Adrenal Gland Pathology II: Adrenal Gland Dysfunction PDF

ENDOCRINE PATHOLOGY II: ADRENAL GLAND DYSFUNCTION Amal Sahyoun, PhD Assistant Professor, College of Dental Medicine [email protected] LEARNING OBJECTIVES Understand the etiologies and pathophysiology of adrenal gland dysfunction Identify the clinical features and laboratory findings of adrenal...

ENDOCRINE PATHOLOGY II: ADRENAL GLAND DYSFUNCTION Amal Sahyoun, PhD Assistant Professor, College of Dental Medicine [email protected] LEARNING OBJECTIVES Understand the etiologies and pathophysiology of adrenal gland dysfunction Identify the clinical features and laboratory findings of adrenal gland dysfunction Identify diagnostic approaches and treatment of adrenal gland dysfunction PRIMARY ADRENAL INSUFFICIENCY ADRENAL GLAND PATHOLOGY Hyperfunction Hypofunction Neoplasms Hyper aldosteronism Primary: Conn syndrome Hypercortisolism Primary: Cushing syndrome Adrenocortical insufficiency Primary acute: Waterhouse-Friderichsen Primary chronic: Addison disease Adrenocortical adenoma Adrenocortical carcinoma Androgenital syndromes Virilization syndromes Chromaffin cells Pheochromocytoma Neuronal cells Neuroblastic tumors PRIMARY ADRENAL INSUFFICIENCY - Adrenal gland can’t produce enough hormones particularly aldosterone and cortisol due to damage of the adrenal cortex - Primary due to underlying problem is localized to the adrenal gland itself, rather than a problem of a hormone that acts on the adrenal gland or elsewhere in the body (secondary adrenal insufficiency) - It can be either acute or chronic o Acute: Waterhouse-Friderichsen syndrome o Chronic: Addison disease ADDISON DISEASE -Due to progressive destruction of the adrenal gland from a variety of causes (see table).  In high income countries: most common cause is autoimmune destruction o Body’s immune cells mistakenly attack the healthy adrenal cortical tissues. o The pathology is not clear  Other countries, most common cause is infectious due to tuberculosis o The infection spreads from the lungs to the adrenal glands causing inflammation and destruction in the adrenal cortex  Metastatic carcinoma is another important cause o Cancer spread to the adrenal cortex from somewhere else in the body such as lung, breast, stomach and colon ADDISON DISEASE: CLINICAL MANIFESTATIONS -Despite the causes, adrenal cortex has a high functional reserve - The symptoms are dependent on the adrenal gland layer(s) destroyed:  Zona glomerulosa: Aldosterone levels drops  hyperkalemia, hyponatremia, hypovolemia, hypotension and metabolic acidosis When electrolyte changes along with hypovolemia  cravings for salty food, nausea, vomiting, fatigue and dizziness. ADDISON DISEASE: CLINICAL MANIFESTATIONS - The symptoms are dependent on the adrenal gland layer(s) destroyed:  Zona fasciculata: cortisol levels drops Hypoglycemia (weak, tired and disoriented) Overactive pituitary gland producing proopiomelanocortin  Precursor for ACTH  Precursor for melanocyte-stimulating hormone (responsible for skin pigmentation)  Hyperpigmentation in joints such as elbows, knees and knuckles  Also, oral dark pigmentation on the tongue, palate, gingiva and mucosa https://www.ccjm.org/content/89/9/498 ADDISON DISEASE: CLINICAL MANIFESTATIONS - In the presence of stressors:  Injury  Surgery Chronic low aldosterone and/or cortisol  Infection SUDDEN increased need for aldosterone and cortisol Addisonian crisis Extreme pain in back, abdomen or legs Vomiting and diarrhea  dehydration Hypotension  loss of consciousness If untreated  death ADDISON DISEASE: DIAGNOSIS Cortisol measurements Cortisol ACTH Possible Secondary Adrenal insufficiency ACTH measurements ACTH Stimulation test And Aldosterone & renin levels Cortisol Normal Aldosterone and renin Pituitary MRI Secondary Adrenal insufficiency ACTH Possible Primary Adrenal insufficiency No change Cortisol (low) Aldosterone and renin 21-hydroxylase antibodies Adrenal CT/MRI FNA TB Primary Adrenal insufficiency HYPERALDOSTERONISM: TREATMENT - Hormone replacement therapy  Low Cortisol  corticosteroids  Low Aldosterone  Fludrocortisone  Taken for the rest of the life  If stopped  Adrenal crisis - Hypovolemia/ hypotension  IV fluids and vasopressors - Hypoglycemia  IV dextrose WATERHOUSE-FRIDERICHSEN SYNDROME - Sudden increase in blood pressure causing blood vessels in the adrenal cortex to rupture.  Due to severe bacterial infection - Lead to adrenal crisis or acute adrenal insufficiency  Adrenal gland stops producing hormones -Classically associated with Neisseria meningitidis septicemia but also other organisms such as Pseudomonas species, pneumococci, Hemophilus influenzae, staphylococci, etc. -Adrenal cortex hemorrhage: may be due to direct bacterial seeding of small vessels, DIC, or endothelial dysfunction due to microbial products and inflammatory mediators -Clinical: (1) Hypotension leading to shock (2) DIC with skin purpura (3) Addisonian crisis symptoms -Treatment: Antibiotics Glucocorticoids and supplementary hormones ADRENAL MEDULLA PATHOLOGY ADRENAL GLAND PATHOLOGY Hyperfunction Hypofunction Neoplasms Hyper aldosteronism Primary: Conn syndrome Hypercortisolism Primary: Cushing syndrome Adrenocortical insufficiency Primary acute: Waterhouse-Friderichsen Primary chronic: Addison disease Adrenocortical adenoma Adrenocortical carcinoma Androgenital syndromes Virilization syndromes Chromaffin cells Pheochromocytoma Neuronal cells Neuroblastic tumors PHEOCHROMOCYTOMA - Pheo- means dark, chromo- refers to color, cyto- refers to a cell and -oma feres tumor - Pheochromocytoma is a rare adrenal gland tumor where the chromaffin cells darken when they form tumors - Chromaffin cells , in the adrenal medulla, secrete epinephrine and norepinephrine into the blood during fight and flight α Cardiac output Blood pressure Dilated pupils β Blood flow to skeletal muscle Blood sugar PHEOCHROMOCYTOMA - Tumors form when chromaffin cells start to divide uncontrollably leads to massively release catecholamines - The overproduction of catecholamines is mostly common due to tumor in adrenal gland (90%) and rarely as paraganglioma (10%) - Mostly, pheochromocytoma is mostly unilateral, form in one of the adrenal gland  Rarely, bilateral  Other parts of the body where chromaffin cells are found such as in carotid arteries in the neck, bladder and abdominal aorta (paraganglioma) - They are mostly begnin tumor, only 10% can become malignant - Pheochromocytoma is associated with some inherited syndromes such as multiple endocrine neoplasia type 2A and type 2B, Von Hippel-Lindau disease and Sturge-Weber Syndrome (SWS) PHEOCHROMOCYTOMA - Multiple endocrine neoplasia type 2A and type 2B  Mutation in RET gene (proto-oncogene)  oncogene causing cells to divide constantly - Von Hippel-Lindau disease  Mutation in VHL (tumor suppressor protein)  Occurs in eyes, brain, spinal cord, adrenal gland etc. - Sturge-Weber Syndrome (SWS)  Somatic mutations in the GNAQ gene  Abnormal blood vessel development, particularly in the skin and brain MacIntosh, Robert & Shivapuja, Prasanna-Kumar & Krzemien, Michael & Lee, Michael. (2014). Multiple Endocrine Neoplasia Type 2B: Maxillofacial Significance in 5 Cases. Journal of Oral and Maxillofacial Surgery. 72. 2498.e1-2498.e17. 10.1016/j.joms.2014.08.032. Mucosal neuromas PHEOCHROMOCYTOMA: CLASSIC FINDINGS Classic signs and symptoms: - Secondary hypertension i failure o If higher than 180/120 mmHg  Hypertensive urgency f o Break small vessels in heart, brain, eyes and kidneys  hemorrhage and ischemia - Secondary headache - Palpitations - Diaphoresis THE hemov.Stroke Retinal hero SVR Sobocki BK, Perdyan A, Szot O, Rutkowski J. Management of Pheochromocytomas and Paragangliomas: A Case-Based Review of Clinical Aspects and Perspectives. Journal of Clinical Medicine. 2022; 11(9):2591. https://doi.org/10.3390/jcm11092591 PHEOCHROMOCYTOMA: DIAGNOSIS AND TREATMENT Diagnosis: - Measure catecholamines in blood or urine - Measure urinary and serum normetanephrine (NMN) and metanephrine (MN) - If high  perform adrenal CT/MRI to detect if it is adrenal or extra-adrenal Treatment: -Adrenalectomy with venous ligation -Hypertensive crisis: medications to lower blood pressure that blocks alpha (Phenoxybenzamine) AND beta receptors (Propranolol) NEUROBLASTOMA -Neuroblastoma is a tumor of the neural crest cells  Neural cells involved in the development of the sympathetic nervous system. - Most common in infants < 5 years old - Neural crest cells differentiate unto neurons of the sympathetic chain and cells of the adrenal medulla - In neuroblastoma, some neural crest cells in the sympathetic chain or adrenal medulla fail to undergo proper differentiation during fetal development  These cells subsequently give rise to a tumor, typically originating in the adrenal medulla but potentially developing in other regions of the sympathetic chain as well NEUROBLASTOMA -The cause of neuroblastoma is unknown  Associated with mutations on MYCN oncogene and other tumor suppressor genes  Uncontrolled cell growth -3 types of neuroblastoma (based on size and shape of cells)  Undifferentiated: neural crest cells of small round blue cells, due to a lack of cytoplasm, and a large blue nuclei  Poorly differentiated: slightly more differentiated cells, with smaller nuclei and a bit more cytoplasm. Surrounded by neuropil (network of nerve fibers).  Differentiated: cells with lots of cytoplasm and is often surrounded by a substance called Schwannian stroma. Gheisari, Soheila & Catchpoole, Daniel & Charlton, Amanda & Melegh, Zsombor & Gradhand, Elise & Kennedy, Paul. (2018). Computer Aided Classification of Neuroblastoma Histological Images Using Scale Invariant Feature Transform with Feature Encoding. Diagnostics. 8. 56. 10.3390/diagnostics8030056. NEUROBLASTOMA: PATHOGENESIS - CXCL12 is a very know pro inflammatory marker. - If a neuroblastoma cell rupture and its content gets into the blood  it will release chemokine called CXCL12  CXCL12 will reach to the lymph node, liver, bones Immune cells sense high CXCL12 and bone marrow.  One of the main characteristics of this chemokines that it will attract immune cells. So, the immune cells will attack the lymph nodes, liver, bones and bone marrow creating metastatic tumors there. Metastasis Organs: Lymph nodes Liver Bones Bone marrow CXCL12 Migrates towards organs NEUROBLASTOMA: SYMPTOMS - The symptoms of neuroblastoma result from the chemokine release  Fever, weight loss, sweating and fatigue - Other symptoms are dependent on the location of the metastatic tumor  Thoracic region: Lungs  breathing difficulties  Neck: facial nerves  Horner syndrome (miosis, ptosis and anhidrosis)  Spine  neurologic manifestations (muscle and bowel/bladder weakness)  Adrenal medulla  painful abdominal mass with swelling  Bones  bone pain and fractures  fracture at the base of the skull  Fluid and blood to leak into the tissues around the eyes  periorbital ecchymosis  Bone marrow  abnormal RBC, platelets, and WBC  fatigue, easy bruising and infections https://clinicalgate.com/neuroblastoma-8/ NEUROBLASTOMA: DIAGNOSIS AND TREATMENT Diagnosis: - Measure urinary and serum homovanillic acid (HMA) and vanillylmandelic acid (VMA) - CT scan  show location and size of tumor - Complete blood count  determine bone marrow metastasis Treatment: -Depends on size and stage of neuroblastoma -If metastasis  chemotherapy, medication and bone marrow transplantation REFERENCES  Robbins and Cotran Pathologic Basis of Disease, 9th edition or 10th edition. V Kumar; Elsevier Gary D. Hammer and Stephen J. McPhee Pathophysiology of Disease: An Introduction to Clinical Medicine, 8th edition. McGraw Hill. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e