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Minemura M, Fukuda R, Tajiri K, Muraishi N, Murayama A, Hayashi Y, Takahara T, Noguchi A, Yasuda I. Wilson's Disease Suspected to Involve a Novel Genetic Mutation of ATP7B Gene, Requiring a Differential Diagnosis with Non-alcoholic Steatohepatitis. Intern Med 2025; 64:375-379. [PMID: 38960689 PMCID: PMC11867747 DOI: 10.2169/internalmedicine.3673-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Accepted: 05/19/2024] [Indexed: 07/05/2024] Open
Abstract
A 19-year-old Japanese man was referred for a further evaluation of liver dysfunction. Despite the absence of symptoms or obesity, the liver biopsy results were consistent with non-alcoholic steatohepatitis. Subsequent investigations revealed low serum ceruloplasmin, increased urinary copper excretion, and a known mutation c.3809A>G (p.Asn1270Ser) in the copper-transporting enzyme P-type ATPase (ATP7B) gene, leading to a diagnosis of Wilson's disease. A previously unreported variant, i.e., c.3866A>T (p.Asp1289Val) was detected on the patient's other allele and was considered a novel mutation, classified as 'likely pathogenic' according to the American College of Medical Genetics guidelines.
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Affiliation(s)
- Masami Minemura
- Department of Gastroenterology, Toyama University Hospital, Japan
- Department of Community Medical Support, Toyama University Hospital, Japan
| | - Rei Fukuda
- Department of Clinical Genetics, Toyama University Hospital, Japan
| | - Kazuto Tajiri
- Department of Gastroenterology, Toyama University Hospital, Japan
| | - Nozomu Muraishi
- Department of Gastroenterology, Toyama University Hospital, Japan
| | - Aiko Murayama
- Department of Gastroenterology, Toyama University Hospital, Japan
| | - Yuka Hayashi
- Department of Gastroenterology, Toyama University Hospital, Japan
| | - Terumi Takahara
- Department of Gastroenterology, Toyama University Hospital, Japan
| | - Akira Noguchi
- Department of Diagnostic Pathology, Toyama University Hospital, Japan
| | - Ichiro Yasuda
- Department of Gastroenterology, Toyama University Hospital, Japan
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2
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Wu Z, Lv G, Xing F, Xiang W, Ma Y, Feng Q, Yang W, Wang H. Copper in hepatocellular carcinoma： A double-edged sword with therapeutic potentials. Cancer Lett 2023; 571:216348. [PMID: 37567461 DOI: 10.1016/j.canlet.2023.216348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 07/28/2023] [Accepted: 08/08/2023] [Indexed: 08/13/2023]
Abstract
Copper is a necessary cofactor vital for maintaining biological functions, as well as participating in the development of cancer. A plethora of studies have demonstrated that copper is a double-edged sword, presenting both benefits and detriments to tumors. The liver is a metabolically active organ, and an imbalance of copper homeostasis can result in deleterious consequences to the liver. Hepatocellular carcinoma (HCC), the most common primary liver cancer, is a highly aggressive malignancy with limited viable therapeutic options. As research advances, the focus has shifted towards the relationships between copper and HCC. Innovatively, cuproplasia and cuproptosis have been proposed to depict copper-related cellular growth and death, providing new insights for HCC treatment. By summarizing the constantly elucidated molecular connections, this review discusses the mechanisms of copper in the pathogenesis, progression, and potential therapeutics of HCC. Additionally, we aim to tentatively provide a theoretical foundation and gospel for HCC patients.
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Affiliation(s)
- Zixin Wu
- Cancer Research Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, Second Military Medical University, Shanghai, 200438, China; National Center for Liver Cancer, Second Military Medical University, Shanghai, 201805, China
| | - Guishuai Lv
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, Second Military Medical University, Shanghai, 200438, China; National Center for Liver Cancer, Second Military Medical University, Shanghai, 201805, China
| | - Fuxue Xing
- Cancer Research Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, Second Military Medical University, Shanghai, 200438, China; National Center for Liver Cancer, Second Military Medical University, Shanghai, 201805, China
| | - Wei Xiang
- Cancer Research Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, Second Military Medical University, Shanghai, 200438, China; National Center for Liver Cancer, Second Military Medical University, Shanghai, 201805, China
| | - Yue Ma
- Cancer Research Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, Second Military Medical University, Shanghai, 200438, China; National Center for Liver Cancer, Second Military Medical University, Shanghai, 201805, China
| | - Qiyu Feng
- Cancer Research Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, Second Military Medical University, Shanghai, 200438, China; National Center for Liver Cancer, Second Military Medical University, Shanghai, 201805, China.
| | - Wen Yang
- Cancer Research Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, Second Military Medical University, Shanghai, 200438, China; National Center for Liver Cancer, Second Military Medical University, Shanghai, 201805, China.
| | - Hongyang Wang
- Cancer Research Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, Second Military Medical University, Shanghai, 200438, China; National Center for Liver Cancer, Second Military Medical University, Shanghai, 201805, China.
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Schilsky ML, Roberts EA, Bronstein JM, Dhawan A, Hamilton JP, Rivard AM, Washington MK, Weiss KH, Zimbrean PC. A multidisciplinary approach to the diagnosis and management of Wilson disease: 2022 Practice Guidance on Wilson disease from the American Association for the Study of Liver Diseases. Hepatology 2022:01515467-990000000-00207. [PMID: 36151586 DOI: 10.1002/hep.32801] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 09/13/2022] [Indexed: 01/18/2023]
Affiliation(s)
- Michael L Schilsky
- Medicine and Surgery , Yale University School of Medicine , New Haven , Connecticut , USA
| | - Eve A Roberts
- Paediatrics, Medicine, Pharmacology and Toxicology , University of Toronto , Toronto , Ontario , Canada
| | - Jeff M Bronstein
- Neurology , University of California Los Angeles , Los Angeles , California , USA
| | - Anil Dhawan
- Paediatric Liver, GI and Nutrition Centre and MowatLabs , King's College Hospital , London , UK
| | - James P Hamilton
- Medicine , Johns Hopkins University School of Medicine , Baltimore , Maryland , USA
| | - Anne Marie Rivard
- Food and Nutrition Services , Yale New Haven Hospital , New Haven , Connecticut , USA
| | - Mary Kay Washington
- Pathology, Immunology and Microbiology , Vanderbilt University Medical Center , Nashville , Tennessee , USA
| | | | - Paula C Zimbrean
- Psychiatry , Yale University School of Medicine , New Haven , Connecticut , USA
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Mahmud S, Gulshan J, Baidya M, Rashid R, Tasneem F, Hasan AR, Farhana T, Ahmed SS. Outcome of Wilson’s disease in Bangladeshi children: a tertiary center experience. EGYPTIAN LIVER JOURNAL 2022. [DOI: 10.1186/s43066-022-00228-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Abstract
Background
Wilson disease (WD) is an inherited disorder of copper metabolism commonly involving the liver, cornea, and brain. Its incidence is increasing day by day worldwide. Early diagnosis and prompt treatment are the key for best outcome.
Material and methods
A cross-sectional descriptive study was done from January 2014 to December 2019. Sixty children of both genders between 3 and 18 years were diagnosed by clinical and laboratory profile meeting selected criteria.
Results
Mean age was 8.42 ± 2.6 years and male female ratio was 1.5:1. Consanguinity of marriage was found in 38.3% cases. Seventy percent of cases were hepatic, 16.7% were neuropsychiatric, 5.0% were hepatic with neuropsychiatric, and 8.3% cases were manifested asymptomatically. Asymptomatic and hepatic WD were reported between 3 and 10 years and most of the neuropsychiatric and hepatic with neuropsychiatric manifested after 10 years of age. More than 50% cases improved, a little more than 20% children died, 18.4% were unchanged and 6.6% were hepatic added neuropsychiatric manifestations. Most of the asymptomatic (100%) and hepatic (61.9%) cases improved. High mortality was found with 76.9% cases of acute liver failure (ALF), 7.7% case of chronic liver disease (CLD) and 25% cases of CLD with portal hypertension (CLD and PH). Most of the neuropsychiatric cases (90.0%), and approximately two-third (66.6%) of hepatic with neuropsychiatric cases remained unchanged. Neuropsychiatric manifestations were added in 15.4% cases of CLD and 25% cases of CLD with PH patient. The treatment was well tolerated in 66% children without any side effects. Low WBC (6.3%) and platelet count (4.3%), vomiting (6.3%), anorexia (4.3%), loss of taste (4.3%), rash (4.3%), and proteinuria (2.1%) were found in few cases.
Conclusion
Majority of the children were presented with hepatic manifestations. More than half of patients with WD treated by D-penicillamine (DP) were improved. Significant mortality was found in acute liver failure whereas neuropsychiatric presentations had persistent abnormalities. No major side effects of DP was observed in most of the cases. Early diagnosis and prompt treatment were crucial for better outcome.
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Lei L, Tan L, Sui L. A novel cuproptosis-related gene signature for predicting prognosis in cervical cancer. Front Genet 2022; 13:957744. [PMID: 36092887 PMCID: PMC9453033 DOI: 10.3389/fgene.2022.957744] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 07/22/2022] [Indexed: 12/13/2022] Open
Abstract
Purpose: Cuproptosis, a form of copper-induced cell death, can be a promising therapeutic target for refractory cancers. Hence, we conducted this research to explore the association between cuproptosis and prognosis in cervical cancer (CC).Methods: For constructing a prognostic signature based on cuproptosis-related genes from TCGA database, the least absolute shrinkage and selection operator Cox regression was utilized. The GSE44001 cohort was utilized for validation.Results: A total of nine cuproptosis-related genes showed distinct expression in CC and normal samples in TCGA-GTEx cohort. Two risk groups were identified based on a seven-gene signature. A significant decrease in overall survival was observed in the high-risk group (p < 0.001). The risk score (HR = 2.77, 95% CI = 1.58–4.86) was an autocephalous predictor with a better predictive ability than the clinical stage. Functional analysis indicated that immune activities were suppressed more in the high-risk group than in the low-risk group. A total of 11 candidate compounds targeting the signature were identified.Conclusion: A total of seven cuproptosis-related gene signatures were constructed to predict prognosis and propose a new therapeutic target for patients with CC.
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Affiliation(s)
- Lei Lei
- Cervical and Vaginal Precancerous Lesion Diagnosis and Treatment, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Liao Tan
- Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Long Sui
- Cervical and Vaginal Precancerous Lesion Diagnosis and Treatment, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
- *Correspondence: Long Sui,
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Davis CI, Gu X, Kiefer RM, Ralle M, Gade TP, Brady DC. Altered copper homeostasis underlies sensitivity of hepatocellular carcinoma to copper chelation. Metallomics 2020; 12:1995-2008. [PMID: 33146201 PMCID: PMC8315290 DOI: 10.1039/d0mt00156b] [Citation(s) in RCA: 89] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Hepatocellular carcinoma (HCC), the most common primary liver cancer, of which ∼800 000 new cases will be diagnosed worldwide this year, portends a five-year survival rate of merely 17% in patients with unresectable disease. This dismal prognosis is due, at least in part, from the late stage of diagnosis and the limited efficacy of systemic therapies. As a result, there is an urgent need to identify risk factors that contribute to HCC initiation and provide targetable vulnerabilities to improve patient survival. While myriad risk factors are known, elevated copper (Cu) levels in HCC patients and the incidence of hepatobiliary malignancies in Wilson disease patients, which exhibit hereditary liver Cu overload, suggests the possibility that metal accumulation promotes malignant transformation. Here we found that expression of the Cu transporter genes ATP7A, ATP7B, SLC31A1, and SLC31A2 was significantly altered in liver cancer samples and were associated with elevated Cu levels in liver cancer tissue and cells. Further analysis of genomic copy number data revealed that alterations in Cu transporter gene loci correlate with poorer survival in HCC patients. Genetic loss of the Cu importer SLC31A1 (CTR1) or pharmacologic suppression of Cu decreased the viability, clonogenic survival, and anchorage-independent growth of human HCC cell lines. Mechanistically, CTR1 knockdown or Cu chelation decreased glycolytic gene expression and downstream metabolite utilization and as a result forestalled tumor cell survival after exposure to hypoxia, which mimics oxygen deprivation elicited by transarterial embolization, a standard-of-care therapy used for patients with unresectable HCC. Taken together, these findings established an association between altered Cu homeostasis and HCC and suggest that limiting Cu bioavailability may provide a new treatment strategy for HCC by restricting the metabolic reprogramming necessary for cancer cell survival.
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Affiliation(s)
- Caroline I. Davis
- Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Xingxing Gu
- Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Ryan M. Kiefer
- Medical Degree Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Penn Image-Guided Interventions Laboratory, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Martina Ralle
- Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, 97239, USA
| | - Terence P. Gade
- Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Penn Image-Guided Interventions Laboratory, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Donita C. Brady
- Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
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Appenzeller-Herzog C, Mathes T, Heeres MLS, Weiss KH, Houwen RHJ, Ewald H. Comparative effectiveness of common therapies for Wilson disease: A systematic review and meta-analysis of controlled studies. Liver Int 2019; 39:2136-2152. [PMID: 31206982 DOI: 10.1111/liv.14179] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 05/16/2019] [Accepted: 06/04/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Wilson disease (WD) is a rare disorder of copper metabolism. The objective of this systematic review was to determine the comparative effectiveness and safety of common treatments of WD. METHODS We included WD patients of any age or stage and the study drugs D-penicillamine, zinc salts, trientine and tetrathiomolybdate. The control could be placebo, no treatment or any other treatment. We included prospective, retrospective, randomized and non-randomized studies. We searched Medline and Embase via Ovid, the Cochrane Central Register of Controlled Trials, and screened reference lists of included articles. Where possible, we applied random-effects meta-analyses. RESULTS The 23 included studies reported on 2055 patients and mostly compared D-penicillamine to no treatment, zinc, trientine or succimer. One study compared tetrathiomolybdate and trientine. Post-decoppering maintenance therapy was addressed in one study only. Eleven of 23 studies were of low quality. When compared to no treatment, D-penicillamine was associated with a lower mortality (odds ratio 0.013; 95% CI 0.0010 to 0.17). When compared to zinc, there was no association with mortality (odds ratio 0.73; 95% CI 0.16 to 3.40) and prevention or amelioration of clinical symptoms (odds ratio 0.84; 95% CI 0.48 to 1.48). Conversely, D-penicillamine may have a greater impact on side effects and treatment discontinuations than zinc. CONCLUSIONS There are some indications that zinc is safer than D-penicillamine therapy while being similarly effective in preventing or reducing hepatic or neurological WD symptoms. Study quality was low warranting cautious interpretation of our findings.
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Affiliation(s)
| | - Tim Mathes
- Institute for Research in Operative Medicine, Faculty of Health, School of Medicine, Witten/Herdecke University, Cologne, Germany
| | - Marlies L S Heeres
- Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Karl Heinz Weiss
- Department of Internal Medicine IV, Medical University of Heidelberg, Heidelberg, Germany
| | - Roderick H J Houwen
- Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Hannah Ewald
- University Medical Library, University of Basel, Basel, Switzerland.,Basel Institute for Clinical Epidemiology and Biostatistics, Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland
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Carrier P, Debette-Gratien M, Jacques J, Loustaud-Ratti V. Cirrhotic patients and older people. World J Hepatol 2019; 11:663-677. [PMID: 31598192 PMCID: PMC6783402 DOI: 10.4254/wjh.v11.i9.663] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 06/18/2019] [Accepted: 07/16/2019] [Indexed: 02/06/2023] Open
Abstract
The global population is aging, and so the number of older cirrhotic patients is increasing. Older patients are characterised by a risk of frailty and comorbidities, and age is a risk factor for mortality in cirrhotic patients. The incidence of non-alcoholic fatty liver disease as an aetiology of cirrhosis is increasing, while that of chronic viral hepatitis is decreasing. Also, cirrhosis is frequently idiopathic. The management of portal hypertension in older cirrhotic patients is similar to that in younger patients, despite the greater risk of treatment-related adverse events of the former. The prevalence of hepatocellular carcinoma increases with age, but its treatment is unaffected. Liver transplantation is generally recommended for patients < 70 years of age. Despite the increasing prevalence of cirrhosis in older people, little data are available and few recommendations have been proposed. This review suggests that comorbidities have a considerable impact on older cirrhotic patients.
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Affiliation(s)
- Paul Carrier
- Fédération d’Hépatologie, Centre Hospitalier Universitaire Dupuytren de Limoges, Limoges 87042, France
- Faculté de Médecine et de Pharmacie de Limoges, Rue Docteur Marcland, Limoges 87042, France
| | - Marilyne Debette-Gratien
- Fédération d’Hépatologie, Centre Hospitalier Universitaire Dupuytren de Limoges, Limoges 87042, France
- Faculté de Médecine et de Pharmacie de Limoges, Rue Docteur Marcland, Limoges 87042, France
| | - Jérémie Jacques
- Service de Gastroentérologie, Centre Hospitalier Universitaire Dupuytren de Limoges, Limoges 87042, France
| | - Véronique Loustaud-Ratti
- Fédération d’Hépatologie, Centre Hospitalier Universitaire Dupuytren de Limoges, Limoges 87042, France
- Faculté de Médecine et de Pharmacie de Limoges, Rue Docteur Marcland, Limoges 87042, France.
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Fukutomi K, Sakamori R, Furuta K, Shigekawa M, Yamada R, Kodama T, Hikita H, Yakushijin T, Tatsumi T, Honma K, Morii E, Takehara T. Hepatocellular carcinoma in a case of Wilson's disease with non-cirrhotic liver. ACTA ACUST UNITED AC 2017. [DOI: 10.2957/kanzo.58.519] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Affiliation(s)
- Keisuke Fukutomi
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine
| | - Ryotaro Sakamori
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine
| | - Kunimaro Furuta
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine
| | - Minoru Shigekawa
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine
| | - Ryoko Yamada
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine
| | - Takahiro Kodama
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine
| | - Hayato Hikita
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine
| | - Takayuki Yakushijin
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine
| | - Tomohide Tatsumi
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine
| | - Keiichiro Honma
- Department of Diagnostic Pathology, Osaka University Hospital
| | - Eiichi Morii
- Department of Diagnostic Pathology, Osaka University Hospital
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine
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10
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Liu Z, Yang W, Long G, Wei C. Trace Elements and Chemotherapy Sensitivity. Biol Trace Elem Res 2016; 173:283-90. [PMID: 26961293 DOI: 10.1007/s12011-016-0667-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Accepted: 02/29/2016] [Indexed: 12/31/2022]
Abstract
Trace elements might be associated with the development of hepatocellular carcinoma (HCC) and the efficacy of chemotherapy against HCC. Therefore, this study aimed to explore the association between trace elements and efficacy of chemotherapy in patients with HCC. Cancer, cancer-adjacent, and cancer-free tissues were collected intraoperatively from 55 patients with HCC between January 2001 and April 2004 at the Affiliated Tumor Hospital of Guangxi Medical University in Guangxi (China), a high HCC incidence area in the world. Trace element levels were analyzed by atomic absorption spectrophotometry. In vitro sensitivity of cancer cells to five chemotherapeutic drugs (5-fluorouracil, doxorubicin, cisplatin, carboplatin, and mitomycin) was tested using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in cancer cells from 32 patients. Zinc, copper, manganese, and selenium levels had the same gradient distribution in different liver tissues: cancer < cancer-adjacent < cancer-free tissues. Copper levels of cancer tissues were negatively correlated with body weight (r = -0.278, P = 0.027), while manganese and selenium levels were negatively correlated with age (r = -0.297, P = 0.015; r = -0.285, P = 0.018, respectively). Simple correlation analyses revealed that the carboplatin sensitivity was negatively correlated with selenium levels of cancer tissues, while doxorubicin sensitivity was negatively correlated with manganese levels (r = -0.497, P = 0.004). Partial correlation analyses showed that doxorubicin sensitivity only was negatively correlated with manganese levels (r = -0.450, P = 0.014). These results suggest that the selenium and manganese content in primary HCC tissues could influence the response of the HCC cells to carboplatin and doxorubicin. These preliminary results provide a basis for future studies.
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Affiliation(s)
- Zhihui Liu
- The First Chemotherapy Department, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi Province, 530021, China
| | - Weiping Yang
- Department of ultrasonography, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi Province, 530021, China
| | - Gang Long
- Guangxi Center of Analysis and Test Research, Nanning, Guangxi Province, 530022, China
| | - Changyuan Wei
- Department of Breast Surgery, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi Province, 530021, China.
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Abstract
Hepatic involvement in Wilson disease (WD) manifests as a diffuse chronic disease in the majority of patients. However, in a subset of patients focal liver lesions may develop, presenting with a wide range of imaging features. The majority of focal liver lesions in patients with WD are benign nodules, but there are reports that have described malignant liver tumors or dysplastic nodules in these patients. Because of the possibility of malignant transformation of liver nodules, major concerns have been raised with respect to the management and follow-up of patients with WD in whom focal liver lesions have been identified. The assessment of liver involvement in patients with WD is generally performed with ultrasonography. However, ultrasonography conveys limited specificity so that magnetic resonance (MR) imaging is often performed to improve lesion characterization. This review was performed to illustrate the spectrum of MR imaging features of focal liver lesions that develop in patients with WD. It is assumed that familiarity with the MR imaging presentation of focal liver lesions in WD may help clarify the actual nature of hepatic nodules in patients with this condition.
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12
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Mukai Y, Wada H, Eguchi H, Yamada D, Asaoka T, Noda T, Kawamoto K, Gotoh K, Takeda Y, Tanemura M, Umeshita K, Hori Y, Morii E, Doki Y, Mori M. Intrahepatic cholangiocarcinoma in a patient with Wilson's disease: a case report. Surg Case Rep 2016; 2:29. [PMID: 27005296 PMCID: PMC4803712 DOI: 10.1186/s40792-016-0156-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Accepted: 03/17/2016] [Indexed: 12/22/2022] Open
Abstract
The incidence of hepatobiliary malignancies, and especially intrahepatic cholangiocarcinoma (ICC), for patients with Wilson’s disease (WD), is very low, even for cirrhotic patients. A 44-year-old male was admitted to our department for treatment of a liver tumor. He was diagnosed with WD at the age of 15. According to radiological findings, his liver tumor was a suspected hepatocellular carcinoma (HCC) or a combined hepatocellular and cholangiocellular carcinoma. A partial resection of liver segments 8 (S8) and 5 (S5) was subsequently performed due to the intraoperative suspicion of intrahepatic metastasis at the surface of S5. Postoperative histology revealed that the resected portion of S8 contained an ICC; the removed S5 portion comprised a regenerative nodule with hemosiderosis. To date, the patient has survived without tumor recurrence for more than 44 months following surgery. A survey of the literature, inclusive of case reports, would suggest that surgical resection is the primary course of action for a WD patient with ICC, if liver function can be preserved and curative resection performed.
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Affiliation(s)
- Yosuke Mukai
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2-E2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Hiroshi Wada
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2-E2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2-E2, Yamadaoka, Suita, Osaka, 565-0871, Japan.
| | - Daisaku Yamada
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2-E2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Tadafumi Asaoka
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2-E2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Takehiro Noda
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2-E2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Koichi Kawamoto
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2-E2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Kunihito Gotoh
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2-E2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yutaka Takeda
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2-E2, Yamadaoka, Suita, Osaka, 565-0871, Japan.,Department of Surgery, Kansai Rosai Hospital, Osaka, Japan
| | - Masahiro Tanemura
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2-E2, Yamadaoka, Suita, Osaka, 565-0871, Japan.,Department of Surgery, Osaka Police Hospital, Osaka, Japan
| | - Koji Umeshita
- Division of Health Sciences, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Yumiko Hori
- Department of Diagnostic Pathology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Eiichi Morii
- Department of Diagnostic Pathology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2-E2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Masaki Mori
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2-E2, Yamadaoka, Suita, Osaka, 565-0871, Japan
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13
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Zuccoli G, Yannes MP, Nardone R, Bailey A, Goldstein A. Bilateral symmetrical basal ganglia and thalamic lesions in children: an update (2015). Neuroradiology 2015; 57:973-89. [DOI: 10.1007/s00234-015-1568-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2015] [Accepted: 07/15/2015] [Indexed: 01/09/2023]
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Pfeiffenberger J, Mogler C, Gotthardt DN, Schulze-Bergkamen H, Litwin T, Reuner U, Hefter H, Huster D, Schemmer P, Członkowska A, Schirmacher P, Stremmel W, Cassiman D, Weiss KH. Hepatobiliary malignancies in Wilson disease. Liver Int 2015; 35:1615-1622. [PMID: 25369181 DOI: 10.1111/liv.12727] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2014] [Accepted: 10/30/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUNDS & AIMS Reports of hepatobiliary malignancies in Wilson disease are sparse. The aim of this study was to evaluate hepatobiliary malignancies in Wilson disease patients concerning the clinical course of tumour disease and pathological analysis of tumour tissue. METHODS Multicenter cohort study of patients with confirmed diagnosis of Wilson disease treated at the Second Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland, the university hospitals Heidelberg, Duesseldorf and Dresden, Germany, and the Department of Hepatology, University Leuven, Belgium. Occurrence, treatment and outcome of hepatobiliary tumours were analysed retrospectively. RESULTS Of a total of 1186 patients, fourteen developed hepatobiliary malignancies. Eight were hepatocellular carcinomas (HCC) and six were intrahepatic cholangiocellular carcinomas (ICC). The prevalence of hepatobiliary malignancies in the cohort was 1.2% and the incidence was 0.28 per 1000 person years. Pathological analysis of tumour material showed no abnormal copper concentration. CONCLUSIONS The rate of hepatobiliary malignancies in Wilson disease is very low, even in cirrhotic patients. As a result of the relevant number of ICC in addition to HCC histological analysis through surgical resection or biopsy should be mandatory when a suspect liver lesion is detected. The influence of copper depletion from Wilson disease-specific medical treatment on tumour activity remains to be elucidated.
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Affiliation(s)
- Jan Pfeiffenberger
- Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany; Liver Cancer Center Heidelberg, University Hospital Heidelberg, Heidelberg, Germany
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15
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van Meer S, de Man RA, van den Berg AP, Houwen RHJ, Linn FHH, van Oijen MGH, Siersema PD, van Erpecum KJ. No increased risk of hepatocellular carcinoma in cirrhosis due to Wilson disease during long-term follow-up. J Gastroenterol Hepatol 2015; 30:535-9. [PMID: 25160780 DOI: 10.1111/jgh.12716] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/11/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Data on risk of hepatocellular carcinoma (HCC) in patients with Wilson disease are scarce. We determine HCC risk in a well-defined cohort of Wilson patients. METHODS All patients with a confirmed diagnosis of Wilson disease (Leipzig score ≥ 4) in three Dutch university referral hospitals were included in this retrospective cohort study. End of follow-up was defined as date of diagnosis of HCC, liver transplantation, death, or last available hospital visit. Also, a meta-analysis was performed to determine incidence and mortality rate of HCC in Wilson disease based on all published cohorts. RESULTS In total, 130 patients with Wilson disease were followed during a median follow-up of 15 years (range 0.1-51.2). At baseline, cirrhosis was present in 74 patients (57% of total: 64% compensated, and 36% decompensated). At end of follow-up, liver disease severity was improved, stable or deteriorated in 20%, 46%, and 24% of all cases (10% unknown), respectively. Two patients developed HCC (one despite excellent decoppering after 50 years follow-up, the other with newly diagnosed Wilson disease). Estimated annual HCC risk for all patients was 0.09% (95% confidence interval [CI]: 0.01-0.28). Subgroup analysis in cirrhotic patients revealed an annual HCC risk of 0.14% (95% CI: 0.02-0.46). The meta-analysis showed an annual HCC risk of 0.04% (95% CI: 0.01-0.10) and HCC mortality rate of 2.6/10 000 person-years (95% CI: 0.7-7.0). CONCLUSIONS Even in case of cirrhosis, HCC risk is low in Wilson disease. Our data do not support regular HCC surveillance in Wilson disease.
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Affiliation(s)
- Suzanne van Meer
- Department of Gastroenterology and Hepatology, University Medical Center, Utrecht, The Netherlands
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16
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Harada M. Pathogenesis and management of Wilson disease. Hepatol Res 2014; 44:395-402. [PMID: 24450973 DOI: 10.1111/hepr.12301] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2013] [Revised: 01/09/2014] [Accepted: 01/14/2014] [Indexed: 02/08/2023]
Abstract
Hepatolenticular degeneration, commonly known as Wilson disease, is an autosomal recessive inherited disease of abnormal copper metabolism, characterized by the accumulation of copper in the body due to decreased biliary excretion of copper from hepatocytes. Wilson disease protein, ATP7B, functions in copper excretion into bile and in copper secretion to the bloodstream coupled with ceruloplasmin synthesis. Various kinds of mutations of ATP7B cause Wilson disease. Wilson disease is a rare genetic disease that can be treated pharmacologically. Recognition and prompt diagnosis are very important, because Wilson disease is fatal if left untreated. In this review, I summarize the pathogenesis and management of Wilson disease.
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Affiliation(s)
- Masaru Harada
- Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
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Thattil R, Dufour JF. Hepatocellular carcinoma in a non-cirrhotic patient with Wilson's disease. World J Gastroenterol 2013; 19:2110-3. [PMID: 23599633 PMCID: PMC3623991 DOI: 10.3748/wjg.v19.i13.2110] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2012] [Revised: 12/03/2012] [Accepted: 12/15/2012] [Indexed: 02/06/2023] Open
Abstract
We report the exceptional case of hepatocellular carcinoma in a non-cirrhotic patient, whose Wilson’s disease was diagnosed at the unusual age of 58 years. The liver histology revealed macrovesicular steatosis with fibrosis, but no cirrhosis. The disease was treated with D-penicillamine for 3 years until acute discomfort in the right upper quadrant led to detection of multifocal hepatocellular carcinoma, which was successfully resected. The histological examination confirmed the malignant nature of the 4 lesions, which were classified according to Edmondson and Steiner as poorly differentiated hepatocellular carcinoma grade 3. The non-tumoral parenchyma showed 80% steatosis with ballooned cells, lobular inflammation, septal fibrosis but no cirrhosis. Hepatocellular carcinoma is rare in Wilson’s disease, especially in the absence of cirrhosis. The literature’s 28 published cases are reviewed and the contributory role of copper in the hepatocarcinogenic process is discussed.
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18
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Characteristics of neurological Wilson's disease without Kayser–Fleischer ring. J Neurol Sci 2012; 323:183-6. [DOI: 10.1016/j.jns.2012.09.013] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2012] [Revised: 09/03/2012] [Accepted: 09/10/2012] [Indexed: 12/28/2022]
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Wilson disease: Canadian perspectives on presentation and outcomes from an adult ambulatory setting. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2012; 26:333-9. [PMID: 22720274 DOI: 10.1155/2012/123431] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
BACKGROUND Wilson disease (WD) is a rare disorder of copper metabolism. OBJECTIVE To describe the authors' clinical experience with a cohort of 48 adult patients followed in an ambulatory setting. METHODS A retrospective chart review of patients with a diagnosis of WD was performed. RESULTS Fifty-nine charts were identified and 11 were excluded on further review. At diagnosis, 14 patients were asymptomatic, with 13 hepatic, 15 neurological and six mixed hepatic⁄neurological presentations. Ceruloplasmin levels were low (<0.20 g⁄L) in 94%, and 24 h urinary copper levels high (>0.60 µmol⁄L) in 95% of cases. D-penicillamine was the most common initial therapy (48%), with zinc the most common at review (65%). Overall, biopsy and ultrasound reports documented cirrhosis in 53%. Portal hypertension, defined as splenomegaly (>12.0 cm), reversed portal venous flow on ultrasound or varices⁄gastropathy on endoscopy was seen in 63%. At last review, 39% had elevated aspartate aminotransferase (>34 U⁄L) and⁄or alanine aminotransferase levels (>40 U⁄L). One death and one transplant occurred, while three patients had encephalopathy, two became jaundiced, two developed ascites and one experienced variceal bleed. Of 21 neurological presenting patients, 14 improved compared with baseline, with four making almost complete recovery. Eleven patients experienced documented episodes of neurological decline, including four with non-neurological presentation. Diagnostic magnetic resonance imaging showed basal ganglia (64%), brainstem (64%) abnormalities and atrophy (36%); follow-up showed basal ganglia lesions (50%) and atrophy (55%). CONCLUSION WD is a diverse chronic disease with generally favourable outcomes for patients who respond to initial therapy, which can be managed predominantly in an ambulatory setting.
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Kodama H, Fujisawa C, Bhadhprasit W. Inherited copper transport disorders: biochemical mechanisms, diagnosis, and treatment. Curr Drug Metab 2012; 13:237-50. [PMID: 21838703 PMCID: PMC3290776 DOI: 10.2174/138920012799320455] [Citation(s) in RCA: 124] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2011] [Revised: 03/07/2011] [Accepted: 05/16/2011] [Indexed: 12/14/2022]
Abstract
Copper is an essential trace element required by all living organisms. Excess amounts of copper, however, results in cellular damage. Disruptions to normal copper homeostasis are hallmarks of three genetic disorders: Menkes disease, occipital horn syndrome, and Wilson's disease. Menkes disease and occipital horn syndrome are characterized by copper deficiency. Typical features of Menkes disease result from low copper-dependent enzyme activity. Standard treatment involves parenteral administration of copper-histidine. If treatment is initiated before 2 months of age, neurodegeneration can be prevented, while delayed treatment is utterly ineffective. Thus, neonatal mass screening should be implemented. Meanwhile, connective tissue disorders cannot be improved by copper-histidine treatment. Combination therapy with copper-histidine injections and oral administration of disulfiram is being investigated. Occipital horn syndrome characterized by connective tissue abnormalities is the mildest form of Menkes disease. Treatment has not been conducted for this syndrome. Wilson's disease is characterized by copper toxicity that typically affects the hepatic and nervous systems severely. Various other symptoms are observed as well, yet its early diagnosis is sometimes difficult. Chelating agents and zinc are effective treatments, but are inefficient in most patients with fulminant hepatic failure. In addition, some patients with neurological Wilson's disease worsen or show poor response to chelating agents. Since early treatment is critical, a screening system for Wilson's disease should be implemented in infants. Patients with Wilson's disease may be at risk of developing hepatocellular carcinoma. Understanding the link between Wilson's disease and hepatocellular carcinoma will be beneficial for disease treatment and prevention.
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Affiliation(s)
- Hiroko Kodama
- Department of health Dietetics, Teikyo Heisei University, Toshima-ku, Tokyo.
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Hayashi H, Shinohara T, Goto K, Fujita Y, Murakami Y, Hattori A, Tatsumi Y, Shimizu A, Ichiki T. Liver structures of a patient with idiopathic copper toxicosis. Med Mol Morphol 2012; 45:105-9. [PMID: 22718296 DOI: 10.1007/s00795-011-0556-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2011] [Accepted: 07/06/2011] [Indexed: 11/28/2022]
Abstract
This is the first report describing the liver structures of a Japanese patient with idiopathic copper toxicosis, which should be differentiated from hepatolenticular degeneration of Wilson disease. An 11-year-old Japanese boy presented with ascites associated with biochemical liver damage. Involvement of hepatitis virus was ruled out by laboratory tests. Because urinary copper excretion was increased, Wilson disease was highly suspected, but the serum level of ceruloplasmin was normal, and Kayser-Fleischer rings were not detected by slit lamp examination. Brain images were within normal limits. ATP7B analysis was negative for mutations. Liver specimen showed cirrhosis associated with chronic active hepatitis. Almost all hepatocytes were positive for orcein-stained granules. Mallory bodies were found in some hepatocytes. Fatty change was minimal, and there were no glycogenated nuclei in the parenchyma. Combined regimens of trientine and zinc for 6 months improved the decompensated state of liver function. After 2.5 years of treatment, a second liver biopsy was performed. The post-treatment liver showed complete disappearance of portal inflammation and remarkable decrease in cuprothionein granules. Mallory bodies disappeared from the parenchyma. An abundance of hepatocellular Mallory bodies and heavy copper loading limited to the liver may be specific to idiopathic copper toxicosis.
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Affiliation(s)
- Hisao Hayashi
- Department of Medicine, Aichi Gakuin University School of Pharmacy, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya, 464-8650, Japan.
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Giannelli G, Mazzocca A, Fransvea E, Lahn M, Antonaci S. Inhibiting TGF-β signaling in hepatocellular carcinoma. Biochim Biophys Acta Rev Cancer 2011; 1815:214-23. [PMID: 21129443 DOI: 10.1016/j.bbcan.2010.11.004] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2010] [Revised: 11/18/2010] [Accepted: 11/20/2010] [Indexed: 12/17/2022]
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Ikegawa S, Hiraoka A, Shimizu Y, Hidaka S, Tazuya N, Ichiryu M, Nakahara H, Tanabe A, Tanihira T, Hasebe A, Miyamoto Y, Ninomiya T, Hirooka M, Kumagi T, Abe M, Hiasa Y, Onji M, Michitaka K. Hepatocellular carcinoma in a case of Wilson's disease treated with radiofrequency ablation therapy. Intern Med 2011; 50:1433-7. [PMID: 21720066 DOI: 10.2169/internalmedicine.50.5203] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
A 37-year-old Japanese man was diagnosed with liver cirrhosis due to Wilson's disease in 2001 and treated with D-penicillamine. Thereafter, he was admitted to our hospital for further examination of a space occupying lesion in the liver. The patient was diagnosed with hepatocellular carcinoma (HCC) (7th segment, 2.5 cm in diameter) in May 2010 and treated with radiofrequency ablation therapy. Biopsy findings from a non-cancerous area revealed a fatty liver, though cirrhotic nodules were not found. Long-term treatment for Wilson's disease may improve hepatic fibrosis, and careful screening for HCC by abdominal imaging is needed in such cases.
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Bem RSD, Muzzillo DA, Deguti MM, Barbosa ER, Werneck LC, Teive HAG. Wilson's disease in southern Brazil: a 40-year follow-up study. Clinics (Sao Paulo) 2011; 66:411-6. [PMID: 21552664 PMCID: PMC3072000 DOI: 10.1590/s1807-59322011000300008] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2010] [Accepted: 11/17/2010] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Long-term data on the clinical follow-up and the treatment effectiveness of Wilson's disease are limited because of the low disease frequency. This study evaluated a retrospective cohort of Wilson's disease patients from southern Brazil during a 40-year follow-up period. METHODS Thirty-six Wilson's disease patients, diagnosed from 1971 to 2010, were retrospectively evaluated according to their clinical presentation, epidemiological and social features, response to therapy and outcome. RESULTS Examining the patients' continental origins showed that 74.5% had a European ancestor. The mean age at the initial symptom presentation was 23.3 ± 9.3 years, with a delay of 27.5 ± 41.9 months until definitive diagnosis. At presentation, hepatic symptoms were predominant (38.9%), followed by mixed symptoms (hepatic and neuropsychiatric) (30.6%) and neuropsychiatric symptoms (25%). Kayser-Fleischer rings were identified in 55.6% of patients, with a higher frequency among those patients with neuropsychiatric symptoms (77.8%). Eighteen patients developed neuropsychiatric features, most commonly cerebellar syndrome. Neuroradiological imaging abnormalities were observed in 72.2% of these patients. Chronic liver disease was detected in 68% of the patients with hepatic symptoms. 94.2% of all the patients were treated with D-penicillamine for a mean time of 129.9 ± 108.3 months. Other treatments included zinc salts, combined therapy and liver transplantation. After initiating therapy, 78.8% of the patients had a stable or improved outcome, and the overall survival rate was 90.1%. CONCLUSION This study is the first retrospective description of a population of Wilson's disease patients of mainly European continental origin who live in southern Brazil. Wilson's disease is treatable if correctly diagnosed, and an adequate quality of life can be achieved, resulting in a long overall survival.
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Affiliation(s)
- Ricardo Schmitt de Bem
- Gastroenterology and Hepatology Service, Internal Medicine Department, Federal University of Parana, Curitiba, Paraná, Brazil.
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Takeyama Y, Yokoyama K, Takata K, Tanaka T, Sakurai K, Matsumoto T, Iwashita H, Ueda SI, Hirano G, Hanano T, Nakane H, Morihara D, Nishizawa S, Yoshikane M, Anan A, Kakumitsu S, Kitamura Y, Sakamoto M, Irie M, Iwata K, Shakado S, Sohda T, Watanabe H, Hirose S, Hayashi H, Noritomi T, Yamashita Y, Sakisaka S. Clinical features of Wilson disease: Analysis of 10 cases. Hepatol Res 2010; 40:1204-11. [PMID: 21040274 DOI: 10.1111/j.1872-034x.2010.00728.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
AIM The diagnosis of Wilson disease is based on the results of several clinical and biochemical tests. This study aimed to clarify the clinical features and spectrum of Wilson disease, including severe Wilson disease. METHODS Between 1985 and 2009, 10 patients with clinical, biochemical or histological evidence of Wilson disease were either diagnosed or had a previously established diagnosis confirmed at Fukuoka University Hospital. Severe Wilson disease was defined by a serum prothrombin time ratio of more than 1.5 or serum prothrombin activity of less than 50%. The 10 Wilson disease patients were divided into two groups, one containing three non-severe patients and the other containing seven severe patients, and the biochemical features of the patients in these two groups were compared. RESULTS The mean age at diagnosis was 21.5 ± 11.7 years (range, 7-39). Decreased serum ceruloplasmin, enhanced 24-h urinary copper excretion, presence of Kayser-Fleischer rings and histological signs of chronic liver damage were confirmed in 100%, 100%, 66.7% and 100% of patients, respectively. Severe Wilson disease patients had higher levels of serum ceruloplasmin and serum copper (P < 0.05, P < 0.05, respectively) than non-severe patients. CONCLUSION In severe Wilson disease patients, the serum ceruloplasmin and serum copper levels were higher than those in non-severe Wilson disease patients.
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Affiliation(s)
- Yasuaki Takeyama
- Departments of Gastroenterology and Medicine Pediatrics Ophthalmology Surgery The Division of Advanced Clinical Research for Viral Hepatitis and Liver Cancer, Fukuoka University Faculty of Medicine Department of Medicine, Hakujyuji Hospital Department of Hepatology, Japanese Red Cross Fukuoka Hospital Department of Gastroenterology, Fukuoka City Medical Association Hospital Department of Internal Medicine, Fukuseikai Hospital, Fukuoka, Japan
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Abstract
Triethylenetetramine (TETA), a Cu(II)-selective chelator, is commonly used for the treatment of Wilson's disease. Recently, it has been shown that TETA can be used in the treatment of cancer because it possesses telomerase inhibiting and anti-angiogenesis properties. Although TETA has been used in the treatment of Wilson's disease for decades, a comprehensive review on TETA pharmacology does not exist. TETA is poorly absorbed with a bioavailability of 8 to 30%. It is widely distributed in tissues with relatively high concentrations measured in liver, heart, and kidney. It is mainly metabolized via acetylation, and two major acetylated metabolites exist in human serum and urine. It is mainly excreted in urine as the unchanged parent drug and two acetylated metabolites. It has a relatively short half-life (2 to 4 hours) in humans. The most recent discoveries in TETA pharmacology show that the major pharmacokinetic parameters are not associated with the acetylation phenotype of N-acetyltransferase 2, the traditionally regarded drug acetylation enzyme, and the TETA-metabolizing enzyme is actually spermidine/spermine acetyltransferase. This review also covers the current preclinical and clinical application of TETA. A much needed overview and up-to-date information on TETA pharmacology is provided for clinicians or cancer researchers who intend to embark on cancer clinical trials using TETA or its close structural analogs.
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Affiliation(s)
- Jun Lu
- School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand.
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Sócio SDA, Ferreira AR, Fagundes EDT, Roquete MLV, Pimenta JR, Campos LDF, Penna FJ. Doença de Wilson em crianças e adolescentes: diagnóstico e tratamento. REVISTA PAULISTA DE PEDIATRIA 2010. [DOI: 10.1590/s0103-05822010000200002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
OBJETIVO: Descrever as formas de apresentação, as alterações laboratoriais ao diagnóstico e o tratamento de crianças e adolescentes com doença de Wilson. MÉTODOS: Estudo descritivo e retrospectivo de 17 crianças e adolescentes com doença de Wilson atendidos no Ambulatório de Hepatologia Pediátrica do Hospital das Clínicas da Universidade Federal de Minas Gerais no período de 1985 a 2008. Os dados foram coletados dos prontuários e durante as consultas ambulatoriais. RESULTADOS: A idade ao diagnóstico variou de 2,8 a 15,1 anos, com média de 8,8±0,9 anos. A forma de apresentação predominante foi hepática (53%), seguida por assintomáticos provenientes de triagem familiar. O anel de Kayser-Fleischer foi encontrado em 41% dos pacientes. A ceruloplasmina encontrava-se alterada em 15/17 pacientes e o cobre urinário variou de 24 a 1000mcg/24h (mediana: 184mcg/24h). O tratamento instituído foi a D-penicilamina. Observaram-se efeitos colaterais em cinco crianças, sem necessidade de interrupção ou troca da medicação. As respostas clínica e laboratorial, com níveis normais de aminotransferases, foram evidenciadas em 14 pacientes após mediana de 10,7 meses de tratamento. Três crianças morreram (uma por hepatite fulminante e duas com complicações da insuficiência hepática grave), apesar do tratamento. CONCLUSÕES: A doença de Wilson é rara na faixa etária pediátrica. A forma de apresentação predominante é a hepática. Seu diagnóstico se baseia principalmente em dosagem de ceruloplasmina baixa, cobre livre e cobre em urina de 24 horas elevados, mas exige alto grau de suspeição. Apresenta boa resposta e tolerância ao tratamento medicamentoso.
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Wilson's disease: long-term follow-up of a cohort of 24 patients treated with D-penicillamine. Eur J Gastroenterol Hepatol 2010; 22:564-71. [PMID: 20042865 DOI: 10.1097/meg.0b013e3283353df8] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
BACKGROUND AND STUDY AIMS Detailed data on long-term effectiveness of various drug therapies in Wilson's disease (WD) are lacking. Therefore, we retrospectively reviewed our patient cohort treated with D-penicillamine. PATIENTS AND METHODS This study reports on the clinical presentation, the diagnostic evaluation, and the disease course in 24 WD patients treated long-term (15+/-12 years, between 1969 and 2009) with D-penicillamine. RESULTS The overall survival in our cohort was 91.6%. Twenty-two of 24 patients had liver disease at presentation, 17 of 24 patients (71%) had cirrhosis, 11 of whom had complications of cirrhosis. Six of 11 of these patients showed hepatological improvement (five of six) or stabilization (one of six), three of 11 were transplanted, one of 11 died, one of 11 discontinued follow-up. In the six of 17 cirrhotic patients without complications, improvement (four of six) or stabilization (two of six) occurred. Of all other patients (seven of 24), five of seven showed improvement (three of five) or stabilization (two of five), hepatological deterioration occurred only in one patient due to poor therapy compliance and one of seven discontinued follow-up. Neuropsychiatric symptoms were present in 13 of 24 at presentation and resolved in one of 13, decreased in seven of 13, stabilized in four of 13 and worsened in one of 13 patients (due to poor compliance). In general, we observed a favorable hepatological and neurological evolution with D-penicillamine. CONCLUSION Despite the presence of liver disease or neuropsychiatric symptoms at baseline in all but one of the patients, we report beneficial results on liver and neurological disease after very long-term treatment with D-penicillamine, thereby adding to its reputation as 'first-line' therapy in WD.
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Ikubo A, Hotta K, Sakai M, Yamaji K, Mitsuno M, Samejima R, Tabuchi M, Yunotani S, Handa M, Yamasaki F. Resected multiple hepatocellular carcinoma associated with Wilson's disease presenting with neurological complication: Report of a case. ACTA ACUST UNITED AC 2010. [DOI: 10.2957/kanzo.51.379] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
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Triethylene tetramine dihydrochloride (trientine) in children with Wilson disease: experience at King's College Hospital and review of the literature. Eur J Pediatr 2009; 168:1061-8. [PMID: 19066958 DOI: 10.1007/s00431-008-0886-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2008] [Accepted: 11/19/2008] [Indexed: 01/31/2023]
Abstract
Our aim was to review our experience of trientine as chelation therapy in children with Wilson disease (WD) and compare to that reported in the literature. We made a retrospective review of the medical notes of 16 of 96 (17%) children diagnosed with WD between 1981 and 2006. Children were 6.6 to 15 years old. Only three received trientine as initial therapy [parental choice (two), allergic reactions to penicillamine (one) during the penicillamine challenge], 13 of 16 were converted from penicillamine to trientine because of reactions to penicillamine: haematuria in four, bone marrow suppression in three, neutropenia in three. Trientine was discontinued in three due to allergic rash, low copper excretion and one with compliance problems requiring transplantation. Seventy-five per cent of children presented with chronic liver disease. Kayser-Fleischer rings were noticed in eight of 16, Wilson Ferenci score range was between 4 and 10 (nl < 4). Laboratory indices remained relatively stable. In line with previous reports, trientine was used mainly as secondary treatment when there were severe side effects with penicillamine. Whilst the current evidence is low quality, it appears that trientine is as efficacious as penicillamine and small population studies show a lower side effect profile.
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Wiggelinkhuizen M, Tilanus MEC, Bollen CW, Houwen RHJ. Systematic review: clinical efficacy of chelator agents and zinc in the initial treatment of Wilson disease. Aliment Pharmacol Ther 2009; 29:947-58. [PMID: 19210288 DOI: 10.1111/j.1365-2036.2009.03959.x] [Citation(s) in RCA: 94] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND No consensus is available on the optimal initial treatment in Wilson disease. AIM To assess systematically the available literature of treatment in newly presenting patients with a presymptomatic, hepatic or neurological presentation of Wilson disease. METHODS A systematic literature search of the MEDLINE, EMBASE and COCHRANE databases was performed. Original studies on clinical efficacy of D-penicillamine, trientine, tetrathiomolybdate or zinc monotherapy as initial treatment in Wilson disease were included. A descriptive analysis of the relevant published data was performed. RESULTS One randomized trial and 12 observational studies met the inclusion criteria. These studies were quite heterogeneous and generally of low validity. Nevertheless, according to currently available data, patients with hepatic presentation of Wilson disease are probably most effectively treated by D-penicillamine. Zinc seems to be preferred above d-penicillamine for treatment of presymptomatic and neurological patients, as in these subgroups, the tolerance profile is in favour of zinc, while no obvious differences in clinical efficacy could be observed. CONCLUSIONS There is lack of high-quality evidence to estimate the relative treatment effects of the available drugs in Wilson disease. Therefore, multicentre prospective randomized controlled comparative trials are necessary.
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Affiliation(s)
- M Wiggelinkhuizen
- Department of Paediatric Gastroenterology, University Medical Centre Utrecht, Utrecht, The Netherlands
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Abstract
The prevalence of chronic liver disease is increasing in the elderly population. With a mostly asymptomatic or non-specific presentation, these diseases may easily go undiagnosed. Abnormal liver function tests of unknown cause are a common reason for referral to secondary care. Investigating the older person with abnormal liver function is important; even with mild abnormalities, the same vigilance should be applied to an older person as in a young person. Liver biopsy is safe but often overlooked in this age group and may provide useful information to diagnose, direct therapy and prognosticate. Treatment options are similar for all age groups, with a few subtle differences, although further evidence is frequently required for the older population. Morbidity and age-adjusted mortality are often more severe in older people, and therefore early diagnosis and intervention is important. Presented here are the most common chronic liver diseases that geriatricians are likely to encounter in clinical practise. Their epidemiology, clinical features, investigation, treatment and mortality are described with a particular focus on the elderly population.
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Affiliation(s)
- James Frith
- Biomedical Research Centre in Ageing, Liver Theme and Institute of Cellular Medicine, Newcastle University, Newcastle NE2 4HH, UK
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Affiliation(s)
- Eve A Roberts
- Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, and Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada
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Chiarla C, Giovannini I, Siegel JH. Patterns of correlation of plasma ceruloplasmin in sepsis. J Surg Res 2007; 144:107-10. [PMID: 17688883 DOI: 10.1016/j.jss.2007.03.024] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2006] [Revised: 02/20/2007] [Accepted: 03/12/2007] [Indexed: 11/26/2022]
Abstract
BACKGROUND In sepsis, plasma ceruloplasmin (Cp, mg/L) is known to increase as part of the acute phase response. However, there is poor knowledge of the patterns of increase and correlation with changes in other biochemical variables, and our study has been performed to investigate this aspect. MATERIALS AND METHODS A total of 213 simultaneous measurements of Cp and other acute phase proteins, biochemical variables, and amino acids were performed on nine patients with severe sepsis, and processed by regression analysis. RESULTS Mean Cp was 478 +/- 119 mg/L (median 488, range 242-784). Significant direct correlations between Cp and C-reactive protein, alpha-1-antitrypsin and alpha-2-macroglobulin (P < 0.001 for all) were all simultaneously influenced by the level of alkaline phosphatase, which was an independent determinant of increased Cp (P < 0.001). Cp increased further with decreasing plasma pH and increasing triglyceride, taurine levels, and distance from the onset of sepsis (P < 0.001 for all). The maximum increases in Cp were associated with the presence of cholestasis, increasing triglyceride levels, and metabolic acidosis. With regard to septic liver dysfunction, while signs of cholestasis were mostly reflected in greater increases in Cp, increasing bilirubin in the presence of normal alkaline phosphatase was mostly correlated with abnormal increases in cyst(e)ine, cystathionine, and tyrosine levels. CONCLUSIONS These data characterize the patterns of correlation of Cp within the biochemical abnormalities of sepsis, and may provide new insights into the pathophysiology of septic hepatobiliary dysfunction.
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Affiliation(s)
- Carlo Chiarla
- IASI-CNR Center for Pathophysiology of Shock, Catholic University School of Medicine, Rome, Italy.
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McMilin KD, Dasgupta S. Allogeneic transplantation and the risk for transmission of genetic disease: the heritable cancer disorders. Stem Cells Dev 2007; 16:191-212. [PMID: 17521232 DOI: 10.1089/scd.2006.0080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
With the development of new approaches to transplantation therapy, such as those building upon the potential found in stem cells, it is vital to pursue a clear understanding of transplantation risks. Allogeneic transplantation presents risk for the transmission of disease of various types, including genetic disease. Predisposition to develop cancer is a feature of numerous genetic disorders, and it may be transmissible by transplantation. Some genetic disorders predisposing to cancer are remarkably common, either worldwide or in specific populations, and they could pose significant risk. Hence, to reduce risk to recipients, there is reason to exclude from donation those potential donors (including embryos) harboring certain germ-line mutations. However, the frequent absence of readily identifiable features might confound the effort to exclude those who harbor mutation. Thus, it is also important to consider the magnitude of risk that they represent. For some disorders, life-threatening cancer is highly likely to develop in those individuals born with germ-line mutation, but whether recipients would face the same risk from transplanted mutation is not always evident. Given the diversity of pathways that lead to cancer, there may be diverse factors that impact the likelihood for cancer to develop in the recipient, with some factors decreasing and others increasing the risk. One factor of special concern is the possibility that manipulation of donor cells, prior to transplantation, might introduce additional genetic or epigenetic abnormality, thereby increasing the risk.
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Affiliation(s)
- Kenneth D McMilin
- Alabama and Central Gulf Coast Region, American Red Cross Blood Services, Birmingham, AL 35205, USA.
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Mirsaev TR. Experimental study of hepatoprotective activity of hydroxymethyluracil. Bull Exp Biol Med 2007; 143:575-6. [PMID: 18239770 DOI: 10.1007/s10517-007-0183-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Hepatoprotective activity of pyrimidine derivative hydroxymethyluracil was studied on the model of acute paracetamol-induced liver damage in rats. Hydroxymethyluracil was shown to produce a strong hepatoprotective effect.
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Affiliation(s)
- T R Mirsaev
- Bashkir State Medical University, Ufa, Russia.
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Akbar SMF, Horiike N, Onji M. Immune therapy including dendritic cell based therapy in chronic hepatitis B virus infection. World J Gastroenterol 2006; 12:2876-83. [PMID: 16718812 PMCID: PMC4087804 DOI: 10.3748/wjg.v12.i18.2876] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a global public health problem. Of the approximately 2 billion people who have been infected worldwide, more than 400 million are chronic carriers of HBV. Considerable numbers of chronic HBV carriers suffer from progressive liver diseases. In addition, all HBV carriers are permanent source of this virus. There is no curative therapy for chronic HBV carriers. Antiviral drugs are recommended for about 10% patients, however, these drugs are costly, have limited efficacy, and possess considerable side effects.
Recent studies have shown that immune responses of the host to the HBV are critically involved at every stage of chronic HBV infection: (1) These influence acquisition of chronic HBV carrier state, (2) They are important in the context of liver damages, (3) Recovery from chronic HBV-related liver diseases is dependent on nature and extent of HBV-specific immune responses. However, induction of adequate levels of HBV-specific immune responses in chronic HBV carriers is difficult. During the last one decade, hepatitis B vaccine has been administered to chronic HBV carriers as a therapeutic approach (vaccine therapy). The present regimen of vaccine therapy is safe and cheap, but not so effective. A dendritic cell-based therapeutic vaccine has recently been developed for treating chronic HBV infection. In this review, we will discuss about the concept, scientific logics, strategies and techniques of development of HBV-specific immune therapies including vaccine therapy and dendritic cell-based vaccine therapy for treating chronic HBV infection.
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Affiliation(s)
- Sk Md Fazle Akbar
- Third Department of Internal Medicine, Ehime University School of Medicine, To on City, Ehime 791-0295, Japan.
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Kumagi T, Horiike N, Abe M, Kurose K, Iuchi H, Masumoto T, Joko K, Akbar SF, Michitaka K, Onji M. Small hepatocellular carcinoma associated with Wilson's disease. Intern Med 2005; 44:439-43. [PMID: 15942090 DOI: 10.2169/internalmedicine.44.439] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
We report a 66-year-old male patient with hepatocellular carcinoma (HCC) associated with Wilson's disease. The patient presented with unresolving abnormal liver function test, decreased serum ceruloplasmin levels and increased 24-hour urine copper excretion. Liver biopsy specimen revealed the presence of increased levels of copper and features suggestive of Wilson's disease. Abdominal imaging showed the existence of a small HCC. Three years after chemoembolization and microwave coagulation therapy for HCC, he died of hepatic failure, which apparently resulted from chemoembolization. Patients with Wilson's disease should be screened for HCC. We should elude therapies such as chemoembolization in these patients.
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Affiliation(s)
- Teru Kumagi
- Third Department of Internal Medicine, Ehime University School of Medicine, Japan
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