Pruritus is one of the most common complaints among patients referred to a dermatology clinic. "Chronic generalized pruritus" is described as the sensation of itching on the entire body surface, which lasts at least 6 or more weeks. This symptom can be a disabling phenomenon for patients and may sometimes interfere with daily activities such as sleep. If specific dermatological findings are observed, the physician easily comes to a diagnosis and treats the condition, whereas, when primary lesions are not detected, the diagnosis can become challenging, and some patients have to undergo extensive evaluations. The association between some systemic disorders and chronic generalized pruritus is widely known and confirmed. Many infections have been associated with pruritus, but few are considered to cause chronic generalized pruritus without any characteristic skin lesions. We aimed to gather all the available data on infectious causes of chronic generalized pruritus with no diagnostic cutaneous lesions to assist fellow physicians in the process of evaluation of these challenging cases.

Chronic hepatitis C virus (HCV) infection is associated with several extrahepatic manifestations. Patients with HCV may develop mixed cryoglobulinemia and its sequelae, ranging from cutaneous and visceral vasculitis to glomerulonephritis and B-cell non-Hodgkin lymphoma. HCV-infected patients have increased rates of insulin resistance, diabetes, and atherosclerosis, which may lead to increased cardiovascular morbidity and mortality. Neurological manifestations of HCV infection include fatigue and cognitive impairment. The mechanisms causing the extrahepatic effects of HCV infection are likely multifactorial and may include endocrine effects, HCV replication in extrahepatic cells, or a heightened immune reaction with systemic effects. Successful eradication of HCV with interferon alfa and ribavirin was shown to improve some of these extrahepatic effects; sustained virological response is associated with resolution of complications of cryoglobulinemia, reduced levels of insulin resistance, reduced incidence of diabetes and stroke, and improved fatigue and cognitive functioning. The availability of new interferon-free, well-tolerated anti-HCV treatment regimens is broadening the spectrum of patients available for therapy, including those in whom interferon was contraindicated, and will likely result in greater improvements in the extrahepatic manifestations of HCV. If these regimens are shown to confer significant benefit in the metabolic, cardiovascular, or neuropsychiatric conditions associated with HCV infection, extrahepatic manifestations of HCV may become a major indication for treatment even in the absence of liver disease.

Cholestasis develops either from a defect in bile synthesis, impairment in bile secretion, or obstruction to bile flow, and is characterized by an elevated serum alkaline phosphatase and gamma-glutamyltransferase disproportionate to elevation of aminotransferase enzymes. Key elements to the diagnostic workup include visualization of the biliary tree by cholangiography and evaluation of liver histology. The hope is that recent advances in understanding the genetic factors and immune mechanisms involved in the pathogenesis of cholestasis will lead to newer therapeutic interventions in the treatment of these diseases.

Uremic pruritus is one of the most common disabling problems in patients with chronic renal failure. Few studies have evaluated itching and cutaneous manifestations in hemodialysis-dependent patients.

The aim of this prospective study was to identify the prevalence of pruritus and cutaneous changes affecting patients undergoing hemodialysis.

The degree of itching in 70 patients treated at the Haemek Medical Center Hemodialysis Unit, in northern Israel, was scored according to presence and severity. We examined the relationship between the quality of dialysis and the frequency of pruritus, and identified concurrent cutaneous disorders.

Pruritus was a common problem in the study cohort and affected 74.3% of hemodialysis patients at some point. The main characteristics of pruritus were a general pattern in 65.7% and mild intensity in 78.3% of observed patients. Duration of hemodialysis varied between 3 months and 13 years. There was no correlation between occurrence of pruritus and demographic or medical parameters (sex, type of kidney disease, regular medications or duration of hemodialysis) of the patients. Higher dialysis efficacy, as expressed by dialyser clearance, volume distribution of area, dialysis duration (Kt/v), may reduce the prevalence of pruritus (P < 0.02). None of the blood and chemical values considered (hemoglobin, creatinine, urea, phosphorus, calcium, albumin, parathormone and alkaline phosphatase) revealed any statistically relevant differences between pruritus groups. The appearance of foot ulcers was different between diabetic and nondiabetic individuals undergoing hemodialysis (P < 0.001).

Pruritus is still a common problem in hemodialysis-dependent patients. The prevalence of xerosis and excoriations was high in patients undergoing replacement therapy. Efficient replacement hemodialysis may provide a clinical benefit.

Pruritus is a complication of liver disease. It can have a marked negative impact on quality of life; when intractable, it is an indication for liver transplantation. The cause of this type of pruritus is unknown. There is, however, evidence to suggest that the pruritus associated with liver disease is mediated, at least in part, by endogenous opioids. A central mechanism has been proposed. Therapeutic interventions have concentrated on the removal of presumed and unknown pruritogens from the circulation, hepatic enzyme induction, and, over the past decade, opiate antagonists, the first specific treatment for the pruritus of cholestasis. Other pharmacologic interventions that change neurotransmission have recently been reported to decrease the pruritus in patients with liver disease, as has a newly developed system that applies albumin-based dialysis. These interventions are promising, but they must be tested in properly controlled behavioral trials.

Cutaneous eruptions related to hepatitis C virus (HCV), a major cause of hepatitis in the setting of blood transfusion, intravenous drug abuse, organ transplantation, and hemodialysis, are typically reported as isolated cases. We encountered 35 cases of HCV infection associated with cutaneous eruptions. The present study evaluates paraffin-embedded, formalin-fixed tissue sections stained with hematoxylin and eosin from biopsy specimens of skin lesions from 35 patients seropositive for HCV. In 20 cases, reverse transcriptase polymerase chain reaction (RT-PCR) was performed using a probe for HCV RNA; the RNA was detected through the action of alkaline phosphatase on the chromogen nitroblue tetrazolium and bromochloroindolyl phosphate. The clinical spectrum comprised dermatomyositis-like photodistributed eruptions, palpable purpura, folliculitis, violaceous and perniotic acral lesions, ulcers, nodules, and urticaria. Lesions were also classified histopathologically by the dominant reaction pattern: vasculopathies of neutrophilic, lymphocytic, and granulomatous vasculitis and pauci-inflammatory subtypes (15 patients); palisading granulomatous inflammation (3 patients); sterile neutrophilic folliculitis (5 patients); dermatitis herpetiformis (1 patient); lobular panniculitis composed of neutrophilic lobular panniculitis in 2 patients and benign cutaneous polyarteritis nodosa in 1 patient; neutrophilic dermatoses, including neutrophilic urticaria, neutrophilic eccrine hidradenitis, and pyoderma gangrenosum (3 patients); interface dermatitis (3 patients); and low-grade lymphoproliferative disease of B-cell lineage representing marginal zone lymphoma in 1 patient and a clonal plasmacellular infiltrate in another patient. In most cases, whereas 1 of the aforementioned disorders defined the dominant reaction pattern, there was an accompanying secondary reaction pattern, defining a hybrid picture. Endothelial changes including endothelial cell enlargement and effaced heterochromatin with margination of the chromatin to the nuclear membrane were seen in several cases; in some cases similar cytopathic changes also involved the supporting pericytes, eccrine ductular cells, or keratinocytes. The RT-PCR analyses in 8 of 20 cases examined revealed HCV RNA expression in a focal, weak fashion in endothelia and perivascular inflammatory cells in those cases showing vasculopathic changes. Viral parasitism of endothelia may be important in cutaneous lesional propagation in the setting of HCV infection. Cross-reactivity between endogenous and viral antigens, leading to cellular and/or type II immune reactions; viral tropism to B lymphocytes, resulting in B cell expansion with resultant autoantibody production; and circulating immune complexes containing monoclonal cryoglobulins may also be of pathogenetic importance. Tropism of the virus to B lymphocytes provides a mechanism for the development of low-grade clonal B cell lymphoproliferative disease in this setting.

Hepatitis C is an important and common cause of chronic hepatitis and cirrhosis. Cutaneous manifestations are often the first signs of infection. Dermatologists must be aware of these manifestations, because early diagnosis is the best treatment. HCV Ab by ELISA should be ordered in patients with LCV-urticarial vasculitis, cryoglobulinemia, lichen planus, Sjögren's syndrome, unexplained pruritus, PCT, PAN, chronic urticaria, patients starting methotrexate, unexplained pruritus, and any patient initiating therapy with a potentially hepatotoxic drug.

Pruritus is the most common symptom of skin disease. Even in the absence of primary cutaneous findings, severe and extensive pruritus often is associated with systemic disease. This review considers briefly the physiology of pruritus and discusses the various systemic diseases often accompanied by this bothersome symptom. In addition to exploring the possible mechanisms and potential therapies of itching in selected disorders, this review presents general recommendations for evaluating patients with unexplained pruritus and management guidelines for alleviating their discomfort.

Pruritus of unknown origin is a common complaint, and systemic causes must be considered. However, there is little data on how frequently systemic causes are responsible or whether any patient characteristics make a systemic cause more likely.

We attempted to determine how frequently pruritus of unknown origin had a systemic etiology in an outpatient population seen in a university dermatology department and whether any patient characteristics made a systemic explanation more likely.

This is a retrospective study using chart reviews and telephone interviews to collect data.

Of 50 patients, 11 had a systemic cause of pruritus. Pruritus was the initial symptom of systemic disease in 7 of these patients. No patient characteristics were statistically associated with systemic causes of pruritus.

Pruritus of unknown origin was the initial symptom of a systemic disease in 7 of 50 patients presenting to a dermatology clinic with this complaint. The underlying diseases included hypothyroidism, gastric adenocarcinoma, hepatitis C, HIV, laryngeal carcinoma, graft-versus-host disease, and chronic lymphocytic leukemia.

The prevalence of pruritus was prospectively determined in 310 patients of whom 119 had hepatitis C virus infection, 91 hepatitis C virus and human immunodeficiency virus, 51 human immunodeficiency virus infection alone, 31 hepatitis B virus and human immunodeficiency virus coinfection and 18 were HBsAg carriers.

Patients in the first three groups were more likely to complain of itching (22%, 28% and 25%, respectively) than HBsAg carriers (8.2%, p=0.01. Laboratory data were not different between groups, except for the human immunodeficiency virus group, whose alkaline phosphatase levels were highest, and CD4 counts were lowest (median 30 cells/mm3). Patients with hepatitis C, including those with human immunodeficiency virus, had similar hepatitis C virus RNA levels in patients with or without pruritus. There was no difference in hepatic inflammation or fibrosis between those with and those without pruritus.

20% of patients with chronic hepatitis C and 8% of hepatitis B patients complain of pruritus. Patients with pruritus have laboratory and histologic parameters comparable to those without.

An association between mixed cryoglobulinaemia (MC) and hepatotropic viruses, chiefly hepatitis C virus (HCV), has been widely reported. The presence of HCV genomic sequences or HCV-related viral proteins in the serum, purified cryoglobulins, peripheral blood mononuclear cells and into several tissues has suggested an important triggering role for HCV in MC patients. However, only few reports investigated the presence of HCV in cutaneous vasculitis and its potential pathogenetic role. Biopsies of cutaneous purpuric lesions from 5 MC female patients (aged from 40 to 80 years) were carried out for virological and histopathological evaluation. A leukocytoclastic vasculitis pattern was found in 4/5 subjects, while the presence of HCV RNA was detected in 3/5. In only 3 cases biopsy specimens were sufficient for immunohistochemical and direct immunofluorescence (DIF) studies. Immunohistochemical evaluation was performed by means of alkaline phosphatase and monoclonal anti-alkaline phosphatase (APAAP) immune-complexes. In the same skin specimen APAAP and DIF findings were compared with the presence/absence of HCV genomic sequences (PCR technique). In 1 MC patient, the detection of HCV-RNA was associated to a prevalent CD8+ T suppressor pattern with a perivascular and subjunctional distribution as well as an intense expression of second class (HLA-DR) and intercellular adhesion (ICAM-1) molecules on basal keratinocytes, endothelial cells and perivascular infiltrate. These findings suggest a marked inflammatory activation that spreads from endothelial cells to keratinocytes and Langerhans cells. In the 2 HCV-RNA negative specimens the scanty immunopathological staining could indicate a residual activity due to the previous inflammatory event triggered by cryoglobulins. The deposition of circulating HCV-containing immune complexes (CIC) in the skin could be the initial pathogenic event for cryoglobulinemic vasculitis; subsequently CIC could spread from the vascular bed to the perivascular tissue and then could be very rapidly eliminated. If confirmed in larger patients' series these findings could definitely demonstrate a direct role of HCV in the pathogenesis of cryoglobulinemic vasculitis.

Hepatitis C virus (HCV) is a common cause of chronic hepatitis and is frequently associated with extrahepatic disease. Recently, cutaneous disorders have been a presenting manifestation of HCV infection. Porphyria cutanea tarda (PCT) is one of the cutaneous diseases associated with hepatitis C. PCT manifests in an acute form with tense bullae and erosions and in a chronic form with milia, scarring, and sclerodermatous changes. HCV has also been implicated as a cause of vasculitis through immune complex deposition. We report a patient in whom HCV was associated with sclerodermoid PCT and a medium vessel vasculitis. This case underscores the importance of HCV and its potential cutaneous manifestations, as well as the importance of recognizing cutaneous manifestations of internal disease that may be the first clue to diagnosis of HCV.

Pruritus is a common symptom in cholestatic liver disease but is rare in chronic hepatitis C. Eight patients with chronic hepatitis C and severe pruritus were compared with regard to biochemical, serological, and histological features to eight disease controls with primary biliary cirrhosis and seven with cirrhosis due to hepatitis C. Among those with severe pruritus associated with chronic hepatitis C, serum aminotransferases were raised in all, alkaline phosphatase in four, and gamma-glutamyl-transpeptidase levels in all except one. Serum cholylglycine levels were elevated in seven of eight patients. Liver biopsies showed moderate to severe fibrosis in all patients and cirrhosis in five. Compared to control subjects with cirrhosis due to hepatitis C but no pruritus, ductopenia, and cholestatic changes were prominent, although less so than in controls with primary biliary cirrhosis. Chronic hepatitis C with moderate to severe fibrosis may result in low-grade cholestasis with pruritus, possibly in association with bile duct disappearance.

Hepatitis C virus (HCV) is a bloodborne agent transmitted by apparent and inapparent parenteral procedures representing a frequent cause of liver disease world-wide. Both acute and chronic HCV infection may affect the liver as well as various non-hepatic tissues. Numerous extrahepatic disorders have been recognised in association with HCV infection among which dermatological diseases occupy a central part. Cutaneous necrotising vasculitis, mixed cryoglobulinemia, porphyria cutanea tarda and lichen planus are the major skin diseases frequently associated with HCV infection, but other skin disorders, such as Adamantiadis-Behçet syndrome, erythema multiforme and nodosum, malacoplakia, urticaria and pruritus, may also be linked to hepatitis C. Further studies are necessary to establish or refute an aetiopathogenetic role of HCV in these conditions. Skin manifestations are also part of the clinical picture of other extrahepatic disorders associated with HCV infection, such as thyroid dysfunction and HCV-related thrombocytopenia. The response to interferon alpha (alpha-IFN) therapy in skin diseases is unpredictable with some patients ameliorating, others remaining stationary and others deteriorating.

Pruritus is a common symptom of chronic cholestatic liver diseases but is considered rare in chronic hepatitis. We observed pruritus to be an unusually common complaint in patients with advanced chronic hepatitis C. We reviewed the records of 175 chronic hepatitis C patients to identify patients with severe, diffuse, unexplained pruritus; 12 consecutive prospective patients undergoing liver biopsy for chronic hepatitis C served as controls. Assessment included laboratory biochemical tests and assessment of liver pathology by stage, grade, hepatic activity index, and a bile duct score. Pruritus was present in nine (5.1%) patients. Serum AST, ALT, alkaline phosphatase, GGTP, total bilirubin, and ferritin were similar in pruritics and controls. Pruritics had higher serum bile acids (2028.4 +/- 223.1 mmol/liter vs 423.1 +/- 194.3, P < 0.001), higher transferrin saturation (57.5 +/- 6.8% vs 33.2 +/- 3.3, P < 0.01), and lower HCV RNA by bDNA (24.5 +/- 12.7 x 10(5) vs 172.7 +/- 54.1 x 10(5), P < 0.05). Pathology revealed cirrhosis in 6/9 (66.6%) pruritics vs 1/12 (8.3%) controls (P < 0.01). Pruritics had higher pathologic stage (3.7 +/- 0.2 vs 2.2 +/- 0.4, P < 0.01), grade (4.4 +/- 0.2 vs 2.1 +/- 0.2, P < 0.001), activity index (14.3 +/- 1.9 vs 8.6 +/- 1.9, P < 0.025), and bile duct score (7.6 +/- 0.6 vs 4.7 +/- 0.4, P < 0.01). Of eight pruritics treated with IFN-alpha2b, two had complete ALT response and one relapsed. Pruritus followed a relapsing course and only three patients partially responded despite a variety of interventions. In conclusion, pruritus is a common complication of advanced CHC. Its presence is associated with high serum bile acids, advanced pathology and bile duct abnormalities. The clinical course of pruritus is relapsing and response to therapy is inconsistent. These features suggest that pruritus in CHC has a pathogenesis that may vary from that of chronic cholestatic diseases.

Infection with hepatitis C virus (HCV) may affect not only the liver but also various nonhepatic tissues and organs and may combine with many etiologically unrelated diseases and morbid conditions. Numerous nonhepatic manifestations in HCV infection have been previously reported. For some (eg, cryoglobulinemia), the association is well established. For others, such as sialadenitis and lichen planus, the association is probable (but not completely documented) and, for the remainder, the associations are weak. Extrahepatic manifestations may result from immunological mechanisms as well as virus invasion and replication in the affected extrahepatic tissues and organs. Thyroid abnormalities, primarily Hashimoto's disease, and isolated increases of anti-thyroid antibodies (ATPO) appear to be more frequent in chronic hepatitis C than B or D, with high ATPO titers clustering mainly among females. Interferon-alpha (IFN-alpha) therapy is associated with development of thyroid dysfunction in 5.5-12.9% of patients, usually exposing preexisting subclinical thyroid abnormalities. Mixed cryoglobulinemia (MC) is commonly found (36-45%) in patients with chronic HCV infection; however, only in a minority of cases does it become clinically manifested as systemic vasculitis with purpura, neuropathy, or Raynaud's phenomenon. In a number of patients, MC may terminate in non-Hodgkin's B-cell lymphoma. Treatment of these lymphoproliferative disorders with IFN-alpha is advocated. Idiopathic thrombocytopenia is now recognized more frequently in association with chronic HCV infection and is usually aggravated by IFN-alpha therapy. Patients with porphyria cutanea tarda (PCT) have demonstrated serological markers of HCV infection in 62-82% of cases. The usefulness of IFN-alpha in PCT remains to be demonstrated. Lichen planus has also been found in association with chronic HCV infection, particularly when severe or affecting the oral cavity. Other nonhepatic manifestations have also been reported in HCV infection such as diabetes, corneal ulceration, uveitis, and sialadenitis. These manifestations deserve further study and documentation. Finally, markers of autoimmunity occur with high frequency in chronic HCV infection; however, combination with the classical syndrome of autoimmune hepatitis is rare. In the presence of various autoantibodies, the clinical features of chronic hepatitis C do not appear to be modified and, contrary to general perception, IFN-alpha therapy within randomized controlled trials should not be withheld since the response rate to IFN-alpha does not appear to differ in the presence or absence of low titers of these markers.

Hepatitis C virus (HCV) infection induces variable skin manifestations.

Our purpose was to determine whether there is an association between HCV infection and urticaria.

Antibody to HCV (anti-HCV) and HCV genotypes were determined in patients with urticaria and in a control population.

Anti-HCV was detected in 19 (24%) of 79 patients with urticaria, and HCV RNA was detected in 17 (22%). Genotypes of HCV were II/1b in 12 (71%), III/2a in 4 (24%), and IV/2b in 1 (6%). The 17 patients with HCV RNA were older (53 +/- 14 vs 41 +/- 14 years, p < 0.01), and their eruption lasted longer (35% vs 6%, p < 0.05) and left pigmentation more frequently (53% vs 3%, p < 0.001). They had higher levels of alanine aminotransferase (67 +/- 34 vs 25 +/- 17 U/L, p < 0.001), aspartate aminotransferase (51 +/- 23 vs 21 +/- 8 U/L, p < 0.001), zinc turbidity test (12.8 +/- 3.1 vs 9.3 +/- 3.7 Kunkel units, p < 0.001), and IgG (1919 +/- 320 vs 1622 +/- 349 mg/100 ml, p < 0.01) than the patients without HCV RNA.

HCV could be a significant cause of urticaria. Chronic urticaria associated with HCV infection has peculiar clinical, serologic, and biochemical characteristics that could make it a distinct clinical entity with an indication for interferon therapy.

The hepatitis C virus causes both hepatic and extrahepatic disorders, particularly as regards dermatology. The link between essential mixed cryoglobulinemias and the C virus infection has been clearly evidenced., whereas its frequency seems low in other systemic vasculitis such as polyarteritis nodosa. Similarly, the link between C virus hepatopathy and porphyria cutanea tarda is now proven. Lichen planus is also described as being associated with this virus, but further epidemiological studies are required to determine the exact prevalence of lichen in C virus hepatopathy cases. Finally, various cutaneous disorders, such as urticaria, erythema multiforme, dermo-hypodermitis, etc, occasionally arise during acute or chronic hepatitis C.

To emphasize the ongoing role of chronic hepatitis C virus (HCV) infection in the cause or exacerbation of severe dermatologic disorders.

We present two case reports to outline the pertinent findings in hepatitis C-related cryoglobulinemia, leukocytoclastic vasculitis, and lichen planus and discuss the main disorders associated with chronic HCV infection.

Chronic HCV infection has recently been recognized in association with various skin disorders. The most commonly reported association is the triad of leukocytoclastic vasculitis, cryoglobulinemia, and chronic HCV infection. Other cutaneous disorders associated with HCV infection include porphyria cutanea tarda, lichen planus, erythema nodosum, urticaria, erythema multiforme, and polyarteritis nodosa.

Patients with onset or exacerbation of these disorders should undergo assessment for HCV infection.