Why does no single sign settle the diagnosis?
Cortisol is the main glucocorticoid, and chronic excess of it changes many tissues. The changes do not happen in one place. Fat moves, skin thins, muscle breaks down, bone weakens and mood shifts, and each tissue gives its own clue. In full-blown Cushing’s syndrome, all the changes related to a high cortisol concentration are present.
In practice, though, the diagnosis is suspected from a mixture of findings. Why a mixture? Because some findings are common in the general population, so they only raise the question. Many findings in this syndrome are very common and have more likely causes, so a single common finding only raises the question and the clues must be read together.
The non-specific clues are obesity, irregular menstruation and hypertension. Each of them is common in the general population, so on its own each only raises the question.
Other findings are specific enough to support the diagnosis. The literature describes some of these, including proximal muscle weakness, as more discriminatory. They are truncal obesity, ecchymoses, plethora, proximal muscle weakness and osteopenia. They are easiest to follow tissue by tissue: fat, skin, muscle, bone and mood.
Fat: why does the body change shape?
The tissue-by-tissue account starts with fat. One of the very first symptoms patients report is increased deposition of fat in the body. It shows as weight gain and an inability to control weight.
The filling of sites that are not normally filled with fat can be a good clue for the diagnosis. Fat filling the supraclavicular region is the buffalo hump. When the temporal fossa fills with fat, it leads to instability of eye position.
Fat can also fill the epidural space. Fat there can lead to neurological deficits.
Skin: why does it thin, tear and bruise?
The same change that moves fat also acts on the skin that covers it. Loss of subcutaneous tissue can show as skin tenting. Plethora is a red, flushed face. Facial plethora is common in patients who have lost subcutaneous tissue.
Plethora may be under-diagnosed in patients with black skin. In the other direction, exposure to wind and ultraviolet light can increase skin erythema, and so can cause over-diagnosis of plethora.
Purple striae are another skin sign. Purple striae wider than 1 cm are virtually pathognomonic of Cushing’s syndrome, and they are among the signs the literature calls more discriminatory. They can be seen on the abdomen, buttocks, thigh, breast and arm.
Why does the skin tear? Cortisol reduces collagen synthesis, so the dermis thins. Cortisol also increases collagen breakdown. The skin becomes fragile, and it tears when it is stretched.
Not every stria counts. Silvery striae and healing striae are mostly seen due to obesity or in the postpartum period, and they are not related to Cushing’s syndrome. The purple colour of the striae does not depend on ACTH-dependent pigmentation, and it can also be seen in primary adrenal causes.
Hair and acne: why do they change?
Skin is also the surface where hair and acne show, so these come next. Hirsutism is a possible symptom of Cushing’s syndrome. Vellus hypertrichosis is the presence of hair on the forehead and upper cheek of a woman’s face. It could be a distinguishing symptom between Cushing’s syndrome and other common causes of hirsutism in women.
The presence of acne is also a sign of Cushing’s syndrome. Mostly pustular acne is suggestive of androgenic acne, whereas papular acne is suggestive of glucocorticoid excess.
Muscle: why is the weakness near the trunk?
Hair and acne show on the surface; the muscles are the next layer, and their weakness is what the bedside tests check. Proximal muscle weakness with preservation of distal muscle strength is the hallmark of the diagnosis of Cushing’s syndrome.
Why proximal? Glucocorticoid excess shifts the muscle protein balance toward breakdown. It increases protein degradation and reduces protein synthesis, and fast-twitch (type 2) fibres are preferentially affected.
That gives the bedside questions. Stair climbing and straightening up are the tasks that Cushing syndrome-associated myopathy impairs. The clinician can:
- ask about difficulty climbing stairs;
- ask about difficulty getting up from bed without using the hands;
- ask the patient to stand up from a chair without using the arms, which tests the hip flexor muscles.
An inability to perform a squat manoeuvre could suggest Cushing’s syndrome, but it could also suggest other myopathic disorders.
Bone: why do bones break?
The muscle changes show in how a person moves; bone is the next tissue, and a fracture can be the only sign. Osteopenia is a loss of bone mass. A fracture could be the only sign of Cushing’s syndrome, especially in men. The most common fractures are of the foot, ribs and vertebrae.
Avascular necrosis of bone is a rare complication of iatrogenic hypercortisolism. It mostly occurs at the hip bones.
Mood: why does the brain change?
Bone and muscle changes show on the body; the brain shows the changes in mood and sleep. Most patients with Cushing’s syndrome experience psychological challenges.
Irritability is one of them. It can manifest as a decreased threshold for uncontrollable verbal outbursts, and it can be the very first symptom in these patients. The other challenges include crying, fatigue, restlessness, depressed mood, decreased libido, insomnia and anxiety.
If each of these clues can come from something common, how does a clinician show that cortisol is really in excess?