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Wilson disease
Classification and external resources
Mutations in the gene coding for ATP7B are present in the majority of patients with Wilson's disease. Wilson disease protein (also called ATP7B) is an ATPase that transports Copper.
ICD-10 E83.0
ICD-9 275.1
OMIM 277900
DiseasesDB 14152
MedlinePlus 000785
eMedicine med/2413  neuro/570 ped/2441
MeSH D006527

Wilson's disease or hepatolenticular degeneration is an autosomal recessive genetic disorder in which copper accumulates in tissues; this manifests as neurological or psychiatric symptoms and liver disease. The International Statistical Classification of Diseases and Related Health Problems (most commonly known by the abbreviation ICD) provides codes to classify Diseases The International Statistical Classification of Diseases and Related Health Problems 10th Revision ( ICD -10) is a coding of diseases and signs symptoms abnormal findings E00-E35 - Endocrine diseases (E00-E07 Thyroid gland / Thyroid hormone ( Congenital iodine-deficiency syndrome ( The International Statistical Classification of Diseases and Related Health Problems (most commonly known by the abbreviation ICD) provides codes to classify Diseases The following is a list of codes for International Statistical Classification of Diseases and Related Health Problems. The Mendelian Inheritance in Man project is a Database that catalogues all the known Diseases with a genetic component, and—when possible—links them The Diseases Database is a free Website that provides information about the relationships between medical conditions Symptoms, and Medications. MedlinePlus, with the MedlinePlus Medical Encyclopedia, is a website network containing Health information from the world's largest medical Library eMedicine is an online clinical medical knowledge base that was founded in 1996 by Scott Plantz and Richard Lavely two medical doctors Medical Subject Headings ( MeSH) is a huge Controlled vocabulary (or metadata system for the purpose of indexing journal articles and books A genetic disorder is a condition caused by abnormalities in Genes or Chromosomes While some diseases such as Cancer, are due to genetic abnormalities acquired Copper (ˈkɒpɚ is a Chemical element with the symbol Cu (cuprum and Atomic number 29 Tissue is a cellular organizational level intermediate between cells and a complete organism Psychiatry is a medical specialty which exists to study, prevent, and treat Mental disorders in Humans Psychiatric The liver is a vital organ in the human body and is present in Vertebrates and some other animals It is treated with medication that reduces copper absorption or removes the excess copper from the body, but occasionally a liver transplant is required. Medication, also referred to as medicine, can be loosely defined as any substance intended for use in the diagnosis cure mitigation treatment or prevention of disease Liver transplantation or hepatic transplantation is the replacement of a diseased Liver with a healthy liver Allograft. [1]

The condition is due to mutations in the ATP7B gene. In biology mutations are changes to the Nucleotide sequence of the Genetic material of an organism Wilson disease protein (also called ATP7B) is an ATPase that transports Copper. A single abnormal copy of the gene is present in 1 in 100 people, who do not develop any symptoms (they are carriers). A genetic carrier (or just carrier) is a person or other organism that has inherited a genetic trait or Mutation, but who does not display that If a child inherits the gene from both parents, they may develop Wilson's disease. Symptoms usually appear between the ages of 6 and 20 years, but cases in much older patients have been described. Wilson's disease occurs in 1 to 4 per 100,000 people. [1] Wilson's disease is named after Dr Samuel Alexander Kinnier Wilson (1878-1937), the British neurologist who first described the condition in 1912. Samuel Alexander Kinnier Wilson ( December 6, 1878 - May 12, 1937) was a British Neurologist who was born in Cedarville New Jersey [2]

Contents

Signs and symptoms

The main sites of copper accumulation are the liver and the brain, and consequently liver disease and neuropsychiatric symptoms are the main features that lead to diagnosis. The liver is a vital organ in the human body and is present in Vertebrates and some other animals The brain is the center of the Nervous system in animals All Vertebrates and the majority of Invertebrates have a brain [1] Patients with liver problems tend to come to medical attention earlier, generally as children or teenagers, than those with neurological and psychiatric symptoms, who tend to be in their twenties or older. Some are identified only because relatives have been diagnosed with Wilson's disease; many of these patients, when tested, turn out to have been experiencing symptoms of the condition but haven't received a diagnosis. [3]

Liver disease

Liver disease may present as tiredness, increased bleeding tendency or confusion (due to hepatic encephalopathy) and portal hypertension. Hepatic encephalopathy (sometimes hepatoencephalopathy) is a potentially-reversible Neuropsychiatric abnormality in the setting of Liver failure, whether In Medicine, portal hypertension is Hypertension (high blood pressure in the Portal vein and its branches The latter, a condition in which the pressure on the portal vein is markedly increased, leads to esophageal varices (blood vessels in the esophagus) that may bleed in a life-threatening fashion, splenomegaly (enlargement of the spleen) and ascites (accumulation of fluid in the abdominal cavity). In Medicine ( Gastroenterology) esophageal varices are extremely dilated sub-mucosal Veins in the Esophagus. The esophagus or oesophagus (see American and British English spelling differences) sometimes known as the gullet, is an organ in Splenomegaly is an enlargement of the Spleen, which usually lies in the left upper quadrant (LUQ of the Human abdomen. In Medicine ( Gastroenterology) ascites (also known as peritoneal cavity fluid, peritoneal fluid excess, hydroperitoneum or more On examination, signs of chronic liver disease such as spider naevi (small distended blood vessels, usually on the chest) may be observed. A spider angioma (also known as a nevus araneus, spider nevus, or vascular spider) is a type of Angioma found slightly below the skin's Chronic active hepatitis has caused cirrhosis of the liver in most patients by the time they develop symptoms. Cirrhosis is a consequence of chronic Liver Disease characterized by replacement of liver tissue by fibrous Scar tissue as well as regenerative While most people with cirrhosis have an increased risk of hepatocellular carcinoma (liver cancer), this risk is relatively very low in Wilson's disease. Hepatocellular carcinoma (HCC also called hepatoma) is a primary malignancy (cancer of the Liver. [1]

About 5% of all patients are diagnosed only when they develop fulminant acute liver failure, often in the context of a hemolytic anemia (anemia due to the destruction of red blood cells). Acute liver failure is the appearance of severe complications rapidly after the first signs of liver disease (such as Jaundice) and indicates that the liver has sustained severe Hemolytic anemia is Anemia due to Hemolysis, the abnormal breakdown of Red blood cells (RBCs either in the Blood vessels (intravascular hemolysis This leads to abnormalities in protein production (identified by deranged coagulation) and metabolism by the liver. Coagulation is a complex process by which Blood forms Clots It is an important part of Hemostasis (the cessation of blood loss from a damaged vessel whereby The deranged protein metabolism leads to the accumulation of waste products such as ammonia in the bloodsteam. Ammonia is a compound with the formula N[[hydrogen H3]] It is normally encountered as a Gas with a characteristic pungent Odor When these irritate the brain, the patient develops hepatic encephalopathy (confusion, coma, seizures and finally life-threatening swelling of the brain). The brain is the center of the Nervous system in animals All Vertebrates and the majority of Invertebrates have a brain Hepatic encephalopathy (sometimes hepatoencephalopathy) is a potentially-reversible Neuropsychiatric abnormality in the setting of Liver failure, whether Cerebral edema (cerebral oedema in British English) is an excess accumulation of water in the intracellular and/or extracellular spaces of the Brain. [1]

Neuropsychiatric symptoms

About half the patients with Wilson's have neurological or psychiatric problems. Most patients initially have mild cognitive deterioration and clumsiness, as well as changes in behavior. Specific neurological symptoms then follow, often in the form of parkinsonism (increased rigidity and slowing of routine movements) with or without a typical hand tremor, ataxia (lack of coordination) or dystonia (twisting and repetitive movements of part of the body). Parkinsonism (also known as Parkinson's syndrome, atypical Parkinson's, or secondary Parkinson's) is a neurological Syndrome characterized Tremor is an unintentional somewhat rhythmic muscle movement involving to-and-from movements (oscillations of one or more parts of the body Ataxia (from Greek α- as a negative prefix + -τάξις, meaning "lack of order" is a neurological sign and symptom consisting Dystonia is a neurological Movement disorder in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures Seizures and migraine appear to be more common in Wilson's disease. An epileptic seizure is caused by excessive and/or hypersynchronous electrical Neuronal activity and is usually self-limiting Migraine is a neurological Syndrome characterized by altered bodily experiences painful headaches and nausea [1]

Psychiatric problems due to Wilson's disease may include behavioral changes, depression, anxiety and psychosis. Major depressive disorder, also known as major depression, unipolar depression, unipolar disorder, clinical depression, or simply depression Anxiety is a physiological and psychological state characterized by Cognitive, Somatic, Emotional and Behavioral components Psychosis (from the Greek ψυχή "psyche" for mind or soul and -οσις "-osis" for abnormal condition with adjective psychotic [1]

Other organ systems

A Kayser-Fleischer ring in a patient with symptoms suggestive of Wilson's disease
A Kayser-Fleischer ring in a patient with symptoms suggestive of Wilson's disease

Various medical conditions have been linked with copper accumulation in Wilson's disease:

Diagnosis

Location of the basal ganglia, the part of the brain affected by Wilson's disease
Location of the basal ganglia, the part of the brain affected by Wilson's disease

Wilson's disease may be suspected on the basis of any of the symptoms mentioned above, or when a close relative has been found to have Wilson's. Most patients have slightly abnormal liver function tests such as a raised aspartate transaminase, alanine transaminase and bilirubin level. Liver function tests (LFTs or LFs which include liver enzymes, are groups of Clinical biochemistry laboratory blood assays designed to give information about the Aspartate Transaminase ( AST) also called serum glutamic oxaloacetic transaminase ( SGOT) or aspartate aminotransferase ( ASAT/AAT Alanine transaminase or ALT is a Transaminase Enzyme ( It is also called serum glutamic pyruvic transaminase (SGPT or alanine aminotransferase Bilirubin (formerly referred to as hematoidin) is the yellow breakdown product of normal Heme Catabolism. If the liver damage is significant, albumin may be decreased due to an inability of damaged liver cells to produce this protein; likewise, the prothrombin time (a test of coagulation) may be prolonged as the liver is unable to produce proteins known as clotting factors. Albumin (Latin albus white refers generally to any Protein with water Solubility, which is moderately soluble in concentrated salt solutions and experiences The prothrombin time ( PT) and its derived measures of prothrombin ratio ( PR) and international normalized ratio ( INR) are measures Coagulation is a complex process by which Blood forms Clots It is an important part of Hemostasis (the cessation of blood loss from a damaged vessel whereby [1] Alkaline phosphatase levels are relatively low in patients with Wilson's-related acute liver failure. Alkaline phosphatase ( ALP) ( is a Hydrolase Enzyme responsible for removing Phosphate groups from many types of molecules including [4] If there are neurological symptoms, magnetic resonance imaging (MRI) of the brain is usually performed; this shows hyperintensities in the part of the brain called the basal ganglia in the T2 setting. The basal ganglia (or basal nuclei) are a group of nuclei in the Brain interconnected with the Cerebral cortex, Thalamus and Spin-spin relaxation time, known as T2, is a time constant in Nuclear Magnetic Resonance and Magnetic Resonance Imaging. [5]

There is no totally reliable test for Wilson's disease, but levels of ceruloplasmin and copper in the blood, as well of the amount of copper excreted in urine during a 24 hour period, are together used to form an impression of the amount of copper in the body. Ceruloplasmin (or caeruloplasmin) is officially known as ferroxidase or iron(IIoxygen oxidoreductase. The gold standard or most ideal test is a liver biopsy. In Medicine, a gold standard test or criterion standard test is a Diagnostic test or benchmark that is regarded as definitive A biopsy (in Greek: βίος life and όψη look/appearance is a Medical test involving the removal of cells or tissues [1]

Ceruloplasmin

Ceruloplasmin
Ceruloplasmin

Levels of ceruloplasmin are abnormally low (<0. Ceruloplasmin (or caeruloplasmin) is officially known as ferroxidase or iron(IIoxygen oxidoreductase. 2 gram/liter) in 80-95% of cases. [1] It can, however, be present at normal levels in people with ongoing inflammation as it is an acute phase protein. Inflammation ( Latin, inflamatio, to set on fire is the complex biological response of vascular tissues to harmful stimuli such as Pathogens Acute-phase proteins are a class of Proteins whose plasma concentrations increase (positive acute phase proteins or decrease (negative acute phase proteins in response to Low ceruloplasmin is also found in Menkes disease and aceruloplasminemia, which are related to, but much rarer than, Wilson's disease. Menkes disease (also called the kinky hair disease or Menkes kinky hair syndrome) is a disorder that affects Copper levels in the body Aceruloplasminemia is an Autosomal Recessive disorder of Iron Metabolism characterized by progressive Neurodegeneration of the [1][5]

The combination of neurological symptoms, Kayser-Fleisher rings and a low ceruloplasmin level is considered sufficient for the diagnosis of Wilson's disease. In many cases, however, further tests are needed. [5]

Serum and urine copper

Serum copper and more importantly urine copper are elevated in Wilson's disease. Urine is collected for 24 hours in a bottle with a copper-free liner. Levels above 100 μg/24h (1. 6 μmol/24h) confirm Wilson's disease, and levels above 40 μg/24h (0. 6 μmol/24h) are strongly indicative. [1] High urine copper levels are not unique to Wilson's disease; they are sometimes observed in autoimmune hepatitis and in cholestasis (any disease obstructing the flow of bile from the liver to the small bowel). Anomalous presentation of Human leukocyte antigen (HLA class II on the surface of Hepatocytes possibly due to Genetic predisposition or Acute liver infection In Medicine, cholestasis is a condition where Bile cannot flow from the Liver to the Duodenum. [5]

In children, the penicillamine test may be used. Penicillamine is a Pharmaceutical of the chelator class It is sold under the trade names of Cuprimine and Depen. A 500 mg oral dose of penicillamine is administered, and urine collected for 24 hours. If this contains more than 1600 μg (25 μmol), it is a reliable indicator of Wilson's disease. This test has not been validated in adults. [5]

Liver biopsy

One other investigations have indicated Wilson's disease, the ideal test is the removal of a small amount of liver tissue through a liver biopsy. A biopsy (in Greek: βίος life and όψη look/appearance is a Medical test involving the removal of cells or tissues This is assessed microscopically for the degree of steatosis and cirrhosis, and histochemistry and quantification of copper are used to measure the severity of the copper accumulation. In cellular Pathology, steatosis (also called fatty change, fatty degeneration or adipose degeneration) is the process describing Cirrhosis is a consequence of chronic Liver Disease characterized by replacement of liver tissue by fibrous Scar tissue as well as regenerative Histology (from the Greek = 'tissue' is the study of the microscopic anatomy of cells and tissues of Plants and A level of 250 μg of copper per gram of dried liver tissue confirms Wilson's disease. In the Metric system, a microgram is 1/1000000 of a Gram (1 × 10-6 or 1/1000 of a milligram is one of the smallest units of weight/mass commonly used Occasionally, lower levels of copper are found; in that case, the combination of the biopsy findings with all other tests could still lead to a formal diagnosis of Wilson's. [1]

In the earlier stages of the disease, the biopsy typically shows steatosis (deposition of fatty material), increased glycogen in the nucleus, and areas of necrosis (cell death). Fatty liver, also known as fatty liver disease ( FLD) steatorrhoeic hepatosis, or steatosis hepatitis, is a reversible condition where Glycogen is a Polysaccharide of Glucose (Glc which functions as the secondary short term energy storage in Animal cells In Cell biology, the nucleus (pl nuclei; from Latin la ''nucleus'' or la ''nuculeus'' "little nut" or kernel is a membrane-enclosed Necrosis (in Greek Νεκρός = "dead" is the name given to unnatural Death of cells and living tissue. In more advanced disease, the changes observed are quite similar to those seen in autoimmune hepatitis, such as infiltration by inflammatory cells, piecemeal necrosis and fibrosis (scar tissue). Inflammation ( Latin, inflamatio, to set on fire is the complex biological response of vascular tissues to harmful stimuli such as Pathogens In advanced disease, finally, cirrhosis is the main finding. In acute liver failure, degeneration of the liver cells and collapse of the liver tissue architecture is seen, typically on a background of cirrhotic changes. Histochemical methods for detecting copper are inconsistent and unreliable, and taken alone are regarded as insufficient to establish a diagnosis. [5]

Genetic testing

Mutation analysis of the ATP7B gene, as well as other genes linked to copper accumulation in the liver, may be performed. Once a mutation is confirmed, it is possible to screen family members for the disease as part of clinical genetics family counselling. Medical genetics is the specialty of Medicine that involves the diagnosis and management of Hereditary disorders Medical genetics differs from Human genetics [1]

Genetics

Wilson's disease has an autosomal recessive pattern of inheritance.
Wilson's disease has an autosomal recessive pattern of inheritance.
Main article: ATP7B

The Wilson's disease gene (ATP7B) has been mapped to chromosome 13 (13q14. Wilson disease protein (also called ATP7B) is an ATPase that transports Copper. Chromosome 13 is one of the 23 pairs of Chromosomes in Humans People normally have two copies of this chromosome 3) and is expressed primarily in the liver, kidney, and placenta. The kidneys are complicated organs that have numerous biological roles The placenta is an Ephemeral organ present in placental Vertebrates, such as Eutherial Mammals and Sharks during Gestation The gene codes for a P-type (cation transport enzyme) ATPase that transports copper into bile and incorporates it into ceruloplasmin. P-type (or E1-E2-type ATPases constitute a superfamily of cation transport enzymes present both in prokaryota and eukaryota whose members mediate membrane flux of all common biologically ATPases are a class of Enzymes that catalyze the Decomposition of Adenosine triphosphate (ATP into Adenosine diphosphate (ADP and Bile or gall is a bitter yellow or green Alkaline fluid secreted by Hepatocytes from the Liver of most Vertebrates In many species Ceruloplasmin (or caeruloplasmin) is officially known as ferroxidase or iron(IIoxygen oxidoreductase. [1] Mutations can be detected in 90% of patients. Most (60%) are homozygous for ATP7B mutations (two abnormal copies), and 30% have only one abnormal copy. Zygosity refers to the genetic condition of a Zygote. In genetics zygosity describes the similarity or dissimilarity of DNA between Homologous 10% have no detectable mutation. [3]

Although 300 mutations of ATP7B have been described, in most populations the cases of Wilson's disease are due to a small number of mutations specific for that population. For instance, in Western populations the H1069Q mutation (replacement of a histidine by a glutamine at position 1069 in the gene) is present in 37-63% of cases, while in China this mutation is very uncommon and R778L (arginine to leucine at 778) is found more often. Histidine (abbreviated as His or H) is one of the 20 standard Amino acids present in Proteins In the Nutritional sense in Glutamine (abbreviated as Gln or Q; the abbreviation Glx or Z represents either glutamate or Glutamic acid) is one of the 20 Arginine (abbreviated as Arg or R) is an α- Amino acid. The L-form is one of the 20 most common natural amino acids Leucine (abbreviated as Leu or L) is an α- Amino acid with the Chemical formula HO2CCH(NH2CH2CH(CH32 Relatively little is known about the relative impact of various mutations, although the H1069Q mutation seems to predict later onset and predominantly neurological problems, according to some studies. [1][6]

A normal variation in the PRNP gene can modify the course of the disease by delaying the age of onset and affecting the type of symptoms that develop. PRNP ( PRioN Protein (Creutzfeld-Jakob disease Gerstmann-Sträussler-Scheinker syndrome fatal familial insomnia) is a Gene that provides instructions to make a This gene produces prion protein, which is active in the brain and other tissues and also appears to be involved in transporting copper. PRNP ( PRioN Protein (Creutzfeld-Jakob disease Gerstmann-Sträussler-Scheinker syndrome fatal familial insomnia) is a Gene that provides instructions to make a [7] A role for the ApoE gene was initially suspected but could not be confirmed. [6]

The condition is inherited in an autosomal recessive pattern, which means both copies of the gene have mutations. In order to inherit it, both of the parents of an individual must carry an affected gene. Most patients have no family history of the condition. [6] People with only one abnormal gene are called carriers (heterozygotes) and may have mild, but medically insignificant, abnormalities of copper metabolism. [5]

Wilson's disease is the commonest of a group of hereditary diseases that cause copper overload in the liver. All can cause cirrhosis at a young age. The other members of the group are Indian childhood cirrhosis (ICC), endemic Tyrolean infantile cirrhosis and idiopathic copper toxicosis. These are not related to ATP7B mutations, but only ICC has been linked to mutations in the KRT8 and the KRT18 gene. Keratin 8, also cytokeratin 8 and CK8, is a Keratin Protein. It is often paired with Keratin 18. Keratin 18 is a Type I cytokeratin. It is together [6]

Pathophysiology

Normal absorption and distribution of copper. Cu = copper, CP = ceruloplasmin, green = ATP7B carrying copper.
Normal absorption and distribution of copper. Cu = copper, CP = ceruloplasmin, green = ATP7B carrying copper.

Copper is needed by the body for a number of functions, predominantly as a cofactor for a number of enzymes such as ceruloplasmin, cytochrome c oxidase, dopamine ß-hydroxylase, superoxide dismutase and tyrosinase. Copper (ˈkɒpɚ is a Chemical element with the symbol Cu (cuprum and Atomic number 29 A cofactor is a non-protein Chemical compound that is bound (either tightly or loosely to an Enzyme and is required for Catalysis. The Enzyme cytochrome c oxidase or Complex IV () is a large Transmembrane protein complex found in Bacteria and the Mitochondrion Dopamine β-hydroxylase (DBH is an Enzyme that converts Dopamine to Norepinephrine:Synonyms Aromatic L-amino acid decarboxylase ( Tryptophan The enzyme superoxide dismutase ( SOD,) catalyzes the Dismutation of Superoxide into Oxygen and Hydrogen peroxide. Tyrosinase (monophenol monooxygenase ( CAS number: 9002-10-2 is an Enzyme that catalyses the Oxidation of Phenols (such as [6]

Copper enters the body through the digestive tract. A transporter protein on the cells of the small bowel, copper membrane transporter 1 (CMT1), carries copper inside the cells, where some is bound to metallothionein and part is carried by ATOX1 to an organelle known as the trans-Golgi network. Enterocytes, or intestinal absorptive cells, are Simple columnar Epithelial cells found in the Small intestines and Colon. Solute carrier family 31 (copper transporters member 1, also known as SLC31A1, is a human Gene. Metallothionein (MT is a family of Cysteine -rich low molecular weight (MW ranging from 3500 to 14000 Da) Proteins MTs have the capacity to ATX1 antioxidant protein 1 homolog (yeast, also known as ATOX1, is a human Gene. The Golgi apparatus (also called the Here, in response to rising concentrations of copper, an enzyme called ATP7A releases copper into the portal vein to the liver. ATP7A ( ATPase Cu++ transporting alpha polypeptide (Menkes syndrome) is a Human Gene that provides instructions to make a Protein that Liver cells also carry the CMT1 protein, and metallothionein and ATOX1 bind it inside the cell, but here it is ATP7B that links copper to ceruloplasmin and releases it into the bloodstream, as well as removing excess copper by secreting it into bile. Bile or gall is a bitter yellow or green Alkaline fluid secreted by Hepatocytes from the Liver of most Vertebrates In many species Both functions of ATP7B are impaired in Wilson's disease. Copper accumulates in the liver tissue; ceruloplasmin is still secreted, but in a form that lacks copper (termed apoceruloplasmin) and rapidly degraded in the bloodstream. [6]

When the amount of copper in the liver overwhelms the proteins that normally bind it, it causes oxidative damage through a process known as Fenton chemistry; this damage eventually leads to chronic active hepatitis, fibrosis (deposition of connective tissue) and cirrhosis. Fenton's reagent is a solution of Hydrogen peroxide and an Iron Catalyst that is used to Oxidize Contaminants or Waste waters Hepatitis (plural hepatitides) implies injury to the Liver characterized by the presence of Inflammatory cells in the tissue of Fibrosis is the formation or development of excess fibrous Connective tissue in an organ or tissue as a reparative or reactive process as opposed to a formation of Fibrous Cirrhosis is a consequence of chronic Liver Disease characterized by replacement of liver tissue by fibrous Scar tissue as well as regenerative The liver also releases copper into the bloodstream that is not bound to ceruloplasmin. This free copper precipitates throughout the body but particularly in the kidneys, eyes and brain. In the brain, most copper is deposited in the basal ganglia, particularly in the putamen and globus pallidus (together called the lenticular nucleus); these areas normally participate in the coordination of movement as well as playing a significant role in neurocognitive processes such as the processing of stimuli and mood regulation. The basal ganglia (or basal nuclei) are a group of nuclei in the Brain interconnected with the Cerebral cortex, Thalamus and "Putamen" is also a botanical term for the stone in a Fruit, such as a Peach. The globus pallidus ( Latin for "pale globe" is a sub- cortical structure of the Brain. The lentiform nucleus or lenticular nucleus comprises the Putamen and the Globus pallidus within the Basal ganglia. Damage to these areas, again by Fenton chemistry, produces the neuropsychiatric symptoms seen in Wilson's disease. [6]

It is not clear why Wilson's disease causes hemolysis, but various lines of evidence suggest that high levels of free (non-ceruloplasmin bound) copper have a direct effect on either oxidation of hemoglobin, inhibition of energy-supplying enzymes in the red blood cell, or direct damage to the cell membrane. Hemoglobin ( also spelled haemoglobin and abbreviated Hb or Hgb) is the Iron -containing Oxygen -transport Metalloprotein Red blood cells are the most common type of Blood cell and the Vertebrate body's principal means of delivering Oxygen to the body tissues via the Blood The cell membrane (also called the plasma membrane, plasmalemma, or "phospholipid bilayer" is a Selectively permeable Lipid bilayer [8]

Treatment

Medical treatment

Various treatments are available for Wilson's disease. Some increase the removal of copper from the body, while others prevent the absorption of copper from the diet. In general, a diet low in copper-containing foods (mushrooms, nuts, chocolate, dried fruit, liver, and shellfish) is recommended. A mushroom is the fleshy Spore -bearing Fruiting body of a Fungus, typically produced above ground on soil or on its food source Nut is a general term for the large dry oily Seeds or Fruit of some Plants. Chocolate ( pronounced or /-ˈələt/ comprises a number of raw and processed foods that are produced from the seed of the tropical Cacao tree The term fruit has different meanings dependent on context and the term is not synonymous in Food preparation and Biology. Shellfish is a Culinary and Fisheries term for those aquatic Invertebrate animals that are used as Food: various species of molluscs [1]

Generally, penicillamine is the first treatment used. Penicillamine is a Pharmaceutical of the chelator class It is sold under the trade names of Cuprimine and Depen. This binds copper (chelation) and leads to excretion of copper in the urine. Chelation is the binding or complexation of a bi- or multidentate Ligand. Hence, monitoring of the amount of copper in the urine can be done to ensure a sufficiently high dose is taken. Penicillamine is not without problems: about 20% of patients experience a side effect or complicaton of penicillamine treatment, such as drug-induced lupus (causing joint pains and a skin rash) or myasthenia (a nerve condition leading to muscle weakness). Systemic lupus erythematosus ( SLE or lupus,) is a chronic autoimmune disease that can be fatal though with recent medical advances fatalities are becoming Myasthenia gravis (literally "serious muscle-weakness" from Greek μύς "muscle" "weakness" and Latin gravis In those who presented with neurological symptoms, almost half experience a paradoxical worsening in their symptoms. While this phenomenon is also observed in other treatments for Wilson's, it is usually taken as an indication for discontinuing penicillamine and commencing second-line treatment. [1][5] Patients intolerant to penicillamine may instead be commenced on trientine hydrochloride, which also has chelating properties. Triethylenetetramine, abbreviated TETA and trien is an Organic compound with the formula 2 Some recommend trientine as first-line treatment, but experience with penicillamine is more extensive. [5] A further agent with known activity in Wilson's disease is tetrathiomolybdate. Ammonium tetrathiomolybdate is the Chemical compound with the formula 2 This is still regarded as experimental,[5] although some studies have shown a beneficial effect. [1]

Once all results have returned to normal, zinc (usually in the form of zinc acetate) may be used instead of chelators to maintain stable copper levels in the body. Zinc (ˈzɪŋk from Zink is a Metallic Chemical element with the symbol Zn and Atomic number 30 Zinc acetate is the Chemical compound with the formula Zn(O2CCH32 but more commonly refers to the dihydrate Zn(O2CCH32(H2O2 Zinc stimulates metallothionein, a protein in gut cells that binds copper and prevents their absorption and transport to the liver. Metallothionein (MT is a family of Cysteine -rich low molecular weight (MW ranging from 3500 to 14000 Da) Proteins MTs have the capacity to Zinc therapy is continued unless symptoms recur, or if the urinary excretion of copper increases. [5]

In rare cases where none of the oral treatments are effective, especially in severe neurological disease, dimercaprol (British anti-Lewisite) is still occasionally necessary. Dimercaprol ( INN) or British anti-Lewisite (abbreviated BAL) is a compound developed by British biochemists at Oxford University during This treatment is injected intermuscularly (into a muscle) every few weeks, and has a number of unpleasant side effects such as pain. Intramuscular injection is the injection of a substance directly into a Muscle. [9]

People who are asymptomatic (for instance those diagnosed through family screening or only as a result of abnormal test results) are generally treated, as the copper accumulation may cause long-term damage in the future. It is unclear whether these people are best treated with penicillamine or zinc acetate. [5]

Liver transplantation

Liver transplantation is the only cure for Wilson's disease, but is used only in particular scenarios because of the numerous risks and complications associated with the procedure. Liver transplantation or hepatic transplantation is the replacement of a diseased Liver with a healthy liver Allograft. It is used mainly in patients with fulminant liver failure who fail to respond to medical treatment, or in patients with advanced chronic liver disease. Liver transplantation is avoided in severe neuropsychiatric illness, in which its benefit has not been demonstrated. [1][5]

Other species

Hereditary copper accumulation has been described in Bedlington Terriers,[10] where it generally only affects the liver. The Bedlington Terrier is a Breed of Terrier named after the Mining town of Bedlington, Northumberland It is due to mutations in the COMMD1 (or MURR1) gene. Copper metabolism (Murr1 domain containing 1, also known as COMMD1, is a human Gene. [11] In patients with non-Wilsonian copper accumulation states (such as Indian childhood cirrhosis), no COMMD1 mutations could be detected to explain their genetic origin. [12]

History

The disease bears the name of the British physician Dr Samuel Alexander Kinnier Wilson (1878-1937), a neurologist who described the condition, including the pathological changes in the brain and liver, in 1912. The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom, the UK or Britain,is a Sovereign state located Samuel Alexander Kinnier Wilson ( December 6, 1878 - May 12, 1937) was a British Neurologist who was born in Cedarville New Jersey [2] Wilson's work had been predated by, and drew on, reports from the German neurologist Dr Carl Westphal (in 1883), who termed it "pseudosclerosis", by the British neurologist Dr William Gowers (in 1888), and by Dr Adolph Strümpell (in 1898), who noted hepatic cirrhosis. Carl Friedrich Otto Westphal ( March 23, 1833 – January 27, 1890) was a German neurologist and psychiatrist from Berlin Sir William Richard Gowers ( 20 March 1845 &ndash 4 May 1915) was a British neurologist. Adolph Strümpell ( June 29, 1853 -- 1925 full name Ernst Adolf Gustav Gottfried von Strümpell was a German neurologist who was born in Estate [13] Prof John N. Cumings made the link with copper accumulation in both the liver and the brain in 1948. [14] The occurence of hemolysis was noted in 1967. [15]

Cumings, and simultaneously the New Zealand neurologist Dr Derek Denny-Brown, working in the USA, first reported effective treatment with metal chelator British anti-Lewisite in 1951. Derek Ernest Denny-Brown OBE (1901 &ndash 20 April 1981) was a neurologist. Dimercaprol ( INN) or British anti-Lewisite (abbreviated BAL) is a compound developed by British biochemists at Oxford University during [16][17] This treatment had to be injected but was one of the first therapies available in the field of neurology, a field that classically was able to observe and diagnose but had few treatments available. [13][18] The first effective oral chelation agent, penicillamine, was discovered in 1956 by the British neurologist Dr John Walshe. Penicillamine is a Pharmaceutical of the chelator class It is sold under the trade names of Cuprimine and Depen. [19] In 1982, Walshe also introduced trientine,[20] and was the first to develop tetrathiomolybdate for clinical use. [21] Zinc acetate therapy initially made its appearance in the Netherlands, where physicians Schouwink and Hoogenraad used it in 1961 and in the 1970s, respectively, but it was further developed later by Brewer and colleagues at the University of Michigan. The University of Michigan Ann Arbor ( U of M, U-M, UM or simply Michigan) is a top-ranked Coeducational public research [9][22]

The genetic basis of Wilson's disease and linkage to ATP7B mutations was elucidated in the 1980s and 1990s by several research groups. [23][24]

References

  1. ^ a b c d e f g h i j k l m n o p q r s t u v w x Ala A, Walker AP, Ashkan K, Dooley JS, Schilsky ML (2007). "Wilson's disease". Lancet 369 (9559): 397-408. doi:10.1016/S0140-6736(07)60196-2. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 17276780.  
  2. ^ a b Kinnier Wilson SA (1912). "Progressive lenticular degeneration: a familial nervous disease associated with cirrhosis of the liver" (PDF). Brain 34 (1): 295-507. doi:10.1093/brain/34.4.295. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document.  
  3. ^ a b c Merle U, Schaefer M, Ferenci P, Stremmel W (2007). "Clinical presentation, diagnosis and long-term outcome of Wilson's disease: a cohort study". Gut 56 (1): 115-20. doi:10.1136/gut.2005.087262. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 16709660.  
  4. ^ Shaver WA, Bhatt H, Combes B (1986). "Low serum alkaline phosphatase activity in Wilson's disease". Hepatology 6 (5): 859-63. PMID 3758940.  
  5. ^ a b c d e f g h i j k l m Roberts EA, Schilsky ML (2003). "A practice guideline on Wilson disease" (PDF). Hepatology 37 (6): 1475-92. doi:10.1053/jhep.2003.50252. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 12774027.  
  6. ^ a b c d e f g de Bie P, Muller P, Wijmenga C, Klomp LW (November 2007). "Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with molecular defects and disease phenotypes". J. Med. Genet. 44 (11): 673–88. doi:10.1136/jmg.2007.052746. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 17717039.  
  7. ^ Grubenbecher S, Stüve O, Hefter H, Korth C (2006). "Prion protein gene codon 129 modulates clinical course of neurological Wilson disease". Neuroreport 17 (5): 549-52. doi:10.1097/01.wnr.0000209006.48105.90. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 16543824.  
  8. ^ Lee, GR (1999). "Chapter 48: acquired hemolytic anaemias resulting from direct effects of infectious, chemical or physical agents", in Lee GR, Foerster J, Lukens J et al: Wintrobe's clinical hematology, 10th vol 1, Williams & Wilkins, 1298. ISBN 0-683-18242-0.  
  9. ^ a b Walshe JM (July 1996). "Treatment of Wilson's disease: the historical background". QJM 89 (7): 553–5. PMID 8759497.  
  10. ^ Sternlieb I, Twedt DC, Johnson GF, et al (1977). "Inherited copper toxicity of the liver in Bedlington terriers". Proc. R. Soc. Med. 70 Suppl 3: 8-9. PMID 122681.  
  11. ^ van De Sluis B, Rothuizen J, Pearson PL, van Oost BA, Wijmenga C (2002). "Identification of a new copper metabolism gene by positional cloning in a purebred dog population". Hum. Mol. Genet. 11 (2): 165-73. PMID 11809725.  
  12. ^ Müller T, van de Sluis B, Zhernakova A, et al (2003). "The canine copper toxicosis gene MURR1 does not cause non-Wilsonian hepatic copper toxicosis". J. Hepatol. 38 (2): 164-8. PMID 12547404.  
  13. ^ a b Robertson WM (February 2000). "Wilson's disease". Arch. Neurol. 57 (2): 276–7. PMID 10681092.  
  14. ^ Cumings JN (1948). "The copper and iron content of brain and liver in the normal and in hepato-lenticular degeneration" (PDF). Brain 71 (Dec): 410-5. doi:10.1093/brain/71.4.410. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 18124738.  
  15. ^ McIntyre N, Clink HM, Levi AJ, Cumings JN, Sherlock S (February 1967). "Hemolytic anemia in Wilson's disease". N. Engl. J. Med. 276 (8): 439–44. PMID 6018274.  
  16. ^ Cumings JN (March 1951). "The effects of B. A. L. in hepatolenticular degeneration". Brain 74 (1): 10–22. PMID 14830662.  
  17. ^ Denny-Brown D, Porter H (December 1951). "The effect of BAL (2,3-dimercaptopropanol) on hepatolenticular degeneration (Wilson's disease)". N. Engl. J. Med. 245 (24): 917–25. PMID 14882450.  
  18. ^ Vilensky JA, Robertson WM, Gilman S (September 2002). "Denny-Brown, Wilson's disease, and BAL (British antilewisite [2,3-dimercaptopropanol])". Neurology 59 (6): 914–6. PMID 12297577.  
  19. ^ Walshe JM (January 1956). "Wilson's disease; new oral therapy". Lancet 267 (6906): 25–6. doi:10.1016/S0140-6736(56)91859-1. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 13279157.  
  20. ^ Walshe JM (March 1982). "Treatment of Wilson's disease with trientine (triethylene tetramine) dihydrochloride". Lancet 1 (8273): 643–7. doi:10.1016/S0140-6736(82)92201-2. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 6121964.  
  21. ^ Harper PL, Walshe JM (December 1986). "Reversible pancytopenia secondary to treatment with tetrathiomolybdate". Br. J. Haematol. 64 (4): 851–3. PMID 3801328.  
  22. ^ Brewer GJ (January 2000). "Recognition, diagnosis, and management of Wilson's disease". Proc. Soc. Exp. Biol. Med. 223 (1): 39–46. PMID 10632959.  
  23. ^ Tanzi RE, Petrukhin K, Chernov I, et al (1993). "The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene". Nat. Genet. 5 (4): 344-50. doi:10.1038/ng1293-344. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 8298641.  
  24. ^ Bull PC, Thomas GR, Rommens JM, Forbes JR, Cox DW (1993). "The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene". Nat. Genet. 5 (4): 327-37. doi:10.1038/ng1293-327. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 8298639.  

External links

The Human Genome Organisation (HUGO is an organization involved in the Human Genome Project, a project about mapping the human genome Who Named It? is an English-language dictionary of medical eponyms and the People associated with their identification The United States National Library of Medicine ( NLM) operated by the United States federal government, is the world's largest Medical library. "NIH" redirects here For other meanings of NIH see NIH (disambiguation. See Washington (disambiguation for other uses The University of Washington, founded in 1861, is a public research University
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