The following article was written by user ‘canal_of_schlemm‘ from r/steroids Reddit
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 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.
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.
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 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 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 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.
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.
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.
Liver Function Tests
LFTs can be done to assess hepatic function. These are not exactly conclusive and require some sort of follow up to assess the degree of severity. Often this will be some sort of imaging or biopsy. Most of these biomarkers are assessed in a multiplication of the upper limit of normal (ULN), which is the top end of the normal range.
Aminotransferases are enzymes that are used in the synthesis of amino acids. There are two aminotransferases that are checked as part of an LFT.
Aspartate Transaminase (AST)
Reference range: 8 – 40 IU/L. While AST is found in the liver, this enzyme is also found in great quantities in cardiac and skeletal muscle. Because of these other sources, AST alone is not a good indicator of liver damage. Essentially, AST does not require the entire cell to be damaged for it to enter the plasma, where ALT does. This is due to its location within the cell. If AST is elevated then there is a good possibility that the source of the AST is from muscle damage. This can be caused by myocardial infarction (heart attack), rhadomyolysis, and even resistance training. This is why slightly elevated AST levels should not be of concern if you lift frequently.
Alanine Transaminase (ALT)
Reference range: ≤ 52 IU/L. Much like AST, ALT is an enzyme used to catalyze the synthesis of amino acids. Unlike AST, ALT is found predominantly in the liver and requires significant damage to hepatocytes for it to be released in to the plasma.
AST to Platelet Ratio Index (APRI)
This typically won’t be included in lab tests, but it is easy to figure out. An online calculator can be found here. APRI has been shown to be a predictor of liver cirrhosis.
Alkaline Phosphatase (ALP)
Reference rage: 30 – 120 IU/L. ALP is an enzyme that is located within hepatic biliary ducts. Elevations in plasma concentrations of this enzyme are indicative of either cholestasis or biliary obstruction. In these pathologies, ALT and AST may remain unaffected.
Reference range: 0.1-1.0 mg/dL. Bilirubin is a byproduct of hemoglobin catabolism. The heme group of hemoglobin is broken down into biliverdin, then bilirubin, which is transported to the liver for the production of bile salts along with urobilin (the pigment that makes urine yellow) and stercobilin (the pigment that makes feces brown). High hepatic sources of bilirubin are indicative of cirrhosis or hepatitis.
Another biomarker used int he diagnosis of cholestasis.
Hepatotoxic drug withdrawal is the widely accepted treatment for drug induced liver damage.
TUDCA is a bile acid that was found in bears. It is currently being researched in the treatment of ophthalmologic and neurologic conditions. TUDCA has been shown to reduce cholestasis, hepatic steatosis, cirrhosis, and transient liver enzyme levels. The extent of this efficacy still needs more research and clinical trials. No research exists to support its use in zonal necrosis, peliosis hepatis, or hyperplasia. Buy TUDCA here.
This is bullshit, don’t waste your money.
This is bullshit, don’t waste your money.