{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T20:43:33Z","timestamp":1773780213804,"version":"3.50.1"},"reference-count":17,"publisher":"BMJ","issue":"10","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Clin Pathol"],"published-print":{"date-parts":[[1981,10]]},"abstract":"<jats:p>In primary biliary cirrhosis (PBC) liver copper retention occurs as a complication of cholestasis. By analogy with Wilson's disease, it has been suggested that copper retention is hepatotoxic in PBC, and this has been the rationale for the use of D-penicillamine in this disease. The hypothesis that copper is hepatotoxic in PBC has not been tested and in this study we have evaluated the role of liver copper retention in the pathogenesis of PBC. Sixty-four patients with PBC have been studied. Fifty-four had increased liver copper concentrations. Liver cell synthetic function was well preserved. All the patients had normal prothrombin times, and only two had subnormal serum albumin concentrations. There was no correlation between liver copper concentrations and the degree of liver cell damage assessed biochemically (aspartate transaminase), and histologically. Electron microscopy was performed on liver biopsies from five patients with markedly increased liver copper concentrations. The liver cell ultrastructure was compatible with cholestasis. Liver cells contained electron dense lysosomes, which were shown to contain copper and sulphur by x-ray probe microanalysis. The characteristic organelle changes associated with copper toxicity in Wilson's disease were not observed. The biochemical, histological, and histochemical differences between PBC complicated by liver copper retention, and Wilson's disease, indicates that there are differences in the handling of copper in these disease. In this study we could find no evidence to suggest that copper plays an important role in the pathogenesis of liver dysfunction in PBC.<\/jats:p>","DOI":"10.1136\/jcp.34.10.1071","type":"journal-article","created":{"date-parts":[[2007,6,9]],"date-time":"2007-06-09T00:50:46Z","timestamp":1181350246000},"page":"1071-1075","source":"Crossref","is-referenced-by-count":38,"title":["Is copper hepatotoxic in primary biliary cirrhosis?"],"prefix":"10.1136","volume":"34","author":[{"given":"O","family":"Epstein","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B","family":"Arborgh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M","family":"Sagiv","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R","family":"Wroblewski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P J","family":"Scheuer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S","family":"Sherlock","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[1981,10,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1498","DOI":"10.1136\/bmj.2.5371.1498","article-title":"Relation between cirrhosis and trace metal content of the liver","volume":"ii:","author":"Hunt, A.H.; Parr, R.M.; Taylor, D.M.","year":"1963","unstructured":"Hunt AH, Parr RM, Taylor DM, et al. Relation between cirrhosis and trace metal content of the liver. Br Med J 1963;ii:1498-1501.","journal-title":"Br Med J"},{"key":"ref_2","first-page":"831","article-title":"A controlled trial of D-penicillamine therapy in primary biliary cirrhosis","volume":"i:","author":"Jain, S.; Scheuer, P.J.; Samourian, S.","year":"1974","unstructured":"Jain S, Scheuer PJ, Samourian S, et al. A controlled trial of D-penicillamine therapy in primary biliary cirrhosis. Lancet 1974;i:831-4.","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1016\/S0016-5085(77)80012-7","article-title":"Effect of D-penicillamine on copper retention in patients with primary biliary cirrhosis","volume":"72","author":"sDeering TB; ER, Dickson; CR, Fleming","year":"1977","unstructured":"sDeering TB, Dickson ER, Fleming CR, et al. Effect of D-penicillamine on copper retention in patients with primary biliary cirrhosis. Gastroenterology 1977;72: 1208-12.","journal-title":"Gastroenterology"},{"key":"ref_4","first-page":"\"*\" # \"715","article-title":"Livercopper levels in liver disease. Studies using neutron activation analysis. Lancet 1968; ii: 1310-3","volume":"198099","author":"Smallwood, R.A.; Williams, H.A.; Rosenoer, V.M.","unstructured":";289:674-8.","journal-title":"Am JPathol; Progress in liver diseases IV; Sternlieb 1. Tho sigificance of variations in the distribution of copper in liver dlMse"},{"key":"ref_5","first-page":"511","author":"London, Grune; Stratton","year":"1972","unstructured":"Smallwood RA, Williams HA, Rosenoer VM, et al. Livercopper levels in liver disease. Studies using neutron activation analysis. Lancet 1968;ii:1310-3. * Goldfischer S, Popper H. Sternlieb 1. Tho sigificance of variations in the distribution of copper in liver dlMse. Am JPathol 198099:715-30Q 7 Sternileb I. Evolution of the hopatic lesions in Wilson's disease (hepatolenticular degemration). In: Popper H, Schaffner F. Progress in liver diseases IV. New York and"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1056\/NEJM196802152780702","article-title":"Prevention of Wilson's disease in asymptomatic patients","volume":"278","author":"Sternlieb, I.; Scheinberg, I.H.","year":"1968","unstructured":"London: Grune and Stratton, 1972:511-25.","journal-title":"N Engl J Med"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1016\/S0016-5085(19)34045-4","article-title":"Mitochondrial and fatty changes in hepatocytes of patients with Wilson's disease","volume":"55","author":"Sternlieb, I.","year":"1968","unstructured":"Sternlieb I, Scheinberg IH. Prevention of Wilson's disease in asymptomatic patients. N Engl J Med 1968;278: 352-9.","journal-title":"Gastroenterology"},{"key":"ref_8","first-page":"189","article-title":"Disturbances of copper and iron metabolism","volume-title":"biopsy interpretation","author":"Scheuer, P.J.","year":"1980","unstructured":"Sternlieb I. Mitochondrial and fatty changes in hepatocytes of patients with Wilson's disease. Gastroenterology 1968;55:354-67.","edition":"3rd ed"},{"key":"ref_9","first-page":"152","article-title":"Electron microscopic observations in primary biliary cirrhosis","volume":"81","author":"Klion, F.; Schaffner, F.","year":"1966","unstructured":"Scheuer PJ. Disturbances of copper and iron metabolism. In: Scheuer PJ, ed. Liver biopsy interpretation 3rd ed. London: Baill6re Tindall, 1980:189-92.","journal-title":"Arch Pathol"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1016\/S0016-5085(19)32737-4","article-title":"Ultrastructural aspects of primary biliary cirrhosis and other types of cholestatic liver disease","volume":"67","author":"Chedid, A.; Spellburg, N.A.; DeBeer, A.","year":"1974","unstructured":"Klion F, Schaffner F. Electron microscopic observations in primary biliary cirrhosis. Arch Pathol 1966;81:152-61.","journal-title":"Gastroenterology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1136\/jcp.31.8.784","article-title":"Histological demonstration of copper and copper-associated protein in chronic liver disease","volume":"31","author":"Jain, S.; Scheuer, P.J.; Archer, B.","year":"1978","unstructured":"Chedid A, Spellburg NA, DeBeer A. Ultrastructural aspects of primary biliary cirrhosis and other types of cholestatic liver disease. Gastroenterology 1974;67:858-69.","journal-title":"J Clin Pathol"},{"key":"ref_12","first-page":"1105","article-title":"Le cuivre dans la cirrhose biliare de l'enfant","volume":"6","author":"Stemlieb, I.; Harris, R.C.; Scheinberg, I.H.","year":"1965","unstructured":"Jain S, Scheuer PJ, Archer B, et al. Histological demonstration of copper and copper-associated protein in chronic liver disease. J Clin Pathol 1978;31:784-90.","journal-title":"Rev Int Hepatol"},{"key":"ref_13","first-page":"179","article-title":"Copper in childhood liver disease. A histologic, histochemical and chemical survey. Arch Pathol 1972; 93: 249-55. ' Bloomer LC, Lee GR. Normal hepatic copper metabolism","volume-title":"Metals and the liver. New York and","author":"Reed, G.B.; Butt, E.M.; Landing, H.","year":"1978","unstructured":"Stemlieb I, Harris RC, Scheinberg IH. Le cuivre dans la cirrhose biliare de l'enfant. Rev Int Hepatol 1965;6:1105-10."},{"key":"ref_14","first-page":"\"14p\" # \"12","article-title":"The subcellular distribution of copper in normal subjects and patients with primary biliary crirhosis and Wilson's disease","volume":"58","author":"Y, Karino T, Ohfa G.","year":"1979","unstructured":"Reed GB, Butt EM, Landing H. Copper in childhood liver disease. A histologic, histochemical and chemical survey. Arch Pathol 1972;93:249-55. ' Bloomer LC, Lee GR. Normal hepatic copper metabolism. In: Powell LW, ed. Metals and the liver. New York and Basel: Marcel Dekker, 1978:179-239.","journal-title":"Clin Sci; Orcein positive granules in the hepatocytes in chronic intrahepatic cholestasis"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1080\/00365521.1976.12097149","article-title":"Orcein positive hepatocellular material in long standing biliary disease II Ultrastructural studies","volume":"11","author":"Sipponen, P.","year":"1976","unstructured":"Jenkins WJ, Evan J, Epstein 0. The subcellular distribution of copper in normal subjects and patients with primary biliary crirhosis and Wilson's disease. Clin Sci 1979;58:14p 45A. 1 Nakanuma Y, Karino T, Ohfa G. Orcein positive granules in the hepatocytes in chronic intrahepatic cholestasis. Virchows Arch [Pathol Anat] 1979;382:12-20.","journal-title":"ScandJ Gastroenterol"},{"key":"ref_16","first-page":"274","article-title":"D-penicillamine in primary biliary cirrhosis: apparent beneficial effects in spite of a lack of correlation with changes in hepatic copper concentrations. Gastroenterology 1978; 79: 964A. \" Epstein 0","volume":"300","author":"Fleming, C.R.; Lindor, K.D.; Dickson, E.R.","year":"1979","unstructured":"Sipponen P. Orcein positive hepatocellular material in long standing biliary disease II Ultrastructural studies. ScandJ Gastroenterol 1976;11:553-7.","journal-title":"N Engl J Med; Reduction of immune complexes and immunoglobulins induced by D-penicillamine in primary biliary cirrhosis"},{"key":"ref_17","first-page":"1275","article-title":"D-penicillamine treatment improves survival in primary biliary cirrhosis (Lancet)","volume":"ii:","author":"Epstein 0, Jain S, Lee R","year":"1981","unstructured":"Fleming CR, Lindor KD, Dickson ER et al. D-penicillamine in primary biliary cirrhosis: apparent beneficial effects in spite of a lack of correlation with changes in hepatic copper concentrations. Gastroenterology 1978; 79:964A. \" Epstein 0, De Villiers D, Jain S et al. Reduction of immune complexes and immunoglobulins induced by D-penicillamine in primary biliary cirrhosis. N Engl J Med 1979;300:274-8."}],"container-title":["Journal of Clinical Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jcp.34.10.1071","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,6]],"date-time":"2025-12-06T08:23:01Z","timestamp":1765009381000},"score":1,"resource":{"primary":{"URL":"https:\/\/jcp.bmj.com\/lookup\/doi\/10.1136\/jcp.34.10.1071"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1981,10]]},"references-count":17,"journal-issue":{"issue":"10","published-online":{"date-parts":[[1981,10,1]]},"published-print":{"date-parts":[[1981,10]]}},"alternative-id":["10.1136\/jcp.34.10.1071"],"URL":"https:\/\/doi.org\/10.1136\/jcp.34.10.1071","relation":{},"ISSN":["0021-9746","1472-4146"],"issn-type":[{"value":"0021-9746","type":"print"},{"value":"1472-4146","type":"electronic"}],"subject":[],"published":{"date-parts":[[1981,10]]}}}