LIVER RESEARCH
ISSN 2379-4038
Review
Corresponding author
*
David A. Sass, MD, FACP, FACG, AGAF,
FAASLDAssociate Professor of Medicine
Division of Gastroenterology and
Hepatology, Sidney Kimmel Medical
College, Jefferson University, 132 S.
10th Street, Main Building, Suite 480,
Philadelphia, PA 19107, USA
Tel. (215) 955-8900
Fax: (215) 503-2146
E-mail: david.sass@jefferson.edu
Volume 1 : Issue 1
Article Ref. #: 1000LROJ1101
Article History
Received: February 18th, 2015
Accepted: March 23rd, 2015
Published: March 24th, 2015
Citation
Shah SC, Sass DA. Cardiac Hepa-
topathy: A review of liver dysfunc-
tion in heart failure. Liver Res Open
J. 2015; 1(1): 1-10. doi: 10.17140/
LROJ-1-101
Copyright
2015 Sass DA. This is an open
access article distributed under the
Creative Commons Attribution 4.0
International License (CC BY 4.0),
which permits unrestricted use,
distribution, and reproduction in
any medium, provided the original
work is properly cited.
Liver Res Open J
http://dx.doi.org/10.17140/LROJ-1-101
Open
Journal
Cardiac Hepatopathy: A Review of
Liver
Dysfunction in Heart
Failure
Shailja C. Shah1 and David A. Sass2*
1
Fellow, Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, 1468
Madison
Ave, New York, NY 10029, USA
2
Associate Professor of Medicine, Division of Gastroenterology and Hepatology, Sidney Kim-
mel Medical College, Jefferson University, 132 S. 10th Street, Main Building, Suite 480,
Phila- delphia, PA 19107, USA
ABSTRACT
The unique dual circulation of the liver confers relative protection against ischemic
injury; however, low oxygen tension in the microcirculation (sinusoidal blood of the hepatic
acinus) may render hepatocytes in zone 3 relatively vulnerable to ischemic injury and
necrosis. Severe congestive heart failure is associated with two distinct forms of liver
dysfunction under the umbrella term cardiac hepatopathy. The two entities include: jaundice
related to passive congestion (congestive hepatopathy from backward cardiac failure) and
acute hepatocellular necrosis caused by impaired hepatic perfusion (hypoxic hepatitis from
forward cardiac failure). This article provides a comprehensive, up-to-date review on the topic
and focuses on the epi- demiology, pathology, pathogenesis, clinical manifestations,
diagnostic testing and treatment strategies pertaining to liver disease in circulatory failure.
KEYWORDS: Congestive hepatopathy; Hypoxic hepatitis; Ischemic hepatitis; High-gradient
ascites; Nutmeg liver; Heart failure.
ABBREVIATIONS: LVAD: Left-ventricular assist device; SAAG: Serum ascites-albumin
gradient; IVC: Inferior Vena Cava; LFTs: Liver Function Tests; AST: Aspartate
amino- transferase; ALT: Alanine aminotransferase; TIPS: Transjugular Intrahepatic
Portosystemic Shunt; GGT: Gamma Glutamyl Transpeptidase; LDH: Lactate dehydrogenase;
PT: Pro- thrombin Time; INR: International Normalized Ratio; ICU: Intensive Care Unit;
RAAS: Renin-angiotensin-aldosterone system; MARS: Molecular Adsorbent Recirculating
System.
INTRODUCTION
The relationship between cardiac and hepatic dysfunction has been a well-recognized
entity for over two centuries.1 Yet, the complexity and nuances of the association still remain
a topic of intense interest and research. Studies dealing with this topic are relatively few, not
rarely with contradictory results. There are several reasons for the variant results: heart failure
etiology has changed over the years, being mainly related to rheumatic valvular disease in the
earliest studies and to ischemic cardiomyopathy more recently.2 Also, the outcome of heart
failure has dramatically improved due to superior medical therapies, not to mention
widespread use of heart transplantation. Thus, cardiac cirrhosis, once the paradigm of liver
involvement in heart failure, is now rare.
Concomitant hepatic and cardiac disorders may be categorized according to etiology.
That is: (i) cardiac disease affecting the liver, (ii) hepatic disease affecting the heart, or (iii)
cardiac and hepatic disease secondary to a shared etiology.3,4 In this review, we chose to fo-
Page 1
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cus on cardiac hepatopathy, Open
or hepatic pathology secondary Journal
to cardiac dysfunction.2 As will

Liver Res Open J Page 2

be described herein, cardiac hepatopathy includes a spectrum failure from cardiomyopathy,11 severe pulmonary hypertension
of altered clinical, biochemical, histological, and hemodynamic or cor
disturbances. It is classically described in the setting of either
acute or chronic heart failure. However, clinical and pathoge-
netic factors related to both conditions often co-exist.

MACRO- AND MICROCIRCULATION OF THE LIVER

In order to understand the range of hepatic abnormali-

ties that characterize cardiac hepatopathy, it is important to first
appreciate the unique anatomy and physiology of the liver.

Macrocirculation

The liver has a rich dual blood supply derived from

both the portal and systemic vascular compartments: the portal
vein supplies two thirds of hepatic blood flow and the hepatic
artery is responsible for the remaining third.5 Although the
blood supply from the portal vein is less oxygenated compared
to the hepatic artery, the portal vein supply is full of nutrients as
it drains the vascular beds of the stomach, intestine, and
spleen. An under- standing of how the liver regulates its dual
blood supply is also critical, especially with respect to
compensatory mechanisms in the face of hemodynamic
compromise. In order to maintain con- stant sinusoidal pressure
to the hepatic beds, the liver employs an autoregulatory
mechanism whereby a decrease in blood flow via the portal
vein is matched by a compensatory dilation of the hepatic artery
and thus increased flow and maintenance of per- fusion.5
However, the opposite does not hold in that a decrease in
hepatic arterial blood flow that occurs secondary to a reduced
cardiac output in left heart failure is not matched by a
compensa- tory increase in portal venous inflow.1,6,7

Microcirculation

Liver architecture has been traditionally described in

terms of the histological unit and the functional unit. The histo-
logical (or classical) unit of the liver is the lobule, while the
functional unit of the liver is the acinus.8 The classical lobule is
hexagonal in shape, bounded by the portal triads with the
central vein at the center, and can be divided into concentric,
centri- lobular, midzonal, and periportal parts. The acinus is
diamond- shaped and has at its center a line connecting two
portal triads. The acinus is divided into zone 1 (periportal), zone
2 (transition), and zone 3 (centrilobular) according to the
direction of flow of oxygen- and nutrient-rich blood from zone
1 closest to the portal triad to zone 3 surrounding the terminal
hepatic vein.9

CONGESTIVE HEPATOPATHY

Congestive hepatopathy refers to the spectrum of

chronic liver injury attributed to passive hepatic congestion
aris- ing in the setting of right-sided heart failure or any cause
of in- creased central venous pressure,10 including biventricular
pulmonale,12 constrictive pericarditis13 as well as valvulopathies
such as mitral stenosis14 and tricuspid regurgitation. This
condi- tion was first described by Dame Sheila Sherlock in her
seminal work on the topic in 1951.1

Histopathology and
Pathogenesis

On gross examination, the congested liver is an en-

larged, purple-hued organ with prominent hepatic veins. The
cut surface conforms to the classic nutmeg appearance,
reflect- ing the alternating pattern of hemorrhage and necrosis
of zone
3 (red) with normal or slightly steatotic areas in zones 1 and 2
(yellow) (Figure 1).

Figure 1: Cut surface of the congested liver reminiscent of the classic nutmeg appearance
which is caused by chronic passive congestion of the central veins with hemorrhage and
necro- sis in zone 3. Red cells pool and distend the sinusoids around the central vein. These
regions develop a darker red-violet color, in contrast to the surrounding tan liver parenchyma.

In the face of decreased perfusion, zone 1 hepatocytes

are the least susceptible to necrosis, while zone 3 hepatocytes
are the most susceptible. Furthermore, zone 3 hepatocytes are
the most susceptible to damage induced by passive congestion
secondary to right heart failure (Figure 2). Hepatic sinusoids
lack a basement membrane and have a characteristic
fenestrated, discontinuous endothelial lining that also contains
macrophages specific to the liver (Kupffer cells). The
hepatocytes themselves are separated from the sinusoids by an
interstitial space, the Space of Disse. Under normal physiologic
conditions, free flow through the sinusoidal fenestrations
ensures a low hydrostatic pressure.15 With passive congestion
of the liver in right heart failure, the increased hydrostatic
pressure produces sinusoidal edema and hemorrhage, which
eventually compromises oxygen- ation.

Although the pathogenesis of fibrosis in cardiac he-

patopathy is relatively well-characterized, it still remains
unclear as to why some cardiac patients develop hepatic
pathology and others do not, as the stage of congestive heart
failure does not
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seem to correlate well with Open secondary to hepatomegaly ing includes a pulsatile liver,
hepatic fibrosis and Journal
The incidence of and stretching of Glissons which essentially results from
cirrhosis.1,2,15-17 congestive hepatopathy, capsule. An additional vol- ume overload of the right
Prolonged or repeated significant fibrosis or cardiac physical find- atrium.23 Importantly, loss of
episodes of hepatic cirrhosis ranges between 15% the pul- satile liver in chronic
congestion with fi- brosis to 65% of pa- tients with cardiac disease is more
may very rarely lead to so- significant heart failure.2,20,21 concerning than its positive
called cardiac cirrhosis. It By todays accounts car- diac presence,23,24 as loss of
must be noted, however, that cirrhosis is rare. In a study by pulsatility implies
the entity of cardiac cirrhosis, Myers et al.2 of 83 subjects progression to cardiac
also referred to as congestive with heart failure, significant fibrosis or cirrhosis and
cirrhosis, is somewhat fibrosis with architectural warrants attention.
elusive, with some authors distor- tion was found in only
not considering it true 19% of cases with only one Patients w
cirrhosis.18 Uniquely, the individual having an Symptom/Sign failure
fibrosis of cardiac established diagnosis of
hepatopathy is predominantly cirrhosis. In a smaller series Hepatomegaly

around the cen- tral hepatic of 59 patients awaiting Marked hepatomegaly

veins with relative sparing of
the portal tracts (re- verse
lobulation), although
extension is possible with
repeated attacks.1,18,19 This is
distinct from other etiologies
of cirrhosis, in which fibrosis
generally occurs first in the
area around the portal tract.
(> 5cm below right costal margin)
cardiac transplant or Left-
ventricular as- sist device Peripheral edema
(LVAD) placement, Pleural effusion
congestive changes were seen Ascites
universally with 19% having Splenomegaly
histologic changes consistent Jaundice
with cirrhosis.22 Data extracted from Richman, SM et.al. a
study of 175 patients with right-sided
heart failure.25
C Tabl
l e 1:
Cong
i estiv
e
n Hepa
i topat
hy:
c Sign
s
a and
l symp
toms
.

F
e Other common, yet
a nonspecific, findings include
t pe- ripheral edema, pleural
u effusion, splenomegaly, and
r jaundice (Table 1). Ascites is
e also clinically present in up
s to 20% of pa- tients with
congestive hepatopathy
Figure 2: H/E section of liver (10x In the majority of (although 41% at autopsy
magnification) with sinusoidal dilation in
zone 3. As the severity of the lesion patients, the clinical picture is have ascites).25 However, it
increases, the sinusoids around the central
vein become distended with extravasated domi- nated by signs and must be noted that the ascites
red cells and there is adjacent hepatocyte
plate atrophy.
symptoms of right-sided heart is a result of right-sided heart
failure rather than those of failure and not intrinsic liver
liver disease (Table 1). dysfunc- tion, as is the case in
I Hepatomegaly is the most other causes of cirrhosis.
n
c common manifestation with Although the Se- rum ascites-
i reports as high as 95% to albumin gradient (SAAG) is
d 99% in acute or chronic heart greater than 1.1 g/dL,
e failure. A mild, dull, right consistent with portal
n
c
upper quadrant pain is often hypertension, the ascitic fluid
e present and is likely protein level is
 LIVER RESEARCH
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characteristically high, and Open
oftentimes >2.5 g/dL. This Journal
high pro- tein content is an
indication of the preserved
synthetic function of the
liver,26 a finding unique to
cardiac cirrhosis and critical
in differentiating it from
other causes of cirrhosis. The
under- lying
pathophysiology of cardiac
ascites remains uncertain,
but some have proposed that
sinusoidal hypertension with
disrup- tion of fenestrae
ultimately allows for
exudation of a protein rich
fluid.6,26 Other useful ascitic
fluid parameters are the
Lactate de- hydrogenase
(LDH), and red cell counts,
as these generally tend to be
higher in cardiac cirrhosis.26

Congestive changes
can readily be seen on
abdominal imaging. Liver
ultrasonography typically
shows hepatomegaly with a
homogeneous increase in
echogenicity throughout the
liv- er and dilation of the
suprahepatic veins and
Inferior Vena Cava (IVC).
Computed tomography and
magnetic resonance imaging
will similarly demonstrate
hepatomegaly, distension of
the he- patic veins and IVC,
early reflux of contrast
material from the right
atrium to the IVC, and a
heterogeneous, mottled-
appearing liver parenchyma,
often referred to as a mosaic
pattern, which corresponds
to the nutmeg liver seen on
gross inspection.27 As- cites,
pleural and pericardial
effusions are also frequently
report- ed.

In terms of
hemodynamic parameters,
heart failure pa- tients
exhibit an increased right
atrial pressure and the free
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Open
Journal
 LIVER RESEARCH
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wedged hepatic venous Open
et al. correlated alterations in useful than albumin level at
pressures are also commonly Liver Function TestsJournal
(LFTs) Decreased albumin tracking progression of
elevated, with a normal with either acute or chronic (seen in about 30-50% of cardiac he- patopathy based
hepatic venous pressure decompensated right-sided cases) is a very nonspecific on the observation that PT
gradient.28,29 This finding of heart failure regardless of finding, as it is fails to correct with Vitamin
normal intrahepatic portal etiology or severity of heart overwhelmingly common in K34 but does usually correct
pressures is clinically disease.25 hospitalized patients and with compensation of heart
relevant and likely underlies, In acute dysfunction, both those with chronic diseases. failure, suggesting a direct
at least in part, the minimal excretory function and With re- spect to synthetic effect on hepatic synthesis.
hepatic symptoma- tology parenchymal destruction were function, Prothrombin Time The PT is mildly abnormal in
associated with the majority most pronounced, while a (PT) may be more 80% of cases. Although
of cases of cardiac hepatopa- cholestatic pattern was most serum ammonia level is
thy. pronounced in chronic occasionally increased,
decompensation, findings that hepatic encephalopathy is not
Histologically, have been corroborated in a a salient feature of congestive
relative sparing of the portal more recent study by Myers heart failure.35
tracts from fibrosis a et al.2
distinguishing factor of T
cardiac cirrhosis compared to Elevated serum r
e
other etiologies of cirrhosis bilirubin is also a common
a
as previously noted also finding in car- diac t
likely contributes to the lack hepatopathy, except perhaps m
of stigmata classically in constrictive pericarditis,31,32 e
associated with portal with reports of mild elevation n
t
hypertension. Spider (usually <3 mg/dL and
angiomata and portosystemic mostly unconjugated) in up
The cornerstone of
shunts like hemorrhoidal to 70% of patients.6,15,25 The
management of all forms of
plexus varices, caput hyperbiliru- binemia in
con- gestive hepatopathy,
medusae, and esopha- geal congestive heart failure is
from asymptomatic, mild
varices are very rarely, if at multifactorial and likely
elevations in he- patic indices
all, present in cases of results from a combination of
to cardiac cirrhosis is targeted
cardiac hepatopathy.6,15,30 hepatocellular dysfunction,
toward treating the
Even with progression to ob- struction secondary to
underlying cardiac
cirrhosis, hepatic symptoms passive congestion and
dysfunction and any triggers
and manifestations of portal pressure atrophy of the
accounting for acute
hypertension do not pre- canaliculi, pulmonary
decompensation.
dominate, which is again in infarction, bile thrombi,
Reversibility of biochemical
contrast to cirrhosis of other hemolysis, and
aberrations in cardiac
etiolo- gies. medications.1,31 Increases in
hepatopathy was described as
the serum bilirubin have been
early as 1930 when Jol- liffe
Congestive heart shown to correlate with the
et al. reported normalization
failure results in a broad severity of right atrial
of liver biochemistries with
range of liver biochemical pressure and passive
restoration of appropriate
abnormalities. Generally, a congestion.1,33 Bilirubin is
cardiac function.24
hepatocellular pattern with significantly more elevated in
predominantly elevated patients with physical exam
Jaundice, hepatic
transaminases is seen in findings of volume overload,
congestion and ascites may
hypoxic hepatitis, which is a such as S3 gallop or
respond dramatically to
rare occurrence given that the pulmonary crackles, thus
therapy with diuretics;
liver is rela- tively protected implicating its value as a
however these drugs should
from hypoperfusion and prognostic factor and
be used with caution to avoid
hypoxia. More contem- indicator of more severe
dehydration, hypotension and
porary research describes the hemodynamic dysfunction.4
hepatic ischemia by
biochemical profile in Despite the common finding
precipitating zone 3
congestive heart failure as of hyperbilirubine- mia, the
necrosis.36 It is of vital
mostly cholestatic. In their presence of clinical jaundice
importance to maintain an
study in the 1960s, Richman is not common.
 LIVER RESEARCH
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adequate cardiac output. Open
function typically remains
Serial large-volume Journal
stable and even when cardiac
paracenteses can relieve cirrhosis and ascites ensue,
symptoms in those with patients with congestive
diuretic-refractory tense hepatopathy rarely develop
cardiac ascites6,37,38 but over other features of hepatic
time can lead to protein loss insufficiency.1 Fulminant
and exacerbate the protein liver failure, although
malnutrition com- monly documented, seems to be
seen in those with advanced restricted to those with
heart failure. Transjugular superimposed ischemic liver
Intrahepatic Portosystemic injury rather than passive
Shunts (TIPS) or peritoneal- congestion alone.45,46
venous shunts are contra-
indicated in this population Several studies have
as they can lead to addressed the prognostic
exacerbation of the impor- tance of liver
underlying heart failure. function abnormalities in
Cautious use of predicting short and
anticoagulants is advised
because patients have a
baseline mild increase in
PT/INR and are especially
sensitive to warfarin and
other related compounds.39 In
patients refractory to medi-
cal therapy who are suitable
operative candidates, both
LVAD implantation40,41 and
cardiac transplantation42 have
been shown to improve and
reverse the congestive liver
injury associated with the
failing heart. In select
patients with established
cirrho- sis, combined heart
and liver transplant is a
feasible option.43
Recently, there has been a
report of possible reversal of
cardiac cirrhosis with heart
transplantation alone,
effectively removing the
source of the insult.44
However, such cases are the
excep- tion.

P
r
o
g
n
o
s
i
s

Over time, hepatic

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long-term outcomes. More Open
recent Hist namic derangements as
According to the CHARM literature has Journal
proposed
opa
evidenced by the low
thol
investigators, abnormal levels hypoxic hepatitis as a more ogy incidence of hepatic damage
of total bilirubin, direct appropriate name than shock and in the face of shock and
bilirubin, alkaline phos- liver51 and/or isch- emic Etio circulatory collapse.
pat
phatase, and albumin are hepatitis52 given that, However, the compensatory
hog
statistically significant regardless of etiology ene mechanisms are notably
prognosticators of outcome (cardiogenic or otherwise), sis overwhelmed in the face of
Total bilirubin was the underlying mechanism persistent hypotension or
reportedly more predictive of appears to be hy- poxia Cardiovascular severe hypoxemia and
adverse prognosis than even even in the absence of disease is recognized as the underly- ing cardiac
the New York Heart ischemia.34 Classically, most com- mon cause of dysfunction. Virtually any
Association functional class, ischemic hepatitis was used hypoxic hepatitis, underlying cause of shock or hemo-
left ventricular ejection because of the histological over 70% of cases, while the dynamic instability can result
fraction, diabetes mel- litus, appearance of centrilobular remaining 30% of cases are in ischemic injury to the liver
and serum creatinine.20,47 necrosis, loss of hepatocytes, split equally between re- (see table 2 for a complete list
Batin et al demonstrated that and sinusoidal con- gestion spiratory failure and of causes).
the greatest prognosticators with erythrocyte sepsis.57,34 The association of
in chronic heart failure were extravasation, but a heart disease with increased Heart Failure with or without cardiogenic s
- Right ventricular failure
AST and total bilirubin;48 characteristically proclivity toward developing - Right ventricular myocardial infar
while in a Japanese chronic unremarkable inflammatory hypoxic hepatitis might stem - Pulmonary embolism
- Cor pulmonale
heart failure study, total infiltrate.34,53 Although from passive congestion of - Primary pulmonary hypertension
bilirubin, alkaline centrilobular necrosis is a the liver compromising its - Left ventricular failure
- Ischemic cardiomyopathy
phosphatase and GGT levels critical part of the disease, relative resistance to ischemia - Non-ischemic dilated cardiomyop
were all as- sociated with histologic confirmation is and hypoxia. The liver is nor- - Valvular dysfunction
worsened outcomes.49 seldom obtained.50,53 mally well-equipped to Hypovolemic shock
- Hemorrhage
compensate for and withstand - Dehydration
H I hemody- - Major burns
Y n Other systemic disorders
P c - Major trauma (crush injury)
O i - Sepsis
X d - Heat stroke
- Vasculitis
I e
C n Rare causes
c - Sickle cell crisis
- Carbon monoxide poisoning
H e - Dissecting aortic aneurysm
E - Hepatic artery occlusion in the setting of a liv
pre-existing portal vein thrombosis
P Because of increased
A awareness and recognition of Table 2: Causes of Hypoxic Hepatitis.
T
I
the possibility of hypoxic
C
T hepatitis accounting for l
I elevated amin- otransferases, i
S it is now identified as the n
most common cause of acute i
Hypoxic hepatitis is c
liver injury , even exceeding a
defined as an acute and drug-induced liver injury and l
reversible significant acute viral hepatitis.53,54 It is
elevation of serum AST and well-reported that the f
ALT levels to more than e
incidence is highest in cardiac
a
20 times the upper limit of care and surgical intensive t
normal in the absence of care units, with some reports u
known acute hepatitis or identifying up to 22% of r
hepatocellular injury and patients55 compared to a e
with an appropriate clini- cal s
recently reported 11% in
picture specifically involving medical intensive care units50
acute circulatory, cardiac, or Patients with
and less than 1% incidence in
respiratory failure.50 hypoxic hepatitis tend to be
the non-critical care units.56
older, pre- dominantly male
and acutely ill in the
 LIVER RESEARCH
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intensive care unit.55 Open
Signs and symptoms of acute Journal
liver injury are usually
absent, in contrast to other
causes of acute liver injury.
The clinical pre- sentation is
usually consistent with
cardiac compromise53,57 al-
though some individual
studies have reported a
variety of other symptoms,
ranging from predominantly
gastrointestinal with nausea,
vomiting and diarrhea58 to an
encephalopathic picture with
altered mental status or even
coma.34,59 The latter picture
of acute fulminant hepatic
failure, although rare, is
more likely to occur in the
presence of underlying
congestive heart failure or
cirrhosis.34 There are no
unique physical examination
findings although some
patients exhibit right upper
quadrant tenderness to
palpation.

Despite the
potential nonspecific and
variable symp- tomatology,
hypoxic hepatitis is more
commonly diagnosed in-
cidentally with routine liver
function tests anywhere from
2-24 hours after an episode
of systemic hypotension.
Laboratory abnormalities in
hypoxic hepatitis are
consistent with a hepato-
cellular pattern. First, there is
a marked increase in
aminotrans- ferases and
Lactate dehydrogenase
(LDH), with AST and LDH
rising most sharply and
peaking in the first 12-48
hrs, while the rise and peak
ALT is not as dramatic.50,59
Moreover, maximal el-
evation of ALT is less than
AST and given the longer
half-life of
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Open
Journal

ISSN 2379-4038
ALT, it reaches normal
levels later than AST. Even
so, the ami- notransferase
levels characteristically fall
by greater than 50% within
72 hours of resolution of the
underlying insult and return
to normal within 7-10
days.34,50,60 Increases in LDH
level tend to be massive and
ALT/LDH ratio of less than
1.5 often distin- guishes
ischemic injury from other
forms of acute hepatitis.61 It
is of interest to note that the
liver may not retain its
normal archi- tecture after
regeneration if the reticular
framework is damaged. The
most common compensatory
responses seem to be either
thickening of hepatocellular
plates with preservation of
trabe- cular and cord-like
pattern or nodular masses of
hepatocytes.19,62
The latter, known as nodular
regenerative hyperplasia, is
less common but can
manifest as a grossly granular
or nodular liv- er.18
The integrity of
hepatic synthetic function is
also com- promised in
hypoxic hepatitis, as
determined by PT/INR. If the
INR remains above 1.5
despite adequate stores of
Vitamin K, the diagnosis of
acute liver failure is
appropriate.63 Synthetic func-
tion is also of prognostic
importance, with INR above
2.0 associ- ated with an
independent increase in
mortality.50
Elevated lactate is
also a common biochemical
ab- normality in hypoxic
hepatitis although Fuhrmann
et al. noted its lack of
independent predictive value
in mortality.50 Rarely,
laboratory abnormalities can
even include consumptive
LIVER RESEARCH
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coagu- lopathy, whichOpen
can be certain, as one report found ten is not a true hepatic
Journal
asymptomatic or symptomatic that hypoxic hepatitis was encephalopathy and is
and most often related to the only an independent risk actually a conse- quence of
underlying etiology. Bilirubin factor in those requiring the inciting factor leading to
may be mildly elevated and vasopressor therapy.50 hypoxic brain damage.
tends to peak after the Importantly, the cause of
transaminases and LDH lev- death is usually not due to
els begin to decline. The hepatic fail- ure but related to Because this entity is
effects of systemic the underlying precipitating essentially an observed
hypotension are not isolated factor itself, such as sepsis or labora- tory abnormality,
to the liver, and increases in cardiac decompensation.50,53 albeit an alarming one,
creatinine level from acute Moreover, although en- treatment is targeted at
tubular necrosis are nearly cephalopathy is frequently identifying and addressing
universal early in the clinical noted in hypoxic hepatitis, it the inciting event. Awareness
course. most of- of potential exacerbating
factors, such as mechanical
The differential ventilation or
diagnosis for hypoxic vasoconstrictors that may
hepatitis includes acute viral compromise hepatic blood
hepatitis, autoimmune flow, as well as metabolic
hepatitis, drug-induced liver monitoring to prevent
injury (e.g. acetaminophen), derangements like hy-
acute Wilsons disease and poglycemia and lactic
acute vascular thrombosis e.g. acidosis50 are essential. Also
hepatic artery and portal vein important is recognizing that
thrombo- sis. While viral other organs may be
hepatitis and alcoholic implicated, including ini-
hepatitis can usually be tiation of systemic
differentiated from hypoxic inflammatory response
hepatitis based on the syndrome with pos- sible
ALT:AST and AST:ALT disseminated intravascular
ratios, respectively, it may be coagulation,64 new or
difficult to differentiate drug- worsened respiratory
induced hepatitis from compromise with
hypoxic hepatitis. hepatopulmonary syndrome,65
car- diac compromise with
T
myocardial infarction, or
r renal compro- mise with
e acute kidney injury.
a
t
m Several experimental
e therapies have been
n
t described. To improve
hepatosplanchnic blood flow,
infusion of renal-dose do-
Early recognition
pamine66 has been suggested,
and management is critical
but to date no proven clinical
and is the primary prognostic
ben- efit has been shown.
factor. The importance of
Adenosine infusion has been
recognizing hy- poxic
used in animal models but
hepatitis is underscored by
there are no human data to
reports of associated
support its use in this set-
mortality in Intensive Care
ting. Other investigators have
Unit (ICU) patients of over
suggested a role of
50%.50,53 However, its role as
antioxidants6 or N-
an independent risk factor in
acetylcysteine,67 however
ICU patients is still un-
these findings are only
 LIVER RESEARCH
ISSN 2379-4038 http://dx.doi.org/10.17140/LROJ-1-101
limited to case reports and However, because Open this
thus need to be corroborated hepatic ailment occurs Journal
in the
in randomized controlled critically ill patients, survival
trials. Nitric oxide has in most series is rather poor.
shown some promise, given In the largest pub- lished
its role as an endothelin series to date (142 episodes
antagonist and consequent in 10 years of surveillance):
ability to counter the 1-month and 1-year
vasoconstriction of hepatic survivals were 53% and 28%
vascular beds in ischemia.68 respec- tively.53 Fulminant
Similarly, research has been hepatic failure rarely occurs
focused on angiotensin and seems to be restricted to
receptor II blockers and ACE patients with longstanding
inhibitors as possible congestive heart failure,
antagonists of Renin- cardiac cirrhosis45 or other
angiotensin-aldosterone forms of chronic liver
system (RAAS) activation, a disease.
pathway very much
implicated in hypoxic
hepatitis.69 Molecular Adsor-
bent Recirculating System
(MARS) and single-pass
albumin dialysis, both of
which have shown benefit in
acute and acute- on-chronic
liver failure, have also been
researched as potential
therapeutic modalities in
hypoxic hepatitis but with
uncertain benefit.70-72 To
date, no liver-specific
treatments have been prov-
en to improve outcome.
Furthermore, hypoxic
hepatitis is not an indication
for liver transplantation as
the hepatic derangements are
reversible with correction of
the underlying disorder.

P
r
o
g
n
o
s
i
s

The majority of
patients with hypoxic
hepatitis follow a benign
self-limited course with
complete resolution of
transami- nases to normal
values within 3 to 7 days of
the inciting event.57
 LIVER RESEARCH
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Open
Journal
 LIVER RESEARCH
ISSN 2379-4038 http://dx.doi.org/10.17140/LROJ-1-101
C The authors have
Open & hepatol. 2009; 3(1): 51- 8. Rappaport AM. The
O no conflicts of Journal 64. doi: microcirculatory hepatic unit.
N 1 Microvasc
C
interest to
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L
U . doi: 10.1016/0026-
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I RS 5
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NA 6
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Hepatic injury as a AC
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disease is a relatively W 4 Physiol. 1980; 21: 1-
common, but often poorly LE 7 63.
recognized, syndrome. An D 4
GE
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M 10. Megalla S, Holtzman D,
circulation and normal liver EN 2
Aronow WS, et al. Prediction
archi- tecture is important to TS 4
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appreciate how the
3 patients with right heart
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1 17(10): 537-541.
leading to the associated De- partment of Pathology,
clini- cal, biochemical and Drexel University College of .
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histologic features. The Medicine, Philadelphia, PA
1 Marsh WH, Lee WM.
hepatic manifesta- tions of for kindly providing the
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