Wilson’s Disease

At age 24, a young woman (let’s call her Ann) was healthy, vibrant, and carefree. After her 25th birthday, Ann began to experience upper limb tremors. Within 4 months, the tremors progressed to all of Ann’s limbs, followed by bouts of mania. Due to the neuropsychological presentations, a psychiatrist prescribed Ann haloperidol, chlorpromazine, and propranolol to treat the mania. A further regimen of levodopa and carbidopa was prescribed by a neurophysician to treat the atypical Parkinson’s. After 4 years of progressive symptoms, with no signs of improvements, stereotactic surgery was recommended. In the hopes of minimizing and ultimately eliminating Ann’s tremors, she underwent a thalamotomy, destroying the affected part of her thalamus. After surgery Ann’s tremors decreased. The following month she developed severe mania and was referred to another institution. Upon admission, a diagnosis of unspecified organic psychosis was considered. Shortly thereafter, the correct diagnosis of Wilson disease (WD) was finally made. Following treatment, Ann began to improve.

Due to its nature and obscurity across all specialties of the health care system, WD is often misdiagnosed. One study analyzed medical records of 307 patients with WD and found that about 63% were referred with the wrong diagnosis. Misdiagnosis of WD can run the gamut of various conditions, from flat feet to various types of hepatitis, cirrhosis, hepatomegaly, splenomegaly, nephritis, multiple neurodegenerative diseases, psychosis, anemia, arthritis, and many more. 

It is suggested that the prevalence of WD may be in upwards of 1 in 30,000 people, and as many as 1 in 90 individuals may be asymptomatic carriers. WD occurs from a mutation in an autosomal recessive gene resulting in a disorder of copper metabolism with the resultant accumulation of copper in liver and brain tissues. The majority of people (60%) tested for this disease are heterozygous (2 different abnormal haplotypes), and many times homozygosity (2 of the same abnormal haplotypes) stems from consanguineous origins. Approximately 10% of patients do not have identifiable mutations. To date, there are 380 confirmed different mutations that play a role in the pathogenesis of this disease, with another 120 suspected mutations. To develop the disease, a patient must inherit 2 copies of the defective gene, 1 from each parent. If individuals receive only 1 abnormal gene, they will not become ill themselves but are considered carriers and can pass the gene to their children. Diagnosing WD can be extremely difficult because every patient presents with different symptoms and with varying ages of onset, possibly because of its heterozygous nature.

The abnormal ATP7B gene, which causes WD, resides on chromosome 13. The ATP7B gene encodes an ATP-driven copper transporter also named ATP7B. The ATP7B protein is expressed in several tissues, including the liver, central nervous system, kidneys, mammary glands, and others. Its primary function in the liver is to maintain copper homeostasis. In healthy individuals, ATP7B transports excess copper out of intracellular fluid and into hepatic tubules and vesicles (trans-Golgi network). Copper is then either excreted into bile as waste or used to convert apoceruloplasmin to functional ceruloplasmin, the major circulating copper transporter.

With early diagnosis, WD is a very treatable condition, but it is always fatal without treatment. Before effective treatment, the median survival rate of an individual presenting with neurological symptoms of WD was 2 to 5 years. Typically, WD becomes symptomatic later in life. However, initial onset ranging from 5 to 35 years of age has been reported, with a peak incidence at around 17 years of age. A small minority may present with symptoms after 40 years, and cases have been cited as early as 3 years of age. Initially the liver can sequester excess copper but eventually reaches a maximum load resulting in copper toxicity and subsequent hepatic damage. With the liver no longer able to capture excess copper, it travels through the circulatory system as free-unbound copper, where it gets deposited into various tissues. Once deposited in the brain, particularly the lenticular nucleus, it wreaks havoc on the central nervous system, resulting in a variety of neuropsychological symptoms.

About 6% to 12% of all emergency liver transplants are due to WD, disproportionally affecting females at a rate of 4 to 1. Patients with WD generally present with either hepatic or neurological symptoms, and about 20% present with hematologic, psychiatric, renal, or osteochondrotic symptoms. Clinical hepatic presentations include acute hepatitis, chronic active hepatitis, cirrhosis, and hepatic failure. Often, but not exclusively, initial hepatic symptoms are seen in a younger age of onset between 11 and 15 years. WD patients who initially present with neurological disorders tend to be older, between the ages of 20 and 40 years. Even in neurological presentations of WD, there is some subclinical liver disease. In older individuals, Parkinson’s may be a common misdiagnosis of neurological WD due to the similarity of symptoms, including tremor and rigor. Unlike their older counterparts, typical neurological symptoms for younger patients may be chorea and dystonia. A diagnosis of WD should be considered in every young person presenting with movement disorders.

Kayser-Fleischer (KF) rings, a telltale sign of WD: as copper is deposited in the eye, KF rings may be seen with a slit-lamp examination. The KF rings appear as golden-brown or brownish-green rings in the corneal limbus (encircling the iris). Although there is some dispute as to whether KF rings are pathognomonic indicators of WD, they can be seen in nearly 100% of patients with neurological manifestations of WD. In patients who present with hepatic symptoms, KF rings can be seen roughly 50% of the time. Tests to confirm WD should include serum ceruloplasmin/copper, 24-hour urine copper test, and presence of KF rings (particularly with comorbid neurological symptoms). A liver biopsy to determine quantitative levels of hepatic copper above 200 mg/g of dry weight tissue is the gold standard test for WD.

A liver transplant may cure WD, but with chelation therapy patients can live normal lives. In WD, patients who have progressed to the point of hepatic failure must receive a liver transplant, which seems to have a corrective effect on copper metabolism. There are conflicting reports and it remains unclear if a liver transplant is as effective in correcting severe neurological manifestations. Once a diagnosis of WD has been confirmed, chelation therapy should commence immediately, and that therapy should be based on the symptomatic presentation. Penicillamine is the standard first-line treatment but has side effects including neurological worsening. Trientine is considered a second-line therapy when penicillamine is contraindicated, but also has neurological side effects. Tetrathiomolybdate is not yet approved as a treatment for WD but does show promise and may offer less severe side effects.

Reference

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