Article Text

Common variable immunodeficiency disorder (CVID)-related liver disease: assessment of the main histological aspects using novel semiquantitative scoring systems, image analysis and correlation with clinical parameters of liver stiffness and portal hypertension
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  1. Hiroshi Silva1,
  2. Camila Gabriela Xavier de Brito1,
  3. Andrew Hall1,2,
  4. Nadia Eden2,3,
  5. Henry Somers2,3,
  6. Niall Burke2,3,
  7. Siobhan O Burns4,5,
  8. David Lowe4,5,
  9. Douglas Thorburn2,3,
  10. Neil Halliday2,3,
  11. Alberto Quaglia1,3
  1. 1 Department of Cellular Pathology, Royal Free London NHS Foundation Trust, London, UK
  2. 2 Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London, UK
  3. 3 Institute for Liver and Digestive Health, University College London, London, UK
  4. 4 Institute of Immunity and Transplantation, University College London, London, UK
  5. 5 Department of Immunology, Royal Free London NHS Foundation Trust, London, UK
  1. Correspondence to Dr Camila Gabriela Xavier de Brito; camila.xbrito{at}gmail.com

Abstract

Aims We aimed to investigate the relationship between T-cell-mediated sinusoidal injury, nodular regenerative hyperplasia like changes (NRH-LC) and fibrosis, clinical measures of fibrosis and portal hypertension, and progression rate in common variable immunodeficiency disorder (CVID)-related liver disease.

Methods This is a retrospective single-centre study. Liver biopsies from CVID patients with liver disease were reviewed to assess for NRH-LC, fibrosis and elastosis, including collagen and elastin proportionate areas. CD3 positive T-cells infiltration and sinusoidal endothelial changes by CD34 expression were quantified by image analysis and a semiquantitative method, respectively. These findings were correlated with liver stiffness measurements (LSM) and hepatic venous pressure gradient (HVPG).

Results NRH-LC and pericellular elastosis were present in most biopsies (32/40 and 38/40, respectively). All biopsies showed fibrosis, which was limited to pericellular in 21/40 (52.5%) and included bridging fibrous septa in 19/40 (47.5%). 28/40 liver biopsies showed enhanced sinusoidal expression of CD34. There were more CD3 positive cells in biopsies with NRH-LC compared with those without. There was no significant correlation between LSM, HVPG and fibrosis/elastosis scores. Five of seven patients with at least two biopsies showed progression in fibrosis stage.

Conclusions NRH-LC and fibrosis in CVID patients often coexist along with the presence of sinusoidal endothelial changes and sinusoidal lymphocytic infiltration. Fibrosis progresses over time, and significant fibrosis can be observed in young patients (<30 years old), potentially reflecting a more aggressive form of CVID-related liver disease. Further studies are necessary to investigate the relationship between histological findings, clinical measures of fibrosis and portal hypertension and outcome.

  • fibrosis
  • LIVER
  • Immune System Diseases

Data availability statement

Data are available on reasonable request.

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WHAT IS ALREADY KNOWN ON THIS TOPIC

  • Liver disease is a major complication of common variable immunodeficiency disorder (CVID), associated with nodular regenerative hyperplasia like changes (NRH-LC) as well as fibrosis.

WHAT THIS STUDY ADDS

  • Demonstration of the coexistence of fibrosis, NRH-LC and pericellular elastosis, quantification of liver fibrosis and elastosis by image analysis and illustration of sinusoidal endothelial changes by CD34 immunohistochemistry. Comparison of histology findings and clinical measures such as liver stiffness measured by FibroScan and hepatic venous pressure gradient.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

  • Clinical parameters may not be sufficient to predict fibrosis in CVID patients, therefore, histological assessment of the liver in CVID patients is informative and contributes to the investigation of the pathogenesis of CVID-related liver injury.

Introduction

Common variable immunodeficiency disorder (CVID) is the most common symptomatic adult primary immunodeficiency disorder, with a prevalence between 0.001 and 6.9 per 100 000 population, showing wide variations between geographical regions.1 2 Although the underlying pathogenesis remains largely unknown, current understanding suggests that primary B-cell dysfunction with defective T-cell and antigen presenting cell functions are contributing factors.3 4 CVID is considered a heterogeneous group of diseases with variable phenotypic presentations hallmarked by antibody deficiency, recurrent infections and failure to respond to vaccines. CVID may be accompanied by immune dysregulation resulting in autoimmunity and inflammatory complications.5

The systemic manifestations of CVID may affect the liver, gastrointestinal tract, lungs, reticuloendothelial system and cause immune-mediated cytopaenias. Liver involvement is common with a reported prevalence ranging between 5% and 79%.6–12 In our recent study of 218 cases at the Royal Free London NHS Foundation Trust, a tertiary care centre in the UK, liver involvement was calculated at 42%.13 Nodular regenerative hyperplasia (NRH) is the most frequently described liver pathology among CVID patients, but granulomatous disease, infections, malignancies, cholangiopathy, autoimmune hepatitis and fibrosis are also associated with the disease.14–16

There is a wide range of reported incidence of NRH in liver biopsies from CVID patients varying between 5% and 80%.9 17 However, there is only limited literature regarding the frequency and pattern of liver fibrosis. One biopsy series demonstrated coexistent cirrhosis in almost one third of CVID patients with NRH.6 Another study evaluating liver stiffness measurements (LSM) in CVID patients presenting with deranged liver function tests showed an LSM of ≥7.3 kPa in 33.8% of the study population, suggesting the presence of at least moderate fibrosis in one-third of patients.10 A recent study from the UK that evaluated liver involvement in CVID patients and their survival rates showed that the outcomes of the patients with NRH is poor and further worsens when associated with cirrhosis and/or portal hypertension.18 We have shown recently19 that fibrosis is invariably associated with the deposition of elastic fibres; and the deposition of elastic fibres along hepatocytes is often observed in the context of steatohepatitis and vascular disorders, suggesting that damage to the space of Disse stimulates pericellular/perisinusoidal fibrosis.

T-cell-mediated sinusoidal endothelial injury is thought to be part of the pathogenesis of liver disease in CVID. The sinusoidal endothelial cells have a unique configuration of features that include the presence of fenestrae and the expression of a specific set of antigens.20 Changes to the configuration of sinusoidal endothelial cells to a more generic endothelial phenotype can be demonstrated by the presence of CD34 on the cell membrane.

As the pathology of liver disease in CVID has not been well characterised and the clinical outcomes of those with liver disease are impaired, including suboptimal outcomes from liver transplantation,21 22 early identification of liver fibrosis is important in understanding the natural history and provide optimal management for CVID patients.

We have, therefore, reviewed the histological patterns of liver injury in a large retrospective cohort of liver biopsies from CVID patients and correlated our findings with clinical data, as part of our multidisciplinary collaborative programme on CVID-related liver injury. The aim of our work was to (1) investigate the relationships between T-cell-mediated sinusoidal injury and changes to the sinusoidal endothelium using immunohistochemistry, (2) assess the presence of NRH and quantify fibrosis and elastosis, (3) correlate these histological findings with clinical measures of fibrosis and portal hypertension and (4) assess the progression of liver fibrosis in CVID patients.

Methods

Case selection and exclusion criteria

This is a retrospective single-centre study. Data from 62 CVID patients who underwent at least one liver biopsy were collected from our institutional databases. CVID was defined following clinical diagnosis by a consultant immunologist, in line with current international guidelines, typically characterised by hypogammaglobulinaemia, recurrent infection and a failure to respond to pneumococcal or tetanus vaccination.5 Biopsy slides from all the cases were rereviewed along with the clinical information. Twenty-two cases were excluded from the study (as they showed concomitant other pathologies or had insufficient slides and tissue). The remaining 40 cases were included in the final analysis (figure 1).

Figure 1

Case selection and exclusion criteria. CVID, common variable immunodeficiency disorder.

Medical records from the selected patients were reviewed to collect demographic data and information about previous FibroScan and hepatic venous pressure gradient (HVPG) results.

Histological assessment

All biopsies were evaluated with the HE stain, picro-Sirius red (SR) for collagen, Victoria blue (VB) for elastic fibres and reticulin for NRH assessment. NRH was defined as parenchymal nodularity due to the presence in at least part of the biopsy sample of two populations of hepatocytes differing in size, because of nodules composed of thickened liver cell plates and with boundaries composed of compressed cell plates.23 Coexistent fibrosis was not considered an exclusion criterion for the diagnosis of NRH, as in our experience and the experience of others,6 24 features of NRH and fibrosis are often observed together in liver biopsies from CVID patients. In line with the proposal by Crotty et al, 24 we applied the term NRH-like changes (NRH-LC) to this specific CVID setting and documented presence or absence of NRH-LC.

Fibrosis assessment

Fibrosis assessment was performed by a semi quantitative scoring system using the SR stain designed specifically for the purpose of this study and based on a preliminary assessment of the fibrosis pattern in this patient cohort.

  1. No fibrosis.

  2. Patchy and focal pericellular fibrosis.

  3. Diffuse pericellular fibrosis.

  4. Bridging fibrosis.

  5. Nodule formation/cirrhosis.

Collagen proportionate area (CPA) was measured as described in previous studies22 25 (see online supplemental file).

Supplemental material

Elastic fibres assessment

The presence of elastic fibres in a pericellular distribution and within fibrous septa was assessed as follows using the VB stain and adapted from our previous work.26 Pericellular elastic fibres were classified as stage 0 (absent), stage 1 (very occasional delicate perihepatocyte strands visible only at high magnification ×400 and after extensive search), or stage 2 (perihepatocytic elastic strands obvious at ×100 or ×200 magnification).

Parenchymal EPA was calculated for 40 biopsies with available VB stains using multispectral imaging (see online supplemental file).

CD3 counts and CD34 expression

CD3 and CD34 immunostaining were performed on 28 cases out of the 40, these were the cases where the tissue was sufficient to assess the parenchymal T lymphocytosis and capillarisation (see online supplemental file).

CD34 immunostaining for the capillarisation was graded as below.27

0—Not increased (ie, staining only septal endothelium and endothelium of limiting plate of the nodule).

1—Marginal (non-confluent patches).

2—Focal (confluent patches showing diffuse CD34 immunostaining).

3—Diffuse incomplete (confluent areas showing diffuse CD34 immunostaining with very minimal non-staining areas).

4—Diffuse complete (CD34 staining was seen in the whole biopsy).

Assessment of fibrosis progression in patients with multiple liver biopsies

Seven of the 40 patients in our cohort had undergone a previous liver biopsy at least 12 months before the index biopsy. We assessed fibrosis/elastosis progression using the available connective tissue stains in this subgroup. Fibrosis in these biopsies was also classified using the same semi quantitative method as above.

Liver stiffness and HVPG measurements

Liver stiffness measured using FibroScan and HVPG were recorded as part of routine investigations. Values for each investigation were obtained from clinical records. HVPG measures within a year of biopsy date (n=27) and FibroScan measurements not more than 4 years from the biopsy date (n=17) were included in the analysis.

Statistical analysis

Ordinal and nominal categorical data are expressed as frequencies. Due to the limited size of the population, the data were considered non-parametric for the purposes of reporting statistics, therefore, continuous data are reported as medians and IQRs. Categorical data were compared using χ2 test or Fisher’s exact test, when necessary. Mann-Whitney or Kruskal-Wallis tests were used to compare continuous data between groups. Spearman’s rank order correlation was used to compare between continuous data. A critical alpha level was set as p<0.05 (two tailed). All statistical analyses were performed by using IBM SPSS Statistics (V.29.0).

Results

The median age of the patients in our cohort was 47.5 years (IQR 39–59.25) and 23/40 (57.5%) patients were female.

Overall histological findings

NRH-LC and fibrosis were commonly observed in patients with CVID: NRH-LC was present in most biopsy samples (32/40, 80%) and fibrosis was present in all 40 biopsy samples. Fibrosis was limited to pericellular in 21/40 (52.5%) samples, as either stage 1 (7/40, 17.5%) or stage 2 (14/40, 35%). Bridging fibrous septa were observed in 19/40 (47.5%) samples, either stage 3 (17/40, 42.5%) or stage 4 (2/40, 5%) (figure 2). Of note, pericellular fibrosis coexisted in all of those with bridging fibrosis (stages 3 and 4).

Figure 2

Fibrosis scoring in CVID liver biopsies using the picrosirius red stain: (A) focal pericellular fibrosis (arrows), (B) diffuse pericellular fibrosis (arrows), (C) bridging fibrosis and (D) nodule formation (×10 magnification). CVID, common variable immunodeficiency disorder.

Elastosis was present in nearly all cases of CVID that we assess. Pericellular elastic fibres were also present in most (38/40, 95%) samples, and graded as stage 1 in 29/40 (72.5%) and stage 2 in 9/40 (22.5%) (figure 3).

Figure 3

Liver biopsy showing diffuse pericellular fibrosis on the picrosirius red stain (A) and pericellular elastosis on the Victoria blue stain (B) in the same area (×20 magnification).

Median parenchymal CPA, combined CPA and EPA were 4.26% (IQR 2.79%–6.73%), 9.02% (IQR 7.16%–12.82%) and 0.46% (IQR 0.17%–1.97%), respectively.

CVID cases showed an increase in the number of CD3 positive cells in comparison to normal livers. Median parenchymal CD3 density in CVID liver biopsies was 206.52 cells/mm3, which was significantly higher than the median parenchymal CD3 density observed in the normal liver biopsies (61.12 cells/mm3, p=0.0017). Similarly, the median portal/stromal and combined CD3 density in CVID liver biopsies were 419.61 and 209.15 cells/mm3, respectively, which was significantly higher than the corresponding values in the normal liver biopsies (161.29 and 72.55, respectively, p=0.015 and 0.013) (figure 4).

Figure 4

CD3 positive cells in a normal liver (A) and a CVID liver biopsy (B) (×20 magnification). CVID, common variable immunodeficiency disorder.

All 28 CVID liver biopsies assessed showed enhanced sinusoidal expression of CD34 at variable degrees. Sixteen out of 28 cases (57.14%) showed a diffuse pattern of capillarisation (grade 3 or 4) (figure 5).

Figure 5

CD34 expression in CVID liver biopsies: marginal (A), focal (B), diffuse incomplete (C) and diffuse complete (D) (×10 magnification). CVID, common variable immunodeficiency disorder.

Comparison between cases with NRH-LC present (NRH-LC-P) and cases with NRH-LC absent (NRH-LC-A)

There were no significant differences observed between biopsies with NRH-LC present compared with those where NRH-LC were absent with regard to fibrosis and elastosis scores, CPA, EPA, CD34 sinusoidal stain, LSM or HVPG measurements (table 1). Although all three CD3 density parameters were higher in the NRH-LC-P group compared with the NRH-LC-A group, there was not a significant difference between the two groups (table 2).

Table 1

NRH-LC comparison with histological/clinical parameters

Table 2

Comparison of CD3 density* between NRH-LC-A and NRH-LC-P groups

Relationship between fibrosis score and EPA, CPA and CD3 density

Combined CPA and EPA values showed a significant gradual increase with increasing fibrosis stage. Median combined CPA values ranged between 8.22% and 29.34% for stages 1–4 and there was a significant difference in median CPA when comparing stages 1 and 4. EPA values were also significantly different between stages 1 and 3 (table 3).

Table 3

Fibrosis stage comparison with histological/radiological parameters

Similarly, median parenchymal CD3 density increased with fibrosis stages (stage 1: 145.81, stage 2: 206.03, stage 3: 276.65). The median parenchymal CD3 density in the normal livers was 61.12 (IQR 123.23–314.03). Tissue was not adequate for the additional stains in the two stage 4 cases (table 3).

There was a significant association between fibrosis stage and CD34 expression (p=0.0377), with more diffuse changes observed with higher fibrosis stages (table 3).

Correlation between histological features and LSM and HVPG measurements

LSM and HVPG values were available for 17 and 27 of the patients who underwent liver biopsy, respectively.

The median of available LSM was 10.9 kPa (IQR 8.1 kPa–14.6 kPa) and the median HVPG measurement was 7 mm Hg (IQR 5.5 mm Hg–9.5 mm Hg), in the range of portal hypertension (≥6 mm Hg, ≤10 mm Hg).

Median LSM was 9.9 kPa, 8.1 kPa, 11.75 kPa and 33.2 kPa in fibrosis stages 1–4, respectively, and median HVPG was 9.0 mmHg, 6.0 mmHg, 6.0 mmHg and 9.0 mmHg, in fibrosis stages 1–4, respectively (table 4).

Table 4

LSM* and HVPG* and fibrosis stages

Interestingly, EPA and LSM showed moderate correlation (rs=0.567) what was statistically significant (p=0.018, figure 6B). There was no correlation between combined CPA and LSM (p=0.171, figure 6A) or HVPG (p=0.772) nor when comparing EPA and HVPG (p=0.240).

Figure 6

Liver stiffness measurements (LSM) and their relationship with (A) combined (parenchymal and portal/stromal) collagen proportionate area (CPA) and (B) elastin proportionate area (EPA).

Figure 7 illustrates the breakdown of biopsy findings according to the available FibroScan and/or HVPG measurements. Of note, NRH-LC and diffuse pericellular fibrosis were observed in one patient with normal FibroScan reading, also, diffuse pericellular fibrosis and NRH-LC were observed in two patients who had LSM>7 kPa but normal HVPG measurements, and NRH-LC and bridging fibrosis in one patient with normal HVPG and no available LSM readings. Taken together, these cases suggest that the relationship between histological features including pericellular fibrosis, bridging fibrosis and NRH-LC and non-invasive LSM or HVPG is complex and not linear.

Figure 7

Biopsy findings according to the available FibroScan and/or HVPG measurements. HVPG, hepatic venous pressure gradient; NRH-LC-A, nodular regenerative hyperplasia-like changes absent; NRH-LC-P, NRH-LC-present.

Relationship between age group and histology findings

The median age of patients without NRH-LC was 59.5 years (IQR 56.5–61.5) compared with 45.5 years (IQR 38.25–51.5) for the group with NRH-LC on biopsy (p=0.033).

Regarding age groups, NRH-LC was present in most patients (3/4, 75%) less than 30 years old, in all patients 31–49 years old and absent in most patients (7/8, 87.5%) above 50 years old. This correlation was significant (p=0.016).

In terms of fibrosis scores and age group, 75% (n=3) of the patients less than 30 years old had bridging fibrosis (stage 3). Whereas, 64.7% (11/17) of the patients over 50 years old had either focal or diffuse perisinusoidal fibrosis (stage 1 or 2) and 35.3% (6/17) had bridging fibrosis (table 5), possibly suggesting a greater tendency for advanced fibrosis in younger patients. The distribution of CPA as well as fibrosis scores, EPA and CD3 density did not show a correlation with either age or age groups.

Table 5

Fibrosis stage comparison with age group

Fibrosis progression over time

Seven patients had a previous liver biopsy specimen available. The median time between biopsies was 50 months (IQR 37.5–75.5 months).

The indications for the repeat biopsies fall into the two following groups: assessment of the cause of persistently or progressively abnormal liver function tests (LFTs) or progression of portal hypertension; with the exception of case 4, which was to investigate decompensation in the setting of disseminated Cryptococcus infection. A few patients had immunosuppressive treatment between biopsies, as noted in table 6.

Table 6

Cases with more than one biopsy at least 1 year apart

The biopsies showed at least mild progression in fibrosis stage in five (5/7), including 3/7 which progressed from mild pericellular fibrosis to bridging fibrosis. Two patients (ages 28 years old and 72 years old) did not show progression (table 6).

Discussion

Our study is the result of a multidisciplinary collaboration caring for a large cohort of CVID patients in a tertiary care setting. We have demonstrated that liver disease is a common complication of CVID affecting 91/218 (41.74%) of our patients13 In this study we have carried out a detailed histological assessment of liver biopsies from CVID patients. We have focused on features considered to be responsible for the development of liver complications in CVID patients, where an immune-mediated injury to the vascular endothelium is believed to trigger NRH-LC and fibrosis.28 29 We also correlated our histological observations with clinical measures of fibrosis and portal hypertension and investigated fibrosis progression in patients who had multiple biopsies.

NRH is traditionally defined as ‘presence of multiple 1–2 mm nodules separated by regions of hepatocyte atrophy with little or no fibrous septation’17 and affects a variable proportion of CVID patients according to different studies.6–8 Changes consistent with NRH were present in the majority (80%) of our patients. In contrast to its traditional definition, and in line with other recent studies, NRH-LC and fibrosis in CVID patients are not mutually exclusive but tend to coexist. In a detailed recent histological study on liver biopsies from CVID patients, Crotty et al 24 described a distinctive pattern of delicate pericellular fibrosis in the majority (23/26) of their samples and proposed the term ‘NRH-LC’ in the specific setting of CVID, to clarify the terminology. We believe that fibrosis starts at a pericellular level and progresses to the formation of septa later, based on the following observations: (1) the presence of focal or diffuse pericellular fibrosis in all biopsies; (2) the concomitant presence of bridging fibrous septa in some cases and (3) the interval change observed in those patients with multiple biopsies where pericellular fibrosis alone was observed in the first biopsy and bridging fibrosis in the second. The coexistence of NRH-LC, pericellular fibrosis, altered sinusoidal endothelium configuration and the prominent intrasinusoidal infiltrate of CD3 positive lymphocytes, all support the hypothesis of a T-cell-mediated injury to sinusoidal endothelial cells resulting in a vascular flow disturbance triggering NRH-LC and a concomitant fibrogenic response.12 28 29 It is also possible that CVID-related NRH-LC is different from NRH caused by other pathologies, such as obliterative vasculopathy.

Our digital CD3 counting method showed that CD3 positive lymphocytes are more numerous in CVID patients with NRH-LC than in those without. Further studies are required to demonstrate whether infiltrating CD3-positive lymphocytes predict fibrosis and clinical outcomes.29 This may be important, as it would instruct the use of immunosuppressive or immunomodulatory treatments in patients with high CD3 counts to prevent the development of worsening chronic liver disease.

Pericellular fibrosis in some of our cases was mild and focal. Conventionally, it has been challenging to differentiate the apparent enhancement of the ambient pericellular/perisinusoidal collagen strands due to hepatic plate atrophy between NRH-LC nodular areas from true fibrosis. In our approach, the presence of delicate pericellular elastic fibres, absent in normal conditions, allowed us to confirm the presence of pericellular damage, as has previously been shown in alcohol-related liver injury.26

To our knowledge, this is the first study applying digital image analysis of histology specimens to quantify collagen and elastin fibres in liver biopsies from CVID patients. CPA has consistently been shown to correlate with semiquantitative fibrosis scores and predict clinical outcomes in various liver disorders.22 25 30 In our series, there was a significant correlation between the increase in combined CPA values and fibrosis semiquantitative stage, and although there is a weak trend of LSM and CPA increasing together (figure 6A), this was not statistically significant (r=0.348, p=0.171). We also could not find a correlation with CPA and HVPG measurements. The lack of association between HVPG and overall fibrosis stage may be due to the ubiquitous presence of pericellular fibrosis, which may not significantly contribute to increases in HVPG. The correlation between EPA and LSM is a novel finding and suggests the EPA could represent a more sensitive marker than CPA in the assessment of CVID liver injury. Further studies are necessary to confirm this observation. The partial correlation between histological and clinical measurements of fibrosis in our study could also be related to its retrospective nature, the relatively small number of patients with available HVPG and FibroScan readings, the variable time interval between clinical readings and liver biopsy and sampling variation. Of interest, however, is the fact that of the three patients in our series who had either a normal HVPG or FibroScan, all showed pericellular fibrosis, two had NRH-LC, and one also bridging fibrosis. These observations support the role of liver biopsy in gauging liver injury in CVID patients, particularly in the assessment of patients with portal hypertension.

Finally, our study shows that NRH-LC tends to be more common in younger patients, as the majority of patients younger than 30 years had NRH-LC and bridging fibrosis. These findings suggest that the early manifestation of CVID-related liver disease could reflect a more severe form of the disease.

Conclusions

Our study shows that NRH-LC and fibrosis in CVID patients often coexist along with the presence of sinusoidal endothelial changes and sinusoidal lymphocytic infiltration, which would fit with the hypothesis proposed by Malamut et al 28 of a T-cell-mediated injury to the sinusoidal endothelium resulting in vascular flow disturbance and NRH-LC as well as fibrogenesis. CPA correlates with our novel dedicated semiquantitative scoring system of CVID liver fibrosis and pericellular elastosis measurement is a valuable tool in the diagnosis of subtle pericellular fibrosis. The pathology observed in CVID is associated with progressive liver fibrosis, and significant fibrosis can be observed in young patients (<30 years old), potentially reflecting a more aggressive form of CVID-related liver disease.

Data availability statement

Data are available on reasonable request.

Ethics statements

Patient consent for publication

Ethics approval

Research was carried out under ethical approval Ref: 07/Q0501/50 granted by the Hampstead NHS Research Ethics Committee.

References

Supplementary materials

  • Supplementary Data

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Footnotes

  • HS and CGXdB are joint first authors.

  • Handling editor Yoh Zen.

  • Contributors HSilva and AQ conceived the study design. HSilva, CGXdB and AQ reviewed and scored all slides; HSilva and CGXdB acquired and analysed data and contributed equally as co-first authors to drafting the manuscript, AH performed image analysis, immunohistochemistry and contributed to the writing and revising of the manuscript. NE, HSomers, NB, SOB, DL, NH and DT collected clinical data. NH was involved in interpretation of results, editing the manuscript and contributing to data analysis. AQ, NH and DL critically reviewed the manuscript. AQ is responsible for the overall content as the guarantor. All authors revised the content and have approved the final version for publication.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.