Jeonghoon Ha

Parathyroid hormone and vitamin D are associated with the risk of metabolic obesity in a middle-aged and older Korean population with preserved renal function: A cross-sectional study

Background In general, obesity is a major contributor to metabolic syndrome (MetS) and is associated with insulin resistance (IR). Metabolically obese but normal weight (MONW) individuals present metabolic abnormalities and features of MetS despite having a normal range of body mass index (BMI). In recent years, different subtypes of obesity have been introduced, including metabolically healthy obese (MHO) and metabolically obese obese (MOO). Also, it has been reported that vitamin D and parathyroid hormone (PTH) are possibly linked with MetS. Methods and findings In this study, we aimed to evaluate the association between serum 25(OH)D, serum PTH, and the risk of metabolic obesity in four subtypes using nationally representative survey data for a Korean population conducted between 2008 and 2010. Of the 29,235 Korean participants, 18,997 subjects aged under 50 years were excluded. Participants with diabetes (n = 1,520), renal insufficiency (glomerular filtration rate [GFR] < 45 ml/min/1.73 m2, chronic kidney disease [CKD] stage 3b, 4, and 5 according to KDOQI classification [1]) (n = 49), history of treatment for osteoporosis (n = 455), insufficient data (n = 1,613), and fasting time less than 8 hours prior to blood collection (n = 771) were excluded for analysis. Ultimately, 5,830 adults (2,582 men and 3,248 women) were eligible for the present study. And, subtypes of obesity were divided into four types: Metabolically healthy normal weight (MHNW), Metabolically healthy obese (MHO), Metabolically obese but normal weight (MONW), and Metabolically obese obese (MOO). Female subjects with metabolic obesity were more likely to have higher levels of PTH and Male subjects with metabolic health were more likely to have higher serum 25(OH)D levels Conclusion We concluded that a positive association between serum PTH concentration and metabolic obesity among female subjects and an inverse relationship between serum 25(OH)D levels and the risk of metabolic obesity were found among male subjects. Further prospective studies are necessary to explore the biological mechanisms underlying these sex-specific findings.

Prognostic Value of Preoperative Anti-thyroglobulin Antibody in Differentiated Thyroid Cancer

The coexistence of differentiated thyroid cancer (DTC) and thyroid autoimmune disease could represent a better or worse prognosis. This study investigated the prognostic importance of preoperative anti‐thyroglobulin antibody (TgAb) in DTC patients.

Photoacoustic analysis of thyroid cancer in vivo: a pilot study

Thyroid cancer is one of the most prevalent cancers. About 3-8% of the people in the United States have thyroid nodules, and 5-15% of these nodules are malignant. Fine-needle aspiration biopsy (FNAB) is a standard procedure to diagnose malignity of nodules. However, about 10-20% of FNABs produce indeterminable results, which leads to repeat biopsies and unnecessary surgical operations. We have explored photoacoustic (PA) imaging as a new method to identify cancerous nodules. In a pilot study to test its feasibility, we recruited patients with thyroid nodules (currently 36 cases with 21 malignant and 15 benign nodules), acquired in vivo PA and ultrasound (US) images of the nodules in real time using a recently-developed clinical PA/US imaging system, and analyzed the acquired data offline. The preliminary results show that malignant and benign nodules could be differentiated by utilizing their PA amplitudes at different excitation wavelengths. This is the first in vivo PA analysis of thyroid nodules. Although a larger-scale study is needed for statistical significance, the preliminary results show the good potential of PA imaging as a non-invasive tool for triaging thyroid cancer.

Recombinant human Tsh stimulated thyroglobulin levels at remnant ablation predict structural incomplete response to treatment in patients with differentiated thyroid cancer

Abstract In patients with differentiated thyroid cancer, stimulated thyroglobulin (sTg) levels after thyroid hormone withdrawal (THW) at remnant ablation (RA) and at 6 to 12 months are known to have good prognostic value. This study aimed to evaluate the prognostic impacts and best cutoff values of sTg levels under recombinant human thyroid stimulating hormone (rhTSH) treatment at RA and at follow-up. A total of 151 patients were enrolled, of whom 77 were followed up with rhTSH-stimulated Tg (rhTSH-sTg) and 74 with THW-stimulated Tg (THW-sTg) at 6 to 12 months after rhTSH-aided RA. Risk stratification, response to treatment (excellent, indeterminate, biochemical incomplete, and structural incomplete response [SIR]), and clinical outcome were accessed by revised American Thyroid Association (ATA) guideline criteria. Seven out of 151 (4.6%) patients were confirmed to have SIR during the median follow-up of 79.0 months; 3 in the rhTSH group and 4 in the THW group. One hundred thirty-two out of 151 (87.4%) patients were confirmed to have excellent response; 68 (51.5%) in the rhTSH group and 64 (48.5%) in the THW group. The cutoff values of sTg for predicting SIR to treatment at rhTSH-aided RA, THW-sTg, and rhTSH-sTg were 4.64 ng/mL (sensitivity 85.7%, specificity 76.4%, negative predictive value [NPV] 99.2%), 2.41 ng/mL (sensitivity 100%, specificity 94.3%, NPV 100%), and 1.02 ng/mL (sensitivity 66.7%, specificity 94.6%, NPV 98.6%), respectively. sTg levels using rhTSH at both RA and follow-up has a high NPV and are as effective as using THW for predicting SIR. The risk classification according to the revised ATA guidelines can be used effectively to supplement rhTSH-aided sTg levels to predict better clinical outcomes.

Cholestyramine Use for Rapid Reversion to Euthyroid States in Patients with Thyrotoxicosis

Cholestyramine (CS) is an ion exchange resin, which binds to iodothyronines and would lower serum thyroid hormone level. The use of CS added to conventional antithyroid drugs to control thyrotoxicosis has been applied since 1980s, and several studies indicate that using CS in combination with methimazole (MZ) produces a more rapid decline in serum thyroid hormones than with only MZ treatment. Our recent retrospective review of five patients taking high dose MZ and CS, compared to age-, gender-, initial free thyroxine (T4) level-, and MZ dose-matched 12 patients with MZ use only, showed more rapid decline of both free T4 and triiodothyronine levels without more adverse events. CS could be safely applicable short-term adjunctive therapy when first-line antithyroid medications are not enough to adequately control severe thyrotoxicosis or side effects of antithyroid drug would be of great concern.

Risk factors for hypothyroidism in euthyroid thyroid nodule patients with lymphocytic thyroiditis on fine needle aspiration cytology

Background/Aims Lymphocytic thyroiditis as cytology diagnosis from fine needle aspiration (FNA) is frequently detected in patients with thyroid nodules. However, the clinical outcome for upcoming hypothyroid events has been rarely clarified in euthyroid patients. Methods We retrospectively reviewed the data of patient who had lymphocytic thyroitidis on FNA cytology of thyroid nodule from January 2005 to December 2010 at a tertiary referral hospital. In total, 109 patients with follow-up thyroid function tests (TFT) were enrolled. Final outcomes included overt and subclinical hypothyroidism with thyroid stimulating hormone (TSH) levels ≥ 10 mIU/L. Potential parameters predicting clinical hypothyroidism were analyzed by multivariate analysis. Results Over the mean follow-up duration of 51.6 months, 14 out of 109 patients (12.8%) developed clinical hypothyroidism that required thyroid hormone replacement. The median onset time to hypothyroidism was 16 months (range, 3 to 88) and ≥ 60% of patients experienced clinical hypothyroidism within 1 year. By multivariate analysis, background thyroiditis (relative risk [RR], 9.78; p = 0.004), thyroid peroxidase antibody positivity (RR, 9.90; p = 0.003), nodule size (RR, 1.24; p < 0.001), and initial TSH (RR, 1.47; p = 0.009) were the independent risk factors for predicting hypothyroidism in euthyroid patients. Conclusions Hypothyroidism frequently occurs during the follow-up in euthyroid patients with thyroid nodules which show lymphocytic thyroiditis on FNA cytology. Close surveillance and regular TFT are needed in high-risk patients for upcoming clinical hypothyroidism.

Gender specific association of parathyroid hormone and vitamin D with metabolic syndrome in population with preserved renal function

The association of parathyroid hormone (PTH) and vitamin D with Metabolic syndrome (MetS) was evaluated using representative data from the Korean population. Data from 7004 subjects aged 50 or older with preserved renal function (excluding chronic kidney disease stage 3b to 5) who were included in the Korean National Health and Nutrition Examination Survey between 2008 and 2010 were analysed. Higher PTH levels (pg/ml) were observed in subjects with MetS than in those without MetS among both genders (60.1 (58.6–61.6) vs. 62.4 (60.7–64.2) in males p = 0.018, 60.7 (59.4–62.1) vs. 63.9 (62.4–65.6) in females, p < 0.001). For females, PTH levels were significantly higher in subjects with MetS than in those without MetS after adjustment for possible covariates. Lower 25(OH)D levels were significantly associated with MetS only in male subjects (p = 0.004). As the number of MetS components increased, a significant rise in PTH levels (p for trend 0.005 in males and 0.024 in females) and a decrease in 25(OH)D levels (p for trend < 0.001 in males and 0.053 in females) were observed. In conclusion, among subjects with preserved renal function, PTH levels were possibly associated with MetS in females, whereas vitamin D levels exhibited a possible link to MetS in males.

Male-specific association between subclinical hypothyroidism and the risk of non-alcoholic fatty liver disease estimated by hepatic steatosis index: Korea National Health and Nutrition Examination Survey 2013 to 2015

Non-alcoholic fatty liver disease (NAFLD) is a prevalent liver disease encompassing a broad spectrum of pathologic changes in the liver. Metabolic derangements are suggested to be main causes of NAFLD. As thyroid hormone is a main regulator of energy metabolism, there may be a link between NAFLD and thyroid function. In previous studies, the association between NAFLD and thyroid function was not conclusive. The aim of this study was to clarify the relationship between NAFLD and thyroid function, focusing on subclinical hypothyroidism, using nationwide survey data representing the Korean population. NAFLD was defined as a hepatic steatosis index of 36 or higher. Based on the analysis of nationwide representative data, subclinical hypothyroidism was related to a high risk of NAFLD in males, but not in females. Our study showed that thyroid function might play a substantial role in the development of NAFLD, especially in males. Further study to elucidate the underlying mechanism of gender specific association of mild thyroid dysfunction and NAFLD would be required.

Calcification Patterns in Papillary Thyroid Carcinoma are Associated with Changes in Thyroid Hormones and Coronary Artery Calcification

Recent studies suggested that a lower serum thyroid hormone level is associated with more vascular calcification. However, it has been rarely evaluated whether lower thyroid hormone levels affect the calcification of thyroid cancer and there is a relationship between calcification patterns of papillary thyroid carcinoma (PTC) and coronary artery calcification (CAC). The study was divided into two groups: First, we retrospectively reviewed 182 PTC patients and examined the correlation between PTC calcification patterns and CAC by coronary computed tomography (CT). Second, the correlation between the calcification pattern of PTC and thyroid hormone concentration was investigated (n = 354). The calcification pattern of PTC was evaluated by thyroid ultrasonography and classified into four groups: no-calcification, microcalcification, macrocalcification, and mixed-calcification. In PTC patients with microcalcification and mixed calcification, more CAC was observed and coronary calcium score (CCS) was higher. Lower free T4 and higher thyroid-stimulating hormone (TSH) levels were associated with microcalcification and mixed calcification, not with macrocalcification and no calcification. PTC with microcalcification and mixed calcification showed more aggressive phenotypes like lymph node metastasis and more advanced TNM (tumor, node, and metastasis) stage than those with no calcification and macrocalcification. Calcification patterns of PTC showed close association with thyroid hormone levels and CAC. Further research is needed to determine how these findings are related to cardiovascular risk and disease-specific mortality.

A case of Pneumocystis jiroveci pneumonia after bendamustine-based chemotherapy for refractory diffuse large B-cell lymphoma

TO THE EDITOR: Pneumocystis jiroveci is a potential cause of virulent pneumonia in patients with impaired immunity, especially cell-mediated immunity. Increasing emphasis on prophylaxis using trimethoprim-sulfamethoxazole (TMP-SMX) has resulted in a decreasing incidence of Pneumocystis jiroveci pneumonia (PJP) in some diseases, such as human immunodeficiency virus (HIV) infection and lymphocytic leukemia. However, there are no standard guidelines for PJP prophylaxis in patients with other lymphoproliferative disorders. We report a case of PJP that occurred after a course of rituximab-bendamustine (RB) chemotherapy without TMP-SMX prophylaxis in a patient with refractory diffuse large B-cell lymphoma (DLBCL). We also review the literature on PJP in connection with bendamustine-containing chemotherapy. This patient was a 74-year-old man with DLBCL and a history of 8 cycles of R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, prednisolone) chemotherapy for stage IV DLBCL. Although he initially showed partial response to treatment, a significant proportion of lesions persisted after chemotherapy. Moreover, disease progression was noted 1 month after completion of first-line chemotherapy. Because the patient was deemed ineligible for high-dose chemotherapy, RB chemotherapy (rituximab 375 mg/m2 on day 1 and bendamustine 90 mg/m2 on days 2-3 q 28 days) was prescribed. After the first cycle of RB, the patient presented with fever. Chest radiography showed consolidation in both lung fields (Fig. 1A). A sequentially-performed chest computed tomography (CT) scan revealed ground-glass opacities in both lungs (Fig. 2). The white blood cell and absolute neutrophil counts were 3,820/µL and 1,940/µL, respectively. Lymphocyte fraction was 34%. The CD4 lymphocyte count was not assessed. Serum immunoglobulin (Ig) G level was 850 mg/dL (700–1,600). C-reactive protein level was 107.04 mg/L. The results of a respiratory viral study with nasal swab and serologic evaluation for mycoplasma and chlamydia were negative. Serum lactate dehydrogenase level was 911 IU/L. Arterial blood gas measurement on room air revealed hypoxemia (PaO2: 45.5 mmHg). Fig. 1 A chest X-ray showed consolidation in right lower lung field (A). Followed-up chest X-ray which was performed 10 days after TMP-SMX treatment showed interval regression of consolidation in right lung field (B). Fig. 2 A chest computed tomography (CT) scan revealed newly noted diffuse and multifocal patchy ground glass opacity and consolidation in both lungs (right side predominant). Empirical treatment was initiated using piperacillin and tazobactam. Based on the clinical course and chest CT finding, TMP-SMX (15 mg/kg) was initiated to target a possible Pneumocystis jiroveci infection. Prednisolone (1 mg/kg) was added to treat hypoxia. The sputum polymerase chain reaction (PCR) test was positive for Pneumocystis jiroveci. Because of the patients high oxygen demand and delirious mental status, we could not confirm the organism through broncho-alveolar lavage, but repeated sputum PCR tests were consistently positive for Pneumocystis jiroveci. After 10 days of TMP-SMX therapy, PCR testing showed negative conversion with radiologic improvement (Fig. 1B). However, the patients condition rapidly deteriorated after this transient improvement. Eventually, the patient died despite intensive treatment. PJP is one of the most serious opportunistic infections among immunocompromised patients with lymphoproliferative disorders. In particular, long-term use of corticosteroids or chemotherapy with fludarabine has been recognized as a risk factor for PJP based on clinical experience and data from clinical studies [1]. Therefore, for patients with the aforementioned risk factors, prophylaxis with TMP-SMX is recommended. However, in the case of DLBCL patients treated with R-CHOP chemotherapy, prophylaxis with TMP-SMX is not routinely used. Generally, prophylaxis is recommended in immunocompromised adult patients without HIV when the risk of PJP is greater than 3.5% [2]. However, according to a few reports, the incidence of PJP after rituximab-based chemotherapy in DLBCL patients was just 2–3% [3]. Some studies, however, have reported a significantly increased incidence (6–13%) of PJP during dose-dense R-CHOP (q 14 days), but it is believed that this increased incidence is due to dose-dense steroids rather than the cytotoxic agents in the R-CHOP regimen. Consequently, there is no consensus about the necessity of routine prophylaxis with TMP-SMX in DLBCL patients treated with R-CHOP. According to the National Comprehensive Cancer Network guidelines, RB chemotherapy is recommended for patients with relapsed/refractory DLBCL but who are not eligible for high-dose chemotherapy. Bendamustine is a unique alkylating agent with anti-metabolic activity and a favorable toxicity profile and is effective in a wide range of lymphoproliferative disorders. However, there have been no large-scale analyses of PJP and bendamustine-containing chemotherapy. According to one review, PJP was identified in only 2 (1.1%) of 176 patients [4]. Most subsequent trials of RB in lymphoma patients did not specify the incidence of PJP in the safety profile, although a few studies described pneumonia as a significant complication [5]. Given that a diagnosis of PJP may be difficult to make, it is possible that the actual incidence is under-estimated. In practice, a few case studies have reported PJP during bendamustine-containing chemotherapy (Table 1). In 2 of the cases, the low absolute lymphocyte or low CD4 counts of the host were underlined. Ito et al. [10] noted that CD4+ cell count decreased significantly while serum Ig level showed modest change in patients with relapsed or refractory low grade B-cell lymphoma during RB chemotherapy. Based on these results, the authors concluded that RB therapy was related to impaired cell-mediated immunity, leading to an increased risk of intracellular organism infections including Pneumocystis jiroveci. Some physicians have suggested monitoring lymphocyte or CD4 counts for patients receiving bendamustine. For example, Brugger and Ghielmini [11] recommend bimonthly monitoring of CD4-helper T-cell counts during bendamustine-containing chemotherapy and initiation of PJP prophylaxis for patients with counts of <200/µL. When deciding whether to employ prophylactic treatment, it is also important to consider concomitant drugs, patient age, underlying diseases, and previous chemotherapy history. Table 1 Clinical characteristics of 5 cases of Pneumocystis jiroveci pneumonia during bendamustine-containing chemotherapy. As bendamustine is increasingly used in lymphoma patients, physicians should be aware of its potentially serious infectious complications. Considering the fatality rate of PJP, prophylaxis and monitoring for PJP are required for patients on bendamustine chemotherapy who are elderly, heavily pre-treated, or currently in a refractory/relapsed status.