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The influence of lactose intolerance and other gastro-intestinal tract disorders on L-thyroxine absorption

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Abstract

The preferred treatment for hypothyroidism is oral levothyroxine (LT4) ingestion, in doses that ensure a sustained state of hormonal balance. 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 malabsorption 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 pseudomalabsorption. 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.
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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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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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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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.
References
1. Ruchala M, Szczepanek E. Hypothyroidism in primary care. Family
Medicine & Primary Care Review 2009; 11: 732–740.
2. Benvenga S, Bartolone L, Squadrito S et al. Delayed intestinal absorption
of levothyroxine. Thyroid 1995; 5: 249–253.
3. Munoz-Torres M, Varsavsky M, Alonso G. Lactose intolerance revealed
by severe resistance to treatment with levothyroxine. Thyroid 2006;
16: 1171–1173.
4. Bach-Huynh TG, Nayak B, Loh J et al. Timing of levothyroxine admin-
istration affects serum thyrotropin concentration. J Clin Endocrinol
Metab 2009; 94: 3905–3912.
5. Lamson MJ, Pamplin CL, Rolleri RL, Klein I. Quantitation of a substantial
reduction in levothyroxine (T4) absorption by food. Thyroid 2004; 14: 876.
6. Wenzel KW, Kirschsieper HE. Aspects of the absorption of oral L-thy-
roxine in normal man. Metabolism 1977; 26: 1–8.
7. Bolk N, Visser TJ, Kalsbeek A et al. Effects of evening vs morning thy-
roxine ingestion on serum thyroid hormone profiles in hypothyroid
patients. Clin Endocrinol (Oxf) 2007; 66: 43–48.
8. Elliott DP. Effect of levothyroxine administration time on serum TSH in
elderly patients. Ann Pharmacother 2001; 35: 529–532.
9. Campbell NR, Hasinoff BB, Stalts H et al. Ferrous sulfate reduces thy-
roxine efficacy in patients with hypothyroidism. Ann Intern Med 1992;
117: 1010–1013.
10. John-Kalarickal J, Pearlman G, Carlson HE. New medications which
decrease levothyroxine absorption. Thyroid 2007; 17: 763–765.
11. Madhava K, Hartley A. Hypothyroidism in thyroid carcinoma follow-up:
orlistat may inhibit the absorption of thyroxine. Clin Oncol (R Coll
Radiol) 2005; 17: 492.
12. Sachmechi I, Reich DM, Aninyei M et al. Effect of proton pump inhibi-
tors on serum thyroid-stimulating hormone level in euthyroid patients
treated with levothyroxine for hypothyroidism. Endocr Pract 2007; 13:
345–349.
13. Sherman SI, Tielens ET, Ladenson PW. Sucralfate causes malabsorption
of L-thyroxine. Am J Med 1994; 96: 531–535.
14. Singh N, Singh PN, Hershman JM. Effect of calcium carbonate on the
absorption of levothyroxine. JAMA 2000; 283: 2822–2825.
15. Siraj ES, Gupta MK, Reddy SS. Raloxifene causing malabsorption of
levothyroxine. Arch Intern Med 2003; 163: 1367–1370.
16. Berg JA, Mayor GH. A study in normal human volunteers to compare
the rate and extent of levothyroxine absorption from Synthroid and
Levoxine. J Clin Pharmacol 1992; 32: 1135–1140.
17. Blakesley V, Awni W, Locke C et al. Are bioequivalence studies of
levothyroxine sodium formulations in euthyroid volunteers reliable?
Thyroid 2004; 14: 191–200.
323
Endokrynologia Polska/Polish Journal of Endocrinology 2012; 63 (4)
SZKOLENIE
PODYPLOMOWE
18. Hennessey JV. Levothyroxine dosage and the limitations of current bio-
equivalence standards. Nat Clin Pract Endocrinol Metab 2006; 2: 474–475.
19. Nowak N, Łoza B. Lactose intolerance in psychiatric practice. Rev Clin
Neuropsychiatry 2010; 2: 137–176.
20. Lilja JJ, Laitinen K, Neuvonen PJ. Effects of grapefruit juice on the absorp-
tion of levothyroxine. Br J Clin Pharmacol 2005; 60: 337–341.
21. Deiana L, Marini S, Mariotti S. Ingestion of large amounts of papaya fruit and
impaired effectiveness of levothyroxine therapy. Endocr Pract 2012; 18: 98–100.
22. Liel Y, Harman-Boehm I, Shany S. Evidence for a clinically important ad-
verse effect of fiber-enriched diet on the bioavailability of levothyroxine
in adult hypothyroid patients. J Clin Endocrinol Metab 1996; 81: 857–859.
23. Bell DS, Ovalle F. Use of soy protein supplement and resultant need for
increased dose of levothyroxine. Endocr Pract 2001; 7: 193–194.
24. Benvenga S, Bartolone L, Pappalardo MA et al. Altered intestinal absorp-
tion of L-thyroxine caused by coffee. Thyroid 2008; 18: 293–301.
25. Hutyra T, Iwańczak B. Lactose intolerance: pathophysiology, clinical
symptoms, diagnosis and treatment. Pol Merk Lek 2009; 26: 148.
26. Swora E, Grzymislawski M. Selected aspects of diagnostics and treat-
ment of some diseases causing malabsorption syndrome. Gastroenterol
Pol 2012; 19: 21–24.
27. Eadala P, Waud JP, Matthews SB i wsp. Quantifying the ‘hidden’ lactose
in drugs used for the treatment of gastrointestinal conditions. Aliment
Pharmacol Ther 2009; 29: 677–687.
28. d’Esteve-Bonetti L, Bennet AP, Malet D et al. Gluten-induced enteropathy
(coeliac disease) revealed by resistance to treatment with levothyroxine
and alfacalcidol in a sixty-eight-year-old patient: a case report. Thyroid
2002; 12: 633–636.
29. Silva CM, Souza MV. [Autoimmune hypothyroidism nonresponsive to
high doses of levothyroxine and severe hypocalcemia]. Arq Bras Endo-
crinol Metabol 2005; 49: 599–603.
30. Caputo M, Brizzolara R, Schiavo M et al. Occurrence of overt celiac
disease in the elderly following total thyroidectomy. J Endocrinol Invest
2006; 29: 831–833.
31. McDermott JH, Coss A, Walsh CH. Celiac disease presenting as resistant
hypothyroidism. Thyroid 2005; 15: 386–388.
32. Khandwala HM, Chibbar R, Bedi A. Celiac disease occurring in a patient
with hypoparathyroidism and autoimmune thyroid disease. South Med
J 2006; 99: 290–292.
33. Jiskra J, Limanova Z, Vanickova Z et al. IgA and IgG antigliadin, IgA
anti-tissue transglutaminase and antiendomysial antibodies in patients
with autoimmune thyroid diseases and their relationship to thyroidal
replacement therapy. Physiol Res 2003; 52: 79–88.
34. Virili C, Bassotti G, Santaguida MG et al. Atypical celiac disease as cause
of increased need for thyroxine: a systematic study. J Clin Endocrinol
Metab 2012; 97: E419–E422.
35. Ruchala M, Kosowicz J, Baumann-Antczak A et al. The prevalence of
autoantibodies to: myosin, troponin, tropomyosin and myoglobin in
patients with circulating triiodothyronine and thyroxine autoantibodies
(THAA). Neuro Endocrinol Lett 2007; 28: 259–266.
36. Hadithi M, de Boer H, Meijer JW et al. Coeliac disease in Dutch patients
with Hashimoto’s thyroiditis and vice versa. World J Gastroenterol 2007;
13: 1715–1722.
37. Collins D, Wilcox R, Nathan M et al. Celiac disease and hypothyroidism.
Am J Med 2012; 125: 278–282.
38. Annibale B, Negrini R, Caruana P et al. Two-thirds of atrophic body
gastritis patients have evidence of Helicobacter pylori infection. Heli-
cobacter 2001; 6: 225–233.
39. Centanni M, Gargano L, Canettieri G et al. Thyroxine in goiter, Helico-
bacter pylori infection, and chronic gastritis. N Engl J Med 2006; 354:
1787–1795.
40. Bugdaci MS, Zuhur SS, Sokmen M et al. The role of Helicobacter pylori
in patients with hypothyroidism in whom could not be achieved nor-
mal thyrotropin levels despite treatment with high doses of thyroxine.
Helicobacter 2011; 16: 124–130.
41. Paśnik K. Chirurgiczne leczenie otyłości. Gastroenterol Pol 2009; 16:
135–139.
42. Padwal R, Brocks D, Sharma AM. A systematic review of drug absorp-
tion following bariatric surgery and its theoretical implications. Obes
Rev 2010; 11: 41–50.
43. Stone E, Leiter LA, Lambert JR et al. L-thyroxine absorption in patients
with short bowel. J Clin Endocrinol Metab 1984; 59: 139–141.
44. Rubio IG, Galrao AL, Santo MA et al. Levothyroxine absorption in mor-
bidly obese patients before and after Roux-En-Y gastric bypass (RYGB)
surgery. Obes Surg 2012; 22: 253–258.
45. Radaeli Rde F, Diehl LA. Increased levothyroxine requirement in
a woman with previously well-controlled hypothyroidism and intestinal
giardiasis. Arq Bras Endocrinol Metabol 2011; 55: 81–84.
46. Seppel T, Rose F, Schlaghecke R. Chronic intestinal giardiasis with isolated
levothyroxine malabsorption as reason for severe hypothyroidism — im-
plications for localization of thyroid hormone absorption in the gut. Exp
Clin Endocrinol Diabetes 1996; 104: 180–182.
47. Liwanpo L, Hershman JM. Conditions and drugs interfering with
thyroxine absorption. Best Pract Res Clin Endocrinol Metab 2009;
23: 781–792.
48. Srinivas V, Oyibo SO. Levothyroxine pseudomalabsorption and thyrox-
ine absorption testing with use of high-dose levothyroxine: case report
and discussion. Endocr Pract 2010; 16: 1012–1015.
49. Mussig K, Morike K, Klein R i wsp. [Hypothyroidism due to pseudo-mal-
absorption of levothyroxine — Case 12/2009]. Dtsch Med Wochenschr
2009; 134: 2514.
... The American and European Thyroid Associations recommend that L-thyroxine be taken with water consistently 60 min before breakfast or at bedtime, 2-4 h after the last meal, for optimal constant absorption [4,10]. Despite this, many different factors, both physiological (pregnancy, elderly age) 2 of 11 and pathophysiological (Helicobacter pylori-associated gastritis, autoimmune gastritis, lactose intolerance, celiac disease, small intestinal bacterial overgrowth, and bariatric surgery), and even some food ingredients might influence levothyroxine's bioavailability and thus its therapeutic effect [11][12][13][14]. ...
... Clinical data showed that therapy with liquid LT4 in 85% glycerol and 96% ethanol solutions was more efficient and provided better thyroid hormones control and enabled less frequent need of TSH level monitoring in replacement therapy in hypothyroid patients and TSH suppression therapy, while being an adjunct treatment in well-differentiated thyroid cancer patients [15][16][17][18][19][20][21][22][23][24]. Furthermore, it enabled the elimination of LT4 malabsorption issues related to gastrointestinal diseases, such as gastritis, celiac disease, small intestinal bacterial overgrowth, as well as in patients after bariatric surgery, or who underwent polytherapy [13,[15][16][17][25][26][27][28][29][30][31]. ...
Article
Full-text available
Levothyroxine (LT4) is a standard therapy in hypothyroidism; however, its bioavailability and therapeutic effects might be affected by many factors. Data shows that therapy with liquid LT4 characterized by quicker pharmacokinetics provides better thyroid hormones control than tablet LT4. We addressed the quality of life (QoL) and efficacy of the new ethanol-free formula of liquid LT4 (Tirosint®SOL) treatment in 76 euthyroid patients with primary (PH, n = 46) and central hypothyroidism (CH, n = 30), and compared the results to retrospective data on equivalent doses of tablet L-T4 therapy. After 8 weeks of liquid LT4 therapy, we found a significant improvement in QoL in both PH and CH patients. TSH levels were unaltered in PH patients. Free hormone levels (fT4 and fT3) increased in all the patients, with the exception of fT3 in the CH group. SHBG and low-density lipoprotein (LDL) also improved. Liquid LT4 therapy provided a better thyroid hormone profile and improvement in patients’ QoL than the tablet form, which was possibly due to the more favorable pharmacokinetics profile resulting in better absorption, as suggested by the increased free thyroid hormone levels. In summary, this is the first study addressing the QoL in hypothyroid patients, including primary and central hypothyroidism, treated with liquid LT4 formula in everyday practice.
... Indeed, in our study, liquid LT4 managed to normalize TSH concentrations in patients without any known causes of LT4 absorption disturbances, as well as in those with malabsorption: with gastric bypass (Patient 2), partial small and large intestine resection (Patient 14), scleroderma (Patient 16), gluten intolerance (Patient 3), celiac disease (Patient 9, Patient 23), atrophic gastritis (Patient 27), and polytherapy (Patient 19, Patient 27, Patient 29). Among numerous causes of LT4 malabsorption, intolerance to tablet excipients should also be mentioned [7,26]. Tirosint-SOL is the first alcohol-free liquid LT4 formulation, containing only the active sub-stance, glycerine, and water, thus minimizing the risk of excipient allergy or intolerance. ...
Article
Full-text available
It is estimated that hypothyroidism treatment may be either suboptimal or excessive in about 32-45% patients treated with L-thyroxine (LT4). There are multiple possible causes of poor control of hypothyroidism, including narrow LT4 therapeutic index, food and drug interactions, comorbidities, and patient non-adherence. Some of these obstacles could possibly be overcome with the novel liquid LT4 formulation. Liquid LT4 reaches maximum blood concentration about 30 minutes faster than the tablet form. Faster pharmacokinetics might lead to more efficient LT4 absorption, as suggested by a recent real-world study in patients with primary and central hypothyroidism. Liquid LT4 treatment led to increased free thyroxine (FT4) and sex hormone binding globulin (SHBG) with decreased low-density lipoprotein (LDL) cholesterol concentration and substantially improved quality of life for the patients. Herein we present a series of 31 patients with hypothyroidism of different aetiologies treated with the novel liquid LT4 formulation in standard clinical care in light of the latest scientific publications on liquid LT4 formula. We observed normalization of thyroid function tests shortly after introduction of liquid LT4, irrespective of concurrent diseases or concomitant medications that could diminish LT4 absorption. In more detail, the treatment with liquid LT4 managed to normalize thyroid-stimulating hormone (TSH) concentrations in patients without any known causes of LT4 absorption disturbances, as well as in those with malabsorption: with gastric bypass, partial small and large intestine resection, scleroderma, gluten intolerance, celiac disease, atrophic gastritis, and polytherapy. In conclusion, considering many factors disturbing LT4 absorption, hypothyroidism therapy with liquid LT4 seems to be a particularly effective option.
... Impaired bioavailability should be suspected in all patients taking more than 2 µg/Kg per day, and poor adherence to therapy is a possible cause of treatment failure (pseudomalabsorption) [5]. However, LT4 absorption can be altered by physiological conditions such as pregnancy, aging, or diet, or by drugs, as well as several pathological conditions affecting the digestive system, such as celiac disease, atrophic gastritis, inflammatory bowel disease, and lactose intolerance [6][7][8][9][10]. ...
Article
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Purpose: to determine lactose intolerance (LI) prevalence in women with Hashimoto's thyroiditis (HT) and assess the impact of LI on LT4 replacement dose. Methods: consecutive patients with HT underwent Lactose Breath Test and clinical/laboratory data collection. Unrelated gastrointestinal disorders were carefully ruled out. Lactose-free diet and shift to lactose-free LT4 were proposed to patients with LI. Results: we enrolled 58 females (age range, 23-72 years) with diagnosis of HT. In total, 15 patients were euthyroid without treatment, and 43 (74%) euthyroid under LT4 (30 of them with a LT4 formulation containing lactose). Gastrointestinal symptoms were present in 84.5% of patients, with a greater prevalence in change in bowel habits in lactose-intolerant patients (p < 0.0001). The cumulative LT4 dose required did not differ in patients with or without LI. No significant difference in both TSH values and LT4 dose were observed in patients shifted to lactose-free LT4 and diet at 3 and 6 months compared to baseline. Conclusion: the prevalence of LI in patients with HT was 58.6%, not different from global prevalence of LI. In the absence of other gastrointestinal disorders, LI seems not to be a major cause of LT4 malabsorption and does not affect the LT4 required dose in HT patients.
... LI should be considered in the differential diagnosis of gastrointestinal diseases that may cause malabsorption of L-T4 [4,5]. 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 [10]. ...
Article
We describe a case of a 38-year-old woman who, after radioactive iodine therapy for Graves' disease, developed severe hypothyroidism despite receiving a high dose of levothyroxine (L-T4) tablet as replacement therapy. Her thyroid stimulating hormone (TSH) remained to be high despite the dose of L-T4 tablets to 400 μg/day after treatment for hypothyroidism, and the patient complained of general malaise and edema of the legs. Reduced intestinal absorption of L-T4 is the most common cause of failure to achieve the therapeutic target in hypothyroid patients receiving replacement therapy. She was admitted to our hospital for severe hypothyroidism due to resistance to treatment with L-T4 tablet. Our patient was found to have lactose intolerance (LI) by a detailed examination during hospitalization. Therefore, we assumed that LI was impairing intestinal absorption of L-T4 tablet in our patient, leading to severe hypothyroidism. The patient was switched to the powder formulation of L-T4 at the same daily dose, and serum levels of thyroid-stimulating hormone and thyroid hormones normalized. This is the case in which hypothyroidism due to reduced absorption of L-T4 tablet in a patient with LI was resolved by switching to L-T4 powder formulation.
... As many as 75.9% of patients with Hashimoto's thyroiditis suffer from lactose intolerance; hence products containing lactose should be eliminated from their diet, after positive diagnostic tests. It's essential information as not observing the restrictions, while having lactose intolerance, causes a decrease in the bioavailability of levothyroxine, and thus patients will require higher doses of the medication [29,31,32]. Similarly, gluten-free diet should be observed, when there is coexistence of celiac disease or non-celiac gluten intolerance, which are significantly more prevalent in Hashimoto's disease. ...
Article
Full-text available
Thyroid disorders account for a majority of endocrine diseases. The most frequent among them are Hashimoto's thyroiditis, thyroid nodules and cancer with hyperthyroidism or hypothyroidism. Many thyroid patients travel a lot and therefore require appropriate guidance from their doctor. The aim of the review article is to discuss various aspects of travel in order to determine the optimal travel conditions for thyroid patients. Thyroid travelers must be well prepared for their journey. They should put particular emphasis on the choice of destination, the season and iodine resources at the planned place of stay. Before going on a journey, they are advised to check their health insurance, buy enough medications, prepare a copy of prescriptions and all other necessary documents. Depending on the means of transport, a few precautions should be taken to avoid infections or worsening of thyroid symptoms during travel. To deal with unpredictable events which might occur at the place of stay, travelers are recommended to take a first-aid kit containing basic medications. It needs to be stressed that many drugs are responsible for thyroid function disruptions and should only be used after consultation with a healthcare professional. Avoiding stress, maintaining good night's rest, as well as following a healthy diet, are all of great importance in managing thyroid diseases. Observing a few simple rules can minimize the frequency of flare-ups and the occurrence of the life-threatening thyroid storm. Traveling is an inseparable element of life for many people. Therefore, ensuring that patients are well informed about how to travel safely may prevent unwanted health events during travel.
... 16 The frequency of L-T4 dose changes, the need for unexpectedly high doses, and the failure of L-T4 to control the symptoms of hypothyroidism associated with tablets are known to correlate with the presence of GI comorbidities. 17 In an L-T4 malabsorption case of a patient with gastroparesis, changing from L-T4 sodium tablets to a gelatin capsule formulation seemed to correct thyroid function assays. 18 In addition, an L-T4 oral solution was shown to be more effective than the tablet formulations in controlling TSH levels in patients with hypothyroidism suffering from gastric disorders, malabsorption, or drug interference, and also in patients without malabsorptive disorders. ...
Article
Full-text available
Background: Levothyroxine (L-T4) is used as a standard-of-care treatment in patients with hypothyroidism. L-T4 is absorbed throughout the small intestine, and consistent drug absorption is required for successful treatment. Patients with Hashimoto's disease (autoimmune thyroiditis) often have food and medication sensitivities, as well as comorbid gastrointestinal (GI) disorders detrimental to L-T4 absorption. Case presentation: This case report describes a 51-year-old female patient with long-standing Hashimoto's disease and multiple sensitivities to food chemicals and medications. The patient suffered from GI symptoms and poor thyroid-stimulating hormone (TSH) control. She was switched to compounded thyroxine/triiodothyronine medication due to her multiple allergies, with only mild improvement in thyroid function and no symptom resolution. She was subsequently diagnosed with gastroparesis and small intestinal bacterial overgrowth (SIBO). Because of further worsening of her GI symptoms and weight loss, she was switched to levothyroxine sodium oral solution (Tirosint®-SOL), which contains only three ingredients-levothyroxine, water, and glycerol-which was well tolerated and led to normalization of TSH levels. Conclusion: Malabsorption of L-T4 is often seen in patients with Hashimoto's disease-related hypothyroidism and comorbid GI conditions, such as gastroparesis and SIBO. L-T4 tablets and a compounded oral suspension were inefficiently absorbed, leading to suboptimal TSH control. Switching to levothyroxine sodium oral solution resulted in sustained TSH control with subsequent resolution of symptoms. No side effects or reactions to the medication were observed, despite the patient's multiple allergies and sensitivities to food chemicals and medications.
... Due to the narrow therapeutic index and multiple factors affecting the drug absorption (e.g. patients' non-compliance, meaning too short interval to food intake), restoring euthyroidism may be challenging [2]. Absorption of liquid LT4 is 30 min quicker than LT4 in tablet form, thus minimizing the risk of drug malabsorption [3]. ...
... 7 For patients with malabsorption on L-T4 therapy presenting with poor TSH control, disorders such as celiac disease should be considered as differential diagnoses. 4,8 Addison's disease (adrenal insufficiency) may also cause treatment-refractory hypothyroidism. 2,9 In this case report, following diagnosis of Addison's disease, the patient was prescribed treatment with fludrocortisone and prednisone. ...
Article
Full-text available
Implementing a gluten‐free diet and switching to the levothyroxine oral solution significantly improved malabsorptive and hypothyroid symptoms in a patient with hypothyroidism, Addison's disease, and celiac disease without the need to increase levothyroxine dosage. Implementing a gluten‐free diet and switching to the levothyroxine oral solution significantly improved malabsorptive and hypothyroid symptoms in a patient with hypothyroidism, Addison's disease, and celiac disease without the need to increase levothyroxine dosage.
... LT4 is classified as having a narrow therapeutic index, indicating that small differences in dose or blood concentrations may lead to therapeutic failure (under-or overtreatment) [6]. Malabsorption syndromes, various drugs and foods may affect T4 absorption influencing therapy [7][8][9]. While most patients report improved well-being during LT4 therapy, some patients remain inadequately treated with elevated TSH levels and/or persistent symptoms [10]. ...
Article
Introduction: Over the past several years new evidence on management of hypothyroidism has emerged and has influenced recommendations from professional bodies. The presentation of hypothyroid patients has also changed and increasingly new cases are diagnosed by indiscriminate screening often identifying cases with minor biochemical disturbances. Little is known about the physician responses and attitudes to this changing landscape. THESIS (Treatment of Hypothyroidism in Europe by Specialists: an International Survey) is a large-scale survey of European physicians who treat patients with hypothyroidism. Here we document current practices of Polish physicians relating to the use of thyroid hormones in hypothyroid and euthyroid patients. Methods: Members of the Polish Society of Endocrinology were invited to participate in the web-based THESIS survey. Results: 423 (54.6% of the 774 invited) completed the survey. The majority of respondents (74.2%) would prescribe thyroid hormones for euthyroid patients for certain indications, such as female infertility with elevated thyroid antibodies (63.4%), simple goiter (40.9%), unexplained fatigue (12.1%), obesity (9.7%), hypercholesterolemia (9.0%) and depression (9.2%). Nearly all physicians (96.0%) declared that the treatment of choice for hypothyroidism is levothyroxine (LT4). However, around one-third (30.3%) were also using LT4 and liothyronine (LT3) combination treatment; LT3 alone was rarely prescribed (1.7%) and none prescribed desiccated thyroid extract. The majority of respondents preferred LT4 tablets. Among alternative formulations, liquid LT4 was most commonly recommended for patients unable to take LT4 in the fasting state (26.0%) and patients with malabsorption (19.9%). Respondents considered prescribing dietary supplements (such as selenium and iodine) in hypothyroid patients with coexisting autoimmune thyroiditis (29.6%) or at the patients' request (32.2%). LT4 + LT3 combination therapy was used by 32.2% when symptoms persisted notwithstanding normal serum TSH concentration. Psychosocial factors, comorbidities and the burden of chronic disease were considered as the most likely causes for persistent symptoms. Conclusions: Apart from clinical practice recommendations, other factors influence the thyroid hormone therapy patterns. Moreover, certain areas of clinical practice were identified (the use of thyroid hormones in euthyroid subjects and the use of dietary supplements) which are not in accordance with the current evidence.
Article
Even though levothyroxine sodium pentahydrate tablets have been in the market since 1955, there continue to be recalls due to sub potency. We have comprehensively reviewed the factors affecting its stability in solid oral dosage forms. A compilation of marketed formulation compositions enabled the identification of the potential ‘problem excipients’. Two excipient properties, hygroscopicity and microenvironmental acidity, appeared to be responsible for inducing drug instability. In drug products, depending on the formulation composition and storage conditions, the pentahydrate can dehydrate to highly reactive levothyroxine sodium monohydrate, or undergo salt disproportionation to the free acid form of the drug. The USP assay method (HPLC based) is insensitive to these different physical forms of the drug. The influence of physical form of levothyroxine on its chemical stability is incompletely understood. The USP has five product-specific dissolution tests reflecting the complexity in its evaluation.
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Hypothyroidism is, besides diabetes, the most frequent chronic endocrine disorder. Increasing incidence of hypothyroidism, initially insidious course together with serious clinical consequences make the general practitioner every day faces the difficulties of selection those patients requiring diagnostics and therapy of the thyroid, at the level of primary or secondary medical care. The aim of the present study is to summarize the current state of knowledge on the classification, methods of diagnosis and guidelines on the follow-up and therapeutic approach in different types of hypothyroidism, which might be applied in everyday practice.
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Roux-en-Y gastric bypass (RYGB) modifies the anatomical structure of the upper intestine tract, reduces gastric acid secretion, and may impair LT4 absorption. The aim of this study was to evaluate the LT4 absorption in morbidly obese patients before and after RYGB. Thirty morbidly obese patients were divided in two groups: The NS group included 15 patients before RYGB surgery (BMI = 43.1 ± 4 kg/m(2)), and the S group included 15 patients after surgery (BMI = 37.3 ± 4 kg/m(2)). Two baseline samples were collected, and 600 μg of oral LT4 tablets were administered. Blood samples were collected at 30, 60, 120, 180, 240, 300, and 1440 min. Serum-free T4 (FT4), total T4 (TT4), and TSH were measured at each time point. The increase in TT4, FT4, and TSH (ΔTT4, ΔFT4, and ΔTSH) was calculated, subtracting from the baseline mean value. The pharmacokinetics parameters regarding LT4 absorption, maximum ΔTT4, and area under the curve(AUC) of both ΔTT4 and ΔFT4 were significantly higher in the S group compared with the NS group (p < 0.05). It was observed, however, that there was a significant delay in the absorption of LT4 in the S group. Basal serum TSH and leptin levels were higher in the NS group (p = 0.016 and 0.026, respectively), whereas basal serum TT4, FT4, ΔTSH, and the AUC of ΔTSH were similar between groups. In this study, we have demonstrated that Roux-en-Y bypass surgery does not diminish LT4 absorption. A small but significant delayed absorption of LT4, however, was observed in patients after surgery.
Article
Surgical treatment of obesity began in the middle of last century. Increasing number of overweight and obese people and development of new surgical techniques and methods have considerably contributed to the progress of bariatric surgery. Long-term follow-up of patients undergoing surgical treatment allowed us to define these procedures as safe and beneficial both medically and in raising the quality of life. Widening of indications to surgical treatment of obesity is associated with a possibility to perform these procedures in children as well as in people over 65 years of age.
Article
Context The effect of calcium carbonate on the absorption of levothyroxine has not been studied systematically. Such a potential drug interaction merits investigation because concurrent treatment with both drugs is common, particularly in postmenopausal women.Objective To investigate the potential interference of calcium carbonate in the absorption of levothyroxine.Design Prospective cohort study conducted from November 1998 to June 1999, supplemented with an in vitro study of thyroxine (T4) binding to calcium carbonate.Setting Veterans Affairs Medical Center in West Los Angeles, Calif.Patients Twenty patients (age range, 27-78 years; n=11 men) with hypothyroidism who were taking a stable long-term regimen of levothyroxine were included in the study. All patients had serum free T4 and thyrotropin values in the normal range before beginning the study.Intervention Subjects were instructed to take 1200 mg/d of elemental calcium as calcium carbonate, ingested with their levothyroxine, for 3 months.Main Outcome Measures Levels of free T4, total T4, total triiodothyronine (T3), and thyrotropin, measured in all subjects at baseline (while taking levothyroxine alone), at 2 and 3 months (while taking calcium carbonate and levothyroxine), and 2 months after calcium carbonate discontinuation (while continuing to take levothyroxine).Results Mean free T4 and total T4 levels were significantly reduced during the calcium period and increased after calcium discontinuation. Mean free T4 levels were 17 pmol/L (1.3 ng/dL) at baseline, 15 pmol/L (1.2 ng/dL) during the calcium period, and 18 pmol/L (1.4 ng/dL) after calcium discontinuation (overall P<.001); mean total T4 levels were 118 nmol/L (9.2 µg/dL) at baseline, 111 nmol/L (8.6 µg/dL) during the calcium period, and 120 nmol/L (9.3 µg/dL) after calcium discontinuation (overall P=.03). Mean thyrotropin levels increased significantly, from 1.6 mIU/L at baseline to 2.7 mIU/L during the calcium period, and decreased to 1.4 mIU/L after calcium discontinuation (P=.008). Twenty percent of patients had serum thyrotropin levels higher than the normal range during the calcium period; the highest observed level was 7.8 mIU/L. Mean T3 levels did not change during the calcium period. The in vitro study of T4 binding to calcium showed that adsorption of T4 to calcium carbonate occurs at acidic pH levels.Conclusions This study of 20 patients receiving long-term levothyroxine replacement therapy indicates that calcium carbonate reduces T4 absorption and increases serum thyrotropin levels. Levothyroxine adsorbs to calcium carbonate in an acidic environment, which may reduce its bioavailability.
Article
▪ Objective: To determine whether simultaneous ingestion of ferrous sulfate and thyroxine reduces the efficacy of thyroid hormone in patients with primary hypothyroidism. ▪ Design: Uncontrolled clinical trial. ▪ Setting: Outpatient research clinic of a tertiary care center. ▪ Patients: Fourteen patients with established primary hypothyroidism on stable thyroxine replacement. ▪ Intervention: All patients were instructed to ingest simultaneously, a 300-mg ferrous sulfate tablet and their usual thyroxine dose every day for 12 weeks. ▪ Results: After 12 weeks of ferrous sulfate ingestion with thyroxine, the mean level of serum thyrotropin (thyroid stimulating hormone, TSH) rose from 1.6 ± 0.4 to 5.4 ± 2.8 mU/L (P < 0.01), but the free thyroxine index did not change significantly. Subjective evaluation using a clinical score showed that nine patients had an increase in symptoms and signs of hypothyroidism; the mean score for the 14 patients changed from 0 to 1.3 ± 0.4 (P = 0.011). When iron and thyroxine were mixed together in vitro, a poorly soluble purple complex appeared that indicated the binding of iron to thyroxine. ▪ Conclusions: Simultaneous ingestion of ferrous sulfate and thyroxine causes a variable reduction in thyroxine efficacy that is clinically significant in some patients. The interaction is probably caused by the binding of iron to thyroxine.
Article
Replacement T4 dose in hypothyroid patients bearing both chronic autoimmune thyroiditis and atypical celiac disease (CD) has been analyzed. Replacement T4 dose has been analyzed in 35 hypothyroid patients with Hashimoto's thyroiditis (HT) and atypical CD, as defined by the American Gastroenterological Association. We have evaluated the ability of the same dose of T4 to reach target TSH in 21 patients before and during gluten-free diet (GFD). In the remaining 14 patients, noncompliant with GFD, we analyzed replacement T4 dose and compared it with that in a similar group consisting of 68 patients with hypothyroid HT but no evidence of celiac sprue or other conditions interfering with T4 absorption. In patients with isolated HT, the desired serum TSH (median=1.02 mU/liter) was reached in all patients after 5±2 months of treatment at a median T4 dose of 1.31 μg/kg·d. After a similar period and dose of T4, higher levels of TSH (median=4.20 mU/liter) were observed in patients with HT and CD. In 21 CD patients, target TSH (median TSH=1.25 mU/liter) has been attained after 11±3 months of GFD without increasing T4 dose (1.32 μg/kg·d). In the remaining 14 patients, who were noncompliant with GFD, target TSH has also been achieved but at a higher T4 dose (median=1.96 μg/kg·d; +49%; P=0.0002) than in hypothyroid patients without CD. Atypical CD increases the need for T4. The effect was reversed by GFD or by increasing T4 dose. Malabsorption of T4 may provide the opportunity to detect CD that was overlooked until the patients were put under T4 therapy.
Article
Celiac disease is more common in patients with hypothyroidism. Malabsorption of levothyroxine has not been studied in this population. We sought to determine if levothyroxine dosing was influenced by the presence and treatment of celiac disease. This retrospective study was conducted at an academic medical center. Cases had hypothyroidism and celiac disease. Controls had hypothyroidism alone and were selected randomly through the endocrinology clinic records. Celiac disease was defined as representative pathology with positive serology. Age, sex, height, weight, body mass index, creatinine, and medical comorbidity were assessed for cases and controls. The levothyroxine dose and weight-based levothyroxine dose necessary to maintain a euthyroid state was evaluated for controls, and before and after celiac disease therapy for cases. Celiac disease was identified in 152 patients, and 22 patients had concomitant hypothyroidism (14.5%). Seven cases met inclusion criteria. Overall, 200 control patients were identified. The mean celiac disease pretreatment levothyroxine dose and weight-based levothyroxine dose needed to maintain a euthyroid state were higher in cases than in controls (154 μg vs 106 μg, P=.007, and 2.6 μg/kg vs 1.3 μg/kg, P <.001). Doses decreased significantly after treatment of celiac disease (154 μg vs 111 μg, P=.03; and 2.64 μg/kg vs 1.89 μg/kg, P=.04). All cases required at least 125 μg of levothyroxine initially to maintain a euthyroid state. Levothyroxine malabsorption likely occurs with hypothyroidism and untreated celiac disease. Absorption may improve after celiac disease treatment. Screening for celiac disease in patients with hypothyroidism requiring elevated levothyroxine doses warrants further investigation.