Is there any association between losartan use and hepatic injury in adults?

Comment by InpharmD Researcher

Hepatic injury caused by losartan has been rarely reported in the literature. Transient serum aminotransferase elevations have been reported in <2% of patients in controlled studies and a recent retrospective study from Korea reported an incidence of drug-induced liver injury to be 1.3% with losartan. Reports of acute hepatic injury have been published in the literature with onset in these cases within 1 to 8 weeks of treatment initiation; symptoms typically resolved with drug discontinuation. The potential mechanism for hepatic injury caused by losartan remains unclear.

Background

According to the LiverTox, use of losartan has been associated with a low rate of transient serum aminotransferase elevations (<2%) in controlled studies, not significantly higher compared to placebo. In most cases, the reported cases were temporary and required no dose modifications. Similarly, rare incidences of clinically apparent acute liver injury have been linked to losartan therapy, with a typical onset within 1 to 8 weeks of treatment initiation, during which the serum enzyme pattern is typically hepatocellular with an acute hepatitis-like clinical syndrome. While prolonged and relapsing cholestasis has also been observed, cases of vanishing bile duct syndrome or chronic liver injury are not published within literature. In patients who develop angiotensin receptor antagonist-related enteropathy caused by fatty liver and steatohepatitis due to the diarrhea and malnutrition, elevated aminotransferase levels may occur. Based on available evidence, the likelihood score was graded as C, indicating probable cause of rare instances of clinically apparent liver injury. The specific mechanism of losartan-induced hepatotoxicity remains largely unknown, and management generally involves avoidance of other angiotensin II receptor blockers, although cross sensitivity to liver injury within the therapeutic class has yet to be established. [1]

One referenced case report published in 1997 described a 46 year old man who developed fatigue, anorexia, nausea and jaundice two weeks after switching from enalapril (10 mg daily for 3 months) to losartan (50 mg daily) for the management of essential hypertension. He had no history of liver disease, jaundice, excessive alcohol use, risk factors for viral hepatitis or previous serious drug reactions. Four weeks after initiating losartan and two weeks after symptom onset, the patient developed jaundice and had a low grade fever and mild hepatic tenderness. Laboratory tests revealed moderate elevations in serum bilirubin (9.6 mg/dL) with marked elevations in serum aminotransferase levels (ALT 2,574 U/L, AST 2,042 U/L) and alkaline phosphatase (738 U/L). Hepatitis A, B and C as well as biliary obstruction were ruled out. The decision was made to withhold losartan upon admission, and atenolol was started. The patient improved rapidly and four months later he was asymptomatic with all liver tests normal. Jaundice and symptoms reappeared upon rechallenge with losartan (25 mg daily) and losartan was again stopped; six weeks later liver tests again returned to normal. [1], [2]

A 2023 retrospective cohort analysis using electronic health records from six hospitals in Korea (N= 10,852) aimed to develop and validate a multicenter-based, multi-model, time-series deep learning model for predicting drug-induced liver injury (DILI) in patients taking angiotensin receptor blockers (ARBs). The overall incidence rate for all ARBs was 1.15%, with losartan having the highest incidence rate (1.3%) compared to valsartan (1.28%), candesartan (1.21%), irbesartan (1.07%), telmisartan (1%0, and olmesartan (0.85%). The model used in the study indicated that variables such as hematocrit, albumin, prothrombin time, and lymphocytes were important in predicting DILI. [3]

References:

[1] LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Losartan. [Updated 2017 Jan 13]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK547842/
[2] Bosch X. Losartan-induced hepatotoxicity. JAMA. 1997;278(19):1572.
[3] Heo S, Yu JY, Kang EA, et al. Development and Verification of Time-Series Deep Learning for Drug-Induced Liver Injury Detection in Patients Taking Angiotensin II Receptor Blockers: A Multicenter Distributed Research Network Approach. Healthc Inform Res. 2023;29(3):246-255. doi:10.4258/hir.2023.29.3.246
Literature Review

A search of the published medical literature revealed 6 studies investigating the researchable question:

Is there any association between losartan use and hepatic injury in adults?

Level of evidence

D - Case reports or unreliable data  Read more→


Please see Tables 1-6 for your response.

 

Drug-Induced Liver Injury Due to Losartan

Design

Case report

N= 1

Case presentation

A 66-year-old Caucasian man with medical history of hypertension, treated with losartan 50 mg daily for the previous three weeks had a history of hospitalization previously for drug-induced liver injury (DILI) attributed to a dietary supplement at the time. During the first hospitalization, consumption of alcohol, herbs, toxins and infectious, autoimmune, and hereditary causes were excluded. Both losartan and the supplement were held, and the supplement was assumed to be the main cause of DILI due to a more likely established association. Two weeks after losartan was restarted, the patient complained of acute abdominal pain, nausea, vomiting and after one week developed icteric skin and choluria. Physical examination noted skin and sclerotic jaundice, hepatomegaly with slightly painful palpation and no signs of encephalopathy. Laboratory tests showed aspartate transaminase (AST) 2,522 IU/L, alanine transaminase (ALT) 3,603 IU/L, alkaline phosphatase (ALP) 184 IU/L, gamma-glutamyl transferase (GGT) 375 IU/L, international normalized ratio (INR) 1.65, thrombocytopenia to 101,000 and hyperbilirubinemia with total bilirubin of 5.28 mg/dL and direct bilirubin of 3.23 mg/dL. Viral serologies (hepatitis A, B, C, and E) and HIV 1 and 2 tests were negative. Abdominal ultrasound was normal. Autoimmune hepatitis (AIH) was excluded by testing for anti-nuclear, anti-mitochondrial, anti-smooth muscle, and anti-neutrophil cytoplasm PR3 and MPO, with SLA/LP being negative; Simplified AIH score was 1. Both infectious and infiltrate diseases were excluded and angiography excluded portal system thrombosis and ischemic lesions. After losartan was held for the first six days, the patient has increased blood concentrations of AST (3,055 IU/L), ALT (4,315 IU/L), GGT (524 IU/L), ALP (171 IU/L), and bilirubin (19.23 mg/dL). At this time, prednisone 1 mg/kg/d was started and the patient progressively improved. 

Study Author Conclusions

In cases of acute hepatitis, all drugs should be investigated including angiotensin II receptor antagonists, which are widely used. Once the offending drug has been identified, it should be suspended because re-exposure can result in more severe disease. 
References:

Diogo J, Monteiro R, Coelho C, Ghiletchi A, Leão R, Loureiro C. Drug-Induced Liver Injury Due To Losartan. Eur J Case Rep Intern Med. 2021;8(11):002856. Published 2021 Nov 25. doi:10.12890/2021_002856

 

Losartan-Induced Severe Hepatic Injury: A Case Report and Literature Review

Design

Case Report 

N= 1

Case presentation

A 61-year-old woman with history of hypertension, diabetes, and hypothyroidism presented to the emergency room with high-grade fever, lethargy, and loss of appetite for a couple of days. The patient had taken over-the-counter Chinese cold preparation (containing acetaminophen and diphenhydramine) without relief. She vomited twice and was extremely dizzy on the day of admission. On presentation, she was febrile to 101.1°F, respiratory rate of 18 breaths per min, blood pressure of 112/59 mmHg. Laboratory tests showed alanine transaminase (ALT of 1,371 IU/L and aspartate transaminase (AST) of 1,315. Total bilirubin was 0.7 mg/dL and direct bilirubin was 0.1 mg/dL. Alkaline phosphatase (ALP) was 75 IU/L. Computed tomographic scan of the abdomen and pelvis (without oral or intravenous contrast) showed mild hepatic steatosis. The patient was started on N-acetylcysteine (NAC) due to transaminitis and liver function was closely monitored. All home medications (including losartan and amlodipine) were held. Serum amylase and lipase levels were normal, hepatitis panel (A, B, and C) was negative, anti-mitochondrial and anti-smooth muscle antibodies were negative, alpha-one anti-trypsin and serum ceruloplasmin levels were normal. With ongoing treatment, the patient clinically improved and AST and ALT levels decreased to 215 IU/L and 444 IU/L, respectively. She was discharged on day five with down-trending liver enzymes; losartan was part of the differential for the acute liver insult, and patient and family were counseled to refrain from further use. 

The patient returned to the emergency room two days later with severe lethargy and vomiting. Laboratory tests showed ALT of 3,444 IU/L and AST 5,232 IU/L. Upon questioning, the patient's family stated they have her two doses of 100 mg of losartan; losartan was stopped and NAC was started. Over a few days in the hospital the patient's liver enzymes trended down; the patient and family were counseled to strictly refrain from further use of losartan. 

Study Author Conclusions

 Losartan and other angiotensin receptor blockers have very rarely been reported to cause acute liver injury. By reporting this case, we aim to increase awareness among physicians to always rule out losartan as a cause of unexplained elevation in aminotransferases. We also want to emphasize that once these drugs have been found to be the causative agent for the insult, patients should be strictly counseled not to use them again, as the acute liver injury may advance unto the need for liver transplantation. 
References:

Patti R, Sinha A, Sharma S, Yoon TS, Kupfer Y. Losartan-induced Severe Hepatic Injury: A Case Report and Literature Review. Cureus. 2019;11(5):e4769. Published 2019 May 28. doi:10.7759/cureus.4769

 

Losartan-induced Ischemic Hepatocellular Hepatotoxicity: A Case Report and Literature Review

Design

Case Report

N= 1

Case presentation

 A 65-year-old Hispanic female with medical history of hypertension presented with acute abdominal pain that was associated with nausea and nonbilious emesis for two days; she did not have fever, chills, or jaundice. Losartan 50 mg was started for hypertension four months prior to presentation and she denied taking any other medications or supplements. She also had no history of tobacco or alcohol use. Patient denied any episodes of palpitation or light-headedness in the past. On physical exam, the patient had epigastric and right upper quadrant tenderness. Initial laboratory results showed aspartate aminotransferase 1,018 IU/L, alanine transaminase 1,184 IU/L, alkaline phosphatase 142 IU/L, total bilirubin 2.7 mg/dL, and direct bilirubin 1.3 mg/dL; total protein, albumin, and prothrombin time were at normal levels, as were serum amylase and lipase levels. Viral hepatitis (A, B, and C) panel was negative, acetaminophen serum level, antinuclear antibody, and anti-smooth muscle antibody titers were undetectable and patient had normal white cell and eosinophilic counts. Hepatobiliary iminodiacetic acid/hepatobiliary scan showed a patent cystic duct and a magnetic resonance cholangiopancreatography showed normal common bile duct diameter without filling defects. Losartan was held on admission and her clinical symptoms and laboratory results improved rapidly during the first four days of hospitalization. Liver biopsy was done on day 8 which showed normal hepatic tissue without any abnormal findings. The patient was discharged home on day 9 without re-challenge with losartan. 

Study Author Conclusions

 In summary, losartan and other angiotensin receptor blockers (ARBs) are well-tolerated commonly used medications. However, in the presence of an unexplained liver injury, the possibility of drug related hepatotoxicity should be always ruled out in patients treated with losartan or other ARBs despite its rarity. To the best of our knowledge, we are reporting the 6th case of losartan-induced hepatitis and possibly the first report of a losartan-induced ischemic liver injury in the adult population.
References:

Al-Halawani MZ, Thawabi M, Asslo F, Shaaban H, Shamoon F, Baddoura WJ. Losartan-induced Ischemic Hepatocellular Hepatotoxicity: A Case Report and Literature Review. J Family Med Prim Care. 2014;3(3):272-274. doi:10.4103/2249-4863.14163

 

Losartan-Induced Hepatic Injury

Design

Case report

N= 1

Case presentation

A 52-year-old female was admitted with dark urine, jaundice, weakness, and right upper abdominal discomfort. She was taking losartan 50 mg/d for hypertension for eight months, steroid and beta-2-agonist inhalers for asthma for two years, and 0.1 mg/d of thyroxin after thyroidectomy for two years. Five months after initiation of losartan she developed jaundice and fever; alanine transferase (ALT) and aspartate transaminase (AST) were 750 U/L. After discontinuation of losartan for three weeks, these test results improved (approximately 200 U/L) and losartan was continued; two weeks later she experienced symptoms again and was hospitalized. 

Physical examination showed scleral jaundice; laboratory tests showed AST of 1,093 U/L, ALT of 941 U/L, alkaline phosphatase of 419 U/L, lactic dehydrogenase of 358 U/L, gamma-glutamyl-transferase of 176 U/L, total bilirubin of 8.9 mg/dL with a direct fraction of 5.75 mg/dL. Prothrombin activity was 82% and international normalized ration was 1.12. Additional serologic tests showed negative hepatitis A immunoglobulin M (IgM), hepatitis B surface antigen, hepatitis B core IgM and IgG, hepatitis B antibody, hepatitis C antibody, hepatitis C virus-RNA; anti-double-stranded DNA, antimitochondrial antibody, and liver-kidney microsomal antibody; fluorescent antinuclear antibody was weakly positive. Ultrasonography and computed tomography were normal except for a small stone in the gallbladder; retrograde cholangiography was normal. Serum alpha-1-antitrypsin level (180 mg/dL) and daily copper excretion in urine (38.5 mcg) were normal. Liver biopsy showed chronic hepatitis, moderate to severe inflammatory reaction, and mild fibrosis. 

Losartan was discontinued, and two months later the patients AST and ALT levels were 150 U/L and within four months these values were normal. The patient was doing well at a 2-year follow-up after losartan was discontinued. 

Study Author Conclusions

 Although rare, drug-induced hepatic toxicity may be seen in patients taking losartan. Because it causes hepatic injury during the initial phase of the treatment period, the clinician should be aware of this side effect when prescribing this drug. 
References:

Tabak F, Mert A, Ozaras R, et al. Losartan-induced hepatic injury. J Clin Gastroenterol. 2002;34(5):585-586. doi:10.1097/00004836-200205000-00022

 

Hepatic Injury Associated with Losartan

Design

Case report

N= 1

Case presentation

A 77-year-old white male with history of heartburn was prescribed losartan 50 mg/d for essential hypertension, which was discovered during evaluation for a transient ischemic attack. His baseline serum creatinine (SCr) was 0.9 mg/dL and concomitant medications included ditazole (platelet aggregation inhibitor) 400 mg/d and almagate. He denied alcohol use. Six weeks later he presented with a 3-week history of asthenia, anorexia, and 5-kg weight loss; the patient reported taking losartan 50 mg three times a day due to misunderstanding of directions. Physical examination showed a thin male without signs of chronic liver disease and no organomegaly. Laboratory tests showed SCr 1.9 mg/dL, blood urea nitrogen 25 mg/dL, total bilirubin 1.7 mg/dL, aspartate aminotransferase (AST) 115 U/L, alanine aminotransferase (ALT) 410 U/L, and gamma-glutamyl transferase (GGT) 89 U/L. Alkaline phosphatase, leukocyte and eosinophil counts, and prothrombin activity were normal. Serology for hepatitis viruses (A, B, C, cytomegalovirus, and Epstein-Barr virus) and screening for autoimmune liver disorders were negative. Ultrasonogram of the upper abdomen showed a normal liver and no expanded bile ducts. Losartan was discontinued, while other medications were continued. Within one month, the patient clinically improved and laboratory results returned to normal: bilirubin 0.9 mg/dL, AST 22 U/L, ALT 27 U/L, GGT 17 U/L, alkaline phosphatase 175 U/L, SCr 1.2 mg/dL. Losartan rechallenge was not attempted; patient had been followed for 18 months and remained asymptomatic.    

Study Author Conclusions

 Clinicians should be aware of the possibility of a severe adverse reaction in patients prescribed losartan. 
References:

Andrade RJ, Lucena MI, Santalla F. Hepatic injury associated with losartan. Ann Pharmacother. 1998;32(12):1371. doi:10.1345/aph.18087a

 

Marked Hepatotoxicity Associated with Losartan Treatment

Design

Case report

N= 2

Case presentation 1

A 55-year-old woman with renovascular hypertension, history of cholelithiasis, and unilateral renal artery stenosis treated twice with balloon angioplasty without any effect on the elevated blood pressure was subsequently started on losartan 50 mg daily. Three weeks after, the patient starting having episodes of marked interscapular pain, which she initially attributed to her cholelithiasis. Blood pressure was 110/80 mmHg, alanine aminotransferase (ALT) was 650 U/L, aspartate aminotransferase (AST) was 635 U/L, alkaline phosphatase (ALP) was 396 U/L, and bilirubin was 23 Umol/L (laboratory values were normal prior to losartan initiation). At day 30 treatment was discontinued and laboratory tests normalized over one month; pain episodes also subsided during this time. Ultrasonography showed cholelithiasis without signs of biliary stasis. 

Case presentation 2

A 46-year-old woman with primary hypertension was treated with losartan for a few months and referred to the hospital due to retrosternal pain. Chest X-ray, myocardial enzyme pattern, and electrocardiography at rest and during exercise were normal. Laboratory tests showed increased ALT to 311 U/L, AST to 300 U/L, and lactate dehydrogenase to 984 U/L. Losartan was discontinued and laboratory values gradually improved within a few weeks; pain episodes also subsided during this time.  

Study Author Conclusions

 The present observations are to our knowledge the first to be published describing marked hepatotoxicity during losartan treatment. Since no secondary provocation test was carried out in our patients it is not absolutely certain that the syndrome of thoracic pain and raised liver enzymes were actually caused by losartan. Despite this, the cases have been reported to alert clinicians to similar incidents during treatment of hypertension with losartan or other angiotensin II type 1 receptor antagonists. 
References:

Nygaard B, Strandgaard S. Marked hepatotoxicity associated with losartan treatment. Blood Press. 1996;5(3):190-191. doi:10.3109/08037059609062128