Does Alpha 1 antitrypsin (A1AT) deficiency cause bone marrow failure?

Alpha-1 Antitrypsin Deficiency Does Not Cause Bone Marrow Failure

Alpha-1 antitrypsin (A1AT) deficiency is not associated with bone marrow failure. Based on the available evidence, there is no established connection between A1AT deficiency and bone marrow dysfunction 1.

Clinical Manifestations of Alpha-1 Antitrypsin Deficiency

Alpha-1 antitrypsin deficiency primarily affects two major organ systems:

1. Respiratory System:

   • Premature emphysema and COPD, particularly basilar, pan-lobular emphysema 1
   • Adult-onset asthma with persistent airflow obstruction
   • Unexplained bronchiectasis

2. Hepatic System:

   • Chronic liver disease
   • Liver cirrhosis
   • Hepatocellular carcinoma
   • PAS-D positive inclusions in hepatocytes due to protein polymerization 1

Other Documented Associations

While A1AT deficiency has been linked to several other conditions, bone marrow failure is not among them. The guidelines document several other potential associations:

• Vascular Manifestations: Some studies have investigated potential links between A1AT deficiency and:

  • Abdominal aortic aneurysms (evidence is weak) 1
  • Intracranial aneurysms (results are equivocal) 1
  • Arterial dissections (based on limited case reports) 1

• Nephropathy:

  • ANCA-positive vasculitic complications in adults 1
  • Glomerular changes in children with A1AT-associated liver disease 1

Experimental Therapeutic Connections to Bone Marrow

While A1AT deficiency doesn't cause bone marrow failure, there are interesting therapeutic connections:

• Bone marrow stem cell therapy has been investigated as a potential treatment for A1AT deficiency-related liver disease 2
• Transplantation of bone marrow-derived stem cells in mice with human A1AT-Z mutation showed improvement in liver pathology 2

Hematologic Applications of Alpha-1 Antitrypsin

Alpha-1 antitrypsin has been studied as a treatment for certain hematologic conditions:

• A1AT has shown efficacy as a treatment option for steroid-refractory acute graft versus host disease (SR-aGVHD) following allogeneic hematopoietic stem cell transplantation, with response rates up to 70% 3

Diagnostic Considerations

The diagnosis of A1AT deficiency involves:

• Phenotyping of A1AT protein in serum by isoelectric focusing
• Genetic testing with DNA sequencing of the SERPINA1 gene
• Measurement of serum A1AT levels (though this alone is insufficient for diagnosis) 1

Clinical Implications

For patients with suspected A1AT deficiency:

• Focus evaluation on respiratory and hepatic manifestations
• Consider targeted testing in patients with:
  • Early-onset emphysema (age <45 years)
  • Emphysema without significant smoking history
  • Basilar-predominant emphysema
  • Unexplained liver disease
  • Family history of A1AT deficiency, emphysema, or unexplained liver disease 1

In summary, while A1AT deficiency is an important genetic disorder with significant clinical implications for lung and liver health, it does not cause bone marrow failure based on current medical evidence.