Thyroid hormones, thyroxine (T4), and triiodothyronine (T3) play an essential role in metabolism, growth, and development. Hypothyroidism in adults manifests with a variety of symptoms, such as fatigue, weight gain, constipation, dry skin, and cold intolerance. A study conducted across eight cities in India found that 10.95% and 8.02% of adults were suffering from hypothyroidism and subclinical hypothyroidism (SCH), respectively. Hypothyroidism is more common in women and people aged more than 65 years.
Since the clinical picture can vary considerably, the diagnosis of hypothyroidism is predominantly biochemical. Thyroid function tests (TFTs) are among the most commonly requested laboratory investigations. A survey among 2364 physicians found that 57% of them would recommend thyroid-stimulating hormone (TSH) testing for a healthy 55-year-old woman.
Hypothyroidism has several detrimental effects, including decreased cardiac output, secondary hypertension, and atherosclerosis. SCH, defined as raised TSH values with normal free T4 values, is associated with higher cholesterol levels and is an independent risk factor for aortic atherosclerosis and myocardial infarction. Early diagnosis and treatment in these cases may be beneficial, especially in younger individuals. Further, SCH can progress to overt hypothyroidism with an annual incidence of 1%–5% depending on TSH levels and thyroid antibody status. SCH in pregnancy can lead to adverse outcomes for both the mother and fetus.
TSH levels are influenced by multiple factors, including age, sex, genetics, circadian variation, BMI, pregnancy, iodine intake, smoking, and exposure to environmental pollutants such as perchlorate. Recent studies have shown that TSH can also be affected by food intake, with postprandial TSH being lower than the fasting value.
There is a lack of consensus about whether thyroid tests should be conducted in fasting or postprandial state, or at a fixed time of the day. This leads to confusion among patients, laboratories as well as clinicians since there is insufficient evidence to institute well-founded guidelines. Successful management of overt and SCH largely depends on early diagnosis, initiation of treatment, follow-up, and monitoring, all of which rely on TFTs. Thus, it is imperative to have a uniform protocol regarding TFT conduction and interpretation.
With this background, we propose this study with the following objectives:
- To evaluate the difference in serum TSH, free T3, and free T4 levels between fasting and postprandial blood samples
- To study the association of postprandial change in TFT with age, sex, and thyroid illness.
SUBJECTS AND METHODS
Sixty consecutive patients (age 18–65 years) attending the institution blood collection center from August 2019 to September 2019 were selected. They were divided into two groups:
- Group A: Patients with a known diagnosis of thyroid dysfunction who are on drug therapy
- Group B: Patients without a known history of thyroid dysfunction.
Patients previously operated for pituitary lesions (central hypopituitarism) or thyroidectomy were excluded. Any patient's TSH level, if found undetectable, was excluded from the study data.
Three millilitre blood sample was drawn from the patients in a plain vial in the morning between 8:00 and 9:00 am, after a 12-h overnight fast. Then, the patients were instructed to come after breakfast, 2 h later, and another sample was taken. Informed written consent was obtained prior to phlebotomy.
Serum samples were analyzed by Elecsys Electrochemiluminescence Immunoassay for TSH, free T3, and free T4 estimation.
The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The trial was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the institutional ethics committee and informed consent was obtained from all individual participants.
Institutional laboratory reference values
- TSH: 0.27–4.2 mIU/L
- Free T3: 3.1–6.8 pmol/L
- Free T4: 12–22 pmol/L.
Any deviation from the above values was considered abnormal. Patients were accordingly labeled as overt hypothyroid (high TSH, low fT4), subclinical hypothyroid (high TSH, normal fT4), euthyroid (normal TSH and fT4), subclinical hyperthyroid (low TSH, normal fT4), and overt hyperthyroid (low TSH, high fT4).
Data were entered into a spreadsheet and analyzed using STATA Version 14 (StataCorp LLC, 4905 Lakeway Drive, College Station, Texas 77845-4512, USA). Numerical data were expressed as the mean (± standard deviation). Differences in fasting and postprandial TSH, fT3, and fT4 levels were analyzed by the paired t-test. Mean differences in the two groups were compared using unpaired t-test. P ≤ 0.05 was considered statistically significant.
Our study population consisted of 60 subjects aged 18–65 years (mean age = 39.18 years). Fifty (83.33%) subjects were female, while 10 (16.66%) were male. Twelve (20%) were known cases of hypothyroidism on replacement therapy (Group A), while 48 (80%) had no previous history of thyroid disease (Group B).
In the fasting state, in Group A, four (33%) patients had SCH, while eight (66%) were euthyroid. In Group B, four (8%) patients had SCH, whereas 44 (91%) were euthyroid. According to postprandial values, two (4%) patients from Group B who had SCH in a fasting state were reclassified as euthyroid.
Mean (±standard deviation) serum TSH, fT4, and fT3 values in fasting and postprandial state are given in Table 1.
TSH values declined after meal consumption in 48 (80%) of the subjects, remained unchanged in three (5%), and increased in nine (15%) subjects.
A statistically significant mean change of −0.30 mIU/L (95% confidence interval [CI]: −0.18 to −0.42 mIU/L) was observed in serum TSH values after food intake (P 0.0000039). Similarly, fT3 values were also reduced (mean = −0.21 pmol/L, 95% CI: −0.12 to −0.30 pmol/L, P 0.000024). The mean postprandial change in fT4 values was −0.34 pmol/L (P 0.067).
The trend of a significant decrease in TSH values after food intake was maintained across both Group A (P 0.015) and Group B (P 0.0001) [Table 2], as well as males (P 0.02) and females (P 0.000027) [Table 3] when analyzed separately. The same was true for all age groups [Table 4], except 26–35 years (n = 17, P 0.055).
The mean decline in TSH value was greater in Group A (-0.38 mIU/L) as compared to Group B (-0.28 mIU/L) [Table 2]. Similarly, females had a greater mean decline in TSH value (-0.32 mIU/L) as compared to males (-0.20 mIU/L) [Table 3]. Figure 1 plots the postprandial change in serum TSH value of the participants with their age.
In addition, we observed a positive correlation between the change in TSH values and the change in fT4 (R = 0.46, P 0.0002) and fT3 (R = 0.48, P 0.0001) [Figures 2 and 3].
We observed a significant decline in TSH values after food consumption. We found similar results in both the groups (Group A: known hypothyroid on replacement therapy, and Group B: not a known case of thyroid dysfunction), suggesting that replacement therapy is unlikely to interfere with this observation. When analyzed separately, TSH was reduced after food intake in different age groups as well as both males and females. While the mean decline was slightly greater in Group A and in females, the difference was not statistically significant.
Previous studies have reported a similar postprandial decline in TSH. The precise mechanism behind this remains unclear. A possible explanation is that food consumption causes an increase in circulating somatostatin levels, which, in turn, suppresses TSH secretion from the pituitary. Somatostatin is well known to inhibit TSH secretion. In an experimental study, acute hyperglycemia induced by oral glucose intake suppressed TSH secretion by stimulating hypothalamic somatostatin release. In addition, Kamat et al. theorized that the decline in TSH after eating would also depend on the composition of the meal. They showed that a normocaloric meal caused TSH to decline postprandially, whereas a hypocaloric, isobulk meal did not.
We also observed that fT3 (P 0.000024) and fT4 (P 0.065) declined after meals. This could be a direct response to the decrease in TSH. Further, we found a weak positive correlation between the postprandial change of TSH, with that of fT3 and fT4. The reason for this observation is not clear and possibly reflects the direct response of thyroid hormone production to decreasing TSH levels. To our knowledge, previous studies have not shown a significant change in fT4 or fT3.
Currently, the guidelines to interpret TFTs do not specify the time of blood sampling or whether the test should be conducted in a fasting/nonfasting state. Two patients (3.3%) in our study were subclinical hypothyroid (TSH = 5.3 and 4.4 mIU/L) according to the fasting sample but euthyroid (TSH = 3.2 and 4.1 mIU/L, respectively) according to the postprandial sample.
This ambiguity may significantly affect diagnosis and management, particularly in clinical scenarios where minor variations in TSH are relevant. For instance, follow-up and monitoring of therapy in hypothyroid patients relies only on TSH measurement. After starting medication, TSH is assessed after 4 to 12 weeks, then at 6 monthly intervals, and annually once it stabilizes, to determine adequacy of treatment. Even in euthyroid patients, precision in TSH values can be important as recent evidence suggests that dynamic TSH changes correlate with increased risk of chronic kidney disease. SCH and maternal hypothyroidism are diagnosed based only on TSH values. SCH in pregnancy can lead to serious complications, including miscarriage, preterm delivery, gestational diabetes, hypertension, low birth weight, and impaired brain development in the fetus.
Scobbo et al. observed 100 patients and reported that 97 of them showed a TSH decline in postprandial late morning samples as compared to fasting early morning samples. Kamat et al. and Nair et al. demonstrated similar findings. Patel et al. studied 114 patients aged between 15 and 60 years and concluded that euthyroid, subclinical hypothyroid as well as overt hypothyroid patients all showed a postprandial decline in TSH. Bajaña et al. measured TSH levels in 20 healthy volunteers in fasting state as well as 1, 2, and 4 hours after eating. TSH was highest in fasting state, lowest 1 h after eating, and subsequently increased but remained lower than the fasting level.
Thus, substantial evidence indicates a need to standardize TFTs with respect to timing and meal consumption in order to avoid misdiagnosis in such cases.
Another factor that could explain the postprandial decline is the diurnal variation of TSH secretion. We collected the fasting samples between 8 and 9 AM and postprandial samples 2 h later. Similar studies by Mirjanic-Azaric et al. and Mahadevan et al. aimed to ascertain the difference between the effects of food intake and time of sampling. They analyzed the TSH change in postprandial as well as extended fasting state and concluded that the blood sampling time affected TSH irrespective of food intake.
However, TSH levels were shown to be affected by meal composition and also by oral glucose intake, suggesting that it may be premature to rule out the effect of meals and explain the change in TSH only by the timing of testing.
Thus, whether the TSH suppression in our study was affected by food intake, or blood sampling time, or both is unclear. Further research is needed to appropriately distinguish between the effects of these two variables.
We recommend that laboratories implement fasting state TFTs to ensure uniformity in conduction and interpretation.
Our study found a statistically significant difference in TSH values before and after food intake. This difference may have a significant effect on the diagnosis and management of thyroid patients. It may be particularly relevant in cases where minor fluctuations in TSH are pertinent. We recommend that laboratories implement fasting state TFTs to ensure uniformity in conduction and interpretation.
Financial support and sponsorship
This study was selected for the ICMR STS-2019 Program and a stipend was received from ICMR upon selection.
Conflicts of interest
There are no conflicts of interest.
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