Adriana G. Ioachimescu

The Lipid Accumulation Product and All‐cause Mortality in Patients at High Cardiovascular Risk: A PreCIS Database Study

The BMI is the most frequently used marker to evaluate obesity‐associated risks. An alternative continuous index of lipid over accumulation, the lipid accumulation product (LAP), has been proposed, which is computed from waist circumference (WC, cm) and fasting triglycerides (TGs) (mmol/l): (WC − 65) × TG (men) and (WC − 58) × TG (women). We evaluated LAP and BMI as predictors of mortality in a high‐risk cohort. Study population included 5,924 new consecutive patients seen between 1995 and 2006 at a preventive cardiology clinic. Fifty‐eight percent of patients were discordant for their LAP and BMI quartiles. Patients whose LAP quartile was greater than BMI quartile had higher mortality compared with those with LAP quartile was lower than BMI quartile (8.2 vs. 5.4% at 6 years, P = 0.007). After adjustment for age, gender, smoking, diabetes mellitus, blood pressure, low‐density lipoprotein‐cholesterol (LDL‐C) and high‐density lipoprotein‐cholesterol (HDL‐C), (ln)LAP was independently associated with mortality (hazard ratio (HR) = 1.46, P < 0.001). BMI was not associated with increased mortality (HR = 1.06, P = 0.39). Adding LAP to a model including traditional risk factors for atherosclerosis increased its predictive value (C statistic 0.762 vs. 0.750, P = 0.048). Adding BMI to the same model did not change its predictive value (0.749 vs. 0.750, P = 0.29). Subgroup analyses showed that LAP predicted mortality in the nondiabetic patients (adjusted HR for (ln)LAP 1.64, P < 0.001), but did not reach significance in the diabetic patients (HR = 1.21, P = 0.11). In conclusion, LAP and not BMI predicted mortality in nondiabetic patients at high risk for cardiovascular diseases. LAP may become a useful tool in clinical practice to stratify the risk of unfavorable outcome associated with obesity.

Silent corticotroph adenomas: Emory University cohort and comparison with ACTH-negative nonfunctioning pituitary adenomas.

BACKGROUND Silent corticotroph adenomas (SCAs) are clinically nonfunctioning pituitary adenomas (NFPAs) with positive staining for corticotropin (ACTH) by immunohistochemistry. Whether SCAs behave more aggressively than NFPAs without ACTH immunoreactivity (ACTH negative) remains controversial. OBJECTIVE To compare characteristics and outcomes of SCAs with ACTH-negative NFPAs and to identify predictors of aggressive outcome. Primary composite endpoint included the first of any of the following events: progression, recurrence, or death. METHODS We reviewed all cases of SCAs and all ACTH-negative macroadenomas operated on between April 1995 and December 2007 by 1 neurosurgeon. RESULTS Our retrospective cohorts included 33 SCAs followed for 42.5 months (median) (range, 6.7-179.0 months) and 126 ACTH-negative patients followed for 42 months (range, 6-142 months). SCA were younger (mean ± SD; 49.6 ± 14.1) than ACTH-negative patients (55.6 ± 12.8, P = .02). Tumor diameter was similar (2.8 ± 1.0 cm); cavernous sinus invasion was present in 45.5% of SCAs and 30.2% of ACTH-negative NFPAs (P = .09). Postoperative tumor residual was detected in 53.1% of SCAs and 49.6% of ACTH-negative patients. Radiation was administered in 40.6% of SCAs at 16 months (range, 3-149 months) and 33.3% of ACTH-negative patients at 13 months (range, 3-94) postoperatively. Progression of residual tumor occurred in 24.2% of SCAs and 11.1% of ACTH-negative patients (P = .08); recurrence was similar (6.0% SCAs vs 5.5% ACTH-negative patients). Cumulative event-free survival rates were not significantly different between the 2 groups (P = .3). Age, sex, tumor size, cavernous sinus invasion, or SCA subtypes were not associated with outcome. CONCLUSION SCA patients were younger, but exhibited similar postoperative tumor regrowth rates as ACTH-negative macroadenomas while using a similar adjuvant radiation protocol. Long-term follow-up is warranted because predictors of regrowth are currently lacking.

Pituitary carcinoma in situ.

OBJECTIVE Pituitary carcinomas are extremely rare tumors associated with poor prognosis despite surgery, radiation, and chemotherapy. The hallmark of diagnosis implies subarachnoid, brain, or systemic tumor spread. METHODS We report a case of rapid transformation of atypical nonfunctioning pituitary adenoma to a carcinoma. RESULTS A 64-year-old woman presented with sudden onset of ophthalmoplegia. Magnetic resonance imaging (MRI) scan showed a pituitary macroadenoma (2.2 x 2.1 cm) with invasion of the right cavernous sinus. Biochemical data was consistent with a nonfunctioning pituitary adenoma. Pathology showed a pituitary adenoma with negative immunohistochemistry for pituitary hormones. The patient returned a month later with weakness, lethargy, and a dilated nonreactive right pupil. MRI showed an invasive large mass (5 x 4.7 cm). After an emergent second transsphenoidal surgery, histopathologic examination revealed a widely infiltrative neoplasm invading the overlying mucosa and showing a high mitotic activity and necrosis and a very high Ki-67 (MIB-1) proliferation index (80%). MIB-1 retrospectively performed on the first specimen was also elevated (30%). Soon after the second surgery, MRI showed a 7.9 x 8.0 cm mass that metastasized to dura mater and extended into the right orbit, right middle cranial fossa, nasopharynx, clivus, posterior fossa, and along the right tentorium cerebelli, resulting in significant compression of the brainstem. CONCLUSION Development of a pituitary carcinoma from an adenoma is an exceptional occurrence and predictors of such course are currently lacking. A very high Ki-67 proliferation index should raise concern of a pituitary carcinoma in situ or premetastatic carcinoma.

The pituitary stalk transection syndrome: multifaceted presentation in adulthood

The pituitary stalk transection syndrome was characterized after introducing the MRI scan in the evaluation of children with hypopituitarism. Its prevalence and natural history into adulthood have not been clearly established. We present 4 cases of stalk transection syndrome diagnosed by the adult endocrinologist that reflect its pleiotropic manifestations. In all cases, MRI showed pathognomonic findings with small anterior pituitary, diminutive or absent infundibulum and ectopic posterior pituitary at the median eminence. Clinical presentation occurred in childhood or the second decade of life. The hormonal deficits were variable in severity and onset, with adrenal insufficiency diagnosed in the second and forth decade in three patients, and absent in another. Growth hormone deficiency was diagnosed before age 10 in three cases and at age 20 in one case with normal spontaneous linear growth. Hypothyroidism had onset in the first or second decade of life and hypogonadism was diagnosed during work-up for lack of pubertal development in all cases. The pituitary stalk transection syndrome should be considered in patients who were previously thought to have idiopathic GH deficiency or multiple pituitary hormone deficiencies. Presence of MRI characteristics compatible with the pituitary stalk transection syndrome should prompt a full pituitary hormonal evaluation. Long-term follow-up by the adult endocrinologist is warranted as new hormone deficiencies might appear later in life.

Acromegaly and bone disease.

Purpose of reviewTo provide an update on current understanding of osteoporosis associated with acromegaly. Recent findingsPatients with acromegaly have an increased risk of morphometric vertebral fractures. This seems to correlate with acromegaly activity and its duration, but it persists after biochemical control is achieved. Coexistent hypogonadism, diabetes mellitus and over-replacement with glucocorticoids have additional detrimental effects. Bone mineral density can be normal, increased or decreased, and is usually discordant with occurrence of fractures. However, a decrease in the hip bone mineral density during follow-up has been associated with development of new vertebral fractures. Bone turnover markers are increased and tend to normalize after biochemical control of acromegaly. Hypercalcemia rarely occurs in acromegaly and may be parathyroid hormone-dependent or 1,25 dihydroxy-vitamin D dependent. The latter improves with biochemical control of acromegaly. SummaryScreening with thoracic and lumbar vertebral radiographs is indicated in patients with acromegaly. We recommend biochemical control of acromegaly, treatment of hypogonadism and other risk factors of osteoporosis and avoiding supraphysiologic doses of glucocorticoids. Further studies are needed to understand mechanisms of skeletal fragility in acromegaly and clinical impact of vertebral fractures. Further studies of tailored therapy for patients with acromegaly and osteoporosis are also needed.

Adrenal Incidentalomas: A Disease of Modern Technology Offering Opportunities for Improved Patient Care

Adrenal incidentalomas (AIs) are found in approximately 4% of patients undergoing abdominal imaging, with peak prevalence in the sixth and seventh decades of life. Detection of AI warrants clinical, biochemical, and radiological evaluation to establish its secretory status and risk of malignancy. Careful review of the lipid content, size, and imaging phenotype of an adrenal mass is needed to evaluate the risk for malignancy. Identification of an AI may be an opportunity to identify an underlying secretory tumor that may have been otherwise unrecognized. A practical approach to investigation and follow-up of AIs is presented in this article.

Contemporary Indications for Transsphenoidal Pituitary Surgery

OBJECTIVE To analyze current indications for transsphenoidal pituitary surgery. METHODS The current literature regarding transsphenoidal surgery for all subtypes of pituitary adenomas and other sellar lesions was examined. Alternate approaches for pituitary surgery were also reviewed. RESULTS Transsphenoidal surgery continues to be the mainstay of surgical treatment for pituitary tumors, and has good outcomes in experienced hands. Pre- and postoperative management of pituitary tumors remains an important part of the treatment of patients with pituitary tumors. CONCLUSIONS Even as medical and surgical treatment for pituitary tumors evolves, transsphenoidal surgery remains a mainstay of treatment. Outcomes after transshenoidal surgery have improved over time. Neurosurgeons must be aware of the indications, risks and alternatives to transsphenoidal pituitary surgery.

Calcium and Bone Turnover Markers in Acromegaly: A Prospective, Controlled Study.

Context Acromegaly has been associated with calcium-phosphate and bone turnover alterations. Controlled studies of these interactions are sparse. Objective To evaluate calcium and bone metabolism in active and treated acromegaly. Design/Setting/Patients We conducted a controlled, prospective study at a tertiary referral center. We studied 22 patients with acromegaly referred for surgical or medical therapy (ACM) and 22 with nonfunctioning pituitary adenomas referred for surgery (control). Main Outcome Measures Calcium (serum and urine), phosphorus, parathyroid hormone (PTH), 25-hydroxy- and 1,25-dihydroxy-vitamin D, bone turnover markers [serum C-terminal telopeptide of type 1 collagen (CTX) and procollagen type 1 N-terminal propeptide (P1NP)], and cytokines [receptor activator of nuclear factor κB ligand (RANK-L) and osteoprotegerin (OPG)] at baseline and 3 to 6 months after treatment. Results At baseline, the ACM group had lower PTH levels than controls (36.3 ± 13.9 pg/mL vs 56.0 ± 19.9 pg/mL) and higher phosphorus (4.34 ± 0.71 mg/dL vs 3.55 ± 0.50 mg/dL) (P < 0.01). Groups had similar levels of serum and urine calcium and 25-hydroxy- and 1,25-dihydroxy-vitamin D. The ACM group had higher bone turnover markers than control; P1NP and CTX were strongly correlated (r2 = 0.82, P < 0.05). CTX was dependent on age and disease group but not on sex or gonadal status. After treatment of acromegaly, serum calcium (9.52 ± 0.43 mg/dL to 9.26 ± 0.28 mg/dL), phosphorus (4.34 ± 0.71 mg/dL to 3.90 ± 0.80 mg/dL), and CTX (0.91 ± 0.75 ng/mL to 0.63 ± 0.68 ng/mL) decreased, while PTH increased (36.3 ± 13.9 pg/mL to 48.9 ± 16.7 pg/mL) (P < 0.01). 25-hydroxy-vitamin D, P1NP, and RANK-L/OPG ratio did not change significantly. Conclusion Acromegaly patients exhibited PTH-independent calcium-phosphate alterations and enhanced coupled bone formation and resorption. Within 6 months of treatment, bone resorption decreased, whereas RANK-L/OPG changes were inconsistent.

Pathogenesis of marked pituitary enlargement and increased serum thyroid-stimulating hormone in primary hypothyroidism.

Longstanding untreated primary hypothyroidism may lead to pituitary enlargement on account of thyrotroph hyperplasia (1). Imaging has a low specificity to differentiate pituitary hyperplasia from an adenoma. An accurate diagnosis is of the utmost importance, as hyperplasia will resolve with thyroid hormone supplementation, while thyroidstimulating hormone (TSH)–secreting adenomas usually require surgical intervention. We present a case of postpartum autoimmune hypothyroidism associated with pituitary gland enlargement and a TSH level of almost 1400 lIU/mL, which is the highest level reported in an adult with autoimmune hypothyroidism. A previously healthy 23-year-old Caucasian woman noticed weight gain, cold intolerance, hair loss, and fatigue 3 months postpartum. She subsequently developed headaches, blurred vision, and cessation of her menstrual cycles. Family history was remarkable for hypothyroidism. She was evaluated 10 months postpartum and did not have a goiter, myxedema, or other endocrine stigmata. A formal visual field exam showed bitemporal hemianopsia. Laboratory data showed a markedly elevated TSH of 1398 lIU/mL (repeated 1362, normal: 0.34– 5.6), low free thyroxine (T4; 2.83 pM/L, normal: 6.44–20.59), low free triiodothyronine (T3; 1.54 pM/L, normal: 3.7–6.47), and mildly elevated prolactin (1,260.8 pM/L, normal: 43.5– 1,043.5). Pituitary magnetic resonance imaging (MRI) showed a uniformly enlarged pituitary gland with homogeneous contrast enhancement, suprasellar extension, impingement on the anterior aspect of the optic chiasm, and no involvement of the cavernous sinuses (see Supplementary Data, available online at www.liebertonline.com/thy). The patient was initiated on 88 mcg of oral levothyroxine (LT4) daily (1.6 mcg/kg). Two weeks later, TSH was 123lIU/mL, with normal free T4 (10.3 pM/L) and free T3 (3.7 pM/L). Heterophile antibodies against TSH (scantibodies heterophile blocking reagent) were negative, and thyroid microsomal antibodies were elevated (254 units/L, normal 60% of the pituitary size. The dose of LT4 was increased to 100 mcg (1.9 mcg/kg). Nine months after the diagnosis, TSH normalized at 1.93 lIU/mL and MRI demonstrated a normal pituitary gland (see Supplementary Data). The differential diagnosis of elevated TSH includes primary hypothyroidism, TSH-secreting pituitary adenoma, lab interference due to antibodies directed against TSH, and thyroid hormone resistance. Our patient had primary autoimmune hypothyroidism as shown by decreased T3 and T4, elevated microsomal antibodies, normal alpha-subunit ratio to TSH, and absence of heterophile antibodies against TSH. Even more, the patient experienced resolution of symptoms, visual field defects, laboratory abnormalities, and pituitary enlargement after LT4 replacement. As imaging cannot reliably distinguish a TSH-secreting pituitary adenoma from pituitary enlargement due to primary hypothyroidism, a thorough clinical and biochemical evaluation and repeated pituitary imaging are required to make the diagnosis and to avoid unnecessary surgical intervention. Pituitary enlargement as a result of untreated primary hypothyroidism was reported initially in 1851 by B. Niepce, but its pathogenesis remains uncertain. In humans, histology studies showed thyrotroph cell hyperplasia (large, oval cells with eccentric nucleus, abundant cytoplasm, and prominent Golgi complexes are called ‘‘thyroidectomy cells’’) and multifocal lactotroph hyperplasia (1). The thyrotroph cell hyperplasia is attributed to a loss of thyroxine feedback inhibition at the hypothalamic level and subsequent overproduction of thyrotropin-releasing hormone (TRH). However, the relative contribution of these factors is unclear. In vitro experiments with TRH perfusion of pituitary cultures caused a greater

SIGNIFICANT ELEVATION OF GROWTH HORMONE LEVEL IMPACTS SURGICAL OUTCOMES IN ACROMEGALY

OBJECTIVE Transsphenoidal adenomectomy (TSA) is first-line treatment for acromegaly. Our aim was to determine the impact of pre-operative biochemical parameters on the outcomes of surgery. METHODS Retrospective case series of 79 consecutive acromegalics operated between 1994 and 2013. Inclusion criteria were: first TSA, pathology-confirmed growth hormone (GH) adenoma, and follow-up >3 months. Biochemical remission was defined as normal insulin-like growth factor 1 (IGF-1) without adjuvant therapy during follow-up. RESULTS Median follow-up was 35.4 months (range, 3 to 187 months). Logistic regression analysis showed that the best model to predict long-term remission included the following pre-operative markers: GH, tumor diameter, and cavernous sinus invasion (CSI) (area under the curve, 0.933). A threshold GH of 40 ng/mL was associated with long-term remission (sensitivity, 97%; specificity, 42%). Group A (GH >40 ng/mL) comprised 19 patients (9 men); age, 43 ± 13 years; tumor diameter, 2.7 ± 1.0 cm; 73.7% with CSI; and pre-operative median GH, 77.8 ng/mL (interquartile range [IQR], 66.7 to 107.0 ng/mL). Three patients (15%) in group A achieved remission at 3 months, but 2 patients recurred during follow-up. Group B (GH ≤40 ng/mL) comprised 60 patients (25 men); age, 47 ± 13 years; tumor diameter, 1.6 ± 1.0 cm; 35% with CSI, preoperative median GH, 6.9 ng/mL (IQR, 3.4 to 16.9 ng/mL). Thirty-five patients (58%) in group B achieved remission at 3 months without recurrence during follow-up. Group A had larger tumors and a higher proportion of tumors with CSI (P<.05). CONCLUSION Both GH and IGF-1 should be measured pre-operatively, as highly elevated GH levels negatively impact long-term surgical remission. This strategy allows early identification of patients who require adjuvant therapy and may decrease time to biochemical control.