Edited by: Lilia Castillo-Martinez, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), Mexico
Reviewed by: Ximena Rosas-Flota, National Autonomous University of Mexico, Mexico; Carlos Reyes-Torres, Monterrey Institute of Technology and Higher Education (ITESM), Mexico
This article was submitted to Clinical Nutrition, a section of the journal Frontiers in Nutrition
†These authors have contributed equally to this work and share first authorship
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The estimated overall prevalence of cholelithiasis is 10–15% in the general population, with some differences across countries and the majority of patients being asymptomatic (
Several previous reports have demonstrated an increased incidence of gallbladder disease in patients with SBS on long-term parenteral nutrition (PN) (
Decreased oral intake or the lack enteral feeding and the use of long-term PN predispose patients to sludge and cholelithiasis formation by promoting stasis in the biliary tree (
Therefore, this study aimed to provide comprehensive and long-term data on the incidence of cholelithiasis in a cohort of patients with SBS to identify the prevalence, risk factors, and clinical consequences of cholelithiasis in adult patients with SBS to aid in the development of protective interventions.
The study was conducted in accordance with the principles of the Declaration of Helsinki, and the study protocol was approved by the ethics committee of Jinling Hospital (Identifier: 2020ZFYJ-014-05) and registered at ClinicalTrials.gov (Identifier: NCT04867538). Because of the retrospective nature of the study, patient consent for inclusion was waived.
This was a retrospective cohort study of a prospectively maintained audit database of all patients with SBS managed at Jinling Hospital. All adults with SBS admitted to Jinling Hospital's Intestinal Failure Clinical Nutrition Center from January 2010 to December 2019 were retrospectively identified from the hospital records database included in this study. The prospective database was maintained to guide nutrition support therapy for patients with chronic intestinal failure (CIF) (including oral diet, parenteral/enteral nutrition, and home parenteral/enteral nutrition). Our Intestinal Failure Clinical Nutrition Center established a special nutrition support team (an interdisciplinary team composed of gastroenterologists, surgeons, pharmacists, clinical dietitians, and nurses) that is responsible for developing nutrition support programs and plans and performing long-term follow-up after discharge of each patient with IF associated with SBS.
The inclusion criteria were as follows: adults with SBS and an expected survival time of more than 6 months. SBS was defined as intestinal malabsorption disorder caused by extensive bowel resection with a remnant small intestine length <200 cm (
Patient demographic data at admission, including age, sex, height, body weight, the body mass index (BMI), presence of diabetes mellitus, presence of hypertension, nutritional risk screening 2002 (NRS-2002) score, patient-generated subjective global assessment (PG-SGA) grade, and serum concentrations of albumin, prealbumin, transferrin, retinol-binding protein, insulin-like growth factor-1, total bilirubin, direct bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma glutamyltransferase, blood urea nitrogen, hemoglobin, and platelets, were collected from the database. PN dependence, primary disease, and intestinal anatomy (including the type of anatomy, remaining length of the small intestine, type of remaining small intestine [mainly the remnant jejunum or ileum], and the presence of an intact ileocecal valve, colon-in-continuity, and colon integrity) were also recorded.
According to anatomical criteria, SBS can be classified into three types: type I: end-jejunostomy (patients undergoing end-jejunostomy have the ileum and colon completely removed, while a portion of the jejunum is retained and forms the end of the intestine) (
At admission, patients with SBS were asked about their history of cholelithiasis. The diagnosis of cholelithiasis at any point during the period of SBS follow-up was recorded, along with the modality and indication for investigation that resulted in the diagnosis (symptoms suggestive of cholelithiasis, abnormal liver function test results, or incidental findings) (
Patients with SBS were divided into two groups: cholelithiasis and non-cholelithiasis. Patients were classified into the cholelithiasis group if they had been definitively diagnosed with cholelithiasis after SBS diagnosis, or if symptomatic or asymptomatic cholelithiasis was confirmed on abdominal imaging (CT, MRI, or ultrasonography). The symptoms, types of complications of cholelithiasis, and their consequent management were also recorded. All patients were followed-up at the Intestinal Failure Clinical Nutrition Center's outpatient clinic at Jinling Hospital at least every 6 months during the study period.
Numerical data are presented as mean ± standard deviation or median (range). Categorical variables are expressed as number and percentage. We used the Kolmogorov-Smirnov test to assess whether continuous data were normally distributed. We performed group comparisons using the chi-square test or Fisher exact tests for categorical variables, and the Student
As depicted in
Flow diagram of patients with short bowel syndrome included in the study.
The patients' mean age was 50.0 ± 16.2 years, and 236 (68.4%) were male. The median BMI was 18.2 (range, 16.4–21.2 kg/m2), median NRS-2002 score was 4.0 (range, 3.0–5.0), and PG-SGA grades were as follows: grade A in 36 (10.4%) patients, grade B in 133 (38.6%), and grade C in 176 (51.0%). Thirteen (3.8%) patients had type 2 diabetes mellitus, and 47 (13.6%) were hypertensive. The median duration of SBS was 36 months (range, 16–72 months). Additionally, 117 (34.0%) patients required PN at admission, while 70 (20.3%) required home PN (HPN) after hospital discharge. Baseline characteristics of the study population are shown in
Demographic and laboratory tests for the study population.
345 | 72 (20.9) | 273 (79.1) | NA | |
Age (years) | 51.0 (39.0–61.0) | 50.0 (39.3–61.8) | 51.0 (38.0–61.0) | 0.691 |
Sex | ||||
Female | 109 (31.6) | 30 (41.7) | 79 (28.9) | |
Male | 236 (68.4) | 42 (58.3) | 194 (71.1) | |
Height (cm) | 168 (162–172) | 167 (162–170) | 168 (162–172) | 0.185 |
Body weight (kg) | 51.0 (45.0–60.0) | 49.5 (43.5–59.0) | 52.0 (45.0–60.0) | 0.208 |
BMI (kg/m2) | 18.2 (16.4–21.2) | 17.5 (16.2–21.3) | 18.4 (16.5–21.1) | 0.330 |
Diabetes mellitus (%) | 13 (3.8) | 2 (2.8) | 11 (4.0) | 0.620 |
Hypertension (%) | 47 (13.6) | 11 (15.3) | 36 (13.2) | 0.645 |
PG-SGA | ||||
A | 36 (10.4) | 4 (5.6) | 32 (11.7) | |
B | 133 (38.6) | 22 (30.6) | 111 (40.7) | |
C | 176 (51.0) | 46 (63.9) | 130 (47.6) | |
NRS2002 | 4.0 (3.0–5.0) | 4.0 (3.3–5.0) | 4.0 (3.0–5.0) | 0.524 |
PN dependence (%) | ||||
Yes | 116 (33.7) | 34 (47.2) | 82 (30.1) | |
No | 228 (66.3) | 38 (52.7) | 190 (69.9) | |
Duration of SBS (months) | 36 (16–72) | 37 (17–74) | 36 (15–71) | 0.235 |
Albumin (g/L) | 35.5 ± 7.1 | 36.7 ± 6.5 | 35.2 ± 7.2 | 0.093 |
Prealbumin (mg/L) | 213 (144–283) | 216 (154–292) | 212 (134–273) | 0.539 |
Transferrin (g/L) | 2.1 ± 0.77 | 2.1 ± 0.76 | 2.1 ± 0.78 | 0.986 |
RBP (mg/L) | 34.5 (23.0–45.8) | 34.0 (24.0–45.0) | 35.0 (22.0–46.5) | 0.813 |
IGF-1 (ug/L) | 127 (70–173) | 144 (107–231) | 114 (69–158) | 0.150 |
TBIL (μmol/L) | 17.1 (10.6–28.2) | 17.8 (12.2–33.6) | 16.4 (10.1–27.2) | 0.120 |
DBIL (μmol/L) | 7.2 (3.6–13.2) | 8.5 (4.5–18.8) | 6.7 (3.4–12.7) | 0.109 |
ALT (U/L) | 33.0 (20.0–59.8) | 34.0 (18.3–61.0) | 33.0 (20.3–59.0) | 0.994 |
AST (U/L) | 28.0 (18.0–50.5) | 27.5 (18.0–51.3) | 28.0 (18.0–50.5) | 0.953 |
ALP (U/L) | 99 (69–161) | 109 (74–194) | 97 (69–156) | 0.281 |
γ-GT (U/L) | 49 (20–126) | 56 (20–147) | 48 (20–116) | 0.580 |
Triglyceride (mmol/L) | 1.22 (0.80–1.90) | 1.17 (0.78–1.88) | 1.25 (0.82–1.90) | 0.602 |
Cholesterol (mmol/L) | 2.78 (2.14–3.59) | 2.97 (2.19–4.03) | 2.71 (2.11–3.47) | 0.144 |
BUN (mmol/L) | 5.8 (4.0–8.1) | 5.7 (4.1–9.1) | 5.8 (3.9–8.0) | 0.379 |
Serum creatinine (mmol/L) | 57.0 (44.0–78.4) | 60.4 (43.2–96.7) | 56.1 (44.0–77.0) | 0.272 |
Hemoglobin (g/L) | 107.4 ± 24.7 | 105.8 ± 22.2 | 107.9 ± 25.3 | 0.516 |
PLT (x109/L) | 186 (131–235) | 164 (129–227) | 192 (132–238) | 0.140 |
The most common underlying diseases were mesenteric ischemia (
The underlying diseases in adult patients with SBS with and without cholelithiasis.
345 | 72 | 273 | NA | |
The etiology of SBS (%) | 0.392 | |||
Mesenteric ischemia | 122 (35.4) | 23 (31.9) | 99 (36.3) | |
Surgical complications | 109 (31.6) | 18 (25.0) | 91 (33.3) | |
Volvulus | 53 (15.4) | 14 (19.4) | 39 (14.3) | |
Trauma | 27 (7.8) | 8 (11.1) | 19 (7.0) | |
Crohn's disease | 8 (2.3) | 3 (4.2) | 5 (1.8) | |
Radiation enteritis | 21 (6.1) | 4 (5.6) | 17 (6.2) | |
Others | 5 (1.4) | 2 (2.8) | 3 (1.1) |
Overall, 64 (18.6%) patients had end-jejunostomy with no colon-in-continuity, 124 (35.9%) had jejuno-colonic anastomosis with partial colon-in-continuity, and 157 (45.5%) had jejuno-ileal anastomosis with an intact colon. The mean residual small intestine length was 80.8 ± 45.6 cm, and the median length was 80 cm (range, 50–104 cm). In total, 247 (71.6%) patients had the main remnant jejunum, and 256 (74.2%) patients had colon integrity (
The intestinal anatomy of adult patients with SBS with and without cholelithiasis.
345 | 72 | 273 | NA | |
Anatomy type | 0.758 | |||
Jejunostomy (type I) | 64 (18.6) | 14 (19.4) | 50 (18.3) | |
Jejunocolic anastomosis (type II) | 124 (35.9) | 28 (38.9) | 96 (35.2) | |
Jejunoileal anastomosis (type III) | 157 (45.5) | 30 (41.7) | 127 (46.5) | |
Remaining small intestine length (cm) | 0.628 | |||
Mean | 80.8 ± 45.6 | 82.7 ± 46.1 | 80.2 ± 45.5 | |
Median | 80 (50–104) | 80 (56–108) | 80 (50–104) | |
Remaining small intestine type | ||||
Jejunum predominantly | 247 (71.6) | 60 (83.3) | 186 (68.1) | |
Ileum predominantly | 98 (28.4) | 12 (16.7) | 87 (31.9) | |
Ileocecal valve intact | 165 (47.8) | 33 (45.8) | 132 (48.4) | 0.704 |
Colon in continuity | 281 (81.4) | 58 (80.6) | 223 (81.7) | 0.826 |
Colon integrity | 256 (74.2) | 51 (70.8) | 205 (75.1) | 0.463 |
According to the Kaplan–Meier analysis, the incidence of cholelithiasis was 20.9% (72/345) over an observation period of 10 years; the remaining 273 (79.1%) patients had no cholelithiasis (
Kaplan–Meier plot showing adult patients with short bowel syndrome without cholelithiasis during the 10-year period.
Patients were divided according to the occurrence of cholelithiasis into the cholelithiasis group (
According to Cox proportional hazard model analyses, the independent predictors for cholelithiasis in the overall population of patients with SBS are shown in
The Cox proportional hazard model analysis of the independent variables associated with cholelithiasis in adult with SBS.
Age (years) | |||
<65/≥65 | 0.562 | 0.844 | 0.475–1.498 |
Sex | |||
Male/Female | 0.062 | 1.572 | 0.977–2.528 |
Remaining small intestine (cm) | |||
>100/ ≤ 100 | 0.113 | 1.698 | 0.882–3.267 |
Ileocecal valve intact | |||
Yes/No | 0.802 | 0.934 | 0.546–1.596 |
Colon integrity | |||
Yes/No | 0.351 | 1.321 | 0.736–2.371 |
Colon in continuity | |||
Yes/No | 0.898 | 0.961 | 0.525–1.760 |
Remaining small intestine type | |||
Mainly remnant ileum/jejunum | 2.163 | 1.156–4.047 | |
PN dependence | |||
No/Yes | 1.783 | 1.077–2.952 |
Of the 72 patients in the cholelithiasis group, 44 were asymptomatic, with cholelithiasis found incidentally on abdominal imaging. Twenty-eight patients with cholelithiasis developed symptoms and/or complications, including 23 with acute cholecystitis and cholangitis and five with acute pancreatitis (
The complication in adult patients with SBS with and without cholelithiasis.
345 | 72 | 273 | NA | |
Acute cholecystitis or cholangitis (%) | 44 (12.8) | 23 (31.9) | 21 (7.7) | |
Acute pancreatitis (%) | 8 (2.3) | 5 (6.9) | 3 (1.1) | |
20(5.8) | 13(18.1) | 7(2.6) | ||
Cholecystectomy or ES (%) | 25 (7.2) | 14 (19.4) | 11 (4.0) | |
PTGD (%) | 7(2.0) | 1 (1.4) | 6 (2.2) | 0.665 |
To our knowledge, this is the largest study to specifically explore the incidence, risk factors, and clinical consequences of cholelithiasis in a longitudinal cohort of adults with SBS. The incidence of cholelithiasis in adults with SBS was 20.9% during the 10-year observation period, and the median duration from SBS diagnosis to the development of cholelithiasis was approximately 15 months. The independent risk factors for cholelithiasis in adults with SBS were the type of remaining small intestine (mainly the remnant jejunum) and PN dependence. Moreover, cholelithiasis was associated with adverse clinical consequences in some patients with SBS.
Individuals with SBS are susceptible to cholelithiasis, which can result in adverse clinical consequences. Our study found that the incidence rate of cholelithiasis was 20.9% in adults with SBS. Previous studies with smaller populations (119 patients, 109 patients, 81 patients, and 71 patients) found the following prevalence rates of cholelithiasis: 6.2–47% in patients with chronic intestinal failure (CIF) receiving HPN (
The risk factors predisposing patients to cholelithiasis formation include obesity, diabetes mellitus, estrogen and pregnancy, hemolytic diseases, and cirrhosis in the general population (
Previous studies have reported that more than one-third of patients with SBS develop cholelithiasis during the course of their disease, usually within the first 2 years after resection (
In the current study, 61.2% of patients with cholelithiasis were asymptomatic, while 38.8% were symptomatic, which is significantly lower than 77.4% of long-term home parenteral nutrition patients with cholelithiasis were symptomatic that reported in previous study (
The present study's results have implications in the role of surgical intervention (including cholecystectomy, endoscopic sphincterotomy, and percutaneous transhepatic gallbladder drainage) in SBS, especially in patients with symptomatic cholelithiasis. Although previous studies uniformly recommended prophylactic cholecystectomy (
Although the present study is based on a clinical audit database prospectively maintained at Jinling Hospital's Intestinal Failure Clinical Nutrition Center over several decades, it has several significant limitations. First, this was a retrospective, single-institution study performed at a tertiary hospital center. Second, there were no data regarding the composition of cholelithiasis. Third, as most patients with SBS from our Intestinal Failure Clinical Nutrition Center were adults, we only evaluated the incidence and risk factors for cholelithiasis in adults with SBS. The prevalence and risk factors for cholelithiasis in pediatric patients remain unclear. Fourth, the absolute risk of cholelithiasis attributable to SBS remains unknown due to the lack of a normal control group of patients without SBS. Lastly, even though the detailed and regular follow-up of a large cohort of patients receiving long-term parenteral support was a key strength of the present study, the patients did not undergo formal planned surveillance with regular ultrasonography, only cross-sectional imaging or ultrasonography as required for clinical reasons. Although the percentage of patients who developed cholelithiasis in the present study was high, our figures might still represent an underestimation. Therefore, large, multicenter, prospective studies focusing on the formation of cholelithiasis in both pediatric and adult patients with SBS should be conducted in the future.
Adult patients with SBS are at a particularly high risk of developing cholelithiasis. The independent predictors of cholelithiasis were type of remaining small intestine (mainly the remnant jejunum) and PN dependence. Cholelithiasis can lead to adverse clinical consequences that should be closely monitored and require prophylactic intervention.
The original contributions presented in the study are included in the article/
The studies involving human participants were reviewed and approved by the Research Ethics Committee of the Jinling Hospital. The ethics committee waived the requirement of written informed consent for participation.
XW and XG equally contributed to the conception and design of the study. LZ and SW contributed to the design of the study. SW and YX contributed to the acquisition and analysis of the data. YX, DZ, and DS contributed to the analysis of the data. XG, LZ, and DS contributed to the acquisition, analysis, and interpretation of the data. All authors drafted the manuscript, critically revised the manuscript, agreed to be fully accountable for ensuring the integrity and accuracy of the work, and read and approved the final manuscript.
This study was supported by the National Natural Science Foundation of China (81470797, 81770531), the Science Foundation of Outstanding Youth in Jiangsu Province (BK20170009), the National Science and Technology Research Funding for Public Welfare Medical Projects (201502022), and Military Medical Innovation Project (18CXZ031).
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
We thank Yupeng Zhang, Tingting Gao, and Paixu Chen for aiding data collection. We also thank Editage for the language polishing.
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