Upper Half Of Normal Range Research Articles

6409 Successful Treatment Of Severe Ectopic ACTH-dependent Cushing’s Syndrome With Osilodrostat

Abstract Disclosure: K.A. Lee: None. C. Mendes Pessoa: None. W. Huang: Consulting Fee; Self; WH, Honoraria from Consulting and Speaking received from Recordati Rare Disease. Background: Cushing’s syndrome due to ectopic ACTH secretion is rare and may progress rapidly, making treatment very challenging. Previous case reports have described therapeutic options including adrenal steroidogenesis inhibitors, bilateral adrenalectomy (BAL), and adrenal embolization with success. Clinical Case: A 27-year-old woman with metastatic neuroendocrine tumor presented with sudden onset and rapidly progressing symptoms of fatigue, muscle weakness, acne and weight gain within two weeks. Laboratory findings confirmed severe Cushing’s syndrome due to ectopic ACTH secretion: AM cortisol 173.4 µg/dL (5-25), ACTH 1425 pg/mL (7.2-63.3), 24 hour urine cortisol 29,498 mcg/24hr (4-50), DHEA-Sulfate 1314 µg/dL (65 - 380), and testosterone 133 ng/dL (0-100). She was also found to have severe hypokalemia, hypocalcemia and hyperglycemia (despite an HbA1C of 6.2 at 2 weeks before presentation). CT- scan showed diffuse thickening of the bilateral adrenal glands. Due to widely metastatic disease in the peritoneum, BAL was considered non-feasible. The patient was admitted to hospital and initiated on osilodrostat at 20mg twice daily (after correction of hypokalemia) with close monitoring of her electrolytes, cortisol, EKG and steroid withdrawal symptoms. There was a rapid improvement of cortisol levels in response to osilodrostat. During treatment, she developed steroid withdrawal symptoms for which she was started on medium dose hydrocortisone. Bilateral adrenal arterial embolization was attempted but ultimately needed to be converted to right only adrenal gland embolization due to a hypertensive urgency and difficulty with catheterization. Her symptoms of Cushing’s syndrome significantly improved with the treatment. During her hospitalization, her hypokalemia was managed with spironolactone and potassium supplement, hypocalcemia with calcium supplement, and hyperglycemia with basal and bolus insulins. With significant improvement of cortisol levels, her hypocalcemia and hyperglycemia resolved and required no further treatment. Her potassium levels normalized and spironolactone was stopped. She remains on potassium supplement to keep K level at upper half of normal range to avoid long QTc. After discharge, her morning cortisol levels (before morning dose of hydrocortisone) continued to decrease and her osilodrostat dose was gradually tapered to 5mg once daily at night. Hydrocortisone was continued as part of the block-and-replace regimen. Conclusion: This case described a unique sudden onset and rapid progression of ectopic ACTH dependent Cushing’s syndrome and successful utilization of a block-and-replace approach by using the steroidogenesis inhibitor osilodrostat in prompt control of the hypercortisolism and related comorbidities. We also explored the feasibility of adrenal embolization for definitive management in the context of unfeasible BAL. Presentation: 6/2/2024

Basal Serum Thyroxine Level should Guide Initial Thyroxine Replacement Dose in Neonates with Congenital Hypothyroidism

Objective:Initial high-dose sodium levothyroxine (Na-LT4) (10-15 μg/kg/day) replacement for primary congenital hypothyroidism (CH) is recommended in guidelines. However, high-dose Na-LT4 risks iatrogenic hyperthyroidism. The aim of this study was to investigate the normalizing effect of varying initial doses of Na-LT4 on serum thyroid hormone levels.Methods:Fifty-two patients were analyzed retrospectively. The patients were classified into mild (27/51.9%), moderate (11/21.1%) and severe (14/26.9%) CH, based on initial free thyroxine (fT4) levels. Time taken to achieve target hormone levels was compared within groups.Results:Initial mean Na-LT4 doses for mild, moderate and severe disease were 6.9±3.3, 9.4±2.2 and 10.2±2 μg/kg/day. Serum fT4 levels reached the upper half of normal range (>1.32 ng/dL) in a median of 16, 13 and 16 days in patients with mild, moderate and severe CH with the mean time from initial treatment to first control visit of 14.8±6 days (range 1-36). There was no significant difference in terms of time to achieve target fT4 hormone levels according to disease severity (p=0.478). Seven (25.9%), eight (72.7%) and eight (57.1%) patients experienced hyperthyroxinemia (serum fT4 >1.94 ng/dL) in the mild, moderate, and severe CH groups at the first visit, respectively (p=0.016).Conclusion:Not all patients diagnosed with CH require high-dose Na-LT4. Initial dose of Na-LT4 may be selected on the basis of pretreatment thyroid hormone levels. Some patients with moderate and severe CH, experienced iatrogenic hyperthyroxinemia even though the dose was close to the lower limit of the recommended range in guidelines. We suggest that lower initial doses may be appropriate with closer follow-up within the first week.

The Clinical Spectrum of Resistance to Thyroid Hormone Alpha in Children and Adults

Resistance to thyroid hormone alpha occurs due to pathogenic, heterozygous variants in THRA. The entity was first described in 2012 and to date only a small number of patients with varying severity have been reported. In this review, we summarize and interpret the heterogeneous clinical and laboratory features of all published cases, including ours. Many symptoms and findings are similar to those seen in primary hypothyroidism. However, thyroid-stimulating hormone levels are normal. Free triiodothyronine (T3) levels are in the upper half of normal range or frankly high and free thyroxine (T4) levels are low or in the lower half of normal range. Alterations in free T3 and free T4 may not be remarkable, particularly in adults, possibly contributing to underdiagnosis. In such patients, low reverse T3 levels, normo- or macrocytic anemia or, particularly in children, mildly elevated creatine kinase levels would warrant THRA sequencing. Treatment with L-thyroxine results in improvement of some clinical findings.

Low initial dose of levothyroxine for treatment of congenital hypothyroidism

To evaluate the results of treatment of infants with congenital hypothyroidism (CH) with a low initial dosage of levothyroxine. 138 newborns with primary CH detected by neonatal screening were divided into 3 groups according to levels of serum TSH, TT(3) and TT(4): sub-clinical CH (TSH >50 mU/L), mild CH (TT(4) <54 nmol/L), severe CH (TT(4)<54 nmol/L and TT(3)<1.2 nmol/L). The initial dose of levothyroxine was (3.5 +/-1.0) microg/(kg.d) for sub-clinical CH group, (4.3 +/-0.7)microg/(kg.d) for mild CH group and (4.7 +/- 0.6)microg/(kg.d) for severe CH group. Follow-up evaluation was carried out at 1, 2 and 3 months of age by measuring serum levels of TT(3), TT(4) and TSH. The time, when clinical signs and symptoms were eliminated and serum levels of TT(3), TT(4) and TSH normalized, was recorded. Development Quotient (DQ) testing was performed when CH cases were about 2 years old. The mean initial dose of levothyroxine in 138 cases was (4.3 +/-0.9)microg/(kg.d). In one month the serum TT(3) and TT(4) levels returned to normal, while for TSH levels 67.4 % cases reached normal range in 2 months and 84.1 % in 3 months. Two months after therapy, the levels of TT(3) and TT(4) reached to the upper half of normal range and there were no signs or symptoms of hypothyroidism. The time for all cases in 3 groups to reach the normal clinical and biochemical indicators was similar (P=0.925). The dosage for cases with low circulating thyroxine before treatment was higher than that of the other groups (P<0.01). The average DQ score of 18 cases after treatment was 116.7 +/- 17.0. he levothyroxine dosage of (4.3 +/- 0.9)microg/(kg.d) is appropriate for the initial treatment of the majority of infants with CH. However it is better to individualize the dosage for each case.