Blood Vessel Response to Vasodilator Agent Can Help Determine FAP Severity, Study Suggests

A noninvasive evaluation of the response of skin blood vessels to a vasodilator compound can help detect the extent of nerve cell damage in patients with familial amyloid polyneuropathy (FAP), researchers suggest.

This finding was reported in the study, “Axon reflex–mediated vasodilation is reduced in proportion to disease severity in TTR-FAP,” published in the journal Neurology Genetics.

FAP is characterized by progressive damage to peripheral nerve cells, leading to abnormal temperature and pain sensations in the extremities. However, evaluating the extent of damage can be challenging, mostly due to the lack of objective and quantitative assessment tools.

In this study, researchers evaluated the diagnostic potential of skin blood vessel responsiveness to assess the severity of neuropathy, or nerve damage, in FAP patients.

The study recruited six women with confirmed genetic mutations in the TTR gene. A man with generalized analgesia (inability to feel pain) due to nerve damage caused by another disease was included as a positive control, and 10 healthy volunteers were also enrolled.

An evaluation of neurological symptoms and physical impairment revealed that three patients were mildly affected, exhibiting only small nerve fiber damage. The remaining patients had higher neurological scores, showing small and large nerve fiber neuropathy. Still, all participants were at stage 1 of the clinical staging of FAP.

By using the quantitative sensitivity test in the feet and hands, which is commonly used in the clinics to evaluate the extent of neuropathy, the researchers could confirm that the patients had lower scores than healthy volunteers. This was particularly noticeable in the feet, with significantly different sensitivity to both cold and warm temperatures.

Next, using a noninvasive method, the researchers applied two doses of histamine to the skin of the participants’ forearms and lower legs, and measured changes in blood vessel response by laser Doppler imaging (LDI-flare).

Histamine is well-known for promoting immune responses such as allergic reactions, but it also has the capacity to promote vessel dilation by activating nerve cells. It has been proposed that, by measuring the response to histamine stimulus to the skin’s blood vessels, it could be possible to evaluate the extent of peripheral nerve cell damage.

The team was unable to detect differences between patients and healthy volunteers in response to the stimulus when applied to the forearm. In contrast, the results obtained on the legs revealed that patient response to the highest histamine dose was 1.7-1.9 times lower.

This result was in line with the results from the quantitative sensitivity test, showing that “the detection thresholds for cold and warm were clearly more abnormal in the feet compared with the hands,” the researchers said.

The intensity of the response to histamine on the leg was found to be inversely correlated with the clinical status of the patient. All three patients who had more severe nerve damage, determined by the neurological impairment score-lower limbs (NIS-LL), also had a lower blood vessel response to the histamine stimulus.

This correlation with disease severity is of particular importance because, until now, only nerve-related biomarkers obtained from skin biopsies have shown such a relationship.

In addition, the researchers found that this noninvasive assessment method could be used to distinguish patients from healthy controls, with a diagnostic potential similar to the quantitative sensitivity test.

These results “provide a rationale for the use of reflex-mediated neurogenic cutaneous vasodilatation in response to histamine in a larger scale. In addition, it could “potentially serve as a useful biomarker assessing TTR-FAP severity,” even in patients at early stages of the disease, according to the researchers.