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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Tamoxifen

Last Update: August 20, 2020.

OVERVIEW

Introduction

Tamoxifen is a nonsteroidal antiestrogen that is widely used in the treatment and prevention of breast cancer. Long term tamoxifen therapy has been associated with development of fatty liver, steatohepatitis, cirrhosis, and rare instances of clinically apparent acute liver injury.

Background

Tamoxifen (ta mox' i fen) is referred to as a selective estrogen receptor modulator with tissue specific actions, having estrogenic agonist effects on bone, brain and liver, but antagonist activity on breast tissue. Tamoxifen may also have other, as yet undefined, anticancer effects. Adjuvant therapy with tamoxifen has been shown to prolong survival in women with early stage breast cancer and to decrease the risk of de novo breast cancer as well as recurrence in women at high risk. Tamoxifen was approved for use in the United States in 1977 and is still widely used, being considered a first line adjuvant therapy for breast cancer. Current indications include both treatment of breast cancer and reduction of breast cancer risk in women at high risk. Tamoxifen is available in 10 and 20 mg tablets generically and under several trade names such as Nolvadex and Tamone. Tamoxifen is also available as an oral solution (10 mg/5 mL). The usual dose for treating breast cancer is 20 to 40 mg daily, and for secondary prevention is 20 mg once daily for five years. Common side effects include hot flashes, nausea, diarrhea, amenorrhea, altered menses, weight change and fluid retention. Rare but potentially severe adverse events include stroke, pulmonary embolus and venous thromboses, uterine cancer and other malignancies.

Hepatotoxicity

Tamoxifen has been associated with rare instances of idiosyncratic, clinically apparent liver injury, typically arising within the first six months of treatment and having variable presentations with cholestatic, mixed or hepatocellular pattern of enzyme elevations. Immunoallergic features (fever, rash, eosinophilia) are uncommon, as are autoantibodies. Some instances have been severe with signs of hepatic failure, but most cases are self-limited.

More commonly, long term tamoxifen therapy has been linked to the development of fatty liver and steatohepatitis. In some prospective studies, up to one third of women have developed fatty liver during 1 to 3 years of tamoxifen therapy, as shown by routine imaging using computerized tomography. Fatty liver usually becomes demonstrable within 1 to 2 years of starting tamoxifen but is usually not accompanied by symptoms, although serum aminotransferase levels may be elevated modestly in up to half of patients. Liver biopsy may demonstrate steatohepatitis and a proportion of women develop hepatic fibrosis. Several instances of cirrhosis have been described after therapy with tamoxifen for 3 to 5 years. Serum aminotransferase elevations and fatty liver generally improve once tamoxifen is stopped, but the improvement may be slow and in rare instances, signs and symptoms of portal hypertension persist. While the frequency of hepatic steatosis during tamoxifen therapy is higher in women with higher body weight and body mass index (BMI), the appearance of fatty liver is usually not accompanied by change in body weight and does not relate to alcohol use or receipt of adjuvant chemotherapy. Because steatohepatitis is usually (although not always) accompanied by minor serum aminotransferase elevations, monitoring of serum enzymes during long term tamoxifen therapy is often recommended.

In addition, long term tamoxifen therapy has also been linked to isolated cases of peliosis hepatis, hepatic cysts and several cases of hepatocellular carcinoma in women with no other risk factors for this tumor. However, in large retrospective analyses, no increase in hepatocellular carcinoma in women taking tamoxifen for 5 years has been demonstrated, although these same studies did show an increase in rates of endometrial carcinoma. Tamoxifen also been linked to an increased risk of venous thromboses, and instances of portal vein thrombosis with combinations of portal hypertension and esophageal variceal bleeding have been reported.

Finally, tamoxifen use has been associated with development of symptomatic porphyria cutanea tarda (PCT), presenting after 1 to 4 years of use with skin fragility, hypertrichosis and reddish urine and accompanied by elevations in urinary porphyrins and mild serum aminotransferase elevations. Tamoxifen related cases usually arise without other risk factors for PCT such as iron overload, alcohol abuse or hepatitis C virus infection. Stopping tamoxifen is followed by gradual improvement in symptoms, decrease in porphyrin excretion and improvement in liver enzymes.

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

Mechanism of Injury

The acute form of liver injury attributed to tamoxifen use is probably due to an idiosyncratic reaction to a metabolite of the medication rather than its estrogenic effects. In contrast, the induction of fatty liver and triggering of porphyria cutanea tarda are likely due to estrogenic effects on the liver in the setting of a genetic predisposition to fatty liver disease or porphyria cutanea tarda.

Outcome and Management

While fatty liver arises in at least one third of women treated with tamoxifen for up to 5 years, clinically significant steatohepatitis is less common. Nevertheless, monitoring of serum aminotransferase levels during tamoxifen therapy is appropriate. In women with persistent elevations in ALT levels, the relative benefits and risks of continuing tamoxifen therapy must be weighed. Factors to help in the decision, include noninvasive tests for hepatic fibrosis (platelet count), imaging of the liver and, in some instances, liver biopsy. Switching to aromatase inhibitors such as anastrozole, letrozole or exemestane is another option. These agents may also cause or exacerbate fatty liver disease, but the risk appears far less than with tamoxifen. Other approaches short of stopping tamoxifen therapy include nutritional advice and weight loss, abstinence from alcohol, and possibly medical therapies for nonalcoholic steatohepatitis (which are currently investigational and have not been shown to be specifically helpful in tamoxifen induced fatty liver). The possible development of serious hepatic fibrosis and portal hypertension can be assessed noninvasively by serial determinations of platelet count, but may require liver biopsy to document.

Drug Class: Antineoplastic Agents, Antiestrogens

CASE REPORTS

Case 1. Clinically apparent, acute liver injury due to tamoxifen.(1)

A 75 year old woman developed nausea, vomiting and mild serum enzyme elevations 10 weeks after starting tamoxifen (10 mg twice daily) for metastatic breast cancer. She was treated with prednisolone (5 mg daily) and antiemetics, but continued to be symptomatic and serum enzymes and bilirubin continued to rise (Table). She had no history of liver disease, denied alcohol use and had no risk factors for viral hepatitis. Tests for hepatitis A and B were negative. Ultrasound of the abdomen showed no gallstones or evidence of biliary obstruction. A liver biopsy showed cholestasis and portal inflammation with minimal bile duct changes. All medications were stopped except for prednisolone, and liver test abnormalities began to decrease towards near normal levels. Tamoxifen was restarted for 12 days and she was monitored closely. Within 9 days she became symptomatic with nausea and vomiting and serum enzyme levels began to rise, peaking a few days after tamoxifen was stopped and then returning again towards normal. Shortly thereafter, she died of cerebral metastases. On autopsy, she had small hepatic metastases, but no evidence of biliary obstruction.

Key Points

Medication:Tamoxifen (20 mg daily)
Pattern:Mixed (alkaline phosphatase levels were raised, but no values given)
Severity:3+ (jaundice, hospitalization)
Latency:10 weeks
Recovery:2-3 weeks
Other medications:Prednisolone, antiemetics

Laboratory Values

Time After
Starting		Time After
Stopping		ALT*
(U/L)		Bilirubin
(mg/dL)		Other
0380.7Tamoxifen started
4 weeks350.9
10 weeks540.9Symptoms (nausea)
14 weeks07354.1Worsening symptoms
15 weeks1 week6705.3
16 weeks2 weeks1103.5
19 weeks5 weeks541.0Nausea resolved
21 weeks7 weeks501.4
Time After restarting Time After Stopping Tamoxifen restarted
1 week0791.1Symptoms (nausea)
2 weeks1 week2581.8
3 weeks2 weeks1801.3
5 weeks4 weeks641.2
Normal Values <45 <1.2
*

Values estimated from Figure.

Comment

The clinical presentation of symptomatic liver injury 10 weeks after starting tamoxifen and recurrence of a similar pattern of injury within 2 weeks of restarting provides strong evidence for the role of tamoxifen in causing the liver injury. Cases of acute liver injury with jaundice due to tamoxifen have been reported, but are rare and represent an idiosyncratic reaction. More common is fatty liver disease which can be associated with significant steatohepatitis and result in cirrhosis. However, steatosis and steatohepatitis rarely cause jaundice and are usually minimally symptomatic and respond slowly to withdrawal of tamoxifen. Furthermore, in this patient, ultrasonography and ultimately autopsy did not demonstrate significant steatosis. While tests for hepatitis C and E were not available to exclude those diagnoses, the reappearance of injury on rechallenge makes it likely that tamoxifen was the primary cause of symptoms and liver test abnormalities.

Case 2. Nonalcoholic steatohepatitis induced by tamoxifen therapy.(2)

A 37 year old woman was found to have abnormal serum enzymes during long term tamoxifen therapy. Two years previously, she had been found to have bilateral breast cancers and underwent bilateral mastectomies followed by reconstructive breast surgery. The breast cancer tissue was human estrogen receptor negative. She was started on long term tamoxifen (20 mg daily) and goserelin (3.6 mg implant monthly) therapy. Before starting therapy, her serum enzymes were normal (Table), but one year later they were found to be elevated. She had no symptoms of liver disease and specifically denied fatigue, nausea and abdominal pain. She had no history of liver disease and denied alcohol use. She had no risk factors for viral hepatitis and was not taking other medications. Physical examination showed no fever, rash, abdominal tenderness or enlargement of liver or spleen. She was mildly overweight (body mass index 28.5), but had not gained weight in the previous year. Laboratory results showed moderate elevations in serum aminotransferase levels (ALT 150 U/L, AST 138 U/L) with normal alkaline phosphatase, bilirubin (0.3 mg/dL), albumin (4.5 g/dL) and prothrombin time (INR 1.1). Fasting blood glucose and lipids were normal. Tests for hepatitis A, B and C were negative as were autoantibodies. Serum ceruloplasmin was normal (34.4 mg/dL). Ultrasound of the abdomen suggested fatty liver. A liver biopsy showed severe macrovesicular steatosis with lobular hepatitis, and mild pericellular fibrosis without Mallory bodies, compatible with steatohepatitis. The combination of ursodeoxycholic acid, vitamin C and vitamin E were started and tamoxifen continued. Serum enzymes remained elevated and six months later began to rise reaching a peak of an ALT 770 U/L, AST 810 U/L, despite minimal or no rise in alkaline phosphatase and bilirubin levels. At this point, the patient began to complain of fatigue, nausea, vague abdominal discomfort, dark urine and itching. Tamoxifen and goserelin were discontinued. A repeat liver biopsy showed less steatosis, but increased lobular inflammation, ballooning degeneration and fibrosis with multiple Mallory bodies. Over the next several months, serum aminotransferases decreased minimally.

Key Points

Medication:Tamoxifen (20 mg daily)
Pattern:Hepatocellular (R=15)
Severity:1+ (serum enzyme elevations only with symptoms)
Latency:2 years
Recovery:Incomplete after 2 months
Other medications:Goserelin

Laboratory Values

Time After
Starting		Time After
Stopping		ALT
(U/L)		Alk P
(U/L)		Bilirubin
(mg/dL)		Other
PrePre24550.71 month before surgery
18 months150650.2
20 months189750.3Liver biopsy
21 months143670.3Vitamin E and ursodiol
23 months149650.3
26 months292640.4
29 months07701120.5Tamoxifen stopped
30 months1 month5671030.5Liver biopsy
31 months2 months4181020.4
Normal Values <40 <104 <1.2

Comment

Fatty liver develops in up to one third of women treated with tamoxifen, but is usually benign and not associated with serum enzyme elevations, symptoms or progressive liver disease. In a proportion of patients, however, the accumulation of fat is associated with appearance of inflammation and cell injury (steatohepatitis) which can lead to progressive fibrosis and ultimately to cirrhosis. Serum aminotransferase levels are usually minimally elevated. In this case, ALT elevations were dramatic and persistent, leading to liver biopsy and attempts to treat the fatty liver injury using ursodiol and vitamin E while continuing tamoxifen. These interventions appeared to have no effect, and serum enzymes continued to rise. A follow up liver biopsy showed worsening of the injury and progressive fibrosis. Stopping tamoxifen led to improvements in serum enzyme elevations, but the improvement was slow and incomplete at the time she was last seen.

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Tamoxifen – Generic, Nolvadex®, Tamone®

DRUG CLASS

Antineoplastic Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NUMBERMOLECULAR FORMULASTRUCTURE
Tamoxifen 10540-29-1 C26-H29-N-O image 134990041 in the ncbi pubchem database

CITED REFERENCES

1.
Blackburn AM, Amiel SA, Millis RR, Rubens RD. Tamoxifen and liver damage. Br Med J (Clin Res Ed). 1984;289:288. [PMC free article: PMC1442108] [PubMed: 6430441]
2.
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. [PMC free article: PMC4446235] [PubMed: 25754159]

ANNOTATED BIBLIOGRAPHY

References updated: 20 August 2020

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    (58 year old woman developed porphyria cutanea tarda after four years of tamoxifen therapy for breast cancer [bilirubin 0.5 mg/dL, ALT 48 U/L, Alk P 84 U/L] with no iron overload, hepatitis C or alcohol abuse, symptoms and liver tests improving on stopping tamoxifen).
  • Kanda T, Yokosuka O, Chiba T, Kojima H, Fukai K, Imazeki F, Saisho H. Nippon Shokakibyo Gakkai Zasshi. 2002;99:1119–21. [A case of steatohepatitis associated with tamoxifen] [PubMed: 12355903]
  • Günel N, Coskun U, Toruner FB, Sancak B, Yilmaz E, Cengiz O, Elbeg S, et al. Serum leptin levels are associated with tamoxifen-induced hepatic steatosis. Curr Med Res Opin. 2003;19:47–50. [PubMed: 12661780]
    (Among 34 women, 15 [44%] developed hepatic steatosis as detected by ultrasonography 3 months after starting tamoxifen for breast cancer; body weight and cholesterol did not change, but leptin levels rose in those developing steatosis but not in those without).
  • Nishino M, Hayakawa K, Nakamura Y, Morimoto T, Mukaihara S. Effects of tamoxifen on hepatic fat content and the development of hepatic steatosis in patients with breast cancer: high frequency of involvement and rapid reversal after completion of tamoxifen therapy. Am J Roentgenol. 2003;180:129–34. [PubMed: 12490491]
    (Among 67 women with breast cancer treated with tamoxifen followed with annual CT scans of the liver, 43% developed steatosis, all within 2 years, which was severe in 6% and which improved to baseline after therapy; no patient developed cirrhosis).
  • Murata Y, Ogawa Y, Saibara T, Nishioka A, Takeuchi N, Kariya S, Onishi S, et al. Tamoxifen-induced non-alcoholic steatohepatitis in patients with breast cancer: determination of a suitable biopsy site for diagnosis. Oncol Rep. 2003;10:97–100. [PubMed: 12469151]
    (Among 38 Japanese women with breast cancer treated with tamoxifen, CT scans of the liver showed increased fat in 13 [34%], which was often patchy and greater in the right than left lobe).
  • Ogawa Y, Murata Y, Saibara T, Nishioka A, Kariya S, Yoshida S. Follow-up CT findings of tamoxifen-induced non-alcoholic steatohepatitis (NASH) of breast cancer patients treated with bezafibrate. Oncol Report. 2003;10:1473–8. [PubMed: 12883726]
    (Among 333 Japanese women with breast cancer treated with tamoxifen, CT scans of the liver showed marked fat in 15 who then underwent liver biopsy which showed steatohepatitis in 14; adding bezafibrate allowed for continuation of tamoxifen, and improvements in liver fat were demonstrated in 5 of 6 patients).
  • Elefsiniotis IS, Pantazis KD, Ilias A, Pallis L, Mariolis A, Glynou I, Kada H, et al. Tamoxifen induced hepatotoxicity in breast cancer patients with pre-existing liver steatosis: the role of glucose intolerance. Eur J Gastroenterol Hepatol. 2004;16:593–8. [PubMed: 15167162]
    (Among 60 women with breast cancer receiving tamoxifen who had hepatic steatosis before starting tamoxifen, serum ALT levels rose in 26 [43%], and more commonly in those with higher BMI, glucose, cholesterol and triglyceride levels at baseline; ALT levels fell to normal within 6 months in all 18 patients who stopped tamoxifen).
  • Bruno S, Maisonneuve P, Castellana P, Rotmensz N, Rossi S, Maggioni M, Persico M, et al. Incidence and risk factors for non-alcoholic steatohepatitis: prospective study of 5408 women enrolled in Italian tamoxifen chemoprevention trial. BMJ. 2005;330:932. [PMC free article: PMC556336] [PubMed: 15746106]
    (Among 5408 Italian women with breast cancer treated with tamoxifen or placebo for 5 years, 64 developed persistent de novo elevations in serum ALT which was attributable to fatty liver in 52 [control 0.7% vs tamoxifen 1.3%]; hazard ratio [HR] for fatty liver was 2.0 for tamoxifen, but association was limited to overweight [HR 3.2] or obese [HR 5.4] women and none developed signs of cirrhosis).
  • Nagaie T, Hashimoto M, Kai M, Yamashiata N, Kondo J, Tokunaga M, Miyazaki M, et al. Changes in hepatic parenchymal ultrasound images in tamoxifen medication patients. Gan To Kagaku Ryoho. 2005;32:1925–8. [PubMed: 16282728]
    (Abstract only; among 156 women with breast cancer treated with tamoxifen, 36% developed ultrasound changes indicative of fatty liver, most within 6-12 months of starting).
  • Ohnishi T, Ogawa Y, Saibara T, Nishioka A, Kariya S, Fukumoto M, Onishi S, et al. CYP17 polymorphism and tamoxifen-induced hepatic steatosis. Hepatol Res. 2005;33:178–80. [PubMed: 16890174]
    (Among 180 women treated with tamoxifen for breast cancer, 57 [32%] developed hepatic steatosis as shown by CT; risk was higher [odds ratio=1.9] in those with CYP17 polymorphisms associated with higher serum estrogen levels).
  • Grieco A, Forgione A, Miele L, Vero V, Greco AV, Gasbarrini A, Gasbarrini G. Fatty liver and drugs. Eur Rev Med Pharmacol Sci. 2005;9:261–3. [PubMed: 16237810]
    (Review of drugs that can cause steatosis including amiodarone and tamoxifen).
  • Liu CL, Huang JK, Cheng SP, Chang YC, Lee JJ, Liu TP. Fatty liver and transaminase changes with adjuvant tamoxifen therapy. Anticancer Drugs. 2006;17:709–13. [PubMed: 16917217]
    (Ultrasound evidence of fatty liver developed in 53% of 156 Taiwanese women with breast cancer treated with tamoxifen vs 13% of 62 who received chemotherapy alone; rate increased over time, reversing slowly with stopping tamoxifen, but 21% of cases still had steatosis 48 months afterwards).
  • Ahmed MH, Osman KA, Osman MM. Invasive and non-invasive investigations for tamoxifen-induced non-alcoholic steatohepatitis (NASH): the benefit of computed tomography scan guided liver biopsy. Pathology. 2006;38:270–1. [PubMed: 16753757]
    (Letter discussing the role of liver biopsy in making the diagnosis of steatohepatitis in patients on tamoxifen and the focal distribution of fat in the liver shown by CT scan).
  • Ahmed MH, Osman KA. Tamoxifen induced-non-alcoholic steatohepatitis(NASH): has the time come for the oncologist to be diabetologist. Breast Cancer Res Treat. 2006;97:223–4. [PubMed: 16322887]
    (Letter discussing the pathogenesis of steatohepatitis stressing the need to monitor liver tests, lipids and fasting glucose levels in patients on tamoxifen).
  • Bilici A, Ozguroglu M, Mihmanli I, Turna H, Adaletli I. A case-control study of non-alcoholic fatty liver disease in breast cancer. Med Oncol. 2007;24:367–71. [PubMed: 17917083]
    (Cross sectional ultrasound study of 125 women with breast or ovarian cancer and 40 controls demonstrated high rate of steatosis [63-77%, 48% in controls], with highest rates in women on tamoxifen [71%]).
  • Takamura T, Shimizu A, Komura T, Ando H, Zen Y, Minato H, Matsushita E, et al. Selective estrogen receptor modulator raloxifene-associated aggravation of nonalcoholic steatohepatitis. Intern Med. 2007;46:579–81. [PubMed: 17473493]
    (53 year old woman with mild fatty liver disease developed worsening liver enzymes after starting raloxifene for osteoporosis, which improved upon stopping, with ALT rising from 179 to 356 and falling to 118 U/L 3 months after stopping).
  • Osman KA, Osman MM, Ahmed MH. Tamoxifen-induced non-alcoholic steatohepatitis: where are we now and where are we going? Expert Opin Drug Saf. 2007;6:1–4. [PubMed: 17181445]
    (Opinion article recommending monitoring of liver enzymes during tamoxifen therapy [particularly in overweight and obese patients] and intervening if ALT levels rise to 1.5 times ULN, with therapy directed at altering risk factors for fatty liver disease).
  • 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. [PMC free article: PMC3654244] [PubMed: 18955056]
    (Among 300 cases of drug induced liver disease in the US collected between 2004 and 2008, no cases were attributed to tamoxifen).
  • Ashraf M, Biswas J, Majumdar S, Nayak S, Alam N, Mukherjee KK, Gupta S. Tamoxifen use in Indian women--adverse effects revisited. Asian Pac J Cancer Prev. 2009;10:609–12. [PubMed: 19827879]
    (Among 3000 Indian women with breast cancer treated with tamoxifen, 55% developed fatty liver, which usually resolved upon stopping; no clinical features given).
  • Saphner T, Triest-Robertson S, Li H, Holzman P. The association of nonalcoholic steatohepatitis and tamoxifen in patients with breast cancer. Cancer. 2009;115:3189–95. [PubMed: 19484789]
    (Among 1100 women and 5 men with breast cancer in a tumor registry, 24 [2.2%] also had the diagnosis of nonalcoholic steatohepatitis [NASH], 17 of whom developed it after the diagnosis of breast cancer, including 2% of those who received tamoxifen and 0.3% of those who did not; ALT elevations improved slowly upon stopping, mean time to normalization being 23 months, occurring in 14 of 16 subjects).
  • Rabaglio M, Ruepp B., Soft/Text/Perche Steering Committee. Death due to liver failure during endocrine therapy for premenopausal breast cancer. Acta Oncol. 2010;49:874–6. [PubMed: 20482225]
    (Among 4500 women enrolled in trials of tamoxifen versus exemestane and ovarian function suppression, 2 developed acute liver failure, one on exemestane and one tamoxifen; 36 year old on tamoxifen for 10 months was found to have hepatomegaly and fatty liver and died suddenly one month later, autopsy showing cirrhosis and steatosis; few details of liver tests provided).
  • Cruz MJ, Alves S, Baudrier T, Azevedo F. Porphyria cutanea tarda induced by tamoxifen. Dermatol Online J. 2010;16:2. [PubMed: 20875323]
    (53 year old woman developed symptoms of porphyria cutanea tarda a year after starting tamoxifen for breast cancer and at 3 years evaluation showed ALT 70 U/L, GGT 130 U/L, but without iron overload, hepatitis C or alcohol abuse; symptoms, porphyrin levels and liver tests abnormalities resolved within 6 months of switching to letrozole).
  • Ahbeddou N, Belbaraka R, Fetohi M, Errihani H. Tamoxifen-induced hepatotoxicity. Indian J Cancer. 2011;48:385. [PubMed: 21921356]
    (46 year old woman developed jaundice 4 weeks after starting tamoxifen [laboratory values not given], resolving within 6 weeks of stopping).
  • 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: 23419359]
    (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, but none of the 96 were attributed to tamoxifen).
  • 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: 24552865]
    (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 attribute to tamoxifen).
  • Amacher DE, Chalasani N. Drug-induced hepatic steatosis. Semin Liver Dis. 2014;34:205–14. [PubMed: 24879984]
    (Review of the medications that can cause hepatic steatosis and steatohepatitis including amiodarone, tamoxifen, lomitapide, mipomersen, and antiretroviral and chemotherapy agents).
  • Lin Y, Liu J, Zhang X, Li L, Hu R, Liu J, Deng Y, et al. A prospective, randomized study on hepatotoxicity of anastrozole compared with tamoxifen in women with breast cancer. Cancer Sci. 2014;105:1182–8. [PMC free article: PMC4462391] [PubMed: 24975596]
    (Among 353 Chinese postmenopausal women with early stage breast cancer [ER+] treated with tamoxifen or anastrozole, the 3 year cumulative rate of fatty liver was higher with tamoxifen [41% vs 15%] although rates of abnormal liver tests were not [24.6% vs 24.7%])).
  • 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. [PMC free article: PMC4446235] [PubMed: 25754159]
    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 49 were attributed to antineoplastic agents, including 4 due to tamoxifen).
  • Rabinowich L, Shibolet O. Drug induced steatohepatitis: An uncommon culprit of a common disease. Biomed Res Int. 2015;2015:168905. [PMC free article: PMC4529891] [PubMed: 26273591]
    (Review of the pathogenesis of fatty liver caused by medications mentions that tamoxifen appears to enhance fatty acid synthesis and decrease in triglyceride secretion).
  • Hsu A, Belkin E, Han S, Pellish R. Tamoxifen-associated portal vein thrombosis causing severe oesophageal variceal bleeding. BMJ Case Rep. 2015;2015:bcr2015209988. [PMC free article: PMC4693120] [PubMed: 26315359]
    (46 year old woman on long term tamoxifen for breast cancer developed portal vein thrombosis and esophageal variceal bleeding with normal liver tests and imaging demonstrating portal vein thrombosis, responding to variceal banding, nadolol for portal hypertension and stopping tamoxifen, eventually without further bleeding and treatment with aromatase inhibitors).
  • Satapathy SK, Kuwajima V, Nadelson J, Atiq O, Sanyal AJ. Drug-induced fatty liver disease: An overview of pathogenesis and management. Ann Hepatol. 2015;14:789–806. [PubMed: 26436351]
    (Review of drugs that cause fatty liver disease and pathogenesis of fat accumulation and steatohepatitis).
  • Yang YJ, Kim KM, An JH, Lee DB, Shim JH, Lim YS, Lee HC, et al. Clinical significance of fatty liver disease induced by tamoxifen and toremifene in breast cancer patients. Breast. 2016;28:67–72. [PubMed: 27240168]
    (Among 1061 women with breast cancer and normal baseline ALT levels seen over a 1 year period in an Asian medical center, ALT elevations occurred in 45 of 618 [7.7%: peak values 46-237 U/L] who received SERMs vs 22 of 406 [4.5%] who did not; furthermore, fatty liver by imaging tests was found in 47 of 122 [42%] on SERM therapy vs 19 of 95 [20%] controls; nevertheless, no patient developed cirrhosis or died of liver disease).
  • Wadood A, Chesner R, Mirza M, Zaman S. Tamoxifen precipitation of familial hypertriglyceridaemia: a rare cause of acute pancreatitis. BMJ Case Rep. 2016;2016:bcr2016214837. [PMC free article: PMC4986136] [PubMed: 27489062]
    (36 year old woman with familial hypertriglyceridemia and ER+ breast cancer developed recurrent episodes of pancreatitis associated with high serum levels of triglycerides that stopped once tamoxifen was discontinued).
  • Yan M, Wang J, Xuan Q, Dong T, He J, Zhang Q. The relationship between tamoxifen-associated nonalcoholic fatty liver disease and the prognosis of patients with early-stage breast cancer. Clin Breast Cancer. 2017;17(3):195–203. [PubMed: 28089627]
    (Among 646 patients with early stage breast cancer treated with tamoxifen, 221 developed fatty liver and had a slightly lower disease free survival [but not overall survival] and predictive factors for fatty liver included body mass index, triglyceride levels, LDL cholesterol levels and ALT levels after 6 months of therapy).
  • Miele L, Liguori A, Marrone G, Biolato M, Araneo C, Vaccaro FG, Gasbarrini A, et al. Fatty liver and drugs: the two sides of the same coin. Eur Rev Med Pharmacol Sci. 2017;21(1) Suppl:86–94. [PubMed: 28379591]
    (Review of the pathogenesis of fatty liver and steatohepatitis caused by medications including amiodarone, tamoxifen, methotrexate, valproate and antiretroviral and chemotherapy agents).
  • Hong N, Yoon HG, Seo DH, Park S, Kim SI, Sohn JH, Rhee Y. Different patterns in the risk of newly developed fatty liver and lipid changes with tamoxifen versus aromatase inhibitors in postmenopausal women with early breast cancer: A propensity score-matched cohort study. Eur J Cancer. 2017;82:103–14. [PubMed: 28651157]
    (In a retrospective cohort study of 328 Korean women with breast cancer receiving antiestrogen adjuvant therapy, fatty liver as detected by ultrasound arose in 13 per 100 patient years on tamoxifen versus 8 per 100 on aromatase inhibitors [anastrozole or letrozole], and those on tamoxifen were more likely to progress [42% vs 10%]).
  • Chang HT, Pan HJ, Lee CH. Prevention of tamoxifen-related nonalcoholic fatty liver disease in breast cancer patients. Clin Breast Cancer. 2018;18:e677–e685. [PubMed: 29287963]
    (In a retrospective analysis of 266 women with early breast cancer treated with tamoxifen, 123 had fatty liver and risk factors for its development or worsening were baseline BMI and whether the patient engaged in regular physical activity, suggesting that exercise might be an effective means of preventing development of fatty liver in women on tamoxifen).
  • Wyffels K, Horsmans Y. Tamoxifen-induced hepatotoxicity caused by drug interaction with direct-acting antiviral agents for hepatitis C. J Oncol Pharm Pract. 2019;25:2038–40. [PubMed: 30563414]
    (68 year old man with hemophilia B and chronic hepatitis C had a sudden rise in serum enzymes [bilirubin 2.0 mg/dL, ALT 548 U/L, Alk P 76 U/L] 7 weeks after starting direct antiviral therapy [Viekira Pak], which resolved with stopping tamoxifen that he had been taking for breast cancer in remission, suggesting that drug-drug interactions with tamoxifen may cause serious adverse events; he was later able to tolerate tamoxifen after clearance of HCV).
  • Meunier L, Larrey D. Chemotherapy-associated steatohepatitis. Ann Hepatol 2020: S1665-2681(20)30004-1. [PubMed: 32061473]
    (Review of the chemotherapeutic agents that have been linked to fatty liver and steatohepatitis including 5-fluorouracil, irinotecan, methotrexate, tamoxifen, corticosteroids and asparaginase many of which cause fat accumulation because of mitochondrial injury, which arises with prolonged therapy, can become chronic, but usually reverses once the agent is stopped).
  • Hong J, Huang J, Shen L, Zhu S, Gao W, Wu J, Huang O, et al. A prospective, randomized study of Toremifene vs. tamoxifen for the treatment of premenopausal breast cancer: safety and genital symptom analysis. BMC Cancer. 2020;20:663. [PMC free article: PMC7364473] [PubMed: 32677982]
    (Among 92 women with early breast cancer treated with tamoxifen vs toremifene for one year, fatty liver arose in a similar proportion: 32% vs 27%]).
  • Yoo JJ, Lim YS, Kim MS, Lee B, Kim BY, Kim Z, Lee JE, et al. Risk of fatty liver after long-term use of tamoxifen in patients with breast cancer. PLoS One. 2020;15:e0236506. [PMC free article: PMC7392315] [PubMed: 32730287]
    (Among 900 women with breast cancer treated between 2007 and 2017 with tamoxifen, an aromatase inhibitor or no therapy for a median of 49 months, de novo development of fatty liver was more frequent with tamoxifen as was worsening of underlying fatty liver, but neither seemed to affect overall survival).

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