The Impact of Exposure to Previous Disasters on Hospital Disaster Surge Capacity Preparedness in Finland: Hospital disaster surge capacity preparedness.

OBJECTIVE: As disasters are rare and high-impact events, it is important that the learnings from disasters are maximized. The aim of this study was to explore the effect of exposure to a past disaster or mass casualty incident (MCI) on local hospital surge capacity planning. METHODS: The current hospital preparedness plans of hospitals receiving surgical emergency patients in Finland were collected (n = 28) and analyzed using the World Health Organization (WHO) hospital emergency checklist tool. The surge capacity score was compared between the hospitals that had been exposed to a disaster or MCI with those who had not. RESULTS: The overall median score of all key components on the WHO checklist was 76% (range 24%). The median surge capacity score was 65% (range 39%). There was no statistical difference between the surge capacity score of the hospitals with history of a disaster or MCI compared to those without (65% for both, P = 0.735). CONCLUSION: Exposure to a past disaster or MCI did not appear to be associated with an increased local hospital disaster surge capacity score. The study suggests that disaster planning should include structured post-action processes for enabling meaningful improvement after an experienced disaster or MCI.

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

BACKGROUND: Pathogenesis of progressive liver fibrosis in biliary atresia after successful portoenterostomy remains unclear. We related hepatic expression of transforming growth factor beta (TGF-ß) 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.

Very low bilirubin after portoenterostomy improves survival of the native liver in patients with biliary atresia by deferring liver fibrogenesis.

BACKGROUND: Progression of fibrosis and ensuing complications determine the postoperative course of patients operated on for biliary atresia. We evaluated predictors of the progression of fibrosis in the native liver after operative treatment. METHODS: Among patients whose bilirubin decreased to <34 µmol/L after portoenterostomy (n = 41), predictors of follow-up cirrhosis and the progression of fibrosis were analyzed with logistic regression and survival of their native liver was evaluated with the Kaplan-Meier method. Areas under receiving operating characteristic were used to define optimal cutoffs. RESULTS: After median follow-up of 5.2 years (interquartile range 1.6-10.2) after portoenterostomy, liver biopsies showed cirrhosis in 53% of patients, and the Metavir stage remained stable or decreased in 38%. The development of cirrhosis was predicted by total or conjugated bilirubin ≥170/120 µmol/L at the time of portoenterostomy (P ≤ .009); normalization of bilirubin within 1.9 months (P = .002); total or conjugated bilirubin ≥ 12.5/7.5 µmol/L (P = .002) and aspartate aminotransferase-to-platelet ratio ≥ 0.55 at 3 months postoperatively (P = .001); and total or conjugated bilirubin ≥ 7.5/2.5 µmol/L (P ≤ .001), aspartate aminotransferase-to-platelet ratio ≥ 0.63 (P = .004), and gamma glutamyl transferase ≥ 266 U/L (P = .007) at 6 months postoperatively. In multiple regression analysis, conjugated bilirubin ≥ 2.5 µmol/L at 6 months increased the risk of cirrhosis 35-fold (P = .020), and other predictors were not predictive. Total or conjugated bilirubin < 12.5/7.5 µmol/L (P ≤ .014), aspartate aminotransferase-to-platelet ratio < 0.55 at 3 months (P = .006), and total or conjugated bilirubin < 7.5/2.5 µmol/L at 6 months postoperatively (P ≤ .014) were the strongest predictors of a stable, nonprogressive fibrosis. Decreases in total or conjugated bilirubin to < 12.5/7.5 µmol/L by 3 months and to < 7.5/2.5 µmol/L by 6 months improved survival of the native liver (log-rank P ≤ .025). Age at follow-up or at portoenterostomy, anatomic type of biliary atresia, use of postoperative steroids, and episodes of cholangitis were unrelated to the progression of fibrosis or the development of cirrhosis (P = not significant). CONCLUSION: Among patients whose serum bilirubin normalizes after portoenterostomy, its rapid decrease to very low levels prolongs the survival of their native liver by delaying the progression of fibrosis.

Treatment Policy and Liver Histopathology Predict Biliary Atresia Outcomes: Results after National Centralization and Protocol Biopsies.

BACKGROUND: Different treatment policies can influence biliary atresia outcomes, but the pathophysiology of expanding fibrosis occurring even after successful portoenterostomy remains unclear. STUDY DESIGN: Clearance of jaundice (COJ) (bilirubin <20 µmol/L), native liver survival, and overall survival rates of biliary atresia patients were analyzed before and after national centralization of management, as well as in relation to native liver histopathology of protocol biopsies. RESULTS: Of the 59 patients, 35 were managed after centralization and received standardized postoperative adjuvant therapy, including corticosteroids. After centralization, age at portoenterostomy decreased from 73 days to 54 days (p = 0.014) and COJ rate increased from 42% to 80% (p = 0.005), 5-year native liver survival increased from 38% to 70% (p = 0.014), and 5-year overall survival increased from 68% to 94% (p = 0.007). High-grade portal inflammation at portoenterostomy predicted COJ (odds ratio 3.66; p = 0.011) and slower fibrosis progression (ß = -0.74; p = 0.005). Native liver survival was extended in patients with high-grade portal inflammation (p = 0.002) and in patients whose bilirubin normalized within 3 months (p < 0.001). Portal inflammation and cholestasis reduced only after COJ (p < 0.001), and persisting ductal reaction, reflected by cytokeratin 7-positive proliferating bile ductules and periportal hepatocytes, correlated with follow-up fibrosis (r = 0.454 to 0.763; p < 0.001 to 0.003). Cytokeratin 7 immunopositivity of periportal hepatocytes increased after COJ (p = 0.015) and was the only predictor of follow-up liver fibrosis (ß = 0.36; p = 0.002) in multiple regression. CONCLUSIONS: Biliary atresia outcomes improved significantly after centralization and standardized management. Resolution of cholestasis and reduction of high-grade portal inflammation postoperatively predict slower fibrosis progression and improved native liver survival, and persisting ductal reaction parallels progressive native liver fibrosis despite COJ.

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.

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.