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.
The misdiagnosed patient’s statement
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.”
The authors’ learning points
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].
What is central hypothyroidism (CeH)?
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.
A rare condition, or rarely diagnosed?
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(Glyn, Harris & Allen, 2017, citing Lania, Persani & Beck-Peccoz, 2008)
in 80 000 –120 000 individuals.”
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.
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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/1.73m2 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.
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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,(Bland & Frymoyer, 1970)
• intervertebral disk disease,
• psychoneurosis and
• nonspecific “arthritis” or rheumatism.
All patients recovered completely on thyroid-replacement therapy.”
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.
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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 103 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)
Hypothyroid eyelids: ptosis
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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
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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”:
• 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)
Hypothyroid cholesterol levels
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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
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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.)
Medications that can cause transient CeH
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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;(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.”
Family history of autoimmune diseases
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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,(Boaelert et al, 2010)
• systemic lupus erythematosus,
• Addison’s disease,
• celiac disease, and
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.
A possible cause: Autoimmune hypophysitis without MRI signs
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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.
Diagnostic tools for discerning CeH in thyroid lab results
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.
Click to expand section
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
Click to expand section
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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7 thoughts on “23 years of misdiagnosed central hypothyroidism with a normal TSH: Case study”
Not doing Free T4 and Free T3, seemingly due both to perceptions of costs and also ignorance as to interpretation, is a disaster.
UK costs have been tracked down and the incremental cost of adding FT4 and FT3 is small compared with the rest of the costs of doing any blood test, even just TSH.
Many people who buy expensive sporty cars insist on having a rev counter and speedometer. Why? If you know your road speed and gear, you can derive the revs. So why not just abandon rev counters?
Of course, the truth is that in an uncertain world, a rev counter showing a reading that is out of kilter with speed/gear does help – maybe slipping clutch? And getting the right engine speed before engaging clutch helps with smooth driving.
And you know if you go to a hospital carpark, a majority of the expensive sporty cars with rev counters will be owned by doctors.
Any oddities in the relationship among TSH, FT4 and FT3 both have their own stories to inform and can help identify issues in the testing. For example, macro-TSH or other antibody interference.
If the medical establishment is so sure TSH alone is adequate let them sit this test. You take a number of real sets of results – TSH, FT4 and FT3. Then erase one of those results for each patient. Now work out what the missing number should be. And then mark them on accuracy of their guesses. (Sorry, but I just cannot get myself to use the word “estimates”.) Then repeat but only provide TSH results and expect FT4 and FT3 results to be guessed.
Each and every failure of these tests represents a real person who is likely to suffer mistreatment. That the percentage could be low is irrelevant to those individuals. But I actually expect their guesses to be poor much of the time.
Thanks for the good analogy! And the rest of the comment. Food for thought!
You’ve hit the nail on the head there completely.
Thyroid treatment in the UK is worse than it’s ever been ( in my opinion ) . There seem to be fewer and fewer endocrinologist who specialise in thyroid treatment, most appear to be experts in Diabetes , to the complete detriment of thyroid patients.
Even when diagnosed it can be a nightmare getting the correct treatment if you don’t respond to levothyroxine mono therapy .
In my own case, I was finally diagnosed hypothyroid after years of being told I was perfectly well, with a steadily rising TSH and very low free T4 and T3 levels. I had every hypothyroid symptom under the sun , but they were all ignored because my TSH was high “normal”.
I did not improve on levothyroxine alone , my T4 rose nicely ( T3 was never tested , even when requested). It was only when I paid for private blood tests that I found that my T3 had hardly moved from its starting point. I also had a genetic test and I was found to be positive for the DIO2 gene mutation ( which can impair conversion of T4 to T3) . Despite me providing all this evidence the NHS still refused to supplement my treatment regime with a small amount of T3 , the endocrinologist advised me to buy my own T3 off the internet.
I eventually plucked up the courage to do this , and after adding a small dose of T3 daily , my symptoms started to disappear, my T4/T3 results became balanced and I started to feel normal again.
I am still being refused the T3 on the NHS on cost grounds ( the Endo) and lack of knowledge of the medication ( the GP).
Heaven help anyone who is unable to fend for themselves and who does not the courage to do what I did , you can lose the confidence and motivation to help yourself when you are suffering from hypothyroidism, and it seems that many doctors are unable/ unwilling to look beyond the “magic” TSH number, believing it to be revelatory, which judging from this article it most definitely is not.
Thanks very much for sharing your struggles with the NHS here. Isn’t it odd that your endo advised you to get your own T3 online? So glad you were able to source it. Yes it takes courage to take your health into your own hands, but what else can we do in such situations? You did well.
There is another cause of central hypothyroidism that is not mentioned in this article – hydrocephalus.
I was diagnosed a few years ago with Normal Pressure Hydrocephalus (NPH) – an accidental discovery after a CT scan checking for stroke. At the time I was in my 50s. I was told after multiple tests and MRIs that the condition has existed since birth, infancy, or childhood, but no cause could be given with any certainty at my age. I was given treatment for the NPH, but it could fail at any time.
My pituitary is squashed in one direction and stretched in another. My TSH is much better than the subject described in this article, but is still not good enough to give me adequate levels of Free T4 and Free T3, so treatment has been essential. Since trying to get taken seriously when TSH is under 10 is virtually impossible in the UK I treat my own thyroid hormone levels and have done for several years. I am terrified of what my future holds as I get older and can no longer cope with sourcing thyroid hormones online.
Sarah, thanks for informing us about your central hypo condition. I hadn’t heard about it before. In your 50s! It’s sad that the UK can’t put you in a separate category for TSH and hormone testing. It is not right that we have to struggle so hard to source hormones our bodies require. We need a community to look after each other when we get older, since some of us do not have children or large families.
Thank you for this very informative article. My 15 year old daughter has had TSH and free T4 tested twice while having many symptoms of hypothyroid but the endo will not order a free T3. Her TSH was 1.0 (.5-4) with a T4 of 12.9 (10-23). Follow up 4 months later TSH 2.27 (.4-4.88) Free T4 9.8 (8.8-17.7). These values seem to fit with a central hypothyroid diagnosis on your graph. The endo says her thyroid is fine as they are within the ref ranges. She has had a weight gain of 15kg in 6 months along with many other symptoms. Cholesterol is high. She was an elite dancer and can no longer dance. What do you suggest we do?