eMedicine Specialties > Dermatology > Viral Infections

Cutaneous Manifestations of Hepatitis C

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Arthur P Birnkrant, MD, Clinical Instructor, Department of Dermatology, University of Medicine and Dentistry of New Jersey

Updated: Sep 8, 2009

Introduction

Background

The hepatitis C virus (HCV) is an RNA virus. HCV is a major cause of both acute and chronic hepatitis. Persons become infected mainly through parenteral exposure to infected material by blood transfusions or injections with nonsterile needles. Persons who inject illegal drugs, people who snort cocaine with shared straws, and health care workers who are at risk for needlestick and other exposures are at highest risk for HCV infection. Another major risk factor for HCV is high-risk sexual behavior. The incidence of acute HCV infection has sharply decreased in the United States during the past decade, but its prevalence remains high (approximately 2.7 million Americans) because chronic hepatitis C (CHC) infection develops in approximately 75% of patients acutely infected.

Most patients with acute and chronic infection are asymptomatic. Patients and health care providers may detect no indications of the conditions for long periods; however, chronic hepatitis C infection and chronic active hepatitis are slowly progressive diseases and result in severe morbidity in 20-30% of infected persons. Astute observation and integration of findings of extrahepatic symptoms, signs, and disease are often the first clues to underlying HCV infection.

Cutaneous symptoms or findings relevant to HCV infection manifest in 20-40% of patients presenting to dermatologists and in a significant percentage (15-20%) of general patients. HCV is suggested and must appear in the differential diagnosis of these patients to avoid missing this important but occult factor in clinical disease in the appropriate setting.

Extrahepatic manifestations of hepatitis C virus are numerous.¹ The most prevalent and most closely linked with HCV is essential mixed cryoglobulins with dermatologic, neurologic, renal, and rheumatologic complications. A less definite relationship to HCV is observed with systemic vasculitis, porphyria cutanea tarda, and the sicca syndromes.

HCV is a major public health problem because it causes chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). HCV also induces extrahepatic manifestations such as mixed cryoglobulinemia, porphyria cutanea tarda, leukocytoclastic vasculitis, lichen planus (LP), and sicca syndrome, all of which should be regarded as early markers of a potentially fatal chronic liver disease.²

Pathophysiology

Chronic hepatitis C infection is associated with many extrahepatic manifestations in joints, muscles, neural and gastrointestinal tissues, and skin. In this article, the many dermatologic manifestations of hepatitis C virus (HCV) are classified according to diseases with proven or suspected etiology or causation.

Primary causation results from direct infection of HCV in the skin, lymphocytes, dendric antigen-presenting cells, and blood vessels. An example of this type of disorder is the recent finding of epidermal cells with HCV-RNA particles.

Secondary causation occurs when HCV infection manifests in the skin due to epiphenomena resulting from the disruption of immune responses. Leukocytoclastic vasculitis due to cryoglobulinemia is a good example of a specific skin manifestation resulting from the production of immunoglobulins, with rheumatoid characteristics causing an immune complex–mediated vasculitis.

Another category of dermatologic manifestations in HCV infections in a causative schema includes those diseases in which an association has been identified, but the details of causation have not yet been clarified. Porphyria cutanea tarda (PCT) is a good example of this type of HCV-related disease in which causation is unexplained but undeniable. In patients with PCT, 70% are HCV positive.

Neoplastic dermatologic manifestations are another category of extrahepatic findings.

Dermatologic manifestations are associated with treatments of HCV infection, especially interferon.

The last category is suspected associations of the disorder in a causative schema. HCV genomic analysis by means of arduous gene sequencing of many viruses has led to the division of HCV into genotypes based on homology. Arabic numerals denote the genotype, and a letter denotes the subtype for lesser homology within each genotype.³

• Genotype 1a occurs in 50-60% of patients in the United States. This type is difficult to eradicate using current medications.
• Genotype 1b occurs in 15-20% of patients in the United States. Subtype 1b is difficult to eradicate using current medications. This type is most prevalent in Europe, Turkey, and Japan.
• Genotype 1c occurs in less than 1% of patients in the United States.
• Genotypes 2a, 2b, and 2c occur in 10-15% of patients in the United States. These subtypes are widely distributed and are most responsive to medication.
• Genotypes 3a and 3b occur in 4-6% of patients in the United States. These subtypes are most prevalent in India, Pakistan, Australia, and Scotland.
• Genotype 4 occurs in less than 5% of patients in the United States. It is most prevalent in the Middle East and Africa.
• Genotype 5 occurs in less than 5% of patients in the United States. It is most prevalent in South Africa.
• Genotype 6 occurs in less than 5% of patients in the United States. It is most prevalent in Hong Kong and Macao.

Frequency

United States

The prevalence of hepatitis C virus (HCV) seropositivity in the United States was 3.9 million persons.⁴ In persons who were seropositive, 65% were aged 30-49 years, and 74% of patients demonstrating positive results were positive for HCV RNA, meaning active viral replication continued to occur. An estimated 2.7 million persons have chronic hepatitis C infection. Genotype 1a occurs in 57% of patients; genotype 1b occurs in 17%. From 1989-1993, the occurrence of HCV decreased 80%, from 50 cases per 100,000 to approximately 28,000 new cases per year. Decreased transfusion-associated disease and a dramatic decrease in intravenous drug use account for this change.

International

Worldwide, 170 million persons have hepatitis C virus (HCV) infection, which represents 3% of the world population.⁵ The prevalence of HCV antibody is less than 3% in developed nations. The prevalences are as high as 70% in highly endemic countries, such as Egypt; the high prevalences relate to specific practices that transmit the disease at specific times in the population.

Mortality/Morbidity

• Although acute hepatitis C virus (HCV) infection is usually mild, chronic hepatitis results in at least 75% of patients.³ While liver enzyme levels may be in the reference range, the presence of persistent HCV-RNA levels discloses chronic infection. Biopsy samples of the liver also reveal chronic liver disease in patients. Cirrhosis develops in 20-50% of patients with chronic hepatitis C infection. Liver failure and hepatocellular carcinoma can eventually result. Hepatocellular carcinoma occurred in 11-19% of patients. The risk of cirrhosis and hepatocellular carcinoma doubles in patients who have undergone transfusion.⁶
• Two studies of compensated cirrhosis in the United States and Europe showed that decompensation occurred in 20% of patients and that hepatocellular carcinoma occurred in approximately 10% of patients.^7,8 The survival rate at 5 and 10 years was 89% and 79%, respectively. The onset of chronic hepatitis C infection early in life often leads to less serious consequences.^9,10 Hepatitis B virus (HBV) infection, iron overload, and alpha 1-antitrypsin deficiency may play a role in the progression of chronic hepatitis C infection to HCV-related cirrhosis.^11,12
• Chronic hepatitis C infection and its major sequelae (cirrhosis and hepatoma) are responsible for 8,000-10,000 deaths a year.

Race

Race and ethnicity do not relate to hepatitis C virus (HCV). HCV infection is associated with lower economic status, less education, and groups other than whites.

Sex

No sex preponderance occurs with hepatitis C virus (HCV) infection. Sex differences were not significant.⁴

Age

Of individuals positive for hepatitis C virus (HCV) antibodies, 65% are aged 30-49 years. Younger age at infection often relates to lesser consequences of the infection. Infection is uncommon in persons aged 20 years and younger and is more prevalent in persons older than 40 years.^13,14 Data suggest the presence of age-related methods of infection, such as nonsterile medical procedures, including vaccination and parenteral drug treatment.¹⁵

Clinical

History

• Lichen planus:  LP is a pruritic papulosquamous disorder involving the skin, scalp, nails, oral mucosa, and genitalia.^{19,20,21,22,23,24,25,26}
  • The lesions and pathology are often typical unlike many papulosquamous skin disorders, such as seborrhea, atopic dermatitis, and contact dermatitis; these skin disorders have scaling, erythema, and pruritus and are included in the differential diagnosis of LP but lack its pathologic and clinical specificity. Intracellular HCV infection of epithelial cells is proven for LP.²⁶
  • Often, the papular lesions of LP suddenly appear on the volar acral surfaces of the wrists and arms and are pruritic. Oral symptoms are less common, but painful erosions can occur in oral lichen planus (OLP). Hair loss in lichen planopilaris, exquisite pruritus of markedly hypertrophic plaques on the lower legs in hypertrophic LP, and painful genital erosions can be presenting findings
  • The prevalence of oral, cutaneous, pharyngeal, and/or vulval LP in 87 HCV-infected patients was 19.5%.²⁷ Another study found no significant association between cutaneous lichen planus and HCV infection.²⁸
  • A retrospective analysis of 808 Italian patients with oral lichen planus showed that 137 of them were infected with HCV.²⁹

Lichen planus. Courtesy of Walter Reed Army Medical Center Dermatology.

Lichen planus. Courtesy of Walter Reed Army Medical Center Dermatology.

Lichen planus. Courtesy of Walter Reed Army Medical Center Dermatology.

Lichen planus (hypertrophic type). Courtesy of Walter Reed Army Medical Center Dermatology.

Lichen planus (oral lesions). Courtesy of Walter Reed Army Medical Center Dermatology.

Lichen planus (volar wrist). Courtesy of Walter Reed Army Medical Center Dermatology.

• Acral necrolytic erythema³⁰ : The symptomatology of acral necrolytic erythema includes pruritus associated with recurrent, erythematous, papular eruptions with blisters and erosions on the dorsal aspects of the feet and ankles. Pain is common with variable-sized erosions. Chronic lesions are hyperkeratotic plaques with erosions and peripheral erythema preferring the acral parts of the legs. These lesions provide unusually specific markers for HCV infection.
• Sialadenitis: Symptoms include dry eye and sicca syndrome due to chronic destruction of the major and minor salivary glands by capillaritis.
• Mooren corneal ulceration: Serious corneal ulcerations are often linked to HCV infection. Cross-reactivity to the HCV envelope protein and a corneal antigen appears to be causative. Pain, lacrimation, and loss of sight result.³¹
• Leukocytoclastic reactions (some): This tends to appear as an eruption of palpable purpura on the lower extremities. It may represent an HCV immune complex disease.

• Cryoglobulinemia: Leukocytoclastic vasculitis occurs with type II mixed cryoglobulinemia in the skin and mucous membranes. Leukocytoclastic vasculitis also occurs with necrotizing small vessel vasculitis of the skin, kidneys, joints, and eyes. Disorders of this type belong to a group termed mixed cryoglobulinemia syndrome. These disorders display palpable purpura of the legs (which is worse distally and inferiorly), livido reticularis, ulcerations, urticaria, symmetric polyarthritis, myalgias, cutis marmorata, and fatigue. The symptomatology is pruritus, pain, or Raynaud phenomenon resulting from vasculitic sludging in the postcapillary venules of immunologic material.
  • In all cases of cryoglobulinemia, an inflammatory reaction occurs with an influx of polymorphonuclear cells. Variable vascular damage and occlusion results in worsening degrees of pathology and symptoms; such pathology includes livido vasculitis with perturbation of superficial and deep vascular reflexes and mottling blue changes of the skin (cutis marmorata); pruritus; painful ulcerations of significant size resulting from arteriolar occlusion; and through-and-through necrosis of epidermis, dermis, and fat. Significantly, HCV localized to the intravascular debris and recently to the vessel wall establishes specificity to these reactions. Perhaps the clinical variability of vasculitic reactions is related to the degree of specificity of the vasculitis.
  • Urticarial vasculitis with HCV infection presents with painful urticarial blanching plaques of the limbs and chest that fade to residual hyperpigmented areas.³² The 2 cases presented lacked cryoglobulins. Complete disappearance of arthralgias and skin and liver disease occurred with clearance of HCV infection, suggesting that urticarial vasculitis may result from HCV immune complex disease.

Cold agglutinin disease indistinguishable from cryoglobulinemia. Courtesy of Walter Reed Army Medical Center Dermatology.

Cryoglobulinemia, palpable purpura, dysproteinemic purpura, and leukocytoclastic vasculitis (small vessel vasculitis). Courtesy of Walter Reed Army Medical Center Dermatology.

• Sialadenitis: Dry mouth without dry eyes is the most prominent symptom of sialadenitis associated with HCV infection. Sialadenitis is an inflammatory disorder of the salivary, parotid, sublingual, and minor glands. Findings include xerostomia resulting from a chronic lymphocytic infiltrate and destruction of the salivary glands. Sjögren disease and its markers ssRo and ssLa are not found.^24,33 As many as 15% of patients with chronic hepatitis C infections have sicca syndrome.
• Mooren corneal ulcer: Serious corneal ulcerations begin at the rim or periphery and can progress singly or multiply and bilaterally to destroy the cornea. Symptoms of ulceration are eye pain, inflammation, tearing, and loss of vision due to corneal opacity and destruction.
• Antiphospholipid syndrome is a serious multisystemic illness resulting from pathologic production of the antiphospholipids anticardiolipin and lupus anticoagulant. These IgG molecules (sometimes IgM or immunoglobulin A [IgA] in less severe variants) bind to platelets, vascular endothelium, beta-2 lipoproteins, prothrombin, and other phospholipids. The resultant pathologic processes depend on the locale of the process. Severe coagulopathies in the eye, the brain, the kidney, and large vessels result in symptomatology referable to vascular destruction or bleeding in these organs.

• Liver failure in chronic hepatitis C infection: This results from cirrhosis, autoimmune hepatitis, cholangitis, and hepatocellular carcinoma. Symptoms of liver failure are identical to symptoms caused by other conditions, such as ascites, jaundice, and liver failure.
• Thyroid failure: Thyroid destruction then failure occurs. Symptoms of hypothyroidism are noted.

Prurigo nodularis. Courtesy of Walter Reed Army Medical Center Dermatology.

Prurigo nodularis. Courtesy of Walter Reed Army Medical Center Dermatology.

Prurigo nodularis. Courtesy of Walter Reed Army Medical Center Dermatology.

Vitiligo. Courtesy of Walter Reed Army Medical Center Dermatology.

Chronic urticaria. Courtesy of Walter Reed Army Medical Center Dermatology.

Urticaria (secondary to penicillin). Courtesy of Walter Reed Army Medical Center Dermatology.

Erythema nodosa. Courtesy of Walter Reed Army Medical Center Dermatology.

Erythema nodosa. Courtesy of Walter Reed Army Medical Center Dermatology.

Erythema multiforme. Courtesy of Walter Reed Army Medical Center Dermatology.

Erythema multiforme. Courtesy of Walter Reed Army Medical Center Dermatology.

Erythema multiforme. Courtesy of Walter Reed Army Medical Center Dermatology.

Erythema multiforme of the oral mucosa. Courtesy of Walter Reed Army Medical Center Dermatology.

Erythema multiforme (Stevens-Johnson syndrome). Courtesy of Walter Reed Army Medical Center Dermatology.

Physical

Physical findings of extrahepatic dermatologic conditions associated with hepatitis C virus (HCV) infection have largely been presented in History. Physical findings of the disorders and diseases are clarified below.

• Primary dermatologic disorders of chronic hepatitis C in which HCV infection of the skin is proven or suggested
  • LP presents as flat-topped pruritic papules or coalescent plaques on the extensor surfaces of the limbs and trunk. Some individual lesions may have a purple-red hue, a fine retiform surface scale (termed Wickham striae), and an angular appearance. Involvement of the scalp hair is a cause of alopecia of the scarring variety (termed lichen planopilaris). The leaf-shaped alopecic areas appear like fingertips touching the scalp with normal intervening areas. Oral involvement with buccal lesions is common. Gum, lip, and tongue involvement can be a chronic premalignant disorder. Lesions lack the specificity of skin lesions and present as purple-red mucosal patches. Occasionally, prurigolike nodules with heaped keratotic material on a thickened base occur on the limbs and trunk. Lesions on the genitalia can be nonspecific and are one cause of vulvar pruritus.
  • The lesions of acral necrolytic erythema are flaccid bullae and described as large, painful, partially eroded, violaceous patches on the proximal half of the dorsal aspect of the feet extending over the medial and lateral malleolus.³⁰
  • Some leukocytoclastic reactions may occur.
    • Palpable purpura is the classic presentation of mixed cryoglobulinemia as leukocytoclastic inflammatory reactions in the skin.
    • Type III cryoglobulinemia results when no specific antigenicity of the immune reactants is identifiable. In this case, HCV may serve as one of the antigens. In chronic hepatitis C infection, 50% of patients have identifiable cryoglobulin levels.
    • Type II cryoglobulinemia was present in two thirds of patients with IgM rheumatoid factor. Clinicians can identify the lesions by their purpuric and elevated nature and red or purple spots on the lower legs. Specific identification is by skin biopsy. The lesions result in ulcerations of various sizes and depths because the small venules and arterioles are obstructed, damaged, or ruptured by the inflammation generated by sludging of viscous immune reactants. Polyfunctional rheumatoid factor, usually IgM, attaches to available IgG molecules, forming enormous molecules that congeal and clog small vessels and vasa vasorum of the skin and joints. Associated neutrophilic inflammatory infiltrate leads to vascular injury and ulcerations of the lower leg, which are often exquisitely painful.
  • Sialadenitis associated with HCV infection can present as a sicca syndrome with dry eyes and mouth and ulcerations from destruction of the salivary and meibomian glands.
• Secondary dermatologic disorders of chronic hepatitis C infection (mostly as a result of perturbations of the immune system)
  • Cryoglobulinemia with leukocytoclastic and necrotizing small vessel vasculitis of the skin, kidneys, joints, and eyes. Physical findings in the skin include palpable purpura and ulcerations on the lower legs.
  • Sialadenitis presents as dry eyes and dry oral and nasal mucosa. Ulcerations occur late in the evolution of this disorder.
  • In Mooren corneal ulcer, corneal ulcers form on one or both eyes beginning at the periphery or limbus.
  • Antiphospholipid syndrome results in protean physical findings in the brain, kidneys, eyes, skin, joints, and major vessels because of thrombus formation and bleeding in these major organs.
  • Autoimmune, not further categorized
    • Behçet disease is described as presenting with oral, eye, and genital ulcerations that result from an unknown vasculitic process.
    • Canities may occur. Stories abound of people's hair suddenly turning white. Chronic hepatitis C infection is one of the causes of the sudden disruption of the melanizing function of follicles.
    • Prurigo nodularis clinically appears as heaped keratotic masses on a thickened inflammatory base. Relentless scratching eventually causes excoriated masses in areas that the patient can easily reach; such areas include the shoulders, arms, upper part of the trunk, thighs, and anterior parts of the lower legs.
    • See Lichen Planus for a discussion of the condition.
    • Scarring alopecia and sclerodermatous changes may occur on the hands, back, and chest.⁵⁸ A patient presented with erosions and blisters on the hands and back and sclerodermoid thickening and scarring of this skin in the setting of PCT.
    • Immune thyroiditis is the most common extrahepatic manifestation of chronic hepatitis C infection. Findings depend on the state of the thyroid destructive process. Findings of a diffusely enlarged gland and hyperthyroidism are noted early. A normal size and a granular feel as well as normal function are noted at one point, and, later, hypothyroidism with a shrunken gland is found because much of the thyroid is destroyed.
    • In thrombocytopenia, low platelet counts result in the spontaneous asymptomatic appearance of flat areas of petechiae, purpura, and ecchymosis of the skin. Dependent areas are often involved first. Easy bruising is noted.
    • In vitiligo, areas of complete loss of pigmentation occur, and white spots develop on the skin.
    • Symmetric polyarthritis with livido reticularis is noted.⁵⁵
    • Generalized granuloma annulare with HCV infection disappears with appropriate treatment of chronic hepatitis C infection.⁵⁴
• Tertiary dermatologic disorders (nonspecific disorders manifested because of organ failure or because disease is manifested in the skin)
  • Physical findings of liver failure result from cirrhosis, autoimmune hepatitis, cholangitis, and hepatocellular carcinoma. Findings include ascites, jaundice, upper GI tract bleeding, and various accompaniments of chronic and acute liver decompensation.
  • Physical findings of hypothyroidism include coarsened and thickened dry hair and skin and myxedematous plaques on the shins (see Hypothyroidism).
• Dermatologic manifestations of HCV infection in which the cause is uncertain but the association is certain: PCT is manifested by blisters, vesicles, and milia on the acral dorsal surfaces of the extremities, especially the tops of the hands. Often, hypertrichosis of the temples, pigmentary changes, scarring, sclerodermatous changes, and chloracne are present, and ulcerations with dystrophic calcifications result from skin fragility.
• Dermatologic manifestations of malignancies associated with chronic hepatitis C disease
  • Like all lymphomas, NHL appears as nodal masses with physical signs referable to the area where they develop and disrupt.
  • Clinical findings of verrucous squamous cell carcinoma of the tongue include a thickened patch in OLP on the tongue.⁵⁹ A possible relationship exists to altered TP53 gene transformation in squamous cell carcinoma and hepatoma in cirrhosis.
  • MALT syndrome appears as mass lesions in the orbit or in a gut-associated area (eg, salivary gland or intra-abdominal, hepatic, or other area).
  • Hepatoma physically appears as a mass lesion in the liver; a metastatic lesion, often to the brain or lung; and metabolic disruptions of those organs.
• Dermatologic manifestations of treatments for HCV infection
  • Lichen myxedematosus may worsen during interferon alfa-2a therapy for chronic active hepatitis.⁶⁰ Asymptomatic, 2- to 4-mm, flesh-colored papules on the upper and lower extensor surfaces of the arms are noted. Lichen myxedematosus papules contain depositions of mucin in patients without thyroid disease who often have paraproteinemias. A localized form affects the head and neck, upper limbs, lower limbs, or trunk. A generalized form is termed scleromyxedema and affects large areas with sclerosis.
  • Capillaritis is associated with interferon alfa treatment of HCV infection.⁵¹ Pigmented purpuric eruptions on the lower legs consist of fine petechiae that appear after beginning treatment.
  • Erosive OLP and epidermolytic hyperkeratosis may occur during interferon alfa-2b therapy for chronic hepatitis C infection. These conditions appear with erythematous, scaly plaques on the scalp, chest, back, buttocks, legs, and genitalia and painful ulcerations in the mouth. The skin lesions are psoriasiform with a reddened base and variable heaped-up scale. Wickham striae occur on the lips and intraorally.⁵⁰
• Possible associations
  • Some patients with HCV infection have an asymptomatic, solitary, 5- to 10-mm diameter, dome-shaped reddish papule on the face, which represents arteriovenous hemangioma and occurs with increased frequency.
  • Gougerot-Blum disease is a manifestation of HCV infection.⁵⁶ Lesions of capillaritis on the lower legs are noted with fine petechiae in various distributions.

Causes

The causes of extrahepatic dermatologic manifestations of hepatitis C virus (HCV) infection relate to the nature of the virus, the method of infection, host responses to HCV infection, and myriad feedback considerations. HCV is a flavivirus with a positive sense single-strand RNA (ssRNA); the ends of the RNA are conserved. HCV RNA encodes 3300 amino acids. The polyprotein encoded is cleaved by host and viral proteases to yield at least 9 polypeptide proteins, core peptides, and viral envelope proteins E1 and E2 (which encode for glycoprotein spikes set in the host cell membrane derived envelope).

Six nonstructural (NS) proteins, termed NS2, NS3, NS4a, NS4b, NS5a, and NS5b, include RNA polymerase, cyclase, and other proteins necessary for viral replication. Hypervariable regions of the E2 envelope protein are responsible for quasi-species generation. Some nonessential sequences of NS genes also create variability in antigenic structure. Mutation of NS3 sections results in escape mutants that conserve essential viral functions while interfering with host T-cell function by down-regulating interleukin 2 and interferon gamma function and up-regulating interleukin 10.⁴³

The chronicity of infection also relates to inoculum size, with high rates and worse disease in patients who have undergone transfusions and organ transplantation. The resulting persistent infection and immune stimulation create the many immunologic epiphenomenon, such as LP, mixed cryoglobulinemia, and thyroiditis. A generation of factors unfavorable to apoptosis control functions may favor malignant transformation in chronic hepatitis C infection.

• Primary dermatologic disorders of chronic hepatitis C infection
  • Lichen planus: HCV particles are found in immune lymphocytes, macrophages, and dendritic cells, as well as in epithelial cells and cells of blood vessels.^26,61,62
    • In LP, HCV replicates in OLP epithelial cells of lesional and nonlesional skin cells. What role this plays in developing the LP host response is not known. HCV perturbs the class II host response by impairing the ability of the dendritic or antigen-presenting cell to stimulate a good T-cell response.⁶³
    • Lower expression of interferon gamma and interleukin 12 causes a blunted T-cell response to allostimulatory non–self-related new antigen. Another mechanism of class II immune response inhibition results from the hypervariable region (HVR-1) of envelope protein E2 suppressing CD4⁺ lymphocytes, which are stimulated to respond to HCV. The HVR-1 acts as a T-cell receptor antagonist.⁶⁴
    • A theory of causation, termed the superantigen theory of immune stimulation (which includes LP and many other immune-related disorders in which exact causation is a mystery), suggests that the human leukocyte antigen (HLA) class II response was disturbed. Superantigens, such as bacterial proteins and toxins, were proposed to act outside the HLA binding site to broadly stimulate an immune nonspecific response of wide varieties of T cells, including antiself immune responses.
  • Some leukocytoclastic reactions: Type II cryoglobulinemias in which IgM is the macromolecular rheumatoid antibody are more common than type III cryoglobulinemias. IgG was directed toward NS proteins and structural proteins. IgM antigen was the core protein, suggesting cross-reactivity to IgG.⁶⁵ Co-affinity of IgM anticore antibody to IgG may be a mechanism in the formation of the cryoprecipitate.
  • Sialadenitis: This condition is a capillaritis of the accessory and main salivary glands and the eyes.
• Secondary dermatologic disorders of chronic hepatitis C infection (mostly as a result of perturbations of the immune system)
  • Cryoglobulinemia: Leukocytoclastic vasculitis of the skin, kidneys, joints, and eyes is present. Immune stimulation of T-cell clones in HCV infection produces monoclonal macroglobulins with co-affinity to a constituent of HCV and IgG. Stimulation of this rheumatoid factor is driven by anti-HCV activity sustained by the ongoing mutation of the virus. The same pathogenesis is involved for NHL associated with HCV.
    • The mean cryoprecipitate result was 2% in one study⁶⁵ but can be greater. Immunoglobulin M (IgM) directed to a core protein sequence of HCV was also directed to a homologous immunoglobulin G (IgG) heavy-chain amino acid sequence. IgG was directed to structural and nonstructural components of HCV. The material is usually monomeric IgM molecules with high affinity for IgG (also termed rheumatoid IgM molecules or rheumatoid factor).
    • Type I cryoglobulinemias are caused by macroglobulins, such as in Waldenström macroglobulinemia, or IgG in which sludging results from massive molecules congealing in cooled venules of the lower leg.
    • Type II mixed cryoglobulins have a monoclonal rheumatoid species but vary in the IgG antigen, which is nonspecific.
    • Type III mixed cryoglobulinemias result from specific reactions of immunoglobulins to a single or well-defined antigen or various antigens, but the antibody species and the antigen are not monoclonal.
  • Sialadenitis: This condition can result from acute bacterial or viral infection or autoimmune disease, as in Sjögren disease.
  • Mooren corneal ulcer: Cross-reactivity to HCV envelope protein and a corneal antigen appears to be causative. A HCV envelope protein shares the antigenic specificity of this protein, resulting in Mooren ulcer in HCV infection. Other common etiologic causes may occur.
  • Antiphospholipid syndrome: Immune reactant immunoglobulins with antiphospholipid activity are present.
  • Autoimmune, not further categorized
    • Behçet disease: Behçet syndrome is believed to result from an unknown immunologic cause and results in a vasculitis that can cause coagulation and destruction of arteries and veins.
    • Canities: Illness and disease can affect melanogenesis of the hair.
    • Prurigo nodularis: A report of HCV infection with prurigo nodularis has been published.³⁷
    • Lichen planus: Lichen planus is most likely an immunologically mediated reaction.
    • Sialadenitis: This condition may result from an HCV infection in the salivary gland epithelium and may be a primary disorder of the glands.
    • Thyroiditis: Destructive inflammation results in early hyperthyroidism. As more of the gland is destroyed, thyroid function normalizes and then becomes subnormal in a hypothyroid picture.
    • Thrombocytopenia: Thrombocytopenia may be due to a number of causes. These include disorders producing diminished platelet production, altered platelet distribution, and increased platelet destruction. For example, an acute viral infection may produce an acquired defect in diminished platelet production. Medications may give increased platelet destruction. Low platelet counts result in the spontaneous asymptomatic appearance of flat areas of petechiae, purpura, and ecchymosis of the skin.
    • Vitiligo: A case of hair turning white as a result of HCV infection was reported.
• Tertiary dermatologic disorders (nonspecific disorders manifesting because of organ failure or because disease manifests in the skin): Persistent viral particles, persistent HCV hepatitis, and transformation are promoted by means already stated.
• Dermatologic manifestations of HCV infection in which the cause is uncertain but the association is certain
  • Proposed etiologic mechanisms for the relationship of chronic hepatitis C infection and PCT include oxidative stress from chronic hepatitis C and other viral infections (HBV and HIV) of hepatocytes that affect uroporphyrin decarboxylase (UDC) function. HIV infection causes increased serum porphyrin levels.⁶⁶ Patients with hereditary PCT and patients with hemochromatosis have sufficient UDC redundant function to prevent the appearance of symptoms. Cytochrome P4501A2, metabolically active iron, chronic hepatitis C, long-term alcohol intake, and estrogens affect the rate of conversion of uroporphyrinogen to uroporphyrin by oxidation in hepatocytes. An increase in delta5-ALA synthetase activity can present excess uroporphyrin to the hepatocyte.
  • The clinical and immunologic pattern of expression of Sjögren syndrome associated with chronic HCV infection was analyzed.⁶⁷ HCV-associated Sjögren syndrome is indistinguishable from the primary form in most cases. Chronic HCV infection was suggested as an exclusion criterion for the classification of primary Sjögren syndrome because the virus may be implicated in the development of Sjögren syndrome in a specific subset of patients. The phrase "Sjögren syndrome secondary to HCV" was recommended.
• Dermatologic manifestations of malignancies associated with chronic hepatitis C disease
  • Non-Hodgkin lymphoma: A protein amino acid sequence of HCV core protein has homology to a heavy-chain IgG sequence. The viral recognition reaction producing macroglobulin rheumatoid species antibodies may drive the mixed cryoglobulinemia reaction, and it may also cause lymphomagenesis.
  • Verrucous cell carcinoma of the tongue and OLP with HCV infection and replication: A possible relationship to altered TP53 gene transformation exists with squamous cell carcinoma and hepatoma in cirrhosis.
  • MALT syndrome: A study concerning the association of HCV and NHLB showed a prevalence of HCV of 37%.⁴⁶ Patients were older, and more patients were female than male. A closer association to immunocytoma was found than to MALT syndrome. Thirteen of 20 cases of immunocytoma had HCV infection, and localization to the orbit and mucosal surfaces was more common. HCV localized to a parotid lymphoma associated with a mixed cryoglobulinemia showed viral proliferation in parotid epithelial cells and not in NHLB cells.⁴⁷ Epstein-Barr virus and herpesvirus type 5 are the other sialotropic viruses not present in the reported cases. Local carcinogenic functions of HCV, effect on the p53 system, immunoregulation, perturbations, and malignant transformation were considered in the etiology of the conditions.
  • Hepatoma: The ends of HCV RNA are conserved. HCV core protein is a multifunctional protein with a role in apoptosis-antiapoptosis regulation of cell multiplication and tumor control.⁵³ The death domain of tumor necrosis factor 1 and the cytoplasmic tail of lymphotoxin beta bind to the core protein. Nuclear factor kappa B (NF-kB) is activated in core peptide-transfected hepatoma cells and in HCV-infected liver tissue. NF-kB activation causes resistance to apoptotic signals in transfected HCV-containing cells. An evasion mechanism of host surveillance by means of NF-kB activation is proposed as one method of viral persistence in the chronic hepatitis C state and in carcinogenesis.
• Dermatologic manifestations of treatments for HCV infection: Interferon therapy increases the incidence of immune epiphenomenon and autoimmune disorders.

Differential Diagnoses

Other Problems to Be Considered

Acral necrolytic erythema
Sialadenitis
Mooren corneal ulcer
Antiphospholipid syndrome
Canities
Prurigo nodularis
Thyroiditis
Thrombocytopenia
Polyarteritis nodosa
Pruritus
Dermatologic manifestations of liver failure
Dermatologic manifestations of thyroid destruction and failure
Non-Hodgkin lymphoma 
MALT syndrome
Hepatoma
Dermatologic manifestations of interferon alfa therapy
Livido reticularis
Symmetric polyarthritis
Arteriovenous hemangioma

Workup

Laboratory Studies

• US Preventive Services Task Force clinical guideline summary - Screening for hepatitis C in adults: recommendation statement⁶⁸

Histologic Findings

Histologic and other findings should be sought in standard references concerning each disorder.

Treatment

Medical Care

Treatment of patients with extrahepatic dermatologic manifestations of hepatitis C virus (HCV) infection is the same as that of HCV infective state and the customary treatments of the individual conditions. Many, if not all, of the dermatologic manifestations disappear when appropriate HCV treatment or viral clearance occurs. Malignant conditions may even disappear with effective therapy for the underlying chronic hepatitis C infection.

• Currently, medical treatment of patients with HCV infection consists of interferon and ribavirin therapy.
• Medical therapy for patients with individual extrahepatic dermatologic manifestations of HCV infection depends on the condition.

Also see the clinical guideline summary from the British Association for Sexual Health and HIV: United Kingdom national guideline on the management of the viral hepatitides A, B, and C 2008.⁶⁹

Consultations

• Involving specialists for both treatment and follow-up care often maximizes the care of individuals with extrahepatic cutaneous manifestations of hepatitis C virus (HCV). Monitoring of liver status and liver disease progression is beyond the usual purview of dermatologists and may necessitate consultation with gastroenterologists and hepatic specialists in the care of patients.
• Cutaneous manifestations, serious vasculitis, lymphomas, hepatomas, and metabolic disorders may require high-level management with a team approach. Individual specialists may be an important resource in the care of patients.

Follow-up

Further Outpatient Care

• Treatment of various primary, secondary, tertiary, hepatitis C virus (HCV)–related, and associated conditions is for the individual conditions. The continued successful care of patients requires attention to the underlying HCV infection of the hepatocytes and the extracutaneous disorder of symptoms.

Deterrence/Prevention

• Deterrence and prevention of the cutaneous manifestations of hepatitis C virus (HCV) are the same as in acute HCV. The primary concerns are to avoid inoculation of the virus into healthy persons through contaminated blood and organs, to prevent needlestick in at-risk groups (eg, health care workers), and to avoid high-risk behavior (eg, sharing cocaine-snorting straws and contaminated needles in pursuit of addictive drugs); all of these measures markedly reduce the likelihood of HCV infection.

Prognosis

• The prognosis of patients with dermatologic manifestations of hepatitis C virus (HCV) infection rests on the success of therapy for the underlying HCV. At this time, many successes show that eradication of HCV infection is the key factor in the prognosis. The importance of discovering HCV infection magnifies as new therapies develop.

Patient Education

• For excellent patient education resources, visit eMedicine's Skin, Hair, and Nails Center. Also, see eMedicine's patient education article Bruises.

Miscellaneous

Medicolegal Pitfalls

• Failure to diagnose an underlying condition and inappropriate or inadequate discovery and planning or treatment perpetuate hepatitis C virus (HCV) and create suboptimal care situations. The clinician  must decide how to proceed in situations in which underlying HCV is suggested by an existing history of risk factors. He/she must be comfortable with the level of skill in identifying HCV infection and must be aware of the success and failure of tests available to be willing to proceed with diagnosis. Likewise, individual cutaneous manifestations of HCV may be uncommon and unfamiliar. The severity of the disease makes early diagnosis and exacting care more critical.
• Failure of diagnosis leaves the clinician at risk if proper care to diagnose or seek further help was not taken. Reading about HCV creates awareness of the possibility of HCV in at-risk patients, especially in patients who present with cutaneous or other extrahepatic manifestations consistent with HCV infection. Accurate and timely diagnosis of HCV is more critical as better drugs become available for the treatment of HCV. At-risk individuals with markers of HCV disease must be properly diagnosed.

Special Concerns

• Transmission from mother to child in utero relates to HIV/HBV co-infection and density of viral infection with hepatitis C virus (HCV).
  • While particle density of HCV infection of approximately 100 particles per milliliter produced no vertical transmission to the baby, 1 million HCV particles per milliliter resulted in a transmission rate of 36%.⁷⁰
  • Overall, transmission to babies was 6% in mothers who were HCV-antibody positive and 10% in mothers who were HCV-RNA positive.

Multimedia

Media file 1: Cold agglutinin disease indistinguishable from cryoglobulinemia. Courtesy of Walter Reed Army Medical Center Dermatology.

Media file 2: Cryoglobulinemia, palpable purpura, dysproteinemic purpura, and leukocytoclastic vasculitis (small vessel vasculitis). Courtesy of Walter Reed Army Medical Center Dermatology.

Media file 3: Cutis marmorata. Courtesy of Walter Reed Army Medical Center Dermatology.

Media file 4: Erythema multiforme, bull's-eye lesions. Courtesy of Walter Reed Army Medical Center Dermatology.

Media file 5: Erythema dyschromicum perstans. Courtesy of Walter Reed Army Medical Center Dermatology.

Media file 6: Erythema dyschromicum perstans. Courtesy of Walter Reed Army Medical Center Dermatology.

Media file 7: Erythema nodosa. Courtesy of Walter Reed Army Medical Center Dermatology.

Media file 8: Erythema nodosa. Courtesy of Walter Reed Army Medical Center Dermatology.

Media file 9: Erythema multiforme. Courtesy of Walter Reed Army Medical Center Dermatology.

Media file 10: Erythema multiforme. Courtesy of Walter Reed Army Medical Center Dermatology.

Media file 11: Erythema multiforme. Courtesy of Walter Reed Army Medical Center Dermatology.

Media file 12: Erythema multiforme of the oral mucosa. Courtesy of Walter Reed Army Medical Center Dermatology.

Media file 13: Erythema multiforme (Stevens-Johnson syndrome). Courtesy of Walter Reed Army Medical Center Dermatology.

Media file 14: Palmar erythema. Courtesy of Walter Reed Army Medical Center Dermatology.

Media file 15: Granuloma annulare. Courtesy of Walter Reed Army Medical Center Dermatology.

Media file 16: Disseminated superficial (actinic) keratosis. Courtesy of Walter Reed Army Medical Center Dermatology.

Media file 17: Disseminated superficial (actinic) keratosis. Courtesy of Walter Reed Army Medical Center Dermatology.

Media file 18: Lichen planus. Courtesy of Walter Reed Army Medical Center Dermatology.

Media file 19: Lichen planus. Courtesy of Walter Reed Army Medical Center Dermatology.

Media file 20: Lichen planus. Courtesy of Walter Reed Army Medical Center Dermatology.

Media file 21: Lichen planus (hypertrophic type). Courtesy of Walter Reed Army Medical Center Dermatology.

Media file 22: Lichen planus (oral lesions). Courtesy of Walter Reed Army Medical Center Dermatology.

Media file 23: Lichen planus (volar wrist). Courtesy of Walter Reed Army Medical Center Dermatology.

Media file 24: Lymphoma cutis. Courtesy of Walter Reed Army Medical Center Dermatology.

Media file 25: Henoch-Schönlein purpura. Courtesy of Walter Reed Army Medical Center Dermatology.

Media file 26: Palpable purpura. Courtesy of Walter Reed Army Medical Center Dermatology.

Media file 27: Purpura in hemophilia (factor VIII deficiency). All ecchymoses and bland petechiae are in the differential diagnosis of thrombocytopenic purpuras, including thrombocytopenia secondary to hepatitis C virus in which an autoantibody to platelets is present. Courtesy of Walter Reed Army Medical Center Dermatology.

Media file 28: Progressive pigmented purpuric eruption. Courtesy of Walter Reed Army Medical Center Dermatology.

Media file 29: Progressive pigmented purpura (photo rotated 90°). Courtesy of Walter Reed Army Medical Center Dermatology.

Media file 30: Progressive pigmented purpura (Gougerot-Blum disease). Courtesy of Walter Reed Army Medical Center Dermatology.

Media file 31: Progressive pigmented purpura (Schamberg disease). Courtesy of Walter Reed Army Medical Center Dermatology.

Media file 32: Thrombocytopenic purpura. Courtesy of Walter Reed Army Medical Center Dermatology.

Media file 33: Prurigo nodularis. Courtesy of Walter Reed Army Medical Center Dermatology.

Media file 34: Prurigo nodularis. Courtesy of Walter Reed Army Medical Center Dermatology.

Media file 35: Prurigo nodularis. Courtesy of Walter Reed Army Medical Center Dermatology.

Media file 36: Chronic urticaria. Courtesy of Walter Reed Army Medical Center Dermatology.

Media file 37: Urticaria (secondary to penicillin). Courtesy of Walter Reed Army Medical Center Dermatology.

Media file 38: Nodular vasculitis. Courtesy of Walter Reed Army Medical Center Dermatology.

Media file 39: Henoch-Schönlein purpura, palpable purpura, and leukocytoclastic vasculitis. Courtesy of Walter Reed Army Medical Center Dermatology.

Media file 40: Vitiligo. Courtesy of Walter Reed Army Medical Center Dermatology.

Media file 41: Vitiligo. Courtesy of Walter Reed Army Medical Center Dermatology.

Media file 42: Waldenström hypergammaglobulinemic purpura. Courtesy of Walter Reed Army Medical Center Dermatology.

References

1. Sterling RK, Bralow S. Extrahepatic manifestations of hepatitis C virus. Curr Gastroenterol Rep. Feb 2006;8(1):53-9. [Medline].

2. Maticic M. Lichen planus in hepatitis C virus infection: an early marker that may save lives. Acta Dermatovenerol Alp Panonica Adriat. Mar 2007;16(1):3-6. [Medline].

3. Bonkovsky HL, Mehta S. Hepatitis C: a review and update. J Am Acad Dermatol. Feb 2001;44(2):159-82. [Medline].

4. Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med. Aug 19 1999;341(8):556-62. [Medline].

5. Hepatitis C: global prevalence. Wkly Epidemiol Rec. Nov 14 1997;72(46):341-4. [Medline].

6. Gordon SC, Bayati N, Silverman AL. Clinical outcome of hepatitis C as a function of mode of transmission. Hepatology. Aug 1998;28(2):562-7. [Medline].

7. Hu KQ, Tong MJ. The long-term outcomes of patients with compensated hepatitis C virus-related cirrhosis and history of parenteral exposure in the United States. Hepatology. Apr 1999;29(4):1311-6. [Medline].

8. Fattovich G, Giustina G, Degos F, et al. Effectiveness of interferon alfa on incidence of hepatocellular carcinoma and decompensation in cirrhosis type C. European Concerted Action on Viral Hepatitis (EUROHEP). J Hepatol. Jul 1997;27(1):201-5. [Medline].

9. Seeff LB, Miller RN, Rabkin CS, et al. 45-year follow-up of hepatitis C virus infection in healthy young adults. Ann Intern Med. Jan 18 2000;132(2):105-11. [Medline].

10. Vogt M, Lang T, Frosner G, et al. Prevalence and clinical outcome of hepatitis C infection in children who underwent cardiac surgery before the implementation of blood-donor screening. N Engl J Med. Sep 16 1999;341(12):866-70. [Medline].

11. Obando J, Tororelli K, Banner B. Iron: the major HFE gene mutation and chronic hepatitis C [abstract]. Gastroenterology. 1999;118:A593.

12. Banner BF, Karamitsios N, Smith L, Bonkovsky HL. Enhanced phenotypic expression of alpha-1-antitrypsin deficiency in an MZ heterozygote with chronic hepatitis C. Am J Gastroenterol. Sep 1998;93(9):1541-5. [Medline].

13. Nakashima K, Ikematsu H, Hayashi J, Kishihara Y, Mutsutake A, Kashiwagi S. Intrafamilial transmission of hepatitis-C virus among the population of an endemic area of Japan. JAMA. Nov 8 1995;274(18):1459-61. [Medline].

14. Osella AR, Misciagna G, Leone A, Di Leo A, Fiore G. Epidemiology of hepatitis C virus infection in an area of Southern Italy. J Hepatol. Jul 1997;27(1):30-5. [Medline].

15. Kiyosawa K, Tanaka E, Sodeyama T, et al. Transmission of hepatitis C in an isolated area in Japan: community-acquired infection. The South Kiso Hepatitis Study Group. Gastroenterology. Jun 1994;106(6):1596-602. [Medline].

16. Cacoub P, Poynard T, Ghillani P, et al. Extrahepatic manifestations of chronic hepatitis C. MULTIVIRC Group. Multidepartment Virus C. Arthritis Rheum. Oct 1999;42(10):2204-12. [Medline].

17. Cacoub P, Renou C, Rosenthal E, Cohen P, Loury I, Loustaud-Ratti V. Extrahepatic manifestations associated with hepatitis C virus infection. A prospective multicenter study of 321 patients. The GERMIVIC. Groupe d Etude et de Recherche en Medecine Interne et Maladies Infectieuses sur le Virus de l Hepatite C. Medicine (Baltimore). Jan 2000;79(1):47-56. [Medline].

18. Dervis E, Serez K. The prevalence of dermatologic manifestations related to chronic hepatitis C virus infection in a study from a single center in Turkey. Acta Dermatovenerol Alp Panonica Adriat. Sep 2005;14(3):93-8. [Medline].

19. Chuang TY, Stitle L, Brashear R, Lewis C. Hepatitis C virus and lichen planus: A case-control study of 340 patients. J Am Acad Dermatol. Nov 1999;41(5 Pt 1):787-9. [Medline].

20. Nagao Y, Sata M, Kage M, Kameyama T, Ueno T. Histopathological and immunohistochemical study of oral lichen planus-associated HCV infection. Eur J Intern Med. Oct 2000;11(5):277-282. [Medline].

21. Nagao Y, Sata M, Fukuizumi K, Ryu F, Ueno T. High incidence of oral lichen planus in an HCV hyperendemic area. Gastroenterology. Sep 2000;119(3):882-3. [Medline].

22. Parodi A, Divano MC, Rebora A. Serologic markers of autoimmune chronic hepatitis in patients with lichen planus. Eur J Dermatol. 1996;6:30-1.

23. Sanchez-Perez J, De Castro M, Buezo GF, Fernandez-Herrera J, Borque MJ, Garcia-Díez A. Lichen planus and hepatitis C virus: prevalence and clinical presentation of patients with lichen planus and hepatitis C virus infection. Br J Dermatol. Apr 1996;134(4):715-9. [Medline].

24. Mignogna MD, Lo Muzio L, Lo Russo L, Fedele S, Ruoppo E, Bucci E. Oral lichen planus: different clinical features in HCV-positive and HCV-negative patients. Int J Dermatol. Feb 2000;39(2):134-9. [Medline].

25. Mignogna MD, Lo Muzio L, Favia G, Mignogna RE, Carbone R, Bucci E. Oral lichen planus and HCV infection: a clinical evaluation of 263 cases. Int J Dermatol. Aug 1998;37(8):575-8. [Medline].

26. Arrieta JJ, Rodriguez-Inigo E, Casqueiro M, et al. Detection of hepatitis C virus replication by In situ hybridization in epithelial cells of anti-hepatitis C virus-positive patients with and without oral lichen planus. Hepatology. Jul 2000;32(1):97-103. [Medline].

27. Nagao Y, Kawasaki K, Sata M. Insulin resistance and lichen planus in patients with HCV-infectious liver diseases. J Gastroenterol Hepatol. Apr 2008;23(4):580-5. [Medline].

28. Maticic M, Poljak M, Lunder T, Rener-Sitar K, Stojanovic L. Lichen planus and other cutaneous manifestations in chronic hepatitis C: pre- and post-interferon-based treatment prevalence vary in a cohort of patients from low hepatitis C virus endemic area. J Eur Acad Dermatol Venereol. Jul 2008;22(7):779-88. [Medline].

29. Carbone M, Arduino PG, Carrozzo M, et al. Course of oral lichen planus: a retrospective study of 808 northern Italian patients. Oral Dis. Apr 2009;15(3):235-43. [Medline].

30. Khanna VJ, Shieh S, Benjamin J, et al. Necrolytic acral erythema associated with hepatitis C: effective treatment with interferon alfa and zinc. Arch Dermatol. Jun 2000;136(6):755-7. [Medline].

31. Monroe LR. Fatal sight: Mooren's ulcer. EyeNet Magazine. April 1998;2(4).

32. Hamid S, Cruz PD Jr, Lee WM. Urticarial vasculitis caused by hepatitis C virus infection: response to interferon alfa therapy. J Am Acad Dermatol. Aug 1998;39(2 Pt 1):278-80. [Medline].

33. Haddad J, Deny P, Munz-Gotheil C, et al. Lymphocytic sialadenitis of Sjögren's syndrome associated with chronic hepatitis C virus liver disease. Lancet. Feb 8 1992;339(8789):321-3. [Medline].

34. Domingo P, Ris J, Martinez E, Casas F. Erythema nodosum and hepatitis C. Lancet. Dec 1 1990;336(8727):1377. [Medline].

35. Davis GL, Esteban-Mur R, Rustgi V, et al. Interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. International Hepatitis Interventional Therapy Group. N Engl J Med. Nov 19 1998;339(21):1493-9. [Medline].

36. Reichel M, Mauro TM. Urticaria and hepatitis C. Lancet. Sep 29 1990;336(8718):822-3. [Medline].

37. Neri S, Raciti C, D'Angelo G, Ierna D, Bruno CM. Hyde's prurigo nodularis and chronic HCV hepatitis. J Hepatol. Jan 1998;28(1):161-4. [Medline].

38. Bulaj ZJ, Phillips JD, Ajioka RS, et al. Hemochromatosis genes and other factors contributing to the pathogenesis of porphyria cutanea tarda. Blood. Mar 1 2000;95(5):1565-71. [Medline].

39. Cribier B, Petiau P, Keller F, et al. Porphyria cutanea tarda and hepatitis C viral infection. A clinical and virologic study. Arch Dermatol. Jul 1995;131(7):801-4. [Medline].

40. Luppi M, Longo G, Ferrari MG, et al. Clinico-pathological characterization of hepatitis C virus-related B-cell non-Hodgkin's lymphomas without symptomatic cryoglobulinemia. Ann Oncol. May 1998;9(5):495-8. [Medline].

41. De Re V, De Vita S, Marzotto A, et al. Sequence analysis of the immunoglobulin antigen receptor of hepatitis C virus-associated non-Hodgkin lymphomas suggests that the malignant cells are derived from the rheumatoid factor-producing cells that occur mainly in type II cryoglobulinemia. Blood. Nov 15 2000;96(10):3578-84. [Medline].

42. Domingo JM, Romero S, Moreno JA, Domingo JA, Callen L, Gutierrez M. Hepatitis C virus infection and mixed cryoglobulinemia in patients with lymphoproliferative diseases. Haematologica. Jan 1999;84(1):94-6. [Medline].

43. Wang H, Eckels DD. Mutations in immunodominant T cell epitopes derived from the nonstructural 3 protein of hepatitis C virus have the potential for generating escape variants that may have important consequences for T cell recognition. J Immunol. Apr 1 1999;162(7):4177-83. [Medline].

44. Guastafierro S, Sessa F, Tirelli A. Biclonal gammopathy and platelet antibodies in a patient with chronic hepatitis C virus infection and mixed cryoglobulinemia. Ann Hematol. Aug 2000;79(8):463-4. [Medline].

45. Chang KM, Gruener NH, Southwood S, et al. Identification of HLA-A3 and -B7-restricted CTL response to hepatitis C virus in patients with acute and chronic hepatitis C. J Immunol. Jan 15 1999;162(2):1156-64. [Medline].

46. Vallisa D, Berte R, Rocca A, et al. Association between hepatitis C virus and non-Hodgkin's lymphoma, and effects of viral infection on histologic subtype and clinical course. Am J Med. May 1999;106(5):556-60. [Medline].

47. De Vita S, Sansonno D, Dolcetti R, et al. Hepatitis C virus within a malignant lymphoma lesion in the course of type II mixed cryoglobulinemia. Blood. Sep 1 1995;86(5):1887-92. [Medline].

48. Ramos-Casals M, la Civita L, de Vita S, et al. Characterization of B cell lymphoma in patients with Sjögren's syndrome and hepatitis C virus infection. Arthritis Rheum. Feb 15 2007;57(1):161-70. [Medline].

49. Villano SA, Vlahov D, Nelson KE, Cohn S, Thomas DL. Persistence of viremia and the importance of long-term follow-up after acute hepatitis C infection. Hepatology. Mar 1999;29(3):908-14. [Medline].

50. Schlesinger TE, Camisa C, Gay JD, Bergfeld WF. Oral erosive lichen planus with epidermolytic hyperkeratosis during interferon alfa-2b therapy for chronic hepatitis C virus infection. J Am Acad Dermatol. Jun 1997;36(6 Pt 1):1023-5. [Medline].

51. Gupta G, Holmes SC, Spence E, Mills PR. Capillaritis associated with interferon-alfa treatment of chronic hepatitis C infection. J Am Acad Dermatol. Nov 2000;43(5 Pt 2):937-8. [Medline].

52. Kono T, Kobayashi H, Ishii M, Nishiguchi S, Taniguchi S. Synchronous development of disseminated superficial porokeratosis and hepatitis C virus-related hepatocellular carcinoma. J Am Acad Dermatol. Nov 2000;43(5 Pt 2):966-8. [Medline].

53. Tai DI, Tsai SL, Chen YM, et al. Activation of nuclear factor kappaB in hepatitis C virus infection: implications for pathogenesis and hepatocarcinogenesis. Hepatology. Mar 2000;31(3):656-64. [Medline].

54. Granel B, Serratrice J, Rey J, et al. Chronic hepatitis C virus infection associated with a generalized granuloma annulare. J Am Acad Dermatol. Nov 2000;43(5 Pt 2):918-9. [Medline].

55. Shearer CM, Jackson JM, Callen JP. Symmetric polyarthritis with livedo reticularis: a newly recognized manifestation of hepatitis C virus infection. J Am Acad Dermatol. Oct 1997;37(4):659-61. [Medline].

56. Chima N, Houghton JP, Igwegbe I, et al. Gougerot-Blum disease as a manifestation of hepatitis C infection. J Cutan Pathol. 2000;27:569.

57. Fernandes SS, Carvalho J, Leite S, et al. Erythema induratum and chronic hepatitis C infection. J Clin Virol. Apr 2009;44(4):333-6. [Medline].

58. Jackson JM, Callen JP. Scarring alopecia and sclerodermatous changes of the scalp in a patient with hepatitis C infection. J Am Acad Dermatol. Nov 1998;39(5 Pt 2):824-6. [Medline].

59. Carrozzo M, Carbone M, Gandolfo S, Valente G, Colombatto P, Ghisetti V. An atypical verrucous carcinoma of the tongue arising in a patient with oral lichen planus associated with hepatitis C virus infection. Oral Oncol. May 1997;33(3):220-5. [Medline].

60. Rongioletti F, Rebora A. Worsening of lichen myxedematosus during interferon alfa-2a therapy for chronic active hepatitis C. J Am Acad Dermatol. May 1998;38(5 Pt 1):760-1. [Medline].

61. Ferri C, Zignego AL, Bombardieri S, et al. Etiopathogenetic role of hepatitis C virus in mixed cryoglobulinemia, chronic liver diseases and lymphomas. Clin Exp Rheumatol. Nov-Dec 1995;13 Suppl 13:S135-40. [Medline].

62. Sansonno D, Cornacchiulo V, Iacobelli AR, Di Stefano R, Lospalluti M, Dammacco F. Localization of hepatitis C virus antigens in liver and skin tissues of chronic hepatitis C virus-infected patients with mixed cryoglobulinemia. Hepatology. Feb 1995;21(2):305-12. [Medline].

63. Kanto T, Hayashi N, Takehara T, et al. Impaired allostimulatory capacity of peripheral blood dendritic cells recovered from hepatitis C virus-infected individuals. J Immunol. May 1 1999;162(9):5584-91. [Medline].

64. Frasca L, Del Porto P, Tuosto L, et al. Hypervariable region 1 variants act as TCR antagonists for hepatitis C virus-specific CD4+ T cells. J Immunol. Jul 15 1999;163(2):650-8. [Medline].

65. Hartmann H, Schott P, Polzien F, et al. Cryoglobulinemia in chronic hepatitis C virus infection: prevalence, clinical manifestations, response to interferon treatment and analysis of cryoprecipitates. Z Gastroenterol. Nov 1995;33(11):643-50. [Medline].

66. Lim HW, Pereira A, Sassa S, Kim M, Zolla-Pazner S. Early-stage HIV infection and hepatitis C virus infection are associated with elevated serum porphyrin levels. J Am Acad Dermatol. Dec 1998;39(6):956-9. [Medline].

67. Ramos-Casals M, Loustaud-Ratti V, De Vita S, et al. Sjogren syndrome associated with hepatitis C virus: a multicenter analysis of 137 cases. Medicine (Baltimore). Mar 2005;84(2):81-9. [Medline].

68. [Guideline] U.S. Preventive Services Task Force. Screening for hepatitis C virus infection in adults: recommendation statement. Ann Intern Med. Mar 16 2004;140(6):462-4. [Medline].

69. [Guideline] British Association for Sexual Health and HIV. United Kingdom national guideline on the management of the viral hepatitides A, B, and C 2008. National Guidelines Clearinghouse. 2008.

70. Ohto H, Terazawa S, Sasaki N, et al. Transmission of hepatitis C virus from mothers to infants. The Vertical Transmission of Hepatitis C Virus Collaborative Study Group. N Engl J Med. Mar 17 1994;330(11):744-50. [Medline].

71. Abe Y, Tanaka Y, Takenaka M, Yoshida H, Yatsuhashi H, Yano M. Leucocytoclastic vasculitis associated with mixed cryoglobulinaemia and hepatitis C virus infection. Br J Dermatol. Feb 1997;136(2):272-4. [Medline].

72. Akiyama M, Inamoto N. Arteriovenous haemangioma in chronic liver disease: clinical and histopathological features of four cases. Br J Dermatol. Mar 2001;144(3):604-9. [Medline].

73. Bonkovsky HL, Poh-Fitzpatrick M, Pimstone N, et al. Porphyria cutanea tarda, hepatitis C, and HFE gene mutations in North America. Hepatology. Jun 1998;27(6):1661-9. [Medline].

74. Cacoub P, Hausfater P, Musset L, Piette JC. Mixed cryoglobulinemia in hepatitis C patients. GERMIVIC. Ann Med Interne (Paris). Feb 2000;151(1):20-9. [Medline].

75. De Re V, De Vita S, Marzotto A, et al. Pre-malignant and malignant lymphoproliferations in an HCV-infected type II mixed cryoglobulinemic patient are sequential phases of an antigen-driven pathological process. Int J Cancer. Jul 15 2000;87(2):211-6. [Medline].

76. Dega H, Frances C, Dupin N, et al. [Pruritus and the hepatitis C virus. The MULTIVIRC Unit]. Ann Dermatol Venereol. Jan 1998;125(1):9-12. [Medline].

77. Eng MA, Kallemuchikkal U, Gorevic PD. Hepatitis C virus, autoimmunity and lymphoproliferation. Mt Sinai J Med. Mar 2000;67(2):120-32. [Medline].

78. Galossi A, Guarisco R, Bellis L, Puoti C. Extrahepatic manifestations of chronic HCV infection. J Gastrointestin Liver Dis. Mar 2007;16(1):65-73. [Medline].

79. Geissler M, Gesien A, Tokushige K, Wands JR. Enhancement of cellular and humoral immune responses to hepatitis C virus core protein using DNA-based vaccines augmented with cytokine-expressing plasmids. J Immunol. Feb 1 1997;158(3):1231-7. [Medline].

80. Gordon SC, Patel AH, Kulesza GW, Barnes RE, Silverman AL. Lack of evidence for the heterosexual transmission of hepatitis C. Am J Gastroenterol. Dec 1992;87(12):1849-51. [Medline].

81. Harada K, Tsuneyama K, Sudo Y, Masuda S, Nakanuma Y. Molecular identification of bacterial 16S ribosomal RNA gene in liver tissue of primary biliary cirrhosis: is Propionibacterium acnes involved in granuloma formation?. Hepatology. Mar 2001;33(3):530-6. [Medline].

82. Kanazawa K, Yaoita H, Tsuda F, Okamoto H. Hepatitis C virus infection in patients with urticaria. J Am Acad Dermatol. Aug 1996;35(2 Pt 1):195-8. [Medline].

83. Kontochristopoulos GJ, Aroni K, Anagnostopoulos G, Nakopoulou L, Tassopoulos NC. Erythema dyschromicum perstans and hepatitis C virus infection. Int J Dermatol. May 2001;40(5):346-8. [Medline].

84. Laganovic M, Jelakovic B, Kuzmanic D, et al. Complete remission of cryoglobulinemic glomerulonephritis (HCV-positive) after high dose interferon therapy. Wien Klin Wochenschr. Jul 7 2000;112(13):596-600. [Medline].

85. Longombardo G, Ferri C, Marchi S, et al. Immune response to an epitope of the NS4 protein of hepatitis C virus in HCV-related disorders. Clin Immunol Immunopathol. May 1998;87(2):124-9. [Medline].

86. Lopes LM, Lopes EP, Silva E, et al. Prevalence of hepatitis C virus antibodies in primary glomerulonephritis in Brazil. Am J Nephrol. 1998;18(6):495-7. [Medline].

87. Mendez P, Saeian K, Reddy KR, et al. Hepatitis C, cryoglobulinemia, and cutaneous vasculitis associated with unusual and serious manifestations. Am J Gastroenterol. Aug 2001;96(8):2489-93. [Medline].

88. Moran MJ, Fontanellas A, Brudieux E, et al. Hepatic uroporphyrinogen decarboxylase activity in porphyria cutanea tarda patients: the influence of virus C infection. Hepatology. Feb 1998;27(2):584-9. [Medline].

89. Polzien F, Schott P, Mihm S, Ramadori G, Hartmann H. Interferon-alpha treatment of hepatitis C virus-associated mixed cryoglobulinemia. J Hepatol. Jul 1997;27(1):63-71. [Medline].

90. Schmidt-Mende J, Bieck E, Hugle T, et al. Determinants for membrane association of the hepatitis C virus RNA-dependent RNA polymerase. J Biol Chem. Nov 23 2001;276(47):44052-63. [Medline].

91. Schott P, Polzien F, Muller-Issberner A, Ramadori G, Hartmann H. In vitro reactivity of cryoglobulin IgM and IgG in hepatitis C virus-associated mixed cryoglobulinemia. J Hepatol. Jan 1998;28(1):17-26. [Medline].

92. Schott P, Pott C, Ramadori G, Hartmann H. Hepatitis C virus infection-associated non-cryoglobulinaemic monoclonal IgMkappa gammopathy responsive to interferon-alpha treatment. J Hepatol. Aug 1998;29(2):310-5. [Medline].

93. Thomas DL, Astemborski J, Rai RM, et al. The natural history of hepatitis C virus infection: host, viral, and environmental factors. JAMA. Jul 26 2000;284(4):450-6. [Medline].

94. Toth CM, Pascual M, Chung RT, et al. Hepatitis C virus-associated fibrosing cholestatic hepatitis after renal transplantation: response to interferon-alpha therapy. Transplantation. Nov 15 1998;66(9):1254-8. [Medline].

Keywords

hepatitis C virus, hepatitis C virus skin disease, HCV skin disease, lichen planus, acral necrolytic erythema, sialadenitis, chronic hepatitis C, cryoglobulinemia, leukocytoclastic vasculitis, Mooren corneal ulcer, antiphospholipid syndrome, Behcet's disease, Behcet disease, canities, Hyde's prurigo nodularis, Hyde prurigo nodularis, thyroiditis, thrombocytopenia, vitiligo, polyarteritis nodosa, pruritus, urticaria, hepatic failure, thyroid failure, porphyria cutanea tarda, non-Hodgkin lymphoma, verrucous squamous cell carcinoma of the tongue, mucosa-associated lymphoid tumor syndrome, MALT syndrome, hepatoma, lichen planus, erythema dyschromicum perstans, disseminated superficial actinic porokeratosis, hepatocellular cancer, granuloma annulare, symmetric polyarthritis, livido reticularis, arteriovenous hemangiomas, Gougerot-Blum disease, capillaritis of the lower legs, Schamberg's disease, Schamberg disease, progressive pigmented purpura

Contributor Information and Disclosures

Author

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi
Disclosure: Nothing to disclose.

Coauthor(s)

Arthur P Birnkrant, MD, Clinical Instructor, Department of Dermatology, University of Medicine and Dentistry of New Jersey
Arthur P Birnkrant, MD is a member of the following medical societies: American Academy of Dermatology and American Society for MOHS Surgery
Disclosure: Nothing to disclose.

Medical Editor

Craig A Elmets, MD, Director of Dermatology, Departments of Dermatology, Pathology, and Environmental Health Sciences; Professor, The Kirklin Clinic, University of Alabama at Birmingham
Craig A Elmets, MD is a member of the following medical societies: American Academy of Dermatology, American Association of Immunologists, American College of Physicians, American Federation for Medical Research, and Society for Investigative Dermatology
Disclosure: Palomar Medical Technologies Stock None; Amgen Consulting fee Review panel membership; Astellas Consulting fee Review panel membership; Massachusetts Medical Society Salary Employment; Abbott Laboratories Grant/research funds Independent contractor

Pharmacy Editor

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, Northside Clinic
David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Managing Editor

Jeffrey P Callen, MD, Professor of Medicine, Chief, Division of Dermatology, University of Louisville School of Medicine
Jeffrey P Callen, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and American College of Rheumatology
Disclosure: Amgen Honoraria Consulting; Abbott Honoraria Consulting; Electrical Optical Sciences Honoraria Consulting; Centocor Honoraria Consulting; Medicis Honoraria Consulting; Celgene Honoraria Consulting

CME Editor

Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University
Catherine Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Michael Birnkrant, BS, to the development and writing of this article.

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