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Abstract
Gastrointestinal bleeding is a common problem encountered in the emergency department and in the primary care setting. Acute or overt gastrointestinal bleeding is visible in the form of hematemesis, melena or hematochezia. Chronic or occult gastrointestinal bleeding is not apparent to the patient and usually presents as positive fecal occult blood or iron deficiency anemia. Obscure gastrointestinal bleeding is recurrent bleeding when the source remains unidentified after upper endoscopy and colonoscopic evaluation and is usually from the small intestine. Accurate clinical diagnosis is crucial and guides definitive investigations and interventions. This review summarizes the overall diagnostic approach to gastrointestinal bleeding and provides a practical guide for clinicians.
Core tip: This review provides a practical diagnostic guide for clinicians who encounter patients with suspected gastrointestinal bleeding in the hospital and primary health care settings. Clinical presentations of gastrointestinal bleeding are classified as overt (acute), occult (chronic) or obscure and the corresponding diagnostic algorithms are illustrated through review of the key evidence and consensus guidelines. Upper endoscopy and colonoscopy are the mainstay of initial investigations. Angiography and radionuclide imaging are best suited for acute overt gastrointestinal (GI) bleeding. Capsule endoscopy and deep enteroscopy play significant roles in the diagnosis of obscure GI bleeding, usually from the small bowel.
INTRODUCTION
Gastrointestinal (GI) bleeding is a common problem medical practitioners encounter in the emergency department and in the primary care setting[]. Annual hospital admissions for GI bleeding in the United States and United Kingdom have been estimated at up to 150 patients per 100000 population with a mortality rate of 5%-10%[-]. While GI bleeding can be potentially life-threatening, it has been shown that many cases can be safely managed on an outpatient basis[]. The accurate diagnosis of GI bleeding relies on prompt resuscitation, initial risk evaluation, provisional clinical diagnosis followed by appropriate definitive investigation which enables specific interventions. This review provides a practical diagnostic guide for clinicians who may encounter patients with suspected GI bleeding.
DEFINITIONS
Overt (acute) vs occult (chronic) vs obscure
Although GI bleeding can be a result of benign pathology, life-threatening hemorrhage, varices, ulceration and malignant neoplasms need to be considered and carefully excluded[,]. Given the wide range of underlying pathology and the differences in their appropriate diagnostic approach, it is crucial for clinicians to define the type of GI bleeding based on clinical presentation.
Depending on the rate of blood loss, GI bleeding can manifest in several forms and can be classified as overt, occult or obscure. Overt GI bleeding, otherwise known as acute GI bleeding, is visible and can present in the form of hematemesis, “coffee-ground” emesis, melena, or hematochezia. Occult or chronic GI bleeding as a result of microscopic hemorrhage can present as Hemoccult-positive stools with or without iron deficiency anemia[,]. The American Gastroenterological Association defines occult GI bleeding as the initial presentation of a positive fecal occult blood test (FOBT) result and/or iron-deficiency anemia when there is no evidence of visible blood loss to the patient or clinician[]. Obscure GI bleeding refers to recurrent bleeding in which a source is not identified after upper endoscopy and colonoscopy. Obscure bleeding may be either overt or occult[-].
Upper vs lower
Upper GI bleeding includes hemorrhage originating from the esophagus to the ligament of Treitz, at the duodenojejunal flexure[]. Lower GI bleeding is defined as bleeding that originates from a site distal to the ligament of Treitz[]. In recent years upper GI bleeding has been redefined as bleeding above the ampulla of Vater within reach of an upper endoscopy; lower GI bleeding has been further subdivided into mid GI bleeding coming from the small bowel between the ampulla of Vater to the terminal ileum, and lower GI bleeding coming from the colon[].
OVERT (ACUTE) GI BLEEDING
Epidemiology
Acute GI bleeding is a major cause of hospital admissions in the United States, which is estimated at 300000 patients annually[]. Upper GI bleeding has an annual incidence that ranges from 40-150 episodes per 100000 persons and a morality rate of 6%-10%[-]; compared with lower GI bleeding which has an annual incidence ranging from 20-27 episodes per 100000 persons and a mortality rate of 4%-10%[,]. Acute GI bleeding is more common in men than women and its prevalence increases with age[,].
Etiology and pathophysiology
Acute upper GI bleeding may originate in the esophagus, stomach, and duodenum. Upper GI bleeding can be categorized based upon anatomic and pathophysiologic factors: ulcerative, vascular, traumatic, iatrogenic, tumors, portal hypertension. The commonest causes of acute upper GI bleeding are peptic ulcer disease including from the use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), variceal hemorrhage, Mallory-Weiss tear and neoplasms including gastric cancers[]. Other relatively common causes include esophagitis, erosive gastritis/duodenitis, vascular ectasias and Dieulafoy’s lesions[]. Significant geographical variations in pathophysiology exist for esophageal varices and peptic ulceration between the East and the West, with East Asians having a stronger association with non-alcoholic cirrhosis and helicobacter pylori as their respective etiologies which generally have a more favorable prognosis[,]. However, esophageal varices and peptic ulcer disease are nevertheless major causes of upper GI bleeding in both Eastern and Western societies[,].
Acute lower GI bleeding may originate in the small bowel, colon or rectum[]. The causes of acute lower GI bleeding may also be grouped into categories based on the pathophysiology: vascular, inflammatory, neoplastic, traumatic and iatrogenic. Common causes of lower GI bleeding are diverticular disease, angiodysplasia or angiectasia, neoplasms including colorectal cancer, colitis including Crohn’s disease and ulcerative colitis, and benign anorectal lesions such as hemorrhoids, anal fissures and rectal ulcers[].
In the special setting where the patient is known to have an abdominal aortic aneurysm or an aortic graft, acute GI bleeding should be considered secondary to aortoenteric fistula until proven otherwise[].
Initial evaluation
Rapid assessment and resuscitation should precede diagnostic evaluation in unstable patients with acute severe bleeding[]. Once hemodynamic stability is assured, patients should be evaluated for the immediate risk of rebleeding and complications, as well as the underlying source of bleeding. For acute upper GI bleeding, risk scores such as the Rockall Score and Glasgow Blatchford Score (GBS) have been developed and validated[,]. Patients with minimal or intermittent bleeding who are stratified as low risk can be evaluated in an outpatient setting, allowing more effective utilization of limited hospital in-patient resources[]. While the Rockall score uses endoscopic findings, the GBS is based upon the patient’s clinical presentation such as systolic blood pressure, pulse, presence of melena, syncope, hepatic disease, cardiac failure and laboratory parameters such as blood urea nitrogen and hemoglobin. A meta-analysis found that a GBS of zero decreases the likelihood of requiring urgent intervention (likelihood ratio 0.02, 95%CI: 0-0.05)[]. Therefore, the GBS may be best suited for initial risk evaluation of suspected acute upper GI bleeding, such as in the emergency department setting.
As in the diagnosis of any disease, the clinical history, physical examination and initial laboratory findings are crucial in determining the likely sources of bleeding which would help direct the appropriate definitive investigation and intervention. A medication history here is particularly important, especially on the use of aspirin and other NSAIDs.
Clinical presentation
Upper GI bleeding usually presents with hematemesis (vomiting of fresh blood), “coffee-ground” emesis (vomiting of dark altered blood), and/or melena (black tarry stools). Hematochezia (passing of red blood from rectum) usually indicates bleeding from the lower GI tract, but can occasionally be the presentation for a briskly bleeding upper GI source[]. The presence of frank bloody emesis suggests more active and severe bleeding in comparison to coffee-ground emesis[]. Variceal hemorrhage is life threatening and should be a major consideration in diagnosis as it accounts for up to 30% of all cases of acute upper GI bleeding and up to 90% in patients with liver cirrhosis[].
Lower GI bleeding classically presents with hematochezia, however bleeding from the right colon or the small intestine can present with melena[]. Bleeding from the left side of the colon tends to present bright red in color, whereas bleeding from the right side of the colon often appears dark or maroon-colored and may be mixed with stool[].
Other presentations which can accompany both upper and lower GI bleeding include hemodynamic instability, abdominal pain and symptoms of anemia such as lethargy, fatigue, syncope and angina[]. Patients with acute bleeding usually have normocytic red blood cells. Microcytic red blood cells or iron deficiency anemia suggests chronic bleeding. In contrast to patients with acute upper GI bleeding, patients with acute lower GI bleeding and normal renal perfusion usually have a normal blood urea nitrogen-to-creatinine or urea-to-creatinine ratio[]. In general, anatomic and vascular causes of bleeding present with painless, large-volume blood loss, whereas inflammatory causes of bleeding are associated with diarrhoea and abdominal pain[].
When patients with known abdominal aortic aneurysm or aortic graft present with above symptoms of GI bleeding, aortoenteric fistula most commonly at the duodenum should be strongly suspected. In this case, urgent computed tomography (CT) abdomen or CT angiogram is indicated to look for loss of tissue plane between the aorta and duodenum, contrast extravasation and the presence of gas indicating graft infection. Upper endoscopy prior to surgical intervention may help exclude other diagnoses when CT findings are not definitive[,]. The details of these investigations are discussed later in this review.
Investigations
Options for the investigation of acute GI bleeding include upper endoscopy and/or colonoscopy, nuclear scintigraphy, CT angiogram and catheter angiography. The investigation of choice would be guided by the suspected location of bleeding (upper vs lower GI) based on clinical presentation. In most circumstances, the standard of care for the initial diagnostic evaluation of suspected acute GI bleeding is urgent upper endoscopy and/or colonoscopy, as recommended by guidelines from the American College of Gastroenterology and the 2010 International Consensus Recommendations[,]. As investigations are being planned, infusions of proton pump inhibitor or octreotide should be initiated for suspected bleeding peptic ulcer and varices respectively[,].
Upper endoscopy
In patients with acute upper GI bleeding, upper endoscopy is considered the investigation of choice[]. Early upper endoscopy within 24 h of presentation is recommended in most patients with acute upper GI bleeding to confirm diagnosis and has the benefit of targeted endoscopic treatment (Figure (Figure1),1), resulting in reduced morbidity, hospital length of stay, risk of recurrent bleeding and the need for surgery[]. Endoscopic evacuation of hematoma or blood clot may enable visualization of underlying pathology such as a visible vessel in a peptic ulcer and allows directed endoscopic hemostatic therapy[,]. The reported sensitivity and specificity of endoscopy for upper gastroduodenal bleeding are 92%-98% and 30%-100%, respectively[]. Risks of upper endoscopy include aspiration, side-effects from sedation, perforation, and increased bleeding while attempting therapeutic intervention. The airway should be secured by endotracheal intubation in the case of massive upper GI bleeding.
Upper endoscopic findings in patients with suspected upper gastrointestinal bleeding. Esophageal varices (A), Dieulafoy’s lesion in the stomach (B), gastric antral vascular ectasia (watermelon stomach) in the antrum of the stomach pre and post argon plasma coagulation therapy (C, D).
The use of nasogastric-tube insertion and gastric lavage in all patients with suspected upper GI bleeding is controversial and studies have failed to demonstrate a benefit in clinical outcomes[,]. The use of prokinetics such as erythromycin and metoclopramide as a single dose before upper endoscopy promotes gastric emptying and clearance of blood, clots and food. Two meta-analyses have demonstrated the use of a prokinetic agent improved visibility at endoscopy and significantly reduced the need for repeat endoscopy[,]. In particular, the use of erythromycin was associated with a decrease in the amount of blood in the stomach, reduced amount of blood transfusion and shorter length of hospital stay[]. Therefore prokinetics such as erythromycin before upper endoscopy should be recommended for patients with major bleeding who are expected to have large amount of blood in the stomach.
The practice of routine second look endoscopy after hemostasis is achieved on first endoscopy remains controversial. Two meta-analyses of randomized controlled trials have shown that second look endoscopy significantly reduced peptic ulcer rebleeding but did not improve overall mortality[,]. Due to the relatively small number of subjects studied, suboptimal hemostatic measures used and the lack of proton pump inhibitor use in those trials, the 2010 International Consensus Recommendations did not recommend routine use of second look endoscopy but stated it may be useful in selected patients with high risk of re-bleeding[]. This should be considered particularly when there are concerns of suboptimal prior endoscopy and potential missed lesions.
In cases of acute upper GI bleeding where upper endoscopy is non-diagnostic in which a bleeding site cannot be identified or treated, the next investigation depends on the patient’s hemodynamic stability. If the patient is unstable with large volume upper GI blood loss, patient should proceed to urgent surgery, such as an exploration and partial gastrectomy for uncontrolled bleeding gastric ulcer[]. Intraoperative endoscopy may be a useful adjunct during surgery to help localize the source of bleeding[,]. If the patient is hemodynamically stable with low volume bleeding, repeat endoscopy may be considered. Colonoscopy should also be considered in the setting of melena to exclude a right-sided colonic source of bleeding, as discussed later.
Further imaging should be considered after non-diagnostic upper endoscopy with or without colonoscopy and the options include CT angiography, catheter angiography and nuclear scintigraphy[], all of which are discussed separately in later sections of this review. Upper GI barium studies are contraindicated in the setting of acute upper GI bleeding because they may interfere with subsequent investigations or surgery[], and due to the risk of barium peritonitis if there is a pre-existing perforation of the bowel wall[].
Colonoscopy
In acute lower GI bleeding, the diagnostic approach is somewhat more variable. Colonoscopy and CT angiogram are the two diagnostic tools of choice for evaluation of acute lower GI bleeding[]. The American College of Gastroenterology guidelines suggest that colonoscopy should be the first-line diagnostic modality for evaluation and treatment of lower GI bleeding[]. Studies have indicated that colonoscopy identifies definitive bleeding sites (Figure (Figure2)2) in 45%-90% of patients[]. Advantages of colonoscopy include direct visualization, access to tissue biopsy and endoscopic hemostatic therapy, and as an initial diagnostic test has a higher sensitivity[,]. However, there are several limitations to colonoscopy in the setting of acute lower GI bleeding, including potential inadequate bowel preparation, the inability to evaluate most of the small bowel, as well as risks associated with sedation, perforation and bleeding similar to upper endoscopy[]. In patients with inadequate bowel preparation, the sensitivity drops significantly and successful treatment may only be possible in as few as 21% of patients in the acute setting[]. It has been advocated that urgent colonoscopy in this setting should be preceded by a rapid purge with isotonic colonic lavage 4-6 liters orally until the effluent passed is diluted pink in color. This rapid purge may require the use of a nasogastric tube and a prokinetic agent such as metoclopramide. This is based on the findings that blood or stool in the colon can obscure the bleeding source during urgent colonoscopy[,].
Colonoscopic findings in patients with suspected lower gastrointestinal bleeding. Colonic angiodysplasia (A) and radiation proctopathy (B).
It is recommended by the American College of Radiology that colonoscopy be utilized as the initial modality in hemodynamically stable patients (allowing for adequate bowel preparation) and angiography in those are who are hemodynamically unstable with massive lower GI bleeding[]. It should be noted that colonoscopy is also indicated in the evaluation of patients presenting with melena who have negative upper endoscopy to exclude a right-sided colonic source of bleeding.
In cases where the source of bleeding is unidentified after upper endoscopy and/or colonoscopy, the utilization of subsequent diagnostic modalities should be guided by clinical presentation, hemodynamic stability and local expertise with the individual tests. No large randomized trials have demonstrated superiority of a particular strategy. The next section will outline the diagnostic use of CT angiography, catheter angiography and radionuclide imaging in acute GI bleeding.
CT angiography
CT angiography requires the rate of ongoing arterial bleeding to be at least 0.5 mL/min to reliably show extravasation of contrast into the bowel lumen to identify a bleeding site[]. A systematic review of the diagnostic accuracy of CT angiography demonstrated a sensitivity of 86% and specificity of 95% in the evaluation of patients with acute GI bleeding[]. The potential advantages of CT angiogram in diagnosis of acute GI bleeding include its minimally invasive nature and its wider availability in comparison to catheter angiography[]. It can also demonstrate neoplasms or vascular malformations and provide evidence of recent bleeding, such as hyperdense blood in bowel lumen[,]. Active GI bleeding is diagnosed by extravasation of contrast into the bowel lumen, which appears as an area of high attenuation on the arterial phase scan which increases on the venous phase scan (Figure (Figure3A-D).3A-D). By demonstrating the precise site of bleeding and the underlying etiology, CT angiography is useful for directing and planning definitive treatment whether it be through endoscopy, catheter angiography or surgery[]. If the gastrointestinal bleeding is intermittent and the initial CT is negative, a repeat CT angiogram can be performed when rebleeding occurs[].
73-year-old man with per rectal bleeding and active gastrointestinal hemorrhage. Contrast enhanced computed tomography (CT) angiogram images show extravasation of contrast into the lumen of the ascending colon, with pooling of contrast which increases from the arterial phase (A, B) to the delayed venous phase (C, D). Diverticula are seen arising from the medial wall of the ascending colon indicating the etiology of bleeding. Following the CT angiogram, the patient underwent catheter angiography, which demonstrated blush of contrast from the right colic branch of the superior mesenteric artery (E). Selective catheterization of the right colic artery demonstrates the bleeding focus more clearly (F). Gelfoam and coil embolization was subsequently performed.
Disadvantages of CT angiography is the lack of therapeutic capability, risk of contrast induced nephropathy in patients with renal impairment and contrast allergy[]. It has been suggested that the role of CT angiography in evaluation of patients with acute GI bleeding is in those who are stable and when upper endoscopy or colonoscopy is unable to locate the site of bleeding. Patients with massive GI hemorrhage with hemodynamic instability are recommended to proceed directly to catheter angiography or urgent surgery[].
Catheter angiography
Catheter angiography can detect bleeding at rates of 0.5 to 1.5 mL/min[,]. It is used often in suspected acute lower GI bleeding due to anatomical availability of end arteries and is more challenging in acute upper GI bleeding due to the presence of multiple collateral vessels[]. In comparison to other imaging modalities it offers the advantages of being both a diagnostic and therapeutic tool allowing for infusion of vasoconstrictive drugs and/or embolization (Figure (Figure3E3E and F). It also does not require bowel preparation. The sensitivity for a diagnosis of acute GI bleeding is 42%-86% with the specificity close to 100%[]. Other factors that may affect the sensitivity of angiography include intermittent bleeding, procedural delays, atherosclerotic anatomy, and venous or small vessel bleeding[,].
Complications include access-site hematoma or pseudoaneurysm, arterial dissection or spasm, bowel ischemia, and contrast-induced nephropathy or allergic reaction. Complications occur in 0%-10% of patients undergoing angiography, with the incidence of serious complications occurring in < 2% of patients[,]. It is recommended that catheter angiography be reserved for patients in whom endoscopy is not feasible due to severe bleeding with hemodynamic instability, or in those with persistent or recurrent GI bleeding and a non-diagnostic upper endoscopy and/or colonoscopy[].
Radionuclide imaging
The threshold rate of GI bleeding for localization with radionuclide scanning is 0.1 mL/min, and this is the most sensitive imaging modality for GI bleeding[]. Nuclear scans are either technetium-99m (99mTc) sulphur colloid or 99mTc pertechnetate-labelled autologous red blood cells. The short half-life of 99mTc sulphur colloid is a limitation as this means that patients must be actively bleeding during the few minutes the label is present in the intravascular space, and repeat scanning for intermittent bleeding is not possible without reinjection. 99mTc pertechnetate-labelled red blood cell scan allows for frequent abdominal images up to 24 h if necessary and is more commonly utilized for investigation of patients with obscure, intermittent bleeding. The main disadvantage of this test is poor anatomic localization of the bleeding site, and this poorly predicts subsequent angiogram results[,]. Furthermore, radionuclide only provides functional data, and is unable to diagnose the pathological cause of GI bleeding. Although advocated as a guide for surgical resection, surgical planning should not be based on only a positive nuclear scan[].
All imaging studies have the advantage of allowing the clinician to identify the location of bleeding throughout the GI tract, especially those originating from the small bowel. However, their use is often limited by the need for active bleeding at the time of investigation. Other diagnostic modalities such as push enteroscopy, deep small bowel enteroscopy and capsule endoscopy may be of value when the above described investigations prove to be non-diagnostic and when patients are hemodynamically stable with low volume bleeding. These studies will be discussed in the subsequent section evaluating chronic occult GI bleeding.
OCCULT (CHRONIC) GI BLEEDING
Epidemiology
Chronic occult GI bleeding occurs in the setting of a positive FOBT and/or iron deficiency anemia. Iron deficiency is the most common cause of anemia worldwide. In developed countries the major cause of iron deficiency is secondary to chronic blood loss[]. In the United States, it is estimated that 5%-11% of women and 1%-4% of men are iron deficient and 5% and 2% of adult women and men have iron deficiency anemia, respectively[]. Iron deficiency anemia has traditionally been attributed to chronic occult GI bleeding, especially in groups other than premenopausal women, and warrants further investigation of the gastrointestinal tract, including for colorectal cancer[].
Etiology and pathophysiology
Chronic occult GI bleeding may occur anywhere in the GI tract, from the oral cavity to the anorectum[]. In a systematic review of five prospective studies, 29%-56% of patients had an upper GI source and 20%-30% of patients had a colorectal source of occult GI bleeding diagnosed by the means of upper endoscopy and colonoscopy. These studies were unable to identify a source in 29%-52% of patients[]. Causes of chronic occult GI bleeding can be broadly categorized into mass lesions, inflammatory, vascular, and infectious[]. More common causes include colorectal cancer (especially right-sided colon), severe esophagitis, gastric or duodenal ulcers including from the use of aspirin and other NSAIDs, inflammatory bowel disease, gastric cancer, celiac disease, vascular ectasias (any site), diverticula, and portal hypertensive gastropathy. Non-GI sources of blood loss such as hemoptysis and oropharyngeal bleeding can also cause a positive FOBT[]. A small bowel source accounts for a high percentage of patients with chronic occult GI bleeding and negative findings on upper endoscopy and colonoscopy[], which is classified as obscure GI bleeding.
Clinical presentation
Patients with iron deficiency anemia may or may not be symptomatic. Rockey[] recommended that initial investigation be directed towards the location of specific symptoms if possible. In the absence of symptoms, particularly in the elderly, the colon should be evaluated first, and if this is negative, upper GI tract is further investigated[]. A targeted history is of value to discern symptoms of unintentional weight loss (suggestive of malignancy), use of aspirin or other NSAIDs (ulcerative mucosal injury), antiplatelet or anticoagulant use, family history, liver disease, and previous gastrointestinal tract surgery[]. Physical signs could indicate presence of an underlying condition such as celiac disease, inflammatory bowel disease, Plummer-Vinson syndrome, and Peutz-Jeghers syndrome[].
Investigations
Once a patient has been identified as having positive FOBT and/or iron deficiency anemia, multiple diagnostic procedures are available for investigation of the GI tract. The choice and sequence of procedures will depend on clinical suspicion and symptoms[]. Endoscopic measures include upper endoscopy, colonoscopy, deep enteroscopy, or capsule endoscopy. CT colonography, CT and magnetic resonance (MR) enterography are some of the radiographic investigations utilized in the evaluation of patients with chronic occult GI bleeding. The role of barium enema, small bowel series, enteroclysis, standard CT or MR imaging and nuclear scans have substantially declined due to their low diagnostic yield and the advent of capsule endoscopy[]. The choice of investigation should also incorporate consideration of patient risk factors and preference. In general, colonoscopy and upper endoscopy are the initial investigations of choice for chronic occult GI bleeding[].
Colonoscopy and upper endoscopy
The 2007 American Gastroenterological Association guidelines on obscure GI bleeding recommended that the evaluation of a patient with a positive FOBT depends upon whether iron deficiency anemia is present. Patients with positive FOBT and no anemia should first be investigated with a colonoscopy (if upper GI symptoms present then also upper endoscopy) whereas patients with iron deficiency anemia should undergo both upper endoscopy and colonoscopy[]. Patients with negative findings on upper endoscopy and colonoscopy without anemia do not require further investigations, but those with anemia should be referred for further investigation of the small bowel. The initial small bowel investigation of choice, when available, is wireless capsule endoscopy[].
Capsule endoscopy, push enteroscopy and deep enteroscopy
Wireless capsule endoscopy is a simple, non-invasive method to study the small intestine for evaluation of small intestinal occult GI bleeding (Figure (Figure4).4). The diagnostic yield in patients with chronic occult and obscure GI bleeding (after negative upper endoscopy and colonoscopy) ranges from 55%-92% for capsule endoscopy[,] in comparison to 25%-30% for push endoscopy[,]. A meta-analysis of 14 studies demonstrated that the diagnostic yield of capsule endoscopy was superior to push enteroscopy (63% vs 28%) and barium studies (42% vs 6%)[]. Capsule endoscopy also avoids the higher rates of morbidity and mortality associated with push enteroscopy[]. Capsule endoscopy is less useful in evaluating colonic sources of bleeding because of retained stool, battery life and poor field of vision due to the colon’s large diameter[]. Complications related to the procedure are rare and include capsule retention and obstruction[].
Jejunal angiodysplasia as seen on capsule endoscopy.
Push enteroscopy can evaluate the GI tract to 60-80 cm of the proximal jejunum. However, with the availability of deep enteroscopy, which can reach to the distal small bowel, the use of push enteroscopy has diminished. Three systems widely used are: the double balloon endoscopy system, the single balloon enteroscope system, and the Endo-Ease Discovery SB small bowel enteroscope or spiral enteroscope, and may be performed via the oral or anal route[]. Studies comparing the three different modalities are lacking. The advantage of deep enteroscopy over capsule endoscopy is that it can also be a therapeutic modality. The diagnostic yield of double-balloon enteroscopy varies from 40%-80% and therapeutic success ranging between 15%-55%[,].
Radiographic imaging modalities
Historically, an upper GI series with small bowel follow-through and/or enteroclysis was the next test performed, but in recent years, where available, CT and MR enterography have superseded these older radiographic modalities.
CT enterography involves ingestion of a neutral contrast agent to distend the small bowel which enables better evaluation of the small bowel wall in comparison to barium solutions. The alternative is MR enterography which has the advantage of not using ionizing radiation allowing serial imaging of the small bowel.
Compared to capsule endoscopy, CT enterography provides better visualization of the entire small bowel wall and shows extra-enteric complications of small bowel disease, whereas capsule endoscopy allows direct visualization of the small bowel mucosa and has a higher sensitivity for mucosal processes[].
OBSCURE GI BLEEDING
Obscure GI bleeding accounts for 5% of patients of all cases of GI bleeding, both acute overt and chronic occult[,]. It is defined as recurrent bleeding when the source remains unidentified after endoscopic procedures and is most commonly caused by bleeding from the small intestine. The commonest causes of obscure GI bleeding include small bowel tumors, vascular anomalies such as angiodysplasias and varices, diverticula and Celiac disease. The emphasis in diagnosis of obscure GI bleeding is the investigation of the small bowel[].
Repeat upper endoscopy and/or colonoscopy should be considered as one study using double-balloon enteroscopy showed that 24.3% of obscure GI bleed were of non-small bowel origin and within the reach of conventional upper and lower endoscopes[]. The already mentioned small bowel investigations using capsule endoscopy and deep enteroscopy techniques (including double-balloon enteroscopy, single-balloon enteroscopy and spiral enteroscopy) have enabled the diagnosis of substantially more cases of obscure GI bleeding. Independent series showed that capsule endoscopy had a diagnostic yield of 53%-68% in obscure GI bleeding, led to a specific intervention in the majority of patients and was associated with a significant reductions in hospitalizations and blood transfusions[,]. In a randomized controlled trial in patients with iron deficiency anemia and obscure GI bleeding, capsule endoscopy identified a bleeding source significantly more than push enteroscopy (50% vs 24%, P = 0.02)[]. Double-balloon enteroscopy was shown in a systematic review to have a diagnostic yield of approximately 68% in obscure GI bleeding[]. A meta-analysis of studies comparing capsule endoscopy and double-balloon enteroscopy concluded comparable diagnostic yield (60% vs 57%, P = 0.42) in small bowel disease and obscure GI bleeding[]. Capsule endoscopy has the major advantage of being less invasive than deep enteroscopy but the major advantage of deep enteroscopy techniques is their ability to perform treatment at the same time. The choice between capsule endoscopy and deep enteroscopy should be individualized for each patient and one approach may be initial capsule endoscopy followed by a directed deep enteroscopy as directed intervention[].
CT or MR enterography may be considered as an alternative investigation for small bowel disease due to its ability to visualize the small bowel wall and extra-enteric complications, especially when capsule endoscopy and deep enteroscopy are non-diagnostic. In patients with signs of active bleeding, the above mentioned technetium-99 radionuclide scan, CT angiography and catheter angiography should be considered to help locate the lesion prior to intervention.
CONCLUSION
GI bleeding can be caused by a wide range of pathologies and they differ in onset, location, risk and clinical presentation. In patients with active GI bleeding who are unstable, acute resuscitation should precede any investigations. Accurate clinical diagnosis is crucial in determining the investigation of choice and specific treatment interventions. The correct diagnostic algorithm (Figure (Figure5)5) relies on a good understanding of the type of GI bleeding, risk evaluation and clinical presentation which may indicate the nature and source of bleeding. Upper endoscopy and colonoscopy are the mainstay of initial investigations. Angiography and radionuclide imaging are best suited for acute overt GI bleeding. Capsule endoscopy and deep enteroscopy play significant roles in the diagnosis of obscure GI bleeding, usually from the small bowel.
Diagnostic algorithms. A: Acute overt; B: Chronic occult; C: Obscure. CT: Computed tomography; MR: Magnetic resonance; GI: Gastrointestinal; FOBT; Fecal occult blood test.
Footnotes
P- Reviewer: Delgado JS, Gurvits GE, Goenka MK, Maehata Y, Sivandzadeh GR S- Editor: Wen LL L- Editor: A E- Editor: Wang CH
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Primo-Vascular System as Presented by Bong Han Kim
1Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn, AL 36849, USA
2School of Kinesiology, Auburn University, Auburn, AL 36849, USA
3Edward Via College of Osteopathic Medicine, Auburn, AL 36849, USA
Received 29 September 2014; Revised 1 January 2015; Accepted 5 January 2015
Academic Editor: John H. Barker
Copyright © 2015 Vitaly Vodyanoy et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
In the 1960s Bong Han Kim discovered and characterized a new vascular system. He was able to differentiate it clearly from vascular blood and lymph systems by the use of a variety of methods, which were available to him in the mid-20th century. He gave detailed characterization of the system and created comprehensive diagrams and photographs in his publications. He demonstrated that this system is composed of nodes and vessels, and it was responsible for tissue regeneration. However, he did not disclose in detail his methods. Consequently, his results are relatively obscure from the vantage point of contemporary scientists. The stains that Kim used had been perfected and had been in use for more than 100 years. Therefore, the names of the stains were directed to the explicit protocols for the usage with the particular cells or molecules. Traditionally, it was not normally necessary to describe the method used unless it is significantly deviated from the original method. In this present work, we have been able to disclose staining methods used by Kim.
1. Introduction
In the early 1960s, Bong Han Kim discovered and described a new vast anatomical vascular system that he believed underpins the acupuncture meridian system. During the three years from 1962 to 1965 Kim published five reports [1–5]. Four of Kim’s reports were translated into English as two books [6, 7]. He analyzed and described this new anatomical system that he named as Bonghan system. It was obvious from his publications that Kim had far-reaching scientific goals, but, in 1965, his research ceased, and his fate became unknown [8, 9].
Following Dr. Kim’s disappearance, his findings remained dormant for many years. In 2002, the scientific group of Dr. Kwang-Sup Soh initiated a series of experiments that validated many of Kim’s results. This research has ignited a new interest in this anatomical vascular system that now is termed primo-vascular system (PVS) [10]. Soh and his colleagues have described the major achievements of Bong Han Kim in the understanding of structure and functions of PVS, as well as the experimental and theoretical results obtained by Kim during the relatively short time [10]. Kim offered a comprehensive picture of primo-vascular system. Kim presented the structural architecture that he had observed, which included organ, tissue, cells, and molecules involved in the function of PVS [7]. A short list of his techniques consisted of microsurgery, light and electron microscopies, and time-lapsed photography. Instead of dye-labeled antibodies he used fluorescent and nonfluorescent histochemistry with a large variety of stains, radioactive tracers, microautoradiography, and emission spectral analysis. He also perfected cell analysis, nucleic acid analysis, ultracentrifugation, cell culture, cell development, tissue regeneration, chromatography, electrophoresis, embryology, physiology, and electrophysiology [6, 7]. Kim gave a vivid description of primo-nodes and primo-vessel, which are two major components of primo-vascular system.
In this work, we have recreated structural models of the PVS node and vessels as they were described by Kim and compare these models with our optical experimental data and results found so far in the literature.
2. Terminology
Shortly before the first International Symposium on Primo-Vascular System, which was held in Jecheon, Korea, during September 17-18, 2010, Dr. Kwang-Sup Soh suggested that it would be important to agree upon a single terminology for the Bonghan system. It was agreed that the following terms would be adopted: Bonghan system (BHS) = primo-vascular system (PVS), Bonghan duct (BHD) = primo-vessel (PV), Bonghan corpuscle (BHC) = primo-node (PN), Bonghan ductule = P-subvessel, Bonghan liquor = primo-fluid (P-fluid), and Sanal = p-microcell.
The present work includes detailed presentations of PVS structures that require additional new terms as follows:periductium= p-vessel external jacket;wall of the Bonghan ductule + outer membrane of Bonghan ductule = external envelope of p-subvessel;outer membrane of Bonghan corpuscle = primo-node capsule;sanalosome= p-microcell nucleosome;sanaloplasm= p-microcell nucleoplasm;small nucleus-like structures = small (immature) p-microcell = progenitors of multipotent stem cells;large nucleus-like structure = large (mature) p-microcell = multipotent stem cell; sanalization = conversion of cell into p-microcell.
3. A Brief Old History
For many, the acupuncture meridian system is nothing more than a network of lines drawn on a body map and labeled with hieroglyphs. For others, the exact positions and locations of acupuncture points and meridians result from a few thousand years’ empirical practices of acupuncturists. It seems that no theoretical or anatomical background for the location and morphology of these points is available. On the contrary, there is strong evidence that information on the acupuncture points and meridians is based on the anatomical knowledge used in ancient Chinese surgical practices [11–13]. Anatomical dissections are mentioned in the Huang-Di Nei-Jing Ling-Shu, one of the oldest traditional books relating to Chinese medicine that describes anatomical structures of acupuncture points [14]. The most important source of information and exact anatomical description of acupuncture points is the classic Tong Ren, the Copper Man by Wang Wei-Yi published around 1027 A.D. (cited by Schnorrenberger [11]).
Due to the considerable difference between ancient and modern anatomical nomenclature, it is difficult to comprehend the full extent of the morphological properties of acupuncture points described by ancient scholars. It seems that detailed descriptions of anatomical structures given in the ancient Chinese sources would require microscopic histological examination. It is not known if ancient Chinese medical doctors used any magnifying tools in their anatomical work. The first recorded use of a microscope can be traced 4,000 years back to the Chow-Foo Dynasty. Ancient Chinese text refers to the construction of a magnifying tube filled with water with a refractive single lens in the lower end of this tube. By filling the tube with water at different level, they attained different level of magnification [15]. The highest magnification possible, 150x, would be powerful enough to see many morphological features that can be observed in modern microsurgery. Therefore, it would be very exciting to find a correspondence between ancient and modern anatomical nomenclature to comprehend the vast morphological knowledge that might have been available 2000 years ago. Additionally, there is evidence that acupuncture was practiced in Central Europe over 5200 years ago [16, 17].
Based upon the ancient literature, it is not clear whether ancient Chinese doctors knew the specific morphology of an acupuncture point. However, it is clear that the ancient knowledge of acupuncture meridians was more detailed and explicit. In contrast to the western view of meridians as mere lines on the skin, the classical Chinese text indicates that the meridians, in fact, possess a three-dimensional topology. They run deep inside the human body connecting with internal organs. In ancient Chinese text they are referred to as “Jing Mai” (pulsing vessels) [13] that carry Qi, nutrition, defensive factors, and liquid [18, 19]. The Qi is known to have many different meanings. In most cases, it is interpreted as a special substance or liquid that is in “a constant state of flux and varying states of aggregation” [18]. “Jing” is often translated as “essence.” Congenital Jing is a substance that is received from one’s parents at conception and which governs the growth and regeneration processes from the conception to death.
Huang-Di determined that Jing Mai also participated at the earliest stages of the human embryo development. He explains the creation of a human being by the combination of the female ovum Jing with a male sperm Jing. It involves Jing Mai (pulsing vessels) at the unfolding of brain and spinal cord tissues that correspond to the ectoderm layer, one of the three germ layers recognized in embryology [13, 14, 20].
Rephrasing the ancient Chinese concept of acupuncture meridians (Jing Mai), one can say that ancient Chinese medical doctors viewed the meridians as a three-dimensional vascular system. The system is carrying a special liquid (Qi) which contains genetic material (Jing) that is initially obtained after conception.
Ironically, putative primo-vessels have been discovered in Europe before the discovery of lymphatic vessels/system. In 1622, Gasparo Aselli, a professor of anatomy and surgery, Pavia, Italy, found vessels in the mesentery of dog that were filled with a white liquid. These white vessel structures ran through the mesentery and along the surface of the intestines and emitted a milky fluid when cut. Because of the milky appearance of the vessels, Aselli named these structures as lacteis venis or milky veins. Aselli stated that the liquid in these vessels is transformed in blood. Later, this statement was rejected by the researchers working with lymphatic vessels [21, 22], but Aselli is still credited as the discoverer of the lymphatic system. It is interesting to note that Aselli may have, in fact, described the existence of primo-vessels because the hematopoiesis that he described was also documented to be in the internal primo-node. It was later demonstrated by Kim [5, 7].
In 1874, Louis-Antoine Ranvier, who discovered nodes of Ranvier, also described unusual structures in the omentum of new born animals. He described these structures as being elongated or round, occasionally branched elements, containing red and white corpuscles [23]. About a quarter of the century later, Marchand [24] also found and described similar structures in the animal omentum. He described them as elongated elements, accompanied by blood vessels and associated with the production of all types of blood cells. In 1909, analyzing the interaction of various vital stains and colloidal metals with these structures, Goldman [25] reported that this type of “reticular-endothelial” system can be identified by trypan blue stain. Trypan blue belongs to the group of benzidine dyes containing trypan red and pyrrhol blue. He indicated that the pyrrhol blue particles create granular inclusion in the cells of these systems, which he named as “pyrrhol cells.”
Maximow, the scientist who coined the name “stem cell” [26], also described structures and functions of hematopoietic systems as scaffolds or niches for stem cell maturation and subsequent development of blood cells: “… they appear as sharply outlined, polymorphous, flat, spindle shaped or branched elements, often containing inclusions and are then easily distinguishable from the fibroblasts. They may also assume a flat shape and line blood or lymph channels. More than by a peculiar histological structure all these elements are characterized by a series of very important functional properties. Being endowed with ample prospective potencies they can produce, provided external conditions are favorable for hemocytoblasts (hematopoietic stem cells) and different types of blood cells. It is difficult to choose a suitable general name for these elements of the connective tissue, remaining throughout the whole life in an undifferentiated embryonic condition. They represent a vast cell system, distributed all over the body, over various organs and assuming, according to their position, manifold histological aspects. As we have seen, single parts of this cell system have been described by various investigators under different names. However, the idea of the close interrelation or even identity of all these cells, the fact that they form one entity, one vast group of elements with a very prominent function in the body, has made headway slowly” [27]. In this relatively short paragraph, Maximow described the essence of the primo-vascular system that was independently discovered by Bong Han Kim, which he subsequently named as Bonghan system [1–7, 28, 29].
4. Summary of Kim’s Findings on Primo-Vascular System
In the 1960s, Bong Han Kim, a North Korean scientist and professor of Pyongyang Medical College, suggested that the superficial acupuncture meridian system represented a fundamental vascular system. He injected radioactive phosphorus (P32) into a rabbit primo-node and documented that the P32 tracked or followed the acupuncture meridians [6]. Kim revealed that he separated DNA granules (p-microcells) from the primo-vessels and stimulated their proliferation under artificial conditions [7].
Importantly, radioactive visualization of the acupuncture meridians was reported again [30–32]. The research teams injected the radioisotope technetium (Tc99) at acupoints and described that the effective radiotracer pathways coincided with acupuncture meridians. A physical reality of acupuncture meridians was also confirmed by the increase in electroconductivity, hydraulic conductance, and propagation of acoustic waves [32–34]. Furthermore, infrared light delivered at acupoints was shown to travel in tracks detectible on the skin and these tracks correspond to traditional acupuncture meridians [35].
Three uniquely critical anatomical structures were reported as having both distinctive functions and structures. These are (1) superficial nodes positioned at the acupuncture points; (2) profound nodes in deep tissues located in and around blood and lymphatic vessels and internal organs; and (3) primo-vessels that connect all nodes which comprises the primo-vascular system. Kim proposed that p-microcells, DNA-containing granules, mature in the Bonghan system and produce small cells that are transported through ducts to replace aged and dying cells. These small cells, as described by Kim, behaved like multipotent stem cells [7].
5. Primo-Vascular Node and Vessels
According to Kim, a primo-vessel connects primo-nodes, and a primo-node is linked with primo-vessels.
5.1. Primo-Vessels
Kim recognized four different types of primo-vessels as follows. (1) The primo-vessels floating in the blood and lymphatic vessels were named as the internal (intravascular) primo-vessels. (2) The primo-vessels distributed on the surface of the organs, independent of the blood and lymphatic vessels and neuronal axons, were named as the intraexternal primo-vessels. (3) The primo-vessels running along the outer surface of the walls of blood and lymphatic vessels were named as the external (extravascular) primo-vessels. The external primo-vessels sometimes run, either independently of blood vessels or along neuronal axons. (4) The primo-vessels distributed in the internal and the peripheral nervous system, running inside the central canal of the spinal cord and the cerebral ventricles, were named as the neural primo-vessels [7].
The anatomical structure of different types of primo-vessels varies, but all of them share some common features. The primo-vessel is composed of 1–20 p-subvessels of 3–25 μm in diameter (Figure 1(a)) [7]. The bundle of p-subvessel of the primo-vessel is laid into an external jacket composed of endothelial cells with 6–12 μm round or oval nuclei.