Still Disease and the Liver—An Underappreciated Association

Liver dysfunction is common in adult-onset Still disease (AOSD); indeed, liver dysfunction is one of the diagnostic criteria described by Yamaguchi and colleagues.¹ Among the collagen vascular diseases, AOSD is associated with the highest incidence of liver dysfunction, with a reported range of 35—85%.² Liver involvement in AOSD can vary from asymptomatic aminotransferase elevations to life-threatening fulminant hepatic failure (FHF) requiring liver transplantation (LT). Liver dysfunction and FHF may occur at the time of AOSD diagnosis, during the corticosteroid taper, or many years after diagnosis when symptoms are well controlled.^3,4 In the case by Hogan and colleagues, the authors describe a case of AOSD with severe hepatic dysfunction that was successfully treated with parenteral corticosteroid therapy; had this therapy not been successful, this patient could have developed FHF and had a poor outcome.⁵ This case highlights some pertinent issues for clinicians who manage these complex and potentially fatal cases.

Symptoms of AOSD can be easily overlooked or attributed to another diagnosis, as these symptoms can be nonspecific and may overlap with other diseases. Indeed, the patient described by Hogan and colleagues was evaluated by 3 physicians (a primary care physician, a rheumatologist, and a dermatologist) without a definitive diagnosis being made; the patient was then given a trial of prednisone and subsequently commenced on sulfasalazine by a second rheumatologist but did not show much improvement.

Liver toxicity secondary to sulfasalazine has been reported in patients with AOSD. Caspi and colleagues reported 2 young adults with juvenile rheumatoid arthritis who developed abnormal liver chemistry test results following treatment with sulfasalazine at doses of 1.5 g and 2 g daily; these abnormalities resolved with discontinuation of the drug.⁶ Liver dysfunction is known to occur at even lower doses of sulfasalazine (500 mg twice daily).⁷ As sulfasalazine is commonly prescribed for rheumatologic disorders, clinicians should be cognizant of the fact that it can cause liver dysfunction, even at low doses, in patients with AOSD.

Clinicians should not attribute liver dysfunction in AOSD patients to an associated autoimmune liver disease or autoimmune hepatitis (AIH) until a thorough evaluation has been completed. A positive antinuclear antibody (ANA) test result is not sufficient to diagnose AIH, as ANA is positive in up to 10% of AOSD patients and the general population; hypergammaglobulinemia is also common in AOSD.⁸

Liver biopsy findings are important when establishing a diagnosis of AIH in patients with AOSD. Histologic features of AOSD patients with liver dysfunction include periportal mononuclear infiltrates, Kupffer-cell hyperplasia, lobular inflammation, focal hepatocellular degeneration, periportal fibrosis, and massive or submassive hepatic necrosis. Ground glass—like cytoplasmic inclusions typically seen in chronic hepatitis B infection and sinusoidal dilatation typically associated with venous outflow impairment have also been described in AOSD patients with elevated liver enzyme levels.^9,10 The utility of a liver biopsy in patients with AOSD and liver dysfunction is debatable.¹¹ Although its direct role in establishing the diagnosis of AOSD is limited, liver histology may provide valuable information regarding previously undiagnosed concomitant liver pathology, which may influence the therapeutic strategy and eventual outcome of liver dysfunction in patients with AOSD.

A thorough search for previously undiagnosed hepatitis B virus (HBV) infection is also vital (including assessment of hepatitis B core antibody and hepatitis B surface antibody status if hepatitis B surface antigen testing is negative), as FHF secondary to HBV reactivation is well reported in patients on steroid therapy, chemotherapy, and anti—tumor necrosis factor (anti-TNF) agents.^12–15 Antiviral drugs must be commenced if HBV infection is confirmed. Michel and colleagues described a patient with AOSD and inactive chronic HBV infection who developed FHF requiring LT after the second dose of infliximab (Remicade, Janssen).¹⁶ Interestingly, there was no evidence (either serologic or histologic) for HBV reactivation as the cause of hepatic failure; the authors concluded that infliximab per se was the primary cause of the fulminant hepatitis.¹⁶ Infliximab-induced AIH is well described and has also been reported to cause FHF requiring LT.^17–19 Overall, causes of liver dysfunction in patients with collagen vascular diseases include drug-induced liver injury (26.1%), primary biliary cirrhosis (15.9%), fatty liver (7.6%), AIH (4.2%), viral hepatitis (1.3%), and the collagen vascular disease itself (15.5%). Collagen vascular disease itself is reported to be the most common cause of liver dysfunction in patients with AOSD.²

Portal vein thrombosis in the setting of AOSD with mildly elevated liver enzyme levels has been described and reinforces the importance of liver imaging in these patients.²⁰ Hemophagocytic syndrome (HPS) is associated with AOSD in up to 12% of cases and may induce FHF.²¹ HPS, also known as macrophage activation syndrome, is a severe and potentially life-threatening condition that can be induced by chronic rheumatic diseases, including AOSD.²² This condition is characterized by fever, hepatosplenomegaly, lymphadenopathy, skin rash, lung infiltration, and liver dysfunction. Coagulopathy, hyperferritinemia, and hypertriglyceridemia are common. A conclusive diagnosis is established by histology demonstrating phagocytosis of hematopoietic precursor cells in the bone marrow, lymph nodes, liver, or spleen. Current therapy for HPS includes treatment of the underlying disease, intensification of immunosuppression, chemotherapy, plasmapheresis, whole blood exchange, and bone marrow or stem cell transplantation.¹⁷

As Hogan and colleagues mention in their report, the immunologic pathways involved in the pathogenesis of AOSD are of increasing and significant interest.⁵ Several cytokines have been well characterized in the pathogenesis of AOSD, including interleukin (IL)-1, IL-6, IL-18, and TNF-α.²³ IL-18, in particular, is thought to play a pivotal role in the inflammatory cascade by orchestrating the T helper 1 cell response and inducing other cytokines, such as IL-1B, IL-8, TNF-α and interferon-γ. IL-18 is thought to mediate the hepatotoxic manifestations of AOSD and has been found to correlate significantly with serum aminotransferase levels.²⁴ Levels of circulating IL-18 are markedly increased in patients with FHF and acute hepatitis compared to patients with chronic liver diseases, suggesting that a substantial increase in IL-18 level is specific for and plays an important role in acute liver injury in humans.²⁵ Extremely high serum IL-18 levels have been reported in patients with FHF associated with AOSD. Priori and colleagues demonstrated a marked increase in IL-18 expression by activated macrophages and Kupffer cells within the liver parenchyma of a patient with AOSD and hepatic involvement who was resistant to corticosteroids but not in a control liver with drug-induced hepatitis; this increase in IL-18 expression was accompanied by an associated increase in IL-18 serum concentration.²⁶ Serum levels of IL-18 are now thought to correlate with disease activity and disease severity, and serum levels of IL-18 appear to serve as an early predictor of liver dysfunction. Insights into immunologic pathways and cytokine hyperproduction explain the rationale for employing anti-TNF agents (infliximab, etanercept [Enbrel, Immunex], adalimumab [Humira, Abbott]), anti—IL-1 (anakinra [Kineret, Biovitrum AB]), and anti—IL-6 (tocilizumab [Actemra, Genentech]) in the therapeutic strategy of AOSD.^27,28 These agents are used in addition to the conventional treatment regimens of nonsteroidal anti-inflammatory drugs, corticosteroids, and disease-modifying antirheumatic drugs (DMARDS) such as methotrexate, cyclosporine, hydroxychloroquine, gold, penicillamine, azathioprine, leflunomide, and cyclophosphamide.²⁹ Liver enzyme levels must be monitored in patients taking nonsteroidal anti-inflammatory drugs and DMARDS. Methotrexate is known to cause steatosis, hepatic fibrosis, and FHF; azathioprine is associated with nodular regenerative hyperplasia (a cause of noncirrhotic portal hypertension) and deranged liver enzyme levels.^29,30 Hydroxychloroquine and leflunomide have both been reported to cause severe hepatitis and FHF.^31,32

Some authors have suggested that the degree of liver dysfunction reflects the activity of the original disease, as liver enzyme levels improve in parallel with recovery of the collagen disease following steroid therapy, as in the case described by Hogan and coauthors.⁵ In a series of 104 AOSD patients in which over 60% of patients developed liver dysfunction at the onset of AOSD, 72% of patients achieved a complete response after 4 weeks of corticosteroid therapy; however, relapse rates up to 46.9% were noted.³³ Leukocytosis above 3 × 10⁴ cells/μL, a ferritin level greater than 1,500 ng/mL, an erythrocyte sedimentation rate above 100 mm/h, and a starting steroid dose below 40 mg/d of prednisone are all risk factors for disease relapse. Steroid-refractory AOSD cases have been successfully treated with anakinra, tocilizumab, and cyclosporine.^27,28,34,35 Occasionally, FHF ensues despite high-dose corticosteroid treatment and salvage therapies, with potentially fatal outcomes. Urgent transfer of the patient to a tertiary center and evaluation for LT is warranted under these circumstances. The timely diagnosis and treatment of AOSD, exhaustive exclusion of other liver pathology, recognition of potentially fatal hepatic failure, and expeditious evaluation for LT as described by Hogan and colleagues are key steps in managing patients with AOSD and liver dysfunction.⁵