ORIGINAL ARTICLE

Decrease in TSH levels after lactose restriction in Hashimoto’sthyroiditis patients with lactose intolerance

Mehmet Asik • Fahri Gunes • Emine Binnetoglu • Mustafa Eroglu •

Neslihan Bozkurt • Hacer Sen • Erdem Akbal • Coskun Bakar •

Yavuz Beyazit • Kubilay Ukinc

Received: 31 July 2013 / Accepted: 12 September 2013 / Published online: 28 September 2013

� Springer Science+Business Media New York 2013

Abstract We aimed to evaluate the prevalence of lactose

intolerance (LI) in patients with Hashimoto’s thyroiditis

(HT) and the effects of lactose restriction on thyroid

function in these patients. Eighty-three HT patients taking

L-thyroxine (LT4) were enrolled, and lactose tolerance tests

were performed on all patients. Lactose intolerance was

diagnosed in 75.9 % of the patients with HT. Thirty-eight

patients with LI were started on a lactose-restricted diet for

8 weeks. Thirty-eight patients with LI (30 euthyroid and 8

with subclinical hypothyroidism), and 12 patients without

LI were included in the final analysis. The level of TSH

significantly decreased in the euthyroid and subclinical

hypothyroid patients with LI [from 2.06 ± 1.02 to 1.51 ±

1.1 IU/mL and from 5.45 ± 0.74 to 2.25 ± 1.88 IU/mL,

respectively (both P \ 0.05)]. However, the level of TSH

in patients without LI did not change significantly over the

8 weeks (P [ 0.05). Lactose intolerance occurs at a high

frequency in HT patients. Lactose restriction leads to

decreased levels of TSH, and LI should be considered in

hypothyroid patients who require increasing LT4 doses,

have irregular TSH levels and are resistant to LT4

treatment.

Keywords Lactose intolerance � Hashimoto’s

thyroiditis � Hypothyroidism � L-Thyroxine

malabsorption

Introduction

Hypothyroidism is a common thyroid disorder worldwide.

The main treatment for hypothyroidism is oral L-thyroxine

(LT4) replacement, irrespective of the cause. Such treatment

may be insufficient in some hypothyroid patients because of

patient non-compliance or drug-induced malabsorption in

the alimentary tract [1–3]. Alimentary tract malabsorption

can be caused by many factors, including incorrect time of

the last meal [4], concomitant use of drugs [5], nutritional

habits [6, 7] and alimentary tract disorders [8]. The increased

need for LT4 may be an indication of emerging intestinal

disorders such as coeliac disease [9], short bowel syndrome

[10] and lactose intolerance (LI) [11].

LI is relatively common among those of Turkish and

Mediterranean descent [12, 13]. Although genetic lactase

deficiency is a primary cause of LI, a decrease in lactase

activity may occasionally be asymptomatic [11]. The lac-

tase enzyme is the rate-limiting step of lactose digestion. In

LI patients, the lactose molecule cannot be hydrolyzed into

glucose and galactose. LI is diagnosed using an elimination

diet, hydrogen tests, lactose tolerance tests or small intes-

tinal biopsies [1].

M. Asik (&) � M. Eroglu � K. Ukinc

Department of Endocrinology and Metabolism, Faculty

of Medicine, Canakkale Onsekiz Mart University, Kepez,

Canakkale, Turkey

e-mail: mehmetzu@yahoo.com

F. Gunes � E. Binnetoglu � N. Bozkurt � H. Sen

Department of General Medicine, Faculty of Medicine,

Canakkale Onsekiz Mart University, Canakkale, Turkey

E. Akbal

Department of Gastroenterology, Faculty of Medicine,

Canakkale Onsekiz Mart University, Canakkale, Turkey

C. Bakar

Department of Public Health, Faculty of Medicine, Canakkale

Onsekiz Mart University, Canakkale, Turkey

Y. Beyazit

Department of Gastroenterology, Canakkale Government

Hospital, Canakkale, Turkey

123

Endocrine (2014) 46:279–284

DOI 10.1007/s12020-013-0065-1

LT4 is absorbed by the jejunum, ileum and, to a lesser

extent, the duodenum in both euthyroid and hypothyroid

patients [14]. LI occurs when a considerable amount of

lactose is not absorbed in the intestines because of a lactase

deficiency in the small intestinal brush border. Undigested

lactose draws water into the intestinal lumen and leads to

bacterial fermentation. This causes osmosis and accelerates

small intestinal transit, which reduces contact time between

lactose and residual enzymes and further decreases the

hydrolysis of lactose [15]. This increases the degree of

maldigestion, which may lead to insufficient LT4 absorp-

tion. Many LT4 formulations contain lactose, and patients

with LI may require elevated LT4 doses to maintain a

euthyroid status [11]; however, there is insufficient data on

the prevalence of LI in patients with hypothyroidism as

well as the effect of lactose restriction on LT4 treatment.

Therefore, to fill this research gap, we aimed to evaluate

the frequency of LI in patients with hypothyroidism and the

effects of lactose restriction on thyroid function in hypo-

thyroid patients with LI.

Patients and methods

Eighty-three patients with Hashimoto’s thyroiditis (HT)

were enrolled in this study, and all were being treated with

LT4 upon admission. The average duration of illness was 3

(0.8–25) years. The average age of the patients was

44.65 ± 10.16 years. At the time of the first admission, the

thyroid status of the patients was as follows: euthyroid,

63.9 % (n = 53); subclinical, 22.9 % (n = 19); overt

hypothyroidism, 3.6 % (n = 3); and subclinical hyperthy-

roidism, 9.6 % (n = 8). Each participant signed an informed

consent, in accordance with the Declaration of Helsinki. This

study was approved by the local ethics committee of Ca-

nakkale Onsekiz Mart University.

All patients were screened and evaluated in the

Department of Endocrinology and Gastroenterology. LI

was diagnosed after a positive lactose load test (LLT) [16].

The LLT was positive if the level of glucose was B20 mg/

dL above baseline at 60 and 120 min. The level of anti-

gliadin antibody was also measured in all participants. Four

patients were diagnosed with coeliac disease and were

excluded from the study.

We were required to adjust the LT4 doses of some

patients because of extremely high or low TSH levels

(n = 18). However, we did not change the LT4 dose of 8 LI

patients who had a mildly high TSH level (4.66–6.8 pmol/L).

Since we aimed to evaluate alterations in the levels of TSH

and free-T4 (fT4) in patients with a constant dose of LT4, we

excluded 18 patients whose dose was changed after the first

admission. We also excluded nine euthyroid and two sub-

clinical hypothyroid patients from the initial group because

of a lack of follow-up. Fifty patients with HT (38 with LI and 12

without LI) were evaluated in the final study. Patients with LI

included 30 euthyroid and 8 subclinical hypothyroid patients,

while those without LI were exclusively euthyroid patients. The

study flow of all patients is summarised in Fig. 1.

Once LI was confirmed, a dietary lactose restriction was

started. Patients with LI were recommended to avoid dairy

products such as milk, modified or evaporated milk, but-

termilk, soft cheeses, margarine, feta, curd, skimmed milk

powder and whey powder [17]. All control patients were

also advised to restrict intake of these foods in the morning.

All study participants were recommended to take LT4

while fasting and to wait for 1 h before eating. They were

also advised to avoid grapefruit juice, coffee and products

rich in fibre and soya meal, especially in the morning.

At the beginning and end of the study, the levels of TSH,

fT4, calcium and parathormone (PTH) were measured in

all study participants.

Patients were excluded from the study if they were using

medications such as raloxifene; bile-binding acids; chole-

styramine; orlistat; colestipol; proton pump inhibitors; and

preparations including iron, aluminium or calcium [5].

Patients who were pregnant or diagnosed with diabetes

mellitus, known coeliac disease, and/or other related ali-

mentary tract disorders such as occult or overt inflamma-

tory bowel disease were excluded from the study. Patients

referred for bowel resection surgery were also excluded.

The diagnosis of HT was proven by a characteristic ultr-

asonographic pattern and the presence of high titres ([34 IU/

mL) of anti-thyroid peroxidase antibodies (anti-TPO). Only

one brand of medication, Euthyrox� (Merck KGaA, Ger-

many), was used in LT4 treatment. Tests for detection of anti-

endomysium and anti-gliadin antibodies (IgA and/or IgG)

were conducted to identify possible cases of coeliac disease.

The levels of serum glucose and calcium were analysed

using a standard autoanalyser. The reference ranges for the

serum levels of anti-TPO, fT4, TSH, intact PTH and calcium

were 0–34 IU/mL, 0.93–1.7 pmol/L, 0.270–4.2 IU/mL,

15–65 pg/mL and 8.5–10.2 mg/dL, respectively. Intact PTH,

TSH, anti-TPO and fT4 were measured using an electro-

chemiluminescence immunoassay ‘ECLIA’ on a Roche Co-

bas E601 analyser (Roche Diagnostics, Indianapolis, USA).

The assay reagents were also obtained from Roche Diag-

nostics. IgA, IgG, anti-endomysium and anti-gliadin anti-

bodies were measured using the indirect immunofluorescence

method (EUROIMMUN, Lubeck, Germany). The IgA and

IgG reactivities of the endomysium and gliadin (GAF-3X)

antibodies were confirmed by a positive reaction at 1:10.

Statistical analysis

SPSS software (Version 19.0; IBM, Chicago, IL, USA) was

used for the statistical analysis, and a P value of\0.05 was

280 Endocrine (2014) 46:279–284

123

considered to be statistically significant. Adjustment to

normal distribution was evaluated by the Kolmogorov–

Smirnov test, and all numerical data were expressed as a

mean, SD or median (interquartile range). Differences

between groups were evaluated using the Mann–Whitney

U test for nonparametric data, Student’s t test for parametric

data and Chi square test at the initial stage. The differences

between values before and after lactose restriction were

evaluated using the paired sample t test (for parametric

data) and Wilcoxon test (for nonparametric data).

Results

Eighty-three patients with HT taking LT4 were included in

the present study. LI was diagnosed in 75.9 % (n = 63) of

the patients. Coeliac disease was diagnosed in 4.8 % (n = 4)

of the patients, and all of the coeliac patients had LI. These

four patients with coeliac disease and secondary LI were

excluded from the study. The rate of primary LI was 74.7 %

(n = 59).

In the final analysis, age; gender; body mass index;

duration of disease; the daily LT-4 dose; and serum levels

of PTH, calcium, TSH and fT4 were not significantly dif-

ferent before and after lactose restriction in euthyroid

patients with and without LI. The anthropometric and

biochemical features of all patients with and without LI are

summarised in Table 1.

In both euthyroid and subclinical hypothyroid LI groups,

the level of TSH significantly decreased from 2.06 ± 1.02

to 1.51 ± 1.1 IU/mL (Fig. 2) and from 5.45 ± 0.74 to

2.25 ± 1.88 IU/mL (both P \ 0.05), respectively, follow-

ing lactose restriction. The level of TSH in the euthyroid

patients without LI remained unchanged (1.94 ± 1.05 and

Fig. 1 Study enrolment

diagram. Abbrevations: HT

hashimoto’s thyroiditis, LI

lactose intolerance. Thyroid

functional status: E euthyroid,

SCH subclinical hypothyroid,

sH subclinical hyperthyroid, OH

overt hypothyroid

Endocrine (2014) 46:279–284 281

123

2.46 ± 1.62 IU/mL; P [ 0.05 at the beginning and at the

end of the study, respectively). The levels of PTH, fT4 and

calcium also did not change significantly (Table 2).

Discussion

The prevalence of LI varies among different races, and

ranges from 7 to 95 % worldwide [12]. In a study by

Tuncbilek et al. [13], the prevalence of LI in a healthy adult

population was 37 %. However, this study had a relatively

small study population (n = 30) and cannot be expected to

reflect the prevalence of LI in a Turkish population. The

prevalence of LI in healthy subjects is likely higher in

Turkey. The rate of LI in other Mediterranean countries

ranged from 63 to 86 % in healthy subjects [12]. In most

studies, as in our current study, the LLT was used as a

primary diagnostic test. Different results may have been

observed because LI is partly associated with autoimmune

processes and because it is a regional disease. Although

many studies have explored the prevalence of LI in distinct

pathologic conditions, there is no data depicting the rates

of LI in patients with autoimmune thyroid diseases. Our

study is the first to demonstrate a high rate of LI in patients

with HT.

In LI, lactose accumulation leads to bacterial over-

growth, gas formation and an altered intestinal

Table 1 Clinical and laboratory characteristics of study participants

Patients

without LI

Patients

with LI

P value

Euthyroid (n) 12 30

Mild hypothyroidism (n) – 8

Gender (F/M)

Euthyroid 11/1 29/1 n.s.a

Mild hypothyroidism – 8/0 –

Age (years)

Euthyroid 47.9 ± 8.73 45.67 ± 10.28 n.s.b

Mild hypothyroidism – 35.5 ± 9.87 –

BMI (kg/m2)

Euthyroid 29.27 ± 3.67 27.54 ± 5.77 n.s.b

Mild hypothyroidism – 30.34 ± 4.59 –

LT4 dose/weight (lg/kg/day)

Euthyroid 0.89 ± 0.38 1.13 ± 0.44 n.s.b

Mild hypothyroidism – 1.36 ± 0.94 –

TSH (IU/mL)

Euthyroid 1.94 ± 1.05 2.06 ± 1.02 n.s.b

Mild hypothyroidism – 5.45 ± 0.74 –

fT4(pmol/L)

Euthyroid 1.25 ± 0.17 1.31 ± 0.23 n.s.b

Mild hypothyroidism – 1.18 ± 0.28 –

PTH (pg/mL)

Euthyroid 63.18 ± 24.5 64.58 ± 28.69 n.s.b

Mild hypothyroidism – 53.3 ± 19.48 –

Serum Ca (mg/dL)

Euthyroid 9.63 ± 0.43 9.56 ± 0.39 n.s.b

Mild hypothyroidism – 9.63 ± 0.43 –

Duration of HT (years)

Euthyroid 4 (0.16–20) 3 (0.16–10) n.s.b

Mild hypothyroidism – 1 (0.08–20) –

n.s. not significant, HT Hashimoto’s thyroiditis, LI lactose intoler-

ance, F/M female/male, BMI body mass index, LT4 L-thyroxine, TSH

thyrotropin, fT4 free-T4, PTH parathormonea Chi square testb Mann–Whitney U test

Fig. 2 Box plot presentation of TSH levels before and after lactose

restriction in the euthyroid LI group

Table 2 Laboratory parameters of patients before and after lactose

restriction with and without LI

Patients without

LI (E) (n = 12)

Patients with LI

(E) (n = 30)

Patients with LI

(SCH) (n = 8)

TSH (IU/mL)

Before diet 1.94 ± 1.05 2.06 ± 1.02* 5.45 ± 0.74*

After diet 2.46 ± 1.62 1.51 ± 1.1 2.25 ± 1.88

fT4(pmol/L)

Before diet 1.25 ± 0.17 1.31 ± 0.23 1.18 ± 0.28

After diet 1.21 ± 0.22 1.31 ± 0.27 1.24 ± 0.26

PTH (pg/mL)

Before diet 63.18 ± 24.5 64.58 ± 28.69 53.3 ± 19.48

After diet 61.19 ± 31.67 61.33 ± 22.67 57.61 ± 22.26

Serum Ca (mg/dL)

Before diet 9.63 ± 0.43 9.56 ± 0.39 9.63 ± 0.43

After diet 9.79 ± 0.25 9.56 ± 0.43 9.69 ± 0.45

LI lactose intolerance, E euthyroid, SCH subclinical hypothyroidism,

TSH thyrotropin, fT4 free-T4, PTH parathormone

* P \ 0.05(change of parameters before and after lactose restriction)

282 Endocrine (2014) 46:279–284

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environment, which may cause intestinal villus injury. LI

could, therefore, impair intestinal absorption and disrupt

the entero-hepatic circulation of LT4. A lactose-free diet

led to a decrease in the TSH level without the need for

alteration in the LT4 dose. This supports our aforemen-

tioned hypothesis. However, in our patients, the level of

fT4 did not significantly decrease after lactose restriction.

Hypothyroidism can cause small changes in the level T4

and larger changes in the level of TSH. However, these

changes are smaller when the T4 levels are within the

normal range [18]. The reason for the lack of significant

change in the fT4 levels in our study may be that the fT4

levels in our subjects were normal at the beginning of the

study.

The symptoms of LI improved 2–3 weeks after lactose

restriction [19]. It takes nearly 4–6 weeks for the TSH

levels to be affected by any change in L-thyroxine treatment.

Therefore, our study was designed such that the follow-up

period was 8 weeks. Although the level of TSH signifi-

cantly decreased in patients with LI, there was no significant

change in the level of fT4, possibly because of the relatively

short follow-up period. A significant change in the level of

fT4 may be observed in a longer-term trial.

Coeliac disease occurs in 2–5 % of patients with auto-

immune thyroid disease [20]. The results of our study are

similar to those of the abovementioned studies, but the

prevalence of coeliac disease slightly increased in HT

patients with LI. As we only noted coeliac disease among

HT patients with LI, these patients should be closely

monitored for the presence of coeliac disease. Conversely,

Ojetti et al. [21] found that up to 24 % of patients with LI

suffered from coeliac disease, which is in contrast with our

findings.

We started patients with LI on a lactose-restricted diet,

which included restricting the consumption of dairy foods.

However, this type of diet may be nutritionally disadvan-

tageous; a decreased intake of calcium and phosphorus

may lead to bone mineralisation. Therefore, we evaluated

the PTH and calcium levels before and after the lactose-

restricted diet and found that they did not change. A lac-

tose-restricted diet may, however, result in long-term bone

mineralisation.

Lactose is often an auxiliary ingredient of many com-

mercially available medications [22] including LT4 prep-

arations. It was recently demonstrated that lactose-

containing drugs may cause symptoms of LI [22], and

lactose in LT4 preparations could lead to an impairment of

thyroxine absorption in susceptible individuals [11]. In our

study, we used a lactulose-containing LT4 preparation, as

there was no other available option. If we had used LT4

without lactose in the patients with LI, the results of our

study might have been more remarkable. Vita et al. [23]

recently introduced a novel liquid LT4 formulation

containing only T4, glycerin, water and soft gelatin, which

should improve LT4 absorption. In patients with alimen-

tary tract diseases, such as LI, intestinal LT-4 absorption

may be improved by this new formulation.

In conclusion, the frequency of LI in HT patients was

very high in our study. A dietary restriction of lactose led

to a decrease in the level of TSH in HT patients with LI and

may decrease the need for LT4 treatment. Therefore, we

suggest that in the case of hypothyroid patients with higher

LT4 dose requirements, irregular TSH levels and a resis-

tance to LT4 treatments, LI should be considered while

making a diagnosis.

Conflict of interest The authors have nothing to disclose.

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