A Closer Look at Steroid Liver Toxicity

Pop quiz time! True or false?

1) 17-alpha alkylated steroids are harder for the liver to metabolize, so it has to work harder to break them down.
2) All 17- alpha alkylated steroids are liver toxic.
3) Non 17-alpha alkylated steroids are not liver toxic.

It may surprise you to know all of the above are false . Read on to learn why.

It’s a well known fact that 17-alpha alkylated steroids are liver toxic. Just how toxic depends on who you listen to. The media and many physicians think they are deadly, whereas many online ‘bros’ think they are practically harmless. There seems to be a lot of confusion on the subject, even by those who are well read on the subject of steroids. The truth is that it depends heavily on the individual using the steroid, as well as the actual steroid being used; and the dose and the duration of use. Hopefully we can dispel some rumors and gain an understanding of how these substances are toxic, and how to reduce or prevent toxicity as well!
Toxic Effects

What are the known toxic effects of oral steroids? By far the most common toxicity seen is intrahepatic cholestasis. In general, cholestasis is any condition where bile flow is stopped, and with oral anabolics it occurs within the liver. Normally, bile is released into the small intestine and where its main function is to aid the in the absorption of fats and fatlike substances. This stoppage prevents bile salts from being released into the bile duct, causing a buildup within the hepatocyte. This buildup can be toxic to the hepatocytes over time. Jaundice, a yellowing of the skin and eyes, is related to cholestasis. This occurs because bilirubin (a product of red blood cell breakdown), is normally eliminated through the bile. During cholestasis, this builds up and produces a yellowish color in the skin and eyes, and is a tell tale sign that something bad is happening. Jaundice is a rare thing to see except in newborn babies, and a healthcare professional should be sought out if you notice these symptoms. The type of cholestasis normally seen from oral steroid use is clinically categorized as ‘bland cholestasis’ because there is no inflammation accompanying the cholestasis. This type of cholestasis is fully reversible upon cessation of the offending agent.

In addition to cholestasis, other reported toxic effects are peliosis hepatis and hepatic adenoma. Peliosis hepatis is the presence of blood-filled cavities in the liver. This is a rare occurrence, and the theory is that peliosis hepatis results because of liver blood outflow obstruction at the junction of sinusoids and centrilobular veins. What causes this? It is believed to be related to cholestasis, which causes growth (swelling) of the hepatocytes. In AAS users the obstruction may be due to the prolapse of hyperplasic hepatocytes into the hepatic venule wall. This is good news because this means if cholestasis can be prevented, so can peliosis hepatis.

Hepatic adenoma is mentioned several times in the literature as a possible effect of oral steroid use. The prevalence of this is extremely rare and seems to only occur after months or years of continuous use. It is very likely associated with prolonged cholestasis as well. In my opinion, it should not be a concern unless someone in your family has got this from an oral steroid (including birth control pills), and the real focus of safety should be on preventing cholestasis.

Liver Anatomy and Function

The liver has numerous important functions in the body, but its relevant functions for this article include drug metabolism and excretion, and secretion of bile salts and bicarbonate for digestion.

When orally ingested testosterone is absorbed in the small intestine it is transported to the liver via the portal vein. Here it is nearly 100% metabolized to a 17-keto steroid by the enzyme 17-hydroxy steroid dehydrogenase. This reaction is very rapid and only when high amounts of testosterone are ingested does the enzyme system get saturated, allowing some testosterone to get by unchanged. Other reactions are possible such as reduction of the ketone group on the 3 carbon, but these are not as important to toxicity of the steroid.

With 17-alpha alkylated steroids, this conversion from a 17-hydroxy to a 17-keto steroid is prevented. This is key, and if you remember anything from this article, remember the next few sentences. The main difference between 17-aa’s and regular steroids is that one retains a free 17 hydroxyl group and one does not, when going through the liver. The reason that 17-aa are toxic is because the free hydroxyl is able to be conjugated with glucuronic acid, forming a D ring 17-glucuronide. It is not the 17-aa steroid that is liver toxic but rather its 17-glucuronide metabolite. So it’s not that these steroids are harder to metabolize, but rather the way they are metabolized causes them to be toxic.

This fact goes for androgens as well as estrogens, 17-alpha alkylated and non 17-alpha alkylated steroids. Let me clarify that last part, normal steroids would be liver toxic if they did not get metabolized to the 17-keto steroid, so it may be more correct to say they are potentially toxic, but are not in normal use. An intravenous infusion of estradiol-17- glucuronide, testosterone-17-glucuronide or dihydrotestosterone-17-glucuronide would cause cholestasis just as oral methyltestosterone or ethinylestradiol does.

So what about the supposedly liver friendly oxandrolone? The following excerpt summarizes why it is liver friendly:

Unlike other orally administered C17alpha-alkylated AASs, the novel chemical configuration of oxandrolone confers a resistance to liver metabolism as well as marked anabolic activity. In addition, oxandrolone appears not to exhibit the serious hepatotoxic effects (jaundice, cholestatic hepatitis, peliosis hepatis, hyperplasias and neoplasms) attributed to the C17alpha-alkylated AASs.

I submit that its resistance to metabolism (17-glucuronidation) is the reason for its lack of toxicity.

So we now know 17-glucuronides are to blame for liver toxicity. Now let’s examine how they cause cholestasis. Bile flow is regulated in two ways; bile salt independent flow, and bile salt dependent flow.

Bile salt independent flow is a passive process controlled mainly by the osmotic factors glutathione and bicarbonate. The exact mechanisms are not known, but it is known that biliary glutathione levels decrease significantly soon after a toxic steroid is administered. The total hepatic glutathione increases, which seems to indicate that glutathione transport to the bile duct becomes impaired. Bicarbonate transport to the bile is similarly impaired, but it is not due to impaired transporters, rather the gradient becomes diminished by some type of bicarbonate reuptake. These processes occur rapidly and are the first toxicities observed.

Bile salt dependent flow is an active process that is controlled by numerous membrane bound transporters. Specifically ATP bind cassette (ABC) transporters transport the bile salts from the blood into the hepatocyte (basolateral), and then from the hepatocyte to the bile (canilicular). The pumping of bile salts into the bile is the main force that drives bile flow, which is what we want for normal functioning. Although both basolateral and canilicular transporters are probably involved in hormone induced cholestasis, the most examined is the canilicular bile salt export pump (BSEP). Oral steroid glucuronides are known to interact with the promoter region of the gene for this transporter and to repress its expression. Besides repression of the gene, other factors may decrease the BSEP function as well. The transport of the BSEP from its point of synthesis to the canilicular membrane can be impaired in cholestasis, providing functional transporters in the wrong place within the cell.

Finally there is the genetic component. There is a great deal of genetic variation in ABC transporters among the population. Certain people are at a higher risk for developing cholestasis than others, and in the near future it will be possible for you to determine what genetic polymorphisms you have in your hepatic transporters. This should be very valuable information for anyone who is planning on taking a potentially liver toxic drug, whatever it may be. In the meantime, the best method for determining if you are at risk for cholestatic problems is to look to your family. Cholestatic conditions to be mindful of are cholestasis of pregnancy, progressive familial intrahepatic cholestasis, benign recurrent intrahepatic cholestasis, and Dubin-Johnson syndrome. Having close relatives which any of these conditions possibly puts you at a greater risk of having toxicity issues with oral AAS.

In this article, we have explored the specifics how oral steroids cause liver dysfunction that can lead to toxicity. In part 2 of this article, we will look at methods to prevent or eliminate the major toxicities associated with using oral AAS.
References

J Clin Gastroenterol 39, Supp. 2, April 2005

Toxicol Lett. 1994 Dec;74(3):221-33.

Drugs. 2004;64(7):725-50.

Histopathology. 1977 Jul;1(4):225-46.

Drug Metab Rev. 1983;14(5):1005-19.

J Pharmacol Exp Ther. 1981 Jul;218(1):63-73.

Int J Sports Med (1981 May):2(2):101-5