Copper accumulation in the liver

Disorders of Copper Accumulation. One of the most enigmatic diseases of copper accumulation is Wilson s Disease where copper accumulates in the liver, brain, eyes, and kidneys, leading to symptoms of... 

Copper is detectable histochemically using rubianic acid, which reacts with the metal to yield a black precipitate. Such techniques have shown that the copper accumulates in the hepatic cell first leaving the Kupffer cell free of copper. In the hepatic cell, at first the metal is diffused throughout the cytoplasm, but later it accumulates to form a metallic halo around the nucleus. Copper accumulation in the liver cell precedes the development of cirrhosis. The copper is widely distributed among the brain cells, but the largest concentration of metal is usually found in the basal ganglia. The type of nerve cell involved in copper accumulation in Wilson s disease has not been unequivocally identified. 

Although chelation is not helpful for Alzheimer s disease patients, it is the key to treating patients with dementia due to Wilson s disease. Wilson s disease is a genetically inherited disorder that usually strikes before age 30. The disease causes toxic levels of copper to accumulate in the liver, brain, eyes, and kidney. Untreated, Wilson s disease leads to tremors, cirrhosis, depression, psychosis, dementia, and ultimately death. Chelation with penicillamine (Cuprimine) can stop and even reverse the accumulation of copper. 

Copper toxicity lends In accumulate in the liver The capacity to tolerate copper varies considerably with lhe species. Sheep arc most susceptible. Sw ine have a much grcaler tolerance and copper may be added to the swine diet lor pharmacological reasons tl or example, use as an anthelminthic lo control internal parasites)... 

Wilson disease is an autosomal recessive disorder of copper transport (Figure 1). It results in the toxic accumulation of copper in various tissues, but mainly in the liver, kidney, and brain. Wilson disease occurs worldwide with an average prevalence of about 1 in 30 000 in most populations. The age of onset for Wilson disease is variable and can extend from 3-4 years into the mid-50s. There are three phases in the progression of the disease. In the first phase, copper accumulates in the cytoplasm of hepatocytes. As more copper is absorbed, in the second phase the increased concentration of... 

Hepatolenticular degeneration (Wilson s disease) is caused by a genetic failure to eliminate copper absorbed from food so that it accumulates in the liver, brain, cornea and kidneys. Chelating copper in the gut with penicillamine (p. 293) or trientine can establish a negative copper balance (with some clinical improvement if treatment is started early). The patients may also develop cirrhosis, and the best treatment for both may be orthotopic liver transplantation. 

Disturbance of Copper Metabolism. A profound and characteristic disturbance of the metabolism of copper is the cardinal biochemical feature of Wilson s disease. The earUest evidence of this came from Germany, where in 1913 Rumpel (R20) found increased copper and silver content of the liver in patients with so-called pseudosclerosis. Siemerling and Oloff (S27) as far back as 1922 suggested that the pseudosclerosis of Westphal-Striimpell is actually due to accumulation of copper salts in the nervous system, liver, and eye. These early observations were not followed up for over 20 years, until Glazebrook (G7) in 1945 reported high copper content in the liver and brain of a patient with Wilson s disease, and increased... 

WD-XRF wavelength dispersive-X-ray emission spectrometrywhich is visible microscopically siderosis deposition of iron in tissues and organs WHO World Health Organisation widy sign a dark pigment precipitation in hair roots at the fourth or fifth day after the intake of a toxic dose of thallium Wilson s disease recessive autosomal, hereditary disease (if untreated, results in invalidity and death) in which toxic amounts of copper are accumulated in the liver and central nervous system XPS X-ray photoelectron spectrometry XRF X-ray fluorescence spectrometry... 

Silver accumulated in the liver with each increase of dietary silver, and this significantly increased hepatic copper and iron content (Table VI). However, silver had no influence on the zinc content of the liver. Dietary selenium significantly increased the silver content of the liver, consistent with the results of Wagner et al. (1975). The metabolic interaction of silver with copper in the rat is in agreement with findings by others using the chick (Hill et al, 1964 Peterson and Jensen, 1975b). 

Another disease related to a dysfunction in copper metabolism is Wilson s disease. Unlike in Menkes patients, copper in Wilson s patients is readily absorbed through the intestine and into the ceU. Within the cell, however, abnormally low levels of the copper-storage protein cemloplasmin are present. As a result, copper accumulates in the cytosol and is eventually released into the blood stream. The clinical manifestations of Wilson s disease are liver disease and neurological damage. 

It therefore appears reasonable to state that there is an incontrovertible relationship between the deposition of excess copper stores and the development of structural and fimctional defects in certain tissues. This sequence of events can be reversed by the establishment of a negative copper balance with chelating agents. As copper is an enzyme poison there seems little doubt that the metal must be implicated in the pathological changes observed. Now since it has been demonstrated that, in Wilson s disease, copper accumulates in the brain 2ind liver in concentrations sufficient to inhibit essential enzymes, then it must be asked how 2ind why this... 

A considerable amount of the gold that accumulates in the kidneys and liver of mammalian species is bound to MTs. This buildup of gold in the kidneys is accompanied by elevated levels of renal copper to form copper-rich, gold-bearing MTs. In cell lines that overproduce MT, there is commonly a resistance to the cytotoxic effects of gold compounds. This resistance is also seen often in parent lines that have been repeatedly exposed to gold complexes. The mechanisms of resistance include but are not limited to enhanced biosynthesis of MT [102]. 

Wilson s disease is another autosomal recessive disease leading to cirrhosis. Protein abnormalities result in excessive copper deposition in body tissues. The faulty protein is responsible for facilitating copper excretion in the bile, so copper accumulates in hepatic tissue. High copper levels within hepatocytes are toxic, and fibrosis and cirrhosis may develop in untreated patients. Those with Wilson s disease usually present with symptoms of liver or neurologic disease while still in their teens. 

Copper is associated with two important life-threatening diseases in man, the pathologies of both being due to defective intracellular copper transport. Menke s disease is characterized by progressive cerebral degeneration, essentially due to insufficient copper absorption, and Wilson s disease is due to excessive copper accumulation in liver, accompanied by liver disease and haemolytic crises. 

Hogstad, O. 1996. Accumulation of cadmium, copper and zinc in the liver of some passerine species wintering in central Norway. Sci. Total Environ. 183 187-194. 

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