The hepatitis C virus (HCV ) Acute hepatitis Chronic hepatitis. Extrahepatic diseases have been associated with chronic HCV infection, and in most cases appear to be directly related to the viral infection.
Extrahepatic Manifestations of Hepatitis C Virus Infection Endocrine Salivary Glands (sialadenitis) Ophtalmic ( uveitis, ulcers) Hematologic/lymphoid organs Skin Renal Autoimmune diseases Neurologic and Cognitive impairment Miscellaneou s * S.J. Hadziyannis. (Review). J Viral Hepatitis 1997; 4:9
HEMATOLOGIC DISORDERS <ul><li>Essential mixed cryoglobulinemia. Monoclonal gammopathies (which may be associated with multiple myeloma). Lymphoma </li></ul><ul><li>Monoclonal gammopathies </li></ul>
Essential mixed cryoglobulinemia : <ul><li>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 can also involve the kidneys, peripheral nerves, and brain. </li></ul>
<ul><li>HCV infection appears to play an etiologic role in most patients with essential mixed cryoglobulinemia. As an example, three studies of 101 patients with this disorder found that 95 (95 percent) had one or more of the following signs of HCV infection . </li></ul>
<ul><li>* Circulating anti-HCV antibodies * The presence of polyclonal IgG anti-HCV antibodies within the cryoprecipitate * HCV RNA in the plasma and particularly the cryoprecipitate </li></ul><ul><li> Agnello, V, Chung, RT, Kaplan, LM. N Engl J Med 1992; 327:1490. Pozzato, G, Mazzaro, C, Crovatto, M, et alBlood 1994; 84:3047. Misiani, R, Bellavita, P, Fenili, D, et al 1992; 117:573 . </li></ul>
<ul><li>Causal relationship between HCV and essential mixed cryoglobulinemia </li></ul><ul><li>1-HCV antibodies in the vessel walls of skin biopsies obtained from patients with mixed cryoglobulinemia and cutaneous vasculitis. 2-Cryoglobulin levels decrease and skin lesions and symptoms improve in association with a reduction in HCV virus when patients respond to treatment with IFN. </li></ul>
<ul><li>Unfortunately, not all patients with </li></ul><ul><li>HCV infection and cryoglobulinemia respond to IFN. </li></ul><ul><li>In addition, a reduction in cryoglobulin titers is not directly associated with a decrease in serum ALT or HCV RNA . </li></ul>
<ul><li>Treatment of patients with cryoglobulinemia due to HCV should be based upon the presence of cryoglobulinemia symptoms </li></ul><ul><li>The response should be assessed by symptomatic improvement of cryoglobulinemia, a reduction in cryocrit, and an increase in serum complement levels. </li></ul>
<ul><li>Complete responses may be more common in patients with low pretreatment levels of viremia and with high dose interferon regimens . </li></ul><ul><li> . Casato, M, Agnello, V, Pacillo, LP, Blood 1997; 90:3865. </li></ul>
Monoclonal gammopathies: <ul><li>HCV may be a risk factor for the development of monoclonal gammopathies. </li></ul><ul><li>The prevalence of monoclonal gammopathies was noted to be increased in patients with chronic liver disease . </li></ul><ul><li>Heer, M, Joller-Jemelka, H, Fontana, A, et al. Liver 1984; 4:255. </li></ul>
Lymphoma : <ul><li>Multiple reports have described an association between HCV infection and NHL. A meta-analysis that included 48 studies concluded that the prevalence of HCV in patients with B-cell NHL was 15 percent, much higher than the general population (around 1.5 percent) and in patients with other hematologic malignancies (2.9 percent) suggesting that HCV has an etiologic role. </li></ul><ul><li>Gisbert, JP, Garca-Buey, L, Pajares , JM, Moreno-Otero, R Gastroenterology 2003; 125:1723. </li></ul>
<ul><li>1-The hypothesis that cryoglobulinemia may arise from chronic stimulation of the immune system by HCV, which may predispose to a lymphoproliferative disorder. </li></ul>
2-patients with HCV are more likely to have translocation with overexpression of the antiapoptotic bcl-2 proto-oncogene and bcl-2 rearrangements, suggesting that bcl-2 may be a contributing factor to lymphoma development .
3-Some HCV-associated lymphomas produce soluble immunoglobulin directed against the E2 protein .This observation supports the hypothesis that some HCV-associated lymphomas originate from B cells that were initially activated by the HCV-E2 protein. Zignego, AL, Giannelli, F, Marrocchi, ME, et al. Hepatology 2000; 31:474.
DIABETES MELLITUS : <ul><li>HCV infection has been linked to DM in several epidemiologic studies. An illustrative study of 1117 patients with chronic viral hepatitis found that diabetes was present in significantly more patients with HCV compared to HBV infection (21 versus 12 percent). HCV genotype 2a was overrepresented among the diabetic patients. </li></ul>
In a case-control trial, the prevalence of HCV infection was significantly higher among patients with DM compared to controls (4.2 versus 1.6 percent). A transgenic animal model suggested that the HCV core gene may be directly involved in the development of insulin resistance.
Risk factors for the development of DM in HCV infected patients Older age. Obesity. Severe liver fibrosis. Family history of DM. Patients undergoing liver transplantation for HCV also appear to be at increased risk, for developing DM following transplantation.
The cause of these associations is unknown, but their magnitude may be overestimated based upon the retrospective nature of the above reports and the following factors .
1-Parenteral exposures. 2- HCV infection becomes chronic more often than HBV infection. 3-Cirrhosis, which may be associated with impaired glucose tolerance.
4- HCV has also been linked to insulin resistance without overt diabetes. It has been suggested that the associated insulin resistance may contribute to fibrosis progression. Petit, JM, Bour, JB, Galland-Jos, C, et al. J Hepatol 2001; 35:279. Bigam, DL, Pennington, JJ, Carpentier, A, et al. Hepatology 2000; 32:87. Hadziyannis, S, Karamanos, B. Gastroenterology 2003; 125:1695
AUTOIMMUNE DISORDERS : <ul><li>A number of autoimmune disorders have been associated with HCV infection, including </li></ul><ul><li>Autoantibody formation. </li></ul><ul><li>Thyroid disease. </li></ul><ul><li>Sialadenitis. </li></ul><ul><li>Autoimmune idiopathic Thrombocytopenic purpura. </li></ul>
These antibodies are typically present in low titer, and do not appear to influence the presentation or course of infection; they are not usually associated with extrahepatic disease. However, their presence may result in diagnostic difficulties; as an example, the HCV-infected patient with arthralgias, arthritis, and rheumatoid factor positivity may be initially misdiagnosed as having rheumatoid arthritis.
Autoantibodies : <ul><li>Autoantibodies are common in patients with chronic HCV infection; antinuclear antibodies, antibodies directed against the Fc portion of IgG (rheumatoid factor), anticardiolipin antibodies, smooth muscle antibodies, or antithyroid antibodies are detected in 40 to 65 percent of patients. </li></ul>
In this setting, testing for other RA-associated autoantibodies infrequently observed in patients with HCV infection, such as anti-citrullinated peptide (anti-cyclic citrullinated peptid or CCP) antibodies, may be helpful diagnostically.
Autoantibodies may first become detectable or can increase in titer during IFN treatment. However, since their presence does not affect the disease course or the response to treatment, autoantibody formation is not a reason to stop therapy.
Antibodies to actin and to liver/kidney microsomes (anti-LKM-1) are characteristic of types 1 and 2 autoimmune hepatitis, respectively. These antibodies have been detected in some patients with chronic HCV infection, particularly in Europe .
Most patients with HCV and anti-LKM-1 antibodies, appear to benefit from IFN to the same extent as patients with chronic HCV without such antibodies. However, such patients need meticulous monitoring during IFN treatment, since flares of ALT&AST without subsequent clearance of HCV RNA have been observed.
This observation suggests that these patients may behave as if they had autoimmune hepatitis. In support of this hypothesis is the finding that when patients with CHCV with or without anti-LKM-1 Ab were compared, the viral load was lower in the patients with anti-LKM-1 Ab even though both groups had disease of similar severity. Furthermore, some of these patients have responded to prednisone and azathioprine, directed against presumed autoimmune hepatitis.
One possible method of determining whether the hepatitis is primarily due to HCV or autoimmune hepatitis is that the anti-LKM-1 Ab in patients with HCV are directed at different epitopes of cytochrome P450 2D6 (CYP2D6, the target antigen) from that seen with autoimmune hepatitis .
Thrombocytopenia in patients with chronic hepatitis c virus infection By Dr. Abd El –Fattah Fahmy Hanno Dr. Amina Hussein Hassab Dr. Dallal Nasr El-Dein El-Kaffash Dr. Fatma Dessouky Zayed * Tropical medicine and clinical pathology department
<ul><li>From the study the following could be concluded </li></ul><ul><li>Hypersplenism is not the only mechanism of thrombocytopenia in chronic HCV. </li></ul><ul><li>Chronic infection with HCV may induce an immune reaction resulting in thrombocytopenia as evidenced by the high titre of PAIgG and its negative correlation to the platelet count in HCV patients with thrombocytopenia . </li></ul>
Thyroid disease : <ul><li>Thyroid disorders are common in patients with CHCV, particularly women. One of the largest studies included 630 consecutive patients with HCV (without cirrhosis) who were compared with 389 subjects from an iodine-deficient area, another control group of 268 persons from an area of iodine sufficiency, and 86 patients with chronic hepatitis B. </li></ul>
Mean TSH levels were significantly higher and free T3 and T4 levels significantly lower in patients with HCV than in all other groups. Patients with HCV were more likely than controls to have hypothyroidism (13 versus 3 to 5 percent ), anti-thyroglobulin antibodies (17 versus 9 to 10 percent), and anti-thyroidperoxidase antibodies (21 versus 10 to 13 percent)
Another report suggested that thyroid abnormalities were seen predominantly in women . Overall, antithyroid antibodies are present in 5 to 17 percent of patients with HCV infection, and thyroid disease, primarily hypothyroidism, occurs in 2 to 13 percent of patients. The highest prevalence of both thyroid antibodies and thyroid disease is found in older women. However, whether or not the prevalence is higher than in age- and sex-matched controls is controversial .
A separate issue is the development of thyroid disease in patients with HCV infection who are treated with IFN. Approximately 1 to 5 % of such patients develop painless thyroiditis. Other thyroid abnormalities can also occur, including Graves' disease and permanent hypothyroidism, or increased serum antithyroid antibody concentrations without thyroid dysfunction.
The changes in thyroid function usually appear after three months of therapy, but can occur as long as IFN is given. The risk of any form of thyroid disease is greater in those patients who have increased serum antithyroid antibody concentrations before the initiation of therapy, a finding which suggests that IFN in some way exacerbates underlying thyroid autoimmune disease.
The presence of antithyroid peroxidase antibodies appears to be the most significant risk factor for the development of thyroid dysfunction during IFN therapy. Other risk factors may include female gender, older age, and the presence of other autoantibodies. Women with CHC and high antithyroid peroxidase antibody titers are at particular risk. Thyroid dysfunction may resolve following the discontinuation of IFN treatment.
In summary, all patients receiving IFN should be monitored for thyroid disease, particularly women and patients with preexisting antithyroid antibodies. IFN therapy usually can be continued while hypothyroidism is being treated. On the other hand, we have usually stopped IFN in patients who develop clinically apparent hyperthyroidism. . Lienesch, D, Morris, Metzger, A, et al. J Rheumatol 2005; 32:489. . Zauli, D, Ghetti, S, Grassi, A, et al. Hepatology 1997; 25:1105.
Sialadenitis: <ul><li>A lymphocytic sialadenitis suggestive of Sjogren's syndrome has been described in patients with CHCV infection. </li></ul><ul><li>A study of 137 patients with Sjogren's syndrome and HCV suggested that the clinical and immunologic features were indistinguishable from Sjogren's syndrome in patients without HCV . </li></ul><ul><li>. Ramos-Casals, M, Loustaud-Ratti, V, De Vita, S, Zeher, M. Medicine (Baltimore) 2005; 84:81. </li></ul>
Autoimmune idiopathic thrombocytopenic purpura: <ul><li>Anti-HCV Ab occur in 10 to 19 percent of patients with autoimmune idiopathic thrombocytopenic purpura (ITP). However, the diagnosis of autoimmune ITP usually predates HCV infection, suggesting that the latter results from the transfusion of blood products. On the other hand, ITP has been reported to develop during IFN therapy for HCV. </li></ul>
Thus, the relationship between autoimmune ITP and HCV remains to be clarified. . Pawlotsky, JM, Bouvier, M, Fromont, P, et al. J Hepatol 1995; 23:635.
Myasthenia gravis : <ul><li>An association between myasthenia gravis (MG) and HCV infection has been suggested in case reports, although a causal association has not been clearly established. MG has also been described in association with administration of IFN, possibly because of exacerbation of preexisting subclinical disease. . Halfon, P, Levy, M, San Marco, M, et al. 1996; 3:329 </li></ul>
Sarcoidosis: <ul><li>Sarcoidosis has been described in association with HCV, mostly in the setting of antiviral therapy . </li></ul>
OCULAR DISEASE: <ul><li>HCV infection has been associated with a variety ophthalmologic disorders including corneal ulcers (Mooren's ulcer), uveitis, and scleritis, and sicca syndrome in patients with HCV-related Sjogren's syndrome. In addition, ophthalmologic disorders (cotton wool spots retinal hemorrhages,, and rarely retinal artery or vein obstruction) can occur during IFN therapy. </li></ul><ul><li>Moder, KG, Poterucha, JJ, Mahr, MA. J Clin Rheumatol- 2000 </li></ul>
RENAL DISEASE <ul><li>Glomerular disease may occur in patients with chronic HCV infection. The most common patterns are membranoproliferative glomerulonephritis (usually associated with essential mixed cryoglobulinemia) and, less frequently, membranous nephropathy . </li></ul>
Several series have reported that anti-HCV antibodies are nearly universal in patients with both membranoproliferative disease and cryoglobulinemia; the pathogenesis appears to relate to deposition of immune complexes containing anti-HCV and HCV RNA in the glomeruli.
IFN is indicated in patients with mixed cryoglobulinemia and membranoproliferative glomerulonephritis. A number of studies have reported a beneficial response to antiviral therapy in this setting, and the reduction in proteinuria correlates with a fall in HCV RNA.
However, long-term responses to interferon are unusual; maintenance treatment may be required, and renal function is often not improved by treatment. Johnson, RJ, Gretch, DR, Couser, WG, et alKidney Int 1994; 46:1700.
DERMATOLOGIC DISEASE: <ul><li>A variety of dermatologic diseases may be associated with HCV infection. </li></ul>
Porphyria cutanea tarda <ul><li>Porphyria cutanea tarda (PCT) is a skin disease caused by a reduction of hepatic uroporphyrinogen decarboxylase activity that is characterized by photosensitivity, skin fragility, bruising, and vesicles or bullae that can become hemorrhagic. </li></ul>
There is a strong association between the sporadic form of PCT and HCV infection. The precise mechanism by which HCV infection might cause or act as a trigger for PCT in predisposed subjects is not known
All patients with PCT should be screened for HCV infection, as well as other potential precipitating factors. Treatment with IFN should be considered in HCV-infected patients.
Leukocytoclastic vasculitis : leukocytoclastic vasculitis may occur in conjunction with essential mixed cryoglobulinemia, presenting clinically with palpable purpura and petechiae that usually involve the lower extremities. Skin biopsy demonstrates cutaneous vasculitis with dermal blood vessel destruction associated with neutrophilic infiltration in and around the vessel wall .
Other tissues, particularly the lower extremity peripheral nerves, may show similar vasculitic changes involving the vasa nervorum. This may be manifested clinically as a peripheral neuropathy which, as in other forms of vasculitis, is typically asymmetric (also called a mononeuritis multiplex). Daoud, MS, Gibson, LE, Daoud, S, el-Azhary , RA. Mayo Clin Proc 1995; 70:559.
Lichen planus : <ul><li>Lichen planus (LP) is characterized by flat-topped, violaceous, pruritic papules with a generalized distribution. It can also involve mucus membranes, hair, and nails. </li></ul><ul><li>LP may be mediated through the cellular immune response, although the actual precipitating mechanism is not known. Skin biopsy demonstrates a dense lymphocytic infiltration in the upper dermis. </li></ul>
LP can be seen in patients with a variety of liver diseases, particularly advanced liver disease; anti-HCV antibodies are present in 10 to 40 percent of these patients but a cause-and-effect relation is uncertain . There are also reports of the development or exacerbation of LP during IFN treatment for CHCV; the lesions improved when IFN was stopped Protzer, U, Ochsendorf, FR, Leopolder-Ochsendorf, A, Holtermuller, KH. Gastroenterology 1993; 104:903.
Necrolytic acral erythema : <ul><li>Necrolytic acral erythema is a pruritic, psoriasis-like skin disease characterized by a sharply marginated, erythematous to hyperpigmented plaques with variable scale and erosion on the lower extremities. In a series of 30 patients who presented with the disorder, all were found to have antibodies to HCV Biopsy specimens showed psoriaform changes, keratinocyte necrosis and papillomatosis. </li></ul>
Improvement was observed in a patient who had been treated for HCV with IFN and subsequent relapse nine months after discontinuation). Topical and systemic corticosteroids had a variable benefit. Other reports have confirmed improvement with IFN and also suggested a benefit from oral zinc sulfate. Abdallah, MA, Hull, C, Horn, TD. Arch Dermatol 2005; 141:85.
MUSCULOSKELETAL: <ul><li>Hepatitis C-associated osteosclerosis is a rare disorder characterized by a marked increase in bone mass during adult life. While most cases have been reported in patients with a history of intravenous drug abuse, it has also been seen with hepatitis C after blood transfusion. </li></ul>
Periosteal, endosteal and trabecular bone thickening occurs throughout the skeleton with the exception of the cranium. During active disease, forearm and leg pain are common, bone remodeling (turnover) is high, and bone mineral density is two- to three-fold higher than age-matched controls.
The increased remodeling may respond to calcitonin, but spontaneous remission has also been described. Abnormalities in insulin-like growth factors (IGF-1 and IGF-II) or their binding proteins may contribute to the increase in bone formation in this disorder .
MYOCARDITIS AND CARDIOMYOPATHY : <ul><li>HCV has been associated with myocarditis and cardiomyopathy in reports from Japan. The pathogenesis is unclear. </li></ul>
NEUROCOGNITIVE DYSFUNCTION : <ul><li>Several studies have suggested that HCV infection may be associated with neurocognitive dysfunction even without advanced liver disease. </li></ul><ul><li>The potential mechanisms are unclear. </li></ul>
Neurological manifestations of hepatitis C: Double blind clinical and electrophysiological study .
Abd El fatah Hano 1 , Alaa Eldin Abdo 1 , Ayman farid Elshayeb 1 ,Hamdy Khamis 2 , Ibrahim Khalil 2 and Akram Degheady 3 Departments of Tropical Medicine 1 , Physical Medicine 2 and clinical pathology 3 , Faculty of Medicine, Alexandria University
In patients with chronic HCV and liver cirrhosis, various mechanisms were postulated for this hepatic neuropathy. 1-Mtabolic inhibition of the axonal membrane function 2-Metabolic damage to Schwann cells and even a possibly disordered insulin metabolism, something similar to diabetic neuropathy.
In conclusion, peripheral neuropathy may be associated with chronic HCV with and without liver cirrhosis. It usually occurs in CG+ cases and less often in those without detectable CG. Moreover, the present findings suggest that patients with chronic HCV experience cognitive difficulties that may interfere with their daily activities and quality of life. The condition worsens by the development of cirrhosis.