Correlation Between The Neurological Deterioration Of Hepatolenticular Degeneration And Free Copper And Its Risk Factors

Background: Wilson’s disease is an autosomal recessive disorder.The pathogenesis is mainly caused by the inhibition of ATP7 B protein synthesis leading to bile copper exclusion.The accumulation of copper in the body leads to liver cell and/or brain nerve cell damage.The current treatment plan is mainly to reduce the intake of copper through a low-copper diet and the copper accumulated in the body by the chelating agent,which usually achieves a good therapeutic effect.However,some patients have symptoms worsening after the application of chelating agents.This deterioration is mainly manifested in the initial treatment of WD patients with brain damage(especially dystonia-type),in which penicillamine causes neurological deterioration.The most reported,the highest probability,if the original treatment plan is maintained at this time,it often affects the prognosis.However,the current pathogenesis of neurological deterioration after treatment is not very clear,and many related treatments and methods are accumulated through a small number of clinical experience,lacking a clear prospective evidence-based basis.The relevant mechanisms and risk factors of the WD neurological symptoms deterioration are urgently needed for further study,which will play a positive role in improving the prognosis of WD patients.Objective: 1.Through the study of brain-type WD treatment,neurological symptoms worsening group,improvement group,maintenance group,serum copper,free copper,relative free copper(serum free copper / serum total copper),Chinese version of the UWDRS scores and their correlations,screening for meaningful clinical indicators leading to deterioration of neurological symptoms,and further understanding of the pathogenesis of WD neurological symptoms.2.To analyze the UWDRS score,free copper,brain MRI imaging and other biochemical indicators in patients with brain WD,and to explore the risk factors leading to the deterioration of WD neurological symptoms.Method: 1.77 cases of brain type(brain type and brain-visceral type)WD patients were included in the study,and their free copper,relative free copper,serum copper,ceruloplasmin,before treatment,4th treatment,and 8th treatment were analyzed.Copper oxidase,serum zinc,24-hour urinary copper and UWDRS scores were classified into deterioration group,improvement group and maintenance group according to clinical outcomes.Statistical analysis showed differences among the three groups,and analysis of free copper and relative free copper.Based on the correlation between the UWDRS scores and the trends of free copper and relative free copper during the treatment,the effects of free copper on the deterioration of WD neurological function were further studied.2.According to the changes of UWDRS scores and clinical efficacy during WD treatment,the patients were divided into three groups: the deterioration group,the maintenance group and the improvement group.The ordered Logistic scores were used to analyze Whether the initial UWDRS score and the initial brain MRI damage,free copper,malondialdehyde(MDA)and various biochemical indicators are risk factors for neurological deterioration.Result: 1.There was no significant difference in the neurological deterioration rate between the WD dystonia,mental disorder,Parkinson’s syndrome and brain-visceral type 4 clinical types(χ2 = 4.118,bilateral P = 0.685).2.There was no significant difference in the rate of WD neurological deterioration between the DMPS conventional therapy group and the titration therapy group(χ2 value=0.435,bilateral P=0.804).3.There were significant differences between the free copper deterioration group and the improvement group,the deterioration group and the maintenance group(P =0.000,P=0.001),while there was no difference between the improvement group and the maintenance group(P=0.713);relatively free copper(The serum free copper/serum total copper)group was significantly different from the improvement group and the maintenance group(P =0.000,P=0.021),while there was no difference between the improvement group and the maintenance group(P=0.126);serum copper,There were no statistical differences between the two groups(P=0.558,P=0.783,P=0.958).4.There were no significant differences in free zinc,relative free zinc(serum free zinc/serum total zinc),serum zinc,24-hour urinary copper,and 24-hour urinary zinc between the three groups(P= 0.393,0.132,0.680,0.994,0.532,both P>0.05).5.There was no significant difference in the severity of the Goldstein ADL between the three groups.There was a statistically significant difference between the three groups of UWDRS.There was a statistical difference between the worse and worse groups(P=0.004),worsening group and maintenance.There were no statistical differences between the group,the maintenance group and the improvement group(P=0.134,P=0.099).6.The correlation between UWDRS score and free copper value is poor,and it has a certain correlation with relative free copper,which is positively correlated(r=0.521,bilateral P=0.000).7.In the brain-type WD patients,the free copper and relative free copper of the three groups showed a gradual decline trend,while the serum copper deterioration group increased first and then decreased;the free copper,the relatively free copper,the fourth course of treatment The course of treatment was still higher than that of the improvement group and the maintenance group.The difference was statistically significant(P=0.000,P=0.000,P=0.002,P=0.000).There was no treatment between the third group and the third course of serum copper.Statistical difference(P=0.416,P=0.617).8.There was no significant difference in the rate of change of free copper,the rate of change of free copper and the rate of change of free copper in the eighth course of treatment(P=0.163,P=0.064).There was no statistical difference between the three groups(P= There was a statistical difference between the three groups in the 8th course of treatment.There was a statistical difference between the improvement group and the deterioration group,the improvement group and the maintenance group(P = 0.001,P=0.013).There was no significant difference between the deterioration group and the maintenance group(P=0.179).9.The change rate of free copper and the change rate of relative free copper in the fourth course and the eighth course were poorly correlated with the change rate of UWDRS score(r=0.120,r=0.154,r=0.156,r=0.020).10.Univariate ordered logistic regression analysis indicated that the deterioration of WD neurological symptoms was associated with UWDRS score(P=0.006)and free copper(P=0.006),both P<0.05,and gender(P=0.128),brain MRI lesions.The number(P=0.144),malondialdehyde(P=0.165),total bilirubin(P=0.111),albumin(P=0.134),and uric acid(P=0.081)may be related,both P<0.2.11.Multivariate ordered logistic regression analysis showed UWDRS scores(β=0.062,P=0.005),brain MRI lesions(β=0.836,P=0.040),free copper(β=0.259,P=0.036),Albumin(β=-1.183,P=0.020)is an independent factor affecting the deterioration of WD neurological symptoms.The number of brain MRI lesions is the most important factor affecting the deterioration of WD neurological symptoms.Conclusion: 1.There was no significant difference in the rate of neurological symptoms in various clinical types of brain-type WD.There was no significant difference in the rate of neurological deterioration between the two DMPS treatment regimens(conventional therapy,titration therapy).2.The free copper and relative free copper in the deteriorating group of brain-type WD patients were significantly higher than those in the improvement group and the maintenance group.The UWDRS score of the deteriorating group was significantly higher than that of the improvement group,and the UWDRS had a positive correlation with the relative free copper.3.The free copper and relative free copper of patients with brain-type WD showed a downward trend after treatment,and the patients with clinical symptoms improved rapidly at the late stage of copper treatment.4.The baseline UWDRS score is higher,the number of brain MRI lesions is higher,the higher the free copper level before treatment,and the lower the albumin,the more likely it is to have neurological symptoms after the treatment of copper.The number of MRI lesions is the most important factor.