Pantoprazole is a proton pump inhibitor (PPI) and a potent inhibitor of gastric acidity which is widely used in the therapy of gastroesophageal reflux and peptic ulcer disease. Pantoprazole therapy is associated with a low rate of transient and asymptomatic serum aminotransferase elevations and is a rare cause of clinically apparent liver injury.
Pantoprazole, (pan toe' pra zole) like other PPIs, blocks 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 final common step in gastric acid production. Pantoprazole is a prodrug and is converted to the active form 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. Pantoprazole was the fourth PPI approved for use in the United States (2000) and now is in wide use. Pantoprazole is available as delayed release tablets of 20 and 40 mg, and in 40 mg vials for parenteral use generically and under the brand name of Protonix. The typical dose of pantoprazole for peptic ulcer disease is 40 mg once daily for 4 to 8 weeks with similar long term maintenance doses. Twice daily doses are recommended for more severe cases of gastrointestinal reflux and peptic ulcer disease, and doses of up to 240 mg daily for Zollinger-Ellison syndrome. Pantoprazole is very well tolerated. Side effects are uncommon and usually mild, and include diarrhea, nausea, vomiting, abdominal discomfort, flatulence, skin rash, headaches and dizziness.
Despite its wide use, pantoprazole has only rarely been associated with hepatic injury. In large scale, long term trials of pantoprazole, 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 small number of cases of clinically apparent liver disease attributed to pantoprazole have been published, but the clinical pattern of injury has resembled acute hepatic necrosis which has been described with other proton pump inhibitors. Clinically apparent liver injury due to proton pump inhibitors generally arises within the first 4 weeks of therapy and is characterized by an acute hepatocellular pattern of injury with rapid recovery upon withdrawal. Rash, fever and eosinophilia are rare, as is autoantibody formation. In large case series of drug induced liver injury, pantoprazole has accounted for few instances of symptomatic acute liver injury.
Mechanism of Injury
The acute onset and rapid recurrence of hepatic injury with proton pump inhibitors suggests a hypersensitivity reaction, but may merely reflect altered metabolism or acute toxicity of a metabolic byproduct. Pantoprazole is metabolized predominantly by hepatic CYP 2C19 with lesser metabolism by CYP 3A4. Drug interactions may occur with agents that share these pathways of metabolism.
Outcome and Management
The mild and asymptomatic elevations in serum aminotransferase that have been observed during pantoprazole therapy are usually transient and may resolve even without dose modification. Clinically apparent liver injury due to pantoprazole is rare, but calls for prompt withdrawal of the agent. Cases of acute liver failure due to proton pump inhibitors have been described, but are exceedingly rare. There is no information about cross reactivity among the various PPIs after pantoprazole hepatotoxicity, but the PPIs all share a benzimidazole structure, and caution should be used in attempting to reintroduce another PPI after clinically apparent PPI associated hepatic injury.
Case 1. Acute liver injury due to pantoprazole.
[Modified from: Cordes A, Vogt W, Maier KP. [Pantoprazole-induced hepatitis]. Dtsch Med Wochenschr 2003; 128: 611-4. German. PubMed Citation]
A 46 year old woman with symptoms of gastroesophageal reflux developed epigastic pain 8 days after starting pantoprazole. She denied jaundice, dark urine, fever, rash or poor appetite. She had no history of liver disease, jaundice, alcohol abuse or risk factors for viral hepatitis. She took no other medications. Her serum aminotransferase levels had been normal 3 days previously when she underwent a routine upper endoscopy under midazolam anesthesia (which showed changes suggestive of gastroesophageal reflux disease). On examination, she had no fever, jaundice, rash, hepatomegaly or tenderness. Laboratory tests showed moderate elevations in serum aminotransferase levels and bilirubin of 1.0 mg/dL (Table). The alkaline phosphatase levels were normal, but lactic dehydrogenase was slightly elevated (LDH 686 U/L, normal <240). The white blood cell count was normal without eosinophilia. Tests for hepatitis A, B and C and for autoantibodies were negative. An ultrasound showed a gallstone without evidence of biliary obstruction. Pantoprazole was stopped. Serum bilirubin and ALT levels rose for a day and then began to fall and were near normal one week later. A liver biopsy was not done and she was not reexposed to pantoprazole or other proton pump inhibitors.
|Medication:||Pantoprazole (dose not given)|
|Pattern:|| Hepatocellular (R=37)|
||3+ (jaundice, hospitalization)|
||8 days to onset of symptoms, 9 days to jaundice|
|Other medications:||Intravenous midazolam, 3 days before onset|
|Time After Starting
||Time After Stopping
||Alk P (U/L)
| Normal Values
* Values estimated from Figure 1.
This patient developed a mild hepatitis-like syndrome within 8-9 days of starting pantoprazole. The pattern of serum enzyme elevations was hepatocellular, but the LDH elevation suggested an acute hepatic necrosis-like clinical picture, which was further supported by the rapidity of improvement on stopping pantoprazole. Other possibilities were that the injury was due to midazolam anesthesia or to an undocumented episode of hypotension during the upper endoscopy, but both of those possibilities are unlikely. The signature pattern of short latency to onset of an acute hepatic necrosis with prompt improvement on stopping is typical of proton pump associated hepatotoxicity.
REPRESENTATIVE TRADE NAMES
Pantoprazole – Generic, Protonix®
Product labeling at DailyMed, National Library of Medicine, NIH
||CAS REGISTRY NUMBER
References Last Updated: 15 January 2014
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