thyroid microsomal antibody positivity but without gastric parietal cell antibody positivity

Journal of the Formosan Medical Association (2019) 118, 1218e1224

Available online at www.sciencedirect.com

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Original Article

Blood profile of atrophic glossitis patients with thyroglobulin antibody/thyroid microsomal antibody positivity but without gastric parietal cell antibody positivity Ying-Shiung Kuo a,b, Yu-Hsueh Wu a,c, Julia Yu-Fong Chang b,c,d, Yi-Ping Wang b,c,d, Yang-Che Wu b,c, Andy Sun b,c,* a

Department of Dentistry, Far Eastern Memorial Hospital, New Taipei City, Taiwan Department of Dentistry, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan c Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei, Taiwan d Graduate Institute of Oral Biology, School of Dentistry, National Taiwan University, Taipei, Taiwan b

Received 27 March 2019; accepted 2 April 2019

KEYWORDS Atrophic glossitis; Iron deficiency; Folic acid deficiency; Hyperhomocysteinemia; Thyroglobulin antibody; Thyroid microsomal antibody

Background/purpose: Our previous study found that 304 of 1064 atrophic glossitis (AG) patients have thyroglobulin antibody (TGA) positivity and/or thyroid microsomal antibody (TMA) positivity but without gastric parietal cell antibody positivity (GPCA‫־‬TGAþ/TMAþAG patients). This study mainly assessed whether the serum TGA/TMA positivity was significantly associated with anemia, hematinic deficiencies, and hyperhomocysteinemia in GPCA‫־‬TGAþ/ TMAþAG patients. Methods: The mean blood hemoglobin (Hb), iron, vitamin B12, folic acid, and homocysteine levels were measured and compared between 304 GPCA‫־‬TGAþ/TMAþAG patients and 476 GPCA-negative, TGA-negative, and TMA-negative AG patients (GPCA‫־‬TGA‫־‬TMA‫־‬AG patients) or 532 healthy control subjects. Results: We found significantly lower MCV and lower mean blood Hb and iron levels as well as significantly greater frquencies of microcytosis, macrocytosis, blood Hb, iron, vitamin B12, and folic acid deficiencies and hyperhomocysteinemia in 304 GPCA‫־‬TGAþ/TMAþAG patients than in 532 healthy control subjects. However, no significant differences in the MCV and mean blood Hb, iron, vitamin B12, folic acid, and homocysteine leve1s as well as no significant differences in the frequencies of microcytosis, macrocytosis, blood Hb, iron, and folic acid deficiencies, and hyperhomocysteinemia were discovered between 304 GPCA‫־‬TGAþ/TMAþAG patients and 476 GPCA‫־‬TGA‫־‬TMA‫־‬AG patients. The 304 GPCA‫־‬TGAþ/TMAþAG patients had a significantly

* Corresponding author. Department of Dentistry, National Taiwan University Hospital, No. 1, Chang-Te Street, Taipei 10048, Taiwan. Fax: þ2 2389 3853. E-mail address: [email protected] (A. Sun). https://doi.org/10.1016/j.jfma.2019.04.002 0929-6646/Copyright ª 2019, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Blood profile in atrophic glossitis patients

1219

greater frquency of serum vitamin B12 deficiency than 476 GPCA‫־‬TGA‫־‬TMA‫־‬AG patients. Conclusion: The disease of AG itself plays a significant role in causing anemia, hematinic deficiencies, and hyperhomocysteinemia in GPCA‫־‬TGAþ/TMAþAG patients. However, the serum TGA/TMA-positivity is not significantly associated with anemia, serum iron and folic acid deficiencies, and hyperhomocysteinemia in GPCA‫־‬TGAþ/TMAþAG patients. Copyright ª 2019, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).

Introduction Atrophic glossitis (AG) is a common oral manifestation defined as having partial or complete absence or flattering of filiform papillae on the dorsal surface of the tongue.1 AG usually reflects the deficiencies of some major nutrients including riboflavin, niacin, pyridoxine, vitamin B12, folic acid, and iron in the body.1 However, other disorders including protein-calorie malnutrition, candidiasis, Helicobacter pylori colonization, xerostomia, and diabetes mellitus are also the etiologies of AG.2e6 Our previous study showed that 26.7%, 28.4%, and 29.8% of 1064 AG patients have serum gastric parietal cell antibody (GPCA), thyroglobulin antibody (TGA), and thyroid microsomal autoantibody (TMA, also known as anti-thyroid peroxidase antibody, anti-TPO antibody) positivities, respectively.7 Moreover, we also demonstrated that 19.0%, 16.9%, 5.3%, 2.3%, and 11.9% of 1064 AG patients have blood hemoglobin (Hb), iron, vitamin B12, and folic acid deficiencies and hyperhomocysteinemia, respectively.8 Because GPCA can induce destruction of gastric parietal cells, resulting in failure of intrinsic factor and hydrochloric acid (HCl) production,9,10 which in turn may lead to vitamin B12 deficiency, pernicious anemia, hyperhomocysteinemia, and iron deficiency in some GPCA-positive patients.11e15 Thus, we also found 22.2%, 19.7%, 10.9%, 1.4%, and 18.0% of 284 GPCA-positive AG patients have blood Hb, iron, vitamin B12, and folic acid deficiencies and hyperhomocysteinemia, respectively.14 However, we have not yet known whether the serum TGA positivity and/or TMA positivity (TGA/TMA positivity) plays a significant role in causing anemia, hematinic deficiencies, and hyperhomocysteinemia in the 304 GPCA-negative TGA/TMA-positive AG (GPCA‫־‬TGAþ/TMAþAG) patients. In our oral mucosal disease clinic, patients with AG, burning mouth syndrome, oral lichen planus, recurrent aphthous stomatitis, and oral submucous fibrosis are commonly encountered and patients with Behcet’s disease are less frequently seen.7,8,14e56 For these six particular groups of patients, complete blood count, serum iron, vitamin B12, folic acid, homocysteine, GPCA, TGA, and TMA levels are frequently examined to assess whether these patients have anemia, hematinic deficiencies, and serum GPCA, TGA, and TMA positivities.7,8,14e56 To assess the role of serum TGA/TMA positivity in the development of anemia, hematinic deficiencies, and hyperhomocysteinemia in AG patients, 304 GPCA‫־‬TGAþ/

TMAþAG patients, 476 GPCA-negative, TGA-negative, and TMA-negative AG patients (GPCA‫־‬TGA‫־‬TMA‫־‬AG patients), and 532 age- and sex-matched healthy control subjects were retrieved from our previous studies and included in this study.7,8,14,15 The mean blood Hb, iron, vitamin B12, folic acid, and homocysteine levels in these 304 GPCA‫־‬TGAþ/TMAþAG patients, 476 GPCA‫־‬TGA‫־‬TMA‫־‬AG patients, and 532 healthy control subjects were measured and compared one another to assess whether the serum TGA/ TMA positivity was a significant factor causing anemia, hematinic deficiencies, and hyperhomocysteinemia in GPCA‫־‬TGAþ/TMAþAG patients.

Materials and methods Subjects This study included 304 (29 men and 275 women, age range 29e90 years, mean age 62  12 years) GPCA‫־‬TGAþ/TMAþAG patients.7 For evaluation of the role of serum TGA/TMA positivity in causing anemia, hematinic deficiencies, and hyperhomocysteinemia in AG patients, 476 (70 men and 406 women, age range 20e90 years, mean age 62  14 years) GPCA‫־‬TGA‫־‬TMA‫־‬AG patients and 532 (75 men and 457 women, age range 20e89 years, mean age 62  14 years) age- and sex-matched healthy control subjects were retrieved from our previous studies and included in this study.7,8,14,15 All the patients and control subjects were seen consecutively, diagnosed, and treated in the Department of Dentistry, National Taiwan University Hospital from July 2007 to July 2017. The diagnoses of AG in our original 1064 AG patients as well as their inclusion and exclusion criteria have been described in our previous studies.7,8,14,15 Healthy control subjects had dental caries, pulpal disease, malocclusion, or missing of teeth but did not have any oral mucosal or systemic diseases.7,8,14,15 In addition, none of the AG patients had taken any prescription medication for AG at least 3 months before entering the study. The blood samples were drawn from our AG patients and healthy control subjects for measurement of complete blood count, serum iron, vitamin B12, folic acid, and homocysteine concentrations as well as serum GPCA, TGA, and TMA levels. All the AG patients and healthy control subjects signed the informed consent forms before entering the study. This study was reviewed and approved by the Institutional Review Board at the National Taiwan University Hospital.

Comparisons of means of parameters between 304 GPCA‫־‬TGAþ/TMAþAG patients and 532 healthy control subjects by Student’s t-test. Comparisons of means of parameters between 304 GPCA‫־‬TGAþ/TMAþAG patients and 476 GPCA‫־‬TGA‫־‬TMA‫־‬AG patients by Student’s t-test. a

b

<0.001 0.799 0.649 0.103 0.239 0.883 0.414 0.821 87.3  31.4 (n Z 406) 705.3  263.5 15.1  6.7 8.6  6.6 0.024 <0.001 <0.001 0.020 >0.999 0.467 0.060 0.746 89.5  7.6 14.1  1.8 (n Z 70) 12.9  1.4 (n Z 406) 91.7  34.3 (n Z 70)

90.4  3.5 15.1  0.8 (n Z 75) 13.6  0.7 (n Z 457) 104.3  28.0 (n Z 75) 98.5  27.6 (n Z 457) 697.9  226.1 14.9  5.8 8.1  2.0

90.2  31.7 (n Z 275) 702.4  277.7 14.7  6.6 8.5  5.0

Homocysteine (mM) Women

Iron (mg/dL)

Vitamin B12 (pg/mL)

Folic acid (ng/mL)

89.5  7.9 13.8  2.0 (n Z 29) 13.1  1.3 (n Z 275) 89.3  31.5 (n Z 29)

The MCV and mean blood concentrations of Hb, iron, vitamin B12, folic acid, and homocysteine in 304 GPCA‫־‬TGAþ/TMAþAG patients, 476 GPCA‫־‬TGA‫־‬TMA‫־‬AG patients, and 532 healthy control subjects are shown in Table 1. Because men and women usually had different normal blood Hb and iron levels, these two mean levels were calculated separately for men and women. We found significantly lower MCV and lower mean blood Hb and iron levels in 304 GPCA‫־‬TGAþ/TMAþAG patients than in 532 healthy control subjects (all P-values < 0.05, Table 1). However, there were no significant differences in the mean serum vitamin B12, folic acid, and homocysteine levels between 304 GPCA‫־‬TGAþ/TMAþAG patients and 532 healthy control subjects. Moreover, no significant differences in the MCV and mean blood Hb, iron, vitamin B12, folic acid, and homocysteine leve1s were discovered between 304 GPCA‫־‬TGAþ/TMAþAG patients and 476 GPCA‫־‬TGA‫־‬TMA‫־‬AG

GPCA‫־‬TGAþ/TMAþAG patients (n Z 304) a P-value b P-value GPCA‫־‬TGA‫־‬TMA‫־‬AG patients (n Z 476) Healthy control subjects (n Z 532)

Results

Men

Comparisons of the mean corpuscular volume (MCV), the mean blood levels of Hb, iron, vitamin B12, folic acid, and homocysteine between 304 GPCA‫־‬TGAþ/TMAþAG patients and 476 GPCA‫־‬TGA‫־‬TMA‫־‬AG patients or 532 healthy control subjects were performed by Student’s t-test. The differences in frequencies of microcytosis, macrocytosis, blood Hb, iron, vitamin B12, and folic acid deficiencies, and hyperhomocysteinemia between 304 GPCA‫־‬TGAþ/TMAþAG patients and 476 GPCA‫־‬TGA‫־‬TMA‫־‬AG patients or 532 healthy control subjects were compared by chi-square test. The result was considered to be significant if the P-value was less than 0.05.

Women

Statistical analysis

Hb (g/dL)

The methods of determination of serum GPCA, TGA, and TMA levels in our AG patients and healthy control subjects have been described in our previous studies.7,20,32,38,43

Men

Determination of serum GPCA, TGA, and TMA levels

MCV (fL)

The complete blood count and serum iron, vitamin B12, folic acid, and homocysteine concentrations were determined by the routine tests performed in the Department of Laboratory Medicine of National Taiwan University Hospital as described previously.8,14,15 This study defined the Hb and hematinic deficiencies according to the World Health Organization (WHO) criteria. Thus, men with Hb < 13 g/dL and women with Hb < 12 g/dL were defined as having Hb deficiency or anemia.57 Patients with serum iron level <60 mg/dL,13,50 vitamin B12 level <200 pg/mL58 or folic acid level <4 ng/mL59 were defined as having iron, vitamin B12 or folic acid deficiency, respectively. Moreover, patients with the serum homocysteine level >12.1 mM (which was the mean serum homocysteine level of healthy control subjects plus two standard deviations) were defined as having hyperhomocysteinemia.8,14,15

Group

Determination of complete blood count and serum iron, vitamin B12, folic acid and homocysteine concentrations

Y.-S. Kuo et al. Table 1 Comparisons of mean corpuscular volume (MCV) and mean blood concentrations of hemoglobin (Hb), iron, vitamin B12, folic acid, and homocysteine between 304 gastric parietal cell antibody (GPCA)-negative but thyroglobulin antibody (TGA)-positive and/or thyroid microsomal antibody (TMA)-positive atrophic glossitis (AG) patients (GPCA‫־‬TGAþ/TMAþAG patients) and 476 GPCA-negative, TGA-negative, and TMA-negative AG patients (GPCA‫־‬TGA‫־‬TMA‫־‬AG patients) or 532 healthy control subjects.

1220

20 (3.8) a

b

Comparisons of frequencies of parameters between 304 GPCA‫־‬TGAþ/TMAþAG patients and 532 healthy control subjects by chi-square test. Comparisons of frequencies of parameters between 304 GPCA‫־‬TGAþ/TMAþAG patients and 476 GPCA‫־‬TGA‫־‬TMA‫־‬AG patients by chi-square test.

0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

0 (0.0)

0.003 0.600 49 (10.3) 0.033 0.126 1a (3.4) <0.001 0.016 9 (1.9) <0.001 0.141 78 (16.4) <0.001 0.468 9 (1.9) <0.001 0.727 39 (8.2)

<0.001 0.141 93 (19.5)

27 (8.9) 4 (1.3) 16 (5.3) 46 (15.1) 46 (15.1) 9 (3.0)

Hyperhomocysteinemia (>12.1 mM) Folic acid deficiency (<4 ng/mL) Vitamin B12 deficiency (<200 pg/mL) Iron deficiency (<60 mg/dL) Hemoglobin deficiency (Men < 13 g/dL, women < 12 g/dL)

Patient number (%)

Macrocytosis (MCV  100 fL)

22 (7.2)

GPCA‫־‬TGAþ/TMAþAG patients (n Z 304) a P-value b P-value GPCA‫־‬TGA‫־‬TMA‫־‬AG patients (n Z 476) Healthy control subjects (n Z 532)

This study predominantly assessed whether the serum TGA/ TMA positivity was a significant factor causing anemia, hematinic deficiencies, and hyperhomocysteinemia in the GPCA‫־‬TGAþ/TMAþAG patients. The rationale for the study design was that if the GPCA‫־‬TGAþ/TMAþAG patients had severer statuses of anemia, hematinic deficiencies, and hyperhomocysteinemia than the GPCA‫־‬TGA‫־‬TMA‫־‬AG patients, then the serum TGA/TMA-positivity could be a significant factor causing anemia, hematinic deficiencies, and hyperhomocysteinemia in the GPCA‫־‬TGAþ/TMAþAG patients. Our results found no significant differences in the mean blood Hb, iron, vitamin B12, folic acid, and homocysteine leve1s as well as no significant differences in the frequencies of blood Hb, iron, and folic acid deficiencies and hyperhomocysteinemia between 304 GPCA‫־‬TGAþ/ TMAþAG patients and 476 GPCA‫־‬TGA‫־‬TMA‫־‬AG patients. In

Microcytosis (MCV < 80 fL)

Discussion

Group

patients, suggesting that the serum TGA/TMA-positivity does not play a significant role in causing the anemia, hematinic deficiencies, and hyperhomocysteinemia in 304 GPCA‫־‬TGAþ/ TMAþAG patients (Table 1). In addition, the 476 GPCA‫־‬TGA‫־‬TMA‫־‬AG patients do have significantly lower MCV and lower mean blood Hb and iron levels than 532 healthy control subjects (all P-values < 0.05, Table 1); these blood data have been published in our previous study.15 We also found significantly greater frequencies of microcytosis, macrocytosis, blood Hb, iron, vitamin B12, and folic acid deficiencies, and hyperhomocysteinemia in 304 GPCA‫־‬TGAþ/TMAþAG patients than in 532 healthy control subjects (all P-values < 0.05, Table 2). However, there were no significant differences in the frequencies of microcytosis, macrocytosis, blood Hb, iron, and folic acid deficiencies, and hyperhomocysteinemia between 304 GPCA‫־‬TGAþ/TMAþAG patients and 476 GPCA‫־‬TGA‫־‬TMA‫־‬AG patients. The frequency of vitamin B12 deficiency was significantly greater in 304 GPCA‫־‬TGAþ/TMAþAG patients than in 476 GPCA‫־‬TGA‫־‬TMA‫־‬AG patients (P Z 0.016). These findings suggest that the serum TGA/TMA-positivity is not significantly associated with the anemia, serum iron and folic acid deficiencies, and hyperhomocysteinemia in 304 GPCA‫־‬TGAþ/TMAþAG patients, but the disease of AG itself does play a significant role in causing the anemia, hematinic deficiencies, and hyperhomocysteinemia in 304 GPCA‫־‬TGAþ/TMAþAG patients. In this study, 46 (15.1%) of 304 GPCA‫־‬TGAþ/TMAþAG patients were diagnosed as having anemia according to the WHO criteria.57 In addition to having anemia (men with Hb < 13 g/dL and women with Hb < 12 g/dL), macrocytic anemia was diagnosed as having MCV  100 fL,48 normocytic anemia as having MCV between 80 and 99.9 fL,33e35 microcytic anemia as having MCV < 80 fL,52 iron deficiency anemia (IDA) as having MCV < 80 fL and iron < 60 mg/ dL,13,50 and thalassemia trait-induced anemia as having the red blood cell count > 5.0 M/mL, the MCV < 74 fL, and a Mentzer index (MCV/RBC) < 13.51 By these definitions, of 46 anemic GPCA‫־‬TGAþ/TMAþAG patients, four had macrocytic anemia rather than pernicious anemia, 28 had normocytic anemia, seven had IDA, and another seven had thalassemia trait-induced anemia (Table 3).

1221 Table 2 Comparisons of frequencies of microcytosis (mean corpuscular volume or MCV < 80 fL), macrocytosis (MCV  100 fL), blood hemoglobin, iron, vitamin B12, and folic acid deficiencies, and hyperhomocysteinemia between 304 gastric parietal cell antibody (GPCA)-negative but thyroglobulin antibody (TGA)-positive and/or thyroid microsomal antibody (TMA)-positive atrophic glossitis (AG) patients (GPCA‫־‬TGAþ/TMAþAG patients) and 476 GPCA-negative, TGA-negative, and TMA-negative AG patients (GPCA‫־‬TGA‫־‬TMA‫־‬AG patients) or 532 healthy control subjects.

Blood profile in atrophic glossitis patients

1222

Y.-S. Kuo et al.

Table 3 Anemia types of 46 anemic gastric parietal cell antibody (GPCA)-negative but thyroglobulin antibody (TGA)-positive and/or thyroid microsomal antibody (TMA)-positive atrophic glossitis (AG) patients (GPCA‫־‬TGAþ/TMAþAG patients). Anemia type

GPCA‫־‬TGAþ/TMAþAG p atients (n Z 304) Macrocytic anemia Normocytic anemia Iron deficiency anemia Thalassemia trait-induced anemia Total

Patient number (%) Patient number (%)

Mean corpuscular volume (fL)

Vitamin B12 deficiency (<200 pg/mL)

Iron deficiency (<60 mg/dL)

Folic acid deficiency (<4 ng/mL)

4 (8.7) 28 (60.9) 7 (15.2) 7 (15.2) 46 (100.0)

100 80e99.9 <80 <74

3 1 1 0 5

0 (0) 10 (35.7) 7 (100.0) 2 (28.6) 19 (41.3)

0 2 0 0 2

addition, the 304 GPCA‫־‬TGAþ/TMAþAG patients had a significantly greater frquency of serum vitamin B12 deficiency than the 476 GPCA‫־‬TGA‫־‬TMA‫־‬AG patients. These findings indicate that the serum TGA/TMA-positivity is not a significant factor causing anemia, iron and folic acid deficiencies, and hyperhomocysteinemia in GPCA‫־‬TGAþ/ TMAþAG patients. Moreover, significantly lower mean blood Hb and iron levels and significantly greater frequencies of blood Hb, iron, vitamin B12, and folic acid deficiencies and hyperhomocysteinemia were demonstrated in 304 GPCA‫־‬TGAþ/TMAþAG patients than in 532 healthy control subjects, suggesting that the disease of AG itself does play a significant role in causing anemia, hematinic deficiencies and hyperhomocysteinemia in 304 GPCA‫־‬TGAþ/TMAþAG patients. Our previous study also discovered that 476 GPCA‫־‬TGA‫־‬TMA‫־‬AG patients had significantly lower mean blood Hb and iron levels and significantly greater frequencies of blood Hb, iron, vitamin B12, and folic acid deficiencies and hyperhomocysteinemia than those in 532 healthy control subjects.15 These findings also confirm that the disease of AG itself is a significant factor causing anemia, hematinic deficiencies and hyperhomocysteinemia in 476 GPCA‫־‬TGA‫־‬TMA‫־‬AG patients. Our previous studies and this study found anemia in 202 (19.0%) of 1064 AG,8 63 (22.2%) of 284 GPCAþAG,14 139 (17.8%) of 780 GPCA‫־‬AG,14 38 (21.5%) of 177 GPCAþTGA‫־‬TMA‫־‬AG,15 93 (19.5%) of 476 GPCA‫־‬TGA‫־‬TMA‫־‬AG,15 and 46 (15.1%) of 304 GPCA‫־‬TGAþ/TMAþAG patients. These findings indicate that in the subgroups of AG patients, GPCApositive AG patients with or without TGA/TMA positivity tend to have the highest frequency of anemia (21.5e22.2%) and GPCA‫־‬TGAþ/TMAþAG patients have the lowest frequency of anemia (15.1%).8,14,15 For the iron deficiency in the subgroups of AG patients, the iron deficiency was noted in 180 (16.9%) of 1064 AG,8 56 (19.7%) of 284 GPCAþAG,14 124 (15.9%) of 780 GPCA‫־‬AG,14 36 (20.3%) of 177 GPCAþTGA‫־‬TMA‫־‬AG,15 78 (16.4%) of 476 GPCA‫־‬TGA‫־‬TMA‫־‬AG,15 and 46 (15.1%) of 304 GPCA‫־‬TGAþ/ TMAþAG patients. These findings indicate that in the subgroups of AG patients, GPCA-positive AG patients with or without TGA/TMA positivity are prone to have the highest frequency of iron deficiency (19.7e20.3%) and GPCA‫־‬TGAþ/ TMAþAG patients have the lowest frequency of iron deficiency (15.1%).8,14,15 The above findings also confirm the influence of GPCA positivity on the reduced absorption of

(75) (3.6) (14.3) (0) (10.9)

(0) (7.1) (0) (0) (4.3)

iron from the stomach and duodenum and the subsequent iron deficiency.8,14,15 For the vitamin B12 deficiency in the subgroups of AG patients, vitamin B12 deficiency was noted in 56 (5.3%) of 1064 AG,8 31 (10.9%) of 284 GPCAþAG,14 25 (3.2%) of 780 GPCA‫־‬AG,14 15 (8.5%) of 177 GPCAþTGA‫־‬TMA‫־‬AG,15 9 (1.9%) of 476 GPCA‫־‬TGA‫־‬TMA‫־‬AG,15 and 16 (5.3%) of 304 GPCA‫־‬TGAþ/TMAþAG patients. These findings indicate that in the subgroups of AG patients, GPCA-positive AG patients with or without TGA/TMA positivity do have the highest frequency of vitamin B12 deficiency (8.5e10.9%) and GPCA‫־‬TGA‫־‬TMA‫־‬AG patients have the lowest frequency of vitamin B12 deficiency (1.9%).8,14,15 Moreover, the above findings also confirm a significant influence of GPCA positivity on the decreased absorption of vitamin B12 from the terminal ileum and the subsequent vitamin B12 deficiency.8,14,15 For the folic acid deficiency in the subgroups of AG patients, the folic acid deficiency was noted in 24 (2.3%) of 1064 AG,8 4 (1.4%) of 284 GPCAþAG,14 20 (2.6%) of 780 GPCA‫־‬AG,14 2 (1.1%) of 177 GPCAþTGA‫־‬TMA‫־‬AG,15 16 (3.4%) of 476 GPCA‫־‬TGA‫־‬TMA‫־‬AG,15 and 4 (1.3%) of 304 GPCA‫־‬TGAþ/TMAþAG patients. These findings suggest that in the subgroups of AG patients, GPCA‫־‬TGA‫־‬TMA‫־‬AG patients have the highest frequency of folic acid deficiency (3.4%) and GPCAþTGA‫־‬TMA‫־‬AG patients have the lowest frequency of folic acid deficiency (1.1%).8,14,15 Moreover, the above findings also suggest that GPCA positivity does not have a significant interference on the folic acid absorption from the jejunum that in turn results in folic acid deficiency.8,14,15 For the hyperhomocysteinemia in the subgroups of AG patients, the hyperhomocysteinemia was noted in 127 (11.9%) of 1064 AG,8 51 (18.0%) of 284 GPCAþAG,14 76 (9.7%) of 780 GPCA‫־‬AG,14 29 (16.4%) of 177 GPCAþTGA‫־‬TMA‫־‬AG,15 49 (10.3%) of 476 GPCA‫־‬TGA‫־‬TMA‫־‬AG,15 and 27 (8.9%) of 304 GPCA‫־‬TGAþ/TMAþAG patients. GPCA-positive AG patients with or without TGA/TMA positivity do have the highest frequency of hyperhomocysteinemia (16.4e18.0%) and GPCA‫־‬TGAþ/TMAþAG patients have the lowest frequency of hyperhomocysteinemia (8.9%).8,14,15 Moreover, the above findings also provide evidence that GPCA positivity does have a significant influence on the reduced absorption of vitamin B12 from the terminal ileum and the subsequent vitamin B12 deficiency and hyperhomocysteinemia.8,14,15

Blood profile in atrophic glossitis patients After analyses of the frequencies of anemia, hematinic deficiencies, and hyperhomocysteinemia in AG patients and in different subgroups of AG patients, we further conclude that the GPCA positivity plays a significant role in causing anemia, iron and vitamin B12 deficiencies, and hyperhomocysteinemia in AG patients. The serum GPCA positivity does not have a significant influence on folic acid deficiency in AG patients.8,14,15 Moreover, the serum TGA/TMApositivity is not significantly associated with anemia, hematinic deficiencies, and hyperhomocysteinemia in GPCA‫־‬TGAþ/TMAþAG patients, but the disease of AG itself does play a significant role in causing anemia, hematinic deficiencies, and hyperhomocysteinemia in AG patients.

Conflicts of interest The authors have no conflicts of interest relevant to this article.

Acknowledgements This study was supported by the grants (No. 102-2314-B002-125-MY3 and No. 105-2314-B-002-075-MY2) of Ministry of Science and Technology, Republic of China.

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