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The liver, AAS-induced Hepatotoxicity, and Liver Protectants. EXCELLENT READ.

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    The liver, AAS-induced Hepatotoxicity, and Liver Protectants. EXCELLENT READ.






    If all this info has beem posted before I apologize. But I found these two write-ups on AAS liver damage and thought they were too good to ignore. What I really like about them is that they are backed by real references. The one thing that was an eye opener for me was that loss of appetite and/or heartburn while on AAS is most likely an early indicator of cholestasis of the liver.

    Its alot of info but it is a MUST READ for anybody using or thinking of using AAS. In fact I think somebody should make this a STICKY. I'm just gonna cut and paste so hear it goes:

    PART 1

    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

    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:

    - Nausea
    - Malaise
    - Anorexia, loss of appetite
    - Vomiting
    - 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).

    IMPORTANT: 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)

    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.

    IMPORTANT: 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.

    Further reading:

    Oral Steroids

    Steroids Side Effects

    Effects of Steroids

    REFERENCES:
    1. Cellular distribution of androgen receptors in the liver. Hinchliffe SA, Woods S, Gray S, Burt AD. J Clin Pathol. 1996 May;49(5):418-20.
    2. Liver toxicity of a new anabolic agent: methyltrienolone (17-alpha-methyl-4,9,11-estratriene-17 beta-ol-3-one). Kruskemper, Noell. steroids. 1966 Jul;8(1):13-24.
    3. T. Feyel-Cabanes, Compt. Rend. Soc. Biol. 157, 1428 (1963).
    4. anabolic-androgenic steroids and liver injury. M Sanchez-Osorio et al. Liver International ISSN 1478-3223 p. 278-82.
    5. Ursodeoxycholic acid and bile-acid mimetics as therapeutic agents for cholestatic liver diseases: an overview of their mechanisms of action. Poupon R. Clin Res Hepatol Gastroenterol. 2012 Sep;36 Suppl 1:S3-12. doi: 10.1016/S2210-7401(12)70015-3.
    6. Tauroursodeoxycholic acid inserts the bile salt export pump into canalicular membranes of cholestatic rat liver. Dombrowski F, Stieger B, Beuers U. Lab Invest. 2006 Feb;86(2):166-74.
    7. Tauroursodeoxycholic acid reduces bile acid-induced apoptosis by modulation of AP-1. Pusl T, Vennegeerts T, Wimmer R, Denk GU, Beuers U, Rust C. Biochem Biophys Res Commun. 2008 Feb 29;367(1):208-12. doi: 10.1016/j.bbrc.2007.12.122. Epub 2007 Dec 27.
    8. Bile acids for viral hepatitis. Chen W, Liu J, Gluud C. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD003181.
    9. Tauroursodeoxycholic acid for the treatment of HCV-related chronic hepatitis: a multicenter placebo-controlled study. Crosignani A, Budillon G, Cimino L, Del Vecchio Blanco C, Loguercio C, Ideo G, Raimondo G, Stabilini R, Podda M. Hepatogastroenterology. 1998 Sep-Oct;45(23):1624-9.
    10. Effect of tauroursodeoxycholic acid on bile acid-induced apoptosis in primary human hepatocytes. Benz, Angerm?ller, Otto, Sauer, Stremmel, Stiehl. European Journal of Clinical Investigation Volume 30, Issue 3, pages 203?209, March 2000.
    11. The protective effects of n-acetylcysteine against acute hepatotoxicity. Sahin S, Alatas O. Indian J Gastroenterol. 2013 Mar 10.
    12. The biochemistry of acetaminophen hepatotoxicity and rescue: a mathematical model. Ben-Shachar R, Chen Y, Luo S, Hartman C, Reed M, Nijhout HF. Theor Biol Med Model. 2012 Dec 19;9:55. doi: 10.1186/1742-4682-9-55.
    13. Antifibrotic and antioxidant effects of N-acetylcysteine in an experimental cholestatic model. Galicia-Moreno M, Favari L, Muriel P. Eur J Gastroenterol Hepatol. 2012 Feb;24(2):179-85. doi: 10.1097/MEG.0b013e32834f3123.
    14. Acute cholestasis-induced renal failure: effects of antioxidants and ligands for the thromboxane A2 receptor. Holt S, Marley R, Fernando B, Harry D, Anand R, Goodier D, Moore K. Kidney Int. 1999 Jan;55(1):271-7.
    15. Pharmacokinetics of N-acetylcysteine in man. Borgstr?m, L.; K?gedal, B.; Paulsen, O. (1986). European Journal of Clinical Pharmacology 31 (2): 217?222. doi:10.1007/BF00606662. PMID 3803419.
    16. Long-term administration of N-acetylcysteine decreases hydrogen peroxide exhalation in subjects with chronic obstructive pulmonary disease. Kasielski, M; Nowak, D (2001). Respiratory Medicine 95 (6): 448?56. doi:10.1053/rmed.2001.1066. PMID 11421501.
    17. Efficacy of oral long-term -acetylcysteine in chronic bronchopulmonary disease: A meta-analysis of published double-blind, placebo-controlled clinical trials. Grandjean, E; Berthet, P; Ruffmann, R; Leuenberger, P (2000). Clinical Therapeutics 22 (2): 209?21. doi:10.1016/S0149-2918(00)88479-9. PMID 10743980.
    18. The effect of oral N-acetylcysteine in chronic bronchitis: a quantitative systematic review. Stey, C.; Steurer, J.; Bachmann, S.; Medici, T.C.; Tram?r, M.R (2000). European Respiratory Journal 16 (2): 253?62. doi:10.1034/j.1399-3003.2000.16b12.x. PMID 10968500.
    19. Oral mucolytic drugs for exacerbations of chronic obstructive pulmonary disease: systematic review. Poole, P.; Black, PN (2001). BMJ 322 (7297): 1271?4. doi:10.1136/bmj.322.7297.1271. PMC 31920. PMID 11375228.
    20. N-Acetyl Cysteine as a Glutathione Precursor for Schizophrenia?A Double-Blind, Randomized, Placebo-Controlled Trial. Berk, Michael; Copolov, David; Dean, Olivia; Lu, Kristy; Jeavons, Sue; Schapkaitz, Ian; Anderson-Hunt, Murray; Judd, Fiona; Katz, Fiona (2008). Biological Psychiatry 64 (5): 361?8. doi:10.1016/j.biopsych.2008.03.004. PMID 18436195.
    21. N-Acetyl Cysteine for Depressive Symptoms in Bipolar Disorder?A Double-Blind Randomized Placebo-Controlled Trial. Berk, M; Copolov, D; Dean, O; Lu, K; Jeavons, S; Schapkaitz, I; Andersonhunt, M; Bush, A (2008). Biological Psychiatry 64 (6): 468?75. doi:10.1016/j.biopsych.2008.04.022. PMID 18534556.
    22. A randomized Controlled Pilot Trial of Oral N-Acetylcysteine in Children with Autism. Harden, Antonio Y.; Fung, Lawrence K.; Libove, Robin A.; Obukhanych, Tetyana V.; Nair, Surekha; Herzenberg, Leonore A.; Frazier, Thomas W.; Tirouvanziam, Rabindra (2012). Biol Psych 71 (11): 956?961. doi:10.1016/j.biopsych.2012.01.014.
    23. N-Acetyl Cysteine for Depressive Symptoms in Bipolar Disorder?A Double-Blind Randomized Placebo-Controlled Trial. Michael Berk, David L. Copolov, Olivia Dean, Kristy Lu, Sue Jeavons, Ian Schapkaitz, Murray Anderson-Hunt, Ashley I. Bush (2008). Biological Psychiatry 64: 468?475.
    24. A Double-Blind Randomized Controlled Trial of N-Acetylcysteine in Cannabis-Dependent Adolescents. Gray, KM; Carpenter (1). Am J Psychiatry 169: 805?812.
    25. An open-label trial of N-acetylcysteine for the treatment of cocaine dependence: A pilot study. Mardikian, P; Larowe, S; Hedden, S; Kalivas, P; Malcolm, R (2007). Progress in Neuro-Psychopharmacology and Biological Psychiatry 31 (2): 389?94. doi:10.1016/j.pnpbp.2006.10.001. PMID 17113207.
    26. Is Cocaine Desire Reduced by N-Acetylcysteine? Larowe, S. D.; Myrick, H.; Hedden, S.; Mardikian, P.; Saladin, M.; McRae, A.; Brady, K.; Kalivas, P. W.; Malcolm, R. (2007). American Journal of Psychiatry 164 (7): 1115?7. doi:10.1176/appi.ajp.164.7.1115. PMID 17606664.
    27. Improvement of immune functions in HIV infection by sulfur supplementation: Two randomized trials. Breitkreutz, Raoul; Pittack, Nicole; Nebe, Carl Thomas; Schuster, Dieter; Brust, J?rgen; Beichert, Matthias; Hack, Volker; Daniel, Volker; Edler, Lutz (2000). Journal of Molecular Medicine 78 (1): 55?62. doi:10.1007/s001090050382. PMID 10759030.
    28. Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment. De Flora, S.; Grassi, C.; Carati, L. (1997). European Respiratory Journal 10 (7): 1535?41. doi:10.1183/09031936.97.10071535. PMID 9230243.
    29. S-Nitrosothiols signal hypoxia-mimetic vascular pathology. Palmer, Lisa A.; Doctor, Allan; Chhabra, Preeti; Sheram, Mary Lynn; Laubach, Victor E.; Karlinsey, Molly Z.; Forbes, Michael S.; MacDonald, Timothy; Gaston, Benjamin (2007). Journal of Clinical Investigation 117 (9): 2592?601. doi:10.1172/JCI29444. PMC 1952618. PMID 17786245.


  2. #2
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    PART 2

    The ultimate LIVER thread and info on orals and ORAL TOXICITY!!

    This post might deserve a sticky, seeing as though there is no definitive post around here concerning liver health and oral C17 alpha alkylated anabolics. No post stating what specifically happens inside the liver when C7AA steroids are consumed, what they do inside, what happens over prolonged periods, and what is the best thing to do and take in order to solve the problem. The answers to all of these questions have recently piqued my interest because in one of my biochemistry courses, we just so happen to be covering certain aspects of liver function and the biochemical processes that occur inside it. We specifically touched upon the use of ursodeoxycholic acid (UDCA) for regulating proper liver function (specifically, BILE FLOW) in the midst of liver damage from things like alcohol, hepatitis C, etc. I also ran into a small issue post-cycle that I thought may have been a liver issue (lucky it doesn't seem like it was), and that caused me to look further into this. Some or much of this information may already be known, but I feel the need to spread word about it and post this here to educate people who might be asking the same questions.

    I'm a really busy guy, and I don't have very much time to take everything I have read and conjure it up into my own words here. So, to save time, I am simply going to copy and paste my findings from other sources into this post, and provide references to them.

    I am, for the most part, going to just copy and paste a whole post I already made in a previous thread I posted in where a forum member was asking about liver protection, oral anabolics, etc. where I explained everything to him. Here it is, folks:

    ------------------------------------------------------------------------------

    I want to start off by saying this: milk thistle is garbage. TUDCA (Tauroursodeoxycholic acid) is quite literally the primary and ONLY liver protectant people should be using if they are taking C17 Alpha Alkylated oral anabolic steroids. I think that Liv 52 is okay to use as well. But, if you could only pick ONE product and throw the rest away, I would say TAKE THE TUDCA!!!! Research has shown that it is the ONLY thing that is effective at treating anabolic steroid SPECIFIC induced cholestasis of the liver. Off the top of my head, one company that makes a product with TUDCA in it is Thermolife in their Liver Longer supplement, but they have seemed to be out of stock for a long while now. I know it is possible to pick up generic TUDCA if you look hard enough online. Just google it!

    If you can find TUDCA elsewhere, get it as soon as you can.

    As a matter of fact, using a liver support supplement such as TUDCA may even INCREASE the oral absorption and bioavailability of the steroid because it prevents cholestasis of the liver. You have to understand what happens in the liver when you use C17 alkylated orals. Cholestasis is defined as an impairment of bile flow in the liver. I don't know if you remember your highschool biology class, but bile is an extremely important component of the liver and of our body, because bile serves dual purposes:

    1. In a way, it acts as a waste removal sewage fluid for the liver. All of the byproducts (not all necessarily bad, but stuff that your liver needs to remove on a regular basis or else it will harm the liver from an unhealthy buildup) that your liver creates from all the work it does in metabolizing a bazillion billion different things every day, gets collected as bile. In turn, bile salts really 'clean' the liver out.

    2. Bile and the bile salts within it are very important to our digestion, especially of fats. It's stored in the gall bladder and then pumped into your duodenum (upper section of your small intestine) when you eat food to aid in digestion, as it assists in the breakdown of fats and such.

    Now, in a nutshell, what happens when your liver gets 'damaged' from oral steroids is: (and i'm not going to get into the specific chemistry of it for ease of explanation to the layman) the liver is overloaded from processing the C17 alkylation on the anabolic steroid you are ingesting. What happens as a result is that it causes a slow down of bile flow in the liver, because the liver is getting so overloaded with the processes it is trying to undergo. The impairment of bile flow in the liver is known as cholestasis, and is a direct result of C17 alkylated steroid use . When bile flow is slowed down too much (or has outright STOPPED), the bile salts, which are very toxic to the liver cells, will start to damage those liver cells. The key idea here is BILE FLOW, and you'll see this repeated a lot in this post! The liver needs to keep churning bile through itself in all of its cells in order to clean out the metabolites resulting from all of the biochemical processes it's doing every second!

    I don't have much time on me, so for further explanation I am going to quote a couple articles I found that explain in more detail what TUDCA does and how it literally is the ONLY liver support compound that is useful, to a much larger degree than anything else, at combating cholestasis:


    A few words on the hepatotoxicity of 17a-methylated androgens/anabolics
    1. 17a-methylated androgens/anabolics are hepatotoxic.
    The liver toxicity of steroids is an under-researched field, but there seems to be a strong correlation between how easily the body can metabolize a steroid & its toxicity. Metribolone -- a truly excessively toxic compound -- is often referred to in the literature as a 'non-metabolizable androgen'. (1, 2, 3, etc.) Mibolerone , another deadly-toxic anabolic steroid, is also effectively 'non-metabolizable': The main metabolite of mibolerone in humans is... unchanged mibolerone. And by a very wide margin.

    Methylstenbolone, which is resistant to 17b-HSD and 3b-HSD, is obviously difficult for the body to clear. It should therefore be no safer, no less toxic, than Superdrol or M1T -- compounds which share very similar traits.


    2. Liver injury due to oral anabolic use typically manifests itself as cholestasis.
    Hepatotoxicity induced by oral anabolic compounds tends to be characterized by enlargement of periportal hepatocytes, impairment of bile flow & dramatically increased serum levels of AST, ALT and GGT. In other words, cholestasis... but let's examine this a little bit further.

    The word "cholestasis" gets thrown around a lot, but it can mean two very different things: The physical obstruction of hepatic bile flow -or- the impairment of bile secretion. In the former case, there is a mechanical block in the bile duct system; in the latter, bile is held in hepatocytes or cholangiocytes as it cannot be secreted. In both cases, what happens thereafter is that the retained hydrophobic bile salts -- which are strongly cytotoxic -- lead to cellular injury, then apoptosis, then necrosis, often followed by an inflammatory reaction and tissue fibrosis. This tissue damage, if advanced enough, can physically destroy bile ducts, worsening the condition.

    The obstruction of bile flow is typically not something you'd experience after exposure to any toxin; it is the almost exclusive domain of inherited or autoimmune diseases which leave fibrotic lesions or scar-tissue in the liver, such as cystic fibrosis, primary biliary cirrhosis, and so on. Exposure to oral anabolic compounds can, however, result in the second form of cholestasis -- bile retention in hepatocytes -- thus the enlarged hepatocytes observed after their use.


    3. There are three fundamental ways of preventing/treating cholestasis:
    1. Metabolic induction of hydrophobic bile acid detoxification
    2. Stimulation of impaired bile secretion
    3. Protection of hepatocytes from the toxic effects of hydrophobic bile acids and/or inhibition of hepatocyte apoptosis.

    Cholestatic liver damage is caused by bile acid accumulation... But not all bile acids are toxic. Generally speaking, the fewer hydroxyl groups they bear, the more hydrophobic and cytotoxic they are. Hence lithocholic acid is markedly cytotoxic, deoxycholic acid is very slightly cytotoxic, and cholic acid is essentially non-cytotoxic. Treatment #1 would involve hastening the metabolic conversion of the more toxic bile acids to hydrophilic, less toxic compounds --- or increasing the synthesis of hydrophilic bile acids from cholesterol, which would decrease the cytotoxicity of the entire bile pool as a whole. This can seemingly be achieved with the oral administration of ursodeoxycholic acid (UDCA), which has been reported to activate the PXR/SXR nuclear receptor in hepatocytes, which then activates bile acid?metabolizing enzymes. It is reasonable to assume that Tauroursodeoxycholic acid (TUDCA), the taurine conjugate of UDCA, should have the same effect.

    As for #2... Bile secretion at the level of the hepatocyte is carried out by a group of transporter proteins: The bile salt export pump (BSEP), the phospholipid export pump (MDR3), the canalicular bilirubin conjugate export pump (MRP2), and a chloride-bicarbonate anion exchanger (AE2) for bicarbonate excretion. BSEP is the driving factor behind bile-acid dependent secretion, and MRP2/AE2 are the major forces behind bile-acid-independent bile secretion. Hydrophilic bile acids such as UDCA & TUDCA (and even, partially, cholic acid) have been shown to increase expression of BSEP mRNA; they activate BSEP coactivators by binding to the Farnesoid X Receptor (the "bile acid receptor"); they phosphorylate the BSEP protein via a Ca+/PKCa-mediated mechanism; lastly, they stimulate Cl -/HCO3 - exchange via this same PKCa induction, thus increasing AE2 levels.
    Taken together, the above effects drastically enhance secretion of potentially toxic bile acids.

    #3 can be complicated, but I will explain briefly: Certain toxic bile salts activate the Fas Death Receptor on hepatocytes. This leads to a cascade of dozens of protein interactions & ultimately to cell death. TUDCA, UDCA, and certain other compounds can diminish Fas?induced apoptosis, but, as far as I am aware, the exact mechanism is not known at this time. Fas activation here is not ligand-dependent, so the 'obvious' mechanism is out the window. The mechanism could, however, involve activation of the EGFR, which activates MAPK & the MAPK-mediated 'survival pathway' in hepatocytes; it might also involve inhibition, somewhere along the line, of the proapoptotic proteins Bax and Bid.


    4. Recommendations
    I strongly recommend TUDCA or UDCA to anybody considering a cycle containing oral androgens, for what should by now be obvious reasons. They are extremely potent at preventing or reversing 17aa-androgen-mediated liver damage. There's really no excuse not to take them, in my opinion, and I would advise you not to run a cycle if you can't afford them. Oral androgens can send you straight to the ER if the right precautions are not taken, & your health is much more important than a few more pounds of here-today-gone-tomorrow muscle.

    Silymarin and silybin, the milk thistle extracts, are very strong antioxidants and free-radical scavengers in hepatic tissue. They impede hepatic lipid peroxidation, increase glutathione concentrations, and even have anti-inflammatory and tissue-regenerative properties... Other plant-extracted compounds, such as celastrol, have similar effects... But while these extracts are excellent to take for general liver health, they are weak protection and not an appropriate treatment for cholestasis, as they do not appear to impact bile acid secretion/metabolism at pharmacologically-relevant doses. Silymarin did increase bile secretion and improve bile acid metabolism in rats -- but that effect was primarily noticed at a dose of 100mg/kg, administered via i.p. injection (100% bioavailability), and therefore doesn't have much bearing on humans who take much smaller amounts orally (~10% bioavailability).
    ...But Primordial Performance's "Liver Juice" is silymarin/silybin attached to an excellent delivery complex, and should be quite effective if taken 3x/day. It is the best milk thistle supplement out there, in my opinion.

    NAC is also a fine antioxidant and glutathione-booster, but it suffers from poor bioavailability & is usually very underdosed in commercially-available supplements... So I wouldn't bother with it.

    Sanofi-Aventi (or is it just 'Sanofi' these days?) manufactures the popular phospholipid-complex product "Essentiale" and "Essentiale Forte". The phosphatidylcholine therein has been shown to help protect hepatic cell membranes against the damaging effects of chenodeoxycholic acid, can inhibit lipid peroxidation, and can induce cytochrome P450, which stimulates the metabolic clearance of bile acids... So there's a reason that it's the most popular OTC liver support in Europe and Asia... But "Essentiale" can be hard to find in the USA -- and, on its own, I don't believe that it is totally adequate protection for users of oral androgens.

    And Liv-52? Mostly a waste of money. A blend of mild antioxidants is all there is to it.

    The bottom line here is this: Oral anabolics/androgens are hepatotoxic. Period. If you are going to use them, I implore you to take sensible precautions. Antaeus shall release a novel and powerful liver-support product in the very near future. In the meantime, there's Thermolife's "Liver Longer" and Primordial's "Liver Juice". Both are cheap enough that there's no excuse not to take them.


    Another article:


    How do 17-aa oral steroids cause liver damage?

    Despite a lot of discussion on the forums about the "toxicity" of different oral steroids, most users are unaware of the mechanism or implications around these "toxic effects" (which is probably the reason why most users have yet to find an effective cure for the toxic effects).

    Let me shed some light on this ambiguous topic.

    17-aa steroids are toxic to the liver because they inhibit the excretory functions of the liver. (1-7)

    More specifically, the more "liver toxic" a 17-aa steroid is, the more it inhibits the production and flow of bile from the liver.

    Bile salts are known as the liver's "cleansing agents" because they act as "soaps" that carry away the toxins and flush them into the intestines for excretion. If the bile flow is restricted in the liver, then the liver cannot rid itself of toxins. When the liver loses its ability to excrete toxins, it creates a buildup of toxins throughout the entire body. (1-13)

    This condition is known as cholestasis [Kola-sta-sis]. By definition, cholestasis is a condition where the flow of bile cannot flow from the liver. (1) This is the most common liver condition developed from 17-aa steroids. (1-7)

    If a liver becomes cholestatic for too long, the condition can begin damaging liver cells by causing necrosis (premature death of liver cells) from excessive toxin build up in the liver. This can eventually lead to cirrhosis of the liver (development of fibrous scar tissue) when the liver attempts to regenerate the damaged liver cells. This leads to loss of liver function from the replacement of healthy liver cells with fibrous connective tissue. (2)

    Although cholestasis is reversible and generally not a lethal condition, it can lead to the more serious problems mentioned above if left untreated -- not to mention costly medical bills.

    To avoid serious health complications it's important to protect the liver before it becomes cholestatic or seriously damaged from prolonged cholestasis (which I will explain later).



    What are signs that my liver is damaged?

    When the liver has been damaged by oral steroids there are certain signs that may become obvious to the user.

    Here are some of the most common signs indicating you may have a serious liver issue. Warning signs usually appear in the following order, with the later signs being the most serious -

    ? Reduced appetite
    ? Nausea and fever
    ? Excessive Itchiness
    ? Yellow eyes or skin (jaundice)
    ? Very dark urine (dark amber colored)
    ? Bloody stools


    Waiting for all these signs to appear means you have waited too long. You want to take action BEFORE these signs appear. This is why I advise getting full lab values on liver function before, during and after any 17-aa oral steroid cycle. If performing lab tests for liver function, the following values are considered normal.


    Normal Values -

    Total bilirubin range: 0.3-1.7 mg/dl

    Alanine aminotransferase (ALT) range: 10-40 IU/L

    Aspartate aminotransferase (AST) range: 10-40 IU/L

    Alkaline phosphatase (ALP) range: 34-125 IU/L

    Gamma-glutamyl-transpeptidase (GGT) range: 7-32 IU/L

    Levels above these normal values doesn't necessarily mean you have liver damage. It is common for healthy weight training athletes or bodybuilders to be slightly outside of the "normal" ALT, AST and ALP values. Therefore these "Danger Values" have been established as more appropriate levels to indicate a serious liver toxicity issue. (1-7)


    Danger Values -

    Total bilirubin: 10 mg/dl or higher

    Alanine aminotransferase (ALT): 50 IU/L or higher

    Aspartate aminotransferase (AST): 50 IU/L or higher

    Alkaline phosphatase (ALP): 150 IU/L or higher

    Gamma-glutamyl-transpeptidase (GGT) range: 50 IU/L or higher
    NOTE: Historical research from 17-aa oral steroid induced liver toxicity suggests that lab values higher than the "Danger Values" indicate that you may be suffering from cholestasis (1-7) If your lab values are higher than the "Danger Values" listed above you should discontinue any current oral steroid use and seek medical treatment.

    If the above lab tests are not an option, it is possible to get an affordable at home test for bilirubin levels, which can help diagnose a liver damage from a 17-aa oral steroid. There are tests available, such as the TestMedica Liver Home Scan, which can be purchased online for less than $5 per test. Although these home based tests lack accuracy or true diagnosis ability, it can offer a valuable insight about the condition of the liver and is recommended for any steroid user not able to get lab tests done in a clinical setting.



    How can I protect my liver?

    To prevent cholestasis, the primary condition caused by oral steroid use, it is important to ensure there is ample hydrophilic bile acid available in the liver for the proper clearance of toxins. There are two reliable options for this.

    1. The first option is the drug known as Ursodiol - a.k.a. ursodeoxycholic acid. This naturally occurring bile acid is used for its ability to detoxify the liver by clearing out less hydrophilic bile acids and other toxins that cause a toxic build up, such as 17-aa oral steroids. (4,5)

    Ursodiol is typically prescribed to patients admitted to the hospital for steroid induced liver toxicity, but unfortunately, it is an expensive prescription drug, and not easily obtainable.

    Typical dose - 1000-1200mg/day before, during and after cycle


    One more small thing I found someone post on another forum:


    Everytime now that I take an oral AAS, I get massive heartburn within 3 days. I even tried an injectable oral and still got acid reflux within a week. So, I did some research and found some interesting information. This is just a random post I found on Google.


    http://www.********.com/forums/archi...p/t-36636.html
    Everyone seems to miss what is happening here. If an oral kills your appetite, it is because it is too toxic for the liver. I forget exactly what happens, but to summarize, when the liver is overloaded it causes a slowing of digestion, and a backflow of bile, which is why you also see people complaining of acid reflux on harsh 17aa's. The only way to really cure your appetite is to drop the anadrol . Perhaps next time around run with liv. 52 and alpha lipoic acid?



    From what I read, bile helps with digestion. Now, when I take an oral AAS, the pain I get is similar to acid reflu/heartburn, but not exactly. It feels more like the food I eat just sits in my stomach and rots, never digesting. Lets say I eat some tacos on Tuesday, by Thursday morning I am still burping that taste up.That always made me wonder if orals cause heartburn or something similar.




    Now read this
    http://www.emoryhealthcare.org/liver...blems.html#PBC

    In primary biliary cirrhosis, inflammation destroys the bile ducts and prevents bile from escaping the liver. The accumulated bile damages healthy liver tissue, eventually leading to cirrhosis (scarring). As scar tissue replaces healthy liver tissue, the liver loses its ability to function. All this happens very slowly. People with PBC can lead healthy, symptom-free lives for 10 years or more after diagnosis.

    Though primary biliary cirrhosis is often asymptomatic, especially early on, the most common symptom is extreme itching, especially in the arms, legs and back. Other symptoms include fluid buildup in the abdomen or legs, jaundice (yellowing of the eyes and skin), or fatty deposits and darkening of the skin under the eyes.

    The standard treatment for PBC is a daily dose of a medication called ursodiol. Ursodiol improves liver function and increases life expectancy in people with PBC. Other medications may be indicated for controlling symptoms


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    Your first post directly contradicts your second post. Weird.

    Have you read this?




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    Quote Originally Posted by heavyiron View Post
    Your first post directly contradicts your second post. Weird.

    Have you read this?
    I did. What did I miss??

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