Anastrozole is considered a drug with a mild 'liver' profile, and for most people this is true. But the liver is the main organ of its transformation, and the mechanism of action itself - the suppression of estrogens - has remote consequences for fat metabolism in the liver. The editorial team examines what exactly is known about the effect of anastrozole on the liver and which indicators are worth paying attention to.
How the liver processes anastrozole
After taking a tablet, anastrozole is almost completely absorbed from the intestine. Only about 40% of the drug binds to plasma proteins, so a significant part of it circulates in free form. The half-life is about two days, so a stable concentration is established in about a week of daily intake.
The main part of the drug is transformed in the liver. Metabolism occurs by several pathways: N-dealkylation, hydroxylation with the participation of cytochromes (in particular CYP3A4) and glucuronidation. The main circulating metabolite - triazole - is pharmacologically inactive with respect to aromatase. According to the package insert, less than 10% of the dose is excreted unchanged in the urine.
Such a profile means that the liver is responsible for the elimination of anastrozole, but the drug itself does not form reactive toxic metabolites in significant quantities - at least, neither preclinical nor clinical data indicate this. This distinguishes it from a number of other drugs for which liver damage is a frequent problem.
In people with stable alcoholic cirrhosis, the pharmacokinetic studies cited in the package insert did not reveal significant changes in the elimination of anastrozole, so with mild and moderate impairment of liver function no dose correction is envisaged. However, there are no data for severe hepatic insufficiency, and here caution is needed.
Direct hepatotoxicity: what has been described
In large randomized studies, in particular ATAC, where thousands of women took anastrozole for five years, serious liver damage was not a noticeable problem. In the package insert, among adverse reactions, an increase in liver enzymes (ALT, AST, alkaline phosphatase, GGT) and bilirubin is mentioned, as well as very rare cases of hepatitis.
The LiverTox database of the US National Institutes of Health describes anastrozole as a drug that rarely causes a slight increase in transaminases, while clinically pronounced drug-induced liver damage occurs only in isolated reports. The mechanism of such cases is unknown; they are regarded as idiosyncratic reactions not directly related to the dose.
Compared with tamoxifen, for which steatosis and rare severe hepatitis are well described, anastrozole has a calmer 'liver' profile. However, this comparison concerns postmenopausal women taking the standard dose; there is much less data on other groups and regimens.
In the sports environment anastrozole is often combined with oral 17-alpha-alkylated steroids. In that case, changes in liver enzymes are almost always caused precisely by the steroids, which are able to cause cholestasis, peliosis and liver tumors. It is incorrect to attribute the deviations to anastrozole or, conversely, to consider it a 'protection' of the liver.
Estrogens, fat and the liver
A less obvious but interesting aspect is the effect of deep suppression of estrogens on fat metabolism in the liver. Estradiol participates in the regulation of insulin sensitivity, the oxidation of fatty acids and the export of lipids from hepatocytes. When estrogens are lacking, the liver is more inclined to accumulate fat.
Convincing evidence of this is provided by descriptions of men with a congenital aromatase deficiency. In the patient described by Maffei and colleagues (2004), liver steatosis, insulin resistance and disorders of lipid metabolism were found; part of the changes decreased with estradiol replacement therapy. This indicates that estrogens formed by aromatase are important for liver health in men as well.
Whether long-term intake of anastrozole in standard doses leads to clinically significant steatosis has not been unambiguously established. Individual observational studies in oncology patients reported the development of fatty liver disease on aromatase inhibitors, but their results are limited by design and concomitant factors (obesity, age, chemotherapy).
In practice this means that people with obesity, type 2 diabetes or already detected fatty liver disease should take this potential effect into account and pay attention to body weight, nutrition and physical activity during treatment.
| Mechanism | Essence | Strength of evidence |
|---|---|---|
| Idiosyncratic damage | Rare hepatitis not related to dose | Isolated clinical reports |
| Increase in enzymes | Asymptomatic rise in ALT/AST, GGT | Described in the package insert |
| Estrogen deficiency → steatosis | Disorders of lipid metabolism in hepatocytes | Models, aromatase deficiency, observational data |
| Changes in blood lipids | Possible increase in cholesterol | Described in the package insert |
Liver diseases and interactions
Several groups of people require caution:
- patients with severe hepatic insufficiency, for whom pharmacokinetic data are lacking;
- people with non-alcoholic fatty liver disease and metabolic syndrome;
- those who regularly consume alcohol;
- persons who simultaneously take potentially hepatotoxic drugs or oral anabolic steroids.
As for drug interactions, anastrozole in clinical concentrations does not significantly inhibit the main liver cytochromes, so it rarely changes the level of other drugs. The reverse effect is more important: in studies tamoxifen lowered the concentration of anastrozole in the blood, which is one of the reasons why these drugs are not combined.
Estrogen-containing drugs (hormone replacement therapy, combined contraceptives) counteract the effect of anastrozole and are not combined with it. This does not concern the liver directly, but it is important for understanding why the list of 'compatible' drugs should be agreed with a doctor.
Herbal remedies and 'hepatoprotectors' with unproven action should not be added without consultation: some plant supplements are themselves able to cause liver damage, complicating the search for the cause of deviations in tests.
Which tests make sense
Before starting treatment it is reasonable to perform basic liver tests: ALT, AST, alkaline phosphatase, GGT and bilirubin. They give a reference point against which subsequent results can be compared. In the presence of steatosis risk factors, a liver ultrasound is useful.
During long-term intake, liver tests are usually monitored periodically, together with a lipid panel, since anastrozole can raise cholesterol. The frequency is determined by the doctor in view of concomitant diseases and other drugs.
In interpretation it is important to remember the muscular source of AST and ALT: intense training a day or two before the test can raise these indicators without any liver damage. In doubtful cases, a simultaneous determination of creatine kinase helps.
Alarming symptoms - jaundice, dark urine, pain in the right hypochondrium, severe weakness, itching - require immediate consultation regardless of previous normal tests.
Editorial conclusions
Anastrozole is mainly metabolized by the liver into inactive compounds, and direct hepatotoxicity is not characteristic of it: asymptomatic changes in enzymes and rare cases of hepatitis have been described.
A more subtle risk is associated with the mechanism of action itself: a deep estrogen deficiency can contribute to disorders of fat metabolism in the liver, which is especially important for people with metabolic syndrome.
Monitoring of liver tests and lipids, attention to body weight and avoidance of hepatotoxic combinations are a reasonable basis for safe treatment.
We also recommend reading 'Toremifene and the liver', 'The effect of anastrozole on the lipid profile and bone tissue' and 'Tests during the use of anastrozole'.
References
- Arimidex (anastrozole) tablets. Prescribing information. U.S. Food and Drug Administration.
- LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Anastrozole. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases.
- Maffei L, Murata Y, Rochira V, et al. Dysmetabolic syndrome in a man with a novel mutation of the aromatase gene: effects of testosterone, alendronate, and estradiol treatment. J Clin Endocrinol Metab. 2004;89(1):61–70.
- Baum M, Buzdar AU, Cuzick J, et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet. 2002;359(9324):2131–2139.
- Santen RJ, Brodie H, Simpson ER, et al. History of aromatase: saga of an important biological mediator and therapeutic target. Endocr Rev. 2009;30(4):343–375.
- Pope HG Jr, Wood RI, Rogol A, et al. Adverse health consequences of performance-enhancing drugs: an Endocrine Society scientific statement. Endocr Rev. 2014;35(3):341–375.
Andriy Melnyk
A strength-sports coach and author of programs for beginner and intermediate levels. Writes about training planning.
