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. 2022 Jan;149(1):400-409.e3.
doi: 10.1016/j.jaci.2021.05.028. Epub 2021 Jun 1.

Nodular regenerative hyperplasia in X-linked agammaglobulinemia: An underestimated and severe complication

Cristiane J Nunes-Santos  1 , Christopher Koh  2 , Anjali Rai  2 , Keith Sacco  3 , Beatriz E Marciano  3 , David E Kleiner  4 , Jamie Marko  5 , Jenna R E Bergerson  3 , Michael Stack  3 , Maria M Rivera  2 , Gregory Constantine  6 , Warren Strober  7 , Gulbu Uzel  3 , Ivan J Fuss  7 , Luigi D Notarangelo  3 , Steven M Holland  3 , Sergio D Rosenzweig  8 , Theo Heller  9
Affiliations

Nodular regenerative hyperplasia in X-linked agammaglobulinemia: An underestimated and severe complication

Cristiane J Nunes-Santos et al. J Allergy Clin Immunol. 2022 Jan.

Abstract

Background: Late-onset complications in X-linked agammaglobulinemia (XLA) are increasingly recognized. Nodular regenerative hyperplasia (NRH) has been reported in primary immunodeficiency but data in XLA are limited.

Objectives: This study sought to describe NRH prevalence, associated features, and impact in patients with XLA.

Methods: Medical records of all patients with XLA referred to the National Institutes of Health between October 1994 and June 2019 were reviewed. Liver biopsies were performed when clinically indicated. Patients were stratified into NRH+ or NRH- groups, according to their NRH biopsy status. Fisher exact test and Mann-Whitney test were used for statistical comparisons.

Results: Records of 21 patients with XLA were reviewed, with a cumulative follow-up of 129 patient-years. Eight patients underwent ≥1 liver biopsy of whom 6 (29% of the National Institutes of Health XLA cohort) were NRH+. The median age at NRH diagnosis was 20 years (range, 17-31). Among patients who had liver biopsies, alkaline phosphatase levels were only increased in patients who were NRH+ (P = .04). Persistently low platelet count (<100,000 per μL for >6 months), mildly to highly elevated hepatic venous pressure gradient and either hepatomegaly and/or splenomegaly were present in all patients who were NRH+. In opposition, persistently low platelet counts were not seen in patients who were NRH-, and hepatosplenomegaly was observed in only 1 patient who was NRH-. Hepatic venous pressure gradient was normal in the only patient tested who was NRH-. All-cause mortality was higher among patients who were NRH+ (5 of 6, 83%) than in the rest of the cohort (1 of 15, 7% among patients who were NRH- and who were classified as unknown; P = .002).

Conclusions: NRH is an underreported, frequent, and severe complication in XLA, which is associated with increased morbidity and mortality.

Keywords: CVID; HSCT; Primary immunodeficiency; alkaline phosphatase; hepatomegaly; inborn errors of immunity; liver disease; portal hypertension; splenomegaly; thrombocytopenia.

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Conflict of interest statement

Conflict of interest

The authors declare no competing financial interests.

Figures

Figure 1.
Figure 1.
Timeline of liver biopsies in the NIH XLA cohort. Dashed lines represent duration of follow-up not included in the analysis because of unknown NRH status. NRH = nodular regenerative hyperplasia; Pt= patient.
Figure 2.
Figure 2.
Nodular regenerative hyperplasia in a patient with X-linked agammaglobulinemia. A. There is vague nodularity with areas of sinusoidal dilation and mild, patchy, sinusoidal lymphocytic infiltrates (H&E, 100x). B. The Masson stain shows delicate perisinusoidal fibrosis in areas of sinusoidal dilation (Masson Trichrome, 400x). C. The reticulin framework is distorted by nodular areas of wide liver cell plates bounded by narrowed plates. (Reticulin, 200x). D. A biopsy taken 7 years later shows persistence of nodularity. (Reticulin, 200x).
Figure 3.
Figure 3.
Longitudinal evaluation of platelet counts according to NRH status. Y axis represents platelet counts (K/uL); X axis represents years of follow-up. Inverted triangles correspond to liver biopsies. NRH = nodular regenerative hyperplasia.
Figure 4.
Figure 4.
Suggested diagnostic algorithm for NRH in XLA. NRH = nodular regenerative hyperplasia; XLA = X-linked agammaglobulinemia.
See this image and copyright information in PMC

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