The Flushing Patient

The flushing patient: Differential diagnosis, workup, and treatment J Am Acad Dermatol 2006;55:193-208

Introduction • Cutaneous flushing – Resulting from changes in cutaneous blood flow triggered by multiple conditions – Common, benign diseases, such as rosacea or climacterum – Other serious diagnoses; carcinoid syndrome, pheochromocytoma, mastocytosis, and anaphylaxis

Definition • Defined as a sensation of warmth accompanied by visible reddening of the skin. • Usu. Most prominent in the classis “bluish area,” including the face, neck and upper portion of the chest, and upper limbs

Definition II • Flushing – episodic or constant • Episodic attacks are generally mediated by release of endogenous vasoactive mediators or by drugs • Repetitive episodes over long periods (persistent flushing) • May produce fixed facial erythema with telangiectases and a cyanotic tinge

Differential Diagnosis

Fever • Most common cause of “hot flushes”, associated with night sweats • Prompt a fever workup, which may reveal an infectious or noninfectious cause

Benign Cutaneous Flushing • Triggered by emotion, exercise, temperature changes, and foods or beverages, esp. spicy foods • Associated findings – a feeling of warmth and cognitive dysfunction • Hyperthermia, Emotional flushing, Foods, beverages, and alcohol

Rosacea • Acne rosacea- another common cause • May present with transient or persistent central facial flushing, erythmea, visible blood vessels, and often papules and pustules • 4 broad subtypes: erythematotelangiectatic, papulopustular, phymatous, and ocular

Rosacea

Rosacea II • Primary manifestation – Persistent erythema, usu. Longer than 3 months – Flushing episodes, lasting longer than 10 mins

• Important to exclude polycythemia vera, connective tissue disease, carcinoid syndrome, systemic mastocytosis

Climacteric Flushing • Common cause of flushing, affecting 50%~85% of women who undergo natural menopause • Perimenopausal flushing presents as transient episodes of intense heat sensation, flushing of the chest, head, and neck, and profuse drenching sweats • Frequently followed by chills, palpitations and a sense of anxiety • Episodes last 3-5 mins and may occur as many as 20 times a day

Carcinoid Syndrome • Classical triad: flushing, GI hypermotility and Rt sided cardiac failure. Lesser incidence of bronchoconstriction • 95% of p’ts have flushing at some point during disease; the most frequent sign • CS occurs in 10% of p’ts with carcinoid tumors; malignant enterochromaffin or Kulchitsky cells derived from neuroendocrine lineage • 13% had metastasis at time of diagnosis and 24% carcinoid p’ts had more than 1 tumor

Carcinoid Syndrome II • Flushes ossicated with gastric tumors are reddish-brown with variegated margination and occurs as wheals over the entire body, including palms and soles and intensely pruritic • Flushes assoicated with bronchoconstriction are bright red and confluent, cover most of the body, last hours to days, and usu. Associated with chemosis, facial edema, severe hypotension, and oliguria • P’ts with CS flushing may develop thick skin changes with venous telangiectasia and bluish coloration of the chin, nose and malar area

Carcinoid Syndrome III • P’ts generally presents with hypotension and tachycardia during flushing • Flushing may be provoked by foods, pharmalocologic triggers and any stimuli that increase adrenergic activity • Likelihood of flushing in CS is dependent on tumor-derived mediators and the extent of liver metastasis

Carcinoid Syndrome IV • Tumor derived vasodilator : 5-HT, substance P, histamine, serotonin, catecholamines, PG, kallikrein, kinins, tachykinins, neuropeptide P, VIP, motilin, and gastric related peptides • CS diagnosed by measuring 24-hr urine 5HIAA, a major urinary metabolite of 5-HT • Flushing in CS can be blocked with somatostatin, analogs also decrease tumor progression

Pheochromocytoma • Also known as chromaffin tumor, present with flushing and hypertension • Chromaffin cells derived most often from the adrenal medulla, produce, store and release catecholamines • HTN most common finding. • Attacks last a few minutes to a few hours • Associated with flushing or pallor, elevated BP and tachycardia • Commonly present with headaches, sweating, palpitations, a sense of apprehension and impending doom, chest or abd pain.

Pheochromocytoma II • Diagnosed by 24hr urine fractionated metanephrines, metabolites of catecholamines • Abdominal CT, abdominal aortography or nuclear scintigraphy with radioactive iodine • Surgical resection by laparoscopic adrenalectomy is the definitive treatment and may be curative

Mastocytosis • A rare disease caused by tissue infiltration with increased numbers of mast cells • More common in childhood than in adulthood • Presents in the children with the characteristic skin eruption of urticaria pigmentosa (>90%)

Urticaria pigmentosa

Darier sign • Darier sign is a change observed after stroking the skin of a person with systemic mastocytosis or urticaria pigmentosa. In general, the skin becomes swollen, itchy and red. • Result of stimulation; mast cells release several potent vasodilators; histamine and PG D2, TNF α

Mastocytosis II • Diagnosis usu. straightforward if characteristic lesions of urticaria pigmentosa present • Elevated plasma concentrations of mast cell mediators, such as histamine and tryptase • Elevated 24hr urine excretion of histamine and PG D2 • Histopathologic analysis of cutaneous mastocytosis lesions revealing multifocal or diffuse mast cell aggregates

Mastocytosis III •

Classified into 4 categories I.

Indolent mastocytosis, cutaneous or systemic II. Mastocytosis associated with hematologic disease III. Lymphadenopathic mastocytosis with eosinophilia IV. Mast cell leukemia

Mastocytosis IV • No cure for mastocytosis • Avoidance of precipitating factors • Flushing and hypotension from mastocytosis can be reversed with IV epinephrine • Combined blockade pf H1 and H2 receptors prevents the vasodilatory effects of histamine

Anaphylaxis • Life threatening condition that may present with flushing • Most often presents with flushing, urticaria and angioedema • Hypotension, upper airway edema, pulmonary symptoms, rhinitis, headaches and substernal chest pain

Medullary Ca. of the thyroid • Malignant tumor of the parafollicular C cells • May present with protracted flushing of the face and upper extremities, discoloration, and telangiectasias • Neoplastic cells are derived from neural crest • Inheritance pattern may be sporadic or AD

Pancreatic cell tumor • Vasoactive intestinal polypeptide (VIP) tumor classically present with VernerMorrison syndrome: watery diarrhea, hypokalemia, and achlorhydria • Also rarely present with flushing during attacks • VIP tumor is diagnosed by a high plasma VIP level in the setting of stool volume greater than 1L per day

Renal cell carcinoma • RCC may cause flushing via secretion of prostaglandin or via pituitary downregulation from release of gonatotropins • Classic triad: gross hematuria, flank pain and abdominal mass • Tx of choice: Nephrectomy

Pharmacologic mediators

Pharmacologic mediators

Differential Diagnosis

Unilateral flushing • May result from contralateral sympathetic nerve lesions that produce Horner syndrome (ptosis, miosis, and anhidrosis) • Leading to contralateral, unaffected facial reddening

Medications

Summary

Summary