Biliary copper excretion

Davis, W., Chowrimootoo, G.F.E., Seymour, C.A. Defective biliary copper excretion in Wilson s disease the role of caeruloplasmin. Eur. J. Clin. Invest. 1996 26 893-901... 

Wilson s disease is an autosomal recessive disease of copper metabolism. It has a prevalence of 1 in 30,000 live births in most populations. The disease has a highly variable clinical presentation. It is characterized by impairment of biliary copper excretion, decreased incorporation of copper into ceruloplasmin, and accumulation of copper in the liver and, eventually, in the brain and other tissues. The biochemical findings include low serum ceruloplasmin, high urinary copper excretion, and high hepatic copper content. Some patients have normal serum cerulo-plasmia levels, and heterozygous individuals do not consistently show reduced levels of this protein. 

Idiopathic (Indian) childhood cirrhosis is a disorder of progressive liver failure in early childhood, with marked accumulation of hepatic copper usually resulting in death from liver failure. Although the etiology of this disorder in unknown, in all such cases the serum ceruloplasmin is elevated, suggesting a defect in biliary copper excretion beyond the point of entry into the secretor pathway. Originally described in infants... 

Mohan P, Failla M, Bremner I, Arthur-Smith A and Kerzner B (1995) Biliary copper excretion in the neonatal rat role of glutathione and metallo-thionein. Hepatology 21 1051-1057. 

Two inherited human diseases that represent abnormal copper metabolism are Menkes syndrome and Wilson s disease. Menkes syndrome, with symptoms similar to those of copper deficiency, is characterized by a progressive brain disease, abnormally low copper concentrations in Uver and other tissues, and diminished ability to transfer copper across the absorptive cells of the intestinal mucosa. Wilson s disease (hepatolenticular degeneration) is the only significant example of copper toxicity in humans. Wilson s disease is an autosomal recessive disorder that affects normal copper homeostasis and is characterized by excessive retention of hepatic copper, decreased concentration of serum ceruloplasmin, impaired biliary copper excretion, and hypercupremia. Systemic manifestations of Wilson s disease are hepatic and renal lesions and hemol5dic anemia. Certain strains of mutant rats with reduced excretion of... 

A word of comment on the high Cu64 content of the bile seems justifiable, since the exact chemical form of copper excreted in the bile has not been determined. The possibility that ceruloplasmin or some copper-containing metabolite of ceruloplasmin is normally excreted in the bile has not been carefully examined. The abnormal elevation of the serum ceruloplasmin level in acute biliary obstruction (7), and the abnormally low serum ceruloplasmin seen in some cases of advanced liver disease, particularly Wilson s disease (2, 3), are in keeping with the liver being the site of ceruloplasmin synthesis and excretion. 

Bile contains a large number of diverse proteins, some resulting from leakage of hepatocellular protein and others derived from plasma (A9, R6). In certain cases, the liver may secrete specific proteins into bile to bind and thus prevent the reabsorption of potential toxins and thus facilitate fecal excretion of these substances (S3). As an example, copper is excreted principally by the biliary route, bound to a carrier protein that prevents intestinal absorption of the biliary copper (G6). The GST can bind a wide range of substances and we have studied the GST content of human bile using material obtained from intact gallbladders following removal at cholecystectomy. 

Hepatic accumulations of copper may occur with any biliary excretion disturbance, as the biliary tract is the major route of copper excretion in humans. Sometimes, patients with primary biliary cirrhosis may have as high hepatic copper as in WD. Evidently, high liver copper deposits in biliary cirrhosis are secondary to a different pathological cause than WD, and the removal of copper using D-penicillamine will not benefit the cirrhotic patient. 

Biliary excretion is the only mechanism for copper elimination, and the amount of copper excreted in the bile is direcMly proportional to the size of the hepatic copper pcx)l. Becanse hepatic nptake of dietary copper in not saturable, hepatic copper accumulation can easily be induced. Toxicity of copper, however, depends on its molecailar asscx iation and subcellular Icxnhzation rather than on its concentration in the Uver. MetaUothionein-bound copper is nontoxic. Several metals including zinc crtn induce metaUothionein synthesis. 

Excess copper is the result of either excessive copper absorption or ineffective copper excretion. The most common diseases associated with copper excess are (1) Wilson s disease, a genetic disease resulting in mutations in the Wilson s disease P-type ATPase and excessive hepatocyte copper accumulation (2) renal disease, in patients on hemodialysis due to kidney failure when dialysate solutions become contaminated with excess copper and (3) biliary obstruction. Excessive use of copper supplements may also contribute to copper toxicity and is clinically manifested by severe anemia, nausea and vomiting, abdominal pain, and diarrhea. 

Retention of radiocopper injected into humans is high only 10% is excreted within 72 h in urine and feces, and 50% in four weeks (Aaseth and Norseth 1986). Most (72%) of the unabsorbed copper is excreted in the feces primarily by way of the biliary duct, the salivary glands, or the intestinal mucosa a minor portion is excreted by way of sweat and menses (Schroeder et al. 1966 USEPA 1980 ATSDR 1990). In mammals, copper is excreted mainly via the bile in association with glutathione or unidentified high-molecular-weight molecules. However, the transport mechanisms of copper from liver cells into bile are essentially unknown (Aaseth and Norseth 1986). In rats, biliary excretion of copper is increased by increased flow of bile, increased body temperature, or administration of adrenal steroids (Sugawara et al. 1994). 

In mammals, phenobarbital and phenytoin increase serum ceruloplasmin concentrations (Aaseth and Norseth 1986). Chronic copper poisoning in sheep is exacerbated when diets contain heliotrope plants (Heliotropium sp., Echium spp., Senecio sp.). Aggravated effects of the heliotrope plants include reduced survival and a twofold to threefold increase in liver and kidney copper concentrations when compared to control animals fed copper without heliotropes (Howell et al. 1991). Rats given acutely toxic doses of 2,3,7,8-tetrachlorodibenzo-para-dioxin had elevated concentrations of copper in liver and kidney because of impaired biliary excretion of copper (Elsenhans et al. 1991). Morphine increases copper concentrations in the central nervous system of rats, and dithiocarbam-ates inhibit biliary excretion (Aaseth and Norseth 1986). In human patients, urinary excretion of copper is increased after treatment with D-penicillamine, calcium disodium EDTA, or calcium trisodium diethylenetriamine penta acetic acid (Flora 1991). 

Sugawara, N., D. Li, M. Katakura, and C. Sugawara. 1994. Biliary excretion of copper in Fischer rats treated with copper salt and in Long-Evans Cinnamon (LEC) rats with an inherently abnormal copper metabolism. Biol. Trace Elem. Res. 46 125-134. 

Yu, S., C.E. West, and A.C. Beynen. 1994. Increasing intakes of iron reduce status, absorption and biliary excretion of copper in rats. Brit. Jour. Nutr. 71 887-895. 

Figure 18.4 Proteins involved in copper uptake, incorporation into ceruloplasmin and biliary excretion in normal and Wilson s disease hepatocytes. (From Crichton and Ward, 2006. Reproduced with permission from John Wiley Sons., Inc.)...

Caeruloplasmin Copper-incorporating a glycoprotein true function remains unclear but acts as a copper donor and oxidative enzyme Low caeruloplasmin levels may be seen in cirrhosis (especially primary biliary cirrhosis) as caeruloplasmin is excreted hepatically Levels increased in infection, injury or inflammation. Low levels are found in Wilson s disease, which is an autosomal recessive disorder of copper metabolism it results in copper deposition in the liver, basal ganglia and eyes, and culminates in cirrhosis and neurological impairment... 

Biliary excretion of copper and iron is important. Major losses of iron can be caused by internal bleeding. Thus women during their menstrual periods will be in negative iron balance unless proper nutrition is observed. Blood loss via the gastrointestinal tract, as in ulcers or some forms of cancer, leads quickly to loss of utilizable or stored iron. ... 

Copper The daily intake from food is 0.8—2.0 mg it is released into the portal vein via copper-transporting ATPase. The transport of copper, which is toxic in its free form, is effected by the binding to ceruloplasmin, albumin and transcuprin. Copper is bound to reduced glutathione and metallothionein in the hepatocytes and distributed to various organelles or incorporated into enzymes. The biological effects of copper are manifold and essential for some cellular functions, (s. p. 50) Copper is toxic not only in its free form, but also in cases of overload (e. g. cirrhosis in childhood due to the consumption of water from copper pipes). Copper homoe-ostasis is regulated via biliary excretion (normal value about 1.2-2.0 mg/day), so that the normal value in serum is 75-130 fg/dl. (321, 323, 370, 383, 386) (s. p. 102)... 

Wilson s disease often involves low plasma levels of ceruloplasmin, increased plasma nonceruloplasmin copper, and increased urinary copper. The disease can involve a tenfold increase in liver copper lev els. The normal value for hepatic copper is 20 to 50 pg/g of liver dry weight). Outward signs of the disease include episodes of jaundice, vomidng, and tiredness. Bone disorders such as osteoporosis can also occur. The neurological damage includes a loss in coordination. V ilson s disease does not result in mental retardation. The rate of incorporation of copper into ceruloplasmin is reduced and biliary excretion decreases to 20 to 40% the normal rate. 

Thyroid, adrenal, and pituitary hormones are known to influence copper metabolism indirectly, presumably by reducing its biliary excretion, whereas hormones of the gonads, particularly estrogen, increase ceruloplasmin by synthesizing the protein in a manner that is independent of copper concentration in the liver (103), Our own observations on the relationship of hormones and ultratrace-metals metabolism will be mentioned later in this review. SuflBce it to say that aging and its influence on mineral metabolism in general may be mediated through altered hormonal activity. 

The chemical nature of the hormone seems to have varying effect on copper metabolism. Gonadal hormones, for example, increase ceruloplasmin by a mechanism of de novo synthesis of the protein independent of copper concentration in the liver, whereas hormones of the thyroid, adrenal, and pituitary influence copper metabolism in an indirect manner by decreasing its biliary excretion 144),... 

FIGURE 21.15 Proteins involved in copper uptake, incorporation into ceruloplasmin and biliary excretion in normal and Wilson s disease... 

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