Next Article in Journal
Gender-Related Differences in Prodromal Multiple Sclerosis Characteristics: A 7-Year Observation Study
Next Article in Special Issue
Incidence of COVID-19 Hospitalisation in Patients with Systemic Lupus Erythematosus: A Nationwide Cohort Study from Denmark
Previous Article in Journal
Therapeutic Applications of Resveratrol in Hepatic Encephalopathy through Its Regulation of the Microbiota, Brain Edema, and Inflammation
Previous Article in Special Issue
Patient-Reported Outcomes for Quality of Life in SLE: Essential in Clinical Trials and Ready for Routine Care
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
JCM
Volume 10
Issue 17
10.3390/jcm10173820
jcm-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Usefulness of Clinical and Laboratory Criteria for Diagnosing Autoimmune Liver Disease among Patients with Systemic Lupus Erythematosus: An Observational Study

by
Rebecca Heijke
1,
Awais Ahmad
2,
Martina Frodlund
3,
Lina Wirestam
3,
Örjan Dahlström
4,
Charlotte Dahle
2,
Stergios Kechagias
5 and
Christopher Sjöwall
3,*
1
Clinic of Internal Medicine, Region Jönköping County, SE-553 05 Jönköping, Sweden
2
Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection/Clinical Immunology, Linköping University, SE-581 85 Linköping, Sweden
3
Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection/Rheumatology, Linköping University, SE-581 85 Linköping, Sweden
4
Department of Behavioural Sciences and Learning, Swedish Institute for Disability Research, Linköping University, SE-581 85 Linköping, Sweden
5
Department of Health, Division of Diagnostics and Specialist Medicine/Gastroenterology and Hepatology, Medicine and Caring Sciences, Linköping University, SE-581 85 Linköping, Sweden
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2021, 10(17), 3820; https://doi.org/10.3390/jcm10173820
Submission received: 10 June 2021 / Revised: 10 August 2021 / Accepted: 18 August 2021 / Published: 26 August 2021
(This article belongs to the Special Issue Clinical Features and Long-Term Outcomes of Systemic Lupus Erythematosus)
Browse Figure
Review Reports Versions Notes

Abstract

:
Abnormal liver function tests are frequently observed during follow-up of patients with systemic lupus erythematosus (SLE) but data on co-existence with autoimmune liver diseases (AILD) are scarce. This retrospective study aimed to describe the prevalence of autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) among well-characterized subjects with SLE. We also evaluated whether the presence of autoantibodies to complement protein 1q (C1q) and/or ribosomal P protein (anti-ribP) are, directly or inversely, associated with AIH, as proposed in some reports. The number of screened patients was 287 (86% females), and all cases were included in a regional Swedish cohort. Each subject of the study population met the 1982 American College of Rheumatology classification criteria and/or the Fries’ diagnostic principle. By applying the simplified diagnostic AIH criteria combined with persistent transaminasemia, 40 (13.9%) cases reached at least “probable AIH”. However, merely 8 of these had been diagnosed with AIH (overall AIH prevalence 2.8%). Neither anti-C1q nor anti-ribP associated significantly with AIH. By applying the recent PBC guidelines, 6 (2.1%) cases were found, but only 3 of them had actually been diagnosed with PBC and one additional subject was not identified by the guidelines (overall PBC prevalence 1.4%). Compared to prevalence data from the general Swedish population, both AIH and PBC were highly overrepresented in our study population. The sensitivity of the diagnostic AIH criteria was impeccable but the specificity was less impressive, mainly due to positive ANA and hypergammaglobulinemia. Based on our findings, among subjects with SLE, the AIH criteria are less useful and liver biopsy combined with detection of other AILD-associated autoantibodies should be performed.

1. Introduction

Although involvement of joints, skin, mucous membranes, serosa and kidneys is common among patients with systemic lupus erythematosus (SLE) virtually any organ system may be affected. However, hepatic involvement has not been considered a primary organ manifestation in SLE as it is not included in any of the commonly used and recently updated classification criteria [1,2]. Nevertheless, the British Isles Lupus Assessment Group’s (BILAG) disease activity index includes ‘lupus hepatitis’ as a separate item but liver disease is not reflected in the more widely used SLE disease activity score 2000 (SLEDAI-2K) [1,3,4,5,6]. Still, abnormal liver function tests (LFTs) at any time-point are common in patients with SLE; reported numbers range from 9–60% depending on study population and limitations applied for abnormal values [7,8,9,10,11]. Potential causes of abnormal LFTs in SLE are numerous and include drug-induced liver injury (DILI), steatosis, viral hepatitis, vascular thrombosis and autoimmune liver disease (AILD). However, clinically significant AILD associated with SLE has been reported to be rare, and hepatic liver involvement appears to have a limited influence on mortality [11,12,13,14,15,16].
Observations of ’lupus-associated hepatitis’ or ’lupus hepatitis’ usually refer to an asymptomatic transaminasemia, consistent with SLE disease activity [9,17], which normalizes during glucocorticoid treatment [17]. Lupus hepatitis has been reported in 3–9% of patients [9,18,19]. The histopathological findings of lupus hepatitis are variable and non-specific, but mild portal inflammatory infiltrate, lobular necrosis and fatty infiltration are frequently found [9]. One study reported that intense deposits of complement protein 1q (C1q) were found in the majority of cases with lupus hepatitis, but unfortunately neither circulating C1q levels or anti-C1q antibodies—which often parallel SLE disease activity—were investigated [20,21,22,23]. Presence of autoantibodies to ribosomal P protein (anti-ribP) has been reported to associate with lupus hepatitis or autoimmune hepatitis (AIH), but contradictory results have also been published [17,18,24,25].
Whereas lupus hepatitis has been considered as a manifestation of SLE, AIH is regarded as a separate disease. However, the two conditions often share several features, including hypergammaglobulinemia, arthralgia and presence of antinuclear antibodies (ANA) [26]. Similarly to SLE, AIH also has a female predominance. The histopathology is characterized by progressive hepatocellular necrosis and inflammation, which untreated may lead to cirrhosis and end-stage liver disease. Although AIH prevalence data are uncertain, epidemiological studies from Scandinavia, Spain and New Zealand have estimated a prevalence of 12–25 per 100,000 inhabitants [27,28,29,30].
Data on co-existence of SLE and AIH are scarce [19]. Differential diagnostics may be challenging since elevated LFTs, hypergammaglobulinemia, a positive ANA test and response to glucocorticoid treatment are characteristic of both conditions. Efe et al. found that up to two thirds of SLE patients with abnormal LFTs fulfilled the simplified AIH criteria whereas only approximately 14% had histopathology compatible with AIH [7]. This illustrates that a liver biopsy is often necessary for a definitive diagnosis of AIH among patients with SLE [31].
Primary biliary cholangitis (PBC) constitutes another AILD with female predominance, which is chronic, often progresses, and can result in end-stage liver disease [32]. The prevalence of PBC in Sweden has been estimated to be approximately 15 per 100,000 inhabitants [33]. PBC is typically associated with the presence of anti-mitochondrial antibodies of M2 type (AMA-M2), which, in addition to persistently elevated serum alkaline phosphatase (ALP) and liver histology consistent with PBC, constitutes one of the three diagnostic criteria [34]. In addition, other subtypes of ANA, such as anti-speckled 100-kDa (Sp100), anti-promyelocytic leukemia protein (PML) and anti-glycoprotein 210-kDa (gp210), are also strongly associated with PBC [35]. Whereas the association of PBC with primary Sjögren’s syndrome (SS) is well documented [36,37], co-existence with SLE has been reported as rare [38]. In contrast, however, we recently showed that PBC-associated autoantibodies in SLE are relatively common [39].
The primary aim of the present study was to describe the prevalence of AILD in well-characterized Swedish SLE patients from a tertiary referral center. This was done with support from an experienced hepatologist (S.K.) using different grounds for the diagnoses of AIH and PBC. We further aimed to test whether the presence of anti-C1q and/or anti-ribP antibodies were associated with AIH.

2. Materials and Methods

2.1. Study Population

The study population consisted of 287 patients (248 women, 39 men) diagnosed with SLE (detailed in Table 1). All subjects had been included in the prospective and observational research program Clinical Lupus Register in North-Eastern Gothia (Swedish acronym ‘KLURING’) at the Rheumatology unit, University Hospital in Linköping [40]. Most (284 of 287 (99%)) patients met the Fries’ diagnostic principle and 243 of 287 (84.7%) fulfilled the 1982 American College of Rheumatology (ACR) classification criteria (mean number of fulfilled ACR criteria was 4.8, range 3–9) [5,41]. The study population corresponds to virtually all prevalent and incident adult SLE cases in the catchment area of Region Östergötland (approximately 365,000 adult inhabitants) between September 2008 and May 2020. The medical records of all patients were retrospectively reviewed with a focus on AILD.

2.2. Data Collection

AILD diagnoses, attributed by gastroenterologists among the 287 SLE cases, were retrieved from medical records, reviewed by a hepatologist (S.K.) and considered as ‘golden standard’. Furthermore, we applied the simplified diagnostic AIH criteria and the recent PBC guidelines from the American Association for the Study of Liver Diseases and examined their diagnostic performance in our study population [44,45]. In addition, we recorded the presence of secondary SS (diagnosis confirmed by a rheumatologist and defined according to classification criteria) and antiphospholipid syndrome (APS) [42,43]. Data on liver biopsies and liver imaging were also retrieved.

2.3. Laboratory Analyses

All patients had undergone continuous monitoring of liver enzyme values as was previously described [39]. Levels of IgG (normal range 6.7–15 g/L) and IgM (0.27–2.1 g/L) in plasma were recorded. IgG-ANA was detected by indirect immunofluorescence (IF) microscopy on fixed HEp-2 cells and anti-ribP antibodies were analyzed by FIDIS™ Connective profile, Solonium software v 1.7.1.0 (Theradiag, Croissy-Beaubourg, France) at the Clinical Immunology laboratory, University Hospital in Linköping [46,47]. Anti-C1q antibodies were analyzed by ELISA [48]. Hepatitis B surface antigen (HBsAg) and antibodies against hepatitis C virus (anti-HCV) were assessed by routine methods at the Clinical Microbiology laboratory, University Hospital in Linköping. Autoantibodies associated with AILD were analyzed as previously described [39].

2.4. Statistics

Associations between laboratory variables (categorical) and AILD were examined with Fisher’s exact test for significance and using Φ as a measure of association. p-values ≤0.05 were considered statistically significant. Statistical analyses were performed using the SPSS software version 26.0.0.0 (SPSS Inc., Chicago, IL, USA). Sensitivity (proportion of subjects correctly identified with AILD), specificity (proportion of subjects correctly identified without AILD), accuracy (proportion of correctly classified subjects), positive predictive value (PPV; proportion of AILD-classified subjects that are true AILD) and negative predictive value (NPV; proportion of non–AILD-classified subjects that are true non-AILD), were calculated, including 95% confidence intervals (CI) using the Wilson score method.

2.5. Ethical Approval

Oral and written informed consent were obtained from all participants. The study protocol was approved by the regional ethics review board in Linköping (Decision number M75–08/2008).

3. Results

Of the 287 screened patients, 182 (63.4%) had occasional or persistent elevations of aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), and/or γ-glutamyl transferase (GGT) during follow-up. Less than 10% had elevated LFTs for >3 months. All subjects with confirmed AILD (n = 12) were found among the patients with elevated LFTs. In the subgroup with elevated LFTs (n = 182), 4.4% had a confirmed diagnosis of AIH and 2.2% of PBC.
As illustrated in Figure 1A, we applied the diagnostic AIH criteria to the study population [44]. The prevalence of AIH in the entire study population was 2.8% (n = 8); and establishment of the diagnosis included liver biopsy in 6 of 8 cases. The sensitivity and the NPV of the AIH criteria was high, but the specificity and PPV were lower (Table 2). Among the entire study population, 102 of 226 (45.1%) had hypergammaglobulinemia at least once. HBsAg and anti-HCV were absent in 77 of 102 (75.5%) and IF-ANA was positive (titer > 1:80) in 284 of 287 (99.0%) patients. According to the AIH criteria, 46 (16.0%) reached at least “probable AIH”, even without histopathological evaluation, whereof 40 cases had a history of elevated LFTs (AST and/or ALT). Of note, plasma IgG had not been measured in 61 subjects, which clearly limited the possibility of reaching “probable AIH”. However, a closer review of those reaching “probable AIH” revealed a different explanation than AIH in a majority of cases with elevated LFTs. Still, the presence of hypergammaglobulinemia (≥16 g/L) at any time-point during follow-up was significantly associated with a confirmed diagnosis of AIH (Φ = 0.16, p = 0.015).
Only 4 subjects had a confirmed diagnosis of PBC (1.4%), which included histopathological evaluation in 2 of 4. As shown in Figure 1B, we used the recent diagnostic guidelines for PBC by requiring elevation of ALP in combination with presence of typical PBC-associated antibodies (AMA-M2/Sp100/gp210) [45]. This procedure yielded 6 cases (2.1%). The specificity and the NPV of the guidelines for PBC were impressive, but the sensitivity and PPV among our study population were lower (Table 2).
Anti-C1q antibodies were detected in 60 of 260 subjects (23.1%), but the presence of anti-C1q did not associate significantly with AIH. Anti-ribP antibodies were detected in 17 of 247 patients (6.9%), but in none of those with a confirmed diagnosis of AIH. Altogether, 9 of 17 (52.9%) anti-ribP positive individuals had a history of elevated LFTs, which did not significantly differ from anti-ribP negative subjects. SLE with secondary SS did not associate with either AIH or PBC, although a non-significant trend was observed for the latter (Φ = 0.09, p = 0.16). APS was found in one patient with AIH (12.5%), but in none with PBC.

4. Discussion

Continuous supervision of LFTs is mandatory for patients using disease-modifying anti-rheumatic drugs (DMARDs), such as methotrexate, azathioprine, mycophenolate mofetil, leflunomide or cyclosporine. Abnormal LFTs in the absence of liver-related symptoms are very common during follow-up of patients with SLE. The cause may be obvious but is most often uncertain. Occasionally, the LFTs normalize without specific interventions or with a minor increase of the daily glucocorticoid dose. However, LFTs can also be persistently elevated, which often leads to both further investigations and interruption of a needed and well-functioning DMARD treatment. These cases may be challenging and often require interdisciplinary discussions between rheumatologists, hepatologists and immunologists.
In this study, we aimed to describe the prevalence of AILD among well-characterized SLE patients from a tertiary referral center. We used a previously described cohort in which we had the possibility to longitudinally monitor LFTs, liver imaging, biopsies, concomitant diagnoses, drugs as well as additional laboratory data, including results from autoantibody testing [39,40]. All data were discussed and evaluated by specialists in rheumatology (C.S.), hepatology (S.K.) and immunology (C.D.). The prevalence rates achieved in our study population for established AIH (2.8% among all, and 4.4% among those with elevated LFTs) and PBC (1.4% among all, and 2.2% among those with elevated LFTs) are in line with, or close to, what previously has been published. The recent review by González-Regueiro et al. mentions a prevalence of AIH of approximately 5–10% among SLE patients with abnormal LFTs [31]. For PBC, a lower prevalence (2.5–5%) has been observed [38].
To set these figures into a context, the AILD prevalence rates in our study population can be compared with prevalence data from the general Swedish population. Danielsson-Borssén et al. determined the point prevalence of AIH in 2009 to 17.3/100,000 inhabitants (0.17‰), which strongly contrasts to our finding of 2.8% in SLE [27]. Only older prevalence data from the time span 1973–1982 are available for PBC, when Danielsson et al. reported 15.1/100,000 inhabitants (0.15‰), which is considerably lower than the 1.4% found among patients with SLE herein [33]. Based on these findings, we conclude that both AIH and PBC are over-represented among patients with SLE. Similarly, AIH has been associated with an increased risk of developing systemic autoimmune diseases [49]. This is also in line with the overall empirical knowledge that “one autoimmune disease predisposes to another”. Interestingly, the recent years’ genetic advances have taught us that identical risk genes are shared by several different autoimmune conditions [50,51].
We also took the opportunity to challenge the simplified diagnostic AIH criteria and the recent guidelines for PBC diagnosis. The AIH criteria have previously been criticized for poor performance in SLE, especially with regard to low specificity [7]. However, to the best of our knowledge, their performance has not systematically been evaluated in a population of well-characterized SLE cases. Basically, our findings confirm the observation by Efe et al. and emphasize that liver biopsy is often needed for a definitive diagnosis of AIH among patients with SLE [31]. The PPV of reaching “probable AIH” herein was only 17%. However, plasma IgG ≥ 16 g/L associated significantly with confirmed AIH. This is of relevance as initially high levels of IgG have been associated with poor outcome in patients with combined SLE/AIH [52]. Although the sensitivity and PPV were mediocre, the recent diagnostic guidelines for PBC overall performed slightly better than the AIH criteria in our study population. This was mostly explained by the high diagnostic specificity for the PBC-associated ANA subtypes, compared to the non-specified ANA detected by IF microscopy, which is valid as one of the criteria for AIH.
In SLE, the high prevalence of ANA and hypergammaglobulinemia confers that the other diagnostic markers, i.e., SMA antibodies, antibodies against soluble liver antigen (SLA) or LKM, play a more important role for diagnosing AIH. These antibody specificities as well as PBC-specific ANA, such as Sp100, anti-PML and anti-gp210, in addition to AMA-M2, should therefore be included in the screening algorithm when AILD is suspected. However, in most of our cases reaching the level of ”probable AIH”, these autoantibody specificities had not been requested since their LFTs were not persistently elevated and the clinical suspicion of AILD had therefore not been raised. Furthermore, it is worth noting that for detection of SMA, a serum dilution that results in a cut-off corresponding to the 95th percentile of a healthy population should be used and must be evaluated by each laboratory. According to the diagnostic AIH criteria a serum dilution of 1:40 is recommended, but is actually based on experience from ”the old days” when the quality of the microscopes were much lower than today’s modern equipment [44,47].
Levels of the SLE-associated antibodies anti-C1q and anti-ribP are known to fluctuate over time [22,23,47]. An etiological role for anti-ribP in triggering both lupus hepatitis and AIH has been proposed [18,24,25]. Herein, we considered all patients once positive for anti-ribP or anti-C1q as positive and potential seroconversion over time was neglected. Still, we did not confirm the previously reported association between anti-ribP and AIH. However, according to a detailed review by Bessone et al., the association remains both uncertain and controversial [17]. This study has some limitations. It cannot be excluded that the actual prevalence of AILD in SLE is even greater than what we have estimated here [13]. Guided examination of AILD is usually driven by elevated LFTs, usually over a longer period of time, as the risk of progression to cirrhosis is associated with raised LFTs [53,54]. However, in our study population, none of the cases who reached “probable AIH” had persistently elevated (≥6 months) LFTs. Otherwise, the latter would normally have resulted in a liver biopsy. Nevertheless, from an international perspective, it is worthwhile underlining that the Nordic reference limits regarding AST and ALT are unusually high [55]. Thus, based on the liberal LFT reference intervals we apply in Sweden, it is not impossible that subclinical AILD to some extent may pass under the radar. Another limitation was the ethnic composition of the study population—almost 90% of the enrolled patients were of Caucasian origin. Ethnicity is indeed known to affect both disease severity and manifestations of SLE [56]. Thus, extrapolation of our results to other populations should be done with caution. In contrast, the study has several strengths. For instance, the fact that Swedish health care is universally available to all residents significantly reduces the risk of selection bias and ensures a high coverage of cases. The well-characterized cohort of SLE patients, longitudinally followed by a limited number of experienced rheumatologists at a single tertiary referral center, constitutes another advantage [40,47].

5. Conclusions

In conclusion, both AIH and PBC are overrepresented in SLE. When the diagnostic AIH criteria were applied, even higher numbers were achieved, but the use of these criteria cannot be recommended in patients with SLE. Instead, liver biopsy and detection of autoantibodies with higher diagnostic specificity for AILD could aid in the search (particularly for AIH) among individuals with SLE.

Author Contributions

Conceptualization, R.H., S.K. and C.S.; methodology, R.H., Ö.D., C.D., S.K. and C.S.; R.H., A.A., L.W. and C.S.; software, R.H., Ö.D., L.W., S.K. and C.S.; validation, C.D., S.K. and C.S.; formal analysis, R.H., Ö.D. and C.S.; investigation, R.H., M.F. and C.S.; resources, S.K. and C.S.; data curation, R.H. and C.S.; writing—original draft preparation, C.S.; writing—review and editing, R.H., A.A., M.F., L.W., Ö.D., C.D., S.K. and C.S.; visualization, L.W.; supervision, C.D., S.K. and C.S.; project administration, C.S.; funding acquisition, S.K. and C.S. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by grants from the Medical Research Council of South-Eastern Sweden (FORSS), the Swedish Rheumatism Association, the Region Östergötland (ALF Grants), the Gustafsson Foundation, the King Gustaf V’s 80-year Anniversary foundation and the King Gustaf V and Queen Victoria’s Freemasons foundation.

Institutional Review Board Statement

The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the regional ethics review board in Linköping (Decision number M75–08/2008).

Informed Consent Statement

Oral and written informed consent were obtained from all subjects involved in the study.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Petri, M.; Orbai, A.M.; Alarcon, G.S.; Gordon, C.; Merrill, J.T.; Fortin, P.R.; Bruce, I.N.; Isenberg, D.; Wallace, D.J.; Nived, O.; et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 2012, 64, 2677–2686. [Google Scholar] [CrossRef]
  2. Aringer, M.; Costenbader, K.; Daikh, D.; Brinks, R.; Mosca, M.; Ramsey-Goldman, R.; Smolen, J.S.; Wofsy, D.; Boumpas, D.T.; Kamen, D.L.; et al. 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus. Arthritis Rheumatol. 2019, 71, 1400–1412. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Isenberg, D.A.; Rahman, A.; Allen, E.; Farewell, V.; Akil, M.; Bruce, I.N.; D’Cruz, D.; Griffiths, B.; Khamashta, M.; Maddison, P.; et al. BILAG 2004. Development and initial validation of an updated version of the British Isles Lupus Assessment Group’s disease activity index for patients with systemic lupus erythematosus. Rheumatology 2005, 44, 902–906. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Gladman, D.D.; Ibanez, D.; Urowitz, M.B. Systemic lupus erythematosus disease activity index 2000. J. Rheumatol. 2002, 29, 288–291. [Google Scholar] [PubMed]
  5. Tan, E.M.; Cohen, A.S.; Fries, J.F.; Masi, A.T.; McShane, D.J.; Rothfield, N.F.; Schaller, J.G.; Talal, N.; Winchester, R.J. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982, 25, 1271–1277. [Google Scholar] [CrossRef] [PubMed]
  6. Yee, C.S.; Cresswell, L.; Farewell, V.; Rahman, A.; Teh, L.S.; Griffiths, B.; Bruce, I.N.; Ahmad, Y.; Prabu, A.; Akil, M.; et al. Numerical scoring for the BILAG-2004 index. Rheumatology 2010, 49, 1665–1669. [Google Scholar] [CrossRef] [Green Version]
  7. Efe, C.; Purnak, T.; Ozaslan, E.; Ozbalkan, Z.; Karaaslan, Y.; Altiparmak, E.; Muratori, P.; Wahlin, S. Autoimmune liver disease in patients with systemic lupus erythematosus: A retrospective analysis of 147 cases. Scand. J. Gastroenterol. 2011, 46, 732–737. [Google Scholar] [CrossRef]
  8. Huang, D.; Aghdassi, E.; Su, J.; Mosko, J.; Hirschfield, G.M.; Gladman, D.D.; Urowitz, M.B.; Fortin, P.R. Prevalence and risk factors for liver biochemical abnormalities in Canadian patients with systemic lupus erythematosus. J. Rheumatol. 2012, 39, 254–261. [Google Scholar] [CrossRef]
  9. Piga, M.; Vacca, A.; Porru, G.; Cauli, A.; Mathieu, A. Liver involvement in systemic lupus erythematosus: Incidence, clinical course and outcome of lupus hepatitis. Clin. Exp. Rheumatol. 2010, 28, 504–510. [Google Scholar]
  10. Takahashi, A.; Abe, K.; Saito, R.; Iwadate, H.; Okai, K.; Katsushima, F.; Monoe, K.; Kanno, Y.; Saito, H.; Kobayashi, H.; et al. Liver dysfunction in patients with systemic lupus erythematosus. Intern. Med. 2013, 52, 1461–1465. [Google Scholar] [CrossRef] [Green Version]
  11. Runyon, B.A.; LaBrecque, D.R.; Anuras, S. The spectrum of liver disease in systemic lupus erythematosus. Report of 33 histologically proved cases and review of the literature. Am. J. Med. 1980, 69, 187–194. [Google Scholar] [CrossRef]
  12. Chowdhary, V.R.; Crowson, C.S.; Poterucha, J.J.; Moder, K.G. Liver involvement in systemic lupus erythematosus: Case review of 40 patients. J. Rheumatol. 2008, 35, 2159–2164. [Google Scholar] [CrossRef] [PubMed]
  13. Gibson, T.; Myers, A.R. Subclinical liver disease in systemic lupus erythematosus. J. Rheumatol. 1981, 8, 752–759. [Google Scholar] [PubMed]
  14. Grover, S.; Rastogi, A.; Singh, J.; Rajbongshi, A.; Bihari, C. Spectrum of histomorphologic findings in liver in patients with SLE: A review. Hepat. Res. Treat. 2014, 2014, 562979. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Matsumoto, T.; Yoshimine, T.; Shimouchi, K.; Shiotu, H.; Kuwabara, N.; Fukuda, Y.; Hoshi, T. The liver in systemic lupus erythematosus: Pathologic analysis of 52 cases and review of Japanese Autopsy Registry Data. Hum. Pathol. 1992, 23, 1151–1158. [Google Scholar] [CrossRef]
  16. Ippolito, A.; Petri, M. An update on mortality in systemic lupus erythematosus. Clin. Exp. Rheumatol. 2008, 26, S72–S79. [Google Scholar]
  17. Bessone, F.; Poles, N.; Roma, M.G. Challenge of liver disease in systemic lupus erythematosus: Clues for diagnosis and hints for pathogenesis. World J. Hepatol. 2014, 6, 394–409. [Google Scholar] [CrossRef] [PubMed]
  18. Arnett, F.C.; Reichlin, M. Lupus hepatitis: An under-recognized disease feature associated with autoantibodies to ribosomal P. Am. J. Med. 1995, 99, 465–472. [Google Scholar] [CrossRef]
  19. Miller, M.H.; Urowitz, M.B.; Gladman, D.D.; Blendis, L.M. The liver in systemic lupus erythematosus. Q. J. Med. 1984, 53, 401–409. [Google Scholar]
  20. Zheng, R.H.; Wang, J.H.; Wang, S.B.; Chen, J.; Guan, W.M.; Chen, M.H. Clinical and immunopathological features of patients with lupus hepatitis. Chin. Med. J. 2013, 126, 260–266. [Google Scholar]
  21. Mathsson, L.; Ahlin, E.; Sjowall, C.; Skogh, T.; Ronnelid, J. Cytokine induction by circulating immune complexes and signs of in-vivo complement activation in systemic lupus erythematosus are associated with the occurrence of anti-Sjogren’s syndrome A antibodies. Clin. Exp. Immunol. 2007, 147, 513–520. [Google Scholar] [CrossRef]
  22. Akhter, E.; Burlingame, R.W.; Seaman, A.L.; Magder, L.; Petri, M. Anti-C1q antibodies have higher correlation with flares of lupus nephritis than other serum markers. Lupus 2011, 20, 1267–1274. [Google Scholar] [CrossRef]
  23. Trendelenburg, M. Autoantibodies against complement component C1q in systemic lupus erythematosus. Clin. Transl. Immunol. 2021, 10, e1279. [Google Scholar] [CrossRef] [PubMed]
  24. Ohira, H.; Takiguchi, J.; Rai, T.; Abe, K.; Yokokawa, J.; Sato, Y.; Takeda, I.; Kanno, T. High frequency of anti-ribosomal P antibody in patients with systemic lupus erythematosus-associated hepatitis. Hepatol. Res. 2004, 28, 137–139. [Google Scholar] [CrossRef] [PubMed]
  25. Calich, A.L.; Viana, V.S.; Cancado, E.; Tustumi, F.; Terrabuio, D.R.; Leon, E.P.; Silva, C.A.; Borba, E.F.; Bonfa, E. Anti-ribosomal P protein: A novel antibody in autoimmune hepatitis. Liver Int. 2013, 33, 909–913. [Google Scholar] [CrossRef] [PubMed]
  26. Adiga, A.; Nugent, K. Lupus Hepatitis and Autoimmune Hepatitis (Lupoid Hepatitis). Am. J. Med. Sci. 2017, 353, 329–335. [Google Scholar] [CrossRef]
  27. Danielsson Borssen, A.; Marschall, H.U.; Bergquist, A.; Rorsman, F.; Weiland, O.; Kechagias, S.; Nyhlin, N.; Verbaan, H.; Nilsson, E.; Werner, M. Epidemiology and causes of death in a Swedish cohort of patients with autoimmune hepatitis. Scand. J. Gastroenterol. 2017, 52, 1022–1028. [Google Scholar] [CrossRef] [PubMed]
  28. Gronbaek, L.; Vilstrup, H.; Jepsen, P. Autoimmune hepatitis in Denmark: Incidence, prevalence, prognosis, and causes of death. A nationwide registry-based cohort study. J. Hepatol. 2014, 60, 612–617. [Google Scholar] [CrossRef] [PubMed]
  29. Ngu, J.H.; Bechly, K.; Chapman, B.A.; Burt, M.J.; Barclay, M.L.; Gearry, R.B.; Stedman, C.A. Population-based epidemiology study of autoimmune hepatitis: A disease of older women? J. Gastroenterol. Hepatol. 2010, 25, 1681–1686. [Google Scholar] [CrossRef]
  30. Primo, J.; Maroto, N.; Martinez, M.; Anton, M.D.; Zaragoza, A.; Giner, R.; Devesa, F.; Merino, C.; del Olmo, J.A. Incidence of adult form of autoimmune hepatitis in Valencia (Spain). Acta Gastroenterol. Belg. 2009, 72, 402–406. [Google Scholar]
  31. Gonzalez-Regueiro, J.A.; Cruz-Contreras, M.; Merayo-Chalico, J.; Barrera-Vargas, A.; Ruiz-Margain, A.; Campos-Murguia, A.; Espin-Nasser, M.; Martinez-Benitez, B.; Mendez-Cano, V.H.; Macias-Rodriguez, R.U. Hepatic manifestations in systemic lupus erythematosus. Lupus 2020, 29, 813–824. [Google Scholar] [CrossRef]
  32. Carey, E.J.; Ali, A.H.; Lindor, K.D. Primary biliary cirrhosis. Lancet 2015, 386, 1565–1575. [Google Scholar] [CrossRef]
  33. Danielsson, A.; Boqvist, L.; Uddenfeldt, P. Epidemiology of primary biliary cirrhosis in a defined rural population in the northern part of Sweden. Hepatology 1990, 11, 458–464. [Google Scholar] [CrossRef]
  34. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: The Diagnosis and Management of Patients with Primary Biliary Cholangitis. J. Hepatol. 2017, 67, 145–172. [Google Scholar] [CrossRef]
  35. Invernizzi, P.; Floreani, A.; Carbone, M.; Marzioni, M.; Craxi, A.; Muratori, L.; Vespasiani Gentilucci, U.; Gardini, I.; Gasbarrini, A.; Kruger, P.; et al. Primary biliary cholangitis: Advances in management and treatment of the disease. Dig. Liver Dis. 2017, 49, 841–846. [Google Scholar] [CrossRef] [Green Version]
  36. Tsianos, E.V.; Hoofnagle, J.H.; Fox, P.C.; Alspaugh, M.; Jones, E.A.; Schafer, D.F.; Moutsopoulos, H.M. Sjogren’s syndrome in patients with primary biliary cirrhosis. Hepatology 1990, 11, 730–734. [Google Scholar] [CrossRef]
  37. Hatzis, G.S.; Fragoulis, G.E.; Karatzaferis, A.; Delladetsima, I.; Barbatis, C.; Moutsopoulos, H.M. Prevalence and longterm course of primary biliary cirrhosis in primary Sjogren’s syndrome. J. Rheumatol. 2008, 35, 2012–2016. [Google Scholar] [PubMed]
  38. Shizuma, T. Clinical characteristics of concomitant systemic lupus erythematosus and primary biliary cirrhosis: A literature review. J. Immunol. Res. 2015, 2015, 713728. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  39. Ahmad, A.; Heijke, R.; Eriksson, P.; Wirestam, L.; Kechagias, S.; Dahle, C.; Sjowall, C. Autoantibodies associated with primary biliary cholangitis are common among patients with systemic lupus erythematosus even in the absence of elevated liver enzymes. Clin. Exp. Immunol. 2021, 203, 22–31. [Google Scholar] [CrossRef] [PubMed]
  40. Frodlund, M.; Dahlstrom, O.; Kastbom, A.; Skogh, T.; Sjowall, C. Associations between antinuclear antibody staining patterns and clinical features of systemic lupus erythematosus: Analysis of a regional Swedish register. BMJ Open 2013, 3, e003608. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  41. Fries, J.F.; Holman, H.R. Systemic lupus erythematosus: A clinical analysis. In Major problems in internal medicine; Smith, L.H., Jr., Ed.; W.B. Saunders: Philadelphia, NY, USA, 1975; pp. 8–20. [Google Scholar]
  42. Vitali, C.; Bombardieri, S.; Jonsson, R.; Moutsopoulos, H.M.; Alexander, E.L.; Carsons, S.E.; Daniels, T.E.; Fox, P.C.; Fox, R.I.; Kassan, S.S.; et al. Classification criteria for Sjogren’s syndrome: A revised version of the European criteria proposed by the American-European Consensus Group. Ann. Rheum. Dis. 2002, 61, 554–558. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Miyakis, S.; Lockshin, M.D.; Atsumi, T.; Branch, D.W.; Brey, R.L.; Cervera, R.; Derksen, R.H.; De Groot, P.G.; Koike, T.; Meroni, P.L.; et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J. Thromb. Haemost. 2006, 4, 295–306. [Google Scholar] [CrossRef] [PubMed]
  44. Hennes, E.M.; Zeniya, M.; Czaja, A.J.; Pares, A.; Dalekos, G.N.; Krawitt, E.L.; Bittencourt, P.L.; Porta, G.; Boberg, K.M.; Hofer, H.; et al. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology 2008, 48, 169–176. [Google Scholar] [CrossRef] [PubMed]
  45. Lindor, K.D.; Bowlus, C.L.; Boyer, J.; Levy, C.; Mayo, M. Primary biliary cholangitis: 2018 practice guidance from the American Association for the Study of Liver Diseases. Hepatology 2019, 69, 394–419. [Google Scholar] [CrossRef] [Green Version]
  46. Enocsson, H.; Wirestam, L.; Dahle, C.; Padyukov, L.; Jonsen, A.; Urowitz, M.B.; Gladman, D.D.; Romero-Diaz, J.; Bae, S.C.; Fortin, P.R.; et al. Soluble urokinase plasminogen activator receptor (suPAR) levels predict damage accrual in patients with recent-onset systemic lupus erythematosus. J. Autoimmun. 2020, 106, 102340. [Google Scholar] [CrossRef]
  47. Frodlund, M.; Wettero, J.; Dahle, C.; Dahlstrom, O.; Skogh, T.; Ronnelid, J.; Sjowall, C. Longitudinal anti-nuclear antibody (ANA) seroconversion in systemic lupus erythematosus: A prospective study of Swedish cases with recent-onset disease. Clin. Exp. Immunol. 2020, 199, 245–254. [Google Scholar] [CrossRef] [Green Version]
  48. Sjowall, C.; Mandl, T.; Skattum, L.; Olsson, M.; Mohammad, A.J. Epidemiology of hypocomplementaemic urticarial vasculitis (anti-C1q vasculitis). Rheumatology 2018, 57, 1400–1407. [Google Scholar] [CrossRef] [Green Version]
  49. West, M.; Jasin, H.E.; Medhekar, S. The development of connective tissue diseases in patients with autoimmune hepatitis: A case series. Semin. Arthritis Rheum. 2006, 35, 344–348. [Google Scholar] [CrossRef]
  50. Olafsson, S.; Stridh, P.; Bos, S.D.; Ingason, A.; Euesden, J.; Sulem, P.; Thorleifsson, G.; Gustafsson, O.; Johannesson, A.; Geirsson, A.J.; et al. Fourteen sequence variants that associate with multiple sclerosis discovered by meta-analysis informed by genetic correlations. NPJ Genom. Med. 2017, 2, 24. [Google Scholar] [CrossRef] [Green Version]
  51. Tizaoui, K.; Terrazzino, S.; Cargnin, S.; Lee, K.H.; Gauckler, P.; Li, H.; Shin, J.I.; Kronbichler, A. The role of PTPN22 in the pathogenesis of autoimmune diseases: A comprehensive review. Semin. Arthritis Rheum. 2021, 51, 513–522. [Google Scholar] [CrossRef]
  52. Lim, D.H.; Kim, Y.G.; Lee, D.; Min Ahn, S.; Hong, S.; Lee, C.K.; Yoo, B. Immunoglobulin G levels as a prognostic factor for autoimmune hepatitis combined with systemic lupus erythematosus. Arthritis Care Res. 2016, 68, 995–1002. [Google Scholar] [CrossRef] [Green Version]
  53. Miyake, Y.; Iwasaki, Y.; Terada, R.; Okamaoto, R.; Ikeda, H.; Makino, Y.; Kobashi, H.; Takaguchi, K.; Sakaguchi, K.; Shiratori, Y. Persistent elevation of serum alanine aminotransferase levels leads to poor survival and hepatocellular carcinoma development in type 1 autoimmune hepatitis. Aliment. Pharmacol. Ther. 2006, 24, 1197–1205. [Google Scholar] [CrossRef] [PubMed]
  54. Verma, S.; Gunuwan, B.; Mendler, M.; Govindrajan, S.; Redeker, A. Factors predicting relapse and poor outcome in type I autoimmune hepatitis: Role of cirrhosis development, patterns of transaminases during remission and plasma cell activity in the liver biopsy. Am. J. Gastroenterol. 2004, 99, 1510–1516. [Google Scholar] [CrossRef] [PubMed]
  55. Rustad, P.; Felding, P.; Franzson, L.; Kairisto, V.; Lahti, A.; Martensson, A.; Hyltoft Petersen, P.; Simonsson, P.; Steensland, H.; Uldall, A. The Nordic Reference Interval Project 2000: Recommended reference intervals for 25 common biochemical properties. Scand. J. Clin. Lab. Investig. 2004, 64, 271–284. [Google Scholar] [CrossRef] [PubMed]
  56. Arnaud, L.; Tektonidou, M.G. Long-term outcomes in systemic lupus erythematosus: Trends over time and major contributors. Rheumatology 2020, 59 (Suppl. 5), v29–v38. [Google Scholar] [CrossRef] [PubMed]
Jcm 10 03820 g001 550
Figure 1. Diagrams illustrating the performance of the diagnostic AIH criteria (A) and PBC guidelines (B) among our study population. AIH = autoimmune hepatitis; SLE = systemic lupus erythematosus; PBC = primary biliary cholangitis; LFTs = liver function tests.
Figure 1. Diagrams illustrating the performance of the diagnostic AIH criteria (A) and PBC guidelines (B) among our study population. AIH = autoimmune hepatitis; SLE = systemic lupus erythematosus; PBC = primary biliary cholangitis; LFTs = liver function tests.
Jcm 10 03820 g001
Table
Table 1. Characteristics of the included patients with SLE. Patients with confirmed AILD are shown in separate columns.
Table 1. Characteristics of the included patients with SLE. Patients with confirmed AILD are shown in separate columns.
Background VariablesTotal, n = 287AIH, n = 8PBC, n = 4
Females, n (%)248 (86.4)7 (87.5)3 (75.0)
Age at cohort inclusion, mean years (range)49.0 (20–86)47.8 (22–70)53.2 (28–69)
SLE duration at cohort inclusion, mean years (range)9.4 (0–45)8.0 (0–19)11.0 (1–25)
Caucasian ethnicity, n (%)255 (88.8)7 (87.5)4 (100.0)
Ever smoker (former or current), n (%)121 (42.1)5 (62.5)2 (50.0)
Disease variables
Secondary Sjögren‘s syndrome (defined by classification #), n (%)65 (22.6)2 (25.0)2 (50.0)
Antiphospholipid syndrome (defined by classification §), n (%)56 (19.5)1 (12.5)0 (0)
Patients meeting ≥4 ACR-82 criteria, n (%)243 (84.7)6 (75.0)3 (75.0)
Number of fulfilled ACR-82 criteria, mean (range)4.8 (3–9)4.8 (3–9) 3.8 (3–4)
Clinical phenotypes (ACR-82 defined), n (%)
(1) Malar rash114 (39.7)4 (50.0)0 (0)
(2) Discoid rash43 (15.0)0 (0)0 (0)
(3) Photosensitivity147 (51.2)4 (50.0)3 (75.0)
(4) Oral ulcers34 (11.8)1 (12.5)1 (25.0)
(5) Arthritis220 (76.7)6 (75.0)3 (75.0)
(6) Serositis110 (38.3)3 (37.5)3 (75.0)
Pleuritis106 (36.9)3 (37.5)2 (50.0)
Pericarditis98 (34.1)2 (25.0)2 (50.0)
(7) Renal disorder80 (27.9)2 (25.0)0 (0)
(8) Neurologic disorder16 (5.6)0 (0)0 (0)
Seizures15 (5.2)0 (0)0 (0)
Psychosis3 (1.0)0 (0)0 (0)
(9) Hematologic disorder174 (60.6)5 (62.5)0 (0)
Hemolytic anemia12 (4.2)0 (0)0 (0)
Leukocytopenia86 (30.0)2 (25.0)0 (0)
Lymphopenia112 (39.0)4 (50.0)0 (0)
Thrombocytopenia31 (10.8)0 (0)0 (0)
(10) Immunological disorder152 (53.0)4 (50.0)1 (25.0)
Anti-dsDNA antibody (anti-dsDNA)139 (48.4)4 (50.0)1 (25.0)
Anti-Smith antibody (anti-Sm)19 (6.6)1 (12.5)0 (0)
(11) Antinuclear antibody (IF-ANA) *284 (99.0)8 (100)4 (100)
* Positive by immunofluorescence (IF) microscopy. # According to Vitali C, et al. [42] § According to Miyakis S, et al. [43].
Table
Table 2. Performance of the simplified diagnostic AIH criteria and the recent PBC guidelines [44,45] in the study population to identify SLE patients with confirmed AILD. Cut-off for the AIH criteria was set at ≥6 points (representing “probable AIH”). 95% confidence intervals are shown in parentheses.
Table 2. Performance of the simplified diagnostic AIH criteria and the recent PBC guidelines [44,45] in the study population to identify SLE patients with confirmed AILD. Cut-off for the AIH criteria was set at ≥6 points (representing “probable AIH”). 95% confidence intervals are shown in parentheses.
AIHPBC
Sensitivity1.00 (0.60–1.00)0.75 (0.28–0.97)
Specificity0.86 (0.82–0.90)0.99 (0.97–1.00)
Accuracy0.87 (0.82–0.90)0.99 (0.96–1.00)
PPV0.17 (0.09–0.31)0.50 (0.19–0.81)
NPV1.00 (0.98–1.00)1.00 (0.98–1.00)
PPV = Positive Predictive Value; NPV = Negative Predictive Value; AIH = autoimmune hepatitis; PBC = primary biliary cholangitis.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Heijke, R.; Ahmad, A.; Frodlund, M.; Wirestam, L.; Dahlström, Ö.; Dahle, C.; Kechagias, S.; Sjöwall, C. Usefulness of Clinical and Laboratory Criteria for Diagnosing Autoimmune Liver Disease among Patients with Systemic Lupus Erythematosus: An Observational Study. J. Clin. Med. 2021, 10, 3820. https://doi.org/10.3390/jcm10173820

AMA Style

Heijke R, Ahmad A, Frodlund M, Wirestam L, Dahlström Ö, Dahle C, Kechagias S, Sjöwall C. Usefulness of Clinical and Laboratory Criteria for Diagnosing Autoimmune Liver Disease among Patients with Systemic Lupus Erythematosus: An Observational Study. Journal of Clinical Medicine. 2021; 10(17):3820. https://doi.org/10.3390/jcm10173820

Chicago/Turabian Style

Heijke, Rebecca, Awais Ahmad, Martina Frodlund, Lina Wirestam, Örjan Dahlström, Charlotte Dahle, Stergios Kechagias, and Christopher Sjöwall. 2021. "Usefulness of Clinical and Laboratory Criteria for Diagnosing Autoimmune Liver Disease among Patients with Systemic Lupus Erythematosus: An Observational Study" Journal of Clinical Medicine 10, no. 17: 3820. https://doi.org/10.3390/jcm10173820

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop