International Journal of Pathology; 2004; 2(1):44-46

Case Report

Hepatitis Associated Autoimmune Haemolytic

Anaemia
Nadeem Ikram* Khalid Hassan** and Samina Tufail*
**

*
Department of Pathology, DHQ Hospital, Rawalpindi.
Department of Pathology, Pakistan Institute of Medical Sciences, Islamabad.

There are numerous associations between

diseases traditionally considered non- infectious
with infectious agents. These include peptic ulcer,
coronary heart disease, neuropsychiatric disorders,
haematological disorders and malignancies. Out of
infectious diseases, viral hepatitis is also associated
with many extra hepatic complications, with articular,
renal, neurologic, cutaneous and haemapoietic system
involvement. Several autoimmune phenomena can be
observed in the course of viral hepatitis, including
cryoglobulinemia, glomerulonephritis, systemic lupus
erythematoses and arthritis. Beside these welldocumented problems a rare haematological
complication of viral hepatitis is Autoimmune
Haemolytic Anaemia (AIHA).1, 2
Clinical
significance
of
extrahepatic
auotimmune haemolytic manifestations of hepatitis is
highly variable ranging from sub clinical features or
laboratory
abnormalities
to
overt
clinical
manifestations that may be severe in some patients.
Diagnosis and treatment of HCV- related autoimmune
features has become a clinical challenge in patients
with HCV infection, in whom the combination of a
chronic liver disease and severe autoimmune features
may contribute to an unfavourable prognosis.3
In the present series four cases of viral
hepatitis with AIHA will be described

hypochromic, with spherocytosis and a reticulocyte

count of 5.0%. His liver function tests showed a
bilirubin level of 5.0 mg/dl with a predominant
conjugated component, ALT of 2500 U/l, Alkaline
Phosphatase level of 295U/l and Albumin level of 4.5
g/dl. A blood transfusion was suggested. In blood
bank the patients blood failed to show compatibility
with blood group compatible donors. His Coombs test
(Direct and Indirect) was performed and that was
found to be positive. Serum LDH showed raised
levels (1200 IU/l). Hepatitis Viral studies showed
negative results for Antibodies to Hepatitis C
Virus and Hepatitis B Surface Antigen, but Anti
Hepatitis A virus IgM was positive. Subsequently
the patient was put on steroids and he showed
response to treatment with an improvement
in Haemoglobin level (10.0 g/dl). At present his
liver function tests are within normal limits, but
Coombs test is positive.

Case No 2
A 60 years old lady, who was a known case of
hepatitis C infection. At presentation her ALT was
moderately increased, while her blood counts were
within normal limits.
She was on conservative
management and was not receiving interferon and
ribavarin. She remained stable for some time then
subsequently she developed anaemia. The anaemia
worsened with the course of time and did not
responded to blood transfusions or haematenics
administration. Due to progressive anaemia she was
admitted to hospital. Her peripheral blood films
revealed spherocytosis with reticulocytosis. Her
Coombss test(direct) was performed and that was
turned out as positive.

Case No 1
A seven years old male child presented with
complaints of nausea, vomiting, dark coloured urine,
yellowish discoluration of sclera. On examination he
was having jaundice alongwith pallor and mild
hepatosplenomegaly. On laboratory investigations he
was found anaemic with a haemoglobin level of
5.1g/dl. Red Blood cells morphology was microcytic

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International Journal of Pathology; 2004; 2(1):44-46

Case No 3

haemoglobin can not be explained on the basis of

hypersplenism or any bleeding episode. The blood
film examination showed findings of red blood cells
haemolysis, i.e., anisopoikilocytosis, red cells
fragmentation, polycohromasia and variable degree of
spherocytosis with reticulocytosis and positive
Coombs test (direct and/or indirect). These cases
were diagnosed as autoimmune haemolytic after
excluding all the other causes of anaemia, haemolysis
and autoimmunity. Most of these patients responded
to corticostreoids.4-10 The cases of present study
revealed the manifestations similar to those reported
by other workers. All had a rapid drop in their
haemoglobin levels. Two cases received corticosteroids
and showed improvement in blood counts.
Ramos Casals M et al (2003) identified
folowing cytopenias in Hepatitis C infection patients:
AIHA (17 cases), severe thrombocytpenia (16 cases),
aplastic anaemia (2 cases), severe neutropenia (1 case),
refractory sideroblastic anaemia (1 case) and pure
red cell aplasia (1 case). Patients with HCV related
AIHA showed a higher prevalence of associated
autoimmune diseases (71%), cryglobulinemia (57%)
and Cirrhosis (59%).3
The pathogenic mechanisms behind hepatic
and extrahepatic manifestations of viral hepatitis are
poorly understood. In particular, the importance of
viral genomic changes and host immune factors
remain unclear. Nevertheless, the interaction between
host immune system and virus antigens might play a
significant role in triggering immnopathologic
phenomena.It has been shown
that immune
complexes containing HCV antigen antibodies and
complement can be localized in the liver, kidney, red
blood cells and/or skin of some subjects following the
onset of an immunlogic response to HCV chronic
infection. Presumably, the production of antibodies
reacting with self antigens in these conditions is due to
abnormalities of regulation that are induced in the
immune cells by the infection.10 According to
Fellermann K two mechanisms are responsible for
hepatocyte damage in hepatitis. First a direct
cytopathogenic effect and second a T-cell mediated,
MHC I and II restricted immune response. Shared
epitopes of viral and human antigens presented by
antigen presenting cells might be capable of causing
an autoimmune trigger.7
Interferons are clinically used as antiviral and
antineoplastic agents as well as potentiator of cellular
differentiation. Their mechanism of action is not well
defined, but it is dependent on their recognition
by specific receptors located in some cell membranes,

A thirty-five years old lady was diagnosed as

a case of Hepatitis C viral infection, with Anti HCV
positivity and detection of Hepatitis C virus on PCR
studies. At presentation her blood counts were within
normal limits. She was put on Interferon along with
Ribavarin. During third month of therapy she
developed severe anaemia. Her blood counts showed
a haemoglobin level of 5.0 g/dl alongwith mild
thrombocytpenia and leucopenia. The examination of
red blood cells morphology showed microcytosis,
anisocytosis, poikilocytosis, fragmented cells and
spherocytes, alongwith a reticulocyte count of 9.0%.
Serum LDH was found raised (910 IU/l).
Her direct Coombs test was performed and it
was positive

Case No 4
A thirty years old girl, diagnosed as a case of
vonWillebrands disease 9 years ago, become hepatitis
C seropositive. She manifested mucosal bleeds
(epistaxis, bleeding gums, etc) and ecchymoses
frequently. She was admitted 4 or 5 times, and was
given FFPs as a part of her management. This time, she
came with bleeding from her gums, epistaxis and
menorrhagia alongwith progressive pallor. Her lab
investigations showed: Hb 7.5 G/dl, white cell count
10.5x109/l, platelets 75x109/l, bleeding time 9 minutes;
prothrombin time 15 seconds (control 12 sec); APTT 65
seconds (control 29 seconds); Red cell morphology
showed sphecocytosis and macrocytosis. Her direct
combs test was positive. Bone marrow biopsy show
marked increase and left shift of megakaryocytes. Her
APTT was corrected by adding absorbed plasma (33
seconds) and not corrected by adding aged serum (69
seconds). On the basis of her investigations, she was
diagnosed as having hepatitis C associated AIHA
along with immune-mediated thrombocytopenia. The
patient responded, promptly, to corticosteriods
treatment.

Discussion
Extrahepatic immune problems have a well
defined association with hepatitis, and autoimmune
haemolytic anaemia is a rare accompaniment out of
these. Hepatitis C viral infection is the main reported,
but cases of hepatitis B and A viral infection with
AIHA are also recorded. Most of the reported cases
revealed a sudden and rapid drop in the haemoglobin
level during the course of their disease and this fall in

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International Journal of Pathology; 2004; 2(1):44-46

and their subsequent internalization. Thereafter,
activation/ inhibition processes on different enzymatic
system take place,and these are the basis of the
modification of DNA and of protein synthesis caused
by - IFN. The known biological effects of - IFN are
mainly the participation in the inhibition of cellular
proliferation, the induction of cellular differentiation,
suppression of viral replication, regulation of
haemopoiesis and a modulatory effect on the immune
system. Several reports have documented the
modification of some parameters of the immune
response by - IFN. A decrease in CD8 lymphocytes,
an increase in natural killer cells, low complement
levels, enhanced activity of HLA class I and II
molecules, activation of antibody producing cells and
stimulation of cytotoxic T- lymphocyte have been
described.10-16 Hizawana N et al(1994) demonstrated a
positive lymphocyte stimulation test for IFN- in a
case of HCV infection. All these altered parameters
are partly considered responsible for the development
of autoimmune disorder in patients taking IFN.12
Apart from the above mentioned immunological
alterations it has been pointed out recently that - IFN
treatment can modify some cellular membranes.
Consequently these modified proteins could behave
as autoantigens for an already activated immune
system.11
Immunosupprsesants such as steroids or
azathioprine indicated to control AIHA are
unfavourable for chronic hepatitis C. In addition,
interferon was contraindicated due to AIHA. So, the
therapeutic dilemma is unresolved.7 By considering
the rapid fall in haemoglobin most of the cases
received corticosteroids. The steroids administration
showed a favourable response with pronounced
increase in hemoglobin levels without any
deterioration of the HCV liver disease.17-19
It is possible that different immune alterations
as well as the occurrence of AIHA are more frequent
then reported upto now. The patients could have been
under diagnosed because their anaemia could have
been attributed to other causes. In a case of hepatitis
with rapidly deteriorating haemoglobin level
consideration can be given to AIHA, if all the other
causes are excluded. The relationship of AIHA with

overall course and prognosis of the disease must also

be evaluated.

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