Screening for non-alcoholic fatty liver disease using liver stiffness measurement and its association with chronic kidney disease and cardiovascular complications in patients with type 2 diabetes

doi:10.1016/j.diabet.2019.11.004

Diabetes & Metabolism

Volume 46, Issue 4, September 2020, Pages 296-303

https://doi.org/10.1016/j.diabet.2019.11.004 Get rights and content

Abstract

Aim

Despite the high prevalence and serious clinical implications of non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM), NAFLD is usually overlooked during routine diabetes care. This study explored the proportion of NAFLD cases and increased liver fibrosis (LF), and the association between LF and either chronic kidney disease (CKD) or cardiovascular complications in T2DM patients.

Methods

The study included 137 patients with non-insulin-treated T2DM and no known liver disease consecutively attending our diabetes outpatients’ service who underwent liver ultrasonography and liver stiffness measurement (LSM) using vibration-controlled transient elastography (FibroScan®).

Results

The proportion of patients with hepatic steatosis on ultrasonography was 73.7%, and the proportion with significant LF was 17.5% with an LSM cut-off ≥ 7 kPa or 10.2% with an LSM cut-off ≥ 8.7 kPa. The presence of CKD (estimated GFR < 60 mL/min/1.73 m² and/or abnormal albuminuria) increased significantly across LSM tertiles (from around 15% in tertile 1 to 45% in tertile 3). Cardiovascular complications (previous ischaemic heart disease, ischaemic stroke, permanent atrial fibrillation) also tended to increase across LSM tertiles (from around 15% to 30%). After adjusting for established risk factors and potential confounders, LSM tertile 3 remained significantly associated with an approximately threefold higher risk of prevalent CKD (adjusted OR: 3.28, 95% CI: 1.22–8.90; P = 0.019), but not for cardiovascular complications.

Conclusion

These results suggest that NAFLD and significant LF (as assessed by FibroScan®) are very commonly seen in T2DM outpatients with no known liver disease attending a secondary-care diabetes service, and that increased LF is associated with a greater proportion of chronic vascular complications, especially CKD.

Introduction

Non-alcoholic fatty liver disease (NAFLD) is now recognized to be the most common chronic liver disease worldwide. The condition affects up to a third of adults in the general population of high-income countries, and its prevalence is even higher among patients with type 2 diabetes mellitus (T2DM), affecting up to 70–80% of such patients [1], [2]. Compared with people without diabetes, patients with T2DM are also more likely to have or to develop more severe histological forms of NAFLD, such as non-alcoholic steatohepatitis (NASH), advanced fibrosis and cirrhosis, even in those who have fairly “normal” serum liver enzyme levels [2], [3], [4]. In fact, a recent meta-analysis has confirmed that the global prevalence of biopsy-confirmed NASH among patients with T2DM was around 38%, and that the global prevalence of advanced fibrosis in those with both NAFLD and T2DM was about 17% [2].

It is also important to remember the clinical importance of the bidirectional relationship between NAFLD and T2DM [4], [5]. In particular, the coexistence of NAFLD and T2DM worsens the course of both conditions. Coexisting T2DM not only increases the risk of NAFLD progression to advanced fibrosis and cirrhosis, but also increases the risk of incident hepatocellular carcinoma, liver-related hospital admissions and liver-related deaths [4], [6], [7], [8], [9]. In addition, the presence of NAFLD makes achieving good glycaemic control more difficult, exacerbates hepatic/peripheral insulin resistance and promotes atherogenic dyslipidaemia, thereby further increasing the risk of developing extrahepatic diseases such as chronic kidney disease (CKD) and cardiovascular complications, particularly in T2DM patients with advanced NAFLD [3], [4], [10].

Collectively, these findings support the conclusion that, in patients with T2DM, the diagnosis and treatment of NAFLD should be considered a high clinical priority among diabetologists caring for patients at risk of progressive NAFLD. Therefore, this can also be argued to make a case for systematic screening for NAFLD among patients at high risk of advanced NAFLD, such as those with T2DM. This conclusion is in accordance with guidelines from the 2016 European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO) and Italian Association for the Study of the Liver (AISF) [11], [12], but not the 2016 England and Wales National Institute for Health and Care Excellence (NICE) NAFLD guidelines [13] or the 2018 American Association for the Study of Liver Diseases (AASLD) practice guidelines [14]. In fact, the latter has recommended against systematic screening for NAFLD in patients with T2DM because of the uncertainties surrounding diagnostic tests and treatment options, along with a lack of knowledge related to the long-term benefits and cost-effectiveness of screening [14]. Nevertheless, the AASLD guidelines have recommended that there be a high index of suspicion for NAFLD and NASH in patients with T2DM, and that clinical decision aids, such as vibration-controlled transient elastography (VCTE), may be used to identify those at low or high risk of advanced liver fibrosis, the strongest predictor of long-term adverse clinical outcomes with NAFLD [14]. Indeed, liver stiffness measurement (LSM) by VCTE (also known as FibroScan®) is proving to be a reliable diagnostic tool for non-invasively staging liver fibrosis in patients with various chronic liver diseases, including NAFLD [15].

Yet, despite the high prevalence and serious clinical implications of NAFLD in T2DM patients, this liver disease is frequently overlooked in routine diabetes care [2], [4]. This means that increasing awareness of the importance of NAFLD in patients with T2DM among primary-care physicians, specialists and health policy makers should be a priority.

Thus, the main aim of the present cross-sectional study was to non-invasively screen for the presence of NAFLD and liver fibrosis by using both ultrasonography and VCTE in a well-characterized sample of T2DM outpatients with no known liver disease(s), and to examine whether increased liver fibrosis is associated with the presence of CKD and cardiovascular complications in these patients.

Section snippets

Patients

This study enrolled 137 (48.2% male) patients with non-insulin-treated T2DM who had consecutively attended our diabetes outpatients’ service over a period of approximately 4 months, and agreed to undergo liver ultrasonography and VCTE for diagnosing and staging NAFLD. Excluded were all patients with:

•
a history of significant alcohol consumption (defined as > 20 g/day of alcohol for men and women) or other known causes of chronic liver disease (viral infection, drug use, autoimmunity,

Results

A total of 137 patients (48.2% men) with non-insulin-treated T2DM were included in our study (mean ± SD: age 69.9 ± 7 years; BMI: 28.5 ± 4.7 kg/m²; waist circumference: 100 ± 12 cm; HbA_1c: 6.9 ± 0.8%; median duration of diabetes: 11 years [IQR 6–18]). Of these patients, 28 (20.4%) had established cardiovascular disease [20 (14.6%) patients had previous IHD and eight (8.5%) had either ischaemic stroke or permanent atrial fibrillation]. In addition, 37 (27%) of these patients had CKD [14 (10.2%) had eGFR < 60

Discussion

A major finding of our study is that a substantial proportion of patients with T2DM routinely attending an outpatients’ service had NAFLD and significant or advanced liver fibrosis. Indeed, the majority of these patients (around 75%) revealed hepatic steatosis on ultrasonography, and a significant proportion also had increased liver fibrosis on VCTE: 17.5% had LSM ≥ 7 kPa and 10.2% had LSM ≥ 8.7 kPa (corresponding to Kleiner fibrosis stage ≥ F3 on histology) [14], [19]. It is also worth noting that

Funding

G.T. is supported in part by grants from the University School of Medicine of Verona, Verona, Italy. C.D.B. is supported in part by grants from the Southampton National Institute for Health Research Biomedical Research Centre, Southampton, UK.

Disclosure of interest

The authors declare that they have no competing interest.

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Agile 3+ and Agile 4 are reliable for identifying NAFLD patients with high risk of CKD. Early glycemic control in the prediabetic stage might have a potential renoprotective role in these patients.
MASLD, hepatic steatosis and fibrosis are associated with the prevalence of chronic kidney disease and retinopathy in adults with type 1 diabetes mellitus
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We examined whether metabolic dysfunction-associated steatotic liver disease (MASLD) with or without significant fibrosis (assessed by validated non-invasive biomarkers) was associated with an increased risk of prevalent chronic kidney disease (CKD) or diabetic retinopathy in people with type 1 diabetes mellitus (T1DM).
We performed a retrospective multicenter cross-sectional study involving 1,409 adult outpatients with T1DM, in whom hepatic steatosis index (HSI) and fibrosis (FIB)-4 index were calculated for non-invasively detecting hepatic steatosis (defined by HSI > 36), with or without coexisting significant fibrosis (FIB-4 index ≥ 1.3 or < 1.3). CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m² or urine albumin/creatinine ratio ≥ 3.0 mg/mmol. The presence of diabetic retinopathy was also recorded in all participants.
Patients with MASLD and significant fibrosis (n = 93) had a remarkably higher prevalence of CKD and diabetic retinopathy than their counterparts with MASLD without fibrosis (n = 578) and those without steatosis (n = 738). After adjustment for sex, diabetes duration, hemoglobin A1c, hypertension, and use of antihypertensive or lipid-lowering medications, patients with SLD and significant fibrosis had a higher risk of prevalent CKD (adjusted-odds ratio 1.76, 95 % confidence interval 1.05–2.96) than those without steatosis. Patients with MASLD without fibrosis had a higher risk of prevalent retinopathy (adjusted-odds ratio 1.49, 95 % CI 1.13–1.46) than those without steatosis.
This is the largest cross-sectional study showing that MASLD with and without coexisting significant fibrosis was associated, independently of potential confounders, with an increased risk of prevalent CKD and retinopathy in adults with T1DM.
Association between PNPLA3 rs738409 variant and 5-year estimated glomerular filtration rate decline in post-menopausal women with type 2 diabetes: A panel-data analysis
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Little is known about the relationship between patatin-like phospholipase domain-containing protein-3 (PNPLA3) rs738409 variant and decline in estimated glomerular filtration rate (eGFR) over time in individuals with type 2 diabetes (T2DM).
We enrolled an outpatient sample of 46 post-menopausal women with T2DM and preserved kidney function at baseline (in 2017), who were followed through 2022. eGFR and albuminuria were measured annually. Genotyping of PNPLA3 rs738409 was performed by TaqMan-based RT-PCR system. Overall, 25 (54.3%) patients had PNPLA3 rs738409 CC (homozygous wild-type) genotype and 21 had CG or GG genotypes. During the 5-year follow-up, the presence of rs738409 CG/GG genotypes was associated with faster eGFR decline (coefficient: −6.55; 95% CI −11.0 to −2.08; p = 0.004 by random-effects panel data analysis). This association remained significant even after adjustment for 5-year changes in age, hemoglobin A1c, hypertension status, albuminuria and use of sodium-glucose co-transporter-2 inhibitors or glucagon-like peptide-1 receptor agonists.
This pilot study suggests that in post-menopausal T2DM women with preserved kidney function at baseline, the risk allele (G) of PNPLA3 rs738409 is associated with a faster eGFR decline during a 5-year follow-up, independent of annual changes in common renal risk factors and use of certain glucose-lowering medications.
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In Non-Alcoholic Fatty Liver Disease (NAFLD), events driving early hepatic dysfunction with respect to specific metabolic pathways are still poorly known.
We enrolled 84 subjects with obesity and/or type 2 diabetes (T2D). FibroScan® served to assess NAFLD by controlled attenuation parameter (CAP), and fibrosis by liver stiffness (LS). Patients with LS above 7 kPa were excluded. APRI and FIB-4 were used as additional serum biomarkers of fibrosis. The stable-isotope dynamic breath test was used to assess the hepatic efficiency of portal extraction (as DOB₁₅) and microsomal metabolization (as cPDR₃₀) of orally-administered (¹³C)-methacetin.
NAFLD occurred in 45%, 65.9%, and 91.3% of normal weight, overweight, and obese subjects, respectively. Biomarkers of liver fibrosis were comparable across subgroups, and LS was higher in obese, than in normal weight subjects. DOB₁₅ was 23.2 ± 1.5‰ in normal weight subjects, tended to decrease in overweight (19.9 ± 1.0‰) and decreased significantly in obese subjects (16.9 ± 1.3, P = 0.008 vs. normal weight). Subjects with NAFLD had lower DOB₁₅ (18.7 ± 0.9 vs. 22.1 ± 1.2, P = 0.03) but higher LS (4.7 ± 0.1 vs. 4.0 ± 0.2 kPa, P = 0.0003) than subjects without NAFLD, irrespective of fibrosis. DOB₁₅ (but not cPDR₃₀) decreased with increasing degree of NAFLD (R = −0.26; P = 0.01) and LS (R = −0.23, P = 0.03). Patients with T2D showed increased rate of NAFLD than those without T2D but similar LS, DOB₁₅ and cPDR₃₀.
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Of the 428 titles initially scrutinized, 29 studies fulfilled the criteria and were included, providing data on 390 patients with T1D and 10,487 patients with T2D. Prevalence rates of elevated liver stiffness were 5.2% (95% CI 1.1–9.2) in patients with T1D and 19.8% (95% CI 16.8–22.8) in patients with T2D. In studies performed in patients with T2D, multivariate meta-regression analysis showed that higher body mass index, higher age, a higher proportion of males, lower VCTE cut-off and Asian ethnicity were associated with increased prevalence rates. This model explained 32.7% of the observed heterogeneity. No signs of publication bias were identified by visual inspection of the funnel plot or by Egger’s test.
This meta-analysis indicates that 1 in 20 patients with T1D and 1 in 5 patients with T2D has elevated liver stiffness, indicative of potential significant or advanced liver fibrosis.
American Association of Clinical Endocrinology Clinical Practice Guideline for the Diagnosis and Management of Nonalcoholic Fatty Liver Disease in Primary Care and Endocrinology Clinical Settings: Co-Sponsored by the American Association for the Study of Liver Diseases (AASLD)
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Citation Excerpt :
Specific types of exercise exert different effects in persons with NAFLD. There were no significant differences between aerobic and resistance trainings, but there was more benefit with high-volume continuous training than with low-volume continuous training even with high intensity.190 While there are more data on aerobic exercise, resistance training can improve NAFLD and may be more feasible for persons with poor cardiorespiratory fitness or an inability to participate in aerobic exercise.
To provide evidence-based recommendations regarding the diagnosis and management of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) to endocrinologists, primary care clinicians, health care professionals, and other stakeholders.
The American Association of Clinical Endocrinology conducted literature searches for relevant articles published from January 1, 2010, to November 15, 2021. A task force of medical experts developed evidence-based guideline recommendations based on a review of clinical evidence, expertise, and informal consensus, according to established American Association of Clinical Endocrinology protocol for guideline development.
This guideline includes 34 evidence-based clinical practice recommendations for the diagnosis and management of persons with NAFLD and/or NASH and contains 385 citations that inform the evidence base.
NAFLD is a major public health problem that will only worsen in the future, as it is closely linked to the epidemics of obesity and type 2 diabetes mellitus. Given this link, endocrinologists and primary care physicians are in an ideal position to identify persons at risk on to prevent the development of cirrhosis and comorbidities. While no U.S. Food and Drug Administration-approved medications to treat NAFLD are currently available, management can include lifestyle changes that promote an energy deficit leading to weight loss; consideration of weight loss medications, particularly glucagon-like peptide-1 receptor agonists; and bariatric surgery, for persons who have obesity, as well as some diabetes medications, such as pioglitazone and glucagon-like peptide-1 receptor agonists, for those with type 2 diabetes mellitus and NASH. Management should also promote cardiometabolic health and reduce the increased cardiovascular risk associated with this complex disease.

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Original articleScreening for non-alcoholic fatty liver disease using liver stiffness measurement and its association with chronic kidney disease and cardiovascular complications in patients with type 2 diabetes

Abstract

Aim

Methods

Results

Conclusion

Introduction

Section snippets

Patients

Results

Discussion

Funding

Disclosure of interest

Diabetes Metab

J Hepatol

Clin Gastroenterol Hepatol

J Hepatol

Diabetes Metab

J Hepatol

Lancet

Epidemiological modifiers of non-alcoholic fatty liver disease: focus on high-risk groups

Dig Liver Dis

The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: a systematic review and meta-analysis

J Hepatol

Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis

Nat Rev Gastroenterol Hepatol

Nonalcoholic fatty liver disease and chronic vascular complications of diabetes mellitus

Nat Rev Endocrinol

Newly diagnosed diabetes mellitus as a risk factor for serious liver disease

CMAJ

Mortality from chronic liver diseases in diabetes

Am J Gastroenterol

European association for the study of diabetes (EASD); European association for the study of obesity (EASO); EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease

J Hepatol

AISF position paper on nonalcoholic fatty liver disease (NAFLD): updates and future directions

Dig Liver Dis

Non-alcoholic fatty liver disease (NAFLD): summary of NICE guidance

BMJ.

The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American association for the study of liver diseases

Hepatology

Noninvasive assessment of liver disease in patients with nonalcoholic fatty liver disease

Gastroenterology

Original article
Screening for non-alcoholic fatty liver disease using liver stiffness measurement and its association with chronic kidney disease and cardiovascular complications in patients with type 2 diabetes