Presence Of Steatohepatitis Research Articles

Impact of PNPLA3 in Lean Individuals and in Cryptogenic Steatotic Liver Disease.

Although metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly associated with obesity, around 20% of individuals with hepatic steatosis may nonetheless have normal body mass index, a condition often referred to as lean nonalcoholic fatty liver disease (NAFLD). Under the new nomenclature and definition of MASLD, lean NAFLD can be further divided into lean MASLD (when there is one or more cardiometabolic risk factors) and cryptogenic steatotic liver disease (when there is no cardiometabolic risk factor). Current studies suggest that the at-risk PNPLA3 rs738409 variant is more common among individuals with lean NAFLD than their overweight and obese counterparts. However, even in this group, cardiometabolic risk factors are often required for the development of hepatic steatosis and liver injury. In the general population, PNPLA3 gene polymorphism is associated with an increased risk of MASLD, more severe liver histology (i.e., the presence of steatohepatitis and fibrosis) and future development of hepatocellular carcinoma and cirrhotic complications. Emerging data also suggest that individuals carrying the PNPLA3 GG genotype might have a greater reduction in hepatic steatosis and liver enzymes with lifestyle intervention and metabolic treatments, such as glucagon-like peptide-1 receptor agonists. Studies have not specifically examined the impact of PNPLA3 in lean individuals.

Clinicopathologic features and prognosis of steatohepatitic hepatocellular carcinoma based on varying cutoffs of tumoral steatohepatitic changes.

Steatohepatitic hepatocellular carcinoma (SH-HCC) is currently recognized as a distinct histologic subtype of HCC. The prognosis and specific criteria for determining the amount of steatohepatitis required to define SH-HCC are still unclear. After excluding all recognized HCC subtypes from 505 HCC cases (2010-2019), the remaining cases were categorized as conventional HCC (CV-HCC) (n = 223). The cases classified as SH-HCC (n = 171) were further divided into groups based on the percentage of steatohepatitis: 5% or more, 30% or more, and 50% or more. Hepatitis C virus infection was the predominant underlying liver disease in both the CV-HCC and SH-HCC groups. Metabolic dysfunction-associated steatotic liver disease (formerly nonalcoholic fatty liver disease) was more prevalent in all cases of SH-HCC with different steatohepatitic cutoffs than in cases of CV-HCC. There were no differences in the stage of fibrosis of the background liver between the CV-HCC and SH-HCC groups. SH-HCC with different cutoffs exhibited a notable increase in the presence of glycogenated nuclei, Mallory-Denk bodies, and hyaline globules in tumor cells. Survival analysis did not reveal substantial differences in overall survival between the CV-HCC and SH-HCC groups and among patients with SH-HCC with different steatohepatitis cutoffs. The degree of intratumoral steatohepatitis in patients with SH-HCC does not appear to be a notable prognostic factor. The presence of steatohepatitis in the tumor is better recognized as 1 of the histopathologic patterns of HCC.

От неалкогольной к метаболически ассоциированной жировой болезни печени. Стеатометрия и кардиометаболические факторы как предикторы развития стеатогепатита

Non-alcoholic metabolic dysfunction-associated fatty liver disease is the most common liver sickness linked with the high risk of hepatic and extrahepatic complications. The article provides an overview of changes in the nomenclature of this disease, analysis of risk factors for its development and the results of own research. The aim of the study was to estimate the clinical significance of steatometry (CAP function) by Fibroscan and cardiometabolic factors in assessing the risk of steatohepatitis development. Material and methods. Patients with hepatic steatosis accompanied by metabolic disorders were examined. Steatometry as well as routine physical and laboratory examination, including biochemical blood tests and abdominal ultrasound were provided. Statistical analysis included χ2 test, Spearman's rank correlation test, Student's t-test, Mann–Whitney test, multiple linear regression analysis. Results. 74 patients were included. Main characteristics of the cohort: 62.2% male, mean age – 48.8 years, cases of steatohepatitis – 41.9%. It was revealed that the number of metabolic factors in an individual patient correlated with the presence of steatohepatitis (χ2 = 3.29; p < 0.05) and the severity of steatosis by steatometry (rs = 0.37; p < 0.05). Individual clinical and laboratory parameters influenced the severity of steatosis with varying degrees. The most significant parameters were: abdominal circumference, concentration of HDL, insulin, activity of ALT, GGTP, and the presence of arterial hypertension. Using these indicators, a formula for assessing the risk of severe liver steatosis was created. Conclusion. Steatometry is to be considered as an important diagnostic method for the prognosis assessment in patients who have risk factors for the development and progression of non-alcoholic metabolic dysfunction-associated fatty liver disease. Severe steatosis is a predictor of steatohepatitis. The number of metabolic factors present in an individual patient is important in assessing the risk of severe liver steatosis and steatohepatitis.

Correlation between FIB- 4 Score and Liver Biopsy in Lean Egyptian Patients with Non-Alcoholic Fatty Liver Disease

Background Nonalcoholic fatty liver disease (NAFLD) is a worldwide epidemic with global prevalence estimated at 25%. Although NAFLD is usually associated with obesity, patients who are not obese can also present with NAFLD; this is known as “lean NAFLD.” Lean NAFLD is defined as NAFLD that develops in patients with a body mass index (BMI) <25 kg/m2. The prevalence of lean NAFLD varies from 7% in the United States to as high as 19% in Asia. Unfortunately, being lean (not overweight) does not necessarily lead to better health. A recent large meta analysis by Sookoian and Pirola of almost 2,000 patients with NAFLD who were lean demonstrated that patients with NAFLD who are lean or obese share a common altered metabolic and cardiovascular profile, which in turn may lead to collective risk for adverse cardiometabolic outcomes, including diabetes and ischemic heart disease. Indeed, atherosclerotic cardiovascular disease remains the most common cause of death in all weight categories. NAFLD comprises a wide pathological spectrum ranging from simple steatosis to steatohepatitis (NASH) with variable degrees of fibrosis and cirrhosis. The strongest predictor of fibrosis progression in NAFLD is the presence of steatohepatitis (Trenell et al., 2017). The diagnosis of NASH mandates a liver biopsy, yet the risks and costs associated with a liver biopsy preclude its widespread use. Pain is almost universal, and there is bleeding in approximately 1 in 500 liver biopsies and death in 1 in 10,000, dissuading patients from undergoing the procedure. Moreover, the disproportionately increasing incidence of NAFLD calls for practical and costeffective care and monitoring (Estes et al.,2018). Methods for non-invasive assessment of fatty liver disease and studies in the field have exponentially appeared over the last three decades, offering a safe and more non-invasive practical approach to hepatic fibrosis and steatosis quantification (Castera et al.,2019). Aim of the study Determining the correlation of Fib-4 score and NAFL diagnosed by liver biopsy in lean Egyptian patients Patients and Methods This study had been carried out on 30 subjects, age range above 18 years old, with BMI (18.5-24.9) selected from transplantation donor outpatient clinic at Ain shams university specialized hospital in Cairo after informed consent were taken from the patients Subjects were divided as follow: •Group I: 15 adult patients with NAFLD. •Group II: 15 adult patient with normal liver biopsy who will be educated about lean NAFLD and how to prevent it. Results In the current study we concluded that FIB-4 score is not significant with degree of fibrosis while it has a negative correlation with steatosis assessed by biopsy. FIB-4 failed to discriminate advanced fibrosis. Conversely, it showed acceptable diagnostic performances in exclusion of advanced fibrosis in overweight, obese, and severely obese patients in other studies. (FATIH et al., 2020) Conclusion FIB-4 failed to discriminate advanced fibrosis. Conversely, it showed acceptable diagnostic performances in exclusion of advanced fibrosis in overweight, obese, and severely obese patients. FIB-4 was able to exclude advanced fibrosis with the highest diagnostic accuracy in the subgroup of overweight patients. so fib 4 score can’t be used as a marker of fibrosis nor steatosis in lean NAFLD patients but more like a prognostic value.

Role of EpCAM+ CD133+ extracellular vesicles in steatosis to steatohepatitis transition in NAFLD.

Extracellular vesicles (EVs) have emerged as a potential source of circulating biomarkers in liver disease. We evaluated circulating AV+ EpCAM+ CD133+ EVs as a potential biomarker of the transition from simple steatosis to steatohepatitis. EpCAM and CD133 liver proteins and EpCAM+ CD133+ EVs levels were analysed in 31 C57BL/6J mice fed with a chow or high fat, high cholesterol and carbohydrates diet (HFHCC) for 52 weeks. The hepatic origin of MVs was addressed using AlbCrexmT/mG mice fed a Western (WD) or Dual diet for 23 weeks. Besides, we assessed plasma MVs in 130 biopsy-proven NAFLD patients. Hepatic expression of EpCAM and CD133 and EpCAM+ CD133+ EVs increased during disease progression in HFHCC mice. GFP+ MVs were higher in AlbCrexmT/mG mice fed a WD (5.2% vs 12.1%) or a Dual diet (0.5% vs 7.3%). Most GFP+ MVs were also positive for EpCAM and CD133 (98.3% and 92.9% respectively), suggesting their hepatic origin. In 71 biopsy-proven NAFLD patients, EpCAM+ CD133+ EVs were significantly higher in those with steatohepatitis compare to those with simple steatosis (286.4 ± 61.9 vs 758.4 ± 82.3; p < 0.001). Patients with ballooning 367 ± 40.6 vs 532.0 ± 45.1; p = 0.01 and lobular inflammation (321.1 ± 74.1 vs 721.4 ± 80.1; p = 0.001), showed higher levels of these EVs. These findings were replicated in an independent cohort. Circulating levels of EpCAM+ CD133+ MVs in clinical and experimental NAFLD were increased in the presence of steatohepatitis, showing high potential as a non-invasive biomarker for the evaluation and management of these patients.

Stratifying Non-alcoholic Steatohepatitis With the Non-invasive Ultrasound Markers Shear Wave Dispersion Slope and Shear Wave Velocity: An Animal Study.

We evaluated the significance of the ultrasound (US) markers shear wave dispersion slope (SWDS) and shear wave velocity (SWV) for identification of non-alcoholic steatohepatitis (NASH) and high-risk NASH; the latter was defined as the presence of steatohepatitis, a non-alcoholic fatty liver disease activity score (NAS) ≥4 or a fibrosis stage ≥2. Thirty-six male Sprague-Dawley (SD) rats were assigned to two groups: the study (n=30) and control (n=6) groups. To initiate non-alcoholic steatohepatitis, study group rats were fed a diet deficient in methionine and choline. All rats were examined using ultrasonography to obtain the SWDS and SWV parameters of the liver at the same time points. Fatty liver pathological grades were determined after euthanasia; the livers were categorized in the normal (n=6), NAFL (non-alcoholic fatty liver) (n=10) and NASH (n=20) subgroups based on the NAS scoring system. They were also categorized into subgroups F0 (n=22), F1 (n=3), F2 (n=7) and F3 (n=4) on the basis of the METAVIR (Meta-analysis of Histological Data in Viral Hepatitis) scoring system. Measurement differences between various grades were evaluated by analysis of variance (ANOVA) or the Mann-Whitney U-test. We used logistic regression to calculate a combination of the two parameters for combined assessment of parameters. The diagnostic value of SWDS, SWV and the two-variable model was determined by receiver operating characteristic (ROC) curve analysis. This analysis revealed stepwise increases in SWDS and SWV with increasing NAFLD severity. The accuracy of SWDS in diagnosing NASH was good (area under the ROC curve [AUC]: 0.88) and was superior to that of SWV (AUC: 0.76). The combination of SWV and SWDS exhibited higher performance (AUC: 0.90). SWV was higher than SWDS in participants with a fibrosis grade ≥2 (high-risk NASH). For identification of high-risk NASH, SWV exhibited the best diagnostic performance (AUC: 0.89), which was equivalent to that of the two-variable model (AUC: 0.88) and slightly higher than that of SWDS (AUC: 0.85). This study indicates that of the US-based markers, SWDS outperforms SWV in identifying NASH in rats and that combining the two markers may increase their clinical utility in guiding NAFLD and NASH treatment.

Význam inzulinové rezistence a NAFLD po transplantaci jater na přežívání pacientů a rozvoj chronického onemocnění ledvin

Summary: Introduction: Insulin resistance (IR) is a hallmark of non-alcoholic fatty liver disease (NAFLD), which has been associated with worse long-term survival and more frequent occurrence of chronic kidney disease (CKD) than in patients without NAFLD. The aim of our study was to evaluate the impact of NAFLD and IR on survival and renal function in patients after liver transplantation (LT). Methods: Our prospective study included 96 LT candidates who were observed after LT. We evaluated patient survival and occurrence of CKD (defined as estimated glomerular filtration [eGFR] ≤1.00 mL/s/1.73 m2 or overt proteinuria) 5 years after LT and at the end of follow-up. Clinical, laboratory, MR and elastographic evaluation before and 1 year after LT were performed as well as liver biopsy 1 year after LT. Results: Of the factors present 1 year after LT, higher ALT (P = 0.021), ALP (P = 0.012) and everolimus treatment (P = 0.025) increased the risk of death at the end of follow-up, borderline significance was found also for higher waist circumference (P = 0.058), AST (P = 0.059), HOMA-IR (P = 0.056) and presence of fibrosis stage ≥3 in biopsy (P = 0.055). In addition to the presence of CKD 1 year after LT (P &lt;0.001), other independent posttransplant risk factors of CKD 5 years after LT included presence of IR defined as HOMA-IR ≥3 (OR 4.33; 95% CI 1.25–15.04; P = 0.021) and higher serum high-molecular-weight (HMW) adiponectin (OR 1.25; 95% CI 1.03–1.50; P = 0.021). Of the factors present 1 year after LT, diabetes treated by antidiabetics (P = 0.008), higher serum levels od triglycerides (P = 0.031), C-peptide (P = 0.022) and leptin (P = 0.002) and lower total bilirubin (P = 0.006) were associated with lower eGFR at the end of follow-up. We observed a trend towards higher eGFR levels in patients treated with everolimus (P = 0.055). We did not observe an impact of grade of steatosis and presence of steatohepatitis on biopsy 1 year after LT on survival or renal functions. Conclusion: Presence of IR 1 year after LT independently increased the risk of CKD 5 year after LT. Patients with higher HOMA-IR 1 year after LT had a trend towards worse survival at the end of follow-up. Key words: insulin resistance – non-alcoholic fatty liver disease – liver transplantation – chronic kidney disease – survival

Vitamin D Status and Steatohepatitis in Obese Diabetic and Non-Diabetic Patients.

Background and Aims: The presence of steatohepatitis in obese patients can be multifactorial. The current study tries to determine the differences between diabetic and non-diabetic patients regarding the presence of steatohepatitis. We evaluated sequential liver samples and collected the times of bariatric surgery to assess the presence of NASH in patients with obesity, in the circuit of bariatric surgery. Methods: We performed a retrospective study of 49 patients presenting high-grade obesity in the circuit of bariatric surgery, with liver biopsy. The patients underwent bariatric surgery at a single center in France and were followed for 2 years. The liver biopsies were performed intraoperatively on all 49 patients before the bariatric surgery. The primary endpoint of the study was to evaluate the relationships between steatohepatitis/liver fibrosis and the presence of diabetes and to evaluate the current relationships between the biochemical work-ups. Special importance was accorded to the correlations between vitamin D levels and the presence of hepatic steatosis, due to the antifibrogenic pattern in the liver, as shown in many important papers in the field. Results: Significant correlations were found between the presence of liver fibrosis and the presence of diabetes (p = 0.022), but not regarding the antidiabetic treatment. An important correlation was found between the vitamin D levels and the presence of liver fibrosis, as well as with the levels of A1C hemoglobin and LDL cholesterol levels. Conclusions: Vitamin D deficiency presents a strong correlation with hepatic steatosis in individuals with morbid obesity. Correcting vitamin D deficiency may present a beneficial role in treating hepatic steatosis, diabetes, and cardiovascular risk in patients with morbid obesity.

OBSTRUCTIVE SLEEP APNEA SYNDROME RISK IN PATIENTS WITH NON-ALCOHOLIC FATTY LIVER DISEASE IS ASSOCIATED WITH OBESITY AND PRESENCE OF NASH.

Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease and refers to a wide spectrum of histological abnormalities ranging from simple steatosis (HE) to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis and hepatocellular carcinoma. To assess the risk of obstructive sleep apnea syndrome (OSAS) and relating it to demographic, biochemical and histological data in patients with non-alcoholic fatty liver disease. Cross-sectional cohort study in individuals with biopsy-proven NAFLD. Anthropometric and biochemical parameters, presence of metabolic syndrome and insulin resistance were evaluated. The Berlin Questionnaire (BQ) was applied to assess the risk of apnea and a food record was requested. Based on the BQ, participants were classified as high or low risk for OSAS. In the correlation of sleep apnea with the severity of NAFLD, presence of nonalcoholic steatohepatitis (NASH) and the degree of liver fibrosis were evaluated. Statistical analysis used the chi-square test, Student's t and bivariate logistic regression; values were expressed as mean ± standard deviation. This research project was approved by the Ethics Committee. Regarding the parameters evaluated, significant differences were observed between the groups in terms of body mass index (BMI), waist and neck circumference. In the histological evaluation, patients classified as high risk were more likely to have fibrosis and NASH. In bivariate regression, the BMI, presence of fibrosis and steatohepatitis in the biopsy were independently associated with an elevated risk of the syndrome. A high prevalence of risk for OSAS was observed in the studied group, with a higher risk being independently associated with BMI and presence of steatohepatitis, suggesting that it is a factor associated with the severity of the disease.

FEATURES OF ARTERIAL HYPERTENSION COMBINED WITH OBESITY ACCORDING TO NON-ALCOHOLIC FATTY LIVER DISEASE (STEATOSIS AND STEATOHEPATITIS)

This research was aimed to estimate the course of hypertension on the background of obesity and nonalcoholic fatty liver disease according to its stages (steatosis and steatohepatitis). Ninety patients were evaluated for anthropometric, general-clinical, laboratory, instrumental and immune-enzymatic research methods. With USG, the most characteristic features of fatty liver infiltration and the criteria for the distinction of steatosis from steatohepatitis were revealed, and on the basis of them 2 groups were formed. Thus, the progression of nonalcoholic fatty liver disease to the stage of steatohepatitis was accompanied by a more pronounced increase in blood pressure larger in comparison with steatosis of mass index of myocardium and anterior-posterior size of the left atrium, indicating the progression of structural myocardial disorders. Therefore, the presence of non-alcoholic steatohepatitis in patients with hypertension can be regarded as unfavorable prognostic criteria for the development of heart failure. In the presence of steatohepatitis, more marked changes in lipidograms were noticed for Low-Density Lipoprotein and Triglyceride values and a violation of the functional state of the liver with a cytolytic syndrome on the activity of AST and ALT and the total bilirubin, which may contribute to the progression of liver damage.

P-57 LIVER STEATOSIS AND STEATOHEPATITIS IN LIVER DISEASES OTHER THAN ALCOHOLIC AND NON-ALCOHOLIC FATTY LIVER

Fatty liver disease (FLD) alcoholic and non-alcoholic are prevalent conditions. The damage is determined by steatosis and steatohepatitis with or without fibrosis. There is little information on its role in the progression to significant fibrosis (SF) of chronic liver diseases (CLD) other than FLD. To describe the frequency of steatosis and steatohepatitis in liver biopsies of patients with CLD other than FLD. Observational, retrospective study with biopsies performed between 2015-2018. The presence and degree of steatosis, steatohepatitis and fibrosis were recorded according to the METAVIR scale; F3-F4 is considered SF. 268 biopsies analyzed; 93 with FLD are excluded. 175 are included: 53% autoimmune hepatitis (AIH), 27% primary biliary cholangitis (PBC), 7% viral hepatitis (VH) and 13% others. 74% women; age 52 (18-82) years; 58% had steatosis and 46% had steatohepatitis; 67% fibrosis, which was SF in 61%. Steatosis/steatohepatitis/fibrosis according to etiology: AIH 34%/46%/69%; PBC 19%/9%/53%; VH 77%/15%/39%. When analyzing the presence of SF according to the presence of steatosis or steatohepatitis: in steatosis 36% vs 48% without steatosis; In steatohepatitis there were more SF (65% vs 36%; p = 0.004). According to aetiology SF/non SF: HAI 92%/38% (p = 0.001); PBC 20%/24%; VH 50%/22% (NS). There was a high frequency of steatosis and steatohepatitis in patients with CLD. The presence of steatohepatitis is associated with a higher degree of fibrosis in patients with CLD, particularly in AIH, which may have an impact on the evolution and treatment.

Metabolic dysfunction-associated fatty liver disease increases risk of adverse outcomes in patients with chronic hepatitis B

Background & AimsA recent consensus document has defined metabolic dysfunction-associated fatty liver disease (MAFLD) as hepatic steatosis together with overweight, diabetes, and/or a combination of other metabolic risk factors. The clinical relevance of this novel diagnosis is unknown among patients with chronic hepatitis B (CHB). We studied the association between MAFLD (with or without steatohepatitis) and adverse clinical outcomes in patients with CHB.MethodsWe performed a retrospective long-term follow-up cohort study at 2 tertiary hospitals in patients with CHB who underwent liver biopsy. Biopsies were reassessed for steatosis, degree of fibrosis, and presence of steatohepatitis. Associations with event-free hepatocellular carcinoma (HCC)-free and transplant-free survival were explored.ResultsIn our cohort, 1076 patients were included, median follow-up was 9.8 years (25th–75th percentile: 6.6−14.0), and 107 events occurred in 78 patients, comprising death (n = 43), HCC (n = 36), liver decompensation (n = 21), and/or liver transplantation (n = 7). MAFLD was present in 296 (27.5%) patients and was associated with reduced event-free (adjusted hazard ratio [aHR] 2.00, 95% CI 1.26–3.19), HCC-free (aHR 1.93, 95% CI 1.17–3.21), and transplant-free survival (aHR 1.80, 95% CI 0.98–3.29) in multivariable analysis. Among patients with MAFLD, the presence of steatohepatitis (p = 0.95, log-rank test) was not associated with adverse outcomes.ConclusionsThe presence of MAFLD in patients with CHB was associated with an increased risk for liver-related clinical events and death. Among patients with MAFLD, steatohepatitis did not increase the risk of adverse outcomes. Our findings highlight the importance of metabolic dysfunction in patients with CHB.Lay summaryRecently, metabolic dysfunction-associated fatty liver disease (MAFLD) has been defined as fatty liver disease with signs of metabolic dysfunction. Among patients with chronic hepatitis B, MAFLD was associated with liver-related events and death. Metabolic health assessment should be encouraged among patients with chronic hepatitis B, especially in those with fatty liver disease.

Severity of non-alcoholic steatohepatitis is not linked to testosterone concentration in patients with type 2 diabetes.

Hypogonadism is reported to occur in non-alcoholic fatty liver disease (NAFLD), but earlier studies used low-sensitivity diagnostic techniques (CT, ultrasound), for NAFLD diagnosis. We hypothesized that if hypogonadism was due to NAFLD, and not solely attributable to underlying obesity/diabetes, it would be more severe in the presence of steatohepatitis (NASH). To examine the influence of liver disease on testosterone in males with type 2 diabetes mellitus (T2DM), we used gold-standard liver imaging with MR-spectroscopy (1H-MRS), and performed liver biopsies to grade/stage the NAFLD. In this cross-sectional study, we measured in 175 males with T2DM total and free testosterone, markers of insulin resistance, and intrahepatic triglyceride content (IHTG) by 1H-MRS. Those with NAFLD on imaging underwent a liver biopsy. Total testosterone was higher in the group without NAFLD ("No-NAFLD"; n = 48) compared to isolated steatosis (IS; n = 62) or NASH (n = 65) (385 ± 116 vs. 339 ± 143 vs. 335 ± 127 ng/ml, ptrend 0.03). Testosterone was also lower in obese vs. non-obese subjects in both the No-NAFLD and IS groups (p = 0.06 and p = 0.11, respectively), but not in obese vs. non-obese patients with NASH (p = 0.81). IHTG was independently associated with total testosterone (ß = -4.8, p = 0.004). None of the liver histology characteristics were associated with lower testosterone. NAFLD is linked to lower total testosterone in patients with T2DM, but likely given a common soil of insulin resistance/obesity and not from the severity of liver necroinflammation or fibrosis. Nevertheless, clinicians should consider screening patients with T2DM and NAFLD for hypogonadism.

Non-Alcoholic Steatohepatitis Decreases Microsomal Liver Function in the Absence of Fibrosis.

The incidence of non-alcoholic fatty liver disease (NAFLD) is rising across the globe, with the presence of steatohepatitis leading to a more aggressive clinical course. Currently, the diagnosis of non-alcoholic steatohepatitis (NASH) is based on histology, though with the high prevalence of NAFLD, a non-invasive method is needed. The 13C-aminopyrine breath test (ABT) evaluates the microsomal liver function and could be a potential candidate. We aimed to evaluate a potential change in liver function in NASH patients and to evaluate the diagnostic power of ABT to detect NASH. We performed a retrospective analysis on patients suspected of NAFLD who underwent a liver biopsy and ABT. 440 patients were included. ABT did not decrease in patients with isolated liver steatosis but decreased significantly in the presence of NASH without fibrosis and decreased even further with the presence of significant fibrosis. The predictive power of ABT as a single test for NASH was low but improved in combination with ALT and ultrasonographic steatosis. We conclude that microsomal liver function of patients with NASH is significantly decreased, even in the absence of fibrosis. The ABT is thus a valuable tool in assessing the presence of NASH; and could be used as a supplementary diagnostic tool in clinical practice.

S3257 A Comparison of Non-Obese Non-Alcoholic Fatty Liver Disease (NAFLD) and Obese NAFLD Patients

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is a major cause of liver disease worldwide. The relationship between NAFLD and obesity is well-established. However, it is known that NAFLD can affect the non-obese as well, and less is understood about this population of NAFLD patients. Our study aimed to further investigate possible differences between obese and non-obese NAFLD to further our understanding of non-obese NAFLD. METHODS: An EMR search of appropriately coded patients was performed. Medical records were manually searched for pertinent variables. Non-obese NAFLD was determined those with biopsy-proven NAFLD and BMI ≤30. Of the NAFLD population identified, 64 patients were found to have non-obese NAFLD. Each patient was matched with an obese (BMI >30) NAFLD patient of the same gender and age-decade. A two-tailed students t-test based and chi-squared test were performed to determine differences. RESULTS: A total of 64 non-obese NAFLD (BMI ≤30) patients were identified. Each patient was matched with a >30 BMI patient of the same gender and age-decade; total study size 128 patients (N = 128). There were 27/64 males (42%) and 37/64 females (58%). Average age and BMI of the non-obese vs obese patients was 55 years and 25, and 54 years and 37, respectively. In non-obese vs obese patients, total number affected and means were calculated for a number of pertinent variables including diabetes, dyslipidemia, hemoglobin A1c, CKD stage (mean 0.4 vs 0.7), HDL, LDL, statin usage, HTN, steatosis grade, presence of steatohepatitis, fibrosis score, LDL/HDL ratio, transferrin saturation, ceruloplasmin, ferritin, AST, ALT, platelet count, MPV, APRI score, and Fib4 score. Analysis was then performed to determine any significant differences. This showed that Fib4 was significantly (P = 0.032), even though fibrosis scores between the two groups were not significantly different. A history of dyslipidemia was nearly significant (P = 0.051) as well, but did not meet established P-value cutoffs. CONCLUSION: Our study provides further data on characteristic of and differences between non-obese NAFLD and obese NAFLD populations. It showed significantly different Fib4 score results between the two populations, even though biopsy fibrosis scores were not significantly different. If replicated on further studies, this could suggest uncertainty interpreting Fib4 scores in the non-obese NAFLD population. The study is limited by small sample size. More research is needed to broaden understanding of non-obese NAFLD.Table 1.: Demographics: number of patients in each age/gender grouping in both categories, non-obese and obese NAFLDTable 2.: Comparisons of variables between non-obese (BMI ≤30) and obese (BMI >30) patient populations; x = mean, N = number affectedTable 3.: Statistical analysis between non-obese and obese NAFLD populations showing significantly different values of Fib4 scores between the two populations

Liver transcriptomics highlights interleukin-32 as novel NAFLD-related cytokine and candidate biomarker

ObjectiveEfforts to manage non-alcoholic fatty liver disease (NAFLD) are limited by the incomplete understanding of the pathogenic mechanisms and the absence of accurate non-invasive biomarkers. The aim of this study...

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The role of PNPLA3 (rs738409) c>g variant on histological progression of non-alcoholic fatty liver disease.

Background and AimThe present study aims to investigate the role of genetic variability of the PNPLA3 gene (adiponectin) in predisposition to non-alcoholic fatty liver disease (NAFLD) by comparing NAFLD patients to healthy controls and to investigate any impact of the PNPLA3 genetic variability on the natural course of the disease.Materials and MethodsThis cohort consisted of 174 patients with biopsy-proven NAFLD and 151 healthy controls. DNA was extracted from peripheral blood and the rs738409 C>G single nucleotide polymorphism was assessed using PCR-DNA sequencing.ResultsThe frequency distribution of the GG genotype was significantly higher in NAFLD patients than in controls (p=0.01). In patients with NAFLD, the GG genotype was associated with lower platelet counts (p=0.001), the presence of steatohepatitis (p=0.04) and hepatic fibrosis (p=0.016). After adjustment for age, gender, obesity, and diabetes mellitus, the GG genotype was an independent predictor of significant hepatic fibrosis (adjusted odds ratio =3.031 p=0.012). From the baseline to sequential liver biopsies, the progression of NAS in NAFLD patients was slightly higher in the GG genotype than that of CC and GG genotypes (p=0.18).ConclusionThe PNPLA3 GG genotype is a predisposing factor for the development of hepatic steatosis in NAFLD patients and related to a more severe liver disease.

Evaluating the association of serum ferritin and hepatic iron with disease severity in non-alcoholic fatty liver disease.

Hyperferritinemia, with or without increased hepatic iron, represents a common finding in non-alcoholic fatty liver disease (NAFLD). However, it is unclear whether it reflects hepatic inflammation or true iron-overload and, in case the latter is confirmed, whether this influences disease progression. We therefore explored the association between serum ferritin, degree and pattern of hepatic iron deposition and liver disease severity in patients with NAFLD. We selected 468 patients with biopsy-proven NAFLD from 2 European centres. Iron, hepatic and metabolic parameters were collected at the time of liver biopsy. Iron deposits in hepatocytes and reticuloendothelial cells were assessed and graded. Diagnosis of non-alcoholic steatohepatitis (NASH) and fibrosis staging were performed. A total of 122 (26%) patients had hyperferritinemia, whereas stainable hepatic iron was found in 116 (25%) patients (38% predominantly in hepatocytes, 20% in reticuloendothelial cells and 42% in both). Subjects with stainable hepatic iron, particularly those with a mixed pattern, had higher serum ferritin and transaminases but only a mixed pattern of iron deposition was among the variables significantly associated with presence of NASH. Serum ferritin was not associated with presence of NASH, however it increased with worsening fibrosis stage (F3 compared to F0-F1), and significantly decreased in stage F4. A mixed pattern of hepatic iron deposition is associated with the presence of steatohepatitis, while serum ferritin increases with worsening fibrosis up to pre-cirrhotic stage. In individual NAFLD patients, serum ferritin could be evaluated as part of non-invasive diagnostic panels but not on its own.

Serum high mobility group box 1 protein levels are not associated with either histological severity or treatment response in children and adults with nonalcoholic fatty liver disease.

AimSerum high mobility group box 1 protein (HMGB1) is a proinflammatory molecule that could potentially serve as a biomarker for non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) due to its correlation with degree of liver fibrosis. The aim of the current study was to examine the cross-sectional and longitudinal relationships between serum HMGB1 levels and liver histology in adults and children with NAFLD participating in two large randomized controlled trials.MethodsSerum HMGB1 levels were measured at various time points in adults and children with NAFLD, who participated in PIVENS and TONIC clinical trials respectively. PIVENS trial compared vitamin E or pioglitazone to placebo in adults whereas TONIC trial compared vitamin E or metformin to placebo in children. Participants had liver biopsies at baseline and the end of treatment (96 weeks), and liver histology was reviewed by a central committee of study pathologists.ResultsIn the cross-sectional analyses (n = 205 for PIVENS and 109 for TONIC), there was no significant relationship between serum HMGB1 levels and histological features such as steatosis, ballooning, inflammation, fibrosis, or presence of steatohepatitis in either adults or children. Serum HMGB1 levels did not change significantly during treatment either with placebo, vitamin E therapy (P = 0.81) or pioglitazone (P = 0.09) in the PIVENS trial. Similarly, serum HMGB1 levels did not change significantly during treatment either with placebo, metformin (P = 0.15) or vitamin E (P = 0.23) in the TONIC trial. In the longitudinal analyses (n = 105 for PIVENS and 109 for TONIC), changes in serum HMGB1 levels did not correlate with histologic improvement or resolution of NASH in either adults or children. There was no relationship between serum HMGB1 and ALT levels in either adults or children with NAFLD.ConclusionSerum HMGB1 levels were not associated with histological severity or treatment response in either children or adults with NAFLD.