eMedicine Specialties > Dermatology > Internal Medicine

Pruritus and Systemic Disease

Author: David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic
Coauthor(s): Jared J Lund, MD, Dermatology Resident, Department of Dermatology, Marshfield Clinic, St Joseph's Hospital
Contributor Information and Disclosures

Updated: Jan 22, 2009

Introduction

Background

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: renal pruritus, cholestatic pruritus, hematologic pruritus, endocrine pruritus, pruritus related to malignancy, and idiopathic generalized pruritus.

Pathophysiology

The sensation of pruritus is transmitted through slow-conducting unmyelinated C-polymodal and possibly type A delta nociceptive neurons with free nerve endings located near the dermoepidermal junction or in the epidermis. These neurons appear to be located more superficially and are more sensitive to pruritogenic substances than pain receptors. Activators of these nerves include histamine, neuropeptide substance P,¹ 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. Stimulation of opioid mu receptors accentuates pruritus, while stimulation of kappa receptors and blockage of mu receptors suppress pruritus.

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. Pruritus is relatively absent in persons with acute renal failure; therefore, serum mediators other than urea and creatinine are implicated.

Other theories include elevated levels of circulating histamine in patients receiving HD. Researchers have found increased numbers of mast cells in various organ systems. However, antihistamines are, at best, marginal in the treatment of renal pruritus, suggesting other causative factors.

Parathyroid hormone (PTH) levels are commonly elevated in persons with CRF.¹ Dramatic relief of renal pruritus after subtotal parathyroidectomy has been described, and findings from 1 study confirmed previous case reports. However, other studies have shown no correlation between circulating PTH levels and the intensity of pruritus. Of note, a patient with a PTH-producing bronchogenic carcinoma was reported to have intractable pruritus as the presenting symptom.^2,3,4

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.^5,6 Increased amounts of these ions are also seen in the skin of pruritic patients.

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.

Proliferation of nonspecific enolase-positive sensory nerves in the epidermis has been documented in patients with uremia and may contribute; however, these results must be confirmed.

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, but this theory has been proven incorrect. 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. In support of the last point, 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. In support of this theory, treatment with opioid antagonists may induce an opioid withdrawal–like syndrome.

Perhaps some combination of the pruritogenic substances mentioned above (ie, bile salts, histamine, opioids) induces cholestatic pruritus.

Hematologic pruritus

Iron is a critical factor in many enzymatic reactions. Although iron deficiency has not been proved to be a cause of pruritus, it may contribute to pruritus through a variety of metabolic paths. 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. Mast cell prostaglandins and increased platelet degranulation, which lead to the release of serotonin and prostanoids, are thought to be important mediators of itching, along with iron deficiency, which may be a contributing factor.

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

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.

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.

Frequency

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.

International

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 22-66%. Pruritus appears to affect up to 30% of patients with severe chronic renal insufficiency who are not undergoing dialysis.

The incidence of cholestatic pruritus depends on the underlying etiology. Approximately 60% of patients with primary biliary cirrhosis present with pruritus, and almost all develop pruritus at some point during the course of their disease.

Among patients with polycythemia vera, 48-70% of patients have aquagenic pruritus. Pruritus associated with iron deficiency is uncommon. 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. Pruritus is rare in patients with diabetes mellitus and hypothyroidism.

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. Approximately 35% of patients with Hodgkin disease have pruritus during their clinical course, whereas only approximately 10% have pruritus associated with non-Hodgkin lymphoma. Pruritus is a rare symptom of leukemia.

Mortality/Morbidity

Pruritus causes significant morbidity. Some conditions that cause systemic pruritus appear to be associated with an increased mortality rate.

• In patients receiving HD, renal pruritus is an independent marker for mortality at 3 years.
• Patients with severe, generalized pruritus associated with Hodgkin disease have significantly shorter survival than those with mild or no pruritus.

Sex

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

• Certain causes of cholestasis are more common in women than in men. These include primary biliary cirrhosis (90% of patients are women) and cholestasis of pregnancy. 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. Most patients initially present with fatigue and pruritus, and any women presenting with these symptoms should be suspected to have primary biliary cirrhosis. A positive antimitochondrial antibody finding has 98% specificity for the disease.
• When an older man presents with generalized pruritus and iron deficiency but not anemia, the physician should 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.

Age

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

Clinical

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.

A review of systems is needed to uncover signs and symptoms associated with systemic disease and to direct the physical examination and laboratory evaluation. 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.

• Renal pruritus
  • Symptoms range from paroxysmal discomfort that may remit spontaneously to continuous itching that is present day and night.
  • Approximately 46% of patients have pruritus on a daily basis, whereas 52% report it as appearing weekly or monthly.
  • 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.
  • The vertex of the scalp is a common site of pruritus, and excoriations may be present.
  • Exacerbations are common at night and during or just after HD. The intensity may also increase during summer months.
• 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.
  • Associated symptoms of inflammatory bowel disease may be present in patients with primary sclerosing cholangitis.
• 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. Aquagenic pruritus may occur within minutes of contact with water. However, it 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
  • In most patients, endocrine pruritus is generalized and associated with symptoms of the underlying disease process (eg, hyperthyroidism vs hypothyroidism).
  • 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
  • The symptoms of pruritus may differ in patients with lymphoma compared with symptoms in patients with carcinoma.
  • 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. If localized, the pruritus is commonly present in the areas drained by the lymphatics affected in the disease process.
  • Leukemic pruritus is usually generalized at onset and is less severe than that related to lymphoma.

Physical

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.

Causes

• Renal pruritus occurs in patients with CRF, most often those receiving HD. The exact cause is not known, although toxic substances retained during HD, histamine, opioids, and neural proliferation have been postulated as potential causes.
• The exact mechanism of cholestatic pruritus is not known. However, bile salts, histamine, opioids, and an unknown pruritogen from damaged hepatocytes are postulated as potential causes.
  • Cholestatic pruritus is particularly common with cholestasis caused by primary biliary cirrhosis, primary sclerosing cholangitis, chronic hepatitis C, choledocholithiasis, obstructive carcinoma of the pancreas/biliary system, cholestasis of pregnancy, and end-stage liver disease of any cause.
  • Drug-induced cholestasis may be caused by chlorpropamide, tolbutamide, phenothiazines, erythromycin, anabolic steroids, and oral contraceptives.
• 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)
  • Parvoviral infection
  • Leptospirosis
  • Chemical intoxication with mercury or diamino diphenylmethane
  • Primary cutaneous amyloidosis
  • Starvation
  • Fibromyalgia
  • Chronic fatigue syndrome
  • Dumping syndrome
  • Notalgia paresthetica
  • Adrenergic conditions (adrenergic pruritus)
  • Cholinergic conditions (cholinergic pruritus)

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