Voorkomen en beheer van een afwijkende vrij T4 in combinatie met een normale TSH

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Berichten: 442
Lid geworden op: 08 nov 2014, 17:53

Voorkomen en beheer van een afwijkende vrij T4 in combinatie met een normale TSH

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Voorkomen en beheer van een afwijkende vrij T4 in combinatie met een normale TSH

K.M. van Veggel1*, J.M. Rondeel2, S. Anten3
1Department of Internal Medicine, Isala Hospital (previously employed by Department of Internal Medicine, Alrijne Hospital), Zwolle, the Netherlands, 2Department of Clinical Chemistry, Isala Hospital, Zwolle, the Netherlands,3Department of Internal Medicine, Alrijne Hospital, Leiderdorp, the Netherlands,
*corresponding author: email: k.m.van.veggel@isala.nl

Thyroid function tests may show the combination of a normal concentration of serum thyroidstimulating hormone (TSH) and an increased or decreased level of free thyroxine (free T4). How often this occurs is unclear and not everyone is familiar with how it should be adressed.


We conducted a retrospective cohort study of all adult patients who presented at a non-academic general hospital in the Netherlands between 1 January 2010 and 31 December 2014 and yielded an increased or decreased free T4 in combination with a normal TSH.
Exclusion criteria included the use of thyroid medication, pregnancy, a history of thyroid surgery and treatment with radioactive iodine. The medical records of the patients included were retrieved and evaluated.

Of the 30,143 combined TSH and free T4 measurements in 23,199 individual patients, 1005 measurements (3.33%) in 775 patients (3.34%) yielded an aberrant free T4 in combination with a normal TSH.

398 patients (1.72%) had a persistent aberrant free T4, 349 (87.7%) of whom had a decreased free T4 and 49 (12.3%) an increased free T4.
In 58 of the 398 patients (14.6%) with a persistent abberant free T4 a possible cause was established by the treating physician.
However, upon re-examination of medical files a possible causative factor could be identified in 123 patients (30.9%).

In our study population the prevalence of hyperthyroxinemia or hypothyroxinemia in combination with a normal TSH was 334 per 10.000 patients.
When records were thoroughly searched, identification of potential causative factors increased substantially. Clinicians should be encouraged to check for underlying causes.

Prior to 13 May 2014 concentrations of free T4 and TSH were determined by a Siemens Immulite 1000 immuno-assay analyser. Maximal total coefficients of variation for free T4 and TSH were 12.1% and 17.5%.
Reference values of free T4 and TSH were 10.3-24.5 pmol/l and 0.4-4.0 mU/l. As of 13 May 2014 the laboratory used a chemiluminescent microparticle immunoassay (CMIA; Architect, Abbott Diagnostics USA). The Abbot assay has a dilution factor of 75 before measuring FT4. Maximal total coefficients of variation were 7.8% and 5.3% for free T4 and TSH respectively.
Reference values of free T4 and TSH were 10-19 pmol/l and 0.27-4.2 mU/l, respectively. Concentrations outside the reference range were considered abnormal.

Table 1.
Causes of hypothyroxinemia and hyperthyroxinemia in combination with a normal TSH and corresponding data that have been evaluated in patients’ medical records

- Causes of a normal TSH in combination with a decreased free T4

Causes of a normal TSH in combination with a decreased free T4 - Increased concentrations of TBG: hepatitis, porphyria, estrogen, heroin, methadone, mitotane, 5-fluorouracil, selective estrogen receptor modulators (e.g. tamoxifen, raloxifene), perphenazine
- Increased clearance of thyroxine therapy: phenobarbital, primidone, phenytoin, carbamazepine, oxcarbazepine, rifampicin, growth hormone, sertraline, tyrosine kinase inhibitors (e.g. imatinib, sunitinib), quetiapine, stavudine, nevirapine
- Decreased release of thyroid hormone by the thyroid: lithium
- Critical illness
- Central hypothyroidism: decreased pituitary function due to pituitary adenomas, compressive lesions, cranial surgery or irradiation, empty sella, auto-immune disease, vascular accidents, infiltrative lesions (e.g. hemochromatosis), infections (e.g. tuberculosis), inherited disease

- Causes of a normal TSH in combination with an increased free T4
Causes of a normal TSH in combination with an increased free T4 - Decreased concentrations of TBG: liver failure, nephrotic syndrome, androgens, anabolic steroids, glucocorticoids, nicotinic acid, L-asparginase
- Inhibition of T4 binding to TBG: salicylates, furosemide, free fatty acids, phenytoin, carbamazepine, non-steroidal anti-inflammatory drugs, heparin
- Inhibition of thyroid hormone transport through the plasma membrane: amiodarone
- Critical illness
- Pituitary TSH adenoma (e.g. TSHoma)
- Thyroid hormone resistance

- Assay error (TSH / free T4)

Table 2.
Patient characteristics at baseline

Table 3.
Occurrence of known associated factors (‘risk factors’) for developing an aberrant free T4 concentration in combination with a normal TSH concentration among 504 evaluated patients at baseline

Figure 1.
Summary of the results

Figure 2.
Suggested analysis of hyperthyroxinemia and hypothyroxinemia in combination with a normal TSH

This study demonstrates that in our population of patients screened for thyroid dysfunction in a non-university general hospital 334 per 10,000 patients had a normal TSH in combination with an aberrant free T4.

We also found that many physicians do not follow-up on this condition or record a causative factor.
When medical files are searched thoroughly however, identification of a possible causative factor increases from 14.6% to 30.9%.

Therefore, clinicians should be encouraged to check for additional causes of these aberrant free T4 entities. The largest challenge is not to miss serious underlying conditions like secundary hypothyroidism.

We present a possible strategy for analyse hyperthyroxinemia and hypothyroxinemia in combination with a normal TSH. We believe it is important to deploy a similar strategy in guidelines about thyroid disorders.
Future studies on this topic should be performed to gain more insight about the best way to follow-up on this condition.

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Lid geworden op: 12 sep 2013, 11:36

Re: Voorkomen en beheer van een afwijkende vrij T4 in combinatie met een normale TSH

Bericht door Kiek »

Leuk artikel, Ineke!
Onmiddellijk valt me op dat in table 3, in de rij oorzaken van een normale TSH met een relatief lage FT4 de Cytomel niet genoemd wordt.
Dat is toch wel heel apart als het juist gaat om de vraag waarom FT4 een onverwachte uitslag geeft.

Men weet niet dat zuks gebruikt wordt in de alto-scene, zonder dat er een schildklierziekte is gediagnosticeerd.
Nuchter lab 8.00 uur - dosis pas slikken na het prikken - lees over schildklieren en ervaringen, want deze kennis geeft inzicht. Door Hashimoto een ervaren schildklierhormoongebruikster (geen arts).

Berichten: 442
Lid geworden op: 08 nov 2014, 17:53

Re: Voorkomen en beheer van een afwijkende vrij T4 in combinatie met een normale TSH

Bericht door ineke »

Opvallend is dan ook nog dit artikel
(gehele artikel - zie link).

Dit gaat over de waarden en ijzerdeficientie

Article | Open | Published: 26 April 2018 Nature Scientific
Iron deficiency is associated with Hypothyroxinemia and Hypotriiodothyroninemia in the Spanish general adult population:

Previous studies have suggested that iron deficiency (ID) may impair thyroid hormone metabolism, however replication in wide samples of the general adult population has not been performed.

We studied 3846 individuals free of thyroid disease, participants in a national, cross sectional, population based study representative of the Spanish adult population.
Thyroid stimulating hormone (TSH), free thyroxin (FT4) and free triiodothyronine (FT3) were analyzed by electrochemiluminescence (E170, Roche Diagnostics).
Serum ferritin was analyzed by immunochemiluminescence (Architect I2000, Abbott Laboratories).

As ferritin levels decreased (>100, 30–100, 15–30, <15 µg/L) the adjusted mean concentrations of FT4 (p < 0.001) and FT3 (p < 0.001) descended, whereas TSH levels remained unchanged (p = 0.451).
In multivariate logistic regression models adjusted for age, sex, UI, BMI and smoking status, subjects with ferritin levels <30 µg/L were more likely to present hypothyroxinemia (FT4 < 12.0 pmol/L p5): OR 1.5 [1.1–2.2] p = 0.024, and hypotriiodothyroninemia (FT3 < 3.9 pmol/L p5): OR 1.8 [1.3–2.6] p = 0.001 than the reference category with ferritin ≥30 µg/L.
There was no significant heterogeneity of the results between men, pre-menopausal and post-menopausal women or according to the iodine nutrition status.

Our results confirm an association between ID and hypothyroxinemia and hypotriiodothyroninemia in the general adult population without changes in TSH.

https://www.nature.com/articles/s41598- ... 9/tables/1

https://www.nature.com/articles/s41598- ... /figures/1

Relation between Ferritin levels and thyroid hormones (linear model)
https://www.nature.com/articles/s41598- ... 9/tables/2

Table 3 Prevalence (%) and adjusted Odd Ratios (OR) for presenting high TSH, low FT4 and low FT3 in the study. Individuals according to their Ferritin levels (<30 vs ≥30 µg/L).
https://www.nature.com/articles/s41598- ... 9/tables/3

https://www.nature.com/articles/s41598- ... /figures/2

Our results confirm an association between ID and hypothyroxinemia and hypotriiodothyroninemia in a large sample of thyroid disease free subjects representative of the Spanish general adult population, in models controlled for possible confounding variables such as age, sex, BMI, smoking habit and UI.

These findings are in line with previous studies suggesting that ID may impair thyroid hormone production: ID has been shown to lower FT4 as well as FT3 in rats6,7,8, and small samples of humans with ID, with or without anemia, have been reported to have lower FT4 and FT3 levels than controls without ID9,10. Other previous studies have associated ID with the presence of goiter18, and iron supplementation in children with goiter and ID anemia has been shown to improve the efficacy of iodized oil administration, causing a reduction in glandular size19,20. ID has also been associated with changes in thyroid function in children and adolescents11,13, which improves after its correction12. More recently, ID has been identified as an independent risk factor for the development of hypothyroxinemia and thyroid dysfunction in pregnant women14,15,16,17. To our knowledge, this is the first epidemiological study reporting this association in a wide sample of the adult non-pregnant population, including adult men, as well as pre-menopausal and post-menopausal women.

Interestingly, the association between ID and the decreased levels of FT4 and FT3 found in our study is already significant for serum ferritin levels below 30 μg/l, which is in line with the level suggested by Mast et al.21. This threshold possibly corresponds to the so called “iron depletion state” defined by the WHO22 in which no hematological, cerebral or muscular alterations are observed, however an objective low iron storage is present in the organism. In fact, according to our results, lower ID thresholds (e.g. <15 μg/L) could understate the hypothyroxinemia and hypotriiodothyroninemia associated with ID.

ID may alter the synthesis of thyroid hormones by multiple mechanisms: ID induces ineffective erythropoiesis, thus reducing the transport of oxygen to the different tissues required for multiple enzymatic reactions23. ID has also been shown to increase in-vitro hepatic reverse triiodothyronine deiodination, suggesting that under conditions of ID, thyroid hormones tend to be metabolized by an inactivating route24. Also, ID may lower thyroperoxidase activity and therefore interfere with the synthesis of thyroid hormones25. Although these mechanisms described could be explanatory, our results suggest the implication of additional hypothalamic-pituitary mechanisms, given the lack of TSH response to the decrease in the levels of peripheral hormones. Accordingly, the experiments carried out by Tang et al. in iron deficient rats subjected to low temperatures, showed decreased levels of TSH, FT4 and FT3, which reverted to normal if stimulated with synthetic thyrotropin releasing hormone (THR), suggesting that ID may impair the hypothalamic secretion of THR26. In line with this observation, the study from Eftekhari in Iranian adolescents with ID, showed that despite increases in FT3 and FT4 concentrations, the TSH concentration was unaffected by iron supplementation12. Since no separate mechanism on its own fully explains the results found in our study, it is likely that a combination of mechanisms may be involved.

Our results are limited due to the cross sectional nature of the analyses, so we cannot infer causal mechanisms, however, the results may have clinical implications, especially in pre-menopausal women, where ID is more prevalent. In fact hypothyroxinemia is associated with numerous factors that complicate gestation, such as increased preterm birth or the development of gestational diabetes27 and the development of newborns such as language delay28 or lower intellectual coefficient29. Recently, the persistence of low T4 levels in children born to mothers with hypothyroxinemia and ID until the tenth postnatal day has also been demonstrated30. Thus, the implication of ID in the pathogenesis of these thyroid disorders in pregnancy could open a new perspective for its prevention and early intervention and requires further research. On the other hand, hypothyroxinemia and hypotriiodothyroninemia have not been sufficiently studied in other population groups, so that the existence of some harmful effects in the non-pregnant population cannot be discarded.

In conclusion, we report an association between ID and hypothyroxinemia and hypotriiodothyroninemia in the Spanish general adult population. Several hypothalamic-pituitary and peripheral mechanisms may be involved.
Further prospective and experimental studies are needed to establish causal mechanisms and to expand knowledge in this field.

Gehele artikel

Ook dit artikel nog veel info te vinden en hier wordt ook gesproken over ijzerdeficientie:

International Journal of Clinical Practice
Current evidence for the treatment of hypothyroidism with levothyroxine/levotriiodothyronine combination therapy versus levothyroxine monotherapy

1Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
2AbbVie Inc., North Chicago, IL, USA
James V. Hennessey, Harvard Medical School, Beth Israel Deaconess Medical Center,
Division of Endocrinology, Diabetes and Metabolism, Boston, MA, USA.
Email: jhenness@bidmc.harvard.edu

Open Access

Table 2. Potential causes of persistent symptoms in euthyroid patients receiving LT4
Endocrine/autoimmune Nutritional Lifestyle
Diabetes mellitus Vitamin B12 deficiency Stressful life events
Adrenal insufficiency Folate deficiency Poor sleep patterns
Hypopituitarism Vitamin D deficiency Work‐related exhaustion
Celiac disease Iron deficiency Alcohol excess
Pernicious anaemia Metabolic Others
Haematological Obesity Obstructive sleep apnoea
Anaemia Hypercalcaemia Viral and postviral syndromes
Multiple myeloma Electrolyte imbalance Chronic fatigue syndrome
End‐organ damage Drugs Carbon monoxide poisoning
Chronic kidney disease Beta‐blockers Depression and anxiety
Chronic liver disease Statins Polymyalgia rheumatica
Congestive cardiac failure Opiates Fibromyalgia
• Adapted with permission from Okosieme O, Gilbert J, Abraham P, et al. Management of primary hypothyroidism: statement by the British Thyroid Association Executive Committee. Clin Endocrinol (Oxf)

Table 3. Clinical practice guideline recommendations regarding LT4 monotherapy and LT4/LT3 combination treatment

Our hypothetical patient, who continues to complain of symptoms despite achieving TSH levels consistently within the normal range with LT4 monotherapy, is based on a recognised subset of patients encountered in clinical practice. Available evidence suggests that her persistent symptoms will not be resolved by the addition of LT3 and that they may be due to factors other than thyroid dysfunction.
It is estimated that 5%‐10% of patients with hypothyroidism treated with LT4 with normal TSH levels continue to experience nonspecific symptoms which may be attributed to hypothyroidism.73 Current clinical evidence, however, is not sufficiently strong to support the use of LT4/LT3 combination therapy in patients with hypothyroidism. Several genetic polymorphisms have been investigated in an effort to explore potential mechanisms underlying unsatisfactory treatment results and to provide a predictive marker for success with LT4/LT3 combination treatment in patients who have persistent symptoms; however, results thus far have not been conclusive. Instead, persistent symptoms in patients who are biochemically euthyroid may be caused by several other conditions unrelated to thyroid function. A thorough investigation to determine other potential causes, including endocrine and autoimmune disorders, haematological conditions, end‐organ damage, nutritional deficiencies, metabolic syndromes, concomitant drugs and lifestyle, is warranted.68

Gehele artikel
https://www.ncbi.nlm.nih.gov/pmc/articl ... -72-na.pdf

Douglas S Ross, MD
Section Editor:
David S Cooper, MD
Deputy Editor:
Jean E Mulder, MD

Many conditions result in increases or decreases in serum total thyroxine (T4) and triiodothyronine (T3) concentrations, associated with normal thyroid-stimulating hormone (TSH) concentrations and no symptoms or signs of thyroid dysfunction. This constellation of laboratory values has been referred to as euthyroid hyperthyroxinemia and hypothyroxinemia, respectively. The free T4 should be normal, but many assays will report slightly abnormal values; for example, the free T4 index and many direct free T4 assays report high values in familial dysalbuminemic hyperthyroxinemia (FDH).

In the past, these conditions presented a diagnostic challenge, and many of the patients with them were inappropriately treated for thyroid disease. Today, when most clinicians measure serum TSH as a screening test for thyroid function, a normal serum TSH value is usually not followed by measurement of a total serum T4. With the use of sensitive serum TSH assays and automated "direct" free T4 assays, euthyroid hyper- or hypothyroxinemia frequently remains undetected, with no harm to the patient.
However, the detection of a normal serum TSH concentration associated with a high or low serum T4 concentration, and sometimes free T4 concentration, should immediately alert the clinician to search for one of the causes of euthyroid hyper- or hypothyroxinemia, especially if the patient has no symptoms or signs of either hyper- or hypothyroidism.
This topic will review these conditions. Individual thyroid function tests are discussed in detail separately. (See "Laboratory assessment of thyroid function".)
Both T4 and T3 circulate in blood bound to one of three binding proteins:

https://www.uptodate.com/contents/euthy ... yroxinemia


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