Wilson’s disease,also known ashepatolenticular degeneration，was first reported by Wilson in 1911. It is an autosomal recessive disease dominated by adolescents and a congenital disorder of copper metabolism. Clinically, liver damage, extrapyramidal symptoms and corneal pigment ring are the main manifestations, accompanied by plasma ceruloplasmin deficiency and aminoaciduria.
Alias: Wilson disease; Wilson degeneration; Wilson’s degeneration; Wilson’s disease; Wilson’s syndrome; Hepatolenticular degeneration.
The incidence rate of Wilson’s disease is 0.5/10 to 3/10 million, and the risk of siblings is 1/4. The frequency of heterozygote or disease gene carriers in the population is 1/100 to 1/200, and the positive family history is 25% to 50%. The prevalence rate is about 1 / 30000 live infants, and the heterozygous frequency is about 1%. The vast majority are limited to one generation of siblings or intergenerational inheritance, and the incidence of two consecutive generations is rare. Wilson disease is rare in most European and American countries. In some countries and regions, such as Sardinia and Sicily in the southern part of Italian, southern Israel and Eastern Europe, Jews and Romania have a higher incidence rate, and the incidence rate in Japan is as high as 1/2 million. There is no accurate statistical data in China, but there are quite a few clinically reported cases. According to incomplete statistics, there were 791 domestic literature reports on WD from 1950 to 1998, with 4501 cases reported.
The basic cause of Wilson’s disease is excessive copper deposition in various tissues in the body, especially in the liver, brain, kidney and cornea, resulting in tissue damage and lesions.
Wilson’s disease is an autosomal recessive disease. The involved gene is related to the disorder of copper metabolism. It is closely linked with esterase D gene on chromosome and retinoblastoma gene.
There are several theories about the pathogenesis of Wilson’s disease:
① The defect of normal substances binding to copper in the bile of these patients may be the defect of the binding of goose deoxycholic acid and taurine, resulting in the dysfunction of bile secretion of copper. The evidence that does not support this theory is that there is no qualitative change in bile copper binding protein in these patients, and there is no evidence of abnormal bile acid metabolism in these patients.
② The abnormal synthesis of liver copper binding protein leads to the increase of the affinity of the protein to copper. The evidence supporting this theory is that the binding constant of copper binding protein (liver copper protein) in patients with Wilson disease is four times that in patients with primary biliary sclerosis, but people question the analysis method of the data, Whether the high affinity of abnormal proteins for copper in Wilson’s disease is the formation mechanism of Wilson’s disease needs to be further clarified.
③ The most reasonable theory is that the lysosomes of liver cells participate in the metabolic process of copper. It is observed that the content of lysosomes in liver cells of patients with Wilson disease is 40 times higher than that of the control. It is considered that the defect of lysosomes in liver cells of patients with Wilson disease interferes with the process of copper secretion from lysosomes to bile, resulting in the increase of copper content in liver of patients with Wilson disease.
In short, Wilson’s disease is not due to the increased absorption of copper by the intestine, but due to the disorder of copper secretion by the biliary tract. This disorder is congenital. Patients with genetic defects can not synthesize copper and the positive balance metabolism of copper becomes normal 3 months after birth, which makes the positive balance metabolism of copper persist, resulting in the accumulation of copper in the body. The pathogenesis of Wilson’s disease includes reduced biliary excretion, disorder of ceruloplasmin synthesis, lysosomal defect, metallothionein gene abnormality and regulatory gene abnormality. At present, the previous two theories have been approved by most scholars.
The pathological manifestation of Wilson’s disease is a large amount of copper deposition in tissues. The lesions were characterized in brain tissue, liver, kidney and cornea. The putamen nucleus was the earliest and obvious brain lesion, followed by globus pallidus, caudate nucleus and cerebral cortex. Subthalamic nucleus, red nucleus, substantia nigra, thalamus and dentate nucleus could also be involved. Neurons were significantly reduced or completely lost, axonal degeneration and astrocyte proliferation. Brownish yellow fine copper particles can be seen in the posterior elastic layer of the corneal edge and the cytoplasm of endothelial cells. In severe cases, they can also be seen in the central area of the cornea and stromal cells. Nodules or pseudolobules of different sizes can be seen on the surface and section of the liver, which is quite similar to post necrotic cirrhosis, hepatocyte steatosis and copper containing particles. Under electron microscope, mitochondria in hepatocytes were dense, mitochondrial cristae disappeared and rough endoplasmic reticulum was broken.
The main clinical manifestations are neuropsychiatric symptoms and liver symptoms. It is reported in Europe and America that about 70% of Wilson’s disease patients take neurological symptoms as the first symptom, followed by liver symptoms. Some domestic articles reported that 47.48% of the patients had neurological symptoms and 39.96% had liver symptoms, followed by bone, joint and kidney damage.
Wilson’s disease usually occurs in childhood or adolescence. The average age of patients with liver symptoms is about 11 years old, the average age of patients with neurological symptoms is about 19 years old, and a few can be as late as adulthood. Most patients have neurological symptoms first, a few have liver symptoms first, and a few patients have acute hemolytic anemia, subcutaneous bleeding, epistaxis, renal function damage and mental symptoms. The onset is slow, and a few are acute due to trauma, infection and other reasons. Eventually, there will be symptoms of liver and nerve damage.
The prominent neurological manifestation of Wilson’s disease is extrapyramidal symptoms. The initial manifestations are often movement disorders at school, especially dysgraphia and language difficulties. Tremors of one or both upper limbs can occur, which can be enhanced during random movement and reduced at rest. Severe cases can involve the trunk, lower limbs and head. Sometimes there may be involuntary movements such as dance hand foot ADHD. Myotonia can be intermittent or persistent. Mental symptoms are common, with different manifestations, including aggression, childishness, euphoria, etc. Intelligence can decline. A few patients with Wilson’s disease may have seizures, and the PAP sign is positive.
(1) Tremor: it is a common first symptom. In the early stage, it is often limited to the upper limb. Starting from one side of the hand, it is first small tremor, gradually becomes coarse tremor, and becomes worse when moving at will. It can be static, intentional or postural tremor, and often several forms of tremor are combined. With the progress of the disease, tremor can affect the limbs, head and jaw, and gradually extend to the whole body. Most of them are fast, rhythmic, thick like flapping wings, and intentional tremor aggravated during exercise.
(2) Dysphonia and dysphagia: it shows that the speech voice is low, vague or hoarse, slow or intermittent, and can not make a sound in serious cases, which is caused by the slow movement of tongue, lip, pharynx, throat and jaw; Salivation and dysphagia are also common. They are caused by the rigidity of pharyngeal, lingual and facial muscles. Wilson’s disease is more common in childhood. Speak slowly like reciting poetry, or the tone is flat like chanting scriptures, or the speech stops like eating; Ambiguous, explosive or tremor language can also be used. Dysphagia often occurs in late stage patients.
(3) Muscle tone changes: most patients have gear like and lead tube like increase in muscle tone, which often leads to slow movement, reduced facial expression, difficulty in writing, walking disorder, etc. A few patients with chorea have hypotonia. Dystonia involves facial and oral muscles, such as “mask face”, bitter smile, strange expression or involuntary movement of oral and facial muscles. It involves limbs and trunk, such as limb stiffness, slow movement, slow finger movement, flexion posture and difficulty in changing posture. Abnormal gait shows difficult starting, stiff walking and dragging. In severe cases, it is similar to panic gait of Parkinson’s disease, Body dance like movements and slow movements of hands and feet are not uncommon.
(4) Seizures: rare. It has been summarized that among 418 cases of Wilson’s disease in China, 1L cases (2.6%) had different types of seizures in the course of the disease, of which 10 cases were generalized tonic clonic seizures or partial motor seizures, and only 1 case was absent seizures.
(5) Mental symptoms: in the early stage, the intelligence of patients had no obvious change, but the children with acute onset had mental retardation earlier; Most Wilson’s disease has personality changes, such as decreased self-control, emotional instability, irritability and so on; In severe cases, depression, mania, hallucinations, delusions, impulses, etc. can occur, which can cause self injury. A few patients with mental symptoms as the first symptoms are easy to be misdiagnosed as schizophrenia.
(6) There may be extensive nervous system damage, such as ataxia and language disorder caused by cerebellar damage, tendon hyperreflexia, pathological reflex and pseudobulbar paralysis caused by pyramidal system damage, obesity, persistent high fever and hypertension caused by hypothalamic damage.