Diagnosis Of Primary Hypothyroidism Research Articles

12344 Four-Month Delay In Denosumab Induced Severe Hypocalcemia And Hypophosphatemia. Case Report

Abstract Disclosure: M.M. Eid: None. S. Reutrakul: None. Introduction: Denosumab is a fully human monoclonal antibody that binds to the receptor activator of nuclear factor kappa Β ligand, blocks osteoclast function and reduces bone resorption. Case: A 91 year old male with history of osteoporosis, type 2 diabetes, chronic kidney disease (CKD) and prostate cancer. Presented with fatigue and cold intolerance. Denied confusion, muscle cramp, perioral numbness/tingling, bowel habit change. Medications included empagliflozin 12.5 mg/day, leuprorelin 45 mg every 6 months since 2021 and cholecalciferol 1000IU/day. On examination, he was alert and oriented x 3 with stable vital signs. No thyromegaly. Chvostek's sign was negative. Labs: serum calcium (Ca) 6.5 mg/dl, corrected Ca (Co Ca) 6.7mg/dl(N 8.7-10.4), ionized Ca 0.7mMol/l (N 1.13-1.32), TSH 131uIU/ml (N 0.55-4.78), free T4 0.72ng/dl (N 0.89-1.76), creatinine 1.55mg/dl, GFR 42ml/min/1.73m2, HbA1C 6.1%. EKG with corrected QT interval of 499 msec. Hypocalcemia work up : parathyroid hormone (PTH) 762 pg/ml (N 18.4-80.1), 25 OH vitamin D (Vit D) 37ng/ml (N 30-100), 1,25 OH Vit D 77pg/ml (N 18-72), phosphorus (Phos) 1mg/dl (N 2.4-5.1), magnesium (Mag) 1.7mg/dl (N 1.6-2.6),ALP 59U/L(N 45-117). Clinical impressions were a new diagnosis of primary hypothyroidism and non PTH mediated hypocalcemia with secondary hyperparathyroidism. A thorough review of medication revealed that he received the first dose of denosumab 60 mg 4 months prior to this presentation. Baseline labs 1 month prior to denosumab: Ca/Co Ca 9.1/9.2mg/dl, Phos 4.5mg/dl, PTH 199.6pg/ml, Mag 2.1mg/dl,TSH 2.72 uIU/ml. 2 months after denosumab administration, serum Ca/Co Ca 8.8/8.6mg/dl. He was admitted and received Ca gluconate 2gm IV pushes, calcitriol 0.5 mcg/day and levothyroxine 50 mcg/day and kept on cardiac monitoring. He remained asymptomatic. On the 5th day, serum Ca/Co Ca 8.4/8.6mg/dl, Phos 3mg/dl, Mag 2mg/dl. He was discharged on oral Ca Carbonate, calcitriol and levothyroxine. The second denosumab dose was cancelled. Conclusion: Denosumab is an effective anti-osteoporotic medication but can cause hypocalcemia. The risks for denosumab induced hypocalcemia include renal impairment, Vit D deficiency and lack of Ca/Vit D supplementation. Hypocalcemia usually occurs 1 - 2 weeks after denosumab, corresponding to its peak of action. Checking serum Ca and Vit D with correction of deficiencies before starting denosumab is recommended. In high risk patients with CKD, daily Ca and Vit D supplements are recommended (1). Our case has CKD and developed severe hypocalcemia and hypophosphatemia 4 months after receiving denosumab without other apparent causes for hypocalcemia. Hypothyroidism is likely an incidental diagnosis and not contributing to hypocalcemia in the absence of rhabdomyolysis. Reference: 1.Jalleh R, Basu G, Leu RL, Jesudason S: Denosumab induced severe hypocalcemia in chronic kidney disease. Case Rep Nephrol.2018 Presentation: 6/2/2024

PSAT342 Hypothyroidism After Use Of Immune Checkpoint Inhibitor Therapy In Patient With Graves’ Disease

Abstract Background Immune checkpoint inhibitors (ICIs) are commonly used for many cancers. Thyroid gland involvement is the commonest endocrine toxicity seen with this class of drugs. Most common thyroid dysfunction is thyroiditis followed by hypothyroidism with some cases of recovery. There are rare case reports of Graves’ disease induced by ICIs. However, we report a patient with pre-existing Graves’ disease who developed hypothyroidism after immunotherapy. Clinical Case 66-year-old man with metastatic squamous cell carcinoma of lung was referred to endocrine clinic for suppressed TSH. He was diagnosed with metastatic poorly differentiated lung cancer in September 2018. He received cheamotherapy with carboplatin and paclitaxel from October 2018 to January 2019. He was switched to immune checkpoint inhibitors with programmed cell death protein-1 (PD-1) inhibitor pembrolizumab every 3 weeks from February 2019. ICI therapy was stopped in until July 2019 due to immune mediated hepatitis. He was started on high dose steroids. Lung cancer findings remained stable even after stopping ICIs. Prior to starting ICIs his thyroid functions were consistent with hyperthyroidism. He continued to have suppressed TSH until his 6th cycle of pembrolizumab. TSH was found be significantly elevated prior to his 7th infusion. He was referred to endocrinology for further management. Clinically, patient was asymptomatic except for fatigue. Family history was positive for mother with Graves’ disease. Laboratory results on presentation showed significantly elevated TSH, low thyroxine (T4) and triiodothyronine (T3) consistent with diagnosis of primary hypothyroidism. Thyroid stimulating immunoglobulin (TSI) was positive suggesting autoimmune thyroid disease. Thyroid scan showed decreased 24-hour uptake (0.8%). A diagnosis of immune checkpoint inhibitor (ICI) related hypothyroidism was made. He was started on hormonal replacement with levothyroxine 50 mcg daily. Review of previous thyroid blood tests showed suppressed TSH since October 2016, but he was never treated. Thyroid peroxidase (TPO) antibodies were positive in the past. Thyroid sonogram in December 2016 showed a heterogeneous thyroid with no nodules. A radioactive scan in 1/2017 showed normal 24-hour uptake (12%) with no hot or cold nodules. (Fig 1). Since starting levothyroxine, the dose has been adjusted few times and patient has been doing well. Conclusion This is a unique case of patient with Graves’ disease who was cured because of immune related adverse event from use of immune-checkpoint inhibitor therapy. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Determination of cTSH plasmatic concentration in diagnosis of primary hypothyroidism in dogs: case report

Primary hypothyroidism in dogs presents nonspecific and systemic clinical signs, which precludes diagnosis only through clinical examination, blood count and routine serum biochemistry. Thus, thyroid function tests, together with clinical signs, should be performed for the definitive diagnosis of this endocrinopathy. Four dogs, one male and three females, aged 4 to 10 years, with clinical signs suggestive of hypothyroidism were evaluated for free T4 (fT4) and canine TSH (cTSH) plasma concentrations. In all dogs diagnosed with primary hypothyroidism, an increase was observed. cTSH concentration and free T4 decrease. As they were treated with sodium levothyroxine, there was an improvement in the reevaluation of TSH and fT4 parameters. Blood count and serum biochemistry were performed to help to rule out comorbidities and diseased euthyroid. Definitive diagnosis and follow-up of primary hypothyroidism treatment should be based on determinations of fT4 and cTSH plasma concentrations. It is recommended to rule out the sick euthyroid condition for successful hormone replacement therapy.

Case of Van-Wyk Grumbach syndrome

Background: Hypothyroidism in childhood typically leads to delayed puberty, rarely can it cause precocious puberty - this latter complex is eponymously known as Van-Wyk Grumbach syndrome.
 Case description: We report a case of a seven and a half-year-old girl who was referred with vaginal bleeding after a diagnosis of primary hypothyroidism and starting treatment with levothyroxine. This case report illustrates the typical features of this rare syndrome for primarily educational purposes. Many case reports of Van Wyk Grumbach syndrome have been published in world literature over the past seven decades after the initial description. Though the features of this syndrome are fairly well described previously, the understanding of pathophysiological mechanisms is speculative and still evolving.
 Clinical relevance: Further widespread awareness of the complex will encourage primary physicians and pediatricians to counsel the family of a child before starting treatment for hypothyroidism which will help avoid unnecessary worry and more importantly inadvertent procedures or intervention.

SAT-622 Rhabdomyolysis: A Rare Initial Presentation of Hypothyroidism

Introduction: Hypothyroidism is associated with a spectrum of musculoskeletal abnormalities as thyroid hormone signaling plays an integral role in skeletal muscle development and contractility. Mild to moderate CK elevation is present in majority of patients with symptomatic hypothyroidism. Overt rhabdomyolysis leading to acute kidney injury as a presentation of undiagnosed hypothyroidism is very rare. We present one such case. Case Description: 47-year-old African American woman with past medical history of non-insulin dependent diabetes and hypertension presented with myalgias and generalized edema in bilateral upper and lower extremities for the past 2 months. Outpatient labs revealed a Creatinine Kinase (CK) level of more than 10,000 U/L and an elevated creatinine level at 2 mg/dL. There was no history of trauma, immobilization, abnormal body movements, new drug use or recent fevers. At presentation, vital signs were stable. Physical examination showed non-pitting edema in bilateral upper and lower extremities. Initial work up revealed a creatinine of 2.15 mg/dL and CK level of 9173 U/L. Serum electrolytes were normal. Urine tested negative for myoglobin. Chest X ray and EKG were normal. Further testing revealed a TSH level of 148.7 mcIU/ml with T3 of <0.40 ng/dl and an undetectable T4 level. A diagnosis of primary hypothyroidism with rhabdomyolysis leading to acute kidney injury was made. She was treated with aggressive fluid resuscitation. She was also started on thyroid hormone supplementation with oral Levothyroxine 200 mcg/day. After initiation of treatment, the Creatinine levels trended down to 1.5 mg/dl. The CK levels trended down to 3600 U/L in 6 days after which she was discharged from the hospital. The patient was followed as an outpatient with gradual reduction of the CK levels over months. CK levels after 1 year were 154 U/L. The patient was continued on supplemental thyroid therapy. Discussion: Rhabdomyolysis is breakdown of muscle cells and release of muscle enzymes like Creatinine Kinase, electrolytes and myoglobin into the circulation. Among the various causes of Rhabdomyolysis, the most common are crush injuries, immobilization, seizures, heat stroke, sepsis and drugs like Statins, Colchicine and toxins like alcohol. Endocrinopathies like Hypothyroidism, Hyperthyroidism, Pheochromocytoma and Diabetes Ketoacidosis have been associated with rhabdomyolysis, but they tend to get ignored due to a lower incidence. Hypothyroidism is associated with elevation in CK levels in about 57-90% patients but the level of CK elevation is only mild, less than 10 times the upper limit of normal. Our case describes an uncommon initial presentation of hypothyroidism leading to overt rhabdomyolysis and acute kidney injury. It emphasizes the importance of checking a thyroid profile in a patient with acute elevation in muscle enzymes without an identifiable trigger.

Dysautonomia in a Bitch with Hypothyroidism

Background: Thyroid hormones have important effects on the cardiovascular system, of which the main ones are the increase in the heart response to the autonomic sympathetic nervous system. Heart rate variability is a non-invasive method of assessing autonomic heart modulation, thus being an important form of evaluation in patients with thyroid dysfunctions. This study aimed to report electrocardiographic and heart rate variability data of a dog with hypothyroidism that presented a parasympathetic dysfunction.Case: A 7-year-old female Dalmatian dog was admitted for clinical evaluation in Fortaleza, Brazil. According to the owner, she had been apathetic for a year, had gained weight, always had a sad expression, and her hair was generally brittle and opaque. On physical examination, skin lesions were observed at the end of the spine, extending to the tail region, with the latter showing total alopecia. Low T4 levels confirmed the diagnosis of primary hypothyroidism. Then, a 24-h Holter monitoring was performed, which showed that the animal had sinus arrhythmia associated with moments of second-degree sinoatrial block and rare moments of sinus tachycardia. In addition, moments of premature multifocal ventricular extrasystoles and 1st-degree atrioventricular block were observed. Based on the Holter results, heart rate variability (HRV) was calculated. Regarding the HRV in the frequency domain, 32.16 was obtained in the low frequency (LF) band, 67.84 in the high frequency (HF) band, and the LF / HF ratio was 0.46, with a total power of 5205. As for the HRV in the time domain, RMSSD was 117, pNN50 was 62.64 and SDNN was 384. This showed an increase in the parasympathetic activity of the heart and, due to this increased activity, a second-degree sinoatrial block occurred, which is a sinus function disturbance resulting from the exacerbated parasympathetic activity.Discussion: Beta-adrenergic receptors have their expression and activity altered by thyroid hormones. The sympathetic stimulation on the heart through the activation of these receptors originates a positive inotropic, lusitropic, dromotropic and chronotropic effect. Therefore, in the absence of thyroid hormones, there is a decrease in this stimulation, thus allowing a preponderant parasympathetic tone. In the present report, the increase in the parasympathetic tonus, observed in hypothyroidism, resulted in a reduction in the frequency of sinus firing, slowing of intranodal and sinoatrial conduction, and shortening of the effective refractory period, a combination of factors that led to decreased HR observed in the Holter monitoring. Previous studies have shown that thyroid hormones increase sympathetic activity, mainly in the heart, since they do not act by increasing the production or release of catecholamines, but rather increasing catecholamine response on the heart, due to a positive regulation of Ca2+-ATPase channels of the sarcoplasmic reticulum and beta1-adrenergic receptors. Thus, the observed result was already expected, because in hypothyroidism there is a decrease in these hormones that increase the sympathetic activity on the heart and so, the parasympathetic tone was very evident. The study of heart rate variability allows the simple assessment of the autonomic nervous system imbalance, and may be extremely important in the follow-up of diseases that affect this balance, such as hypothyroidism. Hence, more studies are required to verify the effect of such diseases on heart rate variability, aiming to define associations between the diseases and the alterations, as well as to define parameters of normality for such examinations.

Effect of timing of levothyroxine administration on the treatment of hypothyroidism: a three-period crossover randomized study.

Hypothyroidism is a common clinical problem that is successfully treated with hormone substitutes in the form of levothyroxine (LT4). LT4 is a drug with a narrow therapeutic index and is usually administered by strict rules, standardly at least half an hour before breakfast. The aim of this study was to investigate a possible effect of different timings of administration on thyroid function status and lipid profile. The study included patients with the diagnosis of primary hypothyroidism, which were using a stable dose of levothyroxine. They were randomized into three different groups regarding the timing of LT4 administration in a crossover fashion. Each timing regimen lasted for at least 8 weeks; timing regimen A-half an hour before breakfast; timing regimen B-an hour before the main meal of the day; timing regimen C-at bedtime (minimally 2 h after dinner). The hormones (TSH, fT3, fT4) and lipid profile (triglycerides, HDL-, LDL-, and total cholesterol) were measured before the study, at the beginning of every timing regimen and at the end of the study. Altogether, 84 patients finished the study. Different timings of LT4 administration were non-inferior in comparison to the standard one and between each other. Median differences in TSH level between baseline and timing regimens were: baseline vs. A = -0.017 95% C.I. (-0.400-0.192); baseline vs. B = -0.325 95% C.I. (-0.562-0.023); baseline vs. C = -0.260 95% C.I. (-0.475-0.000). There were no statistically significant differences in either TSH, fT4, or fT3 when compared between all three timing regimens of LT4 administration and the baseline. There were no statistically significant differences in any of the lipid profile parameters (triglycerides, HDL-, LDL-, and total cholesterol) when compared between all three timing regimens of LT4 administration and the baseline. The three investigated timing regimens of LT4 administration were equally efficient and offer additional options regarding the treatment individualization.

Frequecy of hypothyroidism In multi-transfused thalassemic patients in AL- Diwanyia Maternity ??children Hospital

Back ground: hypothyroidism in thalassemic children is not uncommon problem ? and need special attention and frequent patient monitoring.&#x0D; Objective: to establish the frequency of hypothyrodism among multitransfused&#x0D; thalassemic patients depending on clinical and laboratory investigations.&#x0D; Methods: A cross sectional study of thyroid function ,T3,T4, and TSH, was carried out in 120 transfusion-dependent thalassemia and sickle cell anemia patients attended the thalassemic Center in AL-Diwanyia Maternity and Children.Teaching Hospital .The inclusion criteria were 1(the age more than 5 years and 2)receiving frequent blood transfusions at least 6 times per year in the last three years.&#x0D; Result: eight patients have hypothyroidism and had a prevalence of (6.66%). Two patients had low T3 and T4 and elevated TSH with signs and symptoms of hypothyroidism and was already treated with thyroxin ,which consistent with the diagnosis of primary hypothyroidism , and 6 patients had no signs and symptoms of hypothyroidism with normal T3 and T4 but elevated TSH and this was consistent with the diagnosis of subclinical hypothyroidism . No patient of these 8 have family history of hypothyroidism . All affected patients are receiving&#x0D; blood transfusions more than 20 times since the time of diagnosis and all the effected patients have suboptimal iron –chelating therapy as reflected by the high serum ferritin level ( &lt; 1000 ).&#x0D; Conclusion: patient with transfusion dependent hemoglobinpathy need frequent monitoring of their thyroid function at least once yearly to detect early hypothyroidism and start early treatment .

Carpal Tunnel Syndrome in Hypothyroidism.

Carpal Tunnel Syndrome (CTS) is an entrapment neuropathy that occurs due to compression of median nerve in the carpal tunnel and hypothyroidism is one of the important causes of CTS. To study clinical profile of carpal tunnel syndrome in patients with primary hypothyroidism. This was cross-sectional study done in Smt. Kashibai Navale Medical College, Pune, Maharashtra. Adult patients with diagnosis of primary hypothyroidism were included in this study. Patients with other possible causes of CTS were excluded. Detailed medical history was obtained and all patients underwent clinical examination and nerve conduction study by electrophysiological method. Total 36 adult patients were included in this study, 86.1% females and 13.9% males. CTS were found in 6 (16.7%) patients. Increased Body Mass Index (BMI) and presence of clinical symptoms and/or signs of CTS correlated independently with presence of CTS in hypothyroidism. (p-value- 0.03 and < 0.0001 respectively). No correlation was found between gender, age of the patient, duration of disease, serum TSH level, aetiology of the disease, thyroid hormone replacement therapy and occurrence of CTS in hypothyroidism. Increase in BMI is an important risk factor for CTS in hypothyroidism and clinical evidence of CTS is a very sensitive parameter for the same.

A biopsychosocial approach to primary hypothyroidism: treatment and harms data from a randomized controlled trial.

BackgroundHypothyroidism is a common endocrine condition. There is evidence to suggest that, for a proportion of sufferers, the standard medical treatment does not completely reverse the constitutional and neuropsychiatric symptoms brought about by this condition. The management of hypothyroidism follows a biomedical model with little consideration given to alternative management approaches. There exists anecdotal evidence and case reports supporting the use of a biopsychosocial-based intervention called Neuro-Emotional Technique (NET) for this population. The aim of this study was to explore the potential short-medium term clinical efficacy and safety of NET for individuals with primary hypothyroidism.DesignPlacebo-controlled, blinded, parallel groups, randomized trial.MethodsNinety adults with a diagnosis of primary hypothyroidism were recruited from Sydney, Australia. Blinded participants were randomized to either the NET or placebo group and received ten intervention sessions over a six week period. The primary outcome involved the measurement of states of depression using the DASS-42 questionnaire. Secondary outcomes included thyroid function, thyroid autoimmunity testing, SF-36v2 questionnaire, resting heart rate and temperature measurement. Outcomes were obtained at baseline, seven weeks and six months. Questionnaires were completed at the private clinics, and serum measures were obtained and analysed at commercial pathology company locations. Heart rate and temperature were also measured daily by participants. Linear mixed-effects models were used to analyse the continuous outcomes. Unadjusted odds ratios with 95% confidence intervals were calculated for the binary outcomes.ResultsParticipants were randomly allocated to the NET (n=44) and placebo (n=46) groups. A proportion of the sample displayed neuropsychiatric disturbances and alterations in quality of life measures at baseline. There were no statistically significant or clinically relevant changes in the primary or secondary outcomes between the NET and placebo groups at time seven weeks or six months. There were a few short-lived minor adverse events reported in both the NET and placebo groups that coincided with the application of the intervention.ConclusionsThe application of the NET intervention appears to be safe, but did not confer any clinical benefit to the participants in this study and is unlikely to be of therapeutic use in a hypothyroid population.Clinical trials registration numberAustralian and New Zealand Clinical Trials Registry Number: 12607000040460.

Initial catch-up growth in children with hypothyroidism on thyroxine replacement therapy

Background: There is a paucity of observational data from India on initial catch up growth in hypothyroid children started on thyroxine replacement therapy. Methods: We retrospectively studied 44 children and adolescents (32 girls) with a diagnosis of primary hypothyroidism i.e., (thyrotropin > 15 μIU/mL and thyroxine < 55ng/mL). All were started on treatment with oral thyroxine. The dose was adjusted to maintain thyrotropin between 0.5-5 μIU/mL. Height was measured at baseline and at each follow-up visit and height standard deviation scores (HtSDS) were calculated. We studied the therapeutic benefit of thyroxine replacement therapy on growth in the initial couple of years of treatment. Results: Dose of thyroxine required to restore euthyroidism was 4.1±2.5 μg/kg body weight. The dose fell from 9.7±2.4 μg/kg body weight in infants to 3.0±1.5 μg/kg body weight in adolescence (p<0.001). Likewise, the dose per unit body surface area also fell consistently from 207 ± 70.3 μg/m2 in infants to only 89.3±17.9 μg/m2 in adolescents (p<0.001). The initial HtSDS was -2.0±1.5 and this improved by 0.4 to final value of -1.6±1.3 (p < 0.001) after an average follow up of 14.1±2.5 months. The mean catch-up growth velocity, weighted for the duration of follow-up was 7.7 cm/year. Conclusions: The HtSDS deficit because of hypothyroidism is partially regained in the first few years after treatment.

The relationship between thyroid dose and diagnosis of primary hypothyroidism in pediatric brain tumor patients receiving craniospinal irradiation

The aim of this work is to determine if a relationship exists between thyroid dose and incidence of primary hypothyroidism (PH) in children undergoing craniospinal irradiation (CSI). A total of 22 patients received CSI with evaluable thyroid dose information. All patients received concurrent chemotherapy and 21 patients (95%) received adjuvant chemotherapy. Median follow-up was 42.9 months. The incidence of PH in our cohort was 59% at a median time after radiotherapy of 3.5 years (range: 8 months to 7.5 years). Mean thyroid dose appeared to best predict for PH, with a median of 2080 cGy for patients with PH versus 1736 cGy for children without PH (p=0.057). There was no association between the rate of PH and sex, age, CSI dose, minimum thyroid dose and maximum thyroid dose. A relationship may exist between the mean thyroid dose and incidence of PH in patients undergoing CSI. Thus, new strategies to protect the thyroid gland may be warranted.

Progressive pituitary hyperplasia over the course of 2 years demonstrated on magnetic resonance imaging in a patient with long standing, profound primary hypothyroidism

Pituitary hyperplasia secondary to primary hypothyroidism and subsequent regression following thyroid replacement has been well described. We report a 12 year-old male who was retrospectively found to have progressive pituitary hyperplasia over the course of 2 years prior to his diagnosis of primary hypothyroidism, as documented on annual brain magnetic resonance imaging (MRI) for Arnold Chiari Type 1 malformation. He presented to Endocrinology with a 2-year history of fatigue, worsening daily headaches and linear growth deceleration. The diagnosis of primary hypothyroidism as the cause for his pituitary hyperplasia was made. He was started on levothyroxine with subsequent regression of pituitary hyperplasia demonstrated on repeat brain MRI six months later. This case is the first that demonstrates progressive pituitary hyperplasia from early in the course to diagnosis of hypothyroidism. It also illustrates that pituitary hyperplasia noted on routine brain MRI can be a presenting sign of primary hypothyroidism that should prompt endocrinologic evaluation.

The Relationship Between Thyroid Dose and Diagnosis of Primary Hypothyroidism in Pediatric Brain Tumor Patients Receiving Craniospinal Irradiation

Primary hypothyroidism (PH) is a known consequence of craniospinal irradiation (CSI) due to direct irradiation of the thyroid gland. The relationship between thyroid dose and the occurrence of PH in children undergoing CSI has not been extensively reported.

Die canine Hypothyreose – eine diagnostische Herausforderung?

Hypothyroidism is one of the most common endocrinopathies in dogs. Clinical symptoms and hematological and biochemical parameters lead to a first suspicion. To confirm diagnosis can be challenging, however. Determination of total serum T4 concentration is accepted as the primary screening test for the disease, and low serum T4 concentrations are intuitively suggestive of hypothyroidism. However it is well known that low T4 concentrations are frequently encountered in euthyroid dogs with various nonthyroidal diseases and in dogs receiving certain pharmacologic agents. Since assessment of endogenous TSH (canine TSH) using current canine TSH assays shows normal values in a high percentage of hypothyroid dogs (up to 40%), its diagnostic value is only limited. The TSH-stimulation test can still be recognized as the gold standard for the diagnosis of hypothyroidism in dogs. Determination of circulating T4 concentration before and 6 hours after the administration of exogenous TSH (recombinant human TSH, Thyrogen ® ) provides an assessment of the functional reserve capacity of the thyroid gland with minimal change in post-TSH T4 concentration, compared with the basal concentration, expected in dogs with hypothyroidism. Also this test can be influenced by nonthyroidal illness and by medications known to affect thyroid function. This suppressing influence seems to be less pronounced using a higher dose of TSH. Therefore, to improve the discriminatory power of the TSH stimulation test to differentiate between euthyroid-sick and primary hypothyroidism, the higher dose should be used in cases in which testing cannot be delayed. More recently, ultrasonography and scintigraphy have been used for the diagnosis of primary hypothyroidism. Using ultrasonography, a sensitivity of 98% was reported if size and echogenicity of the gland were combined. However, specificity was as low as 77% and care must be taken when measuring the gland because of a relatively high interobserver variability. Preliminary results using scintigraphy to discriminate between hypothyroid and non-thyroidal illness seem promising. However, due to its limited availability and the high expenditure, to date it cannot be used in clinical practice. Therefore, at present, if test results are obscure and a final diagnosis cannot be made, it is recommended to repeat the tests at a later time point.

Hypothyroidism: Clinical Features

Hypothyroidism: Clinical Features

Analysis of TPO gene in Turkish children with iodide organification defect: identification of a novel mutation

The objective was to determine molecular genetic analysis of the TPO gene in Turkish children with iodide organification defect (IOD). Patients with a diagnosis of primary hypothyroidism were evaluated. Subjects having a definite diagnosis of autoimmune thyroiditis, thyroid gland dysplasia and, or iodine deficiency were excluded. A total of 10 patients from nine unrelated Turkish families, with an unknown etiology of hypothyroidism, and with a presumptive diagnosis of IOD were included in the study. A perchlorate discharge test (PDT) was performed to all subjects, and sequence analysis of TPO gene was applied in patients with a positive PDT. Five out of 10 patients have a total IOD, while the five remaining patients have a partial IOD according to PDT results. In two sisters, one has a partial and the other one has a total IOD a novel homozygous nonsense p.Q315X mutation was found in exon 8. Additionally, a previously known homozygous missense p.R314W mutation was detected in the same exon in another patient with a total IOD. No TPO gene mutation was detected in any of the seven remaining patients. Two different TPO gene mutations were found to be responsible for IOD in two unrelated Turkish families from the same ethnic background. More subjects should be screened for detecting the prevalence and spectrum profile of TPO mutations in our population that might be helpful for understanding the pathophysiology of congenital hypothyroidism.

PRIMARY OR SECONDARY HYPOTHYROIDISM?

To the Editor: I was puzzled by the discussion of the case report by Ahmed IM et al.1 Clinical presentation and biochemical tests in 1997 were fully consistent with a diagnosis of primary hypothyroidism (high thyroid stimulating hormone and low free thyroxine serum levels, hyponatremia, tiredness, lethargy). Cortisol level was normal, and thyroxine replacement therapy successfully restored thyroid function. Only 7 years later (clinical conditions are not described) were hypopituitarism and a pituitary macroadenoma seen. In conclusion, although the authors' statement about underdiagnosis of hypopituitarism in older people can be shared, their suggestion that, in this case, early diagnosis of hypopituitarism was missed is not justified. Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the author and has determined that the author has no financial or any other kind of personal conflicts with this letter. Author Contributions: The author is the sole contributor to this letter. Sponsor's Role: None.

TRH Testing in Its Infancy

In contrast to primary hypothyroidism (1:3000 to 1:4000 births), central hypothyroidism due to pituitary or hypothalamic dysfunction is rare in newborns, with a prevalence of 1:25,000 to 1:100,000 births (1, 2). Although less common, central hypothyroidism is important to recognize because it is often accompanied by other pituitary hormone deficiencies that can cause life-threatening hypoglycemia. The hypothalamic-pituitary-thyroid axis undergoes dramatic changes in the transition from the fetal to newborn period (3). Thirty minutes after birth, newborns undergo a TSH surge to above 50 IU/liter, followed by a slow decrease to adult levels by 5–7 d of life. The TSH surge is accompanied by a rapid, 50% increase in total T4 levels that fall to normal infant levels by 3–5 d of life. However, the intrinsic variability of a maturing thyroid axis results in normal ranges for TSH and T4 values that vary among neonatal screening programs. Moreover, the trend toward an earlier discharge of infants and mothers from the hospital means that blood samples are being obtained earlier after birth. Considering these changes, interpreting the newborn screen must be done with sensitivity to the time of collection. When the newborn screen identifies a patient with a low T4 and elevated TSH level ( 40 IU/liter), the diagnosis of primary hypothyroidism is certain and therapy is begun. Although less common, other combinations of abnormal thyroid function tests are possible and usually result in additional testing. For example, if a screen is collected after 4–5 d, a case of mild primary hypothyroidism may have only a slightly elevated TSH and low to low-normal T4, mimicking central hypothyroidism. In contrast, patients with central hypothyroidism could experience a modified TSH surge followed by an increase in total T4 over the first 48–72 h of life, enough to push their T4 values into the normal or slightly elevated range. We know very little about the TSH surge in these patients. T4-binding globulin deficiency, euthyroid sick syndrome, and the hypothyroxinemia of prematurity can also cause low T4 associated with a normal TSH level. Importantly in these entities, free T4 values are usually normal. Unfortunately, immunoassays for free T4 are affected by low binding protein concentrations, resulting in falsely low free T4 levels (4), which further complicates their use in infants. To distinguish among these possibilities, additional testing is needed such as repetitive thyroid and pituitary hormone measurements and imaging of the thyroid and pituitary gland. Testing is an expensive and time-consuming approach and does not always result in a certain diagnosis. Therefore, alternative strategies may aid in the evaluation of these infants. In this issue of JCEM, van Tijn et al. (5) present their experience using the TRH stimulation test in a cohort of infants with low total T4 and normal TSH on newborn screen (6) and in whom they later confirmed multiple pituitary hormone deficiencies and pituitary dysmorphology with stimulation testing and imaging. After the synthesis of TRH in 1969, TRH stimulation testing was used to detect subtle states of thyroid gland dysfunction, acting as an amplifier to exaggerate underlying abnormalities in TSH secretion. As third and fourth generation TSH assays became more sensitive, however, the TRH stimulation test fell out of favor. Normal adults experience a maximum increase in serum TSH 30 min after TRH administration, and TSH levels gradually fall to basal levels by 120 min (7). In adults with pituitary or hypothalamic disease, the rise in TSH follows a different pattern. Often there is a delayed rise in TSH after TRH stimulation followed by a sustained increase. Sometimes the TSH rise is blunted or may be absent, which is more likely to be seen with pituitary disease in adults (8). Finally, an exaggerated TSH rise to TRH stimulation is occasionally noted in patients with central hypothyroidism (9, 10). This effect is thought to be due to the release of bioinactive TSH that is equally detected by immunoassays (11). These patterns have been verified in normal children and in children with hypopituitarism (12). Experience with the TRH test in newborns is extremely limited. There are significant differences in T4 metabolism in younger vs. older infants and children, which could produce different TRH stimulation test patterns in health and disease. The few available studies have used different TRH doses, collected TSH values at different times, and studied infants of various ages and clinical conditions (13–15). No other study has

Parallel Determination of Total Thyroxine and Thyrotropin Concentrations in Diagnosis of Primary Hypothyroidism in the Dog

The objective of the work was to verify the validity of parallel determination of total thyroxine (tT 4 ) and thyrotropin (cTSH) concentrations in the diagnosis of primary hypothyroidism in the dog. The concentrations of total thyroxine and thyrotropin were determined by chemiluminiscence immunoassay in the serum of a total of 117 dogs: 40 negative controls, 66 dogs with euthyroid sick syndrome and 11 patients with primary hypothyroidism. The average tT 4 concentration in the group of healthy dogs was 25.8 ± 5.48 nmol/l and the average cTSH concentration was 0.17 ± 0.13 ng/ml. In the group of patients with primary hypothyroidism the tT 4 concentrations were significantly decreased in 10 out of 11 cases (10.12 ± 2.01 nmol/l), while the cTSH concentrations were significantly increased (2.9 ± 2.04 ng/ml). In one patient with primary hypothyroidism, only the tT 4 concentration was decreased to 9.0 nmol/l, but the cTSH concentration was found to be within the reference range (0.04 ng/ml). The average tT 4 concentration in the group of patients with euthyroid sick syndrome was 11.7 ± 3.16 nmol/l, while the average cTSH concentration in the same group of patients was 0.14 ± 0.12 ng/ml. The concentrations of the two hormones mentioned above were compared between the different groups using the non-parametric Mann-Whitney test. The concentration of tT4 was significantly higher (p < 0.01) in the group of healthy dogs compared to the dogs with primary hypothyroidism and the dogs with euthyroid sick syndrome. The concentration of cTSH was significantly higher ( p < 0.01) in the dogs with primary hypothyroidism compared to the healthy dogs and the dogs with euthyroid sick syndrome. The results of this work show that parallel determination of tT 4 and cTSH represents a highly sensitive and specific method which is suitable for differentiating between primary hypothyroidism and other diseases that significantly reduce tT 4 concentrations. Canine TSH, tT 4 , euthyroid sick syndrome