Clinical Vignette

Approximately 1 year ago, an 18-year-old woman began to have peculiar tremors of her arms and hands as well as difficulty with her speech becoming soft and slurred. This followed an insidiously progressive course to the point of being embarrassing when she was so poorly understood that family and colleagues sometimes found comprehension quite difficult as she started college. Concomitantly, she became irritable and had variable mood swings, at times leading to profound depression. On other occasions, she was belligerent. Within months, she took a medical leave of absence from school.

After initially being thought to be suffering from academic stress leading to profound somatization, she was referred to another neurologist. In addition to a poorly defined rather gross tremor of her arms and hands, a mildly masked bradykinetic facies and dysarthric speech were recognized. Ophthalmic examination demonstrated a gold/brown-pigmented ring at the limbus of his cornea. This was clearly visible with her blue irises. This proved to be a classic Kayser–Fleischer ring. She was mildly jaundiced.

Laboratory investigation demonstrated mildly abnormal general liver function tests (LFTs). Serologies were negative for hepatitis A, B, and C. Her serum ceruloplasmin level was low, and a 24-hour urine copper excretion level was increased. Magnetic resonance imaging (MRI) demonstrated variable degrees of cerebral cortical, brainstem, and cerebellar atrophy. Signal abnormalities were also noted in her putamen, caudate, midbrain, and pons. There was characteristic T2-W globus pallidal hypointensity with T1-W striatal hyperintensity.

Wilson disease (WD) was diagnosed, and she was started on penicillamine. Within 6 weeks, increased bradykinesia, rigidity, and mutism developed. However, these symptoms gradually cleared over the next 6 months. Twelve months later, the patient’s speech had returned to normal, and her behavior had improved, although she still showed some depressive symptoms. Zinc acetate was started as a long-term therapy.

History

WD is a rare hereditary disorder of copper metabolism, biochemically characterized by abnormal accumulation of this essential trace metal in both the liver and the brain, leading respectively to cirrhosis and neuronal degeneration. WD has an autosomal recessive inheritance with a prevalence of approximately 1 case in 30,000 live births and a carrier rate of 1 in 90. Clinical presentations are quite variable. These include primarily neurologic, neuropsychiatric, or hepatic disturbances; less common are acute hemolytic crisis, arthralgias, nephrolithiasis, and cardiac arrhythmias.

This association between cirrhosis and progressive lenticular degeneration was first described by Kinnier Wilson in 1912. Subsequently excess copper deposits were demonstrated in both the liver and basal ganglia in a patient dying of WD. The finding of reduced serum ceruloplasmin level was recognized a few years later. Treatment was initially attempted using dimercaptopropanol (British Anti-Lewisite [BAL]) in 1951; the much more effective penicillamine treatment was introduced 5 years later. WD thus became the first inherited metabolic disorder with specific treatments. More recently, orthotopic liver transplantation performed for patients with WD has cured the disease in some instances, thus revolutionizing its treatment.

Genetics

The genetic defect of WD is the ATP7B gene located on the long arm of chromosome 13. ATP7B binds copper and transports it across cellular membranes using ATP as an energy source. In WD, this defect leads to reduced copper binding to apoceruloplasmin, which normally forms ceruloplasmin. It also leads to decreased secretion of copper into the bile ducts. DNA analysis from patients with WD shows more than 100 mutations, thus complicating the opportunity for DNA diagnosis. Similarly, it is difficult to make a correlation between the various mutations and specific clinical features. Only a few patients are homozygous for the same mutation. The most frequently observed point mutation, H1069Q, results from the substitution of a histidine to a glutamine. This is present in nearly 30% of Wilson patients of European descent.

Hepatic Copper Metabolism

Copper facilitates electron transfer in critical metabolic pathways involving cellular respiration, iron homeostasis, pigment formation, neurotransmitter production, peptide biosynthesis, connective tissue biosynthesis, and antioxidant defense. Within the brain, copper is found in particularly high concentrations in catecholamine-containing neurons. It is a component of the dopamine β-hydroxylase enzyme complex.

Copper balance is maintained entirely by gastrointestinal absorption and biliary excretion; urinary copper excretion cannot adequately compensate for reduced biliary excretion. Approximately 60% of dietary copper is absorbed in the proximal small intestine, most of which enters hepatoportal circulation, where it is rapidly taken up by hepatocytes. These cells regulate copper homeostasis by excretion of copper into the bile. This system is dependent on the degree of copper concentration as sensed by the ATP7B receptor that is located on the trans-Golgi network and the cytoplasmic vesicular compartment near the canalicular membrane. The absence or decreased function of ATP7B results in dysfunction of biliary copper excretion and consequently leads to copper accumulation within the liver.

Ceruloplasmin is a protein synthesized by hepatocytes and is the major carrier of copper in the bloodstream. Copper is thought to be incorporated into this protein via the ATP7B pathway. In WD, absent or diminished function of the ATP7B leads to reduced binding of ceruloplasmin to copper, thereby lowering circulating levels of ceruloplasmin.

Excess copper accumulation results in generation of free radicals, lipid peroxidation of membranes and DNA, and inhibition of protein synthesis leading to hepatocellular injury and necrosis. Release of free copper, from injured hepatocytes, into circulation is thought to be responsible for causing extrahepatic deposition of copper in the brain, kidneys, eyes, and joints.

Clinical Presentation

WD patients have quite variable clinical presentations. Because WD is such an extremely rare disorder, and lacks a precise, stereotyped clinical presentation, these patients are often not diagnosed until long after the onset of their symptomatology. As with the above vignette, there are legendary recitals of individuals being told, not once but a number of times, that they are not organically ill and that a psychiatric evaluation is in order, only to later visit a dedicated physician who takes a careful history and closely examines the patient, often recognizing the classic and diagnostic Kayser–Fleischer (KF) ring and thus making the WD diagnosis.

One might suspect that as the liver is the primary site of both the abnormal copper storage, as well the specific genetic defect, the earliest signs of WD will be identified as having a hepatic origin. However, hepatic involvement is often clinically and laboratory-wise a subtle disorder because the copper accumulates very slowly. Eventually, subclinical cirrhosis develops. Concomitantly, as hepatocytic injury ensues, copper is released into the systemic circulation and subsequently is deposited within various other organs.

The subcortical nervous system is particularly sensitive to the free-ranging excess copper. Approximately 60% of WD patients present with a neurologic disorder (Box 37-1). Often they do not present until young adulthood with a variety of neurologic manifestations, including dysarthria, tremor, dysphagia, bradykinesia, and behavioral disturbance. Speech manifestations vary from rapid articulation to hypophonia and dysarthria. Any young adult patient who develops unexplained speech impairment needs to be evaluated for WD.

A variety of tremors are seen; these range from subtle in the outstretched fingers to severe, coarse, proximal tremors of the arms and legs that are totally different from those in Parkinson disease (PD). The reduced facial expression, bradykinesia, and tremors are sometimes confused with PD but such of course is only seen with rare exception in the WD age group. Upper extremity coarse tremors are quite common. Typically these adventitious movements are posturally dependent. Such tremors are especially prominent when the arms are elevated and flexed at the elbow, giving the appearance of “wing beating” or “chest beating.”

Dystonia, hypertonicity, and choreoathetosis are common symptoms. Tremor and dystonia occur with equal frequency and sometimes coexist. The dystonia is more typically generalized, involving the extremities, neck (torticollis), and face (grimacing) but may be focal, involving a hand. Ultimately, patients may become severely rigid, with a pseudobulbar palsy. Usually, there is no evidence of cranial nerve, cerebellar, peripheral nerve, or skeletal muscle involvement.

Psychiatric disturbances are the presenting feature in at least a quarter of WD patients. However, there is no characteristic behavioral syndrome. Usually, the progressive change in personality develops in an insidious fashion. Irritability and aggression are typical; affective changes include depression and emotional lability. Cognitive changes, anxiety, catatonia, and psychosis are uncommon. A transient psychosis may be uncovered during treatment.

Ophthalmologic manifestations are not only common in WD but also are often crucial to a specific diagnosis. The classic and best-known finding is the dull, yellow-brown pigment at the limbus of the cornea. These are known as KF rings. They (Fig. 37-1) are most dense at the upper and lower poles of the cornea. These result from copper deposition in the Descemet membrane at the limbus of the cornea. KF rings are present in nearly all patients with WD who present primarily with neurologic or psychiatric symptoms. However, the uninitiated physician must maintain a level of clinical suspicion, or the actual identification of these KF rings may be missed on casual examination. This is particularly noticeable in the majority of patients as brown irises are the most common, providing a means for the copper deposition to inconspicuously blend into the human landscape. It is here that our ophthalmologic colleagues provide a major diagnostic keystone. Slit-lamp examination is often absolutely necessary for detection and verification. Early on KF rings are often absent in the asymptomatic individuals and in up to 50% of persons having a hepatic presentation. Other abnormal ophthalmologic signs include reduced saccadic velocity, interruption of smooth pursuit by saccadic intrusions, and sunflower cataracts (15–20% of patients).

Figure 37-1 Wilson Disease.

Primary hepatic dysfunction is manifested in the early teens to the early 20s, although it may present in earlier childhood or late adulthood. This is the most common initial manifestation in childhood, with patients presenting at an average age of 10–13 years, a decade or more earlier than those who present with neuropsychiatric disorders. Symptoms of hepatocellular disease vary from a mild increase of serum transaminases in asymptomatic individuals to chronic hepatitis, portal hypertension, and cirrhosis. In earlier-stage disease, the immunohistochemical stains for copper may be negative because hepatocytic copper is diffusely distributed within the cytoplasm. When WD is unrecognized, fibrosis progresses and eventually cirrhosis develops. Rarely, WD patients can present with a fulminant hepatic failure associated with hemolytic anemia secondary to the acute release of copper into the circulation. Liver biopsy at these stages demonstrates a marked necrosis. In these patients, the alkaline phosphatase level is usually low. Hepatocellular carcinoma is a rare complication of WD.

Diagnosis

Early diagnosis of WD is crucial to effective treatment and potential for a cure. This most depends on astute clinical collation in reference to the sometimes vague signs and symptoms (Box 37-1 and Fig. 37-1). This diagnosis should always be considered in patients between 10 and 40 years old who have unexplained dysarthria or tremor or psychiatric or hepatic disease. Devastating neurologic and hepatic deterioration may be prevented with early diagnosis and treatment.

Slit-lamp examination is required for any patient suspected of having WD. Although present in nearly every patient with neurologic involvement, KF rings may be absent in those who primarily present with hepatic involvement. Furthermore KF rings are not pathognomonic for WD. These are rarely seen in other chronic, severe liver diseases, such as primary biliary cirrhosis.

Ceruloplasmin levels are reduced in patients with WD, often with levels below 20 mg/dL (Box 37-2). A serum ceruloplasmin value less than 20 mg/dL and concomitant slit-lamp definition of a KF ring are diagnostic of WD. In acute liver damage, ceruloplasmin levels may be normal because it is an acute-phase reactant; therefore, a low ceruloplasmin concentration is not an absolute diagnostic test; this may also be seen in hypoproteinemic states.

Daily urinary copper excretion is elevated in WD patients. Its measurement provides a means to monitor the effectiveness of therapy. An elevated non-ceruloplasmin component of plasma copper is increased, filtered by the glomerulus, and incompletely reabsorbed by the renal tubules, causing urinary excretion of copper. The increased renal copper excretion does not adequately compensate for the reduced biliary copper excretion. Measurement of 24-hour copper excretion is a standardized and reliable diagnostic test and is often greater than 100 µg (Box 37-2).

Plasma copper concentration is not a useful or diagnostic laboratory parameter. Total plasma copper (ceruloplasmin bound plus non-ceruloplasmin bound) may be reduced, normal, or increased in WD. However serum free copper levels are elevated in WD patients. This is usually greater than 25 µg/dL. Aminotransferase levels of hepatic enzymes are usually mildly or moderately elevated.

Quantitative liver tissue copper concentrations greater than 250 µg/g of liver tissue are found in homozygous WD patients. Although heterozygotes for WD have elevated hepatic liver copper levels, these are not above the gold standard diagnostic level of 250 µg/g. Elevated liver copper levels can also be seen in patients with other causes of liver disease, including primary biliary cirrhosis and primary sclerosing cholangitis. Normal hepatic copper levels can also be found in patients with WD.

MRI is abnormal in most WD patients, mirroring the underlying basal ganglia pathology of both gliosis and neuronal loss with a concomitant significant increase in copper concentration. There are a wide variety of relatively symmetric MRI abnormalities resulting from combinations of edema, necrosis, cystic changes, and gliosis. These typically involve the striatum (caudate and putamen), globus pallidus, thalamus, and midbrain. Fluid-attenuated inversion recovery (FLAIR) pulse with diffusion-weighted imaging (DWI) and T2WI MRI modalities demonstrate hyperintense lesions but these are isointense to hypointense with TIWI. There is a tendency to confuse some of these images with multiple sclerosis (MS); however, WD white matter lesions are usually larger than those seen in MS. Furthermore, WD lesions do not directly come in contact with the ventricular ependymal something that is so common with MS. In general, brain MRI correlates with the presence or absence of neurologic impairment. The changes may improve with chelation therapy.

Treatment and Prognosis

The primary therapeutic goal in WD is to restore hepatic homeostasis by systemic chelation therapy or orthotopic liver transplantation. Chelation therapies include D-penicillamine and trientine. These agents bind copper in the plasma and organs, promote urinary copper excretion, and prevent copper accumulation in presymptomatic individuals. This therapeutic regime is indicated for symptomatic WD patients who have either neuropsychiatric or hepatic presentations. Clinical improvement is accompanied by marked decrease in hepatic copper content, thereby reversing symptoms and preventing progression of liver disease. KF rings will disappear with either medical or surgical treatment. If the rings return, it suggests noncompliance to medical therapy.

Penicillamine has multiple side effects, including fever, skin rash, thrombocytopenia, nephrotic syndrome, recurrent nephrolithiasis, and acute arthritis seen in up to 20% of patients. Late immune complex–mediated nephropathy, systemic lupus erythematosus, Goodpasture syndrome, oral ulcers, pseudoxanthoma, and autoimmune-mediated myasthenia gravis (MG) may develop.

The most significant adverse effect of penicillamine treatment is the paradoxical worsening or new appearance of neurologic deficits. Estimated to occur in up to 50% of patients, the mechanism is thought to be deposition of mobilized liver copper within the basal ganglia. After 4–6 months of treatment, lower doses are effective for maintenance therapy.

Triethylamine tetramine (trientine) is effective for treating penicillamine-intolerant patients and is also approved for initial, first-line WD therapy. Although less toxic, triethylamine tetramine also has a significant toxicity spectrum including autoimmune MG as well and requires similar monitoring.

Compliance to penicillamine and trientine is best monitored by recording urinary copper excretion. During the early phase of therapy, this should exceed more than 1000 µg/day. Eventually this decreases to 250–500 µg/day even with continuous use of chelation therapy after 4–6 months. Levels less than 250 µg/day suggest noncompliance with therapy.

Zinc salts are also used as an alternative to penicillamine or trientine-intolerant WD patients, as well as for safe and effective maintenance therapy. Zinc salts block intestinal absorption of dietary copper and also stimulate endogenous production of chelators in the liver. These often have a delayed onset of action; therefore, chelation therapy is preferred. Twenty-four-hour urinary copper excretion of patients taking zinc is not typically elevated because zinc prevents the intestinal absorption of copper rather than an increase in urinary copper excretion. Elevated urinary copper levels in these patients suggest noncompliance.

Orthotopic liver transplantation now provides another important treatment option for WD patients, particularly when they are compromised by significant cirrhosis or fulminant liver failure. After liver transplantation, there is no need to continue long-term therapy because the diseased liver (and therefore abnormal copper-transporting protein within the liver) is removed and replaced with a healthy liver. Transplantation may reduce neurologic symptoms in some patients.

Prognosis for compliant patients with WD is excellent, even if cirrhosis is present at time of initiating therapy. Rapid progressive liver failure due to WD carries a poor prognosis, unless liver transplantation is performed. Neurologic and psychiatric impairment are preventable if therapy is instituted in the early stages of disease. Therefore, early diagnostic recognition of WD is a very important challenge to every neurologic, psychiatric, or gastroenterologic physician. Not all patients improve to the same extent, and death may occur from neurologic (e.g., dysphagia) or hepatic complications.