the problem is lack of scientific understanding, two heads to every coin.
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.
Background
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 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-17 position of testosterone allows for oral administration and often alters the relative anabolic potency in relation to the masculinizing effects. The C-17 alkylated testosterones include methyltestosterone, methandrostenolone, oxymetholone, danazol, fluoxymesteone, stanazol, norethandrolone and oxandrolone, 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-17 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 17-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.
Hepatotoxicity
Androgenic and anabolic steroids have been implicated in four distinct forms of liver injury: transient serum enzyme elevations, an acute cholestatic syndrome, chronic vascular injury to the liver (peliosis hepatis) and hepatic tumors including adenomas and hepatocellular carcinoma. These adverse events have been most closely linked with the C-17 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. 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. The frequency of acute cholestasis from androgenic steroids is not well known, but it is likely somewhat dose related and may occur in ~1% of patients treated with methyltestosterone, danazol, stanozolol or oxymetholone. 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 most serious complication of anabolic steroid use is the development of hepatic tumors, either adenoma or hepatocellular carcinoma. The hepatic tumors arise in patients on long term androgenic steroids, usually during therapy of aplastic anemia or hypogonadism, but occasionally in athletes or body builders using anabolic steroids illicitly. Tumors are typically found after 5 to 15 years of use, but onset within 2 years of starting therapy with testerosterone esters has been described. Many of the case reports have occurred in patients with other risk factors for cancer, such as Fanconi’s syndrome, iron overload or chronic hepatitis C (from blood transfusions). However, hepatic adenomas and hepatocellular carcinoma have also been described in patients taking androgenic steroids who have no other evidence of liver disease and normal histology in the nontumor parts of the liver. The pathology of the tumors is usually hepatic adenoma or “well differentiated” hepatocellular carcinoma or hepatic adenoma with areas of malignant transformation. Rare instances of cholangiocarcinoma and angiosarcoma have also been described in patients on long term androgenic steroids. Clinical presentation is generally with right upper quadrant discomfort and a hepatic mass found clinically or on imaging studies. Routine liver tests are often normal unless there is extensive spread or rupture or an accompanying liver disease. Alphafetoprotein levels are usually normal. There is often (but not always) spontaneous regression in the tumor when the anabolic steroids are stopped. Hepatocellular carcinoma arising during anabolic steroid therapy is believed to have a better prognosis than that related to cirrhosis or chronic hepatitis B and C; however, deaths from hepatic rupture or tumor spread and metastasis have been reported in patients with anabolic steroid related hepatocellular carcinoma without cirrhosis.
Finally, nodular regenerative hyperplasia of the liver has been described in rare patients on long term anabolic or androgenic steroids. The condition is usually asymptomatic or associated with mild abdominal discomfort due to hepatomegaly. Rarely, marked nodular regenerative hyperplasia with portal hypertension and splenomegaly has been described. This process may also be related with development of hepatic tumors with androgenic steroids as nodular regeneration is sometimes found in the surrounding “normal” liver.
Mechanism of Injury
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-17 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.
Outcome and Management
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 recovery is often protracted. 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: danazol, fluoxymesterone, methandienone, methenolone, methyltestosterone, nandrolone, norethandrolone, oxandrolone, oxymetholone, stanozolol, testosterone (cypionate, enanthate, propionate).
Statistics: Posted by bigale — Thu Dec 05, 2013 12:30 pm