Hepatolenticular degeneration

Introduction Hepatolenticular degeneration, also known as Wilson's disease, was first reported by Wilson in 1911. This is an autosomal recessive hereditary disease that is common in adolescents and is a congenital copper metabolic disorder. First reported and described by Wilson, it is a kind of cirrhosis caused by hereditary copper metabolism disorder and a brain degeneration disease mainly composed of basal ganglia. Clinically, liver damage, extrapyramidal symptoms and corneal pigment ring are the main manifestations. Early (especially pre-symptomatic) diagnosis and timely and definitive treatment often result in the same life and longevity as healthy people.

Cause

(1) Causes of the disease

Hepatolenticular degeneration is an autosomal recessive hereditary disease. The affected gene is involved in the disorder of copper metabolism, and is closely linked to the esterase D gene located on the chromosome and the retinoblastoma gene.

(two) pathogenesis

The pathogenesis of WD includes the reduction of biliary excretion, ceruloplasmin synthesis disorders, lysosomal defects, metal prion gene abnormalities and regulation of gene abnormalities. At present, most of the previous two theories have been endorsed by most scholars.

1. Copper metabolism synthesis barrier

Most laboratory experiments with 64Cu on copper metabolism in vivo have shown that serum ceruloplasmin reduction is the main reason for copper accumulation in WD. However, the lack of ceruloplasmin has not been fully elucidated. According to the ceruloplasmin electrophoresis, Bichtrrich found that the normal adult is composed of undifferentiated ceruloplasmin D, which is converted into ceruloplasmin C by peptidase in the liver, and then 80% ceruloplasmin C and 20% copper. The cyanoprotein D constitutes ceruloplasmin, while the WD patient only has ceruloplasmin D, and almost no part C, which leads to ceruloplasmin synthesis disorder.

2. Biliary copper excretion disorder

Normal adults need to absorb 2 to 5 mg of copper from food every day. After copper ions enter the body, most of them are firstly combined with albumin to directly react copper, which is transported to the liver and transferred to various globulins in liver cells. It is the 2-globulin that binds firmly to ceruloplasmin (indirect reaction copper). Generally, the total amount of copper in plasma is 90% to 95% in the form of ceruloplasmin. Only about 5% of copper is loosely bound to albumin, amino acids and polypeptides. The latter freely passes through the cell membrane and plasma copper in all organs. Except for exchange, most of the lysosomes are taken out of the feces through the bile duct, and a small amount is excreted by the urine. That is, the copper absorbed by normal people from food, in addition to the physiological needs of the body, the excess copper is mostly excreted from the bile in the bile duct. Frommer took the lead in measuring the copper content in the duodenal juice of 8 patients with WD and 10 patients in the control group. It was found that the WD group was significantly lower than the control group. It was suggested that the bile duct copper barrier was an important cause of copper accumulation in WD patients.

Copper is an essential trace element in the human body and acts as a prosthetic group to participate in the synthesis of many important biological enzymes. Normal adults take 2 to 5 mg of copper daily from the diet, about 30% of which is absorbed into the stomach at the upper end of the stomach, duodenum and jejunum. Most of them are loosely bound to albumin and enter the liver cells. In the liver cells, copper and 2 globulin are firm. Combined with ceruloplasmin (CP), CP has oxidase activity and is dark blue, and the remaining copper is bound to other special copper proteins. The daily bile discharge of normal people is about 1200 g. About 70% of the CP is present in the plasma, and the rest is present outside the blood vessels. 90% to 95% of the copper in the blood circulation binds to the CP. CP has important physiological functions, and can be used as a donor of copper to participate in the synthesis of cytochrome C and other copper proteins. It has a ferrous oxidase function, oxidizes ferrous iron to a high-iron state, and reduces oxygen to water. The remaining copper is excreted from the body through bile, urine and sweat. In patients with WD, ceruloplasmin synthesis disorder, more than 90% of patients with serum CP decreased significantly, but the content of liver anterior ceruloplasmin (Apo-CP) and normal structure, suggesting that biochemical disorders occur in the liver Apo-CP and copper binding, CP synthesis disorders are the basic genetic defects of this disease. Intrahepatic copper metabolism disorder causes serum CP synthesis disorder, resulting in lower serum copper and CP, increased urinary copper excretion, reduced bile duct copper, excessive copper deposition in liver, brain, kidney and cornea, but about 5% of Wilson It is difficult to explain the normal serum CP levels in patients.

In recent years, it has been determined that the CP gene is located on chromosome 13 (13q14-21) and has multiple mutant types. The expression CP is a 132kD glycoprotein, which consists of 1046 amino acid residues and consists of a single polypeptide chain combined with six different types of copper ions. There were no abnormalities in ceruloplasmin precursors in WD patients, and there was no change in genes and expression products. From the genetic point of view, WD serum CP could not be significantly reduced. Gene mutations have obvious genetic heterogeneity. The mutation methods include conversion (AG), transversion (CG), deletion (CCCCC) and insertion (TTT), among which CG transversion is the most common. The resulting amino acid changes (such as histidine to glutamic acid, aspartic acid to serine) and frameshift mutations, the mutations found so far involve the ATPase functional region. Mutations in the WD gene cause changes in the function of the P-type ATPase (also known as ATP7B). The main function of ATP7B is copper transport, partial or complete loss of function, and the inability to transport excess copper ions from the cells, causing the deposition of copper ions in specific organs and tissues. Cause the disease.

There is racial difference in the molecular pathogenesis of WD. The high-frequency mutation point of ATP7B gene in European and American patients is exon 14 and is in the phosphorylation region of ATP7B gene and ATP-binding region. The mutation of two functional regions causes the function to disappear, resulting in enzyme deficiency and transport process. The medium energy causes copper ions to stay in the cells. The high-frequency mutation point exon 8 of Chinese WD patients is in the transmembrane functional region of the whole ATP7B gene, causing the primary and secondary structure changes of the protein, leading to the stagnant cell membrane copper transport and causing disease.

The pathology of WD is characterized by the deposition of large amounts of copper in tissues. The lesions are characteristically distributed in brain tissue, liver, kidney and cornea. The brain lesions were the earliest and obvious in the nucleus, followed by the globus pallidus, caudate nucleus and cerebral cortex. The subthalamic nucleus, red nucleus, substantia nigra, thalamus and dentate nucleus were also involved. Neurons were significantly reduced or completely lost, axonal and astrocyte hyperplasia. In the elastic layer of the corneal margin and in the endothelial cell cytoplasm, brown yellow small copper particles can be deposited, which can also be seen in the central cornea and interstitial cells. Liver surface and cut surface can be seen in different sizes of nodules or pseudolobules, similar to liver cirrhosis after necrosis, hepatic steatosis, containing copper particles. Electron microscopy showed dense mitochondria, disappearance of mitochondria and disruption of rough endoplasmic reticulum in hepatocytes.

an examination

1. Determination of copper content

(1) The determination of copper content in hair is of little value in the diagnosis and differential diagnosis of Wilson's disease.

(2) Determination of muscle copper content Some patients with difficult diagnosis of hepatolenticular degeneration have certain reference value.

(3) Determination of copper content of nails Determination of copper content of nails is a non-invasive inspection method, and its advantages and disadvantages are the same as those of hair copper.

(4) Determination of copper content in bile has a specific value for the diagnosis of Wilson's disease. The amount of copper in the bile of patients with Wilson's disease is significantly reduced.

2. Imaging examination

(1) Liver B-ultrasound examination of hepatolenticular degeneration has its special sonogram, and the sonogram of liver parenchyma is divided into light spot scintillation, rock stratum type, dendritic light according to the degree of liver damage. Band type and nodular type have characteristic diagnostic value for hepatolenticular degeneration. It has a discriminating value for patients with hepatolenticular degeneration and liver cirrhosis (nodular type) who have not developed neurological symptoms and chronic hepatitis cirrhosis. The size and shape of the spleen can be assessed. Can show gallstones, kidney stones, kidney calcium deposition.

(2) Esophageal sputum angiography Splenic portal venography or angiography can further confirm the diagnosis of patients with hepatolenticular degeneration with clinical manifestations of portal hypertension, which is helpful for the formulation of treatment plans.

(3) The significance of bone and joint X-ray examination in the diagnosis of Wilson's disease: 1 X-ray changes of bone and joint are potential diagnostic indicators of this disease. Clinically difficult to diagnose cases, with or without bone and joint symptoms, can be used to help diagnose. 2 In children and adolescents, unexplained pathological fractures or X-ray photographs reveal abnormalities in the wrist and knee joints, taking into account the possibility of hepatolenticular degeneration. 3 When the family is investigated by the proband, it can be used as a supplementary method to determine whether the patient is pre-symptomatic or early symptom.

(3) Cranial CT, MRI Asymptomatic Wilson's disease and brain-free hepatic Wilson's disease: Brain CT scan is more common in brain atrophy, while brain-like hepatolenticular degeneration is The symmetry low density shadow of the basal ganglia is characterized. Therefore, CT scan has an auxiliary diagnostic value for patients with atypical latent, hepatic and cerebral hepatolenticular degeneration, but CT changes in hepatolenticular degeneration are not specific. MRI examination of the hepatolenticular degeneration brain shows a clearer intracranial abnormality than CT, and the clinical significance is similar to CT scan. Invading the basal ganglia nucleus showed bilateral symmetry, and most of the head of the lenticular nucleus and caudate nucleus were involved, while the thalamus was locally involved. Brain stem lesions are mainly pons and midbrain lesions, and rare cerebellar lesions are rare. Therefore, the symmetry basal ganglia abnormal signal accompanied by brain stem lesions is one of the imaging features of hepatolenticular degeneration.

3. Electrophysiological examination

(1) EEG in patients with cerebral hepatolenticular degeneration with cerebral symptoms, abnormal or mild abnormalities in EEG, and EEG in patients with abdominal or hepatic Wilson's disease The graph is moderately and severely abnormal. Electroencephalography helps to diagnose hepatolenticular degeneration with seizures.

(2) Brainstem Auditory Evoked Potential (BAEP) Patients with Wilson's disease may have abnormal BAEP and have certain diagnostic value.

4. Psychological test and IQ test

For other types of hepatolenticular degeneration of mental disorders or hepatic symptoms, psychological tests can be used to distinguish between behavioral disorders or organic psychosis. IQ testing can understand the extent of a patient's mental retardation.

5. Other inspections

(1) Tc colloidal sulfur isotope scanning can clearly show the size and shape of liver and spleen.

(2) Laparoscopy can be seen in the liver hardening nodules, which helps to directly understand the extent of liver damage in patients with Wilson's disease.

Differential diagnosis

diagnosis:

(1) Family genetic history. Parents are close relatives, compatriots with HLD patients or those who die of unexplained liver disease.

(2) Extrapyramidal symptoms, signs and/or liver symptoms such as slow progressive tremor, muscle stiffness, and dyslexia.

(3) The KF ring was confirmed by the naked eye or slit lamp.

(4) Serum ceruloplasmin.

(5) Urinary copper > 50 g / 24h.

(6) Liver copper > 250 g / g (dry weight).

Judgment: Anyone who has the above items (1) to (3) or (2) and (4) can be diagnosed as clinically dominant. Only those having the above items (3) to (5) or (3) to (4) are asymptomatic HLD. Only those (1), (2) or (1), (3) should be suspected of HLD.

Differential diagnosis:

1. Mekes disease and chronic liver disease due to severe protein deficiency, serum CP can be decreased, biliary cirrhosis can also appear KF ring, attention should be paid to identification;

2. This disease has some signs of Parkinson's disease, which can be differentiated from PD according to corneal KF ring, severe ataxia tremor, and serum ceruloplasmin reduction.

3. Must also be differentiated from acute or chronic hepatitis, cirrhosis, small chorea, Huntington's chorea, torsion, senile dementia, psychosis, hepatorenal syndrome, etc.

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