1. What are the surgically correctable causes of hypertension?

Show answer
Renovascular hypertension, pheochromocytoma, Cushing’s syndrome, primary hyperaldosteronism (Conn’s syndrome), coarctation of the aorta, and unilateral renal parenchymal disease. Surgical hypertension accounts for 5% of all hypertensive patients.

2. Which form of surgical hypertension is most common?

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Renovascular hypertension is most common. Although the overall frequency of renovascular hypertension among patients with elevated diastolic blood pressure is about 3%, moderate or severe diastolic hypertension may be caused by renal artery occlusive disease in as many as 25% of cases. Pheochromocytoma, hyperaldosteronism, Cushing’s disease, and coarctation of the aorta each are found in only 0.1% of all hypertensive patients.

3. What are the most common causes of renovascular hypertension?

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Atherosclerosis causes 70% of cases; it affects men twice as often as women. The second most common cause is fibromuscular dysplasia (25%). Of the many pathologic subtypes, the most common is medial fibrodysplasia (85%); it invariably affects women. Last is developmental renal artery stenosis (10%), which is often associated with neurofibromatosis and abdominal aortic coarctation.

4. What clinical criteria support the pursuit of investigative studies for suspected renovascular hypertension?

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Although no clinical characteristics are pathognomonic of renovascular hypertension, the following findings strongly suggest the presence of an underlying renal artery stenotic lesion:

* Hypertension in very young individuals or in women younger than 50 years of age
* Rapid onset of severe hypertension after age 50 years
* Hypertension refractory to three-drug regimens
* Initial presentation with diastolic blood pressure > 115 mmHg or sudden worsening of presumed preexisting hypertension
* Accelerated or malignant hypertension
* Deterioration of renal function after the initiation of antihypertensive agents, especially angiotensin-converting enzyme (ACE) inhibitors
* Systolic or diastolic upper abdominal or flank bruits

5. What is the renin-angiotensin-aldosterone system (RAAS)?

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Renin is released from the juxtaglomerular apparatus of the kidney in response to changes in renal cortical afferent arteriolar perfusion pressure. Renin acts locally and in the systemic circulation on renin substrate (angiotensinogen), a nonvasoactive alpha2 globulin is produced in the liver to form angiotensin I. Angiotensin I undergoes enzymatic cleavage by ACE in the pulmonary circulation to produce angiotensin II, a potent vasopressor responsible for the vasoconstrictive element of renovascular hypertension. Angiotensin II increases adrenal gland production of aldosterone with subsequent retention of sodium and water; this process establishes the volume element of renovascular hypertension.

6. How do ACE inhibitors work?

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Direct inhibition of ACE decreases concentrations of angiotensin II, which leads to decreased vasopressor activity and decreased aldosterone secretion. Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity.

7. Should patients with renovascular hypertension be treated medically or surgically?

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Although prospective randomized studies comparing drug and interventional therapy have not been published, surgical treatment and percutaneous transluminal renal angioplasty (PTRA) have been favored over drug therapy by most clinicians. The key is early recognition of the problem.

8. When should patients with renovascular hypertension be treated with PTRA?

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Clear indications for PTRA include nonorificial atherosclerotic lesions and medial fibrodysplastic lesions limited to the main renal artery.

9. What findings on history and physical examination should lead to a suspicion of pheochromocytoma?

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Pheochromocytomas are tumors primarily of the adrenal medulla and extraadrenal paraganglia cells. Approximately 90% of them are found within the adrenal gland, and the remaining 10% are scattered along the abdominal paravertebral sympathetic chain or in ganglia located remotely (e.g., urinary bladder, pelvic nerves). Tumors are classified as functioning when they produce catecholamines, always autonomously and usually in great excess. The predictable clinical effects of increased endogenous cathecholamine outpouring is sustained hypertension with episodes of increased blood pressure, tachycardia, headache, palpitations, or flushing. Rarely, patients maintain periods of normotension with infrequent and unpredictable paroxysmal episodes of hypertension.

10. How is pheochromocytoma diagnosed?

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Diagnosis is best confirmed by 24-hour urine collection for excreted catecholamines, metanephrines, and vanillylmandelic acid. The best single test to confirm the diagnosis of pheochromocytoma is still debated; some believe that the metanephrine level is the most precise (85%). Plasma catecholamines are also a specific test, but given the variability of results in individual patients and in many assays, the current approach should continue to emphasize the use of urinary catecholamines. Eighty percent of patients with pheochromocytoma have at least one urinary metabolite greater than twice the normal value. The diagnosis of pheochromocytoma should be followed by studies to localize the tumor.
KEY POINTS: SURGICAL HYPERTENSION

1. The causes of surgically correctable hypertension include renovascular hypertension, pheochromocytoma, Cushing’s syndrome, Conn’s syndrome, coarctation of the aorta, and unilateral renal parenchymal disease.
2. The most common cause of renovascular hypertension is atherosclerosis.
3. The diagnosis of pheochromocytoma is confirmed by 24-hour urine collection for excreted catecholamines, metanephrines, and vanillylmandelic acid.
4. Conn’s syndrome is characterized by hypertension, hypokalemia, hypernatremia, metabolic alkalosis, and periodic muscle weakness and paralysis.

11. What is the best test to localize a pheochromocytoma?

Show answer
Computed tomography (CT) scanning, magnetic resonance imaging (MRI), and 131I-metaiodobenzylguanidine (MIBG) scanning are three available imaging modalitites. Because 97% of pheochromocytomas are intraabdominal and almost always > 2 cm, an abdominal CT scan (thin cuts through the adrenal bed from the diaphragm to the aortic bifurcation) rarely misses a lesion and provides good anatomic detail. MRI has been increasingly used because 90% of pheochromocytomas are characteristically bright on T2 weighted images. MIBG is best used in patients who are suspected to have extraadrenal, multifocal, or recurrent pheochromocytoma. It is less sensitive than CT and MRI. MIBG is best reserved for patients at higher risk for multiple or extra-adrenal tumors and malignant pheochromocytoma.

12. Describe the immediate antihypertensive treatment in patients with pheochromocytoma.

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Hypertension from pheochromocytoma is caused by activation of vascular smooth muscle alpha1-receptors, which results in vasoconstriction. Thus, the best acute treatment is intravenous administration of an alpha1-antagonist or -blocker; options include phenoxybenzamine, prazosin, or terazosin. Second-line agents include calcium channel blockers and ACE inhibitors. Antiarrhythmic beta-blockade should be avoided initially because these agents cause both unopposed peripheral alpha1-receptor stimulation and decreased cardiac output (secondary to high vascular resistance). Congestive heart failure may be precipitated by beta-blocking the heart before lowering the blood pressure.

13. How is primary hyperaldosteronism (Conn’s syndrome) diagnosed?

Show answer
Conn’s syndrome, which results from autonomous mineralocorticoid hypersecretion, is characterized by hypertension, hypokalemia, hypernatremia, metabolic alkalosis, and periodic muscle weakness and paralysis, often caused by an aldosterone-secreting adenoma. The syndrome is now identified by the combined findings of hypokalemia, suppressed plasma renin activity despite sodium restriction, and high urinary and plasma aldosterone levels after sodium repletion in hypertensive patients.

14. Why does Cushing’s syndrome or Cushing’s disease cause hypertension?

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Both cause hypercortisolism or excessive amounts of glucocorticoids. In the cardiovascular system, glucocorticoids produce increased cardiac chronotropic and inotropic effects, along with an increased peripheral vascular resistance. Receptors in the distal renal tubules respond to glucocorticoids by increasing tubular resorption of sodium. These receptors belong to a different class from receptors that mediate the more potent actions of aldosterone.

15. What findings suggest aortic coarctation?

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Lower blood pressure in the legs than in the arms and diminished or absent femoral pulses. Rib notching may be evident on chest radiograph in patients with long-standing, hemodynamically significant coarctation. Bruits may be heard over the chest or abdominal wall. Adults may even develop congestive heart failure and renal failure.

16. How does aortic coarctation cause hypertension?

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No single cause has been identified. Mechanical obstruction to ventricular ejection is one component that leads to upper extremity hytertension. Hypoperfusion of the kidneys with resulting activation of the RAAS probably contributes. Abnormal aortic compliance, variable capacity of collateral vessels, and abnormal setting of baroreceptors also have been implicated.

References
BIBLIOGRAPHY
1. Blumenfeld JD, Sealey JE, Schlussel Y, et al: Diagnosis and therapy of primary hyperaldosteronism. Ann Intern Med 121:877-885, 1994. Medline Similar articles
2. Coen G, Calabria S, Lai S, et al: Atherosclerotic ischemic renal disease: Diagnosis and prevalence in an hypertensive and/or uremic elderly population. BMC Nephrol 4:2, 2003. Medline Similar articles
3. Hansen KJ, Deitch JS, Oskin TC, et al: Renal artery repair: Consequences of operative failures. Ann Surg 277:678-690, 1998. Full article
4. Kebebew E, Duh Q-Y: Benign and malignant pheochromocytoma: Diagnosis, treatment and follow-up. Surg Oncol Clin North Am 7:765-789, 1998.
5. Lairmore TC, Ball DW, Baylin SB, et al: Management of pheochromocytomas in patients with multiple endocrine neoplasia type 2 syndromes. Ann Surg 217:595-603, 1993.
6. Nicholson T: Magnetic resonance angiography for the diagnosis of renal artery stenosis. Clin Radiol 58:257, 2003. Medline Similar articles
7. Oskin TC, Hansen KJ, Deitch JS, et al: Chronic renal artery occlusion: Nephrectomy versus revascularization. J Vasc Surg 29:140-149, 1999. Medline Similar articles
8. Palmaz JC: The current status of vascular intervention in ischemic nephropathy. J Vasc Interv Radiol 9:439-543, 1998.
9. Stanley JC: Surgical treatment of renovascular hypertension. Am J Surg 174:102-110, 1997.
10. Wong JM, Hansen KJ, Oskin TC, et al: Surgery after failed percutaneous renal artery angioplasty. J Vasc Surg 30:468-483, 1999. Medline Similar articles

1. What is the prevalence of thyroid nodules and cancer?

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Thyroid nodules increase throughout life. Nodules are four times more common in females than in males, and 50% of 50-year-old women have a palpable nodule. After exposure to radiation, nodules develop at approximately 2% annually, reaching a peak at 25 years. Nodules are 10 times more frequent in glands examined by ultrasound, at surgery, or at autopsy. Fewer than 50% of thyroid nodules that appear solitary on physical examination are truly solitary.
Each year in the United States, there are approximately 15,000 new cases and 1000 deaths due to thyroid cancer. Up to 35% of thyroid glands examined at autopsy contain occult papillary cancer (< 1.0 cm).

2. What is the importance of the distinction between solitary and multiple thyroid nodules?

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Traditionally, multiple thyroid nodules were considered benign and solitary thyroid nodules malignant. However, multiple series suggest that a dominant nodule in a multinodular gland carries the same risk of cancer as a solitary nodule (5%).

3. What is the differential diagnosis of thyroid nodules?

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* Adenoma
o Macrofollicular (colloid)
o Microfollicular
o Embryonal
o Hurthle cell
* Carcinoma
o Papillary
o Follicular
o Medullary
o Anaplastic
o Lymphoma
o Metastatic
* Cyst
* Nodular goiter with a dominant nodule
* Other
o Inflammatory diseases (e.g., Hashimoto’s thyroiditis)
o Developmental abnormalities

4. What features of the history and physical examination indicate a higher risk of cancer?

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Nodules occurring at the extremes of age are more likely to be cancerous, particularly in males. Rapid growth and local invasion raise the possibility of malignancy, but associated symptoms (e.g., hoarseness, dysphagia) are uncommon. A history of radiation exposure increases the frequency of both benign and malignant nodules. A family history of medullary or papillary thyroid cancer or Gardner’s syndrome (i.e., familial polyposis) increases the risk of cancer.
Cancer is more often found in patients with firm, solitary nodules. Fixation to adjacent structures, vocal cord paralysis, and enlarged lymph nodes also are associated with an increased risk of malignancy.

5. What is the proper laboratory evaluation of a patient with a thyroid nodule?

Show answer
The only biochemical test that is routinely needed is a serum thyroid-stimulating hormone (TSH) concentration to identify patients with unsuspected hyperthyroidism. In patients with suspected medullary thyroid carcinoma (MTC), serum calcitonin should be measured. In patients with known medullary carcinoma, serum calcium levels and 24-hour urine collection for assessment of catecholamines and their metabolic products should be done to exclude multiple endocrine neoplasia (MEN II) before thyroidectomy. Patients with MTC should have lymphocyte-derived DNA analysis for ret proto-oncogene mutations.

6. Which single test best predicts the need for surgical intervention?

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The single best test to predict the need for surgery is fine-needle aspiration (FNA). If an adequate specimen is obtained, the three possible results are benign (70%), suspicious (15%), and malignant (5%). FNA is most reliable for the diagnosis of papillary carcinoma and in patients with medullary and anaplastic cancer. It is least reliable in distinguishing benign from malignant follicular and Hurthle cell neoplasms. The overall accuracy exceeds 95% in experienced hands. When FNA reveals cancer, it is 97% correct (3% false-positive rate); when it indicates a benign nodule, cancer is present in 4% of cases (4% false-negative rate). When the FNA is suspicious, 30% of nodules are malignant.

7. What other tests may be useful in the evaluation of a thyroid nodule?

Show answer
Thyroid radionuclide studies with isotopes of either iodine (most common) or technetium often are performed but cannot reliably differentiate malignant from benign nodules. Scans may be useful in patients with indeterminate FNA results and TSH < 1.5 μIU/mL because hyperfunctioning nodules are almost always benign.
Ultrasound categorizes nodules as cystic, solid, or mixed and is the best measure of the size of a nodule. Ultrasound can be used to determine the presence of other nodules in a patient with a solitary nodule on physical examination. It is particularly useful to follow the size of a nodule. Similar to radionuclide scans, ultrasound cannot distinguish malignant from benign nodules; thus, it is not routinely used in the evaluation of a nodule.

8. Should a solitary thyroid nodule be suppressed with thyroxine for 3-6 months to determine whether it is benign or malignant?

Show answer
Most nodules change very little over the short term. In one series, 13% of nodules decreased in size, 22% disappeared, 46% did not change, and 19% enlarged. Studies of thyroxine therapy suggest that drug treatment is not superior to placebo in patients with solitary nodules. Most nodules do not change in size, 30% decrease in size, and a few increase in size. Thus, the response to thyroxine is not a reliable indicator of malignancy.

9. What are the types and distribution of thyroid cancer?

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10. What are the axioms of thyroid surgery?

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* A meticulously dry operative field must be maintained.
* Tissue in the region of the recurrent laryngeal nerve should not be cut or clamped until the nerve is definitively identified.
* Every parathyroid gland should be treated as if it were the last functioning gland.
* If malignancy is suspected, the entire operation should be done as if the lesion were cancer.

KEY POINTS: THYROID NODULES

1. Thyroid nodules are more common in females than in males.
2. The only biochemical test that is routinely needed is a serum thyroid-stimulating hormone concentration to identify patients with unsuspected hyperthyroidism.
3. The single best test to predict the need for surgery is fine-needle aspiration.
4. Thyroid carcinoma should be treated by near-total or total thyroidectomy except in young patients with small, well-differentiated tumors (≤ 1 cm) and no evidence of lymph node or extrathyroidal disease. In such cases lobectomy and isthmusectomy are adequate therapy.

11. What is the minimal extent of thyroidectomy for a solitary thyroid nodule?

Show answer
The goal of surgery is to remove all foci of neoplastic tissue and any palpable cervical adenopathy. With the exception of small lesions in the thyroid isthmus, the minimal procedure for suspected malignancy should be lobectomy, including the isthmus (as a diagnostic biopsy). Enucleation is to be avoided. Frozen section is accurate for papillary, medullary, and anaplastic carcinoma. Frozen section is no more accurate than FNA for follicular and Hurthle cell carcinoma. Functioning “toxic” nodules may be resected by a partial lobectomy because they are usually benign. If the lesion is large, a lobectomy is preferred.

12. What is the most common form of thyroiditis in nodules?

Show answer
Hashimoto’s thyroiditis, subacute thyroiditis, and Reidel struma (rare). These conditions usually do not require surgery. Thyroidectomy is indicated for compressive symptoms or when cancer cannot be excluded.

13. What is the surgical therapy for thyroid carcinoma?

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Thyroid carcinoma should be treated by near-total or total thyroidectomy except in young patients with small, well-differentiated tumors (≤ 1 cm) and no evidence of lymph node or extrathyroidal disease. In such cases, lobectomy with resection of the isthmus is adequate therapy. Near-total thyroidectomy eliminates multifocal cancer in the thyroid, allows postoperative radioiodine for the diagnosis and therapy of metastatic disease, decreases the risk of local-regional recurrence, and improves the accuracy of serum thyroglobulin as a marker for persistent or recurrent disease. Enlarged cervical lymph nodes should be removed and examined by frozen section. If metastatic cancer is identified, a neck dissection is performed. “Berry picking” results in an increased rate of regional recurrence and should be avoided in favor of anatomic dissections.
Because medullary thyroid cancer is not responsive to radioiodine or levothyroxine, a total thyroidectomy should be performed. A central neck dissection is mandatory to evaluate metastatic disease. If the central nodes are positive for cancer on frozen section, an ipsilateral modified neck dissection is performed. The contralateral neck may be observed.
Surgery for anaplastic carcinoma is palliative and usually is limited to debulking and tracheostomy for relief of compressive symptoms.

14. Describe the arterial supply and venous drainage of the thyroid.

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The blood supply to the thyroid gland comes from the superior and inferior thyroid arteries. Occasionally, a midline thyroid imma artery arises from the aortic arch. The superior thyroid artery is the first branch of the external carotid artery. The inferior thyroid artery arises from the thyrocervical trunk.
The three major veins are the superior, middle, and inferior thyroid veins. The superior and middle thyroid veins drain into the internal jugular vein, and the inferior vein drains into the innominate vein.

15. Describe the anatomy of the recurrent laryngeal nerves.

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The right recurrent laryngeal nerve (RLN) arises from the vagus and loops around the right subclavian artery. The left vagus nerve gives off the left RLN and loops around the aorta. The RLNs run obliquely through the neck, usually in the tracheoesophageal groove. Low in the neck, the nerves are more lateral and course medially as they ascend. The right nerve runs more obliquely than the left. Occasionally, the RLN may branch before entering the larynx, usually on the left side. The motor fibers are usually in the most medial branch. In 1% of cases, the right RLN is not recurrent and enters the neck from a lateral and superior direction.

16. What defect results from injury to the RLN?

Show answer
Injury to a single RLN results in a paralyzed vocal cord, which causes a weak, hoarse voice. Patients also have abnormal swallowing and problems with aspiration. Injury to both nerves causes paralysis of both cords and obstruction of airflow. This situation necessitates a tracheostomy. RLN injury occurs in 1% of thyroidectomies.

17. Describe the anatomy of the superior laryngeal nerve and the defect that occurs with its injury.

Show answer
The superior laryngeal nerve gives off the external laryngeal nerve, which runs medial to the superior pole vessels to enter the cricothyroid muscle. This motor nerve (i.e., Amelita Galli-Curci nerve) increases tension of the vocal cords, allowing for high notes. The internal laryngeal nerve provides the sensory innervation to the posterior pharynx. It lies superior to the thyroid cartilage. Injury to the nerve leads to a weak, low voice that lacks resonance. Patients may also have problems with aspiration.

18. What is the other major complication of thyroidectomy?

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Permanent hypoparathyroidism occurs in 1% of patients who have had thyroidectomies.

19. What is the postoperative therapy for well-differentiated thyroid carcinoma?

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Patients with risk factors should be treated with postoperative radioiodine (I-131). Risk factors include older age (> 45 years old), male gender, tumor size, direct local invasion, nodal spread, and distant disease. All patients with well-differentiated thyroid cancer should be treated with levothyroxine (Synthroid) to suppress serum levels of TSH (0.2-0.5 μU/mL). This three-component therapy (i.e., surgery, I-131, levothyroxine) results in the lowest recurrence rate.

20. How should a patient be followed after therapy for well-differentiated thyroid carcinoma?

Show answer
In young, low-risk patients, physical examination of the neck is done every 6 months for 2 years and then yearly thereafter. In high-risk patients, close follow-up includes repeat neck examination in addition to assessment of serum thyroglobulin (Tg) levels, diagnostic radioiodine scans, and cervical ultrasound. Assessment of the serum Tg and scanning depends on the state of the serum TSH. In order to fully evaluate for recurrent disease, the patient should be taken off thyroxine or given recombinent TSH (Thyrogen).
Patients with recurrent cervical disease by palpation or ultrasound should have repeat surgery if the procedure can be performed with low morbidity. After removal of gross disease, patients should be treated with radioiodine. Distant disease should be treated with radioiodine if the metastases take up iodine.

References
WEB SITE
http://www.acssurgery.com
BIBLIOGRAPHY
1. Cady B: Presidential address: Beyond risk groups-a new look at differentiated thyroid cancer. Surgery 124:947-957, 1998. Medline Similar articles
2. Duren M, Siperstein AE, Shen W, et al: Value of stimulated serum thyroglobulin levels for detecting persistent or recurrent differentiated thyroid cancer in high- and low-risk patients. Surgery 126:13-19, 1999. Medline Similar articles Full article
3. Frilling A, Tecklenborg K, Gorges R, et al: Preoperative diagnostic value of [(18)F] fluorodeoxyglucose positron emission tomography in patients with radioiodine-negative recurrent well-differentiated thyroid carcinoma. Ann Surg 234:804-811, 2001. Medline Similar articles Full article
4. Haugen BR, Ridgway EC, McLaughlin BA, McDermott MT: Clinical comparison of whole-body radioiodine scan and serum thyroglobulin after stimulation with recombinant human thyrotropin. Thyroid 12:37-43, 2002.
5. Hay ID, Grant CS, Bergstralh EJ, et al: Unilateral total lobectomy: is it sufficient surgical treatment for patients with AMES low-risk papillary thyroid carcinoma? Surgery 124:958-964, 1998. Full article
6. Moley JF, DeBenedetti MK: Patterns of nodal metastases in palpable medullary thyroid carcinoma: Recommendations for extent of node dissection. Ann Surg 229:880-887, 1999. Medline
7. Rodriguez GJ, Balsalobre MD, Pomares F, et al: Prophylactic thyroidectomy in MEN 2A syndrome: Experience in a single center. J Am Coll Surg 195:159-166, 2002.
8. Singer PA, Cooper DS, Daniels GH, et al: Treatment guidelines for patients with thyroid nodules and well-differentiated thyroid cancer. American Thyroid Association. Arch Intern Med 156:2165-2172, 1996. Medline Similar articles Full article
9. Sivanandan R, Soo KC: Pattern of cervical lymph node metastases from papillary carcinoma of the thyroid. Br J Surg 88:1241-1244, 2001. Medline
10. Stojadinovic A, Hoos A, Ghossein RA, et al: Hurthle cell carcinoma: A 60-year experience. Ann Surg Oncol 9:197-203, 2002. Full article
11. Stojadinovic A, Shaha AR, Orlikoff RF, et al: Prospective functional voice assessment in patients undergoing thyroid surgery. Ann Surg 236:823-832, 2002. Medline Similar articles Full article
12. Udelsman R, Westra WH, Donovan PI, et al: Randomized prospective evaluation of frozen-section analysis for follicular neoplasms of the thyroid. Ann Surg 233:716-722, 2001.

2. What causes hyperthyroidism?

3. How should hyperthyroidism be investigated?

Show answer
A thyroid stimulating hormone (TSH) level is the best intial test. A low TSH with a high serum level of thyroxine (T4) or triiodothyronine (T3) is diagnostic. A high TSH with an increase in free T4 indicates the rare patient with a thyrotropin-producing pituitary tumor.
After the diagnosis of hyperthyroidism is made, the radioactive iodine uptake (RAIU) can differentiate the many causes.

4. What are the three treatment options?

Show answer
Antithyroid drugs (ATD), radioiodine, and surgery.

5. Which drugs are useful for the treatment of hyperthyroidism? What are their mechanisms of action?

Show answer
Methimazole and propylthiouracil (PTU) are the mainstays of treatment. The goal of treatment is remission of Graves’ disease during therapy or euthyroidism before treatment with radioiodine or surgery. Both drugs inhibit organification of iodine and coupling of iodothyronines. PTU also inhibits the peripheral monodeiodination of T4 to T3. Treatment is started with 20 mg/day of methimazole or 100 mg of PTU 3 times/day. The dose may be reduced after 6 weeks of treatment as the patient shows clinical and biochemical improvement. Therapy is usually maintained for 2 years. Patients must be monitored for side effects, which include rash, pruritus, agranulocytosis, hepatitis, cholestatic jaundice, and lupus-like syndrome.

Beta-adrenergic antagonists ameliorate the signs and symptoms of disease. They should not be used alone except for short periods before radioiodine or surgical therapy. Nadolol (80 mg/day) and atenolol (100 mg/day) are the most common agents.
Iodine given as Lugol’s solution (5% iodine and 10% potassium iodide in water, 0.3 mL/day) or potassium iodide (60 mg 3 times/day) inhibits the release of thyroid hormone. It is useful for short-term therapy in preparation for surgery, after radioiodine therapy to hasten the decrease in hormone levels, and for treatment of thyroid storm.

6. What are the indications for and outcome of drug treatment?

Show answer
ATD therapy is reserved for mild hyperthyroidism and a small gland. Long-term remission of Graves’ hyperthyroidism during antithyroid drug therapy occurs in 50% of patients. Relapse is most common in the first 6 months after cessation of treatment.

7. What is the regimen of radioiodine treatment?

Show answer
Radioiodine is the most common therapy. The usual dose of radioiodine is 10 mCi. If hyperthyroidism is not cured, the dose should be repeated in 6 months. Pretreatment with antithyroid drug therapy should achieve a euthyroid state. Steroids prevent progression of ophthalmopathy. Prednisone is used at a dose of 0.5 mg/kg body weight, starting 3 days after radioiodine therapy and continuing for 1 month. The dose is tapered over 2 months.
Pregnancy is an absolute contraindication. Women of childbearing age should be evaluated with a pregnancy test before treatment and should avoid pregnancy for 6 months after treatment. Evidence indicates that radioiodine may exacerbate ophthalmopathy.

8. What is the outcome of radioiodine treatment?

Show answer
Euthyroidism is not achieved for months after treatment. After euthyroidism is achieved, recurrence of hyperthyroidism is rare. Hypothyroidism, the only serious side effect, is dose dependent. It occurs at a rate of 3% per year, affecting 50% of patients at 10 years, and nearly 100% at 25 years.

9. What are the indications for thyroidectomy for hyperthyroidism?

Show answer

* Pregnant patients who are difficult to treat medically
* Patients with large goiters and low radioiodine uptake
* Children
* Noncompliant patients
* Patients with nodules suspected to be cancerous
* Patients with compression of the trachea or esophagus
* Patients with cosmetic concerns
* Patients with ophthalmopathy

10. How should patients be prepared for surgery? Show answer
Any patient with hyperthyroidism should be rendered euthyroid before surgery. Patients may be treated with antithyroid medication and potassium iodine. Beta-adrenergic antagonists should also be used alone or in combination with the above regimen.

11. What is the extent of thyroidectomy?

Show answer
The two surgical options for Graves’ disease are subtotal thyroidectomy or near-total thyroidectomy. The goal of subtotal thyroidectomy is to preserve 8 g of well-vascularized thyroid tissue to avoid hypothyroidism. Because of the small risk of recurrence (10%), however, some surgeons prefer near-total thyroidectomy. In Plummer’s disease, lobectomy or partial thyroidectomy for unilateral lesions and contralateral subtotal thyroidectomy for multiple lesions render the patient euthyroid.

12. What is the incidence of hypothyroidism after surgery?

Show answer
All patients having a near-total thyroidectomy become hypothyroid and need thyroxine replacement. Hypothyroidism occurs in 50% of patients with subtotal thyroidectomy.
KEY POINTS: HYPERTHYROIDISM

1. A thyroid-stimulating hormone (TSH) level is the best initial test.
2. Methimazole and propylthiouracil are the mainstays of medical treatment.
3. The two surgical options for Graves’ disease are subtotal thyroidectomy and near-total thyroidectomy.

13. What is the appropriate treatment for toxic nodular goiter?

Show answer
Hyperthyroidism caused by toxic nodular goiter is permanent and without spontaneous remission; antithyroid drugs are not appropriate long-term therapy. Radioiodine is the most common form of therapy. Larger doses (50 mCi) minimize the risk of persistent hyperthyroidism in such patients, who tend to be older and to have prominent cardiovascular symptoms of hyperthyroidism.

14. What is the appropriate treatment for hyperthyroidism caused by thyroiditis?

Show answer
Subacute thyroiditis should be suspected if the patient has pain and tenderness in the thyroid region. The hyperthyroidism is usually mild and of short duration (i.e., weeks). Patients are treated with a beta-adrenergic antagonist and salicylate or glucocorticoid. Hypothyroidism may occur but is usually not permanent.

15. What is the appropriate treatment for thyroid storm?

Show answer
Thyrotoxic crisis should be treated in the intensive care unit. General measures include hydration, antipyresis (acetaminophen), and nutrition. Specific measures include inhibition of T4 synthesis and conversion to T3 with PTU at a dose of 100 mg orally, via nasogastric tube, or rectally every 6 hours. Iodides inhibit T4 release (saturated solution of potassium iodide, 5 drops by mouth or nasogastric tube every 6 hours). Steroids (dexamethasone, 2 mg every 6 hours) also inhibit T4 release and conversion to T3. Beta-adrenergic antagonists (propranolol or esmolol) may control cardiovascular manifestations. The last-resort management option is T4 removal by plasmapheresis, hemoperfusion, or dialysis.

16. Who performed the first thyroidectomy?

Show answer
Johann von Mikulicz-Radecki performed the first thyroidectomy in 1885.

17. Which surgeon won the Nobel Prize for his work with thyroid disease?

Show answer
Theodor Kocher won the Nobel Prize in medicine in 1909. He was successful in reducing the high mortality rate of thyroidectomy to less than 1%. His most significant achievement was in describing postoperative hypothyroidism as cachexia strumipriva.

References
BIBLIOGRAPHY
1. Bartalena L, Marcocci C, Bogazzi F, et al: Relation between therapy for hyperthyroidism and the course of Graves’ ophthalmopathy. N Engl J Med 338:73-78, 1998. Medline Similar articles Full article
2. David E, Rosen IB, Bain J, et al: Management of the hot thyroid nodule. Am J Surg 170:481-483, 1995. Medline Similar articles Full article
3. Franklyn JA: The management of hyperthyroidism. N Engl J Med 330:1731-1738, 1994. Medline Similar articles Full article
4. Franklyn JA, Daykin J, Drolc Z, et al: Long-term follow-up of treatment of thyrotoxicosis by three different methods. Clin Endocrinol (Oxf) 34:71-76, 1991. Medline Similar articles Full article
5. Kang AS, Grant CS, Thompson GB, van Heerden JA: Current treatment of nodular goiter with hyperthyroidism (Plummer’s disease): Surgery versus radioiodine. Surgery 132:916-923, 2002. Medline Similar articles Full article
6. Miccoli P, Vitti P, Rago T, et al: Surgical treatment of Graves’ disease: Subtotal or total thyroidectomy? Surgery 120:1020-1024, 1996. Full article
7. Singer PA, Cooper DS, Levy EG, et al: Treatment guidelines for patients with hyperthyroidism and hypothyroidism. Standards of Care Committee, American Thyroid Association. JAMA 273:808-812, 1995. Similar articles Full article
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1. What is the prevalence of hyperparathyroidism (HPT)?

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There are approximately 100,000 new cases of HPT annually in the United States. Primary HPT occurs in 1 in 500 women and in 1 in 2000 men older than 40 years. Approximately 10% of patients with primary HPT are referred for surgery.

2. What are the symptoms of hyperparathyroidism?

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“Painful bones, renal stones, abdominal groans, and psychic moans.” The three most common symptoms are fatigue, depression, and constipation. The classic symptoms and signs are:

* Bones: arthralgia, osteoporosis, pathologic fractures
* Stones: renal stones, renal insufficiency, polyuria, polydipsia
* Abdominal groans: pancreatitis, peptic ulcer disease, constipation
* Psychic moans: fatigue, weakness, depression

3. What are the leading causes of hypercalcemia?

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HPT is the most common cause of hypercalcemia among outpatients and the second most common cause in the hospital setting. The most common cause of hypercalcemia in hospitalized patients is malignancy. Primary HPT and malignancy account for 90% of cases of hypercalcemia.

4. What is the differential diagnosis of hypercalcemia?

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* EndocrineHPT
* Hyperthyroidism
* Addison’s disease

* MalignancyBone metastasis
* Paraneoplastic syndromes
* Solid tumors (squamous or small cell lung carcinoma)
* Hematologic malignancy (myeloma, leukemia, lymphoma)

* Increased intakeMilk alkali syndrome
* Vitamin D intoxication
* Granulomatous disease
* Sarcoidosis
* Tuberculosis

* MiscellaneousFamilial hypocalciuric hypercalcemia (FHH)
* Thiazide use
* Lithium use

5. What is the essential laboratory evaluation for HPT?

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Elevated serum calcium (> 10.3 mg/dL) should be assessed at least twice. Hypercalcemia must be associated with elevation of parathyroid hormone (intact). Serum phosphate levels are low in nearly 80% of patients. Serum chloride is increased in 40% of patients. A chloride-to-phosphate ratio greater than 33 suggests primary HPT. Increased alkaline phosphatase levels occur only in the setting of advanced bone disease. A 24-hour urine collection for calcium excretion excludes benign FHH. In patients with primary HPT, the 24-hour urine calcium is > 150 mg/day versus < 100 mg/day in those with FHH.

6. Describe the anatomy of the parathyroid glands.

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The upper parathyroid glands arise from the dorsal part of the fourth brachial pouch along with the lateral lobes of the thyroid. The lower parathyroid glands arise from the dorsal part of the third brachial pouch along with the thymus.
The average weight of a normal parathyroid gland is 35-50 mg. The upper parathyroid gland lies on the posterior portion of the upper half of the thyroid, cephalad to the inferior thyroid artery, and posterior to the recurrent laryngeal nerve. The normal lower parathyroid gland is found on the lateral or posterior surface of the lower pole of the thyroid gland.
Four glands are present in 89% of patients, five in 8%, six in 3%, and < four in 0%.
The upper parathyroid glands' location is more constant. The most common ectopic sites of the upper glands are posterior to the esophagus or in the tracheoesophageal groove down into the posterior superior mediastinum. The lower parathyroid glands are more commonly ectopic and may be in the thyrothymic ligament, thymus, mediastinum (but outside the thymus), or carotid sheath or within the thyroid.

7. What are the indications for parathyroidectomy?

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All patients with symptomatic HPT or with serum calcium 1 mg/dL above normal should benefit from a parathyroidectomy. Careful history indicates the majority of patients (> 90%) have symptoms. The treatment of asymptomatic patients with minimal elevation (10.3-11.0 mg/dL) of serum calcium is controversial. However, at least four factors favor operation:

1. Patients with untreated primary HPT have an increased death rate caused by cardiovascular disease.
2. Patients with HPT have abnormal quality-of-life scores, and these scores improve to normal after operative success.
3. The cost of parathyroidectomy is equivalent to medical follow-up at 5 years.
4. Experienced endocrine surgeons have a high success rate (≥ 95%) with very low morbidity and mortality rates.

8. What localization studies are available, and when are they indicated?

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The single best localization study is the sestamibi scan. Other noninvasive localization studies include ultrasound, computed tomography, and magnetic resonance imaging. Invasive localization procedures include arteriography and venous sampling. The tests are most accurate with a single abnormal parathyroid gland. Localization procedures in cases of hyperplasia may be misleading.
Localization studies are not routinely indicated before an initial operation, but they are mandatory before all reoperative parathyroidectomies for persistent or recurrent HPT and in patients with previous thyroid surgery.
Preoperative sestamibi scintigraphy is used by some surgeons for the initial operation to allow a focused parathyroidectomy or minimally invasive radio-guided parathyroidectomy.

9. What is the pathology of primary HPT?

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Primary HPT is caused by a single adenoma in 87% of cases, hyperplasia in 9%, double adenoma in 3%, and carcinoma in < 1%. In familial HPT, multiple endocrine neoplasia syndromes (MEN I and MEN II), and HPT due to end-stage renal disease, hyperplasia is the rule.

10. Outline the standard surgical strategy of an initial exploration for primary HPT.

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A meticulously dry, blood-free operative field must be maintained. Tissue in the region of the recurrent laryngeal nerve should not be clamped or divided until the nerve is definitively identified. The standard operation is a bilateral neck exploration. If a solitary adenoma and three normal glands are found, the adenoma is removed and one of the normal glands biopsied. Frozen-section examination confirms that the tissue is parathyroid but is unreliable to differentiate adenoma versus hyperplasia. Four-gland enlargement (hyperplasia) indicates either subtotal parathyroidectomy (leaving approximately 50 mg of well-vascularized parathyroid tissue in the neck) or total parathyroidectomy with autotransplantation of 50 mg of parathyroid tissue. If a remnant is left in the neck, it should be marked with a nonabsorbable suture or staple. In the setting of hyperplasia, a thymectomy eliminates the possibility of thymic supernumerary glands. If more than one enlarged gland is found in association with normal-appearing glands (double adenoma), all abnormal glands should be removed.
KEY POINTS: HYPERPARATHYROIDISM

1. It is the most common cause of hypercalcemia among outpatients and the second most common cause in the hospital setting.
2. The three most common symptoms are fatigue, constipation, and depression.
3. The single best localization study is the sestamibi scan.

11. Are there any newer alternatives to the standard operative approach?

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Focused parathyroidectomy, minimally invasive radio-guided parathyroidectomy (MIRP), and endoscopic neck exploration are new techniques. A focused parathyroidectomy uses the preoperative localization to guide a parathyroidectomy, avoiding a bilateral exploration. This approach is combined with intraoperative “rapid” parathyroid hormone assay. The parathyroid hormone is measured by a modified assay before operation and 10 minutes after adequate resection. A postresection level < 50% of the preoperative level and within the normal range predicts success. The MIRP uses a sestamibi scan the morning of surgery and an intraoperative gamma probe to guide parathyroidectomy. The ratio of ex vivo radioactivity to background is measured to determine success and, thus, the end of the operation.

12. What should one do if an adenoma is not found in the usual locations?

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Each normal gland should be biopsied for confirmation and marked. Normal parathyroid glands should not be removed. If three normal glands are identified, the surgeon should assess whether the missing gland is an upper or lower one. A missing upper gland often lies in the tracheoesophageal groove, posterior to the esophagus or in the posterior superior mediastinum. The common mistake is that the upper thyroid is not satisfactorily mobilized and dissection is not carried posterior enough. The location of a missing lower gland is more varied. First, the thyrothymic ligament should be inspected. The thymus then can be resected through the neck incision. If the adenoma is still not found, the surgeon should search for an undescended parathyroid gland. Next, the carotid sheath should be opened. Finally, the thyroid lobe on the side of the missing parathyroid should be palpated or examined by intraoperative ultrasound for nodules. If a nodule is found, a lobectomy is done and the tissue examined by frozen section; it may be an intrathyroidal parathyroid gland. A blind thyroid lobectomy is rarely helpful.
A sternotomy should not be done as part of an initial exploration. If the above maneuvers are unsuccessful in revealing a parathyroid adenoma, the surgeon should stop. A diagram of the location of the identified glands should be made for future reference. Persistent hypercalcemia indicates the need for localization procedures.

13. What is the outcome of surgery for primary HPT?

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The expected cure rate should be ≥ 95% for patients undergoing an initial exploration for primary HPT. Symptomatic improvement exceeds 95%. Quality-of-life scores return to normal at 6 months. After parathyroidectomy, 80% of symptomatic patients have improvement in bone density and renal function. Even in asymptomatic patients, urinary calcium and deoxypyridinoline levels decrease. Patients have fewer episodes of nephrolithiasis, gout, and peptic ulcer disease. Parathyroidectomy also appears to improve longevity in patients with primary HPT.

14. What are the complications of parathyroidectomy?

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Permanent recurrent laryngeal nerve injury occurs in < 1% of patients; however, a temporary nerve paresis occurs in 3%. Temporary hypocalcemia occurs in 10% of patients, but permanent HPT occurs in only 2% of cases. An elevated preoperative alkaline phosphatase level and abnormal renal function may predict which patients are likely to have "hungry bone" syndrome.

15. What are the physical signs of hypocalcemia after surgery?

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Chvostek’s sign is spasm of the facial muscles caused by tapping the facial nerve trunk. Trousseau’s sign is carpal spasm elicited by occlusion of the brachial artery for 3 minutes with a blood pressure cuff.

16. How should patients with hypocalcemia be treated?

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Patients with tetany caused by hypoparathyroidism require emergency treatment with intravenous calcium to prevent laryngeal stridor and convulsions. One ampule of 10% calcium gluconate (90 mg elemental calcium per 10 mL) should be given in 100-mL saline over 20 minutes followed by an infusion of calcium (5 ampules of calcium gluconate in 500 cc of saline) at 50 mL/h. Maintaining calcium levels of 7.5-9.0 mg/dL is adequate. Oral calcium should be started as soon as possible in the form of calcium carbonate (Tums or Oscal) at 2-3 g/day in divided doses (3-4 times/day). Calcium citrate is preferred for patients with renal lithiasis because the citrate may be prophylactic against renal lithiasis. In most patients, vitamin D preparations increase intestinal absorption and can be given as calcitriol (Rocaltrol), 0.25-0.75 mg per day.

17. Define persistent and recurrent HPT.

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Operative success is defined by long-term normocalcemia. Persistent HPT is defined as hypercalcemia within 6 months of surgery; recurrent HPT is defined as hypercalcemia after 6 months.

18. What is the strategy for managing patients with persistent or recurrent HPT?

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First, the patient should be reevaluated to ensure that the hypercalcemia is caused by primary HPT and not some other cause. Patients should be evaluated for familial hypocalciuric hypercalcemia, which does not warrant reoperation. The severity of disease is evaluated to ensure that repeat operation is justified. Previous operative notes and pathology reports should be reviewed to assist in planning repeat therapy. Localization studies should be used extensively. Before reexploration, vocal cord function should be assessed in all patients.
Repeat cervical exploration is done through the previous incision. Because the strap muscles are usually adherent to the thyroid, a lateral approach through the plane between the sternocleidomastoid and strap muscles may be used instead of the usual medial approach. With positive localization studies or retrospective determination of the side of the missing adenoma, the dissection may be limited if an adenoma is found.
An alternative to repeat exploration is angiographic ablation of parathyroid tissue, which is especially useful for mediastinal adenomas because it avoids a median sternotomy. It is performed by delivering ionic contrast through an arterial catheter wedged into the feeding vessel.

19. Who performed the first parathyroidectomy?

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In 1925, Felix Mendl performed the first successful parathyroidectomy at the Hochenegg Clinic in Vienna. His patient was Albert, a 34-year-old tram car conductor who could not work because of severe osteitis fibrosa cystica.

20. Who was Captain Martell?

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An officer in the U.S. Merchant Marine, Captain Martell was the first patient in the United States to undergo surgery for primary HPT. Captain Martell had progressive HPT that reduced his height from 6 feet to a kyphotic 5 feet, 6 inches. After seven operations, the adenoma was finally removed from the mediastinum; however, the captain died in chronic renal failure.

References
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