Publications by authors named "A Mutanen"

34 Publications

Bowel Lengthening Procedures in Children with Short Bowel Syndrome: A Systematic Review.

Eur J Pediatr Surg 2021 Mar 4. Epub 2021 Mar 4.

Pediatric Surgical Centre, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Vrije Universiteit, Amsterdam, The Netherlands.

Introduction:  The aims of the study are to systematically assess and critically appraise the evidence concerning two surgical techniques to lengthen the bowel in children with short bowel syndrome (SBS), namely, the longitudinal intestinal lengthening and tailoring (LILT) and serial transverse enteroplasty (STEP), and to identify patient characteristics associated with a favorable outcome.

Materials And Methods:  MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched from inception till December 2019. No language restriction was used.

Results:  In all, 2,390 articles were found, of which 40 were included, discussing 782 patients. The median age of the patients at the primary bowel lengthening procedure was 16 months (range: 1-84 months). Meta-analysis could not be performed due to the incomparability of the groups, due to heterogeneous definitions and outcome reporting. After STEP, 46% of patients weaned off parenteral nutrition (PN) versus 52% after LILT. Mortality was 7% for STEP and 26% for LILT. Patient characteristics predictive for success (weaning or survival) were discussed in nine studies showing differing results. Quality of reporting was considered poor to fair.

Conclusion:  LILT and STEP are both valuable treatment strategies used in the management of pediatric SBS. However, currently it is not possible to advise surgeons on accurate patient selection and to predict the result of either intervention. Homogenous, prospective, outcome reporting is necessary, for which an international network is needed.
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http://dx.doi.org/10.1055/s-0041-1725187DOI Listing
March 2021

Compromised duodenal mucosal integrity in children with short bowel syndrome after adaptation to enteral autonomy.

J Pediatr Surg 2020 Oct 8. Epub 2020 Oct 8.

Division of Pediatric Surgery, Pediatric Liver and Gut Research Group, Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. Electronic address:

Background: Intestinal adaptation has been extensively studied experimentally, but very limited data is available on human subjects. In this study we assessed intestinal adaption in humans with short bowel syndrome (SBS).

Methods: We comparatively evaluated mucosal hyperplasia, inflammation, barrier function and nutrient transport using histology, immunohistochemistry and qPCR for selected 52 key genes in duodenal biopsies obtained from children with SBS after weaning off parenteral nutrition (n = 33), and matched controls without intestinal pathology (n = 12). Small bowel dilatation was assessed from contrast small bowel series.

Results: Duodenal mucosa of SBS children showed increased histologic inflammation of lamina propria (p = 0.033) and mucosal mRNA expression of tumor necrosis factor (p = 0.027), transforming growth factor (TGF)-β2 (p = 0.006) and caveolin-1 (CAV1; p = 0.001). Villus height, crypt depth, enterocyte proliferation, apoptosis and expression of proliferation and nutrient transport genes remained unchanged. Pathologic small bowel dilatation reduced crypt depth (p = 0.045) and downregulated mRNA expression of interleukin (IL)-6 by three-fold (p = 0.008), while correlating negatively with IL6 (r = -0.609, p = 0.004). Loss of ileocecal valve (ICV) upregulated mRNA expression of toll-like receptor 4 (TLR4), TGF-β1, CAV1, several apoptosis regulating genes, and mRNA expression of zonulin (p < 0.05 for all).

Conclusions: Despite successful adaptation to enteral autonomy, duodenal mucosa of SBS children displayed histologic and molecular signs of abnormal inflammation and regulation of epithelial permeability, whereas no structural or molecular signs of adaptive hyperplasia or enhanced nutrient transport were observed. Excessive dilatation of the remaining small bowel paralleled impaired duodenal crypt homeostasis, while absence of ICV modified regulation of mucosal inflammation, regeneration and permeability.

Level Of Evidence: II.
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http://dx.doi.org/10.1016/j.jpedsurg.2020.09.065DOI Listing
October 2020

Prediction, identification and progression of histopathological liver disease activity in children with intestinal failure.

J Hepatol 2021 Mar 28;74(3):593-602. Epub 2020 Sep 28.

Department of Pediatric Surgery, Pediatric Liver and Gut Research Group, Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. Electronic address:

Background & Aims: Diagnostic criteria, progression risk and optimal monitoring for intestinal failure (IF)-associated liver disease (IFALD) remain undefined. We assessed predictors, non-invasive markers and progression of histopathological liver disease in patients with IF.

Methods: In total, 77 children with IF and median age of 1.7 years underwent diagnostic liver biopsy, which was repeated in 48 patients after 2.9 years with simultaneous evaluation of liver biochemistry, liver stiffness, serum citrulline (a surrogate for viable enterocyte mass), spleen size, esophageal varices and clinical data. Patients were staged according to histopathological liver disease activity: active IFALD (cholestasis and/or inflammation), chronic IFALD (significant fibrosis and/or steatosis), or no IFALD (none of these features).

Results: Diagnostic liver biopsy revealed active, chronic or no IFALD in 48%, 21% and 31% of patients. Active IFALD was segregated by low serum citrulline, parenteral nutrition (PN) dependency and young age, while weaning off PN and older age predicted chronic IFALD. Although the liver histopathology in most patients either normalized (52%) or transformed to a less reactive (chronic) disease stage (23%), 19% of patients retained and 6.3% progressed to an active cholestatic/inflammatory IFALD phenotype. Decreased serum citrulline and PN-dependency also predicted active IFALD in follow-up biopsies. Increased median liver biochemistry values and liver stiffness only associated with active IFALD, which was accurately identified by gamma-glutamyltransferase (GGT), citrulline and liver stiffness, their combinations reaching diagnostic and follow-up AUROC values above 0.90.

Conclusions: Active IFALD, essentially predicted by intestinal disruption and PN-dependency, was accurately detected by GGT, liver stiffness and citrulline, which together with recent advances in clinical management options, provides new avenues for monitoring and targeted liver protection in patients with IF.

Lay Summary: Liver disease is a common and critical complication in patients with intestinal failure, who require intravenous nutrition for survival due to severe intestinal dysfunction. We showed that both intravenous nutrition dependency and intestinal disruption essentially predicted development of active histopathological liver disease, which persisted in 25% of patients during long-term follow-up and could be accurately detected without the need for liver biopsy. Identification of the active and potentially progressive histopathology offers new possibilities for monitoring and targeted liver protection in patients with intestinal failure.
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http://dx.doi.org/10.1016/j.jhep.2020.09.023DOI Listing
March 2021

Perianal Crohn's Disease in Children and Adolescents.

Eur J Pediatr Surg 2020 Oct 17;30(5):395-400. Epub 2020 Sep 17.

Department of Pediatric Surgery, Children's Hospital, Helsinki University Hospital, Helsinki, Finland.

The incidence of Crohn's disease is increasing worldwide. The clinical course of childhood onset Crohn's disease is particularly aggressive with characteristic disease localization in the ileocecal region and colon, often associated with perianal disease. Severe complications of perianal disease include recurrent perianal sepsis, chronic fistulae, fecal incontinence, and rectal strictures that impair quality of life and may require fecal diversion. Care of patients with perianal Crohn's disease requires a multidisciplinary approach with systematic clinical evaluation, endoscopic assessment, and imaging studies followed by combined medical and surgical management. In this review, we provide an update of the epidemiology, pathophysiology, diagnostics, and management of perianal Crohn's disease in children and adolescents.
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http://dx.doi.org/10.1055/s-0040-1716724DOI Listing
October 2020

Parenteral Nutrition-Dependent Children With Short-Bowel Syndrome Lack Duodenal-Adaptive Hyperplasia but Show Molecular Signs of Altered Mucosal Function.

JPEN J Parenter Enteral Nutr 2020 09 27;44(7):1291-1300. Epub 2020 Jan 27.

Section of Pediatric Surgery, Pediatric Liver and Gut Research Group, Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Background: Although adaptive mucosal growth of the remaining small intestine is an essential compensatory mechanism to bowel resection in experimental short-bowel syndrome (SBS), only scarce clinical data are available. We studied structural and molecular mechanisms of intestinal adaptation in children with SBS.

Methods: Fourteen patients, who had been dependent on parenteral nutrition (PN) since neonatal period for a median (interquartile range)1.4 (0.7-6.5) years, were studied at the age of 1.5 (1.0-6.5) years. Median length of remaining small bowel was 33 (12-60) cm, and 6 patients had their ileocecal valve preserved. Six children without gastrointestinal disorders served as age-matched and gender-matched controls. All patients underwent duodenal biopsies. Mucosal microarchitecture, proliferation, apoptosis, inflammation, and epithelial-barrier function were addressed using histology, immunohistochemistry, and quantitative real-time polymerase chain reaction.

Results: Villus height, crypt depth, enterocyte proliferation, and apoptosis were similar in patients and matched controls. Messenger RNA (mRNA) expression of numerous genes regulating gut epithelial-barrier function (TGFB2, CAV1, CLDN1, MUC2, and NLRC4) was significantly altered. Of various nutrient transporters studied, only expression of SLC2A1 encoding facilitative glucose transporter GLUT1 was increased among patients, whereas RNA expression of genes encoding sodium-dependent glucose, sterol, fatty-acid, and peptide transport remained unchanged.

Conclusion: Duodenal mucosal hyperplasia has a limited role in mediating physiological adaptation following intestinal resection among PN-dependent children with SBS. Further clinical studies addressing functional significance of the observed alterations in mucosal RNA expression are warranted.
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http://dx.doi.org/10.1002/jpen.1763DOI Listing
September 2020

Impaired Wnt/β-catenin pathway leads to dysfunction of intestinal regeneration during necrotizing enterocolitis.

Cell Death Dis 2019 10 3;10(10):743. Epub 2019 Oct 3.

Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada.

Necrotizing enterocolitis (NEC) is a devastating neonatal disease characterized by acute intestinal injury. Intestinal stem cell (ISC) renewal is required for gut regeneration in response to acute injury. The Wnt/β-catenin pathway is essential for intestinal renewal and ISC maintenance. We found that ISC expression, Wnt activity and intestinal regeneration were all decreased in both mice with experimental NEC and in infants with acute active NEC. Moreover, intestinal organoids derived from NEC-injured intestine of both mice and humans failed to maintain proliferation and presented more differentiation. Administration of Wnt7b reversed these changes and promoted growth of intestinal organoids. Additionally, administration of exogenous Wnt7b rescued intestinal injury, restored ISC, and reestablished intestinal epithelial homeostasis in mice with NEC. Our findings demonstrate that during NEC, Wnt/β-catenin signaling is decreased, ISC activity is impaired, and intestinal regeneration is defective. Administration of Wnt resulted in the maintenance of intestinal epithelial homeostasis and avoidance of NEC intestinal injury.
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http://dx.doi.org/10.1038/s41419-019-1987-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6776513PMC
October 2019

Interventional Radiology-Guided Procedures in the Treatment of Pediatric Solid Tumors: A Systematic Review and Meta-Analysis.

Eur J Pediatr Surg 2020 Aug 23;30(4):317-325. Epub 2019 Jun 23.

Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Department of Pediatric Surgery and Urology, Descartes University, Université de Paris, Paris, France.

Introduction:  The use of interventional radiology (IR) in the treatment of pediatric solid tumors has markedly increased over the last three decades. However, data on effectiveness of IR-techniques, such as embolization/ablation, are scarce. In this systematic review and meta-analysis, we examined the outcomes of IR-procedures in the treatment of solid tumors in children.

Materials And Methods:  Using a defined search strategy, we searched for studies reporting the use of IR-techniques for pediatric solid tumors from 1980 to 2017. Reports with less than three patients, review, and opinion articles were excluded. The study was conducted under preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. We analyzed dichotomous and continuous variables by appropriate statistical methods.

Results:  Of 567 articles screened, 21 papers met the inclusion criteria (12 retrospective, 7 prospective, and 2 randomized-control trials). Many of the analyzed papers described relatively small cohorts of patients. IR-guided procedures were mainly rescue procedures to treat primarily unresectable tumors, local recurrences, or metastases. Inclusion/exclusion criteria and success definition were not specified in most reports. Major side effects were documented in 17/286 (6%) infants, while minor side effects were self-limiting in most patients. Six studies had a comparison between tumor embolization (127 infants) to surgery or chemotherapy without IR-procedures (113 controls). The meta-analysis showed lower mortality (16 vs. 47%) and surgical time for resection (206 vs. 250 m), higher 2-year tumor-free survival (82 vs. 36%), and favorable histology in IR group ( < 0.001 for all).

Conclusion:  IR-guided techniques are promising in the treatment of pediatric solid tumors. Further prospective (randomized) trials are needed to clarify efficacy.
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http://dx.doi.org/10.1055/s-0039-1692655DOI Listing
August 2020

Altered Bile Transporter Expression and Cholesterol Metabolism in Children With Cholesterol and Pigment Gallstones.

J Pediatr Gastroenterol Nutr 2019 08;69(2):138-144

Section of Pediatric Surgery, Pediatric Liver and Gut Research Group, Children's Hospital.

Objectives: We elucidated pathophysiology of pediatric gallstone disease by assessing liver expression of bile transporters in relation to bile acids and surrogates of cholesterol absorption and synthesis in serum and gallstones.

Methods: RNA expression of canalicular bile transporters in liver biopsies from 32 pediatric gallstone patients and from 6 liver donors (controls) was measured by qRT-PCR (quantitative real-time reverse transcription polymerase chain reaction). Concentrations of cholesterol and precursors, plant sterols and bile acids in gallstones, and in serum of the patients and 82 healthy children were measured. Primary outcomes were the difference in RNA expressions and serum sterol profiles between patients and controls.

Results: Cholesterol stones (CS; n = 15) contained cholesterol >42% and pigment stones (PS; n = 17) <9% of weight. CS patients had markedly lower serum plant sterols (absorption) and higher cholesterol precursors (synthesis) than PS patients or healthy controls. CS contained several times more cholesterol precursors and less plant sterols relative to cholesterol than PS, which were enriched by primary bile acids (12-5.2-fold, P < 0.001). Liver RNA expression of ABCG5/G8 was similarly increased 2.5- to 1.8-fold (P < 0.002) in CS and PS patients, whereas PS patients had higher ABCB11 expression (P < 0.05). In PS bile acid concentration correlated with gallstone plant sterols (R = 0.83, P < 0.0001), and ABCG5 expression with ABCB11 expression (R = 0.27, P = 0.03).

Conclusions: In CS, upregulation of ABCG5/G8 expression associates with low absorption and high gallstone content of cholesterol. In PS, activation of bile acid transport by ACBC11 interconnects with hepatic upregulation of ABCG5/G8 enriching PS with bile acids and plant sterols.
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http://dx.doi.org/10.1097/MPG.0000000000002353DOI Listing
August 2019

Divergent expression of liver transforming growth factor superfamily cytokines after successful portoenterostomy in biliary atresia.

Surgery 2019 05 25;165(5):905-911. Epub 2019 Jan 25.

Pediatric Surgery and Pediatric Transplantation Surgery, Pediatric Liver and Gut Research Group, Children's Hospital, University of Helsinki and Helsinki University Hospital, Finland.

Background: Pathogenesis of progressive liver fibrosis in biliary atresia after successful portoenterostomy remains unclear. We related hepatic expression of transforming growth factor beta (TGF-β) superfamily cytokines to histologic liver injury after successful portoenterostomy.

Methods: Enrolled in our study were 28 patients with biliary atresia who had liver biopsies obtained during and after successful portoenterostomy, which normalized serum bilirubin (<20 µmol/l). Biopsies were evaluated for cholestasis, inflammation, ductal reaction, and fibrosis and were stained immunohistochemically for transforming growth factor beta 1, transforming growth factor beta 2, connective tissue growth factor, and decorin. Respective gene expression (TGFB1, TGFB2, TGFB3, CTGF, DCN) was analyzed at follow-up using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Results were compared with fibrotic and healthy control livers.

Results: After median follow-up of 3.0 years, histologic cholestasis resolved, whereas fibrosis had progressed only in isolated biliary atresia. Liver protein expression of transforming growth factor beta 1 and connective tissue growth factor (P < .001 for both), but not that of transforming growth factor beta 2 or decorin, decreased after successful portoenterostomy, although expression of all four cytokines remained elevated. In accordance with postportoenterostomy changes in protein expression, follow-up ribonucleic acid expression of TGFB2 and DCN, but not that of TGFB1 and CTGF, was upregulated when compared with the controls. Both protein and gene expression of transforming growth factor beta 1 and protein expression of transforming growth factor beta 2, connective tissue growth factor and decorin correlated with METAVIR fibrosis stage. Syndromic patients (n = 12) showed milder fibrosis and lower transforming growth factor beta 1 expression than patients with isolated biliary atresia.

Conclusion: These findings support a central role of transforming growth factor beta superfamily in mediating continuing liver fibrogenesis after successful portoenterostomy. Transforming growth factor beta pathway cytokines responded divergently to clearance of jaundice, which was reflected by differential progression of fibrosis between syndromic and isolated patients.
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http://dx.doi.org/10.1016/j.surg.2018.12.003DOI Listing
May 2019

Autologous Intestinal Reconstructive Surgery in the Management of Total Intestinal Aganglionosis.

J Pediatr Gastroenterol Nutr 2019 05;68(5):635-641

Section of Pediatric Surgery, Pediatric Liver and Gut Research Group, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Objectives: Total/near total intestinal aganglionosis (TIA/NTIA) is the most uncommon and life-threatening form of Hirschsprung disease (HD). The management of TIA/NTIA is challenging and the role of autologous intestinal reconstructive (AIR) surgery is controversial. The objective is to evaluate the effectiveness of AIR in patients with TIA/NTIA.

Methods: Records from children affected by TIA and enrolled in the multicenter international Pediatric Intestinal Rehabilitation and Transplantation Registry were retrospectively reviewed.

Results: Fourteen patients with TIA were identified. TIA diagnosis was confirmed histologically at the median age of 14 days of life. All received a proximal decompressive jejunostomy. Two patients died, 4 patients had satisfactory stoma output with enteral tolerance without additional procedures, 8 underwent 10 AIR procedures (4 Ziegler myotomy-myectomy, 3 transposition of aganglionic ileum with or without myotomy, 2 simple tapering, 1 longitudinal lengthening and tailoring procedure with associated myotomy). AIR significantly reduced median stoma output, from 197 to 31 mL · kg · day (P = 0.0001). The reduction was seen in all patients. In addition, AIR improved enteral tolerance in the long term in 5 of 8 patients (63%), and temporarily in 1, leading to a reduction of parenteral nutrition requirement from 100% to 70% (P = 0.0231).

Conclusions: AIR surgery in carefully selected patients may be useful and effective way to enhance residual bowel absorptive function and to reduce parenteral nutrition requirements. AIR and intestinal transplantation are complementary surgical tools in the complex treatment algorithm of TIA/NTIA.
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http://dx.doi.org/10.1097/MPG.0000000000002260DOI Listing
May 2019

Etiology and prognosis of pediatric short bowel syndrome.

Semin Pediatr Surg 2018 Aug 29;27(4):209-217. Epub 2018 Jul 29.

Division of General and Thoracic Surgery, The Hospital for Sick Children, University of Toronto, Toronto, Canada; Group for Improvement of Intestinal Function and Treatment (GIFT), The Hospital for Sick Children, University of Toronto, Toronto, Canada; Transplant and Regenerative Medicine Centre, The Hospital for Sick Children, University of Toronto, Toronto, Canada. Electronic address:

Pediatric intestinal failure is a complex and devastating condition defined as the inability of the intestine to absorb an adequate amount of fluid and nutrients to sustain life. The primary goal of intestinal failure treatment is to achieve enteral autonomy with a customized treatment plan. Although recent improvements in intestinal failure patient care have led to significant improvements in the morbidity and mortality rate, children with intestinal failure are at risk for multiple complications such as intestinal failure associated liver disease, recurrent septic episodes, central line complications, metabolic bone disease, impaired kidney function, and failure to thrive. In this article, we review the current literature on the etiology and factors affecting prognosis of pediatric IF.
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http://dx.doi.org/10.1053/j.sempedsurg.2018.07.009DOI Listing
August 2018

Serum non-cholesterol sterols and cholesterol metabolism in childhood and adolescence.

Atherosclerosis 2018 11 15;278:91-96. Epub 2018 Sep 15.

Heart and Lung Center, Department of Cardiology, University of Helsinki and Helsinki University Hospital, PO BOX 340, 00029 HUS, Helsinki, Finland.

Background And Aims: The profile of cholesterol metabolism, i.e., high absorption vs. high synthesis, may have a role in the development of atherosclerosis, the early lesions of which can be present already in childhood. Since there is no information on cholesterol metabolism in children from birth to adolescence, we evaluated cholesterol metabolism in 0-15 year-old children and adolescents without dyslipidemia.

Methods: The study population consisted of 96 children (39 girls, 57 boys) divided into age groups <1 (n = 14), 1-5 (n = 37), 6-10 (n = 24), and 11-15 (n = 21) years. Cholesterol metabolism was assessed by analysing serum non-cholesterol sterols, biomarkers of cholesterol synthesis and absorption, with gas-liquid chromatography.

Results: Serum non-cholesterol sterol ratios to cholesterol did not differ between gender. Cholesterol precursors squalene, cholestenol, and desmosterol were higher in the <1 year than in the older age groups, whereas lathosterol was highest in the 11-15 year old. Plant sterols were low in the age group <1 year, after which they did not differ between the groups. Cholestanol was not age-dependent. From the age of 1 year, cholesterol homeostasis was intact. Cholesterol absorption prevailed cholesterol synthesis from 1 to 10 years of age (e.g., lathosterol/cholestanol ratio 0.35 ± 0.03 and 0.45 ± 0.05 in 1-5 and 6-10 vs. 0.66 ± 0.08 in 11-15 year-old (mean ± SE, p < 0.001).

Conclusions: Serum non-cholesterol sterols had different individual profiles by age in childhood and adolescence. From 1 to 10 years of age, cholesterol absorption prevailed cholesterol synthesis. This novel finding emphasizes the importance of dietary aspects related to cardiovascular risk even from early childhood.
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http://dx.doi.org/10.1016/j.atherosclerosis.2018.09.017DOI Listing
November 2018

Short bowel mucosal morphology, proliferation and inflammation at first and repeat STEP procedures.

J Pediatr Surg 2019 Mar 17;54(3):511-516. Epub 2018 Apr 17.

Section of Pediatric Surgery, Pediatric Liver and Gut Research Group, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. Electronic address:

Background: Although serial transverse enteroplasty (STEP) improves function of dilated short bowel, a significant proportion of patients require repeat surgery. To address underlying reasons for unsuccessful STEP, we compared small intestinal mucosal characteristics between initial and repeat STEP procedures in children with short bowel syndrome (SBS).

Methods: Fifteen SBS children, who underwent 13 first and 7 repeat STEP procedures with full thickness small bowel samples at median age 1.5 years (IQR 0.7-3.7) were included. The specimens were analyzed histologically for mucosal morphology, inflammation and muscular thickness. Mucosal proliferation and apoptosis was analyzed with MIB1 and Tunel immunohistochemistry.

Results: Median small bowel length increased 42% by initial STEP and 13% by repeat STEP (p=0.05), while enteral caloric intake increased from 6% to 36% (p=0.07) during 14 (12-42) months between the procedures. Abnormal mucosal inflammation was frequently observed both at initial (69%) and additional STEP (86%, p=0.52) surgery. Villus height, crypt depth, enterocyte proliferation and apoptosis as well as muscular thickness were comparable at first and repeat STEP (p>0.05 for all). Patients, who required repeat STEP tended to be younger (p=0.057) with less apoptotic crypt cells (p=0.031) at first STEP. Absence of ileocecal valve associated with increased intraepithelial leukocyte count and reduced crypt cell proliferation index (p<0.05 for both).

Conclusions: No adaptive mucosal hyperplasia or muscular alterations occurred between first and repeat STEP. Persistent inflammation and lacking mucosal growth may contribute to continuing bowel dysfunction in SBS children, who require repeat STEP procedure, especially after removal of the ileocecal valve.

Level Of Evidence: Level IV, retrospective study.
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http://dx.doi.org/10.1016/j.jpedsurg.2018.04.016DOI Listing
March 2019

Pediatric Intestinal Failure: The Key Outcomes for the First 100 Patients Treated in a National Tertiary Referral Center During 1984-2017.

JPEN J Parenter Enteral Nutr 2018 11 27;42(8):1304-1313. Epub 2018 Apr 27.

Pediatric Liver and Gut Research Group, University of Helsinki, Helsinki, Finland.

Background: Pediatric-onset intestinal failure (IF) remains a severe illness with life-threatening consequences. In this study, we analyzed a single center's outcomes of IF over 3 decades.

Methods: All children with IF who required parenteral nutrition (PN) >2 months or small-intestinal resection ≥50% managed since 1984 were included for retrospective outcome analyses.

Results: In total, 100 patients with median PN duration of 1.2 (interquartile range, 0.4-3.5) years were identified. Causes of IF were short bowel syndrome (SBS; n = 78), primary intestinal motility disorders (n = 14), and congenital intestinopathies (n = 8). Patients with SBS had median 40 (25-60) cm of small bowel remaining. Overall, Kaplan-Meier 5- and 10-year weaning-off estimates were 67% (95% CI, 57-77) and 73% (95% CI, 63-84), respectively. Weaning off PN was predicted by remaining bowel anatomy, multidisciplinary treatment era, and absence of immune deficiency. Catheter-related bloodstream infections decreased from 1.4 to 0.6/1000 PN days (P = .0003) with systematic use of taurolidine locks. None had progressive liver disease. Thirty-one percent of patients with SBS underwent autologous intestinal reconstructive surgery. Five patients received and 2 were listed for isolated intestinal transplantation. Eight patients died, and overall 15-year survival rate estimate was 91% (95% CI, 85-98).

Conclusions: Despite reassuring rates of survival and weaning off PN, long-term PN failed in 14% of patients solely because of catheter complications in the recent era. Achievement of enteral autonomy in those with the shortest remaining small bowel and functional cause of IF remains challenging.
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http://dx.doi.org/10.1002/jpen.1164DOI Listing
November 2018

Perioperative Complications Following Surgery for Necrotizing Enterocolitis.

Eur J Pediatr Surg 2018 Apr 13;28(2):148-151. Epub 2018 Mar 13.

Division of General and Thoracic Surgery, The Hospital for Sick Children, Toronto, Ontario, Canada.

Necrotizing enterocolitis (NEC) is a devastating condition that mainly affects premature infants. Advanced cases of NEC require surgical treatment, which in up to 70% of infants is associated with significant perioperative morbidity including anastomosis- or enterostomy-related complications, sepsis, peritonitis, and wound infections. Moreover, the perioperative complications may compromise the long-term gastrointestinal and neurodevelopmental outcome of patients requiring surgery for NEC.
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http://dx.doi.org/10.1055/s-0038-1636943DOI Listing
April 2018

Complicated Gastroschisis Is Associated with Greater Intestinal Morbidity than Gastroschisis or Intestinal Atresia Alone.

Eur J Pediatr Surg 2018 Dec 4;28(6):495-501. Epub 2017 Oct 4.

Section of Pediatric Surgery, University of Helsinki, Helsinki University Central Hospital, Children's Hospital, Helsinki, Finland.

Aim:  The study aimed to compare outcomes and intestinal morbidity among complicated gastroschisis, isolated gastroschisis, and intestinal atresia.

Methods:  In this retrospective observational single institution study, outcomes and intestinal morbidity were compared among gastroschisis complicated by intestinal atresia or perinatal bowel perforation, isolated gastroschisis, and isolated intestinal atresia. We included two cohorts; the first cohort included 68 consecutive patients with complicated gastroschisis ( = 9), isolated gastroschisis ( = 34), and intestinal atresia ( = 25) managed in our center. The second cohort included 20 patients (12 referred) with intestinal failure due to these underlying etiologies managed by our intestinal rehabilitation team.

Results:  Patients with complicated gastroschisis had a significantly longer need for mechanical ventilation, primary hospital stay, and duration of parenteral nutrition (PN) and developed intestinal failure more often compared with other groups ( < 0.05 for all). Reoperations for surgical complications were also more frequent in patients with complicated gastroschisis ( < 0.05). Among those, who developed intestinal failure, autologous intestinal reconstruction (AIR) surgery was performed in 11 patients with comparable frequency in all groups. Repeated AIR surgery for bowel re-dilatation was required in 3/3 patients with complicated gastroschisis and 0/8 with isolated gastroschisis or intestinal atresia ( = 0.004).

Conclusion:  Complicated gastroschisis is associated with markedly increased intestinal morbidity, reflected by prolonged duration of PN, more frequent reoperations for intestinal complications, and bowel re-dilatation after AIR surgery, when compared with patients with isolated gastroschisis or intestinal atresia.
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http://dx.doi.org/10.1055/s-0037-1607198DOI Listing
December 2018

Small bowel dilation in children with short bowel syndrome is associated with mucosal damage, bowel-derived bloodstream infections, and hepatic injury.

Surgery 2017 09 6;162(3):670-679. Epub 2017 Jul 6.

Pediatric Liver and Gut Research Group, Children's Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, Finland; Section of Pediatric Surgery, Children's Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, Finland. Electronic address:

Background: Liver disease occurs frequently in short bowel syndrome. Whether small bowel dilation in short bowel syndrome could influence the risk of liver injury through increased bacterial translocation remains unknown. Our aim was to analyze associations between small bowel dilation, mucosal damage, bloodstream infections, and liver injury in short bowel syndrome patients.

Methods: Among short bowel syndrome children (n = 50), maximal small bowel diameter was measured in contrast series and expressed as the ratio to the height of the fifth lumbar vertebra (small bowel diameter ratio), and correlated retrospectively to fecal calprotectin and plasma citrulline-respective markers of mucosal inflammation and mass-bloodstream infections, liver biochemistry, and liver histology.

Results: Patients with pathologic small bowel diameter ratio >2.17 had increased fecal calprotectin and decreased citrulline (P < .04 each). Of 33 bloodstream infections observed during treatment with parenteral nutrition, 16 were caused by intestinal bacteria, cultured 15 times more frequently when small bowel diameter ratio was >2.17 (P < .001). Intestinal bloodstream infections were predicted by small bowel diameter ratio (odds ratio 1.88, P = .017), and their frequency decreased after operative tapering procedures (P = .041). Plasma bilirubin concentration, gamma-glutamyl transferase activity, and histologic grade of cholestasis correlated with small bowel diameter ratio (0.356-0.534, P < .014 each), and were greater in the presence of intestinal bloodstream infections (P < .001 for all). Bloodstream infections associated with portal inflammation, cholestasis, and fibrosis grades (P < .031 for each). In linear regression, histologic cholestasis was predicted by intestinal bloodstream infections, small bowel diameter ratio, and parenteral nutrition (β = 0.36-1.29; P < .014 each), while portal inflammation by intestinal bloodstream infections only (β = 0.62; P = .033).

Conclusion: In children with short bowel syndrome, small bowel dilation correlates with mucosal damage, bloodstream infections of intestinal origin, and cholestatic liver injury. In addition to parenteral nutrition, small bowel dilation and intestinal bloodstream infections contribute to development of short bowel syndrome-associated liver disease.
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http://dx.doi.org/10.1016/j.surg.2017.04.018DOI Listing
September 2017

Molecular signature of active fibrogenesis prevails in biliary atresia after successful portoenterostomy.

Surgery 2017 09 24;162(3):548-556. Epub 2017 Jun 24.

Pediatric Surgery and Pediatric Transplantation Surgery, Pediatric Liver and Gut Research Group, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Background: In biliary atresia mechanisms of progressive liver injury leading to need of liver transplantation after successful portoenterostomy remain unknown. A better understanding is a prerequisite for development of novel therapies to extend native liver survival, and we aimed to unravel molecular characteristics of liver injury after successful portoenterostomy.

Methods: Liver biopsies obtained from 28 biliary atresia children during successful portoenterostomy and at median age 3.0 years were studied. Biopsies were analyzed for histology and immunohistochemical expression of collagen 1, myofibroblast marker α-smooth muscle actin, and cytokeratin-7 positive ductal reactions. Hepatic ribonucleic acid (RNA) expression of growth factors and inflammatory cytokines was evaluated. Intestinal failure patients with comparable liver fibrosis and nonfibrotic gallstone patients and donor livers were controls.

Results: After successful portoenterostomy, histologic cholestasis resolved and portal inflammation reduced, while fibrosis along with ductal reactions and overexpression of collagen and α-smooth muscle actin persisted. At follow-up, liver RNA expression of collagen and platelet-derived growth factor was increased, whereas RNA expression of various inflammatory cytokines remained low. Disappearance of periductal α-smooth muscle actin expression after successful portoenterostomy (36% of patients) associated with contracted ductal reactions and reduced progression of fibrosis, collagen accumulation, platelet-derived growth factor RNA expression, and serum levels of bile acids and bilirubin. Fibrosis progressed less rapidly in syndromic than in isolated biliary atresia patients.

Conclusion: These findings suggest that instead of inflammation, molecular signature of active fibrogenesis in association with ductal reactions prevails in long-term native liver survivors with biliary atresia. Patients should be stratified for isolated and syndromic disease forms in interventional studies.
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http://dx.doi.org/10.1016/j.surg.2017.04.013DOI Listing
September 2017

Liver Inflammation Relates to Decreased Canalicular Bile Transporter Expression in Pediatric Onset Intestinal Failure.

Ann Surg 2018 08;268(2):332-339

Section of Pediatric Surgery, Pediatric Liver and Gut Research Group, Children's Hospital, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.

Objective: Although liver disease is a major complication of parenteral nutrition (PN) for intestinal failure (IF), its pathogenesis remains unclear. We investigated potential molecular mechanisms of liver injury in pediatric onset IF.

Methods: Liver expression of canalicular phospholipid (ABCB4), bile acid (ABCB11), and sterol (ABCG5/8) transporters, their upstream regulators LXR and FXR as well as pro-inflammatory cytokines interleukin-6 (IL6) and tumor necrosis factor (TNF) were investigated among patients with IF [age median 3.8 (IQR 1.2 to 11)] in relation to biochemical and histologic liver injury, PN, serum plant sterols, fibroblast growth factor 19, and α-tocopherol.

Results: Patients receiving PN currently (n = 18) showed more advanced liver injury than patients after weaning off PN (n = 30). Histologic portal inflammation strongly segregated PN-dependent (44%) from weaned off patients (3%, P = 0.001) and coupled with progression of cholestasis and liver fibrosis. Patients with portal inflammation demonstrated markedly induced liver RNA expression of IL6 and TNF, repression of FXR and its canalicular bile transporter target gene RNA expression, including ABCB4 and ABCB11 as well as decreased protein expression of ABCB11 and ABCB4. Furthermore, upregulation of LXR and ABCG5/8 RNA expression was suppressed in patients with portal inflammation. Current PN, increased serum levels of plant sterols stigmasterol, avenasterol, and sitosterol along with serum citrulline, a marker of enterocyte mass, predicted portal inflammation.

Conclusions: In pediatric onset IF, current PN delivery synergistically with intestinal compromise promote liver inflammation, which associates with progression of biochemical and histologic liver injury, while reducing expression of canalicular bile transporters.
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http://dx.doi.org/10.1097/SLA.0000000000002187DOI Listing
August 2018

Serum fasting GLP-1 and GLP-2 associate with intestinal adaptation in pediatric onset intestinal failure.

Clin Nutr 2017 10 14;36(5):1349-1354. Epub 2016 Sep 14.

Section of Pediatric Surgery, Pediatric Liver and Gut Research Group, Children's Hospital, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.

Aim: Glukagon-like-peptide-1 (GLP-1) and -2 (GLP-2), produced by intestinal L-cells, are key hormones regulating intestinal transit, secretion, absorption, and mucosal growth. We evaluated naïve fasting serum GLP-1 and GLP-2 levels in pediatric intestinal failure (IF).

Methods: Fifty-five IF patients with median age 4.2 (IQR 1.3-12) years and 47 matched healthy controls underwent measurement of fasting serum GLP-1 and GLP-2.

Results: Serum GLP-2 [19.9 (13.8-27.9) vs 11.6 (7.0-18.6) ng/mL, P < 0.001], but not GLP-1 [6.1 (4.0-15.7) vs 6.4 (3.9-10.7) ng/mL, P = 0.976], levels were increased in IF patients. Serum GLP-2 concentrations were higher in patients with small bowel-colic continuity [21.1 (15.0-30.7) ng/mL] compared to patients with an endostomy [10.4 (6.6-17.9) ng/mL, P = 0.028], whereas no association with preservation of ileum or ileocecal valve was observed. During PN delivery, GLP-2 inversely associated with remaining small bowel length (r = -0.500, P = 0.041) and frequency of PN infusions (r = -0.549, P = 0.042). Serum GLP-1 levels were lower in patients receiving PN currently [4.1 (2.8-5.1)] compared to patients, who had weaned off PN [6.5 (5.1-21.1), P = 0.005], and correlated positively with duration of PN (r = 0.763, P = 0.002) and negatively with percentage parenteral energy requirement (r = -0.716, P = 0.006).

Conclusions: In pediatric IF, serum GLP-2 levels increase in patients with small bowel-colic continuity proportionally to the length of resected small intestine. Increase in serum GLP-1 and GLP-2 levels paralleled reducing requirement for parenteral support. These findings support regulation of intestinal adaption by GLP-2 and GLP-1 in children with IF.
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http://dx.doi.org/10.1016/j.clnu.2016.09.002DOI Listing
October 2017

Increased MMP-7 expression in biliary epithelium and serum underpins native liver fibrosis after successful portoenterostomy in biliary atresia.

J Pathol Clin Res 2016 Jul 12;2(3):187-98. Epub 2016 May 12.

Pediatric Surgery and Pediatric Transplantation Surgery, Pediatric Liver and Gut Research Group, Children's Hospital, University of Helsinki and Helsinki University Hospital Helsinki Finland.

The molecular mechanisms underlying progressive liver fibrosis following surgical treatment of biliary atresia (BA) remain unclear. Our aim was to address hepatic gene and protein expression and serum levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) after successful portoenterostomy (PE), and relate them to histological signs of liver injury, clinical follow-up data and biochemical markers of hepatic function. LIver biopsies and serum samples were obtained from 25 children after successful PE at median age of 3.3 years. Serum MMP concentrations were determined by enzyme-linked immune sorbent assay. Hepatic gene expression of MMPs and TIMPs was analyzed using real-time reverse-transcription PCR. Liver expression of MMP-7 and cytokeratin-7 was studied using immunohistochemistry. Despite effective clearance of biochemical and histological cholestasis following PE, BA patients showed increased hepatic gene expression of MMP-7 (29-fold, p < 0.001), MMP-2 (3.1-fold, p < 0.001), MMP-14 (1.7-fold, p = 0.007), and TIMP-1 (1.8-fold, p < 0.001), when compared to controls. Similar to a biliary epithelial marker cytokeratin-7, expression of MMP-7 localized in biliary epithelium of bile ducts and ductal proliferations and periportal hepatocytes and was increased (p < 0.001) in relation to controls. BA patients had 6-fold higher serum levels of MMP-7 (p < 0.001), which correlated positively with hepatic MMP-7 gene (r = 0.548, p = 0.007) and protein (r = 0.532, p = 0.007) expression. Patients showed a positive correlation between biliary MMP-7 expression and Metavir fibrosis stage (r = 0.605, p = 0.001) and portal fibrosis grade (r = 0.606, p = 0.001). Neither similarly increased MMP-7 expression nor correlation with liver fibrosis was observed in patients with intestinal failure-associated liver disease and comparable Metavir stage. In conclusion, our findings support an unique role of altered hepatic expression of MMP-7 in the progression of liver fibrosis after successful PE and introduce a potential therapeutic target to pharmacologically extend native liver survival by inhibiting MMP-7 hyperactivity. Serum MMP-7 may be a valuable postoperative prognostic tool in BA.
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http://dx.doi.org/10.1002/cjp2.50DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4958739PMC
July 2016

Duodenal Disaccharidase Activities During and After Weaning off Parenteral Nutrition in Pediatric Intestinal Failure.

J Pediatr Gastroenterol Nutr 2017 05;64(5):777-782

*Pediatric Surgery and Pediatric Liver and Gut Research Group †Pediatric Gastroenterology and Pediatric Liver and Gut Research Group, Children's Hospital, Helsinki University Hospital, Finland.

Objectives: Data on factors affecting absorptive function in children with intestinal failure (IF) are sparse. We evaluated duodenal disaccharidase activities and inflammation in relation to parenteral nutrition (PN) and intestinal resection in pediatric onset IF.

Methods: Disaccharidase (maltase, sucrase, and lactase) activities and histologic inflammation were evaluated from duodenal biopsies in 58 patients during PN (n = 23) or full enteral nutrition (n = 40) and in 43 matched controls. The first and the last postresection biopsies were analyzed separately after 4.3 (1.2-9.7) years and 6.5 (2.3-12.4) years, respectively.

Results: During PN, maltase and sucrase activities were 1.6-fold lower and mucosal inflammation more frequent (22% vs 3%) when compared to matched controls (P < 0.05 for both). In patients on full enteral nutrition, activities of maltase and sucrase were significantly higher than that in patients receiving PN and comparable to those of matched controls. Postresection time correlated positively (r = 0.448 and r = 0.369) and percentage length of the remaining small intestine inversely (r = -0.337 and r = -0.407) with maltase and sucrase activity in patients on full enteral nutrition (P < 0.05 for all), whereas proportional length of remaining colon correlated positively with maltase and lactase activity (r = 0.424-0.544, P < 0.05) in patients receiving PN.

Conclusions: In children with IF, PN dependency associated with decreased duodenal maltase and sucrase activities and mucosal inflammation, which may disturb intestinal absorptive function. Localization and extent of intestinal resection and post-resection time correlated with duodenal disaccharidase activities.
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http://dx.doi.org/10.1097/MPG.0000000000001347DOI Listing
May 2017

Features of liver tissue remodeling in intestinal failure during and after weaning off parenteral nutrition.

Surgery 2016 09 4;160(3):632-42. Epub 2016 Jun 4.

Section of Pediatric Surgery, Pediatric Liver and Gut Research Group, Children's Hospital, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland. Electronic address:

Background: Intestinal failure is associated frequently with liver injury, which persists after weaning off parenteral nutrition. We compared features of liver remodeling in intestinal failure during and after weaning off parenteral nutrition.

Methods: Liver biopsies and serum samples were obtained from 25 intestinal failure patients at a median age of 9.7 years (interquartile range: 4.6-18) and from age-matched control patients. Seven patients had been receiving parenteral nutrition for 53 months (22-160), and 18 patients had been weaned off parenteral nutrition 6.3 years (2.4-17) earlier, after having received parenteral nutrition for 10 months (3.3-34). Expression of alpha-smooth muscle actin, collagen 1, proinflammatory cytokines, growth factors, and matrix metalloproteinases (MMPs) was measured.

Results: Significant increases in immunohistochemical expression of alpha-smooth muscle actin and collagen 1 were observed predominantly in portal areas and were similar to increases seen in patients currently receiving parenteral nutrition and in patients weaned off parenteral nutrition. Gene and protein expressions of alpha-smooth muscle actin and collagen were interrelated. Gene expression of ACTA2, encoding alpha-smooth muscle actin, was increased only in patients who were receiving parenteral nutrition currently. Comparable upregulation of interleukin-1 (α and ß), epidermal growth factor, integrin-ß6, and MMP9 gene expression was observed in both patient groups, irrespective of whether they were receiving parenteral nutrition currently. Liver expression and serum levels of TIMP1 and MMP7 were increased only in the patients on parenteral nutrition currently but were not increased after weaning off parenteral nutrition.

Conclusion: Intestinal failure is characterized by abnormal activation of hepatic myofibroblast and accumulation of collagen both during and after weaning off parenteral nutrition. Persistent transcriptional upregulation of proinflammatory and fibrogenic cytokines after weaning off parenteral nutrition suggests that factors other than parenteral nutrition may contribute to intestinal failure-associated liver disease.
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http://dx.doi.org/10.1016/j.surg.2016.04.025DOI Listing
September 2016

Parenteral Plant Sterols Accumulate in the Liver Reflecting Their Increased Serum Levels and Portal Inflammation in Children With Intestinal Failure.

JPEN J Parenter Enteral Nutr 2017 08 9;41(6):1014-1022. Epub 2016 Mar 9.

1 Pediatric Liver and Gut Research Group, Children's Hospital, Helsinki University Hospital, Helsinki, Finland.

Background: Parenteral plant sterols (PSs) are considered hepatotoxic; however, liver PSs and their associations with liver injury in patients with intestinal failure (IF) have not been reported.

Materials And Methods: We analyzed liver and serum PS (avenasterol, campesterol, sitosterol, and stigmasterol) concentrations and ratios to cholesterol and their associations with biochemical and histologic liver damage in children with IF during (n = 7) parenteral nutrition (PN) and after weaning off it (n = 9), including vegetable oil-based lipid emulsions.

Results: Liver avenasterol, sitosterol, and total PS concentrations and cholesterol ratios were 2.4-fold to 5.6-fold higher in PN-dependent patients ( P < .05). Parenteral PS delivery reflected liver avenasterol and sitosterol ratios to cholesterol ( r = 0.83-0.89, P = .02-.04), while serum and liver total PS levels were positively interrelated ( r = 0.98, P < .01). Any liver histopathology was equally common while portal inflammation more frequent (57 vs 0%, P = .02) in PN-dependent patients. All liver PS fractions correlated positively with histologic portal inflammation ( r = 0.53-0.66, P < .05), and their total concentration was significantly ( P = .01) higher among patients with versus without portal inflammation. In PN-dependent patients, liver fibrosis and any histopathology correlated with liver campesterol and stigmasterol levels ( r = 0.79-0.87, P ≤ .03).

Conclusion: Among children with IF, parenteral PSs accumulate in the liver, reflect their increased serum levels, and relate with biochemical liver injury, portal inflammation, and liver fibrosis, thus supporting their role in promoting liver damage.
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http://dx.doi.org/10.1177/0148607116637855DOI Listing
August 2017

[Diaphragmatic rupture: case report of a rare complication of labor].

Duodecim 2015 ;131(8):753-6

A diaphragmatic rupture associated with labor is a rare complication of pregnancy with high fetal and maternal mortality. Due to non-specific symptoms and rareness of the disease the diagnosis can be challenging. We present a case of a healthy 26-year old woman with one previous childbirth who presented upper abdominal pain, tachycardia and dyspnea during labor. Immediately after labor, a left-sided diaphragmatic rupture complicated with ventricle perforation was diagnosed. After prompt diagnosis and immediate surgical care, including thoracotomy and laparotomy, both patient and child experienced a full recovery.
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August 2015

Long-term health-related quality of life of patients with pediatric onset intestinal failure.

J Pediatr Surg 2015 Nov 3;50(11):1854-8. Epub 2015 Jun 3.

Pediatric Surgery, Pediatric Liver and Gut Research Group, Helsinki University Central Hospital and University of Helsinki.

Background: Despite improved survival rates of patients with pediatric intestinal failure (IF), data on health-related quality of life (HRQoL) of IF patients are still scarce. We hypothesized that I) continued parenteral nutrition, underlying intestinal motility disorder, abdominal pain and problematic bowel function would be associated with poorer HRQoL and higher parental stress levels, and II) the time intervals since the latest bowel operation, the latest episode of sepsis, and the latest inpatient care episode would be associated with better HRQoL and lower parental stress.

Methods: Patients with pediatric onset IF and their parents answered questionnaires on HRQoL, parental stress, and bowel-related symptoms. Clinical data were gathered by chart review. Controls matched for age and sex were randomly chosen by the Population Register Centre of Finland.

Results: Thirty-six (73%) IF patients participated at a median age of 9years. Overall HRQoL was similar to healthy peers, and frequent abdominal pain was the only factor associated with poorer HRQoL. Abdominal pain and stool frequency >3 times per day were associated with higher levels of parental stress, whereas longer time intervals since the latest bowel operation or hospitalization were associated with lower parental stress levels.

Conclusion: Long-term HRQoL of pediatric IF patients is comparable to that of healthy peers. Time often eases parental stress, but frequent abdominal pain presents a challenge to the well-being of some patients and requires medical attention.
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http://dx.doi.org/10.1016/j.jpedsurg.2015.05.012DOI Listing
November 2015

Transient elastography and aspartate aminotransferase to platelet ratio predict liver injury in paediatric intestinal failure.

Liver Int 2016 Mar 25;36(3):361-9. Epub 2015 Jun 25.

Pediatric Liver and Gut Research Group, Children's Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.

Background & Aims: We aimed to evaluate the value of AST to platelet ratio (APRI) and transient elastography (TE) as predictors of liver histopathology in children with intestinal failure (IF).

Methods: Altogether 93 liver biopsies from 57 children with parenteral nutrition (PN) duration ≥3 months were analysed. APRI measurement and TE (n = 46) were performed at the time of biopsy.

Results: IF was caused by short bowel syndrome in 75% of patients. At the time of liver biopsy, PN dependent patients (n = 42) were younger with longer PN duration compared to those weaned off PN (n = 51) (2.2 vs. 7.6 years, P < 0.001; 26 vs. 10.5 months, P = 0.043). Elevated transaminase or bilirubin levels were found in 51%, splenomegaly in 26%, and oesophageal varices in 3.5%. Histological fibrosis was present in 61% (Metavir stage F1; 27%, F2; 26%, F3-4; 9%), cholestasis in 25% and steatosis in 22% of biopsy specimens. TE was superior to APRI in prediction of any liver histopathology (fibrosis, cholestasis or steatosis) with areas under the receiving operating curve (AUROC) of 0.86 (95% CI 0.74-0.97) and 0.67 (95% CI 0.58-0.78) respectively. For prediction of ≥F1 and ≥F2 fibrosis, AUROC values for TE were 0.78 (95% CI 0.64-0.93) and 0.73 (95% CI 0.59-0.88), whereas APRI did not correlate with fibrosis stages. For detection of histological cholestasis, the AUROC for APRI was 0.77 (95% CI 0.64-0.89).

Conclusions: Both TE and APRI are promising noninvasive methods for monitoring the development of IF-related liver histopathology. TE values reflected the degree of fibrosis better while APRI detected histological cholestasis more accurately.
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http://dx.doi.org/10.1111/liv.12887DOI Listing
March 2016

Intestinal Microbiota Signatures Associated With Histological Liver Steatosis in Pediatric-Onset Intestinal Failure.

JPEN J Parenter Enteral Nutr 2017 02 30;41(2):238-248. Epub 2016 Sep 30.

2 Section of Pediatric Surgery, Pediatric Liver and Gut Research Group, Children's Hospital, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.

Background: Intestinal failure (IF)-associated liver disease (IFALD) is the major cause of mortality in IF. The link between intestinal microbiota and IFALD is unclear.

Methods: We compared intestinal microbiota of patients with IF (n = 23) with healthy controls (n = 58) using culture-independent phylogenetic microarray analysis. The microbiota was related to histological liver injury, fecal markers of intestinal inflammation, matrix metalloproteinase 9 and calprotectin, and disease characteristics.

Results: Overabundance of Lactobacilli, Proteobacteria, and Actinobacteria was observed in IF, whereas bacteria related to Clostridium clusters III, IV, and XIVa along with overall diversity and richness were reduced. Patients were segregated into 3 subgroups based on dominating bacteria: Clostridium cluster XIVa, Proteobacteria, and bacteria related to Lactobacillus plantarum. In addition to liver steatosis and fibrosis, Proteobacteria were associated with prolonged current parenteral nutrition (PN) as well as liver and intestinal inflammation. Lactobacilli were related to advanced steatosis and fibrosis mostly after weaning off PN without associated inflammation. In multivariate permutational analysis of variance, liver steatosis, bowel length, PN calories, and antibiotic treatment best explained the microbiota variation among patients with IF.

Conclusions: Intestinal microbiota composition was associated with liver steatosis in IF and better predicted steatosis than duration of PN or length of the remaining intestine. Our results may be explained by a model in which steatosis is initiated during PN in response to proinflammatory lipopolysaccharides produced by Proteobacteria and progresses after weaning off PN, as the L plantarum group Lactobacilli becomes dominant and affects lipid metabolism by altering bile acid signaling.
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http://dx.doi.org/10.1177/0148607115584388DOI Listing
February 2017

Loss of ileum decreases serum fibroblast growth factor 19 in relation to liver inflammation and fibrosis in pediatric onset intestinal failure.

J Hepatol 2015 Jun 13;62(6):1391-7. Epub 2015 Jan 13.

Section of Pediatric Surgery, Pediatric Liver and Gut Research Group Helsinki, Children's Hospital, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.

Background & Aims: The pathogenesis of intestinal failure (IF) associated liver disease (IFALD) is uncertain, we therefore investigated the role of FGF19 and pro-inflammatory cytokines has on this disease state.

Methods: Serum FGF19, IL-6 and, TNF-α were measured in 52 IF patients at median age 6.0 years (IQR 2.2-13) after 10 months (4.1-39) on parenteral nutrition (PN). Thirty-nine patients underwent liver biopsies.

Results: In IF patients, FGF19 concentrations were lower and those of IL-6 and TNF-α higher compared to healthy matched controls (p ⩽ 0.001 for all). FGF19 concentrations were further decreased in patients without a remaining ileum [37 pg/ml (IQR 30-68) vs. 74 (35-135) p=0.028], and correlated with remaining ileum length (r = 0.333, p = 0.018) and markers of cholesterol synthesis (r = -0.552 to -0.643, p < 0.001). Patients with histological portal inflammation [30 pg/ml (28-45) vs. 48 (33-100), p = 0.019] or fibrosis [35 pg/ml (30-66) vs. 99 (38-163), p = 0.013] had lower serum FGF19 concentrations than others. FGF19 negatively correlated with portal inflammation grade (r = -0.442, p = 0.005), serum TNF-α (r = -0.318, p = 0.025), METAVIR fibrosis stage (r = -0.441, p = 0.005) and APRI (r = -0.328, p = 0.028). IL-6 was higher during PN [6 pg/ml (2-31)] than after weaning off PN [2 pg/ml (1-5), p = 0.009], correlated weakly with cholestasis grade (r = 0.328, p = 0.044), and tended to associate with histological cholestasis [n = 5, 5 pg/ml (5-267) vs. n=34, 2 pg/ml (1-7), p = 0.058].

Conclusions: In pediatric onset of IF, total or partial loss of ileum decreases serum FGF19 concentration corresponding to hepatic inflammation and fibrosis, along with increased cholesterol synthesis. In contrast, serum IL-6 increases during PN and may associate with concurrent cholestasis. These data suggests that FGF19 may contribute to the pathogenesis of IFALD.
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http://dx.doi.org/10.1016/j.jhep.2015.01.004DOI Listing
June 2015

Surgical rehabilitation of short and dysmotile intestine in children and adults.

Scand J Gastroenterol 2015 Feb 25;50(2):153-61. Epub 2014 Nov 25.

Pediatric Liver and Gut Research Group, University of Helsinki , Helsinki , Finland.

Aims: This is a descriptive study aiming to compare outcomes of intestinal rehabilitation surgery among pediatric and adult intestinal failure (IF) patients with either primary intestinal motility disorders or short bowel syndrome (SBS) treated by our nationwide program.

Methods: Medical records of IF patients (n = 31, 71% children) having undergone autologous intestinal reconstructions (AIR) (n = 25), intestinal transplantation (ITx) (n = 5), or being listed for ITx (n = 2) between 1994 and 2014 were reviewed.

Results: At surgery, median age was 3.4 (interquartile range, 1.0-22.1) in SBS (n = 22) and 16.5 (3.2-26.7) years in dysmotility patients (n = 9) who received median 60% and 83% of energy requirement parenterally, respectively. Median small bowel length was shorter in SBS than dysmotility patients (34 versus 157 cm, p < 0.001). Following AIR, none of the dysmotility patients achieved permanent intestinal autonomy, whereas 68% of SBS patients weaned off parenteral nutrition (PN) (p = 0.022) and none required listing for ITx. Five dysmotility patients who underwent ITx achieved intestinal autonomy. Regarding both AIR and ITx procedures, no significant difference in PN weaning was observed between the two subgroups. At last follow-up, 3.3 (0.6-8.0) years postoperatively, median plasma bilirubin was 6 (4-16) µmol/l, while liver biopsy showed fibrosis (Metavir stage 1-2) in 50% and cholestasis in 8%. Proportion of PN energy requirement had reduced significantly (p = 0.043) among PN-dependent SBS (n = 7) but not among dysmotility patients (n = 5). Overall survival was 90%.

Conclusion: AIR surgery was beneficial among selected SBS patients, whereas in intestinal dysmotility disorders, permanent PN weaning was only achieved by ITx.
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http://dx.doi.org/10.3109/00365521.2014.962607DOI Listing
February 2015