I know this is a long write up, the first half is biochemistry and what happens on a cellular level. The second half is more pertaining to the average AAS user, including a deeper dive into liver functioning tests and liver support.
I highly recommend at least reading the second half, especially the Liver Support section. Hepatotoxicity is a word that is frequently thrown around, everyone’s heard it, everyone thinks they know what it is, but once you ask something beyond surface level, you get a whole lot of conflicting answers. Let’s dive into it.
Overview/Background/General Information/What the fuck actually happens? Drug Metabolism: The human body identifies almost all drugs as foreign substances and subjects them to various chemical processes to make them suitable for elimination. Drug metabolism is typically split into two phases: Phase 1 (oxidation via Cytochrome P450, reduction, and hydrolysis) tends to increase water solubility of the drug and can generate metabolites. Phase 2 further increases water solubility of the drug, inactivating metabolites, thus preparing it for excretion.
- Aside: There has been a lot of questions regarding using high dose psoralens (from grapefruit juice/extract) to inhibit the activity of Cyp3A4 (and the Cyp450 family in general) or consuming large quantities of chargrilled meat to induce the activity Cyp450. DO NOT purposely do this in an attempt to increase the bioavailability of oral steroids. The Cyp450 family is incredibly important enzyme family that is involved in the metabolism (both activation and degradation depending) of statins, oral contraceptives, acetaminophen, anti-depressants, beta-blockers, antiarrhythmic agents, and many, many more. This can cause SEVERE adverse effects.
- Example: Acetaminophen (Tylenol) is often seen as hepatotoxic, it is not. One of the metabolites, NAPQI, is. Under normal conditions, NAPQI is produced in incredibly minor amounts. Alcohol induces Cyp450 enzyme family, which increases the breakdown of Tylenol into NAPQI, causing intensive acute liver damage which can often be fatal in high doses. In short, don’t nurse your hangover with Tylenol, use Advil instead… or better of just don’t drink alcohol.
17α-Alkylated Anabolic Steroids. These AAS contain a methyl or ethyl group on the C17α position, allowing for oral activation. This modification allows the drug to survive hepatic metabolism, limiting the amount of steroid that is broken down, allowing for more drug to reach the bloodstream. Without this modification, the drug is completely broken down by the liver, never reaching systemic circulation. This initial process is called First Pass Metabolism.
First pass metabolism: After a drug is swallowed, it is absorbed by the digestive system and enters the hepatic portal system. It is carried through the portal vein into the liver before it reaches the rest of the body. The liver metabolizes many drugs, sometimes to such an extent that only a small amount of active drug emerges from the liver to the rest of the circulatory system. This first pass through the liver may greatly reduce the bioavailability of the drug. Some oral steroids have a very low bioavailability due to first pass metabolism, thus injectable versions may be used to prevent the initial breakdown, effectively increase bioavailability and reducing liver stress.
- Aside: There have been questions regarding sublingual administration of oral AAS in order to bypass first pass metabolism. In short, very few drugs can be properly absorbed sublingually, Nitroglycerin is a prime example. AAS, although can be manufactured for sublingual absorption it requires a specific method of delivery (sublingual tablets, strips, or sprays for example), which are difficult to obtain and manufacture; it’s not as simple as placing some powder under your tongue. Other drawbacks exist of sublingual administration such as tooth decay and difficulty in dose management.
- Anavar: The exception to the rule: The oral bioavailability of oxandrolone is 97%. The drug is metabolized primarily by the kidneys and to a lesser extent by the liver. Oxandrolone is the only AAS that is not primarily or extensively metabolized by the liver, and this is thought to be related to its diminished hepatotoxicity relative to other AAS. For this reason, there is no reason to ever use injectable anavar (unless poking yourself that often is your kink, no judgement).
In short: Oral Steroid (active) -> Hepatic Breakdown -> Metabolite (inactive) - [aside: not all drugs are orally active, in fact the majority are inactive. For example, codeine (inactive) will be converted into the active form, Morphine, within the liver via Cyp450 enzymes]
In the case of oral AAS, hepatic metabolism can convert an active drug into its inactive form; C17α methylation prevents this. Why is this modification known to be hepatotoxic? The
primary enzyme that normally breaks down hormonal steroids (such as endogenous DHEA, testosterone, estradiol, etc) is 17β-Hydroxysteroid dehydrogenase, 17β-HSD, (and to a minor extent the Cyp450 family) which can no longer break down the methylated drug, thus the liver finds an alternative route for metabolism. The actual specific process is still relatively unknown, but involves a variety of oxidation reactions, inducing an increase of free oxygen radicals within the hepatocytes (liver cells), causing cell death due to oxidative stress.
There is another hypothesis which involves the presence of androgen receptors within the liver. The C17α methylated oral steroid, that is no longer properly broken down, will bind to these receptors, causing a drastic increase of androgenic activity within the liver, leading to hepatoxicity.
In my opinion, it is a mixture of both. Many studies show a direct correlation between the androgenic effect of the oral steroid and the amount of hepatoxicity. The exact link between the two is yet to be determined.
In general, the greater the affinity of C17α methylated oral steroid for the androgen receptor, the more hepatoxicity occurs. Hepatotoxicity is an overlying term: the specifics related to AAS use are Cholestasis (blockage of biliary flow), Steatosis (accumulation of fatty lipids within the liver), Zonal Necrosis (hepatocyte death within a specific zone of the liver), and Peliosis Hepatitis (vascular lesions leading to liver enlargement).
- Aside: Steatosis (fatty liver) has been an observed adverse effect of Nolvadex and Raloxifene
Cholestasis is a condition where bile cannot flow from the liver to the duodenum. It is the most common condition resulting from oral AAS use. In short, bile is continuously produced but cannot leave the liver, causing build up, backflow, and eventually hepatocyte death. Differential symptoms of cholestasis include but are not limited to pruritus (itchiness), jaundice (yellowing of the skin and whites of the eyes), pale stool, and dark urine.
Liver Functioning Tests: What do they mean and why are they relevant?
AST: Aspartate Transaminase: This alone is not a good indication of liver damage. AST is found in abundance within both cardiac and skeletal muscle. An elevated AST value can be caused by something as minor as weightlifting.
ALT: Alanine Transaminase: ALT is found specifically within the liver and is released into the plasma when significant liver stress, including hepatocyte death, occurs. An elevated value is of concern.
- Aside: general rule of thumb (not always true) if both elevated are elevated and if AST>ALT in a ratio of 2:1, suspect alcohol/drug induced damage. If both values are elevated and if ALT>AST in a ratio of 2:1, suspect viral hepatitis.
ALP: Alkaline Phosphatase: ALP is found within the hepatobiliary ducts. An elevated value is commonly indicative of obstruction and bile buildup, signifying cholestasis.
GGT: Gamma-glutamyl Transferase: GGT is an enzyme that is found in many organs throughout the body, with the highest concentrations found in the liver. GGT is elevated in the blood in most diseases that cause damage to the liver or bile ducts.
5’-nucleotidase: The concentration of 5’-nucleotidase protein in the blood is often used as a liver function test in individuals that show signs of liver problems. ALP can be elevated due to both skeletal disorders and hepatic disorders. 5’-nucleosidase is elevated ONLY with hepatic stress, not skeletal, thus allowing for differentiation.
Putting it all together: Cholestasis can be suspected when there is an elevation of both 5'-nucleotidase and ALP enzymes. Normally GGT and ALP are anchored to membranes of hepatocytes and are released in small amounts in hepatocellular damage. In cholestasis, synthesis of these enzymes is induced, and they are made soluble. GGT is elevated because it leaks out from the bile duct cells due to pressure from inside bile ducts. As hepatocyte damage continues, ALT, AST, and unconjugated bilirubin will begin to rise.
In short: Initial liver stress causes 5’-nucleiotidase and ALP to rise, shortly after GGT rises, then finally AST and ALT rise. Thus, with only AST and ALT values, it is difficult to determine the cause and extent of hepatic damage.
Liver Support: NAC/TUDCA/Liv52 NAC: N-Acetyl Cystein NAC is a prodrug of L-cysteine, a precursor of the biological antioxidant glutathione which is able to reduce free radicals within the body. Free radicals, which as discussed above, are associated with causing extensive hepatocyte damage due to the oxidative breakdown of C17α methylated AAS.
In addition to its antioxidant action, NAC acts as a vasodilator by facilitating the production and action of nitric oxide. This property is an important mechanism of action in the prophylaxis of contrast-induced nephropathy and the potentiation of nitrate-induced vasodilation.
- Aside: NAC has been constantly used as an adjunct to multiple neurological disorders including Parkinson’s, Huntington’s, Multiple Sclerosis, Cerebral Ischemia, Alzheimer’s and MANY more due to the potent free radical trapping effect which prevent mitochondrial dysfunction.
Multiple studies have constantly showed NAC decreasing liver functioning tests and improving liver function and mitigating cholestasis. NAC had the ability to vastly improve markers of kidney function and was actually able to even double the rate of sodium excretion, indicating that NAC is may be useful in preventing water retention.
In short, NAC has a vast number of benefits, including hepatoprotective (liver), nephroprotective (kidney), and neuroprotective (neural), and anti-inflammatory effects that have been constantly demonstrated thru literature. Moreover, NAC can and should be used for year-round support since the adverse effects are incredibly mild. There is absolutely NO reason to not be taking NAC.
TUDCA: Tauroursodeoxycholic acid TUDCA is a bile acid taurine conjugate form of UDCA. As discussed above, during cholestasis, bile builds up, creating backflow and inducing hepatocyte death thru apoptosis. Apoptosis, or programmed cell death, is largely influenced by the mitochondria. If the mitochondria are distressed, they release the molecule cytochrome C. Cytochrome C initiates enzymes called caspases to propagate a cascade of cellular mechanisms to cause apoptosis.
TUDCA prevents apoptosis with its role in the BAX pathway. BAX, a molecule that is translocated to the mitochondria to release cytochrome C, initiates the cellular pathway of apoptosis. TUDCA prevents BAX from being transported to the mitochondria, effectively inhibiting hepatocyte death.
Furthermore, TUDCA aids in the processing of toxic bile acids into less toxic forms, resulting in decreased liver stress, further preventing hepatocyte death. Moreover, TUDCA aids in the transport of bile from the liver into the duodenum, effectively unblocking the build up causing cholestasis. Finally, TUDCA has been proven to be an effective treatment for the necro-inflammatory effects of Hepatitis. Study after study has shown that TUDCA greatly improves liver enzyme values.
Why do we recommend only using TUDCA with hepatotoxic oral steroids? The idea is that TUDCA induces liver damage when there is no hepatotoxicity present… but after reading the above, does that make sense? It does not.
I could not find any literature showing that TUDCA induces liver toxicity. The recommendation instead is due to the negative effects of TUDCA on cholesterol values. TUDCA has been shown to greatly decrease HDL levels when taken for extended periods of time. The idea is, if you have a healthy functioning liver, there is no reason to take TUDCA for long periods of time since all you’re doing is decreasing HDL values. That being said, after doing the research and seeing the vast benefits of TUDCA (included bellow, not a comprehensive list), I am beginning to change my perspective on TUDCA use with only hepatotoxic oral AAS.
In short, TUDCA prevents hepatocyte death, enhances hepatocyte function, exhibits anti-inflammatory effects on the liver, neutralizes toxic bile, and prevents bile build up that was caused by the alternative metabolism of C17α methylated AAS. ***THERE IS NO EVIDENCE THAT I HAVE COME ACROSS THAT SHOWS THAT TUDCA ITSELF INDUCES LIVER DAMAGE WHEN USED WITHOUT HEPATOTOXIC DRUGS**\*
TUDCA has a variety of other benefits outside the liver, but I will not go into them this time. In short: - Increasing glucose-induced insulin release via the cAMP/PKA pathway, increasing insulin sensitivity.
- Relieving endoplasmic reticulum (ER) stress. The ER makes sure proteins are folded properly.
- Reducing programmed cell death (apoptosis) in healthy cells. TUDCA prevents the molecule BAX from reaching the mitochondria. BAX causes mitochondria to release cytochrome C, which causes enzymes (caspases) to initiate apoptosis.
- Inactivating Bcl-2-associated death promoter (BAD), a molecule involved in apoptosis.
- Removing toxic bile acids from the liver and preventing them from damaging liver cells
- Exhibits neuroprotective effects via the inhibition of NF-kB
- Preserve photoreceptor function and increases retinal health by increasing rd10
Sources
Liv52 Liv52 is an herbal liver support. There have been medical studies conducted on Liv.52 in recent years, many of which involve its ability to protect the liver from damage by alcohol or other toxins. Liv52 has been shown to exhibit antiperoxidative function, antioxidant effects, anti-inflammatory, diuretic effects and neutralization of toxic products within the liver.
“The results demonstrated that the patients treated with Liv-52 for 6 months had significantly better child-pugh score, decreased ascites, decreased serum ALT and AST. We conclude that Liv-52 possess hepatoprotective effect in cirrhotic patients. This protective effect of Liv-52 can be attributed to the diuretic, anti-inflammatory, anti-oxidative, and immunomodulating properties of the component herbs.”
“Liv.52 enhanced the rate of absorption of ethanol and rapidly reduced acetaldehyde levels, which may explain its hepatoprotective effect on ethanol-induced liver damage.”
“Liv.52 administration reduced the deleterious effects of ethanol. The concentration of acetaldehyde in the amniotic fluid of ethanol-consuming animals was 0.727 microgram/ml. Liv.52 administration lowered it to 0.244 microgram/ml. The protective effect of Liv.52 could be due to the rapid elimination of acetaldehyde.”
That being said, there is conflicting research on Liv52. The studies either show hepatoprotective function or no effect, positive or negative. “There was no significant difference in clinical outcome and liver chemistry between the two groups at any time point. There were no reports of adverse effects attributable to the drug. Our results suggest that Liv.52 may not be useful in the management of patients with alcohol induced liver disease.”
In short, Liv52 can be used if you have the additional funds, it is not the end-all-be-all but can be used as an adjunct. It is an incredibly cheap drug that may improve liver function and exhibit hepatoprotective effects. IT SHOULD IN NO WAY YOUR ONLY LIVER SUPPORT MEDICATION, but there is nothing wrong with using it. Hi all! I recently had my yearly check-up and my total bilirubin was 3.2 mg/dL. Since it was elevated, my doctor ordered another blood test last week to get a breakdown of the bilirubin (I'm assuming to see the direct/indirect bilirubin levels).
I'm still waiting on the results of that blood test, but I was doing some reading about elevated bilirubin levels and I came across some info that said if bilirubin is present in the urine then the elevation is probably caused by direct (conjugated) bilirubin. That means the absence of bilirubin in the urine points to the total bilirubin being made up of indirect (unconjugated) bilirubin. It also said that the absence of urobilinogen points to direct bilirubin levels being high, while normal urobilinogen levels are a characteristic of high levels of indirect bilirubin.
I was wondering if this was true for those of you who have been diagnosed with Gilbert Syndrome. My urine was negative for bilirubin and the urobilinogen was normal, so I'm leaning towards the breakdown probably showing mostly unconjugated bilirubin and being Gilbert Syndrome.
submitted by High bilirubin levels are usually a sign that something’s not quite right in your liver or gallbladder. Some of these conditions aren’t too serious, but it’s important to monitor and treat them. Direct bilirubin 7.5 mg/dl high, indirect bilirubin normal 0.6 mg/dl. Direct bilirubin 11.0 mg/dl high, indirect bilirubin slightly elevated 0.9 mg/dl. 3. Both conjugated and unconjugated bilirubin are elevated, values are almost the same, commonly results from hepatic diseases, for instance: Direct bilirubin 9.0 mg/dl, indirect bilirubin 8.0 ... Cholestasis results from reduced excretion of bile due to a number of disorders [1] and is defined as conjugated bilirubin more than 20% of the total bilirubin when the total bilirubin is 85 [micro]mol/L or more, and 17 [micro]mol/L or more when the total bilirubin is 85 [micro]mol/L or less. High levels of bilirubin can cause a yellowing of your skin and eyes, a condition doctors call jaundice. High bilirubin levels are common in newborns. ... Conjugated (“direct”) bilirubin. Likewise, what does high conjugated bilirubin mean? Bilirubin is a tetrapyrrole produced by the normal breakdown of heme. Most bilirubin is produced during the breakdown of hemoglobin and other hemoproteins. Elevated conjugated bilirubin levels usually indicate hepatobiliary disease. Also, how do I lower my conjugated bilirubin? This includes: Water. Conjugated bilirubin (direct bilirubin) —formed in the liver when sugars are attached (conjugated) to bilirubin. It enters the bile and passes from the liver to the small intestines and is eventually eliminated in the stool. Normally, no conjugated bilirubin is present in the blood. Figure 1. Unconjugated bilirubin and conjugated bilirubin ... Bilirubin comes from the breakdown of red blood cells and is excreted by the liver. High levels of bilirubin can cause jaundice, which is a yellowing of the eyes of skin. Jaundice can occur in ... Liver Inflammation- any liver disease like hepatitis or injuries can cause inflammatory changes in the liver resulting in high bilirubin levels. Infections – high bilirubin level is also observed in infections of the liver. These infections interfere with the conversion of bilirubin in the conjugated form. Thus, bilirubin gets collected in the blood. An increase in the level of conjugated bilirubin means an indication towards hepatobiliary disease. Unconjugated bilirubin generally reacts slowly in the absence of an accelerator namely ethanol. In order to calculate indirect bilirubin the formula of Total bilirubin - Direct bilirubin is used. Direct bilirubin is measured without an accelerator. Conjugated Bilirubin: The conjugated bilirubin has small molecular weight and can be filtered through the kidney. Unconjugated Bilirubin: The unconjugated bilirubin has high molecular weight and cannot be filtered through the kidney. Presence in bile. Conjugated Bilirubin: The conjugated bilirubin is present in bile.
