Intestinal Fatty Acid Binding Protein: A Sensitive Marker in Abdominal Surgery and Abdominal Infection

Abstract

Background:

Intestinal fatty acid binding protein (iFABP) is elevated in plasma by intestinal injury. We investigated the influence of surgical trauma and severe sepsis caused by abdominal and pulmonary infection on plasma iFABP concentrations.

Methods:

Seventy-nine patients were included in this prospective observational study: 31 patients before elective major abdominal surgery (EMS), 33 patients with severe sepsis on admission to the intensive care unit (ICU), and 15 healthy volunteers who served as controls. Blood samples were taken before and after surgery for a period up to 5 d.

Results:

Prior to surgery, EMS patients had increased iFABP concentrations in those patients with intestinal cancer compared with patients without intestinal cancer (217 pg/mL, interquartile range [IQR] I–III 100–369 pg/mL versus 79 pg/mL, IQR I–III: 0–182 pg/mL; p<0.01) and with controls (114 pg/mL, IQR I–III: 103–124 pg/mL; p<0.01). Surgical trauma increased iFABP levels in patients without intestinal cancer (240 pg/mL, IQR I–III 111–305 pg/mL; p<0.01). Within 24 h after surgery, iFABP levels decreased to normal values. Patients with severe sepsis of abdominal origin had elevated concentrations compared with controls (324 pg/mL [IQR I–III 0–649 pg/mL]; p=0.05); in patients with pneumonia, iFABP levels were not significantly increased. Discrimination between intestinal- and pulmonary-induced sepsis was low (area under the curve [AUC] 0.693; 95% confidence interval 0.512–0.874).

Conclusions:

Surgical trauma and severe sepsis lead to elevated iFABP concentrations. However, intestinal malignant disease and in some patients severe sepsis caused by pneumonia also resulted in elevated iFABP concentrations. The results support the idea that epithelial injury of many causes leads to elevated concentrations of iFABP. The value of iFABP for differentiating pulmonary from intestinal sepsis is limited.

Intestinal fatty acid binding protein (iFABP) is produced in enterocytes of the intestinal mucosal layer and is a specific marker for injury of the small intestine [1,2]. Physiologically, iFABP is a soluble protein in the cytoplasm, located in the enterocytes of the duodenum, jejunum, ileum, and colon [3]. The highest tissue concentrations of iFABP are found in the jejunum, where its highest concentration is found in the villus rather than crypt cells, located in the apex rather than the base of intestinal cells [4]. The protein is known to be released rapidly into the circulation after mucosal tissue injury of the small intestinal [1,5]. Based on this mechanism, many investigators have reported a relation between iFABP concentration and small intestinal diseases [6 –9].

Although iFABP is an important marker of intestinal tissue injury, there is only a small amount of data available in the literature regarding plasma iFABP concentrations after major abdominal surgery. We therefore determined in this observational study whether iFABP is elevated after major abdominal surgery resulting from surgical trauma and whether it remains elevated in response to the surgical procedure. Furthermore, we aimed to identify whether iFABP is a useful parameter in post-operative source control in patients with sepsis.

Patients and Methods

Patient population

After approval by the ethics committee of the University Hospital, Frankfurt, Germany, we recruited 64 patients who gave written consent to participate in this study. Either informed consent was obtained from the patient directly or from the patient's legal guardian. Additionally, 15 healthy volunteers were recruited, following consent, as controls (Fig. 1). Inclusion criteria were defined for two different clinical entities, namely elective major surgery (EMS) and severe sepsis.

FIG. 1.

Study design. Three groups included, 64 patients and 15 healthy controls. EMS, elective major surgery

Elective major surgery

Thirty-one patients were recruited prior to EMS (Table 1). The indications for surgical intervention are presented in Table 2. Patients were classified post hoc into two subgroups (Fig. 1): (1) Patients with intestinal cancer (stomach, small bowel, colon) or intestinal infiltration due to a pancreas carcinoma, and (2) patients without intestinal cancer infiltration (Table 2). This group included patients with pancreatitis, lymphoma, or pancreas carcinoma without impact on the intestinal cell line. Ontogenetically the pancreas develops from two diverticula of the duodenum. However, because the adult organ lacks the enterocytes of the duodenum and can be defined primarily as a gland, such relevant intracellular concentrations of iFABP are not to be expected.

Table 1.

Elective Major Surgery Patients

	Prior surgery			Post-Surgery
	All	IC	NIC	All	IC	NIC	Control
No.	31	17	14				15
Gender
Male	23	13	10				7
Female	8	4	4				8
Age (y)	64.5	63.7	68.1
iFABP (pg/mL)	191.4 (0, 314)	217^* (100, 369)	79 (0, 182)	203 (139, 311)	203 (141, 378)	240 (111, 305)	114 (103, 124)
IL-6 (pg/mL)	4 (2, 8)	3 (2,7)	3 (2, 17)	194^** (129, 666)	168^** (114, 377)	550^* (203, 1,632)
IL-10 (pg/mL)	0	0	0	7^** (0, 14)	6^*** (0, 16.2)	7^*** (6, 9)
LBP (pg/mL)	5.6 (4.0, 12.2)	5.7 (3.6, 11.9)	6.1 (5.1, 23.0)	5.9 (4.1, 10.3)	5.7 (3.9, 9.0)	6.4 (4.8, 16.1)
CRP (mg/dL)	0.8 (0.1, 3.5)	0.49 (0,2.18)	2.40 (0.5, 7.8)	0.6 (0.2, 1.7)	0.53 (0.17, 2.0)	0.57 (0.25, 2.23)
PCT (ng/mL)	0.05 (0.03, 0.11)	0.05 (0.01, 0)	0.08 (0.02, 0.23)	0.08^* (0.04, 0.16)	0.08 (0.4, 0.2)	0.10 (0.04, 0.17)

p<0.01; IC significantly higher than NIC and control prior to surgery; ^**p<0.001; ^***p<0.05

Demographic-, cytokine- and iFABP- data of elective major surgery patients versus healthy controls (median, [25%; 75% quartiles])

IC=intestinal cancer/cancer infiltration; NIC=no intestinal cancer/cancer infiltration; IL-6=interleukin 6; IL-10=interleukin 10; LBP=lipopolysaccharide binding protein; CRP=C-reactive protein; PCT=procalcitonin.

Table 2.

Underlying Disease of Elective Major Surgery Group

	No intestinal cancer infiltration	Intestinal cancer/cancer infiltration
Chronic pancreatitis	5
Neuroendocrine carcinoma of the pancreas	2
Pancreatic cystadenocarcinoma		1
Diffuse B-cell lymphoma	1
Pancreatic adenocarcinoma	6	4
Gastric adenocarcinoma		8
Esophageal squamous cell carcinoma		1
Colorectal cancer		2
Enterogeneous duodenal cyst		1

Patients are divided post hoc in respect to histologic findings into a group of patients with intestinal cancer infiltration or primary intestinal carcinoma (IC; n=15) and into a group of patients without intestinal cancer/cancer infiltration (NIC; n=16).

Blood samples and clinical data were obtained immediately prior to surgery, at the end of surgery/admission to the intensive care unit (ICU), and once per day until day five post-surgery. Systemic inflammatory response syndrome (SIRS) criteria and suspicion of sepsis or infection were evaluated daily in all patients.

Severe sepsis

Thirty-three surgery patients with severe sepsis or septic shock were recruited at ICU admission or in the operating room. Inclusion criteria were three or more SIRS criteria and first organ dysfunction no longer than 24 h before ICU admission in accordance to ACCP/SCCM consensus conference criteria [10].

Regarding the source of infection (Fig. 1), two groups were defined: 26 patients with abdominal source of infection and seven patients with pneumonia as the source of sepsis (Table 3). Blood samples and clinical data were obtained at identical time points in all groups: Before surgery, on admission to the ICU, and once daily for five consecutive days.

Table 3.

Demographic and Cytokine Data of Severe Sepsis Patients

	Abdominal sepsis (prior laparotomy)	Abdominal sepsis (admission ICU)	Pulmonary sepsis
n	14	26	7
Male	9	17	6
Female	5	9	1
Age (y)		67.5	69.0
APACHE II		24 (19, 28)	21 (20, 27)
SAPS II		51 (38, 60)	43 (23, 50)
SOFA		11 (8, 16)	6 (3, 9)
IL-6 (pg/mL)	1,798 (507, 8,361)	1,923 (266, 4,966)	234 (67, 11,210)
IL-10 (pg/mL)	51 (12, 216)	52 (27, 128)	19 (10, 75)
LBP (pg/mL)	30 (18.9, 44,3)	30 (24, 43)	27 (23, 56)
CRP (mg/dL)	18.8 (12.6, 23.4)	17.5 (12, 26.2)	18.4 (16.7, 29.7)
PCT (ng/mL)	16.93 (3.68, 68.71)	9.74 (6.59, 54.28)	2.14 (1.23, 6.67)
LOS ICU (d)		8 (4, 16)	13 (5, 21)
LOS hospital (d)		17.5 (9, 37)	16 (14, 27)
28 d survival (%)		57.7	71.4
1 y survival (%)		34.6	57.1

APACHE II=Acute Physiology and Chronic Health Evaluation II Score; SAPS II=Simplified Acute Physiology Score II; SOFA=Sequential Organ Failure Assessment score; IL-6=interleukin 6; IL-10=interleukin 10; LBP=lipopolysaccharide binding protein; CRP=C-reactive protein; PCT=procalcitonin; LOS=length of stay.

Data are depicted as median (25%; 75% quartiles).

Control group

Blood samples of 15 healthy volunteers (ICU staff) served as a control group for plasma concentrations of iFABP (eight males, seven females).

Blood samples

Blood samples were processed immediately, centrifuged, and plasma specimens stored at −80°C until processing.

Determination of cytokines, iFABP

Levels of iFABP (ELISA Test Kit HK406, Hycult Biotech, Uden, The Netherlands) were determined by enzyme-linked immunosorbent assay (ELISA). Interleukin (IL)-6/-10 and lipopolysaccharide binding protein (LBP) were determined by Immulite 2000 (Siemens Medical Solutions Diagnostics GmbH, Bad Nauheim, Germany). Assays were performed according to the manufacturers' instructions.

Statistical analysis

Statistical analysis was performed using Sigma Plot 11.0 (Systat Software, Inc., San Jose, CA). All data were tested for normal distribution (Shapiro-Wilk). Data with a negative test for normal distribution are presented as median with 25%–75% range. A two-tailed p value of less than 0.05 was considered statistically significant. Differences between two time points were estimated by Wilcoxon signed rank test. Mann-Whitney rank sum test was performed to test differences between two groups. Analysis of variance (ANOVA) on ranks was performed (Kruskal-Wallis one-way analysis of variance on ranks) for iFABP concentration. The correlation between iFABP concentration and laboratory parameters was assessed using the Spearman's correlation test (ρ).

Results

Elective major surgery patients

Prior to elective major abdominal surgery, median plasma concentration of iFABP (191 pg/mL; interquartile range [IQR] I–III: 0–314 pg/mL) were not significantly different compared with the control group (114 pg/mL; IQR I–III: 103–124 pg/mL). However, iFABP plasma concentration showed a wide variability in the EMS group (range, <40–1,658 pg/mL). Further analysis revealed a significant difference between patients with intestinal cancer infiltration and without intestinal cancer infiltration (e.g., chronic pancreatitis or pancreas carcinoma) (217 pg/mL (IQR I–III: 100–369 pg/mL) versus 79 pg/mL (IQR I–III 0–182 pg/mL) respectively; p<0.01; Fig. 2). Patients with intestinal cancer demonstrated elevated median iFABP concentration prior to surgery compared with the control group (217 pg/mL versus 114 pg/mL; p<0.01; Fig. 2). The cytokines IL-6 and IL-10, as well as C-reactive protein (CRP), procalcitonin (PCT), and LBP demonstrated no differences between patients with and without intestinal cancer prior to surgery (Table 1).

FIG. 2.

iFABP concentrations at inclusion in all groups. iFABP concentrations in patients with elective major surgery prior to operation at start of anesthesia, severe sepsis at inclusion and control group. iFABP=intestinal fatty acid binding protein; NIC=group of patients without intestinal cancer/cancer infiltration; IC=group of patients with intestinal cancer/cancer infiltration; Pneumonia=severe septic patients with pneumonia as source of infection; Abdominal=severe sepsis patients with abdominal source of infection. *p<0.01 for IC versus NIC and versus control; *p<0.01 abdominal versus control.

Immediately after surgery plasma iFABP concentration in patients without intestinal cancer infiltration increased because of surgical trauma (79 pg/mL prior to surgery, 240 pg/mL after surgery [IQR I–III 111–305 pg/mL], p<0.01). One day after surgery iFABP concentration decreased in EMS patients below 100 pg/mL (range, <40–593 pg/mL; p<0.05; data not shown). In the post-operative follow-up period iFABP concentration decreased to median values below 40 pg/mL. In only 5 patients was a new increase in iFABP concentration detectable. In all these patients suspected or proved infectious complications were present. Two patients developed anastomotic dehiscence with indication for re-laparotomy. Two patients developed bacteremia without a need for further surgical source control. In one patient CRP concentration increased without signs of a defined focus and decreased in response to empiric antibiotic therapy.

Patients with severe sepsis

A total of 33 patients with severe sepsis or septic shock were recruited. In 26 cases peritonitis was identified as the source of sepsis; in seven cases pneumonia (Fig. 1). The median plasma iFABP concentration in patients with an abdominal source of sepsis prior to laparotomy (14/26 patients) was 248 pg/mL (<40–2,891 pg/mL, p<0.05 to controls; Fig. 3). In nine cases iFABP concentrations were not available prior to laparotomy due to logistic reasons; in three patients no laparotomy was performed. In the 23 patients with laparotomy, post-operative median plasma iFABP concentration was 324 pg/mL (<40-8421 pg/mL; p<0.05 to controls). In the group of patients with intestinal-associated severe sepsis no patient demonstrated mesenteric ischemia, yet three patients suffered from ischemia of the colon (<40 pg/mL and 2,891 pg/mL prior to operation, for one patient only post-operative iFABP was available (601 pg/mL).

FIG. 3.

iFABP in patients with severe sepsis. iFABP in severe sepsis patients at inclusion prior to laparotomy or at admission to ICU and in follow-up, comparing source of infection, group pneumonia and group abdomen. iFABP concentrations decrease in the follow-up to detection limit of the ELISA, except for patients with ongoing sepsis or need for renal replacement therapy. iFABP=intestinal fatty acid binding protein; ICU=intensive care unit; ELISA, enzyme-linked immunosorbent assay.

Plasma iFABP concentration of patients with an abdominal source of sepsis neither correlated with inflammatory markers such as IL-6, IL-10, LBP, PCT, CRP, leukocytes, or lactate prior to laparotomy, nor to the mortality after 28 d and 1 y (Table 3). In the patients with abdominal source of sepsis, iFABP concentrations decreased significantly in the first 5 d after study inclusion (Fig. 3). Fourteen of 26 patients reached normal plasma iFABP levels. Three patients died within the first 5 d. One of these patients with multiple organ dysfunction syndrome demonstrated an increase in iFABP up to 8,430 pg/mL after surgery. This patient died within hours after surgery because of septic shock without signs of mesenteric ischemia. However, in 10 patients a new increase in iFABP concentrations within the study period was observed due to new onset of acute kidney injury, ongoing sepsis, or re-laparotomy caused by anastomotic leak (Fig. 3).

Patients with pneumonia as the focus of sepsis had a median plasma iFABP concentration of 120 pg/mL (range, <40–484 pg/mL; Table 3, Fig. 2). There was no significant difference from control group patients. Interleukin-6 and lactate correlated with plasma iFABP concentrations (ρ 0.739, p<0.05; 0.739, p<0.05, respectively). Plasma iFABP concentrations decreased within 48 h with the exception of two patients with acute kidney injury and initiation of renal replacement therapy. In seven patients with pneumonia, plasma iFABP correlated with the 28-d and 1-y mortality (ρ −0.764, p<0.05; ρ −0.875, p<0.01, respectively).

To prove the value of iFABP as biomarker for differentiation between severe sepsis of pulmonary or abdominal origin we tested the sensitivity and specificity in our patients. The AUC was 0.693 (95% confidence interval 0.512–0.874; p=0.024).

Discussion

Previous work has demonstrated that iFABP is an early sensitive and specific marker for mucosal injury of the intestine [1,7,9,11]. We based this preliminary observational study on the hypothesis that elevated plasma iFABP concentrations could only be observed if the integrity of epithelial cells of the intestine is deranged. From this point of view we evaluated whether iFABP plasma concentrations are affected by surgical trauma in patients receiving major abdominal surgery and how long it takes until the integrity of epithelial cells is restored. In the second group of patients we evaluated the value of plasma iFABP concentrations in post-surgical patients re-admitted to the ICU because of sepsis with an abdominal source of infection. Plasma iFABP concentrations of healthy volunteers served as control throughout the study.

We defined a normal range for iFABP in these healthy individuals. Several tests are currently available to determine iFABP in plasma. We determined the normal plasma range to be 91 to 178 pg/mL in healthy volunteers through HK406 (Hycult Biotech) ELISA testing. This finding is corroborated by two studies in the literature, which published iFABP concentrations from a healthy control group (median 84 pg/mL and 61 pg/mL) [6,8].

Expecting these normal plasma iFABP concentrations in patients prior to major abdominal surgery, we interestingly found elevated plasma iFABP concentrations in patients with intestinal malignant disease indication for elective major surgery. One reason for these elevated plasma iFABP concentrations might be an increased intestinal epithelial-cell turnover in intestinal cancer. To date, fatty acid binding protein is not only known as iFABP but is also present in other tissue such as the liver and kidneys (lFABP), the heart (hFABP), and adipocytes (aFABP). In cancer these different forms of FABP are described as tumor-dependent. For example, aFABP correlates positively to tumor size and nodal status in breast cancer [12 –14]. Another aspect might be an inflammatory alteration of the intestine in patients with cancer. In patients with ulcerative colitis, the degree of inflammation correlates with increased plasma iFABP concentrations [9]. However, we found a wide range of iFABP in EMS patients with cancer infiltration of the intestine. One physiologic approach for this might be the varying iFABP concentration in epithelial cells along the intestinal axis [3,4] and the specific location of the intestinal neoplasm. Through samples of the intestine, collected during autopsy, it is known that cytosolic concentration of iFABP decrease significantly from the duodenum to the colon [3]. However, this study was not intended to verify iFABP as a tumor marker. Therefore, further investigation is required to evaluate the usefulness of iFABP in the setting of intestinal malignant neoplasm.

In patients without cancer of the intestine undergoing elective major abdominal surgery, plasma iFABP concentrations prior to surgery did not differ from the control group. There was an increase in iFABP concentrations directly after surgery, supposedly caused by the abdominal trauma. In the following 48 h, plasma iFABP concentrations returned to normal values. This observation is supported by the experimental data of Derikx et al. [1], who demonstrated in an intestinal human ischemia-reperfusion model an immediate increase in plasma iFABP in response to ischemia and a decrease within hours after beginning reperfusion. In conclusion, plasma iFABP concentrations are supposed to be altered by surgical trauma. By prompt normalization after the end of trauma (within 48 h) plasma iFABP concentrations are, in principal, suitable to prove for the usefulness in the post-operative time course to detect patients suffering from abdominal sepsis.

Therefore, we looked at the second part of our study for post-surgical patients suffering from severe sepsis or septic shock. We differentiated patients with primary abdominal septic focus from patients with pneumonia as the source of sepsis. Surgical exploration confirmed the presence of abdominal infection. Intestinal fatty acid binding protein was significantly elevated in patients with sepsis of abdominal origin compared with healthy controls. In patients who deceased early within the observation period from septic shock iFABP concentrations reached values up to 8,430 pg/mL (median, 325 pg/mL; range, <40–8,430 pg/mL). In the literature, some studies reveal comparable data. Thuijls et al. [11] and Cronk et al. [15] investigated patients with mesenteric ischemia. In these patients with intestinal ischemia plasma iFABP concentrations also were increased (653 pg/mL and 1.772 pg/mL) [11,15]. In a systematic review, plasma iFABP is described as an serologic marker for intestinal ischemia with a diagnostic odds ratio of 7.62 and an AUC of 0.78 [16]. Nevertheless, in the studies of Thuijls et al. [11] and Cronk et al. [15], the range of plasma iFABP levels is from detection limit of 40 pg/mL to values up to >50,000 pg/mL. Furthermore, Cronk et al. [15] indicated a wide range of plasma iFABP concentrations (<40 pg/mL to 2,710 pg/mL) in the group of patient with negative laparotomy and in the control group (patients with abdominal pain and no laparotomy).

Intestinal fatty acid binding protein seems to be a sensitive marker for ischemia [2] and also sensitive for an impairment of the intestine induced by low perfusion [1] or inflammation [9]. On the basis of these results and on our data, it might be that iFABP may be also elevated in severe sepsis or septic shock patient if the primary source is not the abdomen but the lung. In our data, three of seven patients with septic shock caused by pneumonia demonstrated elevated plasma iFABP values. In the patients with severe sepsis caused by pneumonia, plasma iFABP concentrations correlated with IL-6, lactate, and mortality, whereas there was no correlation with inflammatory markers and survival in patients with abdominal sepsis and iFABP. One hypothesis for this might be that elevation of iFABP in patients with pneumonia might reflect the severity of illness with an impairment of intestinal perfusion during sepsis. However, these data are limited because of the small study size and we did not perform any evaluation of intestinal perfusion in these patients.

In summary, we demonstrate that after major elective surgery or elimination of an abdominal focus of infection, iFABP plasma concentrations show a typical decrease to normal concentrations within 48 h. On the basis of this there could be several reasons if a new increase of iFABP plasma Concentrations in the post-operative period was be observed. The primary reason might be an infectious post-operative complication of the abdomen with peritonitis or intestinal ischemia. Nevertheless, iFABP might be also elevated in septic shock as a result of other reasons reflecting an impaired integrity of the gut with a release of iFABP into the plasma with a non-abdominal focus of infection. Therefore, iFABP is not suitable to discriminate an abdominal focus after major abdominal surgery from another focus, e.g., pneumonia in patients with severe sepsis or septic shock. In patients with non-abdominal severe sepsis or septic shock the cause of elevated plasma iFABP concentrations has to be evaluated further.

Footnotes

Acknowledgments

We thank Mathis Wahrmann MD, Sven Sartorius, MD and Lara Just, MD for their attendance in collecting data and laboratory analysis.

T.B. and H.W. participated in study design; T.B., K.F., B.S. participated in data collection; T.B., K.F., K.H., K.Z., W.B., H.W., B.S. analyzed and interpreted the data, T.B., B.S. drafted the report; T.B., K.F., K.H., K.Z., W.B., H.W., B.S. critically reviewed the report.

This study was carried out at the University Hospital Frankfurt am Main. This work was supported by a personal grant to T.M.B by the Clinic of Anaesthesiology, Intensive Care Medicine and Pain Therapy.

Author Disclosure Statement

No competing financial interests exist.

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