Wilson disease (WD) is a hereditary autosomal recessive disorder attributed to mutations occurring within the ATP7B gene, and it exhibits a documented prevalence ranging between 1 in 30,000 to 1 in 50,000 individuals [1-5]. The ATP7B gene carries the genetic code for an enzyme termed transmembrane copper-transporting ATPase, which plays a crucial role in facilitating the integration of copper into ceruloplasmin and the subsequent excretion of copper into the bile. A deficiency or malfunction of this enzyme leads to the gradual accumulation of copper in multiple organs, particularly in the liver, nervous system, corneas, kidneys, and heart.

Children diagnosed with WD may present with various clinical manifestations, including asymptomatic liver disease, cirrhosis, or acute liver failure, with or without accompanying neurological and psychiatric symptoms [1]. It is noteworthy that approximately 20% to 30% of WD patients experience acute liver failure, while the majority of untreated individuals progress to develop chronic progressive hepatitis or cirrhosis [6].

ATP7B gene mutations on chromosome 13, including missense and nonsense types, can be homozygous or compound heterozygous. H1069Q is the most common mutation in European and American populations (50%–80%), while R778L prevails in Far East Asian countries (14%–49%) [7-10]. Various ATP7B variants result in distinct disease phenotypes [11-16]. Homozygous H1069Q patients show delayed-onset neurological symptoms, differing from compound heterozygous cases [12,13]. Truncating mutations often lead to acute liver failure [15]. Genotype/phenotype correlation in WD is inconclusive, suggesting a potential role of epigenetics influenced by environmental and nutritional factors [17].

Copper, vital for mitochondrial respiration, enters the body through ATP7A in the intestines, then travels to the liver via the portal system, with a portion excreted through urine and sweat. Within hepatocytes, copper uses CTR1 to reach the trans Golgi network via ATP7B. It incorporates into apoceruloplasmin to form holoceruloplasmin, a major copper-containing protein, and is released into circulation [18]. ATP7B also expels copper into bile via vesicles that reach biliary canaliculi, later excreted in stool. Mutations in ATP7B lead to copper accumulation in the liver and bloodstream, affecting other tissues, causing oxidative stress and cellular damage. Hepatic injury predominates in WD due to the liver’s role in copper homeostasis. Copper initially binds with metallothionein, detected in liver histology with special staining. Over time, copper accumulates in lysosomes, causing hepatic issues and subsequent copper buildup in other tissues. In the brain, copper toxicity leads to damage, particularly in the basal ganglia, thalamus, cerebellum, and brainstem. In the bloodstream, excess copper triggers oxidative damage and Coombs-negative hemolysis. Muscle, kidney, and other tissues also experience adverse effects from copper overload [19-21].

In children, WD can appear at various ages, with a median age of 13 years, but symptomatic cases are rare before age of 3 years [20-23]. Hepatic issues are more frequent in children, but around 4% to 6% may exhibit subtle neurological symptoms. Older children and young adults, typically aged 20 to 30 years, are more likely to display neurological or psychiatric symptoms, with or without liver involvement.

Hepatic Manifestation

Hepatic symptoms in WD range from asymptomatic or incidentally discovered abnormal liver tests to complications like acute liver failure [1]. Early stages may show no symptoms but could include elevated liver enzymes or abnormal ultrasound findings. As the disease progresses, patients may display signs of chronic liver disease or cirrhosis complications. WD should always be considered when a child or young adult presents with abnormal liver tests or clinical features resembling non-alcoholic fatty liver disease or autoimmune liver disease [24,25].

Acute liver failure in WD is a severe form marked by jaundice, hepatitis, hepatomegaly, and coagulopathy, with or without encephalopathy. Acute liver failure is defined as international normalized ratio (INR) ≥1.5 with encephalopathy or INR ≥2.0 regardless of encephalopathy [26]. Some children may have a history of acute self-limited hepatitis-like illness, recurrent jaundice, hemolytic anemia, or elevated transaminases. Some clinicians consider this presentation as acute-on-chronic liver failure, often showing preexisting chronic liver damage on histology. Acute-on-chronic liver failure is defined as acute hepatitis causing jaundice (total bilirubin >5 mg/dL or 85 µmol/L) and coagulopathy (INR>1.5) with ascites and/or hepatic encephalopathy within 4 weeks [27].

Differentiating WD from other causes of hepatic failure involves relatively milder elevation of liver enzymes, high total bilirubin, and low alkaline phosphatase [20,28]. Associated hemolysis due to free copper can contribute to elevated total bilirubin.

Neurological Manifestation

Neuropsychiatric symptoms in children are rare, especially in those under 10 years old, but about 5% to 15% of children with liver issues may experience neurological symptoms [17,29]. These symptoms include incoordination, declining school performance, mild cognitive impairment, language difficulties, or movement disorders like tremors. Psychiatric symptoms can range from behavioral and personality problems to mood disorders, and even psychosis. Brain magnetic resonance imaging is a valuable diagnostic tool for patients with neurological signs/symptoms, revealing hyperintensity lesions in the basal ganglia, thalamus, midbrain, and pontine white matter [30,31]. These findings indicate cerebral involvement in WD. Conversely, high signal intensity lesions in the basal ganglia on T1-weighted images may result from chronic liver disease and may suggest WD with hepatic involvement [17,20].

WD diagnosis relies on clinical features and lab tests. A WD diagnostic score (Table 1) created in 2001 is widely adopted for its diagnostic accuracy and incorporated into the European Association for Study of Liver guidelines [32,33]. Validation studies in children and young adults by Koppikar and Dhawan [34] confirmed its diagnostic value.

Table 1 . The scoring system for the diagnosis of Wilson disease (WD) [32,43].

Score	−1	0	1	2	4
Kayser-Fleischer rings		Absent		Present
Neuropsychiatric symptoms suggestive of WD (or typical brain MRI)		Absent		Present
Coombs-negative hemolytic anemia+high serum copper		Absent	Present
Urinary copper (in the absence of acute hepatitis)		Normal	1-2 ULN	>2×ULN or normal, but >5 ×ULN day after challenge with 2×0.5 g D-penicillamine
Liver copper quantitative	Normal	<5×ULN (<250 µg/g)		>5×ULN (>250 µg/g)
Rhodanine positive hepatocytes (only if quantitative Cu measurement is not available)		Absent	Present
Serum ceruloplasmin (nephelometric assay)		>0.2 g/L	0.1–0.2 g/L	<0.1 g/L
Disease-causing mutations detected		None	1		2

Assessment of the WD diagnostic score: 0–1, unlikely; 2–3, probable; 4 or more, highly likely..

ULN, upper limit of normal..

Mutational analysis is crucial for WD diagnosis, distinguishing carriers from affected presymptomatic patients [7]. However, accessibility and time for genetic tests can vary. Some cases may need additional analysis for large gene defects. Approximately 900 ATP7B mutations have been identified, and most patients have compound heterozygous mutations [20,35]. If only one mutation is found, it could indicate either a carrier or a WD patient awaiting a second mutation. Comprehensive genetic analysis can yield detection rates of 77% to 98% [36,37], allowing for cases with one or no ATP7B variants [35]. In such cases, diagnosis may rely on suggestive laboratory tests and the WD diagnostic score. A recent study proposed measuring ATP7B peptides for direct evidence of variant consequences, even without a second mutation [38].

Indications for liver transplantation (LT) in WD include acute liver failure with severe hepatic insufficiency, coagulopathy, and hepatic encephalopathy, as well as acute-on-chronic liver failure [1,17,39]. LT in neurologic WD cases remains controversial. Children with acute liver failure but without hepatic encephalopathy can be treated with chelation agents, but response may be delayed, taking at least 1 month for prothrombin time improvement and 3 to 12 months for normalization [40]. Deciding when to opt for LT can be challenging. The revised King’s prognostic WD Index helps identify those at risk of failing chelation or facing mortality without LT (Table 2). An index score of ≥11 strongly predicts mortality without LT, with high sensitivity and specificity (93% and 97%, respectively), along with high positive and negative predictive values (92% and 97%, respectively) [41].

Table 2 . The revised King’s prognostic Wilson Index [41,43].

Score	Bilirubin (µmol/L)	INR	AST (IU/L)	WBC (×109/L)	Albumin (g/L)
0	1–100	0–1.29	0–100	0–6.7	>45
1	101–150	1.3–1.6	101–150	6.8–8.3	32–44
2	151–200	1.7–1.9	151–300	8.4–10.3	25–33
3	201–300	2.0–2.4	301–400	10.4–15.3	21–24
4	>301	>2.5	>401	>15.4	<20

INR, international normalized ratio; AST, aspartate transaminase; WBC, white blood cell..

In patients without advanced liver or brain damage, liver function can improve in over 90% of cases within 2 to 6 months. Neurological improvement occurs in 50% to 60% of patients over 1 to 3 years with early and proper pharmacological treatment [39]. Adherence to therapy is crucial for long-term success, and 24-hour urinary copper excretion has been proposed as a monitoring tool in children with WD [42].

In WD, LT is primarily indicated for two conditions: acute liver failure and chronic liver disease. There is also emerging consideration for LT in cases of uncontrolled neurological disease without liver deficiency [43-45]. While acute liver failure is the initial presentation in 5% of WD patients, the rate has been reported as 4% to 6% in the United States [46]. It has been suggested that mortality in these acute liver failure cases reaches 100% without LT [45,46].

Diagnosing WD in cases of acute liver failure remains challenging due to associated difficulties. Key diagnostic tools include 24-hour urine copper levels, hepatic copper concentration, ATP7B gene mutations, the presence of Kayser–Fleischer rings, neurological symptoms, cranial magnetic resonance imaging findings, serum ceruloplasmin and copper levels, and the presence of hemolytic anemia. However, it is important to note that Kayser–Fleischer rings are only observed in about 50% of patients [23]. Serum and urine copper levels are unreliable markers, as they can fluctuate not only in WD but also in other acute liver failure cases [47,48]. These complexities underscore the importance of a thorough and precise differential diagnosis.

Supportive treatments play a crucial role in patients diagnosed with acute liver failure, particularly when there is severe encephalopathy, during living donor preparation, or while waiting for a deceased donor. These treatments encompass various approaches, including exchange transfusion, plasmapheresis, the molecular adsorbent recycling system, therapeutic plasma exchange, and renal replacement therapies [49,50]. Plasma exchange treatments have shown a beneficial effect, particularly in improving serum copper levels, liver function, and kidney function [51].

The decision for LT in cases of chronic liver disease related to WD have received limited attention. It is worth considering that in countries primarily reliant on deceased donor operations, LT decisions are typically based on the Model for End-Stage Liver Disease score, allowing patients to become eligible only as their Model for End-Stage Liver Disease score increases. On the contrary, living donor LT offers an opportunity for WD patients with chronic liver disease in better clinical condition to access LT by preparing suitable living donors under elective circumstances.

Lately, there have been documented cases of central nervous system involvement without concurrent liver failure as a potential third indication for LT in WD [52]. The topic of LT in the context of central nervous system involvement remains a subject of debate, particularly in patients with advanced neurological complications. Nevertheless, reports indicate that LT can either ameliorate or halt the progression of neurological issues [46,53]. Survival rates are notably poor in patients with chronic liver disease and severe neurological involvement [46,54].

In conclusion, LT is an effective treatment approach with a high rate of success in addressing WD-related acute or chronic liver failure.

There was no funding related to this study.

All authors have no conflicts of interest to declare.

Conceptualization: All. Data curation: JIP. Investigation: BHJ. Methodology: JIP. Project administration: JIP. Resources: JIP. Writing – original draft: All. Writing – review & editing: All.