Brown-green pigmented ring on outer limbus of cornea
Introduction
Introduction The brown-green pigment ring on the outer edge of the cornea is one of the symptoms of hepatolenticular degeneration. Because the lack of ceruloplasmin in patients cannot bind to copper, a large amount of copper is deposited in the liver (negative nucleus), cornea and kidney, leading to copper metabolism disorders and causing a series of visceral function and tissue damage; the most common site is Brain basal ganglia, cerebellum, cerebral cortex, cornea, liver, kidney, etc. The cause of the disease is that the autosomal recessive monogenic genetic disease has a positive family history of about 20% to 30% of the majority of the siblings. It was found that there are at least 25 mutations in its gene, which are located on chromosome 13. As for the genetic defects or structural genes that have not yet been identified, the literature reports that the incidence of close relatives is higher but controversial.
Cause
Cause
Causes
The autosomal recessive monogenic genetic disease has a positive family history of about 20% to 30% of the majority of the siblings. It was found that there are at least 25 mutations in its gene, which are located on chromosome 13. As for the genetic defects or structural genes that have not yet been identified, the literature reports that the incidence of close relatives is higher but controversial.
Because the lack of ceruloplasmin in patients cannot bind to copper, a large amount of copper is deposited in the liver (negative nucleus), cornea and kidney, leading to copper metabolism disorders and causing a series of visceral function and tissue damage; the most common site is Brain basal ganglia, cerebellum, cerebral cortex, cornea, liver, kidney, etc. The pathological changes were mainly in the lenticular nucleus, and the cerebral cortex was also damaged. The pathological sections showed that the nucleus and caudate nucleus neurons were degenerated or disappeared, and they were replaced by astrocytes. If the copper is deposited in a large amount in the liver, hepatic enlargement, acute or chronic hepatitis and cirrhosis, and liver atrophy may occur.
Pathogenesis
The pathogenesis of this disease has the following hypothesis:
1. Biliary copper exclusion barriers The use of 64Cu or 67Cu radionuclide examinations found that patients with reduced hepatic bile system copper deposition and copper deposition in the liver or other organs and tissues is a more compelling hypothesis.
2. The existence of abnormal proteins in cells. The hypothesis believes that the production of the mutant gene is an abnormal protein in the cell, or the abnormal enzyme causes the protein to be incompletely hydrolyzed to form an abnormal polypeptide. The abnormal protein or polypeptide mainly exists. In tissues such as liver, brain and kidney, it has an unusually strong affinity for copper, which hinders the synthesis of ceruloplasmin and causes copper to deposit in tissues.
3. Lysosomal Defects Hepatocyte lysosomal defects can not concentrate copper to lysosomes in the early stage, and later cannot release copper into the bile and be discharged, resulting in a large deposition of copper in the liver or other tissues.
4. The ceruloplasmin synthesis disorder Matsuda (1974) used radioimmunoassay to measure the normal ceruloplasmin content in the serum of patients, suggesting that the synthesis process of copper and protocerin is blocked. Pathological changes mainly occur in the nucleus of the nucleus of the lenticular nucleus. Visual observation of the shape of the brain is normal. The striatum is atrophied and the brown nucleus often has a cavity. Pathological biopsy shows that the nucleus and caudate nucleus neurons degenerate or disappear, and are replaced by astrocytes. Some form typical Alzheimer cells, which in turn undergo degeneration. Special staining reveals copper deposits around the capillaries in the damaged area.
In the early stage of liver cirrhosis, hepatic cell necrosis occurs when the steatosis is severe. In the late stage of cirrhosis, the liver is reduced in size, with small nodules on the surface of the lobular sclerosis. Pathological sections showed normal, degenerate, and restored hepatocyte regions with irregular staggered distribution, and connective tissue and small bile duct proliferation.
Examine
an examination
Related inspection
Serum alanine aminotransferase brain CT examination EEG examination
Clinical manifestation
Most of them are slow onset, and there are many extrapyramidal symptoms at the beginning. For example, limb tremors, oscillating muscle tension, involuntary movement, etc., about 20% of mental disorders, and children with mental disorders are the first symptoms. Or learning ability is reduced.
1. The majority of patients with onset of onset are slow onset; a small number of subacute courses progress faster; the latter is more common in children or juvenile patients. The first symptom is more common with extrapyramidal symptoms, and about 120% of those with mental disorders as the first symptom. Children often develop mental symptoms, which are characterized by abnormal mood or decreased learning ability.
2. Psychiatric symptoms The symptoms of hepatolenticular degeneration are diversified, that is, changes in mood abnormalities or personality characteristics may occur in the course of the disease, such as emotional psychosis or schizophrenia-like manifestations, and in the later stages of the disease, the mental decline is more Obviously, severe cases are demented.
Clinically, most of the psychiatric symptoms occur about 1 year after the onset of neurological symptoms, but they can also behave earlier. Emotional disorders are mainly caused by mandatory crying, emotional instability, moodiness, irritability, or apathy and interest reduction (Ouyang Shan, 1990). Depression and anxiety symptoms can also be seen. Personality and behavioral disorders manifest as sluggish, naive, ridiculous, frivolous, arbitrarily lying or stealing, etc. However, impulsive behavior is also not unusual. Logical thinking can also be abnormal and illusory delusions are rare. As the disease progresses, the mental retardation becomes more and more obvious. In the late stage, there is a state of severe dementia. Some patients may have auditory hallucinations, sorrowful delusions or schizophrenia-like manifestations. At the end of the disease, the brain parenchyma is severely damaged. At this time, the patient's daily life is completely unable to take care of themselves.
3. Neurological symptoms and signs The three main signs of this disease are extrapyramidal symptoms, cirrhosis and corneal pigment ring (Kayser-Fleischer ring). In the first symptom, extrapyramidal dyskinesia is very obvious, such as limb tremor arm. It is not uncommon for oscillating muscle tension to increase or tonic involuntary movements such as ataxia, such as unclear hooliganism and difficulty in swallowing.
In most cases, the brown-green pigment ring (Kayser-Fleischer ring) in the outer edge of the cornea has a serum copper oxidase activity to reduce the detection rate of the corneal pigment ring by more than 90%, which has important diagnostic value. This ring is brown or grayish green at the edge of the cornea and is easier to see under the slit lamp. Hepatic damage is caused by hepatomegaly, and the most common late stage of splenomegaly is ascites and cirrhosis.
The disease is a persistent progressive disease, and most of the prognosis is poor. From the appearance of symptoms to death for about 7 to 15 years, mostly due to liver failure or concurrent infection and death.
Complications: Patients with hepatolenticular degeneration have low immune function, which can be secondary to various systemic infections and often die from liver failure or concurrent infection. Some patients have symptoms of pseudobulbar paralysis, such as difficulty swallowing, returning to drinking water, etc., especially in patients who are bedridden are more likely to suffer from fallopian pneumonia urinary tract infection and acne patients with extrapyramidal symptoms, walking difficulties are easy to fall and fractures . In patients with hepatolenticular degeneration, there is portal hypertension and esophageal varices in patients with decompensated cirrhosis. It is prone to acute upper gastrointestinal bleeding and even hemorrhagic shock. The detoxification ability of a few livers is reduced, and hepatic encephalopathy is prone to occur. , liver and kidney syndrome, etc.; some patients with seizures due to brain damage, the above-mentioned various complications often aggravate the condition, seriously affect the treatment effect, prolong the hospitalization time, if not timely and accurate treatment, some patients have a prognosis with no complications. Poor patient.
Extrapyramidal symptoms, corneal pigment ring and serum copper oxidase decrease in absorbance are three important criteria for the diagnosis of this disease. In addition, liver disease or liver disease, increased urinary copper (>50g) is also diagnostic; brain CT and MRI can be For auxiliary diagnosis reference.
Diagnose based on
1. Evidence of organic damage
(1) Brain lesions and liver lesions.
(2) Age of onset and clear genetic history.
(3) Increased muscle tone, tremor, corneal KF ring, etc.
2. Mental symptoms
(1) Intelligent damage is progressively aggravated.
(2) emotional disorders and personality changes.
3. Laboratory inspection
(1) Serum ceruloplasmin and blood copper reduce the decrease of serum copper hydrogenase in urinary copper and copper.
(2) liver function damage SGPT, ZnTTT, etc. increased.
(3) Brain CT and MRI examination showed a low density change in the basal ganglia.
Extrapyramidal symptoms, corneal pigment ring and serum copper oxidase absorbance decreased by 3 items is the key basis for the diagnosis of this disease.
Laboratory inspection:
1. Serum ceruloplasmin and serum copper reduce the content of urinary copper and liver copper. Serum copper oxidase absorbance test was found in 90% of patients with a lower than normal biochemical abnormality of hepatolenticular degeneration. Serum ceruloplasmin determination of normal humans 200 ~ 400mg / L (or 0.25 ~ 0.49OD); children usually less than 200mg / L; 24h urine copper output determination of children significantly increased, often up to 100 ~ 1000ug / 24h; cells The amount of copper contained in normal people is about 20ug/g (dry weight), and the number of children can be as high as 200-3000ug/g.
2. Liver function tests showed an increase in alanine aminotransferase (SGPT) and thymol turbidity test (ZnTTT).
3. Patients with very low blood levels are unfavorable factors for metal complexing agent copper-dissipation therapy. If they are not treated in time, it is often difficult to persist in copper-exposure treatment. Patients with severe liver and kidney dysfunction should also avoid using the liver fibrosis index of liver and kidney dysfunction to understand the severity of cirrhosis in patients, and provide objective observation indicators for anti-fibrosis treatment.
Other auxiliary inspections:
1. EEG examination is about 30% to 50% abnormal, mostly moderate to mild, but not specific.
2. The abnormal rate of brainstem auditory evoked potential is high, up to 90%; the main performance is III-VIPL prolonged, and the amplitude is reduced (Pan Yingfu 1987). This may be the diffuse deposition of copper in the brainstem, causing neuronal degeneration and demyelination changes in the brainstem auditory system.
3. Brain CT scans in 30% to 40% of patients showed bilateral basal ganglion symmetry low-density lesions in the cerebral cortex and brain stem atrophy can also be seen, as well as ventricular enlargement and lateral fissure widening. Magnetic resonance imaging (MRI) is more clear, showing a wider range of lesions than brain CT scans. Not only the ventricle enlarges but also the abnormal signals in the thalamus and brainstem (T1W low signal T2W high signal).
Abnormal changes in EEG and EMG suggest that brainstem evoked potentials before and after impaired treatment of brain and peripheral nerve muscles can be used to help determine the severity and efficacy of brain damage in patients. B-ultrasound can be used to understand the image of the patient's liver. The credit type, spleen enlargement, renal cortical damage and presence or absence of cholelithiasis may help the estimated prognosis of the head CT or MRI. In addition to the special lesions in the basal ganglia can help the diagnosis of this disease, if there is a cerebral cortical atrophy, the formation of softening lesions of the temporal lobe often has poor mental retardation, and should be treated with appropriate brain resuscitation.
Diagnosis
Differential diagnosis
In the differential diagnosis, Alzheimer's disease, such as Parkinson's disease and Huntington's disease, should be identified one by one. Because of the emotional abnormality and the decline of internal driving force, it should be differentiated from schizophrenia and affective disorder.
1. Different from other brain degenerative diseases, there is obvious change of corneal pigment ring copper in CT. MRI examination shows that brain basal ganglia changes and clear liver symptoms can be identified.
2. Identification of functional psychosis The mental symptoms of this disease are mainly brain damage such as personality changes, dementia, etc.; the KF ring laboratory examination characteristic of extrapyramidal symptoms can confirm the diagnosis.
