Diagnosis Biomarkers in Acute Intestinal Ischemic Injury: So Close, Yet So
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Clin Chem Lab Med 2018; 56(3): 373–385 Review Katell Peoc’h*, Alexandre Nuzzo, Kevin Guedj, Catherine Paugam and Olivier Corcos Diagnosis biomarkers in acute intestinal ischemic injury: so close, yet so far https://doi.org/10.1515/cclm-2017-0291 Received April 3, 2017; accepted July 21, 2017; previously published Introduction online August 25, 2017 Acute intestinal ischemic injury (i3) is a life-threatening Abstract: Acute intestinal ischemic injury (i3) is a life- condition associated with a high short-term mortality threatening condition with disastrous prognosis, which rate ranging from 32% to 86%. Such a prognosis remains is currently difficult to diagnose at the early stages of unchanged through decades despite significant improve- the disease; a rapid diagnosis is mandatory to avoid irre- ments in vascular surgery, interventional radiology and versible ischemia, extensive bowel resection, sepsis and resuscitation. In the emergency setting, these catastrophic death. The overlapping protein expression of liver and gut outcomes are closely linked to delays in diagnosis [1] and related to the complex physiopathology of the disease, the treatment, which is of major concern since the early pres- heterogeneity of the disease and its relative rarity could entation of acute i3 is potentially fully reversible when explain the lack of a useful early biochemical marker of i3. using a specific multimodal management that includes Apart from non-specific biological markers of thrombosis, revascularization [1, 2]. However, at this stage, the clinical hypoxia inflammation, and infection, several more spe- presentation is dominated by acute non-specific abdominal cific biomarkers in relation with the gut barrier dysfunc- pain without any other discriminating clinical or biologi- tion, the villi injury and the enterocyte mass have been cal characteristics [3]. As a result, early diagnosis may only used in the diagnosis of acute i3. It includes particularly be achieved by a high degree of clinical suspicion and a D-lactate, intestinal fatty acid-binding protein (FABP) prompt confirmation by an abdominal computed tomog- and citrulline. Herein, we will discuss leading publica- raphy (CT) scan angiography identifying features of both tions concerning these historical markers that point out splanchnic vascular insufficiency and intestinal injury the main limitations reagrding their use in routine clini- [4]. However, selection of patients requiring CT evaluation cal practice. We will also introduce the first and limited remains a challenge due to the lack of an available diag- results arising from omic studies, underlying the remain- nostic sign or biomarker. As a consequence, physicians ing effort that needs to be done in the field of acute i3 bio- have long sought to identify a biomarker or a combination logical diagnosis, which remains a challenge. of markers to ensure a sensitive, specific and early diagno- sis of acute i3. In this study, we will review the basis of the Keywords: biomarker; citrulline; D-dimer; D-lactate; pathophysiology of i3, the conventional past and present intestinal fatty acid-binding protein; intestinal ischemia. strategies for biomarker discovery and their remaining gaps and introduce the new perspectives opened by the “-omics” *Corresponding author: Katell Peoc’h, Biochimie Clinique, Hôpital technologies. We focused in the first part of this review on Beaujon, Université Paris Diderot, UFR de Médecine Xavier Bichat human clinical studies, then we presented the pre-clinical and APHP, HUPNVS, DHU Unity, Clichy, France; and INSERM, UMRs research in the second part since we did not find enough 1149, CRI, Université Paris Diderot, Paris, France, Phone: +33 (0)1 40 87 54 36, E-mail: [email protected] published materials to limit our presentation to humans. Alexandre Nuzzo: SURVI, Hôpital Beaujon, APHP, HUPNVS, DHU Unity, Clichy, France; and Gastroenterologie, Hôpital Beaujon, APHP, HUPNVS, Clichy, France Pathophysiology of i3 Kevin Guedj: SURVI, Hôpital Beaujon, APHP, HUPNVS, DHU Unity, Clichy, France; and INSERM, UMRs 1148, LVTS, Paris, France Catherine Paugam: Anesthésie Réanimation, Hôpital Beaujon, Definition of i3 Université Paris Diderot, UFR de Médecine Xavier Bichat and APHP, HUPNVS, Clichy, France Olivier Corcos: SURVI, Hôpital Beaujon, APHP, HUPNVS, DHU Unity, i3 is an digestive injury related to intestinal vascular Clichy, France; Gastroenterologie, Hôpital Beaujon, APHP, HUPNVS, insufficiency, occlusion or low splanchnic-mesenteric Clichy, France; and INSERM, UMRs 1148, LVTS, Paris, France flow. The pathophysiology of i3 responds to a multi-step 374 Peoc’h et al.: Acute intestinal ischemic injury’s biomarkers process that begins with an intermittent or continuous, relate to intra-parietal arterioles, lesions of ischemia complete or incomplete decrease in digestive blood flow. remain superficial. Subsequent mucosal/submucosal ischemia evolves into Intestinal vascular insufficiency leads to hypoxia, first transmural ischemia, often acute, followed by intestinal with mucosal and submucosal consequences. The hypop- necrosis and death without treatment [5]. erfusion of the intestinal mucosa is responsible for an early Several theories have been proposed to explain how hypoxic cellular desquamation of the intestinal villi. Poly- this non-infectious vascular disease could lead to sys- morphonuclear neutrophils are early major lesional actors temic inflammatory response syndrome (SIRS) followed that adhere and migrate to the ischemic site to ensure the by sepsis and multi-visceral failure [6]. removal of tissue debris during necrosis. Mucosal and sub- mucosal cells switch to anaerobic glycolysis with local pro- duction of lactate initially fully metabolized by the liver. Multistep pathophysiology The increase in intracellular acidosis blocks anaerobic metabolism and the membrane pumps of ionic and acid- Acute mesenteric ischemia (AMI) should be considered base regulation. This leads to a profound alteration of as one of the stages of the i3 process (Figure 1), which cellular homeostasis and, ultimately, to cell death by apop- starts from digestive vascular insufficiency to intestinal tosis [7–9]. Initially, there is a dissociation between high necrosis. Ischemia begins early and superficially and porto-mesenteric blood lactate levels and normal periph- then spreads deep and in the surface of the intestinal eral blood lactate levels due to the active liver metabolism wall. Vascular insufficiency is initially responsible for an [1]. Systemic lactic acidosis is, therefore, a late phenom- inadequacy between inputs and requirements for energy enon, which often indicates intestinal necrosis and the substrates by overcoming the adaptive processes of a onset of a multi-visceral failure [10]. Associated endothe- digestive territory. This loss of homeostasis results from lial lesions can lead to platelet, pro- and anti-thrombotic a sudden decrease or interruption of the splanchnic- agent (protein C, S, and antithrombin) consumption, mesenteric blood flow. The decrease in splanchnic blood which causes the hemorrhagic syndrome. flow in the proximal circulation induces a deep exten- Furthermore, the intestinal neuro-hormonal regu- sion of the ischemia which then becomes transmural and lation of vasomotricity is associated with the activa- gangrenous. Conversely, when perfusion abnormalities tion of the renin-angiotensin-aldosterone system, which Early and reversible i3 Late and irreversible i3 Vascular Mucosal/sub-mucosal Transmural Systemic injury injury injury injury - Renin- Local Acute vascular angiotensin - Transmural - Translocation inflammatory insufficiency activation injury - Autodigestion pathway - Necrosis (low flow - Sympathic - Systemic - Polynuclear - Organ failure and/or stimulation inflammatory afflux occlusion) - Vasospasm Ischemic pathway enteritis - Hypoxia Figure 1: Schematic representation of the time course and physiopathology of i3. i3 is the result of a multistep process that is initially limited, reversible and then became systemic and irreversible and led to death. The pathophysiological process can be divided into two main stages related to the prognosis, the early and reversible phase and the late and irreversible phase. Peoc’h et al.: Acute intestinal ischemic injury’s biomarkers 375 maintains the mucosal oxygen extraction rate. This inflammatory response. Degradation products of pancre- induces a reflex splanchnic arterial vasospasm, irrespec- atic enzymes, residues of bacterial products pass through tive of the initial vascular mechanism, that may prolong the lymphatic, hematogenous or peritoneal barrier and and worsen ischemia despite therapeutic revasculariza- are likely to induce not only a loco-regional but also a tion. This vasoconstriction accompanies, for example, sit- systemic reaction [19, 20]. In animal models, inhibition uations of hypovolemia, during which digestive ischemia of these enzymes results in a decrease in intra-parietal develops before clinical hemodynamic instability [11, 12]. micro-bleeding, systemic inflammatory response, and The disruption of the epithelial barrier resulting from even in mortality in some studies [21]. The action of these mucosal alterations leads to interactions among micro- enzymes would involve degradation of inter-enterocytic organisms, bacterial antigens, endotoxins of the intes- tight junction’s proteins such as E-cadherin. Moreover, tinal lumen with the mucosal and submucosal immune these enzymes would also induce a cleavage of the pro-