+ MODEL

Journal of the Formosan Medical Association xxx (xxxx) xxx

Available online at www.sciencedirect.com

ScienceDirect

journal homepage: www.jfma-online.com

Review Article

Atrophic glossitis: Etiology, serum

autoantibodies, anemia, hematinic
deficiencies, hyperhomocysteinemia, and
management
Chun-Pin Chiang a,b,c,d, Julia Yu-Fong Chang b,c,d,
Yi-Ping Wang b,c,d, Yu-Hsueh Wu a,b, Yang-Che Wu b,c,
Andy Sun b,c,*

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

Received 16 April 2019; accepted 23 April 2019

KEYWORDS Atrophic glossitis (AG) is characterized by the partial or complete absence of filiform papillae
Atrophic glossitis; on the dorsal surface of the tongue. AG may reflect the significant deficiencies of some major
Anemia; nutrients including riboflavin, niacin, pyridoxine, vitamin B12, folic acid, iron, zinc, and
Hematinic deficiency; vitamin E. Moreover, protein-calorie malnutrition, candidiasis, Helicobacter pylori coloniza-
Hyperhomo tion, xerostomia, and diabetes mellitus are also the etiologies of AG. Our previous study found
cysteinemia; the serum gastric parietal cell antibody (GPCA), thyroglobulin antibody (TGA), and thyroid
Gastric parietal cell microsomal antibody (TMA) positivities in 26.7%, 28.4%, and 29.8% of 1064 AG patients, respec-
antibody tively. We also found anemia, serum iron, vitamin B12, and folic acid deficiencies, and hyper-
homocysteinemia in 19.0%, 16.9%, 5.3%, 2.3%, and 11.9% of 1064 AG patients, respectively.
Moreover, GPCA-positive AG patients tended to have relatively higher frequencies of hemoglo-
bin, iron, and vitamin B12 deficiencies and hyperhomocysteinemia than GPCA-negative AG pa-
tients. Supplementations with vitamin BC capsules plus corresponding deficient hematinics for
those AG patients with hematinic deficiencies can achieve complete remission of oral symp-
toms and AG in some AG patients. Therefore, it is very important to examine the complete
blood count, serum hematinic, homocysteine, and autoantibody levels in AG patients before
we start to offer treatments for AG patients.

* Corresponding author. Department of Dentistry, National Taiwan University Hospital, No. 1, Chang-Te Street, Taipei, 10048, Taiwan.
E-mail address: andysun7702@yahoo.com.tw (A. Sun).

https://doi.org/10.1016/j.jfma.2019.04.015
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/).

Please cite this article as: Chiang C-P et al., Atrophic glossitis: Etiology, serum autoantibodies, anemia, hematinic deficiencies, hyper-
homocysteinemia, and management, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.04.015
 + MODEL
2 C.-P. Chiang et al.
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/).
Introduction
The tongue is the mirror of general health or disease.
Glossitis refers to inflammation of the tongue, and atrophic
glossitis (AG) represents partial or complete loss of pre-
dominantly filiform papillae and minorly fungiform papillae
on the dorsal surface of the tongue in addition to glossitis.
The filiform papillae contain a relatively thick layer of
keratinized stratified squamous epithelium that can protect
the underlying connective and nerve cells from chemical,
mechanical and physical stimuli. Moreover, fungiform
papillae consist of plenty of taste cells that are responsible
for mainly sweet and salty taste sensations. AG patients
lacks protective function from filiform papillae and taste
function from taste cells. Therefore, a high proportion of
AG patients may experience pain, burning sensation, and
numbness of the tongue, and dysfunction of taste. The
differential diagnoses of the AG include erythematous
candidiasis, migratory glossitis, median rhomboid glossitis,
and fissured tongue.1
Etiologies of atrophic glossitis
AG can be caused by deficiencies of some major nutrients
including riboflavin, niacin, pyridoxine, folic acid, vitamin
B12, iron, zinc, and vitamin E.1 Our previous study
discovered iron, vitamin B12, and folic acid deficiencies in
26.7%, 7.4%, and 1.7% of 176 AG patients and in 16.9%,
5.3%, and 2.3% of 1064 AG patients, respectively.2,3 Demir
et al.4 showed AG in the 40 (70.2%) of 57 vitamin B12-
deficient infants aged between 6 and 24 months. Bao
et al.5 found zinc deficiency in 13 (24.1%) of 54 AG pa-
tients. Drinke et al.6 demonstrated a significant associa-
tion of vitamin E deficiency with AG and considered the
vitamin E as another nutrient responsible for the devel-
opment of AG.
Moreover, protein-calorie malnutrition, candidiasis,
Helicobacter pylori infection, xerostomia, and diabetes
mellitus are also the etiologies of AG.7e11 Bøhmer and
Mowé7 studied the relationship between AG and nutritional
status in 310 old people recently admitted to hospital and
in 106 randomly selected elderly people at home. They
found the AG in 13.2% of men and 5.6% of women at home
and in 26.6% of men and 37% of women in hospital. The AG
is related to reduced body weight, body mass index, triceps
skinfold thickness, arm-muscle circumference, muscular
strength, activities of daily living, and to decreased serum
levels of cholesterol, ascorbic acid, cholecalcidiol, and
vitamin B12, but not to the levels of zinc or folate. In a
multiple logistic regression model, AG is related only to
cholesterol, muscular strength, and activities of daily
living. They concluded that AG is a marker for malnutrition
and reduced muscle function. In addition, AG is more
Please cite this article as: Chiang C-P et al., Atrophic glossitis: Etiology, serum autoantibodies, anemia, hematinic deficiencies, hyper-
homocysteinemia, and management, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.04.015
commonly found in terminally ill cancer patients with
xerostomia (17%) and in diabetic patients (26.9%).10,11
Mutual cause-and-effect relationship between
hemoglobin or nutrient deficiencies and
atrophic glossitis
There is a mutual cause-and-effect relationship between
hemoglobin (Hb) or nutrient deficiencies and AG. In other
words, blood Hb or nutrient deficiencies may cause AG, and
vice versa AG patients are prone to have blood Hb and
nutrient deficiencies. AG patients are reported to have
significant deficiencies of some major nutrients including
riboflavin, niacin, pyridoxine, folic acid, vitamin B12, iron,
zinc, and vitamin E.1e6 Patients with Hb deficiency have
reduced capacity of the blood to carry oxygen to the dorsal
surface mucosa of the tongue, finally resulting in AG.2,3
Riboflavin is necessary for cellular oxidation-reduction re-
actions.1 Niacin acts as a coenzyme for cellular oxidation-
reduction reactions and is involved in the DNA repair pro-
cess.1,12 Pyridoxine is a cofactor in several enzymatic re-
actions involving the metabolism of amino acids, glucose
and lipids.1,12 Folic acid plays a role in synthesis of DNA and
RNA and in the prevention of genetic alterations.1,12
Vitamin B12 is involved in DNA synthesis, regulatory func-
tions of nervous system, amino acid metabolism, and the
maturation of developing red blood cells in the bone
marrow.1,12 Iron carries oxygen in the Hb and in the
myoglobin and is also necessary for several enzymatic re-
actions.12 Zinc plays roles in various human biological
functions including cell growth, wound healing, normal
immune function, and taste function (the salivary taste-
related gustin is a zinc-containing protein in human pa-
rotid saliva).2,12 High blood homocysteine level may result
in an elevated frequency of thrombosis in the feeding ar-
terioles that supply the oral mucosal cells.2,13,14 The
aforementioned major nutrients are all essential to the
normal functioning of oral epithelial cells and involved in
proliferation and repair of oral epithelial cells. Therefore,
deficiencies of riboflavin, niacin, pyridoxine, folic acid,
vitamin B12, iron, and zinc as well as hyper-
homocysteinemia may result in atrophy of dorsal surface
mucosa of the tongue, finally leading to the formation of
AG. Our previous studies found burning sensation of the
tongue, dry mouth, numbness of the tongue, and dysfunc-
tion of taste in 100.0%, 79.0%, 57.4%, and 27.8% of 176 AG
patients and 98.5%, 70.1%, 50.7%, and 23.5% of 1064 AG
patients, respectively.2,3 Dry mouth can further cause oral
mucosa atrophy. Burning sensation and numbness of the
tongue in AG patients are probably due to loss of protection
of dorsal surface mucosa of the tongue by filiform papillae
and easy access of the free nerve ending in the atrophic
dorsal surface mucosa of the tongue, respectively.2,3
 + MODEL
Atrophic glossitis
Moreover, dysfunction of taste is attributed to loss of taste
buds in fungiform papillae on the dorsal surface and lateral
border of the tongue, decrease secretion of saliva, and
reduction of salivary gustin level.2 Zinc supplementation
can increase salivary gustin level and thus improve taste
function in AG patients with hypogeusia.2 We suggest that
the AG-associated symptoms such as dry mouth, burning
sensation, numbness, and dysfunction of taste all may
interfere with the eating and swallowing function in AG
patients. The eating and swallowing difficulties may result
in reduced food intake that in turn leads to anemia, major
nutrient deficiencies, and hyperhomocysteinemia in a
certain percentage of AG patients.2,3
Serum organ-specific autoantibodies in
atrophic glossitis patients
In our oral mucosa disease clinic, complete blood count and
serum levels of iron, vitamin B12, folic acid, homocysteine,
and organ-specific autoantibodies including gastric parietal
cell antibody (GPCA), thyroglobulin antibody (TGA), and
thyroid microsomal antibody (TMA, also known as anti-
thyroid peroxidase antibody or anti-TPO antibody) in pa-
tients with AG, burning mouth syndrome, oral lichen pla-
nus, recurrent aphthous stomatitis, and oral submucous
fibrosis, and Behcet’s disease are frequently exam-
ined.15e45,45e59 The reasons why we assess the serum GPCA,
TGA, and TMA levels in these specific oral mucosal disease
patients are explained as follows. GPCA can induce
destruction of gastric parietal cells, resulting in failure of
intrinsic factor and hydrochloric acid (HCl) production.60,61
The intrinsic factor deficiency can cause malabsorption of
vitamin B12 from the terminal ileum and finally lead to
vitamin B12 deficiency or pernicious anemia (PA) in some of
the vitamin B12-deficient patients.62,63 The HCL deficiency
can cause malabsorption of iron from the stomach and
upper portion of the duodenum and finally result in iron
deficiency or iron deficiency anemia (IDA).53,64 The vitamin
B12 deficiency may also lead to hyperhomocysteinemia in
AG patients.2,3,16,17 Thus, GPCA positivity may have a sig-
nificant influence on the red blood cell size and blood Hb,
iron, vitamin B12, and homocysteine levels in GPCA-
positive AG patients.16,17 The TGA and TMA are related to
autoimmune thyroiditis (Hashimoto’s thyroiditis) that often
results in hypothyroidism.56,65 In addition, a small propor-
tion of TGA-positive and/or TMA-positive patients may have
hyperthyroidism instead of hypothyroidism.18,35,41,56 The
above explanations are the main reasons why we examine
the serum GPCA, TGA, and TMA in patients with specific
oral mucosal diseases. Our previous study found that 26.7%,
28.4%, and 29.8% of 1064 AG patients and 2.3%, 2.1%, and
2.6% of 532 healthy control subjects have the serum GPCA,
TGA, and TMA positivities, respectively. AG patients have a
significantly higher frequency of GPCA, TGA, or TMA posi-
tivity than healthy control subjects (all P-values < 0.001).15
We also found that 67 (6.3%), 181 (17.0%), and 340 (32.0%)
AG patients and 3 (0.6%), 10 (1.9%), and 8 (1.5%) healthy
control subjects have the presence of three
(GPCA þ TGA þ TMA), two (GPCA þ TGA, GPCA þ TMA, or
TGA þ TMA), or one (GPCA only, TGA only, or TMA only)
organ-specific autoantibody in their sera, respectively.15 Of
Please cite this article as: Chiang C-P et al., Atrophic glossitis: Etiology, serum autoantibodies, anemia, hematinic deficiencies, hyper-
homocysteinemia, and management, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.04.015
3
373 TGA/TMA-positive AG patients whose serum thyroid-
stimulating hormone (TSH) levels are measured, 78.6%,
8.0%, and 13.4% of these TGA/TMA-positive AG patients
have normal, lower, and higher serum TSH levels,
respectively.15
As stated before, 26.7%, 28.4%, and 29.8% of 1064 AG
patients have the serum GPCA, TGA, and TMA positivities,
respectively.15 Because GPCA-positive patients are more
likely to have PA and to develop autoimmune atrophic
gastritis which may subsequently progress to gastric carci-
noma,66,67 and TGA/TMA-positive patients may develop
autoimmune thyroid disease and finally result in thyroid
dysfunction.18,35,41,56,65 Those TGA/TMA-positive AG pa-
tients with either hyperthyroidism or hypothyroidism
should be referred to endocrinology department for further
treatment. Moreover, those GPCA-positive patients should
be referred to department of gastroenterology for endo-
scopic examination of stomach to check for the presence of
autoimmune atrophic gastritis that can be further treated
by medical doctors in that department. In addition, it needs
a long-term follow-up study to assess whether GPCA-
positive AG patients with or without treatment may
develop gastric carcinoma.
Hematinic deficiencies and
hyperhomocysteinemia in atrophic glossitis
patients and their relation to gastric and
thyroid autoantibodies
Hb, iron, vitamin B12, and folic acid deficiencies may result
in AG. Our previous study found Hb, iron, vitamin B12, and
folic acid deficiencies and hyperhomocysteinemia in 19.0%,
16.9%, 5.3%, 2.3%, and 11.9% of 1064 AG patients,3 22.2%,
19.7%, 10.9%, 1.4%, and 18.0% of 284 GPCAþAG patients
with or without TGA/TMA positivity,16 17.8%, 15.9%, 3.2%,
2.6%, and 9.7% of 780 GPCA‫־‬AG patients with or without
TGA/TMA positivity,16 21.5%, 20.3%, 8.5%, 1.1%, and 16.4%
of 177 GPCAþTGA‫־‬/TMA‫־‬AG patients,17 15.1%, 15.1%, 5.3%,
1.3%, and 8.9% of 304 GPCA‫־‬TGAþ/TMAþAG patients, and
19.5%, 16.4%, 1.9%, 3.4%, and 10.3% of 476 GPCA‫־‬TGA‫־‬T-
MA‫־‬AG patients, respectively.18 We found that 284 GPCA-
þAG patients with or without TGA/TMA positivity and 177 GPCAþ
TGA‫־‬/
TMA‫־‬AG patients have relatively higher frequencies of Hb,
iron, and vitamin B12 deficiencies and hyper-
homocysteinemia than other four groups of AG
patients,3,16e18 because serum GPCA may induce gastric
parietal cell destruction that in turn results in malabsorp-
tion of iron and vitamin B12 and finally leads to Hb defi-
ciency and hyperhomocysteinemia in AG patients.16,17 In
addition, 284 GPCAþAG patients with or without TGA/TMA
positivity and 177 GPCAþTGA‫־‬/TMA‫־‬AG patients have rela-
tively higher frequencies of vitamin B12 deficiency and
relatively lower frequencies of folic acid deficiency than
other three groups of AG patients.16e18 Thus, the relatively
higher frequencies of hyperhomocysteinemia in GPCA-
positive AG patients may be mainly caused by vitamin B12
deficiencies in these two specific groups of GPCA-positive
AG patients.16,17 We also found that the TGA/TMA positiv-
ity is not significantly associated the hematinic deficiencies
and hyperhomocysteinemia in AG patients.18
 + MODEL
4 C.-P. Chiang et al.
Anemia in atrophic glossitis patients
As stated in the above section, 1.1%e20.3% of AG patients
of different types have iron, vitamin B12 and folic acid
deficiencies. This can explain why 15.1%e22.2% of AG pa-
tients of different types have anemia.3,16e18 Actually, 284
GPCAþAG patients with or without TGA/TMA positivity and
177 GPCAþTGA‫־‬/TMA‫־‬AG patients have relatively higher
frequencies of anemia than other four groups of AG pa-
tients stated in the above section.3,16e18 Regarding the
subtypes of anemia, normocytic anemia is the most com-
mon type of anemia in our six groups of AG patients.3,16e18
For our two groups of GPCA-positive AG patients, PA is the
second common type of anemia and the number of patients
with macrocytic anemia (including PA and other macrocytic
anemia) is greater than that of patients with microcytic
anemia (including iron deficiency anemia or IDA, thalas-
semia trait-induced anemia, and other microcytic ane-
mia).16,17 Moreover, for the other four groups of AG
patients, IDA is the second common type of anemia and the
number of patients with microcytic anemia (including IDA,
thalassemia trait-induced anemia, and other microcytic
anemia) is greater than that of patients with macrocytic
anemia (including PA and other macrocytic anemia).3,16e18
Management of atrophic glossitis patients
The tongue is the mirror of general health or disease. AG
may reflect the significant deficiencies of some major nu-
trients including riboflavin, niacin, pyridoxine, vitamin B12,
folic acid, iron, zinc, and vitamin E.1e6,12 Moreover,
protein-calorie malnutrition, candidiasis, H. pylori coloni-
zation, xerostomia, and diabetes mellitus are also the eti-
ologies of AG.7e11 Therefore, the management of AG should
be based on a correct diagnosis and understanding the
etiologies of AG.
Our previous study used different vitamin or iron sup-
plement regimens to treat 91 AG patients (24 men and 67
women, age range 24e92 years, mean 61.9  14.1 years).19
AG patients with the serum level of vitamin B12 & 450 pg/
mL, folic acid &6 ng/mL, or iron &70 mg/dL for men and &
65 mg/dL for women are defined as having vitamin B12, folic
acid or iron deficiency, respectively.19 By these definitions,
58 (63.7%), 10 (11.0%), and 28 (30.8%; 7 men and 21 women)
AG patients are found to have vitamin B12, folic acid, and
iron deficiencies, respectively.19 Moreover, our 91 AG pa-
tients can be divided into five groups: group I, patients with
vitamin B12 deficiency only (n Z 39); group II, patients with
folic acid deficiency only (n Z 10); group III patients with
iron deficiency only (n Z 9), group IV, patients with both
vitamin B12 and iron deficiencies (n Z 19); and group V,
patients without definite hematinic deficiencies (n Z 14).
These five different groups of AG patients are treated with
five different hematinic supplement regimens.19 In brief,
all 91 AG patients are treated with oral administration of
vitamin BC capsule (one capsule, twice a day; each capsule
contained 10 mg of vitamin B1, 5 mg of vitamin B2, 5 mg of
vitamin B6, 5 mg of vitamin B12, 20 mg of calcium panto-
thenate, 50 mg of nicotinamide, 150 mg of vitamin C, and
60 mg of calcium). Moreover, groups I, II, and III patients
are treated with additional intramuscular injection of
Please cite this article as: Chiang C-P et al., Atrophic glossitis: Etiology, serum autoantibodies, anemia, hematinic deficiencies, hyper-
homocysteinemia, and management, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.04.015
vitamin B12 (one ampule per week for 2 months and one
ampule per month thereafter; each ampule contained
1000 mg of hydroxocobalamin in 1 ml of distilled water),
oral administration of folic acid tablet (2 tablets per day for
2 months and one tablet per day thereafter; each tablet
contained 5 mg of folic acid), and oral administration of
iron tablet (one tablet per day; each tablet contained
100 mg of Fe (OH)3 polymaltose complex), respectively.
Furthermore, group IV patients are treated with additional
intramuscular injection of vitamin B12 and oral adminis-
tration of iron tablet, and group V patients are treated with
vitamin BC capsules only. In addition, for those AG patients
with dysfunction of taste (n Z 22), additional supplemen-
tation of zinc (two tablets per day for 2 months and one
tablet per day thereafter; each tablet contained 10 mg of
zinc) is given to the patients. The end point of vitamins,
iron or zinc supplement treatments is the disappearance of
all oral symptoms including the burning sensation of oral
mucosa (91 patients), dry mouth (71 patients), numbness of
the tongue (51 patients), and dysfunction of taste (22 pa-
tients). In the study, only the 91 AG patients obtained
complete remission of all oral symptoms are included and
analyzed.19 We found that our supplement treatments for
groups I, II, III, IV, and V patients can reduce the high serum
homocysteine levels to significantly lower levels after a
mean treatment period of 8.3e11.6 months. Moreover, our
supplement treatments for groups I, II, III and IV patients
can increase the corresponding lower mean serum deficient
hematinic levels to significantly higher mean levels after a
mean treatment period of 8.4e11.6 months. In addition,
our five supplement treatments can raise the mean blood
Hb levels from relatively lower to significantly higher levels
after a mean treatment period of 8.3e11.6 months.
Furthermore, our five supplement treatments plus addi-
tional supplementation of zinc for the patients with
dysfunction of taste can result in complete remission of all
oral symptoms after a mean treatment period of 8.3e11.6
months.19 The above findings indicate that examination of
complete blood count and the serum levels of iron, vitamin
B12, and folic acid is very important for treatment of AG
patients.2,3,16e19
Our previous studies showed burning sensation of tongue
mucosa in 100% of 176 AG patients and 98.5% of 1064 AG
patients.2,3 For these patients, topical application of
corticosteroid (dexamethasone or triamcinolone acetonide)
ointment as a thin film 2e3 times per day onto the burning
tongue mucosa is usually sufficient to induce temporary
relief of burning sensation. The available topical cortico-
steroids in Taiwan include dexaltin oral paste (0.1% dexa-
methasone, 5 g/tube), kenalog in orabase (0.1%
triamcinolone acetonide, 5 g/tube), and nincort oral gel
(0.1% triamcinolone acetonide, 6 g/tube). However, the
long-term use of corticosteroid may cause oral candidiasis
which can be treated by antifungal drug (such as mycos-
tatin) for at least two weeks.33
Our previous studies found xerostomia in 79.0% of 176 AG
patients and in 70.1% of 1064 AG patients.2,3 Xerostomia is a
common problem that has been reported in 25% of older
adults.1 A number of developmental, iatrogenic, systemic
and local factors may play a role in causing xerostomia.
However, xerostomia in older adults is more likely the
result of medications (such as antihistamine, decongestant,
 + MODEL
Atrophic glossitis
antidepressant, antipsychotic, sedative, anxiolytic, anti-
hypertensive, and anticholinergic agents), because aged
patients are prone to take drugs associated with xerostomia
to overcome their systemic or psychotic disorders.1 In our
previous studies, the mean age of 176 AG patients is 61.1
years and that of 1064 AG patients is 62.7 years.2,3 There-
fore, it is not surprising to find dry mouth in 70.1%e79.0% of
our AG patients. AG patients with dry mouth can be treated
by artificial salivas, continuous sips of water throughout the
day, taking the sugarless candy to stimulate salivary
secretion, using oral lubricant containing lactoperoxidase,
lysozyme and lactoferrin (e.g., biotene mouth rinse and
Oralbalance moisturizing gel), and systemic administration
of sialagogue such as pilocarpine (Salagen, each tablet
contains 7.5 mg pilocarpine hydrochloride, three to four
times daily; a parasympathomimetic and muscarinic agonist
with particular effect on muscarinic acetylcholine receptor
M3) or cevimeline (Evoxac, 30 mg/cap, three times daily; a
parasympathomimetic and muscarinic agonist with partic-
ular effect on M3 receptors). Both pilocarpine and cevi-
meline are contraindicated in patients with asthma or
narrow-angle glaucoma. The side effects of pilocarpine
and cevimeline include excessive sweating, diarrhea, and
increased heart rate and blood pressure.1 Moreover, if the
dry mouth is secondary to the patient’s medication,
discontinuation or dose modification in consultation with
the patient’s physician may be considered and a substitute
drug can also be tried.1
Numbness of tongue mucosa, usually at the tip or lateral
border of the tongue, is noted in 57.4% of 176 AG patients
and in 50.7% of 1064 AG patients in our previous study.2,3
For these AG patients, intramuscular injection of vitamin
B12 (one ampule per week; each ampule contained 1000 mg
of hydroxocobalamin in 1 ml of distilled water) or oral
administration of vitamin B12 (two capsules per day, each
capsule contained 500 mg of methycobal) for 2e3 months
are effective to reduce the numbness of the tongue in some
of our AG patients.19
AG patients may have concomitant erythematous or
pseudomembranous candidiasis. Our previous study used
periodic acid-Schiff (PAS) stain and 20% potassium hydrox-
ide method to identify candida pseudohyphae or yeasts on
two exfoliative cytologic slides prepared from the atrophic
lesion on the dorsal surface of the tongue of each AG pa-
tient. Candidiasis on the dorsal surface of the tongue is
discovered in 12.5% of 176 AG patients.2 However, Terai and
Shimahara68 showed pseudohyphae of Candida albicans in
14 (82.4%) of 17 AG patients by direct cytologic examina-
tion. They also found that 24 (60%) of 40 AG patients have
pre-disposing factors of candidiasis including diabetes
mellitus, malignancy, systemic steroid therapy, long-term
antibiotic therapy, and others in their medical history.68
Because normal and sufficient saliva can provide cleansing
and antimicrobial activity, an increased prevalence of oral
candidiasis may be noted in AG patients with xerostomia.2
For these AG patients with candidiasis, antifungal drug
(such as mycostatin) should be given to the patients for at
least two weeks to eliminate oral candidiasis.33
H. pylori infection can cause atrophic gastritis which
leads to achlorhydria and intrinsic factor deficiency and
finally results in iron and vitamin B12 deficiencies and
AG.9,60e63 AG patients with H. pylori infection or diabetes
Please cite this article as: Chiang C-P et al., Atrophic glossitis: Etiology, serum autoantibodies, anemia, hematinic deficiencies, hyper-
homocysteinemia, and management, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.04.015
5
mellitus should be referred to gastroenterologist or endo-
crinologist for further treatment, respectively.
Conclusions and important suggestions for
atrophic glossitis patients
1. Maintenance of good oral hygiene is important for the AG
patients, especially those with dry mouth.
2. The AG patients, especially those with burning sensation
of oral mucosa, should avoid the hot, salty, acidic or
spicy food stuffs as well as overwork, extreme fatigue,
and insomnia.
3. Enough nutrition, exercise, and rest may benefit to the
AG patients and prevent them from recurrence of AG.
4. For AG patients, it is very important to examine the
complete blood count, serum hematinic, homocysteine,
and organ-specific autoantibody levels to see whether
these AG patients have anemia, hematinic deficiencies,
hyperhomocysteinemia, and serum autoantibody
positivity.
5. Supplementation of iron, vitamin B12, and folic acid to
those AG patients with corresponding hematinic de-
ficiencies, of zinc to those AG patients with dysfunction
of taste, and of vitamin BC capsule for those AG patients
without definite hematinic deficiencies can result in
partial or complete remission of AG.
6. If the AG patients also have systemic diseases such as
diabetes mellitus, liver or kidney diseases, or H. pylori
infection, these patients should be referred to associ-
ated physicians for further treatment.
7. Treatment of AG should be tailored to each patient
individually and its main goal is to achieve complete
remission of all oral symptoms including the burning
sensation of tongue mucosa, dry mouth, numbness of the
tongue, and dysfunction of taste symptoms and com-
plete recovery of AG.
8. Even if the AG patients are asymptomatic, they should
be re-evaluated every 3e6 months until there is no
recurrence of AG for at least one year.
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-B-
002-125-MY3 and No. 105-2314-B-002-075-MY2) of Ministry
of Science and Technology, Republic of China.
References
1. Neville BW, Damm DD, Allen CM, Chi AC. Oral and Maxillofacial
Pathology. 4th ed. St. Louis: Elsevier; 2016. pp. 11, 12, 191e3,
432, 433, 726e8, 769e74.
2. Sun A, Lin HP, Wang YP, Chiang CP. Significant association of
deficiency of hemoglobin, iron and vitamin B12, high ho-
mocysteine level, and gastric parietal cell antibody
 + MODEL
6 C.-P. Chiang et al.
positivity with atrophic glossitis. J Oral Pathol Med 2012;
41:500e4.
3. Chiang CP, Chang JYF, Wang YP, Wu YC, Wu YH, Sun A. Signif-
icantly higher frequencies of anemia, hematinic deficiencies,
hyperhomocysteinemia, and serum gastric parietal cell anti-
body positivity in atrophic glossitis patients. J Formos Med
Assoc 2018;117:1065e71.
4. Demir N, Do gan M, Koç A, Kaba S, Bulan K, Ozkol HU, et al.
Dermatological findings of vitamin B12 deficiency and
resolving time of these symptoms. Cutan Ocul Toxicol 2014;
33:70e3.
5. Bao ZX, Yang XW, Shi J, Liu LX. Serum zinc levels in 368 pa-
tients with oral mucosal diseases: a preliminary study. Med
Oral Patol Oral Cir Bucal 2016;21:e335e40.
6. Drinka PJ, Langer EH, Voeks SK, Scott L, Morrow FD. Nutritional
correlates of atrophic glossitis: possible role of vitamin E in
papillary atrophy. J Am Coll Nutr 1993;12:14e20.
7. Bohmer T, Mowe M. The association between atrophic glossitis
and protein-calorie malnutrition in old age. Age Ageing 2000;
29:47e50.
8. Terai H, Shimahara M. Atrophic tongue associated with
Candida. J Oral Pathol Med 2005;34:397e400.
9. Gall-Troselj K, Mravak-Stipetic M, Jurak I, Ragland WL,
Pavelic J. Helicobacter pylori colonization of tongue mucosa -
increased incidence in atrophic glossitis and burning mouth
syndrome (BMS). J Oral Pathol Med 2001;30:560e3.
10. Sweeney MP, Bagg J, Baxter WP, Aitchison TC. Oral disease in
terminally ill cancer patients with xerostomia. Oral Oncol
1998;34:123e6.
11. Farman AG. Atrophic lesions of the tongue: a prevalence study
among 175 diabetic patients. J Oral Pathol 1976;5:255e64.
12. Erriu M, Pili FM, Cadoni S, Garau V. Diagnosis of lingual atrophic
conditions: associations with local and systemic factors. A
descriptive review. Open Dent J 2016;10:619e35.
13. Spence JD. Homocysteine-lowering therapy: a role in stroke
prevention? Lancet Neurol 2007;6:830e8.
14. Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M, et al.
Homocysteine lowering with folic acid and B vitamins in
vascular disease. N Engl J Med 2006;354:1567e77.
15. Chiang CP, Chang JYF, Wang YP, Wu YH, Wu YC, Sun A. Gastric
parietal cell and thyroid autoantibodies in patients with atro-
phic glossitis. J Formos Med Assoc 2019 (in press).
16. Chiang CP, Chang JYF, Wang YP, Wu YH, Wu YC, Sun A. Anemia,
hematinic deficiencies, and hyperhomocysteinemia in gastric
parietal cell antibody-positive and -negative atrophic glossitis
patients. J Formos Med Assoc 2019;118:565e71.
17. Chiang CP, Chang JYF, Wang YP, Wu YH, Wu YC, Sun A. He-
matinic deficiencies and hyperhomocysteinemia in gastric pa-
rietal cell antibody-positive or gastric and thyroid
autoantibodies-negative atrophic glossitis patients. J Formos
Med Assoc 2019 (in press).
18. Kuo YS, Wu YH, Chang JYF, Wang YP, Wu YC, Sun A. Blood
profile of atrophic glossitis patients with thyroglobulin anti-
body/thyroid microsomal antibody positivity but without
gastric parietal cell antibody positivity. J Formos Med Assoc
2019 (in press).
19. Sun A, Wang YP, Lin HP, Chen HM, Cheng SJ, Chiang CP. Sig-
nificant reduction of homocysteine level with multiple B vita-
mins in atrophic glossitis patients. Oral Dis 2013;19:519e24.
20. Sun A, Lin HP, Wang YP, Chen HM, Cheng SJ, Chiang CP. Sig-
nificant reduction of serum homocysteine level and oral
symptoms after different vitamin supplement treatments in
patients with burning mouth syndrome. J Oral Pathol Med
2013;42:474e9.
21. Lin HP, Wang YP, Chen HM, Kuo YS, Lang MJ, Sun A. Significant
association of hematinic deficiencies and high blood homo-
cysteine levels with burning mouth syndrome. J Formos Med
Assoc 2013;112:319e25.
Please cite this article as: Chiang C-P et al., Atrophic glossitis: Etiology, serum autoantibodies, anemia, hematinic deficiencies, hyper-
homocysteinemia, and management, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.04.015
22. Chen HM, Wang YP, Chang JYF, Wu YC, Cheng SJ, Sun A. Sig-
nificant association of deficiencies of hemoglobin, iron, folic
acid, and vitamin B12 and high homocysteine level with oral
lichen planus. J Formos Med Assoc 2015;114:124e9.
23. Chang JYF, Chiang CP, Hsiao CK, Sun A. Significantly higher
frequencies of presence of serum autoantibodies in Chinese
patients with oral lichen planus. J Oral Pathol Med 2009;
38:48e54.
24. Chang JYF, Chen IC, Wang YP, Wu YH, Chen HM, Sun A. Anemia
and hematinic deficiencies in gastric parietal cell antibody-
positive and antibody-negative erosive oral lichen planus pa-
tients with thyroid antibody positivity. J Formos Med Assoc
2016;115:1004e11.
25. Chang JYF, Wang YP, Wu YH, Su YX, Tu YK, Sun A. Hematinic
deficiencies and anemia statuses in anti-gastric parietal cell
antibody-positive or all autoantibodies-negative erosive oral
lichen planus patients. J Formos Med Assoc 2018;117:
227e34.
26. Chang JYF, Wang YP, Wu YC, Wu YH, Tseng CH, Sun A. Hema-
tinic deficiencies and anemia statuses in antigastric parietal
cell antibody-positive erosive oral lichen planus patients with
desquamative gingivitis. J Formos Med Assoc 2016;115:860e6.
27. Chang JYF, Chiang CP, Wang YP, Wu YC, Chen HM, Sun A.
Antigastric parietal cell and antithyroid autoantibodies in pa-
tients with desquamative gingivitis. J Oral Pathol Med 2017;
46:307e12.
28. Kuo RC, Lin HP, Sun A, Wang YP. Prompt healing of erosive oral
lichen planus lesion after combined corticosteroid treatment
with locally injected triamcinolone acetonide plus oral pred-
nisolone. J Formos Med Assoc 2012;112:216e20.
29. Sun A, Chang JYF, Chiang CP. Examination of circulating serum
autoantibodies and hematinics is important for treatment of
oral lichen planus. J Formos Med Assoc 2017;116:569e70.
30. Lin HP, Wang YP, Chia JS, Sun A. Modulation of serum anti-
thyroglobulin and anti-thyroid microsomal autoantibody
levels by levamisole in patients with oral lichen planus. J
Formos Med Assoc 2011;110:169e74.
31. Lin HP, Wang YP, Chia JS, Sun A. Modulation of serum antinu-
clear antibody levels by levamisole treatment in patients with
oral lichen planus. J Formos Med Assoc 2011;110:316e21.
32. Wu KM, Wang YP, Lin HP, Chen HM, Chia JS, Sun A. Modulation
of serum smooth muscle antibody levels by levamisole treat-
ment in patients with oral lichen planus. J Formos Med Assoc
2013;112:352e7.
33. Chiang CP, Chang JYF, Wang YP, Wu YH, Lu SY, Sun A. Oral
lichen planus e differential diagnoses, serum autoantibodies,
hematinic deficiencies, and management. J Formos Med Assoc
2018;117:756e65.
34. Sun A, Chen HM, Cheng SJ, Wang YP, Chang JYF, Wu YC,
et al. Significant association of deficiency of hemoglobin,
iron, vitamin B12, and folic acid and high homocysteine
level with recurrent aphthous stomatitis. J Oral Pathol Med
2015;44:300e5.
35. Wu YC, Wu YH, Wang YP, Chang JYF, Chen HM, Sun A. Anti-
gastric parietal cell and antithyroid autoantibodies in patients
with recurrent aphthous stomatitis. J Formos Med Assoc 2017;
116:4e9.
36. Wu YC, Wu YH, Wang YP, Chang JYF, Chen HM, Sun A. Hema-
tinic deficiencies and anemia statuses in recurrent aphthous
stomatitis patients with or without atrophic glossitis. J Formos
Med Assoc 2016;115:1061e8.
37. Wu YH, Chang JYF, Wang YP, Wu YC, Chen HM, Sun A. Anemia
and hematinic deficiencies in anti-gastric parietal cell
antibody-positive and enegative recurrent aphthous stomatitis
patients with anti-thyroid antibody positivity. J Formos Med
Assoc 2017;116:145e52.
38. Lin HP, Wu YH, Wang YP, Wu YC, Chang JYF, Sun A. Anemia and
hematinic deficiencies in anti-gastric parietal cell antibody-
 + MODEL
Atrophic glossitis
positive or all autoantibodies-negative recurrent aphthous
stomatitis patients. J Formos Med Assoc 2017;116:99e106.
39. Chiang CP, Chang JYF, Sun A. Examination of serum hematinics
and autoantibodies is important for treatment of recurrent
aphthous stomatitis. J Formos Med Assoc 2018;117:258e60.
40. Kuo YS, Chang JYF, Wang YP, Wu YC, Wu YH, Sun A.
Significantly higher frequencies of hemoglobin, iron,
vitamin B12, and folic acid deficiencies and of hyper-
homocysteinemia in patients with Behcet’s disease. J For-
mos Med Assoc 2018;117:932e8.
41. Lin HP, Wu YH, Chang JYF, Wang YP, Chen HM, Sun A. Gastric
parietal cell and thyroid autoantibodies in patients with Beh-
cet’s disease. J Formos Med Assoc 2018;117:505e11.
42. Wu YH, Chang JYF, Wang YP, Wu YC, Chen HM, Sun A. Gastric
parietal cell and thyroid autoantibodies in Behcet’s disease
patients with or without atrophic glossitis. J Formos Med Assoc
2018;117:691e6.
43. Wu YH, Chang JYF, Wang YP, Wu YC, Chen HM, Sun A. Hemo-
globin, iron, vitamin B12, and folic acid deficiencies and
hyperhomocysteinemia in Behcet’s disease patients with
atrophic glossitis. J Formos Med Assoc 2018;117:559e65.
44. Chiang CP, Wu YH, Chang JYF, Wang YP, Wu YC, Sun A. He-
matinic deficiencies and hyperhomocysteinemia in gastric pa-
rietal cell antibody-positive or gastric and thyroid
autoantibodies-negative Behcet’s disease patients. J Formos
Med Assoc 2019;118:347e53.
45. Chiang CP, Wu YH, Chang JYF, Wang YP, Chen HM, Sun A. Serum
thyroid autoantibodies are not associated with anemia, he-
matinic deficiencies, and hyperhomocysteinemia in patients
with Behcet’s disease. J Dent Sci 2018;13:256e62.
46. Chiang CP, Hsieh RP, Chen THH, Chang YF, Liu BY, Wang JT,
et al. High incidence of autoantibodies in Taiwanese pa-
tients with oral submucous fibrosis. J Oral Pathol Med 2002;
31:402e9.
47. Wang YP, Wu YC, Cheng SJ, Chen HM, Sun A, Chang JYF.
High frequencies of vitamin B 12 and folic acid deficiencies
and gastric parietal cell antibody positivity in oral sub-
mucous fibrosis patients. J Formos Med Assoc 2015;114:
813e9.
48. Chiang CP, Chang JYF, Wu YH, Sun A, Wang YP, Chen HM. He-
matinic deficiencies and anemia in gastric parietal cell
antibody-positive and -negative oral submucous fibrosis pa-
tients. J Dent Sci 2018;13:68e74.
49. Sun A, Wang YP, Lin HP, Jia JS, Chiang CP. Do all the patients
with gastric parietal cell antibodies have pernicious anemia?
Oral Dis 2013;19:381e6.
50. Sun A, Chang JYF, Wang YP, Cheng SJ, Chen HM, Chiang CP. Do
all the patients with vitamin B12 deficiency have pernicious
anemia? J Oral Pathol Med 2016;45:23e7.
51. Chang JYF, Wang YP, Wu YC, Cheng SJ, Chen HM, Sun A. He-
matinic deficiencies and pernicious anemia in oral mucosal
disease patients with macrocytosis. J Formos Med Assoc 2015;
114:736e41.
Please cite this article as: Chiang C-P et al., Atrophic glossitis: Etiology, serum autoantibodies, anemia, hematinic deficiencies, hyper-
homocysteinemia, and management, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2019.04.015
7
52. Sun A, Chang JYF, Wang YP, Cheng SJ, Chen HM, Chiang CP.
Effective vitamin B12 treatment can reduce serum anti-gastric
parietal cell antibody titer in patients with oral mucosal dis-
ease. J Formos Med Assoc 2016;115:837e44.
53. Wu YC, Wang YP, Chang JYF, Cheng SJ, Chen HM, Sun A. Oral
manifestations and blood profile in patients with iron defi-
ciency anemia. J Formos Med Assoc 2014;113:83e7.
54. Wang YP, Chang JYF, Wu YC, Cheng SJ, Chen HM, Sun A. Oral
manifestations and blood profile in patients with thalassemia
trait. J Formos Med Assoc 2013;112:761e5.
55. Lin HP, Wu YH, Wang YP, Wu YC, Chang JYF, Sun A. Anemia and
hematinic deficiencies in gastric parietal cell antibody-positive
and enegative oral mucosal disease patients with micro-
cytosis. J Formos Med Assoc 2017;116:613e9.
56. Wang YP, Lin HP, Chen HM, Kuo YS, Lang MJ, Sun A. Hemo-
globin, iron, and vitamin B12 deficiencies and high blood ho-
mocysteine levels in patients with anti-thyroid autoantibodies.
J Formos Med Assoc 2014;113:155e60.
57. Chang JYF, Wang YP, Wu YC, Cheng SJ, Chen HM, Sun A. He-
matinic deficiencies and anemia statuses in oral mucosal dis-
ease patients with folic acid deficiency. J Formos Med Assoc
2015;114:806e12.
58. Chang JYF, Wang YP, Wu YC, Cheng SJ, Chen HM, Sun A. Blood
profile of oral mucosal disease patients with both vitamin B12
and iron deficiencies. J Formos Med Assoc 2015;114:532e8.
59. Sun A, Chang JYF, Chiang CP. Blood examination is necessary
for oral mucosal disease patients. J Formos Med Assoc 2016;
115:1e2.
60. Taylor KB, Roitt IM, Doniach D, Coushman KG, Shapland C.
Autoimmune phenomena in pernicious anemia: gastric anti-
bodies. BMJ 1962;2:1347e52.
61. Snow CF. Laboratory diagnosis of vitamin B12 and folate defi-
ciency. A guide for the primary care physician. Arch Intern Med
1999;159:1289e98.
62. Lahner E, Annibale B. Pernicious anemia: new insights from a
gastroenterological point of view. World J Gastroenterol 2009;
15:5121e8.
63. Oh RC, Brown DL. Vitamin B12 deficiency. Am Fam Phys 2003;
67:979e86.
64. Shine JW. Microcytic anemia. Am Fam Physician 1997;55:
2455e62.
65. Dayan CM, Daniels GH. Chronic autoimmune thyroiditis. N Engl
J Med 1996;335:99e107.
66. Lo CC, Hsu PI, Lo GH, Lai KH, Tseng HH, Lin CK, et al. Impli-
cations of anti-parietal cell antibodies and anti-Helicobacter
pylori antibodies in histological gastritis and patient
outcome. World J Gastroenterol 2005;11:4715e20.
67. Lee HW, Hahm KB, Lee JS, Ju YS, Lee KM, Lee KW. Association
of the human leukocyte antigen class II alleles with chronic
atrophic gastritis and gastric carcinoma in Koreans. J Dig Dis
2009;10:265e71.
68. Terai H, Shimahara M. Atrophic tongue associated with
Candida. J Oral Pathol Med 2005;34:397e400.