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Rheumatology 2001; 40: 102-106
© 2001 British Society for Rheumatology

Autoimmune hepatitis and systemic sclerosis: a new overlap syndrome?

I. Marie, H. Levesque, J. L. Tranvouez1, A. François2, G. Riachi3, N. Cailleux and H. Courtois

Department of Internal Medicine, Centre Hospitalier Universitaire de Rouen-Boisguillaume, 76031 Rouen Cedex,
1 Department of Gastroenterology, Centre Hospitalier Universitaire du Havre, 76083 Le Havre Cedex,
2 Department of Cytology and Pathology, Centre Hospitalier Universitaire de Rouen, 76031 Rouen Cedex and
3 Department of Gastroenterology, Centre Hospitalier Universitaire de Rouen, 76031 Rouen Cedex, France


   Abstract
Top
 Abstract
Introduction
 Case reports
 Discussion
 References
 
Objective. We report the cases of two patients with the complete CREST variant (calcinosis, Raynaud's phenomenon, oesophageal dysmotility, sclerodactyly, telangiectasia) of systemic sclerosis (SSc) who developed autoimmune hepatitis.

Results. Our findings suggest that autoimmune hepatitis can be considered to be one of the liver manifestations associated with SSc. Our data also indicate that, because liver involvement may precede skin manifestations, evaluation for SSc is appropriate when autoimmune hepatitis is noted, and that the evaluation should include clinical examination, testing for antinuclear antibodies (especially for anticentromere antibodies) and nailfold capillaroscopy.

Conclusions. From a practical point of view, our two cases emphasize that suspicion of autoimmune hepatitis in SSc patients presenting with cytolytic hepatitis will help to achieve both accurate diagnosis and optimal management.

KEY WORDS: Systemic sclerosis, CREST syndrome, Autoimmune hepatitis.


   Introduction
Top
 Abstract
 Introduction
Case reports
 Discussion
 References
 
Autoimmune hepatitis is an uncommon disorder that is characterized by both biochemical abnormalities and histological liver damage [1–3], i.e. (i) blood hypergammaglobulinaemia with a selective increase in IgG concentration; (ii) serum autoantibodies, i.e. typically antinuclear antibodies, antibodies to smooth muscle, actin, liver–kidney microsome type 1 (anti-LKM1) and antibodies to asialoglycoprotein receptor, soluble liver antigen, liver-pancreas antibody (anti-LP), liver cytosol type 1 (anti-LC1) or perinuclear-staining antineutrophil cytoplasmic antibodies; (iii) interface hepatitis, with piecemeal necrosis and periportal lymphocytoplasmocytic inflammatory infiltrates on histological examination of liver biopsy specimens; and (iv) the absence of evidence of concomitant viral hepatitis (i.e. negative serology for cytomegalovirus, Epstein–Barr virus, herpes simplex virus, hepatitis B surface antigen, antibodies to hepatitis B core antigen, hepatitis C virus and hepatitis A virus). Autoimmune hepatitis has been reported in patients with various diseases, including insulin-dependent diabetes, vitiligo, glomerulonephritis and autoimmune haemolytic anaemia [3, 4]. However, autoimmune hepatitis related to connective tissue disorders has been described as occurring rarely, for example during the course of systemic lupus erythematosus, Sjögren's syndrome and mixed connective tissue diseases [5]. We observed two cases of particular interest, in which the patients with the complete CREST variant (calcinosis, Raynaud's phenomenon, oesophageal dysmotility, sclerodactyly, telangiectasia) of systemic sclerosis (SSc) developed autoimmune hepatitis.


   Case reports
Top
 Abstract
 Introduction
 Case reports
Discussion
 References
 
Patient 1
A 67-yr-old woman was diagnosed with complete CREST variant of SSc in 1990. The cutaneous impairment of the CREST syndrome was characterized by limited cutaneous sclerosis associated with telangiectasias, pitting scars and cutis calcinosis. Systemic manifestations of CREST syndrome included: (i) Raynaud's phenomenon; (ii) oesophageal involvement, characterized by both the absence of peristalsis in the lower two-thirds of the esophageal body and low pressure in the lower oesophageal sphincter; and (iii) interstitial lung disease, i.e. mild bibasilar pulmonary shadowing on computed tomography (CT) and both decreased vital capacity and diffusing capacity of carbon monoxide on pulmonary function tests (92 and 68% of predicted values respectively). Autoantibody screening tests were positive for antinuclear antibodies (1:600) and anticentromere antibody. She received treatment with combined diltiazem and cisapride. In April 1997, the patient presented with mild pain involving the right hypochondrium area. General physical examination was otherwise normal. Liver tests revealed alanine aminotransferase (GPT) 240 U/l (normal range 3–21), aspartate aminotransferase (GOT) 223 U/l (normal range 3–26), {gamma}-glu-tamyltransferase (GGT) 510 U/l (normal range 5–25), alkaline phosphatase 250 U/l (normal range 73–207) and total bilirubin 5 U/l (normal range 2–18). Other routine laboratory investigations were normal, notably prothrombin time (90%). Blood electrophoresis revealed total protein 76 g/l, albumin 38 g/l, polyclonal gammopathy with increased IgG (21 g/l; normal range 6.75–12.65). Abdominal ultrasound examination was normal. Viral serologies (cytomegalovirus, Epstein–Barr virus, herpes simplex virus, hepatitis B surface antigen, antibodies to hepatitis B core antigen, hepatitis C virus, hepatitis A virus, human immunodeficiency virus) were negative. Autoantibody screening was positive for antinuclear antibodies (1: 1000) and anticentromere antibody, and negative for cryoglobulinaemia, antimitochondrial and anti-smooth muscle antibodies, anti-LKM1 antibodies, anticardiolipin and antiphospholipid antibodies and lupus-like anticoagulant. Liver biopsy specimens demonstrated damage consistent with chronic active autoimmune hepatitis, i.e. portal inflammatory infiltrates, composed of both lymphocytes and plasma cells, associated with piecemeal necrosis; lobular necrosis, porto-portal bridging fibrosis and cirrhotic nodules were absent. The diagnosis of autoimmune hepatitis in a patient with CREST syndrome was made. The patient was treated with oral steroid therapy, at an initial dose of 0.7 mg/kg daily (i.e. prednisone 40 mg per day), which resulted in complete resolution of abdominal pain and marked improvement of liver test abnormalities. In December 1999, when the patient was taking prednisone 9 mg daily, there were no abdominal symptoms, and liver tests showed GPT 22 U/l, GOT 14 U/l, GGT 37 U/l, alkaline phosphatase 128 U/l and total bilirubin 3 U/l.

Patient 2
A 48-yr-old woman had a 10-yr history of Raynaud's phenomenon. In February 1999, the patient was admitted for dysphagia that had been developing for 1 month. Physical examination revealed limited cutaneous sclerosis and telangiectasias, and was otherwise normal. Autoantibody screening was positive for antinuclear antibodies (1:1000) and anticentromere antibody. Nailfold capillaroscopy showed organic microangiopathy with enlarged capillary loops. Gastroscopy was normal, and revealed no evidence of oesophagitis. Oesophageal manometry demonstrated low pressure in the lower oesophageal sphincter and an absence of peristalsis in the lower two-thirds of the oesophageal body. Investigations, including pulmonary CT scanning and function tests and salivary gland histology, were within normal limits. CREST syndrome was diagnosed. Laboratory findings were abnormal for GPT (175 U/l), GOT (147 U/l), GGT (250 U/l) and alkaline phosphatase (245 U/l). Blood electrophoresis revealed polyclonal gammopathy, with increased IgG at 35 g/l. Abdominal ultrasound examination was normal. Viral serologies (cytomegalovirus, Epstein–Barr virus, herpes simplex virus, hepatitis B and C, human immunodeficiency virus) were negative. Liver biopsy specimens revealed damage consistent with chronic active autoimmune hepatitis. Autoantibody screening was negative for antimitochondrial and anti-smooth muscle antibodies, anti-LKM1 antibodies, anticardiolipin and antiphospholipid antibodies, lupus-like anticoagulant, cryoglobulinaemia and antineutrophil cytoplasmic anti-bodies. The diagnosis was autoimmune hepatitis in a patient with CREST syndrome. The patient was treated with combined diltiazem and cisapride. Prednisone was started concomitantly at 0.5 mg/kg daily (i.e. 35 mg/day), in association with azathioprine, and this treatment resulted in the complete disappearance of liver test abnormalities. In March 2000, when the patient was taking both prednisone 15 mg daily and azathioprine, there were no abdominal symptoms and liver tests showed GPT 25 U/l, GOT 18 U/l, GGT 27 U/l and alkaline phosphatase 77 U/l.


   Discussion
Top
 Abstract
 Introduction
 Case reports
 Discussion
References
 
SSc is a systemic inflammatory disorder affecting the skin and other organs, especially the gastrointestinal tract [6–10]. Although the prevalence of oesophageal and anorectal impairment in patients with SSc has been reported to be as high as 90% [6–11], liver involvement is considered to be rare in SSc, usually arising during the course of the disease [6, 8, 10–14]. Abu-Shakra et al. [12] noted that only four of 262 SSc patients (1.5%) had chronic liver disease. In a postmortem series of 57 SSc patients, D'Angelo et al. [14] found histological liver damage in 8.8% of cases.

Primary biliary cirrhosis is the liver disorder that is the most frequently encountered in SSc patients [6, 8, 10, 11, 15–26]. It is a chronic progressive cholestatic disease characterized by the destruction of intrahepatic bile ducts and inflammation within the portal tracts, leading to cirrhosis [20]. Largier [27] observed that the prevalence of primary biliary cirrhosis was as high as 51.2% in SSc patients (22 of 43 patients) with liver dysfunction. On the other hand, many authors demonstrated that clinical manifestations of SSc were common in primary biliary cirrhosis, occurring in as many as 3–18% of patients [17, 18, 28]; the majority of these patients, with both SSc and primary biliary cirrhosis, had anticentromere antibody. In a series of 83 patients with primary biliary cirrhosis [17], 17% of patients had concomitant SSc (two with CREST syndrome and 12 with limited cutaneous SSc). Culp et al [18] noted that 20 of 113 patients with primary biliary cirrhosis (18%) had clinical evidence of SSc and variants (eight with CREST syndrome, three with SSc and nine with Raynaud's phenomenon). Interestingly, primary biliary cirrhosis may be more frequent in SSc patients with anticentromere antibody than in those without it (15.8 vs 0%), but the role of anticentromere antibody in the genesis of liver damage remains unclear in SSc [29].

Nodular regenerative hyperplasia of the liver has been reported in association with SSc relatively uncommonly [11, 30–33]. It is defined histologically by nodules of hyperplastic hepatocytes within the liver (without disturbance of the architectural framework, fibrosis or hepatocyte necrosis), and may be responsible for dramatic complications related to portal hypertension in SSc patients [30–33]. As few authors [21] have found both histological damage of nodular regenerative hyperplasia of the liver and primary biliary cirrhosis in patients with CREST syndrome, nodular regenerative hyperplasia of the liver may represent an early histological stage of primary biliary cirrhosis.

Finally, a few isolated observations of SSc patients presenting with additional liver manifestations have been described: (i) idiopathic portal hypertension [22, 34, 35]; (ii) spontaneous rupture of the liver [22]; (iii) massive infarction of the liver [36] (the authors postulated that underlying histological sclerosis of the splanchnic vessels, with large swollen, loosely arranged endothelial cells, was probably the factor that precipitated vasospasm, responsible for the massive necrosis of the liver); and (iv) hepatic duct obstruction related to vasculitis [22].

Our two unusual cases are reminiscent of those reported by Ishikawa et al [37] and Yabe et al [38], who described two Japanese patients with CREST syndrome and autoimmune hepatitis. Twenty-three patients with complete CREST variant were seen at the University of Rouen medical centre between 1990 and 1999. In our population, the prevalence of autoimmune hepatitis was therefore 8.7% (2/23) in this subgroup of SSc patients. In this instance, the diagnosis of autoimmune hepatitis was reasonably definite because our two Caucasian patients with CREST syndrome fulfilled all the diagnostic criteria of the International Auto-immune Hepatitis Group for autoimmune hepatitis [1, 2], i.e. (i) increased GOT and GPT levels with alkaline phosphatase levels less than three times the normal value; (ii) total {gamma}-globulin or IgG levels more than 1.5 times the upper limit of normal; and (iii) high titres of antinuclear antibodies (>1:80). Our patients were negative for anti-mitochondrial, anti-smooth muscle, anti-LKM1 and antineutrophil cytoplasmic antibodies [other liver autoantibodies associated with autoimmune hepatitis (i.e. antibodies to asialoglycoprotein receptor, soluble liver antigen, liver–pancreas and liver cytosol type) were not tested in either patient, as the detection of these antibodies is not yet available in our University hospital]; (iv) characteristic histological liver damage, i.e. interface or periportal hepatitis (histological evidence of damage associated with primary biliary cirrhosis was absent, which excluded primary biliary cirrhosis/autoimmune hepatitis overlap); (v) viral serologies (hepatitis A, B and C, cytomegalovirus, Epstein–Barr virus) were all negative; and (vi) there was no evidence for other causes of liver disorders. The patients had no history of alcohol abuse and they had not received drugs that can idiosyncratically cause hepatitis, including those that can mimic autoimmune hepatitis. Although diltiazem and cisapride have been shown to cause biochemical liver test abnormalities and even clinical hepatitis occasionally, they were clearly not implicated in Patient 2 because this therapy was instituted after the diagnosis of autoimmune hepatitis. Hepatotoxicity of both diltiazem and cisapride can also be excluded in Patient 1, as biochemical liver values returned to normal after the initiation of steroid therapy.

The pathological mechanisms of autoimmune hepatitis in our two patients with CREST syndrome remain unclear, which raises the question of whether the condition arose through a causal association (as part of a continuum) or by chance. However, autoimmune hepatitis may be due in part to dysfunction of both cell and humoral immunity related to SSc, as anticentromere antibody has been detected in 0–13% of patients with autoimmune hepatitis [28, 37, 38]. No definite conclusion can be drawn, and these findings warrant further investigation.

The treatment of autoimmune hepatitis is difficult in patients with SSc, as patients (mainly with diffuse cutaneous SSc) receiving more than 15 mg prednisone daily are at high risk of renal crisis related to their SSc [39]. Our two patients with CREST syndrome were followed very closely initially, and the outcome of their autoimmune hepatitis was favourable. Patient 1 had a disease course that was benign both clinically and biochemically with steroid therapy. Our findings are in accordance with those of other authors [37, 38], who described two SSc patients who showed improvement of autoimmune hepatitis with prednisone as a monotherapy. Patient 2 was successfully given combined therapy with prednisone and azathioprine. Neither of these patients developed complications related to steroid therapy.

We suggest that autoimmune hepatitis can be considered to be one of the liver manifestations associated with SSc. Autoimmune hepatitis occurred late in the course of SSc (at the 7-yr follow-up) in Patient 1, whereas the diagnoses of SSc and autoimmune hepatitis were concomitant in Patient 2. Our findings therefore indicate that, because liver involvement may precede skin manifestations, evaluation for SSc is appropriate when autoimmune hepatitis is noted, and this evaluation should include clinical examination, testing for antinuclear antibodies (especially for anticentromere antibodies) and nailfold capillaroscopy. From a practical point of view, our data also emphasize that suspicion of autoimmune hepatitis in SSc patients presenting with cytolytic hepatitis will help to achieve both accurate diagnosis and optimal management. Finally, physicians, particularly rheumatologists and internists, should be aware of the possibility of such liver damage in patients with SSc.


   Notes
 
Correspondence to: I. Marie, 16 rue Arthur Duval, 76300 Sotteville-lès-Rouen, France Back


   References
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 Abstract
 Introduction
 Case reports
 Discussion
 References
 

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Submitted 18 May 2000; Accepted 4 August 2000


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