Heterogeneity of Liver Disease in Common Variable Immunodeficiency Disorders

Abstract

Common variable immunodeficiency (CVID) is the most frequent primary immunodeficiency (PID) in adulthood and is characterized by severe reduction of immunoglobulin serum levels and impaired antibody production in response to vaccines and pathogens. Beyond the susceptibility to infections, CVID encompasses a wide spectrum of clinical manifestations related to a complex immune dysregulation that also affects liver. Although about 50% CVID patients present persistently deranged liver function, burden, and nature of liver involvement have not been systematically investigated in most cohort studies published in the last decades. Therefore, the prevalence of liver disease in CVID widely varies depending on the study design and the sampling criteria. This review seeks to summarize the evidence about the most relevant causes of liver involvement in CVID, including nodular regenerative hyperplasia (NRH), infections and malignancies. We also describe the clinical features of liver disease in some monogenic forms of PID included in the clinical spectrum of CVID as ICOS, NFKB1, NFKB2, CTLA-4, PI3Kδ pathway, ADA2, and IL21-R genetic defects. Finally, we discuss the clinical applications of the various diagnostic tools and the possible therapeutic approaches for the management of liver involvement in the context of CVID.

Keywords: antibody deficiency; common variable immune deficiency; liver disease; liver transplant; monogenic immune defects; nodular regenerative hyperplasia; primary immuno deficiency; transient elastography.

FIGURE 1

Main causes of liver disease in CVID. The clinical spectrum of CVID includes predisposition to infections, immune-dysregulation-related manifestations (i.e., autoimmunity or lymphocytic infiltration) and malignancies. Liver involvement in CVID may rely on each of these three pathogenetic mechanisms. NRH is the most common histopathologic finding in CVID and is thought to be related, at least in part, to an auto-reactive T-cell intrasinusoidal infiltration, while a subset of patients may present a more severe portal inflammatory infiltration consistent with inferface hepatitis, as observed in autoimmune hepatitis. Splenomegaly is a common clinical feature in CVID patients and contributes to the increase of portal venous pressure, as shown in detail in Figure 2. In past decades, contaminated immunoglobulin preparations were a significant cause of iatrogenic viral hepatitis (i.e., HBV, HCV, CMV, and EBV), while Giardia lamblia, which is a common cause of chronic enteritis in CVID, may affect liver as extra-intestinal localization. Finally, liver may be target of both primary and metastatic malignancies. These latter may be the result of both gastrointestinal cancers (i.e., stomach and colon) and hematological malignancies. The figure was created with Biorender.com.

FIGURE 2

Nodular regenerative hyperplasia (NRH) is the result of an intra-hepatic vasculopathy, leading to the development of hepatocyte nodules that compress surrounding sinusoids, potentially determining perisinusoidal fibrosis. In CVID patients, NRH is associated with a chronic cytotoxic T cell infiltration of liver sinusoidal endothelium. This may cause an alteration of the blood flow through portal system causing the reduction of liver parenchymal perfusion and the increase of portal pressure. The perturbation of portal system flow may also be the result of the hemodynamic changes related to splenomegaly, which causes an increase of splenic venous flow contributing to the increase of portal pressure. The increase of portal pressure could be in turn responsible for a further spleen enlargement. The figure was created with Biorender.com.