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

Abstract

Nodular regenerative hyperplasia (NRH) is associated with high morbidity and mortality in patients with common variable immunodeficiency (CVID). While liver biopsy is the gold standard for NRH diagnosis, a non-invasive technique could facilitate early disease recognition, monitoring, and/or immune intervention. We performed a cross-sectional analysis of ultrasound-based transient elastography (TE) in patients with CVID to evaluate liver stiffness and compared this between patients with (N = 12) and without (N = 6) biopsy-proven NRH. Additionally, these data were compared to a cohort followed at our institution for non-alcoholic fatty liver disease (NAFLD) (N = 527), a disease for which TE has routine diagnostic use. Clinical and pathologic features of NRH were evaluated as correlates of liver stiffness, and receiver operating characteristic curves were used to define a liver stiffness cutoff with diagnostic utility for NRH among CVID patients. CVID patients with NRH had a more severe disease presentation compared to those without. This included increased autoinflammatory disease comorbidities, combined B-cell and T-cell dysfunction, and abnormal liver biochemistries (specifically an increased mean alkaline phosphatase level [proximal to TE, 250 vs. 100 U/L; p = 0.03; peak, 314 vs. 114 U/L; p = 0.02). Results of TE demonstrated a significantly elevated liver stiffness in CVID patients with NRH (mean 13.2 ± 6.2 kPa) as compared to both CVID patients without NRH (mean 4.6 ± 0.9 kPa) and non-CVID patients with NAFLD (mean 6.9 ± 5.5 kPa) (p < 0.01). No single or composite histopathologic feature of NRH correlated with liver stiffness including nodule size, nodule density, sinusoidal dilation, fibrosis, and/or lymphocytosis. In contrast, liver stiffness by TE was significantly correlated with clinical parameters of portal hypertension, including an elevated hepatic venous pressure gradient, an increased splenic longitudinal diameter, presence of varices, and presence of peripheral edema. A liver stiffness of greater than or equal to 6.2 kPa was a clinically significant cutoff for NRH in CVID patients. We propose that TE has diagnostic utility in CVID, particularly in the presence of immunophenotypic features such as combined B-cell and T-cell dysfunction, autoinflammatory comorbidities, and/or abnormal liver tests. Elevated liver stiffness by TE should raise suspicion for NRH in patients with CVID and prompt expedited evaluation by hepatology.

Portal hypertension in common variable immunodeficiency disorders – a single center analysis on clinical and immunological parameter in 196 patients

“…We confirm a high association with other non-infectious manifestations in CVID+PH patients, most significantly with the occurrence of GLILD, other non-pulmonary granulomatous lesions, splenomegaly, and lymphadenopathy (4,5,9,18,19). The higher frequency of affected female patients (82%) and the shorter interval of symptom onset of PH in our cohort differ slightly from previous reports.…”

“…Inspired by the applicability of transient elastography in other chronic liver diseases (38-40), attention has also been drawn to its diagnostic use for identifying hepatic manifestations in CVID patients (4,18,19). All the CVID+PH patients in this study with proven PH (HVPG ≥ 10 mmHg) expressed increased rates of liver stiffness, thereby confirming previous reports and suggesting the early use of this methodology in CVID cases with suspected liver involvement (4,18). However, transient elastography is not widely available and harbors technical challenges, such as in obese patients.…”

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

“…Elevated LSM is associated with liver enzyme abnormalities, NRH-LC, PHTN, and enteropathy in CVID, with cutoffs of 6.2 and 11.2 kPa reported to detect NRH-LC and PHTN, respectively. 9 , 10 , 15 We observed higher LSM in those with evidence of PHTN, although a low value did not exclude PHTN. Therefore, elevation in LSM should prompt assessment for further evidence of liver disease and PHTN; however, a normal LSM does not exclude significant pathology.…”

“…This fits with other cohorts describing cirrhosis (equivalent to stage 4 in the scoring system used here) in one-third of patients with NRH-LC. 7 The association of elevated LSM with NRH-LC and PHTN 9 , 15 may reflect the attendant fibrosis seen with NRH-LC in CVID.…”

“… 6 However, changes in LSM have been shown to be associated with liver enzyme abnormalities, histological changes of NRH, and the presence of complications, including PHTN and enteropathy in CVID. 9 , 10 , 15 We have, therefore, explored the use of LSM in the clinical context of CVID-rLD for the prediction of endoscopic or radiological evidence of PHTN.…”