Flushing

Flushing describes episodes of redness of the skin together with a sensation of warmth or burning of the face, neck and, less frequently, the upper trunk. It is the transient nature of the attacks that distinguishes flushing from the more protracted erythema of photosensitivity or contact allergic dermatitis. Flushing can be an exaggeration of a physiological process or much less likely a manifestation of a serious condition that needs to be identified and treated.

This chapter is set out as follows:

Evaluation of the flushing patient

It is important to consider the clinical characteristics of the flushing before embarking on expensive laboratory evaluation.

• The vast majority of cases of flushing are benign, including physiological, menopausal, rosacea and the Dumping syndrome (post-gastric surgery)
   
• Numerous drugs can cause flushing
   
• Serious causes of flushing are rare, but the clinician needs to be familiar with the red flags, which include:
  • Food and alcohol - although food and alcohol can themselves causing flushing, and aggravate the symptoms of rosacea, they can also trigger flushing in the Carcinoid syndrome and medullary thyroid carcinoma
  • Nature of the flushing
    • ​Flushing in the carcinoid syndrome may be more widespread, sometimes involving the whole body. In some cases patients develop a fixed cyanotic erythema
    • Hemifacial flushing and sweating can occur in patients with contralateral lung cancer invading the spine, Pancoast’s syndrome, and Horner’s syndrome
  • Associated features - a malignant cause may be associated with systemic symptoms such as diarrhoea, wheeze, headache, urticaria, facial oedema, hypertension, hypotension, palpitations, or sweating
     
• The full list of conditions that cause flushing is found below in the section on clinical findings

Physiological flushing (blushing)

• Embarrassment or stress may cause flushing in some individuals in whom the threshold for this response may be low, or the reaction itself unusually intense
• Overheating, such as after exercise, can cause physiological flushing because of the effect of the rise in blood temperature on the thermoregulatory centre in the anterior hypothalamus. A similar mechanism is responsible for facial flushing caused by hot drinks. Additionally, overheating can lower the threshold to flushing from other causes, such as the menopause

Menopausal flushing 

• The majority of postmenopausal women experience flushing associated with sweating, each hot flush lasts for 1-5 minutes
• Certain characteristics suggest the diagnosis of climacteric flushing, such as 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 
• About 65% of postmenopausal women have hot flushes for 1-5 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
• Pharmacological menopause with flushing can be induced by various drugs including 4-hydroxyandrostenedione, danazol, tamoxifen, clomiphene citrate, and leuprolide. Similar symptoms may also occur in men with prostate cancer receiving treatment with gonadotropin-releasing hormone analogues such as buserelin  

Rosacea

• The onset of rosacea is often preceded by a history of episodic flushing
• Rosacea mainly affects the central face (forehead, nose, cheeks and chin) with sparing of peri-oral and peri-orbital skin
• Erythema is initially intermittent but becomes more permanent
• Over time telangiectases develop, which can be the case in long-term flushing of any cause 
• Many, but not all, patients have papules and pustules, with absence of open comedones (blackheads)  

Drugs

Many drugs can cause flushing including:

• All vasodilators 
• All calcium-channel blockers
• Cholinergic drugs
• Sildenafil citrate
• Morphine and other opiates
• Nicotinic acid (not nicotinamide)
• Amyl nitrite and butyl nitrite
• Tamoxifen
• Cyproterone acetate
• Gonadotropin-releasing hormone analogues
• Bromocriptine used in Parkinson’s disease
• Thyrotropin-releasing hormone (TRH)
• Ciclosporin
• Rifampicin  

Food and alcohol

• Food - eating spicy or sour foods, nitrites and sulfites (additives in many foods), thermally hot foods and beverages can cause facial flushing. This gustatory flushing is caused by a neural reflex involving autonomic neurons carried by the branches of the trigeminal nerve
• Alcohol - Asians with certain genotypes show extensive flushing in response to low quantities 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
• Both food and alcohol ingestion can also trigger flushing in carcinoid tumours and medullary thyroid carcinoma  

Dumping syndrome

• Dumping syndrome is a frequent complication of oesophageal, gastric or bariatric surgery
• There is rapid gastric emptying, with the delivery to the small intestine of a significant proportion of solid food as large particles that are difficult to digest. This causes excessive intravascular fluid to move to the intestinal lumen, which results in cardiovascular symptoms, release of several gastrointestinal and pancreatic hormones and late postprandial hypoglycaemia
• Symptoms include fatigue, abdominal pain, vomiting, severe diarrhoea, sweating and flushing  

Carcinoid syndrome

• Carcinoid syndrome describes the manifestations of some carcinoid tumours - flushing, bronchoconstriction, gastrointestinal hypermotility, and cardiac disease. Carcinoid tumours are neuroendocrine tumours derived from a primitive stem cell that may differentiate in to any of various adult endocrine-secreting cells, producing peptides, hormones, and neurotransmitters
• The annual incidence is 1.5 per 100,000 population
• The average age of patients is 50 years, there is no gender predominance 
• The condition may be difficult to diagnose at an early stage, as flushing is typically provoked by common triggers of physiological flushing such as emotional stress, spicy food, exercise or alcohol 
• With time, the flushing may appear without provocation
• Paroxysmal flushing is present in virtually all cases; episodes typically last a few minutes and may be more widespread than other causes of flushing, sometimes involving the whole body. Nearly 75% of carcinoid tumours are gastrointestinal (especially involving the appendix and ileum), 25% are bronchial, and a small number arise at other sites including the larynx, pancreas, gallbladder and ovary. Flushing is described as varying according to the site of the neoplasm. The most common midgut tumours (appendix and ileum) are associated with a gradual development of fixed cyanotic erythema in the flushing distribution, whereas foregut tumours (stomach, pancreas, lung) are associated with a brighter pink flush
• Flushing may be associated with facial oedema, which may persist and lead to telangiectasia 
• Other symptoms, such as diarrhoea, abdominal pain, dyspnoea, wheezing and occasionally syncope, may occur with progression of the tumour, usually not occurring until liver metastases have developed
• With extensive disease, pellagra-like skin lesions can also be seen  

Phaeochromocytoma

• A phaeochromocytoma is a rare, catecholamine-secreting tumour that may precipitate life-threatening hypertension
• The classic history of a patient with a phaeochromocytoma includes spells characterised by headaches, palpitations, and sweating. Flushing is not a common feature  

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 diarrhoea. The flushing is episodic, and, as in the carcinoid syndrome, may be induced by alcohol ingestion  

Harlequin syndrome

• This describes hemifacial flushing and sweating sometimes associated with warmth and anhidrosis of the contralateral arm and leg. This may be induced by exercise
• The suggested cause is a lesion involving preganglionic or postganglionic cervical sympathetic fibres and parasympathetic neurons of the ciliary ganglion
• Harlequin syndrome has been described in patients with a contralateral lung cancer invading the spine, Pancoast’s syndrome, and Horner’s syndrome  

Auriculotemporal Nerve syndrome (Frey’s syndrome)

• This syndrome usually manifests as immediate unilateral or bilateral flushing, or sweating, in the distribution of the auriculotemporal nerve, in response to gustatory or tactile stimuli
• In adults this syndrome is a well-recognised sequela of parotid surgery, trauma, or infection
• It occurs rarely in children, most often noted after the introduction of solid food

• Most patients with flushing do not require investigations
   
• If an underlying systemic disorder is suspected a detailed history and clinical examination should help to direct further work‐up. Investigations may include:

• Bloods - FBC, U+E, LFT, bone biochemistry, glucose and TFT

• 24hr urine tests
• A 24hr urinary 5‐hydroxyindoleacetic acid (5‐HIAA) for suspected carcinoid syndrome
• A 24hr urinary fractionated metanephrines for suspected phaeochromocytoma 
• Please contact your local pathology department, or refer to the Imperial Centre for Endocrinology website, for advice on 24hr urine collections including foods that need to be avoided prior to sample collection

• CXR 

• Reduce / avoid known triggers such as dietary factors and alcohol

• Stop / reduce the dose of any medication that may be causing the flushing, if possible  

• Low‐dose β‐blocker therapy may be useful in some patients with either flushing or blushing. Nonselective β‐blockers decrease sympathetic activity, thereby resulting in vasoconstriction. In addition, their anxiolytic effects may reduce the anxiety that contributes to blushing in some of these patients. Both propranolol (30–120 mg/day) and carvedilol (titrated from 3.25 mg three times a day to 25 mg/day) have been shown to improve symptoms in some patients

• Condition-specific treatment
  • Menopause - treatment options include HRT, clonidine and naloxone
  • Rosacea - refer to the rosacea chapter