Browsing by Author "Goodrich, Nathan P."

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    Mutation Analysis and Disease Features at Presentation in a Multi-Center Cohort of Children With Monogenic Cholestasis
    (Wiley, 2021) Hertel, Paula M.; Bull, Laura N.; Thompson, Richard J.; Goodrich, Nathan P.; Ye, Wen; Magee, John C.; Squires, Robert H.; Bass, Lee M.; Heubi, James E.; Kim, Grace E.; Ranganathan, Sarangarajan; Schwarz, Kathleen B.; Bozic, Molly A.; Horslen, Simon P.; Clifton, Matthew S.; Turmelle, Yumirle P.; Suchy, Frederick J.; Superina, Riccardo A.; Wang, Kasper S.; Loomes, Kathleen M.; Kamath, Binita M.; Sokol, Ronald J.; Shneider, Benjamin L.; Childhood Liver Disease Research Network (ChiLDReN); Pediatrics, School of Medicine
    Objectives: To advance our understanding of monogenic forms of intrahepatic cholestasis. Methods: Analyses included participants with pathogenic biallelic mutations in adenosine triphosphate (ATP)-binding cassette subfamily B member 11 (ABCB11) (bile salt export pump; BSEP) or adenosine triphosphatase (ATPase) phospholipid transporting 8B1 (ATP8B1) (familial intrahepatic cholestasis; FIC1), or those with monoallelic or biallelic mutations in adenosine triphosphate (ATP)-binding cassette subfamily B member 4 (ABCB4) (multidrug resistance; MDR3), prospectively enrolled in the Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis (LOGIC; NCT00571272) between November 2007 and December 2013. Summary statistics were calculated to describe baseline demographics, history, anthropometrics, laboratory values, and mutation data. Results: Ninety-eight participants with FIC1 (n = 26), BSEP (n = 53, including 8 with biallelic truncating mutations [severe] and 10 with p.E297G or p.D482G [mild]), or MDR3 (n = 19, including four monoallelic) deficiency were analyzed. Thirty-five had a surgical interruption of the enterohepatic circulation (sEHC), including 10 who underwent liver transplant (LT) after sEHC. Onset of symptoms occurred by age 2 years in most with FIC1 and BSEP deficiency, but was later and more variable for MDR3. Pruritus was nearly universal in FIC1 and BSEP deficiency. In participants with native liver, failure to thrive was common in FIC1 deficiency, high ALT was common in BSEP deficiency, and thrombocytopenia was common in MDR3 deficiency. sEHC was successful after more than 1 year in 7 of 19 participants with FIC1 and BSEP deficiency. History of LT was most common in BSEP deficiency. Of 102 mutations identified, 43 were not previously reported. Conclusions: In this cohort, BSEP deficiency appears to be correlated with a more severe disease course. Genotype-phenotype correlations in these diseases are not straightforward and will require the study of larger cohorts.
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    Outcomes of Childhood Cholestasis in Alagille Syndrome: Results of a Multicenter Observational Study
    (Wiley, 2020-03) Kamath, Binita M.; Ye, Wen; Goodrich, Nathan P.; Loomes, Kathleen M.; Romero, Rene; Heubi, James E.; Leung, Daniel H.; Spinner, Nancy B.; Piccoli, David A.; Alonso, Estella M.; Guthery, Stephen L.; Karpen, Saul J.; Mack, Cara L.; Molleston, Jean P.; Murray, Karen F.; Rosenthal, Philip; Squires, James E.; Teckman, Jeffrey; Wang, Kasper S.; Thompson, Richard; Magee, John C.; Sokol, Ronald J.; Pediatrics, School of Medicine
    Alagille syndrome (ALGS) is an autosomal dominant multisystem disorder with cholestasis as a defining clinical feature. We sought to characterize hepatic outcomes in a molecularly defined cohort of children with ALGS‐related cholestasis. Two hundred and ninety‐three participants with ALGS with native liver were enrolled. Participants entered the study at different ages and data were collected retrospectively prior to enrollment, and prospectively during the study course. Genetic analysis in 206 revealed JAGGED1 mutations in 91% and NOTCH2 mutations in 4%. Growth was impaired with mean height and weight z‐scores of <−1.0 at all ages. Regression analysis revealed that every 10 mg/dL increase in total bilirubin was associated with a decrease in height z‐score by 0.10 (P = 0.03) and weight z‐score by 0.15 (P = 0.007). Total bilirubin was higher for younger participants (P = 0.03) with a median of 6.9 mg/dL for those less than 1 year old compared with a median of 1.3 mg/dL for participants 13 years or older. The median gamma glutamyl transferase also dropped from 612 to 268 in the same age groups. After adjusting for age, there was substantial within‐individual variation of alanine aminotransferase. By 20 years of age, 40% of participants had developed definite portal hypertension. Estimated liver transplant–free survival at the age of 18.5 years was 24%. Conclusions: This is the largest multicenter natural history study of cholestasis in ALGS, demonstrating a previously underappreciated burden of liver disease with early profound cholestasis, a second wave of portal hypertension later in childhood, and less than 25% of patients reaching young adulthood with their native liver. These findings will promote optimization of ALGS management and development of clinically relevant endpoints for future therapeutic trials.
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    Use of funded multicenter prospective longitudinal databases to inform clinical trials in rare diseases-Examination of cholestatic liver disease in Alagille syndrome
    (Wolters Kluwer, 2022) Shneider, Benjamin L.; Kamath, Binita M.; Magee, John C.; Goodrich, Nathan P.; Loomes, Kathleen M.; Ye, Wen; Spino, Cathie; Alonso, Estella M.; Molleston, Jean P.; Bezerra, Jorge A.; Wang, Kasper S.; Karpen, Saul J.; Horslen, Simon P.; Guthery, Stephen L.; Rosenthal, Philip; Squires, Robert H.; Sokol, Ronald J.; Childhood Liver Disease Research Network (ChiLDReN); Pediatrics, School of Medicine
    The conduct of long-term conventional randomized clinical trials in rare diseases is very difficult, making evidenced-based drug development problematic. As a result, real-world data/evidence are being used more frequently to assess new therapeutic approaches in orphan diseases. In this investigation, inclusion and exclusion criteria from a published trial of maralixibat in Alagille syndrome (ALGS, ITCH NCT02057692) were applied to a prospective longitudinal cohort of children with cholestasis (LOGIC NCT00571272) to derive contextual comparator data for evolving clinical trials of intestinal bile acid transport inhibitors in ALGS. A natural history/clinical care cohort of 59 participants who met adapted inclusion and exclusion criteria of ITCH was identified from 252 LOGIC participants with ALGS with their native liver. Frequency weighting was used to match the age distribution of ITCH and yielded a cohort (Alagille Syndrome Natural History [ALGS NH]) that was very similar to the baseline status of ITCH participants. During a 2-year prospective follow-up there was a significant reduction in pruritus in the weighted ALGS NH cohort as assessed by the clinician scratch score (-1.43 [0.28] -1.99, -0.87; mean [SEM] 95% confidence interval). During the same time period, the total bilirubin, albumin, and alanine aminotransferase levels were unchanged, whereas platelet count dropped significantly (-65.2 [16.2] -98.3, -32.1). Weighted survival with native liver was 91% at 2 years in the ALGS NH. These investigations provide valuable real-world data that can serve as contextual comparators to current clinical trials, especially those without control populations, and highlight the value and importance of funded multicenter, prospective, natural history studies.