Immunoglobulin G4-related disease requiring clinical attention: A case report and review of literature

Abstract

BACKGROUND

Immunoglobulin G4 (IgG4)-related disease (IgG4-RD), a relatively rare immune-mediated chronic inflammatory condition characterized by fibrosis, is capable of affecting multiple organs and systems. Epidemiologically, the disease predominantly affects middle-aged and older men in Asian populations, whereas it shows a female predominance in the corresponding age group in the United States. In IgG4-RD, affected tissues and organs may exhibit diffuse or localized swelling, mimicking neoplastic lesions. IgG4-related cholecystitis (IgG4-CC) represents a manifestation involving the gallbladder, with isolated gallbladder involvement without other organ lesions being exceptionally uncommon.

CASE SUMMARY

A 53-year-old man was admitted to the hospital with abdominal pain. Preoperative evaluations could not exclude gallbladder carcinoma, and surgical intervention was required. Based on intraoperative findings, postoperative pathology, and postoperative serum IgG4 levels, a diagnosis of IgG4-CC was considered. After glucocorticoid therapy, the patient’s general condition substantially improved.

CONCLUSION

For patients present with space-occupying lesions of the gallbladder, IgG4-RD should be included in the differential diagnosis.

Key Words: Immunoglobulin G4; Cholecystitis; Fibrosis; Immune responses; Multidisciplinary treatment; Immunity; Signaling pathway; Glucocorticoids; Gallbladder carcinoma; Case report

Core Tip: This article describes a case of immunoglobulin G4 (IgG4)-related cholecystitis (IgG4-CC) in a patient who presented solely with abdominal pain, no pancreatic or biliary duct involvement was evident. Such an isolated occurrence of IgG4-CC is rare because IgG4-CC represents only one manifestation of IgG4-related disease (IgG4-RD). The clinical presentation of IgG4-RD is complex and highly variable, potentially affecting single or multiple organs and tissues, which increases the risks of misdiagnosis and missed diagnosis in clinical practice. For hepatobiliary and pancreatic surgeons, greater awareness of IgG4-RD is essential to avoid unnecessary surgical interventions.

INTRODUCTION

Immunoglobulin G4-related disease (IgG4-RD), a relatively rare immune-mediated chronic inflammatory condition characterized by fibrosis, is capable of affecting multiple organs and systems throughout the body[1,2]. First recognized in the early 21^st century, IgG4-RD was not officially named until 2011[3]. In 1995, Yoshida et al[4] reported a unique case of pancreatitis in a patient who exhibited elevated immunoglobulin levels and responded well to glucocorticoid treatment. At the time, the condition was considered autoimmune pancreatitis (AIP). In 2003, Kamisawa et al[5] proposed that AIP represents only one clinical manifestation of IgG4-RD[5]. In 2010, Takahashi et al[6] formally introduced the concept of IgG4-RD; in 2011, the condition received its official designation[3]. Relevant diagnostic and treatment guidelines were formally issued in 2015[7]. Epidemiological studies in Japan have revealed an incidence of 0.28-1.08 per 100000 individuals, with a predominance in men over 50 years of age and a male-to-female ratio of 3:1[8]. In China, the mean age at onset is 57.29 ± 14.03 years, with a sex ratio of 1.31:1[9]. Studies in the United States have shown a higher incidence of 1.39 per 100000 population, with a mean age at onset of 56.5 years and a reversed sex ratio of 1:1.36 (male/female)[10]. These epidemiological differences may reflect the relatively recent recognition of IgG4-RD as a distinct clinical entity. IgG4-RD commonly manifests as diffuse or localized swelling of affected tissues and organs, mimicking neoplastic lesions[11]. Pathological examination typically reveals extensive infiltration of IgG4-positive plasma cells, storiform fibrosis, and obliterative phlebitis[12,13]. Additionally, patients with this condition generally respond well to glucocorticoid therapy[14,15]. IgG4-RD has the potential to affect nearly any tissue or organ in the body[16]. Based on the regions involved, the disease is classified into four phenotypes: Hepatobiliary and pancreatic lesions (30%), retroperitoneal fibrosis with or without aortitis (24%), head and neck lesions (24%), and Mikulicz’s syndrome with or without systemic involvement (22%). Among these, hepatobiliary and pancreatic lesions are the most frequent manifestations[4,15,16]. When IgG4-RD involves digestive system organs such as the pancreas, bile ducts, liver, and gastrointestinal tract are involved, the associated symptoms are often complex and difficult to distinguish from neoplasms[17,18]. The exact pathogenesis of IgG4-RD remains unclear, although current evidence suggests the involvement of multiple immune-mediated mechanisms. The innate immune response mediated by Toll-like receptors (TLRs) may play a critical role in the development of IgG4-RD[19]. Overexpression of TLR2 and TLR4 has been observed in IgG4-positive cells[20]; upon TLR activation, peripheral blood mononuclear cells from patients with IgG4-RD produce large quantities of IgG4[21]. These findings suggest that TLR signaling represents a link between innate and adaptive immunity in IgG4-RD[22]. Among the TLRs, TLR4 primarily binds to lipopolysaccharide expressed by Gram-negative bacteria[23,24]. Through activation of the nuclear factor-κB (NF-κB) pathway, TLR4 promotes the release of pro-inflammatory cytokines, including interleukin (IL)-1β, tumor necrosis factor-α (TNF-α), and IL-6, as well as Th2 cytokines (e.g., IL-4 and IL-13). This cytokine milieu drives plasma cells to secrete IgG4 antibodies and contributes to fibrosis[25-28]. TLR4 on biliary epithelial cells may be more directly exposed to gut microbiota via bile[29], whereas TLR4 activation in the pancreas may be more closely associated with pancreatic duct obstruction or local ischemia[30]. Furthermore, the mucus-secreting barrier of the gallbladder mucosa may influence the accessibility of TLR4 Ligands[31].

The tumor-mimicking characteristics of IgG4-RD require its consideration as a differential diagnosis in multisystem diseases, particularly in patients with atypical presentations. This article presents a case of IgG4-related cholecystitis (IgG4-CC) that was initially misdiagnosed as gallbladder cancer.

CASE PRESENTATION

Chief complaints

Abdominal pain for 3 days.

History of present illness

A 53-year-old man was admitted to the hospital with abdominal pain. Three days earlier, he had developed diffuse abdominal pain following improper dietary intake; this pain was most severe in the right lower quadrant and characterized by intermittent intense cramping without nausea or vomiting. The pain did not spontaneously resolve. Symptomatic treatment for appendicitis was administered at a local clinic without clinically significant improvement, prompting further evaluation at our hospital. Since the onset of symptoms, the patient had remained conscious, with a poor appetite, normal bowel and urinary habits, and no substantial weight changes.

History of past illness

The patient had a prior history of syphilis (not in the acute phase) and a 30-year history of smoking and alcohol consumption.

Personal and family history

The patient denied a history of chronic illnesses (e.g., hypertension or diabetes) and reported no family history of hereditary diseases.

Physical examination

The patient weighed 59 kg and measured 165 cm in height. His vital signs were as follows: Body temperature, 36.6 °C; Blood pressure, 128/77 mmHg; Heart rate, 105 beats per minute; And respiratory rate, 20 breaths per minute. Physical examination revealed tenderness throughout the abdomen, most pronounced in the right lower quadrant, accompanied by rebound tenderness and muscle rigidity.

Laboratory examinations

Blood tests upon admission showed a white blood cell count of 16.08 × 10⁹/L, platelet count of 476 × 10⁹/L, and neutrophil count of 13.82 × 10⁹/L. The C-reactive protein level was substantially elevated at 318.5 mg/L; procalcitonin was also elevated at 7.667 ng/mL. Coagulation tests indicated a prothrombin time of 14.8 seconds, activity level of 60.39%, and fibrinogen level of 11.57 g/L. The D-dimer level was elevated at 6.72 μg/mL. Electrolyte tests revealed a bicarbonate level of 17.4 mmol/L. Renal function tests showed a creatinine level of 117.3 μmol/L and urea level of 12.25 ng/mL. The syphilis spiral antibody test result was positive, but no obvious abnormalities were detected in tests for hepatitis B, biochemical markers, tumor markers (carcinoembryonic antigen, alpha-fetoprotein, carbohydrate antigen 19-9), or routine urine and stool analyses. The preoperative open cholecystectomy serum IgG4 Level was 435 mg/dL.

Imaging examinations

Dynamic computed tomography (CT) scans revealed clinically significant thickening of the gallbladder wall at the fundus (Figure 1A). Enhanced CT during the arterial phase showed enhancement of the thickened gallbladder wall (Figure 1B); mild enhancement was observed during the venous and delayed phases (Figure 1C and D). A low-density shadow with surrounding exudation was noted below the gallbladder, indicating possible gallbladder perforation. Enlarged lymph nodes were present in the hepatic hilum, along with multiple low-density shadows and effusion in the abdominal and pelvic cavities, suggesting peritonitis. The gallbladder lesion appeared to involve the intestinal wall, resulting in thickening. The appendix was not visualized. One month after symptom onset, a postoperative open cholecystectomy abdominal CT scan showed persistent thickening of the gallbladder wall, although the abdominal and pelvic effusions had substantially decreased compared with the observations from previous images. Fecalith deposition was observed in the appendix, and the thickening of the intestinal wall due to the gallbladder lesion had improved relative to prior findings (Figure 1E). One week after surgery, a follow-up abdominal CT scan demonstrated good recovery in the surgical area (Figure 1F). At 5 weeks post-surgery, a colonoscopy revealed no major abnormalities, thereby excluding the possibility of intestinal tumors.

Figure 1 Imaging findings (computed tomography) of immunoglobulin G4-related cholecystitis. A: Non-contrast computed tomography (CT) scan at the initial visit showed localized thickening at the gallbladder fundus (arrow); B: Arterial-phase contrast-enhanced CT demonstrated enhancement at the site of thickening in the gallbladder fundus (arrow); C: Venous-phase contrast-enhanced CT revealed persistent enhancement at the thickened area of the gallbladder fundus (arrow); D: Delayed-phase contrast-enhanced CT showed continued enhancement at the thickened site of the gallbladder fundus (arrow); E: Preoperative non-contrast CT scan indicated persistent localized thickening at the gallbladder fundus (arrow); F: Postoperative CT scan 1 week after surgery demonstrated good recovery in the surgical area.

FINAL DIAGNOSIS

The final diagnosis included: (1) IgG4-CC; (2) IgG4-RD; and (3) Syphilis infection (non-acute phase).

TREATMENT

Preliminary considerations included gallbladder carcinoma (GBC), cholecystitis with perforation, xanthogranulomatous cholecystitis (XGC), acute appendicitis with perforation, and intestinal neoplasms. Considering the severity of inflammation, priority was given to ultrasound-guided drainage of the abdominal and pelvic effusions. The drained fluid was purulent. The patient showed improvement and was discharged with the drainage tube in place.

The patient was readmitted 1 month after the drainage procedure for planned surgical exploration. After exclusion of surgical contraindications, an exploratory laparotomy was performed. During the procedure, a space-occupying lesion approximately 3 cm in diameter was identified at the gallbladder fundus. The gallbladder was closely associated with the hepatic flexure of the colon, but no neoplastic lesions were observed in the colon. The appendix appeared normal; no definitive metastatic lesions were detected in the abdominal cavity. The gallbladder was resected, and rapid pathological examination indicated a spindle cell proliferative lesion of the gallbladder with chronic inflammatory cell infiltration. The findings were consistent with an inflammatory lesion, and the surgery was concluded. Postoperative pathological examination revealed extensive infiltration of acute and chronic inflammatory cells in the serosal layer of the gallbladder, along with histiocyte aggregation, multinucleated giant cell reaction, and stromal fibroblast/myofibroblast proliferation. Immunohistochemical analysis showed that IgG4-positive plasma cells accounted for 70% of all IgG-positive plasma cells (exceeding the international diagnostic threshold of 40%), with a cell count of 78 IgG4-positive plasma cells per high-power field (HPF) (surpassing the international diagnostic cutoff of > 10/HPF) (Figure 2). The postoperative serum IgG4 Level was 435 mg/dL. Follow-up CT scans demonstrated good recovery in the surgical area (Figure 1F). Based on the overall findings, the diagnosis was consistent with IgG4-CC. The patient was discharged 1 week after surgery upon recovery.

Figure 2 Pathological findings of immunoglobulin G4-related cholecystitis. A and B: Hematoxylin-eosin staining revealed extensive infiltration of inflammatory and plasma cells, accompanied by fibrotic changes and evident phlebitis. No malignant tumor cells were observed (A: × 200; B: × 400); C: Immunoglobulin G4 (IgG4)-positive plasma cells were detected (× 400); D: IgG4-positive plasma cells were identified (× 400); they comprised more than 40% of IgG-positive plasma cells and exceeded 10 per high-power field.

OUTCOME AND FOLLOW-UP

During routine follow-up 3 weeks post-surgery, the patient remained in good general health without recurrent abdominal pain. The serum IgG4 Level was 471 mg/dL. Rheumatology and immunology specialists at our hospital recommended initiating treatment with prednisone acetate 30 mg once daily (q.d.), calcium carbonate D3 chewable tablets 1.5 g q.d., and calcitriol capsules 0.25 μg q.d. The serum IgG4 Level decreased to 391 mg/dL, prompting adjustment of the prednisone acetate dosage to 27.5 mg q.d. Currently, the patient remains in good condition, adhering to standardized glucocorticoids; the IgG4 Level shows continued decline. Blood tests, including complete blood count, biochemistry, and electrolyte panels, remain within normal ranges. Treatment has achieved the expected outcomes, and the patient is continuing follow-up. Based on the complete treatment process, we have developed a treatment algorithm (Figure 3).

Figure 3 Treatment algorithm for this patient. WBC: White blood cell; CRP: C-reactive protein; PCT: Procalcitonin; FIB: Fibrinogen; Cr: Creatinine; IgG4: Immunoglobulin G4; CT: Computed tomography; HPF: High-power field.

DISCUSSION

The systemic condition IgG4-RD constitutes a chronic, progressive, immune-mediated inflammatory fibrotic disorder that may affect single or multiple organs. It is primarily characterized by elevated serum IgG4 Levels and distinctive histopathological features, including sclerosis and lymphoplasmacytic infiltration[1,2,32]. The disease predominantly affects middle-aged and older men[8] and can involve various organs and tissues. The pancreas is the most commonly affected organ, followed by the bile ducts, gallbladder, salivary glands, lacrimal glands, retroperitoneum, kidneys, lungs, prostate, and lymph nodes, among others[4,15,16,33]. The etiology and pathogenesis of IgG4-RD remain incompletely understood. Diagnosis requires a comprehensive evaluation incorporating multiple auxiliary examinations. The elevation of serum IgG4 Levels can serve as a diagnostic criterion; however, mild IgG4 elevation may also occur in conditions such as cholangiocarcinoma and pancreatic cancer. Therefore, the diagnosis of IgG4-RD requires comprehensive evaluation and differential diagnosis, with histopathological biopsy being particularly crucial[7] (Table 1).

Table 1 Differential diagnosis between immunoglobulin G4-related cholecystitis and gallbladder cancer.

Key points for differentiation		IgG4-related cholecystitis	Gallbladder carcinoma
Clinical features	Demographics	Middle-aged and elderly (> 50 years), with sex ratio variations across regions	Middle-aged to elderly, slightly more females, associated with gallstones
	Symptoms	Mild abdominal pain, jaundice, possible multi-organ involvement	Persistent right upper quadrant pain, weight loss, progressive jaundice, cachexia
	Associated conditions	Often associated with autoimmune pancreatitis, sclerosing cholangitis, retroperitoneal fibrosis	Frequently associated with gallstones/polyps; may metastasize in advanced stages
Laboratory findings	Serum IgG4 Levels	Markedly elevated, > 135 mg/dL, about 70% sensitivity	Usually normal or mildly elevated, nonspecific
	Tumor marker CA19-9	Mildly elevated or normal	Markedly elevated, > 100 U/mL suggests malignancy
	Inflammatory biomarkers (CRP, WBC, etc.)	Mildly elevated in active inflammation	May be elevated, especially with infection
	Liver function tests	Elevated bilirubin and ALP if bile duct involvement	Markedly elevated bilirubin and ALP in obstructive jaundice
Imaging findings	Gallbladder wall changes	Diffuse uniform thickening (> 3 mm) with homogeneous enhancement	Irregular or asymmetric thickening, focal mass or nodule
	Bile duct involvement	Segmental stenosis (long-segment, smooth)	Focal stenosis (rigid, cut-off-like)
	Lymphadenopathy	Common findings (without necrosis or fusion)	May exhibit necrosis, fusion, or capsular invasion
	Other characteristics	May be accompanied by pancreatic enlargement (“sausage-like” appearance)	Liver infiltration and distant metastasis (advanced stage)
Pathological features comparison	Histological features	Dense lymphoplasmacytic infiltration, storiform fibrosis, obliterative phlebitis	Atypical glandular structures, mitotic figures, stromal invasion
	IgG4-positive plasma cell count	> 10/HPF, IgG4/IgG > 40%	Non-specific (occasionally reactive increase)
Treatment response		Glucocorticoid responsiveness (symptomatic/imaging improvement within 2 weeks)	Refractory (requiring surgical resection or chemoradiotherapy)
Prognosis comparison		Favorable (may recur, requires long-term follow-up)	Poor prognosis (5-year survival < 20%, stage-dependent)

IgG4: Immunoglobulin G4; WBC: White blood cell; CRP: C-reactive protein; CA19-9: Carbohydrate antigen 19-9; HPF: High-power field; ALP: Alpha-fetoprotein.

Currently, no unified diagnostic standard exists for IgG4-RD, leading to frequent misdiagnoses or missed diagnoses that delay appropriate treatment. The more widely used diagnostic criteria, revised in 2020[34], include the following. Clinical and imaging features comprise one or more organs with diffuse or localized swelling, masses, or nodules characteristic of IgG4-RD. In cases of single-organ involvement, lymphadenopathy may be disregarded. A key serological feature is an IgG4 Level exceeding 135 mg/dL. Pathological features constitute dense lymphocytic and plasmacytic infiltration accompanied by fibrosis, more than 10 IgG4-positive plasma cells per HPF, storiform fibrosis, and obliterative phlebitis. When IgG4-RD involves digestive system organs such as the pancreas, bile ducts, liver, and gastrointestinal tract, the associated symptoms are often complex and difficult to distinguish from those of tumors[17,18] (Table 1). Involvement of the digestive tract in IgG4-RD commonly manifests as AIP and cholangitis. AIP is further classified into types I and II. Type I AIP, known as IgG4-related AIP (IgG4-AIP), was the first disease identified within the spectrum of IgG4-RD and remains one of the more extensively studied conditions[3]. IgG4-CC represents a manifestation of IgG4-RD involving the gallbladder. In most cases, it is associated with IgG4-AIP or IgG4-related sclerosing cholangitis (IgG4-SC). Instances of IgG4-CC without other organ involvement are rare[35]. The patient described in this article did not exhibit manifestations of IgG4-AIP or IgG4-SC, indicating that the disease involved was uncommon. Patients with IgG4-AIP often experience symptoms such as obstructive jaundice, abdominal discomfort, and weight loss. Imaging studies typically reveal focal or diffuse pancreatic enlargement with a capsule-like rim, giving the pancreas a “sausage-like” appearance[36,37]. IgG4-SC commonly manifests as abdominal pain, pruritus, obstructive jaundice, fever, weight loss, and elevated blood glucose levels. Imaging findings usually indicate varying degrees of bile duct wall thickening and luminal narrowing[38,39]. The patient described in this article initially reported abdominal pain as the primary symptom, without manifestations of obstructive jaundice or abnormal liver function. Imaging findings primarily indicated a gallbladder mass; there were no “sausage-like” changes in the pancreas and no evidence of bile duct wall thickening or narrowing. Consequently, at the initial consultation, the primary differential diagnoses included GBC, XGC, and cholecystitis; IgG4-RD was not considered (Table 1).

A diagnosis of IgG4-CC should align with the comprehensive diagnostic criteria for IgG4-RD, revised in 2020[34]. Clinical manifestations of IgG4-CC include upper abdominal pain, jaundice, fever, and fatigue, which are nonspecific and cannot be distinguished from other gallbladder-related diseases[40]. Therefore, imaging studies play a critical role in diagnosis. Imaging examinations may reveal diffuse or localized thickening of the gallbladder wall[40]. Some reports indicate that localized thickening occurs more frequently than diffuse thickening, hindering differentiation of IgG4-CC from GBC and XGC[41,42] (Table 1). CT and magnetic resonance imaging are routinely used for evaluating gallbladder-related diseases; however, the imaging characteristics of IgG4-CC cannot be fully distinguished from those of GBC and XGC. There is some evidence that positron emission tomography/CT may assist in differentiating IgG4-CC from GBC, although the high cost of this approach limits its clinical applicability. Endoscopic ultrasonography can detect characteristic layered thickening of the gallbladder wall in IgG4-CC. Although few cases have been reported, endoscopic ultrasonography may become a key tool for distinguishing IgG4-CC from GBC in the future[41]. In our case, the patient’s CT scan revealed localized thickening of the gallbladder wall and thickening of the intestinal wall adjacent to the gallbladder; no clinically significant abnormalities were evident in the pancreas or bile ducts. Because of the limited understanding of IgG4-RD, IgG4-CC was not considered preoperatively; serum IgG4 testing was not performed, resulting in misdiagnosis (Table 1). However, given the presence of gallbladder perforation and peritonitis, surgical exploration was necessary. Intraoperative rapid pathological examination suggested an inflammatory lesion, preventing radical surgical resection as typically performed for GBC and thereby reducing surgical trauma.

Postoperative pathological examination in this case revealed extensive infiltration of IgG4-positive plasma cells in the serosal layer (> 10 per HPF, with an IgG4/IgG ratio > 40%), accompanied by a multinucleated giant cell reaction and fibrotic changes. These findings are consistent with the pathological features of IgG4-RD. Notably, obliterative phlebitis and fibrosis represent key pathological hallmarks of this condition. Regarding pathogenesis, although IgG4 antibodies are capable of activating complement C1q via the classical pathway, they primarily activate the complement system through the mannose-binding lectin pathway, generating anaphylatoxins such as C3a and C5a. These molecules recruit eosinophils and mast cells, which in turn release profibrotic factors including transforming growth factor-β (TGF-β) and platelet-derived growth factor[43,44]. Molecular pathology studies have demonstrated substantial upregulation of TLR4 expression in IgG4-positive cells[20]. Activation of TLR4 stimulates the NF-κB signaling pathway, promoting the release of pro-inflammatory cytokines such as IL-1β, TNF-α, and IL-6, while also enhancing the secretion of Th2 cytokines (e.g., IL-4 and IL-13). These mechanisms collectively drive IgG4 antibody production by plasma cells and contribute to the development of fibrosis[25-28]. Activated myofibroblasts further augment collagen deposition through the TGF-β/Smad3 signaling pathway, ultimately resulting in fibrotic occlusion of venous walls[45]. IL-1β released in response to tissue damage can further activate the NF-κB pathway, perpetuating a vicious cycle of chronic inflammation and fibrosis[14]. Immunohistochemical analysis has identified abundant infiltration of FOXP3 + regulatory T cells (Tregs) within fibrotic lesions in patients with IgG4-RD. These FOXP3 + Tregs exhibit spatial co-localization with IgG4-positive plasma cells in fibrotic areas, suggesting synergistic roles in disease progression[46,47]. Clinical observations indicate that effective treatment considerably reduces the proportion of FOXP3 + Tregs in the peripheral blood of patients with IgG4-RD[48]. Multiple studies have confirmed strong positive relationships among the absolute number of FOXP3 + Tregs, the extent of their tissue infiltration, and the severity of fibrosis[46,47]. Longitudinal studies indicate that serum IL-6 and soluble IL-2 receptor (sIL-2R) levels may increase abnormally 3-6 months prior to clinical relapse in IgG4-RD, preceding changes in serum IgG4 concentrations. Mechanistic analyses indicate that IL-6 directly promotes plasma cell differentiation, whereas sIL-2R constitutes a sensitive indicator of T-cell activation. Thus, compared with serum IgG4 Levels which are easily influenced by glucocorticoid therapy IL-6 and sIL-2R may more accurately reflect disease activity[49]. Notably, persistent elevation of the eosinophil-to-lymphocyte ratio has been identified as an independent risk factor for IgG4-RD relapse. This parameter objectively reflects disease activity and serves as a valuable biomarker for predicting recurrence[50]. Based on this evidence, we recommend incorporating regular monitoring of serum IL-6, sIL-2R, and eosinophil-to-lymphocyte ratio into the routine follow-up protocol for patients with IgG4-RD, supplemented by imaging evaluation as needed. Although these markers were not systematically monitored during the early follow-up phase in the present case, subsequent follow-up will include routine assessment of these parameters.

As a chronic immune-mediated fibroinflammatory condition, IgG4-RD has undergone substantial advances in treatment strategies in recent years, evolving from glucocorticoid monotherapy to combination regimens that include immunomodulators and biologic targeted therapies. Nonetheless, the foundational role and optimized use of glucocorticoids remain central to current disease management. In our case, the patient received postoperative prednisone at 30 mg once daily (approximately 0.5 mg/kg/day), followed by gradual tapering based on clinical response, consistent with current practice. A 2025 multicenter study published in Annals of the Rheumatic Diseases validated this approach, demonstrating that glucocorticoids effectively induce remission in most patients with active IgG4-RD[51,52]. The latest consensus recommendations advise the following: (1) For active disease, initiate prednisone at 0.5-0.6 mg/kg/day and maintain for 2-4 weeks; (2) After clinical symptoms and biomarkers improve, reduce the dose by 5-10 mg every 1-2 weeks, with a slower taper once 20 mg/day is reached; and (3) Upon achieving a maintenance dose of 5-10 mg/day, continue for 3-6 months before considering further tapering or discontinuation[52]. In our case, the patient’s prednisone dose was reduced from 30 mg to 27.5 mg over 5 weeks postoperatively, reflecting a cautious tapering strategy consistent with individualized treatment principles. However, the metabolic side effects associated with long-term glucocorticoid use such as diabetes, osteoporosis, and hypertension must not be overlooked, prompting ongoing efforts to optimize glucocorticoid regimens. The introduction of immunomodulators for maintenance therapy and biologic targeted agents is reshaping the treatment landscape of IgG4-RD[43,51,53]. A carefully structured glucocorticoid withdrawal strategy is essential to balance therapeutic efficacy and safety. Recommended principles for glucocorticoid tapering are as follows: (1) Ensure disease stability for at least 6-12 months; (2) Assess serum IgG4 Levels and imaging findings before initiating dose reduction; (3) Implement a slow, stepwise taper (e.g., 2.5 mg per month); (4) Closely monitor clinical symptoms and laboratory parameters during tapering; and (5) Consider transitioning to immunomodulator monotherapy or biologic maintenance therapy as appropriate[52,54]. Notably, elevated baseline levels of IgG4, IgG, total immunoglobulin E (IgE), and peripheral eosinophils have been identified as risk factors for disease relapse, warranting greater caution during glucocorticoid tapering in such patients[54]. The conservative tapering approach adopted in this case aligns with these evidence-based recommendations. A comprehensive glucocorticoid treatment and monitoring protocol was developed specifically for this patient (Figure 4).

Figure 4 Specific regimen and monitoring protocol for glucocorticoid therap. IgG4: Immunoglobulin G4.

The initial misdiagnosis of this IgG4-CC case as gallbladder cancer or perforated cholecystitis was not incidental but arose from multiple contributing factors. Rarity of the disease and lack of awareness: The primary factor underlying misdiagnosis was the extreme rarity of IgG4-CC and insufficient recognition of this condition in clinical practice. IgG4-CC is exceptionally uncommon, and general surgeons rarely encounter such cases, leading to diagnostic blind spots. Compared with the more widely recognized IgG4-related pancreatitis or dacryoadenitis, gallbladder involvement has been rarely reported, resulting in limited clinical awareness[40]. Non-specific clinical manifestations: Another major contributor to misdiagnosis was the non-specific presentation. This patient exhibited diffuse abdominal pain, predominantly in the right lower quadrant, accompanied by signs of peritoneal irritation and a systemic inflammatory response feature commonly associated with acute abdominal conditions, such as appendicitis or perforated cholecystitis. Misleading imaging findings: Radiological misinterpretation played a pivotal role in misdiagnosis. The CT scan revealed localized thickening with enhancement at the gallbladder fundus, pericholecystic exudation, and peritoneal effusion findings that closely resemble gallbladder cancer or perforated cholecystitis. According to existing literature, IgG4-CC typically presents as diffuse or focal thickening of the gallbladder wall with enhancement on contrast imaging, but without malignant features such as infiltrative growth or metastasis[40]. In this case, the enhancement observed during the arterial, venous, and delayed phases was more consistent with inflammation, but it was initially regarded as malignancy. Furthermore, the hypodense area below the gallbladder and surrounding exudation were considered “perforation”, although these findings may have represented inflammatory exudates related to IgG4-RD. Limitations in the diagnostic workflow: This case highlights several systemic shortcomings in the current diagnostic approach to IgG4-RD. Serum IgG4 testing is not routinely conducted for patients with inflammatory conditions, which can result in missed diagnostic indicators. Limitations of biopsy specimens: The initial ultrasound-guided peritoneal fluid aspiration yielded only purulent fluid and failed to provide histopathological evidence. Insufficient multidisciplinary collaboration: When diagnostic uncertainty arose, no timely consultation was initiated with radiology, pathology, or rheumatology specialists. Recent studies emphasize that early multidisciplinary team (MDT) discussions in complex or ambiguous cases can substantially improve diagnostic accuracy[55,56]. Confounding comorbidities: Additional contributing factors included the patient’s medical history. A prior diagnosis of syphilis (non-acute phase) and long-term tobacco and alcohol use may have led clinicians to prioritize infectious or neoplastic causes over autoimmune etiologies.

Based on the above analysis of the causes of misdiagnosis and incorporation of recent clinical research and guideline recommendations, we have developed a systematic strategy to reduce the misdiagnosis rate of IgG4-CC and related conditions.

Enhance clinical awareness and diagnostic vigilance

Improvements to clinical recognition and diagnostic suspicion represent the first step in preventing misdiagnosis. Medical institutions should strengthen continuing medical education on IgG4-RD, particularly in departments likely to experience initial encounters with such patients, including general surgery, gastroenterology, and radiology. Key training priorities should include: (1) The spectrum of multi-organ involvement in IgG4-RD, with emphasis on biliary tract manifestations; (2) Demographic characteristics, notably the predominance in middle-aged and older men; and (3) Diagnostic “red flag” features, such as concurrent multi-organ involvement, steroid-responsive masses or wall thickening, and elevated serum IgG4 Levels[43,51].

Optimize laboratory testing for early detection

In cases of unexplained organ enlargement, wall thickening, or inflammatory lesions, serum IgG4 testing should be incorporated into the routine diagnostic workup, particularly when the initial diagnosis is uncertain or when treatment response is suboptimal. Although elevated serum IgG4 Levels are suggestive of IgG4-RD, they alone are not diagnostic and must be interpreted in conjunction with clinical and histopathological findings[43]. Additional laboratory markers such as serum IgE, peripheral eosinophil count, complement levels, plasmablast count, and IL-33 may provide supplementary diagnostic value[43].

Refine imaging evaluation for differential diagnosis

When imaging reveals gallbladder wall thickening, the following features should be systematically evaluated to support a diagnosis of IgG4-CC: (1) Distribution of thickening (diffuse vs focal); (2) Enhancement pattern (homogeneous delayed vs heterogeneous early); and (3) Associated findings (e.g., involvement of other organs, lymphadenopathy characteristics)[40]. Multimodal imaging enhances diagnostic accuracy: Ultrasound is useful for assessing gallbladder wall thickening patterns; CT/magnetic resonance imaging is valuable for identifying multi-organ involvement; And positron emission tomography/CT provides insight into metabolic activity and systemic disease extent in diagnostically challenging cases[53].

Standardize histopathological diagnosis (gold standard)

Accurate histopathological evaluation requires adequate tissue sampling. In suspected cases of IgG4-CC, fine-needle aspiration cytology is often inadequate. Core needle biopsy or surgical specimens are preferred for definitive diagnosis[53]. In inoperable cases, alternative approaches such as endoscopic ultrasound-guided biopsy should be pursued to obtain diagnostic tissue.

Implement a stepwise diagnostic pathway

Based on recent evidence and insights gained from this case, we propose a stepwise diagnostic approach for unexplained gallbladder wall thickening (see Table 2 for detailed steps). This structured workflow is designed to systematically reduce the risk of misdiagnosis.

Table 2 Diagnostic pathway and key decision points for immunoglobulin G4-related cholecystitis.

Diagnosis phase	Critical examination	Key decision point	Next steps in treatment
Initial suspicion	Medical history, physical examination, serum IgG4	Are there any red-flag signs of IgG4-RD?	If yes: Proceed to next step; if no: Consider alternative diagnoses
Imaging evaluation	Contrast-enhanced CT or contrast-enhanced MRI, ultrasound	Are the imaging findings consistent with IgG4-related cholecystitis?	If consistent: Obtain tissue (for histopathology); if inconsistent but high suspicion remains: MDT discussion
Pathological confirmation	Biopsy specimen or resection specimen	Are the pathological diagnostic criteria for IgG4-RD fulfilled?	If criteria are met: Confirm diagnosis (definitive diagnosis of IgG4-RD); if pathological criteria are fulfilled: Establish definitive diagnosis of IgG4-RD
Treatment monitoring	Symptoms; serum IgG4, IL-6, sIL-2R, ELR; imaging	Is there a response to the administered therapy?	Response to treatment: Supports diagnosis; no response: Re-evaluate

IgG4: Immunoglobulin G4; CT: Computed tomography; MRI: Magnetic resonance imaging; IL: Interleukin; sIL-2R: Soluble interleukin-2 receptor; ELR: Eosinophil-to-lymphocyte ratio; IgG4-RD: Immunoglobulin G4-related disease; MDT: Multidisciplinary team.

IgG4-RD, as a complex multisystem condition, presents diagnostic and therapeutic challenges that exceed the capabilities of any single medical discipline. The MDT approach, which integrates expertise from various specialties, has become essential for optimizing the management of IgG4-RD. Diagnosis requires a comprehensive evaluation that includes clinical, imaging, serological, and pathological evidence. Treatment involves the careful selection of immunosuppressive regimens and management of associated side effects. Follow-up care warrants multi-organ functional assessments tasks that fall beyond the conventional scope of any single specialty[43,55,56]. As demonstrated in this case, the initial misdiagnosis was ultimately corrected through collaboration among pathologists, rheumatologists, surgeons, and radiologists, underscoring the indispensable role of the MDT model.

IgG4-RD is a systemic condition with a complex and varied clinical presentation, which affects single or multiple organs and tissues throughout the body. Its diverse clinical manifestations often result in misdiagnosis or missed diagnosis. The patient in this case had a history of prolonged smoking and alcohol consumption. Although current evidence has not established direct causal relationships of long-term smoking or alcohol use with IgG4-RD, these factors may be linked to certain clinical manifestations or complications such as pulmonary or hepatic involvement and may increase the risk of malignancy, further complicating differential diagnosis[57]. Smoking and alcohol use can both induce genome-wide methylation abnormalities[58,59]. Studies have identified differentially methylated genes, such as FOXP3 in the peripheral blood mononuclear cells of patients with IgG4-RD. Such epigenetic changes may impair Treg function and promote autoimmune responses[58]. Smoking exerts both direct and indirect effects on immune responses associated with inflammation and fibrosis two hallmark features of IgG4-RD[60,61]. Notably, 4-[methylnitrosamino]-1-[3-pyridyl]-1-butanone, a major tobacco-specific carcinogen, activates the NF-κB signaling pathway[61]. This activation promotes the release of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) and Th2 cytokines (IL-4, IL-13), which drive IgG4 antibody production by plasma cells and contribute to fibrosis[25-28]. Importantly, smoking cessation has been associated with significant improvements in IgG4-RD prognosis[57]. Alcohol metabolism generates acetaldehyde, which inhibits histone deacetylase, leading to increased expression of pro-inflammatory factors such as IL-1β and TNF-α, and thus exacerbating fibrotic processes[59]. Chronic alcohol consumption impairs intestinal barrier function, facilitating translocation of microbial products such as lipopolysaccharide. This translocation triggers systemic Th2 and T follicular helper cell polarization and supports IgG4-dominant immune responses[62]. Therefore, smoking and alcohol cessation is strongly recommended for patients with IgG4-RD.

CONCLUSION

For hepatobiliary and pancreatic surgeons, greater awareness and understanding of IgG4-RD are essential. When patients present with space-occupying lesions of the gallbladder, IgG4-RD should be included in the differential diagnosis. Preoperative measurement of serum IgG4 Levels is recommended to avoid unnecessary surgical interventions.