The natural history of cystic fibrosis liver disease a prospective cohort study.

BACKGROUND: Our understanding of the natural history of cystic fibrosis liver disease (CFLD) is limited, leading to uncertainty for patients their families and clinicians when liver abnormalities are identified. AIM: to determine the incidence of CFLD, identify risk factors and document the natural history of liver abnormalities in cystic fibrosis (CF). METHODS: The Irish longitudinal study of CFLD (ILSCFLD) prospectively enrolled 95% of children with CF in 2007. Their liver disease status was classified as (i) advanced liver disease with portal hypertension (CFLD). (ii) nonspecific cystic fibrosis liver disease (NSCFLD) (iii) no liver disease (NoLD) RESULTS: 480/522 (91.9%) children were followed for a median 8.53 years IQR 1.28, of whom 35 (7.29%) had CFLD, 110 (22.9%) NSCFLD and 335 (69.79%) had NoLD. At follow-up 28/445 (6.29%) participants without CFLD at baseline, progressed to CFLD (Incidence 7.51/1000 person years (Pyrs) (95%CI 4.99-10.86). Of these 25/28(89.28%) were <10 years. No participant >10 years of age without clinical or radiological evidence of liver disease at baseline progressed to CFLD. During follow-up 18/35(51.43%) participants with CFLD died or received a transplant, MTx rate 7.75/100 Pyrs (95%CI 4.59-12.25) compared to NSCFLD 2.33/100 Pyrs (95%CI 1.44-3.56) and NoLD 1.13/100 Pyrs (95%CI 0.77-1.59). CFLD was an independent risk factor for mortality in CF. Children with CFLD also had a shorter life expectancy. CONCLUSION: The incidence of CFLD was highest in children under10 years. Children over10 years, with normal hepatic function did not develop CFLD. Research to identify the cause and improve outcome should focus on young children.

The impact of liver disease on mortality in cystic fibrosis-A systematic review.

BACKGROUND: There is conflicting evidence on the impact of liver disease (CFLD) on life expectancy in CF. Therefore the aim of this systematic review was to evaluate the impact of liver disease (CFLD) on mortality in CF. METHODS: The protocol was published at (https://hrbopenresearch.org/articles/3-44/v3) using PRISPMA-P guidelines and registered in Prospero 2020 (CRD42020182885). Three databases were searched for publications (1938-2020) where the outcome was all-cause mortality (defined as death and transplantation) or CF-specific mortality in participants with CFLD. Studies with and without a comparator group were included. Studies were divided into 2 groups based on the definition of CFLD: Group 1 used 2 categories of liver disease (i) liver disease with portal hypertension (PH) (ii) non-specific abnormalities which did not meet the criteria for PH, Group 2 studies only included participants with PH. RESULTS: All 14 eligible studies were observational, with a moderate-high risk of bias, Six of the 14 studies directly compared mortality between those with CFLD and those with no liver disease, and 5/6 demonstrated that those with CFLD had at least 3 time the risk of death compared to those with no liver disease. Pulmonary complications were the primary cause of death. CONCLUSION: This SR demonstrates that liver disease shortens life expectancy in CF, and that pulmonary complications are the primary cause of death in those with CFLD. There has been no improvement in survival for persons with CFLD despite significant improvements in life expectancy for persons with CF who have no evidence of liver disease.

Emerging clinical perspectives in cystic fibrosis liver disease.

PURPOSE OF REVIEW: Liver disease (CFLD) as a complication of cystic fibrosis is recognized as a more severe disease phenotype in both children and adults. We review recent advances in understanding the disease mechanism and consider the implications of new strategies for the diagnosis and management of cystic fibrosis in those with evidence of clinically significant liver disease. RECENT FINDINGS: Evidence suggests that the prevalence of CFLD has not declined with the introduction of newborn screening. Furthermore, children with CFLD, who have been diagnosed with cystic fibrosis following newborn screening continue to have a much higher mortality rate compared with those with no liver disease. There is further data suggesting noncirrhotic obliterative portal venopathy as the predominant pathological mechanism in the majority of children and young adults receiving a liver transplantation. Little progress has been made in developing an accurate noninvasive test for early diagnosis or monitoring disease progression in CFLD. The benefit of new modulator therapies is not well understood in those with established CFLD, whereas the risk of hepatotoxicity as a complication of treatment must be carefully monitored. SUMMARY: Better understanding of the pathophysiology of CFLD would allow a standardized approach to diagnosis, with the potential to improve outcomes for those with CFLD.

Normal liver stiffness and influencing factors in healthy children: An individual participant data meta-analysis.

BACKGROUND & AIMS: Although transient elastography (TE) is used to determine liver stiffness as a surrogate to hepatic fibrosis, the normal range in children is not well defined. We performed a systematic review and individual participant data (IPD) meta-analysis to determine the range of liver stiffness in healthy children and evaluate the influence of important biological parameters. METHODS: We pooled data from 10 studies that examined healthy children using TE. We divided 1702 children into two groups: ≥3 years (older group) and < 3 years of age (younger group). Univariate and multivariate linear regression models predicting liver stiffness were conducted. RESULTS: After excluding children with obesity, diabetes, or abnormal liver tests, 652 children were analysed. Among older children, mean liver stiffness was 4.45 kPa (95% confidence interval 4.34-4.56), and increased liver stiffness was associated with age, sedation status, and S probe use. In the younger group, the mean liver stiffness was 4.79 kPa (95% confidence interval 4.46-5.12), and increased liver stiffness was associated with sedation status and Caucasian race. In a subgroup analysis, hepatic steatosis on ultrasound was significantly associated with increased liver stiffness. We define a reference range for normal liver stiffness in healthy children as 2.45-5.56 kPa. CONCLUSIONS: We have established TE-derived liver stiffness ranges for healthy children and propose an upper limit of liver stiffness in healthy children to be 5.56 kPa. We have identified increasing age, use of sedation, probe size, and presence of steatosis on ultrasound as factors that can significantly increase liver stiffness.

Repeatability of transient elastography in children.

BACKGROUND: Poorly performing diagnostic tests can impact patient safety. Clinical investigations must have good precision and diagnostic accuracy before widespread use in clinical practice. Transient elastography (TE) measures liver stiffness, a surrogate marker of liver fibrosis in adults and children. Studies to evaluate its repeatability and reproducibility (precision) in children are limited. Our aim was to determine (i) the normal range of TE measurements and (ii) the repeatability and reproducibility of TE in healthy children. METHODS: TE was performed in 257 healthy children, of whom 235 (91%, mean age 11.7 years, standard deviation (SD) 2.51, 107 were males (45.5%)) had two valid TE measurements performed, at least 24 h apart, by two operators under similar circumstances. High-quality TE images were obtained for each examination. RESULTS: The normal range of TE was 2.88-6.52 kPa. The mean difference between paired measurements was 0.044 (SD 0.4). The 95% limits of agreement ranged from -0.8 to +0.76 kPa for repeat measurements. There was a difference of >1 kPa between measurements in 61/235 (25.9%) children. The lack of precision was similar across all age groups. CONCLUSIONS: This study demonstrates that TE does not have acceptable precision in healthy children, because random measurement variation results in the lack of agreement between paired measurements. IMPACT: The precision and diagnostic accuracy of a new technology must be determined before it is deployed in children in order to ensure that appropriate clinical decisions are made, and healthcare resources are not wasted. TE is widely used to diagnose liver disease in children without adequate evaluation of the precision (repeatability) of TE either in healthy children or children with liver disease. This study demonstrates that TE does not have adequate precision in children. This study was performed in accordance with methods previously published for children. Refinements to the test protocol, such as duration of fasting or probe size, will have to be evaluated for their impact on precision and accuracy before the test is deployed in research studies or clinical practice.

The impact of liver disease on mortality in cystic fibrosis - a systematic review protocol.

Background Cystic fibrosis (CF) is a multiorgan disease affecting the lungs pancreas and gastrointestinal tract. Pulmonary complications are the most common manifestation of the disease. Recent advances in the treatment of pulmonary complications have resulted in substantial improvement in life expectancy. Less than 10% of persons with CF (PWCF) develop liver disease (CFLD). There is conflicting evidence about impact of liver disease on mortality in CF, with evidence suggesting that CFLD contributes to increased mortality in CF, while other studies suggest that the impact on mortality is limited. Understanding the contribution of liver disease to mortality in CF is essential if further improvements in life expectancy are to be achieved. Objective: To document the impact of liver disease on life expectancy for PWCF. Methods: This systematic review will be conducted in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P 2015). PubMed, Medline and Embase will be searched for English language publications (1949-2020). Studies reporting the outcome for CFLD will be included where the definition of CFLD is outlined clearly in a CF population. Studies with and without a comparator will be evaluated. Clinical trials of ursodeoxycholic acid will be excluded as well as organ transplantation outcome studies. We will examine all-cause and specific causes of mortality.We will include transplantation in our estimates of all-cause mortality. The Axis Risk of Bias Tool for Observational Studies will be used to evaluate the quality of studies. We will provide a narrative synthesis of our findings using tabular formats to highlight any impact of liver disease on mortality in CF. Conclusion: It is anticipated that this review will bring clarity to the question of whether CFLD shortens life expectancy in PWCF and stimulate new approaches to the management of CFLD.

The Role of Host Genetic Polymorphisms in Helicobacter pylori Mediated Disease Outcome.

The clinical outcome of infection with the chronic gastric pathogen Helicobacter pylori is not the same for all individuals and also differs in different ethnic groups. Infection occurs in early life (<3 years of age), and while all infected persons mount an immune response and develop gastritis, the majority of individuals are asymptomatic. However, up to 10-15% develop duodenal ulceration, up to 1% develop gastric cancer (GC) and up to 0.1% can develop gastric mucosa-associated lymphoid tissue (MALT) lymphoma. The initial immune response fails to clear infection and H. pylori can persist for decades. H. pylori has been classified as a group one carcinogen by the WHO. Interestingly, development of duodenal ulceration protects against GC. Factors that determine the outcome of infection include the genotype of the infecting strains and the environment. Host genetic polymorphisms have also been identified as factors that play a role in mediating the clinical outcome of infection. Several studies present compelling evidence that polymorphisms in genes involved in the immune response such as pro and anti-inflammatory cytokines and pathogen recognition receptors (PRRs) play a role in modulating disease outcome. However, as the number of studies grows emerging confounding factors are small sample size and lack of appropriate controls, lack of consideration of environmental and bacterial factors and ethnicity of the population. This chapter is a review of current evidence that host genetic polymorphisms play a role in mediating persistent H. pylori infection and the consequences of the subsequent inflammatory response.

The use of stool specimens reveals Helicobacter pylori strain diversity in a cohort of adolescents and their family members in a developed country.

Helicobacter pylori infection occurs within families but the transmission route is unknown. The use of stool specimens to genotype strains facilitates inclusion of complete families in transmission studies. Therefore, we aimed to use DNA from stools to analyze strain diversity in H. pylori infected families. We genotyped H. pylori strains using specific biprobe qPCR analysis of glmM, recA and hspA. Concentration of H. pylori organisms before DNA isolation enhanced subsequent DNA amplification. We isolated H. pylori DNA from 50 individuals in 13 families. Tm data for at least 2 of the 3 genes and sequencing of the glmM amplicon were analyzed. Similar strains were commonly found in both mothers and children and in siblings. However, 20/50 (40%) individuals had multiple strains and several individuals harbored strains not found in other family members, suggesting that even in developed countries sources of infection outside of the immediate family may exist. Whether infection occurs multiple times or one transmission event with several strains occurs is not known but future studies should aim to analyze strains from children much closer to infection onset. The presence of multiple stains in infected persons has implications for antibiotic sensitivity testing and treatment strategies.

Joint ESPGHAN/NASPGHAN Guidelines for the Management of Helicobacter pylori in Children and Adolescents (Update 2016).

BACKGROUND: Because of the changing epidemiology of Helicobacter pylori infection and low efficacy of currently recommended therapies, an update of the European Society for Paediatric Gastroenterology Hepatology and Nutrition/North American Society for Pediatric Gastroenterology, Hepatology and Nutrition recommendations for the diagnosis and management of H pylori infection in children and adolescents is required. METHODS: A systematic review of the literature (time period: 2009-2014) was performed. Representatives of both societies evaluated the quality of evidence using GRADE (Grading of Recommendation Assessment, Development, and Evaluation) to formulate recommendations, which were voted upon and finalized using a Delphi process and face-to-face meeting. RESULTS: The consensus group recommended that invasive diagnostic testing for H pylori be performed only when treatment will be offered if tests are positive. To reach the aim of a 90% eradication rate with initial therapy, antibiotics should be tailored according to susceptibility testing. Therapy should be administered for 14 days, emphasizing strict adherence. Clarithromycin-containing regimens should be restricted to children infected with susceptible strains. When antibiotic susceptibility profiles are not known, high-dose triple therapy with proton pump inhibitor, amoxicillin, and metronidazole for 14 days or bismuth-based quadruple therapy is recommended. Success of therapy should be monitored after 4 to 8 weeks by reliable noninvasive tests. CONCLUSIONS: The primary goal of clinical investigation is to identify the cause of upper gastrointestinal symptoms rather than H pylori infection. Therefore, we recommend against a test and treat strategy. Decreasing eradication rates with previously recommended treatments call for changes to first-line therapies and broader availability of culture or molecular-based testing to tailor treatment to the individual child.

Outcome in patients with cystic fibrosis liver disease.

BACKGROUND: Liver disease is an important complication in CF. AIMS: To determine if CFLD is a risk factor for mortality in CF, and which baseline characteristics predict all-cause mortality. METHODS: Irish children with CFLD, and their age and gender matched controls were enrolled at baseline and reviewed after 10years to determine which characteristics predict mortality. RESULTS: 72/84 (85.71%) participants were followed, (mean age Cases 21.71yrs SD 6.5, CF controls 23.62 SD 5.6, 22 (61%) males), with no difference in duration of follow-up. Nineteen participants (26.4%) died, 38.9% (14/36) with CFLD and 13.89% (5/36) CF controls (Odds Ratio (OR) 3.94 95% CI:1.23-12.56 p=0.005). In logistic regression, liver disease (OR 4.28 95% CI 1.07-17.16) female gender (OR 12.25 95% CI 2.37-63.24), reduced pulmonary function, (OR 5.11 95% CI 1.09-23.81) were each independent risk factors for mortality in CF. CONCLUSIONS: Liver disease is an independent risk factor for mortality in CF.

An approach to functional abdominal pain in children and adolescents.

For children with chronic abdominal pain, the early introduction of stress as a potential cause is likely to improve outcome. Parents underestimate their child's awareness of and capacity to worry about everyday events. Parents, children, and teachers need to be convinced that functional symptoms are a normal feature of life. The need for empathy and quality discussion between doctor, parents, and child concerning potential causes of stress is critical. All reinforcement should be removed including insistence on continued school attendance. Cognitive behavioural therapy appears to be helpful in resistant cases. Medication such as antidepressants should be avoided unless prescribed by a child psychiatrist.

Live Helicobacter pylori in the root canal of endodontic-infected deciduous teeth.

BACKGROUND: Many polymerase chain reaction (PCR)-based studies have shown that Helicobacter pylori DNA is prevalent in the oral cavity, but reports on the isolation of live bacteria are extremely rare. Thus, it is still unclear whether H. pylori can indeed survive in the oral environment. METHODS: Here we used electron microscopy, selective growth techniques, urease assays, 16S rRNA PCR, and western blotting to investigate the possible presence of live H. pylori in 10 root canal and corresponding plaque samples of endodontic-infected deciduous teeth in three children. RESULTS: Although H. pylori DNA was verifiable by PCR in several plaque and root canal samples, bacterial colonies could only be grown from two root canals, but not from plaque. These colonies were unequivocally identified as H. pylori by microscopic, genetic, and biochemical approaches. CONCLUSIONS: Our findings show that root canals of endodontic-infected teeth may be a reservoir for live H. pylori that could serve as a potential source for transmission.

Helicobacter pylori in pediatrics.

This article reviewed the important publications on Helicobacter pylori research with children between April 2010 and March 2011. The most interesting studies in the last year lend further weight to the evidence for vertical transmission of H. pylori. The discovery of a potential role for jhp0562, the gene which encodes for the cell envelope protein glycosyltransferase, in the progression to peptic ulcer disease is also very interesting as it may provide a novel way to distinguish children at risk of peptic ulcer disease from those who are not, and so determine those who requires treatment to eradicate H. pylori. The rise in non-H. pylori-associated ulcers and erosions continues to be reported with no apparent risk factors for these ulcers identified to date. High levels of treatment failure continue to be reported, and there remains an urgent need for more effective treatment regimes for children.

Liver disease in cystic fibrosis.

PURPOSE OF REVIEW: This review looks at what is currently known about liver disease in cystic fibrosis (CF) in light of the literature over the past year, and what the ongoing challenges are from a clinical and research perspective for the optimal management of cystic fibrosis liver disease (CFLD). RECENT FINDINGS: Patients with CF who develop clinically significant liver disease have a worse overall phenotype, and whereas there is no definite evidence that they have a shorter life expectancy, longer follow-up is required to determine if liver disease is a risk factor for mortality in CF.The development of the ferret and pig animal models of CF with multiorgan involvement is an important breakthrough which will enhance our understanding of the pathogenesis of CFLD, and with which it is hoped novel therapeutic targets for the treatment of CFLD will be identified. SUMMARY: Whereas there is still no effective treatment for liver disease in CF, recent developments of animal models of CFLD will enhance our capacity to develop new therapeutic targets and reduce the impact of liver disease on mortality in CF.

Evidence-based guidelines from ESPGHAN and NASPGHAN for Helicobacter pylori infection in children.

OBJECTIVE: As the clinical implications of Helicobacter pylori infection in children and adolescents continue to evolve, ESPGHAN and NASPGHAN jointly renewed clinical guidelines using a standardized evidence-based approach to develop updated recommendations for children and adolescents in North America and Europe. METHODS: An international panel of 11 pediatric gastroenterologists, 2 epidemiologists, 1 microbiologist, and 1 pathologist was selected by societies that developed evidence-based guidelines based on the Delphi process with anonymous voting in a final face-to-face meeting. A systematic literature search was performed on 8 databases of relevance including publications from January 2000 to December 2009. After excluding nonrelevant publications, tables of evidence were constructed for different focus areas according to the Oxford classification. Statements and recommendations were formulated in the following areas: whom to test, how to test, whom to treat, and how to treat. Grades of evidence were assigned to each recommendation based on the GRADE system. RESULTS: A total of 2290 publications were identified, from which 738 were finally reviewed. A total of 21 recommendations were generated, and an algorithm was proposed by the joint committee providing evidence-based guidelines on the diagnostic workup and treatment of children with H pylori infection. CONCLUSIONS: These clinical practice guidelines represent updated, best-available evidence and are meant for children and adolescents living in Europe and North America, but they may not apply to those living on other continents, particularly in developing countries with a high H pylori infection rate and limited health care resources.