Article

Clinical Characteristics and Prevalence of Celiac Disease in a

Large Cohort of Type 1 Diabetes from Saudi Arabia
Mohammed Hakami 1,† , Saeed Yafei 1,2, *,† , Abdulrahman Hummadi 1 , Raed Abutaleb 1 , Abdullah Khawaji 1 ,
Yahia Solan 1 , Turki Aljohani 1 , Ali Jaber Alhagawy 1 , Amer Al Ali 3 , Shakir Bakkari 4 , Morghma Adawi 3 ,
Maram Saleh 3 , Sayidah Zaylaee 1 , Rashad Aref 1 , Khaled Tahash 1 , Ebrahim Haddad 1 , Amnah Hakami 1 ,
Mohammed Hobani 1 and Ibrahem Abutaleb 5

1 Adult Endocrinology and Diabetes Department, Jazan Endocrinology & Diabetes Center, Ministry of Health,
Jazan 82723, Saudi Arabia
2 Endocrinology Department, Faculty of Medicine and Health Sciences, Taiz University, Taiz 6803, Yemen
3 Pediatric Endocrinology, Jazan Endocrinology & Diabetes Center, Ministry of Health,
Jazan 82723, Saudi Arabia
4 Gastroenterology Department, King Saud Medical City, Riyadh 11421, Saudi Arabia
5 Nursing Department, Ministry of Health, Jazan 45142, Saudi Arabia
* Correspondence: [email protected]
† These authors contributed equally to this work.

Abstract: Background and Objectives: The link between celiac disease (CD) and type 1 diabetes
(T1D) has been well-documented in the medical literature and is thought to be due to a shared
genetic predisposition in addition to environmental triggers. This study aimed to determine the
seroprevalence and biopsy-proven CD (PBCD) prevalence in individuals with T1D from Saudi Arabia
and identify their clinical characteristics and the impact on glycemic control. Materials and Methods:
A total of 969 children and adolescents with confirmed T1D were investigated. Prospective and
Citation: Hakami, M.; Yafei, S.; retrospective data were collected to include clinical, anthropometric, and biochemical data. Total IgA
Hummadi, A.; Abutaleb, R.; Khawaji, and anti-TTG-IgA antibodies were screened to detect seropositive cases. Upper intestinal endoscopy
A.; Solan, Y.; Aljohani, T.; Alhagawy, and biopsy were performed to find BPCD. Results: The seroprevalence of CD was 14.6% (141/969),
A.J.; Ali, A.A.; Bakkari, S.; et al. while BPCD prevalence was 7.5%. Females had a higher prevalence than males: 17.8% vs. 9.8%,
Clinical Characteristics and p < 0.001. The CD group had lower HbA1c and more frequent hypoglycemia than the seronegative
Prevalence of Celiac Disease in a group. Conclusions: This study highlighted the high prevalence of CD in T1D Saudi patients. CD has
Large Cohort of Type 1 Diabetes from
multiple effects on glycemic control, growth, and puberty in children and adolescents with T1D. We
Saudi Arabia. Medicina 2024, 60, 1940.
emphasize the importance of early screening for CD at the time of diabetes diagnosis and periodically
https://doi.org/10.3390/
after that or if any atypical features present, especially anemia, growth delay, underweight, or
medicina60121940
frequent hypoglycemia.
Academic Editor: Åke Sjöholm

Keywords: celiac disease; gluten enteropathy; type 1 diabetes; Saudi Arabia

Received: 12 October 2024
Revised: 7 November 2024
Accepted: 22 November 2024
Published: 25 November 2024
1. Introduction
Celiac disease (CD) is a common autoimmune enteropathy that is characterized by a
specific serological and histological profile triggered by gluten ingestion in a genetically
Copyright: © 2024 by the authors.
predisposed individual [1]. Clinical presentation of CD is classified into classic, non-classic,
Published by MDPI on behalf of
subclinical, potential, and refractory types [2]. Classic CD is more common in children and
the Lithuanian University of Health
mainly presents with intestinal manifestations like diarrhea, anorexia, abdominal distention,
Sciences. Licensee MDPI, Basel,
Switzerland. This article is an open
vitamin deficiencies, iron deficiency anemia, and failure to thrive. The non-classical forms
access article distributed under the
are also common in children and mostly present with symptoms of abdominal pain, anemia,
terms and conditions of the Creative and short stature, while adults are mostly asymptomatic [2]. Patients with untreated CD
Commons Attribution (CC BY) license may be presented with complications like osteoporosis, neurologic disorders, as well as
(https://creativecommons.org/ enteropathy-associated T-cell lymphoma and adenocarcinoma of the jejunum [3].
licenses/by/4.0/).

Medicina 2024, 60, 1940. https://doi.org/10.3390/medicina60121940 https://www.mdpi.com/journal/medicina

Medicina 2024, 60, 1940 2 of 10

Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by an ab-

solute deficiency of insulin secretion. The link between CD and type 1 diabetes has been
well documented in the medical literature and is thought to be due to a shared genetic
predisposition between the two conditions in addition to environmental triggers [3]. The
incidence and prevalence of CD and T1D are rapidly increasing in children and adoles-
cents. Recent estimates indicated that there are about 500,000 new cases of T1D discovered
annually over the world; thus, the prevalence of T1D is increasing by 0.34% annually [4].
Similarly, the incidence of CD has been significantly raised in the last 30 years, most proba-
bly due to changes in environmental and dietary factors [5]. From epidemiological views,
cross-sectional and longitudinal studies in T1D children and adolescents estimated that CD
prevalence ranges from 1.6% to 16.4% worldwide [6]. In the general population, the sero-
prevalence of CD was 1.1% to 1.6% of all ages compared with 0.5–0.9% of biopsy-confirmed
CD [7].
While CD and T1D have different clinical manifestations, they share similar genetic
backgrounds and autoimmune mechanisms, highlighting the complex relationship be-
tween genetics and the environment in developing both conditions [8]. The enteropathy
associated with celiac disease results from the presentation of gliadin peptide fragments by
antigen-presenting cells via human leukocyte antigen (HLA) proteins. About 95% of indi-
viduals with CD carry specific variants of the human leukocyte antigen (HLA), particularly
HLA-DR3/DQ2 and HLA-DQ8, to a lesser extent. Similarly, about 30–50% of patients with
TID are DR3/DR4 heterozygotes, which confers the highest diabetes risk [8]. Additionally,
90% of individuals with T1D have either DQ2 or DQ8 compared with 40% of the general
population [9]. HLA-DQ2 and DQ8 loci are the most important determinants of T1D
susceptibility. T1D individuals who are homozygote for HLA-DR3/DQ2 carry a 33% risk
for the presence of transglutaminase autoantibodies [10]. Despite this genetic background,
T1D and CD have environmental and dietary triggers initiating autoimmune pathogenicity.
The coexistence of CD and T1D presents unique challenges for individuals with both
conditions. Management of T1D in people with CD can be challenging. Individuals with
both conditions must adhere to a strict gluten-free diet to manage celiac disease while
also monitoring their blood sugar levels and administering insulin for T1D. Likewise,
the dietary restrictions for celiac disease may impact blood sugar control in individuals
with type 1 diabetes. Furthermore, in patients with T1D, the coexistence of CD not only
affects intestinal absorption of nutrients, calcium, and skeletal metabolism but also may
contribute to the higher risk of cardiovascular incidents and exaggerated complications,
such as nephropathy, retinopathy, and neuropathy [11]. Either symptomatic or not, CD
diagnosis can be screened by serologic investigations for serum IgA levels and specific
autoantibodies, including anti-endomysium (EMA), anti-tissue transglutaminase (tTG),
and anti-deamidated peptides of gliadin (DGP). CD confirmation small intestine endoscopy
and biopsy to detect pathological enteropathy.
Saudi Arabia is one of the top 10 countries with the highest prevalence and incidence
of type 1 diabetes in children and adolescents below the age of 20 [12]. Worldwide, and
in Saudi Arabia, there is a growing concern about the prevalence of celiac disease in
individuals with type 1 diabetes. The national prevalence of CD in the general population
of Saudi Arabia is unknown, but epidemiological studies estimated CD prevalence between
1.5% and 2.2%, making it one of the highest seroprevalence rates in the world [13,14]. The
high prevalence of T1D and CD in Saudi Arabia is not fully understood and cannot only
be related to genetic factors; environmental and dietary factors might also be involved.
Regarding the prevalence of CD in T1D, studies on children and adolescents reported
diverse results, where the rates ranged from 7.1 to 24.5% in different regions of Saudi
Arabia, which is also higher than the prevalence in Western countries [15–17]. The Saudi
guidelines for the management of T1D in children recommend tests for celiac disease within
one year of T1D diabetes, even in the absence of classic symptoms, and the test should be
repeated within 4–5 years or at any time with clinical reasoning [18].
Medicina 2024, 60, 1940 3 of 10

The objectives of this study were to estimate the seroprevalence and biopsy-proven
prevalence (PBCD) in individuals with T1D, identify their clinical presentation, and assess
the impact on glycemic control and implications for clinical practice.

2. Materials and Methods

2.1. Study Design and Patients
Jazan Endocrinology and Diabetes Center (JEDC) is a high-volume multidisciplinary
care center in southwestern Saudi Arabia. This referral center provides care to more than
13,400 diabetic patients, about 16.8% of whom have T1D. This study is a mixed retrospective
and prospective study that included 969 children and adolescents with confirmed T1D
who attended the pediatric and adolescent endocrinology clinics between March 2020 and
March 2023. Prospective data for this study were collected during the patient’s clinical
visits, while retrospective data were collected from electronic medical records.
Inclusion criteria included all T1D patients between the ages of 2 and 18 years. T1D was
confirmed by clinical profiling, C-peptide, and T1D autoantibodies. Patients with infrequent
visits or deficiency of medical records were managed as new cases to complete their medical
profile before enrollment in the study. Patients with type 2 diabetes, uncategorized diabetes,
diabetes other than T1D, and those who refused to participate in the study were excluded.
Sociodemographic and T1D-related information included age, sex, weight, height, age
of diagnosis, duration of diabetes, and age of CD diagnosis. Clinical, anthropometric, and
biochemical data were recorded. Body mass index (BMI) (kg/m2 ) was calculated from
weight (kg) and height (m) and adjusted for age and sex. Those with a standing height
below 2.5 SD or the 5th percentile for chronological age were considered short. Males
above 14 years or females above 13 years without the appearance of signs of puberty are
considered delayed puberty.
Glycemic control was assessed by HbA1c and ambulatory blood glucose profile (AGP).
Total insulin dose (unit/kg/day), frequency, and severity of hypoglycemia from self-
monitoring records and AGP were recorded. Other biochemical data included hemoglobin
level, liver function test, serum iron, ferritin, vitamin D, and calcium level. In this study, if
CD was already diagnosed before the beginning of the study, their medical records were
retrospectively investigated for clinical, serological, and pathological data to be included in
the prevalence rates.

2.2. Screening for CD

Intestinal and extraintestinal signs and symptoms related to CD were screened. In-
testinal symptoms included chronic abdominal pain, diarrhea, constipation, abdominal
distension, weight loss, vomiting, and anorexia. Extraintestinal symptoms included delayed
puberty, stunted growth, iron-deficiency anemia, vitamin D levels, and liver transaminases.
According to ESPGHAN criteria for diagnosis of CD [19], serologic screening for
CD was performed with measurement of total IgA and anti-tissue transglutaminase
(anti-tTG-IgA). Anti-tTG IgA has high sensitivity, specificity, and positive predictive value
and is the most reliable test for CD screening in people with normal serum IgA levels [20].
In this study, anti-EMA-IgA was requested for patients with low positive Anti-tTG IgA.
The cut-off value of anti-TTG-IgA ≥ 20 IU/mL is considered positive, as per the lab
reference range. The seropositive group included any patient with positive anti-tTG-IgA.
So, we divided the seropositive group into two subgroups.
Patients with anti-tTG Ab above 10× ULN.
Patients with positive anti-tTG IgA < 10× ULN had to repeat the test within 6 months.
If the anti-tTG IgA value < 20 U/mL on the second test, they were excluded from the
endoscopy. For patients with persistent positive anti-tTG, anti-EMA-IgA was requested.

2.3. Endoscopic Study

Seropositive patients were referred for endoscopy and biopsy if they accepted the
procedure. Histological abnormalities associated with CD can be patchy, so at least four
Medicina 2024, 60, 1940 4 of 10

biopsies were taken from the distal duodenum and duodenal bulb of each patient to
confirm the CD. Finally, histological interpretation of the samples was conducted by an
experienced pathologist unaware of the clinical and serologic data. The results were
reported according to the modified Marsh classification [21]. For diagnosis of BPCD,
pathologic reports of Marsh 2 or 3 were considered diagnostic for PBCD. Marsh 2 indicates
normal villi with intraepithelial lymphocytosis and crypt hyperplasia. Marsh 3 indicates
intraepithelial lymphocytosis, crypt hyperplasia, and villous atrophy. Marsh 3 included
three subcategories according to the severity of villous atrophy: March 3a, with mild
villous atrophy, Marsh 3b, with marked villous atrophy, and March 3c, with complete
villous atrophy.
When endoscopy was not accepted, we used the no-biopsy approach for the diagnosis
of CD as recommended by ESPGHAN criteria for diagnosis of CD [19]. CD can be consid-
ered in symptomatic children and adolescents with anti-tTG-IgA ≥ 10× ULN and positive
EMA-IgA in a second serum sample without the need for biopsy.

2.4. Ethical Consideration

This study was performed under the declaration of Helsinki and granted ethical
approval from the Jazan Health Cluster Ethics Committee, Saudi Arabia. Participants
and/or their parents gave a written informed consent on a form explaining the procedure
of the study and the participant’s rights.

2.5. Statistical Analysis

Sociodemographic and clinical characteristics were described by descriptive analysis.
Count and percentage values were calculated for categorical variables. Continuous vari-
ables that follow a normal distribution were summarized as mean ± SD, while medians
represented other variables. For comparison between the seropositive and seronegative
groups, the x2 test was used for categorical variables and the t-test for continuous variables.
When the normality of distribution was not fulfilled, the Mann–Whitney U test was used.
Statistical analyses were conducted using SPSS Version 26 (IBM, Armonk, NY, USA). The
level of significance was determined at p < 0.05.

3. Results
This study included 969 participants with Type 1 diabetes, children below 14 represent
50.7% of the total sample. T1D females accounted for 59.1% of the total sample. The mean
age at inclusion in this study was 14 ± 3.4 years, ranging from 2 to 18 years. The median
duration of diabetes was 4 years (range 0–15 years), and the mean age at diagnosis of T1D
was 9.6 ± 3.7 years (range: 1–17 years). Of the total sample, 37.2% were underweight, 44.8%
had normal BMI, 11.8% were overweight, and 6.2% had obesity. Other sociodemographic
and clinical features of the participants are provided in Table 1.

Table 1. Anthropometric, clinical, and biochemical characteristics.

Seronegative Seropositive
p*
(n = 828) (n = 141)
Gender, males, n (%) 357 (43.1) 39 (9.8) <0.001
Gender, females, n (%) 471 (56.9) 102 (17.8)
Age at inclusion, years 14.9 ± 3.4 13.8 ± 3.6 <0.001
Age at T1D diagnosis, years 9.9 ± 3.7 8.1 ± 3.3 <0.001
Duration of diabetes, years 5 ± 2.9 5.7 ± 3.2 0.010
HbA1c, % 9.5 ± 1.6 8.8 ± 2.1 <0.001
BMI, kg/m2 22.5 ± 4.6 19.1 ± 4.2 <0.001
Medicina 2024, 60, 1940 5 of 10

Table 1. Cont.

Seronegative Seropositive
p*
(n = 828) (n = 141)
Anemia, n (%) 213 (25.7%) 56 (41.1) <0.001
Short stature, n (%) 204 (24.6) 45 (31.9) 0.68
Hypoglycemia, n (%) 165 (19.9) 44 (31.2) 0.003
Recurrent DKA, n (%) 162 (19.6) 37 (26.3) 0.07
Vitamin D3 deficiency, n (%) 234 (28.3) 72 (51.1) <0.001
* p-value was calculated for seropositive vs. the seronegative group.

3.1. CD Seroprevalence
Anti-tTG IgA was >10× ULN in 96 patients (group 1) and <10× ULN in 68 patients
(group 2). Those with Anti-tTG IgA titers < 10× ULN had to repeat the serology within
6 months. After the exclusion of 23 patients who became negative within 6 months, the
final sample included 141 patients. So, the seroprevalence of CD in this study is 14.6%
(141/969). Females had a higher prevalence of CD than males: 17.8% vs. 9.8%, p < 0.001.
Serum IgA level was above the normal range in all patients. Upon review of medical
records, 34 patients were known CD patients (24.1%) before inclusion in the study.
From the seropositive group, eighty-nine patients (63.1%) were diagnosed within two
years of T1D diagnosis, and 29.8% were diagnosed within five years of T1D onset. The mean
delay between diagnosis of T1D and CD was 3.8 ± 2.7 years. The BMI was higher in the
seronegative group, 22.5 ± 4.6 kg/m2 , compared with the seropositive, 19.1 ± 4.2 kg/m2
(p < 0.001).
Typical and atypical symptoms reported by the CD patients included gastrointestinal
symptoms reported by 40.5%. The CD group had lower HbA1c (8.8 ± 2.1% vs. 9.5 ± 1.6%,
p < 0.001) and more frequent episodes of hypoglycemia compared with T1D without CD
31.2% vs. 19.9%, p = 0.003. Recurrent admission due to DKA was documented in 26.3% of
the CD group compared with 19.6% in the seronegative group, p > 0.05. About 31.9% of the
seropositive group had short stature, 51.2% had vitamin D deficiency, and 41.1% had iron
deficiency anemia. Other features in the CD group are presented in Table 2.

Table 2. Clinical features in patients with type 1 diabetes and celiac disease.

Clinical Symptoms, n = 141 %

Abdominal pain 23.8
Diarrhea 24.1
Constipation 6.4
Anemia 41.1
Short stature 31.9
Delayed puberty 9.2
Vitamin D deficiency 51.2

3.2. Histopathology Findings

Endoscopic examination was performed on 109 patients who accepted the proce-
dure. Histopathological changes compatible with the diagnosis of CD were confirmed in
73 patients (Figure 1). Thus, the prevalence of biopsy-proven CD was 7.5%. Thirty-six pa-
tients had Marsh 3c, 19 patients had Marsh 3b, and 18 patients had Marsh 3a. Symptomatic
patients with anti-tTG IgA above 10× ULN who refused the endoscopy were regarded as
confirmed CD and started on a gluten-free diet if EMA-IgA was also positive.
 patients (Figure 1). Thus, the prevalence of biopsy-proven CD was 7.5%. Thirty-six pa-
tients had Marsh 3c, 19 patients had Marsh 3b, and 18 patients had Marsh 3a. Symptomatic
Medicina 2024, 60, 1940 6 of 10
patients with anti-tTG IgA above 10× ULN who refused the endoscopy were regarded as
confirmed CD and started on a gluten-free diet if EMA-IgA was also positive.

Figure 1. Marsh 3b with intraepithelial lymphocytosis (left) and marked villous atrophy (right).
Figure 1. Marsh 3b with intraepithelial lymphocytosis (left) and marked villous atrophy (right).

4. Discussion
This study was conducted in the Jazan area of Saudi Arabia. Jazan Jazan is a highly popu- popu-
located in the southwestern
lated region located southwestern area area of of Saudi
Saudi Arabia. There is a growing concern
about the
about theprevalence
prevalenceofofceliacceliac disease
disease in the
in the SaudiSaudi population,
population, especially
especially in individuals
in individuals with
with Understanding
T1D. T1D. Understanding the relationship
the relationship between between
these two these two conditions
conditions is crucial is crucial for im-
for improving
proving
the the management
management and treatment
and treatment of patientsofwith patients
both with bothThis
diseases. diseases.
studyThisis thestudy is the
first study
first included
that study thata included
large numbera large number
of T1D of T1D
patients from patients
Saudi from
Arabia.SaudiTheArabia. The most
most important
important
result result
obtained obtained
from from
this study this the
is that study is that the seroprevalence
seroprevalence of CD was 14.6%of(141/969),
CD was 14.6% while
the BPCD while
(141/969), prevalence was 7.5%
the BPCD (73/969).
prevalence wasCD 7.5%was(73/969).
observed CDmorewas often
observed among morefemales,
often
especially those with longer diabetes duration: 17.8% vs. 9.8%,
among females, especially those with longer diabetes duration: 17.8% vs. 9.8%, p < 0.001.p < 0.001. The CD group
had
The more frequent
CD group had hypoglycemia
more frequent and lower HbA1c.
hypoglycemia and lower HbA1c.
Many
Many studies
studiesusing
usinganti-tTG
anti-tTGIgA IgAantibody
antibody screening
screening in different
in different regions of Saudi
regions Ara-
of Saudi
bia havehave
Arabia reported a high
reported prevalence
a high of CDof
prevalence inCDT1Dinpatients, frequencies
T1D patients, largely largely
frequencies differ among
differ
reports. The reported
among reports. seroprevalence
The reported of CD inofT1D
seroprevalence CDwas 7.3%,
in T1D was19.7%,
7.3%,and 21.2%
19.7%, andin21.2%
Jeddah,in
11.5% and 24.5% in Riyadh, 10.4% in Aseer, and 7.1 in Abha [16,17,22–26].
Jeddah, 11.5% and 24.5% in Riyadh, 10.4% in Aseer, and 7.1 in Abha [16,17,22–26]. A meta- A meta-analysis
of eight studies
analysis of eightinstudies
T1D Saudi
in T1Dpatients found that
Saudi patients found15.8% of15.8%
that them ofwere
them seropositive for CD,
were seropositive
while
for CD, while 12.8% had biopsy-proven CD [15]. This relatively high prevalence inArabia
12.8% had biopsy-proven CD [15]. This relatively high prevalence in Saudi Saudi
is comparable
Arabia to othertostudies
is comparable conducted
other studies in otherincountries
conducted in the Arab
other countries in theregion but much
Arab region but
higher than what
much higher than was
whatreported in Western
was reported countries
in Western [27,28].[27,28].
countries RecentRecent
studies from Arab
studies from
countries using Anti-TTG
Arab countries IgA reported
using Anti-TTG a CD prevalence
IgA reported of 9.1% in
a CD prevalence of Morocco [29], 16.6%
9.1% in Morocco in
[29],
Jordan [30], 17% in Oman [31], and only 5% in Qatar [32]. The high
16.6% in Jordan [30], 17% in Oman [31], and only 5% in Qatar [32]. The high prevalence of prevalence of diseases
that havethat
diseases a genetic
have abackground might be might
genetic background relatedbe inrelated
part to in
thepart
hightorates of consanguinity
the high rates of con-
among the Saudi population. Several studies on the Saudi
sanguinity among the Saudi population. Several studies on the Saudi population population reported thatreported
consan-
guinity might be above 50%, and the major form is first-cousin
that consanguinity might be above 50%, and the major form is first-cousin marriages marriages [33,34]. However,
genetics and consanguinity
[33,34]. However, are not
genetics and the sole factors
consanguinity are not thatthe
cansole
explain thisthat
factors high canprevalence
explain this of
T1D
highand CD. Different
prevalence of T1Dvariables
and CD.could be implicated,
Different variables including viral infections,
could be implicated, nutritional
including viral
factors, lifestyle changes, breastfeeding practices, and exposure to different environmental
infections, nutritional factors, lifestyle changes, breastfeeding practices, and exposure to
pollutants and toxins [12].
different environmental pollutants and toxins [12].
One explanation for this high prevalence might be related to dietary, environmental,
One explanation for this high prevalence might be related to dietary, environmental,
and genetic susceptibility shared by families in our region. The diversity of the results
and genetic susceptibility shared by families in our region. The diversity of the results
between different studies of Saudi Arabia could be explained by the different study designs,
between different studies of Saudi Arabia could be explained by the different study de-
age of patients, sample size, genetic and geographical background, and other factors that
signs, age of patients, sample size, genetic and geographical background, and other factors
mandate further national research from all regions of this country.
that mandate further national research from all regions of this country.
Regarding gender prevalence, our data confirm that CD is more prevalent in females
Regarding gender prevalence, our data confirm that CD is more prevalent in females
with T1D (1.8:1). This is similar to other epidemiological studies over the world and in
with T1D (1.8:1). This is similar to other epidemiological studies over the world and in
Saudi Arabia, where prevalence in females is double that in males [15,28]. Although T1D is
Saudi Arabia, where prevalence in females is double that in males [15,28]. Although T1D
equally prevalent among both genders in most populations, the high prevalence of CD in
T1D females suggests that hidden triggers could potentiate autoimmune pathogenesis in
the small intestine of the females. Some authors postulated intestinal microbiota, but the
exact reasons for this CD predominance in females are still not fully understood and likely
involve a combination of genetic, hormonal, and environmental factors [35].
Medicina 2024, 60, 1940 7 of 10

CD can occur at any age, but individuals with younger age at diabetes diagnoses are
at greater risk, especially if diabetes was diagnosed before the age of five [6,36]. However,
this was not a consistent finding, as other reports found marginal differences or no differ-
ences [30,37]. In our cohort, people who have diabetes diagnosed before the age of five
have a similar tendency for CD as those diagnosed with T1D above the age of five, but the
longer duration of diabetes was associated with a higher prevalence of CD.
In the current study, 91.9% of CD patients were diagnosed within 5 years of T1D onset.
This finding is similar to other cohorts from different studies, namely Saudi Arabia [17,22],
Jordan [30], India [38], and Italy [39]. This sequential co-occurrence has traditionally been
attributed to shared environmental and genetic factors, especially the HLA-DR3-DQ2 and
DR4-DQ8 haplotypes [40]. Thus, we emphasize the early screening for CD in T1D within
one year of diagnosis, which is recommended by the diabetes guidelines [41]. About
one-third of the CD cases in this study were diagnosed after two years of diabetes onset;
this also emphasizes the need for yearly screening of CD in T1D, at least for the first five
years. This recommendation becomes mandatory if patients have clinical features related
to CD, recurrent hypoglycemia, or uncontrolled diabetes [42].
Traditionally, patients with T1D and CD are mostly asymptomatic, while some might
present with atypical features or have features related to the impact of CD on diabetes [3].
The reported prevalence of asymptomatic patients with CD and T1D ranges from 35.7%
to 62.5% [8,43]. Regardless of the type of symptoms, there is often a prolonged delay
between symptom onset and celiac disease diagnosis. Among the 141 patients diagnosed
with CD in our study, most of them were asymptomatic or had non-specific symptoms.
Gastrointestinal symptoms were reported in 40.5%, and recurrent hypoglycemia in 31.2%
of the CD group. About 31.9% of CD cases have short stature, 51.2% are deficient in vitamin
D, and 41.1% have iron deficiency anemia. Two surveys in Germany found that people
with T1DM and CD had lower weight and height [44,45].
The American and the European guidelines for the diagnosis of CD proposed that
CD could be diagnosed in symptomatic children and adolescents without the need for
intestinal biopsy, provided that the level of TGA-IgA was 10-fold or more than the ULN
and positive result of the EMA tests in a second blood sample [19,46]. The reliability of this
no-biopsy approach for CD diagnosis was confirmed in a prospective multicenter study
with a positive predictive value (PPV) of >99% [47]. In our study, the histopathological
changes compatible with the diagnosis of CD were confirmed in 73 out of 109 patients who
accepted the endoscopy procedure. The histopathology reports found that patients with
partial or complete villous atrophy had higher levels of anti-tTG. These findings were also
documented in previous studies, where the level of anti-tTG > 10× ULN had a positive
correlation with the degree of villous atrophy [17,47].
In the present study, patients with CD had lower HbA1c and more frequent hypo-
glycemia than those with T1D alone. This impact of CD on HbA1c was more prominent in
symptomatic patients who have recurrent episodes of hypoglycemia. Studies on the impact
of CD on diabetes control are inconsistent [3,17,45]. Some studies reported lower HbA1c,
especially in the newly diagnosed symptomatic patients with malabsorption, other studies
reported higher HbA1c, especially in adults with delayed diagnosis of CD, and some
studies did not find any difference in HbA1c in those with and without CD [17,48,49]. The
inconsistency between results is related to different factors, including the age of patients,
delay in screening for CD, presence of symptoms, the effect of gluten-free diets, and other
factors that affect glycemic control [3]. Insulin requirement in the seropositive CD diabetic
patients was found by some authors to be lower than that in the seronegative groups, at
least before the introduction of a gluten-free diet [6,22]. However, other studies found no
difference in daily insulin doses [16].
There are important limitations to consider when interpreting the findings of this
study. It is important to note that future prospective national studies may provide a
more comprehensive understanding of CD prevalence and associated factors in the Saudi
population. This study also did not investigate the genetic background of those with or
Medicina 2024, 60, 1940 8 of 10

without CD, which is another limitation. Although this approach is not a recommendation
for the diagnosis of CD, it will be more robust if we investigate the genetic basis of CD and
T1D in this country with a high prevalence of both diseases. Additionally, future studies
may consider exploring the impact of gluten-free diets on glycemic control, continuous
glucose monitoring variables, and growth charts in our community.

5. Conclusions
This study highlighted the high prevalence of CD in Saudi patients with T1D and
investigated the detrimental effect of CD on glycemic control in children and adolescents.
We emphasize the importance of early screening for CD at the time of diabetes diagnosis
and periodically thereafter, or if any atypical features present, especially anemia, growth
delay, underweight, or frequent hypoglycemia.

Author Contributions: Conceptualization, S.Y. and Y.S.; methodology, A.H. (Abdulrahman Hummadi),
A.J.A., M.A. and S.B.; software, S.Z. and M.H. (Mohammed Hobani); validation, R.A. (Raed Abutaleb)
and A.K.; formal analysis, R.A. (Rashad Aref) and T.A.; investigation, A.A.A., M.A., K.T., E.H., R.A.
(Rashad Aref), and I.A.; resources, K.T.; data curation, M.S., M.H. (Mohammed Hobani) and A.H.
(Amnah Hakami); writing—original draft, S.Y. and R.A. (Raed Abutaleb); writing—review and edit-
ing, M.H. (Mohammed Hakami), A.K. and S.B.; visualization, Y.S.; supervision, A.H. (Abdulrahman
Hummadi); project administration, T.A. and E.H. All authors have read and agreed to the published
version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: This study was conducted in accordance with the Declaration
of Helsinki. It was reviewed and approved by The Jazan Health Cluster Ethics Committee, Saudi
Arabia. Approval No. H-10-Z-141, 2432 on 15 July 2024.
Informed Consent Statement: Written informed consent was obtained from Participants and/or
their parents on a form explaining the procedure of the study and the participant’s rights. This article
did not contain identifying characters or personal information, and the patient agreed to publish
the study.
Data Availability Statement: All the necessary information is provided within the manuscript. Any
other data that support the findings of this study are available from the first author upon request.
Conflicts of Interest: The authors declare no conflicts of interest.

References
1. El-Metwally, A.; Toivola, P.; AlAhmary, K.; Bahkali, S.; AlKhathaami, A.; AlSaqabi, M.K.; Al Ammar, S.A.; Jawed, M.; Alosaimi,
S.M. The Epidemiology of Celiac Disease in the General Population and High-Risk Groups in Arab Countries: A Systematic
Review. BioMed Res. Int. 2020, 2020, 6865917. [CrossRef]
2. Caio, G.; Volta, U.; Sapone, A.; Leffler, D.A.; De Giorgio, R.; Catassi, C.; Fasano, A. Celiac disease: A comprehensive current
review. BMC Med. 2019, 17, 142. [CrossRef] [PubMed]
3. Akirov, A.; Pinhas-Hamiel, O. Co-occurrence of type 1 diabetes mellitus and celiac disease. World J. Diabetes 2015, 6, 707–714.
[CrossRef] [PubMed]
4. Ogrotis, I.; Koufakis, T.; Kotsa, K. Changes in the Global Epidemiology of Type 1 Diabetes in an Evolving Landscape of
Environmental Factors: Causes, Challenges, and Opportunities. Medicina 2023, 59, 668. [CrossRef] [PubMed]
5. King, J.A.; Jeong, J.; Underwood, F.E.; Quan, J.; Panaccione, N.; Windsor, J.W.; Coward, S.; deBruyn, J.; Ronksley, P.E.; Shaheen,
A.A.; et al. Incidence of Celiac Disease Is Increasing Over Time: A Systematic Review and Meta-analysis. Am. J. Gastroenterol.
2020, 115, 507–525. [CrossRef]
6. Pham-Short, A.; Donaghue, K.C.; Ambler, G.; Phelan, H.; Twigg, S.; Craig, M.E. Screening for Celiac Disease in Type 1 Diabetes: A
Systematic Review. Pediatrics 2015, 136, e170–e176. [CrossRef]
7. Singh, P.; Arora, A.; Strand, T.A.; Leffler, D.A.; Catassi, C.; Green, P.H.; Kelly, C.P.; Ahuja, V.; Makharia, G.K. Global Prevalence of
Celiac Disease: Systematic Review and Meta-analysis. Clin. Gastroenterol. Hepatol. 2018, 16, 823–836.e822. [CrossRef]
8. Camarca, M.E.; Mozzillo, E.; Nugnes, R.; Zito, E.; Falco, M.; Fattorusso, V.; Mobilia, S.; Buono, P.; Valerio, G.; Troncone, R. Celiac
disease in type 1 diabetes mellitus. Ital. J. Pediatr. 2012, 38, 10. [CrossRef]
9. Ide, A.; Eisenbarth, G.S. Genetic susceptibility in type 1 diabetes and its associated autoimmune disorders. Rev. Endocr. Metab.
Disord. 2003, 4, 243–253. [CrossRef]
Medicina 2024, 60, 1940 9 of 10

10. Bao, F.; Yu, L.; Babu, S.; Wang, T.; Hoffenberg, E.J.; Rewers, M.; Eisenbarth, G.S. One third of HLA DQ2 homozygous patients with
type 1 diabetes express celiac disease-associated transglutaminase autoantibodies. J. Autoimmun. 1999, 13, 143–148. [CrossRef]
11. Rohrer, T.R.; Wolf, J.; Liptay, S.; Zimmer, K.P.; Fröhlich-Reiterer, E.; Scheuing, N.; Marg, W.; Stern, M.; Kapellen, T.M.; Hauffa, B.P.;
et al. Microvascular Complications in Childhood-Onset Type 1 Diabetes and Celiac Disease: A Multicenter Longitudinal Analysis
of 56,514 Patients from the German-Austrian DPV Database. Diabetes Care 2015, 38, 801–807. [CrossRef] [PubMed]
12. Robert, A.A.; Al-Dawish, A.; Mujammami, M.; Dawish, M.A.A. Type 1 Diabetes Mellitus in Saudi Arabia: A Soaring Epidemic.
Int. J. Pediatr. 2018, 2018, 9408370. [CrossRef] [PubMed]
13. Al-Hussaini, A.; Troncone, R.; Khormi, M.; AlTuraiki, M.; Alkhamis, W.; Alrajhi, M.; Halal, T.; Fagih, M.; Alharbi, S.; Bashir,
M.S.; et al. Mass Screening for Celiac Disease Among School-aged Children: Toward Exploring Celiac Iceberg in Saudi Arabia. J.
Pediatr. Gastroenterol. Nutr. 2017, 65, 646–651. [CrossRef]
14. Aljebreen, A.M.; Almadi, M.A.; Alhammad, A.; Al Faleh, F.Z. Seroprevalence of celiac disease among healthy adolescents in
Saudi Arabia. World J. Gastroenterol. 2013, 19, 2374–2378. [CrossRef] [PubMed]
15. Safi, M.A. Celiac disease in type 1 diabetes mellitus in the Kingdom of Saudi Arabia. Characterization and meta-analysis. Saudi
Med. J. 2019, 40, 647–656. [CrossRef] [PubMed]
16. Saadah, O.I.; Al-Agha, A.E.; Al Nahdi, H.M.; Bokhary, R.Y.; Bin Talib, Y.Y.; Al-Mughales, J.A.; Al Bokhari, S.M. Prevalence of
celiac disease in children with type 1 diabetes mellitus screened by anti-tissue transglutaminase antibody from Western Saudi
Arabia. Saudi Med. J. 2012, 33, 541–546.
17. Al-Hussaini, A.; Sulaiman, N.; Al-Zahrani, M.; Alenizi, A.; El Haj, I. High prevalence of celiac disease among Saudi children with
type 1 diabetes: A prospective cross-sectional study. BMC Gastroenterol. 2012, 12, 180. [CrossRef]
18. Bin-Abbas, B.S.; Al Qahtani, M.A. Clinical guidelines for the management of type 1 diabetes in children in Saudi Arabia endorsed
by the Saudi Society of Endocrinology and Metabolism, (SSEM). Int. J. Pediatr. Adolesc. Med. 2014, 1, 97–101. [CrossRef]
19. Husby, S.; Koletzko, S.; Korponay-Szabó, I.; Kurppa, K.; Mearin, M.L.; Ribes-Koninckx, C.; Shamir, R.; Troncone, R.; Auricchio, R.;
Castillejo, G.; et al. European Society Paediatric Gastroenterology, Hepatology and Nutrition Guidelines for Diagnosing Coeliac
Disease 2020. J. Pediatr. Gastroenterol. Nutr. 2020, 70, 141–156. [CrossRef]
20. Girard, C.; De Percin, A.; Morin, C.; Talvard, M.; Fortenfant, F.; Congy-Jolivet, N.; Le Tallec, C.; Olives, J.-P.; Mas, E. Accuracy of
Serological Screening for the Diagnosis of Celiac Disease in Type 1 Diabetes Children. Medicina 2023, 59, 1321. [CrossRef]
21. Oberhuber, G.; Granditsch, G.; Vogelsang, H. The histopathology of coeliac disease: Time for a standardized report scheme for
pathologists. Eur. J. Gastroenterol. Hepatol. 1999, 11, 1185–1194. [CrossRef] [PubMed]
22. Aljulifi, M.Z.; Mahzari, M.; Alkhalifa, L.; Hassan, E.; Alshahrani, A.M.; Alotay, A.A. The prevalence of celiac disease in Saudi
patients with type 1 diabetes mellitus. Ann. Saudi Med. 2021, 41, 71–77. [CrossRef] [PubMed]
23. Al-Hakami, A.M. Pattern of thyroid, celiac, and anti-cyclic citrullinated peptide autoantibodies coexistence with type 1 diabetes
mellitus in patients from Southwestern Saudi Arabia. Saudi Med. J. 2016, 37, 386–391. [CrossRef]
24. Al-Agha, A.E.; Alafif, M.M.; Abd-Elhameed, I.A. Glycemic control, complications, and associated autoimmune diseases in
children and adolescents with type 1 diabetes in Jeddah, Saudi Arabia. Saudi Med. J. 2015, 36, 26–31. [CrossRef]
25. Alshareef, M.A.; Aljabri, K.S.; Bokhari, S.A.; Al Jiffri, A.M.; Elsaoud, H.M.A.; Akl, A.F.; Fageeh, S.M.; Alreffi, A.N.; Eltayeb, A.A.;
Aljabri, N.K. The prevalence of celiac disease in Saudi patients with type 1 diabetes mellitus: Cross sectional study. Int. J. Diabetes
Metab. Disord. 2016, 1, 1–4.
26. Alghamdi, R.A.; Alghamdi, A.H.; Fureeh, A.A. Sero-prevalence of celiac disease among symptom-free type 1 diabetes mellitus in
Al-Baha region, Saudi Arabia. J. Pharm. Biol. Sci. 2018, 13, 22–26.
27. Nederstigt, C.; Uitbeijerse, B.S.; Janssen, L.G.M.; Corssmit, E.P.M.; de Koning, E.J.P.; Dekkers, O.M. Associated auto-immune
disease in type 1 diabetes patients: A systematic review and meta-analysis. Eur. J. Endocrinol. 2019, 180, 135–144. [CrossRef]
[PubMed]
28. Taczanowska, A.; Schwandt, A.; Amed, S.; Tóth-Heyn, P.; Kanaka-Gantenbein, C.; Volsky, S.K.; Svensson, J.; Szypowska, A. Celiac
disease in children with type 1 diabetes varies around the world: An international, cross-sectional study of 57 375 patients from
the SWEET registry. J. Diabetes 2021, 13, 448–457. [CrossRef]
29. Belhiba, O.; Bousfiha, A.A.; Jennane, F. Prevalence of celiac disease in Moroccan children with type 1 diabetes mellitus: A 16-year
cross-sectional study. Qatar Med. J. 2023, 2023, 37. [CrossRef]
30. Odeh, R.; Alassaf, A.; Gharaibeh, L.; Ibrahim, S.; Khdair Ahmad, F.; Ajlouni, K. Prevalence of celiac disease and celiac-related
antibody status in pediatric patients with type 1 diabetes in Jordan. Endocr. Connect. 2019, 8, 780–787. [CrossRef]
31. Al-Sinani, S.; Sharef, S.W.; Al-Yaarubi, S.; Al-Zakwani, I.; Al-Naamani, K.; Al-Hajri, A.; Al-Hasani, S. Prevalence of celiac disease
in omani children with type 1 diabetes mellitus: A cross sectional study. Oman Med. J. 2013, 28, 260–263. [CrossRef] [PubMed]
32. Alyafei, F.; Soliman, A.; Alkhalaf, F.; Sabt, A.; De Sanctis, V.; Elsayed, N.; Waseef, R. Prevalence of β-cell antibodies and associated
autoimmune diseases in children and adolescents with type 1 diabetes (T1DM) versus type 2 diabetes (T2DM) in Qatar. Acta
Biomed. 2018, 89, 32–39. [CrossRef] [PubMed]
33. Warsy, A.S.; Al-Jaser, M.H.; Albdass, A.; Al-Daihan, S.; Alanazi, M. Is consanguinity prevalence decreasing in Saudis?: A study in
two generations. Afr. Health Sci. 2014, 14, 314–321. [CrossRef] [PubMed]
34. Khayat, A.M.; Alshareef, B.G.; Alharbi, S.F.; AlZahrani, M.M.; Alshangity, B.A.; Tashkandi, N.F. Consanguineous Marriage and Its
Association with Genetic Disorders in Saudi Arabia: A Review. Cureus 2024, 16, e53888. [CrossRef]
Medicina 2024, 60, 1940 10 of 10

35. Jansson-Knodell, C.L.; Hujoel, I.A.; West, C.P.; Taneja, V.; Prokop, L.J.; Rubio-Tapia, A.; Murray, J.A. Sex Difference in Celiac Disease
in Undiagnosed Populations: A Systematic Review and Meta-analysis. Clin. Gastroenterol. Hepatol. 2019, 17, 1954–1968.e1913.
[CrossRef]
36. Cerutti, F.; Bruno, G.; Chiarelli, F.; Lorini, R.; Meschi, F.; Sacchetti, C. Younger age at onset and sex predict celiac disease in
children and adolescents with type 1 diabetes: An Italian multicenter study. Diabetes Care 2004, 27, 1294–1298. [CrossRef]
37. Larsson, K.; Carlsson, A.; Cederwall, E.; Jönsson, B.; Neiderud, J.; Jonsson, B.; Lernmark, Å.; Ivarsson, S.A.; Skåne Study Group.
Annual screening detects celiac disease in children with type 1 diabetes. Pediatr. Diabetes 2008, 9, 354–359. [CrossRef]
38. Bhadada, S.K.; Kochhar, R.; Bhansali, A.; Dutta, U.; Kumar, P.R.; Poornachandra, K.S.; Vaiphei, K.; Nain, C.K.; Singh, K. Prevalence
and clinical profile of celiac disease in type 1 diabetes mellitus in north India. J. Gastroenterol. Hepatol. 2011, 26, 378–381. [CrossRef]
39. Greco, D.; Pisciotta, M.; Gambina, F.; Maggio, F. Celiac disease in subjects with type 1 diabetes mellitus: A prevalence study in
western Sicily (Italy). Endocrine 2013, 43, 108–111. [CrossRef]
40. Hagopian, W.; Lee, H.S.; Liu, E.; Rewers, M.; She, J.X.; Ziegler, A.G.; Lernmark, Å.; Toppari, J.; Rich, S.S.; Krischer, J.P.; et al.
Co-occurrence of Type 1 Diabetes and Celiac Disease Autoimmunity. Pediatrics 2017, 140, e20171305. [CrossRef]
41. American Diabetes Association Professional Practice Committee. 14. Children and Adolescents: Standards of Care in
Diabetes—2024. Diabetes Care 2023, 47, S258–S281. [CrossRef]
42. Fröhlich-Reiterer, E.; Elbarbary, N.S.; Simmons, K.; Buckingham, B.; Humayun, K.N.; Johannsen, J.; Holl, R.W.; Betz, S.;
Mahmud, F.H. ISPAD Clinical Practice Consensus Guidelines 2022: Other complications and associated conditions in children
and adolescents with type 1 diabetes. Pediatr. Diabetes 2022, 23, 1451–1467. [CrossRef] [PubMed]
43. DeMelo, E.N.; McDonald, C.; Saibil, F.; Marcon, M.A.; Mahmud, F.H. Celiac Disease and Type 1 Diabetes in Adults: Is This a
High-Risk Group for Screening? Can. J. Diabetes 2015, 39, 513–519. [CrossRef] [PubMed]
44. Fröhlich-Reiterer, E.E.; Kaspers, S.; Hofer, S.; Schober, E.; Kordonouri, O.; Pozza, S.B.; Holl, R.W. Anthropometry, metabolic
control, and follow-up in children and adolescents with type 1 diabetes mellitus and biopsy-proven celiac disease. J. Pediatr. 2011,
158, 589–593.e582. [CrossRef]
45. Kaspers, S.; Kordonouri, O.; Schober, E.; Grabert, M.; Hauffa, B.P.; Holl, R.W. Anthropometry, metabolic control, and thyroid
autoimmunity in type 1 diabetes with celiac disease: A multicenter survey. J. Pediatr. 2004, 145, 790–795. [CrossRef]
46. Rubio-Tapia, A.; Hill, I.D.; Semrad, C.; Kelly, C.P.; Greer, K.B.; Limketkai, B.N.; Lebwohl, B. American College of Gastroenterology
Guidelines Update: Diagnosis and Management of Celiac Disease. Off. J. Am. Coll. Gastroenterol. ACG 2023, 118, 59–76. [CrossRef]
47. Werkstetter, K.J.; Korponay-Szabó, I.R.; Popp, A.; Villanacci, V.; Salemme, M.; Heilig, G.; Lillevang, S.T.; Mearin, M.L.; Ribes-
Koninckx, C.; Thomas, A.; et al. Accuracy in Diagnosis of Celiac Disease Without Biopsies in Clinical Practice. Gastroenterology
2017, 153, 924–935. [CrossRef]
48. Leeds, J.S.; Hopper, A.D.; Hadjivassiliou, M.; Tesfaye, S.; Sanders, D.S. High prevalence of microvascular complications in adults
with type 1 diabetes and newly diagnosed celiac disease. Diabetes Care 2011, 34, 2158–2163. [CrossRef]
49. Hansen, D.; Brock-Jacobsen, B.; Lund, E.; Bjørn, C.; Hansen, L.P.; Nielsen, C.; Fenger, C.; Lillevang, S.T.; Husby, S. Clinical benefit
of a gluten-free diet in type 1 diabetic children with screening-detected celiac disease: A population-based screening study with 2
years’ follow-up. Diabetes Care 2006, 29, 2452–2456. [CrossRef]

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual
author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to
people or property resulting from any ideas, methods, instructions or products referred to in the content.