Educational objective: Review of methods for protein measurements in urine.
A 24-hour urine collection and determination of albumin in it is, of course, a gold standard for the detection of microalbuminuria. Screening, however, can be achieved more simply by measurement of albumin in urine samples. Positive results must be confirmed by 24-hour urine collection (to distinguish from transient causes of microalbuminuria – fever, heart failure, exercise, and poor glycemic control, etc.).
Urine specimens may be random or timely. Random urine samples suffer from dependence of albumin concentration of the urine production at the time of the test. To minimize this affect, timely urine samples may be used, and in this case early morning samples are most consistent in terms of volume production. However, this dependence on volume may be entirely avoided by calculation of the albumin-to-creatinine ratio in the urine specimen. A value above 30mg/g suggests albumin excretion above 30 mg/day and, thus, microalbuminuria.
Educational objective: Review of risk factors for nephropathy in diabetic patients.
There are several risk factors that are associated with increased risk for the development of diabetic nephropathy. Genetic factors appear to play a role since family members of patients with nephropathy have a higher risk for development of the disease than those whose diabetic family members are free of nephropathy.
Increased blood pressure has been shown to be an independent risk factor for development of nephropathy, a risk particularly increased in patients with poor glycemic control (HBA1C > 12%). Poor glycemic control is by itself an independent risk factor. Increased glomerular filtration rate is an additional risk factor and appears to be even more so in patients with type 1 diabetes mellitus than in those with type 2.
Race is an important risk factor, with Blacks, Mexicans, and Pima Indians having a risk of 3-6 times greater than Caucasians (which may be reflective of socioeconomic level). Plasma prorenin level is also important, and elevated levels (reflecting defective conversion to rennin) rather than decreased levels are associated with increased risk for development of nephropathy.
However, none of these risk factors have predictive power in individual patients. Despite this, strict blood pressure control and glycemic control should be the goal in every patient.
A 74-year-old white female is admitted to the hospital because her daughter thinks that she has become different and has started doing weird things for the last couple of days. She complains of headache, mild nausea, and dizziness. Her past medical history is positive for hypertension and mild non-insulin dependent diabetes mellitus. She is on therapy with glyburide, enalapril and hydrochlorothiazide, which was started about a month ago. Her physical exam is unremarkable. There are no orthostatic changes in her blood pressure or pulse rate. Her vital signs are normal. Her neurological exam is also normal. During the exam she becomes easily distracted, she is not able to follow the conversation, she is oriented only for herself but not for time and place.
Laboratory studies reveal the following; Na-102 meq/l, K-3.5 meq/l, Cl-102 meq/l, CO2-27 meq/l, BUN-11 mg/dl, Cr-1.0 mg/dl, serum uric acid-3.6 mg/dl, urine specific gravity-1.019, urine Na – 39 mmol/l. Urine was negative for protein and glucose. What is the most likely cause for her hyponatremia?
Educational objective: Review the causes of hyponatremia.
This 74-year-old woman has euvolemic hyponatremia because she has normal vital signs and nothing to suggest extracellular fluid (ECF) depletion or excess. The following conditions can cause hyponatremia with normal ECF volume: the syndrome of inappropriate antidiuretic hormone secretion (SIADH), hypothyroidism, glucocorticoid deficiency, pharmacologic agents, and primary polydipsia.
In this patient diuretic-induced hyponatremia is suggested by the history of a recent change in her antihypertensive regimen as well as by the mild hypokalemia. The clinician should recall, however, that plasma aldosterone is increased in many patients with SIADH, accounting for the absence of low serum bicarbonate level and for the frequent presence of hypokalemia even in patients not receiving diuretics. Hydrochlorothiazide is a frequent cause of drug-induced hyponatremia in elderly persons. Brain metastasis with SIADH could cause a similar pattern of laboratory abnormalities, but in this patient there is no history of any other symptoms leading to this diagnosis. Patient does not have symptoms of hyperglycemia or hypothyroidism.
A 72-year-old man with a more than 20-year history of hypertension and diabetes mellitus presents to the emergency room with complaints of headache, nausea and proximal muscle weakness. He has not been compliant with the therapy of hypertension and diabetes mellitus. Also, he states that 10 years ago he was told that his kidneys “were not doing well”. Physical examination is remarkable for elevated BP-170/105 mm/Hg and decreased sensation for light touch and pin prick below the knees.
His laboratory studies are as follows:
Na-144 meq/l Ca-8.1 mg/dl K-4.6 meq/l P-5.6 mg/dl CO2-19 meq/l albumin-3.4 g/dl Cl-109 meq/l alk. phosphatase-370 IU/l BUN-61 mg/dl AST-23 IU/l Cr-5.4 mg/dl
Which of the following tests is most likely to uncover the cause for this patient’s elevation of alkaline phosphatase?
Educational objective: Review the features of renal osteodystrophy.
This 72-year-old patient with a long history of hypertension, diabetes mellitus, and renal problems of at least 10 years duration presents with chronic renal insufficiency (CRF). The CRF is associated with several disorders of mineral metabolism. Those disorders are referred to as renal osteodystrophy. The most common disorder is osteitis fibrosa cystica, the bony changes of secondary hyperparathyroidism. The two main sources of elevated serum alkaline phosphatase are liver problems and bone disease. The fact that AST are normal makes liver a highly unlikely source in this case. The way to prove bone problems related to renal insufficiency is to perform bone densitometry. This patient has hyperphosphatemia, which leads to hypocalcemia, which in turn stimulates secretion of parathyroid hormone. High parathyroid hormone levels lead to high bone turnover with osteoclastic bone resorption. Clinically, patients experience bony pain and proximal muscle weakness. Radiographically, the lesions are most prominent in the phalanges and in the lateral ends of clavicles.
Educational objective: Review risk factors for osteoporosis.
Osteoporosis Risk Factors:
Behavioral Low calcium diet Low sun exposure Nulliparity Sedentary life style
Drugs and toxins Excessive alcohol intake Chronic anticonvulsant use Chronic glucocorticoid use Chronic high dose heparin use Smoking Primary hyperparathyroidism
Medical conditions Cushing’s disease Hyperthyroidism Hypogonadism Liver disease Multiple myeloma Renal disease
Genetic predisposition Early menopause Family history Female gender White and Asian race Small body frame
Age is the most important risk factor in the development of osteoporosis.
Educational objective: Review current recommendation for adequate dietary calcium and vitamin D intake for postmenopausal female population.
Dietary intervention for the prevention of osteoporosis (primary and secondary) consists of adequate intake of calcium and Vitamin D. The recommendation of the National Institute of Health for calcium intake among men and women over 65 years of age is 1500 mg/day (this means elemental calcium). For women taking estrogen replacement therapy the recommendation is to take at least 1000 mg/day. Inadequate calcium intake has been linked with age-related osteoporosis and hence is particularly important in the geriatric population.
The average U.S. diet contains 400-800 mg of elemental calcium, and the average need for supplementation is about 1000 mg/day.
A 53-year-old female has been in menopause for two years. She declined estrogen replacement therapy because of fear of breast cancer with which one of her sisters was affected and died 4 years ago. However, she is interested in osteoporosis prevention. Physician offered her to start therapy with alendronate. She wishes to know more about this medication and its side effects before making a decision about therapy.
Which of the following statements about this medication is true?
Educational objective: Review the features of alendronate therapy for osteoporosis.
Alendronate belongs to the class of bisphosphonates. The mechanism of action of the alendronate is the inhibition of osteoclast activity and bone resorption. It was shown in a three-year trial that bone density increases 5-10% and reduces rate of fractures by about 50%. A relative disadvantage of alendronate is its poor absorption from the gastrointestinal tract. Because of that, medication must be taken with a large glass of water on an empty stomach 30 minutes prior to ingestion of any food or beverage or medication for that day. It is relatively contraindicated in patients with gastroesophageal reflux disease. There are no known effects on the cardiovascular system or on cancer risk. The long-term effects of alendronate are not known. Medication is relatively expensive (about $50 per month).
Educational objective: Review diagnostic procedures for insulinoma.
Demonstrating fasting hypoglycemia and an inadequate response of insulin to the hypoglycemia makes diagnosis of insulinoma. The goal is to assess the plasma insulin level and the counter regulatory hormone response while the plasma glucose level is low. Assays should be carried out for glucose, insulin, C-peptide, cortisol, toxins (alcohol), and drugs (sulfonylurea). Demonstration that hypoglycemia is accompanied by inappropriate insulin levels sharply narrows the clinical possibilities.
If the patient is not seen during a hypoglycemic episode, the approach is somewhat different. Patients are fasted under close supervision for up to 72 hours, followed, if necessary, by an exercise tolerance test. Most patients with insulinoma develop hypoglycemia within 24 hours. Diagnostic assays for above substances may then be carried out.
Glucagon level determination is not helpful in any way in assessment of hypoglycemia.
A 65-year-old black female with a history of hypertension and smoking (1 pack per day since age 30) comes in for follow-up. She is not a diabetic and has no personal or family history of coronary artery disease. Her fasting lipid profile is as follows:
Triglycerides: 198 Total Cholesterol: 257 LDL: 151 HDL: 55
What therapy would you initiate for this patient?
Educational objective: Review recommendation for treatment of hyperlipidemia.
The following are guidelines for treatment of hyperlipidemia:
Initiate diet Initiate drug therapy No CAD; less than 2 risk factor >160mg/dl >190mg/dl No CAD; 2 or more risk factor >130mg/dl >160mg/dl Patient with CAD >100mg/dl >130mg/dl
Educational objective: Review the formula for calculation of LDL.
LDL cholesterol is calculated according to following formula: LDL = Total cholesterol - HDL cholesterol - triglycerides/5.
Using this formula results in an LDL cholesterol of 178.
A 47-year-old man was seen in the emergency room for an episode of vomiting some blood. Patient stated that he had a long history of intermittent abdominal pains that were in the past relieved significantly by eating. He denied any weight loss, although he has always been thin. His bowel movements are regular and his stools are usually large, smelly and soft. There is no significant family history of gastrointestinal malignancies, peptic ulcer disease or inflammatory bowel disease that the patient was aware of. He uses ibuprofen occasionally for his chronic left knee pain, which he ascribes to arthritis due to an old sport-related injury. He has taken six 400-milligram tablets within the last week. He is a construction worker and has been under a lot of stress due to the possibility of losing his job because of downsizing in the company.
His initial laboratory data were as follows:
Na – 141 K- 4.1 Cl – 109 CO2 – 28 Cr – 1.1 BUN – 13 Glucose – 89 Albumin – 4.1 Ca – 12.1 AST – 27 ALT – 45 Alk.P – 113 INR – 1.0 Hb – 12.2 Hct – 17.2 WBC – 9.7 Platelets - 134, 000
Endoscopy of the upper gastrointestinal tract revealed a gastric ulcer with a bleeding vessel. Bleeding was successfully stopped by sclerosing the vessel. A mucosal biopsy was performed and the patient was started on a proton pump inhibitor. Which of the following tests is indicated in this patient?
Educational objective: Review indication for serum gastrin measurement in patients with peptic ulcer disease.
This patient has several features that should raise the possibility of Zollinger-Ellison syndrome (gastrinoma). These are hypercalcemia in the face of peptic ulcer disease, and concomitant bulky, smelly diarrhea.
Indications for measurement of serum gastrin level in patients with peptic ulcer disease include all of the following: -Multiple ulcers or ulcers in unusual locations -Ulcers resistant to therapy or with frequent recurrences -Ulcers requiring surgery -Extensive family history of peptic ulcer disease -Postoperative ulcer recurrence -Severe esophagitis -Basal hyperchlorhydria -Unexplained diarrhea or steatorrhea -Hypercalcemia -Family history of pancreatic islet, pituitary, or parathyroid tumor -Prominent gastric or duodenal folds on endoscopy
Ref: Harrison’s Principles of Internal Medicine, 14th edition. Part eleven, Disorders of the Gastrointestinal System. 1997:1613-4.
An 85-year-old female fell at home and sustained a left wrist fracture. In the course of management of this fracture she underwent bone densitometry measurement by dual energy x-ray absorptiometry which revealed the bone density in her lumbar spine to be a 1.5 standard deviation below average and in her hip to be 1.27 below. She is taking one multivitamin every day as well as a 400-mg calcium pill. Examination of the pills revealed that the calcium is in carbonate form. She also likes to drink milk and usually drinks two glasses per day. She does not take any other medications.
Which of the following would be the best management step in this case?
Educational objective: Review current calcium supplementation recommendation for prevention of osteoporosis.
Although there is still considerable debate about the efficacy of calcium supplementation in prevention of osteoporosis it is clear that supplementation of postmenopausal females whose diets contain less than 650 mg/day of calcium and Vitamin D results in suppression of bone loss.
Optimal calcium intake is very hard to determine because it involves expensive and complicated studies of calcium balance. In addition it appears that optimal calcium intake may change in different periods of life. The current recommendation advises optimal calcium intake to be at 1000 mg/day level until puberty onset, when it changes to 1500 mg/day until end of growth and development, at which time it is again 1000 mg/day.
The woman in question needs to increase her calcium intake to 1000 mg daily. There is no need for additional Vitamin D supplementation since she is already taking at least 400 IU in multivitamins, which is the current recommendation (400-800 IU/day). Calcium in citrate maleate form is better absorbed from the intestines than carbonate, but this difference is small and the citrate form is much more expensive.
Ref: NIH Consensus Conference. Optimal Calcium Intake. NIH Consensus Development Panel on Optimal Calcium Intake. JAMA 1994:272(24):1942-48.
A 54-year-old female patient with a history of Sjögren’s syndrome presented with renal colic and was diagnosed with a renal stone. There was no fever or chills. She has been nauseated several times during the last several days but did not vomit at any time, and did not have any diarrhea.
Concomitant laboratory results were as follows: Na – 139 K – 3.3 Cl – 114 CO2 – 18 Cr – 1.4 BUN – 14 Glucose – 99 Ca – 9.1 Total protein – 6.7 Albumin – 3.9 AST – 28 ALT – 34 Alk.Phos.- 121
Urinalysis revealed the following: pH – 6.8 Blood – positive Glucose – negative Bacteria – negative Lk.esterase – Negative
Fractional excretion of bicarbonate was less than 10%.
Which one of the following is most likely the cause of her acidosis?
Educational objective: Review features of renal tubular acidosis.
This patient most likely has renal tubular acidosis type 1 (RTA 1) secondary to Sjögren’s syndrome. RTA 1 is in most instances a secondary disorder and associated with such conditions as Sjögren’s syndrome, lupus, chronic active hepatitis, and hypergammaglobulinemia. A minority is inherited, most commonly as an autosomal dominant trait; but X-linked, autosomal recessive, and sporadic cases have been described.
RTA 1 is a disorder of the distal nephron in which there is either deficiency in hydrogen ion secretion from the blood to the urine, or increased back-diffusion of hydrogen ions back to the blood. This result in decreased daily acid secretion and leads to metabolic acidosis. Acidosis is hyperchloremic metabolic acidosis (normal anion gap), and is associated with hypokalemia. Despite acidosis, urine cannot be maximally acidified and urinary pH is always over 5.5. Because of acidosis, renal tubule calcium reabsorption is diminished, resulting in hypercalciuria and diminished citrate excretion. This leads to development of renal stones and nephrocalcinosis. Rickets may develop in children, and osteomalacia in adults. Fractional excretion of bicarbonate is always below 10% (to compensate for acidosis).
RTA 4 is associated with hypoaldosteronism and is associated with hyperkalemia. In this disorder urinary pH may be lower than 5.5, and there is no association with nephrolithiasis
Ingestion of acids leads to high anion gap metabolic acidosis; there are no reasons to suspect this form of acidosis in this patient. Chronic obstructive pulmonary disease leads to respiratory acidosis, which is usually well compensated. Acidosis of renal insufficiency is seen in end-stage renal disease.
Educational Objective: Illustrate differences in varices formed by splenic vein occlusion vs. portal vein hypertension.
This patient has splenic vein occlusion due to her episodes of pancreatitis. The short gastric veins have become dilated, producing gastric and not esophageal varices. Reducing pressure in the portal system by surgery, TIPS, or pharmacology will not help this situation. Sclerotherapy and banding are a poor second-best therapy to splenectomy.
A 65-year-old man has a long history of alcoholism but is now abstinent. He describes frequent episodes of dull, boring epigastric discomfort radiating to his back. His amylase and lipase levels are normal as is his upper endoscopy. A plain film of his abdomen shows midline calcifications. An MRCP shows a normal pancreatic duct and no evidence of biliary stones.
For therapy of this man’s pain you should order:
Educational Objective: Illustrate therapeutic options for chronic pancreatitis.
Educational Objective: Review the evaluation of pancreatic necrosis.
Up to 80% of patients with severe pancreatitis will develop pancreatic necrosis. The usual time of onset is during the second or third week. Symptoms and signs are pain, fever, and elevated WBC. The diagnosis is made by using a bolus infusion of contrast material during CT scan to demonstrate necrotic areas of the gland.
Your patient has been hospitalized for two weeks with severe pancreatitis. He has fever, abdominal pain, and a persistently elevated WBC. A dynamic CT scan has revealed an area of pancreatic necrosis and a fine needle aspiration of the area has been done.
If the gram stain is negative you would:
Educational Objective: Review the management of pancreatic necrosis.
If the necrotic area is sterile it still has a 40% chance of becoming infected in the future. Treatment with antibiotics lowers this risk. Pancreatic necrosis resolves without complications in 60% of patients.
If the necrotic area is infected, it carries a 60 to 100% mortality treated medically; therefore, surgical debridement is the therapy of choice and can lower mortality to about 20%.
Educational Objective: Review therapy of diabetes in cystic fibrosis.
Endocrine pancreatic dysfunction is seen in about 7% of cystic fibrosis as the pancreas is destroyed by chronic pancreatitis. Because the primary defect is loss of the islets of Langerhans, therapies with agents that treat insulin resistance or stimulate more insulin production are doomed to failure.
An elderly female patient with diabetes mellitus type 2 had a routine checkup with her primary care physician. Interim history revealed no difficulties with medication regimen and no episodes of hypoglycemia. There was an occasional episode of polyuria, but overall there were no signs of poor control. There were no symptoms of target organ damage. Physical examination revealed mildly decreased sense of vibration in both feet, and somewhat diminished pulses over both arteries dorsalis pedis. Laboratory findings were entirely normal with exception of HbA1C-8.9% and microalbumin in a random urine sample of 43 mg/L. This is the first time that her microalbumin turned out to be above normal range.
What is the significance of this finding?
Educational objective: Review of diagnosis for significant microalbuminuria in diabetic patients.
A 24-hour urine collection is the best method for detection of microalbuminuria (gold standard). However, collection is cumbersome and often not complete. Because of this, screening for microalbuminuria is usually performed using either timed urine collection or an early morning specimen to minimize changes in the urine volume production that are common during the day. Random urine specimen is still used despite all the drawbacks. Microalbuminuria is unlikely if albumin excretion is below 20 ìg/min in a timed urine sample or if concentration is less than 20-30 mg/l in a random specimen. Higher values (especially just a little above these values) may represent false positive findings and should be confirmed by a 24-hour urine collection.
Microalbuminuria is not an indication of either renal biopsy or renal ultrasound.
A 39-year-old moderately obese man (body mass index – 33.2) has been diagnosed with diabetes mellitus type 2 after complaining of excessive thirst and urination for the last several weeks. His HbA1C at the time of diagnosis was 8.7%. In the next three months he reduced his body weight significantly, reaching a body mass index of 27.1, by using an intense exercise program and strict diet. His repeated HbA1C was 7.4%, and most of his home glucose measurements were in the range of 80-160 mg/dl. His urine analysis at the follow up visit revealed significant microalbuminuria despite negative finding on first visit.
What is the most likely explanation for his microalbuminuria?
Educational objective: Illustrate importance of false positive findings of microalbuminuria.
Recently it was recommended for increase in the reliability of the detection of the microalbuminuria in random urine samples of diabetic patients to use albumin-to-creatinine ratio. There are, however, two important caveats that must be considered to maximize the reliability of the test.
Vigorous exercise may cause transient increase in albumin excretion and patients should refrain from exercise in the 24 hours prior to test.
Correlation between results of random sample test and 24-hour urine collections is the best if random urine samples are taken in mid-morning.
The fact that patient in question did not have microalbuminuria at the time of diagnosis (before institution of exercise program) suggests exercise as a cause. Diet and such a fast development of diabetic nephropathy are highly unlikely.
Independent renal disease is also much less likely in this setting than exercise-induced microalbuminuria.
Educational objective: Illustrate relation of microalbuminuria to renal histology.
Renal biopsy in diabetic patients with microalbuminuria may vary from relatively normal histologic findings to the clear evidence of diabetic nephropathy. Classical description of focal segmental glomerulosclerosis is not, however, seen in the majority of the patients with overt diabetic nephropathy (this form of the histologic changes is pathognomonic, however).
Normal renal histology is the most common finding in renal biopsy of the patients with microalbuminuria below 45 mg/day.
Educational objective: Review screening recommendation for microalbuminuria in diabetic patients.
Microalbuminuria represents the stage of diabetic nephropathy in which treatment is often successful in preventing progressive renal disease. The ability of angiotensin converting enzyme inhibitors to effectively slow progression of renal impairment in diabetic patients has led to development of recommendations for screening of both diabetics with type 1 and type 2 diseases in yearly intervals. However, screening can be deferred for five years after onset of the disease in type 1 diabetes because microalbuminuria is uncommon until that time. This is not the case with type 2 diabetes in which it is estimated that disease was present on average 5 to 7 years before diagnosis.
Educational objective: Review the therapy for hyperparathyroidism.
This patient has what is most likely a primary hyperparathyroidism. These patients are usually asymptomatic and discovered accidentally as having mild hypercalcemia. This may easily be managed with adequate hydration. Whether these patients can be just monitored is controversial, but therapy must be instituted if complications are present. The most appropriate therapy is surgical parathyroidectomy, and it should be performed on this patient with renal stone disease. Vitamin D and calcium supplementation are contraindicated in this patient since this can result in worsening hypercalcemia. The same is true for thiazide diuretics use, which diminishes urinary calcium excretion.
Educational Objective: Review pancreatic endocrine tumor syndromes.
Ref: 1-. O’Shea D, Bloom S R: Gastrointestinal Endocrine Tumors. Bailliere’s Clinical Gastroenterology 10:571-766, 1996.
Educational objective: Illustrate one difference between MEN-I and MEN-II.
Multiple endocrine neoplasia Type-I involves the pancreatic islets most commonly with a gastrinoma producing Zollinger-Ellison Syndrome (PUD, diarrhea, GERD); up to 5% of Zollinger-Ellison patients will also have ACTH secretion by the gastrinoma. Hyperparathyroidism causes elevation of calcium and renal stones. Tumors of the anterior pituitary can cause elevation of prolactin levels causing galactorrhea.
MEN II is associated with medullary thyroid cancer and pheochromocytoma (hypertension).
Ref: 1. O’Shea D, Bloom S R: Gastrointestinal Endocrine Tumors. Baillier’s Clinical Gastroenterology. 10:571-766, 1996.
Educational objective: Review clinical and laboratory features of hypothyroidism in adults.
This patient presents with clinical signs and symptoms characteristic of hypothyroidism in an adult patient. Of the all tests listed, the serum TSH level is the one to be used in this patient. In fact, TSH measurements should be combined with determination of free thyroxin (FT4). The reason for this is that the patient has a typical presentation, and both tests have the ability to distinguish between primary hypothyroidism (low FT4, and high TSH) and secondary (or tertiary) hypothyroidism (low FT4, and low TSH).
Educational objective: Review important diagnostic points in patients with TSH deficiency.
The TSH (or ACTH) deficiency is relatively unusual and usually indicates panhypopituitarism. Hence, patients with secondary hypothyroidism or hypoadrenilism should undergo a complete assessment of pituitary function and neuroradiologic studies, since panhypopituitarism and large pituitary tumors are common in this setting. Serum prolactin measurements are also essential, since prolactinomas are the most frequent pituitary tumors in adults.
Empty sella syndrome occurs when the subarachnoidal space extends into the sella turcica, partially filling it with cerebrospinal fluid. This process causes remodeling and enlargement of the sella and flattening of the pituitary gland.
Primary empty sella syndrome is caused most commonly by a congenital defect of diaphragma sellae (5-23% incidence on autopsy), and also by pituitary surgery, radiation, and postpartum pituitary infarction (Sheehan’s syndrome). In addition, prolactin-secreting or growth hormone-secreting pituitary adenomas may undergo subclinical hemorrhagic infarction and cause contraction of the overlying suprasellar cistern downward to the sella. Therefore, the presence of an empty sella does not exclude the possibility of a coexisting pituitary tumor.
Most patients are middle-aged women. Many have hypertension. Serious clinical manifestations are uncommon. Spontaneous cerebrospinal fluid rhinorrhea and visual field impairment may rarely occur.
Educational objective: Review diagnostic work-up in cases of galactorrhea.
Prolactin hypersecretion is the most common endocrine abnormality due to hypothalamic-pituitary disorders, and prolactin is the hormone most commonly secreted in excess by pituitary adenomas. The clinical manifestations of prolactin excess are the same regardless of the cause. The classic features are galactorrhea and amenorrhea in females and galactorrhea and decreased libido or impotence in men. Although the sex distribution of prolactinomas is approximately equal, microadenomas (up to 1 cm in size) are more common in females, presumably because of earlier recognition of the endocrine consequences of prolactin excess.
Educational objective: Review therapeutic options for pituitary adenomas.
Pituitary adenomas are treated with surgery, irradiation, and drugs that suppress hypersecretion by the adenoma or it's growth. Pituitary surgery is the initial therapy of choice at many centers, and a transsphenoidal microsurgical approach to the sella turcica is the procedure of choice.
Pituitary radiation is usually reserved for patients with larger tumors and those who have had incomplete resection of large pituitary adenomas. Conventional radiation using high-energy sources in total doses of 4000-5000 cGy given in daily doses of 180-200 cGy is most commonly employed.
Heavy particle irradiation (alpha-particles or protons), and gamma-knife radiosurgery (stereotactic CT-guided delivery of cobalt-60 gamma radiation) are also used.
Medical management of pituitary adenomas includes use of bromocriptine (and other dopamine agonists) for treatment of hyperprolactinemia (and few patients with acromegaly and Cushing’s disease), and use of octreotide acetate (an somatostatin analog) in therapy of acromegaly and TSH-secreting adenomas. Somatostatin itself is not used in therapy.
Educational objective: Review causes of prolactinemia.
There are many causes of hyperprolactinemia besides the pituitary tumor (and those causes must be excluded in the workup of the patient with high prolactin (PRL) levels). Physiologic causes of high PRL are pregnancy, nursing, nipple stimulation, exercise, stress, and sleep. Pharmacologic causes are TRH, estrogen, VIP, all dopamine antagonists (phenothiazines, haloperidol, metoclopramide, reserpine, methyldopa, amoxapine and opiates), MAO inhibitors, verapamil and licorice. Hypothalamic/pituitary stalk lesions, neuraxis irradiation, chest wall lesions (through nipple stimulation reflex), spinal cord lesions, hypothyroidism, chronic renal failure and severe liver disease are also causes of hyperprolactinemia. Lymphocytic hypophysitis is a rare condition leading to hyposecretion of PRL (other causes are hypophiseal destruction, pseudohypoparathyroidism, GABA, and dopamine agonist administration).
Educational objective: Review prognosis of patients with prolactin secreting pituitary adenomas.
In patients with microadenomas, bromocriptine successfully reduces prolactin (PRL) levels to normal in about 80% of the cases. Approximately 10% of patients cannot tolerate the drug long-term because of persisting side effects. Another 10% are resistant to the effects of bromocriptine. Correction of hyperprolactinemia allows the recovery of normal gonadal function (mechanical contraception should be advised if pregnancy is not desired). In patients with microadenomas who become pregnant, the risk of expansion of the adenoma is less than 5% (patient and physician should be aware of this risk).
At present there is no evidence that bromocriptine causes permanent resolution of PRL-secreting microadenomas, and virtually all patients have resumption of hyperprolactinemia following discontinuation of therapy even after several years.
Educational objective: Review clinical features of acromegaly.
This patient has classic symptoms of acromegaly (hypersecretion of the growth hormone – GH). Excessive GH secretion may be secondary to hypothalamic dysfunction, but in most cases it is due to primary pituitary disorder. Pituitary adenomas are present in virtually all patients and are usually greater than 1 cm in diameter. Hyperplasia alone is rare, and nonadenomatous anterior pituitary tissue does not exhibit somatotroph hyperplasia when examined histologically. In addition, there is a return of normal GH levels and dynamic control of GH secretion following selective removal of pituitary adenoma.
Patients with acromegaly (GH secreting pituitary adenoma) have glucose intolerance in 70% of the cases, and hyperinsulinism in 50% of the cases. GH-induced insulin resistance elicits these abnormalities.
Other disturbances of the endocrine system include: Irregular or absent menses Decreased libido or impotence v Hypothyroidism Galactorrhea Gynecomastia Hypoadrenalism
Local manifestations of the pituitary adenoma include enlarged sella turcica, headache, and visual disturbances.
Educational objective: Review diagnostic procedures for acromegaly.
Acromegaly is usually clinically obvious and can be readily confirmed by assessment of growth hormone (GH) secretion. Basal fasting GH level is elevated in more than 90% of patients, but a single test is not adequate because of the fluctuating nature of GH secretion (and also, it is not a dynamic test). Measurements of IGF-1 is a useful means of confirming the diagnosis of GH hypersecretion (those are elevated in virtually all patients with acromegaly – but some commercial assays are not reliable).
Suppression with oral glucose is the simplest and most specific dynamic test for acromegaly. In healthy subjects, oral administration of 100 g of glucose causes a reduction of the GH level to less than 2 ng/mL (93 pmol/L) at 60 minutes. In acromegaly, GH level may decrease, increase, or show no change, but it does not decrease to less than 2 ng/mL, and this lack of response establishes the diagnosis.
Additional procedures that may be helpful are GH stimulation with TRH, the absence of nocturnal GH surge, and paradoxical suppression of GH by levodopa, dopamine, bromocriptine, or apomorphine. These procedures are usually unnecessary except in patients with mild acromegaly with normal or mildly elevated GH levels and equivocal response to glucose suppression.
Educational objective: Review therapeutic options for acromegaly.
The initial therapy of choice is transsphenoidal microsurgery because of its high success rate, rapid reduction of growth hormone (GH) levels, the low incidence of postoperative hypopituitarism, and low surgical morbidity rate. Normalization of GH levels is achieved in over 80% of patients with small adenomas (less than 2 cm), whereas in those with larger tumors and basal GH levels greater than 50 ng/mL (2325 mmol/L), and particularly in those with major extrasellar extension of the adenoma, success rate may be as low as 30-60%.
Conventional external beam supervoltage irradiation is successful in 60-80% of patients, although GH levels may not return to normal until years after irradiation. The incidence of hypopituitarism is also higher than with surgery. Because of these reasons irradiation is reserved for those with persistent elevated GH levels after surgery.
Heavy particle irradiation is more rapidly effective than the conventional method, but because of the irradiation field size limitation, it can be used only in patients with smaller tumors and with no extrasellar expansion. Incidence of hypopituitarism has been reported up to 40%.
Therapy with radioactive implants is limited to a few centers, and because of development of hypopituitarism, CSF rhinorrhea, and meningitis it has not gained acceptance.
Octreotide acetate is effective in about 65% of cases, it is given as subcutaneous injection three times a day and it is expensive. Therefore, it is mostly used in patients who have had incomplete response to surgery or who are awaiting the effect of radiotherapy.
Educational objective: Review adequate postoperative monitoring of patients with acromegaly.
Patients who underwent a surgical removal of GH secreting pituitary adenoma should be seen 4-6 weeks after the operation for assessment of GH secretion and pituitary function. Those with persisting GH hypersecretion should receive further therapy with radiation or octreotide acetate. Patients with postoperative GH levels under 10 ng/mL (460 mmol/L) should have follow-up GH and IGF-1 determination at 6 month intervals for 2 years and yearly thereafter. Late hypopituitarism after surgery alone does not occur. Patients treated with radiotherapy should have biannual assessment of GH secretion and annual assessment of anterior pituitary function, since the incidence of late hypopituitarism is appreciable and increases with time following irradiation.
Educational objective: Review changes that occur in patients with acromegaly after successful therapy.
In patients with successful reduction of growth hormone hypersecretion (acromegaly or gigantism), there is cessation of bone overgrowth. In addition these patients experience considerable clinical improvement, including reduction in soft tissue bulk of the extremities, decreased facial puffiness, increased energy, and cessation of hyperhidrosis, heat intolerance, and oily skin. Headache, carpal tunnel syndrome, arthralgias, and photophobia are also reversible with successful therapy. Glucose intolerance and hyperinsulinemia as well as hypercalciuria are also reversed in most cases.
Educational objective: Review endocrine abnormalities in Cushing’s disease and the most common cause. Cushing’s disease is a primary pituitary disorder. The endocrine abnormalities in Cushing’s disease are as follows: 1. Hypersecretion of ACTH with bilateral adrenocortical hyperplasia and hypercortisolism 2. Absent circadian periodicity of ACTH and cortisol secretion 3. Absent responsiveness of ACTH and cortisol to stress (hypoglycemia or surgery) 4. Abnormal negative feedback of ACTH secretion by glucocorticoids 5. Subnormal responsiveness of GH, TSH, and gonadotropins to stimulation Iatrogenic disease is the most common cause of Cushing’s syndrome, which is a state of hyperglucocorticoidism regardless of the cause.
Educational objective: Review features of Nelson’s syndrome.
The clinical appearance of an ACTH-secreting pituitary adenoma following bilateral adrenalectomy in patents with Cushing’s disease was initially described by Nelson in 1958. It seems likely that Nelson’s syndrome represents clinical progression of a preexisting adenoma after restraint of hypercortisolism on ACTH secretion and tumor growth is removed. The pituitary tumors in patients with classic Nelson’s syndrome are among the most aggressive and rapidly growing of all pituitary tumors. These patients present with hyperpigmentation and with manifestation of expanding intrasellar mass lesion. Visual field defects, headache, cavernous sinus invasion with extraocular muscle palsies, and even malignant changes with local and distant metastases may occur. Pituitary apoplexy may also complicate the course of these tumors.
Elevated ACTH levels and radiographic changes of sella turcica (MRI may accurately define extent of tumor) establish the diagnosis.
Educational objective: Review features of TSH secreting pituitary adenoma.
Thyrothropin-secreting pituitary adenomas are rare tumors manifested as hyperthyroidism with goiter in the presence of elevated TSH. Patients with TSH-secreting tumors are often resistant to routine ablative thyroid therapy, requiring large, often multiple doses of I131 and several operations for control of thyrotoxicosis. Tumors are often large and cause visual impairment that alerts the physician to pituitary abnormality. These patients do not have extrathyroidal systemic manifestations of Graves’ disease such as ophtalmopathy or dermopathy. In a few patients pituitary TSH hypersecretion may be present without a detectable adenoma.
Treatment should be directed initially at the adenoma via transsphenoidal microsurgery. However, additional therapy is usually needed due to the large size of these tumors. Octreotide acetate therapy normalizes TSH and T4 levels in more than 70% of these patients and the tumor may shrink in about 40% of patients.
Pituitary irradiation is also an option, and this patient may further require thyroid ablation to control the thyrotoxicosis.
Educational objective: Review the mechanism of action of ADH.
The major renal effect of the antidiuretic hormone (ADH) is to increase the water permeability of the luminal membrane of the collecting duct epithelium. In the absence of ADH, permeability of the epithelium is very low and reabsorption of water decreases, leading to polyuria. When ADH is present, epithelial permeability increases markedly, and water is reabsorbed as the collecting ducts traverse the renal medulla of ever-increasing osmolality up to a maximum of 1200 mosm/kg at the tip of the papilla. Thus, maximal ADH effect results in low urine flow, and high urine osmolality. With ADH deficiency, urine flow may be as high as 15-20 mL/min and urine osmolality is less than 100 mosm/kg.
Educational objective: Review causes of neurogenic diabetes insipidus.
Causes of neurogenic diabetes mellitus: -Hypophysectomy, complete or partial (may be due to trauma) -Surgery for suprasellar tumors (about 20% in transsphenoidal approach) -Idiopathic -Familial -Tumors or cysts (intra- and suprasellar- raniopharyngiomas, etc.) -Histiocytosis -Granulomas (in sellar and suprasellar area) -Infections (in sellar and suprasellar area) -Interruption of blood supply -Autoimmune
Hypokalemia causes nephrogenic diabetes insipidus.
Educational objective: Review causes of nephrogenic diabetes insipidus.
Causes of nephrogenic diabetes insipidus: - Chronic renal disease - Hypokalemia - Protein starvation - Hypercalcemia - Sickle cell disease - Sjogren’s syndrome - Medications – lithium, fluoride, methoxyflurane anesthesia - Demeclocycline, colchicine - Congenital defect - Familial
Cyclophosphamide is one of the medications that causes vasopressin release, and as such it is the cause of a syndrome of inappropriate ADH secretion.
Educational objective: Review interpretation of tests used in evaluation of polyuria.
Interpretation of the tests used in evaluation of polyuria: - Plasma and urine osmolality: A urine osmolality less than that of plasma is consistent with neurogenic or nephrogenic diabetes insipidus; if both urine and plasma are dilute, that is consistent with psychogenic polydipsia. - Dehydration test: If serum osmolality is less than 295 mosm/kg, allow no fluids for 12-18 h. Measure urine flow, urine specific gravity, urine and plasma osmolality every 2 hours. Terminate study if body weight falls more than 3%. - A rise in urine osmolality above that of plasma osmolality indicates psychogenic polydipsia. - Urine specific gravity of less than 1.005 (or 200 mosm/L) indicates either neurogenic or nephrogenic diabetes insipidus. - Serum vasopressin level at the conclusion of dehydration test: Normal or high vasopressin level usually indicates nephrogenic diabetes insipidus.
Inject 5 units of aqueous vasopressin or 1 µg DDAVP subcutaneously. Measurement of urine flow and urine and plasma osmolality is done. Rise in urine osmolality above that of the plasma indicates neurogenic diabetes insipidus; failure of urine osmolality to rise indicates nephrogenic diabetes insipidus.
It is important to have in mind that plasma osmolality is usually low with psychogenic polydipsia and SIADH, while it is high with any form of diabetes insipidus.
Educational objective: Emphasize association of bronchogenic carcinoma and SIADH.
Conditions associated with syndrome of inappropriate ADH secretion (SIADH): - Malignant lung disease, particularly bronchogenic carcinoma. - Nonmalignant lung disease (eg, tuberculosis, pneumonias) - Tumors at other sites (especially lymphoma, sarcoma) - Central nervous system trauma and infections
Drugs that stimulate vasopressin release: clofibrate, chlorpropamide, thiazides, carbamazepine, phenothiazines, vincristine, cyclophosphamide, opiates.
Endocrine disease – adrenal insufficiency, myxedema, anterior pituitary insufficiency.
Nephrogenic diabetes insipidus is not a cause of hyponatremia. The rest of the options may cause hyponatremia, but in different clinical conditions.
Educational objective: Review therapy for SIADH.
The treatment of SIADH depends upon the underlying cause. A patient with a drug-induced disorder should be treated by withholding the drug. In patients with bronchogenic carcinomas treatment is more complicated and prognosis is often poor. Treatment aims to return plasma osmolality to normal without causing further expansion of the extracellular fluid compartment (this, however, occurs in cases when hyperosmotic solutions are given).
Fluid restriction is the simplest form of treatment, but in the long term the excessive thirst associated with this treatment may be difficult to manage.
If plasma osmolality is low and rapid correction is required, diuretics such as furosemide or ethacrynic acid can be employed. These agents prevent the concentration gradient in the medulla from building up and thus decrease the effectiveness of vasopressin. Because diuresis is accompanied by significant urinary losses of potassium, calcium and magnesium, these electrolytes should be replaced by intravenous infusion.
In an emergency situation with severe hyponatremia, hypertonic saline (3%) or normotonic saline (0.9%) may be administered intravenously. However, this must be done with caution, since fluid overload may precipitate heart failure or circulatory collapse, and overly rapid correction may cause central pontine myelinolysis.
Drugs that reduce the effect of vasopressin on the kidney may be useful, too. Demeclocycline 1-2 g/d orally, causes a reversible form of nephrogenic diabetes insipidus, countering the effects of SIADH. However, demeclocycline is nephrotoxic, and renal function must be monitored carefully. Lithium carbonate has a similar effect, but therapeutic doses are so close to the toxic dose that it is rarely used.
Educational objective: Review factors influencing final body height.
Genetic factors clearly influence the final height of an individual, and good correlation between average parental height and the child’s height exists.
Worldwide, the most common cause of short stature is poverty and its effects. Poor nutrition, poor hygiene, and poor health influence growth both before and after birth. In people of the same ethnic group and the same geographic location, variation in stature is often attributable to these factors. Malnutrition accounts for most of this effect, but it is important to have in mind that malnutrition may occur in the midst of plenty and should be suspected in any disorder of growth (dieting, anorexia, bulimia, etc.).
Aberrant intrafamilial dynamics, psychologic stress, or psychiatric disease can inhibit growth either by altering endocrine function or by secondary effects on nutrition.
Chronic diseases also interfere with growth (asthma, congestive heart failure). In some cases final height may be normal because of prolongation of growth period.
Acute febrile illnesses have no measurable effect on final height.
Educational objective: Review diagnostic criteria for short stature.
Pathologic short stature is usually more than 3.5 SD below the population average, but the diagnosis of pathologic short stature should not usually be based on a single measurement. Serial measurements are required because they allow for the determination of the growth velocity, which is a much more sensitive index of the growth process than the single height determination. Three criteria for pathologically short stature should be considered.
Educational objective: Review the features of different imaging methods for imaging area of thyroid gland and lower neck.
Thyroid ultrasonography is particularly useful for measuring the size of the gland or individual nodules, and for evaluation of the effects of therapy. Also, it is useful to differentiate between solid and cystic lesions. However, this technique is limited to thyroid tissue in the neck and cannot be used for substernal lesions.
Nuclear medicine scans of the thyroid may give a rough estimate of the size and nodularity but no finer details can be elicited.
Chest x-ray may be able to detect some substernal lesions, but certainly is not the method of choice for this purpose.
MRI provides an excellent image of the thyroid gland, including posterior or substernal extension of goiter (or malignancy). MRI is invaluable for the demonstration of tracheal compression from a large goiter, tracheal invasion or local extension of a thyroid malignancy, or metastases to local or mediastinal lymph nodes.
The presence of a white, cheesy, or mucous material suggests external otitis. The pain and tenderness of the ear on manipulation are common on physical examination. This patient is also a diabetic, which increases the risk for infection. Therefore, this patient should be treated with a topical antibiotic. Lavage or instrumentation of the ear as well as use of parenteral antibiotics or topical cerumenolytic agents are contraindicated in the management of external otitis. External otitis must be differentiated from malignant otitis in a diabetic patient due to markedly different approach and potentially fatal complications of the later condition.
The most common presenting symptom and sign of malignant otitis are severe unrelenting otalgia and otorrhea. The degree of drainage varies from copious, foul-smelling, greenish exudate to minimal accumulation of moisture. The mainstay of therapy for malignant otitis is a systemic antipseudomonal antibiotic for 4 to 8 weeks.
Educational objective: Review appropriate diagnostic procedures for thyroid nodule evaluation.
Fine-needle aspiration biopsy of a thyroid nodule has proved to be the best method for differentiation of benign from malignant thyroid disease. It is performed as an outpatient procedure and requires no preparation. A No. 25 - 1.5-inch needle is inserted into the nodule and moved in and out until a small amount of bloody material is seen in the hub of the needle. The needle is then removed, and the content of the needle is expressed onto the clean slide. A thin smear is prepared using another clean glass slide.
The slides are fixed and stained (Wright’s, Geimsa’s or Papanicolau’s stain). The sensitivity of the technique is about 95%, and specificity also about 95%. For best results this method requires adequate tissue sample and a trained cytologist to interpret it.
Educational objective: Review significance of cold nodule visible on thyroid scintigraphy.
Radionuclide scans of the thyroid (using Iodine-123 or Technetium-99m) are useful for determination of the functional status of the thyroid gland (and nodules). Functioning thyroid nodules (those which accumulate radionuclide) are called “hot” nodules, and nonfunctioning are called “cold” nodules. The incidence of malignancy in hot nodules is about 1%, but they may become toxic, producing enough hormone to suppress the rest of the gland and produce thyrotoxicosis. About 16% of surgically removed cold nodules have been malignant. Radionuclide scanning is also useful in looking for large substernal goiters, and particularly, for distant metastases from thyroid cancer (whole body scan). For these purposes Iodine-131 is preferred because of long half-life (about 8 days).
Educational objective: Review different thyroid autoantibodies
Thyroid autoantibodies include: - Thyroglobulin antibody (Tg Ab) - Thyroid peroxidase antibody (formerly called microsomal antibody) (TPO Ab) - TSH receptor stimulating antibody (TSH-R Ab stim) - TSH receptor blocking antibody (TSH-R Ab block)
Tg Ab and TPO Ab have been measured by hemagglutination, ELISA and RIA assays. Hemagglutination is much less sensitive than the later two.
TSH-R Ab stimulating and blocking are measured by a bioassay using human thyroid cells in culture and measuring the increase in thyroid AMP following incubation with serum of IgG. The test for stimulating TSH-R Ab is positive in 90% of patients with Graves’ disease and negative in Hashimoto’s disease, nontoxic goiter, or toxic nodular goiter.
Educational objective: Review clinical features and pathophysiology of neonatal hypothyroidism when mother has Hashimoto’s thyroiditis.
This infant presents with a clinical picture suggestive of hypothyroidism. Neonatal hypothyroidism may result from endemic goiter (due to iodine deficiency), failure of thyroid to descend and develop during embryonic development, and also from placental transfer of TSH receptor blocking antibodies from a mother with Hashimoto’s thyroiditis, which may result in thyroid agenesis (athyreotic cretinism). Other rare causes include administration of iodides, antithyroid drugs, or radioiodine during pregnancy.
The introduction of routine screening of newborns for TSH or T4 has been a major achievement in the early diagnosis of neonatal hypothyroidism. A serum T4 below 6 ìg/dL or serum TSH over 30 ìU/ml is indicative of neonatal hypothyroidism.
Educational objective: Emphasize importance of exclusion of significant cardiac disease before start of levothyroxine supplementation.
Historically, treatment of patients with myxedema and heart disease, particularly coronary artery disease, was very difficult because levothyroxine replacement was frequently associated with exacerbation of angina, heart failure, or myocardial infarction. Today, when coronary angioplasty and coronary artery bypass surgery are widely available, patients with hypothyroidism and signs and symptoms of coronary artery disease should be first evaluated and treated for their cardiac condition, after which levothyroxine replacement is much better tolerated.
Educational objective: Review similarities between hypothyroidism and depression in the elderly.
Hypothyroidism is often associated with depression, which may be quite severe. Also, albeit more rarely, myxedematous may become confused, paranoid, or even manic (“myxedema madness”). Screening of psychiatric admissions with FT4 and TSH is an efficient way to find those patients who will frequently respond to levothyroxine therapy alone or in combination with psychopharmacologic agents. Levothyroxine is also used in low dose to potentiate antidepressive therapy in the patients with major depression.
Educational objective: Review clinical features of myxedematous coma.
Myxedema coma is the end stage of untreated hypothyroidism. It is characterized by progressive weakness, stupor, hypoventilation, hypoglycemia, hyponatremia, water intoxication and hypothermia, which end in shock and death. The patient or family member may recall previous thyroid disease, radioiodine therapy, or thyroidectomy. Onset is gradual. Body temperature may be as low as 24ºC (75ºF), and patients are usually bradycardic. Also most of the time they have clinical signs of long standing hypothyroidism. The laboratory clues to the diagnosis of myxedema coma include lactescent serum, high serum carotene, elevated serum cholesterol, and increased cerebrospinal fluid protein. Of course, low FT4 and high TSH are the rule. Myxedema coma is rare disorder, but it may be more common in the future with the increasing use of radioiodine for treatment of Graves’ disease. Since it occurs mostly in older patients with underlying pulmonary and vascular disease, the mortality rate is very high.
Educational objective: Review therapy for myxedematous coma.
The pathophysiology of myxedema coma involves three major aspects: (1) CO2 retention and hypoxia, (2) fluid and electrolyte imbalance, and (3) hypothermia. The CO2 retention and hypoxia are probably due to a marked depression in the ventilatory responses to hypoxia and hypercapnia, although other factors may also play a role. Impairment of ventilatory drive is often severe, and assisted ventilation is almost always necessary. Thyroid hormone therapy in patients with myxedema corrects the hypothermia and markedly improves the ventilatory response to hypoxia. The major fluid and electrolyte disturbance is water intoxication due to syndrome of inappropriate ADH secretion. This presents with hyponatremia and is managed by water restriction. Hypothermia is frequently not recognized due to use of clinical thermometers that cannot measure below 34ºC (93ºF); thermometers with broader scale must be used. Active rewarming of the body is contraindicated because it may induce vasodilatation and vascular collapse. A rise in body temperature is a useful indicator of the therapeutic effectiveness of thyroxin.
Disorders that may precipitate myxedema coma include heart failure, pneumonia, pulmonary edema, pleural or peritoneal effusions, ileus, excessive fluid administration, or administration of sedatives or narcotics. These, of course, must be addressed in the treatment of the myxedematous patient.
Educational objective: Review appropriate monitoring of patients on levothyroxine therapy.
In primary hypothyroidism, the goal of therapy is to maintain plasma TSH within the normal range. Plasma TSH should be measured 2-3 months after initiation of therapy. The dose of thyroxine then should be adjusted in 12- to 25-mcg increments at intervals of 6-8 weeks until plasma TSH is normal. Thereafter, annual TSH measurement is adequate to monitor therapy
Educational objective: Review causes of thyrotoxicosis.
Conditions associated with thyrotoxicosis: Diffuse toxic goiter (Graves’ disease) Toxic adenoma (Plummer’s disease) Toxic multinodular goiter Subacute thyroiditis Hyperthyroid phase of Hashimoto’s thyroiditis Thyrotoxicosis factitia Rare forms – ovarian tumors, metastatic thyroid carcinoma (follicular), hydatiform mole, “hamburger thyrotoxicosis’, TSH-secreting pituitary tumor, pituitary resistance to T3 and T4
Educational objective: Review clinical features of Graves’ disease.
This person presents with the classic clinical signs of hyperthyroidism and dermopathy suggestive of Graves’ disease. Common manifestations of Graves’ disease include palpitations, nervousness, easy fatigability, hyperkinesias, diarrhea, excessive sweating, intolerance to heat, and preference for cold. There is often a marked weight loss without loss of appetite. Thyroid enlargement, thyrotoxic eye signs (described below), and mild tachycardia commonly occur.
More rare manifestations include thyroid osteopathy (subperiostal bone formation – especially on metacarpal bones) and onycholysis. Dermopathy of Graves’ disease is also rare (2-3% of patients) and is usually associated with ophtalmopathy and a very high titer of the TSH-R stimulating antibody. The skin is markedly thickened and cannot be picked up between the fingers, it is most pronounced over distal tibias, and it is due to accumulation of glycosaminoglycans. Thyroid ophtalmopathy is due to infiltration of the extraocular muscles with lymphocytes, and edema in an acute inflammatory reaction, which causes proptosis of the ocular globe and impaired muscle movement causing diplopia.
Patient is presenting with signs of hyperthyroidism, elevated FT4, and low TSH. He does not have any eye symptoms or signs. Which of the following tests is the appropriate next step in the workup?
Educational objective: Review the role of radioiodine uptake measurements in patients with hyperthyroidism.
A laboratory finding of an elevated FT4 and a suppressed TSH makes a diagnosis of hyperthyroidism. If thyroid ophtalmopathy is present, diagnosis of Graves’ disease may be made without further tests. If the eye signs and symptoms are absent and the patient is hyperthyroid with or without goiter, a radioiodine uptake test should be done. An elevated uptake is diagnostic of Graves’ disease or toxic nodular goiter. A low uptake is seen in patients with spontaneously resolving hyperthyroidism, as in subacute thyroiditis or a flare-up of Hashimoto’s thyroiditis. Low uptakes will also be found in patients who are iodine-loaded, or are on T4 therapy, or, rarely, in association with struma ovarii.
Educational objective: Review atypical presentations of Grave’s disease.
In the syndrome of familial dysalbuminemic hyperthyroxinemia, an abnormal albumin-like protein is present in serum that preferentially binds T4 but not T3. This results in elevation of FT4 and T4; but free T4, T3 and TSH are normal. Also, the signs and symptoms of hyperthyroidism are absent. It is important to recognize this euthyroid state and differentiate it from hyperthyroidism. All other options are in fact described variants of Grave’s disease presentation which must be recognized to avoid delay in the diagnosis.
Educational objective: Recognize signs of neutropenia in patients taking PTU.
Besides the rash that occurs in about 5% of patients, the most important side effect of the antithyroid therapy with propylthiouracil or methimazole is agranulocytosis, which occurs in approximately 0.5% of patients. Agranulocytosis requires immediate cessation of all antithyroid drug therapy, institution of appropriate antibiotic therapy, and shifting to an alternative therapy, usually radioactive iodine. Agranulocytosis is usually heralded by sore throat and fever. Thus, all patients receiving antithyroid drugs are instructed that if sore throat and fever develops, they should stop the drug, obtain a white blood cell and differential count, and see their physician. If the white blood cell is normal, the antithyroid drug can be resumed.
Cholestatic jaundice, angioneurotic edema, hepatocellular toxicity, and acute arthralgia are other serious but rare side effects that also require cessation of therapy. Skin rash usually can be managed by a simple administration of antihistamines, and unless it is severe it is not an indication for discontinuation of the therapy.
Educational objective: Review consequences of thyroid surgery.
Subtotal thyroidectomy is the treatment of choice for patients with very large glands or multinodular goiters. The patient is prepared with antithyroid drugs until euthyroid (usually about 6 weeks). In addition, starting 2 weeks before the day of the surgery, the patient is given saturated solution of potassium iodide, 5 drops twice daily. This regimen has been shown empirically to diminish the vascularity of the gland and to simplify surgery.
Total thyroidectomy is usually not necessary unless the patient has severe progressive ophtalmopathy. However, if too much thyroid tissue is left behind, the disease will relapse. Most surgeons leave 2-3 g of thyroid tissue on either side of the neck. Many patients, however, require thyroid supplementation after surgery because of hypothyroidism.
Hypoparathyroidism and recurrent laryngeal nerve injury occur as complications of surgery in about 1% of cases. Carotid sinus is well outside the operative field and is not affected by it.
Educational objective: Review basic features of radioiodine therapy.
In the U.S.A., sodium iodide (I131) is the preferred treatment for most patients over age 21. In many patients without underlying heart disease, radioactive iodine may be given immediately in the dosage of 80-120 ìCi/g of thyroid tissue estimated on the basis of physical examination and sodium I123 scan. Dosage is also corrected for iodine uptake according to the following formula:
I 131 (ìCi/g) X thyroid weight X 100/24-h RAI uptake = dose
In patients with underlying heart disease, severe thyrotoxicosis, or large glands (>100g), it is desirable to achieve a euthyroid state before radioactive iodine is started. These patients are treated with antithyroid drugs until they are euthyroid. Medication is then stopped for 5-7 days, radioactive iodine uptake and scan are performed, and dose is calculated based on weight and uptake. For these patients dose is somewhat greater – 100-150 ìCi/g thyroid tissue. Following the administration of radioactive iodine, the gland will shrink, and the patient will usually become euthyroid over period of 6-12 weeks.
The major complication of radioactive iodine therapy is hypothyroidism, which ultimately develops in 80% or more of patients who are adequately treated. However, this complication may indeed be the best assurance that hyperthyroidism will not reoccur. Serum FT4 and TSH levels should be followed, and when hypothyroidism develops, prompt levothyroxine replacement should be started.
Educational objective: Review therapeutic options for ophthalmopathy associated with Grave’s disease.
Management of ophthalmopathy due to Graves’ disease requires cooperation between endocrinologist and ophthalmologist. Total surgical or radioiodine thyroid ablation certainly prevents recurrence of the Graves’ disease and relapses of thyrotoxicosis, which may reactivate ophtalmopathy. A course of prednisone after radioiodine therapy will prevent a transient rise in thyroid antibodies. Keeping the patient’s head elevated during the night will diminish periorbital edema. For those with severe acute inflammatory reaction, a short course of corticosteroids (eg, prednisone, 100 mg/d for 7-14 days), then every other day in diminishing dose for 6-12 weeks is prescribed. If corticosteroid therapy is not effective, external x-ray irradiation of the retrobulbar area may be helpful. The lens and anterior eye chamber must be shielded.
In severe cases where vision is threatened, orbital decompression can be used. This can be achieved by transantral approach through maxillary sinus, removing the floor and lateral wall of the orbit. An alternative approach is beneath the globe removing the pars of the floor and walls of the orbit. Both approaches are quite effective and may reduce exophtalmos by 5-7 mm in each eye. After the acute process has subsided, the patient is frequently left with double vision or lid abnormalities owing to muscle fibrosis and contractures. These can be corrected by cosmetic lid surgery or eye muscle surgery.
Educational objective: Review therapeutic options for thyrotoxicosis during pregnancy.
Thyrotoxicosis in pregnancy presents a special problem. Radioactive iodine is contraindicated because it crosses the placenta freely and may injure the fetal thyroid. Two alternative approaches are available. If the disease is detected in the first trimester, the patient may be prepared with propylthiouracil, and a subtotal thyroidectomy can be performed safely during the mid trimester. It is essential to provide thyroid supplementation for the rest of the pregnancy. Another option is to treat a patient with antithyroid drugs throughout the pregnancy, postponing the decision regarding long-term management until after pregnancy. The dosage of the antithyroid drugs must be kept at the minimum necessary to control the disease, because these drugs cross the placenta and may affect the function of the fetal thyroid gland. The FT4 and FT4 I should be maintained in the upper range of normal. Breast-feeding is not contraindicated because propylthiouracil is not concentrated in the milk.
Educational objective: Review therapy for Plummer’s disease.
A functioning adenoma hypersecreting T3 and T4 will cause hyperthyroidism (Plummer’s disease). These adenomas start out as “hot nodules” on the thyroid scan, slowly increase in size, and gradually suppress the rest of the thyroid. The typical patient is an older individual (usually over 40) who has noted recent growth of a long-standing thyroid nodule. Symptoms of weight loss, weakness, shortness of breath, palpitations, tachycardia, and heat intolerance are noted. Infiltrative ophtalmopathy is never present. Physical examination reveals a definitive nodule on one side with very little thyroid tissue on other side.
Laboratory studies usually reveal suppressed TSH and marked elevation in serum T3 levels, often with only borderline high thyroxin level. Toxic adenomas are almost always follicular adenomas and almost never malignant. They are usually easily managed by administration of antithyroid drugs (PTU or methimazole) followed by treatment with radioactive iodine or unilateral thyroid lobectomy.
Radioactive iodine in doses of 20-30 mCi is usually required to destroy benign neoplasm.
Educational objective: Review the role of radioiodine therapy in toxic multinodular goiter.
This disorder usually occurs in older patients with a long-standing multinodular goiter. The goiter may be small or large, or even substernal. Radioiodine scan reveals multiple functioning nodules in the gland.
The management of the toxic multinodular goiter is difficult. Control of the hyperthyroidism with antithyroid drugs, followed by subtotal thyroidectomy would seem to be the therapy of choice, but often these patients are elderly and have illnesses that make them poor candidates for surgery. The toxic nodules may be destroyed by radioactive iodine, but the multinodular goiter remains; other nodules can become toxic later in life and require multiple doses of radioiodine for therapy.
Educational objective: Emphasize the risk of amiodarone for development of thyrotoxicosis.
Amiodarone is an antiarrhythmic drug that contains 37.3% iodine. In the body, it is stored in fat, myocardium, liver and lung. The half-life of the amiodarone in the body is approximately 50 days. About 2% of patients treated with amiodarone develop iodine-induced thyrotoxicosis. This presents a very difficult problem.
Patients taking amiodarone usually have a serious underlying heart disease, and in many cases amiodarone cannot be discontinued. If the thyrotoxicosis is mild, it can often be controlled with methimazole (40-60 mg/day) while amiodarone therapy continues. If the disease is severe, KCIO4 in a dose of 250 mg every 6 hours may be added to saturate the iodide trap and prevent further uptake of iodide.
Long-term therapy with KCIO4 has been associated with aplastic anemia and requires careful monitoring. The only way to eliminate the large store of intrathyroidal hormone would be to surgically remove the goiter. This would be feasible only if the patient could withstand the stress of a thyroidectomy.
Educational objective: Review the etiology of nontoxic goiter.
Etiology of nontoxic goiter:
The common feature of all these conditions is a low level of thyroid hormones and a consequent high level of TSH, which induces thyroid cell hyperplasia.
Educational objective: Review possible etiology of subacute thyroiditis.
Subacute thyroiditis, also termed granulomatous, giant cell or de Quervain’s thyroiditis is viral in origin. Symptoms of thyroiditis usually follow those of an upper respiratory infection and include pronounced asthenia, malaise, and symptoms referable to stretching of the thyroid capsule, principally pain over the thyroid or pain referred to the lower jaw, ear or occiput. Referred pain may predominate. Occasionally, thyrotoxicosis may be associated with the disorder. A number of viruses, including mumps virus, coxsackievirus, and adenoviruses have been implicated, either by finding the virus in a biopsy specimen taken from the gland or by demonstration of rising titers of viral antibodies in the blood during the course of infection.
A 52-year-old postmenopausal woman with an intact uterus presents to your office requesting treatment for hot flashes and vaginal dryness. She has heard about hormone replacement therapy but does not want to resume menstruation. Her father had a myocardial infarction at age 51, and her mother had a hip fracture at age 80. Her paternal grandmother died of breast cancer in her seventies.
The physical examination, including breast examination, is normal. A recent mammogram showed no abnormalities. Laboratory studies show a total cholesterol concentration of 208 mg/dL; HDL cholesterol of 41 mg/dL; and triglycerides of 103 mg/dL. A dual X-ray absorptiometry (DEXA) bone density study shows normal bone density in the spine but a diminished density at the femoral neck.
The best therapy for this woman is:
The best therapy for this woman is daily low-dose continuous estrogen and progesterone. She has symptoms of estrogen deficiency (hot flashes and vaginal dryness) and is at increased risk for cardiovascular disease (positive family history and abnormal lipid profile) as well as osteoporotic fractures (positive family history and decreased bone density in the hip area). Vaginal estrogen creams will help vaginal symptoms but have no effect on hot flashes or risk from cardiovascular disease or osteoporosis. The use of PO or transdermal estrogens alone is contraindicated in women with a uterus because of their effect on endometrium (hyperplasia). The addition of progesterone provides protection against the effects of unopposed estrogen.
Among the regimens that combine estrogen with progesterone, transdermal estrogen preparations have the least beneficial effect on the lipid profile; therefore an oral estrogen/progesterone regimen is preferable in this woman. Since she does not wish to resume uterine bleeding, therapy with low-dose continuous estrogen and progesterone is more likely to result in an atrophic endometrium and amenorrhea than cyclic estrogen–progesterone regimens. The family history of breast cancer in one second-degree relative is not a contraindication to the use of estrogen.
Bisphosphonate therapies are shown to have beneficial effects on bone mineral density but there is no effect on rest of the postmenopausal syndrome.
A morbidly obese 44-year-old man is 180cm tall and weighs 148 kg (body mass index, 43.7kg/m2). He has poorly-controlled hypertension on a diuretic and b-blocker, and diabetes mellitus with glycosylated hemoglobin 11%, and currently takes metformin 1 g twice daily. Previous efforts at exercise and dietary therapy, including a very low-calorie diet, have failed in multiple occasions over the last 10 years.
The treatment that would most likely produce long-term weight reduction in this patient is:
Vertical gastric banding and gastrojejunal bypass are surgical procedures that have similar efficacy causing weight loss and may be indicated in a small subset of patients with morbid obesity (body mass index greater than 40 kg/m2), particularly those patients who have other cardiovascular risk factors that cannot be medically controlled, such as hypertension and diabetes. Jejunoileal bypass has adverse health consequences, and jaw wiring has high failure rates.
The NIH Consensus Development Conference Panel in 1991 concluded that patients whose body mass index exceeds 40 kg/m2 are potential candidates for surgery if they strongly desire weight loss, and that weight-reduction surgery has been reported to improve comorbid conditions such as hypertension, sleep apnea and obesity-associated hypoventilation, frank diabetes mellitus, glucose intolerance, and serum lipid abnormalities. Weight regain is common in long-term follow-up of surgically treated patients, although it is probably less than that of patients treated with nonsurgical measures. Surgery is primarily a “last-resort” option for morbidly obese patients when all nonsurgical measures have failed, particularly for patients with uncontrolled comorbid diseases that have serious health consequences and that might improve with weight reduction.
Exercise is a useful adjunct to dietary therapy, both because of the mild additional weight loss it may promote and the fact that it may preserve lean muscle mass as body fat is reduced. However, even vigorous exercise programs only produce modest weight loss. Since previous dieting has failed in this patient (including a very low calorie diet program, that is, < 800 kcal/d), it is unlikely that either exercise or behavioral therapy plus dieting will produce substantial long-term weight loss in this morbidly obese patient.
Appetite suppressants combined with dieting can produce greater weight loss than dieting alone. However, most patients regain weight once pharmacotherapy is discontinued, and therefore the current debate is whether chronic use of appetite suppressants may be warranted in some patients. Cyclic use is typically not recommended, especially because some experts are concerned about the adverse health consequences of the wide fluctuations in body weight associated with periodic intense dieting followed by regain of weight. Another drug that has proven to be effective in clinical trials is dexfenfluramine, but additional weight loss attributable to dexfenfluramine (compared to placebo) is modest (3 to 5 kg), and primary pulmonary hypertension is a rare but serious potential complication.
Hyperpigmentation in patients with Cushing’s syndrome is induced by increased ACTH secretion. ACTH is the principal pigmentary hormone in humans. It acts by binding to melanocyte-stimulating hormone receptors. Degree of hyperpigmentation is dependent upon duration and the degree of ACTH secretion. Hyperpigmentation occurs most often in patients with ectopic ACTH syndrome, less often in pituitary overproduction of ACTH, and not at all in patients with adrenocortical tumors in whom ACTH secretion is suppressed. Hyperpigmentation in Cushing’s syndrome patients is less pronounced than in patients with primary adrenal insufficiency.
Increased release of epinephrine, glucagons, and to a lesser degree, growth hormone and cortisol are the most important components of the response of the body to hypoglycemia. Insulin secretion, of course, diminishes. Secretion of the aldosterone is not associated with blood glucose levels in any significant way.
The following thresholds have been identified in the response to graded reductions in blood glucose:
These thresholds were established with measurements of arterialized venous blood in which the glucose concentration is approximately 3 mg/dL higher than the in venous blood.
Primary adrenocortical insufficiency (Addison’s disease) is characterized by inadequate secretion of the adrenal steroids resulting from partial or complete destruction of the adrenal gland.
Etiologic causes are as follows:
Educational objective: Review laboratory findings in subacute thyroiditis.
Laboratory studies in subacute thyroiditis vary with the course of the disease. Initially, T3 and T4 are elevated and TSH is low. As the disease progresses T3 and T4 will drop to low levels and TSH will rise. During the acute phase, the most consistent laboratory finding is elevated erythrocyte sedimentation rate (sometimes as high as 100 mm/h by the Westergren scale) and extremely low radioactive iodine uptake (after the acute phase radioiodine uptake will gradually rise to the normal levels, reflecting the recovery of the gland from the acute insult). Thyroid antibodies are not usually detected in the serum.
A 37-year-old female presents with an enlarged and tender thyroid gland for the last 1 week. Physical examination reveals modest enlargement of the thyroid but exquisite tenderness on palpation. There is no erythema of the overlying skin and no fluctuation that would suggest abscess.
Heart rate is 72 min, blood pressure 117/67 mm/Hg, T3 and T4 are in the normal range. ESR is 78 mm/h, and radioiodine uptake is 3%.
Which of the following medications would be the most appropriate for this patient?
Educational objective: Review therapy for subacute thyroiditis.
This patient has symptoms, signs, and laboratory results consistent with subacute thyroiditis. In most cases, only symptomatic treatment is necessary. In mild cases acetaminophen (500 mg four times daily) is a good choice. If pain, malaise, and fever are more disabling, a short course of nonsteroidal anti-inflammatory drug (eg, ibuprofen) or a glucocorticoid such as prednisone for 7-10 days may be necessary to reduce the inflammation. Levothyroxine (0.1-0.15 mg/day) is indicated during the hypothyroid phase of the illness in order to prevent re-exacerbation of the disease induced by the rising levels of TSH. In about 10% of patients, permanent hypothyroidism ensues and long-term levothyroxine therapy is necessary.
Educational objective: Review medications that interfere with levothyroxine therapy.
Reasons for changing levothyroxine dose in patients on a previously stable dosage:
Requirement for increased dose:
Requirement for decreased dose:
Educational objective: Emphasize importance of â-blockers in therapy of hyperthyroidism.
In many tissues, hyperthyroidism is associated with an enhanced number of â-adrenergic receptors. The ensuing increase in â-adrenergic activity is responsible for many of the symptoms associated with this disorder. It also explains the ability of B-blockers to ameliorate many of the symptoms, including palpitations, tachycardia, tremulousness, anxiety, and heat intolerance.
Propranolol in high doses (above 160 mg/day) can also decrease the plasma T3 concentration by as much as 30%, probably via inhibition of the 5’-monodeiodinase that converts T4 to T3 (propranolol has a short half-life and this severely limits its clinical utility). Atenolol, and metoprolol cause minimal reduction in plasma T3 levels, while sotalol and nadolol produce no reduction.
The B-blockers should be given to all hyperthyroid patients who do not have a contraindication to their use. They are typically co-administered with anti-thyroid drugs.
Educational objective: Review effects of hypothyroidism on bone.
Overt hyperthyroidism is associated with accelerated bone remodeling, reduced bone density, osteoporosis, and an increase in fracture rate. Bone density changes may or may not be reversible with therapy. These changes in bone metabolism are associated with negative calcium balance, hypercalciuria, and, rarely, hypercalcemia (in about 8% of patients). Histomorphometric studies of iliac crest bone biopsies revealed that cortical bone is affected to a much greater extent than trabecular bone. The extent of the reduction in bone density in most studies of hyperthyroid patients ranges from 10-20%. The extent of reversibility is unclear, but just calcium supplementation is clearly not enough to ensure reversibility or diminished resorption (treatment of hyperthyroidism is, of course, the mainstay of the prevention of bone loss in these patients).
Educational objective: Review lipid abnormalities in hypothyroidism.
Many hypothyroid patients have high serum concentrations of total cholesterol and low-density-lipoprotein (LDL) cholesterol, and some have high serum concentrations of triglycerides, intermediate-density lipoproteins, apoprotein A-1, and apoprotein B.
Using Frederickson’s classification, it was shown that about 56% of hypothyroid patients have type IIa dyslipidemia (hypercholesterolemia), 34% have type IIb (hypercholesterolemia and hypetriglyceridemia), 1.5% type IV (hypertriglyceridemia), and 8.5% no abnormality.
HDL cholesterol concentrations have been reported as high, normal, and low in different series.
Educational objective: Review cardiac effects of hypothyroidism.
The major cardiovascular changes that occur in hypothyroidism include a decrease in cardiac contractility and mass, a reduction in heart rate, and an increase in peripheral vascular resistance. Symptoms and signs of cardiovascular dysfunction are not common or prominent in patients with hypothyroidism. Exertional dyspnea and exercise intolerance are typical, although these symptoms are probably due to decreased activity or muscle dysfunction in most cases. Bradycardia is the most common rhythm disturbance, but premature ventricular beats are seen, and, rarely, ventricular tachycardia with a long QT interval (torsade de pointes).
Approximately 20-40% of the patients with hypothyroidism have hypertension, even though cardiac output is reduced. A few patients have a pericardial effusion, which is rarely hemodynamically important. Periorbital edema and nonpitting edema of the hands and feet are characteristic features of hypothyroidism and are due to interstitial accumulation of glycosaminoglycans, with associated water retention.
Educational objective: Review the features of anaplastic thyroid cancer.
Anaplastic thyroid carcinomas are undifferentiated tumors of the thyroid follicular epithelium. Anaplastic carcinomas are very aggressive tumors with a disease-specific mortality approaching 100%. Early recognition is essential to allow prompt initiation of therapy and to maintain hope for significant response. The annual incidence of anaplastic carcinoma is about two per million persons.
Approximately 20% of patients with anaplastic carcinoma have a history of differentiated thyroid carcinoma, and another 20-30% have associated differentiated carcinoma. The great majority are papillary carcinomas, but follicular have been described.
Nearly all patients with anaplastic thyroid cancer present with a thyroid mass. However, the disease has already spread either locally within the neck or distantly in more than 90% of the cases. In the neck the affected structures include perithyroidal fat and muscle, lymph nodes, larynx, trachea, esophagus, tonsil, and great vessels. Distant metastases are found in 15-50% of the patients. The lungs are the most common site of distant metastases (90% of the patients with distant disease). Other sites of metastases are bone, brain and skin.
Symptoms include neck pain and tenderness, compression (and invasion) of upper airways with dyspnea (35%), dysphagia (30%), hoarseness (25%), cough (25%). Less common symptoms are chest pain, bone pain, headache, confusion, or abdominal pain from metastases. All other options are highly unlikely.
Educational objective: Review pathophysiology of Hashimoto’s disease.
Hashimoto’s thyroiditis is thought to be an immunologic disorder in which lymphocytes become sensitized to thyroidal antigens. There are three most important thyroid autoantibodies: thyroglobulin antibody (Tg Ab), thyroid peroxidase antibody (formerly known as microsomal antibody) (TPO Ab), and TSH receptor-blocking antibody (TSH-R Ab block). During the early phases of Hashimoto’s thyroiditis, Tg Ab is markedly elevated and TPO Ab is slightly elevated. Later Tg Ab may disappear but TPO Ab will be present for many years. TSH-R Ab-block is found in patients with atrophic thyroiditis and myxedema and in mothers giving birth to infants with no detectable thyroid tissue (athyreotic cretins).
Antimitochondrial antibodies are present in patients with primary biliary cirrhosis and autoimmune hepatitis.
Educational objective: Review pathohistologic findings in Hashimoto’s disease.
This patient has clinical and laboratory features of Hashimoto’s thyroiditis. The pathology of Hashimoto’s thyroiditis involves heavy infiltration of lymphocytes totally destroying the thyroidal architecture. Lymphoid follicles and germinal centers may be formed. The follicular epithelial cells are frequently enlarged and contain basophilic cytoplasm (Hurtle cells).
Extensive fibrosis of the thyroid gland extending outside the gland and involving overlying muscle and surrounding tissues is characteristic of Riedel’s struma.
Marked atypia of the follicular epithelium with visible mitoses is only a part of the histologic picture of the thyroid cancer. Infiltration of the glandular tissue with polymorphonuclear leucocytes and areas of the necrosis may be seen in rare pyogenic thyroiditis (bacterial seeding of the thyroid tissue).
Educational objective: Review risk of thyroid cancer after radiation exposure.
The incidence of thyroid lesions after irradiation has been carefully studied. As little as 6.5 cGy to the thyroid gland received during the radiation treatment for tinea capitis has been reported to cause cancer in 0.11% of exposed children. Radiation therapy delivered to the thymus results in a much higher radiation dose to the thyroid (100-400 cGy), and incidence of cancer in the thyroid gland attributed to this source ranges from 0.5% to 5%.
X-ray therapy to the neck and chest was in the past given to children for acne and chronic upper respiratory infections. Dose delivered to the thyroid was 200-1500 cGy and resulted in development of nodular goiters in up to 27% of cases and cancer in 5-7% (these tumors develop 10-40 years after irradiation with peak incidence in the range of 20-30 years). Similar incidence (40% for nodular goiter and 6% for thyroid cancer) was found in cases of irradiation due to radioactive fallout where doses to the thyroid were estimated at 700-1400 cGy.
Radioiodine ablation therapy exposes the thyroid to doses of around 10,000 cGy and is rarely associated with development of thyroid cancer, presumably because the thyroid gland is largely destroyed by these doses, so that incidence of thyroid cancer is extremely low.
Educational objective: Review relative ratios of different thyroid carcinomas.
Approximate frequency of malignant thyroid tumors
Papillary carcinoma 75% Follicular carcinoma 16% Medullary carcinoma 5% Undifferentiated carcinoma 3% Miscellaneous (lymphoma, fibrosarcoma squamous cell, hemangioendotelioma, teratoma, and metastatic cancers) 1%
A 73-year-old Caucasian woman wants to assess her risk of osteoporosis. She has a 53-year history of smoking but currently does not smoke. She began menopause at age 53 and has not taken any hormonal replacement therapy. She is thin, with a body mass index of 24. All laboratory findings are within the normal range.
Dual x-ray bone densitometry is performed and reveals average bone density in the lumbar spine of 0.5 standard deviations (SD) above the average for young adults with uneven distribution of the bone density. Bone density of the L3 is 2.3 SD over the average while L2 and L4 are 1.5 SD below the average. Measurement over the trochanteric region of the left hip reveals bone density of 3.5 SD below the average.
Which of the following statements best describes her bone status?
Educational objective: Review diagnostic criteria for osteoporosis.
The World Health Organization defines osteoporosis as a bone mineral density of 2.5 standard deviations (SD) or more below the average peak bone density (peak bone mass and density are achieved during young adulthood). There is no need to have a fracture to establish the diagnosis (as was necessary in the past). Osteopenia is a milder form of bone loss and is defined as bone density between 1-2.5 SD below the young adult average.
This patient has clearly severely diminished bone density in the areas of the hip. Her bone density in the lumbar spine area is still normal on average, but uneven distribution of density in the area suggests bone condition that is altered with degenerative changes, bone spurs, and even compressive fractures that may not be easily detected using only densitometry as a imaging modality. These changes and others (overlying vascular calcifications and scoliosis) make the lumbar area less than ideal for the assessment of bone mineral status in the elderly, although imaging in the lateral projection may overcome these difficulties.
Educational objective: Emphasize diabetes mellitus and acromegaly as independent risk factors for development of colonic carcinoma.
There is increasing evidence that diabetes mellitus is an independent risk factor for the development of colorectal cancer. The Nurses’ Health Study is the prospective cohort study of about 120,000 women that found that relative risk for colon cancer in women with diabetes is increased (relative risk – 1.43). This association was maintained even when results were adjusted for age, body mass index, and other covariates.
A possible explanation for this association is in hyperinsulinemia. Insulin is known to be an important growth factor for colonic mucosal cells and a stimulator of colonic tumor cell growth.
Other options offered as answers have no association with colorectal cancer.
The only other endocrinologic condition known to increase the risk of colorectal cancer is acromegaly.
Educational objective: Emphasize ability of captopril to produce a false positive ketone test on routine urinalysis.
Diagnosis of diabetic ketoacidosis (DKA) is suspected from the history and the presence of hyperglycemia with a high anion gap metabolic acidosis. Confirmation requires demonstration of glycosuria and ketonuria or ketonemia. Testing for ketones is usually done with nitroprusside based tests (reagent sticks or tablets). Captopril particularly, but also sulfhydryl drugs (Penicillamine, etc.), can interact with the nitroprusside reagent to produce a false positive ketone test. Captopril is widely used in the treatment of diabetic nephropathy and hypertension in patients with DM. In a patient suspected of having DKA and taking captopril, a diagnosis must be made on clinical grounds or by the measurement of â-hydroxybutyrate.
Educational objective: Review the changes in potassium metabolism during DKA.
Although most patients presenting with DKA have initially elevated blood levels of potassium, this is not the reflection of increased body stores. In fact, their potassium stores are depleted (on average 3-5 mg/kg at presentation). Both renal (increased urinary losses due to the glucose osmotic diuresis and maintenance of electroneutrality as ketoacid anions are excreted) and gastrointestinal losses (vomiting and diarrhea) contribute to the potassium loss.
However, blood potassium level is most commonly either normal or elevated because of translocation of potassium out of the cells into the extracellular fluid. Acidemia had been thought to play a major role in this response, but other mechanisms may be involved (hyperkalemia occurs also in nonketotic hyperglycemia despite lack of acidosis).
Educational objective: Review therapy of DKA.
Treatment of DKA consists of correction of acidosis, hyperglycemia, and hyperosmolality by the effects of administration of insulin, correction of hyperglycemia and hypovolemia by infusion of the fluid, and correction of potassium and phosphate depletion. However, repletion of phosphate depletion should be done only in patients who remain hypophosphatemic 12-24 hours after correction of acidosis, and then it should be administered by oral supplementation rather than IV route. Studies have shown no benefit of early IV supplementation of phosphate (as potassium phosphate addition to IV fluid), and there have been several cases of hyperphosphatemia described (even one case of seizure).
Educational objective: Review the appropriate use of insulin infusion in patients with DKA.
Insulin infusion for patients with DKA acts to lower plasma glucose levels (decreased hepatic glucose production and enhancement of peripheral utilization), diminish ketone bodies production (reduction in lipolysis and glucagon secretion), and possibly enhance ketone body utilization. Infusion should be adjusted to result in an hourly decrease of blood glucose level of 100-200 mg/dl (correction of the fluid deficit also contributes to decreasing glucose levels somewhat). Faster rates of correction may lead to rapid fluid shifts and cerebral edema.
Bicarbonate abnormality (reflecting metabolic acidosis) will be corrected parallel to hyperglycemia by the insulin infusion.
Educational objective: Emphasize fact that if blood glucose is not decreasing adequately it is necessary to double the dose of insulin infusion in patients with DKA.
The usual starting dose of insulin infusion is 8-15 units per hour (after loading dose of 15-20 U is given initially to saturate any anti-insulin antibodies that may be present). This dose is large enough to drop the blood glucose concentration for as much as 500 mg/dl per hour in normal individuals made hyperglycemic by the combination of glucose infusion and somatostatin administration. However, the response of patients in DKA is not as brisk, and it reflects a partial insulin resistance. That is the reason for such high hourly infusion rates. Some patients are, however, resistant even to these doses, and the hourly dose should be doubled if the expected reduction in the plasma glucose concentration is not seen within two or three hours.
Indications for measurement of serum gastrin level in patients with peptic ulcer disease include all of the following:
This patient with chronic pancreatitis and normal ductal diameter would not be helped by procedures designed to alleviate ductal pressure such as stents (temporary) or longitudinal pancreaticojejunostomy. Pancreatic enzymes can inhibit cholecystokinin release but only if a rapid release formula is used and its degradation is decreased by acid suppression.
A 62-year-old man with his first episode of pancreatitis has been in the hospital under your care for the last two weeks. His pain has been difficult to control. He has a low-grade fever and his WBC’s have not decreased below 16,000.
You decide to:
If renal biopsy is performed in patients with recent onset diabetes mellitus type 2 with microalbuminuria of 40 mg/day, which of the following would be the most likely histologic finding?
