Randomized Placebo Controlled Clinical Study of Dill ( Anethum Graveolens L. ) in Thyroiditis and Nodular Goiter Patients

Abstract

Thyroid nodules are common and affect half of the general population by the age of 60 years. The cause is believed to be due to hypothyroidism, mutational changes, and autoimmunity leading to thyroid carcinoma. Dill, a traditional herbal remedy, has been used to treat thyroid dysfunctions such as hyperthyroidism and hypothyroidism. This study evaluates the effects of dill (Anethum graveolens L.) on patients with thyroiditis and nodular goiter. A study was conducted on patients with benign thyroid nodules. They were divided into two groups; placebo (=35) and dill group (n = 33). Dried and ground dill was put into hydroxypropyl methylcellulose capsules and patients were given three capsules per day for 90 days. Various tests were conducted at the beginning and end of the study, including thyroid stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), anti-thyroid peroxidase (anti-TPO), anti-thyroglobulin (anti-Tg), and C-reactive protein (CRP) analysis, and thyroid nodule dimensions were measured by ultrasound. Statistical analysis was performed. After 90 days of treatment with dill extract, patients showed significant reductions in TSH, FT4, anti-TPO, and CRP levels, as well as a decrease in thyroid nodule sizes as demonstrated by ultrasonography. The dill-treated group had significantly decreased TSH (P = .020), FT4 (P = .001), anti-TPO (P = .004), CRP (P = .003) levels, and nodule sizes (P = .001) at the beginning and end of the study. Compared to the control group, the dill group had significantly decreased TSH (P = .009), fT4 (P < .001), anti-TPO (P = .001), CRP (P < .001) levels and nodule sizes (P < .001), which reached normal values. A. graveolens suppressed inflammation of the thyroid gland, reduced nodule size, and normalized TSH levels. Dill supplementation should be recommended for the treatment of thyroid nodules in selected patients.

INTRODUCTION

Anethum graveolens L. (dill), is a flavoring agent from the Apiaceae family.^1,2 Dill has various medicinal properties including antihyperlipidemic, antihypercholesterolemic, antimicrobial, antifertility, antidiabetic, and anti-inflammatory effects. It is traditionally used in Anatolian and Iranian medicine to treat menstrual and stomach-related problems, impotence, and as a diuretic and stimulant. Dill essential oil is also used in uterus cancer treatment.⁹ The plant contains carvone, limonene, and alpha phellandrene in its essential oil, while its leaves contain phenolic acids with antioxidant activities and flavonoids such as rosmarinic acid, chlorogenic acid, p-coumaric acid, quercetin, kaempferol, myricetin, isorhamnetin, and catechins.

Thyroiditis is an autoimmune inflammation of the thyroid gland and constitutes 5% of thyroid diseases.¹³ The most common forms of chronic autoimmune thyroiditis are Graves’ disease and Hashimoto’s thyroiditis.¹⁴ Thyroid nodules are the most common endocrine disorder, and half of the general population has at least one thyroid nodule by the age of 60 years. Thyroid nodules formed by autoimmune effects are thought to cause hypothyroidism, mutational changes, and thyroid carcinoma in 7–15% of patients.^15,16 High TSH levels are defined as an independent risk factor for autoimmunity, inflammation, and thyroid cancer.¹⁷ The incidence of thyroid dysfunction is higher in women.¹⁸

Herbal medicines have been used to treat thyroid dysfunctions such as hyperthyroidism, hypothyroidism, and goiter.¹⁹ Dill is a popular folk remedy for thyroid diseases, but not recommended for hypothyroidism.²⁰ Studies have shown the effectiveness of dill in improving thyroid functions and reducing high TSH levels in laboratory animals.²¹ However, there is no clinical evidence available to support the efficiency of dill on thyroiditis and nodular goiter in humans.

Our study examined the effects of dill on patients with thyroiditis and nodular goiter. We evaluated hormone levels and anti-inflammatory markers and compared thyroid nodule sizes using ultrasonography.

MATERIALS AND METHODS

Producing dill dosage forms

This study was approved by the Research Ethics Committee of Bezmialem Foundation University in accordance with the ethical principles of the Declaration of Helsinki, with a protocol number of 2016/4791. Aerial parts of A. graveolens were purchased from an organic farm in Kocaeli, Turkey. The herbal material was dried and ground into a fine powder. Size 1 hydroxypropyl methylcellulose (HPMC) capsules (Capsugel, NJ) were filled with 300 mg of dill powder using a Karnavati Minicap (Gujarat, India) pilot scale capsule filling machine. High-density polyethylene containers with plastic caps and silica gel desiccants were used for packaging. Placebo was prepared using maltodextrin and all products were produced under good manufacturing practices.

Essential oil yield and composition

The essential oil and phenolic compositions of fine dill powder were analyzed using hydrodistillation and Gas Chromatography-flame ionization detector-mass spectrometry (GC-FID/MS) analysis. The samples were injected using an auto-injector and analyzed in triplicate using an Agilent 7890B GC-FID (Santa Clara, CA, USA) coupled with an Agilent 5977E mass spectrometer (Santa Clara, CA, USA). The compounds were identified using the Wiley Registry of Mass Spectral Data 9th edition and NIST 11 Mass Spectral Library (NIST11/2011/EPA/NIH). The FID data were used to calculate relative percentages.

Phenolic composition

Dill fine powder was extracted with 80% methanol and hydrolyzed with HCl to yield phenolic compounds. The extracts were analyzed using Perkin Elmer Flexar UHPLC (MA, USA) coupled with a TOF-MS system. Rosmarinik asit, klorojenik asit, p-kumarik asit, sinamik asit, kuersetin, kaempferol, mirisetin, izorhamnetin ve kateşin reference substances (Sigma–Aldrich, St. Louis, MO) were used for identification and quantification of dill phenolic composition. Separation was carried out on a GL-Sciences ODS-3 column with a flow rate of 1 mL/min.

Amount of total phenolic, total flavonoid, and radical scavenging activity

About 500 mg of dill powder was extracted with 100 mL 80% methanol to estimate the amounts of total phenolic (gallic acid equivalent), total flavonoid (quercetin equivalent), and 1,1-Diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity. Previously described methods were used without any modification with an Agilent Cary 60 UV-Vis Spectrophotometer (Santa Clara, CA).

Dill powder analysis

In our study, dill powder yielded 0.6 ± 0.07% essential oil. The composition of essential oil was; α-pinene 0.98 ± 0.07, myrcene 0.29 ± 0.11, α-phellandrene 17.89 ± 0.83, limonene 12.40 ± 0.66, sabinene 2.53 ± 0.71, p-cymene 2.27 ± 0.13, dill ether 6.80 ± 0.95, dihydrocarvone 1.11 ± 0.54, carvone 54.70 ± 1.28, phellandrene epoxide 0.28 ± 0.03, and other terpenes 0.75 ± 0.24 as relative FID peak area percentages. Carvone was the most abundant essential oil component. The amounts of aglycon forms of phenolic compounds were; quercetin 149.8 ± 2.13, isorhamnetin 138.6 ± 3.48, kaempferol 19.5 ± 2.15, myricetin 11.1 ± 1.88, rosmarinic acid 12.3 ± 2.46, chlorogenic acid 292.2 ± 22.57, p-coumaric acid 18.7 ± 3.61, cinnamic acid 11.3 ± 2.36, and catechin 1.3 ± 0.7 in mg/100-gram dill powder. Chlorogenic acid was the most abundant phenolic component. Total phenolic and flavonoid amounts were found to be 32 ± 1.42 and 13 ± 0.92 mg/g in dill powder, respectively. The free DPPH radical scavenging capability of the dill powder was measured as 12 ± 1.12%.

Clinical trial design, patient selection, and daily dosage

The study was planned as a single-blind randomized controlled trial. Patients who had benign thyroid nodules on fine needle aspiration biopsy were older than 18 years and euthyroid were included in the study. Patients who had previously undergone thyroid surgery were pregnant, had a known autoimmune disease, and were allergic to dill were excluded. A 90-day clinical study was conducted on 68 adult patients with benign thyroid nodules and euthyroid goiter. When selecting the dose of dill weed, the doses used in previous clinical trials were taken as reference and therefore dose–response assessment was not required.^4,20,21 The placebo control group (35 patients) received 3 × 300 mg placebo capsules daily, while the Dill treatment group (33 patients) took 3 × 300 mg dry dill powder capsules daily. All patients were over 18 years old, non-pregnant, and not using any prescription drugs.

Collection of blood samples and measuring nodule sizes

Blood samples were collected at the beginning and at the end of the study for thyroid stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), anti-thyroid peroxidase (anti-TPO), anti-thyroglobulin (anti-Tg), and C-reactive protein (CRP) analysis. Nodule sizes were also measured at the beginning and at the end of the trial with ultrasonography to identify the changes and effectiveness of dill dosage forms.

Statistical analysis

Statistical tests were conducted to analyze the data. The Shapiro–Wilk test was used to test the normal distribution of the continuous data. Two-group comparisons were performed using the Mann–Whitney U test and Independent Sample t test. The Chi-squared test was used for categorical comparisons. Two dependent group comparisons were performed using the Paired t test and Wilcoxon test. Linear regression analysis with forward selection was used to evaluate the effect of independent variables on the difference in TSH value. Results were reported with 95% confidence intervals (CI) and related P values. Continuous variables were expressed with median (minimum: maximum) and mean ±standard deviation values and categorical variables were expressed with frequency (percent) values. SPSS 22 was used for all analyses. P < .05 was considered statistically significant.

RESULTS

The mean age of the dill treatment group was 37.48 ± 11.88 years and most of them were female (72.7%). Of these patients, 39.4% had a familial history of thyroiditis and most (63.6%) had nodular goiter. The mean age of the placebo group was 41.11 ± 14.71 years and the majority were female (71.4%). Of these patients, 28.6% had a familial history of thyroiditis and most (65.7%) had multinodular goiter (Table 1).

Table 1.

Demographic and Clinical Variables of the Patients

Demographic and clinical variables	Clinical trial groups
Demographic and clinical variables	Placebo controlled	Dill powder treated	P value
Gender
Female	25 (%71.4)	24 (%72.7)	.905
Male	10 (%28.6)	9 (%27.3)	.905
Family history of thyroiditis
Not Present	25 (%71.4)	20 (%60.6)	.346
Present	10 (%28.6)	13 (%39.4)	.346
Goitre type
Diffuse Goitre	7 (%20)	0 (0)	<.001
Multinodular Goitre	23 (%65.7)	12 (%36.4)
Nodular Goitre	5 (%14.3)	21 (%63.6)
Average age	41.11 ± 14.71	37.48 ± 11.88	.269

TSH, FT4, anti-TPO, and CRP levels were significantly decreased after 90 days of dill treatment and goiter nodule sizes were remarkably reduced after dill therapy. TSH (P = .020), FT4 (P = .001), anti-TPO (P = .004), CRP (P = .003) levels, and nodule sizes (P = .001) were found to be significantly decreased in the dill given group. On the other side, substantial increases were observed in FT4 (P = .046), anti-TPO (P = .005), anti-Tg (P < .001), CRP (P = .043) levels, and nodule sizes (P = .031) in the placebo group (Table 2).

Table 2.

Biochemical Analysis Results and Nodule Sizes within Groups

Groups	Parameters	Initial day	Final day	P value
Dill treated	TSH (uIU/mL)	2.69 ± 1.32	2.18 ± 1.17	.020
	FT3 (pmol/L)	4.04 ± 0.77	3.83 ± 0.76	.252
	FT4 (pmol/L)	14.08 ± 2.28	12.28 ± 1.97	.001
	Anti-TPO (IU/mL)	18.55 (0.09–4135.40)	14.15 (0.10–1398.70)	.004
	Anti-Tg (IU/mL)	4.35 (0.62–972.65)	5.99 (0.94–478.01)	.214
	CRP (mg/L)	5.17 (0.10–21.74)	2.60 (0.06–6.71)	.003
	Nodule Size (mm)	22.69 ± 8.02	21.03 ± 7.38	.001
Placebo controlled	TSH (uIU/mL)	1.46 (0.03–5.19)	1.70 (0.35–4.31)	.128
	FT3 (pmol/L)	2.69 ± 1.32	2.18 ± 1.17	.419
	FT4 (pmol/L)	12.77 (6–17.32)	13.11 (11.42–17.15)	.046
	Anti-TPO (IU/mL)	1.35 (0.01–1852.20)	1.70 (0.07–1692)	.005
	Anti-Tg (IU/mL)	1.93 (0.13–6372.20)	2.40 (0.23–6536)	<.001
	CRP (mg/L)	2.40 (0.30–16.40)	2.45 (0.30–17.50)	.043
	Nodule Size (mm)	18.30 ± 7.86	19.12 ± 7.97	.031

Anti-Tg, anti-thyroglobulin; anti-TPO, anti-thyroid peroxidase; CRP, C-reactive protein; FT3, free triiodothyronine; FT4, free thyroxine; TSH, thyroid stimulating hormone.

When both groups were compared, TSH (P = .009), FT4 (P < .001), anti-TPO (P = .001), CRP (P < .001) levels, and nodule sizes (P < .001) were significantly decreased in the dill group compared to the placebo control group. It is observed that the inflammatory response decreased in the dill-treated group, and accordingly, normalization of thyroid function tests began (Table 3).

Table 3.

Biochemical Analysis Results and Nodule Sizes between Groups

Parameters	Placebo controlled	Dill treated	P value
Δ * FT3	0.100 ± 0.72	−0.213 ± 1.04	.155
Δ FT4	0.673 ± 1.91	−1.79 ± 2.81	<.001
Δ TSH	0.306 (−2.87/1.64)	−2.50 (−2.76/2.21)	.009
Δ Anti-TPO	0.43 (−160.20/70.86)	−4.63 (−2736.70/15.01)	.001
Δ Anti-Tg	0.41 (−0.40/163.80)	−0.37 (−859.45/33.05)	.083
Δ CRP	0.200 (−1.40/2.37)	−1.93 (−17.44/6.12)	<.001
Δ Nodule Size	1 (−4/6.60)	−2 (−5/4)	<.001

Δ: Changes (Δ) of the values between initial and final days.

Anti-Tg, anti-thyroglobulin; anti-TPO, anti-thyroid peroxidase; CRP, C-reactive protein; FT3, free triiodothyronine; FT4, free thyroxine; TSH, thyroid stimulating hormone.

According to the results of the linear regression analysis conducted to examine the effect of dill powder on TSH levels -which is distinctive in thyroid disease-depending on gender, age, family history, and study groups; the overall significance of the model was found to be P = .010 and the percentage of independent variables was explained as 83%. The variables included in the model -gender, age, and family history—did not have a significant effect on TSH values (all P > .05) in both groups while the only significant effect on TSH levels was found to be the study groups themselves. Consuming dill affected the TSH levels with a P value of .010 and decreased it 0.689 times in comparison to the placebo group (Table 4).

Table 4.

Results of Linear Regression Analysis

Dependent variable: TSH	β	S.E.	%95 CI (lower/upper)	P value
Constant	0.179	0.180	(−0.181/0.539)	.324
Gender	0.034	0.294	(−0.554/0.622)	.909
Age	−0.002	0.010	(−0.02/0.019)	.877
Family History of Thyroiditis	0.257	0.275	(−0.293/0.807)	.354
Groups	−0.689	0.259	(−1.205/−0.172)	.010

Adjusted R Square = 0.83; CI, confidence interval; S.E., standard error; TSH, thyroid stimulating hormone.

DISCUSSION

A. graovelens is one of the popular herbal remedies indicated for thyroid diseases, especially for hyperthyroidism and goiter; however, no clinical data was found except one survey and a case report.²⁰ FT4 and TSH levels showed a significant decrease after dill treatment while they both increased in the placebo group. The decrease in TSH levels in dill treated group is in concordance with previous studies.^20,21

The effect of dill on FT4 may be related to iodothyronine deiodinase enzyme inhibition which is responsible for activation and deactivation of thyroid hormones.^22,23 Another possible mechanism for the decrease in FT4 levels may be the inhibition of thyroid peroxidase by dill flavonoids as the dietary flavonoids are already known for their potency on inhibiting thyroid peroxidase.^24,25 Because of the feedback mechanism as the TSH decreases FT4 should be increased and vice versa.²⁵ Here in this situation, TSH and FT4 significantly decreased at the same time in the treatment group and increased in the placebo group.

Autoimmune thyroid disease is the most common form of thyroid dysfunction which causes various forms of thyroiditis.¹³ Thyroid autoimmunity is characterized by thyroid autoantibodies, especially anti-TPO and anti-Tg which accompany inflammation of the thyroid gland.¹⁴ Ninety days of dill treatment significantly reduced anti-TPO while anti-TPO and anti-Tg levels in the placebo group were remarkably ascended.

C-reactive protein is a marker of inflammation or infection. It is synthesized by hepatocytes and its concentration increases rapidly as a response to various infectious or inflammatory conditions.²⁶ CRP levels were remarkably attenuated during dill treatment whereas the concentrations were increased in the placebo group. The effect of consuming dill on decreasing CRP levels might be due to the decrease of anti-TPO levels which causes inflammation of the thyroid gland and might be the antioxidant and anti-inflammatory capabilities of phenolic compounds.²⁷

Thyroid nodules could be determined 2–20% by palpation, 19–67% with ultrasound, and 8–65% by autopsy in 8–65% of adult patients.¹⁵ The prevalence of thyroid nodules increases with age, female gender, iodine deficiency, and radiation exposure.¹⁶ The prevalence of malignancy ranges between 4.0% and 6.5% in biopsied thyroid nodules.¹⁷ Continuous TSH stimulation due to chronic iodine deficiency in the formation of thyroid nodules causes hyperplasia, large colloid deposition, and nodule development in thyroid follicles.¹⁵ Another obvious reason for the thyroid nodule formation is chronic thyroiditis, inflammation in thyroid follicles causes the expansion of monoclonal cells and follicle cells which causes nodule formation.^15,17,28 The thyroid nodule sizes were significantly reduced in the dill treatment group and increased in the placebo group.

The disappearance of a thyroid nodule relating to dill was previously reported in a subclinical hyperthyroid patient.²⁴ Shrinking of thyroid nodules could be linked to the decrease of FT3, FT4, and especially TSH hormone levels. anti-TPO and anti-TG levels -the most important markers of thyroiditis-were also decreased alongside CRP. Constituents of dill might have an antioxidant impact over these parameters which reverses the inflammation of the thyroid gland.

CONCLUSION

Aerial parts of A. graveolens are usually mentioned as an herbal remedy indicated for hyperthyroid disorders and goiter in public. As a result of this study, it was determined that dill significantly regulated TSH and FT4 levels and decreased anti-TPO and CRP values, possibly by regulating inflammation. Nodule sizes decreased, confirming the ethnomedicinal recommendation of dill for the treatment of thyroid nodules. Dill can easily be considered as an alternative treatment for euthyroid goiter. Research with a larger series will reveal this situation more clearly.

ETHICS COMMITTEE APPROVAL

This study is approved by the Research Ethics Committee of Bezmialem Foundation University according to the Declaration of Helsinki ethical principles with a protocol number of 12.2019/21.

CLINICAL TRIAL REGISTRY NUMBER

The clinical trial registration number of our study is NCT04482907. (https://cdek.pharmacy.purdue.edu/trial/NCT04482907).

INFORMED CONSENT

Written informed consent was obtained from all participants who participated in this study.

Footnotes

AUTHOR DISCLOSURE STATEMENT

No potential conflict of interest relevant to this article was reported.

FUNDING INFORMATION

No funding was received for this article.

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