Systematic Reviews and Meta-analyses of the Procedure-specific Risks of Thrombosis and Bleeding in General Abdominal, Colorectal, Upper Gastrointestinal, and Hepatopancreatobiliary Surgery.

OBJECTIVE: To provide procedure-specific estimates of symptomatic venous thromboembolism (VTE) and major bleeding after abdominal surgery. BACKGROUND: The use of pharmacological thromboprophylaxis represents a trade-off that depends on VTE and bleeding risks that vary between procedures; their magnitude remains uncertain. METHODS: We identified observational studies reporting procedure-specific risks of symptomatic VTE or major bleeding after abdominal surgery, adjusted the reported estimates for thromboprophylaxis and length of follow-up, and estimated cumulative incidence at 4 weeks postsurgery, stratified by VTE risk groups, and rated evidence certainty. RESULTS: After eligibility screening, 285 studies (8,048,635 patients) reporting on 40 general abdominal, 36 colorectal, 15 upper gastrointestinal, and 24 hepatopancreatobiliary surgery procedures proved eligible. Evidence certainty proved generally moderate or low for VTE and low or very low for bleeding requiring reintervention. The risk of VTE varied substantially among procedures: in general abdominal surgery from a median of <0.1% in laparoscopic cholecystectomy to a median of 3.7% in open small bowel resection, in colorectal from 0.3% in minimally invasive sigmoid colectomy to 10.0% in emergency open total proctocolectomy, and in upper gastrointestinal/hepatopancreatobiliary from 0.2% in laparoscopic sleeve gastrectomy to 6.8% in open distal pancreatectomy for cancer. CONCLUSIONS: VTE thromboprophylaxis provides net benefit through VTE reduction with a small increase in bleeding in some procedures (eg, open colectomy and open pancreaticoduodenectomy), whereas the opposite is true in others (eg, laparoscopic cholecystectomy and elective groin hernia repairs). In many procedures, thromboembolism and bleeding risks are similar, and decisions depend on individual risk prediction and values and preferences regarding VTE and bleeding.

Role of preoperative in-hospital delay on appendiceal perforation while awaiting appendicectomy (PERFECT): a Nordic, pragmatic, open-label, multicentre, non-inferiority, randomised controlled trial.

BACKGROUND: Appendicectomy remains the standard treatment for appendicitis. No international consensus exists on the surgical urgency for acute uncomplicated appendicitis, and recommendations vary from surgery without delay to surgery within 24 h. Longer in-hospital delay has been thought to increase the risk of perforation and further morbidity. Therefore, we aimed to compare the rate of appendiceal perforation in patients undergoing appendicectomy scheduled to two different urgencies (<8 h vs <24 h). METHODS: In this pragmatic, open-label, multicentre, non-inferiority, parallel, randomised controlled trial in two hospitals in Finland and one in Norway, patients (aged ≥18 years) with presumed uncomplicated acute appendicitis were randomly assigned (1:1) to an appendicectomy scheduled within 8 h or within 24 h to determine whether longer in-hospital delay (time between randomisation and surgical incision) is not inferior to shorter delay. Patients were excluded in cases of pregnancy, suspicion of perforated appendicitis (C-reactive protein level of ≥100 mg/L, fever >38·5°C, signs of complicated appendicitis on imaging studies, or clinical generalised peritonitis), or other reasons requiring prompt surgery. The recruiters were on-duty surgeons who decided to proceed with the appendicectomy. The randomisation sequence was generated using block randomisation with randomly varying block sizes and stratified by hospital districts; neither physicians nor patients were masked to group assignment. The primary outcome was perforated appendicitis diagnosed during surgery analysed in all patients who received an appendicectomy by intention to treat. The absolute difference in rates of perforated appendicitis was compared between the groups. Complications and other safety outcomes were analysed in all patients who received an appendicectomy. A margin of 5 percentage points was used to establish non-inferiority. This trial was registered at ClinicalTrials.gov (NCT04378868) and is closed to accrual. FINDINGS: Between May 18, 2020, and Dec 31, 2022, 2095 patients were assessed for eligibility, of whom 1822 were randomly assigned to appendicectomy scheduled within 8 h (n=914) or 24 h (n=908). After randomisation, 19 (1%) of 1822 patients were excluded due to protocol violation. 1803 patients were included in the intention-to-treat analyses, 985 (55%) of whom were male and 818 (45%) female. Appendiceal perforation rate was similar between groups (77 [8%] of 907 patients assigned to the <8 h group and 81 [9%] of 896 patients assigned to the <24 h group; absolute risk difference 0·6% [95% CI -2·1 to 3·2], p=0·68; risk ratio 1·065, 95% CI 0·790 to 1·435). No significant difference was found between the complication rates within 30 days (66 [7%] of 907 patients in the <8 h group vs 56 [6%] of 896 patients in the <24 h group; difference -1·0% [-3·3 to 1·3]; p=0·39), and no deaths occurred during this follow-up period. INTERPRETATION: In patients with presumed uncomplicated acute appendicitis, scheduling appendicectomy within 24 h does not increase the risk of appendiceal perforation compared with scheduling appendicectomy within 8 h. The results can be used to allocate operating room resources, for example postponing night-time appendicectomy to daytime. FUNDING: The Finnish Medical Foundation, Mary and Georg Ehrnrooth's Foundation, Biomedicum Helsinki Foundation, and the Finnish Government.

The unrestricted global effort to complete the COOL trial.

BACKGROUND: Severe complicated intra-abdominal sepsis (SCIAS) has an increasing incidence with mortality rates over 80% in some settings. Mortality typically results from disruption of the gastrointestinal tract, progressive and self-perpetuating bio-mediator generation, systemic inflammation, and multiple organ failure. A further therapeutic option may be open abdomen (OA) management with negative peritoneal pressure therapy (NPPT) to remove inflammatory ascites and attenuate the systemic damage from SCIAS, although there are definite risks of leaving the abdomen open whenever it might possibly be closed. This potential therapeutic paradigm is the rationale being assessed in the Closed Or Open after Laparotomy (COOL trial) ( https://clinicaltrials.gov/ct2/show/NCT03163095 ). Initially, the COOL trial received Industry sponsorship; however, this funding mandated the use of a specific trademarked and expensive NPPT device in half of the patients allocated to the intervention (open) arm. In August 2022, the 3 M/Acelity Corporation without consultation but within the terms of the contract canceled the financial support of the trial. Although creating financial difficulty, there is now no restriction on specific NPPT devices and removing a cost-prohibitive intervention creates an opportunity to expand the COOL trial to a truly global basis. This document describes the evolution of the COOL trial, with a focus on future opportunities for global growth of the study. METHODS: The COOL trial is the largest prospective randomized controlled trial examining the random allocation of SCIAS patients intra-operatively to either formal closure of the fascia or the use of the OA with an application of an NPPT dressing. Patients are eligible if they have free uncontained intraperitoneal contamination and physiologic derangements exemplified by septic shock OR severely adverse predicted clinical outcomes. The primary outcome is intended to definitively inform global practice by conclusively evaluating 90-day survival. Initial recruitment has been lower than hoped but satisfactory, and the COOL steering committee and trial investigators intend with increased global support to continue enrollment until recruitment ensures a definitive answer. DISCUSSION: OA is mandated in many cases of SCIAS such as the risk of abdominal compartment syndrome associated with closure, or a planned second look as for example part of "damage control"; however, improved source control (locally and systemically) is the most uncertain indication for an OA. The COOL trial seeks to expand potential sites and proceed with the evaluation of NPPT agnostic to device, to properly examine the hypothesis that this treatment attenuates systemic damage and improves survival. This approach will not affect internal validity and should improve the external validity of any observed results of the intervention. TRIAL REGISTRATION: National Institutes of Health ( https://clinicaltrials.gov/ct2/show/NCT03163095 ).

The Critical View of Safety in Laparoscopic Cholecystectomy: User Trends Among Residents and Consultants.

BACKGROUND: The Critical View of Safety (CVS) aims at preventing bile duct injuries (BDIs) in laparoscopic cholecystectomy (LCC). This study investigated CVS utilization among surgeons. METHODS: Photos from LCCs were scored for satisfactory CVS. Rates of satisfactory CVS, BDIs, and postoperative complications among residents and consultants were compared. A lecture on CVS was given halfway through the study. RESULTS: The study comprised 1532 patients. Residents had higher rates of satisfactory CVS in elective LCCs compared with consultants (34.9% vs. 23.0%, P <0.001), but not in emergency LCCs (18.4% vs. 15.0%, P =0.252). No significant differences in BDIs or postoperative complications emerged between residents and consultants. After the lecture, elective LCCs were photographed more frequently (80.3% vs. 74.0%, P =0.032), but rates of satisfactory CVS, BDIs, and postoperative complications remained unchanged. CONCLUSIONS: Utilization of CVS can be affected by a single lecture but affecting rates of satisfactory CVS may require stronger interventions.

Systematic reviews of observational studies of Risk of Thrombosis and Bleeding in General and Gynecologic Surgery (ROTBIGGS): introduction and methodology.

BACKGROUND: Venous thromboembolism (VTE) and bleeding are serious and potentially fatal complications of surgical procedures. Pharmacological thromboprophylaxis decreases the risk of VTE but increases the risk of major post-operative bleeding. The decision to use pharmacologic prophylaxis therefore represents a trade-off that critically depends on the incidence of VTE and bleeding in the absence of prophylaxis. These baseline risks vary widely between procedures, but their magnitude is uncertain. Systematic reviews addressing baseline risks are scarce, needed, and require innovations in methodology. Indeed, systematic summaries of these baseline risk estimates exist neither in general nor gynecologic surgery. We will fill this knowledge gap by performing a series of systematic reviews and meta-analyses of the procedure-specific and patient risk factor stratified risk estimates in general and gynecologic surgeries. METHODS: We will perform comprehensive literature searches for observational studies in general and gynecologic surgery reporting symptomatic VTE or bleeding estimates. Pairs of methodologically trained reviewers will independently assess the studies for eligibility, evaluate the risk of bias by using an instrument developed for this review, and extract data. We will perform meta-analyses and modeling studies to adjust the reported risk estimates for the use of thromboprophylaxis and length of follow up. We will derive the estimates of risk from the median estimates of studies rated at the lowest risk of bias. The primary outcomes are the risk estimates of symptomatic VTE and major bleeding at 4 weeks post-operatively for each procedure stratified by patient risk factors. We will apply the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to rate evidence certainty. DISCUSSION: This series of systematic reviews, modeling studies, and meta-analyses will inform clinicians and patients regarding the trade-off between VTE prevention and bleeding in general and gynecologic surgeries. Our work advances the standards in systematic reviews of surgical complications, including assessment of risk of bias, criteria for arriving at the best estimates of risk (including modeling of the timing of events and dealing with suboptimal data reporting), dealing with subgroups at higher and lower risk of bias, and use of the GRADE approach. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021234119.

The critical view of safety and bile duct injuries in laparoscopic cholecystectomy: a photo evaluation study on 1532 patients.

BACKGROUND: Laparoscopic cholecystectomy (LCC) carries a 0.3-1.8% risk of bile duct injury (BDI). This study investigated if intraoperative photo documentation of the critical view of safety (CVS) is related to lower rates of BDIs and postoperative complications in LCC. METHODS: Surgeons were instructed to take photos of the view before clipping the cystic duct and artery. Two independent raters scored the photos 0-6 using predefined criteria for CVS. Mean scores of ≥4.5 were satisfactory. RESULTS: The study consisted of 1532 patients undergoing LCC between April 2018 and October 2019. CVS was satisfactory in 354 (23.1%), unsatisfactory in 823 (53.7%), and photos were missing in 355 (23.2%) patients. Patients with satisfactory CVS had the lowest BDI rate compared with unsatisfactory CVS or missing photos (0.3% vs. 1.0% vs. 2.3%, p = 0.012). Four major BDIs (Strasberg D-E) occurred, but none in patients with satisfactory CVS. Patients with satisfactory CVS had the lowest postoperative complication rate compared with patients with unsatisfactory CVS or without photos (4.8% vs. 7.9 vs. 9.9%, p = 0.011). Of patients with acute cholecystitis, 15.7% had satisfactory CVS, whereas 26.8% without cholecystitis had satisfactory CVS (p < 0.001). CONCLUSION: Intraoperative photo documentation of satisfactory CVS is associated with lower rates of BDIs and complications.

INtravenous Contrast computed tomography versus native computed tomography in patients with acute Abdomen and impaired Renal functiOn (INCARO): a multicentre, open-label, randomised controlled trial - study protocol.

INTRODUCTION: CT is the primary imaging option for acute abdominal pain in adults. Intravenous (IV) contrast media use improves CT quality but may cause post-contrast acute kidney injury (PC-AKI). Retrospective studies show no association between reduced baseline renal function and IV contrast CT, but, to our knowledge, no data from randomised controlled trials exist. METHODS AND ANALYSIS: The INCARO (INtravenous Contrast computed tomography versus native computed tomography in patients with acute Abdomen and impaired Renal functiOn) trial is a multicentre, open-label, parallel group, superiority, individually randomised controlled trial comparing IV contrast-enhanced CT to native CT in patients requiring emergency abdominal or body CT with impaired renal function defined as an estimated glomerular filtration rate (eGFR) of 15 to 45 mL/min/1.73 m2. The primary outcome is a composite of all-cause mortality or renal replacement therapy (RRT) within 90 days from CT. Secondary outcomes are AKI measured by KDIGO (The Kidney Disease: Improving Global Outcomes) criteria within 72 hours from CT, organ dysfunction defined by mSOFA (modified Sequential Organ Failure Assessment) criteria after 48 hours from CT, alive and hospital-free days within 90 days after CT, and time from imaging to definitive treatment. All-cause mortality, need for RRT and renal transplant in long-term follow-up are also measured. The calculated sample size is 994 patients. Patient recruitment is estimated to take 3 years. ETHICS AND DISSEMINATION: The Ethics Committee of Helsinki University Hospital approved the study. The findings will be disseminated in peer-reviewed academic journals. TRIAL REGISTRATION NUMBER: NCT04196244.

Poor performance of noninvasive predictors of esophageal varices during primary prophylaxis surveillance in biliary atresia.

OBJECTIVE: Our objective was to analyze performance of noninvasive markers for significant esophageal varices in relation to outcomes of endoscopic surveillance and primary prophylaxis in biliary atresia (BA). METHODS: This was a prospective follow-up study of a national cohort of BA patients born between 1989 and 2017, including 72 consecutive patients who underwent variceal surveillance endoscopies. The risk for developing significant varices (grade ≥ 2) and variceal bleeding was compared between successful (postoperative total bilirubin ≤34 µmol/L) and failed portoenterostomy (PE) patients. AUROC analyses and Wilcoxon signed ranks test were used to assess accuracy of noninvasive measures to predict the presence of significant varices after successful PE. RESULTS: In total, 72 patients underwent 471 endoscopies during 427 follow-up years. Among 45 successful PE patients (63%), varices appeared later [at median age 1.6 (0.7-14) vs. 0.8 (0.4-1.9) years] and bled less often [7% vs. 41%, p < 0.001 for both] than after failed PE. Liver biochemistry, stiffness, and predictive scores showed poor accuracy for the presence of significant varices. After failed PE, lowered plasma albumin concentration predicted varices with an AUROC of 0.69 (95% CI 0.52-0.85, p = 0.030). After successful PE the varices prediction rule with AUROC 0.72 (95% CI 0.64-0.79) was the most accurate predictor. Individual predictors showed no meaningful changes between the two consecutive endoscopies leading to discovery of varices. CONCLUSION: Accurate targeting of endoscopies based on noninvasive predictors remains difficult during primary variceal prophylaxis protocol in BA. The differing prognoses after successful and failed PE should be considered in variceal surveillance and future studies. TYPE OF STUDY: Diagnostic/prognosis study. LEVEL OF EVIDENCE: Level II.

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

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.

Quality of Life and Parental Worrying in a National Cohort of Biliary Atresia Children Living With Their Native Livers.

OBJECTIVES: The aim of the study was to evaluate health-related quality of life (HRQoL) and parental distress in a national cohort of children with biliary atresia (BA) with their native livers in relation to BA complications and HRQoL of normal population controls. METHODS: We invited all Finnish children with BA surviving with their native livers at age 2 to 18 years to participate in 2009 and in 2014. Parents filled the Pediatric Quality of Life Inventory (PedsQL) proxy questionnaire, a survey of their child's health and evaluated parental distress on a visual-analog scale from 0 to 7. Overall participation rates were 80% (12/15) for the longitudinal and 83% (20/24) for the cross-sectional assessment. A control population of 324 children matched for age and sex was randomly picked, and 108 (33%) participated. RESULTS: Overall, patients and controls had comparable HRQoL. Patients reported significantly lower scores for school functioning (P = 0.004) as depicted by missing school or day care due to hospital visits. Eighty-five percent of parents reported extreme worry (7.0) when hearing their child's BA diagnosis. At 6 years after diagnosis, parents reported significantly less worry: median score 3.8 (interquartile range 3.0-5.4, P < 0.001 for difference). Parents of patients with optimal health were less worried than parents whose children's health was suboptimal: median worry score 3.3 (3.0-4.8) versus 5.3 (3.8-5.9), P = 0.05. CONCLUSIONS: BA patients' HRQoL was comparable to matched peers in general but reduced by missing school days due to frequent hospital visits. At diagnosis, parents experienced considerable worry that diminished over the years after successful portoenterostomy, especially if the child's health was optimal.

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

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.

APRi predicts native liver survival by reflecting portal fibrogenesis and hepatic neovascularization at the time of portoenterostomy in biliary atresia.

BACKGROUND: Aspartate aminotransferase-to-platelet ratio index (APRi) may be useful noninvasive prognostic tool in biliary atresia (BA). We studied whether APRi predicts native liver survival and parallels biochemical and immunohistological signs of liver injury and fibrogenesis at the time of Kasai portoenterostomy (PE). METHODS: Serum and liver specimens were obtained at PE from 29 BA patients for liver biochemistry including APRi, histology and immunohistochemical analysis of collagen 1, α-SMA and CD34. APRi values were related to native liver survival and other clinical data as well as serum liver biochemistry, liver histology and immunohistochemistry at PE. RESULTS: Median age at PE was 63 (range 7-141) days and median APRi was 0.92 (0.13-6.39). APRi had strong positive correlations with patient age (r=0.684, p<0.001) and biochemical signs of hepatocyte injury and cholestasis. APRi showed no significant correlations with Metavir (r=0.336, p=0.223) or Ishak (r=0.289, p=0.262) global fibrosis scores nor with liver collagen 1 expression (r=0.260, p=0.222). In contrast, portal fibrosis score (r=0.515, p=0.013), predominantly portal α-SMA expression (r=0.519, p=0.015) and amount CD34-positive microvessels in the centrizonal region (r=0.604, p=0.004) correlated positively with APRi. Patients (n=10) who underwent liver transplantation had significantly higher APRi at presentation (1.34 vs. 0.77, p=0.017) compared to those who survived with native liver (n=19). CONCLUSIONS: APRi correlates with portal fibrosis, expression of α-SMA and the amount of CD34-positive microvessels, suggesting that APRi predicts native liver survival by reflecting portal myofibroblastic cell activation, fibrogenesis and associated neovascularization.

Metabolic syndrome after pediatric liver transplantation.

Half of adult liver transplantation (LT) recipients develop metabolic syndrome, but the prevalence after childhood LT remains unknown. We conducted a national cross-sectional study of all living patients who had undergone LT between 1987 and 2007 at an age less than 18 years. We gathered information on blood pressure, body composition, serum lipids, glucose metabolism, and histological liver fat content. The diagnostic criteria for metabolic syndrome of the American Heart Association and the International Diabetes Federation were used. After a median post-LT follow-up time of 12 years, half of all patients had no components of metabolic syndrome. The prevalence of overweight/obesity was 20%, and the prevalence of hypertension was 24%. Serum triglycerides were high in 9%, and high-density lipoprotein levels were low in 23%. Fasting glucose levels were impaired in 14%, but none had diabetes. Altogether, 9 patients (14%) had metabolic syndrome. Moderate liver steatosis found in protocol liver biopsy samples was associated with the accumulation of metabolic syndrome features (P = 0.01). No significant associations were found between immunosuppressive medications and metabolic syndrome. In conclusion, the prevalence of metabolic syndrome after childhood LT is similar to the prevalence in the general population of the same age. Guidelines for the general population, therefore, seem valid for the prevention and treatment of metabolic syndrome after pediatric LT as well.

Myofibroblastic cell activation and neovascularization predict native liver survival and development of esophageal varices in biliary atresia.

AIM: To study the relation between collagen 1, α-smooth muscle actin (α-SMA) and CD34 expression and the most essential portoenterostomy (PE) outcomes. METHODS: Liver specimens were obtained at PE from 33 biliary atresia (BA) patients for immunohistochemical analysis of collagen 1, α-SMA and CD34. Liver biopsies from 35 organ donors were used as controls. Expression patterns were related to clinical data including age at PE, serum total and conjugated bilirubin concentration at the time of PE and during follow-up, incidence of esophageal varices in follow-up upper gastrointestinal endoscopies, and native liver survival as well as to detailed histopathological findings. RESULTS: Collagen 1 (16.4% vs 4.5%, P < 0.0001), α-SMA (17.9% vs 4.6%, P < 0.0001) and CD34 (4.9% vs 3.8%, P = 0.017) were markedly overexpressed in BA patients compared with controls. Patients who underwent liver transplantation by age of two years had significantly higher expression of collagen 1 (18.6% vs 13.7%, P = 0.024), α-SMA (20.4% vs 15.4%, P = 0.009) and CD34 (5.9% vs 4.0%, P = 0.029) at PE compared with native liver survivors. CD34-positive microvessels were identified in the centrizonal region close to central vein in every BA patient. In majority of BA cases (56%) neovascularization was frequent as CD34-positive microvessels were observed in over half of the hepatic lobules. In controls, the CD34-positive microvessels were rare as they were completely absent in 40 % and were found in less than 5 % of the hepatic lobules in the rest. The difference between BA patients and controls was significant (P < 0.0001). Patients who developed esophageal varices by two years had significantly higher expression of CD34 at PE compared with patients without varices (5.6% vs 4.0%, P = 0.019). Expression of α-SMA (r = 0.758, P < 0.0001) and collagen 1 (r = 0.474, P = 0.016), and the amount of CD34-positive microvessels (r = 0.356, P = 0.047) were related to patient age at PE. CONCLUSION: Hepatic myofibroblastic cell activation, fibrogenesis and neovascularization are enhanced in BA, progress with increasing PE age and relate to native liver survival and development of esophageal varices.

Native liver histology after successful portoenterostomy in biliary atresia.

BACKGROUND: Biliary atresia is the most common indication for childhood liver transplantation. The effects of successful portoenterostomy (PE) on native liver histology remain unclear. AIMS: We assessed changes in native liver histology after a successful PE in relation to liver function and clinical outcomes. METHODS: In total, 70 native liver biopsies of 44 biliary atresia patients were obtained at PE (n=30), 4.2 years after successful PE (n=23) and 1.1 years after failed PE (n=17), and reviewed for cholestasis, fibrosis, inflammation, and cytokeratin 7 (CK7) immunopositivity (chronic cholestasis). Ten transplant donor livers served as controls. RESULTS: After a successful PE [serum bilirubin 11 (2 to 35) µmol/L at biopsy], histologic native liver cholestasis completely resolved in 83% of the patients and portal inflammation significantly decreased. Nevertheless, enhanced fibrosis [Metavir stage 2 (1-4) vs. 4 (1-4)], bile duct proliferation [grade 2 (1-2) vs. 1 (0-2)], and periportal CK7 immunostaining [grade 1 (0-2) vs. 1 (0-4)] persisted in 100%, 87%, and 61% of subjects, respectively. Metavir fibrosis stage corresponded cirrhosis (stage 4) in 52% of the patients, associated with the presence of portal hypertension, and correlated with serum-conjugated bilirubin (r=0.601, P=0.002), bile duct proliferation (r=0.657, P=0.001), and CK7 positivity (r=0.657, P=0.001). Aspartate transferase to platelet ratio index predicted native liver fibrosis and development of esophageal varices. The degree of fibrosis and portal inflammation at PE were unrelated to native liver survival. CONCLUSIONS: Despite resolution of cholestasis and decreasing inflammation, bile duct proliferation, periportal CK7 immunostaining, and fibrosis persist after successful PE. Fibrosis is associated with biochemical cholestasis, bile duct proliferation, CK7 immunopositivity (chronic cholestasis), and development of portal hypertension.

[Biliary atresia]. / Sappitieatresia.

Biliary atresia is a rare, neonatal, progressive cholestatic liver disease caused by fibroinflammatory obstruction of the biliary tree. Typical symptoms include prolonged neonatal jaundice, pale stools, and conjugated hyperbilirubinemia. Treatment starts with portoenterostomy, where fibrotic remnants of the extra hepatic bile ducts are replaced with small intestine. Best operative results are achieved among the youngest patients treated in specialized centres. Despite clearance of jaundice after a successful operation, fibrotic change of the liver continues in most. Liver transplantation serves as a salvage procedure if the portoenterostomy fails, or complications of liver cirrhosis develop after an initially successful portoenterostomy. In Finland, biliary atresia treatment was centralized in 2005. Of the patients treated thereafter, 90% are alive and over 80% with their native livers.

Low-dose steroids associated with milder histological changes after pediatric liver transplantation.

Controversy remains about the role of protocol liver biopsy for symptom-free recipients and about the long-term use of low-dose steroids after pediatric liver transplantation (LT). We conducted a national cross-sectional study of pediatric recipients who underwent LT between 1987 and 2007. Liver biopsy samples were taken from 54 patients (82% of survivors) after a median posttransplant follow-up of 11 years, and they were reviewed by 2 pathologists blinded to the clinical data. Biopsy samples from 18 patients (33%) showed nearly normal histology with no inflammation, fibrosis, or steatosis. Portal inflammation was detected in 14 samples (26%), showed no correlation with anti-nuclear antibodies, and was less frequent in the 35 patients whose immunosuppression included steroids (14% versus 47% of patients not using steroids, P = 0.008). Fibrosis was present in 21 biopsy samples (39%). According to the Metavir classification, 16 were stage 1, 3 were stage 2, and 2 were stage 3. The fibrosis stage correlated negatively with serum prealbumin levels (r = -0.364, P = 0.007) and positively with chronic cholestasis (cytokeratin 7 staining; r = 0.529, P < 0.001) and portal inflammation (r = 0.350, P = 0.01). Microvesicular steatosis was found in 23 biopsy samples (43% of patients in 5%-80% of hepatocytes), and it correlated with the body mass index (r = 0.458, P < 0.001) but not with steroid use. The age of the allograft (donor age plus follow-up time) correlated with higher serum gamma-glutamyltransferase (r = 0.472, P < 0.001) and conjugated bilirubin levels (r = 0.420, P = 0.002) as well as chronic cholestasis (r = 0.299, P = 0.03). The biopsy findings led to treatment changes in 10 patients (19%), whereas only 1 complication (subcapsular hematoma) was encountered. In conclusion, continuing low-dose steroids indefinitely after pediatric LT may have a positive effect on the long-term histological state of the liver graft. Allograft aging may lead to chronic cholestasis and thus contribute to the development of liver fibrosis.

Galactose half-life is a useful tool in assessing prognosis of chronic liver disease in children.

In children, optimal timing of liver transplantation (LT) is crucial, but reliable prognostic tools for chronic liver diseases are scarce. We assessed the predictive value of galactose half-life (Gal½) for LT or death. A retrospective search of hospital database 2003-2010 revealed 92 consecutive children with chronic liver disease (36 biliary atresia) whose liver function was assessed with Gal½ measurement. Gal½, follow-up data, and liver biochemistry were recorded and pediatric/model for end-stage liver disease (P/MELD) scores calculated. Patients listed for LT or those who died within 1 year of the Gal½ measurement (Group 1) were compared to those surviving without listing (Group 2). Predictive value of Gal½ and P/MELD for listing for LT was assessed with area under the receiver operating characteristic curve (AUROC) analysis. Group 1 had markedly increased median Gal½ [17.0 (interquartile range 12.5-28.5) min] and higher P/MELD [13 (-1-23)] compared with group 2, [10.5 (9.5-12.5) min and -1 (-8-8); P < 0.001 for both]. Both Gal½ and P/MELD (P < 0.001) predicted listing or death with respective AUROCs of 0.808 (95% CI 0.704-0.913) and 0.780 (0.676-0.890), and 85% sensitivity and 69% specificity for Gal½≥12.0 min. Gal½ is a useful tool when evaluating 1-year prognosis in children with chronic liver disease.

Endoscopic surveillance and primary prophylaxis sclerotherapy of esophageal varices in biliary atresia.

OBJECTIVES: Evidence-based recommendations on endoscopic screening and prophylactic treatment of esophageal varices in patients with biliary atresia (BA) are scarce. We assessed the efficiency of endoscopic surveillance and risk factors of esophageal varices and associated upper gastrointestinal bleeding. METHODS: A total of 47 consecutive children with BA and portoenterostomy underwent yearly endoscopies and prophylactic injection sclerotherapy of esophageal varices between 1987 and 2009. The median follow-up was 1.7 years (range 0.5-18.9) and overall 2-year survival 71%. Disease characteristics, clearance of jaundice, laboratory tests reflecting liver function and hypersplenism, as well as sonographic signs of portal hypertension were related to endoscopic findings and bleeding episodes. RESULTS: Grade 2 to 3 varices developed with similar frequency after failed (18/28, 64%) and successful portoenterostomy (10/19, 53%) in 28 patients. Following failed portoenterostomy, esophageal varices were encountered significantly earlier (8 [4-23] vs. 19 [4-165] months, P = 0.004), and they reappeared after eradication more often (16/16 vs. 4/10, P = 0.001). Varices bled only after failed portoenterostomy (13/28 vs. 0/19, P < 0.001). Increased serum bilirubin concentration >40 µmol/L at 3 months after portoenterostomy was a risk factor of upper gastrointestinal bleeding (odds ratio [OR] 17, 95% confidence interval [CI] 1.7-175, P = 0.017). CONCLUSIONS: In future studies as well as clinical surveillance of BA patients' varices, successful and failed portoenterostomy patients should be approached as separate groups with divergent prognoses. After failed portoenterostomy, surveillance should start early, for example, at 6 months.

National centralization of biliary atresia care to an assigned multidisciplinary team provides high-quality outcomes.

BACKGROUND AND AIMS: Effects of caseload and organization of care on outcomes of biliary atresia (BA) remain unclear. We compared outcomes before and after national centralization of BA treatment in Finland with a population of 5.4 million people and 60,000 live births/year. METHODS: All children born in Finland from 1987 to 2010 with BA were included. Complete patient identification was ascertained from the national Register of Congenital Malformations. Hospital records were reviewed for confirmation of the diagnosis, treatment, and follow-up data. Clearance of jaundice (serum bilirubin ≤ 20 µmol/l) and survival modalities were compared before and after centralization from five centers to Helsinki. RESULTS: The incidence of BA was 1 in 20,100 live births. A total of 72 BA patients of whom 64 had undergone surgery for BA were identified. After centralization, the median caseload per center increased from 0 (range, 0-3) to 4 (2-5) patients/year (p < 0.001), clearance of jaundice rate increased from 27% to 75% (p = 0.001), 2-year jaundice-free native liver survival from 25% to 75% (p = 0.002), transplant-free survival from 27% to 75% (p = 0.005), and overall survival from 64% to 92% (p = 0.082). Baseline patient characteristics including type of BA and age at portoenterostomy remained unaltered. In a logistic regression analysis including treatment era, operating center, BA splenic malformation syndrome, and age at portoenterostomy as variables, only treatment in Helsinki after centralization predicted clearance of jaundice (odds ratio 4.2; 95% confidence interval 1.05-16.5; p = 0.043). CONCLUSIONS: In small countries, BA treatment should be centralized to appointed multidisciplinary teams allowing high quality results with a median of four cases/year.