Indications and successes of intestinal transplantation in children in the 21st century: A retrospective cohort study.

AIMS: To report the results and successes of intestinal transplantation (ITx) in the most active European centres, to emphasize that, although it is a difficult procedure, it should remain a therapeutic option for children with total, definitive and complicated intestinal failure when intestinal rehabilitation fails. METHODS: We retrospectively collected data about all patients less than 18 receiving an ITx from 2010 to 2022 in 8 centres, and outcomes in July 2022. RESULTS: ITx was performed in 155 patients, median age 6.9 years, in 45% for short bowel syndromes, 22% congenital enteropathies, 25% motility disorders, and 15% re-transplantations. Indications were multiple in most patients, intestinal failure-associated liver disease in half. The graft was in 70% liver-containing. At last follow up 64% were alive, weaned from parenteral nutrition, for 7.9 years; 27% had died and the graft was removed in 8%, mostly early after ITx. DISCUSSION: ITx, despite its difficulties, can give a future to children with complicated intestinal failure. It should be considered among the therapeutic options offered to patients with a predicted survival rate lower than that after ITx. Patients should be early discussed within multidisciplinary teams in ITx centres, to avoid severe complications impacting the results of ITx, or even to avoid ITx.

Genetic variants regulating insulin receptor signalling are associated with the severity of liver damage in patients with non-alcoholic fatty liver disease.

BACKGROUND/AIMS: The aim of this study was to assess the effect of functional ENPP1(ectoenzyme nucleotide pyrophosphate phosphodiesterase 1)/PC-1 (plasma cell antigen-1) and IRS-1 (insulin receptor substrate-1) polymorphisms influencing insulin receptor activity on liver damage in non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, whose progression is associated with the severity of insulin resistance. PATIENTS AND METHODS: 702 patients with biopsy-proven NAFLD from Italy and the UK, and 310 healthy controls. The Lys121Gln ENPP1/PC-1 and the Gly972Arg IRS-1 polymorphisms were evaluated by restriction analysis. Fibrosis was evaluated according to Kleiner. Insulin signalling activity was evaluated by measuring phosphoAKT levels by western blotting in a subset of obese non-diabetic patients. RESULTS: The ENPP1 121Gln and IRS-1 972Arg polymorphisms were detected in 28.7% and 18.1% of patients and associated with increased body weight/dyslipidaemia and diabetes risk, respectively. The ENPP1 121Gln allele was significantly associated with increased prevalence of fibrosis stage >1 and >2, which was higher in subjects also positive for the 972Arg IRS-1 polymorphism. At multivariate analysis, the presence of the ENPP1 121Gln and IRS-1 972Arg polymorphisms was independently associated with fibrosis >1 (OR 1.55, 95% CI 1.24 to 1.97; and OR 1.57, 95% CI 1.12 to 2.23, respectively). Both polymorphisms were associated with a marked reduction of approximately 70% of AKT activation status, reflecting insulin resistance and disease severity, in obese patients with NAFLD. CONCLUSIONS: The ENPP1 121Gln and IRS-1 972Arg polymorphisms affecting insulin receptor activity predispose to liver damage and decrease hepatic insulin signalling in patients with NAFLD. Defective insulin signalling may play a causal role in the progression of liver damage in NAFLD.

Primary Prophylaxis for Gastrointestinal Bleeding in Children With Biliary Atresia and Portal Hypertension Candidates for Liver Transplantation: A Single-Center Experience.

BACKGROUND: Cirrhosis for biliary atresia (BA) is associated with risk of gastrointestinal bleeding (GB) from gastroesophageal varices due to portal hypertension. Primary prophylaxis of GB is controversial in children who are candidates for liver transplantation (LT). The aim of the study was to define the management of gastroesophageal varices and to identify the benefit of primary prophylaxis for GB in BA children waiting for LT. METHODS: A retrospective single-center study including all BA children listed for LT in 2008-2016. Clinical, endoscopical, and biochemical data were analyzed. RESULTS: Of 82 children, 50 (61%) did not receive primary prophylaxis and did not present any episode of bleeding, 16 (19.5%) underwent primary prophylaxis, and 16 (19.5%) presented spontaneous GB and received secondary prophylaxis. Children without primary prophylaxis and GB were younger than patients with primary prophylaxis and those with GB (7.7 years [range, 4.1-37.9 years] vs 11.2 years [range, 5.1-43 years]; P = .03 vs 10.7 years [range, 6.9-39.9 years], respectively; P = .004). Seventy-five percent of GB occurred in children older than 8 months. Fifteen (93.8%) children with GB presented esophageal varices (grade III = 10 [62.5%]) and 10 (62.5%) required endoscopic treatments, consisting mainly of sclerotherapy. Median time to LT was similar for children with or without bleeding (2 months [range, 0-17.7 months] vs 2.2 months [0-17.9 months], respectively; P = .89). After 45.5 months (range, 13.7-105.5 months) of follow-up, the overall patient survival was 97.6%. At the intention-to-treat analysis, the survival rate was 100% for patients without bleeding episode and 87.5% for children with GB (P = .16). CONCLUSIONS: Despite the risk of GB being not clinically predictable in children with BA waiting for LT, our experience suggests that primary prophylaxis of GB might be unnecessary in children younger than 6 months, while it should be considered in older children. Thus, the occurrence of GB does not delay the timing of transplantation.

Prevalence of life-threatening complications in pediatric patients affected by intestinal failure.

Intestinal failure (IF) is defined as the reduction of functional gut mass necessary to maintain health and growth in children. Causes of IF include short bowel syndrome (SBS), neuromuscular intestinal disorders (NID), and severe protracted diarrhea (SPD). If patients require long-term parenteral nutrition (PN); they can now be discharged on home PN (HPN), thus improving their quality of life. Children requiring long-term PN are at high risk of developing life-threatening IF complications that hinder HPN, namely, IF associated liver disease (IFALD), catheter-related infections (CRI), and thrombosis. The goal of our study was to retrospectively evaluate the prevalence of life-threatening complications among IF patients according to the HPN indication. From January 1989 to May 2006, 60 IF patients (41 boys and 19 girls) underwent prolonged HPN. Total program duration was 46,391 days (127 total years, mean 2.1 years per patient). Indications for HPN were SBS in 36 cases, SPD in 19 cases, or NID in 5 cases. In our experience patients affected by SBS displayed a significantly higher prevalence of life-threatening complications than patients with other IF causes. Sixteen (27%) among 60 patients developed IFALD. CRI and thrombosis prevalence were 1.4/1000 central venous catheter (CVC) days and 0.2/1000 CVC days respectively. SBS seemed to lead to life-threatening complications more often than other HPN indications. SBS patients on long-term PN therefore require careful management to identify complications early, and they seem to be the candidates for early referral to small bowel transplantation centers.

Long-term parenteral nutrition in pediatric autoimmune enteropathies.

Severe and protracted or persistent diarrhea (SPD) is the most severe form of diarrhea in infancy and has also been defined as intractable diarrhea when it leads to dependence on total parenteral nutrition (TPN). One of the rare causes of SPD is represented by autoimmune enteropathy that is characterized by life-threatening diarrhea mainly occurring within the first years of life, persistent villous atrophy in consecutive biopsies, resistance to bowel rest, and evidence of antigut autoantibodies. We evaluated 10 patients (seven boys, mean age at diagnosis 18 months; range: 0 to 160 months) fulfilling criteria of autoimmune enteropathy to assess dependence on TPN. TPN was first required in all patients to avoid dehydration and electrolytic imbalance. All patients were dependent on immunosuppressive therapy (steroid, azothioprine, cyclosporine, tacrolimus). Three patients died of sepsis: two during TPN while in the hospital, and one at home after he was weaned off TPN. Five patients are weaned off TPN after a mean period of 18 months; they are actually on oral alimentation with a cow milk-free diet after a period of enteral nutrition with elemental formula. One underwent total colectomy and bone marrow transplantation and one developed an IPEX syndrome. One patient is still dependent on TPN for 24 months. She is on home parenteral nutrition. Patients with diagnosis of IPEX syndrome require parenteral support with three or four infusion per week. TPN represents a fixed step in the management of autoimmune enteropathy, but it may be considered as an interim treatment while waiting for intestinal adaptation, at least in some selectioned case of autoimmune enteropathy. Bone marrow transplantation should be considered and reserved for those patients with severe complications due to home parenteral nutrition, or in those that are really dependent on parenteral nutrition.

Intractable diarrhea of infancy with congenital intestinal mucosa abnormalities: outcome of four cases.

Microvillous inclusion disease (MID) and epithelial dysplasia (ED) or tufting enteropathy are the most frequent causes of intractable diarrhea with persistent villous atrophy and indefinite dependence on total parenteral nutrition (PN) from early infancy. Since these are intractable diseases, they have been proposed to be elective indication for early bowel transplantation in order to avoid complications, such as PN-related liver disease, that would require a combined small bowel-liver transplant. We describe four cases of intractable diarrhea, two with MID and two with ED, seeking to discover whether these diseases are really elective, early indications for bowel transplant. Among our four patients, only one with ED underwent transplantation. The prognosis of small bowel transplant is still poor and worse than that of prolonged HPN. Further study is necessary to achieve a safe HPN program. Referral for transplant (small bowel only or combined with liver) should be considered when there is a venous access reduction and/or severe and irreversible liver disease.

Energy expenditure and insulin sensitivity evaluation in obese children affected by hepatosteatosis.

OBJECTIVES: The aim of our study was to evaluate the physical and sedentary activities and energy expenditure (EE) in a group of children affected by non-alcoholic fatty liver disease (NAFLD), compared with normal and obese subjects, using a physical activity questionnaire (PAQ) and a SenseWear armband (SWA). METHODS: Forty NAFLD (10 females), 41 lean (NRM; 11 females) and 30 obese (OB; 10 females), age- and pubertal stage-matched, children were included. RESULTS: Sedentary activity (PAQ) was similar in NAFLD and NRM but less in OB, while SWA showed that NAFLD spent less time in physical activity and more in sedentary activities compared with NRM, but not with OB. Insulin sensitivity index result is related to active EE (cal kg(-1) d(-1) ) in NAFLD, while homeostatic model assessment index result was negatively related to total EE in OB. CONCLUSIONS: Regular physical activity must be encouraged in all obese children affected by NAFLD or not, and SWA might be a possible valid tool for evaluating actual EE.

A protective effect of breastfeeding on the progression of non-alcoholic fatty liver disease.

OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disease characterised by accumulation of large-droplet fat in hepatocytes with possible progression to inflammation and fibrosis. Breastfeeding has benefits for child health, both during infancy and later in life, reducing the risk of manifestations of the metabolic syndrome. Here we investigated the association between early type of feeding (breastfed versus formula-fed and duration of breastfeeding) and later NAFLD development. STUDY DESIGN: We investigated 191 young Caucasian children (3-18 years old) with NAFLD consecutively enrolled between January 2003 and September 2007 in our centre. 48% of these children (n = 91) had been breastfed for a median (interquartile range) time of 8 (7) months. RESULTS: After correction for age, waist circumference, gestational age and neonatal weight, the odds of non-alcoholic steatohepatitis (NASH) (OR 0.04, 95% CI 0.01 to 0.10) and fibrosis (OR 0.32, 95% CI 0.16 to 0.65) were lower in breastfed versus not breastfed infants. Moreover, the odds of NASH (OR 0.70, exact 95% CI 0.001 to 0.87) and fibrosis (OR 0.86, exact 95% CI 0.75 to 0.98) decreased for every month of breastfeeding. CONCLUSIONS: This observational study suggests that earlier feeding habits might affect the clinical expression of NASH from 3 to 18 years later, with an apparent drug-like preventive effect of breastfeeding.

Psychosocial condition after liver transplantation in children: review of the literature from 2006 to 2008.

Pediatric liver transplantation is the treatment of choice for end-stage liver disease of various causes. With most patients surviving long term after surgery, questions and concerns nowadays focus on morbidity and quality of life. Characterizing health-related quality of life (HRQOL) after liver transplantation provides a more complete estimate of the overall health of liver transplant candidates and recipients. HRQOL remains, however, a wide concept, with various interpretations in the literature, varying from medical assessment of physical status to considering various nonmedical aspects. Among the former aspects, concerns are commonly addressed about physical health and the psychological and/or social functioning of both transplanted children and their families. This detailed review of the most relevant papers analyzing of HRQOL after pediatric liver transplantation published between January 2006 and September 2008 includes the psychosocial aspects in children/adolescents, parents, and/or family members after liver transplantation, emphasizing limitations inherent to "measuring" and analyzing HRQOL aspects.