Anabolic Steroids & Liver [GI]

[Michael Scally MD]

Medina-Caliz I, Garcia-Cortes M, Gonzalez-Jimenez A, et al. Herbal and Dietary Supplement-induced Liver Injuries in the Spanish DILI Registry. Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 2018. http://www.cghjournal.org/article/S1542-3565(18)30010-7/abstract

BACKGROUND & AIMS: There have been increasing reports of liver injury associated with use of herbal and dietary supplements, likely due to easy access to these products and beliefs among consumers that they are safer or more effective than conventional medications. We aimed to evaluate clinical features and outcomes of patients with herbal and dietary supplement-induced liver injuries included in the Spanish DILI Registry.

METHODS: We collected and analyzed data on demographic and clinical features, along with biochemical parameters, of 32 patients with herbal and dietary supplement-associated liver injury reported to the Spanish DILI registry from 1994 through 2016. We used analysis of variance to compare these data with those from cases of liver injury induced by conventional drugs or anabolic androgenic steroid-containing products.

RESULTS: Herbal and dietary supplements were responsible for 4% (32 cases) of the 856 DILI cases in the registry; 20 cases of DILI (2%) were caused by anabolic androgenic steroids. Patients with herbal and dietary supplement-induced liver injury were a mean age of 48 years and 63% were female; they presented a mean level of alanine aminotransferase 37-fold the upper limit of normal, 28% had hypersensitivity features, and 78% had jaundice. Herbal and dietary supplement-induced liver injury progressed to acute liver failure in 6% of patients, compared to none of the cases of anabolic androgenic steroid-induced injury and 4% of cases of conventional drugs. Liver injury after repeat exposure to the same product that caused the first DILI episode occurred in 9% of patients with herbal and dietary supplement-induced liver injury vs none of the patients with anabolic androgenic steroid-induced injury and 6% of patients with liver injury from conventional drugs.

CONCLUSION: In an analysis of cases of herbal and dietary supplement-induced liver injury in Spain, we found cases to be more frequent among young women than older patients or men, and to associate with hepatocellular injury and high levels of transaminases. Herbal and dietary supplement-induced liver injury is more severe than other types of DILI and re-exposure is more likely. Increasing awareness of the hepatoxic effects of herbal and dietary supplements could help physicians make earlier diagnoses and reduce the risk of serious liver damage.

 

[Michael Scally MD]

Sumida Y, Yoneda M. Current and future pharmacological therapies for NAFLD/NASH. Journal of gastroenterology 2017. https://link.springer.com/article/10.1007%2Fs00535-017-1415-1

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide, and there is no approved pharmacotherapy. The efficacy of vitamin E and pioglitazone has been established in nonalcoholic steatohepatitis (NASH), a progressive form of NAFLD. GLP-1RA and SGLT2 inhibitors, which are currently approved for use in diabetes, have shown early efficacy in NASH, and also have beneficial cardiovascular or renal effects. Innovative NASH therapies include four main pathways. The first approach is targeting hepatic fat accumulation. Medications in this approach include modulation of peroxisome proliferator-activator receptors (e.g., pemafibrate, elafibranor), medications targeting farnesoid X receptor axis [obeticholic acid; OCA)], inhibitors of de novo lipogenesis (aramchol, ACC inhibitor), and fibroblast growth factor-21 analogues. A second target is oxidative stress, inflammation, and apoptosis. This class of drug includes apoptosis signaling kinase 1 (ASK1) inhibitor and emricasan (an irreversible caspase inhibitor). A third target is intestinal microbiomes and metabolic endotoxemia. Several agents are in ongoing trials, including IMMe124, TLR4 antagonist, and solithromycin (macrolide antibiotics). The final target is hepatic fibrosis, which is strongly associated with all-cause or liver-related mortality in NASH. Antifibrotic agents are a cysteine-cysteine motif chemokine receptor-2/5 antagonist (cenicriviroc; CVC) and galectin 3 antagonist. Among a variety of medications in development, four agents such as OCA, elafibranor, ASK1 inhibitor, and CVC are currently being evaluated in an international phase 3 trial for the treatment of NASH. Within the next few years, the availability of therapeutic options for NASH will hopefully curb the rising trend of NASH-related diseases.

 

[Michael Scally MD]

[OA] Severe Cholestasis and Bile Cast Nephropathy Induced by Anabolic Steroids Successfully Treated with Plasma Exchange

A 35-year-old male was admitted to the hospital for progressive jaundice, colicky abdominal pain, vomiting, and severe pruritus. He also reported dark urine and pale stools. He had no significant past medical history except for dyslipidemia on lifestyle modification and binge drinking of approximately 1 liter during the weekends.

Twelve weeks prior to presentation, he started a regimen for weight loss and muscle building consisting of 3 different types of anabolic steroids: stanozolol (100 mg, 3 times/week, intramuscular), trenbolone (100 mg, 3 times/week, intramuscular), and testosterone propionate (50 mg, 3 times/week, intramuscular). In addition to the anabolic steroids, he was taking 12 capsules daily consisting of dietary supplements such as T3 liothyronine, creatine, conjugated linoleic acid with olive oil, and amino acids.

This led to the development of jaundice and severe pruritus with serum total bilirubin reaching 41.22 mg/dL. Despite supportive care with fluid and albumin therapy, serum creatinine was progressively increasing.

He underwent 6 successful sessions of plasma exchange (PE) with marked improvement at the end of the sessions. Three months after discharge, the patient's creatinine and total bilirubin levels were 1.08 mg/dL and 1.2 mg/dL, respectively.

El Khoury C, Sabbouh T, Farhat H, Ferzli A. Severe Cholestasis and Bile Cast Nephropathy Induced by Anabolic Steroids Successfully Treated with Plasma Exchange. Case reports in medicine 2017;2017:4296474. https://www.hindawi.com/journals/crim/2017/4296474/

 

[Michael Scally MD]

[OA] Blood Biochemical Markers of Competitive Bodybuilding Athletes Users of Anabolic Androgenic Steroids and/or Growth Hormone (AAS/GH), Strength Athletes Drugs Free and Sedentary Persons

Many professional athletes and those frequenting gyms use Anabolic Androgenic Steroids and/or Growth Hormone (AAS/GH), to improve performance and aesthetics. The aim of this study was to compare the blood markers of 03 groups with 08 volunteers in each:
· bodybuilders using AAS/GH (A),
· amateur strength athletes drugs free (B) and
· sedentary individuals as control (C).

The tests Kruskall-Wallis (ANOVA Non-Parametric) and followed by the Dunn was carried out (p<0,05).

There was a significant increase in Group A in comparison with B and C to: GH, lactate dehydrogenase, urea, aspartate aminotransferase, alanine aminotransferase, low-density-lipoprotein cholesterol (LDL), total cholesterol/high-density-lipoprotein cholesterol (HDL) and LDL/HDL ratios; and reduced levels of: sex hormone binding globulin, insulin, HDL.

The creatine phosphokinase was increased in Groups A and B, and creatinine in A regarding C but equal B.

The groups were equal for TT and free testosterone, cortisol, leptin, ALP, TC, TAG, VLDL-c, homocysteine and TT/cortisol ratio.

These results suggest that users of AAS/GH were exposed to a higher systemic risk, but not so intense as expected. In this way, point out that AAS/GH user’s protocols, should be consider the interactivity of diet, training and genetic for the building the standard position to bodybuilding and strength athletes.

Fett CA, Maruyama M, Brandão CF, Fett WC. Blood Biochemical Markers of Competitive Bodybuilding Athletes Users of Anabolic Androgenic Steroids and/or Growth Hormone (AAS/GH), Strength Athletes Drugs Free and Sedentary Persons. International Journal of Sports Science. 2018; 8(1):1-7. Blood Biochemical Markers of Competitive Bodybuilding Athletes Users of Anabolic Androgenic Steroids and/or Growth Hormone (AAS/GH), Strength Athletes Drugs Free and Sedentary Persons

 

[Michael Scally MD]

[OA] Milla Castellanos M, Gutierrez Martinez E, Sevillano Prieto A, Rodriguez Ramos P, Praga Terente M. Bile cast nephropathy associated with severe liver dysfunction caused by anabolic steroids. Nefrologia 2018. Redirecting / Redirecting

Acute kidney injury (AKI) is a common and significant com-plication in patients with liver failure (LF).1AKI related to increased bilirubin levels has been well known since the beginning of the 20th century. This condition has received different names: cholestatic nephropathy, jaundice-related nephropathy, bile cast nephropathy and bile nephropathy.

We present an unusual case of AKI due to severe hyper-bilirubinaemia caused by anabolic steroids (AS) used for body-building. This is a 40-year-old man, with no previous medical history of interest, who came to the clinics for symptoms of jaundice, hypocholia, choluria, itching and asthenia. The patient presented with no substance abuse and reported that he had been taking Animal-Pak® and EA Havoc® vitamin supplements the previous month.

 

[Nicolaus]

I apologize if this has already been addressed...but can tren A cause low alkaline phosphatase???

 

[Michael Scally MD]

I apologize if this has already been addressed...but can tren A cause low alkaline phosphatase???

Low! Not that I am aware of.

Why the concern?

 

[Michael Scally MD]

Serum Testosterone and Non-alcoholic Fatty Liver Disease

BACKGROUND & AIMS: Testosterone plays a role in predisposing individuals to cardiovascular and metabolic diseases, but its effects differ between men and women. We investigated the association between serum total testosterone and non-alcoholic fatty liver disease (NAFLD) in adults in the US.

METHODS: A cross-sectional analysis of data from participants in the 2011-2012 National Health and Nutrition Examination Survey was performed. Subjects with significant alcohol consumption and those with viral hepatitis were excluded. We used the highest sex-specific quartiles of serum total testosterone as references. Suspected NAFLD was diagnosed when serum alanine aminotransferase was > 30 IU/L for men and > 19 IU/L for women.

RESULTS: Of the 4,758 subjects (49.4% men), the prevalence of suspected NAFLD was inversely correlated with the sex-specific quartiles of testosterone in men and women. In a multivariate model, low total testosterone levels were associated with progressively higher odds of suspected NAFLD in men after adjusting for age, obesity, and other metabolic risk factors (p values for trends < 0.01).

When the women were divided into two groups according to menopausal status, a significant correlation was observed only in the postmenopausal women (p values for trends < 0.01). The adjusted odds ratios (ORs) for suspected NAFLD were 1.72-1.99 in men and 2.15-2.26 in postmenopausal women (lowest quartile vs. highest quartile).

CONCLUSIONS: In this nationally representative sample of adults in the US, low total testosterone levels were associated with suspected NAFLD in men and postmenopausal women independent of known risk factors. This article is protected by copyright. All rights reserved.

Yim JY, Kim J, Kim D, Ahmed A. Serum Testosterone and Non-alcoholic Fatty Liver Disease in Men and Women in the US. Liver international: official journal of the International Association for the Study of the Liver 2018. Serum Testosterone and Non‐alcoholic Fatty Liver Disease in Men and Women in the US

 

[Michael Scally MD]

Niedfeldt MW. Anabolic Steroid Effect on the Liver. Current Sports Medicine Reports 2018;17. Anabolic Steroid Effect on the Liver : Current Sports Medicine Reports

Anabolic steroids are synthetic derivatives of testosterone shown to increase muscle size and strength. Chemical substitutions on the testosterone molecule cause increased potency and duration of action. The 17-α-alkylation modification allows steroids to be taken orally, but the slower clearance in the liver makes them more hepatotoxic.

The frequency and severity of side effects depends on several factors including the formulation of the drug, route of administration, dosage, duration of use, and individual sensitivity and response. Anabolic steroid users tend to take supraphysiologic doses or multiple steroids and other drugs simultaneously which increases risk of adverse effects.

Hepatotoxicity can be seen as elevated liver transaminases, acute cholestatic syndrome, chronic vascular injury, hepatic tumors, and toxicant-associated fatty liver disease, as well as significant changes in lipoproteins. Many of these changes will stabilize or reverse with cessation of steroid use, but some can be life-threatening. Over-the-counter supplements can be contaminated with anabolic steroids, causing hepatotoxicity in unsuspecting consumers.

 

[m314]

Low! Not that I am aware of.

Why the concern?

Is there some mechanism to cause low alkaline phosphatase that's common with AAS users? Mine came back low in my last test. I've seen this question asked several times on steroid forums without much of an answer.

 

[Michael Scally MD]

Kato K, Abe H, Hanawa N, et al. Hepatocellular adenoma in a woman who was undergoing testosterone treatment for gender identity disorder. Clinical journal of gastroenterology 2018. https://link.springer.com/article/10.1007%2Fs12328-018-0854-4

A 32-year-old Japanese woman was admitted to our hospital for the diagnosis and treatment of multiple liver tumors. She had been receiving 125 mg testosterone enanthate every 2 weeks following female-to-male gender identity disorder (GID) diagnosis at 20 years of age.

Ultrasonography, computed tomography, and magnetic resonance imaging showed 11 hepatic nodular tumors with a maximum diameter of 28 mm. Liver tumors with hepatocellular adenoma (HCA) were diagnosed with needle biopsy. Segmentectomy of the left lateral lobe including two lesions, subsegmentectomy of S6 including two lesions, enucleation of each tumor in S5 and S7, and open surgical radiofrequency ablation for each tumor in S4 and S7 were performed.

Immunohistochemical specimens showed that the tumor cells were diffusely and strongly positive for glutamine synthetase and that the nuclei were ectopically positive for beta-catenin. Thus, the tumors were diagnosed as beta-catenin-activated HCA (b-HCA). Transcatheter arterial chemoembolization plus subsequent radiofrequency ablation was performed for the 3 residual lesions in S4 and S8.

Although testosterone enanthate was being continued for GID, no recurrence was observed until at least 22 months after the intensive treatments. HCA development in such patients receiving testosterone should be closely monitored using image inspection.

 

[Michael Scally MD]

[OA] Association Between Cholesterol Gallstones and Testosterone Replacement Therapy in A Patient with Primary Hypogonadism

A 16-year-old boy had a past medical history of primary hypogonadism, due to bilateral anorchia. He presented with gallstones located in the gallbladder and a mild dilatation of the intrahepatic biliary tree. The histology study reported cholesterol gallstones.

The patient had been treated with testosterone replacement therapy since infancy. We suggest a possible correlation between testosterone replacement therapy and the presence of cholesterol gallstones.

Squarza S, Rossi UG, Torcia P, Cariati M. Association between cholesterol gallstones and testosterone replacement therapy in a patient with primary hypogonadism. Revista de gastroenterologia de Mexico 2018. https://www.sciencedirect.com/science/article/pii/S037509061830082X

 

[Flathead Fred]

Hey Doc, any clinical studies that you can dig up on coffee enemas and liver health? Not a joke as I am a believer in them just curious as to what you can find on your side of the house. Thanks

 

[Michael Scally MD]

Side Effects of Anabolic Steroids Used by Athletes at Unaizah Gyms, Saudi Arabia: A Pilot Study

BACKGROUND: A large number of Saudi athletes are recently shown to use androgenic anabolic steroid (AAS) products to achieve rapid muscle growth without realizing the serious health risks of these drugs. Aim of this study was to elucidate the side effects encountered with prolonged use of AAS products by Saudi athletes.

METHODS: A cross-sectional study was conducted, in which 16 regular gym members, 12 of them used AAS, were asked to answer a questionnaire and provide blood samples following current AAS course completion. Hemoglobin, serum proteins, lipid profile and hematological parameters were measured. Meanwhile, the parameters of kidneys, liver, heart, and immune system function were monitored.

RESULTS: The subjects reported taking a 3-month course of an AAS comprising three compounds (testosterone enanthate, nandrolone decanoate and methandienone).

A two-week gap separated every two courses, during which tamoxifen citrate (40 mg per day) and clomiphene citrate (10 mg per day) were taken to control serum testosterone levels.

The intake of AAS one course had remarkable effects on some parameters related to kidney function. However, AAS three courses or more treatments showed abnormal liver and heart enzymes.

Moreover, endogenous testosterone levels decreased dramatically with prolonged use of AAS (more than 10 courses).

Alpha 2 protein increased by taking more than 10 courses, which might cause acute phase reactant of liver infection or inflammation.

CONCLUSIONS: AAS products must be controlled by Saudi ministry of health and should not be taken randomly without the supervision of the healthcare professional.

Almaiman AA, Almaiman SH, Elagamy EI, et al. Side effects of anabolic steroids used by athletes at Unaizah Gyms, Saudi Arabia: a pilot study. The Journal of sports medicine and physical fitness 2018. https://www.minervamedica.it/en/journals/sports-med-physical-fitness/article.php?cod=R40Y9999N00A18042005#

 

[Michael Scally MD]

[OA] Coelho RC, dos Santos Fernandes G, Sternberg C. Exploring the link between anabolic-androgenic steroids abuse for performance improvement and hepatocellular carcinoma: a literature review. Braz J Oncol. 2018;14(47):1-8. http://brazilianjournalofoncology.com.br/wp-content/uploads/2018/04/E-175_corrigido-5.pdf

Introduction: Hepatocellular carcinoma (HCC) corresponds to 90% of primary malignant liver cell carcinomas and is a leading cause of cancer-related death worldwide.

Objective: This compilation of cases aimed to identify evidence of correlation between anabolic androgen steroids (AAS) abuse for performance improvement by healthy subjects and HCC.

Methods: We performed a literature review and identified 935, 1148, 12 and 3 articles in Pubmed, Embase, Scopus and Lilacs, respectively. Only studies, reviews and case reports evaluating the association between androgens and hepatocarcinoma were included with no restrictions in time span or language.

Further on, we excluded studies and case reports which patients were receiving therapeutic androgens and collected data only of those reporting androgen intake to improve physical performance.

Results: Six articles fulfilled the inclusion criteria, excluding the duplicates. HCC onset after AAS abuse seems to occur at earlier ages than those related to chronic hepatitis B/C, chronic alcohol consumption and nonalcoholic steatohepatitis (NASH). Timeframe ranged from two to seven years in the cases reports presented here.

Many AAS subtypes were used by patients depicted in the case reports, so it is difficult to conclude if a specific AAS is safer or more harmful than the other. Carcinogenic mechanisms are poorly understood, but pre-clinical evidence shows that androgen receptors and oxidative stress may play a pivotal role in its development.

Conclusion: The evidence that HCC has been linked to long term AAS abuse for performance improvement is scant but some association is suggested. AAS must be taken only under specialized supervision and the putative correlation with HCC calls for public policies to make high risk populations aware of the risks of misuse and self-administration.

 

[Michael Scally MD]

Gupta S, Naini BV, Munoz R, et al. Hepatocellular Neoplasms Arising in Association With Androgen Use. The American Journal of Surgical Pathology 2016;40. Hepatocellular Neoplasms Arising in Association With... : The American Journal of Surgical Pathology

Correlation between androgen use and hepatocellular neoplasia is well established. However, there are no detailed studies of the histopathology and immunohistochemical/molecular profile of these tumors. We studied 9 patients with androgen-associated hepatocellular neoplasms.

In addition to histology, immunostains for liver fatty acid–binding protein, β-catenin, glutamine synthetase, C-reactive protein, and serum amyloid A were utilized for tumor subtyping. Molecular testing using Solid Tumor Targeted Cancer Panel was performed on 3 cases.

The neoplasms were predominantly seen in male individuals (7/9). Two patients (22%) had multifocal lesions. All lesions had architectural and 4/9 had cytologic atypia. Cholestasis was present in 6/9 cases. Reticulin was focally disrupted in 5/9 cases. Given the clinical setting, all lesions were classified as well-differentiated hepatocellular neoplasms of uncertain malignant potential.

In cases with follow-up (6/9 cases, 67%), there were no recurrences or metastases. On the basis of the immunoprofile, 7 (78%) cases were β-catenin activated (including 1 hepatic adenoma with concurrent hepatocyte nuclear factor 1α inactivation) and 2 (22%) had inflammatory phenotype. Somatic mutations in CTNNB1 were detected in all 3 tested cases (all β-catenin activated by immunostain), all involving exon-3.

Our data indicate that androgen-associated hepatocellular neoplasms most often develop in male individuals and always show some degree of atypia and/or focal reticulin disruption. Most are β-catenin activated, often harboring CTNNB1 exon-3 mutations, and a minority is inflammatory type. Although β-catenin and inflammatory pathways likely play a role in pathogenesis, the heterogenous molecular profile suggests there are other (yet to be characterized) primary oncogenic mechanisms in this unique tumor type.

 

[Michael Scally MD]

Hepatic Adenomas: Classification, Controversies, and Consensus

Key points

· Hepatocellular adenomas are classified using immunostains in order to identify tumors at greatest risk for malignant transformation and for hemorrhage.

· These three rare types of hepatocellular adenomas do not fit as well in the current classification system, but are also at high risk for malignancy: androgen related hepatocellular adenomas, pigmented hepatocellular adenomas, myxoid hepatocellular adenomas.

· Risk factors formalignant transformation include patient gender, patient age, adenoma size, cytological atypia, beta-catenin activation, adenoma subtype.

Torbenson M. Hepatic Adenomas: Classification, Controversies, and Consensus. Surgical pathology clinics 2018;11:351-66. https://www.surgpath.theclinics.com/article/S1875-9181(18)30007-2/abstract

 

[Michael Scally MD]

Botanicals and Hepatotoxicity

The use of botanicals, often in the form of multi‐ingredient herbal dietary supplements (HDS), has grown tremendously in the past three decades despite their unproven efficacy. This is paralleled by an increase in dietary supplement‐related health complications, notably hepatotoxicity.

This article reviews the demographics and motivations of dietary supplement (DS) consumers and the regulatory framework for DS in the US and other developed countries. It examines in detail three groups of multi‐ingredient HDS associated with hepatotoxicity:

· OxyElite Pro (two formulations),
· green tea extract‐based DS, and
· “designer anabolic steroids.”

These examples illustrate the difficulties in identifying and adjudicating causality of suspect compound(s) of multi‐ingredient HDS‐associated liver injury in the clinical setting. The article outlines future directions for further study of HDS‐associated hepatotoxicity as well as measures to safeguard the consumer against it.

Roytman Marina M, Poerzgen P, Navarro V. Botanicals and Hepatotoxicity. Clinical Pharmacology & Therapeutics 2018. https://doi.org/10.1002/cpt.1097

 

[Dr JIM]

Gupta S, Naini BV, Munoz R, et al. Hepatocellular Neoplasms Arising in Association With Androgen Use. The American Journal of Surgical Pathology 2016;40. Hepatocellular Neoplasms Arising in Association With... : The American Journal of Surgical Pathology

Correlation between androgen use and hepatocellular neoplasia is well established.


.

Really since when, according to who, and based upon what definition of "neoplasia"?

 

[Michael Scally MD]

[OA] Performance-Enhancing Drugs Abuse Caused Cardiomyopathy and Acute Hepatic Injury in a Young Bodybuilder

A number of performance-enhancing drugs (PEDs) are used illicitly to improve muscle strength by the bodybuilders. The misuse of these drugs is associated with serious adverse effects to different organs.

A previously healthy 22-year-old male bodybuilder after taking stanozolol, clenbuterol, and triiodothyronine for 10 days presented to the hospital with symptoms of icteric sclera, progressive dyspnea, intermittent cough, and bloody sputum. He was diagnosed with dilated cardiomyopathy and acute hepatic injury.

Rapidly progressive dilated cardiomyopathy and acute hepatic injury among bodybuilders in such a short period of time have not been reported. People using these drugs must monitor liver and cardiac functions regularly, and they should discontinue using PEDs after diagnosis of liver or cardiac abnormalities. Physicians should always consider the possibility of the PED abuse in the context of a young athlete suffering cardiomyopathy or hepatic injury.

Li C, Adhikari BK, Gao L, et al. Performance-Enhancing Drugs Abuse Caused Cardiomyopathy and Acute Hepatic Injury in a Young Bodybuilder. American journal of men's health 2018. SAGE Journals: Your gateway to world-class journal research