Professor Jiaqiang Zhou from Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, holds that the clinical manifestations of normocalcemic primary hyperparathyroidism (NPHPT) mainly include the following aspects:
Renal Damage: Predominantly Nephrolithiasis
The kidney is the major target organ of NPHPT, with core manifestations being nephrolithiasis and nephrocalcinosis, with an incidence ranging widely from 4% to 29%.The mechanism is related to renal tubular resistance to PTH and CaSR gene polymorphisms, leading to abnormal calcium excretion and subsequent stone formation or nephrocalcinosis.
Skeletal Damage: High Risk of Osteoporosis and Fracture
Skeletal involvement is the most common complication of NPHPT.More than 50% of patients have osteopenia, and 40% meet the criteria for osteoporosis.A study in female NPHPT patients showed that 56.8% had osteoporosis and 10.8% had already sustained fragility fractures.
Skeletal damage in NPHPT is similar to that in classic PHPT:it impairs the microarchitecture of bone tissue and disturbs calcium and vitamin D metabolism, thereby increasing fracture risk.
Cardiovascular and Non‑specific Symptoms
Patients with NPHPT have a significantly higher cardiovascular risk than healthy individuals,often accompanied by hypertension, diabetes, hyperlipidemia and other risk factors,although the association with coronary artery calcification score (CCS) remains controversial.
Among non‑specific symptoms, 63% of patients experience fatigue;other symptoms may include insomnia, abdominal pain, myalgia, thirst and polyuria.Elevated serum PTH is independently associated with muscular dysfunction, impairing quality of life.
Comparison between NPHPT and Classic Hypercalcemic PHPT
Core Biochemical Markers
NPHPT: normal serum calcium / ionized calcium + elevated PTH
Classic PHPT: hypercalcemia + elevated PTH
PTH levels in NPHPT are lower than those in classic PHPT.Glandular Lesions
NPHPT has a higher incidence of multiglandular disease (MGD) (13%–37%) than classic PHPT (6.8%), and the affected glands are smaller.
Traini et al. (154 NPHPT, 577 PHPT): MGD rate 13% in NPHPT vs. 6.8% in PHPT (P<0.05)
Wade et al. (93 NPHPT): MGD rate up to 37%
Parathyroid adenoma volume in NPHPT is smaller than in PHPT.Complications
Cardiovascular risk factors are similar between the two groups.
The incidence of skeletal complications (osteoporosis, fracture) is comparable:
NPHPT 25%–57% vs. classic PHPT 44% in some studies.
The incidence of nephrolithiasis in NPHPT varies widely (4%–29%) but is similar to that in classic PHPT.Genetic Features
A study of 27 NPHPT and 31 PHPT patients showed that:NPHPT had significantly different gene frequencies at OPG (rs2073618) and ESR1 (rs9340799, rs2234693) loci compared with controls and classic PHPT.
It also demonstrated unique two‑locus genotype associations (e.g., ESR1‑RANKL, VDR‑OPG) and more rare multigenic locus genotypes.This suggests that genetic diversity may underlie the phenotypic differences between NPHPT and classic PHPT,and specific genotypes can be used to subclassify NPHPT.