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Mechanism of injury
Congestive hepatopathy (passive liver congestion) is a potential sequela of several disorders associated with
severely impaired right heart function, including constrictive pericarditis, mitral stenosis, severe tricuspid regur-
gitation, cor pulmonale, and advanced heart failure and cardiomyopathy (
Table 9.1) [7].
Injury to the liver secondary to heart failure happens primarily via two mechanisms: hepatic congestion and
ischemia reperfusion injury
[2]. Due to the absence of valves in the hepatic veins, pressure from the inferior vena
cava can accumulate and impact the upstream sinusoidal vascular bed. The result of this pressure is centrilobular
congestion, sinusoidal dilatation, and perivenular fibrosis
[8]. Heart failure often results in a low output state as
well, allowing for the presence of ischemia reperfusion injury to occur in the liver. This mechanism of hepatic
injury will be explored in further detail in our section on hypoxic hepatitis.
Clinical manifestations
Patients with passive hepatic congestion are normally asymptomatic. Thus, the presence of the condition is often
suggested by the presence of abnormal hepatic biochemical testing during routine or incidental evaluation. Those
who are symptomatic may present with jaundice which could mimic obstructive jaundice
[9]. Alternatively,
patients can present with markedly elevated aminotransferases which can mimic acute viral hepatitis
[10].
The predominant clinical manifestation outside of the liver in the setting of passive hepatic congestion will be
centered around signs of right heart failure. As outlined by Kavoliuniene et al., the diagnosis of congestive hepato-
pathy can be defined by four criteria: first, structural heart disease impairing right ventricular function; second,
signs and symptoms of right heart failure including elevated jugular venous pressure, hepatomegaly, hepatojugular
reflux, pitting edema and ascites; third, elevation of serum markers of hepatic cholestasis including alkaline phos-
phatase, total bilirubin, and gamma-glutamyl transferase; and fourth, exclusion of other causes of liver damage
[7].
The most common laboratory finding in patients with congestive hepatopathy is elevated total bili rubin
[11].
This laboratory finding is present in a majority of patients with congestive hepatopathy, with levels normally less
than 3 mg/dL
[12]. Serum aminotransferases are elevated in a third of patients, typically less than 23 times the
upper limit of normal
[13]. Serum albumin is decreased in 30 to 50% of patients, though rarely below 2.5 g/dL
[3]. Finally, the prothrombin time can also be mildly elevated in many patients and this appears to be at least
somewhat independent of impaired hepatic synthesis of coagulation factors
[14].
The physical examination can reveal the presence of ascites. In this case, diagnostic paracentesis with ascitic fluid
analysis is helpful to distinguish ascites of cardiogenic sources from hepatic ascites. Cardiogenic ascites is typified
by high fluid protein count greater than 2.5 g/dL and serum albumin to ascites ratio greater than 1.1
[15].
Imaging findings
Numerous imaging modalities can aid in the diagnosis of passive hepatic congestion and its complications.
Modalities to consider include radiographs, ultrasound, CT, MRI, elastography among others.
Radiographs do not play a prominent role in the evaluation of congestive hepatopathy. Findings, if present,
would consist of findings associated with severe heart failure including cardiac chamber enlargement, pulmonary
artery enlargement, or pericardial calcifications in the case of constrictive pericarditis. The vena cava and azygos
vein may also be enlarged
[16].
Ultrasound can often help aid in the evaluation of the hepatic vasculature in the setting of congestive hepato-
pathy. Hepatic vein dilation can be seen on grayscale ultrasound. The normal right hepatic vein diameter is
5.66.2 mm; it increases to 8.8 mm in the setting of congestive heart failure and to 13.3 mm in the setting of
congestive heart failure with pleural effusion
[17]. There can be a loss of the normal variation in venous diameter
TABLE 9.1 Causes of passive liver congestion.
(1) Advanced right heart failure and cardiomyopathy.
(2) Constrictive pericarditis.
(3) Mitral stenosis.
(4) Severe tricuspid regurgitation.
(5) Cor pulmonale.
Adapted from Kavoliuniene A, Vaitiekiene A, Cesnaite G. Congestive hepatopathy and hypoxic hepatitis in heart failure: a cardiologist’s point of view. Int J Cardiol. 2013;166
(2013):554558.
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with respirations seen in the hepatic veins and vena cava [18]. Certain etiologies of congestive hepatopathy can
demonstrate typical findings on the duplex waveform investigation of the hepatic veins. The normal hepatic
venous waveform is referred to as triphasic, though it has two antegrade waves (during ventricular systole and
ventricular filling) and two retrograde waves (during atrial contraction and atrial filling at the end of systole)
[16]. In the setting of constrictive pericarditis, an extra retrograde hepatic venous wave may be seen at the end of
diastole, whereas in tricuspid regurgitation the normal antegrade pulsation during systole can be diminished. Of
note, in advanced fibrosis due to congestive hepatopathy, the stiffening of the hepatic parenchyma can dampen
all waveforms
[19].
As is the case with ultrasound, the hepatic veins and inferior vena cava are usually dilated and readily identi-
fiable on CT or MRI
[16]. Atypical hepatic venous to hepatic venous shunts can also form [20]. If a portosystemic
shunt is seen, however, this would imply the presence of cirrhosis [16].
There are several parenchymal and perfusion abnormalities on CT and MRI that are suggestive of congestive
hepatopathy. Noncontrast CT can demonstrate low attenuation adjacent to hepatic veins corresponding to edema
and fibrosis
[21]. This can also be seen on noncontrast MRI, which may also suggest peripheral distribution of
edema within the hepatic parenchyma. All of these findings are brought into better prominence with the addition
of intravenous contrast, usually best seen in the portal phase of enhancement
[20].
Chronic passive hepatic congesti on eventually leads to an increase in hepatic parenchymal stiffness
[22]. This
increase in stiffness can be detected by Mr elastography. Studies have demonstrated a correlation between liver
stiffness decreasing and clinical improvement of heart failure after diuretic therapy, pericardiectomy, or valve
replacement
[23]. In Mr elastography, congestio n in the liver is found to be heterogeneous, with the greatest areas
of stiffness occurring along the periphery of the liver
[24].
Pathologic findings
Congestive hepatopathy has been an entity on the minds of clinicians for at least two centuries; in 1833, British
anatomist Francis Kiernan coined the phrase “nutmeg liver” describing the gross pathologic description of the
liver in the setting of chronic congestion
[25]. As more studies of the pathologic changes seen in congestion began
to emerge, Frank Mallory more completely described the features of centrilobular necrosis in autopsy specimens
in 1901
[8]. This ushered in an era in the 20th century of significant advancement in the understanding of the
pathologic interplay between cardiac and hep atic disease. In many cases, the term “cardiac cirrhosis” had been
used to describe the findings of central-to-central or central-to-portal bridging fibrosis with nodularity seen in
congestive hepatopathy. However, this was likely owing to a less narrow definition of cirrhosis at the time. The
term “cardiac liver fibrosis” is more apt, owing to a difference in liver histology in cases of congestive hepatopa-
thy and true cirrhosis
[13].
Chronic heart failure leads to changes in the liver that result from downstream effects of chronic hepatic
venous outflow obstruction in the setting of congestion
[8]. On a histologic level, this manifests as centrilobular
congestion, sinusoidal dilatation, hepatocyte atrophy (especially centrilobular atrophy), and a spectrum of perive-
nular, perisinusoidal, and bridging fibrosis accompanied by regenerative hyperplasia emerging from periportal
areas
[8,26]. “Cardiac sclerosis” is a histopathologic term to describe fibrosis around centrilobular veins and
within perisinusoidal spaces
[27]. In the setting of late-stage congestive hepatopathy, extensive centrilobular
fibrosis can induce a ductular reaction in portal tracts as well as periportal fib rosis which can mimic biliary
obstruction
[28]. As we discuss in a later section, changes in the liver associated with chronic heart failure such
as those noted above can compound the effects of incoming ischemic or hypoxic injury, leading to entities such
as hypoxic hepatitis
[8].
Management
The mainstay of management of congestive hepatopathy is treating the underlying heart disease giving rise to
passive congestion and decreased forward flow. This can lead to an improvement in ascites and hepatic enzyme
elevation
[29].
From a pharmacologic perspective, ACE inhibitors, beta-blockade, and diuretics serve as the mainstay of man-
agement for heart failure and subsequently congestive hepatopathy. Unless contraindicated or not tolerated, ACE
inhibitors or ARBs along with beta-blockade are indicated for heart failure with reduced ejection fraction as per the
2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure
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[30]. Diuretics are recommended in patients with heart failure and with clinical signs or symptoms of volume over-
load
[31]. With appropriate diuretic therapy, jaundice, congestion, and ascites can respond dramatically [13].
In the setting of advanced liver disease, caution should be employed in the aggressive use of ACE inhibitors,
beta-blockers, and diuretics. In early, well-compensated cirrhosis, the reninangiotensinaldosterone system
does not appear to play an important role in maintaining the basal vascular tone
[32]. This suggests the adminis-
tration of ACE inhibitors in early liver disease may not have an outsized deleterious effect on the hemodynamics
of these patients
[33]. On the other hand, patients with decompensated cirrhosis demonstrate significant activa-
tion of the reninangiotensinaldosterone system in an effort to compensate for peripheral vasodilation seen in
this condition. In this setting, blockade of one of the main systems acting to maintain arterial pressure risks sig-
nificant deleterious effects on systemic and renal hemodynamics
[33]. Beta-blockers have a well-described role in
cirrhosis, significantly reducing the risk of variceal hemorrhage in patients with high-risk varices for primary
prophylaxis or reducing the risk of rebleed after hemorrhage event for secondary prophylaxis
[34]. However, in
more advanced cirrhosis, espe cially with refractory ascites, patients may be very dependent on the cardiac output
to maintain adequate systemic blood pressure and beta-blockers can decrease cardiac output
[35]. A French study
showed that in patients with refractory ascites, mortality was higher in patients on nonselective beta-blockers at
the time of presentation than those not on these agents
[36]. The significance of this finding is still up for debate,
and a subsequent study has even shown improved survival with the use of the nonselective beta-blocker carvedi-
lol in the setting of cirrhosis and small ascites
[37]. Thus beta-blocker use in advanced cirrhosis requires close
observation and care to avoid excessive arterial pressure decreases. Finally, diuretics also have a well-established
role in the management of volume overload in both heart failure and liver disease. Similar to ACE inhibitors and
beta-blockade, diuretics should be used with caution in heart failure with concomitant hepatic disease to avoid
dehydration and hypotension and in severe cases hepatic ischemia and hepatorenal syndrome
[29].
Prognosis
Prognosis in congestive hepatopathy is generally driven by the severity of the heart disease. While the liver
disease rarely contributes significantly to prognosis in these patients, elevated serum aminotransferases and
decreased serum albumin during admissions for acute decompensated heart failure are associated with poorer
long-term outcomes
[38]. Chronic hepatic congestion can lead to severe fibrosis and cirrhosis. In these patients,
significant decompensation such as variceal bleeding appears to be less common than in patients with cirrhosis
of alternative etiologies
[39]. Higher scores on measures of liver fibrosis in the setting of heart failure are also
associated with higher rates of all-cause mortality in patients with congestive hepatopathy
[40].
Summary
Passive liver congestion occurs as a result of several entities, all ostensibly involving right-sided heart failure.
Patients are normally asymptomatic at presentation, though they can present with symptomatic heart failure or
ascites. Management is centered around treating the underlying heart failure which can result in improvement in
ascites and resolution in aminotransferase elevations. The prognosis of passive liver congestion is dri ven by the
severity of the cardiac disease which precipitated it.
Hypoxic hepatitis
Diffuse liver injury around the central veins, also known as centrilobular necrosis, was noted by Bynum et al.
in 1979 as the pattern of necrosis seen in the liver in the setting of circulatory failure with a dramatic rise in ami-
notransferases
[41]. The clinical entity is often described as “shock liver” or “ischemic hepatitis” in the medical
literature; however, “hypoxic hepatitis” may be more descriptive for an amalgam of pathogenic mechanisms
[7].
In the setting of acute circulatory failure, hepatic ischemia is not the only pathogenic mechanism, but it is joined
by systemic blood flow reduction and passive congestion, which may predispose hepatocytes to more significant
hypoxic injury from hypotension
[7,42,43].
The diagnosis of hypoxic hepatitis can be defined by three criteria: (1) clinical setting resulting in reduced oxy-
gen delivery or utilization by the liver, (2) a significant and often transient increase in serum aminotransferase
levels; and (3) the exclusion of other potential causes of liver injury such as drug or virally induced hepatitis
[29,44] (Table 9.2).
126 9. Passive liver congestion and hypoxic hepatitis
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Mechanism of injury
Hypoxic hepatitis was conventionally thought to be the result of cardiogenic shock; however, evidence sug-
gests this is not the solely responsible event
[3,45]. In fact, patients with chronic passive liver congestion can
develop hypoxic hepatitis even in the setting of mild circulatory disturbances
[2]. In the setting of chronic passive
congestion, hepatocytes can compensate for diminished blood flow to the liver by upregulating oxygen extrac-
tion. This mechanism can reach a limit, however, resulting in hepatocellular hypoxia and necrosis when mild cir-
culatory disturbances occur in addition to chronic congestion
[46].
As noted previously, the liver has a robust blood supply derived from two sources: the portal venous and the
hepatic arterial systems. It is a buffer system to help prevent the precise injury sustained in hypoxic hepatitis.
The robust dual blood supply circuitry is the first line of defense against anoxic liver injury. In addition, the
hepatic sinusoids are remarkably permeable, which facilitates oxygen extraction to up to 90% efficiency
[47].
Finally, the liver is capable of releasing adenosine to dilate the hepatic vasculature to augment hepatic blood
flow in the setting of decreased cardiac output
[48].
While the pathophysiology of hypoxic hepatitis is multifactorial, the predominant mechanism can vary depend-
ing on the underlying condition
[44]. The likely primary contributory factor, and the most well-studied, is passive
congestion from right-sided heart failure. In one study, among patients with at least 15 minutes of systemic hypo-
tension, underlying organic heart disease (with 94% being right-sided heart failure) most commonly predicted the
development of hypoxic hepatitis
[43]. Subsequent studies corroborated these findings by demonstrating elevated
central venous pressures, reduced delivery of oxygen, and reduced hepatic blood flow in patients with hypoxic
hepatitis along with elevated mean pulmonary capillary wedge pressure and systemic vascular resistance
[42,44,45]. Thus, a precipitating decompensation in circulatory blood flow to the liver in the setting of chronic pas-
sive hepatic congestion can significantly predispose a patient toward the development of hypoxic hepatitis [46].
The same studies that demonstrated elevated central venous pressures in the setting of patients with hypoxic
hepatitis as a result of cardiac failure also suggested a second predisposing etiology at play in total body hypox-
emia. In cohorts of patients with chronic respiratory failure, average levels of arterial oxygen were very low
(3234 mmHg) in the setting of hypoxic hepatitis
[42,45]. As oxygen delivery is a function of not only cardiac out-
put but also oxygen saturation, the typically low arterial pressures of oxygen in chronic respiratory failure can pre-
dispose patients toward hypoxic liver damage in any setting with reduced blood flow to the liver
[44,49,50].
Another common setting for hypoxic hepatitis is septic shock
[51]. Here, the proposed mechanism for the
development of hypoxic hepatitis is not a failure in cardiac output or oxygen saturation (i.e., delivery), but rather
an inability for hepatocytes to extract and utilize the oxygen delivered to them
[44,52]. There is evidence to show
increased splanchnic blood flow—and, thus, increased oxygen delivery—in the setting of septic shock
[53].
However, the data also suggest that inflammatory mediators, particularly the systemic release of endotoxins,
impede the hepatocyte’s ability to extract oxygen from the blood
[54,55].
Finally, while the above mechanisms describe how impairments in cardiac output, oxygen saturation, and oxygen
extraction can all predispose to hypoxic hepatitis, oxygen deficiency may not be the only process capable of injuring
hepatocytes. Ischemia reperfusion injury is the paradoxical exacerbation of hypoxic cellular damage after the restora-
tion of oxygen delivery
[2]. In hepatocytes, ischemia reperfusion injury generally follows the development of reactive
oxygen species; we describe it in more detail in the section on pathologic findings of hypoxic hepatitis.
Clinical manifestations
Hypoxic hepatitis occurs most often in the elderly, with mean ages between 64 and 70 years old, in men, and
in those suffering from multiple medical comorbidities including heart failure and chronic respiratory failure
[42,45,56]. Hypoxic hepatitis is one of the leading causes of dramatic rises in serum aminotransferases in inten-
sive care units (ICU); the diagnosis manifests in two of every 1000 hospitalized patients and in 2.5 of every 100
TABLE 9.2 Criteria for diagnosing hypoxic hepatitis.
(1) Clinical setting resulting in reduced oxygen delivery or utilization by the liver.
(2) A significant and often transient increase in serum aminotransferase levels.
(3) The exclusion of other potential causes of liver injury such as drug or virally induced hepatitis.
Adapted from Henrion J, Schapira M, Luwaert R, Colin L, Delannoy A, Heller FR. Hypoxic hepatitis: clinical and hemodynamic study in 142 consecutive cases. Medicine.
2003;82(2003):392406.
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ICU patients [44,5658]. Other data suggest that even these estimates may be too conservative, and up to 10% of
all ICU patients receive a diagnosis of hypoxic hepatitis
[59].
In general, there are no specific clinical symptoms that refer to hypoxic hepatitis as the clinical course is usu-
ally asymptomatic
[7]. Some patients, however, can demonstrate symptoms consistent with other forms of hepati-
tis, including nausea, emesis, anorexia, malaise, right upper quadrant pain, and occasionally jaundice
[13].
Patients can present with changes in mental status, but these more often represent cerebral hypoperfusion and
hypoxia rather than hepatic encephalopathy, which is a rare presenting manifestation
[29,43,60].
As noted previously, an acute increase in serum aminotransferases is a hallmark criterion for hypoxic hepatitis
[39]. There is commonly a sharp elevation in alanine aminotransferase to 1020 times the upper limit of normal
followed by a greater than 50% decrease within 72 hours (assuming the precipitating factor has been removed)
[13]. There is often an even sharper initial increase in aspartate aminotransferase, which classically peaks at
around 24 hours prior to declining to a level lower than the alanine aminotransferase
[61].
An important factor that aids in differentiating hypoxic hepatitis from other causes of marked rises in ser um
aminotransferases, especially acute viral etiologies, is an increase in serum lactate dehydrogenase. While an early
rise in serum lactate dehydrogenase is characteristic of hypoxic hepatitis, it is unusual in the setting of viral hepa-
titis. The serum alanine aminotransferase to lactate dehydrogenase ratio being less than 1.5 also favors the diag-
nosis of hypoxic hepatitis and helps to differentiate this condition from acute viral hepatitis
[7,62,63].
In contrast to serum aminotransferases levels, markers of cholestasis do not normally play a prominent role in
hypoxic hepatitis. Alkaline phosphatase levels do not usually rise to greater than two times the upper limit of
normal. Serum bilirubin concentration normally tails after serum aminotransferase levels begin to decline and
rarely rises above four times the upper limit of normal
[13].
As for other markers of liver synthetic function, serum albumin level is not helpful in diagnosis and prognosis,
whereas serum international normalized ratio can be. Serum albumin is a negative acute phase reactant and may
be decreased in the setting of hypoxic hepatitis; however, there are several confounders that can also decrease
serum albumin, which diminishes its clinical significance
[64]. Coagulation markers can, however, accurately
indicate acute alterations in hepatic synthetic function, and elevation of the international normalized ratio to
above 1.5 is a diagnostic criterion for acute liver failure
[65]. Specifically, in patients with hypoxic hepatitis, an
international normalized ratio of greater than 2 is an independent risk factor for all-cause mortality
[7,66].
Imaging findings
Noninvasive imaging can support the diagnosis of hypoxic hepatitis. Abdominal ultrasonography can show
dilation of the inferior vena cava and suprahepatic veins due to passive congestion
[67]. Chest radiography may
reveal cardiomegaly, pulmonary vascular congestion, and pleu ral effusion
[68]. Echocardiography can frequently
demonstrate impaired systolic function and significant pulmonary arterial hypertension. Electrocardiograph y can
suggest underlying cardiac disease, including evidence of left-ventricular hypertrophy, conduction abnormalities,
atrial arrhythmias, or myocardial ischemia/infarction
[67]. More advanced cross-sectional imaging such as com-
puted tomography or magnetic resonance imaging is not required for the diagnosis of hypoxic hepatitis, but it
can assist in excluding other causes of hepatitis
[44].
An exciting avenue for further investigation is hepatic blood flow evaluation. One method is to measure galactose
clearance, as the liver metabolizes 90%95% of blood galactose
[69]. Unfortunately, this method gives accurate
results only if galactose extraction is complete at the first passage through the liver and when it is the only site of
elimination
[64]. Due to these limitations, galactose clearance is not a method used commonly in clinical practice [7].
Another method introduced for the study of hepatic function in the setting of acute hepatic injury and hypoxic hepa-
titis is the indocyanine green plasma disappearance rate
[70]. Indocyanine green is a cyanine dye used in multiple
medical diagnostic modalities, and its plasma disappearance rate is the quotient between indocyanine green extrac-
tion and clearance
[7]. The indocyanine green plasma disappearance rate holds promise for the assessment of hepatic
function in acute settings as the liver eliminates the dye nearly entirely into the bile without any enterohepatic reup-
take. Still, further studies are needed to confirm its clinical application in the setting of hypoxic hepatitis
[64].
Pathologic findings
The diagnosis of hypoxic hepatitis is clinical mainly based on the three criteria outlined previously. Liver
biopsy carries significant risk in acutely ill patients, especially those with significant coagulopathy. Nonetheless,
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a liver biopsy may be necessary when the diagnosis is unclear, such as when serum aminotransferase elevations
do not reach typical peaks
[71].
When a biopsy is performed, the typical pathological findings of hypoxic hepatitis include necrosis of the
hepatocytes in the area adjacent to the central vein (zone 3), also known as centrilobular hepatic necrosis. Zone 3
is particularly vulnerable to rapid shifts in circulatory blood flow as blood normally travels from the portal
region (zone 1) to the central vein, by which point the blood is relatively oxygen-deplete. Centrilobular hepatic
necrosis draws contrast histologically between hypoxic hepatitis and many other pri mary hepatic diseases that
tend to demonstrate more periportal or panlobular hepatic injury patterns
[68].
As discussed earlier, ischemia reperfusion injury to hepatocytes is possible after the restoration of oxygen
delivery. There is early activation of Kupffer cells followed by a late activation of polymorphonuclear cells (also
known as “neutrophilic hepatitis”). The result is excess intracellular calcium, the release of cytokines and chemo-
kines, oxidative stress from reactive oxygen species, mitochondrial damage, and disruption of hepatic microcircu-
lation
[2,72]. Histologically, the liver demonstrates centrilobular (zone 3) coagulative necrosis, which can
progress to involve zone 2 hepatocytes [8]. Nitric oxide may be protective against ischemia reperfusion injury to
hepatocytes
[73].
Management
The management of hypoxic hepatitis revolves around the correction of the underlying precipitating hemody-
namic disorders. Given the heterogeneity of predisposing conditions, this can present a clinical challenge. One
small study of 14 patients with hyp oxic hepatitis involved initiation of medical treatment of heart failure with
diuretics and inotropes along with vasodilators to optimize cardiac function and reduce elevated filling pres-
sures. Signs of cardiac failure resolved in all patients within a mean of 5 days, and aminotransferases returned to
normal within a mean of 7 to 10 days
[67].
No definitive data exist to support the routine use of inotropes in the setting of hypoxic hepatitis. One article
proposed dobutamine as a potential augment to hepatic splanchnic blood flow in patients with hypoxic hepatitis
after demonstrating its successful use in a patient with circulatory collapse following mitral valve replacement
[74]. In another small study of 10 patients, dopamine was shown to improve hepatic splanchnic blood flow; how-
ever, this study involved patients who did not have underlying chronic heart disease [75]. The generalizability of
either of these small studies to the broader population of patients with hypoxic hepatitis is likely limited.
One European study demonstrated a risk-adjusted positive treatment effect in hypoxic hepatitis using statin
therapy. In this study, 851 patients admitted consecutively to medical ICUs were assessed for the presence of
hypoxic hepatitis, and 87 met criteria (10%). Stratification on statin use before admission demonstrated that statin
therapy was associated with improved 28-day survival (albeit not 90-day or 1-year survival)
[76].
One treatment modality that has shown promise in other presentations of severe liver disease is N-
acetylcysteine. A 2009 prospective, double-blind study demonstrated that N-acetylcysteine administration in the
setting of nonacetaminophen etiologies of acute liver failure with mild encephalopathy improved transplant-free
survival
[77]. As the standard of care for all comers with acute liver failure has evolved to include N-
acetylcysteine, its efficacy in hypoxic hepatitis remains unestablished
[64]. Another experimental modality of
note is the molecular adsorbent recirculating system (MARS), which provides extracorporeal albumin dialysis to
target small hydrophobic molecules normally detoxified by a healthy liver
[44]. Again, we look to treatment in
acute liver failure as a proof of concept. A large, multicenter study examining the efficacy of MARS in acute liver
failure was unable to demonstrate a mortality benefit
[78]. However, a more recent study has shown improved
short-term survival of patients with acute-on-chronic liver failure and multiple organ failure, suggesting that
MARS treatment may bridge to hepatic recovery or eventual transplantation
[79]. Despite showing some promise
in treating acute liver failure, there remains insufficient evidence to support wide adoption of MARS across the
clinical spectrum. There are no data on MARS as a specific therapy for hypoxic hepatitis. Moreover, while hyp-
oxic liver injury can be severe, liver transplantation is rarely indicated or possible given the severity of predispos-
ing conditions
[80].
Prognosis
As hypoxic hepatitis often occurs in the setting of significant systemic disease, the prognosis is generally poor
[56]. In-hospital mortality has ranged from 51% to 59% in two separate pooled reviews [56,81]. In one study, worse
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prognosis was associated with higher (as well as prolonged time to) peak levels of serum aspartate aminotransfer-
ase, lactate, and lactate dehydrogenase
[82]. Eventual mortality is rarely due to liver failure in the setting of hypoxic
hepatitis; instead, morbidity and mortality are generally driven by underlying cardiovascular disease
[83].
Summary
Hypoxic hepatitis is a common and underrecognized etiology of acute liver injury in hospitalized (especially
ICU) patients. It manifests as marked aminotransferase elevations in states of reduced oxygen delivery or utiliza-
tion by the liver. Prompt recognition is vital but often challenging given missed, transient hypotensiv e episodes.
Indeed, one in two patients with hypoxic hepatitis will not be hypotensive at the time of presentation
[42,43].
Management centers around treating the underlying hemodynamic disorders. Unfortunately, the prognosis is
poor even with early diagnosis, with about half of patients with hypoxic hepatitis dying on initial
hospitalization.
Conclusion
Passive hepatic congestion is an often overlooked consequence of right heart failure. Similarly, hypoxic hepatitis
is an often overlooked diagnosis in the absence of an overt hypotensive event (which often goes undetected). Many
studies have identified congestive heart failure as a vital prerequisite to precipitate hypoxic hepatitis. These two
entities can thus be considered to be on a spectrum of liver disease occurring in the setting of right heart failure,
starting with mild passive hepatic congestion on one side and ending with hypoxic hepatitis on the other.
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132 9. Passive liver congestion and hypoxic hepatitis
II. Hepatobiliary system in heart failure
https://t.me/medicina_free
CHAPTER
10
Histopathology of the liver in heart failure
Paradis Vale
´
rie
Pathology Department, Beaujon Hospital, Paris University, Paris, France
Introduction
Liver parenchyma is highly sensitive to hypoxia and then may display significant damage in patients with
heart failure. According to the duration and severity of the heart disease, acute or chronic signs are recognize d.
In acute situations, liver pattern injuries, defining “shock liver” or “ischemic/hypoxic hepatitis (HH),” affect up
to 3% of patients in intensive care units, with a poor prognosis. HH is characterized by liver cell necrosis occur-
ring around centrilobular veins in the absence of other potential clinical conditions leading to liver cell necrosis,
particularly drug or viral-induced hepatitis. In addition to heart failure (accounting for more than 90% of cases of
HH), HH may be observed in patients with respiratory failure or septic toxic shock. The current diagnosis of HH
is based on a set of three criteria
[1] clinical states predisposing to HH [2], severe and transient increase in serum
transaminases, and [3] exclusion of other causes of centrilobular liver necrosis [1,2]. Accordingly, liver biopsy is
not mandatory for the diagnosis but remains indicated in cases of doubtful diagnosis
[3].
Natural history
Development of HH usually follows a stepw ise process in a patient suffering from cardiac or pulmonary defi-
ciency and facing an acute event as acute pulmonary edema, arrhythmia, respiratory distress, myocardial infarc-
tion, or sepsis
[14]. The natural course and outcome of patients with HH are multifactorial, depending on the
extent and duration of liver injury, as evaluated by transaminases serum levels and international normalized
ratio, and also on the underlying disease such as septic shock
[3]. Furthermore, HH may also promote aggrava-
tion of organ failure, especially lung and kidneys.
While serum transaminases (particularly aspartate aminotransferase) and lactate dehydrogenase dramatically
increase, with a peak at 24 hou rs, clinical signs of liver injury (painful hepatomegaly, hepatojugular reflux, and
ankle edema) are observed in approximately half of cases
[13]. In the follow-up, liver enzymes rapidly decrease,
returning to normal levels at 1015 days. Prothrombin activity decrease is early observed with a recovery after
1 week. Mild elevation in serum bilirubin is a common hallmark of HH
[1,2].
Pathological analysis
In patients with heart failure, two main patterns of liver injury may be observed depending on the chronicity
of the underlying clinical state predisposing to HH.
In an acute injury, histological analysis of liver of the patients with HH shows typical lesions of centrilobular necro-
sis of varying extent according to the severity of heart failure
[5]. Severe cases might lead to fulminant hepatic failure
[68]. The first description of this pattern of centrilobular necrosis was reported by Mallory from an autopsy series of
1190 cases
[9]. The necrotic zone, sharply demarcated, is characterized by coagulative liver cell necrosis, composed of
133
Cardio-Hepatology.
DOI:
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