case study for hypothyroidism

Case report
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Published: 03 March 2021

Severe primary hypothyroidism in an apparently asymptomatic 19-year-old woman: a case report

Rania Dannan ORCID: orcid.org/0000-0003-2456-572X 1 ,
Sulaiman Hajji 2 &
Khaled Aljenaee 2

Journal of Medical Case Reports volume 15 , Article number: 108 ( 2021 ) Cite this article

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Hypothyroidism is diagnosed on the basis of laboratory tests because of the lack of specificity of the typical clinical manifestations. There is conflicting evidence on screening for hypothyroidism.

Case presentation

We report a case of an apparently healthy 19-year-old Kuwaiti woman referred to our clinic with an incidental finding of extremely high thyroid-stimulating hormone (TSH), tested at the patient’s insistence as she had a strong family history of hypothyroidism. Despite no stated complaints, the patient presented typical symptoms and signs of hypothyroidism on evaluation. Thyroid function testing was repeated by using different assays, with similar results; ultrasound imaging of the thyroid showed a typical picture of thyroiditis. Treatment with levothyroxine alleviated symptoms and the patient later became biochemically euthyroid on treatment.

There is controversy regarding screening asymptomatic individuals for hypothyroidism; therefore, it is important to maintain a high index of suspicion when presented with mild signs and symptoms of hypothyroidism especially with certain ethnic groups, as they may be free of the classical symptoms of disease.

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We report a case of an apparently healthy 19-year-old Kuwaiti woman referred to our clinic with an incidental finding of extremely high thyroid-stimulating hormone (TSH), tested at the patient’s insistence as she had a strong family history of hypothyroidism. Despite no stated complaints, the patient presented typical symptoms and signs of hypothyroidism on evaluation. This raised the question of who should be screened for hypothyroidism. Screening for hypothyroidism refers to the measurement of thyroid function in asymptomatic populations who are at high risk of having thyroid disease, or patients who have mild, nonspecific symptoms, such as tiredness. Here, we summarize the conflicting evidence regarding screening for hypothyroidism, and emphasize the importance of maintaining a high index of suspicion for hypothyroidism even when presented with mild signs and symptoms.

A previously healthy, seemingly asymptomatic 19-year-old woman was referred to us by her general practitioner because of an extremely high TSH level of 1099 mlU/L, detected on random testing at the patient’s request because of her family’s history of autoimmune thyroid disease. The patient reported fatigue with excessive sleepiness lasting more than 14 hours per day, depressed mood, inexplicable weight gain, decreased appetite, hair loss, constipation, and menorrhagia, all indicative of a hypothyroid state. There was no history of chronic medical conditions or regular medication use, although the patient reported the use of over-the-counter paracetamol for headaches and dysmenorrhea. Physical examination showed normal vital parameters (weight 72 kg; height 160 cm; blood pressure 124/80 mmHg; pulse 56 bpm) and classical signs of hypothyroidism: periorbital puffiness and loss of outer third of her eyebrows and dry skin that was not coarse. Neck examination showed no scars and upward thyroid movement with deglutition, a smooth palpable goiter without nodules, and no palpable lymph nodes. Lower limb tone and power were intact despite slow relaxation of ankle reflexes.

Laboratory findings from before and after treatment initiation are presented in Table 1 . At the baseline in April 2019, the patient’s TSH was 1099 mlU/L (Roche assay) and free thyroxin (T4) was 0.7 pmol/L; the TSH level was retested in a Siemens assay, with a similar result (TSH 991 mlU/L). A subsequent anti-thyroid peroxidase (anti-TPO) antibodies test showed high levels (42 lU/mL). Complete blood count, renal function, liver enzymes, and lipid profile were tested; the hemoglobin level was 10 g/dL, with a microcytic hypochromic picture, most likely due to iron-deficiency anemia because the ferritin level was 6 ng/mL. The lipid profile showed dyslipidemia (total cholesterol 6.50 mmol/L, low-density lipoprotein 4.09 mmol/L, triglycerides 1.56 mmol/L). Renal function was normal. Ultrasound imaging of the thyroid showed diffuse cystic changes replacing much of the normal thyroid tissue with a “Swiss cheese” appearance (Fig. 1 ). The patient was started on levothyroxine in April 2019, and subsequent TSH and free T4 tested in December 2019 were 2.320 mIU/L and 17.5 pmol/L, respectively; symptom resolution was noted after a few weeks on levothyroxine (100 µg) supplementation, and the patient became biochemically euthyroid after 6 months.

Ultrasound of the thyroid showing diffuse cystic changes replacing much of the normal thyroid tissue with a “Swiss cheese” appearance

Hypothyroidism is a disorder of thyroid hormone deficiency that affects 0.2–5.3% of Europeans and 0.3–3.7% of Americans [ 1 ]. Clinical manifestations vary by patient age as well as the duration and severity of thyroid hormone deficiency. Therefore, a definite diagnosis is primarily made on the basis of biochemical testing [ 2 ]. There is an ongoing debate about the optimal normal ranges of TSH and T4. A TSH level higher than 4.2–4.5 mlU/L and a free T4 less than 10 pmol/L confirms hypothyroidism [ 3 ]. Therapy aims to supplement thyroxine to alleviate signs and symptoms of hypothyroidism, and to normalize serum thyrotropin without overtreatment [ 2 ].

In younger populations, typical symptoms of hypothyroidism are usually present and can facilitate diagnosis, whereas a diagnosis in the elderly is difficult because of seemingly asymptomatic presentation and thus necessitates a high index of suspicion in clinicians to predict hypothyroidism [ 2 ]. Moreover, symptoms and signs of hypothyroidism vary from person to person depending on age, gender, and origin [ 4 , 5 , 6 ]. Table 2 presents the commonest symptoms and signs of patients with hypothyroidism in Saudi Arabia, Oman, and Australia; in all three countries, tiredness, which was documented in 56%, 25%, and 84% of patients, respectively, was the most common presenting symptom [ 4 , 5 , 6 ]. Our patient presented with symptom unawareness despite an extremely high TSH level incidentally detected on biochemical testing, but had typical symptoms of hypothyroidism on clinical evaluation. This raises the question of hypothyroidism screening: who should be screened? And when should they be screened?

Screening for hypothyroidism refers to the measurement of thyroid function in asymptomatic populations who are at high risk of having thyroid disease, or patients who have mild, nonspecific symptoms, such as tiredness. Screening is carried out by measuring serum TSH levels [ 6 ], but there are conflicting recommendations on screening. The American Thyroid Association (ATA) recommends screening for hypothyroidism in all adults 35 years and older every 5 years and in certain high-risk individuals [ 6 ]. However, the US Preventative Task Force (USPTF) found insufficient evidence for screening of thyroid dysfunction and emphasizes the uncertainties surrounding potential clinical benefits [ 7 ]. Similarly, the Royal College of Physicians in London found no justification for screening for hypothyroidism even in the elderly and individuals with a strong family history of thyroid disease [ 8 ]. Exceptions include screening of newborn babies for congenital hypothyroidism and patients with previous thyroid surgery or radioactive iodine treatment as well as patients receiving long-term lithium or amiodarone therapy [ 8 ]. There are no strong recommendations for screening of the non-pregnant asymptomatic population for hypothyroidism. Therefore, many asymptomatic patients with overt hypothyroidism could remain undiagnosed and untreated.

Our 19-year-old patient presented to the clinic with no complaints, but further assessment revealed typical signs and symptoms of hypothyroidism and a TSH level higher than 1000 mlU/L. All symptomatic patients should be evaluated for hypothyroidism, but screening of asymptomatic individuals is controversial and not recommended by certain organizations. This report is presented to recommend a lowering of the screening threshold for hypothyroidism and to motivate physicians to boost their index of suspicion to diagnose the disease, especially with certain ethnic groups, as they may be free of the classical symptoms so severe hypothyroidism can be missed.

Availability of data and materials

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

Abbreviations

Anti-thyroid peroxidase

American Thyroid Association

High-density lipoprotein

Low-density lipoprotein

Mean corpuscular volume

Thyroid-stimulating hormone

The United States Preventive Services Task Force

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Kuwaiti Board of Internal Medicine, Ahmadi, Kuwait

Rania Dannan

Al-Adan Hospital, Kuwait City, Kuwait

Sulaiman Hajji & Khaled Aljenaee

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RD was responsible for the literature review and writing of the article and is the corresponding author; SH edited the manuscript and gained consent from the patient; KJ supplied most of the patient information and images. All authors read and approved the final manuscript.

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Correspondence to Rania Dannan .

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Dannan, R., Hajji, S. & Aljenaee, K. Severe primary hypothyroidism in an apparently asymptomatic 19-year-old woman: a case report. J Med Case Reports 15 , 108 (2021). https://doi.org/10.1186/s13256-021-02677-w

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DOI : https://doi.org/10.1186/s13256-021-02677-w

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23 years of misdiagnosed central hypothyroidism with a normal TSH: Case study

In this post, I’ll comment on the case study of a woman who suffered for 23 years with undiagnosed central hypothyroidism between 1992 and 2015 (age 34 to age 57) because her TSH was repeatedly in normal range.

She developed impaired kidney function, muscle damage, and pericardial effusion.

Who saved the day? A biochemist working at the laboratory.

The authors of the 2017 article — Glyn, Harris, and Allen — reported that:

“the clinical biochemist reviewed the patient’s results and elected to add on an fT4 to her thyroid function tests.”

Upon finally testing both Free T3 (FT3) and Free T4 (FT4) in 2015, these were her laboratory results:

TSH: 1.55 mU/L (0.3 – 5.5)
FT4: <0.3* pmol/L (12 – 22) *below the assay’s limit of detection.
FT3: 0.4 pmol/L (3.1 – 6.8)

She was finally referred to specialists in endocrinology.

This study and its excellent policy suggestions are not yet informing policies at laboratories.

The study is available in full text for public view here:

Glyn, T., Harris, B., & Allen, K. (2017). Lessons learnt from a case of missed central hypothyroidism. Endocrinology, Diabetes & Metabolism Case Reports , 2017 (1). https://doi.org/10.1530/EDM-17-0112

In this review, I’m going to let the patient’s voice speak first, and then I’ll report on what the doctors reported in their article while sharing further research and resources.

First, I provide background information:

The misdiagnosed patient’s statement

The authors’ learning points, what is central hypothyroidism (ceh), a rare condition, or rarely diagnosed, case presentation.

Then, I show that many clues could have pointed to her hypothyroid state.

Hypothyroid kidneys

Hypothyroid joints, hypothyroid muscles, hypothyroid eyelids: ptosis.

Hypothyroid heart: pericardial effusion

Hypothyroid cholesterol levels

Other hormones: LH, FSH, and cortisol

Medications that can cause transient CeH

Family history of autoimmune diseases.

I’ll conclude with suggestions and tips:

A possible cause: Autoimmune hypophysitis without MRI signs

Diagnostic tools for discerning ceh in thyroid lab results.

Clinical judgment is key. Laboratory reference ranges do not provide TSH interpretation guides to physicians or patients, so this article includes simple and free tools for interpreting TSH, FT3 and FT4 relationships to spot central hypothyroidism.

One cannot judge whether the TSH is “inappropriately normal” due to hypothalamic or pituitary compromise without comparing the TSH to normal TSH-FT4 and TSH-FT3 relationships in health.

The Free T4 and Free T3 hormone results hold TSH accountable, just like journalists and historians hold our political leaders accountable.

Thyroid hormones can verify whether TSH is telling the truth. They have the physiological authority to question the testimony of an isolated TSH result.

It is rare to hear from the patient themselves in a scientific case study article. This one included a few paragraphs from the patient herself.

“I feel I have been the victim of too many specialists working in isolation and seeking over-complicated answers and diagnoses – with of course the best of intentions. I feel extremely frustrated that time and again specialists and GPs overlooked the obvious explanation and did not carry out fT3 and fT4 blood tests . I feel the quality of my life has been severely impacted – so many investigations at great expense and with potentially negative impact (X-rays, etc.), multiple chronic health conditions and persistent low mood. I feel my life could have been very different if I had been correctly diagnosed at the outset! I am now on 150 µg Levothyroxine. I have more energy, my face shape is changing, and ptosis [drooping eyelids] is not an issue. I am always extremely warm and have found managing my temperature difficult. But I do feel in better health. On my first visit to the Endocrinology Department [in 2015], I had to pause every few minutes whilst walking. I used to fall asleep in the chair all the time, had lots of back and muscle pains and was very constipated. All these things are beginning to change. My life would have been different if my underactive thyroid had been diagnosed in a timely manner. I will forever be grateful to the clinical biochemist who spotted my abnormal results.”

Now hear the takeaway points from the physicians, with strong policy advice to protect patients.

• “Isolated central hypothyroidism is very rare, but should be considered irrespective of previous thyroid disorders. • If clinicians have a strong suspicion that a patient may have hypothyroidism despite normal TSH, they should ensure they measure fT3 and fT4. • Laboratories that do not perform fT3 and fT4 routinely should review advice sent to requesting clinicians to include a statement explaining that a normal TSH excludes primary but not secondary hypothyroidism . • Thyroid function tests should be performed routinely in patients presenting with renal impairment or a raised CK [creatine kinase].

In the literature, central hypothyroidism is often abbreviated CeH. Glyn and colleagues’ 2017 article says that CeH is

“characterised by insufficient thyroid gland stimulation by TSH , resulting from hypothalamic or pituitary dysfunction.”

This is an excellent simple definition and ought to be applauded.

One of the problems with diagnosis of CeH is that its definition sometimes leads people to imagine it must always occur in isolation from diseases of the thyroid gland .

Central, pituitary, hypothalamic or “secondary” hypothyroidism has been defined in opposition to “primary” thyroid disease affecting the thyroid gland:

“a hypothyroid state caused by an insufficient stimulation by thyrotropin (TSH) of an otherwise normal thyroid gland .” (Persani, Cangiano & Bonomi, 2019)

Here’s the problem: She was a patient with a history of Graves’ hyperthyroidism who had had a partial thyroidectomy. Her thyroid gland was certainly not “otherwise normal.”

Definition of CeH by exclusion can backfire when physicians engage in analyzing signs and symptoms. It can mistakenly exclude patients like this woman who have had both a primary and a secondary (central) thyroid disorder.

It is certainly easier to spot CeH in a patient with an “otherwise normal” thyroid gland, and more difficult to spot it when other thyroid disorders can cloud the diagnostic parameters.

Glyn and colleagues have usefully pointed out that primary and central thyroid diseases can overlap in the same patient:

“Isolated central hypothyroidism is very rare, but should be considered irrespective of previous thyroid disorders .”

They should have said “previous or concurrent thyroid disorders.”

This woman’s Graves’ hyperthyroidism was resolved, but it’s possible that her diagnosed Graves’ autoimmunity and her hemithyroidectomy that may have clouded the CeH diagnosis.

This is such an important point that I’ve written a separate post on this very topic for patients who acquire CeH during treatment for primary thyroid failure : “ Screening for central hypothyroidism during thyroid therapy .” Without a proper CeH diagnosis during therapy, doctors may mistakenly think the patient is becoming hyperthyroid due to a lowering TSH. They may underdose the patient and permit either FT4 or FT3 to fall low or low-normal for the sake of achieving TSH-centric policy targets, at the expense of a patient’s health.

It is unfortunate that Glyn and colleagues’ 2017 article begins with a statement about the incidence rate for CeH that was very outdated:

“Central hypothyroidisim is rare with an incidence of 1 in 80 000 –120 000 individuals.” (Glyn, Harris & Allen, 2017, citing Lania, Persani & Beck-Peccoz, 2008)

Two of the coauthors of the 2008 article they cited offered a very different statistic in 2017, showing the rate had risen:

“The global prevalence of central hypothyroidism ranges from 1 in 20,000 to 1 in 80,000 individuals in the general population and it is a rare cause of hypothyroidism ( 1 in 1,000 patients with hypothyroidism ).” (Beck-Peccoz et al, 2017, “Central hypothyroidism—A neglected thyroid disorder.” )

The inaccuracy and thin evidence base of such estimates is a major obstacle to diagnosis. Back in 2001, the supposed rarity of the CeH diagnosis was cited as a reason to push back against a call to test Free T4:

“what other disease with an incidence of <50 cases per million population do we screen for?” (Price & Weetman, 2001)

In 2019, Persani and colleagues suspected CeH was not as rare as statistics have led scientists to believe:

“The addition of acquired forms of CeH … raises the suspicion that the prevalence of CeH in the general population is underestimated.” (Persani et al, 2019)

Underdiagnosis of CeH can be a result of medical misunderstanding due to:

too narrow an understanding of its etiology (causes),
too narrow a view of its clinical manifestations, both in terms of severity (mild to severe) and diversity (effects on various organs and tissues), and
too narrow a view of the biochemical abnormalities of the TSH-FT4 (and FT3) relationship necessary for diagnosis, especially since it may manifest while a person is being treated with thyroid hormones.

The list of “acquired” causes of CeH has been expanded in recent years:

The laboratory values of FT4 and TSH used for initial screening have now been expanded to include not just a low TSH with low FT4, but

“low, or even low–normal, free T4 with inappropriately low/normal TSH” (Persani et al, 2019)

The key to diagnosis is the “inappropriateness” of the FT4 to the TSH, namely, the TSH not rising high enough to signify a low or low normal FT4.

Although Persani and others claim that the clinical manifestations of CeH are usually “mild,” in fact, they may range from mild to severe, depending on both FT4 and FT3 levels.

The severity of clinical signs and symptoms depends on where the most active thyroid hormone Free T3 falls, not just the FT4 level. Circulating levels of Free T3 are utilized by all tissues, including the brain, to top up variable rates of T4-T3 conversion in tissues that express different thyroid deiodinases (D1, D2, or D3) (Bianco et al, 2019). Cardiovascular, liver and kidney function in particular are highly sensitive to circulating T3 levels, and these disorders have higher mortality and morbidity rates when T3 is low (Anderson et al, 2018)
Clinical signs and symptoms may also become complicated by other health disorders acquired while being left in an untreated, hypothyroid state for months, years, or — as in this woman’s case — decades. Chronic illness and inflammation can lower the T4-T3 conversion rate by upregulating D3 enzyme activity in any affected tissue, even in tissues where D3 is not normally expressed in health (Bianco et al, 2019).

As a result of widespread medical ignorance and laboratory testing policies, CeH is likely underdiagnosed, and we do not know truly how “rare” or “common” it is.

Giving incidence rates can be very misleading when the reality is that central hypothyroidism is “a neglected thyroid disorder” (Beck-Peccoz et al, 2017).

Glyn and colleagues describe the woman’s thyroid history as beginning at age 26 with the diagnosis of Graves’ hyperthyroidism after irregular menstrual cycles and “a number of miscarriages.” (Why not quantify the number of miscarriages?)

She went on carbimazole medication for Graves’ disease and “had a successful pregnancy in 1990.”

She had a subtotal thyroidectomy.

Then, she had a second successful pregnancy in 1992.

Then her CeH started to manifest itself in hypothyroid symptoms:

“Over the next few years, the patient complained of increasing tiredness, aching muscles and joints, with evidence of a proximal myopathy, predominantly affecting her upper arms. Her TSH was checked on multiple occasions and was consistently 2.0–2.5 IU/L. “

The period in which her TSH fell in the range of 2.0–2.5 is not listed in her laboratory results table, but it was likely between 1993-2008, labeled “euthyroid” in the table:

However, a TSH value in isolation is not a “euthyroid” value. It could be a statistically “normal” reference value.

The word “euthyroid” in the TSH column is misleading in light of our current scientific knowledge. It has been a traditional medical belief that whenever TSH is normal, thyroid hormones must also be acceptable, and the entire body must be in an “euthyroid” state.

She was not euthyroid at the time, since her hypothyroidism was manifesting itself in other organ systems.

Given the surprisingly discordant TSH, FT4 and FT3 results in October 2015, it’s important that they double checked:

“A repeat sample was sent and yielded identical results. There was no evidence of interference with the assay.” (Glyn et al, 2017)

Here is a summary of the other laboratory findings collected shortly after October 2015, when she was finally discovered to have laboratory signs of CeH and was referred to endocrinology.

I’ve added some reference range information not provided from Glyn and colleagues, to aid interpretation, and annotated the sources of the information.

Many clues could have pointed to her hypothyroid state.

Why did it take until 2015 for a clinical biochemist to order the FT3 and FT4? Some of the following health conditions, symptoms, and biochemical were present years before, and some additional tests performed only after October 2015 could have been ordered earlier if there had been due clinical suspicion of central hypothyroidism.

As her case continued to evolve after the birth of her second child in 1993, “By 2000 … she developed impaired renal [kidney] function.” In fact, the case study authors write

“she was referred to the renal department in light of progressive renal impairment . No clear cause for this was found.”

“No clear cause for this was found” — not only because the physicians mistakenly believed her normal TSH ruled out hypothyroidism, but perhaps also because of a lack of research at the time, or poorly disseminated research, on the strong correlation between hypothyroidism and kidney function.

In 2012, an article on thyroid disorders and kidney disease stated clearly that

“Hypothyroidism is associated with reduced GFR”. (Basu & Mohaptra, 2012)

And more recently, in 2018, it was found that neither TSH nor FT4 was correlated with eGFR (Estimated Glomerular Filtration Rate) as much as FT3:

“In multivariable models including TSH, FT3 and FT4 together, eGFR [measurements combined with creatinine and cystatin C] and CrCl [creatinine clearance] were all positively related to FT3 (P≤0.001), translating into a 2.61 to 2.83mL/min/1.73m 2 increase in eGFR measures and a 3.92mL/min increase in CrCl per 1pmol/L increment in FT3 .” (Anderson et al, 2018)

This emphasizes that testing Free T3, not just TSH and FT4, can be useful when investigating kidney health status.

This patient was also diagnosed with “Erosive osteoarthritis” by rheumatology specialists. It is “a progressive disease affecting the interphalangeal joints of the hand” (Ulusoy et al, 2011).

Apparently the rheumatologists also missed the differential diagnosis, despite literature pointing to hypothyroidism as a cause.

“Hypothyroidism has been associated with osteoarthritis (OA) and inflammatory forms of arthritis and with several well defined connective tissue diseases, which in turn can cause arthritis. (Tagoe et al, 2012)

Way back in 1970, Bland and Frymoyer published an article demonstrating the rheumatological manifestations of hypothyroidism. Their abstract reads as follows:

“In 74 patients, referred between 1954 and 1967 to our Rheumatology Unit because of arthritis, we suspected hypothyroidism on clinical grounds. Laboratory confirmation was obtained in 38; • five had no objective signs of arthritis, and • 22 were excluded as having other causes for rheumatic symptoms and signs. • The remaining 11 patients had a variety of rheumatic syndromes as their principal manifestation of myxedema. Diagnoses with which myxedema joint disease was confused were • serum-negative rheumatoid arthritis, • intervertebral disk disease, • osteoarthritis , • fibrositis, • psychoneurosis and • nonspecific “arthritis” or rheumatism. All patients recovered completely on thyroid-replacement therapy .” (Bland & Frymoyer, 1970)

It is sad that physicians were willing to consider “psychoneurosis” as a cause of arthritis when they failed to connect the dots between joint pain and thyroid hormones.

The misdiagnosed woman’s muscle pain prompted a test for creatine kinase (CK) , which rose “above 1000” — their Figure 1 graph shows CK at 1700 IU/L (reference 25 – 200 IU/L).

Let’s look at how abnormal it is to have a CK above 1000 (which is as 10 3 on the x-axis) (Beyer et al, 1998).

These graphs, compared with the patient’s CK result and hormone levels, reveals how high the TSH ought to have been, if she had had the ability to secrete TSH, given her near-undetectable levels of FT3 and FT4.

Although Beyer found high TSH is statistically associated with high CK, there is no direct causal connection between high TSH and CK at the molecular level. As one can see in this patient’s case, a high TSH was not necessary to elevate CK, only low thyroid hormones were necessary. This is case is one of many examples of a statistical association between TSH and tissue hypothyroidism without a direct cause-effect relationship.

Instead, in hypothyroidism, the lack of T3 and active 3,5-T2 hormone seems to be implicated in creatine kinase-related genes in muscle mitochondria (Silvestri et al, 2018).

Mitochondria are highly implicated in hypothyroid elevation of creatine kinase, and yet in this misdiagnosed patient, Glyn and coauthors reported that:

“The aetiology was thought more likely to be autoimmune , rather than mitochondrial in origin, and further extensive tests were undertaken.”

NOTE: In Beyer’s graphs above, the paradox of low Free T3 in this graph sometimes being associated with normal CK values can be explained. The patient’s concurrent Free T4 matters to the health of muscle tissue. Deiodinase type 2 converts T4 to T3 within muscle cells while circulating FT3 entering cells supplement the T3 levels generated in cells. The inclusion of “subclinical hypothyroid” patients with mid- to high-normal levels of FT4 caused confusion. Another study of only overtly hypothyroid patients found Total T3 (Free T3 was not measured) inversely associated with CK levels, compared with TSH and Total T4 (Ranka & Mathur, 2003)

This patient developed bilateral ptosis (drooping eyelids) at the time her CK levels first rose above 1000. This is not just a coincidence.

In hypothyroidism involving a normal FT3 level, ptosis is likely to be rare. But in severe hypothyroidism, ptosis occurs.

Another case study (Jain et al, 2016) found ptosis associated with severe hypothyroidism, elevated CK, very low FT3 and FT4, TSH over 100, and many other symptoms of hypothyroidism.

In Jain’s case study, myasthenia gravis, an autoimmune disease affecting neuromuscular function, was ruled out.

Myasthenia is more strongly associated with Graves’ disease than with Hashimoto’s thyroiditis (Amin et al, 2020), and the patient in the case study had been treated for Graves’ disease.

Glyn and colleagues do not mention the misdiagnosed woman being tested for myasthenia gravis, but it is possible that during the years of investigation it was covered, since it is one of the known causes of ptosis, and since she was investigated for autoimmune diseases in general (discussed in the next section).

Interestingly, myasthenia tends to worsen during treatment for Graves’ disease, not during the hyperthyroid phase:

“ See-saw relationship between these two pathologies, MG [myasthenia gravis] and GD [Graves’ disease], has been reported in the past by some authors. Treating one pathology may worsen the other which will make it a challenge to treat both pathologies. Myasthenia gravis gets worse by the use of antithyroid drugs through immunomodulatory effects. Beta-blockers and corticosteroids cause a worsening of weakness in myasthenia patients.]” (Amin et al, 2020)

Importantly, Amin and colleagues’ review of the overlap between myasthenia and thyroid diseases talk about the risk of misdiagnosis of either disease when their similarities and potential coexistence is not understood:

“ Similarities in clinical features among both pathologies have resulted in not detecting the other autoimmune disease , which then appears as an unusual outcome, disease severity, and treatment failure. (Amin et al, 2020)

Hypothyroid heart: Pericardial effusion

The climax of the misdiagnosed woman’s suffering came in 2015, shortly before the clinical biochemist decided to test FT4:

“During work-up for a further muscle biopsy, she was found to have a significant (2 cm) pericardial effusion. She was referred to Cardiology, who felt that the pericardial effusion was chronic and not compromising, but the aetiology [cause] was unclear . A cardiac MRI was arranged to better characterise it.”

As explained by Cedars-Sinai hospital , pericardial effusion is “the buildup of extra fluid in the space around the heart. If too much fluid builds up, it can put pressure on the heart. This can prevent it from pumping normally.”

The size of the pericardial effusion can be graded by ultrasound. The patient’s 2 cm effusion was “large”:

“Generally, • small effusions cause an echo-free space in systole and diastole of less than 10 mm [1 cm]; • moderate effusions, 10-20 mm [1-2 cm]; and • large effusions, greater than 20 mm [2cm]. The size of pericardial effusion is a powerful predictor of overall prognosis.” Singh (2020)

The Cedars-Sinai website overview lists many causes of pericardial effusion, but hypothyroidism is not in the list. However, “kidney failure” is listed.

Yet the cardiologists said “the aetiology [cause] was unclear.”

Another case study of a patient with hypothyroidism and pericardial effusion discussed the connection:

“The occurrence of pericardial effusion in hypothyroidism appears to be dependent on the severity of the disease. Pericardial effusion (PE) may be a frequent manifestation in myxedema, an advanced severe stage, as previously found, but is rarely associated with mild hypothyroidism. The recent studies, concluded that PE is extremely infrequent in hypothyroidism, with an incidence of 3% to 6%. (Patil et al, 2011)

This emphasizes the extreme nature of the misdiagnosed patient’s hypothyroidism.

Other articles associate pericardial effusion with extreme cases of myxedema coma (Dhakal et al, 2015; Taguchi et al, 2007).

In 2015, scientists assessed the hospital records of 250 patients with chest pain without chronic heart disease or heart failure to see whether their T3 levels and/or their high-sensitivity cardiac troponin test result (hs-cTnT; an indicator of heart muscle trauma) could predict outcomes including more than just pericardial effusion — “sudden cardiac death, ischemic stroke, newly developed atrial fibrillation, pericardial effusion and thrombosis.” Over approximately 15 months, 6.8% of patients developed one of these endpoints. Their analysis discovered:

“notably higher overall occurrence rate in patients with hs-cTnT levels ≥0.014 ng/mL and in patients with T3 <60 ng/dL. An exaggerated hazard was observed in patients with combined high hs-cTnT and low T3 levels. After adjustment, the hazard ratio for overall events in patients with high hs-cTnT/low T3 versus normal hs-cTnT/T3 was 11.72 (95% confidence interval, 2.83-48.57; P = 0.001).” (Lee et al, 2015)

In other words, if patients without any sign of cardiac problems have chest pain with low T3 combined with high hs-cTnT, they have an average 12-fold risk of adverse events like pericardial effusion, stroke or sudden death, which is a high risk.

We are not told if the misdiagnosed patient had hs-cTnT levels checked, but such may not be present in “chronic” pericardial effusions.

Scientists point to low T3 hormone in the heart muscle, which can be caused by metabolic depletion of T3 secondary to many diseases and trauma to the heart, or simply, by means of severe hypothyroidism:

“the availability of T3 dramatically diminishes in the myocardium … The exact mechanism underlying this condition remains unclear, although some evidence indicates increased capillary permeability and reduced lymphatic drainage from the pericardial space.” (Jankauskas et al, 2021)

This poor woman’s cholesterol levels were out of the ballpark.

Total Cholesterol 12.5 mmol/L (ref < 5.2)
LDL Cholesterol 9.5 mmol/L (ref 2.6 – 3.3)

Non-HDL cholesterol is directly and inversely related to Total T3 in large populations, as shown by Martin et al, 2017.

Unit conversion by MediCalc :

“Non-HDL” cholesterol includes more than just LDL cholesterol.
Her LDL cholesterol alone was 9.5 mmol/L, so what would all her non-HDL have been? Higher.

Why does cholesterol rise in hypothyroidism? Why is T3 implicated?

According to Duntas and Brenta, 2018,

T3 controls cholesterol biosynthesis through a binding protein called SREBP-2.

When T3 is low, not only is more cholesterol produced, but LDL cholesterol receptors become dull and can’t properly sense how much cholesterol there is.

The Low T3 also causes changes in the cholesterol clearance rate via its loss of control over an enzyme that degrades cholesterol (HMG-CoA).

Also, T3 is involved indirectly because only T3 hormone (not T4’s other metabolite Reverse T3) can be converted to an active form of T2 hormone (3,5-T2), and T2 has control of another part of the cholesterol system:

“Recently, 3,5-diiodothyronine (T2) , a natural thyroid hormone derivative, was found to repress the transcription factor carbohydrate-response element-binding protein (ChREBP) and also to be involved in lipid catabolism and lipogenesis , though via a different pathway than that of T3.” (Duntas and Brenta, 2018)

Duntas and Brenta caution that while standard thyroid hormone (levothyroxine) “could therapeutically reverse” this high cholesterol state, the “potency of the effects may be age-and sex-dependent.”

Why have people forgotten cholesterol as a sign of hypothyroidism?

Cholesterol used to be a major test in thyroid diagnosis before the TSH rose to prominence. Now it appears to be a measurement of cardiovascular health risk alone, disconnected from thyroid.

See this historic cholesterol graph that was reported by Bartels in 1950.

NOTES: The dotted line in Bartels’ graph showing the cutoff at the top says “average cholesterol level of myxedema” — “Myxedema” is a word that used to be used interchangeably with “hypothyroidism.” The term is now almost exclusively used to refer to “myxedema coma,” a life-threateningly severe degree of hypothyroidism.

The graph shows how powerfully a T3-containing thyroid medication, desiccated thyroid, can treat hypercholesteremia — even though the people treated were not at the level of myxedema.

Other hormones: LH, FSH, and Cortisol

Central hypothyroidism due to pituitary or hypothalamic injury or dysfunction usually affects more than just TSH secretion (Persani et al, 2019). Isolated TSH deficiency is extremely rare.

Often Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) — the “gonadotropins” — are affected because they have a similar molecular structure and origin in the pituitary.

Her LH was 10.7 and FSH was 38.7
Reference ranges from Bpac NZ site says that for postmenopausal women, LH > 15, and FSH >20.

Glyn and colleagues said they were “lower than expected for post-menopausal values,” so perhaps they had different ranges (not provided) from their laboratory.

ACTH (which stimulates cortisol release) and GH (growth hormone), can also be affected in CeH. Growth hormone was not mentioned in this study.

However, the misdiagnosed patient’s cortisol was not low, at 582 nmol/L.
Cortisol “above 420 nmol/L normally excludes adrenal failure.” ( Exeter laboratory )

It is a myth that long-standing hypothyroidism results in adrenal insufficiency. In a study of cortisol and hypothyroidism, the most severe, untreated hypothyroid patients with TSH over 100 and FT4 and FT3 very low below range, the average basal cortisol level was only slightly lower than healthy, age-matched controls:

348.9 in cases, and
361.7 in controls.

Only 6 out of 15 of the “severe hypothyroid” group had a cortisol lower than 550 nmol/L within 30 to 60 minutes after cosyntropin stimulation administration (Rodríguez-Gutiérrez et al, 2014). (The time of day of the stimulation test does not affect results.)

For her osteoarthritis, this woman was treated with steroids and anti-inflammatory meds.

This likely contributed to the inability of her TSH to rise above reference range to signal her true state of hypothyroidism.

Corticosteroids such as prednisone / pednisolone are known to reduce TSH concentrations by means of their ability to reduce hypothalamic TRH secretion.

Persani’s article on CeH lists the following:

“Drugs inhibiting TSH secretion: (a) glucocorticoids; [including corticosteroids ](b) dopamine; (c) cocaine; (d) anti-epileptics; (e) anti-psychotics; (f) metformin” (Persani et al, 2019)

In 2015, a group of scientists studied the hypothalamus glands of corticosteroid-treated patients at autopsy:

“we found a decrease in TRH mRNA expression in the [hypothalamic] PVN of corticosteroid-treated patients. This may explain somewhat lower serum TSH in patients treated with pharmacological doses of corticosteroids .” (Alkemade et al, 2015)

This medication could have contributed to her TSH remaining no higher than 2.5 mU/L for many years when she was thought to be “euthyroid.”

In addition to having herself had autoimmune Graves’ hyperthyroidism in the past, this misdiagnosed patient had a

“strong family history of autoimmune disorders.”

A study of over 3000 cases (2,791 with Graves, 495 with Hashimoto’s) revealed that Graves’ patients tended to have a parent with hyperthyroidism, and Hashimoto’s patients tended to have a parent with hypothyroidism.

Even within the patient with Graves’ disease, other autoimmune diseases could coexist, which made it seem logical for them to investigate these at the time:

“ Rheumatoid arthritis was the most common coexisting autoimmune disorder (found in 3.15% of Graves’ disease and 4.24% of Hashimoto’s thyroiditis cases). Relative risks of almost all other autoimmune diseases in Graves’ disease or Hashimoto’s thyroiditis were significantly increased (>10% for • pernicious anemia, • systemic lupus erythematosus, • Addison’s disease, • celiac disease, and • vitiligo).” (Boaelert et al, 2010)

However, they didn’t have to blame a non-thyroidal autoimmune disease if they had tested FT4, seen the clear anomaly, and then tested FT3 to confirm.

Although the patient’s MRI scan investigating the cause of her CeH appeared to rule it out, an autoimmune pituitary disease called “ autoimmune hypophysitis ” can sometimes cause pituitary hormone secretion problems.

(“Hypophysis” is a medical term for the pituitary gland.)

Like Hashimoto’s, autoimmune hypophysitis entails a process of “lymphocytic infiltration” of pituitary tissue. It seems to be associated with the post-partum phase, that is, after pregnancy. It can occur before, during, or after the diagnosis of the other disorders closely associated with it: primary autoimmune hypothyroidism and adrenal insufficiency (Catruegli et al, 2005; De Bellis et al, 2013).

A recent article cited Glyn and colleagues’ case study when suggesting this autoimmune etiology of CeH in conjunction with a primary thyroid disorder (Boronat, 2020).

In Boronat’s study, the patient began not with Graves’ disease, but with subclinical hyperthyroidism caused by an autonomous thyroid nodule.
Similar to Glyn’s patient’s case, an MRI was performed, and negative findings were used to dismiss the possibility of CeH. CeH only became biochemically evident after the patient became hypothyroid .
Hypothyroidism developed in Boronat’s patient not after a partial thyroidectomy, but after the treatment of the thyroid nodule with radioiodine.
Similar to Glyn’s case study patient, testing all three hormones TSH, FT4 and Total T3 later revealed CeH in which the normal TSH was inappropriate to the low FT4, but Boronat’s case was not as severely hypothyroid because Total T3 was still in range.
A second MRI and pituitary antibody test came back negative. Therefore while the fact of CeH was evident, its etiology (cause) was not yet evident.
Boronat’s patient was prescribed levothyroxine treatment, and like Glyn’s patient, experienced years of symptom relief.
However, in later years, after menopause, Boronat’s patient developed other pituitary deficiencies, including cortisol and growth hormone deficiencies that each required hormone treatment. Boronat’s article provides a supplement with extensive laboratory test results.

Boronat’s discussion reported the rationale for the diagnosis of autoimmune hypophysitis despite negative MRI findings:

“this case highlights the fact that isolated central hypothyroidism can be rarely acquired in adulthood , even when it is the only initial manifestation of a slowly progressive multiple pituitary failure . There was no previous history of traumatic brain injury, brain irradiation or intake of drugs able to block TSH secretion. So, even though pituitary antibodies were negative and imaging studies were not characteristic , the most plausible cause for this exceptional presentation of hypopituitarism is lymphocytic hypophysitis , which uses to show a particular propensity to injure TSH-producing cells. Other cases of isolated central hypothyroidism secondary to autoimmune hypophysitis have been described, and, in fact, one study reported a tendency for the rest of the pituitary function to deteriorate over time in some of patients .” (Boronat, 2020)

Boronat cited another published case study that concluded in a similar way with the diagnosis of autoimmune hypophysitis (Barbesino et al, 2012).

Boronat cited Glyn’s case study to illustrate another case with apparently isolated CeH overlaid on progressive hypothyroidism, even though no cause was found for the CeH.

It is possible that Glyn’s misdiagnosed patient could develop other pituitary hormone deficiencies in the future. It would be wise to be vigilant to symptoms and test when they appear, as Boronat discussed.

Once a person has a laboratory history that includes not only TSH but FT3 and FT4 hormone levels, two tools can help bring to light the characteristic TSH mismatch.

As mentioned above, many of the signs of hypothyroidism are more sensitive to circulating T3 in context than to TSH or T4 in isolation, so I show how FT3 and the FT3:FT4 ratio can play a role in confirming diagnosis — as well as in adjusting thyroid treatment long after the diagnosis of hypothyroidism.

1. Plot TSH-FT4 results onto Hadlow’s graphs.

The simplest diagnosis can be made by plotting the patient’s laboratory history on a population graph by Hadlow et al, 2013.

Simply do two things:

Replace the X axis and Y axis bold numbers for the reference range boundaries (Hadlow’s FT4 of 10 – 20 pmol/L and TSH 0.4 to 4.0) with your own reference ranges for FT4 (for example, 9 – 22 pmol/L OR 0.8 – 1.1 ng/dL) and TSH, since ranges vary from lab to lab. Then alter the other axis numbers to fit.
Draw dots that represent TSH-FT4 relationships at each lab test.

Notice that the TSH on the Y axis uses a logarithmic scale .

The more test results you can plot on the graph over time that fall into the CeH zone, the more confirmation you will have that it’s not just a temporary anomaly.

Consider how far below the “ski hill” of normal results the plotted results are — that shows the degree of central hypothyroidism evident in the result, whether mild or severe.

The “central hypo zone” includes both pre-treatment levels and thyroid hormone therapy levels, since the TSH-FT4 relationship remains abnormal and some may acquire central hypothyroidism during thyroid therapy.

As I’ve explained in blue text just under the graph, the “Central hypo zone” covers some territory of mildly high TSH, the “subclinical hypothyroid” zone. This may seem paradoxical until one understands that if the hypothalamus’ TRH secretion or signaling are the main source of dysfunction , the pituitary may still produce mildly excess TSH when thyroid hormones are low. However, the TSH molecules will not be as bioactive in stimulating a thyroid gland. This type of central hypothyroidism is sometimes called “tertiary hypothyroidism,” yet it involves the pituitary as well.

In the next graph below, Hadlow provided a close-up view focusing on the center of the graph above. This one shows male and female adults’ normal TSH-FT4 relationships, this time with a linear (rather than logarithmic) TSH scale on the X axis.

The “central hypo zone” would continue to the left of the graph as FT4 levels come closer to being undetectable.

2. SPINA-Thyr analysis and the FT3:FT4 ratio

Another diagnostic tool that reveals abnormal pituitary secretion is the free SPINA-Thyr endocrinology research program available as a downloadable file online. (See our walkthrough and links at “ Analyze thyroid lab results using SPINA-Thyr .”)

The misdiagnosed patient’s laboratory results were entered into an Excel spreadsheet to make the table shown below, with abnormal results in gray shading.

Only the results AFTER levothyroxine therapy were given GD (Global deiodinase) and TSHi (TSH index) results because the FT4 level at diagnosis was not precise.

I added the column showing FT3:FT4 ratio (FT3 divided by FT4 in pmol/L), which is not in SPINA. This simple calculation can be compared with results from healthy controls (which is an average ratio of 0.31-0.33 at all TSH levels in normal range). If the patient is on LT4 therapy, the ratio can be compared with the published research on the ratios of patients with no thyroid function on LT4 therapy (See “ Gullo: LT4 monotherapy and thyroid loss invert FT3 and FT4 per unit of TSH .”)

In Midgley’s 2015 analysis of treated thyroid patients, the “GD” (global deiodinase efficiency) result was used by researchers to divide LT4-treated patients into three categories:

poor converters of T4 hormone to T3 hormone (<23 nmol/s),
intermediate converters (23–29 nmol/s)
good converters (>29 nmol/s).

(Midgley et al, 2015; See “ Are you a poor T4 converter? How low is your Free T3? “)

The misdiagnosed patient’s response to levothyroxine therapy shows two facts:

Central hypothyroidism is still clearly evident during thyroid therapy because the TSH index is still low, showing abnormal pituitary TSH response to FT4 levels.
The patient ‘s GD shows she was was a “good to intermediate converter” but then suddenly became a “poor converter” after the first year of therapy.

Many patients with central hypothyroidism, despite having healthy thyroids, have poor converter status with FT3:FT4 ratios equal to those of a person with a total thyroidectomy after thyroid cancer (Hirata et al, 2015).

Since the FT4 and FT3 were so incredibly low at diagnosis, the misdiagnosed patient may have no remaining thyroid gland function in addition to having central hypothyroidism.

It would be wise to perform an ultrasound to measure the thyroid volume of the remaining thyroid tissue since partial thyroidectomy, and her TSH-receptor antibody status. She could have either severe thyroid gland atrophy or TSH-receptor blocking antibodies interfering with the function of her remaining thyroid tissue after partial thyroidectomy. Atrophic thyroiditis and/or blocking hypothyroidism can happen to both Hashimoto’s and non-Hashimoto’s patients if they have Graves’ TSH receptor genes or antibodies, as this patient did (See “ The THIRD type of autoimmune thyroid disease: Atrophic Thyroiditis “).

The patient’s FT3 was abnormally low in relation to her FT4 at the time of publication in 2017. Therefore, if she is symptomatic, her FT4 will likely need to be higher than most other patients with central hypothyroidism to achieve euthyroid and symptom-free FT3 levels. The probability of symptom-free FT3 levels increase as this hormone level rises mid-range or higher while on LT4 therapy (Hoermann et al, 2019).

If she cannot achieve her hypothyroid-symptom-free FT3 level while on LT4 therapy without higher FT4 levels causing hyperthyroid cardiac symptoms, then combination T3-T4 therapy or desiccated thyroid therapy are the next logical alternatives because they permit euthyroidism at a lower-normal FT4 level. High-normal FT4 poses a risk for cardiac problems while high-normal or mildly high FT3 is associated with the least cardiovascular risk of all (See “ Prevalence rates for 10 chronic disorders at various FT4, TSH and FT3 levels “).

The risk of acquired central hypothyroidism exists throughout life. Hypothalamus and pituitary response can become compromised by any one of a wide range of injuries, genetic problems, diseases, or medications. This disorder can creep up slowly in people already diagnosed with a primary thyroid disease.

In a person with untreated (or undertreated) central hypothyroidism, the TSH does not always fall below range. TSH can be “inappropriately normal” (Persani et al, 2019). But in another person with the same low or low-normal FT4 and FT3 levels, a healthy hypothalamic and pituitary response would elicit a high TSH.

Human institutions, not nature, have placed TSH in the judgment seat presiding over all things having to do with the thyroid, but TSH secretion is fallible.

TSH has the potential to be a far more useful diagnostic screening test when it is combined with FT3 and FT4 testing.

The failure of TSH to behave normally in relationship to FT3 and FT4 is diagnostic of a far wider range of thyroid disorders, not just central hypothyroidism, but also poor T4-T3 conversion during therapy for all types of hypothyroidism.

Clinicians must be equipped to judge TSH as appropriate or inappropriate to thyroid hormone levels, in addition to assessing clinical signs and symptoms that scream “systemic hypothyroidism” as loudly as they can.

Glyn and colleagues’ recommendation to laboratories is worth repeating again:

“ Laboratories that do not perform fT3 and fT4 routinely should review advice sent to requesting clinicians to include a statement explaining that a normal TSH excludes primary but not secondary hypothyroidism . ”

As seen in this patient’s history, TSH’s inappropriate behavior was missed.

Without being held accountable to FT3 and FT4 results, TSH’s voice thunders like an omniscient god. Institutions, not nature, give TSH the unjustified authority to dismiss severe signs:

kidney hypothyroid status with low eGFR levels,
muscle hypothyroid status with high Creatine Kinase levels and ptosis
heart hypothyroid status shown pericardial effusion, and
cholesterol hypothyroid status.

How many times must a political leader tell a lie before he or she is mistrusted and everything he or she says is fact-checked by external authorities?

How many times must the TSH test fail to guide diagnosis and treatment until physicians, not just clinical biochemists, have the wisdom and freedom to question TSH by ordering FT4 and FT3?

Missing the correct diagnosis of hypothyroidism due to institutionalized blind faith in TSH can lead to many other chronic health disorders, many unnecessary and costly tests, many specialist visits, and preventable suffering and disability.

The patient should have the last words.

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Published: 19 May 2022

Hypothyroidism

Layal Chaker 1 , 2 , 3 , 4 ,
Salman Razvi ORCID: orcid.org/0000-0002-9047-1556 5 ,
Isabela M. Bensenor ORCID: orcid.org/0000-0002-6723-5678 6 ,
Fereidoun Azizi 7 ,
Elizabeth N. Pearce 8 &
Robin P. Peeters 1 , 2

Nature Reviews Disease Primers volume 8 , Article number: 30 ( 2022 ) Cite this article

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Endocrine system and metabolic diseases
Immunopathogenesis
Thyroid diseases

A Publisher Correction to this article was published on 10 June 2022

This article has been updated

Hypothyroidism is the common clinical condition of thyroid hormone deficiency and, if left untreated, can lead to serious adverse health effects on multiple organ systems, with the cardiovascular system as the most robustly studied target. Overt primary hypothyroidism is defined as elevated thyroid-stimulating hormone (TSH) concentration in combination with free thyroxine (fT 4 ) concentration below the reference range. Subclinical hypothyroidism, commonly considered an early sign of thyroid failure, is defined by elevated TSH concentrations but fT 4 concentrations within the reference range. Hypothyroidism is classified as primary, central or peripheral based on pathology in the thyroid, the pituitary or hypothalamus, or peripheral tissue, respectively. Acquired primary hypothyroidism is the most prevalent form and can be caused by severe iodine deficiency but is more frequently caused by chronic autoimmune thyroiditis in iodine-replete areas. The onset of hypothyroidism is insidious in most cases and symptoms may present relatively late in the disease process. There is a large variation in clinical presentation and the presence of hypothyroid symptoms, especially in pregnancy and in children. Levothyroxine (LT4) is the mainstay of treatment and is one of the most commonly prescribed drugs worldwide. After normalization of TSH and fT 4 concentrations, a considerable proportion of patients treated with LT4 continue to have persistent complaints, compromising quality of life. Further research is needed regarding the appropriateness of currently applied reference ranges and treatment thresholds, particularly in pregnancy, and the potential benefit of LT4/liothyronine combination therapy for thyroid-related symptom relief, patient satisfaction and long-term adverse effects.

Primary hypothyroidism and quality of life

Assessment and treatment of thyroid disorders in pregnancy and the postpartum period

The ageing thyroid: implications for longevity and patient care

Introduction.

Thyroid hormone is essential for the normal development of many human tissues and regulates the metabolism of virtually all cells and organs of the human body throughout life. Hypothyroidism, the clinical condition of thyroid hormone deficiency, is a common disorder in the general population. Overt hypothyroidism is defined by thyroid-stimulating hormone (TSH) levels above the upper limit of the reference range while levels of free thyroxine (fT 4 ) are below the lower limit of the reference range. The reference range is typically statistically defined by the 2.5th and 97.5th percentiles of the measured circulating thyroid hormone values in populations defined as healthy. In subclinical hypothyroidism, TSH levels are elevated but fT 4 levels are still within the reference range. Untreated hypothyroidism, especially overt hypothyroidism, can lead to serious adverse effects on multiple organ systems, both in the short and long term. Most adult patients with hypothyroidism have acquired hypothyroidism, which originates either in the thyroid (primary hypothyroidism) or in the pituitary or hypothalamus (central hypothyroidism). Hypothyroidism can also result from severe iodine deficiency because the synthesis of thyroid hormone requires the trace element iodine. Chronic autoimmune thyroid disease, Hashimoto thyroiditis, is the most common cause of primary hypothyroidism in iodine-replete areas. Because thyroid hormone is also essential for multiple aspects of normal development in childhood, most developed countries have established neonatal screening programmes to detect congenital hypothyroidism (prevalence of 1 in 500–3,000 newborns, depending on ethnicity) 1 , 2 as well as programmes to prevent severe iodine deficiency (for example, universal salt iodization).

The onset of hypothyroidism is insidious in most cases and symptoms may present late in the disease process. Symptoms are generally non-specific and the most common include fatigue, cold intolerance and constipation. As a consequence, there is a large variation in clinical presentation and the presence of symptoms has a low sensitivity and positive predictive value (that is, symptoms are not specific to hypothyroidism) for diagnosis. Therefore, detection of high TSH and low fT 4 levels is the hallmark of diagnosis 3 (Fig. 1 ).

Most symptoms attributed to hypothyroidism are common in the general population and are non-specific. Less common symptoms of hypothyroidism (not shown) include dry skin (when severe, a non-pitting oedema termed myxoedema), hoarseness, anaemia (usually normochromic and normocytic but occasionally macrocytic), increased thrombosis risk (due to impaired coagulation and fibrinolysis) and various neurological (carpal tunnel syndrome and encephalopathy), musculoskeletal (myalgia and increased serum creatine kinase levels) and metabolic (hyponatraemia and increase in serum creatine kinase levels) symptoms.

Levothyroxine (LT4), a synthetic form of T 4 that is the mainstay of treatment for hypothyroidism, is the third most commonly prescribed drug in the United States, with over 100 million prescriptions 4 , 5 . Data from commercially insured patients revealed that an estimated 7% of the population have an active LT4 prescription, with 30% of patients displaying normal thyroid function values at initiation of therapy 6 . After normalization of TSH and fT 4 concentrations, up to 15% of patients treated with LT4 continue to have persistent complaints, which may require evaluation for alternative diagnoses 7 . In this Primer, we discuss the pathophysiology, diagnosis, optimal treatment and quality of life of patients with hypothyroidism as well as current knowledge gaps and research priorities.

Epidemiology

Primary hypothyroidism.

Primary hypothyroidism is a common disorder worldwide (Fig. 2a ; Supplementary Table 1 ), with iodine deficiency and Hashimoto thyroiditis as the principal causes. Other less common causes of primary hypothyroidism include congenital, drug-related, iatrogenic and infiltrative diseases (Table 1 ). Prevalence estimates from the general population typically do not distinguish between causes of primary hypothyroidism and depend on several factors, including the population studied and the definition used (for example, whether subclinical hypothyroidism is included). In the USA, National Health and Nutrition Examination Survey data showed a prevalence of hypothyroidism (both overt and subclinical) of 4.6% 8 . A US screening study showed a prevalence of 0.4% and 9% for overt and subclinical hypothyroidism, respectively, with the latter increasing to over 20% among women 75 years of age or older 9 . In a meta-analysis from Europe, the prevalence of overt and subclinical hypothyroidism was 0.37% and 3.8%, respectively, including both diagnosed and undiagnosed cases, and the estimated incidence of hypothyroidism was 226 cases per 100,000 individuals per year 10 .

a | Worldwide prevalence of overt hypothyroidism based on epidemiological studies (Supplementary Table 1 ). The median value was calculated for countries for which data are available from multiple studies. b | Global iodine nutrition status in 2021 (ref. 186 ) based on iodine intake in the general population as assessed by median urinary iodine concentration (mUIC) in school-aged children from studies conducted between 2005 and 2020.

Primary hypothyroidism prevalence is highest in populations with high iodine intake or severe iodine deficiency as compared with populations with a sufficient iodine status 11 (Fig. 2b ). The prevalence decreases with the declining severity of iodine deficiency and increases as iodine intake shifts from mild deficiency to optimal or excessive intake. Furthermore, improvement in iodine status also increases thyroid antibody positivity 12 and therefore the risk of Hashimoto thyroiditis.

Hypothyroidism occurrence is dependent on genetic, inherent (for example, sex) and environmental factors. A meta-analysis of genome-wide association studies (GWAS), which included more than 70,000 participants from 22 cohorts, identified 42 loci for circulating TSH levels within the reference range 13 . Only 7 of these 42 loci were linked to hypothyroidism, including thyroid peroxidase ( TPO ), which encodes an enzyme crucial for the synthesis of thyroid hormone 13 . Individuals with a TSH-based genetic risk score in the highest quartile had a 2.5-fold increased odds of hypothyroidism compared with individuals with a genetic risk score in the lowest quartile 13 . No differences were found between men and women in genetic variants for TSH and fT 4 in sex-stratified GWAS meta-analyses 13 . Nevertheless, the risk of developing primary hypothyroidism is up to tenfold higher in women than in men, suggesting an important contribution of non-genetic factors 14 .

TPO antibody concentrations are lower in smokers than in non-smokers 15 , 16 . Furthermore, TSH levels are lower in current smokers than in former smokers, and lower in former smokers than in never smokers 15 , 16 . Smoking initiation results in a significant decrease in serum TSH levels after 1 year in men. Obesity is associated with higher serum TSH levels in adults and children, although the directionality of the relationship is under discussion and may even be bidirectional 17 , 18 . Children born small for gestational age have higher serum TSH levels than children born appropriate for gestational age and are consequently more often diagnosed with subclinical hypothyroidism 19 . Environmental factors that have been implicated in hypothyroidism and Hashimoto thyroiditis include vitamin D and selenium deficiency, and moderate alcohol intake 16 .

Central and peripheral hypothyroidism

Central hypothyroidism is a rare disorder that may be due to secondary hypothyroidism (pathology of the pituitary) or due to tertiary hypothyroidism (pathology of the hypothalamus) and can be congenital or acquired (Table 1 ). Incidence estimates for congenital central hypothyroidism range from 1:21,000 to 1:160,000 (refs 20 , 21 ), with variability attributed at least in part to differences in neonatal diagnostic strategies. The most common causes of central hypothyroidism in adults include pituitary adenoma, infiltrative disease and radiotherapy. Increased use of immune-checkpoint inhibitors in the setting of cancer treatment over the past decade has resulted in a surge in hypophysitis-related central hypothyroidism, although the exact mechanisms are still poorly understood 22 . Peripheral hypothyroidism (that is, extra-thyroidal) denotes a diverse group of disorders with defects that reduce the effectiveness of thyroid hormone through altered cell membrane transport and metabolism. These rare disorders may be caused by (congenital) genetic alterations causing decreased sensitivity to the biological activity of chemically intact hormones and typically tissue-specific hypothyroidism. Another example of peripheral hypothyroidism is consumptive hypothyroidism, which is due to an increased expression of type 3 iodothyronine deiodinase (DIO3, an enzyme that inactivates thyroid hormone) in tumours (for example, gastrointestinal stromal tumours) 23 .

Mechanisms/pathophysiology

Physiological aspects.

Thyroid hormone production and release are regulated by a very sensitive feedback loop, the hypothalamus–pituitary–thyroid axis (Fig. 3 ). Thyrotropin-releasing hormone (TRH) produced in the hypothalamus controls production of TSH by the anterior pituitary gland. TSH in turn regulates the production and secretion of the two forms of thyroid hormone by the thyroid gland: T 4 and the more bioactive hormone triiodothyronine (T 3 ) 24 . Serum TSH levels follow a circadian rhythm: levels are highest between 9 pm and 5 am and lowest between 4 pm and 7 pm (ref. 25 ). The thyroid gland secretes predominantly T 4 and, to a lesser extent, T 3 , which accounts for up to only ~20% of circulating T 3 . The remaining T 3 is produced by peripheral tissues, such as liver and skeletal muscle, by the activating enzymes type 1 and type 2 iodothyronine deiodinase (DIO1 and DIO2, respectively), which cleave an iodine atom from T 4 (ref. 26 ). Most circulating T 4 and T 3 is bound to transport proteins such as thyroxine-binding globulin (TBG), transthyretin and albumin. Only ~0.02% of T 4 and ~0.2% of T 3 are present in an unbound form and this fT 4 and free T 3 (fT 3 ) can be measured for diagnostic purposes 27 .

Thyrotropin-releasing hormone (TRH) neurons receive various central modulators and other inputs. Thyroid hormone receptor-β2 (TRβ2) expressed in TRH neurons mediates feedback regulation by thyroid hormones. Type 2 iodothyronine deiodinase (DIO2) is required for the production of the active thyroid hormone triiodothyronine (T 3 ) from thyroxine (T 4 ). Production and release of thyroid-stimulating hormone (TSH) from the anterior pituitary is modulated by both thyroid hormones and TRH. In the periphery, only the free fraction of thyroid hormones can be transported into target cells. The effects of thyroid hormones are mediated via interaction of the active hormone T 3 with the nuclear T 3 receptor, which together bind to thyroid response elements (TREs) and modulate the expression of thyroid hormone-responsive genes. TRs, nuclear T 3 receptors. Adapted from refs 187 , 188 , Springer Nature Limited.

Most biological activities of thyroid hormone are mediated by binding of T 3 to the nuclear T 3 receptors (TRs), which bind to thyroid response elements (TREs) in thyroid hormone-responsive genes and modulate their expression. The two thyroid receptor genes THRA and THRB encode thyroid hormone receptor-α (TRα; also known as THRα) and TRβ (also known as THRβ), respectively. Alternative splicing and different promoter usage results in the production of three THRα and three THRβ isoforms, of which TRα1, TRβ1 and TRβ2 bind to T 3 . TRα1 and TRβ1 are ubiquitously expressed, TRα1 preferentially in brain, heart, and bone and TRβ1 preferentially in liver, kidney and thyroid. TRβ2 has a more restricted expression pattern but is the predominant isoform expressed in the pituitary gland and is thereby essential for the negative regulation of TSH 28 . Intracellular T 3 concentrations strongly determine the biological activity of thyroid hormone. Different processes are involved in the regulation of intracellular thyroid hormone concentrations, such as the fT 4 and fT 3 concentrations in serum, the activity of the intracellular DIO1, DIO2 and DIO3 enzymes that can activate or inactivate thyroid hormone, and transporter proteins at the cell membrane that facilitate uptake and efflux of T 4 and T 3 . Only fT 4 and fT 3 are available for transport into thyroid hormone-target cells 29 , 30 , 31 .

Primary hypothyroidism has various causes, mostly affecting thyrocyte function, and a wide range of underlying pathophysiological mechanisms (Table 1 ). Chronic autoimmune thyroiditis is the most common cause of primary hypothyroidism and most typically manifests as Hashimoto thyroiditis. Many factors potentially contribute to and might interact in the development of chronic autoimmune thyroiditis, including genetic and environmental factors, micronutrients (mainly iodine and selenium), drugs, infiltration and/or infection, immune system defects (for example, polyglandular syndromes), and molecular mimicry between microbial and host antigens 32 . High concentrations of anti-thyroid antibodies (predominantly anti-TPO (TPOAb) and antithyroglobulin antibodies) are present in most patients with autoimmune thyroiditis but also occur in ~10% of the euthyroid general population 8 . In pregnancy, TPOAb positivity is seen in 2–17% of women and may accompany higher serum TSH levels during the first trimester 14 . In more than 40% of pregnant women with thyroid autoimmunity, serum fT 4 concentration falls in the hypothyroid range during late pregnancy, which may complicate diagnosing overt hypothyroidism during the third trimester 33 . This is due to inadequate maternal thyroid capacity in response to increased demands in thyroid hormone production imposed by stimulation of the thyroid by human chorionic gonadotropin, increases in TBG, and changes in placental deiodination and renal clearance of iodine during pregnancy 34 . The rates of miscarriages and preterm delivery are increased in pregnant women with thyroid autoimmunity 35 . A negative association of TPOAb positivity during pregnancy with neurodevelopment of offspring has been suggested but needs to be further investigated 36 .

Chronic autoimmune thyroiditis has been attributed to failure of T cell-mediated inflammatory responses through complex mechanisms involving antigen-presenting T cells and B cells, amongst others (Fig. 4 ). Infiltration of thyroid tissue by lymphocytes, mainly T helper 1 (T H 1) cells, can directly alter thyroid follicular cell function through the actions of IL-1, TNF and IFNγ 37 , 38 . Chemokines (small chemoattractant molecules that are structurally similar to cytokines) have also been implicated in thyroid infiltration, which may be induced by IFNγ 39 .

Thyroid autoimmunity is the result of the interplay of genetic and environmental factors that cause damage to thyroid cells, leading to autoantigen release and presentation. Entry of autoreactive immune cells into the thyroid leads to activation of cellular and humoral immune responses, cytokine production, and cytotoxicity and apoptosis. T H 1, T helper 1; TSHR, thyroid-stimulating hormone receptor.

Iodine is an essential micronutrient and is crucial for the biosynthesis of thyroid hormone. Both iodine deficiency and iodine excess may cause hypothyroidism but overt hypothyroidism mainly occurs in the context of severe iodine deficiency and is commonly accompanied by goitre 40 . A high dietary intake of iodine is well tolerated in most individuals, but following exposure to high iodine levels in high-risk individuals (such as those who are prone to Hashimoto thyroiditis), the synthesis of thyroid hormone can be inhibited by the so-called Wolff–Chaikoff effect without resumption of iodine organification after a few days 41 . Hypothyroidism with or without goitre may therefore be observed following chronic administration of large doses of iodine from iodinated contrast material, the heavily iodinated antiarrhythmic amiodarone, the topical antiseptic povidone-iodine or iodine-containing thyroid supplements that are available without prescription 42 . Optimal functioning of the thyroid gland is also dependent on the essential trace element selenium, which directly affects thyroid hormone metabolism and redox processes 43 ; insufficient selenium intake is associated with elevated risk of thyroid disease 44 .

Both internal and external irradiation of the thyroid gland may cause hypothyroidism. Radioactive iodine ( 131 I) therapy may be administered for treatment of hyperthyroidism or thyroid cancer. Ablative doses of radioiodine recommended to treat Graves disease (autoimmune hyperthyroidism) cause permanent hypothyroidism in most patients 45 . Radioiodine treatment of toxic nodular goitre or non-toxic nodular goitre (enlarged thyroid with or without hyperthyroidism, respectively) results in hypothyroidism in ~25% of patients 46 , 47 . External radiation with doses ≥25 Gy (2,500 rad) to the head and neck region for malignant tumours may cause permanent hypothyroidism in >50% of patients 48 . Total thyroidectomy or near-total thyroidectomy in the context of thyroid cancer, Graves disease or multinodular goitre treatment are important causes of iatrogenic overt hypothyroidism. Subtotal thyroidectomy results in hypothyroidism in ~50% of patients 49 .

Other causes of hypothyroidism include transient thyroiditis or forms of destructive thyroiditis. Postpartum thyroiditis with subsequent hypothyroidism is common, resulting in an estimated prevalence of postpartum thyroid dysfunction of 2–10% 50 . Overt and subclinical hypothyroidism are seen in 14–27% of patients with primary thyroid lymphoma and 30–40% of patients with Reidel thyroiditis 51 , 52 , 53 . Hypothyroidism due to thyroid infection with Pneumocystis jirovecii , tuberculosis and brucellosis have been reported 54 , 55 . COVID-19-related thyroid dysfunction has been reported, with hypothyroidism mainly described as a consequence of subacute thyroiditis, although the exact mechanism is not yet clear 56 . Hypothyroidism is also more common in patients with other autoimmune diseases, particularly type 1 diabetes mellitus, autoimmune gastric atrophy and coeliac disease (for example, occurring as part of autoimmune poly-endocrinopathies).

Hypothyroidism may occur following administration of a range of medications through various processes that interfere with endogenous thyroid function 57 . For example, 20% of patients treated with lithium will develop hypothyroidism. Lithium increases intrathyroidal iodine content, diminishes coupling of iodotyrosine residues to T 4 and T 3 , and inhibits thyroid hormone release 58 . Hypothyroidism occurs in 5–15% of individuals receiving amiodarone 59 . Clinically relevant thyroid dysfunction occurs in 58% and 32% of patients treated with IFNα and IL-2, respectively, in part due to activation of autoimmune processes 60 . Hypothyroidism occurs in 18–52% of patients receiving tyrosine kinase inhibitor therapy 61 . Immune-checkpoint inhibitors are associated with immune-related adverse events, including thyroid dysfunction and hypophysitis, which can lead to central hypothyroidism. More than 20% of patients treated with anti-CTLA4 or anti-PD1 monoclonal antibodies, but mainly with both in combination, develop either thyroiditis, with potentially subsequent hypothyroidism, or primary hypothyroidism 62 , and up to 15% develop hypophysitis 63 , 64 .

Cigarette smoking causes a decrease in serum TSH and TPOAb levels and a decreased risk of hypothyroidism in patients with underlying chronic autoimmune thyroiditis 15 . Numerous naturally occurring environmental chemicals, herbicides, pesticides and industrial chemicals have been reported to cause thyroid hypofunction 65 .

Congenital primary hypothyroidism may be caused by an absent, underdeveloped or ectopic thyroid gland (dysgenesis) or by defective thyroid hormone biosynthesis (dyshormonogenesis). Mutations in TSHR , FOXE1 , NKX2-1 , PAX8 and NKX2-5 have been implicated in thyroid dysgenesis and those in SLC5A5 , TPO , DUOX2 , DUOXA2 , SLC6A4 and DHEAL1 have been implicated in dyshormonogenesis. Most cases of congenital hypothyroidism are due to thyroid ectopy, with fewer than 5% of cases attributable to a mutation in a gene involved in differentiation, migration or growth of the thyroid 66 , 67 .

Central hypothyroidism is characterized by insufficient stimulation of the normal thyroid gland by TSH, resulting in a defect in thyroid hormone production. Congenital central hypothyroidism is very rare, whereas acquired disease is more common, occurs mainly in adults, has a variable pathogenesis and is most frequently caused by pituitary adenoma (Table 1 ). In most cases, the thyrotroph defect is combined with multiple other hormone deficiencies 68 . The concentration of serum TSH is often within the reference range in patients with central hypothyroidism but the secreted TSH isoform, although immunoreactive, has severely impaired biological activity. Therefore, the combination of inappropriately normal serum TSH and low circulating fT 4 levels is common in patients with central hypothyroidism 69 . In addition, transient or reversible forms of the disease may occur in patients with prolonged thyrotoxicosis, newborns of hyperthyroid mothers, and individuals treated with somatostatin, glucocorticoids, antineoplastic agents or dopaminergic compounds 68 , 69 , 70 .

Peripheral hypothyroidism denotes a diverse group of disorders with defects that reduce the effectiveness of thyroid hormone through altered cell membrane transport and metabolism and are rare causes of hypothyroidism 71 . These disorders include consumptive hypothyroidism (for example, upregulation of DIO3 in tumour cells) as well as tissue-specific hypothyroidism due to decreased sensitivity to thyroid hormone in patients with mutations in, for example, MCT8 , THRA or THRB , each of which contribute to a specific set of clinical signs and symptoms.

Diagnosis, screening and prevention

Common symptoms and clinical presentation.

Hypothyroidism has clinical implications for nearly all organs and can therefore be associated with a multitude of symptoms of varying severity, depending on the degree of thyroid hormone deficiency, irrespective of the cause 72 .

Almost all of the manifestations associated with hypothyroidism are either due to a generalized reduction of metabolic processes (for example, symptoms such as fatigue, cold intolerance, bradycardia and weight gain) or to accumulation of matrix glycosaminoglycans in tissue interstitial spaces (leading to coarse hair and hoarseness of voice). The symptoms of hypothyroidism can range from mild, with few or almost no symptoms (especially in subclinical hypothyroidism) to very severe (including presentation with life-threatening myxoedema coma ). The onset of hypothyroidism in most cases is insidious and, therefore, symptoms and signs can be vague, wide-ranging and present late in the disease process, thus making it difficult to distinguish from other conditions. One of the most common symptoms is fatigue or tiredness. Other common symptoms include dry skin, weight gain and constipation (Fig. 1 ). Reduced gastrointestinal tract and gallbladder motility 73 have been suggested as underlying mechanisms for constipation, gallbladder hypotonia and bile duct stone formation in hypothyroidism. Mild hepatocellular dysfunction may occur and hypothyroidism is considered a risk factor for non-alcoholic fatty liver disease and occasional steatohepatitis 74 . Impaired glomerular function, changes in renal tubular function, impaired free water clearance and hyponatraemia have all been described in hypothyroidism 75 . Overt hypothyroidism in adults can contribute to entrapment neuropathies (such as carpal tunnel syndrome) and metabolic polyneuropathies, impaired memory, poor concentration, musculoskeletal symptoms, sleep apnoea, depression, and other psychiatric disturbances 76 . Severe and sustained hypothyroidism results in increased vascular resistance, decreased cardiac output, and decreased left ventricular function 77 . Other cardiovascular effects include myocardial injury, pericardial effusion and elements of metabolic syndrome, including hypertension, increased waist circumference and dyslipidaemia 78 , 79 .

However, most symptoms and signs associated with hypothyroidism are non-specific and do not by their presence confirm the diagnosis. Furthermore, a number of the common symptoms attributed to hypothyroidism have a high prevalence in adults 80 . For example, in a study of individuals attending a health fair, 12% of individuals with overt hypothyroidism, 7.4% of those with mild (or subclinical) hypothyroidism and 7.7% of those who were euthyroid reported hypothyroid symptoms 9 . Thus, the presence of symptoms of hypothyroidism alone has a low sensitivity and positive predictive value. Furthermore, it is uncertain how many of the symptoms attributed to hypothyroidism (such as fatigue or weight gain) might be related to ageing, particularly as serum TSH levels have been suggested to increase with age 81 . In fact, an increased severity of symptoms might predict hypothyroidism as a study reported a likelihood ratio of 8.7 for the presence of hypothyroidism when patients reported changes in seven or more symptoms in the previous year 3 . Nevertheless, utilizing symptoms alone to diagnose hypothyroidism would lead to an unacceptably high proportion of euthyroid individuals being falsely diagnosed with hypothyroidism 82 , 83 . Patients with hypothyroidism might present with one or more symptoms of hypothyroidism or when abnormal thyroid test results are noted as part of routine screening tests in the setting of other medical conditions such as dyslipidaemia, atrial fibrillation, cognitive decline, unexplained weight gain or subfertility. As thyroid function testing is frequently ordered, it is not surprising that many individuals are diagnosed with incidental, usually subclinical, hypothyroidism 84 . Diagnosing hypothyroidism is particularly challenging in pregnant women and in children. In pregnancy, patients with hypothyroidism may present with one or more symptoms that are typically associated with hypothyroidism (for example, tiredness or weight gain) but may be misattributed to the pregnancy itself. In practice, especially in regions without screening strategies, most women are diagnosed late in the course of pregnancy, either incidentally or due to screening for thyroid dysfunction in those presenting with associated complications such as gestational hypertension or pre-eclampsia 85 , 86 . Because of the importance of thyroid hormone for normal brain development in early life, gestational hypothyroidism caused by iodine deficiency, untreated or undiagnosed overt hypothyroidism during pregnancy, and untreated congenital hypothyroidism can cause severe neurocognitive and psychomotor dysfunction in offspring. Cretinism, a condition caused by a severe gestational iodine deficiency, is characterized by severely stunted physical and mental growth in early childhood 87 . In children, prolonged and severe overt hypothyroidism might present not only with the typical symptoms observed in adults (such as fatigue, unexplained weight gain or cold intolerance) but also with goitre, delayed growth or delayed puberty 88 .

Myxoedema coma

Myxoedema coma is the most extreme form of hypothyroidism and can progress to death unless diagnosed and treated promptly. Myxoedema coma has a mortality rate of 50–60%; thus, early recognition is vital 89 . Myxoedema coma might present de novo or, more likely, might be precipitated in a patient with hypothyroidism by a number of drugs, systemic illnesses (such as pneumonia) or other causes 89 . Myxoedema coma is more commonly seen in older women in winter and might present with the typical signs of severe hypothyroidism as well as hypothermia, hyponatraemia, hypercarbia and hypoxaemia. It is critical that treatment with thyroid hormone therapy is initiated promptly, ideally in an intensive care unit setting 89 . However, the type of thyroid hormone to administer (thyroxine, triiodothyronine or both) is unclear. In addition to thyroid hormone therapy, adjunctive measures, such as ventilation, warming, fluids, antibiotics, vasopressor agents and corticosteroids, are equally essential for survival 89 .

Diagnostic workflow

Prior to the advent of biochemical testing of thyroid function, symptoms and signs of hypothyroidism were the mainstays of hypothyroidism diagnosis. The presence of signs such as delayed ankle reflexes, low basal metabolic rate and bradycardia helped to confirm the diagnosis but both mild and severe forms of hypothyroidism were likely under-recognized.

The advent of assays for estimating thyroid function (initially the levels of circulating thyroid hormones in the 1950s and then TSH in the 1960s) was a game-changer. The ability to measure serum TSH and thyroid hormone levels (initially by radio-immunoassays and later by immunoassays) meant that milder forms could be detected and also that patients could be treated with much lower doses of thyroid hormone 90 .

Biochemical testing of thyroid function, usually with third-generation immunoassays, currently remains the cornerstone of accurate diagnosis of thyroid dysfunction. Measurement of serum TSH levels is the most reliable marker for assessing thyroid status in most patients, provided that pituitary disease is excluded and patients are not on medications that alter TSH secretion. There is a log-linear relationship between TSH and thyroxine: a twofold decrease in fT 4 levels is associated with a 100-fold increase in circulating TSH 91 . However, the TSH–fT 4 relationship might be non-linear in some individuals and influenced by age, sex, smoking and TPOAb status 16 . An abnormal circulating TSH level is the earliest indicator of thyroid dysfunction as the hypothalamus and pituitary register that fT 4 has changed from its genetically determined set point for a particular individual 92 . There are various patterns of thyroid function tests to help diagnose thyroid dysfunction (Fig. 5 ).

The first step in assessing a patient with suspected primary hypothyroidism is to measure serum thyroid-stimulating hormone (TSH) levels. If serum TSH levels are persistently elevated, peripheral thyroid hormone levels should be measured to differentiate between subclinical and overt hypothyroidism. Levothyroxine (LT4) therapy should be initiated for all patients with overt hypothyroidism. LT4 treatment might be initiated for persistently subclinical hypothyroidism in patients who are ≤70 years of age, who have symptoms potentially caused by hypothyroidism, with cardiovascular risk factors, goitre, positive thyroid peroxidase antibody (TPOAb), are planning pregnancy, and/or have a serum TSH level persistently >10 mIU/l. Most patients with subclinical hypothyroidism and over 70 years of age can be monitored without therapy. Patients with subclinical hypothyroidism not started on LT4 therapy should have their thyroid function monitored periodically. A low serum TSH level together with low peripheral thyroid hormone levels raises suspicion of central hypothyroidism and pituitary function should be assessed. Elevated serum TSH with elevated peripheral thyroid hormone levels can be due to assay interference, a TSH-secreting pituitary adenoma (TSHoma), resistance to thyroid hormone (RTH) or familial dysalbuminaemic hyperthyroxinaemia (FDH). CVD, cardiovascular disease; fT 3 , free triiodothyronine; fT 4 , free thyroxine. a Central hypothyroidism can present with a normal TSH level and a low fT 4 level. In individuals with a high risk of central hypothyroidism (for example, pituitary adenoma), simultaneous measurement of TSH and fT 4 is recommended.

Measuring circulating markers of thyroid autoimmunity (TPOAb or anti-thyroglobulin antibodies) or detecting a diffusely hypoechogenic, heterogeneous pattern by ultrasonography are not required to diagnose hypothyroidism but may be useful to confirm autoimmunity as the underlying cause.

Differential diagnosis

As the symptoms of hypothyroidism are non-specific and variable, many other conditions with similar presentations should be considered (Box 1 ). True subclinical hypothyroidism must be distinguished from the recovery phase of non-thyroidal illness when serum TSH levels are often transiently elevated (having been low or normal during the acute phase) and serum fT 4 levels are usually normal 93 . For patients with apparent subclinical hypothyroidism, it is therefore recommended that thyroid function should be retested after 8–12 weeks to determine whether the TSH elevation is persistent. Observational studies showed that 30–50% of individuals who initially had high serum TSH levels have normal levels on retesting 94 . Interference with the laboratory analytes, usually by human anti-animal antibodies, can also lead to a diagnostic conundrum. Overestimation of TSH levels due to interference with the TSH assay or the presence of macro-TSH can lead to misdiagnosed hypothyroidism 95 . Rarely, individuals with resistance to thyroid hormone due to THRB mutation (high TSH and high fT 4 levels), or TSH or TRH resistance (normal fT 4 levels), can occasionally be misdiagnosed with hypothyroidism. A lack of typical hypothyroidism symptoms or an unusual pattern of thyroid function test results should lead to the diagnosis being questioned.

Box 1 Differential diagnoses of hypothyroidism based on similar presenting symptoms

Endocrine conditions

Addison disease: may present with increased thyroid-stimulating hormone levels that normalize after glucocorticoid replacement is commenced

Obesity (particularly if associated with obstructive sleep apnoea)

Hypopituitarism

Type 1 diabetes mellitus

Hypercalcaemia

Autoimmune conditions

Coeliac disease

Pernicious anaemia

Rheumatoid arthritis

Chronic end organ damage conditions

Chronic kidney disease

Chronic liver disease

Chronic heart failure

Haematological conditions

Iron deficiency anaemia

Multiple myeloma

Nutritional deficiencies

Vitamin B 1 , B 12 or D deficiency

Folate deficiency

Mental health conditions

Chronic stress

Poor sleep pattern

Chronic fatigue syndrome

Fibromyalgia

Post-viral syndromes

Screening for hypothyroidism

Screening for hypothyroidism entails assessing thyroid function in asymptomatic individuals who are not known to have thyroid dysfunction but are at risk of having thyroid disease. Despite the high prevalence of hypothyroidism in the general population, easy diagnosis (by a simple serum TSH test) and availability of cheap treatment, there is no evidence that early detection and treatment improves clinical outcomes. Some organizations, such as the American Thyroid Association, American Association of Clinical Endocrinologists and the Latin American Thyroid Society, recommend screening at different intervals among individuals above a particular age, ranging from every 5 years for individuals >35 years of age to an unspecified period for individuals ≥60 years of age, particularly among women 96 , 97 . However, in 1996, the Royal College of Physicians in the UK concluded that screening of the general population is unjustified given the low number of overt hypothyroidism cases detected with screening 98 . Similarly, in 2015, the US Preventive Services Task Force concluded that the available evidence was inadequate to determine the balance of benefits and harms of screening 99 . A potential explanation for the variation in screening strategies among different organizations could be differences in emphasis. Screening could potentially identify many individuals with mildly increased serum TSH levels, particularly among older individuals or those with obesity, but robust evidence that treatment is beneficial is lacking. However, individuals at high risk of thyroid dysfunction might benefit from screening, including those with risk factors for hypothyroidism (for example, goitre, previous treatment for hyperthyroidism such as radioactive iodine therapy or partial thyroidectomy, a history of neck irradiation, on medications affecting thyroid function, or the presence of other autoimmune diseases). Screening for hypothyroidism should be considered in patients with dyslipidaemia, hyponatraemia, unexplained high levels of muscle enzymes, macrocytic anaemia, or pericardial or pleural effusions without any other cause 97 . Furthermore, individuals at high risk of developing thyroid disease, such as those with Down syndrome, Turner syndrome or pituitary disease, should also be assessed regularly for the development of hypothyroidism.

In women of childbearing age, targeted case-finding for thyroid dysfunction should be considered in pregnant women from areas of moderate to severe iodine deficiency, women with symptoms potentially attributable to thyroid dysfunction, those with a personal and/or family history of thyroid disease, or in women with recurrent miscarriage or unexplained infertility 97 . In pregnancy, screening for milder forms of hypothyroidism is controversial and remains a matter of debate owing to the possibility of overtreatment and the lack of evidence that treatment of mild thyroid dysfunction with thyroid hormones improves neurocognitive outcomes in offspring 100 , 101 .

The benefit of screening for congenital hypothyroidism in newborns using dried blood spot tests for thyroid function is beyond doubt; this has been one of the major success stories of newborn screening programmes. Congenital hypothyroidism is one of the most common preventable causes of intellectual impairment. As most infants with this condition have no obvious clinical manifestations and no family history, it is not possible to target a high-risk group. Universal newborn screening programmes are available in many countries and have led to normal or near-normal neurocognitive outcomes in the majority of infants with congenital hypothyroidism 102 .

Dietary modifications to prevent hypothyroidism in individuals at risk

Universal salt iodization has been successful in reducing hypothyroidism in areas where severe iodine deficiency was previously prevalent 11 . Even so, iodine deficiency remains an important public health concern despite global efforts to combat it with iodization programmes. Adequate intake of iodine is important for all individuals but might be especially important in those with underlying autoimmune thyroid disease as iodine deficiency may trigger or worsen hypothyroidism 11 . The recommended daily dose of iodine is 90 μg for pre-school children, 120 μg for school children, 150 μg in adults and 250 μg in pregnancy 103 . Chronic excessive iodine intake can also cause alterations in thyroid function — usually increased serum TSH levels — in susceptible individuals. Maintaining an optimal iodine intake is crucial, particularly in pregnancy 104 .

Selenium supplementation may reduce TPOAb levels in patients with autoimmune thyroid disease in the short to medium term 105 . However, the clinical relevance of TPOAb reduction is unclear and the long-term safety of selenium supplementation is yet to be established. There is insufficient evidence that such therapy normalizes increased serum TSH levels in individuals with chronic autoimmune thyroid disease 106 .

Thyroid hormone replacement with LT4

LT4 therapy is the mainstay of treatment for hypothyroidism. Treatment can reduce tissue manifestations and improve quality of life and might also benefit neurodevelopment in infants and young children. Typical full replacement doses in adults are 1.6 µg/kg/day (ref. 7 ). Lower starting doses might be used in older individuals, those with mild hypothyroidism or those with untreated cardiovascular disease. Because weight-based dosing might overestimate the requirements of individuals with obesity, BMI-adjusted dosing algorithms have been developed 107 . In patients with primary hypothyroidism, treatment is targeted to the normalization of serum TSH levels. In patients with central hypothyroidism, serum TSH levels are largely uninformative and treatment should instead target a serum fT 4 level in the upper half of the reference range 108 . Treatment leads to resolution of hypothyroidism symptoms in most patients, although the non-specific nature of symptoms means that they could also be due to other causes. Serum TSH levels should be monitored 6 weeks after initiation of treatment or any change in dose and then every 6–12 months thereafter. Thyroid hormone under-replacement and over-replacement (outside the setting of thyroid cancer, when TSH-suppressive dosing might be desired to reduce the risk for tumour recurrence) should be avoided owing to the potential for cardiac and bone toxicity and the increased mortality risk 108 , 109 , 110 . LT4 should be taken consistently, ideally 60 min before breakfast but taking LT4 30 min before breakfast or at bedtime on an empty stomach is also acceptable 111 . TSH levels should be monitored after starting or stopping medications that might interfere with LT4 absorption, binding or metabolism 57 (Table 2 ). Malabsorption of LT4 might also occur following bariatric surgery or owing to gastrointestinal disorders. In patients with malabsorption, treatment with liquid rather than tablet LT4 formulations might help to stabilize TSH levels 112 .

Treatment of subclinical hypothyroidism in adults

The risk for progression from subclinical to overt hypothyroidism is ~2–4% annually and is more likely when patients have postitive TPOAb 113 . Elevated serum TSH levels, particularly >10 mIU/l, are associated with increased cardiovascular and mortality risks 114 , 115 . However, no consensus currently exists as to whether subclinical hypothyroidism requires treatment. Trials of LT4 in individuals ≥65 years of age have found no clear symptomatic benefit 116 , 117 . Similarly, a trial of LT4 in patients with acute myocardial infarction and subclinical hypothyroidism found no improvement in left ventricular function 118 . A meta-analysis suggested that LT4 might decrease mortality in patients with subclinical hypothyroidism aged <65–70 years old but not in older individuals 119 . Although one guideline recommends against treatment when TSH levels are <20 mIU/l (ref. 120 ), most authors suggest individualized consideration of low-dose LT4 in patients, especially those ≤70 years of age, who have symptoms potentially referable to hypothyroidism, cardiovascular risk factors, goitre, positive TPOAb, are planning pregnancy, and/or have a serum TSH level persistently >10 mIU/l (refs 97 , 121 , 122 , 123 ) (Fig. 5 ).

Treatment in pregnant women

The developing fetus relies entirely on maternal thyroid hormones during critical phases of early brain development (usually before gestation weeks 16–20). Untreated overt hypothyroidism in pregnancy is associated with increased risks for miscarriage, preterm delivery, gestational hypertension, pre-eclampsia, low birthweight, fetal death and impaired child intellectual development 97 , 124 . Overt hypothyroidism in pregnancy requires prompt LT4 initiation 34 , 125 . Whether milder forms of maternal thyroid hypofunction require treatment in pregnancy remains controversial. Maternal subclinical hypothyroidism is associated with increased risks for pregnancy loss, placental abruption, premature rupture of membranes, preterm delivery, and neonatal death 126 , 127 . Maternal hypothyroxinaemia (low fT 4 in the setting of normal serum TSH levels) has also been associated with adverse obstetric and child neurodevelopmental outcomes 126 , 128 . However, clinical trials to date have not clearly shown a benefit of LT4 treatment for subclinical hypothyroidism or hypothyroxinaemia in pregnancy 129 , 130 , 131 . Current recommendations in clinical practice guidelines are variable (Table 3 ). Most pregnant women on LT4 therapy will require an increase in LT4 dosing (25–30% as soon as pregnancy is diagnosed) to maintain euthyroidism during gestation, when serum TBG levels are markedly increased and thyroid hormone is rapidly metabolized by placental DIO3. Serum TSH levels should be closely monitored, approximately every 4 weeks during the first half of gestation 34 . In pregnancy and the pre-conception period, LT4 dosing should target a serum TSH level of <2.5 mIU/l (refs 34 , 125 ).

Treatment of women with subfertility

Small randomized trials have demonstrated that LT4 treatment started before conception improves assisted reproductive technology outcomes when the baseline TSH level is >4.0 mIU/l, particularly in women who are positive for TPOAb 132 . The recommended TSH target level in treated women is <2.5 mIU/l (ref. 133 ). Although overt hypothyroidism should always be treated, it is not known whether pre-conception treatment of subclinical hypothyroidism improves fertility or pregnancy outcomes in women who conceive without assisted reproduction 134 .

Treatment in infants and children

Because thyroid hormone is important for normal growth and neurodevelopment in early life, infants with congenital hypothyroidism are unable to produce an adequate amount of thyroid hormones to maintain physiological tissue levels after birth and require rapid initiation of LT4 therapy within the first 2 weeks after delivery. Starting LT4 doses in infants should be 10–15 µg/kg daily 7 . Follow-up laboratory and clinical evaluations should occur every 1–2 weeks until the serum TSH level normalizes, every 1–3 months until 12 months of age, and then every few months thereafter until growth is completed. Therapy should be targeted to keep the serum TSH within the age-specific reference range in children with primary hypothyroidism and fT 4 in the upper half of the reference range in children with central hypothyroidism. In children without a clear underlying cause of permanent congenital hypothyroidism, re-evaluation of the pituitary–thyroid axis should be performed at about 3 years of age to determine whether ongoing LT4 treatment is needed.

Younger children require higher doses of LT4 per kilogram of body weight than older children: 4–6 µg/kg is recommended from 1–3 years of age, 3–5 µg/kg from 3–10 years of age, and 2–4 µg/kg for 10–16 years of age 7 . Most children with subclinical hypothyroidism do not progress to overt hypothyroidism and most are asymptomatic. Treatment of subclinical hypothyroidism in children over 3 years of age is generally considered only when serum TSH levels are >10 mIU/l, particularly in the setting of TPOAb positivity, hyperlipidaemia 135 or concerns about growth velocity 136 . Children with milder TSH elevation can be monitored without therapy 137 .

Treatment in older patients

Individuals >65–70 years of age are at increased risk of adverse effects from excessive LT4 dosing, including cardiac arrhythmia, progressive heart failure, increased bone turnover leading to osteoporosis, catabolic muscle loss, impaired quality of life and increased mortality 138 . Therefore, it is often recommended to start with low LT4 doses (25–50 µg daily) and to titrate doses gradually in individuals >65 years of age, particularly in those with known cardiovascular disease. There may be a physiological increase in serum TSH levels with normal ageing 139 , which argues against treatment of modest TSH elevations in older patients. If therapy for subclinical hypothyroidism is elected, it is particularly important to confirm the persistence of TSH elevations above age-appropriate levels over time prior to treatment initiation as thyroid function might normalize spontaneously in almost 50% of individuals ≥65 years of age 140 . It is also important to avoid overtreatment and targeting a serum TSH levels of 4–6 mIU/l has been advocated in patients >70 years of age 7 .

Challenges in treatment

A minority of patients feel unwell on LT4 despite optimal TSH levels 141 . Normalization of serum TSH level typically might not fully normalize serum T 3 levels, and it is plausible that persistent symptoms on LT4 monotherapy might result from low systemic or tissue-specific T 3 levels, particularly in individuals with polymorphisms in DIO2 , who might not efficiently convert T 4 into the active hormone T 3 (ref. 142 ). Although multiple trials have examined whether therapy with a combination of LT4 and liothyronine (LT3; a synthetic form of T 3 ) improves quality of life, results are inconclusive 141 . Combination T 3 and T 4 therapy can be tried in individual patients who feel unwell on LT4 alone as long as they are closely monitored and other causes for symptoms have been excluded 143 . However, there is agreement that T 3 -containing therapies should not be used in pregnancy 34 , 97 , 125 , 143 or in young children 144 . During gestation, maternal T 3 does not reach the fetal brain and thus treatment of pregnant women with T 3 -containing therapies incurs a risk for fetal hypothyroidism and impaired brain development, even when maternal TSH level is normalized. The effects of T 3 administration on brain development in paediatric patients have not been studied. Hypothyroidism following postpartum thyroiditis is common and may be transient. Therefore, withdrawal of LT4 therapy after 6–12 months might be appropriate in these cases.

Quality of life

Overt hypothyroidism is a chronic disease that might be associated with a decrease in health-related quality of life (HRQOL) 145 , 146 . Although several instruments are available to evaluate HRQOL in patients with thyroid disease, the 84-item instrument Thyroid Patient Related Outcome (ThyPRO) is the most commonly used and has been identified as the most appropriate tool for patients with hypothyroidism 147 . ThyPRO has good responsiveness for the detection of relevant treatment effects for use in clinical trials 148 , 149 . A 39-item shortened version, ThyPRO-39, is currently available and includes a composite measure score to evaluate HRQOL 150 .

ThyPRO scores in patients with untreated overt and subclinical hypothyroidism show that HRQOL is severely impacted in these patients compared with the general population 145 . After 6 months of LT4 treatment, improvement in HRQOL is observed but full recovery is not achieved. These results are in agreement with observational studies that report persistence of hypothyroid symptoms after treatment with LT4 (refs 151 , 152 , 153 , 154 , 155 , 156 ). Persistence of residual symptoms in patients with hypothyroidism after treatment has been described in up to 15% of patients 145 , 155 , 157 and has been attributed to the inability of LT4 monotherapy to fully restore tissue-specific euthyroidism. Factors unrelated to thyroid dysfunction, such as the stigma and the labelling effect of receiving the diagnosis of a chronic disease 158 , the need to take medications every day, or even a specific effect of autoimmunity on HRQOL 145 , 157 , have also been hypothesized to contribute to reduced HRQOL. However, it is important to highlight that these persistent symptoms might also be related to the presence of other chronic diseases or even to the medication used to treat these comorbidities.

Three meta-analyses of randomized, placebo-controlled trials in patients with hypothyroidism reported no difference in HRQOL using only LT4 compared with a combination of LT4 and LT3 (refs 159 , 160 , 161 ). There was also no improvement in HRQOL using different doses of LT4 (refs 162 , 163 , 164 ) or desiccated thyroid extract 165 . Another meta-analysis showed no difference in clinical outcomes, including quality of life, between adults with hypothyroidism treated with combination LT4 and LT3 therapy and those treated with LT4 monotherapy (although a higher proportion of patients preferred combination therapy); however, the evidence was of low-to-moderate quality 159 . Of note, most randomized controlled trials were limited by small sample sizes 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 , 172 . Furthermore, men have been under-represented in many studies. Only a few trials have used HRQOL 167 , 169 , 172 or thyroid-specific HRQOL instruments 162 , 163 , 165 , 166 , 171 , 172 as the primary outcome. Furthermore, trials have included participants with variable underlying causes of hypothyroidism 163 , 165 , 166 , 169 , 171 , 172 .

The TRUST trial is the largest trial to compare LT4 versus placebo for the treatment of subclinical hypothyroidism using ThyPRO as the main outcome in individuals ≥65 years of age. This trial demonstrated no clear benefit of LT4 treatment on HRQOL during 1 year of follow-up 117 . A meta-analysis of 21 randomized controlled trials conducted between 1984 and 2017, including the TRUST Trial, reported similar findings 173 . A more recent analysis that combined data from the TRUST study and the IEMO 80-plus study did not show any benefits of treatment of subclinical hypothyroidism in individuals ≥80 years of age 116 . However, in both TRUST and IEMO, the HRQOL score at baseline of included individuals with subclinical hypothyroidism was better than in the general population, which might have compromised the ability to detect an improvement in HRQOL after treatment 174 .

The benefit of thyroid hormone treatment for subclinical hypothyroidism in younger adults remains unclear as previous findings suggest a differential effect of treatment on HRQOL dependent on age 175 , whereas the majority of high-quality randomized controlled trials were performed in older people 116 , 117 . Although studies have consistently underlined the issue of residual symptoms in treated patients with hypothyroidism 155 , it is unclear what the underlying mechanisms are and how to tackle this issue in a personalized manner.

Although the causes and consequences of hypothyroidism were initially described over a century ago 90 , essential information regarding prevalence, genetic causes, environmental factors, and thresholds for diagnosis, treatment and management optimization for hypothyroidism are still limited.

Prevalence and incidence data for primary hypothyroidism are lacking for many regions around the world. Furthermore, despite the importance of newborn screening programmes for the early detection and treatment of congenital hypothyroidism, over 70% of the world population is not screened at birth, hampering estimates of congenital hypothyroidism occurrence 176 and, more importantly, hampering timely treatment. With ever-changing risk factors for thyroid disease (for example, iodine nutrition status and ageing populations), researchers, clinicians and policymakers require available and up-to-date statistics.

The heritability of TSH levels has been estimated at 65% while, in the largest GWAS to date all 42 significant associations together accounted for 33% of the genetic variance in TSH levels, displaying clear polygenicity 13 . While increasing the sample size in future GWAS will contribute to the search for the missing heritability, improved techniques (such as whole-genome sequencing) are expected to have a substantial impact as well. In addition to genetic and inherent factors (for example, sex), environmental risk factors, including smoking and BMI, are known to influence thyroid function. However, the variability explained by age, sex, smoking, BMI, TPOAb levels and alcohol use combined only accounts for ~7% of TSH and 5% fT 4 variation 16 . Therefore, study of other risk factors, including endocrine-disrupting chemicals, is needed to determine their contribution to thyroid dysfunction, perhaps starting at pre-conception or conception.

Optimal iodine intake is required to avoid hypothyroidism. Although salt iodization has been implemented in more than 120 countries worldwide, mild-to-moderate iodine deficiency is still a public health problem in many regions. Additionally, salt is increasingly consumed from commercially processed foods that typically do not use fortified salt, leading to shifts in iodine status at a national and regional level. Salt iodization programmes require careful monitoring to avoid either population iodine deficiency or excess 177 . The groups most vulnerable to iodine deficiency are young infants, especially up to 6 months of age, and pregnant and lactating women as iodine deficiency in utero and in early life may lead to cognitive impairment in offspring. Low iodine intake by lactating mothers leads to low breast milk iodine content, which is important as this might be the only source of iodine for neonates up to 6 months of age 178 . Several national surveys suggest that many pregnant women currently have an insufficient iodine intake 179 . In a study in pregnant women from the UK, the median urinary iodine concentration was 85.3 μg/l, classifying this group as iodine deficient 179 . WHO recommends that optimal iodine nutrition in pregnant women is achieved when the median urinary iodine concentration in women is 150–249 μg/l (outside of pregnancy, this value is 100–199 µg/l). Achieving the recommended iodine intake in pregnancy remains a challenge.

Hypothyroidism in pregnancy poses particular challenges with regard to diagnosis and, subsequently, treatment thresholds. Maternal subclinical hypothyroidism has been reported in ~4% of all pregnancies 180 and has been suggested to be adversely related to pregnancy outcomes and child development 181 . However, to date, consensus is lacking regarding serum TSH thresholds for treatment initiation and discussion concerning the definition of thyroid dysfunction in pregnancy is ongoing.

Diagnosis of hypothyroidism relies on laboratory measurements of serum TSH and fT 4 levels. Reference ranges of TSH and fT 4 , defined by the 2.5th and 97.5th percentiles, have been criticized owing to their arbitrary nature and that they do not consider the potential long-term risk of serious diseases 99 . Both subclinical and overt hypothyroidism as well as low-to-normal thyroid function, have been associated with an increased risk of coronary heart disease and cardiovascular risk factors such as non-alcoholic fatty liver disease. These associations have been replicated in large collaborations involving individual participant-level meta-analyses of longitudinal cohort studies 115 but also in multiple Mendelian randomization studies, underlining the causal relationship 17 , 182 . To date, it has proved difficult to incorporate adverse clinical outcomes in the definition of subclinical hypothyroidism. However, identifying relevant cut-offs of serum TSH and fT 4 levels is imperative for a clinically meaningful definition of hypothyroidism and establishing potential treatment thresholds.

Furthermore, age-specific cut-offs for serum TSH levels have been suggested to avoid overtreatment of older individuals, particularly in the context of subclinical hypothyroidism 140 . This notion is based on the assumption that TSH levels increase with ageing. To date, three cohorts have investigated serum TSH levels longitudinally, with conflicting results 16 , 81 , 183 . Two studies, one from Australia ( n = 1,100) 184 and the other from the USA ( n = 834) 81 , 183 , found that serum TSH levels increase with age, while a study from the Netherlands ( n = 1,225) reported no change in TSH level with increasing age 16 . Furthermore, the Australian study showed that the increase in serum TSH levels over time was smallest in people with the highest TSH level at baseline 184 . These discrepant findings warrant further research in larger populations of community-dwelling adults to identify relevant age-specific cut-offs.

Thyroid hormones undergo tissue-specific metabolism, including deiodination, sulfation, glucuronidation, deamination and decarboxylation, thereby producing a wide variety and quantity of thyroid hormone metabolites 184 . In animal studies and a few human studies with a small sample size, different thyroid hormone metabolites have distinct effects on the cardiovascular system and cardiovascular risk factors 185 . However, to date, information is lacking on the importance of these thyroid hormone metabolites in predicting outcomes in patients with cardiovascular disease and their potential usefulness as determinants of cardiovascular disease incidence in the general population, including in individuals with hypothyroidism.

Residual symptoms and other hypothyroidism manifestations in patients treated for hypothyroidism have been attributed to the inability of LT4 monotherapy to restore truly normal thyroid physiology, especially a normal serum T 4 to T 3 ratio. Therefore, several trials have investigated the effectiveness of LT3 and LT4 combination therapy, with mixed results. This inconsistency has been attributed to generally small sample sizes and the potential variability in the proportion of participants carrying the DIO2 T92A single-nucleotide polymorphism (SNP). Unresponsiveness to monotherapy in a subset of patients with hypothyroidism is hypothesized to be related to the presence of this SNP, which reduces the activity of DIO2 and therefore decreases the conversion of T 4 into T 3 . However, in a meta-analysis assessing the effect of combination therapy, none of the included studies reported the proportion of patients with this SNP 159 . The T3-4-Hypo trial (NL74281.078.21), a national randomized, placebo-controlled, double-blind, multicentre trial of LT4 and LT3 combination therapy in the Netherlands in patients with autoimmune hypothyroidism, with an anticipated target size of 600 participants, might provide more information about the potential benefit of combination therapy in the future. Whether LT4 therapy in combination with slow-release LT3 would be beneficial is not clear, especially as the safety of long-term therapy has yet to be investigated.

Change history

10 june 2022.

A Correction to this paper has been published: https://doi.org/10.1038/s41572-022-00373-7

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Layal Chaker & Robin P. Peeters

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Layal Chaker

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA

Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK

Salman Razvi

Centro de Pesquisa Clínica e Epidemiológica, Hospital Universitário, Divisão de Clínica Médica, Universidade de São Paulo, São Paulo, SP, Brazil

Isabela M. Bensenor

Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran

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Introduction (L.C., S.R., I.M.B., F.A., E.N.P. and R.P.P.); Epidemiology (L.C., S.R., I.M.B., F.A., E.N.P. and R.P.P.); Mechanisms/pathophysiology (L.C., S.R., I.M.B., F.A., E.N.P. and R.P.P.); Diagnosis, screening and prevention (L.C., S.R., I.M.B., F.A., E.N.P. and R.P.P.); Management (L.C., S.R., I.M.B., F.A., E.N.P. and R.P.P.); Quality of life (L.C., S.R., I.M.B., F.A., E.N.P. and R.P.P.); Outlook (S.R., I.M.B., F.A., E.N.P. and R.P.P.); Overview of Primer (R.P.P.).

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R.P.P. has received speaker fees from IBSA Pharmaceuticals. S.R. has received speaker fees from Merck, IBSA and Abbott Pharmaceuticals (manufacturers of thyroid hormones). L.C., I.M.B., F.A. and E.N.P. declare no competing interests.

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Supplementary information.

The phenomenon that consists of the acute inhibition of iodine organification in thyroid follicles and thyroid hormone release due to iodine excess.

The incorporation of iodine into thyroglobulin.

Removal of the entire thyroid gland.

Removal of most of the thyroid gland except for <1 g of thyroid tissue to minimize risk of damaging the recurrent laryngeal nerve.

Removal of most of the thyroid gland except for ~4–8 g of tissue to maintain euthyroidism.

Anterior pituitary cells that produce thyroid-stimulating hormone in response to thyrotropin-releasing hormone from hypothalamic thyrotropin-releasing hormone-producing neurons.

Severe hypothyroidism resulting in a loss of homeostasis, often presenting as altered mental state, hypothermia, hypotension, hyponatraemia and other symptoms, which can lead to coma.

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Chaker, L., Razvi, S., Bensenor, I.M. et al. Hypothyroidism. Nat Rev Dis Primers 8 , 30 (2022). https://doi.org/10.1038/s41572-022-00357-7

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Myxedema Coma: Case Report and Literature Review

Affiliations.

1 Internal Medicine, Rutgers-New Jersey Medical School/Trinitas Regional Medical Center, Elizabeth, USA.
2 Internal Medicine, St. George's University, True Blue, GRD.
3 Internal Medicine, Trinitas Regional Medical Center, Elizabeth, USA.
PMID: 34194879
PMCID: PMC8235691
DOI: 10.7759/cureus.15277

Myxedema coma is a life-threatening manifestation of hypothyroidism associated with altered mental status, hypothermia, and symptoms related to the slowing of other organ systems. It can occur as a culmination of severe, longstanding hypothyroidism or be precipitated by acute stressors such as infection, myocardial infarction, cold exposure, and surgery in patients with poorly controlled hypothyroidism. Given the high mortality rate and acuity with which the disease presents, treatment with thyroid hormone replacement should be initiated upon suspicion of the disease even prior to obtaining laboratory confirmation. Stress doses of hydrocortisone should also be given until coexisting adrenal insufficiency is excluded. We present a case of a 58-year-old male who presented to the emergency department after being found on the floor of his house. Physical examinations and laboratory results were significant for myxedema coma and the patient was given levothyroxine with improvement of symptoms and mild change in thyroid hormone levels during hospitalization.

Keywords: congenital hypothyroidism; free t4; hypothyroidism; myxedema coma; thyroid-stimulating hormone (tsh).

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Published: 05 September 2020

Ramifications of untreated hypothyroidism: case report of cognitive impairment and acute psychosis in an elderly female

Janette C. Leal ORCID: orcid.org/0000-0002-7560-3688 1 &
Allison H. Beito 1

Annals of General Psychiatry volume 19 , Article number: 48 ( 2020 ) Cite this article

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Hypothyroidism is a common condition in the general population. While myxedema is a known complication, we present a case highlighting a late-onset presentation of psychosis with confounding cognitive impairment in a patient who believed she no longer needed thyroid replacement medication because of her advanced age.

Introduction

Hypothyroidism is a common condition in the older population, estimated to afflict 5–20% of elderly women [ 1 ]. With an aging population, cases are expected to become more widespread in the near future. While psychiatric presentations of hypothyroidism were initially described in the late 1880s, and the term “myxedema madness” was added to the literature in 1949 [ 2 , 3 ], ensuing cases over the years have highlighted the true diversity of potential psychotic presentations. Elderly patients in particular may demonstrate affective disturbance, cognitive dysfunction, and a wide range of psychotic symptoms, without a predictable progression of medical or psychiatric symptoms [ 2 , 3 ]. Psychiatric presentations of hypothyroidism require a vigilant approach to investigation for thyroid disturbance, as left untreated, hypothyroidism may lead to excess morbidity.

Here, we present one case of hypothyroidism-related psychosis and cognitive impairment treated in our hospital, with the purpose of further illustrating the range of potential presentations of which providers should be aware.

Case presentation

A 79-year-old, married, Caucasian female was brought to medical attention by her husband. She had suffered 2 weeks of escalating delusions of pregnancy, hallucinations with observed response to internal stimuli at home, and agitation with increasing suspiciousness toward family members. Her previous medical history was pertinent for treated hypothyroidism of 50 years duration, hyperlipidemia, diverticulosis, Vitamin D deficiency, and mild osteoarthritis. She had no family or personal history of formally diagnosed psychiatric disorders. She was high school graduate, retired housecleaner and teacher’s aide, who lived independently in a house with her husband. She had no lifetime history of any substance use. Interestingly, she had been hospitalized 1 year prior to this presentation, for uncontrolled hypothyroidism and paranoid thoughts associated with medication non-adherence. At that time, thyroid replacement had been re-initiated with improvement in paranoia.

Prior to this admission, the patient insisted that she had been impregnated by an intruder into her home, and possessed delusional thoughts that her abdomen was filled with embryos, necessitating caesarian section. She was willing to seek medical attention only for the purpose of scheduling a caesarian section. Her husband observed her speaking to family members who were not present, and she referred to ideas of reference, that she was hearing the voices of individuals from nearby towns, which were broadcasted over her television, and also surveilling her. She possessed a delusional thought that her sister was making plans to bomb her home. She endorsed stopping her home levothyroxine dose (100 mcg daily) 2 weeks prior, and expressed conviction that she no longer needed the medication, due to her advanced age, after hearing that a friend had discontinued their own levothyroxine.

Upon presentation, the patient complained only of mild abdominal discomfort “fullness”, but otherwise had no other physical nor specific psychiatric complaints. She denied concerns with mood. She believed she was in the Emergency Department for a caesarian section. She was unable to coherently provide a history of present illness, insisting that she was presenting for surgery, and making other unrelated delusional comments “I took a fireball to the head.” She possessed no vital sign abnormalities, with heart rate of 63 and blood pressure of 140/69. She had no obvious physical exam abnormalities, including dry skin, thinning hair, edema, hoarseness, goiter, or macroglossia. Cognitive screening revealed deficiencies in calculation and delayed recall with Mental Status Exam [ 4 ] score of 25/38 (with construction not performed), despite full orientation and level of alertness. Lab evaluations revealed no abnormalities in blood count or electrolytes, however TSH was elevated to 403 mIU/L, free T4 was undetectable, and T3 was diminished at 1.7 ng/dL. TPO antibodies were not collected. She also demonstrated elevated total serum cholesterol (224 mg/dL) and triglycerides (303 mg/dL). Serum vitamin D levels were diminished at 20 ng/mL. Workup was negative for infections including a normal urinalysis, CBC and BMP.

The patient was treated with initial dosing of IV levothyroxine and was then transitioned back to PO levothyroxine at 100 mcg daily. Vitamin D replacement was initiated. She demanded to leave the hospital, and after determination that she did not possess decision-making capacity secondary to psychosis, she was placed on a psychiatric hold and the treatment team petitioned her home county for mental health commitment. She was started on therapy with olanzapine 10 mg daily, for ongoing paranoia and delusional thoughts. Her cognitive screening score had improved marginally to 30/38 by her admission to inpatient psychiatry, though still with difficulty with delayed recall and calculation.

Throughout her month-long psychiatric stay, and with ongoing treatment with levothyroxine and olanzapine, our patient’s psychotic symptoms slowly improved. Her delusion of pregnancy resolved, and she exhibited no further hallucinations or ideas of reference. Her TSH improved to a level of 64 mIU/L, and free T4 returned to normal range.

After discharge, the patient returned home, and discontinued her medications (levothyroxine and olanzapine) as she continued to believe that she is old and no longer needed it. She was re-hospitalized a month later after presenting to the emergency department with abdominal pain requesting to have “babies flushed out of her”. Per chart review, she has been medication complaint since, living at home with her husband and following up periodically with her PCP.

Hypothyroidism, an extremely common medical condition, is particularly widespread among female and elderly patients, afflicting between 5 and 20% of elderly females [ 1 ]. While medical sequelae, including dyslipidemia, constipation, cold intolerance, fatigue, thinning hair, hoarseness, joint and muscle pain, and myxedema are commonly appreciated, the physical signs and symptoms in elderly patients may be mild, absent or atypical [ 1 ]. Psychiatric manifestations of hypothyroidism were initially recognized in the late 1880s, and include mood disturbance, cognitive impairment, and psychotic symptoms. While the mechanism is not fully understood, it is appreciated that a large percentage of thyroid hormone receptors reside in the brain (in the amygdala and hippocampus), and decreased conversion from T4 to T3 (active thyroid hormone) in elderly patients could be one mechanism predisposing this cohort to neuropsychiatric symptoms [ 1 , 2 ].

Asher first coined the term ‘myxedema madness’ in his 1949 case series [ 2 , 3 ], describing 14 different presentations of psychosis (most in older females) secondary to hypothyroidism. Even 70 years ago, he emphasized that this was a common phenomenon, which was often unrecognized by medical practitioners. Later estimates indicate that up to 15% of patients with hypothyroidism will present with psychiatric, rather than medical, symptoms [ 5 ]. A 1999 investigation of admissions of elderly patients to a geriatric psychiatry unit, found that over 1/3 of them had unrecognized medical conditions, with the top three including hypothyroidism [ 6 ]. Later case reports have described symptoms ranging from paranoia, delusions, and hallucinations, to catatonia, Capgras syndrome, and even mania in elderly patients with untreated hypothyroidism [ 7 , 8 , 9 ]. While some patients experience concomitant medical signs and symptoms, in many patients, the psychiatric or behavioral disturbance is the sole manifestation of an underlying endocrine disorder. We were fortunate in this case, that the patient had a clear history of hypothyroidism preceding the onset of psychotic symptoms, and a clear collateral history provided by family indicating she had become non-adherent to thyroid replacement. This prompted investigation of thyroid hormone levels immediately on presentation, and thyroid replacement was initiated without delay. In other circumstances, diagnosis can be more difficult. While the patient had a history of mild paranoid personality traits, she, like several other patients described in case studies, arrived to medical attention with a first episode of psychosis in older age, which should prompt an investigation of an organic etiology rather than attribution of symptoms to idiopathic psychiatric disturbance. The most challenging aspect of the case lied in the development of delusions specifically surrounding thyroid hormone replacement, in that the patient maintained conviction that she no longer needed to take her levothyroxine. This delusion persisted even after initiation of treatment, and left her vulnerable to non-adherence, relapse of psychotic symptoms, and medical morbidity. While her county commitment included provisions for Jarvis petition with mandatory administration of antipsychotic medications, no provision can mandate adherence to thyroid replacement therapy.

In hypothyroidism-induced psychiatric symptoms, thyroid replacement remains the gold-standard in treatment, however even with proper replacement, symptoms may take several months to abate [ 5 ]. For this reason, several providers in later case reports have described using short-term treatment with antipsychotics to ease distressing psychotic symptoms. The use of haloperidol, olanzapine, and risperidone has been described with success [ 5 , 7 , 8 , 9 ]. In this case, we found concomitant treatment with olanzapine and levothyroxine to be efficacious in reduction of psychotic symptoms, although it was impossible to quantify how much benefit was attributed to the antipsychotic. As the patient relapsed in follow-up prior to normalization of her thyroid hormone levels, we are unable to recommend a specific duration of therapy with antipsychotics as they were not able to be successfully tapered in the outpatient setting.

Similar to uncertainty the mechanism of development of neuropsychiatric symptoms of hypothyroidism, there remains question surrounding the degree of reversibility of these symptoms when adequate thyroid replacement has been achieved. Asher observed that a few of his original case subjects had persistent psychotic symptoms even after treatment [ 3 ]. It is theorized that metabolic impairment secondary to hypothyroidism may have the potential to cause irreversible CNS damage related to blood flow abnormalities and/or glucose metabolism [ 7 ]. We unfortunately did not observe a full restoration of our patient to previous level of cognitive function, as her delusional thoughts surrounding thyroid hormone replacement persisted. We were unable to obtain follow-up cognitive screening after hospitalization, and it was therefore uncertain if her mild cognitive deficits in delayed recall and calculation were a product of psychosis, cognitive impairment secondary to hypothyroidism, or an underlying cognitive impairment that had not been previously elucidated.

Hypothyroidism remains a common and important organic cause of neuropsychiatric symptoms, particularly in elderly female patients. All elderly patients presenting with cognitive decline and new-onset psychiatric or behavioral disturbance warrant screening of thyroid status as a potentially contributing factor. While thyroid replacement remains the standard treatment, addition of antipsychotic medications may be helpful to ease particularly distressing and long-lived symptoms in elderly patients. The optimal duration of antipsychotic therapy is unknown. This, in addition to several other case studies, illustrates the diversity of possible presentations of ‘myxedema madness’, heightening the need for vigilance in screening and diagnosis in order to prevent treatment delay and patient morbidity.

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JL is responsible for the initial draft and concept. AB is responsible for manuscript review and enhancement. The authors would like thank Dr. Teresa Rummans for the guidance and review of this manuscript. Both authors read and approved the final manuscript.

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Leal, J.C., Beito, A.H. Ramifications of untreated hypothyroidism: case report of cognitive impairment and acute psychosis in an elderly female. Ann Gen Psychiatry 19 , 48 (2020). https://doi.org/10.1186/s12991-020-00300-8

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Hashimoto’s thyroiditis. A case study of overt hypothyroidism

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This case describes a 32-year-old man who presents with subtle symptoms and signs but has florid Hashimoto’s thyroiditis. The diagnosis and treatment of Hashimoto’s thyroiditis are straightforward; however, there can be some complexities in how levothyroxine therapy is used.

Case scenario

A 32-year-old man presents to his GP with fatigue, which has been gradual in onset over the past six to 12 months. There has been no weight or appetite change, but he has mild constipation. His sleep patterns are unchanged.

He works in IT, is single and lives alone, following a break up one year prior. His past medical history is unremarkable, except for glandular fever at age 17 years. He is prone to mild anxiety but has not needed formal treatment for this. He has a healthy lifestyle; he exercises regularly and is a nonsmoker who drinks alcohol on weekends only (weekly intake of <60 g). There is a family history of hemithyroidectomy for benign thyroid nodular disease in his mother and his paternal grandfather had pernicious anaemia.

On examination, he is clinically euthyroid with normal blood pressure of 110/70 mmHg and a resting pulse of 60 beats per minute. Neck examination reveals a diffuse nontender goitre, just above normal thyroid size. Eye examination is normal apart from mild periorbital puffiness. There are no peripheral rashes. Cardiovascular, neurological and gastroenterological examinations are unremarkable.

Blood tests reveal a raised thyroid stimulating hormone (TSH) level of 105 mIU/L (reference range [RR] 0.4 to 4.0), free triiodothyronine (FT3) level within the reference range at 3.4 pmol/L (RR 2.6 to 6.0), a low free thyroxine (FT4) level of 8.9 pmol/L (RR 9 to 19) and an antithyroid peroxidase (anti-TPO) antibody titre of greater than 1300 mIU/L (RR <40). Full blood count, serum calcium and biochemistry are normal.

A diagnosis of autoimmune thyroid disease (AITD), specifically Hashimoto’s disease, is made.

What levothyroxine dose is needed initially?

This presentation is consistent with overt hypothyroidism secondary to Hashimoto’s thyroiditis. Thyroid hormone replacement with levothyroxine is indicated. A reasonable starting dose of levothyroxine is 1.6 mcg/kg body weight, with typical starting doses of 50 to 75 mcg daily, although a lower starting dose should be considered in older patients and those with a history of cardiac disease. 1 The dose is related to lean body mass and this generally translates to 75% measured body weight.

When should TSH be remeasured and how should the levothyroxine dose be titrated?

TSH levels can take four to six weeks to fully respond to any adjustments in levothyroxine dosage. It is important to remember that if thyroid function tests are repeated earlier than this the values will not be at steady state.

Which thyroid autoantibodies should be tested in the context of an elevated TSH level? Please advise how to interpret their presence or absence.

Anti-TPO antibodies, also known as thyroid microsomal antibodies (TMAbs), and antithyroglobulin antibodies (TgAbs) are tested at the outset, noting that the former are more likely to be raised. Some authors have suggested that measurement of TgAbs is not needed in AITD (except in the context of monitoring serum thyroglobulin in patients who have had total thyroidectomy for thyroid cancer). 2

Not all patients with AITD will have positive antithyroid antibodies. 3 Serial monitoring of antithyroid antibodies is not recommended as the levels do not guide the effectiveness of therapy; this is done by monitoring the TSH level. In contrast, measurement of TSH-receptor antibodies can be performed every four to six months in the follow up of patients with Graves’ disease as it helps to guide management and predict remission.

What are the indications for arranging imaging in the setting of hypothyroidism and which imaging investigation(s) are appropriate?

Thyroid imaging is not routinely required when diagnosing hypothyroidism unless there is clinical asymmetry or suspected nodularity on clinical examination. The imaging of choice to evaluate this would be a thyroid ultrasound scan. 4 This would not need to be followed by further imaging unless there was a clinical change or new indication, such as nodular disease.

Thyroid isotope functional scanning is not needed in Hashimoto’s disease and can cause confusion as it may show a diffuse increased pattern of isotope uptake (as seen in Graves’ disease). Thyroid isotope scanning is most useful in distinguishing Graves’ from thyroiditis (e.g. subacute or drug-induced), and from toxic nodules.

When would a pituitary or hypothalamic cause of hypothyroidism be suspected?

Secondary hypothyroidism is characterised by a TSH level in the low end of the normal range or below normal, and a FT4 level also low or low-normal (i.e. the TSH level is inappropriately low for the FT4 level). In some healthy individuals, a low-normal TSH level and low-normal FT4 level can be observed. Careful history needs to be evaluated and specialist input should be considered. In secondary hypothyroidism, FT3 levels tend to be low-normal and can be preserved in the normal range until the very late stages of both primary and secondary hypothyroidism (unless the patient is very sick or is taking amiodarone). Trends of thyroid function in different causes of hypothyroidism are outlined in Table 1 .

In hospitalised patients who are unwell, it is important to remember that thyroid function abnormalities can occur transiently as a sick euthyroid picture. This may resemble a pattern of secondary hypothyroidism. In sick euthyroid picture, the FT3 level is often low, with either normal or suppressed TSH and FT4 levels. Unless there is clinical suspicion of secondary hypothyroidism, in which case treatment should be considered, thyroid function should be repeated when the patient is well again.

What initial dose is appropriate for elderly patients or those with cardiac disease?

A starting dose of 25 to 50 mcg levothyroxine per day is recommended, depending on the age, body weight and degree of cardiac dysfunction. In most forms of cardiac disease, including arrhythmia, cardiac failure and ischaemic heart disease, gentle up-titration of levothyroxine should be considered, aiming to avoid over-replacement. 5

Anecdotally, some patients (including young people) experience anxiety symptoms, including palpitations, when levothyroxine is first commenced; even before the TSH has corrected down to normal. It may be necessary to reduce the starting levothyroxine dose further and then titrate upwards more gradually. There are occasional rare cases where TSH normalisation causes intolerable anxiety, and in these cases, a higher TSH level target of above 10 m IU/L might be acceptable, as long as the FT4 level is normal.

When could weekly dosing of levothyroxine be considered?

Ideally levothyroxine should be taken daily but its half-life of one week means that occasional missed doses are not problematic. If compliance is difficult, then the total dose for one week may be taken as a single dose. This approach is sometimes adopted under supervision for patients with psychiatric illness. 6

Should patients use the same type of levothyroxine (i.e. Eutroxsig vs Oroxine vs Eltroxin vs Levoxine) throughout their treatment in case of differences between the brands?

It is generally recommended that patients should continue with the same brand as anecdotally there can be minor differences in the bioavailability of different brands (e.g. a bigger dose of the newer non-refrigerated brand, Eltroxin, is sometimes needed). 7 However, the literature suggests that overall the bioavailability differences between brands are minimal.

What is the appropriate initial treatment target?

The treatment is targeted to achieve a TSH level in the normal range, ideally with resolution of symptoms. Exceptions to this would be in the case of a high-risk thyroid cancer patient, where post-thyroidectomy TSH level targets are individualised according to the evidence-based guidelines. Pregnancy is another circumstance where TSH level targets will differ, especially in relation to trimester and presence of positive anti-TPO antibodies (although this is an area where there is lack of general consensus). 2 Occasionally, patients have poor tolerance of levothyroxine symptomatically, for example those with intercurrent cardiac arrhythmias or significant anxiety, as mentioned earlier; in these cases, it may be acceptable to have a higher TSH level target (e.g. <10 mIU/L) as long as the FT4 level is in the normal range.

If the TSH level is still elevated after four to six weeks of levothyroxine treatment, what are the possible explanations and what is the suggested management?

It may take several months to reach target TSH levels in some patients, requiring ongoing titration of levothyroxine dosing. It is important to check adherence at each dose titration. Adherence should be checked by questioning the patient on when and how they take their tablets. It is advised that levothyroxine is usually taken in the morning on an empty stomach with no food or other medications for at least 30 minutes (or at bedtime, at least two hours after dinner). It is important to avoid calcium and iron tablets at the same time. 8 Impaired absorption may also be a contributing factor in some cases where it is difficult to normalise the TSH level on standard doses of levothyroxine (e.g. levothyroxine absorption in the small bowel may be affected in patients with coeliac disease).

Sometimes the TSH level may normalise but the FT4 level is elevated; this might be explained by the patient having their blood drawn soon after taking their morning levothyroxine dose. Ideally thyroid function testing should be performed pre-dose or six hours after their levothyroxine dose.

A significant change in body weight, especially of lean body mass, may explain a sudden change in levothyroxine dose requirement. It is wise to avoid too high an incremental change in dose at each dose adjustment.

Once the TSH level is in the target range and symptoms have resolved, what is the recommended frequency of monitoring the thyroid function tests?

When stability is achieved, it is acceptable to monitor the TSH level annually (or sooner if symptoms develop in the interim). 4 If frequent recent dose adjustments have been required then the TSH level will need more frequent monitoring. If a woman is considering pregnancy, thyroid function should be checked before conception and then at regular intervals (e.g. four to six weekly, throughout pregnancy). The woman should be advised that once a pregnancy test is positive, she should increase her levothyroxine dose by 30%, to reflect what happens in normal euthyroid women during pregnancy. 9 This is required because thyroid binding globulin levels rise during pregnancy.

What are the indications for referral of patients to a specialist in the setting of hypothyroidism?

Patients who have instability in levothyroxine dosing and persistence of symptoms, such as fatigue, may benefit from specialist referral. Patients may also need reassurance that rising antithyroid antibody titres are not sinister and do not need serial measurement. Levothyroxine requirements can rise by 30% in the first trimester in pregnancy and specialist input should be considered at this crucial stage to maintain the TSH level in the normal range. 4

In cases where patients are using or considering liothyronine (T3) replacement, either alone or in combination with T4 replacement, they should be referred for specialist input as this requires careful evaluation. 7 There is also an emergence of thyroid extract being used by the general population. This is not endorsed by the Therapeutic Goods Administration or the Endocrine Society of Australia. 7

When would you suspect poor adherence to treatment and can you provide some strategies for how to best manage this problem?

If there is significant instability in levothyroxine dosing without clear cause, adherence should be assessed. Persistently elevated TSH levels despite dosage adjustments, or significantly higher levothyroxine doses compared to a weight-based predicted dose requirement should trigger the clinician to question if there is poor adherence. 10

Ways to increase adherence include asking patients to set a reminder for their medication, either as a physical reminder or on their phone. Most refrigerated forms of thyroid hormone replacement come in a metal strip, thus cutting out the weekly required dose and keeping this separate can help keep track of the dose. Nonrefrigerated forms of thyroid hormone replacement can be kept in a weekly pill organiser to help increase compliance. Given the long half-life of thyroid hormone replacement, it is possible to dose every second day or even once a week to help improve compliance. 6

What are some potential drug interactions with levothyroxine and how might these affect the thyroid function test results? What should be the advice to patients taking these medications?

There are multiple medications that may interact with levothyroxine absorption, action or metabolism. Possible drug interactions with levothyroxine and some practical points are outlined in Table 2 .

Case continued

The patient achieves euthyroidism with levothyroxine replacement. His siblings are keen to be evaluated for hypothyroidism and both his brother and sister (aged 23 and 30 years respectively) are found to have normal TSH levels but mildly positive anti-TPO titres. With gradual dose weaning and monitoring of TSH levels, the patient is able to stop taking levothyroxine after three years. He has ongoing annual TSH level surveillance .

A 32-year-old man is diagnosed with florid Hashimoto’s thyroiditis after presenting with fatigue and a small diffuse goitre. His TSH and TMAb levels are very high but his FT3 level remains in the normal range, with a FT4 level just below the normal range. He becomes euthyroid with levothyroxine replacement and achieves remission over three years. TSH level surveillance allowed appropriate levothyroxine adjustment whilst on therapy and also appropriate monitoring to ensure the level remained in the normal range after levothyroxine weaning and cessation. ET

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Medicine (Baltimore)
v.99(11); 2020 Mar

Clinical case report

Introduction:.

The incidence of Hashimoto's thyroiditis among patients who have Turner syndrome (TS) has increased, but Graves’ disease (GD) in patients with TS is rarely reported. Here we report a rare case of TS with GD accompanied by hypogonadotropic hypogonadism.

Patient concerns:

We report the case of a 16-year-old girl who complained nervousness, fatigue, marasmus, heat intolerance, sweating, palpitation, and tremor lasting for more than a month. She had no medical history.

TS was diagnosed of the results of karyotyping demonstrated a gene karyotype of 46, X, i (X)(q10). GD was also diagnosed in this patient following the detection of thyroid function analysis.

Interventions:

Methimazole was administered after identification of GD. Due to the absence of secondary sex characteristics, the patient was given a conjugated estrogen preparation for 1 year, followed by the addition of estradiol cyproterone tablets for the onset of menstruation.

The hyperthyroidism symptoms of the patient had improved both clinically and laboratory tests after methimazole therapy. She was treated with estrogen and estradiol cyproterone, and the uterus and secondary sexual characteristics of the patient developed during 1 year follow-up.

Conclusion:

TS generally presents as hypergonadotropic hypogonadism. However, hypogonadotropic hypogonadism cannot completely exclude TS. The diagnosis of this disease depends on chromosomal examination. The disease should be detected and treated as early as possible to improve life quality of the patient.

1. Introduction

It is well known that Turner syndrome (TS) is among the most common chromosomal abnormalities resulted from structural or numeric abnormalities in the X chromosome. [ 1 – 3 ] It is found in 1/2000 to 1/3000 live-born females. [ 4 ] Characteristic physical abnormalities include a short stature, broad chest, webbed neck, kidney abnormalities, cubitus valgus, edema of the hands or feet, cardiac anomalies, gonadal dysgenesis, and delayed puberty. [ 1 , 5 ]

Patients with TS suffer from an increasing risk of autoimmune thyroid disorders, celiac disease, vitiligo, psoriasis, type 1 diabetes, adrenocortical insufficiency, juvenile idiopathic arthritis, and inflammatory bowel disease. [ 6 – 9 ] Hashimoto's thyroiditis (HT) is more frequent in patients who have TS. [ 10 , 11 ] From perspectives of pathogenic mechanism in autoimmune thyroiditis, a higher incidence of Graves’ disease (GD) might also be expected in TS patients. However, the connection between GD and this syndrome is significantly more infrequent than expected. [ 3 , 12 ] The aim of our study was to report a case of TS with GD.

2. Case presentation

This study was approved by the ethics committee of the First People's Hospital of Chongqing Liang Jiang New Area. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

In 2017, a 16-year-old girl first visited our hospital and complained nervousness, fatigue, marasmus, heat intolerance, sweating, palpitation, and tremor lasting for more than a month. Physical examination revealed smooth, moist, and warm skin; mild exorbitism, and diffused thyroid gland enlargement. Fine finger tremor was not detected. The patient's heart rate was 148 beats/minutes, the blood pressure was 112/66 mm Hg, and precordial systolic murmur of grade 1 was detected. Her height was 132 cm, the weight was 22 kg, and body mass index was 12.6 kg/m 2 . The patient's external genitalia were juvenile, with a pubertal state of A1M1P1 (Tanner staging). Hormonal assays, chromosomal karyotyping, X-ray analysis of bone age, abdominal and pelvic ultrasound, echocardiography, pelvic magnetic resonance imaging (MRI), and pituitary MRI were performed. Her bone age was 12 years old. The results of bone marrow puncture suggested iron deficiency anemia. Pituitary MRI revealed partial empty sella (Fig. (Fig.1A). 1 A). The results of karyotyping demonstrated a gene karyotype of 46, X, i (X)(q10), indicating TS.

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Object name is medi-99-e19518-g001.jpg

(A) Pituitary MRI revealed partial empty sella. (B) The uterus and both ovaries could not be identified by pelvis ultrasonography. MRI = magnetic resonance imaging.

Thyroid function analysis presented that the thyroid-stimulating hormone (TSH) level was 0.01 μIU/mL (normal range, 0.38–5.57 μIU/mL), the free (f) T4 level 3.16 ng/dL (normal range, 0.78–1.86 ng/dL), the free T3 level 6.46 pg/mL (normal range, 1.8–3.8 pg/mL), the antithyroglobulin antibody level 2321.7 IU/mL (normal range, 0.00–95.00 IU/mL), the antithyroid peroxidase antibody level 10,000 IU/mL (normal range, 0.00–25.00 IU/mL), and the TSH receptor antibody level >300 IU/L (normal range, 0.00–1.50 IU/L). GD was indicated by the results above, and methimazole was provided. The dose of methimazole was adjusted according to thyroid hormone levels.

Other hormonal tests demonstrated that the prolactin level was 3.10 ng/mL (reference range, 4.1–28.9 ng/mL) and the testosterone level was 8.95 ng/mL (reference range, 9.81–82.1 ng/mL). The patient's estradiol level was less than 25.00 pg/mL (reference range, 40.7–424.6 pg/mL), the luteinizing hormone level was less than 0.2 mIU/mL, and the level of follicle-stimulating hormone was less than 1.0 mIU/mL. The ovaries and uterus failed to be detected by pelvis ultrasonography (US) (Fig. (Fig.1B), 1 B), MRI, or computed tomography. Due to the absence of secondary sex characteristics, the patient was given a conjugated estrogen preparation for 1 year, followed by the addition of estradiol cyproterone tablets for the onset of menstruation. At the latest follow-up (17 years old), the patient's breasts had developed to Tanner stage 2. The patient's bone age was 13.5, and pituitary-enhanced MRI indicated that she still had partially empty sella (Fig. (Fig.2A). 2 A). Neither ovary could be detected by pelvis US; however, a small uterus was identified (Fig. (Fig.2 2 B).

An external file that holds a picture, illustration, etc.
Object name is medi-99-e19518-g002.jpg

(A) Pituitary-enhanced MRI indicated partially empty sella. (B) A small uterus was detected, and both ovaries could not be identified on pelvis ultrasonograph.MRI = magnetic resonance imaging.

3. Discussion

TS has a high incidence of autoimmune diseases, including HT, celiac disease, diabetes mellitus, inflammatory bowel disease, GD, and adrenocortical insufficiency, in girls. [ 13 , 14 ] Excess autoimmune antibodies likely result from X chromosome defects. [ 15 , 16 ] Haploinsufficiency of more than 10 genes located on the X chromosome was related to the immune regulating process, influenced the regulation of the immune response and led to altered immune tolerance. [ 15 , 17 ] Another mechanism suggested the upregulation of pro-inflammatory cytokines contributed to the increasing susceptibility of girls with TS to Autoimmune thyroid disease. [ 18 ] The reasons why the thyroid gland was an autoimmune target in TS patients have not yet been clearly identified, but the predilection could be elucidated based on the close connection between the thyroid autoimmunity and female gender. [ 19 ]

The present patient exhibited a diffused thyroid gland and thyrotoxicosis longer than approximately 1 month. The result of serum analysis was highly positive for antithyroid antibodies. [ 12 , 20 ] In contrast to the well-recognized combination of TS and HT, the combination of TS and GD is rather rare. [ 21 , 22 ] The next issue is why TS accompanied by hyperthyroidism is rare, compared with TS with HT. [ 3 , 23 ] This may be elucidated if typical GD and HT involve different autoimmune processes. [ 24 , 25 ] Since TS belongs to sex chromosome disorder, it is likely that the combination of these 2 disorders is attributed to a specific gene. [ 26 , 27 ] Considering the high susceptibility of patients with TS to autoimmune disease, human leukocyte antigen genes analysis is of vital importance. [ 6 , 28 ] To date, there has been no clear explanation to explain this problem. In conclusion, the connection between GD and TS is far from elucidated, and we cannot exclude that the 2 diseases are just related by chance. [ 29 ] In our patient, treatment with thiamazole was continued and the thyroid function has stayed within normal ranges.

TS generally presents as hypergonadotropic hypogonadism, [ 30 ] but this patient presented with hypogonadotropic hypogonadism. This may be related to the patient's vacuolar sella turcica, which can compress the pituitary tissue and displace the pituitary stalk, thus leading to a decline in hypophysis function; in addition, this may be related to the patient's malnutrition. The patient was given successively estrogen and estradiol cyproterone treatment to develop the uterus and secondary sexual characteristics.

4. Conclusion

Vigilance for TS is required when young girls exhibit hyperthyroidism accompanied by growth retardation and gonadal dysplasia. A decrease in the gonadotropin expression cannot completely exclude TS. The diagnosis of this disease depends on chromosomal examination. The disease should be detected and treated as early as possible to improve the short-term and even long-term life quality of the patient.

Acknowledgments

The authors are appreciative to AJE ( https://www.aje.com/ ) for language editing.

Author contributions

Conceptualization: Mei Yang.

Project administration: Hongmin Zhang, Xingyu Zhang.

Supervision: Mei Yang.

Writing – original draft: Hongmin Zhang.

Writing – review & editing: Hongmin Zhang, Mei Yang.

Abbreviations: GD = Graves’ disease, HT = Hashimoto's thyroiditis, MRI = magnetic resonance imaging, TS = Turner syndrome, TSH = thyroid-stimulating hormone, US = ultrasonography.

How to cite this article: Zhang H, Zhang X, Yang M. Clinical case report: A case of Turner syndrome with Graves’ disease. Medicine . 2020;99:11(e19518).

Informed written consent was obtained from the patient's guardians for publication of this case report and accompanying images.

The authors have no conflicts of interest to disclose.

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A Case Study of Hypothyroidism and High T3, Low Metabolism, High Triglycerides, and Liver Dysfunction

This isn’t something you see every day.

So, it makes for an interesting case study.

There’s a lot going on here, including a case of hypothyroidism and high T3.

When working with clients, we typically discuss health history, symptoms, lab work, etc. in order to help paint the bigger picture of what’s really happening in the body.

We then take all of that information and look for patterns and clues that point to certain common hormonal and metabolic dysfunctions.

Oftentimes we find many indicators that all point to the same problem(s).

Sometimes the answers are less obvious. In these cases, we have to narrow down the culprits and do some experimentation in order to isolate the problem(s).

Let’s see what sense we can make of this interesting case.

Hypothyroidism and High T3 Case Study Background

This case study is a 64 year old post menopausal female experiencing many thyroid symptoms including:

Excess Abdominal Fat
Hypertension
Low Body Temperature
Always Cold
Thinning Eyebrows
Restless Sleep
Muscle Weakness
Difficulty Concentrating

The following are the pertinent lab results for discussion:

TSH – <0.005 IU/mL (0.450 – 4.50)
T4, free – 1.26 ng/dL (0.82 – 1.77)
T3 – 204 ng/dL (71 – 180)
Reverse T3 – 17.0 ng/dL (9.2 – 24.1)
Cholesterol, Total – 238 mg/dL (100 – 199)
Triglycerides – 401 mg/dL (0 – 149)

The subject currently uses 2.5 grains of Nature-throid and additional desiccated thyroid multi-dosed throughout the day.

The subject is concerned about their abnormal thyroid hormone labs.

Temperature and Pulse are as follows:

Basal Waking Temperature – Consistently low and fluctuates on a daily basis between 96.5 F (35.8 C) and 97.7 F (36.5 C).
Post Breakfast Temperature – Often drops to below Basal Waking Temperature indicating elevated nighttime/morning stress hormones.
Afternoon Temperature – Consistently low, never rising above 97.7 F (36.5 C).

Interesting Thyroid Observations, Patterns, and Clues

The first things to stand out in this case were the common symptoms associated with elevated cortisol , which is common in hypothyroidism.

Elevated Cholesterol
Elevated Triglycerides
Post Breakfast Body Temperature Drop

This elevated cortisol is something that will be mentioned throughout the case study, as you’ll see in a minute.

I also suspect, given the symptoms above, that there is some degree of insulin resistance, which is also commonly found in cases of elevated cortisol.

Additional testing may be needed to determine this.

Hypothyroidism and High T3

According to the lab values provided above, particularly the elevated T3, the subject would likely be incorrectly diagnosed as hyper-thyroid by their doctor.

While her T3 levels are above the recommended reference range, it’s important to ALWAYS observe symptoms along with temperature and pulse when assessing thyroid function.

Want to learn how to do this yourself?

I cover everything you need to know about thyroid testing and more in this FREE training called The Ultimate Thyroid Testing Protocol .

You can access this training here .

Her basal morning body temperature is consistently low and never reaches close to normal throughout the day.

If she were truly hyper-thyroid, her body temperature would be above normal, not suppressed.

She would also exhibit hyper-thyroid symptoms instead of the common hypothyroid symptoms of which she complains, such as always feeling cold.

When we see high T3 levels and low body temperature, we know that thyroid hormone (T3) is being blocked and not being used properly.

In some cases, we find this being caused by either low cholesterol or low vitamin A, yet both have been ruled out in this case.

Her reverse-T3 is higher than we like to see, which can be another factor.

Ideally we like to see reverse-T3 at the low end of the reference range.

It often increases in response to stress in an attempt to reserve energy by inhibiting metabolism and the use of T3.

The suspected elevated cortisol mentioned above is likely at play here.

Elevated cortisol will block thyroid function at the liver by increasing the conversion of inactive thyroid hormone (T4) into reverse-T3.

Because of this, the subject would likely be a good candidate for T3-Only thyroid hormone therapy.

Her TSH is suppressed, which we would expect given the amount of thyroid hormone she is using.

This isn’t a concern and is often desirable.

Hypothyroidism and High Triglycerides

Triglycerides are often misunderstood but can be a very telling sign of thyroid and metabolic dysfunction.

When you consume carbohydrates, they are first and foremost metabolized and used for energy production.

What carbohydrates are not required for energy production are then stored in the liver in the form of glycogen.

Think of glycogen as your fuel reserves that are stored and used between meals and during the night when you’re not eating anything.

Your liver needs usable thyroid hormone (T3) along with other nutrients in order to store and release glycogen.

Keep in mind that this client is using T3 properly.

Carbohydrates that aren’t used for energy or stored in the liver as glycogen are then converted into the storage form of fatty acids known as triglycerides.

What’s interesting is that the subject’s triglycerides are extremely elevated, above 400.

While triglycerides themselves aren’t necessarily dangerous, they can help explain the underlying dysfunctions that are the real problem.

In this case, it’s a sign of impaired oxidative metabolism, potential insulin resistance, and likely issues with the liver storing and releasing glycogen.

In other words, if you can’t metabolize carbohydrates or store them in your liver, then your body has no choice but to store them as triglycerides.

The elevated cortisol does come into play here as well.

Cortisol’s primary function is to break down muscle tissue protein and convert it into glucose/carbohydrate.

This is likely raising the subject’s blood sugar/glucose. Yet, since she can’t metabolize that glucose, it’s being forced into storage as even more triglycerides.

It’s also worth noting that if excessive protein is being broken down, it can limit the amount of protein available to support liver and thyroid function.

So, getting adequate dietary protein becomes increasingly important as well.

Focus should be placed on restoring healthy oxidative metabolism, which will likely correct the high triglycerides.

Case Study Recommendations

As mentioned previously, the subject may be a good candidate for T3-Only thyroid hormone therapy.

But there’s a lot more than can be done as well.

Focus should be placed on determining the underlying cause of the elevated cortisol, such as blood sugar instability, excessive exercise, estrogen dominance, elevated serotonin, etc.

Hypothyroidism is a common cause of blood sugar instability, so further observation of dietary practices should be done to determine if this is a probable cause.

The subject mentioned exercising by hiking anywhere from 5-10 miles and experiencing fatigue within a couple of hours.

This would be considered excessive exercise for just about any hypothyroidism sufferer and can stimulate significant cortisol production.

Serotonin is another common cause of elevated cortisol, which I suspect may be an issue given some of the subject’s other symptoms.

It may be worth testing for serotonin to confirm or rule it out.

It would also be important to ensure that adequate protein was being consumed.

Focus should also be placed on improving liver health, restoring oxidative metabolism, and improving insulin resistance.

To do this, we would first focus on B-Vitamins, particularly Thiamine (Vitamin B1), Niacinamide (Vitamiin B3), and Biotin (Vitamin B7), all found in our Vitamin B Thyroid Complex .

Higher therapeutic doses of Niacinamide (Vitamin B3) may be necessary.

( Note : Want to learn more about the benefits of Thiamine (Vitamin B1)? Take a look at this post on “ Thiamine and Thyroid: 3 Hidden Thyroid Benefits You Don’t Want to Miss ”.)

In addition, stimulating healthy oxidative metabolism through the use of coffee/caffeine, magnesium, and calcium can be helpful.

Click here for additional resources on magnesium .

Click here for additional resources on calcium .

Aside from the additional testing that may prove helpful, we would work on implementing these recommendations as a starting point while continuing to observe temperature and pulse throughout the process.

We would then retest after two to three months to observe changes and further fine-tune the recommendations based on the results.

As you can see, there’s a lot that we can learn from observing symptoms and labs and interpreting them with respect to temperature and pulse.

By doing so, we can often discover the underlying the hidden underlying issues that we can then correct to help restore thyroid function and metabolism.

Want a simple way to get started yourself?

It covers thyroid testing extensively and gives you the exact blueprint of where I always start when working with my clients.

About the Author: Tom Brimeyer

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Will I be able to loose weight eating this diet . I also am loosing hair , have bad dry skin and even scaly patches on my arms and legs , also all my nails are paper thin and broken . I’ve been on thyroid medicine for around 50 years . Its isnt working any more . Help

Thanks for this Tom. Very interesting. I’d love to read more case studies in the future, if you care to share them.

A post-menopausal and a peri-menopausal woman both have lowered progesterone, which could raise cortisol.

I agree. These case studies will help me try to figure out after 8 years why I can’t get off my WP Thyroid, can’t seem to lower my blood sugar, and fix my metabolism. I don’t eat sugar, processed foods, nor grains…but concentrate on healthy fats, grassfed/pasture raised proteins, berries, green apples, mineral supplementation, oodles of supplements to support adrenals, chelate the heavy metals, removed amalgams through biological dentist, etc. Just found out I have Epstein-Barr Virus, so maybe this is the reason my thyroid numbers drop when I try to drop my WP Thyroid med. I’m tired of being fat. So, again, THANKS TOM! I’m always on the look-out for anything else I can do to stop this madness in my body, and these case studies are VERY helpful!

Ooops, one more comment. I’ve also been able to drop my TGB antibodies from over 400 down to 3. TPO has never been an issue….but again, can’t seem to get my blood sugar and metabolism fixed…and get off WP Thyroid medication. Grrrrrrr

Thanks for the excellent video. I’m looking forward to receiving the next two. I’m currently being tested for hypothyroidism and Hashimoto. My blood tests seem to be normal but I have all the symptoms of hypothyroidism. I feel terrible but it’s hard to get doctors to agree on what’s wrong with me. I have been on meds for over ten years but in the last few years my body is going crazy. Thanks again for the information.

Thank you for another amazing info. I’m on your Hypothyroid Revolution diet plan and bought all the supplements and I’m doing just great finally and trying to tune in my needs day by day. What is your thoughts about Black seed supplements (nigella sativa)? I see there is this new trend, they advertise it as a solution literally for everything. Is it safe in your opinion? Thanks for everything

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Case Study week 7

ORIGINAL RESEARCH article

Overweight as a biomarker for concomitant thyroid cancer in patients with graves’ disease.

Department of Surgery, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

The incidence of concomitant thyroid cancer in Graves’ disease varies and Graves’ disease can make the diagnosis and management of thyroid nodules more challenging. Since the majority of Graves’ disease patients primarily received non-surgical treatment, identifying biomarkers for concomitant thyroid cancer in patients with Graves’ disease may facilitate planning the surgery. The aim of this study is to identify the biomarkers for concurrent thyroid cancer in Graves’ disease patients and evaluate the impact of being overweight on cancer risk. This retrospective cohort study analyzed 122 patients with Graves’ disease who underwent thyroid surgery at Seoul St. Mary’s Hospital (Seoul, Korea) from May 2010 to December 2022. Body mass index (BMI), preoperative thyroid function test, and thyroid stimulating hormone receptor antibody (TR-Ab) were measured. Overweight was defined as a BMI of 25 kg/m² or higher according to the World Health Organization (WHO). Most patients (88.5%) underwent total or near-total thyroidectomy. Multivariate analysis revealed that patients who were overweight had a higher risk of malignancy (Odds ratios, 3.108; 95% confidence intervals, 1.196–8.831; p = 0.021). Lower gland weight and lower preoperative TR-Ab were also biomarkers for malignancy in Graves’ disease. Overweight patients with Graves’ disease had a higher risk of thyroid cancer than non-overweight patients. A comprehensive assessment of overweight patients with Graves’ disease is imperative for identifying concomitant thyroid cancer.

1 Introduction

Graves’ disease (GD) is an autoimmune disease that causes hyperthyroidism by stimulating the thyroid gland to produce excessive thyroid hormone due to the presence of thyroid stimulating hormone receptor antibody (TR-Ab) ( 1 – 4 ). Surgical intervention is required for the management of GD in cases of failed medical therapy, severe or rapidly progressing disease with compressive symptoms, concomitant thyroid cancer, worsening Graves’ ophthalmopathy, or based on patient’s preference ( 1 , 5 – 7 ).

The reported incidence of concomitant thyroid cancer in patients with GD varies, ranging from 1% to 22%, and some studies reported that the incidence of thyroid cancer is higher in patients with GD than the incidence in the general population ( 8 – 11 ). Although the relationship between GD and thyroid cancer is unclear, GD can make the diagnosis and management of thyroid nodules more challenging ( 12 – 16 ). In patients with GD and concomitant thyroid cancer, most surgeries are planned after nodules are diagnosed by ultrasound or fine-needle aspiration biopsy (FNAB). However, thyroid cancer is occasionally identified incidentally in the pathologic examination after surgery ( 17 – 19 ). These cases are indications that surgery was necessary, and cancer could have been missed if surgery had not been performed for other reasons. Therefore, identifying biomarkers for concomitant thyroid cancer in patients with GD may facilitate planning the surgery and more thorough screening, even if a nodule is not discovered before surgery.

Previous studies have identified risk factors for concomitant thyroid cancer in patients with GD, including TR-Ab, preoperative nodules, previous external radiation, and younger age ( 13 , 20 – 24 ). Regardless of the existence of GD, morbid obesity affects the incidence and aggressiveness of thyroid cancer in euthyroid patients ( 25 – 29 ). However, few studies have investigated the relationship between thyroid cancer in patients with GD and obesity. In a study of 216 GD patients, those with thyroid cancer had significantly higher body mass index (BMI) compared to those without thyroid cancer ( 30 ). Since weight loss is common in patients with GD ( 31 ), investigations into the relationship between being overweight or obese and GD are needed. The aim of this study was to identify biomarkers for concurrent thyroid cancer in patients with GD and identify the effects of being overweight on cancer risk.

2 Materials and methods

2.1 patients.

We retrospectively reviewed the medical charts and pathology reports of 132 patients with GD who underwent thyroid surgery from May 2010 to December 2022 at Seoul St. Mary’s Hospital (Seoul, Korea). Five patients with newly diagnosed GD after lobectomy, one patient with distant metastasis of thyroid cancer at initial diagnosis, one patient who underwent the initial operation at a different hospital, two patients with insufficient data, and one patient who was lost to follow-up were excluded from the study. Thus, 122 patients were included in the analysis ( Figure 1 ). The mean follow-up duration was 52.8 ± 39.6 months (range, 4.8–144.0 months).

Figure 1 Participant flow diagram of patient selection. GD, Graves’ disease.

Overweight was defined as a BMI of 25 kg/m² or higher according to the World Health Organization (WHO) and the International Association for the Study of Obesity (IASO) ( 32 ). WHO and IASO define obesity as a BMI of 30 or above ( 33 , 34 ). However, only 7 (5.7%) patients were obese in the present study, according to these criteria (BMI ≥ 30 kg/m²). Moreover, Asian countries have lower cut-off values due to a higher prevalence of obesity-related diseases at lower BMI levels ( 35 ). As this study included Korean individuals, the patients were divided by a BMI of 25, which is the standard for overweight defined by WHO and for obesity in Asia ( 36 ).

2.2 Preoperative management and follow-up assessment

Height and weight were assessed in all patients the day prior to surgery to mitigate potential measurement and temporal biases. BMI was calculated by dividing the weight in kilograms by the square of their height in meters (kg/m2). The duration of GD was defined as the number of years between the date of initial diagnosis and the date of surgery. Disease status was assessed using the serum thyroid function test (TFT), including thyroid stimulating hormone (TSH), triiodothyronine (T3), free thyroxine (T4), and TR-Ab levels before surgery, either as outpatients or after hospital admission. Pathology reports were used to review the final results after surgery.

Patients with GD received treatment based on the 2016 American Thyroid Association (ATA) guidelines for hyperthyroidism ( 1 ). Patients with concomitant thyroid cancer were managed according to the 2015 ATA management guidelines for differentiated thyroid cancer ( 37 ). After the thyroidectomy, all patients discontinued antithyroid drugs and started taking L-T4 at a daily dosage suitable for their body weight (1.6 μg/kg). Patients with concomitant thyroid cancer were closely monitored every 3–6 months during the first year and then annually thereafter. Thyroid ultrasonography was conducted annually for patients with cancer.

2.3 Primary endpoint

The primary endpoint was the rate of overweight in GD patients with and without concomitant thyroid cancer.

2.4 Statistical analysis

Continuous variables were reported as means with standard deviations, while categorical variables were presented as numbers with percentages. Continuous variables were compared with Student’s t-tests and Mann-Whitney test, and categorical characteristics were compared using Pearson’s chi-square tests or Fisher’s exact tests. Univariate Cox regression analyses were conducted to determine the biomarkers for postoperative hypoparathyroidism and malignancy in patients with GD. Statistically significant variables were included in the multivariate Cox proportional hazard model. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Statistical significance was defined as p-values < 0.05. The Statistical Package for the Social Sciences (version 24.0; IBM Corp., Armonk, NY, USA) was used for all statistical analyses.

3.1 Baseline clinicopathological characteristics of the study population

Table 1 presents the clinicopathological characteristics of the 122 patients in the study. The average age was 45.7 years (range, 15–77), and the average BMI was 23.4 kg/m2 (range, 17.2–37.0). 35 patients (28.7%) were classified as overweight. The mean disease duration was 5.9 years, and the mean gland weight was 105.6 grams (range, 7.6–471.4). Most patients (110 patients, 90.2%) underwent total or near-total thyroidectomy; 11 (9.0%) patients underwent lobectomy, and one patient (0.8%) underwent total thyroidectomy with modified radical neck dissection (mRND). The 11 patients who underwent lobectomy exhibited proper regulation of thyroid function prior to surgery, and preoperative diagnosis confirmed the existence of unifocal cancer or follicular neoplasm with a size smaller than 2cm (range, 0.3-1.8). The pathology was benign in 79 (64.8%) patients, while 43 (35.2%) patients exhibited malignant pathology. The preoperative TFT showed a mean TSH level of 1.7 ± 7.8 mIU/L (range, 0.0–77.9), a mean T3 level of 1.7 ± 0.7 ng/mL (range, 0.5–5.1), a mean free T4 level of 1.4 ± 0.7 ng/dL (range, 0.3–4.1), and a mean TR-Ab level of 26.4 ± 35.7 IU/L (range, 0.3–292.8). Forty-four patients (36.1%) underwent surgery due to refractory disease or medication complications, 31 (25.4%) patients underwent surgery due to huge goiters with compressive symptoms, 10 patients (8.2%) underwent surgery due to ophthalmopathies, and 37 (30.3%) patients underwent surgery due to cancer or follicular neoplasm diagnoses before surgery. Postoperative complications were described in Supplementary Table 1 . Unilateral vocal cord palsy (VCP) occurred in 3 (2.5%) patients, and no bilateral VCP occurred. Hypoparathyroidism was transient in 48 (39.3%) patients and permanent in 3 (2.5%) patients. No cases of hematoma or thyroid storm occurred.

Table 1 Baseline clinicopathological characteristics of the study population.

3.2 Clinicopathological characteristics of thyroid cancer in patients with Graves’ disease

Table 2 shows the clinicopathological characteristics of the 43 patients diagnosed with thyroid cancer. 42 (97.7%) patients were diagnosed with PTC, while 1 (2.3%) patient had minimally invasive Hürthle cell carcinoma. Thirty-four (79.1%) patients were preoperatively diagnosed with papillary thyroid cancer (PTC) or Hürthle cell neoplasm, while cancers were discovered incidentally in 9 (20.9%) patients. Ten (23.3%) patients underwent lobectomy, 32 (74.4%) patients underwent total or near-total thyroidectomy, and one (2.3%) patient underwent total thyroidectomy with mRND. The most prevalent subtype of PTC was the classic type, accounting for 81.0% of PTC cases. Follicular, tall cell, and oncocytic variants comprised 7.1%, 4.8%, and 7.1% of PTC cases, respectively. The average tumor size was 0.9 cm (range, 0.1–3.4 cm). Multifocalities were observed in 19 (44.2%) patients and bilaterality was observed in 11 (25.6%) patients. Lymphatic invasion, vascular invasion, and perineural invasion were observed in 12 (27.9%), 1 (2.3%), and 2 (4.7%) patients, respectively.

Table 2 Clinicopathological characteristics of thyroid cancer in Graves’ disease.

As shown in Table 3 , the 34 patients who were preoperatively diagnosed with cancers were compared with the 9 patients with incidentally discovered cancers after surgery. No differences in BMI were detected between the two groups (23.3 ± 3.7 vs. 24.4 ± 4.1; p = 0.450). Gland weight was significantly lighter in patients with preoperatively diagnosed cancers compared with gland weights in the incidentally discovered group (35.3 ± 40.1 vs. 119.2 ± 62.9; p < 0.001). TR-Ab levels were significantly lower in the preoperatively diagnosed group compared with the levels in the incidentally discovered group (5.5 ± 5.3 vs. 31.4 ± 28.9; p = 0.005). Tumor size was significantly larger in the preoperatively diagnosed group compared with the size in the incidentally discovered group (1.0 ± 0.7 vs. 0.4 ± 0.2, p = 0.001). The causes of surgery were also significantly different between the two groups ( p < 0.001). In the incidentally discovered cancer group, 66.7% of the patients underwent surgery due to refractory disease or medication complications, 22.2% due to large goiters, and 11.1% due to nodules detected on preoperative ultrasound. In contrast, all surgeries were performed due to the preoperative detection of cancer in the group with preoperative diagnosis.

Table 3 Comparison of thyroid cancers in Graves’ disease with or without preoperative pathologic diagnosis.

3.3 Comparison of Graves’ disease subgroups with or without thyroid cancer

Patients with GD with or without thyroid cancer were compared, as shown in Table 4 . Patients with GD and thyroid cancer were significantly more overweight (BMI ≥ 25 kg/m2) than patients with GD without thyroid cancer (44.2% vs. 20.3%; p = 0.005). The duration of GD was longer in patients without cancer than the duration in patients with cancer (6.9 ± 7.1 vs. 3.9 ± 4.0 years; p = 0.003). Gland weights were significantly heavier in patients without cancer compared with patients with cancer (134.7 ± 88.9 vs. 52.9 ± 56.6 g; p < 0.001). Preoperative TR-Ab was significantly higher in patients without cancer compared with TR-Ab levels in patients with cancer (34.9 ± 40.1 vs. 10.9 ± 17.2 IU/L; p < 0.001).

Table 4 Comparison between sub-groups of Graves’ disease with or without thyroid cancer.

3.4 Univariate and multivariate analyses of biomarkers for malignancy in patients with Graves’ disease

Univariate analysis revealed that being overweight, the duration of GD, gland weight, and preoperative TR-Ab were significant biomarkers for malignancy in patients with GD ( Table 5 ). In the multivariate analysis, being overweight, lighter gland weight, and lower postoperative TR-Ab levels were confirmed as biomarkers for malignancy. Being overweight emerged as the most significant biomarker for malignancy (OR, 3.108; 95% CI, 1.196–8.831; p = 0.021).

Table 5 Univariate and multivariate analyses of biomarkers for malignancy in patients with Graves’ disease.

4 Discussion

The present study aimed to investigate the biomarkers for concomitant thyroid cancer in patients with GD and identify the effects of being overweight on cancer risk. Patients with GD and concomitant thyroid cancer were more likely to be overweight compared to patients with GD without cancer. In addition, overweight patients had a significantly increased risk of developing thyroid cancer compared to non-overweight patients.

In GD, TR-Ab stimulates the TSH receptor, leading to increased production and release of thyroid hormones. Excessive thyroid hormone affects entire body tissues, including thermogenesis and metabolic rate. GD symptoms vary by hyperthyroidism severity and duration ( 1 , 2 , 31 ).

The reported incidence of concomitant thyroid cancer in GD ranges from 1% to 22% ( 8 – 11 , 38 , 39 ). Since this study included GD patients who meet the surgical indications, the cohort demonstrated a higher prevalence of thyroid cancer compared to the general GD population. The frequency of cancer in patients with GD is consistent with the frequency in the general population. All types of thyroid cancer can occur in GD patients; PTC is the most common cancer followed by FTC ( 8 , 40 ). While surgery is not the primary treatment for GD, surgical intervention may be performed in cases that meet specific surgical indications ( 1 , 2 ). According to the 2016 ATA guidelines for hyperthyroidism, near-total or total thyroidectomy is recommended for surgical intervention of GD ( 1 ). However, 11 patients underwent lobectomy in our study; these patients maintained a euthyroid state with preoperatively detected nodules, and the decision to perform lobectomy was made based on the individual preferences of the patients and the multidisciplinary medical team. GD did not recur in any of the 11 patients who underwent lobectomies.

Numerous studies have demonstrated that thyroid cancer is more aggressive in obese and overweight patients, irrespective of the coexistence of GD ( 26 – 28 , 41 , 42 ). In a case-control study, Marcello et al. showed that being overweight (BMI ≥ 25 kg/m2) is associated with an increased risk of thyroid cancer (OR, 3.787; 95% CI, 1.110–6.814, p < 0.001) ( 27 ). GD is a hypermetabolic disease, which usually causes weight loss, and obesity is not common in patients with GD ( 31 ). Weight gain is a useful indicator for evaluating initial treatment success for hyperthyroidism, but weight loss should be considered differently in obese patients. Hoogwerf et al. reported that despite greater weight loss at the time of the initial diagnosis of GD, obese patients were still morbidly obese and had higher thyroid function values compared to non-obese patients ( 43 ). The diagnosis of hyperthyroidism may be delayed in these patients as weight loss is often perceived as a positive outcome. The results of our study agree with earlier studies and are supported by an OR of 3.108, which is similar to the OR of 3.787 reported in the Marcello study ( 27 ).

The mean tumor size in this study was 0.9 cm, which was similar to previous studies concerning thyroid cancer in patients with GD. In a study by Hales et al., the average size of thyroid cancer in patients with GD was 0.91 cm, which was significantly smaller than the average size in the euthyroid group (0.91 vs. 2.33 cm) ( 44 ). However, previous studies demonstrated a more aggressive thyroid cancer phenotype in patients with GD ( 9 , 45 ). In addition, Marongju et al. revealed a higher degree of aggressiveness in some patients with microcarcinoma and GD compared to controls, even when tumor characteristics were favorable, which conflicts with other studies ( 45 ). The presence of both thyroid cancer and GD is a surgical indication, regardless of the size of the cancer. Thus, microcarcinoma in GD should not be overlooked.

Lower preoperative TR-Ab were biomarkers for malignancy in patients with GD in this study. TR-Ab, which promotes hyperthyroidism by inducing the production and release of thyroid hormones, is a diagnostic biomarker for GD ( 13 , 20 ). Several studies have explored the link between TR-Ab and concurrent thyroid cancer in patients with GD and showed that TR-Ab can potentially trigger thyroid cancer by continuously stimulating thyroid cells ( 20 , 46 ). However, other studies did not detect an association between TR-Ab and concomitant thyroid cancer in patients with GD, which is consistent with our findings ( 16 , 40 , 47 ). Yano et al. demonstrated that elevated TR-Ab was significantly associated with smaller tumor size in patients with GD and had no significant impact on multifocality or lymph node metastasis ( 40 ). Similarly, Kim et al. concluded that the behavior of thyroid cancer is not affected by TR-Ab ( 16 ). We attributed these results to the fact that patients with GD and cancer may undergo surgery due to the detection of nodules that were relatively well-controlled with medication for a long time. On the other hand, in the GD without cancer group, surgery is often performed due to uncontrolled hyperthyroidism despite medication, and TR-Ab levels may be higher. Future research should investigate the association between TR-Ab levels and thyroid cancer risk in larger studies to clarify the contradictory findings in previous studies.

The lighter gland weight was a biomarker for the concomitant thyroid cancer; however, measuring the gland weight before surgery is not feasible in clinical practice. Nonetheless, ultrasound can estimate thyroid volume preoperatively using the ellipsoidal formula: Volume = (π/6) × Length × Width × Depth. The overall thyroid volume can be derived by adding together the volume calculations for both lobes ( 48 ). Future studies will focus on applying this method clinically and investigating the link between preoperative thyroid dimensions and the prevalence of concomitant thyroid cancer.

This study’s strengths include long follow-up duration with more than 100 patients, providing robust results. Additionally, the study included various demographic and clinical factors, providing a comprehensive evaluation of thyroid cancer biomarkers in patients with GD. Of note, this study focused on the effect of being overweight in patients with GD, rather than the general population. However, the relationship between GD, thyroid cancer, and overweight is complex and may involve a variety of factors, including genetics, hormonal imbalances, and lifestyle factors.

This study has several limitations. First, its retrospective design and relatively small sample size may have introduced selection and information bias. Second, the study was conducted in the Korean population, limiting generalizability to other populations. Lastly, BRAF and TERT assessments were conducted in a limited cohort, insufficient to represent the entire study population, and there is a paucity of data on the molecular characteristics and genetic information for thyroid cancer. Further research should investigate the effects of being overweight on thyroid cancer risk in a diverse population of patients with GD to determine whether the results are generalizable. In addition, more investigations into the long-term postoperative outcomes of patients with GD with and without concomitant thyroid cancer may provide a more comprehensive evaluation of surgical outcomes.

5 Conclusions

Overweight individuals with GD have a higher risk of developing concomitant thyroid cancer. This highlights the importance of thorough screening and comprehensive evaluations specifically tailored to overweight GD patients to detect and prevent thyroid cancer. Further research is needed to elucidate the underlying mechanisms and the effects of being overweight on thyroid cancer risk in GD patients in the general population.

Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethics statement

The studies involving humans were approved by Institutional Review Board of Seoul St. Mary’s Hospital, The Catholic University of Korea (IRB No: KC23RISI0054 and date of approval: 2023.04.21). The studies were conducted in accordance with the local legislation and institutional requirements. The ethics committee/institutional review board waived the requirement of written informed consent for participation from the participants or the participants’ legal guardians/next of kin because due to the retrospective nature of this study.

Author contributions

JP: Writing – review & editing, Writing – original draft, Visualization, Validation, Investigation, Formal analysis, Data curation, Conceptualization. SA: Writing – review & editing, Software, Data curation. JB: Writing – review & editing, Supervision, Software, Resources, Methodology. JK: Writing – review & editing, Supervision, Resources, Methodology. KK: Writing – review & editing, Writing – original draft, Visualization, Validation, Software, Resources, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization.

The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fendo.2024.1382124/full#supplementary-material

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Keywords: Graves’ disease, thyroid cancer, overweight, thyroid stimulating hormone receptor antibodies, BMI - body mass index

Citation: Park J, An S, Bae JS, Kim JS and Kim K (2024) Overweight as a biomarker for concomitant thyroid cancer in patients with Graves’ disease. Front. Endocrinol. 15:1382124. doi: 10.3389/fendo.2024.1382124

Received: 05 February 2024; Accepted: 03 April 2024; Published: 22 April 2024.

Reviewed by:

Copyright © 2024 Park, An, Bae, Kim and Kim. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Kwangsoon Kim, [email protected]

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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Severe primary hypothyroidism in an apparently asymptomatic 19-year-old woman: a case report

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23 years of misdiagnosed central hypothyroidism with a normal TSH: Case study

The misdiagnosed patient’s statement

Hypothyroid kidneys

Hypothyroid cholesterol levels

Medications that can cause transient CeH

A possible cause: Autoimmune hypophysitis without MRI signs

Many clues could have pointed to her hypothyroid state.

Hypothyroid heart: Pericardial effusion

Other hormones: LH, FSH, and Cortisol

1. Plot TSH-FT4 results onto Hadlow’s graphs.

2. SPINA-Thyr analysis and the FT3:FT4 ratio

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