Wilson disease is a rare autosomal recessive disease that occurs due to mutations in the ATP7B gene that interfere with normal hepatic copper transport and cause copper buildup in hepatocytes, leading to progressive liver damage.1 The disease predominantly affects the liver and basal ganglia of the brain, however, it can affect other organ systems as well. The majority of patients with Wilson disease experience liver impairment within the first 10 years of life. Neuropsychiatric symptoms typically appear in the third or fourth decade of life. Although Wilson disease is uncommon, it can be fatal if it is not identified and treated.2

Histological abnormalities usually appear before the onset of clinical symptoms. Initially, steatosis, or fatty change, occurs along with infrequent lipogranulomas and minimal inflammation. Thin fibrous septa extend from the portal tracts. If left untreated, these early abnormalities develop into chronic hepatitis, which frequently resembles chronic viral hepatitis on histological examination. Cirrhosis may then follow.1 

Liver Histological Findings 

Liver biopsy is recommended when clinical and laboratory results are not diagnostic or in the presence of unexplained liver disease or abnormal liver test results. It can help in the quantification of hepatic copper levels and the assessment of hepatic inflammation. Wilson disease shows a wide range of pathological changes, varying from findings typical of toxic liver disease to inflammatory changes as seen in viral or autoimmune disorders. Hence, there are no specific histological changes, and they can mimic various diseases. The predominant findings are steatosis (microvesicular and macrovesicular), inflammatory infiltrates, glycogenation in the nuclei of liver cells, hepatocellular anisonucleosis of variable degree, and portal fibrosis.3,4 

Histological findings are varied and depend on disease presentation and stage.5 

Early (Precirrhotic) Stage

Macrovesicular steatosis occurs early in the disease process and can be the only histological finding. Exceptions to this are a disease presentation of acute liver failure or the late stages of severe acute hepatitis, which do not show steatosis. Other findings on liver biopsy include mild to moderate hepatocellular anisocytosis and anisokaryosis. Glycogen is deposited in the nuclei of most periportal hepatocytes. Hepatocytes die via apoptosis and necrosis. The hepatic parenchyma and sinusoids may include acidophilic (apoptotic) bodies, but necrotic foci are typically not seen. In the early stages of disease, portal mononuclear inflammation is generally very low or nonexistent. However, as the disease progresses, there is more infiltration of lymphocytes in the portal regions along with periportal interface activity and ductular reaction. Morphology can thus mimic autoimmune hepatitis, chronic viral hepatitis, or other types of chronic liver disease. Thin fibrous septa connecting portal tracts are seen in the early disease stages. With disease progression, there are increases in portal, periportal, or bridging fibrosis and the severity of inflammation, and in absence of treatment, the disease can progress to cirrhosis.6 Fulminant hepatitis in Wilson disease shows extensive necrosis of hepatocytes with parenchymal collapse. It is difficult to differentiate it from other etiologies of fulminant hepatitis.5

Cirrhotic Stage

Patients with untreated Wilson disease develop cirrhotic disease at variable rates irrespective of whether they had a clinically evident pre-existing phase of chronic hepatitis. Cirrhosis-related nodules are well defined and predominantly macronodular, less frequently mixed macro-/micronodular or mostly micronodular. Additionally, extensive fibrosis is noted. The nodular parenchyma exhibits steatosis, glycogenated hepatocyte nuclei, and varying numbers of necrotic and apoptotic hepatocytes, similar to the noncirrhotic stage. Hepatocytes with ballooned degeneration and Mallory-Denk bodies are scattered throughout nodules or located at their peripheries. Mallory-Denk bodies are similar to those found in chronic cholestatic disease and steatohepatitis. The perinodular connective tissue septa have little ductular response, mild to moderate chronic inflammation, and interface activity, all of which are indicative of active cirrhosis.6 

Special Stains and Immunohistochemistry

The assessment of hepatic copper concentration on liver biopsy is significant in the diagnosis of Wilson disease since excessive copper accumulation in the hepatocytes is a pertinent indicator of the disease. Useful histochemical stains include the Timm’s silver, rhodanine, and rubeanic acid stains for copper, as well as the orcein, aldehyde fuchsin, and Victoria blue stains for copper-related proteins. These stains are neither entirely sensitive nor fully specific. Positive staining using orcein shows large, irregular, dark brown granules. Small black or greenish black granules appear in the intracytoplasmic perinuclear region or canalicular side of hepatocytes on Timm’s stained slides when there is a slight accumulation of copper, and when there is a massive accumulation, the entire cytoplasm of the hepatocyte is packed with coarse granules. When stained with rhodanine, copper buildup appears as tiny red granules.3 

Immunohistochemistry using markers like ceruloplasmin, metallothionein, and ATP7B can also be done on liver biopsy samples from patients with Wilson disease.6 

Brain Histological Findings

Lesions in the striatum of the basal ganglia are the most characteristic brain lesions identified in Wilson disease patients with neurological manifestations. However, lesions can be more diffuse and involve the pons, midbrain, thalamus, dentate nucleus, and, less commonly, cortex and corpus callosum. Large cortical-subcortical lesions have very rarely been described.

Histology of the lesions shows an increase in cellularity that occurs due to the proliferation of modified astrocytes called Alzheimer types of glia and specific cells, known as Opalski cells, that are characteristic of Wilson disease. Despite the fact that patients with dystonic syndrome tend to have putamen lesions, clinicopathological correlations do not exist. Additionally, neither the severity of the neuropathological findings nor the neuropsychiatric clinical manifestations are linked with the cerebral copper content.7 

References

  1. ​​Wilson disease: slide 15 of 32. Webpathology.com. Accessed September 26, 2022.
  2. Chaudhry HS, Anilkumar AC. Wilson disease. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2022. Updated May 8, 2022. Accessed September 26, 2022.
  3. Soylu NK. Histopathology of Wilson disease. In: Gayam V, Engin O, eds. Liver Pathology. London, UK: IntechOpen; 2020. Accessed September 26, 2022. doi:10.5772/intechopen.95105
  4. Wilson’s disease. Libre Pathology. Updated January 9, 2017. Accessed September 26, 2022.
  5. Nalbantoglu I, DiDomenico P. Liver & intrahepatic bile ducts: metabolic diseases: Wilson disease. PathologyOutlines.com. Updated March 15, 2022. Accessed September 26, 2022.
  6. Lackner C, Denk H. Histopathology of Wilson disease. In: Kerkar N, Roberts EA, eds. Clinical and Translational Perspectives on Wilson Disease. Cambridge, MA: Academic Press; 2019:257-270. doi:10.1016/B978-0-12-810532-0.00023-9
  7. Poujois A, Mikol J, Woimant F. Wilson disease: brain pathology. Handb Clin Neurol. 2017;142:77-89. doi:10.1016/B978-0-444-63625-6.00008-2

Reviewed by Hasan Avcu, MD, on 9/30/2022.

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