clinical manifestations of hepatitis c

HEPATITIS C 1089-3261/97 $0.00 + 2 0

CLINICAL MANIFESTATIONS OF HEPATITIS C

Rolland C. Dickson, MD

Hepatitis C is a common problem that affects approximately 1.4% of the US popu1ation.l Thus, the recognition and understanding of the varied clinical manifestations of HCV (Table 1) are important because they often impact on disease course and clinical management. This article will discuss clinical manifestations that are established, partially established, and speculative. The discussions have been arranged under the major headings of Hepatic, Hematologic, Autoimmune, Renal, and Dermatologic, which further emphasizes the wide variety of potential clinical presentations of the hepatitis C virus.

HEPATIC MANIFESTATIONS

Acute Hepatitis

The clinical presentation of acute hepatitis C has been best described in the post-transfusion patients. Elevation of serum aminotransferases usually occurs first between 6 and 8 weeks after exposure, with a range of 2 to 26 weeks.2 Serum aminotransferases were more than 15 times normal in 74% (79/106), 6 to 15 times normal in 22% (23/106), and 2.6 to 5 times normal in 4% (4/106) of patients ~ tud ied .~ Unlike hepatitis A, which usually is symptomatic in adults? acute hepatitis C most often is asymptomatic. Symptoms, such as loss of appetite, weight loss, or fatigue, occurred in less than 30% of patients, and typically are so mild that they do not interfere with daily ro~ t ine .~ Jaundice occurs in less

From the Section of Hepatobiliary Diseases, University of Florida, Gainesville, Florida

CLINICS IN LIVER DISEASE

VOLUME 1 * NUMBER 3 - NOVEMBER 1997 569

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Table 1. CLINICAL MANIFESTATIONS OF HEPATITIS C VIRUS

Hepatic Renal Acute hepatitis Glomerulonephritis Chronic hepatitis Membranoproliferative glomerulonephritis Cirrhosis Dermatologic Hepatocellular carcinoma Leukocytoclastic vasculitis

Hematologic Lichen planus Cryoglobulinemia Porphyria cutanea tarda 6-cell lymphoma

Plasmacytoma MALT

Autoimmune Autoantibodies Thyroiditis Sjogren’s syndrome Idiopathic thrombocytopenia purpura

than one third of all patients? 37, 96 although serum bilirubin greater than 3 mg/L was reported in 70% (74/106) of symptomatic patients in one series.’

Fulminant hepatic failure (FHF) resulting from HCV is unusual. Farci et a1 described a case of FHF following a blood transfusion that strongly implicated the involvement of hepatitis C virus. Serial serum RNA levels correlated with the both the course of FHF and with aminotransferase levels. High HCV RNA levels were seen at the peak of aminotransferases and fell below detectable limits before death, and HCV antigens were demonstrated on postmortem liver biopsy.38 The presence of HCV RNA in non-A, non-B FHF has been reported to range from 0% to 60% (mean, 11%; 19/175).7, 20, 41, 137 Nonetheless, given the high prevalence of hepatitis C, the overall risk of FHF must be extremely low. The risk factors for FHF are unknown, although high levels of virus could play a role, especially in the immunosuppressed. Fulminant hepatic failure related to hepatitis C has been observed after withdrawal of chemotherapy or immunosuppression in patients with chronic hepatitis C.47, 136

767 96,

Chronic Hepatitis

Acute HCV progresses to chronic hepatitis in at least 60% to 70% of cases and develops independent of any identifiable risk factors5, 31, 36

The incidence of chronic infection, as determined by the persistence of HCV RNA rather than elevation of serum aminotransferases, is even higher, approaching Most patients with chronic hepatitis have asymptomatic enzyme elevations and detectable HCV antibody. Reports have described either few clinical signs or symptoms, nonspecific symptoms, or symptoms similar to those of uninfected blood donors.23, 87, lZo

Fatigue is the most common complaint in symptomatic patients, followed by abdominal pain, anorexia, and weight loss. Jaundice is unusual except in patients with advanced cirrhosis. On examination, hepatomeg-

CLINICAL MANIFESTATIONS OF HEPATITIS C 571

aly is the most common physical finding. Splenomegaly usually is limited to patients with cirrhosis or coexisting lymphoma.96, 134

Aminotransferases are characteristically elevated only mildly. Up to one third of patients have normal serum alanine aminotransferase (ALT) levels; only about 25% have an ALT more than twice n ~ r m a l . ~ However, there is a wide variability in enzyme elevation when patients are followed over time. In those with ALT elevations, the levels are persistently elevated in only 26% of cases and elevated in most determinations in 22%. ALT levels fluctuate between normal and elevated in 17%; 30% to 40% had only occasional ALT elevations over a 12- to 18-month period of testing4 Sheen described transient aminotransferase flares in 11.9% of patients with chronic hepatitis C each year. The flares were associated with an increase in viral load in the majority but occasionally appeared to be associated with a change in viral genotype, suggesting reinfection. Unlike hepatitis B, these flares usually were histologically mild and were not associated with subsequent development of cirrhosis or viral clearance .Iz2

Aminotransferase levels in patients with chronic hepatitis C have limited clinical significance except during treatment. There is poor correlation between aminotransferase elevation and histology. One study found higher ALT levels in patients with piecemeal necrosis than in those without, although there was considerable overlap. Only a 10-fold or greater elevation of serum ALT was predictably associated with piecemeal necrosis.56 Two other studies did find an overall correlation of aminotransferase elevation and histologic lz1 However, in individual patients there was little predictive value, and some with normal aminotransferases had severe histologic changes?, 98 Thus, with the exception of markedly elevated aminotransferases, the ALT level in an individual patient is not a reliable marker of underlying histologic activity or disease severity. The presence of HCV RNA initially was thought to be a better candidate as a predictor of active disease because it was present in most patients with normal aminotransferases who had active disease. However, HCV RNA is also present in patients with normal or minimal changes in histology and normal aminotransferases, raising the possibility of a ”healthy carrier ~tate.”’~, 53, Overall, the level of HCV RNA correlates poorly with histology (see article by Fried). HCV genotype also may play a role because one report suggested that a disproportionate number of patients who had normal or slightly elevated aminotransferases and mild histologic inflammation had genotype 2a (see article by Fried).lZ5

Cirrhosis

The development of histologic cirrhosis is silent in most patients. Clinical symptoms or laboratory tests have been demonstrated to be of little value in making the diagnosis.53 The risk of developing cirrhosis appears to be related to the degree of inflammation and fibrosis present

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on liver biopsy at any given time, and varies from less than 2% risk per year in those with mild disease to over 10% in patients with severe inflarnmati~n.’~~ Fattovich reported a series of 384 patients with an initial uncomplicated presentation of cirrhosis secondary to HCV.40 Physical examination revealed a palpable firm liver in 79%, splenomegaly in 34’10, and stigmata of chronic liver disease in only 31%. Laboratory testing revealed a normal total bilirubin in 60% and a normal albumin in 90%. Alpha fetoprotein (AFP) was greater than 10 in 43%. The probability of developing decompensated cirrhosis was 12% at 3 years, 18% at 5 years, and 29% at 10 years, with a yearly incidence of 3.9% during the first 5 years. The risk of developing hepatocellular carcinoma (HCC) risk was 4% at 3 years, 7% at 5 years, and 14% at 10 years, with a 1.4% incidence per year during the first 5 years. Survival probability after the diagnosis of cirrhosis was 96%, 91%, and 79% at 3, 5, and 10 years, respectively, but decreased to 50% at 5 years after the onset of the first major complication. Bilirubin, presence of physical stigmata of liver disease, older age, and thrombocytopenia were all predictors of a poor outcome. In other studies, age,131 alcoh01,1~~ and genotype lb105 have been reported to predict development of cirrhosis.

Hepatocellular carcinoma is a significant complication of HCV infection, although it rarely occurs in the absence of cirrhosis.”, 133 HCC usually is associated with increased AFP (mean, 22,730 ng/mL; range, 7.4 to 183,915).9R AFP levels in those without HCC usually are normal but may be minimally elevated (<lo0 ng/mL), especially in patients with ~ i r rhos is .~~ An increased risk of HCC has been associated with genotype l b independent of age, gender, and child’s classification,’26 although further validation of this observation is required.

EXTRAHEPATIC MANIFESTATIONS

There are several potential mechanisms for extrahepatitic manifestations of HCV infection including (1) direct viral cytopathic injury; (2) injury produced by tissue deposition of host/viral immune complexes; (3) viral-induced immunologic response, such as formation of autoantibodies or activation of specific T lymphocytes; (4) induction of monoclonal or polyclonal lymphocytes, leading to lymphoproliferative disorders; and (5) injury produced by indirect effects of inflammatory response, such as viral-induced cytokines or mediator release (tumor necrosis factor (TNF) interferons). The best-documented mechanism at this point is injury produced by deposition of host/viral immune complexes, as occurs with cryoglobulinemia.

Hematologic

Mixed Cryoglobulinemia Mixed cryoglobulinemia is a lymphoproliferative disorder that

can lead to deposition of circulating immune complexes in small- to


medium-sized blood vessels. It often presents with the clinical triad of palpable purpura, arthralgias, and weakness, but also can involve the kidneys, nerves, and brain. Type 1 cryoglobulins consist of monoclonal immunoglobulins or free light chains, which precipitate in the cold and do not form rheumatoid factor. They are associated with multiple myeloma, Waldenstrom's macroglobulinemia, and other lymphoproliferative disorders. Type I1 cryoglobulins consist of mixtures of polyclonal IgG and a monoclonal immunoglobulin, usually IgM with anti-IgG activity (rheumatoid factor). Type I11 cryoglobulins have both polyclonal IgG and polyclonal IgM; the latter has rheumatoid-factor activity. Type I cryoglobulins can directly precipitate with cold exposure, whereas types I1 and 111 precipitate only as a complex formed by the IgG and rheumatoid factor. Type I1 and I11 cryoglobulinemia occur in association with a variety of viral, bacterial, and parasitic diseases, chronic liver disease, autoimmune diseases, glomerulonephritis, malignancy, and lymphoproliferative diseases. When cryoglobulinemia occurs without association with a primary disease, other than Sjogrens syndrome, it is termed essential cryoglobulinemia.lO, l6 Early reports suggested an association with hepatitis B virus infection, but this was not borne out in subsequent 75, lo9

Recent evidence suggests a strong relationship between HCV infection and mixed cryoglobulinemia. HCV antibodies were found in 42% to 54%, and HCV RNA in up to 84% of patients with essential mixed type I1 cryoglobulinemia. This was significantly higher than the 1% to 2% prevalence of HCV infection in healthy volunteers and patients with other rheumatologic dis0rders.l. 44 HCV RNA and HCV antibodies also have been detected in cryoprecipitates, typically at far higher concentra- tions than in serum and supernatant.2, 9, 7y, HCV antibodies have also been isolated within the immunoglobulin deposits located in the vessel walls on skin biopsy in patients with mixed cryoglobulinemia and cutaneous vasculitis. Although these vascular deposits were not always associated with active inflammation, they were not found in HCV patients without cryoglobulinemia or HCV-negative patients with other vascular lesions. This suggests that tissue deposition may precede the vascular inflammatory response.118

The second line of evidence to support the role of HCV in the pathogenesis of cryoglobulinemia is the improvement in skin lesions and symptoms, decrease or loss of cryoglobulins, and reduction in viral RNA that occurs with interferon 67, Decrease or loss cryoglobulinemia is not always associated with loss of HCV RNA by PCR. However, these reports did not quantitate the level of viremia, and it may well have decreased. Persistent loss of HCV RNA and normaliza- tion of ALT is also associated with sustained loss of cryoglobulinemia, but relapse of viremia with reappearance of cryoglobulinemia is very common.45, 51, y1

The final evidence suggesting a relationship of cryoglobulinemia to HCV infection is the relatively common detection of cryoglobulins in patients with hepatitis C. Although cryoglobulins are found in 19% to

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54% of patients, symptoms occur in only 25% of these. It is not clear why cryoglobulins form in patients with hepatitis C, and further investigation is required.61 Duration of HCV infection and severity of histologic inflammation do not appear to be causative, though cryoglobulins are more common in patients with cirrhosis.54, 79, lo6, 138 Most data suggest that the HCV genotype is also not a significant factor, but the level of viremia may play a role.54, Io6, lz9, l4I Decreased clearance of circulating antigen/antibody complexes resulting from hepatic injury or overload of the reticuloendothelial system or Kupffer cells, cross-reactivity of viral and host determinants, polyclonal lymphocyte activation, host genetic composition, and environmental factors are all possible factors that may influence expression of the disease and deserve further investigation.

Lymphoma

An increased prevalence of anti-HCV (20% to 40%) has been described in patients with B-cell non-Hodgkins lymphoma (NHL), but not in other hematologic malignan~ies.~~, 80,95 Two large series found that the strongest correlation was in the subset of immunocytoma, a low-grade malignancy that has been associated with cryoglobulinemia.85, lZ8 The possibility that HCV cryoglobulinemia could progress to a NHL was further supported by Pozzi and colleagues in a study involving 31 patients with mixed cryoglobulinemia and HCV RNA detectable in the serum and bone marrow. Bone marrow biopsy confirmed low-grade NHL in 12 (39%) and reactive nonmonoclonal bone marrow infiltration in 11 (36%). Long-term follow-up demonstrated progression of the lymphoproliferative disorders in over 50% of these patients. Interest- ingly, although HCV RNA was detectable in all of the patients, clinical and biochemical evidence of liver disease was present in only 48%, and HCV antibodies were undetectable in sorne.”O

It is unclear whether the development of NHL is related to a direct oncogenic effect of HCV on lymphocytes or whether polyclonal or monoclonal proliferation is induced by viral stimulation or chronic inflammation. Both positive and negative (replicative) strands of HCV RNA have been identified in the peripheral mononuclear cells of patients with chronic hepatitis C93, 142 and cryogl~bulinemia.~~ Furthermore, HCV RNA has been isolated from the involved lymph nodes of B-cell NHL ~atients.9~ However, HCV is an RNA virus and does not integrate in host DNA. It also has no known oncogenes and lacks reverse tran- scriptase, which would make a direct oncogenic effect less likely.61

Interferon treatment appears to be effective for some patients with HCV-associated lymphomas. Treatment for 1 year in 20 patients with mixed cryoglobulinemia, detectable HCV RNA in serum, and monoclonal %-cell expansion in peripheral blood resulted in response in four patients with loss of detectable HCV in the peripheral blood and bone marrow, resolution of B-cell expansion in PBMC, and loss of the monoclonal B-lymphocyte infiltrate in the bone marrow in three. The fourth patient lost RNA in serum, but not bone marrow, and had persistence


of the monoclonal marrow infiltrate. This suggests that viral replication itself may underlie the B-cell monoclonal pr~liferation.~~ HCV has also been described in association with MALT lymphomas, raising the possibility that HCV, like Helicobacter pylori, may play a role in this low-grade B-cell NHL.81

Although these data are preliminary, they suggest that HCV may be a factor in the development of some cases of B-cell NHL. These patients may benefit from antiviral therapy. Because clinically apparent liver disease is absent in most of these patients and anti-HCV may be lacking, testing for HCV RNA should be considered, especially in the subpopulation of immunocytoma and MALT lymphoma patients.

Aplastic Anemia

The development of aplastic anemia has been reported following post-transfusion HCV hepatitis in association with anti LKM-1 antibody and ~ryoglobulinemia.'~~ In larger series, however, there was no difference in the prevalence of anti-HCV in hepatitis-associated aplastic anemia and aplastic anemia of other causes.108 Furthermore, detection of HCV RNA correlated only with the number of blood transfusions re- ceived after development of aplastic anemia.60 Thus, although HCV may occur with hepatitis-associated aplastic anemia, it probably is rare.

Autoimmune

A utoan tibodies

It has become clear that HCV infection is associated with both an increased expression of autoantibodies and an increased prevalence of autoimmune disorders. Antinuclear antibody, smooth muscle antibody, or antithyroid antibodies are detected in 40% to 65% of patients with chronic hepatitis C.25, 49, lo4 However, the presence of these autoantibodies does not appear to influence the clinical presentation or course of the disease. Furthermore, there is no difference in gender, histologic severity of hepatitis, or response to treatment between those HCV patients with and without antibodies.21, 73 LKMl antibodies, the pathognomonic antibody in autoimmune hepatitis (AIH) type 11, has been detected in Euro- pean patients with chronic hepatitis C. Anti-HCV is detectable in 88% of 49% of and 48% of German patients with anti- LKMl,s8 but in none of the English patients.24* 73 AIH type I1 is very rare in North American patients, so there are few data regarding them. However, in the European patients with anti-LKM-1, there appear to be clinical differences between those with and without anti-HCV. Patients with both antibodies are more often male, older, and with less active disease than those without HCV antibodies. They also tended to respond to interferon rather than to steroids. This led to the suggestion that

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these patients truly have chronic hepatitis C with a secondary, but nonpathologic, anti-LKM1. Thus, type I1 autoimmune hepatitis has now been classified as type IIa (HCV-negative and truly an autoimmune hepatitis) and type IIb (chronic hepatitis C with an associated autoanti- body).52, 7*, *8 The serum of this latter group reacts to different antigens or epitopes of LKM-1 than of those with type IIa.2Z, 82, y4, 139 Molecular mimicry between GOR 47-1 and a 33AA segment of P450-IID6 recog- nized by anti-LKM1 in AIH type IIa has been Anti-GOR is present in 60% to 80% of patients with hepatitis C. Interestingly, no specific HCV sequences have been identified that demonstrate significant homology with cytochrome P450-IID6.89 Furthermore, HCV infection does not appear to induce anti P450-IID6.26 The possibility that host factors may play an important role in this association was suggested by the observation that most patients who develop classic autoimmune hepatitis during interferon treatment for HCV have HLA haplotypes similar to those present in patients with classic autoimmune hepatitkS0

In summary, in most patients with chronic hepatitis C, autoantibodies have little clinical significance and probably are epiphenomena. In some cases, it appears that AIH develops after HCV infection. In these, HCV may have acted as a "trigger" for autoimmune disease in a genetically susceptible host. Alternatively, patients with AIH may acquire HCV infection. Finally, false-positive anti-HCV sometimes can be detected in patients with classic type I AIH.19, w y2, loo

Autoimmune Disorders

Czaja noted immunologic disease in 23% of patients with HCV infections, although this is less than that observed in patients with AIH. HCV patients with immunologic disease were more likely to be HLA- DR4 positive than were those without (68% vs 27%) or controls (30%). This haplotype is common in patients with AIH and suggests that HCV could act as a stimulus to autoimmune disease in a genetically susceptible Autoimmune disorders do not appear to be viral genotype- dependent.Io6

Thyroid Disease. Thyroid disorders are the most commonly associated autoimmune diseases in patients with chronic hepatitis C. Antithy- roid antibodies are present in 5.2% to 12.5% of patients with hepatitis C. Thyroid disease, primarily hypothyroidism, is present in 3.1% to 5.5% of patients. The highest prevalence of both thyroid antibodies and thyroid disease was found in older women.12, 83, 135 However, one study raised doubt about this association by finding no difference in the prevalence of thyroid antibodies or disease between normal blood donors and those with hepatitis C.48 Interferon may induce antithyroid antibodies and thyroid disease, which often resolve following interferon treatment. This phenomenon occurs primarily in patients with antithyroid antibodies, and usually resolves following cessation of interferon therapy.69, 72, 97

Patients should be monitored for thyroid disease during interferon ther-


apy, especially women and patients with pre-existing antithyroid antibodies.

Sjogren’s Syndrome. Sjogren’s syndrome consists of chronic lymphocytic infiltration of salivary and lacrimal glands and immune complex deposition. It is thought to be an autoimmune disease. Lymphocytes are primarily activated T cells but can include B cells. There is an associated oligoclonal B-cell activation that may result in hypergammag- lobulinemia, immune complexes, and SSA (anti-Ro), SSB (anti-La), or RF. The syndrome of dry eyes and dry mouth (sicca syndrome) results from a progressive destruction of exocrine glands, but extraglandular tissues also can be Sicca symptoms also can be secondary to any infiltrative process that interrupts neurovascular innervation of the glands or affects the ability of the glands to secrete/*

Lymphocytic sialadenitis consistent with Sjogren’s syndrome was initially described in 57% of patients with chronic hepatitis C.57 How- ever, more recent studies in patients with primary Sjogren’s syndrome found that HCV infection was either at or below the baseline prevalence of the infection in the popu1ation.l3, HCV patients with Sjogren’s commonly have lymphocytic capillaritis (17% to 49%), but it tends to be a milder form than what is seen in the primary form. Only 14% had the severe histologic lesions, such as seen in ”true” Sjogren’s syndrome. The majority of lesions in HCV patients were pericapillary, rather than periductal, and did not destroy vessel walls. Furthermore, the lymphocytic sialadenitis seen with HCV was not associated with xerophthalmia or Ro/SS-A antibodies, although xerostomia is common (8%-36%).13, lo4

Finally, the lymphocytic infiltrate of the minor salivary glands in HCV patients is predominantly CD8, which contrasts with what is observed in primary Sjogren’s. The clinical and pathologic differences suggest that HCV is associated with chronic lymphocytic sialadenitis and not a true primary Sjogren’s syndrome.66

Autoimmune Idiopathic Thrombocytopenia Purpura (AITP). A potential pathogenic role of HCV in autoimmune idiopathic thrombocytopenia purpura was suggested when anti-HCV was reported in 19% of 112 patients with AITP.lZ7 In addition, case reports have described the development or exacerbation of idiopathic thrombocytopenia purpura during interferon therapy for hepatitis C.8, lZ4 However, a follow-up study of 139 French patients with AITP found anti-HCV in 14 of 139 (10%) French patients, but HCV predated the diagnosis of AITP in only 5 of 139 (3.6%). This study suggested that the higher prevalence of anti- HCV simply reflects the increased exposure of these patients to blood products.loS

In summary, HCV is commonly associated with both autoantibodies and autoimmune diseases. However, care must be used to distinguish between true and incidental association^.^^, 65 Most data at this point suggest that the increased propensity for the autoimmune features is more host than viral related, and in some cases may be the result of immune response to the HCV virus.

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Renal

HCV has increasingly been associated with membranoproliferative glomerulonephritis (MPGN) and nephrotic syndrome. In a series of 226 patients with chronic renal insufficiency before initiation of dialysis, Garcoa-Valdecasas found anti-HCV in 16.6% of patients with glomerulonephritis (GN) but not in patients with other renal diseases.51 This association is increased markedly in the presence of cryoglobulinemia. Pasquariello found anti-HCV to be present in all 26 patients with MPGN and cryoglobulinemia. Similarly, Misiani detected anti-HCV in 98% of patients with GN and cryoglobulinemia compared with 2% of con- t r o l ~ . ~ ~ , Io3

HCV antibodies and HCV RNA have been found in both circulating antigedantibody complexes and cryoprecipitate of patients with MPGN and nephrotic range proteinuria. In addition, immune complex deposition, cryoglobulin-like structures, and HCV core proteins have been demonstrated in the glomeruli of these patients.27, 63, 64, lo2, Interferon treatment has resulted in decreased proteinuria, which correlated with loss of HCV RNA. However, no improvement was seen in renal function, and relapse of viremia and renal disease was common.132 These data suggest that HCV may be a critical factor in the development of GN and MPGN in some patients. The etiology appears to be related to immune complex deposition associated with cryoglobulinemia or to HCV antigen deposition followed by an immune reaction.

Dermatologic

Leukocytoclastic Vasculitis

Leukocytoclastic vasculitis is a consequence of cryoglobulinemia that usually presents clinically with palpable purpura and petechiae, which involves the lower extremities. Biopsy demonstrates cutaneous vasculitis with dermal blood vessel destruction associated with neutro- philic infiltration in and around the vessel wall.27

Lichen Planus Lichen planus (LP) is a skin rash that occurs in less than 1% of the

general population and persists for a long time. It presents as flat- topped, violaceous, pruritic papules in a generalized distribution. There is a high incidence of mucosal involvement, and it can also involve hair and nails. LP is thought to be immunologically mediated, involving T- cell-mediated pathways. Biopsy of the lesion demonstrates a dense lymphoctic infiltration in the upper dermis “hugging” the epider- mis.I4, 112 Anti-HCV are present in 10% to 38% of patients with LP, and may correlate with severer liver d i ~ e a s e . ~ ~ , ” ~ , 132 However, the mechanism by which HCV might act in the pathogenesis of LP is unclear. Interest-


ingly, there have been several case reports of development or exacerbation of lichen planus during interferon treatment of HCV. Marked improvement occurred in lesions following discontinuation of interferon.'O, Thus, although it is unclear whether HCV plays a pathogenic role in LP, treatment for HCV can worsen LP, making identifica- tion and close follow-up important during initiation of IFN treatment.

Porphyria Cutanea Tarda

Porphyria cutanea tarda (PCT) presents with photosensitivity, skin fragility, bruising, and vesicles or bullae that can become hemorrhagic. Pigmentation, depigmentation, hirsutism, and a sclerodermoid appear- ance subsequently may develop. The underlying abnormality is thought to be a reduction of hepatic uroporphyrinogen decarboxylase activity. However, extrinsic factors, such as ethanol, estrogens, or iron overload, are thought to be needed for the clinical manifestation of disease. In the most common form of the disease (type I), decreased enzyme activity is limited to the hepatocytes, whereas the defect is present in erythrocytes and other cell types in the familial form (type II).29, 55 Liver injury is common, with steatosis and siderosis the most ~ornmon.'~ HCV antibodies have been found in 62% to 91% of patients with PCT, although the prevalence may be lower in Germany. The high prevalence of HCV antibodies has led to speculation that HCV is a critical factor in the development of the disease, but whether HCV represents a true stimulus of disease or is only a cofactor is currently unknown.3o, 39, 42, 59, 99, I3O

Regardless of its potential role in pathogenesis, the high prevalence of HCV in PCT patients suggests that these patients should be screened for HCV.

SUMMARY

Hepatitis C is a common cause of viral hepatitis that progresses to chronic infection in the majority of patients. Clinically, the infection is generally asymptomatic, but it may present with a wide variety of symptoms. Cirrhosis, hepatocellular carcinoma, cryoglobulinemia, autoantibodies, and glomerulonephritis have been strongly associated with HCV. There is a probable association with autoimmune disease and NHL. More information is needed to determine whether lichen planus, PCT, and other disorders are part of the growing clinical spectrum or just coincidental associations with chronic liver disease.

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clinical manifestations of hepatitis c

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