Iatrogenic hypercortisolism

Iatrogenic hypercortisolism is an endocrine condition caused by prolonged exposure to exogenous glucocorticoids at doses exceeding physiological requirements, leading to the development of a clinical phenotype consistent with Cushing syndrome and, at the same time, suppression of the hypothalamic-pituitary-adrenal axis, with a risk of adrenal insufficiency when treatment is reduced or withdrawn. It is the most common form of Cushing syndrome in clinical practice because it reflects the widespread use of corticosteroids for inflammatory, autoimmune, respiratory and oncological diseases and in transplantation, and because it may arise not only from systemic treatment but also from routes regarded as local when the amount actually absorbed becomes clinically significant.

The distinguishing feature, compared with endogenous forms, is that the glucocorticoid excess does not result from increased adrenal production but from an external source that, through negative feedback, reduces CRH and ACTH, promoting atrophy of the adrenal cortex. This produces a characteristic clinical paradox: the patient may display signs of hypercortisolism while endogenous cortisol is biochemically low or inappropriately reduced. This coexistence of clinical hypercortisolism and axis vulnerability is the central issue guiding suspicion, diagnosis, treatment and follow-up.

The epidemiology of iatrogenic hypercortisolism reflects the prevalence of glucocorticoid therapy across different clinical specialties and, rather than being represented by a single incidence rate, is more accurately described as a continuum of risk determined by cumulative dose, duration, potency of the active compound, route of administration and individual susceptibility. In practical terms, the condition is common because glucocorticoids are used both in chronic regimens, including inflammatory arthritis, vasculitis, lupus, intestinal diseases, severe asthma, selected cases of chronic obstructive pulmonary disease, transplantation and haematological malignancies, and in repeated courses that patients may not perceive as long-term therapy but that are nevertheless sufficient to produce prolonged biological exposure.

Oral or parenteral systemic therapy remains the most typical setting. However, a substantial proportion of cases results from non-systemic routes when cumulative absorption becomes clinically relevant, including high doses of inhaled corticosteroids, extensive topical application or application under occlusion, high-potency dermatological preparations, prolonged ocular instillation, repeated intra-articular injections and, more generally, regimens in which total exposure exceeds the recovery capacity of the axis. In children, the combination of a relatively larger body surface area, a more permeable skin barrier and inappropriate use of potent topical preparations increases the risk, with presentations that may be severe and outcomes influenced by the speed of recognition.

A particularly important epidemiological issue is that of pharmacological interactions. Medications that inhibit corticosteroid metabolism, particularly through CYP3A4 inhibition, can transform doses considered safe into substantial systemic exposure. The combination of inhaled fluticasone with boosted antiviral therapy such as ritonavir or cobicistat is a representative clinical model because it can rapidly induce a Cushingoid phenotype and axis suppression, even without intentionally prescribed systemic therapy. Similar mechanisms may occur with some azole antifungal agents or other potent enzyme inhibitors, making a careful treatment review essential when clinical signs are inconsistent with the reported dose.

Non-pharmacological risk factors modify the clinical presentation. Advanced age, cardiovascular comorbidities, diabetes, osteoporosis, muscle frailty and chronic kidney disease amplify the clinical consequences of glucocorticoid excess. At the same time, interindividual variability in receptor sensitivity and pharmacokinetics helps explain why some patients develop pronounced signs at moderate doses, whereas others tolerate greater exposure with a less evident phenotype. The underlying inflammatory state and concomitant use of other immunosuppressive treatments also influence the frequency of complications, particularly infections.

From an epidemiological perspective, it is also useful to distinguish two outcomes that often coexist but do not occur at the same time. Iatrogenic hypercortisolism describes the ongoing excess and its metabolic, cardiovascular and musculoskeletal complications, whereas axis suppression and the risk of adrenal insufficiency become predominant when dose reduction is attempted. The natural history is therefore biphasic: toxicity caused by excess initially prevails, followed during tapering or after withdrawal by the risk of relative or absolute glucocorticoid deficiency, particularly during acute stress.

The aetiology of iatrogenic hypercortisolism is, by definition, the administration or absorption of exogenous glucocorticoids. The clinically crucial point is that actual exposure does not always correspond to prescribed exposure. Compound potency, formulation, frequency of use, adherence, self-medication, repeated as-needed use, topical application over large areas, high-dose inhalation and pharmacological interactions may produce a biological burden greater than expected. The underlying disease for which the corticosteroid is prescribed is not merely the clinical context but directly affects management because it limits the speed of dose reduction and influences the choice of steroid-sparing strategies.

Pathogenesis results from chronic activation of glucocorticoid receptors in target tissues, with a pattern of effects that varies according to dose and duration. At the central level, exogenous excess exerts negative feedback on the hypothalamus and pituitary gland, reducing CRH and ACTH secretion. Persistent ACTH reduction leads to atrophy of the zona fasciculata and zona reticularis of the adrenal gland. This explains vulnerability during withdrawal: when the exogenous source is reduced, the axis may be unable to promptly restore adequate production, resulting in adrenal insufficiency that may emerge even while residual Cushingoid signs are still present.

At the metabolic level, glucocorticoids promote insulin resistance, increase hepatic gluconeogenesis, stimulate lipolysis with fat redistribution and increase appetite, generating a characteristic phenotype with increased visceral and facial fat and a relative loss of lean mass. Muscle proteolysis and inhibition of protein synthesis contribute to proximal myopathy, while inhibition of osteoblast activity, increased bone resorption and alterations in calcium and vitamin D metabolism lead to reduced bone mass and a higher fracture risk. This damage may develop early and progress silently, making skeletal risk a central determinant of functional prognosis.

In the cardiovascular system, chronic exposure increases blood pressure through several mechanisms, including enhanced vascular sensitivity to catecholamines, activation of the renin-angiotensin system in some settings, sodium retention particularly with compounds that have greater mineralocorticoid activity, and vascular remodelling. The atherometabolic effect also results from deterioration in glycaemic control and lipid profile, together with a paradoxically prothrombotic and proinflammatory environment. The skin and connective tissues exhibit catabolic effects through skin thinning, capillary fragility, easy bruising, striae and delayed wound healing, while immunosuppression predominates in the immune system, increasing the risk of opportunistic infections and reactivation of latent infections.

At the neuropsychiatric level, glucocorticoids influence limbic and cortical circuits, potentially causing insomnia, irritability, mood disturbances, anxiety and, in some cases, psychotic manifestations or cognitive impairment. In children, excess interferes with growth and maturation and may cause suppression of the somatotropic axis, pubertal abnormalities and changes in body composition with long-term consequences. During pregnancy and the postpartum period, exposure must be assessed with even greater caution because it interacts with physiological adaptations of the axis and with specific maternal and fetal risks.

The pathophysiology of iatrogenic hypercortisolism is therefore a model of multisystem toxicity in which the unifying feature is loss of the pulsatile and circadian physiology of cortisol and its replacement by a pharmacological signal that is often continuous and not synchronised with biological rhythms. This loss of endocrine timing helps explain why, for the same daily dose, different administration regimens may have different effects on metabolism, sleep and axis recovery, and why treatment must consider not only how much glucocorticoid is administered, but also how and for how long it is given.

The clinical presentation of iatrogenic hypercortisolism often develops gradually and may be confused with effects of the underlying disease or with changes related to physical inactivity, stress and weight gain. During the medical history, the patient may report progressive weight gain with central redistribution, easy fatigability and loss of strength, particularly in proximal muscles, with difficulty climbing stairs or rising from a seated position. Insomnia, restlessness, irritability and mood changes are common and may be associated with increased appetite and carbohydrate cravings. In patients with diabetes, glycaemic control may deteriorate rapidly, whereas individuals without diabetes may develop postprandial hyperglycaemia, often more pronounced in the afternoon and evening.

On physical examination, cutaneous signs and body composition provide important diagnostic clues, including a rounded face, dorsocervical fat accumulation, thin skin with bruising, capillary fragility, broad erythematous striae, acne or folliculitis and delayed wound healing. Protein catabolism results in loss of muscle mass with proximal weakness, while connective tissue fragility may promote hernias and musculoskeletal pain. Blood pressure may be elevated or more difficult to control, and peripheral oedema may develop, particularly in the presence of sodium retention or cardiac and renal comorbidities.

Infectious manifestations are often an indirect indicator of glucocorticoid excess, including recurrent skin infections, respiratory exacerbations, candidiasis and an atypical course of common infections, sometimes with attenuated fever and less pronounced inflammatory markers. In patients receiving other immunosuppressive treatments, the cumulative risk increases and presentation may be subtle, requiring a lower threshold for diagnostic investigation. Haematologically, neutrophilic leukocytosis caused by demargination may be incorrectly interpreted as a primary sign of infection unless the pharmacological context is considered.

Bone and joint involvement may present as dorsal or lumbar pain caused by vertebral fractures even without major trauma, loss of height, or thigh or hip pain that should raise suspicion of osteonecrosis, together with worsening of pre-existing osteoarthritis. In children, in addition to the Cushingoid phenotype, a key sign is deceleration of linear growth with relative weight gain, which distinguishes hypercortisolism from many common causes of overweight.

A specific clinical feature of iatrogenic hypercortisolism is the possible coexistence, during the same phase, of signs of excess and symptoms of relative deficiency when treatment is reduced. During tapering, the patient may experience severe fatigue, myalgia, orthostatic hypotension, nausea and reduced tolerance to stress. These symptoms may be interpreted as a recurrence of the underlying disease but often reflect adrenal insufficiency caused by axis suppression. This overlap makes clinical assessment particularly complex and requires integrated evaluation of the overall presentation, the objectives of immunological therapy and endocrine safety.

Finally, the clinical presentation is influenced by the route of administration. In cases caused by inhaled or topical preparations combined with a pharmacological interaction, Cushingoid signs may appear relatively rapidly with profound axis suppression, despite the patient not reporting systemic corticosteroid use. In these cases, the quality of the pharmacological history, including nasal sprays, creams, eye drops and antiretroviral or azole therapy, is critical to prevent diagnostic delay and potentially severe complications.

Iatrogenic hypercortisolism should be suspected whenever a patient exposed to glucocorticoids progressively develops signs consistent with Cushing syndrome, particularly proximal weakness, broad striae, easy bruising, central weight gain and worsening hypertension or glycaemic control. Suspicion must not be limited to patients receiving oral therapy because many clinically relevant exposures are concealed within inhaled, nasal, topical or injected preparations, or within repeated intermittent regimens. The clinical question must therefore shift from whether the patient takes corticosteroids to what their total glucocorticoid exposure is.

Suspicion should increase in the presence of recurrent infections or an atypical infectious course, premature osteoporosis or fragility fractures, development of cataracts or glaucoma in susceptible settings, and new neuropsychiatric abnormalities in patients without a previous history. In children, the combination of weight gain and growth deceleration is particularly suggestive and requires prompt assessment of exposure, which is often related to prolonged or inappropriate use of topical or inhaled corticosteroids.

A setting with high predictive value is the presence of medications that can enhance systemic exposure, particularly potent inhibitors of corticosteroid metabolism. Development of a Cushingoid phenotype in a patient using fluticasone or another inhaled steroid who begins treatment with ritonavir or cobicistat should be regarded as a clinical priority because axis suppression may be profound and the risk of adrenal insufficiency high. Similar reasoning applies to combinations with some azole antifungal agents, particularly when inhaled or topical exposure is substantial.

Clinical suspicion must also be bidirectional and include the withdrawal phase. A patient who has received glucocorticoids for several weeks or months and who develops marked fatigue, hypotension, nausea, hypoglycaemia or disproportionate systemic symptoms during dose reduction may have adrenal insufficiency, even if phenotypic signs of hypercortisolism persist. In these cases, the most dangerous error is to attribute all symptoms to the underlying disease and accelerate withdrawal, thereby increasing the risk of adrenal crisis during intercurrent stressors such as infections or surgery.

Finally, unreported or unrecognised exposure should be considered, including self-medication, compounded preparations, contaminated herbal products or treatments prescribed by several clinicians without coordination. The purpose of clinical suspicion is not only to identify the syndrome, but also to reconstruct the trajectory of exposure and anticipate the risks of the next phase, which often involves attempting to reduce treatment and establishing an endocrine safety plan.

The diagnosis of iatrogenic hypercortisolism is primarily clinical and history-based and relies on demonstrating exogenous exposure capable of explaining the phenotype. Unlike endogenous forms, in which autonomous cortisol production is investigated, the priority is to identify all sources of glucocorticoids, including systemic therapy, inhalers and nasal sprays, creams and ointments, eye drops, injections, combination preparations and possible pharmacological interactions that increase bioavailability. A detailed history of dose and duration, including repeated courses, helps estimate the likelihood of axis suppression and establish a safe dose-reduction plan.

Biochemically, exogenous excess suppresses the axis, so endogenous ACTH and cortisol concentrations may be low. This does not exclude the syndrome but supports it in the appropriate context. For the same reason, screening tests used for endogenous Cushing syndrome do not have the same role in iatrogenic disease. The objective is not to demonstrate overproduction but to assess residual axis function when treatment is reduced and when adrenal insufficiency is suspected. The distinction between ongoing toxicity caused by excess and deficiency risk during dose reduction must guide the selection of investigations.

According to the joint recommendations of the European Society of Endocrinology and the Endocrine Society on glucocorticoid-induced adrenal insufficiency, risk assessment and diagnostic strategy depend on the intensity of exposure and the clinical phase. In many cases, dose reduction can be planned without immediate testing after short-term exposure, whereas prolonged exposure or the presence of Cushingoid signs increases the likelihood of suppression and makes laboratory assessment more relevant.

Diagnostic assessment of iatrogenic hypercortisolism

• Reconstruction of exposure: glucocorticoid type, potency, route of administration, cumulative dose, duration, repeated courses and assessment of medications that increase bioavailability.
• Phenotypic assessment: cutaneous signs, body composition, proximal myopathy, hypertension, glycaemic abnormalities, bone fragility and infection pattern.
• Assessment of axis suppression: measurement of morning cortisol during dose reduction towards physiological levels and, when indicated, dynamic testing to estimate adrenal response capacity.
• Assessment of risk during stress: identification of patients requiring education, stress-dose plans and strategies to prevent adrenal crisis during infections, trauma or procedures.

The differential diagnosis mainly concerns two areas. The first is distinguishing iatrogenic hypercortisolism from uncomplicated weight gain, metabolic syndrome and depressive disorders, which may mimic some features but do not explain the characteristic combination of skin fragility, typical striae, proximal myopathy and accelerated osteoporosis. The second is differentiating iatrogenic disease from endogenous forms when the history is uncertain or unreliable. In this setting, endocrine guidelines on the diagnosis of Cushing syndrome emphasise that exogenous glucocorticoid use must always be carefully excluded before complex investigations are initiated because it is the most common cause of a Cushingoid phenotype.

In patients undergoing dose reduction, axis assessment helps determine whether withdrawal is safe and how the recovery period should be managed. Adrenal function may remain impaired for a variable and unpredictable period, and the principal clinical risk is not an isolated laboratory value but the inability to respond to acute stress. In patients with prolonged exposure and probable suppression, the working diagnosis therefore also includes the development of a prevention plan comprising education about symptoms of insufficiency and instructions for fever, gastroenteritis, surgery or trauma.

Finally, diagnosis must be completed by assessing complications, including blood pressure, glycaemic profile, lipid status, thromboembolic risk in selected settings, skeletal status and investigation for vertebral fractures when clinically suspected. This step is not ancillary because glucocorticoid reduction is slow in many patients and control of complications determines medium-term functional prognosis.

Classification of iatrogenic hypercortisolism is useful when oriented towards clinical practice by linking exposure to the risk of complications and adrenal insufficiency during dose reduction. A first distinction concerns the route of administration: oral or parenteral systemic therapy, inhaled or nasal therapy, topical cutaneous treatment, ocular treatment, injections and combinations of these routes. This distinction is fundamental because it changes risk perception and the likelihood that exposure will be underestimated, particularly in local forms that become systemic because of high doses or interactions.

A second classification is based on the exposure profile: continuous chronic therapy, repeated courses, high doses over a short period followed by rapid reduction, or intermittent regimens that maintain subtle suppression of the axis. Different phenotypes are associated with these patterns. Continuous chronic therapy promotes cumulative metabolic and osteoporotic complications, whereas high doses may rapidly precipitate mood disturbances, marked hyperglycaemia and immunosuppression. Repeated intermittent regimens may produce a fluctuating clinical picture in which periods of excess alternate with symptoms of relative deficiency as the dose falls.

From an endocrine perspective, it is useful to distinguish the phase of active hypercortisolism from the phase of axis recovery. Complications caused by excess predominate in the first phase, while severity in the second phase is defined by the likelihood of clinically significant adrenal insufficiency. The presence of Cushingoid signs, particularly in patients receiving prolonged therapy, increases the probability of profound suppression and requires a more cautious reduction, whereas the absence of obvious signs does not exclude suppression, especially in certain populations or with specific routes of administration.

Clinical severity may be described in terms of organ involvement. A mild form may present with weight gain and insomnia without major complications, while a moderate form includes difficult-to-control hypertension, diabetes or significant osteopenia. Severe forms include fragility fractures, recurrent or severe infections, major myopathy, marked psychiatric disturbances and suspected osteonecrosis. In children, severity is primarily defined by the effect on growth and development, with consequences that may persist even after normalisation if diagnosis is delayed.

Finally, a functional classification considers factors that make correction difficult, including an unavoidable need for glucocorticoids to control the underlying disease, lack of steroid-sparing alternatives or clinical settings in which rapid reduction is hazardous. In these cases, the objective is not immediate elimination of exposure but minimisation to the lowest effective dose and systematic prevention of complications, with a monitoring plan that integrates immunological and endocrine requirements.

Treatment of iatrogenic hypercortisolism differs from that of endogenous forms because the source of excess is external and, in most cases, the cornerstone is reduction of exposure to the lowest effective dose or, whenever possible, complete withdrawal. The objective is twofold: to reduce multisystem toxicity caused by excess while preventing clinically significant adrenal insufficiency during tapering. This requires an individualised plan that considers the underlying disease, the risk of recurrence, therapeutic alternatives and the patient’s vulnerability.

The first step is to review glucocorticoid therapy and identify steroid-sparing strategies or local alternatives when appropriate. In many inflammatory diseases, optimisation of immunomodulators, biological treatments or other therapies allows overall exposure to be reduced. In respiratory disease, rationalisation of inhaled therapy and use of the lowest effective dose reduce risk, while in dermatitis the choice of lower-potency compounds, intermittent use and limitation of occlusion and extensive application are decisive. When pharmacological interactions are present, correcting the hazardous combination is often the true causal treatment because it interrupts the source of unintended overexposure.

Dose reduction must be planned with awareness of axis suppression. Current endocrine recommendations emphasise that abrupt discontinuation is appropriate only after short-term exposure, whereas prolonged therapy requires gradual tapering. The most delicate phase occurs when physiological doses are approached because the exogenous contribution becomes similar to daily requirements and the ability of the axis to resume function becomes critical for safety. When symptoms consistent with adrenal insufficiency occur, dose reduction may need to be slowed, and management as adrenal insufficiency may be indicated until adequate recovery has been documented.

Prevention and management of complications are essential. Skeletal risk requires early intervention, including adequate calcium and vitamin D intake when indicated, fracture risk assessment and anti-osteoporotic treatment according to recommendations for glucocorticoid-induced osteoporosis in patients at risk. Metabolically, hyperglycaemia and steroid-induced diabetes must be managed promptly and treatment adapted to the typically postprandial and afternoon pattern, while hypertension requires therapeutic optimisation and reduction of sodium intake. Assessment of infection risk includes preventive strategies and a low diagnostic threshold for potentially severe infections, particularly in patients who are immunosuppressed because of the primary indication for treatment.

Management of axis recovery requires patient education. In individuals with probable or documented suppression, it is essential to provide information about symptoms of insufficiency, the need to temporarily increase the dose during stress and the importance of reporting glucocorticoid exposure when receiving emergency care. In selected settings, temporary physiological replacement therapy and stress-dose protocols may prevent acute events, particularly during gastrointestinal infections, high fever or invasive procedures.

Finally, some patients cannot completely discontinue glucocorticoids because of the underlying disease. In these cases, treatment consists of making exposure as physiological as possible by reducing dose and duration, minimising evening administration when compatible with disease control and systematically monitoring complications. The realistic objective is to reduce the biological burden and protect target organs, recognising that therapeutic success is represented not only by regression of the Cushingoid phenotype but also by prevention of fractures, severe infections, metabolic decompensation and adrenal crisis.

Follow-up of iatrogenic hypercortisolism must be structured and prolonged because complications may emerge even after dose reduction and recovery of the axis may require a variable period. Monitoring begins by assessing clinical regression of Cushingoid signs and changes in blood pressure, glycaemia, body weight, muscle strength and sleep quality. It is important to recognise that changes in body composition may improve slowly and that myopathy often requires weeks or months to recover, particularly in older patients or those with comorbidities.

Endocrine surveillance focuses on hypothalamic-pituitary-adrenal axis function during and after tapering. When physiological doses are approached, follow-up must include clinical assessment for symptoms of insufficiency and, when indicated, targeted laboratory measurements to guide safe withdrawal. A practical principle is that normalisation of well-being and stress tolerance is as important as isolated values because the greatest risk is failure to respond to acute stress. In patients with documented or highly probable suppression, follow-up must also confirm that the patient understands management rules for fever, gastroenteritis, trauma or procedures.

Metabolic follow-up must be active. Glucocorticoid reduction may rapidly improve glycaemia, but some patients continue to have overt diabetes, particularly when predisposed, and require structured diabetes care. Similarly, blood pressure may decrease without necessarily returning to normal, and cardiovascular assessment must consider overall risk and the presence of target-organ damage. The lipid profile may change over time and should be interpreted within the overall cardiometabolic risk.

Skeletal monitoring is a major prognostic determinant. In prolonged exposure or in patients at high risk, assessment of bone mineral density and fracture risk is appropriate, with attention to vertebral fractures even when symptoms are minimal. In patients with persistent mechanical pain involving the hip or shoulder, suspicion of osteonecrosis should be maintained and an appropriate diagnostic pathway established. Motor rehabilitation and recovery of muscle strength should be incorporated into follow-up gradually and with consideration of cardiovascular safety.

In children, follow-up must include growth, pubertal development and recovery of the previous height trajectory, together with review of topical or inhaled treatments and their appropriate use. In all patients, periodic review of treatment remains essential to prevent recurrent overexposure, particularly when several specialists are involved or when the underlying disease requires frequent adjustments. Effective follow-up makes exposure visible and manageable over time, reducing both toxicity caused by excess and the risk of crisis caused by deficiency.

The prognosis of iatrogenic hypercortisolism primarily depends on three factors: the duration and intensity of exposure, the promptness of recognition and the ability to reduce the dose without precipitating the underlying disease or causing clinically significant adrenal insufficiency. In many patients, regression of the Cushingoid phenotype and metabolic improvement are progressive and substantial after dose reduction. However, some complications may cause long-term consequences, particularly involving the skeleton and cardiovascular risk. Functional prognosis is especially influenced by myopathy and bone fragility, which increase the risk of falls, fractures and loss of independence.

The most dangerous acute complication is adrenal crisis, which may occur during withdrawal or rapid dose reduction, or during intercurrent stress in a patient whose axis has not recovered. Risk is greater with profound suppression, marked Cushingoid signs and prolonged treatment, but crisis may also occur after apparently moderate exposure when tapering is too rapid or acute illness develops. Prognosis therefore concerns not only recovery from Cushing syndrome but also the safety of the transition phase and patient education.

Infectious complications are an important determinant of morbidity. Immunosuppression increases the risk and severity of common and opportunistic infections and may attenuate clinical signs such as fever and inflammatory responses, delaying diagnosis. At the same time, hypercortisolism promotes cutaneous complications, impaired wound healing and worsening comorbidities that further increase risk. In patients with underlying immune-mediated or oncological disease, cumulative risk is greater and requires a multidisciplinary approach.

The skeleton is affected by complications that are both common and disabling, including glucocorticoid-induced osteoporosis, vertebral and non-vertebral fractures, reduced quality of life and, in selected cases, osteonecrosis, particularly after high doses or intense exposure. Cardiovascular complications include hypertension, worsening atherometabolic risk and a possible increase in thrombotic risk in susceptible settings. Steroid-induced diabetes and hyperglycaemia worsen outcomes in many clinical conditions and contribute to infections and microvascular complications, making glycaemic control an important prognostic objective.

Neuropsychiatric complications, which are often underestimated, may include persistent insomnia, mood disturbances, anxiety and reduced cognitive performance, affecting treatment adherence and functional recovery. In children, effects on growth and development are prognostically important because recovery may require a prolonged period and permanent consequences may remain after prolonged exposure. Overall, prognosis is favourable when exposure is recognised early, dose reduction is planned and complications are actively prevented and treated through integration between endocrinology, the specialty managing the underlying disease and preventive medicine.