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Endocrine Disorders

We’re going to talk about the adrenal, we’re going to do some calcium, we’re then going to do a bit of pituitary apoplexy, the thyroid storm and then hypoglycemic emergencies at this time. The signs and symptoms of adrenal insufficiency are well known to you. I will just remind you that the majority of patients when they present with an adrenal insufficiency will present in very much a nonspecific way with weakness and fatigue, weight loss, some hyperpigmentation, hypertension including postural dizziness being the most common symptoms. Some patients will be found to have the classic hyponatremia and hyperkalemia, GI disturbance such as nausea. Remember that not everybody with typical primary adrenal insufficiency is going have the classic hyponatremia.

Hypercalcemia may occur and it’s usually an elevation in the total calcium but not the ionized calcium and once you treat the adrenal insufficiency the calcium normalizes. Then nonspecific muscle and joint pains are all symptoms that can occur as part of the manifestation of adrenal insufficiency.

The causes are many. The most common is the autoimmune, hypoadrenalism. Remember that we’re seeing an increased incidence of granulomatous disease and particularly HIV related disease causing a total destruction of the adrenal and you need to destroy more than 90% of your adrenal.

With many patients being on an increasing number of drugs today, I think it’s important always to remember that there are certain drugs that can either interfere with adrenal steroidogenesis or can increase the metabolism of steroids. So metyrapone is methyl hydroxylase inhibitor that will inhibit production of cortisol. Ketoconazole inhibits adrenal enzymes and therefore corticosteroid synthesis and aminoglutethimide and mitotane.

It is important to recognize causes of secondary adrenal insufficiency as far as the pituitary is concerned and we do see pituitary hypothalamic disease in isolated ACTH deficiency as causes of adrenal insufficiency. Remember that anybody who’s been on pharmacological steroids for ten days or more is at risk for the development of adrenal insufficiency and they need to be covered with stress dose steroids if there is a condition that determines it.

Following cure of Cushing’s syndrome, patients may be adrenally insufficient for months, sometimes even years, while their pituitary adrenal axis is recovering. Clearly surgery or radiation to the pituitary is another cause.

How do these patients present? They can present in a subacute manner which is mild nausea with some vomiting and hypertension over a few days to a severe life-threatening crisis characterized by profound hypertension and shock plus the features of the precipitating event and there usually is one. In most cases, there is a precipitating reason why patients present with a crisis. In fact, for most of the crises that we see in endocrinology, there is often an underlying precipitating illness or an event, many times unrelated to the underlying endocrine lesion that leads to the crisis developing.

Patients classically will have hyponatremia and hyperkalemia with hypoglycemia and hypercalcemia also being present. But remember that patients who present, for example, with a profound diarrhea may not necessarily have the hyperkalemia associated with acute adrenal insufficiency.

It’s important to make a diagnosis early and to take your blood for that diagnosis early before you start therapy with steroids. Once you started therapy with hydrocortisone, any measurement of endogenous cortisol production is going to be impaired. So take blood immediately for cortisol and ACTH and if there’s time and the patient’s illness determines that you have 30-60 minutes, do an ACTH stimulation test, give 250 micrograms of ACTH and measure both the cortisol and the aldosterone response to ACTH administration. This is particularly useful sometimes in distinguishing primary from secondary adrenal insufficiency and at least once you’ve done the test, you know that you can go back and look at the results without having to worry about what you’ve given the patient and how it interferes with the measurement of those things that you want to measure.

Once you’ve taken your blood for your investigation, start steroids immediately. Give stress dose steroids which comprise 100 mg of hydrocortisone intravenously immediately and taper as rapidly as you can, usually over the next one to three days or longer if the condition determines that you can only taper over a longer period of time.

It’s not necessary to give any mineral or corticoid when you give such high doses of pharmacological doses of steroids because these high doses of glucocorticoids have mineral and corticoid effects. So we only start mineral and corticoid replacement once the dose of hydrocortisone is down to a more physiologic range which should be in the region of

Let’s move onto calcium. Most patients with hyperparathyroidism and hypercalcemia present in an asymptomatic way and from time to time we do see patients with underlying hypercalcemia who develop an illness that leads to the precipitation of a severe hypercalcemic crisis. This is characterized by mental status changes and cardiovascular dysfunction.

The causes of severe hypercalcemia may be related to the suppression of PTH, a so-called PTH dependent disease – and we do see patients with primary hyperparathyroidism who can present with a hypercalcemic crisis. Although as I said, the majority of the patients will not, this does happen on occasion.

The most common of the so-called PTH gene dependent causes are clearly those patients who have malignant disease and malignant hypercalcemia can be caused by the suppression of PTH to light peptide or PTH to related peptide such as from solid tumors of the lung or caused by the suppression of humoral factors such as occurs in various lymphoproliferative or myeloproliferative disorders.

The other causes of hypercalcemia rarely are associated with a hypercalcemic crisis. So if anybody presents with a hypercalcemic crisis, the most common cause is a hyperparathyroidism or malignant disease.

Clinically the patients will present dehydrated with an altered level of consciousness and in a state potentially either with cardiovascular collapse or some form of cardiovascular compromise. Usually, but not always, the hypercalcemia is severe with a calcemia about 14 mg/deciliter and you need to recognize it. To distinguish the parathyroid from the non-parathyroid causes of hypercalcemia you should get a PTH, and a PTH with a peptide if it’s possible.

Specific treatment aimed at reducing calcium levels is instituted in the form of calcitonin or bisphosphonate. Calcitonin generally works much more reactively than bisphosphonates do and there’s no harm in using both of these drugs if need be. Mithramycin or plicamycin is very rarely used today. If these approaches to lowering the calcium prove ineffective, then sometimes dialysis is required. Treat the underlying cause. Treat the symptomatic problems such as cardiovascular compromise.

To move to hypocalcemia, this is characterized by a variety of causes which may be related to a deficiency of PTH – a so-called absolute deficiency as is seen in hypoparathyroidism, what I call a relative deficiency which we may see sometimes in states of magnesium deficiency. Magnesium is a cofactor required for adequate PTH action and so if your patients are magnesium deficient, they will have impaired action of PTH and sometimes even impairments of secretion of PTH. You correct the magnesium and you correct the PTH problem. Very rarely do we see syndromes of resistance to PTH. Vitamin D deficiency similarly may be an absolute deficiency or resistance to vitamin D such as in some of the congenital effects of acquired conditions.

There are situations where calcium is sequestered into the tissues. Acute pancreatitis, rhabdomyolysis, effusion of phosphate and massive tumor lysis may all be associated with the development of hypocalcemia. Where there’s increase in osteoblastic activity. This is classically seen following

Drugs are listed over here. Some cytotoxic agents can cause hypocalcemia and then very rarely, there are some other drugs such as pentamidine, foscarnet and ketoconazole whose use may be associated with the development of hypocalcemia.

These patients present with abnormal neurologic sensations and neuromuscular irritability and excitability on the one hand and on the other hand they present with cardiovascular manifestations. So then those abnormal neurologic sensations may range from periorbital numbness and paresthesia to

Now to one respect you’ve got a number of pituitary conditions. I mentioned pituitary apoplexy. I will remind you that this is a devastating illness which is associated with potential mortality. It’s characterized by infarction in the pituitary gland, usually where there’s a preexisting tumor or sometimes an enlarged gland. This is the classical Sheehan’s syndrome as it was described by Sheehan so many years ago in patients who infarcted their pituitaries because of postpartum hypertension, enlarged glands that are associated with pregnancy. The pituitary enlarges two to three-fold during pregnancy and is at risk from the compromised blood supply if blood pressures drop significantly.

Patients will present with a syndrome that’s classic of headache, of visual deficit, ophthalmoplegia and altered mental status and these deficits are related to the anatomical relations of the pituitary and the visual deficits are usually bitemporal hemianopia and the ophthalmoplegia is usually III, IV or VI cranial nerve abnormalities. The presentation is often acute and may lead to coma or death if untreated. Occasionally, many somewhat more subacute with symptoms evolving over a period of days.

Now, the most common symptoms are clearly the headache, the visual disturbance, the ocular palsies, some nausea and vomiting, altered mental status, meningismus, hemiparesis may occur as well. Plus remember that there may features of the underlying tumor, particularly if it’s a functional tumor.

The differential diagnosis is that of a subarachnoid hemorrhage or meningitis and therefore we need to sometimes evaluate these patients to rule out these conditions by doing a CT of the head. A lumbar puncture may be necessary and clearly all patients being evaluated need baseline pituitary function tests.

Most of these patients, in fact 100% of patients in one study, had evidence of hypogonadism with 90% being growth hormone deficient, two-thirds having hyperprolactinemia, two-thirds being renally insufficient and just about half having hypothyroidism. A small percentage of patients had diabetes insipidus at the time of presentation.

Putting up this slide is really just a reminder that the most important replacement therapy that’s required is steroids and that the other hormones, once evaluated, can be replaced thereafter but the most important treatment is supportive for steroids. So medically we give stress dose steroids. We will give other hormone replacement less acutely and the most important thing is to submit these patients or refer these patients for decompressive surgery because delayed surgical treatment can affect potentially the outcome, both the morbidity and the mortality, from the condition.

The prognosis will depend on how long the patient’s symptoms have been present and sometimes the patients are seen soon enough and the prognosis is acute enough we may even have some reversal of the endocrine abnormalities. Improvement of the visual fields in ophthalmoplegia is either partial or, very rarely, total may occur if the treatment is rapid.

We’re now going to move to the thyroid and then we’ll end the session on diabetic emergencies and I’m going to spend a few minutes talking about thyroid storm. Thyroid storm is seen much less commonly today. It’s usually precipitated by an intercurrent event. The clinical manifestations are related to the precipitating event, in a so-called state of accelerated thyrotoxicosis, and one really needs a triad of abnormalities to diagnose thyroid storm. You need fever, a change in mental status, evidence of multisystem involvement including abnormal liver function tests.

In your syllabus I have supplied for you criteria for the diagnosis of thyroid storm and they’ve given a variety of points to the presence or absence of some of the symptoms associated with this condition. I refer you to that in your syllabus but I don’t have time to go through it with you now. The important point is that there are conditions associated with a rapid increase in thyroid hormone levels that can lead to the development of a thyroid storm. Thyroid surgery in a patient who is previously untreated. Following radioiodine therapy there have been rare reports of thyroid storm in patients previously untreated, sudden cessation of antithyroid drugs and lack of followup may lead to thyroid storm. The use of iodinated contrast dyes has sometimes been associated with a thyroid storm and finally there has been a report – I haven’t seen one – of a vigorous thyroid palpation. That has to be a pretty vigorous thyroid palpation that causes a thyroid storm but I put it there because there has been a report in the literature.

Conditions associated with non-thyroidal illness, so to speak. Any surgical procedure in a patient with untreated thyrotoxicosis can lead to thyroid storm and that’s probably the most common setting – that and the presence of an intercurrent infection where we are called in to evaluate a patient who potentially has a thyroid storm or severe accelerated thyrotoxicosis. Previously undiagnosed thyrotoxicosis in a patient who presents with a non-thyroidal illness requiring surgery or an infection. But these other conditions listed over here can all be associated with the precipitation of a thyroid storm.

Lithium has occasionally been used to inhibit thyroid hormone release in patients who are allergic to iodine but we prefer, if possible, to use iodine. So we give first a large dose of thioamide, then we inhibit thyroid hormone release by giving large doses of iodine for seven to ten days. We diminish the peripheral manifestations of thyroid hormone – we try and prevent thyroid hormone from acting peripherally or being converted from T4 to T3 which is the more biologically active hormone and inhibition of T4 to T3 can occur with PTU as opposed to Tapazole, dexamethasone has been shown to inhibit T4 to T3 conversion, propranolol has been shown to do this as has this ipodate which is the iodinated contrast agent, all inhibit T4 to T3 conversion.

Hypoglycemia and ketosis may not necessarily parallel each other in severity. So what we see on the left hand side is factors that lead to a certain relative deficiency of insulin – people withdrawing insulin, a beta cell failing or people not adjusting the insulin dose to accommodate the increasing insulin requirements that occur sometimes through stress such as illness. Then, of course, we have situations where increase in insulin resistance is present in combination with this and I should also point out that the electrolyte abnormalities, the acidosis per se, the counter regulatory hormones and the hyperosmotic state all contribute to the insulin resistance that is so typically associated with DKA. So it’s important to remember that these are patients who need large doses of insulin and, in fact, the infusion of insulin that we provide to patients does really increase plasma insulin concentrations significantly.

The hormonal abnormalities, I will just remind you, are deficiency of insulin, increase glucagon, increase in cortisol, increasing other counter regulatory hormones such as growth hormone and catecholamine and this all leads to an increase in production of glucose by the liver, either production or breakdown of glucose from glycogen, diminished uptake of glucose by peripheral tissues and increase in lipolysis and ketogenesis. So insulin deficiency, increased glycogenolysis, increased gluconeogenesis. There’s also diminished glucose utilization, hence hyperglycemia, increasing ketogenesis, increase in lipolysis, there is also diminished ketone utilization. The ketones are not excreted by the kidneys as well as they should be and that contributes to hyperketonemia.

The clinical manifestations relate to hyperglycemia, glycosuria, osmotic diuresis, hypervolemia, hyperosmolarity, cellular dehydration. In fact, the altered mental status is more related to the levels of glucose and osmolality than it is to the acidosis.

The metabolic abnormalities that you’ll find are classically the pure metabolic acidosis but you may see a combination of ketoacidosis and hyperchloremic acidosis usually occurs as a result of therapy or during therapy. There will be sometimes mixed acid based disturbances which may be present including the combination of a metabolic alkalosis with a metabolic acidosis, respiratory alkalosis and don’t forget uremia and lactic acidosis can also occur in the presence of DKA.

I’m not going to say too much about the acid based disturbances and how you calculate them because there will be a whole lecture on acid base in your renal section tomorrow. But a few small little vignettes may help you in trying to quickly assess whether or not this is a pure acid based disturbance or a mixed acid base disturbance.

The rule of thumb that is sometimes very helpful is to remember that in a pure acidosis, the PCO2 should equal the last two numbers of the pH. So you have a pH of 7.27, the PCO2 is somewhere round about 30. If the PCO2 is lower than you would expect, you probably are dealing with a superimposed respiratory alkalosis. If the PCO2 is higher than you’d expect, you’re probably dealing with a superimposed respiratory acidosis. If the pH is higher than you would predict from the PCO2 and the anion gap is much higher than you would have expected, then you’re probably dealing with a mixed acid base disturbance.

Patients with DKA have lost a lot of water and electrolyte and this slide summarizes for you the average losses in a 70 kg person with established DKA – up to 7 liters of fluid, up to 450 milliequivalents of sodium, 400 milliequivalents of potassium, up to 1.5 gm of calcium and 150 millimoles of phosphate.

The treatment is really based on the underlying pathophysiology. You want to treat the hyperglycemia, the hypertonicity and you therefore need to give insulin and free water. You’re going to treat the ketoacidosis by giving insulin in the first place and if that’s not enough or the patient is severely acidotic, you will have to give bicarbonate. You’re going to treat the fluid and electrolyte losses with insulin, sodium chloride, potassium and other electrolytes that need to be replaced.

Potassium deficiency is often severe and the initial serum potassium may be low, normal or high. It will decline, guaranteed, when you start insulin therapy and these were patients who developed complete renal failure. So you need to start potassium as soon as you know what the initial potassium level is and have shown that the patient is not in renal failure, is passing urine. In your syllabus, there’s a small, little algorithm giving you a guide as to how much potassium to replace based on the current potassium level.

Bicarbonate therapy should be instituted if the pH is less than 7, if there’s hypotension, not responding to intravenous fluids, where the cardiac arrhythmias occur with hypokalemia, hypoventilation or coma. In severe acidosis, patients will in fact hypoventilate rather than hyperventilate once acidosis is very severe and profound acidosis will be associated with coma although the more mild forms of acidosis are less likely to be associated

Remember that bicarbonate therapy is not without its problems and that by giving bicarbonate therapy, if you’re too liberal with your bicarbonate, you may have an overshoot alkalosis, a paradoxical CSF alkalosis, altered tissue oxygenation because you shift the oxygen dissociation curve to the left, hypokalemia, volume overload, increased CO2 production and, in effect, paradoxically there will be increase in ketoacid production if you give too much bicarbonate.

There are a couple of exceptions one should always remember. We can see patients with DKA who have near normal glycemia. This classically occurs in patients using insulin infusion pumps, particularly now that patients are using Humalog because Humalog has a much shorter half life than NPH insulin. If pumps fail, patients can rapidly become ketoacidotic within hours and so we can see what we call euglycemic DKA.

Alkalemic DKA will occur in the patient who has severe vomiting and a metabolic alkalosis in addition to the metabolic acidosis and we’ve seen patients with pHs of about 7.5 with diabetic ketoacidosis.

Finally, why should we get non-ketonemic DKA? This is to remind me to tell you that the acid test which is used to test for ketones reaction measures only acetoacetate and not beta-hydroxy butyrate. So if you have hypoxic conditions or if you have the presence of a significant alcohol