Addison's disease Neuroendocrine tumors Paraneoplastic syndromes Miklós Tóth Professor of Medicine and Endocrinology 9 th April, 2018 Semmelweis University 2nd Department of Medicine
Addison's disease Miklós Tóth Professor of Medicine and Endocrinology 9 th April, 2018 Semmelweis University 2nd Department of Medicine
Definition Addison's disease results from progressive destruction of adrenals, which must involve > 90% of the glands before adrenal insufficiency appears.
Common causes of Addison's disease Autoimmune destruction of adrenal glands accounting for about 85% of cases; in developing nations Autoimmune destruction involves cell-mediated and humoral-mediated autoimmune adrenalitis Tuberculosis is the most common cause in the third world Bilateral adrenal hemorrhage patients who receive anticoagulation medication positive lupus anticoagulant or antiphospholipid antibodies Several medications may inhibit cortisol biosynthesis medications to treat adrenal cancer medications to treat HIV wasting, such as dronabinol
Rare causes of Addison's disease Sarcoidosis Amyloidosis Fungal infections AIDS complications Hemochromatosis Polyglandular endocrine syndromes Adrenoleukodystrophy Adrenomyelodystrophy Congenital factors, including hypoplasia, familial glucocorticoid insufficiency, and enzyme defect
Epidemiology of Addison's disease Incidence New cases: 0.6/100,000 of population per year. Prevalence Total: 4-11/100,000 of population.
Clinical features of primary adrenal insufficiency I.
Clinical features of primary adrenal insufficiency II.
Addisonian crisis Extreme hypotension Circulatory collapse Fever of unknown etiology Weight loss, dehydration Hypoglycemia
Hormonal abnormalities in Addisonian patients - low se. cortisol - no increase folowing ACTH administration - elevated pl. ACTH - low se. aldosterone - increased plasma renin activity
Assessment of etiology Immune adrenalitis other autoimmune disorders vitiligo, thyreoiditis, celiac disorder adrenal CT: adrenal atrophy anti-adrenal antibodies Destruction of adrenal glands CT: metastases, malignant lymphoma, tuberculosis, etc. Hereditery disorders most frequent: congenital adrenal hyperplasia
Incidence of autoimmune disorders in patients with autoimmune adrenal insufficiency
Secondary adrenal insufficiency Pathology of the pituitary that eventually affects the adrenal glands long-term glucocorticoid use glucocorticoid withdrawal pituitary tumors infiltrative diseases of the pituitary pituitary apoplexy pituitary/cranial/neck radiation
Treatment of acute adrenal insufficiency I.
Treatment of acute adrenal insufficiency II.
Treatment of chronic primary adrenal insufficiency in adults
reatment of chronic primary adrenal insufficiency in adults
Treatment of chronic primary adrenal insufficiency in adults
Key points - Addison's disorder I. Addison disease develops as a result of bilateral adrenal cortex destruction Both cortisol and aldosterone production are usually reduced Autoimmune destruction of the adrenal glands is the most common cause in the western world, but infections such as tuberculosis, hemorrhage, adrenal vein thrombosis, and carcinoma are also known to significant causes Tuberculosis remains the most common cause worldwide of Addison disease The onset of Addison disease is often gradual, and symptoms of the disease can be difficult to recognize. It may go undetected until an illness or other stress precipitates adrenal crisis
Key points - Addison's disorder I. Treatment should not be withheld to confirm diagnosis. Treatment should be the priority, as the disease is fatal if it remains untreated Diagnosis is made with rapid, high-dose adrenocorticotropic hormone (ACTH) stimulation testing. If the patient is hypovolemic, dexamethasone and intravenous normal saline should be given before stimulation testing is performed Drug therapy is with a combination of glucocorticoids and mineralocorticoids. Glucocorticoid doses needs to be doubled when patients have an episode of minor fever, infection, minor trauma, or minor physical (not emotional) stress Intravenous stress-dose corticosteroids are needed for surgery requiring general anesthesia and for major trauma
Neuroendocrine tumors Miklós Tóth Professor of Medicine and Endocrinology 9 th April, 2018 Semmelweis University 2nd Department of Medicine
Definition of NETs Neoplasms of the neuroendocrine cells Common features production of neuropeptides and hormones large, dense-core, intracellular secretory granules (seen only by EM) absence of neural structures Neuroendocrine cells distribute widely in the body largest numbers located in the GI tract, pancreas, and lungs Embryonic development some NE cells are directly derived from the neurocrest most NE cells differentiate from local epithelial cells
Classification of NETs Location of primary tumor GI tract, lung, etc. Functioning vs. non-functioning Prognosis low, intermediate, high grades
Incidence of neuroendocrine tumors U.S. SEER Program, 1974-2005
Proliferation activity - ENETS grading
Survival of NET patients as a function of ENETS tumor grade
Clinical manifestations of carcinoid syndrome flush, teleangiectasias, pellagra-like dermatitis diarrhoea and abdominal cramps endocardial fibrosis of right heart, tricuspidal and pulmonary valvular stenosis and insufficiency
Epidemiology of carcinoid syndrome Davar et al. J Am Coll Cardiol 69: 1288 1304, 2017
Serotonin biosynthesis Mechanism of action of telotristat 5-HIAA: 5-hydroxy-indol-acetic ac
Clinical significance of 5-HIAA excretion 5-HIAA excretion correlates with severerity of endocardial fibrosis mesenterial fibrosis overall survival
Flush - carcinoid syndrome
Neoplasms of the endocrine pancreas Primary tumor Frequency of within the pancreas metastases (%) (%) Gastrinoma 50-70 60 Insulinoma 99 10 VIPoma 85 50 Glucagonoma 100 60 Nem-functioning 100 60 Carcinoid <5 100
Treatment aims Control of tumor growth Control of hormone excess
Most important factors influencing therapeutic decisions Site and type of the primary tumor TNM stage and grade Extent of liver involvement Hormonal activity Performance status Availability of various therapeutic modalities
Therapeutic modalities in the treatment of NETs Control of tumor growth Surgical excision Debulking surgery Treatment of liver mets surgical resection alcohol ablation embolisation chemoembolisation radioembolization termoablation radiofrequency ablation Liver transplantation Drug treatment somatostatin analogues α-interferon chemotherapy everolimus sunitinib bevacizumab? Targeted irradiation 131 I-MIBG 90 Yt octreotide 177 Lu octreotide
Liver metastases approached by combined surgical approach Neuroendocrinology, 87: 47-62, 2008
Radiofrequency ablation
Insulinoma in the pancreatic tail
Radiofrequency ablation of pancreatic NET
Selective intraarterial chemoembolisation of liver mets
Drug Hormone excess Grade Primery site SSTR status octreotide + G1 midgut + low tumor burden Special considerations lanreotide + G1 + placebo-controlled data on antiproliferative activity pending interferon? Drug treatment of neuroendocrine tumors ENETS consensus guideline - 2011 STZ + 5FU +/- G1-G2 pancreas progressive in short-term (3-6 months) or high tumor burden or symptomatic TEM/CAP +/- G2 pancreas progressive in short-term1or high tumor burden or symptomatic; contraindication for STZ-based regimen everolimus +/- G1-G2 pancreas insulinoma, chemotherapy contraindicated sunitinib +/- G1-G2 pancreas contraindication for chemotherapy PRRT +/- G1-G2 any + extended disease; extrahepatic mets (if tumor burden not too high); high uptake of tumor lesions on Octreoscan and limited disease amenable to surgery after down-staging cispl+etop +/- G3 any +/- all poorly differentiated NEC Pavel, Neuroendocrinology 2012;95:157 176
Drug treatment of metastatic NETs Uppsala, 2012 WHO, grade 1 Ki-67 < 2% ------------------------ Ki-67 < 5% (pnet) WHO, grade 2 Ki-67 < 2-20% ---------------------------- Ki-67 : 5-20% (pnet) WHO, grade 3 Ki-67 > 20% Ki-67: 21-55% Ki-67 > 55% SSA interferon everolimus PRRT combination streptozocin+5-fu everolimus sunitinib temozolomide± capecitabine PRRT temozolomide ±capecitabine +bevacizumab (FOLFOX) (FOLFIRI) cis-/carboplatin +etopozide : in case of hormonal excess syndrome + SSA
Targeted irradiation therapy of NETs
Peptide receptor radionuclide therapy (PRRT)
Radioactive somatostatin analogues for the therapy of NETs 111 In-DTPA-octreotide 90 Y-DOTA-Tyr 3 -octreotide (DOTATOC) 90 Y- DOTA-lanreotide (DOTALAN) 90 Y- DOTA-Tyr 3 -octreotate (DOTATATE) 177 Lu -DOTA-Tyr 3 -octreotate ( 177 Lu -DOTATATE) 177 Lu ~ 131 I (DOTANOC) DOTA: = Tetra-aza-cyclo-dodecane-tetraacetic acid
Grading of radionuclide uptake at SSR scintigraphy Krenning's scale Grade Appearance of SSR scintigraphy 0 No radionuclide accumulation in known tumor lesions 1 Suspected but not certain uptake in known tumor lesions 2 Accumulation in known tumor lesions, intensity less or equal to normal liver uptake 3 Clear uptake in known tumor lesions, higher than liver uptake 4 Intense uptake in known metastases
NETTER-1 - PRRT in Inoperable, Progressive, Somatostatin Receptor Positive Midgut Carcinoids Two treatment arms: 177 Lu-DOTA0-Tyr 3 -Octreotate plus Octreotid LAR 30 mg vs. Octreotide LAR 60 mg/ Primary outcome measures: progression free survival Estimated Enrollment: 200 Study Start Date: September 2012 Estimated Study Completion Date: December 2017 Estimated Primary Completion Date: December 2014 http://clinicaltrials.gov
Lutetium-177 (177Lu) Dotatate treatment of advanced, progressive, somatostatin-receptor positive midgut neuroendocrine tumors Strosberg, N Engl J Med, 376:125-35, 2017
Side effects of PRRT Bone marrow toxicity - cytopenia, usually mild Myelodysplastic syndrome, leukemias - rare Renal toxicity - can be prevented by amino acid infusions
Radioembolization
Paraneoplastic syndromes Miklós Tóth Professor of Medicine and Endocrinology 9 th April, 2018 Semmelweis University 2nd Department of Medicine
Paraneoplastic syndromes Some cancer-bearing individuals develop signs and symptoms that cannot readily be explained by the anatomic distribution of the tumor or by the elaboration of hormones indigenous to the tissue from which the tumor arose; these are known as paraneoplastic syndromes. 10% of persons with cancer
Significance of paraneoplastic syndromes They may be the earliest manifestation of an occult neoplasm. In affected patients they can cause significant clinical problems and may even be lethal. They may mimic metastatic disease and therefore confound treatment.
Main classes of paraneoplastic syndromes Endocrinopathies Nerve and Muscle syndromes Dermatologic Disorders Vascular and Hematologic Changes Others
Clinical Syndromes Cushing syndrome Syndrome of inappropriate antidiuretic hormone secretion Hypercalcemia Hypoglycemia Polycythemia Major Forms of Underlying Cancer Endocrinopathies Small-cell carcinoma of lung Pancreatic carcinoma Neural tumors Small-cell carcinoma of lung Intracranial neoplasms Squamous cell carcinoma of lung Breast carcinoma Renal carcinoma Adult T-cell leukemia/lymphoma Ovarian carcinoma Fibrosarcoma Other mesenchymal sarcomas Renal carcinoma Cerebellar hemangioma Hepatocellular carcinoma Causal Mechanism ACTH or ACTH-like substance Antidiuretic hormone or atrial natriuretic hormones Parathyroid hormone-related protein (PTHRP), TGF-α, TNF, IL-1 Insulin or insulin-like substance Erythropoietin
Clinical Syndromes Myasthenia Disorders of the central and peripheral nervous system Major Forms of Causal Mechanism Underlying Cancer Nerve and Muscle syndromes Bronchogenic carcinoma Immunologic Thymic neoplasms Breast carcinoma Dermatologic Disorders Gastric carcinoma Acanthosis Immunologic; secretion of Lung carcinoma nigricans epidermal growth factor Uterine carcinoma Bronchogenic carcinoma Dermatomyositis Immunologic Breast carcinoma Osseous, Articular, and Soft Tissue Changes Hypertrophic osteoarthropathy Bronchogenic carcinoma Unknown and clubbing of Thymic neoplasms the fingers
Clinical Syndromes Hypertrophic osteoarthropathy and clubbing of the fingers Venous thrombosis (Trousseau phenomenon) Disseminated intravascular coagulation Nonbacterial thrombotic endocarditis Major Forms of Underlying Causal Mechanism Cancer Osseous, Articular, and Soft Tissue Changes Bronchogenic carcinoma Thymic neoplasms Unknown Vascular and Hematologic Changes Pancreatic carcinoma Bronchogenic carcinoma Other cancers Acute promyelocytic leukemia Prostatic carcinoma Advanced cancers Tumor products (mucins that activate clotting) Tumor products that activate clotting Hypercoagulability Red cell aplasia Thymic neoplasms Unknown Others Nephrotic syndrome Various cancers Tumor antigens, immune complexes
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