ChapterPDF Available

Low-Dose Naltrexone Treatment of Hashimoto’s Thyroiditis

Authors:

Abstract

Chronic lymphocytic thyroiditis, also known as Hashimoto’s thyroiditis, is the most common cause of spontaneously occurring hypothyroidism in adults in the United States. Treatment for this condition is thyroid hormone replacement once hypothyroidism develops since there is no known effective treatment to halt the underlying thyroiditis that eventually destroys the thyroid gland. Selenium supplements have been reported to reduce anti-thyroid antibody titers significantly but not to prevent the eventual development of hypothyroidism. Low-dose naltrexone (LDN) has been promoted in books and on Internet websites as an effective treatment to reduce thyroid inflammation and symptoms in patients with this condition. However, there is no published scientific data to substantiate these claims.
317© Springer Nature Switzerland AG 2019
M. T. McDermott (ed.), Management of Patients
with Pseudo- Endocrine Disorders,
https://doi.org/10.1007/978-3-030-22720-3_24
Chapter 24
Low-Dose Naltrexone
Treatment ofHashimoto’s
Thyroiditis
MichaelT.McDermott
A 51-year-old man came to the office to establish care with an
endocrinologist. He just moved to this community from out
of state. He was diagnosed years ago with hypothyroidism
and low testosterone; he doesn’t recall the tests that were
done to establish these diagnoses. He currently takes levothy-
roxine 225 mcg daily, liothyronine 5 mcg BID and Depo-
testosterone 100mg every week. He feels generally well but
has chronic anxiety and trouble sleeping. He has some fatigue
but says that his current medication regimen helps consider-
ably. His previous doctor told him that his TSH, which is usu-
ally low, is not an accurate measure of his thyroid status since
he has severe fatigue when his TSH is normal. He was told
that his treatment goal should be to keep his free T4 and free
T3 levels within the normal range but that his symptoms are
the most reliable indicator of the adequacy of his thyroid
hormone therapy. He has done extensive Internet research
that has confirmed that, as his previous doctor told him, the
M. T. McDermott (*)
University of Colorado Hospital, Aurora, CO, USA
e-mail: michael.mcdermott@cuanschutz.edu
michael.mcdermott@cuanschutz.edu
318
TSH is not a good test for him. A previous MRI of his pitu-
itary gland was normal. He also read information during his
research that Hashimoto’s thyroiditis may be improved or
cured with low-dose extended-release compounded naltrex-
one therapy. He requests that a prescription for low-dose
naltrexone be sent to his local compounding pharmacy that
has told him they will compound it for him if he has a pre-
scription from a physician. His most recent labs are as fol-
lows: TSH 0.01mU/L, free T4 1.8ng/dl, and free T3 2.4pg/ml.
Discussion
Hashimoto’s thyroiditis (chronic lymphocytic thyroiditis) is
the most common etiology of primary hypothyroidism in
adults in the United States. Hashimoto’s thyroiditis is a
genetically based chronic inflammatory condition that leads
to gradual but progressive destruction of the thyroid gland,
rendering it unable to make sufficient amounts of thyroid
hormone to meet the needs of peripheral tissues [1].
Hashimoto’ s thyroiditis is the most common of all autoim-
mune diseases. While a genetic predisposition plays a domi-
nant role in its development, environmental factors may also
have an important influence. Nutritional factors, for example,
have been linked to a higher risk for developing Hashimoto
s thyroiditis; these include iodine excess, selenium deficiency,
and possibly deficiencies of iron and vitamin D [2].
Interestingly, selenium supplementation has been shown to
reduce thyroid autoantibody titers in patients with
Hashimoto’s thyroiditis; however, there is no evidence that
selenium reverses or prevents progression of their thyroid
dysfunction [3].
The diagnosis of Hashimoto’s thyroiditis is made by dem-
onstrating elevated levels of anti-thyroid peroxidase anti-
bodies (anti-TPO) and/or anti-thyroglobulin antibodies
(anti-Tg) in the circulation. However, measurement of these
anti- thyroid antibodies in hypothyroid subjects is a contro-
versial topic. Routine antibody measurement is not recom-
M. T. McDermott
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319
mended in the current clinical practice guidelines of the
American Association of Clinical Endocrinologists (AACE)
and the American Thyroid Association (ATA) [4] because
adults with hypothyroidism not due to iatrogenic causes
(surgery, radioiodine ablation) or medications nearly always
have Hashimoto’s thyroiditis; therefore, thyroid autoanti-
body testing offers little additional information and does
not usually affect treatment decisions. However, some pro-
viders find it beneficial to demonstrate to their patients that
their hypothyroidism has an autoimmune etiology; this may
also facilitate a discussion about the increased risk of devel-
oping other autoimmune disorders for which increased vigi-
lance may be useful. Thyroid sonography is not generally
indicated in the evaluation of hypothyroidism unless thy-
roid nodules are palpable on physical examination or have
been identified incidentally by other imaging studies; when
performed it often shows a hypoechogenic pattern in the
thyroid parenchyma in patients with chronic lymphocytic
thyroiditis [1].
The treatment of Hashimoto’s thyroiditis is thyroid hor-
mone replacement once hypothyroidism develops as a
result of the chronic lymphocytic inflammation.
Levothyroxine (LT4) is the recommended replacement
medication and should be given in doses sufficient to main-
tain the serum TSH level within the reference range [4, 5].
The majority of affected patients will have relief or resolu-
tion of their symptoms with this therapy. However, as dis-
cussed in the previous chapter, some patients may continue
to experience symptoms consistent with thyroid hormone
deficiency despite adequate LT4 replacement therapy [6
14]. Some providers may then choose a trial of combination
LT4 plus liothyronine (LT3) in roughly a 10:1T4 to T3 ratio
or porcine desiccated thyroid extract (DTE), which has
approximately a 4:1T4 to T3 ratio. Neither of these are con-
sidered first-line therapy, but the ATA and AACE guideline
authors concede that while there is no evidence for superi-
ority of these combined T4/T3 regimens on symptoms or
other outcomes and there is no long- term safety data, it is
Chapter 24. Low-Dose Naltrexone Treatment…
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320
reasonable to consider a trial of combined therapy in
patients who continue to suffer symptoms despite adequate
LT4 therapy (see more complete discussion of this issue in
the previous chapter) [4, 5].
Nonetheless, the ATA survey (discussed in the previous
chapter) of 12,000 hypothyroid patients that showed wide-
spread dissatisfaction with their thyroid hormone replace-
ment therapy [13] consisted of 60% who were taking LT4
alone, 25% who were taking combination LT4/LT3, and
10% who were taking DTE or a compounded thyroid hor-
mone preparation. Therefore, even the available combina-
tion T4/T3 regimens do not resolve all symptoms in some
patients.
Blogs fromaHashimoto’s Disease Website
(Unedited)
I am currently going through this now. I feel like crap, no
energy depressed moody dizzy ect. My labs have been in
range and my Endo doctor says my symptoms are not
related to Hashimoto because my thyroid test are in range.
But they cant find any other issues so now they are just
treating me like I am crazy and a Hypochonchiac when I
tell them what I’m experiencing.
This is exactly what thyroid patients go through, doctors
dismissing our symptoms when labs are in-range. They
do not realize they are relying on outdated lab values or
that the difference between in-range and optimal can
make a dramatic improvement in our quality of life.
And yet we continue to be ignored by a majority of
endocrinologists and thyroid specialists. Seven out of
eight thyroid patients are women. Is it any wonder we
are ignored?
Yes it is BS but what’s even worse is being sick for 30years
and them telling you you’re fine when you know you
aren’t. Then you are finally diagnosed and they tell you
well this isn’t something traditional medicine treats its
M. T. McDermott
michael.mcdermott@cuanschutz.edu
321
more of a holistic health thing. Are you serious!!! I do feel
better now on Armour and healthy diet than I ever did on
Synthroid so that’s a plus.
Endocrinologists are trained but not educated.
A Cure forHashimoto’s Thyroiditis Is Not
Currently Available
The most commonly cited explanation for persistent symp-
toms in hypothyroid patients who are treated with LT4 or T4/
T3 combinations and have serum TSH levels within the refer-
ence range or even within the “optimal range” of 0.45–
2.0mU/L is that the symptoms may not be thyroid-related or
endocrine-related at all [15]. However, data from one study
suggested that chronic lymphocytic thyroiditis may possibly
cause symptoms that are independent of and not related to
thyroid hormone levels [16]. Furthermore, multiple other
autoimmune conditions are known to occur more commonly
in patients with chronic lymphocytic thyroiditis [17, 18], add-
ing to the complexity of symptom management. So, the
important question arises: is it possible that Hashimoto’s
thyroiditis itself could be cured before there is extensive thy-
roid inflammation and gland destruction?
Autoimmune diseases that destroy some organ systems
(joints, kidneys, liver, central nervous system, eyes, skin) are
often treated with aggressive immunosuppressive therapies
because relatively simple replacement therapies for these
organ systems are not available. Due to the frequent side
effects and significant toxicities of immunosuppressive agents,
they have not been well studied and are not indicated in
patients with Hashimoto’s thyroiditis. Instead, affected
patients are generally monitored until they develop mild
hypothyroidism, at which point thyroid hormone replace-
ment therapy is initiated.
Therefore, there is interest in finding therapies that are
more benign than currently available immunosuppressive
agents and that could potentially be used to reduce or abolish
Chapter 24. Low-Dose Naltrexone Treatment…
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322
the thyroid inflammation to prevent further thyroid destruc-
tion or possibly even allow thyroid regeneration. For exam-
ple, as mentioned above, selenium supplementation has been
shown to reduce thyroid autoantibody titers in patients with
this condition; disappointingly, however, there is no evidence
that selenium can reverse or prevent progression of thyroid
dysfunction [3]. So here is where the murky origins of low-
dose naltrexone as a treatment for Hashimoto’s thyroiditis
begin.
Background onLow-Dose Naltrexone
Endogenous opioids and opioid antagonists are proposed to
play a role in healing and repair of tissues. This has led to the
use of low-dose naltrexone (LDN) as a possible treatment for
numerous disorders [20]. Dr. Bernard Bihari, “a LDN pioneer
and champion” is featured in a 2002 online video describing
his work with LDN; an online tribute credits him with
improving the lives and relieving symptoms in “tens of thou-
sands (some say hundreds of thousands) of people with mul-
tiple sclerosis, rheumatoid arthritis, lupus, HIV/AIDS, and
even cancer” [19]. In her book Honest Medicine, Julia
Schopick proposes LDN as an “effective, time-tested, inex-
pensive treatment for life-threatening diseases” to include
“multiple sclerosis, epilepsy, liver disease, lupus, rheumatoid
arthritis, and other disorders” [20].
Scientific Evidence forLow-Dose Naltrexone
Is there credible science to support these claims? In a 2007
study published in the American Journal of Gastroenterology,
Dr. Jill Smith did report significant improvements in the
Crohn’s Disease Activity Index during 12weeks of treatment
with LDN and for 4weeks after discontinuation of the medi-
cation in patients with active Crohn’s disease [21]. Other
studies followed with mixed results. Subsequently, a 2018
M. T. McDermott
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Cochrane Database Systematic Review of this issue con-
cluded that there is “insufficient evidence to allow any firm
conclusions regarding the efficacy and safety of LDN for
patients with active Crohn’s disease” [22].
I have searched all credible sources and have found no
published evidence that LDN is beneficial in patients with
thyroid or other endocrine disorders, autoimmune or other-
wise. As devoted and well-educated clinician scientists and
experts in the field, we should always be seeking innovative
approaches to evaluation and treatment of our patients who
are suffering from endocrine diseases and pseudo-endocrine
disorders since our primary goal is to relieve suffering and
improve our patients’ quality of life. Our evaluation and man-
agement recommendations must, in my opinion, be individu-
alized and innovative but should also be evidence-based to
ensure that the safety and welfare of our patients is foremost
in our plans.
What Is theBest Way toManage this Patient’s
Symptoms andConcerns andtoPractice
Good Medicine?
It is critically important to educate patients regarding medi-
cal information they find on the Internet. This has been well
covered in other chapters, so I will briefly say only that
patients should be informed that both good information and
unreliable and unsubstantiated information can be found on
the Internet. One must be careful to determine the source of
the information given in order to evaluate its credibility. In
this case, some Internet sites make claims of significant ben-
eficial effects of LDN but without solid scientific evidence to
substantiate these claims. A review of the existing scientific
literature does show some initial reports of benefit in patients
with Crohn’s disease, but a large Cochrane systemic review of
all existing studies did not find evidence for benefit. LDN has
not been studied in patients with Hashimoto’s thyroiditis.
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This information is worth discussing with the patient.
Doing so indicates that you acknowledge that he/she is
seeking relief of symptoms that are adversely affecting his/
her quality of life and respects his/her initiative for investi-
gating measures that might be taken to improve quality of
life. At the same time, it emphasizes that you, as the physi-
cian, practice evidence-based medicine and do not believe
that the use of unproven therapies is good medical
practice.
However, because this patient has sought out your opinion
and entrusted his healthcare to you, it is incumbent upon the
provider to show him respect and compassion. Listening care-
fully, examining him, offering to order additional testing, if
appropriate, and discussing alternative explanations for his
symptoms and management options that emphasize healthy
lifestyle measures and treatment with evidence-based thera-
pies, if they are available, are always appropriate and can go a
long way toward symptom resolution and good quality of life.
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M. T. McDermott
michael.mcdermott@cuanschutz.edu
... Although no studies in thyroid disease have been published, LDN has been proposed as an alternative add-on to regular hypothyroid therapy. Some patients report astounding improvements [2], and there are patients and doctors who claim that LDN may be beneficial in autoimmune thyroid disease, but definitive evidence is lacking [3]. ...
Article
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Background: Low dose naltrexone (LDN) is reported to have beneficial effects in several autoimmune diseases. The purpose of this study was to examine whether starting LDN was followed by changes in the dispensing of thyroid hormones to patients with hypothyroidism. Methods: We performed a quasi-experimental before-after study based on the Norwegian Prescription Database. Study participants were identified by using reimbursement codes for hypothyroidism. Cumulative dispensed Defined Daily Doses and the number of users of triiodothyronine (T3) and levothyroxine (LT4) 1 year before and after the first LDN prescription was compared in three groups based on LDN exposure. Results: We identified 898 patients that met the inclusion criteria. There was no association between starting LDN and the subsequent dispensing of thyroid hormones. If anything, there was a tendency towards increasing LT4 consumption with increasing LDN exposure. Conclusion: The results of this study do not support claims of efficacy of LDN in hypothyroidism.
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Background: Approximately 15% more patients taking levothyroxine (LT4) report impaired quality of life compared to controls. This could be explained by additional diagnoses independently affecting quality of life and complicating assignment of causation. This study sought to investigate the underpinnings of reduced quality of life in hypothyroid patients and to provide data for discussion at a symposium addressing hypothyroidism. Methods: An online survey for hypothyroid patients was posted on the American Thyroid Association Web site and forwarded to multiple groups. Respondents were asked to rank satisfaction with their treatment for hypothyroidism and their treating physician. They also ranked their perception regarding physician knowledge about hypothyroidism treatments, need for new treatments, and life impact of hypothyroidism on a scale of 1-10. Respondents reported the therapy they were taking, categorized as LT4, LT4 and liothyronine (LT4 + LT3), or desiccated thyroid extract (DTE). They also reported sex, age, cause of hypothyroidism, duration of treatment, additional diagnoses, and prevalence of symptoms. Results: A total of 12,146 individuals completed the survey. The overall degree of satisfaction was 5 (interquartile range [IQR] = 3-8). Among respondents without self-reported depression, stressors, or medical conditions (n = 3670), individuals taking DTE reported a higher median treatment satisfaction of 7 (IQR = 5-9) compared to other treatments. At the same time, the LT4 treatment group exhibited the lowest satisfaction of 5 (IQR = 3-7), and for the LT4 + LT3 treatment group, satisfaction was 6 (IQR = 3-8). Respondents taking DTE were also less likely to report problems with weight management, fatigue/energy levels, mood, and memory compared to those taking LT4 or LT4 + LT3. Conclusions: A subset of patients with hypothyroidism are not satisfied with their current therapy or their physicians. Higher satisfaction with both treatment and physicians is reported by those patients on DTE. While the study design does not provide a mechanistic explanation for this observation, future studies should investigate whether preference for DTE is related to triiodothyronine levels or other unidentified causes.
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Background: Hashimoto's thyroiditis (HT) is considered to be the most common autoimmune disease. It is currently accepted that genetic susceptibility, environmental factors, and immune disorders contribute to its development. With regard to nutritional factors, evidence implicates high iodine intake and deficiencies of selenium and iron with a potential relevance of vitamin D status. To elucidate the role of nutritional factors in the risk, pathogenesis, and treatment of HT, PubMed and the Cochrane Library were searched for publications on iodine, iron, selenium, and vitamin D and risk/treatment of HT. Summary: Chronic exposure to excess iodine intake induces autoimmune thyroiditis, partly because highly iodinated thyroglobulin (Tg) is more immunogenic. Recent introduction of universal salt iodization can have a similar, though transient, effect. Selenoproteins are essential to thyroid action. In particular, the glutathione peroxidases protect the thyroid by removing excessive hydrogen peroxide produced for Tg iodination. Genetic data implicate the anti-inflammatory selenoprotein S in HT risk. There is evidence from observational studies and randomized controlled trials that selenium/selenoproteins can reduce thyroid peroxidase (TPO)-antibody titers, hypothyroidism, and postpartum thyroiditis. Iron deficiency impairs thyroid metabolism. TPO, the enzyme responsible for the production of thyroid hormones, is a heme (iron-containing) enzyme which becomes active at the apical surface of thyrocytes only after binding heme. HT patients are frequently iron deficient, since autoimmune gastritis, which impairs iron absorption, is a common co-morbidity. Treatment of anemic women with impaired thyroid function with iron improves thyroid-hormone concentrations, while thyroxine and iron together are more effective in improving iron status. Lower vitamin D status has been found in HT patients than in controls, and inverse relationships of serum vitamin D with TPO/Tg antibodies have been reported. However, other data and the lack of trial evidence suggest that low vitamin D status is more likely the result of autoimmune disease processes that include vitamin D receptor dysfunction. Conclusions: Clinicians should check patients' iron (particularly in menstruating women) and vitamin D status to correct any deficiency. Adequate selenium intake is vital in areas of iodine deficiency/excess, and in regions of low selenium intake a supplement of 50-100 μg/day of selenium may be appropriate.
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Background: Hypothyroidism is often diagnosed, and subsequently treated, due to health-related quality of life (HRQL) issues. However, HRQL following treatment has never previously been assessed in longitudinal descriptive studies using validated instruments. Objective: To investigate disease-specific (ThyPRO) and generic (SF-36) HRQL, following levothyroxine therapy in patients with hypothyroidism due to autoimmune thyroiditis. Methods: This prospective cohort study was set at endocrine outpatient clinics at two Danish university hospitals. Seventy-eight consecutive patients were enrolled and completed HRQL questionnaires before, six weeks, and six months after initiation of levothyroxine therapy. Normative ThyPRO (n = 739) and SF-36 (n = 6,638) data were available for comparison and changes in HRQL following treatment were estimated and quantified. Results: Prior to treatment, all ThyPRO scales were significantly impacted (p<0.0001), compared to the general population sample. The same was observed for seven of eight SF-36 scales, the exception being Bodily Pain. Tiredness (ThyPRO) and Vitality (SF-36) were the most markedly impacted scales. After six weeks of treatment, nine of thirteen ThyPRO scales had significantly improved. ThyPRO improvements were consistent at six months, where five of eight SF-36 scales had also significantly improved, but deficits persisted for a subset of both ThyPRO and SF-36 scales. Conclusions: In this population of hypothyroid patients, HRQL was widely affected before treatment, with tiredness as the cardinal impairment according to both ThyPRO and SF-36. Many aspects of HRQL improved during the first six months of LT4 therapy, but full recovery was not obtained. Our results may help clinicians inform patients about expected clinical treatment effects.
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Context Custom-compounded bioidentical hormone therapy (HT) has become widely used in current endocrine practice, which has led to unnecessary risks with treatment. Objective This scientific statement reviews the pharmacology and physiology of popular compounded hormones and the misconceptions associated with these therapies. The hormones reviewed include: estradiol and estrogens, progesterone and progestins, testosterone, dehydroepiandrosterone, levothyroxine, and triiodothyronine. Results Overall, there is a general lack of standardization and quality control regarding how custom-compounded bioidentical hormones are produced and administered, leading to the possibility of overdosing, underdosing, or contamination. There is also recent evidence of patient harm and death associated with treatment, as seen with fungus-contaminated glucocorticoid preparations. With estrogen, progestin, and dehydroepiandrosterone treatments, the practice of baseline hormone measurements to replace “abnormal” hormone deficiencies has no basis in medical practice. Furthermore, there is no evidence that monitoring compounded HT with serial salivary or blood testing is effective, except in the case of thyroid hormone. Finally, no evidence supports the popularized notion that custom-compounded bioidentical hormones have fewer risks when compared with Food and Drug Administration (FDA)-approved hormone treatments. Conclusion The widespread availability of FDA-approved bioidentical hormones produced in monitored facilities demonstrates a high quality of safety and efficacy in trials; therefore, there is no rationale for the routine prescribing of unregulated, untested, and potentially harmful custom-compounded bioidentical HTs. Clinicians are encouraged to prescribe FDA-approved hormone products according to labeling indications and to avoid custom-compounded hormones.
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Background: Crohn's disease is a transmural, relapsing inflammatory condition afflicting the digestive tract. Opioid signalling, long known to affect secretion and motility in the gut, has been implicated in the inflammatory cascade of Crohn's disease. Low dose naltrexone, an opioid antagonist, has garnered interest as a potential therapy. Objectives: The primary objective was to evaluate the efficacy and safety of low dose naltrexone for induction of remission in Crohn's disease. Search methods: A systematic search of MEDLINE, Embase, PubMed, CENTRAL, and the Cochrane IBD Group Specialized Register was performed from inception to 15 January 2018 to identify relevant studies. Abstracts from major gastroenterology conferences including Digestive Disease Week and United European Gastroenterology Week and reference lists from retrieved articles were also screened. Selection criteria: Randomized controlled trials of low dose naltrexone (LDN) for treatment of active Crohn's disease were included. Data collection and analysis: Data were analyzed on an intention-to-treat basis using Review Manager (RevMan 5.3.5). The primary outcome was induction of clinical remission defined by a Crohn's disease activity index (CDAI) of < 150 or a pediatric Crohn's disease activity index (PCDAI) of < 10. Secondary outcomes included clinical response (70- or 100-point decrease in CDAI from baseline), endoscopic remission or response, quality of life, and adverse events as defined by the included studies. Risk ratios (RR) and 95% confidence intervals (CI) were calculated for dichotomous outcomes. The methodological quality of included studies was evaluated using the Cochrane risk of bias tool. The overall quality of the evidence supporting the primary outcome and selected secondary outcomes was assessed using the GRADE criteria. Main results: Two studies were identified (46 participants). One study assessed the efficacy and safety of 12 weeks of LDN (4.5 mg/day) treatment compared to placebo in adult patients (N = 34). The other study assessed eight weeks of LDN (0.1 mg/kg, maximum 4.5 mg/day) treatment compared to placebo in pediatric patients (N = 12). The primary purpose of the pediatric study was to assess safety and tolerability. Both studies were rated as having a low risk of bias. The study in adult patients reported that 30% (5/18) of LDN treated patients achieved clinical remission at 12 weeks compared to 18% (3/16) of placebo patients, a difference that was not statistically significant (RR 1.48, 95% CI 0.42 to 5.24). The study in children reported that 25% of LDN treated patients achieved clinical remission (PCDAI < 10) compared to none of the patients in the placebo group, although it was unclear if this result was for the randomized placebo-controlled trial or for the open label extension study. In the adult study 70-point clinical response rates were significantly higher in those treated with LDN than placebo. Eighty-three per cent (15/18) of LDN patients had a 70-point clinical response at week 12 compared to 38% (6/16) of placebo patients (RR 2.22, 95% CI 1.14 to 4.32). The effect of LDN on the proportion of adult patients who achieved a 100-point clinical response was uncertain. Sixty-one per cent (11/18) of LDN patients achieved a 100-point clinical response compared to 31% (5/16) of placebo patients (RR 1.96, 95% CI 0.87 to 4.42). The proportion of patients who achieved endoscopic response (CDEIS decline > 5 from baseline) was significantly higher in the LDN group compared to placebo. Seventy-two per cent (13/18) of LDN patients achieved an endoscopic response compared to 25% (4/16) of placebo patients (RR 2.89; 95% CI 1.18 to 7.08). However, there was no statistically significant difference in the proportion of patients who achieved endoscopic remission. Endoscopic remission (CDEIS < 3) was achieved in 22% (4/18) of the LDN group compared to 0% (0/16) of the placebo group (RR 8.05; 95% CI 0.47 to 138.87). Pooled data from both studies show no statistically significant differences in withdrawals due to adverse events or specific adverse events including sleep disturbance, unusual dreams, headache, decreased appetite, nausea and fatigue. No serious adverse events were reported in either study. GRADE analyses rated the overall quality of the evidence for the primary and secondary outcomes (i.e. clinical remission, clinical response, endoscopic response, and adverse events) as low due to serious imprecision (sparse data). Authors' conclusions: Currently, there is insufficient evidence to allow any firm conclusions regarding the efficacy and safety of LDN used to treat patients with active Crohn's disease. Data from one small study suggests that LDN may provide a benefit in terms of clinical and endoscopic response in adult patients with active Crohn's disease. Data from two small studies suggest that LDN does not increase the rate of specific adverse events relative to placebo. However, these results need to be interpreted with caution as they are based on very small numbers of patients and the overall quality of the evidence was rated as low due to serious imprecision. Further randomized controlled trials are required to assess the efficacy and safety of LDN therapy in active Crohn's disease in both adults and children.
Article
Hypothyroidism is a common condition of thyroid hormone deficiency, which is readily diagnosed and managed but potentially fatal in severe cases if untreated. The definition of hypothyroidism is based on statistical reference ranges of the relevant biochemical parameters and is increasingly a matter of debate. Clinical manifestations of hypothyroidism range from life threatening to no signs or symptoms. The most common symptoms in adults are fatigue, lethargy, cold intolerance, weight gain, constipation, change in voice, and dry skin, but clinical presentation can differ with age and sex, among other factors. The standard treatment is thyroid hormone replacement therapy with levothyroxine. However, a substantial proportion of patients who reach biochemical treatment targets have persistent complaints. In this Seminar, we discuss the epidemiology, causes, and symptoms of hypothyroidism; summarise evidence on diagnosis, long-term risk, treatment, and management; and highlight future directions for research.
Article
Background: Selenium supplementation may decrease circulating thyroid autoantibodies in patients with chronic autoimmune thyroiditis (AIT), but the available trials are heterogenous. This study expands and critically reappraises the knowledge on this topic. Methods: A literature search identified 3366 records. Controlled trials in adults (≥18 years of age) with AIT, comparing selenium with or without levothyroxine (LT4), versus placebo and/or LT4, were eligible. Assessed outcomes were serum thyroid peroxidase (TPOAb) and thyroglobulin (TgAb) autoantibody levels, and immunomodulatory effects. After screening and full-text assessment, 16 controlled trials were included in the systematic review. Random-effects meta-analyses in weighted mean difference (WMD) were performed for 3, 6, and 12 months of supplementation in two different populations: one receiving LT4 therapy and one newly diagnosed and LT4-untreated. Heterogeneity was estimated using I2, and quality of evidence was assessed per outcome, using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guidelines. Results: In LT4-treated populations, the selenium group had significantly lower TPOAb levels after three months (seven studies: WMD = -271 [confidence interval (CI) -366 to -175]; p < 0.0001; I2 = 45.4%), which was consistent at six months (three studies) and 12 months (one study). TgAb decreased at 12 months, but not at three or six months. In LT4-untreated populations, the selenium group showed a decrease in TPOAb levels after three months (three studies: WMD = -512 [CI -626 to -398]; p < 0.0001, I2 = 0.0%), but not after 6 or 12 months. TgAb decreased at 3 months, but not at 6 or 12 months. Quality of evidence was generally assessed as low. Study participants receiving selenium had a significantly higher risk than controls of reporting adverse effects (p = 0.036). Conclusions: Selenium supplementation reduced serum TPOAb levels after 3, 6, and 12 months in an LT4-treated AIT population, and after three months in an untreated AIT population. Whether these effects correlate with clinically relevant measures remains to be demonstrated.
Article
Introduction: Hypothyroidism requires life-long thyroid hormone replacement therapy in most patients. Oral levothyroxine (L-T4) is an established safe and effective treatment for hypothyroidism but some issues remain unsettled. Methods: The Italian Association of Clinical Endocrinologists (AME) appointed a panel of experts to provide an updated statement for appropriate use of thyroid hormone formulations for replacement of hypothyroidism. The AACE protocol for standardized production of clinical practice guidelines was followed. Results: Levothyroxine is the first choice in replacement therapy. TSH should be maintained between 1.0 and 3.0 mIU/L in young subjects and at the upper normal limit in elderly or fragile patients. Achievement of biochemical targets, patient's well-being and adherence to treatment should be addressed. In patients with unstable serum TSH a search for interfering factors and patient compliance is warranted. Liquid or gel formulations may be considered in subjects with hampered L-T4 absorption or who are not adherent to breakfast waiting time after L-T4 administration. Replacement therapy with L-T4 and L-T3 combination is generally not recommended. A trial may be considered in patients with normal values of serum TSH who continue to complain of symptoms of hypothyroidism only after coexistent non-thyroid problems have been excluded or optimally managed. L-T3 should be administered in small (L-T4/L-T3 ratio: 10-20/1) divided daily doses. Combined therapy should be avoided in elderly patients or those with cardiac risk factors and in pregnancy. Conclusions: L-T4 therapy should be aimed at resolution of symptoms of hypothyroidism, normalization of serum TSH and improvement of quality of life. In selected cases, for achieving adherence to treatment or patient's well-being, the use of liquid L-T4 formulations or of combined LT-4/L-T3 treatment may be considered.
Article
Background: There has been recent debate within the thyroid field regarding whether current upper limits of the TSH reference range should be lowered. This debate can be better informed by investigation of whether variations in thyroid function within the reference range have clinical effects. One important target organ for thyroid hormone is the brain, but little is known about variations in neurocognitive measures within the reference range for thyroid function. Methods: This was a cross-sectional study of 132 otherwise healthy hypothyroid subjects receiving chronic replacement therapy with levothyroxine (L-T4) who had TSH levels across the full span of the laboratory reference range (0.34-5.6 mU/L). Subjects underwent detailed tests of health status, mood, and cognitive function, with an emphasis on memory and executive functions. Results: Subjects with low-normal (≤2.5 mU/L) and high-normal (>2.5 mU/L) TSH levels did not differ on most tests of health status, mood, or cognitive function, and there were no correlations between TSH, free T4, or free T3 levels and most outcomes. There was, however, a suggestion that thyroid function affected performance on the Iowa Gambling Task, which mimics real life decision-making. Subjects with low-normal TSH levels made more advantageous decisions than those with high-normal TSH level. Conclusions: Variations in thyroid function within the laboratory reference range do not appear to have clinically relevant effects on health status, mood, or memory in L-T4 treated subjects. However, decision making, which encompasses many executive functions, may be affected. Unless further studies strengthen this finding, these data do not support narrowing the TSH reference range.
Article
Background: Several screening studies have indicated an increased prevalence of celiac disease (CD) among individuals with autoimmune thyroid disease (ATD) but estimates have varied substantially. We aim to examine the prevalence of CD in patients with ATD. Methods: Data source: Systematic review of articles published in PubMed Medline or EMBASE until September 2015. Non-English papers with English-language abstracts were also included, as were research abstracts without full text available when relevant data were included in the abstract. Search terms included "celiac disease" combined with "hypothyroidism" or "hyperthyroidism" or "thyroid disease". Data synthesis: Fixed-effects inverse variance-weighted models were used. Meta-regression was used to examine heterogeneity in subgroups. Results: A pooled analysis, based on 6,024 ATD patients, found a prevalence of biopsy-confirmed CD of 1.6% (95% CI=1.3-1.9%). Heterogeneity was large (I2 = 70.7%). The prevalence was higher in children with ATD (6.2%; 95%CI=4.0-8.4%), than in adults (2.7%) or in studies examining both adults and children (1.0%). CD was also more prevalent in hyperthyroidism (2.6%; 95%CI=0.7-4.4%) than in hypothyroidism (1.4%; 95%CI=1.0-1.9%) Conclusions: About 1 in 62 patients with ATD have biopsy-verified CD. We argue that patients with ATD should be screened for CD given this increased prevalence.