Publications
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Bjerkreim, Betty Ann; Hammerstad, Sara Salehi; Lee-Ødegård, Sindre & Eriksen, Erik Fink
(2026).
Assessment of biomarkers of thyroid hormone action across three thyroid hormone replacement regimens in hypothyroidism.
Frontiers in Endocrinology.
17.
doi:
10.3389/fendo.2026.1919606.
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Westbye, Alexander Bauer; Dahll, Louise J. Koren; Bredahl, May Kristin Lyamouri; Thorsby, Per Medbøe & Hammerstad, Sara Salehi
(2026).
Thyroxine Treatment of Adult RTHα Patients: Safety, Efficacy, and Metabolomic Changes.
Thyroid.
ISSN 1050-7256.
36(7),
p. 788–794.
doi:
10.1177/10507256261460201.
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Background: Resistance to thyroid hormone alpha (RTHα) is a rare genetic disorder with symptoms of hypothyroidism, but normal or close-to-normal thyroid function tests. Treatment with levothyroxine (L-T4) may be beneficial. This study investigated the efficacy, safety and biochemical changes of high-dose L-T4 and liothyronine (L-T3) treatment. Methods: Four RTHα (Ala263Val) patients were treated with L-T4 (1.75 µg/kg) in a pilot open-label study and monitored for three years. Quality of life (QoL) was assessed using ThyPro. Analysis of auxiological- and biochemical-parameters, bone mineral density (BMD) and exploratory metabolomics was performed. A partial replacement of L-T4 with L-T3 was attempted. Results: Treatment with L-T4 increased FT4, FT3, and rT3 to supraphysiological concentrations (relative to reference intervals) and suppressed thyroid-stimulating hormone with no adverse effects. Heart rate, bone markers, and sex hormone-binding globulin transiently increased. Several classes of lipids were reduced. BMD appeared unaltered. Patients reported improved QoL. One patient presented a short non-sustained ventricular tachycardia on L-T3 + L-T4. Conclusions: L-T4 treatment of adult RTHα patients was safe and improved QoL in adherent patients.
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Hammerstad, Sara Salehi; Lee, Hanna J.; Tomer, Yaron & Stefan-Lifshitz, Mihaela
(2025).
Immune checkpoint inhibitors associated thyroiditis: mechanisms and clinical outcomes.
Journal of Endocrinological Investigation.
ISSN 0391-4097.
48,
p. 2001–2012.
doi:
10.1007/s40618-025-02608-2.
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Background
Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment improving prognosis in many cancers. However, ICI often trigger immune-related adverse events (irAEs) that can affect various organ systems, leading to significant clinical challenges. The most frequent irAEs are those affecting the endocrine glands, reported in approximately 10% of treated patients. Thyroid dysfunction is the most common endocrine irAEs, mainly associated with PD-1/PD-L1 blockade therapies. Transient asymptomatic thyrotoxicosis is the most common form of clinical presentation, often followed by hypothyroidism. Interestingly, several studies have demonstrated that irAEs correlate with the response to cancer therapy and with improved overall survival (OS). The mechanisms underlying thyroid irAEs are not fully elucidated but complex interactions between genetic predisposition to thyroid autoimmunity, distinct immune mechanisms and thyroid cell intrinsic mechanisms are thought to drive thyroiditis associated with ICI therapy.
Purpose
In this review we discuss the latest data on clinical features of thyroid irAEs, proposed mechanisms and their association with improved survival.
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Dahll, Louise J. Koren; Westbye, Alexander Bauer; Vinorum, Kristin; Sejersted, Yngve; Barøy, Tuva & Thorsby, Per Medbøe
[Show all 7 contributors for this article]
(2023).
Clinical and Biochemical Characteristics of Untreated Adult Patients With Resistance to Thyroid Hormone Alpha.
Journal of the Endocrine Society (JES).
7(8).
doi:
10.1210/jendso/bvad089.
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Background: Thyroid hormone resistance due to pathogenic variants in thyroid hormone receptor alpha (THRA) is rare and descriptions of patients are sparse. The disorder is probably underdiagnosed as patients may have normal thyroid function tests. Treatment with thyroxine in childhood improves clinical symptoms. However, it is not clear if treatment has beneficial effects if started in adulthood.
Cases: We investigated 4 previously untreated Caucasian adult first-degree-related patients with the THRA c.788C > T, p.(Ala263Val) variant identified by a gene panel for intellectual disability in the index patient. Clinical data and previous investigations were obtained from medical reports.
Results: During childhood and adolescence, short stature, short limbs, metacarpals, and phalanges, and delayed bone age maturation were observed. Delayed motor and language development and decreased intellectual and learning abilities were described. Abdominal adiposity, round face, and increased head circumference were common features. All individuals complained of tiredness, constipation, and low mood. While thyrotropin (TSH) and free thyroxine (FT4) were within the reference range, free triiodothyronine (FT3) was high. FT4/FT3 ratio and reverse T3 were low. Other main features were low hemoglobin and high LDL/HDL ratio.
Conclusion: Investigation of 4 first-degree-related adult patients with untreated resistance to thyroid hormone alpha (RTHα) revealed more pronounced phenotype features and hypothyroid symptoms than previously described in patients treated with levothyroxine from childhood or adolescence. The delay in diagnosis is probably due to normal thyroid function tests. We suggest that THRA analysis should be performed in patients with specific clinical features, as treatment in early childhood may improve outcomes.
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Bjerkreim, Betty Ann; Hammerstad, Sara Salehi; Gulseth, Hanne Løvdal; Berg, Tore Julsrud; Lee-Ødegård, Sindre & Eriksen, Erik Fink
(2022).
Thyroid Signaling Biomarkers in Female Symptomatic Hypothyroid Patients on Liothyronine versus Levothyroxine Monotherapy: A Randomized Crossover Trial.
Journal of Thyroid Research.
ISSN 2090-8067.
2022.
doi:
10.1155/2022/6423023.
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Background. Levels of thyroid-stimulating hormone (TSH) are believed to reflect degree of disease in patients with hypothyroidism, and normalization of levels is the treatment goal. However, despite adequate levels of TSH after starting levothyroxine (LT4) therapy, 5–10% of hypothyroid patients complain of persisting symptoms with a significant negative impact on quality of life. This indicates that TSH is not an optimal indicator of intracellular thyroid hormone effects in all patients. Our aim was to investigate different effects of LT3 and LT4 monotherapy on other biomarkers of the thyroid signaling pathway, in addition to adverse effects, in patients with residual hypothyroid symptoms. Methods. Fifty-nine female hypothyroid patients, with residual symptoms on LT4 monotherapy or LT4/liothyronine (LT3) combination therapy, were randomly assigned in a non-blinded crossover study and received LT4 or LT3 monotherapy for 12 weeks each. Measurements, including serum analysis of a number of biochemical and hormonal parameters, were obtained at the baseline visit and after both treatment periods. Results. Free thyroxine (FT4) was higher in the LT4 group, while free triiodothyronine (FT3) was higher in the LT3 group. The levels of reverse triiodothyronine (rT3) decreased after LT3 treatment compared with LT4 treatment. Both low-density lipoprotein (LDL) and total cholesterol levels were reduced, while sex hormone-binding globulin (SHBG) increased after LT3 treatment compared with LT4 treatment. The median TSH levels for both treatment groups were within the reference range, however, lower in the LT4 group than in the LT3 group. We did not find any differences in pro-B-type natriuretic peptide (NT pro-BNP), handgrip strength, bone turnover markers, or adverse events between the two treatment groups. Conclusion. We have demonstrated that FT4, FT3, rT3, cholesterol, and SHBG show significantly different values on LT4 treatment compared with LT3 treatment in women with hypothyroidism and residual symptoms despite normal TSH levels. No differences in general or bone-specific adverse effects were demonstrated. This trial is registered with NCT03627611 in May 2018.
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Bjerkreim, Betty Ann; Hammerstad, Sara Salehi & Eriksen, Erik Fink
(2022).
Bone Turnover in Relation to Thyroid-Stimulating Hormone in Hypothyroid Patients on Thyroid Hormone Substitution Therapy.
Journal of Thyroid Research.
ISSN 2090-8067.
2022.
doi:
10.1155/2022/8950546.
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Background. Bone turnover markers (BTMs) have emerged as a useful tool for monitoring bone remodeling activity in the skeleton, and their serum levels correlate with bone loss rates in osteoporotic and normal individuals. Whether the same holds for other metabolic bone diseases is still subject to discussion. Methods. We analyzed the relation between levels of BTMs and TSH in 79 females on thyroid hormone substitution therapy for hypothyroidism. Based on the reference range for TSH (0.2–4.0 mU/L) in our lab, we assessed BTMs in five different groups of patients based on the following criteria: (1) hypothyroidism (TSH >4.0); (2) TSH in the high normal range (1.0–4.0); (3) TSH in the low normal range (0.2–1.0); (4) TSH below the normal range (0.01–0.2); (5) TSH undetectable (<0.01). We studied the relationship between TSH and four different bone markers: procollagen type 1 N-terminal propeptide (PINP), C-terminal cross-linking telopeptide of type 1 collagen (CTX), osteocalcin (OC), and bone specific alkaline phosphatase (BSAP). In a subgroup of patients, bone mineral density was assessed by a DXA scan. Results. PINP emerged as the most sensitive and dynamic BTM for assessment of bone turnover in this patient group, achieving significant rho values on nonparametric correlation analysis for both TSH (rho −0.47; p = 0.0001) and FT4 (rho 0.27; p = 0.018). CTX and OC also revealed significant correlations to TSH, albeit with lower rho values (−0.37 and −0.24, respectively). Categorical analysis showed that bone turnover increased significantly, albeit with pronounced interindividual variability for TSH values below the lower limit of normal (0.2 mU/l), with the most severe affected being women exhibiting suppression of TSH. Further analysis of loss rates by DXA in a limited subgroup of patients showed that this was accompanied by accelerated bone loss. Conclusion. PINP is the most sensitive marker of bone turnover in thyroid disorders. TSH values below the lower limit of normal are associated with increased bone turnover and accelerated bone loss, however, with pronounced interindividual variations. Assessment of PINP may be a valuable tool in cases where there is concern about possible adverse effects of thyroid hormone substitution therapy on bone.
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Weider, Therese; Genoni, Angelo; Broccolo, Francesco; Paulsen, Trond Harder; Dahl-Jørgensen, Knut & Toniolo, Antonio
[Show all 7 contributors for this article]
(2022).
High prevalence of common human viruses in thyroid tissue.
Frontiers in Endocrinology.
13,
p. 1–11.
doi:
10.3389/fendo.2022.938633.
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Introduction: Evidence points to viral infections as possible triggers of autoimmune thyroid disease (AITD), but little is known about the prevalence of common viruses in the thyroid gland. Using a novel approach based on virus enrichment in multiple cell lines followed by detection of the viral genome and visualization of viral proteins, we investigated the presence of multiple human viruses in thyroid tissue from AITD patients and controls.
Methods: Thyroid tissue was collected by core needle biopsy or during thyroid surgery from 35 patients with AITD (20 Graves’ disease and 15 Hashimoto’s thyroiditis). Eighteen thyroid tissue specimens from patients undergoing neck surgery for reasons other than thyroid autoimmunity served as controls. Specimens were tested for the presence of ten different viruses. Enteroviruses and human herpesvirus 6 were enriched in cell culture before detection by PCR and immunofluorescence, while the remaining viruses were detected by PCR of biopsied tissue.
Results: Forty of 53 cases (75%) carried an infectious virus. Notably, 43% of all cases had a single virus, whereas 32% were coinfected by two or more virus types. An enterovirus was found in 27/53 cases (51%), human herpesvirus 6 in 16/53 cases (30%) and parvovirus B19 in 12/53 cases (22%). Epstein-Barr virus and cytomegalovirus were found in a few cases only. Of five gastroenteric virus groups examined, only one was detected in a single specimen. Virus distribution was not statistically different between AITD cases and controls.
Conclusion: Common human viruses are highly prevalent in the thyroid gland. This is the first study in which multiple viral agents have been explored in thyroid. It remains to be established whether the detected viruses represent causal agents, possible cofactors or simple bystanders.
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Weider, Therese; Richardson, Sarah J.; Morgan, Noel G.; Paulsen, Trond Harder; Dahl-Jørgensen, Knut & Hammerstad, Sara Salehi
(2021).
HLA Class I Upregulation and Antiviral Immune Responses in Graves Disease.
Journal of Clinical Endocrinology and Metabolism (JCEM).
ISSN 0021-972X.
106(4),
p. 1763–1774.
doi:
10.1210/clinem/dgaa958.
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Abstract Context The origin of Graves disease (GD) remains elusive. However, evidence of an association between GD and viral infections is emerging. Human leukocyte antigen (HLA) class I presents viral antigens to circulating immune cells and plays a crucial role in the defense against viral infections. Objective This work aimed to investigate HLA class I expression, enterovirus presence, and the viral immune response proteins signal transducer and activation of transcription 1 (STAT1) and protein kinase R (PKR) in thyroid tissue from GD patients. Methods We collected thyroid tissue from core needle biopsies or surgical specimens from 48 GD patients and 24 controls. Standard immunohistochemistry was used to detect HLA class I and enteroviral capsid protein 1 (VP1) on formalin-fixed and paraffin-embedded tissue. STAT1 and PKR were examined by combined immunofluorescence staining. HLA class I expression score was the main outcome measure. Results The HLA class I expression score, which takes both proportion and intensity of immunostaining into account, was significantly higher in GD patients (3.1 ± 3.3) than in controls (0.5 ± 0.9) (P &lt; .001). Significantly more VP1 positive thyroid cells were found GD samples (50.1 ± 30.5%) than in controls (14.9 ± 10.5%) (P &lt; .001). STAT1 and HLA class I were found within the same thyroid cells and PKR and VP1 were also colocalized within thyroid cells. Conclusion HLA class I is upregulated in GD and enterovirus protein is prevalent in thyroid tissue. The colocalization of HLA class I with STAT1 and VP1 with PKR indicates an antiviral tissue response. These findings support the concept of a link between viral infections and GD.
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Hammerstad, Sara Salehi; Celius, Elisabeth Gulowsen; Husby, Henrik; Sørensen, Ingvild M. & Norheim, Ingrid
(2021).
Management of Severe Graves' Hyperthyroidism in Pregnancy Following Immune Reconstitution Therapy in Multiple Sclerosis.
Journal of the Endocrine Society (JES).
5(6).
doi:
10.1210/jendso/bvab044.
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Abstract Context Alemtuzumab (ALZ), a CD52 monoclonal antibody, is highly efficacious in multiple sclerosis; however, side effects are common. Autoimmune thyroid disease (Graves’ disease and Hashimoto thyroiditis) is a well-known complication of ALZ. Treatment of ALZ-induced Graves’ disease can be challenging, and even more difficult during pregnancy. Case description We present a case of severe ALZ-induced Graves’ disease with a rapid increase in thyrotropin receptor antibodies (TRAb 240 IU/L) and thyrotoxicosis in early pregnancy. Treatment with high doses of antithyroid medication was needed. There was high risk of both fetal and neonatal thyrotoxicosis. Serial fetal sonography showed normal development. The newborn baby presented high levels of TRAb (240 IU/L) and developed neonatal thyrotoxicosis on day 8. Adequate monitoring, treatment, and follow-up of the newborn baby ensured normal thyroid function until disappearance of TRAb 6 weeks after birth. Conclusion Multiple sclerosis patients treated with ALZ may develop severe Graves’ disease with an increased risk of both fetal and neonatal thyrotoxicosis. Close follow-up with a multidisciplinary approach is needed to ensure a healthy outcome.
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Poma, Anello Marcello; Hammerstad, Sarah Salehi; Genoni, Angelo; Basolo, Alessio; Dahl-Jorgensen, Knut & Toniolo, Antonio
(2021).
Immune transcriptome of cells infected with enterovirus strains obtained from cases of autoimmune thyroid disease.
Microorganisms.
9(4),
p. 1–16.
doi:
10.3390/microorganisms9040876.
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Sletner, Line; Jenum, Anne Karen; Qvigstad, Elisabeth & Hammerstad, Sara Salehi
(2021).
Thyroid Function during Pregnancy in A Multiethnic Population in Norway.
Journal of the Endocrine Society (JES).
5(7),
p. 1–12.
doi:
10.1210/jendso/bvab078.
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Abstract Context Ethnic differences in thyroid function during pregnancy have been reported. However, it is unclear if this is equally valid across ethnic groups within multiethnic populations. Objective We aimed to assess ethnic differences in thyrotropin (TSH) and free thyroxine (FT4), and the prevalence of thyroid dysfunction and thyroid autoimmunity during pregnancy. Methods In a population-based cohort of 785 pregnant women in Oslo, Norway, TSH, FT4, and thyroid peroxidase antibodies (TPO Abs) were measured twice: at gestational week (GW) 15 and 28, and urine iodine concentration at GW 15. Associations were assessed using multivariate linear regression. Results We found ethnic differences in TSH levels at both time points, but not for fT4. South Asians had 0.42 mU/L (95% CI, 0.20-0.64) higher TSH than Europeans in GW 15. This difference persisted after adjusting for covariates (including TPO Ab positivity and iodine status), and increased further as pregnancy progressed. In contrast, East Asians had the lowest TSH. No new cases of overt hypothyroidism were detected in early pregnancy, but subclinical hypothyroidism was found in 6.6% among all, highest in South Asians (14.2%). Hyperthyroidism early in pregnancy was observed in 3.7% (almost all subclinical), highest in East Asians (11.9%). The prevalence of TPO Ab positivity was 4%, highest in South Asians (8%). Conclusion In a multiethnic population of presumably healthy women, we found ethnic variations in TSH but not FT4 levels throughout pregnancy. South Asians had higher TSH and more subclinical hypothyroidism, not explained by their higher prevalence of TPO Ab positivity. Larger studies are needed to define ethnic- and trimester-specific reference ranges in pregnancy.
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Bøhmer, Thomas; Bachtyari, Zivar; Sommer, Christine & Hammerstad, Sara Salehi
(2020).
Auto regulatory capacity of the thyroid gland after numerous iodinated contrast media investigations.
Scandinavian Journal of Clinical and Laboratory Investigation.
ISSN 0036-5513.
80(3),
p. 191–195.
doi:
10.1080/00365513.2019.1709658.
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Weider, Therese; Richardson, Sarah; Morgan, Noel; Paulsen, Trond; Dahl-Jørgensen, Knut & Hammerstad, Sara Salehi
(2020).
Upregulation of HLA Class i and Antiviral Tissue Responses in Hashimoto's Thyroiditis.
Thyroid.
ISSN 1050-7256.
30(3),
p. 432–442.
doi:
10.1089/thy.2019.0607.
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Background: Hashimoto's thyroiditis (HT) is a common autoimmune disease of unknown origin. However, viral infections have been implicated as triggers for autoimmunity. Human leukocyte antigen (HLA) class I presents antigens to circulating immune cells and plays a crucial role in the defense against viral infections. This study aimed to investigate the presence of enterovirus and HLA class I expression in one of the largest HT thyroid tissue cohorts to date. In addition, viral receptors and viral immune response proteins were examined. Methods: Thyroid tissue samples from 46 HT patients were obtained using core needle biopsy. Thyroid tissue collected during neck surgery for other reasons than thyroid autoimmunity served as controls. Standard immunohistochemistry on formalin-fixed, paraffin-embedded tissue samples were used to detect HLA class I, enteroviral capsid protein 1 (VP1), and coxsackie and adenovirus receptor (CAR) in thyroid cells. A subset of the samples was examined with combined immunofluorescence staining for signal transducer and activator of transcription 1 (STAT1) and protein kinase R (PKR). Results: Significantly more HLA class I-positive samples were found in the HT group (31 out of 46 [67.4%]) than in the control group (5 out of 24 [20.8%]) (p < 0.001). Moreover, the semiquantitative score assessing the grade of HLA class I expression was significantly higher in the HT group (3.9 ± 3.1) than in the control group (0.5 ± 0.9) (p < 0.001). In addition, STAT1 was colocalized with HLA class I, and PKR and VP1 were also found and were colocalized together. VP1 was detected in both controls and the HT samples, with slightly more VP1+ thyroid cells in the HT samples (20.1% ± 16.4%) than in controls (14.9% ± 10.5%). Finally, the presence of CAR in thyroid cells was confirmed. Conclusion: The current study confirmed that HLA class I hyperexpression is a defining feature of HT. Thyroid cells express CAR, thus making them susceptible to enterovirus infection. The colocalization of HLA class I with STAT1 and VP1 with PKR indicates an intracellular, antiviral host response. These findings support the concept of a firm link between viral infection and autoimmune thyroid diseases.
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Lee, Hanna J.; Li, Cheuk Wun; Hammerstad, Sara Salehi; Stefan, Mihaela & Tomer, Yaron
(2015).
Immunogenetics of autoimmune thyroid diseases: A comprehensive review.
Journal of Autoimmunity.
ISSN 0896-8411.
64,
p. 82–90.
doi:
10.1016/j.jaut.2015.07.009.
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Hammerstad, Sara Salehi
(2014).
Genetic analysis in young-age-of-onset Graves' disease reveals new susceptibility loci.
Journal of Clinical Endocrinology and Metabolism (JCEM).
ISSN 0021-972X.
99(7),
p. 1387–1391.
doi:
10.1210/jc.2013-4358.
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Hammerstad, Sara Salehi; Tauriainen, S; Hyöty, Heikki; Paulsen, Trond Harder; Nordheim, Ingrid & Dahl-Jørgensen, Knut
(2013).
Detection of enterovirus in the thyroid tissue of patients with graves' disease.
Journal of Medical Virology.
ISSN 0146-6615.
85(3),
p. 512–518.
doi:
10.1002/jmv.23476.
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Hammerstad, Sara Salehi; Nordheim, Ingrid; Paulsen, Trond; Amlie, Lise-Marit & Eriksen, Erik Fink
(2013).
Excessive Decrease in Serum Magnesium After Total Thyroidectomy for Graves' Disease Is Related to Development of Permanent Hypocalcemia.
World Journal of Surgery.
ISSN 0364-2313.
37(2),
p. 369–375.
doi:
10.1007/s00268-012-1843-2.
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Dec. 18, 2023 11:59 AM
- Last modified
Jan. 23, 2024 10:31 AM
