conventionally , calculated daily dose of levothyroxine ( lt4 ) is recommended for otherwise healthy and middle - aged patients for initiating treatment for primary hypothyroidism . the recommended initiating dose of lt4 is 1.6 g / kg body weight in overt primary hypothyroidism of autoimmune etiology .
lower dose of lt4 is required in the elderly and has been suggested to be related to the decline in the lean body mass ( lbm ) .
however , fixed dose of lt4 has been suggested as starting dose for overt hypothyroidism .
hashimoto 's thyroiditis is the most common cause of primary hypothyroidism in iodine - sufficient areas and may have indolent course as suggested by studies in individuals of autoimmune subclinical hypothyroidism .
the usual course of progression in hashimoto 's thyroiditis is gradual loss of thyroid function .
follow - up studies of the individuals with subclinical hypothyroidism in the elderly showed that a significant proportion of subclinical hypothyroidism cases with elevated or normal thyroid peroxidase antibody had normalization of serum thyrotropin ( thyroid - stimulating hormone [ tsh ] ) , while others progressed to overt hypothyroidism .
similar study in children showed a variable rate of progression of subclinical hypothyroidism to either overt hypothyroidism or normalization of thyroid profile .
hence , it can be presumed that in overt autoimmune primary hypothyroidism cases , the degree of thyroid damage may be variable .
studies have evaluated the magnitude of replacement doses in primary hypothyroidism based on body weight .
although the average replacement dose of lt4 is approximately 1.6 g / kg body weight in autoimmune hypothyroidism , the range of required dose is wide and varies from 2550 to 200225 g / kg body weight . the recommended dose of 1.6 g / kg is based on the assumption of minimal residual thyroid function .
in addition , studies have shown that lt4 requirement in autoimmune thyroiditis is lesser when compared to complete athyrotic individuals .
hence , it can be presumed that the lt4 requirement to maintain euthyroidism in autoimmune hypothyroidism cases depends on the residual functional thyroid tissue , and the current recommended dose of lt4 in autoimmune hypothyroidism , i.e. , 1.6 g / kg body weight , may not be required by all the individuals of primary hypothyroidism .
the aim of this study was to find the range of lt4 dose based on body weight ( d / w ) and lt4 dose based on ideal body weight ( d / ibw ) , and to find the determinants of lt4 requirement needed to maintain euthyroidism in individuals of primary autoimmune hypothyroidism .
adults were enrolled prospectively from the follow - up cohort of the outpatient endocrinology department of the hospital visiting between may 2015 and january 2016 .
individuals enrolled included men and women between ages 18 and 85 years with primary autoimmune hypothyroidism and on treatment for at least 1 year and on minimum dose of at least 25 g of lt4 daily .
hashimoto 's thyroiditis was defined as clinically presence of firm diffuse goiter or positive thyroid peroxidase antibody .
the inclusion criteria included stable ambulatory patients with primary hypothyroidism , currently biochemically euthyroid based on the latest tsh report from the central laboratory with reference range serum tsh ( 0.44.5
miu / l ) , lt4 dose administration in the morning and empty stomach dosing , and maintenance of food and beverages gap of at least 1 h with the lt4 .
exclusion criteria included noncompliant individuals , other than morning empty stomach administration of lt4 , food gap with lt4 of < 1 h , being on medication known to hamper lt4 absorption within 4 h of lt4 , hypothyroidism other than of autoimmune etiology like postradioiodine , thyroid cancer postsurgery , posttotal thyroidectomy , pregnancy , and central hypothyroidism .
historical values of serum tsh was not taken , and a recent value from the central laboratory was compulsory for enrollment .
institutional review board approval was taken for the study and written informed consent was obtained from all the participants before enrollment .
all consecutive patients willing for enrollment and meeting the inclusion and exclusion criteria were enrolled in the study . the data collected included age , gender , height , body weight , menopausal status for women , compliance with medication , co - prescription within 4 h of lt4 , and food gap with lt4 . body weight was recorded with electronic weighing scales .
ideal body weight ( ibw ) was calculated based on devine formula as follows : women over 152 cm , 45 kg + 2.3 kg for each additional 2.5 cm ; for women under 152 cm , 45 kg  2.3 kg for each additional 2.5 cm ; for men over 152 cm , 48 kg + 2.7 kg for each additional 2.5 cm
the latest tsh done in the central laboratory of the institute and the current lt4 dose were noted .
serum tsh analysis was performed by chemiluminescence immunoassay method ( roche cobas e411 ) with functional sensitivity of 0.005 miu / l , and normal range 0.44.5
lyophilized quality control material ( bio - rad ) was used with mean values of three levels of controls  0.46 , 5.52 , and 34.2 miu / l .
the inter- and intra - assay variability levels were 2.9 and 3 miu / l , respectively .
continuous variables were summarized as means and standard deviations and range as minimum and maximum values .
the percentile of lt4 absolute dose , d / w , and dose based on ideal body weight ( d / ibw ) was calculated at 25 , 50 , and 75 percentile .
anova was used to compare the groups , and bonferroni correction was used as post hoc test .
correlation was assessed by pearson 's method and all the correlation analyses were two tailed .
initially , all the variables were entered with stepwise , forward , and backward method of variable entry to find the best predictive independent variables and finally enter method was used with all the best predictive variables .
adults were enrolled prospectively from the follow - up cohort of the outpatient endocrinology department of the hospital visiting between may 2015 and january 2016 .
individuals enrolled included men and women between ages 18 and 85 years with primary autoimmune hypothyroidism and on treatment for at least 1 year and on minimum dose of at least 25 g of lt4 daily .
hashimoto 's thyroiditis was defined as clinically presence of firm diffuse goiter or positive thyroid peroxidase antibody .
the inclusion criteria included stable ambulatory patients with primary hypothyroidism , currently biochemically euthyroid based on the latest tsh report from the central laboratory with reference range serum tsh ( 0.44.5
miu / l ) , lt4 dose administration in the morning and empty stomach dosing , and maintenance of food and beverages gap of at least 1 h with the lt4 .
exclusion criteria included noncompliant individuals , other than morning empty stomach administration of lt4 , food gap with lt4 of < 1 h , being on medication known to hamper lt4 absorption within 4 h of lt4 , hypothyroidism other than of autoimmune etiology like postradioiodine , thyroid cancer postsurgery , posttotal thyroidectomy , pregnancy , and central hypothyroidism .
historical values of serum tsh was not taken , and a recent value from the central laboratory was compulsory for enrollment .
institutional review board approval was taken for the study and written informed consent was obtained from all the participants before enrollment .
all consecutive patients willing for enrollment and meeting the inclusion and exclusion criteria were enrolled in the study . the data collected included age , gender , height , body weight , menopausal status for women , compliance with medication , co - prescription within 4 h of lt4 , and food gap with lt4 . body weight was recorded with electronic weighing scales .
ideal body weight ( ibw ) was calculated based on devine formula as follows : women over 152 cm , 45 kg + 2.3 kg for each additional 2.5 cm ; for women under 152 cm , 45 kg  2.3 kg for each additional 2.5 cm ; for men over 152 cm , 48 kg + 2.7 kg for each additional 2.5 cm
the latest tsh done in the central laboratory of the institute and the current lt4 dose were noted .
serum tsh analysis was performed by chemiluminescence immunoassay method ( roche cobas e411 ) with functional sensitivity of 0.005 miu / l , and normal range 0.44.5 miu / l .
lyophilized quality control material ( bio - rad ) was used with mean values of three levels of controls  0.46 , 5.52 , and 34.2 miu / l .
the inter- and intra - assay variability levels were 2.9 and 3 miu / l , respectively .
continuous variables were summarized as means and standard deviations and range as minimum and maximum values .
the percentile of lt4 absolute dose , d / w , and dose based on ideal body weight ( d / ibw ) was calculated at 25 , 50 , and 75 percentile .
anova was used to compare the groups , and bonferroni correction was used as post hoc test .
correlation was assessed by pearson 's method and all the correlation analyses were two tailed .
initially , all the variables were entered with stepwise , forward , and backward method of variable entry to find the best predictive independent variables and finally enter method was used with all the best predictive variables .
a total of 346 individuals ( a total of 290 women ; 214 premenopausal and 76 postmenopausal women , and 56 men ) meeting the inclusion and exclusion criteria were enrolled in the study consecutively .
the median duration of hypothyroidism and mean age of individuals were 4 years and 42.1 years , respectively .
the duration of hypothyroidism ranged from 1 to 25 years , and age ranged from 18 years to 76 years . during the study , all individuals had their serum tsh in the target range ( 0.45 miu / l ) as per protocol , and the mean serum tsh was 2.56
group comparison was done using one - way anova with bonferroni correction as post hoc test .
the descriptive clinical and biochemical data of the enrolled individuals in both the genders separately the absolute lt4 daily dose ( add ) ranged from minimum of 25 g to maximum of 200 g with mean of 77.1  30 g .
the dose at 25 percentile , 50 percentile , and 75 percentile was 50 , 75 , and 100 g , respectively .
the mean lt4 daily d / w was 1.21  0.50 g / kg and dose ranged from 0.3 to 2.82 g / kg ; dose at 25 percentile , 50 percentile , and 75 percentile was 0.84 , 1.16 , and 1.5 g / kg , respectively .
the mean daily lt4 daily d / ibw was 1.58  0.63 g / kg of ibw and dose ranged from 0.42 g / kg to 3.5 g / kg of ibw ; dose at 25 percentile , 50 percentile , and 75 percentile was 1.13 , 1.53 , and 1.97 g / kg , respectively .
the parameters of individuals were compared between men , premenopausal women , and postmenopausal women as shown in table 1 .
there was no significant difference in mean add or d / w between men , postmenopausal women , and premenopausal women , although premenopausal women required significantly higher d / ibw compared to men .
the add , d / w , and d / ibw at 25 percentile , 50 percentile , and 75 percentile for men , premenopausal women , and postmenopausal women are shown in table 2 . among the anthropometric measures , weight
correlated positively and significantly with add ( r = 0.2 , p < 0.001 ) and significantly and negatively with d / w ( 0.36 , p < 0.001 ) , although no correlation was found with ibw .
similarly , height correlated significantly and positively with add ( r = 0.17 , p < 0.001 ) and significantly and negatively with d / ibw ( 0.23 , p = 0.001 ) , although no correlation was found with d / w .
the percentile of age of individuals , doses of levothyroxine , and duration of hypothyroidism in both genders separately age correlated significantly with d / w ( r = 0.2 , p < 0.001 ) but not with add or d / ibw . on comparing age quartiles for d / w , a significant difference was found between 1 quartile versus 2 , 3 , and 4 quartile .
the mean d / w in 1 age quartile was 1.4 g / kg , 2 quartile was 1.15 g / kg , 3 quartile was 1.13 g / kg , and 4 quartile was 1.13 g / kg .
the correlation of age with body mass index ( bmi ) was also statistically significant ( r = 0.29 , p < 0.001 ) , suggesting a potential role of change in body composition affecting the correlation of age with d / w .
the partial correlation of age with d / w showed a significant trend ( p = 0.05 ) even after adjusted for bmi .
duration of hypothyroidism correlated significantly with add ( r = 0.2 , p = 0.001 ) , d / w ( r = 0.2 , p < 0.001 ) , and d / ibw ( r = 0.2 , p < 0.001 ) .
on comparing the mean d / w , d / ibw , or absolute lt4 daily dose between the groups based on duration of hypothyroidism , 1 quartile was significantly different from 3 and 4 and between 2 and 4 for d / w .
there was a significant correlation between bmi and add ( r = 0.12 , p < 0.02 ) , d / w ( r = 0.13 , p = 0.01 ) , and d / ibw ( r 0.38 , p = 0.001 ) .
kg / m , group 2 bmi 18.523 kg / m , group 3 bmi > 2330 kg / m , and group 4 > 30 kg / m ) .
on comparing the groups by repeated - measures anova with post hoc bonferroni correction , no significant difference was found between the bmi groups in add and d / ibw , but a significant difference in d / w was found between bmi groups 1 and 3 , 1 and 4 , 2 and 3 , 2 and 4 , and 3 and 4 .
the mean d / w was as follows : group 1 : 1.6 g / kg , group 2 : 1.5 g / kg , group 3 : 1.2 g / kg , and group 4 : 1.0 g / kg . the correlation coefficient of d / w and d / ibw with independent variables is adjusted for covariates [ table 3 ] . in univariate regression model , gender ,
for d / w , age , duration of hypothyroidism , weight , and bmi were significant predictors , and gender , duration of hypothyroidism , height , ibw , and bmi were significant predictors for d / ibw by univariate regression model .
the partial correlation of exploratory variables after adjusting for covariates for levothyroxine daily doses the multivariate regression by linear regression model was used to find the determinants of add , d / w , and d / ibw , and the result is shown in table 4 .
multivariate model predicting levothyroxine dose / kg body weight , age , duration of hypothyroidism , and body mass index as independent variables^ the p - p plot of regression standardized residuals .
( a ) model for levothyroxine dose based on daily dose , ( b ) model for absolute levothyroxine daily dose , and ( c ) model for levothyroxine daily dose based on ideal body weight
lt4 is given as a replacement therapy for hypothyroidism , and the dose depends on the demand which in turn dependent on endogenous thyroid hormone production .
the level of thyroid hormones in the blood circulation is determined by the endogenous secretion of thyroid hormones , their metabolism , and exogenous replacement therapy . to maintain euthyroid range of serum tsh and t4 ,
conventionally , the recommended starting dose of lt4 in autoimmune hypothyroidism cases is 1.6 g / kg d / w . patients with minimal residual thyroid function due to autoimmune etiology require 1.61.8 g / kg of actual body weight , although some studies suggest a higher dose of 2.02.1 g / kg .
the etiology of a patient 's hypothyroidism affects the d / w and may reflect degree of residual function as suggested by higher d / w requirement in athyreotic patients posttotal thyroidectomy versus patients with hashimoto 's thyroiditis .
this study showed age - related decline in d / w as shown by significant negative correlation between age and d / w , and significantly higher d / w requirement in individuals in 1 age quartile versus 2 , 3 , and 4 quartile , although no similar difference was for add and d / ibw .
showed that age - based difference in lt4 dose is due to difference in body weight and gender , while study by santini et al .
showed a significant negative correlation ( p < 0.03 ) of age with d / w which disappeared when adjusted for lbm and hence suggested that the age - related decrease in lbm is responsible for decrease in lt4 dose .
the findings of this study are similar to the above - mentioned studies that the significance of age for d / w decreased when adjusted for bmi , but a trend of significance was still seen although lean muscle mass was not analyzed in this study .
this study enrolled long - standing cases of spontaneous onset primary hypothyroidism for which hashimoto 's thyroiditis is the most common cause .
at least 75% of cases in this study required dose 1.5 g / kg of lt4 d / w that is lesser than recommended starting dose of 1.6 g / kg of lt4 .
a study of long - term follow - up of adults with subclinical hypothyroidism for more than 9 years showed that on an average , 28% of patients progressed to overt hypothyroidism , while 68% patients remained in the subclinical state , suggesting a variable course in each patient . in the same study
, it was shown that residual thyroid reserve and high titer of thyroid peroxidase antibody were significant predictors for development of overt hypothyroidism on follow - up .
this study showed that duration of hypothyroidism was predictors of add , d / w , and d / ibw .
in addition , individuals in the lowest quartile of duration of hypothyroidism ( 12.3 years ) had significantly lower mean either add , d / w , or d / ibw compared to 3 and 4 quartile , and 2 quartile from 4 quartile .
the findings of this study suggest progressive decrease in residual thyroid function and that not all cases have minimal residual thyroid function at the onset .
the gender - based significant difference in the mean add and d / ibw was seen in this study , although no gender difference was seen in mean d / w .
the significantly higher d / ibw in premenopausal compared to male became insignificant when adjusted for height , suggesting that the difference in the gender - based difference in d / ibw is mainly due to difference in anthropometry .
similar gender - based difference was found in other studies . although bmi was not significantly different between male and female , ibw was significantly higher in men compared to postmenopausal or premenopausal women due to greater height in men .
d / w was similar between male and female , but d / ibw was lower in men compared to premenopausal or post- menopausal women .
the lower d / ibw requirement in males , and almost similar dose requirement for d / w in both gender suggests that lt4 requirement of fat mass exists , although much lower than that of lbm .
hence , this study suggests that the d / w or d / ibw requirement is variable and not one size and varies between individuals probably depending on the residual thyroid function reserve .
this study has strengths such as large population size , confirmed compliance with medication , and recently confirmed euthyroidism , although it has many limitations as being cross - sectional , and functional reserve and lbm were not evaluated .
primary autoimmune hypothyroidism patients require a variable dose of lt4 , and the dose progressively increases with duration of hypothyroidism .
gender has no direct effect on lt4 dose , and the difference in dose is based on difference in anthropometry between both the genders .
 objectives : the recommended starting dose of levothyroxine ( lt4 ) in primary hypothyroidism is 1.6 g / kg body weight and is based on presumption of minimal residual thyroid function in autoimmune hypothyroidism . 
 this study aimed at finding the range and determining factors for lt4 dose in long - standing hypothyroidism.methods:a cross - sectional study of individuals with primary autoimmune hypothyroidism on lt4 replacement was done between march 2015 and january 2016 . 
 individuals enrolled were euthyroid based on recent serum thyroid - stimulating hormone . 
 the inclusion criteria included lt4 intake in the morning empty stomach , maintenance of at least 1-h food gap , not on medications known to hamper lt4 absorption within 4 h of dosing , diagnosis of hypothyroidism at least for 1 year , and on a minimum 25 g lt4 . 
 p < 0.05 was considered statistically significant.results:a total of 346 individuals ( 290 women and 56 men ; 214 premenopausal and 76 postmenopausal women ) were enrolled . 
 the mean duration of hypothyroidism and age were 5.7 years and 42.1 years , respectively . 
 the range and mean of absolute lt4 daily dose ( add ) , lt4 dose based on body weight ( d / w ) , and lt4 dose based on ideal body weight ( d / ibw ) were 25200 g daily and 77.1 g , 0.32.82 g / kg and 1.21 g / kg , and 0.423.5 g / kg and 1.58 g / kg , respectively . 
 duration of hypothyroidism was significant predictors of add , d / w , and d / ibw . 
 gender - based difference in add and d / ibw was explained by gender difference in anthropometry.conclusion:long-standing primary autoimmune hypothyroidism has variable dose requirement of lt4 for achieving euthyroidism and may be dependent on the degree of residual functional thyroid . 
 duration of hypothyroidism was significant positive predictor for either add , d / w , or d / ibw . 