Endocrinology

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square-bullet The American Diabetes Association (ADA) defines DM as follows:
FPG ≥126 mg/dL, which should be confirmed with repeat testing on a different day. Fasting is defined as no caloric intake for at least 8 hr.
Sx of hyperglycemia and a casual (random) plasma glucose ≥200 mg/dL. Classic sx of hyperglycemia include polyuria, polydipsia, and unexplained weight loss.
An OGTT with a plasma glucose ≥200 mg/dL 2 hr after a 75-g (100 g for pregnant women) glucose load
HBA1c ≥6.5%
square-bullet Prediabetes: glucose levels > nl but not high enough to meet the criteria for dx DM
Impaired fasting glucose: FBS 100 to 125 mg/dL
Impaired glucose tolerance: after OGTT, a 2-hr plasma glucose 140 to 199 mg/dL
HBA1c value 5.7% to 6.4%
square-bullet Table 5-1 describes diagnostic categories for diabetes mellitus and at-risk states.

PE

Diabetic Retinopathy

a. Nonproliferative (background diabetic retinopathy)
i. Initially: microaneurysms, capillary dilation, waxy or hard exudates, dot and flame hemorrhages, atrioventricular shunts
ii. Advanced stage: microinfarcts with cotton wool exudates, macular edema
b. Proliferative retinopathy: formation of new vessels, vitreous hemorrhages, fibrous scarring, and retinal detachment

Diabetic Neuropathy

a. Distal sensorimotor polyneuropathy
i. Sx: paresthesia, hyperesthesia, or burning pain involving bilateral distal extremities, in a “stocking-glove” distribution. It can progress to motor weakness and ataxia.
ii. PE: ↓ pinprick sensation, sensation to light touch, vibration sense, and loss of proprioception. ↓ DTRs and atrophy of interossei muscles can also be seen.
b. Autonomic neuropathy
i. GI: esophageal motility abnlities, gastroparesis, diarrhea (usually nocturnal)
ii. GU: neurogenic bladder (hesitancy, weak stream, and dribbling), impotence
iii. Orthostatic hypotension: postural syncope, dizziness, lightheadedness
c. Polyradiculopathy: painful weakness and atrophy in the distribution of ≥1 contiguous nerve roots
d. Mononeuropathy involving cranial nerves III, IV, or VI or peripheral nerves

Diabetic Nephropathy

Pts have pedal edema, pallor, weakness, uremic appearance.

Foot Ulcers

They occur in 15% of individuals with DM (incidence rate, 2%/yr) → leading causes of hospitalization and amputation in U.S. They result from combination of PVD, repeated trauma (unrecognized because of sensory loss), and superimposed infection.
a. Sx: less than would be expected from clinical findings, resulting from loss of sensation related to peripheral neuropathy
b. Dx: assessment of pedal pulses, sensation (using a 10-g monofilament)
c. Prevention: strict glucose control, pt education, prescription footwear, podiatric care, evaluation for surgical interventions

Neuropathic Arthropathy (Charcot’s Joints)

Bone or joint deformities result from repeated trauma (secondary to peripheral neuropathy).

Necrobiosis Lipoidica Diabeticorum

Plaquelike reddened areas with a central area that fades to white yellow are found on the anterior surfaces of the legs.

TABLE 5-1

General Comparison of the Two Types of Diabetes Mellitus

Type 1 Type 2
Previous terminology Insulin-dependent diabetes mellitus (IDDM), type I, juvenile-onset diabetes Non–insulin-dependent diabetes mellitus, type II, adult-onset diabetes
Age at onset Usually <30 yr, particularly childhood and adolescence, but any age Usually >40 yr, but any age
Genetic predisposition Moderate; environmental factors required for expression; 35%-50% concordance in monozygotic twins; several candidate genes proposed Strong; 6%-90% concordance in monozygotic twins; many candidate genes proposed; some genes identified in maturity-onset diabetes of the young
Human leukocyte antigen associations Linkage to DQA and DQB, influenced by DRB (3 and 4) (DR2 protective) None known
Other associations Autoimmune; Graves’ disease, Hashimoto’s thyroiditis, vitiligo, Addison’s disease, pernicious anemia Heterogeneous group, ongoing subclassification based on identification of specific pathogenic processes and genetic defects
Precipitating and risk factors Largely unknown; microbial, chemical, dietary, other Age, obesity (central), sedentary lifestyle, previous gestational diabetes
Findings at diagnosis 85%-90% of patients have one and usually more autoantibodies to ICA512/Ia-2/IA-2β, GAD65, insulin (IAA) Possibly complications (microvascular or macrovascular) caused by significant preceding asymptomatic period
Endogenous insulin levels Low or absent Usually present (relative deficiency), early hyperinsulinemia
Insulin resistance Only with hyperglycemia Mostly present
Prolonged fast Hyperglycemia, ketoacidosis Euglycemia
Stress, withdrawal of insulin Ketoacidosis Nonketotic hyperglycemia, occasionally ketoacidosis

GAD, glutamic acid decarboxylase; IA-2/IA-2β, tyrosine phosphatases; IAA, insulin autoantibodies, ICA, islet cell antibody; ICA512, islet cell autoantigen 512 (fragment of IA-2).

From Andreoli TE (ed): Cecil Essentials of Medicine, 6th ed. Philadelphia, Saunders, 2005.

Detection and DX of Gestational DM (GDM)

square-bullet OGTT
square-bullet Women with GDM should be screened for diabetes 6 to 12 wk post partum.

Lab Screening in Diabetics

square-bullet Screening for diabetic retinopathy: Alb/Cr ratio (microalb) in a random spot urine collection or by 24-hr urine collection for alb, CrCl
square-bullet Dx of microalbuminuria (30-299 mg/24 hr) should be based on 2 to 3 ↑ levels within a 3- to 6-mo period because of marked variability in day-to-day alb excretion
square-bullet Labs in DM: HBA1c, urine microalbumin, fasting lipid panel, serum Cr, and electrolytes; TSH, vitamin B12 level, IgA TTG Ab (for celiac disease screen) in type 1 DM
square-bullet Daily monitoring with glucose test strips: type 1 DM and pregnant women on insulin ≥3 ×/day. T2 DM not on insulin, 1-2×/day

Treatment

ADA and European Association for the Study of Diabetes recommend: “Intervention at the time of Dx with metformin in combination with life style changes (diet and exercise) and continuing timely augmentation of Rx with additional agents (including early initiation of insulin Rx) as a means of achieving adequate glycemic control
1. Diet
a. Calories
i. Start with 15 calories/lb of ideal body weight; ↑ 20 calories/lb for an active person and 25 calories/lb if the pt does heavy physical labor.
ii. The calories are distributed as 45% to 65% carbohydrates; <30% fat, with saturated fat limited to <7% of total calories; and 10% to 30% protein; daily cholesterol <300 mg.
iii. The emphasis should be on complex carbohydrates rather than simple and refined starches and on polyunsaturated instead of saturated fats in a ratio of 2:1.
iv. The glycemic index compares the ↑ in blood sugar after the ingestion of simple sugars and complex carbohydrates with the ↑ that occurs after the absorption of.
2. Exercise: Exercise program must be individualized and built up slowly. Consider beginning with 15 min of low-impact aerobic exercise 3 ×/wk and increasing the frequency and duration to 30 to 45 min of moderate aerobic activity (50% to 70% of maximum age predicted heart rate) to 3 to 5 days/wk. In the absence of contraindications, resistance training 3 ×/wk should be encouraged.
3. Weight loss: to ideal body weight if the pt is overweight
Maintain HbA1c <7%. HbA1c 7.5 or higher may be reasonable in elderly pts with limited life expectancy and ↑ risk of hypoglycemia.
When the previous measures fail, oral hypoglycemic agents (Table 5-2) should be added to the regimen in type 2 DM. If renal function is not significantly impaired (creat < 1.3), metformin is the preferred initial hypoglycemic agent. GLP-1 agonists and dipeptidyl peptidase-4 inhibitions are preferred as additional oral hypoglycemics but cost is a limiting factor, especially in elderly patients.
Insulin: indicated for all pts with type 1 DM and for pts with type 2 DM whose condition cannot be adequately controlled with diet and oral agents. Insulin Rx may be started with oral agents at 0.3 unit/kg, or as replacement, starting at 0.6 to 1 unit/kg. Table 5-3 describes commonly used types of insulin.
a. The risks of insulin Rx include weight gain, hypoglycemia, and in rare cases, allergic or cutaneous reactions.
b. Replacement insulin Rx should mimic nl release patterns.
i. 50% to 60% of daily insulin can be given as a long-acting insulin (NPH, ultralente, glargine, detemir) injected qd or bid.
ii. 40% to 50% can be short-acting (regular) or rapid-acting (lispro, aspart, glulisine) to cover mealtime carbohydrates and correct ↑ current glucose levels.
Continuous subcutaneous insulin infusion (CSII, or insulin pump) provides better glycemic control than does conventional Rx. It should be considered for DM in childhood or adolescence and during pregnancy.
The Diabetes Control and Complications Trial (DCCT) showed that intensive Rx for glucose control ↓ the development and progression of complications of type 1 DM. In this trial, the risks for retinopathy, nephropathy, and neuropathy were ↓ by 70%, 54%, and 64%, respectively.
Low-dose aspirin (ASA; 81 mg/day): for primary prevention in diabetic pts with one additional CV risk factor, including age >40 yr, cigarette smoking, HTN, obesity, albuminuria, hyperlipidemia, and family hx of CAD
Statins: DM >40 yr with ≥1 risk factor for CAD; LDL goal <100 mg/dL, <70 mg/dL if overt CAD
BP control: SBP <130 DBP <80 mm Hg. Use ACEI to ↓ albuminuria and prevent CKD regardless of presence of HTN.
Bariatric surgery: consider in adults with BMI >35 kg/m2 and type 2 diabetes
Hypoglycemia Rx: conscious person → glucose tab or gel 15 to 20 g; unconscious → IM glucagon
Neuropathy Rx: duloxetine, pregabalin, gabapentin
Diabetic gastroparesis Rx: endoscopic injection of botulinum toxin into the pylorus and gastric electrical stimulation (using f electrodes placed laparoscopically in the muscle wall of the stomach antrum and connected to a neurostimulator)
Nephropathy: ACEIs or ARBs (if intolerant to ACEIs)
Glycemic control in hospitalized pts: Avoid intensive insulin Rx. The ACP recommends a target blood glucose level of 140 to 200 mg/dL if insulin Rx is used. Table 5-4 describes an insulin sliding scale.

1. Diabetic Ketoacidosis

Metabolic decompensation in diabetic pts usually precipitated by an infectious process (≤40% of cases). Poor compliance w/insulin Rx and severe medical illness (e.g., CVA, MI) are other common causes. Consider cocaine abuse in middle age DM w/multiple DKA admissions.

Diagnosis

PE
square-bullet Evidence of dehydration (tachycardia, hypotension, dry mucous membranes, sunken eyeballs, poor skin turgor)
square-bullet Clouding of mental status
square-bullet Tachypnea w/air hunger (Kussmaul’s respiration)
square-bullet Fruity breath odor (caused by acetone)

TABLE 5-2

Oral Antidiabetic Agents and Monotherapy

Sulfonylureas Biguanides α-Glucosidase Inhibitors Incretin Mimetics Meglitinides Dipeptidyl Peptidase-4 Inhibitor
Generic name Glimepiride, glyburide, glipizide, chlorpropamide, tolbutamide Metformin Acarbose, miglitol Exanatide, liraglutide Repaglinide, nateglinide Sitagliptin, linagliptin, saxagliptin
Mode of action ↑↑ Pancreatic insulin secretion chronically ↓↓HGP; ↓ peripheral IR; ↓ intestinal glucose absorption Delays PP digestion of carbohydrates and absorption of glucose ↑ Insulin secretion ↑↑ Pancreatic insulin secretion acutely Potentiates insulin synthesis and release
Preferred patient type Diagnosis age >30 yr, lean, diabetes <5 yr, insulinopenic Overweight, IR, fasting hyperglycemia, dyslipidemia PP hyperglycemia Type 2 DM PP hyperglycemia, insulinopenic
Therapeutic effects
↓ HBA1c (%) 1-2 1-2 0.5-1 ↓ HBA1c by 0.7 -0.9 1-2 ↓ HBA1c by 0.5%
↓ FPG (mg/dL) 50-70 50-80 15-30 40-80
↓ PPG (mg/dL) ≈90 80 40-50 30
Insulin levels
Weight —/↓
Lipids ↓ LDL
↓↓TG
Side effects Hypoglycemia Diarrhea, lactic acidosis Abdominal pain, flatulence, diarrhea Nausea, headache, diarrhea Hypoglycemia (low risk)
Dose(s)/day 1-3 2-3 1-3 Variable from daily to weekly 1-4+ 1
Maximum daily dose (mg) Depends on agent 2550 150 (<60-kg BW)
300 (>60-kg BW)
16 (repaglinide)
360 (nateglinide)
100
Range/dose (mg) Depends on agent 500-1000 25-50 (<60-kg BW)
25-100 (>60-kg BW)
0.5-4 (repaglinide)
60, 120 (nateglinide)
50-100
Optimal administration time ≈30 min premeal (some with food, others on empty stomach) With meal With first bite of meal Preferably <15 (0-30 min) before meals (omit if no meal)
Main site of metabolism/excretion Hepatic/renal, fecal Not metabolized/renal Only 2% absorbed/fecal Renal Hepatic/fecal

image

HGP, Hepatic glucose production; IR, insulin resistance; PP, postprandial; PPG, postprandial plasma glucose.

Values combined from numerous studies; values are also dose dependent.

From Andreoli TE (ed): Cecil Essentials of Medicine, 6th ed. Philadelphia, Saunders, 2005.

TABLE 5-3

Types of Insulin

Preparation Brand Onset (hr) Peak (hr) Duration (hr) Route
Insulin aspart NovoLog <0.25 1-3 3-5 SC
Insulin aspart protamine/insulin aspart NovoLog Mix 70/30 <0.25 1-4 24 SC
Insulin detemir Levemir 1 None 24 SC
Insulin glargine Lantus 1.1 None ≥24 SC
Insulin glulisine Apidra ≤0.25 1 2-4 SC, IV§
Insulin lispro Humalog <0.25 1 3.5-4.5 SC
Insulin lispro protamine/insulin lispro Humalog Mix 75/25 ≤0.25 0.5-1.5 24 SC
Humalog Mix 50/50 ≤0.25 1 16 SC
Insulin injection regular (R) Humulin R 0.5 2-4 6-8 SC, IM, IV
Novolin R 0.5 2.5-5 8 SC, IM, IV
Insulin isophane suspension (NPH)/regular insulin (R) Humulin 70/30 0.5 2-12 24 SC
Humulin 50/50 0.5 3-5 24 SC
Novolin 70/30 0.5 2-12 24 SC
Insulin isophane suspension (NPH) Humulin N 1-2 6-12 18-24 SC
Novolin N 1.5 4-12 24 SC

image

Injectable insulins listed are available in a concentration of 100 units/mL; Humulin R, in a concentration of 500 unit/mL for SC injection only, is available by prescription from Lilly for insulin-resistant patients who are hospitalized or under close medical supervision.

Recombinant (using E. coli).

Recombinant human insulin analogue (using E. coli).

Recombinant (using S. cerevisiae).

§ IV to be used in a clinical setting under proper medical supervision.

From Ferri FF: Ferri’s Clinical Advisor 2010. Philadelphia, Mosby, 2010.

TABLE 5-4

Regular Insulin (SC) Sliding Scale

Finger Stick Blood Glucose Mild Scale Moderate Scale Aggressive Scale
<60 1 amp (25 g) D50 or orange juice, call MD 1 amp D50 or orange juice, call MD 1 amp D50 or orange juice, call MD
60-150 No insulin No insulin No insulin
151-200 No insulin 3 units 4 units
201-250 2 units 5 units 6 units
251-300 4 units 7 units 10 units
301-350 6 units 9 units 12 units
351-400 8 units 11 units 15 units
>400 10 units, call physician 13 units, call physician 18 units, call physician

image

From Nguyen TC, Abilez OJ (eds): Practical Guide to the Care of the Surgical Patient: The Pocket Scalpel. Philadelphia, Mosby, 2009.

square-bullet Lipemia retinalis in some pts
square-bullet Possible evidence of precipitating factors (infected wound, pneumonia)
square-bullet Abd tenderness in some pts
Labs
square-bullet Glucose level is generally >250 mg/dL; urine and serum ketones (+) (usually 7-10 mmol/L).
square-bullet ABGs reveal acidosis: arterial pH usually <7.30 w/Pco2 >40 mm Hg.
square-bullet Serum electrolytes:
Serum bicarbonate is usually <18 mEq/L.
Serum K+: may be ↓, nl, or ↑. There is always significant total body K+ depletion regardless of the K+ level.
Serum Na+: usually ↓ (pseudohyponatremia) as a result of ↑↑ glucose, dehydration, and lipemia. Assume 1.6 mEq/L ↓ in extracellular Na+ for each 100 mg/dL↑ in glucose.
Calculate the AG: AG = Na+ (Cl + HCO3).
In DKA, the AG is ↑ (generally >15); hyperchloremic metabolic acidosis may be present in unusual circumstances when both the GFR and the plasma volume are well maintained.

image

FIGURE 5-1 Management of DKA and HHS. (From Goldman L, Schafer AI [eds]: Goldman’s Cecil Medicine, 24th ed. Philadelphia, Saunders, 2012.)

square-bullet CBC w/diff, U/A, urine and blood cultures to r/o infectious precipitating factor
square-bullet Serum Ca2+, Mg2+, and PO4-3; plasma PO4-3and Mg2+ levels may be significantly depressed and should be rechecked within 24 hr because they may ↓ further w/correction of DKA.
square-bullet ↑ BUN and Cr secondary to significant dehydration
square-bullet Amylase, LFTs should be checked in pts w/abd pain.
Imaging
CXR is helpful to r/o infectious process. The initial CXR may be nl if the pt has significant dehydration. Repeat CXR after 24 hr if pulmonary infection is strongly suspected.

Treatment

square-bullet Fluid replacement (the usual deficit is 6-8 L), insulin Rx, electrolyte replacement
square-bullet Consider bicarbonate Rx (Fig. 5-1).

2. Hyperosmolar Non-Ketotic Coma, Honk

Definition

This is a state of extreme hyperglycemia, marked dehydration, serum hyperosmolarity, mental status changes, and absence of ketoacidosis.

Etiology

square-bullet Infections, 20% to 25% (e.g., pneumonia, UTI, sepsis)
square-bullet New or previously unrecognized diabetes (30%-50%)
square-bullet Reduction or omission of diabetic medication
square-bullet Stress (MI, CVA)
square-bullet Drugs: diuretics (dehydration), phenytoin, diazoxide (impaired insulin secretion)

Diagnosis

H&P
square-bullet Evidence of extreme dehydration (poor skin turgor, sunken eyeballs, dry mucous membranes)
square-bullet Neurologic defects (reversible hemiplegia, focal seizures)
square-bullet Orthostatic hypotension, tachycardia
square-bullet Evidence of precipitating factors (pneumonia, infected skin ulcer)
square-bullet Coma (25% of pts), delirium
Labs
square-bullet Hyperglycemia: serum glucose usually >600 mg/dL
square-bullet Hyperosmolarity: serum osmolarity usually >340 mOsm/L
square-bullet Serum Na+: may be ↓, nl, or ↑; if nl or ↑, the pt is severely dehydrated because glucose draws fluid from intracellular space = ↓ serum Na+; the corrected Na+ can be obtained by the serum Na+ concentration by ↑ 1.6 mEq/dL for every 100 mg/dL ↓ in the serum glucose level above nl.
square-bullet Serum K+: may be ↓, nl, or ↑; regardless of the initial serum level, the total body deficit is approximately 5 to 15 mEq/kg.
square-bullet Serum bicarbonate: usually >12 mEq/L (average is 17 mEq/L)
square-bullet Arterial pH: usually >7.2 (average is 7.26). Both serum bicarbonate and arterial pH may be lower if lactic acidosis is present.
square-bullet ↑ BUN: Azotemia (prerenal) is usually present (BUN generally ranges from 60-90 mg/dL).
square-bullet ↓ PO4-3: hypophosphatemia (average deficit is 70-140 mM)
square-bullet ↓ Ca2+: hypocalcemia (average deficit is 50-100 mEq)
square-bullet ↓ Mg2+: hypomagnesemia (average deficit is 50-100 mEq)
square-bullet CBC w/diff, U/A, blood and urine cultures should be performed to r/o infectious etiology.

Treatment

square-bullet Vigorous IV fluid replacement, electrolyte replacement, insulin Rx (see Fig. 5-1)

B. Hypoglycemia

Definition

Hypoglycemia can be arbitrarily defined as a plasma glucose level <50 mg/dL. To establish the dx, the following 3 criteria are necessary:
square-bullet Presence of sx
Adrenergic: sweating, anxiety, tremors, tachycardia, palpitations
Neuroglycopenic: seizures, fatigue, syncope, headache, behavior changes, visual disturbances, hemiplegia
square-bullet ↓ Plasma glucose level in symptomatic pt
square-bullet Relief of sx after ingestion of carbohydrates

Etiology

square-bullet Reactive hypoglycemia
Hypoglycemia usually occurs 2 to 4 hr after a meal rich in carbohydrates.
These pts never have sx in the fasting state and rarely experience loss of consciousness secondary to their hypoglycemia.
Pts who have had subtotal gastrectomy rapidly absorb carbohydrates. This causes an early plasma glucose level followed by a late insulin surge that reaches its peak when most of the glucose has been absorbed and that results in hypoglycemia.
Pts with type 2 (non–insulin-dependent) diabetes can experience hypoglycemia 3 to 4 hr postprandially secondary to a delayed and prolonged second phase of insulin secretion.
Congenital deficiencies of enzymes necessary for carbohydrate metabolism and functional (idiopathic) hypoglycemia are additional causes of reactive hypoglycemia.
square-bullet Fasting hypoglycemia
Sx usually appear in the absence of food intake (at night or during early morning).
Etiology: insulinoma, mesenchymal tumors that synthesize insulin-like hormones, adrenal failure, glycogen storage disorders, severe liver disease or renal disease
square-bullet Iatrogenic or drug-induced: hypoglycemic drugs, excessive insulin replacement, factitious, ethanol-induced hypoglycemia

Diagnosis

square-bullet When the plasma glucose level is ↓ (e.g., fasting state), the plasma insulin level should also be ↓. Any pt presenting w/fasting hypoglycemia of unexplained cause should have the following tests drawn during the hypoglycemic episode (Table 5-5):
Plasma glucose
Plasma insulin level
Plasma C-peptide
Plasma and urine metabolites of sulfonylurea levels and meglitinides
square-bullet Factitious hypoglycemia should be considered, especially if the pt has ready access to insulin or oral hypoglycemic agents (e.g., medical or paramedical personnel, family members who are diabetic or in the medical profession).
square-bullet Pancreatic islet cell neoplasms (insulinomas) are usually small (<3 cm), single, insulin-producing adenomas. Measurement of inappropriately serum insulin levels despite ↓ plasma glucose level after prolonged fasting (24-72 ↑ hr) is pathognomonic of these neoplasms.

TABLE 5-5

Hypoglycemia in Nondiabetic Pt. Laboratory Differentiation of Factitious Hypoglycemia and Insulinoma

Lab Insulinoma Exogenous Insulin Oral Hypoglycemic Agents (Sulfonylurea/Meglitinides)
Plasma glucose
Serum insulin ↑↑
Plasma and urine sulfonylureas/meglitinides Absent Absent Present
C-peptide N/↓

image

Treatment

square-bullet Variable, depending on etiology of hypoglycemia

C. Anterior Pituitary Disorders

1. Hypopituitarism

Partial or complete loss of secretion of one or more pituitary hormones results from diseases of the hypothalamus or pituitary gland.

Etiology

Hypopituitarism is the result of destruction of pituitary cells caused by
square-bullet Pituitary tumors
Macroadenomas >10 mm
Microadenomas ≤10 mm
square-bullet Pituitary apoplexy caused by hemorrhage or infarction of the pituitary gland
square-bullet Pituitary radiation Rx
square-bullet Pituitary surgery
square-bullet Empty sella syndrome w/enlargement of the sella turcica and flattening of the pituitary gland (from extension of the subarachnoid space and filling of CSF into the sella turcica)
square-bullet Infiltrative disease including sarcoidosis, hemochromatosis, histiocytosis X, Wegener’s granulomatosis, and lymphocytic hypophysitis
square-bullet Infection (TB, mycosis, and syphilis)
square-bullet Head trauma
square-bullet Internal carotid artery aneurysm

Diagnosis

H&P
Sx are related to the lack of one or more hormones or mass effect.
square-bullet Mass effect → headaches, visual field disturbances
square-bullet Corticotropin deficiency
Fatigue and weakness
Hypotension, hair loss
square-bullet Thyrotropin deficiency
Fatigue and weakness, weight gain, cold intolerance, constipation
Bradycardia, ↓ DTR, pretibial edema, hair loss
square-bullet Gonadotropin deficiency
Loss of libido, erectile dysfunction, amenorrhea, hot flashes, dyspareunia, infertility
Gynecomastia w/lack of hair growth and ↓ muscle mass
square-bullet GH deficiency
Growth retardation in children
Fatigue, hypoglycemia
↓ Muscle mass, obesity
square-bullet Hyperprolactinemia
Galactorrhea
Hypogonadism
square-bullet Vasopressin deficiency
Polyuria, polydipsia
Hypotension, dehydration
Baseline Labs
square-bullet Corticotropin deficiency:
↓ Serum AM cortisol level (<3 g/dL)
square-bullet Thyrotropin deficiency:
TSH and free T4 measurements
Primary hypothyroidism: ↑ TSH, ↓ free T4
Secondary hypothyroidism: nl/↓ TSH, ↓ free T4
square-bullet Gonadotropin deficiency:
FSH, LH, estrogen, and testosterone measurements
In men ↓ testosterone levels, nl/↓ FSH and LH levels
In premenopausal women w/amenorrhea, ↓ estrogen w/nl/↓ FSH and LH levels
square-bullet GH deficiency:
↓ Serum IGF-1
Provocative testing for pituitary insufficiency is summarized in Table 5-6.
Imaging
square-bullet MRI of pituitary

Treatment

square-bullet Hormone replacement Rx and surgery, irradiation, or medications in pts w/pituitary tumors
square-bullet Acute situations such as adrenal crisis and myxedema coma are discussed separately.
square-bullet Long-term Rx: lifelong and requires the following hormone replacement Rx:
ACTH deficiency: hydrocortisone 20 mg PO q AM and 10 mg PO q PM or prednisone 5 mg PO q AM and 2.5 mg PO q PM. Dexamethasone or prednisone is often preferred because of longer duration of action.
LH and FSH deficiency:
In men, testosterone replacement
In women who are not interested in fertility, conjugated estrogen 0.3 to 1.25 mg/day and held the last 5 to 7 days of each month w/the addition of medroxyprogesterone 10 mg/day given during days 15 to 25 of the nl menstrual cycle. In those who have secondary hypogonadism and wish to become pregnant, pulsatile GnRH may be of benefit.

TABLE 5-6

Tests of Pituitary Insufficiency

Hormone Test Interpretation
Growth hormone (GH) Insulin tolerance test: Regular insulin (0.05-0.15 U/kg) is given IV and blood is drawn at 30, 0, 30, 45, 60, and 90 min for measurement of glucose and GH. If hypoglycemia occurs (glucose <40 mg/dL), GH should increase to >5 μg/L.
Arginine-GHRH test: GHRH 1 μg/kg IV bolus followed by 30-min infusion of l-arginine (30 g) Normal response is GH > 4.1 μg/L.
Glucagon test: 1 mg IM with GH measurements at 0, 60, 90,120, 150 and 180 min Normal response is GH >3 μg/L.
Adrenocorticotropic hormone (ACTH) Insulin tolerance test: Regular insulin (0.05-0.15 U/kg) is given IV and blood is drawn at 30, 0, 30, 45, 60, and 90 min for measurement of glucose and cortisol. If hypoglycemia occurs (glucose <40 mg/dL), cortisol should increase by >7 μg/dL or to >20 μg/dL.
CRH test: 1 μg/kg ovine CRH IV at 8 am with blood samples drawn at 0, 15, 30, 60, 90, 120 min for measurement of ACTH and cortisol In most normal individuals, the basal ACTH increases twofold to fourfold and reaches a peak (20-100 pg/mL). ACTH responses may be delayed in cases of hypothalamic dysfunction. Cortisol levels usually reach 20-25 μg/dL.
Metyrapone test: Metyrapone (30 mg/kg to max 2 g) at midnight with measurements of plasma 11-deoxycortisol and cortisol at 8 am. ACTH can also be measured. A 3-day test is also available. Basal cortisol should be >5-6 μg/dL before test. A normal response is 11-deoxycortisol >7.5 μg/dL or ACTH >75 pg/mL. Plasma cortisol should fall below 4 μg/dL to ensure an adequate response.
ACTH stimulation test: ACTH 1-24 (cosyntropin), 0.25 mg IM or IV. Cortisol is measured at 0, 30, and 60 min. A normal response is cortisol >18 μg/dL. In suspected hypothalamic-pituitary deficiency, a low-dose (1-μg) test may be more sensitive.
Thyroid-stimulating hormone (TSH) Basal thyroid function tests: free T4, free T3, TSH Low free thyroid hormone levels in the setting of TSH levels that are not appropriately increased.
Luteinizing hormone (LH), follicle-stimulating hormone (FSH) Basal levels of LH, FSH, testosterone, estrogen Basal LH and FSH should be increased in postmenopausal women. Low testosterone levels in conjunction with low or low-normal LH and FSH are consistent with gonadotropin deficiency.
GnRH test: GnRH (100 μg) IV with measurements of serum LH and FSH at 0, 30, and 60 min In most normal persons, LH should increase by 10 IU/L and FSH by 2 IU/L. Normal responses are variable, and repeated stimulation may be required.
Clomiphene test: Clomiphene citrate (100 mg) is given orally for 5 days. Serum LH and FSH are measured on days 0, 5, 7, 10, and 13. A 50% increase should occur in LH and FSH, usually by day 5.
Multiple hormones Combined anterior pituitary test: GHRH (1 μg/kg), CRH (1 μg/kg), GnRH (100 μg) are given sequentially IV. Blood samples are drawn at 30, 15, 30, 60, 90, and 120 min for measurements of GH, ACTH, LH, and FSH. Combined or individual releasing hormone responses must be evaluated in the context of basal hormone values and may not be diagnostic (see text).

Values are with polyclonal assays.

From Goldman L, Schafer AI (eds): Goldman’s Cecil Medicine, 24th ed. Philadelphia, Saunders, 2012.

square-bullet TSH deficiency: levothyroxine 0.05 to 0.15 mg/day
square-bullet GH deficiency: GH is generally not used in adults; however, it can be given at 0.04 to 0.08 mg/kg/day SC in children.
square-bullet ADH deficiency: Desmopressin (DDAVP) 10 to 20 μg by intranasal spray or 0.05 to 0.1 mg PO bid is used in pts w/DI.

2. Anterior Pituitary Hyperfunction Secondary to Pituitary Neoplasms

square-bullet Pituitary adenomas are classified by their size (macroadenomas ≥10 mm) and function
GH→ acromegaly
PRL→ prolactinoma
ACTH→ Cushing’s disease

H&P

Prolactinomas
square-bullet Females: galactorrhea, amenorrhea, oligomenorrhea with anovulation, infertility
square-bullet Estrogen deficiency leading to hirsutism, ↓ vaginal lubrication, osteopenia
square-bullet Males: ↓ libido or hypogonadism
GH-Secreting Pituitary Adenoma: Acromegaly
square-bullet Coarse facial features, oily skin, prognathism, carpal tunnel syndrome
square-bullet Osteoarthritis, hx of ↑ hat, glove, or shoe size, visual field deficits
Corticotropin-Secreting Pituitary Adenoma: Cushing’s Disease
square-bullet Truncal obesity, round facies (moon face)
square-bullet Dorsocervical fat accumulation (buffalo hump), hirsutism, acne, menstrual disorders
square-bullet HTN, striae, bruising, thin skin, hyperglycemia
Thyrotropin-Secreting Pituitary Adenoma
square-bullet Sx: thyrotoxicosis, goiter, visual impairment

Diagnosis

Prolactinoma
square-bullet ↑ PRL levels are correlated with tumor size.
square-bullet Level >200 ng/mL is diagnostic, with levels of 100 to 200 ng/mL being equivocal.
Acromegaly
square-bullet First screening tests are the measurement of serum IGF-1 ↑, postprandial serum GH, and TRH stimulation test.
square-bullet Follow with an OGTT.
square-bullet Failure to suppress serum GH to <2 ng/mL with an oral load of 100 g glucose is considered conclusive.
square-bullet A GH-releasing hormone level >300 ng/mL is indicative of an ectopic source of GH.
Cushing’s Disease
square-bullet Nl or slightly ↑ corticotropin levels ranging from 20 to 200 pg/mL
square-bullet Level <10 pg/mL usually indicates an autonomously secreting adrenal tumor.
square-bullet Level >200 pg/mL suggests an ectopic corticotropin-secreting neoplasm.
square-bullet Cushing’s disease can be assessed by absence of cortisol suppression with the low-dose dexamethasone test but with the presence of cortisol suppression after the high-dose test.
square-bullet 24-hr urine collection should demonstrate an ↑ level of cortisol excretion.
Thyrotropin-Secreting Pituitary Adenoma
square-bullet Highly sensitive thyrotropin assays, which evaluate the presence of thyrotoxicosis, are among the ways to detect a thyrotropin-secreting tumor.
square-bullet Free α subunit is secreted by >80% of tumors, with the ratio of the α subunit to thyrotropin <1.
square-bullet With central resistance to thyroid hormone, the ratio is <1.
square-bullet ↑ serum levels of both T3 and T4
Imaging
square-bullet MRI of the pituitary and hypothalamus
square-bullet CT scan only when MRI is unavailable or is otherwise contraindicated

Treatment

Surgery
square-bullet Selective transsphenoidal resection of the adenoma is used for acromegaly, Cushing’s disease, and thyrotropin-secreting pituitary adenomas.
square-bullet RadioRx is reserved for pts who have not responded to surgical Rx and who still have sx of the adenoma.
square-bullet Bilateral adrenalectomy is performed in pts with Cushing’s disease after failure of other therapies; complications requiring lifelong hormone replacement or Nelson’s syndrome may occur.
RadioRx
square-bullet Generally reserved for pts who have not responded to surgical Rx
square-bullet Used with varying degrees of success in all the different pituitary adenomas
Medical
Prolactinoma
square-bullet Bromocriptine or cabergoline

Acromegaly
square-bullet Octreotide
Cushing’s Disease
square-bullet Ketoconazole, which inhibits the cytochrome P-450 enzymes involved in steroid biosynthesis, is effective in managing mild to moderate disease in daily oral doses of 600 to 1200 mg.
square-bullet Metyrapone and aminoglutethimide can be used to control hypersecretion of cortisol but are generally used when preparing a pt for surgery or while waiting for a response to radioRx.
Thyrotropin-Secreting Pituitary Adenoma
square-bullet Ablative Rx with either radioactive iodide or surgery
square-bullet Octreotide

D. Fluid Hemostasis Disorders

1. Diabetes Insipidus (DI)

Definition

This polyuric disorder results from insufficient production of ADH (pituitary [central, neurogenic] DI) or unresponsiveness of the renal tubules to ADH (nephrogenic DI).

Etiology

Central (Neurogenic) DI
square-bullet Idiopathic
square-bullet Neoplasms of brain or pituitary fossa (craniopharyngiomas, metastatic neoplasms from breast or lung)
square-bullet Post-therapeutic neurosurgical procedures (e.g., hypophysectomy)
square-bullet Head trauma (e.g., basal skull fx)
square-bullet Granulomatous disorders (sarcoidosis or TB)
square-bullet Histiocytosis (Hand-Schüller-Christian disease, eosinophilic granuloma)
square-bullet Familial (autosomal dominant)
square-bullet Other: interventricular hemorrhage, aneurysms, meningitis, postencephalitis, MS
Nephrogenic DI
square-bullet Drugs: lithium, amphotericin B, demeclocycline, methoxyflurane anesthesia
square-bullet Familial: X-linked
square-bullet Metabolic: hypercalcemia or hypokalemia
square-bullet Other: sarcoidosis, amyloidosis, pyelonephritis, polycystic disease, sickle cell disease, postobstructive condition

Diagnosis

H&P
square-bullet Polyuria: urinary volumes ranging from 2.5 to 6 L/day
square-bullet Polydipsia (predilection for cold or iced drinks)
square-bullet Neurologic manifestations (seizures, headaches, visual field defects)
square-bullet Evidence of volume contractions
Labs
square-bullet ↓ Urine specific gravity (≤1.005)
square-bullet ↓ Urine osmolality (usually <200 mOsm/kg) even in the presence of high serum osmolality
square-bullet Hypernatremia, plasma osmolarity, hypercalcemia, hypokalemia
square-bullet Water deprivation test confirms dx.
Imaging
square-bullet MRI of the brain if neurogenic DI is confirmed

Treatment

square-bullet Central DI: desmopressin acetate (DDAVP)
square-bullet Nephrogenic DI: adequate hydration, low-Na+ diet and chlorothiazide to induce mild Na+ depletion, amiloride 5 mg PO bid initially

2. Syndrome of Inappropriate Antidiuretic Hormone (SIADH, SIAD) Secretion

This syndrome is characterized by excessive secretion of ADH in absence of nl osmotic or physiologic stimuli.

Etiology

square-bullet Neoplasm: lung, oropharynx, stomach, duodenum, pancreas, brain, thymus, bladder, prostate, endometrium, mesothelioma, lymphoma, Ewing’s sarcoma
square-bullet Pulmonary disorders: pneumonia, aspergillosis, pulmonary abscess, TB, bronchiectasis, emphysema, CF, status asthmaticus, respiratory failure associated w/positive-pressure breathing
square-bullet Intracranial disease: trauma, neoplasms, infections (meningitis, encephalitis, brain abscess), hemorrhage, hydrocephalus, MS, GBS
square-bullet Postoperative period: surgical stress, ventilators w/positive pressure, anesthetic agents
square-bullet Drugs: nicotine, chlorpropamide, thiazide diuretics, vasopressin, desmopressin, oxytocin, chemotherapeutic agents (vincristine, vinblastine, cyclophosphamide), carbamazepine, phenothiazines, MAOIs, tricyclic antidepressants, narcotics, nicotine, clofibrate, haloperidol, SSRIs, NSAIDs
square-bullet Other: acute intermittent porphyria, myxedema, psychosis, delirium tremens, ACTH deficiency (hypopituitarism), general anesthesia, endurance exercise

Diagnosis

H&P
square-bullet Delirium, lethargy, and seizures may be present if the hyponatremia is severe or of rapid onset.
square-bullet Manifestations of the underlying disease may be evident (e.g., fever from an infectious process or headaches and visual field defects from an intracranial mass).
square-bullet ↓ DTR and extensor plantar responses may occur w/severe hyponatremia.
square-bullet The pt is generally normovolemic or slightly hypervolemic; edema is absent.
Labs
square-bullet Demonstration through laboratory evaluation of excessive secretion of ADH in absence of appropriate osmotic or physiologic stimuli. Labs reveal
Hyponatremia
Urinary osmo > serum osmo
Urinary Na+ >30 mEq/L
Normal BUN, Cr (indicative of nl renal function and absence of dehydration)
↓ Uric acid
square-bullet For diagnostic purposes, pt should have nl thyroid, adrenal, and cardiac function and no recent or concurrent use of diuretics.
Imaging
square-bullet CXR: r/o neoplasm, pneumonia

Treatment

square-bullet In emergency situations (seizures, coma), SIADH can be treated w/combination of
Hypertonic saline solution (slow infusion of 250 mL of 3% NaCl). Infuse 3% saline (513 mmol/L) at a rate of 1 to 2 mL/kg of BW/hr to ↑ serum Na+ by 1-2 mmol/L/hr.
Furosemide, 20 to 40 mg IV: ↑ serum Na+ concentration by causing diuresis of urine that is more dilute than plasma and prevents extracellular fluid volume expansion.
square-bullet The rapidity of correction varies according to the degree of hyponatremia and if the hyponatremia is acute or chronic; in general, the serum Na+ concentration should be corrected only halfway to nl in the initial 24 hr. A prudent approach is to ↑ serum Na+ concentration by <0.5 mEq/L/hr and to limit the total ↑ to 8 to 12 mmol/L during the first 24 hr.
square-bullet Close monitoring of the rate of correction (every 2-3 hr) is recommended to avoid overcorrection. In pts w/hyponatremia of chronic duration, correction of serum Na+ level by >12 mmol/L during a period of 24 hr = ↑ risk of osmotic demyelination.
square-bullet Conivaptan (20-40 mg/day IV) and tolvaptan (15 mg PO initially) are selective arginine vasopressin (AVP) antagonists useful in selected hospitalized pts w/moderate to severe hyponatremia. Potential problems associated w/their use are infusion site reactions (50% of pts) and risk of osmotic demyelination if serum Na+ levels are corrected too rapidly.
Long-term Rx
square-bullet Depending on the underlying cause, fluid restriction may be needed indefinitely. Monthly monitoring of electrolytes is recommended in pts w/chronic SIADH.
square-bullet Demeclocycline 300 to 600 mg PO bid: useful in pts w/chronic SIADH (e.g., secondary to neoplasm), but use w/caution in pts w/hepatic disease; side effects include nephrogenic DI and photosensitivity. This medication is also very expensive.

Clinical Pearl

square-bullet SIAD is the most frequent cause of hyponatremia (50% of hyponatremia cases in hospital setting).

E. Thyroid Disorders

1. Interpretation of Thyroid Function Studies

image

FIGURE 5-2 Diagnostic approach to thyroid testing. N, normal.

TABLE 5-7

Findings in Thyroid Function Tests in Various Clinical Conditions

Condition T4 FT4I T3 FT3I TSH TSI TRH Stimulation
Hyperthyroidism
Graves’ disease +
Toxic nodular goiter
Pituitary TSH-secreting tumors
T3 thyrotoxicosis N N +,
T4 thyrotoxicosis N N +,
Hypothyroidism
Primary +,
Secondary ↓, N
Tertiary ↓, N N
Peripheral unresponsiveness ↑, N ↑, N ↑, N ↑, N N, ↑

image

-, variable; FT3I, free T3 index; FT4I, free T4 index; TSI, thyroid-stimulating immunoglobulin.

From Tilton RC, Barrows A: In Hohnadel DC, Reiss R (eds): Clinical Laboratory Medicine. St. Louis, Mosby, 1992.

2. Hyperthyroidism

Etiology

square-bullet Graves’ disease (diffuse toxic goiter): 80% to 90% of all cases of hyperthyroidism
square-bullet Toxic multinodular goiter (Plummer’s disease)
square-bullet Toxic adenoma
square-bullet Iatrogenic and factitious
square-bullet Transient hyperthyroidism (subacute thyroiditis, Hashimoto’s thyroiditis)
square-bullet Rare causes: hypersecretion of TSH (e.g., pituitary neoplasms), struma ovarii, ingestion of large amount of iodine in a pt w/preexisting thyroid hyperplasia or adenoma (Jod-Basedow phenomenon), hydatidiform mole, carcinoma of thyroid, amiodarone Rx

Diagnosis

H&P
square-bullet Tachycardia, tremor, hyperreflexia, anxiety, irritability, emotional lability, panic attacks, heat intolerance, sweating, appetite, diarrhea, weight loss, menstrual dysfunction (oligomenorrhea, amenorrhea). The presentation may be different in elderly pts (see later).
square-bullet Pts w/Graves’ disease may present w/exophthalmos, lid retraction, lid lag (Graves’ ophthalmopathy). The following signs and sx of ophthalmopathy may be present: blurring of vision, photophobia, lacrimation, double vision, deep orbital pressure. Clubbing of fingers associated w/periosteal new bone formation in other skeletal areas (Graves’ acropachy) and pretibial myxedema may also be noted.
Labs (Fig. 5-3)
square-bullet ↑ Free T4
square-bullet ↑ Free T3: generally not necessary for dx
square-bullet ↓ TSH (unless hyperthyroidism is a result of the rare hypersecretion of TSH from a pituitary adenoma in which case ↑ TSH)
square-bullet Thyroid Abs useful in selected cases to differentiate Graves’ disease from toxic multinodular goiter (absent thyroid Abs)
Imaging
square-bullet 24-hr RAIU is useful to distinguish hyperthyroidism from iatrogenic thyroid hormone synthesis (thyrotoxicosis factitia) and from thyroiditis.
square-bullet An overactive thyroid = ↑ uptake, whereas iatrogenic thyroid ingestion and painless or subacute thyroiditis = nl or ↓ uptake.
image

FIGURE 5-3 Diagnostic algorithm for hyperthyroidism.

square-bullet The RAIU results also vary w/the etiology of the hyperthyroidism:
Graves’ disease: diffuse homogeneous uptake
Multinodular goiter: heterogeneous uptake
Hot nodule: single focus of uptake

Treatment

square-bullet Antithyroid drugs (thionamides): methimazole inhibits thyroid hormone synthesis by blocking production of thyroid peroxidase. Adjunctive Rx to alleviate α-adrenergic sx of hyperthyroidism involves propranolol 20 to 40 mg PO q6h; dosage is gradually ↑ until sx are controlled.
square-bullet RAI is the Rx of choice for pts >21 yr of age who have not achieved remission after 1 yr of antithyroid drug Rx.
square-bullet Subtotal thyroidectomy is indicated in obstructing goiters, in any pt who refuses RAI and cannot be adequately managed w/antithyroid medications (e.g., pts w/toxic adenoma or toxic multinodular goiter), and in pregnant pts who cannot be adequately managed w/antithyroid medication or develop side effects to them.

Clinical Pearl

square-bullet Elderly hyperthyroid pts may have only subtle signs (weight loss, tachycardia, fine skin, brittle nails). This form is known as apathetic hyperthyroidism and is manifested by lethargy rather than with hyperkinetic activity. An enlarged thyroid gland may be absent. Coexisting medical disorders (most commonly cardiac disease) may also mask the sx. These pts often have unexplained CHF or new-onset AF.

3. Thyroid Storm

Acute life-threatening exacerbation of hyperthyroidism

Diagnosis

square-bullet Tremor, tachycardia/tachyarrhythmias, fever (as high as 105.8° F)
square-bullet Sweating, diarrhea, vasodilatation
square-bullet Lid lag, lid retraction, proptosis, goiter
square-bullet Change in mental status (psychosis, coma, seizures)
square-bullet Other: precipitating factors (infection, trauma), CHF, hepatosplenomegaly, jaundice
Labs
square-bullet ↑ Free T4, ↓ TSH

Treatment

square-bullet Replace fluid deficit aggressively (daily fluid requirement may reach 6 L); use solutions containing glucose and add multivitamins to the hydrating solution.
square-bullet Propylthiouracil (PTU) 800 mg initially (PO/NG tube)/PR, then 200 to 300 mg PO/PR q6h (allergy PTU, methimazole 80-100 mg PO/PR followed by 40 mg PO/PR q8h).
square-bullet Inhibition of stored thyroid hormone from the gland:
Iodide can be administered as Telepaque (iopanoic acid) 1 g PO once daily or Na+ iodine 250 mg IV q6h, or, saturated solution of K+ iodide (SSKI), 5 gtt PO q8h, or Lugol’s solution, 10 gtt PO q8h. It is important to administer PTU or methimazole 1 hr before the iodide to prevent the oxidation of iodide to iodine and its incorporation in the synthesis of additional thyroid hormone.
Corticosteroids: Dexamethasone 1 to 2 mg IV q6h or hydrocortisone 100 mg IV q6h for approximately 48 hr is useful to inhibit thyroid hormone release, impair peripheral conversion of T3 from T4, and provide additional adrenocortical hormone to correct deficiency (if present).
square-bullet Suppression of peripheral effects of thyroid hormone: β-adrenergic blockers: Administer propranolol 80 to 120 mg PO q4 to 6h. Propranolol may also be given IV 1 mg/min for 2 to 10 min under continuous ECG and blood pressure monitoring. β-Adrenergic blockers must be used with caution in pts with severe CHF or bronchospasm. Cardioselective β-blockers (e.g., esmolol or metoprolol) may be more appropriate for pts with bronchospasm, but these pts must be closely monitored for exacerbation of bronchospasm because these agents lose their cardioselectivity at ↑ doses.
square-bullet Control of fever with acetaminophen 325 to 650 mg q4h; avoid aspirin because it displaces thyroid hormone from its binding protein
square-bullet Rx of any precipitating factors (e.g., abx if infection is strongly suspected)

4. Hypothyroidism

Etiology

square-bullet Primary hypothyroidism >90% of the cases
Hashimoto’s thyroiditis: most common cause of hypothyroidism after 8 yr of age
Idiopathic myxedema (nongoitrous form of Hashimoto’s thyroiditis)
Previous Rx of hyperthyroidism (radioiodine Rx, subtotal thyroidectomy)
image

FIGURE 5-4 Diagnostic algorithm for hypothyroidism.

Subacute thyroiditis
Radiation Rx to the neck (usually for malignant disease)
Iodine deficiency or excess
Drugs (lithium, PAS, sulfonamides, phenylbutazone, amiodarone, thiourea)
Congenital (approximately 1 case per 4000 live births)
Prolonged Rx w/iodides
Secondary hypothyroidism: pituitary dysfunction, postpartum necrosis, neoplasm, infiltrative disease causing deficiency of TSH
Tertiary hypothyroidism: hypothalamic disease (granuloma, neoplasm, or irradiation causing deficiency of TRH)
Tissue resistance to thyroid hormone: rare

Diagnosis

H&P
square-bullet Skin: dry, coarse, thick, cool, sallow (yellow color caused by carotenemia); nonpitting edema in skin of eyelids and hands (myxedema) secondary to infiltration of SC tissues by a hydrophilic mucopolysaccharide substance
square-bullet Hair: brittle and coarse; loss of outer third of eyebrows
square-bullet Facies: dulled expression, thickened tongue, thick, slow-moving lips
square-bullet Thyroid gland: may or may not be palpable (depending on the cause of the hypothyroidism)
square-bullet Heart sounds: distant, possible pericardial effusion
square-bullet Pulse: bradycardia
square-bullet Neurologic: delayed relaxation phase of the DTRs, cerebellar ataxia, hearing impairment, poor memory, peripheral neuropathies w/paresthesia
square-bullet Musculoskeletal: carpal tunnel syndrome, muscle stiffness, weakness
Labs (see Table 5-7; Fig. 5-4)
square-bullet TSH: ↑ TSH may be nl if pt has secondary or tertiary hypothyroidism, pt is receiving dopamine or corticosteroids, or the level is obtained after severe illness.
square-bullet ↓ Free T4
square-bullet Other common laboratory abnlities: hyperlipidemia, hyponatremia, and anemia
square-bullet Antimicrosomal and antithyroglobulin Ab titers: useful only when autoimmune thyroiditis is suspected as the cause of the hypothyroidism

Treatment

square-bullet Levothyroxine 25 to 100 μg/day, depending on pt’s age and severity of the disease. The dose may be ↑ every 6 to 8 wk, depending on the clinical response and serum TSH level. Elderly pts and pts w/CAD should be started w/12.5 to 25 μg/day (higher doses may precipitate angina).

Clinical Pearls

square-bullet Periodic monitoring of TSH level is an essential part of Rx. Pts should be evaluated w/office visit and TSH levels every 6 to 8 wk until the pt is clinically euthyroid and the TSH level is normalized.
square-bullet For monitoring Rx in pts w/central hypothyroidism, measurement of serum free T4 level rather than TSH is appropriate; it should be maintained in the upper half of the nl range.
square-bullet Pregnant pts also have ↑ requirements. Women w/hypothyroidism should generally ↑ their levothyroxine dose by approximately 30% as soon as pregnancy is confirmed and have frequent testing.

5. Subclinical Hypothyroidism

square-bullet Frequency: 10% to 15% of elderly
square-bullet Labs: ↑ serum TSH and a nl free T4 level
square-bullet Associated with an ↑ risk of CHD events (particularly in those with a TSH concentration of ≥10 mU/L)
square-bullet Rx: Levothyroxine if TSH ≥10 mU/L and with presence of goiter or thyroid autoantibodies

6. Myxedema Coma

square-bullet This is a life-threatening complication of hypothyroidism.

Etiology

square-bullet Decompensation of hypothyroidism secondary to
Sepsis
Exposure to cold weather
CNS depressants (sedatives, narcotics, antidepressants)
Trauma, surgery

Diagnosis

H&P
square-bullet Profound lethargy or coma
square-bullet Hypothermia (rectal temperature <35° C [<95° F]); often missed by using ordinary thermometers graduated only to 34.5° C
square-bullet Bradycardia, hypotension (secondary to circulatory collapse)
square-bullet Delayed relaxation phase of DTR, areflexia
square-bullet Myxedema facies
square-bullet Alopecia, macroglossia, ptosis, periorbital edema, nonpitting edema, doughy skin
square-bullet Bladder dystonia and distention
Labs
square-bullet ↑↑ TSH (if primary hypothyroidism), ↓ free T4

Treatment

square-bullet Levothyroxine 5 to 8 μg/kg (300-500 μg) IV infused over 15 min, then 100 μg IV q24h.
square-bullet Glucocorticoids should also be administered until coexistent adrenal insufficiency can be r/o → hydrocortisone hemisuccinate 100 mg IV bolus, followed by 50 mg IV q12h or 25 mg IV q6h until initial plasma cortisol level is confirmed nl.
square-bullet IV hydration w/D5NS

7. Thyroiditis

Classification and Etiology

square-bullet Hashimoto’s thyroiditis (autoimmune)
square-bullet Painful subacute thyroiditis (follows URI): subacute thyroiditis, giant cell thyroiditis, de Quervain’s thyroiditis, subacute granulomatous thyroiditis, pseudogranulomatous thyroiditis
square-bullet Painless postpartum thyroiditis: subacute lymphocytic thyroiditis
square-bullet Suppurative thyroiditis (infectious etiology thus febrile with nuchal rigidity/erythema)
square-bullet Riedel’s thyroiditis (slowly enlarging hard mass): fibrous thyroiditis
Labs
square-bullet TSH, free T4: may be nl, ↓, ↑
square-bullet ↑ WBC with left shift occurs with subacute and suppurative thyroiditis.
square-bullet Antimicrosomal Abs (>90%), Hashimoto’s thyroiditis, (65%) silent thyroiditis
square-bullet Serum thyroglobulin levels ↑ subacute and silent thyroiditis, factitious hyperthyroidism (↓or absent serum thyroglobulin level)
Imaging
square-bullet 24 hr RAIU: Graves’ disease (↑ RAIU), thyroiditis (nl or ↓ RAIU)

Treatment

square-bullet If hypothyroid: levothyroxine 25 to 50 μg/day initially and monitor TSH q 6 to 8wk
square-bullet Control sx of hyperthyroidism: β-blocker (e.g., propranolol 20-40 mg PO q6h)
square-bullet If pain → NSAIDs, if refractory → prednisone 20 to 40 mg qd
square-bullet If suppurative thyroiditis → IV abx and drain abscess

8. Evaluation of Thyroid Nodule

Epidemiology and Risk Factors for Malignancy

square-bullet Incidence of thyroid nodules ↑ after age 45 yr, more frequently in women
square-bullet ↑ Risk malignancy: nodule ≥2 cm, regional lymphadenopathy, fixation to adjacent tissues, age <40 yr, sx of local invasion (dysphagia, hoarseness, neck pain, male sex, family hx of thyroid cancer or polyposis [Gardner syndrome]), rapid growth during levothyroxine Rx

W/up, Labs/Imaging
square-bullet FNA biopsy best diagnostic study; accuracy can be >90%
square-bullet TSH, T4, and serum thyroglobulin levels
square-bullet Serum calcitonin if suspect medullary carcinoma of the thyroid/family hx
square-bullet Thyroid U/S to evaluate size, composition (solid vs. cystic), and dimensions
square-bullet Thyroid scan with technetium-99m pertechnetate, iodine-123, or iodine-131 in selected pts (Fig. 5-5)
image

FIGURE 5-5 Diagnostic evaluation of solitary thyroid nodule in euthyroid patient. High risk for malignancy: nodule >2 cm, age <40 years, male sex, regional lymphadenopathy, fixation to adjacent tissues, history of previous head and neck irradiation.

9. Thyroid Carcinoma

Three major types are recognized (Table 5-8).
square-bullet Papillary carcinoma
Psammoma bodies (calcific bodies present in papillary projections)
Spread via lymphatics/local invasion
square-bullet Follicular carcinoma
Incidence ↑ with age
May metastasize hematogenously to bone → pathologic fractures
Tends to concentrate iodine (useful for radiation Rx)

TABLE 5-8

Characteristics of Thyroid Cancers

Type of Cancer Percentage of Thyroid Cancers (%) Age of Onset (yr) Treatment Prognosis
Papillary 80 40-80 Thyroidectomy, followed by radioactive iodine ablation Good
Follicular 15 45-80 Thyroidectomy, followed by radioactive iodine ablation Fair to good
Medullary 3 20-50 Thyroidectomy and central compartment lymph node dissection Fair
Anaplastic 1 50-80 Isthmusectomy followed by palliative x-ray treatment Poor
Lymphoma 1 25-70 X-ray therapy and/or chemotherapy Fair

image

From Andreoli TE, Benjamin IJ, Griggs RC, Wing EJ: Andreoli and Carpenter’s Cecil Essentials of Medicine, 8th ed. Philadelphia, Saunders, 2010.

square-bullet Anaplastic carcinoma
Two very aggressive histologic types: small cell (less aggressive, 5-yr survival 20%) and giant cell (death usually within 6 mo of dx)
square-bullet MTC:
Unifocal: found sporadically in elderly pts
Bilateral: assoc w/MEN-II pheochromocytoma + hyperparathyroidism (↑ plasma calcitonin)
H&P
square-bullet Presence of thyroid nodule/painless swelling
square-bullet Most common type (50%-60%) is papillary carcinoma.
square-bullet Median age at dx: 45 to 50 yr; female 3:1
square-bullet Hoarseness and cervical lymphadenopathy
W/up
square-bullet FNA biopsy; thyroid function studies are generally nl.
square-bullet Thyroid U/S, thyroid scanning with iodine-123 or technetium-99m

Treatment

square-bullet Thyroidectomy

F. Calcium Homeostasis Disorders

1. Calcium Formulas

See Box 5-1.
Box 5-1Calcium Formulas
The correction of Ca based on the serum albumin and globulin levels is calculated as:
% Ca2+ bound = 8(albumin) + 2(globulin) + 3
Another formula to correct CCa based on total protein is:
Corrected Ca2+ = Measured Ca2+/(0.6 + [total protein/8.5])
A quick bedside formula for calculation of the corrected Ca is:
Corrected Ca2+ = Measured Ca2+ – albumin + 4

2. Hypercalcemia

Etiology

square-bullet Malignant disease (20%-30% of cancers), 4 types:
Humoral hypercalcemia of malignancy (80%): breast cancer, MM, and lymphoma; caused by secretion of PTHrP by the tumors → bone resorption and renal retention of Ca2+
Local osteolytic hypercalcemia (<20%): squamous cell cancer (e.g., lung, head and neck, esophagus), renal or ovarian cancer, breast cancer, some lymphomas, and endometrial cancer; caused by osteoclastic bone resorption in areas surrounding the malignant cells within the marrow space
Secretion of 1,25(OH)2D by lymphomas (<1%) → osteoclastic bone resorption and intestinal absorption of Ca2+
Ectopic hyperparathyroidism (<0.01%); caused by ectopic secretion of PTH
square-bullet Hyperparathyroidism bone resorption, GI absorption, and renal absorption from
Parathyroid hyperplasia, adenoma
Hyperparathyroidism or renal failure w/secondary hyperparathyroidism
square-bullet Granulomatous disorders → GI absorption (e.g., sarcoidosis)
square-bullet Paget’s disease → bone resorption (seen only during periods of immobilization)
square-bullet Vitamin D intoxication, milk-alkali syndrome → GI absorption
square-bullet Thiazides → renal absorption
square-bullet Other causes: familial hypocalciuric hypercalcemia, thyrotoxicosis, adrenal insufficiency, prolonged immobilization, vitamin A intoxication, recovery from acute kidney injury (AKI), lithium administration, pheochromocytoma, SLE

Diagnosis

H&P
square-bullet GI: constipation, anorexia, N/V, pancreatitis, ulcers
square-bullet CNS: confusion, obtundation, psychosis, lassitude, depression, coma
square-bullet GU: nephrolithiasis, renal insufficiency, polyuria, ↓ urine-concentrating ability (nephrogenic DI), nocturia, nephrocalcinosis
square-bullet Musculoskeletal: myopathy, weakness, osteoporosis, pseudogout, bone pain
square-bullet Other: HTN, metastatic calcifications, band keratopathy, pruritus
square-bullet Most pts are asymptomatic at the time of dx.
Hx
square-bullet FHx of hypercalcemia such as MEN syndromes or familial hypocalciuric hypercalcemia (the latter is a benign autosomal dominant condition of ↑ serum Ca2+, ↓ urinary Ca2+, ↓ fractional excretion of Ca2+ [generally <1%], and a nl PTH → parathyroidectomy not indicated)
square-bullet Inquire about intake of milk and antacids (milk-alkali syndrome), intake of thiazides, lithium, large doses of vitamins A or D.
square-bullet Inquire whether pt has any bone pain (MM, metastatic disease) or abd pain (pancreatitis, PUD).
PE
square-bullet Look for evidence of primary neoplasm (e.g., breast, lung).
square-bullet Check eyes for evidence of band keratopathy (found in medial and lateral margin of the cornea).
Labs (Fig. 5-6)
square-bullet Initial labs: serum Ca2+, alb, PO4-3, Mg, alk phos, electrolytes, BUN, Cr, PTH, and 24-hr urine Ca2+ collection. In pts w/abnl alb levels, it is important to measure the serum level of ionized Ca2+ to correct for the abnl alb. If the ionized Ca2+ is not available, the total Ca2+ can be corrected for a low alb level by adding 0.8 mg/dL to the total Ca2+ level for every 1.0 g/dL of serum alb below the level of 3.5 g/dL.
square-bullet If the hx suggests ↓ intake of vitamin D (e.g., in food faddists w/intake of megadoses of fat-soluble vitamins), check serum vitamin D level (1,25-dihydroxyvitamin D).
square-bullet The iPTH distinguishes primary hyperparathyroidism from hypercalcemia caused by malignant disease when the serum Ca level is >12 mg/dL.
square-bullet ↑↑ Urinary cyclic AMP = primary hyperparathyroidism, although certain nonparathyroid malignant neoplasms also produce levels of urinary cyclic AMP.
square-bullet ↑ PTHrP = hypercalcemia-associated malignant neoplasms.
Imaging
square-bullet Bone survey may show evidence of subperiosteal bone resorption (suggesting PTH excess).
square-bullet Parathyroid localization w/technetium-99m sestamibi: high sensitivity and specificity for single adenomas
square-bullet ECG: shortening of the QT interval

image

FIGURE 5-6 Diagnostic algorithm for hypercalcemia. (From Ravel R: Clinical Laboratory Medicine, 6th ed. St. Louis, Mosby, 1995.)

Treatment

Acute Severe Hypercalcemia (serum Ca 13 mg/dL or symptomatic pt)
square-bullet Vigorous IV hydration w/NS. Usual administration rate is 200 to 500 mL/hr, depending on the baseline level of dehydration, renal function, and the CV and mental status of the pt.
square-bullet NS infusion = inhibition of proximal tubular Na+ and Ca2+ reabsorption → increased delivery of Na+ and water to distal nephron → ↑ urinary Ca2+ excretion
square-bullet IV bisphosphonates to inhibit osteoclast bone resorption: zoledronate (4 mg IV over a 15-min period in a solution of 50 mL of NS or D5W). In pts with impaired kidney function can use denosumab to ↓ osteoclast mediated bone resorption
square-bullet PO4-3 repletion: Hypophosphatemia occurs in most pts w/hypercalcemia due to cancer. Serum PO4-3 level should be kept in the range of 2.5 to 3 mg/dL. Serum phosphorus and Cr levels should be closely monitored. PO4-3 replacement should be PO (e.g., 250 mg Neutra-Phos PO qid until serum phosphorus level is >3.0 mg/dL).
square-bullet Loop diuretics (e.g., furosemide 20-40 mg IV) can worsen dehydration and should not be administered until full hydration has been achieved. Thiazide diuretics are contraindicated because they will stimulate rather than inhibit renal Ca reabsorption.

3. Hypocalcemia

Etiology

square-bullet Renal insufficiency: hypocalcemia caused by
↑ Ca deposits in bone and soft tissue secondary to ↑ serum PO4-3 level
↓ Production of 1,25-dihydroxyvitamin D
↑ Loss of 25-OHD (nephrotic syndrome)
square-bullet Hypoalbuminemia: Each ↓ in serum alb (g/L) will ↓ serum Ca by 0.8 mg/dL but will not change free (ionized) Ca.
square-bullet Vitamin D deficiency
square-bullet Malabsorption (most common cause)
Inadequate intake
↓ Production of 1,25-dihydroxyvitamin D (vitamin D–dependent rickets, renal failure)
↓ Production of 25-OHD (parenchymal liver disease)
↑ 25-OHD catabolism (phenytoin, phenobarbital)
End-organ resistance to 1,25-dihydroxyvitamin D
square-bullet Hypomagnesemia: hypocalcemia caused by
↓ PTH secretion
Inhibition of PTH effect on bone
square-bullet Pancreatitis, hyperphosphatemia, osteoblastic mets: Hypocalcemia is secondary to Ca deposits (bone, abd).
square-bullet Pseudohypoparathyroidism: autosomal recessive, short stature, shortening of metacarpal bones, obesity, mental retardation. The hypocalcemia is secondary to congenital end-organ resistance to PTH.
square-bullet Idiopathic hypoparathyroidism, surgical removal of parathyroids (e.g., neck surgery)
square-bullet Hungry bones syndrome: rapid transfer of Ca from plasma into bones after removal of a parathyroid tumor
square-bullet Sepsis
square-bullet Massive blood transfusion (as a result of EDTA and calcium chelation in blood)

Diagnosis

H&P
square-bullet Neuromuscular irritability
Chvostek’s sign: facial twitch after a gentle tapping over the facial nerve (can occur in 10%-25% of nl adults)
Trousseau’s sign: carpopedal spasm after inflation of BP cuff above the pt’s systolic BP for a 2- to 3-min duration
square-bullet Tetany, paresthesias, myopathy, seizures, muscle spasm or weakness
square-bullet Psychiatric disturbances: psychosis, depression, impaired cognitive function
square-bullet Soft tissue calcifications, ocular cataracts
square-bullet CV: arrhythmias, CHF, QT interval, hypotension
Labs (Table 5-9 and Fig. 5-7)
square-bullet Serum alb: to r/o hypoalbuminemia
square-bullet BUN, Cr: to r/o renal failure
square-bullet Serum Mg: to r/o severe hypomagnesemia
square-bullet Serum PO4-3, alk phos: to differentiate hypoparathyroidism from vitamin D deficiency
image

FIGURE 5-7 Diagnostic algorithm for hypocalcemia. (From Ferri FF: Ferri’s Best Test: A Practical Guide to Clinical Laboratory Medicine and Diagnostic Imaging, 2nd ed. Philadelphia, Mosby, 2010.)

TABLE 5-9

Laboratory Differential Diagnosis of Hypocalcemia

Diagnosis Plasma Tests Urine Tests Comments
Ca PO4 PTH 25(OH)D 1,25(OH)2D cAMP cAMP After PTH TmP/GFR TmP/GFR After PTH Ca
Hypoparathyroidism N/↓ N ↑↑ ↓↓ N/↓ Deficiency of PTH
Pseudohypoparathyroidism
Type I ↑↑ N NC N/↓ Resistance to PTH; patients may have Albright’s hereditary osteodystrophy and resistance to multiple hormones
Type II N ↑↑ N N/↓ Renal resistance to cAMP
Vitamin D deficiency N/↓ ↑↑ ↓↓ N/↓ ↓↓ Deficient supply (e.g., nutrition) or absorption (e.g., pancreatic insufficiency) of vitamin D
Vitamin D–dependent rickets
Type I N/↓ ↑↑ N ↓↓ Deficient activity of renal 25(OH)D-1α-hydroxylase
Type II N/↓ ↑↑ N ↑↑ ↓↓ Resistance to 1,25(OH)2D

image

(OH)D, hydroxycholecalciferol D; OH2D, dihydroxycholecalciferol; TmP, renal threshold for phosphorus.

From Moore WT, Eastman RC: Diagnostic Endocrinology, 2nd ed. St. Louis, Mosby, 1996.

square-bullet Serum PTH
↑↑ PTH: pseudohypoparathyroidism
↑ PTH: vitamin D deficiency
↓ PTH: hypoparathyroidism

Treatment

square-bullet Acute, severe symptomatic hypocalcemia caused by hypoparathyroidism or vitamin D deficiency: Give a slow IV bolus (over 15 min) of 10 to 30 mL of a 10% Ca gluconate solution followed by an infusion of 4 g Ca gluconate in 500 mL D5W over 4 hr (1 g Ca gluconate = 10 mL 10% Ca gluconate).
square-bullet Hypoalbuminemia
Improve nutritional status.
Ca replacement is not indicated because the free (ionized) Ca is nl.
square-bullet Hypomagnesemia: Correct the Mg deficiency.
Severe hypomagnesemia (serum Mg level <0.8 mEq/L): Give 1 g (8 mEq) of a 10% Mg sulfate solution IV slowly (during 15 min).
Moderate to severe hypomagnesemia (serum Mg level 0.8-1.3 mEq/L): Give one 2-mL ampule of a 50% Mg solution IM; may repeat q4-6h.
square-bullet Chronic hypocalcemia caused by hypoparathyroidism or vitamin D deficiency
Ca supplementation: 1 to 4 g/day of elemental Ca (e.g., Ca carbonate, 650 mg PO qid, will provide 1 g of elemental Ca/day)
Vitamin D replacement
square-bullet Chronic hypocalcemia caused by renal failure
Reduction of hyperphosphatemia w/phosphate-binding antacids
Vitamin D and oral Ca supplementation (as noted earlier)

G. Adrenal Gland Disorders

1. Cushing’s Syndrome

This clinical disorder is associated w/glucocorticoid excess secondary to exaggerated adrenal cortisol production or chronic glucocorticoid Rx. Cushing’s disease is Cushing’s syndrome caused by pituitary ACTH excess.

Etiology

square-bullet Iatrogenic from chronic glucocorticoid Rx (most common) (↓ ACTH, ↑ cortisol)
square-bullet Pituitary ACTH excess (Cushing’s disease) (↑ ACTH, ↑ cortisol)
square-bullet Adrenal neoplasms (30%) (↓ ACTH, ↑ cortisol)
square-bullet Ectopic ACTH production (neoplasms of lung, pancreas, kidney, thyroid, thymus; 10%) (↑↑ ACTH, ↑↑ cortisol)

Diagnosis

H&P
square-bullet HTN
square-bullet Central obesity w/rounding of the facies (moon facies); thin extremities
square-bullet Hirsutism, menstrual irregularities, hypogonadism
square-bullet Skin fragility, ecchymoses, red-purple abd striae, acne, poor wound healing, hair loss, facial plethora, hyperpigmentation (when there is ACTH excess)
square-bullet Psychosis, emotional lability, paranoia
square-bullet Muscle wasting w/proximal myopathy
Labs
square-bullet Initial screening test is the overnight dexamethasone suppression test (Fig. 5-8):
Dexamethasone 1 mg PO given at 11 PM
Plasma cortisol level measured 9 hr later (8 AM)
Plasma cortisol level <2 μg/dL (55 nmol/L) excludes Cushing’s syndrome. Levels >5 μg/dL (138 nmol/L) suggest Cushing’s syndrome. Levels 2 to 5 μg/dL (55-138 nmol/L) require additional testing with 24-hr urine free cortisol testing (>100 μg/24 hr in Cushing’s syndrome) and midnight salivary cortisol measurement (↑ in Cushing’s syndrome). Nl diurnal variation leads to a cortisol nadir around midnight; therefore, a cortisol level >7.5 μg/dL is 96% sensitive and 100% specific for the dx of Cushing’s syndrome.
If necessary, dx of Cushing’s syndrome can be confirmed with low-dose 2-day dexamethasone suppression and dexamethasone plus CRH.
Other lab tests reveal hypokalemia, hypochloremia, metabolic alkalosis, hyperglycemia, hypercholesterolemia.
Plasma ACTH is useful to determine the cause of Cushing’s syndrome (see Fig. 5-8).
image

FIGURE 5-8 Clinical diagnosis and management of Cushing’s syndrome. (From Cameron AM: Current Surgical Therapy, 10th ed. Philadelphia, Saunders, 2011.)

Imaging
square-bullet CT scan of adrenal glands: indicated in suspected adrenal Cushing’s syndrome
square-bullet MRI of pituitary gland w/gadolinium: indicated in suspected pituitary Cushing’s syndrome

Treatment

Rx varies w/cause:
square-bullet Pituitary adenoma: Transsphenoidal microadenomectomy is the Rx of choice in adults. Pituitary irradiation is reserved for pts not cured by transsphenoidal surgery. In children, pituitary irradiation may be considered initial Rx because 85% of children are cured by radiation. Stereotactic radioRx (photon knife or gamma knife) is effective and exposes the surrounding neuronal tissues to less irradiation than in conventional radioRx. Total bilateral adrenalectomy is reserved for pts not cured by transsphenoidal surgery or pituitary irradiation.
square-bullet Adrenal neoplasm: surgical resection of the affected adrenal; glucocorticoid replacement for approximately 9 to 12 mo after the surgery to allow time for the contralateral adrenal to recover from its prolonged suppression
square-bullet Bilateral micronodular or macronodular adrenal hyperplasia: bilateral total adrenalectomy
square-bullet Ectopic ACTH: surgical resection of the ACTH-secreting neoplasm; control of cortisol excess w/metyrapone, aminoglutethimide, mifepristone, or ketoconazole; control of the mineralocorticoid effects of cortisol and 11-deoxycorticosteroid w/spironolactone. Bilateral adrenalectomy is a rational approach to pts w/indolent, unresectable tumors.

2. Primary Adrenocortical Insufficiency (Addison’s Disease)

Disorder characterized by inadequate secretion of corticosteroids resulting from partial or complete destruction of all three layers of the adrenal glands.

Etiology

square-bullet Autoimmune destruction of the adrenals (80% of cases)
square-bullet TB (15% of cases)
square-bullet Carcinomatous destruction of the adrenals
square-bullet Adrenal hemorrhage (anticoagulants, trauma, coagulopathies, pregnancy, sepsis); adrenal infarction (arteritis, thrombosis)
square-bullet AIDS (adrenal insufficiency develops in 30% of pts w/advanced AIDS)
square-bullet Other: sarcoidosis, amyloidosis, postoperative, fungal infection, megestrol acetate Rx, etomidate Rx

Diagnosis

H&P
square-bullet Hyperpigmentation, hypotension, generalized weakness, amenorrhea, and loss of axillary hair in female pts
Labs (Fig. 5-9)
square-bullet Perform rapid ACTH (cosyntropin) test: 250 μg ACTH by IV push; measure cortisol level at 0, 30, 60 min. Cortisol level <18 μg/dL at 30 min or 60 min suggests adrenal insufficiency. Measure plasma ACTH level: ↑ level indicates primary adrenal insufficiency, nl/↓ level indicates secondary adrenal insufficiency.
square-bullet ↑ K+, ↓ Na+ and Cl, ↓ glucose, ↑ BUN/Cr ratio (prerenal azotemia), mild normocytic normochromic anemia, neutropenia, lymphocytosis, eosinophilia (significant dehydration may mask the hyponatremia and anemia), ↓ 24-hr urinary cortisol, 17-OHCS, and 17-KS and ↑ ACTH (if primary adrenocortical insufficiency)
image

FIGURE 5-9 Diagnostic algorithm for adrenal insufficiency (Addison’s disease). (From Ferri FF: Ferri’s Best Test: A Practical Guide to Clinical Laboratory Medicine and Diagnostic Imaging, 2nd ed. Philadelphia, Mosby, 2010.)

Treatment

Chronic Adrenocortical Insufficiency
square-bullet Hydrocortisone, 15 to 20 mg PO q AM and 5 to 10 mg in late afternoon or prednisone 5 mg in AM and 2.5 mg at hs
square-bullet Oral fludrocortisone 0.05 to 0.20 mg/day (if the pt has primary adrenocortical insufficiency). The dose is adjusted on the basis of the serum Na+ level and the presence of postural hypotension or marked orthostasis.
square-bullet Monitor serum electrolytes, VS, and BW periodically: Advise liberal Na+ intake.
square-bullet Pts should be instructed to ↑ glucocorticoid replacement in times of stress and to receive parenteral glucocorticoids if diarrhea or vomiting occurs.
Addisonian Crisis
square-bullet Acute complications of adrenal insufficiency characterized by circulatory collapse, dehydration, N/V, hypoglycemia, and hyperkalemia
square-bullet Draw plasma cortisol level; do not delay Rx until confirming lab results are obtained.
square-bullet Administer hydrocortisone 50 to 100 mg IV q6h for 24 hr; if pt shows good clinical response, gradually taper dosage and change to PO maintenance dose (usually prednisone, 7.5 mg/day).
square-bullet Provide adequate volume replacement w/D5NS solution until hypotension, dehydration, and hypoglycemia are completely corrected. Large volumes (2-3 L) may be necessary in the first 2 to 3 hr to correct the volume deficit and hypoglycemia and to avoid further hyponatremia.
square-bullet Identify and correct any precipitating factor (e.g., sepsis, hemorrhage).

3. Disorders of Mineralocorticoid Secretion

a. Hypoaldosteronism

Etiology
square-bullet Hyporeninemic hypoaldosteronism (renin-angiotensin dependent): ↓ aldosterone production as a result of ↓ renin production; pt has renal disease secondary to various factors (e.g., DM, interstitial nephritis, MM).
square-bullet Hyperreninemic hypoaldosteronism (renin-angiotensin independent): Renin production by the kidneys is intact; defect is in aldosterone biosynthesis or in the action of angiotensin II. Common causes are meds (ACEIs, heparin), lead poisoning, aldosterone enzyme defects, and severe illness.

H&P

square-bullet HTN, muscle weakness, cardiac arrhythmias
Diagnosis
Labs
square-bullet ↑ K+, nl or ↓ Na+
square-bullet Hyperchloremic metabolic acidosis (caused by the absence of hydrogen-secreting action of aldosterone)
square-bullet ↑ BUN and Cr (secondary to renal disease)
square-bullet Hyperglycemia (DM is common in these pts)
W/up
square-bullet Measurement of PRA after 4 hr of upright posture can differentiate hyporeninemic from hyperreninemic causes. Nl/↓ renin levels = renin-angiotensin dependent, ↑ renin levels = renin-angiotensin independent.
square-bullet Renin-aldosterone stimulation test
Hyporeninemic hypoaldosteronism: ↓ stimulated renin and aldosterone levels
End-organ refractoriness to aldosterone action: ↑ stimulated renin and aldosterone levels
Adrenal gland abnlity: ↑ stimulated renin and ↓ aldosterone levels
Treatment
square-bullet Low-K diet with liberal Na intake (≥4 g of NaCl/day)
square-bullet Avoidance of ACEIs and K+-sparing diuretics
square-bullet Judicious use of fludrocortisone (0.05 to 0.1 mg PO every morning) in pts with aldosterone deficiency associated with deficiency of adrenal glucocorticoid hormones
square-bullet Furosemide 20 to 40 mg qd to correct hyperkalemia of hyporeninemic hypoaldosteronism

b. Hyperaldosteronism (Conn’s syndrome)

Syndrome characterized by hypokalemia, HTN, ↓ PRA, and ↑ aldosterone secretion

Etiology

square-bullet Aldosterone-producing adenoma (>60%)
square-bullet Idiopathic hyperaldosteronism (>30%)
square-bullet Glucocorticoid-suppressible hyperaldosteronism (<1%)
square-bullet Aldosterone-producing carcinoma (<1%)

Diagnosis

square-bullet 24-hr urine test for aldosterone and K+ levels (K+ >40 mEq and aldosterone >15 μg)
square-bullet The renin-aldosterone stimulation test (posture test) to differentiate idiopathic hyperaldosteronism (IHA) from aldosterone-producing adenoma (APA). Pts with APA have a ↓ in aldosterone levels at 4 hr, whereas pts with IHA have an ↑ in aldosterone levels.
square-bullet As a screening test for primary aldosteronism, an ↑ plasma aldosterone-renin ratio (ARR), drawn randomly from pts taking hypertensive drugs, is predictive of primary aldosteronism. ARR is calculated by dividing plasma aldosterone (mg/dL) by PRA (mg/mL/hr). ARR >100 is considered ↑.
square-bullet Bilateral adrenal vein sampling (AVS) may be done to localize APA when adrenal CT scan is equivocal. In APA, ipsilateral/contralateral aldosterone level is >10:1, and ipsilateral venous aldosterone concentration is very high (>1000 ng/dL).
H&P
square-bullet If significant hypokalemia: muscle cramping, weakness, paresthesias
square-bullet HTN
square-bullet Polyuria, polydipsia
Labs
square-bullet Routine labs can be suggestive but are not diagnostic of primary aldosteronism. Common abnlities are
Spontaneous hypokalemia or moderately severe hypokalemia while receiving conventional doses of diuretics
Possible alkalosis and hypernatremia
Imaging
square-bullet Adrenal CT scans (with 3-mm cuts) or MRI to localize neoplasm
square-bullet Adrenal scanning with iodocholesterol (NP-59) or 6-β-iodomethyl-19-norcholesterol after dexamethasone suppression. The uptake of tracer is ↑ in those with aldosteronoma and absent in those with IHA and adrenal carcinoma.

Treatment

square-bullet Low-Na+diet
square-bullet Control of BP and hypokalemia with spironolactone, amiloride, or ACEIs
square-bullet Surgery (unilateral adrenalectomy) for APA

H. Pheochromocytoma

Definition

Catecholamine-producing tumors that originate from chromaffin cells of the adrenergic system. Secrete both NE and epi, but NE is predominant amine; 25% of pheos are familial (MEN II, neurofibromatosis, von Hippel–Lindau).

Diagnosis

H&P
square-bullet HTN: sustained (55%) or paroxysmal (45%)
square-bullet Headache (80%): paroxysmal, described as “pounding” and severe
square-bullet Palpitations (70%): w/ or w/o tachycardia
square-bullet Hyperhidrosis (60%): most evident during paroxysmal attacks of HTN
square-bullet PE may be entirely nl if done in a sx-free interval; during a paroxysm, there is ↑↑ BP, profuse sweating, visual disturbances (caused by hypertensive retinopathy), dilated pupils (secondary to catecholamine excess), paresthesias in the LEs (caused by severe vasoconstriction), tremor, tachycardia.
Labs
square-bullet Plasma-free metanephrines show ↑ normetanephrines >2.5 pmol/mL or ↑ metanephrine >1.4 pmol/mL.
square-bullet 24-hr urine collection for metanephrines reveals ↑ metanephrines.
square-bullet Clonidine suppression test: Used to distinguish between levels of plasma norepinephrine caused by release from sympathetic nerves and those from pheo. A ↓ (<50%) in plasma NE levels after clonidine administration is nl, whereas persistent ↑ = pheochromocytoma.
Imaging
square-bullet Abd CT (88% sensitivity): useful in locating pheochromocytomas >0.5 inch in diameter (90%-95% accurate); >90 % of pheos arise in adrenal medulla
square-bullet MRI: 100% sensitivity
square-bullet Scintigraphy w/131I-MIBG: 100% sensitivity. NE analogue localizes in adrenergic tissue; useful in locating extra-adrenal pheochromocytomas.
square-bullet 6-[18F]Fluorodopamine PET: used when biochemical test results are + but other imaging cannot locate the tumor

Treatment

Laparoscopic removal of the tumor (surgical resection for both benign and malignant disease):
square-bullet Preoperative stabilization w/combination of phenoxybenzamine, β-blocker, metyrosine, and liberal fluid and salt intake starting 10 to 14 days before surgery
square-bullet HTN crisis preoperatively and intraoperatively controlled w/phentolamine 2 to 5 mg IV q1-2h PRN or nitroprusside used in combination w/β-adrenergic blockers

I. Carcinoid Syndrome

square-bullet Sx complex characterized by paroxysmal vasomotor disturbances, diarrhea, and bronchospasm resulting from amines and peptides (serotonin, bradykinin, histamine) produced by tumors arising from neuroendocrine cells
square-bullet Located in appendix (40%), small bowel (20%; 15% in the ileum), rectum (15%), bronchi (12%), esophagus, stomach, colon (10%), ovary, biliary tract, pancreas (3%)

Diagnosis

H&P
square-bullet Cutaneous flushing (75%-90%)
square-bullet Red-purple flushes starting in the face, then spreading to the neck and upper trunk
square-bullet The flushing episodes last from a few minutes to hr (longer lasting flushes may be associated w/bronchial carcinoids).
square-bullet Dizziness, tachycardia, and hypotension may be associated w/the cutaneous flushing.
square-bullet Diarrhea (>70%): often associated w/abd bloating and audible peristaltic rushes
square-bullet Intermittent bronchospasm (25%)
square-bullet Facial telangiectasia
square-bullet Tricuspid insufficiency, pulmonic stenosis from carcinoid heart lesions
Labs
square-bullet ↑ 24-hr urinary 5-hydroxyindoleacetic acid (5-HIAA)
square-bullet Biochemical screening can also be done w/plasma chromogranin A.

Imaging

square-bullet CXR: to detect bronchial carcinoids
square-bullet CT of abd to detect liver mets
square-bullet Iodine-123–labeled somatostatin (123I-SS) scintigraphy

Treatment

square-bullet Surgical resection
square-bullet Octreotide or lanreotide for flushing and diarrhea
square-bullet Interferon α may be used as an additive Rx when sx persist.
square-bullet Percutaneous embolization and ligation of the hepatic artery can ↓ the bulk of the tumor in the liver and provide palliative Rx of tumors w/hepatic mets.

J. Multiple Endocrine Neoplasia

Classification

MEN I (Wermer’s Syndrome)

Tumors or hyperplasia of anterior pituitary, enteropancreatic neuroendocrine system (insulinoma, gastrinoma, glucagonoma), parathyroid, and other tissues . MENI is commonly known as the 3P’s (pituitary, pancreas, parathyroid tumors)
square-bullet Possible associated conditions:
Adrenocortical adenoma or hyperplasia
Thyroid adenoma or hyperplasia
Renal cortical adenoma
Carcinoid tumors
GI polyps
Skin angiofibromas and skin collagenomas
square-bullet Clinical manifestations:
Peptic ulcer and its complications (gastrinoma)
Hypoglycemia (insulinoma)
Hypercalcemia or nephrocalcinosis
Watery diarrhoea (vipoma)
Headache, visual field defects, secondary amenorrhea
Multiple SC lipomas
Other: flushing, acromegaly, Cushing’s syndrome, hyperthyroidism

MEN II (Sipple’s Syndrome, MEN IIA)

Associated w/MTC, pheochromocytoma, and hyperparathyroidism
square-bullet Clinical manifestations:
Neck mass (caused by MTC)
HTN
Headache, palpitations, sweating
Hypercalcemia, nephrocalcinosis, osteitis fibrosa cystica
square-bullet Relatives of affected persons should be screened to detect medullary carcinoma at an early stage; screening can be accomplished with
Pentagastrin test: unreliable because it does not distinguish C-cell hyperplasia from small carcinomas
DNA analysis: reliable method for identification of MEN IIA gene carriers

MEN III (Multiple Mucosal Neuroma Syndrome, MEN IIB)

Associated w/MTC, pheochromocytoma, and multiple mucosal neuromas. Possible associated conditions: intestinal ganglioneuromatosis, marfanoid habitus
square-bullet Clinical manifestations:
Neck mass (caused by MTC)
Headache, palpitations, sweating, HTN
Mucosal neuromas (initially noted as whitish, yellow-pink nodules involving lips and anterior third of tongue)
Marfan-like habitus (w/absence of CV abnlities and lens subluxation)
Peripheral neuropathy (caused by neuromatous plaques overlying the posterior columns of the spinal cord, cauda equina, and sciatic nerve)

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