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Relationship between Helicobacter pylori infection and bone mineral

density: a retrospective cross-sectional study


Bo-Lin Pan,1 Chih-Fang Huang,1 Seng-Kee Chuah,2 Jui-Chin Chiang,1 and Song-Seng Loke 1

Author information ► Article notes ► Copyright and License information ► Disclaimer

Abstract

Background
Osteoporosis is a silent health problem characterized by decreased bone mineral density
(BMD) with a risk of spine and hip fractures. Approximately half of the hip fractures globally
result from osteoporosis. According to data from the National Health Insurance Research
Database between 1996 and 2010 in Taiwan, the high annual incidence rate of hip fracture
was 472.1 per 100,000 patients per year, higher than that in other Asian countries and even in
the world. The in-hospital mortality rates were between 0.85 to 2.26% [1]. The spine and hip
fractures resulted from osteoporosis could induce patients to become bedridden and needing
care. Mortality and disability-associated osteoporosis have significant impact on prognosis
and are a burden affecting patients, their families, society, and the health system. Early
identification of the risk of decreased BMD and osteoporosis is very important. Previous
study has revealed that the risk factors of osteoporosis include age, sex, low body mass index
(BMI), steroid use and chronic alcohol consumption [2, 3]. Recently, several gastrointestinal
diseases such as inflammatory bowel disease, peptic ulcer disease and atrophic gastritis have
been suspected of being risk factors for osteoporosis [4–6].
Helicobacter pylori (H. pylori) infection is strongly associated with chronic gastritis, peptic
ulcers, gastric cancer, and mucosa-associated lymphoid tissue lymphoma [7]. Several studies
have reported H. pylori also plays a role in extra-digestive disorders including cardiovascular,
neurological, skin disease and diabetes mellitus [8].
H. pylori infection can induce individual inflammatory and immune reactions, which can
regulate bone turnover. Several research studies have reported that H. pylori infection is a
risk factor of osteoporosis [9, 10], but this finding is controversial in other studies [11, 12].
To our knowledge, only one study has evaluated the relationship between H. pylori infection
and osteoporosis in Taiwan, but the result was only found in elderly females [10]. Therefore,
we aimed to investigate whether H. pylori infection was associated with decreased BMD in a
general population undergoing routine health examination in Taiwan.
Go to:

Methods

Subjects
This retrospective cross-sectional study was performed by using the data from the health
examination database in a medical center of the southern Taiwan. We included subjects who
were aged greater than 20 years, had undergone upper gastrointestinal endoscopy with the
Campylobacter-like organism test (CLO test) and dual energy X-ray absorptiometry scan
(DEXA) from January 2013 to December 2013. Subjects with missing data and gastric cancer
were excluded. The study was approved by the Chang Gung Medical Foundation Institutional
Review Board (IRB No.: 201701187B0). Since this is a retrospective study, a written consent
is waived by an IRB and is deemed unnecessary.
The medical records showed information on sex, age, waist circumstance, lipid profile, H.
pylori testing, BMD, and the findings of upper gastrointestinal endoscopy. BMI was
calculated as the weight in kilograms divided by the height in meters squared. Peptic ulcer or
gastro-esophageal reflux disease (GERD) were diagnosed by upper gastrointestinal
endoscopy.

Definition of H. pylori infection


The present of H. pylori infection was determined by CLO test via upper gastrointestinal
endoscopy. CLO test is a rapid diagnostic test and is performed during upper gastrointestinal
endoscopy. A biopsy of mucosa from the stomach is placed into the medium consisting of
urea and an indicator. If H. pylori is present, the urease produced by H. pylori converts urea
to ammonia, which increases the pH of the medium and then changes its color from yellow to
red. In this health examination, all examinations were self-paid, CLO test was performed not
only for peptic ulcer, but also performed under subjects request although no peptic ulcer was
found by upper gastrointestinal endoscopy.

Determination of bone mineral density


BMD was measured by DEXA. The T-score is the number of standard deviations by which a
given measurement differs from the mean for a normal young adult reference population.
According to the World Health Organization definition [13], osteoporosis is defined as T-
score ≤ − 2.5, and the osteopenia is defined as a T-score between − 1 and − 2.5. Decreased
BMD in the present study included osteoporosis and osteopenia.

Statistical analysis
All data are described as the mean ± standard deviation for continuous variables and as
numbers and percentages for categorical variables. SPSS software version 19.0 (IBM Corp.,
Armonk, NY, USA)) was used for the statistical analysis. The characteristics of subjects were
compared by χ2-test for the categorical variables and Student’s t-test for the continuous
variables. Univariate logistic regression analysis and multivariate logistic regression analysis
were conducted to analyze the odds ratio (OR) of significant factors associated with
decreased BMD. Besides, to minimize confounding effect of age due to nonrandomized
assignment, propensity scores were calculated using a logistic regression model and the
covariate, age. A 1:1 matched study group was created by the Greedy method with NCSS
software (NCSS 10, NCSS Statistical software, Kaysville, Utah). After adjusting the age,
univariate logistic regression analysis and multivariate logistic regression analysis were used
to evaluate factors associated with decreased BMD. The strength of association was reported
as OR with 95% confidential interval (CI) and P-values. All statistical assessments were two-
sided and considered significant if P < 0.05.

Results

Prevalence of H. pylori infection and decreased BMD


We enroll 942 subjects who participated in the health examination and underwent
biochemistry blood examination, upper gastrointestinal endoscopy with CLO test and the
bone mineral density examinations. Seventy-five subjects were excluded due to missing data
in some biochemical variables. Of the 867 subjects in final analysis with the mean age of
55.9 ± 11.3 years, 381(43.9%) subjects had H. pyloriinfection, and 556 (64.1%) subjects had
decreased BMD. The numbers of female and male subjects were 299 (34.5%) and 568
(65.5%). Table 1 shows the baseline characteristics of all participants.
Table 1
Baseline characteristics

Participants
N = 867

Sex

Female n, % 299(34.5%)

Male n, % 568(65.5%)

Age (years old) 55.9 ± 11.3

BMI(Kg/m2) 24.9 ± 3.6

Waist circumference(cm) 85.1 ± 10.4

Total cholesterol(mg/dl) 195.7 ± 35.7

HDL cholesterol(mg/dl) 56.5 ± 15.6


Participants
N = 867

Triglyceride(mg/dl) 131.9 ± 84.7

LDL cholesterol(mg/dl) 113.4 ± 32.4

Decreased BMD, n % 556(64.1%)

Peptic ulcer n, % 351(40.5%)

GERD n, % 187(21.6%)

H. pylori infection n, % 381(43.9%)

BMI body mass index, LDL low-density lipoprotein, HDL high-density lipoprotein, BMD bone mineral
density, GERDgastro-esophageal reflux disease, H. pylori Helicobacter pylori

Differences between the subjects with normal and decreased BMD


Table 2 compares the characteristics between the normal BMD group and the decreased
BMD group. In decreased BMD group, the portion of woman was higher than a normal BMD
group (37.2% versus 29.6%, P = 0.023), the age was significantly older (59.4 ± 9.8 versus
49.8 ± 11.3, p < 0.001) and BMI was significantly lower (24.7 ± 3.5 versus
25.4 ± 3.7, p = 0.006) than the normal BMD group. Besides, lipid profiles except for
triglyceride were significantly higher than in the normal BMD group. Comparing the
gastrointestinal disorder between these two groups, the prevalence of peptic ulcer was
significantly higher in the decreased BMD group (p = 0.032), but the GERD was lower in the
decreased BMD group (p = 0.741). The prevalence of H. pylori infection was 39.9% and
46.2% in the normal BMD group and decreased BMD group respectively (P = 0.071).
Table 2
Differences between normal BMD group and decreased BMD group
Normal BMD Decreased BMD p value
n = 311 n = 556

Sex 0.023*

Male n, % 219(70.4%) 349(62.8%)

Female n, % 92(29.6%) 207(37.2%)

Age (years old) 49.8 ± 11.3 59.4 ± 9.8 < 0.001*

BMI(Kg/m2) 25.4 ± 3.7 24.7 ± 3.5 0.006*

Waist circumference(cm) 85.9 ± 10.1 84.7 ± 10.5 0.08

Total cholesterol(mg/dl) 191.2 ± 34.5 198.2 ± 36.2 0.005*

HDL cholesterol(mg/dl) 54.4 ± 14.9 57.8 ± 15.8 0.002*

Triglyceride(mg/dl) 136.8 ± 83.8 129.2 ± 85.2 0.205

LDL cholesterol(mg/dl) 110.0 ± 31.5 115.3 ± 32.7 0.021*


Normal BMD Decreased BMD p value
n = 311 n = 556

Peptic ulcer n, % 111(35.7%) 240(43.2%) 0.032*

GERD n, % 69(22.2%) 118(21.2%) 0.741

H. pylori infection n, % 124(39.9%) 257(46.2%) 0.071

*Indicates a significant difference, p < 0.05


BMI body mass index, LDL low-density lipoprotein, HDL high-density lipoprotein, BMD bone mineral
density, GERDgastro-esophageal reflux disease, H. pylori Helicobacter pylori

Simple and multiple stepwise logistic regression analyses of variables associated


with decreased BMD
Simple logistic regression (Table 3) showed decreased BMD was significantly associated
with the female gender (OR 0.71, 95% CI 0.53–0.94, P = 0.023), advanced age (OR 1.09,
95% CI 1.07–1.10, P < 0.001), low BMI (OR 0.95, 95% CI 0.91–0.99, P = 0.006), total
cholesterol (OR 1.01, 95% CI 1.00–1.01, P = 0.005), low-density lipoprotein (LDL)
cholesterol (OR 1.01, 95% CI 1.00–1.01, P = 0.021), high-density lipoprotein (HDL)
cholesterol (OR 1.02, 95% CI 1.00–1.02, P = 0.002), and peptic ulcer disease (OR 1.37, 95%
CI 1.03–1.82, P = 0.032). The multivariate analysis that was conducted with these risk factors
revealed that only advanced age (OR 1.09, 95% CI 1.08–1.11, P < 0.001), and low BMI (OR
0.91, 95% CI 0.87–0.95, P < 0.001) were independently significantly associated with
decreased BMD. The H. pyloriinfection was not independently significantly associated with
decreased BMD (OR 1.30, 95% CI 0.98–1.71, P = 0.071).
Table 3
Regression analysis for association of decreased BMD with different variables
Variables Simple logistic p value multiple stepwise logistic p value
regression regression
OR (95% CI) OR (95% CI)

Sex 0.71(0.53–0.94) 0.023*

Age 1.09(1.07-1.10) < 0.001* 1.09(1.08-1.11) < 0.001*

BMI 0.95(0.91-0.99) 0.006* 0.91(0.87-0.95) < 0.001*

Waist 0.99(0.98–1.00) 0.08


circumference

Total cholesterol 1.01(1.00–1.01) 0.005*

HDL cholesterol 1.02(1.00–1.02) 0.002*

TG 1.00(0.99-1.001) 0.207

LDL cholesterol 1.01(1.00–1.01) 0.021*

Peptic ulcer 1.37(1.03–1.82) 0.032*

GERD 0.95(0.68-1.32) 0.74


Variables Simple logistic p value multiple stepwise logistic p value
regression regression
OR (95% CI) OR (95% CI)

H. pylori infection 1.30(0.98–1.71) 0.071

*Indicates a significant difference, p < 0.05


BMI body mass index, LDL, low-density lipoprotein, HDL high-density lipoprotein, BMD bone mineral
density, GERD gastro-esophageal reflux disease, H. pylori Helicobacter pylori

Because the confounding effect of age was strong with nonrandomized assignment,
propensity score-matching was used for age adjustment. The 234 well-balanced pairs of
participants, with a 1:1 ratio after propensity score matching of age, were evaluated for risk
factor of decreased BMD. In these propensity score-matched participants, the mean age was
53.3 ± 10.35 years in the normal BMD group and 53.4 ± 10.33 years in the decreased BMD
group. There was no significant difference in age between the two groups (p = 0.961). The
covariates of these well-balanced pairs of participants were conducted for simple and
multiple stepwise logistic regression analysis. In simple logistic regression, the BMI (OR
0.92, 95% CI 0.87–0.97, P = 0.001), waist circumstance (OR 0.98, 95% CI 0.96–
0.99, P = 0.006) and H. pylori infection (OR 1.60, 95% CI 1.11–2.30, P = 0.012) were
significantly associated with decreased BMD. In multivariate analysis, H. pylori infection
(OR 1.62, 95% CI 1.12–2.35, P = 0.011) and BMI (OR 0.92, 95% CI 0.87–0.97, P = 0.001)
were independent significant risk factors of decreased BMD without confounding effect of
age (Table 4).
Table 4
Regression analysis for association between decreased BMD and different variables after
propensity score matching

Variables Simple logistic p value Multiple stepwise logistic p value


regression regression
OR (95% CI) OR (95% CI)

Sex 0.80(0.54–1.19) 0.27

BMI 0.92(0.87–0.97) 0.001* 0.92(0.87-0.97) 0.001*


Variables Simple logistic p value Multiple stepwise logistic p value
regression regression
OR (95% CI) OR (95% CI)

Waist 0.98(0.96–0.99) 0.006*


circumference

Total cholesterol 1.00(0.99–1.01) 0.257

HDL 1.01(1.00–1.02) 0.082

TG 1.00(0.99–1.001) 0.672

LDL 1.00(0.99–1.01) 0.425

Peptic ulcer 1.10(0.75–1.60) 0.632

GERD 0.88(0.56–1.38) 0.564

H. pylori infection 1.60(1.11–2.30) 0.012* 1.62(1.12-2.35) 0.011*

*Indicates a significant difference, p < 0.05


BMI body mass index, LDL low-density lipoprotein, HDL high-density lipoprotein, BMD bone mineral
density, GERDgastro-esophageal reflux disease, H. pylori Helicobacter pylori

Discussion
The main finding of this retrospective cross-sectional study revealed that advanced age and
low BMI were significant risk factors of decreased BMD in the nonrandomized assignment.
In addition, H. pyloriinfection was significantly associated with decreased BMD in selected
propensity score-matched participants with respect to age. In other words, H. pylori infection
was a risk factor of decreased BMD without the confounding effect of age, because the age
corresponded to an increase in risk of osteoporosis [2].
This result was compatible with the past studies regarding the association between H.
pylori infection and decreased BMD [10, 12, 14]. Several possible mechanisms might explain
this finding. First, H. pyloriinfection may result in chronic gastritis and induce systemic
inflammation with the release of cytokines, including tumor necrosis factor- 훼, interleukin-1
and interleukin-6 [15]. These inflammatory cytokines are known to result in bone resorption,
so H. pylori infection may affect bone turnover indirectly [16]. The second mechanism was
that chronic H. pylori infection might cause the gastric mucosal atrophy which would
decrease acid secretion. The hypochlorhydric stomach affects calcium absorption, calcium
homeostasis and bone mass [17]. In addition, the low serum vitamin B12 level was found in
the patients with H. pylori infection [18]. If the serum vitamin B12 levels are low, the folate
becomes trapped as methyltetrahydrofolate and then interrupts for folate-related DNA
synthesis. This reaction is an important factor of bone remodeling, so the low level of vitamin
B12 may result in decreased BMD [19].
Besides, H. pylori infection was treated with the eradication therapy as triple or quadruple
regimen, such as a proton pump inhibitor, clarithromycin, amoxicillin or tetracycline, and
metronidazole, with or without bismuth. One study described cytokine gene expression as
significantly decreasing after H. pylori was eradicated [20]. In a meta-analysis, mucosal
atrophy of the stomach was improved after successful eradication therapy [21]. Because the
cytokines result in bone resorption and gastric mucosal atrophy affects calcium metabolism,
the improvement of gastric mucosa and decreased inflammatory cytokine by successful
eradication therapy might be able to decrease the incidence of osteoporosis. Two studies
support this hypothesis. Hong-Mo Shih et al. reported the incidence of osteoporosis relatively
reduced in early eradication of H. pylori group, compared to the late eradication group by an
analysis from the National Health Insurance Database in Taiwan [22]. In Japan, the success
of H. pylori eradication may contribute to decrease the risk of osteoporosis. In our study, we
found that H. pylori infection was independently significantly associated with decreased
BMD after age adjustment, but eradication of H. pylori was not recorded in this health
examination database. A further prospective cohort study is necessary to confirm that BMD
would be improved after triple or quadruple H. pylori eradication therapy.
Advanced age and low BMI are well-known risk factors of osteoporosis and bone fracture
[2]. From the National Health and Nutrition Examination Survey (NHANES) 2005–2006 in
US, 49% of US women age 50 years and older had decreased BMD, and 30% of older men
had decreased BMD [23]. The prevalence rates of BMD from Nutrition and Health Survey in
Taiwan 2005–2008 was higher in advanced age. In females, the prevalence rate was 50.3% in
the 60 years and older group, and increased to 63.7% in the 70 years and older group. In
male, the prevalence rate was 18.6% in the 60 years and older group, and increased to 45.4%
in those aged 70 years and older [24]. One research showed that the weight loss appears to
increase the rate of hip bone loss, even in obese men undergoing voluntary weight reduction
[25]. This present study reported a similar result where the advanced age and low BMI had
the strong association with the decreased BMD.
Several researches have reported that the GERD was associated with osteoporosis. However,
the vertebral fractures or kyphosis were also found in these studies [26–28]. In the present
study, the GERD was not significantly associated with decreased BMD. Because this study
was derived from the health examinations, these subjects may be healthy relatively without
any bone deformities. Besides, two studies revealed peptic ulcer disease was an independent
risk factor for osteoporosis [6, 29]. The mechanism of this association was not clear. The
malabsorption of calcium and macroelements due to the defective stomach and duodenal
epithelium in which inflammation at these sites results may play a role in bone metabolism.
Our result showed the peptic ulcer was not a risk factor of decreased BMD, but it tended to
be associated with decreased BMD in univariate logistic regression analysis. The disorder of
the small intestine may affect the absorption of these substances more than disorders of the
stomach and duodenum.
There were several limitations in our study. First, our study was conducted in a single
hospital, which might not be representative of other settings. Second, retrospective studies
based on abstraction of medical records are constrained by the accuracy and completeness of
such records. Third, some laboratory data, including serum calcium, serum phosphorus,
serum specific alkaline phosphatase or serum vitamin D level were unavailable, because this
study was retrospective from the health examination.

Conclusions
In conclusion, advanced age and low BMI were independent significant risk factors of
decreased BMD in this retrospective study. Besides low BMI, H. pylori infection was
independently significantly associated with decreased BMD in selected propensity score-
matched participants with respect to age. Further prospective cohort studies including the
potential important factors are required to confirm this association in the Taiwan population.

Acknowledgments
We appreciated the Biostatistics Center, Kaohsiung Chang Gung Memorial Hospital for
statistics work.

Funding
This study was not supported by any grant.

Availability of data and materials


The datasets used and analysed during the current study will be available from the
corresponding author on reasonable request.

Abbreviations

BMD Bone mineral density

BMI Body mass index

CI Confidential interval
CLO test Campylobacter-like organism test

DEXA Dual energy X-ray absorptiometry scan

GERD Gastro-esophageal reflux disease

H. pylori Helicobacter pylori

HDL High-density lipoprotein

LDL Low-density lipoprotein

Authors’ contributions
PBL analyzed the data and drafted the paper; HCF, CSK, CJC performed the research; LSS
designed the research and revised the paper. All authors read and approved the final
manuscript.

Notes

Ethics approval and consent to participate


This study was approved by the Chang Gung Medical Foundation Institutional Review Board
(IRB No.: 201701187B0). Since this is a retrospective study, a written consent is waived by
an IRB and is deemed unnecessary.

Competing interests
CSK is a member of the editorial board of this journal. All other authors declare that they
have no competing interests.

Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and
institutional affiliations.

Contributor Information
Bo-Lin Pan, Email: moc.liamg@etthomas.
Chih-Fang Huang, Email: moc.liamg@gnafihc.eniluap.
Seng-Kee Chuah, Email: wt.ten.dees@kshauhc.
Jui-Chin Chiang, Email: wt.gro.hmgc@yregraM.
Song-Seng Loke, Email: wt.gro.hmgc.mda@ekol.

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osteoporosis in patients with peptic ulcer disease: a Nationwide population-based
study. Medicine (Baltimore) 2016;95(16):e3309. doi: 10.1097/MD.0000000000003309.
Osteoporosis as an initial manifestation in a patient with Crohn's
disease: A case report
Hongyun Wei,1 Chunhui Ouyang,1 Dehong Peng,2 Fanggen Lu,1 and Jie Zhang1

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Abstract

Introduction
Bone loss is considered to be a disabling complication of inflammatory bowel disease (IBD)
(1). Bone mineral density (BMD) testing results of patients with IBD from seven medical
facilities, ranging from January 1996 to October 2006, were reviewed to determine the
prevalence rate of osteoporosis (2). A total of 317 bone density tests were conducted in 2,035
patients, and osteoporosis was detected in 26% of patients and osteopenia in 48% (2).
Another study involving 70 patients with IBD demonstrated that osteoporosis was observed
in 13.2% of patients and osteopenia in 46.1% (3). The dominant risk factors leading to
osteoporosis in IBD are considered to be age, intestinal malabsorption, long-term use of
steroids, lack of exercise or supplementation of calcium and vitamin D, and smoking (4). In
addition, inflammation and proinflammatory cytokines serve a key role in bone loss and
increase the risk of fracture (5), including interleukin (IL)-6 and tumor necrosis factor (TNF)
(6). However, the published literature regarding osteoporosis in IBD has associated it with
the aforementioned risk factors. Osteoporosis as a complication is common in patients with
IBD, followed by the above risk factors, while it rarely presents as a primary manifestation in
patients with Crohn's disease (CD). A previous study observed that severe osteoporosis
presented in a 12-year-old boy with CD, and no history of steroid use was tracked (7). To the
best of our knowledge, no reports of osteoporosis as an initial manifestation of IBD in adults
exist. The present case report describes a case of osteoporosis as an initial manifestation in an
adult patient with CD without the aforementioned risk factors. Notably, using steroids and
biological agents ameliorated low back pain (LBP) in the patient. Considering the
relationship between inflammation and bone loss, it was hypothesized that osteoporosis, in
the present case, is a primary manifestation of CD.
Go to:

Case report
A 43-year-old male presented at the Second Xiangya Hospital of Central South University
(Changsha, China) with worsening symptoms of LBP in July 2015 and was compulsively
posed in a lateral position. No abdominal or digestive syndromes were observed. The dietary
intake of the patient had not changed; however, the patient had lost 15 kg of body weight in
12 months. As demonstrated in Fig. 1, X-rays revealed thoracolumbar spine degeneration
(Fig. 1A). A 1 year supply of medicinal calcium preparation (Caltrate®; 600 mg/day orally;
Wyeth; Pfizer, Inc., New York, NY, USA; and 1α-OH vitamin D3; Teva Pharmaceutical
Industries, Ltd., Petach Tikva, Israel; oral soft capsule, 0.25 µg/day) was unable to improve
LBP. A computed tomography (CT) scan was subsequently performed, revealing
thoracolumbar spine degeneration and mesenteric lymph node tumescence (Fig. 1B), as did
single photon emission CT (Fig. 1C). The patient was therefore referred to the
Gastroenterology department in July 2015.
Open in a separate window
Figure 1.
Examination of bone and intestinal manifestation under colonic endoscopy. (A-C) Bone loss was
identified following radical examination. (D) The patient demonstrated clubbing of the fingers and
feet. (E and F) Colonoscopy indicated an inflamed and strictured ileocecal valve. (G and H) Biopsy
under colonoscopy revealed chronic active colitis with ulcers and inflammatory granulation tissue
suggestive of Crohn's disease (G, magnification, ×100; H, magnification, ×400). (I) Biopsy under
duodenal-balloon enteroscopy demonstrated chronic active colitis with necrosis and ulceration in the
small intestine (magnification, ×100).
The patient had no history of long-term use of corticosteroids and no bone fractures, and had
a 10-year history of cigarette smoking at a rate of 6 cigarettes/day. The body weight of the
patient was 71.6 kg and body mass index was 23.92. Physical examination revealed pressing
pain in the cervical, lumbar and thoracic vertebrae and obvious clubbing of the fingers and
feet (Fig. 1D). Other inspections of the lung, heart and abdomen proved unremarkable.
Laboratory data revealed a serum hemoglobin (Hb) level of 103 g/l (normal range, 130–175
g/l; Sysmex® XN-Series; Sysmex Corporation, Kobe, Japan), serum albumin level of 23.9 g/l
(normal range, 40–55 g/l; Hitachi Modular 7600 chemistry analyzer; Hitachi, Ltd., Tokyo,
Japan), an erythrocyte sedimentation rate (ESR) of 50 mm/h (normal range, 1–15 mm/h,
automatic ESR analyzer Monitor-100; Vital Diagnostics, Forli, Italy), C-reactive protein
(CRP) level of 63.5 mg/l (normal range, 0–8.0 mg/l; IMMAGE® 800; Beckman Coulter, Inc.,
Brea, CA, USA) and reduced serum 25-hydroxy vitamin D level of 37 nmol/l (normal range,
75–250 nmol/l; ADVIA Centaur XP chemiluminescence immunoanalyzer; Siemens
Healthcare Diagnostics Manufacturing, Ltd., Dublin, Ireland). No positive results were
identified for serum parathyrin, gonadin, calcium, phosphate, magnesium, alkaline
phosphatase and human leukocyte antigen-B27.
A dual-energy X-ray absorptionmetry scan (DXA) of the lumbar spine revealed a severe
reduction in BMD (lumbar Z-score, −2.9 SD; T-score, −3.0 SD). Colonoscopy demonstrated
an inflamed and strictured ileocecal valve, with less inflammation in the ascending,
transverse colon, sigmoid colon and rectum, compatible with CD; however, the coloscope
could not pass through the restricted ileocecal valve (Fig. 1E and F). An ileocecal valve
biopsy indicated chronic active colitis with ulcers and inflammatory granulation tissue
suggestive of CD (Fig. 1G and H). The biopsy tissue was fixed in 4% formaldehyde for 6 h at
35°C, then cut into 4-µm-thick sections and stained with hematoxylin and eosin for 20 min at
room temperature. The sections were observed using an Olympus BX53F light microscope
(Olympus Corporation, Tokyo, Japan). An abdominal CT scan indicated marked symmetric
segmental thickening at the jejunum wall (Fig. 2A and B). Duodenal-balloon enteroscopy
demonstrated segmental ulceration and stricture in the jejunum (Fig. 2C). A jejunum biopsy
revealed chronic active colitis with necrosis and ulceration (Figs. 1I and and2D).2D). The
tissue sections were fixed and stained as above. After excluding tuberculosis via a chest X-
ray and T-SPOT® (cat. no. TB.300 CN; Oxford Immunotec Global PLC, Abingdon, UK), the
patient was diagnosed with CD according to World Health Organization criteria (8). The
presenting CD activity index (CDAI) was 231.0 (9).

Figure 2.
CT scan and endoscopy examination prior to and following treatment. (A and B) CT demonstrated
marked symmetric segmental thickening at the jejunum wall prior to treatment (white arrows). (C)
Segmental ulceration and stricture in the jejunum under duodenal-balloon enteroscopy was observed
and (D) chronic active colitis with ulceration was revealed under the microscope (magnification,
×400) prior to treatment. (E) Reduced mesenteric lymph node under CT and (F) improved intestinal
inflammation under capsule endoscopy was observed following treatment. CT, computed
tomography.
Prednisone (Zhejiang Xianju Pharmaceutical Co., Ltd., Zhejiang, China) 60 mg/day was
prescribed with a concomitant dose of 100 mg azathioprim (Shanghai Xinyi Pharmaceutical
Co., Ltd., Shanghai, China) daily in September 2015 for 8 months. LBP began to show
improvement 5 days after treatment. However, by April 2016, the CRP level was 57.60 mg/l,
the CDAI was 284, and a second DXA revealed no improvement of BMD (lumbar Z-score,
−3.1 SD; T-score, −3.2 SD). In addition, hypertension, an adverse effect of prednisone, was
tracked. Given this result and the patient's insensitivity to steroids, prednisone was switched
to adalimumab (Humira®; 40 mg/2 weeks, subcutaneous injection; Vetter Pharma
International GmbH, Ravensburg, Germany) in May 2016. By November 2016, CRP and
ESR were maintained at normal levels (7.12 mg/l and 10 mm/h, respectively), Hb level was
158 g/l and the CDAI was 148.0. DXA revealed an improved BMD (lumbar Z score, −1.9
SD; T-score, −2.1 SD) and abdominal CT scan demonstrated improved mineralization, with
sclerosis of vertebral bodies and intestinal inflammation (Fig. 2E). Nevertheless, capsule
endoscopy indicated no significant improvement of small intestinal disease (Fig. 2F). The
patient is still undergoing treatment with biological agents and is followed up every 2
months. The patient provided written informed consent for publication of the present case
report.

Discussion
Reduced bone density is an extra-intestinal manifestation and a common complication of IBD
(10). However, osteoporosis as an initial symptom of IBD is rare. The present report detailed
a case of osteoporosis as a presenting manifestation of CD, and osteoporosis was improved
following treatment of CD with glucocorticoids.
The possible reasons leading to osteoporosis in IBD are corticosteroid use, smoking and gut
inflammation (10). No history of corticosteroid use and metabolic bone disease were tracked
in the present patient. Smoking alone did not suitably explain osteoporosis. Therefore, the
inflammatory activity of CD itself may be a main contributor to osteoporosis (11). One of the
possible mechanisms of osteoposrosis in IBD is malabsorption. Calcium deficiency and low
vitamin D levels occurred as a result of small intestinal dysfunction in the present patient. A
previous 5-year study identified that low vitamin D levels are common in patients with IBD,
and IBD patients with low mean vitamin D levels demonstrated worse disease activity, worse
pain and higher requirement for steroids (4). The use of vitamin D may improve osteoporosis
(12); however, this was not the case for the present patient. LBP was not improved following
treatment with calcium and vitamin D. Furthermore, although BMD improved following
steroid and biological treatment, endoscopic performance was not notably improved in the
present case. This phenomenon suggested that malabsorption may be a partial cause of
osteoporosis in CD, and osteoporosis may be the result of extra-intestinal inflammation.
In the present case, prednisone and azathioprim were prescribed, and the LBP began to
improve following treatment, indicating that osteoporosis was associated with inflammation.
Immune-associated inflammation also participated in the genesis of bone loss, as previously
reported (13). T cell reconstitution is accompanied by increased bone resorption and
decreased BMD (14). Proinflammatory cytokines may also contribute to bone loss and
increase the risk of fracture (5). A previous study demonstrated that IL-6 levels were higher
in patients with CD than the levels in controls (15). Thus, steroids were able to reduce LBP in
the present case. Nevertheless, the present patient suffered from adverse effects and
insensitivity to steroids, so adalimumab, an anti-TNF antibody, was administered, which
resulted in improved BMD and CDAI. TNFs are cytokines that are associated with bone loss,
and the pathway involved is the receptor activator of nuclear factor-κB, which is expressed
on the surface of osteoblasts (16). Additionally, interferon regulatory factor-1 (IRF1) is
regarded as a genetic risk for IBD, and a mutant murine model of IRF1−/− indicated that IRF1
deficiency was related to decreased proliferation of bone marrow-derived osteoblast
precursors and increased mineralization activity, suggesting its role in regulating bone
metabolism (17). Accordingly, bone loss may be an initial manifestation of CD.
In conclusion, for bone loss, the possibility of small intestinal CD should be considered, and
CD as the primary disease should be treated actively. Adequate calcium supplements should
be administered to patients with CD, physical activity should be encouraged, and smoking or
excessive alcoholic intake should also be avoided.

Acknowledgements
Not applicable.

Funding
No funding was received.

Availability of data and materials


The datasets used and/or analyzed during the current study are available from the
corresponding author on reasonable request.

Authors' contributions
CO performed endoscopy examination. DP performed the magnetic resonance imaging and
computed tomography scans. FL and HW collected the data and wrote the manuscript. JZ
analyzed the data and revised the manuscript.

Ethics approval and consent to participate


The patient provided written informed consent for the publication of this case report.

Consent for publication


The patient provided written informed consent for the publication of any associated data and
accompanying images.

Competing interests
The authors declare that they have no competing interests.

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Int J Crit Illn Inj Sci. 2018 Jul-Sep; 8(3): 149–153.

doi: 10.4103/IJCIIS.IJCIIS_17_18
PMCID: PMC6116304

PMID: 30181972

The relationship between fluid resuscitation and intra-abdominal


hypertension in patients with blunt abdominal trauma
Soudabeh Vatankhah, Rahim Ali Sheikhi,1 Mohammad Heidari,2 and Parisa Moradimajd1

Author information ► Copyright and License information ► Disclaimer

Abstract

INTRODUCTION
Intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS) are
associated with increased morbidity and mortality among critically ill patients.[1,2,3,4,5]
IAH/ACS not only affects the function of intra-abdominal organs but also causes
physiological changes and malfunctioning of organs beyond the abdominal cavity because of
the limited space and its close anatomic relationship with contiguous cavities. From the
pathophysiological perspective, IAH/ACS can cause cardiovascular, respiratory and renal
dysfunction and ultimately cause multiple organ failure. IAH may be acute or chronic and
might turn into a fatal ACS in case of sudden functional changes in vital organs such as
cardiovascular, respiratory, and renal systems.[1,2,3,4] Primary IAH/ACS is a condition
associated with injury or disease in the abdominopelvic cavity[1] and mostly observed in
patients with severe abdominopelvic trauma, severe pelvic fractures with hemorrhage and
retroperitoneal hematoma, liver-transplant patients and in those who suffer intra-abdominal
bleeding for any reasons and require radiological interventions and urgent damage control
surgeries.[6] Ileus, retroperitoneal edema, ascites, mesenteric ischemia, severe pancreatitis,
peritonitis, and space-occupying lesions such as tumor are examples that less involved in the
creation of this syndrome.[7] Whereas IAH/ACS occurs as a result of a condition that
originates outside the abdomen in a scenario lacking primary intraperitoneal injury or
intervention.[1,8,9] This state appears to be related to visceral, abdominal wall, and
retroperitoneal edema such as severe hypovolemic shocks, in which massive volumes of
different fluids are required to be administered to resuscitate and restore patient's
hemodynamic status.[9] Critically ill patients may develop a positive fluid balance because of
(a) excessive fluid administration during the initial resuscitation phase of a patient who
presents with hypovolemic shock,[6,7,8,9,10] (b) too little fluid removal or mobilization
following the initial resuscitation phase,[8,9] (c) the type of fluids
administered,[1,2,3,4,5,11,12,13] and (d) any combination of the above.[11,12,13] In the
trauma setting, hemorrhagic shock requiring laparotomy for hemorrhage control is a major
risk factor for IAH/ACS. Resuscitation with large amounts of crystalloids, activation of
inflammatory mediators leading to capillary leakage, and reperfusion injury contribute to
intestinal edema, which may increase the risk of IAH and subsequent ACS.[4,5,6,7,8]
Hypervolemia coupled with severe inflammatory reactions can increase the risk of ACS in
patients.[14,15,16,17,18] Rapid administration of large-volume fluids can also contribute to
this condition.[9,10,13,19] Whereas fluids should be seen as drugs with indications, contra-
indications and potential beneficial and adverse effects. Therefore, not only the type of fluids
but also dose, timing, and speed of administration may influence the effect of the
fluid.[15,16,17,18]
The volume of resuscitative fluid administered during trauma-associated shock, typically
hemorrhagic shock is believed to correlate with the risk of ACS, with crystalloid
resuscitation, in particular, being singled out as a major culprit.[5,6,7,8,20] Therefore, in the
appropriate clinical setting, a high index of suspicion, judicious measurement of intra-
abdominal pressure (IAP), and early evaluation for organ dysfunction are necessary for early
identification and intervention, with the goal of reducing the associated morbidity and
mortality and any measure that safely reduces the amount of fluid given without
compromising resuscitation may reduce the incidence and severity of IAH/ACS and hence
improve outcomes. The goal of our study was to investigate the relationship between IAH
and fluid resuscitation in patients presenting to hospital with blunt abdominal trauma and to
recall risk of IAH/ACS during traumatic hemorrhagic shock resuscitation.

MATERIALS AND METHODS


The present descriptive-analytical study was conducted to investigate the relationship of IAH
and ACS with fluid resuscitation in patients presenting to hospital with blunt abdominal
trauma in a 1-year period. The study population was patients with blunt abdominal trauma
who referred to the emergency department of the hospital. The inclusion criteria include as
follows: nonpenetrating abdominal trauma patient whose abdominal trauma was confirmed
by an emergency physician or ultrasound or computerize tomography scanning. Patients who
did not satisfy themselves or their companions for entering the study, the person who did not
have a Foley catheter for any reason or had a history of the problem in urinary tract, and
patients with damage to the genitalia region were excluded from the study.
IAP can be measured by direct or indirect measurement methods. The direct method that
measure IAP from the peritoneal cavity is invasive and not always possible in emergency
departments. Indirect IAP measurement is noninvasive and can be applied from the bladder
cavity. Over the years, the indirect IAP measurement through the bladder evolved as the gold
standard method for the measurement of IAP.[20] The bladder acts as a passive diaphragm
whose pressure accurately reflects IAP with fluid volumes of 50–100 ml.[1,20,21] Thus,
Bladder pressure measurement used in the present study.

Ethical approval
The present study was approved by Ethical Committee Medical Sciences University of
Ahvaz. After selecting the eligible participant, the researcher was introduced to them, and the
objectives of the study were elaborated for the participants. The informed consent was
obtained from the subjects, and they were assured that their information will remain
confidential.
The data collection tools comprised checklists of demographic information and other data
required in the study. IAP measurement tools consisted of Foley catheters, intravenous sets,
normal saline solutions, 50-ml syringes, sterile gloves, and rulers. Blunt abdominal trauma
patients admitted to the emergency department who confirmed by emergency physicians,
abdominal ultrasound, and computed tomography scan and had a urinary catheter was
selected. Urine drainage bags were then removed from Foley catheters, and 60 ml of normal
saline solution was instilled into the bladder after disinfecting the urinary catheter's tip in a
fully sterile fashion (in children, the amount of liquid is injected into the bladder 1 ml/kg up
to 20 ml).
The sterile intravenous set was then connected to the Foley catheter's tip at a 90° angle with
the patient's hip, and the pubic symphysis was set as a baseline. The measurement was
performed 30-60 s after instillation to allow bladder detrusor muscle relaxation. The clamp
was then opened to let the fluid column rise through the intravenous set from the bladder. A
ruler was used to measure the maximum intravenous fluid height from the baseline when the
fluid level remained constant at end expiration. This was first performed upon the patient's
admission to the emergency department and repeated every 4 h up to 24 h after the
admission.
The World Society of ACS (WSACS) The WSACS defines IAP as the pressure within the
abdominal cavity, measured at end-expiration in a relaxed, supine patient. It defines IAH as a
sustained elevation of IAP >12 mmHg. The WSACS defines ACS as a sustained increase of
IAP >20 mm Hg that is associated with the onset of organ dysfunction.[18,19,20,21]
Currently, no standardized definitions specific for infants and children are available. Children
have lower mean arterial pressures than adults do, so multiorgan failure may occur in
children at lower IAP thresholds than those defined by WSACS. As a result, lower IAP cutoff
values of 12 and 15 mm Hg have been used to define ACS in children.[17,18,19,20,21,22]
For an individual child, the actual IAP value may be less important than the impact of the
pressure on organ function. Hence, ACS in a child may be more appropriately defined as an
IAP of >10 mm Hg with evidence of new organ dysfunction or failure.[21,22] Therefore,
intra-bladder pressure, urine volume, blood oxygenation, and blood pressure were used to
diagnose IAP and ACS.
For IAPs exceeding 20 cmH2O (15 mmHg) in adult and 13.6 cm H2O (10 mmHg), the patient
was identified as an IAH sample. ACS refers to IAPs exceeding 15 mmHg (10 mmHg in
children) coupled with the impairment of vital systems such as the cardiovascular, renal, and
respiratory system The researcher then confirmed the ACS if two out of three symptoms,
including decreased urine output (<0.5 ml/kg/h), hypotension (blood pressure <90 mm/Hg in
adult and <70 mm/Hg in children), and hypoxemia (O2saturation <80%) persist.[14,20,21]
The amount and type of the fluids administered were recorded in all the patients on their
admission then the relationship between ACS and the amount of the fluids received from
admission was evaluated. Descriptive and inferential statistics were used to statistically
analyze the data and frequency distribution tables to classify and summarize the data. The
collected and classified data were analyzed in SPSS package 18.0 for Windows (PASW
Statistics for Windows Chicago: SPSS Inc.).

RESULTS
The findings revealed 28 cases (28%) with ACS in a total of 100 patients presenting to
hospital emergency departments with blunt abdominal trauma, whose IAP was measured over
1 year period. The majority of the study subjects with abdominal trauma (87%) and 23 people
(82.14%) of the cases diagnosed with ACS were men, while 5 (17.86%) cases with ACS were
women. The Fisher's exact test found no significant relationships between gender and the
prevalence of ACS [P = 0.508, Table 1].
Table 1
Distribution of the participants in terms of developing abdominal compartment syndrome and
gender
In terms of age distribution, the majority of the patients presenting with abdominal trauma
(76%) and whose IAP was measured as well as those diagnosed with ACS (64.28%) were
15–39 years old. The Fisher's exact test showed no significant relationships between age and
the prevalence of ACS (P = 0.599) [Table 2].
Table 2
Distribution of the participants according to age

Based on the mean amount of fluid administration, the study patients with ACS received
6107 ml of crystalloids including Ringer's, lactated Ringer's and 0.9% saline solutions as well
as 3.86 blood bags (965 ml), 5.56 fresh frozen plasma (FFP) bags (1390 ml), and 6.20
platelets bags (310 ml) within the first 24 h from hospital admission, while the subjects
without ACS received on average 4493 ml of crystalloids, 0.83 blood bag (207.5 ml), 0.19
FFP bag (700 ml), and 0.07 platelets bag (3.5 ml) over the same period. The mean volumes of
all four types of the fluids received are therefore found to be higher in the patients with ACS
than in those without ACS. The t-test also confirmed significant differences between the
patients with and without ACS in terms of the amount of the fluids received (P < 0.001)
[Table 3]. The results also showed that people with pelvic fracture had a significantly higher
incidence of abdominal compartment syndrome than the rest of the patient (P < 0.001) [Table
4].
Table 3
Subjects in the amount and type of fluid intake in 24 h

Table 4
Distribution of the participants according specific injury
DISCUSSION
The study conducted on 1976 patients in 2016 by Hwabejire et al. titled, “ACS in trauma
patients with hemorrhagic shocks” found 122 (6.2%) patients with ACS who had received
significantly higher volumes of fluids compared to those without ACS.[11] This study is
consistent with the present study in terms of the significant relationship observed between
fluid resuscitation and IAH in the two groups with and without ACS. The present study,
however, found a significantly higher prevalence of ACS in the study subjects than the figure
obtained by Hwabjire et al. This difference can be justified by the fact that the present study
was conducted on patients with blunt abdominal trauma, whose abdominal injuries were
confirmed by the emergency department physician or clinical studies such as ultrasound, and
that abdominal trauma and visceral damage can underlie IAH and ACS, while the former
study was conducted on trauma subjects diagnosed with shocks.
The study conducted over a 7-year period by Cothren et al. found 54 patients with ACS, 41
(75.9%) of whom were posttraumatic and 13 (24.1%) suffered the syndrome due to internal
problems. All subjects including the surgical and medical patients also received a mean
volume of 16.5 ± 1.5 L fluids in the first 24 h.[22] The study conducted by Oda et al., (2006)
titled “Resuscitation fluid volume and ACS in patients with major burns” found 8 (16.6%)
patients in 48 cases with burns >30% TBSA to have developed ACS within a mean duration
of 18.3 h after the injury. The resuscitation volume was also 0.4 ± 0.11 L/kg of body weight
within the first 24 h of presentation, suggesting significant relationships between IAH and
resuscitation volume. The patients with ACS also were found to have received 300 ml/kg of
body weight fluids within the first 24 h.[21] Although this study was conducted on burn
patients, the significantly positive relationship found between fluids volume and IAH is
consistent with the present study. Moreover, the higher prevalence obtained in the present
study can be a result of selecting patients with blunt abdominal trauma as the study
population. The systematic review conducted by Azzopardi et al. on ACS in adults with
severe burns found that high volume of fluids administered can increase the risk of ACS and
that crystalloid fluids can be proposed as one of the main causes of ACS when IAP is not
monitored.[13] Which is consistent with the present study.
A review of the studies conducted on ACS and its relationships with the volume of
administered fluids, suggests that prompting administration of large fluids volume is one of
the main factors contributing to IAH and ACS. Therefore, patients who for any reason are
required to prompting administration of large fluid volumes, such as patients with extensive
burns, severe abdominal trauma, retroperitoneal hematoma, unstable pelvic fractures with
bleeding, hemorrhagic shock, extensive abdominal surgery, must be vigilant and with
consecutive measurement of IAP, control of cardiovascular, respiratory, and renal function,
and closely monitor the exact amount of administrated fluids prevent an increase in IAP and
its progress to ACS. Because it is highly lethal syndrome and, as is clear from the results of
this research of 28 patients diagnosed with this syndrome, 21 (75%) patients died.
CONCLUSIONS
Patients with blunt abdominal trauma and severe injury such as pelvic fracture, internal
bleeding, and damage to vital organs in the abdomen that resuscitate with a large volume of
liquids because of hemodynamic shock, are associated with IAH/ACS and high mortality and
morbidity rate.[1,2,3,4,21,22] Thus, ACS is a clinically important problem in critically ill
patients in which massive volumes of different fluids are required to be administered to
resuscitate and restore their hemodynamic status.[7,8] That can be ameliorated by early
recognition of IAH, optimal fluid resuscitation, and appropriate medical or surgical
intervention for IAH and impending ACS. Bedside critical care and appropriate clinical
setting, nurses are responsible for accurately measuring IAP and alerting physicians about
important observed changes. Nurses “knowledge of IAH and ACS, awareness of the patients
at risk for IAH, and recognition of IAH and progression to ACS are important. Especially
control the amount of administered crystalloid fluids prevents the progression of IAP to ACS
as a seriously fatal condition. A high index of suspicion, judicious measurement of IAP,
active IAP surveillance for at-risk patients, and early evaluation for organ dysfunction are
essential in early detection and management of ACS.

Financial support and sponsorship


Nil.

Conflicts of interest
There are no conflicts of interest.

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