Intensive lifestyle treatment for non-alcoholic fatty liver disease in children with severe obesity: inpatient versus ambulatory treatment.

BACKGROUND/AIMS: Lifestyle intervention is the only established therapy for non-alcoholic fatty liver disease (NAFLD). The optimal treatment schedule and predictors of response of this treatment have not been established in children. We aimed to evaluate the 2-year efficacy of an inpatient versus ambulatory intensive lifestyle intervention for treating NAFLD in children with severe obesity. METHODS: A cohort study of 51 severely obese non-diabetic children (mean age 14.7 (±2.4) years; BMI-z-score 3.5 (±0.5)) with liver steatosis were non-randomly allocated to inpatient treatment (2 or 6 months), ambulatory treatment or usual care. Proton Magnetic Resonance Spectroscopy determined liver steatosis and serum alanine aminotransferase (ALT) at 6 months were the primary outcome measures. Baseline variables were evaluated as predictors of treatment response. RESULTS: Liver steatosis had disappeared in 43, 29 and 22% and serum ALT normalized in 41, 33 and 6% at the end of 6 months in the inpatient, ambulatory or usual care treatment groups, respectively. Only the proportions of ALT normalization in inpatient and ambulatory treatment compared with usual care were significantly higher. Treatment effects of inpatient and ambulatory treatment were sustained at 1.5 years follow-up. No baseline characteristic, including PNPLA3 polymorphism or leptin, was consistently predictive for treatment response. CONCLUSIONS: A 6-month intensive inpatient and ambulatory lifestyle treatment in children with severe obesity reverses NAFLD in a minority of patients. This study suggests that inpatient compared with ambulatory intensive treatment does not importantly increase treatment success. Further efforts to optimize and individualize lifestyle interventions and additional treatments options are needed particular for children with severe obesity resistant to conventional lifestyle interventions.

Gallstone disease in severely obese children participating in a lifestyle intervention program: incidence and risk factors.

INTRODUCTION: Cholelithiasis is increasingly encountered in childhood and adolescence due to the rise in obesity. As in adults, weight loss is presumed to be an important risk factor for cholelithiasis in children, but this has not been studied. METHODS: In a prospective observational cohort study we evaluated the presence of gallstones in 288 severely obese children and adolescents (mean age 14.1±2.4 years, body mass index (BMI) z-score 3.39±0.37) before and after participating in a 6-month lifestyle intervention program. RESULTS: During the lifestyle intervention, 17/288 children (5.9%) developed gallstones. Gallstones were only observed in those losing >10% of initial body weight and the prevalence was highest in those losing >25% of weight. In multivariate analysis change in BMI z-score (odds ratio (OR) 3.26 (per 0.5 s.d. decrease); 95% CI:1.60-6.65) and baseline BMI z-score (OR 2.32 (per 0.5 s.d.); 95% CI: 1.16-4.70) were independently correlated with the development of gallstones. Sex, family history, OAC use, puberty and biochemistry were not predictive in this cohort. During post-treatment follow-up (range 0.4-7.8 years) cholecystectomy was performed in 22% of those with cholelithiasis. No serious complications due to gallstones occurred. CONCLUSION: The risk of developing gallstones in obese children and adolescents during a lifestyle intervention is limited and mainly related to the degree of weight loss and initial body weight.

Oral vancomycin is associated with improved inflammatory bowel disease clinical outcomes in primary sclerosing cholangitis-associated inflammatory bowel disease (PSC-IBD): A matched analysis from the Paediatric PSC Consortium.

BACKGROUND: Data on oral vancomycin for primary sclerosing cholangitis (PSC)-associated inflammatory bowel disease (IBD) are limited. AIMS: Using data from the Paediatric PSC Consortium, to examine the effect of vancomycin on IBD activity. METHODS: In this retrospective multi-centre cohort study, we matched vancomycin-treated and untreated patients (1:3) based on IBD duration at the time of primary outcome assessment. The primary outcome was Physician Global Assessment (PGA) of IBD clinical activity after 1 year (±6 months) of vancomycin. We used generalised estimating equations (GEE) to examine the association between vancomycin and PGA remission, adjusting for IBD type, severity and medication exposures. Secondary outcomes included serum labs and endoscopic remission (global rating of no activity) among those with available data and also analysed with GEE. RESULTS: 113 PSC-IBD patients received vancomycin (median age 12.7 years, 63% male). The matched cohort included 70 vancomycin-treated and 210 untreated patients. Vancomycin was associated with greater odds of IBD clinical remission (odds ratio [OR] 3.52, 95% CI 1.97-6.31; adjusted OR [aOR] 5.24, 95% CI 2.68-10.22). Benefit was maintained in sensitivity analyses restricted to non-transplanted patients and those with baseline moderate-severe PGA. Vancomycin was associated with increased odds of endoscopic remission (aOR 2.76, 95% CI 1.002-7.62; N = 101 with data), and with lower CRP (p = 0.03) and higher haemoglobin and albumin (both p < 0.01). CONCLUSION: Vancomycin was associated with greater odds of IBD clinical and endoscopic remission. Additional, preferably randomised, controlled studies are needed to characterise efficacy using objective markers of mucosal inflammation, and to examine safety and define optimal dosing.

A high rate of post thrombotic complication in pediatric portal vein thrombosis.

INTRODUCTION: Portal vein thrombosis (PVT) is a rare disease in children and may be complicated by portal hypertension (PH), hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PPHTN) but their incidence and risk factors are unknown. METHODS: An observational, retrospective cohort study of all consecutive children (≤18 years) with PVT treated at the Emma Children's Hospital Amsterdam University Medical Centers between January 1996 and January 2022 was conducted to identify the incidence and risk factors of these post thrombotic complications (PTC) in pediatric patients. RESULTS: In total 43/ 703 thrombosis patients had PVT (boys 72.1 %; mean age 1.3 ± 0.5 years). Overall, 51 % of patients developed PH (n = 22), complicated by PPHTN in one of them. In 16 of 22 patients, PVT presented with portal hypertension. Clinically relevant bleeding due to portal hypertension occurred in 13 (59.1 %) patients with PH. The mean age at the first clinically relevant bleeding was 5.1 ± 5.9 years. Risk factors for the development of PH were lack of complete thrombus resolution (OR 24.3, 95 % CI 1.2-7.0; p = 0.008) and unprovoked VTE (OR, 35.4; 95 % CI 1.4-6.3; p = 0.012). Median time from PVT to PH was 137 days (range: 0 days to 5.04 years). CONCLUSION: We demonstrated that half of the patients develop PH after PVT, with a lack of thrombus resolution and unprovoked VTE as independent risk factors. This high incidence underlines the importance of long-term standardized follow-up of patients after PVT and standard screening in patients at risk of PTC.

[Non-alcoholic fatty liver disease; a full-bodied epidemic]. / Niet-alcoholische leververvetting.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of fatty liver disease. NAFLD is defined as the presence of fatty liver disease observed in imaging or histopathological examinations when there is no secondary cause such as excessive alcohol use or use of certain medications. NAFLD encompasses a whole spectrum, from simple steatosis to steatohepatitis ('non-alcoholic steatohepatitis', NASH), fibrosis and - ultimately - cirrhosis and hepatocellular carcinoma. Several factors play a role in the complex pathogenesis of NAFLD such as genetic predisposition, overweight, insulin resistance, inflammation, bile salts, gut microbiome and nutrition. Patients with NAFLD have an increased risk of developing type 2 diabetes mellitus, cardiovascular disease and malignancies such as hepatocellular carcinoma. To date, no medicines have been authorised for the treatment of NAFLD. The cornerstone of NAFLD treatment is lifestyle adjustment aimed at weight reduction.

Cirrhosis associated with decreased survival and a 10-year lower median age at death of cystic fibrosis patients in the Netherlands.

BACKGROUND: Up to 10% of patients with Cystic Fibrosis develop cirrhotic CF-related liver disease with portal hypertension: CF cirrhosis (CFC). In a nationwide study, we aimed to determine the role of CFC on survival in the Netherlands between 1 and 1-2009 and1-1-2015. METHODS: We identified all CFC patients in the Netherlands, based on ultrasonographic liver nodularity and portal hypertension. A non-cirrhotic control group was obtained from the national Dutch CF patient registry. We compared groups with regards to baseline lung function and nutritional status and survival and age at death over a 6-year period. In case of death of CFC patients, the clinical reported cause was recorded. RESULTS: At baseline, we found no significant difference in lung function and nutritional status between the CFC patients (N = 95) and controls (N = 980). Both the 6-year survival rate (77 vs. 93%; P < .01) and the median age at death (27 vs. 37 years; P = .02) was significantly lower in CFC compared to controls. In the deceased CFC patients, the reported primary cause of death was pulmonary in 68% of cases, and liver failure related in 18% of cases. CONCLUSIONS: In the Netherlands, the presence of CFC is associated with a higher risk for early mortality and an approximately 10-year lower median age at death. This substantial poorer outcome of CFC patients was not reflected in a lower baseline lung function or a diminished nutritional status. However, in the case of mortality, the reported primary cause of death in CFC patients is predominantly pulmonary failure and not end-stage liver disease.

Screening for non-alcoholic fatty liver disease in children: do guidelines provide enough guidance?

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the industrialized world in children. Its high prevalence and important health risks make NAFLD highly suitable for screening. In practice, screening is widely, albeit not consistently, performed. AIM: To review the recommendations on screening for NAFLD in children. METHOD: Recommendations on screening were reviewed from major paediatric obesity guidelines and NAFLD guidelines. A literature overview is provided on open questions and controversies. RESULTS: Screening for NAFLD is advocated in all obesity and most NAFLD guidelines. Guidelines are not uniform in whom to screen, and most guidelines do not specify how screening should be performed in practice. Screening for NAFLD remains controversial, due to lack of a highly accurate screening tool, limited knowledge to predict the natural course of NAFLD and limited data on its cost effectiveness. CONCLUSIONS: Guidelines provide little guidance on how screening should be performed. Screening for NAFLD remains controversial because not all conditions for screening are fully met. Consensus is needed on the optimal use of currently available screening tools. Research should focus on new accurate screening tool, the natural history of NAFLD and the cost effectiveness of different screening strategies in children.

Raised faecal calprotectin is associated with subsequent symptomatic relapse, in children and adolescents with inflammatory bowel disease in clinical remission.

BACKGROUND: Reliable data on inflammatory biomarkers for predicting relapse of paediatric inflammatory bowel disease (IBD) are lacking. AIM: To investigate the predictive value of faecal calprotectin (FC) and CRP for symptomatic relapse in pediatric IBD in clinical remission. METHODS: In this cross-sectional cohort study, patients <18 years with Crohn's disease or ulcerative colitis in clinical remission ≥3 months were included. At baseline, clinical and biochemical disease activity were assessed using the abbreviated-Pediatric Crohn's Disease Activity Index or Pediatric Ulcerative Colitis Activity Index, and FC and CRP respectively. Disease course over the subsequent 12 months was retrospectively assessed. RESULTS: In total, 114 patients (56% males; median age 14.9 years) were included. Baseline FC was higher in patients that developed symptomatic relapse [median (IQR), relapse 370 µg/g (86-1100) vs. remission 122 µg/g (40-344), P = 0.003]. Baseline FC was predictive of symptomatic relapse within 6 months [HR per 250 µg/g (95% CI): 1.46 (1.21-1.77), P < 0.001], with good predictive accuracy (AUC: 0.82). Optimal FC cut-off was 350 µg/g, with positive and negative predictive value of 41% and 96%. Baseline CRP was higher in patients that developed symptomatic relapse [median (IQR), relapse 1.0 µg/g (0.6-5.0) vs. remission 1.0 µg/g (0.4-2.0), P = 0.033]. Baseline CRP was predictive of symptomatic relapse within 6 months from baseline [HR per 1 mg/L (95% CI): 1.10 (1.02-1.19), P = 0.011], with fair predictive accuracy (AUC: 0.72). Optimal CRP cut-off was 1.0 mg/L, with positive and negative predictive value of 21% and 94%. CONCLUSIONS: Faecal calprotectin and CRP are predictive of symptomatic relapse and may be valuable in management of paediatric IBD in clinical remission.

The prevalence of irritable bowel syndrome-type symptoms in paediatric inflammatory bowel disease, and the relationship with biochemical markers of disease activity.

BACKGROUND: A large proportion (25-46%) of adults with inflammatory bowel disease in remission has symptoms of irritable bowel syndrome (IBS), which are thought to reflect ongoing inflammation. Data on paediatric inflammatory bowel disease patients are lacking. AIM: To investigate (i) the prevalence of IBS-type symptoms in paediatric inflammatory bowel disease patients in remission and (ii) the relationship of IBS-type symptoms with biochemical markers of disease activity. METHODS: This cross-sectional study included all patients (<18 years) with Crohn's disease or ulcerative colitis attending the out-patient clinic of one of three Dutch hospitals between March 2014 and June 2015. Clinical disease activity was determined using the abbreviated-PCDAI or PUCAI. Biochemical disease activity was assessed using faecal calprotectin and serum CRP. IBS-symptoms were assessed using physician-administered Rome III-questionnaires. RESULTS: We included 184 patients (92 female; mean age: 14.5 years) (Crohn's disease: 123, ulcerative colitis: 61). The prevalence of IBS-type symptoms in children with inflammatory bowel disease in clinical remission was 6.4% (95% CI: 2.5-11.1%; Crohn's disease: 4.5%; ulcerative colitis: 10.8%). Prevalence of IBS-type symptoms in children with faecal calprotectin <250 µg/g was 16.1% (95% CI: 7.6-25.8%; Crohn's disease: 16.7%; ulcerative colitis: 10.8%). No difference in faecal calprotectin or CRP was found between patients in clinical remission with or without IBS-type symptoms (faecal calprotectin: IBS+ median 58 µg/g, IBS- 221 µg/g, P = 0.12; CRP: IBS+ median 1.4 mg/L, IBS- 1.1 mg/L, P = 0.63). CONCLUSIONS: The prevalence of IBS-type symptoms in children with inflammatory bowel disease is highly dependent on the definition of remission. Nonetheless, the prevalence is much lower than that previously reported in studies in adult inflammatory bowel disease patients. IBS-type symptoms appear to be unrelated to gastrointestinal inflammation.

[The treatment of chronic hepatitis C virus infection in children]. / De behandeling van kinderen met chronische hepatitis C.

A 9-year-old boy, a 15-year-old boy, and a 6-year-old girl were infected with chronic hepatitis C virus (HCV). They had no physical complaints and a virus genotype that was favourable to treatment with peginterferon-alpha and ribavirin. The younger boy and the girl had liver fibrosis and were treated for 6 months; the virus was eradicated from the boy's plasma and the fibrosis diminished, while the girl's plasma virus was again present shortly after the end of treatment. In the older boy with no fibrosis, treatment was temporarily suspended due to behaviour problems. HCV infection is a frequent cause of chronic hepatitis in children. A better understanding of its natural history, improvements in the efficacy of treatment, and more favourable outcomes seen in children compared with adults have gradually changed the consideration to treat children with chronic HCV infection over the last 10 years. The decision whether or not to treat depends primarily on the degree of liver damage, virus genotype, and the psychological condition and motivation of the patient. Screening patients at risk for chronic HCV infection and careful follow-up for liver damage in those with HCV infection have become even more important given the new insights regarding treatment.

Ultrasonography is not more reliable than anthropometry for assessing visceral fat in obese children.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Visceral fat accumulation is a risk factor for obesity-related complications. Waist circumference is used in clinical practice to assess visceral adiposity. WHAT THIS STUDY ADDS: Ultrasound is not superior to waist circumference for assessing visceral obesity in obese children. The optimal site for measuring waist circumference in obese children is at the smallest body circumference between xiphisternum and umbilicus. OBJECTIVE: Visceral fat accumulation is a well-established risk factor for obesity-related complications. In children, it has not been determined whether ultrasonography is superior to waist measurement for assessing visceral fat. Moreover, the optimal site for waist measurement has not been determined. DESIGN: In a prospective cohort of 92 severely obese children and adolescents (age 13.9 ± 2.2 years, body mass index z-score 3.29 ± 0.33), we evaluated the performance of ultrasonography and two different methods of waist circumference measurement, using magnetic resonance imaging as the reference standard. RESULTS: Waist circumference, defined as the smallest body circumference between xiphisternum and umbilicus had the strongest correlation with visceral fat quantity (r = 0.69 all, r = 0.68 girls, r = 0.64 boys). It was not outperformed by ultrasonography (r = 0.60 all, r = 0.62 girls, r = 0.50 boys) and correlated significantly better than the World Health Organization standard for waist measurement, midway between lower margin of the last rib and the crest of the ilium, (r = 0.51 all, r = 0.39 girls, r = 0.46 boys). CONCLUSIONS: Waist circumference measurement, defined as the smallest body circumference between xiphisternum and umbilicus, is the preferred non-invasive technique for daily clinical practice to assess visceral fat accumulation in severely obese children and adolescents. There is no place for ultrasonography for the quantification of visceral fat in this group.