Hepatotoxicity
It is a well-known fact that most oral anabolic steroids, as well as a select few injectable anabolic steroids induce a measure of liver toxicity (properly referred to as hepatotoxicity) in the body. The range of hepatotoxicity that these compounds can cause varies a great deal, ranging from very minor to serious life-threatening damage. The word "liver toxicity" and "hepatotoxicity" is thrown around a lot in bodybuilding circles and throughout the anabolic steroid using community, but how many people actually understand what these terms mean? How many people actually know what specifically it is that is "toxic" about the anabolic steroid in the liver? What is it that actually happens to the liver cells (hepatocytes)? The majority of people who throw around the words "liver toxic" will not be able to answer those questions at all. This is where that should change. After reading through this post, you will understand why certain anabolic steroids cause hepatotoxicity, what hepatotoxicity actually is, and how it affects the body, and most importantly: what you can do about it and what liver protectants to take.
Drug Metabolism
When it comes to drug metabolism, the liver’s primary function is to metabolize the drug into a form that is suitable for elimination by the kidneys. The main goals of this metabolism is to reduce fat solubility, make the drug water soluble, and to decrease its biological activity so that it stops working. This occurs for not only foreign substances (known as xenobiotics, which drugs are considered), but also endogenous chemicals. Drug metabolism in the liver exists in two main phases, phase I and phase II.
Phase I: Phase I metabolism happens primarily in the smooth endoplasmic reticulum of hepatocytes. The main purpose of this phase is to make lipid soluble compounds water soluble. This typically renders the metabolites of the drug to be inactive, but not always. This is the phase that we want to focus on with oral steroids, and is where the C17aa comes into play in protecting the steroid from being degraded by the liver.
Phase II: Phase II metabolism takes place in the cytosol of hepatocytes. In this phase, the products from phase I will undergo conjugation to increase their water solubility.
The efficacy of the enzymes used in drug metabolism are age-dependent. In newborns and the geriatric, the ability to metabolize drugs is greatly decreased. Smoking can increase the efficacy of drug metabolism through the inhalation of polycyclic aromatic hydrocarbons. This is most noticeably manifested in the increased metabolic activity of caffeine.
Anabolic Androgenic Steroids
C17-Alpha Alkylation & What It Does
It's common knowledge that oral steroids are known as being liver toxic, while injectable anabolic steroids are not (at least not to as great of an extent as orals are). There is a reason for this, and that is: C17-alpha alkylation (C17aa). Without the C17aa modification, very little of the anabolic steroid when ingested will survive hepatic metabolism (liver metabolism), and not enough of it will reach the bloodstream to produce any noticeable effects. It was then discovered at one point, that by modifying the chemical structure by adding a methyl group (also known as an alkyl group) to the 17th carbon on the steroid structure (also known as carbon 17-alpha), it would allow the anabolic steroid to become more resistant to the hepatic metabolism that would previously render the majority of the ingested steroid into inactive metabolites. This chemical bonding of a methyl group onto the 17th carbon is what is known as C17-alpha alkylation. It is because of C17-alpha alkylation, that the anabolic steroid becomes orally active and bioavailable – without it, the anabolic steroid would not survive liver metabolism. However, the negative downside in this case is that of increased hepatotoxicity (increased liver toxicity). C17-alpha alkylation allows an anabolic steroid to become more resistant to hepatic breakdown, and any compound that is further resistant to hepatic breakdown will always have greater hepatotoxicity associated with it for various reasons. But how does this happen?
C17aa effectively alters the chemical structure enough to block the enzyme 17beta-hydroxysteroid dehydrogenase (17beta-HSD) from interacting with the hormone in the liver, which would normally metabolize the steroid into an inactive metabolite. However, the liver is now forced to metabolize the anabolic steroid through other means. At this point in time, it is unknown as to how exactly the C17aa modification causes hepatotoxicity, but it is strongly hypothesized that because the liver contains a high concentration of androgen receptors[1] , the now unaltered and unmetabolized anabolic steroid (which is now instantly highly active) that is making the first pass through the liver will exhibit heavy amounts of androgenic activity in the liver because its metabolism has been blocked. Because it is being ingested orally, and therefore makes the first pass through the liver, the liver then becomes exposed to massive concentrations of these active anabolic steroids immediately, rather than through the injection route of administration where the anabolic steroid does not have to make a first pass through the liver (and therefore the liver is not exposed to massive amounts of active androgens all at once). The fact that studies have demonstrated that the greater the androgenic strength an oral anabolic steroid exhibits, the worse the hepatotoxicity is, lends credence to the theory that androgenic activity is correlated with hepatotoxicity in oral AAS.[2][3]
Trenbolone
Trenbolone does not possess C17-alpha alkylation, however, it is known to possess ever so small amounts of hepatotoxicity. This is believed to be because of the nature of Trenbolone’s chemical structure, which causes Trenbolone to exhibit a higher resistance to hepatic metabolism and breakdown even though it is not C17-alpha alkylated. The small amount of hepatotoxicity is not a large cause for concern at all, as Trenbolone’s minute amount of liver toxicity does not even reach the amounts of toxicity exhibited by oral C17-alpha alkylated anabolic steroids. The slight hepatotoxicity can be a concern for individuals with pre-existing liver problems (known or unknown) and this should be kept in mind. Every potential Trenbolone user should always have blood work (see Liver Function Tests below) done in order to monitor liver enzyme readings regardless, and a proven liver support supplement (see Liver Protection below) can be utilized during a Trenbolone cycle for the extra assurance of proper liver function.
Drug Induced Hepatotoxicity
Drug induced hepatotoxicity can have many causes. Some medications cause direct damage to hepatocytes while others block certain metabolic processes. As an example, acetaminophen itself is not the source of hepatotoxicity, but rather one of its metabolites. When taken in extreme quantities, this metabolite accumulates because the enzymes required are unable to keep up in phase II metabolism and cell damage occurs. Likewise, mitochondrial damage can increase oxidative stress which can damage hepatocytes.
These causes are categorized in seven general categories based on the mechanism of hepatotoxicity. The main categories where AAS and ancillaries are implicated are:
Steatosis: Steatosis is the accumulation of triglycerides in the liver. Liver function tests (LFTs) are unreliable when it comes to the diagnosis of hepatic steatosis. Often will have an AST/ALT ratio < 1. Imaging and possible biopsy is required to make an accurate diagnosis. AST and ALT both upwards of 4 times ULN. Tamoxifen and Raloxifene have been shown to induce hepatic steatosis.
Zonal Necrosis: Zonal necrosis is essentially the death of cells in a specific zone of the liver. This is the most common manifestation of hepatotoxicity. This will cause an increase in ALT with normal ALP levels. This can be caused by C-17-alpha-alkylated (C17aa) steroids.
Cholestasis: Cholestasis is the impediment of biliary flow from the liver through the biliary tract. This is the cause of jaundice. The increase in bilirubin causes a yellowing of the skin and that is occurs with itching. C17aa steroids may cause hepatotoxic cholestasis. This can be seen on labs as normal levels of ALT and > 2 times ULN ALP. The mechanism of this is not well known. Testosterone and 19-nortestosterone compounds have been implicated in cases of hyperbilirubinemia, but rarely to the point of jaundice. (More on this below).
Hyperplasia and Neoplasia: C17aa compounds have been implicated in cases of hepatic hyperplasia and neoplasia, essentially cancer. However, non-C17aa steroids have also been noted as a cause of liver cancer in medical case reports.
Vascular Lesions: These vascular lesions are known as Peliosis Hepatis. These lesions are present on endothelial cells of hepatic vasculature and is typically asymptomatic. This can eventually lead to hepatomegaly (enlarged liver) and frequently death if untreated.
Effects of liver damage include jaundice, ankle edema, gynecomastia, increased bleeding due to decrease in clotting factor synthesis. Most of these effects come from deficiencies in synthesis of their respective plasma proteins. For example, damage to hepatocytes that are responsible for synthesis of SHBG will result in a decrease in SHBG. This will alter the free estrogen/free androgen ratio, potentially inducing gynecomasta. Likewise, a decrease in plasma proteins will change the blood colloid osmotic pressure, causing a change in capillary net filtration pressure leading to edema in the lower extremities.
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