Elevated levels of serum ferritin, a marker of hepatic iron overload and inflammation, may be associated with metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatic fibrosis.

To determine the prevalence of MASLD and significant hepatic fibrosis among patients with type 2 diabetes mellitus (T2DM) and hyperferritinaemia.

This is a cross-sectional analysis of a prospective cohort of 523 adults (64% female) aged 50-80 with T2DM and without a diagnosis of haemochromatosis. MASLD and significant fibrosis were defined as magnetic resonance imaging-proton density fat fraction (MRI-PDFF) ≥ 5% and magnetic resonance elastography (MRE) ≥ 3.0 kPa, respectively. Hyperferritinaemia was defined as serum ferritin ≥ 200 ng/mL in females or ≥ 300 ng/mL in males. The primary objective was to determine the prevalence of MASLD and significant fibrosis in hyperferritinaemia.

The mean age and body mass index were 64.1 (±8.1) years and 31.5 (±5.9) kg/m2, respectively. The overall prevalence of hyperferritinaemia was 20.5% (n = 107). The prevalence of MASLD (78.5% vs. 62.1%, p = 0.001) and significant fibrosis (35.5% vs. 22.1%, p = 0.002) were higher in participants with hyperferritinaemia than those without. Hyperferritinaemia remained an independent predictor of MASLD (OR 2.01; 95% CI 1.19-3.39; p = 0.009) and significant fibrosis (OR 2.33; CI 1.43-3.77; p = 0.001), even after adjustment for age, sex, obesity and insulin use.

Approximately 80% of people with hyperferritinaemia and T2DM have MASLD, and more than a third have significant hepatic fibrosis. Hyperferritinaemia may be a useful biomarker for MASLD and significant fibrosis in people with T2DM.

Background: The Fibrosis-4 (FIB-4) index is widely recommended as a first-tier method for screening advanced hepatic fibrosis; however, its diagnostic performance is known to be suboptimal in patients with Type 2 diabetes mellitus (T2DM). We aim to propose a modified FIB-4, using the parameters of the existing FIB-4, tailored specifically for diabetic patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Methods: A total of 1503 patients who underwent liver biopsy were divided into T2DM (n = 517) and non-T2DM (n = 986) groups. The model was developed using multiple regression analysis in the derivation cohort and validated in the validation cohort. Diagnostic accuracy was evaluated using the area under the receiver operating characteristic (AUC) curves. Results: Among the 1503 individuals, those with T2DM were older, more likely to be male, and had a higher prevalence of advanced hepatic fibrosis (≥F3) compared to non-T2DM individuals. Independent risk factors for advanced fibrosis in T2DM included age, AST, AST/ALT ratio, albumin, triglycerides, and platelet count. The optimized FIB-4 model for T2DM with MASLD (Diabetes Fibrosis Index) demonstrated superior diagnostic accuracy (AUC 0.771) compared to the FIB-4 (AUC 0.735, p = 0.012). The model showed a higher negative predictive value than the original FIB-4 across all age groups in the diabetic group. Conclusions: The newly optimized FIB-4 model for T2DM with MASLD (Diabetes Fibrosis Index), incorporating a non-linear predictive model, improves diagnostic performance (AUC) and the negative predictive value in MASLD with T2DM.

Liver fibrosis is associated with increased cardiovascular disease (CVD) risk and mortality. However, it is unknown how these risks compare in those with pre-diabetes (pre-DM) or diabetes (DM). We examined the association of FIB-4 levels, an indicator of liver fibrosis, with CVD risk and mortality according to DM status.

Prospective, longitudinal cohort study.

We examined 13,326 U.S. adults (6.7 % with DM) with FIB-4 measures classified as low (<1.30), intermediate (1.30- < 2.67), high (2.67- < 3.25), and very high (≥3.25). National Death Index linkage provided mortality status for CVD, liver-related, and all causes over 17.5 years.

We calculated 10-year ASCVD risk in persons without known ASCVD. Cox regression examined the relation of FIB-4 with mortality by DM status.

High/very high FIB-4 levels were greater in those with (2.2 %) vs. without (0.4 %) DM (p < 0.0001). Higher FIB-4 scores and DM were associated with greater estimated ASCVD risks (p < 0.0001); 44.5 % of those at high /very high FIB-4 levels had ≥20 % estimated ASCVD risk. CVD mortality hazard ratios (HRs) (95 % CI) associated with high/very high FIB-4 in those with pre-DM and DM were 8.76 (3.66-20.95), and 0.89 (0.22-3.53), respectively, and for total mortality were 5.46 (3.16-9.43), and 2.07 (0.90-4.74), respectively, which were attenuated after adjustment.

Our findings indicate the need for increased efforts to identify those at risk of liver fibrosis in adults with pre-DM or DM to prevent CVD and total mortality.

The objective of this study was to determine the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) in young compared with older adults.

Individuals (n = 1420) with (63%) and without type 2 diabetes mellitus (T2D; 37%) who attended internal medicine clinics and did not have a known history of MASLD underwent laboratory evaluation and transient elastography to assess for hepatic steatosis and fibrosis. Magnetic resonance elastography and liver biopsy were recommended when indicated.

A total of 243 participants were ages <45 years, and 1177 were ages ≥45 years. Obesity, T2D, and metabolic syndrome were highly prevalent in young adults. Frequencies of steatosis and fibrosis were high in young adults (50.2% and 7.5% vs. older adults 52.7% and 9.9%, respectively) and were significantly higher in those with both obesity and T2D (71.1% and 15.7%, respectively; p < 0.01). In young adults, T2D and obesity were the strongest risk factors for hepatic fibrosis (odds ratios 4.33 [95% CI: 1.37-13.68] and 1.16 [95% CI: 1.07-1.25], respectively; p < 0.05).

There is a high prevalence of clinically significant hepatic fibrosis in young adults with cardiometabolic risk factors. Up to one in seven young adults with obesity and T2D had clinically significant hepatic fibrosis on elastography. This highlights the need to screen young adults with cardiometabolic risk factors for MASLD for early detection and intervention.

Chronic liver diseases (CLD), cirrhosis, and hepatocellular carcinoma (HCC) cause significant morbidity and mortality. Unfortunately, patients with CLD often go undiagnosed until progression to cirrhosis and HCC. We aimed to determine the proportion of primary care patients with severe liver disease outcomes that had missed or delayed CLD diagnoses.

This retrospective cohort study evaluated primary care patients with a diagnosis of cirrhosis, HCC, or other severe liver disease outcome between 2012 and 2021. The outcomes of interest were missed and delayed diagnoses of CLD, defined as the absence of a CLD diagnosis (missed) or first appearance of CLD on the same day as the cirrhosis diagnosis (delayed). Univariate analyses were performed to describe the cohort. Multivariable logistic regression models analyzed the association of aminotransferase elevations with the outcomes of interest.

Of 667 patients with cirrhosis or HCC, 133 (20%) had a missed CLD diagnosis, and 243 (36%) had a delayed CLD diagnosis. Alcohol-related liver disease was the most common etiology among patients with missed/delayed diagnoses. A lower proportion of patients with missed/delayed diagnoses had an elevation in ALT or AST compared to patients with timely diagnoses (61% vs. 77%, p < 0.001). Elevated aminotransferase values were associated with lower odds of a missed/delayed diagnosis (OR 0.47; 95%CI 0.34-0.66).

Most patients with cirrhosis or HCC had missed or delayed diagnoses of CLD in the context of probable overreliance on aminotransferase elevation for CLD detection. Enhanced screening for high prevalence CLD, especially alcohol, in primary care is needed.

This study aims to investigate the relationship between Sodium Glucose Co-transporter-2 inhibitors (SGLT2i) treatment and fibrosis in patients with Metabolic dysfunction-associated steatotic liver disease (MASLD) combined with Type 2 Diabetes Mellitus (T2DM) and Major Adverse Cardiovascular and Cerebrovascular Events (MACCEs).

A case-control study was conducted, involving 280 patients with MASLD combined with T2DM treated at the First Affiliated Hospital of Xinjiang Medical University from January 2014 to October 2023. Among these patients, 135 received SGLT2i treatment. The association between the Fibrosis-4 (FIB-4) index and the occurrence of MACCEs, as well as the association between the Aspartate Aminotransferase-to-Platelet Ratio Index (APRI) scores and MACCEs, were evaluated.

The FIB-4 index and APRI scores were significantly lower in the SGLT2i treatment group compared to the non-SGLT2i group (1.59 vs 1.25, P<0.001). SGLT2i treatment tended to reduce the occurrence of MACCEs compared to non-SGLT2i treatment (45.5% vs 38.5%, P=0.28). All patients who developed MACCEs in the non-SGLT2i treatment group had higher FIB-4 index (1.83 vs 1.35, P=0.003). Additionally, after SGLT2i treatment for a median duration of 22 months, patients showed significant reductions in blood glucose, APRI, and FIB-4 index.

SGLT2i treatment significantly reduces the occurrence of MACCEs and liver fibrosis in patients with MASLD combined with T2DM. The FIB-4 index may serve as a potential surrogate marker for predicting the occurrence of MACCEs.

There are limited data on the prevalence and treatment of at-risk metabolic dysfunction-associated steatohepatitis (MASH) among patients with type 2 diabetes (T2DM) in the United States.

To estimate the prevalence of at-risk MASH in a prospectively recruited cohort of adults with T2DM using new nomenclature endorsed by multiple societies.

This prospective study enrolled adults aged ≥50 with T2DM from primary care and endocrinology clinics in southern California from 2016 to 2023. Metabolic dysfunction-associated steatotic liver disease (MASLD) was defined by an magnetic resonance imaging proton density fat fraction ≥5% and at least one metabolic risk factor without any other chronic liver disease or secondary cause for hepatic steatosis.

We included 530 adult patients with T2DM. The mean (±SD) age and body mass index (BMI) were 64.4 (±8.1) years and 31.5 (±6.1) kg/m2, respectively. Among patients with T2DM, the prevalence of MASLD, at-risk MASH and cirrhosis was 69.6%, 13.6% and 6.8%, respectively. Among patients with co-existing T2DM and obesity, the prevalence of MASLD, at-risk MASH and cirrhosis was 77.8%, 15.9% and 9.0%, respectively, and was higher than in participants without obesity (p < 0.0001, 0.0543 and 0.0128, respectively).

Among adults aged ≥50 years with T2DM, the prevalence of MASLD, at-risk MASH and cirrhosis is high, posing a significant risk for liver-related morbidity and mortality. Approximately 14% of patients with T2DM may be candidates for pharmacologic therapies specific to MASH-related fibrosis.

Data on the effects of liver fibrosis and hepatic steatosis on outcomes in individuals living with diabetes are limited. Therefore, we investigated the predictive value of the fibrosis and the severity of hepatic steatosis for all-cause mortality in individuals living with diabetes.

A total of 1903 patients with diabetes from the Third National Health and Nutrition Examination Survey (NHANES III) dataset were enrolled. Presumed hepatic fibrosis was evaluated with Fibrosis-4 index (FIB-4). The mortality risk and corresponding hazard ratio (HR) were analyzed with the Kaplan-Meier method and multivariable Cox proportional hazard models.

Over a median follow-up of 19.4 years, all-cause deaths occurred in 69.6%. FIB-4 ≥ 1.3 was an independent predictor of mortality in individuals living with diabetes (HR 1.219, 95% confidence interval [CI]: 1.067-1.392, p = 0.004). Overall, FIB-4 ≥ 1.3 without moderate-severe steatosis increased the mortality risk (HR 1.365; 95%CI 1.147-1.623, p < 0.001). The similar results were found in individuals living with diabetes with metabolic dysfunction-associated fatty liver disease (MAFLD) (HR 1.499; 95%CI 1.065-2.110, p = 0.020), metabolic syndrome (MetS) (HR 1.397; 95%CI 1.086-1.796, p = 0.009) or abdominal obesity (HR 1.370; 95%CI 1.077-1.742, p = 0.010).

Liver fibrosis, as estimated by FIB-4, may serve as a more reliable prognostic indicator for individuals living with diabetes than hepatic steatosis. Individuals living with diabetes with FIB-4 ≥ 1.3 without moderate-severe steatosis had a significantly increased all-cause mortality risk. These findings highlight the importance of identifying and monitoring those individuals, as they may benefit from further evaluation and risk stratification.

Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent condition in the general population. Although recent studies have demonstrated a link between NAFLD and lipoprotein(a), a low-density lipoprotein-like particle synthesized in the liver, its precise physiological role and mechanism of action remain unclear. This study aimed to investigate the relationship between lipoprotein(a) levels and development of NAFLD and hepatic fibrosis in Korean adults. A total of 1501 subjects who underwent abdominal ultrasonography at least twice as part of a health checkup program were enrolled. Biochemical and ultrasonography results were analyzed longitudinally, and the degree of hepatic fibrosis was calculated in subjects with NAFLD using serum biomarkers, such as fibrosis-4 (FIB-4). During the 3.36-year follow-up period, 352 patients (23.5%) were diagnosed with NAFLD. The subjects were categorized into 4 groups based on their lipoprotein(a) levels. Remarkably, the incidence of NAFLD decreased as the lipoprotein(a) levels increased. Following logistic regression analysis and adjustment for various risk factors, the odds ratio for the development of NAFLD was 0.625 (95% CI 0.440-0.888; P = .032) when comparing the highest to the lowest tertile of lipoprotein(a). However, no significant association was observed between the occurrence of hepatic fibrosis and lipoprotein(a) levels in subjects with NAFLD. Lipoprotein(a) levels have been identified as a significant predictor of NAFLD development. Additional large-scale studies with extended follow-up periods are required to better understand the effect of lipoprotein(a) on NAFLD and hepatic fibrosis.

Recently, the American Gastroenterological Association and the American Association for the Study of Liver Diseases developed clinical pathways to evaluate populations at high risk for NAFLD. We assessed the diagnostic performance of the new guidance in a well-phenotyped cohort of patients with Type 2 diabetes mellitus (T2DM).

This prospective study enrolled patients age ≥50 years with T2DM. Participants underwent a standardized clinical research visit with MRI and ultrasound-based assessment of liver fat and stiffness and Enhanced Liver Fibrosis (ELF) testing. Of 417 participants (36% men) with T2DM with FIB-4 and MRE data, the prevalence of NAFLD was 64% and 12% had advanced fibrosis (MRE≥3.63 kPa). Applying the American Gastroenterological Association pathway of FIB-4 and vibration-controlled transient elastography, the false negative rate was 3.3% and 18% would qualify for specialty referral. Applying the FIB-4 + ELF American Association for the Study of Liver Diseases pathway, the false negative rate was 4.5%, but 50% would qualify for specialty referral. Applying higher ELF cut points improved the pathway, yielding a similar false negative rate of 4.9% but decreased specialty referral to 27%.

Validation of the American Gastroenterological Association clinical pathway in a prospectively recruited cohort with T2DM revealed a low false negative rate and avoided specialty referral in a large percentage of patients. The American Association for the Study of Liver Diseases pathway with FIB-4 + ELF resulted in a high rate of specialty referral, which improved with the utilization of higher ELF cut points and may serve as an alternative for primary care and endocrinology clinics without access to vibration-controlled transient elastography.

Chronic liver diseases are a major global health concern.

this study investigated the links between medical, clinical, anthropometric, and dietary factors with dysfunction-associated steatotic liver disease (MASLD) in the Lebanese population using a case-control approach to uncover factors influencing visceral obesity, sarcopenia, and sarcopenic obesity.

a total of 120 participants (20-70 years old) were divided into case and control groups based on liver disease diagnosis. Patient information was gathered through a questionnaire encompassing demographics, medical history, and beverage consumption. Anthropometric and body composition data were collected in a clinical setting.

our findings indicated a clear association between the presence of MASLD and obesity, hypertension, and diabetes. The positive association with higher body mass index and all three conditions remained consistent even when data was stratified by case and control groups. A greater proportion of MASLD patients exhibited sarcopenic obesity. Furthermore, MASLD cases showed higher consumption of sugary beverages and a reduced intake of milk and water in their diets.

this study shed light on the health attributes and diets of the Lebanese population with liver diseases and suggested more research in this area and in a more ethnically diverse population.

Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease, with type 2 diabetes mellitus (T2DM) as a major predictor. Insulin resistance and chronic inflammation are key pathways in the pathogenesis of T2DM leading to NAFLD and vice versa, with the synergistic effect of NAFLD and T2DM increasing morbidity and mortality risks. This meta-analysis aims to quantify the prevalence of NAFLD and the prevalence of clinically significant and advanced fibrosis in people with T2DM.

MEDLINE and Embase databases were searched from inception until 13 February 2023. The primary outcomes were the prevalence of NAFLD, non-alcoholic steatohepatitis (NASH) and fibrosis in people with T2DM. A generalised linear mixed model with Clopper-Pearson intervals was used for the analysis of proportions with sensitivity analysis conducted to explore heterogeneity between studies.

156 studies met the inclusion criteria, and a pooled analysis of 1 832 125 patients determined that the prevalence rates of NAFLD and NASH in T2DM were 65.04% (95% CI 61.79% to 68.15%, I2=99.90%) and 31.55% (95% CI 17.12% to 50.70%, I2=97.70%), respectively. 35.54% (95% CI 19.56% to 55.56%, I2=100.00%) of individuals with T2DM with NAFLD had clinically significant fibrosis (F2-F4), while 14.95% (95% CI 11.03% to 19.95%, I2=99.00%) had advanced fibrosis (F3-F4).

This study determined a high prevalence of NAFLD, NASH and fibrosis in people with T2DM. Increased efforts are required to prevent T2DM to combat the rising burden of NAFLD.

CRD42022360251.

Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are independent risk factors for cardiovascular disease (CVD).

To examine the clinical utility of liver fat quantification for determining CVD risk among a well-phenotyped cohort of patients with T2DM.

This was a cross-sectional analysis of a prospective cohort of adults aged ≥50 with T2DM. Liver fat was quantified with magnetic resonance imaging proton-density-fat-fraction (MRI-PDFF), an advanced imaging-based biomarker. Patients were stratified into a higher liver fat group (MRI-PDFF ≥ 14.6%), and a lower liver fat group (MRI-PDFF < 14.6%). The co-primary outcomes were CVD risk determined by Framingham and Atherosclerotic Cardiovascular Disease (ASCVD) risk scores. High CVD risk was defined by risk scores ≥20%.

Of the 391 adults (66% female) in this study, the mean (±SD) age was 64 (±8) years and BMI 30.8 (±5.2) kg/m2 , respectively. In multivariable analysis, adjusted for age, gender, race, and BMI, patients in the higher liver fat group had higher CVD risk [OR = 4.04 (95% CI: 2.07-7.88, p < 0.0001)] and ASCVD risk score [OR = 2.85 (95% CI: 1.19-6.83, p = 0.018)], respectively.

Higher liver fat content increases CVD risk independently of age, gender, ethnicity and BMI. These findings raise the question whether liver fat quantification should be incorporated into risk calculators to further stratify those with higher CVD risk.

Non-alcoholic fatty liver disease (NAFLD), and particularly liver fibrosis, has been suggested as a risk factor of chronic kidney disease (CKD). Given that NAFLD affects every fourth person globally, better insight is needed. Our aim was to investigate the association between hepatic fibrosis and CKD in patients with type 2 diabetes and to compare different methods for diagnosing liver fibrosis in this study population.

Cross-sectional study including patients with type 2 diabetes with CKD stages 3-5 (N = 50) or without CKD (N = 50). CKD was defined as estimated glomerular filtration rate <60 mL/min/1.73 m2 with or without proteinuria. Three methods were used to detect significant liver fibrosis defined as either ≥8 kilopascal measured by transient elastography (FibroScan®), fibrosis-4 (FIB-4) score ≥2.67, or NAFLD fibrosis score (NFS) >0.675.

Significant liver fibrosis was found in 38% and 28% of the patients with and without CKD, respectively, using at least one of the three methods. Both FIB-4 score and NFS were significantly higher in patients with CKD (p < 0.0009 and p < 0.0001, respectively), although insignificant after adjustments for age, sex, body mass index, and duration of diabetes. In patients without CKD, a significant association between steatosis and fibrosis was observed (p = 0.0007).

Our data do not support any strong independent association between liver fibrosis and established CKD as assessed by FibroScan, FIB-4 score, and NFS, respectively.

Most noninvasive tests (NITs) for hepatic fibrosis are designed for middle-aged patients with chronic liver disease. We compared the diagnostic performance of major NITs (aspartate aminotransferase-to-platelet ratio index [APRI], Fibrosis-4 index, and nonalcoholic fatty liver disease fibrosis score) for a community-based cohort.

This cross-sectional study analyzed 8775 participants who underwent magnetic resonance elastography at community health check-up centers. Advanced hepatic fibrosis (≥F3) was defined by magnetic resonance elastography thresholds of 3.6 kPa. The diagnostic performance of 3 NITs was evaluated according to the etiology of liver disease, sex, metabolic syndrome, obesity, and increased aminotransferase levels in 4 age groups.

The APRI generally showed the best area under the receiver operating characteristic curve in patients aged 45 years or younger, and it was statistically significant in patients with chronic viral hepatitis and alcoholic fatty liver disease (P < .043). The best APRI cut-off value for detecting advanced hepatic fibrosis was 0.4, with a sensitivity and specificity of 75.8% and 73.5%, respectively, in the community-based cohort. The APRI showed balanced sensitivity and specificity across all age groups, whereas the other metrics showed low sensitivity in those aged <45 and low specificity in those >65 years.

The APRI showed better sensitivity and negative predictive value than the Fibrosis-4 index and the nonalcoholic fatty liver disease fibrosis score in community-based populations with mixed etiology, and, thus, can be performed as the primary test in young adults (age, ≤45 y).

While nonalcoholic fatty liver disease is a leading cause of end-stage liver disease, most patients with nonalcoholic fatty liver disease do not develop cirrhosis and its complications. Therefore, risk stratification using inexpensive, noninvasive screening modalities is critical to avoid overdiagnosis and overtreatment of a large proportion of the population. In this review, we discuss the data supporting screening and current professional society recommendations on this topic. Screening for at-risk nonalcoholic fatty liver disease is recommended in patients with risk factors including diabetes, the metabolic syndrome, hepatic steatosis, and elevated aminotransferases. Screening typically consists of noninvasive testing using serum biomarkers followed by elastography using specialized imaging modalities. This sequential screening approach accurately identifies both high- and low-risk patients and is cost-effective when applied to at-risk populations. In conclusion, screening for advanced nonalcoholic fatty liver disease in the primary care setting is a crucial part of identifying high-risk patients who may benefit from aggressive intervention while avoiding overtreatment of patients at low risk of liver-related complications.

There are limited prospective data on patients with type 2 diabetes mellitus (T2DM) specifically enrolled and systematically assessed for advanced fibrosis or cirrhosis due to non-alcoholic fatty liver disease (NAFLD). Therefore, we aimed to evaluate the prevalence of advanced fibrosis and cirrhosis in a prospectively recruited cohort of adults with T2DM.

This prospective study enrolled adults aged ≥50 years with T2DM, recruited from primary care or endocrinology clinics. Participants underwent a standardized clinical research visit with MRI-proton density fat fraction (MRI-PDFF), magnetic resonance elastography (MRE), vibration-controlled transient elastography (VCTE) and controlled-attenuation parameter. NAFLD was defined as MRI-PDFF ≥5% after exclusion of other liver diseases. Advanced fibrosis and cirrhosis were defined by established liver stiffness cut-off points on MRE or VCTE if MRE was not available.

Of 524 patients screened, 501 adults (63% female) with T2DM met eligibility. The mean age and BMI were 64.6 (±8.1) years and 31.4 (±5.9) kg/m2, respectively. The prevalence of NAFLD, advanced fibrosis and cirrhosis was 65%, 14% and 6%, respectively. In multivariable adjusted models, adjusted for age and sex, obesity and insulin use were associated with increased odds of advanced fibrosis (odds ratio 2.50; 95% CI 1.38-4.54; p = 0.003 and odds ratio 2.71; 95% CI 1.33-5.50; p = 0.006, respectively). Among 29 patients with cirrhosis, two were found to have hepatocellular carcinoma and one patient had gallbladder adenocarcinoma.

Utilizing a uniquely well-phenotyped prospective cohort of patients aged ≥50 years with T2DM, we found that the prevalence of advanced fibrosis was 14% and that of cirrhosis was 6%. These data underscore the high risk of advanced fibrosis/cirrhosis in adults aged ≥50 years with T2DM.

Non-alcoholic fatty liver disease (NAFLD) is common in patients with type 2 diabetes (T2DM), however, there are limited prospective data characterizing the prevalence of advanced fibrosis and cirrhosis using the most accurate non-invasive biomarkers of liver fat and fibrosis. We show that 14% of older adults with T2DM have advanced fibrosis and 6% have cirrhosis, which places them at risk for liver failure and liver cancer. Accurate prevalence rates and comparative analysis regarding the diagnostic accuracy of non-invasive tests in this population will guide the optimal screening strategy and future cost-effectiveness analyses. These results will inform future Hepatology and Endocrinology practice guidelines regarding NAFLD screening programs in older adults with T2DM.

A panel of 9 experts in nonalcoholic steatohepatitis gathered to assess multiple components of the diagnostic process.

The Clinical Assertion Statements covered screening of patients with type 2 diabetes for high-risk nonalcoholic fatty liver disease, which-if any-noninvasive tests could determine whether to delay or defer biopsy, whether primary care providers and endocrinologists should routinely calculate Fibrosis-4 (FIB-4) scores in patients with nonalcoholic fatty liver disease or those at risk for it, optimal noninvasive tests to stage fibrosis, the need to consider fibrosis in patients with normal transaminase levels, periodic monitoring for progressive fibrosis, whether patients should undergo biopsy before pharmacotherapy, and the clinical utility of genetic testing.

Evidence was presented to support or refute each Clinical Assertion Statement; the panel voted on the nature of the evidence, level of support, and level of agreement with each Statement. Panel level of agreement and rationale of each Clinical Assertion Statement are reported here.

NASH-related liver transplants are increasing because of the obesity epidemic, but the influence of T2DM on various levels of BMI among NASH recipients is unclear.

We analyzed data retrieved from SRTR on 4,515 patients. We divided patients by BMI into five groups: normal weight; overweight; class 1 obesity; class 2 obesity; and class 3 obesity. Statistical analysis was done.

Patients in the NASH group with T2DM had a lower patient and graft survival than patients without T2DM (5-year patient and graft survival: 77.5% vs. 79.8%; P = 0.001 and 76.4% vs. 78.2%; P = 0.002, respectively). Multivariate Cox proportional regression showed an independent association between T2DM and decreased patient and graft survival (HR, 1.170; P = 0.015 and HR, 1.133; P = 0.048, respectively). In the lean and the class 3 obesity NASH groups, patients with T2DM had lower patient and graft survival than the patients without T2DM. In the class 3 obesity NASH group, T2DM was independently associated with decreased patient survival (HR, 1.581; P = 0.027).

Our research reveals that the focus of the post-transplantation treatment should be different for different BMI patients.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, affecting approximately 25% of the general population worldwide, and is forecasted to increase global health burden in the 21st century. With the advancement of non-invasive tests for assessing and monitoring of steatosis and fibrosis, NAFLD screening is now feasible, and is increasingly highlighted in international guidelines related to hepatology, endocrinology, and pediatrics. Identifying high-risk populations (e.g., diabetes mellitus, obesity, metabolic syndrome) based on risk factors and metabolic characteristics for non-invasive screening is crucial and may aid in designing screening strategies to be more precise and effective. Many screening modalities are currently available, from serum-based methods to ultrasonography, transient elastography, and magnetic resonance imaging, although the diagnostic performance, cost, and accessibility of different methods may impact the actual implementation. A two-step assessment with serum-based fibrosis-4 index followed by imaging test vibration-controlled transient elastography can be an option to stratify the risk of liverrelated complications in NAFLD. There is a need for fibrosis surveillance, as well as investigating the cost-effectiveness of different screening algorithms and engaging primary care for first-stage triage screening.

Cardiometabolic disease refers to the spectrum of chronic conditions that include diabetes, hypertension, atheromatosis, non-alcoholic fatty liver disease, and their long-term impact on cardiovascular health. Histological studies have confirmed several modifications at the tissue level in cardiometabolic disease. Recently, quantitative MR methods have enabled non-invasive myocardial and liver tissue characterization. MR relaxation mapping techniques such as T₁, T_1ρ, T₂ and T₂* provide a pixel-by-pixel representation of the corresponding tissue specific relaxation times, which have been shown to correlate with fibrosis, altered tissue perfusion, oedema and iron levels. Proton density fat fraction mapping approaches allow measurement of lipid tissue in the organ of interest. Several studies have demonstrated their utility as early diagnostic biomarkers and their potential to bear prognostic implications. Conventionally, the quantification of these parameters by MRI relies on the acquisition of sequential scans, encoding and mapping only one parameter per scan. However, this methodology is time inefficient and suffers from the confounding effects of the relaxation parameters in each single map, limiting wider clinical and research applications. To address these limitations, several novel approaches have been proposed that encode multiple tissue parameters simultaneously, providing co-registered multiparametric information of the tissues of interest. This review aims to describe the multi-faceted myocardial and hepatic tissue alterations in cardiometabolic disease and to motivate the application of relaxometry and proton-density cardiac and liver tissue mapping techniques. Current approaches in myocardial and liver tissue characterization as well as latest technical developments in multiparametric quantitative MRI are included. Limitations and challenges of these novel approaches, and recommendations to facilitate clinical validation are also discussed.

Liver fibrosis is an important prognosis marker in non-alcoholic fatty liver disease (NAFLD). Biopsy has been considered the gold-standard method for measuring liver fibrosis; however, it is an invasive procedure. Non-invasive diagnostic tools have been developed, such as clinical scores and magnetic resonance elastography (MRE), which is the most accurate non-invasive method to determine liver fibrosis. Thus, the aim was to determine the NAFLD Fibrosis Score (NFS) and the Fibrosis-4 Score (FIB-4) cut-off points that best identify NAFLD patients at risk for developing liver fibrosis.

Single-center cross-sectional study with prospective recruitment of NAFLD (training-cohort) and MAFLD (validation-cohort) patients undergoing MRE. The NFS and the FIB-4 cut-off points that best-differentiated patients with fibrosis, using the MRE as the standard method, were determined.

Two cohorts were analyzed, a training cohort that included the initial 183 patients with NAFLD and a validation cohort that included 289 patients. In the training cohort, 60.1% had mild steatosis and 11.5% had liver fibrosis ≥ F1 by MRE. ROC curves were developed for FIB-4 and NFS, and the cut-off points chosen were 1.505 (sensitivity=85% and specificity=86%) for FIB-4 and -0.835 (sensitivity=100% and specificity=70%) for NFS, showing greater specificity than the cut-off points currently used (51% and 76%, respectively). The two cohorts exhibited similar characteristics and similar sensitivity and specificity results for the chosen cut-off points.

This study has shown cut-off points with greater specificity and excellent sensitivity to guide the indication for further liver evaluation by MRE in NAFLD patients.

Nonalcoholic fatty liver disease (NAFLD) is increasing in prevalence worldwide. NAFLD is associated with excess risk of all-cause mortality, and its progression to nonalcoholic steatohepatitis (NASH) and fibrosis accounts for a growing proportion of cirrhosis and hepatocellular cancer and thus is a leading cause of liver transplant worldwide. Noninvasive precise methods to identify patients with NASH and NASH with significant disease activity and fibrosis are crucial when the disease is still modifiable. The aim of this study was to examine the clinical utility of corrected T1 (cT1) vs magnetic resonance imaging (MRI) liver fat for identification of NASH participants with nonalcoholic fatty liver disease activity score ≥4 and fibrosis stage (F) ≥2 (high-risk NASH).

Data from five clinical studies (n = 543) with participants suspected of NAFLD were pooled or used for individual participant data meta-analysis. The diagnostic accuracy of the MRI biomarkers to stratify NASH patients was determined using the area under the receiver operating characteristic curve (AUROC).

A stepwise increase in cT1 and MRI liver fat with increased NAFLD severity was shown, and cT1 was significantly higher in participants with high-risk NASH. The diagnostic accuracy (AUROC) of cT1 to identify patients with NASH was 0.78 (95% CI, 0.74-0.82), for liver fat was 0.78 (95% CI, 0.73-0.82), and when combined with MRI liver fat was 0.82 (95% CI, 0.78-0.85). The diagnostic accuracy of cT1 to identify patients with high-risk NASH was good (AUROC = 0.78; 95% CI, 0.74-0.82), was superior to MRI liver fat (AUROC = 0.69; 95% CI, 0.64-0.74), and was not substantially improved by combining it with MRI liver fat (AUROC = 0.79; 95% CI, 0.75-0.83). The meta-analysis showed similar performance to the pooled analysis for these biomarkers.

This study shows that quantitative MRI-derived biomarkers cT1 and liver fat are suitable for identifying patients with NASH, and cT1 is a better noninvasive technology than liver fat to identify NASH patients at greatest risk of disease progression. Therefore, MRI cT1 and liver fat have important clinical utility to help guide the appropriate use of interventions in NAFLD and NASH clinical care pathways.

Nonalcoholic fatty liver (NAFL) and its sequelae are growing health problems. We performed a genome-wide association study of NAFL, cirrhosis and hepatocellular carcinoma, and integrated the findings with expression and proteomic data. For NAFL, we utilized 9,491 clinical cases and proton density fat fraction extracted from 36,116 liver magnetic resonance images. We identified 18 sequence variants associated with NAFL and 4 with cirrhosis, and found rare, protective, predicted loss-of-function variants in MTARC1 and GPAM, underscoring them as potential drug targets. We leveraged messenger RNA expression, splicing and predicted coding effects to identify 16 putative causal genes, of which many are implicated in lipid metabolism. We analyzed levels of 4,907 plasma proteins in 35,559 Icelanders and 1,459 proteins in 47,151 UK Biobank participants, identifying multiple proteins involved in disease pathogenesis. We show that proteomics can discriminate between NAFL and cirrhosis. The present study provides insights into the development of noninvasive evaluation of NAFL and new therapeutic options.

There are several reports on the prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD). However, the prevalence of advanced hepatic fibrosis in MAFLD is largely unknown. We aimed to evaluate the prevalence of advanced fibrosis in MAFLD.

A total of 6775 subjects from nationwide 13 health check-up centres were included in this cross-sectional study. Fatty liver was evaluated using ultrasonography. Significant (≥F2) and advanced (≥F3) hepatic fibrosis were defined by MRE thresholds of 3.0 kPa (range: 2.99-3.65 kPa) and 3.6 kPa (range: 3.4-3.9 kPa) respectively. The sex- and age-standardized prevalence of MAFLD and hepatic fibrosis was estimated.

The sex- and age-standardized prevalence of MAFLD was 33.9%. The prevalence of obesity (BMI ≥25 kg/m² ) in MAFLD was 71.1%, and 79.0% of obese subjects had MAFLD. The prevalence of diabetes in MAFLD was 13.3%, and 73.6% of subjects with diabetes had MAFLD. The sex- and age-standardized prevalence of significant (≥F2) and advanced hepatic fibrosis (≥F3) amongst MAFLD was 9.7% (range: 3.0-9.8%) and 3.0% (range: 2.6-4.6%) respectively. The prevalence of advanced hepatic fibrosis in overweight/obese (group I), lean (group II) and diabetic (group III) MAFLD was 2.3%, 3.1% and 9.5% respectively.

The sex- and age-standardized prevalence of advanced fibrosis was 3.0% (range: 2.6-4.6%) in subjects with MAFLD.

In patients with NAFLD, those with type 2 diabetes mellitus (DM) have a high risk of progression to HCC. However, the determinants of HCC risk in these patients remain unclear.

We assembled a retrospective cohort of patients with NAFLD and DM diagnosed at 130 facilities in the Veterans Administration between 1/1/2004 and 12/31/2008. We followed patients from the date of NAFLD diagnosis to HCC, death, or 12/31/2018. We used landmark Cox proportional hazards models to determine the effects of anti-DM medications (metformin, insulin, sulfonylureas) and glycemic control (percent of follow-up time with hemoglobin A1c < 7%) on the risk of HCC while adjusting for demographics and other metabolic traits (hypertension, obesity, dyslipidemia). We identified 85,963 patients with NAFLD and DM. In total, 524 patients developed HCC during a mean of 10.3 years of follow-up. Most common treatments were metformin monotherapy (19.7%), metformin-sulfonylureas (19.6%), insulin (9.3%), and sulfonylureas monotherapy (13.6%). Compared with no medication, metformin was associated with 20% lower risk of HCC (HR, 0.80; 95% CI, 0.93-0.98). Insulin had no effect on HCC risk (HR, 1.02; 95% CI, 0.85-1.22; p = 0.85). Insulin in combination with other oral medications was associated with a 1.6 to 1.7-fold higher risk of HCC. Adequate glycemic control was associated with a 31% lower risk of HCC (HR, 0.69; 95% CI, 0.62-0.78).

In this large cohort of patients with NAFLD and DM, use of metformin was associated with a reduced risk of HCC, whereas use of combination therapy was associated with increased risk. Glycemic control can serve as a biomarker for HCC risk stratification in patients with NAFLD and diabetes.

To assess reproducibility and fibrosis classification accuracy of magnetic resonance elastography (MRE)-determined liver stiffness measured manually at two different centers, and by automated analysis software in adults with nonalcoholic fatty liver disease (NAFLD), using histopathology as a reference standard.

This retrospective, cross-sectional study included 91 adults with NAFLD who underwent liver MRE and biopsy. MRE-determined liver stiffness was measured independently for this analysis by an image analyst at each of two centers using standardized manual analysis methodology, and separately by an automated analysis. Reproducibility was assessed pairwise by intraclass correlation coefficient (ICC) and Bland-Altman analysis. Diagnostic accuracy was assessed by receiver operating characteristic (ROC) analyses.

ICC of liver stiffness measurements was 0.95 (95% CI: 0.93, 0.97) between center 1 and center 2 analysts, 0.96 (95% CI: 0.94, 0.97) between the center 1 analyst and automated analysis, and 0.94 (95% CI: 0.91, 0.96) between the center 2 analyst and automated analysis. Mean bias and 95% limits of agreement were 0.06 ± 0.38 kPa between center 1 and center 2 analysts, 0.05 ± 0.32 kPa between the center 1 analyst and automated analysis, and 0.11 ± 0.41 kPa between the center 2 analyst and automated analysis. The area under the ROC curves for the center 1 analyst, center 2 analyst, and automated analysis were 0.834, 0.833, and 0.847 for distinguishing fibrosis stage 0 vs. ≥ 1, and 0.939, 0.947, and 0.940 for distinguishing fibrosis stage ≤ 2 vs. ≥ 3.

MRE-determined liver stiffness can be measured with high reproducibility and fibrosis classification accuracy at different centers and by an automated analysis.

• Reproducibility of MRE liver stiffness measurements in adults with nonalcoholic fatty liver disease is high between two experienced centers and between manual and automated analysis methods. • Analysts at two centers had similar high diagnostic accuracy for distinguishing dichotomized fibrosis stages. • Automated analysis provides similar diagnostic accuracy as manual analysis for advanced fibrosis.

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.