Serum immunoglobulin G4 and immunoglobulin G1 for distinguishing immunoglobulin G4-associated cholangitis from primary sclerosing cholangitis

Abstract

The recent addition of immunoglobulin (Ig)G4-associated cholangitis (IAC), also called IgG4-related sclerosing cholangitis (IRSC), to the spectrum of chronic cholangiopathies has created the clinical need for reliable methods to discriminate between IAC and the more common cholestatic entities, primary (PSC) and secondary sclerosing cholangitis. The current American Association for the Study of Liver Diseases practice guidelines for PSC advise on the measurement of specific Ig (sIg)G4 in PSC patients, but interpretation of elevated sIgG4 levels remains unclear. We aimed to provide an algorithm to distinguish IAC from PSC using sIgG analyses. We measured total IgG and IgG subclasses in serum samples of IAC (n = 73) and PSC (n = 310) patients, as well as in serum samples of disease controls (primary biliary cirrhosis; n = 22). sIgG4 levels were elevated above the upper limit of normal (ULN = >1.4 g/L) in 45 PSC patients (15%; 95% confidence interval [CI]: 11-19). The highest specificity and positive predictive value (PPV; 100%) for IAC were reached when applying the 4 × ULN (sIgG4 > 5.6 g/L) cutoff with a sensitivity of 42% (95% CI: 31-55). However, in patients with a sIgG4 between 1 × and 2 × ULN (n = 38/45), the PPV of sIgG4 for IAC was only 28%. In this subgroup, the sIgG4/sIgG1 ratio cutoff of 0.24 yielded a sensitivity of 80% (95% CI: 51-95), a specificity of 74% (95% CI: 57-86), a PPV of 55% (95% CI: 33-75), and a negative predictive value of 90% (95% CI: 73-97).

Conclusion: Elevated sIgG4 (>1.4 g/L) occurred in 15% of patients with PSC. In patients with a sIgG4 >1.4 and <2.8 g/L, incorporating the IgG4/IgG1 ratio with a cutoff at 0.24 in the diagnostic algorithm significantly improved PPV and specificity. We propose a new diagnostic algorithm based on IgG4/IgG1 ratio that may be used in clinical practice to distinguish PSC from IAC.

Fig. 1

HISORt diagnostic criteria (histology, imaging, serology, other organ involvement, and response to therapy) for IgG4-associated cholangitis (IAC). Adapted from Ghazale et al.,⁷ Alderlieste et al.,¹⁵ and Maillette de Buy Wenniger et al.¹⁶

Fig. 2

Scatterplot of sIgG4 in PSC, IAC, and PBC patients. Lower limit of normal (LLN)−1×, 1×-2×, 2×-4x, and >4x ULN are marked with different shades of gray. The bar across each column represents the median value. Statistic bars represent PSC versus PBC, PSC versus IAC, and IAC versus PBC comparisons by Mann-Whitney's U test.

Fig. 3

ROC curves of sIgG4 for diagnosis of IAC versus PSC patients in the test (A) and validation cohorts (B). Arrows are pointing toward the ULN of sIgG4 (1.4 g/L) and the optimal cut-off value (2.5 g/L).

Fig. 4

Scatterplot of sIgG4/sIgG1 in PSC and IAC patients with a sIgG4 between 1.4 and 2.8 g/L. The ratio cut-off value of 0.24 is shown as a dotted line. The bar across each column represents the median value.

Fig. 5

Proposed algorithm for distinguishing IAC from PSC using sIgG4 and sIgG4/sIgG1 ratio analysis.