It is widely accepted that WD is not as rare as once believed, especially after the identification of ATP7B[3]. Since abnormal biliary excretion of copper due to ATP7B gene mutation is the etiology, liver abnormalities are the most common initial manifestation and 40–70% patients diagnosed as WD are on the basis of the presence of liver lesions[4]. In this case, coexistence of asymptomatic and unexplained cirrhosis become the key of diagnosis of this patients. Neuropsychiatric symptoms are another common findings which are at a rate of 50%[5],and the tremor hands is another clue in our case. Till to now, many atypical organs with copper deposition are reported and this leads to different and complex corresponding clinical symptoms and also leads to difficulty of diagnosis (Table.2). Given the difficulties of diagnosing WD, a weighted diagnostic scoring system, also known as Leipzig criteria, are established to help clinicians to evaluate patients for WD better. The system encompasses many key investigations involving clinical, biochemical, and even molecular genetic testing for making the diagnosis[6]. Although WD can be diagnosed with increased accuracy given better understanding of the disorder and also the addition of molecular diagnostic testing, one thing has not changed with time that WD is still a disease which can be delayed or missed the diagnosis easily. Therefore, the report of special cases will make clinicians better aware of the disease.
In this case, the patient’s earliest symptoms appeared in adulthood and kidney abnormalities including hematuria, proteinuria and renal dysfunction are his initially manifested. Renal involvement is a relatively rare manifestation, especially as initial presentation of WD. Some case reports have demonstrated that renal involvement has different manifestation, such as glomerulonephritis, nephrotic syndrome, IgA nephropathy, IgM nephropathy, even renal function impairment. However, renal tubular function disorder, which can manifest renal tubular acidosis, aminoaciduria, and Fanconi syndrome, is relatively common compare to glomerular injury. A retrospective study analyzed 25 children with WD involving with renal injury and proved that renal tubular injury is relatively common injury. This is mainly attributed to the more deposition of copper in the epithelium of proximal and distal convoluted tubules, which cause basement membrane thicken and further interfere with the reabsorption function of renal tubules. In our case, a relatively serious tubular injury inconsistent with glomerular lesions was found. It further proved the deposition of copper in tubular epithelial cells. IgA nephropathy is another pathologic change in the case. At present, the precise pathogenesis of IgA nephropathy associated with WD remains uncertain. While IgA nephropathy is more likely to be associated with WD-induced liver damage than with the direct copper deposition, since no copper depositons were found in glomeruli, such as in our case or another cases[7]. But different from our case, in that case, the kidney showed only IgA nephropathy without tubular damage, and no copper deposition in tubular epithelial cells. In some studies, it had been mentioned that the decreased ability of the liver to clear immunoglobulin and immune complexes may lead to their increase in serum and deposition in the glomerulus, thereby causing nephropathy and membranoproliferative glomerulonephritis (MPGN). Gunduz reported a case of a boy diagnosed with WD, whose liver injury had manifested as cirrhosis, the renal biopsy histopathology showed MPGN with deposition of IgA[8]. Similarly, a report described a case in Pakistan of WD complicated with IgM nephropathy[9].
Although the clinical manifestations, kidney pathology and abnormal copper metabolism of this patient nearly confirm the diagnosis of WD, investigation of gene mutation is necessary. There are several disorders appear to qualify as mimics of WD, also known as disease-mimic of WD[10]. For example MEDNIK syndrome with mutations in AP1S1 have manifestations including liver damage consistent with WD, neurological involvement, even with low serum ceruloplasmin, elevated basal 24h urinary copper excretion and some degree of hepatocellular copper overload[11]. In this case, there are two mutations in ATP7B identified to support the diagnosis. Till to now, there are more than 500 known disease-associated mutations, but no single mutation is regarded as dominant mutation. Most patients are compound heterozygotes with a different mutation on each allele of the gene[12]. May be the different mutation in one patient contribute to the individually manifestation.
Once a diagnosis of WD is established, treatment must be initiated. D-penicillamine and zinc salts are still standard first-line treatment. After treatment, symptoms of the patient are relieved. In recent years, efforts have been made to find new drugs to treat WD, including oral medicines (such as trientine) that increase life-long adherence [13], and methanobactins, a new drug that promotes copper excretion[14]. New therapeutic strategies are still in need [15, 16].
In conclusion, our case is a rare case of WD with kidney disease as the first symptom.We reported the first case that IgA nephropathy and renal tubular injury caused by copper deposition coexist in WD patients, which is also a very important clue for us to analyze the condition and ultimately diagnose WD. From the case, we should know the possibility of WD in patients of renal disease, especially with suspicious neurological or hepatic abnormalities. Although with the improvement of copper metabolism monitoring methods and the popularization of gene monitoring, the diagnosis of WD has become more and more convenient and accurate, the disease is still an easily missed and misdiagnosed disease, so case report is helpful for clinicians to know more about special WD disease and improve the diagnostic rate.