Alpha1 antitrypsin deficiency liver disease

Introduction to 1 antitrypsin deficiency liver disease Alpha1 anti-trypsindeficiency-associated liver disease (alpha1anti-trypsindeficiency-associatedliverdisease) is a metabolic liver disease caused by hereditary 1 antitrypsin deficiency, and is expressed as an autosomal recessive inheritance (codominant expression). basic knowledge The proportion of illness: 0.005% Susceptible people: good for adult men and women Mode of infection: non-infectious Complications: upper gastrointestinal bleeding cirrhosis

The cause of 1 anti-trypsin deficiency liver disease

(1) Causes of the disease

1-antitrypsin (1-AT)-deficient liver disease is a congenital metabolic disease caused by the lack of 1-antitrypsin, a component of the antagonistic protease in serum.

(two) pathogenesis

Serum proteases produced in whole body cells can cause inflammatory chain reaction and complement activation in target organs. There are also a group of substances that inhibit protease activity in normal humans, called proteinase inhibitors, which are widely distributed in plasma and lymphocytes. Liquid, urine, saliva, tears, bronchial secretions, cerebrospinal fluid, cervical mucus, semen, colostrum and other cytoplasm of tissue cells, protease inhibitors participate in a variety of physiological and pathological processes, 1 antitrypsin (1 -AT) is a major protease inhibitor in serum. It is a glycoprotein synthesized by hepatocytes with a molecular weight of 50,000 to 60,000. It is in the position of 1 during electrophoresis separation. After being released into plasma, it constitutes the main component of 1-globulin. , accounting for about 90% of 1-globulin, 4% of all serum proteins. 1-AT is an acute phase reaction protease inhibitor that inhibits a variety of endogenous and exogenous proteases, such as trypsin. Chymotrypsin, elastase, thrombin, plasmin, kallikrein, and certain bacterial and viral products with protease properties, etc. Su, remove toxins, control of infection, inflammation, and other functions to prevent self-digestion, the inflammatory reaction, stress, trauma, pregnancy, or a tumor may also stimulate the release of 1-AT, the serum level of this enzyme can be increased.

1-AT forms a 1:1 strong complex with elastase, which is later decomposed in the blood circulation. This complex binds to the serum protease receptor of hepatocytes, thereby stimulating hepatocytes to produce 1-AT. In the case, 1-AT can control the activity of more than 90% of serum elastase, and sialic acid (N-acetylneuraminic acid) on the 1-AT molecule is very important for its biological activity, and the residue of sialic acid 1-AT is eliminated. That is, it loses its activity and is quickly cleared from the blood circulation. The 1-AT that does not contain sialic acid residues cannot be released into the blood after hepatocyte synthesis, and accumulates in liver cells, which can cause liver cell damage.

The family research report on 1-AT deficiency has shown that the 1-AT allele (alleles) expresses the protease inhibitor gene (Pi gene), and Fagerhol et al believe that the so-called Pi gene that controls 1-AT synthesis is located. Alleles on autosomes were analyzed by thin-layer gel focusing technique for human 1-AT electrophoretic mobility. It was found to be polymorphic in the population, and more than 75 1-AT variants have been identified, but large Most of them are not clinically significant or very rare, and are named B, C, D, E, F, G, L, M, N, P, S, V, W, X, Z, etc., and alleles are respectively PiM. PiS, PiZ, etc. indicate that the homozygous genotype is represented by PiMM, PiSS, etc., and the heterozygotes are represented by PiMZ, PiSZ, etc., which are collectively referred to as the Pi gene system, and the gene encoding 1-AT is located on the long arm of chromosome 14 (14q24. 3-32.1), the various phenotypes of the Pi gene system, the serum protease inhibitory activity is different from the concentration of 1-AT, PiM is a gene with normal function, and most normal people are homozygous for PiM (PiMM) , the serum 1-AT content is normal, the function is also normal, with the homozygous PiZ gene (PiZZ) The serum 1-AT content in the individual is seriously deficient, only about 15% of normal people. This type of person often has obstructive pulmonary disease and juvenile cirrhosis, and there is a moderate lack of 1-AT content in homozygous PiSS serum. About 60% of normal people, this person also has a tendency to emphysema and cirrhosis, heterozygous PiMZ, PiSZ and other individuals also have a tendency to emphysema and cirrhosis, Jeppson et al. Peptid mapping It was found that a glutamic acid in the peptide chain of the Pi3- variant protein of 1-AT deficiency was replaced by lysine, one glutamic acid was replaced by glutamine, and the PiSS variant glutamic acid was replaced by valine.

1-AT is produced in the rough endoplasmic reticulum of hepatocytes and transported to the Golgi for secretion. There is a hypothesis that the protein misfolding conformation associated with allelic mutations may cause 1-AT to remain in The endoplasmic reticulum cannot be released into the Golgi device. Because of this misfolding change, the normal concealed area may be exposed and contact with different ligand receptors, but not as an effective molecular release. The abnormal 1-AT is retained in The endoplasmic reticulum causes accumulation, excretion is reduced, and its degradation rate in cells depends on gene regulation. The pathophysiology of hepatocyte damage caused by 1-AT deficiency is still controversial. It is believed that liver damage is secondary to 1-AT in the liver. Accumulation of the rough endoplasmic reticulum of cells may change the degradation of abnormal 1-AT in hepatocytes, and the perioric acid Schiff test in homozygous and heterozygous hepatic endoplasmic reticulum of patients with 1-AT deficiency (Periodic acid schiff, PAS) positive amylase-resistant granules support this hypothesis.

There are 3 outcomes for 1-AT deficiency: some people may be healthy for life; most people have severe emphysema in young and middle-aged patients; some people have liver disease in infancy, but few have lungs at the same time. People with emphysema and cirrhosis, it is not clear why some people have severe liver disease, while others are asymptomatic. They think that liver damage is caused by many factors, such as elastase can break down elastic fibers and cause emphysema. Lesions, but under normal circumstances, elastase inhibitors can inhibit the activity of this enzyme, avoid emphysema, the study found that PiZ is more prone to chronic obstructive pulmonary disease (COPD), congenital 1-AT deficiency with genetic susceptibility, It needs to be combined with the acquired external factors to produce pathogenic effects. Smoking is more dangerous. For example, smokers have increased lung macrophages and large lysosomes. NO2 produced by tobacco combustion can stimulate macrophages in the lungs. And neutrophils release elastase, and 1-AT deficiency is prone to lung tissue damage due to weakened ability to inhibit protease, causing chronic obstructive pulmonary disease, 1-AT deficiency occurs in the liver It is not related to lung diseases. 1-AT deficiency is the main factor of 1-AT deficiency liver disease. There are other factors involved, and the activity of protease in the body is increased, which is the susceptibility of the liver to other pathogenic factors and toxic substances. Caused by liver damage, Gam suggested that the intestinal barrier may be absorbed into the liver due to destruction or defects of the intestinal barrier, and the lysosomal enzyme is released by the uptake of the liver Kupffer cells, which is destructive when the human body lacks 1-AT; Or because of the retention of 1-AT in the liver cells, after the enterotoxin enters the liver, the proteolytic enzyme with protective effect in the liver cells is inhibited by excessive 1-AT to damage the liver cells; or due to 1-AT in the liver cells. It inhibits the production of endogenous proteases in the liver, so that it can not fight intestinal toxic substances, causing liver damage.

Histopathological changes vary with the age of the patient. Liver specimens of the affected infant show bile duct paucity, intrahepatic cholestasis with or without inflammatory enlargement, mild inflammatory changes or Fatty changes, some characteristic PAS-positive diastase resistant globules can be seen in the liver cells. This small body can be strongly stained with fluorescein-labeled 1-AT antiserum and has 1-AT antigenicity ( Figure 1), this granular inclusion is located on the endoplasmic reticulum of hepatocytes and increases with age, indicating that the lack of 1-AT in patients is due to the accumulation of 1-AT that cannot be released into the liver and accumulate in the liver cells. Patients with homozygous PiZZ phenotype are more likely to have progressive liver damage in infants with 1-AT deficiency. If there is no improvement, progressive liver damage can occur, and fibrous tissue in the portal vein area proliferates, gradually forming interlobular fibrosis, which can be further summarized. Sterile or large nodular cirrhosis, homozygous 1-AT deficiency can cause primary liver cancer.

1 anti-trypsin deficiency liver disease prevention

1. Non-smoking 1-antitrypsin deficiency should be absolutely banned, smoking can aggravate 1-antitrypsin deficiency emphysema.

2. Prevention and treatment of complications For those with only mild liver damage, long-term supportive treatment is needed; for patients with portal hypertension, it is feasible for portal or spleno-renal shunt.

3. Liver transplantation should be performed for liver transplantation. Since liver is the only place to synthesize 1-antitrypsin, liver transplantation can not only cure liver disease, but also correct 1-antitrypsin deficiency. It is considered that liver transplantation is An effective method for the treatment of end-stage cirrhosis of the chest, the donor liver of the PiMM phenotype for liver transplantation is expected to improve the survival rate and improve the condition.

11 antitrypsin deficiency liver disease complications Complications upper gastrointestinal bleeding cirrhosis

Hepatosplenomegaly, upper gastrointestinal bleeding caused by esophageal varices, neonatal liver cholestatic, if there is no improvement, it can gradually develop progressive liver damage, progress to cirrhosis or even death.

1 anti-trypsin deficiency liver disease symptoms common symptoms bleeding tendency bloating liver splenomegaly jaundice upper gastrointestinal bleeding liver failure varicose veins

1-AT deficiency liver disease can be found for the first time in infants and young children, and there is no liver lesions in this period. Chronic liver disease manifests after adulthood, and 8% to 12% of newborns with PiZZ-type 1 antitrypsin deficiency Cholestatic jaundice occurs within 1 month after birth, serum bilirubin can be as high as 340 mol/L, serum alkaline phosphatase (ALP) activity can reach 150-1300 U/L, and the child's weight gain is slow, lethargy, easy Irritated, there is no bile stool, half of the children of 3 months old age have high transaminase, serum aspartate aminotransferase (AST) activity can reach 80 ~ 600U / L, 12% ~ 15% of alpha 1 antitrypsin deficiency children appear Liver cirrhosis, manifested as abdominal distension, hepatosplenomegaly, upper gastrointestinal bleeding caused by esophageal varices, but also may have bleeding tendency in other parts such as purpura. Most patients have neonatal liver cholestatic for about 7 months to 1 year. Can be subsided, if there is no improvement, it can gradually develop progressive liver damage, progress to cirrhosis or even death, cirrhosis can also occur in adulthood, but there are few cirrhosis in middle-aged and elderly, adulthood The incidence is more common in heterozygous Patients with subtype 1-AT deficiency liver disease have slower development and different clinical manifestations. It is reported that the risk of liver failure in patients with heterozygous 1-AT deficiency liver disease is significantly increased. 120 PiZZ newborns reported by Sreger There are 14 long-term obstructive jaundice in the children, neonatal hepatitis and cirrhosis in childhood, emphysema in adulthood, adult 1 antitrypsin deficiency cirrhosis can be asymptomatic, clinical manifestations of cirrhosis may occur, Liver cancer, more common in patients over 50 years of homozygous patients.

For patients with non-infectious chronic hepatitis, patients with unexplained hepatosplenomegaly, cirrhosis and portal hypertension should be considered for the possibility of 1-AT deficiency liver disease. It should also be noted that a small number of liver cancers are caused by 1-AT deficiency.

Serum protein electrophoresis shows that 1 globulin deficiency often indicates the disease. Direct determination of 1 antitrypsin can confirm the diagnosis, but the genetic phenotype analysis should be emphasized. Because the production of 1-AT is affected by these factors, the diagnosis should be based on phenotypic analysis. Not only based on 1-AT level detection.

Liver cell biopsy.

Examination of 1 antitrypsin deficiency liver disease

1. Determination of serum 1-antitrypsin concentration (normal value 2000 ~ 3000mg / L): 10% ~ 15% less than normal, may be helpful for diagnosis, but can not be diagnosed, because in acute inflammation, serum 1-anti-pancreas The protease concentration may increase.

2.pi phenotypic analysis The identification of 1-antitrypsin phenotype can be established by isoelectric focusing or agar electrophoresis under acidic conditions. Currently, PCR technology has been used to detect 1-antitrypsin variants, which is not only rapid but sensitive. It is highly sexual and requires very little cellular material. This technique is useful for confirming diagnosis, population screening, and prenatal diagnosis.

Liver biopsy showed liver cirrhosis. PAS staining showed characteristic inclusion bodies in liver cells. Fluorescence staining showed that blue particles, ie 1-antitrypsin antibody fluorescent bands, were accumulated in the liver cells.

Diagnosis and differential diagnosis of 1 antitrypsin deficiency liver disease

1. The identification of cholestatic drug-induced liver damage and extrahepatic obstructive jaundice depends on detailed medical history, various allergic manifestations and B-ultrasound, CT, MRI, retrograde cholangiopancreatography and other examinations.

2. Liver cirrhosis has chronic hepatitis, schistosomiasis infection, long-term alcohol abuse and other medical history, liver function, B-ultrasound, CT, liver biopsy and other helpful identification.

The material in this site is intended to be of general informational use and is not intended to constitute medical advice, probable diagnosis, or recommended treatments.