Subclinical Hypothyroidism

D. Allen Brantley, M.D.D. Allen Brantley, M.D.

Internal Medicine Resident Grand Internal Medicine Resident Grand RoundsRounds

January 12, 1999January 12, 1999

CASE 1

■ MH is a 47 yowf who presented with MH is a 47 yowf who presented with palpitations for the past 3-4 months. She palpitations for the past 3-4 months. She denied any chest pain or SOB.denied any chest pain or SOB.

■ Further history revealed occasional Further history revealed occasional nervousness as well as a change in bowel nervousness as well as a change in bowel habits from “normal stools” to frequent habits from “normal stools” to frequent loose stools.loose stools.

CASE 1 (cont.)

■ PMH:PMH: G2P2 G2P2■ Fam Hx:Fam Hx: No h/o early MI or CAD. ? h/o No h/o early MI or CAD. ? h/o

thyroid disease.thyroid disease.■ Meds:Meds: None, including stimulants, None, including stimulants,

decongestants, herbal drugs, or any decongestants, herbal drugs, or any alternative medicines.alternative medicines.

■ All:All: NKDA NKDA

CASE 1 (cont.)

■ PE:PE: Vitals: Temp 98.6 BP 130/78 HR 108 Vitals: Temp 98.6 BP 130/78 HR 108✦ Gen: Pleasant, NADGen: Pleasant, NAD✦ HEENT: No proptosis or lid lagHEENT: No proptosis or lid lag✦ Neck: Mild diffuse enlargement of the thyroid Neck: Mild diffuse enlargement of the thyroid

gland. No defined nodulesgland. No defined nodules✦ CV: Tachy with regular rhythm, No M/R/GCV: Tachy with regular rhythm, No M/R/G✦ Lungs: CTALungs: CTA✦ Abd: soft, NTAbd: soft, NT✦ Ext: No edemaExt: No edema✦ Neuro: Nonfocal, Reflexes 3+ bilat.Neuro: Nonfocal, Reflexes 3+ bilat.

CASE 1 (cont.)

■ Labs:Labs: TSH < 0.5 mU/L (NL 0.5-5.0 TSH < 0.5 mU/L (NL 0.5-5.0 mU/L)mU/L)

Total TTotal T44 15 ug/dL (NL 5-11 ug/dL) 15 ug/dL (NL 5-11 ug/dL)

■ Diagnosis:Diagnosis: Hyperthyroidism, probable Hyperthyroidism, probable Graves’ DiseaseGraves’ Disease

CASE 2

■ RP is a 58 yowf who presented with c/o RP is a 58 yowf who presented with c/o fatigue, weakness, and weight gain of 30 fatigue, weakness, and weight gain of 30 pounds over the past 4-6 months.pounds over the past 4-6 months.

■ Further history indicated cold intolerance, Further history indicated cold intolerance, some difficulty with concentration, and dry some difficulty with concentration, and dry skin. skin.

CASE 2 (cont.)

■ PMH:PMH: Tension headaches. Seasonal Tension headaches. Seasonal allergies with associated rhinitis. allergies with associated rhinitis.

■ PSH:PSH: s/p C-section s/p C-section■ FamHx:FamHx: No history of thyroid disease. No history of thyroid disease.■ Meds:Meds: OTC pain relievers and Claritin D OTC pain relievers and Claritin D

PRN PRN■ All:All: NKDA NKDA

CASE 2 (cont.)

■ PE:PE: Vitals: Temp 98.3 BP 142/89 HR 84 Wt. 168 lbs. Vitals: Temp 98.3 BP 142/89 HR 84 Wt. 168 lbs. (130 lbs. approx. 8 months ago)(130 lbs. approx. 8 months ago)

✦ Gen: Overweight wf, in NADGen: Overweight wf, in NAD✦ HEENT: OP no lesions, Tongue normalHEENT: OP no lesions, Tongue normal✦ Neck: No JVD, No LA, Thyroid gland not palpableNeck: No JVD, No LA, Thyroid gland not palpable✦ CV: RRRCV: RRR✦ Lungs: CTALungs: CTA✦ Abd: obese, soft, NTAbd: obese, soft, NT✦ Ext: 1+ pitting edemaExt: 1+ pitting edema✦ Neuro: Reflexes symm., but slow relaxationNeuro: Reflexes symm., but slow relaxation✦ Skin: dry and coolSkin: dry and cool

CASE 2 (cont.)

■ Labs:Labs: TSH: 23 mU/L TSH: 23 mU/L

Total T4: 2.1 ug/dLTotal T4: 2.1 ug/dL

Antithyroid antibodies are positiveAntithyroid antibodies are positive

■ Diagnosis:Diagnosis: Overt Hypothyroidism, Overt Hypothyroidism, probable Hashimoto’s diseaseprobable Hashimoto’s disease

Introduction

■ Subclinical Hypothyroidism (SH)Subclinical Hypothyroidism (SH) can be can be defined as a state in which an asymptomatic defined as a state in which an asymptomatic person has a normal serum Tperson has a normal serum T44 concentration concentration in the face of an increased serum TSH.in the face of an increased serum TSH.

■ SHSH can also be defined by an elevated TSH can also be defined by an elevated TSH with normal levels of Twith normal levels of T44, Free T, Free T44, and T, and T33..

■ This later definition does not mention the This later definition does not mention the presence or absence of symptoms.presence or absence of symptoms.

■ In contrast, In contrast, Overt Hypothyroidism (OH)Overt Hypothyroidism (OH) is is suggested by an elevated TSH and a suggested by an elevated TSH and a decreased thyroxine level, often in the decreased thyroxine level, often in the presence of clinical symptoms.presence of clinical symptoms.

■ The mean incidence of spontaneous OH is The mean incidence of spontaneous OH is 3.5/1000/year in women and 0.6/1000/year 3.5/1000/year in women and 0.6/1000/year in men, with an average age of 58-59 at in men, with an average age of 58-59 at time of diagnosis.time of diagnosis.

■ The prevalence of SH can be estimated for The prevalence of SH can be estimated for females greater than age 60 to be females greater than age 60 to be 11.6-13.6% and for males greater than age 11.6-13.6% and for males greater than age 60 to be 2.9-5.7%. 60 to be 2.9-5.7%.

Prevalence of Increased Serum Thyrotropin Concentrations

Source Sex Age, years Prevalence,%

Tunbridgeet al., 1977

FemaleMale

>18>18

7.52.8

Bagchi etal., 1990

FemaleMale

>55>55

8.54.4

Sawin et al.,1985

FemaleMale

>60>60

13.65.7

Parle et al.,1991

FemaleMale

>60>60

11.62.9

■ SH is the SH is the most commonmost common condition found by condition found by screening with 5-10% of adult women screening with 5-10% of adult women having an elevated TSH. Frequently, these having an elevated TSH. Frequently, these persons are asymptomatic.persons are asymptomatic.

What does this mildly elevated TSH mean anyway ?

Causes of Hypothyroidism

■ SH is caused by the same disorders which SH is caused by the same disorders which cause OH.cause OH.

■ The most common cause of hypothyroidism The most common cause of hypothyroidism is is Hashimoto’s DiseaseHashimoto’s Disease or autoimmune or autoimmune thyroiditis.thyroiditis.

■ Autoimmune thyroiditis is often associated Autoimmune thyroiditis is often associated with increased titers of antithyroid with increased titers of antithyroid antibodies.antibodies.

Causes of Hypothyroidism

■ Chronic autoimmune Chronic autoimmune thyroiditisthyroiditis

■ Treated Graves’ Treated Graves’ DiseaseDisease

■ Head and Neck Head and Neck SurgerySurgery

■ Radiation therapy to Radiation therapy to the head, neck, chestthe head, neck, chest

■ Iodine deficiencyIodine deficiency■ Medications: lithium, Medications: lithium,

iodine, amiodaroneiodine, amiodarone■ HypopituitarismHypopituitarism■ IdiopathicIdiopathic■ CongenitalCongenital

■ Paranoids are people also; they have Paranoids are people also; they have their own problems. It’s easy to their own problems. It’s easy to criticize them; but if everybody hated criticize them; but if everybody hated you, you’d be paranoid too.you, you’d be paranoid too.

■ Why should the physician care about a Why should the physician care about a mildly elevated TSH in an otherwise mildly elevated TSH in an otherwise asymptomatic patient ?asymptomatic patient ?

Potential Complications of Subclinical Hypothyroidism■ 1) Progression of Subclinical 1) Progression of Subclinical

Hypothyroidism to Overt Hypothyroidism to Overt HypothyroidismHypothyroidism

■ 2) Symptoms related to Subclinical 2) Symptoms related to Subclinical HypothyroidismHypothyroidism

■ 3) Hyperlipidemia3) Hyperlipidemia

Progression of Subclinical Hypothyroidism to Overt Hypothyroidism:■ The presence of antithyroid antibodies is a The presence of antithyroid antibodies is a

strong indicator or who will progress to strong indicator or who will progress to OH.OH.

■ Older age and higher TSH level increase a Older age and higher TSH level increase a patient’s risk for conversion to OH.patient’s risk for conversion to OH.

■ Younger women and those with lower TSH Younger women and those with lower TSH levels (6 to 9 mU/L) have a lower risk for levels (6 to 9 mU/L) have a lower risk for OH.OH.

■ Does treatment actually improve outcome Does treatment actually improve outcome with regards to the progression of with regards to the progression of Subclinical Hypothyroidism to Overt Subclinical Hypothyroidism to Overt Hypothyroidism ?Hypothyroidism ?

■ Unfortunately, no studies have looked Unfortunately, no studies have looked specifically at the progression of SH to OH.specifically at the progression of SH to OH.

■ Therefore, no studies have focused on the Therefore, no studies have focused on the degree of disability or morbidity associated degree of disability or morbidity associated with being newly, overtly hypothyroid.with being newly, overtly hypothyroid.

■ Given the lack of evidence, close follow-up Given the lack of evidence, close follow-up is felt to be an alternative to treatment.is felt to be an alternative to treatment.

Does Treatment Improve Symptoms in Patients with Subclinical Hypothyroidism ?■ Common symptoms which can be related to Common symptoms which can be related to

SH include muscle cramps, dry skin, cold SH include muscle cramps, dry skin, cold intolerance, constipation, poor energy intolerance, constipation, poor energy levels, fatigue, and mental slowness levels, fatigue, and mental slowness (All of (All of which can also be related to being a which can also be related to being a resident!)resident!)

■ Three trials have looked at the relationship Three trials have looked at the relationship between SH and symptoms and the benefit between SH and symptoms and the benefit of treatment.of treatment.

Cooper et al.

■ Double-blind, placebo-controlled trialDouble-blind, placebo-controlled trial■ 33 patients (only 1 male)33 patients (only 1 male)■ Most patients had been treated previously Most patients had been treated previously

for Graves’ disease and now had SH.for Graves’ disease and now had SH.■ Results based on a questionnaire on Results based on a questionnaire on

hypothyroid symptoms.hypothyroid symptoms.■ 20 euthyroid controls given same questions20 euthyroid controls given same questions

Cooper et al. (cont.)

■ The euthyroid controls had on average 1 The euthyroid controls had on average 1 less symptom than the study patients.less symptom than the study patients.

■ Treatment was for one year.Treatment was for one year.■ The results suggest that those treated with The results suggest that those treated with

thyroxine tend to improve, while those thyroxine tend to improve, while those treated with placebo tend to have either no treated with placebo tend to have either no change in their symptoms or a slight change in their symptoms or a slight worsening of them.worsening of them.

Nystrom et al.

■ Double-blind, 12 month, cross-over studyDouble-blind, 12 month, cross-over study■ 17 females greater than age 50 with SH17 females greater than age 50 with SH■ No prior h/o thyroid diseaseNo prior h/o thyroid disease■ Data gathering involved a questionnaire Data gathering involved a questionnaire

regarding symptoms, psychometric testing regarding symptoms, psychometric testing and specifically asking about subjective and specifically asking about subjective feelings of improvement.feelings of improvement.

Nystrom et al. (cont.)

■ Based on the patients responses to the Based on the patients responses to the question of subjective improvement, 9 of 17 question of subjective improvement, 9 of 17 improved.improved.

Jaeschke et al.

■ Randomized, double-blinded, placebo-Randomized, double-blinded, placebo-controlled trialcontrolled trial

■ 32 patients (most women) > 55 with SH32 patients (most women) > 55 with SH■ Outcome measures included: (1) symptom Outcome measures included: (1) symptom

related questions, (2) sickness impact related questions, (2) sickness impact profile, and (3) a battery of cognitive profile, and (3) a battery of cognitive testing.testing.

Jaeschke et al. (cont.)

■ The study found improvement in the The study found improvement in the composite memory score of the treatment composite memory score of the treatment group compared to placebo.group compared to placebo.

■ No other outcome measure, including the No other outcome measure, including the symptom questionnaire, demonstrated a symptom questionnaire, demonstrated a trend in favor of treatment.trend in favor of treatment.

Summary of Trials Considering Clinical Symptoms

Trial Result

Cooper et al. Favors treatment

Nystrom et al. Equivocal

Jaeschke et al. Treatment Notbeneficial

Does Treatment Improve Hypercholesterolemia in patients with Subclinical Hypothyroidism ?■ Tanis et al.Tanis et al. performed a meta-analysis on performed a meta-analysis on

the effects of thyroid hormone replacement the effects of thyroid hormone replacement in patients with SH and OH.in patients with SH and OH.

■ Thirteen studies involving patients with SH Thirteen studies involving patients with SH were examined. A total of 278 patients were examined. A total of 278 patients were included.were included.

Tanis et al. (cont.)

■ 12 of the 13 studies demonstrated a 12 of the 13 studies demonstrated a decrease in cholesterol levels with decrease in cholesterol levels with treatment.treatment.

■ The weighted decrease in cholesterol was The weighted decrease in cholesterol was 6%.6%.

■ The effect was greater (~9% decrease) in The effect was greater (~9% decrease) in patients with a pretreatment cholesterol of patients with a pretreatment cholesterol of > 6.5 mmol/L (6.2 mmol/L = 240 mg/dL).> 6.5 mmol/L (6.2 mmol/L = 240 mg/dL).

Tanis et al. (cont.)

■ The cholesterol reduction was much more The cholesterol reduction was much more dramatic in patients with OH, with a 15 to dramatic in patients with OH, with a 15 to 47% cholesterol reduction.47% cholesterol reduction.

■ With thyroid hormone replacement, the With thyroid hormone replacement, the mean total cholesterol normalized in nearly mean total cholesterol normalized in nearly all studies involving patients with OH.all studies involving patients with OH.

Danese et al.

■ Cost-utility analysis with computer model.Cost-utility analysis with computer model.■ They reference studies involving SH which They reference studies involving SH which

suggest a 6 to 13% reduction in total suggest a 6 to 13% reduction in total cholesterol with thyroid replacement.cholesterol with thyroid replacement.

■ Treatment appears to be more effective in Treatment appears to be more effective in patients with a cholesterol of > 6.2 mmol/L patients with a cholesterol of > 6.2 mmol/L or in patients with a TSH > 10 mU/L.or in patients with a TSH > 10 mU/L.

■ The studies by Tanis et al. and Danese et al. The studies by Tanis et al. and Danese et al. suggest that patients with SH and suggest that patients with SH and hypercholesterolemia will have a 6 to 13% hypercholesterolemia will have a 6 to 13% reduction in total cholesterol with reduction in total cholesterol with treatment.treatment.

■ The observed 6 to 13% decrease in The observed 6 to 13% decrease in cholesterol may or may not translate into a cholesterol may or may not translate into a meaningful reduction in cardiovascular risk.meaningful reduction in cardiovascular risk.

■ Standard therapies such as Bile acid resins, Standard therapies such as Bile acid resins, Niacin, and HMG-CoA reductase inhibitors Niacin, and HMG-CoA reductase inhibitors typically reduce total cholesterol by 15 to typically reduce total cholesterol by 15 to 25%.25%.

■ The more standard therapies likely provide The more standard therapies likely provide more cholesterol reduction, and therefore more cholesterol reduction, and therefore more reduction in cardiovascular risk than more reduction in cardiovascular risk than does hormone replacement alone in SH.does hormone replacement alone in SH.

Should We Screen for Thyroid Disease?

■ The U.S. Preventative Services Task Force The U.S. Preventative Services Task Force in 1996 recommended against screening in 1996 recommended against screening asymptomatic adults.asymptomatic adults.

■ Danese et al. recommend measurement of Danese et al. recommend measurement of TSH in patients 35 years and older during TSH in patients 35 years and older during routine health examinations.routine health examinations.

■ Helfand et al. recommend screening women Helfand et al. recommend screening women older than 50 years of age for unsuspected older than 50 years of age for unsuspected but symptomatic thyroid disease.but symptomatic thyroid disease.

■ Obviously, there is no consensus of opinion Obviously, there is no consensus of opinion and it is difficult to know what type of and it is difficult to know what type of screening -if any - should be done.screening -if any - should be done.

How Would You Treat Subclinical Hypothyroidism ?

■ Typical effective doses in SH may be as Typical effective doses in SH may be as low as 25-50 ug/day.low as 25-50 ug/day.

■ It takes 6 to 8 weeks for the TSH to reach It takes 6 to 8 weeks for the TSH to reach steady-state after a dosage change.steady-state after a dosage change.

Should We Treat Subclinical Hypothyroidism ?

■ 1) Progression of Subclinical 1) Progression of Subclinical Hypothyroidism to Overt Hypothyroidism to Overt HypothyroidismHypothyroidism

■ 2) Symptoms related to Subclinical 2) Symptoms related to Subclinical HypothyroidismHypothyroidism

■ 3) Hyperlipidemia3) Hyperlipidemia

Progression to Overt Hypothyroidism

■ No studies have been performed to assess No studies have been performed to assess the morbidity associated with being newly, the morbidity associated with being newly, overtly hypothyroid.overtly hypothyroid.

■ Close follow-up may be a reasonable Close follow-up may be a reasonable alternative to treatment, given the lack of alternative to treatment, given the lack of data available.data available.

Symptoms Related to Subclinical Hypothyroidism

■ The three previously mentioned studies are The three previously mentioned studies are too small to draw any definite conclusions.too small to draw any definite conclusions.

■ The benefit of treating patients with SH in The benefit of treating patients with SH in an effort to improve symptoms, often very an effort to improve symptoms, often very nonspecific, is questionable at best.nonspecific, is questionable at best.

■ One should not expect or be comfortable One should not expect or be comfortable with the idea that SH will often explain with the idea that SH will often explain common symptomatology.common symptomatology.

Hypercholesterolemia

■ The average reductions in total cholesterol The average reductions in total cholesterol by the treatment of Subclinical by the treatment of Subclinical Hypothyroidism are modest.Hypothyroidism are modest.

■ Treatment with thyroid hormone is not Treatment with thyroid hormone is not likely to reduce a patient’s cardiovascular likely to reduce a patient’s cardiovascular risk to the same degree as standard risk to the same degree as standard therapies.therapies.

■ According to Helfand et al., “the available According to Helfand et al., “the available evidence is not sufficient to recommend for evidence is not sufficient to recommend for or against treatment of subclinical or against treatment of subclinical hypothyroidism.”hypothyroidism.”

■ This paper does expose particular patient This paper does expose particular patient populations that are more or less likely to populations that are more or less likely to respond to treatment.respond to treatment.

■ Women greater than 50 years of age with Women greater than 50 years of age with SH with a TSH > 10 mU/L have the highest SH with a TSH > 10 mU/L have the highest risk of complications.risk of complications.

■ Women with a TSH > 10 mU/L and a Women with a TSH > 10 mU/L and a cholesterol of greater than 6.2 mmol/L, tend cholesterol of greater than 6.2 mmol/L, tend to experience greater reductions in to experience greater reductions in cholesterol levels with treatment.cholesterol levels with treatment.

■ Younger women, men, and those with mild Younger women, men, and those with mild elevations in TSH (<10 mU/L) have a lower elevations in TSH (<10 mU/L) have a lower risk of complications and the benefits of risk of complications and the benefits of treatment are even less certain.treatment are even less certain.

Potential Complications of Treatment

■ Atrial Fibrillation and Osteoporosis are the Atrial Fibrillation and Osteoporosis are the two main complications seen with the two main complications seen with the overtreatment of subclinical overtreatment of subclinical hypothyroidism as well as overt hypothyroidism as well as overt hypothyroidism.hypothyroidism.

■ Maintaining the TSH within the normal Maintaining the TSH within the normal range helps to prevent these complications.range helps to prevent these complications.

Conclusions

■ There is no evidence that treating SH to There is no evidence that treating SH to prevent OH actually reduces morbidity.prevent OH actually reduces morbidity.

■ Treating symptoms with thyroid Treating symptoms with thyroid replacement in the context of SH may or replacement in the context of SH may or may not be beneficial.may not be beneficial.

■ The effect of thyroid replacement on The effect of thyroid replacement on hypercholesterolemia in patients with SH hypercholesterolemia in patients with SH appears to be minimal.appears to be minimal.

Conclusions (cont.)

■ Screening of men and women less than 50 Screening of men and women less than 50 years of age is probably not useful unless years of age is probably not useful unless the patient is symptomatic.the patient is symptomatic.

■ Older age (> 50 years of age), female Older age (> 50 years of age), female gender, TSH > 10mU/L, and the presence gender, TSH > 10mU/L, and the presence of antithyroid antibodies all confer greater of antithyroid antibodies all confer greater chance of progression to OH and to chance of progression to OH and to complications related to the thyroid.complications related to the thyroid.

Conclusions (cont.)

■ Women older than 50 years of age with a Women older than 50 years of age with a TSH > 10 mU/L, and women with TSH > TSH > 10 mU/L, and women with TSH > 10 mU/L as well as a cholesterol > 6.2 10 mU/L as well as a cholesterol > 6.2 mmol/L are more likely to benefit from mmol/L are more likely to benefit from thyroid replacement.thyroid replacement.

■ Younger women, men and patients with Younger women, men and patients with mildly elevated TSH (6 to 9 mU/L) are less mildly elevated TSH (6 to 9 mU/L) are less likely to benefit from treatment.likely to benefit from treatment.

Conclusions (cont.)

■ Atrial Fibrillation and Osteoporosis, which Atrial Fibrillation and Osteoporosis, which are potential complications from the are potential complications from the overtreatment of SH, can be minimized by overtreatment of SH, can be minimized by maintaining the TSH within the normal maintaining the TSH within the normal range.range.

CASE 3

■ 72 yowf presents with c/o fatigue, 72 yowf presents with c/o fatigue, constipation, and dry skin. TSH is 13.4 constipation, and dry skin. TSH is 13.4 mU/L, Total TmU/L, Total T44 is 7.2 ug/dL, and total is 7.2 ug/dL, and total cholesterol 270 mg/dL. Antithyroid cholesterol 270 mg/dL. Antithyroid antibodies are positive.antibodies are positive.

■ This patient is an older female with This patient is an older female with antithyroid antibodies, both of which antithyroid antibodies, both of which increase risk of progression to OH.increase risk of progression to OH.

CASE 3 (cont.)

■ Additionally, she has a cholesterol > 6.5 Additionally, she has a cholesterol > 6.5 mmol/dL and her symptoms may represent mmol/dL and her symptoms may represent early thyroid failure.early thyroid failure.

■ Conclusion:Conclusion: Favors Treatment. Favors Treatment.

CASE 4

■ 37 yowf presents with c/o depression, 37 yowf presents with c/o depression, fatigue, and mental slowness. TSH 8.2 mU/fatigue, and mental slowness. TSH 8.2 mU/L and Total TL and Total T44 is 6.9 ug/dL. Antithyroid is 6.9 ug/dL. Antithyroid antibodies are negative.antibodies are negative.

■ This patient is young, has a mildly elevated This patient is young, has a mildly elevated TSH, and is negative for antithyroid TSH, and is negative for antithyroid antibodies. Her risk of progression to OH is antibodies. Her risk of progression to OH is low.low.

CASE 4 (cont.)

■ Her symptoms may well be related to Her symptoms may well be related to clinical depression and if so, she should be clinical depression and if so, she should be treated appropriately.treated appropriately.

■ Conclusion:Conclusion: Favors No Treatment. Favors No Treatment.

■To steal ideas from one person To steal ideas from one person is plagiarism; to steal from is plagiarism; to steal from many is research.many is research.