Thyroid diseases are often encountered in clinical practice, and it has been estimated that about 42 million people in India suffer from such disorders. Overall prevalence of primary hypothyroidism, in a population-based study conducted in 2013 involving more than five thousand adult subjects across 8 major cities of India, was 10.95% with Kolkata, West Bengal having the highest (21.67%) [1]. Currently, the mainstay of management of hypothyroidism, irrespective of aetiology, is oral administration of levothyroxine sodium (LT4). More than half of the LT4-treated patients in India have serum thyroid stimulating hormone (TSH) above the target range [2]. Non-compliance, inadequate dosing, inappropriate timing of LT4 administration and use of co-medications are the common reasons of elevated TSH in these patients [3]. Ingested LT4 tablets undergo disintegration and dissolution in the acidic environment of the stomach and are subsequently absorbed from jejunum and ileum. Approximately 60-82% of the total dose is absorbed within 3 hours of administration [4]. A prerequisite for adequate absorption of LT4 tablet is its active ingredient being in aqueous solution within stomach, which is further determined by intra-gastric pH and nature of excipients, amongst others. In-vitro studies, performed at 25 °C, have shown that this aqueous solubility decreases as pH increases from 1 reaching a nadir between 3 and 7, and then increases as the pH increases further [5]. The median fasting intra-gastric pH in adults varies between 1.5 and 1.7 during early morning. Any factor that raises intra-gastric pH, may also alter the ionization status and conformational characteristics of the LT4 molecule, thereby interfering with efficiency of intestinal absorption of the hormone [6].
Proton pump inhibitors (PPIs) are used to treat a variety of gastro-intestinal conditions like erosive esophagitis due to gastroesophageal reflux disease (GERD), hypersecretory conditions including Zollinger Ellison syndrome, Helicobacter pylori infection, non-steroidal anti-inflammatory drugs (NSAIDs)-induced ulcers, prevention of re-bleeding in peptic ulcers, and prophylaxis for stress ulcers in critically ill patients. They are even more frequently used as an over the counter (OTC) drug for dyspepsia across the world, including India [7]. Since gastrointestinal manifestations like dyspepsia or nausea due to delayed gastric emptying are not uncommon in patients with hypothyroidism, PPIs are often prescribed to them [8, 9]. PPIs increase intragastric pH and can potentially impair absorption of orally administered LT4 tablet. The precise prevalence of PPI use in patients with hypothyroidism is largely unknown; however, retrospective studies like the Thyroid Epidemiology, Audit and Research Study (TEARS) or data extracted from the Italian general practice Health Search CSD Longitudinal Patient Database (HSD) found that PPI co-prescription varies from 8 to 69.8% in LT4-treated subjects [10, 11].
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Effect of PPI on gastric acid suppression depends to some extent on time of the drug intake. In a randomized, double-blind, two-period crossover comparative study, significantly greater increase in 24-hour median intra-gastric pH was noted following pre-breakfast (8:00 AM) administration of 40 mg pantoprazole compared to pre-dinner (7:00 PM) administration (3.3 vs. 2.7) [12]. There are handful of prospective studies that looked into the alteration in thyroid function test (TFT) in patients being treated with both LT4 tablet and one of the PPIs. However, none of these studies or the other retrospective studies evaluated the effect of timing of administration of PPI on TFT in LT4-treated patients [6, 13, 14]. We hypothesized that absorption of orally administered LT4 tablet is variably altered if PPI is taken in the morning versus at night. The objectives of this study were (A) to assess the effect of co-prescription of pantoprazole on TFTs in patients with overt primary hypothyroidism being treated with LT4, and (B) to determine the effect of pantoprazole, administered at different time points of the day, on TFTs in the same cohort.
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