Endocrine Flashcards
How Is DM Classified?
○ DM type 1 (DM1) is an autoimmune process involving pancreatic beta-cell destruction.
- There is absolute insulin deficiency.
- Its development is associated with other autoimmune conditions, particularly thyroid disease (15–30% DM1 patients), autoimmune gastritis/pernicious anemia (5–10%), and Addison’s disease (0.5%) [1]. DM1 accounts for 5–10% of patients with diabetes.
○ DM type 2 (DM2) occurs as a consequence of progressive reduction in insulin secretion and the coexisting development of insulin resistance.
- Risk factors for the development of DM2 include obesity, age > 45 years, positive family history for DM, sedentary lifestyle, and race (indigenous Americans, Hispanic/Latino Americans, and African Americans are at higher risk).
- DM2 accounts for ≥90% of
patients with diabetes.
○ Gestational DM (GDM) occurs in up to 10% of pregnancies.
- It is defined as diabetes diagnosed during the second or third trimester of pregnancy that is not clearly overt DM.
- It almost always resolves after delivery.
- However, the occurrence of GDM does increase maternal risk for subsequent development of DM2 in later years.
○ Secondary DM occurs secondary to another medical condition, e.g., cystic fibrosis, hemochromatosis, chronic
pancreatitis, Cushing’s disease, and drug-/chemical-induced
disease.
An important issue for the perioperative
○ physician is the underdiagnosis of DM in the general population.
- It is estimated that one in five patients with DM is unaware that they have the disease
What Complications Is the Patient with Diabetes Mellitus (DM) Subject to in the Perioperative Period?
○ Elevated blood glucose levels are associated with impaired wound healing and increased risk of infection.
○ Metabolic decompensation secondary to mismanagement of diabetes drugs leads to diabetic ketoacidosis (DKA) or
hyperosmolar hyperglycemic state (HHS).
○ Hypoglycemia may go unrecognized due to its symptoms being masked by general anesthesia.
○ Diabetics with autonomic neuropathy are predisposed to intra- and postoperative hemodynamic instability due to impaired mechanisms to compensate for intravascular volume changes.
○ Patients with diabetic autonomic neuropathy have a high incidence of gastroparesis and silent myocardial ischemia.
○ Autonomic dysfunction and resultant hypercapnia may be responsible for a diminished response to hypoxia and an
exaggerated respiratory depressant response to opioids
What Target Blood Glucose Level Should
We Aim for Preoperatively?
○ Optimization of baseline glycemic control is a pivotal concern.
○ The American Diabetes Association guidelines recommend a target glucose range of 80–180 mg/dL (4.4–10.0 mmol/L) for most noncritically ill hospitalized patients.
○ Blood glucose levels that trend persistently or significantly above this should be addressed preoperatively if possible.
What End-Organ Abnormalities Associated with Diabetes Are of Particular Concern
Perioperatively?
○ End-organ abnormalities due to macro- and microangiopathy are responsible for the increased morbidity and mortality
associated with DM.
○ Macrovascular complications include
coronary artery and cerebrovascular disease.
○ Macrovascular complications are more common if the disease is long-standing, if glucose levels are poorly controlled, or if there is coexisting hypertension, tobacco use, hyperlipidemia, and a sedentary lifestyle.
○ Long-term DM patients should be
considered high risk for perioperative myocardial ischemia.
○ Microvascular complications of particular concern peri-operatively include diabetic nephropathy and neuropathy.
○ Autonomic neuropathy with gastroparesis increases the
risk of aspiration.
○ If a peripheral or central neuraxial block is planned, a baseline neurological assessment is prudent, to establish the extent (if present) of peripheral neuropathy.
How Should the Patient with DM Be Evaluated Preoperatively?
• What type of DM does the patient have?
• Age of onset, long-term control (HbA1c), and fasting/pre-meal glucose values
• History of hyperglycemic emergencies: DKA and HHS
• History of hypoglycemic episodes
• Medications: oral therapy and/or insulin, including basal and corrective doses and time taken
• If available, a diary of the patient’s fasting, pre-meal, and nighttime glucose values along with the amount of insulin given
• Long-term noncardiac complications: nephropathy, peripheral neuropathy, autonomic neuropathy (gastro-esophageal reflux disease, reported early satiety, chronic diarrhea, lack of sweating), and retinopathy
• Long-term cardiovascular complications: coronary artery disease, hypertension, cerebrovascular disease, and peripheral vascular disease
○ Physical Exam
The physical exam should focus on the cardiovascular, pulmonary, renal, and neurologic systems.
• Assess for signs of diabetic autonomic neuropathy (orthostatic hypotension and
resting tachycardia).
• Joint mobilization should also be assessed, focusing on mouth opening and cervical spine mobility. DM1 patients
may develop stiff joint syndrome with diminished mobility of the cervical spine and resultant difficult intubation [4].
○ Investigations
• Laboratory investigations include HbA1c value, 24-hour urinary albumin, and serum creatinine.
• Preoperative elevated baseline blood glucose may indicate increased risk for post-operative wound infection [5].
• A baseline ECG is a prerequisite. In addition to elucidating information pertaining to rate and rhythm, other
markers of cardiac disease, e.g., Q waves indicative of a previous myocardial infarct, or hypertensive changes, may be seen. Many diabetics present with silent ischemia diagnosed on routine ECG.
• Further cardiac evaluation—e.g.,
exercise stress test, myocardial perfusion scan, and echocardiography—is performed commensurate with the
complexity of the planned surgery and the patient’s perioperative risk for a major adverse cardiac event
Should Elective Surgery Be Cancelled Because of a High Preoperative HbA1c
Value?
○ HbA1c is a measure of average blood glucose over a 3-month period (the life of a red blood cell).
○ A high preoperative HbA1c level is associated with poor surgical outcome in cardiac and noncardiac surgery.
○ Several studies have suggested that HbA1c could be used as a risk stratification tool to predict perioperative hyperglycemia and other morbidities postoperatively.
○ Halkos et al. demonstrated that a HbA1c > 7% was associated with a significantly increased risk of renal failure, deep surgical wound infection, and prolonged hospital stay after coronary artery bypass grafting.
○ An HbA1c of 8.6% was associated with a fourfold increase in mortality.
○ The Association of Anaesthetists of Great Britain and Ireland suggests delaying elective surgery for optimization of glycemic control when the HbA1c >8.5%.
○ The American Diabetes Association has not provided an optimal HbA1c target for patients undergoing elective surgery but recommends a target of <7% in general .
○ No study has compared the effect of actively reducing HbA1c preoperatively versus not reducing it. However, the observational evidence points toward a target of <7% for elective surgery.
○ Therefore, if the surgery can wait, it seems reasonable to attain optimal long-term glycemic control as guided by the HbA1c.
What Medications Should We Expect to See in the Preoperative Patient with DM?
○ Insulin Ultra-short and short-acting, intermediate-acting, and long-acting preparations exist.
- Most commercial insulin contains beef insulin as the primary component, or a
combination of beef and pork. -Recombinant DNA techniques have allowed the production of human insulin.
-Advantages include more rapid absorption, less immunogenicity than
beef-pork insulin, and comparable effectiveness to animal insulins.
- Insulin can be delivered via portable pen injectors, closed-loop systems (e.g., insulin infusion intravenously), or open-loop systems such the insulin pump.
○ Oral Hypoglycemic Agents Major groups include α-glucosidase inhibitors (e.g., acarbose), meglitinide (e.g., repaglinide or nateglinide), biguanides (e.g., metformin),
sulfonylureas (e.g., glibenclamide, glipizide, glimepiride, gliquidone), thiazolidinediones (e.g., pioglitazone), and dipeptidyl peptidase-4 (DPP-IV) inhibitors (e.g., sitagliptin, saxagliptin, vildagliptin) and SGLT-2 inhibitors also known as gliflozins (e.g., dapagliflozin).
-The FDA released a safety statement in 2015 regarding reports of DKA occurring with SGLT-2 inhibitors. As a result of this statement, the American College of Endocrinology recommends holding the drug 24 hours before elective surgery.
○ Incretin Analogs (Liraglutide) One of the main physiological effects of incretins is to rapidly increase insulin and decrease
glucagon secretion in response to an oral glucose load.
○ Angiotensin-Converting Enzyme (ACE) Inhibitors or Angiotensin Receptor Blockers Either, but not both together, is recommended for the treatment of nonpregnant diabetic patients with modestly elevated urinary albumin
excretion (20–299 mg/day) and strongly recommended when urinary albumin excretion ≥300 mg/day or estimated
GFR <60 ml/min/1.73 m2
What Terminology Is Used to Describe
Commonly Used Insulin Regimens Outside
of the Operating Room Environment?
○ Basal Insulin Administered to manage hepatic glucose output.
-It may be given intravenously or subcutaneously.
○ Bolus Insulin (Meal Insulin) Administered to cover carbohydrate in a meal.
-It is short- and fast-acting insulin that is administered subcutaneously Correction Insulin Added to or subtracted from meal insulin or given at bedtime to correct for glucose outside of the target range.
- It is the same insulin as bolus insulin and is administered subcutaneously.
What Is the Significance of Rosuvastatin Use in a Diabetic Patient?
○ The risk of cardiovascular disease in diabetic patients is increased in the presence of dyslipidemia, in particular that due to elevated LDL cholesterol.
○ The American Diabetes Association, in 2016 guidelines, follows American Heart
Association/American College of Cardiology guidelines by setting no LDL cholesterol goal but recommending a 50% reduction from baseline.
○ A moderate to high intensity statin
such as rosuvastatin can be used for this purpose
What Factors Contribute to the Development of DKA or HHS Perioperatively?
• Sepsis and infections (urinary tract infections, pneumonia, infected wounds, and upper respiratory tract infections)
• New onset of diabetes
• Treatment noncompliance
• Alcohol and illicit drug use
• Site of injection complications interfering with adequate absorption of insulin, e.g., lipodystrophy
Surgery and Hypoglycemic Agents:
An Approach
○ Perioperative management of the diabetic patient’s therapy should be tailored to, among other factors, random glucose values and HbA1c.
○ Intravenous insulin infusion therapy adjusted by sliding scale is not a panacea for the insulin-dependent diabetic.
○ The goal of treatment is avoidance of hypo- and hyperglycemic episodes from when fasting starts preoperatively until the patient is eating and drinking normally after surgery.
○ Decide if interruption of hypoglycemic therapy is required by determining the fasting time and the projected number of meals that will be missed perioperatively.
○ Patients who are unlikely to miss more than one meal can often be managed by manipulation of their normal medication or even continuation in certain cases.
○ Previously, all oral hypoglycemic drugs were stopped perioperatively. It may be rational—indeed, possibly safer—to continue metformin, a drug that works by preventing glucose levels from rising, in patients undergoing a short starvation period, i.e., scheduled first on the operating slate with one projected missed mea
○ Metformin should be withheld in patients with pre-existing renal impairment or with the use of nephrotoxic agents, e.g., contrast media.
○ Agents that act by lowering glucose concentration, e.g., sulfonylureas and insulin, should be stopped or have their regular dose modified during periods of starvation.
○ Basal insulin is often inappropriately held in the perioperative setting.
-The patient described above was on a basal bolus insulin therapy (BBIT) regime with basal long-acting insulin at night in addition to preprandial short-acting insulin.
-Basal insulin controls hepatic glucose output, which increases with fasting and surgical stress.
-Continuation of basal insulin in DM1 is imperative to prevent ketoacidosis.
-Basal insulin improves glycemic control and reduces hospital complications when compared to sliding scale insulin alone in DM1 undergoing general surgery [14].
○ Time of surgery is important to consider, especially in patients that take 100% of their normal basal insulin dose.
○ Finally, the Enhanced Recovery After Surgery (ERAS) Society recommends carbohydrate-rich drinks up to 2 hours before surgery .
-This increases insulin sensitivity and decreases the risk of postoperative hyperglycemia.
-This is a contentious issue in diabetic patients as there is a risk of aspiration secondary to delayed gastric emptying [16].
- Further investigation is required before preoperative carbohydrate loading can be recommended without qualification in diabetic patients
T/F
Patients with diabetic autonomic neuropathy have a high incidence of silent myocardial ischemia
T
T/F
HbA1c is a measure of average blood glucose over a 6-month period
F
T/F
A high preoperative HbA1c level is associated with poor surgical outcome in noncardiac surgery.
T
The American Diabetes Association suggests delaying elective surgery for optimization of glycemic control when the HbA1c > 8.5%
F
The Association of Anaesthetists of
Great Britain and Ireland suggests delaying elective surgery
for optimization of glycemic control when the HbA1c >8.5%
[6] (Table 17.1) [9]. The American Diabetes Association has
not provided an optimal HbA1c target for patients undergoing
elective surgery but recommends a target of <7% in general
T/F
ACE inhibitors are frequently used in diabetic patients with elevated urinary albumin excretion.
T
Basal insulin may only be administered via the intravenous route.
F
Bolus insulin is given to cover the carbohydrate
ingested in a meal
T/F
All oral hypoglycemic medications should be discontinued preoperatively on the day of surgery
F
Metformin may be continued preoperatively on the day of surgery if the planned starvation period is of short duration
T
T/F
For patients with pre-existing renal impairment, it is safe to administer metformin preoperatively on the day of surgery.
F
What Is the Difference Between
Thyrotoxicosis and Hyperthyroidism?
○ Thyrotoxicosis is a condition resulting from the effects of excessive circulating thyroid hormone of any cause or source.
○ Hyperthyroidism is a form of thyrotoxicosis that occurs when the excessive thyroid hormone originates from the thyroid gland.
○Causes of non-hyperthyroid thyrotoxicosis include excessive levothyroxine use and pharmacologic thyroiditis, e.g., caused by iodine-containing drugs such as amiodarone.
What Is Graves’ Disease and What
Distinguishes It from Other Causes
of Hyperthyroidism?
Graves’ disease is the most common cause of hyperthyroid-
ism. It is an autoimmune condition more prevalent in females
and in patients between 30 and 60 years old. Thyroid-
stimulating hormone (TSH) receptor antibodies stimulate
thyroid gland growth and promote thyroid hormone synthe-
sis and secretion (Fig. 18.2). A radioiodine thyroid scan will
show normal or high uptake indicating excess new thyroid
hormone synthesis. A radioiodine scan that shows near-
absent uptake will be seen when hyperthyroidism is due to
viral, radiation-, or drug-induced thyroiditis. Laboratory
findings seen with Graves’ disease include elevated T3 and
T4 (T3 is typically higher in Graves’ disease and T4 is higher
in subacute thyroiditis), decreased TSH, and elevated TSH
receptor antibody level (Fig. 18.3) [1].
How Can a Patient with Hyperthyroidism
Gain Weight?
Hyperthyroidism causes weight loss in most patients. Some
patients gain weight due to stimulation of the appetite and/or
treatment of hyperthyroidism
What Is the Significance of a Long QT
Interval in a Patient with Hyperthyroidism?
○ Hyperthyroidism is associated with cardiac complications.
- Atrial fibrillation is the most common cardiac abnormality occurring in approximately 10–25% of hyperthyroid patients [2].
- The QT interval represents the time for ventricular depolarization and repolarization. It is dependent on heart
rate, i.e., a faster heart rate leads to a shorter QT interval.
- Therefore, QTc estimates the QT interval corrected for a heart rate of 60 bpm. A prolonged QT interval places the patient at increased risk for tachyarrhythmias, e.g., torsades de pointes and ventricular fibrillation.
- The correlation between hyperthyroidism and prolonged QT interval has been previously noted [3].
- Indeed, there is an association between levels of T4 and QTc [3].
- The etiology is not precisely known but may be related to the effect of thyroid
hormone on the cardiac myocyte.
- The QTc frequently reverts to a normal range once the patient becomes biochemically euthyroid [4].
Is There a Link Between Pulmonary
Hypertension and Hyperthyroidism?
Hyperthyroidism is associated with changes in cardiac out-
put, blood pressure, and systemic and pulmonary vascular
resistance. Most patients with pulmonary hypertension and
thyroid disease are older with toxic multinodular goiter.
Again, the etiology is not entirely known (see relationship
between thyroid and cardiovascular disease in the following
question). There may be a direct effect of thyroid hormone
on pulmonary vasculature. Patients with hyperthyroidism
should be considered at risk for pulmonary hypertension.
Patients with newly diagnosed pulmonary hypertension
should be investigated for thyroid disease, as it may be a
reversible cause of pulmonary hypertension.
What Complications Is the Patient
with Thyrotoxicosis Subject
to in the Perioperative Period?
- Thyroid Storm
This is a rare and life-threatening exacerbation of
hyperthyroidism brought on by acute illness, trauma, and
thyroid or non-thyroid surgery. Discontinuation of, or
poor compliance with, antithyroid medication is a risk
factor. Thyroid storm can be diagnosed clinically by
severe tachycardia, hypotension, cardiac failure, and
hyperpyrexia in the patient under anesthesia. Delirium,
extreme anxiety, and altered consciousness progressing to
coma can be seen in the awake patient. - Cardiovascular Changes
Arrhythmias, most frequently sinus tachycardia or
atrial fibrillation, systemic and pulmonary hypertension,
coronary ischemia, and heart failure can be seen with
suboptimal disease control. The extent of involvement of
the adrenergic system versus that of direct thyroid
hormone stimulation and the interaction between these
two systems is unknown. For instance, many of the
adrenergic-like effects are mediated via T3 stimulation of
cardiac myocytes. In addition, many components of the
cardiac beta-adrenergic system are regulated by thyroid
hormone. Treatment with beta-blockade improves most
of the cardiovascular concerns associated with hyper-
thyroidism. Of note, treatment of tachyarrhythmia in the
thyrotoxic cardiac patient with beta-blockade is the first-
line therapy. In the patient with overt cardiac failure, a
cautious trial of short-acting beta-blockade (e.g., esmolol)
may be used [5]. - Airway Complications
In addition to concerns regarding intubation at induc-
tion of anesthesia as outlined below, the thyroidectomy
patient can develop a number of postoperative airway
complications. Airway obstruction may occur secondary
to hematoma, tracheomalacia, recurrent laryngeal nerve
damage, or hypocalcemic laryngeal tetany [6]. Unilateral
recurrent laryngeal nerve damage may result in hoarseness
or may be asymptomatic. Bilateral recurrent laryngeal
nerve damage can result in aspiration pneumonia or com-
plete airway occlusion requiring immediate intubation [7].
How Should the Patient with Thyrotoxicosis
Be Evaluated Preoperatively?
History
A wide spectrum of symptoms is seen, depending on circu-
lating levels of T3 and T4. These are outlined by system in
Table 18.2. Of particular relevance to the anesthesiologist are
symptoms that may indicate a difficult intubation. A goiter
causing tracheal compression, retrosternal goiter, or cancer-
ous goiter may indicate tracheal obstruction and warrant CT
investigation of the size of the mass, its precise location, and
the degree of tracheal compression. Positional dyspnea has
been reported by 75% of patients with a retrosternal goiter
[8]. Dysphagia has been reported as the second most com-
mon symptom (43% patients with retrosternal goiter) [9]
How Should the Patient with Thyrotoxicosis Be Evaluated Preoperatively?
Physical Exam
○ A thorough airway examination is imperative. Most patients with a large goiter, whether retrosternal or causing tracheal deviation, can be intubated with direct laryngoscopy.
○ An observational study of over 300 patients having thyroid surgery reported that the classic predictive criteria for difficult intubation – small mouth opening, short neck, Mallampati class 3 or 4, reduced neck mobility, and short thyromental distance – were reliable predictors of difficult intubation in
patients having thyroid surgery.
- A large palpable goiter, mediastinal extension, tracheal compression or deviation, and malignancy were not associated with difficult intubation
[10].
- Regardless, for the authors there are two principal causes for concern that reduce our threshold for awake fiber-optic intubation:
(1) malignancy leading to fibrosis and associated immobile larynx and
(2) severe tracheal compression.
Retrosternal goiter may be diagnosed clinically by detection of caudal extension of the goiter below the sternal notch.
- Superior vena cava syndrome has been reported in 5–9% of patients with retrosternal goiter [11]. Pemberton’s sign will confirm this diagnosis, i.e., with arms raised for 1–2 minutes, a large goiter will inhibit venous return, causing venous engorge-ment, facial edema, cyanosis, and respiratory distress.
How Should the Patient with Thyrotoxicosis
Be Evaluated Preoperatively?
Investigations
• Free T3 and T4 (free hormone is the best indicator of
thyroid status)
• TSH
• TSH receptor antibody
• Radioactive iodine uptake
• Ultrasound
• CT
What Specific Medications Should We Expect to See in the Preoperative Patient with Thyrotoxicosis?
Two categories of drug are used:
(1) those that inhibit thyroid hormone synthesis and
(2) those that inhibit the adrenergic-like effects of excess thyroid hormone.
○ Thyroid hormone synthesis is reviewed in Fig. 18.4.
○ Dietary iodide compounds are trapped in the thyroid epithelial follicular cells and oxidized to iodinium ions (I+) by thyroid peroxidase. TSH from the anterior pituitary stimulates synthesis of the Na/I transporter, thyroid
peroxidase, and thyroglobulin. Thyroglobulin (specifically its tyrosine amino acid) stored in thyroid colloid is iodinated in a process known as organification to monoiodotyrosine (MIT) and diiodotyrosine (DIT). These molecules are then conjugated (again by thyroid peroxidase) to form
triiodothyronine (T3) and tetraiodothyronine (T4). The final steps in the process are proteolysis of thyroglobulin and release of T3 and T4. The ratio of T4:T3 release to plasma is approximately 3:1. T4 is subsequently metabolized to T3 by deiodination in the liver and kidney. T3 is 3–5 times more active than T4 and is responsible for most activity attributed to thyroid hormone.
○ Thionamides Methimazole and propylthiouracil inhibit thyroid hormone synthesis at the organification and conjugation steps. As stores of thyroid hormone can last for months, clinical effects of propylthiouracil and methimazole may not be seen for up to 2 months. Methimazole is the first line of therapy. It is faster acting (though still expected to take between 3 and 8 weeks to be effective), has less potential for hepatotoxicity, and has a longer half-life that facilitates once-daily dosing [12]. Adverse effects associ-
ated with thionamide use include rash, hepatotoxicity, and agranulocytosis [13]. Iodine (e.g., Lugol’s solution/potassium iodide) inhibits thyroid hormone secretion within hours of administration. It also inhibits thyroid hormone synthesis at the stage of organification/iodination of thyroglobulin tyrosine. Its effect is maximal at 10–20 days but can be short lived. Its use is
recommended as an adjunct in the preoperative preparation of the patient with Graves’ disease or for the treatment of thyroid storm.
Glucocorticoids inhibit the conversion of T4 to T3 and reduce thyroid hormone secretion.
Beta-blockade is used for control of hyper-adrenergic symptoms. It is frequently started with methimazole to achieve a euthyroid state. The target is a heart rate of 90 bpm.
What Is the Goal of Preoperative Optimization of hypethyroidism Prior to Surgery?
○ Whenever possible, the patient should be rendered clinically and biochemically euthyroid prior to surgery. This can take several months. TSH levels may remain suppressed, and this is not considered a contraindication to elective surgery. If a euthyroid state cannot be realized, heart rate is the most important factor to control with beta-blockade.
There are three principal treatment options for hyperthyroidism – antithyroid drugs, radioactive iodine, and thyroidectomy [13]. Indications for surgery are local compressive symptoms, risk of malignancy, and hyper-
thyroidism. Our patient had significant clinical and biochemical hyperthyroidism. She could not takemethimazole due to a hypersensitivity reaction – an urticarial rash with pruritis. Radioactive iodine ablation would have been a reasonable alternative for management of this patient’s
hyperthyroidism, but when presented with treatment options,
she decided to undergo thyroidectomy. The patient was informed of the risks associated with thyroid storm, and subsequent to this conversation, in consultation with an endocrinologist and the patient’s general surgeon, she was started on propylthiouracil. She tolerated this well, even
though there is a risk of developing an adverse reaction with one thionamide if intolerant of the other. Surgery was deferred for 2 months until a state of biochemical and clinical euthyroidism was achieved.
True/False Questions
Beta-blockade is contraindicated in patients with known cardiac disease.
.
Provide a Brief Overview of Adrenal Gland Physiology Including Hormone Production
The adrenal gland consists of two distinct components, the outer cortex and the inner medulla. The adrenal cortex is responsible for the production of glucocorticoid, mineralocorticoid, and androgen hormones. CRH produced by the hypothalamus stimulates the anterior pituitary to synthesize ACTH (Fig. 19.2) [5, 6]. ACTH in turn regulates adrenocortical secretion of glucocorticoids. Aldosterone is the main mineralocorticoid secreted by the adrenal cortex in response to regulation by the renin-angiotensin system.
The adrenal medulla is a component of the sympathetic nervous system and is responsible for synthesis of catecholamines, e.g., norepinephrine and epinephrine. It is of no significance in the context of adrenal insufficiency,
which, as indicated above, may be more appropriately termed adrenocortical insufficiency
