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Section Editor : Mark Feldman, MD Deputy Editor, Anne C Travis, MD, MSc, FACG
Last literature review version 18.2: May 2010 | This topic last updated: August 17,
2009 (More)
INTRODUCTION
high patient morbidity and medical care costs. In a study from one large health
maintenance organization, the annual incidence of hospitalization for acute UGI bleeding
was 102 per 100,000; the incidence was twice as common in males as in females, and
ground like material) and/or melena (black, tarry stools) (table 1). A nasogastric tube
lavage which yields blood or coffee-ground like material confirms this clinical diagnosis.
However, lavage may not be positive if bleeding has ceased or arises beyond a closed
pylorus. The presence of bilious fluid suggests that the pylorus is open and, if lavage is
negative, that there is no active upper GI bleeding distal to the pylorus. In comparison,
hematochezia (bright red or maroon colored blood or fresh clots per rectum) is usually a
sign of a lower GI source (defined as distal to the ligament of Treitz). Although helpful,
the distinctions based upon stool color are not absolute since melena can be seen with
proximal lower GI bleeding, and hematochezia can be seen with massive upper GI bleeding
[2-4]. (See "Approach to the adult patient with lower gastrointestinal bleeding".)
This topic review will summarize issues related to bleeding from peptic ulcers and
esophageal varices. Other causes of bleeding are presented on their corresponding topic
reviews. An overall approach to the patient with an upper GI bleed, the treatment of
bleeding peptic ulcers, and the less common causes of UGI bleeding are discussed
CATEGORIES
UGI bleeding can be classified into several broad categories based upon anatomic
and pathophysiologic factors (table 1). Several endoscopic studies have described the most
common causes [5-7]. Results have varied, possibly reflecting trends over time or
• A prospective series of 1000 cases of severe UGI bleeding at the UCLA and West Los
Angeles Veterans Administration Medical Centers published in 1996 found the following
• Other — 11 percent
• More recent data suggest that the proportion of cases caused by peptic ulcer disease
has declined [6,8]. Peptic ulcers were responsible for only 21 percent of episodes of upper
database between 1999 and 2001 [6]. The most common cause was nonspecific mucosal
abnormalities (42 percent), while esophageal inflammation accounted for about 15 percent,
and varices about 12 percent. Other causes (arteriovenous malformations, Mallory-Weiss
tears, and tumors) each accounted for less than 5 percent of cases. Among ulcer cases,
gastric ulcers were more common than duodenal ulcers representing about 55 percent of
all ulcers.
• A large database study focused on 243,428 upper endoscopies performed between 2000
and 2004 in a practice setting (rather than in tertiary care) [7]. The most common
endoscopic findings in patients with upper gastrointestinal bleeding were an ulcer (33
percent) followed by an erosion (19 percent). Gastric ulcers were more common than
duodenal ulcers (55 versus 37 percent). Patients with variceal bleeding were excluded
1) [5]. There are four major risk factors for bleeding peptic ulcers [9,10]:
• Stress
• Gastric acid
Reduction or elimination of these risk factors reduces ulcer recurrence and rebleeding
rates [11-14].
superficial gastric mucosa and appears to be transmitted by the fecal-oral route. The
bacterium generally does not invade gastroduodenal tissue. Instead, it renders the
underlying mucosa more vulnerable to acid peptic damage by disrupting the mucous layer,
liberating enzymes and toxins, and adhering to the gastric epithelium. In addition, the host
immune response to H. pylori incites an inflammatory reaction which further perpetuates
infection".)
asymptomatic and does not progress. In some cases, however, altered gastric secretion
coupled with tissue injury leads to peptic ulcer disease, while in other cases, gastritis
due to persistent immune stimulation of gastric lymphoid tissue, gastric lymphoma [15-18].
H. pylori eradication should be attempted for all patients who are diagnosed with
the infection and who have peptic ulcer disease to prevent ulcer recurrence and rebleeding
[19,20]. In one report of 19 published studies, for example, the recurrence rates in cured
versus noncured H. pylori infection was 6 versus 67 percent for duodenal ulcer, and 4
versus 59 percent for gastric ulcer [20]. Various multidrug regimens, which usually
combine one or two antibiotics plus an antisecretory agent, have eradication rates in the
cause of gastrointestinal ulceration [22-25]. NSAID-induced injury results from both local
effects and systemic prostaglandin inhibition. The majority of these ulcers are
bleeding ulcer disease are at increased risk for recurrent ulcer and complications [26-28].
NSAIDs also have been implicated as an important factor for non-healing ulcers [29]. (See
Stress — Stress related ulcers are a common cause of acute UGI bleeding in
patients who are hospitalized for life-threatening non-bleeding illnesses [30]. Patients
with these secondary episodes of bleeding have a higher mortality than those admitted to
the hospital with primary UGI bleeding [31]. The risk of stress ulcer-related bleeding is
increased in patients with respiratory failure and those with a coagulopathy [32]. Primary
pump inhibitors decreases the risk of stress related mucosal damage and UGI bleeding in
high-risk patients [33-35]. (See "Stress ulcer prophylaxis in the intensive care unit".)
Gastric acid — Gastric acid and pepsin are essential cofactors in the pathogenesis
diffusion of hydrogen ions, resulting in intramural acidosis, cell death, and ulceration [36].
Rarely, hyperacidity is the sole cause of peptic ulceration, as in patients with the
maneuver in patients with active UGI bleeding. (See "Approach to upper gastrointestinal
bleeding in adults".)
active bleeding from peptic ulcers. The most commonly used are injection and
ESOPHAGOGASTRIC VARICES
The prospective series of 1000 patients at the UCLA and West Los Angeles
Veterans Administration Medical Centers found that esophagogastric varices were the
second most common cause of UGI bleeding, accounting for 14 percent of episodes
segmental portal hypertension. The most common causes of systemic portal hypertension in
the United States are alcoholic liver disease and chronic active hepatitis. (See "Prediction
Isolated gastric varices can result from segmental portal hypertension due to
obstruction of the splenic vein from pancreatic carcinoma or chronic pancreatitis (picture
3). In addition, secondary gastric varices may develop after obliteration of esophageal
varices with endoscopic therapies. The risk factors for bleeding from gastric varices are
similar to the risk factors for bleeding from esophageal varices [37]. (See "Prediction of
[5]. If endoscopy is inconclusive and gastric variceal bleeding is suspected, one of the
• Endoscopic ultrasound may be useful for differentiating gastric varices from gastric
folds.
• Portal vein angiography or an abdominal CT scan may show venous collaterals and
• Barium X-rays may image large esophageal varices or large gastric folds suggestive of
• Capsule endoscopy of the esophagus (PillCam ESO) may represent a minimally invasive
alternative to endoscopy for the detection of esophageal varices and portal hypertensive
Prognosis — Variceal bleeding stops spontaneously in over 50 percent of patients, but the
mortality rate approaches 70 to 80 percent in those with continued bleeding. Each episode
of variceal hemorrhage is associated with a 30 percent risk of mortality [38]. The risk of
obliterate residual varices. However, long-term survival depends upon the severity of liver
disease and may not be improved following successful variceal obliteration. The
administration of a nonselective beta blocker such as propranolol can also decrease the
cirrhosis".)
The onset of massive UGI bleeding from gastroesophageal varices usually signifies
advanced liver disease (Child class B or C). Liver transplantation is the only treatment that
of the relatively high rate of bleeding from esophageal varices and the high mortality
associated with this complication. Prophylactic propranolol or nadolol therapy is the only
cost-effective therapy in this setting [39]. Endoscopic variceal ligation also may be
sclerotherapy is not indicated due to the risks and complications of this procedure
cirrhosis".)
Various treatments are available for acute hemostasis. Endoscopic band ligation and
sclerotherapy continue to be the most commonly used. (See "General principles of the
available for patients. (See "Patient information: Upper endoscopy" and "Patient
disease in adults".) We encourage you to print or e-mail these topic reviews, or to refer
patients to our public web site, www.uptodate.com/patients, which includes these and
other topics.
REFERENCES
2. Jensen, DM, Machicado, GA. Diagnosis and treatment of severe hematochezia. The
3. Zuckerman, GR, Trellis, DR, Sherman, TM, Clouse, RE. An objective measure of stool
color for differentiating upper from lower gastrointestinal bleeding. Dig Dis Sci 1995;
40:1614.
92:231.
6. Boonpongmanee, S, Fleischer, DE, Pezzullo, JC, et al. The frequency of peptic ulcer as
9. Hunt, RH, Malfertheiner, P, Yeomans, ND, et al. Critical issues in the pathophysiology
and management of peptic ulcer disease. Eur J Gastroenterol Hepatol 1995; 7:685.
10. Hallas, J, Lauritsen, J, Villadsen, HD, et al. Nonsteroidal anti-inflammatory drugs and
11. Graham, DY, Hepps, KS, Ramirez, FC, et al. Treatment of H. pylori reduced the rate
12. Tytgat, GN. Peptic ulcer and Helicobacter pylori: Eradication and relapse. Scand J
reduces the possibility of rebleeding in peptic ulcer disease. Gastrointest Endosc 1995;
41:1.
15. Nakamura, S, Yao, T, Aoyagi, K, et al. Helicobacter pylori and primary gastric
1997; 79:3.
16. Parsonnet, J, Hansen, S, Rodriguez, L, et al. Helicobacter pylori infection and gastric
17. Pajares, JM. H. pylori infection: Its role in chronic gastritis, carcinoma and peptic
18. Shibata, T, Imoto, I, Ohuchi, Y, et al. Helicobacter pylori infection in patients with
19. Soll, AH. Medical treatment of peptic ulcer disease. JAMA 1996; 275:622.
20. Hopkins, RJ, Girardi, LS, Turney, EA. Relationship between H. pylori eradication and
110:1244.
21. Walsh, JH, Peterson, WL. The treatment of Helicobacter pylori infection in the
upper gastrointestinal bleeding and perforation. Dig Dis 1995; 13 Suppl 1:89.
gastrointestinal disease: Pathophysiology, treatment and prevention. Dig Dis 1995; 13:119.
25. Lanas, A, Perez-Aisa, MA, Feu, F, et al. A nationwide study of mortality associated
with hospital admission due to severe gastrointestinal events and those associated with
26. Hansen, JM, Hallas, J, Lauritsen, JM, et al. Non-steroidal anti-inflammatory drugs
and ulcer complications: A risk factor analysis for clinical decision-making. Scand J
28. Smalley, WE, Ray, WA, Daugherty, JR, et al. Nonsteroidal anti-inflammatory drugs
and the incidence of hospitalizations for peptic ulcer disease in elderly persons. Am J
Comparison of the causes and prognosis in primary and secondary bleeders. Scand J
32. Cook, DJ, Fuller, HD, Guyatt, GH, et al. Risk factors for gastrointestinal bleeding in
34. Cook, DJ, Reeve, BK, Guyatt, GH, et al. Stress ulcer prophylaxis in critically ill
35. Balaban, DH, Duckworth, CW, Peura, DA. Nasogastric omeprazole: Effects on gastric
36. Peterson, WL. The role of acid in upper gastrointestinal haemorrhage due to ulcer
and stress-related mucosal damage. Aliment Pharmacol Ther 1995; 9(Suppl 1):43.
37. Kim, T, Shijo, H, Kokawa, H, et al. Risk factors for hemorrhage from gastric fundal
38. Smith, JL, Graham, DY. Variceal hemorrhage. A critical evaluation of survival
39. Teran, JC, Imperiale, TF, Mullen, KD, et al. Primary prophylaxis of variceal bleeding
variceal bleeding in cirrhotic patients with high-risk esophageal varices. Hepatology 1997;
25:1346.
41. Sarin, SK, Lamba, GS, Kumar, M, et al. Comparison of endoscopic ligation and
propranolol for the primary prevention of variceal bleeding. N Engl J Med 1999; 340:988.
42. Prophylactic sclerotherapy for esophageal varices in men with alcoholic liver disease.
43. Jutabha R, Jensen DM, Martin P, Savides T, Han SH, Gornbein J. Randomized study
comparing banding and propranolol to prevent initial variceal hemorrhage in cirrhotics with
Section Editor : Bruce A Runyon, MD Deputy Editor, Anne C Travis, MD, MSc, FACG
Last literature review version 18.2: May 2010 | This topic last updated: April 5,
2010 (More)
INTRODUCTION
Cirrhosis affects 3.6 out of every 1000 adults in North America, and is responsible
for over one million days of work loss and 32,000 deaths annually. A major cause of
bleeding have a 70 percent risk of recurrent hemorrhage within one year of the bleeding
episode [3].
While several modalities are available for primary prophylaxis of variceal bleeding, many
are associated with significant adverse effects. (See "Primary prophylaxis against variceal
to 75 percent of patients who will never have variceal bleeding. The formation and
progression of varices and the predictive factors and risk classification for bleeding will
be reviewed here.
FORMATION OF VARICES
Portal pressure is determined by the product of portal flow volume and resistance
to outflow from the portal vein. Portal hypertension (defined as hydrostatic pressure >5
mmHg) results initially from obstruction to portal venous outflow. Obstruction may occur
is the most common cause of portal hypertension; in these patients, elevated portal
pressure results from both increased resistance to outflow through distorted hepatic
Varices develop in order to decompress the hypertensive portal vein and return
blood to the systemic circulation. They are seen when the pressure gradient between the
portal and hepatic veins rises above 12 mmHg; patients with lower values neither form
varices nor bleed. The portal-hepatic venous pressure gradient is obtained by hepatic
venous catheterization, with measurement of the difference between the wedged hepatic
venous pressure (which approximates the sinusoidal and portal pressures in cirrhosis) and
the free hepatic venous pressure. This procedure is routinely performed in many European
centers but only rarely in the United States. Although it does not predict the size of
varices, it may be useful for monitoring the success of therapy aimed at lowering portal
pressures, such as beta blockers. A systematic review of 12 studies found that a reduction
of the hepatic vein pressure gradient to ≤12 was associated with a significant reduction in
An illustrative study evaluated the relation between the hepatic vein pressure
gradient and the formation of and bleeding from varices [6]. The following observations
were noted:
• The gradient did not predict the size of varices, being similar in those with large and
small varices.
PROGRESSION OF VARICES
cirrhosis has not been extensively evaluated. One of the largest prospective studies
included 206 cirrhotic patients (113 without varices and 93 with small esophageal varices
• New varices developed in 5 percent at year one, and 28 percent at year three.
• Small varices progressed in size at a rate of 12 percent in year one, and 31 percent at
year three.
• Progression was predicted by the Child-Pugh score, the presence of red wale marks on
• The two-year risk of bleeding was significantly higher in patients with small varices at
PREDICTIVE FACTORS
Numerous clinical and physiologic factors are useful in predicting the risk of
• Location of varices
• Size of varices
• Appearance of varices
• Clinical features of the patient
• Variceal pressure
Location of varices
The most common sites for development of varices are the distal esophagus,
stomach, and rectum, although theoretically varices may develop at any level of the
gastrointestinal (GI) tract below the esophagus. Varices develop deep within the
submucosa in the mid-esophagus, but become progressively more superficial (nearer the
mucosa) in the distal esophagus. Thus, esophageal varices at the gastroesophageal junction
have the thinnest coat of supporting tissue and are most likely to rupture and bleed.
Varices in the gastric fundus also bleed frequently. Gastric varices are often
classified according to their location, which correlates with their risk of hemorrhage:
• Varices in direct continuity with the esophagus along the lesser and greater curves of
the stomach are called gastroesophageal varices (GOV) types 1 and 2 respectively.
• Isolated gastric varices in the fundus (IGV1) occur less frequently than GOVs (10 versus
90 percent) [8].
The relationship between the site of the varices and clinical risk was illustrated in a
prospective study of 568 consecutive patients with varices, 393 of whom were bleeding
[8]. The mean transfusion requirement in patients with bleeding gastric varices was higher
than in those with esophageal varices (4.8 versus 2.9 units per patient). Bleeding from
isolated gastric varices in the fundus (IGV1) occurred much more frequently than either
GOVs or isolated gastric varices at other loci in the stomach (IGV2) (figure 1).
Size of varices — The risk of variceal bleeding correlates independently with the diameter
(size) of the varix.The explanation for the relationship between variceal size and bleeding
risk is derived from Laplace's law; small increments in the vessel radius result in a large
increase in wall tension (which is the force tending to cause variceal rupture).
There are several ways in which esophageal variceal size is quantified; none are exact and
all involve subjective evaluation. A commonly employed system of classification includes the
• F2: Enlarged tortuous varices that occupy less than one-third of the lumen
• F3: Large coil-shaped varices that occupy more than one-third of the lumen
leads to overestimation.
Appearance of varices
have been correlated with an increased risk of hemorrhage [7,8,11]. Among these features
• Red wale marks are longitudinal red streaks on varices that resemble red corduroy wales
(picture 2).
• Cherry red spots are discrete red cherry-colored spots that are flat and overlie varices.
• Hematocystic spots are raised discrete red spots overlying varices that resemble "blood
blisters."
Clinical features
Several clinical features of the patient are related to the risk of variceal
hemorrhage [12]:
• The degree of liver dysfunction is an important predictor of variceal hemorrhage. The
concentration, bilirubin level, prothrombin time, and the presence of ascites and
encephalopathy (table 1). A higher score in this classification scheme is associated with a
episode. As an example, while only one-third of all patients with cirrhosis experience
after an index bleed. These bleeding episodes may be considered as "early" or "late" with
respect to their temporal relationship to the index bleed; one-third of patients with an
index bleed will rebleed within six weeks, and one-third will rebleed after six weeks [3].
The risk of early rebleeding is greatest in the first 48 hours after admission and declines
subsequently.
Risk factors for early and late rebleeding are listed in the table (table 2) [10,12,13]. The
risk of early rebleeding is greatest immediately after cessation of active hemorrhage (50
percent of such episodes occur within 48 hours) and subsides over time.
noninvasively with a pressure-sensitive endoscopic gauge [14]. The variceal pressure may
be an important predictor for variceal hemorrhage. In one study, for example, 87 patients
with cirrhosis and large esophageal varices who had never had variceal bleeding were
followed for 12 months [15]. Variceal hemorrhage developed in 28 patients (32 percent).
Variables predictive of a first bleed included: the level of variceal pressure; risk
classification using the Child class, variceal size, and endoscopic appearance of varices (see
below); and the interval between diagnosis of varices and the start of the study.
Specifically, the incidence of variceal bleeding with different levels of variceal pressure
was as follows:
• ≤13 mmHg - 0/25 (0 percent)\
Adding variceal pressure (categorized as > or ≤15.2 mmHg) to the risk classification
RISK CLASSIFICATION
The Child class, variceal size, and presence of red wale markings can be used to
calculate a prognostic index that numerically quantifies the risk of variceal hemorrhage in
an individual patient (table 3) [9]. The calculated risk is greatest in the first one to two
years from the time of identification of these risk factors. As an example, a patient with
Child class C cirrhosis and tense ascites who has large varices with red signs has an
Such a patient is clearly a candidate for prophylactic therapy to prevent bleeding. (See
One study evaluated variables that predicted the presence of high risk varices (ie
medium to large varices) in 1000 patients with HCV who had advanced fibrosis but
compensated liver function [16]. Such varices were vanishingly rare in those with a platelet
count over 150,000 (negative predictive value of 99 percent). Whether these data can be
Educational materials on this topic are available for patients. (See "Patient
information: Screening for esophageal varices".) We encourage you to print or e-mail this
SUMMARY
measures.
• Numerous clinical and physiologic factors are useful in predicting the risk of variceal
hemorrhage in patients with cirrhosis. These include, the location, size and appearance of
varices, their pressure and clinical features of the patient. (See 'Predictive
factors' above.)
• These factors can be considered together to help predict the risk of hemorrhage in an
REFERENCES
1. Smith, JL, Graham, DY. Variceal hemorrhage. A critical evaluation of survival analysis.
2. DeDombal, FT, Clarke, JR, Clamp, SE, et al. Prognostic factors in upper GI bleeding.
3. Graham, DY, Smith, JL. The course of patients after variceal hemorrhage.
1992; 21:149.
5. D'Amico, G, Garcia-Pagan, JC, Luca, A, Bosch, J. Hepatic vein pressure gradient
8. Sarin, SK, Lahoti, D, Saxena, SP, et al. Prevalence, classification and natural history of
9. Prediction of the first variceal hemorrhage in patients with cirrhosis of the liver and
esophageal varices. A prospective multicenter study. The North Italian Endoscopic Club
for the Study and Treatment of Esophageal Varices. N Engl J Med 1988; 319:983.
11. Kim, T, Shijo, H, Kokawa, H, et al. Risk factors for hemorrhage from gastric fundal
1992; 21:85.
14. Bosch, J, Bordas, JM, Rigau, J, et al. Noninvasive measurement of the pressure of
16. Sanyal, AJ, Fontana, RJ, Di Bisceglie, AM, et al. The prevalence and risk factors
associated with esophageal varices in subjects with hepatitis C and advanced fibrosis.