Jonathan S. LoPresti

Unique Alterations of Thyroid Hormone Indices in the Acquired Immunodeficiency Syndrome (AIDS)

STUDY OBJECTIVE To determine alterations in serum thyroid hormone indices in patients with human immunodeficiency virus (HIV) infection. DESIGN Prospective, single-blind study. SETTING Large metropolitan hospital where 20% of all patients with the acquired immunodeficiency syndrome (AIDS) in Los Angeles are treated. PATIENTS Twenty-six inpatients with bronchoscopy-proven Pneumocystis carinii pneumonia and AIDS. Outpatients included 10 persons seropositive for HIV, 10 with AIDS-related complex, and 10 with AIDS. MAIN RESULTS There were 19 survivors and 7 nonsurvivors of P. carinii infection. Serum triiodothyronine (T3) values generally remained normal until hospitalization, with nonsurvivors having lower values than survivors (0.56 +/- 0.1 nmol/L compared with 1.3 +/- 0.1 nmol/L, P less than 0.002, respectively). Reverse triiodothyronine (rT3) levels were low in persons with AIDS-related complex (0.21 +/- 0.02 nmol/L, P less than 0.001) and in AIDS outpatients (0.17 +/- 0.02 nmol/L, P less than 0.001). Normalization of rT3 occurred after patients were hospitalized (0.28 +/- 0.01 nmol/L). Serum thyroxine-binding globulin values rose with progression of HIV infection (seropositive, 369.7 +/- 18.1 nmol/L, P less than 0.005; AIDS-related complex, 419.1 +/- 37.0 nmol/L, P less than 0.005; AIDS, 423.3 +/- 31.9 nmol/L, P less than 0.005; survivors, 476.3 +/- 24.6 nmol/L, P less than 0.001), whereas nonsurvivors had normal values. All values are compared with normal values (T3, 2.3 +/- 0.04 nmol/L; rT3, 0.28 +/- 0.01 nmol/L; thyroxine-binding globulin, 288.2 +/- 6.9 nmol/L). CONCLUSIONS Infection with HIV produces unique alterations in thyroid function. A progressive decline in rT3 and elevation in thyroxine-binding globulin accompany advancing HIV infection. The persistence of a normal T3 despite progression of HIV infection may contribute to weight loss. A low serum T3 on admission correlates with mortality.

Technology Insight: 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.

Serum Basal Thyroglobulin Measured by a Second-Generation Assay Correlates with the Recombinant Human Thyrotropin-Stimulated Thyroglobulin Response in Patients Treated for Differentiated Thyroid Cancer

BACKGROUND Recombinant human thyrotropin (rhTSH) stimulation is frequently used to assess the disease status of patients treated for differentiated thyroid cancer (DTC) when basal (unstimulated) thyroglobulin (b-Tg) is below the assay sensitivity limit. The objective of this study was to determine relationships between the b-Tg and the 72-hour rhTSH-stimulated Tg (rhTSH-Tg) using a second-generation immunochemiluminometric assay with a functional sensitivity of 0.05 ng/mL (microg/L). METHODS Serum Tg was measured in paired b-Tg and rhTSH-Tg specimens from 1029 rhTSH tests performed on 849 TgAb-negative patients during long-term monitoring for DTC. RESULTS Basal Tg correlated with rhTSH-Tg across b-Tg concentrations ranging from 0.05 to 1000 ng/mL (microg/L) (r = 0.85, p < 0.0001). The b-Tg concentration was unrelated to age, sex, basal TSH, 72-hour TSH, or the Tg fold response (rhTSH-Tg/b-Tg). Further, only 2/655 (0.3%) tests with b-Tg below 0.1 ng/mL (microg/L) had rhTSH-Tg above 2.0 ng/mL (microg/L) (2.9 and 3.8 ng/mL [microg/L], respectively). Thirty-three patients with three or more rhTSH tests performed over a 2- to 5-year period displayed high indexes of individuality for both the 72-hour TSH and the Tg fold response (indexes of individuality = 0.30 and 0.38, respectively). Basal Tg measured using a first-generation assay with a functional sensitivity of 0.9 ng/mL (microg/L) failed to reliably detect an rhTSH-Tg response above 2.0 ng/mL (microg/L). CONCLUSIONS An rhTSH-Tg response above 2.0 ng/mL (microg/L) was highly unlikely when b-Tg was below 0.1 ng/mL (microg/L). Second-generation b-Tg measurements correlated with the degree of rhTSH-Tg stimulation and thus the likelihood of having rhTSH-Tg above the customary cut-off of 2.0 ng/mL (microg/L), whereas b-Tg measured by a first-generation assay did not. Correlations between four different assays showed that the use of a fixed Tg cut-off was influenced by assay selection. Patients receiving repetitive rhTSH tests had highly reproducible rhTSH-Tg/b-Tg fold responses, suggesting that repetitive testing is unnecessary and that second-generation measurement of b-Tg trends without rhTSH stimulation would be satisfactory for the long-term monitoring of most patients with DTC.

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 β2-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. Clin Cancer Res; 20(23); 6034–44. ©2014 AACR.

How sensitive (second-generation) thyroglobulin measurement is changing paradigms for monitoring patients with differentiated thyroid cancer, in the absence or presence of thyroglobulin autoantibodies

Purpose of reviewTo discuss new insights regarding how sensitive (second-generation) thyroglobulin immunometric assays (Tg2GIMAs), (functional sensitivities ⩽0.10 &mgr;g/L) necessitate different approaches for postoperative thyroglobulin monitoring of patients with differentiated thyroid cancer (DTC), depending on the presence of thyroglobulin autoantibodies (TgAbs). Recent findingsReliable low-range serum thyroglobulin measurement has both enhanced clinical utility and economic advantages, provided TgAb is absent (∼75% DTC patients). Basal [nonthyroid-stimulating hormone (TSH) stimulated] Tg2GIMA measurement obviates the need for recombinant human TSH stimulation because basal Tg2GIMA below 0.20 &mgr;g/L has comparable negative predictive value (>95%) to recombinant human TSH-stimulated thyroglobulin values below the cutoff of 2 &mgr;g/L. Now that radioiodine remnant ablation is no longer considered necessary to treat low-risk DTC, the trend and doubling time of low basal thyroglobulin values arising from postsurgical thyroid remnants have recognized prognostic significance. The major limitation of Tg2GIMA testing is interference by TgAb (∼25% DTC patients), causing Tg2GIMA underestimation that can mask disease. When TgAb is present, the trend in TgAb concentrations (measured by the same method) can serve as the primary (surrogate) tumor-marker and be augmented by thyroglobulin measured by a TgAb-resistant class of method (radioimmunoassay or liquid chromatography-tandem mass spectrometry). SummaryThe growing use of Tg2GIMA measurement is changing paradigms for postoperative DTC monitoring. When TgAb is absent, it is optimal to monitor the basal Tg2GIMA trend and doubling time (using the same method) in preference to recombinant human TSH-stimulated thyroglobulin testing. When TgAb is present, interference renders Tg2GIMA testing unreliable and the trend in serum TgAb concentrations per se (same method) can serve as a (surrogate) tumor-marker.

BRAFV600E 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.

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, β-blockade, glucocorticoids, and iodides within 24 hours of diagnosis. CT patients received thionamides and β-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.

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.

Assessing Thyroid Function in Hospitalized Patients

Severe nonthyroidal illness requiring hospitalization in an individual without a history of preexisting thyroid disease produces a series of well-orchestrated and predictable alterations in serum thyroid hormone indices. The changes in circulating thyroid hormone values have come to be known as the nonthyroidal illness syndrome. Most commonly, these assume the form of a low triiodothyronine (T3) state in which serum total and free T3 concentrations are decreased in the face of normal circulating total and free thyroxine (T4) levels which, then, can progress to the low T3/T4 state in which both T3 and T4 values are reduced. This spectrum of change becomes more pronounced as the underlying disease transitions to more severe life-threatening illness. Concurrent with these alterations in T4 and T3 levels, a rise in the circulating reverse triiodothyronine (rT3) concentration is also observed. Despite the fall in T4 and T3 values, little clinical evidence of hypothyroidism can be found. In addition, serum thyrotropin (TSH) levels generally remain in the normal range [1–3]. It is interesting to note that all of these changes are reversible with resolution of the inciting event (Fig. 10.1). This constellation of biochemical changes and clinical findings has also led to the use of descriptor euthyroid sick syndrome, which is used interchangeably with the nonthyroidal illness syndrome [4]. However, with recent evidence demonstrating a more local tissue regulation rather than a global response in the thyroid hormone axis being responsible for the alterations in circulating thyroid hormone levels, it may be better to use the more general descriptive expressions of low T3 and low T3/T4 states. In addition, this begs the question as to whether serum thyroid hormone values accurately reflect the true thyroid status of the hospitalized patient.