Measuring thyroglobulin and thyroglobulin autoantibody in patients with differentiated thyroid cancer.

Measurement of serum thyroglobulin is primarily used as a tumor marker in the postoperative management of patients with differentiated thyroid cancer. Unfortunately, the technical quality of current thyroglobulin assay methods varies and influences the clinical utility of this test. Two different methodologic approaches are used to measure serum thyroglobulin: the original competitive radioimmunoassay methodology and noncompetitive immunometric assay methods. Although the newer immunometric assays offer the technical benefits of eliminating the use of isotopes, using smaller specimen volumes, and having higher sensitivity potential, shorter turnaround times and the convenience of automation, immunometric assays also have a higher propensity for interference from both thyroglobulin autoantibodies and heterophilic antibodies, if present in the specimen. It is critical that physicians understand the technical limitations inherent in thyroglobulin measurement in order to effectively use this test for the postoperative management of patients with differentiated thyroid cancers.

Does Reverse Triiodothyronine Testing Have Clinical Utility? An Analysis of Practice Variation Based on Order Data from a National Reference Laboratory.

BACKGROUND: Clinical laboratories are under pressure to increase value by improving test utilization. The clinical utility of reverse triiodothyronine (rT3) is controversial. A study was conducted to identify order patterns that might suggest inappropriate utilization of rT3. METHODS: All orders for thyroid tests placed over a period of one year at a national reference laboratory were reviewed. Order patterns by client (hospital) and by provider were analyzed. A Pareto analysis was conducted to determine the percentage of orders placed as a function of the percentage of providers. A systematic review of the indexed literature and an informal review of the web were conducted to identify indications for rT3 testing. RESULTS: There were 402,386 orders for 447,664 thyroid tests, including 91,767 orders for rT3. These orders were placed by 60,733 providers located at 1139 different organizations. Only 20% of providers who ordered thyroid tests placed an order for rT3. Of those who placed an order for rT3, 95% placed two orders or fewer for rT3. One hundred providers (0.1% of the 60,733 providers who placed orders for thyroid tests) accounted for 29.5% of the orders for rT3. Of the 100 providers, 60 with the highest order volumes for rT3 were classified as practitioners of functional medicine. A systematic review of Medline found little evidence to support the high volumes of orders for rT3. A survey of Web sites for functional medicine suggests that rT3 is useful for the diagnosis of rT3 dominance and can be used to direct triiodothyronine replacement therapy. CONCLUSIONS: There is wide practice variation in rT3 testing. A high proportion of tests are ordered by a relatively small proportion of providers. There is little evidence to support high volumes of rT3 testing placed by some practitioners.

Clinical features and hospital outcomes in thyroid storm: a retrospective cohort study.

CONTEXT: Thyroid storm (TS) is a rare but life-threatening manifestation of thyrotoxicosis. Predictive features and outcomes remain incompletely understood, in part because studies comparing TS with hospitalized thyrotoxic patients have rarely been performed. OBJECTIVES: Our objectives were to compare the diagnosis and outcomes in TS versus hospitalized compensated thyrotoxic (CT) patients and to assess differences in diagnostic classification using the Burch-Wartofsky scores (BWSs) or Akamizu (Ak) criteria for identifying TS. DESIGN, SETTING, AND PATIENTS: This was a retrospective cohort study of hospitalized patients during a 6-year period at an academic tertiary hospital, with age ≥ 18 years, TSH <0.01 mIU/L, and clinically diagnosed TS or CT. OUTCOME MEASURES: In-patient mortality, hospital and intensive care unit length of stay, intubation, and ventilator duration were assessed. RESULTS: Twenty-five TS and 125 CT patients were identified and analyzed. All but 1 TS patient received thionamides, ß-blockade, glucocorticoids, and iodides within 24 hours of diagnosis. CT patients received thionamides and ß-blockade alone. In the acute hospital setting, rates of fever (>100.4 °F), heart rate (>100 beats/min), altered mentation, and a precipitating event were all higher for TS than for CT patients. Altered mentation was the only clinical feature significantly different between TS and the subset of CT patients defined as TS by BWS or Ak criteria (P < .001). TS patients had greater in-patient mortality, hospital and intensive care unit length of stay, and ventilation requirements than CT patients. CONCLUSIONS: In acutely hospitalized thyrotoxic patients, the presence of central nervous system dysfunction distinguished clinically diagnosed TS from patients with BWS- or Ak-defined TS. Because TS patients had significantly worse outcomes in this study, thyrotoxic patients with possible TS and central nervous system dysfunction may derive the greatest benefit from aggressive supportive and TS-specific treatments.

Is an isolated TSH elevation in chronic nonthyroidal illness "subclinical hypothyroidism"?

CONTEXT: Elevated TSH with normal T4 frequently occurs with chronic kidney, liver, and heart diseases. Whether isolated TSH elevations represent mild thyroid gland failure has not been established. EVIDENCE ACQUISITION: PubMed was searched for longitudinal studies in chronic heart, liver, or kidney disease documenting persistent isolated TSH elevations or progression to overt hypothyroidism. EVIDENCE SYNTHESIS: Four articles met inclusion criteria. In 16 end-stage renal failure patients, four had isolated TSH elevations. All normalized within 14 months. In 452 systolic heart failure patients, 20 had isolated TSH elevations, five of 20 were persistent, and none progressed to overt hypothyroidism within 6 months. In 207 untreated chronic hepatitis C patients, 12 had isolated TSH elevations and four had increased TSH with reduced free T4; all were female, and 14 had positive antithyroid antibodies. After 1 year, two of 12 developed "clinical hypothyroidism." In 72 chronic hepatitis C patients, nine females had positive antithyroid antibodies. Two antibody-negative patients had TSH 5-6 mU/L with reduced free T4. After 1 year, three of four with positive antithyroid antibodies and baseline TSH < 4 mU/L had elevated TSH with reduced free T4. CONCLUSIONS: In chronically ill patients, there is inadequate evidence to determine: 1) that isolated TSH elevations usually persist or progress to overt hypothyroidism; 2) the etiology and clinical significance of isolated TSH elevations; and 3) whether levothyroxine therapy is indicated for persistent isolated TSH elevations. Thus, isolated TSH elevations in chronic renal, cardiac, or liver diseases have not been documented to indicate mild thyroid gland failure.

MHC class I loss is a frequent mechanism of immune escape in papillary thyroid cancer that is reversed by interferon and selumetinib treatment in vitro.

PURPOSE: To evaluate MHC class I expression on papillary thyroid cancer (PTC) and analyze changes in MHC expression and associated immune activation with current and experimental treatments for thyroid cancer using in vitro PTC cell lines. EXPERIMENTAL DESIGN: MHC class I expression and assessment of tumor-infiltrating leukocyte populations were evaluated by immunohistochemistry. PTC cell lines were analyzed for HLA-ABC expression by flow cytometry following tyrosine kinase inhibitor, IFNα or IFNγ, or radiation treatment. Functional changes in antigenicity were assessed by coculture of allogeneic donor peripheral blood leukocytes (PBL) with pretreated or untreated PTC cell lines and measurement of T-cell activation and cytokine production. RESULTS: Both MHC class I and ß2-microglobulin expression was reduced or absent in 76% of PTC specimens and was associated with reduced tumor-infiltrating immune cells, including effector (CD3(+), CD8(+), CD16(+)) and suppressor (FoxP3(+)) populations. Treatment of PTC cell lines with the MEK1/2 inhibitor selumetinib or IFN increased HLA-ABC expression. This phenotypic change was associated with increased T-cell activation (%CD25(+) of CD3(+)) and IL2 production by PBL cocultured with treated PTC cell lines. Additive effects were seen with combination selumetinib and IFN treatment. CONCLUSIONS: MHC class I expression loss is frequent in human PTC specimens and represents a significant mechanism of immune escape. Increased antigenicity following selumetinib and IFN treatment warrants further study for immunotherapy of progressive PTC.

In search of an unstimulated thyroglobulin baseline value in low-risk papillary thyroid carcinoma patients not receiving radioactive iodine ablation.

BACKGROUND: The clinical use of serum thyroglobulin (Tg) as a tumor marker in papillary thyroid cancer (PTC) patients following total thyroidectomy continues to evolve, due in part to the introduction of more sensitive (second generation) Tg immunometric assays (Tg(2G)IMA, functional sensitivity ≤ 0.10 ng/mL), and the implementation of new recommendations against radioactive iodine ablation (RAIA) for patients at the lowest risk of recurrence. As a result, there is a need to establish the optimal timing and interpretation of serum Tg values while on levothyroxine-induced suppression of thyrotropin (TSH) in thyroidectomized PTC patients with a thyroid remnant. This study examines the pattern of decline and eventual baseline value of unstimulated Tg (uTg) concentrations following total thyroidectomy in patients with low-risk PTC who did not receive RAIA. METHODS: The medical records of consecutive patients with thyroid cancer seen at the Los Angeles County + USC Medical Center were retrospectively reviewed. Serial uTg and TSH values from Tg-antibody negative low-risk PTC patients treated with total thyroidectomy and no RAIA were analyzed. Patients were stratified by degree of TSH suppression to assess the effect on uTg. Serial postoperative uTg values were evaluated for the temporal pattern of decline and ultimate baseline. Patients with medullary thyroid cancer (MTC) were studied as a surgical reference group. RESULTS: Records from 577 consecutive thyroid cancer patients were reviewed, of which 36 met all criteria for inclusion. By 6 months, uTg fell to <0.5 ng/mL in 61% of patients and all patients demonstrated uTg < 0.5 ng/mL 2 years after surgery. During a median follow up of 5.7 years, uTg values remained below this level. The median uTg values in patients with papillary microcarcinoma, PTC, and MTC were similar at 0.11, 0.12, and 0.09 ng/mL, respectively. Further decline in uTg was not observed once the TSH was <0.5 mIU/L. CONCLUSIONS: The uTg values during TSH suppression in Tg antibody-negative, low-risk PTC patients who did not receive RAIA were below 0.5 ng/mL by 6 months postoperatively in most cases and remained stable over the duration of patient follow-up.

BRAF V600E in papillary thyroid carcinoma is associated with increased programmed death ligand 1 expression and suppressive immune cell infiltration.

BACKGROUND: There remain a small number of patients with papillary thyroid cancer (PTC) who suffer recurrence, metastases, or death. While mutation of the BRAF gene, corresponding to the constitutively active BRAF(V600E) protein, has been associated with worse clinical outcomes in thyroid cancer, the reasons underlying this observation are presently unknown. Disruption of endogenous host immune surveillance and promotion of tumor immune escape is one mechanism by which BRAF(V600E) tumors may achieve more aggressive behavior. This study evaluated the relationship between BRAF(V600E) status and known strategies of tumor-mediated immune suppression. METHODS: Tissue sections of PTC tumors from 33 patients were evaluated by immunohistochemistry for tumor-expressed suppressive ligands and enzymes and effector and suppressor populations of tumor-infiltrating immune cells. Presence of BRAF(V600E) was evaluated by direct DNA sequencing of PTC specimens and the results correlated with tumor-expressed molecules and tumor-infiltrating immune cell populations, as well as patient characteristics and pathologic findings. RESULTS: BRAF(V600E) tumors more often express high levels of immunosuppressive ligands programmed death ligand 1 (53% vs. 12.5%) and human leukocyte antigen G (41% vs. 12.5%) compared to BRAF wild-type tumors. There was no association between indoleamine 2,3-dioxygenase 1 expression and BRAF(V600E) status. Furthermore, BRAF(V600E) tumors demonstrate both lower CD8(+) effector to FoxP3(+) regulatory T cell, and CD68(+) pan-macrophage to CD163(+) M2 macrophage ratios, indicating relative increases in suppressive T cell and macrophage components, respectively. CONCLUSIONS: Overall, BRAF(V600E) PTC tumors display a broadly immunosuppressive profile and evidence of disturbed host tumor immune surveillance that may contribute to the poorer outcomes observed in this subset of patients with thyroid cancer.