Versatility of Anabolic Androgenic Steroid–Induced Hepatotoxicity

Abstract

The modified derivatives of testosterone, termed as androgenic steroids are indicated in the management of hypogonadism, visceral obesity and metabolic disorders. Anabolic androgenic steroids (AASs) however are surreptitiously used by athletes and body builders for cosmetic purpose owing to their anabolic effects on muscle mass and strength. The unsurveilled use of AASs subjects these users to various side effects involving multiple systems such as the endocrine, genitourinary, hepatobiliary, central nervous, musculoskeletal and psychosocial system. The liver is a hormone-sensitive organ owing to abundance of androgen receptors and is vulnerable to a wide array of hepatotoxicity ranging from asymptomatic liver enzyme elevation to life-threatening subacute liver failure. The type of drug-induced liver injury (DILI) due to AASs can be hepatocellular injury, cholestasis, fatty liver disease, chronic vascular injury and neoplastic disease. Herein, we report three cases of AAS-related DILI associated with AAS abuse.

The anabolic androgenic steroid (AAS) is a synthetic analogue of testosterone, used for medically approved indications such as primary and secondary hypogonadism, aplastic anaemia, bone marrow failure, human immunodeficiencies with chronic muscle wasting syndromes, endometriosis, fibrocystic diseases of the breast and hereditary angioedema.¹ It is also surreptitiously used by athletes and body builders for its ergogenic properties. Among three million AAS users in the United States, 70–75% are noncompetitive athletes who use it off-label, without physician consultation.¹ AAS drugs have been reported to cause deleterious effects on the heart, lipid profile, mental status and hepatic function. AAS-related drug-induced liver injury (DILI) may range from asymptomatic liver enzyme elevation to a life-threatening liver failure.¹ The pattern of injury may vary from hepatocellular injury, cholestasis, chronic vascular injury causing peliosis hepatis, fatty liver disease to rarely tumours.^2,3 Herein, we report three cases of AAS-related DILI that are different with respect to the type of drug usage, the pathological pattern of injury and clinical features.

Case report

Table 1 shows different patterns of clinical presentation and outcomes associated with AAS intake.

Table 1.

Different Patterns of Clinical Presentation and Outcomes Associated With AAS Intake.

Patient details	Case 1	Case 2	Case 3
Age and gender	31 years, male	24 years, male	36 years, male
Comorbidities	Diabetes mellitus	None	None
Type and dosage of AAS intake	Oxymetholone, 50 mg twice a day	Intramuscular testosterone decanoate, fortnightly Oral stanozolol, once daily	Intramuscular nandrolone decanoate, once a week
Duration of consumption	2 months	3 years	2 months
Clinical presentation	Progressive jaundice with pruritus, pale stool	Right hypochondrial pain, nausea	Jaundice, right hypochondrial pain
Blood tests at presentation
Total bilirubin (mg/dL)	35.6	0.6	7.4
Direct bilirubin (mg/dL)	24.7	0.3	4.8
AST (U/L)	34	30	387
ALT (U/L)	40	28	498
ALP (U/L)	294	110	170
GGT (U/L)	64	28	30
Albumin (g/dL)	3.7	4.5	3.8
Platelets (lakh/cumm)	4.2	3.3	4.8
INR	0.99	1.0	1.8
Other investigations	HAV, HBV, HCV and HEV: negative. ANA, ASMA, AMA, anti-LKM antibodies: negative. Serum ceruloplasmin levels and 24-h urinary copper excretion within the normal range.	HBV and HCV: negative. Alpha-fetoprotein level: 4.5 ng/mL (normal).	HAV, HBV, HCV and HEV: negative. ANA, ASMA, AMA, anti-LKM antibodies: negative. Serum ceruloplasmin levels and 24-h urinary copper excretion within the normal range.
Type of hepatotoxicity	Cholestatic	Hepatocellular carcinoma with multiple adenomas	Steatohepatitis
R factor for DILI	0.3	Not applicable	8.8
RUCAM score	+8	Not applicable	+8
CT of the abdomen with triphasic study	Hepatomegaly, mild splenomegaly and minimal ascites.	Three arterially enhancing lesions of 8 cm, 5 cm and 2 cm in segments 5 and 7 of the right lobe	Hepatomegaly with fatty infiltration
Histology	DILI with significant bilirubinostasis and mild sinusoidal collagenisation	Multifocal well-differentiated hepatocellular neoplasm of uncertain malignant potential (HUMP) without microvascular or macrovascular invasion.	Fatty deposition and hepatocytic ballooning
Treatment	Medical management, TPE	TACE followed by right hemihepatectomy	Medical management, TPE
Duration of illness	6 months	3 months	4 months
Recovery	Complete	Complete	Complete

AAS = anabolic androgenic steroid; AST = aspartate aminotransferase; ALP = alkaline phosphatase; ALT = alanine aminotransferase; GGT = gamma-glutamyl transferase; RUCAM = Roussel Uclaf Causality Assessment Method; CT = computed tomography; DILI = drug-induced liver injury; TPE = therapeutic plasma exchange; TACE = transarterial chemoembolization; INR = International normalized ratio.

Case 1

A 31-year-old gentleman with diabetes presented with fatigue, progressive jaundice with intense pruritus and pale stools of 4-week duration. The patient had been taking 50 mg of oxymetholone twice a day for two months to promote body building, before the illness. He denied any history of alcohol intake or any other substance abuse. His admission liver function tests (LFTs) revealed cholestasis, with negative viral serology (HAV, HEV, HBV, HCV, HSV) and an autoimmune profile (ANA, SMA, AMA). The results of screening for tropical infections such as malaria, leptospirosis and dengue were negative. His echocardiography was normal. A triple-phase computed tomography (CT) demonstrated hepatomegaly, a patent portal vein and hepatic veins, mild splenomegaly and minimal ascites, with no evidence of collaterals. The Roussel Uclaf Causality Assessment Method (RUCAM) score was +8, and the R factor was 0.3. The percutaneous liver biopsy was suggestive of features of DILI with largely maintained lobular architecture, prominent centrilobular hepatocanalicular bilirubinostasis with cholestatic rosettes and mild centrilobular sinusoidal collagenisation (Figure 1A). Mild lobular lymphocytic inflammation was noted. Occasional apoptotic body was noted. Kupffer cells showed pigment deposition. The portal tracts showed expansion with mild lymphocytic inflammation. There was no dysplasia. There was no evidence of bridging fibrosis or cirrhosis.

Figure 1.

(A) Bright-field microscopy displaying liver biopsy with cholestasis (case 1; H&E). (B) Bilirubin trend and correlation with plasma exchange depicted in the line diagram. (C) Bright-field microscopy displaying liver tumour with prominent pseudoacinar transformation (case 2; H&E). (D) Bright-field microscopy displaying peliosis hepatis (case 2; H&E). H&E = haematoxylin and eosin.

With peak bilirubin levels increasing to 51 mg/dL from 36 mg/dL, he underwent 8 sessions of therapeutic plasma exchange (TPE) over a period of 6 weeks for intractable pruritus at an outside hospital. By the 7th week of hospitalization with us, the patient became significantly sarcopenic and developed an episode of grade 1 hepatic encephalopathy (HE; serum ammonia = 102 μmol/L) with acute kidney injury, with creatinine levels increasing to 1.8 mg/dL. This was treated with correction of coagulopathy using fresh frozen plasma, anti-HE measures, terlipressin, human albumin and 2 further sessions of TPE, and the patient was prepared for living donor liver transplantation owing to subacute liver failure (SALF). From the end of the 8th week, there was gradual decline in cholestasis, with drop in total bilirubin levels to 12 mg/dL over the next three weeks. With drop in bilirubin levels, significant improvement was noticed in nutrition and performance status. At 12-week follow-up, there was complete normalization of LFTs, with improvement in liver CT volumetry (Figure 1B). In this case, AAS-induced SALF recovered with medical management without the need for liver transplantation.

Case 2

A 27-year-old male athlete presented with right hypochondrial pain and nausea. There was history of administration of intramuscular injectable drugs coupled with oral AAS intake for 3 years for improving muscle mass. There was no history of alcohol consumption or other substance abuse, and he was a nonsmoker. There was no family history of haemochromatosis. The serum ferritin level was 356 μg/L. On CT evaluation, there were three arterially enhancing lesions of 8 cm, 5 cm and 2 cm in segments 5 and 7 of the right lobe. Liver biopsy and immunohistochemistry suggested possibility of well-differentiated hepatocellular carcinoma (HCC). Transarterial chemoembolization (TACE) was performed for multifocal right lobe tumours. Eight weeks after TACE, CT showed lipoidal uptake by tumour with residual lesions in segment 5 and few new areas of arterial enhancement in segment IV B. The patient underwent right hepatectomy with nonanatomical resection of segment IV B tumour with curative intent. Light microscopy showed multifocal nonencapsulated well-differentiated hepatocellular neoplasm of uncertain malignant potential (HUMP) without vascular or perineural invasion (Figure 1C) and multiple cystically dilated spaces filled with blood cells and bordered by hepatocytes (peliosis hepatis) (Figure 1D). The tumour demonstrated round to polygonal cells forming trabeculae and prominent pseudoacinar architecture. There was mild anisomorphism with enlarged nuclei and small nucleoli. The tumour showed bile production. Focal reticulin loss was noted. No mitotic activity was noted. Focal necrosis secondary to TACE was noted. The patient remains disease free 18 months after resection.

Case 3

A 36-year-old gentleman presented with right hypochondrial pain, jaundice and reduced appetite. There was significant transaminitis as per baseline LFTs, with an International normalized ratio (INR) of 1.8; however, his viral serology results (HAV, HBV, HCV, HDV, HEV, HSV), tests for autoimmune markers (ANA, SMA, AMA, LKM autoantibodies) and screening for Wilson disease were negative. There was no history of alcohol consumption. There is no history of weight gain or family history of metabolic syndrome. On further questioning, the patient revealed that he was taking intramuscular nandrolone decanoate once a week for 2 months with dietary supplements for gaining muscle mass. CT of the abdomen showed significant hepatomegaly with fatty infiltration. Liver biopsy showed steatosis and hepatocytic ballooning with rarefied cytoplasm. The R factor was 8.8, and the RUCAM score was +8. Over 8 weeks of hospitalization, there was progressive cholestasis and transaminitis, which improved after the patient received 6 sessions of TPE. On outpatient follow-up at 3 months, there was significant improvement in LFTs.

Discussion

Endogenous testosterone is a male sex hormone with anabolic properties that stimulates muscle growth and androgenic properties that stimulates male sexual characteristics. AASs are synthetic analogues of testosterone that bind to androgen receptors (ARs) and have predominant anabolic effects targeting muscle growth, by promoting protein synthesis, and have less androgenic properties such as male pattern baldness and prostate hypertrophy.^3,4 The structural modification such as alkylation of the C-17 position of testosterone achieves relative anabolic potency with less androgenic properties, whereas oxidation of the 17β-hydroxy group creates 17-keto metabolites and increases hydrophobicity with longer duration of action. AASs are available as injectables (testosterone propionate, decanoate, cypionate and enanthate), as transdermal patches and in oral formulations (methenolone, methandienone, oxymetholone, stanozolol and oxandrolone). AASs work through three main effects: (1) turning on protein synthesis to build muscle mass, (2) through a proposed anticatabolic effect and (3) through a psychological effect. AASs may increase aggressiveness, allowing the user to intensify their training, indirectly increasing muscle size and strength.⁵

Bond et al⁴ proposed the role of hepatocellular oxidative stress, AR activation leading to an increase in reactive oxygen species levels and AR activation increasing mitochondrial beta-oxidation as a mechanism of AAS hepatotoxicity. Severe hepatotoxicity related to AAS abuse is a serious concern, particularly young adults and athletes being the most vulnerable group. The salient observation in these reports is that the type of hepatotoxicity is dependent on the type of AAS, number of agents and duration of consumption.¹ Long-term consumption of injectables clubbed with oral preparations and polypharmacy predisposes one to development of hepatocellular adenoma (HA), HUMP and HCC.^2,3,6,7 The cholestatic injury and steatohepatitis noted in the first and third case, generally presents after short duration of AAS consumption and clinically manifest with SALF, with a prolonged plateau in clinical symptoms and biochemistry parameters; however, medical management and supportive therapies such as TPE accelerates hepatic regeneration, as observed in our cases. The period of medical management can take as long as 3 months, as seen in our patients, and this can avoid liver transplantation. Similar observations were seen in study by Stolz et al⁸ of 44 male patients with severe protracted cholestasis who recovered over a median period of 94 days (range, 34–459 days) without the need for liver transplantation. There is limited supportive evidence for use of TPE in such cases except indications such as intractable pruritus and development of liver failure owing to DILI, as in our first case.^9,10 A case report by El Khoury et al¹¹ showed successful use of TPE in AAS-induced cholestasis–related bile cast nephropathy. There are also reports of higher risk of kidney injury with AAS-related DILI, with an odds ratio of 1.26, with 21.5 times the upper limit of normal being the best bilirubin cut-off point for predicting acute kidney injury risk.¹²

Development of hepatic tumours is a potentially serious complication of AAS use. Benign HA or tumour with malignant potential (HUMP and HCC) all has been reported in the literature. The liver is a hormone-sensitive organ with oestrogen receptors and ARs; thus, tumours can arise through use of either oral contraceptives or anabolic steroids.³ The tumour in our case was morphologically compatible with diagnosis of HUMP. Bedossa et al¹³ proposed the diagnosis of HUMP for anabolic steroid–induced hepatocellular neoplasms in 2014. These tumours morphologically resemble well-differentiated HCC. These neoplasms are predominantly seen in men and can be multifocal.² These tumours demonstrate architectural and variable cytologic atypia. Cholestasis and focal disruption of reticulin has also been described. There are no recurrences or any evidence of metastases in these tumours. Our patient is also disease free, with a follow-up of 18 months. The AAS has also been linked to peliosis hepatis, a rare condition presenting with hypervascular lesions in the liver resulting in multiple blood-filled ranging from several millimetres to 3 cm randomly distributed throughout the liver.¹⁴ There is no specific treatment for peliosis hepatis owing to AAS use except supportive care as the condition can at least partially reverse with cessation of steroid use.

The surreptitious AAS abuse is a major concern, especially in terms of risk of developing hepatotoxicity. The spectrum of hepatotoxicity is versatile from acute cholestasis, steatohepatitis to HUMP. The type of AAS, the pattern, duration and multiple drugs are predictors of the type of AAS hepatotoxicity. Long duration and consumption of multiple AASs predispose one to HUMP, which may require surgical intervention such as resection or liver transplantation. Cholestasis, steatohepatitis and peliosis hepatis due to AASs may be reversible without need for liver transplantation with supportive therapy.

Credit authorship contribution statement

Vaibhav Patil, Dinesh Jothimani and Mukul Vij planned and designed the study. Kavya Harika and Deepti Sachan collected the data. Mukul Vij prepared the histological findings and images for the study. Vaibhav Patil, Abdul Rahman Hakeem and Mukul Vij prepared the final draft of the manuscript. The final draft was reviewed and revised by Mohamed Rela.

Ethics committee approval

Local trust board ethics approval was obtained.

Conflicts of interest

The authors have none to declare.

Funding

The authors received no financial support for the research, authorship and/or publication of this article.