hepatolenticular degeneration in children
Introduction
Introduction to Hepatolenticular Degeneration in Children Hepatolenticular degeneration (HLD) is a disease in which hereditary copper metabolism is abnormal. It is characterized by copper deposition in the liver, brain, kidney, cornea and other tissues, causing a series of clinical symptoms. In recent years, the genetic characteristics, pathogenesis, pathological changes, clinical features, early diagnosis, genetic diagnosis, treatment, etc. of the disease The research has made great progress. It has been proven that the disease is completely treatable. The disease has been reported in various parts of China, and has done a very good job in early diagnosis, early treatment and DNA analysis. basic knowledge Sickness ratio: 0.0001% Susceptible people: children Mode of infection: non-infectious Complications: splenomegaly, epilepsy, childhood obesity, hypertension
Cause
Causes of hepatolenticular degeneration in children
(1) Causes of the disease
Hepatolenticular degeneration is an autosomal recessive copper metabolism disorder, and the disease-causing gene is located at the distal end of chromosome 13 of the long arm.
(two) pathogenesis
Pathogenesis
The defect gene is located on chromosome 13q14.3, and the gene product is P-type copper transport ATPase. The basic biochemical lesion is copper excretion disorder, causing copper to deposit in various tissues in the body. The daily intake of copper from normal people is about 1~5mg, about 40% of which is absorbed into the plasma by the intestine, and is quickly transported to the liver. It synthesizes ceruloplasmin in the liver and then enters the blood circulation. Normally, about 95% of the copper in the plasma is copper blue. In the form of protein, a small amount of copper is loosely bound to albumin, which is an -globulin, which is the main carrier of copper transport in the liver, and is a copper donor for the synthesis of various copper-containing enzymes. Pigment C oxidase, superoxide dismutase, dopamine hydroxylase, etc. all contain copper. The content of ceruloplasmin in normal children's plasma is 200-400 mg/L (20-40 mg/dl). Low, the body's copper is mainly discharged from the bile by the stool, the urinary copper is very small, when the hepatolenticular degeneration, the copper metabolism abnormalities are mainly as follows:
1 bile discharge copper is significantly reduced, indirect method to measure the patient's bile copper discharge is only 20% to 40% of ordinary people;
2 The binding rate of copper to ceruloplasmin decreased, and the reduction of ceruloplasmin in blood is one of the main manifestations of this disease. It has been thought that liver ceruloplasmin dysfunction is its basic biochemical defect. Further research proves that serum of HLD patients The ceruloplasmin precursor-apocopicoin (unbound copper) is not low, only the total ceruloplasmin bound to copper is reduced, so the binding of copper to ceruloplasmin is reduced, instead of copper synthesis in the liver. The decline of cytoplasmic capacity may be one of the basic defects of this disease. Due to the disorder of bile excretion, the copper metabolism in the body is positively balanced, the liver copper is increased, copper is gradually accumulated in the liver, and copper is transferred from the blood circulation to various tissues in the body. It gradually deposits in the brain, kidney, cornea, and may also deposit in blood cells, bones and joints. Excessive copper has toxic effects on tissues, destroying mitochondria, peroxide bodies, lysosomes, etc. Injury, in addition, abnormal copper metabolism may also affect iron metabolism in this disease, and iron-binding globulin in plasma is reduced.
The pathogenesis and course of the disease are related to the accumulation process of copper in the body. It can be divided into the following stages: the first stage is asymptomatic, and copper begins to accumulate in the liver until it reaches the level of poisoning. In liver cells, it binds to proteins such as metal thionein (MT). The second stage is liver damage. Copper accumulates in the liver beyond the level of poisoning. A part of copper is released into the blood circulation and deposited in extrahepatic tissues and organs. Degeneration, necrosis, fibrosis and cirrhosis, similar to the process of chronic hepatitis; a small number of patients progress faster, may have pathological changes similar to acute or even acute severe hepatitis, and may be accompanied by acute intravascular hemolysis, the third stage is extrahepatic During the symptom period, the accumulation of copper in the tissues outside the liver reaches or exceeds the level of poisoning, and the corresponding symptoms appear.
2. Pathological changes
(1) Liver: cirrhosis, subacute yellow liver atrophy, mitochondrial abnormalities in liver cells can be seen under electron microscope.
(2) Brain: The lesion is mainly in the basal ganglia, especially in the nucleus, cerebral cortex, thalamus, red nucleus, substantia nigra, and pons.
Prevention
Prevention of hepatolenticular degeneration in children
Whether the carrier of the defective gene can detect the heterozygosity of the disease for genetic counseling; prenatal diagnosis of the disease is possible, and the pregnancy can be terminated if necessary.
Complication
Complications of hepatolenticular degeneration in children Complications, splenomegaly, epilepsy, obesity, hypertension
Splenomegaly, cirrhosis, pyramidal tract sign, seizures, obesity, hypertension, renal glucosuria, amino aciduria, proteinuria, hematuria, Fanconi syndrome, acute hemolysis, hemorrhage, osteoporosis, bone (cartilage) Degeneration, joint deformity, can cause severe liver failure, death within a few weeks, can be complicated by hemolytic anemia and hemorrhagic anemia, hypersplenism anemia.
Symptom
Symptoms of Hepatolenticular Degeneration in Children Common Symptoms Consonant Hepatolenticular Degeneration Ataxia Hemolytic Anemia Arrhythmia Hyperthermia Whole Blood Cell Reduction Astragalus Ascites Loss of Appetite
(1) Neuropsychiatric symptoms:
1. Early tremor is often limited to the upper limbs, gradually extending and the whole body. It is characterized by rapid, rhythmic, coarse and pulsating posture tremors, and may have intentional tremors that are aggravated during exercise.
2. dysphonia and dysphagia are more common in childhood HLD speech is slow like a poem, or flat tone like chanting, or speech breaks like eating; can also be ambiguous, fulminant or tremor language dysphagia often occurs In advanced patients.
3. Changes in muscle tone In most patients, the muscle tension is gear-like and lead-tube-like, which often leads to slow movement, reduced facial expression, difficulty in writing, and walking obstacles. A small number of dance patients with hypotonia.
4. Seizures are less common. Of the 418 HLDs, 11 (2.6%) had different types of seizures during the course of the disease, 10 of which were generalized tonic-clonic seizures or partial seizures, and only 1 was a seizure.
(B) Liver symptoms with liver symptoms as the first symptoms are:
1. Usually about 5 to 10 years old. As the copper ion deposition in the liver is supersaturated, it causes acute liver failure, that is, abdominal hepatolenticular degeneration. Clinical manifestations include generalized burnout, lethargy, loss of appetite, nausea and vomiting, abdominal distension and high jaundice, and the condition deteriorates rapidly. More than one week to one month or so of death, often after his compatriots have been diagnosed with HLD, the disease may be considered when reviewing the medical history.
2. About half of the patients in the 5 to 10 years old, transient jaundice, short-term alanine aminotransferase increased or / and mild ascites, and soon recovered quickly. When neurological symptoms appear several years later, the liver may be slightly enlarged or inaccessible, and liver function may be mildly damaged or normal, but B-ultrasound has been damaged to varying degrees.
3. Slow appetite, mild jaundice, hepatomegaly and ascites in children, which is similar to the manifestation of cirrhosis. After several months to several years, the symptoms of digestive tract are prolonged or worse, and tremors, muscle stiffness and other nerves gradually appear. Symptoms Once the symptoms of the neurological symptoms appear, the liver symptoms rapidly deteriorate and fall into the liver coma more than a few weeks to 2 to 3 months. Therefore, children with cirrhosis of unknown cause are children.
Examine
Examination of pediatric hepatolenticular degeneration
1. Determination of serum ceruloplasmin and copper oxidase activity
Serum ceruloplasmin reduction is an important basis for the diagnosis of this disease, but ceruloplasmin reduction can also be seen in nephrotic syndrome, some malabsorption syndrome, loss of protein bowel disease, Menkes disease, etc., patients with hepatolenticular degeneration In combination with severe liver failure, the serum ceruloplasmin value can be normal. In this case, other indicators should be comprehensively analyzed.
The strength of serum copper oxidase activity is directly proportional to the amount of serum ceruloplasmin, so its activity assay can indirectly reflect serum ceruloplasmin content.
2. Determination of copper content in the body
(1) serum copper, often lower than normal, normal human serum copper 14.13 ~ 20.41 (mol · L) 90 ~ 130 (g · dl), the majority of patients with this disease in 4.71 ~ 14.13mol / L (30 ~ 90g / dl) In some patients, due to the fact that ceruloplasmin is not too low or normal, direct reaction of copper (bound with albumin) increases and serum copper is normal or elevated.
(2) urinary copper, high urinary copper is one of the significant biochemical abnormalities of this disease. Normal people have urinary copper below 50g/d. The urinary copper in patients with this disease is more than 100g/d before treatment.
3. Renal function test
Increased urinary amino acid excretion, proteinuria or transient diabetes.
Brain CT and MRI examination: CT scan is of great value in the diagnosis of this disease. More than half of the asymptomatic patients or liver type patients show ventricular enlargement, cortical or brain stem atrophy, basal ganglia low density area and other abnormalities, MRI can be sensitively reflected The lesions in the typical part of the basal ganglia of this disease, clinical improvement and temporary deterioration may be accompanied by corresponding changes in abnormal signal intensity.
Diagnosis
Diagnosis and diagnosis of hepatolenticular degeneration in children
diagnosis
The diagnosis of Wilson's disease is mainly based on clinical features and laboratory tests. If there is a positive family history, the diagnosis is easier to establish. Children or adolescents should think of the following symptoms when they have the following symptoms:
1. Unexplained extrapyramidal or other neurological symptoms or unexplained spirits, abnormal behavior.
2. Unexplained liver disease.
3. An acute hemolysis crisis of unknown cause.
4. Unexplained tubular insufficiency or bone changes.
If you suspect this disease, you should first check the corneal KF ring and the above laboratory tests. Most of them can be diagnosed. If you can't confirm the diagnosis, you can use the radioactive copper determination and liver activity to detect the copper content of the liver tissue. If it is positive, it will help the diagnosis.
Differential diagnosis
The reduction of ceruloplasmin can also be seen in nephrotic syndrome, protein deficiency malnutrition, malabsorption syndrome, chronic hepatitis, etc.; in addition to the disease, urinary copper increase is also seen in biliary obstruction and nephrotic syndrome, should be noted, if Can not be diagnosed, you can consider liver puncture to measure liver copper quantitation, or do nuclear examination to clear the differential diagnosis.
