Wilson disease

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Classification according to ICD-10
E83.0 Wilson disease
ICD-10 online (WHO version 2019)

The Wilson's disease or Wilson's disease ( synonyms hepatolenticular degeneration ( latin Degeneratio hepatolenticularis ), copper storage disease , Wilson's disease , pseudosclerosis Westphal or Westphal Strümpellsche pseudosclerosis ) is an autosomal - recessive inherited disease in which by a more or mutations of copper metabolism in the liver is disturbed. As a result, there is a reduced copper excretion via the bile , which results in an increased accumulation of copper in the liver, the eye, the central nervous system and other organs. This results in a diverse pattern of symptoms, which manifests itself primarily in liver damage and neurological deficits. The disease is well manageable with drugs that lower the level of copper in the blood or prevent it from being absorbed. The last alternative is liver transplantation . The disease was named after the British neurologist Samuel Alexander Kinnier Wilson .

Congenital copper storage diseases are also more common in domestic dogs, especially in the Bedlington Terrier (→ Congenital copper storage disease in dogs ).

The term hepatolenticular degeneration for Wilson's disease is considered out of date, since damage caused by copper accumulation is not only found in the lens nucleus (nucleus lentiformis), but in the entire brain.

frequency

The incidence is given depending on the population between 1: 30,000 and 1: 300,000 inhabitants. The mutated gene is distributed worldwide, around one in a hundred healthy people is heterozygous and can therefore potentially pass the disease on to their children. Due to the autosomal - recessive inheritance , a resulting statistical risk of a sick person also to suffer for four siblings: from the first The risk for children of a sick patient is 1: 200.

genetics

Autosomal recessive inheritance: the disease only becomes manifest if both copies of a gene carry the defect, mutation carriers with only one defective gene copy are phenotypically healthy

The cause of the disease is a mutation in the ATP7B gene , the "Wilson gene", which is located on chromosome 13 (locus 13q14.3). This codes for the " Wilson protein ", a copper-binding, cation- transporting ATPase . More than 370 different mutations of the Wilson gene comprising 21 exons are known, which explains the different course of Wilson's disease and makes genetic diagnosis difficult. The frequency of different mutations in the Wilson gene is explained by its great length compared to other genes. Most patients with the disease have two different mutations of the gene on each of their chromosomes. The point mutation His1069Gln in exon 14 is most common (50 to 80%) in Central Europe.

Pathophysiology

The mutation results in a malfunction of the Wilson protein in the liver cells , which is responsible, among other things, for the transport of copper from the liver into the bile . In Wilson's disease, the copper is not excreted with the bile and thus through the stool, as is usual in healthy people, but is stored in the organism and unfolds its toxic effect in various organs . The exact mechanism by which the high copper level damages the cells has not yet been conclusively clarified. It is believed that the excess of copper promotes the formation of radicals within the cells.

The primary place of accumulation of copper is the liver, another frequently affected organ is the eye. The central nervous system is also affected in around 45% of patients . In around 15%, the red blood cells are damaged by the copper. Toxic accumulation in the kidneys and heart muscle is rare .

Age distribution

Often the disease manifests itself in the second or third decade of life. However, the timing is very variable. Cases have also been described in which the first symptoms appeared in childhood from the age of six. First manifestations beyond the age of 32 are rare, but patients have also been described in whom symptoms of the disease only became apparent in old age. One case report referred to a two-year-old patient in whom the disease could be diagnosed in early childhood due to abnormal laboratory values.

Symptoms

liver

The liver is very often damaged because the liver cells are the primary location for copper storage and are the first to be affected by the overload. However, the extent of liver damage is very variable. The spectrum ranges from an asymptomatic increase in transaminases or liver enlargement to rapid and very severe (fulminant) liver inflammation ( hepatitis ) with a life-threatening course. The classic course, however, is chronic; if left untreated, fatty liver disease eventually develops into cirrhosis of the liver , which ultimately ends in failure of the organ. However, Wilson's disease is not associated with an increased risk of developing liver cell cancer. A massive destruction of liver cells can release large amounts of copper, which can lead to fulminant hepatitis. In around 5% of patients, fulminant liver failure leads to the initial diagnosis without the disease being recognized beforehand.

eyes

Kayser-Fleischer corneal ring, a brown ring created by copper deposits on the edge of the iris

Symptoms in the eyes of the sick people are also frequent. The Kayser-Fleischer corneal ring shows itself as a golden-brown to greenish edge that surrounds the iris . It is caused by the deposition of copper in the cornea and occurs in 95% of patients with neurological symptoms, but only in a little over 50% of patients with primary liver involvement. Night blindness can also be triggered by copper storage. An ophthalmological examination can also detect sunflower cataracts in some of the patients . This is understood to mean yellow-brown copper deposits in the lens of the eye , which, however, do not impair visual performance. The disease can also trigger strabismus or inflammation of the optic nerve .

Central nervesystem

The main symptom of the disease ( cardinal symptom) in the central nervous system is a movement disorder, which is also known as flapping tremor: The disease causes very variable, sometimes Parkinson -like or chorea-like symptoms such as involuntary jerky jerks or tremors of the extremities . The tone of the muscles can be decreased or increased ( rigor ). It can also express itself in slurred language . Also, coordination disorders , disorders of fine motor skills , muscle cramps and swallowing difficulties occur. Increased salivation has been described as a possible vegetative disorder . Spasticity and epileptic seizures are rare . In addition to these diverse neurological symptoms, in a total of 10% of cases there are a number of possible psychiatric impairments. Wilson's disease can trigger reductions in intellectual performance , subcortical dementia , impairment of social interaction as well as depression and psychoses .

Less common symptoms

A massive breakdown of liver cells can release large amounts of copper, which can damage the blood cells and lead to hemolytic anemia . Damage to the kidneys and heart muscle is rare. If untreated, kidney damage can turn into nephrotic syndrome and progress to kidney failure . The disease can cause cardiomyopathy in the heart muscle . In addition to these rather rare places of manifestation , damage to the bone has also been described. Wilson's disease can cause or promote osteomalacia and osteoporosis .

diagnosis

Diagnosing Wilson's disease is not always easy to make. The reasons for this are on the one hand the rarity of the disease and on the other hand the variety of possible symptoms. Wilson's disease should be ruled out, especially in children and adolescents, if the liver values ​​are unclear and neurological symptoms cannot be clearly explained.

The technically simplest examination is the inspection of the eye with a slit lamp . The Kayser-Fleischer ring is a noticeable sign of the disease, but it is not detectable in all patients; If the neurological symptoms are dominant, it is almost mandatory (obligatory), and far less often if the symptoms are predominantly hepatic.

Laboratory tests

Typical laboratory value changes are also groundbreaking, but not present in all patients. The transporting protein ceruloplasmin is reduced in the serum as a result of the disturbed copper balance. It should be noted that ceruloplasmin is an acute phase protein and can therefore give a false high value in the context of inflammation. The total copper content in the blood is often low. However, the proportion of free copper is often increased. The copper levels in the urine are often increased. The Coombs test is another indicator in connection with possible hemolytic anemia . If the laboratory is normal, the penicillamine test is recommended . The free copper in the urine is measured after administration of 500 mg penicillamine . However, the test is only standardized for children, which significantly limits its informative value in adults. If the copper value in the six-hour urine collection is above 600 µg, the test indicates the presence of Wilson's disease. If the test results are not clear, the radio copper test can be carried out. The incorporation of radioactively marked copper into the ceruloplasmin is monitored over a period of 48 hours. The scoring model of the 8th international Wilson's disease conference is often used for the overall analysis of all laboratory tests, which are not unambiguous per se. It sums up all possible results and thus enables a comparatively valid diagnosis.

Liver biopsy

A liver biopsy can be performed as an invasive diagnostic measure . If the copper content is more than 250 µg / g liver tissue and ceruloplasmin is low, Wilson's disease can be assumed. Elevated copper values ​​in the liver are also found in other diseases of this organ, for example primary biliary cirrhosis . The copper value in a cirrhotically converted liver can also turn out to be false negative, since the content of copper-storing liver cells is reduced in favor of connective tissue cells. Despite these sources of error, liver biopsy is the gold standard in diagnosing Wilson's disease.

Neurological and neuroradiological examinations

If the diagnosis of Wilson's disease is confirmed, a neurological examination and an MRI of the central nervous system are recommended. The repetition of the examinations during the course enables the success of the therapy to be monitored.

Molecular Genetic Studies

Several gene loci can be responsible for Wilson's disease. Around 300 mutations have now been described for the most common locus. The disease is often triggered by compound heterozygosity. Homozygous cases are very rare. Likewise, the correlation between genetic changes and clinical manifestation can often vary significantly.

pathology

In some cases, the disease-related copper storage in the liver can already be detected in the tissue at an early stage ( histologically ). The colors used to make copper visible are rhodanine or rubeanic acid. However, since detection can often fail despite the presence of the disease, copper stains are of limited diagnostic value.

At an advanced stage, enlarged liver cells can be seen under the microscope , which often have glycogen inclusions in the cell nuclei . Often there is also a picture similar to hepatitis with lymphocytes that infiltrate the connective tissue fibers (septa) and portal fields of the liver, in which vessels and bile ducts run. The histological picture is therefore not specific for the disease even in the advanced stage and does not allow a reliable diagnosis. In the final stage of liver damage, the picture turns into cirrhosis . This can appear small or mixed small and large nodules. In 50% of the cases, Mallory bodies can be detected, which also occur with alcoholic liver damage .

In the brain, under the microscope, an increase in glial cells with spongy loosening of the brain tissue can be seen. Typical (but not specific to the disease) are the so-called Opalski cells , named after the discoverer, the Polish neurologist Adam Opalski (1897–1963), which are degenerated astrocytes with granular cytoplasm .

therapy

diet

A low-copper diet is difficult to follow because copper is found in a large number of foods. Even with maximum adherence to diet rules, it is not recommended as the only treatment. As part of the diet, it is advisable to avoid the consumption of liver, kidneys, brain, chocolate, cocoa, nuts, mushrooms, beans, raisins and crustaceans.

Chelating agents

Chelating agents are primarily used for drug therapy . These drugs form chelate complexes with copper and thus trap it from the blood. The water-soluble complexes, together with the copper, are excreted into the urine via the kidneys. There are two drugs available - D - penicillamine and trientine . Which drug should be the first choice has so far been controversial.

In the guideline of the German Society for Neurology from 2005 on Wilson's disease, penicillamine is still recommended as the first choice. The most limiting side effect of the use of penicillamine is that in 20% of cases the neurological symptoms worsen. For this reason, the Anglo-American literature does not recommend the use of penicillamine as the drug of first choice in patients with neurological symptoms. To circumvent this problem, the guideline recommends gradually increasing the dose of the drug, since the neurological deterioration is due to the initially increased copper level in the blood as a result of the therapy. To date, however, there is no evidence for this practice . Other possible side effects of penicillamine therapy are hearing impairment, skin reactions, fever , kidney damage and lupus erythematosus . Furthermore, penicillamine acts as an antagonist to vitamin B6 , so that a substitution of the vitamin is appropriate. Penicillamine should not be used during pregnancy and is also excreted in breast milk.

Trientine can be used as an alternative chelate complexing agent. It is now recommended as the drug of first choice in the Anglo-American literature. According to these authors, it has a more favorable side-effect profile and does not cause neurological deterioration as often as penicillamine. Pancytopenia is a rare side effect . The drug is also teratogenic. In contrast to penicillamine, no kidney damage or hypersensitivity reactions have been reported. Trientine is said to have a weaker copper-binding effect than penicillamine. Since there are no randomized studies that directly compare the two drugs with each other, this topic is still controversial today.

In any case, it is undisputed that both chelating agents have to be taken around one to two hours after eating, since the absorption of the medication at the same time as food is insufficient.

Copper uptake inhibitors

Zinc preparations are also possible. Zinc changes the metabolism of the intestinal cells in such a way that less copper is absorbed. In contrast to the chelating agents, zinc does not cause any damage to unborn children and can therefore be used during pregnancy and breastfeeding. 10% of patients experience reflux esophagitis (heartburn) or nausea as side effects.

Another inhibitor of copper uptake called tetrathiomolybdate is currently being tested in the United States and Canada . Together with albumin and freshly absorbed copper , the active ingredient forms complexes in the blood that are metabolized by the liver and excreted in the bile. A first randomized study showed a more favorable side effect profile in terms of worsening neurological symptoms compared to Trientinen.

Follow-up and therapy regimen

The success of therapy with chelating agents can be monitored by determining the amount of copper in the 24-hour urine collection. With copper uptake inhibitors, the success of the treatment can be followed via the copper content of the stool. The patient's compliance with zinc preparations can be determined from the zinc content of the urine. Furthermore, the determination of proteins in the urine is advisable in order to be able to follow the course of kidney function. The course of the liver damage can be monitored by ultrasound examinations and the determination of the transaminases . In order to follow the course of the neurological damage, the neurological examination with the aid of a score is appropriate. Imaging procedures ( computed tomography , magnetic resonance tomography ) and electroencephalography can also provide information about the course of the disease during therapy. During the course of therapy, care must be taken to ensure that the copper level does not fall below the body's needs. The first signs of a copper deficiency are anemia or a decrease in the number of white blood cells ( leukopenia ).

Depending on the success of the therapy, this can be adjusted individually. Some authors advocate using zinc supplements after emptying the copper stores with chelating agents. Still others are in favor of a combination treatment of both. Some authors also consider lifelong therapy with chelating agents to be useful.

Liver transplant

In severe cases with severe liver damage, an organ transplant can be sought. The disease is cured because the patient receives healthy liver cells from the donor organ without genetic defects. In a critical worsening of the disease due to excessively high copper levels, until a transplant has been made possible, free copper can be bound through the infusion of albumin as an emergency .

Asymptomatic patients

If a patient is diagnosed with Wilson's disease, a screening in his family for asymptomatic patients is necessary. It should include the patient's siblings as well as the children. Since a search for the more than 250 mutations is impractical, a haplotype analysis is carried out. This does not look for the more than 250 mutations, but rather it is proven whether the relatives have inherited the corresponding chromosome areas that carry mutations from their parents. If someone who is homozygous for the disease is diagnosed in this way without showing symptoms, treatment with zinc supplements is indicated ( indicated ). This is to prevent the body of the person concerned from becoming saturated with copper in the first place.

forecast

If left untreated, Wilson's disease led to death within 2 to 7 years if it occurred early (in childhood) and primarily internal complications (liver failure, kidney failure, hemolysis ); the life expectancy is more favorable in the later onset predominantly neurologically or psychiatrically conspicuous patients (over 10 to 40 years creeping course).

Detected at an early stage and treated for life, Wilson's disease can be regarded as easily treatable. Life expectancy then does not differ from healthy people. If left untreated or as severe Wilson's disease, the disease is often fatal. Neurological deficits can be cured by therapy if they have not already existed for several years. If the damage to the liver has not already led to liver cirrhosis , this damage can also be influenced by the therapy.

In around three quarters of patients, the progression of the disease can be halted or symptoms can be reduced. Patients who suffered primarily from neurological symptoms have a worse outcome than patients in whom liver damage is the leading factor.

Research history

The disease, known under various names, was first discovered and described in 1854 by Friedrich Theodor von Frerichs . A more detailed presentation was made in 1898 by Carl Friedrich Otto Westphal and Adolf von Strümpell . The naming favored today was based on the comprehensive description by Samuel Alexander Kinnier Wilson in his doctoral thesis, for which he received an award in 1912. The ophthalmologists Bernhard Kayser (1869–1954) and Bruno Fleischer described copper deposits in the cornea of ​​the eye (Kayser-Fleischer corneal ring). In 1948, John Nathaniel Cumings (1906–1974) identified a disorder of the copper metabolism as the cause.

The first attempt at therapy with a chelating agent was made in 1951 with 2,3-dimercaptopropanol. Until then, the disease resulted in the death of the patient in most cases. In 1956, penicillamine was described as effective and replaced the older drug because penicillamine is more effective and has fewer side effects. It was established in 1967 that the disease can cause hemolytic anemia . In 1969, triethylenetetramine was introduced as an alternative chelating agent. Therapy with zinc compounds also began in the 1960s.

The affected gene ATP7B was located on the long arm of chromosome 13 (13q14.3) by several independent research groups in 1993.

See also

literature

Guidelines

Textbooks

  • Anthony Fauci et al .: Harrison's Principles of Internal Medicine. Volume 2, New York 2008.
  • Herbert Renz-Polster , Steffen Krautzig: Basic textbook internal medicine. 4th edition. Munich 2008
  • Andreas Straube, Wieland Hermann: Wilson's disease. In: Thomas Brandt, Johannes Dichgans, Hans Christoph Diener (eds.): Therapy and course of neurological diseases. 5th edition. Kohlhammer, Stuttgart 2007, ISBN 978-3-17-019074-0 .
  • Raphael Rubin, David Strayer and others: Rubin's Pathology. 5th edition. Philadelphia 2008.
  • Ursus-Nikolaus Riede: General and Special Pathology. Stuttgart 2004.

Articles in trade journals

Web links

Individual evidence

  1. ↑ Olsson et al: Determination of the frequencies of ten allelic variants of the Wilson disease gene (ATP7B), in pooled DNA samples. In: Eur J Hum Genet. 2000; 8 (12), pp. 933-938. PMID 11175281
  2. ↑ a b c d e f g R. Rubin, E. Rubin: The Liver and Biliary System. In: R. Rubin, D. Strayer et al.: Rubin's Pathology. 5th edition. Philadelphia 2008, pp. 653f.
  3. ↑ a b c d e G. Brewer: Wilson Disease. In: A. Fauci et al: Harrison's Principles of Internal Medicine. Volume 2, New York 2008, pp. 2449-2552.
  4. ↑ a b c d e f g h i j k l m n o p q H. Renz-Polster, S. Krautzig: Basic textbook internal medicine. 4th edition. Munich 2008, pp. 921-923.
  5. ^ J. Trojanowski, L. Kenyon, T. Bouldin: The Nervous System. In: R. Rubin, D. Strayer et al.: Rubin's Pathology. 5th edition. Philadelphia 2008, p. 1214.
  6. ^ A. Beyersdorff, A. Findeisen: Wilson's disease: Case report of a two-year-old child as first manifestation. In: Scandinavian Journal of Gastroenterology. 2006 Apr; 41 (4), pp. 496-497; PMID 16635921
  7. ↑ a b c d e f g h i j k l m Guideline of the German Society for Neurology on Wilson's disease created in 2003, updated in 2005, available online as html, last accessed on September 11, 2008.
  8. ↑ a b c d e f g h i j k l m n o A. Ala, A. Walker, K. Ashkan, J. Dooley, M. Schilsky: Wilson's Disease. In: The Lancet . 2007 Feb 3; 369 (9559), pp. 397-408, PMID 17276780
  9. ^ European Association for the Study of the Liver: EASL Clinical Practice Guidelines: Wilson's disease . In: Journal of hepatology . tape 56 , no. 3 . ELSEVIER, 2012, p. 671–685 , doi : 10.1016 / j.jhep.2011.11.007 (English).
  10. ↑ Atlas of Ophthalmology online, available as html ; Last accessed on October 13, 2008.
  11. ^ RM Bonelli, JL Cummings: Frontal-subcortical dementias. In: Neurologist. 2008 Mar; 14 (2), pp. 100-107. PMID 18332839 .
  12. ↑ C. Lang, D. Müller, D. Claus, KF Druschky: Neuropsychological findings in treated Wilson's disease. In: Acta Neurol Scand. 1990 Jan; 81 (1), pp. 75-81. PMID 2330819 .
  13. ↑ EuroWilson: Diagnosis , accessed November 22, 2012.
  14. ↑ Gerd Herold: Internal Medicine. Cologne, 2009, p. 516.
  15. ↑ Wilson Disease Scoring System: http://www.eurowilson.org/professional/diagnosis/index.phtml#Scoring-system
  16. ^ A b Roberts EA, Schilsky ML: Diagnosis and treatment of Wilson disease: an update. Hepatology. 2008 Jun; 47 (6): 2089-111. PMID 18506894
  17. ↑ H. Denk, HP Dienes, M. Trauner: Liver and intrahepatic biliary tract. In: Ursus-Nikolaus Riede: General and Special Pathology. Stuttgart 2004, p. 789.
  18. ↑ A. Opalski: About a special kind of glial cells in the Wilson pseudosclerosis group. In: Journal for the whole of neurology and psychiatry. (1930) 124 (1), pp. 420-425.
  19. ↑ U. Merle, M. Schaefer, P. Ferenci, W. Stremmel: Clinical presentation, diagnosis and long-term outcome of Wilson's disease: a cohort study. In: Good. 2007 Jan; 56 (1), pp. 115-120. Epub 2006 May 18; PMID 16709660
  20. ↑ Cf. also Ludwig Weissbecker: The hepatolenticular degeneration (Wilson disease, Westphal-Strümpell pseudosclerosis). In: Ludwig Heilmeyer (ed.): Textbook of internal medicine. Springer-Verlag, Berlin / Göttingen / Heidelberg 1955; 2nd edition ibid. 1961, p. 1114 f.
  21. ^ JN Cumings: The copper and iron content of brain and liver in the normal and in hepato-lenticular degeneration. In: Brain: a journal of neurology. Volume 71, Pt. December 4, 1948, pp. 410-415, ISSN  0006-8950 . PMID 18124738 .
  22. ↑ JM Walshe: Wilson's disease; new oral therapy. In: The Lancet . 1956 Jan 7; 270 (6906), pp. 25-26. PMID 13279157
  23. ↑ N. McIntyre, HM Clink, AJ Levi, JN Cumings, S. Sherlock: Hemolytic anemia in Wilson's disease. In: New England Journal of Medicine . 1967 Feb 23; 276 (8), pp. 439-444, PMID 6018274
This article was added to the list of excellent articles on October 27, 2008 in this version .