Antibodies to carbonic anhydrase and IgG4 levels in idiopathic chronic pancreatitis: relevance for diagnosis of autoimmune pancreatitis

Abstract

Background: Increased serum antibodies against carbonic anhydrase II (CA-II Ab) or IgG4 levels have been reported in cases of autoimmune chronic pancreatitis (ACP).

Aim: To assess the relevance of serum CA-II Ab and IgG4 levels for the diagnosis of ACP in idiopathic CP (ICP) versus alcoholic CP and Sjogren's syndrome (SS).

Subjects: This was a multicentre study involving 227 subjects divided into four groups: ICP (n = 54), normal controls (n = 54, paired by age and sex with ICP patients), alcoholic CP (n = 86), and SS (n = 33).

Methods: CA-II Ab was measured by ELISA and confirmed by western blotting. A score of easy clinical use with major clinical, morphological, and biochemical parameters for the diagnosis of ACP was applied.

Results: The percentage of patients with increased serum CA-II Ab was higher in the ICP group (28%) than in controls (1.9%) and in patients with alcoholic CP (10.5%), but lower than in patients with SS (64%). The proportion with elevated IgG4 levels was higher in the ICP group (15%) compared with controls (1.9%) and SS (0%) but not significantly different from alcoholic CP (8%). Most ICP patients (7/8) with high IgG4 levels exhibited increased CA-II Ab and a compatible ACP score. A definitive diagnosis of ACP by histological analysis was associated with other autoimmune disorders, an increase in both serum IgG4 and CA-II Ab levels, and IgG4 positive plasma cells.

Conclusions: The increase in serum IgG4 levels was strongly associated with elevated CA-II Ab levels, manifestations compatible with ACP, and lymphoplasmacytic infiltration when surgical specimens were available.

Figure 1

Serum levels of antibodies against carbonic anhydrase II (A) and IgG4 levels (B) in normal controls, in patients with alcoholic or idiopathic chronic pancreatitis (CP), and in patients with Sjögren’s syndrome. Median values are indicated. The normal range was 700–1200 mg/dl for serum IgG levels and 60–130 mg/dl for IgG4 levels. Statistical significance is indicated as follows: **p<0.01 versus healthy subjects; ††p<0.01 versus patients with idiopathic pancreatitis.

Figure 2

(A) Association between antibodies to carbonic anhydrase II and IgG4 levels in patients with idiopathic chronic pancreatitis (ICP). Association between a diagnosis compatible with autoimmune pancreatitis in ICP patients based on the proposed diagnostic score and antibodies to carbonic anhydrase II (B) or IgG4 levels (C). The p value for statistical significance is shown (χ² of Pearson (A, C) and χ² for linear trend (B)).

Figure 3

Representative histological images. (A) Pancreatic duct surrounded by a prominent lymphoplasmacytic infiltrate and collagen deposits (arrows). (B) Pancreatic vein showing dense lymphoplamacytic infiltrate and perivenular fibrosis (haematoxylin-eosin, ×200 for all images). (A) and (B) correspond to case No 1 in table 4 ▶. (C) Prominent interstitial fibrosis and diffuse lymphoplamacytic infiltrate, which corresponds to patient No 3 in table 4 ▶. (D) Pancreatic duct surrounded by a mononuclear lymphoplamacytic infiltrate which corresponds to patient No 4 in table 4 ▶.

Figure 4

Representative immunohistochemical images with IgG4 immunostaining. (A) Pancreatic duct surrounded by a severe lymphoplasmacytic infiltrate predominantly of IgG4 positive plasma cells. (B) Prominent IgG4 positive plasma cells within a dense lymphoplamacytic infiltrate surrounding a pancreatic artery. (A) and (B) correspond to case No 1 in table 4 ▶. (C) Abundant IgG4 positive plasma cells together with some IgG4 negative plasma cells, which corresponds to patient No 3 in table 4 ▶. (D) Diffuse fibrosis around a vein with severe mononuclear lymphoplamacytic infiltrate containing abundant IgG4 positive plasma cells, which corresponds to patient No 4 in table 4 ▶. Amplifications were: ×40 for A and B, ×1000 for C, and ×200 for D.