WILSON DISEASE
Wilson disease (WD), or hepatolenticular degeneration, is the principal disorder of copper metabolism affecting the liver (12,25,30,40,42). A high index of suspicion for this disorder is needed since both the clinical manifestations and biopsy findings may vary. This neurologically debilitating and ultimately fatal disease should be considered in the evaluation of every young patient with unexplained liver disease. Most patients present between the ages of 5 and 30 years, but the disease occurs as late as the seventh decade (17,40). The usual clinical laboratory tests are not specific (Table 16.1), and the liver biopsy may be the only way to establish the diagnosis (25).
WD follows tissue injury caused by copper overload in liver and other organs because of decreased excretion of copper in the biliary tract (7,27). Increasing amounts of copper are excreted in the urine, but a positive copper balance remains and copper is deposited in the liver and brain, as well as in other tissues, including the cornea (Kayser-Fleischer rings), kidneys, striated muscle, bones, and joints. The liver is universally affected, although clinical manifestations are not always prominent.
Clinical features vary greatly, with hepatic, neurologic, hematologic, and psychiatric manifestations (4,5,10,12,17,28,30,38,40,46,49) (Table 16.2). Most patients present with hepatic disease, often in a manageable stage (25,30,46). Neuropsychiatric presentations indicate advanced disease, with some patients not having had signs or symptoms of liver disease despite considerable evidence of liver injury, including cirrhosis (17,42).
Copper accumulates in liver cell lysosomes beginning in early childhood and is then released into the blood stream. This is a gradual process, and signs and symptoms can begin in middle adolescence, with increasing fatigue, jaundice, and elevated serum transaminase values. This chronic hepatitis picture is clinically indistinguishable from other forms of chronic hepatitis. As many as 50% of patients are cirrhotic at presentation (25,26,40,44). Hepatocellular carcinoma may develop (8,24,36).
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TABLE 16.1 Clinical Laboratory Tests in Wilson Disease |
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Approximately 25% of patients present with an acute hepatitis picture. This can be severe and accompanied by acute hemolytic anemia, most likely caused by the rapid release of copper into the circulation. Fulminant hepatitis, with severe hemolytic anemia, coagulopathy, renal insufficiency, and often death, is occasionally seen in teenagers without prior evidence of liver disease (4,13,18,38,43,46,49). This form can go unrecognized because of the acuteness and severity of presentation; in fatal cases autopsy may not be performed or the histologic features, which are nonspecific, may not suggest WD.
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TABLE 16.2 Patterns of Presentation in Wilson Disease |
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Genetics
This autosomal recessive disorder occurs in 1 in 30,000 births, with a carrier frequency of 1 in 400. The gene is localized to chromosome 13, where it is in linkage disequilibrium with a red blood cell enzyme esterase D, as well as with the gene for retinoblastoma. The specific locus is thought to be at the ATP7B site (7,9,12,23,34,37). Mutations, frequently found in affected individuals, are thought to be quite heterogeneous (12,21). The gene encodes a putative copper-transporting protein that is almost exclusively expressed in the liver (9). Gene mutations lead to copper accumulation as a result of production of defective liver-specific copper transporter (4,7,12,48) that cannot adequately deliver copper into the bile, leading to its accumulation in tissues (16,39). There is no evidence of a genetically derived deficiency of ceruloplasmin production (11). Various phenotypic presentations are associated with specific mutations (37). WD has been associated with other genetically determined conditions, such as Gilbert disease and thalassemia minor, both of which can contribute to masking of the more serious diagnosis.
The earliest, but nonspecific, laboratory finding is the elevation of serum transaminase values, often before signs or symptoms are manifest (40). Low serum ceruloplasmin levels suggest the diagnosis, but ceruloplasmin is an acute-phase reactant and values can be normal, even in wellestablished WD. Serum copper values are almost always decreased, although the ceruloplasmin-free fraction is increased. Urine copper determination can screen for WD, but increased values are nonspecific. Most specific is measurement of incorporation of orally administered radiocopper into ceruloplasmin. In WD this incorporation is decreased, but the test is not widely available.
The diagnosis is often established by the presence of Kayser-Fleischer corneal rings when seen with reduced serum ceruloplasmin levels. Neither is specific or universal, and determination of hepatic copper concentration may be required (3,22). In WD, copper levels of 250 to 3,000 µg/g dry weight can be demonstrated, although heterozygotes have values near reference range. Copper levels can be reliably quantified from formalin-fixed paraffin-embedded tissue (19). There may be considerable variation in copper content in the cirrhotic liver, particularly in fibrous tissue-rich, hepatocyte-poor samples that are submitted for assay (15,20,33), and values less than 250 µg/g dry weight should not exclude the diagnosis (16). Copper increases in the liver in other conditions (Table 16.3).
Pathology
Histologic alterations may be seen in biopsies obtained at all stages of the disease but vary considerably from patient to patient (1,2,25,26,40,41,44). The most constant feature is the variability of the findings.
Although the hallmark of WD is the accumulation of copper in hepatocytes, both copper and copper-associated protein (26,39) may not be histochemically demonstrable in many cases, and either copper assay or ultrastructural studies of the liver biopsy may be required to confirm the diagnosis, particularly in precirrhotic stages (16).
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TABLE 16.3 Conditions Associated with Elevated Hepatic Copper Levels |
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EARLY STAGE. There may be only mild hepatocellular damage, with slight variation in cell and nuclear size, including increased numbers of binucleate hepatocytes, which can resemble mild acute viral hepatitis. Individual swollen hepatocytes as well as isolated acidophilic bodies are sometimes seen, most prominent in zone 1 but observed throughout the lobule. Portal inflammation may be slight or absent. Slight macrovesicular steatosis with no particular distribution pattern is often, but not invariably, associated with increased numbers of glycogenated nuclei (e-Figs. 16.1-16.3). This latter feature is seen mostly in zone 1 (Fig. 16.1). In less than 25% of case, minimal copper is present in zone 1 hepatocytes (Fig. 16.2). Rarely, the picture of submassive necrosis is seen.
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FIGURE 16.1 Photomicrograph of Wilson disease showing prominence of glycogenated nuclei in zone 1 (periportal) hepatocytes (hematoxylin-eosin, original magnification ×400). |
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FIGURE 16.2 Photomicrograph of Wilson disease showing copper deposition in zone 1 hepatocytes (rubeanic acid, original magnification ×400). |
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FIGURE 16.3 Photomicrograph of Wilson disease showing a histologic picture of chronic hepatitis with interface hepatitis (piecemeal necrosis) (hematoxylin-eosin, original magnification ×100). |
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FIGURE 16.4 Photomicrograph of Wilson disease showing macronodular cirrhosis (hematoxylin-eosin, original magnification ×100). |
PRECIRRHOTIC STAGE. Inflammation and hepatocyte necrosis can increase with progression (1,2,23,40,41,44). Portal inflammation, with prominent interface hepatitis and necrosis, particularly in zone 1, occurs. Lymphocytes are prominent, and polymorphonuclear leukocytes may be seen. There is increased portal collagen and fibrosis extending into the lobule. The biopsy can resemble chronic viral or autoimmune hepatitis (Fig. 16.3, e-Fig. 16.4). Early-stage changes can persist. Steatosis, microvesicular as well as macrovesicular, is seen. Multinucleate giant hepatocytes can form. Uncommonly, there are lipofuscin-like coarse copper granules, but in zone 1 rather than 3 (1,2,26,40,41).
CIRRHOTIC STAGE. Micronodular cirrhosis progressively transforms to mixed or predominantly macronodular pattern with broad bands of parenchymal collapse (Fig. 16.4, e-Figs. 16.5-16.9). Early and precirrhotic stage changes are admixed. Hepatocytes are variable with anisonucleosis and necrosis, and many polymorphonuclear leukocytes, may be seen. Mallory hyalin is common (Fig. 16.5, e-Fig. 16.10), most often in paraseptal hepatocytes but also elsewhere in the nodule, often with ballooned cells. Ductular reaction is quite prominent, and cholesta sis is common (Fig. 16.6, e-Figs. 16.7, 16.8, 16.11). Copper-associated protein and/or copper can be histochemically demonstrated in many cases, typically irregularly distributed (e-Fig. 16.12) (15,19,20,25,32,33,45).
FULMINANT STAGE. In the absence of clinical or morphologic evidence of some other cause for fulminant hepatic failure, WD should always be considered. The biopsy is indistinguishable from that of other forms of fulminant hepatic failure (4,13,28,38). Parenchymal collapse and regenerative nodules are seen. Many cirrhotic WD patients have fulminant failure (42). With massive necrosis and few viable liver cells, copper assay may not be useful.
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FIGURE 16.6 Photomicrograph of cirrhotic stage of Wilson disease showing ductular reaction and cholestasis (hematoxylin-eosin, original magnification ×100). |
Histochemistry
Copper-associated protein can be demonstrated with Victoria blue, orcein (Shikata), or Gomori aldehyde-fuchsin. Copper can be seen after staining with rhodanine, rubeanic acid, or Timm silver sulfide. A recently developed method for demonstrating copper is a modification of the rhodanine stain, but is technically easier to perform and can be completed in 2 hours rather than overnight (e-Figs. 16.12, 16.13) (14). Fetal liver is useful as control tissue for copper stains. Absence of copper or copper-associated protein, demonstrated by histochemical methods, does not exclude the diagnosis of WD (16,25,35) (Table 16.4). The key features of WD are summarized in Table 16.5.
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FIGURE 16.5 Photomicrograph of Wilson disease showing Mallory hyalin in zone 1 hepatocytes (hematoxylin-eosin, original magnification ×400). |
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TABLE 16.4 Histochemical Techniques Used to Identify Copper and Copper-Binding Protein |
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INDIAN CHILDHOOD CIRRHOSIS
Indian Childhood Cirrhosis, a disease of young children with high mortality, occurs almost exclusively in India (6,47). Genetic factors likely play a role, although increased copper ingestion from household water supplies may also contribute. Hepatocellular swelling may be prominent early. Mallory hyalin is usually found, with scattered foci of necrosis and focal accumulation of neutrophils. Pericellular fibrosis, similar to that of alcoholic liver disease, is seen, but steatosis is not prominent. Hepatocytes generally contain large amounts of copper and copper-associated protein. Cirrhosis ultimately ensues.
MENKES DISEASE (KINKY HAIR DISEASE)
Menkes disease is caused by a defective gene that regulates copper metabolism. Copper accumulates at higher than normal levels in the kidney and intestinal lining, but at abnormally low levels in the brain and liver, and, consequently, the liver is not affected (12,29,30). The responsible gene is closely related to that of WD (12,48).
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TABLE 16.5 Key Features of Wilson Disease |
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