Tamir Miloh

Improved Adherence and Outcomes for Pediatric Liver Transplant Recipients by Using Text Messaging

OBJECTIVE: The goal was to improve immunosuppressant adherence for pediatric patients with orthotopic liver transplants by using text messaging (TM). METHODS: A prospective study of sending TM reminders to the primary medication administrator (patient or caregiver) for pediatric transplant recipients was performed. Patient records were reviewed, comparing the year before and the year of the study. The SD of serum tacrolimus levels was used as an indicator of adherence. RESULTS: Forty-one patients provided consent. The median age was 15 years (range: 1–27 years), and the median age at the time of transplantation was 2 years (range: 4 months to 23 years). Fourteen patients (34%) were male. In 29 of 41 cases, the medications were self-administered by the patient. The mean duration of study was 13 ± 1.5 months. Twenty-two patients were receiving 1 immunosuppressant, 14 were receiving 2, and 5 were receiving 3. Thirteen patients (37%) stopped the study after 4 months. The mean tacrolimus level SD decreased from 3.46 μg/L before the study to 1.37 μg/L (P < .005). The number of immunosuppressants taken and patient self/caregiver medication administration did not significantly affect the results. The number of acute cellular rejection episodes decreased from 12 to 2 during the study. Risk factors for rejection were older age (17.67 vs 13.28 years) and administration of >1 immunosuppressant. CONCLUSION: We observed significant improvement in medication adherence and a reduction in rejection episodes with TM reminders for pediatric recipients of liver transplants.

A Retrospective Single-Center Review of Primary Sclerosing Cholangitis in Children

BACKGROUND & AIMS Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammation and progressive bile duct fibrosis. There are limited data on pediatric PSC. METHODS We performed a retrospective chart review of 47 pediatric patients with PSC. RESULTS The mean age at diagnosis was 11 +/- 4.9 years. Symptoms occurred before presentation in 81% of patients; inflammatory bowel disease was found in 59% and autoimmune hepatitis (overlap syndrome) in 25% of patients. Magnetic resonance cholangiography revealed both extrahepatic and intrahepatic, isolated intrahepatic, isolated extrahepatic, and no biliary involvement (small-duct PSC) in 40%, 14%, 10%, and 36%, respectively. Advanced fibrosis (stage >II) was present in 65%. Colonoscopy revealed pancolitis, rectal sparing, and normal findings in 24%, 24%, and 18%, respectively. All patients were treated with ursodeoxycholic acid (UDCA); 9 with overlap syndrome also received immunosuppressants. Fifteen patients without overlap syndrome had positive autoimmune markers and responded to UDCA monotherapy. Liver transplantation was performed in 9 patients (3 with overlap syndrome and 2 with small-duct PSC) at a median time of 7 years after diagnosis. The 10-year posttransplant survival rate was 89%. CONCLUSIONS In one of the largest single-center studies of children with PSC, we found that most children with PSC had inflammatory bowel disease or autoimmune overlap and advanced fibrosis at diagnosis. Levels of alanine aminotransferase and gamma-glutamyl transferase were highest in patients with overlap syndrome and lowest in those with small-duct PSC. Levels of serum liver enzymes normalized after therapy with UDCA, including patients with positive autoimmune markers without histologic features of autoimmune hepatitis.

The membrane protein ATPase class I type 8B member 1 signals through protein kinase C zeta to activate the farnesoid X receptor

Prior loss‐of‐function analyses revealed that ATPase class I type 8B member 1 [familial intrahepatic cholestasis 1 (FIC1)] posttranslationally activated the farnesoid X receptor (FXR). Mechanisms underlying this regulation were examined by gain‐of‐function studies in UPS cells, which lack endogenous FIC1 expression. FXR function was assayed in response to wild‐type and mutated FIC1 expression constructs with a human bile salt export pump (BSEP) promoter and a variety of cellular localization techniques. FIC1 overexpression led to enhanced phosphorylation and nuclear localization of FXR that was associated with FXR‐dependent activation of the BSEP promoter. The FIC1 effect was lost after mutation of the FXR response element in the BSEP promoter. Despite similar levels of FIC1 protein expression, Byler disease FIC1 mutants did not activate BSEP, whereas benign recurrent intrahepatic cholestasis mutants partially activated BSEP. The FIC1 effect was dependent on the presence of the FXR ligand, chenodeoxycholic acid. The effect of FIC1 on FXR phosphorylation and nuclear localization and its effects on BSEP promoter activity could be blocked with protein kinase C zeta (PKC ζ) inhibitors (pseudosubstrate or small interfering RNA silencing). Recombinant PKC ζ directly phosphorylated immunoprecipitated FXR. The mutation of threonine 442 of FXR to alanine yielded a dominant negative protein, whereas the phosphomimetic conversion to glutamate resulted in FXR with enhanced activity and nuclear localization. Inhibition of PKC ζ in Caco‐2 cells resulted in activation of the human apical sodium‐dependent bile acid transporter promoter. Conclusion: These results demonstrate that FIC1 signals to FXR via PKC ζ. FIC1‐related liver disease is likely related to downstream effects of FXR on bile acid homeostasis. Benign recurrent intrahepatic cholestasis emanates from a partially functional FIC1 protein. Phosphorylation of FXR is an important mechanism for regulating its activity. (HEPATOLOGY 2008;48:1896‐1905.)

β-Klotho and FGF-15/19 inhibit the apical sodium-dependent bile acid transporter in enterocytes and cholangiocytes

beta-Klotho, a newly described membrane protein, regulates bile acid synthesis. Fibroblast growth factor-15 (FGF-15) and FGF receptor-4 (FGFR4) knockout mice share a similar phenotype with beta-Klotho-deficient mice. FGF-15 secretion by the intestine regulates hepatic bile acid biosynthesis. The effects of beta-Klotho and FGF-15 on the ileal apical sodium bile transporter (ASBT) are unknown. beta-Klotho siRNA treatment of the mouse colon cancer cell line, CT-26, and the human intrahepatic biliary epithelial cells (HIBEC) resulted in upregulation of endogenous ASBT expression that was associated with reduced expression of the farnesoid X receptor (FXR) and the short heterodimer partner (SHP). Silencing beta-Klotho activated the ASBT promoter in CT-26, Mz-ChA-1 (human cholangiocarcinoma), and HIBEC cells. Site-directed mutagenesis of liver receptor homolog-1 (mouse) or retinoic acid receptor/retinoid X receptor (RAR/RXR) (human) cis-elements attenuated the basal activity of the ASBT promoter and abrogated its response to beta-Klotho silencing. siSHP, siFXR, or dominant-negative FXR treatment also eliminated the beta-Klotho response. FGF-15 secretion into cell culture media by CT-26 cells was diminished after siFGF-15 or sibeta-Klotho treatment and enhanced by chenodeoxycholic acid. Exogenous FGF-19 repressed ASBT protein expression in mouse ileum, gallbladder, and in HIBEC and repressed ASBT promoter activity in Caco-2, HIBEC, and Mz-ChA-1 cells. Promoter repression was dependent on the expression of FGFR4. These results indicate that both beta-Klotho and FGF-15/19 repress ASBT in enterocytes and cholangiocytes. These novel signaling pathways need to be considered in analyzing bile acid homeostasis.

Brief Report: Deficits in Health Care Management Skills Among Adolescent and Young Adult Liver Transplant Recipients Transitioning to Adult Care Settings

OBJECTIVE The purpose of the present study was to describe and compare mastery of health care management in adolescent (aged 14-17 years) and young adult recipients of a liver transplant (age ≥ 18 years) expected to transfer from pediatric to adult care settings. METHODS Fifty-two liver transplant recipients completed the Developmentally Based Skills Checklist, which asks how often patients independently engage in specific health care management skills. RESULTS Overall, young adult patients reported greater health care management than adolescents. However, less than half of the young adults surveyed reported consistently managing their liver disease independently, making their own appointments, and understanding insurance issues. CONCLUSIONS Our results suggest that liver transplant recipients display inconsistency with regards to how frequently they engage in health management behaviors. Future work will address intervention development to remedy this first aspect of transition to adulthood such that patients are better prepared before moving to adult care centers.

Liver transplantation for children with Wilson disease: comparison of outcomes between children and adults.

Arnon R, Annunziato R, Schilsky M, Miloh T, Willis A, Sturdevant M, Sakworawich A, Suchy F, Kerkar N. Liver transplantation for children with Wilson disease: comparison of outcomes between children and adults.
Clin Transplant 2011: 25: E52–E60.

Recommendations for Probiotic Use--2015 Update: Proceedings and Consensus Opinion

This paper describes the consensus opinion of the participants in the 4th Triennial Yale/Harvard Workshop on Probiotic Recommendations. The recommendations update those of the first 3 meetings that were published in 2006, 2008, and 2011. Recommendations for the use of probiotics in necrotizing enterocolitis, childhood diarrhea, inflammatory bowel disease, irritable bowel syndrome and Clostridium difficile diarrhea are reviewed. In addition, we have added recommendations for liver disease for the first time. As in previous publications, the recommendations are given as A, B, or C ratings.

A Clinical Prediction Rule and Platelet Count Predict Esophageal Varices in Children

BACKGROUND & AIMS The validation of noninvasive tests to diagnose esophageal varices is a priority in children because repeated endoscopic evaluations are too invasive. We measured the ability of a previously developed noninvasive clinical prediction rule (CPR) to predict the presence of esophageal varices in children. METHODS We analyzed data from 108 children, younger than age 18, who received endoscopies at 8 centers, to assess portal hypertension from chronic liver disease or portal vein obstruction. Blood test and abdominal ultrasound scan results were obtained within 4 months of endoscopy. Grading of varices identified by endoscopy was confirmed by independent blinded review. Spleen size, based on data from the ultrasound scan, was expressed as a standard deviation score relative to normal values for age. RESULTS Of the children studied, 74 had esophageal varices (69%), including 35 with large varices (32%). The best noninvasive predictors of esophageal varices of any size were as follows: platelet:spleen size z-score ratio (area under the receiver operating characteristic curve [AUROC], 0.84; 95% confidence interval [CI] 0.75-0.93), CPR (AUROC, 0.80; 95% CI, 0.70-0.91), and platelet count (AUROC, 0.79; 95% CI, 0.69-0.90). The positive predictive values for the CPR and platelet count were 0.87 and 0.86, the negative predictive values were 0.64 and 0.63, the positive likelihood ratios were 3.06 and 2.76, and the negative likelihood ratios were 0.64 and 0.63, respectively. Based on positive and negative predictive values, the most accurate noninvasive tests were the CPR and platelet counts. CONCLUSIONS Noninvasive tests such as CPR and platelet count can assist in triaging children for endoscopy to identify esophageal varices.

Pediatric liver transplantation for primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease in children. The aim of this study was to determine the characteristics and outcomes of children with PSC who were listed for liver transplantation (LT). Children who underwent transplantation for PSC according to the Studies of Pediatric Liver Transplantation (SPLIT) registry were compared to age‐matched children with chronic liver disease who underwent transplantation for other indications. Seventy‐nine patients (2.6% of the SPLIT cohort) required LT for PSC. The mean duration of the post‐LT follow‐up was 36.6 ± 32.7 months. Ulcerative colitis and Crohns disease were diagnosed before LT in 46.0% and 3.3% of the patients, respectively, and inflammatory bowel disease (IBD) was diagnosed after LT in another 9.8%. The mean age at LT was 12.6 ± 3.9 years, and the mean waiting time was 10.2 ± 12.9 months. The mean z scores for height and weight at LT were significantly lower for the PSC group versus the non‐PSC group. For the PSC group, the 1‐ and 5‐year patient survival rates were 98.7% and 86.6%, respectively, and the 1‐ and 5‐year graft survival rates were 93.0% and 76.1%, respectively. Intrahepatic biliary strictures in the first 6 months post‐LT and cholangitis in the first 30 days post‐LT were more common in the PSC group versus the non‐PSC group (3.8% versus 0.8% for intrahepatic biliary strictures, P = 0.03, and 5.1% versus 1.1% for cholangitis, P = 0.01). Recurrent PSC was diagnosed in 9.8% of the patients at a mean of 18.7 ± 13.8 months after LT. IBD was associated with an increased risk of death (log‐rank P = 0.01) and recurrent PSC (P = 0.02). Five years post‐LT, the mean aspartate aminotransferase level was 60 ± 45 IU/L, and the mean gamma‐glutamyltransferase level was 209 ± 302 IU/L; both levels were significantly higher than the levels for non‐PSC patients. In conclusion, children with PSC had patient and graft survival rates equaling those of age‐matched children who underwent transplantation for other indications. IBD was associated with worse outcomes. Recurrence was observed in 9.8%, and the PSC patients had higher mean liver enzyme levels 5 years post‐LT. Liver Transpl 17:925–933, 2011.

Adolescent transplant recipients as peer mentors: A program to improve self-management and health-related quality of life

The purpose of this study was to examine the safety, feasibility, acceptability, and preliminary efficacy of a cross‐age peer mentoring program created to improve adherence and psychosocial outcomes for pediatric liver transplant recipients. Twenty‐two participants were assigned to a “mentor now” or “mentor later” waitlist control group. Tacrolimus SD, a validated measure of adherence, was assessed for six months pre‐ and post‐intervention for both groups. Self‐report measures of self‐management and HRQOL were completed at recruitment and three months after training. Participant report indicated the acceptability of the intervention. Clinically significant improvement in adherence was detected. No significant changes on the psychosocial outcome measures at follow‐up were observed. This study demonstrated that an outpatient‐based mentoring program is a safe, feasible, and acceptable option to incorporate within a pediatric liver transplant program with potential for promising application in other transplantation populations as well. These results also suggest that the program may have been associated with meaningful improvement in adherence, although further evaluation is warranted.