Anand K. Annamalai

A Comprehensive Study of Clinical, Biochemical, Radiological, Vascular, Cardiac, and Sleep Parameters in an Unselected Cohort of Patients With Acromegaly Undergoing Presurgical Somatostatin Receptor Ligand Therapy

CONTEXT Attainment of safe GH and IGF-1 levels is a central goal of acromegaly management. OBJECTIVE The aim of this study was to determine the extent to which reductions in GH and IGF-1 concentrations correlate with amelioration of radiological, metabolic, vascular, cardiac, and respiratory sequelae in a single unselected patient cohort. STUDY DESIGN This was a prospective, within-subject comparison in 30 patients with newly diagnosed acromegaly (15 women and 15 men: mean age, 54.3 years; range, 23-78 years) before and after 24 weeks of lanreotide Autogel (ATG) therapy. RESULTS Reductions in GH and IGF-1 concentrations and tumor volume were observed in all but 2 patients (median changes [Δ]: GH, -6.88 μg/L [interquartile range -16.78 to -3.32, P = .000001]; IGF-1, -1.95 × upper limit of normal [-3.06 to -1.12, P = .000002]; and pituitary tumor volume, -256 mm(3) [-558 to -72.5, P = .0002]). However, apnea/hypopnea index scores showed highly variable responses (P = .11), which were independent of ΔGH or ΔIGF-1, but moderately correlated with Δweight (R(2) = 0.42, P = .0001). Although systolic (P = .33) and diastolic (P = .76) blood pressure were unchanged, improvements in arterial stiffness (aortic pulse wave velocity, -0.4 m/s [-1.2 to +0.2, P = .046]) and endothelial function (flow mediated dilatation, +1.73% [-0.32 to +6.19, P = .0013]) were observed. Left ventricular mass index regressed in men (-11.8 g/cm(2) [-26.6 to -1.75], P = .019) but not in women (P = .98). Vascular and cardiac changes were independent of ΔGH or ΔIGF-1 and also showed considerable interindividual variation. Metabolic parameters were largely unchanged. CONCLUSIONS Presurgical ATG therapy lowers GH and IGF-1 concentrations, induces tumor shrinkage, and ameliorates/reverses cardiac, vascular, and sleep complications in many patients with acromegaly. However, responses vary considerably between individuals, and attainment of biochemical control cannot be assumed to equate to universal complication control.

A novel mass spectrometry-based method for determining insulin-like growth factor 1: assessment in a cohort of subjects with newly diagnosed acromegaly

To develop an alternative method to immunoassay for the quantitative analysis of insulin‐like growth factor 1 (IGF‐1) using a mass spectrometry (MS)‐based approach.

Low DHEAS: A Sensitive and Specific Test for Detection of Subclinical Hypercortisolism in Adrenal Incidentalomas

Context Subclinical hypercortisolism (SH) occurs in 5% to 30% of adrenal incidentalomas (AIs). Common screening tests for adrenocorticotropin-independent hypercortisolism have substantial false-positive rates, mandating further time and resource-intensive investigations. Objective To determine whether low basal dehydroepiandrosterone sulfate (DHEAS) is a sensitive and specific screening test for SH in AI. Setting and Patients In total, 185 patients with AI were screened for adrenal medullary (plasma metanephrines) and cortical [1 mg overnight dexamethasone suppression test (ONDST), 24-hour urinary free cortisol (UFC), serum DHEAS, plasma renin, and aldosterone] hyperfunction. Positive ONDST [≥1.8 mcg/dL (≥50 nmol/L)] and/or UFC (more than the upper limit of reference range) results were further investigated. We diagnosed SH when at least 2 of the following were met: raised UFC, raised midnight serum cortisol, 48-hour dexamethasone suppression test (DST) cortisol ≥1.8 mcg/dL (≥50 nmol/L). Results 29 patients (16%) were diagnosed with SH. Adrenocorticotropin was <10 pg/mL (<2.2 pmol/L) in all patients with SH. We calculated age- and sex-specific DHEAS ratios (derived by dividing the DHEAS by the lower limit of the respective reference range) for all patients. Receiver operating characteristic curve analyses demonstrated that a ratio of 1.12 was sensitive (>99%) and specific (91.9%) for the diagnosis of SH. Cortisol following 1 mg ONDST of 1.9 mcg/dL (53 nmol/L) was a sensitive (>99%) screening test for SH but had lower specificity (82.9%). The 24-hour UFC lacked sensitivity (69%) and specificity (72%). Conclusion A single basal measurement of DHEAS offers comparable sensitivity and greater specificity to the existing gold-standard 1 mg DST for the detection of SH in patients with AIs.

Increased Prevalence of Gallbladder Polyps in Acromegaly

INTRODUCTION Several studies have suggested an increased prevalence of benign and malignant tumors in acromegaly, particularly colonic neoplasms. The gallbladders epithelial similarity to the colon raises the possibility that gallbladder polyps (GBP) may occur more frequently in acromegaly. PATIENTS AND METHODS Thirty-one patients with newly diagnosed acromegaly (14 females, 17 males; mean age 54.7 yr, range 27-76 yr) were referred to our center between 2004 and 2008. All had pituitary adenomas and were treated with somatostatin analogs prior to transsphenoidal surgery. Biliary ultrasonography was performed at the time of referral. In a retrospective case-cohort study, we compared the prevalence of GBP in these scans with those of 13,234 consecutive patients (age range 20-80 yr) presenting at the hospital for abdominal/biliary ultrasound during the same time interval. Associations between GH and IGF-I levels and GBP in acromegaly were also examined. RESULTS There was a higher prevalence of GBP in patients with acromegaly compared with controls (29.03 vs 4.62%, P = 0.000008); relative risk was 6.29 (95% confidence interval 3.61-10.96). Eight of nine patients with acromegaly and GBP were older than 50 yr of age. GH levels were higher in those with GBP (median 30.8 μg/liter, interquartile range 10.9-39.1) than those without (8.2 μg/liter, interquartile range 6.0-16.0), but IGF-I levels were comparable. CONCLUSIONS This is the first study to demonstrate an increased prevalence of GBP in patients with newly diagnosed acromegaly. Further studies are required to determine whether these patients are at increased risk of developing gallbladder carcinoma and to define the role, if any, of biliary ultrasound surveillance.

Familial adrenocortical carcinoma in association with Lynch syndrome

Context: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis. Although the majority of childhood ACC arises in the context of inherited cancer susceptibility syndromes, it remains less clear whether a hereditary tumor predisposition exists for the development of ACC in adults. Here, we report the first occurrence of familial ACC in a kindred with Lynch syndrome resulting from a pathogenic germline MSH2 mutation. Case: A 54-year-old female with a history of ovarian and colorectal malignancy was found to have an ACC. A detailed family history revealed her mother had died of ACC and her sister had previously been diagnosed with endometrial and colorectal cancers. A unifying diagnosis of Lynch syndrome was considered, and immunohistochemical analyses demonstrated loss of MSH2 and MSH6 expression in both AACs (proband and her mother) and in the endometrial carcinoma of her sister. Subsequent genetic screening confirmed the presence of a germline MSH2 mutation (resulting in deletions of exons 1–3) in the proband and her sister. Conclusion: Our findings provide strong support for the recent proposal that ACC should be considered a Lynch syndrome-associated tumor and included in the Amsterdam II clinical diagnostic criteria. We also suggest that screening for ACC should be considered in cancer surveillance strategies directed at individuals with germline mutations in DNA mismatch repair genes.

Needle(s) in the Haystack – Synchronous Multifocal Tumor Induced Osteomalacia

This is the author accepted manuscript. The final version is available from Endocrine Society via http://dx.doi.org/10.1210/jc.2015-3854

Acute shrinkage of a giant prolactinoma, masquerading as an erosive skull base tumour, with cabergoline

A 27-year-old Chinese male presented with a 2-year history of headache and a right temporal field defect. A magnetic resonance imaging (MRI) scan revealed a 5cm tumour in the sphenoid with bilateral cavernous sinus extension and posterior …

Successful treatment of residual pituitary adenoma in persistent acromegaly following localisation by 11C-methionine PET co-registered with MRI

OBJECTIVE To determine if functional imaging using 11C-methionine positron emission tomography co-registered with 3D gradient echo MRI (Met-PET/MRI), can identify sites of residual active tumour in treated acromegaly, and discriminate these from post-treatment change, to allow further targeted treatment. DESIGN/METHODS Twenty-six patients with persistent acromegaly after previous treatment, in whom MRI appearances were considered indeterminate, were referred to our centre for further evaluation over a 4.5-year period. Met-PET/MRI was performed in each case, and findings were used to decide regarding adjunctive therapy. Four patients with clinical and biochemical remission after transsphenoidal surgery (TSS), but in whom residual tumour was suspected on post-operative MRI, were also studied. RESULTS Met-PET/MRI demonstrated tracer uptake only within the normal gland in the four patients who had achieved complete remission after primary surgery. In contrast, in 26 patients with active acromegaly, Met-PET/MRI localised sites of abnormal tracer uptake in all but one case. Based on these findings, fourteen subjects underwent endoscopic TSS, leading to a marked improvement in (n = 7), or complete resolution of (n = 7), residual acromegaly. One patient received stereotactic radiosurgery and two patients with cavernous sinus invasion were treated with image-guided fractionated radiotherapy, with good disease control. Three subjects await further intervention. Five patients chose to receive adjunctive medical therapy. Only one patient developed additional pituitary deficits after Met-PET/MRI-guided TSS. CONCLUSIONS In patients with persistent acromegaly after primary therapy, Met-PET/MRI can help identify the site(s) of residual pituitary adenoma when MRI appearances are inconclusive and direct further targeted intervention (surgery or radiotherapy).

Hypopituitarism, pulmonary infiltration and a spontaneously resolving occipital mass

A 34-year-old man presented with a 12-month history of progressive tiredness and weight loss. Further questioning elicited symptoms of polyuria, polydipsia, reduced libido and erectile dysfunction. He had a 20-pack-a-year smoking history. Physical examination was notable for sparse androgenic hair, loss of muscle bulk and 15 ml testes bilaterally. Biochemical profiling excluded diabetes mellitus, but confirmed partial anterior and posterior hypopituitarism [LH 0.2 U/l (RR 1.5–9.3), FSH 0.9 U/l (RR 1.4–8.1), testosterone 1.1 nmol/l (RR 7.4–25.7), FT4 5.9 pmol/l (RR 5.0–19.6), TSH 2.25 mU/l (RR 0.49–3.95), post-Synacthen® cortisol 463 nmol/l (RR > 550), water deprivation test urine osmolalities: baseline 132 mOsm/kg; 8 hr 147 mOsm/kg; post-desmopressin (2 mcg) 616 mOsm/kg]. Magnetic resonance imaging (MRI) of the brain showed infundibular thickening with contrast enhancement (Figure 1A) and absence of the posterior pituitary bright spot, but no other lesions. A screen for inflammatory and infiltrative disorders [ANCA, ANA, immunoglobulins (including IgG4), serum ACE, ESR and CRP] proved unremarkable. Cerebrospinal …

More than just morning sickness

### Learning Point for Clinicians Hyperemesis gravidarum occurs in ∼1% of all pregnancies. One- to two-thirds of these women develop gestational hyperthyroidism due to β-human chorionic gonadotropin (β-hCG)- mediated activation of the thyroid stimulating hormone (TSH) receptor. Thiamine has a limited storage pool of only a few weeks and an acute deficiency leading to Wernicke’s encephalopathy can occur in the setting of hyperemesis gravidarum and gestational hyperthyroidism. An 18-year-old primigravida presented with a fall at 16 weeks gestation. She had experienced persistent nausea, vomiting and weight loss since conception. On examination, angular stomatitis, confusion, ataxia, horizontal nystagmus, ophthalmoplegia and bilateral lower limb weakness were noted. Investigations revealed ketonuria but with normal blood chemistry. β Human chorionic gonadotropin (β-hCG) levels (81 290 IU/L) were consistent with gestation and abdominal ultrasound confirmed a 16-week singleton pregnancy. A provisional diagnosis of hyperemesis gravidarum with Wernicke’s encephalopathy was made. Consistent with this, magnetic resonance imaging (MRI) of the brain revealed bilateral …