Introduction

Patients with type 2 diabetes (T2D) have a high prevalence of non-alcoholic fatty liver disease (NAFLD) (1). The most validated non-invasive method to assess liver steatosis and fibrosis is transient elastography (TE), whereas some new ultrasound-based technologies still lack substantial clinical evidence in this setting (2,3). In this line we aimed to evaluate performance of Shear Wave Measurement (SWM) and Attenuation (ATT) Measurement by Fujifilm to diagnose liver steatosis and fibrosis in the cohort of patients with T2DM, using TE as the reference.

Aims & Methods

Consecutive outpatients with T2D (N=147) were referred for controlled attenuation parameter (CAP) and liver stiffness measurements (LSM) to assess the presence of liver steatosis and fibrosis by using TE. The presence of any grade of liver steatosis was considered in patients with CAP≥297 dB/m, and advanced fibrosis in those with LSM≥10 kPa by TE, which served as the reference method (4,5). All consented patients also underwent SWM and ATT (by Fujifilm Arietta 65), as the investigated methods, and their results were compared to LSM and CAP as measured by TE. All measurements were performed in fasting patients, whereas patients with conditions that might have influenced the results of LSM (ALT>5xULN, congestive liver disease, biliary obstruction, infiltrative liver neoplasms) were excluded.

Results

Of 147 included patients with T2D, 76 (51.7%) were females, average age 66, median Body Mass Index 30.5 kg/m², 113 (76,9%) had arterial hypertension, 111 (75,5%) dyslipidemia, 27 (18.4%) were smokers, 26 (17.7%) reported risky alcohol consumption. As for TE, M probe was used in 104 (70.7%) patients, median LSM was 5.9 kPa, median CAP 290 dB/m. Any grade of steatosis (CAP≥297 dB/m) was detected in 62 (42,2%) patients, and advanced fibrosis (LSM≥10 kPa) in 17/145 (11.6%) patients by using TE. Median SWM was 5.5 kPa, and median ATT 0.62 dB/cm/MHz. We observed good correlation between LSM as measured by TE and SWM (Pearson's R=0.68, 95 CI: 0.58-0.76, p<0,001), whereas SWM produced lower (mean -0,7 unit, Bland-Altman) LSM values in comparison to TE. SWM had AUROC of 0.905 at the LSM cut-off ≥ 8.3 kPa (Youden) to diagnose advanced fibrosis (sen. 76.5%, specif. 93.8%). LSM by SWM optimized for ruling-in and ruling-out advanced fibrosis were respectively ≥10.1 kPa (specif. 97%) and <6.2 kPa (sens. 94.1%). Presence of advanced fibrosis would be missed in 23.5%, 41.2% and 5.8% patients by using reported LSM cut-offs (≥ 8.3, ≥10.1 and <6,2 kPa respectively). In multivariate analysis only platelet count (OR 0.979; CI 0.96-0.998, p=0.03) and LSM as measured by TE (OR 1.197; CI 1.031-1.391, p=0.02) were significantly associated with LSM measured by SWM. Correlation between ATT and CAP was poor (Pearson' R=0.31, 95 CI: 0.16-0.45, p<0.001), as was the overall diagnostic performance of ATT to diagnose any grade of liver steatosis (AUROC 0.673 at the cut-off ≥0.66 dB/cm/MHz (Youden); sens. 56.5%, specif. 75.3%). ATT cut-offs optimized for ruling-in and ruling-out any steatosis were ≥0.75 dB/cm/MHz (specif. 89.4%), and <0.50 dB/cm/MHz (sens. 88.7%) respectively. Presence of any steatosis would be missed in 43.5%, 62.9% and 11.2% by using reported ATT cut-offs (≥0.66, ≥0.75 and <0.50 dB/cm/MHz respectively).

Conclusion

SWM reliably recognizes presence of advanced liver fibrosis in patients with T2D. The diagnostic performance of ATT was suboptimal, and this should be further investigated by using more reliable reference methods, such as liver biopsy or magnetic resonance.

References

1. Leite NC, Villela-Nogueira CA, Pannain VLN et al. Histopathological stages of non-alcoholic fatty liver disease in type 2 diabetes: Prevalences and correlated factors. Liver Int. 2011 doi: 10.1111/j.1478-3231.2011.02482.x.
2. Tovo CV, Villela-Nogueira CA, Leite NC, Panke CL, Port GZ, Fernandes S, et al. Transient hepatic elastography has the best performance to evaluate liver fibrosis in non-alcoholic fatty liver disease (NAFLD). Annals of Hepatology [Internet]. 2019 May [cited 2019 Dec 6];18(3):445–9.
3. Dietrich C, Bamber J, Berzigotti A, Bota S, Cantisani V, Castera L, et al. EFSUMB Guidelines and Recommendations on the Clinical Use of Liver Ultrasound Elastography, Update 2017 (Long Version). Ultraschall in der Medizin - European Journal of Ultrasound. 2017 Apr 13;38(04):e16–47.
4. Petroff D, Blank V, Newsome PN, Shalimar, Voican CS, Thiele M, et al. Assessment of hepatic steatosis by controlled attenuation parameter using the M and XL probes: an individual patient data meta-analysis. The Lancet Gastroenterology & Hepatology. 2021 Mar;6(3):185–98.
5. Franchis R de, Bosch J, Garcia-Tsao G, Reiberger T, Ripoll C, Abraldes JG, et al. Baveno VII – Renewing consensus in portal hypertension. Journal of Hepatology [Internet]. 2021 Dec 29;0(0). Available from: https://www.journal-of-hepatology.eu/article/S0168-8278(21)02299-6/fulltext

Introduction

Patients with non-alcoholic fatty liver disease (NAFLD) are at a higher risk of developing cardiovascular disease (CVD).

Aims & Methods

This study aimed to determine if there is an association between increased steatosis and fibrosis with a higher risk of CVD in patients with diabetes mellitus (DM). This study enrolled 288 patients with DM who were over 40 years of age, between January and August 2023, after excluding viral hepatitis, cirrhosis, and cancers. Patients provided written informed consent and underwent clinical measurements and answered questions about their past medical history. The following measurements and data were taken: body weight (BW), body mass index (BMI), waist circumference (WC), laboratory data, presence of hypertension, dyslipidemia, alcohol consumption, and smoking. The degree of steatosis was estimated using the fatty liver index {FLI, (e^{(0.953×ln(triglyceride, TG)+0.139×BMI+0.718×ln(gamma-glutamyltrasnsferase, GGT)+0.053×WC-15.745)})/(1+ e^{(0.953×ln(TG)+0.139×BMI+0.718×ln(GGT)+0.053×WC-15.745)})×100}, hepatic steatosis index {HSI, 8x(alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ratio+BMI (+2, if female; +2, if diabetes mellitus)}, and controlled attenuation parameter (CAP by FibroScan^®). The degree of fibrosis was estimated using the fibrosis-4 (FIB-4) index, NAFLD fibrosis score (NFS), and liver stiffness (LS by FibroScan^®). CVD was defined as ischemic heart disease or hemorrhagic or ischemic stroke. The past history of CVD was asked and reported by trained nurses and chart review.

Results

The mean age was 60±9 years old, and the proportion of males was 54.9% (n=158). The mean CAP and LS values were 273±48 dB/m and 6.8±3.5 kPa, respectively. The CAP values were correlated with BW (r=0.473, p<0.001), BMI (r=0.618, p<0.001), WC (r=0.565, p<0.001), FLI (r=0.603, p<0.001), and HSI (r=0.622, p<0.001). The LS values were correlated with BW (r=0.230, p<0.001), BMI (r=0.446, p<0.001), WC (r=0.371, p<001), and FIB-4 (r=0.419, p<0.001). The LS values were not correlated with NFS. Ninety three (32.3%) patients had CVD and 57 patients were male. The mean age (62±9 vs. 58±9 years, p=0.001), BW (73.2±13.2 vs. 69.1±12.9 kg, p=0.013), BMI (27±4.1 vs. 25.6±3.7 kg/m², p=0.004), and WC (91.5±10 vs. 87.7±9.6 cm, p=0.002) were higher in patients with CVD than in those without CVD. The prevalence of HTN (81.7% vs. 41.5%, p<0.001) and dyslipidemia (75.3% vs. 61.5%, p=0.021) were also higher in patients with CVD. However, the prevalence of alcohol consumption (18.3% vs. 26.7%) and smoking (48.4% vs. 47.7%) were not different between the two groups. The CAP value (275±48 vs. 271±49 dB/m), FLI (51±29 vs. 43±27), and HSI (39±6 vs. 38±6) were not different between the two groups. The LS value (7.4±3.8 vs. 6.5±3.3 kPa, p=0.049) and FIB-4 (1.5±0.9 vs. 1.2±0.7, p=0.006) were higher in patients with CVD than those without CVD. However, NFS (-0.8±1.2 vs. -1.1±3.1, p=0.335) was not different between the two groups. Multivariate logistic regression analysis revealed that age [odds ratio (OR): 1.059, 95% confidence interval (CI): 1.023-1.095, p=0.001], hypertension (OR: 4.843, 95% CI: 2.611-8.985, p<0.001), and BW (OR: 1.032, 95% CI: 1.008-1.056, p=0.008) were significant risk factors for CVD. However, the LS and FIB-4 were not risk factors for CVD.

Conclusion

In contrast to the steatosis, the fibrosis estimated by LS and FIB-4 were associated with the risk of CVD in patients with DM. However, multivariate analysis did not show the LS and FIB-4 as risk factors for CVD.

Introduction

Non-alcoholic fatty liver disease (NAFLD) is a common liver disease frequently associated with type 2 diabetes mellitus (T2DM). This systematic review and meta-analysis aims to quantify the prevalence of NAFLD and non-alcoholic steatohepatitis (NASH) among individuals with T2DM and evaluate the spectrum of liver fibrosis within this cohort.

Aims & Methods

Medline and Embase databases were searched to identify relevant studies published in English, from inception until 13th February 2023. Original articles reporting crude data necessary to calculate the prevalence of NAFLD or NASH in a T2DM population were included. NAFLD was diagnosed based on the criteria set by the American Association for The Study of Liver Diseases (AASLD) guidelines, while liver biopsies were required to identify NASH. Fibrosis was evaluated through non-invasive and invasive techniques.
T2DM was defined by glycohemoglobin ≥ 6.5%, fasting plasma glucose ≥ 7mmol/l, self-reported diabetes, or use of anti-diabetic medications.

Results

124 studies consisting of 1,689,498 individuals with T2DM were analysed. The prevalence of NAFLD in T2DM patients from population-based settings was 57.93% (95% CI: 49.55% to 65.88%). The pooled prevalence of NAFLD was 63.71% (95%CI: 59.94% to 67.32%), while the pooled prevalence of NASH was 31.46% (95%CI: 14.25% to 55.91%). Interestingly, the prevalence of NASH in T2DM patients was 49.55% (95% CI: 28.31% to 70.95%) in Western countries, while only 9.73% (95% CI: 1.84% to 38.28%) in Eastern countries. The frequency of clinically significant fibrosis (F2-4) was 19.82% (95%CI: 13.13% to 28.80%), and the frequency of advanced fibrosis (F3-4) was 14.08% (95%CI: 10.21% to 19.10%) among T2DM patients with NAFLD. This increased to 37.48% (95%CI: 22.16% to 55.80%) and 36.54% (95%CI: 19.05% to 58.49%) respectively among T2DM patients with NASH.

Conclusion

There is a high prevalence of NAFLD and NASH in individuals with T2DM, with nearly a fifth of T2DM individuals with NAFLD affected by liver fibrosis. Clinical management of patients with T2DM should include specific interventions aimed at the targeted prevention, diagnosis and management of NAFLD and its complications.

Introduction

Type 2 diabetes mellitus (T2DM) is associated with end-organ injury and is a major risk factor for non-alcoholic fatty liver disease (NAFLD) and advanced liver disease. Despite the high relevance of NAFLD in T2DM, it remains unconsidered in the routine screening of T2DM-related comorbidities in the German diabetes disease management program (DMP).

Aims & Methods

The aim of this prospective cohort study was to assess the prevalence of liver disease from NAFLD and associated clinical risk factors in primary care centers participating in the diabetes DMP in Germany. A total of 175 participants with the diagnosis of T2DM were enrolled in two primary care outpatient centers within the diabetes DMP. The prevalence of steatosis, fibrosis, and cirrhosis was assessed non-invasively using vibration-controlled transient elastography (VCTE). Steatosis was defined as a controlled attenuation parameter (CAP) of ≥ 275 dB/m. Liver fibrosis and cirrhosis were defined as a liver stiffness measurement (LSM) of ≥ 8 kPa and ≥ 15 kPa, respectively. Multivariable logistic regression analysis with stepwise selection was performed to identify clinical predictors of liver fibrosis and cirrhosis.

Results

The majority of participants were male (62%, n = 109), and the median age was 66 years (IQR 59; 71). The median BMI was 31.1 kg/m² (IQR 27.7; 35.3), with 58.9% (n = 103) of the participants being obese. The median HbA1c was 7.0% (IQR 6.5; 7.8). The prevalence of hepatic steatosis, fibrosis, and cirrhosis was 77.1%, 42.3%, and 12%, respectively. NAFLD was identified in the majority of participants (69.9%; n = 121). Obese individuals showed the highest median LSM values (11.3 kPa, IQR 9.4; 16.2). In multivariable logistic regression analysis, obesity was associated with increased odds of hepatic fibrosis (OR = 4.818, 95% CI 2.243-10.350) and cirrhosis (OR = 3.873, 95% CI 1.073-13.977). Although higher blood levels of HbA1c correlated with liver fibrosis, it did not remain an independent predictor.

Conclusion

The prevalence of advanced liver disease is high within the diabetes DMP in Germany. People with T2DM and obesity are at an increased risk to exhibit liver fibrosis, and eventually cirrhosis. Building on VCTE for risk stratification within the DMP would allow identifying the subgroup recommended for intensified management.

Introduction

The incidence and severity of metabolic dysfunction-associated steatotic liver disease (MASLD) are notably higher in individuals diagnosed with type 2 diabetes mellitus (T2DM). However, studies evaluating the progression of MASLD in patients with T2DM and normal serum aminotransferase (ALT) levels are limited.

Aims & Methods

This 5-year prospective cohort study aimed to evaluate the progression of MASLD in T2DM patients with normal ALT. People with type 2 diabetes who had MASLD (defined by controlled attenuation parameter (CAP) >250 dB/min) and ALT levels that stayed normal (defined by ALT ≤40 IU/L for at least two occasions spanning at least six months) at Rajavithi Hospital, Bangkok, from November 2016 to 2017 were included. We excluded patients with viral hepatitis and alcohol consumption exceeding moderate levels. Transient elastography (TE) and CAP measurements were performed at baseline and ≥5 years of follow-up. The cutoffs to define significant and advanced fibrosis were TE >8 kPa and TE >12 kPa, respectively. All patients were instructed to reduce their weight and abstain from herbal remedies; medications for comorbidities were prescribed without limitations, subject to the physician's assessment. (most patients were under endocrinologist care.)

Results

The study included 84 patients, 57% of whom were female and had a mean age of 58.5 years. Of these, 62% were obese, with a mean BMI of 28.6 kg/m2. At baseline, the median TE was 6.92±3.35 kPa; 57 (68%) had no significant fibrosis, 22 (26%) had significant fibrosis, and 5 (6%) had advanced fibrosis, and after a 5-year follow-up, the median TE was 6.54±3.57 kPa; 69 (82%) had no significant fibrosis, 15 (18%) had significant fibrosis, and 2 (2%) had advanced fibrosis. During the follow-up, fibrosis decreased in 45 (54%), remained stable in 6 (7%), and increased in 33 (39%) patients, while a small proportion of patients experienced changes in the stages of fibrosis: 1.2% progressed from significant to advanced fibrosis; 17.4% regressed from advanced to significant fibrosis or transitioned from significant to no fibrosis; 12.8% remained stable with significant and advanced fibrosis; and the majority (66.3%) remained without significant fibrosis. A significant factor associated with fibrosis progression was alcohol consumption (p=0.013), while the use of angiotensin receptor blockers (p=0.042) was associated with fibrosis regression. Significant factors associated with steatosis progression included high baseline BMI (p=0.013), an increase in BMI ≥ 5% (p=0.04), high fasting plasma glucose, and LDL cholesterol levels, while a decrease in BMI ≥ 5% (p=0.002) the use of calcium channel blockers (p=0.038) and coffee consumption >3 cups per day (p=0.031) were associated with steatosis regression. ALT elevation during the follow-up occurred in a small proportion of patients, and it was not significantly associated with fibrosis or steatosis progression.

Conclusion

The majority of MASLD patients with T2DM and normal ALT maintained a relatively stable liver disease during 5 years of follow-up. Obesity, weight gain, alcohol consumption, and inadequate metabolic control were all associated with the progression of MASLD, whereas weight loss, coffee consumption, angiotensin receptor blockers, and calcium channel blockers were all associated with the improvement of MASLD.

Disclosure

I have nothing to disclose

Introduction

Metabolic Dysfunction–Associated Steatotic Liver Disease (MASLD) is currently the leading cause of chronic liver disease worldwide, affecting more than 65% of patients with Type 2 Diabetes Mellitus (T2DM). The aim of our study was to determine the prevalence of MASLD among T2DM patients, with or without coexisting significant fibrosis, to assess its association with diabetic complications, and to identify the factors linked to MASLD in our population.

Aims & Methods

We conducted a retrospective, descriptive, and analytical study including T2DM patients admitted to the Endocrinology Department in 2019. MASLD diagnosis was based on the presence of hepatic steatosis detected by abdominal ultrasound or a Hepatic Steatosis Index (HSI) >36. Fibrosis was assessed using the Fibrosis-4 (FIB-4) index (with a threshold of ≥1.3 or <1.3). Chronic Kidney Disease (CKD) associated with T2DM was defined by an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m² and/or dipstick-positive proteinuria (>1+). Diabetic Peripheral Neuropathic Pain (DPNP) was assessed using the Douleur Neuropathique 4 (DN4) questionnaire, and Diabetic Retinopathy was diagnosed via dilated eye examination.

Results

Among the 202 patients included, the median age was 57 years (±12 years) with a marked female predominance (sex ratio = 2.6). Regarding comorbidities, 58.4% of patients had hypertension and 34.2% had dyslipidemia. The median Body Mass Index (BMI) was 27 kg/m² (±5.62), with overweight or obesity present in 61.4% of the cohort. The median duration of diabetes was 10 years (±7.8 years). Impaired renal function (eGFR <60 ml/min/1.73 m²) was found in 9.9% of patients, and proteinuria in 6.9%. Diabetic neuropathy (DN4 score ≥4) was present in 7.9% of patients, while diabetic retinopathy was diagnosed in 37.6% of cases.
The prevalence of MASLD in our cohort was 73.3%. The median FIB-4 score was 0.91 (±0.63), with 25.7% of patients presenting a FIB-4 >1.3. Statistical analysis identified several factors significantly associated with the presence of MASLD: female sex (p=0.004), dyslipidemia (p=0.004), BMI (p<0.001), alanine aminotransferase (ALT) levels (p<0.001), low-density lipoprotein cholesterol (LDL-C) levels (p=0.006), and triglyceride levels (p=0.013). In particular, higher BMI was strongly associated with MASLD (Odds Ratio [OR] = 1.970; 95% Confidence Interval [CI]: 1.580–2.460; p<0.001), as were elevated ALT levels (OR = 1.115; 95% CI: 1.053–1.18; p<0.001).
However, after adjustment, LDL-C levels (p=0.163), triglycerides (p=0.402), dyslipidemia (p=0.329), and sex (p=0.360) were no longer significantly associated with MASLD. Finally, a significantly higher proportion of CKD was observed in patients with MASLD (22.3%) compared to those without MASLD (9.2%, p=0.036), although this association was not maintained in the subgroup with advanced fibrosis (FIB-4 >1.3).

Conclusion

Our study confirmed the high prevalence of MASLD among patients with T2DM. Early screening is therefore essential, particularly in female patients and in those presenting with chronic kidney disease or other associated cardiometabolic risk factors such as obesity and dyslipidemia.

References

Younossi ZM, Golabi P, Price JK, Owrangi S, Gundu-Rao N, Satchi R, Paik JM. The Global Epidemiology of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis Among Patients With Type 2 Diabetes. Clin Gastroenterol Hepatol. 2024 Oct;22(10):1999-2010.e8. doi: 10.1016/j.cgh.2024.03.006. Epub 2024 Mar 21. PMID: 38521116.

Introduction

Patients with diabetes mellitus (DM) are at increased risk of developing cardiovascular disease (CVD). Hepatic fibrosis is common among patients with DM and is associated with liver-related events. However, its impact on CVD risk remains unclear.

Aims & Methods

This study aimed to prospectively assess the association between hepatic fibrosis and CVD risk in patients with DM.
A total of 323 patients with DM were prospectively enrolled from January 2022, excluding those with viral hepatitis, overt cirrhosis, or cancer. Clinical measurements and CVD history were recorded. The following parameters were assessed: body weight (BW), body mass index (BMI), waist circumference (WC), laboratory data [aspartate aminotransferase, alanine aminotransferase (ALT), gamma-glutamyl transferase, platelet count, hemoglobin A1C, cholesterol, and triglycerides], presence of hypertension (HTN), dyslipidemia, alcohol consumption, smoking status, liver steatosis measured by the controlled attenuation parameter (CAP) using FibroScan®, and current anti-DM medications. Hepatic fibrosis was quantified by liver stiffness measurement (LSM) using FibroScan®, assessed at baseline and after two years. CVD was defined as ischemic heart disease or ischemic/hemorrhagic stroke.

Results

A total of 277 patients completed the two-year follow-up and underwent repeat LSM. The mean age was 57±12 years, and 56.3% were male. The baseline mean LSM was 6.9±3.7 kPa. A history of CVD was present in 86 (31%) patients, while 6 (3.2%) developed new CVD events during follow-up. Among the new CVD cases, 3 were cardiac events, and 3 were neurovascular events. LSM decreased in 157 patients (d-LSM group) and increased in 120 patients (i-LSM group). The mean LSM change was -1.7±2 kPa in the d-LSM group and +1.5±1.3 kPa in the i-LSM group. The d-LSM group had significantly higher baseline ALT (39±30 vs. 32±21 IU/L, p=0.018), CAP (281±51 vs. 264±49 dB/m, p=0.005), and LSM (7.9±4.2 vs. 5.7±2.3 kPa, p<0.001) than the i-LSM group. Alcohol consumption was more prevalent in the i-LSM group (30.8% vs. 17.8%., p=0.011). There were no significant differences between the two groups in mean age (57±13 vs. 57±10 years, p=0.738), male proportion (51.6% vs. 62.5%, p=0.07), BW (72±16 vs. 72±14 kg, p=0.93), BMI (26.7±4.7 vs. 26.1±4.1 kg/m², p=0.233), WC (90±12 vs. 89±10 cm, p=0.816), HTN (58% vs. 48.3%, p=0.111), dyslipidemia (68.2% vs. 62.5%, p=0.326), laboratory results excluding ALT, or smoking status (45.2% vs. 49.2%, p=0.515). The use of metformin (91.1% vs. 95.8%, p=0.121), pioglitazone (1.9% vs. 2.5%, p=1.0), and insulin (7% vs. 9.2%, p=0.51) did not differ significantly between the two groups. When stratified by LSM change, the incidence of new CVD was 2% (1/49) in patients with a decrease LSM of ≤-2 kPa, 2% (4/198) in those with changes between -2 and +2 kPa, and 3.3% (1/30) in those with an increase of ≥+2 kPa (p=0.897).

Conclusion

Hepatic fibrosis, as measured by LSM, can change dynamically in patients with DM. Although this was an observational study, a decrease in LSM was not associated with a reduced risk of CVD. Therefore, LSM monitoring may have limited value in assessing CVD risk in this population.