SLE is a chronic, systemic autoimmune disease that primarily affects young women. SLE is characterized by a complex and heterogeneous clinical presentation, with the potential to involve multiple organs and tissues throughout the body. The liver is one of the important target organs in SLE. Reports indicate that 25%-50% of SLE patients may experience liver abnormalities during the course of the disease [1]. While the role of SLE in causing asymptomatic liver disease is still debated, many experts recognize that SLE often leads to subclinical liver dysfunction, known as lupus hepatitis [2]. Lupus hepatitis is a nonspecific reactive liver disease primarily caused by complement deposition and vasculitis-induced organic damage in the liver [3–4]. Lupus hepatitis is frequently associated with SLE flares or clinical activity, and it can be diagnosed only by ruling out secondary causes of liver involvement [2]. In the reported case, the patient was diagnosed with SLE and presented with asymptomatic elevation of liver enzymes. We ruled out drug-induced liver injury, fatty liver, autoimmune liver disease, and viral hepatitis, suggesting that the asymptomatic elevation of liver enzymes was likely due to SLE itself. However, despite active treatment for SLE and improvement in other symptoms, the asymptomatic elevation of liver enzymes persisted for more than 2 years, which prompted us to actively search for the underlying cause.
Previous studies have indicated that drug-induced liver injury is a major cause of abnormal liver function in SLE patients, with an occurrence rate of approximately 31% in SLE patients with liver dysfunction [5]. SLE patients are prone to drug-induced liver injury due to their high levels of oxidative stress [6]. Nonsteroidal anti-inflammatory drugs (NSAIDs), azathioprine, and methotrexate are the most common drugs associated with liver injury, followed by cyclophosphamide and leflunomide. HCQ, MMF, cyclosporine, tacrolimus, and corticosteroids rarely cause liver injury. In most cases, drug-induced liver dysfunction is mild and transient, and liver function can usually recover with a dose reduction or discontinuation of the medication [7–8]. Although HCQ and MMF rarely cause liver damage, we recommended discontinuing these medications to exclude drug-induced liver injury. However, after the discontinuation of these medications, the patient’s liver function did not improve. Instead, the SLE itself became active.
Autoimmune hepatitis (AIH) is a chronic liver disease of unknown aetiology characterized by a T-cell-mediated immune response against liver self-antigens, leading to hepatocyte necrosis and inflammation. Diagnosis is based on elevated serum transaminases, increased levels of IgG, presence of autoantibodies (ANA, anti-smooth muscle antibodies, and anti-liver-kidney microsome type 1 antibodies), and histological findings in liver biopsy samples, such as interface hepatitis and lymphoplasmacytic infiltrates [9]. The occurrence rate of AIH in SLE patients with liver dysfunction is approximately 5%-10% [10–11]. In the patient whose case is reported here, AIH-related antibodies were negative, but the liver biopsy sample showed pathological features similar to AIH, although nonspecific.
SLE patients undergoing immunosuppressive therapy are more susceptible to viral infections, which can result in liver dysfunction [10]. The patient was screened for hepatitis B virus, hepatitis C virus, Epstein‒Barr virus, herpes simplex virus, varicella-zoster virus, and human immunodeficiency virus, and the results of all these tests were negative.
WD is a rare autosomal-recessive disorder characterized by copper metabolism dysfunction due to mutations in the ATP7B gene. The resulting copper toxicity primarily affects the liver and brain [12]. WD is classified into different types based on symptoms, including hepatic, neurological, mixed, and other types. In adolescents, the hepatic type has a higher occurrence rate than other types. The liver manifestations in WD patients can vary, ranging from asymptomatic elevation of liver enzymes to significant liver cirrhosis (compensated or decompensated) or acute liver failure. Reports indicate that 18%-23% of WD patients experience asymptomatic elevation of liver enzymes [13]. Similarly, the most common liver manifestation in SLE patients is asymptomatic elevation of liver enzymes, which was the main reason for the delayed diagnosis for our patient. However, in SLE patients who respond well to effective treatment, liver function abnormalities typically improve. Therefore, in SLE patients with well-controlled disease who present with unexplained elevation of liver enzymes, the possibility of WD should be considered.
K-F rings are a typical ophthalmic manifestation of WD. Reports indicate that K-F rings are present in nearly 100% of patients with neurological WD, 40%-50% of patients with hepatic involvement, and 20%-30% of asymptomatic patients [14]. In our patient, there were no K-F rings in either eye. Therefore, an absence of K-F rings does not exclude the diagnosis of hepatic WD. Serum ceruloplasmin measurement is a safe and simple screening test for WD. However, importantly, serum ceruloplasmin can also be decreased in diseases such as Menkes disease, nephrotic syndrome, protein-losing enteropathy, and various chronic liver diseases. Additionally, in 5%-15% of WD patients, ceruloplasmin levels may be normal or only slightly lower than the normal range [15]. In the cases of WD reported at our centre, decreased ceruloplasmin levels were detected at the time of diagnosis. However, the presence of LN in the patient, presenting as nephrotic syndrome, led us to consider that the decreased ceruloplasmin levels may be related to significant protein loss in LN, which was also a factor contributing to the delayed diagnosis. The measurement of 24-hour urinary copper excretion may be the best screening test for WD, and a value exceeding 100 µg in a 24-hour urine collection has diagnostic value for WD [16]. Therefore, in patients suspected of having hepatolenticular degeneration, serum ceruloplasmin and 24-hour urinary copper excretion should be examined. Especially in patients with significant proteinuria and decreased ceruloplasmin levels where the cause of the decrease cannot be distinguished due to protein loss, further clarification can be achieved through the measurement of 24-hour urinary copper excretion.
The treatment of WD includes drug therapy, symptomatic therapy, diet therapy, and liver transplantation. Penicillamine is commonly used as the first-line treatment in acute and/or symptomatic WD [12]. However, penicillamine is not recommended in patients with coexisting WD and SLE due to the potential induction of lupus. In the limited literature available on the coexistence of WD and SLE, we identified nine other patients apart from our patient [17–25]. Among these patients, six received therapy with intravenous sodium dimercaptopropane sulfonate and/or oral zinc sulfate, which led to an improvement in WD symptoms [17, 20, 22–25]. In one patient, penicillamine was initially prescribed but was changed to oral zinc due to worsening central nervous system symptoms after two weeks; however, the patient unfortunately passed away 41 days after admission [21]. Plasma exchange was used to treat fulminant liver failure in another patient, but the patient died five days after admission [18]. Our patient underwent liver transplantation three months after being diagnosed with WD because her liver enzymes remained abnormal despite receiving oral zinc. Liver transplantation is a curative option, as it replaces the affected liver, provides normal ATP7B protein, restores normal biliary copper excretion (preventing disease recurrence), and facilitates the removal of copper from extrahepatic sites where it may be toxic [26]. Liver transplantation is indicated for patients with liver disease who do not respond to medical treatment, have fulminant or advanced liver failure, and/or significant portal hypertension [27]. With advancements in liver transplantation technology, the clinical indications for WD patients receiving liver transplantation have been expanded, which has led to satisfactory outcomes. Studies in which large databases were analysed have reported one-year and five-year survival rates of approximately 90% in WD children who underwent liver transplantation [28, 29]. Unfortunately, our patient passed away four days after liver transplantation.