hepatolenticular degeneration
Introduction
Introduction to hepatolenticular degeneration Hepatolenticular degeneration is a hereditary disease mainly caused by adolescents, caused by copper metabolism disorders. It is characterized by cirrhosis, basal ganglia softening and degeneration, corneal pigment ring (Kayser-Fleischer ring), accompanied by ceruloplasmin deficiency and amino aciduria. Also known as Wilson's disease. basic knowledge The proportion of illness: 0.0002% Susceptible people: adolescents who are born in 10 to 25 years old Mode of infection: non-infectious Complications: dysphagia, urinary tract infection, hemorrhoids, fracture, portal hypertension, upper gastrointestinal bleeding, hepatic encephalopathy, hepatorenal syndrome, epilepsy
Cause
Cause of hepatolenticular degeneration
Etiology
The basic cause of the disease is excessive deposition of copper in various tissues of the body, especially in the liver, brain, kidney, cornea, etc., leading to tissue damage and lesions.
Pathogenesis
There are several theories about the mechanism of hepatolenticular degeneration: 1 The normal substance defects in the bile of this kind of patients combined with copper may be the defects of chewing deoxycholic acid and taurine, leading to copper dysfunction in bile secretion. Evidence that does not support this doctrine is that there is no qualitative change in bile copper-binding proteins in this class of patients, and there is no evidence that such patients have abnormal bile acid metabolism. 2 abnormalities in the synthesis of copper-binding protein in the liver, resulting in increased affinity of the protein for copper. The evidence supporting this theory is that the binding constant of copper-binding protein (hepatic copper protein) to copper in patients with Wilson disease is a patient with primary biliary cirrhosis. The constant is 4 times, but people have questioned the analysis method of data. Therefore, whether the high affinity of abnormal protein for copper in Wilson's disease is the formation mechanism of Wilson's disease needs further clarification. 3 The most reasonable theory is that the lysosomes of liver cells participate in the metabolic process of copper. It is observed that the lysosomal content of liver cells in patients with Wilson disease is 40 times higher than that of the control, and the lysosomal defects of liver cells in patients with Wilson disease are considered. It interferes with the process by which copper is secreted by lysosomes into the bile, resulting in an increase in copper in the liver of patients with Wilson's disease.
In short, Wilson's disease is not due to increased intestinal absorption of copper, but due to biliary tract secretion of copper, this disorder is congenital, patients with genetic defects, can not be combined with copper positive balance metabolism within 3 months after birth Normal, the copper positive equilibrium metabolism persists, resulting in the accumulation of copper in the body.
Pathological change
First, the liver
The earliest histological changes were glycogen degeneration in the hepatocytes of the peri-lobular area under light microscopy. The nucleus glycogen is agglomerated or vacuolated and has a moderate degree of fat infiltration. The fat droplets are composed of triglycerides, and the number of fat droplets increases and the fusion increases. Steatosis is similar in morphology to alcoholic steatosis. The organelles that coexist with steatosis or have undergone lesions before steatosis are mitochondria, with increased mitochondria volume, membrane separation, sputum expansion, crystal arrangement, vacuoles, The matrix is significantly granular. Mitochondrial changes may be associated with steatosis in pathogenesis. With the treatment of D-penicillamine, mitochondrial changes can be alleviated or even disappeared, indicating that changes in mitochondria are caused by the toxic effects of copper.
The rate of change of the liver from fat infiltration to cirrhosis varies greatly from person to person. Some patients may develop chronic active hepatitis, may have mononuclear cell infiltration, mostly lymphocytes and plasma cells, may have clastic necrosis, and this necrosis may cross the boundary plate, may have liver parenchyma collapse, bridging necrosis It is distinguished from liver fibrosis, a chronic active hepatitis. Liver lesions can be naturally relieved, and can progress to large nodular cirrhosis or rapidly develop into fulminant hepatitis, which is poorly treated.
In the process of cirrhosis, there may be inflammatory cell infiltration or substantial necrosis of the liver parenchyma, eventually forming cirrhosis with large nodular or large nodule nodules. The fiber separation can be wide or narrow, bile duct hyperplasia, but also accompanied by There are some pathological changes in the early stage of Wilson's disease such as ribosome degeneration and steatosis.
Second, the brain
The whole nervous system can be involved, and the nucleus, the nucleus, the caudate nucleus, the insula and the nucleus are more heavily involved, and the nucleus is the most prominent in the nucleus. The cerebral hemisphere can be atrophied to varying degrees, the lenticular nucleus shrinks, softens, and forms small cavities. Histology shows degeneration and necrosis of nerve cells, astrocyte hypertrophy, hyperplasia, and degeneration.
Third, the kidney
Copper sinks in the proximal convoluted tubules, showing fatty degeneration and watery degeneration.
Fourth, the cornea
Copper deposits form a brown-green pigmentation around the Descemet membrane behind the cornea, called the Kayser-Fleischer ring.
Prevention
Hepatolenticular degeneration prevention
1. Prevention and treatment of this disease should be diagnosed early, correct the positive balance of copper metabolism in patients, pay attention to reduce the copper content of food (<1mg / d), limit the diet containing more copper, such as nuts, chocolate, peas, broad beans, corn , mushrooms, shells and snails, honey, animal liver and blood, high amino acid, high protein diet can promote urinary copper excretion.
2. Determination of serum ceruloplasmin, serum copper, urinary copper and copper content of dermal fibroblasts in vitro in family members of WD patients can help to find homozygous and heterozygous WD symptoms before the symptoms, and the homozygotes can be detected early before symptoms. Treatment, heterozygotes should be contraindicated to marry heterozygotes to avoid homozygote in their offspring, prenatal examination if found to be homozygous, should terminate the pregnancy to prevent the source of the patient.
Complication
Hepatolenticular degeneration complications Complications dysphagia urinary tract infections acne fractures portal hypertension upper gastrointestinal bleeding hepatic encephalopathy hepatorenal syndrome epilepsy
In patients with hepatolenticular degeneration, the immune function is partially low. Some patients have symptoms of pseudobulbar paralysis, such as difficulty swallowing, returning to drinking water, etc. Especially in patients who have been bedridden for a long time, they are more likely to have hypostatic pneumonia, urinary tract infection and hemorrhoids. Patients with extrapyramidal symptoms, walking difficulties, easy to fall and fractures, patients with hepatolenticular degeneration in the decompensated period of cirrhosis with portal hypertension combined with esophageal gastric varices, prone to acute upper gastrointestinal bleeding, or even occur Hemorrhagic shock; a small number of liver detoxification ability, prone to hepatic encephalopathy, hepatorenal syndrome, etc.; some patients with seizures due to brain damage, these complications often aggravate the condition, seriously affecting the treatment effect, so that Patients with prolonged hospital stays, if not timely, accurate treatment, some patients with poor prognosis compared with patients without complications.
Symptom
Hepatolenticular degeneration symptoms Common symptoms Hepatolenticular degeneration inattention Deficit spider
Although there is copper accumulation in the liver during infancy, there are few liver disease symptoms before the age of 6 years, and 50% before the age of 15 years, occasionally 60 years old, 42% of the initial symptoms are liver disease, 34% In the nervous system, 10% are psychiatric symptoms, 12% are endocrine or bloodline symptoms secondary to liver disease, 1% are renal damage manifestations, and about 25% of patients have more than two systemic manifestations at the same time.
First, the liver
The onset of liver disease is often younger. The clinical manifestations vary widely, and can be manifested as acute or chronic hepatitis, fulminant hepatic failure, or cirrhosis. Therefore, the clinical manifestations of liver disease caused by Wilson disease are not specific. In the asymptomatic period or early stage of cirrhosis, liver function can be normal, or only a slight increase in transaminase, multiple onset of disease, presenting a chronic course. Beginning with fatigue, fatigue, anorexia, jaundice, spider mites, splenomegaly, and hypersplenism, eventually leading to portal hypertension, ascites, varicose veins, and liver failure.
Wilson's disease patients often shrink or normal size of the liver, with characteristics of cirrhosis after necrosis, ascites, esophageal varices bleeding as the initial performance. In addition, clinical manifestations, biochemical tests, and histological examinations are similar to those of chronic active hepatitis. Some patients occasionally find the KH ring or have neuropsychiatric symptoms before they think of the disease and get a diagnosis. Therefore, for patients under the age of 35 who are HBsAg-negative chronic liver disease, the disease should be considered and laboratory tests should be performed to establish a diagnosis.
Second, the nervous system
The nervous system manifests itself in patients between the ages of 12 and 30, almost always accompanied by a KF ring. It begins to be mild, but it progresses to a serious degree if it is not treated in time. In the early stage, there were wrist tremors, grimacing, stuttering and writing difficulties. At the same time, there were gait stiffness, difficulty swallowing, limbs were fluctuating and strong, expressions were poor and fixed, and they were constantly flowing and intellectually acceptable. EEG is a non-specific slow wave that does not help diagnosis. In addition, at this time, CT examination showed no specific expression of brain evoked potentials. MRI is more sensitive to CT in measuring brain, cerebellum and brainstem lesions, but asymptomatic people are often normal, and liver function tests are more normal.
Third, mental symptoms
It is characterized by abnormal behavior, manic depression or schizophrenia, and dementia. There are at least four mental disorders: emotional abnormalities, behavioral abnormalities, schizophrenia, and cognitive impairment. In the above aspects, treatment can only be partially relieved.
Eyes
The KF ring is located at the posterior membrane of the cornea. It is brown or green, or golden yellow, and can be as wide as 2 mm. It can be seen with a diagonal light or the naked eye. This pigment ring is related to the distribution, density and size of the copper particles. The KF ring is almost always associated with neurological symptoms, but in asymptomatic children or liver damage, especially with chronic active hepatitis, there is no KF ring. The appearance of the KF ring is helpful for diagnosis, but it is not a characteristic manifestation of Wilson's disease. Long-term intrahepatic cholestasis, chronic active hepatitis with cirrhosis and cryptogenic cirrhosis in childhood can cause copper deposition in the cornea and other organs due to copper excretion of bile.
Sunflower-like cataract is also a rare ocular manifestation of Wilson's disease, often coexisting with the KF ring. This feature often disappears faster than the KF ring when treated with D-penicillamine.
Fifth, the blood system
Acute intravascular hemolysis often occurs in Wilson's disease, and hemolysis is evident in at least 15% of patients. Hemolysis is often transient and self-limiting, often more than a few years before liver disease, and there is often no KF ring in hemolysis. Therefore, for patients with hemolysis below 20 years of age, hemolysis should be excluded from other reasons due to biochemical examination. Patients with Wilson's hemolysis have negative blood Coombs test and belong to non-spherical red blood cell hemolysis. Occasionally, acute hemolysis and acute liver failure occur at the same time, indicating that the condition is severe, often dying in liver or kidney failure within a few weeks.
The cause of hemolysis is unknown. Some people think that because the liver releases copper into the blood in a short period of time, red blood cells ingest large amounts of copper, leading to oxidative damage to cell membrane and hemoglobin. It is also believed that the toxic effect of copper is the oxidation of cell membrane phospholipids.
In addition, patients with liver damage, acute liver failure, severe decompensated cirrhosis, decreased synthesis of coagulation factors, poor platelet mass, splenomegaly can cause thrombocytopenia and leukopenia, and these patients with Wilson disease have bleeding tendency.
Sixth, the kidney
Wilson's disease has varying degrees of impaired renal function, including decreased glomerular filtration rate, reduced renal blood flow, and tubular lesions. Among them, the proximal convoluted tubule may have amino aciduria, diabetes, increased uric acid (with low serum uric acid), high urine phosphorus, high urinary calcium, proteinuria, and the latter includes low molecular globulin and hydroxyproline polypeptide produced by collagen decomposition; The pH of the distal convoluted tubules is reduced to below 5.2, which is also the cause of the formation of kidney stones. Penicillamine can significantly improve renal function, but occasionally the side effects of penicillamine-induced nephrotic syndrome and Goodpastures-like syndrome.
Seven, bones
There may be decalcification, bone softening, rickets, spontaneous fractures, subcapsular cysts, osteoarthritis, isolated osteochondritis and softening calcification. Clinical symptoms are often not obvious. Patients may have knee or other large joint pain and stiff.
Eight, other
The heart may have arrhythmia, cardiomyopathy and autonomic dysfunction, secondary to endocrine changes in liver disease, young women with amenorrhea, male developmental delay, breast development, pancreatic damage with pancreatic insufficiency and diabetes, nail arch blue, The amount of copper added increases.
The natural course of the disease is divided into four phases: Phase I: Copper is accumulated in the cytoplasm of the liver until it reaches saturation, clinically asymptomatic; Phase II: Copper is transferred from the cytoplasm to the lysosome, and partially released into the blood. The redistribution of copper in most (60%) patients is gradual, and the clinical manifestations are not obvious. However, such a process progresses rapidly, a sudden increase in blood copper can cause hemolysis, and rapid redistribution in the liver can cause liver necrosis or chronic activity. Hepatic failure may occur in hepatitis III; stage III: copper accumulation in extrahepatic tissue, cirrhosis, nerve, corneal and renal damage, clinical manifestations, hemolysis, death from liver failure, or remission Asymptomatic; this period of performance is diverse, such as slow progression of cirrhosis, chronic copper storage, patients can be asymptomatic for many years, but the progress is fast clinically dangerous; Stage IV: the remission period after long-term treatment of complexes.
Examine
Hepatolenticular degeneration check
Laboratory inspection
1. Determination of serum CP and serum copper oxidase activity is an important diagnostic basis for this disease
1 serum ceruloplasmin determination: WD patients with serum CP <0.2g / L (normal value of 0.26 ~ 0.36g / L), or even zero, serum CP value and disease, duration of disease and copper drive efficacy, can not be used as disease monitoring or efficacy Observed indicators; neonatal serum CP value is only 1/5 of normal people, then rapidly increased, reaching adult level in 2 to 3 months; serum CP correction formula for children before 12 years old: CP value after correction = serum CP measurement value × [(12-age) × 1.7]; attention should be paid to the reduction of serum CP also seen in nephrotic syndrome, chronic active hepatitis, primary biliary cirrhosis, some malabsorption syndrome, protein-calorie deficiency malnutrition;
2WD patients with serum CP oxidase activity <0.2 density (normal value 0.2 ~ 0.532 optical density).
2. Trace copper determination
1 serum copper determination: normal humans 14.7 ~ 20.5mmol / L, 90% of WD patients with serum copper decreased, serum copper has nothing to do with the condition and efficacy, primary biliary cirrhosis, chronic active hepatitis, nephrotic syndrome and severe nutrition Serum copper in patients with dysplasia can also be reduced;
2 Determination of urinary copper: Most WD patients have a significant increase in urinary copper in 24 hours. After taking copper-discharging drugs, urinary copper is further increased. After the large amount of copper accumulated in the body, the amount of urinary copper is gradually reduced. The amount of urinary copper can be used as a clinical adjustment for copper-receiving dose. Index; WD patients usually have urinary copper >200g/24h (normal <50g/24h), up to 1200g/24h, a few patients are normal or slightly higher; penicillamine load test: normal and untreated after oral penicillamine The patient's urinary copper increased significantly, but the patient was more significant; chronic active hepatitis, primary cirrhosis and other urinary copper levels also increased;
3 Determination of liver copper: it is a diagnostic WD gold standard, because it is difficult to generally accept liver puncture, can not be used as a routine examination, biochemical examination can not be confirmed in the case of determination of liver copper is necessary, normal liver copper content 50g / g dry weight, WD patients Mostly 250g/g dry weight, liver copper content in heterozygous and liver disease patients can be increased, but not more than 250g / g dry weight, puncture liver tissue just newborn cirrhosis nodules can appear false negative;
4 Determination of copper content in fibroblasts from in vitro cultured skin: As reported by Chan et al. (1980), Chen et al. (1994) established a stable in vitro cultured skin fibroblast model for WD patients, heterozygous and normal human skin. Fibroblasts were subcultured in vitro. The cytoplasmic copper/protein ratio of WD patients after incubated with high concentration of copper was much higher than that of heterozygous group and normal control group. There was no overlap between them, and atypical cases could be diagnosed.
5 Determination of radioactive copper: Oral or intravenous injection of 64Cu or 67Cu, tracer observed with ceruloplasmin dynamics, healthy human radioactive copper into the blood and plasma protein binding, the first peak blood concentration, radioactive copper into the liver and In combination with hepatic copper protein (including Apo-CP), the plasma radioactive copper concentration decreased, and the copper-containing copper protein released into the blood showed a second peak blood concentration; the patient may have four abnormalities: the liver ingested copper barrier to make the first The peak of secondary radioactive copper concentration is prolonged; the secondary concentration peak of radioactive copper and CP binding barrier does not occur; the biliary copper exclusion disorder reduces the radioactive copper excretion in the feces and increases the excretion in the urine; the radioactive copper is prolonged in the body.
3. Liver and kidney function tests Some patients with WD may have no abnormal liver function in the early stage. Liver damage may have different degrees of liver function abnormalities such as decreased serum total protein, increased -globulin, etc.; renal dysfunction may lead to increased serum urea nitrogen and creatinine , urine protein, etc.
Film degree exam
1. X-ray examination of bone and joints: About 96% of patients have abnormal X-ray of the bones and joints. The double wrists are most often damaged, showing osteoporosis, osteoarthritis, osteomalacia, calcification around the joints or joints, spontaneous fractures and vertebral cartilage. Inflammation and so on.
2. The imaging abnormality rate of neuroimaging is about 85%. CT shows that the bilateral lenticular symmetry low-density area has diagnostic value. The common lateral ventricle and the third ventricle are slightly enlarged, and the brain and cerebellar sulcus are widened. Atrophy, red nucleus and dentate nucleus low density, no change in imaging after treatment, MRI showed bilateral lenticular symmetry involvement, T2W showed concentric lamellar enhancement, substantia nigra dense band, gray matter around the cerebral aqueduct and cerebral High signal, the thalamus is less affected.
3. EEG examination showed that about 50% of WD patients had abnormalities, EEG changes were more consistent with the severity of the lesions, and EEG was improved after treatment with penicillamine and dimercaptopropanol.
4. Evoked potential examination can confirm the subclinical damage of the sensory system of the disease, the abnormal rate of brainstem auditory evoked potential (BAEP) is the highest, the latency and peak interval of each wave are prolonged; the visual evoked potential (VEP) is N1, N2, P1 wave PL Prolonged; somatosensory evoked potential (SEP) also changed.
5. Positron emission tomography (PET) WD patients can show a decrease in brain local glucose metabolism rate (rCMRG), lenticular nucleus, and rCMRG changes earlier than CT, which is valuable for early diagnosis of WD.
6. Gene diagnosis WD patients and family members routine biochemical tests found that in patients, heterozygous and normal people between 10% ~ 25% overlap data, affecting the detection specificity, genetic diagnosis for pre-symptomatic diagnosis and heterozygous detection is superior Sex,
1 restriction fragment length polymorphism (RFLP) linkage analysis: Figus et al (1989) first applied RFLP to genetic testing of 17 families without disease, and domestic and foreign scholars used this method to conduct linkage analysis on many WD families. Many patients with symptoms and phenotypes of normal heterozygotes or carriers of pathological genes;
2 Microsatellite marker analysis: In 1993, the cDNA fragment of WD was cloned abroad, and several microsatellite markers near the WD gene were obtained. Thomas used several new microsatellite DNAs to analyze the family of WD patients, suggesting that haplotypes contribute to WD. Family identification and other member diagnosis;
3 Semi-nested PCR-enzyme digestion analysis: direct detection of mutations in the exon 14 His1069GLn gene of WD patients;
4MspI digestion: Ma Shaochun et al (1998) found that Chinese WD patients in the No. 8 exon 778 codon mutation accounted for 28.8%, is a high frequency mutation site in Chinese WD patients;
5 Fluorescence PCR method: Huang Fan et al (1999) used fluorescence PCR technology to diagnose 5 homozygous Arg778Leu mutations and 21 heterozygotes in 66 WD families. The total detection rate was 39.4%. Sensitive to the cut.
Diagnosis
Diagnosis and identification of Wilson's disease
diagnosis
1. Patients with HLD who are highly suspected of having the following conditions must have a slit lamp to check for corneal KF ring and copper metabolism test.
(1) Compatriots of patients with HLD have been confirmed.
(2) Among the siblings, those who died of acute severe hepatitis (fullinant hepatitis) or other liver diseases (especially viral antigen antibody negative for viral hepatitis).
(3) Children or adolescents with unexplained cirrhosis of the liver, transient jaundice, salivation, tremors, dance-like movements or mental disorders, need to pay attention to the identification of HLD, if necessary, further slit lamp and copper metabolism check.
2. Diagnostic criteria
(1) Family genetic history, parents are close relatives, and their compatriots have HLD patients or die from unexplained liver diseases.
(2) Extra-pyramidal 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 <200 mg/L.
(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, with only the above items (3) to (5) or (3) to ( 4) Those who are asymptomatic HLD, only those in (1), (2) or (1), (3), should be suspected of HLD.
Differential diagnosis
The clinical manifestations of this disease are complex, the patient has no neurological manifestations, clinical misdiagnosis is quite common when various systemic symptoms appear, and the identification should be considered from both the liver and the nervous system.
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, serum ceruloplasmin reduction, etc.
3. Must also be differentiated from acute or chronic hepatitis, cirrhosis, small chorea, Huntington's chorea, torsion, senile dementia, psychosis, liver and kidney syndrome.
