Abrupt danazol stop in HAE can cause temporary hepatitis: Study
Doctors suggest tapering drug slowly to protect against liver inflammation
Suddenly stopping long-term preventive treatment with danazol — a hormone therapy being phased out in hereditary angioedema (HAE) — caused temporary hepatitis, or an inflammation of the liver, for five adults with HAE in the Netherlands, a new study found.
According to the researchers, these findings suggest that doctors should consider tapering this androgen slowly when discontinuing its use in HAE patients.
“This study is the first to demonstrate that abrupt discontinuation of long-term danazol use causes a transient, self-limiting hepatitis,” the researchers wrote, though noting “normalization [occurred] within 17 weeks,” or about four months.
“These findings should drive the design of future clinical trials involving patients,” the team added.
The study, “Transient hepatitis as a Novel Withdrawal Phenomenon After Danazol Discontinuation in Hereditary Angioedema,” was published as a clinical communication in The Journal of Allergy and Clinical Immunology: The Practice.
HAE is a rare, chronic type of angioedema that occurs due to genetic mutations that are usually inherited from a patient’s biological parents. Similar to other types of angioedema, it is marked by recurrent, sudden episodes of swelling that can occur anywhere in the body.
Side effects common with use of androgens like danazol
Androgens are hormones similar to testosterone — the male sex hormone — that can be used to prevent swelling in HAE. But while androgens reduce the number of attacks, they can also cause many side effects, including acne, mood changes, weight gain, menstrual problems, and even damage to the liver.
With safer options now available, doctors no longer recommend androgens. However, when patients on long-term treatment discontinue the use of such medications, they may experience temporary symptoms such as fatigue and mood swings.
In this study, a research team from the University of Amsterdam described five patients who developed hepatitis after stopping danazol, which had not been reported before.
After one patient developed temporary hepatitis after stopping long-term treatment with danazol, doctors at Amsterdam UMC investigated the occurrence of this condition in other individuals with HAE who had stopped danazol in 2024. The last liver test, taken before stopping danazol, was used as a baseline to compare any changes.
Three of the five total patients were women, and two were men, with ages ranging from 51 to 65. These individuals had been on danazol for a median of 30 years, with weekly doses ranging from 300 to 1,400 mg. While on treatment, all liver tests and scans were normal. None of the patients drank alcohol heavily or took medications known to damage the liver.
After stopping danazol, all showed an increase in liver enzymes — particularly alanine transaminase, or ALT, and aspartate transferase, or AST — which signified damage. ALT in the blood increased to levels as high as 337 units per liter (U/L; normal is below 34), and AST up to 101 U/L (normal is below 40).
These levels returned to normal within 12-17 weeks “without medical intervention,” the researchers noted.
None of the patients showed signs of liver failure, such as jaundice or yellowing of the skin, confusion, or problems with blood clotting. Tests ruled out other possible causes of hepatitis, including viral infections or autoimmune diseases, and problems with iron or copper metabolism.
First report of hepatitis after stopping danazol, researchers say
A liver biopsy — a small sample of tissue — collected from one patient seven weeks after stopping danazol showed mild inflammation and signs that the liver was healing. The cells responsible for cleaning damaged tissue, called Kupffer cells, were active, and the liver’s blood vessels appeared slightly widened but without scarring.
Hepatitis after stopping danazol had never been described before, according to the researchers. This finding suggests that a temporary form of inflammation may develop more often than expected after long-term treatment with androgens, even at low doses, the team noted.
Future research should investigate whether gradual tapering could mitigate the risk of hepatitis observed upon [danazol] withdrawal.
Some clinical studies testing potential treatments for HAE have reported increased liver enzymes in patients who had recently stopped androgens. Increases in ALT were observed only in patients who had discontinued danazol shortly before starting the new treatment.
According to the researchers, this study suggests that these increases are likely caused by stopping androgens, rather than by the new treatments. To avoid confusion, future clinical testing should wait at least three months between stopping danazol and starting another treatment, the team suggested.
“In this study, all patients underwent abrupt cessation of danazol,” the researchers wrote, adding that the findings have “practical implications for monitoring patients undergoing transition away from … androgen therapy.”
Further, the team concluded, “future research should investigate whether gradual tapering could mitigate the risk of hepatitis observed upon [danazol] withdrawal.”
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