Studies on levels of penicillamine-induced cupriuresis in heterozygotes of Wilson's disease

doi:10.1016/0026-0495(67)90079-0

Metabolism

Volume 16, Issue 6, June 1967, Pages 507-513

https://doi.org/10.1016/0026-0495(67)90079-0 Get rights and content

Abstract

Ten heterozygotes for Wilson's disease, all parents of Wilson's disease patients, were compared with 10 Wilson's disease patients and 26 normal subjects for their respective 24-hour urinary copper excretions before and after 1 Gm. doses of penicillamine. The mean urinary copper excretion by the heterozygotes was significantly higher than that of the normal subjects and significantly lower than that of the homozygotes for the Wilson's disease. Differences were greater after penicillamine ingestion. Ranges for the normal subjects and the heterozygotes overlapped markedly thereby precluding any identification of heterozygotes. Heterozygotes and homozygotes for the disease had virtually separate ranges of urinary copper excretion after penicillamine ingestion. These results suggest a slight tendency for tissue copper accumulation in the heterozygote. Twenty-four hour urinary copper excretion after penicillamine ingestion coupled with total plasma copper level was found to distinguish heterozygotes from those homozygous for Wilson's disease.

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Cited by (38)

Wilson disease
2019, Seminars in Diagnostic Pathology
Wilson disease (WD) is an inherited disorder of copper metabolism. The resultant defective handling of copper results in toxic effects on the hepatocytes and increased copper in the circulation. Copper accumulates in other organ sites especially the central nervous system. WD occurs worldwide, usually between 5 and 35 years; a wider age range is now recognized. Clinical presentations are diverse and include combinations of hepatic, neurological, ophthalmic and psychiatric manifestations. Biochemical abnormalities such as serum ceruloplasmin and 24-h urinary copper excretion are important for the diagnosis but are not always abnormal in WD. They can overlap with non-WD causes. Patients may present with hepatic or neurological disease or combinations thereof. Approx. 50% of WD patients present with liver disease. Liver presentation is variable: asymptomatic abnormal liver tests, chronic hepatitis picture, cirrhosis, and acute liver failure. Similarly, the histology has several different patterns: mild nonspecific changes, steatosis or steatohepatitis, chronic hepatitis, and acute hepatitis with submassive or massive necrosis. None of these are specific for WD. Aids to the histologic diagnosis include special stains for copper and copper associated protein, and copper concentration in liver tissue. The biopsy is performed in the context of the clinical algorithms for the diagnosis of WD put forth by the clinical hepatology organizations such as the European Association for the Study of Liver Disease and the American Association for the Study of Liver Disease. The discovery of the responsible gene ATP7B has made the molecular diagnosis feasible through genetic testing and sequencing of the gene.
Wilson's disease: A master of disguise
2019, Parkinsonism and Related Disorders
Citation Excerpt :
The 24-h urine copper values below this cutoff exclude WD. Intermediate values between 50 and 100 μg/24 h may be seen in heterozygous (carrier) individuals and require further investigation [3,37]. Affected symptomatic children with WD may also have 24-H urine copper values below the conventional cutoff and lowering this value in pediatric patients has been suggested.
Wilson's disease (WD), in contrast to many neurogenetic metabolic diseases, can be very effectively treated in acute and chronic stages of the disease. However, early recognition is paramount because delays in treatments have much higher risk of unfavorable clinical outcomes. Identification of WD remains challenging because it is a great imitator and requires a high index of suspicion for correct and timely diagnosis. Initial neurologic problems can be seen in approximately 40%–50% of patients and the rest has either hepatic or primarily psychiatric manifestations. Neurologic and neuropsychiatric problems in WD are quite nonspecific and we discuss the most common clinical problems associated with early and late stages of the disease. Many patients with neurologic symptoms do not have any obvious hepatic symptoms. Most common neurologic abnormalities include dysarthria, dystonia, tremor and Parkinsonism. In spite of its phenotypic heterogeneity, laboratory abnormalities, reflecting abnormal copper homeostasis, are very specific and the diagnosis of WD remains laboratory based. We review most important challenges and pitfalls in laboratory evaluation of WD, including emerging role of genetic testing. Pharmacologic treatments need to be life-long and are focused on restoration of negative copper balance without inducing iatrogenic copper deficiency. The gold standard of therapy is chelation of excessive copper. Chelators may induce further clinical deterioration in some treated patients. We also review most promising novel therapeutic approaches that appear to better control non-ceruloplasmin or free copper because elevation of free copper may be responsible for paradoxical neurologic worsening.
Diagnosis of Hepatic Wilson Disease
2019, Wilson Disease: Pathogenesis, Molecular Mechanisms, Diagnosis, Treatment and Monitoring
Wilson disease (WD) is a rare autosomal recessive disorder of copper metabolism with a variety of clinical and biochemical manifestations. WD should be considered in patients with unexplained liver impairment or neuropsychiatric abnormalities. Currently, there are several diagnostic parameters postulated for WD, but no single test has been specific enough. Therefore, several diagnostic algorithms that include copper parameters and other surrogate markers like alkaline phosphatase have been evaluated. Worldwide since 2001, a diagnostic scoring system has been used, and since 2012, the WD scoring system has been adopted into the diagnostic algorithm included in the European Association for the Study of the Liver (EASL) guidelines. The availability of liver transplantation is a lifesaving treatment option for patients with WD presenting with encephalopathy and liver failure, but it has a potential of misuse in severe decompensated liver disease where chelation therapy could improve the liver disease avoiding the need for liver transplantation. In this chapter, a critical appraisal will be conducted of each parameter for the diagnosis of WD, together with other proposed diagnostic parameters.
Biochemical Markers
2019, Wilson Disease: Pathogenesis, Molecular Mechanisms, Diagnosis, Treatment and Monitoring
A century after the initial description of the disease, biochemical markers of Wilson disease (WD) continue to evolve. The classical association of a low cupremia, low Cp, and high cupruria remains the gold standard. Each marker taken separately does not have much value, but the triad allows to set the diagnosis of WD in the majority of cases. Likewise, liver biopsy with copper determination still has a place in certain situations, but the procedure is invasive, the method of hepatic copper determination is not standardized, and the threshold for diagnosis remains discussed. Since a few years, the relative exchangeable copper (REC = CuEXC/total serum copper ratio) and the exchangeable copper (CuEXC), two new biochemical markers based on the direct determination of exchangeable copper independently of the ceruloplasmin assay, had proved their value. REC is an excellent biomarker for the diagnosis of WD offering 100% sensitivity and 100% specificity with a threshold > 18.5%. REC is also a promising tool for family screening, especially for heterozygous ATP7B carriers who could present with slight copper anomalies. Elevated CuEXC at diagnosis orientates toward the presence of extrahepatic involvement. Moreover, it correlates with the severity of the retinal and cerebral lesions due to copper overload.
Biochemical diagnosis of Wilson disease
2018, Clinical and Translational Perspectives on WILSON DISEASE
Wilson disease (WD, OMIM #277900) is an autosomal recessive copper accumulation disorder mainly affecting the liver and the brain. WD is potentially fatal but effective treatment is available. The pivotal point to achieve the best outcome relies on a timely and accurate diagnosis. Historically, diagnosis of WD was based on the Sternlieb’s criteria with at least two of the followings: typical neurological symptoms, presence of Kayser-Fleischer rings by slit lamp examination and a serum ceruloplasmin concentration <0.20 g/L. In modern practice, scoring systems entail a more comprehensive diagnostic approach, in which a variety of biochemical tests are included. Commonly used biochemical tests will be discussed including serum ceruloplasmin concentration, serum free copper concentration, or non-ceruloplasmin-bound copper concentration, 24-hour urinary copper excretion (baseline and postpenicillamine challenge), hepatic copper quantitation, aspartate aminotransferase/alanine aminotransferase ratio, alkaline phosphatase/total bilirubin ratio and lipid metabolism in WD. Use of biochemical tests for the diagnosis of WD should not be overemphasized when DNA analysis is nowadays the most decisive diagnostic tool which is more readily available in clinical laboratories.
Diagnosis of Wilson disease
2017, Handbook of Clinical Neurology
Clinical presentation of Wilson disease can vary widely; therefore diagnosis is not always straightforward. Wilson disease is not just a disease of children and young adults, but may present at any age. The key features of Wilson disease are liver disease and cirrhosis, neuropsychiatric disturbances, Kayser–Fleischer rings, and acute episodes of hemolysis, often in association with acute liver failure. Diagnosis is particularly difficult in children and in adults presenting with active liver disease. None of the available laboratory tests is perfect and may not be specific for Wilson disease. A detailed neurologic examination is required for all cases. Neuroimaging and electrophysiologic methods are helpful. To overcome the diagnostic challenge, several clinical signs (Kayser–Fleischer rings, neurologic symptoms) and laboratory features (copper in serum, urine, liver; serum ceruloplasmin; genetic testing) are scored 0 (absent) to 2 (present) and the Leipzig score is calculated. If the score is ≥ 4, the diagnosis of Wilson disease is very likely. For asymptomatic siblings of index patients, mutation analysis is the most reliable approach.

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^☆: This study was supported in part by funding under U. S. Public Law 480, Section 104 (c).

¹: Jun-Bi Tu, M.D.: Instructor, Department of Neurology and Psychiatry, National Taiwan University Hospital, and Medical Research Fellow in Departments of Biochemistry and Clinical Investigation, U. S. Naval Medical Research Unit No. 2, Taipei, Taiwan, Republic of China.

²: R. Quentin Blackwell, Ph.D.: Head, Department of Biochemistry, U. S. Naval Medical Research Unit No. 2, Taipei, Taiwan, Republic of China. Mailing Address: Box 14, APO San Francisco 96263.

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Studies on levels of penicillamine-induced cupriuresis in heterozygotes of Wilson's disease☆

Abstract

Amer. J. Med.

Amer. J. Med.

Amer. J. Med.

Lancet

Amer. J. Med.

Genetic considerations in Wilson's disease

Wilson's disease

Ann. Rev. Med.

Lancet: Search for the heterozygote in Wilson's disease

A genetic, biochemical and clinical study of Wilson's disease among Chinese in Taiwan

Acta Paediat. Sinica

Microdetermination of copper in biological material

Biochem. J.

The metabolic disorder in hepato-lenticular degeneration

Quart. J. Med.