Publications by authors named "Marialena Mouzaki"

70 Publications

Sarcopenia is highly prevalent in children with autoimmune liver diseases and is linked to visceral fat and parent-perceived general health.

Liver Int 2021 Nov 24. Epub 2021 Nov 24.

Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

Background: Patients with autoimmune hepatitis (AIH) and primary or autoimmune sclerosing cholangitis are at nutritional risk; their body composition and has not been extensively studied. We aimed to describe their body composition and identify clinical links.

Methods: Using magnetic resonance imaging (MRI), two reviewers segmented total psoas muscle area (tPMSA), visceral fat area (VFA) and subcutaneous fat area (mm ) and measured visceral and subcutaneous thickness (mm). Clinical, laboratory and quality of life (QoL; using PedsQL) data were collected. Sarcopenia was defined as tPMSA ≤5th percentile. Analysis of variance, Wilcoxon rank test and multivariable modelling were performed. A paediatric cohort with non-alcoholic fatty liver disease (NAFLD) was used as a comparator following propensity score matching.

Results: Fifty-eight patients with autoimmune liver disease (AILD) (33 [57%] with AIH) were included: median age 16 years (interquartile range [IQR]: 13-18), 33 (57%) male. Median time from diagnosis to MRI was 15 months (IQR: 2-39 months). Two patients (3%) had a BMIz indicative of mild malnutrition. tPMSA was measurable in 52 subjects (90%). Of those, 25 (48%) had sarcopenia. Sarcopenic patients had a lower blood urea nitrogen compared to non-sarcopenic (median [IQR]: 9.5 [8.0, 12.0] vs 11 [10, 14] mg/dL; P = .023). There was no difference in corticosteroid use between groups. The VFA of sarcopenic patients was higher (3156 [2064, 7492]) vs 2084 [688, 3092]) mm ; P = .005). Patient-reported QoL negatively associated with VFA and general health negatively associated with VFA. Compared with NAFLD, the odds ratio for sarcopenia with AILD was 14.5 (95% confidence interval: 2.3-90.7).

Conclusion: In autoimmune liver diseases, sarcopenia is highly prevalent, associated with increased visceral fat and QoL.
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http://dx.doi.org/10.1111/liv.15108DOI Listing
November 2021

Stratification by obesity class, rather than age, can identify a higher percent of children at risk for non-alcoholic fatty liver disease and metabolic dysfunction.

Pediatr Obes 2021 Oct 18:e12862. Epub 2021 Oct 18.

Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, College of Medicine, University of Kentucky, Lexington, Kentucky, USA.

Background: An increasing number of clinical practice guidelines recommend screening children with obesity for non-alcoholic fatty liver disease (NAFLD). However, there is limited evidence regarding what parameters should be used to initiate the screening.

Objective: The objective of this study was to determine whether obesity class rather than age group can identify a higher percent of children at risk of NAFLD as assessed by abnormal alanine aminotransferase (ALT).

Methods: This is a cross-sectional study in a regional referral clinic for evaluation of obesity. Children were stratified by age group or by obesity class, and data obtained at first visit were analysed.

Results: Of the 784 children, 482 were ≥10, 209 were 6 to 9 and 93 were 2 to 5 years of age. Abnormal ALT was observed in 32.1%, 46.9% and 61.0% of children with class I, II or III obesity, respectively (p < 0.001), while the risk of abnormal ALT did not differ in very young (2-5), young (6-9), or children older than 10 years. A multivariable analysis showed that class II and class III obesity were associated with 2.1-fold (1.27-3.72) and 4-fold (2.41-6.96) greater odds of abnormal ALT compared with class I obesity. African-American children had lower risk of abnormal ALT (0.27), whereas Hispanic children had higher risk (2.37). Obesity class was a better predictor of abnormal ALT than age, especially in girls. Furthermore, 66.7% of boys (p = 0.009) and 69% of girls (p < 0.001) with abnormal ALT exhibited additional signs of metabolic dysfunction.

Conclusion: Obesity class is more strongly associated with abnormal ALT than age.
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http://dx.doi.org/10.1111/ijpo.12862DOI Listing
October 2021

Impedance-based measures of muscle mass can be used to predict severity of hepatic steatosis in pediatric nonalcoholic fatty liver disease.

Nutrition 2021 Nov-Dec;91-92:111447. Epub 2021 Aug 10.

Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. Electronic address:

Objectives: The objective of this study was to investigate the association between measures of body composition based on bioelectrical impedance analysis (BIA) and histologic severity of liver disease in a pediatric cohort with nonalcoholic fatty liver disease (NAFLD).

Methods: This was a cross-sectional study of patients < 20 y old with histologically confirmed NAFLD followed in our Steatohepatitis Center from 2017 to 2019. Contemporaneous body-composition data were obtained using a multifrequency octopolar BIA device (InBody 370, InBody, Seoul, South Korea). BIA data collected were skeletal muscle mass, appendicular muscle mass, and percentage body fat. Skeletal and appendicular muscle mass were corrected for height (dividing by the square of height), generating their respective indices. Univariate linear and logistic regression, followed by multivariable logistic regression analyses, were used.

Results: Of the 79 children included (27% female, 73% male; 38% Hispanic; median age, 13 y; median body mass index Z-score, 2.43), the median NAFLD Activity Score was 4 (interquartile range, 3-5). In multivariable regression analyses, the skeletal muscle mass index was negatively associated with hepatic steatosis after controlling for confounders (odds ratio, 0.76; 95% confidence interval, 0.62-0.93). Similarly, the appendicular muscle mass index was negatively associated with severity of hepatic steatosis severity (odds ratio, 0.69; 95% confidence interval, 0.53-0.90). In contrast, percentage body fat was not associated with hepatic steatosis. NAFLD Activity Score, lobular inflammation, ballooning scores, and fibrosis stage were not associated with measures of body composition.

Conclusions: There is an inverse association between BIA-based measures of muscle mass and severity of hepatic steatosis in children with NAFLD. BIA data could further inform clinical decision making in this context.
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http://dx.doi.org/10.1016/j.nut.2021.111447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8595713PMC
August 2021

50 Years Ago in TheJournalofPediatrics: MCTs: Are They what We want Them to Be?

J Pediatr 2021 Sep;236:94

Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

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http://dx.doi.org/10.1016/j.jpeds.2021.05.057DOI Listing
September 2021

Standardized Feeding Protocol Improves Delivery and Acceptance of Enteral Nutrition in Children Immediately After Liver Transplantation.

Liver Transpl 2021 10 13;27(10):1443-1453. Epub 2021 Jul 13.

Transplant and Regenerative Medicine Centre, University of Toronto, Toronto, Ontario, Canada.

Delivery of adequate nutrition after liver transplantation (LT) surgery is an important goal of postoperative care. Existing guidelines recommend early enteral nutrition after abdominal surgery and in the child who is critically ill but data on nutritional interventions after LT in children are sparse. We evaluated the impact of a standardized postoperative feeding protocol on enteral nutrition delivery in children after LT. Data from 49 children (ages 0-18 years) who received a LT prior to feeding protocol implementation were compared with data for 32 children undergoing LT after protocol implementation. The 2 groups did not differ with respect to baseline demographic data. After protocol implementation, enteral nutrition was started earlier (2 versus 3 days after transplant; P = 0.005) and advanced faster when a feeding tube was used (4 versus 8 days; P = 0.03). Protocol implementation was also associated with reduced parenteral nutrition use rates (47% versus 75%; P = 0.01). No adverse events occurred after protocol implementation. Hospital length of stay and readmission rates were not different between the 2 groups. In conclusion, implementation of a postoperative nutrition protocol in children after LT led to optimized nutrient delivery and reduced variability of care.
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http://dx.doi.org/10.1002/lt.26102DOI Listing
October 2021

Body composition measured by bioelectrical impedance analysis is a viable alternative to magnetic resonance imaging in children with nonalcoholic fatty liver disease.

JPEN J Parenter Enteral Nutr 2021 Apr 2. Epub 2021 Apr 2.

Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

Objective: To determine the relationship between bioelectrical impedance analysis (BIA) and magnetic resonance imaging (MRI) obtained measures of body composition in children with nonalcoholic fatty liver disease (NAFLD).

Methods: Youth with obesity and NAFLD who had BIA and abdominal MRI testing were included. BIA measured skeletal muscle mass (SMM), appendicular lean mass (ALM), trunk muscle mass (TMM), and percent body fat. MRI measured total psoas muscle surface area (tPMSA) and fat compartments. Univariate analysis described the relationship between BIA- and MRI-derived measurements. Multivariable regression analyses built a model with body composition measured via MRI.

Results: 115 patients (82 (71%) male, 38 (33%) Hispanic, median age14 years) were included. There was a strong correlation between tPMSA and SMM, ALM, and TMM (correlation coefficients [CCs]: 0.701, 0.689, 0.708, respectively; all P < .001). Higher SMM, ALM, and TMM were associated with higher tPMSA. This association remained after controlling for age, sex, ethnicity, type 2 diabetes mellitus status, and body mass index z-score. Total fat mass by BIA and MRI-determined total, subcutaneous, and intraperitoneal fat area correlated significantly (CCs: 0.813, 0.808, 0.515, respectively; all P < .001). In univariate regression, higher total fat mass by BIA was associated with increased total fat area and increased fat in each of the four regions measured by MRI. After controlling for confounders, the association between total fat mass by BIA and total fat area by MRI persisted.

Conclusions: BIA measures of muscle and fat mass correlate strongly with MRI measures of tPMSA and fat areas in children with obesity and NAFLD.
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http://dx.doi.org/10.1002/jpen.2113DOI Listing
April 2021

Alternative Etiologies of Liver Disease in Children With Suspected NAFLD.

Pediatrics 2021 04;147(4)

Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;

Objectives: To determine the prevalence of alternative causes of liver disease in a cohort of youth with overweight and obesity undergoing evaluation for suspected nonalcoholic fatty liver disease (NAFLD).

Methods: Multicenter, retrospective cohort study of patients aged ≤18 years with overweight and obesity and evidence of elevated serum aminotransferases and/or hepatic steatosis on imaging, referred for suspected NAFLD to Cincinnati Children's Hospital Medical Center (2009-2017) or Yale New Haven Children's Hospital (2012-2017). Testing was performed to exclude the following: autoimmune hepatitis (AIH), Wilson disease, viral hepatitis (B and C), thyroid dysfunction, celiac disease, α-1 antitrypsin deficiency, and hemochromatosis.

Results: A total of 900 children with overweight and obesity (63% boys, 26% Hispanic ethnicity) were referred, with a median age of 13 years (range: 2-18). Most had severe obesity ( = 666; 76%) with a median BMI score of 2.45 (interquartile range [IQR]: 2.2-2.7). Median alanine aminotransferase level at presentation was 64 U/L (IQR: 42-95). A clinically indicated liver biopsy was performed in 358 children (40%) at a median of 6 months (IQR: 1-14) post initial visit; of those, 46% had confirmed nonalcoholic steatohepatitis. Positive autoantibodies were observed in 13% of the cohort, but none met criteria for AIH. Only 19 (2%) were found to have other causes of liver disease, with no cases of viral hepatitis or Wilson disease detected.

Conclusions: In a large, multicenter cohort, the vast majority of children with overweight and obesity with presumed or confirmed NAFLD tested negative for other causes of liver disease. In contrast to a previous pediatric report, no patient was diagnosed with AIH.
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http://dx.doi.org/10.1542/peds.2020-009829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015155PMC
April 2021

Under-reporting of Hepatic Steatosis in Children: A Missed Opportunity for Early Detection.

J Pediatr 2021 07 19;234:92-98.e2. Epub 2021 Mar 19.

Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH. Electronic address:

Objective: To determine the prevalence of underreporting of hepatic steatosis found incidentally on computed tomography (CT).

Study Design: Retrospective cross-sectional study including patients <18 years of age who had undergone unenhanced abdominal CT for evaluation of nephrolithiasis. Hepatic and splenic attenuation were measured independently by 2 reviewers. Hepatic steatosis was defined using various previously established criteria (4 original criteria designed to detect moderate/severe steatosis and 3 secondary criteria designed to identify mild steatosis). Radiology reports and clinical notes were reviewed for documentation of steatosis. Serum alanine aminotransferase levels were collected. Kappa statistics were used to assess agreement between reviewers.

Results: A total of 584 patients were included. Agreement between reviewers' measurements for categorical classification of presence of steatosis was excellent (kappa statistic agreement >87%). The prevalence of hepatic steatosis ranged from 3% to 35%, depending on the criterion. Using absolute liver attenuation <48 Hounsfield units (most likely reflective of the truth, given alanine aminotransferase distribution and body mass index data), the prevalence was 7% (n = 42). Steatosis was reported for only 12 of 42 (28%) of these patients and was documented in clinical notes in only 3 of those cases.

Conclusions: Hepatic steatosis is underreported as an incidental finding of CT for nephrolithiasis. Given the prevalence and silent nature of nonalcoholic fatty liver disease, a high level of suspicion is needed, so as not to miss the opportunity to identify steatosis in childhood.
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http://dx.doi.org/10.1016/j.jpeds.2021.03.016DOI Listing
July 2021

An update on the role of the microbiome in non-alcoholic fatty liver disease pathogenesis, diagnosis, and treatment.

Curr Treat Options Gastroenterol 2020 Jun 2;18(2):270-280. Epub 2020 May 2.

NAFLD Research Center, Division of Gastroenterology, Department of Medicine, University of California at San Diego.

The microbiome was originally postulated to contribute to the pathogenesis of NAFLD when the first studies of dysbiosis in NAFLD were reported. Since then, a number of studies have investigated this finding further, in order to discern whether the dysbiosis is the result of the metabolic dysregulation seen with NAFLD or a contributor to the pathogenesis of this condition.
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http://dx.doi.org/10.1007/s11938-020-00290-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946055PMC
June 2020

Microbiota-Driven Activation of Intrahepatic B Cells Aggravates NASH Through Innate and Adaptive Signaling.

Hepatology 2021 Aug;74(2):704-722

Department of Integrative Biology & Physiology, University of Minnesota Medical School, Minneapolis, MN.

Background And Aims: Nonalcoholic steatohepatitis is rapidly becoming the leading cause of liver failure and indication for liver transplantation. Hepatic inflammation is a key feature of NASH but the immune pathways involved in this process are poorly understood. B lymphocytes are cells of the adaptive immune system that are critical regulators of immune responses. However, the role of B cells in the pathogenesis of NASH and the potential mechanisms leading to their activation in the liver are unclear.

Approach And Results: In this study, we report that NASH livers accumulate B cells with elevated pro-inflammatory cytokine secretion and antigen-presentation ability. Single-cell and bulk RNA sequencing of intrahepatic B cells from mice with NASH unveiled a transcriptional landscape that reflects their pro-inflammatory function. Accordingly, B-cell deficiency ameliorated NASH progression, and adoptively transferring B cells from NASH livers recapitulates the disease. Mechanistically, B-cell activation during NASH involves signaling through the innate adaptor myeloid differentiation primary response protein 88 (MyD88) as B cell-specific deletion of MyD88 reduced hepatic T cell-mediated inflammation and fibrosis, but not steatosis. In addition, activation of intrahepatic B cells implicates B cell-receptor signaling, delineating a synergy between innate and adaptive mechanisms of antigen recognition. Furthermore, fecal microbiota transplantation of human NAFLD gut microbiotas into recipient mice promoted the progression of NASH by increasing the accumulation and activation of intrahepatic B cells, suggesting that gut microbial factors drive the pathogenic function of B cells during NASH.

Conclusion: Our findings reveal that a gut microbiota-driven activation of intrahepatic B cells leads to hepatic inflammation and fibrosis during the progression of NASH through innate and adaptive immune mechanisms.
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http://dx.doi.org/10.1002/hep.31755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8377092PMC
August 2021

Can Baseline Characteristics be Used to Predict Liver Disease Outcomes in Pediatric Nonalcoholic Fatty Liver Disease?

Obesity (Silver Spring) 2021 01 13;29(1):171-176. Epub 2020 Nov 13.

Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

Objective: Longitudinal studies on childhood predictors of nonalcoholic fatty liver disease (NAFLD) progression are lacking. The objective of this study was to determine whether baseline clinical or laboratory measures predict liver disease outcomes in a pediatric NAFLD cohort.

Methods: A retrospective study of patients with presumed NAFLD was conducted using baseline and follow-up clinical and laboratory measures. Disease outcomes were defined using the mean serum alanine aminotransferase (ALT) levels from 24 to 36 months after the first visit. Logistic regression assessed the relationship between ALT progression/regression and predictor variables. Multivariable regression determined the best model for predicting the ALT outcome. Markov process modeling explored the likelihood for a patient to transition between ALT states.

Results: Of a total of 816 patients identified, 144 had sufficient data. Regression was seen in 26%, whereas 30% progressed. No baseline clinical or laboratory measurements had a significant effect on disease outcomes. Markov modeling demonstrated that subjects were more likely to either remain in their baseline ALT group or worsen rather than improve.

Conclusions: Routinely obtained baseline clinical or laboratory measures cannot help risk-stratify youth with presumed NAFLD in terms of long-term outcomes. Close clinical, radiographic, and histologic evaluation of patients is warranted to determine those at risk of progression.
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http://dx.doi.org/10.1002/oby.22999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902314PMC
January 2021

Muscle Mass Is Linked to Liver Disease Severity in Pediatric Nonalcoholic Fatty Liver Disease.

J Pediatr 2020 08;223:93-99.e2

Division of Gastroenterology, Hepatology, and Nutrition, University of Cincinnati College of Medicine, Cincinnati, OH; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH. Electronic address:

Objective: To investigate the association between muscle mass and liver disease severity in pediatric patients with non-alcoholic fatty liver disease (NAFLD).

Study Design: This was a retrospective study of patients aged <20 years followed from 2009 to 2018. Muscle mass was estimated in all patients by measuring magnetic resonance imaging-based total psoas muscle surface area (tPMSA) and correcting for height (tPMSA index = tPMSA/height). Two cohorts were studied, one with histological confirmation of NAFLD (n = 100) and the other with magnetic resonance imaging (MRI) evidence of hepatic steatosis (n = 236). Histology was scored using Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) criteria. MRI-measured proton density fat fraction (PDFF) and liver stiffness were collected. Demographic, clinical, and socioeconomic status (using a validated Community Deprivation Index [CDI]) were assessed as covariates. Univariate regression analyses, followed by multivariable regression analyses, were used to determine the relationships between tPMSA index and NAS, MRI-PDFF, and liver stiffness, adjusting for clinical, demographic, and CDI variables.

Results: In the multivariable regression analyses, higher steatosis score was associated with a lower tPMSA index (OR, 0.73; 95% CI, 0.56-0.96) and younger age (OR, 0.84; 95% CI, 0.73-0.97). Liver PDFF was also significantly associated with the tPMSA index (P = .029), sex (P = .019), and CDI (P = .005). In contrast, liver stiffness was not associated with tPMSA in multivariable analyses.

Conclusions: tPMSA index was independently associated with both imaging and histological features of hepatic steatosis severity in children. Future studies should directly explore the presence and directionality of causative links between muscle mass and steatosis, as well as whether interventions that enhance muscle mass can reduce disease severity in children with NAFLD.
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http://dx.doi.org/10.1016/j.jpeds.2020.04.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017767PMC
August 2020

Significance of autoantibody seropositivity in children with obesity and non-alcoholic fatty liver disease.

Pediatr Obes 2021 01 8;16(1):e12696. Epub 2020 Jul 8.

Section of Gastroenterology and Hepatology, Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut.

Background: Autoantibodies are frequently positive in adults with nonalcoholic fatty liver disease (NAFLD) without concurrent autoimmune hepatitis (AIH). The clinical significance of this is unknown in children.

Objective: To determine the prevalence of autoantibody positivity in pediatric NAFLD and to evaluate its association with disease severity.

Methods: Multicenter, retrospective study of patients ≤18 years of age with biopsy-confirmed NAFLD. Descriptive statistics were used and groups were compared using Wilcoxon-Mann Whitney or χ testing, and multivariable logistic regression was used for binary or ordinal outcomes.

Results: One hundred and thirty six patients with a median age of 14 years were included. The median body mass index Z-score was 2.5 (interquartile range 2.2, 2.6). Positive antinuclear antibody (ANA), anti-smooth muscle antibody (ASMA), anti-liver-kidney microsomal antibody, or any combination of autoantibodies were observed in 22%, 14%, 0%, and 33% of patients, respectively. The proportion of patients with a steatosis score ≥2 was significantly higher in those with positive ANA (P = .045). In the multivariable regression analysis, positive ANA was associated with increased odds of steatosis score ≥2 (odds ratio, 5.91; 95% confidential interval, 1.50-23.26), after controlling for potential confounders. No other significant histology differences were seen between the groups.

Conclusions: Positive ANA and ASMA are common in children with NAFLD; however, anti-LKM positivity is not. ANA positivity is associated with more severe steatosis.
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http://dx.doi.org/10.1111/ijpo.12696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006542PMC
January 2021

Evolving Role for Pharmacotherapy in NAFLD/NASH.

Clin Transl Sci 2021 01 25;14(1):11-19. Epub 2020 Aug 25.

Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent, dynamic disease that occurs across the age spectrum and can lead to cirrhosis and hepatocellular carcinoma. There are currently no US Food and Drug Administration (FDA) approved treatments for NAFLD; however, this is a field of active research. This review summarizes emerging pharmacotherapies for the treatment of adult and pediatric NAFLD. Investigated pharmacotherapies predominantly target bile acid signaling, insulin resistance, and lipid handling within the liver. Three drugs have gone on to phase III trials for which results are available. Of those, obeticholic acid is the single agent that demonstrates promise according to the interim analyses of the REGENERATE trial. Obeticholic acid showed reduction of fibrosis in adults with nonalcoholic steatohepatitis (NASH) taking 25 mg daily for 18 months (n = 931, reduction in fibrosis in 25% vs. 12% placebo, P < 0.01). Ongoing phase III trials include REGENERATE and MAESTRO-NASH, which investigates thyroid hormone receptor-β agonist MGL-3196. Outcomes of promising phase II trials in adults with NASH are also available and those have investigated agents, including the fibroblast growth factor (FGF)19 analogue NGM282, the GLP1 agonist liraglutide, the FGF21 analogue Pegbelfermin, the sodium glucose co-transporter 2 inhibitor Empagliflozin, the ketohexokinase inhibitor PF-06835919, the acetyl-coenzyme A carboxylase inhibitor GS-0976, and the chemokine receptor antagonist Cenicriviroc. Completed and ongoing clinical trials emphasize the need for a more nuanced understanding of the phenotypes of subgroups within NAFLD that may respond to an individualized approach to pharmacotherapy.
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http://dx.doi.org/10.1111/cts.12839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877845PMC
January 2021

Glomerular Hyperfiltration Is Associated with Liver Disease Severity in Children with Nonalcoholic Fatty Liver Disease.

J Pediatr 2020 07 4;222:127-133. Epub 2020 May 4.

Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, OH. Electronic address:

Objectives: To determine the prevalence of renal impairment in a large cohort of youths with histologically confirmed nonalcoholic fatty liver disease (NAFLD), and to determine its association with liver disease severity.

Study Design: Clinical, laboratory, and histology data were collected retrospectively in a pediatric cohort with biopsy-confirmed NAFLD at a tertiary care center between 2010 and 2017. Histological NAFLD severity was scored using validated criteria. Glomerular filtration rate (GFR) was calculated and categorized as low (<90 mL/min/1.73 m), normal (90-136 mL/min/1.73 m), or high (>136 mL/min/1.73 m). Univariate and multivariate modeling were used to determine differences between the GFR groups and to control for confounders.

Results: The cohort comprised 179 patients (82% non-Hispanic; median age; 14 years; IQR, 12-16 years). One-third of the patients had abnormal renal function, including 36 (20%) with glomerular hyperfiltration and 26 (15%) with low GFR. In multivariable logistic regression, compared with normal GFR, hyperfiltration was independently associated with higher NAFLD activity score (aOR, 2.96; 95% CI, 1.49-5.87; P = .002), after adjusting for age, sex, ethnicity, obesity severity, presence of type 2 diabetes mellitus, and medications.

Conclusions: In this large cohort with histologically confirmed NAFLD, renal impairment was highly prevalent and associated with liver disease severity, independent of obesity severity. Screening patients with confirmed NAFLD for renal complication is recommended.
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http://dx.doi.org/10.1016/j.jpeds.2020.03.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218655PMC
July 2020

Prevention of Childhood Obesity: A Position Paper of the Global Federation of International Societies of Paediatric Gastroenterology, Hepatology and Nutrition (FISPGHAN).

J Pediatr Gastroenterol Nutr 2020 05;70(5):702-710

Department of Pediatrics, San Paolo Hospital, University of Milan, Milan, Italy.

Global childhood obesity increased more than 8-fold over 40 years, inducing a very large personal, societal, and economic burden. Effects of available treatments are less than satisfactory; therefore, effective prevention is of high priority. In this narrative review, we explore preventive opportunities. The available evidence indicates large benefits of improving nutrition and lifestyle during early life, such as promoting breast-feeding and improving the quality of infant and early childhood feeding. Promoting healthy eating patterns and limiting sugar-containing beverage consumption from early childhood onwards are of great benefit. Regular physical activity and limited sedentary lifestyle and screen time alone have limited effects but are valuable elements in effective multicomponent strategies. The home environment is important, particularly for young children, and can be improved by educating and empowering families. School- and community-based interventions can be effective, such as installing water fountains, improving cafeteria menus, and facilitating regular physical activity. Reducing obesogenic risk factors through societal standards is essential for effective prevention and limiting socioeconomic disparity; these may comprise food, drink, and physical activity standards for day cares and schools, general food quality standards, front-of-pack food labeling, taxation of unhealthy foods, restriction of food advertisements to children, and others. Effective prevention of childhood obesity is not achieved by single interventions but by integrated multicomponent approaches involving multiple stakeholders that address children, families, and societal standards. Pediatricians and their organizations should be proactive in supporting and empowering families to support their children's health, and in promoting societal measures that protect children.
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http://dx.doi.org/10.1097/MPG.0000000000002708DOI Listing
May 2020

Body Composition Using Air Displacement Plethysmography in Children With Inflammatory Bowel Disease.

J Pediatr Gastroenterol Nutr 2020 07;71(1):52-58

Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Medical Centre, Cincinnati, OH.

Objective: The aim of the study was to assess the body composition of children with inflammatory bowel disease (IBD) and to study the accuracy of clinically available tools in predicting excess body fatness. We aimed at also exploring the influence of adiposity on pharmacokinetics during early Infliximab exposure.

Methods: Prospective cohort study in 5- to 17-year-old children with IBD initiating Infliximab therapy. Patient demographic, phenotypic, and laboratory data at the time of Infliximab initiation were recorded. Body composition was assessed using air displacement plethysmography (ADP). fat mass index (FMI = fat mass [kg]/(height [m])) was calculated to determine excess adiposity (defined as FMI ≥75th centile). Anthropometrics (weight, height, mid upper arm circumference [MUAC] and triceps skin fold thickness [TSF]) were obtained and MUAC and TSF measurements were used to calculate arm fat area (AFA) and arm muscle area z-scores. Statistical analysis was applied as appropriate.

Results: Fifty-three (68% male; 55% Crohn disease [CD], 45% ulcerative colitis [UC], median [IQR] age 15 [13-16] years) children with IBD were included. Twenty-four percentage of children with IBD (21% CD, 29% UC) had excess adiposity. Four children (31%) with FMI ≥75th centile were not identified by body mass index (BMI) alone (kappa of 0.60), and 2 children (15%) were not identified by AFA z-score alone. The intra- and interobserver reliability of MUAC and TSFT measurements was excellent. There was no difference in Infliximab trough levels at the end of induction between those with FMI less than or ≥75th centile.

Conclusions: Excess adiposity affects approximately 1 in 4 young patients with IBD and can be missed by routine obesity screening. Our exploratory study did not raise concerns of underexposure to infliximab in those children with excess adiposity during early drug exposure.
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http://dx.doi.org/10.1097/MPG.0000000000002683DOI Listing
July 2020

Identifying Predictors of Response to Vitamin E for the Treatment of Pediatric Nonalcoholic Steatohepatitis.

JPEN J Parenter Enteral Nutr 2020 09 27;44(7):1301-1307. Epub 2020 Jan 27.

Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

Background: A subset of patients with nonalcoholic steatohepatitis (NASH) respond to treatment with vitamin E. The characteristics of responders are not known. The objective of this study was to investigate the outcomes of vitamin E use in clinical practice and to determine factors associated with response to treatment.

Methods: A pediatric cohort with NASH treated with vitamin E for 6-24 months was studied retrospectively. Vitamin E response was defined as alanine aminotransferase (ALT) normalization or >50% ALT reduction from baseline. Univariate and multivariate logistic regression was used to determine the predictors of response to vitamin E. Available paired liver biopsy data were analyzed to determine histologic response.

Results: Of the 151 children prescribed vitamin E, 73 met inclusion/exclusion criteria. Of those, 28 (38%) were vitamin E responders. Higher baseline serum alkaline phosphatase (ALP) levels, steatosis grade, and Nonalcoholic Fatty Liver Disease Activity Score (NAS) were associated with response to vitamin E (ALP: odds ratio [OR], 14.1; 95% CI, 1.7-118.6; steatosis: OR 2.5; 95% CI, 1.2-5.0; NAS: OR 1.6; 95% CI, 1.1-2.4). In a multivariate logistic regression model, ALP and steatosis grade rendered an area under the curve of 0.75 (P < .001) for the prediction of response to treatment. Ballooning, NAS, and portal inflammation improved significantly with vitamin E in the subcohort (n = 15) with paired liver biopsies.

Conclusions: Vitamin E treatment was associated with significant ALT response in 38% of children. Baseline serum ALP levels and steatosis grade were associated with response to treatment.
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http://dx.doi.org/10.1002/jpen.1766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590297PMC
September 2020

Methamphetamine-induced Acute Esophagitis in a 16-Year-old Girl.

J Pediatr Gastroenterol Nutr 2020 04;70(4):e86-e87

Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center.

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http://dx.doi.org/10.1097/MPG.0000000000002644DOI Listing
April 2020

Severe obesity is associated with liver disease severity in pediatric non-alcoholic fatty liver disease.

Pediatr Obes 2020 02 27;15(2):e12581. Epub 2019 Oct 27.

Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.

Background: Paediatric non-alcoholic fatty liver disease (NAFLD) is highly prevalent among children with obesity. The primary objective of this study was determining whether obesity severity is associated with NAFLD severity. By using paediatric classifications for severe obesity, clinicians may be able to better risk stratify patients, which in turn would guide more effective management and treatment.

Methods: Retrospective cohort study including patients followed at Cincinnati Children's Medical Center for NAFLD. Patients were categorized as overweight or class I, II, III obese based on established body mass index (BMI) cut-offs. Liver disease severity was determined using biochemical, imaging (magnetic resonance elastography [MRE]), and histologic evidence of liver injury.

Results: Three cohorts were studied individually based on the method used to assess disease severity (biochemical n = 767, imaging n = 366, and histology n = 249). Between the three cohorts, there were significant differences in age, proportion of patients with class II and class III obesity, and serum alanine transaminase (ALT) levels. In the biochemistry cohort, the odds of having ALT > 80 U/L were highest in patients with class III obesity (P = .026). In the imaging cohort, liver stiffness was significantly different between BMI groups of patients (P = .001). In the histology cohort, those with class III obesity had significantly higher odds of NAFLD activity score (NAS) ≥ 5 (P = .012).

Discussion: Obesity severity is associated with liver disease severity. Patients with more severe obesity are more likely to have more advanced liver disease, a finding that can assist in risk stratification, as well as monitoring and treatment approaches.
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http://dx.doi.org/10.1111/ijpo.12581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006543PMC
February 2020

Community Socioeconomic Deprivation and Nonalcoholic Fatty Liver Disease Severity.

J Pediatr Gastroenterol Nutr 2020 03;70(3):364-370

Division of Gastroenterology, Hepatology and Nutrition.

Background And Objectives: Nonalcoholic fatty liver disease (NAFLD) is linked to obesity. Obesity is associated with lower socioeconomic status (SES). An independent link between pediatric NAFLD and SES has not been elucidated. The objective of this study was to evaluate the distribution of socioeconomic deprivation, measured using an area-level proxy, in pediatric patients with known NAFLD and to determine whether deprivation is associated with liver disease severity.

Methods: Retrospective study of patients <21 years with NAFLD, followed from 2009 to 2018. The patients' addresses were mapped to census tracts, which were then linked to the community deprivation index (CDI; range 0--1, higher values indicating higher deprivation, calculated from six SES-related variables available publicly in US Census databases).

Results: Two cohorts were evaluated; 1 with MRI (magnetic resonance imaging) and/or MRE (magnetic resonance elastography) findings indicative of NAFLD (n = 334), and another with biopsy-confirmed NAFLD (n = 245). In the MRI and histology cohorts, the majority were boys (66%), non-Hispanic (77%-78%), severely obese (79%-80%), and publicly insured (55%-56%, respectively). The median CDI for both groups was 0.36 (range 0.15-0.85). In both cohorts, patients living above the median CDI were more likely to be younger at initial presentation, time of MRI, and time of liver biopsy. MRI-measured fat fraction and liver stiffness, as well as histologic characteristics were not different between the high- and low-deprivation groups.

Conclusions: Children with NAFLD were found across the spectrum of deprivation. Although children from more deprived neighborhoods present at a younger age, they exhibit the same degree of NAFLD severity as their peers from less deprived areas.
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http://dx.doi.org/10.1097/MPG.0000000000002527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054652PMC
March 2020

Vitamin D deficiency: prevalence and association with liver disease severity in pediatric nonalcoholic fatty liver disease.

Eur J Clin Nutr 2020 03 23;74(3):427-435. Epub 2019 Aug 23.

Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

Background/objectives: To determine associations between serum 25-hydroxyvitamin D (25(OH)-D) concentrations and histologic nonalcoholic fatty liver disease (NAFLD) severity.

Subjects/methods: Clinical, laboratory, and histology data were collected retrospectively in a pediatric cohort with biopsy-confirmed NAFLD. Serum 25(OH)-D concentrations were used to define vitamin D deficiency (≤20 ng/ml), insufficiency (21-30 ng/ml), and sufficiency (≥31 ng/ml).

Results: In all, 234 patients (78% non-Hispanic, median age 14 years) were included. The majority (n = 193) were either vitamin D insufficient (50%) or deficient (32%). Eighty-four patients (36%) reported taking vitamin D supplements at the time of biopsy; serum 25(OH)-D concentrations were not higher in those supplemented. There were no differences in the demographic, clinical, and laboratory characteristics of the three vitamin D status groups. Severity of steatosis, ballooning, lobular/portal inflammation, and NAFLD activity score were also not different between the groups. The proportion of patients with significant fibrosis (stage ≥ 2) was higher in those with insufficiency (29%) compared to those who were sufficient (17%) or deficient (15%, p = 0.04). After controlling for important covariates selected from age, body mass index, ethnicity, vitamin D supplementation, and season, the insufficient group had increased odds of a higher fibrosis score compared to the sufficient group (adjusted OR, 2.04; 95%CI, 1.02-4.08).

Conclusions: Vitamin D deficiency and insufficiency are common in children with NAFLD, but not consistently related with histologic disease severity. Prospective longitudinal studies are needed to determine optimal dosing strategies to achieve sufficiency and to determine whether adequate supplementation has an impact on histology.
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http://dx.doi.org/10.1038/s41430-019-0493-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006544PMC
March 2020

Nutrition Support of Children With Chronic Liver Diseases: A Joint Position Paper of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition.

J Pediatr Gastroenterol Nutr 2019 10;69(4):498-511

Children's Hospital of Colorado, University of Colorado School of Medicine, Aurora, CO.

Chronic liver disease places patients at increased risk of malnutrition that can be challenging to identify clinically and treat. Nutrition support is a key aspect of the management of these patients as it has an impact on their quality of life, morbidity, and mortality. There are significant gaps in the literature regarding the optimal nutrition support for patients with different types of liver diseases and the impact of these interventions on long-term outcomes. This Position Paper summarizes the available literature on the nutritional aspects of the care of patients with chronic liver diseases. Specifically, the challenges associated with the nutritional assessment of these subjects are discussed, and recently investigated approaches to determining the patients' nutritional status are reviewed. Furthermore, the pathophysiology of the malnutrition seen in the context of chronic liver disease is summarized and monitoring, as well as treatment, recommendations are provided. Lastly, suggestions for future research studies are described.
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http://dx.doi.org/10.1097/MPG.0000000000002443DOI Listing
October 2019

Relationship between abdominal fat stores and liver fat, pancreatic fat, and metabolic comorbidities in a pediatric population with non-alcoholic fatty liver disease.

Abdom Radiol (NY) 2019 09;44(9):3107-3114

Department of Radiology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 5031, Cincinnati, OH, 45229, USA.

Purpose: To define the relationship between compartmental abdominal fat stores, liver and pancreatic fat fractions, and type 2 diabetes mellitus (T2DM) in children with non-alcoholic fatty liver disease (NAFLD).

Methods: This was a retrospective study of patients with NAFLD who underwent abdominal MRI between August 2015 and July 2017. Using an axial multi-echo Dixon-based sequence, liver fat fraction (LFF) and pancreatic fat fraction (PFF) were measured. The fat image was used to quantify abdominal fat depots (thickness, cross-sectional area) at the L2 vertebral level. Multivariable models with stepwise selection were created for prediction of LFF, PFF, and T2DM status based upon variables of clinical interest.

Results: 86 patients (70% male, 25% Hispanic, 58% Caucasian, 11% African American) with a mean age of 14.2 ± 3.2 years were included. 19 (22%) patients were pre-diabetic or diabetic. Only ethnicity was a predictor of LFF (P = 0.0023) with Hispanic ethnicity associated with the highest LFF. Depending on the model, either total abdominal fat area (P = 0.0003) or patient weight (P = 0.008) were the only predictors of PFF. No patient variable predicted T2DM status.

Conclusions: In our population, there was an association between ethnicity and LFF, with the highest LFF in Hispanics. The presence or severity of hepatic steatosis could not be predicted based on patient size or the distribution of abdominal fat in our cohort. Neither LFF nor PFF were predictive of T2DM.
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http://dx.doi.org/10.1007/s00261-019-02123-yDOI Listing
September 2019

Insights into the evolving role of the gut microbiome in nonalcoholic fatty liver disease: rationale and prospects for therapeutic intervention.

Therap Adv Gastroenterol 2019 23;12:1756284819858470. Epub 2019 Jun 23.

NAFLD Research Center, Division of Gastroenterology, Department of Medicine, University of California at San Diego, ACTRI Building, 1W202, 9452 Medical Center Drive, La Jolla, CA 92037, USA.

Nonalcoholic fatty liver disease (NAFLD) is diagnosed across the age spectrum and contributes to significant morbidity and mortality. The pathophysiology of NAFLD is not entirely understood; however, recent evidence has implicated the intestinal microbiome. Through the effects on host appetite, energy expenditure, digestion, gene expression, intestinal permeability, as well as immune activation, a dysbiotic microbiome can contribute to the development and progression of the hepatocellular steatosis, inflammation and fibrosis seen in the context of NAFLD. As such, intestinal microbiota and products of their metabolism have been targeted as treatment approaches for NAFLD.
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http://dx.doi.org/10.1177/1756284819858470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591661PMC
June 2019

Psychotropic Medications Are Associated With Increased Liver Disease Severity in Pediatric Nonalcoholic Fatty Liver Disease.

J Pediatr Gastroenterol Nutr 2019 09;69(3):339-343

Division of Gastroenterology, Hepatology and Nutrition.

Objectives: The aim of the study was to determine whether pediatric patients with nonalcoholic fatty liver disease (NAFLD) exposed to psychotropic medications have more severe liver disease compared to their counterparts who are not on these medications. We hypothesize that use of psychotropic agents is associated with liver disease severity.

Methods: Children and adolescents with biopsy-confirmed NAFLD were included in this study. Histology data, detailed clinical information, and results of serum biochemistries performed within 3 months of the liver biopsy were collected retrospectively. Univariate and multivariate modeling was used to determine differences between the groups and to control for confounders.

Results: A total of 228 patients were included, 17 (8%) of whom where on psychotropic medications at the time of the liver biopsy. Patients on psychotropic medications were more likely to also be on metformin (53% vs 18%, P < 0.01) and antihypertensive medications (29% vs 8%, P < 0.01) compared to children with NAFLD who were not on psychotropic agents. There were no differences in regards to biochemical evidence of liver injury, insulin resistance, and dyslipidemia between the groups. On histology, however, the use of psychotropic medications was associated with increased steatosis severity (score 2.4 vs 1.9, P = 0.04) and increased likelihood of having an NAFLD Activity Score ≥5 (seen in 59% vs 35% or patients; P = 0.05, respectively).

Conclusions: In this large cohort of children with biopsy-confirmed NAFLD, the use of psychotropic medications was associated with increased liver disease severity. Exposure to psychotropic agents should be considered when risk stratifying children with NAFLD.
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http://dx.doi.org/10.1097/MPG.0000000000002401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8525622PMC
September 2019

Virtual Reality: New Insights Regarding the Prevalence of Nonalcoholic Fatty Liver Disease in Children and Adolescents with Obesity Using Magnetic Resonance Imaging.

J Pediatr 2019 04;207:8-10

Department of Radiology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio.

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http://dx.doi.org/10.1016/j.jpeds.2018.12.025DOI Listing
April 2019

Extremely low levels of low-density lipoprotein potentially suggestive of familial hypobetalipoproteinemia: A separate phenotype of NAFLD?

J Clin Lipidol 2019 May - Jun;13(3):425-431. Epub 2019 Feb 14.

Division of Gastroenterology, Hepatology and Nutrition, University of Cincinnati School of Medicine, Cincinnati, OH, USA.

Background: Low-density lipoprotein cholesterol (LDL-C) levels below 50 mg/dL may suggest familial hypobetalipoproteinemia, particularly in patients with hepatic steatosis. The prevalence of hypobetalipoproteinemia in cohorts with nonalcoholic fatty liver disease (NAFLD) is not known, and it is not clear whether the severity of liver disease of these patients is different. The objective of this study was to address these questions in a large pediatric NAFLD cohort.

Methods: Retrospective study of children followed at the Steatohepatitis Center of a tertiary care center from August 2010 to October 2017. Patients with secondary causes of hepatic steatosis and those on statins were excluded.

Results: Of the 740 patients included, 58 (8%) had hypobetalipoproteinemia. These patients were younger (P = .04), had a lower body mass index (P < .01) and waist circumference (P = .01), and were less likely to be on metformin (P = .01). In spite of that, serum aminotransferase levels were not different between those with low, normal, and high LDL-C levels. Of the 222 patients who had both lipid and histology data available, the steatosis score was higher in those with low LDL-C compared to those with normal or elevated LDL-C, a result that trended toward significance (P = .06). The severity of inflammation and fibrosis did not differ between the groups. When all patients with hypertriglyceridemia were excluded, steatosis severity was higher in those with low LDL-C (P = .04).

Conclusion: Hypobetalipoproteinemia is common among patients with NAFLD and is associated with similar liver disease severity in spite of a leaner phenotype and a more favorable metabolic profile.
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http://dx.doi.org/10.1016/j.jacl.2019.02.002DOI Listing
May 2020

Omega-3 for nonalcoholic fatty liver disease in children.

Can Fam Physician 2019 01;65(1):34-38

An overweight 12-year-old male patient with nonalcoholic fatty liver disease has had little improvement in liver steatosis or triglyceride levels over the past 2 years. Is omega-3 supplementation useful in managing his condition? Nonalcoholic fatty liver disease in children is prevalent in the Canadian population and can lead to liver fibrosis, cirrhosis, transplant, and reduced life expectancy. There is no recommended pharmacologic treatment of nonalcoholic fatty liver disease. Omega-3 fatty acids are associated with small improvements in liver steatosis and triglyceride concentrations. There are conflicting results with regard to liver function test results and insulin resistance, and while there might be histologic improvement revealed on biopsy, there is little evidence that fibrosis is improved. In children who have struggled to be consistent with the changes needed in their diet, particularly those with elevated triglyceride levels, there might be a role for omega-3 supplementation while continuing to focus on the mainstays of treatment (diet and physical activity); however, further research is still needed.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347303PMC
January 2019

Successful Management of Ketogenic Parenteral Nutrition: A Pediatric Case Study.

JPEN J Parenter Enteral Nutr 2019 08 20;43(6):815-818. Epub 2018 Dec 20.

Division of Neurology, The Hospital for Sick Children, Toronto, Ontario, Canada.

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http://dx.doi.org/10.1002/jpen.1490DOI Listing
August 2019
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