JAMA Diagnostic Test Interpretation January 15, 2019

Immunoglobulin G4 Levels

Sajan Jiv Singh Nagpal, Suresh T. Chari

JAMA. 2019;321(2):202-203. doi:10.1001/jama.2018.16665Case

A 67-year-old man with type 2 diabetes mellitus and hyperlipidemia was evaluated for unintentional weight loss of 28 lb (12.7 kg) and increasing fasting blood glucose values over the past 6 months. A computed tomography scan showed diffuse enlargement of the pancreas with peripheral hypoenhancement but no discrete mass. Soft tissue surrounded the infrarenal abdominal aorta, extended along the common iliac arteries, and obstructed the left ureter, causing hydronephrosis. He was referred for evaluation of possible malignancy. Laboratory studies including immunoglobulin G subgroup 4 (IgG4) levels are shown in the Table. Fine-needle aspiration of the pancreas showed no malignancy. Colonoscopy results 8 months ago were normal.

一名67岁2型糖尿病及高脂血症的男性患者在6个月内体重下降12.7 kg，空腹血糖水平升高。CT扫描显示胰腺弥漫性增大，周围呈低密度，但未发现肿物。软组织包绕肾下腹主动脉，并沿髂总动脉延伸，阻塞左侧输尿管导致肾盂积水。患者接受了肿瘤相关筛查。包括免疫球蛋白G亚组4 (IgG4)在内的实验室检查见下表。胰腺细针穿刺未发现恶性肿瘤。8个月前的结肠镜结果正常。

Patient’s Laboratory Values and Reference Ranges 患者实验室检查结果及参考值

Q: What Would You Do Next? 下一步应该做什么?

A: Test results indicate presence of IgG4-related disease. 实验室检查结果提示IgG4相关疾病

Test Characteristics 检查特点

IgG4-related disease is a relapsing, immune-mediated, multiorgan, fibroinflammatory disease (characterized by intense inflammation and fibrosis) that presents similarly to a nonspecific malignant, infectious, and inflammatory condition. IgG4 is a subclass of IgG that accounts for less than 5% of the total IgG in healthy adults.^1,2 The sensitivity of any elevation of IgG4 for diagnosing IgG4-related disease is approximately 70% and the specificity is 85%. Some criteria for diagnosing IgG4-related disease use a 2-fold elevation of IgG4 levels as the threshold for a positive test, in which case the sensitivity is approximately 60% and the specificity is 90%.^1,3,4 Because the prevalence of IgG4-related disease is low (4.6 cases per 100 000),⁵ the positive predictive value of IgG4 elevation is only 36%.³ IgG4 may be elevated in conditions other than IgG4-related disease. For example, IgG4-related disease is elevated in 7% to 10% of patients with pancreatic cancer, cholangiocarcinoma, primary sclerosing cholangitis, acute pancreatitis, and healthy individuals.³ The precise role of IgG4 in the pathogenesis of IgG4-related disease remains unknown. Elevated IgG4 levels in IgG4-related disease may result from type 2 helper cell activation, in response to prolonged exposure to an unknown antigen.^2,6 The 2018 Medicare reimbursement for the IgG4 assay is $9.90.

IgG4相关疾病是一种复发性，免疫介导的多器官纤维炎症性疾病（特点为强化炎症反应及纤维化），其临床表现与非特异性肿瘤、感染与炎症相似。IgG4是IgG的一种，占健康成人总IgG的不足5%。IgG4水平升高诊断IgG4相关疾病的敏感性约为70%，特异性为85%。IgG4相关疾病的某些诊断标准将IgG4水平升高2倍作为检查结果阳性的判断标准，此时敏感性约为60%，特异性为90%。由于IgG4相关疾病的发生率很低（每100000人4.6例），因此，IgG4升高的阳性预期值仅为36%。除IgG4相关疾病外，其他疾病也可有IgG4水平升高。例如，约7-10%的胰腺癌、胆管癌、原发性硬化性胆管炎、急性胰腺炎及健康成人中IgG4升高。IgG4在IgG4相关疾病的发病机制中的确切作用尚不明确。IgG4相关疾病中IgG4水平升高可能源于未知抗原长期暴露导致的2型辅助细胞活化。2018年，美国Medicare对IgG4检测的报销费用为$9.90。

Application of Test Results to This Patient 本例患者检查结果的应用

Individual organ manifestations of IgG4-related disease were previously regarded as unrelated disease entities (eg, autoimmune pancreatitis, IgG4-associated cholangitis, Mikulicz disease, retroperitoneal fibrosis, orbital pseudolymphoma, interstitial lung disease, IgG4-related tubulointerstitial nephritis) but are now considered part of a single disease process that involves various organs. Multiple organs may be involved successively or at the same time. IgG4-related disease typically affects males in a 3:1 ratio.^1,2 An isolated elevation of IgG4 levels is not diagnostic of IgG4-related disease, but a combination of elevated IgG4 levels and typical imaging features (diffuse/localized swelling of the pancreas with peripheral hypoenhancement) is diagnostic, as in this patient with autoimmune pancreatitis and retroperitoneal fibrosis.⁷ In such typical cases, a biopsy is not required for diagnosis.⁷ However, as manifestations of IgG4-related disease are often mass forming, a fine-needle aspiration should be performed to rule out malignancy.

既往认为，IgG4相关疾病的各个器官表现并不相关（如自身免疫性胰腺炎，IgG4相关胆管炎，Mikulicz病，腹膜后纤维化，眼眶假性淋巴瘤，间质性肺病，IgG4相关小管间质性肾炎），但目前认为是单一疾病过程累及各个器官的表现。多个器官可序贯或同时受累。IgG4相关疾病患者男女比例为3:1。单纯IgG4水平升高不能诊断IgG4相关疾病，但结合典型的影像学表现（胰腺弥漫性/局灶性肿胀伴边缘低密度）可确诊，正如本例自身免疫性胰腺炎及腹膜后纤维化患者。上述典型病例无需活检即可诊断。然而，由于IgG4相关疾病常表现为肿物，因此可通过细针穿刺排除肿瘤。

IgG4-related disease can also be diagnosed based on characteristic histology. However, samples from fine-needle aspiration are typically inadequate for histologic diagnosis of IgG4-related disease. Tissue diagnosis of IgG4-related disease requires preserved architecture, such as that obtained from a core or wedge biopsy or resection specimens. Histologic findings are similar across affected organs and are characterized by lymphoplasmacytic infiltration, storiform (cartwheel) fibrosis, and obliterative phlebitis. Staining the histopathology specimen facilitates calculation of the absolute number and relative proportion of IgG4+ cells from the total number of IgG+ plasma cells, which are components of the histologic criteria for IgG4-related disease.⁸

IgG4相关疾病也可根据特征性组织学表现进行诊断。然而，细针穿刺取得的标本通常不足以进行IgG4相关疾病的组织学诊断。IgG4相关疾病的组织学诊断往往需要粗针或楔形活检或切除标本。受累器官的组织学发现相似，包括淋巴浆细胞浸润，席纹状（车辐状）纤维化及阻塞性静脉炎。对组织学标本进行染色有助于计算IgG+浆细胞中IgG4+细胞的绝对及相对数量，这是IgG4相关疾病组织学诊断标准的重要项目。

What Are Alternative Diagnostic Testing Approaches? 其他的诊断方法？

Specific laboratory tests alone cannot diagnose IgG4-related disease. Approximately 60% of patients with IgG4-related disease have elevated serum IgE levels, approximately 25% have elevated inflammatory markers such as C-reactive protein, and approximately one-third have elevated levels of eosinophils and antinuclear antibody.⁴

单纯依据特异性实验室检查不能诊断IgG4相关疾病。约有60%的IgG4相关疾病患者血清IgE水平升高，约25%的患者炎症标志物如C-反应蛋白升高，约1/3患者嗜酸性粒细胞及抗核抗体水平升高。

Levels of IgG4 are unreliable for assessing response to treatment and can rebound above normal in up to 70% patients after withdrawal of glucocorticoid treatment.⁹ Even patients with a false-positive elevation of IgG4 (ie, not related to underlying IgG4-related disease) can have improvement in IgG4 levels with steroids, presumably due to reduced inflammation.¹⁰ Therefore, IgG4 levels cannot be used to measure responsiveness to therapy. Repeat imaging, along with specific laboratory testing, depending on the organ involved (eg, liver biochemistries in cases with autoimmune pancreatitis or IgG4-associated cholangitis) are often the best indicators of response to treatment.

根据IgG4水平不能可靠评估治疗反应，多达70%的患者停用糖皮质激素后IgG4可再次升高。即使IgG4水平假性升高的患者（即与IgG4相关疾病无关）在激素治疗后IgG4水平也可改善，可能因炎症反应减弱导致。因此，IgG4水平不能用于评估治疗反应。根据受累器官复查影像学检查，结合特异性实验室检查（如自身免疫性胰腺炎或IgG4相关胆管炎患者的肝脏功能检查）常常是提示治疗反应的最佳指标。

Patient Outcomes 患者预后

The patient was prescribed prednisone, 40 mg/daily, for 1 month followed by a prednisone taper over 8 weeks. Repeat computed tomographic scan 2 weeks after starting treatment showed significant improvement in pancreatic inflammation. A ureteral stent was placed for ureteral stenosis due to retroperitoneal fibrosis and left hydronephrosis. At 3-month follow-up, liver biochemistry levels were normal. At 6-month follow-up, pancreatic changes and hydronephrosis had resolved, and the ureteral stent was removed. The patient had a relapse 3 years after presentation, which was treated again with corticosteroids. The patient was relapse free at his most recent follow-up (3 months ago).

本例患者使用强的松40 mg/d，一个月后逐渐减量，8周后减停。开始治疗后2周复查CT显示胰腺炎症显著改善。置入输尿管支架缓解腹膜后纤维化导致的输尿管狭窄及左侧肾盂积水。3个月随访时，肝脏功能正常。6个月随访时，胰腺改变及肾盂积水缓解，遂去除输尿管支架。3年后患者病情复发，再次使用皮质激素治疗。最近一次（3个月前）随访时患者没有复发表现。

Clinical Bottom Line 临床要点

• Immunoglobulin G subgroup 4 (IgG4)-related disease is a relapsing, immune-mediated, fibroinflammatory disease (characterized by intense inflammation and fibrosis) that resembles malignant, infectious, and inflammatory conditions in its presentation and can affect multiple organs. IgG4相关疾病是一种复发性，免疫介导的多器官纤维炎症性疾病（特点为强化炎症反应及纤维化），其临床表现与非特异性肿瘤、感染与炎症相似，可累及多个器官
• Elevated IgG4 levels are insufficient for diagnosing IgG4-related disease. In the case of pancreatic involvement from IgG4-related disease (ie, autoimmune pancreatitis), a combination of elevated IgG4 levels and characteristic imaging features can lead to a diagnosis without biopsy. IgG4水平升高不足以诊断IgG4相关疾病。对于IgG4相关疾病导致胰腺受累的患者（即自身免疫性胰腺炎），综合IgG4水平升高及影像学特征性表现可无需活检确诊IgG4相关疾病。
• Alternatively, a core or wedge biopsy can be obtained for a histologic diagnosis of IgG4-related disease. Histology is similar across all involved organs. 此外，粗针或楔形活检标本可用于组织学诊断IgG4相关疾病。所有受累器官的组织学表现相似。
• Corticosteroids should be used for treating the initial episode and relapses. 皮质激素用于初治性或复发性IgG4相关疾病的治疗。
• Levels of IgG4 commonly increase after treatment. An isolated elevation in IgG4 levels is insufficient evidence for relapse in the absence of other clinical data. 治疗后IgG4水平通常升高。没有其他临床证据的情况下，单纯IgG4水平升高不足以作为疾病复发的证据。