The flushing patient: Differential diagnosis, worku

p, and treatmentJ Am Acad Dermatol 2006;55:193-208

Introduction

• Cutaneous flushing– Resulting from changes in cutaneous blood fl

ow triggered by multiple conditions– Common, benign diseases, such as rosacea o

r 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 mont

hs– Flushing episodes, lasting longer than 10 min

s

• 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 5-HIAA, 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 a

nd tachycardia• Commonly present with headaches, sweating, p

alpitations, 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 categoriesI. Indolent mastocytosis, cutaneous or syste

mic

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 Verner-Morrison 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