Transcript Pruritus
Pruritus Pruritus, or itch, is defined as an unpleasant sensation that provokes the desire to scratch. Generalized pruritus may be classified into the following categories on the basis of the underlying causative disease: renal pruritus, cholestatic pruritus, hematologic pruritus, endocrine pruritus, pruritus related to malignancy, and idiopathic generalized pruritus. The sensation of pruritus is transmitted through slow-conducting unmyelinated C- and possibly type A delta nociceptive neurons with free nerve endings located near the dermoepidermal junction or in the epidermis. Activators of these nerves include histamine, neuropeptide substance P, serotonin, bradykinin, proteases (eg, mast cell tryptase), and endothelin (which stimulates the release of nitric oxide). Impulses are transmitted from the dorsal root ganglion to the spinothalamic tract. Opioids are known to modulate the sensation of pruritus, both peripherally and centrally. 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. Other theories include elevated levels of circulating histamine in patients receiving HD. Researchers have found increased numbers of mast cells in various organ systems. Parathyroid hormone (PTH) levels are commonly elevated in persons with CRF. Elevated levels of divalent ions, such as calcium, magnesium, and phosphate, are thought to play a role. Marked improvement of pruritus resulting from low dialysate calcium and magnesium concentrations has been reported Decreased transepidermal elimination of pruritogenic substances, xerosis, elevated levels of serum bile acids, and increased epidermal vitamin A levels all may contribute to the condition. Elevated serum levels of serotonin are seen in patients with CRF. Serotonin is important in the transmission of pain and may be a contributing factor. Pruritus in CRF also may be a possible manifestation of peripheral neuropathy. Opioid accumulation may contribute to itching in persons with CRF and overexpression and activation of opioid mu receptors. Mixed results with the use of opioid antagonists in the treatment of renal pruritus have led to conflicting opinions about the role of opioids. An immune hypothesis has also been suggested. In patients with CRF, a systemic inflammatory response involving overexpression of activated type 1 helper T lymphocytes (which secrete interleukin 2) may induce pruritus. UV-B, thalidomide, and tacrolimus all target mediators of this inflammation. Elevated ferritin and low transferrin and albumin levels have been correlated with the severity of pruritus. 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. In addition, indirect hyperbilirubinemia does not induce pruritus. Other theories implicate elevated venous histamine levels, retention of pruritogenic intermediates in bile salt synthesis, and high hepatic concentrations of bile salts resulting in hepatic injury and release of a pruritogenic substance. Rifampin and ursodeoxycholic acid decrease intrahepatic concentrations of bile salts and provide some relief of cholestatic pruritus. The accumulation of endogenous opioids, which modulate pruritus and increase opioidergic tone in the brain, is of recent interest because opioid antagonists have been shown to partially relieve cholestatic pruritus. Hematologic pruritus 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 vera have increased numbers of circulating basophils and skin mast cells, which have been correlated with itching. The itch typically occurs during cooling after a hot shower. Endocrine pruritus 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 Release of toxins and the immune system have been suggested to play roles in malignancy-related pruritus. In patients with Hodgkin disease, leukopeptidase and bradykinin appear to be the pruritogenic mediators released as an autoimmune response is mounted against malignant lymphoid cells. Carcinoid syndrome may be associated with pruritus triggered by serotonin. An underlying systemic disease is reported in 10-50% of patients who seek medical attention for pruritus. The incidence of renal pruritus appears to be decreasing among patients receiving HD, most likely because of improvements in HD technique. Although previous data showed that as many as 85% of patients on HD are affected, new reports suggest the rate is 2266%. Approximately 60% of patients with primary biliary cirrhosis present with pruritus. Among patients with polycythemia vera, 4870% of patients have aquagenic pruritus. Hyperthyroidism is the most common cause of endocrine pruritus. The rate is 4-11%, and the condition is especially prevalent in patients with untreated Graves disease. The rate of malignancy in patients presenting with generalized pruritus is less than 1-8%. Pruritus is commonly associated with Hodgkin disease and was once considered a B symptom of the disease. History Primary dermatologic disorders can cause pruritus, and these must be excluded before a systemic cause is considered. 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. Renal pruritus Symptoms range from paroxysmal discomfort that may remit spontaneously to continuous itching that is present day and night. Pruritus is localized in 56% of patients and is most often seen on the back, abdomen, head, and shunt arms. The remaining patients usually present with generalized pruritus. Cholestatic pruritus Cholestatic pruritus is characterized by an intermittent, mild, and insidious onset that may be generalized or localized. Pruritus is typically worse on the hands and feet and in areas under tight-fitting clothing. Pruritus and fatigue are commonly the presenting symptoms of patients with primary biliary cirrhosis. Hematologic pruritus Although hematologic pruritus related to iron deficiency remains controversial, the pattern that has been described is most often generalized; however, it may be localized, especially to the perianal and vulvar regions. Patients with polycythemia vera may have aquagenic pruritus (after a hot bath or shower) with a prickly sensation, but this is not specific. Endocrine pruritus In most patients, endocrine pruritus is generalized. Pruritus associated with diabetes mellitus is another controversial association. The described pruritus is often localized to the vulva or anus and usually is due to candidal or dermatophytic infection. However, unrelenting pruritus of the scalp is reported in association with diabetes mellitus. Pruritus and malignancy 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. It is most common in patients with Hodgkin disease (nodular sclerosing subtype). 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. Physical Renal pruritus: Diffuse xerosis and halfand-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. Hematologic pruritus may be seen in association with the following conditions: Iron deficiency Polycythemia rubra vera Hypereosinophilic syndrome Essential thrombocythemia Myelodysplastic syndrome Endocrine pruritus may be seen in association with the following disorders: Hyperthyroidism Hypothyroidism Diabetes mellitus Hyperparathyroidism Hypoparathyroidism The following malignancies are known to have the potential to cause itching: Hodgkin disease Non-Hodgkin lymphoma Leukemias Paraproteinemias and myeloma Carcinoid syndrome Sipple syndrome (multiple endocrine neoplasia) Solid tumors, including GI malignancies, CNS tumors, and lung cancer. A variety of other systemic disorders are associated with pruritus, including the following: Drug-induced pruritus without a rash Mastocytosis HIV infection and AIDS Sarcoidosis Eosinophilia-myalgia syndrome Dermatomyositis Scleroderma Systemic lupus erythematosus Sjögren syndrome Neurofibromatosis Hemochromatosis 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) Leptospirosis Primary cutaneous amyloidosis Starvation Fibromyalgia Chronic fatigue syndrome Notalgia paresthetica Adrenergic conditions (adrenergic pruritus) Cholinergic conditions (cholinergic pruritus) Laboratory Studies When a primary dermatologic condition is excluded and a systemic cause is suspected, certain laboratory tests may aid diagnosis. If suspicion is low concerning a systemic disease, a 2-week trial of therapy with oilated soap for bathing, emollients for after the bath, and oral antihistamines may be attempted. If this fails, a laboratory evaluation is indicated. CBC count with differential. Serum creatinine and blood urea nitrogen values. Serum alkaline phosphatase and bilirubin, direct and indirect. Thyrotropin and thyroxine: The results assist in ruling out hypothyroidism and hyperthyroidism. Fasting glucose value, if prompted by signs or symptoms Stool for occult blood in patients aged 40 years or older: A positive result suggests possible malignancy in the GI tract. HIV antibody test, if risk factors are present Skin biopsy for routine pathology and immunofluorescence to exclude subacute occult autoimmune conditions such as pemphigoid and dermatitis herpetiformis. Medical Care The treatment for pruritus of systemic disease varies depending on the underlying etiology. However, without eradication of the underlying systemic disease, treatment is often palliative at best and can be frustrating for both the patient and physician. Certain therapies, such as antihistamines and emollients, offer marginal benefit. Renal pruritus Physical therapy with UV-B therapy is a treatment of choice. Patients have reported months of remission after 6-8 treatments. UV-B reduces cutaneous phosphorus, decreases the number of dermal mast cells, and reduces epidermal vitamin A levels. However, UV-B treatment increases the risk of nonmelanoma skin cancer Capsaicin 0.025% cream is effective for localized pruritus due to CRF, as has been shown in doubleblinded, placebo-controlled studies. Tacrolimus 0.03% ointment has shown promising results for localized renal pruritus in a prospective study, but randomized placebo-controlled studies are needed. Tacrolimus is a calcineurin inhibitor, it decreases the differentiation of type 1 helper T lymphocytes, and it reduces the production of interleukin 2. Erythropoietin. Thalidomide. Cholestatic pruritus Cholestyramine is the first-line therapy, followed by rifampin and opioid antagonists. Rifampin, a hepatic enzyme inducer, is effective for pruritus of cholestasis. Naloxone, may relieve pruritus, but intravenous administration limits its use outside the hospital setting. Oral naltrexone is also effective. Hematologic pruritus Iron deficiency responds to treatment with iron, which should be continued until ferritin levels are normalized. Patients with pruritus due to polycythemia vera may benefit from aspirin, which is considered the first-line therapy. Cimetidine, danazol, cholestyramine, UV-B light therapy, and psoralen with UV-A therapy have all been shown to help. Endocrine The pruritus pruritus of hypothyroidism is secondary to xerosis and should be treated with emollients and thyroid hormone replacement. Pruritus secondary to hyperthyroidism improves with the correction of thyroid function.