Distinctive aspects of peptic ulcer disease, Dieulafoy's lesion, and Mallory-Weiss syndrome in patients with advanced alcoholic liver disease or cirrhosis

Table 1 Differential diagnosis of acute upper gastrointestinal bleeding in an alcoholic with advanced liver disease

Bleeding lesion	Endoscopic appearance	Pathophysiology	Nonsurgical treatment	Ref.
Etiologies related to portal hypertension
Esophageal varices	Serpiginous, bluish-grey, vessels protruding from the mucosa into the lumen that typically are largest just above the gastroesophageal junction	Varices provide a conduit for venous blood blocked from traversing through the liver because of cirrhosis to return to the heart	Endoscopy: variceal banding, variceal sclerotherapy	Garcia-Tsao et al[13], Beppu et al[14]
			Angiography: TIPS
			Other: balloon tamponade, octreotide
Gastric varices	Serpiginous, bluish-grey, vessels protruding from the mucosa into the lumen that are most commonly located in the gastric cardia, fundus or body	Varices provide a conduit for venous blood blocked from traversing through the liver because of cirrhosis to return to the heart	Angiography: TIPS Other: balloon tamponade, octreotide Endoscopy: cyanoacrylate injection therapy	Garcia-Pagán et al[15]
		Formation of gastric varices may be promoted by endoscopic obliteration of esophageal varices
Duodenal varices	Resemble esophageal varices in endoscopic appearance, but are located within duodenum	Rare site of varices which may be promoted by prior esophageal variceal banding or sclerotherapy and prior duodenal surgery	Endoscopy: variceal banding or sclerotherapy	Copelan et al[16], Matsui et al[17]
			Angiography:
			TIPS, angiographic occlusion therapy by embolization or balloon occlusion
Portal hypertensive gastropathy	Mosaic or snake-skin appearance of gastric mucosa, especially of the gastric fundus and proximal gastric body, due to dilated, ectatic, superficial mucosal vessels	Network of microcirculation that drains venous blood blocked from passing through the cirrhotic liver to return to the left atrium	TIPS	Patwardhan et al[18], Thuluvath et al[19]
Etiologies possibly related to portal hypertension
Gastric antral vascular ectasia	Intensely erythematous streaks on longitudinal folds oriented towards the pylorus in the antrum	May be related to stretch of antral vessels from duodenal bulb prolapse. Vascular engorgement from portal hypertension or from hormonal abnormalities (e.g., hyperestrogenemia with cirrhosis) may also contribute to lesion pathogenesis	Endoscopic therapy: APC, thermocoagulation, electrocoagulation, or radiofrequency ablation.	McGorisk et al[20], Payen et al[21]
Etiologies possibly related to alcoholism or advanced liver disease
Peptic ulcer disease	Focal ulcer: (depressed) crater covered by mucopurulent material	Major causes in general population include H. pylori infection or NSAID use. Idiopathic PUD is increasingly noted. Gastric infections or gastric malignancy may mimic PUD. Pathogenesis of PUD in ALD and cirrhosis discussed in text	Endoscopic therapy: discussed in text	Siringo et al[22], Vergara et al[23], Kamalaporn et al[24], D’Amico et al[25]
Mallory- Weiss tear	Longitudinally oriented erythematous tear or crack in the mucosa that straddles the gastroesophageal junction	Laceration due to mucosal trauma from retching or vomiting. Frequently associated with binge drinking or chronic alcoholism	Endoscopic therapy: discussed in text	Paquet et al[26], Schuman et al[27], Jensen et al[28]
Dieulafoy’s lesion	Elevated, pigmented spot that projects into the lumen from the mucosal surface without surrounding ulceration	Caliber-persistent artery near mucosal surface can erupt through thin overlying mucosal cells and cause bleeding	Endoscopic therapy: injection therapy, band ligation, electrocoagulation, APC	Cappell[29], Jeon et al[30], Nojkov et al[31]
			Angiography: local embolization
			Surgery: wedge resection

TIPS: Transjugular intrahepatic portosystemic shunt; APC: Argon plasma coagulation; PUD: Peptic ulcer disease; H. pylori: Helicobacter pylori; ALD: Alcoholic liver disease; NSAID: Nonsteroidal anti-inflammatory drug.

Table 2 Clinical characteristics of patients with cirrhosis presenting with upper gastrointestinal bleeding unrelated to portal hypertension predominantly from peptic ulcers

Ref.	No. of parents	ALD (%)	Mean age	Prevalence of PUB (%)	Mortality (%)	Predictors of mortality	Rebleeding rate (%)	Length of follow-up
González-González et al[52]	160	“Most”	56.5 ± 14.4	50.6	13.8	High BUN, Low albumin, Active ulcer bleeding, Need for endoscopic therapy, Cryptogenic cirrhosis	1.9	NA
Seo et al[61]	107	43	55.8 ± 11	60	14.5	Failure to control bleeding, High creatinine, High AST, High Child-Pugh score, PVT	9.3	6 wk
Morsy et al[62]	93	NA	55.3 ± 11.2	30	14	Bacterial infection, Shock, Early rebleeding, Low albumin, Low hemoglobin, Endoscopic therapy	4.3	Short-term (in-hospital)
Siringo et al[22]	85	40	62 ± 12	41	231	Low hemoglobin,	0	6 wk
						Encephalopathy
						Alcoholism, High bilirubin, PVT, High Child-Pugh score,
						High AST/ALT levels, HCC
Rudler et al[63]	29	24 (83)	55.0 ± 9.0	29 (100)2	1 (3)	NA	2 (7)	30 d

¹Mortality from all etiologies of non-variceal GI bleeding;

²PUD presence - study inclusion criteria. BUN: Blood urea nitrogen; PVT: Portal vein thrombosis; AST/ALT: Aspartate aminotransferase/alanine aminotransferase; HCC: Hepatocellular carcinoma; NA: Not available.

Table 3 Key clinical findings regarding peptic ulcer disease in patients with alcoholic cirrhosis

Key finding
Increased prevalence of PUD in patients with cirrhosis. Most common etiology of non-variceal hemorrhage in cirrhotics
Advanced cirrhosis (Child-Pugh stage C) more strongly associated with PUD than early cirrhosis (Child-Pugh stage A)
Most patients with PUD associated with cirrhosis are asymptomatic
Patients with cirrhosis are more likely to bleed from PUD than other patients with PUD
Higher frequency of complications from bleeding PUD in patients with cirrhosis
Higher rate of re-bleeding from PUD in cirrhotics
Alcohol impairs ulcer healing and decreases patient compliance with anti-ulcer therapy
Higher mortality from PUB in cirrhotics compared to non-cirrhotics
Cirrhotic patients with PUD do not have a higher rate of H. pylori infection than non-cirrhotics with PUD

PUD: Peptic ulcer disease; PUB: Peptic ulcer bleeding; H. pylori: Helicobacter pylori.

Table 4 Key clinical findings in Dieulafoy’s Lesion associated with chronic liver disease

Key findings	Rationale	Ref.
Typically presents with acute severe bleeding	Micropulsatile bleeding produced by rent in an arteriole which is under high pressure	Nojkov et al[31], Luis et al[94]
Bleeding typically painless	Primary vascular event (bursting of a persistent-caliber vessel) without associated inflammation or ulceration	Cappell[29]
Appears at endoscopy as an elevated pigmented protuberance with minimal surrounding erosion and no ulceration	Formed by a caliber-persistent artery that erupts through superficial overlying cells on mucosal surface	Nojkov et al[31], Lee et al[93]
Lesion most commonly located in stomach, typically within 6 cm below the gastroesophageal junction along the lesser curve	This gastric region is not perfused by a submucosal plexus, but instead is perfused directly from tributaries of the right and left gastric arteries	Cappell et al[29], Fockens et al[90], Lee et al[95]
Often (up to 30% of cases) missed at initial esophagogastroduodenoscopy (EGD)	Missed at EGD because lesion is small and inconspicuous	Nojkov et al[31], Chung et al[96]
Incidence of 1.5% among general population of patients with upper GI bleeding		Fockens et al[90], Chaer et al[97]
High (25%) mortality if untreated at EGD, which is reduced to about 10% with endoscopic therapy	High risk of rebleeding if not treated endoscopically. Rebleeding is frequently massive	Romãozinho et al[98]
Dieulafoy’s lesion may be associated with cirrhosis		Akhras et al[91], Baettig et al[92]
Bleeding from a Dieulafoy’s lesion is associated with alcoholism	Alcohol may precipitate DL rupture manifesting as GI bleeding by weakening the dilated (caliber-persistent) arteriolar wall in Dieulafoy’s lesion	Baettig et al[92], Lee et al[95]

GI: Gastrointestinal; EGD: Esophagogastroduodenoscopy.

Table 5 Summary of clinical features of acute gastrointestinal bleeding from Mallory-Weiss syndrome in patients with underlying liver disease

Key findings	Ref.
Findings generally associated with Mallory-Weiss syndrome
Characterized by longitudinally oriented mucosal lacerations in the distal esophagus or very proximal stomach	Knauer[101]
Accounts for about 5% of acute upper GI bleeding	Michel et al[100]
Mortality of bleeding from Mallory-Weiss syndrome is only about 3%-5%. Risk factors for mortality include age > 65 yr and significant comorbidities	Ljubičić et al[105]
Findings associated with Mallory-Weiss syndrome associated with alcoholism
MWS strongly associated with alcoholism	Knauer[101]
MWS very frequently (40%-80%) associated with alcoholism or recent binge drinking	Watts et al[106]
Overall prevalence of bleeding from MWS in cirrhosis is up to 10%	del Olmo et al[38], Feng et al[82]
Alcoholics with portal hypertension have higher prevalence of bleeding from MWS (up to 16%)	Paquet et al[26], Schuman et al[27]
MWS may be the first bleeding episode in > 1/3 (37%) of these patients
Patients with cirrhosis have more severe bleeding from MWS and more likely to rebleed from MWS (compared to non-cirrhotics)	Schuman et al[27], Jensen et al[28], Kim et al[107]
Re-bleeding risk particularly high in alcoholics
Contradictory data on effect of portal hypertension on severity of bleeding from MWS	Schuman et al[27], Jensen et al[28]
Bleeding from MWS can precipitate liver failure with its attendant mortality in about 3% of patients with alcoholic cirrhosis	del Olmo et al[38]

GI: Gastrointestinal; MWS: Mallory-Weiss syndrome.

Table 6 Special considerations in therapy for alcoholics with liver disease presenting with acute upper gastrointestinal bleeding

Recommended clinical practice	Rationale	Ref.
Consider early intubation for severe upper GI bleeding in a patient with alcoholism or alcoholic cirrhosis	These patients are at higher risk of aspiration because variceal bleeding related to alcoholism or cirrhosis is frequently massive, arises from the esophagus which is much closer to the trachea than other types of gastroduodenal bleeding; and the patient may be obtunded from hepatic encephalopathy from cirrhosis	Herrera[109], Rudolph et al[110]
Avoid sedatives and narcotics in patients with advanced liver disease	May precipitate hepatic encephalopathy from cirrhosis	Bamji et al[120], Prabhakar et al[121]
Monitor for hepatic encephalopathy	Patients with advanced cirrhosis at risk for hepatic encephalopathy	Rahimi et al[122]
Monitor for delirium tremens	Acute alcoholic withdrawal in hospital can induce delirium tremens	Ferguson et al[123], Holloway et al[124]
Avoid over-transfusion (maintain hemoglobin level at about 8 gm/dL)	Over-transfusion may exacerbate variceal bleeding by increasing portal hypertension	Herrera[109]
Patients often have thrombocytopenia which may contribute to the bleeding	Thrombocytopenia due to splenic sequestration from splenomegaly from portal hypertension and from direct alcohol toxicity to bone marrow	Pradella et al[125]
Patients often have a prolonged INR which may contribute to the bleeding	INR prolonged due to inadequate synthesis of liver-dependent clotting factors, such as factor V, due to advanced liver disease	Lata et al[126]
Administer thiamine	Prevent Wernicke’s syndrome from thiamine deficiency which is common in alcoholics	Hack et al[127]
Monitor for electrolyte abnormalities which may be more prominent in alcoholics		Knochel[117]
Consider early (urgent) esophagogastroduodenoscopy	Important to distinguish esophageal variceal bleeding from other etiologies of upper GI bleeding because esophageal variceal bleeding has different therapies	Buccino et al[37], del Olmo et al[38]
Consider empiric octreotide therapy before endoscopy	Alcoholics or patients with cirrhosis frequently have GI bleeding from esophageal varices which can be treated by octreotide therapy	Ludwig et al[128]
Perform paracentesis, as necessary, to exclude spontaneous bacterial peritonitis	Patients with cirrhosis and ascites are at high risk to develop spontaneous bacterial peritonitis due to mild immunosuppression with cirrhosis	Goulis et al[119]
Administer antibiotics in the presence of acute GI bleeding in a cirrhotic patient	Empiric antibiotic therapy lowers mortality because of decreased sepsis	Bernard et al[118]
Monitor BUN and creatinine levels to detect early hepatorenal syndrome. Avoid nephrotoxic medications such as NSAIDs	At high risk for renal deterioration due to decreased renal perfusion associated with cirrhosis and hypovolemia from GI hemorrhage	Ginès et al[129]
Exclude acute portal vein thrombosis in patients who suddenly develop severe esophageal varices by abdominal imaging studies (e.g., Doppler ultrasound or CT angiography)	Portal vein thrombosis in a patient with preexistent cirrhosis may exacerbate the portal hypertension and cause acute variceal bleeding	D’Amico et al[25]

GI: Gastrointestinal; INR: International normalized ratio; BUN: Blood urea nitrogen; NSAIDs: Nonsteroidal anti-inflammatory drugs.

Table 7 Local endoscopic therapies

Injection therapies

Dilute epinephrine

Sclerotherapy

Ablation therapies

Contact methods

Thermocoagulation: heater probe

Electrocoagulation: BICAP (bipolar electrocoagulation probe), Gold Probe

Noncontact methods

APC (argon plasma coagulation)

Mechanical therapy

Banding

Hemoclips

Endoscopic suturing

Table 8 Classification of endoscopic stigmata of recent hemorrhage for acute upper gastrointestinal bleeding from peptic ulcer disease

Endoscopic SRH	Endoscopic appearance	Endoscopic therapy	Endoscopic therapy and rationale for therapy
Major SRH
Active bleeding	Active bleeding observed at EGD	Yes	Reduction from 90% to 15% risk of ongoing bleeding with performance of endoscopic therapy
Nonbleeding visible vessel	Pigmented elevation (projection) from ulcer base, whether red, blue or gray in color	Yes	Reduction from about 50% to 15% risk of rebleeding with performance of endoscopic therapy
Intermediate SRH
Adherent clot	Focal clot that is resistant to removal by mild-to-moderate irrigation	Recommended by most endoscopists
Active oozing of blood	Active oozing observed at EGD	Generally recommended	May reduce risk of rebleeding from 28% to 15% with endoscopic therapy
Minor SRH
Flat pigmented spot	Pigmented spot, whether red, blue or gray, which lies flat on the ulcer base	No	Low risk of rebleeding of about 13% with medical therapy alone
No SRH
Homogeneous, clean-based ulcer	Simple ulcer with no bleeding, no adherent clot, no visible vessel and no pigmented spot	No	Extremely low risk of rebleeding of about 4% that does not warrant the risks of endoscopic therapy

Adapted from Cappell[135]. SRH: Stigmata of recent hemorrhage; EGD: Esophagogastroduodenoscopy.

Table 9 Efficacy of endoscopic therapy for gastrointestinal bleeding from Dieulafoy's lesion in cirrhotics

Endoscopic procedure(Number of patients)	Hemostatictechnique	Lesion location	Study type	Follow-up	Patient outcome	Ref.
EGD (12)1	Epinephrine + Polidocanol	Stomach/duodenum	Retrospective	5 mo	No rebleeding, 3 of cirrhotic pts died from hepatic decompensation within 5 mo	Baettig et al[92]
EGD (6)	Not reported	Stomach/duodenum	Retrospective	NA (6 yr period reviewed)	No rebleeding in 5 of 6 pts (83%), 1 pt (17%) underwent surgery for rebleeding	Akhras et al[91]
EGD (5)	Histoacryl (3)	Stomach	Retrospective	18 mo	No rebleeding	Cheng et al[159]
	Epinephrine + heater probe (2)
EGD (4)	Hemoclip	Stomach/duodenum	Prospective	54 mo	9% of whole cohort of 34 pts rebled. No data whether any of the cirrhotics rebled	Yamaguchi et al[160]
EGD (2)	Rubber band ligation	Stomach	Retrospective	30 d	No rebleeding, 1 of 2 pts died from hepatic decompensation within 30 d	Mumtaz et al[157]
EGD (1)	Argon plasma coagulation	Stomach	Retrospective	29 mo	No rebleeding	Iacopini et al[158]

¹Includes 4 patients with cirrhosis and 8 patients who actively abused alcohol. EGD: Esophagogastroduodenoscopy; pts: Patients.

Table 10 Efficacy of endoscopic therapy for gastrointestinal bleeding from Mallory-Weiss syndrome in cirrhotics

Number of patients	HemostasisTechnique	n (%) with active alcohol abuse	Time of EGD	Study type	Follow-up	Outcome	Ref.
55	Aetoxysklerol injection	40 (73)	Within 6 h	Retrospective	2 yr	No rebleeding or death	Paquet et al[26]
141	Epinephrine injection/elec-trocoagulation	6 (43)	Within 24 h	Retrospective	5 yr	No rebleeding or death2	Schuman et al[27]
7	Band ligation 4	Not reported	Within 12 h	Retrospective	5 d	No rebleeding or death	Lecleire et al[165]
	Hemoclips and epinephrine 3
3	Heater probe/Bicap electrocoagulation	3 (100)	“Urgently” after presentation	Retrospective	17 mo	Failed to control bleeding in 1/3 pts (33%)	Jensen et al[28]
1	Hemoclip and Endoscopic band ligation	1 (100)	“Emergent-ly” at presentation	Retrospective	NA	Failed to stop bleeding with both techniques; patient underwent surgery and died of liver failure 3 d after surgery	Yin et al[104]

¹Only 3 of the 14 patients treated endoscopically;

²Three deaths reported out of the overall cohort of 42 patients presenting with bleeding from MWS. None of the deaths were related to MWS or liver disease. EGD: Esophagogastroduodenoscopy; MWS: Mallory-Weiss syndrome.