The development of a non-invasive model to predict the presence of non-alcoholic steatohepatitis in patients with non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is an advanced and aggressive form of non-alcoholic fatty liver disease (NAFLD), which remains difficult to diagnose without a liver biopsy. Hyperferritinemia has increasingly been associated with the presence of NASH. Hence, we sought to explore the relationship between ferritin and NASH and to develop a composite model based on ferritin to predict the presence of NASH. METHODS: A total of 405 patients with biopsy-proven NAFLD were enrolled in the study. Comparison was explored to assess differences between patients with and without NASH, upon which a scoring model was established using variables found to be independent predictors of NASH. RESULTS: Among all patients with NAFLD, 291 (72%) had biopsy-proven NASH, and 114 (28%) had non-NASH. Mean age was 48 ± 12 years, and 56% were female. Ferritin was significantly higher in NASH compared with non-NASH patients (184 vs 126, respectively; P < 0.001) but lacked diagnostic accuracy for predicting NASH alone (area under the curve [AUC 0.62]). The addition of other significant variables such as aspartate aminotransferase, body mass index, platelet count, diabetes, and hypertension to ferritin improved the prediction of NASH with an AUC 0.81 (95% confidence interval: 0.76-0.86). Internal validation of the model using imputed data sets demonstrated that AUC did not change materially. CONCLUSIONS: While higher ferritin was significantly associated with NASH, ferritin alone lacked diagnostic accuracy to predict NASH. However, incorporating several easily obtainable variables with ferritin allowed the construction of a novel scoring system that can be easily applied in the clinical setting to guide management of NAFLD.

Renin-angiotensin system and fibrosis in non-alcoholic fatty liver disease.

BACKGROUND & AIMS: Therapeutic options are limited for patients with non-alcoholic fatty liver disease (NAFLD). One promising approach is the attenuation of necroinflammation and fibrosis by inhibition of the renin-angiotensin system (RAS). We explored whether the risk of fibrosis was associated with the use of commonly used medications in NAFLD patients with hypertension. Specifically, we sought to determine the association between RAS blocking agents and severity of hepatic fibrosis in NAFLD patients with hypertension. METHODS: Cross-sectional study where clinical information including demographics, anthropometry, medical history, concomitant medication use, biochemical and histological features were ascertained in 290 hypertensive patients with biopsy proven NAFLD followed at two hepatology outpatient clinics. Stage of hepatic fibrosis was compared in patients with and without RAS blocker use. Other risk factors for fibrosis were evaluated from the electronic medical records and patient follow-up. RESULTS: Baseline characteristics of hypertensive patients treated with and without RAS blockers were similar except for less ballooning (1.02 vs. 1.31, P = 0.001) and lower fibrosis stage (1.63 vs. 2.16, P = 0.002) in patients on RAS blockers On multivariate analysis, advancing age (OR: 1.04; 95%CI: 1.01-1.06, P = 0.012) and presence of diabetes (OR: 2.55; 95%CI: 1.28-5.09, P = 0.008) had an independent positive association, while use of RAS blockers (OR: 0.37; 95%CI: 0.21-0.65, P = 0.001) and statins (OR: 0.52; 95%CI: 0.29-0.93, P = 0.029) had a negative association with advanced fibrosis. CONCLUSION: Hypertensive patients with NAFLD on baseline RAS blockers had less advanced hepatic fibrosis suggesting a beneficial effect of RAS blockers in NAFLD.

Liver transplantation arrests and reverses muscle wasting.

Muscle wasting, sarcopenia, is common in advanced cirrhosis and predicts adverse outcomes while awaiting and following liver transplantation. Frequent post-transplant worsening of sarcopenia has attracted recent interest. It is unknown whether this serious problem is an expected metabolic consequence of transplantation or results from confounding conditions such as recurrent allograft liver disease or avoidable post-transplant complications. To clarify this question, we studied pre- and post-transplant muscle mass in a retrospective cohort of 40 patients transplanted for three diseases - alcoholic cirrhosis, non-alcoholic steatohepatitis cirrhosis, and primary sclerosing cholangitis cirrhosis - in whom allograft disease recurrence was monitored and excluded, and who lacked common post-transplant muscle wasting complications such as sepsis, renal failure, ischemia, and cholestasis. We measured skeletal muscle index (SMI) using computed tomography before and 12-48 months after transplant. SMI as a categorical variable significantly improved, from 18 patients above the normal cutoff pre-transplant to 28 post-transplant (p = 0.008). SMI increases were greatest in patients with the lowest pre-transplant SMI (p < 0.01). As a continuous variable, mean SMI remained stable, with a non-significant trend toward improvement. We conclude that after liver transplantation sarcopenia does not progress but is arrested and frequently improves in the absence of confounding conditions.

A prospective analysis of factors associated with decreased physical activity in patients with cirrhosis undergoing transplant evaluation.

BACKGROUND: Physical activity (PA) has been associated with improved recovery time after transplantation. Handgrip strength has been related to post-transplant outcomes. AIM: To evaluate predictors of PA and grip strength in patients with cirrhosis undergoing liver transplant evaluation. METHODS: Single-center, prospective analysis. RESULTS: One hundred patients were evaluated (54% male, mean age 53 ± 9). Common etiologies of liver disease were non-alcoholic steatohepatitis (27%), hepatitis C (22%) and alcoholic liver disease (21%). Mean model of end-stage liver disease (MELD) score was 13.5. Forty-one percent had a history of smoking. Ninety-three patients completed the International Physical Activity Questionnaire (IPAQ). The median total PA score was 33 metabolic equivalent (MET)-min/wk. The mean total grip strength was 62.1 ± 22 lb. Total grip strength was found to be an independent predictor of low-moderate PA (OR 4.7, 95% CI 1.4-16.2, p = 0.038), and smoking was the only significant factor associated with reduced grip strength (OR 3.4, 95% CI 1.4-8, p = 0.005). CONCLUSIONS: Patients with end-stage liver disease undergoing liver transplant evaluation have reduced total PA by IPAQ. Total grip strength was found to be a significant predictor of low-moderate PA in patients with cirrhosis. Smoking is a risk factor for reduced grip strength, an important indicator of muscle wasting in cirrhotics.

Age impacts ability of aspartate-alanine aminotransferase ratio to predict advanced fibrosis in nonalcoholic Fatty liver disease.

BACKGROUND AND AIM: While histological differences have been reported between pediatric and adult nonalcoholic fatty liver disease (NAFLD), potential age-related changes in serum transaminases and liver histology remain largely unexplored. Our study sought to investigate the clinical and histological characteristics of NAFLD across age. METHODS: This was a prospective cross-sectional study of 502 biopsy-proven NAFLD patients. Clinical data were evaluated and compared among different age groups; group A (ages 18-44), B (ages 45-64), and C (≥ ages 65). RESULTS: 34.9, 56.0, and 9.1 % of the cohort were distributed among group A, B, and C, respectively. While the prevalence of nonalcoholic steatohepatitis (NASH) was comparable across age groups, the prevalence of advanced fibrosis increased with age (p = 0.000). Although the mean ALT progressively decreased with age; 87, 64, 56 U/L in group A, B, and C, respectively (p = 0.000), there was no difference in mean AST (p = 0.939) across age. The AST:ALT ratio (AAR) progressively increased from 0.7, 0.9, and 1.1 in group A, B, and C, respectively (p = 0.000). In group C, an AAR ≥ 1 was found in 74 and 40 % of patients with and without advanced fibrosis. CONCLUSION: With advancing age, ALT levels progressively declined while AST levels remained stable, leading to a higher AAR. Although higher AAR is often used as a surrogate measure of advanced fibrosis, advancing age can also contribute to increased AAR. In fact, an AAR ≥ 1 was found in significant number of elderly patients without advanced fibrosis. Consequently, an increased AAR may be a function of decreasing ALT with age in addition to progressive fibrosis.

Liver tissue lipids in metabolic dysfunction-associated steatotic liver disease with diabetes and obesity.

BACKGROUND: Diabetes and obesity are associated with altered lipid metabolism and hepatic steatosis. Studies suggest that increases in lipid accumulation in these patients with metabolic dysfunction-associated steatotic liver disease (MASLD) are not uniform for all lipid components. This study evaluates this variation. METHODS: A comprehensive lipidomic analysis of different lipid groups, were performed on liver tissue and plasma samples obtained at the time of histology from a well-defined cohort of 72 MASLD participants. The lipid profiles of controls were compared to those of MASLD patients with obesity, diabetes, or a combination of both. RESULTS: MASLD patients without obesity or diabetes exhibited distinct changes in the lipid profile of their liver tissue. The presence of diabetes or obesity further modified these lipid profiles (e.g., ceramide 47:7;4O), with positive or negative correlation (p < 0.05). A step-wise increase (long-chain fatty acids, triglycerides, and ceramides) or decrease (ultra-long fatty acids, diglycerides, and phospholipids) for lipid groups was observed compared to control among patients with MASLD without obesity or diabetes to MASLD patients with obesity as a single risk factor, and MASLD patients with obesity and diabetes. Changes in lipids observed in the plasma did not align with their corresponding liver tissue findings. CONCLUSION: The changes observed in the composition of lipids are not similar in patients with obesity and diabetes among those with MASLD. This highlights the different metabolic processes at play. The presence of obesity or diabetes in patients with MASLD exacerbates these lipid derangements, underscoring the potential for targeted intervention in MASLD patients.

Liver Tissue Proteins Improve the Accuracy of Plasma Proteins as Biomarkers in Diagnosing Metabolic Dysfunction-Associated Steatohepatitis.

BACKGROUND: Biomarkers for metabolic dysfunction-associated steatohepatitis (MASH) have been considered based on proteomic and lipidomic data from plasma and liver tissue without clinical benefits. This study evaluated proteomics-based plasma and liver tissue biomarkers collected simultaneously from patients with metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS: Liver tissue and plasma samples were collected during liver biopsy to diagnose MASLD. Untargeted proteomics was performed on 64 patients. RESULTS: Twenty plasma proteins were up- or downregulated in patients with MASH compared with those without MASH. The potential biomarkers utilizing the best combinations of these plasma proteins had an area under the receiver operating curve (AUROC) of 0.671 for detecting those with MASH compared with those without it. However, none of the 20 plasma proteins were represented among the significantly regulated liver tissue proteins in patients with MASH. Ten of them displayed a trend and relevance in liver tissue with MASLD progression. These 10 plasma proteins had an AUROC of 0.793 for MASH identification and higher positive and negative predictive values. CONCLUSION: The plasma and liver protein expressions of patients with MASH were not directly comparable. Plasma protein biomarkers that are also expressed in liver tissue can help improve MASH detection.

Radiologic-histological correlation of hepatocellular carcinoma treated via pre-liver transplant locoregional therapies.

BACKGROUND: Locoregional therapies (LRTs) are treatments to achieve local control of hepatocellular carcinoma (HCC). Correlation between radiologic response to LRT and degree of induced tumor necrosis is not well understood. The aim of this study was to evaluate different levels of radiologic response after pre-liver transplant (LT) LRT and its correlation with percentage of tumor necrosis on explanted histopathology. METHODS: Institutional Review Board approved LT database was queried for treated HCC in patients undergoing LT. Radiologic response was evaluated to predict tumor necrosis in the explanted liver. Tumor response was evaluated 1 to 3 months after LRT with computed tomography or MRI via Response Evaluation Criteria in Solid Tumors (RECIST), and European Association for the Study of the Liver (EASL) guidelines. LRT was repeated as needed until time of LT. Histological tumor necrosis was graded as complete (100%), partial (50%-99%), or poor (<50%). RESULTS: Between 2002 and 2011, 128 patients (97 men and 31 women) received pre-LT LRT including transarterial therapy (93), radiofrequency ablation (20), or combination of both (15). The mean age of the patients was 58+/-9 years. Their mean follow-up was 35+/-27 months. The median waitlist time was 55 days. One hundred (78%) patients had HCC within the Milan criteria at the initial radiologic diagnosis. Nineteen (15%) of the patients had complete tumor necrosis on histopathology analysis. Fifty (39%) of the patients exhibited partial necrosis, 52 (41%) showed poor or no necrosis and 7 (5%) showed progressive disease. The overall pre-LT radiologic staging was correlated with explant pathology in 73 (57%) of the patients. Underestimated tumor stage was noted in 49 (38%) patients, and overestimated tumor stage in 6 (5%) patients. The post-LT 3-year overall survival and disease free survival were 82% and 80%, and the rates for complete and partial tumor necrosis were 100% vs 78% (P=0.02) and 100% vs 75% (P=0.03), respectively. CONCLUSIONS: In the current era, interpretation of radiologic response after LRT for HCC does not correlate accurately with histologic tumor necrosis. Total tumor necrosis is the goal of LRT; therefore, evolution in its performance is needed. Similarly, ways to predict therapy induced tumor necrosis via radiological investigation need to be improved.

Accuracy of ultrasonographic fatty liver index using point-of-care ultrasound in stratifying non-alcoholic fatty liver disease patients.

BACKGROUND: The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing in the USA. Some of these patients develop non-alcoholic steatohepatitis (NASH), which can progress to cirrhosis. Ultrasound imaging is one of the most used modalities for diagnosing hepatic steatosis. Primary care providers are increasingly using point-of-care ultrasound (POCUS), which could increase the number of subjects diagnosed with NAFLD. This study evaluates the accuracy of POCUS in identifying patients with NASH. METHODS: Patients with hepatic steatosis without excess alcohol intake or other liver diseases undergoing liver biopsy were included in this study. These patients underwent POCUS and vibration-controlled transient elastography (VCTE) evaluations within 3 months of a liver biopsy. A comparison of POCUS data with liver histology and VCTE were made to assess the validity of POCUS evaluation in diagnosing NAFLD and NASH. RESULTS: The steatosis score from the liver histology had a low correlation with the controlled attenuation parameter score from VCTE ( r  = 0.27) and a moderate correlation with the grade of steatosis detected by the POCUS exam ( r  = 0.57). The NAFLD activity score on histology was found to correlate with the ultrasonographic fatty liver index (USFLI) from the POCUS exam ( r  = 0.59). A USFLI ≥ 6 diagnosed NASH with a sensitivity of 81%, and a value of ≤3 ruled out the diagnosis of NASH with a sensitivity of 100%. CONCLUSION: The provider can use the POCUS exam in clinical practice to diagnose NAFLD and reliably stratify patients who have NASH.

Loco-regional therapy in patients with Milan Criteria-compliant hepatocellular carcinoma and short waitlist time to transplant: an outcome analysis.

OBJECTIVES: Liver transplantation (LT) in Milan Criteria (MC) hepatocellular carcinoma (HCC) has excellent outcomes. Pre-transplant loco-regional therapy (LRT) has been used to downstage HCC to meet the MC. However, its benefit in patients with a brief waiting time to transplant remains unclear. This study evaluated outcomes in patients with short waitlist times to LT for MC-compliant HCC. METHODS: Patients undergoing LT for MC HCC at either of two transplant centres between 2002 and 2009 were retrospectively evaluated for outcome. Patients for whom post-transplant follow-up amounted to <12 months were excluded. RESULTS: A total of 225 patients were included, 93 (41.3%) of whom received neoadjuvant LRT. The median waiting time to transplant was 48 days. Mean post-transplant follow-up was 32.2 months. Overall and disease-free survival at 1 year, 3 years and 5 years were 93.1%, 82.4% and 72.6%, and 91.3%, 79.3% and 70.6%, respectively. There was no difference in overall (P= 0.94) and disease-free survival (P= 0.94) between groups who received and did not receive pre-LT LRT. There were also no disparities in survival or tumour recurrence among categories of patients (with single tumours measuring <3 cm, with single tumours measuring 3-5 cm, with multiple tumours). CONCLUSIONS: Loco-regional therapy followed by rapid transplantation in MC HCC appears not to have an impact on post-transplant outcome.

Accuracy of steatosis and fibrosis NAFLD scores in relation to vibration controlled transient elastography: An NHANES analysis.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is highly prevalent and increasing in the United States. Based on patient characteristics and biochemical profiles, predictive indices have been formulated to evaluate the presence and severity of NAFLD. This study evaluates the accuracy of these indices versus vibration-controlled transient elastography (VCTE™) to screen at-risk populations for NAFLD. METHODS: Subjects from the NHANES datasets (2017-2018) without other liver diseases with completed VCTE™ data were studied (n = 5062). Hepatic steatosis and fibrosis scores were calculated and compared with controlled attenuation parameter (CAP) and elastography measurements of VCTE™, respectively. RESULTS: The prevalence of NAFLD was 58.5%. Against a CAP cut-off value of ≥238 dB/m for diagnosing fatty liver, the US fatty liver index [US-FLI] had the highest positive predictive value (90%) and specificity (63.7%). The coefficient of correlation against CAP was strong for fatty liver index [FLI] (r = 0.645) and US-FLI (r = 0.608). The hepatic steatosis index [HSI] had the highest negative predictive value (82.1%) and sensitivity (75%) for ruling out steatosis. HSI and FLI, which use commonly obtained clinical parameters, had a high diagnostic odds ratios (21.2 and 18.6, respectively) compared to US-FLI (4.97), which requires insulin levels in the calculation. These findings were similar across all ethnicities studied. CONCLUSION: US-FLI is a reliable scoring system to diagnose patients with fatty liver. HSI and FLI are more easily calculated and can be used in clinical practices to diagnose NAFLD in at-risk populations.

Stage of fibrosis and portal pressure correlation in nonalcoholic steatohepatitis.

BACKGROUND: Hepatic venous pressure gradient (HVPG) measurement correlates with staging of liver fibrosis. Patients with nonalcoholic steatohepatitis (NASH) have a different pattern of fibrosis compared with hepatitis C virus (HCV) with possible alterations in pressures. AIM: The aim of this study was to compare portal pressures with the stage of fibrosis in NASH in comparison with other liver diseases. PATIENTS AND METHODS: Records of all patients who had undergone transjugular liver biopsy with pressure measurements between January 2001 and June 2013 were reviewed. Wedge hepatic venous pressure (WHVP) and HVPG were compared with stages of fibrosis in liver diseases of different etiologies. RESULTS: Among 142 patients included in this study, the liver disease etiology was as follows: HCV (26.6%) and NASH (24.6%), with the remaining (38.7%) grouped under other categories. The mean age of the patients was 51.2±11.5 years, with more men with HCV (73.1%) compared with NASH (51.4%) in terms of etiology (P=0.046). There were strong correlations between the stage of fibrosis with both the HVPG (r=0.64; P<0.0001) and the WHVP (r=0.63; P<0.0001) in NASH patients. Compared with HCV patients, NASH patients had a lower HVPG (3.4±2.4 vs. 7.5±11 mmHg/stage; P=0.01) with a coefficient estimate of -0.24 (P=0.017) and WHVP (9.6±5.5 vs. 14.6±15.2 mmHg/stage; P=0.03) for the stage of fibrosis. CONCLUSION: HVPG and WHVP measurements were strongly correlated with stages of fibrosis in NASH. Patients with NASH had lower HVPG and WHVP for each stage of fibrosis compared with HCV patients. This raises the concern of underestimation of pressures by HVPG in NASH etiology for the stage of disease or increased fibrosis despite lower pressures in them.

Nonalcoholic steatohepatitis recurrence and rate of fibrosis progression following liver transplantation.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is known to recur following liver transplantation (LT). Metabolic risk factors increase with immunosuppression. However, the rate of fibrosis progression following LT for NASH while on immunosuppression is less clear. AIM: The incidences of steatosis, NASH, and fibrosis following LT for NASH were quantified and compared with those transplanted for alcoholic liver disease (ALD). PATIENTS AND METHODS: Records of all NASH patients and 1 : 2 match with ALD transplant recipients between 2001 and 2006 were reviewed retrospectively. Patients without liver biopsies beyond 2 months following LT were excluded. RESULTS: NASH patients (n=77) were older (P=0.0006) and less likely male (P<0.001) than ALD patients (n=108). The incidence of steatosis, NASH, and fibrosis stage increased at 1, 3, and 5 years in both groups. Although steatosis and nonalcoholic fatty liver disease activity scores were higher, fibrosis was lower in NASH compared with ALD (0.43 vs. 1.0 stage/year; P=0.0045). The incremental increase in the rate of fibrosis was faster in the first year compared with 4-5 years (0.8 vs. 0.04 stage/year) following LT. The rate of fibrosis progression during 4-5 years was decreased in NASH compared with ALD recipients (0.04 vs. 0.33 stage/year; P=0.015). NASH etiology was associated with reduced rate of fibrosis progression (odds ratio=0.67) on multivariate analysis. CONCLUSION: Despite having more steatosis and inflammation, progression of fibrosis was slower in NASH compared with ALD recipients. Fibrosis progression slows with time following LT on immunosuppression and approximates the pretransplant progression rate by year 5.

Renal dysfunction in cirrhosis: pathophysiology, diagnosis, and management.

The development of decompensation in patients with cirrhosis is associated with increased mortality. Renal function gradually deteriorates with significant hemodynamic changes associated with decompensated liver disease, but may also rapidly decrease in response to precipitating events. Newer definitions of renal dysfunction may result in early diagnosis, this along with the use of sensitive markers helps in accurate determination of renal function in cirrhosis. Although renal dysfunction progresses slowly in cirrhotic patients, it is associated with increased mortality. Prompt intervention with appropriate management reduces the risk of renal dysfunction, as well as improving survival and quality of life. Appropriate management may include the removal of precipitating causes and use of pharmacological agents supporting circulatory dysfunction. Outcomes following treatment of this condition remain a major concern, especially in patients who develop hepatorenal syndrome. Transplantation of the liver or kidney and liver may be the only option when other modalities of treatment fail. Early transplantation may benefit these patients.

Role of transplantation in the treatment of benign solid tumors of the liver: a review of the United Network of Organ Sharing data set.

IMPORTANCE: The role of orthotopic liver transplantation for the treatment of benign solid liver tumors (BSLT) is not well defined. OBJECTIVE: To analyze outcomes in the United Network of Organ Sharing data set of patients with a diagnosis of BSLT who underwent transplantation. DESIGN, SETTING, AND PARTICIPANTS: A retrospective analysis of the United Network of Organ Sharing data set was performed for all (N = 87,280) patients who underwent transplantation for BSLT in the United States from October 1, 1988, through January 31, 2013. MAIN OUTCOMES AND MEASURES: Demographics, clinicopathological characteristics, distribution of the procedures by region and state, and overall survival rates. RESULTS: During the study period, 147 liver transplants (0.17%) were to treat BSLT. Sixty-two patients (42.2%) had adenomas, 29 (19.7%) had focal nodular hyperplasia, 25 (17.0%) had hemangiomas, 11 (7.5%) had hepatic epithelioid hemangioendotheliomas, and 20 (13.6%) were classified as having unknown benign tumors. The overall 1-, 3-, and 5-year survival rates were 90.9%, 85.2%, and 81.8%, respectively. Using multivariable analysis, we found that age was the only independent factor associated with patient survival. The overall 5-year survival rate for patients older than 50 years was 88% compared with 91% in younger individuals (95% CI, 148-384; P = .005). Region 3 (Alabama, Arkansas, Florida, Georgia, Louisiana, Mississippi, and Puerto Rico) contributed the maximum number (33 [22.4%]) of these transplants. CONCLUSIONS AND RELEVANCE: Although liver transplantation cannot be considered a first-line treatment, it is a valid therapeutic option in selected patients who are not amenable to resection. Only 0.17% of the transplants in the United States are performed for this indication, with satisfying long-term results. Age was an independent predictor of patient survival. Further studies are needed to better understand the role of liver transplantation in the treatment of BSLT.

Clinical spectrum of non-alcoholic fatty liver disease in diabetic and non-diabetic patients.

BACKGROUND: While non-alcoholic fatty liver disease (NAFLD) has been well characterised in patients with diabetes mellitus (DM), less is known about NAFLD in non-DM patients. We investigated the clinical characteristics of NAFLD patients with and without DM and accuracy of the NAFLD fibrosis score (NFS) in these two NAFLD groups. METHODS: Clinical, biochemical and histological variables were evaluated in this prospective cross-sectional study of 503 patients with biopsy proven NAFLD. Comparisons between patients with and without DM were analysed. NFS was correlated with liver histology to assess its robustness in patients with and without DM. RESULTS: There were 503 biopsy proven NAFLD patients with 48% of the cohort being diabetic. Relative to patients without DM, patients with DM were older (52 vs. 46 years, p < 0.001), with higher proportion of females (70% vs. 54%, p < 0.001), higher BMI (37 vs. 35, p = 0.009), higher prevalence of hypertension (73% vs. 44%, p < 0.001), higher prevalence of NASH (80.2% vs. 64.4%; p < 0.001) and advanced fibrosis (40.3% vs. 17.0%; p < 0.001). A considerable amount of patients without DM still had NASH (64%) and advanced fibrosis (17%). The clinical utility of the NFS differed between NAFLD patients with and without DM, with sensitivity to exclude advanced fibrosis being 90% of NAFLD patients with DM but only 58% of patients without DM. CONCLUSION: Patients with DM have more severe NAFLD based on histology. However, NASH and advanced fibrosis also occur in a considerable proportion of NAFLD patients without DM. The lower utility of the NFS in NAFLD patients without DM emphasises the heterogeneous nature of the NAFLD phenotype.