Extrahepatic Manifestations of Hepatitis C Virus
Richard K. Sterling, MD and S. Bralow, MD
Richard K. Sterling, MD
Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University Health System, 1200 E. Broad Street, West Hospital, Room 1492, Richmond, VA 23298, USA.
Current Gastroenterology Reports Feb 2006 Vol 8 Issue 1, 8:53-59
ABSTRACT. Given the high prevalence of chronic hepatitis C virus (HCV) infection, its clinical sequelae account for a significant proportion of patients presenting to gastroenterologists and hepatologists. Whereas the hepatic manifestations of hepatitis C are well described, including hepatitis, cirrhosis, and the development of hepatocellular carcinoma, the extrahepatic manifestations, though common, are less well appreciated. Although nonspecific, fatigue and arthralgias are very common in those with chronic hepatitis C. Extrahepatic syndromes have been reported in as much as 36% of HCV patients, but the exact prevalence is not known. Patients with these syndromes can be divided into those with a high degree of association and those with a more moderate or mild association with HCV. The most prevalent extrahepatic diseases with the highest degree of association with HCV are the essential mixed cryoglobulins with skin, neurologic, renal, and rheumatologic complications.
Non-cryoglobulin diseases with a less definite relationship to HCV include systemic vasculitis, splenic lymphoma, porphyria cutanea tarda, and the sicca syndromes. This article highlights the pathophysiology and clinical manifestations of these disorders. Treatment of these extrahepatic manifestations is directed at the HCV virus itself as well as the extrahepatic organ affected and often requires a multidisciplinary approach.
Table 1. Extrahepatic diseases associated with hepatitis C virus
Strong and proven association
Mixed cryoglobulinemia (MC)
Purpura: cutaneous vasculitis
Type 1 membranoproliferative glomerulonephritis (MPGN)
Asthenia: fatigue, weakness
Non-cryoglobulinemia systemic vasculitis (PAN)
B-cell non-Hodgkin's lymphoma
Porphyria cutanea tarda
Type 2 diabetes mellitus
Since 1989, when the hepatitis C virus (HCV) was identified and recognized as the major component of the so-called non-A, non-B transfusion hepatitis, the clinical course of HCV has been well described. It has been estimated that nearly 3% of the world's population, or 170 million individuals, have been infected with HCV [
1**]. In developed countries the incidence is lower, but in endemic areas it may reach 10% to 30% . In the United States, the overall prevalence has been estimated at 1.8% or 3.9 million people, with 2.7 million chronically infected. In developing countries, HCV appears to be related to medical procedures, vaccinations, and parenteral drug use. Since 1989, the incidence of acute HCV has declined by about 80% in the United States due to screening of blood products, but the overall prevalence of chronic HCV has not decreased significantly. At least 60% of HCV is now due to illicit drug use.
The onset of acute HCV is often difficult to substantiate because of the mild or nearly absent symptoms marking the acute and chronic phases of this disease. By dating the time of the last known exposure to the virus, one can estimate the incubation period, which ranges from 6 to 7 weeks on average but has been reported to be as short as 2 weeks and as long as 26 weeks . Chronic HCV is said to be present if the viremia or elevation of serum alanine aminotransferase (ALT) persists longer than 6 months. Once an individual is exposed, chronic HCV develops in 60% to 70% of cases and can progress to cirrhosis in approximately 20% of infected persons . Hepatic decompensation or hepatocellular carcinoma may develop in approximately 20% of patients with cirrhosis, and approximately 13% of these patients die, or approximately 4% of all those infected [1**]. Mild symptoms usually persist for two to three decades before complications occur. Consequently, HCV has been labeled a
"silent epidemic," and the natural course is slow but progressive. Because of its ability to activate the immune system yet avoid elimination, chronic infection can result in accumulation of immune complexes and stimulate antibodies, which can result in extrahepatic conditions.
Extrahepatic Manifestations of Chronic HCV
Extrahepatic syndromes have been reported in up to 36% of HCV patients, but the exact prevalence is not known. As many as 36 different syndromes have been reported to be related to HCV, but many of these instances are only case reports [4*]. These syndromes can be divided into those with a high degree and those with a more moderate or mild association with HCV (Table 1). Severe fatigue is the most common extrahepatic manifestation of HCV and frequently interferes with quality of life [5*]. Fatigue associated with liver disease typically is mild after adequate sleep and progresses throughout the day or after prolonged activity. In those who have fatigue from the time they awaken (so-called morning fatigue) alternative causes should be explored, such as depression or sleep apnea. Fatigue from chronic HCV usually decreases with a sustained virologic response (SVR) but occasionally persists.
Arthralgias are also common in patients with chronic HCV [6, 7]. Because rheumatoid factor (RF) is often positive in patients with chronic HCV, elevations in RF require differentiation from rheumatoid arthritis. Elevations in RF are also seen in the majority of patients with cryoglobulinemia, and an elevated RF in the right clinical circumstance requires testing for this condition.
Hepatitis C virus has lymphocyte tropism, and when associated with mixed cryoglobulins, the virus has a strong affinity to bind with B lymphocytes via CD81-producing autoantibodies, which are commonly elevated in HCV [1**, 8]. Autoimmune hepatitis (AIH) must therefore be ruled out, but autoantibody titers are usually lower in HCV . Furthermore, when compared with HCV, there is no female preponderance, no association with HLA-DR, and no other clinical manifestations of AIH in these patients with nonspecific elevations in autoantibodies.
High degree of association
The most prevalent extrahepatic diseases with the highest degree of association with HCV are the essential mixed cryoglobulins, with skin, neurologic, renal, and rheumatologic complications . However, only a small number of patients with mixed cryoglobulinemia develop extrahepatic manifestations. Non-cryoglobulin diseases with a less definite relationship to HCV include systemic vasculitis, splenic lymphoma, porphyria cutanea tarda (PCT), and the sicca syndromes. The mechanism by which HCV promotes many of these extrahepatic disorders is still not completely clear.
Cryoglobulin complexes were first described in 1966 as the cause for a triad of symptoms: purpura, arthralgias, and fatigue . Cryoglobulins are immunoglobulins that precipitate in the cold and are classified into three types: type I is composed of monoclonal immunoglobulins and usually associated with malignancies of the immune system; type II is composed of polyclonal IgG and monoclonal IgM; and type III is composed of polyclonal IgG and polyclonal IgM . Types II and III are referred to as mixed cryoglobulinemia (MC), and the IgM usually has RF activity. When no precipitating factor is identified, the syndrome is termed essential MC (EMC). Until the discovery of HCV, hepatitis B virus (HBV) was implicated in MC. However, since the discovery of HCV, it has emerged as the major etiology of EMC .
The prevalence of HCV in MC is estimated at 45% to 90% . The majority of these patients are asymptomatic. Clinically significant cryoglobulinemia occurs in only a fraction of those with chronic HCV. This discrepancy has not been fully explained, and there may be host genetic factors that predispose patients with chronic HCV to MC, including HLA haplotypes B8 and DR3, as well as viral factors. HCV genotype 2a has been reported to be more prevalent in MC, but this finding has not been confirmed .
Clinically, patients with MC present with arthralgias, symmetrical arthritis, fatigue, vasculitis, palpable purpura (from a leukocytoclastic vasculitis) (Fig. 1), and neuropathy. Cutaneous leukocytoclastic vasculitis or palpable purpura occurs only in the presence of MC, with a frequency reported to be as high as 40% to 95%, which makes this condition the most frequent extrahepatic manifestation . HCV antigens are found in the skin lesions and respond to combination interferon (IFN) therapy. The purpuric lesions are most often on the legs, back, or trunk. The dermal capillaries become plugged with precipitated MC, and neutrophilic infiltrates involve the walls of the small vessels. However, necrosis seldom occurs. The skin lesions usually appear in the winter and are intermittent, lasting 3 to 10 days and leaving an area of brownish pigmentation. Raynaud's phenomenon and acrocyanosis with digital ulceration occur in 25% of patients.
Renal involvement occurs in up to 50% of patients and usually presents as glomerular disease [1**, 13**]. HCV- associated glomerular diseases include membranous glomerulonephritis (MGN), membranous nephropathy (MN), and membranoproliferative glomerulonephritis (MPGN), with the vast majority of patients having type I MPGN. Laboratory testing shows positive HCV RNA, proteinuria, microscopic hematuria, mild to moderate renal insufficiency, hypocomplementemia (especially low C4 with modest depression of CH50 and C3), and elevated C1q binding . The pathogenesis of MGN includes glomerular deposition of immune complexes containing HCV antigens, anti-HCV IgG antibodies, and IgM RF (anti-IgG antibodies) . This results in local complement activation and an inflammatory infiltrate. HCV RNA is concentrated over 100-fold relative to serum in the cryoprecipitate. On renal biopsy, the circulating immune complexes localize to the subendothelium and mesangium to initiate local
inflammation . This results in a proliferative lesion with thickening of the capillary membranes. Immunofluorescence demonstrates granular staining of the capillary walls with IgM, IgG, and C3. In addition, tubulointerstitial fibrosis and vasculitis of the small and medium arteries can be seen. In patients with HCV-associated MN, there is normal cellularity with basement membrane thickening, granular capillary wall deposits of IgG and C3 on immunofluorescence, and subepithelial immune deposits seen on electron microscopy. Occasionally, patients with chronic HCV can develop membranous nephropathy in the absence of cryoglobulins or evidence of MC. In these patients, RF is negative and serum complement levels are normal.
Arthralgias frequently occur in HCV but show no evidence of arthritis except in the presence of MC . Joint pain and stiffness usually affect the proximal interphalangeal, metacarpophalangeal joints, and knees and are precipitated by cold exposure. Generalized weakness hampers the quality of life. An SVR may reduce the severity, but fatigue may continue as long as cryoglobulins are present.
Neurologic manifestations of the HCV-MC complex are usually confined to the peripheral nervous system and are reported in over 80% of these patients . Sensory deficiencies of the lower legs are more common than motor losses. Polyneuropathies are often bilateral but may be asymmetrical, producing painful paresthesias or hypoesthesia. The sensory symptoms may persist for months to years before any motor defect becomes clinically evident. Electromyography can demonstrate an axonal involvement of the sensory potentials and later a delay in motor conduction. Motor abnormalities alone have not been reported. Nerve biopsies may reveal a loss of myelinated fibers in axons and mononuclear infiltrates around the small vessels with deposits of mixed cryoglobulins producing the vasculitis . In a few cases complement components, C3, C4, and C1q, have been found. HCV without MC can also be associated with peripheral neuropathies, and HCV RNA strands can be seen in perineural cells.
An elevated RF is seen in over 70% of HCV patients and can be a useful screening test for those suspected of having MC. In these patients, the diagnosis of MC requires the measurement of cryoglobulins. However, because many laboratories do not perform this test routinely, false-negative results exist and the diagnosis can still be made in the presence of other positive clinical and laboratory findings. The majority of patients with HCV-associated MC have significant hepatitis or advanced fibrosis. However, MC has been reported in those with normal liver enzymes and mild histology when HCV is diagnosed early in the course of the disease .
Treatment options for HCV-associated MC include corticosteroids, cytotoxic agents, plasmapheresis, and direct antiviral therapy with IFN and ribavirin . The objective is to reduce the formation and inflammation associated with cryoglobulins. Because the formation of cryoglobulins is in part related to interaction of HCV RNA and its antibodies, treatment with IFN to eradicate HCV RNA is the logical approach. Experience with IFN has been limited. Overall, clinical improvements in proteinuria, renal function, vasculitis, and purpura are reported in patients who achieve virologic response . Unfortunately, relapse is common when therapy is discontinued. Although the sustained loss of HCV RNA is higher with IFN and ribavirin combination therapy, there are few data related to patients with MC. We and others have had success in controlling MC symptoms with long-term maintenance IFN. With the development of pegylated IFN, this may now be a viable long-term option in selected
patients. In those that present with an acute nephritic syndrome and signs of acute vasculitis, a more aggressive approach using pulse corticosteroids and cyclophosphamide with or without plasmapheresis has been suggested.
Moderate degree of association
Whereas extrahepatic diseases associated with MC have a strong relationship with HCV, many other disorders without MC have been reported with less proof, mostly in isolated case reports. Although periarteritis nodosum (PAN) is rarely associated with HCV, in contrast with HBV, the differential diagnosis may be difficult . PAN is a life-threatening disease with systemic necrotizing vasculitis involving and occluding medium-sized vessels with a mixed inflammatory infiltrate . Cerebral angiitis, ischemic abdominal vasculitis with intermittent pain, and hypertension with renal insufficiency result in a confusing pattern. The neuropathy is multifocal, with severe sensorimotor involvement. The mechanism for the association has not been established, and there are clear-cut pathologic differences from HCV-MC vasculitis.
A recent meta-analysis of patients with B-cell non-Hodgkin's lymphoma (NHL) reported an elevated prevalence of HCV of 15%, suggesting that HCV had a causative role in certain forms of lymphoma. Splenic lymphoma with villous lymphocytes (SLVL) is an indolent chronic B-cell lymphoproliferative disorder similar to NHL. In a French study of a group of patients with SLVL, nine had concomitant HCV, were treated with combined IFN and ribavirin without chemotherapy, and had a hematologic response along with the viral response . HCV RNA has been isolated from infected lymph nodes in patients with a low-grade lymphoma called immunocytoma. HCV has also been recovered from the gastric mucosa of other low-grade lymphomas called marginal cell lymphomas (MALT) . HCV patients with these MALT lymphomas are reported to have a 10-fold increased risk of developing B-cell NHL. The association of HCV with these low-grade lymphomas suggests a causative role for HCV, but that role is still
A possible mechanism of disease has been proposed indicating that HCV stimulates the immune system, producing cryoglobulins that predispose to a lymphoproliferative disorder. HCV patients are more likely than control subjects to have overexpression of the anti-apoptotic bcl-2 protooncogene, and this may play a role in lymphoma development . The association of HCV with B-cell NHL remains in question. Viral replication has not been proved to occur in normal B cells, and the prevalence of B-cell NHL is low in long-term follow-up of HCV-MC patients.
Sicca syndrome was considered a direct manifestation of HCV infection because both conditions have high concentrations of MC. Both disorders have a high incidence of lymphocytic sialadenitis (58%), according to Haddad et al. . Only 30% of HCV patients with sialadenitis have xerostomia, and none have xeroopthalmia or SSB antibodies, which are typical in SjÃ¶gren syndrome . Salivary biopsies in HCV patients demonstrate changes that are different from those found in SjÃ¶gren syndrome and similar to many viral infections. These findings include pericapillary lymphocytic infiltration with no damage to the glandular structures . SjÃ¶gren syndrome does not respond to anti-HCV therapy even after SVR. Polymerase chain reaction studies have demonstrated HCV in tears and saliva but not in the glandular tissue of the salivary gland . Studies with transgenic mice have demonstrated that E1 and E2 glycoproteins have a direct effect in producing sialadenitis . Clinical
differences between patients with SjÃ¶gren system and those with HCV-induced sicca syndrome include male rather than female predominance, low association with HLA DR3, and absence of serum antinuclear antibodies.
Porphyria cutanea tarda (PCT) is a cutaneous disease process associated with photosensitizing action on accumulated porphyrins in the skin, resulting in increased skin fragility, hypertrichosis of light-exposed areas, chloracne, hyperpigmentation, sclerodermoid changes, dystrophic calcifications with ulcerations, scarring, alopecia, and onycholysis [2, 22*, 23**]. Traditionally these findings are manifest clinically by the blisters, vesicles, and/or milia seen on the dorsal aspect of hands and other sun-exposed areas (Fig. 2).
The proposed mechanism of injury for this phenotypic _expression is from the accumulation of uroporphyrin and other highly carboxylated porphyrins in the epidermis and their resultant photoactivation. As these oxidized metabolites diffuse from the plasma into the upper dermis, because of their water-soluble nature, they are exposed to photoactivation, creating reactive oxygen singlets that in turn form free radicals. These free radicals are then involved in the activation of the local complement cascades, resulting in the splitting of the dermis through bullae formation in the subepidermal layer . Bullae formation and resultant splitting are the phenotypic _expression that identifies most patients as carriers of the genetic defect that reduces the activity of uroporphyrinogen decarboxylase (URO-D).
Many disease processes are speculated to propagate the phenotypic _expression of sporadic PCT by hypothesized mechanisms that remain poorly understood. It is now relatively well established that there is a definitive link between HCV infection and PCT [23**]. The literature, while sparse on treatment options and mechanisms of injury in HCV-induced PCT, repeatedly illustrates evidence that HCV infection is related to an increased phenotypic _expression of PCT when compared with that seen in the general population. It is also suggested that the prevalence of HCV infection in phenotypic PCT is more complex than was initially expected, based on the wide variance in the proportion of PCT patients in their coinfection with HCV based on geographic location. The presence of iron overload together with HCV suggests the possibility of HLA-linked hereditary hemochromatosis and HFE gene analysis for C282Y and H63D mutations should be performed .
In the United States, HCV infection is found in almost 60% of patients with PCT, compared with 2% prevalence in the general population . Patients with HCV infection with a genetic URO-D deficiency are at risk not only for dermal manifestations; mounting evidence also suggests that the concomitant HCV infection superimposed on PCT results in earlier liver dysfunction. This accelerated dysfunction not only manifests itself through earlier _expression of phenotypic PCT, when compared with non-HCV-infected PCT patients, but is also seen as worse histology on biopsy. The link to earlier phenotypic _expression in HCV-infected patients invariably leads back to an increase in hepatic porphyrin levels. This increase in porphyrin levels is also believed to have an increased carcinogenic effect, as demonstrated by a 15% prevalence of hepatocellular carcinoma development within a decade after phenotypic _expression of PCT .
Although the exact mechanism of how HCV infection and PCT phenotypic _expression are linked has not yet been established, there has been no evidence linking the two in a reverse fashion. PCT has not been shown to increase the likelihood of HCV infection . The most reasonable hypothesis set forth in the literature is that the phenotypic _expression of PCT is not solely catalyzed by an HCV infection but rather requires a combination of genetic, infectious, and environmental factors. HCV seems to provide an accelerating catalyst to this system by allowing the decompartmentalization of hepatocytic iron, giving rise to "free iron." This free iron in an oxidized form further inhibits the conversion of uroporphyrinogen to coproporphyrinogen by URO-D, allowing for uroporphyrinogen to undergo oxidation to uroporphyrin . This buildup of porphyrin, and eventual leakage out of the hepatocytes, results in an increase in plasma porphyrin levels. These are then transported to and
absorbed by peripheral tissues where they are sun-activated, and phenotypic _expression is observed.
Although modifications to lifestyle habits, such as sun avoidance, long-sleeve clothing, and ultraviolet protection with sun blocks, are used to help decrease the incidence of phenotypic PCT _expression, the majority of effective treatment has focused on porphyrin reduction, mainly through depletion of iron store. The goal of therapy is to reduce total oxidized iron levels to prevent the further inhibition of an already genetically predisposed decreased functioning of URO-D. The reduction of free iron and prevention of hepatic uroporphyrin overload prevent the acceleration of phenotypic PCT _expression and hepatic injury. To this end there have been three major modalities of treatment: venesection with total body iron depletion, low-dose chloroquine therapy, and chelation with desferrioxamine . The use of alcohol or estrogens should also be avoided .
Mild degree of association
Thrombocytopenia is noted in about 41% of HCV patients and may result from hypersplenism, autoantibodies, or a defect in thrombopoietin. This defect is inversely correlated with hepatic fibrosis. Anti-HCV antibodies were found in 19% of patients with immunologic thrombocytopenia . Antiplatelet IgG was noted in 88% of patients with HCV and in 47% of patients with HBV . In a few patients with HCV and thrombocytopenia, IFN therapy led to an increase in platelets along with a viral response. These findings suggest a direct effect of HCV on platelet formation, but usually the thrombocytopenia precedes the HCV by a considerable time.
Type 2 diabetes mellitus was found in 21% of a group of HCV patients, compared with only 12% of a matched group of HBV patients, whereas the prevalence of cirrhosis was comparable . No significant difference was shown between the groups in the absence of cirrhosis, and HCV did not predict glucose intolerance in the absence of cirrhosis. Autoantibodies also were not increased in HCV without cirrhosis. HCV RNA has been found in the pancreas, suggesting a direct effect on beta-cell dysfunction, and may cause some of the observed insulin resistance together with cirrhosis . Antiviral therapy on glucose tolerance brings mixed results. An increase in hepatic clearance may cause a decrease in free fatty acids but no change in insulin response. IFN may further an autoimmune process against beta-cells, inducing type 2 diabetes mellitus in genetically susceptible patients.
Autoimmune thyroiditis may be the most common autoimmune disorder found in HCV patients . Antithyroid antibodies are particularly prevalent in older women with or without HCV. Patients with HCV have a higher thyroid-stimulating hormone level and significantly lower T3 and T4 on average compared with a control group or patients from an iodine-deficient area . Hypothyroidism is more frequent in both sexes with HCV than in control patients but especially in patients with positive antithyroid antibodies prior to IFN treatment. IFN may exacerbate an underlying thyroid immune disease, and thyroid dysfunction may improve when the antiviral therapy is discontinued. Consequently, all patients and especially women should have thyroid antibodies studied prior to IFN therapy. Whether HCV is a direct cause for hypothyroidism is still controversial.
Lichen planus (LP) has been reported to be associated with many chronic liver diseases. The prevalence of HCV antibodies in association with LP has been reported to be 29%, whereas with HBV it was 12% and with hepatitis A virus it was 16%. Marked variation is shown in reports from different geographic areas: 62% in Japan, 4% in northern France, and 0% in Great Britain. A causative role for HCV is uncertain, but the LP lesions may progress with IFN therapy and improve with the cessation of antiviral therapy [34, 35]. The lesions progress with the duration of the HCV infection. They have a generalized distribution and a high incidence of oral mucocutaneous involvement. The lesions are described as flat-topped, violaceous pruritic papules (Fig. 3). LP may be initiated through a cellular immune response, but the actual mechanism is unknown.
In the presence of significant viremia, extrahepatic problems require adequate treatment with an appropriate pegylated IFN and ribavirin protocol. There are several caveats to be considered. IFN therapy may increase the level of autoantibodies and confuse HCV with autoimmune hepatitis. Usually the antibodies decrease along with the viral load. Fatigue and depression may increase during therapy and may not improve in conjunction with SVR (note from Jules Levin: fatigue was the main side effect I experienced while taking therapy, but since completing therapy with SVR 2 years ago pre-therapy fatigue and cognitive impairment I was experiencing is greatly improved, I have not felt better in many years). Hematologic decreases may be improved with IFN, but they usually become more severe and require close observation. IFN may exacerbate thyroid dysfunction, but it usually improves when therapy is discontinued; therefore, thyroid supplements need monitoring while patients are on
anti-HCV therapy. Finally, in genetically susceptible patients, IFN may cause autoimmune damage to the beta cells of the pancreas, producing overt diabetes. Adequate treatment of HCV requires monitoring of these extrahepatic manifestations.
Extrahepatic manifestations of chronic HCV are common and have been reported in as much as 36% of HCV-infected patients. Most symptoms are nonspecific and include fatigue and arthralgias. True extrahepatic syndromes can be divided into those with a high degree and those with a more moderate or mild association with HCV. The most prevalent extrahepatic disease with the highest degree of association with HCV is EMC with skin, neurologic, renal, and rheumatologic complications. Non-cryoglobulin diseases with a less definite relationship to HCV include systemic vasculitis, splenic lymphoma, porphyria cutanea tarda, and the sicca syndromes. As such, testing for HCV should be done in individuals who present with these conditions. Treatment of these extrahepatic manifestations is directed at the HCV virus itself as well as the extrahepatic organ affected and often requires a multidisciplinary approach.
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