HomeMethodsStatementsThe Liver

HCV SKIN DISEASES

Pruritus (Itchy Skin) and HCV

Objective. Determine the characteristics of pruritis in a selected population of patients with positive hepatitis C virus serology. Patients and methods. In a retrospective study, we re-examined outpatient reports for patients who consulted for pruritis from January 1993 to April 1996 and were followed in a hepatology unit for hepatitis C infection. The following data were collected: age, sex, risk factors, HIV and HBV serologies, duration of pruritis and diagnosis, ALAT, gamma GT and total bilirubin, METAVIR score, HCV RNA PCR, search for cryoglobulins, antiviral and dermatology treatments. There were 1,060 patients followed in the hepatology unit during this period. including 327 with cirrhosis.

Results. Twenty-seven patients were retained for study, 16 men and 11 women, mean age 53 years. None of the patients had HIV infection, 7 had a past history of hepatitis B infection (positive for anti-Hbc antibodies). Median duration of pruritis prior to consultation was 3 months (95 p. 100 CI : 3 months-2 years). Pruritis was associated with non-specific lesion in 19 cases (70 p. 100: 95 p. 100 CI: 51-85 p. 100). There were excoriated eczema-like lesions in 11 cases (41 p. 100: 95 p. 100 CI: 15-49 p. 100). Other causes were urticaria in 5 cases (18 p. 100: 95 p. 100 CI: 7-36 p. 100), including 1 case of urticarial vasculitis with cryoglobulinemia, 2 cases with atopic dermatitis, and 1 case of primary biliary cirrhosis. In four cases, lichen planus was associated. Skin biopsies were obtained in 10 patients and showed eczema-like alterations in 9 and urticarial vasculitis in 1. Mean ALAT and gamma GT levels were 2.6 N (95 p. 100 CI: 1.9 N-3.3 N) and 2.2 N (95 p. 100 CI: 1.4 N-3 N) respectively, including 11 cases without cholestasis (normal gamma Gt). PCR was positive in 13 cases out of 15. Cryoglobulinemia was found in 10 cases out of 24. At consultation, 3 patients were given ursolvan, 7 interferon, 1 ursolvan with ribavirin, and 3 an interferon-ribavirin combination. Dermatology treatment associated antihistamine agents, emollients, and corticosteroids. This population of hepatology patients referred for pruritis comprised 2.5 p. 100 of all patients (95 p. 100 CI: 1.7-3.6 p. 100). Among them, 1.8 p. 100 (95 p. 100 CI: 1.1-2.7 p. 100) had eczema-like lesions associated with cutaneous xerosis.

Discussion. Pruritis in our patient population was generally associated with non-specific excoriations, prurigo or xerosis in 19 cases (70 p. 100). As only ambulatory patients were retained for analysis, this is not a comprehensive population and the percentage of non-specific pruritis, evaluated at 1.8 p. 100: is probably an underestimation. Cholestasis cannot explain alone these manifestations since 11 patients had normal gamma GT levels. Several etiologies could he involved: a direct effect of HCV, interferon. A prospective study should allow an estimation of frequency, risk factors and possible impact on quality of life.

Itchy skin linked to hepatitis C infection

In a study of 19 patients referred for treatment for severely itchy skin, 4 (21%) were found to have hepatitis C, according to a report in the October issue of Digestive Diseases and Sciences. And another study of 122 hepatitis C patients showed that about 4% had severe itchy skin, known medically as pruritus.

Hepatitis C is a viral infection of the liver that can lead to liver failure and the need for liver transplant. Dr. Jay H. Hoofnagle, of the National Cancer Institute, Bethesda, Maryland, and colleagues took a closer look at eight of the patients from the studies, who were aged 35 to 68, had been diagnosed with hepatitis from 1 to 20 years previously, and had pruritus as the major or first symptom of the disease.

Liver biopsies revealed that all patients had liver damage similar to that seen in cholestasis, a liver disease caused by stagnation of the bile in the bile ducts. Itchy skin is a ommon side effect of cholestasis.

The authors conclude that ``pruritus may be the dominant symptom in patients with chronic hepatitis C and, if severe enough, may be a factor in making a decision regarding liver transplantation.''

The cyclic behaviour of NANB hepatitis as basis for standardized diagnostic. 

Liehr H, Seelig R, Seelig HP Dev Biol Stand 1983;54:509-13 

Efforts were made to characterize the clinical and biochemical behaviour of NANB hepatitis in 51 patients. 15 patients had osttransfusion NANB hepatitis, 36 a sporadic form of the disease. The patients' complaints predominantly were nausea and vomiting (64%), in about each 25% cardial complaints, lassitude, muscle pain and fever were observed. An eczema in a kind of maculopapular eruptions was frequently seen. The ratio of SGOT/SGPT was almost never less 1.0, Gamma-GT was consistently increased. The biochemical changes relapsed frequently. In posttransfusion NANB hepatitis the relapses were observed to occur predominantly around day 21, 28, 42, 49, 56, 63, 70, 77, and in further weekly intervals. 
PMID: 6140198, UI: 84085515 

 Chronic hepatitis C and skin diseases: a review.

AUTHOR: Daoud MS, Gibson LE, Daoud S, el-Azhary RA, Department of Dermatology, Mayo Clinic Rochester, Minnesota 55905, USA.; SOURCE: Mayo Clin Proc 1995 Jun;70(6):559-64

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

DESIGN: 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.

RESULTS: 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.

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

Skin diseases associated with hepatitis C virus infection. 

J Eur Acad Dermatol Venereol 1998 Jan;10 (1):12-21 Hadziyannis SJ Academic Department of Medicine, Hippokration General Hospital,  Athens, Greece.

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-Behcet 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.

Hepatitis C Virus in Dermatology

Arch Dermatol. 1995;131:1185-1193  Jean-Michel Pawlotsky, MD; Daniel Dhumeaux, MD; Martine Bagot, MD, PhD

Background:
Hepatitis C virus (HCV) is the main causative agent of parenterally transmitted non-A, non-B viral hepatitis. Infections with HCV may be associated with disorders of various organs other than the liver, essentially through immunologic mechanisms.

Objectives:
To provide an update on HCV and to review and discuss dermatologic disorders directly or indirectly related to HCV-induced liver disease.

Observations:
The main dermatologic disorders in HCV infection include (1) vasculitis (mainly cryoglobulin-associated vasculitis, the cause of which is HCV in most cases, and, possibly, some cases of polyarteritis nodosa); (2) sporadic porphyria cutanea tarda; (3) cutaneous and/or mucosal lichen planus; and (4) salivary gland lesions, characterized by lymphocytic capillaritis, sometimes associated with lymphocytic sialadenitis resembling that of Sjoegren's syndrome.

Conclusions:
Hepatitis C virus is the cause of, or is associated with, various dermatologic disorders. In patients with such disorders, HCV infection must be sought routinely because antiviral therapy may be beneficial in some of them.

Hepatitis C Virus–Related Skin Diseases

Marie-Sylvie Doutre, MD

THE HEPATITIS C virus (HCV) was identified 10 years ago thanks to research in molecular biology.1 At present, HCV infection is a major public health problem in many countries, with the worldwide prevalence of HCV markers ranging from from 0.1% to 5% (including 150 million chronic carriers). Infection becomes chronic in 70% to 80% of cases and is complicated by cirrhosis within 20 years of contamination in about 20% of them. Once the cirrhotic process has begun, the incidence of hepatocellular carcinoma ranges from 1% to 4%. Factors leading to more severe liver injury include excessive alcohol comsumption, older age at the time of initial infection, immunosuppression, and specific genotypes. During the course of HCV infection, many extrahepatic manifestations have been reported.2
 

IS THIS VIRUS CAPABLE OF INDUCING CUTANEOUS DISEASES?
YES, CERTAINLY.

Hepatitis C viral infection is clearly involved in cases of mixed cryoglobulinemia (MC) and porphyria cutanea tarda (PCT). Recent evidence has incriminated HCV in many cases that, in the past, would have been diagnosed as essential MC. This syndrome is characterized by palpable purpura, arthralgias, and general weakness associated with cryoglobulins composed of different immunoglobulins with a monoclonal component (rheumatoid factor) in type II and polyclonal immunoglobulins in type III.

Since the initial observations in 1990,3 several reports have described MC in about half of all patients with chronic hepatitis.4-8 Patients with cryoglobulinema had cirrhosis more frequently and had a longer history of hepatitis than those without.9 Similarly, 50% to 90% of patients with MC had anti-HCV antibodies and liver dysfunction.

Affected patients often present with signs and symptoms of vasculitis involving one or more organ systems. An increasing number of recent reports suggest that cutaneous lesions are a major presenting feature in some patients and even lead to the discovery of occult HCV infection.10 There is a correlation between the presence of palpable purpura, the most frequent cutaneous lesion, and cryoglobulin levels. Several findings confirm that HCV is the etiologic agent for MC and that the virus may be involved in the pathogenesis of the vasculitis.10 Hepatitis C virus RNA sequences and HCV antibodies have been found in sera and cryoprecipitates, more concentrated in cryoprecipitates than in supernatants.11 By immunohistochemical or in situ hybridization methods, HCV has been found in association with IgM and IgG in the cutaneous vasculitic lesions of some patients.12-14 More often than not, type I interferons have proven effective in treating cryoglobulinemia and improving the results of liver function tests, which suggests a direct role for HCV in the development of MC.15, 16 On the other hand, in systemic vasculitis, as in polyarteritis nodosa, HCV does not seem to play an important role.17-19

A very strong association (50%-90%) between sporadic PCT and HCV infection has been demonstrated in patients from the European Mediterranean basin (Italy, Spain, and France),20-27 the United States,28 and Japan.29 In other countries (eg, Germany and New Zealand), the prevalence is low, indicating that there is not significant association between HCV and PCT.30, 31 Hepatitis C viral infection is associated with an increased severity of liver histologic changes, chronic hepatitis, and cirrhosis. Some cases of hepatocellular carcinoma complicating PCT may also be linked to HCV infection.

Yes, Probably.
 
Lichen planus (LP) is possibly associated with HCV infections. In 1991, LP was described in a patient with chronic hepatitis and HCV antibodies.32 Since then, numerous cases of LP associated with HCV infection have been published. Several studies have been performed to gather information on the prevalences of HCV infection in patients with LP. The reported prevalence of HCV infection in patients with LP show wide variations, from 3.8% in France33 to 62% in Japan,34 probably owing to the various techniques used to detect HCV: second- or third-generation assays (enzyme-linked immunosorbent assays or immunoblot assays) for the detection of anti-HCV antibodies and polymerase chain reaction for the detection of HCV RNA. Account must also be taken of the prevalence of the infection in a control population from the same geographic region.

Yes, Perhaps.
 
Various skin diseases have also been described with HCV infection: acute and chronic urticaria,35-37 pruritus and prurigo,38 and psoriasis.39 However, epidemiological studies are essential to determine the real prevalence of these dermatoses in the course of HCV infection. The prospective case-controlled study of Cribier et al40 in this issue of the ARCHIVES proves that at least in Europe, HCV rates in chronic urticaria are similar to those of the general population.

HOW DOES THE VIRUS ACT?

In cryoglobulinemia, one possible mechanism is that antigen-antibody complexes made of viral particles and anti-HCV antibodies might be linked by IgM pentamers with rheumatoid factor activity directed at anti-HCV antibodies. Immune complexes initiate activation of endothelial cells, leading to altered vascular permeability, neutrophil infiltration, and vessel wall damage. However, the presence of a cryoglobulin does not necessarily result in vascular damage, which depends on the presence of factors of the complement in the cryoprecipitate, the physical and chemical characteristics of the antigen-antibody complex, and probably on other local and/or circulatory factors. An alternative mechanism was suggested by the findings of HCV in vascular endothelial cells. Antibodies or T cells sensitized to HCV-containing endothelial cells may initiate the process.

In PCT, HCV probably acts as a nonspecific factor that reveals the enzymatic deficit of uroporphyrinogen decarboxylase in a genetically determined terrain. The role of HCV in LP remains unclear: is it an alteration of epidermal antigenicity? A replication of virus in skin and mucosal lesions? This latter hypothesis is in fact unlikely, since treatment with interferons more often than not results in the eruption or aggravation of lesions.41 

HOWEVER, WHY DO THESE SIGNS APPEAR ONLY IN CERTAIN PATIENTS? 

Viral, genetic, or environnemental factors may be reponsible for cutaneous diseases associated with HCV infection only in some patients. Several reasons have been proposed.

Viral Genotypes?
 
The distribution of HCV genotypes varies according to the region studied. In most studies there is no predominance of any given genotype compared with a control population devoid of any cutaneous manifestation.⁴²

In cryoglobulins, no predominance of a genotype has been noted except in 2 Italian studies.^{43, 44} Three studies reported the genotype distribution of HCV-infected patients with LP; this was similar to that of patients with chronic hepatitis without LP.^45-47

Viral Load?
 
Quantitation of viral load by reverse-transcription polymerase chain reaction may offer a reliable marker of disease status. However, viral load does not influence the occurrence of cutaneous signs in relation to a cryoglobulin.

Genetic Predisposition of the Host?
 
Hepatitis C virus induces nonhepatic autoimmune manifestations only in susceptible individuals, particularly those carrying the HLA A1, B8, DR3 haplotypes or the DR4 allotype.⁴⁸ Recently, mutations in the HFE gene associated with hereditary hemochromatosis (Cys 282 tyr, His 63 Asp) have been associated with sporadic and familial PCT, suggesting that inheritance of hemochromatosis alleles may be a susceptibility factor for the development of the disease.^{49, 50} Hepatitis C viral infection and these mutations might synergize to produce clinically manifest PCT.

Coinfections With Other Viruses?
 
Coinfection with hepatitis B virus and HCV is frequent in PCT. Anti–hepatitis B virus and anti-HCV antibodies and/or hepatitis B virus DNA and HCV RNA were simultaneously detected in the serum of about 30% of patients.^23-26 In patients with human immunodeficiency virus, both the human immunodeficiency virus and the HCV are etiologic factors for PCT. However, HCV probably plays the major role.

Hepatitis G virus is part of RNA virus, transmitted by the same route as HCV. Some studies suggest that hepatitis G virus is not associated with extrahepatic manifestations.^40-51

When faced with leukocytoclasic vasculitis, a PCT, and probably a lichen, especially an oral, erosive lichen, the physician must look for a possible HCV infection. With other cutaneous diseases such as psoriasis and prurigo, no systematic screening is possible without further epidemiological studies, like that of Cribier et al⁴⁰ with chronic urticaria.

Author/Article Information Marie-Sylvie Doutre, MD Department of Dermatology Haut-Leveque Hospital 33604 Pessac, France 


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ABSTRACT  |  FULL TEXT  |  PDF

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Necrolytic acral erythema is a distinctive skin lesion that occurs almost exclusively with hepatitis C infection, according to a report from Egypt.

Necrolytic erythemas are a group of disorders characterized clinically by erythematous lesions that frequently develop blisters and microscopically by epidermal necrolytic changes involving mostly the upper part of the epidermis. Necrolytic erythemas include: necrolytic migratory erythema (NME), which is seen most frequently with a glucagonoma syndrome, in which an alpha cell tumor of the pancreas and, less frequently, a bronchial carcinoma secretes large quantities of glucagon that may contribute to hypoaminoacidemia, glucose intolerance, and cutaneous necrotic lesions; acrodermatitis enteropathica (AE), that results from congenital or acquired zinc deficiency; biotin deficiency, and essential fatty acid deficiency, which both produce skin lesions identical to those of AE and pseudoglucagonoma syndrome that was described with chronic active hepatitis and exhibited NME- like lesions in the skin.

In this study, researcher Mohamed E. Darouti and Abu El Ela described a new type of necrolytic erythema that developed almost exclusively on the top of the feet in seven patients with active viral hepatitis C. The researchers termed the erythema necrolytic acral erythema (NAE).

"The lesions of necrolytic acral erythema described share all the microscopic and some of the clinical features of the other necrolytic erythemas; however, the necrolytic acral erythema is typically not associated with central clearing," they wrote ("Necrolytic Acral Erythema: A Cutaneous Marker of Viral Hepatitis C," International Journal of Dermatology, April 1996;35(4):252-257). "In its early stage, it appears in the form of dusky erythematous areas with flaccid blisters found particularly on the margins of the lesions. Chronic lesions have a thick surface, very similar to that of erythrokeratoderma; however, a rim of dusky erythema is always present at the periphery. Acute exacerbation is the rule and it is always associated with deterioration of liver function. During acute exacerbations, blisters reappear and the burning sensation and tenderness may become intolerable."

With regard to diagnosis, necrolytic acral erythema may be confused with necrolytic migratory erythema because both conditions occur with chronic active hepatitis and both conditions are associated with low levels of amino acids. Necrolytic acral erythema differs, however, because it is not annular and is restricted to the acral parts, most particularly the dorsa of the feet. The authors noted that necrolytic acral erythema may also be confused with psoriasis or erythrokeratoderma, but the absence of scales in addition to the presence of flaccid blisters and the dusky erythema can differentiate necrolytic acral erythema from these conditions.

Darouti and Ela found that amino acid infusion in some patients resulted in temporary improvement of the skin lesions; however, the lesions recurred while the patients were still on the amino acid treatment. This, they noted, may indicate that the hypoaminoacidemia is not entirely related to the pathogenesis of necrolytic acral erythema.

"Several questions concerning necrolytic acral erythema await to be answered," they wrote. "Some of these are: (1) why are the lesions confirmed to the dorsa of feet (2) are the lesions related to low amino acid levels or the virus itself and (3) what is the incidence of necrolytic acral erythema among patients with hepatitis C. Further studies are being carried out to answer some of these questions."

The corresponding author for this study is Mohamed El Darouti, 47 Falaki Street, Post No. 11461, Bab El louk, Cairo, Egypt.

THE PHENOMENA OF LEG PIGMENTATION IN CASES OF CHRONIC LIVER DISEASE Y.A.

ELGHAFFAR, M.E.ELWAHAB, S.M. SALEH, A.A.RAOUF,H.M.LIMOUNE. LIVER Institute. Dept of Med. Dep. of biochemistry - Menofeia university The aim of this work was to study this phenomenon, its relative frequency, its relation to various forms of chronic liver disease its correlation to other features of chronic liver disease, its pathogenesis and the underlying mechanisms of its production. This study included 54 male and female patients with chronic liver disease presenting with pigmentation of skin on the dorsum of their feet. The subjects were divided into 3 groups according to the severity of skin pigmentation. Fifty male and female patients with chronic liver disease without skin pigmentation were also included in this work as a control group. Patients and controls were selected from inpatients and outpatients of the department of medical hepatology of liver institute of Menoufyia University. The study was done in the period from october 1992 to june 1995. The study included : history, clinical examination, urine and stool analysis, rectal biopsy for patients who were negative for bilharzial ova in urine and stool analysis, liver function tests, bleeding and coagulation time, total s. iron, virologic liver profile for HB cAb, HBeAg, HBeAb, HBsAb and anti HCV, ultrasonographic examination of abdomen, direct liver biopsy, and skin biopsy. Skin pigmentation in our studied patients appeared as bilateral permanent diffuse area of hyperpigmented skin on a big part or the whole of the dorsum of the foot extending in some patients into the shaft of the leg above the ankle joint. In conclusion, it is seen that the phenomenon of pigmentation of the dorsum of the foot has significantly apositive association with : yellow color of the sclera, abdominal distention, bleeding per nose and gums, and disturbed levels of consciousness vascular spiders, and edema of lower limbs decreased size of the liver (shrunken liver), and increased size of spleen (mild splenomegaly), positive schistosomiasis(both in stool &rectal snip), increased level of total s. proteins and decreased level s . albumin, increased level of total s. iron, HCV-Ab, HBcAb. ascites, and increased diameter of the portal vein (portal hypertension) and hemosiderin, hyaline degenerative changes, and melanin of skin biopsy. Thus, we can conclude that the finding of pigmentation of the foot can be considered a confirmatory sign of cirrhosis in the presence of positive histopathology of the liver and a useful suggestive sign of cirrhosis in the absence of histopathlogy.  
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