IgG4 related disease (IgG4-RD) is a multisystemic disorder which has only recently been recognized. IgG4 related sclerosing cholangitis (IgG4-SC) is the biliary manifestation of the disease, often in association with autoimmune pancreatitis (AIP). In this review, we provide an overview of IgG4-RD, with a focus on the biliary manifestations. In particular, we describe the important differential diagnoses of IgG4-SC that need to be considered, namely, primary sclerosing cholangitis (PSC) and cholangiocarcinoma, and provide a management algorithm. Finally, we highlight future directions and unanswered questions which will provide new insights into this exciting and evolving disease entity. 1. Introduction IgG4 related disease (IgG4-RD) is a new and emerging disease entity. It was first identified as a multisystemic disease in 2003, in patients with autoimmune pancreatitis (AIP) [1, 2]. Multiorgan involvement has been reported to occur in more than 60% of patients with IgG4-RD [3, 4], with a wide range of organs affected, including pancreas, kidneys, biliary tree, liver, salivary gland, orbit, breast, pericardium, aorta, skin, lungs, prostate, meninges, and pituitary [5–8]. Asymptomatic lymphadenopathy can also occur, affecting 80% of patients with AIP [9]. The epidemiology of IgG4-RD is difficult to determine as it depends on the primary organ at presentation. Extrapolating data from patients with type-1 AIP, IgG4-RD appears to be a disease predominantly affecting middle aged/older men (60 years) [10, 11]. This seems to be the case in patients that present with either single organ disease or multiorgan disease [10]. 2. IgG4 Related Disease Previously recognized conditions are unified by the diagnosis of IgG4-RD and include Ormond’s disease (retroperitoneal fibrosis), Riedel’s thyroiditis, Mikulicz’s disease (salivary gland enlargement), and Kuttner’s tumour (sclerosing sialadenitis). Patients often present with tumefactive (mass-forming) lesions and, therefore, are suspected to have malignancy [12]. Clinical features at presentation depend upon the organ that is involved. Constitutional symptoms such as pyrexia and weight loss affect less than 10% of patients [12]. The pathogenesis of IgG4-RD is incompletely defined, but evidence would suggest a possible role for autoimmunity and allergy. Inflammation and subsequent fibrosis in IgG4-RD appear to be driven by T helper 2 (Th2) cells and regulatory T cells (Treg cells) compared to Th1 or Th17 subsets in other autoimmune diseases [13]. The proposed role of allergy appears to have originated from the
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