‘ACE Phenotyping’ Method May Help Identify Systemic Sarcoidosis

Technique involves measuring ACE activity originating in other tissues, not total blood levels

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Clinical researchers have proposed a new type of biochemical analysis called ACE phenotyping that may help diagnose sarcoidosis involvement outside of the lungs. 

A new type of biochemical analysis called ACE phenotyping may help diagnose sarcoidosis involvement outside the lungs, a study proposes.

“We believe that our method allows for the noninvasive detection of patients with systemic sarcoidosis,” the researchers wrote.

The study, “Predictive potential of ACE phenotyping in extrapulmonary sarcoidosis,” was published in Respiratory Research.

A feature of sarcoidosis is the formation of clumps of inflammatory cells called granulomas in the body’s organs. The lungs are most commonly affected, where it’s referred to as pulmonary sarcoidosis, but it also may affect many organs simultaneously — called systemic sarcoidosis. Determining the exact extent of disease involvement is important for providing appropriate care.

The enzyme ACE (angiotensin-converting enzyme) is normally present in many tissues and also in sarcoidosis-associated granulomas. It plays important roles in regulating blood pressure. While elevated ACE levels are common with sarcoidosis, prior research has shown that simply measuring these levels is not a useful biomarker for sarcoidosis as they don’t reflect disease activity.

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Depending on where it’s made, the ACE enzyme has a slightly different shape due to small differences in sugar molecules attached to the protein chain.

Over three decades of studying the protein, a team of scientists in the U.S. and Russia has generated a number of antibodies that can specifically bind to ACE that originates from a particular tissue. Using these antibodies, the researchers here propose a new analytical strategy called ACE phenotyping or ACE fingerprinting.

Immune cell ACE offers clues

This method involves measuring total ACE activity using standardized enzyme assays, then using the antibodies to determine the portion of ACE enzyme that originates from different bodily tissues.

Normally, most ACE in the blood originates from the lungs. The researchers proposed that an increased proportion of ACE from immune cells may signify sarcoidosis activity outside the lungs. They emphasized that this method looks at proportions of ACE enzyme from different tissues, rather than total enzyme levels in the blood.

“A major limitation in the use of serum [blood] ACE measurements as a valid biomarker for sarcoidosis is the observation that ACE levels can be elevated in other disease processes. Our novel ACE fingerprinting approach helps address this problematic issue,” they wrote.

As a proof of concept for this approach, the researchers analyzed blood samples from 20 patients at a lung clinic. Based on ACE phenotyping, eight of them had results indicative of sarcoidosis outside the lungs. PET scans of two of them confirmed sarcoidosis-like inflammation outside the lungs.

The researchers also noted a patient who had high ACE levels, but did not show ACE phenotyping results indicative of sarcoidosis. This patient was ultimately determined to have hyperthyroidism instead.

“This example demonstrates the potential of this approach to “rule out” systemic sarcoidosis despite the presence of an elevated ACE level,” the researchers wrote. “The potential to exclude extrapulmonary [outside-the-lungs] organ involvement with a relatively noninvasive and less costly test than PET scanning represents a significant clinical advance.”

In a final set of tests, the scientists analyzed ACE in the blood of 68 people with diagnosed sarcoidosis. While these patients generally had higher ACE levels than people without the disease, ACE phenotyping did not show a significant distinction between those with or without clear clinical signs of involvement outside the lungs.

The researchers speculated that the ACE phenotyping method may only be able to identify extrapulmonary involvement once granuloma formation has passed a certain threshold of disease burden. More research into this potential biomarker is needed, they said.

“The ACE phenotyping method has the potential [to] add significant value very early in the evaluation process for patients with suspected sarcoidosis. If utility and accuracy is confirmed in additional studies, we propose it be added to the algorithm for sarcoidosis evaluation as early as the first clinical visit in which sarcoidosis is suspected,” the researchers said.