Subclinical thyroid disease: clinical applications

Subclinical hypothyroidism and hyperthyroidism are diagnoses based on laboratory evaluation with few if any clinical signs or symptoms. Subclinical hypothyroidism is defined as an elevation in serum thyroid-stimulating hormone (TSH) above the upper limit of the reference range (0.45-4.5 mIU/L) with normal serum FT₄ concentration; subclinical hyperthyroidism is defined as a decrease in serum TSH below the reference range with normal serum FT₄ and T₃ concentrations. Though these conditions represent the earliest stages of thyroid dysfunction, the benefits of detecting and treating subclinical thyroid disease are not well established. Most persons found to have subclinical thyroid disease will have TSH values between 0.1 and 0.45 mIU/L or between 4.5 and 10 mIU/L, for which the benefits of treatment are not clearly established; treatment may be beneficial in individuals with serum TSH lower than 0.1 mIU/L or higher than 10 mIU/L. This article illustrates approaches to managing patients with subclinical hypothyroidism and hyperthyroidism through 5 case scenarios that apply the principles of evidence-based medicine. Because of the substantial uncertainty concerning the consequences of untreated subclinical hypothyroidism and hyperthyroidism, as well as the benefit of initiating treatment, patient preferences are important in deciding on management of subclinical disease.      

Thyroid status, cardiovascular risk, and mortality in older adults

Context  Previous studies have suggested that subclinical abnormalities in thyroid-stimulating hormone levels are associated with detrimental effects on the cardiovascular system. Objective  To determine the relationship between baseline thyroid status and incident atrial fibrillation, incident cardiovascular disease, and mortality in older men and women not taking thyroid medication. Design, Setting, and Participants  A total of 3233 US community-dwelling individuals aged 65 years or older with baseline serum thyroid-stimulating hormone levels were enrolled in 1989-1990 in the Cardiovascular Health Study, a large, prospective cohort study. Main Outcome Measures  Incident atrial fibrillation, coronary heart disease, cerebrovascular disease, cardiovascular death, and all-cause death assessed through June 2002. Analyses are reported for 4 groups defined according to thyroid function test results: subclinical hyperthyroidism, euthyroidism, subclinical hypothyroidism, and overt hypothyroidism. Results  Individuals with overt thyrotoxicosis (n = 4) were excluded because of small numbers. Eighty-two percent of participants (n = 2639) had normal thyroid function, 15% (n = 496) had subclinical hypothyroidism, 1.6% (n = 51) had overt hypothyroidism, and 1.5% (n = 47) had subclinical hyperthyroidism. After exclusion of those with prevalent atrial fibrillation, individuals with subclinical hyperthyroidism had a greater incidence of atrial fibrillation compared with those with normal thyroid function (67 events vs 31 events per 1000 person-years; adjusted hazard ratio, 1.98; 95% confidence interval, 1.29-3.03). No differences were seen between the subclinical hyperthyroidism group and euthyroidism group for incident coronary heart disease, cerebrovascular disease, cardiovascular death, or all-cause death. Likewise, there were no differences between the subclinical hypothyroidism or overt hypothyroidism groups and the euthyroidism group for cardiovascular outcomes or mortality. Specifically, individuals with subclinical hypothyroidism had an adjusted hazard ratio of 1.07 (95% confidence interval, 0.90-1.28) for incident coronary heart disease. Conclusion  Our data show an association between subclinical hyperthyroidism and development of atrial fibrillation but do not support the hypothesis that unrecognized subclinical hyperthyroidism or subclinical hypothyroidism is associated with other cardiovascular disorders or mortality.      

Triiodothyronine levels in athyreotic individuals during levothyroxine therapy

Jacqueline Jonklaas, MD, PhD; Bruce Davidson, MD; Supna Bhagat, MD; Steven J. Soldin, PhD

JAMA. 2008;299(7):769-777.

Context  Thyroidal production of triiodothyronine (T₃) is absent in athyreotic patients, leading to the suggestion that T₃ deficiency may be unavoidable during levothyroxine (LT₄) therapy. However, trials evaluating therapy with combined LT₄ and T₃ have failed to demonstrate any consistent advantage of combination therapy.

Objective  To determine whether T₃ levels in patients treated with LT₄ therapy were truly lower than in the same patients with native thyroid function.

Design, Setting, and Patients  A prospective study conducted in the General Clinical Research Center, Georgetown University Medical Center, Washington, DC, between January 30, 2004, and June 20, 2007, of 50 euthyroid study participants aged 18 to 65 years who were scheduled for total thyroidectomy for goiter, benign nodular disease, suspected thyroid cancer, or known thyroid cancer. Following thyroidectomy, patients were prescribed LT₄. Patients with benign thyroid disease and thyroid cancer were treated to achieve a normal and suppressed serum thyroid-stimulating hormone (TSH) level, respectively. The LT₄ dose was adjusted as necessary postoperatively to achieve the desired TSH goal.

Main Outcome Measure  Thyroxine (tetraiodothyronine [T₄]), T₃, and TSH levels were measured twice preoperatively and twice postoperatively.

Results  By the end of the study, there were no significant decreases in T₃ concentrations in patients receiving LT₄ therapy compared with their prethyroidectomy T₃ levels (mean, 127.2 ng/dL; 95% confidence interval [CI], 119.5-134.9 ng/dL vs 129.3 ng/dL; 95% CI, 121.9-136.7 ng/dL; P = .64). However, free T₄ concentrations were significantly higher in patients treated with LT₄ therapy (mean, 1.41 ng/dL; 95% CI, 1.33-1.49 ng/dL) compared with their native free T₄ levels (1.05 ng/dL; 95% CI, 1.00-1.10 ng/dL; P < .001). Serum TSH values of 4.5 mIU/L or less were achieved in 94% of patients by the end of the study. The T₃ concentrations were lower in the subgroup of patients whose therapy had not resulted in a TSH level of 4.5 mIU/L or less (P < .001).

Conclusion  In our study, normal T₃ levels were achieved with traditional LT₄ therapy alone in patients who had undergone near-total or total thyroidectomy, which suggests that T₃ administration is not necessary to maintain serum T₃ values at their endogenous prethyroidectomy levels.

     

Thyroid function and mortality in patients treated for hyperthyroidism

Context  Hyperthyroidism has been reported to cause excess all-cause and circulatory mortality. Whether this can be reversed is unknown, as is the influence of mild persisting thyroid dysfunction and treatment-induced hypothyroidism. Objectives  To determine whether radioiodine treatment is associated with increased mortality and to determine the influences of mild thyroid dysfunction and the development of overt hypothyroidism treated with thyroxine (T₄). Design, Setting, and Participants  A population-based study of 2668 individuals aged 40 years or older treated for overt hyperthyroidism with radioiodine in the West Midlands region of England from 1984-2002. Main Outcome Measures  Cause of death compared with age- and period-specific mortality in England and Wales and assessment of the influence of T₄ therapy for radioiodine-induced hypothyroidism and subclinical thyroid dysfunction on mortality. Results  In 15 968 person-years of follow-up, 554 died vs 487 expected deaths (standardized mortality ratio [SMR], 1.14; 95% confidence interval [CI], 1.04-1.24, P=.002). Increased risks of all-cause and circulatory deaths vs age- and period-specific mortality were observed in follow-up in those not requiring, or prior to, T₄ therapy. These increased risks were not observed during follow-up on T₄ therapy (circulatory disease SMR prior to T₄, 1.33; 95% CI, 1.14-1.53 vs SMR, 0.91; 95% CI, 0.70-1.17 during T₄). Patients receiving T₄ had decreased risk of mortality vs risk in the period not requiring, or prior to, T₄ therapy (all-cause mortality hazard ratio [HR], 0.65; 95% CI, 0.54-0.79; circulatory mortality HR, 0.65; 95% CI, 0.48-0.87). Increased all-cause mortality vs the background population was observed in the period prior to T₄ therapy in follow-up associated with low, normal, and high serum thyrotropin. The SMR for ischemic heart disease increased slightly when analyzed by serum thyrotropin, high serum thyrotropin being the highest SMR (low thyrotropin SMR, 1.06; 95% CI, 0.75-1.45; normal thyrotropin SMR, 1.17; 95% CI, 0.76-1.71; high thyrotropin SMR, 1.48; 95% CI, 0.86-2.37). Comparison within the cohort showed that mild hypothyroidism prior to T₄ therapy was associated with increased risk of mortality from ischemic heart disease vs biochemical euthyroidism (HR, 2.08; 95% CI, 1.04-4.19). Conclusions  Patients treated with radioiodine for hyperthyroidism had increased mortality vs age- and period-specific mortality in England and Wales, a finding no longer evident during T₄ therapy. This supports treating hyperthyroidism with doses of radioiodine sufficient to induce overt hypothyroidism. The association within the cohort of mortality from ischemic heart disease with subclinical hypothyroidism suggests T₄ replacement should be considered should this biochemical abnormality develop after radioiodine therapy.      

Effect of calcium carbonate on the absorption of levothyroxine

Context  The effect of calcium carbonate on the absorption of levothyroxine has not been studied systematically. Such a potential drug interaction merits investigation because concurrent treatment with both drugs is common, particularly in postmenopausal women. Objective  To investigate the potential interference of calcium carbonate in the absorption of levothyroxine. Design  Prospective cohort study conducted from November 1998 to June 1999, supplemented with an in vitro study of thyroxine (T₄) binding to calcium carbonate. Setting  Veterans Affairs Medical Center in West Los Angeles, Calif. Patients  Twenty patients (age range, 27-78 years; n=11 men) with hypothyroidism who were taking a stable long-term regimen of levothyroxine were included in the study. All patients had serum free T₄ and thyrotropin values in the normal range before beginning the study. Intervention  Subjects were instructed to take 1200 mg/d of elemental calcium as calcium carbonate, ingested with their levothyroxine, for 3 months. Main Outcome Measures  Levels of free T₄, total T₄, total triiodothyronine (T₃), and thyrotropin, measured in all subjects at baseline (while taking levothyroxine alone), at 2 and 3 months (while taking calcium carbonate and levothyroxine), and 2 months after calcium carbonate discontinuation (while continuing to take levothyroxine). Results  Mean free T₄ and total T₄ levels were significantly reduced during the calcium period and increased after calcium discontinuation. Mean free T₄ levels were 17 pmol/L (1.3 ng/dL) at baseline, 15 pmol/L (1.2 ng/dL) during the calcium period, and 18 pmol/L (1.4 ng/dL) after calcium discontinuation (overall P<.001); mean total T₄ levels were 118 nmol/L (9.2 µg/dL) at baseline, 111 nmol/L (8.6 µg/dL) during the calcium period, and 120 nmol/L (9.3 µg/dL) after calcium discontinuation (overall P=.03). Mean thyrotropin levels increased significantly, from 1.6 mIU/L at baseline to 2.7 mIU/L during the calcium period, and decreased to 1.4 mIU/L after calcium discontinuation (P=.008). Twenty percent of patients had serum thyrotropin levels higher than the normal range during the calcium period; the highest observed level was 7.8 mIU/L. Mean T₃ levels did not change during the calcium period. The in vitro study of T₄ binding to calcium showed that adsorption of T₄ to calcium carbonate occurs at acidic pH levels. Conclusions  This study of 20 patients receiving long-term levothyroxine replacement therapy indicates that calcium carbonate reduces T₄ absorption and increases serum thyrotropin levels. Levothyroxine adsorbs to calcium carbonate in an acidic environment, which may reduce its bioavailability.      

Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial

Context  Observational studies have reported associations between circulating total homocysteine concentration and risk of cardiovascular disease. Oral administration of folic acid and vitamin B₁₂ can lower plasma total homocysteine levels. Objective  To assess the effect of treatment with folic acid and vitamin B₁₂ and the effect of treatment with vitamin B₆ as secondary prevention in patients with coronary artery disease or aortic valve stenosis. Design, Setting, and Participants  Randomized, double-blind controlled trial conducted in the 2 university hospitals in western Norway in 1999-2006. A total of 3096 adult participants undergoing coronary angiography (20.5% female; mean age, 61.7 years) were randomized. At baseline, 59.3% had double- or triple-vessel disease, 83.7% had stable angina pectoris, and 14.9% had acute coronary syndromes. Interventions  Using a 2 x 2 factorial design, participants were randomly assigned to 1 of 4 groups receiving daily oral treatment with folic acid, 0.8 mg, plus vitamin B₁₂, 0.4 mg, plus vitamin B₆, 40 mg (n = 772); folic acid plus vitamin B₁₂ (n = 772); vitamin B₆ alone (n = 772); or placebo (n = 780). Main Outcome Measures  The primary end point was a composite of all-cause death, nonfatal acute myocardial infarction, acute hospitalization for unstable angina pectoris, and nonfatal thromboembolic stroke. Results  Mean plasma total homocysteine concentration was reduced by 30% after 1 year of treatment in the groups receiving folic acid and vitamin B₁₂. The trial was terminated early because of concern among participants due to preliminary results from a contemporaneous Norwegian trial suggesting adverse effects from the intervention. During a median 38 months of follow-up, the primary end point was experienced by a total of 422 participants (13.7%): 219 participants (14.2%) receiving folic acid/vitamin B₁₂ vs 203 (13.1%) not receiving such treatment (hazard ratio, 1.09; 95% confidence interval, 0.90-1.32; P = .36) and 200 participants (13.0%) receiving vitamin B₆ vs 222 (14.3%) not receiving vitamin B₆ (hazard ratio, 0.90; 95% confidence interval, 0.74-1.09; P = .28). Conclusions  This trial did not find an effect of treatment with folic acid/vitamin B₁₂ or vitamin B₆ on total mortality or cardiovascular events. Our findings do not support the use of B vitamins as secondary prevention in patients with coronary artery disease. Trial Registration  clinicaltrials.gov Identifier: NCT00354081      

Ketoconazole for early treatment of acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. The ARDS Network

Context  Three clinical studies have suggested that ketoconazole, a synthetic imidazole with anti-inflammatory activity, may prevent the development of acute respiratory distress syndrome (ARDS) in critically ill patients. However, the use of ketoconazole as treatment for acute lung injury (ALI) and ARDS has not been previously studied. Objective  To test the efficacy of ketoconazole in reducing mortality and morbidity in patients with ALI or ARDS. Design  Randomized, double-blind, placebo-controlled trial conducted from March 1996 to January 1997. Setting  Twenty-four hospitals associated with 10 network centers in the United States, constituting the ARDS Network. Patients  A total of 234 patients with ALI or ARDS. Intervention  Patients were randomly assigned to receive ketoconazole, 400 mg/d (n=117), or placebo (n=117), initiated within 36 hours of fulfilling study entry criteria and given enterally for up to 21 days. Main Outcome Measures  Primary outcome measures were the proportion of patients alive with unassisted breathing at hospital discharge and the number of days of unassisted breathing (ventilator-free days) during 28 days of follow-up. Secondary outcome measures included the proportion of patients achieving unassisted breathing for 48 hours or more, the number of organ failure–free days, and changes in plasma interleukin 6 (IL-6) and urinary thromboxane A₂ metabolites (thromboxane B₂ [TXB₂] and 11-dehydro-TXB₂). Results  In-hospital mortality (SE) was 34.1% (4.3%) for the placebo group and 35.2% (4.3%) for the ketoconazole group (P=.85). The median number of ventilator-free days within 28 days of randomization was 9 in the placebo group and 10 in the ketoconazole group (P=.89). There were no statistically significant differences in the number of organ failure–free days, pulmonary physiology, or adverse events between treatment groups. The median serum ketoconazole level was 1.25 µg/mL and serum levels greater than 0.5 µg/mL were detected in 96% of patients assayed. Plasma IL-6, urinary TXB₂, and 11-dehydro-TXB₂ levels were unaffected by ketoconazole. Conclusions  In these patients with ALI or ARDS, ketoconazole was safe and bioavailable but did not reduce mortality or duration of mechanical ventilation or improve lung function. These data do not support the use of ketoconazole for the early treatment of ALI or ARDS.      

Supplemental perioperative oxygen and the risk of surgical wound infection: a randomized controlled trial

Context  Supplemental perioperative oxygen has been variously reported to halve or double the risk of surgical wound infection. Objective  To test the hypothesis that supplemental oxygen reduces infection risk in patients following colorectal surgery. Design, Setting, and Patients  A double-blind, randomized controlled trial of 300 patients aged 18 to 80 years who underwent elective colorectal surgery in 14 Spanish hospitals from March 1, 2003, to October 31, 2004. Wound infections were diagnosed by blinded investigators using Centers for Disease Control and Prevention criteria. Baseline patient characteristics, anesthetic treatment, and potential confounding factors were recorded. Interventions  Patients were randomly assigned to either 30% or 80% fraction of inspired oxygen (FIO₂) intraoperatively and for 6 hours after surgery. Anesthetic treatment and antibiotic administration were standardized. Main Outcome Measures  Any surgical site infection (SSI); secondary outcomes included return of bowel function and ability to tolerate solid food, ambulation, suture removal, and duration of hospitalization. Results  A total of 143 patients received 30% perioperative oxygen and 148 received 80% perioperative oxygen. Surgical site infection occurred in 35 patients (24.4%) administered 30% FIO₂ and in 22 patients (14.9%) administered 80% FIO₂ (P=.04). The risk of SSI was 39% lower in the 80% FIO₂ group (relative risk [RR], 0.61; 95% confidence interval [CI], 0.38-0.98) vs the 30% FIO₂ group. After adjustment for important covariates, the RR of infection in patients administered supplemental oxygen was 0.46 (95% CI, 0.22-0.95; P = .04). None of the secondary outcomes varied significantly between the 2 treatment groups. Conclusions  Patients receiving supplemental inspired oxygen had a significant reduction in the risk of wound infection. Supplemental oxygen appears to be an effective intervention to reduce SSI in patients undergoing colon or rectal surgery. Trial Registration  ClinicalTrials.gov Identifier: NCT00235456      

Role of vitamin K2 in the development of hepatocellular carcinoma in women with viral cirrhosis of the liver

Context  Previous findings indicate that vitamin K₂ (menaquinone) may play a role in controlling cell growth. Objective  To determine whether vitamin K₂has preventive effects on the development of hepatocellular carcinoma in women with viral cirrhosis of the liver. Design, Setting, and Participants  Forty women diagnosed as having viral liver cirrhosis were admitted to a university hospital between 1996 and 1998 and were randomly assigned to the treatment or control group. The original goal of the trial was to assess the long-term effects of vitamin K₂ on bone loss in women with viral liver cirrhosis. However, study participants also satisfied criteria required for examination of the effects of such treatment on the development of hepatocellular carcinoma. Interventions  The treatment group received 45 mg/d of vitamin K₂ (n = 21). Participants in the treatment and control groups received symptomatic therapy to treat ascites, if necessary, and dietary advice. Main Outcome Measure  Cumulative proportion of patients with hepatocellular carcinoma. Results  Hepatocellular carcinoma was detected in 2 of the 21 women given vitamin K₂ and 9 of the 19 women in the control group. The cumulative proportion of patients with hepatocellular carcinoma was smaller in the treatment group (log-rank test, P = .02). On univariate analysis, the risk ratio for the development of hepatocellular carcinoma in the treatment group compared with the control group was 0.20 (95% confidence interval [CI], 0.04-0.91; P = .04). On multivariate analysis with adjustment for age, alanine aminotransferase activity, serum albumin, total bilirubin, platelet count, -fetoprotein, and history of treatment with interferon alfa, the risk ratio for the development of hepatocellular carcinoma in patients given vitamin K₂ was 0.13 (95% CI, 0.02-0.99; P = .05). Conclusion  There is a possible role for vitamin K₂ in the prevention of hepatocellular carcinoma in women with viral cirrhosis.      

Distribution of and factors associated with serum homocysteine levels in children: Child and Adolescent Trial for Cardiovascular Health

Context  Although evidence suggests that homocysteine is a risk factor for cardiovascular disease in adults, little information exists on homocysteine levels in children. Objectives  To describe the distribution of serum homocysteine concentrations among children and to examine the association between homocysteine levels and several characteristics, including serum levels of folic acid and vitamins B₁₂ and B₆. Design  Cross-sectional analysis. Setting  School-based cohort from California, Louisiana, Minnesota, and Texas. Participants  A total of 3524 US schoolchildren, aged 13 and 14 years, from the Child and Adolescent Trial for Cardiovascular Health (completed in 1994). Measurement was conducted in 1997. Main Outcome Measure  Nonfasting serum total homocysteine concentration. Results  The distribution of homocysteine values ranged from 0.1 to 25.7 µmol/L (median, 4.9 µmol/L). Geometric mean homocysteine concentration was significantly higher in boys (5.22 µmol/L) than girls (4.84 µmol/L); blacks (5.51 µmol/L) than whites (4.96 µmol/L) or Hispanics (4.93 µmol/L); nonusers of multivitamins (5.09 µmol/L) than users (4.82 µmol/L); and smokers (5.19 µmol/L) than nonsmokers (5.00 µmol/L). Serum homocysteine was significantly inversely correlated with serum levels of folic acid (r=-0.36; P=.001), vitamin B₁₂ (r=-0.21; P=.001), and vitamin B₆ (r=-0.18; P=.001). Serum homocysteine was not significantly associated with serum lipid levels or family history of cardiovascular disease and was only weakly related to body mass index and systolic blood pressure. After multivariate adjustment, homocysteine remained independently associated with sex, race, serum folic acid and vitamin B₁₂ levels, and systolic blood pressure. Conclusions  The distribution of homocysteine levels in children is substantially lower than that observed for adults; however, a small percentage of children are still potentially at elevated risk for future cardiovascular disease. Serum folic acid may be an important determinant of homocysteine levels in children.