Characterization of gallbladder disease in metachromatic leukodystrophy across the lifespan

Abstract

Metachromatic leukodystrophy (MLD) is a progressive demyelinating disorder resulting from the toxic accumulation of sulfatides. The stereotyped neurodegeneration of MLD is well understood, and cases are categorized into subtypes by age at neurologic onset: late infantile (LI), juvenile (J), and adult. The systemic burden of disease, such as gallbladder involvement, however, is less well characterized. It is important to understand the longitudinal trajectory of gallbladder complications in MLD and its relationship with neurologic progression as this has the potential to identify cases of active disease before neurologic onset. Additionally, as newborn screening is established in MLD, it will inform clinical care during the presymptomatic period. To address this knowledge gap, we leveraged a retrospective natural history study of MLD and published cases in the medical literature. Medical records from subjects consented to a natural history study were used to collect information of disease course, including gallbladder abnormality. Neurologic function was retrospectively assessed using the gross motor function classification scale (GMFC-MLD). Additionally, a comprehensive review identified published cases of MLD with subject-level information around gallbladder disease. Data was summarized using descriptive statistics, Fisher's exact test for significance, and survival analysis with log rank test. The natural history cohort includes 40 subjects with gallbladder reports (imaging or pathology). The first gallbladder evaluation occurred after neurologic onset in 35/40 cases. Gallbladder abnormalities were noted in 36 subjects, often within the initial evaluation (97.2 %). There was no difference in the time to first gallbladder abnormality (log rank: p = 0.4170) and risk of polyps or higher (log rank: p = 0.6414) between the LI- and non-LI subtypes. The level of gallbladder involvement does not correlate with GMFC-MLD score (Fisher's exact: p = 0.321). A review of the literature identified 87 additional cases of MLD with mention of gallbladder status across 40 published studies. Gallbladder involvement was noted in 74 cases and occurred at similar rates across subtypes (X² = 4.68, p = 0.7925). Overall, the study showed a high prevalence of gallbladder complications in MLD. Gallbladder abnormalities were commonly found at first evaluation, even in pre- or early symptomatic disease. Since gallbladder disease has the potential to progress to malignancy, this supports the integration of regular gallbladder monitoring as clinical care and its potential as a predictive biomarker supporting disease onset.

Keywords: Gallbladder; Gallbladder screening; Longitudinal natural history study; Metachromatic leukodystrophy.

Fig. 1.

Kaplan-Meier Curve of gallbladder abnormalities. A) Time to MLD disease onset and first gallbladder abnormality in LI-MLD. B) Time to MLD disease onset and first gallbladder abnormality in non-LI MLD. C) Comparison of time to occurrence of polys, dysplasia or cancer, from neurologic disease onset between Li- and non-LI MLD cohorts. Of note, one subject had gallbladder abnormality identified before neurologic disease onset and hence was censored at time 0.

Fig. 1.

Kaplan-Meier Curve of gallbladder abnormalities. A) Time to MLD disease onset and first gallbladder abnormality in LI-MLD. B) Time to MLD disease onset and first gallbladder abnormality in non-LI MLD. C) Comparison of time to occurrence of polys, dysplasia or cancer, from neurologic disease onset between Li- and non-LI MLD cohorts. Of note, one subject had gallbladder abnormality identified before neurologic disease onset and hence was censored at time 0.

Fig. 2.

Comparison of frequency of gallbladder pathologies and neurological function at time of gallbladder evaluation. Gallbladder features were categorized according to described levels of increasing severity. Within each level, the distribution of neurologic function based on the GMFC-MLD score assigned within ±30 days of the gallbladder evaluation is plotted: high functioning M0-M2 (light blue), lower functioning M3-M4 (medium blue), and lowest function M5-M6 (dark blue).

Fig. 3.

Pathological evaluation of gallbladder surgical specimen (Patient 2). A. Gross inspection of the gallbladder specimen showed the macroscopic view of the opened gallbladder showing a frond-like polypoid lesion located at the fundus. Lower (B) and higher (C) power view of gallbladder by H&E staining demonstrating clusters of foamy macrophages within the lamina propria of the papillary excrescences.

Fig. 4.

Diagram of included published reports. In total, the review identified 40 published articles and 87 cases of MLD with mention of gallbladder status. This included 36 subjects with Li-MLD, 34 Juvenile MLD and 14 with Adult-onset MLD.

Fig. 5.

Gallbladder disease in MLD by subtype. A) In the natural history cohort, gallbladder involvement is presented in swim lane plots in the late-infantile MLD (top) and non-late-infantile MLD (bottom) subtypes. The grey circles, by colour gradient, represent gallbladder features with white indicating normal gallbladder and darker shades indicating severe gallbladder features. Individual subjects are represented by a single lane with depiction of age at onset of neurological symptoms (broken line). Age at diagnosis is represented by red crosses and cholecystectomy by crossed squares. For subjects that underwent MLD therapy, yellow triangles mark the age at treatment. A crossed square without an overlapping solid circle is used when the gallbladder abnormality is unknown from the medical record. B) In the published cohort, the distribution of gallbladder involvement in the published cohort by subtypes is shown (87 individual cases, 112 evaluations. Gallbladder abnormality categories within each MLD disease subtype are plotted: LI MLD (triangle), juvenile MLD (circle), and adult (square). Longitudinal results were available for 20 subjects, often obtained serially. When no detailed age data was available, the encounters were separated by 0.1 years for visualization. C) Incidence of severe gallbladder abnormalities (polyp or greater) across MLD subtypes as shown by Kaplan-Meier curves, comparing the onset of severe gallbladder (polyps, dysplasia, cancer) abnormalities by MLD subtype. Comparison of risk of occurrence between LI-MLD (light blue), J-MLD, (dark blue) and Adult (grey) subjects across published and GLIA-CTN natural history cohort, anchored from age at neurological disease onset on the x-axis. Six subjects with evaluations prior to neurologic disease onset were censored at time 0; 5 subjects had severe gallbladder abnormalities pre-onset and for one did not report any subsequent evaluations.

Fig. 5.

Gallbladder disease in MLD by subtype. A) In the natural history cohort, gallbladder involvement is presented in swim lane plots in the late-infantile MLD (top) and non-late-infantile MLD (bottom) subtypes. The grey circles, by colour gradient, represent gallbladder features with white indicating normal gallbladder and darker shades indicating severe gallbladder features. Individual subjects are represented by a single lane with depiction of age at onset of neurological symptoms (broken line). Age at diagnosis is represented by red crosses and cholecystectomy by crossed squares. For subjects that underwent MLD therapy, yellow triangles mark the age at treatment. A crossed square without an overlapping solid circle is used when the gallbladder abnormality is unknown from the medical record. B) In the published cohort, the distribution of gallbladder involvement in the published cohort by subtypes is shown (87 individual cases, 112 evaluations. Gallbladder abnormality categories within each MLD disease subtype are plotted: LI MLD (triangle), juvenile MLD (circle), and adult (square). Longitudinal results were available for 20 subjects, often obtained serially. When no detailed age data was available, the encounters were separated by 0.1 years for visualization. C) Incidence of severe gallbladder abnormalities (polyp or greater) across MLD subtypes as shown by Kaplan-Meier curves, comparing the onset of severe gallbladder (polyps, dysplasia, cancer) abnormalities by MLD subtype. Comparison of risk of occurrence between LI-MLD (light blue), J-MLD, (dark blue) and Adult (grey) subjects across published and GLIA-CTN natural history cohort, anchored from age at neurological disease onset on the x-axis. Six subjects with evaluations prior to neurologic disease onset were censored at time 0; 5 subjects had severe gallbladder abnormalities pre-onset and for one did not report any subsequent evaluations.