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| ORIGINAL ARTICLE |
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| Year : 2022 | Volume
: 21
| Issue : 1 | Page : 58-64 |
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Cholelithiasis in children and adolescents with sickle cell disease: Experience in a resource-limited setting
Oluwafunmilayo Funke Adeniyi1, Adeseye Micheal Akinsete1, Emuobor Aghoghor Odeghe2, Omodele Abosede Olowoyeye3, Ogonna Faustina Okeke4, Justina Oyioza Seyi-Olajide5, Adebola Akinsulie6
1 Department of Paediatrics, Paediatric Gastroenterology Unit, College of Medicine, Lagos University Teaching Hospital, University of Lagos, Idi-Araba, Nigeria
2 Department of Internal Medicine, Gastroenterology Unit, College of Medicine, Lagos University Teaching Hospital, University of Lagos, Lagos, Nigeria
3 Department of Radiology, College of Medicine, Lagos University Teaching Hospital, University of Lagos, Lagos, Nigeria
4 Department of Radiology, Lagos University Teaching Hospital, College of Medicine, Lagos University Teaching Hospital, University of Lagos, Lagos, Nigeria
5 Department of Surgery, Paediatric Surgery Unit, Lagos University Teaching Hospital, Lagos, Nigeria
6 Department of Paediatrics, Oncology Unit, College of Medicine, Lagos University Teaching Hospital, University of Lagos, Idi-Araba, Nigeria
| Date of Submission | 03-Sep-2020 |
| Date of Acceptance | 23-Feb-2021 |
| Date of Web Publication | 18-Mar-2022 |
Correspondence Address:
Oluwafunmilayo Funke Adeniyi
Department of Paediatrics, Paediatric Gastroenterology Unit, College of Medicine, Lagos University Teaching Hospital, University of Lagos, Idi-Araba, Lagos
Nigeria
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/aam.aam_81_20
 Abstract | | |
Background: Sickle cell disease (SCD) remains prevalent in Nigeria and can be complicated by cholelithiasis even in children. There is still a dearth of knowledge about the occurrence of cholelithiasis in these children. The present study is aimed to determine the prevalence of cholelithiasis in pediatric SCD in Lagos and documents relevant socio-demographic and clinical correlates. Subjects and Methods: This was a cross-sectional study of children and adolescents aged 1–19 years with SCD attending the Paediatric Haematology Clinic of the Lagos University Teaching Hospital. One hundred and forty-seven children were consecutively recruited into the study over 3 months and they all had sonographic examination of the gall bladder. The association between cholelithiasis, sociodemographic data, clinical symptoms, laboratory parameters, and the use of hydroxyurea was also documented. Results: The median age (range) of the study participants was 9.0 (1–19) years and majority were males (59.9%). The prevalence of cholelithiasis was 13.6% and the condition was most prevalent in adolescents (21.4%) compared to the younger children (6.5%). All the children with cholelithiasis were asymptomatic. Age and the frequency of crisis were significantly associated with cholelithiasis on multivariate analysis (P = 0.03, 0.045, respectively). The use of hydroxyurea was not significantly related to the occurrence of cholelithiasis. Conclusion: The prevalence of cholelithiasis observed in this study is high. Routine screening of older children and adolescents with SCD, especially with the frequent crisis is suggested. Longitudinal studies to establish the relationship between hydroxyurea and cholelithiasis is also advocated.
| Abstract in French | | |
Résumé
Contexte: La drépanocytose (SCD) reste répandue au Nigéria et peut être compliquée par une cholélithiase même chez les enfants. Il y a encore un manque de connaissances sur la survenue de la cholélithiase chez ces enfants. La présente étude vise à déterminer la prevalence de la cholélithiase dans la drépanocytose pédiatrique à Lagos et documente les corrélats sociodémographiques et cliniques pertinents. Sujets et méthodes: ce était une étude transversale menée auprès d'enfants et d'adolescents âgés de 1 à 19 ans atteints de drépanocytose et fréquentant la clinique d'hématologie pédiatrique de Lagos Hôpital universitaire. Cent quarante-sept enfants ont été recrutés consécutivement dans l'étude pendant 3 mois et ils ont tous eu un examen échographique de la vésicule biliaire. L'association entre cholélithiase, données sociodémographiques, symptômes cliniques, laboratoire paramètres, et l'utilisation de l'hydroxyurée a également été documentée. Résultats: l'âge médian (intervalle) des participants à l'étude était de 9,0 (1–19) ans et la majorité étaient des hommes (59,9%). La prévalence de la cholélithiase était de 13,6% et la maladie était la plus répandue chez les adolescents (21,4%) par rapport aux enfants plus jeunes (6,5%). Tous les enfants atteints de cholélithiase étaient asymptomatiques. L'âge et la fréquence des crises étaient significativement associée à la cholélithiase sur l'analyse multivariée (P = 0,03, 0,045, respectivement). L'utilisation de l'hydroxyurée n'était pas significativement liées à la survenue de cholélithiase. Conclusion: La prévalence de la cholélithiase observée dans cette étude est élevée. Dépistage de routine les enfants plus âgés et les adolescents atteints de SCD, en particulier avec la crise fréquente, sont suggérés. Études longitudinales pour établir la relation entre l'hydroxyurée et la cholélithiase est également préconisée.
Mots-clés: Adolescents, enfants, cholélithiase, Nigéria, drépanocytose
Keywords: Adolescents, children, cholelithiasis, Nigeria, sickle cell disease
How to cite this article:
Adeniyi OF, Akinsete AM, Odeghe EA, Olowoyeye OA, Okeke OF, Seyi-Olajide JO, Akinsulie A. Cholelithiasis in children and adolescents with sickle cell disease: Experience in a resource-limited setting. Ann Afr Med 2022;21:58-64 |
How to cite this URL:
Adeniyi OF, Akinsete AM, Odeghe EA, Olowoyeye OA, Okeke OF, Seyi-Olajide JO, Akinsulie A. Cholelithiasis in children and adolescents with sickle cell disease: Experience in a resource-limited setting. Ann Afr Med [serial online] 2022 [cited 2023 Jun 1];21:58-64. Available from: https://www.annalsafrmed.org/text.asp?2022/21/1/58/339937 |
| Introduction | |  |
Cholelithiasis is a condition that is uncommon in children, especially in black children from sub-Saharan Africa.[1] The known predisposing factors to the condition include hemolytic diseases, pancreatitis, inflammatory Bowel Disease , and drugs.[2] The chronic hemolysis which occurs in sickle cell disease (SCD) makes children with the disease, particularly susceptible to cholelithiasis.[2]
SCD is the commonest inherited hemoglobinopathy seen in West Africa and in Nigeria in particular.[1],[3] The condition is characterized by chronic hemolysis which results in significant production of bilirubin. The bilirubin produced can lead to the formation of pigment gall stones which is one of the important features of the disease.[3],[4],[5],[6],[7],[8] In addition, abnormalities in gallbladder function or bile acid metabolism can contribute to gallstone formation in patients with SCD.[3],[4],[5],[6],[7] The occurrence of gallstones is one of the most important gastrointestinal manifestations of SCD.[1],[3],[5] Cholelithiasis should be considered as a potential diagnosis when a child with SCD experiences recurrent abdominal pain.[1],[3],[9],[10]
The prevalence of cholelithiasis in patients with SCA has been observed to increase progressively with age, affecting up to 15% of children with SCA younger than 10 years of age and <50% of those older than 30 years.[9],[10] Despite the increased incidence of gallstones in SCA, it appears that symptomatic biliary tract disease is rare.[1],[3],[9],[10] Nevertheless, the condition can be complicated with calculus cholecystitis which can be fatal.[1],[3],[9],[10]
Cholelithiasis in children with SCD has been diagnosed with cholecystography in the past[11],[12] but more recent studies have employed the use of sonography in the diagnosis of the condition.[13],[14],[15],[16],[17] In Sub-Saharan Africa, there is still a dearth of literature on cholelithiasis in children most especially among children with SCD in southwestern Nigeria. Additionally, the relationship between the condition and the use of hydroxyurea which has become a standard of treatment in sickle disease is yet to be explored.
The aim of this study was to sonographically determine the prevalence of cholelithiasis in children and adolescents with SCD seen at the Lagos University Teaching Hospital (LUTH) and document any sociodemographic, clinical, and relevant laboratory features. The use of hydroxyurea in the children was also documented.
| Subjects and Methods | | |
Study design and participants
This cross-sectional study was carried out at the Paediatric hematology clinic of LUTH, Lagos. The clinic receives referrals from within and outside Lagos. The sample size for the study was determined with the Cochrane formula[18] for prevalence studies. The minimum sample size was calculated using a prevalence of 4.8% of cholelithiasis observed in a previous study done in Northern Nigeria[13] at 95% confidence interval, 5% degree of absolute precision with 1.96 as standard normal deviation, and 20% attrition. The minimum size obtained was 100.
Children and adolescents aged 1–19 years with SCD who were in steady state,[19] and whose caregivers gave consent were recruited into the study over a 3-month period (June 2019–August 2019) during which the sample size was achieved. SCD was confirmed by hemoglobin electrophoresis performed with cellulose acetate electrophoresis at PH (8.2–8.6). Participants with a history of cholecystectomy and those who were uncooperative were excluded from the study.
Data collection
Data from each participant were recorded in a standard pro forma and this included sociodemographic parameters namely: Age, gender, ethnicity, religion, and socioeconomic status. The socioeconomic class of the patients was determined by the parental occupation and educational level according to Oyedeji[20] classification and three major social classes, namely upper, middle and lower class was to classify the study participants.[20] A brief history was taken from the parents/patients with emphasis on history suggestive of biliary tract pathology i.e., chronic abdominal pain (right hypochondrial or epigastric pain lasting up to an hour, accompanied by indigestion), nausea and vomiting related to meals, color of stools, especially steatorrhea or worsening of jaundice were documented. The use of hydroxyurea by the study participant was also noted.
Each study participant was weighed on a regularly calibrated scale in light clothing and weight was documented to the nearest kilogram (kg). The length/height of each participant was determined to the nearest centimeter (cm) with the infantometer/stadiometer where applicable. The body mass indices (BMI) in the children were determined using the formula: BMI (kg/m2) = weight in kg/height in meters.[2] The presence of significant clinical features related to cholelithiasis was recorded in the proforma.
Sonographic examination
The Abdominal ultrasound procedure was explained to the parents/patient in simple language for easy understanding. All the study participants were scanned with a B-mode MINDRAY ultrasound machine using a probe frequency of 3.5–5.0 MHz by an experienced radiologist. The study participants were scanned in the supine and when necessary in the left lateral decubitus position. The transducer was applied after the application of the gel in the right upper quadrant of the abdomen and the liver image was identified following cranial and caudal movements of the transducer in the transverse plane. The gall bladder was subsequently identified as a dark i.e., sonolucent oblong or ovoid-shaped organ in the undersurface of the liver.
Gall stones were identified by observing a significantly reflective echogenic mass within the gallbladder lumen, “with obvious or conspicuous posterior acoustic shadowing.”[21] Gall stones usually move with a change in the position of the patient (rolling stone sign).[21]
Blood sample collection
Each child had blood samples taken to determine hematocrit (packed cell volume), white cell count, serum bilirubin, alkaline phosphatase (ALP) and gamma glutamyl transferase (GGT) levels. Each participant observed to have cholelithiasis was referred to the gastroenterology and the paediatric surgery clinics for further review and follow up.
Statistical analysis
The data were analyzed with the SPSS version 21 (IBM SPSS Statistics for Windows, Version 21.0. Armonk, NY: IBM Corp) statistical package and basic descriptive statistics were done. Continuous data and categorical data were compared using the student t-test, Chi-square test, and Fischer's exact test where applicable. The presence of cholelithiasis was analyzed in relation to age, sex, and the hematological (hematocrit, white blood cell) and biochemical parameters (serum bilirubin, alkaline phosphate, and GGT levels). Bivariate logistic regression was performed to determine any factors associated with the occurrence of cholelithiasis in the children.
Ethical considerations
Details of the study and its relevance were explained to parents and caregivers of the study participants following which verbal and written, informed consent was obtained before the commencement of the study. Assent was also obtained for children 7 years and above. Ethical approval for the study was also obtained from the LUTH Health Research and Ethical Committee.
| Results | | |
One hundred and fifty-four children with hemoglobinopathy were approached to participate in the study but 147 (95.4%) children and adolescents were eventually recruited into the study. [Table 1] shows the baseline characteristics of all the study participants. Three (2%) of the study participants had hemoglobin SC (HbSC) and 59.9% of the study participants were male. The median (range) age of the children was 9.0 (1–19) years. A significant proportion 70 (47.6%) of the study participants were adolescents and more than half of the 83 (56.5%) belonged to the middle socioeconomic class. Thirty-six (24.5%) of the study participants were on hydroxyurea. Sixteen (16) of the study participants had elevated GGT levels. The median (interquartile range) values of the anthroprometric parameters and laboratory parameters of the study participants are also outlined in [Table 1].
Cholelithiasis and correlates
Cholelithiasis was present in 20 participants giving a prevalence of 13.6%. 15 (75%) had multiple calculi (stones), while 5 (25%) had single stones.
In terms of clinical features, 10 of the study participants with gall stones had a history of chronic abdominal pain but the pain was not compatible with biliary colic. None of the children had steatorrhea or any other symptoms suggestive of cholelithiasis at the time of diagnosis.
[Table 2] highlights the age categories, gender, anthropometry, and use of hydroxyurea in relation to the presence or absence of cholelithiasis. None of the children with HbSC had cholelithiasis. The prevalence of cholelithiasis increased with age and was >3 times higher in the adolescents (21.4%) compared to the younger children (6.5%) (r = 0.349, P = 0.005). The prevalence of gallstones increased with increase in the number of crisis in the children but this was not statistically significant (P = 0.68). The occurrence of gall stones was not significantly associated with gender (P = 0.145), blood transfusions in the last 1 year (P = 0.687), and the use of hydroxyurea (0.782) on univariate analysis. | Table 2: Cholelithiasis in relation to age, sex, anthropometry use of hydroxyurea in the study participants
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The BMI (median [interquartile range (IQR)]) was similar in the 2 groups ([15.1 (14.1–17.1) and 15.7 (14.5–17.6)], respectively, P = 0.492). One hundred and twenty-six (85.7%) of the study participants were underweight and none of the children with cholelithiasis were overweight or obese.
The laboratory indices studied in the subjects is shown in [Table 3]. The mean cell volume (MCV), mean corpuscular hemoglobin and the total bilirubin were significantly larger in the participants with cholelithiasis than in those without the condition (P = 0.013, 0.042 and 0.007, respectively) on univariate analysis. The other hematological indices and biochemical indices were not significantly different in the two groups as shown in [Table 3]. | Table 3: Laboratory indices in relation to the presence or absence of cholelithiasis in the study participants
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Binary logistic regression was performed to determine the factors associated with the occurrence of cholelithiasis as shown in [Table 4]. Only the age (P = 0.033) and the number of crisis in the last 1 year (P = 0.045) were found to be significantly related to the occurrence of cholelithiasis. | Table 4: Binary logistic regression to determine factors associated with cholethiasis in children with sickle cell disease
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| Discussion | | |
The prevalence of cholelithiasis in children with SCD obtained in this study was 13.6%. This finding is comparable with the prevalence (11.5%) documented in Sudan by Attalla et al.[14] but much higher than the prevalence reported recently in North-East Nigeria (4.6%) by Ajani et al.[13] There is a dearth of literature on cholelithiasis in sickle disease in the country especially from the south western region but available old reports have also documented low prevalences in children suggesting an increase in the prevalence of the condition among this group of children. Akinyanju and Ladapo[11] in Ibadan and Akamaguna et al.[12] in Benin with the use of oral cholecystography documented a prevalence of 6% and 5% respectively, while Adekile and Makanjuola[22] in 1985 who employed a similar method in combination with ultrasonography in the diagnosis of cholelithiasis also reported a lower prevalence (4.4%) in children below 17 years. The reason for the higher prevalence observed in our study is not clear but may be related to factors such as diet, lifestyle changes, etc.
The prevalence of cholelithiasis in studies where the participants included children and adults is variable. Inah and Ekanem[15] documented a prevalence of 10% in a study with subjects aged 1.5 years–55 years with the sonographic method while in Brazil; Gumiero et al.[16] studied children and adults with SCD from age 7 months to 33 years and documented a much higher prevalence of 45%. Generally, the reported prevalence in the adult population is much higher than what has been reported in the pediatric age group and varies between 24% and 50%.[23] It appears that the documented prevalence of cholelithiasis in SCD may be related to the selection criteria, age group studied and possibly the diagnostic methods. The sonographic method nevertheless has been proven to be a sensitive method of diagnosing the condition.[21],[22],[23],[24]
In the present study, the prevalence of cholelithiasis was observed to increase with age and was most prevalent in the adolescent age group. This is similar to the observation of previous workers[5],[13],[14],[15],[23],[24],[25] and it appears that the occurrence of cholelithiasis begins in late childhood and by the age of 18 years 30% of sickle cell patients would have developed cholelithiasis.[14] This trend can probably be explained by the repeated progressive sickling of the red cells with increasing age leading to deposition of pigment stones in the gall bladder.[2],[4],[5],[6],[7] Pubertal influence on the occurrence of the condition has also been postulated and this may be a possible explanation for the findings in the present study.[5],[13],[14],[15],[23],[24],[25] Cholelithiasis has been reported to be prevalent in females especially in the adult population[3],[9] and this has also been observed in some paediatric studies,[15],[23] however this was not observed in this study. In the present cohort, there was no difference in the BMI in those with and without cholelithiasis. This is consistent with the findings of workers in Calabar, southeast Nigeria.[15] Overweight and obesity have been linked to the occurrence of cholelithiasis, especially in adult patients[24] but obesity is an uncommon finding in children with SCD[2],[3] and none of the children in our cohort with gallstones were overweight or obese.
History of blood transfusions was not significantly related to cholelithiasis in this present study. However, some workers have reported a weakly positive relationship between the occurrence of cholelithiasis and history blood transfusions.[15] On the other hand, binary logistic regression performed in our study showed a positive relationship between the number of vaso-occlusive crises (VOC) and cholelithiasis. The increased sickling which occurs with frequent episodes of crisis may possibly explain this finding. Another possible reason for the positive relationship between the number of VOCs and gallstones may be that patients with both complications could have a more severe phenotype of the disease.[4],[5],[6],[7]
None of the study participants with gall stones had evidence of biliary colic. This clinical finding has been reported in both pediatric and adult studies.[10],[13],[14],[15] However, some authors have observed that the majority of the study participants were asymptomatic.[24],[25] Gumiero et al.[16] found that 14 out of 101 patients studied were symptomatic at diagnosis but 34 subsequently became symptomatic during follow-up visits. Other workers have reported that symptoms typical of biliary colic were common in patients with gallstones in their series[5],[14],[26],[27],[28],[29] but biliary colic symptoms appear to be more prominent in adults and it is difficult to predict how soon children with cholelithiasis would become symptomatic.[5],[14],[26],[27],[28],[29] The complications of cholelithiasis which can be fatal include cholangitis, cholecystitis, choledocholithiasis, trapping of the bile stone in the gallbladder neck, etc.,[6],[7] and these can also occur in children with SCA.[30] Such complications can result in biliary colic, fever, right upper quadrant pain, and cholestatic jaundice with raised liver transaminases and especially the GGT.[4],[5],[6] Symptomatic and complicated cholelithiasis warrants both medical and surgical interventions (i.e. cholecystectomy which can be done laparoscopically preferably).[5],[7],[9],[10],[31] The treatment of the asymptomatic cholelithiasis in the SCA patient remains controversial though some physicians advocate elective cholecystectomy to prevent the occurrence of fatal complications.[9],[10]
None of the hematological parameters evaluated in our study was observed to be significantly related to cholelithiasis with binary logistic regression. Alhawsawi et al.[32] on the other hand observed a larger MCV in children with cholelithiasis in their cohort but this was not consistently so in our study as on multivariate analysis the MCV was not significantly related to cholelithiasis. The total bilirubin levels in the children with gallstones were higher than in those without gall stones in this present study and this has also been documented by Webb et al.[33] The markers of cholangiopathy (ALP and GGT) on the other hand were not significantly different in the children with and without cholelithiasis in our study. Sarnaik et al.[23] also made a similar observation. These workers have suggested that abnormal liver function tests were not an accurate predictor of the presence of the gallstones.
The use of hydroxyurea has become standard therapy in the management of SCD because of its documented benefits of increasing Hemoglobin F levels and thus reducing hemolysis in this condition.[32],[33] Thus it is expected that hydroxyurea should reduce the occurrence of cholelithiasis. However, in our cohort there was no significant relationship between hydroxyurea use and the occurrence of cholelithiasis and a protective effect of the drug could not be documented. There also lies the possibility that some of the children in our cohort may have developed the gall stones before the commencement of the medication. This observation is similar to the findings of workers in Brazil[30] however, there are still conflicting reports on the use of the medication and the occurrence of cholelithiasis even in the pediatric age group.[2],[5],[8],[32],[33]
This present study was carried out in a resource-limited setting where hydroxyurea is not readily available due to cost limitations, so most of the patients in the hematology clinic were not on the medication and this accounted for the percentage of the participants in this study on hydroxyurea. In addition, we were unable to track the HbF levels in the cohort studied due to logistic and financial constraints encountered at the time of the study which was self-funded by the authors.
| Conclusion | | |
The prevalence of cholelithiasis in this study is higher than previous studies done among Nigerian children with SCD and increased with age. The condition was more prevalent in the adolescent age group and the affected children were asymptomatic.
Thus, it is advocated that older children, especially adolescents with SCD should be routinely screened for cholelithiasis to prevent subsequent complications. Routine screening is more important for children with frequent crisis. Larger longitudinal studies to evaluate determinants of cholelithiasis and its relationship with hydroxurea use in this group of children are advocated.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
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| 29. | Walker TM, Hambleton IR, Serjeant GR. Gallstones in sickle cell disease: Observations from The Jamaican Cohort study. J Pediatr 2000;136:80-5. |
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| 32. | Alhawsawi ZM, Alshenqeti AM, Alqarafi AM, Alhussayen LK, Turkistani WA. Cholelithiasis in patients with paediatric sickle cell anaemia in a Saudi hospital. J Taibah Univ Med Sci 2019;14:187-92. |
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[Table 1], [Table 2], [Table 3], [Table 4]
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