IgG4RD is a systemic disease characterized by infiltration of IgG4 immunopositive plasma cells,elevated serum IgG4 concentrations, and swelling of multiple organs, as well as nice response to treatment with glucocorticoids[2, 3]. The main laboratory findings are elevated serum IgG4, hypergammaglobulinemia, and eosinophilia. The pathogenesis is currently unknown, and the main idea is that autoimmunity and infection are potential immune triggers for IgG4-RD, and that a central element of the etiopathogenesis of IgG4-RD involves antigen presentation by B cells to CTLs. Interactions between B cells and other CD4 T lymphocytes, such as follicular T helper cells, drive the class switch to IgG4, leading to overexpression of cytokines represented by type 2 helper T(Th 2) cells and activation of regulatory T (Treg) cell, which promotes massive infiltration of inflammatory cells, that can lead to organ damage[4]. Patients usually present with nonspecific symptoms and are referred to various departments. When IgG4-RD affects organs such as the lungs, kidneys, and digestive tract, it presents as tumor-like swelling and needs to be differentiated from malignancy or other autoimmune diseases (including antineutrophil cytoplasmic antibody-associated vasculitis, idiopathic multicenter Castleman disease (iMCCD), and Rosai-Dorfman disease. When IgG4-RD affects the lungs, it is called IgG4-related lung disease (IgG4 RLD). Lymphoplasmacytic infiltration occurs in both IgG 4-RLD and iMCCD, and the lungs of patients with IgG4-RLD present with fibrosis and eosinophilic infiltration of the perivascular stromal area with obliterative phlebitis, while iMCCD lung lesions are seen in the alveoli adjacent to the perilymphatic stromal area[5].
Rosai-Dorfman disease can present with lymphadenopathy whose histopathology shows a predominance of histiocytes with large amounts of cytoplasm in which lymphocytes are engulfed (also known as emperipolesis or Rosai-Dorfman cells). This pathology also shows positive staining for S-100 protein and negative CD1a marker. Both IgG4-RD and Rosai-Dorfman disease possess hypergammaglobulinemia,and there is a degree of speculation of an overlap[6]. When IgG4-RD affects the kidneys, the most common manifestation is plasma cell-rich tubulointerstitial nephritis (TIN), called IgG4-related TIN (IgG4-TIN) [7–10]. Features include eosinophil infiltration, specific distribution of renal parenchymal lesions(the margin between affected and unaffected areas is very clear) immunoglobulins, and complement deposition in the tubular basement membrane (TBM) [8–11]. Corticosteroids can distinguished IgG4-RD from other disorders by their therapeutic effects. IgG4-RD responds rapidly to glucocorticoid therapy, and patients with idiopathic multicenter Castleman disease (iMCCD) respond partially to steroid therapy and respond to immunosuppressant and/or anti-IL-6 therapy.
More than 90% of hypercalcemia is caused by primary hyperparathyroidism and malignancy. IgG4RD is rarely combined with hypercalcemia. To our knowledge, only several cases of IgG4RD with hypercalcemia were previously reported. The PTH level is an important node in the diagnosis of hypercalcemia. Hypercalcaemia can be divided into PTH-dependent hypercalcaemia and non-PTH-dependent hypercalcaemia. PTH-dependent hypercalcemia is usually caused by parathyroid adenoma and hyperplasia. Cansu et al. reported that a woman with IgG4RD was combined with parathyroid adenoma with high PTH and blood calcium,pathological manifestations of lymphoplasmacyte infiltration after parathyroidectomy, and IgG4/IgG ratio was > 50%[12]. PTH-dependent hypercalcemia can also be caused by antibodies that inactivate the parathyroid calcium-sensitive receptor, a woman with multiple autoimmune processes, elevated serum calcium and PTH levels, response to glucocorticoid administration, pathology after subtotal parathyroidectomy,patchy lymphocyte infiltration of normal glands, considered the presence of IgG4 autoantibodies to calcium-sensitive proteins, resulting in hypocalciuria hypercalcemia[13] .
Hasegawa et al.reported a patient with IgG4RD involving systemic lymph nodes, liver, and salivary glands with elevated calcium and serum levels of intact PTH, and no abnormalities on Tc-99m methoxyisobutylisonitrile(MIBI) scintigraphy, thyroid ultrasonography, ultimately considering transient hypercalcemia associated with IgG4 disease[14]. Kawakita et al. presented a 40-year-old male who was hospitalized with renal impairment and severe hypercalcemia, and Tc-99m MDP SPECT showed increased ectopic uptake in the heart, lungs, stomach, and kidneys, finally, autopsy revealed an increase in osteoclasts in the bone marrow, and IgG4-RD with osteolytic hypercalcemia is considered[15].
The cause of non-PTH-dependent hypercalcemia is unknown. In the present case, the patient's PTH is below normal, suggesting non-PTH-dependent hypercalcemia and the next should be to evaluate for potential malignancy[16]. Through various laboratory, radiological, and histological examinations, we ruled out other causes of hypercalcemia, such as solid tumors, lymphomas, multiple myeloma, and drug side effects. Therefore, the etiology of IgG4RD with high blood calcium needs to be further studied. Hypercalcemia, abnormal calcium metabolism, easy to precipitate in an alkaline environment, so metastatic calcification is easy to occur in lung, kidney, stomach, and other soft tissues with high pH values[17–19].Tc-99m MDP SPECT/CT can detect extraosseous metastatic calcifications promptly, not only assess the degree of metastatic calcifications, but also help diagnose the disease and avoid the need for invasive biopsy, and may be the most sensitive technique for early detection of metastatic calcifications. For patients with renal insufficiency, unknown etiology hypercalcemia and elevated serum IgG4; we should carefully assess the possibility of IgG4RD. Tc-99m MDP SPECT/CT examination can timely detected metastatic calcification and contribute to appropriate treatment.