The liver, AAS-induced Hepatotoxicity, and Liver Protectants
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 hepatoxocitiy 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.
C17-Alpha Alkylation and What It Does
The first point to address is that it is 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 hepatoxicity is, lends credence to the theory that androgenic activity is correlated with hepatotoxicity in oral AAS(2)(3).
Cholestasis is the most common form of liver damage that is characteristic of the use/abuse
of oral anabolic steroids
(4). It is the condition whereby bile is unable to properly flow throguhout the liver and into the duodenum (the first section of the small intestine that connects to the stomach). This can occur as the result of a physical (also known as a mechanical) blockage, such as gallstones or a tumor formation causing blockage. The other form of blockage is in the form of a chemical blockage (also known as metabolic cholestasis), which is cholestasis that is resultant of a disruption of the hepatic cells' ability to properly manufacture and flow bile. C17AA anabolic steroids
cause metabolic (chemical) cholestasis. Metabolic cholestasis can also be the result of a hereditary genetic dysfunction, and there are plenty of other substances, drugs, and medications that can cause cholestasis as well. In order to understand cholestasis, it is important to know what bile is and what it does for us.
Bile is a dark green/yellow to brown fluid that is manufactured by the cells of the liver, and consists of 85% water, 10% bile salts, 3% muscuous and pigments, 1% fats, and 0.7% inorganic salts. The primary function of bile is to digest fats that are consumed in food, making it a very important component in the digestion and processing of food. Because it is involved in the digestion and breakdown of fats, it is very important for the proper breakdown and absorption of fat-based and fat soluble compounds (such as many types of vitamins). In addition to this, bile serves to act as an excretion vehicle for the transport of metabolites out of the liver, such as bilirubin which is a metabolic byproduct as a result of the liver cells recycling red blood cells. Finally, an additional function that bile serves (and this is very important) is the neutralizing of acidity of the contents of the stomach (as a result of stomach acid) before it enters the intestines. A simultaneous role bile plays in that process is also a disinfectant, killing bacteria that could be in the ingested food.
When the C17AA anabolic steroids
inhibit the flow of bile in the liver, bile will build up in the small bile ducts of the liver forming plugs (known as canalicular bile plugs). The cells of the liver (hepatocytes) will continue to attempt to excrete bile as they normally would, but as bile accumulates due to the plugs, enough pressure will build until the lining cells of the bile ducts rupture. As a result, bile spills out onto other cells and tissue, resulting in cell death. Cells will begin to build up with bile as well (more common in intrahepatic chemical/metabolic cholestasis), and without proper flow of bile, the cells will die. This build-up of bile is known as a bile pool, and while not all of the bile acids contained in the bile pool are hepatotoxic, most of them are, and this is why the bile pool accumulation results in liver cell death. C17AA anabolic steroids
cause intracellular bile retention within the hepatocytes (bile accumulation inside
the liver cells).
Symptoms of cholestasis:
- Anorexia, loss of appetite
- Abdominal pain/burning (almost like heartburn/burning sensations due to the lack of bile being excreted to neutralize the acidity of stomach content entering the duodenum). VERY IMPORTANT: what is commonly mistaken for heartburn by many people while using oral C17AA anabolic steroids is actually varying stages of cholestasis.
- Pruritus (itching)
- Clay colored dark stool
- Pale stool (strong indication of physical/mechanical cholestasis rather than metabolic/chemical cholestasis)
- Dark amber colored urine
- Jaundice (strong indication of physical/mechanical cholestasis, but can occur with metabolic/chemical intrahepatic cholestasis if it reaches worsened stages)
Although cholestasis can normally be recovered from if C17AA steroids
are halted early enough, the body might require months before liver function is properly restored, and this is why it is very important to maintain proper liver function during the use of C17AA compounds with the supplementation of a proper liver support compound.
UDCA/TUDCA (Ursodeoxycholic Acid / Tauroursodeoxycholic Acid)
Ursodeoxycholic acid (UDCA) and tauroursodeoxycholic acid (TUDCA) are bile acids themselves that are non-toxic to the liver and in fact have been proven to exhibit the exact opposite - they assist in bile flow through various different pathways which will be covered shortly. TUDCA is simply the taurine conjugate of UDCA (UDCA with a taurine amino acid bound to it), which has been claimed to exhibit greater oral bioavailability, but both variants have been proven to work very effectively. UDCA and TUDCA used to be extracted from the liver of bears, but synthetic methods have since been developed in order to manufacture these compounds, as well as the ability to derive them from other sources.
By far the most effective liver support compound available, UDCA and TUDCA are compounds that serve to speed up the metabolic transition of toxic bile acids to less toxic bile acids, and they also serve to increase the manufacture of non-toxic bile acids from cholesterol(5). The result is a decrease in the toxicity of the bile pool. Remember when I mentioned above that liver toxicity from oral anabolic steroids
(in the really bad stages) results in bile building up in the hepatocytes (liver cells) until they rupture and bile spills out onto other cells killing them? Well, the bile being spilled out consists of mostly toxic bile salts. UDCA and TUDCA are beneficial non-toxic bile salts that will essentially balance out the toxicity of the bile pool and serve to neutralize the toxicity making it less toxic to the surrounding resident liver cells. UDCA and TUDCA have also shown to increase amounts of the bile salt export pump (a transporter protein) in the liver cells, thus increasing the flow of bile as a result(6). What this means is that they will facilitate the flow of bile in the liver so that the bile pool will not remain stagnant damage the surrounding liver cells. A good analogy to explain this is using the 'hot potato' analogy where a group of people in a circle are throwing a hot potato around from person to person fairly quickly. As long as the hot potato is passed around at a constant pace, no single person's hand will get burned, but if the hot potato is to remain in one person's hand for too long, they will end up doing damage to their hands by being burned (which is much like a stagnant bile pool in the liver damaging the surrounding cells). These compounds have also demonstrated to serve as antiapoptotics in liver cells, which means they effectively block the transcription factor known as AP-1, which is activated during cholestasis due to various toxic bile salts that will activate death receptors on liver cells(7).
UDCA and TUDCA are by far the best quintessential treatments for both the prevention of cholestasis, as well as the recovery from it. They are, quite literally, the compounds specific
to the treatment and mitigation of oral C17-alpha alkylated anabolic steroid
liver toxicity - this cannot be said of any other liver support supplement/compound. In addition to treating cholestasis very effectively, it has demonstrated in studies to also reduce the risk of hepatitis B, where they had significantly decreased the risk of having abnormal serum alanine aminotransferase activity at the end of treatment compared to the beginning(8). Other studies have also shown that UDCA and TUDCA are beneficial in the treatment necroinflammatory liver disease, such as (and especially for) hepatitis C-related chronic hepatitis in which bile duct damage and some degree of cholestasis are frequently seen at histology, and the study had observed that TUDCA had significantly improved the biochemical expression of chronic hepatitis(9). In general, TUDCA seems to prevent hepatic cell death(10).
Dosing of TUDCA and UDCA:
500mg daily for the maintenance of healthy liver function during the use of a C17AA oral during a cycle. 1,000mg or higher daily for the purpose of repairing the liver following heavy hepatotoxicity and hepatocyte damage from cholestasis (and/or for individuals with serious liver disorders).
Do not exceed 8 weeks of TUDCA/UDCA use, as it can increase negative cholesterol values. It is reccomended to use these bile salts only during a cycle of oral C17AA anabolic steroids
, or for the purpose of liver repair following periods of significant hepatotoxicity from the use of these compounds. Other compounds should be sought after for general year-round liver support.
What About Other Liver Protectants?
UDCA and/or TUDCA should be considered first above all else when using hepatotoxic anabolic steroids
, as they treat the mechanisms specific to cholestasis. Milk thistle, which contains silymarin and silybin are known as being powerful antioxidants in the liver in particular. Many studies have been conducted on the efficiency and have demonstrated them to exhibit a plethora of beneficial properties in liver tissue. However, milk thistle is not very effective for treating cholestasis in particular. As a general liver health support, it is not too bad. However, almost all of the studies performed on milk thistle?s effectiveness had administered the test subjects the compound via injection, which would provide near 100% bioavailability. Milk thistle consumed orally is a different story, unless it is delivered in a special delivery complex. Milk thistle should otherwise serve as a very beneficial addition to UDCA and TUDCA, but should not be substituted as a first-line treatment for cholestasis. TUDCA should be reserved for the first-line treatment of cholestasis and should be the primary liver protectant while on a cycle of C17-alpha alkylated oral anabolic steroids
NAC (N-acetylcysteine) is an excellent liver protectant/support compound that has demonstrated effectiveness in mitigating hepatotoxicity(11) as well as successfully treating acetaminophen (Tylenol) induced hepatotoxicity(12), which is an added benefit for NAC that TUDCA does not do. NAC has also demonstrated some pretty good effectiveness at mitigating and preventing cholestasis as evidenced by studies. One particular study administered 300mg/kg of NAC orally to rats for 28 days, and not only did NAC administration reduce elevations of liver enzyme values that would otherwise be high without NAC administration, it also seemed to improve renal (kidney) function as well(13)! That same study indicated, though, that NAC's activity in ameliorating cholestasis is not through the same pathway as TUDCA. NAC's ability to prevent or cure cholestasis stems from its antioxidant and immunomodulatory properties. Acetylcysteine serves to increase the glutathione reserves in the body and, together with glutathione, they both directly bind to toxic metabolites. This serves to protect hepatocytes (liver cells) from succumbing to toxicity from Tylenol or cholestasis. TUDCA instead operates through the direct action of essentially 'balancing' the content of bile salts (TUDCA is itself a bile salt), and while it does assist in mitigating cholestasis, it does not do anything for Tylenol-related toxicity. Another study also investigated NAC's ability to help alleviate cholestasis, which focused a little more on the observation of the renal (kidney) related effects, and found that in addition to improved liver enzyme values, NAC had the ability to vastly improve markers of kidney function and was actually able to even double the rate of sodium excretion(14). This would also strongly indicate that NAC might prove very useful for the elimination of sodium and its related water retention in the body, which is something that might be of particular interest for anabolic steroid
using individuals who might be having problems with water retention during a cycle.
The problem, however, with NAC is that it has demonstrated very poor oral bioavailability(15), and this is the reason as to why high oral doses of NAC were utilized in studies for the treatment of Tylenol poisoning compared to when the subjects were administered NAC through the IV (intravenous) route of administration. Aside from NAC's ability as a nephroprotective (kidney protecting) and hepatoprotective (liver protecting) agent, it is well documented to serve a myriad of other benefits to the body. This includes, but is not limited to: the treatment of lung disease, smoking-related lung problems, and COPD(16)(17)(18)(19), the treatment of psychiatric conditions such as schizophrenia, bipolar disorder, depression, and obsessive symptoms(20)(21)(22)(23). NAC is also currently undergoing investigation of its involvement in the treatment of other disorders and diseases, such as the treatment of cannabis dependence in adolescents(24), the ability to reduce cocaine cravings(25)(26), the treatment of AIDS (due to NAC's ability to augment the immune system)(27), fighting against the flu(28), as well as countless other potential applications. Although these benefits of NAC do not pertain to the main topic at hand (liver support during anabolic steroid
use), it is very informative and helpful to know and understand that NAC has potential applications that are extremely far reaching beyond simply liver and kidney function.
Dosing of NAC:
As previously mentioned, there are issues in regards to poor oral bioavailability with NAC. IV and inhalation formats of NAC do exist, but are generally prescription-only, depending on which country. However, the oral format of NAC is generally widely available for purchase almost anywhere. Be sure to look for a NAC product that has chelated it to an element or compound to provide greater bioavailability. With that being said, a proper dose for the purpose of maintenance of liver health during a cycle of C17-alpha alkylated anabolic steroids
would be in the range of 1,000mg - 2,000mg of NAC per day. NAC can be used year-round as a general liver support, and should be run at 1,000mg per day or less when not
utilizing C17-alpha alkylated oral anabolic steroids
Studies have demonstrated that high doses of NAC can cause lung and hear damage(29) due to the fact that NAC is metabolized in the body to S-nitroso-N-acetylcysteine (SNOAC). In large enough amounts, SNOAC leads to significantly increased blood pressure in the lungs and the right ventricle of the heart. This is why it is advised to not exceed the standard dose of 1,000mg - 2,000mg per day while on C17AA oral anabolic steroids
. Other than this warning, it should be mentioned that the implications of long-term NAC use (at any
dose range) are currently unknown and have not been investigated. This is not to say that long term use is a bad thing, but that we simply do not know if the outcome is indeed good or bad.
A final word: TUDCA should be every anabolic steroid
user's first choice for on-cycle liver protection during the use of oral C17-alpha alkylated anabolic steroids
. Following this, NAC is an excellent choice if TUDCA cannot be located, and can also be used as a year-round general liver protectant.
Steroids Side Effects
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