Long-term follow-up and liver outcomes in children with cystic fibrosis and nodular liver on ultrasound in a multi-center study

Daniel H Leung; Wen Ye; Sarah J Schwarzenberg; A Jay Freeman; Joseph J Palermo; Alexander Weymann; Estella M Alonso; Wikrom W Karnsakul; Karen F Murray; Janis M Stoll; Suiyuan Huang; Boaz Karmazyn; Prakash Masand; John C Magee; Adina L Alazraki; Alexander J Towbin; Jennifer L Nicholas; Nicole Green; Randolph K Otto; Marilyn J Siegel; Simon C Ling; Oscar M Navarro; Roger K Harned; Michael R Narkewicz; Jean P Molleston; CFLD Research Network

doi:10.1016/j.jcf.2022.07.017

Long-term follow-up and liver outcomes in children with cystic fibrosis and nodular liver on ultrasound in a multi-center study

J Cyst Fibros. 2023 Mar;22(2):248-255. doi: 10.1016/j.jcf.2022.07.017. Epub 2022 Aug 16.

Authors

Daniel H Leung¹, Wen Ye², Sarah J Schwarzenberg³, A Jay Freeman⁴, Joseph J Palermo⁵, Alexander Weymann⁶, Estella M Alonso⁷, Wikrom W Karnsakul⁸, Karen F Murray⁹, Janis M Stoll¹⁰, Suiyuan Huang², Boaz Karmazyn¹¹, Prakash Masand¹, John C Magee¹², Adina L Alazraki¹³, Alexander J Towbin¹⁴, Jennifer L Nicholas¹⁵, Nicole Green¹⁶, Randolph K Otto¹⁷, Marilyn J Siegel¹⁸, Simon C Ling¹⁹, Oscar M Navarro²⁰, Roger K Harned²¹, Michael R Narkewicz²², Jean P Molleston²³; CFLD Research Network

Affiliations

¹ Department of Pediatrics, Baylor College of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Texas Children's Hospital, 6621 Fannin St, CCC 1010.00, Houston, TX 77030, USA.
² Department of Biostatistics, University of Michigan, 1420 Washington Heights, M4073 SPH II, Ann Arbor, MI 48109, USA.
³ Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of Minnesota, 2450 Riverside Save S AO-201, Minneapolis, MN 55454, USA.
⁴ Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Healthcare of Atlanta, Emory University, 2015 Uppergate Drive, NE, Atlanta, GA 30322, USA.
⁵ Department of Pediatrics, Division of Gastroenterology, University of Cincinnati College of Medicine, 3333 Burnet Avenue, MLC 2010, Cincinnati, OH 45229, USA.
⁶ Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, The Ohio State University College of Medicine, 700 Children's Drive, Columbus, OH 43205, USA.
⁷ Department of Pediatrics, Pediatric Gastroenterology, Hepatology and Nutrition, Northwestern University Feinberg School of Medicine, 225 E. Chicago Avenue, Box 57, Chicago, IL 60611, USA.
⁸ Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Johns Hopkins University School of Medicine, 600 N Wolfe Street, CMSC-2, Baltimore, MD 21287, USA.
⁹ Pediatric Institute and Cleveland Clinic Children's, Cleveland Clinic, 8950 Euclid Avenue, R3, Cleveland, OH 44195, USA.
¹⁰ Department of Pediatrics, Division of Gastroenterology, Pediatric Hepatology and Nutrition, Washington University School of Medicine in St. Louis, One Children's Place, Suite 8116, St. Louis, MO 63110, USA.
¹¹ Department of Radiology and Imaging Sciences, Indiana University School of Medicine, 550 N. University Blvd, Rm 0663, Indianapolis, IN 46202, USA.
¹² Department of Surgery, University of Michigan School of Medicine, 1500 E Medical Center Drive, UH South Rm 6689, Ann Arbor, MI 48109, USA.
¹³ Department of Radiology, Children's Healthcare of Atlanta, Emory University, 1405 Clifton Rd NE, Atlanta, GA 30322, USA.
¹⁴ Department of Radiology, University of Cincinnati College of Medicine, 234 Goodman Street, PO Box 670761, Cincinnati, OH 45267, USA.
¹⁵ Department of Radiology, Division of Pediatric Imaging, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
¹⁶ Department of Pediatrics, Division of Gastroenterology and Hepatology, Seattle Children's Hospital, 4800 Sand Point Way NE, PO Box 5371, Seattle, WA 98105, USA.
¹⁷ Department of Radiology, Seattle Children's Hospital, 4800 Sand Point Way NE, MA.7.220, Seattle, WA 98105, USA.
¹⁸ Edward Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 South Kingshighway Blvd, St. Louis, MO 63110, USA.
¹⁹ Department of Paediatrics, Division of Gastroenterology, Hepatology and Nutrition, University of Toronto, 555 University Ave ON, Toronto, M5G 1X8, Canada.
²⁰ Department of Diagnostic Imaging, Division of Pediatric Imaging, University of Toronto, 263 McCaul St 4th floor, Toronto, ON M5T 1W7, Canada.
²¹ Department of Radiology-Diagnostics, University of Colorado School of Medicine, 13123 East 16th Avenue, B125, Aurora, CO 80045, USA.
²² Department of Pediatrics, Section of Pediatric Gastroenterology, Hepatology and Nutrition, Digestive Health Institute, Children's Hospital Colorado, University of Colorado School of Medicine, 13123 East 16th Avenue, B290, Aurora, CO 80045, USA.
²³ Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Riley Hospital for Children at IU Health, Indiana University School of Medicine, 705 Riley Hospital Drive, ROC 4210, Indianapolis, IN 46202, USA. Electronic address: jpmolles@iu.edu.

PMID: 35985930
DOI: 10.1016/j.jcf.2022.07.017

Abstract

Background: Nodular liver (NOD) in cystic fibrosis (CF) suggests advanced CF liver disease (aCFLD); little is known about progression of liver disease (LD) after detection of sonographic NOD.

Methods: Clinical, laboratory, and ultrasound (US) data from Prediction by Ultrasound of the Risk of Hepatic Cirrhosis in CFLD Study participants with NOD at screening or follow-up were compared with normal (NL). Linear mixed effects models were used for risk factors for LD progression and Kaplan-Meier estimator for time-to-event.

Results: 54 children with NOD (22 screening, 32 follow-up) and 112 NL were evaluated. Baseline (BL) and trajectory of forced expiratory volume, forced vital capacity, height/BMI z-scores were similar in NOD vs NL. Platelets were lower in NOD at BL (250 vs 331×10³/microL; p < 0.001) and decreased by 8600/year vs 2500 in NL. Mean AST to Platelet Ratio Index (1.1 vs 0.4; p < 0.001), Fibrosis-4 Index (0.4 vs 0.2, p < 0.001), and spleen size z-score (SSZ) [1.5 vs 0.02; p < 0.001] were higher in NOD at BL; SSZ increased by 0.5 unit/year in NOD vs 0.1 unit/year in NL. Median liver stiffness (LSM) by transient elastography was higher in NOD (8.2 kPa, IQR 6-11.8) vs NL (5.3, 4.2-7, p < 0.0001). Over 6.3 years follow-up (1.3-10.3), 6 NOD had esophageal varices (cumulative incidence in 10 years: 20%; 95% CI: 0.0%, 40.0%), 2 had variceal bleeding, and 2 underwent liver transplantation; none had ascites or hepatic encephalopathy. No NL experienced liver-related events.

Conclusions: NOD developed clinically evident portal hypertension faster than NL without worse growth or lung disease.

Keywords: ALT, alanine aminotransferase; APRI, aspartate aminotransferase to platelet ratio index; AST, aminotransferase; CAP, continuous attenuation parameter; CFRD, cystic-fibrosis-related diabetes; CFTR, cystic fibrosis transmembrane regulator; Cirrhosis; Cystic fibrosis liver disease; FEV1, forced expiratory volume in one second; FIB4, fibrosis index based on four factors; FVC, forced vital capacity; GGT, gamma-glutamyl transferase; IGT, impaired glucose tolerance; INR, international normalized ratio; LSM, liver stiffness measurement; NL, normal; NOD, nodular; PELD, pediatric end-stage liver disease; PUSH, prediction by ultrasound of the risk of hepatic cirrhosis; US, ultrasound; Ultrasound; VCTE, vibration controlled transient elastography; WBC, white blood cell count; abbreviations: CF, cystic fibrosis.

Publication types

Multicenter Study
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Child
Cystic Fibrosis* / complications
Cystic Fibrosis* / epidemiology
Cystic Fibrosis* / pathology
Elasticity Imaging Techniques*
Esophageal and Gastric Varices* / pathology
Follow-Up Studies
Gastrointestinal Hemorrhage / pathology
Humans
Hypertension, Portal*
Liver / diagnostic imaging
Liver / pathology
Liver Cirrhosis / diagnostic imaging
Liver Cirrhosis / etiology