Catastrophic ACTH-secreting pheochromocytoma: an uncommon and challenging entity with multifaceted presentation.

Summary: Cushing's syndrome due to ectopic adrenocorticotropic hormone (ACTH) secretion (EAS) by a pheochromocytoma is a challenging condition. A woman with hypertension and an anamnestic report of a 'non-secreting' left adrenal mass developed uncontrolled blood pressure (BP), hyperglycaemia and severe hypokalaemia. ACTH-dependent severe hypercortisolism was ascertained in the absence of Cushingoid features, and a psycho-organic syndrome developed. Brain imaging revealed a splenial lesion of the corpus callosum and a pituitary microadenoma. The adrenal mass displayed high uptake on both 18F-FDG PET/CT and 68Ga-DOTATOC PET/CT; urinary metanephrine levels were greatly increased. The combination of antihypertensive drugs, high-dose potassium infusion, insulin and steroidogenesis inhibitor normalized BP, metabolic parameters and cortisol levels; laparoscopic left adrenalectomy under intravenous hydrocortisone infusion was performed. On combined histology and immunohistochemistry, an ACTH-secreting pheochromocytoma was diagnosed. The patient's clinical condition improved and remission of both hypercortisolism and catecholamine hypersecretion ensued. Brain magnetic resonance imaging showed a reduction of the splenial lesion. Off-therapy BP and metabolic parameters remained normal. The patient was discharged on cortisone replacement therapy for post-surgical hypocortisolism. EAS due to pheochromocytoma displays multifaceted clinical features and requires prompt diagnosis and multidisciplinary management in order to overcome the related severe clinical derangements. Learning points: A small but significant number of cases of adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome are caused by ectopic ACTH secretion by neuroendocrine tumours, which is usually associated with severe hypercortisolism causing severe clinical and metabolic derangements. Ectopic ACTH secretion by a pheochromocytoma is exceedingly rare but can be life-threatening, owing to the simultaneous excess of both cortisol and catecholamines. The combination of biochemical and hormonal testing and imaging procedures is mandatory for the diagnosis of ectopic ACTH secretion, and in the presence of an adrenal mass, the possibility of an ACTH-secreting pheochromocytoma should be taken into account. Immediate-acting steroidogenesis inhibitors are required for the treatment of hypercortisolism, and catecholamine excess should also be appropriately managed before surgical removal of the tumour. A multidisciplinary approach is required for the treatment of this challenging entity.

[Thyrotoxic hypokalemic periodic paralysis: a rare complication of a common disease]. / Paralisi periodica ipopotassiemica tireotossica: una rara complicanza di una malattia comune.

Thyrotoxic periodic paralysis (TPP) is an uncommon but potentially lethal manifestation of hyperthyroidism characterized by muscle paralysis and hypokalemia. We have reported 3 cases of TPP in male patients, which manifested with morning muscle weakness evolved into paralysis. In all patients were found severe hypokalemia, abnormalities on electrocardiogram, and Graves' hyperthyroidism. Intravenous potassium administration led to normalization of potassium levels, and resolution of neurological symptoms. In addition, beta blockers and methimazole were started. Two patients required total thyroidectomy for poor control of hyperthyroidism with antithyroid drug. In patients presenting with periodic paralysis or diffuse muscle weakness thyroid function should be investigated in order to find out the cases secondary to unknown hyperthyroidism and to start an early appropriate combined therapy. The correct management of TPP can prevent serious cardiopulmonary complications.

Good Clinical Practice of the Italian Society of Thalassemia and Haemoglobinopathies (SITE) for the Management of Endocrine Complications in Patients with Haemoglobinopathies.

BACKGROUND: The treatment of endocrinopathies in haemoglobinopathies is a continually expanding research area; therefore, recommendations supporting the appropriateness of treatments are a pressing need for the medical community. METHODS: The Management Committee of SITE selected and gathered a multidisciplinary and multi-professional team, including experts in haemoglobinopathies and experts in endocrinopathies, who have been flanked by experts with methodological and organizational expertise, in order to formulate recommendations based on the available scientific evidence integrated by personal clinical experience. The project followed the systematic approach for the production of clinical practice guidelines according to the methodology suggested by the National Center for Clinical Excellence, Quality and Safety of Care (CNEC). RESULTS: Out of 14 topics, 100 clinical questions were addressed, and 206 recommendations were elaborated on. The strength of recommendations, panel agreement, a short general description of the topic, and the interpretation of evidence were reported. CONCLUSIONS: Good Practice Recommendations are the final outcome of translational research and allow one to transfer to the daily clinical practice of endocrine complications in haemoglobinopathies.

[The Management of Endocrine Complications in Patients with Haemoglobinopathies: Good Clinical Practice of the Italian Society of Thalassemia and Haemoglobinopathies (SITE).] / Le principali complicanze endocrinologiche nelle emoglobinopatie: buone pratiche cliniche della Società Italiana Talassemie ed Emoglobinopatie (SITE).

BACKGROUND: The treatment of endocrinopathies in haemoglobinopathies is a continually expanding research area; therefore, recommendations supporting the appropriateness of treatments are a pressing need for the medical community. METHODS: The Management Committee of SITE selected and gathered a multidisciplinary and multiprofessional team including experts in haemoglobinopathies and experts in endocrinopathies, who have been flanked by experts with methodological and organizational expertise, in order to formulate recommendations based on the available scientific evidence integrated by clinical experience. The project followed the systematic approach for the production of clinical practice guidelines according to the methodology suggested by the National Center for Clinical Excellence, Quality and Safety of Care (CNEC). RESULTS: Out of 14 topics 100 clinical questions were addressed and 206 recommendations were elaborated. Strength of recommendations, panel agreement, general description of the topic, and interpretation of evidence were reported. CONCLUSIONS: Good Practice Recommendations are the final outcome of translational research and allow to transfer the latest research knowledge to the daily clinical practice of endocrine complications in haemoglobinopathies.

Thyroid lymphoma: a rare tumor requiring combined management.

Thyroid lymphoma is a rare disease which occurs mainly in elderly females. Most patients with thyroid lymphoma have Chronic Lymphocytic Thyroiditis (CLT), suggesting a role of chronic antigen stimulation in the development of the disease. We present two cases of thyroid Diffuse Large B-cell Lymphoma (DLBCL) diagnosed after surgery (subtotal thyroidectomy) by means of combined histology and immunohistochemistry (positive staining for CD-20) in two elderly female patients presenting at our institution for compressive symptoms (dysphonia in patient 1, dysphagia in patient 2) due to a gross neck mass. Fine-needle aspiration was compatible with lymphocytic thyroiditis in the first patient and was indeterminate in the second patient. The first patient had a long-lasting history of hypothyroidism due to CLT and was on L-thyroxine replacement therapy, whereas the second patient had normal thyroid function and negative thyroid autoantibodies. After surgery both patients underwent chemotherapy (cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) plus rituximab). At one-year follow-up both patients were disease-free. Thyroid lymphoma is an uncommon tumor which requires prompt diagnosis and combined management for a high rate of cure to be achieved.

Unrecognized Pseudohypoparathyroidism Type 1A as a Cause of Hypocalcemia and Seizures in a 64-Year-Old Woman.

Pseudohypoparathyroidism type 1A (PHP1A) is usually diagnosed in childhood or early adulthood. We describe the case of a 64-year-old woman admitted to the Neurological Unit for recurrent episodes of loss of consciousness and seizures. Glycemia and ECG were normal, while hypocalcemia was noted. Clinical history revealed carpo-pedal spasm since the age of 30 years, cognitive impairment, hypothyroidism since early adulthood, and menopause at 30 years. She was taking oral calcium and cholecalciferol for chronic hypocalcemia. Physical features suggested Albright's osteodystrophy. Blood calcium was confirmed low, with increased parathyroid hormone, moderate 25OH-vitamin D deficiency, and normal creatinine. Brain CT scan revealed calcifications of the basal ganglia, cortical and subcortical white matter, and cerebellum. Therapy was switched to oral calcitriol, with normalization of calcium levels; levetiracetam was started and no further seizures occurred. The clinical diagnosis of PHP1A was confirmed by molecular analysis, which demonstrated the heterozygous c.568_571del mutation of the GNAS gene. Our report illustrates the natural history of a patient with PHP1A, which went undiagnosed until the age of 64 years, with multi-hormonal resistance and clinical sequelae evolving throughout life, and underlines the importance of diagnosing this rare disease, which has a great impact on patients and their family life.

Non-functioning pituitary adenoma database: a useful resource to improve the clinical management of pituitary tumors.

OBJECTIVE: The long-term outcome of non-functioning pituitary adenoma (NFPA) patients is not clearly established, probably due to the low annual incidence and prolonged natural history of these rare tumors. The aim of this study was to evaluate clinical data at presentation and long-term post-surgery and radiotherapy outcome in a cohort of patients with NFPA. DESIGN AND METHODS: A computerized database was developed using Access 2000 software (Microsoft Corporation, 1999). Retrospective registration of 295 NFPA patients was performed in seven Endocrinological Centers of North West Italy. Data were analyzed by STATA software. RESULTS: The main presenting symptoms were visual defects (67.8%) and headache (41.4%) and the most frequent pituitary deficit was hypogonadism (43.3%), since almost all tumors were macroadenomas (96.5%). Surgery was the first choice treatment (98% of patients) and total debulking was achieved in 35.5%. Radiotherapy was performed as adjuvant therapy after surgery in 41% of patients. At the follow-up, recurrence occurred in 19.2% of patients without post-surgical residual tumor after 7.5 +/- 2.6 years, regrowth in 58.4% of patients with post-surgical remnant after 5.3 +/- 4.0 years and residue enlargement in 18.4% of patients post-surgically treated with radiotherapy after 8.1 +/- 7.3 years. CONCLUSIONS: Our database indicates that the goal of a definitive surgical cure has been achieved during the last decade in a low percentage of patients with NFPA. This tumor database may help to reduce the delay between symptom onset and diagnosis, to assess prognostic parameters for the follow-up of patients with different risk of recurrence and to define the efficacy and safety of different treatments and their association with mortality/morbidity.

[Acromegaly: multifaceted clinical presentation of a rare disease of the elderly. Report of two cases with long-term follow-up]. / Acromegalia: presentazione clinica eterogenea di una rara malattia dell'anziano. Descrizione di due casi con follow-up a lungo termine.

We report two cases of acromegaly in elderly patients. Both patients had markedly invasive GH-secreting macroadenomas, which caused hugely increased circulating GH levels (over 90 ng/ml). The first patient, 79 year-old, presented with goitre and severe osteoarthrosis, refused surgery and was treated with various somatostatin analogues (ultimately accompanied by cabergoline), without satisfactory control of the disease. The second patient, 67-year-old, presented with symptoms secondary to hypopituitarism, which had been previously misdiagnosed. These symptoms resolved with the appropriate substitutive therapy, which led to a significant improvement in her condition. However, two transphenoidal operations, radiotherapy and long-term somatostatin agonist therapy were required to control GH hypersecretion satisfactorily. The authors wish to underline that acromegaly is a rare but not negligible disorder in the elderly, which can affect the whole body functions and cause severe morbidities. In the two cases presented somatostatin agonists alone were not able to control the tumoral hypersecretion adequately. The prompt discovery (usually through a simple clinical evaluation) of this disease in the elderly, confirmed by hormonal and morphological evaluation, together with a multidisciplinary (medical, surgical, radiotherapeutic) approach can improve their quality of life and increase life expectancy.

Residual pituitary function after brain injury-induced hypopituitarism: a prospective 12-month study.

CONTEXT: Traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH) are conditions at high risk for the development of hypopituitarism. OBJECTIVE: The objective of the study was to clarify whether pituitary deficiencies and normal pituitary function recorded at 3 months would improve or worsen at 12 months after the brain injury. DESIGN AND PATIENTS: Pituitary function was tested at 3 and 12 months in patients who had TBI (n = 70) or SAH (n = 32). RESULTS: In TBI, the 3-month evaluation had shown hypopituitarism (H) in 32.8%. Panhypopituitarism (PH), multiple (MH), and isolated (IH) hypopituitarism had been demonstrated in 5.7, 5.7, and 21.4%, respectively. The retesting demonstrated some degree of H in 22.7%. PH, MH, and IH were present in 5.7, 4.2, and 12.8%, respectively. PH was always confirmed at 12 months, whereas MH and IH were confirmed in 25% only. In 5.5% of TBI with no deficit at 3 months, IH was recorded at retesting. In 13.3% of TBI with IH at 3 months, MH was demonstrated at 12-month retesting. In SAH, the 3-month evaluation had shown H in 46.8%. MH and IH had been demonstrated in 6.2 and 40.6%, respectively. The retesting demonstrated H in 37.5%. MH and IH were present in 6.2 and 31.3%, respectively. Although no MH was confirmed at 12 months, two patients with IH at 3 months showed MH at retesting; 30.7% of SAH with IH at 3 months displayed normal pituitary function at retesting. In SAH, normal pituitary function was always confirmed. In TBI and SAH, the most common deficit was always severe GH deficiency. CONCLUSION: There is high risk for H in TBI and SAH patients. Early diagnosis of PH is always confirmed in the long term. Pituitary function in brain-injured patients may improve over time but, although rarely, may also worsen. Thus, brain-injured patients must undergo neuroendocrine follow-up over time.

Late-onset metastasis of renal cell carcinoma into a hot thyroid nodule: an uncommon finding not to be overlooked.

We report the case of a 74-year-old man with a four-year history of right nephrectomy for clear cell renal carcinoma (CCRC) who was diagnosed with hyperthyroidism. On ultrasound (US), a 5 cm solid isohypoechoic nodule with intranodular vascularization was found in the left thyroid lobe. The nodule was deemed autonomous on (99m)Tc thyroid scan. Methimazole was started and serum thyroid hormone levels quickly normalized; euthyroidism was maintained with a very low dosage of antithyroid drug. Over time, compressive symptoms and local pain occurred and US revealed growth of the nodule. Total thyroidectomy was performed and the combined histological and immunohistochemical evaluation deemed the nodule compatible with metastasis of CCRC; on 2-year follow-up, no tumor relapse was ascertained. In patients with a history of cancer, a thyroid nodule, even if hyperfunctioning, must be suspected of being a metastasis and investigated. Hot nodules, which are largely benign, may be vulnerable to metastatic colonization owing to their rich vascularization. In these cases, surgery may be curative.

[Screening for thyroid disorders in elderly patients]. / Screening per la funzionalità tiroidea nei pazienti anziani ricoverati.

In elderly patients, thyroid diseases may remain undiagnosed due to the lack of specificity of the clinical presentation. Thyroid function alterations seem to be more common in older persons than in adults. The aim of our study was to evaluate the incidence of thyroid function alterations in 300 elderly patients admitted to the division of Internal Medicine of the local hospital in Levanto, in a one-year period. Thyroid function alterations were discovered in 12.6% of the patients and considering the group of patients in whom a thyroid function alteration was demonstrated, 45% of them were affected by hypothyroidism (10.7% overt primary hypothyroidism, 28.9% sub-clinical hypothyroidism, 5.4% hypothyroidism secondary to hypopituitarism), 15.6% by hyperthyroidism (overt 7.8% , subclinical 7.8%), and 39.4% showed a low T3 syndrome. Our data confirm the high incidence of previously unrecognized thyroid diseases in the elderly patients admitted to an hospital and the profit that these patients can receive from the appropriate diagnosis at the admission and justify the cost of routine testing for FT4 and TSH in every person at hospital admission.

Hypopituitarism in the elderly: two case-reports with heterogeneous presentation.

Hypopituitarism (HYPO) is an under-investigated disease in older patients. Symptoms, which may be life-threatening, are aspecific and often attributed to aging and/or related morbidities. We describe here the cases of two elderly patients who were ultimately diagnosed as having HYPO, the clinical presentations and etiologies of which were different. In the first patient, an invasive non-secreting pituitary macroadenoma causing HYPO was detected on brain morphological evaluation for head trauma secondary to falling. Glucocorticoid replacement therapy was started. Thyroid function evaluation showed hyperthyroidism (due to a known toxic multinodular goiter), which was already on treatment with methimazole; ultimately, after withdrawal of the antithyroid drug, secondary hypothyroidism occurred. The patient underwent non-radical pituitary surgery. Cognitive function, gait impairment and falling, which had previously been attributed only to aging, improved markedly after cortisone acetate and L-thyroxine replacement therapy. The second patient was hospitalized one month after the onset of hypotension, edema and pain in the legs, and progressive psychomotor impairment, which ultimately resulted in an intermittent soporous state. She was diagnosed as having global anterior HYPO secondary to empty sella, which caused severe multifaceted clinical and biochemical abnormalities (hyponatremia, pancytopenia, rhabdomyolysis). After treatment with i.v. fluids and hydrocortisone, the patient's clinical condition and biochemical alterations improved, and normalized over time with oral cortisone acetate and Lthyroxine combination therapy. Several protean symptoms that impair the quality of life of elderly patients are usually ascribed to aging. Such symptoms should be investigated with regard to possible HYPO, treatment of which can result in significant clinical benefit.

Hyperthyroidism unmasked several years after the medical and radiosurgical treatment of an invasive macroprolactinoma inducing hypopituitarism: a case report.

INTRODUCTION: Measuring thyroid stimulating hormone levels alone may be insufficient to appropriately evaluate thyroid function. Reduced thyroid stimulating hormone levels associated to normal/reduced FT4 levels should prompt investigation of pituitary function, on suspicion of hypopituitarism. Pituitary macroadenomas are the most common cause of hypopituitarism; among these, macroprolactinomas are usually treated with dopamine-agonist therapy. Hypopituitarism does not preclude the development of primary hyperthyroidism. This report describes the case of a patient with a final diagnosis of macroprolactinoma inducing hypopituitarism, who subsequently developed hyperthyroidism due to a toxic thyroid nodule. CASE PRESENTATION: A 62-year-old man underwent biochemistry and thyroid function assessment for asthenia. Reduced thyroid stimulating hormone levels were associated to slightly decreased FT4 levels and low-normal FT3 levels; thyroid ultrasonography showed a multinodular goiter. Thyroid scan with (99m)Tc-pertechnetate revealed an autonomous left nodule with suppression of the surrounding parenchyma. Pituitary investigation showed partial hypopituitarism associated to increased prolactin levels: 182-200 ng/ml. Magnetic resonance imaging revealed a large (2.2 cm) invasive macroadenoma. To avoid a possible high-dose hook effect, the patient's serum was diluted; the resulting PRL levels of around 1800 ng/ml prompted the final diagnosis of macroprolactinoma. Reduced libido and erectile dysfunction were ascertained. In addition to replacement therapy with L-thyroxine and testosterone, cabergoline was started and was progressively increased to high doses (4 g/week); this yielded a significant but incomplete reduction of PRL levels (63-99 ng/ml). Sexual function improved. The macroadenoma shrank over the first two years of therapy, but subsequently enlarged slightly. Following stereotactic radiosurgery, the tumor stabilized and prolactin almost normalized (22 ng/ml) on therapy. Over the years, thyroid nodule volume was unmodified, but hyperthyroidism on L-thyroxine therapy was found, and increased FT3 levels with suppressed thyroid stimulating hormone levels were confirmed off-therapy. Thyroid scan confirmed the left autonomous nodule, which was successfully treated with methimazole. CONCLUSION: Reduced thyroid stimulating hormone levels associated to normal/reduced free-thyroid hormone levels may be the first clue to unsuspected hypopituitarism. Moderately increased prolactin levels in the presence of a large macroadenoma warrant serum dilution in order to avoid a possible hook effect. Stereotactic radiosurgery is a useful non-invasive tool in the management of pituitary tumors. A pre-toxic thyroid nodule with low secretory activity may initially be masked by the coexistence of secondary hypothyroidism, but may lead to overt hyperthyroidism over time.

Intrathyroidal parathyroid carcinoma as cause of hypercalcemia and pitfall of localization techniques: clinical and biologic features.

OBJECTIVE: To describe an unusual case of intrathyroidal parathyroid carcinoma (PC), which was retrospectively diagnosed in a woman who underwent surgical treatment of a recurrent nodular goiter. METHODS: We report the clinical and biologic features of an intrathyroidal PC, discuss the challenges with distinguishing PC from parathyroid adenoma, and review the related literature. RESULTS: A 67-year-old woman sought medical attention for dysphagia attributable to the recurrence of a normal functioning multinodular goiter. Thyroid ultrasonography disclosed a 3-cm solid inferior nodule. Because she refused surgical treatment and a trial of levothyroxine was unsuccessful, periodic follow-up examinations were scheduled. At 1-year follow-up, hypercalcemia (12.1 to 12.6 mg/dL) and low phosphorus levels (2.0 to 2.3 mg/dL) were found, and parathyroid hormone (PTH) levels were profoundly increased (481 to 721 pg/mL). Neck ultrasonography showed a large hypoechogenic solid nodule, not clearly cleaved from the right thyroid lobe, which was possibly compatible with an enlarged parathyroid gland; however, a sestamibi scan was negative. During total thyroidectomy, intraoperative frozen sections of the intrathyroid nodule were compatible with nodular goiter with cellular pleomorphism. Final histologic examination showed cellular nests with nuclear pleomorphism and invasive behavior into the thyroid tissue and likely into the vessels, in conjunction with immunohistochemical negativity for thyroglobulin and strong positivity for PTH. These findings were highly suggestive of and supported the diagnosis of PC. Postoperatively, calcium levels normalized, and PTH values declined considerably but remained slightly increased. Vitamin D supplementation helped normalize the PTH levels. The patient has undergone follow-up for 5 years and has shown no morphologic or biochemical signs of tumor recurrence. CONCLUSION: PC is a rare entity but should be suspected in patients with hypercalcemia, substantially increased PTH levels, and a neck mass. In such patients, techniques such as sestamibi scanning may fail to localize the neoplasm. Surgical treatment remains the preferred technique for an optimal outcome of the disease. Nevertheless, lifelong follow-up is necessary.

Clinically non-functioning pituitary macroadenomas in the elderly.

BACKGROUND AND AIMS: The aim of the present study was to evaluate the clinical presentation, characteristics and post-surgical outcome of non-functioning pituitary macroadenomas (NFPM) in elderly patients. METHODS: 27 patients (65-81 years; 13 Males, 14 Females) with NFPM (20-45 mm in diameter) were studied. The symptoms prompting neuroradiological studies were vision alterations in 52%, and dizziness, loss of memory, confusion, headache and depression in 29%; in 19% of patients, the disease was incidentally discovered during computed tomography (CT) or magnetic resonance imaging (MRI) for head trauma or cerebral ischemic attacks. RESULTS: Endocrinological evaluation on diagnosis showed global anterior hypopituitarism in 33% and partial hypopituitarism in 37% of patients. Immunohistochemistry showed signs of neurosecretion in most NFPM (chromogranin-A in 55%, gonadotropins in 19%, ACTH in 3.7%). Ki-67 antigen expression was indicative of low proliferative activity. Surgery was highly effective in improving alterations in vision and compressive symptoms, but was unable to restore normal pituitary function in established hypopituitarism in most cases. Eight patients (31%) were free of disease on subsequent MRI (follow-up 1-6 years). In 18 (69%) patients, a post-surgical residue was present. Of these, 6 (33%) underwent radiotherapy in the following years, owing to an increase in the volume of the remnants, and six (33%) underwent additional surgical treatment, followed by radiotherapy for further signs of growth in two. In the remaining patients, a small intrasellar remnant was stable on yearly MRI. CONCLUSIONS: in elderly patients, the development of hypopituitarism is often overlooked and the initial diagnosis of NFPM may be delayed. This can expose patients to the risks of unrecognized hypopituitarism and jeopardize post-surgical outcome.