Wilson’s disease (WD) is a rare inherited disorder of copper metabolism characterized by the accumulation of excess copper, primarily affecting the liver and the brain. If left untreated, this condition can lead to severe organ damage. The historical journey to understand and name WD involved over a century of fragmented medical observations before it was formally recognized as a distinct medical entity.
Early Descriptions of Symptoms
The existence of the condition now known as Wilson’s disease was hinted at long before it was formally recognized. Throughout the 19th century, physicians observed patients presenting with a confusing combination of neurological and hepatic issues, including tremors, rigidity, difficulty speaking, and signs of liver failure.
In 1883, German neurologist Karl Westphal described a condition he termed “pseudo-sclerosis” due to its resemblance to multiple sclerosis. Around the same time, researchers like Bernhard Kayser and Bruno Fleischer noted distinct golden-brown pigmented rings around the cornea of the eye in some patients with neurological problems. These observations, later named Kayser-Fleischer rings, were significant clinical findings. However, they were not yet connected as part of a single, defined disease entity.
The Landmark Description of 1912
The year 1912 marks the true discovery of Wilson’s disease as a distinct medical entity, thanks to the meticulous work of the British neurologist Samuel Alexander Kinnier Wilson. His monograph, published in the journal Brain, formally correlated the seemingly disparate symptoms observed in patients. He detailed the clinical presentation of a fatal familial nervous disease associated with cirrhosis of the liver.
Wilson named the condition “Progressive Lenticular Degeneration,” or hepatolenticular degeneration, based on the pathological damage he observed in the liver and the lenticular nucleus of the brain. He distinguished it from earlier fragmented descriptions by cohesively correlating the neurological and hepatic pathology. His analysis involved twelve clinical cases. The formal publication of this comprehensive analysis in 1912 defined the condition, forever linking his name to the disease.
Establishing Copper as the Root Cause
While Dr. Wilson provided the definitive clinical description, the underlying cause of the disease remained a mystery for decades. Wilson himself suspected a toxin originating from the liver was responsible for the neurological damage. The first clue pointing toward the correct mechanism came in 1913, when excess copper was found in the liver of a patient who died from the newly described disease.
It was not until the late 1940s and early 1950s that the role of copper was definitively established as the primary pathology. In 1948, John Cumings demonstrated that copper accumulated excessively in the brains and livers of patients. Further research in the 1950s confirmed that the condition was an inherited disorder. The genetic defect causing the metabolic failure was finally pinpointed in 1993 with the identification of the ATP7B gene on chromosome 13. This gene encodes a copper-transporting ATPase, and its dysfunction prevents the liver from properly excreting excess copper, leading to its toxic buildup throughout the body.
Developing Effective Therapies
The understanding that copper accumulation was the cause immediately opened the door to effective treatment. The first attempt at copper removal occurred shortly after the 1948 discovery, using British Anti-Lewisite (BAL). Although BAL increased copper excretion, it was impractical for long-term use.
The true revolution in treatment came in 1956 when physician John Walshe introduced D-penicillamine as an orally effective drug. This chelating agent binds to excess copper, allowing it to be excreted through the urine, fundamentally changing the prognosis from a fatal condition to a manageable one. Later, in the 1970s, another chelating agent, trientine, was developed. Zinc salts also emerged as a therapeutic option, working by blocking the absorption of copper from the digestive tract. These developments transformed Wilson’s disease into a treatable illness requiring lifelong management.