Wilson's disease in patients presenting with liver disease: A diagnostic challenge
Abstract
BACKGROUND & AIMS: In patients with Wilson's disease presenting with liver involvement, the correct diagnosis is often missed or delayed. The aim of this study was to find an algorithm for diagnosis of this difficult patient group. METHODS: Clinical and laboratory findings of 55 patients with Wilson's disease were evaluated at diagnosis before treatment. Presenting symptom was chronic liver disease in 17 patients, fulminant hepatic failure in 5 patients, hemolysis in 3 patients, and neurological disease in 20 patients, and 10 patients were detected by family screening (siblings). Evaluation included neurological and ophthalmologic examination, routine laboratory tests, and parameters of copper metabolism including liver copper content in 43 liver biopsy specimens. RESULTS: In the whole group, serum ceruloplasmin level was <20 mg/dL in 73%, urinary copper excretion was increased in 88%, and liver copper content was elevated in 91% at diagnosis. Kayser-Fleischer rings were detected in 55%. In contrast to patients with neurological disease (90% Kayser-Fleischer rings, 85% low ceruloplasmin), only 65% of patients presenting with liver disease were diagnosed by these typical findings. Ceruloplasmin levels were lower in patients with Kayser-Fleischer rings or with neurological disturbances than in patients without these symptoms. CONCLUSIONS: The commonly used clinical and laboratory parameters are not sufficient to exclude the diagnosis of Wilson's disease in patients with liver disease of unknown origin. (Gastroenterology 1997 Jul;113(1):212-8)
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Wilson's disease: overview
2023, Medicina ClinicaLa enfermedad de Wilson (EW) es una enfermedad hereditaria rara causada por la deficiencia del trasportador ATP7B. La proteína codificada por este gen facilita la incorporación del cobre a la ceruloplasmina. Por lo tanto, la EW condiciona una acumulación de cobre principalmente en el hígado y en el sistema nervioso central. Su espectro clínico es amplio, desde pacientes asintomáticos hasta enfermedad hepática crónica, fallo hepático agudo o síntomas neurológicos. El diagnóstico se establece mediante la combinación de signos y pruebas diagnósticas como medición de ceruloplasmina, excreción urinaria de cobre, cuantificación de cobre en tejido seco y estudio genético. Las terapias farmacológicas deben ser mantenidas de por vida e incluyen fármacos quelantes del cobre como la D-penicilamina o la trientina e inhibidores de la absorción de cobre como las sales de zinc. El trasplante hepático debe ser una opción en la enfermedad hepática terminal.
Wilson's disease (WD) is an uncommon hereditary disorder caused by a deficiency in the ATP7B transporter. The protein codified by this gene facilitates the incorporation of the copper into ceruloplasmin. Therefore, WD accumulates copper primary in the liver and secondary in other organs, such as the central nervous system. It represents a wide spectrum of disease, ranging from being asymptomatic in some patients to promote an acute liver failure in others. The diagnosis requires a combination of clinical signs and symptoms, as well as some diagnostic tests such as the measurement of serum ceruloplasmin, the urinary excretion of copper, the liver biopsy or the genetic testing. The treatment must be maintained lifelong and includes some drugs such as chelating agents (penicillamine and trientine) and inhibitors of the copper absorption (zinc salts). Lastly, the liver transplant should be an option for patients with end-stage liver disease.
Wilson disease
2023, Comprehensive Guide to Hepatitis AdvancesWilson disease is an autosomal recessive inherited disorder of hepatic copper metabolism resulting in liver disease and/or neuropsychiatric disease. Diagnosis of neurologic disease is straightforward if the following symptoms are present: Kayser–Fleischer rings, typical neurologic symptoms, and low serum ceruloplasmin levels. Diagnosis is more complex in patients presenting with liver diseases. None of the commonly used parameters alone allows a diagnosis with certainty. A combination of various laboratory parameters is necessary to firmly establish the diagnosis. In the future, limited mutation analysis may plan an important diagnostic role. Recently, a group of international experts proposed a score based on a variety of tests and clinical symptoms. The validity of this score has to be assessed prospectively. Treatment requires life-long administration of copper chelators (d-penicillamine, trientine). A frequently used alternative is zinc. None of these treatments was tested by prospective randomized controlled studies. Liver transplantation is reserved for severe or treatment-resistant cases with advanced liver disease, while experience with the refractory neuropsychiatric disease is limited.
Metallothionein immunohistochemistry has high sensitivity and specificity for detection of Wilson disease
2022, Modern PathologyDiagnosis of Wilson disease (WD) can be difficult because of its protean clinical presentations, but early diagnosis is important because effective treatment is available and can prevent disease progression. Similarly, diagnosis of WD on liver biopsy specimens is difficult due to the wide range of histologic appearances. A stain that could help identify WD patients would be of great value. The goal of this study was to use mass spectrometry-based proteomics to identify potential proteins that are differentially expressed in WD compared to controls, and could serve as potential immunohistochemical markers for screening. Several proteins were differentially expressed in WD and immunohistochemical stains for two (metallothionein (MT) and cytochrome C oxidase copper chaperone (COX17)) were tested and compared to other methods of diagnosis in WD including copper staining and quantitative copper assays. We found diffuse metallothionein immunoreactivity in all liver specimens from patients with WD (n = 20); the intensity of the staining was moderate to strong. This staining pattern was distinct from that seen in specimens from the control groups (none of which showed strong, diffuse staining), which included diseases that may be in the clinical or histologic differential of WD (steatohepatitis (n = 51), chronic viral hepatitis (n = 40), autoimmune hepatitis (n = 50), chronic biliary tract disease (n = 42), and normal liver (n = 20)). COX17 immunostain showed no significant difference in expression between the WD and control groups. MT had higher sensitivity than rhodanine for diagnosis of WD. While the quantitative liver copper assays also had high sensitivity, they require more tissue, have a higher cost, longer turnaround time, and are less widely available than an immunohistochemical stain. We conclude that MT IHC is a sensitive immunohistochemical stain for the diagnosis of WD that could be widely deployed as a screening tool for liver biopsies in which WD is in the clinical or histologic differential diagnosis.
Investigation and management of Wilson's disease: a practical guide from the British Association for the Study of the Liver
2022, The Lancet Gastroenterology and HepatologyWilson's disease is an autosomal-recessive disorder of copper metabolism with hepatic, neurological, psychiatric, ophthalmological, haematological, renal, and rheumatological manifestations. Making a diagnosis can be challenging given that no single test can confirm or exclude the disease, and diagnostic delays are common. Treatment protocols vary and adverse effects, including paradoxical neurological worsening, can occur. In this Review, we provide a practical guide to the diagnosis of Wilson's disease. We include recommendations on indications for testing, how to interpret results, and when additional investigations are required. We also cover treatment initiation, ideally under the guidance of a specialist centre for Wilson's disease, and the principles behind long-term management. This guidance was developed by a multidisciplinary group of Wilson's disease experts formed through the British Association for the Study of the Liver. The guidance has been endorsed by the British Society of Gastroenterology and approved by the Association of British Neurologists.
Non-invasive diagnosis and follow-up of rare genetic liver diseases
2022, Clinics and Research in Hepatology and GastroenterologyRare genetic liver diseases can result in multi-systemic damage, which may compromise the patient's prognosis. Wilson's disease and alpha-1 antitrypsin deficiency must be investigated in any patient with unexplained liver disease. Cystic fibrosis screening of new-borns is now implemented in most high-prevalence countries. The diagnosis of these diseases can be strongly suggested with specific non-invasive tests. Molecular analysis gene for these diseases is long and tedious but is recommended to confirm the diagnosis and help for the family screening. Liver biopsy is not systematic and is discussed when it helps diagnosis. Currently, for these three diseases, non-invasive fibrosis markers could identify patients with risk of cirrhosis and complications. Rare genetic liver diseases can result in multi-systemic damage, which may compromise the patient's prognosis. Wilson's disease, must be investigated in any patient with unexplained liver disease and/or unexplained neurological or neuropsychiatric disorders. The diagnosis is based on a combination of clinical, biological features, including copper balance. The exchangeable copper/total copper ratio is a new sensible and specific biological marker, useful for the diagnosis of the disease. Timely diagnosis and treatment will prevent serious complications from the disease. Neurological evaluation and familial screening are essential in patients with Wilson's disease