Itching in diseases of the internal organs

Itching is an unpleasant sensation on the skin that usually causes a desire to scratch. Of course, the word “unpleasant” can mean different things to different people (1). Itching may also be a physiological process if scratching helps remove a potentially harmful stimulus, or it may be caused by medications or mental health conditions (2).

Itching differs from sensations such as tingling, burning, pain, and pressure. It should be emphasized that itching is a symptom rather than a disease itself and is a subjective sensation. It may sometimes be accompanied by papules, moisture, hyperpigmentation, lichenification, pyoderma, or other secondary skin changes.

Itching can be mild, moderate, or severe, and it may disrupt sleep and daily activities, cause discomfort, and increase irritability. It can also become a significant source of stress. Itching may be acute or chronic, and localized or widespread (1, 2).

The pathogenesis of itching varies depending on the underlying disease. In oncological, hepatic, and renal conditions, itching is often caused by toxins circulating in the bloodstream. In leukemia and lymphomas, itching may result from histamine and leukopeptidase released by circulating basophils and other leukocytes. In patients with Hodgkin’s lymphoma, itching is associated with increased levels of kininogen, histamine, and bradykinin precursors, while in carcinoid conditions, it is linked to elevated serotonin levels.

Patients undergoing cytotoxic chemotherapy, radiotherapy, or biological therapy may also experience itching. In these cases, it may be caused by skin dryness after radiation therapy or as a side effect of chemotherapy and biological treatments.

Itching may be acute or chronic, localized or generalized (8). It can be classified into the following types (9):

1. Itching associated with skin diseases, when mediators act on free nerve endings.
2. Itching associated with internal organ diseases.
3. Idiopathic itching, when the cause is unclear.

In this article, we review the main internal organ diseases and conditions that can cause itching. The most common causes are presented in Table 1.

Table 1. Most Common Causes of Skin Itching

We will briefly discuss the main causes of itching in patients with internal organ diseases.

Cholestatic itching

Patients with liver diseases and intrahepatic or extrahepatic cholestasis often experience itching (10). It may also accompany primary biliary cirrhosis, primary sclerosing cholangitis, viral hepatitis B and C, autoimmune hepatitis, biliary tract carcinoma, and alcoholic liver cirrhosis.

The pathogenesis of cholestatic itching remains poorly understood, as the main substance responsible for itching has not yet been clearly identified. Some authors suggest that itching is caused by bile acids in the blood (cholemia) or skin, but the correlation between bile acid concentration in the skin and the intensity of itching is relatively weak (10).

For patients with cholestatic itching, treatments such as phototherapy, cholestyramine, and plasmapheresis—which reduce or eliminate unidentified circulating substances—may be helpful. Antihistamines may be used as additional therapy to relieve itching. Good results have also been reported with ursodeoxycholic acid or ondansetron (11).

Itching in chronic kidney failure and dialysis patients

In chronic kidney failure and uremia, itching is one of the most common and distressing symptoms. It occurs in approximately 15% of cases (12), often accompanied by skin damage due to scratching. It is even more common in patients undergoing hemodialysis, affecting 50–90% of individuals. Itching in these patients may be localized or generalized (13). Notably, itching is not typical in acute kidney failure.

The pathogenesis of uremic itching is still not fully understood and is likely multifactorial. Contributing factors may include iron deficiency, histamine release, disturbances in calcium and phosphate metabolism, secondary hyperparathyroidism, proliferation of mast cells in the skin, hypervitaminosis A, allergic reactions to substances used in hemodialysis, dysfunction of motor, sensory, and autonomic nerves, and endogenous opioids (14).

Treatment options include ultraviolet radiation therapy, emollients, activated charcoal, cholestyramine, and phosphate-binding agents. In some cases, parathyroidectomy may be performed to reduce itching. Increased histamine levels have not been clearly linked to uremic itching, and therefore antihistamines are generally not effective (15, 16).

For patients undergoing dialysis, it is recommended to minimize exposure to substances that may trigger itching by using complement non-activating dialysis membranes. It is also known that itching often decreases or disappears after kidney transplantation (17, 18).

Itching in hematologic diseases

Itching is a common symptom in hematologic diseases. In polycythemia vera, characterized by increased production of all three blood cell lines, itching may occur after contact with water or after a hot bath. Aquagenic itching can be an early sign of polycythemia vera (19).

In some cases, itching may be so severe that patients avoid bathing altogether. It is associated with the release of histamine and other substances from an increased number of circulating basophils. Antihistamines are generally not very effective, while treatments such as salicylates, photochemotherapy, or α-interferon may provide better results (20, 21).

Iron deficiency is often associated with itching, even in the absence of anemia, and symptoms may improve with iron supplementation.

In older adults, itching may be a sign of an underlying malignant tumor, which can also lead to anemia.

Itching may also occur in patients with hemochromatosis, a condition characterized by excessive iron accumulation in the body (22).

Approximately 30% of patients with Hodgkin’s lymphoma experience itching, which may be an early symptom of the disease. In such cases, itching often decreases after radiotherapy or chemotherapy.

Itching is not typical in chronic leukemia, multiple myeloma, or lymphosarcoma and is rare in granulomatous diseases.

Endocrine-related itching

Occasionally, patients with diabetes mellitus experience itching. It may be generalized, but is more often localized to the head, genital, or anal area. It can be related to skin candidiasis or, more commonly, to poor glycemic control and elevated blood glucose levels (23). Itching in patients with diabetes may also be associated with neuropathy, dry skin, and medication effects. Treatment involves proper diabetes management and antifungal therapy when indicated.

Since the beginning of the 20th century, itching associated with hyperparathyroidism and hypoparathyroidism has been recognized (24). Its mechanism remains unclear. Increased blood flow and elevated skin temperature may contribute to itching in hyperparathyroidism. Itching associated with myxedema is rare and is most likely due to dry skin. Itching and even chronic urticaria may also be linked to autoimmune thyroiditis, in which antibodies are formed against thyroglobulin and TSH receptors. In such cases, treatment with levothyroxine is appropriate.

Abnormal parathyroid gland function may also contribute to itching. Secondary hyperparathyroidism in chronic kidney disease is another potential factor in uremic pruritus. In primary hypothyroidism, dry skin and skin candidiasis are likely the main causes of itching (26).

Hormonal changes during menopause may also trigger vulvar itching in women (27).

Itching and oncological diseases

Generalized itching is only rarely associated with carcinomas of the lung, stomach, colon, prostate, breast, or pancreas (28, 29).

Pruritus is a common symptom in conditions such as systemic mastocytosis and may also be associated with telangiectasia (30). Human skin mast cells predominantly contain tryptase, whereas mast cells in the alveoli and gastrointestinal mucosa mainly contain chymase. This difference may help distinguish cutaneous from systemic mastocytosis (31, 32).

Pruritus associated with carcinoid syndrome is sometimes accompanied by flushing and is caused by serotonin produced by enterochromaffin tumor cells (33). Treatment with anti-serotonin medications can reduce pruritus.

Some authors report an association between pruritus and brain tumors, with nasal itching observed in up to half of cases (34). However, the relationship between pruritus and tumors is not always clear. Itching may result from immunological mechanisms, toxic metabolites, iron deficiency, or dry skin. Tumor removal may reduce or eliminate pruritus, whereas antihistamines are generally ineffective in such cases.

Chemotherapeutic agents and radiation therapy may also cause pruritus (36–38).

Neurogenic pruritus

Neurological disorders such as stroke, multiple sclerosis, brain tumors, and brain abscesses may sometimes cause severe generalized or localized pruritus (38, 39). This type of pruritus is often paroxysmal and unilateral. Treatment with amitriptyline, which inhibits serotonin reuptake, may help reduce symptoms.

Patients with neuropathic pain more often report tingling rather than itching.

Psychiatric and psychogenic pruritus

Emotional stress, psychological trauma, anxiety, depression, and psychosis can exacerbate pruritus. In adults, approximately 10% of generalized pruritus cases are attributed to psychological causes (40).

Older individuals, particularly women, may develop a delusional parasitosis syndrome, in which they believe they are infested with insects such as mites, ants, or flies and repeatedly scratch their skin (41, 42). In such cases, treatment with antipsychotic medications is effective.

Before diagnosing pruritus of psychological or psychiatric origin, it is essential to rule out dermatological and internal diseases.

Drug-induced pruritus

Pruritus may occur as an adverse effect of various medications. This may be due to direct effects on the skin or indirect effects such as drug-induced hepatotoxicity or nephrotoxicity. Medications that may cause pruritus include morphine, other opioids, angiotensin-converting enzyme inhibitors, analgesics, vitamin A, contrast agents, gold compounds, chloroquine, and sulfonamides (3). These substances may persist in skin macrophages for prolonged periods (4). In such cases, antihistamines are generally ineffective.

Treatment of pruritus

In many cases, symptomatic treatment of pruritus includes avoiding frequent bathing, irritating fabrics, alcohol-induced vasodilation, hot foods or beverages, and stress (5). Patients may be treated with first- or second-generation antihistamines (5, 36). A non-sedating H1 receptor antagonist, quifenadine (Fenkarol®), may be a suitable option.

This drug does not cross the blood–brain barrier due to its low lipophilicity and therefore does not cause sedation (only about 0.05% reaches the brain) (6, 7). It and its metabolites are eliminated from the body within 48 hours, mainly via urine (44%), with the remainder excreted through bile and lungs. Quifenadine also activates the enzyme diamine oxidase, which breaks down endogenous histamine by approximately 30%, in addition to blocking H1 receptors. It is absorbed from the gastrointestinal tract at about 45% within 30 minutes and reaches peak plasma concentration within 60 minutes (6).

Classical sedating H1 receptor blockers such as diphenhydramine, clemastine, and chlorpheniramine may cause sedation, impaired motor function, and drowsiness, but are sometimes prescribed for pruritus, especially in the evening (11, 18). Tricyclic antidepressants may also be effective. Other treatment options include phototherapy, cholestyramine, and capsaicin (21, 36). The primary treatment for pruritus caused by internal diseases is the management of the underlying condition (5, 9–11).

Kotryna Linauskienė, MD Laura Malinauskienė Vilnius University Center of Pulmonology and Allergology

Journal "Internistas"