Activity of a Combination of Physiological Modulators in Limiting Side Effects in Patients Suffering from Primary Hypothyroidism during Levothyroxine Treatment

Research Article

Austin J Nutr Metab. 2015;2(2): 1018.

Activity of a Combination of Physiological Modulators in Limiting Side Effects in Patients Suffering from Primary Hypothyroidism during Levothyroxine Treatment

Umberto Cornelli¹, Andrea Ledda², Gianni Belcaro² and Annarosa Finco³*

¹Loyola University School of Medicine, Chicago, USA

²University of Chieti-Chieti, Italy

³Ox Res Dept- Cor Con International S.r.l. Parma, Italy

*Corresponding author: Annarosa Finco, Cor Con International Srl- Oxidation Research Department, Parma, Strada Langhirano 264/1A Parma (PR), Italy

Received: May 12, 2015; Accepted: June 25, 2015; Published: June 30, 2015

Abstract

Design: The combination of Physiological Modulators (CPMs) was shown to decrease the occurrence of side effects in the initial phase of treatment with LT4.

Objective: The aim was to determine whether this action occurred also during stable chronic treatment with LT4.

Methods: Double-blind randomized trial in 48 outpatients (two groups) of patients under treatment with LT4 at doses ranging from 50 to 125μg/day from at least one year. Patients were treated respectively with placebo (Group A) and CPMs (Group B) for 30 days. T3, T4, TSH, plasma hydroperoxides (Carr. U.) and hs-CRP were measured. Side effects (anxiety/restlessness, sweating, palpitations and headache) and discomfort were assessed daily using a questionnaire.

Results: Hormone balance (T3, T4 and TSH) was adequate in both groups. After 30 days of treatment, a significant decrease (t-test p<0.001) in hydroperoxides levels from 385 ± 21.0 to 317 ± 37.7 Carr U together with a decrease in hs-CRP from 4.1 ± 1.11 to 3.6± 0.92 mg/L was observed only in the group treated with CPMs. In the group treated with placebo no significant reduction was shown. The incidence of side effects and the number of days with daily discomfort were significantly reduced in the group treated with CPMs. Between 79 % and 90% showed a decrease in side effects and daily discomfort.

Conclusions: Use of CPMs significantly reduces the incidence of side effects and daily discomfort during chronic treatment with LT4.

Keywords: T4; T3; TSH; Hydro peroxides; hs-CRP; LT4 side effects

Introduction

The report on Adverse Events Reporting in Patients Treated with Levothyroxine (LT4) [1] indicates that 23 % of the cases are affected by side effects due exclusively to LT4 treatment.

In a previous trial [2], it was observed that in the initial stage of treatment of the primary hypothyroidism with LT4, side effects can arise, although not serious in nature, and cause moderate daily discomfort. This discomfort was mainly due to symptoms such as anxiety/restlessness, sweating, palpitations and headache that were concomitant with the increase in plasma hydroperoxides (an index of oxidative stress or OS) and to the rise in serum levels of hs-CRP.

This condition leads to limitations in working activity, but could be significantly reduced using a combination of Physiological Modulators [CPMs] consisting of vitamin E, procyanidins, astaxanthin, lipoic acid and lycopene at low dosages [3].

Some of the side effects tend to fade away over time, both because the patient gets used to putting up with them and due to metabolic/ psychological compensation that allows them to “live” with the disorders. What remains almost constant is the OS that can still become excessive on account of intercurrent diseases (hypertension, acute or chronic inflammation, diabetes, dyslipidemia or flu), habits (smoking and high oxidized fat diet) or use of drugs (among which contraceptives stand out as “stressors”) [4].

These conditions can persist even with stable LT4 treatment, which can be revealed through careful investigation (high hs-CPR, hydroperoxides or other OS markers), and this may still lead to a cohort of side effects. The most frequently reported among these are anxiety/restlessness, palpitations, sweating and a number of various other relatively rare symptoms, including muscle cramps, insomnia and gastric and dietary disorders.

Although all these symptoms are sporadic, they are unpredictable and unpleasant.

The use of CPMs with antioxidant and anti-inflammatory actions may curb this reactive condition, which may be defined as an “inflammatory redox” reaction. This condition may be triggered when LT4 levels increase in proportion to daily absorption: there is inevitably a “wave peak” during the first 3-4 hours after it is taken.

In this double-blind trial against placebo, we aimed to determine the action of CPMs in reducing the frequency of side effects in subjects who had been receiving stable treatment with LT4 for at least one year, regardless of the dose used.

Methods

Patients, inclusion and exclusion criteria

We analyzed 48 outpatients (18 M and 30 F) aged between 42 and 59, affected by primary hypothyroidism with mono or plurinodular goitre. All subjects had undergone biopsy to determine the state of their thyroid and were affected both with autoimmune and nonautoimmune primary hypothyroidism. They were administered hormone replacement therapy with LT4 (Euthyrox®-Merck) at doses of between 50 and 125 μg/day and belonging to the same brand. The dosage of LT4 was established by the Endocrinology departments where the patients belonged, and was stable for at least one year and the admitted. The trial was carried out with continuous treatment with the products under examination for a period of 30 days. The patients were divided into two groups (A and B) of 24 subjects each, balanced by sex, LT4 dose, and length of LT4 treatment. .

All the participants were informed about the scope of the trial and gave their informed consent.

The admission criteria included subjects with TSH values < 10 μU/dL and 22 < BMI < 30.

Female subjects in menopause were admitted only if they had been in menopause for at least two years without ongoing estrogen replacement therapy. Smoking was not among the exclusion criteria. Subjects with dyslipidemia were admitted only in case they had been under treatment for at least 6 months. Hypertension was not grounds for exclusion provided it had been suitably treated for not less than 6 months.

Subjects treated with fish oils were excluded as these can increase plasma hydroperoxides that add to any oxidative stress caused by LT4.

Subjects undergoing weight-loss therapy or who are on a diet to lose weight and patients affected with any kind of tumor were excluded. Females taking oral contraceptives were not admitted since these products cause substantial OS [4].

Treatments

The protocol consisted of treatment with LT4 at stable doses ranging from 50 to 125μg/day for at least one year, according to standard conditions (taken on an empty stomach in the morning, followed by breakfast after 30 minutes). The levothyroxine treatment was not changed for the whole 30-day period.

CPMs or placebo was prepared in type 0 capsules. Group A was treated with CPMs and group B with placebo. The two treatments were indistinguishable (four 10 capsule blister packs).

Up to 32 days of treatment were allowed if the thirtieth day fell on a Saturday. All treatments consisted of 1 capsule/day, taken just before going to bed at night. The capsules were administered in the evening in order to prevent the interference with the absorption of LT4, which was administered in the morning.

Type of experiment

The study was a double-blind randomized trial.

Variables considered: We analyzed T4, T3 and TSH levels, levels of hydroperoxides (d-ROMs test in terms of Carr.U.) as an index of OS [5], and C-reactive protein (hs-CRP) as an index of systemic inflammation. Measurements were taken on two occasions: at baseline and after 30 (32) days of treatment with CPMs or placebo.

The occurrence of side effects of hormone replacement therapy that are considered most frequent, i.e. anxiety/restlessness, sweating, palpitation, headache and insomnia was also assessed. The subjects were given two fifteen-day diaries in which they had to note the above listed symptoms every day. There were also blank spaces for reporting “other symptoms”.

All the subjects were instructed to record the occurrence or absence of the symptoms shown through a score ranging from 0 to 4, where 0 was no symptom and 4 was sufficiently serious to suggest the subject went to the center for tests and/or to change the dose of LT4.

Each sheet covered a period of 15 days; therefore the frequency of each symptom could vary from 0 (never occurred) to 15 (occurred every day) and its total score was the sum of the two fifteen-day periods.

Besides the score, the patient was asked to mark “M” if the effect was observed before 2 pm, “S” if it was observed after 2 pm (the afternoon/evening period) and “MS” if the symptom was observed both in the morning and evening. These reports were used in order to establish whether there was a rough correlation between LT4 levels and the observed effect. Since LT4 was administered in the morning, a prevalence of “M” might suggest that the effects were related to the LT4 “wave peak”.

There were therefore two fifteen-day reports for all the variables taken into consideration for each subject.

The days during which the subject reported physical or mental discomfort that limited their performance of daily chores and/or working activities were also assessed and recorded so that this aspect could be compared with the side effects. These “days of discomfort” (dd) were assessed overall at the end of the 30-day treatment period.

If subjects suffered from any illnesses during the trial, their data were excluded from the final results.

Laboratory mthods: Serum T4 and T3 levels were measured using radio immunological methods (Diagnostic Products Corporation, Los Angeles). Serum T3 levels were measured using a radio immunological method (Magic T3 Radioimmunoassay, Bayer Corporation Diagnostic Division, Tarrytown NY). TSH levels were measured immunologically with the TTSH immulite 2000 (X) kit. OS was determined using the d-ROMs test, which measures plasma hydroperoxides in terms of Carr. U. (1 Carr. U. =0.08 mg H2O2/dL) [5] using the FRAS4 system (H&D srl -Parma-Italy). Triglycerides and total cholesterol levels were measured using an enzymatic method (Roche-Germany). hs-CRP levels were measured using an immunoturbidimetric method (Denka Seiken, Tokyo).

All the samples were taken in patients following overnight fasting and between 7:30 and 8:30 am before the LT4 treatment. Four 5 mL blood samples were drawn from a brachial vein. To perform the d-ROMs test, the plasma was collected in the amount of 0.5 mL and kept at -80°C until the measurement was made.

Statistical analysis

Means and standard deviations (SD) were calculated for all data. Differences in the variables in the groups were analyzed using Student’’s t-test. The chi-square test (both with Yates correction and Fisher’s exact) was used to assess differences in frequency. Fisher’s exact test was used when the expected frequency was less than 5. The required sample size was calculated on the basis of hydroperoxide levels. Considering a type a error of 0.05, type 1-β error of 0.9, and mean differences of 1 SD, groups of 10 subjects were sufficient to achieve a power of greater than 0.9.

Compliance

Compliance with the protocol was measured by counting the remaining tablets returned by the patients (50-tablet blister packs of LT4 at various doses) and remaining capsules (four 10-capsule blister packs).

Results

Two subjects (one in each group) did not complete the trial because they caught flu during the first few days. All the other subjects completed the trial and compliance was almost total (100%).

Table 1 shows the general characteristics of the two groups, which were equivalent for all the variables taken into account (t-test p > 0.05 for all comparisons between groups). Thyroid balancing was satisfactory at the doses of LT4, which were similar in both groups.

Citation: Cornelli U, Ledda A, Belcaro G and Finco A. Activity of a Combination of Physiological Modulators in Limiting Side Effects in Patients Suffering from Primary Hypothyroidism during Levothyroxine Treatment. Austin J Nutr Metab. 2015;2(2): 1018.