Hypothyroidism in the Elderly: Who Should Be Treated and How?

Hypothyroidism is among the most frequent chronic diseases in the elderly, and levothyroxine (l-T4) is worldwide within the 10 drugs more prescribed in the general population. Hypothyroidism is defined by increased serum thyroid-stimulating hormone (TSH) values and reduced circulating free thyroid hormones, whereas subclinical hypothyroidism (sHT) is characterized by free hormone fractions within the normal ranges and has been divided into two classes, depending on circulating TSH levels (above or below 10 mIU/L). Given that during aging, a natural trend toward higher values of circulating TSH has been reported, it is necessary to verify carefully the diagnosis of sHT to tailor an appropriate follow-up and ad hoc therapy, avoiding unnecessary or excessive treatment. In the current review, we evaluate the state of the art on hypothyroidism in the elderly with special focus on the effect of sHT on cognition and the cardiovascular system function. We also summarize the recommendations for a correct diagnostic workup and therapeutic approach to older people with an elevated TSH value, with special attention to the presence of frailty, comorbidities, and poly therapy. In conclusion, personalized therapy is crucial in good clinical practice, and in the management of older patients with sHT, multiple factors must be considered, including age-dependent TSH cutoffs, thyroid autoimmunity, the burden of comorbidities, and the possible presence of frailty. l-T4 is the drug of choice for the treatment of hypothyroid older people, but the risk of overtreatment, potential adverse drug reactions, and patient compliance should always be considered and thyroid status periodically reassessed.

Potential drug-drug interactions in Alzheimer patients with behavioral symptoms.

The use of multi drug regimens among the elderly population has increased tremendously over the last decade although the benefits of medications are always accompanied by potential harm, even when prescribed at recommended doses. The elderly populations are particularly at an increased risk of adverse drug reactions considering comorbidity, poly-therapy, physiological changes affecting the pharmacokinetics and pharmacodynamics of many drugs and, in some cases, poor compliance due to cognitive impairment and/or depression. In this setting, drug-drug interaction may represent a serious and even life-threatening clinical condition. Moreover, the inability to distinguish drug-induced symptoms from a definitive medical diagnosis often results in addition of yet another drug to treat the symptoms, which in turn increases drug-drug interactions. Cognitive enhancers, including acetylcholinesterase inhibitors and memantine, are the most widely prescribed agents for Alzheimer's disease (AD) patients. Behavioral and psychological symptoms of dementia, including psychotic symptoms and behavioral disorders, represent noncognitive disturbances frequently observed in AD patients. Antipsychotic drugs are at high risk of adverse events, even at modest doses, and may interfere with the progression of cognitive impairment and interact with several drugs including anti-arrhythmics and acetylcholinesterase inhibitors. Other medications often used in AD patients are represented by anxiolytic, like benzodiazepine, or antidepressant agents. These agents also might interfere with other concomitant drugs through both pharmacokinetic and pharmacodynamic mechanisms. In this review we focus on the most frequent drug-drug interactions, potentially harmful, in AD patients with behavioral symptoms considering both physiological and pathological changes in AD patients, and potential pharmacodynamic/pharmacokinetic drug interaction mechanisms.

Cardiovascular risk and quality of life in elderly people with mild thyroid hormone deficiency.

Subclinical hypothyroidism (sHT) is a common condition in the general population, the prevalence increases with age, especially in women. An association between sHT and increased coronary heart disease (CHD) and heart failure (HF) risk and mortality has been described. However, this association is far to be established in older people (>65 years), especially in the oldest old (>85 years). Individuals with sHT may experience symptoms that resemble those observed in the overt form of the disease, leading to an impaired quality of life (QoL). Although very old people are frequently frail and potentially more susceptible to the effects of a disease, few studies were designed to assess the effect of sHT on QoL in this subset of population. Interestingly, the serum TSH concentration curve of general population has a skewed distribution with a "tail" toward higher values, which is amplified with aging. Thus, the diagnosis of sHT and the interpretation of its potential effects on CV function and QoL in older people may be a challenge for the clinician. Giving these premises, we reviewed the English scientific literature available on National Library of Medicine (www.pubmed.com) since 1980 regarding hypothyroidism, sHT, elderly, cardiovascular risk, CHD or HF events and mortality, health-related QoL, and LT4 therapy. Consistent results among large prospective cohort studies suggest an age-independent relationship between sHT and HF progression, while an impact of sHT on CHD events and mortality is essentially reported in young adults (aged below 65-70 years) with long-lasting disease. Scanty data are available on QoL of older people with sHT (>65 years) and, generally, no significant alterations are described.

Cognitive function and quality of life in mild thyroid hormone deficiency.

Subclinical hypothyroidism (sHT) is very common in general population, especially in women and older people. sHT individuals may experience symptoms that resemble those observed in overt hypothyroidism, resulting in impaired quality of life (QOL). Asymptomatic patients may suffer a reduction in perceived health status due to the awareness of disease. Cognitive function represents one of the most important domains of the QOL questionnaires. Given the intrinsic relationship between cognitive status and QOL it is worth to address these topics together, in a systematic review of the literature. Thus, we reviewed the English scientific literature available on National Library of Medicine (www.pubmed.com) sine 1980 regarding hypothyroidism, sHT, elderly, L-thyroxine (LT4) therapy, QOL, cognition, brain. We supplemented the search with records from personal files, textbooks, and relevant articles. The possible link, at molecular level, between cognition and thyroid failure was also assessed. Conflicting results on the association between sHT and cognitive and health related QOL impairment are still present, although the most recent, naturalistic studies did not find any significant relationship. Interestingly, a reduction in health related QOL is frequently reported in patients with thyroid autoimmune diseases regardless of thyroid dysfunction. We also report most significant patents on the topic.

Vestibular disorders in euthyroid patients with Hashimoto's thyroiditis: role of thyroid autoimmunity.

INTRODUCTION: A relationship between vestibular disorders and thyroid autoimmunity independently from thyroid function has been postulated. AIM: To shed more light on the actual relationship between vestibular lesions and Hashimoto's thyroiditis (HT) regardless of thyroid function. METHODS: Forty-seven patients with HT (89·4% F; aged 48·3 ± 12·7 years), 21 with multinodular goitre (MNG; 57·1% F; 54·1 ± 9·8 years) and 30 healthy volunteers (56·7% F; 50·7 ± 13·9 years) were enrolled. Inclusion criteria were the presence of normal thyroid function tests and no clinical history of vestibular dysfunction. Each subject was submitted to complete vestibular evaluation [Caloric Test, Vestibular evoked myogenic potentials (VEMPs), Head Shaking Test (HST)]. RESULTS: 52·2% of HT patients showed an alteration of VEMPs and 44·7% of caloric test (P < 0·0001 for both). None of the MNG patients showed any vestibular alteration, while one healthy control showed an altered caloric test. A correlation was found between vestibular alterations of HT patients and the degree of serum TPOAb level, not affected by age and serum TSH value. By logistic regression analysis, the absence of thyroid autoimmunity significantly reduced the risk of vestibular alterations: HR 0.19 (95%CI: 0·003-0.25, P = 0·0004) for caloric test; HR 0·07 (95%CI: 0·02-0·425, P < 0·0001) for VEMPs; and HR 0·22 (95%CI: 0·06-0·7, P = 0·01) for HST. CONCLUSION: In euthyroid HT patients, a significant relationship between subclinical vestibular damage and the degree of TPOAb titre was documented. This finding suggests that circulating antithyroid autoantibodies may represent a risk factor for developing vestibular dysfunction. An accurate vestibular evaluation of HT patients with or without symptoms is therefore warranted.

Clinical aggressiveness and long-term outcome in patients with papillary thyroid cancer and circulating anti-thyroglobulin autoantibodies.

OBJECTIVE: The association between papillary thyroid cancer (PTC) and Hashimoto's thyroiditis is widely recognized, but less is known about the possible link between circulating anti-thyroglobulin antibody (TgAb) titers and PTC aggressiveness. To shed light on this issue, we retrospectively examined a large series of PTC patients with and without positive TgAb. METHODS: Data on 220 TgAb-positive PTC patients (study cohort) were retrospectively collected in 10 hospital-based referral centers. All the patients had undergone near-total thyroidectomy with or without radioiodine remnant ablation. Tumor characteristics and long-term outcomes (follow-up range: 2.5-24.8 years) were compared with those recently reported in 1020 TgAb-negative PTC patients with similar demographic characteristics. We also assessed the impact on clinical outcome of early titer disappearance in the TgAb-positive group. RESULTS: At baseline, the study cohort (mean age 45.9 years, range 12.5-84.1 years; 85% female) had a significantly higher prevalence of high-risk patients (6.9% vs. 3.2%, p<0.05) and extrathyroidal tumor extension (28.2% vs. 24%; p<0.0001) than TgAb-negative controls. Study cohort patients were also more likely than controls to have persistent disease at the 1-year visit (13.6% vs. 7.0%, p=0.001) or recurrence during subsequent follow-up (5.8% vs. 1.4%, p=0.0001). At the final follow-up visit, the percentage of patients with either persistent or recurrent disease in the two cohorts was significantly different (6.4% of TgAb-positive patients vs. 1.7% in the TgAb-negative group, p<0.0001). At the 1-year visit, titer normalization was observed in 85 of the 220 TgAb-positive individuals. These patients had a significantly lower rate of persistent disease than those who were still TgAb positive (8.2% vs. 17.3%. p=0.05), and no relapses were observed among patients with no evidence of disease during subsequent follow-up. CONCLUSIONS: PTC patients with positive serum TgAb titer during the first year after primary treatment were more likely to have persistent/recurrent disease than those who were consistently TgAb-negative. Negative titers at 1 year may be associated with more favorable outcomes.

Is subclinical hypothyroidism a cardiovascular risk factor in the elderly?

CONTEXT: The negative impact of subclinical hypothyroidism (sHT) on cardiovascular risk, widely recognized in young adults (aged <55-60 y), is still debated in the elderly (>65 y), especially in the oldest olds (>80 y). EVIDENCE ACQUISITION: We searched Medline for reports published with the following search terms: "hypothyroidism," "subclinical hypothyroidism," "ageing," "elderly," "L-thyroxin," "thyroid," "guidelines," "treatment," "quality of life," "cardiovascular risk," "heart failure," "coronary heart disease" (CHD), "atherosclerosis," and "endothelial dysfunction." We limited our search to reports in English published after 1980, although we incorporated some reports published before 1980. We supplemented the search with records from personal files, textbooks, and relevant articles. Analyzed parameters included the epidemiology of thyroid failure, the effect of thyroid hormone on the aging process, cardiovascular function, and CHD risk factors. We also included the potential benefits of L-T4 therapy on the quality of life, cardiovascular events, and survival. EVIDENCE SYNTHESIS: TSH levels increase with age, even in older people without thyroid disease. Most longitudinal studies show an increased risk for CHD events and mortality in sHT participants. This increase is less evident in the elderly, mainly in cases of serum TSH values above 10 mIU/L. Lower mortality rate in a cohort of the oldest olds (>85 y) has been reported. CONCLUSIONS: sHT in older people should be not regarded as a unique condition, and moderately old patients (aged <70-75 y) could be considered clinically similar to the adult population, albeit with a higher optimal TSH target value. Conversely, the oldest old subjects should be carefully followed with a wait-and-see strategy, generally avoiding hormonal treatment. The decision to treat elderly people is still an unresolved clinical challenge--first, due to a lack of appropriately powered randomized controlled trials of L-T4 in sHT patients, examining cardiovascular hard endpoints in various classes of age; and second, because of the negative effects of possible overtreatment.

Subclinical hypothyroidism and heart failure risk in older people.

CONTEXT: Although the negative impact of subclinical hypothyroidism (sHT) in terms of cardiovascular risk in young adults is mostly acknowledged it remains to be established in the elderly, especially in the oldest old. EVIDENCE ACQUISITION: We searched Medline for reports published with the following search words: hypothyroidism, sHT, ageing, elderly, L-thyroxin, thyroid, guidelines, treatment, quality of life, cardiovascular risk, heart failure (HF), ischemic heart disease (IHD), endothelial dysfunction. The search was restricted to reports published in English since 1980, but some reports published before 1980 were also incorporated. We supplemented the search with records from personal files and references of relevant articles and textbooks. Parameters analyzed included epidemiology of sHT and thyroid failure the effect of thyroid hormone on ageing process and cardiovascular function as well as the potential benefits of L-thyroxin therapy on quality of life, HF progression and events. EVIDENCE SYNTHESIS: TSH levels increase with age, even in older patients without thyroid disease, in whom higher TSH value might favor longevity; better quality of life and lower IHD mortality in the oldest old population has been reported yet. However, at odds with the relationship between sHT and IHD risk and mortality, which shows a clear age dependent feature, vanishing in the last decades of life, the detrimental effect of sHT on HF progression and events remains evident also in older patients, although no data are available in the oldest old population. CONCLUSIONS: The lack of specific randomized trials enrolling either old or very old subjects, aimed at evaluate the efficacy of hormonal replacement on overall survival and cardiovascular risk reduction along with the negative effects of possible over-treatment, makes the decision to treat older people a still unresolved clinical challenge. Moreover, the possibility that restoring euthyroidism may be harmful in the elderly should be always taken into account.

Acute portal vein thrombosis precipitated by indomethacin in a HCV-positive elderly patient.

BACKGROUND: An increased risk of venous thromboembolism has been reported in patients treated with non-steroidal anti-inflammatory drugs (NSAIDs). We describe a case of acute portal vein thrombosis (PVT) in a hepatitis C virus (HCV)-positive elderly patient following administration of indomethacin. CASE PRESENTATION: A 79-year-old HCV-positive man was hospitalized for severe abdominal pain, nausea and vomiting, 15 days after starting indomethacin for back pain. Clinical signs and imaging evaluations disclosed a picture of PVT. Indomethacin was discontinued, and the patient was started on fondaparinux and antithrombin. He was discharged 15 days later due to improvement of his clinical conditions. Thirty days later, a follow-up ultrasound did not show appreciable signs of PVT. The time elapsing between the start of analgesic therapy and PVT onset suggests a role of indomethacin as the triggering agent. Indomethacin could have precipitated PVT by a combination of at least two detrimental mechanisms: 1) direct action on liver vascular endothelium by inhibition of prostacyclin biosynthesis; 2) damage to the intestinal mucosa, followed by inflammatory and pro-coagulant activation of portal endothelium upon exposure to bacterial endotoxins. CONCLUSIONS: This case can be of interest to physicians, who should exert caution when prescribing NSAIDs for inflammatory pain in patients with background inflammatory dysfunctions of the portal vein endothelium.

Age and gender substantially influence the relationship between thyroid status and the lipoprotein profile: results from a large cross-sectional study.

BACKGROUND: Conflicting data are reported on the association between mild thyroid failure and lipid profile, primarily regarding serum triglyceride values and patients with slightly elevated thyrotropin (TSH, <10 mIU/L). In this study, we assessed the possible influence of gender and age on this relationship. METHODS: The study included 2308 consecutive patients who were seen for suspected or diagnosed thyroid disease (1874 women, 434 men, mean age 47.5±14.1 and 46.9±14.0 years, respectively) and on whom studies of thyroid status and lipoprotein profile were conducted after an overnight fast. Patients with uncontrolled diabetes mellitus and those taking lipid-lowering drugs were excluded. RESULTS: There were 628 patients receiving L-thyroxine who had a diagnosis of hypothyroidism: 200 were hyperthyroid, and 120 were still hypothyroid. Overall, 648 patients were hypothyroid, and 290 were hyperthyroid. No gender difference in the frequency of TSH values in the ranges studied (i.e., TSH frequency distribution) was observed. Total cholesterol (TC) and low-density lipoprotein cholesterol (LDLc) values (p<0.0003 and p<0.003, respectively) as well as the LDL/high-density lipoprotein cholesterol (HDLc) ratio (p<0.03) were elevated not only in unselected women with TSH values in the 4th TSH group (>10 mIU/L) but also in those of the 3rd group (3.6-10.0 mIU/L) who were older than 50 years (TC and LDLc p=0.01, LDL/HDLc ratio p=0.02 vs. euthyroid women). Among unselected men, only those of the 4th TSH group had elevated triglyceride (p<0.0001) but not cholesterol values. However, men of the 3rd and 4th TSH group who were older than 65 years had significantly higher TC, LDLc, and LDL/HDLc values as well (p=0.03, p=0.02 and p=0.01, respectively vs. euthyroid men). In the final model of stepwise regression for predicting each lipid parameter variation on the basis of age, TSH, free thyroxine (FT4), and body mass index (BMI) analysis, age had the highest standardized coefficient (0.36 and 0.37, respectively), followed by TSH (0.20 and 0.11, respectively) and FT4 (-0.11 and -0.09, respectively) when looking at TC and LDLc; whereas BMI had the highest standardized coefficient (0.28), followed by age (0.15) and TSH (0.11) when looking at triglyceride variation. CONCLUSIONS: This study confirms a gender differentiation in the relationship between hypothyroidism and the lipid profile, which is substantially influenced by age, especially in patients with mild thyroid impairment (TSH<10 mIU/L).

Clarithromycin-induced rhabdomyolysis: a case report.

Rhabdomyolysis is a clinical and laboratory syndrome that is caused by various etiologies, involving the skeletal muscle. Clarithromycin, like other macrolides, is an inhibitor of CYP450 3A4, the major enzyme responsible for the metabolism of several drugs, in particular some statins. Rhabdomyolysis related to macrolide-statin interaction has previously been described. To date, rhabdomyolysis induced by clarithromycin has been described in only one previous report. We describe the case of a 90-year-old Caucasian male, admitted to the University Hospital of Pisa for dyspnea, who developed rhabdomyolysis associated with clarithromycin administration.

Off-label use of sunitinib in patients with advanced, epithelial thyroid cancer: a retrospective analysis.

Tyrosine kinase receptors play an important role in tumor angiogenesis and, their implication in epithelial thyroid tumor growth has been highlighted. Sunitinib is a novel tyrosine kinase inhibitor, approved in 2006 by Food and Drug Administration for the treatment of advanced renal cell and gastrointestinal stromal tumors. Preliminary promising results have been also obtained in patients with RAI-resistant thyroid neoplasia. In the current study, our experience on 9 patients with advanced thyroid epithelial cancer is analyzed and discussed in relation to the new patents in this field. According to RECIST criteria, partial response was obtained in 5/9 (55.5%) patients at 3 months and in 6/9 (66.6%) at 6 months. Median treatment follow-up was 13.0 months and median overall survival and progression-free survival were 20 [95% confidence interval (CI) 9.3 - 30.6] and 21 months (95% CI 6.9 - 35.1), respectively. One case of severe thoracic hemorrhage was observed, the most common adverse events being represented by fatigue, (44.4% ), skin rash (33.3% ), headache (33.3% ), and one case each of hypertension, macrocytosis and acute pneumonia. These results confirm sunitinib as a potential useful tool for the treatment of advanced thyroid cancers and may open the way for new patents of molecules with more specific target selectivity.

Non-thyroidal illness syndrome and short-term survival in a hospitalised older population.

BACKGROUND: non-thyroidal illness syndrome (NTIS) has been associated with an adverse clinical outcome. OBJECTIVE: to evaluate the prevalence of NTIS, its impact on patients' survival and the possible pathogenic role of systemic inflammation. DESIGN: observational cross-sectional analysis. PARTICIPANTS AND SETTING: three hundred and one acutely ill older patients (156 women; median age 81 years, range 65-101) consecutively admitted to a primary care unit. METHODS: serum FT(3), FT(4) and thyrotropin levels as well as acute inflammation indexes were evaluated. RESULTS: the NTIS prevalence (specifically low T3 syndrome) was 31.9%. A significant association was found between NTIS and acute renal failure (P = 0.006), New York Heart Association classification (NYHA) IV heart failure (P = 0.003) and metastasised cancer disease (P = 0.0002). Serum FT(3) values correlated inversely with serum C-reactive protein (P < 0.0001), lactate dehydrogenase (P = 0.0004), fibrinogen (P = 0.03) and erythrocyte sedimentation rate (P < 0.0001) values, and progressively decreased with increasing tertiles of age (P = 0.0004). The mortality rate was significantly higher (P = 0.0002) among patients with low T3 syndrome, which emerged as the sole predictive factor of death (odds ratio 4.3; 95% confidence interval 1.7-10.5). CONCLUSIONS: low T3 syndrome is very common in the hospitalised older population, emerging as the most sensitive independent predictor of short-term survival. Serum FT(3) determination should be included in the assessment of short-term prognosis of acutely ill older patients.

1513A>C polymorphism in the P2X7 receptor gene in patients with papillary thyroid cancer: correlation with histological variants and clinical parameters.

INTRODUCTION: The modulation of the purinergic receptor P2X7 may be implicated in human carcinogenesis. The 1513A>C and 489C>T polymorphisms of P2X7R gene induce loss of function and gain of function, respectively. AIM: The aim of the study was to assess the frequency of both 1513A>C and 489C>T polymorphisms in patients with papillary thyroid carcinoma (PTC) and to evaluate the possible association with clinical and histological features. PATIENTS AND METHODS: P2X7R analysis was performed in lymphocytes from 121 PTC patients (100 women, 21 men; aged 43.4 +/- 13.6 yr), 100 matched healthy subjects, and 80 patients with nodular goiter. RESULTS: The minor allele frequency for 1513A>C polymorphism in PTC patients with the classical variant was similar to controls (0.21 and 0.20, respectively), whereas it resulted in a significant increase in patients with the follicular variant (0.36; P = 0.01 vs. classical variant, and P = 0.005 vs. controls). In detail, 13.6% of patients with PTC follicular variant were homozygous for the 1513C allele, compared to 2.6% of patients with the classical variant and 2% of controls. Moreover, a positive relationship between 1513A>C polymorphism and either cancer diameter (Rho = 0.22; P = 0.02) or TNM stage (Rho = 0.38; P < 0.001) was found. No significant difference in the genotype frequency of 489C>T polymorphism between PTC patients and healthy controls was observed (0.42 and 0.47, respectively). CONCLUSIONS: Our data show, for the first time, a strong association between 1513A>C polymorphism of P2X7R gene and the follicular variant of PTC. Further studies are needed to confirm the possible role of this polymorphism as a novel clinical marker of PTC follicular variant and its usefulness in selecting patients with different clinical outcome.