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\title{Epidemiology and risk factors for gallstones in the paediatric and adult
population in the city of Al-Ahsa}



\author[1]{samia alfuraikh}%
\author[2]{sara algubaisi}%
\author[1]{lubna ALhamad}%
\author[1]{Khadiga  Mahmoud Hussein}%
\affil[1]{King Abdulaziz Hospital}%
\affil[2]{Prince Sultan Military Medical City}%


\vspace{-1em}



  
  \date{May 04, 2024}


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\selectlanguage{english}
\begin{abstract}
Background and Aims: Cholelithiasis is a common upper gastrointestinal
tract disorder in the Kingdom of Saudi Arabia. Analyses of risk factors
for gallstone formation may explain the need for lifestyle
modifications. Therefore, our aim was to identify sex- and age-related
differences in the prevalence and risk factors for gallstones among
Saudi individuals in the city of Al-Ahsa. Methods: The medical records
of patients, [?]1 year of age, with a radiologically confirmed diagnosis
of gallstones, between 2014 through 2016, were retrieved and relevant
demographic and clinical data extracted. Risk factors for cholelithiasis
for all age groups were identified. Results: A total of 618 patients had
radiologically confirmed gallstones over the 3-year period of
observation. The prevalence was higher among females than males (73\%
versus 27\%, respectively) in all age groups. In the paediatric group,
the prevalence of gallstones was higher among girls with obesity and
those with sickle cell disorders. Advanced age, a higher body mass
index, high low-density lipoproteins, triglycerides, and cholesterol
were independently associated with cholelithiasis in both gender of all
age groups. Hepatitis B and C were not found to be risk factors for
cholelithiasis. Conclusions: Older age, female sex, a high body mass
index, and hyperlipidaemia are major risk factors for gall stones
formation among all age groups. Haemolytic anaemia, namely sickle cell
disease, is a prevalent risk factor in paediatric population.%
\end{abstract}%



\sloppy


\textbf{Introduction}

An imbalance in the chemical constituents of bile components can result
in the formation of gallstones of varying size and
shape\textsuperscript{{[}1{]}}. Cholesterol supersaturation, gallbladder
dysfunction and nucleation defect play key roles in the pathogenesis of
gallstone formation \textsuperscript{{[}2{]}}. Gallstones are classified
into pure cholesterol stones, pigment stones, and mixed composition
stones \textsuperscript{{[}1,2{]}}. Cholesterol stones are yellow in
colour, more commonly found in adults, and might dissolve with bile acid
therapy \textsuperscript{{[}3{]}}. Pigment stones are classified into
brown or black types. Black pigment stones are more common in patients
with liver cirrhosis or chronic haemolytic
anaemias\textsuperscript{{[}4{]}}.

Epidemiological studies have revealed geographical influences on the
prevalence rate of gallstones \textsuperscript{{[}5,6{]}}. Worldwide,
there appears to be higher rates of cholelithiasis in Western Caucasian,
Hispanic, and Native American populations, with the rates being lower
among East European, African American, and Asian
populations\textsuperscript{{[}6{]}}.

The prevalence of gallstones in the Kingdom of Saudi Arabia (KSA),
however, has not been well established to date and may in fact vary from
region to region across the KSA \textsuperscript{{[}7{]}}. In 2007,
community-based study of the Asir region of the KSA, Abu-Eshy et al.
reported a prevalence rate of 11.7\% \textsuperscript{{[}8{]}}. In 2014,
Alawad et al. reported a prevalence rate of 10.9\% in the Hail region of
the northern KSA. \textsuperscript{{[}9{]}}. A screening of 1018
patients by using ultrasound, identified a prevalence rate of 23\% in
the city of Al Madina. \textsuperscript{{[}10{]}}. A cross sectional
study performed in the city of Riyadh in 2017 reported a prevalence rate
of gallstones of 8.6\% \textsuperscript{{[}11{]}}.

Numerous adult studies have reported an association between the
development of cholesterol gallstones and the following factors:
obesity, a western diet, type 2 diabetes, metabolic syndrome, advanced
age, female sex, parity, rapid weight loss, oestrogen therapy, total
parenteral nutrition, genetic factors, and
ethnicity\textsuperscript{{[}12{]}}. By contrast, pigmented stones are
principally caused by haemolytic blood disorders, such as sickle cell
disease. The highest estimated prevalence of sickle cell disease in the
KSA is in the eastern region \textsuperscript{{[}13{]}}. A premarital
screening program identified a prevalence rate in adult population for
sickle cell trait (SCT) of 17\% and 1.2\% for sickle cell disease (SCD),
while a new born screening program reported 21\% for SCT and 2.6\% for
SCD in eastern province \textsuperscript{{[}14{]}}. Considering that
50-85\% of patients with sickle cell anaemia will develop pigmented
gallstones \textsuperscript{{[}15{]}}, the population of Al-Ahsa, a
large oasis located in the eastern province of the KSA, would be at
highest risk for gallstones in the KSA \textsuperscript{{[}16{]}}.

Our aim in this study was to identify the prevalence and risk factors
for gallstones in the city of Al-Ahsa, based on age and sex and to find
if haemolytic anemia is a risk factor in all age group. To the best of
our knowledge, no previous study has systematically analysed the
relationship between sex- and age-related risk factors and gallstone
formation.

\textbf{Methods and Materials}

Statement of ethics

The study protocol was approved by International Medical Research Centre
Scientific Committee (SP 17/036/A), and the Institutional Review Board
(IRBC/354/17).

Study design

We conducted a retrospective chart review among patients, [?]1 year of
age, with radiologically confirmed cholelithiasis at King Abdul Aziz
Hospital (KAH) in the city of Al-Ahsa. The data collected for three
consecutive years, 2014, 2015, and 2016, using electronic and manual
medical records. Excluded were patients under the age of 1 year, as well
as those with primary anatomic abnormalities of biliary system, with
ultrasound confirming biliary sludge without gall stones, and patients
with incomplete data.

The following demographic (age, sex, weight, and height) and biochemical
parameters (lipid profile, serum amylase level, hepatitis B and C
serology, sickle cell test, and electrophoresis) were extracted from the
charts. Medical and social histories were screened for medication,
smoking, alcohol use, and the presence of other comorbidities, such as
diabetes and thyroid disease. For analysis, patients were classified
based on their age and body mass index (BMI). Age was classified into
the following three groups: group 1, 0-18 years; group 2, 19-60 years;
and group 3, \textgreater{}60 years. The World Health Organization (WHO)
classification of BMI was used, as follows: overweight, 25[?]0--29[?]9
kg/m2, or obese, [?]30 kg/m2.

Sample size was calculated using the following formula: N= (Z1-Alpha) 2
x (pq)/E. For this sample size calculation, we used the previously
published prevalence rate of cholelithiasis among Saudi population of
11.7\% \textsuperscript{{[}8{]}}, at power of 0.80 and margin of error
of 0.05. Taking into consideration a rate of missing variables in the
medical charts of 50\%, a sample size of 480 patients would be necessary
to identify predictive factors for gallstones. After screening, we
included 636 patients in our study group.

Statistical analysis

Descriptive statistics (mean and standard deviation, or count and
frequency) were used for the following variables: sex and age
distribution; height, weight and the calculated BMI; hepatitis B and C
status; presence or absence of sickle cell disorders; total serum levels
(with normal cut offs indicated) of cholesterol ([?]5.2 mmol/L),
high-density lipoproteins (HDL, 1.0-1.3 mmol/L), low-density
lipoproteins (LDL, [?]2.59 mmol/L), amylase (40-140 U/L), and triglyceride
(TG, [?]1.7 mmol/L); and thickness of the gall bladder wall (\textless{}3
mm).

Multivariate logistic regression analyses were used to identify
significant independent risk factors for cholelithiasis. The odds ratio
(OR), and associated 95\% confidence interval (CI), for cholelithiasis
was calculated for each independent factor, adjusted for sex and age. p
value \textless{}0.05 was considered significant.

All analyses were performed using SPSS (version 20, IBM, Chicago, IL,
USA).

\textbf{Results}

Of the 643 patients, with radiological confirmation of gallstones,
enrolled into our study, 25 patients were excluded due to missing data,
with the final analysis being based on the data of 618 patients, 185
males and 433 females. The age, gender, and BMI distribution of our
study cohort is shown in Table 1.

The following groups were formed for analysis: group 1, 45 paediatric
patients, with a mean age of 12.2\selectlanguage{ngerman}±7.08 years of girls and 12.6±5.52
years for boys; group 2, 509 middle-age adults, with a mean age of
38.7±10.4 years for women and 37.9±10.4 for men; and group 3, 64 older
patients (\textgreater{}60 years of age), with a mean age of 71.6±8.13
for women and 73.8±9.99 years for men.

\textbf{Distribution by BMI}

The distribution of patients in each age group (groups 1 through 3) by
BMI classification is shown in Table 1. About 42\% of patients in group
1 (paediatric group) were obese (BMI \selectlanguage{english}[?]30 kg/m2) and 20\% were overweight
(BMI, 25-29.9 kg/m2). In group 2 (middle-age adults), 55\% were obese
and about 34\% were overweight. In group 3 (older patients), 44\% were
obese and 37.5\% were overweight. Across all three groups, a BMI \selectlanguage{english}[?]30
kg/m2 (obese) was more frequent among females than males, respectively,
as follows: group 1, 45.4\% versus 33\%; group 2, 58\% versus 48.7\%;
and group 3, 46\% versus 40\%. These sex-specific differences in the
proportion of obese individuals were all significant.

\textbf{Distribution by lipid profile}

The distribution of patients in each age group by their lipid profile is
shown in Table 2. Of note, this information was available for a smaller
number of patients in each age group, as follows: 14 patients in group 1
(paediatric), 212 in group 2 (middle-age adults), and 34 in group 3
(older patients).

In group 1, 57\% of patients had a high cholesterol level, with 43\%
having a high TG level in each gender. HDL levels were low in 14.3\% of
males and 43\% of females tested in group 1, with LDL levels being high
in 28.6\% of males and 57\% of females tested.

In group 2, lipid profiles were available for 69 of the 148 male
patients; high cholesterol level was identified in 83\%, and high TG
level in 86\%. LDL level was high in 55\%, and a HDL level
\textless{}1.3 mmol/L in 72.5\%. For women, lipid profiles were
available for 143 of 361 patients enrolled, with high cholesterol
identified in 94\%, with high TGs in 93\%, high LDL in 73\%, and low HDL
in 50\%.

In group 3, lipid profiles were available in 11 of 25 men, with 91\% of
these men having high cholesterol, 82\% had a TG level \textgreater{}1.7
mmol/l, 55\% LDL \textgreater{}2.59 mmol/L, and 64\% a HDL
\textless{}1.3 m mol/L. Lipid profiles were available in 23 of the 39
women in this group, with 70\% of these women having high cholesterol,
74\% high TG values, 74\% high LDL, and 65\% low HDL.

\textbf{Proportion of the population with haemolytic anaemia}

The prevalence and distribution of haemolytic anaemia is shown in Table
3. In group 1, 25\% of boys and 30\% of girls tested positive for sickle
cell disease. In group 2, this proportion decreased 5.8\%, with no
significant differences between-sex, while in group 3, of the 40
patients who underwent testing, only 1 man tested positive.

\textbf{Distribution by viral hepatitis status}

The distribution of patients who tested positive for HBV or HCV is shown
in Table 3. None of the 20 patients in group1 tested positive for HBV,
and only 1 girl had positive serology for HCV. In group 2, HBV screening
was performed in 378 patients, with a positive serology in 9 patients
(2.4\%). HCV screening was performed in 267 patients, with a positive
serology identified in 2 women (1\%). In group 3, none of the patients
tested showed positive serology for HBV; while for HCV, of the 34 women
tested, a positive serology was identified in 3 (8.8\%).

\textbf{Complications and outcome of gallstones}

With the exception of 43 patients, all others required cholecystectomy.
Cholecystectomy was performed laparoscopically in the majority of
patients, with only 4 required an open approach, with one of these being
a case of conversion from laparoscopic to open. Bariatric surgery was
performed at the same time in 6 patients. Post-cholecystectomy recovery
was unremarkable in all patients, with no significant morbidity and no
incidence of mortality.

At time of presentation, biliary pancreatitis, with high serum amylase
level, was evident in half (50\%) of the females and 44\% of the males
in group 1 (paediatric). In group 2, 65\% of 100 males, compared to 55\%
of 210 females, presented with an elevation of serum amylase. In group
3, a high serum amylase level was identified in 87.5\% of males and 72\%
of females.

Cholecystitis, identified by a thickening of the gall bladder wall
(GBWT) on ultrasound, was identified in 5 children (one male 8.3\% and 4
females 12.1\%), compared to 72\% of women and 8\% in Men in group 2.
28\% of women and 18\% of men in group 3 showed GBWT.

\textbf{Comparison of risk factors among males and females Table-4}

In the male population, the binary multivariate logistic regression
analyses showed significant association of gall stone with the following
variables; advancing age (OR 0.403, 95\% CI 0.23-0.72, P=0.002), Obesity
(OR 0.51, 95\% CI 0.32-0.83, P=0.006), triglycerides (OR 0 .464, 95\% CI
0.257-0.837,P=0.011), LDL (OR 1.683, 95\%CI 1.159-2.445, P=0.006);
sickle cell anemia (OR15.31, 95\% CI 3.60- 65.04, P=0.001). While no
significant association with Total cholesterol (OR1.024, 95\% CI 0.649-
1.616, P=0. 91) and HDL (OR0.639, 95\% CI 0.140-2.909, P= 0.563).

Hepatitis B and hepatitis C were not found to be correlated with the
prevalence of gall stones (p\textgreater{}0.05).

In the female population, the binary multivariate logistic regression
analyses showed \textbf{advancing age} of 19-60 years (OR 2.484, 95\% CI
1.39-4.43, P\textless{}0.002), increased \textbf{BMI} (OR 1.95, 95\%
CI1.393- 4.431, P\textless{}0.006); \textbf{elevated total serum
cholesterol} (OR=2.657 CI of 0.999-7.067 P=0.050)
;\textbf{triglycerides} (OR 2.156, CI 1.194 -3.892,P=0
.011),\textbf{HDL} (OR 2.57, CI 1.086- 6.109 , P=0.032); \textbf{LDL}
(OR 5.478, CI 1.348-22.261, P=0.017) and sickle cell anemia (OR16.786,
CI 3.965-71.064, P \textless{}0.0001) were significantly associated with
the risk of cholelithiasis.

Hepatitis B and C were not significantly correlated with prevalence of
gall stones (p\textgreater{}0.05). (Table-3)

\textbf{Discussion}

The rising prevalence of gallstone disease in the Saudi population is a
cause of concern. In 1990, an increase in the frequency of
cholecystectomy in the eastern province of the KSA was noticed, which
reflect the increase in the incidence of
gallstones\textsuperscript{{[}17{]}}. Transabdominal ultrasound provides
the ideal diagnostic tool to accurately determine the prevalence of
gallstone disease; a sit is a safe imaging technique with high
sensitivity and specificity for gallstones \textsuperscript{{[}6{]}}. In
our study, we included patients with a diagnosis of gallstones confirmed
by transabdominal ultrasound at KAH in Al-Ahsa city, over 3 consecutive
years to evaluate the prevalence and sex- and age specific risk factors
for cholelithiasis. The KAH is one of the Ministry of National Guard
hospitals in the KSA that provides primary, secondary, and tertiary
healthcare services to National Guard employees and their families, as
well as eligible Saudi citizens referred from other hospitals. It has a
total bed capacity of about 300 beds. Annually about
220cholecystectomies are performed in our hospital, with 10\% being
paediatric cases. This is comparable to the data for King Fahad Hospital
in Almadinah Almounawarah, with a 500-bedcapacity, where 400
cholecystectomies are performed on average per
year\textsuperscript{{[}18{]}}.We note that we excluded patients under
the age of 1 year from our study as the aetiology of cholelithiasis in
infants is unique, generally being related to congenital anatomical
disorders, genetic diseases, ceftriaxone therapy, and total parenteral
nutrition \textsuperscript{{[}19{]}}. Gallstones in infancy can present
with cholestasis, pale stools, sepsis, and abdominal pain but, more
often, is asymptomatic and resolves spontaneously without surgical
intervention \textsuperscript{{[}20{]}}. Our findings of a higher
prevalence of gallstones in females than males agree with previously
published international observations which reported a 2-fold higher
increase in the risk for gallstones in women compared to
men\textsuperscript{{[}21-22-23{]}}. Similarly, a higher prevalence
among women than men has been reported for the
KSA\textsuperscript{{[}8-9-10-11{]}}. The underlying pathophysiology for
gall stone formation in women could be related to effects of sex
hormones on bile secretion and function of the gall bladder; this is
supported by a specifically higher risk of gallstone formation after
menopause and in post-menopausal women using oestrogen
therapy\textsuperscript{{[}24-25-26{]}}. These findings related to
cholesterol stones, with the prevalence of pigmented stone being almost
equal among both sex in countries where pigmented stone is more
prevalent, as in Taiwan \textsuperscript{{[}27{]}}. Female sex was also
found to be a risk factor for gallstones in children, where 73\% of
cases in our paediatric population were girls. Again, this finding
agrees with previously published data \textsuperscript{{[}28{]}}.
Obesity and overweight are well recognized for their strong association
with gallstone disease. People with obesity have a higher incidence of
cholelithiasis, cholecystitis, and cholesterolosis compared to lean
individuals \textsuperscript{{[}29{]}}. In our study group, obesity was
a strong risk factor for gallstone formation in both paediatric and
adult patients. Our findings also suggest that the epidemic of obesity
in Saudi children has contributed significantly to the striking increase
in paediatric gallstone disease. This concurs with the findings of Mehta
et al. who reported that a strong association between paediatric gall
bladder cholelithiasis and obesity (P=0.03) \textsuperscript{{[}28{]}}.
In our study a higher BMI among adults was the most important
preventable risk factor that appears to largely account for the high
prevalence of gallstone (Pvalue 0.05). In good agreement with our study,
Hung et al., in their population-based case control study, reported
obesity to be a strong predictor for the development of gallstones (OR
1.89, 95\%CI 1.18-3.04, Pl=0.008), with women being at a higher risk for
gallstones than men (OR 1.91, 95\%CI 1.07-3.41, P=0.030
)\textsuperscript{{[}30{]}}. Analogous findings were reported by in a
Mendelian randomized study that showed that an increase BMI among women
was a causative factor for cholelithiasis (P=0.001) {[}31{]}. It has
been reported that 20-30\% of all gallstones in children are due to
haemolytic diseases such as sickle-cell disease, hereditary
spherocytosis and thalassemia \textsuperscript{{[}32{]}}. In 40-50\% of
paediatric cases, the underlying cause of gallstones is due to another
known aetiology, including total parenteral nutrition, prolonged
fasting, ileal disease or ileal resection, frusemide therapy, congenital
biliary diseases, such as a choledochal cyst, chronic liver disease and
progressive familial intrahepatic cholestasis (PFIC). Around 30-40\% of
cases are idiopathic in nature \textsuperscript{{[}20{]}}.

Gallstone is a common complication in children with haemoglobinopathies
because of the recurrent episodes of haemolysis leading to an increase
in bilirubin excretion and pigment gallstones formation. The development
of pigment gallstones in patients with sickle cell disease is largely
age-dependent, with 15\% of cases being in children \&lt;10 years of
age, 22\% in children 10-14 years of age, and 36\% in children 15-18
years of age, with a reported prevalence of 50\% by the age of 22
years\textsuperscript{{[}33{]}}. Our study findings revealed a
noteworthy relationship between gallstone formation and sickle cell
anemia among paediatric patients, with girls being at higher risk than
boys (30.3\% versus 25\%). The findings from the Howard University
Centre for Sickle Cell Disease study agreed with our findings, with
gallstones reported in 70.6\% of girls with sickle cell anaemia,
compared to 55.1\% in boys\textsuperscript{{[}34{]}}. While Dooki et al.
reported a lower rate of cholelithiasis among children with haemolytic
anaemia of 13.6\textsuperscript{{[}35{]}}, Chabchoub et al from Tunisia
reported similar prevalence to our study with 36.8\% of paediatric
patients with gallstones had haemolytic anaemias.
\textsuperscript{{[}36{]}}. By contrast, in our adult group, males with
sickle cell disorders were at a higher risk for gallstones than females.
A retrospective review by Martin et al. \textsuperscript{{[}37{]}}
reported that 25.7\% of adult patients with sickle cell disease
presented with an increased incidence of gallstone formation. Analogous
findings were reported by Gumerio et al., with an incidence rate of
gallstone formation of 45\% among patients with sickle cell-haemoglobin
C disease and heterozygous sickle cell disease/beta-thalassemia (S\selectlanguage{greek}β\selectlanguage{english}),
with the average age of onset of cholelithiasis in this group being 12.5
years\textsuperscript{{[}38{]}}. Laparoscopic cholecystectomy is the
treatment of choice in children with clinically symptomatic disease,
with the best treatment option for asymptomatic cases being a source of
debate \textsuperscript{{[}39{]}}. As an example, whereas the Brazilian
study \textsuperscript{{[}37{]}} and the Jamaican
study\textsuperscript{{[}40{]}} recommended conservative management for
asymptomatic children due to lack of significant complications over a
period of observation of 8 years, other investigators still recommend
elective cholecystectomy as the gold standard therapy in children with
sickle cell disease with asymptomatic cholelithiasis to prevent
potential complications, such as cholecystitis and choledocholithiasis,
as well as postoperative complications (sickle cell crisis) when
emergency cholecystectomy is performed \textsuperscript{{[}37{]}}.

In our analyses, high serum cholesterol (p=0.027), TG (P=011), and LDL
(P=0.006), and low HDL (P=0.03) were associated with a higher risk of
gallstones, particularly among women. These findings were in good
agreement with previous cross-sectional and prospective
investigations\textsuperscript{{[}41,42{]}}. A population-based study
conducted in China by Andreotti et al. \textsuperscript{{[}42{]}}
reported that high serum levels of TG and low levels of HDL were
associated with an elevated risk for biliary stones, as well as biliary
tract cancer. Malik et al. \textsuperscript{{[}43{]}} agreed that the
prevalence of cholelithiasis was higher among women than men with a
hyperlipidaemic profile (80\% versus 71.42\%). This study also revealed
that hypercholesteremia was the most common abnormality in both sexes,
followed by hypertriglyceridemia, and that lipid profiles improved up to
6 months after cholecystectomy, but that HDL remained unchanged. A
spectrometric study further supported these findings, reported a linear
correlation between high cholesterol and the rate of gallstones
(P=0.05), with a similar linear correlation for LDL levels (P\&lt;
0.001) \textsuperscript{{[}44{]}}. Bhatti et al. reported strong
relationship between gallstone formation and a fatty liver, particularly
among adult females \textsuperscript{{[}41{]}}. The occurrence of
cholelithiasis was not associated with either hepatitis B or C infection
in our study. Analogous findings were reported in a systemic literature
review, indicating a null relationship between hepatitis B infection and
cholelithiasis \textsuperscript{{[}45{]}}. Of note, a community-based
study in Taiwan did report a positive linear relationship between
gallstone formation and hepatitis C, but not B, among
males\textsuperscript{{[}46{]}}. Our findings could be explained by the
fact that the prevalence of hepatitis B is rapidly declining in the KSA
due to the premarital screening program and efficacy of the immunization
program by our national health organization. Finally, we did identify
that 13.4\% of our patients in the 2015 had type 2 diabetes, with a
comparable prevalence rate of 10\% in 2016. We note that 25.5\% of
patients in both years used Calcium and vitamin D supplementation for
not less than 2 months prior to surgery. Data for 2014 was incomplete
regarding this information.

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\end{enumerate}

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