Clinical features of Wilson disease

Abstract

Wilson disease (WD) presents often as a chameleon with a plethora of mild and discrete symptoms. As disease of young aged people, the clinical diagnosis is extremely difficult and misdiagnoses are frequent. Tremor, dysarthria and hepatomegaly sometimes suggest alcoholic liver disease which is a disaster for the patients. Due to the only moderate abnormality of liver function tests the disease is underestimated in its severity with a fatal prognosis when not adequately treated. Therefore, it is the challenge to consider WD as diagnosis, particularly in young patients with unclear liver disease, neuropsychiatric disorders or hemolysis.

Keywords: Kayser-Fleischer rings; clinical manifestation; copper overload; diagnosis.

Figure 1

Pathogenetic view of WD. (A) Absorbed copper binds to albumin for transport via portal blood to hepatocytes, where it enters through the plasma membrane-localized copper transporter (CTR1). Within the cell it is immediately deposited bound to MT. The so-called antioxidant protein 1 (ATOX1) serves as chaperone for delivery to the TGN, where ATP7B transports copper into the lumen for binding to apo-ceruloplasmin (Apo-CP) which as copper-loaded ceruloplasmin (Cu-CP) is excreted to blood (main copper bound protein in blood). A second vesicular pathway directs copper from the TGN to bile, also mediated by ATP7B. (B) In WD ATP7B is lacking prohibiting TGN directed transfer of copper to ceruloplasmin and bile. Consequently, copper is intermediately accumulated in the stimulated MT pool, from where it is deposited in lysosomes. (C) In the destructive phase the copper-loading capacity of lysosomes is exceeded. They burst and release there acidic, free copper-loaded content to cytosol which results in cellular damage and finally cell death. This causes the release of cellular free copper to blood. It is bound loosely to albumin and delivered to other organs, particularly to the brain. There cellular damage occurs via free radical injury. WD, Wilson disease; TGN, trans-Golgi-network.

Figure 2

Kayser-Fleischer rings. (A) One of the most striking clinical signs that appears in WD is the appearance of a brownish-yellow ring that is visible around the corneo-scleral junction. These rings are named after B. Kayser and B. Fleischer and consist of annular copper deposits in the Descemet’s membrane; (B) these changes are best detectable in a slit-lamp examination.