Non-medicalization of medical science: Rationalization for future

Table 1 Causes of elevated thyrotropin levels

Transient increase in TSH	Permanent increase in TSH
Non-thyroidal illness	Assay interference
Thyroiditis	TSH hormone resistance
Medications: Amiodarone and Lithium	Adrenal insufficiency
Lack of adherence to treatment	Obesity

TSH: Thyrotropin.

Table 2 Guideline recommendations for treatment of subclinical hypothyroidism

Degree of subclinical hypothyroidism	ATA 2012[36]	ETA 2013[37]	NICE 2019[38]
TSH > 10 mIU/L	Levothyroxine should be considered. (Grade B)	Younger patients (< 65 to 70 yr): Treatment with levothyroxine is recommended, even in the absence of symptoms. (Grade 2); Older patients (> 70 yr): Treatment with levothyroxine should be considered if clear symptoms of hypothyroidism are present or if the risk of vascular events is high. (Not a graded recommendation, but part of the treatment algorithm)	All adults (on 2 occasions, 3 mo apart) consider treatment.
TSH: ULN to 10 mIU/L	Treatment should be considered on the basis of individual factors (i.e., symptoms suggestive of hypothyroidism, a positive test for antibodies to thyroid peroxidase, or evidence of atherosclerotic cardiovascular disease, heart failure, or associated risk factors for these diseases). (Grade B, because of a lack of randomized, controlled trials)	Younger patients (< 65 to 70 yr): A trial period of treatment with levothyroxine should be considered when symptoms suggestive of hypothyroidism are present. (Grade 2); Older patients (especially > 80 to 85 yr): Careful follow-up with a wait-and-see strategy, generally avoiding hormonal treatment, is recommended. (Grade 3)	Age < 65 years (on 2 occasions, 3 mo apart): Consider a 6-mo trial of levothyroxine if symptoms are present.

ATA: American Thyroid Association; ETA: European Thyroid Association; NICE: National Institute for Health and Care Excellence; TSH: Thyrotropin.

Table 3 Criteria for prediabetes

	WHO[39]	ADA[40]
FPG (mg/dL)	110-125	100-125
2-h plasma glucose (mg/dL)	140-199	140-199
HbA1c (%)		5.7-6.4

ADA: American Diabetes Association; FPG: Fasting plasma glucose; HbA1c: Hemoglobin A1c; WHO: World Health Organization.

Table 4 Criteria for defining osteopenia

Category	Definition	Treatment recommendation
“Moderate risk”, Endocrine Society guidelines 2019[74]	Clinical: No prior hip or spine fractures, BMD T-score at the hip and spine both above -2.5, 10-yr hip fracture risk < 3% or risk of major osteoporotic fractures < 20%	Reassess fracture risk in 2-4 yr. Country-specific guidelines for treatment
ISBMR guidelines 2021[75]	BMD T-score between -1.0 and -2.5 at the femoral neck or lumbar spine, 10-yr probability of a hip fracture ≥ 3.5%, or a 10-yr probability of a major osteoporosis-related fracture ≥ 10.5% based on the FRAX tool (based on limited data in Indians)	Advisable to initiate treatment

BMD: Bone mineral density.

Table 5 Clinical spectrum of preclinical conditions: Looking at hard facts

	Prediabetes	Subclinical hypothyroidism	Osteopenia	MACS
Clinical disease	Diabetes	Overt primary hypothyroidism	Osteoporosis	Cushing’s syndrome
Prevalence of preclinical condition	5.5%-53.1%[43], IFG -6.2%[41], IGT -10.6%[41]	4.3%-15%[20]	54%-80%[65]	5%-48%[6]
Prevalence of clinical condition	10.5%[41]	0.2%-5.3%[19]	2%-26.3%[64]	0.3% of patients with adrenal incidentalomas[5]
Dx criteria	FPG: 100-125, 2-h PPG: 140-199, HbA1C: 5.7-6.4	Elevated TSH level with a fT4 level that is within the population specific range	T-score between -1 to -2.5	Abnormal 1-mg dexamethasone suppression test with absent stigmata of Cushing’s disease.
Progression	5%-18.3%[54,55,60]	2%-6%[22]	16% risk of major osteoporotic fracture in 10 years[67]	< 1%[13]
Regression/reversal	19%[54]	60%[21]	Stays static or progresses	2%-44%[6,11]
Long-term sequelae	Microvascular and macrovascular complications of diabetes, Cardiovascular risk	Markers of cardiovascular function (such as left ventricular diastolic function) and lipid profile deteriorate with subclinical hypothyroidism	Fractures	Hypertension, Diabetes, Dyslipidemia, Osteoporosis
Short-term consequences		Fatigue, muscle weakness, cold intolerance
Preventive options	Lifestyle and behavioural therapy, drugs	Lifestyle and behavioural therapy, drugs	Lifestyle and behavioural therapy, drugs	Lifestyle and behavioural therapy, drugs, surgery
Pharmacotherapy	Metformin	L-thyroxine	Calcium and vitamin D	Mifepristone, metyrapone
Surgery	-	-	-	Adrenalectomy
True prevention	x	x	x	x
Adverse effects of treatments available	B12 deficiency	Bone loss, cardiac arrhythmias in elderly	Overtreatment can predispose to hypervitaminosis D	Hypocortisolism
Recommendations/Guidelines	Metformin should be considered in those with BMI ≥ 35 kg/m2, those aged < 60 yr, and women with prior gestational diabetes mellitus with IGT	TSH > 10 mIU/L, consider treatment; TSH < 10 mIU/L, consider treatment if symptoms suggestive of hypothyroidism, positive antibodies to thyroid peroxidase, or evidence of atherosclerotic cardiovascular disease, heart failure, or risk factors for these diseases	Country-specific guidelines for treatment	Individualized approach to consider patients with ‘autonomous cortisol secretion’ due to a benign adrenal adenoma and comorbidities potentially related to cortisol excess for adrenal surgery
Grade of recommendation	Level of evidence A[58]	Grade B, BEL 1 (Best evidence rating level)[36]	-	(⊕OOO) Very low level of evidence/recommendation[3]

MACS: Minimal autonomous cortisol excess; IFG: Impaired fasting glucose; IGT: Impaired glucose tolerance; FPG: Fasting plasma glucose; HbA1C: Hemoglobin A1c; PPG: Photoplethysmography; TSH: Thyrotropin; BMI: Body mass index.