Etiology
Main causes
Infectious
Viral gastroenteritis
Norovirus
Bacterial gastroenteritis
Salmonella
Campylobacter
E. coli
Mechanical obstruction
Small bowel obstruction
Adhesions
Tumors
Hernias
Large bowel obstruction
Malignancy
Volvulus
Diverticular disease
Organic gastrointestinal disorders
Inflammatory
Pancreatitis
Cholecystitis
Hepatitis
Inflammatory bowel disease
Malignancy
Pancreatic adenocarcinoma
Vascular disease
Mesenteric ischemia
Systemic inflammatory disorder
SLE
Systemic sclerosis
Sjögren’s syndrome
Behçet’s disease
Henoch-Schönlein purpura
Motility disorders
Enteric dysmotility
CIPO
Functional disorders
Irritable bowel syndrome
Infectious Causes
Acute gastroenteritis is a major cause of diarrheal illness associated with nausea, vomiting, fever, or abdominal pain. Approximately 375 million episodes of acute gastroenteritis occur each year leading to 600,000 hospitalizations and 5,000 deaths [6, 7]. Acute gastroenteritis is most prevalent in children under the age of 5 years with an estimated prevalence of 8 % while prevalence in adults is estimated to be 3–7 % [7–9].
Viruses are the most common causes of acute gastroenteritis. Norovirus is the most common cause of acute gastroenteritis in the USA and accounts for 50 % of acute diarrheal outbreaks [10]. Enclosed populations such as on cruise ships, nursing homes, dormitories, and hospitals are particularly susceptible to Norovirus. Rotavirus, norovirus, adenovirus, and astrovirus are common viral causes of gastroenteritis in infants and young children [11, 12].
Bacterial infections are much less common causes of acute gastroenteritis with studies reporting positive stool cultures ranging from 1.5 to 5.6% [13]. However, in severe cases of diarrhea (≥4 unformed stools per day for more than 3 days), stool cultures were positive in 87 % of cases [14]. Data from the Centers for Disease Control and Prevention report Salmonella were the most commonly identified bacterial pathogen (16.2 cases per 100,000 people) leading to gastroenteritis in the USA in 2012 [15]. Campylobacter (14.3 cases), Shiga toxin-producing E. coli 0157:H7 strain (1.1 cases), vibrio (0.4 cases), and Yersinia (0.3 cases) were also identified as bacterial causes of acute gastroenteritis.
Acute infectious gastroenteritis can be classified into non-inflammatory (typically viral, milder disease) vs. inflammatory (mostly invasive or toxin-producing bacterial, more severe disease). If vomiting is the predominant symptom, viral gastroenteritis or foodborne illness with a preformed toxin should be suspected. Stool samples are generally not necessary but should be obtained in severe cases, fevers (≥38.5 °C), persistent diarrhea (≥14 days duration), or presence of dysentery. High-risk individuals, including elderly or immunocompromised patients, hospitalized patients and/or those receiving antibiotics (testing for Clostridium difficile), people employed as food handlers, nursing home residents, or day-care workers should also have stool samples obtained.
Mechanical Obstruction
Mechanical obstruction of the bowel presents when there is interruption in the normal flow of intestinal contents. Bowel obstruction is a substantial cause of morbidity and mortality, accounting for approximately 15% of ER visits for evaluation of abdominal pain [16]. The bowel progressively dilates as intestinal secretions and swallowed air accumulate proximal to the point of mechanical obstruction [17]. If the process of bowel dilatation continues, luminal pressure eventually can compromise vascular perfusion to the bowel leading to ischemia, necrosis, and perforation. A closed loop obstruction, where a segment of bowel is obstructed proximally and distally, may undergo progressive dilatation rapidly and is at high risk for development of volvulus and subsequent ischemia [18].
Obstruction can occur anywhere along the gastrointestinal tract with the small bowel being the most common location (75 %) for mechanical obstruction [19]. The main risk factor for small bowel obstruction (SBO) is prior abdominal surgery leading to postoperative adhesions, seen in approximately 60% of cases [20]. Lower abdominal surgeries, including appendectomies, colorectal surgery, gynecologic procedures, and hernia repairs are associated with higher risk for the development of adhesive disease [21, 22]. Tumors and complicated hernias are the next most common causes of bowel obstruction in the USA and Europe followed by Crohn’s disease, gallstones, volvulus, and intussusception [19, 23].
Clinically, patients can present with acute onset of abdominal pain, nausea, emesis, abdominal distention, and progressive obstipation. Symptoms can vary depending on the extent (partial vs. complete), etiology, and location (proximal vs. distal) of the obstruction. Patients with distal obstruction often present with severe abdominal pain and marked distention as the proximal bowel acts as a reservoir. Meanwhile, patients with more proximal obstruction typically present with more pronounced nausea and emesis with less abdominal distention.
Organic Gastrointestinal Disorders
Acute Pancreatitis
Acute pancreatitis is a common disorder that accounts for over 220,000 hospital admissions annually in the USA. Despite advancement in our understanding of the disease, mortality has not improved over the past few decades and ranges between 10 and 30 % in those with severe disease [24]. Acute pancreatitis results from inappropriate activation of trypsinogen to trypsin, which leads to zymogen activation, pancreatic autodigestion, and ultimately pancreatic inflammation [25]. This inflammatory cascade is not limited to the pancreas and may progress to a systemic inflammatory response syndrome, multi-organ failure, or even death.
The etiology of acute pancreatitis is gallstones in approximately 40 % of cases and is more likely in Caucasian females over the age of 60 [26]. Alcohol accounts for an additional 35 % of cases and is more common in men [24]. There appears to be a complex but dose-dependent risk between alcohol consumption and the development of pancreatitis [27]. Metabolic abnormalities (e.g., hypertriglyceridemia), bile duct obstruction (e.g., tumor, pancreas divisum), post-ERCP pancreatitis, medications (e.g., azathioprine, thiazides, and estrogens), autoimmune, and trauma are less common causes of acute pancreatitis.
Acute pancreatitis is characterized by epigastric pain radiating to the back. Approximately 90 % of patients will also have presence of nausea and vomiting [28]. Serum amylase and lipase levels are more than three times the upper limit of normal. Abdominal imaging with computed tomography (CT), magnetic resonance imaging (MRI), or ultrasound may demonstrate inflammatory changes around the pancreas. Acute pancreatitis is a clinical diagnosis with characteristic symptoms in the setting of elevated pancreatic enzymes and/or abnormal radiographic imaging.
Mesenteric Ischemia
Mesenteric ischemia is a collection of diverse conditions resulting in impaired blood flow to the gut. Mesenteric ischemia can be classified into acute and chronic forms. It can be further subdivided into arterial, venous, and non-occlusive forms.
Acute Mesenteric Ischemia
Acute mesenteric ischemia (AMI) is a rare but life-threatening condition. AMI accounts for less than 1 per 1,000 hospital admissions but mortality can range between 30 and 90 % depending on the etiology [29, 30]. Because of its relative infrequency, AMI may be missed leading to delayed diagnosis and potentially worse outcomes. One study from Sweden suggested that mortality may exceed 90 % and AMI was only considered in the differential diagnosis in 33 % of cases [30].
The etiology of AMI can be divided into occlusive and non-occlusive causes. Occlusive causes account for the vast majority of cases (85 %) with embolization to the mesenteric arterial circulation (40–50 %) accounting for the majority of cases. Atrial fibrillation, prior myocardial infarction with subsequent impaired wall motion, and structural heart disease with right-to-left shunts are common risk factors. Because of the acute occlusion from embolic sources, collateral circulation is limited and symptoms typically progress rapidly. The superior mesenteric artery (SMA) is more commonly involved than the celiac axis or inferior mesenteric artery because of the less acute angle of takeoff from the aorta [31]. The embolus typically obstructs distal to the jejunal and middle colic SMA branches and most often affects the mid jejunum [32].
Thrombotic causes account for approximately 25 % of cases and is typically seen in patients with underlying atherosclerotic disease. Thrombotic AMI is generally more insidious in presentation as there is often collateral flow around pre-existing atherosclerotic disease. Up to 50–75 % of patients have prior symptoms of post-prandial abdominal pain and weight loss, which suggests underlying chronic mesenteric ischemia [33]. Rupture of an unstable plaque, often at the origin of the SMA, leads to AMI. Thrombotic AMI has the highest mortality, perhaps a consequence of the proximal obstruction leading to involvement of a larger segment of bowel [29].
Mesenteric venous thrombosis (MVT) accounts for less than 5 % of all AMI cases [29]. Hypercoagulable state (including factor V Leiden, prothrombin 20210 mutation) is the predominant risk factor but other predisposing factors include malignancy, portal hypertension, and intra-abdominal inflammatory processes (e.g., diverticulitis, pancreatitis, inflammatory bowel disease). MVT carries the most favorable prognosis compared to other forms of AMI with an overall mortality of 44 % on a large, systematic review [29]. However, more recent studies suggest mortality rates may actually be 10–20 % possibly due to better diagnostic studies and prompt initiation of treatment [34–36].
Non-occlusive causes are responsible for approximately 20–30 % of AMI but incidence is declining due to improved care of critically ill patients as well as use of systemic vasodilators in heart failure [37]. Despite the decline in incidence, mortality from non-occlusive mesenteric ischemia (NOMI) is extremely high likely due to the co-morbid conditions associated with this population. Risk factors for NOMI are conditions associated with low flow state, including severe cardiovascular disease, sepsis, or drugs that reduce intestinal perfusion [38].
Clinically, patients with AMI typically present with severe periumbilical abdominal pain that is out of proportion to the physical exam. Nausea and vomiting are common associated symptoms. Embolic causes of AMI typically have acute onset of abdominal pain while thrombotic causes of AMI will often have a long history of intestinal angina prior to acute worsening of pain. Personal history of thromboembolic disease or family history of clotting disorders should alert one to the possibility of MVT while suspicion for NOMI should be high in history of low-flow states, such as severe cardiomyopathy.
In contrast to the severity of abdominal pain, the exam is typically benign and unimpressive. Leukocytosis with white blood cell count greater than 15,000/mL and elevated lactate are seen in 90 % of cases [39, 40]. Lactate levels may also correlate with severity of injury, extent of injury, and even patient outcomes [39, 41]. Diagnosis is typically made by radiographic studies with the gold standard being angiography. More recently, CT angiography has supplanted angiography as a noninvasive means for diagnosing AMI. MR angiography can also be considered, but the long acquisition times associated with MRI limit its utility in the diagnosis of AMI.
Chronic Mesenteric Ischemia
Chronic mesenteric ischemia (CMI) is a relatively uncommon disease mainly due to the significant collateral vascular network in the gut. CMI is defined by the presence of typical symptoms in the setting of high-grade narrowing or occlusion of at least two major visceral arteries (celiac axis, superior mesenteric artery, or inferior mesenteric artery). Atherosclerotic narrowing at the origin of the celiac or superior mesenteric artery is the cause of CMI in the vast majority of cases [42]. Less common causes of CMI include median arcuate ligament syndrome (compression of the celiac artery from the median arcuate ligament of the diaphragm), fibromuscular dysplasia, vasculitis (e.g., polyarteritis nodosum, Takayasu arteritis), and aortic dissection [38].
Clinically, patients typically present with the classic triad of post-prandial abdominal pain, sitophobia (fear of eating), and weight loss. Patients describe a dull, crampy epigastric abdominal pain that starts shortly after a meal and lasts 1–2 h which is also described as “intestinal angina.” One study suggests that symptoms occur because of hypoperfusion of the small intestine as blood is shunted to the stomach [43]. Nausea, vomiting, diarrhea, and early satiation may be seen in one-third of patients.
There is a marked female predominance (3:1) in CMI and most patients are typically over the age of 60. Tobacco use is common with smoking being reported by 57 % of patients in one report [44]. Atherosclerotic disease in other vascular beds is also common with approximately 50 % of patients exhibiting coronary artery disease, cerebrovascular disease, or peripheral vascular disease.
Imaging demonstrating high-grade stenosis or occlusion of at least two major mesenteric vessels in the context of typical symptoms confirms the diagnosis of CMI. CT angiography is often used as the initial test given its non-invasive approach as well as sensitivity and specificity exceeding 90 %. Duplex ultrasonography of the mesenteric vessels can also be considered. Sensitivity is approximately 90 % for high-grade stenosis (>50 % occlusion) of the superior mesenteric or celiac arteries [45–47]. Furthermore, a negative duplex ultrasonography can essentially rule out CMI given the high negative predictive value of duplex ultrasonography [48].
Systemic Autoimmune Diseases
Systemic Lupus Erythematosus (SLE)
Systemic autoimmune diseases can present with a variety of gastrointestinal manifestations including nausea and vomiting. Systemic lupus erythematosus (SLE) can affect any part of the gastrointestinal tract from the mouth to the rectum. GI symptoms from SLE are common and may occur in more than 50 % of patients [49]. Oral ulcers are the most common GI manifestation of SLE, but one series reports prevalence of nausea and vomiting in 50 % of patients [50].
Onset of symptoms such as abdominal pain, nausea, and vomiting may herald more severe, potentially life-threatening disease activity including lupus mesenteric vasculitis (LMV). Prevalence of LMV is reported to be anywhere from 0.2% to 6.4 % in Western countries [49]. LMV is a small vessel vasculitis that can involve both small arteries and venules. Deposition of immune complexes, C3 complement, and fibrinogen may be seen histologically [51]. Abdominal pain, nausea, and vomiting are frequent symptoms seen in LMV and are almost always seen in the context of active disease elsewhere. Vasculitis can progress to ischemia and infarction with sequelae including gastrointestinal bleeding, stricture formation, and perforation. Pneumatosis cystoides intestinalis (PCI) may rarely be present. Contrary to other conditions where PCI is a benign condition, PCI is associated with necrotizing enterocolitis in LMV and can occasionally lead to perforation [52].
Scleroderma
Progressive systemic sclerosis (scleroderma) is a connective tissue disorder characterized by proliferative vascular lesions with subsequent fibrosis of organs and multiple organ systems. The GI tract is the most commonly involved non-cutaneous organ in 90% with nearly all patients (98.9 %) displaying GI symptoms [53]. Abdominal distention was the most common symptom (87.8 %), followed by heartburn (68.9 %), diarrhea (67.8 %), abdominal pain (68.9 %), nausea (61.1 %), and vomiting (60.9 %).
Scleroderma may affect the entire GI tract from mouth to anus and is believed to occur as a consequence of initial vascular damage, subsequent tissue ischemia, leading to collagen deposition and fibrosis in the GI vasculature and smooth muscle [54]. Involvement of the small bowel is the second most common organ in the gastrointestinal tract behind the esophagus. Small bowel dysmotility may be seen in 40–88 % of scleroderma patients with antroduodenal manometry showing evidence of reduced activity and hypomotility in the fasting state [55, 56]. This may manifest with symptoms of nausea, early satiety, anorexia, and malabsorption with one study suggesting that nausea and vomiting may be seen in 57 % of patients [57]. Small intestinal dysmotility is associated with increased morbidity and may lead to life-threatening conditions including pseudo-obstruction as well as small intestinal bacterial overgrowth.
Motility Disorders
Gastrointestinal motor activity is controlled by the enteric nervous system (ENS). The ENS sends signals to smooth muscle in the gut which then generates pressure changes responsible for propulsive motility. Alterations in either the ENS or smooth muscle involved in this process may lead to gut dysmotility. There is a continuum of chronic GI symptoms including abdominal pain, nausea, vomiting, distention, and constipation which ranges from functional GI disorders (diagnosed using symptom-based criteria such as the Rome criteria) [58], to enteric dysmotility (abnormal antroduodenal manometry in the absence of visceral dilatation) [59] and chronic intestinal pseudo-obstruction (CIPO) (manometric abnormalities in addition to radiologic criteria) [60] (Fig. 4.1). Mild abnormalities in gut motility may be seen in functional GI disorders, such as irritable bowel syndrome or chronic idiopathic constipation, while more severe dysmotility may be seen in rare but potentially life-threatening diseases, such as CIPO.
Fig. 4.1
The relative prevalence and relationship between functional gastrointestinal disorders (FGIDs), enteric dysmotility, and CIPO. FGIDs are defined by specific symptom criteria while enteric dysmotility is defined by manometric abnormalities. CIPO is defined by manometric abnormalities in the presence of radiologic evidence of dilated bowel. FGID functional gastrointestinal disorders, CIPO chronic intestinal pseudo-obstruction
Enteric Neuropathy
The enteric nervous system (ENS) is comprised of a vast network of neurons distributed throughout the entire GI tract as well as the biliary tract and pancreas. The ENS is a collection of ~ 500 million neurons that is unique in its ability to control most gut functions including regulating secretion and absorption, vascular tone, and motility largely independent of the central nervous system (CNS) [61]. Enteric neuropathies, or disruption of normal ENS function, may lead to GI disorders and symptomatology. Enteric neuropathy can be classified as primary (idiopathic) vs. secondary (part of a systemic disease). Enteric neuropathy can also be classified histopathologically as inflammatory or degenerative in nature.
Inflammatory Neuropathies
Inflammatory neuropathies are characterized by a dense lymphoplasmacytic infiltrate involving the myenteric or submucosal plexuses as well as the axonal processes of the ENS (Fig. 4.2). Involvement of the myenteric plexus, or myenteric ganglionitis, is more common and often secondary to other disease processes.
Fig. 4.2
Representative histopathology illustrating degenerative and inflammatory enteric neuropathies. (a) Degenerative neuropathy. A myenteric ganglion is shown with numerous degenerate neurons with different features including normal neurons (depicted by white arrows), shrunken, apoptotic neurons (thin black arrows), and frank degeneration (thick black arrows). Samples were stained using hematoxylin and eosin (original magnification ×180). (b) Inflammatory neuropathy. The myenteric ganglion contains numerous small inflammatory cells (original magnification ×320). (c) Periganglionic and intraganglionic T cells demonstrated by CD3 immunostaining (black arrows). Residual myenteric neurons are depicted by white arrows (original magnification ×320) (Reprinted with permission from Knowles [61])
Paraneoplastic Syndromes
Paraneoplastic syndromes may lead to an inflammatory neuropathy with subsequent involvement of the stomach (gastroparesis), small bowel (intestinal pseudo-obstruction), and colon (constipation, colonic inertia, or megacolon). The most common malignancy associated with paraneoplastic enteric neuropathy is small cell lung cancer [62] but other malignancies including bronchial carcinoid [63], thymoma [64], neuroblastoma [65], and ovarian cancer [66] have also been reported. Antineuronal antibodies directed against the RNA-binding protein family Hu (ANNA-1 or anti-Hu) are the most common autoantibody expressed [67, 68]. Anti-voltage-gated Ca2+ channel (P/Q- and N-type) antibodies are most often detected in Lambert-Eaton myasthenic syndromes related to small cell lung cancer [69]. After anti-Hu, antibodies targeting the N-type Ca2+ channels are the most common autoantibodies in paraneoplastic enteropathies. Antibodies directed against the Purkinje cell protein Yo (anti-Yo, anti-Purkinje cell cytoplasmic) as well as anti-ganglionic type acetylcholine receptors may also be observed (Table 4.2) [70].
Table 4.2
Anti-neuronal antibodies in inflammatory neuropathy
Anti-neuronal autoantibodies | Molecular target | Associated paraneoplastic syndrome | Associated malignancy | GI motor disorder |
|---|---|---|---|---|
ANNA-1 (Anti-Hu) | HuD, HuC, HuR, Hel-N1 | Opsoclonus myoclonus; ataxia | SCLC | Gastroparesis, CIPO, megacolon |
Anti-VGCC | Voltage-gated Ca2+ channels, including P/Q and N-type channels | Lambert-Eaton syndrome | SCLC | CIPO |
Anti-ganglionic acetylcholine receptors | Nicotinic receptors | Dysautonomia | Thymoma, SCLC | Gastroparesis, CIPO, constipation |
Anti-Yo | Cdr2 | Paraneoplastic cerebellar degeneration | Gynecologic tumors (e.g., ovary) | CIPO |
Systemic Inflammatory Disease
Systemic inflammatory diseases commonly have associated gastrointestinal manifestations. Inflammatory infiltrates of plasma cells, lymphocytes, and mast cells involving both the myenteric and submucosal plexus have been well described in Crohn’s disease and may predict early post-operative recurrence of disease [71]. The finding of enteric ganglionitis in other conditions is unclear. Low-grade lymphocytic myenteric ganglionitis in the proximal jejunum was described in 9 of 10 patients with severe irritable bowel syndrome (IBS) [72]. These authors proposed that an inflammatory enteric neuropathy might contribute to sensorimotor abnormalities seen in IBS. Interestingly, enteric neuropathy classically shows a dense lymphocytic infiltrate associated with neuronal degeneration and loss, severe impairment in gut motility, and occasionally associated with bowel dilatation [70, 73]. However, there were relatively few lymphocytes (1.9–7.1 per ganglion) seen in IBS patients. This raises the possibility that the degree of inflammatory infiltrate in the myenteric plexus may predict the severity of neuromuscular dysfunction with milder cases exhibiting symptoms typical of functional GI disorders while severe cases may present with intestinal failure, pseudo-obstruction, and/or bowel dilatation.
Degenerative Neuropathies
Diabetes Mellitus
Diabetes mellitus can affect the entire gastrointestinal tract. As such, symptoms of abdominal pain, nausea, postprandial fullness, diarrhea, and constipation are more common in diabetics than healthy controls. Diarrhea or constipation (15.6 %) was the most prevalent symptom while nausea and vomiting were seen in 5.2 % and 1.7 %, respectively [74].
Animal models of diabetes mellitus show a decrease in the number of enteric neurons throughout the gastrointestinal tract [75–77]. Studies in humans have also demonstrated neuronal loss related to diabetes mellitus. Full thickness gastric biopsy samples in diabetic gastroparesis patients have exhibited loss of neurons, particularly nitrergic neurons as shown by decreased expression of nNOS compared with matched controls [78].
Studies also consistently report loss of interstitial cells of Cajal (ICC) in diabetic gastroenteropathy as well [79]. ICC are mesenchymal cells that are critically important for normal gastrointestinal motility. They act as pacemaker cells and lead to a generation of slow wave transmission in the GI tract. They also modulate neurotransmission between motor neurons of the enteric nervous system, efferent input from the autonomic nervous system, and smooth muscle cells in the GI tract [80]. Loss of ICC as a result of diabetes mellitus may lead to impaired pacemaker activity, altered neurotransmission, and dysmotility in the GI tract.
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