Anabolic-androgenic steroids and liver injury.Ask about use of anabolic steroids in young men with unexplained cholestasis to prevent progressive liver injury. In the face of increasing societal pressure to achieve bodily perfection, young men in particular sometimes turn to anabolic steroids to help them achieve the body they want. The health consequences of this choice are often overlooked. We describe two cases of severe cholestatic liver disease in young men who had taken anabolic steroids with the aim of androgenic anabolic steroids liver their body image. A 32 year old man presented with a seven day history of nausea, vomiting, and jaundice associated with severe androgenic anabolic steroids liver. He had no medical history of will prednisone increase wbc and had not taken any prescribed medications for several years.
Androgenic/Anabolic steroid-induced toxic hepatitis. - PubMed - NCBI
Androgenic steroids are used for male sex hormone replacement and in the therapy of malignancies. The androgens also have anabolic effects and are used in catabolic or muscle wasting states.
The synthetic anabolic steroids are also widely used illicitly for body building. Many synthetic androgenic steroids are capable of causing cholestatic liver injury and long term use of androgens is associated with development of liver tumors including hepatocellular carcinoma and hepatic adenoma. Testosterone is the major male sex hormone and is produced by the male testes in men and to a lesser extent by the adrenal glands in both men and women.
Unmodified testosterone is not orally available, so it must be given intramuscularly, sublingually or by transcutaneous patch. Modifications of testosterone have been developed that are more bioavailable or have a longer duration of action. Modification by esterification testosterone cypionate, enanthate and propionate maintains the virilizing effects of testosterone, but increases potency and duration of action. Alkylation of the C position of testosterone allows for oral administration and often alters the relative anabolic potency in relation to the masculinizing effects.
The C alkylated testosterones include methyltestosterone meth" il tes tos' ter one , methandrostenolone meth an" droe stene' oh lone , oxymetholone ox" i meth' oh lone , danazol dan' a zol , fluoxymesteone floo ox" i mes' ter one , stanazol stan oh' zoe lol , norethandrolone nor eth' an drone and oxandrolone ox an' droe lone , and have been extensively evaluated as a means of increasing weight gain and muscle development in catabolic states as well as to improve athletic performance.
They have also been used to treat aplastic anemia and bone marrow failure of several causes. They are often well tolerated and have limited virilizing activity.
However, the C alkylated androgenic steroids have all been implicated in cases of liver injury, including prolonged cholestasis, peliosis hepatis, nodular regeneration, hepatic adenomas and hepatocellular carcinoma.
In contrast, the esterified testosterones have only rarely been implicated in causing cholestasis, although their long term use may increase the risk of hepatic tumors and nodular transformation, but seemingly at a much lower rate than the alkylated testosterones. Current uses of androgenic steroids include androgen deficiency, breast cancer, postpartum breast engorgement, hereditary angioneurotic edema, endometriosis and fibrocystic breast disease.
The androgenic steroids are also used off label and illegally as a means of increasing muscle mass and athletic performance. The abuse of anabolic steroids is particularly common among body builders and young male athletes, although their use has been banned from the Olympics and in major professional and college sports.
Recently, anabolic steroids have been found in some nutritional supplements available over-the-counter or via the internet which are advertised as increasing a sense of well being and muscle mass or as an aid to body building. Androgenic and anabolic steroids have been implicated in four distinct forms of liver injury: These adverse events have been most closely linked with the C alkylated testosterones, although tumors have also been associated with unmodified and esterified testosterone preparations.
Use of androgenic steroids is associated with a variable rate of serum enzyme elevations which are usually asymptomatic and self limited. Such elevations have been most closely linked to danazol and oxymethalone, but are usually transient and do not require dose adjustment or discontinuation.
More importantly, therapy with anabolic steroids is linked to a distinctive form of acute cholestasis. The liver injury generally arises within 1 to 4 months of starting therapy, but may be delayed to as long as 6 to 24 months Case 1. The onset is usually insidious with development of nausea, fatigue and itching followed by dark urine and jaundice.
Jaundice and pruritus can be prolonged even if the anabolic steroids are discontinued promptly. Typically, serum enzyme elevations are quite modest, with ALT and alkaline phosphatase levels that are less the 2 to 3 times elevated and that are sometimes normal despite deep jaundice. Serum ALT levels may be somewhat high early during injury, but then fall to moderate or low levels.
Liver biopsy typically shows a bland cholestasis with minimal inflammation and hepatocellular necrosis. Bile duct injury is typically absent or mild and vanishing bile duct syndrome rarely ensues. Cholestasis has not been described in patients receiving unmodified testosterone by injection or transdermal patch. This clinical phenotype of bland cholestasis is so typical of anabolic steroids, that the diagnosis can be suspected in a patient who denies taking anabolic steroids or who is taking an herbal formulation meant to increase muscle strength or energy and that contains an anabolic steroid even though it is not labelled as such.
Use of anabolic steroids has also been linked to vascular changes in the liver referred to as peliosis hepatis. Peliosis hepatis is a rare syndrome in which there are blood filled enlarged sinusoids and cysts focally or throughout the liver.
There is usually an accompanying sinusoidal dilatation and loss of the normal endothelial barrier. The liver may be enlarged, deep red in color and fragile. Peliosis hepatis most typicaly occurs in patients with advanced wasting diseases tuberculosis, cancer , but has also been associated with long term use of anabolic steroid therapy for aplastic anemia and hypogonadism as well as in body building.
Serum enzyme levels are usually normal or are mildly and nonspecifically elevated. Patients may present with right upper quadrant discomfort and hepatomegaly or with sudden abdominal pain and vascular collapse due to hepatic rupture and hemoperitoneum. Peliosis may also be an incidental finding found on imaging of the liver or during abdominal surgery or at autopsy.
Peliosis associated with anabolic steroids usually reverses, at least in part, with stopping therapy. Peliosis can involve other organs, most typically the spleen.
The androgens act by engagement of intracellular androgenic steroid receptors which are translocated to the nucleus and attach to androgen response elements on DNA inducing a cassette of androgen stimulated genes that are important in cell growth and development. An unregulated growth stimulus to hepatocytes is the likely cause of nodular regeneration and hepatic tumors related to anabolic steroid use. The cause of cholestasis due to the C substituted androgens is not well defined, but high doses cause a similar cholestasis in some animal models.
The syndrome is similar to cholestasis of pregnancy and the jaundice associated with high doses of estrogens or birth control pills and may be due to partial lack or variant of bile salt transporter proteins.
The severity of liver injury due to anabolic steroids ranges from minor, transient serum enzyme elevations to profound and prolonged cholestasis, as well as hepatic peliosis and benign and malignant liver tumors. The first priority in management should be stopping the androgenic steroid. Unfortunately, athletes and body builders may resist this recommendation. Merely decreasing the dose of androgenic steroid or switching to another formulation is not appropriate and should be specifically discouraged.
Patients being treated for hypogonadism may be switched to an unmodified form of testosterone, given by injection or cutaneous patch. Patients with marked cholestasis may be benefitted by symptomatic therapy of pruritus and fat soluble vitamin supplementation. Ursodiol is often used in drug induced cholestasis, but is efficacy has never been shown in a controlled prospective manner. Use of corticosteroids is usually ineffective and should be avoided. The syndrome is usually reversable with stopping therapy, but full recovery is often delayed.
In addition, fatalities have been reported, usually due to marked cholestasis complicated by malnutrition, renal failure and associated opportunitistic infections. Representative androgenic steroids include the following: Anabolic steroids nandrolone, stanozolol Pattern: A very typical case of severe cholestasis due to anabolic steroid use.
Because the steroids were being used without medical supervision, the dose and actual duration of use of each preparation was unclear, but cholestasis usually arises within 4 to 12 weeks of starting a C alkylated androgenic steroid. The jaundice can be severe and prolonged and accompanied by severe pruritus and marked weight loss. The serum enzymes are typically minimally elevated except for a short period immediately after stopping therapy.
The pattern of enzyme elevations can be hepatocellular, cholestatic or mixed. Ma Huang has also been implicated in cases of drug induced liver injury, but is associated with an acute hepatocellular pattern of injury.
Hormonal derivatives and related drugs. Expert review of effects of androgenic steroids on the liver published in ; two forms of hepatic injury occur with anabolic steroids: Chitturi S, Farrell GC. Adverse effects of hormones and hormone antagonists on the liver.
Review of hepatotoxicity of androgenic steroids including cholestasis, vascular disorders, benign tumors and hepatocellular carcinoma. Textbook of pharmacology and therapeutics. Jaundice during methyltestosterone therapy. Am J Med ; 8: Jaundice of hepatic origin during the course of methyltestosterone therapy. N Engl J Med ; Am J Clin Pathol ; Testosterone therapy for the pruritus of obstructive jaundice. Br Med J ; 2: Jaundice due to methyl testosterone therapy.
Ann Intern Med ; Jaundice due to methyltestosterone therapy. J Lancet ; Jaundice during administration of methylestrenolone. J Clin Endocrinol ; Complications during administration of methylestrenolone.
A six-month evaluation of an anabolic drug, norethandrolone, in underweight persons. Bromsulphalein BSP retention and liver function. Am J Med ; Cholestasis produced by administration of norethandrolone. Oral methyltestosterone and jaundice.
Br Med J ; 1: Jaundice associated with norethandrolone Nilevar therapy. Dtsch med Wschr ; Peliosis hepatic after administration of fluoxymesterone. Can Med Assoc J ; Changes in bile canaliculi produced by norethandrolone: J Lab Clin Med ; Effects of anabolic steroids on liver function tests and creatine excretion.
Studies of hepatic function during methandienone therapy. Jaundice associated with norethindrone acetate therapy.