How Alpha 1 Antitrypsin Deficiency Leads to Liver Disease

A1AT Deficiency Liver Disease: Early Signs and When to Get Tested

Alpha-1 antitrypsin (A1AT) deficiency leads to the accumulation of abnormal A1AT protein within liver cells (hepatocytes). This buildup can result in liver inflammation and scarring (cirrhosis) and may increase the risk of liver cancer. The condition is caused by a mutation in the A1AT gene, which produces a misfolded protein that becomes trapped in the liver.

What is Alpha-1 Antitrypsin Deficiency?

Alpha-1 antitrypsin (AAT) deficiency is a genetic disorder in which your body does not produce enough AAT. AAT protects your lungs and liver from damage caused by the enzyme neutrophil elastase.

A1AT deficiency occurs due to mutations in the genes, leading to the development of lung diseases, like chronic obstructive pulmonary disease (COPD), emphysema, and liver cirrhosis. Lower levels of A1AT make the lungs more vulnerable to damage from smoke and pollutants.

What are the liver diseases that occur due to A1AT deficiency?

Alpha-1 antitrypsin deficiency can lead to a range of liver diseases, which we will discuss in detail in the following section. These include:

• Neonatal Hepatitis: A mutation in the A1AT gene alters the normal production and function of A1AT protein in the liver. Deficient protein accumulates, failing to protect the liver from damage, which eventually triggers a series of events that may lead to inflammation, cell damage, and liver dysfunction. These types of inflammatory conditions of the liver that affect newborns typically appear between one and two months of age.
• Chronic Hepatitis: A1AT deficiency promotes the accumulation of abnormal protein within the hepatocytes (liver cells). Constant retention of misfolded protein within the lumen of the hepatocyte’s endoplasmic reticulum initiates the pathogenesis of liver disease. Chronic inflammation can also activate hepatic stellate cells, which produce collagen and lead to fibrosis of the liver cells.
• Cirrhosis: Mutations in the SERPINA1 gene, which codes for AAT, lead to the production of a dysfunctional AAT protein. The ZZ genotype is the most strongly associated with severe deficiency and significant risk for both liver and lung disease. Other combinations, like SZ, can also lead to clinical manifestations.
• Hepatocellular Carcinoma: In A1AT deficiency, your liver produces a mutant version of the A1AT protein, known as the Z protein, which gets released into the bloodstream. Due to intracellular accumulation within the ER of hepatocytes, it forms larger protein globules, causing a disruption in the normal functioning of liver cells. Chronic cirrhosis increases the risk of developing hepatocellular carcinoma.
• End-Stage Liver Disease (ESLD): Excess accumulation of A1AT protein in the liver cells can eventually disrupt the normal functioning of the entire liver. The presence of Z-fold protein within your bloodstream triggers proteotoxic stress, causing damage to hepatocytes. Buildup of scar tissue can progress to abnormal liver function, eventually leading to critical end-stage liver disease.

What are the symptoms of A1AT liver disease?

Alpha-1 antitrypsin deficiency can lead to liver diseases, exhibiting several symptoms. The following list includes some common symptoms of A1AT liver disease:
 

• Jaundice: Yellowing of the skin and a whitish appearance of the eyes are common symptoms of A1AT deficiency liver disease.
• Swelling: Oedema or swelling in the legs and ascites (swelling of your abdomen) is common in liver diseases due to A1AT deficiency.
• Itchy Skin: Pruritus, or constant itching across the whole body, is a common symptom for individuals suffering from A1AT deficiency liver disease.
• Abdominal Pain: Individuals suffering from liver diseases due to deficiencies in A1AT protein experience pain or discomfort in their abdominal region.
• Dark Urine: It occurs due to elevated levels of bilirubin, excreted by your kidneys. Due to damage in the A1AT protein, the liver could not manage bilirubin levels and release them into the bloodstream.
• Fatigue: Individuals frequently experience constant fatigue or tiredness due to toxin buildup and disruption in energy management in hepatocytes.
• Bleeding: Frequent bleeding when brushing teeth or nosebleeds occurs because your liver cannot properly aid in the blood clotting mechanism.
   

How to Diagnose A1AT Liver Disease?

Doctors diagnose A1AT liver disease through a combination of blood tests, genetic testing, and liver biopsy. These include:

• Blood Tests: A proper blood test measures the amount of AAT in your blood. Lower levels may indicate AAT deficiency, but this test is not conclusive.
• Genetic Testing: Common genotype and phenotype tests can confirm and identify specific mutations in the SERPINA1 gene, responsible for AAT deficiency.
• Chest X-ray: A chest X-ray can assess lung damage and help doctors rule out other conditions.
• Liver Biopsy: In certain cases, doctors may recommend a liver biopsy to assess any liver damage.
   

Early diagnosis and management of A1AT deficiency are crucial to prevent or delay the development of severe complications. Individuals with AAT deficiency must receive genetic counselling to understand their inheritance patterns and potential risks for family members.