What are the implications of abnormal Alpha 1 and Alpha 2 (alpha one and alpha two) globulin levels in the blood?

Alpha One and Alpha Two Globulins: Clinical Implications of Abnormal Levels

Abnormal alpha-1 and alpha-2 globulin levels in the blood are important indicators of various pathological conditions, with alpha-1 antitrypsin deficiency being the most clinically significant alpha-1 globulin disorder, and acute phase reactions being the most common cause of elevated alpha-2 globulins. 1

Alpha-1 Globulins

Alpha-1 Antitrypsin (AAT)

• Alpha-1 antitrypsin is the major antiprotease in plasma that functions primarily to inhibit neutrophil elastase 1
• AAT deficiency occurs due to inheritance of two protease inhibitor (Pi) deficiency alleles in the SERPINA1 gene, with Pi*ZZ being the most common severe deficiency phenotype 1
• Normal plasma concentration of AAT is relatively high, and significant reduction leads to clinical manifestations 1

Clinical Implications of Alpha-1 Antitrypsin Deficiency

• Pulmonary manifestations:

  • Predisposes to chronic obstructive pulmonary disease (COPD), particularly basilar, pan-lobular emphysema 1
  • Early onset emphysema is a hallmark of severe AAT deficiency 1
  • Patients with moderate to severe lung function impairment may benefit from augmentation therapy 1

• Hepatic manifestations:

  • Liver disease results from accumulation of mutant AAT Z protein within the endoplasmic reticulum of hepatocytes 1
  • Can manifest as neonatal hepatitis, cirrhosis in children and adults, and hepatocellular carcinoma 1
  • The "accumulation theory" is the most widely accepted explanation for liver injury in AAT deficiency 1

• Other manifestations:

  • Associated with panniculitis, vasculitis, and possibly psoriasis 1
  • Some studies have linked AAT deficiency with chronic urticaria and acquired idiopathic angioedema 1

Alpha-1 Microglobulin

• Abnormal levels may be seen in various conditions but are less specific than AAT 2
• Unlike beta-2 microglobulin, alpha-1 microglobulin is rarely elevated in neoplastic diseases (only 16.4% of cases) 2
• Levels may be decreased in liver cirrhosis while beta-2 microglobulin levels are elevated in the same condition 2

Alpha-2 Globulins

Major Components

• Alpha-2 macroglobulin (α2M): A large glycoprotein that inhibits a broad spectrum of proteases 3
• Alpha-2 antiplasmin (α2AP): A serine protease inhibitor that circulates at 0.7–1 μM concentration 1
• Haptoglobin and ceruloplasmin: Important acute phase reactants 4

Clinical Implications of Abnormal Alpha-2 Globulin Levels

Elevated Alpha-2 Globulins

• Acute phase reactions:

  • Infections, inflammation, tissue damage, and malignancies can cause elevated alpha-2 globulins 5
  • Alpha-2 globulins are significantly increased in cancer patients compared to healthy individuals (13.5±4.8% vs. 11.3±2.1%) 5

• Malignancies:

  • Significantly raised in Hodgkin's disease 4
  • Serum haptoglobin (an alpha-2 component) is increased in Hodgkin's disease, acute leukemia, lymphosarcoma, and reticulum cell sarcoma 4
  • Ceruloplasmin (another alpha-2 component) is raised in all reticuloses 4
  • Alpha-2 globulin levels, along with alpha-1 globulin levels, have diagnostic value for discriminating between cancer patients and healthy individuals 5

• Nephrotic syndrome:

  • Alpha-2 macroglobulin levels may be elevated due to its large molecular size preventing urinary loss 3

Decreased Alpha-2 Globulins

• Liver disease:

  • Decreased synthesis of alpha-2 macroglobulin and other alpha-2 components 3

• Protein-losing enteropathy:

  • Loss of proteins including alpha-2 globulins through the gastrointestinal tract 3

• Malnutrition:

  • Decreased synthesis of plasma proteins including alpha-2 globulins 5

Alpha-2 Antiplasmin (α2AP) in Hemostasis

• Inhibits plasmin in a two-stage process involving binding between lysine residues and subsequent conformational change 1
• Forms a stable plasmin-α2-antiplasmin (PAP) complex with a circulating half-life of 0.5 days 1
• Protects fibrin from premature lysis by becoming crosslinked to fibrinogen and fibrin by activated factor XIII 1
• Deficiency can lead to a hemorrhagic tendency 1

Diagnostic Considerations

• Serum protein electrophoresis is the primary method to detect abnormalities in alpha-1 and alpha-2 globulin fractions 5
• Specific assays for individual components (e.g., AAT, alpha-2 macroglobulin) provide more detailed information 1, 3
• The albumin/globulin ratio is typically decreased in patients with elevated alpha globulins (0.92±0.30 in cancer patients vs. 1.21±0.16 in healthy controls) 5
• Genetic testing for AAT deficiency should be considered in patients with early-onset emphysema, unexplained liver disease, or family history of AAT deficiency 1

Clinical Approach to Abnormal Alpha Globulin Levels

• For decreased alpha-1 globulins, consider AAT deficiency and perform specific testing for AAT levels and phenotype 1
• For elevated alpha-1 and alpha-2 globulins, evaluate for acute phase reactions, malignancies, and inflammatory conditions 4, 5
• Consider the pattern of abnormalities in conjunction with clinical presentation to guide further diagnostic workup 5