Analysis of risk factors for neurological symptoms in patients with purely hepatic Wilson’s disease at diagnosis

Hepatolenticular degeneration (HLD), also known as Wilson's disease (WD), is an autosomal recessive disorder of copper metabolism. The prevalence of this disease is 1/26000 ~ 1/30000 globally, and the population carrier rate is approximately 1/90 [1, 2]. The abnormal WD gene is localized in the long arm of chromosome 13q14.3. This gene encodes P-type adenosine triphosphatase (ATP7B) that is copper transporter [3]. Mutated ATP7B causes the functional loss of a copper transporter, resulting in the decreased synthesis of ceruloplasmin and impairment of hepatic biliary copper excretion. This leads to the progressive copper deposition in the liver and other organs, such as brain, kidneys, and cornea. Clinical manifestations of this disease include hepatic, neurological, and psychiatric signs and symptoms [4].

Symptomatic patients with WD are classified as hepatic, neurological, or mixed depending on their clinical presentation, liver imaging, liver enzymes, and magnetic resonance imaging (MRI) of the brain [5]. The majority of patients with WD present with hepatic and neurological symptoms. Liver involvement is more common in WD, with either clinically asymptomatic or symptomatic liver involvement, and when WD patients with hepatic symptoms are not diagnosed and treated timely, they may develop neurological symptoms, such as tremor, slurred speech, and drooling [5, 6]. Neurological symptoms are tricky in the therapy of WD, and the therapeutic efficacy is mainly poor. How to more effectively prevent the development of neurological symptoms and identify the high-risk factors for neurological symptoms has noticeably attracted clinicians' attention. The present study aimed to analyze 14 patients with purely hepatic WD symptoms who developed neurological symptoms during follow-up and to evaluate the risk factors for neurological symptoms.

It is broadly accepted that WD is an autosomal recessive inherited disorder of copper metabolism. Its clinical and pathological manifestations are the consequences of excessive accumulation of copper in the brain, liver, kidneys, and cornea [8]. The clinical manifestations of WD vary from an asymptomatic state, chronic liver disease, and acute hepatic failure to a neuropsychiatric presentation [9]. Besides, WD is one of the few hereditary diseases that can be successfully treated with medication. Early diagnosis and timely treatment are conducive to effectively controlling WD, whereas undertreatment or poor adherence can be life-threatening [10]. Patients with purely hepatic WD mainly present with unexplained elevated ALT and AST levels, and their age at the time of diagnosis is typically between 5 and 35 years. WD is generally limited to hepatic symptoms without neurological symptoms that can be clinically alleviated with timely treatment [11‐13]. In treating patients with purely hepatic WD without neurological symptoms, some patients gradually developed neurological symptoms. Although therapeutic approaches for WD have shown significant advancement, the options for pharmacological treatment options are still limited, especially for WD patients with neurological symptoms [14‐16].

What factors cause the development of neurological symptoms in patients with purely hepatic WD? However, there is no unified understanding of this disease. At present, treatment options for patients with WD include medical therapy and liver transplantation. Copper chelators, such as PCA, are the first-line and effective treatment options for WD. Zinc salts, such as ZG, are maintenance drugs for treating WD as they reduce copper absorption from the intestinal tract. PCA and ZG are used in combination as the primary medical treatment for patients with WD [17, 18]. When WD patients with neurological symptoms are treated with PCA, the copper in the body is mobilized to the blood, brain, and other tissues. The copper transported into the brain may lead to cell dysfunction and necrosis, causing the deterioration of neurological symptoms [19]. Studies demonstrated that the deterioration of neurological deterioration occurs during anti-copper treatment, involving the mobilization and redistribution of hepatic copper [19‐21]. In recent years, few studies have analyzed the risk factors of early neurological deterioration in neurological WD. These studies were mainly based on clinical and imaging data, such as age, liver cirrhosis, splenomegaly, location of brain MRI lesions in pons and thalami, neurological phenotype, and severe gene mutation types [22‐24]. Recent studies have shown that high serum neuro-filament light chain (sNfL) level is a significant risk factor for neurological deterioration, and biochemical detection of sNfL level has been essentially performed for evaluating neurological deterioration in neurological WD [25, 26].

The above-mentioned studies [22‐26] mainly aimed to explore the risk factors and assess the deterioration of neurological symptoms in neurological WD. In the present study, all patients with purely hepatic WD were given the combined treatment of PCA and ZG, while 14 (20.59%) of the 68 patients with purely hepatic WD developed neurological symptoms during follow-up. The worsening of neurological symptoms in patients with neurological WD mainly occurs within 2–6 weeks after anti-copper treatment [7]. In the present study, patients with purely hepatic WD did not develop neurological symptoms within a short period (2–6 weeks), and 14 of whom developed neurological symptoms at 0.5–5 years after diagnosis and anti-copper treatment. These patients ruled out the emergence of acute neurological symptoms caused by stress factors, such as traumatic, surgical, or emotional events [27]. It was suggested that there is a significant difference between the risk factors of developed neurological symptoms in purely hepatic WD and the deterioration of neurological symptoms in neurological WD. Neurological symptoms of these patients were either subacute or chronic. It is noteworthy that there may be other factors that cause neurological symptoms in patients with purely hepatic WD.

The results of the MRI of the brain showed that 13(92.86%) patients in the NH-WD group had abnormalities. Among 14 patients in the NH-WD group, it was revealed that 3 patients had low signal intensity on T1WI, and high signal intensity on T2WI and DWI (Fig. 1), indicating that the brain damage in these 3 patients was in the acute or subacute stage [28]. In the H-WD group, no patient with low signal intensity on T1WI and high signal intensity on T2WI and DWI was found, while the proportion of abnormal signals on MRI of the brain was as high as 81.48% (44/54), indicating that copper caused a substantial brain damage and imaging changes in more patients with hepatic WD. Neurological symptoms may occur when brain damage reaches a certain degree. The above-mentioned results indicated that MRI of the brain is of great significance for the assessment of status of patients with H-WD, especially when neurological symptoms occur.

The results of the present study revealed that during the diagnosis and treatment of patients with purely hepatic WD, the elevated ALT and AST levels and 24-h urinary copper level in the NH-WD group were higher than those in the H-WD group, and the adherence to low-copper diet and the average daily oral doses of PCA and ZG in the NH-WD group were lower than those in the H-WD group. Insufficient administration of PCA and ZG in the NH-WD group may prevent copper from being excreted from the body promptly, leading to toxic copper accumulation in the liver, damaging liver cells, and elevated ALT and AST levels. The 24-h urinary copper level in the NH-WD group was also higher, suggesting that the NH-WD group had more copper that was not excreted from the body. This could be related to the insufficient administration of PCA and/or ZG.

Univariate analysis revealed that the adherence to low-copper diet in the NH-WD group was lower than that in the H-WD group. However, logistic regression analysis indicated that the low adherence to low-copper diet was not a high-risk factor in the NH-WD group using the NH-WD group as the control. Recently, several studies have shown that low adherence to low-copper diet is of great significance for controlling damage to target organs caused by copper accumulation [29, 30]. It is still essential to pay further attention to the dietary treatment of patients with purely hepatic WD and reduce the intake of copper to alleviate reduce the damage of copper to target organs, such as the liver and brain.

Logistic regression analysis showed that insufficient doses of PCA and ZG influenced the neurological symptoms of patients with purely hepatic WD. The poor medication adherence may be an important reason for the inadequate dosages of PCA and ZG. In the NH-WD group, a limited number of patients (n = 3) could have a strict low-copper diet and a regular oral intake of sufficient doses of PCA and ZG, whereas still developed neurological symptoms. It was found that patients' 24-h urinary copper levels were not high when PCA was used for anti-copper treatment. However, the 24-h urinary copper level was significantly elevated when sodium 2,3-dimercaptopropane-1-sulfonate was used for copper excretion. This suggests that oral PCA treatment for these patients is inadequate for copper excretion. Patients may receive sodium dimercaptosulphonate, dimercaptosuccinic acid, and trientine [31] as copper excretion drugs, and it is recommended to monitor 24-h urinary copper levels to ensure the efficacy of anti-copper treatment. The biomarker sNfL can also be detected to predict the occurrence (or deterioration) of neurological symptoms [25, 26]. Treating patients with purely hepatic WD should follow individualized treatment, and the selection of appropriate and efficient anti-copper drugs is worthy of further investigation [5].

The present study had some limitations. First, the retrospective design and the exclusion of patients with incomplete data might lead to bias. Second, this study was a single-center study with a relatively small sample size, which might hinder the applicability of the finding. Therefore, additional large-scale, multi-center longitudinal studies will be required to eliminate the above-mentioned limitations.

In conclusion, the development of neurological symptoms in patients with purely hepatic WD was closely associated with the low doses of PCA and ZG, and the poor efficacy of individualized anti-copper therapy. In the anti-copper treatment of patients with purely hepatic WD, it is of great significance to promote patients' educational levels, monitor treatment response, and follow the principle of individualized treatment to prevent the development of neurological symptoms.