Hanna Lampela

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

Abstract 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.

Effects of long-term parenteral nutrition on serum lipids, plant sterols, cholesterol metabolism, and liver histology in pediatric intestinal failure.

Background and Objective: Plant sterols (PS) in parenteral nutrition (PN) may contribute to intestinal failure–associated liver disease. We investigated interrelations between serum PS, liver function and histology, cholesterol metabolism, and characteristics of PN. Patients and Methods: Eleven patients with intestinal failure (mean age 6.3 years) receiving long-term PN were studied prospectively (mean 254 days) and underwent repeated measurements of serum lipids, noncholesterol sterols, including PS, and liver enzymes. PS contents of PN were analyzed. Liver biopsy was obtained in 8 patients. Twenty healthy children (mean age 5.7 years) served as controls. Results: Median percentage of parenteral energy of total daily energy (PN%) was 48%, including 0.9 g · kg−1 · day−1 of lipids. Respective amounts of PN sitosterol, campesterol, avenasterol, and stigmasterol were 683, 71, 57, and 45 &mgr;g · kg−1 · day−1. Median serum concentrations of sitosterol (48 vs 7.5 &mgr;mol/L, P < 0.001), avenasterol (2.9 vs 1.9, P < 0.01), stigmasterol (1.9 vs 1.2, P < 0.005), but not that of campesterol (9.8 vs 12, P = 0.22), were increased among patients in relation to controls, and correlated with PN% (r = 0.81–0.88, P < 0.005), but not with PN fat. Serum cholesterol precursors were higher in patients than in controls. Serum liver enzymes remained close to normal range. Glutamyl transferase correlated with serum PS (r = 0.61–0.62, P < 0.05). Liver fibrosis in 5 patients reflected increased serum PS (r = 0.55–0.60, P = 0.16–0.12). Conclusions: Serum PS moderately increase during olive oil–based PN, and correlate positively with PN% and glutamyl transferase. Despite well-preserved liver function, histology often revealed significant liver damage.

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 &mgr;mol/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.

General health, health-related quality of life and sexual health after pediatric liver transplantation: a nationwide study.

The long‐term impact of pediatric liver transplantation (LT) and its complications on general health, health‐related quality of life (HRQoL) and sexual health were assessed. We conducted a national cross‐sectional study of all pediatric recipients who underwent LT between 1987 and 2007. Of 66 survivors, 57 participants (86%) were compared to randomly chosen healthy controls (n = 141) at 10.7 ± 6.6 years posttransplant. PedsQL4.0, SF‐36, DISF‐SR and AUDIT questionnaires for appropriate age groups were used. Patients and controls <7 years had similar HRQoL and 54% of patients aged over 7 scored within the controls’ normal range on all HRQoL domains. In adult survivors, physical functioning and general health were decreased (p < 0.05). Biliary complications, reoperations and obesity were independently associated with reduced HRQoL (p < 0.05 for all). Still 64% of adult survivors considered their health excellent. Sexual health was similar to controls but LT recipients may experience problems with their orgasm strength (p = 0.050) and condom‐based contraception was more common after LT than among controls (58% and 12%, p < 0.001). In conclusion, normal HRQoL and sexual health are achievable post‐LT.

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 = 0.009). Fibrosis was present in 21 biopsy samples (39%). According to the Metavir classification, 15 were stage 1, 4 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 = 0.546, 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 = 0.517, 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 = 0.305, 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. Liver Transpl 19:145–154, 2013.

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) &mgr;mol/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.

Cholesterol metabolism altered and FGF21 levels high after pediatric liver transplantation despite normal serum lipids.

Liver transplantation (LT) predisposes to metabolic derangements and increases the risk for cardiovascular disease. We conducted a national cross‐sectional study of all pediatric recipients who underwent LT between 1987 and 2007. We measured serum levels of noncholesterol sterols (surrogate markers of cholesterol synthesis and intestinal absorption) and fibroblast growth factor 21 (FGF21) in 49 patients (74% of survivors) at a median of 10 years posttransplant and in 93 controls matched for age and gender. Although serum cholesterol levels were similar in patients and controls, patients displayed increased whole‐body synthesis and decreased intestinal absorption of cholesterol compared with controls (lathosterol to cholesterol ratio 129 ± 55 vs. 96 ± 41, respectively, p < 0.001; campesterol to cholesterol ratio 233 ± 91 vs. 316 ± 107, respectively; p < 0.001). Azathioprine (r =–0.383, p = 0.007) and low‐dose methylpredisolone (r =–0.492, p < 0.001) were negatively associated with lathosterol/sitosterol ratio reflecting a favorable effect on cholesterol metabolism. FGF21 levels were higher in patients than in controls (248 pg/mL vs. 77 pg/mL, p < 0.001). In healthy controls, FGF21 was associated with cholesterol metabolism, an association missing in LT recipients. Normal serum lipids are achievable in long‐term survivors of pediatric LT, but changes in cholesterol metabolism and increased FGF21 levels may explicate later cardiovascular risk.

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. Liver Transpl 20:1185–1192, 2014.

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.