Case of autoimmune hepatitis with overlap systemic lupus erythematosus
- 1 Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
- 2 Internal Medicine, The University of Kansas School of Medicine, Wichita, Kansas, USA
- 3 Internal Medicine, Mercy St Vicent Medical Center, Toledo, Ohio, USA
- 4 Gastroenterology and Hepatology, Icahn School of Medicine at Mount Sinai (Elmhurst) Hospital, New York City, New York, USA
- Correspondence to Dr Daniela Goyes; Daniela.GoyesVaca@luhs.org
Abstract
Autoimmune hepatitis (AIH) is an autoimmune liver disease characterised by the presence of autoantibodies including antinuclear antibodies, anti-smooth muscle antibody and hypergammaglobulinaemia. Systemic lupus erythematosus (SLE) is a systemic disease that can affect multiple organs. Coexistence of AIH and SLE as an overlap syndrome occurs in about 1%–2.6% of the AIH cases. Since both conditions share common autoimmune features, their coexistence can pose a diagnostic dilemma which can result in a delay in treatment. We present here a challenging case of a middle-aged woman with AIH in remission who later developed new-onset fatigue, pleural effusion and splenomegaly.
Background
Autoimmune hepatitis (AIH) is a chronic inflammation of the liver characterised by autoantibodies and globulins in serum. Patients with AIH usually have other concomitant diseases that shared the common immune-mediated pathogenesis such as autoimmune thyroiditis, primary biliary cholangitis and rheumatoid arthritis.1 2 AIH–systemic lupus erythematosus (SLE) overlap syndrome, however, is considered rare.2 AIH and SLE are different disease entities but have similar clinical manifestations.3 In late-onset SLE, pleuritis and/or pericarditis can be the primary presenting features.2 The coexistence of AIH and SLE can pose a diagnostic challenge and delays appropriate management.
Case presentation
Our patient is a 48-year-old Caucasian woman with a medical history of Hashimoto’s thyroiditis, hypertension, hyperlipidaemia and obesity. She initially presented with influenza-like illness and fatigue for 1–2 weeks. During that time, she also experienced urine discoloration, right upper quadrant pain and some loose stools. Physical examination was unremarkable. She had significantly elevated serum aminotransferases with alanine aminotransferase (ALT) 806 U/L, aspartate aminotransferase (AST) 724 U/L and alkaline phosphatase 343 U/L concerning for acute hepatitis. Her hepatic synthetic function tests reported international normalised ratio (INR) 1.2, bilirubin 7.8 mg/dL, direct bilirubin 5.4 mg/dL and albumin 3.8 g/dL. Subsequent work-up noted negative antinuclear antibody (ANA), positive anti-smooth muscle antibody (ASMA) 1:640, elevated IgG level at 2392 mg/dL and cytomegalovirus (CMV) IgM positive. Her liver biopsy was consistent with the diagnosis of AIH (figure 1A) with moderate to severe portal, periportal and lobular predominantly mononuclear inflammation with apoptotic hepatocytes (figure 1B) and prominent plasma cells (figure 1C). Specifically, there was no feature of acute CMV infection and absence of the typical owl’s eyes inclusion bodies. Of note, 20%–30% of patients with AIH have negative ANA at initial presentation.4 With the convincing pathological findings and other positive autoimmune markers, she was initiated on immunotherapy with azathioprine 50 mg and prednisone 40 mg daily and achieved normalisation of serum aminotransferases. Prednisone was gradually tapered off. Her AIH stayed in remission on maintenance azathioprine 25 mg daily.
(A) Liver biopsy. Moderate to severe portal, periportal and lobular predominantly mononuclear inflammation with prominent plasma cells and apoptotic hepatocytes. No confluent necrosis. The findings are consistent with severely active hepatitis with prominent plasma cell component. (B) Apoptotic hepatocyte. (C) Cluster of plasma cells.
Three years later, the patient presented with new-onset fatigue, left-sided pleuritic chest pain associated with progressive shortness of breath. Initial examination was unremarkable except for tachycardia.
Investigations
Due to worsening of pulmonary symptoms, she had further evaluation. Chest radiograph noted mediastinal widening and bilateral pleural effusions. Subsequent CT scan confirmed pleural effusion and there was an extensive mediastinal and axillary lymphadenopathy (figure 2). CT scan also reported enlarged spleen measuring 17.3 cm and many borderline enlarged retroperitoneal lymph nodes (figure 2).
Torso CT scan with contrast, October 2017. Bilateral pleural effusion and splenomegaly size of 17.3 cm.
Significant laboratory results were leucopenia 2000/μL, haemoglobin 104 g/L, platelet count 157×109/L. Her erythrocyte sedimentation rate was >130 mm/hour and C reactive protein was markedly elevated at 91.8 mg/dL. Her serum aminotransferases were elevated with ALT 126 IU/L, AST 335 IU/L and alkaline phosphatase 202 IU/L. Her hepatic synthetic function tests were also abnormal with INR 1.4, total bilirubin 1.3 mg/dL and albumin 2.9 g/dL.
Differential diagnosis
Given this spectrum of clinical findings, infectious work-up was initiated. She was again found to have positive IgM for CMV and valacyclovir 900 mg two times per day was initiated but discontinued when CMV PCR was negative. Her IgM for Lyme disease (Borrelia burgdorferi) was also tested positive and she received 2 weeks of doxycycline. She experienced increased shortness of breath despite the therapy.
The patient was subsequently hospitalised. Pleural fluid analysis showed an exudative effusion with pleural effusion protein to serum protein ratio 3.4, pleural effusion lactate dehydrogenase (LDH) to serum LDH ratio 0.64. Cytology was negative for neoplastic cells. Given her mother’s history of T-cell lymphoma, she underwent a bone marrow biopsy that was negative for high-grade lymphoma and there is no morphological features of leukaemia. In addition, she underwent cervical lymph node biopsy which was negative for any infectious and/or lymphoproliferative disorders. Tuberculosis testing with QuantiFERON-TB Gold and HIV test were negative. During her hospital stay, she experienced joint pain that involved bilateral knees, ankles, proximal interphalangeal, elbows, wrists, and right heel and mouth sore. Additional rheumatological evaluation revealed persistent cytopenia, now elevated ANA titre of 1:640 with diffuse pattern, positive double-stranded DNA, positive anti-Smith antibody (Smith-Ab), positive Sjogren’s antibody (SS-A) and low C3 level.
Her clinical and laboratory profiles met the diagnostic criteria of SLE with multiorgan involvement; namely, leucopenia, serositis, arthralgias, splenomegaly and lymphadenopathy with positive biochemical.5 The presentation was consistent with an overlap syndrome of reactivated AIH and SLE.
Treatment
She was started on prednisone 40 mg, hydroxychloroquine 200 mg two times per day and azathioprine 200 mg once daily. She achieved normalisation of serum aminotransferases (ALT 26 and AST 30 IU/L) and resolution of cytopenia within 2 months. Her repeat CT scan 2 months after initiation of therapy reported significant improvement of pleural effusion and reduced spleen size to 14.3 cm (figure 3).
Torso CT scan, December 2017. Resolution of pleural effusion with decrease size of spleen to 14.3 cm.
Her SLE and AIH remained in remission on dual therapy with low-dose prednisone 5 mg and azathioprine 250 mg daily, and her spleen size further reduced to 12 cm.
Outcome and follow-up
Her disease course has been marked by lupus flares and continuous steroid usage. She was started on belimumab in an attempt to wean her off of the steroids. She is currently on azathioprine, belimumab and tapering prednisone.
Discussion
AIH is a chronic inflammatory disorder of unknown aetiology that can affect patients of all races, ages and both genders.1 It is characterised by the presence of autoantibodies, and hepatitis with elevated serum aminotransferases and classical histological findings of portal and periportal inflammation, lymphoplasmacytic infiltration and rosetting of hepatocytes.1 6 According to the scoring system of the International Autoimmune Hepatitis Group for the diagnosis of AIH, our patient reached the criteria based on female sex (+2), ALT:AST ratio <1.5 (343:724) (+2), elevated IgG (2392) (+3), ASMA >1:80 (+3), negative hepatitis viral markers (+3), negative drug history (+1), average alcohol intake <25 g/day (+2), liver biopsy with predominantly lymphoplasmacytic infiltrate (+1), presence of other autoimmune diseases such as Hashimoto’s thyroiditis (+2). The pretreatment aggregate score was 19 total points, which indicated a definite diagnosis.7 8 AIH is further subdivided into two types based on the presence of specific autoantibodies. Type 1 corresponds to a positive ANA and/or ASMA, while type 2 is positive for anti-liver–kidney microsomal antibody type 1 and/or anti-liver cytosol type 1.1
AIH broadly falls into two major spectrums; one with predominantly hepatic involvement and the other one being coexistence of AIH with extrahepatic manifestations called overlap syndrome.9 Concurrent extrahepatic manifestations including thyroiditis, diabetes type 1 and ulcerative colitis, range from 20% to 49%.10 Other conditions such as rheumatoid arthritis (2%–4%), Sjogren syndrome (1%–7%) and SLE (1%–2.6%) have been reported at a lower frequency.10
SLE is a chronic autoimmune condition characterised by multisystem involvement that leads to variable clinical and serological manifestations.11 The complexity of its clinical presentation makes SLE difficult to define. New classification criteria were developed by the European League Against Rheumatism and the American College of Rheumatology.5 According to this criterion, the patient must have a score of 10 or more to fulfil the diagnosis.5 Our patient had leucopenia (+3), oral sore (+2), pleural effusion (+5), joint involvement (+6), low C3 level (+3), positive Smith-Ab and SS-A (+6), with a total score of 25. She, therefore, fulfilled the criteria for a diagnosis of SLE.
Hepatic involvement in SLE is not uncommon. Transient slight non-specific elevation in the serum aminotransferase can occur in 25%–50% of the cases.12 Distinct liver pathology has been reported in patients with SLE. The aetiology of liver conditions usually falls into three major categories: (1) immune-mediated hepatic involvement, (2) vascular-related hepatic involvement13 and (3) non-autoimmune-mediated disease.12
Immune-mediated hepatic involvement includes lupus hepatitis and SLE with autoimmune liver diseases such as illustrated by our case of AIH–SLE overlap syndrome. SLE and AIH are different diseases, even when they share clinical, serological and biochemical markers.12 Few studies suggest existence of positive anti-ribosomal P antibodies highly indicative marker of AIH–SLE overlap syndrome and it does not represent lupus hepatitis only.14 However, liver biopsy is considered the most reliable tool to differentiate the aetiology of the liver inflammation.15 The presence of predominantly lobular inflammation with a slight lymphoid infiltrates is more suggestive of SLE.15
Majority of immune-mediated hepatitis present with acute elevation in liver enzymes associated with flare symptoms, such as fatigue, low-grade fever, joint pain with evidence of serositis including pericarditis and pleuritis.16 Also, pleuritis is the most common pulmonary manifestation of SLE.17 In a prospective analysis that investigated the characteristics of pleural effusion in SLE, 3 of 17 patients had pleural effusion as their first manifestation of the disease. They also showed haematological abnormalities such as leucopenia similar to our patient.17
Another clinical sign in our case report is splenomegaly during acute SLE presentation. That posed a diagnostic challenge for the presence of splenomegaly in this patient with pre-existing AIH broadened the differential diagnosis to include portal hypertension secondary to progressive advanced hepatic fibrosis. As the SLE improved, the spleen returned to normal size. The spleen enlargement in SLE is due to a response to an increased demand for stem cell resources from bone marrow to spleen which is driven by the granulocyte-colony stimulating factor.18
Management of AIH–SLE overlap syndrome and AIH is similar. Early introduction of glucocorticoids is the gold-standard therapy followed by an immunosuppression agent such as azathioprine, a calcineurin inhibitor. Some patients, however, require more aggressive immunotherapy with dual immunosuppressive therapy to achieve remission.
The second category of hepatic involvement in SLE is attributed to the presence of antiphospholipid antibodies which has been reported in ~18% cases of SLE.13 19 These antibodies can lead to thrombosis of hepatic venous outflow which produces congestion of the liver and manifests as Budd-Chiari syndrome.13
Third category is non-autoimmune-mediated liver damage, such as viral hepatitis infection or drug-induced injury in the context of increased susceptibility to SLE.12
Another important learning point in this case is the false-positive serology for CMV and Lyme infection which can easily be misinterpreted and result in delay in management of AIH–SLE overlap syndrome. While it is essential to rule out infectious process in any immunocompromised patients, it is important to recognise that false-positive serological markers for infections such as HIV, infectious mononucleosis, syphilis, hepatitis C, dengue fever and Lyme disease are common in autoimmune conditions.20 For these infectious aetiologies, a positive serological test needs to be further validated by a confirmatory diagnostic modality such as reverse transcription-PCR.
Learning points
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This case highlights the importance of a multidisciplinary care to improve patient outcomes.
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Patients can struggle to get appropriate treatment and care due to lack of awareness of rare diseases that can be related to AIH.
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We recognise that false-positive serological markers for infections are common in autoimmune conditions.
Acknowledgments
Dr Daryl Lau for case discussion, guidance and proofreading.
Footnotes
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Twitter @dgoyesv, @vijayramreddym, @hepatology
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DG and VRM contributed equally.
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Contributors DG, VM, RI and AA-K—planning. DG, VM, RI and AA-K—conduct. DG, VM, RI and AA-K—reporting. DG, VM, RI and AA-K—conception and design. DG, VM, RI and AA-K—writing (review and editing).
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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.
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Competing interests None declared.
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Patient consent for publication Obtained.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.
References
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