Literature

Clinical Pearls & Morning Reports


Published April 8, 2020

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Is alpha1-antitrypsin deficiency associated with a delay in diagnosis?

Alpha1-antitrypsin (AAT) deficiency is one of the most common genetic diseases. Most persons carry two copies of the wild-type M allele of SERPINA1, which encodes AAT, and have normal circulating levels of the protein. Read the NEJM Review Article here.

Clinical Pearls

Q: What is the primary role of AAT?

A: AAT inhibits neutrophil elastase, which, when unopposed, can cleave many of the structural proteins of the lung as well as innate immune proteins. AAT also binds a variety of proteins and fatty acids, and loss or moderation of these functions as a result of AAT deficiency may increase inflammation. AAT levels can rise by 100% in persons with a normal proteinase inhibitor (PI) genotype (MM) during the acute-phase response, but the increase is markedly attenuated in persons with severe deficiency alleles.

Q: Does AAT affect only the lungs and liver?

A: Although lung and liver disease are the most prominent disorders associated with AAT deficiency, several other conditions have been reported in persons with the PI ZZ genotype. Among them, neutrophilic panniculitis is characterized by painful subcutaneous nodules and the presence of neutrophil infiltrates in the subcutis; it occurs in less than 1% of persons with the PI ZZ genotype. Disorders that are overrepresented in persons with AAT deficiency include antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, chronic kidney disease, diabetes, and metabolic alterations, with decreased levels of serum triglycerides and very-low-density lipoproteins.

Morning Report Questions

Q: Is AAT deficiency associated with a delay in diagnosis?

A: The clinical manifestations of lung disease associated with AAT deficiency are mainly indistinguishable from those of nonhereditary emphysema. This is partly why severe AAT deficiency remains undiagnosed in approximately 90% of cases, with an interval of 5 to 7 years from the onset of symptoms to diagnosis. The classic clinical description of lung disease associated with AAT deficiency is of early-onset obstructive lung disease in persons with moderate cigarette consumption and panacinar emphysema affecting mainly the lower lobes. Rigid adherence to these indicators to prompt testing has led to underdiagnosis, late diagnosis, and misdiagnosis of AAT deficiency. Up to 37% of people with severe AAT deficiency have predominantly upper-lobe involvement, with bronchiectasis as a common radiologic manifestation. Even when this diagnostic algorithm is used for young people with chronic obstructive pulmonary disease (COPD), AAT deficiency is often diagnosed late, at a point when the lung disease has become irreversible. 

Q: Does AAT have a potential role in the course of diseases other than AAT deficiency?

A: The antiinflammatory and tissue-protective properties of AAT are underscored by several studies suggesting its usefulness in transplantation medicine. AAT can ameliorate experimentally induced kidney and lung ischemia–reperfusion injury and augment the function of murine and porcine lung transplants. Treatment with AAT has been shown to have an antiinflammatory effect on insulin-sensitive tissues and was beneficial in experimental islet-transplantation models, reducing islet-cell loss and inducing immune tolerance. These data prompted phase 1 and 2 clinical trials that showed the safety and side-effects profile of AAT administration in children with type 1 diabetes. Treatment with AAT induces immune tolerance and increases regulatory T cells. This process is of particular relevance in graft-versus-host-disease (GVHD), a potentially lethal consequence of allogeneic hematopoietic stem-cell transplantation. In keeping with the data from islet transplantation, AAT administration decreased mortality and reduced proinflammatory cytokine levels in three different mouse models of GVHD. Further trials are needed to assess the efficacy of AAT in humans.

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