Cushing's syndrome and chronic venous ulceration – a clinical challenge

Abstract

Cushing's syndrome is a condition caused by high levels of glucocorticoids, or most commonly as a result of prolonged exposure to exogenous steroids. Clinical features include diabetes, hypertension, obesity, skin atrophy, immune suppression and delayed wound healing. We report a patient with iatrogenic Cushing's syndrome, in whom long‐term topical steroid therapy was used to treat varicose eczema, which contributed to the development of type 2 diabetes, morbid obesity, sleep apnoea and chronic wound sepsis. In this case, repeated hospital admissions and systemic antibiotics were associated with considerable comorbidity. Aggressive local treatment, consisting of potassium permanganate soaks and irrigating gels, was highly effective in reducing the amount of exudate, pain and preventing from further deterioration of the patient's legs.

INTRODUCTION

Cushing's syndrome is an endocrine disorder characterised by high levels of glucocorticoids, which may be either ‘endogenous’, arising from an adrenal, pituitary or ectopic source, or ‘exogenous’, secondary to prolonged corticosteroid therapy (1). Clinical manifestations include diabetes, obesity, hypertension and proximal muscle weakness (1). Skin atrophy, bruising, immune suppression and delayed healing are also common features (1), which may occur in association with the medical comorbidities and cause considerable difficulties with wound management.

In this report, we describe the treatment of chronic venous ulcers in a woman with Cushing's syndrome and also discuss with the wound healing in this condition.

CASE HISTORY

A 69‐year‐old retired nursing sister was referred to a multidisciplinary wound healing unit for the management of venous ulcers and neuropathic leg pain. She had a previous history of chronic varicose eczema, treated with topical steroid therapy for several years. By this time, she developed morbid obesity [wt 130 kg, body mass index (BMI) 56], type 2 diabetes, hypertension and obstructive sleep apnoea that required continuous non invasive positive pressure ventilation (NIPPV). Eventually, she became wheelchair‐bound. Drug therapy included insulin, simvastatin, aspirin, angiotensin‐converting enzyme (ACE) inhibitors, salbutamol inhalers and diuretics.

On examination, there was evidence of facial plethora, thin skin, a prominent cervical fat pad, abdominal striae and generalised obesity. Blood pressure was 150/70. Both legs were oedematous and erythematous. Multiple ulcerated areas producing green exudate were visible on both lower legs. On both feet, monofilament and vibration sensation were diminished, pulses were absent, but arterial Doppler signals were elicited.

A clinical diagnosis was made of distal diabetic polyneuropathy, chronic venous ulceration, eczema and pseudomonas colonisation with underlying Cushing's syndrome most probably secondary to long‐term topical steroids.

For the ulcers, she was given topical steroid creams and silver sulfadiazine cream (flamazine®), silver containing sodium carboxymethyl cellulose dressings (aquacel Ag®) and three layer compressive bandaging. Gabapentin was prescribed for neuropathic pain. Topical steroids were discontinued after several days, to facilitate the investigations for Cushing's syndrome, but because of her severe disabilities, the patient did not consent to dynamic endocrine tests. Computed tomography (CT) scans of the adrenals, pituitary glands and chest showed no abnormalities, and so a presumptive diagnosis of iatrogenic Cushing's was made.

Several weeks later, the patient presented with severely infected, oedematous leg wounds and was requiring opiates for pain control, so she was admitted in the hospital.

LABORATORY INVESTIGATIONS

Erythrocyte sedimentation rate (ESR) was 90 mm/h [NR 0–30] suggestive of infection, and Hba1c 7·8% [NR 4–6] indicating suboptimal diabetic control. There was evidence of iron deficiency anaemia; haemoglobin 7·9 g/dl [NR 11·5–16·5]; mean corpuscular haemoglobin (MCH) 23·8 [NR 27–32]; mean corpuscular volume (MCV) 76·5 [NR 78–101]; serum iron 7 µmol/[NR 10–36] and transferrin saturation 10·5% [NR 14–50]. Blood cultures were found to be negative after 48 hours. Skin swabs from leg wounds grew with mixed Gram‐negative organisms, including Pseudomonas sp. Venous Doppler's showed no occlusive thrombus in either leg.

MANAGEMENT

The patient was treated with intravenous teicoplanin, ceftazidime and metronidazole and diuretic therapy. Iron deficiency anaemia was managed with aspirin cessation and blood transfusions. As a consequence of treatment with diuretics, antibiotics and use of contrast CT scans, her renal function, which was previously normal, deteriorated [urea 14·1 mmol/l (NR 2·5–7); Creatinine 299 Umol/l (NR 50–100)]. She developed myoclonic jerking, drowsiness and hypoventilation secondary to opiate and gabapentin accumulation. Her condition eventually stabilised, and she was discharged after 6 weeks.

The patient had two further prolonged hospital admissions for the infection in her leg ulcers, each time resulting in renal failure, drug toxicity, decreased consciousness and respiratory depression. In the light of these events, a revised management plan was formulated.

Avoidance of hospitalisation and ‘containment’ rather than complete ‘cure’ of infection were the objectives of treatment. Aggressive topical therapy, consisting of daily potassium permanganate soaks (2–4 tablets per day for 20 minutes) to act as an astringent and topical antimicrobial, and Prontosan® gel and irrigation solution to act as topical antimicrobial were used. Opiates were only taken prior to soaking the legs. Graduated compression bandaging was continued. Topical steroids were used infrequently, for up to 7 days only. Inpatient admission and systemic antibiotics were reserved at the event of ‘life threatening sepsis'. Diagnostic investigations were limited to blood tests and plain X‐rays only. Intravenous iron was used for the treatment of anaemia, in preference to blood transfusion to prevent fluid overload.

The patient has responded to this treatment protocol, remained out of hospital for over 12 months and lost 7 kg of weight (1, 2, 3).

Figure 1.

(A) Right leg – at initial presentation. (B) Right leg – same time different angle.

Figure 2.

Right leg – improved.

Figure 3.

Left leg – better.

DISCUSSION

Our patient developed iatrogenic Cushing's syndrome, almost certainly as a consequence of prolonged topical steroid therapy for varicose eczema. Although these drugs are effective in the treatment of many dermatological disorders, long‐term use carries risks of hypercortisolaemia and adrenal suppression (2). Courses should be limited to 1–2 weeks (3), although even after 7 days exogenous glucocorticoids were shown to reduce the tensile strength of wounds (4).

A number of pathophysiological abnormalities in Cushing's syndrome affect wound healing. Collagen content per unit area and skin thickness are reduced in comparison with normal controls (5). Reduced percentages of CD4 helper/inducer cells and natural killer cell activity were identified in lymphocyte subset analysis, signifying impaired immune function (6). Animal models of Cushing's syndrome have also shown reductions in tissue specific heat shock proteins, which affect cellular stress responses associated with normal wound healing, (7). Diabetes is also a common feature of Cushing's syndrome, and the adverse effects of hyperglycaemia on wound healing are well recognised (8).

In this patient with Cushing's syndrome, multiple medical comorbidities and venous ulceration, the risks of hospitalisation and drug toxicity outweighed the benefits of controlling infection with systemic antibiotics. This form of treatment is often unsuccessful in eradicating organisms, which have become embedded in biofilms, because of poor penetration of the glycocalyx and the emergence of resistant strains (9). Local treatment with potassium permanganate soaks and Prontosan gel® was highly effective in decontaminating the bacterial biofilm and reducing the amount of exudate.