bubble_chart Overview

Alpha₁-antitrypsin deficiency is a congenital metabolic disorder caused by a deficiency of the antiprotease component—alpha₁-antitrypsin (abbreviated as alpha₁-AT) in the blood, inherited through an autosomal recessive pattern. The clinical features include neonatal hepatitis, cirrhosis in infants and adults, liver cancer, and lung qi tumors.

bubble_chart Pathogenesis

During protein electrophoresis, α₁-AT is located within the α₁ globulin leucorrhea. α₁-AT is a glycoprotein synthesized by the liver, with a half-life of approximately 4 to 5 days. In serum, there are substances that inhibit trypsin activity, among which α₁-AT accounts for 90% of this effect. In addition to inhibiting trypsin activity, α₁-AT can also inhibit chymotrypsin, coagulation factor XII cofactor, and the action of neutrophil neutral proteases. α₁-AT is present in tears, duodenal fluid, saliva, nasal secretions, cerebrospinal fluid, pulmonary secretions, and breast milk. The concentration of α₁-AT in amniotic fluid is equivalent to 10% of that in serum. Inflammatory stimulation, tumors, pregnancy, or estrogen therapy can increase serum α₁-AT levels by 2 to 3 times, but these stimuli are almost ineffective in patients with α₁-AT deficiency.

Normally, both exogenous and endogenous proteases exist in the human body, such as bacterial toxins and proteases released from leukocyte disintegration, which can damage the liver and other organs. α₁-AT can antagonize these enzymes to maintain the integrity of tissue cells. When α₁-AT is deficient, these enzymes can erode liver cells, especially in newborns whose intestinal digestion and absorption functions are not fully developed, allowing more macromolecular substances to enter the bloodstream. The livers of infants with α₁

-AT deficiency are more susceptible to damage. Additionally, α₁-AT also plays roles in regulating immune responses, influencing the clearance of antigen-antibody immune complexes, complement activation, and inflammatory reactions, and can inhibit platelet aggregation and fibrinolysis. When α₁-AT is deficient, the mechanisms maintaining these bodily balances are disrupted, leading to tissue injury.

bubble_chart Pathological Changes

The pathological features of the liver are characterized by round or oval deposits within hepatocytes around the lobules, with diameters ranging from 1 to 40 μm. These spherical deposits increase in size with age and become more visible as the infant matures. On HE staining, they appear eosinophilic in the hepatocyte cytoplasm and are most clearly distinguishable with PAS staining after amylase treatment.

Immunofluorescence and immunocytology reveal that the deposited inclusions are α₁-AT, which can also be observed in homozygotes. The density and extent of these inclusions do not seem to have a definitive correlation with the presence or absence of liver disease manifestations, but the absence of these deposits means no liver disease occurs, suggesting that these inclusions may play a role in the

mechanism of disease. Under electron microscopy, dilated rough endoplasmic reticulum in hepatocytes contains characteristic, variably shaped deposits, while the Golgi apparatus does not. The amount of deposits varies greatly among individuals and can also be seen in bile duct cells. Additionally, hepatocytes may show glycogen accumulation, vacuoles, lipofuscin, and

gall fel stasis. In newborns with the Pizz phenotype, if accompanied by ₁

-AT deficiency and gall fel stasis-induced jaundice, the liver exhibits the following three pathological manifestations:

1. Hepatocyte

injury, characterized by swelling of eyelid enlargement of hepatocytes, relatively mild inflammatory cell infiltration (mostly mononuclear), with or without liver fibrosis, possibly accompanied by cholestasis but without bile thrombi in the portal area.

2. Portal fibrosis and bile duct proliferation

, featuring extensive portal fibrosis, even resembling cirrhosis, with significant bile duct proliferation. Jaundice resolves before 6 months, but the liver and spleen progressively enlarge and harden. Two cases later developed portal hypertension, although the extrahepatic bile ducts were normal in these patients.

3. Small bile duct dysplasia

, with normal liver structure, mild hepatocyte injury, only slight portal fibrosis, but a significant reduction in bile duct numbers. Gall fel stasis is scattered within the liver lobules, and the clinical course involves progressive jaundice accompanied by cutaneous pruritus and hypercholesterolemia.

bubble_chart Clinical Manifestations

In the first week after birth, there may be gall fel stasis jaundice, acholic stool, and dark urine. Physical examination may reveal hepatomegaly. Generation and transformation indicators show signs of obstructive jaundice, which usually disappears by 2 to 4 months, but cirrhosis may develop after 2 years of age.

In adults, most α₁-AT deficiency patients present with prominent portal hypertension as the initial symptom. Patients often die from upper consumptive thirst gastrointestinal bleeding and/or hepatic unconsciousness, frequently accompanied by lung qi swelling. The incidence of cirrhosis and liver cancer is higher in males than in females.

In cirrhosis patients caused by α₁-AT deficiency, the incidence of liver tumors is very high, with most originating from hepatocytes and some from bile ducts.

bubble_chart Treatment Measures

There is currently no specific treatment, so the best approach is to prevent the occurrence of α₁-AT deficiency. If both parents are PiZz heterozygotes, their offspring have a 25% chance of exhibiting the PiZz phenotype. Directly sampling umbilical bleeding from the fetus at 15–17 weeks of gestation for PiZz phenotype analysis has definite value in terminating pregnancy for fetuses at risk of developing the condition. For patients with α₁-AT deficiency, the more promising treatment methods include: ① liver transplantation; ② using genetic engineering techniques to implant the Z gene into patients to enable them to produce α₁-AT; ③ gene recombination.