Refractory Pruritus 




Pruritus, or itch, is defined as an unpleasant sensation that provokes the desire to scratch. Certain systemic diseases have long been known to cause pruritus that ranges in intensity from a mild annoyance to an intractable, disabling condition. Generalized pruritus may be classified into the following categories on the basis of the underlying causative disease: 

a.        renal pruritus 

b.       cholestatic pruritus 

c.        hematologic pruritus 

d.       endocrine pruritus 

e.       pruritus related to malignancy 

f.         idiopathic generalized pruritus

Primary dermatologic disorders can cause pruritus, and these must be excluded before a systemic cause is considered. (be sure to exclude dermatitis herpetiformis). Therefore, a thorough history, including the onset, duration, severity, location, provoking factors, time relation, and relationship to activities such as bathing should be discussed with the patient who presents with pruritus. 

 A detailed drug history is required to exclude medications that can cause itching. A history of alcohol abuse may indicate chronic liver disease. A review of potential emotional stresses and mental health history may reveal a psychiatric cause.

Clues supporting a systemic cause include the insidious onset of generalized pruritus rather than an acute presentation.


Physical examination assists in differentiating between systemic causes of pruritus and primary dermatologic conditions. When systemic disease underlies pruritus, patients may have normal-appearing skin or secondary lesions, such as excoriations, prurigo nodules, lichen simplex chronicus, or signs of a secondary bacterial infection. Patients may have the butterfly sign, which is an area of relative hypopigmentation or normal skin on the middle of the back in combination with areas of postinflammatory hyperpigmentation in locations accessible to the patient's hands. Other signs of systemic disease are as follows:

         Renal pruritus: Diffuse xerosis and half-and-half nails may be seen. The patient may have signs of peripheral neuropathy and uremia. 

         Cholestatic pruritus: Signs of liver disease include jaundice, spider angiomata, Dupuytren contractures, white nails, gynecomastia in men, xanthelasma, splenomegaly, and ascites. 

         Endocrine pruritus: Patients with hypothyroidism have brittle nails and dry, course skin and hair. Patients with hyperthyroidism may have warm, smooth, and fine skin. They may also have chronic urticaria and angioedema. Other signs are fever, tachycardia, exophthalmos (associated with Grave disease), and atrial fibrillation. 

         Hematologic pruritus: Patients with iron deficiency may have pallor if they have anemia; they might also have glossitis and angular cheilitis. Polycythemia vera may result in a ruddy complexion around the lips, cheeks, nose, and ears, along with hypertension and splenomegaly. 

         Pruritus and malignancy: Patients with Hodgkin disease may have ill-defined hyperpigmentation of the skin, ichthyosis, nontender lymphadenopathy, and splenomegaly.


Renal pruritus

Renal pruritus can occur in patients with chronic renal failure (CRF) and is most often seen in patients receiving hemodialysis (HD). This term is synonymous with uremic pruritus; however, the condition is not due to elevated serum urea levels. The actual pruritogenic substance has yet to be identified 


Cholestatic pruritus

Cholestasis, or a decrease or arrest in the flow of bile, is associated with pruritus. The deposition of bile salts in the skin was thought to directly cause a pruritogenic effect, but this theory has been proven incorrect. In addition, indirect hyperbilirubinemia does not induce pruritus.  

Primary biliary cirrhosis is thought to be an autoimmune disease that causes destruction of the small and medium bile ducts, leading to cholestasis. It most often occurs in women in the fourth or fifth decade of life, but it can occur in women as young as 20 years of age.  Any women presenting with fatigue and pruritus should be suspected to have primary biliary cirrhosis. A positive antimitochondrial antibody finding has 98% specificity for the disease.  Pruritus is typically worse on the hands and feet and in areas under tight-fitting clothing

Hematologic pruritus

Hematologic pruritus may be seen in association with the following conditions:

         Iron deficiency 

         Polycythemia rubra vera 

         Hypereosinophilic syndrome 

         Essential thrombocythemia 

         Myelodysplastic syndrome

Patients with pruritus and iron deficiency may not be anemic; this observation suggests that pruritus may be related to iron and not hemoglobin.

Patients with polycythemia HYPERLINK ""  HYPERLINK ""vera have increased numbers of circulating basophils and skin mast cells, which have been correlated with itching. Patients with polycythemia vera may have aquagenic pruritus (after a hot bath or shower) with a prickly sensation, but this is not specific. Aquagenic pruritus may precede the development of the disease by several years. Patients may report headache, visual disturbances, weight loss, night sweats, and vertigo. Other symptoms include redness, warmth, and pain (erythromelalgia) of the digits.

Endocrine pruritus

Endocrine pruritus may be seen in association with the following disorders:



         Diabetes mellitus 



Hyperthyroidism has been associated with pruritus. Excess thyroid hormone may activate kinins from increased tissue metabolism or may reduce the itch threshold as a result of warmth and vasodilation.

Hypothyroidism is also implicated because pruritus is likely secondary to xerosis.

Diabetes mellitus is another possible cause, but cause and effect remain unproven. Metabolic abnormalities, autonomic dysfunction, anhydrosis, and diabetic neuropathy all may contribute.


Pruritus and malignancy

The following malignancies are known to have the potential to cause itching:

         Hodgkin disease 

         Non-Hodgkin lymphoma 


         Paraproteinemias and myeloma 

         Carcinoid syndrome 

         Sipple syndrome (multiple endocrine neoplasia) 

         Solid tumors, including GI malignancies, CNS tumors, and lung cancer

Numerous reports have linked pruritus to almost every type of malignancy. Release of toxins and the immune system have been suggested to play roles in malignancy-related pruritus.

When an older man presents with generalized pruritus and iron deficiency but not anemia, consider the possibility of cancer, and routine screening tests (eg, fecal occult blood test, serum ferritin test, and urinalysis) may assist in diagnosing the cancer. 

Pruritus due to carcinoma results in moderate-to-severe itching with changes in intensity and location over the course of the disease. Common sites are the extensor surfaces of the upper extremities and the anterior surfaces of the lower legs. Pruritus of the nostrils has been associated with brain tumors.

 Pruritus due to lymphoma may precede the diagnosis by 5 years. The pruritus is described as intolerable, continuous, and severe and is accompanied by a burning sensation. It may begin on the lower extremities and progress to the whole body

Leukemic pruritus is usually generalized at onset and is less severe than that related to lymphoma.

Pruritus and Neural Pathway

Peripheral and Central Sensitization result in abnormal neural pathway in that area that causes the itch scratch cycle


Psychogenic/Neurogenic Pruritus

         Excessive impulse to scratch, gouge or pick at skin in the absence of dermatologic cause

         Predominantly female with average age of onset between 30 and 45 years.

         Associated psychiatric disorders: depression, obsessive-compulsive disorder, anxiety, somatoform disorders, mania, psychosis and substance abuse


         Consider psychogenic itch in patients who have recurring physical symptoms and demand an examination despite repeated negative results

         Consider acute psychological factors: loss of a loved one, unemployment, relocation, social or professional issues, and marked preoccupation with itching of his/her skin

         Skin changes are found on areas accessible to the patient's hand (face, arms, legs, abdomen, thighs, upper back and shoulders)

         Changes range from discrete superficial excoriations, erosions, and ulcers, to thick, darkened nodules and colorless atrophic scars

         Burning is a common complaint


Other Causes of Pruritus

A variety of other systemic disorders are associated with pruritus, including the following:

         Drug-induced pruritus without a rash 


         HIV infection and AIDS 


         Eosinophilia-myalgia syndrome 

         Autoimmune (Dermatomyositis, Scleroderma ,Systemic lupus erythematosus,Sjögren syndrome, Fibromyalgia, Chronic Fatigue Syndrome) 

         Notalgia paresthetica(pruritus of mid back)

         Brachio Radial Neuropathy(pruritus down arm)

         Meralgia Paresthetica(pruritus of anterolateral thigh)

         Chemical intoxication with mercury or diamino diphenylmethane 

         Primary cutaneous amyloidosis 


         Multiple sclerosis 

         Brain abscess 

         Parasitic infections, including those due to hookworms, pinworms, Trichinella spiralis (trichinosis), Gnathostoma spinigerum (gnathostomiasis), Giardia species, Ascaris species (ascariasis), or Onchocerca species (onchocerciasis) 

         Parvoviral infection 



United States

Pruritus occurs in approximately 20% of adults. It is present in approximately 25% of patients with jaundice and in 50% of patients receiving renal dialysis.


The sex of the patient does not seem to be associated with pruritus in systemic diseases.


Pruritus is more common in elderly people. Age is not related to the development of pruritus in systemic disease.



         Pruritic Panel:CBC with diff, CMP, TSH, ESR(sed rate), ANA screen, HIV screen, IGE

         If eosinophils elevated without a diagnosis, repeat monthly.  

         If eosinophils remain elevated:  

a.        check for lymphadenopathy 

b.       SPEP with immunofixation electrophoresis

c.        UPEP  

d.       If above negative, discuss with PCP so that all cancer screenings completed.

         Women over 20 years of age, Antimicrobial antibody to rule out Primary Biliary Cirrhosis

         Anti-IgE Antibody, Triptase (**QUEST ONLY)

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