Loss of gastric interstitial cells of Cajal in patients with hereditary transthyretin amyloidosis

Abstract

Background: Hereditary transthyretin (TTR) amyloidosis is a systemic neuropathic disorder caused by TTR gene mutations. Gastrointestinal complications are common and the underlying mechanisms remain unclear. The interstitial cells of Cajal (ICC) function as pacemaker cells in the gastrointestinal tract and are important for gastrointestinal motility. The aim of this study was to investigate the densities of gastric ICC and nerves in patients with TTR amyloidosis compared to non-amyloidosis controls.

Methods: Antral wall autopsy specimens from 11 Japanese ATTR V30M patients and 10 controls were analyzed with immunohistochemistry and computerized analysis. Antibodies to c-Kit and TMEM16A were used to assess ICC and an antibody to PGP 9.5 was used to assess nervous tissue. The study was approved by a Japanese ethical committee.

Results: The densities of c-Kit-immunoreactive (IR) ICC were significantly lower in the circular and longitudinal muscle layers of patients compared to controls (p = 0.004 for both). Equivalent results were found for TMEM16A-IR ICC. There were no significant differences in PGP 9.5-IR cells in the circular or longitudinal muscle layers between patients and controls (p = 0.173 and 0.099, respectively).

Conclusions: A loss of gastrointestinal ICC may be an important factor for the digestive disturbances in hereditary TTR amyloidosis.

Figure 1.

Immunohistochemic analyses of gastric antrum wall autopsy specimens visualizing c-Kit-IR ICC (dark brown) in (A) a patient with hereditary TTR amyloidosis and (B) a non-amyloidosis control. A × 40 objective (40×/0.70, Pl Fluotar, Leica) was used for the analyses. IR = immunoreactive. ICC = interstitial cells of Cajal. TTR = transthyretin.

Figure 2.

Immunohistochemic analyses of gastric antrum wall autopsy specimens visualizing TMEM16A-IR ICC (dark brown) in (A) a patient with hereditary TTR amyloidosis and (B) A non-amyloidosis control. A ×40 objective (40×/0.70, Pl Fluotar, Leica) was used for the analyses.

Figure 3.

Immunohistochemic analyses of gastric antrum wall autopsy specimens visualizing PGP 9.5-IR nervous tissue (dark brown) in (A) a patient with hereditary TTR amyloidosis and (B) A non-amyloidosis control. A ×40 objective (40×/0.70, Pl Fluotar, Leica) was used for the analyses. PGP 9.5 = protein gene product 9.5.

Figure 4.

The relative volume densities of gastric c-Kit-IR ICC and PGP 9.5-IR nervous tissue in patients with hereditary TTR amyloidosis and non-amyloidosis controls were quantified with immunohistochemistry and computerized image analysis. (A) There were significant differences in c-Kit-IR ICC in both the circular and longitudinal muscle layers (z = −2.98, p = 0.004, for both). (B) No significant differences in PGP 9.5-IR nervous tissue were found in the circular or longitudinal muscle layers (z = −1.41, p = 0.173 and z = −1.66, p = 0.099, respectively).