Macro-TSH in Covid-19 Patients with an Underlying Thyroid Condition: A Case Series and Literature Review

  

    
Patient 1
  
  

    
Date
    
TSH
    
FT4
    
FT3
  
  

    
10/11/19
    
0.598
    
 
    
 
  
  

    
01/14/19a
    
0.462
    
1.24
    
 
  
  

    
HA: 03/29/20b
    
0.915
    
0.67
    
<1.07
  
  

    
04/08/20
    
15.95
    
0.88
    
1.36
  
  

    
04/16/20c
    
15.079
    
0.92
    
1,91
  
  

    
04/21/20
    
16.02
    
0.95
    
2.01
  
  

    
05/29/20
    
0.015
    
1.49
    
 
  
  

    
aTPOAb: 0.49; bTRAb: 1.09; cTPOAb: 0.33
  
  

    
Patient 2
  
  

    
Date
    
TSH
    
FT4
    
FT3
  
  

    
06/05/19a
    
0.544
    
1.18
    
 
  
  

    
HA: 04/03/20
    
0.303
    
0.66
    
1.43
  
  

    
04/27/20b
    
40.036
    
0.83
    
1.81
  
  

    
05/07/20
    
25.348
    
0.89
    
2.48
  
  

    
05/22/20c
    
1.263
    
1.0
    
 
  
  

    
aTGAb: 1.16; bTPOAb: 1.43; cTGAb: 0.34; TG: 0.66
  
  

    
Patient 3
  
  

    
Date
    
TSH
    
FT4
    
FT3
  
  

    
08/20/18
    
0.832
    
 
    
 
  
  

    
03/13/20
    
5.363
    
0.84
    
1.27
  
  

    
HA: 03/24/20
    
3.198
    
0.58
    
1.27
  
  

    
04/14/20
    
28.62
    
0.67
    
1.83
  
  

    
04/17/20a
    
22.44
    
0.82
    
1.52
  
  

    
04/30/20
    
10.54
    
1.52
    
2.71
  
  

    
06/16/20
    
0.702
    
0.87
    
2.78
  
  

    
07/13/20
    
0.964
    
 
    
 
  
  

    
aTPOAb: 2.71
  
  

    
Normal reference range: TSH: 0,5-4,0    μU/mL; FT4: 0,8-2,0 ng/dL; FT3: 1,7-4,0 pg/mL; TPOAb: 0,0-5,61 U/mL; TGAb:    0,0-4,11 U/mL; TG: 1,4-78,0 ng/dL; TRAb: <2 U/L; HA: Hospital Admission. 
  

Table 5: Laboratory values at hospital admission.

Other useful techniques for sample processing are the heterophilic antibody blocking agents (HBR of Scantibodies Laboratory INC) (Table 3) and exclusion chromatography, which was not available due to the safety measures required for COVID-19-positive samples.

Renal function should also be considered, as TSH-IgG complexes, which have a high molecular weight, disappear slowly from circulation. Also, their levels increase upon renal failure due to decreased clearance of macro-TSH [21] (decreased glomerular filtration) (Table 4).

Discussion

Thyroid endocrine alterations in patients diagnosed with symptomatic SARS-CoV-2 infection remain underrated due to their unknown physiopathological mechanism.

Viral infection causes a significant generalized inflammatory response and a considerable increase in the levels of circulating cytokines (mainly IL-2, IL-7, TNF-a, IFN-a, IFN-γ, NF-κB, and IL-6) [8-23,26,27], which may cause pulmonary [3] and thyroid damage in patients suffering from this infection.

Brancatella et al. have recently reported the first case of Subacute Thyroiditis (SAT) [28-30] following SARS-CoV-2 infection [27], suggesting the thyroid gland as a target organ of SARS-CoV-2. It is well known that SAT is generally preceded by an upper respiratory pathway infection, as it has been reported during the outbreaks of echovirus, coxsackievirus, paramyxovirus, adenovirus, orthomyxovirus, Epstein-Barr virus, hepatitis E virus, human immunodeficiency virus, cytomegalovirus, dengue virus, and rubella virus [31]. Additionally, it is noteworthy that thyroid hormones also seem to prevent the efficacy of certain viruses, such as herpes simplex virus, due to the stimulation of intracellular defense immune mechanisms mediated by natural killer cells, as well as the immunostimulant effect associated with interferons [9].

During the 2002 Coronavirus Strain (SARS-CoV) outbreak, damage in the follicular cells of thyroid glands was detected in autopsies of infected patients [32]. Wei et al found a significant decrease in thyrotrope cells [32], suggesting that the endocrine cells of the adenohypophysis may be damaged by the coronavirus, partly explaining why TSH secretion cannot be stimulated by the negative feedback cycle with decreased T3 and T4 concentrations.

The Angiotensin II Converting Enzyme (ACE2) is the main entry receptor for SARS-CoV and SARS-CoV-2 cellular invasion, facilitating direct damage by the virus during infection [33]. Li et al recently reported that the ACE2 receptor is expressed at high concentrations in the thyroid gland [33,34], suggesting that this gland is a potential target for direct viral damage.

The underlying mechanism for thyroid and hypophysial function damage is still unknown, but it is generally believed to be caused by a direct glandular viral infection, which is evidenced by the wide intracellular distribution of viral nucleic acid and the post-viral inflammatory reaction in genetically predisposed subjects [32,35,36]. Human Leukocyte Antigen (HLA) haplotypes, especially HLA-Bw35, but also HLA-B67, HLA-B15/62, and HLA-Drw8, have been reported as predisposing factors for thyroiditis [31,35]. Indirect damage, i.e. damage caused by the host’s immune hyperactivity as a consequence of a systemic inflammatory response, is considered to be another cause of the disease.

Thyroid impairment caused by SARS-CoV-2 has a dynamic evolution [36], progressing toward gradual recovery.

In this way, a decrease in TSH and other thyroid hormones was observed compared to the normal range [36], but, surprisingly, the decrease was lower than in patients without COVID-19.

Evidence suggests that these patients develop transient central hypothyroidism [37]. It is likely that the changes in thyroid function, characterized by decreased thyrotropin-releasing hormone mRNA levels in the hypothalamic paraventricular nucleus (possibly cytokinedependent) observed in patients with this severe disease, are protective because they avoid excessive tissue catabolism. Abnormalities have also been observed in TSH glycosylation, which could decrease their bioactivity [38].

As a result, T3 or T4 replacement therapy could be expected to have a favorable effect on mortality. However, this was not the case. In randomized trials on severely ill patients with decreased T3 and T4 levels, T3 or T4 replacement did not affect mortality as opposed to the control group. Based on this evidence, a new randomized, double-blind, placebo-controlled trial (Thy-Support, ClinicalTrials. gov Identifier: NCT04348513) will be conducted to study the effect of high (intravenous) doses of T3 for improving recovery of critically ill COVID-19 patients [8].

It is known that about 15%–20% of hospitalized patients and 50% of patients admitted to the ICU have low T4 levels (low T4 syndrome) due to decreased concentration of one or more transport proteins (TBG, transthyretin [TTR] or Thyroxine-Binding Prealbumin [TBPA], and albumin). As TBG is the main transport protein, serum T4 decrease could be caused by an alteration in abnormal glycosylation binding or dissociation during circulation [39].

Moreover, most hospitalized patients have low T3 concentrations (low T3 syndrome). About 80% of circulating T3 is produced by peripheral 5'-deiodination of T4, a reaction catalyzed by 5'-monodeiodinases (D1 and D2) in different organs (muscle, liver, and kidney). Since 5'-monodeiodination decreases in any nonthyroid disease, even a mild one, the 5’-monodeiodinase (D3) activity, which converts T4 into reverse T3 (rT3) [40], will be predominant.

The changes in thyroid function will vary depending on the severity of the disease. Hence, low FT3 concentration has been correlated with a longer hospital stay, ICU admission, mechanical ventilation requirement [41], and increased mortality of patients with acquired pneumonia [26,42].

FT4 levels have also been correlated with the outcomes of critical patients. Values < 0.3 ng/dL have been associated with mortality rates > 85% [43].

It has been suggested that inactivation of T4 to T3 conversion during the disease course may be a beneficial way of adaptation.

This study demonstrates the presence of TSH increase in patients with SARS-CoV-2 infection and an underlying thyroid condition, caused by the presence of an autoimmune complex formed by the association of TSH with G-IgG immunoglobulin called macro-TSH, an analytical alteration that has not been described in the existing literature. As the size of a TSH molecule is 28 kDa, it is freely filtrated through the renal glomerulus. However, when the IgG-TSH complex is formed, its size increases to approximately 180 kDa, which impedes renal filtration and causes its accumulation, resulting in a slower renal clearance.

The IgG-TSH molecule is biologically inactive but variably immunoreactive depending on the method used [17]. The multiple concentrations observed with all the available analytical methods may be because when macro complexes are formed, TSH epitopes are more or less exposed, resulting in a different reactivity based on the design of each assay. Precipitation with polyethylene glycol has been used to detect this interference, with a quite low TSH percentage being recovered, suggesting the presence of a molecule with higher molecular weight, such as HAMA or any other antibody [44], interfering in TSH determination. We believe that if TSH levels >10 μU/L are higher than 65% after polyethylene glycol precipitation, the presence of macro-TSH should be suspected.

The TSH values measured by the polyethylene glycol precipitation test were lower, although not markedly lower and the patients had polyethylene glycol-precipitation TSH ratios greater than 65%, but no greater than 75% as is expected by the studies presented by Hattori et al, possibly due to infection SARS-COV-2 and that this arbitrary cut-off point was obtained in patients with no known pathology [25]. This variability is very possible that is secondary to the infection by SARS-COV-2 and / or its severity.

Normal / decreased TSH and FT4 levels were obtained with a HBR tube. HAMA and rheumatoid factor, which can act like heterophile antibodies, were undetectable in these patients.

At present, the most widely used technique to detect macro- TSH is precipitation with polyethylene glycol, which has displaced gel filtration chromatography as it is an expensive technique not available in most Hospitals [18].

These antibodies can also be detected by serial dilution of samples through this interference, obtaining non-proportional results.

The clinical significance of macro-TSH is currently not known. Because TSH measurements are uncertain in these situations, the patients who have macro-TSH should be followed up clinically or maybe with FT4 levels. On the other hand, macro-TSH should be kept in mind when higher than expected levothyroxine dosages are needed in order to achieve the therapeutic target of serum TSH in patients with thyroidectomy [19,20].

Macro-TSH was screened by adding PEG to serum in order to precipitate γ-globulin fractions [25,45,46] being its prevalence is not well known. Macro-TSH seems to be a heterogeneous entity which can be suspected when normal FT4 levels are associated to elevated TSH levels, and when substances that commonly interfere with TSH assays, including heterophilic antibodies, human anti-mouse/animal antibodies and rheumatoid factors have been excluded [47]. Macro-TSH can also occur in patients with TSH concentrations within reference ranges [48].

To date, the bulk of data on macro TSH prevalence have been provided by studies by Hattori et al. [25,45,46]. This study was conducted in a group of 681 patients with subclinical hypothyroidism and no underlying thyroid disease of interest and using an arbitrary cut-off point for TSH precipitable with PEG (> 75%), these authors found a prevalence of macro TSH of 1.6% after gel filtration [45].

Subsequently, in other study with 1901 sera from patients with subclinical hypothyroidism, in whom the presence of HAMA had been excluded, the prevalence of macro TSH decreased to 0.8% [25]. Mills et al. reported a similar prevalence (0.6%) [49] in patients with TSH levels greater than 10 μU/L. We should keep in mind that even commercial TSH immunoassay systems cannot be completely free from interference by HAMA.

There are no data on cohorts of patients with thyroidectomy, and even less, with concomitant SARS-COV-2 infection in the pandemic that we are suffering.

In the study by Giustin et al. [50], PEG-precipitable TSH was 39.3% ± 1.9% in patients who had undergone total thyroidectomy for thyroid cancer. These percentages appear to be somewhat lower than those reported in 681 samples from subjects with a clinical diagnosis of subclinical hypothyroidism (21% to 100%, on average 63%) [45]. Furthermore, in this group of patients, according to the arbitrary cutoff point of ≥80%, the prevalence of macro TSH (3.1%) was higher than that reported in subclinical hypothyroidism [25,45,49]. It is not clear if this difference is due to the different cohort of patients or to the lack of gel filtration or HAMA tests [50].

Loh et al. [51] reported that the majority of macro TSH patients were women without symptoms of thyroid disorders, except for one with clinical features of hyperthyroidism, and Hattori et al. [25] stated that macro TSH is predominant in samples from elderly patients and that autoimmune mechanisms could be involved in the generation of macro TSH [45] therefore COVID-19 could be a trigger of the autoimmune mechanisms.

In our opinion, more data are needed to attribute macro TSH in SARS-COV-19 patients and underlying thyroid pathology. The macro-TSH should not be ruled out in patients with SARS-COV-2 infection because there is no high precipitation with PEG. A lower recovery with PEG (> 65%) could be compatible in patients with COVID-19. There are many unanswered questions in patients with COVID-19 and this article could lead to new unexplored research.

Detection of macro TSH should be performed in particular conditions such as positive COVID-19 patients and underlying thyroid pathology, such as Kadoya et al indicated in patients with sleep disorders [52].

Our study has several limitations:

1. The study group includes few subjects with underlying thyroid disease and positive COVID-19.

2. Other laboratory procedures such as gel filtration chromatography were not performed because it is an expensive technique and is not available in most centers, with PEG precipitation currently being the most widely used technique.

3. The PEG-precipitable TSH cutoff was arbitrarily set very similar to the Hattori study in patients with subclinical hypothyroidism.

4. Results from the other patients were not available due to the safety measures required for COVID-19 positive samples..

Key Points

1. To date, patients with COVID-19 and underlying thyroid disease have not been studied.

2. The patients were perfectly controlled before suffering the coronavirus infection.

3. Thyroid function returned to normal when the patient recovered from COVID-19.

4. No correlation between thyroid study and clinical pathology. Without criteria for ESS.

5. All patients were treated differently (different drugs). Therefore, we can rule out drug interference.

6. Levothyroxine dose adjustment did not produce the desired effect, despite being patients with prolonged admissions. TSH levels were not normalized with levothyroxine therapy; this suggested that the secretion of TSH and the formation, dissociation, and clearance of the TSH-anti-TSH autoantibody complexes were equilibrated, at the elevated levels of macro TSH and normal levels of free TSH.

7. It is important to closely monitor patients diagnosed with thyroid cancer or other thyroid pathology to detect possible interference with SARS-COV-2 in the thyroid study, and to avoid overdosing or treating patients incorrectly.

8. Macro-TSH is currently detected quickly and easily with PEG test and the cut-off point is arbitrary, but we consider that if precipitation is greater than 65% and with discrepancies in the clinical and laboratory results (TSH > 10μU/L) the patients should be closely monitored.

9. Therefore, patients with subclinical hypothyroidism who have serum TSH levels above 10 μU/L may be candidates for the screening of macro TSH, especially those who have extremely high levels of TSH.

10. Diagnosis of macro TSH is clinically important because it may change the therapeutic strategy.

11. The nature of the non-IgG-associated macro TSH remains to be elucidated, but it might be an aggregate of highly glycosylated TSH analogous to non-IgG-associated macro PRL.

In conclusion, free TSH levels after PEG precipitation are on average 30-40% lower than serum TSH levels in subjects without a history of thyroid carcinoma or other significant thyroid pathology. The presence of macro TSH could be a more common phenomenon than is thought in patients with COVID-19 and underlying thyroid disease. Patients suspected of having macro TSH should be followed for a long time, due to the hypothesis of a long persistence of the immunoglobulin G-TSH complex [46]. It is necessary to evaluate more serum samples in similar patients and avoid unnecessary exogenous hyperthyroxinemia.

Our data demonstrate that, in assessing the adequacy of FT4 dosage after total thyroidectomy in thyroid cancer patients, the individual balance of FT4 and macro TSH must also be considered.

Although the prevalence of macro TSH was higher in older people, it has also been observed in patients of childbearing age. Therefore, it is very important to distinguish elevated serum TSH levels caused by macro TSH from those caused by monomeric TSH in patients with subclinical hypothyroidism. At present, there are no TSH immunoassay platforms that do not cross-react with macro TSH. Therefore, we recommend that when hormone replacement therapy for subclinical hypothyroidism is considered, screening for macro TSH should be performed [25].

In 1995, Tamaki [53] was the first author to suggest the presence of high molecular weight TSH as the cause of transient high TSH levels. This was subsequently confirmed by other researchers [54]. The actual prevalence of this macro-TSH interference in adults or newborns is unknown because it has been poorly described in the existing literature [26,53,54], but it is considered to be very low (0.17%–1.6%) [54].

For this reason, TSH determination is not adequate for assessing thyroid function in these patients because the concentration measured does not reflect the actual biologically active concentration. Moreover, this interference may not always be identified, especially when the TSH increase is moderate, and it can be confused with ESS. Hence, if the presence of this complex is confirmed, assessment of the patient’s thyroid function by TSH determination is not valid.

In summary, it is important to consider that in severely ill patients with COVID-19 and high concentration of TSH and thyroid hormones within reference ranges or lack of response to treatment, one of the possible causes to be considered is the presence of macro- TSH. Its detection is recommended to optimize thyroid treatment.

Ethical considerations

Ethical approval was not received because of the retrospective nature of the case report.

Ethical approval was not received due to the descriptive nature of the cases reports.

Author contributions

All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

Competing interests

The funding organizations played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication.

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