Keywords
acute severe hepatitis - parvovirus hepatitis - autoimmune hepatitis - case report
Introduction
Human parvovirus, a member of the Parvoviridae family, is a nonenveloped deoxyribonucleic
acid virus. Infection of parvovirus B19 is globally prevalent, with infection being
widespread among children and relatively uncommon in adults.[1] The virus spreads primarily through respiratory droplets; secondary infections occur
through household contacts. Parvovirus-related diseases can be grouped into common
and uncommon, with common ones being—fifth disease in children, arthropathy in adults,
transient aplastic crisis in patients with increased erythroid proliferation (underlying
hemolytic disease), persistent anemia in patients with immunocompromised or immunodeficiency
status, and hydrops fetalis in fetus. Uncommon presentations can include hepatitis,
myocarditis, meningoencephalitis, vasculitis, and Guillain–Barre syndrome. The manifestations
could be due to viremia, virus-related cytotoxic effects, and immune-mediated injury.[1]
There is sufficient evidence to suggest that parvovirus B19 infection can cause a
spectrum of liver diseases, from elevation of transaminases to acute hepatitis to
fulminant hepatic failure and even chronic hepatitis. It can also cause fatal macrophage
activating syndrome and fibrosing cholestatic hepatitis. Presentation as acute hepatitis
or fulminant liver failure has been mainly reported in the pediatric age groups but
has also been reported in adults, albeit infrequently. In adults, parvovirus B19 hepatitis
course is less severe and shows complete and spontaneous remission. Fulminant hepatic
failure induced as a result of acute B19 infection remains a rare clinical entity
and may be underreported due to infrequent testing and lack of awareness. We report
a similar case of parvovirus infection presenting as acute severe hepatitis and initially
misdiagnosed as autoimmune hepatitis (AIH), but subsequently, a proper diagnosis could
be made, and unnecessarily prolonged immunosuppression could be prevented.[2]
Case Summary
A 17-year-old girl with no comorbidities or addictions presented with low-grade fever
associated with dry cough and myalgia for 4 days, followed by the onset of jaundice.
There was no history of change in the sensorium, gastrointestinal (GI) bleeding, itching,
or abdominal distension. There was no past or family history of jaundice. She denied
a history of prescription as well as alternative medication intake. She was initially
evaluated elsewhere and found to have hemoglobin of 5 g/dL with normal platelet and
total leukocyte counts. She received two units of packed red blood cell transfusion
and was referred to our center.
On general physical examination, she was found to have icterus, and per abdomen examination,
it revealed hepatosplenomegaly. However, there were no stigmata of chronic liver disease.
Ultrasound of the abdomen revealed a liver span of 16 cm with normal echotexture and
mild splenomegaly. Liver biochemistry revealed total bilirubin of 40 mg/dL with raised
transaminases suggestive of hepatocellular jaundice, and her coagulation parameters
were preserved. Etiological workup for jaundice revealed negative serology for hepatotropic
viruses (including surface antigen, anti-hepatitis C virus antibody, and immunoglobulin
M [IgM] for hepatitis A and E virus). AIH profile revealed positive antinuclear antibody
(ANA; titer 1:40) but negative for antismooth muscle antibody and liver-kidney microsomal
antibody. Serum IgG was marginally above upper limit normal (1678 mg/dL; normal range
700–1600 mg/dL). Her serum ceruloplasmin was within the normal limit (27 mg/dL), and
slit lamp examination was negative for the Kayser–Fleischer ring. Anemia workup revealed
a normal iron profile and vitamin B12 levels, but indirect and direct Coombs tests
were positive. Her other hemolytic workup, including serum lactate dehydrogenase and
glucose-6 phosphate dehydrogenase, were within normal limits, and peripheral blood
film did not show any evidence of hemolysis. Upper GI endoscopy showed no varices
or portal hypertensive changes. Serial investigations revealed worsening of jaundice,
as tabulated in [Table 1]. She underwent a liver biopsy because of high suspicion of AIH, which showed interface
hepatitis and ductular proliferation suggestive of AIH ([Fig. 1]). Her simplified AIH score was 5, and she was started on steroids and ursodeoxycholic
acid. She showed both clinical and biochemical responses to the initial treatment
and was referred to the gastroenterology department for further management. Given
her atypical initial presentation with severe anemia and respiratory symptoms to begin
and preserved coagulation parameters and absence of any other decompensation despite
very high bilirubin, a possibility of acute fulminant hepatitis secondary to atypical
viral infection was kept, and samples were sent for atypical virus panel (Epstein–Barr
virus [EBV], cytomegalovirus [CMV], varicella-zoster virus, herpes simplex virus,
and parvovirus IgM). Her parvovirus serology was found to be positive, and a final
diagnosis of parvovirus-related aplastic anemia with acute severe hepatitis was kept.
The patient improved symptomatically with the normalization of liver enzymes and cytopenia
on serial investigations, and steroids were gradually tapered over the next 6 weeks.
Even after one and half years of follow-up, there was no relapse, further confirming
the diagnosis of parvovirus-related acute hepatitis.
Table 1
Serial investigations of the patient showing improvement with the treatment
|
Investigations at various interval
|
Baseline investigations
|
Investigations after 2 weeks (prednisolone started)
|
Investigations after 3 weeks
|
Investigations at 6 weeks follow-up
(prednisolone tapered and stopped)
|
Investigations at 6 months of follow-up
|
Investigations at 18 months of follow-up
|
|
Hemoglobin (g/dL)
|
8.7
|
8.7
|
8.8
|
10
|
11.2
|
10.9
|
|
TLC (per cumm)
|
3380
|
4000
|
5900
|
6000
|
7800
|
7300
|
|
Plt (in lacs)
|
2.1
|
2.2
|
2.9
|
3
|
3.3
|
2.9
|
|
Bilirubin (T/D)
|
40/21
|
53/24
|
13.8/9.2
|
2.3/1.4
|
0.9/0.2
|
0.8/0.2
|
|
AST/ALT/ALP
|
756/256/41
|
614/136/106
|
144/120/-
|
131/89/193
|
31/27/112
|
28/33/104
|
|
TP/ALB
|
8.0/3.2
|
7/3.52
|
6.9/3.8
|
6.1/3.6
|
7.1/4.4
|
7.2/4.3
|
|
INR
|
1.3
|
1.3
|
1.14
|
0.98
|
1.04
|
1.0
|
Abbreviations: ALB, albumin; ALP, alkaline phosphatase; ALT, alanine transaminase;
AST, aspartate transaminase; Bilirubin (T/D), total and direct bilirubin; INR, international
normalization ratio; Plt, platelet count; TLC, total leukocyte count; TP, total protein.
Fig. 1 Histopathological examination of the liver biopsy specimen showed an expanded portal
tract with interface hepatitis with the presence of chronic inflammatory cells (lymphocytes
- red arrow, plasma cells - black arrow) along with ductular proliferation (green
arrow) (hematoxylin and eosin, 200 × ).
Discussion
Parvovirus B19 is an erythrovirus of the Parvoviridae family and can lead to various
clinical presentations in pediatric and adult age groups. Its primary mode of transmission
is through respiratory droplets, but it can also spread through blood transfusions
and the placental routes. The principal member of the Parvoviridae family, parvovirus
B19 is an erythrovirus, spreads predominantly in erythroid progenitor cells and a
small number of other cells, such as fetal liver, stem cells and bone marrow cells,
and megakaryocytic leukemia cell lines maintained with erythropoietin. B19 can also
infect hepatocytes because of globosides and glycosphingolipids in their cell membrane,
like erythroid precursors. Parvovirus B19 predominantly affects school-going children,
and less frequent manifestations are seen in pregnant women, immunocompromised individuals
of all ages, and people who suffer from different types of hematological disorders.
Parvovirus B19 infection can present with a variety of clinical diseases and syndromes.
The viral infection is suspected in cases of sudden drop of hemoglobin and onset of
transient aplastic anemia in immunosuppressed or immunocompetent patients. It is confirmed
by either positive serology, polymerase chain reaction analysis, or in situ hybridization
in a biopsy specimen.[3]
Liver involvement is uncommon in parvovirus infection, but it can range from mild
elevation of transaminases to fulminant liver failure. According to a study by Mih
́aly et al, parvovirus B19-related hepatitis may occur in 4.1% of patients infected
by this virus.[4] Around 50 cases of B19-related hepatitis have been reported in the literature, with
the majority being acute hepatitis and being self-limiting with excellent prognosis.
However, the prognosis becomes grave if it progresses to fulminant hepatitis and acute
liver failure (ALF). Its mechanism of injury is via two mechanisms: (1) direct cytotoxicity—via
NS1-cyclin-dependent kinase activation of caspase 3 and 9 and (2) immune-mediated
interferon gamma, tumor necrosis factor-α, interleukin-2 receptors, and reduced interleukin-1.
Limited data are available regarding hepatic involvement due to parvovirus and is
mainly reported as case reports or small case series.[5]
[6]
[7] Hepatitis due to atypical viral infection is to be suspected when there is other
system involvement like in CMV or EBV colitis, pneumonitis, and pharyngitis may be
present, while in case of parvovirus, there is hematological system involvement like
in the index case. Our case was initially misdiagnosed as AIH because of positive
ANA, suspected autoimmune hemolytic anemia because Coombs test was positive, and liver
biopsy was also suggestive. Liver biopsy in parvovirus hepatitis displays cellular
and canalicular cholestasis, apoptosis, and variable amounts of necrosis depending
upon the immune status of the host and the severity of liver involvement and can mimic
AIH. However, the clinical presentation was atypical for AIH and Coombs test could
be falsely positive due to a recent blood transfusion. Moreover, due to the absence
of stigmata of chronic liver disease/portal hypertension (normal platelet count, no
varices on endoscopy), a diagnosis of parvovirus hepatitis was considered, and steroids
were tapered with advice to close follow-up. The patient is doing well, and there
is no clinical or biochemical recurrence even after one and half years of follow-up,
further confirming the diagnosis of parvovirus hepatitis.
There are no specific treatment guidelines for infection caused by the B19 virus,
and most of the symptoms and elevation of liver enzymes presented during the infection
stage resolve without any treatment. In case of acute and fulminant hepatitis, standard
critical intensive care unit care is the same as for ALF management. Steroids are
found to be beneficial in recovery in fulminant hepatitis cases. Combination therapy
consisting of an intravenous infusion of immunoglobulin, dehydrohydrocortisone, and
subcutaneous injections of granulocyte colony-stimulating factor for 3 months has
been tried.[8] A case report published by Singh et al of a 16-year-old presenting with ALF was
managed successfully by therapeutic plasma exchange.[9] This showed that this modality can be used as a bridge to liver transplant or recovery
from this illness.
Conclusion
The case described here suggests that parvovirus B19 infection may be associated with
the development of acute hepatitis. Infection with parvovirus B19 should be considered
in the differential diagnosis of patients presenting with acute hepatitis of unknown
etiology, especially in the presence of concomitant hematological involvement. Parvovirus
hepatitis can mimic other common causes of hepatitis in the index case; it was confused
by positive ANA titer and suggestive histopathology. Proper history and interpretation
of investigations are essential as misdiagnosis as AIH could have resulted in antecedent
risk of lifelong immunosuppression and stigma of chronic illness.
