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

Abstract

Common variable immunodeficiency (CVID) is one of the inborn errors of immunity that have the greatest clinical impact. Rates of morbidity and mortality are higher in patients with CVID who develop liver disease than in those who do not. The main liver disorder in CVID is nodular regenerative hyperplasia (NRH), the cause of which remains unclear and for which there is as yet no treatment. The etiology of liver disease in CVID is determined by analyzing the liver injury and the associated conditions. The objective of this study was to compare CVID patients with and without liver–spleen axis abnormalities in terms of clinical characteristics, as well as to analyze liver and duodenal biopsies from those with portal hypertension (PH), to elucidate the pathophysiology of liver injury. Patients were divided into three groups: Those with liver disease/PH, those with isolated splenomegaly, and those without liver–spleen axis abnormalities. Clinical and biochemical data were collected. Among 141 CVID patients, 46 (32.6%) had liver disease/PH; 27 (19.1%) had isolated splenomegaly; and 68 (48.2%) had no liver–spleen axis abnormalities. Among the liver disease/PH group, patients, even those with mild or no biochemical changes, had clinical manifestations of PH, mainly splenomegaly, thrombocytopenia, and esophageal varices. Duodenal celiac pattern was found to correlate with PH (p < 0.001). We identified NRH in the livers of all patients with PH (n = 11). Lymphocytic infiltration into the duodenal mucosa also correlated with PH. Electron microscopy of liver biopsy specimens showed varying degrees of lymphocytic infiltration and hepatocyte degeneration, which is a probable mechanism of lymphocyte-mediated cytotoxicity against hepatocytes and enterocytes. In comparison with the CVID patients without PH, those with PH were more likely to have lymphadenopathy (p < 0.001), elevated β2-microglobulin (p < 0.001), low B-lymphocyte counts (p < 0.05), and low natural killer-lymphocyte counts (p < 0.05). In CVID patients, liver disease/PH is common and regular imaging follow-up is necessary. These patients have a distinct immunological phenotype that may predispose to liver and duodenal injury from lymphocyte-mediated cytotoxicity. Further studies could elucidate the cause of this immune-mediated mechanism and its treatment options.

Common variable immunodeficiency disorder-related liver disease is common and results in portal hypertension and an increased risk of death

“… 9 PHTN was a common complication of CVID-rLD, occurring in 44% of patients with CVID-rLD. This frequency is similar to patients with NRH (31%–55%) and with other reports of CVID-rLD (21%–75%) 2 , 6 , 7 , 12 , 17 , 18 and demonstrates that CVID-rLD is associated with significant clinical sequalae.…”

“…The epidemiology and natural history of liver disease in CVID have been challenging to define due to the changing etiology as the risk of viral hepatitis receded and changing patterns of screening as the importance of liver disease has been recognized. The published prevalence of liver disease in patients with CVID ranges from 5% to 79%, 2 – 4 , 7 – 12 and our estimate of 42% sits within the middle of this range. By including all patients with CVID from our center, who were well screened (LFTs measured in all and abdominal imaging in 94%) this is likely a reasonable estimate of the prevalence in this tertiary patient cohort.…”

“…We recently reported changes of capillarisation in the liver sinusoidal endothelium, providing direct evidence of vascular changes in CVID-rLD. 29 Lymphocytes have also been observed at sites of focal hepatocyte damage in CVID 12 raising the possibility of additional immune-mediated parenchymal injury. Whether these phenomena occur due to intrinsic immune dysregulation in CVID or secondary to other phenomena remains unknown.…”

“…Prevalence estimates for nonviral liver disease in CVID (hereby termed CVID-related liver disease (CVID-rLD) range from 5% to 79%, 2 – 4 , 7 – 12 reflecting the differing cohorts studied, definitions of liver disease, and approaches to screening. However, CVID-rLD has been associated with adverse outcomes, with an elevated hazard of mortality and accelerated time to death.…”

Is there a role for microbiome-based approach in common variable immunodeficiency?

“…Gastrointestinal (GI) manifestations are common in CVID ranging between 15 and 50% [ 41 – 43 ]. GI complications of CVID can involve any part the gastrointestinal tract, but the most commonly affected sites are the small bowel, the colon, the stomach and the liver [ 42 , 44 , 45 ]. Small bowel villous atrophy can be present mimicking celiac disease, but patients with CVID typically do not respond to a gluten-free diet (GFD) and they do not express the typical HLA genes associated with celiac disease [ 46 ].…”