In this article, we will be exploring one of the less talked about symptoms of Alagille syndrome (ALGS): bone pathology.
ALGS is a multifaceted disease, and scientists know patients with ALGS have a higher incidence of fragility fractures in the lower limbs. The theory about the reason for this is similarly multifaceted: aberrant Notch-mediated bone metabolism, dysfunctional osteoblasts due to elevated bilirubin levels, and an unbalanced diet due to cholestasis and steatorrhea.
We will be examining 2 papers involving ALGS and bone health:
- The first is a case report by Maharjana et al on the pathological fracture of the femur of a patient with ALGS.
- The second is a study conducted by Kindler et al attempting to characterize bone health in children with ALGS.
Femur Fracture in a Pediatric Patient
A team of Indonesian researchers wrote a case report of a pediatric patient with ALGS who experienced a femur fracture. We will attempt to summarize the case report and present only its most pertinent features.
The 6-year-old boy slipped and fell down while dressing himself, resulting in pain and deformity on his right thigh. His only past medical history was inspissated bile syndrome, diagnosed at 3 months of age. A physical examination revealed a prominent forehead, deep-set eyes, icteric skin, and posterior angulation of the right thigh with a 2 cm leg-length discrepancy.
The first x-ray revealed complete cortical discontinuity of the middle part of the femoral shaft of the right thigh. A thoracolumbar x-ray was then conducted, revealing the “butterfly vertebrae” sign (that is, a sagittal cleft in the vertebral body of the 6th thoracic vertebrae). Abdominal ultrasonography revealed a contracted gallbladder with sludge in it.
“Laboratory investigation revealed a more dominant conjugated hyperbilirubinemia (total bilirubin 35.49 mg/dL, direct bilirubin 25.55 mg/dL, indirect bilirubin 9.94 mg/dL), and a more dominant increase in alkaline phosphatase (532 U/L) than alanine transaminase (86.7 U/L) and aspartate transaminase (182.8 U/L), indicating a cholestatic disease,” the research team wrote. All of these tests pointed to a diagnosis of ALGS.
Read more about ALGS diagnosis
The patient was prescribed propranolol to lower his hepatic portal pressure and ursodeoxycholic acid to improve bile flow. Multivitamins with added calcium, Vitamin E, and Vitamin K were also prescribed. The physicians performed an early hemi spica cast under fluoroscopy to achieve accurate anatomical reduction. At 2 months, the patient’s bone pathology has significantly improved; hence, the cast was removed and physical rehabilitation started. At 4 months, the patient had recovered both anatomically and functionally.
“Up until now, there is still no clear consensus regarding how the best treatment is in pediatric diaphyseal femoral fracture, let alone in pathologic fracture due to metabolic disease such in this case,” Maharjana et al wrote.
The physicians, in this case, chose to do a spica casting as it is feasible for children, relatively inexpensive, and decreases hospital length-of-stay. The patient’s recovery after 4 months demonstrated that the physicians’ bet paid off.
Inferior Bone Health
Kindler et al recruited 10 children with ALGS aged between 8 and 21 years for their study on the effects of ALGS on bone geometry and other relevant parameters of disease progression, such as bilirubin levels. All of these patients were receiving treatment at the Children’s Hospital of Philadelphia in Pennsylvania.
“Diagnosis of ALGS was based on the presence of a) bile duct paucity and b) 3 of the 5 typically occurring clinical features including cholestasis, ophthalmologic abnormalities, characteristic facial features, congenital heart disease, and butterfly vertebrae,” the study team wrote.
Read more about ALGS testing
The advantage of this study is its use of cutting-edge technology such as dual-energy x-ray absorptiometry (DXA) and high resolution peripheral quantitative computed tomography (HR-pQCT).
Among the findings from this study were:
- Children with ALGS had smaller and thinner tibia cortical bone diaphyses compared to children without ALGS.
- Children with ALGS had fewer and more separated trabeculae compared to children without ALGS.
- Higher bilirubin levels were inversely associated with bone density.
- Markers of cholestasis were indicative of inferior bone health.
- Among the 10 patients studied, a total of 6 fractures were reported. This suggests that bone fractures are among the most significant clinical outcome in ALGS bone health.
“In summary, we report novel evidence linking ALGS with inferior cortical and trabecular bone geometry and microarchitecture,” Kindler et al wrote. “Decreased cortical thickness of the tibia, associated with increased endosteal circumference, and distal 1/3 radius areal bone mineral density by DXA were particularly pronounced . . . Collectively, these results expand on earlier studies implicating ALGS in lower bone mass and increased fracture risk.”
The Importance of Screening
From both of these studies, it is clear that bone pathology is a common characteristic of ALGS patients. The implication for healthcare professionals is that they should prioritize the screening of bone pathologies when assessing patients with ALGS.
In addition, should any bone pathology be discovered, physicians should ensure that it is appropriately treated, possibly with the help of an orthopedic physician. Examining how a metabolic disease such as ALGS affects multiple systems can serve as a reminder to all physicians of the importance of treating a patient holistically.
Maharjana MA, Suyasa IK, Kawiyana IKS, Nugraha HK. Pathological fracture of the femur in Alagille syndrome: a case report. J Clin Orthop Trauma. Published online December 19, 2019. doi: 10.1016/j.jcot.2019.12.009
Kindler JM, Mitchell EL, Piccoli DA, et al. Bone geometry and microarchitecture deficits in children with Alagille syndrome. Bone. 2020;141:115576. doi:10.1016/j.bone.2020.115576