Endocrine Emergencies

Causes

DKA typically occurs in patients with type 1 diabetes. Previously undiagnosed patients can present for the first time with DKA. In patients with known diabetes, a precipitant illness and poor compliance with insulin are the most common causes. Patients who have a poor understanding of their disease might stop their insulin when they are not eating due to illness states and this can lead to DKA. Patients can wrongly assume that if they are not taking in food and sugar, they will not require exogenous insulin.

Incidence of DKA has been estimated at around eight episodes per 1000 patients with diabetes per year (Faich et al., 1983), with a mortality rate of 0.67% (Lin et al., 2005), and this has marked regional variation. Early recognition and treatment are vital to keep mortality and morbidity rates as low as possible. Common precipitants of DKA are

Signs and symptoms

The classic triad of symptoms in DKA are

Often, patients will have been developing symptoms for some time leading to profound dehydration at presentation. This is caused by large renal fluid losses due to excess urinary glucose. In clinical practice, an elevated capillary blood glucose and clinical signs of dehydration require urgent management. Ketones in the urine are often helpful early in the presentation but are not specific. Starvation, dehydration and exercise can also cause production of ketones. Box 1 summarizes the key aspects of the initial assessment of a patient presenting with possible DKA.

Treatment

Patients with suspected DKA require urgent admission to hospital. The mainstay of treatment is adequate fluid resuscitation and administration of insulin in an appropriate dose to switch off ketogenesis. This can often require coadministration with glucose to allow adequate amounts of insulin to be given while avoiding hypoglycaemia. The aim of the treatment is to abolish toxic ketonaemia rather than the achievement of normoglycaemia.

As with any medical emergency, it is important to explain the problem to the patient and discuss the most appropriate course of action. Patients may be frightened and may not have realized the potential seriousness of the situation. If the patient is acutely unwell, oxygen can be given via a non-rebreathe bag (if available) while awaiting transfer to hospital by ambulance.

Once the patient has been discharged, it can be helpful to review the circumstances surrounding the acute deterioration if the patient was previously known to have type 1 diabetes. It is important to discuss the patient's insulin regime and ensure that the patient is aware of the importance of continuing and increasing insulin during periods of illness. Ketostix (which detect ketones in the urine) is a useful tool for patients to enable them to detect when they are becoming unwell and need to seek advice from a professional.

Box 2 contains some alternative diagnoses, which may present in a similar way to DKA. Patients with recurrent episodes of DKA should be reviewed regularly and any relevant psychosocial factors identified and addressed. ‘Sick day rules’ for all patients with insulin-treated diabetes should be reinforced at their annual review.

Treatment

Treatment involves prompt recognition and reversal of the low blood glucose. If the patient is conscious and able to swallow, manage by administration of a sugary drink or food. Typically, 15–20 g of carbohydrate is used and this can avoid over-correction with rebound hyperglycaemia. Symptoms should begin to improve within 5 minutes but full recovery may take up to 20 minutes.

Other options include glucose gel to the mouth and gums, glucagon administration or intravenous glucose. If the patient is unable to take food or fluids orally due to an impaired conscious level or lack of cooperation, urgent help should be requested in the form of an ambulance. Intramuscular glucagon may be used in refractory hypoglycaemia where intravenous access has not been established or in a pre-hospital setting. GPs who work in a setting where urgent help can take a while to arrive should consider carrying glucagon.

After an episode of hypoglycaemia, it is important to educate the patient about how to avoid hypoglycaemic episodes, recognize the warning symptoms and start treatment early to reverse hypoglycaemia. When symptoms occur frequently, it may be useful for the patient to record a diary of symptoms, including their activity levels, details of meals and timing and dosage of anti-diabetic medications, to try to identify reversible causes which can be addressed. Depending on the severity and frequency of hypoglycaemic episodes, the patient may require follow up with a diabetes specialist.

Rarely, it may be necessary to admit the patient to hospital for observation and investigation of hypoglycaemia. This is particularly in patients who do not have a diagnosis of diabetes, in order to investigate other causes of hypoglycaemia such as factitious insulin administration or an underlying endocrine disorder.

Potential pitfalls

Beta-blockers may blunt the sympathetic drive, which is responsible for the early signs of hypoglycaemia so patients may not complain of symptoms until their blood glucose becomes dangerously low. A lack of hypoglycaemia awareness can have significant impact on a patient's lifestyle and ability to drive. Diabetics with autonomic neuropathy (often as a complication of long-term diabetes) can also lose the ability to sense typical hypoglycaemic symptoms. Conversely, patients with poor glycaemic control often complain of sympathetic symptoms early when their blood glucose is normal or high. They do not require glucose so should monitor their capillary blood glucose levels when they get these symptoms.

Thyroid disease

The thyroid is a bow-tie shaped gland that sits in the anterior portion of the neck just inferior to the thyroid cartilage (Adam's apple) and is involved in the production of hormones that regulate the body's metabolic rate. It is stimulated by thyroid-stimulating hormone (TSH), which is produced by the pituitary gland. The thyroid produces two hormones, triiodothyronine (T3) and thyroxine (T4), both of which are synthesized using iodine.

Hyperthyroidism

The most common cause of hyperthyroidism is overstimulation of the thyroid gland by autoantibodies reactive to the TSH receptor (Graves' disease). This results in an excess of T3 and T4 and produces symptoms of hyperthyroidism (which include tachycardia, palpitations, anxiety, weight loss, sweats and eye signs). Other causes of hyperthyroidism include toxic multinodular goitre and toxic adenoma. A non-tender goitre is usually present in Graves’ disease, whereas toxic multinodular goitre is typically associated with pain on palpation.

Thyroid storm

Thyroid storm is a severe form of thyrotoxicosis and can result in end organ damage, especially to the heart. It is a rare complication of hyperthyroidism found in less than 10% of hospitalized patients suffering from hyperthyroidism but untreated; it has a mortality of 80–90%. It can occur in men and women of any age and can be the presenting episode. However, thyroid storm is more common in those with preexisting thyroid disorders, who may be treatment resistant or non-compliant.

Signs and symptoms

Early diagnosis and management reduce the high mortality rate from this condition. Symptoms are due to the large excess production of thyroid hormones and their corresponding increased metabolic effects on multiple organ systems. Box 4 outlines these signs and symptoms.

The differential diagnosis for such a symptom complex is large and includes central nervous system infections, sepsis and psychosis. It is worth noting that thyroid function tests (TFTs) cannot differentiate who will go on to develop thyroid storm; the diagnosis is based on TFTs suggesting hyperthyroidism along with corresponding symptoms of thyroid storm. If severe thyrotoxic symptoms are present, the patient should be referred directly to hospital rather than awaiting confirmatory TFTs.

Management involves urgent hospital admission, which may include intensive care support. In the pre-hospital setting, supportive measures may be useful. Fever can be treated by peripheral cooling with towels and a fan, as well as the administration of paracetamol. Beware NOT to give salicylates as these will displace the T4 from thyroid-binding globulin and worsen symptoms.

In hospital, the mainstay of treatment is to remove any precipitating cause and to beta-block the patient to improve sympathetic symptoms, while administering high-dose anti-thyroid drugs under close observation. Eventual treatment may involve surgery or radioactive iodine to control the thyroid gland once the patient is stabilized.

Hypothyroidism

Hypothyroidism has a number of causes. Atrophic autoimmune hypothyroidism is associated with lymphoid infiltration of the gland and eventual fibrosis. It is four times more common in females than males and the risk increases with age. Autoimmune thyroiditis, such as Hashimoto's, typically affects females and middle-aged and older women. It is due to autoantibody production against the thyroid followed by immune-mediated destruction and resulting hypothyroidism as T3 and T4 are no longer produced in sufficient quantities. With the ‘foot off the pedal’, the body's metabolism becomes correspondingly sluggish.

The thyroid gland can also become underactive due to iatrogenic factors, usually resulting from treatment of hyperthyroidism. Following radioactive iodine treatment, the gland can be damaged to such an extent that it can no longer function, and similarly, after thyroid surgery, if not enough glandular tissue remains to supply the body with the quantity of thyroid hormones it requires. Amiodarone, a drug used to treat cardiac arrhythmias, can also cause hypothyroidism and it is important to monitor TFTs before treatment and then every 6 months while on treatment.

Postpartum thyroiditis can also occur where the gland becomes inflamed and hyperactive, followed by a period of underactivity typically occurring 3–8 months after the woman has given birth. It affects 5–10% of women in the postpartum period and usually resolves spontaneously. Pituitary disease leading to low TSH with low thyroid hormone levels is a less common cause.

Myxoedema coma

Myxoedema coma is a state of decompensated hypothyroidism ultimately resulting in coma and death if not recognized and treated. Although termed ‘myxoedema coma’, the absence of coma does not exclude the condition and it may more appropriately be referred to as ‘myxoedema crisis’.

This condition commonly develops in patients with a preexisting diagnosis of hypothyroidism from any cause (in which there is inadequate hormone replacement) but may rarely be the presenting episode of a thyroid disorder.

Presentation

Clinical symptoms are due to a severe lack of thyroid hormones and present as an extreme form of hypothyroidism with a fatality of up to 30%, even with adequate treatment. A history of hypothyroid symptoms are usually present such as cold intolerance, lethargy or constipation and a slow progression of these symptoms although faster progression can occur with other metabolic stresses. The clinical features include

Myxoedema coma presents almost exclusively in patients over 60 years of age (Rehman, 2005). Potential precipitants are listed in Box 5. Think of it in the elderly female patient who is slowly becoming more withdrawn over time, particularly in the winter, and may be non-specifically unwell. These patents are particularly prone to myxoedema crisis because of the increased incidence of hypothyroidism in women with increasing age, combined with the increased thermoregulatory pressures from the cold.

As with thyroid storm, the diagnosis should be suspected on clinical grounds and the patient referred urgently to hospital for support and therapy rather than await the results of TFTs. It may also be of benefit to check the patient's blood glucose as hypoglycaemia is common and may suggest concomitant adrenal insufficiency. Treatment in hospital is likely to involve intensive care, passive external warming and intravenous administration of adequate quantities of replacement thyroid hormones.

Addison's disease

Addison's disease is a form of primary adrenal insufficiency characterized by malfunction of the entire adrenal cortex. Other causes include metastatic tumours or infections such as tuberculosis (TB) or human immunodeficiency virus. In 1855, when Thomas Addison first described the new ‘disease of the supra-renal capsules’ that was later to be named after him, the most common cause of this condition was tuberculous infiltration of the adrenal gland. In modern times, 90% of cases are of autoimmune origin resulting from the action of organ-specific antibodies.

Addison's disease tends to appear insidiously over 2–3 years. The condition is sometimes known as ‘bronze skin disease’ as hyperpigmentation of the skin creases, lips, mouth and surgical scars is common. This results from lack of negative feedback of cortisol on the pituitary gland and subsequent excess production of ACTH. The precursors of ACTH share characteristics with melanocyte-stimulating hormone and cause increased production of melanin and thus hyperpigmentation.

Symptoms may be vague and insidious. Other typical symptoms of Addison's disease include anorexia, weight loss, weakness, postural hypotension and depression. Patients may have a low serum sodium and raised potassium due to a lack of aldosterone production, and this may be the presenting feature.

The diagnosis is made using a short Synacthen (synthetic ACTH) challenge test. For patients taking prednisolone, this should be stopped 24 hours prior to the test. A 9 a.m. blood sample is taken to test cortisol levels. Immediately afterwards, an intramuscular or intravenous dose of 250 μg of Synacthen is given. The response to the Synacthen is measured with a further blood test 30 minutes afterwards:

Addisonian crisis

Addisonian crisis is an endocrine emergency whereby a patient who was previously in a hypoadrenal state is physiologically challenged and lacks the ability to produce adequate quantities of stress hormones as a response. Typically, this challenge is in the form of infection, surgery or trauma.

Addisonian crisis may also occur in patients known to have Addison's disease who fail to increase their steroids in the face of infections (typical ‘sick day rules’ include a doubling of the usual dose of steroids). More rarely in patients with known Addison's disease, drugs such as rifampicin or phenytoin, which accelerate the metabolism of cortisol, may lead to a crisis if the patient is undertreated with steroid replacement. Most crises caused by rifampicin occur within 2 weeks of initiating therapy.

Very rarely Addisonian crisis may occur in previously well patients who develop an acute adrenal haemorrhage. This is typically associated with meningococcal septicaemia, when it is known as Friderichsen-Waterhouse, a condition known as waterhouse friedrichson syndrome (the detection of which gained Dr. Carter his residency in an early episode of the US television series ER).

Presenting features of Addisonian crisis are summarized in Box 6. It is important to note that Addisonian crisis can result in cardiovascular collapse and death if not recognized and treated.

Treatment, as with the other endocrine emergencies, is best carried out urgently in hospital with access to intensive care and close monitoring. It will typically involve rapid intravenous fluid replacement with the administration of glucocorticoids, such as dexamethasone or hydrocortisone. For the GP, adequate education of the patient at risk of Addisonian crisis is of paramount importance. Patients on long-term steroid therapy should be instructed to increase steroid intake when unwell or due to undergo elective surgery. For mild illness, patients should double their normal dose of steroids.

Consider prescribing Efcortesol (hydrocortisone) 100 mg to patients at risk of Addisonian crisis for intramuscular self-administration or administration by other family members in case of emergency. This should be kept in the fridge and patients should ensure that they replace it before its expiry date. It is important to teach patients and other family members how to administer an intramuscular injection. Stress that injection cannot treat Addisonian crisis but merely acts as a life saving aid to buy time while they wait for an ambulance to arrive.