Outcomes of Childhood Cholestasis in Alagille Syndrome: Results of a Multicenter Observational Study

Abstract

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.

Figure 1

Schematic to represent study design. This schematic illustrates the time of study entry, time to complication event, time to liver transplant or death, and the censoring of six classes of example subjects. The solid black dot represents the onset of cholestasis. The horizontal dotted lines indicate the time period prior to study entry. The white circle represents the time of study enrollment. The red “x” represents the time of complication event (e.g., bone fracture). The black and white squares represent the time of liver transplant/death and censoring, respectively. Although example participants A, B, C, and D were enrolled and observed in the LOGIC study at various time points after birth, the subjects in groups E and F experienced liver transplant/death before the opportunity to be enrolled, and therefore were not observed in the study. In addition, not all events were observed in A, B, C, and D due to right censoring and left censoring. For example, the event time of complication was censored by liver transplant/death for participant A. Participant B experienced the complication event before liver transplant/death. Subject C experienced the complication event before being enrolled, and the time of the complication event was retrospectively collected. For subject D, the complication did not happen before he or she was censored (dropped out of the LOGIC study or the data were cut off to retrieve the analysis data set). Abbreviation: LOGIC, Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis.

Figure 2

Laboratory characteristics among survivors by age. Individual participant laboratory values are shown over time with the median and interquartile range shown in blue and P values. The P values are from tests for trends in laboratory values by age in generalized estimating equation models accounting for correlation among repeated measures within participants. Serum bilirubin, cholesterol, and GGT are higher earlier in life but improve in many children. The platelet count progressively falls over childhood. Due to sparse data after age 20 years, only laboratory values measured at age 20 or younger are presented. Abbreviations: GGTP, gamma‐glutamyl transpeptidase; and IQR, interquartile range.

Figure 3

Prevalence of pruritus and xanthoma among survivors by age. Pruritus, as measured by CSS, and the burden of xanthomas improve over time in ALGS survivors with native livers. CSS scores the physical manifestations of pruritus as follows: 0 = none, 1 = rubbing or mild scratching when undistracted, 2 = active scratching without evident skin abrasions, 3 = abrasion evident, 4 = cutaneous mutilation, hemorrhage, and scarring evident.

Figure 4

Cumulative incidence of hepatic complications and portal hypertension. The cumulative incidence of ascites, splenomegaly, and thrombocytopenia increase with age, resulting in an increase in the onset of definite clinically evident portal hypertension as defined by (1) ascites treated by diuretics, (2) presence of esophageal or gastric varices, or (3) both splenomegaly (spleen palpable > 2 cm below costal margin) and fewer than 150,000/mm³ platelets. Abbreviation: PHT, portal hypertension.

Figure 5

Transplant‐free survival in ALGS. The method for calculating survival accounted for left truncation and estimated the transplant‐free survival at the age of 18.5 years as 24% (95% CI: 16%, 36%). There was no liver or transplant/death observed at age 20 or older in this cohort. The estimated survival curve was truncated at the age of 20 years.