Hepatitis C Virus Infection: A Simple and Updated Approach for Extrahepatic Manifestations

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Hepatitis C Virus Infection: A Simple and Updated Approach for Extrahepatic Manifestations

Also See:

Skin findings In Hepatitis C

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Rash Hepatitis C /Lichen planus

HCV Rash; Mixed Cryoglobulinemia

Hepatitis C Rash: Porphyria cutanea tarda

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Hepatitis C Virus as a Multifaceted Disease: A Simple and Updated Approach for Extrahepatic Manifestations of Hepatitis C Virus Infection...

Authors:Khattab MADepartment of Internal Medicine, Minia University, Minia, Egypt.Eslam MDepartment of Internal Medicine, Minia University, Minia, EgyptAlavian SM2 Baqiyatallah Research Center for Gastroenterology and Liver Disease, Baqiyatallah University of Medical Sciences, Tehran, IR IranCorrespondence:Mahmoud Aboelneen Khattab,Department: Department of Internal Medicine, Minia UniversityAddress: Department of Internal Medicine, Minia University, Minia, Egypt, p.o.Box: 61111City: MiniaCountry: EgyptE-mail: mkhattababmed@...Tel: +20-225191818, +20-862378181Fax: +2086242813Abstract:Hepatitis C virus infection is an emerging disease and a public health problem in the world. There are accumulating data regarding extra hepatic manifestation of HCV, such as rheumatologic manifestations, endocrine,

hematologic, dermatologic, renal, neurologic, and systemic manifestations. The therapy of them needs more attention to some exacerbations of extra hepatic manifestation and in some situation it needs different approaches. In this review we tried to provide latest evidence for extra hepatic manifestation and management of them.Manuscript:IntroductionHepatitis C virus (HCV) is a major cause of liver-related morbidity and mortality worldwide and represents a major public health problem (1-6). HCV can spread parenterally through contact with infected blood, transfusion of infected blood and its products, intravenous drug use, contamination during medical procedures, and a lack of attention to health precautions. Despite a declining incidence of new infections (7, 8), the burden of the disease, both in terms of mortality and cost, is expected to increase over the next decade, and HCV infection will maintain to be a potential cause

of morbidity and mortality and need for transplantation in the future (9, 10). It is estimated that around 170 to 200 million individuals are living with HCV infection worldwide (11, 12), and there is significant geographical variation in the prevalence of HCV infection across countries and regions (1, 13). Although HCV is a hepatotropic virus, in some patients the primary manifestations of infection occur outside the liver. There is a growing body of evidence to support the idea that HCV can replicate efficiently in extrahepatic tissues including the PBMC. Autoimmune manifestations are common in patients chronically infected by HCV (14). These manifestations can be dominant, whereas the hepatic disease can be quiescent or mild. More recently, there has been growing interest in the relationship between HCV and Sjogren's syndrome (SS), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE(15). Depending on the pathogenic and epidemiological

evidence provided by different studies; the extrahepatic manifestations of HCV infection (EHMs-HCV) can be classified into four categories:1. EHMs-HCV characterized by a very strong association demonstrated by both epidemiological and pathogenetic evidence (e.g., mixed cryoglobulinemia);2. EHMs-HCV include disorders for which the significant association with HCV infection is supported by enough data to clearly show a higher prevalence of HCV than in controls but still have unclear pathogenic mechanisms (e.g., B-cell-derived non-Hodgkin's lymphoma [NHL], diabetes mellitus, porphyria cutanea tarda, lichen planus);3. EHMs-HCV includes the associations for which the high prevalence in HCV populations could be due to HCV infection or confounding factors, and thus these associations still require confirmation and a more detailed characterization with respect to similar pathologies of different etiology or idiopathic nature (e.g., idiopathic

pulmonary fibrosis, autoimmune thyroiditis, sicca syndrome, noncryoglobulinaemic nephropathies and glomerulonephritis, and aortic atherosclerosis);4. EHMs-HCV includes only anecdotal observations (e.g., growth hormone defficiency, chronic pruritus, cardiomyopathy, psoriasis, peripheral or central neuropathies, chronic polyarthritis, rheumatoid arthritis, polyarthritis nodosa, behcet's syndrome, poly or dermatomyositis, necrolytic acral erythema, and autoimmune hemolytic anemia).1. Mixed CryoglobulinemiaMixed Cryoglobulinemia (MC) is the most documented and closely associated disorder with HCV (16, 17). The prevalence of HCV-infected patients with coexisting circulating MC ranges from less than 10% to greater than 50%; however, overt vasculitis manifestations are seen in only 2% to 3% of these patients (18-20). This variability may represent geographic and population-specific factors involved in the development of MC, differences in the

definition of the disease, and laboratory techniques for diagnosis. The disease occurs as a result of chronic immune-system stimulation leading to B-cell clonal expansion and immune-complex (IgG, IgM, RF complement, HCV-LDL/VLDL) production. These immune complexes will often take the form of cryoglobulins (21-23). Cryoglobulins are monoclonal or polyclonal immunoglobulins that reversibly precipitate at low temperatures; cryoglobulinemia occurs when these proteins are present in the circulation (24). Clinical manifestations of MC are secondary to a systemic immune-complex-related vasculitis involving small vessels.Diagnosis of CryoglobulinemiaNowadays, there are no standardized criteria for the diagnosis of MCS. However, valuable classifications have been proposed by the Italian Group for the Study of Cryoglobulinemia (24). Diagnosis is based on clinicopathological and laboratory findings. Cryoglobulinemia may be suspected if the patient has

positive rheumatoid factors. Clinically, asymptomatic serum MC can be found in some individuals chronically infected with HCV (24, 25); a condition that may precede the clinical onset of the disease by years or decades. Glomerulonephritis, peripheral neuropathy, and generalized vasculitis are the common complications of cryoglobulinemia (26-28).Palpable purpura (Figure. 1) is the most common clinical finding, occurring in 90% of cases. The association between MC and severe liver damage or steatosis has been discussed widely (29-31). Several studies have shown an epidemiological association between MC and severe liver damage (29). However, the pathogenetic mechanisms of such an association have not been clearly identified. The laboratory work-up of cryoglobulinemia vasculitis includes cryoglobulin testing, quantification of total serum protein and immunoglobulins, complement levels, evaluation of serum for monoclonal gammopathy, RF activity,

virological markers (anti-HCV antibodies, HCV RNA, hepatitis B virus serology, hepatitis B virus DNA, and others), blood chemistry, and urine analysis. Leukocytoclastic vasculitis, involving medium- and, more often, small-sized blood vessels (arterioles, capillaries, and venules) is the typical pathological finding of involved tissues. Leukocytoclastic vasculitis is easily detectable by means of skin biopsy of recent vasculitis lesions (within the first 24 to 48 hours (24, 32, 33)..

..Figure 1. Nonblanching erythematosus papules are the notable findings of these palpable purpura, which are characteristic of the vasculitis associated with MC.Treatment optionsTreatment can eradicate HCV infection (etiologic therapy), suppress B-cell clonal expansion and cryoglobulin production (pathogenetic therapy), or ameliorate symptoms (symptomatic therapy).Etiologic therapyUnder ideal circumstances, the treatment of MC aims to eradicate the HCV infection. Treatment of MC with interferon (IFN) therapy is associated with a relatively poor response (34, 35); however, PEG-IFN plus RBV show better results (36, 37). The goal of therapy in those patients is not limited to a sustained virologic response; rather, patients might see an improvement in their renal manifestations with prolonged treatment courses. However, clinical improvements are often transient and

restricted to patients with mild to moderate disease activity (36-38). Moreover, IFN therapy can induce an exacerbation of various vasculitis manifestations (i.e., glomerulonephritis, neuropathy), and RBV, due to its renal elimination, may be contraindicated in patients with severe renal impairment.Pathogenetic therapyThis therapy is currently used when antiviral therapy is not recommended. Treatment should be limited to the time (weeks or months) required for symptom remission. Several alternative therapies may be adopted, which include corticosteroids due to its anti-inflammatory and immunosuppressive actions (at high doses: 1 mg/kg daily or 0.5-1 g). However, the disadvantage of favoring the etiologic agent is that it can lead to increased viral replication (39). Immunosuppressive drugs (e.g., Cyclophosphamide, Chlorambucil, and Azathioprine) are used to suppress antibody and cryoglobulin production (40, 41). The most effective and

commonly used cytotoxic drug is Cyclophosphamide, given orally at doses of 2 mg/kg per day. Recently; Mycophenolate Mofetil (1 g twice a day) can be used as a less toxic alternative to Cyclophosphamide for the induction of remission in MC vasculitis; Mycophenolic Acid is more selective than Cyclophosphamide in inhibiting lymphocyte proliferation and functions. Interestingly, Mycophenolic Acid seems to reduce viremia in HCV-infected renal or heart-transplant recipients due to its ability to inhibit inosine monophosphate dehydrogenase, the same target enzyme inhibited by RBV (42). However, data supporting this approach are limited and almost exclusively derived from anecdotal reports (43). For patients unresponsive to treatment with steroids or other immunosuppressants, the administration of the novel immunosuppressant Rituximab; a chimeric monoclonal antibody directed against CD20 antigen on B cells, has been recently proposed for the pathogenetic

treatment of HCV-related MC (44, 45). By depleting B cells, Rituximab has the potential to reduce the development of plasma cells, thereby limiting Cryoglobulin production. Rituximab, at the standard dose of 375 mg/m2 weekly for 4 weeks proved to be a safe and effective treatment for most patients with HCV-MC, leading to significant clinical improvement as a consequence of both B-cell depletion and decreases in serum Cryoglobulin levels (44-48). Although fever, chills, nausea, vomiting, urticaria, orthostatic hypotension, and bronchospasm occur in more than 80% of patients, these side effects are generally mild and limited to the infusion period. An increase in viral load, without significant variations in liver-function tests, has been detected after rituximab treatment (44) To reduce HCV replication, a combination of Rituximab with antiviral agents has been suggested.Because the median duration of the response to Rituximab therapy is about 1 year,

a relapse of cryoglobulinemic vasculitis may develop following treatment. Relapses are preceded by peripheral B-cell repletion. It is unknown whether maintenance therapy with Rituximab is better than retreatment after relapse. Plasmapheresis can be used as an effective adjuvant therapy to treat severe exacerbations of cryoglobulinemic vasculitis, particularly active cryoglobulinemic glomerulonephritis. Both traditional plasma exchange and double-filtration plasma exchange are able to markedly reduce the levels of circulating immune complex, especially the cryoglobulins. Oral Cyclophosphamide (50 to 100 mg/day for 2 to 6 weeks) during the tapering of apheretic sessions can reinforce the beneficial effect of plasma exchange; moreover, it can prevent the rebound phenomenon that may be observed after the discontinuation of aphaeresis (33).Symptomatic TherapyThe hypoantigenic diet (LAC) diet consists of a diet with reduced content of alimentary

macromolecules with high antigenic properties, allowing for more efficient removal of CGs by the reticuloendothelial system. This diet can improve minor manifestations of the disease (purpura, arthralgias, paresthesias) and is generally prescribed at the initial stage of the disease (49). Colchicine, an anti-inflammatory agent with a relatively selective effect for gouty arthritis, has been proposed for MC patients with mild to moderate levels of the disease. In an uncontrolled trial, colchicine (1 mg/day for 6 to 48 months) improved clinical and laboratory variables (particularly cryocrit; (50). However, its toxicity and the availability of alternative, less toxic agents have substantially lessened its use.2. Lymphoproliferative disorders (LPD)HCV-associated LPD can be observed during the course of MC or in non-MC-related idiopathic forms (51). A recent, large-scale, retrospective cohort study suggests that HCV infection confers a 20-30%

increased risk of NHL overall (52). These results were confirmed in a meta-analysis by Dal Maso and Franceschi, which included 15 case-controlled studies and 3 cohort studies and demonstrated a pooled risk ratio (relative risk [RR]) of 2.0 (95% CI, 1.8 to .2) for the cohort studies and 2.5 (95% CI, 2.1 to 3.1) for the case-controlled studies for the development of B-cell NHL in HCV-infected patients (53). The meta-analysis did not show differing RRs for NHL subtypes. From a histopathological point of view, although virtually all types of lymphoid malignancy can be found in patients with HCV infection, the strongest association is with NHL, and the vast majority of NHL is low grade with predominantly extranodal involvement. According to the REAL/WHO classifications, the most prevalent HCV-associated LPDs are follicular lymphoma, B-cell chronic lymphocytic leukemia or small lymphocyte lymphoma, diffuse large B-cell lymphoma, and marginal zone lymphoma,

including the mucosa-associated lymphoid tissue lymphoma (54). Overall, marginal-zone lymphoma appears to be the most frequently encountered low-grade B-cell lymphoma in HCV patients (55). Regarding the pathogenesis of the HCV-associated LPDs, the majority of studies pinpoint two presumable mechanisms. The first is indirect; specifically, by relying on the chronic nature of HCV infection, chronic antigenic stimulation may lead to an overexpression of B-cells favoring certain clones. This mechanism could explain the immune dysregulation leading to autoimmunity, MC, and eventually malignant transformation (56). The second mechanism is direct, relying on the particular lymphotropism of HCV and therefore on the high invasion of B-cells by HCV (57). Both mechanisms lead simultaneously through complex, multistep, pathogenic pathways. There may be genetic and environmental factors that further explain the final steps to malignant transformation. Rearrangement

of the antiapoptotic bcl-2 gene with t(14;18) translocation is the most common chromosomal translocation in lymphoid cancers, especially follicular lymphoma, a subtype of NHL. Thirty-five percent of patients with chronic HCV infection have evidence of the t(14;18) translocation in their peripheral mononuclear cells, which may further contribute to lymphomagenesis (58). Mutations in other oncogenes, such as c-myc, and regulators of apoptosis may be the important missing link to our understanding of lymphomagenesis in the setting of chronic HCV infection.Hepatitis C Virus and Monoclonal GammopathySerum monoclonal gammopathy (MG) is an extrahepatic manifestation of HCV infection. A prospective study by Andreone et al. found 11% of monoclonal bands in HCV-positive patients versus 1% in HCV-negative patients, demonstrating a significant prevalence of monoclonal gammopathy in HCV-related liver disease (59). Actually, a few HCV positive patients

with MG can be considered affected by myeloma according to clinico-pathological characteristics; the US Veterans Affairs database evaluated by Giordano et al. revealed an increased risk for the development of Waldenström's macroglobulinemia (hazard ratio=2.76) with no associated increased risk of development of multiple myeloma in HCV patients (52).Therapy for HCV-related LPDRecent studies support the rationale for the use of antiviral therapy in the context of low-grade HCV-positive NHL regardless of histological subtype (60-62).Interestingly, in these studies, there is a clear correlation between HCV viral-load reduction and clinical response in LPD-infected patients. In intermediate and high-grade NHL, chemotherapy is usually necessary and antiviral treatment may serve as maintenance therapy after the completion of chemotherapy (63). Because chemotherapy may lead to a substantial increase in the levels of viremia, cautious monitoring

of the HCV RNA levels and transaminases is important; still, a consecutive exacerbation of the infection, making discontinuation of chemotherapy mandatory, is not unlikely to occure (63). Regular monitoring of transaminases during treatment is essential because HCV-positive patients seem to experience increased short-term hepatic toxicity from chemotherapy. The use of rituximab either in monotherapy or in combination with antiviral treatment or chemotherapy or both appears promising (64, 65), however more studies are needed to define the actual role of rituximab in treatment and recovery.3. HCV-associated arthritis (HCV-AR)Rheumatologic complications of HCV infection are common and include MC, vasculitis, Sjogren's syndrome, arthritis, and fibromyalgia (66, 67). There is a well-defined picture of arthritis associated with the presence of MC that consists of an intermittent mono- or oligoarticular, nondestructive arthritis affecting large-

and medium-size joints (66, 68). Joint involvement is the most frequent extrahepatic manifestation of HCV infection. The HCV-associated rheumatic manifestation varies from 2% to 23%, depending on the geographic region and the design of the studies (69-73). HCV-AR commonly presents as a rheumatoid-like, symmetrical polyarthritis (SP) involving mainly small joints or less commonly as intermittent mono- or oligoarthritis in large joints (IMO(74, 75). The different diagnosis between SP and other polyarthritides, especially rheumatoid arthritis (RA), can be a clinical challenge (68, 72). HCV-AR is similar to RA, but it usually runs a relatively benign course that, in contrast to true RA, is typically nondeforming and is not associated with articular bony erosions. Furthermore, unlike classic RA, ESR is elevated only in about half of the patients, and subcutaneous nodules are absent (76). In the diagnosis; SP frequently meets American College of

Rheumatology's classification criteria for RA. However, anticyclic citrullinated peptide antibodies (anti-CCP) provide an important clue in distinguishing RA from HCV-AR because anti-CCP is considered to be specific for RA (77, 78). Positive HCV antibody and HCV RNA, as well as the absence of bony erosions and subcutaneous nodules may be useful in distinguishing between HCV-related arthritis and RA. Risk factors for HCV infection such as transfusion and IV drug abuse or a history of hepatitis should be included in the history of present illness of any patient with polyarthritis (79). In such patients serologic studies for hepatitis C should be performed (79). Table 1 may provide help in these differentiations.Table 1. Comparison between HCV-associated arthritis and rheumatoid arthritis

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.*In patients with HCV-associated arthritis and MC: RF positivity (virtually 100%). Low C4 levels (50-85%)TreatmentThe optimal treatment for HCV-related arthritis has not yet been established and very little evidence about the treatment of HCV-AR has been reported in the literature (76). Patients with HCV-AR in the absence of cryoglobulinemia have been treated successfully with NSAIDs, hydroxychloroquine, and low doses of prednisone (80). The IMO subset is usually responsive to low doses of corticosteroids with or without hydroxychloroquine (33). Administration of antiviral treatment (IFN) has not been

associated with significant improvement, and in certain cases has exacerbated articular symptoms (80, 81). In a small number of resistant cases, methotrexate was successfully used without significant adverse effects on liver function. Nevertheless, extreme caution with very close monitoring of liver function and viremia levels is needed for patients starting such therapy (81). Another study examined penicillamine as a potential treatment; however, despite an improvement of symptoms, penicillamine did not lead to a complete remission of the disease, and there is no information yet in the literature about the safety of this therapy (82).In addition, new data has emerged about the role of Cyclosporine in suppressing HCV replication by targeting the cyclophilin B protein, which interacts with the C-terminal region of NS5B and appears to stimulate the RNA binding activity involved in HCV RNA replication (83). These favorable results are predominant for

HCV genotype 1b and 4a (84, 85). Because CsA is currently administered to treat several autoimmune disorders including inflammatory joint diseases (86, 87), it may have a potential role in HCV-AR therapy as well. Anti-TNF therapy for RA in the setting of HCV appears to be safe and well tolerated, without apparent influence on the underlying HCV infection; however, the usually nonaggressive course of HCV-related arthritis does not justify the therapeutic use of anti-TNF (88). Recently, a trial evaluated the safety and efficacy of Etanercept in a small group of HCV-AR. Although Etanercept has been reported to be safe, its efficacy does not seem promising, especially given that it produced lower results than those obtained in patients with RA (89). The treatment of RA in patients with coexisting HCV infection is also problematic. First-line disease-modifying drugs such as Methotrexate and Leflunomide are potentially hepatotoxic and should be used with

extreme caution (90, 91). In mild cases, Hydroxychloroquine can be tried first with and without low doses of Prednisone (<7.5> . Figure 2. Mechanisms of HCV-induced renal injury

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Table 2. Glomerular disease associated with HCV

..TreatmentFor all patients, the decision to initiate treatment should be made after weighing the possible benefits and harms of therapy. The recommended therapeutic strategy depends on the severity of the kidney disease. For all patients, the same renoprotective measures (blood-pressure-lowering drugs and antiprotinuric agents) commonly used in patients with chronic nephropathies should be used in patients with HCV-associated GN. Diuretics, lipid-lowering agents, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are potentially beneficial in patients with HCV-associated GN (99). In a recent meta-analysis of clinical, controlled trials of the two treatments (antiviral versus immunosuppressive) described for HCV-related GN, the majority of patients had cryoglobulinemic GN (96). The primary endpoint was the frequency of patients with a reduction of proteinuria (return of

proteinuria to normal or a decrease of at least 50%) by the end of therapy. Pooling the results from this study demonstrated that proteinuria decreased more commonly after standard IFN-doses than with corticosteroid therapy and the OR was 3.86 (95% CI, 1.44; 10.33; P=0.007); however, both treatments failed to improve renal function. The authors concluded that the antiviral therapies were more effective than immunosuppressive therapy in lowering proteinuria levels in patients with HCV-related GN, at least in the short term. Therefore, the first-line treatment for patients with mild to moderate clinical and histological kidney damage is antiviral therapy. In case of severe renal involvement (nephrotic syndrome, nephritic syndrome, progressive renal failure, or a high activity score of glomerulonephritis on light microscopy), the initial treatment may consist of sequential administration of immunosuppressive therapies (plasmapheresis, corticosteroids, and

cyclophosphamide). Caution should be taken using immunosuppressive therapy in patients with HCV-associated GN because of a concern regarding viral replication (100). For patients unresponsive to steroid and immunosuppressive therapy, preliminary data support the use of rituximab for the treatment of HCV-associated GN (101). This is a human-mouse chimeric monoclonal antibody that selectively depletes B-cell by binding to CD20 cell surface antigen (102). It has been suggested that rituximab has a marked antiproteinuric effect through interference with monoclonal IgM production, cryoglobulin synthesis, and renal deposition of immune complexes (ICs). Recent data notes that Rituximab combined with Peg-IFNα/ribavirin is well-tolerated and more effective than Peg-IFNα/ribavirin in HCV-MC. In a recent prospective cohort study of 38 HCV-MC patients who received a combination of Rituximab (375mg/m² once a week for 1 month) followed by weekly Peg-IFNα (2a,

180mcg or 2b, 1.5mcg/kg) plus ribavirin (600-1,200 mg) daily for 48 weeks were compared to 55 HCV-MC patients who received the same Peg-IFNα and ribavirin treatments. Compared with Peg-IFNα and ribavirin, patients who received rituximab plus Peg-IFNα and ribavirin had a shorter time to clinical remission, better renal-response rates, and a high tolerance for treatment with no worsening of HCV RNA under rituximab (103). Another very recent, long-term trial confirmed these results, which may last for over 3 years (104).5. HCV and ThrombocytopeniaSeveral studies have shown that thrombocytopenia is frequently observed in patients with chronic hepatitis C infection (69, 105-108), and a variety of pathogenic mechanisms that are implicated in this abnormal finding are portal hypertension and hypersplenism in the cirrhosis stage, autoimmune reaction to platelets, and direct infection of platelet and megakaryocytes by HCV infection. This may be a

sign of extrahepatic manifestation of chronic hepatitis C (109). In cirrhotic patients, sequestration of platelets in the enlarged spleen secondary to portal hypertension can cause thrombocytopenia (105). However, thrombocytopenia also occurs in patients with chronic hepatitis C without cirrhosis. Another mechanism is autoimmune reaction to platelets (110, 111). Some reports indicated that HCV infection may reflect the expression of platelets-associated immunoglobulin G(PAIgG), which can lead to platelets destruction by the reticulo-endothelial system (112, 113). In addition, several studies have suggested that HCV may have a direct pathogenic role in the process leading to thrombocytopenia (105, 114). The incidence of mild thrombocytopenia (defined as a platelet count under 150,000/μl) is between 41% and 50% in patients with HCV infection, whereas severe thrombocytopenia (defined as a platelet count under 50,000/μl) is less common (105,

115).6. Cutaneous Manifestations of HCVIn addition to MC-related purpura, HCV infection also has been associated with several cutaneous disorders as noted below.PruritusPruritus is a presenting symptom in 20% of patients (116). Although, the pathogenesis is uncertain, both peripheral (increased plasma level of bile salts) and central mechanisms (increased plasma level of opioids) have been proposed (116). The combination of both bile-salt-lowering and opioid-antagonist strategies appears reasonable in the management of pruritus of cholestasis; treatment options include topical antipruritics, systemic antihistamines, rifampin, naloxone or naltrexone, and ultraviolet B phototherapy (116).Porphyria Cutanea Tarda (PCT)PCT is a photosensitivity disorder caused by a decrease in functional uropophryinogen decarboxylase (UROD) and an increase in circulating porphyrins. The prevalence of HCV infection in patients with

porphyria is high, ranging from 40% to 50% (Figure 3) (117). HCV does not seem to induce alteration of porphyrin metabolism, although it may induce the disease in genetically predisposed individuals. Meanwhile, some authors suggest that PCT might be related to HCV-induced hepatic iron overload (117). The highest rates of PCT have been observed in patients with HCV-related liver cirrhosis, suggesting that cirrhosis may play a role in its development. Antiviral therapy seems to ameliorate cutaneous lesions, but there is still no randomized clinical trial (117). . .Figure 3. Erosions, crust, and blisters are evident on the hands of this patient with PCT.Lichen Planus (LP)HCV has been implicated in triggering LP (118). In a recent meta-analysis, LP patients were observed to have significantly higher risk of being HCV seropositive (odds ratio 4.85; 95% CI 3.58-6.56) than controls. A similar odds ratio of having lichen planus was found among HCV patients (4.47; 95% CI 1.84-10.86). Subanalyses indicated that the variability in the association between HCV and lichen planus seemed only partial and dependent on geographic effect Studies. (118). Data from Egypt reveal that the prevalence of LP among CHC patients is around 4% (119). Data suggest that skin and mucosal lesions may be caused by direct action of the virus or immunological response, especially when erosive oral lesions are present, and recently HCV-induced insulin resistance has been

implicated in the pathogenesis of LP (118, 120). The skin and the oral cavity are easy to observe, so the presence of LP can be potentially used as a potential marker of HCV in asymptomatic patients (Figure 4) (121)..

..Figure. 4. The polygonal purple papules of LP are evident on the forearms of a patient with HCV.TreatmentLP is associated with a variable response to IFN treatment, and both improvement and exacerbation of symptoms have been reported. The uses of steroids, either topical or injectable, are also used in managing the symptoms (120).Link between HCV and other clinical disorders7. Sicca syndromeSjögren's syndrome (SS) is an autoimmune disease that involves the exocrine glands and generally induces xerostomia and xeroftalmia (sicca syndrome) due to an involvement of salivary and lachrymal glands in the presence of immunological alterations represented by antinuclear autoantibodies and antiepithelial neutrophil-activating peptide (ANA, SSA/Ro, SSB/La). In the absence of an associated systemic autoimmune disease, patients with similar manifestations can be defined as

affected by primary SS. The clinical spectrum of the syndrome ranges from an organ-specific autoimmune disease to a systemic process with different manifestations. SS is recognized in large portions of MC patients (122, 123), and was also observed in CHC patients by Haddad et al. in 1992 (124). In a recent cohort from Egypt, SS's prevalence was reported to be around 9% (73). This syndrome closely resembles primary SS; however, it typically lacks ANA, SSA/Ro, and SSB/La. The pathogenic role of HCV infection in SS remains an issue of debate (125). It has been proposed that HCV infection is a criterion to rule out a primary diagnosis of SS, especially if cryoglobulinemia and hypocomplementemia are present and anti-SSA/Ro antibodies are absent (126, 127).8. Idiopathic pulmonary fibrosis (IPF)A pathogenic link between HCV infection and IPF has been suggested by the higher frequency of HCV markers in patients with IPF (128, 129). Whether CHC is

linked to pulmonary fibrosis directly or indirectly through underlying cryoglobulinaemia and vasculitis remains issue of discussion (130).9. Cardiomyopathy and atherosclerosisA causal relationship with HCV infection has been suspected for several myocardial impairments, including dilated cardiomyopathy, hypertrophic cardiomyopathy, and chronic myocarditis. The pathogeneses of these HCV-associated myocardial impairments probably rely on autoimmune phenomena with the particular involvement of the human major histocompatibility (MHC) class II antigen (131). Moreover, the recent determination of a significantly higher prevalence of carotid or coronary artery atherosclerosis in patients with HCV infection (132, 133) is noteworthy. The recent finding of HCV RNA sequences in plaque tissue strongly suggests an active local infection. This in turn makes it conceivable that the virus may exert local action in carotid atherosclerosis (134).10.

NeuropathyHCV-neuropathy presents with peripheral neuropathy that involves the legs and is typically very painful, with progression to muscle weakness in some patients. The disorder results from immune-complex deposits within the vasa nervorum of the peripheral nerves leading to vasculitis (135). Antiviral therapy should be applied cautiously in the presence of neuropathy. Although cases of HCV-related peripheral neuropathy responsive to antiviral therapy with IFNα and ribavirin have been described (136), several authors have reported an aggravation of pre-existing MC-related neuropathy or even de novo occurrence of demyelinating polyneuropathy during IFN-α or PEG-IFN-α treatment (137). Therefore, it is presumable that genetic susceptibility and other idiosyncratic factors may influence the response of the HCV-associated neuropathy to IFNα, making close monitoring of the course of this EHM during IFNα treatment indispensable.11. Thyroid

and HCVAutoimmune thyroid diseases (AITDs) are complex diseases that develop as a result of interactions between genetic, epigenetic, and environmental factors. Significant progress has been made in our understanding of the genetic and environmental triggers contributing to AITD. The high prevalence of AITDs has been reported in HCV-infected patients before and after IFNα therapy (138). Two well-documented environmental triggers of AITD, HCV infection and IFNα therapy, should be given more attention in the field (139). Chronic HCV infection has been shown to be associated with an increased incidence of clinical and subclinical autoimmune thyroiditis (i.e., the presence of thyroid antibodies in euthyroid subjects). The pattern of thyroid disorders observed in HCV infection is characterized by the presence of increased circulating antithyroid peroxidase antibodies (AbTPO) and an increased risk of hypothyroidism in AbTPO-positive subjects (109, 140).

The Autoantibodies against internal organs such as the thyroid are common before therapy with IFNα (141). In some cases, antibodies against IFN appear after IFN therapy with in HCV-infected patients (142). Moreover, IFNα therapy for chronic HCV infection is associated with subclinical or clinical thyroiditis in up to 40% of cases, which can be autoimmune or nonautoimmune thyroiditis. In some cases, IFN induced thyroiditis (IIT) in chronic HCV patients may result in severe symptomatology necessitating the discontinuation of therapy. Although the epidemiology and clinical presentation of HCV- and IFN-induced thyroiditis have been well-characterized, the mechanisms causing these conditions are still poorly understood.Treatment: In cases of symptomatic hyperthyroidism, discontinuation of therapy is recommended. In hypothyroidism, adding thyroid hormone can alleviate the symptoms, making it possible to continue therapy. Thyroid-function tests should be

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Skin findings In Hepatitis C

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Thursday, November 18, 2010

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CRYOGLOBULINEMIACryoglobulins are found in 19 to 54 percent of patients with HCV infection, symptoms occur in only 25 percent of these. The name literally means “cold antibody in the bloodâ€, which refers to the chemical properties of the antibodies that cause this disease: cryoglobulins are antibodies that precipitate under cold conditions

,Hepatitis C is recognized as the most common cause of mixed cryoglobulinemia. Most of the people with cryoglobulinemia from hepatitis C have had their hepatitis for a long time or have cirrhosis. People with higher concentrations of hepatitis C RNA in their blood do not seem to have a higher risk of having cryoglobulinemia. Usually the cryoglobulins are in low concentration and cause no symptoms. About twenty-percent of people with hepatitis C and cryoglobulinemia have symptoms. Symptoms most often associated with cryoglobulinemia include mild fatigue, joint pains, or itching.

Occasionally, people with cryoglobulinemia develop vasculitis (inflammation of the blood vessels) which can cause purpura (purple skin lesions), Raynaud's phenomenon (the hands turn white, then blue, and then red from constriction and subsequent dilation of the blood vessels), or numbness in the hands and feet. The presence of cryoglobulinemia does not effect people's response to interferon. In fact, some people with vasculitis have improvement in the vasculitis as their liver tests improve on interferon.,.Related Information:

Rituximab Plus Peg-Interferon-alpha/Ribavirin Compared with Peg-Interferon-alpha/Ribavirin in Hepatitis C-Related Mixed Cryoglobulinemia

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CRYOGLOBULINEMIAhttp://www.hcvadvocate.org/hcsp/articles/Bonkovsky-2.html

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Viruses - Hepatitis C

Dr. J. Perri, M.D.Sunday, November 14, 2010 at 11:52AM

Hepatitis C (HCV) is a very common chronic viral infection that I encounter frequently in both my The Woodlands dermatology and Conroe dermatology clinics.

HCV is a single stranded RNA virus that is usually transmitted through exposure to HCV contaminated blood such as in blood transfusions that have not been properly screened or through IV drug use, unlike Hepatitis B virus which is usually sexually transmitted. Less than 1/3 of patients are symptomatic on initial infection with HCV.

Chronic infections occur in up to 80% of patients with HCV, which may present with liver cirrhosis, liver cancer or liver failure 10 to 20 years after the primary infection.

Skin findings are very common in HCV.

Vasculitis can occur which appears as palpable purpuric (bruises) papules and nodules. Cyroglobulinemia type 2 is due to a circulating cryoglobulin type 2 that can occur in 1% of all HCV patients and results in a leukocytoclastic vascultitis, livedo reticularis, and urticaria as the skin findings. Cryoglobulinemia can also cause inflammation of the joints, kidneys, and peripheral nerves. Porphyria Cutanea Tarda (PCT) is another skin disease due to HCV in which patients present with tense bullae (blisters) on the dorsum of their hands and forearms.

Lichen planus is a rash consisting of red itchy papules on the skin and white lacy patches and ulcers in the mouth that can be due to HCV. Necrolytic acral erythema is a skin rash unique to HCV in which patients develop scaly red plaques on their palms and soles. Most of the HCV dermatoses respond to treatment of the HCV infection with Interferon and Ribavirin

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Hepatitis C- Cryoglobulinemia

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Hepatitis C- Porphyria Cutanea Tarda

Related Information: Hepatitis C Rash: Porphyria cutanea tarda

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Hepatitis C- Lichen Planus

Related Article: Rash Hepatitis C /Lichen planus /Photos Photo Source

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Rash Hepatitis C /Lichen planus /Photos

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Sunday, October 10, 2010

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A study on the association with hepatitis B and hepatitis C in 1557 patients with lichen planus

S Birkenfeld1, J Dreiher1,2, D Weitzman3,AD Cohen1,2,*

Article first published online: 27 JUL 2010DOI: 10.1111/j.1468-3083.2010.03809.x

AbstractBackground

Previous reports have demonstrated contradicting results on the association between lichen planus and hepatitis.Objectives

The aim of this study was to investigate the association between lichen planus and viral hepatitis.Methods

Patients with lichen planus were compared with controls regarding the prevalence of viral hepatitis in a case-control study using logistic multivariate regression models. The study was performed utilizing the medical database of Clalit Health Services.Results

The study included 1557 lichen planus patients over the age of 20 years and 3115 age- and gender-matched controls. The prevalence of hepatitis C in patients with lichen planus was higher than that in the control group (1.9%, 0.4% respectively, less then 0.001

In a multivariate analysis, lichen planus was associated with hepatitis C (OR 4.19, 95% CI 2.21; 7.93). The prevalence of hepatitis B in patients with lichen planus was similar to that in the control group (0.9%, 0.5% respectively, P = 0.12). A multivariate analysis revealed that lichen planus was not associated with hepatitis B (OR 1.69, 95% CI 0.82; 3.47).

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Conclusion

Lichen planus is associated with hepatitis C but not with hepatitis B. Physicians who care for patients with lichen planus should consider screening patients with lichen planus for hepatitis C

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What is lichen planus ?Lichen planus is a skin condition that causes purple or reddish-purple bumps that may be itchy. The bumps have flat tops and are uneven in shape. If you look at the bumps closely, you might see white scales or flakes on them. Lichen planus commonly affects the inner wrists, the forearms and the ankles. It may also affect the scalp, the nails, the inside of the mouth, the genitals and the anus. On the scalp, lichen planus may cause hair loss. Lichen planus of the nails can cause brittle or split nails. In the mouth, it looks like lacy white patches on the inside of the cheeks or on the tongue. Lichen planus of the mouth, genitals or anus can cause soreness and a burning sensation. Sometimes lichen planus affects areas of skin where you had a cut or burn

What causes lichen planus?In many cases, the cause of lichen planus can't be found. It is not contagious. You can't "catch" it from or "give" it to someone else. It is not caused by stress, but sometimes stress makes it worse.

Some cases may be linked to a virus called hepatitis C. This virus can cause liver disease. Your doctor may want to order a blood test to check for hepatitis C virus. Some medicines can cause lichen planus. It is important to tell your doctor about all the medicines you are taking.

Also See : HCV Rash; Mixed Cryoglobulinemia/Photo

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How will lichen planus affect me?Lichen planus usually causes itching. The itching can be mild or very bad. You may have just a few small bumps or you may have many. The bumps may persist for weeks or months, and may return once they go away. Sometimes, after the bumps go away, they leave a dark brown area on the skin. This is more likely to happen in persons of Asian, Hispanic or African heritage. These brown spots are not scars. They will slowly fade away, but it may take many months.Lichen planus inside the mouth may cause painful sores that make it hard to eat.

How can I be sure I have lichen planus?Only your doctor can tell if you have lichen planus. If you have any of the symptoms listed above, you should see your doctor. Your doctor may want you to have blood tests or a skin biopsy. For a biopsy, a small bit of skin is taken from one of the purple bumps. It is sent to a laboratory to see if it is lichen planus

How is lichen planus treated?There is no cure for lichen planus, but medicine can relieve the itching and help the rash get better. If your itching is very bad, your doctor may suggest an antihistamine (one brand name: Benadryl).Most of the time, the bumps caused by lichen planus go away without any treatment after about a year. If your lichen planus is severe or if you have many bumps, your doctor may prescribe corticosteroid pills. Corticosteroid gels and ointments are used to treat lichen planus of the genitals or anus and lichen planus of the mouth if symptoms are severe. If you have lichen planus of the mouth and your symptoms are mild, you may not need any treatment. Or your doctor may recommend a mouth rinse to relieve any discomfort caused by mouth sores. Corticosteroids have many side effects, so be sure to follow your doctor’s instructions carefully when taking these medicines.Light therapy (also called PUVA) can also be used in the treatment of lichen planus. Or, you could take a pill with a retinoid in it. Retinoids have many side effects. You have to have regular blood tests while you take this medicine.

Lichen planus of the scalp must be treated right away or the hair may never grow back.

http://familydoctor.org/,

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Lichen Planus

,Author: Tsu-Yi Chuang, MD, MPH, Clinical Professor, Department of Dermatology, University of Southern California; Staff Dermatologist, Desert Specialty Group, IncCoauthor(s): Stitle, MD, Staff Physician, Department of Dermatology, Indiana University Medical Center

Contributor Information and Disclosures

Updated: May 7, 2010

,Medscape : See Full Article Here

kLichen planus on the flexor part of the wrist.

Pruritus is common in lichen planus but varies in severity depending on the type of lesion and the extent of involvement. Hypertrophic lesions are extremely pruritic.Oral lesions may be asymptomatic or have a burning sensation, or they may even be painful if erosions are present. In more than 50% of patients with cutaneous disease, the lesions resolve within 6 months, and 85% of cases subside within 18 months. On the other hand, oral lichen planus had been reported to have a mean duration of 5 years. Large, annular, hypertrophic lesions and mucous membrane involvement are more likely to become chronic.Physical

In addition to the cutaneous eruption, lichen planus (LP) can involve the mucous membranes, the genitalia, the nails, and the scalp. The clinical presentation of lichen planus has several forms: actinic, annular, atrophic, erosive, follicular, hypertrophic, linear, pigmented, and vesicular/bullous. The papules are violaceous, shiny, and polygonal; varying in size from 1 mm to greater than 1 cm in diameter (see the image below). They can be discrete or arranged in groups of lines or circles. Characteristic fine, white lines, called Wickham stria, are often found on the papules (see the image below)

Close-up view of lichen planus.

Lichen planus shows Wickham striae (white, fine, reticular scales).

Mucous membrane involvement is common and may be found without skin involvement. Lesions are most commonly found on the tongue and the buccal mucosa; they are characterized by white or gray streaks forming a linear or reticular pattern on a violaceous background (see the image below). Oral lesions are classified as reticular, plaquelike, atrophic, papular, erosive, and bullous. Ulcerated oral lesions may have a higher incidence of malignant transformation in men, but this observation may be confounded by other factors, such as smoking and chewing tobacco. Lesions may also be found on the conjunctivae, the larynx, the esophagus, the tonsils, the bladder, the vulva, and the vaginal vault; throughout the gastrointestinal tract; and around the anus.

Lichen planus on the oral mucosa with ulceration in the center of the lesion appears with whitish papules and plaques in the periphery.

Genital involvement is common in men with cutaneous lichen planus. Typically, an annular configuration of papules is seen on the glans. Less commonly, linear white striae, similar to the lesions on the vulva and the vagina, can be seen on male genitalia. Vulvar involvement can range from reticulate papules to severe erosions. Dyspareunia, a burning sensation, and pruritus are common. Vulvar and urethral stenosis can also be present. Two reports documented that more than 50% women with oral lichen planus had undiagnosed vulvar lichen planus.10,11 Also see the clinical guideline summary, Diagnosis and management of vulvar skin disorders.12In 10% of lichen planus patients, ungual findings are present. Most commonly, nail plate thinning causes longitudinal grooving and ridging. Hyperpigmentation, subungual hyperkeratosis, onycholysis, and longitudinal melanonychia can result from lichen planus. Rarely, the matrix can be permanently

destroyed with prominent pterygium formation. Lichen planus has been linked to childhood idiopathic nail atrophy and may overlap with twenty-nail dystrophy of childhood.Lichen planus patients with a cutaneous eruption may also have follicular and perifollicular violaceous, scaly, pruritic papules on the scalp. These lesions can progress to atrophic cicatricial alopecia that can appear many weeks after the skin lesions have disappeared. Pseudopelade can be a final endpoint.Variations in lichen planus include the following:Hypertrophic lichen planus: These extremely pruritic lesions are most often found on the extensor surfaces of the lower extremities, especially around the ankles. Hypertrophic lesions are often chronic; residual pigmentation and scarring can occur when the lesions eventually clear.

Atrophic lichen planus: Atrophic lichen planus is characterized by a few lesions, which are often the resolution of annular or hypertrophic lesions.

Erosive/ulcerative lichen planus: These lesions are found on the mucosal surfaces and evolve from sites of previous lichen planus involvement.

Follicular lichen planus: Lichen planopilaris is characterized by keratotic papules that may coalesce into plaques. This condition is more common in women than in men, and ungual and erosive mucosal involvement is more likely to be present. A scarring alopecia may result.Annular lichen planus: Lichen planus papules that are purely annular are rare. Annular lesions with an atrophic center can be found on the buccal mucosa and the male genitalia.

Linear lichen planus: Isolated linear lesions may form a zosteriform lesion, or they may develop as a Köbner effect.Vesicular and bullous lichen planus: Most commonly, these lesions develop on the lower limbs or in the mouth from preexisting lichen planus lesions. A rare condition, lichen planus pemphigoides, is a combination of both lichen planus and bullous pemphigoid.Actinic lichen planus: Subtropic or actinic lichen planus occurs in regions, such as Africa, the Middle East, and India. This mildly pruritic eruption usually spares the nails, the scalp, the mucous membranes, and covered areas. Lesions are characterized by nummular patches with a hypopigmented zone surrounding a hyperpigmented center.

Lichen planus pigmentosus: This is a rare variant of lichen planus but can be more common in persons with darker-pigmented skin, such as Latinos or Asians. It usually appears on face and neck. Some believe it is similar to or the same as erythema dyschromicum perstans (ie, ashy dermatosis).Lichen planus pemphigoides: This is a rare form of lichen planus. Blisters subsequently develop on lichen planus lesions. Clinically, histopathologically and immunopathologically, it has features of lichen planus and bullous pemphigoid, it but carries a better prognosis than pemphigoid.

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OverviewDifferential Diagnoses & WorkupTreatment & MedicationFollow-upMultimedia

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HCV Rash; Mixed Cryoglobulinemia/Photo

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Posted by New HCV Drugs

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Cryoglobulins are found in 19 to 54 percent of patients with HCV infection, symptoms occur in only 25 percent of these.

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CRYOGLOBULINEMIA

One-third to one-half of people with chronic hepatitis C infection have cryoglobulinemia (antibodies in the bloodstream attached to the hepatitis C RNA that happen to solidify when cold).

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Hepatitis C is recognized as the most common cause of mixed cryoglobulinemia. Most of the people with cryoglobulinemia from hepatitis C have had their hepatitis for a long time or have cirrhosis. People with higher concentrations of hepatitis C RNA in their blood do not seem to have a higher risk of having cryoglobulinemia. Usually the cryoglobulins are in low concentration and cause no symptoms. About twenty-percent of people with hepatitis C and cryoglobulinemia have symptoms. Symptoms most often associated with cryoglobulinemia include mild fatigue, joint pains, or itching.

,Occasionally, people with cryoglobulinemia develop vasculitis (inflammation of the blood vessels) which can cause purpura (purple skin lesions), Raynaud's phenomenon (the hands turn white, then blue, and then red from constriction and subsequent dilation of the blood vessels), or numbness in the hands and feet. The presence of cryoglobulinemia does not effect people's response to interferon. In fact, some people with vasculitis have improvement in the vasculitis as their liver tests improve on interferon.

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Also See Rituximab Plus Peg-Interferon-alpha/Ribavirin Compared with Peg-Interferon-alpha/Ribavirin in Hepatitis C-Related Mixed Cryoglobulinemia

Palpable Shin LesionsA 41-year-old woman presented complaining of the progressive development of lesions on her lower extremities (see accompanying photos). She had also noted swelling of her right wrist and ankle with associated mild pain. The lesions were located primarily over the shins and medial aspects of both lower extremities, and consisted of erythematous macules, some of which had confluent borders. The lesions were palpable, did not blanch on pressure, and had no overlying warmth or tenderness. Mild swelling of the right ankle was present, although the patient maintained full range of motion. The remainder of the physical examination was unremarkable.The patient had been recently diagnosed with hypertension for which she had been taking an angiotensin-converting enzyme inhibitor (ramipril) for two weeks. The patient had no other chronic medical illnesses. She had a history of intravenous drug

use during adolescence.On laboratory evaluation, she was noted to have proteinuria (1.2 g per day), with a creatinine clearance of 56 mL per minute (0.93 mL per second). Serum aminotransferase levels were mildly elevated: alanine aminotransferase was 123 U per L; aspartate aminotransferase was 139 U per L.

The patient tested positive for hepatitis C virus (HCV) infection, most likely contracted during her years of intravenous drug use.QuestionGiven the patient's history and the results of the physical examination, which one of the following is the correct diagnosis for the disorder shown above?

,A. Drug-induced vasculitis.B. Cellulitis.C. Mixed cryoglobulinemia.D. Lichen planus.E. Porphyria cutanea tarda.

, Discussion.The answer is C:

Mixed cryoglobulinemia.

Her rash is a leukocytoclastic vasculitis caused by cutaneous deposition of cryoimmunoglobulins. Several studies1,2 have established a strong link between HCV infection and mixed cryoglobulinemia, a multisystem disorder that is characterized by deposition of circulating immune complexes in small and medium-sized blood vessels resulting in arthralgias, Raynaud's syndrome and purpura. Kidney, nerve and brain involvement is possible.It is important to obtain a thorough medication history in any patient who presents with a rash, because drug-induced etiologies are among the most common causes of leukocytoclastic vasculitis. Ramipril has been associated with a rash in a small percentage of patients. It often may not be possible to distinguish between a drug-induced vasculitis and a cryoglobulinemic rash by physical examination alone. However, the coincident clinical findings of positive serum HCV antibody, HCV RNA and serum

cryoglobulins make the latter much more likely. In this patient, the rash improved on treatment of HCV infection, despite continued treatment with ramipril.Cellulitis was ruled out by the absence of warmth or tenderness on examination of the leg, as well as absence of systemic manifestations such as a fever or elevated white blood cell count.Lichen planus, a skin rash that occurs in less than 1 percent of the general population, 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 involve the hair and nails. Antibodies to HCV are present in 10 to 38 percent of patients with lichen planus.

Also See Rash Hepatitis C /Lichen planus /Photos

..Porphyria cutanea tarda presents with photosensitivity, skin fragility, bruising, and vesicles and bullae that can become hemorrhagic. The so-called sporadic variety is the most common type, although rare familial forms exist. There is a high prevalence (62 to 91 percent) of HCV antibody positivity in patients with the sporadic form of porphyria cutanea tarda.3 Antiviral therapy with alpha-interferon for the underlying HCV infection can be effective in treating the associated mixed cryoglobulinemia.4 Patients who have no detectable HCV RNA at the end of a course of treatment have significantly improved purpura and serum cryoglobulin levels; however, a rebound phenomenon of clinical and serologic variables has been noted after discontinuation of this therapy.4 Also See Hepatitis C Rash: Porphyria cutanea tarda/Photo
 mAlthough cryoglobulins are found in 19 to 54 percent of patients with HCV infection, symptoms occur in only 25 percent of these.5 Duration of HCV infection and severity of histologic hepatic inflammation do not appear to be related.5 In addition to cryoglobulinemia, other important extrahepatic manifestations of HCV infection include membranoproliferative glomerulonephritis, thyroiditis, porphyria cutanea tarda and lichen planus.6Several types of cryoglobulinemias are recognized. Type I (monoclonal immunoglobulin) is associated primarily with malignant processes of the immune system. Type II (at least one monoclonal immunoglobulin, usually IgM mixed with polyclonal immunoglobulins) and type III (polyclonal only) are also known as mixed cryoglobulinemias. HCV has become one of the most common causes of mixed cryoglobulinemia, although mixed cryoglobulins are also observed with other chronic

infections (e.g., hepatitis B, endocarditis) as well as autoimmune and malignant disorders.7The clinical presentation of mixed cryoglobulinemia is quite variable. Cutaneous leukocytoclastic vasculitis is the most clinically evident manifestation. It usually presents with palpable purpura and petechiae that involve the lower extremities.8 Skin lesions are not always obvious and are sometimes not present. Arthralgias and arthritis may be prominent. The joint involvement is usually a symmetric, nonmigratory polyarthritis involving ankles, wrists, elbows, hands and toes. The most serious manifestation is renal damage due to deposition of the circulating cryoimmunoglobulins. This can present as nephrotic syndrome, glomerulonephritis or acute renal failure. Renal biopsy usually reveals IgM and IgG deposition within subendothelial immune deposits. Treatment of the underlying chronic infection can ameliorate cryoglobulinemia. Corticosteroids and

cytotoxic agents are sometimes used in severe cases.ARSHAD H. MALIK, M.D.PETER MALET, M.D.University of Texas SouthwesternDallas, TexasThe editors of AFP welcome submission of photographs and material for "Photo Quiz." Send photograph and discussion to Marc S. Berger, M.D., C.M., P.O. Box 6825, Wyomissing, PA 19610-0825.REFERENCESWener MH, RJ, Sasso EH, Gretch DR. Hepatitis C virus and rheumatic disease [editorial]. J Rheumatol 1996;23:953-9.Gumber SC, Chopra S. Hepatitis C: a multifaceted disease. Review of extrahepatic manifestations. Ann Intern Med 1995;123: 615-20.Fargion S, Piperno A, Cappellini MD, Sampietro M, Fracanzani AL, Romano R, et al. Hepatitis C virus and porphyria cutanea tardia: eidence of a strong association. Hepatology 1992;16:1322-6.Misiani R, Bellavita P, Fenili D, Vicari O, Marchesi D, Sironi PL, et al. Interferon alpha-2a

therapy in cryoglobulinemia associated with hepatitis C virus. N Engl J Med 1994; 330:751-6.Dickson RC. Clinical manifestations of hepatitis C. Clin Liver Disease 1997;1(3):569-85.Gordon SC. Extrahepatic manifestations of Hepatitis C. Dig Dis 1996;14:157-68.Schifferli JA, French EL, Tissot JD. Hepatitis C virus infection, Cryoglobulinemia, and glomerulonephritis. Advances in Nephrology 1995;24:107-29.Daoud MS, Gibson LE, Daoud S, el-Azhary RA. Chronic hepatitis C and skin diseases: a review. Mayo Clin Proc 1995;70:559-64.

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CRYOGLOBULINEMIA

http://www.hcvadvocate.org/hcsp/articles/Bonkovsky-2.html

Cryoglobulins are antibody complexes that precipitate as serum is cooled and that dissolve on rewarming (1). These complexes contain hepatitis C virus (HCV) particles and can precipitate in the walls of small and medium sized vessels. There are three types (I, II, III) of cryoglobulinemia .Type II or “mixed†cryoglobulinemia (MC) is the one most commonly associated with chronic hepatitis C infection. This type is called “mixed†because the antibodies that are found are of two kinds. One antibody is a polyclonal (i.e., from more than one group of cells) antibody (IgG), and the other antibody is a monoclonal (IgM) directed against the IgG. The frequency with which cryoglobulins are detectable in serum of patients with CHC depends on how carefully samples are handled and upon the methods used for detection of cryoglobulins. Because these proteins precipitate from serum as it is cooled, the blood must be kept at body temperature after it has been obtained until it has clotted and the serum has been drawn off. Then the serum is tested for the abnormal proteins. If this precaution is not observed, the test may be spuriously negative.

The skin, kidney, nerves and joints can be affected by cryoglobulins. Cutaneous leukocytoclastic vasculitis is a skin lesion that appears as palpable purpura (hemorrhages in the skin that result in the appearance of purplish spots or patches) that usually affects the lower extremities over the shins (Fig 1). These lesions are caused by plugging of the dermal capillaries (very small blood vessels in the skin). Successful treatment of the hepatitis C infection with interferon (+ ribavirin) usually results in resolution of the skin lesions.Cryoglobulins also affect the nervous system in some HCV infected patients. The most frequent symptoms and signs are those of chronic sensory polyneuropathy, although acute or subacute encephalopathy has been reported as well (2,3). “Restless leg syndrome†and Guillain-Barré syndrome have also been reported (4). The mechanism of nerve involvement is thought to be MC-well-established related vasculitis of the small blood vessels that supply the nerves. There is no well-established treatment. Treatment with interferon, corticosteroids, or cyclophosphamide (cytoxan) has not shown any consistent results although some patients appear to respond to one or a combination of these drugs (5).

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