Nizatidine is a histamine type 2 receptor antagonist (H2 blocker) which is widely used for treatment of acid-peptic disease and heartburn. Nizatidine has been linked to rare instances of clinically apparent acute liver injury.
Nizatidine (nye za' ti deen) was the fourth histamine type 2 receptor blocker (H2 blocker) introduced into clinical practice in the United States and is a commonly used agent for treatment of duodenal and gastric ulcer and gastroesophageal reflux disease. Other H2 blockers in clinical use include cimetidine, ranitidine and famotidine. The H2 blockers are specific antagonists of the histamine type 2 receptor, which is found on the basolateral (antiluminal) membrane of gastric parietal cells. The binding of the agent to the H2 receptor results in inhibition of acid production and secretion, and improvement in symptoms and signs of acid-peptic disease. The H2 blockers inhibit an early, “upstream” step in gastric acid production and are less potent that the proton pump inhibitors, which inhibit the final common step in acid secretion. Nevertheless, the H2 blockers inhibit 24 hour gastric acid production by about 70% and are most effective in blocking basal and nocturnal acid production. Nizatidine was first approved for use in the United States in 1988 and is now available both by prescription and over-the-counter. The listed indications for nizatidine are duodenal and gastric ulcer disease, gastroesophageal reflux and prevention of stress ulcers. Nizatidine is available by prescription in capsules of 150 and 300 mg in several generic forms and in both oral and parenteral forms under the brand name Axid. Over-the-counter preparations of nizatidine are usually tablets of 75 mg (Axid-AR). Side effects are uncommon, usually minor, and include diarrhea, constipation, fatigue, drowsiness, headache and muscle aches.
Chronic therapy with nizatidine and other H2 blockers is associated with minor elevations in serum aminotransferase levels in 1% to 4% of patients, but similar rates have been reported in placebo recipients. The ALT elevations are usually asymptomatic and transient and may resolve without dose modification. Rare instances of clinically apparent liver injury have been reported in patients receiving nizatidine, but too few cases have been reported to characterize a typical time to onset or pattern of injury. More information is available on the hepatotoxicity of other H2 blockers such as ranitidine and cimetidine which have been implicated in causing clinically apparent liver injury in 1:20,000 to 1:100,000 users. The time to onset of H2 blocker induced liver injury tends to be short, between 1 and 6 weeks of starting. The typical pattern of serum enzyme elevations varies from hepatocellular to cholestatic, most cases being “mixed”. The injury can be severe, but is typically mild-to- moderate in severity and self-limited in course, resolving within 4 to 12 weeks of stopping. Immunoallergic features (rash, fever, eosinophilia) are uncommon, as is autoantibody formation. Liver biopsy histology often shows centrolobular (zone 3) necrosis with mixed cellular infiltrates and mild cholestasis.
Likelihood score: D (possible rare cause of clinically apparent liver injury).
Mechanism of Injury
Nizatidine is metabolized by the microsomal P450 drug metabolizing enzymes and injury may be the result of its activation to a toxic intermediate. Despite its metabolism by the P450 system, nizatidine does not result in significant inhibitor or induction of the enzymes and thus is less likely to cause drug-drug interactions than cimetidine.
Outcome and Management
The hepatic injury caused by nizatidine is usually rapidly reversible with stopping the medication, but an instance of severe hepatitis with incomplete recovery and cirrhosis has been reported (Case 1). Nizatidine has been in use for a shorter time than cimetidine or ranitidine and remains unknown whether there is cross reactivity in hepatic injury between nizatidine and other H2 blockers. If acid suppression is required, use of an unrelated proton pump inhibitor is probably prudent for patients with clinically apparent nizatidine induced liver injury.
The H2 receptor blockers include cimetidine, famotidine, nizatidine, and
ranitidine. General references on all four agents are given together after the
overview section on H2 Blockers, while specific references are given for each drug. See also the Proton Pump Inhibitors.
Case 1. Severe acute liver injury leading to cirrhosis caused by nizatidine.
[Modified from: Chey WD, Kochman ML, Traber PG, Appelman HD, Gumucio JJ. Possible nizatidine-induced subfulminant hepatic failure. J Clin Gastroenterol 1995; 20: 164-7. PubMed Citation]
A 39 year old man developed rash after 7 days and jaundice after 14 days of nizatidine therapy for dyspepsia. Despite the symptoms and jaundice, he continued nizatidine for a total of 28 days. One month after stopping he was still jaundiced and sought medical care. He denied a history of liver disease, exposure to viral hepatitis or recent excessive alcohol intake. He was taking no other medications and had no history of drug allergies. Laboratory testing revealed marked elevations in serum bilirubin, AST and alkaline phosphatase (Table). The prothrombin time was prolonged at 18.7 seconds. Abdominal ultrasound and computerized tomography showed no evidence of gallstones or biliary obstruction, and endoscopic retrograde pancreatocholangiography showed no abnormality of the extra- or intra-hepatic biliary system. Ten weeks after starting and 6 weeks after stopping nizatidine, he was hospitalized because of increasing fatigue, jaundice and abdominal swelling. On physical examination, he was deeply jaundiced and had mild asterixis and ascites. Tests for hepatitis A, B and C were negative and autoantibodies were not present. A liver biopsy showed massive multi-lobular necrosis without significant fibrosis. He was referred for liver transplantation, but was managed conservatively and slowly improved, allowing for discharge from the hospital after 19 days. While liver tests improved, they did not become completely normal, and one year later serum bilirubin, aminotransferases and alkaline phosphatase levels were still abnormal. Upper endoscopy revealed esophageal varices. A liver biopsy several months later revealed irregular, but relatively inactive cirrhosis.
|Medication:||Nizatidine (dose not provided)|
|Pattern:|| Hepatocellular (R=8.8)|
||4+ (jaundice and signs of hepatic failure)|
||2 weeks to onset of jaundice, 8 weeks to laboratory confirmation|
|Other medications:||None mentioned|
|Time After Starting
||Time After Stopping
||Alk P (U/L)
||Nizatidine given for 4 weeks
||Protime 18.7 sec
||Protime 20.0 sec
||Biopsy: massive necrosis
||Protime 13.4 sec
| Normal Values
This patient developed a severe hepatitis within a few weeks of starting nizatidine but continued taking the medication for two weeks after jaundice was noticed by his wife. He still delayed getting medical advice for another month after stopping nizatidine at which time he was deeply jaundiced and had signs of hepatic failure. When he developed ascites and hepatic encephalopathy, he was referred for liver transplant evaluation, but then began to improve spontaneously. He had a slow an incomplete recovery and was found to have cirrhosis on a liver biopsy done over a year later. Follow up is available from the authors. This patient has been followed at the transplant center from which this publication came for more than 15 years after this event and still has borderline hepatic decompensation, but has yet to require liver transplantation. No other source for the liver disease has been identified. Thus, cirrhosis induced by medications may not be completely reversible, but tends to be stable and nonprogressive as long as the medication is not restarted and other forms of hepatic injury (alcohol, hepatitis) are avoided.
REPRESENTATIVE TRADE NAMES
Nizatidine – Generic, Axid®
Product labeling at DailyMed, National Library of Medicine, NIH
||CAS REGISTRY NUMBER
References updated: 25 January 2018
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Chey WD, Kochman ML, Traber PG, Appelman HD, Gumucio JJ. Possible nizatidine-induced subfulminant hepatic failure. J Clin Gastroenterol 1995; 20: 164-7. PubMed Citation (39 year old developed dyspepsia after 1 and jaundice after 2 weeks of nizatidine, not stopping until 4 weeks; 1 month later he was deeply jaundiced [bilirubin 21.7 mg/dL, AST 461 U/L, Alk P 152 U/L, prothrombin time 18.7 sec] and went on to have hepatic failure with ascites and encephalopathy, beginning to improve after referral for liver transplant; one year later he had varices and liver test abnormalities [bilirubin 1.8 mg/dL, ALT 98 U/L, Alk P 252 U/L], liver biopsies showing multilobular collapse acutely and inactive cirrhosis 16 months later: Case 1).
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