Histological Grade Of Steatosis Research Articles

Two faces of the same coin non alcoholic fatty liver disease; with and without diabetes: Comparative clinico pathological analysis: A cross sectional observational study

ABSTRACT Background and Aim: Non-alcohol fatty liver disease (NAFLD) is a metabolic disorder that represents the hepatic manifestation of systemic process, and is a strong risk factor for diabetes Meletus, whereas the presence of DM increases the severity of NAFLD/NASH and its progression. Data on the impact of diabetes on NASH phenotype is sparse from northern India. We studied and compared the clinical profile of NALFD in the presence and absence of DM and the effect of diabetes on NASH. Methods: We did a cross-sectional analysis of data from NAFLD patients (n = 90) who were divided into diabetic and non-diabetic cohorts and their respective demographic, biochemical, imaging and histological features were recorded and compared. Results: Out of 90 patients, 53.3% were females with a mean age of 44 ± 12 years. The mean BMI and WHR of the study cohort were 28.9 ± 3.4 and 1.01 ± 0.15, respectively. The current study showed that 35.8% were diabetics. The mean age and WHR were 52 ± 11 years vs 40 ± 10 years and 1.1 ± 0.17 vs 0.99 ± 0.09, respectively, in diabetic and non-diabetic NAFLD patients. Non-invasive fibrosis scores, including BARD (2.8 vs 1.73), FIB-4 (3.4 vs 2.2) and NFS (0.97 vs −1.13), were significantly higher in diabetic NAFLD compared to non-diabetic NAFLD (P < 0.03). The histological grade of steatosis and fibrosis as depicted by the mean NAS score (5.7 ± 1.2 vs 4.63 ± 0.8) was higher in diabetic NAFLD vs non-diabetic NAFLD; however, only the fibrosis stage was statistically significant between the groups (P < 0.001). Conclusion: Despite the small no of cases, we should conclude that there is a bidirectional relationship between NAFLD and DM where the progression of one increases the rate of progression of other. Diabetic patients have higher risk of NASH and hence increased risk of liver related mortality and should be screened early for NAFLD/NASH.

Soluble CD46 as a diagnostic marker of hepatic steatosis

The increasing prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) incurs substantial morbidity, mortality and healthcare costs. Detection and clinical intervention at early stages of disease improves prognosis; however, we are currently limited by a lack of reliable diagnostic tests for population screening and monitoring responses to therapy. To address this unmet need, we investigated human invariant Natural Killer T cell (iNKT) activation by fat-loaded hepatocytes, leading to the discovery that circulating soluble CD46 (sCD46) levels accurately predict hepatic steatosis. sCD46 in plasma was measured using a newly developed immuno-competition assay in two independent cohorts: Prospective living liver donors (n=156; male=66, female=90) and patients with liver tumours (n=91; male=58, female=33). sCD46 levels were statistically evaluated as a predictor of hepatic steatosis. Interleukin-4-secreting (IL-4+) iNKT cells were over-represented amongst intrahepatic lymphocytes isolated from resected human liver samples. IL-4+ iNKT cells preferentially developed in cocultures with a fat-loaded, hepatocyte-like cell line, HepaRG. This was attributed to induction of matrix metalloproteases (MMP) in fat-loaded HepaRG cells and primary human liver organoids, which led to indiscriminate cleavage of immune receptors. Loss of cell-surface CD46 resulted in unrepressed differentiation of IL-4+ iNKT cells. sCD46 levels were elevated in patients with hepatic steatosis. Discriminatory cut-off values for plasma sCD46 were found that accurately classified patients according to histological steatosis grade. sCD46 is a reliable clinical marker of hepatic steatosis, which can be conveniently and non-invasively measured in serum and plasma samples, raising the possibility of using sCD46 levels as a diagnostic method for detecting or grading hepatic steatosis. F.B. was supported by the Else Kröner Foundation (Award 2016_kolleg.14). G.G. was supported by the Bristol Myers Squibb Foundation for Immuno-Oncology (Award FA-19-009). N.S. was supported by a Wellcome Trust Fellowship (211113/A/18/Z). J.A.H. received funding from the European Union's Horizon 2020 research and innovation programme (Award 860003). J.M.W. received funding from the Else Kröner Foundation (Award 2015_A10).

Hepatic steatosis: Qualitative and quantitative sonographic assessment in comparison to histology.

Globally, B-mode ultrasound is the most common modality used for the diagnosis of hepatic steatosis. We aimed to assess the correlation between qualitative liver ultrasound parameters, attenuation imaging (ATI) and histopathology-diagnosed steatosis grade obtained from liver biopsy. Our secondary aim was to examine the interobserver variability of qualitative ultrasound features. A retrospective cohort study was performed which included adult patients (age ≥ 18 years) who had same-day liver ultrasound, ATI and liver biopsy for grading hepatic steatosis severity between 2018 and 2022. The qualitative US features for hepatic steatosis were independently scored by three radiologists and interobserver variability was examined. Histologic steatosis grade, ATI and qualitative ultrasound parameters were compared. Ninety patients were included; 67% female with a median age of 54 (IQR 39-65) years. The radiologist's overall impression had the highest correlation (very strongly correlated) with histologic steatosis grade (r = 0.82, P < 0.001). ATI coefficient and all qualitative ultrasound B-mode features except for liver echotexture and focal fat sparing were strongly correlated with histologic steatosis grade (r ≥ 0.70, P < 0.001). Most qualitative ultrasound features had good agreement between observers (Kappa statistic 0.61-1.0, P < 0.001), (Kendall coefficient 0.92, P < 0.001). The examined qualitative ultrasound parameters and ATI had good-excellent performance for diagnosing clinically significant hepatic steatosis; however, the radiologist's overall impression had the best correlation with histologic steatosis grade. Our findings suggest an ongoing role for qualitative liver ultrasound assessment of hepatic steatosis despite the emergence of newer quantitative measures.

The discriminatory ability of FibroScan liver stiffness measurement, controlled attenuation parameter, and FibroScan-aspartate aminotransferase to predict severity of liver disease in children.

Vibration controlled transient elastography (FibroScan) is used to predict the severity of liver fibrosis and steatosis. In pediatrics, few studies have been performed directly comparing liver histologic features with FibroScan liver stiffness measurements (LSMs) and controlled attenuation parameters (CAPs). The FibroScan–aspartate aminotransferase (FAST) score, which predicts liver disease severity in adult nonalcoholic fatty liver disease (NAFLD), has not been analyzed in children. The aims of this study were to determine if LSM and CAP correlated with liver histologic fibrosis stage and steatosis grade, respectively, and to determine the predictive capacity of FAST in pediatric NAFLD. Research participants (n = 216) included those with FibroScan within 90 days of a liver biopsy. The ability of LSM, CAP, and FAST to predict severity of liver disease was analyzed by Spearman correlation, linear regression, and receiver operating characteristic and C statistic. Significant correlations were identified between LSM and Ishak fibrosis stages, with the strongest correlation occurring in the non‐NAFLD group (Spearman r = 0.47, p < 0.0001). LSM adequately predicted Ishak stages F0–2 versus F3–F6 (area under the receiver operating characteristic curve [AUROC], 0.73 for all; 0.77 for non‐NAFLD). CAP strongly predicted histologic steatosis grade (r = 0.84; p < 0.0001; AUROC, 0.98). FAST had acceptable discriminatory ability for significant liver disease (AUROC, 0.75). A FAST cutoff ≥0.67 had a sensitivity of 89% but a specificity of only 62% at determining significant liver disease. This study encompasses one of the largest pediatric cohorts describing the accuracy of FibroScan LSM and CAP to predict liver histologic fibrosis stage and steatosis grade, respectively. In order to determine specific LSM, CAP, and FAST cut‐off values for fibrosis stages, steatosis grades, and significant liver disease, respectively, a much larger cohort is necessary and will likely entail the need for multicentered studies.

Developing a New qFIBS Model Assessing Histological Features in Pediatric Patients With Non-alcoholic Steatohepatitis.

BackgroundThe evolution of pediatric non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH) is associated with unique histological features. Pathological evaluation of liver specimen is often hindered by observer variability and diagnostic consensus is not always attainable. We investigated whether the qFIBS technique derived from adult NASH could be applied to pediatric NASH.Materials and Methods102 pediatric patients (<18 years old) with liver biopsy-proven NASH were included. The liver biopsies were serially sectioned for hematoxylin-eosin and Masson trichrome staining for histological scoring, and for second harmonic generation (SHG) imaging. qFIBS-automated measure of fibrosis, inflammation, hepatocyte ballooning, and steatosis was estabilshed by using the NASH CRN scoring system as the reference standard.ResultsqFIBS showed the best correlation with steatosis (r = 0.84, P < 0.001); with ability to distinguish different grades of steatosis (AUROCs 0.90 and 0.98, sensitivity 0.71 and 0.93, and specificity 0.90 and 0.90). qFIBS correlation with fibrosis (r = 0.72, P < 0.001) was good with high AUROC values [qFibrosis (AUC) > 0.85 (0.85–0.95)] and ability to distinguish different stages of fibrosis. qFIBS showed weak correlation with ballooning (r = 0.38, P = 0.028) and inflammation (r = 0.46, P = 0.005); however, it could distinguish different grades of ballooning (AUROCs 0.73, sensitivity 0.36, and specificity 0.92) and inflammation (AUROCs 0.77, sensitivity 0.83, and specificity 0.53).ConclusionIt was demonstrated that when qFIBS derived from adult NASH was performed on pediatric NASH, it could best distinguish the various histological grades of steatosis and fibrosis.

Artificial Intelligence Improves Pathologist Agreement for Fibrosis Scores in Nonalcoholic Steatohepatitis Patients

Artificial Intelligence Improves Pathologist Agreement for Fibrosis Scores in Nonalcoholic Steatohepatitis Patients

Differential Effects of Dietary versus Exercise Intervention on Intrahepatic MAIT Cells and Histological Features of NAFLD.

Background: Mucosal-associated invariant T (MAIT) cells promote inflammation in obesity and are implicated in the progression of non-alcoholic fatty liver disease (NAFLD). However, as the intrahepatic MAIT cell response to lifestyle intervention in NAFLD has not been investigated, this work aimed to examine circulating and intrahepatic MAIT cell populations in patients with NAFLD, after either 12 weeks of dietary intervention (DI) or aerobic exercise intervention (EI). Methods: Multicolour flow cytometry was used to immunophenotype circulating and intrahepatic MAIT cells and measure MAIT cell expression (median fluorescence intensity, MFI) of the activation marker CD69 and apoptotic marker CD95. Liver histology, clinical parameters, and MAIT cell populations were assessed at baseline (T0) and following completion (T1) of DI or EI. Results: Forty-five patients completed the study. DI participants showed decreased median (interquartile range) expression of the activation marker CD69 on circulating MAIT cells (T0: 104 (134) versus T1 27 (114) MFI; p = 0.0353) and improvements in histological steatosis grade post-intervention. EI participants showed increased expression of the apoptotic marker CD95, both in circulating (T0: 1549 (888) versus T1: 2563 (1371) MFI; p = 0.0043) and intrahepatic MAIT cells (T0: 2724 (862) versus T1: 3117 (1622) MFI; p = 0.0269). Moreover, the percentage of intrahepatic MAIT cells significantly decreased after EI (T0: 11.1 (14.4) versus T1: 5.3 (9.3)%; p = 0.0029), in conjunction with significant improvements in fibrosis stage and hepatocyte ballooning. Conclusions: These data demonstrate independent benefits from dietary and exercise intervention and suggest a role for intrahepatic MAIT cells in the observed histological improvements in NAFLD.

Hepatic steatosis: Ultrasound assessment using attenuation imaging (ATI) with liver biopsy correlation.

Hepatic steatosis duration and severity are risk factors for liver fibrosis and cardiometabolic disease. We assessed the diagnostic accuracy of attenuation imaging (ATI), compared with histologic hepatosteatosis grading in adults with varied suspected liver pathologies. Liver biopsy was performed on 76 patients (51 women, 25 men) with non-malignant diffuse parenchymal liver disease, within 4 weeks of multiparametric liver ultrasound including attenuation imaging (ATI). Skin-liver capsule distance (SCD) and body mass index (BMI) were measured. Histologic steatosis was graded none (S0), mild (S1), moderate (S2) or severe (S3). We compared histology and sonographic parameters. The median patient age was 50.5 (range 18-83) years and BMI 28.9 kg/m2 (interquartile range 24.0-33.3). The distribution of histologic steatosis grade was S0 (44%), S1(17%), S2(30%) and S3(9%). Median ATI value for each biopsy steatosis grade was 0.60 (IQR: 0.52-0.65), 0.65 (IQR: 0.6-0.71), 0.83 (IQR: 0.74-0.90) and 0.90 (IQR: 0.82-1.01) dB/cm/MHz for S0, S1, S2 and S3, respectively. The AUC of ATI for detection of any steatosis (S1-S3) and moderate to severe steatosis (S2-S3) was 0.85 (95% CI: 0.75-0.91) and 0.91 (95% CI: 0.83-0.99) with cut-offs of 0.55 and 0.62 dB/cm/MHz. ATI threshold of 0.74 dB/cm/MHz was able to discriminate between S0-S1 and S2-3 with accuracy, CI and kappa statistic of 0.8889, 0.65-0.98 and 0.7534. We found a good correlation between ATI and steatosis grade. The most accurate discrimination was between none to mild (S0-1) and moderate to severe (S2-3) steatosis.

Lipid Profile and Hepatic Fat Content Measured by 1H MR Spectroscopy in Patients before and after Liver Transplantation.

Increased hepatic fat content (HFC) is a hallmark of non-alcoholic fatty liver (NAFL) disease, a common condition in liver transplant recipients. Proton MR spectroscopy (1H MRS) and MR imaging-based proton density fat fraction as the only diagnosis modality enable precise non-invasive measurement of HFC and, also, fatty acid profiles in vivo. Using 1H MRS at 3T, we examined 47 liver transplantation candidates and 101 liver graft recipients. A point-resolved spectroscopy sequence was used to calculate the steatosis grade along with the saturated, unsaturated and polyunsaturated fractions of fatty acids in the liver. The steatosis grade measured by MRS was compared with the histological steatosis grade. HFC, represented by fat fraction values, is adept at distinguishing non-alcoholic steatohepatitis (NASH), NAFL and non-steatotic liver transplant patients. Relative hepatic lipid saturation increases while unsaturation decreases in response to increased HFC. Additionally, relative hepatic lipid saturation increases while unsaturation and polyunsaturation both decrease in liver recipients with histologically proven post-transplant NASH or NAFL compared to non-steatotic patients. HFC, measured by in vivo 1H MRS, correlated well with histological results. 1H MRS is a simple and fast method for in vivo analysis of HFC and its composition. It provides non-invasive support for NAFL and NASH diagnoses.

Relationship Between Histological Features of Non-alcoholic Fatty Liver Disease and Ectopic Fat on Magnetic Resonance Imaging in Children and Adolescents.

Objectives: To investigate the association between ectopic fat content in the liver and pancreas, obesity-related metabolic components, and histological findings of non-alcoholic fatty liver disease (NAFLD) in children.Methods: This cross-sectional study investigated 63 children with biopsy-proven NAFLD who underwent magnetic resonance imaging (MRI), anthropometry, laboratory tests, and body composition analysis. Clinical and metabolic parameters, MRI-measured hepatic fat fraction (HFF) and pancreatic fat fraction (PFF), and histological findings were analyzed.Results: In a total of 63 children (48 boys, median age 12.6 years, median body mass index z-score 2.54), HFF was associated with histological steatosis [10.4, 23.7, and 31.1% in each steatosis grade, P < 0.001; Spearman's rho coefficient (rs) = 0.676; P < 0.001] and NAFLD activity score (rs = 0.470, P < 0.001), but not with lobular inflammation, hepatocyte ballooning, and hepatic fibrosis. PFF was not associated with any histological features of the liver. Waist circumference-to-height ratio and body fat percentage were associated with the steatosis grade (P = 0.006 and P = 0.004, respectively). Alanine aminotransferase was not associated with steatosis but was associated with lobular inflammation (P = 0.008). Lobular inflammation was also associated with high total cholesterol and low-density lipoprotein cholesterol and metabolic syndrome (P = 0.015, P = 0.036, and P = 0.038, respectively).Conclusions: Hepatic steatosis on MRI was only associated with the histological steatosis grade, while elevated serum levels of liver enzymes and lipids were related to the severity of lobular inflammation. Therefore, MRI should be interpreted in conjunction with the anthropometric and laboratory findings in pediatric patients.

Combined analysis of gut microbiota, diet and PNPLA3 polymorphism in biopsy-proven non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is a global health burden. Risk factors for disease severity include older age, increased body mass index (BMI), diabetes, genetic variants, dietary factors and gut microbiota alterations. However, the interdependence of these factors and their individual impact on disease severity remain unknown. In this cross-sectional study, we performed 16S gene sequencing using fecal samples, collected dietary intake, PNPLA3 gene variants and clinical and liver histology parameters in a well-described cohort of 180 NAFLD patients. Principal component analyses were used for dimensionality reduction of dietary and microbiota data. Simple and multiple stepwise ordinal regression analyses were performed. Complete data were available for 57 NAFLD patients. In the simple regression analysis, features associated with the metabolic syndrome had the highest importance regarding liver disease severity. In the multiple regression analysis, BMI was the most important factor associated with the fibrosis stage (OR per kg/m2 : 1.23, 95% CI 1.10-1.37, P<.001). The PNPLA3 risk allele had the strongest association with the histological grade of steatosis (OR 5.32, 95% CI 1.56-18.11, P=.007), followed by specific dietary patterns. Low abundances of Faecalibacterium, Bacteroides and Prevotella and high abundances of Gemmiger were associated with the degree of inflammation, ballooning and stages of fibrosis, even after taking other cofactors into account. BMI had the strongest association with histological fibrosis, but PNPLA3 gene variants, gut bacterial features and dietary factors were all associated with different histology features, which underscore the multifactorial pathogenesis of NAFLD.

FNDC5 polymorphism influences the association between sarcopenia and liver fibrosis in adults with biopsy-proven non-alcoholic fatty liver disease.

The FNDC5 gene encodes the fibronectin type III domain-containing protein 5 that is a membrane protein mainly expressed in skeletal muscle, and the FNDC5 rs3480 polymorphism may be associated with liver disease severity in non-alcoholic fatty liver disease (NAFLD). We investigated the influence of the FNDC5 rs3480 polymorphism on the relationship between sarcopenia and the histological severity of NAFLD. A total of 370 adult individuals with biopsy-proven NAFLD were studied. The association between the key exposure sarcopenia and the outcome liver histological severity was investigated by binary logistic regression. Stratified analyses were undertaken to examine the impact of FNDC5 rs3480 polymorphism on the association between sarcopenia and the severity of NAFLD histology. Patients with sarcopenia had more severe histological grades of steatosis and a higher prevalence of significant fibrosis and definite non-alcoholic steatohepatitis than those without sarcopenia. There was a significant association between sarcopenia and significant fibrosis (adjusted OR 2·79, 95 % CI 1·31, 5·95, P = 0·008), independent of established risk factors and potential confounders. Among patients with sarcopenia, significant fibrosis occurred more frequently in the rs3480 AA genotype carriers than in those carrying the FNDC5 rs3480 G genotype (43·8 v. 17·2 %, P = 0·031). In the association between sarcopenia and liver fibrosis, there was a significant interaction between the FNDC5 genotype and sarcopenia status (P value for interaction = 0·006). Sarcopenia is independently associated with significant liver fibrosis, and the FNDC5 rs3480 G variant influences the association between sarcopenia and liver fibrosis in patients with biopsy-proven NAFLD.

Novel Method for Ultrasound-Derived Fat Fraction Using an Integrated Phantom.

The purpose of this study was to demonstrate the clinical feasibility of an integrated reference phantom method for quantitative ultrasound by creating an ultrasound-derived fat fraction (UDFF) tool. This tool was evaluated with respect to its diagnostic performance as a biomarker for assessing histologic hepatic steatosis and its agreement with the magnetic resonance imaging (MRI) proton density fat fraction (PDFF). Adults (n = 101) with known or suspected nonalcoholic fatty liver disease consented to participate in this prospective cross-sectional study. All patients underwent MRI-PDFF and ultrasound scans, whereas 90 underwent liver biopsy. A linear least-squares analysis used the attenuation coefficient and backscatter coefficient to create the UDFF model for predicting MRI-PDFF. The area under the receiver operating characteristic curve values were 0.94 (95% confidence interval [CI], 0.85-0.98) for histologic steatosis grade 0 (n = 6) versus 1 or higher (n = 84), 0.88 (95% CI, 0.8-0.94) for grade 1 or lower (n = 45) versus 2 or higher (n = 45), and 0.83 (95% CI, 0.73-0.9) for grade 2 or lower (n = 78) versus 3 (n = 12). The Pearson correlation coefficient between UDFF and PDFF was ρ = 0.87 with 95% limits of agreement of ±8.5%. Additionally, the diagnosis of steatosis, defined as MRI-PDFF higher than 5% and 10%, had area under the receiver operating characteristic curve values of 0.97 (95% CI, 0.93-0.99) and 0.95 (95% CI, 0.9-0.98), respectively. The body mass index was not correlated with either UDFF or PDFF. An on-system, integrated UDFF tool provides a simple, noninvasive, accessible, low-cost, and commercially viable clinical tool for quantifying the hepatic fat fraction with a high degree of agreement with histologic biopsy or the MRI-PDFF biomarker.

Active Helicobacter pylori Infection is Independently Associated with Nonalcoholic Steatohepatitis in Morbidly Obese Patients.

Nonalcoholic fatty liver disease (NAFLD) emerges as an important global burden and Helicobacter pylori infection (Hp-I) has been suggested as a risk factor of NAFLD, although controversy exists. This retrospective study aimed to investigate a potential impact of active Hp-I on NAFLD severity in morbidly obese patients, subjected to bariatric surgery and gastric biopsy for documentation of Hp-I. Of 64 eligible participants, 15 (23.4%) were diagnosed with active Hp-I, showing higher rates of nonalcoholic steatohepatitis (NASH) than those without Hp-I (86.7% vs. 26.5%, respectively; p < 0.001). Concerning histological lesions, steatosis grade (p = 0.027), ballooning (p < 0.001), lobular inflammation (p = 0.003), and fibrosis stage (p < 0.001) were also more severe in Hp-I positive patients. Likewise, liver function tests, insulin resistance, dyslipidemia, and arterial hypertension were significantly higher in Hp-I positive patients. Hp-I was independently positively associated with NASH (beta = 3.27; p = 0.002), severe NASH (beta = 2.37; p = 0.018), and the presence of fibrosis (beta = 3.86; p = 0.001) in a binary regression model, after adjustment for potential confounders. In conclusion, active Hp-Ι was independently associated with NASH and fibrosis, findings offering potential clinical implication.

The impact of hepatic steatosis on portal hypertension.

Background and aimsStudies in animal models have suggested that hepatic steatosis impacts on portal pressure, potentially by inducing liver sinusoidal endothelial dysfunction and thereby increasing intrahepatic resistance. Thus, we aimed to evaluate the impact of hepatic steatosis on hepatic venous pressure gradient (HVPG) in patients with chronic liver disease.Method261 patients undergoing simultaneous HVPG measurements and controlled attenuation parameter (CAP)-based steatosis assessment were included in this retrospective study.ResultsThe majority of patients had cirrhosis (n = 205; 78.5%) and n = 191 (73.2%) had clinically significant portal hypertension (CSPH; HVPG≥10mmHg). Hepatic steatosis (S1/2/3; CAP ≥248dB/m) was present in n = 102 (39.1%). Overall, HVPG was comparable between patients with vs. without hepatic steatosis (15.5±7.5 vs. 14.8±7.7mmHg; p = 0.465). Neither in patients with HVPG (<6mmHg; p = 0.371) nor in patients with mild portal hypertension (HVPG 6–9mmHg; p = 0.716) or CSPH (HVPG≥10mmHg; p = 0.311) any correlation between CAP and HVPG was found. Interestingly, in patients with liver fibrosis F2/3, there was a negative correlation between CAP and HVPG (Pearson’s ρ:-0.522; p≤0.001). In multivariate analysis, higher CAP was an independent ‘protective’ factor for the presence of CSPH (odds ratio [OR] per 10dB/m: 0.92, 95% confidence interval [CI]:0.85–1.00; p = 0.045), while liver stiffness was associated with the presence of CSPH (OR per kPa: 1.26, 95%CI: 1.17–1.36; p≤0.001). In 78 patients, in whom liver biopsy was performed, HVPG was neither correlated with percentage of histological steatosis (p = 0.714) nor with histological steatosis grade (p = 0.957).ConclusionHepatic steatosis, as assessed by CAP and liver histology, did not impact on HVPG in our cohort comprising a high proportion of patients with advanced chronic liver disease. However, high CAP values (i.e. pronounced hepatic steatosis) might lead to overestimation of liver fibrosis by ‘artificially’ increasing transient elastography-based liver stiffness measurements.

Is Unenhanced Computed Tomography Reliable in the Assessment of Macrovesicular Steatosis in Living Liver Donors?

In this retrospective study, we aimed to determine the diagnostic value of unenhanced computed tomography in the assessment of macrovesicular steatosis in potential living liver transplant donors by using biopsy as a reference standard. This retrospective study was approved by our institutional review board, and all included patients provided written informed consent. Our study group included 181 donor candidates (mean age of 35.9 ± 9.3 y) who underwent unenhanced computed tomography and subsequent needle biopsy (mean period after scan of 12.74 d) in the right hepatic lobe (at least 2 samples per patient). Histologic degree of macrovesicular steatosis was determined. A radiologist with 10 years of experience assessed steatosis ofthe right hepatic lobe by using 2 methods: (1) a 4-point visual grading system that used attenuation comparison between the liver and hepatic vessels and (2) the liver attenuation index, which was calculated with region of interest measurements of hepatic attenuation. We used statistical analyses to compare accuracy in the diagnosis of macrovesicular steatosis. Our study population was divided into 3 groups according to histologic steatosis grade. Group 1 consisted of 157 candidates with 0% to 5% steatosis, group 2 consisted of 11 candidates with 6% to 15% steatosis, and group 3 consisted of 13 candidates with 16% to 100% steatosis. Mean liver attenuation (in Hounsfield units ± standard deviation) was 58.93 ± 5.07 for group 1, 47.8 ± 4.17 for group 2, and 39.11 ± 6.5 for group 3. Significant differences in liver attenuation were observed between groups using one-way analyses of variance (F = 107307; P < .01). For visual grading, correlation coefficient for computed tomography was 0.959. Unenhanced computed tomography to assess liver attenuation represents an objective and noninvasive means for detection of hepatic steatosis. This method can prevent unnecessary biopsies.

Characterization of spontaneously-developed non-alcoholic fatty liver disease in aged rhesus monkeys

BackgroundNon-alcoholic fatty liver disease (NAFLD) is a global epidemic afflicting 20–30% in the general population. The animal model of NAFLD available at the present are less clinically relevant. In this study. We aimed to establish a NAFLD model of rhesus monkeys and develop an ultrasonographic steatosis score (USS) system to grade hepatic steatosis in this model.MethodsWe performed hepatic ultrasonography and blood biochemical tests on 86 rhesus monkeys with and without metabolic syndrome (MetS), among which 45 animals were further assessed by histopathological analysis.ResultsThe liver histological features of rhesus monkeys NAFLD were resemble to those of NAFLD patients. There was a close correlation between the histological steatosis grade and the USS (Spearman’s coefficient, 0.705, p < 0.001). The USS sensitivity was 87.5% and the specificity was 94.6% when the cut-off was USS2. In addition, the prevalence of MetS was significantly higher in the USS2–3 group. Multiple risk factors of cardiometabolic disease, including obesity, insulin resistance and dyslipidemia were significantly correlated with the USS.ConclusionsNAFLD was developed spontaneously among aging in rhesus monkeys (with increased prevalence in the MetS monkeys), which provided an ideal model for NAFLD. The newly developed USS system can be used to evaluate fatty liver in the rhesus monkey. The model as well as the noninvasive assessment methodology will provide a powerful tool for mechanistic studies and preclinical test of novel therapies for NAFLD.

Non-alcoholic fatty liver disease-associated hepatocellular carcinoma: effect of hepatic steatosis on major hepatocellular carcinoma features at MRI.

To evaluate the effect of hepatic steatosis on LI-RADS® major features at MRI in patients with non-alcoholic fatty liver disease (NAFLD)-associated hepatocellular carcinoma (HCC). HCC and liver parenchyma features at MRI from 48 consecutive patients with NAFLD and histology proven HCC (mean ± SD; 4.5 ± 3.4 cm) were independently reviewed by three radiologists. Inter-rater agreement was determined by prevalence/bias-adjusted kappa. Hepatic fat signal fraction (FS%) was independently calculated. HCC features were compared by FS% at MRI using logistic regression analysis and histologic steatosis grade using Cochran-Armitage test for trend, stratified by cirrhotic liver morphology or histologic fibrosis stage. Receiver operating characteristic curves were generated to determine the sensitivity and specificity for major HCC features by FS%. Major HCC features included arterial phase hyperenhancement (APHE) in 45 (93%), portal venous phase washout (PVWO) in 30 (63%), delayed phase washout (DPWO) in 38 (79%) and enhancing "capsule" in 34 (71%). Cirrhotic morphology was present in 22 (46%). Inter-rater agreement was 0.75 for APHE, 0.42-0.58 for PVWO, 0.58-0.71 for DPWO and 0.38-0.67 for enhancing "capsule". There was an 18%, 14% and 22% increase in the odds of absent PVWO, DPWO and capsule appearance for every 1% increase in hepatic FS% in patients with non-cirrhotic liver morphology (p = 0.011, 0.040 and 0.029, respectively). Hepatic FS% ≥ 14.8% had a sensitivity and specificity of 64 and 100% for absent PVWO and 71 and 90% for absent DPWO in patients with non-cirrhotic liver morphology. Absent washout and capsule appearance are associated with increasing hepatic steatosis in patients with non-cirrhotic, NAFLD-associated HCC. In patients with non-cirrhotic, non-alcoholic fatty liver disease (NAFLD)-associated hepatocellular carcinoma (HCC), absent HCC washout and capsule appearance are associated with increasing hepatic steatosis, thereby potentially impacting the noninvasive imaging diagnosis of HCC in these patients. Lack of washout or capsule appearance in steatotic livers at MRI may require alternative criteria for the diagnosis of HCC in patients with non-cirrhotic NAFLD.

Non-invasive assessment of liver disease in rats using multiparametric magnetic resonance imaging: a feasibility study.

ABSTRACTNon-invasive quantitation of liver disease using multiparametric magnetic resonance imaging (MRI) could refine clinical care pathways, trial design and preclinical drug development. The aim of this study was to evaluate the use of multiparametric MRI in experimental models of liver disease. Liver injury was induced in rats using 4 or 12 weeks of carbon tetrachloride (CCl4) intoxication and 4 or 8 weeks on a methionine and choline deficient (MCD) diet. Liver MRI was performed using a 7.0 Tesla small animal scanner at baseline and specified timepoints after liver injury. Multiparametric liver MRI parameters [T1 mapping, T2* mapping and proton density fat fraction (PDFF)] were correlated with gold standard histopathological measures. Mean hepatic T1 increased significantly in rats treated with CCl4 for 12 weeks compared to controls [1122±78 ms versus 959±114 ms; d=162.7, 95% CI (11.92, 313.4), P=0.038] and correlated strongly with histological collagen content (rs=0.717, P=0.037). In MCD diet-treated rats, hepatic PDFF correlated strongly with histological fat content (rs=0.819, P<0.0001), steatosis grade (rs=0.850, P<0.0001) and steatohepatitis score (rs=0.818, P<0.0001). Although there was minimal histological iron, progressive fat accumulation in MCD diet-treated livers significantly shortened T2*. In preclinical models, quantitative MRI markers correlated with histopathological assessments, especially for fatty liver disease. Validation in longitudinal studies is required.This article has an associated First Person interview with the first author of the paper.

Agreement Between Magnetic Resonance Imaging Proton Density Fat Fraction Measurements and Pathologist-Assigned Steatosis Grades of Liver Biopsies From Adults With Nonalcoholic Steatohepatitis

We assessed the diagnostic performance of magnetic resonance imaging (MRI) proton density fat fraction (PDFF) in grading hepatic steatosis and change in hepatic steatosis in adults with nonalcoholic steatohepatitis (NASH) in a multi-center study, using central histology as reference. We collected data from 113 adults with NASH participating in a multi-center, randomized, double-masked, placebo-controlled, phase 2b trial to compare the efficacy cross-sectionally and longitudinally of obeticholic acid vs placebo. Hepatic steatosis was assessed at baseline and after 72 weeks of obeticholic acid or placebo by liver biopsy and MRI (scanners from different manufacturers, at 1.5T or 3T). We compared steatosis estimates by PDFF vs histology. Histologic steatosis grade was scored in consensus by a pathology committee. Cross-validated receiver operating characteristic (ROC) analyses were performed. At baseline, 34% of subjects had steatosis grade 0 or 1, 39% had steatosis grade 2, and 27% had steatosis grade 3; corresponding mean PDFF values were 9.8%±3.7%, 18.1%±4.3%, and 30.1%±8.1%. PDFF classified steatosis grade 0-1 vs 2-3 with an area under the ROC curve (AUROC) of 0.95 (95% CI, 0.91-0.98), and grade 0-2 vs grade 3 steatosis with an AUROC of 0.96 (95% CI, 0.93-0.99). PDFF cut-off values at 90% specificity were 16.3% for grades 2-3 and 21.7% for grade 3, with corresponding sensitivities of 83% and 84%. After 72 weeks' of obeticholic vs placebo, 42% of subjects had a reduced steatosis grade (mean reduction in PDFF from baseline of 7.4%±8.7%), 49% had no change in steatosis grade (mean increase in PDFF from baseline of 0.3%±6.3%), and 9% had an increased steatosis grade (mean increase in PDFF from baseline of 7.7%±6.0%). PDFF change identified subjects with reduced steatosis grade with an AUROC of 0.81 (95% CI, 0.71-0.91) and increased steatosis grade with an AUROC of 0.81 (95% CI, 0.63-0.99). A PDFF reduction of 5.15% identified subjects with reduced steatosis grade with 90% specificity and 58% sensitivity, whereas a PDFF increase of 5.6% identified those with increased steatosis grade with 90% specificity and 57% sensitivity. Based on data from a phase 2 randomized controlled trial of adults with NASH, PDFF estimated by MRI scanners of different field strength and at different sites, accurately classifies grades and changes in hepatic steatosis when histologic analysis of biopsies is used as a reference.