Upper gastrointestinal bleeding pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2]

Overview

The main inciting event in the pathogenesis of upper gastrointestinal (GI) bleeding is damage to mucosal injury. This mucosal injury can occur at various levels of GI tract. If the damage and bleeding is confined up to ligament of Treitz, it is defined as upper GI bleeding. Regardless of etiology, if the balance of gastric acid secretion and mucosal defenses is disrupted, acid interacts with the epithelium to cause damage.

Pathophysiology

Blood Supply of Foregut

The digestive system is supplied by the celiac artery. The celiac artery is the first major branch from the abdominal aorta, and is the only major artery that supplies the digestive organs.^[1]^[2]^[3]^[4]^[5]^[6]^[7]

Foregut		Blood supply
Esophagus	Upper esophageal sphincter Cervical esophagus	Inferior thyroid artery
	Thoracic esophagus	Aortic esophageal arteries or branches of the bronchial arteries
	Distal esophagus Lower esophageal sphincter	Left gastric artery and left phrenic artery
Stomach	Lesser curvature	Right and left gastric arteries
	Greater curvature	Right and left gastroepiploic arteries
	Gastric fundus	Short gastric arteries
Duodenum	First and second parts	Gastroduodenal artery (GDA) and Superior pancreaticoduodenal artery
Duodenum	Third and fourth parts	Inferior pancreaticoduodenal artery

Blood supply of stomach
Source: By Mikael Häggström.https://commons.wikimedia.org/w/index.php?curid=3416062

Mucosal barrier

The gastric mucosa is protected from the acidic environment by mucus, bicarbonate, prostaglandins, and blood flow.^[8]^[9]^[10]
This mucosal barrier consists of three protective components which include:
- Layer of epithelial cell lining.
- Layer of mucus, secreted by surface epithelial cells and foveolar cells.
- Layer of bicarbonate ions, secreted by the surface epithelial cells.

Diagram of alkaline Mucous layer in stomach with mucosal defense mechanisms
**Source**: By M•Komorniczak (http://creativecommons.org/licenses/by/3.0)], via Wikimedia Commons

The following table demonstrates the defense mechanisms of gastric mucosal barrier:^[11]

Defense mechanisms of gastric mucosal barrier
Mucus layer	Forms a protective gel-like coating over the entire gastric mucosal surface
Epithelial layer	Epithelial cell layer are bound by tight junctions that repel fluids
Bicarbonate ions	Neutralize acids

Pathogenesis

The main inciting event in the pathogeneis of upper GI bleeding is damage to mucosal injury. This mucosal injury can occur at various levels of GI tract. If the damage and bleeding is confined up to ligament of Treitz, it is defined as upper GI bleeding.^[12]^[13]

Etiology	Frequency of occurance
Peptic ulcer disease	50%
Variceal bleeding	20%
Esophagitis, gastritis, and duodenitis	10-15%
Mallory-Weiss tear	15%
Malignancy	3-5%
Arteriovenous malformation	<3%
Gastric antral vascular ectasia	<1%
Dieulafoy lesion	<1%

Regardless of etiology, if the balance of gastric acid secretion and mucosal defenses is disrupted, acid interacts with the epithelium to cause damage.^[14]^[15]^[16]
- Varices are large, tortuous veins and protrude into the lumen, rupturing.^[17]
- Helicobacter pylori disrupts the mucosal barrier and causes inflammation of the mucosa of the stomach and duodenum.^[18]^[19]
- As the ulcer progresses beyond the mucosa to the submucosa the inflammation causes weakening and necrosis of arterial walls, leading to pseudoaneurysm formation followed by rupture and hemorrhage.^[20]
- NSAIDs inhibit cyclooxygenase, leading to impaired mucosal defenses by decreasing mucosal prostaglandin synthesis.^[21]
- During stress, there is acid hypersecretion; therefore, the breakdown of mucosal defenses leads to injury of the mucosa and subsequent bleeding.
- Mucosal defects along with dilated and tortuous vessels in dieulafoy lesion put them at risk for rupture because of necrosis of the arterial wall from exposure to gastric acid.^[22]^[23]^[24]^[25]

NSAIDS

Inhibits cyclooxygenase pathway

COX-1

COX-2

Reduced
mucosal blood flow

Reduced
mucosal and
bicarbonate secreation

Impaired
platelet aggregation

Reduced
angiogenesis

Increased
leucocyte adherence

Impaired defence
Impaired healing

Mucosal Injury

Gross and Microscopic Pathology

		Gross Pathology	Microscopic Pathology
Varices		Large and tortuous veins that protrude into the lumen	Varices may be difficult to demonstrate in surgical specimens
Mallory-Weiss Tear^[26]		Isolated or multiple cleft like mucosal defects	Defects in the esophageal squamous mucosa Cells of acute inflammation Multiple ruptured blood vessels in the lamina propria or submucosa Prior lacerations may show various degrees of healing Granulation tissue Fibrosis^[26] Epithelial regeneration
Esophagitis^[27]	Herpes esophagitis	Shallow ulcers Sharp and raised edges Normal intervening erythematous mucosa	Ground glass inclusion bodies
	Cytomegalovirus esophagitis	Superficial ulcers Well-circumscribed	Intranuclear inclusions CMV infects mesenchymal cells in the lamina propria and submucosa
	Fungal esophagitis	Erythematous Hyperemic Friable Discrete and raised white plaque	Neutrophils within the squamous epithelium
	Pill esophagitis	Discrete ulcers	Not specific and include: Necrosis Eosinophilic infiltrate
	Toxic esophagitis	Mucosal erythema Edema Hemorrhage Necrosis	Acid injury: Coagulative necrosis Eschar Alkaline injury: Liquefactive necrosis Cells of acute inflammation Abundant granulation tissue
Gastroesophageal Reflux Disease^[28]		Mucosal erythema Edema	Basal cell hyperplasia Elongation of the lamina propria papillae Mixed intraepithelial inflammation Neutrophils, eosinophils, and lymphocytes Squamous cell degeneration
Barrett Esophagus^[29]		Mucosal erythema Edema	Columnar metaplasia Mucinous columnar cells Goblet cells, and enterocyte-like cells, among others. Cells of acute inflammation
Acute Gastritis		Mucosal hyperemia associated with: Bleeding Erosions Ulcers	Dilation and congestion of mucosal capillaries, edema, and hemorrhage in the lamina propria Ischemic-type changes such as Degenerated and necrotic epithelium Fibrinoid necrosis Adherent fibrinopurulent debris
Gastric Ulcers^[30]		Solitary, typically less than 2 cm in diameter, and have sharply defined borders. The ulcer edges are usually flat, and the base of the ulcer usually appears smooth. The presence of a radiating pattern of rugal folds is characteristic of peptic ulcers	Fibrinopurulent debris Necrosis Granulation tissue
Portal Hypertensive Gastropathy^[31]		Mosaic pattern of congestion Most commonly involves the fundus	Dilation, tortuosity, and thickening of small submucosal arteries and veins. Mucosal capillaries may also show congestion, dilation, and proliferation.
Gastric Antral Vascular Ectasia^[31]		Linear pattern of mucosal congestion in the antrum termed “watermelon stomach	Antral biopsies show: Congestion Dilated mucosal capillaries Vascular microthrombi The mucosa also shows: Foveolar hyperplasia Fibromuscular hyperplasia Edema and regenerative changes
Reactive (Chemical) Gastropathy		Edema Surface erosions Polypoid changes, and friability	The mucosa shows: Congestion Edema Fibromuscular hyperplasia Foveolar hyperplasia
Peptic Disease		Normal/slightly edematous mucosa Increased friability, erosions, and ulcers	Increased plasma cells Neutrophilic infiltrate Villous blunting The surface epithelium usually shows mucous cell (pseudopyloric) metaplasia
Ischemia		Hypoperfused ulcers	Acute ischemia Mucosal edema Congestion Coagulative necrosis Chronic ischemia Fibrosis Strictures
Structural Abnormalities of Blood Vessels^[32]		Large-caliber artery within the submucosa	Dilated venules and arteriole in direct communication with each other
Inflammatory Bowel Disease		---	Lymphoplasmacytic infiltrate with numerous neutrophils

References

↑ Feldman SE (1970). "Blood supply to stomach". Calif Med. 112 (4): 55. PMC 1501289. PMID 18730308.
↑ Granger DN, Holm L, Kvietys P (2015). "The Gastrointestinal Circulation: Physiology and Pathophysiology". Compr Physiol. 5 (3): 1541–83. doi:10.1002/cphy.c150007. PMID 26140727.
↑ Geboes K, Geboes KP, Maleux G (2001). "Vascular anatomy of the gastrointestinal tract". Best Pract Res Clin Gastroenterol. 15 (1): 1–14. doi:10.1053/bega.2000.0152. PMID 11355897.
↑ Varga F, Csáky TZ (1976). "Changes in the blood supply of the gastrointestinal tract in rats with age". Pflugers Arch. 364 (2): 129–33. PMID 986621.
↑ Matuchansky C, Bernier JJ (1973). "[Prostaglandins and the digestive tract]". Biol Gastroenterol (Paris) (in French). 6 (3): 251–68. PMID 4599528.
↑ Radbil' OS (1974). "[Prostaglandins and the digestive system organs]". Ter. Arkh. (in Russian). 46 (4): 6–14. PMID 4372738.
↑ Robert A (1980). "Prostaglandins and digestive diseases". Adv Prostaglandin Thromboxane Res. 8: 1533–41. PMID 6990725.
↑ Hills BA, Butler BD, Lichtenberger LM (1983). "Gastric mucosal barrier: hydrophobic lining to the lumen of the stomach". Am. J. Physiol. 244 (5): G561–8. PMID 6846549.
↑ Clamp JR, Ene D (1989). "The gastric mucosal barrier". Methods Find Exp Clin Pharmacol. 11 Suppl 1: 19–25. PMID 2657286.
↑ Werther JL (2000). "The gastric mucosal barrier". Mt. Sinai J. Med. 67 (1): 41–53. PMID 10677782.
↑ Forssell H (1988). "Gastric mucosal defence mechanisms: a brief review". Scand. J. Gastroenterol. Suppl. 155: 23–8. PMID 3072665.
↑ van Leerdam ME (2008). "Epidemiology of acute upper gastrointestinal bleeding". Best Pract Res Clin Gastroenterol. 22 (2): 209–24. doi:10.1016/j.bpg.2007.10.011. PMID 18346679.
↑ Boonpongmanee S, Fleischer DE, Pezzullo JC, Collier K, Mayoral W, Al-Kawas F, Chutkan R, Lewis JH, Tio TL, Benjamin SB (2004). "The frequency of peptic ulcer as a cause of upper-GI bleeding is exaggerated". Gastrointest. Endosc. 59 (7): 788–94. PMID 15173790.
↑ Gartner AH (1976). "Aspirin-induced gastritis and gastrointestinal bleeding". J Am Dent Assoc. 93 (1): 111–7. PMID 6499.
↑ Iwamoto J, Saito Y, Honda A, Matsuzaki Y (2013). "Clinical features of gastroduodenal injury associated with long-term low-dose aspirin therapy". World J. Gastroenterol. 19 (11): 1673–82. doi:10.3748/wjg.v19.i11.1673. PMC 3607744. PMID 23555156.
↑ Hawkey CJ (1996). "Non-steroidal anti-inflammatory drug gastropathy: causes and treatment". Scand. J. Gastroenterol. Suppl. 220: 124–7. PMID 8898449.
↑ Quan S, Yang H, Tanyingoh D, Villeneuve PJ, Stieb DM, Johnson M, Hilsden R, Madsen K, van Zanten SV, Novak K, Lang E, Ghosh S, Kaplan GG (2015). "Upper gastrointestinal bleeding due to peptic ulcer disease is not associated with air pollution: a case-crossover study". BMC Gastroenterol. 15: 131. doi:10.1186/s12876-015-0363-6. PMC 4604641. PMID 26467538.
↑ Quan, C (2002). "Management of peptic ulcer disease not related to Helicobacter pylori or NSAIDs". The American Journal of Gastroenterology. 97 (12): 2950–2961. doi:10.1016/S0002-9270(02)05485-0. ISSN 0002-9270.
↑ Malfertheiner, Peter; Chan, Francis KL; McColl, Kenneth EL (2009). "Peptic ulcer disease". The Lancet. 374 (9699): 1449–1461. doi:10.1016/S0140-6736(09)60938-7. ISSN 0140-6736.
↑ Quan S, Frolkis A, Milne K, Molodecky N, Yang H, Dixon E, Ball CG, Myers RP, Ghosh S, Hilsden R, van Zanten SV, Kaplan GG (2014). "Upper-gastrointestinal bleeding secondary to peptic ulcer disease: incidence and outcomes". World J. Gastroenterol. 20 (46): 17568–77. doi:10.3748/wjg.v20.i46.17568. PMC 4265619. PMID 25516672.
↑ Xi B, Jia JJ, Lin BY, Geng L, Zheng SS (2016). "Peptic ulcers accompanied with gastrointestinal bleeding, pylorus obstruction and cholangitis secondary to choledochoduodenal fistula: A case report". Oncol Lett. 11 (1): 481–483. doi:10.3892/ol.2015.3908. PMC 4727103. PMID 26870237.
↑ Stern AI, Korman MG, Hunt PS, Hansky J, Hillman HS, Schmidt GT (1979). "The Mallory-Weiss lesion as a cause of upper gastrointestinal bleeding". Aust N Z J Surg. 49 (1): 13–8. PMID 313784.
↑ Katz PO, Salas L (1993). "Less frequent causes of upper gastrointestinal bleeding". Gastroenterol. Clin. North Am. 22 (4): 875–89. PMID 8307643.
↑ Sabljak P, Velicković D, Stojakov D, Bjelović M, Ebrahimi K, Spica B, Sljukić V, Pesko P (2007). "[Less frequent causes of upper gastrointestinal bleeding]". Acta Chir Iugosl. 54 (1): 119–23. PMID 17633871.
↑ Depolo A, Dobrila-Dintinjana R, Uravi M, Grbas H, Rubini M (2001). "[Upper gastrointestinal bleeding - Review of our ten years results]". Zentralbl Chir (in German). 126 (10): 772–6. doi:10.1055/s-2001-18265. PMID 11727185.
↑ ^26.0 ^26.1 Renoult E, Biava MF, Aimone-Gastin I, Aouragh F, Hestin D, Kures L, Kessler M (1992). "Evolution and significance of Toxoplasma gondii antibody titers in kidney transplant recipients". Transplant. Proc. 24 (6): 2754–5. PMID 1465928.
↑ Rosołowski M, Kierzkiewicz M (2013). "Etiology, diagnosis and treatment of infectious esophagitis". Prz Gastroenterol. 8 (6): 333–7. doi:10.5114/pg.2013.39914. PMC 4027832. PMID 24868280.
↑ Pandit S, Boktor M, Alexander JS, Becker F, Morris J (2017). "Gastroesophageal reflux disease: A clinical overview for primary care physicians". Pathophysiology. doi:10.1016/j.pathophys.2017.09.001. PMID 28943113.
↑ Rajendra S, Sharma P (2017). "Barrett Esophagus and Intramucosal Esophageal Adenocarcinoma". Hematol. Oncol. Clin. North Am. 31 (3): 409–426. doi:10.1016/j.hoc.2017.01.003. PMID 28501084.
↑ Drini M (2017). "Peptic ulcer disease and non-steroidal anti-inflammatory drugs". Aust Prescr. 40 (3): 91–93. doi:10.18773/austprescr.2017.037. PMC 5478398. PMID 28798512.
↑ ^31.0 ^31.1 Garg H, Gupta S, Anand AC, Broor SL (2015). "Portal hypertensive gastropathy and gastric antral vascular ectasia". Indian J Gastroenterol. 34 (5): 351–8. doi:10.1007/s12664-015-0605-0. PMID 26564121.
↑ Gordon FH, Watkinson A, Hodgson H (2001). "Vascular malformations of the gastrointestinal tract". Best Pract Res Clin Gastroenterol. 15 (1): 41–58. doi:10.1053/bega.2000.0155. PMID 11355900.

Template:WikiDoc Sources

[pmid18730308-1] Feldman SE (1970). "Blood supply to stomach". Calif Med. 112 (4): 55. PMC 1501289. PMID 18730308.

[pmid26140727-2] Granger DN, Holm L, Kvietys P (2015). "The Gastrointestinal Circulation: Physiology and Pathophysiology". Compr Physiol. 5 (3): 1541–83. doi:10.1002/cphy.c150007. PMID 26140727.

[pmid11355897-3] Geboes K, Geboes KP, Maleux G (2001). "Vascular anatomy of the gastrointestinal tract". Best Pract Res Clin Gastroenterol. 15 (1): 1–14. doi:10.1053/bega.2000.0152. PMID 11355897.

[pmid986621-4] Varga F, Csáky TZ (1976). "Changes in the blood supply of the gastrointestinal tract in rats with age". Pflugers Arch. 364 (2): 129–33. PMID 986621.

[pmid4599528-5] Matuchansky C, Bernier JJ (1973). "[Prostaglandins and the digestive tract]". Biol Gastroenterol (Paris) (in French). 6 (3): 251–68. PMID 4599528.

[pmid4372738-6] Radbil' OS (1974). "[Prostaglandins and the digestive system organs]". Ter. Arkh. (in Russian). 46 (4): 6–14. PMID 4372738.

[pmid6990725-7] Robert A (1980). "Prostaglandins and digestive diseases". Adv Prostaglandin Thromboxane Res. 8: 1533–41. PMID 6990725.

[pmid6846549-8] Hills BA, Butler BD, Lichtenberger LM (1983). "Gastric mucosal barrier: hydrophobic lining to the lumen of the stomach". Am. J. Physiol. 244 (5): G561–8. PMID 6846549.

[pmid2657286-9] Clamp JR, Ene D (1989). "The gastric mucosal barrier". Methods Find Exp Clin Pharmacol. 11 Suppl 1: 19–25. PMID 2657286.

[pmid10677782-10] Werther JL (2000). "The gastric mucosal barrier". Mt. Sinai J. Med. 67 (1): 41–53. PMID 10677782.

[pmid3072665-11] Forssell H (1988). "Gastric mucosal defence mechanisms: a brief review". Scand. J. Gastroenterol. Suppl. 155: 23–8. PMID 3072665.

[pmid18346679-12] van Leerdam ME (2008). "Epidemiology of acute upper gastrointestinal bleeding". Best Pract Res Clin Gastroenterol. 22 (2): 209–24. doi:10.1016/j.bpg.2007.10.011. PMID 18346679.

[pmid15173790-13] Boonpongmanee S, Fleischer DE, Pezzullo JC, Collier K, Mayoral W, Al-Kawas F, Chutkan R, Lewis JH, Tio TL, Benjamin SB (2004). "The frequency of peptic ulcer as a cause of upper-GI bleeding is exaggerated". Gastrointest. Endosc. 59 (7): 788–94. PMID 15173790.

[pmid6499-14] Gartner AH (1976). "Aspirin-induced gastritis and gastrointestinal bleeding". J Am Dent Assoc. 93 (1): 111–7. PMID 6499.

[pmid23555156-15] Iwamoto J, Saito Y, Honda A, Matsuzaki Y (2013). "Clinical features of gastroduodenal injury associated with long-term low-dose aspirin therapy". World J. Gastroenterol. 19 (11): 1673–82. doi:10.3748/wjg.v19.i11.1673. PMC 3607744. PMID 23555156.

[pmid8898449-16] Hawkey CJ (1996). "Non-steroidal anti-inflammatory drug gastropathy: causes and treatment". Scand. J. Gastroenterol. Suppl. 220: 124–7. PMID 8898449.

[pmid26467538-17] Quan S, Yang H, Tanyingoh D, Villeneuve PJ, Stieb DM, Johnson M, Hilsden R, Madsen K, van Zanten SV, Novak K, Lang E, Ghosh S, Kaplan GG (2015). "Upper gastrointestinal bleeding due to peptic ulcer disease is not associated with air pollution: a case-crossover study". BMC Gastroenterol. 15: 131. doi:10.1186/s12876-015-0363-6. PMC 4604641. PMID 26467538.

[Quan2002-18] Quan, C (2002). "Management of peptic ulcer disease not related to Helicobacter pylori or NSAIDs". The American Journal of Gastroenterology. 97 (12): 2950–2961. doi:10.1016/S0002-9270(02)05485-0. ISSN 0002-9270.

[MalfertheinerChan2009-19] Malfertheiner, Peter; Chan, Francis KL; McColl, Kenneth EL (2009). "Peptic ulcer disease". The Lancet. 374 (9699): 1449–1461. doi:10.1016/S0140-6736(09)60938-7. ISSN 0140-6736.

[pmid25516672-20] Quan S, Frolkis A, Milne K, Molodecky N, Yang H, Dixon E, Ball CG, Myers RP, Ghosh S, Hilsden R, van Zanten SV, Kaplan GG (2014). "Upper-gastrointestinal bleeding secondary to peptic ulcer disease: incidence and outcomes". World J. Gastroenterol. 20 (46): 17568–77. doi:10.3748/wjg.v20.i46.17568. PMC 4265619. PMID 25516672.

[pmid26870237-21] Xi B, Jia JJ, Lin BY, Geng L, Zheng SS (2016). "Peptic ulcers accompanied with gastrointestinal bleeding, pylorus obstruction and cholangitis secondary to choledochoduodenal fistula: A case report". Oncol Lett. 11 (1): 481–483. doi:10.3892/ol.2015.3908. PMC 4727103. PMID 26870237.

[pmid313784-22] Stern AI, Korman MG, Hunt PS, Hansky J, Hillman HS, Schmidt GT (1979). "The Mallory-Weiss lesion as a cause of upper gastrointestinal bleeding". Aust N Z J Surg. 49 (1): 13–8. PMID 313784.

[pmid8307643-23] Katz PO, Salas L (1993). "Less frequent causes of upper gastrointestinal bleeding". Gastroenterol. Clin. North Am. 22 (4): 875–89. PMID 8307643.

[pmid17633871-24] Sabljak P, Velicković D, Stojakov D, Bjelović M, Ebrahimi K, Spica B, Sljukić V, Pesko P (2007). "[Less frequent causes of upper gastrointestinal bleeding]". Acta Chir Iugosl. 54 (1): 119–23. PMID 17633871.

[pmid11727185-25] Depolo A, Dobrila-Dintinjana R, Uravi M, Grbas H, Rubini M (2001). "[Upper gastrointestinal bleeding - Review of our ten years results]". Zentralbl Chir (in German). 126 (10): 772–6. doi:10.1055/s-2001-18265. PMID 11727185.

[pmid1465928-26] 26.0 ^26.1 Renoult E, Biava MF, Aimone-Gastin I, Aouragh F, Hestin D, Kures L, Kessler M (1992). "Evolution and significance of Toxoplasma gondii antibody titers in kidney transplant recipients". Transplant. Proc. 24 (6): 2754–5. PMID 1465928.

[pmid24868280-27] Rosołowski M, Kierzkiewicz M (2013). "Etiology, diagnosis and treatment of infectious esophagitis". Prz Gastroenterol. 8 (6): 333–7. doi:10.5114/pg.2013.39914. PMC 4027832. PMID 24868280.

[pmid28943113-28] Pandit S, Boktor M, Alexander JS, Becker F, Morris J (2017). "Gastroesophageal reflux disease: A clinical overview for primary care physicians". Pathophysiology. doi:10.1016/j.pathophys.2017.09.001. PMID 28943113.

[pmid28501084-29] Rajendra S, Sharma P (2017). "Barrett Esophagus and Intramucosal Esophageal Adenocarcinoma". Hematol. Oncol. Clin. North Am. 31 (3): 409–426. doi:10.1016/j.hoc.2017.01.003. PMID 28501084.

[pmid28798512-30] Drini M (2017). "Peptic ulcer disease and non-steroidal anti-inflammatory drugs". Aust Prescr. 40 (3): 91–93. doi:10.18773/austprescr.2017.037. PMC 5478398. PMID 28798512.

[pmid26564121-31] 31.0 ^31.1 Garg H, Gupta S, Anand AC, Broor SL (2015). "Portal hypertensive gastropathy and gastric antral vascular ectasia". Indian J Gastroenterol. 34 (5): 351–8. doi:10.1007/s12664-015-0605-0. PMID 26564121.

[pmid11355900-32] Gordon FH, Watkinson A, Hodgson H (2001). "Vascular malformations of the gastrointestinal tract". Best Pract Res Clin Gastroenterol. 15 (1): 41–58. doi:10.1053/bega.2000.0155. PMID 11355900.

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