Spectrum of Hepatic Manifestations of Common Variable Immunodeficiency

Abstract

Common variable immunodeficiency (CVID) has a heterogenous clinical presentation and can be challenging to diagnose. Distinct histologic changes have been linked with CVID in several organ systems, which can help identify the correct diagnosis. In this study we review a cohort of hepatic CVID biopsies, to better define the spectrum of histologic and biochemical alterations. We reviewed 26 liver biopsies from 24 patients with CVID, obtained at 4 institutions between 2010 and 2019. Histologic slides were examined, and pathologic, biochemical, and clinical features were recorded. A control cohort of 21 patients with nodular regenerative hyperplasia (NRH) but lacking CVID was also examined. Liver function tests were frequently abnormal, especially alkaline phosphatase (median: 193 IU/L) and aspartate transaminase (median: 56 U/L), elevated in 23 and 17 of 25 biopsies, respectively. Fifteen patients had CVID involvement of other organs. Histologic features of primary biliary cholangitis were present in 2 patients, with florid duct lesions and prominent bile duct injury, in association with positive antimitochondrial antibodies. Among the other 24 biopsies, mild to moderate portal and lobular inflammation were present in 18 and 17 of 24 biopsies, respectively. Overall, 22 of 24 biopsies showed NRH-like changes. Plasma cell were absent. A distinct pattern of pericellular fibrosis was present in 23 of 26 biopsies overall. Involvement ranged from focal centrizonal fibrosis to bridging fibrosis and was accompanied by increased intrasinusoidal lymphocytes in 13 of 24 biopsies. Pericellular fibrosis was identified in 1 of 21 biopsies in the control cohort. Additional findings included granulomatous inflammation or nonhepatocellular foreign body-type multinucleate giant cells, identified in 4 biopsies. Three of 6 examined biopsies also demonstrated focal hepatocellular copper deposition. Hepatic disease in CVID is often associated with elevated alkaline phosphatase and aspartate transaminase and is characterized histologically by the mild nonspecific portal and lobular hepatitis, absence of plasma cells, NRH-like changes, and less commonly, typical histologic features of primary biliary cholangitis. We have also identified a distinctive pattern of delicate pericellular fibrosis that is a helpful clue to the diagnosis of hepatic disease in CVID, especially when accompanied by NRH-like changes.

Liver disease accompanied by enteropathy in common variable immunodeficiency: Common pathophysiological mechanisms

“…As in our study, the liver function test results in that study were slightly abnormal, especially ALP and AST. The classic features of primary biliary cholangitis, which was not observed in our sample, were observed in two of the biopsies evaluated by those authors ( 57 ). Other studies have shown that, in patients with NRH but without CVID, the changes in transaminases and canalicular enzymes are modest, highlighting ALP, which can present a progressive increase even when liver function is preserved ( 25 , 58 ).…”

“…In another study of CVID patients, Crotty et al. ( 57 ) diagnosed PH in 75% of those who underwent liver biopsy. In that study, there was also mild-to-moderate portal inflammation in 75% of the patients and lobular inflammation in approximately 70%.…”

Patients With Common Variable Immunodeficiency (CVID) Show Higher Gut Bacterial Diversity and Levels of Low-Abundance Genes Than the Healthy Housemates

“…Dysregulation of bile acid metabolism related to bacterial dysbiosis has been reported for several conditions (72,73) including a CVID murine model (32). Frequent CVID complications, such as malabsorbtion and/or liver diseases (74)(75)(76), also indicate dysregulation of bile acid metabolism. In fact, splenomegaly was frequent among our CVID patients.…”

Liver Stiffness by Transient Elastography Correlates With Degree of Portal Hypertension in Common Variable Immunodeficiency Patients With Nodular Regenerative Hyperplasia

“…Liver disease is a frequent and underrecognized complication in patients with CVID and can be a consequence of recurrent infectious insults, malignancy, and/or immune dysregulation impacting the liver. The most prevalent liver pathology in patients with CVID is nodular regenerative hyperplasia (NRH), which affects 41%-87% of patients with CVID who undergo liver biopsy (3)(4)(5)(6). NRH is believed to be mediated through T-cell infiltration of the sinusoidal endothelium, causing intra-hepatic vasculopathy.…”

“…In patients with CVID, NRH is characterized histologically by a nodular pattern of alternating areas of hepatic plate expansion and atrophy. NRH-like changes are often accompanied by other histologic features of CVID such as a sinusoidal lymphocytic infiltrate, mild portal and lobular inflammation, and variably prominent sinusoidal fibrosis (6). NRH-like changes may be present on liver biopsy even when clinical manifestations are subtle (such as mildly elevated liver enzymes), making improved diagnostic modalities essential.…”