Influence of age and gender on presentation of symptomatic primary hyperparathyroidismVN Shah1, SK Bhadada1, A Bhansali1, A Behera2, BR Mittal3, V Bhavin4
1 Department of Endocrinology,Postgraduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Surgery,Postgraduate Institute of Medical Education and Research, Chandigarh, India
3 Department of Nuclear Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
4 Statistician and State TB Project Consultant, Ahmedabad, Gujarat, India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0022-3859.97171
Source of Support: None, Conflict of Interest: None
Background: The geographical difference in presentation of primary hyperparathyroidism (PHPT) is known. However, there is sparse literature on the influence of age and gender on presentation of PHPT. Aim: To analyze the effect of age and gender on presentation of symptomatic primary hyperparathyroidism. Setting and Design: This is a retrospective analysis of data from the primary hyperparathyroidism registry of a north Indian tertiary care teaching institute. Materials and Methods: Analysis of 184 histopathologically proven PHPT patients registered between March 1990 and March 2010 from a single centre of north India. PHPT patients were divided into three different age groups i.e. children and adolescents less than 25 years, adults 25-49 years, and ≥ 50 years. Clinical presentations, biochemical parameters and parathyroid weight were compared between different age groups and gender using appropriate statistical methods. Results: Mean age of patients was 38.5±13.8 years with female: male ratio of 7:3. Rickets as presenting manifestations were seen in one child and adolescent each. Prevalence of renal stones (P=0.03) and gall stones (P=0.02) was higher in the adult groups compared to the younger and older. There was no difference in bone pain (P=0.7), fracture (P=0.3), osteitis fibrosa cystica (P=0.2), fatigue (P=0.6) and other symptoms among different age groups. There was no difference in serum calcium, phosphate, parathyroid hormone (PTH) and 25 (OH) D levels among different age groups, however, as expected alkaline phosphatase was higher in adolescents compared to adults (P=0.03). Bone pain and muscle aches (P<0.001), fracture (P=0.04), osteitis fibrosa cystica (P=0.01), and gall stones (P=0.03) were more common among women while renal stones (P=0.05) and pancreatitis (P=0.02) were common in men. Serum calcium and phosphate levels were similar in either sex but parathyroid hormone (iPTH) level was higher among women (P=0.02). Parathyroid adenoma weight was higher in older compared to young but did not reach to a level of statistical significance. Conclusion: Age and gender have substantial influence on presentation of PHPT. Bone pain and rickets were common in children and adolescents while renal stones in adults. Women have more severe disease as musculoskeletal manifestations are common and iPTH levels are also higher compared to men.
Keywords: Age, gender, primary hyperparathyroidism
Primary hyperparathyroidism (PHPT) is characterized by high parathyroid hormone (iPTH) level despite elevated calcium. PHPT is the most common cause of hypercalcemia due to parathyroid adenoma.  The most common presentation of PHPT is asymptomatic in the West due to use of autoanalyzer and serum calcium is a part of the routine screening.  However, this trend has not been documented from India as recent studies still report presentation of PHPT as symptomatic. ,,, PHPT is more common in the fifth and six decade and it's a disease of postmenopausal women  however, presentation of PHPT in India is still at a younger age. ,,, Therefore, these Indian studies clearly depict the differences in presentations of PHPT among Indian subjects compared to Western PHPT subjects.
PHPT is less common in children and adolescents. A few studies showed a higher prevalence of multiglandular disease and more severe disease while another reported no difference in presentations compared to adults.  There are many reports of presentation of PHPT in children and adolescents, , but comparison with adults and older are lacking in the literature. It is well known that gender plays an important role in influencing the incidence and presentation of many diseases. For example, unstable angina and non-ST-elevation myocardial infarction are common in women while ST-elevation myocardial infractions are common in men.  Similarly, it is likely that gender may have some influence on the presentation of PHTP. Literature is spare on this issue and hence, the study was carried out to analyze age and gender difference in presentations of clinical, biochemical and parathyroid size in PHPT.
Patient selection: In this retrospective study, data were retrieved from the PHPT registry of the Department of Endocrinology, PGIMER, Chandigarh, India. The record of patients proved to have PHPT between March 1990 and March 2010 was analyzed for the present study. Diagnosis of PHPT was based on elevated iPTH despite elevated corrected calcium. All patients (n=184) underwent curative parathyroid surgery and histopathology proved parathyroid adenoma. Patients with secondary or tertiary hyperparathyroidism and multiple endocrine neoplasia (MEN) syndrome were excluded. Clinical presentations, biochemical parameters and parathyroid gland weight were recorded and compared among different age groups and between genders. We divided the PHPT patients into three different age groups, i.e. Children and adolescents less than 25 years, adults 25 to 49 years, and ≥50 years. The age group division mentioned here is arbitrary because of the small sample size among different age groups (e.g. children <12, adolescents 12-18, young adults 19-24, adults 25-39, middle-aged 40-59 and ≥60 years). The detailed clinical and biochemical characteristics are provided in supplemental [Table 1] and [Table 2]. Being a retrospective study, ethical committee permission was not obtained as it neither reveals any individual identity nor poses risk of new treatment or modalities out of standard care. 
From 1990 to 2005, serum iPTH and 25 (OH) D were measured with RIA (immunotech kit, Hitachi, Germany). Serum calcium (8.5-11.4 mg/dl) was measured by Clark and Collip method and albumin-adjusted calcium was calculated. After 2005, serum iPTH (15-65 pg/ml) and 25(OH)D (11.1-42.9 ng/ml) were measured by chemiluminescence assay using commercially available kits (Elecsys 2010 system, Roche diagnostic, Germany). Serum calcium (RR) 8.6-10.2 mg/dl , inorganic phosphate (RR) 2.7-4.5 mg/dl, albumin (RR) 3.4-4.8 mg/dl, alkaline phosphatase (RR) 40-129 IU/L, and creatinine (RR 0.4-1.2 mg/dl) were measured by autoanalyzer (Roche diagnostics, Modular P 800).
SPSS 15 was used for analysis of data. Chi-square test was used to compare categorical variables in different age groups and between genders. ANOVA test or Krusker-Walis test was applied for comparing mean of continuous variables among different age groups. Independent t-test or Man-Whitney test was used to compare mean of continuous variables among men and women. P value <0.05 was considered as significant.
Mean age of the patients with PHPT was 38.5±13.8 years with female: male ratio of 7:3. A total of 29 patients (15.7%) were less than 25 years (12 men), 105 (57.1%) were adults (30 men) and 50 (27.2%) were more than 50 years of age (13 men).
Influence of age on presentation of PHPT
Rickets as presenting manifestations were seen only in children and adolescents (one child and one adolescent had rickets). Prevalence of renal stones (P=0.03) and gall stones (P=0.02) were higher in the adult group compared to younger and older. Abdominal pain (P=0.07) though higher in adults was statistically non-significant. There was no difference in bone pain (P=0.7), fracture (P=0.3), osteitis fibrosa cystica (P=0.2), fatigue (P=0.6) and other symptoms among different age groups. There was no difference in serum calcium, phosphate, PTH and 25(OH) D levels among different age groups, however, as expected alkaline phosphatase was higher in adolescents compared to adults (P=0.03) [Table 3].
Influence of gender on presentation of PHPT
Bone pain and muscle aches (P<0.001), fracture (P=0.04), osteitis fibrosa cystica (P=0.01), and gall stones (P=0.03) were more common among women while renal stones (P=0.05) and pancreatitis were common in men. Serum calcium and phosphate levels were similar in either sex but intact parathyroid hormone (iPTH) level was significantly higher among women (P=0.02) [Table 4].
Influence of age and gender on location and weight of parathyroid adenoma
We did not find any difference in location of parathyroid adenoma with age or gender. Left inferior parathyroid adenoma was the commonest location (46.4%) followed by right inferior parathyroid adenoma (30.4%). Parathyroid adenoma weight was 4.4±2.6, 4.2±0.3, 6.4±6.5 in adolescents, adults and old-aged (P=0.3).
The present study reveals a significant influence of age and gender on clinical presentation of symptomatic primary hyperparathyroidism. Rickets is seen only in children and adolescents with PHPT while renal stones and gallstones in adults with PHPT. Women have more severe disease as musculoskeletal manifestations and iPTH levels are higher compared to men.
Mean age of the patients with PHPT was 38.5± 13.8 years in the present study. This is in consonance with the other studies from India which reflects that Indian subjects develop PHPT at a younger age compared to PHPT subjects of the Western world. ,,,
We report two patients who presented as rickets in the present study. There are few case reports of rickets as presenting manifestation of PHPT in the literature. , The possible explanation for rickets in children with PHPT is coexisting vitamin D deficiency which may be further aggravated by elevated PTH levels in PHPT and possibly there may be deleterious effects of continuous and high level of PTH directly on chondrocytes.  We did not notice the difference in symptoms among different age groups except for gallstone and renal stone which are higher in adults. There was no difference in the biochemical parameters among the different age groups. This is again in consonance with other studies. ,
We noted a higher prevalence of bone pain and muscle aches, fracture, osteitis fibrosa cystica, and gall stones among women while renal stones and pancreatitis were common in men. Presence of more symptoms is due to more severe disease in women as reflected by higher iPTH level among women. It is known that even in the general population, gallstone is more common in women and increases with age.  There are conflicting studies without uniform agreement on the higher prevalence of gallstones in patients with PHPT.  The proposed mechanism for enhanced gallstone formation in PHPT is increase in the biliary ionized calcium concentration due to hypercalcemia while elevated PTH is implicated for relaxation of gall bladder, and thus the milieu is in favor of cholelithiasis formation.  However, all these mechanisms need to be proved. Renal stone is more common in men in the general population  and this may be further increased in patients with PHPT because of hypercalciuria.
Intriguingly though gallstones are common in women, pancreatitis is common in men. Gallstone is the most common etiology of pancreatitis in the general population. However, our study reveals that gallstone is not an important etiology for pancreatitis in patients with PHPT. Plausible mechanisms for pancreatitis in patients with PHPT include calcium-phosphate deposition in the pancreatic ducts; calcium-dependent conversion of trypsinogen to trypsin; increased permeability of pancreatic duct due to hypercalcemia; and an apparent direct toxic effect of PTH on the pancreas. , However, a large US population-based recent study revealed no increase in pancreatitis among PHPT patients.  We did not find any difference in parathyroid gland location and weight among different age groups and gender.
To our knowledge this is the first Indian study that compared the presentation of PHPT among different age groups and gender; this may help the clinician to understand variable presentations of PHPT and may help in future to delineate the underlying mechanisms for such different presentations. Furthermore the sample size is relatively large; these are the major strengths of the study. However, the retrospective design may be the limiting factor.
In conclusion, this study reveals that age and gender have a substantial influence on the presentation of PHPT. Bone pain and rickets were common in children and adolescents while renal stones and gallstones in adults. Women have more severe disease as musculoskeletal manifestations are common and iPTH levels are also higher compared to men.
[Table 1], [Table 2], [Table 3], [Table 4]