Rare Mutations in ATT Protein May Lead to Development of AAV, Case Report Suggests

ANCA-associated vasculitis (AAV) may be associated with rare mutations in the alpha-1 antitrypsin (AAT) protein, a new case report suggests.

The study, “Fulminant hepatic failure in the setting of progressive ANCA-associated vasculitis associated with a rare alpha-1 antitrypsin phenotype, ‘PiEE‘,” was published in the journal BMJ Case Reports.

Classical ATT deficiency, caused by mutations in the SERPINA1 gene, commonly appears as lung and liver diseases.

The ATT protein works to prevent an enzyme – called elastase – from breaking down other proteins. But other targets, such as proteinase 3 (PR3) and myeloperoxidase (MPO), may also be inactivated by ATT.

During inflammation, ATT levels increase by four to six times, contributing to the regulation of enzyme activity. But little is known about its impact on immune regulation and autoimmunity.

Researchers at the University of Minnesota presented the case of a 48-year-old woman with ATT deficiency who developed ANCA-associated vasculitis.

The patient complained of muscle pain, fatigue, anorexia, and progressing breathing difficulty, which she had for the last 10 days. She was also showing signs of confusion, and the yellowish tint of her skin and eyes suggested liver damage.

An initial evaluation of her vital signs revealed low oxygenation, low blood pressure, and an accelerated heart beat. Blood analysis revealed a very serious condition with several organs affected. Over the course of a few hours, her condition continued to deteriorate, requiring respiratory support and kidney replacement therapy.

The patient had a clinical history of an autoimmune disorder that had not been fully confirmed. She had structural alterations to her mouth which had progressed over the last two years, leading to difficulty eating, along with chronic tooth pain. During the same period, she also had several episodes of rash, skin redness, and pain. These symptoms contributed to depression and led to her abuse of alcohol and cocaine.

Three months before the present hospitalization, a clinical evaluation led to a presumptive diagnosis of alcohol withdrawal effects and drug-induced lupus. As a result, her condition remained untreated.

But her symptoms persisted and some progressed, leading researchers to look for signs of autoimmune disorder. Exams showed elevated levels of ANCA antibodies, which together with the remaining symptoms, confirmed an autoimmune disease.

A skin biopsy failed to detect vasculitis, but revealed skin fibrosis (scarring) associated with inflammation and degeneration of the fat tissue. Given the lung problems and liver damage, the patient was tested for ATT levels, which revealed a low amount of the protein.

Despite efforts made to identify the cause of her symptoms and to provide a proper treatment, the patient’s condition continued to deteriorate and her family elected to withdraw life-sustaining measures.

At this point, no further testing was authorized, and researchers were unable to determine the causes for the low ATT levels. But the team believes the clinical presentation was consistent with ANCA-associated vasculitis (AAV) and abnormal AAT protein levels due to a rare genetic mutation.

“Two large case series suggest the prevalence of any ANCA-associated vasculitis in patients with any AAT deficiency is approximately 1%–2%,” the researchers wrote. “As we discover more AAT mutations and diagnose more patients, we will need to build on our current knowledge base to provide care for this unique population.”

More studies are needed to fully understand the contribution of AAT deficits in the development of ANCA-associated vasculitis.