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Correspondence to: Maxwell M Chait, MD, FACP, FACG, AGAF, FASGE, The Hartsdale Medical Group, 180 East Hartsdale Avenue, Hartsdale, New York, NY 10530, United States. moc.loa@77igdm
Telephone: +1-914-7252010 Fax: +1-914-7256488
Lower gastrointestinal bleeding (LGIB) is an important worldwide cause of morbidity and mortality in the elderly. The incidence of LGIB increases with age and corresponds to the increased incidence of specific gastrointestinal diseases that have worldwide regional variation, co-morbid diseases and polypharmacy. The evaluation and treatment of patients is adjusted to the rate and severity of hemorrhage and the clinical status of the patient and may be complicated by the presence of visual, auditory and cognitive impairment due to age and co-morbid disease. Bleeding may be chronic and mild or severe and life threatening, requiring endoscopic, radiologic or surgical intervention. Colonoscopy provides the best method for evaluation and treatment of patients with LGIB. There will be a successful outcome of LGIB in the majority of elderly patients with appropriate evaluation and management.
Lower gastrointestinal bleeding (LGIB) is a significant worldwide cause of morbidity and mortality in the elderly. The incidence of LGIB increases with age and is more common in men than women. There are worldwide regional differences in the causes of LGIB. For example, in the countries of Western Europe and the United States diverticulosis coli is common and is also one of the most common causes of LGIB. In Asia, however, diverticulosis coli is not common and is a much less common cause of LGIB. In the United States the incidence of LGIB ranges from 20.5 to 27 per 100 000 persons per year with a greater than 200 fold increase from the third to the ninth decade of life. With projections of ever increasing numbers of the elderly population in the future, health care costs will rise, because the elderly patients tend to increase healthcare costs through longer hospital stays and more utilization of resources. Therefore, one can expect that the worldwide incidence and importance of LGIB will also continue to rise.
The increase in incidence of LGIB in the elderly corresponds to three factors more common in the elderly: the increased incidence of gastrointestinal disease specific to elderly patients, co-morbid diseases and polypharmacy. Gastrointestinal diseases that cause LGIB that are more common in the elderly include diverticulosis coli, vascular ectasia, ischemic colitis and colonic neoplasms. After hemorrhage, the presence of a serious concurrent illness is the second most important factor in predicting mortality among patients with LGIB. Co-morbid diseases more common in the elderly that are associated with an increased incidence and severity of LGIB include cardiovascular disease, cirrhosis, renal disease, diabetes mellitus, and malignancy. Polypharmacy is common in the elderly with the increased use of anticoagulants and non-steroidal anti-inflammatory drugs (NSAIDS) that increase the risk of LGIB.
LGIB can be acute, occult or obscure in nature. Acute LGIB presents as melena or hematochezia. Melena is the passage of black, tarry, foul-smelling stools as a result of degradation of blood to hematin. The source of melena is most often from the upper GI tract. However, it may also be from the small intestine or the right colon. Hematochezia is the passage of bright red blood per rectum, with or without stool. Occult bleeding is bleeding not apparent to the patient and is usually detected with stool guaiac testing. It is the most common presentation of LGIB in the elderly, occurring in 10 % of the adult population. Remarkably, patients can loose up to 100 mL of blood per day and still have grossly normal appearing stools. Obscure bleeding is bleeding in which the source of bleeding is difficult to detect on routine endoscopic and radiologic examinations. The source of bleeding is unidentified in approximately 5 % of patients who present with GI bleeding.
There are many gastrointestinal diseases that cause LGIB in the elderly. There are worldwide regional differences in the causes of LGIB. In the countries of Western Europe and the United States the most common causes of LGIB are diverticular disease and vascular ectasias. Less common causes of LGIB are inflammatory diseases of the colon, neoplasms, postpolypectomy hemorrhage, hemorrhoids, stercoral ulcer and solitary rectal ulcer. Rare causes include Dieulafoy’s lesion and colo-rectal varices[6,7]. In Asia, however, the most common causes of LGIB are hemorrhoids, anal fissures and malignant colorectal neoplasms. Less common causes are benign colorectal neoplasms, ulcerative colitis, infectious colitis, ischemic colitis and radiation colitis. Diverticulosis coli is remarkably a rare cause of LGIB in Asia.
The incidence of diverticulosis coli increases with age from approximately 5% of individuals at age 40% to 65% of individuals at age 85 in the countries of Western Europe and the United States. Although most patients with diverticulosis coli are asymptomatic, it is the most common cause of LGIB. LGIB occurs in approximately 3% to 5% of patients with diverticular disease, usually in the form of hematochezia. The incidence of LGIB ranges from 15% to 48%, depending upon the series. Diverticular hemorrhage can be severe with significant morbidity and a mortality rate of 10% to 20%. Risk factors for LGIB in the elderly include the use of NSAIDS and hard stools due to lack of dietary fiber and constipation[11,12].
A colonic diverticulum is a sac-like protrusion that herniates through the colonic wall through the spaces weakened by the vasa recta. It is postulated that the vasa recta drape over the dome of the thinned-out colonic wall and become more prone to injury. Factors that increase injury include NSAIDS and hard stool. Although about 90% of colonic diverticula are in the left colon, 50%-90% of diverticular LGIB occurs from right-sided colonic diverticula. The increased frequency and severity of right sided diverticular hemorrhage may be due to the fact that right-sided diverticula appear to have wider domes and necks, exposing the vasa recta to injury over a greater length of the vessel. Diverticula may also arise in the small intestine where they may be source of obscure bleeding, such as from a small bowel diverticulum or Meckel’s diverticulum.
LGIB from diverticula presents as painless, acute hematochezia. However, maroon colored stools or melena may occur in bleeding from right sided colonic diverticula and small bowel diverticula. Diverticular LGIB usually ceases spontaneously, with less than 1% of patients requiring greater than four units of blood. However, bleeding can become more hemodynamicaly significant in elderly patients. Factors that increase hemorrhage are co-morbid conditions, such as cardiovascular disease and the use of anticoagulants or NSAIDS.
Vascular ectasia, also termed angiodysplasia can occur in the colon and small intestine. Vascular ectasia occurs with much greater frequency in the elderly than telangiectasia, hemangiomas or congenital arteriovenous malformations. Vascular ectasia is a degenerative lesion of previously normal blood vessels that may occur anywhere in the colon, but more commonly in the cecum and right colon. Small bowel vascular ectasia is the most common source of obscure GI bleeding, occurring up to 60% of cases in Western Europe and the United States[15,16]. On careful histologic examination, these lesions are noted to be ectatic, distorted veins, venules and capillaries, lined only by endothelium and occasionally by a small amount of smooth muscle[17,18]. The mechanism of injury appears to be from repeated episodes of colonic distention associated with transient increases in both luminal pressure and size that result in multiple episodes of increased wall tension and obstruction of submucosal venous outflow, especially at the point where vessels pierce the muscle layers of the colon. After many years, this process leads to dilatation of venules and capillaries with the development of vascular ectasia occurs. Colonic lesions occur most commonly in the right colon because the right colon region has the largest luminal diameter with the highest resting wall tension. Colonic vascular ectasia is noted in over 25% of asymptomatic individuals over the age of 60. There is an association of vascular ectasia and heart disease, specifically aortic stenosis. Vascular ectasia causes LGIB in 12% to 40% of patients, depending upon the study. The bleeding from vascular ectasia is usually subacute, but can be chronic and recurrent, especially in small bowel lesions. LGIB may present as iron deficiency anemia and occult blood positive stools, but may be massive in up to 15% of patients.
LGIB can occur from inflammatory diseases of the colon. The various types of inflammatory diseases of the colon can be indistinguishable upon initial presentation. The findings of abdominal pain, LGIB, fever and dehydration are common to all. Endoscopically, the mucosa may appear edematous, friable and ulcerated in any type of colitis, although certain characteristics can aide in diagnosis as discussed below. The most common forms of inflammatory bowel disease in the elderly are ischemic colitis, infectious colitis, idiopathic inflammatory bowel disease and post irradiation colitis.
Ischemic colitis accounts for 3% to 9% of all cases of LGIB in the elderly[1,21]. Colonic atherosclerosis is almost universal in the elderly and predisposes to ischemic colitis. Ischemic colitis results from reduced blood supply to the colon from a variety such factors as hypotension and vascular embolic events. Although the precipitating event or factors leading to the lesion may not be identified, a history of a hypotension supports the diagnosis. Patients often present with lower abdominal cramping type of pain followed by hematochezia or bloody diarrhea. LGIB is rarely severe. Ischemic colitis commonly involves the watershed areas of the colon which are the right colon, splenic flexure and recto-sigmoid junction. Although usually acute, some patients may develop a chronic colitis resembling idiopathic inflammatory bowel disease. It is most often segmental in nature with rectal sparing, simulating the appearance of Crohn’s disease. It is often unresponsive to standard colitis treatment and may be complicated by perforation or stricture formation that requires surgical intervention.
The elderly have a greater risk for infectious colitis and its complications such as LGIB. The mortality from infectious colitis increases with age. LGIB is rarely massive in patients with infectious colitis. Hematochezia is noted in less than 10% of cases. The most common causes of enteric infections in the elderly are Campylobacter, Salmonella, Shigella, E. Coli 0157: H7 and Clostridium difficile. C. difficile must be considered in elderly patients in long-term care facilities and hospitals and in patients who have recently been treated with antibiotics. Infectious colitis often presents with a history of undercooked fish or meat consumption and during outbreaks of bloody diarrhea in the community and in long term care facilities or hospitals. E. Coli 0157: H7 can cause significant complications, such as acute thrombotic thrombocytopenic purpura and death in the elderly.
Idiopathic inflammatory bowel disease (IBD) occurs in the elderly, although with much less frequency than in younger populations. There is a bi-modality in IBD, with a second peak occurring between the ages of 60 and 70. Approximate 15% of all patients with IBD develop symptoms after the age of 65[28,29]. Although LGIB is common with IBD, severe hematochezia is infrequent. LGIB in IBD accounts for hospitalizations in 6% of patients with Crohn’s disease and 1.4% to 4.2% of patients with ulcerative colitis[30,31].
Post irradiation colitis is a source of LGIB in the elderly because of their higher incidence of malignancy requiring irradiation. It occurs in patients treated for genitourinary cancer, such as prostate cancer and gynecological malignancies. LGIB can be massive or occult with chronic iron deficiency anemia. It can develop acutely or many years after treatment.
Benign and malignant neoplasms of the colon and rectum are a cause of LGIB in 10% to 20% of cases of LGIB. Neoplasms most often present as a change in stool frequency, a change in stool caliber or weight loss. LGIB is the initial presenting symptom in up to 26% of patients with colorectal neoplasms[32,33]. Although LGIB from colorectal neoplasms is usually occult or mild, it can be massive LGIB if there is erosion into a large vessel or if patients are taking anticoagulants or NSAIDS.
The incidence of colonic polyps and thus the necessity of colonoscopic polypectomy rises with advancing age. LGIB is a complication of colonoscopic polypectomy in approximately 0.7% to 2.5% of cases[34,35]. Post-polypectomy hemorrhage is the source of LGIB in approximately 3% of patients. It more commonly follows sessile polyp removal and presents as hematochezia with or without abdominal pain soon after polypectomy. However, it may be delayed in some cases for up to one week after the procedure.
Hemorrhoids are a common source of LGIB in elderly patients. LGIB presents with intermittent low-volume hematochezia, which often coats the stool.
Stercoral ulcers and the solitary rectal ulcer syndrome can be a source of massive LGIB in the elderly. Stercoral ulcers are the result of mucosal damage by hard impacted stool in the rectum, from manipulation or foreign body injury, such as from a rectal tube in the hospitalized patient. The solitary rectal ulcer syndrome is due to rectal prolapse and mucosal damage from constipation and straining.
Rare causes of LGIB are Dieulafoy’s lesion and colonic or rectal varices. Dieulafoy’s lesion is a source of obscure LGIB. It is a large superficial artery underlying a mucosal defect, which is rare and difficult to find when not bleeding. Portal hypertension can cause varices outside the esophagus, including the colon and rectum.
Two factors that directly affect morbidity and mortality in elderly patients with LGIB are co-morbid disease and polypharmacy. Co-morbid diseases, such as cardiovascular disease, diabetes mellitus and malignancy, have a significant impact on the incidence and severity of LGIB. Polypharmacy with the use of NSAIDS and anticoagulants increases bleeding in patients with LGIB.
Co-morbid diseases directly impact LGIB to increase morbidity and mortality in the elderly patient. After hemorrhage, the presence of serious concurrent illness is the second most important factor in predicting mortality among patients with LGIB. Co-morbid diseases that are associated with an increased incidence and severity of LGIB include cardiovascular disease, hypertension, renal disease, diabetes mellitus and malignancy. Atherosclerotic cardiovascular disease affecting the splanchnic circulation is a cause of ischemic bowel disease. Atrial fibrillation is associated with embolic events to the intestine leading to ischemic bowel disease. Aortic valvular disease is associated with vascular ectasia of the colon. Cerebrovascular disease, diabetes mellitus and malignancy profoundly affect the response to LGIB, with prolonged hospitalization due to increased morbidity and an increase in mortality.
Polypharmacy, the use of multiple medications, is common in the elderly population. Medications more commonly used by the elderly that can cause or aggravate LGIB are anticoagulants and NSAIDS. Elderly patients with arthritis use NSAIDS to a significant degree. NSAIDS not only cause upper GI ulceration, but also ulceration of the small intestine and colon. Elderly patients with cerebrovascular disease and atherosclerotic heart disease are often given anticoagulants and aspirin for prevention of embolic events, ischemia, myocardial infarction and stroke. NSAIDS and anticoagulants increase LGIB morbidity and mortality from hemorrhage due to their effect on blood clotting factors[11,12].
The clinical course of LGIB can vary widely in elderly patients from occult bleeding to massive life-threatening hemorrhage and death. Therefore, the evaluation of these patients must be adjusted to the rate and severity of hemorrhage and the clinical status of the patient. The history and physical examination is important, but may be complicated by the presence of visual, auditory and cognitive impairment due to age and co-morbid disease. It may be necessary to call the primary care provider, caregiver and perhaps even the pharmacist to obtain history, such as extent of bleeding, duration of symptoms, presence of co-morbid disease, prior surgical history, drug allergies and recent and current use of medication such as Clopidogrel, warfarin and NSAIDS.
Common presenting symptoms of LGIB may not be evident in the elderly. For example, in elderly patients who are taking NSAIDS, abdominal pain may not be present. Painless hemorrhage that may even be life-threatening can occur. Physical examination to assess the severity of bleeding and status of the patient is important, with emphasis on the presence of orthostatic changes, signs of cardiopulmonary compromise, stigmata of chronic liver disease and evidence of coagulopathy. Orthostatic changes in blood pressure imply a 20% to 40% loss of circulatory volume. In cognitively impaired patients, a mini mental status exam as a measure of cognitive function is indicated on or after admission, if feasible.
Informed consent to procedures may be difficult to obtain in patients who suffer from cognitive dysfunction, since they cannot sufficiently participate in the informed consent process. With the exception of a true life-threatening emergency, every attempt should be made to obtain consent for testing procedures from the patient, if competent, or the surrogate. In the case when a guardian cannot be reached, administrative consent should be obtained.
The timing of tests and the type of intervention should be custom tailored, depending upon the patient’s functional status, the impact on clinical outcome and the available diagnostic strategies. This is most important in the frail elderly patient. However, intervention should not be withheld because of age alone[1-3].
Resuscitation efforts are a cornerstone in the successful management of patients with acute LGIB after the initial evaluation. In the majority of cases, LGIB stops spontaneously with appropriate resuscitation and supportive care. However, LGIB may be severe and life threatening. Endoscopic, radiologic or even surgical intervention may be necessary.
In patients with mild, chronic or occult bleeding with or without iron deficiency anemia, workup can be performed in hospital or as an outpatient, depending upon the clinical state of the patient. If LGIB is severe, the patient should be hospitalized, placed in an intensive care unit, given intravenous fluids and blood transfusions and provided with an adequate airway and oxygenation, as necessary. Laboratory data, including complete blood count, comprehensive metabolic profile, blood typing and cross matching, cardiac enzymes, prothrombin time, a PTT, stool for occult blood, electrocardiogram and chest x-ray should be obtained. In the appropriate setting, evaluation for infection must be done. Most organisms causing infectious colitis can be identified on stool culture. C. difficile colitis is most often diagnosed with stool assay for toxin A and B.
Approximately 10% to 15% of patients presenting with hematochezia may have an upper GI source of bleeding. Therefore, it is important to rule out an upper GI bleeding source. One should perform an NG lavage and confirm the presence of bilious or non-bloody aspirate in elderly patients presenting with hematochezia to help rule out an upper GI source of bleeding. If the NG lavage is positive or there is any suspicion of an upper GI source of hemorrhage, upper GI endoscopy should be performed as the first endoscopic procedure.
Plain x-ray films of the abdomen, CT scan of abdomen and barium enema are most often not helpful in the acute setting for the evaluation of LGIB. However, plain x-ray films of the abdomen may reveal evidence for obstruction or perforation. In patients with severe ischemic bowel disease the “thumb printing” sign may be seen. In the evaluation of more chronic bleeding, flexible sigmoidoscopy and barium enema may be helpful if the patient cannot undergo a complete colonoscopy. When further investigation of intra-abdominal structures is warranted, CT scan of the abdomen may be helpful.
Urgent colonoscopy performed within 24 h of hospitalization following a rapid purge is the best test for evaluation of LGIB, once the patient has been resuscitated and hemodynamically stabilized. Polyethylene sulfate purge causes less associated water and electrolyte abnormalities and may be preferable to saline purge for colonoscopic preparation in the elderly patient with co-morbid renal or cardiovascular disease. If the patient is unable to take the purgative by mouth, the placement of an NG tube for its administration may be necessary. The diagnostic accuracy of colonoscopy in the setting of acute LGIB ranges from 72% the 86% with cecal intubation achieved in 95% patients[41,45,46]. Colonoscopy can reveal the bleeding lesion, such as a bleeding diverticulum, vascular ectasia, or neoplasm. Colonoscopic evaluation in inflammatory bowel disease often reveals edematous, friable and ulcerated mucosa. Differential diagnosis may therefore require careful interpretation of pathologic findings to obtain an accurate diagnosis. Unfortunately, colonoscopy for evaluation of LGIB in the elderly patient may give erroneous results in some cases of vascular ectasia. Vascular ectasia may be confused with traumatic mucosal lesions from the procedure or may not be seen due to volume depletion or administration of meperidine for sedation, which can cause vascular spasm and poor filling of vascular lesions.
In patients with active LGIB where colonoscopy is not feasible due to massive bleeding, radionuclide imaging and abdominal angiography may identify the source of bleeding. For visualizing the bleeding source, radionuclide imaging requires that the bleeding rate be 0.1 to 0.5 mL per minute and abdominal angiography requires greater than 1 mL per minute[47,48]. Accuracy rates for these procedures vary greatly. The accuracy of radionuclide imaging is 24% to 78% and the accuracy of abdominal angiography is 27% to 77% for bleeding localization, depending upon the series.
There are important considerations involving the evaluation of elderly patients with LGIB. Older patients are more likely to have cardiac pacemakers with or without defibrillators, given the high incidence of cardiovascular disease in this age group. Recommendations for management of patients who require endoscopy and have pacemakers and internal defibrillators are not well defined. Cardiology consultation may be indicated. Pacemaker dependent patients should be driven to automatic pacing by placing a magnet on the skin overlying the device whenever monopolar electrosurgical devices are used. The patients who are not in a continuously paced rhythm should be monitored, with a magnet available for continuous pacing if needed. If the status of the patient’s rhythm is not known, great care should be used during electrocautery with EKG monitoring. Intracardiac defibrillators should be inactivated prior to the use of electrocautery. Continuous rhythm monitoring until the defibrillator is reactivated following the procedure must be preformed. Alternative means of tissue removal, destruction or hemostasis should be considered to simplify management of patients with LGIB and defibrillators to control hemorrhage, such as hemo-clips, ligation devices and injection of epinephrine and sclerosing agents. The general dictum of geriatric pharmacology of starting with low doses of medication and slowly advancing to larger doses is all the more important in the sedation of the elderly patient during endoscopy. As in younger adults, midazolam and narcotics are generally used. Initial dosages should be lower and titration should be more gradual. IV sedation guided by ASA criteria can be performed, especially in clinical settings when deeper sedation is required in the elderly patient.
It is estimated that 5% patients with GI bleeding, whether occult or overt, will have a negative upper GI endoscopy and colonoscopy. The scenario of obscure bleeding is more common in elderly patients. Obscure overt bleeding is characterized by persistent and recurrent visible evidence of bleeding, whereas obscure occult GI bleeding is defined as a positive fecal occult blood test after a negative upper GI endoscopy, colonoscopy, and routine small bowel radiographic study. Radionuclide scanning and abdominal arteriography may be helpful when bleeding is sufficient to reveal a lesion.
Newer endoscopic methods are available for evaluation of patients with obscure bleeding. These methods visualize the small intestine, which may be an important source of either overt or occult bleeding in the elderly patient. Wireless capsule endoscopy has become an important tool for the diagnosis of obscure GI Bleeding, being able to non-invasively visualize the entire small intestine[52,53]. Push enteroscopy and double balloon enteroscopy are modalities that provide for both the evaluation and treatment of obscure GI bleeding from the small intestine.
Hemorrhage from LGIB can be controlled in the vast majority of patients. Colonoscopy provides the best method for controlling LGIB as it provides many methods for control of hemorrhage. These include heater probe or bipolar probe thermal coagulation, band ligation, argon plasma coagulation, metallic clips, epinephrine and sclerosing agent injection, and application of fibrous glue[13,23,36,44,45].
Abdominal angiography not only permits the identification of the bleeding source but offers the potential of treatment with intra-arterial infusion of vasopressin or embolization of the bleeding vessel. For persistent bleeding not amenable to control by colonoscopic methods, abdominal angiography with infusion of vasopressin or embolization of the bleeding vessel is successful in about 90% of cases. Intra-arterial vasopressin infusion is successful in controlling the bleeding in up to 90% of patients with diverticular disease and vascular ectasia. However, intolerance to the cardiovascular complications of vasopressin is common in the elderly. Embolization with polyvinyl alcohol particles or microcoils provides a more definitive means of controlling hemorrhage, but may be complicated by intestinal infarction in up in to 20% of patients. Unfortunately, bleeding recurrence can occur in up to 50% of patients, depending upon the series[56,57].
Patients who fail angiographic or endoscopic therapy for control of LGIB require surgery. Every effort should be made to identify the bleeding source prior to referral for surgery, which often requires segmental colectomy. Blind resection is associated with very high rebleeding and mortality rates in the elderly and should only be reserved for the very rare instance of exsanguinating colonic bleeding where immediate life-saving surgery is required[9,58-61]. Blind segmental resection is associated with a re-bleeding rate of 47% and morbidity and mortality rate of 83% and 57% respectively. Localization of bleeding by a positive preoperative angiogram reduces the risk of rebleeding. Surgery may be necessary in up to 24% of patients with massive LGIB from diverticular disease.
Treatment of LGIB in patients with infectious colitis depends on the type of infection and the source of bleeding. Specific antimicrobial therapy is based upon the organism identified. Radiation proctitis can be treated with a variety of agents, including argon plasma coagulation, formalin application, sucralfate enemas and hyperbaric oxygen therapy[31,55,64,65]. Comparative controlled data are limited and it is unknown which therapy is most effective.
In the majority of patients with LGIB treatment is successful. Bleeding is controlled or ceases spontaneously, with less than 1% of patients requiring a transfusion of greater than four units of blood. Jensen and Machicado reported no rebleeding during a 30 mo follow up after endoscopic therapy when compared to a 53% rebleeding rate in patients treated with conservative medical therapy alone. Despite improvements in localization and treatments of LGIB, the mortality rate for severe LGIB remains 10%.
There are specific issues in the elderly patient with co-morbid disease and polypharmacy. For example, Metronidazole used to treat C. difficile colitis may interfere with oxidation of warfarin and induce excessive anticoagulation. General principles for treatment of elderly patients with IBD are the same as for younger patients, although no studies specific to the elderly population are available. However, significant treatment associated complications occur in elderly patients with IBD. For example, osteoporosis is a significant problem in elderly IBD patients on corticosteroids. Older patients with IBD on these agents must be evaluated for osteoporosis and offered prophylaxis with such agents as calcium and vitamin D supplementation and biphosphonates.
In conclusion, LGIB is a significant worldwide cause of increased morbidity and mortality in the elderly. The incidence of LGIB increases with age and corresponds to the increased incidence of specific gastrointestinal diseases that have worldwide regional variation, co-morbid diseases and polypharmacy that occur more common in the elderly. In the majority of elderly patients with LGIB appropriate evaluation and management will lead to a successful outcome.
Peer reviewers: Shotaro Enomoto, MD, PhD, Second Department of Internal Medicine, Wakayama Medical University, 811-1, Kimiidera, Wakayama 641-0012, Japan; Jean-Francois Rey, MD, Hepatogastroenterology Institut Arnault Tzanck, Saint Laurent Du Var Cedex 06721, France
S- Editor Zhang HN L- Editor Hughes D E- Editor Liu N