Pathology of the Liver in Copper Overload

ABSTRACT

Copper accumulation in the liver is associated with cellular and apoptotic injury. Wilson disease is the most well-characterized disorder of disordered copper metabolism. Other less-common disorders include Indian childhood cirrhosis, endemic Tyrolean infantile cirrhosis, and idiopathic copper toxicosis. The histopathologic spectrum of the liver in Wilson disease is extremely variable and overlaps among the different entities, though this review will focus on the pathology of Wilson disease. The findings lack specificity, although characteristic findings are observed. Unlike other disorders of copper overload, the pathologic changes are typically sequential, ranging from little or no significant findings to cirrhosis with or without widespread hepatocellular damage. Steatosis and glycogenated nuclei are frequent. Staining of copper is an unreliable method of diagnosis of Wilson disease, whether there are minimal histologic abnormalities or chronic liver disease. Copper and copper-associated protein accumulation may also be seen in chronic biliary obstructive processes.

KEYWORDS

Wilson disease - copper overload

REFERENCES

• 1 Roberts E A, Schilsky M L. American Association for Study of Liver Diseases (AASLD) . Diagnosis and treatment of Wilson disease: an update.  Hepatology. 2008;  47 (6) 2089-2111
• 2 Scheinberg I, Sternlieb I. Wilson's Disease. Major Problems in Internal Medicine. Vol. 30. Philadelphia: WB Saunders; 1984
• 3 Pilloni L, Coni P, Mancosu G et al.. [Late onset Wilson's disease].  Pathologica. 2004;  96 (3) 105-110
• 4 Salaspuro M P, Pikkarainen P, Sipponen P, Vuori E, Miettinen T A. Hepatic copper in primary biliary cirrhosis: biliary excretion and response to penicillamine treatment.  Gut. 1981;  22 (11) 901-906
• 5 Milkiewicz P, Saksena S, Hubscher S G, Elias E. Wilson's disease with superimposed autoimmune features: report of two cases and review.  J Gastroenterol Hepatol. 2000;  15 (5) 570-574
• 6 Strand S, Hofmann W J, Grambihler A et al.. Hepatic failure and liver cell damage in acute Wilson's disease involve CD95 (APO-1/Fas) mediated apoptosis.  Nat Med. 1998;  4 (5) 588-593
• 7 Müller T, Langner C, Fuchsbichler A et al.. Immunohistochemical analysis of Mallory bodies in Wilsonian and non-Wilsonian hepatic copper toxicosis.  Hepatology. 2004;  39 (4) 963-969
• 8 Hayashi H, Yano M, Fujita Y, Wakusawa S. Compound overload of copper and iron in patients with Wilson's disease.  Med Mol Morphol. 2006;  39 (3) 121-126
• 9 Schilsky M L, Scheinberg I H, Sternlieb I. Prognosis of Wilsonian chronic active hepatitis.  Gastroenterology. 1991;  100 (3) 762-767
• 10 Askari F K, Greenson J, Dick R D, Johnson V D, Brewer G J. Treatment of Wilson's disease with zinc. XVIII. Initial treatment of the hepatic decompensation presentation with trientine and zinc.  J Lab Clin Med. 2003;  142 (6) 385-390
• 11 Walshe J M, Waldenström E, Sams V, Nordlinder H, Westermark K. Abdominal malignancies in patients with Wilson's disease.  QJM. 2003;  96 (9) 657-662
• 12 Ponomarev A B, Kosminkova E N, Generalova S Iu. [Diffuse cholangiocarcinoma in the context of multilobular liver cirrhosis as a manifestation of Wilson-Konovalov disease].  Arkh Patol. 1994;  56 (6) 74-77
• 13 Harada M. Wilson disease and hepatocellular carcinoma.  Intern Med. 2004;  43 (11) 1012-1013
• 14 Cheng W S, Govindarajan S, Redeker A G. Hepatocellular carcinoma in a case of Wilson's disease.  Liver. 1992;  12 (1) 42-45
• 15 Faa G, Nurchi V, Demelia L et al.. Uneven hepatic copper distribution in Wilson's disease.  J Hepatol. 1995;  22 (3) 303-308
• 16 Pilloni L, Lecca S, Van Eyken P et al.. Value of histochemical stains for copper in the diagnosis of Wilson's disease.  Histopathology. 1998;  33 (1) 28-33
• 17 Goldfischer S, Popper H, Sternlieb I. The significance of variations in the distribution of copper in liver disease.  Am J Pathol. 1980;  99 (3) 715-730
• 18 Irons R D, Schenk E A, Lee J C. Cytochemical methods for copper. Semiquantitative screening procedure for identification of abnormal copper levels in liver.  Arch Pathol Lab Med. 1977;  101 (6) 298-301
• 19 Portmann B, Thompson R, Roberts E, Paterson A. Genetic and metabolic liver disease. In: Burt A, Portmann B, Ferrell L, eds. MacSween's Pathology of the Liver. Amsterdam: Elsevier Limited; 2007: 200-326
• 20 Alt E R, Sternlieb I, Goldfischer S. The cytopathology of metal overload.  Int Rev Exp Pathol. 1990;  31 165-188
• 21 Ludwig J, Moyer T P, Rakela J. The liver biopsy diagnosis of Wilson's disease. Methods in pathology.  Am J Clin Pathol. 1994;  102 (4) 443-446
• 22 Motonishi S, Hayashi H, Fujita Y et al.. Copper- and iron-rich matrices in hepatocellular lipofuscin particles of a young male patient: diagnostic ultrastructures for Wilson disease.  Ultrastruct Pathol. 2006;  30 (6) 409-414
• 23 Stromeyer F W, Ishak K G. Histology of the liver in Wilson's disease: a study of 34 cases.  Am J Clin Pathol. 1980;  73 (1) 12-24
• 24 Epstein O, Arborgh B, Sagiv M, Wroblewski R, Scheuer P J, Sherlock S. Is copper hepatotoxic in primary biliary cirrhosis?.  J Clin Pathol. 1981;  34 (10) 1071-1075
• 25 Scheinberg I H, Sternlieb I. Wilson disease and idiopathic copper toxicosis.  Am J Clin Nutr. 1996;  63 (5) 842S-845S
• 26 Baker A, Gormally S, Saxena R et al.. Copper-associated liver disease in childhood.  J Hepatol. 1995;  23 (5) 538-543
• 27 Tanner M S, Portmann B. Indian childhood cirrhosis.  Arch Dis Child. 1981;  56 (1) 4-6
• 28 Lefkowitch J H, Honig C L, King M E, Hagstrom J W. Hepatic copper overload and features of Indian childhood cirrhosis in an American sibship.  N Engl J Med. 1982;  307 (5) 271-277
• 29 Wijmenga C, Müller T, Murli I S et al.. Endemic Tyrolean infantile cirrhosis is not an allelic variant of Wilson's disease.  Eur J Hum Genet. 1998;  6 (6) 624-628