EXTRAHEPATIC

1
EXTRAHEPATIC MANIFETATIONS OF HCV
PROF. ABDEL FATTAH HANNO FACULITY OF
MEDICIN,ALEX. UNIVERISITY.
2
The hepatitis C virus (HCV)Acute
hepatitisChronic hepatitis. Extrahepatic
diseases have been associated with chronic HCV
infection, and in most cases appear to be
directly related to the viral infection.
3
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
• Miscellaneous

S.J. Hadziyannis. (Review). J Viral Hepatitis
1997 49
4
HEMATOLOGIC DISORDERS

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

5
Essential mixed cryoglobulinemia

• 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.

6

• 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 .

7

• Circulating anti-HCV antibodies The presence
  of polyclonal IgG anti-HCV antibodies within the
  cryoprecipitate HCV RNA in the plasma and
  particularly the cryoprecipitate
•   Agnello, V, Chung, RT, Kaplan, LM. N Engl J
  Med 1992 3271490.  Pozzato, G, Mazzaro, C,
  Crovatto, M, et alBlood 1994 843047. 
  Misiani, R, Bellavita, P, Fenili, D, et al 1992
  117573.

8

• Causal relationship between HCV and essential
  mixed cryoglobulinemia
• 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.

9

• Unfortunately, not all patients with
• HCV infection and cryoglobulinemia respond to
  IFN.
• In addition, a reduction in cryoglobulin titers
  is not directly associated with a decrease in
  serum ALT or HCV RNA.

10

• Treatment of patients with cryoglobulinemia due
  to HCV should be based upon the presence of
  cryoglobulinemia symptoms
• The response should be assessed by symptomatic
  improvement of cryoglobulinemia, a reduction in
  cryocrit, and an increase in serum complement
  levels.

11

• Complete responses may be more common in
  patients with low pretreatment levels of viremia
  and with high dose interferon regimens.
•  . Casato, M, Agnello, V, Pacillo, LP, Blood
  1997 903865.

12
Monoclonal gammopathies

• HCV may be a risk factor for the development of
  monoclonal gammopathies.
• The prevalence of monoclonal gammopathies was
  noted to be increased in patients with chronic
  liver disease .
• Heer, M, Joller-Jemelka, H, Fontana, A, et al.
  Liver 1984 4255.

13
Lymphoma

• 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.
• Gisbert, JP, Garca-Buey, L, Pajares, JM,
  Moreno-Otero, R Gastroenterology 2003 1251723.

14

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

15
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.
16
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 31474.
17
DIABETES MELLITUS

• 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.

18
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.
19
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.
20
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 .
21
1-Parenteral exposures. 2-HCV infection
becomes chronic more often than HBV infection.
3-Cirrhosis, which may be associated with
impaired glucose tolerance.
22
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
35279. Bigam, DL, Pennington, JJ, Carpentier,
A, et al. Hepatology 2000 3287.  Hadziyannis,
S, Karamanos, B. Gastroenterology 2003 1251695
23
AUTOIMMUNE DISORDERS

• A number of autoimmune disorders have been
  associated with HCV infection, including
• Autoantibody formation.
• Thyroid disease.
• Sialadenitis.
• Autoimmune idiopathic Thrombocytopenic purpura.

24
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.
25
Autoantibodies

• 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.

26
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.
27
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.
28
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.
29
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 ALTAST without subsequent clearance of
HCV RNA have been observed.
30
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.
31
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. 
32
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

33

• 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.

34
Thyroid disease

• 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.

35
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-thyroidperoxidas
e antibodies (21 versus 10 to 13 percent)
36
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. 
37
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.
38
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.
39
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.
40
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 32489. .
Zauli, D, Ghetti, S, Grassi, A, et al. Hepatology
1997 251105.
41
Sialadenitis

• A lymphocytic sialadenitis suggestive of
  Sjogren's syndrome has been described in patients
  with CHCV infection.
• 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.
• . Ramos-Casals, M, Loustaud-Ratti, V, De Vita, S,
  Zeher, M. Medicine (Baltimore) 2005 8481.

42
Autoimmune idiopathic thrombocytopenic purpura

• 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.

43
Thus, the relationship between autoimmune ITP
and HCV remains to be clarified. .
Pawlotsky, JM, Bouvier, M, Fromont, P, et al. J
Hepatol 1995 23635.
44
Myasthenia gravis

• 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 3329

45
Sarcoidosis

• Sarcoidosis has been described in association
  with HCV, mostly in the setting of antiviral
  therapy.

46
OCULAR DISEASE

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

47
RENAL DISEASE

• 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.

48
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.
49
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.
50
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 461700.
51
DERMATOLOGIC DISEASE

• A variety of dermatologic diseases may be
  associated with HCV infection.

52
Porphyria cutanea tarda

• 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.

53
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
54
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.
55
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 .
56
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 70559.
57
Lichen planus

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

58
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
stoppedProtzer, U, Ochsendorf, FR,
Leopolder-Ochsendorf, A, Holtermuller, KH.
Gastroenterology 1993 104903. 
59
Necrolytic acral erythema

• 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.

60
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 14185.
61
MUSCULOSKELETAL

• 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.

62
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.
63
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.
64
MYOCARDITIS AND CARDIOMYOPATHY

• HCV has been associated with myocarditis and
  cardiomyopathy in reports from Japan. The
  pathogenesis is unclear.

65
NEUROCOGNITIVE DYSFUNCTION

• Several studies have suggested that HCV infection
  may be associated with neurocognitive dysfunction
  even without advanced liver disease.
• The potential mechanisms are unclear.

66
Neurological manifestations of hepatitis C
Double blind clinical and electrophysiological
study.
67
Abd El fatah Hano1, Alaa Eldin Abdo1, Ayman
farid Elshayeb1,Hamdy Khamis2, Ibrahim Khalil2
and Akram Degheady3Departments of Tropical
Medicine1, Physical Medicine2 and clinical
pathology3, Faculty of Medicine, Alexandria
University
68
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.
69
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.
70
Effect of Interferon-alpha Treatment on
Extrahepatic Manifestations of HCV
71

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