Journal of The Association of Physicians of India ■ Vol.

65 ■ December 2017 79

Review Article

Dengue-Induced Hepatic Injury

Darshil Shah1, Pravin Rathi2

of the genotypes are shared among

Abstract the four serotypes. 2 They produce
Dengue has a significant impact on the disease burden in the population different types of manifestations
however, most patients are
residing in tropical countries. It is transmitted by the bite of Aedes
asymptomatic.2 It is transmitted via
mosquito. The virus have got some hepatotoxic effects. Most of the cases
Aedes Aegypti and less commonly
are asymptomatic. However, it should be considered as one of the causes
by Aedes Albopictus. Dengue
of Acute Liver Failure in endemic countries. Our article focuses on the
virus is an RNA virus with a single
pathogenesis, manifestations, investigations and, the treatment options
s t r a n d e d p o s i t i ve s e n s e R N A .
for dengue related hepatic dysfunction. It also encodes for seven non-
structural proteins of which NS1 is
used as a diagnostic antigen in the
Introduction hemorrhagic fever (DHF) and 22,000 initial phase of the disease.
deaths (CDC, 2014). Having a wide WHO Classification, 20091
Dengue Virus infection is one spectrum of clinical presentations,
The modified categorization of
of the important causes of acute severe dengue is categorized as
WHO in 2009 includes dengue with
febrile illness in the tropical and Group C by WHO in 2009, which
or without the warning signs.
subtropical region. It is a self- includes Dengue Hemorrhagic
limiting condition for which no Fever and Dengue Shock Syndrome Majority of studies however still
s p e c i f i c t r e a t m e n t o r e f f e c t i ve (Table 1). 1 The burden of disease classify dengue as Dengue fever,
va c c i n e i s a va i l a b l e . I t i s t h e has increased drastically due to Dengue hemorrhagic fever and
most rapidly spreading mosquito factors such as inadequate water Dengue Shock Syndrome.
borne disease in the world. Fifty supply, relentless urbanization,
million infections occur annually, poor hygiene and viraemic travelers
Pathogenesis and
with 500,000 cases of dengue spreading disease geographically. 2 Pathology
In dengue-endemic countries, Hepatic Dysfunction is an
Table 1: Clinical features of dengue
the disease is an important cause important feature in dengue
Dengue Fever with any 2 of: of acute viral hepatitis. Elevated infection. Dengue virus replicate in
• Nausea AST and ALT levels have been both hepatocytes and kupffer cells.
• Vomiting associated with bleeding3 and This may be because most viral
• Skin rash Dengue hemorrhagic fever.4 particles enter cells by phagocytosis
• Body ache Liver failure has been recognized leading to viral degradation. Viral
• Leukopenia as a complication and unusual replication occurs in smaller
• Any warning sign manifestation of dengue. 1 In this n u m b e r o f K u p f f e r c e l l s . Tw o
Severe • Plasma leakage review we outline the pathogenesis, phases of Kupffer cells have been
Dengue • Bleeding & organ impairment clinical, biochemical parameters described. The first phase occurs
•  Transaminase > 1000 IU/L and management of dengue s l o wl y a f t e r i n f e c t i o n , a n d i s
• Altered Sensorium induced liver dysfunction. mediated by nitric oxide and INF
• Cardiac involvement α production; while the second
Warning • Abdominal pain
Dengue Virus phase is mediated by IL-6 and TNF
Signs • Persistent vomiting α production. 5 The E Protein plays
Dengue virus has 4 serotypes
• Effusion/Ascites (1-4). It belongs to the Flaviviridae a pivotal role in the attachment of
• Bleeding family and genus flavivirus. 65% the virus to the receptor on the host
• Lassitude/restiveness
• Hepatomegaly
1
Gastroenterology Resident, Bombay Hospital and Medical Research Centre, Mumbai, Maharashtra; 2Professor
• Rise in Hct by > 20%
of Gastroenterology, Bombay Hospital and Medical Research Centre, Mumbai, Maharashtra
• Thrombocytopenia < 5000/ Received: 02-10-2017; Revised: 11.07.2017; Accepted: 03-08-2017
mm3
80 Journal of The Association of Physicians of India ■ Vol. 65 ■ December 2017
cells but the nature of the receptor
is yet to be determined. 6
At present, the exact mechanism
of interaction between dengue
virus and hepatocyte is poorly
defined. The interaction varies
with different serotypes. Glucose
regulated protein 78 (GRP78) was
reported to be used by DEN-2 to
gain entry into HepG2 cells (a
human hepatoblastoma cell line). 7
High affinity Laminin receptor was
reported to be used by DEN-1 to
enter liver cells. 8 Heparan sulfate
plays an important role in the
entry of all dengue serotypes into
HepG2 cells. 8 However, the degree
of interaction varies.
The susceptibility of a cell to
infection depends on two factors.
These are: 1) the ability of the
virus to enter the cell, and 2) the
factors within the cell that enable
the virus to replicate successfully.
It is modulated by virus serotype,
strain, and cell type. For example,
HepG2 cells in G2 phase of the cell
cycle have a higher susceptibility to
infection and a higher replication
rate. 9 Children have most of their
cells in G2 phase of the cell cycle;
which may justify as to why they
are more susceptible to severe
forms of dengue.9 The other cellular
proteins reported to be used by
viruses to enter the cells are DC-
Specific ICAM- 3 Grabbing Non-
integrin (DC-SIGN),used by the
virus to gain entry into monocyte-
d e r i v e d d e n d r i t i c c e l l s , 10 a n d
the Fc_ receptor used in cases of
secondary infection to gain entry
into monocytes. 11
The Final outcome of dengue
induced infection of hepatocytes
is apoptosis. Several mechanisms
are involved. These include direct
cytopathic effects of the virus,
mitochondrial dysfunction due to
low flow hypoxia, and the influence
of cellular and humoral immune
factors in the liver. The process of
apoptosis in hepatocytes is different
in a way that it is independent
of p53. Several mechanisms are
involved in apoptosis. Increased
levels of endoplasmic reticulum
stress induce apoptosis and similar
mechanism has been proposed
in other members of flavivirus
genus.12 Transcription factor NF-κB
activation has been implicated in
the induction of apoptosis.13 TRAIL
(Tumor Necrosis Factor-Related
Apoptosis-Inducing Ligand)
expression has been suggested to
be partly responsible for causing
apoptosis. 14 Councilman bodies are
the remnants of cells undergoing
apoptosis.
Different immune responses
are seen in dengue infections
resulting in liver dysfunction of
which the phenomena of antibody
dependent enhancement explain
the cause of more severe disease on
second infection. Effective CD4 and
CD8 cells play important role in
clearance of acute dengue infection.
Serotype specific and serotype
cross reactive memory cells are
formed after primary infection. On
secondary exposure, most serotype
cross reactive CD4+ and CD8+ cells
increase the severity of infection
by producing various cytokines.
During the first three days of illness,
serum concentrations of TNFα,
IL-2, IL-6, and INF-ϒ are highest
while IL-5, IL-10 appear later. 15
L e ve l s o f R A N T E S ( R e g u l a t e d
Upon Activation, Normal T cell
Expressed and Secreted), a CC
chemokine has chemotactic activity
for T cells, monocytes, natural
killer cells, and eosinophils; have
been reported to be higher in
dengue infection. 16
Pathological changes include-
microvesicular steatosis,
hepatocellular necrosis,
Kupffer cell hyperplasia
and destruction, Councilman
bodies and cellular infiltrates at
the portal tract. 17 Dengue virus
c aus es hepat ocellular necrosis
mostly in the midzonal areas
and sometimes the centrilobular
area. Presence of coagulopathy
and thrombocytopenia makes
it difficult to obtain samples.
Recently, autopsy series from
d e n g u e p a t i e n t s i n M ya n m a r
showed varying degrees of liver
damage, mostly showing sinusoidal
congestion predominantly in
midzonal and centrilobular area
with no evidence of significant
fibrosis. 18
Clinical and Laboratory
Profile
Dengue fever indicates a poor
p r o g n o s i s i f l i ve r a n d c e n t r a l
nervous system are involved at
the same time. Dengue can also
result into fulminant hepatitis with
high mortality. Common features
suggesting liver involvement are
the presence of hepatomegaly and
elevated liver enzymes.
Va r i o u s s y m p t o m s s e e n a r e
abdominal pain, anorexia, and
vomiting. 19 Clinically jaundice can
be seen. Hepatomegaly is seen in
both dengue fever (DF) and DHF
but, it is more common in DF. 21
Also, hepatomegaly is seen more
commonly in children than adults.20
Rarely, acalculous cholecystitis
has been reported and one must
watch for impending gall bladder
gangrene. 22
Liver enzymes are raised in 30%
of the cases. 23 Table 2 illustrates
various studies interpreting
liver function abnormalities in
dengue. Wong et al reported that
AST abnormality was higher as
compared to ALT. 24 Souza et al
also reported a similar trend of
AST/ALT elevation in dengue. 4 A
similar study from Taiwan by Kuo
et al also showed 90% abnormality
in AST levels. 3 Damaged myocytes
release AST which could explain
higher levels of AST than ALT
in dengue at earlier stage. AST
is also released from heart,
striated muscle, erythrocytes, etc.,
apart from the liver, whilst ALT
primarily is hepatic in origin. 41
Various studies have shown that
AST and ALT values were higher
in severe forms of dengue than
in uncomplicat ed Deng ue. 4 , 21, 23
Gender vise, transaminitis was
seen more in males than in females
i n a s t u d y f r o m Ve n e z u e l a i n
dengue 3 serotype. 25 But Suoza

Table 2: Liver function abnormalities in dengue
Studies Patients Raised AST
Itha et al26 45 96%
Wong et al24 127 90.6%
Saha et al21 1226 52% (5 times normal
was criteria)
Kuo et al3 270 93.3%
Souza et al4 1585 63.4%
et al reported liver damage more
in females in a large study from
Brazil. 4 Hypoalbuminemia has also
been seen in dengue and its value
has wide range depending on the
severity of the disease. Saha et al
reported low albumin in 12.9%
of the cases which was similar to
the study reported by Wong and
Shen which showed 16.5% cases
t o h a ve h y p o a l b u m i n e m i a . 2 1 , 2 4
However, Itha et al reported
hypoalbuminemia in 76% of the
c a s e s . 26 T h e r e i s a n i n c r e a s e d
bleeding tendency with raised
liver enzymes. 3 Saha et al reported
INR of more than 1.5 in 11% of the
patients. 21 Liver Damage depends
on various factors like Dengue
h e m o r r h a g i c f e ve r , s e c o n d a r y
infection, thrombocytopenia,
female gender, and children. 4,24
Dengue related acute liver failure
has been described before. Majority
of them are reported in children
with few reports in adults. 27 There
have been studies in India as well
which reported dengue related in
ALF in children. Jagdishkumar et
al reported 5 dengue cases in a
study of 27 children with ALF. 28
There was another study reported
from Mumbai which found 5 cases
of dengue associated ALF out of 56
cases. 29 In endemic areas, dengue
can cause worsening of chronic
liver disease resulting in acute
on chronic liver failure. 30 Jha et al
reported 1 case of dengue induced
ACLF out of 52 cases in their
study.31 Sometimes, acetaminophen
overdose can play an important
role in causing acute liver failure
in dengue infected patients. 32
Management
Current management is focused
Journal of The Association of Physicians of India ■ Vol. 65 ■ December 2017
Raised ALT Hypoalbuminemia Raised
bilirubin
96% 76% 30%
71.7% 16.5% 13.4%
50% 12.9% 16.9%
82.2% - 7.2%
45% - -
on meticulous fluid administration
especially during leakage phase
of the illness. There have been
various studies on use of N-Acetyl
cysteine (NAC). Kumarasena,
et al used NAC on 8 patients
and 5 of them recovered from
hepatic encephalopathy and 3
died. 33 There was 1 case reported
which highlighted the importance
of recombinant factor VII A and
NAC in non-acetaminophen
induced Fulminant liver failure
i n C o m p l i c a t e d D H F . 34 T h e
rationale for NAC use is its
ability to restore hepatocellular
glutathione stores and its action
as free radical scavenger. It also
improves antioxidant defense. The
standard regimen for NAC remains
controversial.
Artificial liver support has also
been recently suggested for the
treatment of dengue patients with
liver failure. It aims to provide
temporary support of liver function
and acts as a bridge to liver
transplant. Various modalities
used are: 1) Molecular Adsorbent
Recirculating System (MARS) and
2 ) S PA D ( S i n g l e p a s s a l b u m i n
dialysis). Penafiel, et al (2006),
reported that use of MARS in dengue
infected patient with fulminant
liver failure demonstrated rapid
reversal of the biochemical
profile and an improvement of
encephalopathy. 35 However, it has
some limitations like high cost
and technically difficult to use.
There are few centers which use
albumin dialysis due to low cost,
availability of equipment and easy
to use. Boonsrirat, et al reported
favourable outcomes in liver failure
patients after using SPAD. 36
Kasture et al used Carica papaya
leaf extract in dengue patients
81
and reported increase in platelet
count. However, its use in hepatic
dysfunction is yet to be reported. 37
Celastrol has been reported as
a potential anti-dengue agent
that induces IFN-α expression
and stimulates a downstream
antiviral response, making the
therapy a promising drug. 38 Its
use in hepatic dysfunction needs
t o b e e va l u a t e d . F i n a l l y , l i ve r
transplant becomes the last resort
but it becomes a difficult option
in view of severe hemodynamic
compromise, multiple organ
dysfunctions, and bleeding seen
i n d e n g u e p a t i e n t s . H o we ve r ,
there has been a case report by
Gupta et al on transmission of
dengue from the donor to the
recipient after liver transplant. 39
India being a hyperendemic zone,
screening donors for dengue virus
becomes essential especially during
season time. A vaccine licensed in
several countries and developed by
Sanofi Pasteur (CYD-TDV, named
Dengvaxia) was able to protect, in
the first 25 months of the two Phase
III, 66% of a subset of 9-16 year
old participants but a significantly
lower efficacy (including
negative vaccine efficacy) was noted
for children younger than 9 years
of age. 40 It showed efficacy only
when given to partially immunized
individuals after screening. 40
Conclusion
Dengue has a wide range of
hepatic manifestations. Patients
could have asymptomatic
transaminasemia to liver failure.
Pathogenesis as outlined earlier is
not fully understood. Severity is
seen more in children than adults.
A c e t a m i n o p h e n o ve r d o s e , c o -
infection and underlying chronic
liver disease play an important role
in causing liver failure in dengue
patients. N-Acetylcysteine and
artificial liver support are used
as a bridge to liver transplant,
but there is not enough data to
support their use. Management is
primarily supportive and prognosis
is generally good.
82 Journal of The Association of Physicians of India ■ Vol. 65 ■ December 2017
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