Wow this is very informative! Especially the part about Mastocytosis
sufferers developing rosacea after about 1 year of their flushing side
effect. -Artist

http://www.clevelandclinicmeded.com/diseasemanagement/endocrinology/
flushing/flushing.htm


FLUSHING

Flushing describes episodic attacks of redness of the skin together
with a sensation of warmth or burning of the face, neck, and less
frequently the upper trunk and abdomen.
It is the transient nature of the attacks that distinguishes flushing
from the persistent erythema of photosensitivity or acute contact
reactions. Repeated flushing over a prolonged period of time can lead
to telangiectasia and occasionally to classical rosacea of the face.1

Flushing can be an exaggeration of a physiological process or a
manifestation of a serious condition that needs to be identified and
treated. A biochemical work-up of every case of flushing is neither
practical nor cost-effective; in this chapter, the author will present
guidelines that will help determine when a work-up is warranted.
PREVALENCE

The prevalence of flushing has not been determined.
PATHOPHYSIOLOGY

Redness of the skin may be due to an increased amount of saturated
hemoglobin, an increase in the diameter or actual number of skin
capillaries, or a combination of these factors.2 Flushing is due to
increased blood flow through the skin, causing warmth, and because of
engorgement of the subpapillary venous plexus, redness. The
vasodilatation of flushing may be due to a direct action of a
circulatory vasodilator substance, for example histamine, or it may be
caused by changes in the neurological control of the cutaneous
vasculature in the affected areas. In the face, neck, and upper trunk,
where flushing is most frequent, the neurological control of vascular
tone is predominantly exerted by autonomic vasodilator nerve fibers.
These fibers are found in somatic nerves supplying the affected skin,
including the trigeminal nerve. Since autonomic nerve fibers also
supply eccrine sweat glands, neurally activated flushing is frequently
associated with sweating (wet flushing) as opposed to flushing due to
circulating vasodilator mediators which frequently does not involve
sweating (dry flushing). The presence or absence of sweating has
therefore been proposed as a clinical guide to the mechanisms of
flushing, although in practice this is not always reliable. Examples
of wet flushing are physiological flushing and menopausal flushing. An
example of dry flushing is niacin-provoked flushing.1

The diameter of the blood vessels of the cheeks is wider than
elsewhere, the vessels are nearer to the surface, and there is less
tissue thickness obscuring them. This may explain why flushing occurs
in that limited distribution.3 Polycythemia produces the
characteristic ruddy complexion, but it may also cause a peculiar
coloration termed "erythremia," which is a combination of redness and
cyanosis. The tongue, lips, nose, earlobes, conjunctivae, and
fingertips especially demonstrate this coloration. Erythremia results
when there is a combination of increased amounts of saturated
hemoglobin and desaturated hemoglobin.

In some carcinoid tumors, fibrosis of the right side of the heart may
lead to a combination of stenosis and regurgitation at the tricuspid
valve as well as pulmonary stenosis. If cyanosis occurs, the
combination of flushing and cyanosis may produce the reddish cyanotic
erythremia.2
FLUSHING SYNDROMES

Physiological Flushing:

Embarrassment or anger may cause flushing in some individuals in whom
the threshold for this response may be low or the reaction itself
unusually intense; this is also known as blushing.1,2 Explanation and
reassurance are usually sufficient. If necessary, propranolol or
nadolol may be used to alleviate the symptom.1

Heat causes flushing in many patients, and overheating can lower the
threshold to flushing due to other causes such as menopause.3
Overheating such as after exercise or sauna can cause physiological
flushing due to the effect of the rise in blood temperature on the
thermoregulatory center in the anterior hypothalamus. A similar
mechanism is responsible for facial flushing due to hot drinks, which
cause a rise in temperature of blood in the oral cavity in turn
leading to a rise in temperature of blood perfusing the hypothalamus.
The temperature of hot coffee rather than its caffeine causes
flushing.

A useful maneuver for patients faced with a brief thermal exposure is
to suck on ice chips carried in an insulated cup. This will attenuate
flushing for the first 20 to 30 minutes.3

Menopausal Flushing:

About 80% of postmenopausal women experience flushing associated with
sweating. A similar syndrome may also occur in men with prostate
cancer receiving treatment with gonadotropin-releasing hormone analogs
such as buserelin. About 65% of post-menopausal women have hot flushes
for 1 to 5 years, 26% for 6 to 10 years, and 10% for more than 11
years. There is considerable variation in the frequency, intensity,
and duration of hot flushes within and among individuals. A typical
hot flush begins with a sensation of warmth in the head and face,
followed by facial flushing that may radiate down the neck and to
other parts of the body; it is associated with an increase in
temperature and pulse rate and followed by a decline in temperature
and profuse perspiration over the area of flush distribution. Visible
changes occur in about 50% of women. Each hot flush lasts for 1 to 5
minutes. The primary role of estrogen deficiency has been questioned
and a deficit of thermoregulation has been proposed. Rapid estrogen
withdrawal rather than a low estrogen level by itself is likely to
induce hot flushes.4 Synchronous with the onset of each hot flush is
the release of a pulse of luteinizing hormone; this does not seem
responsible for the hot flush since flushing can occur after
hypophysectomy. The anterior hypothalamus has estrogen and
progesterone receptors, and both hormones can be used effectively to
treat hot flushes through binding with their respective hypothalamic
receptors. Neurotransmitters that may be involved in the pathogenesis
of hot flushes include norepinephrine and other noradrenergic
substances. The central noradrenergic system in the hypothalamus
triggers the hot flushes via α2-adrenergic receptors on the
noradrenergic neurons. Thus, clonidine—an α2-adrenergic agonist—
effectively alleviates hot flushes through reduction of noradrenergic
release.4

Pharmacologic menopause with flushing can be induced by a variety of
drugs: 4-hydroxyandrostenedione, danazol, tamoxifen, clomiphene
citrate and leuprolide. Certain characteristics suggest the diagnosis
of climacteric flushing: drenching perspiration, a prodromal sensation
of overheating before the onset of flushing and sweating, and waking
episodes at night with the typical symptoms. Alcohol can enhance a
menopausal flush.5 Veralipride, an antidopaminergic drug, can cause a
reduction in the frequency and intensity of menopausal flushing in
premenopausal women pretreated with goserelin (gonadotropin-releasing
hormone agonist) for endometriosis.6

Flushing Caused by Drugs:

Other medications that can cause flushing are corticotropin-releasing
hormone, doxorubicin, and niacin (Table 2). Flushing is a side effect
of sildenafil citrate in 12% of patients.7 Systemic administration of
morphine can cause flushing of the face, neck, and upper thorax, which
is thought to be histamine-mediated.5 Patients can develop facial
flushing and/or generalized erythema after epidural or intra-articular
administration of glucocorticoids. The exact pathophysiology is
unclear but it could be related to distention of the joint capsule.8
Table 2:
Flushing Caused By Drugs
All vasodilators
(eg, nitroglycerin, prostaglandins)
All calcium channel blockers
Nicotinic acid (not nicotinamide)
Morphine and other opiates
Amyl nitrite and butyl nitrite
Cholinergic drugs
(eg, metrifonate, and anthelmintic drug)
Bromocriptine used in Parkinson's disease
Thyrotropin releasing hormone (TRH)
Tamoxifen
Cyproterone acetate
Oral triamcinolone
Cyclosporine
Rifampin
Sildenafil citrate
Adapted from reference 2.

Flushing Associated with Alcohol Intake:

Certain oriental genotypes show extensive flushing in response to low
doses of alcohol. They have been found to have higher plasma levels of
acetaldehyde. This abnormality is probably related to a deficiency of
an isoenzyme of liver aldehyde dehydrogenase. This population can be
detected by using an ethanol patch test which produces localized
erythema. A special type of alcohol flush is also associated with
chlorpropamide, the oral anti-hyperglycemic agent. Even small amounts
of alcohol provoke intense flushing within a few minutes of ingestion.
This flushing is not associated with sweating, but in some cases
tachycardia, tachypnea, and hypotension may be seen. The flush is
mediated by elevated acetaldehyde plasma levels and possibly by
release of prostaglandins.

Alcohol ingestion can trigger flushing in carcinoid tumors,
mastocytosis, medullary thyroid carcinoma, and certain lymphoid
tumors.

Trichloroethylene, a chemical that has been abandoned in recent years
because of carcinogenic potential, can cause flushing. When inhaled
following ingestion of alcoholic beverages, a striking cutaneous
reaction results, consisting in the sudden appearance of erythema of
the face, neck, and shoulders—a reaction that has been termed
"degreaser's flush." Nausea and vomiting may also occur.5

Flushing Associated with Food:

Eating spicy or sour foods can cause facial flushing. This gustatory
flushing is due to a neural reflex involving autonomic neurons carried
by the branches of the trigeminal nerve. The flushing may be
unilateral.

The flushing of monosodium glutamate (MSG) is controversial. Oral
challenge with MSG failed to provoke flushing in volunteers with a
history of MSG flushing. Patients should be encouraged to look beyond
MSG at other dietary agents, such as red pepper, other spices,
nitrites and sulfites (additives in many foods), thermally hot foods
and beverages, and alcohol.5 Scromboid fish poisoning (tuna and
mackerel) is due to the ingestion of fish that was left in a warm
temperature for hours. In addition to flushing, patients with
scromboid fish poisoning have sweating, vomiting, and diarrhea. These
symptoms are due to intoxication with histamine, which is thought to
be generated by histidine decarboxylation by bacteria in spoiled fish.

Carcinoid Syndrome:

"Carcinoid syndrome" describes the manifestations of carcinoid tumors:
flushing, bronchoconstriction, gastrointestinal hypermotility, and
cardiac disease. Carcinoid tumors are neuroendocrine tumors that
derive from a primitive stem cell that may differentiate into any of a
variety of adult endocrine-secreting cells, producing a variety of
peptides, hormones, and neurotransmitters. The annual incidence is 1.5
per 100,000 population.9 The average age of patients is 50 years, and
there is no gender predominance.10

Carcinoid syndrome occurs in about 10% of patients with these tumors.
10 In 75% of patients, episodes of severe flushing are precipitated by
exercise, alcohol, stress, and certain foods (spices, chocolate,
cheese, avocados, plums, walnuts,1 red sausage, and red wine). With
time the flushing may appear without provocation.9 The character of
the flush differs depending upon the site of origin of the tumor
(Figures 1 and 2). Tumors of the foregut (stomach, lung, pancreas) are
associated with a bright-red "geographic" flush of a more sustained
duration, as well as lacrimation, wheezing, sweating, and a sensation
of burning. In ileal tumors, the flush is patchier and more
violaceous, intermingled with areas of pallor, and does not last as
long. Flushing of either type may be associated with facial edema that
may persist and lead to telangiectasia and even facial rosacea. With
extensive disease, one can also see pellagra-like skin lesions. (These
result from excessive utilization of tryptophan by the carcinoid
tumor, leaving little for the daily niacin requirement). These lesions
include hyperkeratosis; xerosis; scaling of the legs, forearms, and
trunk; angular cheilitis; and glossitis (Figure 3). Seventy percent of
patients also have watery diarrhea, and 35% develop right-sided
endocardial fibrosis leading to congestive heart failure. Diarrhea and
other gastrointestinal manifestations may precede or coexist with the
flushing.5

Ninety-five percent of all carcinoids are found in the appendix,
rectum, or small intestine.9 The remainder arise outside of the
intestinal tract (ovary, testis). In general, the larger the primary
tumor, the greater the likelihood of metastasis, which provides
prognostic implications.9 Carcinoids of the appendix and rectum rarely
present with the carcinoid syndrome. Forty to 50% of patients with
carcinoids of the small intestine or proximal colon have
manifestations of the carcinoid syndrome.10 Tumors that secrete their
hormonal product into the portal venous system do not cause flushing
because the released amines are inactivated by the liver. In contrast,
liver metastases may escape hepatic inactivation and deliver their
product directly into the systemic circulation and hence cause
flushing.9 Pulmonary or ovarian carcinoids release pharmacological
products directly into the venous circulation, bypassing the portal
system, and can therefore cause symptoms without metastasizing to the
liver.1,10

Pathophysiology
The flushing seen with foregut carcinoids is due to release of
histamine. Flushing seen with ileal carcinoids cannot be explained
solely by the production of serotonin.1 Serotonin may or may not be
released into the circulation during flushing, and intravenous
infusion of serotonin does not cause flushing. Foregut carcinoids do
not generally secrete serotonin but, instead, its precursor, 5-
hydroxytryptamine. Screening should therefore seek this product if the
other metabolites are not elevated.9 Other mediators that have been
proposed include prostaglandins and tachykinins. Tachykinins are
believed to be mediators of the flushing in tumors of the midgut. They
exert vasodilation and contraction of various types of smooth muscle.
These peptides include substance P, substance K, and neuropeptide K.
Urine excretion of histamine is usually increased in patients who have
gastric carcinoid (Table 3).9

Diagnosis
Clinical diagnosis is not difficult in patients with flushing episodes
associated with systemic symptoms (diarrhea, wheezing, and weight
loss) and hepatomegaly. It is more difficult in patients who have
occasional flushing and no associated symptoms.1 Only when there is
reasonable clinical suspicion should biochemical testing be done, and
localization studies must be reserved for those cases proven
biochemically.10 When in doubt, a carcinoid flush can be provoked by
alcohol ingestion (4 mL of 45% ethanol) or the infusion of 6 µg
noradrenaline, an effect that can be blocked by phentolamine (5 to 15
mg intravenously). Calcium gluconate, 10 to 15 mg/kg, administered
intravenously over 4 hours, may produce a flush mimicking a
spontaneous attack.5 Epinephrine reverses flushing in patients with
mastocytosis but provokes flushing in patients with the carcinoid
syndrome. The procedure should only be performed in a controlled
environment. A 1 µg/mL solution of epinephrine in normal saline is
administered by intravenous bolus beginning with an initial dose of 0.
05 µg. The dose is doubled at intervals of 10 minutes until flushing
appears or a until a maximum of 6.4 µg is given. When flushing occurs,
it usually begins within 60 seconds after epinephrine administration
and dissipates after 3 or 4 minutes.10

The diagnosis should be confirmed by determining urinary excretion of
5-hydroxyindoleacetic acid (5-HIAA), the major metabolite of
serotonin, which is normally 2 to 10 mg (10 to 50 µmol) per 24 hours.5
A value of more than 150 µmol/24 hours (30 mg/24 hours) usually
confirms the diagnosis, and in carcinoid syndrome it is often above 40
mg per day.5 This test has a sensitivity of 75% and a specificity of
up to 100%. The degree of elevation of 5-HIAA does not always
correlate with the severity of flushing.9 Excretion fluctuates, so
that repeated measurements may be necessary. Some patients with
carcinoid may lack the metabolic machinery to convert serotonin to 5-
HIAA, so they have high blood levels of serotonin but normal urinary
5-HIAA.5 Dietary factors may cause confusion; the patient should
therefore receive a diet free of the culprit items (Table 4) for 3
days before the urine collection is made. Although the levels of
serotonin in patients with tumors usually far exceed those found after
food ingestion, this precaution helps to exclude carcinoid in
individuals with borderline-high 5-HIAA levels.9 Measuring blood
serotonin is helpful when urinary 5-HIAA is equivocal. Patients with
carcinoid syndrome have very high blood levels of serotonin.
Measurement of serotonin and its metabolites permits the detection of
84% of neuroendocrine tumors. Even carcinoids that predominantly
secrete 5-hydroxytryptophan are associated with increased urinary
excretion of 5-HIAA because the released 5-hydroxytryptophan is
converted to serotonin in other tissues and is subsequently
metabolized to 5-HIAA.9 Chromogranin A, a peptide co-secreted with
serotonin, is elevated in most patients with carcinoid tumors. In the
evaluation of flushing with an equivocal 24-hour urinary 5-HIAA, a
normal plasma chromogranin A value suggests nonendocrine causes. This
test is sensitive but not specific, and its predictive value in
carcinoid is still uncertain.10 Flushing was associated with a rise in
circulating substance P in 80% of patients with gastric carcinoid.
Neurokinin A levels are elevated in certain patients (Tables 4 and 5).
9
Table 4:
Factors That Can Precipitate
Flushing In the Carcinoid Syndrome
Foods and Beverages
Hot food/beverage
Spicy food
Chocolate
Cheeses
Tomatoes
Avocados
Red plums
Walnuts
Eggplant
Alcohol
Emotional Stress
Valsalva maneuver
Straining
Vigorous coughing
Sudden direct pressure on a
large carcinoid tumor
Adapted from reference 2.

Management
Corticosteroids, phenothiazines, and bromocriptine have been effective
in the treatment of patients with bronchial carcinoid tumors. The
mechanism of action of these agents is unknown. Cyproheptadine, a
serotonin antagonist, may control the flushing. Methysergide can
control the diarrhea but has no effect on flushing. Combined
administration of H1 and H2 receptor antagonists may prevent attacks
of flushing in patients with foregut carcinoid tumors that produce
histamine.10 Alpha-interferons may control symptoms of carcinoid
syndrome and produce objective biochemical responses (greater than 50%
suppression of 5-HIAA) that have a median duration of about 4 weeks.10
Since catecholamines are known to precipitate attacks, a trial of
clonidine is worthwhile. Somatostatin is a potent antagonist of the
flushing reaction associated with both gastric and ileal carcinoid
tumors but has a short half-life. The somatostatin analogue octreotide
has a much longer half-life, making subcutaneous therapy possible. It
must be given by subcutaneous injection one to three times a day and
should be titrated in increments of 50 µg every 8 hours.10 Octreotide
lowers plasma levels of serotonin and tachykinins and relieves both
flushing and diarrhea. Amelioration of these manifestations is
accompanied by a marked reduction in the urinary excretion of 5-HIAA.
10 Lanreotide, a long acting analogue of somatostatin administered
intramuscularly every 14 days, is effective at controlling the
flushing of carcinoids.11,12 A depot form of octreotide (Sandostatin
LAR) has been shown to control flushing at a dose of 20 mg
intramuscularly every month.13 Flushing may relapse with continued
treatment.9 The patient should receive an adequate niacin supplement
(nicotinamide rather than nicotinic acid, since the latter causes
flushing) and should avoid foods, agents, and activities that
precipitate symptoms.5

In some patients, failure of medical treatment may necessitate
carrying out hepatic artery embolization. This treatment is based upon
the dependence of metastatic malignant tissue but not healthy liver
parenchyma on an intact hepatic arterial blood supply. Anti-tumor
chemotherapy remains experimental. Alpha-interferon causes symptomatic
relief accompanied by lowering of urinary 5-HIAA. (For more discussion
on the treatment of carcinoid tumors, see Carcinoid Tumor.)

Prognosis
About one-fifth of patients with the carcinoid syndrome undergo a
protracted course. In the remainder, deterioration can be rapid. The
mean survival is about 8 years with some surviving up to 20 years.
Mean survival is 36 months after the first flushing episode.9

Mastocytoses:

Etiology
Mastocytoses are benign proliferative disorders of the
reticuloendothelial system and familial cases have been reported.
Mastocytoses are due to a hyperplastic rather than a neoplastic
process. They are often self-limited, especially in childhood (Table
6). Mast cells possess the enzyme histidine decarboxylase which
enables them to synthesize and store histamine. Other preformed
mediators include tryptase, chymase, and carboxypeptidase. Serotonin
has not been detected in human mast cells.14

Histopathology
There are increased numbers of normal-looking mast cells in the
dermis. These cells may be predominantly perivascular or may show a
nodular distribution. The epidermis is normal, apart from increased
melanization.14

Biochemical Markers
Symptoms of mastocytosis are mainly the result of release of products
of mast-cell activation. Plasma histamine levels are frequently raised
in patients with systemic symptoms, and elevated urinary excretion of
histamine and its metabolite methyl imidazole acetic acid (MIAA) can
also be seen. Plasma tryptase levels can also be elevated.
Prostaglandin D2 (PGD2) is another product of mast-cell activation.
Urinary excretion of this substance and its major metabolites can be
elevated several-fold in patients with mastocytoses. Urine should be
collected within a few hours of an attack.14

Clinical Presentation
Episodic bright-red flushing occurs either spontaneously or after
rubbing the skin or exposure to alcohol or mast-cell degranulating
agents. Flushing attacks may be accompanied by headache, dyspnea and
wheezing, palpitations, abdominal pain, diarrhea, and syncope and may
closely resemble the flushing episodes of the carcinoid syndrome,
especially the foregut variety, which are also mediated by histamine.
Rosacea may develop rarely. PGD2 might be associated with the symptoms
of flushing and diarrhea.14 The flushing of cutaneous mastocytosis
typically lasts more than 30 minutes, unlike the typical carcinoid
flush which lasts less than 10 minutes.5 In urticaria pigmentosa, the
diagnosis is established by demonstrating that gentle rubbing of the
lesional skin causes local itching, redness, and whealing (Darier's
sign). This reaction is due to local histamine release. Darier's sign
may also be demonstrated in nonlesional skin. Confirmation of the
diagnosis is obtained by skin biopsy. In patients with systemic
symptoms, bone-marrow biopsy and liver and spleen scans are usually
performed. Bone scans should only be carried out in the presence of
localized bone symptoms.5,14

Treatment
Treatment of nonlocalized forms of mastocytosis is mainly symptomatic.
Patients should avoid known histamine-degranulating agents.
Antihistamines remain the preferred treatment for most patients with
uncomplicated urticaria pigmentosa. Human skin blood vessels possess
H1 and H2 receptors, which are involved in both vasodilation and
increased vascular permeability evoked by histamine. Thus, combination
treatment with an H1 antihistamine (hydroxyzine, 10 to 20 mg) and H2
antihistamine (cimetidine, 200 to 500 mg) is logical and sometimes
effective at controlling the flushing episodes. Oral administration of
the mast-cell stabilizing agent disodium cromoglycate has proved
effective in some patients. The drug does not decrease urinary
excretion of histamine and the histamine metabolite MIAA. Some experts
recommend using this agent only in patients with systemic mastocytosis
suffering from gastrointestinal symptoms. Photochemotherapy has been
reported to cause symptomatic relief as well as objective reduction in
the population of mast cells and the urinary excretion of MIAA.14

Medullary Thyroid Carcinoma:

The range of substances secreted by medullary carcinoma of the thyroid
is considerable, whether sporadic or familial. Flushing is the most
common symptom after diarrhea. Occurring in one-third of the patients
with diarrhea, there is pronounced episodic flushing, which as in the
carcinoid syndrome may be induced by alcohol ingestion. Calcitonin-
gene related peptide, which is an extremely powerful peripheral
vasodilator, is the most likely mediator that causes flushing.5 The
other possible explanation is that calcitonin stimulates
prostaglandins which in turn cause the symptoms.12

Harlequin Syndrome:

This describes hemifacial flushing and sweating sometimes associated
with warmth and anhidrosis of the contralateral arm and leg (Figure 4)
. This may be induced by exercise. The suggested etiology is a lesion
involving both preganglionic or postganglionic cervical sympathetic
fibers and parasympathetic neurons of the ciliary ganglion.15
Harlequin syndrome has been described in patients with a contralateral
lung cancer invading the spine, Pancoast's syndrome, and Horner's
syndrome.5

Auriculotemporal Nerve Syndrome
(Frey's Syndrome):

This syndrome usually manifests as immediate unilateral or bilateral
flushing and/or sweating in the distribution of the auriculotemporal
nerve in response to gustatory or tactile stimuli. In adults, this
syndrome is a well recognized sequela of parotid surgery, trauma, or
infection. It occurs rarely in children, most often noted after the
introduction of solid food. The flushing is often attributed
erroneously to food allergy. It typically begins at 2 to 6 months of
age when solid foods, mostly fruit, are introduced. Occurring within a
few seconds of eating, it has a peculiar distribution in a triangular
area that extends from the tragus of the ear to the midpoint of the
cheek. It is not associated with sweating and persists for 20 to 60
minutes. The flushing continues to occur for up to 5 years. In adults,
gustatory sweating is the predominant feature of auriculotemporal
nerve syndrome; flushing happens less often. Half of the pediatric
patients with this symptom were delivered with forceps assistance
which possibly causes trauma to the nerve. The likely mechanism is
misdirection of parasympathetic fibers along sympathetic pathways
during the nerve regeneration that follows trauma. This may account
for erythema when eating. The emergence of symptoms several months
after the proposed trauma (usually 3 to 6 months) is probably related
to the time required for nerve regeneration, and it is possible that
vigorous chewing causes intense stimulation of the parotid gland.
Auriculotemporal nerve syndrome is benign in infants and does not tend
to worsen. Furthermore, the severity of the flushing tends to diminish
with age in most patients. The physician can reassure parents and
avoid unnecessary testing and maneuvers16 (Figure 5). A similar
syndrome can develop after facial herpes zoster.17


Figure 5

Flushing with Pseudocarcinoid Syndrome in Secondary Male Hypogonadism:

A series of three male patients with secondary hypogonadism has been
described where flushing was associated with elevated 24-hour urine 5-
HIAA. Flushing disappeared and 5-HIAA levels normalized after starting
testosterone enanthate treatment. Male patients with flushing and
increased urinary 5-HIAA levels should undergo assessment for
hypogonadism after screening for carcinoid tumor.18

Treatments that lower serum testosterone, such as orchiectomy or
luteinizing hormone-releasing hormone analogs, cause hot flushes in
over half of men. Lack of regulatory feedback in the hypothalamus from
circulating serum testosterone is the presumed mechanism. Most often,
hot flushes are only mildly bothersome and can be tolerated without
the need for treatment. However, if flushes are particularly annoying
or problematic, treatment should be offered. Small doses of
diethylstilbestrol are effective in relieving hot flushes but cause
gynecomastia. Megestrol acetate, at a dose of 20 mg bid, completely
eliminates hot flushes in most men, and the dose can be progressively
lowered in some.19

Other Diseases Causing Episodic Flushing:

Cheung et al20 have described a family with monoamine oxidase
deficiency causing episodes of flushing affecting the face and chest
precipitated by emotion or certain foods, followed by diarrhea,
headaches, and sometimes palpitations. Blood serotonin levels in this
family were elevated secondary to decreased activity of monoamine
oxidase. Sertraline hydrochloride controlled the symptoms by depleting
platelet serotonin.

Flushing is rare in patients with pheochromocytoma. If flushing occurs
at all, it is seen after a paroxysm of hypertension, tachycardia,
palpitations, chest pain, severe throbbing headaches, and excessive
perspiration. Pallor is typically present during the attack, and mild
flushing may occur after the attack as a rebound vasodilation of the
facial cutaneous blood vessels.5 Facial flushing and headache can
happen along with sweating of the face, neck, and upper trunk in
patients with spinal cord lesions above T-6. This may occur as an
exaggerated response to bowel or bladder distention.1 Other causes are
certain pancreatic tumors, insulinoma, and POEMS (polyneuropathy,
organomegaly, endocrinopathy, monoclonal proteinemia, and skin
changes). Transient flushing of the face, chest, or arms has been
noted after neurological deterioration secondary to rapid rise in
intracranial pressure.21
ROSACEA

Persistent flushing from whatever cause may eventually lead to
rosacea. The lesions of rosacea that initially occur in the central
convex areas of the face consist of papules and pustules against a
background of erythema, telangiectasia, edema, and eventual permanent
induration or thickening of affected skin.2 Patients with severe
flushing due to mastocytosis can develop rosacea in less than a year
after the onset of flushing episodes.5
EVALUATION OF THE PATIENT WITH
A FLUSHING DISORDER

It is important to consider the clinical characteristics of the
flushing before embarking on expensive laboratory evaluation.5 The
physician should consider four clinical characteristics in the initial
evaluation of a patient with flushing: 1) provocative and palliative
factors, 2) morphology, 3) associated features, and 4) temporal
characteristics.2
Provocative or palliative factors: Certain agents that trigger the
flush suggest an underlying systemic disease as the cause for the
flushing, eg, mastocytosis and carcinoid syndrome. Morphology: Is
there a basic feature that comes and goes? Is the redness patchy or
confluent? What is the color of the flush? Is there cyanosis? Is the
flushing preceded or followed by pallor?2 The morphology of the
flushing may suggest not only the cause of the flushing but also, in
the case of carcinoids, the anatomic origin of the disorder.5
Associated features: These may include respiratory symptoms,
gastrointestinal symptoms, headache, urticaria, facial edema,
hypertension, hypotension, palpitations, or sweating. Temporal
characteristics: These are the frequency of the flushing and the
timing of the specific features during each flushing reaction.
Important information can be obtained from a 2-week diary in which the
patient records qualitative and quantitative aspects of the flushing
event and lists exposure to all exogenous agents.2 When the diagnosis
remains obscure after evaluation of the 2-week diary, the patient is
given an exclusion diet listing foods high in histamine, foods and
drugs that affect urinary 5-HIAA tests, and foods and beverages that
cause flushing. If the flushing reactions completely disappear,
restoring the excluded items individually can identify the causative
agent. If the flushing reactions continue unchanged, then further
metabolic work up may be undertaken.5

Return to Medicine Index
REFERENCES
Greaves MW. Flushing and flushing syndromes, rosacea and perioral
dermatitis. In: Champion RH, et al, eds. Rook/Wilkinson/Ebling
textbook of dermatology, 6th ed., volume 3. Oxford, UK: Blackwell
Scientific, 1998:2099-2104.


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