HYPOTHYROID &COMORBID CONDITIONS

HYPOTHYROIDISM with

• DIABETES• HYPERTENSION• CAD• DYSLIPIDEMIA• OBESITY• PSYCHIATRY

• ALZHEIMER• CVA / HASHIMOTO’S

ENCEPHALOPATHY• CLD• CKD• ELDERLY• PRE OP

HYPOTHYROIDISM WITH DIABETES

THYROID DISORDERS IN INDIA

Prevalence of Thyroid disorders in Eight urban cities of India

Prevalence of Thyroid disorders in Eight urban cities of India

RESULTS….

• Hypothyroidism is highly prevalent 11%• The older population (>35 years) at higher

risk of hypothyroidism(13.11% vs. 7.53%).• Women- 3 times more likely to be affected

by hypothyroidism than men (15.86% vs. 5.02%).  

• Hypertension- 20.4% • Diabetes- 16.2% • TPO positive – 20%

• Inland cities had higher prevalence of hypothyroidism (11.73%) compared to coastal cities (Chennai, Goa, Mumbai) (9.45%). Kolkata recorded the highest prevalence of hypothyroidism (21.67%).

THE THYROID-DIABETES CONNECTION

THYROIDDIABETES

• Autoimmunity• Genetic–Epigenetic interaction•  HLA-DR3 allele• CTLA-4 carries a major genetic risk• PTPN22, FOXP3

Indirect Links

• Thyroid Hormones and Appetite Regulation- patients with TH resistance 

• Thyroid Hormones and Energy Expenditure- increased REE. UCP1 is a major regulator

• Central Interactions of Thyroid Hormones on Glucose and Lipid Regulation

Diabetes and Thyroid

Multifaceted relationship

Some special situations

• Older sulphonylureas can inhibit the synthesis of thyroid hormone (arbutamide, tolbutamide, methahexamide, and possibly chlorpropamide)

• Metformin reduces TSH• Pioglitazone increases orbitopathy(TAO)• Increased Statin Induced myopathy• Thyroid hormone analogues- for treating

Obesity and Diabetes

Polyglandular Autoimmune Endocrinopathy

PGA Type 2

DIABETES PLUS THYROID DISORDERS: LONG-TERM MORTALITY AND MORBIDITY

Morbidity Data

• Sub-clinical hypothyroidism and hyperthyroidism have both been linked to increased cardiovascular risk Endocr Rev 2008;29:76–131.

• Sub-clinical hypothyroidism was associated with a higher frequency of nephropathy  Diabet Med 2007;24:1336–44

• Subclinical hypothyroidism had a higher prevalence of retinopathy Diabetes Care 2010;33:1018–20.

Mortality Data

• Subclinical hyperthyroidism yielded a significant 1.49-fold increase in relative likelihood of death from all cause.   Eur J Endocrinol2008;159:329–41

•  In sub-clinical hypothyroidism age <65yrs all-cause mortality was significantly higher than in the euthyroid population.  J Clin Endocrinol Metab 2008;93: 2998–3007

Screening for Thyroid Dysfunction in Patients with DM

•  Close monitoring of thyroid function particularly in patients with T1DM

• Ty 2 DM- Annual/Bi-annual screening justified in higher risk groups like patients over 50 or 55, particularly with suggestive symptoms, raised antibody titres or Dylipidaemia.

Diabetic practice guidelines for thyroid screening in patients with

diabetes

DM + AITD+ PREGNANCY

• A risky dual gestational endocrinopathy

• Higher rate of infertility, cesarean sections, preterm deliveries, and hypertensive disorders of pregnancy

• Independent risk factor for Pre-ecclampsia and Ecclampsia

• Thyroid disease and type 1 but also type 2 diabetes mellitus (DM) are strongly associated

• Thyrotoxic patients usually lose their glucose control 

• Important clinical implications for insulin sensitivity and treatment requirements. 

• Increased CV risk with SCH•  Increased long-term morbidity and mortality• Periodic screening as per recommendations

HYPOTHYROIDISM WITH OBESITY

• TSH seems to be positively related to the degree of obesity.

• A positive correlation has been identified between serum leptin and serum TSH levels in obese individuals, which could reflect the positive association between TSH and BMI reported in some individuals.

• Leptin, adjusted for BMI, was found to correlate with TSH, which suggests that the increase in TSH and leptin levels in severe obesity could result from the increased amount of fat.

• Interestingly, a moderate increase in total T3 or free T3 (FT3) levels has been reported in obese subjects.

• Progressive fat accumulation was associated with a parallel increase in TSH and FT3 levels irrespective of insulin sensitivity and metabolic parameters, and a positive association has been reported between the FT3 to FT4 ratio and both waist circumference and BMI in obese patients.

• This finding suggests a high conversion of T4 to T3 in patients with central fat obesity due to increased deiodinase activity as a compensatory mechanism for fat accumulation to improve energy expenditure.

ROLE OF LEPTIN

• TSH levels are at the upper limit of the normal range or slightly increased in obese children, adolescents, and adults and are positively correlated with BMI.

AUTO IMMUNITY AND OBESITY

• There is some debate about the link between obesity and the risk of autoimmune thyroid dysfunction (AITD), which is the main cause of hypothyroidism in adults.

• The prevalence of AITD in obesity has been reported to be 12.4% in children and between 10 and 60% in adults.

• This discrepancy may be due to such factors as sex, age, menopausal status, smoking habit, environmental factors, iodine intake, and degree of obesity.

HYPOTHYROIDISM WITH HYPERTENSION

• In a meta-analysis (A) of all cross-sectional studies to investigate an association between SH and blood pressure alterations, there was significant difference in both systolic blood pressure and diastolic blood pressure in SH compared to control groups, with a weighted mean difference of 1.89 mmHg and 0.75 mmHg for systolic and diastolic blood pressure, respectively.

• However, there is no randomized controlled trial investigating whether the treatment could modify blood pressure.

HYPOTHYROIDISM WITH CAD

• The association of SH and heart failure has been demonstrated in elderly patients, but no study has yet assessed this association in younger age groups (A).

• In the Health, Aging, and Body Composition Study (A) SH was related to a higher rate of incident and recurrent congestive cardiac failure with TSH levels of 7.0 mU/L or greater, compared with euthyroid participants, even after adjustment for cardiovascular risk factors.

• Similarly, in the Cardiovascular Health Study (A), subjects with TSH level ≥ 10 mU/L had a moderately elevated risk of heart failure over a mean 12 year follow-up compared to euthyroid subjects. In this study, the risk of congestive heart failure was not increased among older adults with TSH < 10 mU/L.

• More recently, in The Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), SH was significantly associated with a higher rate of heart failure (age- and sex- adjusted) at TSH threshold > 10 mU/L (A) in elderly with known high cardiovascular risk.

• Data concerning the effects of subclinical hypothyroidism on the cardiac function and structure are conflicting.

• There are consistent evidence regarding the association of subclinical hypothyroidism with congestive heart failure in elderly patients, particularly for TSH level > 10 mU/L Grade A, but not for younger patients.

HYPOTHYROIDISM WITH HEART FAILURE

HEART FAILURE

• Heart failure Hypothyroidism has detrimental effects on the cardiovascular system (D). Therefore, in patients with heart failure, it is important to detect it and eventually treat it.

• With regards to SH, it has also been recognized as an important risk factor for HF in older adults.

• A meta-analysis of six prospective cohort studies for a total of 2,068 patients with SH, specifically with TSH > 10 mU/l, showed a higher risk of heart failure (A).

• Therefore, heart failure patients would also be good candidates for whom hypothyroidism must be ruled out (D).

HYPOTHYROIDISM WITH DEPRESSION

• Although it has been related to hypothyroidism, several studies have failed to find a consistent relationship between these two entities.

• On the other hand, in positive TPOAb subjects, depression was found to be more frequent.

• Prevalence of a lifetime of depression was higher in subjects with positive TPOAb (24.2%) in comparison to those without TPOAb (16.7%), with a relative risk of 1.4 (95% CI 1.0-2.1; p = 0.04 after adjustment for confounders) .

• Therefore the need to rule out hypothyroidism in a depressive patient is still an unresolved matter.

• There are controversial results in the published literature regarding the effects of SH on symptoms, quality of life, cognition and depression, but the panel concludes that there are hardly any symptoms or global neuropsychological dysfunction associated with SH (D).

HYPOTHYROIDISM WITH ALZHEIMER’S

HYPOTHYROIDISM WITH ENCEPHALOPATHY

HYPOTHYROIDISM WITH DYSLIPIDEMIA

DYSLIPIDEMIA

• Hypothyroidism is a recognized cause of secondary dyslipidemia and in any person who presents with elevated LDL cholesterol (> 160 mg/dL), it has been recommended to test for hypothyroidism (D).

• A recent prospective study in Japan reported that the prevalence of hypothyroidism was 4.3% in patients with hypercholesterolemia (1.4% with primary overt hypothyroidism, 2.3% with subclinical hypothyroidism, and 0.4% with central hypothyroidism) (B).

• These values are relatively similar to those of the general population, nevertheless, the early detection of hypothyroidism and its treatment with levothyroxine would avoid unnecessary life-long use of antilipemic agents in these patients.

• Thyroid hormone has multiple effects on the lipid synthesis and metabolism, and overt hypothyroidism is consistently associated to lipid abnormalities which are reversible with levothyroxine therapy but this relationship is controversial in patients with SH(D).

• Data emerging from the NHANES III study showed no lipids abnormalities when adjusted for confounding variables (B) and similar results were obtained from the Japanese-Brazilian Thyroid Study in Latin America (A).

• Multiple interventional studies have evaluated the effects of levothyroxine on lipid profiles in patients with SH, with mixed results.

• A meta-analysis of 13 studies found a significant decrease of serum total cholesterol levels following levothyroxine therapy, mainly in patients with elevated cholesterol values, but most of the selected studies had a non-randomized design.

• In contrast, a recent Cochrane systematic review of 12 randomized controlled trials comparing levothyroxine therapy with placebo or no treatment in adults with SH found only marginal evidence indicating that levothyroxine replacement improved total cholesterol levels, but no favorable effects were found on the other parameters of the lipid profile, such as HDL-C, LDL-C, triglycerides, ApoA, ApoB, or Lp(a).

• Most recently, several small randomized controlled trials found favorable effects of levothyroxine replacement therapy on the lipid profile .

HYPOTHYROIDISM WITH RENAL INSULT

HYPOTHYROIDISM WITH LIVER INSULT

• Liver diseases are also frequently associated with thyroid test abnormalities or dysfunctions, particularly elevation of thyroxine-binding globulin and thyroxine.

• Hepatitis C virus infection has been connected with thyroid abnormalities.

• In addition, antithyroid drug therapy may result in hepatitis, cholestasis or transient subclinical hepatotoxicity, whereas interferon (IFN) therapy in liver diseases may also induce thyroid dysfunctions.

• These thyroid-liver associations may cause diagnostic confusions.

• In patients with chronic hepatitis associated with primary biliary cirrhosis (PBC) or chronic autoimmune hepatitis, there is an increased prevalence of autoimmune thyroid disease.

• Thus abnormalities may arise from thyroid gland dysfunction or as a consequence of the liver disease.

• Autoimmune hypothyroidism is a prominent feature in PBC, occurring in 10–25% of patients.

• There is often an increase in total T4 in PBC, due to an increase in thyroid binding globulin levels, and this may mask ‐hypothyroidism, emphasizing the need to perform a free T4 and TSH assay.

NAFLD

• NAFLD was significantly linked to hypothyroidism (30.2% patients in the case group vs 19.5% patients in the control group; p<0.001).

• Additionally, the prevalence of NAFLD and abnormal liver enzyme levels (ALT, which is defined as greater than 33/25 IU/L) progressively increased as the grade of hypothyroidism increased.

• • For patients who had subclinical hypothyroidism, 29.9% of them

had NAFLD, and for patients who had overt hypothyroidism, 36.3% of them had NAFLD (p<0.001).

• Journal of Hepatology, March 2012

HYPOTHYROIDISM WITH ELDERLY

• There is good evidence suggesting that SH is not related to symptoms or with disorders of cognition and mood in older persons (A,B,B), and there is strong evidence (A,A) against treating elderly patients with SH aiming to improve cognitive function, quality of life and symptoms.

• SH has been consistently related to a higher risk of incident and recurrent congestive heart failure in elderly subjects, particularly at TSH level ≥ 10 mU/L (A).

• However, it has been proposed that moderately increased serum TSH levels (4.5-10 mU/L) may represent a protective factor against cardiovascular risk and be associated with prolonged life span (A,A,B,B).

• The panel recommends against routine treatment for elderly (> 65 yr) and very-elderly (> 80 yr) patients with subclinical hypothyroidism at TSH levels < 10 mU/L. Grade A.

• The panel also recommends against treatment of SH if the aim is to improve cognitive function in elderly people Grade A.

HYPOTHYROIDISM INPRE-OP STATUS

• The half-lives of T4 and T3 are 7 and 1.5 days respectively.

• Thus, a patient who is taking T4 does not need to take it on the day of surgery while the patient who is taking T3 does;

• Radiograph the cervical region to determine if goiter is going to interfere with tracheal intubation.

Arq Bras Cardiol 2007; 89(6) : e172-e209

Arq Bras Cardiol 2007; 89(6) : e172-e209

• Subclinical hypothyroidism — Based upon the studies in patients undergoing coronary artery bypass graft (CABG) and percutaneous transluminal coronary angioplasty (PTCA) , panel suggest not postponing surgery in patients with subclinical hypothyroidism (elevated serum TSH, normal free T4).

• Moderate (overt) hypothyroidism — Based upon the retrospective studies cited above panel suggest that patients with moderate overt hypothyroidism undergo urgent or emergent surgery without delay, with the knowledge that minor perioperative complications might develop.

• On the other hand, it is prudent to postpone surgery until the euthyroid state is restored when hypothyroidism is discovered in a patient being evaluated for elective surgery.

Interaction of Metformin and Thyroid Function

• Metformin activates Hepatic AMPK• Transported via OCT1 & OCT2• Metformin crosses BBB• Metformin has the opposite effects on

hypothalamic AMPK•  Counteracts T3 effects at the hypothalamic

level• Suppresses pituitary TSH secretion• Shrinks nodule size- 30%, Metabolic Syndrome and

Related Disorders, 9, 69–75.

• On the other hand, in an individual participant data analysis, CHD outcomes in adults with SH did not differ significantly across age groups, for the specific age.

• In group of 80 years or older, there was neither a significant increased nor decreased risk of total mortality and CHD endpoints (A).

• Physicians should acknowledge that TSH distribution curves for thyroid disease-free subjects appear to shift progressively to higher TSH concentrations with age, suggesting that the increase in median TSH with age mainly reflects population shifts in TSH distribution rather than a thyroid dysfunction (B,D).

• Concerning the operative treatment of patients with hypothyrosis, especially in nonthyroid and emergency surgery, disorders of different organs and systems, associated with hypothyrosis, should be considered.

• When it comes to surgical treatment of patients with hypothyroidism as a co-morbidity, especially in emergency surgery, one think should be kept in mind, that the disturbances of various organs and organ systems, which are associated with hypothyroidism.

• In terms of preoperative preparation, of particular importance are: • • cardiovascular disorders (possible myocardial depression and

bradycardia) • • respiratory system disorders (reduced spontaneous ventilation) • • metabolic disorders and hydroelectrolyte and acidobase

disbalance (especially hyponatremia, and hypoglycemia)1• Due to slow metabolism in patients with hypothyroidism, there is a

risk of an overdose of anesthetics and other medications that are used in the surgical treatment.

• It is therefore necessary to carefully titrate doses, with the general recommendation to reduce dose by 30%

• In patients with expressed hypothyrosis it is necessary to introduce substitution therapy.

• The optimal preparation period before the surgery is 2-4 weeks.

• Patients older than 60 years of age, especially with coronary disease or long term aggravated hypothyrosis, should not be given full doses of substituents in the beginning.