Large parathyroid adenomas: Potential mechanisms to reconcile adenoma size and disease phenotype

Abstract

Parathyroid adenomas weighing more than 3.5 g are reported variously as "atypical", "large" or "giant" parathyroid adenomas. All such adenomas are rare variants accounting for no more than 1.5% of all parathyroid adenomas. Large parathyroid adenomas are often associated with more severe form of the disease, including osteitis fibrosa cystica (OFC) and share many biochemical, histological, and molecular features of both benign and malignant parathyroid neoplasms, and are considered a distinct clinical entity. However, the pathogenesis of oversized parathyroid adenomas and the often-associated skeletal phenotype remains unclear. We present 5 cases of primary hyperparathyroidism (PHPT) with OFC, an uncommon manifestation of contemporary PHPT, associated with larger parathyroid adenomas, seen in the Bone and Mineral Disorders Clinic of the Henry Ford Health in the last 30 years to illustrate the critical role of vitamin D nutrition in the pathogenesis of both the OFC and adenoma size. The estimated prevalence of OFC was very low 0.2%, 5 of the >3000 surgically confirmed cases of PHPT seen during this time. The mean ± SD values were: age: 36.8 ± 22.1 years (4 of the 5 <36years), serum calcium 11.6 ± 1.1 mg/dl, alkaline phosphatase 799 ± 487 IU/L, PTH 1440 ± 477 pg/ml, 25-hydroxyvitamin D 13.0 ± 8.9 ng/ml, 1,25-dihyroxyvitamin D 26.5 ± 13.7 pg/ml, urine calcium 562 ± 274 mg/day, and parathyroid adenoma weight 4.53 ± 2.2 g. Parathyroidectomy led to the resolution of both the biochemical indices and OFC in each patient without recurrence over >10 years of follow-up. Because OFC is a very rare in the West, but very common areas of endemic vitamin D deficiency, we also examined the relationship between vitamin D nutrition, as assessed by serum 25-hydroxyvitamin D level, and parathyroid adenoma weight as well as prevalence of OFC in two large secularly diverse cohorts of patients with PHPT (Detroit, USA and Chandigarh, India). Based on this relationship and the relative prevalence of OFC in these two large cohorts, we propose that vitamin D nutrition (and perhaps calcium nutrition) best explains both the adenoma size and prevalence of OFC.

Keywords: atypical parathyroid adenomas; giant parathyroid adenoma; large parathyroid adenomas; osteitis fibrosa cystica; primary hyperparathyroidism; vitamin D nutrition; vitamin deficiency.

Figure 1

Regression and 95% prediction interval of the relationship between serum 25-hydroxyvitamin D level and parathyroid adenoma weight in the Detroit cohort (n=429). The 5 patients with osteitis fibrosa cystica are depicted (closed dots). Note the location of these 5 adenomas near or above the predicted interval.

Figure 2

Relationship between serum 25-hydroxyvitamin D level and parathyroid adenoma weight in 2 large secularly diverse cohorts. Detroit Cohort: Open Circles and Dashed line (n=429). Indian Cohort: Closed Circles and Solid line (n=426). Data was log transformed because of the non-normal distribution of both variables. Note the lack of inverse relationship in and an upward shift of the Indian PHPT data.

Figure 3

Relationship between serum PTH level and adenoma size. Detroit Cohort: Open circles and bottom solid line (n=426). Indian Cohort: Closed circles and top solid line (n=426). Data was log transformed because of non-normal distribution of both variables. Note the upward and rightward shift of Indian PHPT data. Slopes of regression are not different from each other, but the intercept is higher for the Indian cohort.

Figure 4

Proposed conceptual mechanistic explanation for the pathogenesis of both large adenomas and osteitis fibrosa cystica. It reconciles the Lloyd hypothesis of Type-1 and 2 PHPT and the Parfitt-Rao proposal of set-point and cell-cycle dysfunctions leading to different types of adenoma formation. However, we do yet not know what genes control the set-point. According to this concept, the observed genetic and epigenetic abnormalities are consequences of set-point dysfunction as the initial event.