Liver Transplantation for Hypoparathyroidism Secondary to Wilson’s Disease
Wilson’s disease (WD), an autosomal recessive disorder of copper metabolism, is characterized by mutations in the ATP7B gene, which encodes a copper-transporting ATPase critical for biliary copper excretion and ceruloplasmin (CP) synthesis. The resultant copper accumulation predominantly affects the liver, brain, and eyes, though rare systemic manifestations, including hypoparathyroidism, have been documented. This case report details a 19-year-old male with WD-associated hypoparathyroidism, highlighting the clinical trajectory, diagnostic challenges, and outcomes following orthotopic liver transplantation (OLT).
Clinical Presentation and Disease Progression
The patient’s clinical journey began at 4 months of age with scleral icterus, prompting a diagnosis of WD. Despite lifelong liver-protective therapy, progressive multisystem involvement emerged. By age 9, he exhibited growth retardation, clubbed fingers, and pale nail beds. Skeletal complications manifested at 16 with spontaneous fractures of the right upper limb and left pubic bone. Neuropsychological symptoms—fatigue, personality changes, cognitive decline, seizures, and constipation—developed by age 17, necessitating daily glycerin for bowel motility. At 19, preadmission findings included severe musculoskeletal deformities: thoracic scoliosis (T7, T9, T10–L2 vertebral wedging), lumbar straightening (L1–2, L4–5 wedge deformities), and a protuberant sternum.
Family history revealed consanguineous parents (first cousins) and a paternal cousin who succumbed to WD at age 12. A 3-year-old sibling also carried a WD diagnosis, underscoring the genetic etiology.
Diagnostic Evaluation
On admission, the patient’s height (153 cm) and weight (63.9 kg) reflected stunted growth. Physical findings included alopecia, a rounded face, rickets-like chest deformities, coarse skin, and Kayser-Fleischer (K-F) rings. Laboratory studies confirmed profound hypoparathyroidism: parathyroid hormone (PTH) <2 pg/mL (normal: 15–65 pg/mL), hypocalcemia (2.09 mmol/L), hyperphosphatemia (1.78 mmol/L), and severe vitamin D deficiency (25-hydroxyvitamin D: 6.96 ng/mL). CP levels were markedly reduced (17.1 mg/dL; normal: 20–50 mg/dL), consistent with WD.
Imaging corroborated systemic copper toxicity. Thyroid ultrasonography identified hypoechoic nodules on the right posterior lobe, suspected to involve the parathyroids. Dual-phase ⁹⁹mTc-MIBI parathyroid scintigraphy revealed no tracer uptake in these nodules (Figure 1A), suggesting nonfunctional hyperplasia. Magnetic resonance imaging (MRI) detailed severe thoracic and lumbar spinal deformities (Figures 1B, 1C), indicative of chronic metabolic bone disease.
Liver Transplantation and Postoperative Outcomes
The patient developed acute liver failure, prompting OLT at seven weeks post-admission. Postoperatively, copper metabolism stabilized, with CP rising to 39.1 mg/dL by week three. Serial monitoring of calcium-phosphorus homeostasis demonstrated gradual normalization: serum calcium increased from 2.09 mmol/L to 2.11–2.47 mmol/L, while phosphorus decreased from 1.78 mmol/L to 1.1–1.48 mmol/L (Figure 1E).
PTH levels exhibited a transient spike (26.6 pg/mL) at week two post-transplant, followed by stabilization at 5.9–11.8 pg/mL (Figure 1D). Though suboptimal, these values exceeded preoperative levels (<2 pg/mL), paralleling improvements in calcium balance. The normalization of CP and partial PTH recovery suggested restored copper homeostasis post-OLT, potentially mitigating further parathyroid damage.
Pathophysiological Correlations
WD’s hallmark—hepatic copper accumulation—stems from impaired biliary excretion due to ATP7B mutations. Excess copper deposits in extrahepatic tissues, including the basal ganglia (causing neuropsychiatric symptoms) and cornea (K-F rings). Parathyroid involvement, though rare, arises from direct copper toxicity, leading to glandular destruction and hypoparathyroidism. Histologically, copper deposition incites fibrosis and atrophy, impairing PTH synthesis.
In this case, preoperative ⁹⁹mTc-MIBI imaging demonstrated parathyroid hyperplasia without tracer uptake, indicative of dysfunctional tissue. This aligns with the hypothesis that chronic copper exposure induces hyperplasia as a compensatory response, albeit insufficient to restore PTH secretion.
Role of Liver Transplantation in WD
OLT remains definitive therapy for WD patients with acute liver failure or decompensated cirrhosis unresponsive to chelation therapy (per EASL/AASLD guidelines). By replacing the defective hepatic ATP7B gene product, OLT restores copper metabolism, halts disease progression, and reverses extrahepatic complications. Post-transplant CP normalization (39.1 mg/dL) confirmed functional graft performance, enabling systemic copper mobilization.
The transient PTH surge at week two post-OLT suggests partial parathyroid recovery, possibly due to reduced copper toxicity. However, persistent hypoparathyroidism implies irreversible glandular damage. Whether residual copper deposits can be metabolized post-OLT remains unclear, as parathyroid biopsy was ethically unfeasible. Nonetheless, the correction of calcium and phosphorus levels—despite subnormal PTH—highlights the liver’s central role in mineral homeostasis.
Clinical Implications and Future Directions
This case underscores WD’s multisystemic nature and the diagnostic challenge of hypoparathyroidism in young patients with metabolic bone disease. Early recognition of hypocalcemia, hyperphosphatemia, and low PTH in WD patients is critical to prevent skeletal and neuromuscular sequelae.
OLT’s utility in reversing copper-mediated damage beyond the liver warrants further study. While CP normalization confirms hepatic graft function, parathyroid recovery may depend on the extent of preexisting fibrosis. Long-term follow-up is essential to determine whether PTH levels gradually normalize or stabilize at subclinical thresholds. Additionally, investigations into copper chelation’s efficacy in preventing parathyroid dysfunction could inform pre-transplant management.
Conclusion
This report illustrates the complex interplay between WD and hypoparathyroidism, emphasizing OLT’s role in restoring copper homeostasis. Though hypoparathyroidism persisted post-transplant, the resolution of hypocalcemia and hyperphosphatemia suggests partial functional recovery. OLT may mitigate further parathyroid injury, obviating immediate glandular transplantation. Longitudinal studies are needed to evaluate OLT’s long-term impact on parathyroid function and copper redistribution in WD.
doi.org/10.1097/CM9.0000000000000384
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