Elevated IgG Linked to Greater Cirrhosis, Liver-Related Death Risk in PBC

New research is shedding light on the potential prognostic value of serum immunoglobulin G (IgG) in patients with primary biliary cholangitis (PBC), suggesting increased levels at disease diagnosis are linked to worse outcomes than patients with normal IgG.1

The long-term retrospective analysis included >600 patients with PBC and available data on IgG at first evaluation and found that those with IgG ≥1650 mg/dL more frequently experienced disease progression and liver-related death during follow-up. Of note, normalization of IgG during treatment with ursodeoxycholic acid (UDCA) improved prognosis.1

An autoimmune liver disease characterized by biliary damage and cholestasis, PBC predominantly affects women, affecting an estimated 65 out of every 100,000 women in the US.2 Emerging evidence suggests there is a spectrum between autoimmune hepatitis (AIH), another autoimmune liver disease disproportionately affecting women, and PBC in which biochemical and/or histological features of both diseases are present, referred to as AIH-PBC variant syndrome.3

“Some PBC patients demonstrate high IgG levels at diagnosis without fulfilling other criteria to establish concurrent AIH diagnosis,” George Dalekos, MD, PhD, head of the department of medicine and research laboratory of internal medicine, Greek Expertise Center in Autoimmune Liver Diseases at Larissa General University Hospital, and colleagues wrote.1 “No data exist on the significance of increased IgG levels on disease progression in PBC patients not complying with the diagnosis of AIH/PBC variant.”

To determine the prognostic value of IgG in PBC, investigators retrospectively analyzed prospectively collected data from 675 patients with PBC who had available serum IgG levels at first evaluation and did not meet the Paris criteria for the AIH/PBC variant. They then stratified the cohort into 2 groups: those with normal IgG, defined as IgG <1650 mg/dL (n = 537), and those with increased IgG, defined as ≥1650 mg/dL (n = 138).1

Investigators called attention to significant differences between the groups. Specifically, compared to patients with normal IgG, those with increased IgG were older at disease onset and at diagnosis (P <.001 for both) and more frequently had cirrhosis at disease diagnosis (P <.001).1

The percentage of patients receiving UDCA was similar between the groups (84.5% vs 79%; P = .124), and no patients in either group were receiving immunosuppressive treatment.1

To ensure that cirrhosis was not a factor contributing to increased IgG levels, investigators further analyzed 592 patients without cirrhosis at first evaluation, 495 of whom had normal IgG and 97 of whom had increased IgG. Again, they called attention to significant differences between the groups, including a greater proportion of patients with increased IgG being female (P <.05), older at disease onset and disease diagnosis (P <.001 for both), and having other concurrent autoimmune diseases (P = .01).1

Additional analysis of 514 noncirrhotic patients with >12 months of follow-up revealed a greater risk of cirrhosis (Breslow P <.001; log-rank P = .05) and liver-related death (Breslow P = .034; log-rank P <.05) in those with increased IgG. Investigators then conducted Cox regression analysis according to the level of IgG elevation and identified IgG >1.5xULN as the greatest risk factor for cirrhosis development (hazard ratio [HR], 9.507; 95% CI, 1.221–74.038; P = .032) and liver-related death (HR, 27.140; 95% CI, 3.111–236.783; P = .003).1

Among a subgroup of 82 noncirrhotic patients with increased IgG at initial evaluation who were on UDCA, 43 experienced normalization of IgG levels after treatment initiation. Investigators noted patients who normalized IgG during treatment demonstrated significantly higher rates of alkaline phosphatase and bilirubin normalization compared to those that maintained increased IgG levels (86% vs 53%; P = .002). Additionally, they pointed out there was no statistically significant difference in cirrhosis development between patients with normal IgG and those with normalization of IgG levels after 1 year of UDCA administration (7.0% vs 2.6%; P = .13).1

“This long-term follow-up study demonstrated that increased IgG levels at baseline characterise a subgroup of non-cirrhotic PBC patients with faster disease progression and increased probability of liver-related death,” investigators concluded.1 “These patients could benefit from stricter follow-up and earlier administration of second-line treatments, as normalisation of IgG levels during UDCA treatment in the present study seems to improve prognosis.”

References

1. Rigopoulou EI, Lygoura V, Gabeta S, et al. Increased IgG Levels at Diagnosis Are Associated With Worse Prognosis of Patients With Primary Biliary Cholangitis. Liver International. https://doi.org/10.1111/liv.70074

2. American Liver Foundation. Primary Biliary Cholangitis. March 22, 2024. Accessed April 2, 2025. https://liverfoundation.org/liver-diseases/autoimmune-liver-diseases/primary-biliary-cholangitis-pbc/

3. To U, Silveira M. Overlap Syndrome of Autoimmune Hepatitis and Primary Biliary Cholangitis. Clinics in Liver Disease. 10.1016/j.cld.2018.03.010