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318
Szkolenie podyplomowe/poStgraduate education
Endokrynologia Polska/Polish Journal of Endocrinology
Tom/Volume 63; Numer/Number 4/2012
ISSN 0423–104X
Marek Ruchała MD, PhD, Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznan,
Poland, ul. Przybyszewskiego 49, 60–355 Poznań, Poland, mob. +48 601 748 905, fax: +48 61 869 16 82, e-mail: mruchala@ump.edu.pl
The influence of lactose intolerance and other gastro-intestinal
tract disorders on L-thyroxine absorption
Wpływ nietolerancji laktozy i innych zaburzeń organicznych oraz czynnościowych
przewodu pokarmowego na wchłanianie L-tyroksyny
Marek Ruchała, Ewelina Szczepanek-Parulska, Ariadna Zybek
Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland
Abstract
The preferred treatment for hypothyroidism is oral levothyroxine (LT4) ingestion, in doses that ensure a sustained state of hormonal bal-
ance. Many different factors may significantly influence the absorption of LT4, including: interval between the ingestion of the drug and
the last meal, eating habits, and different functional and organic pathologies of the gastro-intestinal tract.
The main purpose of this paper is to review and systematise the available literature on the subject of the influence of different malabsorp-
tion syndromes on the effectiveness of LT4 preparations.
The need to use high LT4 doses in the substitutional treatment of hypothyroidism is often the very first sign of one of the pathologies that
are connected with malabsorption syndrome, which might have been asymptomatic and undiagnosed previously. Patients who require
more than 2 μg/kg body weight of LT4 per day, with constantly increased thyrotropin level, should be diagnosed with the suspicion of
pseudomalabsorption or real absorption disorder. An LT4 absorption test, using high doses of LT4, may be useful in the diagnosis of pseu-
domalabsorption. After excluding non-compliance, the differential diagnosis should include such disorders as lactose intolerance, coeliac
disease, atrophic gastritis, Helicobacter pylori infection, bowel resection, inflammatory bowel disease, and parasite infection.
Where there is a diagnosis of lactose intolerance, both a low lactose diet and a lactose-free LT4 preparation should be administered to restore
euthyroidism or make it possible to decrease the dose of the LT4 preparation. In coeliac disease, a gluten-free diet usually allows a normalisation
of the need for LT4, as do eradication of the H. pylori infection or parasite colonisation. In cases of atrophic gastritis or inflammatory bowel disease,
treating the underlying diseases and regaining the state of remission may improve the absorption of LT4. In patients after gastro-intestinal tract
surgery, a dose of LT4 higher than that typically used is needed to restore euthyroidism. (Endokrynol Pol 2012; 63 (4): 318–323)
Key words: hypothyroidism, L-thyroxine, malabsorption, lactose intolerance, coeliac disease
Streszczenie
Metodą z wyboru w leczeniu niedoczynności tarczycy jest doustne podawanie L-tyroksyny (LT4) w dawkach pozwalających na utrzymanie
u pacjenta stanu równowagi hormonalnej. Wymienia się wiele czynników, które mogą w istotny sposób wpływać na wchłanianie prepa-
ratu LT4, do których należą między innymi: korelacja czasowa przyjęcia leku i ostatniego posiłku, niektóre nawyki żywieniowe, a także
różne organiczne i czynnościowe patologie przewodu pokarmowego. Głównym celem niniejszej pracy jest przegląd i usystematyzowanie
literatury dotyczącej wpływu różnorodnych zaburzeń wchłaniania na skuteczność podawanych preparatów LT4.
Konieczność stosowania dużych dawek LT4 w leczeniu substytucyjnym niedoczynności tarczycy często jest pierwszym objawem jednego
z zespołów chorobowych, przebiegających z zaburzeniami wchłaniania, które mogą być skąpoobjawowe i wcześniej mogły pozostawać
nierozpoznane. Pacjenci otrzymujący LT4 w dawce większej niż 2 μg/kg mc./dobę, z przetrwale podwyższonymi stężeniami tyreotropiny,
powinni być poddani diagnostyce w kierunku pozornych lub rzeczywistych zaburzeń wchłaniania LT4. Test wchłaniania LT4 z wyko-
rzystaniem jej dużej dawki jest przydatny w diagnozie pozornych zaburzeń wchłaniania. Po wykluczeniu braku współpracy ze strony
pacjenta w diagnostyce różnicowej należy uwzględnić takie patologie, jak: nietolerancja laktozy, celiakia, zanikowe zapalenie błony śluzowej
żołądka, infekcja Helicobacter pylori, stan po resekcji jelita, nieswoiste zapalenie jelita czy, wreszcie, infekcje pasożytnicze.
W przypadku potwierdzenia nietolerancji laktozy należy zastosować preparat LT4 pozbawiony laktozy oraz dietę bezlaktozową w celu uzyskania
eutyreozy bądź możliwości zmniejszenia dawki preparatu LT4. W celiakii zastosowanie diety bezglutenowej zwykle skutkuje normalizacją zapotrze-
bowania na LT4, podobnie jak eradykacja infekcji bakteryjnej H. pylori czy pasożytniczej. W przypadku zanikowego zapalenia błony śluzowej żołądka
czy nieswoistego zapalenia jelita leczenie choroby podstawowej i uzyskanie remisji może doprowadzić do poprawy wchłaniania LT4. U chorych po
operacjach jelit zwykle konieczne jest stosowanie ponadstandardowych dawek LT4 w celu uzyskania eutyreozy. (Endokrynol Pol 2012; 63 (4): 318–323)
Słowa kluczowe: niedoczynność tarczycy, L-tyroksyna, zaburzenia wchłaniania, nietolerancja laktozy, celiakia
Introduction
Irrespective of the cause, the external replacement of
hormonal deficiency constitutes the basic method of hy-
pothyroidism treatment. Oral preparations available com-
mercially contain as an active substance either L-thyroxine
(LT4) sodium or its combination with L-triiodothyronine.
The method of choice in hypothyroidism treatment is oral
administration of LT4 in doses that enable the patient’s
hormonal balance to be maintained [1].
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Endokrynologia Polska/Polish Journal of Endocrinology 2012; 63 (4)
SZKOLENIE
PODYPLOMOWE
There are many difficulties in obtaining and sustain-
ing euthyroidism in a hypothyroid patient that a practic-
ing clinician may come across. In patients treated with
a standard LT4 dose, when a state of compensation is
not achieved, two potential causes of the phenomenon
should be considered: firstly, patient non-compliance,
and secondly, drug malabsorption in the alimentary tract.
Patient non-compliance, also referred to as pseu-
domalabsorption, remains the most frequent cause of
failure to achieve euthyroidism despite large doses of
LT4 (> 2 μg/kg body weight).
L-thyroxine is absorbed from the lumen of the
alimentary tract within hours from the moment of
administration, mainly in the jejunum and ileum and,
to a lesser degree, in the duodenum. Of crucial impor-
tance is the role of acidity of gastric juice; therefore, it is
recommended that preparations be taken on an empty
stomach to maximise the dose absorbed [2, 3].
There are many factors that can significantly affect
LT4 absorption, such as the time elapsed between the
drug administration and the last meal, certain eating
habits, as well as various organic and functional patholo-
gies of the alimentary tract.
It has been proven that absorption is optimal when
LT4 is taken on an empty stomach, whereas it is not so
effective when the preparation is administered directly
with a meal [4–6].
As a standard, LT4 should be taken at least 30 min-
utes before breakfast; such a recommendation can be
found on the leaflets contained in medicine boxes. There
have also been studies suggesting a similar efficacy of
the dose taken before going to sleep; the data available,
however, is not definitive [7, 8].
Drug interactions must also be taken into consid-
eration. Some medications, such as raloxifene, drugs
binding bile acids, cholestyramine, colestipol, proton
pump inhibitors, orlistat, sevelamer, and preparations
containing aluminium, iron or calcium can significantly
reduce LT4 absorption. Thus it is important that those
drugs and LT4 should be administered a few hours
apart [9–15].
A replacement LT4 dose should always be adjusted
individually. The dose, once established, can be changed
during treatment, even in the same patient. The factors
significantly influencing LT4 requirement in a given
patient include: progress of the disease, an increase
or decrease in body weight, pregnancy, and the use of
hormonal drugs such as oral contraception or hormone
replacement therapy. Moreover, various additional
ingredients found in different LT4 preparations can
have an impact on their absorption; therefore, when the
absorption of the LT4 drug is disturbed, it is well worth
trying to replace it with another one made by a different
manufacturer. Studies have shown that LT4 preparations
made by different manufacturers can have different
bioavailability [16–18]. However, interpreting some of
these studies can be difficult owing to, among other
things, the heterogeneity and the small size of the group
investigated, a single measurement of drug concentra-
tion in the blood, a different level of hypothyroidism,
and a lack of correlation in reference to endogenous
free thyroxine (FT4) concentration. It is because of this
last-named factor that labelling of the products as bio-
equivalent is not justified. Ignorance of the above fact in
the procedures recommended by the FDA can result in
iatrogenic hyper- or hypothyroidism when a preparation
is replaced without further screening and the establish-
ment of a new dose. The differences in bioavailability
of preparations of various brands do not result from
those in the active substance (which is LT4) but from the
so-called inert ingredients. These, by definition, should
not have an impact on a patient’s body but, at the same
time, can considerably modify drug absorption. Lactose
is frequently used as an adjuvant [19].
The other factors responsible for LT4 absorption are
eating habits, which result in increased LT4 doses in
such patients. Grapefruit juice minimally slows down
LT4 absorption [20], while papaya consumed in large
amounts has a significantly negative influence on the
degree of drug bioavailability [21], as does a diet rich in
fiber [22]. In vitro studies have shown dose-dependent,
non-specific LT4 absorption by wheat bran and soya
preparations [23]. On the other hand, it is interesting
to note that excessive coffee consumption results in
decreased LT4 absorption [24].
As has already been said, the bioavailability of the
preparations administered is significantly influenced
by concomitant organic and functional alimentary tract
disorders.
The main aim of this paper is a review and systema-
tisation of the literature concerning the impact of dif-
ferent malabsorption phenomena on the effectiveness
of LT4 preparations.
Lactose intolerance
The frequency of lactose intolerance among adult Cau-
casian patients ranges in the literature from 7% to as
much as 20% of a population, which makes it a relatively
common pathology. In Poland, according to different
studies, hypolactasia in adults occurs in 17.39–37.50%
of the population. Lactose intolerance (due to intestinal
lactase deficiency) can be primary (genetics-related) or
secondary (concomitant with many gastrointestinal
tract diseases, very often coeliac disease); persistent
or transient when remission of the main disease can
reinstate the enzyme’s normal activity and eliminate
the symptoms of intolerance.
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SZKOLENIE
PODYPLOMOWE
Primary lactose intolerance occurring in adults
is inherited autosomally recessively and is the most
frequent form of lactose deficiency. The activity of the
enzyme decreases in proportion to age, though total lack
of lactose production is rare. The presenting symptoms
(e.g. abdominal discomfort or pain, nausea, vomiting,
diarrhoea, constipation, flatulence, borborygmus, body
weight loss) are diverse and non-specific. They are
derived from lactose fermentation by colon bacteria
and can often resemble the symptoms of irritable colon
syndrome. It is worth remembering that irritability to
lactose is very individual and changes with age [19,
25, 26].
It should be particularly borne in mind that lactose
often is the so-called auxiliary ingredient (indifferent,
as a rule, to the body) used in many commercially avail-
able medicaments [27], and also in those preparations in
which LT4 is an active substance. Even small amounts
of lactose in patients with intolerance can result in local
digestion and absorption disorders, which is unfavour-
able for the absorption of the active substance itself. The
amount of lactose consumed can be substantial and give
clinical symptoms, especially in the elderly, in whom
polypragmasy is not uncommon.
The diagnosis of lactose intolerance is made using
interview data, an elimination diet and various tests
(hydrogen test, glucose concentration assessment after
standardised lactose dose administration, as well as
small intestine biopsy) [25].
The literature data provides examples of a nega-
tive impact of lactose in medical preparations on
absorption of various drugs, including psychoactive
drugs [19]. One example is that of a female patient
with LT4 malabsorption related to lactose intolerance.
She had primary hypothyroidism with permanently
elevated thyrotropin (TSH) levels. When it comes to
gastrointestinal symptoms, she complained only of
diarrhoea occurring sporadically over the previous
7–8 years. Increasing the dose to 900 μg and additional
therapy with triiodothyronine did not result in the
restoration of euthyroidism. Malabsorption diagnos-
tic tests, including lactose absorption test, revealed
lactose intolerance. LT4 intravenous therapy resulted
in the normalisation of thyroid hormones concen-
trations; then, an LT4 lactose-free preparation and
a lactose-free diet were used. Three months later, the
symptoms regressed and biochemical euthyroidism
was achieved [3].
Coeliac disease
Coeliac disease, an autoimmune ailment of the small
intestine found in genetically predisposed patients,
is characterised by chronic dietary gluten intolerance.
It can manifest itself at any age [26] and the literature
provides numerous examples of cases in which coeliac
disease resulted in LT4 malabsorption.
One of the first such cases was a female patient
after thyreoidectomy who was diagnosed with coeliac
disease at 68 years of age while being investigated for
the causes of LT4 and alphacalcidol malabsorption [28].
The patient’s history revealed persistent hypocalcaemia,
chronic diarrhoea, anaemia and hypoalbuminaemia.
There are also cases of patients in whom LT4 malabsorp-
tion was concomitant with non-specific symptoms of
coeliac disease such as body weight loss, anaemia, elec-
trolyte disorders (hypocalcaemia, hypomagnesaemia)
or osteopenia [29, 30]. In some hypothyroid patients
‘resistance’ to LT4 treatment is the first, and practically
only, symptom suggestive of malabsorption in coeliac
disease, with normal haemoglobin, electrolyte and al-
bumin levels and the absence of any clinical indicators
in the form of gastrointestinal symptoms [31, 32]. In
all those cases, when a gluten-free diet was employed,
daily LT4 requirement was reduced and TSH levels
returned to normal.
A study by Jiskra et al. showed that patients with
hypothyroidism related to autoimmune thyroiditis,
in whom the replacement daily LT4 dose was 125–
–200 μg, presented higher concentrations of anti-gliadin
IgA antibodies than those in whom the daily LT4 dose
was lower (50–100 μg) [33].
Virili et al. carried out the first systematic assess-
ment of an LT4 dose in replacement treatment of
patients with diagnosed hypothyroidism in the course
of chronic thyroiditis and coeliac disease. The study
group consisted of 35 patients with hypothyroidism in
the course of Hashimoto’s thyroiditis and non-classic
coeliac disease. The analysis focused on the LT4 dose
necessary to obtain target TSH values before the in-
troduction of a gluten-free diet (in all patients) and
then in 21 patients on a gluten-free diet (the remain-
ing ones were non-compliant). The LT4 requirement
was compared to a control group of 68 patients with
hypothyroidism in the course of Hashimoto’s disease,
in whom coeliac disease and other ailments that might
contribute to malabsorption were excluded. In patients
with isolated hypothyroidism, target TSH values (me-
dian 1.02 mIU/L) were obtained in all persons after
5 ± 2 months of treatment, with a median daily LT4
dose of 1.31 μg/kg body weight. At the same time, us-
ing a similar LT4 dose, patients with hypothyroidism
and coeliac disease manifested higher TSH values
(median 4.2 mIU/L). In 21 patients, target TSH values
(median 1.25 mIU/L) were obtained over a period of
11 ± 3 months of a gluten-free diet; there was no need to
increase the LT4 dose (median 1.32 μg/kg body weight
daily). In the remaining 14 patients, who were not on
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Endokrynologia Polska/Polish Journal of Endocrinology 2012; 63 (4)
SZKOLENIE
PODYPLOMOWE
a diet, target TSH values (median 1.54 mIU/L) were
obtained following an LT4 dose increase (median 1.96 μg/
/kg body weight daily, +49%, p < 0.0002) compared
to patients with hypothyroidism but without coeliac dise-
ase. The study showed that non-classic coeliac disease
increased LT4 requirement in replacement therapy and
that target TSH values can be attained by the introduc-
tion of a gluten-free diet or an increase of LT4 dose. It
is worth noting that LT4 malabsorption can be the first
signal of coeliac disease [34].
The problem of concomitant hypothyroidism re-
lated to chronic thyroiditis and coeliac disease is quite
common, because the underlying factor in both cases is
an autoimmune process as well as a genetic predisposi-
tion. Thyroid diseases are often accompanied by the
presence of specific antibodies, including those against
thyroglobulin, thyreoperoxidase, and TSH receptor, as
well as such endogenous substances as myosin, tro-
ponin, tropomyosin and myoglobin [35]. It has been
shown that coeliac disease occurs significantly more of-
ten in patients with Hashimoto’s disease compared to
the overall population, whereas Hashimoto’s disease,
in turn, is diagnosed in as many as 21% of patients with
coeliac disease [36]. Suspected coeliac disease must be
verified using serological (tissue transglutaminase and
antiendomysial antibodies) and morphologic tests (en-
doscopic and histopathological confirmation of enteral
villi atrophy) [26]. The estimated LT4 requirement in to-
tal hypothyroidism is 1.0–2.0 μg/kg body weight daily.
The values quoted in the paper by Virili et al. come
within this range, but in patients with concomitant
coeliac disease they are significantly higher compared
to those without malabsorption. While increasing
the LT4 dose in malabsorption patients is not a big
problem, we think that from a clinical point of view
it is important to stress the finding that is potentially
indicative of a diagnosis of non-classic coeliac disease,
the first noticeable clinical manifestation of which can
be LT4 malabsorption. Making a diagnosis of classic
coeliac disease is not usually difficult; however, it is
the non-classic form, especially without concomitant
typical gastrointestinal symptoms, diagnosed only in
adulthood, that does create problems, and very often
the disease goes undiagnosed for a long time. One
should remember that in adults with coeliac disease,
parenteral symptoms are prevalent such as dermal
symptoms (herpetiform dermatitis), anaemia, geni-
to-urinary tract symptoms (delayed puberty, fertility
disorders, early menopause), neurological symptoms
(epilepsy, migraine, depression, ataxia) and other
(muscle weakness, osteoporosis, tetany, short stature,
low body weight, enamel hypoplasia). Estimates put
the ratio of asymptomatic coeliac disease at 1:100–1:300
in a given population, whereas the classic form of the
disease with gastrointestinal symptoms is more than
ten times less frequent [34].
In patients with autoimmune hypothyroidism and
with no other indications, screening for coeliac disease
is not recommended. In those, however, in whom
euthyreosis is attained only after a daily LT4 dose of
more than 2 μg/kg body weight, tests for coeliac disease
should be carried out.
In a recent study, Collins et al. compared the
LT4 requirement in replacement therapy in patients
with hypothyroidism and concomitant coeliac disease,
against the requirement in those with isolated hypo-
thyreosis. The study showed that the LT4 requirement
in the former group, before introduction of a gluten-free
diet, was 2.6 μg/kg body weight compared to 1.3 μg/kg
body weight in the latter group, with coeliac disease
treatment resulting in a significant decrease in LT4 re-
quirement to 1.89 μg/kg body weight [37].
Atrophic gastritis
and Helicobacter pylori infection
Chronic atrophic gastritis is another common factor
modifying LT4 absorption. It is connected with gastric
mucosa colonisation by H. pylori, and could affect as
much as 50% of the world’s population. The main
source of LT4 malabsorption in this case is the reduced
acidity of gastric juice. During H. pylori infection, urease
produced by the microorganisms neutralises the acidity
of gastric juice [38]. Centanni et al. have proven that
patients with multinodular goitre and H. pylori infection
(a 22% increase), with atrophic gastritis (a 27% increase),
or with both diseases occurring simultaneously (a 34%
increase), require LT4 doses that are 22–34% higher to
obtain the target TSH values. In a prospective observa-
tion in patients who developed H. pylori infection at
that time, LT4 requirement increased significantly, the
effect being almost completely reversible when the
infection was eradicated. A similar phenomenon was
observed in patients treated with proton pump inhibitor
(omeprazole); in order to maintain target TSH values,
it was necessary to increase the LT4 dose by 37% [39].
In a recent study, Bugdaci et al. assessed the impact
of H. pylori infection eradication on TSH and thyroid
hormone levels in patients with hypothyroidism who
did not respond earlier to large doses of LT4. All patients
manifested a significant decrease in TSH concentrations;
21% of them, however, developed iatrogenic hyper-
thyroidism. This leads us to conclude that in patients
taking high LT4 doses in replacement therapy of hy-
pothyroidism, H. pylori infection eradication can result
in a significant improvement of LT4 absorption which,
therefore, necessitates a further LT4 dose adjustment
(reduction) [40].
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Marek Ruchała et al. L-thyroxine malabsorption
SZKOLENIE
PODYPLOMOWE
Bowel resections
In recent years, owing to the so-called epidemic of
obesity, there has been a growing amount of bariatric
surgery, the aim of which is to facilitate body weight
reduction in the most obese patients. The method has
become increasingly popular following the develop-
ment of laparoscopic techniques. Its effectiveness has
also been confirmed by numerous literature reports [41].
Studies have also shown that such surgical procedures
have an influence on drug absorption. Evidence point-
ing to a decreased absorption of various preparations
was presented in 15 out of 22 investigations dealing with
an analysis of patients who underwent jejunoileostomy
(Kremen’s operation), and in one out of three studies
concerning an analysis of patients after gastroplasty. In
one study, no malabsorption symptoms were reported
in patients after biliopancreatic diversion. Therefore,
it is necessary to individually adjust the dosage and
monitor the patient postoperatively [42].
LT4 malabsorption occurs also in patients after other
bowel resection surgeries (in the course of so-called
short bowel syndrome). Such patients manifest an in-
creased postoperative requirement for LT4 prepara-
tions. However, no direct correlation has been observed
between the length of the bowel left and the LT4 dose
absorbed [43].
A recent study by Rubio et al. concerning the LT4
absorption test has shown that in patients who under-
went gastric bypass according to the Roux-en-Y method,
LT4 absorption does not decrease, only that the process
becomes slower [44].
Other causes
There are literature reports of a negative impact of
Giardia lamblia infection and that of non-specific
bowel inflammations on LT4 absorption [45–47]. The
case of a 57 year-old female patient is presented, with
well-controlled hypothyroidism over a period of six
years, who developed gastrointestinal symptoms with
a co-existing marked deterioration of hormonal balance.
An adequate control of hypothyroidism using routine
LT4 doses was restored after Giardia lamblia infection
eradication with metronidazole [46].
Conclusions
The need to use high LT4 doses in replacement therapy
of hypothyroidism can be the first symptom of malab-
sorption syndrome, which can be oligosymptomatic
and previously undiagnosed. Patients taking LT4 in
a dose of more than 2 μg/kg body weight daily, with
persistently elevated TSH values, should be diagnosed
with reference to pseudomalabsorption or real LT4 ma-
labsorption. The LT4 absorption test, using a high LT4
dose, plays a role in the diagnosis of pseudomalab-
sorption which is the commonest cause of difficulties
in obtaining euthyreosis in hypothyroid patients [48,
49]. With patient non-compliance excluded, and real
LT4 malabsorption confirmed, a differential diagnosis
must take into consideration such pathologies as lactose
intolerance, coeliac disease, atrophic gastritis, H. pylori
infection, bowel resection postoperative state, inflam-
matory bowel disease and, finally, parasite infections.
Once lactose intolerance has been confirmed via
a lactose absorption test, a lactose-free LT4 preparation
and a lactose-free diet should be used in order to attain
euthyreosis or reduce the dose of LT4 preparation. In
coeliac disease, a gluten-free diet usually results in
the normalisation of LT4 requirement, as does the
eradication of H. pylori infection or one caused by para-
sites. When it comes to atrophic gastritis or inflamma-
tory bowel disease, treatment of the main disease and
its remission can improve LT4 absorption. Patients after
bowel surgery usually require higher than standard
doses of LT4 to attain euthyreosis.
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