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Esomeprazole is the S-isomer of omeprazole, a proton pump inhibitor (PPI) and potent inhibitor of gastric acidity used in the therapy of gastroesophageal reflux and peptic ulcer disease.  Esomeprazole therapy is associated with a low rate of transient and asymptomatic serum aminotransferase elevations and probably shares hepatotoxicity potential with omeprazole, which is a rare cause of clinically apparent liver injury.



Esomeprazole (es" oh mep' ra zole) is the S-isomer of omeprazole and exhibits delayed clearance and thus higher potency on a molar basis than omeprazole, which is a racemic mixture of both S- and R-isomers.  Like other PPIs, esomeprazole binds to and inactivates the H+/K+-ATPase of gastric parietal cells, causing inhibition of the proton pump that transports H+ into the gastric lumen, the final common step in gastric acid production.  Esomeprazole is a prodrug and is converted to the active form (sulfenic acid) in the acidic secretory canaliculi of parietal cells.  Because the inhibition is irreversible, acid secretion is suppressed for 24 to 48 hours until new proton pump molecules have been synthesized and transported to the cell membrane.  Esomeprazole was developed well after omeprazole was introduced into clinical practice and was approved for use in the United States in 2001.  The listed indications for esomeprazole include peptic ulcer disease, gastroesophageal reflux disease and prevention of stress ulcers.  Esomeprazole is available as 20 mg delayed release capsules under the brand name of Nexium.  On a molar basis, esomeprazole is more potent than omeprazole and the recommended dose in adults is 20 mg once daily, with twice daily doses for more severe cases of gastrointestinal reflux and peptic ulcer disease, and doses of up to 60 mg daily for Zollinger-Ellison syndrome.  Combinations of esomeprazole with antibiotics for 10 to 14 days are effective and recommended for eradication of H. pylori infection.  Esomeprazole is very well tolerated.  Side effects are uncommon and usually mild;  they include diarrhea, nausea, vomiting, abdominal discomfort, flatulence, skin rash, headaches and dizziness.



Despite their wide use, esomeprazole and omeprazole have only rarely been associated with hepatic injury.  In large scale, long term trials of esomeprazole, serum ALT elevations have occurred in less than 1% of patients and at rates similar to those that occur with placebo or comparator drugs.  Only a few cases of clinically apparent liver disease due to esomeprazole have been published, but more have been reported with omeprazole.  The typical characteristics of esomeprazole and omeprazole associated liver injury are a short latency (1-4 weeks), a hepatocellular pattern of serum enzyme elevations, and rapid recovery on stopping the medication.  Rash, fever and eosinophilia are rare, as is autoantibody formation.  In large case series of drug induced liver injury, esomeprazole and omeprazole have accounted for few instances of symptomatic acute liver injury. 


Likelihood score: B (rare but likely cause of drug induced liver injury).


Mechanism of Injury

The acute onset and rapid recurrence of hepatic injury with esomeprazole and omeprazole suggests a hypersensitivity reaction, but may merely reflect altered metabolism or acute toxicity of a metabolic byproduct.  The usual clinical phenotype is acute hepatic necrosis.  Esomeprazole is metabolized by hepatic CYP 2C19 and may cause drug-drug interactions with other medications metabolized by the same enzyme, but its effects of CYP 3A4 appear to be less than with omeprazole.


Outcome and Management

The mild and asymptomatic elevations in serum aminotransferase that have been observed during esomeprazole and omeprazole therapy are usually transient and may resolve, even without dose modification.  Clinically apparent liver injury due to esomeprazole, however, generally calls for prompt withdrawal of the agent.  Severe injury is uncommon and most cases resolve promptly upon withdrawal.  Acute liver failure from proton pump inhibitors has been described, but is exceedingly rare.  There is no information about cross reactivity among the various PPIs after esomeprazole hepatotoxicity, but cross reactivity with omeprazole should be assumed, and cross sensitivity to other PPIs (which share a benzimidazole structure) is likely, so that caution should be used in attempting to reintroduce another PPI after clinically apparent PPI-associated hepatic injury.

Drug Class:  Antiulcer Agents


Other Drugs in the Subclass, Proton Pump InhibitorsDexlansoprazole, Lansoprazole, Omeprazole, Pantoprazole, Rabeprazole


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Esomeprazole – Nexium®

Antiulcer Agents


Product labeling at DailyMed, National Library of Medicine, NIH

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Esomeprazole 119141-88-7 C17-H19-N3-O3-S Esomeprazole Chemical Structure

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References updated: 19 February 2018

  1. Zimmerman HJ. Proton pump inhibitors. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 720-1.  (Expert review of hepatotoxicity published in 1999 states that aminotransferase elevations occur in ~1% of PPI treated patients, but only 1 case of acute liver injury has been reported with omeprazole, none with the more recently released lansoprazole and pantoprazole).

  2. Wallace JL, Sharkey KA. Pharmacotherapy of gastric acidity, peptic ulcers, and gastroesophageal reflux disease. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1309-22.  (Textbook of pharmacology and therapeutics).

  3. Gustavsson S, Adami HO, Lööf L, Nyberg A, Nyrén O. Rapid healing of duodenal ulcers with omeprazole: Double-blind dose comparative trial. Lancet 1983; 2: 124-5. PubMed Citation  (Controlled trial of two doses of omeprazole in 32 patients with duodenal ulcer reported a high rate of ALT elevations [32%] usually within the first 1-2 weeks, resolving rapidly on withdrawal; peak value was 468 U/L).

  4. Sharma BK, Santana IA, Walt RP, Pounder RE. Omeprazole and liver function tests. Lancet 1983; 2: 346. PubMed Citation  (Letter in response to Gustavsson [1983]; among 17 patients with duodenal ulcer treated with omeprazole, none had ALT or Alk P elevations).

  5. Lööf L, Adami HO, Gustavsson S, Nyberg A, Nyrén O, Lundborg P. Omeprazole: no evidence for frequent hepatic reactions. Lancet 1984; 1: 1347-8. PubMed Citation  (Further follow up on the observation of Gustavsson [193], controlled trial of omeprazole in 60 volunteers monitored carefully for ALT elevations, found no association of drug with ALT elevations, being found in 1 of 30 on omeprazole and 2 of 30 on placebo; two patients with previous ALT elevations had no recurrence on rechallenge).

  6. Lauritsen K, Rune SJ, Bytzer P, Kelbaek H, Jensen KG, Rask-Madsen J, Bendtsen F, et al. Effect of omeprazole and cimetidine on duodenal ulcer. A double-blind comparative trial. N Engl J Med 1985; 312: 958-61. PubMed Citation  (Controlled trial of omeprazole vs cimetidine for 4 weeks in 132 patients with duodenal ulcer disease found no major side effects; one patient on omeprazole had rise of Alk P to 756 U/L, resolving with stopping therapy and 4 had minor AST elevations at the end of therapy [36-54 U/L]).

  7. Solvell L. Safety aspects of omeprazole. Scand J Gastroenterol Suppl 1986; 118: 129-35. PubMed Citation  (Careful analysis of changes in serum ALT levels during omeprazole therapy in prospective studies found little evidence of changes compared to baseline or to placebo treatment; among more than 2500 recipients, only one report of increased ALT and none of hepatitis with jaundice).

  8. Joelson S, Joelson IB, Lundborg P, Walan A, Wallander MA. Safety experience from long-term treatment with omeprazole. Digestion 1992; 51 (Suppl 1): 93-101. PubMed Citation  (Summary of adverse event profile in 2818 patients on long term omeprazole found low rate of side effects, similar in frequency to those on ranitidine or cimetidine; no mention of ALT elevations, hepatitis or jaundice).

  9. Maton PN, Vinayek R, Frucht H, McArthur KA, Miller LS, Saeed ZA, Gardner JD, et al. Long-term efficacy and safety of omeprazole in patients with Zollinger-Ellison syndrome: a prospective study. Gastroenterology 1989; 97: 827-36. PubMed Citation  (40 patients with Zollinger-Ellison syndrome were treated for 6-51 months with omeprazole in doses of 20-120 mg/day; "No patient developed a side effect that could be attributed to omeprazole").

  10. Jochem V, Kirkpatrick R, Greenson J, Brogan M, Sturgis T, Cook-Glenn C. Fulminant hepatic failure related to omeprazole. Am J Gastroenterol 1992; 87: 523-5. PubMed Citation  (62 year old with reflux not responding to ranitidine, developed pain, nausea and fatigue 17 days after starting omeprazole [bilirubin 8.6 mg/dL, ALT 9234 U/L, Alk P 254 U/L, protime >100 seconds], dying 5 days after admission and having massive centrolobular necrosis on autopsy: Case 1, omeprazole).

  11. Sauvet P, Schouler L. [Omeprazole and liver functions]. Rev Med Interne 1992; 13: 359-63. French. PubMed Citation  (Review of the pharmacokinetics and hepatic metabolism of omeprazole and discussion of potential for hepatotoxicity).

  12. Arnold R. Safety of proton pump overview. Aliment Pharmacol Ther 1994; 8 Suppl 1: 65-70. PubMed Citation  (Side effects are uncommon and no more frequent than with cimetidine and ranitidine; "Omeprazole had no clinically relevant effects of laboratory values including ... liver function").

  13. Klinkenberg-Knol EC, Festen HP, Jansen JB, Lamers CB, Nelis F, Snel P, Luckers A, et al. Long-term treatment with omeprazole for refractory reflux esophagitis: efficacy and safety. Ann Intern Med 1994; 121: 161-7. PubMed Citation  (91 patients with refractory esophagitis were treated with omeprazole [20-40 mg/day] for 3-5 years; generally well tolerated and no mention of ALT elevations or hepatotoxicity).

  14. del Rio Fernandez M, Plagaro Cordero ME, de Frutos Arribas JF, Bellido Casado J, Velicia Llanes R. [Hepatic encephalopathy related to omeprazole]. Rev Esp Enferm Dig 1997; 89: 574-5. Spanish. PubMed Citation  (49 year old with diabetes, renal transplant, cirrhosis due to hepatitis C developed disorientation and worsening hepatic encephalopathy 6 days after starting omeprazole, recovering with stopping therapy, enemas and lactulose; authors suggest that omeprazole may have precipitated worsening of liver disease and encephalopathy).

  15. d'Adamo G, Spinelli C, Forte F, Gangeri F. Omeprazole-induced acute interstitial nephritis. Ren Fail 1997; 19: 171-5. PubMed Citation  (Case of acute nephritis arising within a few weeks of starting omeprazole; no liver test abnormalities reported).

  16. Navarro JF, Gallego E, Aviles J. Recurrent severe acute hepatitis and omeprazole. Ann Intern Med 1997; 127: 1135-6. PubMed Citation  (30 year old developed abdominal pain 9 days after starting omeprazole [ALT 1294 U/L], resolving in 4 weeks and arising again 1 week after restarting [ALT 762 U/L]; no mention of bilirubin or Alk P levels).

  17. Christe C, Stoller R, Vogt N. Omeprazole-induced hepatotoxicity? A case report. Pharmacoepidemiol Drug Saf 1998; 7 Suppl 1: S41-4. PubMed Citation  (85 year old with congestive heart failure on long term omeprazole developed fatigue and worsening liver tests, [bilirubin 2.0 mg/dL, ALT 263 rising to 1236 U/L, LDH 870 to 2100 U/L, Alk P 112 U/L], improving on stopping and with mild recurrence on restarting [ALT 500 U/L], patient dying 10 days later of acute myocardial infarction and heart failure).

  18. Koury SI, Stone CK, La Charité DD. Omeprazole and the development of acute hepatitis. Eur J Emerg Med 1998; 5: 467-9. PubMed Citation  (39 year old found to have abnormal liver tests 4 weeks after starting omeprazole [bilirubin 0.6 mg/dL, ALT 262 U/L, Alk P 103 U/L], resolving within 2 weeks of stopping).

  19. Koury SI, Stone CK, La Charité DD. Acute hepatitis induced by omeprazole. Am J Emerg Med 1998; 16: 550-1. PubMed Citation  (34 year old with chronic hepatitis C and peptic ulcer disease developed abdominal pain and nausea 2 weeks after starting omeprazole [bilirubin 0.3 mg/dL, AST 1059 U/L, Alk P 149 U/L]; rapid improvement on stopping).

  20. Romero-Gómez M, Otero MA, Suárez-García E, García Díaz E, Fobelo MJ,
    Castro-Fernández M. Acute hepatitis related to omeprazole. Am J Gastroenterol 1999; 94: 1119-20. PubMed Citation  (34 year old developed jaundice 11 days after starting omeprazole [bilirubin 10.4 mg/dL, ALT 1100 U/L, Alk P 461 U/L], resolving in 6 months of stopping).

  21. Reilly JP. Safety profile of the proton-pump inhibitors. Am J Health Syst Pharm 1999; 56(23 Suppl 4): S11-7. PubMed Citation  (Review of side effects of proton pump inhibitors including long term tolerance).

  22. Martin RM, Dunn NR, Freemantle S, Shakir S. The rates of common adverse events reported during treatment with proton pump inhibitors used in general practice in England: cohort studies. Br J Clin Pharmacol 2000; 50: 366-72. PubMed Citation  (Prescription event monitoring of common side effects of omeprazole, lansoprazole and pantoprazole from the UK found low rates of diarrhea [0.18-0.39/1000 days], abdominal pain [0.17-.21], nausea [0.16-0.22], and headache [0.10-0.17]; no analysis of liver toxicities).

  23. Johnson TJ, Hedge DD. Esomeprazole: a clinical review. Am J Health Syst Pharm 2002; 59: 1333-9. PubMed Citation  (Esomeprazole is the S-isomer of omeprazole and the two are similar in tolerability; no specific discussion of hepatotoxicity).

  24. Russo MW, Galanko JA, Shrestha R, Fried MW, Watkins P. Liver transplantation for acute liver failure from drug-induced liver injury in the United States. Liver Transpl 2004; 10: 1018-23. PubMed Citation  (Among ~50,000 liver transplants reported to UNOS between 1990 and 2002, 270 [0.5%] were done for drug induced acute liver failure, but none were attributed to an H2 blocker or proton pump inhibitor).

  25. de Abajo FJ, Montero D, Madurga M, García Rodríguez LA. Acute and clinically relevant drug-induced liver injury: a population based case-control study. Br J Clin Pharmacol 2004; 58: 71-80. PubMed Citation  (Analysis of General Practice Research Database from UK on 1.6 million persons from 1994-2000 found 128 cases of drug induced liver injury [2.4/100,000 person years]; 3 cases were attributed to cimetidine for an odds ratio of 2.0 compared to controls [n=5000], which was not statistically significant).

  26. Björnsson E, Jerlstad P, Bergqvist A, Olsson R. Fulminant drug-induced hepatic failure leading to death or liver transplantation in Sweden. Scand J Gastroenterol 2005; 40: 1095-101. PubMed Citation  (Survey of all cases of DILI with fatal outcome from Swedish Adverse Drug Reporting system from 1966-2002; 103 cases identified as highly probable, probable or possible, one case attributed to ranitidine and one to omeprazole).

  27. Capitain O, Lortholary A, Abadie-Lacourtoisie S. [Cytolytic hepatitis and esomeprazole during chemotherapy]. Presse Med 2005; 34: 1235-6. French. PubMed Citation  (41 year old woman on cyclic chemotherapy for breast cancer received a single dose of esomeprazole and developed abdominal pain and fatigue, and liver tests were abnormal 7 days later [bilirubin normal, ALT 13 times and Alk P 1.5 times ULN], resolving in 8 days).

  28. El-Matary W, Dalzell M. Omeprazole-induced hepatitis. Pediatr Emerg Care 2005; 21: 529-30. PubMed Citation  (15 year old with Crohn disease and acute gastritis developed jaundice 5 days after starting omeprazole [bilirubin 3.2 mg/dL, ALT 218 U/L, Alk P 3018 U/L, INR 1.9], resolving rapidly, all except Alk P being normal within 6 days of stopping).

  29. Youssef SS, Iskandar SB, Scruggs J, Roy TM. Acute pancreatitis associated with omeprazole. Int J Clin Pharmacol Ther 2005; 43: 558-61. PubMed Citation  (83 year old developed symptomatic pancreatitis 2 months after starting omeprazole [amylase 1,137 U/L, lipase 542 U/L], improving promptly on stopping and recurring within 2 days of restarting [amylase 233 U/L, lipase 648 U/L]; no liver test abnormalities mentioned).

  30. Salgueiro E, Rubio T, Hidalgo A, Manso G. Safety profile of proton pump inhibitors according to the spontaneous reports of suspected adverse reactions. Int J Clin Pharmacol Ther 2006; 44: 548-56. PubMed Citation  (Analysis of PPI related reports to Spanish Pharmacovigilance Database during 2004 found 58 reports of liver injury from PPIs: omeprazole [n=36], lansoprazole [7], pantoprazole [12], rabeprazole [2] and esomeprazole [1], correlating somewhat with relative number of prescriptions; 82% were taking other medications; most "evolved to recovery").

  31. Sánchez Garrido A. [Omeprazole-induced acute cholestatic hepatitis]. Gastroenterol Hepatol 2007; 30: 54. Spanish. PubMed Citation  (37 year old developed jaundice 4 days after starting omeprazole [bilirubin 14.2 mg/dL, ALT 852 U/L, Alk P 539 U/L], with resolution in 3 months).

  32. Sabaté M, Ibáñez L, Pérez E, Vidal X, Buti M, Xiol X, Mas A, et al. Risk of acute liver injury associated with the use of drugs: a multicentre population survey. Aliment Pharmacol Ther 2007; 25:1401-9. PubMed Citation  (Population based survey of 126 cases of acute liver injury due to drugs between 1993-1999 in Spain; 8 were attributed to ranitidine alone [incidence 5.1/100,000 person-years] and 5 to omeprazole alone [2.1/100,000]).

  33. Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. PubMed Citation  (Among 300 cases of drug induced liver disease in the US collected between 2004 and 2008, 2 were attributed to ranitidine, none to cimetidine or omeprazole).

  34. Domínguez-Leñero V, Barrera-Ledesma M, Romero-Alonso M, Garrido Martínez MT.
    [Stevens-Johnson syndrome and toxic hepatitis due to esomeprazole]. Farm Hosp
    2009; 33: 118-9. Spanish. PubMed Citation  (66 year old with dyspepsia developed fever, diarrhea and severe rash 9 days after switching from pantoprazole to esomeprazole [40 mg/day], evolving to full-fledged Stevens Johnson syndrome with hypotension, septic shock, and death from multiorgan [including hepatic] failure; few details given).

  35. Ferrajolo C, Capuano A, Verhamme KM, Schuemie M, Rossi F, Stricker BH, Sturkenboom MC. Drug-induced hepatic injury in children: a case/non-case study of suspected adverse drug reactions in VigiBase. Br J Clin Pharmacol 2010; 70: 721-8. PubMed Citation  (Worldwide pharmacovigilance database contained 9036 hepatic adverse drug reactions in children; no antiulcer medication was listed in the top 40 causes).

  36. Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. PubMed Citation  (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury, but none were linked to antiulcer medications).

  37. Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013; 144: 1419-25. PubMed Citation  (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, but none were attributed to a proton pump inhibitor or antiulcer medication, despite the frequency of their use).

  38. Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America. An analysis of published reports. Ann Hepatol 2014; 13: 231-9. PubMed Citation  (Systematic review of literature of drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases, none of which were attributed to antiulcer medications, either H2 blockers or proton pump inhibitors).

  39. Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. PubMed Citation  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 3 [0.3%] were attributed to a proton pump inhibitor, including one each for esomeprazole, omeprazole and lansoprazole).

  40. Thomas B, Mohamed M, Al Hail M, Awwad FA, Wahba RM, Hassan SB, Omar K, et al. A case of probable esomeprazole-induced transient liver injury in a pregnant woman with hyperemesis. Clin Pharmacol 2016; 8: 199-202. PubMed Citation  (22 year old woman in first trimester developed pain and nausea after starting metoclopramide and esomeprazole [40 mg twice daily] for hyperemesis gravidarum [bilirubin not provded, ALT 267 U/L, Alk P 69 U/L], resolving rapidly on switching to pantoprazole).

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