Diagnostic Pitfalls in Wilson Disease with Autoimmune Features: A Case Report Open Access

Wilson’s disease (WD) is a rare genetic disorder of copper metabolism that results in the pathological accumulation of copper in the liver, brain, and eyes. [1, 2]. Its reported prevalence is 30 per million population [3, 4]. Liver manifestations range from asymptomatic biochemical abnormalities to acute liver failure or overt cirrhosis. Patients with liver disease may later develop neurological or psychiatric symptoms, while those presenting initially with neurological or psychiatric symptoms may subsequently progress to liver failure. Diagnostic tests included serum ceruloplasmin measurement, screening for the Kayser-Fleischer (KF) rings, and 24-h urinary copper excretion. [5]. WD requires lifelong therapy. Asymptomatic patients may be treated with zinc, while symptomatic patients need chelation therapy. Liver transplantation (LT), indicated for decompensated liver disease or acute liver failure, is curative for WD [1, 2, 5].

We report the case of a 33-year-old Bhutanese woman presenting with jaundice persisting for 2 weeks. Her personal and family medical histories were unremarkable, and she denied alcohol or drug use. Clinical examination revealed jaundiced and ascites, with no signs of hepatic encephalopathy. The body mass index was 23 kg/m². Laboratory results unveiled anemia, hepatocellular jaundice (total bilirubin 7.5 mg/dL), international normalized ratio (INR) 2.4 and albumin 1.8 g/dL. The serum-ascites albumin gradient was >1.1, and the ascitic fluid neutrophil count was 80/µL. Bacterial sepsis workup was negative (shown in Table 1). Computed tomography revealed signs of chronic liver disease, excluding obstructive or focal lesions and vascular anomalies. The patient was hospitalized following the diagnosis of decompensated liver cirrhosis with ascites and was referred to the LT team.

Further etiological evaluation (shown in Table 2) revealed positive ANA (1:160), Coombs-positive hemolytic anemia with IgG positivity (shown in Table 3), and elevated IgG levels (3,500 mg/dL). Ceruloplasmin levels were normal, and a 24-h urine collection was conducted to evaluate copper levels. No KF rings or neuropsychiatric manifestations were observed. A probable diagnosis of autoimmune hepatitis (AIH) was admitted and a transjugular liver biopsy was performed, followed by initiation of prednisolone.

The corticosteroid therapy was ineffective (shown in Fig. 1). Further investigation revealed elevated 24-h urine copper (348 μg/day). Liver biopsy showed cirrhotic changes with significant copper deposition (shown in Fig. 2).

Corticosteroids were discontinued and the patient was started on penicillamine and a copper-restricted diet. The diagnosis was later confirmed by genetic testing, which identified a homozygous pathogenic variant, c.3584C>T(p.Ala1995Val). Family screening was not performed because the patient had no siblings or children.

Despite the established therapy, the patient’s condition deteriorated, leading to hepatic encephalopathy and kidney dysfunction, which necessitated ICU admission and urgent LT. The surgery and postoperative period were marked by various complications, ultimately leading to the patient’s death due to infectious complications.

WD is an autosomal recessive disorder caused by mutations in the ATP7B gene on chromosome 13 [1, 2]. The reported prevalence of WD is 30 per million population [3], although recent genetic studies suggest that WD may be more common than previously thought [4].

The clinical presentation of WD is heterogeneous, with onset at any age, the earliest reported at 9 months [6]. Nevertheless, most patients present between 3 and 55 years, with no gender differences [2, 5]. Hepatic presentations are more common in younger patients, ranging from asymptomatic biochemical abnormalities to cirrhosis. Acute hepatitis occurs in up to 25% of patients and can be indistinguishable from acute viral hepatitis, either resolving spontaneously or rapidly progressing to liver failure in up to 20% of cases [1, 7]. WD accounts for 5% of all acute liver failure [8], usually associated with renal failure and nonimmune hemolytic anemia. Chronic presentations include chronic hepatitis (10–30%) and cirrhosis (35–60%) [7]. Neurological manifestations typically appear in the second decade of life or later and include dysarthria, gait abnormalities, dystonia, tremor, and parkinsonism [1, 2, 5]. These symptoms may be chronic or subacute, with some cases progressing rapidly. Psychiatric symptoms of WD are also variable and common, including depression, personality changes, impulsiveness, mood lability, sexual exhibitionism, and psychosis. In a large retrospective study, 51% of WD patients had psychiatric symptoms at diagnosis [9]. Purely psychiatric presentations, seen in 20% of cases [1], often delay diagnosis. The most characteristic ophthalmological feature of WD are the KF rings, present in 40% of patients with hepatic involvement and 90% of those with neurological symptoms [1, 10], though it may also occur in other cholestatic diseases. Sunflower cataracts are rare, with a prevalence of 1.2% in newly diagnosed patients [11]. WD may also affect hematologic, cardiac, renal, skeletal, and endocrine systems.

The diagnosis of WD requires high suspicion, particularly in patients who lack both hepatic and neuropsychiatric symptoms. A thorough history and physical examination should be conducted, and mandatory tests include liver biochemistry, INR, serum ceruloplasmin, optical coherence tomography or ocular slit-lamp examination, 24-h urinary copper excretion test, and abdominal ultrasound. No single test is definitive, but low serum ceruloplasmin (<10 mg/dL) with elevated urinary copper (>40–100 µg/24 h) is suggestive [2, 5, 9, 12]. Liver biopsy is reserved for cases in which noninvasive tests are inconclusive or other etiologies are suspected, with hepatic copper content exceeding 250 µg/g dry weight diagnostic for WD [2, 5]. Quantitative copper analysis is more sensitive than histochemical staining, and histological findings may resemble steatotic liver disease or AIH. For patients with neurological symptoms, magnetic resonance imaging can aid diagnosis, with the “face of the giant panda” sign on T2-weighted images being distinctive, although rare and usually seen in advanced cases [13]. Genetic testing is recommended when other investigations are inconclusive. Over 500 mutations in ATP7B gene have been identified [14], with most patients being compound heterozygotes. The absence of two pathogenic mutations does not exclude WD.

WD presents numerous challenges throughout its course, often beginning with its diagnosis. In our case, WD was thoroughly evaluated from the start through ceruloplasmin levels, urinary copper excretion, and KF rings screening. However, the diagnosis was particularly challenging due to several factors. First, the patient had normal serum ceruloplasmin levels. While low ceruloplasmin is a key diagnostic feature of WD and included in scoring systems such as the Leipzig score, its utility as a marker is limited. Serum ceruloplasmin levels can fluctuate due to its role as an acute-phase reactant, necessitating caution in interpretation. Furthermore, low ceruloplasmin levels can also occur in conditions such as AIH, severe hepatic insufficiency, and familial aceruloplasminemia. An additional diagnostic challenge in our patient was the presence of Coombs-positive hemolytic anemia, indicative of autoimmunity. Although WD is associated with hemolytic anemia, particularly in severe cases, it is characteristically non-autoimmune, making this finding atypical and further complicating the diagnosis. Moreover, WD can mimic other conditions, such as AIH, by presenting with elevated serum immunoglobulins and nonspecific autoantibodies, complicating the differential diagnosis, as observed in our case. This overlap has been reported in the literature. There are 7 reported cases of patients diagnosed with WD presenting features of autoimmune disease, with only three ultimately diagnosed with the coexistence of both conditions [15‒20]. Similar to our case, all cases demonstrated elevated serum immunoglobulins and nonspecific autoantibodies and underwent a trial of corticosteroids, with minimal to no improvement. However, unlike our case, all reported patients had low ceruloplasmin levels, prompting from the beginning the suspicious of WD. This finding facilitated the diagnostic process, even before evaluating urinary copper levels or obtaining liver biopsy results and histology. The absence of low ceruloplasmin in our case added an additional layer of complexity. Hepatic copper quantification could have been helpful as it is a key diagnostic tool particularly in cases with normal ceruloplasmin and elevated urinary copper, as seen here. This test requires meticulous handling: liver tissue must be collected using a disposable suction or cutting needle, placed in a copper-free container without liquid, and promptly frozen or vacuum-dried. Additional needle passes would have been required to obtain sufficient samples [21]. Following consultation with the LT team, hepatic copper quantification was not performed. At that stage, clinical findings strongly supported AIH, and additional procedures were deemed unnecessary due to the associated risks and limited diagnostic benefit, especially since alternative methods to confirm WD were available if needed. Furthermore, the accuracy of hepatic copper quantification is limited by the uneven distribution of copper in the liver, particularly in patients with cirrhosis, which could result in underestimation. While retrospective analysis might suggest this decision was debatable, it was ultimately not critical for establishing the diagnosis. The liver biopsy, even without copper quantification, proved pivotal, as its findings were atypical of AIH and redirected the diagnostic approach.

Several scoring systems assist in diagnosing WD, with the Leipzig score being the most widely recognized and validated in both children and adults [16]. Our patient achieved a Leipzig score of 3 prior to genetic testing, suggesting a possible diagnosis, and 2 prior to histological results. The Berman score, designed for diagnosing WD in liver failure, has had its utility questioned by several authors [5]. In our case, the score was of limited value, as neither ratio was indicative of WD. Simultaneously, the diagnostic criteria of the International Autoimmune Hepatitis Group (IAHG) were also applied. The patient scored 6 on the simplified criteria (probable diagnosis) and 16 on the revised original score (definite autoimmune hepatitis) prior to histology. This underscores the importance of clinical judgment and thorough evaluation, as scoring systems, while valuable diagnostic tools, have limitations and can fail when patients meet criteria for multiple conditions, as seen in our case.

Accurate diagnosis is crucial to enable timely and appropriate treatment. WD requires lifelong therapy with oral chelators like D-penicillamine or trientine. Although no direct comparative trials exist, both drugs have similar efficacy, with trientine being better tolerated [13]. D-penicillamine can cause adverse events requiring discontinuation in approximately 30% of patients [22], and up to 50% may experience a paradoxical worsening of neurological symptoms initially [23]. Tetrathiomolybdate, another chelating agent, is currently undergoing phase III trials [2, 5, 12]. In this case, D-penicillamine was selected after consultation with the LT team. Early referral for LT is essential for patients with decompensated liver disease, as some may not respond to medical therapy [2, 5]. Serial use of prognostic scores, such as the New Wilson Index, helps predict outcomes, with a score ≥11 strongly predicting mortality without LT [24]. As a reference, our patient had an NWI of 12. LT is also necessary for acute liver failure from WD, as survival without surgery is extremely rare. In a large pediatric cohort, only 11% achieved spontaneous recovery [25]. LT is curative, and further treatment is usually unnecessary. However, LT is not recommended as a primary treatment for neurological WD because of inconsistent evidence on resolving neurological symptoms post-transplantation [2, 5, 12].

In conclusion, WD should be considered in the differential diagnosis of unexplained liver disease. A high index of suspicion is essential in cases initially presumed to be AIH unresponsive to corticosteroids.

Ethical approval was not required for this study, in accordance with local/national guidelines. Informed consent was obtained from the patient’s husband for the publication of the medical case and any accompanying images. The CARE Checklist has been completed by the authors for this case report (available at https://doi.org/10.1159/000546205).

The authors have no conflicts of interest to declare.

There are no funding sources to declare.

Sara Ramos Lopes drafted the paper. All authors read and approved the final manuscript.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.