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Dengue Induced Hepatic Injury

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76 Journal of The Association of Physicians of India ■ Vol. 65 ■ December 2017

REVIEW ARTICLE

Dengue Induced Hepatic Injury

Darshil Shah 1, Pravin Rathi 2

family and genus flavivirus. 65%

Abstract of the genotypes are shared among
the four serotypes.2 They produce
Dengue has a significant impact on the disease burden in the population
different types of manifestations
residing in tropical countries. It is transmitted by the bite of Aedes
howe ve r , most pa t i e nt s a r e
mosquito. The virus have got some hepatotoxic effects. Most of the cases
asymptomatic.2 It is transmitted via
are asymptomatic. However,it should be considered as one of the causes
Aedes Aegypti and less commonly
of Acute Liver Failure in endemic countries. Our article focuses on the by Aede s Al bo pi c tu s. D eng u e
pathogenesis, manifestations, investigations and, the treatment options virus is an RNA virus with a single
for dengue related hepatic dysfunction. str an ded po si ti ve sen s e R NA.
I t al so enc ode s f or seven non-
structural proteins of which NS1 is
o f d e ng u e h e mo r r ha gi c f e ve r used as a diagnostic antigen in the
(DHF) and 22,000 deaths (CDC, initial phase of the disease.
Dengue Virus infection 2014). Having a wide spectrum WHO Classification, 20091
i s one of the i mpor tant causes of clinical presentations, severe
The modified categorization of
of a c u te f e bri l e il l nes s i n th e dengue is categorized as Group C
WHO in 2009 includes dengue with
tropical and subtropical region. by WHO in 2009, which includes
or without the warning signs.
It is a self-limiting condition for Dengue Hemorrhagic Fever and
whic h no spec if ic treatment or D engue Shoc k Syndr ome. 1 The Majority of studies however still
effective vaccine is available. It burden of disease has increased classify dengue as Dengue fever,
i s the mo st r api dl y s pr eadi n g drastically due to factors such as Dengue hemorrhagic fever and
mo sq ui to bor ne di sea se i n the inadequate water supply, relentless Dengue Shock Syndrome.
wor l d. Fif t y mill i on i nfecti on s urbanization, poor hygiene and
occur annually, with 500,000 cases v i r a e mi c t r a ve l e r s s pr e a d i n g Pathogenesis and
disease geographically.2 Pathology
Table :
In dengue-endemic countries, H e pa t i c D y sf u n c t i o n i s a n
Dengue Fever with any 2 of: the disease is an important cause i m po r t a n t f e a t u r e i n d e n g u e
• Nausea of acute viral hepatitis. Elevated infection. Dengue virus replicate in
• Vomiting AST and ALT levels have been both hepatocytes and kupffer cells.
• Skin rash as soc i ate d wi t h bl eedi ng 3 and
This may be because most viral
• Body ache D e ngu e he mor r ha gi c fe ve r .4
particles enter cells by phagocytosis
• Leukopenia Liver failure has been recognized
leading to viral degradation. Viral
• Any warning sign as a compl ic ati on and unusual r e pl i c at i o n o c c ur s i n s ma l l e r
Severe • Plasma leakage manifestation of dengue. 1 In this nu mber of Kupf f er c el l s. Tw o
Dengue • Bleeding & organ impairment review we outline the pathogenesis, phases of Kupffer cells have been
• 
Transaminase > 1000 IU/L clinical, biochemical parameters
described. The first phase occurs
• Altered Sensorium and manageme nt of dengue sl o wl y af te r i nf ec ti o n, a nd i s
• Cardiac involvement induced liver dysfunction.
mediated by nitric oxide and INF
Warning • Abdominal pain
Signs • Persistent vomiting
s α production; while the second
phase is mediated by IL-6 and TNF
• Effusion/Ascites Dengue virus has 4 serotypes α production. 5 The E Protein plays
• Bleeding (1-4). It belongs to the Flaviviridae a pivotal role in the attachment of
• Lassitude/restiveness
• Hepatomegaly
1Gastroenterology 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

the virus to the receptor on the host
cells but the nature of the receptor
is yet to be determined. 6
At present, the exact mechanism
of i nt er ac ti on between dengue
virus a nd hepatoc yte is poorly
defi ned. The inter ac ti on va ri es
with different serotypes. Glucose
regulated protein 78 (GRP78) was
reported to be used by DEN-2 to
gai n entr y int o HepG2 c ell s (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
pl ays a n i mpor tant r ol e i n 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 a re: 1) the abi li ty 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
a re mor e susc epti bl e to sever e
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 ve d d en d r i t i c c el l s , 1 0 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
cytopa thic eff ec ts of the vir us,
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
Journal of The Association of Physicians of India ■ Vol. 65 ■ December 2017
levels of endoplasmic reticulum
stress induce apoptosis and similar
mec hani sm has been pr opo sed
in other members of f lavivi rus
genus.12 Transcription factor NF-κB
activation has been implicated in
the induction of apoptosis.13 TRAIL
(Tumor Necrosis Factor-Related
Apoptosis-I nducing Ligand)
expression has been suggested to
be partly responsible for causing
apoptosis.14 Councilman bodies are
the remnants of cells undergoing
apoptosis.
Diff er e nt i mmune r esponses
ar e se en i n de ngue i nf ec ti on s
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.
Ser otype specific and ser otype
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 c oncentrations of TNFα,
IL-2, IL-6, and INF-ϒ are highest
while IL-5, IL-10 appear later. 15
Level s of R ANTES (R egul at ed
Upon Activation, Normal T cell
Ex pressed and Secreted), a CC
chemokine has chemotactic activity
for T c ell s, monoc ytes, natural
killer cells, and eosinophils; have
been r epor te d to be hi gher i n
dengue infection.16
Pathological changes include-
microvesicular steatosis,
hepatocellular necrosis, K u p f f e r
c el l h y per pl a si a and
d e s t r u c ti o n , C o u n c i l ma n
bodies and cellular infiltrates at
the portal tract. 1 7 Dengue virus
c auses hepatoc el l ula r nec r osi s
mo s tl y i n t he mi dz on al a r ea s
and sometimes the centrilobular
area. Presence of coagulopathy
a n d t hr o mb o c y t o pe ni a ma ke s
i t di f fi c ul t to obt ai n sa mpl e s.
R ec ent l y, a uto psy ser i es f r o m
d e n g u e pa t i e n t s i n M ya n ma r
77
showed varying degrees of liver
damage, mostly showing sinusoidal
c o n g e st i o n pr e d o mi n a n t l y i n
midzonal and centrilobular area
with no evidence of significant
fibrosis. 18
Clinical and Laboratory
Profile
Dengue fever indicates a poor
pr og n o si s i f l i ver a nd c entr a l
nervous system are involved at
the same time. Dengue can also
result into fulminant hepatitis.
Common features suggesting
liver involvement are the
presence of hepatomegaly and
elevated liver enzymes. Va r i ou s
sy mpt o ms seen ar e a bdomi nal
pai n, anor exia, 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. 2 1
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 Table 1 illustrates
various studies showing deranged
liver function. Liver enzymes are
raised in 30% of the cases.23 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
hi gher l evel s of AS T than ALT
in dengue at earlier stage. AST
i s a l so re l ea se d f r om h e a r t,
striated muscle, erythrocytes, etc.,
apart from the liver, whilst ALT
primarily is hepatic in origin. 4 1
Various studies have shown that
AST and ALT values were higher
in severe forms of dengue. 4 ,21 ,2 3
Gender vise, transami niti s was
seen more in males than in females
i n a st udy f r o m Vene zuel a i n
dengue 3 ser otype. 2 5 But Suoza
et al reported liver damage more
in females in a large study from
78 Journal of The Association of Physicians of India ■ Vol. 65 ■ December 2017
Table 1: Liver function abormalities 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%
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 l ow albumin in 12.9%
of the cases which was similar to
the study reported by Wong and
Shen which showed 16.5% cases
to ha ve hyp oa l bumi n e mi a. 2 1 ,2 4
H o we ve r , I t h a e t al r e po r t e d
hypoalbuminemia in 76% of the
c as es . 2 6 T he r e i s a n in c r e as ed
bl eedi ng tendenc y wit h r ai sed
liver enzymes.3 Saha et al reported
INR of more than 1.5 in 11% of the
patients. 21 Liver Damage depends
on var ious factor s like Dengue
he mor r ha g i c f ever , sec on dar y
i n f e c ti o n , t h r o mb o c y t o pe n i a ,
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 disea se resulti ng in acute
on chronic liver failure.30 Jha et al
reported 1 case of dengue induced
ACLF out of 5 2 c ase s i n thei r
study.31 Sometimes, acetaminophen
overdose can play an important
role in causing acute liver failure
in dengue infected patients.32
Current management is focused
on meticulous fluid administration
especially during leakage phase
Raised ALT Hypoalbuminemia Raised
bilirubin
96% 76% 30%
71.7% 16.5% 13.4%
50% 12.9% 16.9%
82.2% - 7.2%
45% - -
of the illness. There ha ve been
various studies on use of N-Acetyl
c y s t e in e ( NA C ). K u ma ra se n a,
et al used NAC on 8 pati e nt s
and 5 of the m r ec over ed fr om
hepa ti c enc e phal o pa thy and 3
died.33 There was 1 case reported
which highlighted the importance
of recombinant factor VII A and
NAC i n non-ac etami nophen
induced Fulminant liver failure
i n C o mpl i c a t e d D HF. 34 The
rationale f or 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
a n d ac t s a s a b r i d g e t o l i ve r
tr anspl ant . Vari ou s modal i t i es
used are: 1) Molecular Adsorbent
Recirculating System (MARS) and
2 ) S PAD (Singl e pa s s a l bumi n
dialysis). Penafiel, et al (2006),
reported that use of MARS in dengue
infected patient with fulminant
liver failure demonstrated rapid
r e ve r sa l of t h e b i oc h e mi ca l
pr ofile and an improvement of
encephalopathy. 35 However, it has
some li mitations like high c ost
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 extr ac t i n dengue p ati ents
and reported increase in platelet
count. However, its use in hepatic
dysfunction is yet to be reported. 37
Celastr ol has been reporte d as
a pote nti a l anti - deng ue a ge nt
that i nduc es I FN-α ex pr essi on
and st i mul a te s a dow ns tr ea m
ant i viral r esponse, ma king the
therapy a pr omising drug. 3 8 Its
use in hepatic dysfunction needs
to be eval uat ed. Fi na l l y, l i ver
transplant becomes the last resort
but it becomes a difficult option
in view of severe hemodynamic
c o m p r o mi s e , mu l t i pl e o r g a n
dysfunctions, and bleeding seen
i n deng u e pati ent s. H owev er ,
there has been a case report by
Gupta et al on transmi ssion of
dengue f r om the do nor 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 effi cacy (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 wi de range of
hepatic manifestations. Patients
c oul d have asy mpt oma t i c
transaminasemia to liver failure.
Pathogenesis as outlined earlier is
not fully understood. Severity is
seen more in children than adults.
Ac et a mi n oph en o ve r d o se , c o -
infection and underlying chronic
liver disease play an important role
in causing liver failure in dengue
pati ents. N-Acet ylcystei ne a nd
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.
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