Wilson's disease: revisiting an old friend

World Journal of Hepatology ISSN 1948-5182 (online) World J Hepatol 2021 June 27; 13(6): 620-716 Published by Baishideng Publishing Group Inc WJH https://www.wjgnet.com IJune 27, 2021 Volume 13 Issue 6 World Journal of Hepatology W J H Contents Monthly Volume 13 Number 6 June 27, 2021 REVIEW Glutathione-S-transferases genes-promising predictors of hepatic dysfunction 620 Prysyazhnyuk V, Sydorchuk L, Sydorchuk R, Prysiazhniuk I, Bobkovych K, Buzdugan I, Dzuryak V, Prysyazhnyuk P MINIREVIEWS Wilson's disease: Revisiting an old friend 634 Lucena-Valera A, Perez-Palacios D, Muñoz-Hernandez R, Romero-Gómez M, Ampuero J Balloon-occluded retrograde transvenous obliteration for treatment of gastric varices 650 Waguri N, Osaki A, Watanabe Y Role of chromosome 1q copy number variation in hepatocellular carcinoma 662 Jacobs NR, Norton PA ORIGINAL ARTICLE Retrospective Cohort Study Impact of donor-specific antibodies on long-term graft survival with pediatric liver transplantation 673 Schotters FL, Beime J, Briem-Richter A, Binder T, Herden U, Grabhorn EF Mortality and health care burden of Budd Chiari syndrome in the United States: A nationwide analysis (1998-2017) 686 Alukal JJ, Zhang T, Thuluvath PJ Retrospective Study Comparison of unenhanced magnetic resonance imaging and ultrasound in detecting very small hepatocellular carcinoma 699 Tarao K, Nozaki A, Komatsu H, Komatsu T, Taguri M, Tanaka K, Yoshida T, Koyasu H, Chuma M, Numata K, Maeda S CASE REPORT Distant metastasis of hepatocellular carcinoma to Meckel’s cave and cranial nerves: A case report and review of literature 709 Kim SK, Fujii T, Komaki R, Kobayashi H, Okuda T, Fujii Y, Hayakumo T, Yuasa K, Takami M, Ohtani A, Saijo Y, Koma YI, Kim SR WJH https://www.wjgnet.com II June 27, 2021 Volume 13 Issue 6 World Journal of Hepatology Contents Monthly Volume 13 Number 6 June 27, 2021 ABOUT COVER Editorial Board Member of World Journal of Hepatology, Rui Tato Marinho, FACG, FAASLD, FEBG, MD, PhD, Associate Professor, Head of Department ofof Gastroenterology and Hepatology, Centro Hospitalar Universitário Lisboa Norte, President of Portuguese Society of Gastroenterology, Medical School of Lisbon, Lisboa 1649-035, Portugal. 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All rights reserved. 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA E-mail: [email protected] https://www.wjgnet.com WJH https://www.wjgnet.com 634 June 27, 2021 Volume 13 Issue 6 World Journal of Hepatology W J H Submit a Manuscript: https://www.f6publishing.com World J Hepatol 2021 June 27; 13(6): 634-649 DOI: 10.4254/wjh.v13.i6.634 ISSN 1948-5182 (online) MINIREVIEWS Wilson's disease: Revisiting an old friend Ana Lucena-Valera, Domingo Perez-Palacios, Rocio Muñoz-Hernandez, Manuel Romero-Gómez, Javier Ampuero ORCID number: Ana Lucena-Valera 0000-0003-1460-545X; Domingo Perez-Palacios 0000-0003-1460- 544X; Rocio Muñoz-Hernandez 0000- 0003-3765-6276; Manuel Romero- Gómez 0000-0001-8494-8947; Javier Ampuero 0000-0002-8332-2122. Author contributions: Ampuero J is the guarantor of the article; Lucena-Valera AL, Perez-Palacios D, Muñoz-Hernandez R, and Ampuero J drafted the manuscript; Romero-Gómez M, and Ampuero J performed a critical review of the manuscript; all authors approved the final version of the article, including the authorship list. Supported by Consejería de Salud. Junta de Andalucía, No. PI_0039_2017; and Junta de andalucia, No. 201799903406796. Conflict-of-interest statement: Authors declare no conflict of interests for this article. Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the Ana Lucena-Valera, Domingo Perez-Palacios, Department of Gastroenterology, Hospital Universitario Virgen del Rocio, Sevilla 41013, Spain Rocio Muñoz-Hernandez, SeLiver Group, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, España Manuel Romero-Gómez, Javier Ampuero, Department of Unit of Digestive Diseases, Hospital Universitario Virgen del Rocio, Sevilla 41014, Spain Corresponding author: Javier Ampuero, MD, PhD, Doctor, Research Scientist, Department of Unit of Digestive Diseases, Hospital Universitario Virgen del Rocio, Avda. Manuel Siurot s/n, Sevilla 41014, Spain. [email protected] Abstract Wilson's disease (WD) is a rare condition caused by copper accumulation primarily in the liver and secondly in other organs, such as the central nervous system. It is a hereditary autosomal recessive disease caused by a deficiency in the ATP7B transporter. This protein facilitates the incorporation of copper into ceruloplasmin. More than 800 mutations associated with WD have been described. The onset of the disease frequently includes manifestations related to the liver (as chronic liver disease or acute liver failure) and neurological symptoms, although it can sometimes be asymptomatic. Despite it being more frequent in young people, WD has been described in all life stages. Due to its fatal prognosis, WD should be suspected in all patients with unexplained biochemical liver abnormalities or neurological or psychiatric symptoms. The diagnosis is established with a combination of clinical signs and tests, including the measurement of ceruloplasmin, urinary copper excretion, copper quantification in liver biopsy, or genetic assessment. The pharmacological therapies include chelating drugs, such as D-penicillamine or trientine, and zinc salts, which are able to change the natural history of the disease, increasing the survival of these patients. In some cases of end-stage liver disease or acute liver failure, liver transplantation must be an option to increase survival. In this narrative review, we offer an overview of WD, focusing on the importance of clinical suspicion, the correct diagnosis, and treatment. Key Words: Wilson´s disease; Copper; ATP7B; Ceruloplasmin; Chelator; Liver disease ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved. Lucena-Valera A et al. Wilson's disease: Revisiting an old friend WJH https://www.wjgnet.com 635 June 27, 2021 Volume 13 Issue 6 original work is properly cited and the use is non-commercial. See: htt p://creativecommons.org/License s/by-nc/4.0/ Manuscript source: Invited manuscript Specialty type: Gastroenterology and hepatology Country/Territory of origin: Spain Peer-review report’s scientific quality classification Grade A (Excellent): A Grade B (Very good): B, B Grade C (Good): C Grade D (Fair): 0 Grade E (Poor): 0 Received: January 24, 2021 Peer-review started: January 24, 2021 First decision: March 8, 2021 Revised: March 21, 2021 Accepted: May 8, 2021 Article in press: May 8, 2021 Published online: June 27, 2021 P-Reviewer: El-Shabrawi MH, Janicko M S-Editor: Fan JR L-Editor: Webster JR P-Editor: Wang LL Core Tip: Wilson’s disease (WD) is a rare metabolic disorder caused by the deposition of copper in organs, particularly in the liver and the brain. As the symptoms and clinical presentation can be highly variable, WD is not always suspected. A detailed but practical review is presented to assist clinicians in the diagnosis and management of WD. Citation: Lucena-Valera A, Perez-Palacios D, Muñoz-Hernandez R, Romero-Gómez M, Ampuero J. Wilson's disease: Revisiting an old friend. World J Hepatol 2021; 13(6): 634-649 URL: https://www.wjgnet.com/1948-5182/full/v13/i6/634.htm DOI: https://dx.doi.org/10.4254/wjh.v13.i6.634 INTRODUCTION Wilson's disease (WD) is an autosomal-recessive monogenic disorder characterized by an excessive accumulation of copper, firstly described in 1912 by Kinnear Wilson. The World Health Organization estimates the global prevalence of WD to be between 1/10000 and 1/30000[1]. It is caused by mutations in the ATP7B gene, which encodes a transporter protein with ATPase activity. This transporter is involved in incorporating copper into apoceruloplasmin, which is finally eliminated in bile. When a mutation affects the ATP7B transporter, free copper is released into the bloodstream and is removed by urine instead of feces[2]. Therefore, ATP7B is essential for copper biliary excretion[3]. In this review, we aimed to revise the clinical aspects of WD, including diagnosis, clinical manifestations, and the therapeutic approach, and discuss the future treatment of the disease. GENETICS The ATP7B gene is located on chromosome 13q14.3 and comprises 20 introns and 21 exons, encoding a protein of 165 amino acids[4,5], whose function is the incorporation of copper into ceruloplasmin. Currently, more than 800 mutations have been discovered in the gene[6], of which 380 have confirmed involvement in the pathogenesis of the disease[7,8]. Although mutations have been reported in almost all exons[5], they mainly affect the central regions of the gene (both 8 and 14 exons are the most frequently affected). The most common mutations are H1069Q and R778L in European and Asian populations, respectively[2,4]. Approximately 90%-98% of WD subjects are heterozygous, showing different mutations in each of the alleles encoding the ATP7B. On the other hand, the phenotype and the penetrance of WD can be extremely variable. Even patients carrying two disease-causing mutations do not necessarily have a demonstrable alteration of copper metabolism[9]. Some of the proposed reasons are differences in copper intake, individual antioxidant capacity or susceptibility to liver fibrosis, and hormonal influences[10]. The potential role that epigenetics could have in the gene expression of the disease should be highlighted. Some experimental models have shown changes in DNA methylation through breast milk enriched with methyl groups that could be related to the clinical manifestation of WD[11]. Considering the probability of late-onset, the fact of having asymptomatic cases, and the phenotypic variability, it seems vital to evaluate the previous and next generation of the index case[12]. Both the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD) recommend an appropriate study of the index case taking into account the family history of liver- and brain-related disease[7,13]. These guidelines propose to assess the patient's siblings since the risk of WD is 25% (by presenting two mutations in both alleles). Subsequently, other first-degree family members should be evaluated, although the risk decreases to 0.5%[12]. Lucena-Valera A et al. Wilson's disease: Revisiting an old friend WJH https://www.wjgnet.com 636 June 27, 2021 Volume 13 Issue 6 CLINICAL MANIFESTATIONS There is a wide variety of symptoms involved in WD, which predominantly affect the liver and brain (Table 1). Although WD may be present at any age, it is more common between the ages of 5 and 35. However, it should be investigated in patients with liver failure due to an unknown cause and those with liver disease and neuropsychiatric symptomatology[13]. Asymptomatic patients are commonly diagnosed during the family screening process[7]. Liver symptoms Liver symptoms of WD occur mainly during childhood and adolescence[10]. In these cases, liver involvement appears up to 10 years before neurological manifestations[7]. The clinical spectrum ranges from asymptomatic patients, with mild analytical alterations, to subjects with fulminant liver failure. In this scenario, there are forms of acute (from acute hepatitis to fulminant liver failure) and chronic presentation (from steatosis to compensated and decompensated cirrhosis)[14]. Asymptomatic forms usually have only hepatomegaly, discretely elevated transaminases, or are identified during the screening of an index case[15]. Acute presentation: WD should be suspected in a patient with acute hepatitis, in which viral hepatitis is ruled out. Symptoms are similar to acute viral hepatitis, with jaundice and abdominal pain[14]. This situation, including acute liver injury (manifested by coagulopathy) or acute liver failure (with hepatic encephalopathy), occurs predominantly in women[16]. Beyond these signs and symptoms, the elevation of hemoglobin, cholinesterase, and low alkaline phosphatase are characteristic of acute WD. Sometimes, hemolytic anemia with a negative Coombs test is presented, one of the diagnostic criteria of WD[7]. WD causes 2%-5% of acute liver failure events, showing a fatal prognosis in the absence of liver transplantation (LT) [14]. Chronic hepatitis and cirrhosis: Typically, it starts as a slight transaminase elevation that progresses slowly to fibrosis and, finally, cirrhosis. When it manifests itself as cirrhosis, there is an increased risk of mortality[8]. Sometimes, patients may show splenomegaly uniquely as a sign of portal hypertension. In particular, young patients over three years of age showing cirrhosis should be evaluated for WD[15]. On the other hand, WD can initially be confused with autoimmune hepatitis, as they occur at a similar age and are manifested by jaundice and increased transaminases and gammaglobulins[14]. Also, WD has been described as causing hepatic steatosis, which is identified in up to 15% of biopsies[17]. Neurological symptoms Neurological involvement typically appears after liver manifestations. WD affects the central nervous system mainly through extrapyramidal system dysfunction and bulbar involvement. The most common symptom is dysarthria, particularly in the early stages of the disease[8]. The neurological presentation can also be manifested by tremors, parkinsonism, or involuntary movements, even by cerebellar dysfunction, chorea, or hyperreflexia[14]. Furthermore, dystonia affecting the face and jaw is characteristic, producing a typical sign (Wilson’s face)[15]. Also, a postural tremor is common in WD patients[7]. Psychiatric symptoms Psychiatric symptoms must be considered in WD. In fact, patients showing these symptoms often suffer a delayed diagnosis[18]. In fact, approximately one third of patients develop psychiatric symptoms as the initial manifestation[7]. Typical symptoms are depression and anxiety[14], although changes in behavior or personality or impulsivity can occur[19]. In addition, affective disorders are more common than psychotic spectrum disorders. Ocular manifestations Kayser-Fleischer´s (KF) ring represents a frequent manifestation of WD, which affects the Descemet membrane of the cornea. The slit-lamp examination shows a brown-gold colored ring on the periphery of the cornea[20]. It is present in more than 90% of patients with WD showing neurological involvement but only in half of cases with liver disease. Notably, the KF ring does not affect vision, and its disappearance has been seen in patients undergoing effective treatment and LT[15]. Although it is one of the most typical features of WD, this ring has been described in cholestatic syndromes and other diseases[21]. Lucena-Valera A et al. Wilson's disease: Revisiting an old friend WJH https://www.wjgnet.com 637 June 27, 2021 Volume 13 Issue 6 Table 1 Clinical manifestations Wilson's Disease Clinical Manifestations Liver Hepatomegaly, jaundice, pain in right hypochondria, asthenia, elevation of transaminases, acute liver injury, acute liver failure, cirrhosis (compensated and decompensated), ACLF, steatosis Neurological Dystonia, tremor, dysarthria, dysphagia, Parkinson, chorea Psychiatric Behavioral changes, depression, anxiety, psychosis, school performance deficit, sexual disinhibition Eye Kayser-Fleischer Ring, Cataract Hematologic Hemolytic anemia, coagulopathy, thrombopenia Renal Acute renal failure, nephrolithiasis, urolithiasis, renal tubular acidosis Musculoskeletal Arthropathy, muscle weakness Other Heart disease, pancreatitis, hypoparathyroidism ACLF: Acute-on-Chronic Liver Failure. Other symptomatology As copper can be accumulated in different organs and systems, WD has been associated with arthropathy[22], recurrent muscle weakness due to hypokalaemia[23], cardiomyopathy[24], symptomatic urolithiasis[25], pancreatitis[26], cases of hypoparathyroidism[27], and infertility[28,29]. DIAGNOSIS There are no specific diagnostic tests for WD (Table 2). Instead, a combination of clinical signs and symptoms and some tests are required to achieve the final diagnosis. Ceruloplasmin Ceruloplasmin is the leading copper transporter protein, carrying 90% of serum circulating copper. It is synthesized in the liver and excreted into the circulation from hepatocytes, mostly as holoceruloplasmin (containing six copper atoms) and the remainder as apoceruloplasmin (not joined to copper)[30]. Ceruloplasmin levels may be determined enzymatically by its copper-dependent oxidase activity or by immunological assays. The immunological assay measures the total ceruloplasmin level but not the ceruloplasmin oxidase activity. Therefore, normal levels of ceruloplasmin do not rule out low oxidase activity and WD. For this reason, the use of enzymatic assays is more appropriate[31]. Blood ceruloplasmin levels are typically low (< 0.2 g/L) in patients with WD and neurological involvement. However, they may be higher in up to half of patients with WD[32]. On the other hand, ceruloplasmin levels are not decreased only in WD, but can be reduced in other conditions such as renal or enteric protein loss, malabsorption, end-stage liver disease, or aceruloplasminemia[33]. In addition, up to 20% of healthy heterozygous carriers have low non-pathological levels of ceruloplasmin. Ceruloplasmin is also an acute-phase reactant and may be elevated in inflammation or infections, resulting in false negatives in WD patients with both characteristics[7]. Serum copper Serum copper decreases proportionally with ceruloplasmin levels. WD should be considered when normal or elevated serum copper levels along with decreased ceruloplasmin are identified, as this indicates an increase in the concentration of non-cerulo- plasmin-bound copper[34]. However, in patients with deficient ceruloplasmin levels, low total serum copper levels can be found even though free copper (albumin-bound copper or non-ceruloplasmin bound copper) may be increased. For this reason, only the determination of free copper is important as total serum copper mostly reflects ceruloplasmin-bound copper. To calculate free copper, serum copper must be subtracted from the value of ceruloplasmin and multiplied by 3 (each ceruloplasmin molecule provides 3 mg of copper). Patients with WD have free copper levels between 10-20 mg/dL and symptomatic individuals have levels > 20 mg/dL[35]. Free copper levels may also be increased in cholestatic syndromes and copper intoxication[36] and Lucena-Valera A et al. Wilson's disease: Revisiting an old friend WJH https://www.wjgnet.com 638 June 27, 2021 Volume 13 Issue 6 Table 2 Diagnosis tests for Wilson’s disease Test Normal values Wilson disease False negative False positive Increased levels: Low levels: MalabsorptionHepatic inflammation Malnutrition Estrogen Aceruloplasminemia Pregnancy Menkes’ disease Infection Terminal liver disease Children Nephropathy with renal protein loss Excess zinc ingestion Ceruloplasmin 0.2-0.4 g/L < 0.2 g/L Overestimation by immunological assay Healthy heterozygotes WD Increased levels: Cholestatic syndromes Acute liver failure Non ceruloplasmin bound copper < 0.3 μg/dL > 10 μg/dL Overestimation of ceruloplasmin by immunological assay Copper intoxication Increased levels: Cholestatic syndromes Autoimmune hepatitis Chronic active liver disease or hepatocellular necrosis Urinary copper excretion < 0.6 μmol/24 h; < 40 μg/24 h > 1.6 μmol/24 h; > 100 μg/24 h Incomplete collection; Children Healthy heterozygotes WD Increased levels: Cholestatic syndromes Liver biopsy < 50 μg/g; < 0.8 μmol/g > 250 μg/g; > 4 μmol/g Uneven copper distribution Idiopathic copper toxicosis disorders Present: Neurological WD Absence: 50% hepatic WD Kayser Fleischer rings Absence Asymptomatic WD Primary biliary cholangitis WD: Wilson’s disease. strikingly elevated in acute WD liver failure due to the sudden release of copper from the liver. Determining free copper is challenging due to the inadequacy of ceruloplasmin determination methods. It is preferable to use enzymatically determined ceruloplasmin levels when calculating free copper, but they do not detect apoceruloplasmin and overestimate ceruloplasmin. For this reason, the determination of ceruloplasmin non-bound copper is not commonly used as a diagnostic method[37]. In 2009, a new method called exchangeable copper (CuEXC) was proposed for the direct determination of labile copper. It can be performed routinely and allows a direct and accurate measurement of copper overload, representing an extrahepatic biomarker[38]. For instance, values greater than 2.08 mmol/L suggest a high risk of severe neurological disease[39]. Additionally, CuEXC facilitates calculation of the relative exchangeable copper. When its threshold is higher than 18.5%, this biomarker reaches a sensitivity and specificity close to 100% in WD diagnosis, without the presence of false negatives [40,41]. Therefore, it could differentiate WD from other liver diseases and healthy heterozygous subjects, representing a promising family screening marker[2,42]. Urinary copper excretion Urinary copper excretion in 24 h reflects the amount of circulating non-ceruloplasmin Lucena-Valera A et al. Wilson's disease: Revisiting an old friend WJH https://www.wjgnet.com 639 June 27, 2021 Volume 13 Issue 6 copper and, therefore, represents the excess copper excreted in the urine. In children, a value greater than 0.64 mmol/24 h or 40 g/24 h is suggestive of WD, while the cut-off for adults is 1.6 mmol/24 h (100 g/24 h)[16]. However, in up to 16%-23%, especially in asymptomatic children and siblings, urinary copper excretion may be lower than the values set[34,43]. After D penicillamine (DPA) administration (1.000 mg administered in two doses), urinary copper excretion consists of measuring urinary copper excretion within 24 h on the same day. It has been proven that urinary copper excretion values > 160 μg/24 h is compatible with WD in children[44]. However, this test is not standardized in adults, so it is not currently recommended in that population. The determination of urinary copper excretion is challenging in some scenarios, such as the presence of renal failure and an incomplete or inadequate collection of urine. In addition, patients with autoimmune hepatitis, cholestatic diseases, acute liver failure, or asymptomatic heterozygous patients can show elevated urinary copper excretion[45]. Liver biopsy Liver biopsy is a non-risk-free invasive technique; thus, it is not easy to perform in asymptomatic patients. Its use is limited to patients with compatible clinical or biochemical findings but without a definite diagnosis. WD has no specific histological changes, although there are suggestive changes. Mild steatosis may be observed in patients without risk factors (alcohol, overweight, diabetes mellitus, or dyslipidemia) who are often mistaken to have non-alcoholic fatty liver disease. Furthermore, staining of metallothionein (protein-bound to intrahepatocyte copper) by orcein or lysosomal copper complexes, using rodain or rubenic acid, show liver copper deposits[35]. The sensitivity of these stains increases when the sample is deposited in xylol for 24 h[46]. Despite this, the hepatic accumulation of copper cannot be ruled out with histochemistry as staining only reveals copper deposits in less than 10% of patients. Thus, intrahepatic copper quantification is essential for the diagnosis of WD after a hepatic biopsy. For the determination of copper in dry weight, it is necessary to obtain a significant sample (at least 1 cm) and its placement in a copper-free and dry container. Values greater than 250 μg/g (4 mmol/g) are diagnostic, while values less than 50 μg/g (0.8 μmol/g) make the diagnosis highly unlikely. The major problem of the intrahepatic quantification of copper is the heterogeneity of distribution of liver copper deposits (which could be unrepresentative), as well as the elevation of intrahepatic copper deposits in cholestatic diseases[47]. Neurological and psychiatric assessment Patients with WD, even if they have predominantly hepatic involvement, should be evaluated neurologically. The neurological symptoms in WD are varied, and include Parkinsonian motor alterations and psychiatric symptoms[18]. Magnetic resonance imaging (MRI) shows structural abnormalities with a hyperintensity in the T2 sequence in the basal ganglia, tectum, spinal bulb, thalamus, and brainstem. Also, there is a decreased intensity in the T1 sequence in the basal ganglia[48]. During MRI, the "giant panda face" sign, found in 14% of patients, is characterized by hyperintensity of the tegmentum of the midbrain, especially around the red nucleus, which maintains its normal hypointensity on T2-weighted imaging axial sections of the brain. This sign, along with the tectal and center-protuberance plaque's hyperintensity and the simultaneous involvement of the basal ganglia, thalamus, and brainstem, are practically pathognomonic of WD[49]. Genetic testing Direct sequencing of the ATP7B gene provides the greatest efficiency in clinical molecular diagnosis. The most common mutation (H1069Q) is present in 40%-50% of patients in Western countries; however, 17% of patients with a diagnosis established by the Leipzig criteria do not have any identifiable ATP7B gene mutation[50]. This may be explained by the inability of genetic testing to distinguish disease-specific mutations from polymorphisms of the gene and the absence of analyzing the noncoding regions of the gene, which can also affect gene expression. However, nextgeneration sequencing is becoming a very useful, reliable, time-saving, and costeffective tool for diagnostic testing in the future. How is the diagnosis established? As previously described, a single test does not allow a definite diagnosis of WD. For this reason, a scoring system that combines clinical parameters with biochemical and Lucena-Valera A et al. Wilson's disease: Revisiting an old friend WJH https://www.wjgnet.com 646 June 27, 2021 Volume 13 Issue 6 10.1023/a:1016546223327] Nakada SY, Brown MR, Rabinowitz R. Wilson's disease presenting as symptomatic urolithiasis: a case report and review of the literature. J Urol 1994; 152: 978-979 [PMID: 8051776 DOI: 10.1016/s0022-5347(17)32635-6] 25 Weizman Z, Picard E, Barki Y, Moses S. 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