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

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.

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 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)

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)

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.

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.

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:

1. 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.
2. 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.

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:

1. Central hypothyroidism is still clearly evident during thyroid therapy because the TSH index is still low, showing abnormal pituitary TSH response to FT4 levels.
2. 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“).

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