Scenario (If the parents…)
Transmission (….then the children)
If both parents have the disease…
…then all children will have the disease
If one parent has the disease and one parent is a carrier…
…then there is a 50 % chance that the child will have the disease and a 50 % chance that the child will be a carrier
If only one parent has the disease…
…then all children will be carriers
If both parents are carriers…
…then there is a 25 % chance that the child will have the disease, a 50 % chance that the child will be a carrier, and a 25 % chance that the child will not have the disease or be a carrier
If only one parent is a carrier…
…then there is a 50 % chance that the child will be a carrier and a 50 % chance that the child will not have the disease or be a carrier
If neither parent has the disease and is not a carrier….
….then none of the children will have the disease or be a carrier
Question 2: How does my diet and intake of different foods affect the accumulation of copper in my liver and other organs?
Patient level answer: Foods are absorbed, along with their respective copper content, in the intestines. Patients with Wilson’s disease have impaired copper excretion, leading to unhealthy copper concentrations in the body. Patients with the disease, therefore, should generally avoid foods with high copper concentrations. Foods that should be avoided include shellfish, nuts, chocolate, mushrooms, and organ meats. Patients need to keep in mind environmental exposures, such as copper pipes, containers, or cookware, which may increase copper levels in foods and drinks.
Question 3: Besides changing my diet, how can my Wilson’s disease be treated?
Patient level answer: Wilson’s disease can be treated with medications, including d-penicillamine , trientine , and zinc . d-penicillamine promotes urinary copper excretion with an extensive side effect profile complicated by skin, bone marrow, liver, and kidney problems. Trientine also promotes urinary copper excretion, albeit with less potency, but also with fewer side effects. Zinc interferes with the absorption of copper from the intestines; however, the most problematic side effect is gastric irritation. Lastly, antioxidants, specifically vitamin E, may serve as adjunctive therapy.
Question 4: What can I expect and do I necessarily need a liver transplant down the line?
Patient level answer: Wilson’s disease is present on a spectrum from patients who do not have symptoms to patients afflicted with hematological, ocular, hepatic, neurological, and/or psychiatric symptoms. Potential complications of Wilson’s disease include, but are not limited to, neurological disabilities, hemolytic anemia, scarring of the liver or cirrhosis, and, occasionally, cancer. Liver transplant is necessary when medications fail or liver disease has progressed to liver failure.
Wilson’s disease (WD), or hepatolenticular degeneration , is an inherited autosomal recessive disease initially described by Samuel Alexander Kinnier Wilson in 1912, who initially described some of its protean neurological manifestations . It is caused by a gene mutation on chromosome 13q 14.3 or ATP7B gene encoding a copper-transporting P-type ATPase . The gene is expressed in hepatocytes and functions in the transmembrane transport of copper [2–4]. To identify and manage WD, a rudimentary understanding of copper metabolism is necessary. Copper is initially absorbed via enterocytes in the duodenum and proximal jejunum, transported through the portal circulation bound to albumin, and is eventually delivered to the liver. In the liver, copper is intracellularly bound to the protein metallothionein. Any excess copper acts as a substrate for ATPase, with two major cellular functions: to incorporate copper into ceruloplasmin and to permit copper excretion via the biliary system. Ceruloplasmin not bound to copper is called apoceruloplasmin .
The prevalence of WD is 3–30 in one million individuals . WD is generally diagnosed in patients between the ages of 3 and 35 years, although it can be diagnosed at any age. Clinicians should consider WD when confronting unexplained liver disease, elevated serum aminotransferase, or clinical features of chronic liver disease, particularly, but not necessarily, when concomitant neurological signs and symptoms are present . Although there is no gold standard, a number of clinical and biochemical parameters define WD. A high index of suspicion and appropriate interpretation of the testing is required for early recognition and treatment.
As no single test or finding defines WD, the clinician often uses the preponderance of the evidence to make the diagnosis. The overlap of serological or histological features with other disorders adds complexity to the diagnosis. For instance, serum immunoglobulins and autoantibodies classically seen in autoimmune hepatitis may be present in WD, as may plasma cells on histological evaluation from a liver biopsy. More importantly, patients with presumed autoimmune hepatitis refractory to corticosteroid therapy should be assessed for WD.
Dysfunction in copper metabolism consequently results in toxic copper accumulation in the blood, cornea, brain, and liver. This translates to a spectrum of expression ranging from completely asymptomatic to symptomatic, classically resulting in hepatic and neurological sequelae. The variable and at times incomplete penetrance of the WD gene is responsible for the range of presentation, including its hepatic, neurological, psychiatric, hematological, gastrointestinal, endocrinological, renal, cardiac, skeletal, and ocular symptoms (Fig. 21.1). Notably, neurological symptoms should prompt a neurological evaluation and radiographic imaging of the brain, preferably via magnetic resonance imaging (MRI). Specifically, proton-density MRI sequences remain sensitive in displaying the extent of neuropathology . Histologically, astrocytes are increased within the gray matter associated with swollen glia, liquefaction, and spongiform degeneration. Clinically, in a case series of 25 patients with WD, 11 of the 25 patients, or 44 %, presented with neurological symptoms . Specifically, movement abnormalities are categorized as akinetic–rigid syndromes , similar to Parkinson’s disease, pseudosclerosis dominated by tremor, ataxia, and dystonic syndrome . Behavioral and psychiatric symptoms, particularly in children, consist of personality changes and unstable behavior resulting in deteriorating school performance. In reference to hematological symptoms, Coombs-negative hemolytic anemia is often neglected as a presenting symptom in WD. Marked hemolysis is often associated with severe liver disease. Clinicians should also be aware of ocular signs and symptoms, in particular Kayser–Fleischer rings (Fig. 21.2) and sunflower cataract s caused by copper deposition on Descemet’s membrane in the cornea and lens respectively, necessitating a slit lamp examination [10, 11]. Up to 95 % of patients with neuropsychiatric symptoms have Kayser–Fleischer rings, whereas they are less often encountered in those with a hepatic presentation. In a case series of 30 patients with WD, 14 out of 22 or 63 % of patients without fulminant hepatic failure (FHF) and 6 out of 8 patients or 75 % of patients with FHF presented with Kayser–Fleischer rings . At the same time, the absence of Kayser–Fleischer rings does not exclude the diagnosis of WD and other cholestatic liver diseases (which may also result in excessive copper accumulation due to decreased biliary excretion) have been associated with the development of Kayser–Fleischer rings.
Signs and Symptoms in Wilson’s disease
Kayser–Fleischer ring. Printed with permission of British Journal of Ophthalmology
The natural history of WD is variable, with the most worrisome complication being FHF. It is important to recognize characteristic clinical findings in FHF (Table 21.2) [13–19]. Predominantly in young females (the female:male ratio is 4:1), FHF, if untreated, carries an almost 95 % risk of mortality . Traditionally, a ratio of serum alkaline phosphatase to total bilirubin <1 has been believed to have 86 % sensitivity and 50 % specificity for a diagnosis of fulminant WD [21, 22], a more recent study by Korman et al.  reporting that an alkaline phosphatase to total bilirubin ratio of less than 4 yielded 94 % sensitivity and 96 % specificity for FHF due to WD. Thus, a proportionately low alkaline phosphatase level should be a clue to the clinician with regard to WD, particularly in the patient with FHF. A prognostic scoring system for WD (Table 21.3) was developed by Nazer et al.  with score of 7 and above suggestive of high mortality in a combined pediatric and adult WD population and subsequently, a modified version based on bilirubin, aspartate aminotransferase, albumin, white cell count, and international normalized ratio was prospectively validated in a pediatric population (Table 21.4). Based on the new index, a score greater than 11 predicts a high risk of mortality, a requisite for liver transplantation with sensitivity 93 %, specificity 97 %, positive predictive value 92 %, and negative predictive value 97 % . Patients with advanced fibrosis and cirrhosis are susceptible to complications associated with cirrhosis, which are detailed elsewhere in this text. Although copper chelation therapy does not necessarily lead to regression of advanced fibrosis, disease stabilization with chelation therapy is the rule in those without a fulminant presentation, although a proportion of patients, 15–20 %, experience a worsening of their neurological symptoms with chelation. Lastly, in a retrospective case series of 363 patients with WD, the frequency of malignancy was 0, 4.2, 5.3, and 15 % in the <10 years age group, 10–19 years, 20–29 years, and 30–39 years respectively. In general, malignancy, and particularly hepatocellular carcinoma , is an uncommon complication of WD isolated to those with cirrhosis, who should be screened on a regular basis .
Coombs-negative hemolytic anemia with features of acute intravascular hemolysis
Coagulopathy nonresponsive to parenteral vitamin K
Rapid progression to renal failure
Serum aminotransferases (<2,000 IU/L)
Normal or subnormal serum alkaline phosphatase (<40 IU/L) with an alkaline phosphatase to total bilirubin ratio of less than 4 
Female:male ratio 2:1
Prognostic index according to Nazer et al. 
Serum bilirubin (μmol/L)
Serum aspartate (IU/L)
Prolongation in prothrombin time (s)
New Wilson Index for predicting mortality 
International normalized ratio
White cell count (109/L)
When the diagnosis of WD is suspected, initial testing should be pursued with serum ceruloplasmin , 24-h urinary copper excretion, and slit-lamp examination to assess for Kayser–Fleischer rings. When warranted based on this initial testing, further testing, including the serum free copper concentration, hepatic copper concentration based on biopsy, the d-penicillamine challenge test , and genetic testing are options that can be considered (Table 21.5) .
Standard laboratory tests used to diagnose Wilson’s disease
Serum copper concentration
Most useful during follow-up and to assess response
<200 mg/L in 1 % of controls and 10 % in carriers and known copper deficiency
Hepatic copper concentration
<250 μg/g in 20 % of patients with Wilson’s disease
24 h urinary copper concentration
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