Profound hypothyroidism--a clinical review with eight recent cases: is it right before our eyes?

Clinical Review

Prevalence and Epidemiology

The clinical spectrum of hypothyroidism is diverse, multisystem, and easily overlooked for months or years. (1) Mild cases of thyroid dysfunction are a familiar occurrence in practice, often discovered incidentally by virtue of abnormal thyroid function tests obtained in patients with few or nonspecific symptoms. (2) This is not surprising, for the prevalence of hypothyroidism varies from 1 to 20% depending on age, sex, and presence of antithyroid antibodies. Among 2,779 patients in England, 7.5% of females and 2.8% of males were found to have elevated thyroid-stimulating hormone (TSH) levels above 6 mU/L, with goiter in 8.6%. (3) During 20 years of follow-up, the odds ratio for developing overt hypothyroidism among females increased eightfold with the presence of elevated TSH alone and 38-fold if TSH was elevated and antithyroid antibodies were present; in men the odds ratios were 44- and 173-fold, respectively. The range of TSH levels varied from 6 to 77 mU/L in this cohort. (4) A recent population survey of 25,862 patients in the United States revealed agedependent frequencies of hypothyroidism of 21% among females and 16% among males over the age of 74, with TSH levels ranging from 1 to 80 mU/L. (5) Profound hypothyroidism, however, is rarely reported in the United States, relegated more to historical accounts (6) than to actual practice. To our knowledge, no contemporary series of patients with severe thyroid deficiency has been published. This review will focus on the panorama of manifestations of profound hypothyroidism, update clinicians on diagnosis and management of severe disease, and feature eight illustrative cases.

Etiology

At the time of Gull's first description (7) of severe hypothyroidism (soon termed myxedema (8) based on mucin content ["myx"] and swollen skin ["edema"]) among adults in London, the cause of the syndrome was obscure. Subsequent observations of British citizens who had undergone thyroidectomy revealed a disturbing number of puffy, cold, lethargic, depressed, and socially impaired patients. Further study of 109 cases (9) led to revolutionary insight into myxedema as being due to "annihilation of the function of the thyroid body."

Since then, numerous etiologies have been documented. The most frequently proven antecedents are infectious (viral) or immunologic (Hashimoto) thyroiditis, recent pregnancy, prior irradiation for Graves disease, and thyroidectomy. Less common causes include infiltrative conditions (sarcoid, carcinoma), drug-induced states, inadequate iodine intake, congenital enzyme deficiencies, and disorders relating to TSH resistance. Many cases are idiopathic, with nondiagnostic clinical and laboratory investigations. A complete etiologic classification is presented in Table 1.

Clinical Presentation

Depending on the severity and duration of thyroid deficiency, a myriad of clinical manifestations may lead to the diagnosis. (1) The common denominator is hypometabolism, evidenced by lethargy, cold intolerance, and functional compromise--although these suggestive signs may have insidious onset easily overlooked by the physician seeing the same patient on a long-term basis. The neuropsychiatric symptoms range from mild depression to generalized weakness, sluggishness, forgetfulness, steady personality decline, and psychomotor retardation. Carpal tunnel syndrome and progressive deafness may develop. A characteristic bedside indicator of profound hypothyroidism is prolonged ankle jerk relaxation phase (AJRP). From a dermatologic standpoint, the skin is cool, dry, and rough, with coarse hair, brittle nails, and hair loss. Absence of lateral eyebrows (Queen Anne sign) may be noted. Periorbital and facial edema are usually prominent. Weight gain, or inability to lose weight, with refractory constipation or ileus, are the main gastrointestinal findings. The cardiopulmonary manifestations typically involve poor exercise tolerance, dyspnea on exertion, bradycardia, peripheral edema (wooden, nonpitting), and frank congestive heart failure, often with pleural or pericardial effusions. Low voltage complexes may be evident on the electrocardiogram. Hypoventilation, hoarseness, goiter, and sleep apnea may be noted. In patients of reproductive age, excessive menstrual bleeding, infertility, and reduced libido are common. The spectrum of clinical features of hypothyroidism is presented in Table 2.

Laboratory Investigations

An elevated serum TSH level, coupled with low serum free or total tetraiodothyronine (T4) concentration, is diagnostic of primary hypothyroidism, regardless of etiology. Higher TSH elevations correlate with greater reduction in T4 concentrations. TSH elevations exceeding 20 mU/L, coupled with depressed T4 levels, are predictive of symptomatic disease, while high titers of anti-thyroid peroxidase and antimicrosomal (AMA) antibodies in asymptomatic patients predict eventual progression to overt hypothyroidism. (10, 11) Among a group of 138 women with TSH levels between 1 and 79 mU/L, elevated TSH above 12 mU/L was linked to metabolic compromise in skeletal muscle, myocardial contractility, lipid metabolism, and AJRP. (12) In contrast, the term "subclinical hypothyroidism" applies to asymptomatic patients with mild TSH elevations (less than 20 mU/L) but normal serum T4 concentrations. Among routine laboratory tests, unexplained elevations of creatine phosphokinase (CPK), cholesterol, and red blood cell mean corpuscular volume (MCV) are suggestive of metabolically significant hypothyroidism.

Diagnosis of Hypothyroidism

Because severe hypothyroidism requires months or years to develop, wide variability in clinical presentation may delay or confound diagnosis. (13) In typical practice, multisystem signs and symptoms of a hypometabolic state involving numerous organs in a lethargic, chilly, poorly functioning patient, coupled with a TSH level far exceeding 20 mU/L and depressed T4 concentration, confirm the presence of severe hypothyroidism. More specific manifestations include cold intolerance, fatigue, depression, mental dullness, constipation, coarse skin, hoarseness, puffy eyelids, bradycardia, and delayed AJRP. (14) Marked stupor, confusion, hypothermia, hypoventilation, bradycardia, and somnolence indicate the presence of myxedema coma and require immediate treatment in an intensive care setting. (15) Published scoring systems derived from patients known to be hypothyroid may assist clinicians in clarifying the wide ranging symptoms and findings common in practice. (16)

Treatment of Hypothyroidism

The vast majority of hypothyroid patients will require permanent T4 replacement. In patients with severe thyroid deficiency, older age, or concomitant ischemic heart disease, therapy must begin with low dose thyroxine, such as 25 [micro]g daily, to avoid agitation, palpitations, and angina during emergence from the low metabolic state. (17) The daily dose may be increased gradually every 4 to 6 weeks by 25 [micro]g intervals. Younger patients with less severe disease may safely begin therapy with 50 to 100 [micro]g of thyroxine daily. Prompt symptomatic improvement is quite gratifying in formerly hypometabolic patients, with return of mentation, vigor, thermal stability, and cardiopulmonary function within days to weeks. Once patients return to euthyroid status, with normalization of TSH to less than 5 mU/L, usual replacement doses of thyroxine are 100 to 150 [micro]g daily, commensurate with the known daily glandular production of 100 [micro]g of T4 in normal subjects.

Patients with profound hypothyroidism may also have silent adrenal hypofunction that can be exacerbated by thyroid hormone replacement. Such patients require additional therapy with supplemental corticosteroids (prednisone 5 mg daily, or equivalent) for the first week of thyroid replacement to avoid precipitation of adrenal insufficiency, commonly referred to as Schmidt syndrome. (18) These complications have been recently highlighted by two cases in Kansas with TSH levels of 68 and 230 mU/L coupled with high AMA titers and low cortisol levels. (19) Disoriented, hypothermic patients thought to be in myxedema coma mandate aggressive therapy with intravenous thyroxine, steroids, antibiotics, mechanical ventilation, and external warming for this life-threatening condition.

Follow-up of Hypothyroidism

With gradual replacement of thyroid hormone, most hypothyroid manifestations are reversible over a 6 to 12 month follow-up period. (20) Return to normal physical and social functional status is the expected outcome once full thyroxine doses of 100 to 150 [micro]g daily are achieved. Normalization of TSH, CPK, cholesterol, and MCV should likewise occur within this time frame. Clinicians should follow TSH levels every 6 months thereafter to assure compliance with therapy and adequacy of dosage. For most patients, treatment must be lifelong. Exceptions may apply to females with postpartum autoimmune thyroiditis. In such women, thyroid antibody titers usually normalize within 6 to 12 months after delivery, at which time thyroid hormone replacement may safely be discontinued and TSH levels monitored. (21)

Eight Illustrative Cases

We report a noteworthy series of patients with profound hypothyroidism, with average TSH values of 400 mU/L (range: 205-652 mU/L). All were seen in recent years in one practice after lack of detection by multiple clinicians in diverse specialties at our hospital and other institutions.

A total of 8 patients, ages 24 to 81, are reported. Five (62%) were female; 7 (88%) were white. All patients were evaluated at the Medical College of Georgia between 1989 and 2001. Five were seen as outpatients in the Family Medicine Center for a variety of complaints. Three were admitted to the Family Medicine Inpatient Service after referral from other physicians for diagnoses and laboratory abnormalities not attributed to thyroid deficiency. Suspicion of thyroid dysfunction was first generated in each case by bedside examination and subsequently confirmed by laboratory testing. Rewarding clinical improvement consistently accompanied thyroid hormone replacement, often in dramatic fashion. Laboratory data for all cases is summarized in Table 3.

Case Reports

Patient 1

A 30-year-old white female reported 1 year of fatigue, apathy, hoarseness, neck swelling, and cold intolerance. She worked as a medical receptionist in the presence of several physicians and nurses. She experienced increasing difficulty answering phone calls due to deepened voice quality and delayed responses to callers (Fig. 1). Prior clinical impressions included depression, job stress, and laryngitis. There was no response to antidepressant medication. On examination, she was found to have a deep, gruff voice, periorbital edema, 40 gram goiter, and delayed AJRP. Cholesterol, CPK, and MCV were elevated. Extreme TSH elevation of 417 mU/L and decreased T4 of 1.7 [micro]g/dL confirmed the presence of severe hypothyroidism. AMA titer of 1:1,600 suggested autoimmune thyroiditis as the etiology. She received thyroxine 25 [micro]g daily and prednisone 5 mg daily for 1 week, with upward titration of thyroxine every 4 weeks to a maintenance dose of 125 [micro]g daily. Vigor returned, voice improved, and temperature tolerance normalized within 1 month. Cholesterol, CPK, MCV, and TSH normalized within 5 months. She received advanced medical training and was promoted to a nursing position in the same office.

Patient 2

A 61-year-old white female reported 2 years of fatigue, cold intolerance, mental dullness, dyspnea, hoarseness, dry skin, constipation, anemia, and hyperlipidemia. She had been under the care of five physicians in different specialties, with diagnoses including vocal cord polyps which were resected, diverticulosis with segmental colon resection, anemia requiring transfusion, and elevated cholesterol refractory to high-dose statin medication. On initial evaluation (Fig. 2), she displayed marked psychomotor retardation, cool dry skin, periorbital edema, thick-tongued speech, and delayed AJRP. Cholesterol was elevated despite therapy. CPK was elevated as well. Extreme TSH elevation of 335 mU/L, with decreased T4 less than 1.0 [micro]g/dL and triiodothyronine (T3) of 54 ng/mL confirmed the bedside impression of severe hypothyroidism. She received thyroxine 25 [micro]g daily with prednisone 7.5 mg daily for one week, after which thyroxine was titrated upward every 4 weeks to a maintenance dose of 100 [micro]g daily. Vigor, cognition, cold intolerance, dry skin, and constipation improved within 2 weeks. Voice quality improved in 1 month, at which time TSH decreased to 123 mU/L, CPK normalized to 92 U/L, and cholesterol decreased to 233 mg/dL without statin therapy. At 2 months, she resumed active housework and driving alone. T4 rose to 9 and TSH normalized after 5 months of therapy.

[FIGURE 1 OMITTED]

Patient 3

A 36-year-old white female was referred to the Family Medicine Inpatient Service for disability evaluation. She had suffered 2 years of progressive fatigue, weakness, and apathy, necessitating a rolling walker to ambulate. She claimed to have had "several strokes" and was seen repeatedly by multidisciplinary specialists at an academic center in a major city. Her husband had to feed her and manage all household chores. On examination, she had a depressed mood, delayed verbal responses, juvenile language, periorbital edema, and absent deep tendon reflexes. She required two assistants to stand and ambulate on her walker. Computed tomography revealed no brain infarcts or demyelinating lesions. An electrocardiogram demonstrated low voltage. Cholesterol and CPK were elevated. TSH was markedly elevated at 652 mU/L, with T4 less than 1.0 [micro]g/dL and T3 less than 50 ng/dL, confirming the clinical impression of profound hypothyroidism. The AMA titer was less than 1:100, suggesting an idiopathic etiology. She received thyroxine 25 [micro]g daily with dexamethasone 0.5 mg daily for the first week. Within 2 weeks, she was much stronger, could walk alone, and used adult-level language. T4 rose to 1.5, and TSH decreased to 615. She did not feel a need to pursue disability claims any further and was referred back to her hometown physicians for follow-up care.

[FIGURE 2 OMITTED]

Patient 4

A 38-year-old white male experienced 1 year of progressive fatigue, weakness, lethargy, cold intolerance, mental dullness, and erratic driving while working as a forklift operator and serving as an usher in a large urban church. He was evaluated in the Family Medicine Center at the insistence of his wife who had earlier requested clomiphene for her inability to conceive a second child. An infertility workup revealed no female etiology. The husband's fatigue and apathy were attributed to overwork. He had received radioiodine therapy for Graves disease at age 16, with erratic physician follow-up for over 20 years. On evaluation (Fig. 3), he displayed slow mentation, thick-tongued speech, periorbital edema, and delayed AJRP. The clinical impression of postirradiation hypothyroidism was confirmed by detection of a TSH of 612 mU/L and T4 less than 1.0 [micro]g/dL. Cholesterol and CPK were elevated. Testosterone was low at 146 ng/dL (normal: 270-1070). Semen analysis revealed extensive abnormalities in sperm anatomy and motility. He received thyroxine 50 [micro]g daily with prednisone 5 mg daily for 7 days. Within 6 months, energy level rebounded, eyelid edema resolved, mental acuity returned, driving improved, CPK normalized, and T4 rose to 4.9 [micro]g/dL with TSH down to 29 mU/L, on thyroxine 150 [micro]g daily. TSH, testosterone, and semen analysis normalized in 8 months. The couple celebrated the birth of a healthy daughter 11 months later.

[FIGURE 3 OMITTED]

Patient 5

An 81-year-old black male complained of 2 years of worsening weakness, fatigue, dyspnea, cold intolerance, constipation, and "a bad heart." He had visited an urban emergency department on at least 16 occasions in an 8-month span, with diagnoses including chronic obstructive pulmonary disease exacerbation, bronchitis, decompensated congestive heart failure, and chronic constipation. He was admitted for inpatient evaluation on four occasions for possible myocardial infarction based on dyspnea and unexplained elevations in CPK. Various cardiopulmonary medications were of limited or no benefit. On referral to the Family Medicine Inpatient Service (Fig. 4), he was observed to be mentally dull, with eyes partially open, bradycardia, hypoactive bowel sounds, and absent ankle jerks. CPK was elevated at 3,110 U/L, with 100% MM fraction. MCV was elevated. Clinical suspicion of hypothyroidism was confirmed by TSH of 336 mU/L, with T4 less than 1.0 [micro]g/dL and T3 of less than 50 ng/mL. He was treated with thyroxine 25 [micro]g daily and prednisone 20 mg daily for 1 week (begun the previous week for "chronic obstructive pulmonary disease flare"). Over the next 8 months, vigor and bowel function returned, dyspnea and temperature sensitivity resolved, emergency department visits ceased, CPK normalized, and TSH diminished to 55, with thyroxine titrated to 100 [micro]g daily. TSH returned to normal in 10 months. Overall function dramatically improved, and he avoided nursing home placement.

[FIGURE 4 OMITTED]

Patient 6

A 24-year-old white female had 4 months of fatigue, weakness, irritability, sadness, reduced libido, profuse hair loss, and inability to lose weight, following the birth of her second child 6 months earlier. She assisted her husband with leadership of a large church youth group but found her performance compromised due to worsening fatigue and mood disturbance. She attended a physician-directed weight loss clinic without success and withdrew due to fatigue. Symptoms were attributed to postpartum depression. On initial evaluation, a 30-gram goiter and frontal hair loss were detected, along with normal mentation and AJRP. The clinical impression of hypothyroidism was confirmed by a TSH of 384 mU/L, T4 less than 1.0 [micro]g/mL, and T3 diminished at 49 ng/mL. Values for CPK, MCV, and cholesterol were normal. AMA titer was 1:102,400, documenting the presence of postpartum autoimmune thyroiditis. (21) With thyroxine 50 [micro]g daily and upward titration, she regained strength, endurance, and emotional stability within 3 months, and lost 14 pounds with renewed capacity for aerobic exercise. TSH fell to 3 mU/L, T4 rose to 8.4 [micro]g/mL, and AMA titer decreased to 1:25,600. All laboratory values normalized within 6 months, as did mood and functional status.

Patient 7

A 61-year-old white male had 2 years of slowly worsening weakness, fatiguability, hoarseness, difficulty hearing, cold intolerance, dry skin, constipation, and puffiness of eyelids. Due to progressive dyspnea, deafness, and inability to perform farm chores, he was evaluated by several physicians. Diagnoses included "heart attack" based on elevated CPK levels, and "gallstones" due to nonvisualization of gallbladder on oral cholecystogram. He failed a treadmill stress test due to fatigue and dyspnea. He was referred to the Family Medicine Inpatient Service for cardiac assessment before cholecystectomy. On initial evaluation, he required assistance to ambulate (Fig. 5) and was noted to have psychomotor retardation, coarse skin and hair, gravelly voice, moderate deafness, periorbital edema, bradycardia, and markedly delayed AJRP. CPK was elevated at 898 U/L, with 100% MM fraction. Cholesterol was elevated. Electrocardiogram revealed bradycardia with low voltage but no evidence of myocardial infarction. Liver function tests were normal as was gallbladder ultrasound. The clinical impression of hypothyroidism was confirmed by TSH of 205 mU/L, with decreased T4 less than 1.0 [micro]g/dL and T3 of 54 ng/dL. He received 25 [micro]g of thyroxine daily with prednisone 5 mg daily for 1 week. Within 2 months of thyroxine titration to 100 [micro]g daily, he and his family noted renewed vigor and strength, temperature stability, improved voice and bowel function, and ability to hear normal spoken voice. CPK and cholesterol fell to 194 U/L and 185 mg/dL, respectively. TSH decreased to 168 mU/L, with T4 increased to 1.7 [micro]g/dL and T3 up to 100 ng/dL. Within 6 months of thyroid replacement, TSH normalized and the patient went deer hunting, drove his bulldozer, and chopped firewood without difficulty.

[FIGURE 5 OMITTED]

[FIGURE 6 OMITTED]

Patient 8

A 58-year-old white female wanted a primary care doctor. She had been seeing neurologists for 35 years for management of a posttraumatic seizure disorder and phenytoin refills. On initial visit to the Family Medicine Center, she reported infrequent seizures but over 1 year of worsening fatigue, weakness, dry skin, hair loss, cold intolerance, poor hearing, constipation with bleeding hemorrhoids, memory loss, and depression. Physical examination (Fig. 6) revealed a thin, puffy, dull-appearing female with psychomotor retardation, xerosis, deep voice, poor hearing, eyebrow loss, coarse hair, periorbital edema, and prolonged AJRP. Several large, oozing external hemorrhoids were observed. Phenytoin was in the therapeutic range. The clinical impression of hypothyroidism was confirmed by TSH of 263 mU/L with T4 less than 1.0 [micro]g/dL and T3 of 34 ng/dL. Cholesterol and CPK were normal. Hemoglobin was 5.8 g/dL, with reduced MCV of 64 fL and low transferrin saturation of 1%, consistent with chronic hemorrhoidal blood loss. She was treated with thyroxine 25 [micro]g daily and prednisone 5 mg daily for 7 days, with oral iron supplementation and stool softeners. Within 2 months of thyroxine titration to 100 [micro]g daily, she noted increased vigor and mental acuity (Fig. 7), absence of temperature sensitivity, vast improvement in bowel habits, and reduction in rectal bleeding. TSH fell to 30 mU/L, with T4 increased to 5 [micro]g/dL. Hemoglobin increased to 12.4 g/dL with MCV of 83 fL. At 10 months of follow-up, she felt wonderful, bought new clothes, enjoyed renewed harmony with family and friends, and had a TSH of 4 mU/L, T4 of 6.6 [micro]g/dL, and hemoglobin of 14 g/dL.

Discussion

This memorable cohort of cases clearly demonstrates that some patients with profound hypothyroidism may elude diagnosis for long periods of time, even under the scrutiny of multiple physicians, nurses, hospital and clinic staff, fellow employees, public associates, and family members. The multisystem manifestations of thyroid failure may be subtle in onset, the consequence of a destructive or autoimmune process from decades previously, and require months or years for clinical recognition. (14) Typical signs, symptoms, or laboratory values may be viewed in isolation and are often mistaken for a variety of nonthyroidal conditions. Accurate detection is dependent on correlation of multiple abnormal bedside and laboratory findings in a patient with reduced functional capacity and evidence of a hypometabolic state. Based on the sensitivities and specificities of a recently developed 14-point scoring system, (16) our patients would have been readily diagnosed as hypothyroid according to the constellation of bedside findings evident in each case.

[FIGURE 7 OMITTED]

Several known manifestations of hypothyroidism were shared by 75% or more of our cases, including weakness, fatigue, lethargic mental status, cold intolerance, and periorbital edema, consistent with descriptions in recently published textbooks. (13,15) A prominent bedside finding--and a well-described diagnostic sign of hypothyroidism--was delayed AJRP, present in four of eight cases. (16,20,22) Generalized weakness due to thyroid myopathy is documented by unexplained elevations in CPK approaching 10 times normal values, but without other evidence of muscle involvement. With thyroid replacement, weakness resolves and CPK levels typically correct within 6 months, (20) as was observed in five of our eight cases, in which pretreatment CPK values averaged 1,055 U/L. Hyperlipidemia reflects downregulation of receptors and delayed low-density lipoprotein clearance, with prompt correction with thyroxine therapy. (23,24) In five of our cases, cholesterol was elevated (average: 303 mg/dL) and responded favorably to thyroxine replacement. Elevation of the MCV attributed to ineffective erythropoiesis has been reported in hypothyroid patients (25) and was observed in two of our cases. Each corrected with thyroid hormone replacement alone.

These eight patients are eye-opening reminders to physicians that thoughtful history taking and attentive bedside evaluation are of paramount importance in patients with multisystem disorders. The ability of thyroid failure to masquerade as nonthyroidal illness is well recognized, especially if clinicians limit focus to only one organ system or laboratory value. (26) It is noteworthy that none of these cases had a fatal outcome despite markedly hypometabolic states and long-standing vulnerability to precipitating illness, a tragic sequence described by others. (27-30)

Conclusion

The fact that all eight of the cases described here were seen by one family physician in an academic setting suggests that profound hypothyroidism may be more prevalent than is currently appreciated by busy professionals in primary care or specialty practices across the United States. A nationwide, longitudinal analysis of 17,353 US patients (31) revealed hypothyroidism in 4.6%, from which the authors extrapolated the startling estimate that 8 million Americans "unknowingly have laboratory evidence of thyroid disease." To our knowledge, no case series of patients with such extreme TSH elevations and laboratory abnormalities as we observed has been published in this country. Profound hypothyroidism among central African villagers with huge goiters, TSH levels of 700 to 1,000 mU/L, and high rates of endemic cretinism has been reported and would be instantly recognized by professionals and family members in an overseas setting. (32) Yet our eight patients had somehow "slipped through the cracks" in the sophisticated American medical system.

Moreover, based on the lethargy and metabolic compromise observed in our patients, perhaps the disorder deserves a descriptive pseudonym: "hyposlow-roidism." Presumption of this syndrome as a mere historical curiosity is amplified in a recent textbook (33): "Severe hypothyroidism has become increasingly rare in the US due to physicians' raised level of consciousness regarding the high prevalence in women, and the ease of laboratory diagnosis." Our series would indicate that such cases may not be so rare after all, although obscured by misdiagnosis for long periods of time. We agree with Nicoloff and LoPresti (27) that "the frequency of making this diagnosis is proportional to the physician's awareness of the syndrome." How apt is the claim by the German philosopher von Goethe from 170 years ago: "What is the most difficult thing of all? To see with the eyes, that which lies before the eyes."

One doesn't discover new lands without consenting to lose sight of the shore for a very long time.

--Andre Gide

Table 1. Etiologic classification of primary hypothyroidism (a)

Autoimmune    Hashimoto thyroiditis; post-Graves disease; postpartum
Infectious    acute or subacute viral thyroiditis
Destructive   neck irradiation; postoperative; radioiodine therapy;
                infiltrative conditions
Drug related  PTU; methimazole; lithium; amiodarone; iodides; iodine
                deficiency
Congenital    agenesis; enzymatic deficiencies; TSH resistance; endemic
                cretinism
Idiopathic

(a) PTU, propylthiouracil; TSH, thyroid-stimulating hormone.

Table 2. Multisystem manifestations of hypothyroidism (a)

General           fatigue; asthenia; hypothermia; weight gain; anemia;
                    elevated cholesterol
Dermatologic      dry coarse skin; brittle hair; hair loss; nonhealing
                    skin ulcers; Queen Anne eyebrows; nonpitting
                    peripheral edema
Ear, nose,        hearing loss; hoarseness; thick tongued speech;
  throat            periorbital edema; facial puffiness; goiter
Pulmonary         dyspnea on exertion; hypoventilation; sleep apnea;
                    pleural effusion
Cardiac           bradycardia; congestive heart failure; pericardial
                    effusion; low voltage ECG
Gastrointestinal  anorexia; constipation; paralytic ileus
Genitourinary     menometrorrhagia; loss of libido; impotence;
                    infertility
Neuromuscular     muscle weakness; bradykinesia; delayed ankle jerk
                    relaxation phase; elevated CPK
Psychiatric       depression; apathy; memory loss; personality change;
                    psychomotor retardation; pseudodementia; coma


(a) ECG, electrocardiogram; CPK, creatine phosphokinase.

Table 3. Laboratory values for each patient (a)

          TSH          T4          T3      MCV     Chol      CPK

Normal      0.4-4.7   4.8-11.2    55-137   80-100  100-240     21-232
          mU/L       [micro]/dL  ng/dL    fL       mg/dL    U/L
Case 1    417         1.7        115      105      304        416
Case 2    335        <1.0         54       98      555      1,400
Case 3    652        <1.0        <50       98      330        759
Case 4    612        <1.0         61       91      369      1,616
Case 5    336        <1.0        <50      104      192      3,110
Case 6    384        <1.0         49       99      226        185
Case 7    205        <1.0         54       86      296        898
Case 8    263        <1.0         34       64      178         52
Average   400        <1.0         58       93      303      1,055

(a) TSH, thyroid-stimulating hormone; T4, thyroxine; T3,
triiodothyronine; MCV, red blood cell mean corpuscular volume; Chol,
cholesterol; CPK, creatine phosphokinase.

Acknowledgment

The authors are grateful to Edwin D. Bransome Jr, MD, and to Anthony L. Mulloy, PhD, DO, of the Medical College of Georgia, Division of Endocrinology, for their manuscript insights based on a combined 52 years of practice in endocrinology.

Accepted December 17, 2003.

Copyright [c] 2004 by The Southern Medical Association

0038-4348/04/9705-0490

References

1. Shapiro LE, Surks MI. Hypothyroidism, in Becker KL (ed): Principles and Practice of Endocrinology and metabolism. Philadelphia, Lippincott, Williams, and Wilkins, 2001, ed 3, 445-454.

2. Cooper DS. Subclinical hypothyroidism. N Engl J Med 2001;345:260-265.

3. Tunbridge WMG, Evered DC, Hall R, et al. The spectrum of thyroid disease in a community: the Whickham survey. Clin Endocrinol 1977;7:481-493.

4. Vanderpump MPJ, Tunbridge WMG, French JM, et al. The incidence of thyroid disorders in the community: a twenty year follow up of the Whickham survey. Clin Endocrinol 1995;43:55-68.

5. Canaris GJ, Manowitz NR, Mayor G, et al. The Colorado thyroid disease prevalence study. Arch Intern Med 2000;160:526-534.

6. Nickerson JF, Hill SR Jr, McNeil JH. Fatal myxedema, with and without coma. Ann Intern Med 1960;53:475-493.

7. Gull WW. On a cretinoid state supervening in women in adult life. Trans Clin Soc London 1874;7:180-185.

8. Ord WM. On myxoedema, a term proposed to be applied to an essential condition in the cretinoid affection occasionally observed in middle aged women. Med Chir Trans 1878;61:57-78.

9. Ord WM. Report of a committee of the Clinical Society of London nominated December 14, 1883 to investigate the subject of myxoedema. Trans Clin Soc Lond 1888;298-300.

10. Rosenthal MJ, Hunt WC, Garry PJ, et al. Thyroid failure in the elderly: microsomal antibodies as discriminant for therapy. JAMA 1987;258:209-213.

11. Pearce EN, Farwell AP, Braverman LE. Thyroiditis. N Engl J Med 2003;348:2646-2655.

12. Staub JJ, Althaus BU, Engler H, et al. Spectrum of subclinical and overt hypothyroidism: effect on TSH, prolactin, and thyroid reserve, and metabolic impact on peripheral target tissues. Am J Med 1992;92:631-641.

13. Wiersinga WM. Hypothyroidism and myxedema coma, in Degroot LJ, Jameson JL (eds): Endocrinology. Philadelphia, Saunders, 2001, ed 4, 1491-1506.

14. Chiu AC, Sherman SI. Clinical manifestations and differential diagnosis of hypothyroidism, in Falk SA (ed): Thyroid Disease: Endocrinology, Surgery, Nuclear Medicine, and Radiotherapy. Philadelphia, Lippincott-Raven, 1997, ed 2, pp. 379-391.

15. Heymann WR, Klein A, Ingbar DH, et al. Organ system manifestations of hypothyroidism, in: Braverman LE, Utiger RD [eds], The Thyroid: A Fundamental and Clinical Text. Philadelphia, Lippincott, Williams, and Wilkins, 2000, ed 8, 774-847.

16. Zulewski H, Muller B, Exer P, et al. Estimation of tissue hypothyroidism by a new clinical score: evaluation of patients with various grades of hypothyroidism and controls. J Clin Endocrinol Metab 1997;82:771-776.

17. Hueston WJ. Treatment of hypothyroidism. Am Fam Physician 2001; 64:1717-1724.

18. Carpenter CCJ, Solomon N, Silverberg SG et al. Schmidt's syndrome (thyroid and adrenal insufficiency): a review of the literature and a report of fifteen new cases including ten instances of co-existent diabetes mellitus. Medicine 1964;43:153-180.

19. Graves L III, Klein RM, Walling AD. Addisonian crisis precipitated by thyroxine therapy: a complication of type 2 autoimmune polyglandular syndrome. So Med J 2003;96:824-827.

20. Horak HA, Pourmand R. Endocrine myopathies. Neurol Clin 2000;18:203-213.

21. Muller AF, Drexhage HA, Berghout A. Postpartum thyroiditis and autoimmune thyroiditis in women of childbearing age: recent insights and consequences for antenatal and postnatal care. Endocrin Rev 2001;22:605-630.

22. Laycock M, Pascuzzi R. The neuromuscular effects of hypothyroidism. Semin Neurol 1991;11:288-294.

23. Diekman T, Lansberg PJ, Kastelein JJP, et al. Prevalence and correction of hypothyroidism in a large cohort of patients referred for dyslipidemia. Arch Intern Med 1995;155:1490-1495.

24. Rader DJ, Rosas S. Hypertriglyceridemia, low HDL cholesterol, lipoprotein (a), in thyroid and renal diseases and posttransplantation. Med Clin N Am 2000;84:43-61.

25. Das KC, Mukherjee M, Sarkar TK, et al. Erythropoiesis and erythropoietin in hypo- and hyperthyroidism. J Clin Endocrinol Metab 1975;40:211-220.

26. Klein I. Clinical, metabolic, and organ-specific indices of thyroid function. Endocrin Metab Clinics 2001;30:415-428.

27. Nicoloff JT, LoPresti JS. Myxedema coma: a form of decompensated hypothyroidism. Endocrin Metabol Clin N Am 1993;22:279-291.

28. Jordan RM. Myxedema coma: pathophysiology, therapy, and factors affecting prognosis. Med Clin N Am 1995;79:185-194.

29. Olsen CG. Myxedema coma in the elderly. J Am Bd Fam Pract 1995;8:376-382.

30. Wall CR. Myxedema coma: diagnosis and treatment. Am Fam Physician 2000;62:2485-2490.

31. Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T4, and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002;87:489-499.

32. Geelhoed GW. Metabolic maladaptation: individual and social consequences of medical intervention in correcting endemic hypothyroidism. Nutrition 1999;15:908-932.

33. DeGroot LJ, Larsen PR, Hennemann G. The Thyroid and Its Diseases. New York, Churchill Livingstone, 1996, ed 6, p 347.

RELATED ARTICLE: Key Points

* Profound hypothyroidism may be more common than is appreciated due to insidious progression of symptoms and ability of the syndrome to masquerade as nonthyroidal conditions.

* Key diagnostic features include deteriorating physical and intellectual function, cold intolerance, dry skin, hoarseness, periorbital edema, dyspnea, constipation, weakness, depression, and delayed ankle jerk relaxation phases.

* Laboratory data suggestive of profound hypothyroidism includes elevations in creatine kinase, cholesterol, and mean corpuscular volume, and low voltage on electrocardiogram.

* Detection of profound hypothyroidism as a unifying diagnosis for the multisystem manifestations of this syndrome leads to prompt, dramatic responses to thyroid hormone replacement.

Michael W. Felz, MD, and Amy C. Forren, DO

From the Department of Family Medicine, Medical College of Georgia, Augusta, GA.

Reprint requests to Michael W. Felz, MD, Medical College of Georgia, Department of Family Medicine, HB 4032, Augusta, GA 30912.