An Unusual Association between Juvenile Spondylarthritis and Hepatobilliary Diseases

Affiliation: Pediatric and Adult Rheumatology Department, Emergency County Clinical Hospital “Sf Apostol Andrei”, Constanta City, Romania

Introduction

Celiac disease (CD) is an immune-mediated systemic disorder elicited by gluten and related prolamines in genetically susceptible individuals (1) Arthritis represents an extra-intestinal manifestation of several gastrointestinal diseases, including inflammatory bowel disease and CD. Moreover about two-thirds of nonsteroidal anti-inflammatory drug users demonstrate intestinal inflammation (2). 

Primary sclerosing cholangitis (PSC) is a chronic progressive disorder of unknown etiology that is characterized by inflammation, fibrosis, and structuring of medium and large ducts in the intrahepatic and/or extrahepatic biliary tree; can lead to complications of cholestasis and hepatic failure (3).

Case Presentation

A 13-year-old female presented to our hospital with a history of thoracic pain lasting for two years, with MRI evidence of inflammation at the costo-vertebral levels T4-T7. Her past medical history included intermittent hepatic cytolysis for one year and colicky abdominal pain occurring every two months.

Biologically, the patient had intermittently positive C-reactive protein (CRP), negative immunological tests (rheumatoid factor, ANA, ASMA, AMA), and was weakly positive for GP210. HLA-B27 was negative.

The episodes of abdominal pain coincided with peaks of hepatic cytolysis, occurring approximately every 3–6 months during the first year of illness. This was followed by the onset of moderate and persistent hepatic cholestasis. Apparently, the abdominal symptoms and hepatic cytolysis improved with a strict gluten-free diet, raising an initial suspicion of celiac disease despite the seronegativity for anti-endomysium and anti-transglutaminase antibodies (chart). Given this, immunosuppressive therapy with azathioprine was initiated between October 2022 and March 2023. On October 14, 2024, a cholangio-MRI was performed, revealing severe stenosis with post-stenotic dilation at the level of the left hepatic duct and moderate stenosis of the right hepatic duct, suggestive of sclerosing cholangitis. Additionally, the adolescent tested positive for ANCA antibodies at a titer of 1/80 (N<1/20).

It was decided to resume immunosuppressive therapy and continue biological and MRI monitoring.

Discussion

CD is the most common autoimmune enteropathy, whose clinical manifestations may range from a typical malabsorption syndrome to several apparently unrelated extra-intestinal symptoms. In patients with known CD, abnormal liver enzyme tests also occur (4), as one of the manifold extra-intestinal manifestations of CD. Although the spectrum of liver manifestations associated with celiac disease is particularly wide, two main forms of liver damage namely, cryptogenic and autoimmune, appear to be strictly related to gluten-sensitive enteropathy. The most frequent finding is represented by a cryptogenic hypertransaminasemia, observed in about half of the untreated celiac patients, as an expression of a mild liver dysfunction with a histological picture of nonspecific reactive hepatitis (celiac hepatitis), reverting to normal after 6-12 months of a strict gluten-free diet (5,6). Differently from cryptogenic liver injury, autoimmune liver dysfunction, found in celiac disease, does not usually improve after a gluten-free diet (5).

While CD commonly affects the liver, liver biopsy is not necessary to establish the diagnosis of celiac hepatitis or liver disease. Liver disease in CD can range from mild to severe hepatitis and is termed celiac hepatitis. Celiac hepatitis is characterized by portal and periportal inflammation and lobular inflammation. The inflammatory infiltrates are typically mononuclear and consist of mature lymphocytes with the architecture remaining preserved. These histologic features are, however, nonspecific. Other liver biopsy findings include steatosis, Kupffer cell hyperplasia and fibrosis and, rarely, cirrhosis (7).

CD may be associated with arthritis in some patients; articular involvement was peripheral in 10%, axial in 8% and combined in 9%. The arthritis is typically non erosive and can be either oligo-or-polyarticular.Joint symptoms may precede gastrointestinal manifestations and respond to a gluten-free diet and non steroidal antiphlogistic drugs; a complete remission of articular symptoms and a good puberal and intellectual growth have been observed (8). Some studies did not find a high rate of SpA in CD patients. In contrast, increased rates of autoimmune thyroiditis, SLE, IDDM, and psoriasis were seen in CD (9).

A variety of hepatic and biliary tract disorders may complicate the clinical course of celiac disease. Some of these have been hypothesized to share common genetic factors or have a common immunopathogenesis, such as primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune forms of hepatitis or cholangitis (10). Some authors consider that subjects with CD are more likely to have autoimmune hepatitis, PBC, primary sclerosing cholangitis (PSC) and nonalcoholic fatty liver disease (11). PSC and autoimmune hepatitis are recognized as co-occurring conditions associated with ulcerative colitis. However, the combination of ulcerative colitis, primary sclerosing cholangitis, liver cirrhosis, and celiac disease occurring concurrently has only been reported once before in a female patient despite that this combination of comorbidities is rare (12). A case report of autoimmune cholangitis, a cholestatic liver disorder with biochemical evidence of cholestasis, histological evidence of inflammatory bile duct damage and an absence of anti-mitochondrial antibodies, had been described in a patient with CD (10,13). 

Ankylosing spondylitis (AS) is a chronic systemic inflammatory disease affecting the joints of the spine and sacroiliac joints and only 0.2% of PBC patients had concurrent AS (14).

Conclusion

Sometimes, the axial inflammatory disease is less severe than hepatobiliary inflammation and the patient must be treated multidisciplinary in order to cover the whole involvement and to stop the associated diseases.

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