Omeprazole and esomeprazole are proton pump inhibitors (PPIs) and potent inhibitor of gastric acidity which are widely used in the therapy of gastroesophageal reflux and peptic ulcer disease. Omeprazole and esomeprazole therapy are both associated with a low rate of transient and asymptomatic serum aminotransferase elevations and are rare causes of clinically apparent liver injury.


Omeprazole (oh mep' ra zole), like other PPIs, inhibits gastric acid production by binding to and inactivating the H+/K+-ATPase of gastric parietal cells, causing inhibition of the proton pump that transports H+ into the gastric lumen, the common final step in gastric acid production. Omeprazole 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. Omeprazole was the first PPI approved for use in the United States (1989), initially only for the indication of severe peptic ulcer disease and Zollinger-Ellison syndrome. Subsequently, the indications for its use have broadened to routine peptic ulcer disease, gastroesophageal reflux disease and prevention of stress ulcers.

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. The pharmacokinetics, mechanism of action and clinical efficacy of esomeprazole is quite similar to that of omeprazole. Esomeprazole was approved for use in the United States in 2001 with similar indications as omeprazole includig peptic ulcer disease, gastroesophageal reflux disease and prevention of stress ulcers.

Omeprazole and esomeprazole are two of the most widely used medications in clinical practice with more than 20 million prescriptions filled yearly in the United States alone. Omeprazole is available in multiple forms including 10, 20 and 40 mg standard and delayed release capsules and powder for oral suspension in generic forms and under the brand name of Prilosec. The typical dose of omeprazole 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 120 mg daily for Zollinger-Ellison syndrome. A 10 to 14 day course of omeprazole in combination with antibiotics is effective and recommended for the eradication of H. Pylori infection.

Esomeprazole is also available in multiple forms and typically used in 20 mg delayed release capsules generically and under the brand name 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. Both omeprazole and esomeprazole are very well tolerated and both are now available without prescription in multiple over-the-counter forms. Side effects of omeprazole and esomeprazole are uncommon and usually mild; they include diarrhea, nausea, vomiting, abdominal discomfort, flatulence, skin rash, headaches and dizziness. Severe side effects are rare but can include hypersensitivity reactions. Long-term use of rabeprazole may be associated with bone fractures, acute interstitial nephritis, lupus erythematosus, vitamin B12 deficiency and hypomagnesemia.


Despite their wide use, omeprazole and esomeprazole have only rarely been associated with hepatic injury. In large scale, long term trials , serum ALT elevations occurred in less than 1% of patients and at rates similar to those that occurred with placebo or comparator drugs. A small number of cases of clinically apparent liver disease due to omeprazole or esomeprazole have been published, the frequency of these cases probably being less than 1:100,000 users. A somewhat characteristic clinical phenotype has been described, with most cases arising during the first 1 to 4 weeks of therapy and being marked by an acute hepatocellular pattern of injury, with rapid recovery upon withdrawal. Rash, fever and eosinophilia were rare, as is autoantibody formation. Liver biopsy typically shows prominent centrolobular necrosis, suggestive of an acute, toxic hepatic injury (acute hepatic necrosis); however, recurrence upon rechallenge has been documented in several cases. In some instances, other organ involvement is prominent including rhabdomyolysis, lactic acidosis, renal insufficiency or Stevens Johnson syndrome. In large case series of drug induced liver injury, omeprazole and esomeprazole have accounted for few instances of symptomatic acute liver injury and rare instances of acute liver failure.

Likelihood score: B (rare but likely cause of clinically apparent liver injury).

Mechanism of Injury

The acute onset and rapid recurrence of hepatic injury with omeprazole and esomeprazole 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. Both omeprazole and esomeprazole are extensively metabolized by the hepatic P450 system and have multiple effects on the drug metabolizing system, including inhibition of CYP 2C19 and induction of CYP1A2, effects which may cause significant drug-drug interactions.

Outcome and Management

The mild and asymptomatic elevations in serum aminotransferase that have been observed during omeprazole and esomeprazole therapy are usually transient and may resolve even without dose modification. Clinically apparent liver injury due to these agents, however, generally calls for prompt withdrawal. Severe injury due to omeprazole and esomeprazole is uncommon and most cases resolve promptly upon withdrawal. Cases of acute liver failure due to proton pump inhibitors have been described, but they are exceedingly rare. There is no information about cross sensitivity to liver injury among the various PPIs, but some degree of cross reactivity should be expected between omeprazole and its S-isomer, esomeprazole. Furthermore, the PPIs all share a benzimidazole structure, and caution should be used in attempting to reintroduce another PPI after clinically apparent hepatic injury due to an unrelated PPI.

Drug Class: Antiulcer Agents

Other Drugs in the Subclass, Proton Pump Inhibitors: Dexlansoprazole, Lansoprazole, Pantoprazole, Rabeprazole


Case 1. Acute liver failure attributed to omeprazole.

[Modified from: 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]

A 62 year old man with gastroesophageal reflux was treated with ranitidine (150 mg twice daily) for 10 days without improvement, whereupon he was switched to omeprazole (20 mg daily). Seventeen days later, he presented with a 4 day history of abdominal pain, nausea, vomiting, poor appetite and weakness. He had no previous history of liver disease, alcohol abuse or risk factors for viral hepatitis. He had a long history of hypertension and coronary artery disease and had been taking atenolol (100 mg daily), diltiazem (60 mg twice daily) and aspirin (325 mg daily) chronically. He denied taking acetaminophen. On examination, he was jaundiced and had mild asterixis without rash or peripheral manifestations of cirrhosis. Laboratory testing showed marked elevations in serum aminotransferase levels (ALT 9234 U/L, AST 2952 U/L), bilirubin (8.4 mg/dL) and prothrombin time (>100 seconds), with minimal increase in alkaline phosphatase levels (254 U/L). Serum lactate was elevated at 26.6 mmol/L and ammonia at 38 µmol/L. The peripheral white blood cell count was elevated (18,100 cells/µL) without eosinophilia and creatinine was 2.6 mg/dL. All liver tests had been normal when measured one month previously. Tests for hepatitis A, B and C were negative. He was managed in the intensive care unit but worsened overnight, becoming obtunded and then comatose. He was transferred to a tertiary medical center for possible liver transplantation, but rapidly developed respiratory and renal failure and died five days after his initial presentation. On autopsy, his liver showed massive centrolobular necrosis without fibrosis.

Key Points


This patient developed fulminant hepatic failure and died within 3 weeks of starting omeprazole for gastroesophageal reflux. Spontaneous, idiopathic acute liver failure is very rare, but omeprazole use is common. For these reasons, a person taking omeprazole might develop acute liver failure by chance, unrelated to the medication. However, the onset of liver injury within a few weeks of starting omeprazole and the similarity in time to onset and enzyme pattern to other cases of omeprazole hepatotoxicity suggest that the proton pump inhibitor was the cause. Approximately 10% of causes of hepatocellular jaundice due to medications result in fatality, so that rare instances of proton pump inhibitor induced acute liver injury (which is typically hepatocellular) are likely to result in death. Acute liver failure with a short latency period (1 to 4 weeks) has also been reported with esomeprazole and with rabeprazole therapy.



Omeprazole – Generic, Prilosec®

Esomeprazole – Generic, Nexium®


Antiulcer Agents


Product labeling at DailyMed, National Library of Medicine, NIH



References updated: 15 April 2019

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