic liver disease and to identify additional risk factors which may influence the development of advanced liver disease in people with type 2 diabetes.
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Affiliation(s)
- Joanne R Morling
- Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK
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30
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Rodrigues MH, Bruno AS, Nahas-Neto J, Santos MES, Nahas EAP. Nonalcoholic fatty liver disease and metabolic syndrome in postmenopausal women. Gynecol Endocrinol 2014; 30:325-9. [PMID: 24460502 DOI: 10.3109/09513590.2013.875992] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is considered the most common cause of chronic liver disease in the Western countries. NAFLD includes a spectrum ranging from a simple steatosis to a nonalcoholic steatohepatitis (NASH) which is defined by the presence of inflammatory infiltrate, cellular necrosis, hepatocyte ballooning, and fibrosis and cirrhosis that can eventually develop into hepatocellular carcinoma. Studies emphasize the role of insulin resistance, oxidative stress, pro-inflammatory cytokines, adipokines in the development and progression of NAFLD. It seems to be independently associated with type II diabetes mellitus, increased triglycerides, decreased HDL-cholesterol, abdominal obesity and insulin resistance. These findings are in accordance with the criteria used in the diagnosis of metabolic syndrome (MetS). Here, we will discuss the current knowledge on the epidemiology, pathophysiology and diagnosis of NAFLD and the association of metabolic syndrome in postmenopausal women.
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Affiliation(s)
- Marcio H Rodrigues
- Department of Gynecology and Obstetrics, Botucatu Medical School-Sao Paulo State University , Botucatu, Sao Paulo , Brazil
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31
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Morling JR, Fallowfield JA, Guha IN, Nee LD, Glancy S, Williamson RM, Robertson CM, Strachan MWJ, Price JF. Using non-invasive biomarkers to identify hepatic fibrosis in people with type 2 diabetes mellitus: the Edinburgh type 2 diabetes study. J Hepatol 2014; 60:384-91. [PMID: 24512822 DOI: 10.1016/j.jhep.2013.10.017] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2013] [Revised: 09/05/2013] [Accepted: 10/09/2013] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS It is difficult to determine the different stages of non-alcoholic fatty liver disease without the use of invasive liver biopsy. In this study we investigated five non-invasive biomarkers used previously to detect hepatic fibrosis and determined the level of agreement between them in order to inform future research. METHODS In the Edinburgh Type 2 Diabetes Study, a population-based cohort aged 60-74 years with type 2 diabetes, 831 participants underwent ultrasound assessment for fatty liver and had serum aspartate aminotransferase to alanine aminotransferase ratio (AST/ALT), aspartate to platelet ratio index (APRI), European Liver Fibrosis panel (ELF), Fibrosis-4 Score (FIB4) and liver stiffness measurement (LSM) measured. RESULTS Literature based cut-offs yielded marked differences in the proportions of the cohort with probable liver fibrosis in the full cohort. Agreement between the top 5% of the distribution for each biomarker pair was poor. APRI and FIB4 had the best positive agreement at 76.4%, but agreement for all of the other serum biomarker pairs was between 18% and 34%. Agreement with LSM was poor (9-16%). CONCLUSIONS We found poor correlation between the five biomarkers of liver fibrosis studied. Using the top 5% of each biomarker resulted in good agreement on the absence of advanced liver disease but poor agreement on the presence of advanced disease. Further work is required to validate these markers against liver biopsy and to determine their predictive value for clinical liver-related endpoints, in a range of different low and high risk population groups.
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