The hepatitis C virus (HCVThe hepatitis C virus (HCV))Acute hepatitisAcute hepatitisChronic hepatitis. Chronic hepatitis. Extrahepatic diseases have been Extrahepatic diseases have been associated with chronic HCV infection, and associated with chronic HCV infection, and in most cases appear to be directly related in most cases appear to be directly related

to the viral infectionto the viral infection..

Extrahepatic Manifestations of Extrahepatic Manifestations of Hepatitis C Virus InfectionHepatitis C Virus Infection

EndocrineEndocrine Salivary Glands (sialadenitis)Salivary Glands (sialadenitis)

Ophtalmic ( uveitis, ulcers)Ophtalmic ( uveitis, ulcers) Hematologic/lymphoid organsHematologic/lymphoid organs

SkinSkin RenalRenal

Autoimmune diseasesAutoimmune diseases Neurologic and Cognitive Neurologic and Cognitive

impairmentimpairment

MiscellaneouMiscellaneouss **S.J. Hadziyannis. (Review). J Viral S.J. Hadziyannis. (Review). J Viral Hepatitis 1997; 4:9Hepatitis 1997; 4:9

HEMATOLOGIC DISORDERS

Essential mixed cryoglobulinemia. Essential mixed cryoglobulinemia. Monoclonal gammopathies (which may Monoclonal gammopathies (which may be associated with multiple myeloma). be associated with multiple myeloma). LymphomaLymphoma

Monoclonal gammopathiesMonoclonal gammopathies

Essential mixed cryoglobulinemiaEssential mixed cryoglobulinemia::

Deposition of circulating immune complexes in Deposition of circulating immune complexes in small to medium sized blood vessels. It often small to medium sized blood vessels. It often presents with the clinical triad of palpable presents with the clinical triad of palpable purpura, arthralgias, and weakness, but can purpura, arthralgias, and weakness, but can also involve the kidneys, peripheral nerves, also involve the kidneys, peripheral nerves, and brainand brain..

HCV infection appears to play an etiologic HCV infection appears to play an etiologic role in most patients with essential role in most patients with essential mixed cryoglobulinemia. As an example, mixed cryoglobulinemia. As an example, three studies of 101 patients with this three studies of 101 patients with this disorder found that 95 (95 percent) had disorder found that 95 (95 percent) had one or more of the following signs of one or more of the following signs of

HCV infectionHCV infection. .

* *Circulating anti-HCV antibodiesCirculating anti-HCV antibodies* The presence of polyclonal IgG anti-* The presence of polyclonal IgG anti-HCV antibodies within the HCV antibodies within the cryoprecipitatecryoprecipitate* HCV RNA in the plasma and * HCV RNA in the plasma and particularly the cryoprecipitateparticularly the cryoprecipitate

   Agnello, V, Chung, RT, Kaplan, LM. N Engl J Med 1992; 327:1490.Agnello, V, Chung, RT, Kaplan, LM. N Engl J Med 1992; 327:1490.

   Pozzato, G, Mazzaro, C, Crovatto, M, et alBlood 1994; 84:3047. Pozzato, G, Mazzaro, C, Crovatto, M, et alBlood 1994; 84:3047.   Misiani, R, Bellavita, P, Fenili, D, et al 1992; 117:573 Misiani, R, Bellavita, P, Fenili, D, et al 1992; 117:573..

Causal relationship between HCV and Causal relationship between HCV and essential mixed cryoglobulinemiaessential mixed cryoglobulinemia

11--HCV antibodies in the vessel walls of skin HCV antibodies in the vessel walls of skin biopsies obtained from patients with mixed biopsies obtained from patients with mixed cryoglobulinemia and cutaneous vasculitis. 2-cryoglobulinemia and cutaneous vasculitis. 2-Cryoglobulin levels decrease and skin lesions Cryoglobulin levels decrease and skin lesions and symptoms improve in association with a and symptoms improve in association with a reduction in HCV virus when patients respond reduction in HCV virus when patients respond to treatment with IFNto treatment with IFN..

Unfortunately, not all patients withUnfortunately, not all patients with

HCV infection and cryoglobulinemia HCV infection and cryoglobulinemia respond to IFNrespond to IFN..

In addition, a reduction in cryoglobulin In addition, a reduction in cryoglobulin titers is not directly associated with a titers is not directly associated with a

decrease in serum ALT or HCV RNAdecrease in serum ALT or HCV RNA..

Treatment of patients with Treatment of patients with cryoglobulinemia due to HCV should be cryoglobulinemia due to HCV should be based upon the presence of based upon the presence of cryoglobulinemia symptomscryoglobulinemia symptoms

The response should be assessed by The response should be assessed by symptomatic improvement of symptomatic improvement of cryoglobulinemia, a reduction in cryoglobulinemia, a reduction in cryocrit, and an increase in serum cryocrit, and an increase in serum

complement levelscomplement levels..

Complete responses may be more Complete responses may be more common in patients with low common in patients with low pretreatment levels of viremia and pretreatment levels of viremia and with high dose interferon with high dose interferon regimensregimens..

   . .Casato, M, Agnello, V, Pacillo, LP, Blood 1997; Casato, M, Agnello, V, Pacillo, LP, Blood 1997; 90:386590:3865..

Monoclonal gammopathiesMonoclonal gammopathies::

HCV may be a risk factor for the development HCV may be a risk factor for the development of monoclonal gammopathiesof monoclonal gammopathies..

The prevalence of monoclonal gammopathies The prevalence of monoclonal gammopathies was noted to be increased in patients with was noted to be increased in patients with

chronic liver diseasechronic liver disease. . Heer, M, Joller-Jemelka, H, Fontana, A, et al. Liver Heer, M, Joller-Jemelka, H, Fontana, A, et al. Liver

1984; 4:2551984; 4:255..

LymphomaLymphoma::Multiple reports have described an association Multiple reports have described an association between HCV infection and NHL. A meta-analysis between HCV infection and NHL. A meta-analysis that included 48 studies concluded that the that included 48 studies concluded that the prevalence of HCV in patients with B-cell NHL was prevalence of HCV in patients with B-cell NHL was 15 percent, much higher than the general 15 percent, much higher than the general population (around 1.5 percent) and in patients population (around 1.5 percent) and in patients with other hematologic malignancies (2.9 percent) with other hematologic malignancies (2.9 percent)

suggesting that HCV has an etiologic rolesuggesting that HCV has an etiologic role . .

Gisbert, JP, Garca-Buey, L, PajaresGisbert, JP, Garca-Buey, L, Pajares, JM, Moreno-Otero, , JM, Moreno-Otero, R Gastroenterology 2003; 125:1723R Gastroenterology 2003; 125:1723..

11--The hypothesis that cryoglobulinemia The hypothesis that cryoglobulinemia may arise from chronic stimulation of may arise from chronic stimulation of the immune system by HCV, which may the immune system by HCV, which may predispose to a lymphoproliferative predispose to a lymphoproliferative

disorderdisorder..

22--patients with HCV are more likely to patients with HCV are more likely to have translocation with overexpression of have translocation with overexpression of the antiapoptotic bcl-2 proto-oncogene the antiapoptotic bcl-2 proto-oncogene and bcl-2 rearrangements, suggesting and bcl-2 rearrangements, suggesting that bcl-2 may be a contributing factor to that bcl-2 may be a contributing factor to

lymphoma developmentlymphoma development . .

33--Some HCV-associated lymphomas Some HCV-associated lymphomas produce soluble immunoglobulin directed produce soluble immunoglobulin directed against the E2 protein .This observation against the E2 protein .This observation supports the hypothesis that some HCV-supports the hypothesis that some HCV-associated lymphomas originate from B associated lymphomas originate from B cells that were initially activated by the cells that were initially activated by the HCV-E2 protein.HCV-E2 protein.Zignego, AL, Giannelli, F, Marrocchi, ME, et al. Hepatology Zignego, AL, Giannelli, F, Marrocchi, ME, et al. Hepatology

2000; 31:4742000; 31:474..

DIABETES MELLITUSDIABETES MELLITUS::

HCV infection has been linked to DM in several HCV infection has been linked to DM in several epidemiologic studies. An illustrative study epidemiologic studies. An illustrative study of 1117 patients with chronic viral hepatitis of 1117 patients with chronic viral hepatitis found that diabetes was present in found that diabetes was present in significantly more patients with HCV significantly more patients with HCV compared to HBV infection (21 versus 12 compared to HBV infection (21 versus 12 percent). HCV genotype 2a was percent). HCV genotype 2a was overrepresented among the diabetic overrepresented among the diabetic

patientspatients..

In a case-control trial, the prevalence of In a case-control trial, the prevalence of HCV infection was significantly higher HCV infection was significantly higher among patients with DM compared to among patients with DM compared to controls (4.2 versus 1.6 percent). A controls (4.2 versus 1.6 percent). A transgenic animal model suggested that transgenic animal model suggested that the HCV core gene may be directly the HCV core gene may be directly involved in the development of insulin involved in the development of insulin resistanceresistance..

Risk factors for the development of DM in Risk factors for the development of DM in HCV infected patients HCV infected patients Older age. Older age. Obesity. Obesity. Severe liver fibrosis. Severe liver fibrosis. Family history of DM. Family history of DM. Patients undergoing liver transplantation Patients undergoing liver transplantation for HCV also appear to be at increased for HCV also appear to be at increased risk, for developing DM following risk, for developing DM following transplantationtransplantation..

The cause of these associations is The cause of these associations is unknown, but their magnitude may be unknown, but their magnitude may be overestimated based upon the overestimated based upon the retrospective nature of the above retrospective nature of the above

reports and the following factorsreports and the following factors ..

11--Parenteral exposures.Parenteral exposures.  

2-2-HCV infection becomes chronic more HCV infection becomes chronic more often than HBV infection. often than HBV infection. 3-Cirrhosis, which may be associated with 3-Cirrhosis, which may be associated with impaired glucose toleranceimpaired glucose tolerance..

44--HCV has also been linked to insulin HCV has also been linked to insulin resistance without overt diabetes. It has resistance without overt diabetes. It has been suggested that the associated insulin been suggested that the associated insulin resistance may contribute to fibrosis resistance may contribute to fibrosis progression.progression.

Petit, JM, Bour, JB, Galland-Jos, C, et al. Petit, JM, Bour, JB, Galland-Jos, C, et al. J Hepatol 2001; 35:279.J Hepatol 2001; 35:279.  Bigam, DL, Pennington, JJ, Carpentier, A, et al. Hepatology 2000; Bigam, DL, Pennington, JJ, Carpentier, A, et al. Hepatology 2000; 32:87.32:87.   Hadziyannis, S, Karamanos, B. Gastroenterology 2003; 125:1695 Hadziyannis, S, Karamanos, B. Gastroenterology 2003; 125:1695

AUTOIMMUNE DISORDERSAUTOIMMUNE DISORDERS: : A number of autoimmune disorders have A number of autoimmune disorders have been associated with HCV infection, been associated with HCV infection, includingincluding

Autoantibody formationAutoantibody formation..

Thyroid diseaseThyroid disease..

SialadenitisSialadenitis..

Autoimmune idiopathic Autoimmune idiopathic Thrombocytopenic purpuraThrombocytopenic purpura..

These antibodies are typically present in low These antibodies are typically present in low titer, and do not appear to influence the titer, and do not appear to influence the presentation or course of infection; they are presentation or course of infection; they are not usually associated with extrahepatic not usually associated with extrahepatic disease.disease.However, their presence may result in However, their presence may result in diagnostic difficulties; as an example, the HCV-diagnostic difficulties; as an example, the HCV-infected patient with arthralgias, arthritis, and infected patient with arthralgias, arthritis, and rheumatoid factor positivity may be initially rheumatoid factor positivity may be initially

misdiagnosed as having rheumatoid arthritismisdiagnosed as having rheumatoid arthritis . .

AutoantibodiesAutoantibodies: :

Autoantibodies are common in patients Autoantibodies are common in patients with chronic HCV infection; antinuclear with chronic HCV infection; antinuclear antibodies, antibodies directed against antibodies, antibodies directed against the Fc portion of IgG (rheumatoid the Fc portion of IgG (rheumatoid factor), anticardiolipin antibodies, factor), anticardiolipin antibodies, smooth muscle antibodies, or smooth muscle antibodies, or antithyroid antibodies are detected in 40 antithyroid antibodies are detected in 40

to 65 percent of patientsto 65 percent of patients . .

In this setting, testing for other RA-In this setting, testing for other RA-associated autoantibodies infrequently associated autoantibodies infrequently observed in patients with HCV infection, observed in patients with HCV infection, such as anti-citrullinated peptide (anti-such as anti-citrullinated peptide (anti-cyclic citrullinated peptid or CCP) cyclic citrullinated peptid or CCP)

antibodies, may be helpful diagnosticallyantibodies, may be helpful diagnostically . .

Autoantibodies may first become Autoantibodies may first become detectable or can increase in titer during detectable or can increase in titer during IFN treatment. IFN treatment. However, since their presence does not However, since their presence does not affect the disease course or the response affect the disease course or the response to treatment, autoantibody formation is to treatment, autoantibody formation is not a reason to stop therapynot a reason to stop therapy..

Antibodies to actin and to liver/kidney Antibodies to actin and to liver/kidney microsomes (anti-LKM-1) are microsomes (anti-LKM-1) are characteristic of types 1 and 2 characteristic of types 1 and 2 autoimmune hepatitis, respectively. autoimmune hepatitis, respectively.

These antibodies have been detected in These antibodies have been detected in some patients with chronic HCV infection, some patients with chronic HCV infection, particularly particularly in Europein Europe..

Most patients with HCV and anti-LKM-1 Most patients with HCV and anti-LKM-1 antibodies, appear to benefit from IFN to antibodies, appear to benefit from IFN to the same extent as patients with chronic the same extent as patients with chronic HCV without such antibodies. HCV without such antibodies. However, such patients need meticulous However, such patients need meticulous monitoring during IFN treatment, since monitoring during IFN treatment, since flares of ALT&AST without subsequent flares of ALT&AST without subsequent clearance of HCV RNA have been clearance of HCV RNA have been

observedobserved . .

This observation suggests that these patients may This observation suggests that these patients may behave as if they had autoimmune hepatitis.behave as if they had autoimmune hepatitis.In support of this hypothesis is the finding that when In support of this hypothesis is the finding that when patients with CHCV with or without anti-LKM-1 Ab patients with CHCV with or without anti-LKM-1 Ab were compared, the viral load was lower in the were compared, the viral load was lower in the patients with anti-LKM-1 Ab even though both patients with anti-LKM-1 Ab even though both groups had disease of similar severity. Furthermore, groups had disease of similar severity. Furthermore, some of these patients have responded to some of these patients have responded to prednisone and azathioprine, directed against prednisone and azathioprine, directed against

presumed autoimmune hepatitispresumed autoimmune hepatitis..

One possible method of determining One possible method of determining whether the hepatitis is primarily due to whether the hepatitis is primarily due to HCV or autoimmune hepatitis is that the HCV or autoimmune hepatitis is that the anti-LKM-1 Ab in patients with HCV are anti-LKM-1 Ab in patients with HCV are directed at different epitopes of directed at different epitopes of cytochrome P450 2D6 (CYP2D6, the target cytochrome P450 2D6 (CYP2D6, the target antigen) from that seen with autoimmune antigen) from that seen with autoimmune hepatitishepatitis..  

Thrombocytopenia in Thrombocytopenia in patients with chronic patients with chronic

hepatitis c virus infectionhepatitis c virus infection ByBy

Dr. Abd El –Fattah Fahmy HannoDr. Abd El –Fattah Fahmy Hanno

Dr. Amina Hussein HassabDr. Amina Hussein Hassab

Dr. Dallal Nasr El-Dein El-KaffashDr. Dallal Nasr El-Dein El-Kaffash

Dr. Fatma Dessouky ZayedDr. Fatma Dessouky Zayed

* *Tropical medicine and clinical pathology departmentTropical medicine and clinical pathology department

From the study the following could be concluded

Hypersplenism is not the only mechanism of thrombocytopenia in chronic HCV.

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.

From the study the following could be concluded

Hypersplenism is not the only mechanism of thrombocytopenia in chronic HCV.

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.

Thyroid disease::Thyroid disorders are common in patients withThyroid disorders are common in patients with

CHCV, particularly women. One of the largest CHCV, particularly women. One of the largest studies included 630 consecutive patients studies included 630 consecutive patients with HCV (without cirrhosis) who were with HCV (without cirrhosis) who were compared with 389 subjects from an iodine-compared with 389 subjects from an iodine-deficient area, another control group of 268 deficient area, another control group of 268 persons from an area of iodine sufficiency, persons from an area of iodine sufficiency,

and 86 patients with chronic hepatitis Band 86 patients with chronic hepatitis B..

Mean TSH levels were significantly higher Mean TSH levels were significantly higher and free T3 and T4 levels significantly and free T3 and T4 levels significantly lower in patients with HCV than in all lower in patients with HCV than in all other groups.other groups.Patients with HCV were more likely than Patients with HCV were more likely than controls to have hypothyroidism (13 controls to have hypothyroidism (13 versus 3 to 5 percent ), anti-thyroglobulin versus 3 to 5 percent ), anti-thyroglobulin antibodies (17 versus 9 to 10 percent), and antibodies (17 versus 9 to 10 percent), and anti-thyroidperoxidase antibodies (21 anti-thyroidperoxidase antibodies (21 versus 10 to 13 percent)versus 10 to 13 percent)

Another report suggested that thyroid abnormalities Another report suggested that thyroid abnormalities were seen predominantly in women .were seen predominantly in women .  Overall, antithyroid antibodies are present in 5 to 17 Overall, antithyroid antibodies are present in 5 to 17 percent of patients with HCV infection, and thyroid percent of patients with HCV infection, and thyroid disease, primarily hypothyroidism, occurs in 2 to 13 disease, primarily hypothyroidism, occurs in 2 to 13 percent of patients. percent of patients.

The highest prevalence of both thyroid antibodies The highest prevalence of both thyroid antibodies and thyroid disease is found in older women. and thyroid disease is found in older women. However, whether or not the prevalence is higher However, whether or not the prevalence is higher than in age- and sex-matched controls is than in age- and sex-matched controls is controversialcontroversial..  

A separate issue is the development of thyroid A separate issue is the development of thyroid disease in patients with HCV infection who are disease in patients with HCV infection who are treated with IFN. Approximately 1 to 5 % of treated with IFN. Approximately 1 to 5 % of such patients develop painless thyroiditis. such patients develop painless thyroiditis. Other thyroid abnormalities can also occur, Other thyroid abnormalities can also occur, including Graves' disease and permanent including Graves' disease and permanent hypothyroidism, or increased serum hypothyroidism, or increased serum antithyroid antibody concentrations without antithyroid antibody concentrations without

thyroid dysfunctionthyroid dysfunction..

The changes in thyroid function usually appear The changes in thyroid function usually appear after three months of therapy, but can occur as after three months of therapy, but can occur as long as IFN is given.long as IFN is given.The risk of any form of thyroid disease is The risk of any form of thyroid disease is greater in those patients who have increased greater in those patients who have increased serum antithyroid antibody concentrations serum antithyroid antibody concentrations before the initiation of therapy, a finding before the initiation of therapy, a finding which suggests that IFN in some way which suggests that IFN in some way exacerbates underlying thyroid autoimmune exacerbates underlying thyroid autoimmune

diseasedisease . .

The presence of antithyroid peroxidase The presence of antithyroid peroxidase antibodies appears to be the most significant antibodies appears to be the most significant risk factor for the development of thyroid risk factor for the development of thyroid dysfunction during IFN therapy.dysfunction during IFN therapy.Other risk factors may include female gender, Other risk factors may include female gender, older age, and the presence of other older age, and the presence of other autoantibodies.autoantibodies.Women with CHC and high antithyroid Women with CHC and high antithyroid peroxidase antibody titers are at particular peroxidase antibody titers are at particular risk.risk.Thyroid dysfunction may resolve following the Thyroid dysfunction may resolve following the

discontinuation of IFN treatmentdiscontinuation of IFN treatment . .

In summary, all patients receiving IFN should In summary, all patients receiving IFN should be monitored for thyroid disease, particularly be monitored for thyroid disease, particularly women and patients with preexisting women and patients with preexisting antithyroid antibodies. IFN therapy usually can antithyroid antibodies. IFN therapy usually can be continued while hypothyroidism is being be continued while hypothyroidism is being treated. On the other hand, we have usually treated. On the other hand, we have usually stopped IFN in patients who develop clinically stopped IFN in patients who develop clinically apparent hyperthyroidism.apparent hyperthyroidism.  . . Lienesch, D, Morris, Metzger, A, et al. Lienesch, D, Morris, Metzger, A, et al. J Rheumatol 2005; J Rheumatol 2005; 32:489.32:489.  . Zauli, D, Ghetti, S, Grassi, A, et al. . Zauli, D, Ghetti, S, Grassi, A, et al. Hepatology 1997; Hepatology 1997; 25:110525:1105..

SialadenitisSialadenitis::A lymphocytic sialadenitis suggestive of Sjogren's A lymphocytic sialadenitis suggestive of Sjogren's syndrome has been described in patients with syndrome has been described in patients with CHCV infectionCHCV infection..

A study of 137 patients with Sjogren's syndrome and A study of 137 patients with Sjogren's syndrome and HCV suggested that the clinical and immunologic HCV suggested that the clinical and immunologic features were indistinguishable from Sjogren's features were indistinguishable from Sjogren's syndrome in patients without HCVsyndrome in patients without HCV..

. .Ramos-Casals, M, Loustaud-Ratti, V, De Vita, S, Zeher, M. Ramos-Casals, M, Loustaud-Ratti, V, De Vita, S, Zeher, M. Medicine (Baltimore) 2005; 84:81Medicine (Baltimore) 2005; 84:81..

Autoimmune idiopathic Autoimmune idiopathic thrombocytopenic purpurathrombocytopenic purpura : :

Anti-HCV Ab occur in 10 to 19 percent of patients Anti-HCV Ab occur in 10 to 19 percent of patients with autoimmune idiopathic thrombocytopenic with autoimmune idiopathic thrombocytopenic purpura (ITP). However, the diagnosis of purpura (ITP). However, the diagnosis of autoimmune ITP usually predates HCV infection, autoimmune ITP usually predates HCV infection, suggesting that the latter results from the suggesting that the latter results from the transfusion of blood products. On the other hand, transfusion of blood products. On the other hand, ITP has been reported to develop during IFN ITP has been reported to develop during IFN

therapy for HCVtherapy for HCV . .

Thus, the relationship between Thus, the relationship between autoimmune ITP and HCV remains to autoimmune ITP and HCV remains to be clarified.be clarified.

. Pawlotsky, JM, Bouvier, M, Fromont, P, et al. J Hepatol 1995; 23:635. Pawlotsky, JM, Bouvier, M, Fromont, P, et al. J Hepatol 1995; 23:635..

Myasthenia gravisMyasthenia gravis ::An association between myasthenia gravis An association between myasthenia gravis (MG) and HCV infection has been suggested (MG) and HCV infection has been suggested in case reports, although a causal association in case reports, although a causal association has not been clearly established. MG has also has not been clearly established. MG has also been described in association with been described in association with administration of IFN, possibly because of administration of IFN, possibly because of exacerbation of preexisting subclinical exacerbation of preexisting subclinical disease.disease.. Halfon, P, Levy, M, San Marco, M, et al. 1996; . Halfon, P, Levy, M, San Marco, M, et al. 1996; 3:3293:329

SarcoidosisSarcoidosis::

Sarcoidosis has been described in Sarcoidosis has been described in association with HCV, mostly in the association with HCV, mostly in the

setting of antiviral therapysetting of antiviral therapy . .

OCULAR DISEASEOCULAR DISEASE::HCV infection has been associated with a variety HCV infection has been associated with a variety ophthalmologic disorders including corneal ulcers ophthalmologic disorders including corneal ulcers (Mooren's ulcer), uveitis, and scleritis, and sicca (Mooren's ulcer), uveitis, and scleritis, and sicca syndrome in patients with HCV-related Sjogren's syndrome in patients with HCV-related Sjogren's syndrome. In addition, ophthalmologic disorders syndrome. In addition, ophthalmologic disorders (cotton wool spots retinal hemorrhages,, and (cotton wool spots retinal hemorrhages,, and rarely retinal artery or vein obstruction) can occur rarely retinal artery or vein obstruction) can occur during IFN therapyduring IFN therapy..

Moder, KG, Poterucha, JJ, Mahr, MA. Moder, KG, Poterucha, JJ, Mahr, MA. J Clin Rheumatol- 2000J Clin Rheumatol- 2000

RENAL DISEASERENAL DISEASE

Glomerular disease may occur in patients with Glomerular disease may occur in patients with chronic HCV infection. The most common chronic HCV infection. The most common patterns are membranoproliferative patterns are membranoproliferative glomerulonephritis (usually associated with glomerulonephritis (usually associated with essential mixed cryoglobulinemia) and, less essential mixed cryoglobulinemia) and, less

frequently, membranous nephropathyfrequently, membranous nephropathy . .

Several series have reported that anti-HCV Several series have reported that anti-HCV antibodies are nearly universal in patients antibodies are nearly universal in patients with both membranoproliferative disease with both membranoproliferative disease and cryoglobulinemia; the pathogenesis and cryoglobulinemia; the pathogenesis appears to relate to deposition of immune appears to relate to deposition of immune complexes containing anti-HCV and HCV complexes containing anti-HCV and HCV

RNA in the glomeruliRNA in the glomeruli . .

IFN IFN is indicated in patients with mixed is indicated in patients with mixed cryoglobulinemia and membranoproliferative cryoglobulinemia and membranoproliferative glomerulonephritis.glomerulonephritis. A number of studies have reported a beneficial A number of studies have reported a beneficial response to antiviral therapy in this setting, response to antiviral therapy in this setting, and the reduction in proteinuria correlates and the reduction in proteinuria correlates

with a fall in HCV RNAwith 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 DISEASEDERMATOLOGIC DISEASE::

A variety of dermatologic diseases A variety of dermatologic diseases may be associated with HCV may be associated with HCV

infectioninfection..

Porphyria cutanea tardaPorphyria cutanea tarda Porphyria cutanea tarda (PCT) is a skin disease Porphyria cutanea tarda (PCT) is a skin disease caused by a reduction of hepatic caused by a reduction of hepatic uroporphyrinogen decarboxylase activity uroporphyrinogen decarboxylase activity that is characterized by photosensitivity, skin that is characterized by photosensitivity, skin fragility, bruising, and vesicles or bullae that fragility, bruising, and vesicles or bullae that

can become hemorrhagiccan become hemorrhagic . .

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 All patients with PCT should be screened for HCV infection, as well as screened for HCV infection, as well as other potential precipitating factors. other potential precipitating factors. Treatment with IFN should be Treatment with IFN should be

considered in HCV-infected patientsconsidered in HCV-infected patients . .

Leukocytoclastic vasculitis : Leukocytoclastic vasculitis : leukocytoclastic vasculitis may occur in leukocytoclastic vasculitis may occur in conjunction with essential mixed conjunction with essential mixed cryoglobulinemia, presenting clinically with cryoglobulinemia, presenting clinically with palpable purpura and petechiae that usually palpable purpura and petechiae that usually involve the lower extremities. involve the lower extremities. Skin biopsy demonstrates cutaneous vasculitis Skin biopsy demonstrates cutaneous vasculitis with dermal blood vessel destruction with dermal blood vessel destruction associated with neutrophilic infiltration in and associated with neutrophilic infiltration in and

around the vessel wallaround the vessel wall. .

Other tissues, particularly the lower extremity Other tissues, particularly the lower extremity peripheral nerves, may show similar vasculitic peripheral nerves, may show similar vasculitic changes involving the vasa nervorum. This changes involving the vasa nervorum. This may be manifested clinically as a peripheral may be manifested clinically as a peripheral neuropathy which, as in other forms of neuropathy which, as in other forms of vasculitis, is typically asymmetric (also called a vasculitis, is typically asymmetric (also called a mononeuritis multiplex).mononeuritis multiplex).

Daoud, MS, Gibson, LE, Daoud, S, el-Azhary , RA. Mayo Clin Proc Daoud, MS, Gibson, LE, Daoud, S, el-Azhary , RA. Mayo Clin Proc

1995; 70:5591995; 70:559..

Lichen planusLichen planus ::Lichen planus (LP) is characterized by flat-Lichen planus (LP) is characterized by flat-topped, violaceous, pruritic papules with a topped, violaceous, pruritic papules with a generalized distribution. It can also involve generalized distribution. It can also involve mucus membranes, hair, and nailsmucus membranes, hair, and nails..

LP may be mediated through the cellular LP may be mediated through the cellular immune response, although the actual immune response, although the actual precipitating mechanism is not known. Skin precipitating mechanism is not known. Skin biopsy demonstrates a dense lymphocytic biopsy demonstrates a dense lymphocytic

infiltration in the upper dermisinfiltration in the upper dermis . .

LP can be seen in patients with a variety of LP can be seen in patients with a variety of liver diseases, particularly advanced liver liver diseases, particularly advanced liver disease; anti-HCV antibodies are present in 10 disease; anti-HCV antibodies are present in 10 to 40 percent of these patients but a cause-to 40 percent of these patients but a cause-and-effect relation is uncertain .and-effect relation is uncertain .There are also reports of the development or There are also reports of the development or exacerbation of LP during IFN treatment for exacerbation of LP during IFN treatment for CHCV; the lesions improved when IFN was CHCV; the lesions improved when IFN was stoppedstopped

Protzer, U, Ochsendorf, FR, Leopolder-Ochsendorf, A, Holtermuller, Protzer, U, Ochsendorf, FR, Leopolder-Ochsendorf, A, Holtermuller, KH. Gastroenterology 1993; 104:903KH. Gastroenterology 1993; 104:903..

  

Necrolytic acral erythemaNecrolytic acral erythema ::Necrolytic acral erythema is a pruritic, psoriasis-like Necrolytic acral erythema is a pruritic, psoriasis-like skin disease characterized by a sharply skin disease characterized by a sharply marginated, erythematous to hyperpigmented marginated, erythematous to hyperpigmented plaques with variable scale and erosion on the plaques with variable scale and erosion on the lower extremities. In a series of 30 patients who lower extremities. In a series of 30 patients who presented with the disorder, all were found to presented with the disorder, all were found to have antibodies to HCV Biopsy specimens showed have antibodies to HCV Biopsy specimens showed psoriaform changes, keratinocyte necrosis and psoriaform changes, keratinocyte necrosis and

papillomatosispapillomatosis..

Improvement was observed in a patient who Improvement was observed in a patient who had been treated for HCV with IFN and had been treated for HCV with IFN and subsequent relapse nine months after subsequent relapse nine months after discontinuation). Topical and systemic discontinuation). Topical and systemic corticosteroids had a variable benefit. corticosteroids had a variable benefit. Other reports have confirmed improvement Other reports have confirmed improvement with IFN and also suggested a benefit from with IFN and also suggested a benefit from oral zinc sulfate.oral zinc sulfate.

Abdallah, MA, Hull, C, Horn, TD. Arch Dermatol 2005; 141:85Abdallah, MA, Hull, C, Horn, TD. Arch Dermatol 2005; 141:85..

MUSCULOSKELETALMUSCULOSKELETAL::

Hepatitis C-associated osteosclerosis is a rare Hepatitis C-associated osteosclerosis is a rare disorder characterized by a marked increase disorder characterized by a marked increase in bone mass during adult life. While most in bone mass during adult life. While most cases have been reported in patients with a cases have been reported in patients with a history of intravenous drug abuse, it has also history of intravenous drug abuse, it has also been seen with hepatitis C after blood been seen with hepatitis C after blood

transfusiontransfusion..

Periosteal, endosteal and trabecular bone Periosteal, endosteal and trabecular bone thickening occurs throughout the skeleton thickening occurs throughout the skeleton with the exception of the cranium.with the exception of the cranium.During active disease, forearm and leg During active disease, forearm and leg pain are common, bone remodeling pain are common, bone remodeling (turnover) is high, and bone mineral (turnover) is high, and bone mineral density is two- to three-fold higher than density is two- to three-fold higher than

age-matched controlsage-matched controls . .

The increased remodeling may respond to The increased remodeling may respond to calcitonin, but spontaneous remission has calcitonin, but spontaneous remission has also been described.also been described.Abnormalities in insulin-like growth Abnormalities in insulin-like growth factors (IGF-1 and IGF-II) or their binding factors (IGF-1 and IGF-II) or their binding proteins may contribute to the increase in proteins may contribute to the increase in

bone formation in this disorderbone formation in this disorder . .

MYOCARDITIS AND MYOCARDITIS AND CARDIOMYOPATHYCARDIOMYOPATHY::

HCV has been associated with myocarditis HCV has been associated with myocarditis and cardiomyopathy in reports from and cardiomyopathy in reports from

Japan. The pathogenesis is unclearJapan. The pathogenesis is unclear..

NEUROCOGNITIVE NEUROCOGNITIVE DYSFUNCTIONDYSFUNCTION::

Several studies have suggested that HCV Several studies have suggested that HCV infection may be associated with infection may be associated with neurocognitive dysfunction even without neurocognitive dysfunction even without advanced liver diseaseadvanced liver disease..

The potential The potential mechanisms are unclearmechanisms are unclear..

Neurological manifestations of

hepatitis C: Double blind clinical and

electrophysiological study..

Abd El fatah HanoAbd El fatah Hano11, Alaa Eldin Abdo, Alaa Eldin Abdo11, , Ayman farid ElshayebAyman farid Elshayeb11,Hamdy Khamis,Hamdy Khamis22, ,

Ibrahim KhalilIbrahim Khalil22 and Akram Degheady and Akram Degheady33

Departments of Tropical MedicineDepartments of Tropical Medicine11, , Physical MedicinePhysical Medicine22 and clinical and clinical

pathologypathology33, Faculty of Medicine, , Faculty of Medicine, Alexandria UniversityAlexandria University

In patients with chronic HCV and liver In patients with chronic HCV and liver cirrhosis, various mechanisms were cirrhosis, various mechanisms were postulated for this hepatic neuropathy.postulated for this hepatic neuropathy.1-Mtabolic inhibition of the axonal 1-Mtabolic inhibition of the axonal membrane function membrane function 2-Metabolic damage to Schwann cells and 2-Metabolic damage to Schwann cells and even a possibly disordered insulin even a possibly disordered insulin metabolism, something similar to diabetic metabolism, something similar to diabetic neuropathyneuropathy..

In conclusion, peripheral neuropathy may In conclusion, peripheral neuropathy may be associated with chronic HCV with and be associated with chronic HCV with and without liver cirrhosis.without liver cirrhosis.It usually occurs in CG+ cases and less often It usually occurs in CG+ cases and less often in those without detectable CG.in those without detectable CG. Moreover, the present findings suggest Moreover, the present findings suggest that patients with chronic HCV experience that patients with chronic HCV experience cognitive difficulties that may interfere cognitive difficulties that may interfere with their daily activities and quality of life. with their daily activities and quality of life. The condition worsens by the development The condition worsens by the development of cirrhosisof cirrhosis..

Effect of Interferon-alpha Treatment on Effect of Interferon-alpha Treatment on Extrahepatic Manifestations of HCVExtrahepatic Manifestations of HCV

CONDITIONCONDITIONImprove.Improve.No No ChangeChange

WorseWorse

CryoglobulinemiaCryoglobulinemia++++++++GlomerulonephritisGlomerulonephritis++++++++Autoimmune MarkersAutoimmune Markers++++++Muscular distrophyMuscular distrophy++Lichen PlanusLichen Planus++Corneal ulcerCorneal ulcer++Porphyria CTPorphyria CT++ITPITP++++Thyroid DiseaseThyroid Disease++++