Severe Cardiac and Metabolic Pathology Induced by Steroid Abuse in a Young Individual

Androgenic-Anabolic Steroids (AAS) abuse is known to play an important role in causing the systemic inflammatory response and multiple-organ dysfunction in healthy individuals. Although many of the undesirable effects of steroid abuse have been reported, at present, little is known about the effect of anabolic supplements and the correlation between cardiac and metabolic pathology. This paper presents a case of a 25 year old patient with a complex medical history after 6 months of steroid administration. Myocardial infraction, dyslipidemia, obesity, hyperuricemia, secondary diabetes, and chronic renal disease were identified after clinical and para-clinical examinations. The particularities of this case were interpreted in the context of a literature review, highlighting the effect of multi-organ damage as a result of the uncontrolled use of anabolic steroid supplements.


Introduction
Although it is restricted by law, substance abuse among adolescents represents an important public health concern. Substance use and dependence are among the most prevalent causes of adolescent morbidity and mortality in the United States. The most used substances are ethanol, nicotine, and cannabis, and 1.5% of adolescents use Androgenic-Anabolic Steroids (AAS) [1]. In the general population, a meta-analysis published in 2014 reported that 6.4% of males and 1.6% of females appealed to AAS use in their life although AAS abuse is associated with an approximately 4.6-fold higher mortality rate compared to the general population [2,3]. In a world governed by aesthetic appearance and social networks, methods for improving body composition by lowering the fat/lean mass ratio are issues of extreme interest. Regular exercising and eating a healthy and balanced diet are unfortunately not as fast rewarding as society demands, and therefore, in order to impress, some adolescents often choose methods that are not only illegal but can also put their health and lives in danger.
The general belief is that elite athletes are the biggest AAS consumers, but antidoping regulations are very strict and very few risk their careers. Surveys have shown that up to 80% of anabolic steroids use is by nonathletes, including bodybuilders and young adults [4]. AAS are synthetic derivatives of the male hormone testosterone. In normal doses and over a short time, they can improve muscle strength and increase lean body mass, but sometimes, these steroids are used in doses much higher than the recommended levels [5].
The aim of this case report is to raise awareness of the dangerous possible side effects of steroid misuse and abuse. The article exemplifies the cardiovascular, renal, and metabolic consequences of anabolic steroid administration in a healthy physically active male, in the context of a literature review. Multi-organ damage as a result of uncontrolled use of anabolic steroid supplements will be highlighted in this paper. Physical examination revealed an obnubilated, normal weight (BMI 22.3 kg/m 2 ) male, with dehydrated skin, fruity-smelling breath, and polypnea. The examination of cardiovascular system revealed tachycardia combined with low blood pressure and a weak pulse.
The patient's past medical history was complex and revealed that at age 19, the patient, who was an amateur judo player with no recorded illness but with a family history of diabetes and cardiovascular disease (mother-hypertension, father-myocardial infraction, hypertension, and insulin-dependent diabetes mellitus type 2), was convinced by friends to take AAS in order to increase his muscular mass and sport performance. He followed the friend's advice and took immense doses of AAS IV, alternating the following products each day: 2500 mg testosterone isocaproate, 400 mg testosterone enanthate, 500 mg Stanozolol, 1000 mg Trenbolone, and 500 mg Nadrolone. With these excessive doses, he obtained impressive effects in a short period of time. In less than 6 months, his weight increased from 80 kg to 157 kg, but a few days before finishing the 6 months cycle, he felt severe chest pain shortly after injecting the AAS. He was transported to the Emergency Room, where the EKG showed extensive anterior ST-Elevation Myocardial Infarction (STEMI), and blood samples indicated elevated cardiac necrosis biomarkers (High sensitivity cardiac troponin I (hs-cTnI)). Coronarography was proposed. He refused the procedure but remained admitted in the Cardiology department. At release, the EKG showed QS waves in the range of V1-V4 and Q waves in DI, aVL, presented in Figure 1. At the same time, the echocardiography showed severe systolic disfunction of the LV with apical LV hypokinesia and dilatation, a condition that also persisted in follow-up examinations, as shown in Table 2. Cholesterol levels were high, and dyslipidemia was also diagnosed. Chronic treatment was prescribed for the cardiovascular disease. tivity cardiac troponin I (hs-cTnI)). Coronarography was proposed. He refused the procedure but remained admitted in the Cardiology department. At release, the EKG showed QS waves in the range of V1-V4 and Q waves in DI, aVL, presented in Figure 1. At the same time, the echocardiography showed severe systolic disfunction of the LV with apical LV hypokinesia and dilatation, a condition that also persisted in follow-up examinations, as shown in Table 2. Cholesterol levels were high, and dyslipidemia was also diagnosed. Chronic treatment was prescribed for the cardiovascular disease.  Three years later, at age 23, based on increased blood glucose values and specific symptoms, he was diagnosed with diabetes mellitus. The specialist recommended treatment with a basal-bolus regimen with 30-30-30 IU of rapid acting insulin before meals and 30 IU basal insulin. Unfortunately, the patient was not compliant with the treatment due to glycemic drops after rapid insulin administration and remained without any treatment for diabetes mellitus 2 years until when his condition worsened, as presented above. The fact that the patient was not compliant between 2015 and 2017 regarding his diabetes mellitus treatment is both due to the lack of interest regarding his condition but also due to an improperly prescribed insulin regimen in 2017 with very high doses of rapid-acting insulin, 30-30-30 IU/day, compared to the basal dose of 30 IU/day. In the current presentation, in December 2020, the patient was prescribed a modified insulin therapy regimen with low doses of rapid-acting insulin at a dose of 10-8-8 IU/day and a higher dose of  Three years later, at age 23, based on increased blood glucose values and specific symptoms, he was diagnosed with diabetes mellitus. The specialist recommended treatment with a basal-bolus regimen with 30-30-30 IU of rapid acting insulin before meals and 30 IU basal insulin. Unfortunately, the patient was not compliant with the treatment due to glycemic drops after rapid insulin administration and remained without any treatment for diabetes mellitus 2 years until when his condition worsened, as presented above. The fact that the patient was not compliant between 2015 and 2017 regarding his diabetes mellitus treatment is both due to the lack of interest regarding his condition but also due to an improperly prescribed insulin regimen in 2017 with very high doses of rapid-acting insulin, 30-30-30 IU/day, compared to the basal dose of 30 IU/day. In the current presentation, in December 2020, the patient was prescribed a modified insulin therapy regimen with low doses of rapid-acting insulin at a dose of 10-8-8 IU/day and a higher dose of longacting insulin at a dose of 0-0-34 IU/day in order to avoid hypoglycemia and treatment withdrawal. The patient was also referred to a clinician psychologist in order to better understand his condition, the implications of his actions, and the importance of taking the prescribed treatment.

Paraclinical Examination
Interpretation of the case at its current evaluation is secondary diabetes complicated with diabetic ketoacidosis (DKA). Given the fact that the patient's previous Hba1c levels were not available, the pathophysiology of his diabetes mellitus is unclear, however, given the fact that the patient has a positive family history of diabetes mellitus, our opinion is that his diabetes was accelerated by steroid consumption as well as by the patient having a very high genetic burden of cardiometabolic pathology due to his mother's hypertension, and his father's myocardial infraction, hypertension, and insulin-dependent diabetes mellitus type 2. Further investigations are required to exclude other differential diagnostics such as diabetes type 1 Diagnostics 2021, 11, 1313 4 of 13 (younger age at diagnosis, ketoacidosis episodes) or type 2 diabetes (positive familial history, the presence of dyslipidemia, and hyperuricemia are relevant for metabolic syndrome).
Overall, the complete diagnostic after less than 6 months of steroid administration, over a period of 5 years was as follows: past myocardial infraction, dyslipidemia, obesity, past hyperuricemia, secondary diabetes, and chronic renal disease. All of these features are, in fact, the most feared known effects that may occur after AAS administration.

Discussion
Adverse effects of AAS are known and well documented. Since antiquity, different testicular extracts have been used in order to promote virilization, although effects were mostly placebo due to the low hormonal concentration of the product and the inactivation of orally taken testosterone in first liver pass [6]. A breakthrough was made in 1935, when testosterone was synthetized for the first time, and since then, it has been used along with other steroids to treat gonadal disfunctions [7]. Illicit use was also a fact, and side effects began to appear. Table 3 includes some of the most noticed adverse effects of steroid abuse. As shown above, steroid supplementation is not harmless or without unwanted effects. The cardiovascular system is affected by the promotion of atherogenesis, hypercoagulability, and increased myocardial oxygen requirements caused by hypertrophy. Kaşikçioglu et al. studied the effect of steroids on the cardiac system, presenting cases of myocardial infarction [9]. Chang et al. reviewed the implication of AAS in coagulation, thrombus formation, and fibrinolysis, demonstrating that almost all coagulation factor concentrations are modified after steroid administration [11]. Several studies and case reports presented AAS induced direct myocardial injury, and the most common pathological finding in autopsied hearts revealed LV hypertrophy, frequently associated with fibrosis and myocytolysis [14][15][16]. Even if complications may be more frequent in AAS users suffering acute myocardial infraction (AMI), AAS-related cardiac events are expected to be underreported in the medical literature considering the socio-psychological aspects and the intention to hide AAS use, both for legal reasons and social stigmatization.
In this context, Table 4 presents 20 examples of acute myocardial infarction after AAS abuse. The multiple key components of the cardiovascular system are affected by these substances. Several studies have demonstrated alteration in lipid metabolism after AAS administration, consisting of rising LDL cholesterol and lowering HDL cholesterol concentration, leading to dyslipidemia, one of the most important elements in aterogenesis and cardiovascular disease [3,[57][58][59][60][61]. Glazer et al. reviewed the effect of lowering HDL cholesterol and the increase of insulin resistance caused by AAS, concluding that AAS consumption can lead to an increase in cardiovascular risk that is more than 6 times higher compared to the general population [8].
Regarding blood pressure and endothelial function, other important risk factors in cardiovascular disease, the effects of AAS are controversial. Although some animal model studies have demonstrated the capacity of AAS to lower blood pressure by increasing NO synthetase activity [62,63], multiple clinical studies have demonstrated an increase in both systolic and diastolic blood pressure values after AAS administration [14,64,65].
This explanation may lay in the fact that at high doses, the effect of nitric oxide is neutralized by Reactive Oxygen Species (ROS) generated by increased oxidative stress, resulting in vasospasms combined with high sodium retention [65,66].
Hypercoagulability is a reality after AAS administration and can be explained by the increase in hemoglobin concentration, thromboxane A2, and fibrinogen synthesis, while prostacyclin production is inhibited [11][12][13]21,[67][68][69][70].  Vascular disease and hypercoagulability lead to microcirculatory disfunction in sensible organs such as the heart, brain, and kidney. Parente et al. unraveled the pathophysiology behind the kidney injury due to AAS use [22]. miR-21 and miR-205 are newly identified and useful biomarkers that can be used to detect the potential damage of AAS consumption on kidney tissue, including fibrotic changes connected to their known adverse effects on renal and cardiovascular function [90,91].
A total of nine case reports exemplified in Table 5 presented renal injury in conjunction with cardiac disorders after AAS use. Although there is strong evidence on the relationship between AAS and kidney injury, the pathophysiological mechanisms behind it are multiple and intricate. AAS are thought to have a direct nephrotoxic effect that, when combined with hyperfiltration, cause high creatine levels, leading to focal segmental glomerulosclerosis [92]. On other side, secondary to cholestasis caused by AAS, bile acid nephropathy has been shown to cause acute kidney injury (AKI) [93]. Last, but not to be forgotten, are hypercoagulability and polycythemia, which are secondary to AAS administration and have been proven to cause renal infarction/thrombosis in multiple cases [76,85]. The high protein diet followed by body builders should also be taken into consideration. Most of the time, AAS supplementations is associated with high levels of protein isolates and concentrates. There is enough evidence in the literature to prove the harmful effects on the kidney's glomerular filtration rate (GFR) caused by high protein intake [94][95][96]. 9.
26-year-old male Stanozolol Cholestasis Acute renal failure none [101] The particularity of the case presented in our paper is the development of secondary diabetes. Testosterone is known to increase insulin sensitivity to lower the glycemic index, while testosterone deficit can lead to metabolic syndrome and diabetes [102][103][104]. However, only a few pieces of evidence suggest AAS to be the cause of diabetes development. Table 6 presents briefly two cases of diabetes presenting after consumption of AAS and growth hormone. The causative effect of AAS alone is not powerful in these two cases, as growth hormone is known to raise the blood sugar levels. In a study with 100 participants, Rasmusssen et al. demonstrated lowering insulin sensitivity among AAS users [105], while Geraci et al. suggests that androgens significantly affect insulin sensitivity [55]. Further investigations are required to determine the exact dose-metabolic effect of AAS, as most of the reported studies are limited to the recommended dose, and many consumers exceed these values. Even if there is little evidence directly linking AAS and diabetes, these substances influence some risk of the factors for diabetic disease, such as hypertension, increased body weight, dyslipidemia, and dysfunctions in other systems that can alter the metabolic balance. This aim of our paper was to raise awareness of the real danger represented by the ease of access to different AAS formulations. While elite athletes are subjected to rigorous antidoping testing in conformity with World Anti-Doping Agency (WADA) regulations, the general population, especially young people, is just a few clicks away from receiving an entire pharmacy of AAS [106,107]. Besides the original packaged products, a black market of "home bottled" products exists, where the final product combination, doses, and sterilization are vaguely known.
However, technology advances the role of miRNA are gaining importance because the negative effects of AAS can be detected in different tissues, and these miRNAs can serve as biomarkers of AAS doping abuse, given the fact that AAS induces significant negative effects on gene expression and therefore on cellular function as well [108,109].
Adolescents represent an easy target for this type of products in their desire to show off and impress. The case presented above is a clear example of what happens if AAS are administered without medical consultation. Living with myocardial infraction and diabetes beginning in the early 20s is a serious chronic health condition. The economic implications are hard to estimate, but they should also be taken in consideration. The burden on the health system from this type of patient is heavy and long lasting. A national and international strategy should be considered in order to limit the general population's accessibility to this type of substance.

Conclusions
The use of AAS represents a serious public health issue. As exemplified above, steroids can and will cause immediate or long-term side effects, especially considering that most consumers exceed the recommended doses. It are young healthy people who are at risk. The abuse of AAS drugs has been linked to many pathological conditions, such as acute myocardial infarction, dyslipidemia, hypertension, hepatic dysfunction, kidney injury, infertility, metabolic, neurologic, and psychiatric disorders. We suggest that long-term AAS abuse predisposes young people to multiple organ dysfunction syndromes. The particularity of the case presented in this paper is the development of secondary diabetes as a result of AAS consumption. Informed Consent Statement: Written informed consent was obtained from the patient to publish this paper.
Data Availability Statement: Not applicable.

Conflicts of Interest:
The authors declare no conflict of interest.