Pruritus and Systemic Disease

Pruritus 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.

Pruritus, or itch, is most commonly associated with a primary skin disorder such as xerosis, atopic dermatitis, drug eruption, urticaria, psoriasis, arthropod assault, mastocytosis, dermatitis herpetiformis, or pemphigoid. However, when a primary skin condition cannot be identified as the cause of pruritus, then a systemic or neuropathic cause must be sought. Patients without signs of a primary skin condition should undergo a thorough evaluation of potential systemic causes of itching.

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 and eventually to the thalamus. ^[2]

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.

In the mouse model that mimics atopic dermatitis in humans, the histamine (H4) receptor mediates both TH-2 inflammation and pruritus. ^[3] A variety of interleukins (ILs) and chemokines play a role in the pruritus of atopic dermatitis. IL-4 and IL-13, as well as TH2 chemokines CCL17, CCL22, and CCL26 play a pivotal role in the development of atopic dermatitis inflammation. ^[4] IL-33 induces IL-31, thereby promoting pruritus and scratching behavior. ^[5] IL-31 promotes growth, elongation, and branching of sensory nerves in atopic dermatitis. ^[6]

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. ^{[7, 8, 9]}

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. ^{[10, 11]} 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.

Xerosis in uremic patients may worsen pruritus by reducing the threshold for itch. ^[12]

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.  A newer kappa-opioid receptor agonist, nalfurafine, has shown effectiveness in end-stage renal disease patients. Nalfurafine is only available for intravenous administration. ^{[13, 14]}

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. Pruritus is more common with intraheptic cholestasis than extrahepatic cholestasis. 

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.

One study has proposed that autotaxin, the enzyme that converts lysophosphatidylcholine into lysophosphatidic acid, may be a potential mediator of cholestatic pruritus. ^[15]

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. The fact that aspirin and paroxetine alleviate this form of pruritus suggests that serotonin from platelets may play a role. However, one study showed that the concentration of platelet serotonin was the same in polycythemic patients with and without pruritus. ^[16]

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.

Chronic pruritus without associated skin changes is a risk factor for having undiagnosed hematologic and biliary tract malignancies, but not other malignancies. ^[17]

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.

Cutaneous T-cell lymphoma may cause intractable pruritus and may have the cytokine interleukin 31 as a mediator of itching. ^[18]

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

• Cutaneous T-cell lymphoma

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

• Drug-induced pruritus without a rash

• Mastocytosis

• HIV infection and AIDS

• Hepatitic C infection

• 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)

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.

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.

The prognosis is dependent on the underlying systemic illness that is causing the pruritus. 

Renal pruritus is an independent marker for mortality at 3 years for patients on hemodialysis. Patients with severe generalized pruritus and Hodgkin disease have a poor prognosis. Pruritus that recurs after treatment is useful in detecting recurrence of the cancer.

Many of the therapeutic modalities listed in the Treatment and Medication sections offer only symptomatic control. Only cure of the underlying condition results in complete resolution of pruritus. During treatment to relieve symptoms, every effort should be made to treat the underlying systemic disease.

Patients should be given a clear explanation of their disease and its relationship to pruritus. Patients should be taught how to manage xerosis because this condition may worsen pruritus. Instructions should include keeping the skin well moisturized and avoiding excessive bathing in hot water, low ambient humidity, use of alkaline soaps, and exposure to irritating fabrics. For severe cases, the patient can perform the soak and smear technique, which is the process of hydrating the skin for 20 minutes prior to bedtime, followed by the application of ointment to the wet skin. ^[19]

The following techniques have been found helpful in reducing pruritus in general:

• Avoid hot showers or baths; use tepid water for bathing.
• Use a mild, oilated soap or soap-free cleanser to bathe.
• Apply a moisturizing lotion to the skin after bathing.
• A camphor and menthol lotion is available over the counter (OTC) and may be applied several times a day to relieve itching.
• A low-dose antihistamine like diphenhydramine is available OTC and may be taken several times a day for itching.

The itch-scratch cycle should be discussed, and patients should be encouraged to apply cool washcloths or gentle pressure to the areas and to resist the urge the scratch. Reduction or elimination of stressful factors should be discussed because stress appears to worsen itching.

Patients should be made aware that psychiatrists, social workers, and counselors are available to help them cope with the problems created by pruritus.

For patient education resources, please see the Skin Conditions & Beauty Center.