Current Medical Research and Opinion

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Presentation and complications associated with

cirrhosis of the liver

Fred F. Poordad

To cite this article: Fred F. Poordad (2015) Presentation and complications associated
with cirrhosis of the liver, Current Medical Research and Opinion, 31:5, 925-937, DOI:
10.1185/03007995.2015.1021905

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0300-7995
doi:10.1185/03007995.2015.1021905
Review
Presentation and complications associated with
cirrhosis of the liver
Fred F. Poordad
The Texas Liver Institute, University of Texas Health
Science Center, San Antonio, TX, USA
Address for correspondence:
Fred F. Poordad, MD, Clinical Professor of Medicine,
The Texas Liver Institute, UT Health Science Center at
San Antonio, 607 Camden, Suite 101, San Antonio, TX
78215, USA.
Tel: 210-253-3426; Fax: 210-477-1808;
poordad@uthscsa.edu
Keywords:
Ascites – Hepatic encephalopathy – Portopulmonary
hypertension – Spontaneous bacterial peritonitis –
Hepatorenal syndrome – Varices – Variceal bleeding
Accepted: 18 February 2015; published online: 16 April 2015
Citation: Curr Med Res Opin 2015; 31:925–37
! 2015 Informa UK Ltd www.cmrojournal.com
Current Medical Research & Opinion Vol. 31, No. 5, 2015, 925–937
Article ST-0420.R1/1021905
All rights reserved: reproduction in whole or part not permitted
Abstract
Objective:
To provide an understanding of the detrimental impact of cirrhosis and its complications, strengths and
weaknesses of current treatment options for the management of these complications, and new
developments in this rapidly changing field.
Research design and methods:
Relevant publications were identified via PubMed and Cochrane databases, with additional references
obtained by reviewing bibliographies from selected articles.
Results:
Cirrhosis, a progressive liver disease, is characterized by fibrosis caused by chronic liver injury. Liver fibrosis
impairs hepatic function and causes structural changes that result in portal hypertension. Most patients with
cirrhosis remain asymptomatic until they develop decompensated cirrhosis. At this stage, patients
experience complications associated with portal hypertension (i.e., the abnormal increase in portal vein
pressure), including ascites, spontaneous bacterial peritonitis (SBP), hepatic encephalopathy (HE),
hepatorenal syndrome, portopulmonary hypertension, or variceal bleeding. In addition, intestinal
microbial translocation in patients with cirrhosis might also cause SBP and HE. Because the survival rate
for patients with cirrhosis substantially decreases once complications develop, the key goals in treating
patients with cirrhosis include both managing the underlying liver disease and preventing and treating
related complications. In patients with compensated cirrhosis, the management strategy is to prevent
variceal bleeding and other complications that can lead to decompensated cirrhosis. Patients with
decompensated cirrhosis are typically referred for liver transplantation, and the main focus of pre-
transplant management is to eliminate the cause of cirrhosis (e.g., excess alcohol consumption, hepatitis
virus) and prevent the recurrence of each decompensating complication.
Conclusions:
Although substantial progress has been made to prevent the complications and mortality associated with
cirrhosis, liver transplantation in combination with resolution of the etiology of cirrhosis remains the only
curative option for most patients. Emerging therapies such as anti-fibrotic agents hold promise in potentially
halting or reversing the progression of cirrhosis, even in patients with decompensated cirrhosis.
Introduction
Based on data from the Centers for Disease Control and Prevention (CDC)1,
chronic liver disease and cirrhosis are the 12th leading cause of death in the US.
However, the mortality associated with liver disease may be substantially higher
than the CDC estimate2. In 2010, chronic liver disease and cirrhosis accounted
for 31,903 deaths with an age-adjusted mortality rate of 9.4 per 100,000 indi-
viduals1. A study measuring burden of diseases in the US from 1990–2010
Complications associated with cirrhosis Poordad 925
Current Medical Research & Opinion Volume 31, Number 5 May 2015
estimated a higher number (49,500 in 2010) of deaths due
to cirrhosis and ranked cirrhosis 8th for the years of life lost
because of premature mortality3.
Cirrhosis is a progressive, end-stage liver disease in
which chronic injury to the liver leads to inflammation,
fibrosis, and scarring that converts normal liver architec-
ture to structurally abnormal nodules4. Alcohol abuse
and hepatitis C infection are the most common causes of
cirrhosis in the US; however, non-alcoholic fatty liver dis-
ease is also emerging as a common etiologic factor2,5.
Cirrhosis can be divided into compensated and decompen-
sated stages, with differentiating clinical features and
prognosis6. In the compensated stage, patients may
experience few or no symptoms because the liver is still
functioning sufficiently, even though it may contain
significant fibrotic tissue. The median survival of patients
with compensated liver disease is 6.5 years. With decom-
pensated cirrhosis, however, the liver is extensively
damaged and unable to function properly, and
patients in this stage will eventually develop serious life-
threatening complications. The median survival of
patients with decompensated cirrhosis is 2.5 years6.
Once a complication of cirrhosis develops, the 5-year
survival rate decreases to520%7. Therefore, the treatment
of patients with cirrhosis centers on preventing and
managing complications. This review will highlight the
symptoms, causes, diagnosis, treatment, and management
of major complications of cirrhosis.
Methods
Articles included in this review were identified by system-
atic searches of PubMed and the Cochrane database using
‘cirrhosis AND (‘ascites’ OR ‘hepatic encephalopathy’
OR ‘hepatopulmonary syndrome’ OR ‘hepatorenal syn-
drome’ OR ‘portal hypertension’ OR ‘portopulmonary
hypertension’ OR ‘small intestinal bacterial overgrowth’
OR ‘spontaneous bacterial peritonitis’ OR ‘variceal’ OR
‘variceal bleeding’)’, keywords for articles in English
performed in May 2014. In addition, recent review articles
and treatment guidelines were consulted for general infor-
mation on cirrhosis of the liver and its complications,
prevalence, etiology, and treatment options.
Bibliographies from included articles were reviewed for
additional relevant studies.
Cirrhosis
During chronic liver disease, hepatocyte cell death results
in inflammation that leads to fibrosis4,5. In addition, the
loss of functional hepatocytes results in the loss of liver
function, such as the ability to metabolize bilirubin and
synthesize proteins (e.g., albumin, clotting factors)5,8.
926 Complications associated with cirrhosis Poordad
Under normal conditions, blood flows from splanchnic
circulation (i.e., blood vessels in the gastrointestinal
tract, pancreas, and spleen) to hepatic circulation for the
removal of bacteria and toxins via the portal vein, and
blood is returned to systemic circulation via the hepatic
vein9. Because of fibrosis of the liver, the distortion of
hepatic architecture increases resistance to blood flow
that increases portal blood inflow, resulting in portal
hypertension (i.e., an abnormal increase in pressure
within the portal vein)4,10. Portal hypertension is further
aggravated by splanchnic vasodilation. The portal collat-
erals, which develop at the sites of communication
between portal and systemic circulation, relieve some of
the pressure in the portal system, but may themselves con-
tribute to cirrhosis-related complications such as varices11.
Portal hypertension is usually estimated by the hepatic
venous pressure gradient (HVPG) and is measured by cath-
eterization of a hepatic vein through the jugular vein11. In
healthy individuals, the HVPG ranges from 3–5 mm Hg.
In the compensated stage of cirrhosis, patients initially
have moderate portal hypertension (46 to 510 mm Hg)
with a low risk of decompensation12. However, as portal
hypertension progresses to clinically significant levels
(severe: HVPG of 10 mm Hg), the risk for developing
decompensated cirrhosis increases. Portal hypertension is
a key driver of many of the clinical consequences of
cirrhosis13–15. Development of varices and ascites are
direct complications of portal hypertension; however,
other complications of cirrhosis such as hepatic encephal-
opathy (HE) result from abnormalities in systemic
circulation due to portosystemic shunting. In addition,
intestinal microbial translocation, which stems from
increased intestinal permeability, small intestinal bacterial
overgrowth (SIBO), impaired immunity, and the migra-
tion of bacteria and bacterial endotoxin from the gut to the
lymph nodes and other organs have been implicated in
cirrhosis-related complications, such as spontaneous
bacterial peritonitis (SBP), variceal bleeding, and HE15.
Diagnosis and management
Cirrhosis is diagnosed by its characteristic findings on
clinical examination, laboratory tests, imaging, and histo-
logic examination via liver biopsy13,16. Laboratory
abnormalities in patients with chronic liver disease, such
as thrombocytopenia, increased serum total bilirubin, low
serum albumin, and an increased prothrombin inter-
national normalized ratio (INR), provide information on
the status of hepatic function. Imaging techniques are used
mostly to detect ascites, splenomegaly, hepatic or portal
vein thrombosis, liver surface nodularity, portal flow vel-
ocity, and hepatocellular carcinoma13. Liver biopsy has
long been regarded as the gold standard for diagnosing
cirrhosis, particularly in its early stages, when imaging is
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 Current Medical Research & Opinion Volume 31, Number 5 May 2015

normal or non-invasive measures are equivocal. In later

stages, or when non-invasive tests and imaging are consist- Hepatic encephalopathy

ent with cirrhosis, a biopsy is not necessary for diagnosis.

However, it may still have a role in diagnosing the under-
lying cause of cirrhosis, particularly in conditions of iron or
copper overload, or active alcohol liver disease. The diag-
nostic value of other non-invasive tests that assess liver
stiffness, such as transient elastography, acoustic radiation
force impulse imaging elastography, magnetic resonance Portopulmonary Variceal bleeding
elastography, shear wave elastography, controlled attenu- hypertension

ation parameter, endoscopy, and -fetoprotein, are being

investigated17 and may allow for delineation between asci- Liver damage
tes of cirrhotic vs non-cirrhotic origin18. Once diagnosed,
the severity of cirrhosis is commonly classified with Child- Hepatorenal
syndrome
Turcotte-Pugh (CTP) scores, which are used to evaluate Ascites
the prognosis19,20. Divided into classes A, B, and C, and and peritonitis

noting increasing severity, the CTP scoring system incorp-

Figure 1. Schematic representation of the common complications of
orates the degrees of HE and ascites and the results from cirrhosis.
liver function blood tests (e.g., bilirubin excretion, albu-
min synthesis, and production of clotting factors measured
by prothrombin time or INR)19. Model for End-Stage Liver Stage 1 No Varices
No Ascites
1.0%

Disease (MELD) is another scoring system, which has

Compensated 4.4% 7.0%
eliminated the subjective clinical parameters, and is used
to assess patients for liver transplantation; it is based on Varices
serum bilirubin level, serum creatinine level, and INR21. Stage 2
No Ascites
3.4%

The goals for the management of cirrhosis primarily

6.6% Death
depend on the compensation status of the liver16.
Managing compensated cirrhosis involves both the treat- Ascites ±
Stage 3 20.0%
ment of the etiology of the underlying liver disease and the Varices

early diagnosis or prevention of cirrhosis-associated com- Decompensated 4.0% 7.6%

plications. (Treating the underlying etiology is beyond the
scope of this review article and is extensively reviewed
elsewhere22–24.) Managing decompensated cirrhosis
mainly focuses on treating the complications associated
with cirrhosis and helping to maintain patient quality-
of-life.
Major complications of cirrhosis
Up to 40% of patients with cirrhosis may be asymptomatic
for long periods; however, once complications develop,
progressive deterioration that leads to liver transplantation
or death is typical in these patients25,26. In the US, serious
complications of cirrhosis cause4150 000 hospitalizations
and cost $4 billion annually (2005 dollars)26. Major com-
plications of cirrhosis include variceal bleeding, ascites,
peritonitis, hepatorenal syndrome (HRS), portopulmonary
hypertension (PPH), and HE (Figure 1). Based on data
from two large, natural-history studies (n ¼ 1649 patients),
some investigators have proposed four clinical stages
(or statuses) of cirrhosis that are defined by the presence
or absence of complications and different prognoses
(compensated cirrhosis [stages 1 and 2]; decompensated
cirrhosis [stages 3 and 4]; Figure 2)27: stage 1, absence of
varices and ascites with a 1-year mortality of 1%; stage 2,
Stage 4
Bleeding ±
57.0%
Ascites
Figure 2. Clinical course of cirrhosis with 1-year mortality rates, based on
the clinical stage. Reprinted with permission from D’Amico et al.27.
presence of varices without bleeding or ascites with a
1-year mortality of 3.4%; stage 3, presence of ascites with
or without varices in patients without gastrointestinal
bleeding with a 1-year mortality of 20%; and stage 4,
gastrointestinal bleeding with or without ascites with a
1-year mortality of 57%.
Varices and variceal bleeding
Varices are varicose veins in the esophagus or stomach
that result from portal hypertension14. Gastroesophageal
varices are present in nearly 50% of patients with cirrhosis,
and their presence correlates with portal hypertension
severity16. The formation of gastroesophageal varices in
patients with cirrhosis is triggered by the development
of portosystemic collaterals, and the risk of developing
gastroesophageal varices is higher when the HVPG is
10 mm Hg12,28. Gastric varices are less prevalent than

! 2015 Informa UK Ltd www.cmrojournal.com Complications associated with cirrhosis Poordad 927
Current Medical Research & Opinion Volume 31, Number 5 May 2015
esophageal varices and are present in 20% of patients with
cirrhosis and portal hypertension11.
Variceal bleeding is one of the most serious complica-
tions of cirrhosis and is associated with substantial
mortality29. However, recent advances in the prevention
and management of variceal bleeding have decreased the
incidence of mortality associated with this complication.
In these patients, bacterial infection may act as a trigger
for variceal bleeding and varices by increasing portal
hypertension via cytokine or bacterial byproduct effects
on the vasculature, impairing clotting, and decreasing
endogenous heparinoids15. Variceal bleeding, in turn,
may pre-dispose these patients to further infection, creat-
ing a vicious cycle that substantially impacts mortality.
Variceal size is the most important predictor of variceal
bleeding, with the highest rates of first hemorrhage occur-
ring in patients with large varices (15% per year)10. Other
prognostic factors for variceal bleeding in patients with
cirrhosis include the severity of cirrhosis (CTP classes B
and C) and presence of red wale marks detected by endos-
copy. Although varices may develop when the HVPG
is 10 mm Hg, an HVPG of 12 mm Hg is generally
observed with variceal bleeding12,29,30. An HVPG of
20 mm Hg predicts both failure to control bleeding
and increased mortality in patients with acute variceal
bleeding29. Therefore, monitoring HVPG changes in
patients with cirrhosis provides predictive information
about the risk of developing varices and variceal bleeding.
Diagnosis and management
Esophagogastroduodenoscopy (EGD) is the gold standard
for diagnosing varices and variceal bleeding (Table 1)14.
Based on EGD, varices are classified as either small
(5-mm diameter) or large (45-mm diameter). With
Table 1. Symptoms, diagnosis, and treatment of patients with varices and variceal bleeding14.
Parameter
Symptoms
Diagnostic method
Current treatment
EVL, endoscopic variceal ligation; NSBB, non-selective beta blockers; TIPS, transjugular intra-hepatic portosystemic shunting.
Data from Garcia-Tsao et al.14.
928 Complications associated with cirrhosis Poordad
respect to varices, practice guidelines developed by the
American College of Gastroenterology (ACG) and the
American Association for the Study of Liver Diseases
(AASLD) recommend treating patients with cirrhosis
and portal hypertension based on the stage of portal
hypertension14. Although there are no treatment
recommendations for patients with cirrhosis and portal
hypertension to prevent the development of varices
for those that have not developed varices, the guidelines
recommend monitoring patients by EGD every 2–3 years
(Figure 3)14,31. For patients with non-bleeding varices,
monitoring by EGD should be more frequent (every 1–2
years). In addition, guidelines recommend prophylactic
treatment in patients at increased risk of hemorrhage to
prevent both the growth of small varices and the first epi-
sode of variceal bleeding. Treatment depends on the size of
the varices and the presence of risk factors, such as the
presence of red wale signs on varices and CTP classifica-
tion of B or C14. Non-selective beta blockers (NSBB) such
as propranolol and nadolol are recommended as primary
prophylaxis for variceal bleeding for both small and large
varices. In addition, for patients with large varices, treat-
ment with endoscopic variceal ligation (EVL) is another
option to prevent variceal bleeding and is typically
selected based on either patient preference or intolerance
to NSBB14,32,33.
Acute variceal bleeding is an emergency situation and
requires prompt care to achieve hemodynamic stability
and to avoid bacterial infection; short-term antibiotic
prophylaxis should be initiated14. In addition, pharmaco-
logic therapy with a vasoconstrictor agent such as
somatostatin (or its analogs octreotide and vapreotide)
should be initiated as soon as variceal bleeding is suspected
and should be continued for 3–5 days after the diagnosis is
Characteristics
Non-bleeding varices are generally asymptomatic
Symptoms associated with variceal bleeding can be:
– Passage of black or bloody stools, light-headedness
Esophagogastroduodenoscopy
Primary bleeding prophylaxis in patients with varices
– NSBB (propranolol and nadolol)
– EVL
Variceal bleeding
– Short-term broad-spectrum antibiotic prophylaxis
– Vasopressin and its analogs, terlipressin, somatostatin and its analogs
– EVL or sclerotherapy
– Shunts (TIPS)
– Balloon tamponade to temporarily stop bleeding
Prevention of additional bleeding events in patients surviving variceal bleeding
– NSBB
– EVL
– TIPS
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 Current Medical Research & Opinion Volume 31, Number 5 May 2015

EGD at diagnosis
of cirrhosis

Small varices Large varices

No varices
(≤5 mm) (>5 mm)

Repeat EGD in Low risk High risk NSBB therapy†

2–3 years of bleeding of bleeding* or EVL‡

NSBB therapy
is optional† NSBB therapy†

Figure 3. Management of patients with cirrhosis after results of screening EGD. *Higher risk of bleeding is based on CTP class B and C or presence of varices
with red signs. yNo need of repeat EGD if treated with NSBB. zEVL every 1–2 weeks until obliteration, first surveillance EGD 1–3 months after obliteration,
then every 6–12 months indefinitely. CTP, Child-Turcotte-Pugh; EGD, esophagogastroduodenoscopy; EVL, endoscopic variceal ligation; NSBB, non-selective
beta blockers. Adapted with permission from Cesario et al.31. Data from Garcia-Tsao et al.14.

confirmed by EGD. Endoscopic therapy via EVL (prefer-
ably) or sclerotherapy should be performed within 12 h of
bleeding diagnosis14. Shunt therapy such as transjugular
intra-hepatic portosystemic shunting (TIPS; a shunt
between portal and hepatic veins designed to reduce the
portal pressure) is indicated in patients who have uncon-
trolled bleeding despite pharmacologic and endoscopic
therapies34. In patients with advanced cirrhosis (CTP
classes B and C) and variceal bleeding who are at a high
risk of treatment failure and death, early use of TIPS was
shown to be efficacious in reducing the risks of failure to
control bleeding and variceal re-bleeding35. In addition,
for patients with uncontrolled bleeding, a balloon tampon-
ade can be used to temporarily stop the bleeding until
endoscopic or shunt therapy is performed.
Because patients surviving the first variceal bleeding
event are at a higher risk of bleeding recurrence, the
prevention of additional episodes (i.e., secondary prophy-
laxis) of variceal bleeding should be considered14. In
patients who do not undergo a TIPS procedure for the
first episode of variceal bleeding, prophylaxis with NSBB
should be started before discharge from the hospital. To
prevent additional variceal bleeding events, EVL therapy,
which is superior to sclerotherapy, should be repeated
every 7–14 days until variceal obliteration. Of note,
the combination of an endoscopic procedure with pharma-
cologic therapy is considered superior to either modality
alone29. Although TIPS was shown to be more effective
than pharmacologic therapies in preventing re-bleeding,
it has been associated with higher costs and increased
risk of HE14.
Ascites
Ascites is defined as the presence of excessive fluid in
the peritoneal cavity36. Portal hypertension causes
splanchnic vasodilation and activation of the renin-
angiotensin-aldosterone system, which results in renal
sodium and water retention37. Ascites is the most
common complication of cirrhosis, with 50% of patients
with compensated cirrhosis developing ascites within 10
years of a diagnosis of cirrhosis7,36,38. The development of
ascites in a patient with cirrhosis marks disease progression
to a decompensated stage of cirrhosis, and mortality in
these patients is estimated to be 50% within 2 years36,38.
Therefore, many of these patients are considered
candidates for liver transplantation. In addition, refractory
ascites, defined as ascites resistant to medical therapy39,
develops in520% of patients with ascites and is associated
with a high 1-year mortality rate (50%)11.
Diagnosis and management
Findings upon physical examination, such as a bulging
abdomen and a shifting of the dullness in sound upon per-
cussing the abdomen when the patient shifts from a supine
to a lateral position, may be helpful in the diagnosis of
ascites (Table 2)36,38,40. For diagnosis of lower severity
of ascites, abdominal ultrasound can be used if 100 mL
of peritoneal fluid is present41. The cause of ascites can be
diagnosed by abdominal paracentesis followed by ascitic
fluid analysis40. Evaluating ascitic fluid for cell count
with differential, total protein, and serum ascites albumin
gradient (SAAG, obtained by subtracting the ascitic albu-
min concentration from the serum albumin concentration
obtained on the same day) allows for a differential diagno-
sis of ascites related to cirrhosis. A SAAG value of
1100 mg/dL is an indication of portal hypertension11.
Management of ascites depends on the severity of ascites.
The ACG and AASLD practice guidelines consider
sodium restriction (52000 mg/day) as the mainstay of ther-
apy for mild-to-moderate ascites40. Combination therapy
with spironolactone 100 mg/day, an aldosterone

! 2015 Informa UK Ltd www.cmrojournal.com Complications associated with cirrhosis Poordad 929
Current Medical Research & Opinion Volume 31, Number 5 May 2015
Table 2. Symptoms, diagnosis, and treatment of patients with
ascites36,38,40.
Parameter Characteristics
Symptoms Abdominal distension, nausea, vomiting, early
satiety, dyspnea, and lower extremity
edema
Bulging flanks and shifting dullness in sound
upon percussing the abdomen when the
patient is shifted from supine to the side
position
Diagnostic method Abdominal ultrasound
Abdominal paracentesis with ascitic fluid
analysis
Current treatment Sodium restriction (limit, 2000 mg/day)
Use of diuretics (spironolactone, amiloride,
furosemide)
Large-volume paracentesis
Shunts (TIPS, peritoneovenous)
TIPS, transjugular intrahepatic portosystemic shunting.
Data from Gordon36; Perri38; and Runyon40.
antagonist, and furosemide 40 mg/day is recommended as
first-line diuretic therapy36. Co-administration of these
agents reduces the risk of adverse effects by avoiding the
use of high doses of either diuretic. This combination diur-
etic dose may be titrated upward in a stepwise manner by
maintaining a ratio of spironolactone to furosemide of
100:40, to a maximum dose ratio of 400 mg/day to
160 mg/day, respectively36. If patients develop painful
gynecomastia or significant hyperkalemia with spironolac-
tone therapy, amiloride, a potassium-sparing diuretic, can
be substituted for spironolactone; however, this option has
been shown to be less effective at up to 20 mg/day42.
In patients with ascites that is refractory to diuretics,
diuretic therapy should be discontinued and large-volume
paracentesis should be considered11. Large-volume para-
centesis with up to 5 L of fluid withdrawn at one time is
recommended40. If 45 L of fluid needs to be extracted,
intravenous administration of plasma expanders (e.g.,
albumin) is recommended. Many studies have shown the
efficaciousness of TIPS vs large-volume paracentesis for
managing refractory ascites; however, HE, another com-
plication of cirrhosis, occurred more often with the TIPS
procedure43. One common approach in treating patients
with refractory ascites is to consider TIPS only if patients
require 41 large-volume paracentesis procedure per
month. Because of poor long-term patency, the risk of
complications, and no improvement in survival rate, the
use of peritoneovenous shunts are reserved for patients
who are not candidates for paracentesis, TIPS, or liver
transplant40. More recent data have suggested that early
prophylactic TIPS for refractory ascites may offer a survival
benefit44. Further assessment of this concept will be
required to see if this benefit outweighs the risks of use of
TIPS with this advanced disease population. The
Automated Low-Flow Ascites Pump system
930 Complications associated with cirrhosis Poordad
(ALFApumpÕ ; Sequana Medical AG, Switzerland),
which shunts fluid from the peritoneal cavity to the blad-
der, has arisen as a possible alternative to large volume
paracentesis or TIPS; clinical studies evaluating this new
technology vs standard techniques (e.g., TIPS) are
ongoing45.
Spontaneous bacterial peritonitis
SBP, a secondary complication of ascites, is the develop-
ment of bacterial infection of the ascitic fluid in the
absence of an intra-abdominal source of infection15,46.
Several factors are thought to contribute to the develop-
ment of SBP in patients with cirrhosis and ascites,
including intra-hepatic shunting of infected blood or
prolonged bacteremia related to compromised host
defenses46. SIBO also is implicated in the development
of SBP in patients with cirrhosis and ascites15,47. SBP is
observed in 12% of patients hospitalized with ascites, and
there is a 20% mortality rate among patients with SBP,
despite early diagnosis and prompt treatment48. Therefore,
SBP prophylaxis in patients with ascites is recommended
in high-risk patients (e.g., patients with gastrointestinal
bleeding)37. The three most common pathogens identified
are Escherichia coli, Klebsiella pneumoniae, and Streptococcus
pneumoniae40.
Diagnosis and management
In patients with cirrhosis and ascites, new-onset fever,
abdominal pain, HE, or other signs and symptoms of infec-
tion warrant prompt investigation for SBP. Diagnosis of
SBP involves analyzing the ascitic fluid after abdominal
paracentesis for a high polymorphonuclear cell count
(250 cells/mL) and the absence of an intra-abdominal
and surgically treatable source of sepsis (Table 3)37,40.
Because a polymorphonuclear cell count in ascitic fluid
can be obtained rapidly, this helps determine the need
for empiric antibiotic therapy before results from the
ascitic bacterial culture may be available.
The AASLD practice guidelines recommend
administration of broad-spectrum antibiotics, with third-
generation cephalosporins (e.g., intravenous cefotaxime or
ceftriaxone) as the treatment of choice40. However, use of
broad-spectrum antibiotics in nosocomial settings may
lead to multi-resistant infections40. In such cases, it may
be prudent to select the antibiotic therapy based on local
bacterial susceptibility testing. In patients without emesis,
oral fluoroquinolones may also be administered46.
Albumin may be administered in combination with
antibiotics in patients at high risk of renal failure (serum
creatinine 41 mg/dL, blood urea nitrogen 430 mg/dL, or
total bilirubin44 mg/dL)40. This recommendation is based
on studies that showed that only patients at high risk
of renal failure benefited from albumin infusion in the
www.cmrojournal.com ! 2015 Informa UK Ltd

Table 3. Symptoms, diagnosis, and treatment of patients with SBP37,40.
Parameter Characteristics
Symptoms Fever, abdominal pain or tenderness, enceph-
alopathy, renal failure, acidosis, or peripheral
leukocytosis
Diagnostic method Ascitic fluid (obtained by paracentesis) absolute
polymorphonuclear cell count 250 cells/mL
Current treatment Intravenous antibiotics (third-generation ceph-
alosporin [cefotaxime, ceftriaxone], ampicil-
lin/tobramycin and fluoroquinolones) or oral
antibiotics (fluoroquinolones)
Intravenous albumin in combination with anti-
biotics
Antibiotic prophylaxis in high-risk patientsa
a nostic criteria of HRS include serum creatinine levels
Patients with gastrointestinal bleeding, history of SBP, or low protein level
in the ascitic fluid.
SBP, spontaneous bacterial peritonitis.
Data from Hsu and Huang37; and Runyon40.
treatment of SBP49,50. Antibiotic prophylaxis should be
considered in high-risk patients (e.g., patients with gastro-
intestinal bleeding, a history of SBP, or low total protein
level in the ascitic fluid [51500 mg/dL])36,39. Patients with
cirrhosis and ascites who have been treated for an episode
of SBP should receive long-term prophylaxis with nor-
floxacin or trimethoprim/sulfamethoxazole36. Among
emerging therapies, rifaximin, a minimally absorbed anti-
microbial, has been shown to reduce the risk of SBP in
patients with cirrhosis and ascites51–53.
Hepatorenal syndrome
Although patients with advanced cirrhosis awaiting
liver transplantation are pre-disposed to many serious
complications, HRS, another secondary complication of
ascites, is one of the most challenging complications in
terms of its limited therapeutic options and its association
with significant morbidity and mortality both pre- and
post-liver transplantation54. The alteration in systemic cir-
culation associated with portal hypertension leads to renal
vasoconstriction and results in water and sodium retention
and a reduced glomerular filtration rate (Figure 4)55,56.
HRS is functional renal failure with the absence of histo-
logic changes in the kidney and is considered a potentially
reversible condition. HRS usually develops during the ter-
minal stages of cirrhosis because the systemic circulatory
function deteriorates and is not able to compensate for the
hypovolemia caused by splanchnic storage of blood. The
incidence of HRS in patients with cirrhosis and ascites
is 8% and is associated with poor prognosis57.
There are two types of HRS57. Type 1 is characterized
by rapidly declining renal function (i.e., doubling of initial
serum creatinine to a level42.5 mg/dL in a 2-week period)
and patients have a median survival of 2 weeks (i.e., mor-
tality rate of 50% at51 month). Type 2 is characterized by
steady decline in renal function and is associated with
! 2015 Informa UK Ltd www.cmrojournal.com
Current Medical Research & Opinion Volume 31, Number 5 May 2015
advanced cirrhosis; patients have a median survival of 6
months (i.e., mortality rate of 50% at 6 months). In many
cases, longstanding type 2 HRS leads to irreversible renal
injury from acute tubular necrosis, and patients
awaiting liver transplantation often require dual liver
and kidney transplantation when HRS has led to this
secondary injury.
Diagnosis and management
Because of the lack of specific diagnostic markers, a diag-
nosis of HRS is made based on the exclusion of other
causes of renal failure in patients with cirrhosis58. Key diag-
(41.5 mg/dL) and the presence of ascites (Table 4)40,58.
Indeed, lack of large-volume or treatment-refractory asci-
tes makes the diagnosis of HRS unlikely, and other causes
of renal insufficiency should be sought.
The AASLD guidelines recommend that patients with
type 1 or type 2 be referred for expedited liver transplan-
tation40. Liver transplant is the only curative option for
patients with HRS; however, several pharmacologic agents
that improve renal function provide reasonable options as
supportive therapy until liver transplantation. The guide-
lines recommend albumin infusion along with administra-
tion of vasoactive drugs (e.g., octreotide and midodrine)
for the treatment of type 1 HRS. Treatment with octreo-
tide, midodrine, and albumin in combination significantly
improved short-term survival and renal function in
patients with HRS59. For patients undergoing dialysis for
8 weeks before liver transplantation, kidney transplant-
ation is usually necessary40.
Among the newer treatment options for HRS, terlipres-
sin has been extensively investigated60. Although widely
used in Europe for HRS, terlipressin is not approved in the
US. A meta-analysis of studies with terlipressin for patients
with HRS demonstrated that terlipressin in combination
with albumin infusion was effective in the reversal of HRS
and reduced mortality compared with either albumin
infusion alone or no treatment61.
Portopulmonary hypertension
Pulmonary arterial hypertension, which is an increase in
the resistance to pulmonary arterial pressure because of
portal hypertension, is referred to as PPH62. Although
patients with PPH have more favorable hemodynamics,
mortality rates for these patients are higher
compared with patients with idiopathic pulmonary arterial
hypertension63. PPH is observed in 1–2% of patients with
cirrhosis64. One-year survival of patients with PPH
is 35% without treatment65. Patients with moderate-
to-severe PPH have poor prognoses and are often ineligible
for liver transplantation64. The pathophysiology of PPH is
unclear; however, it is unrelated to the etiology of the
underlying liver disease.
Complications associated with cirrhosis Poordad 931
Current Medical Research & Opinion Volume 31, Number 5 May 2015

Compensated Cirrhosis Decompensated Cirrhosis

Increased intrahepatic Disease progression

vascular resistance Several portal hypertension
Moderate portal hypertension Bacterial translocation

Splanchnic arterial Severe splanchnic

vasodilatation arterial vasodilatation

Markedly reduced effective

arterial blood volume
Increased cardiac output and
Low effective arterial plasma volume insufficient to
blood volume normalize effective arterial
blood volume
Activation of sodium-retaining
and vasoconstrictor systems

Increased cardiac output Sodium and water retention

Increased plasma volume and ascites formation

Further activation of
vasoconstrictor systems
Impairment in cardiac output

Restoration of effective
arterial blood volume Renal failure

Figure 4. Pathogenesis of circulatory abnormalities in compensated and hepatorenal syndrome. Reprinted with permission from Ginès and Schrier56.

Diagnosis and management If there is inadequate response to these medications,

Clinical symptoms of PPH may be subtle or even absent;
however exertional dyspnea may be a presenting feature in
some patients62. Diagnosis is accomplished by echocardio-
gram that detects an increase in right ventricular systolic
pressure or right ventricular dysfunction (Table 5)62,64.
Routine echocardiogram screening for patients undergoing
liver transplantation is recommended in AASLD practice
guidelines to rule out PPH62. Untreated or undiagnosed
PPH is a risk factor for perioperative morbidity and
mortality, and, therefore, is a contraindication for liver
transplantation. Diagnosis of PPH is typically confirmed
by right-heart catheterization64.
Therapies for PPH are mostly based on treatment
options evaluated for idiopathic pulmonary arterial hyper-
tension. For patients with more favorable hemodynamics,
right ventricular function, and liver status, oral
medications such as endothelin receptor antagonists
(e.g., bosentan, ambrisentan) or phosphodiesterase inhibi-
tors (e.g., sildenafil, tadalafil) are usually administered62.
aggressive infusion therapies with prostanoids are con-
sidered. For example, parenteral prostanoid therapy is
administered to patients with more severe PPH.
Improvement of PPH often allows for liver transplan-
tation, whereas a lack of response indicates irreversible
vascular changes and poor peri-transplant outcomes.
Hepatic encephalopathy
HE is a complication of cirrhosis associated with neuro-
psychiatric symptoms and neuromuscular dysfunction of
varying severity66. Synaptic transmission inhibition in
the brain, which is an effect of hyperammonemia, has
been shown to be the effect of glutamine depletion67.
Beyond this, the exact mechanism of HE has not been
elucidated. In acute liver failure, cerebral edema is well
described. However, in chronic liver disease and HE, it
remains hypothetical. Some investigators have postulated
that the combined action of the accumulation of gut-

932 Complications associated with cirrhosis Poordad www.cmrojournal.com ! 2015 Informa UK Ltd

Table 4. Symptoms, diagnosis, and treatment of patients with HRS40,58.
Parameter Characteristics
Symptoms Dilution hyponatremia and arterial
hypotension
Diagnostic methods Major diagnostic criteria
– Cirrhosis with ascites
– Serum creatinine 41.5 mg/dL
– No improvement of serum creatinine to
1.5 mg/dL after 2 days of diuretic
withdrawal or volume expansion with
albumin
– Absence of shock (hypovolemic or
septic)
– No current or recent treatment of
nephrotoxic drugs
– Absence of parenchymal kidney disease
Type 1: rapid decline in renal function (dou-
bling of initial serum creatinine to a level
42.5 mg/dL within 2 weeks)
Type 2: progressive decline in renal function
Current treatment Aggressive expansion of intravascular volume
with albumin and fresh frozen plasma with
vasoactive drugs such as vasopressin
analogs (e.g., terlipressin) and alpha-
adrenergic agonists (e.g., midodrine)
TIPS
Liver transplantation
Renal replacement therapy
HRS, hepatorenal syndrome; TIPS, transjugular intrahepatic portosystemic
shunting.
Data from Runyon40; and Ginès et al.58.
Table 5. Symptoms, diagnosis, and treatment of patients with PPH62,64.
Parameter Characteristics
Symptoms Dyspnea
Diagnostic methods Echocardiography
Right-heart catheterization
Current treatment Endothelin receptor antagonists
(bosentan, ambrisentan)
PDE-5 inhibitors (sildenafil, tadalafil)
Prostanoids (epoprostenol, treprostinil, iloprost)
Liver transplantation
PDE, phosphodiesterase; PPH, portopulmonary hypertension.
Data from Safdar et al.62; and Mancuso et al.64.
derived bacterial toxins, bacterial translocation, inflam-
mation, and oxidative stress might cause cerebral edema,
thus contributing to the pathogenesis of HE68,69. In
patients with chronic liver disease, the development of
HE has also been shown to be the second most important
independent predictor of mortality (second to active alco-
holism in alcoholic liver disease) during a 1-year follow-
up, with a hazard ratio greater than that for the MELD
score (2.16 vs 1.09; p50.0001)70. There is about a 15%
mortality rate among hospitalized patients with cirrhosis
and overt HE71. Patients with HE present a wide variety of
signs and symptoms and are classified with minimal HE
(i.e., subtle alteration in cognitive function as assessed by
! 2015 Informa UK Ltd www.cmrojournal.com
Current Medical Research & Opinion Volume 31, Number 5 May 2015
neuropsychometric tests) or overt HE (i.e., generalized
motor dysfunction with alteration in consciousness and
asterixis)72–74. Minimal HE occurs in up to 70% of patients
with cirrhosis and is difficult to diagnose73. Although
patients with minimal HE are clinically asymptomatic,
minimal HE has a significant impact on patient quality-
of-life and daily functioning, such as an increased risk of
falls and poor driving performance73,75,76. Among patients
with cirrhosis, there is also a higher prevalence of SIBO
in patients with minimal HE compared with patients with-
out minimal HE77. Overt HE is observed in 30–45%
of patients with cirrhosis and is often characterized
by symptomatic episodes followed by periods of
remission78,79.
Diagnosis and management
Neuropsychometric tests for minimal HE include pencil-
and-paper and computerized tests to evaluate cognitive
functions such as vigilance and sustained attention,
orientation, alertness, reaction times, and psychomotor
speed (Table 6)72–74. Clinical tests for diagnosing overt
HE include West Haven Criteria (Conn score), Glasgow
Coma scale, HE Scoring Algorithm, and Mini-Mental
State Examination. Neuropsychologic tests include the
Portosystemic-Encephalopathy-Syndrome test and the
critical flicker frequency test.
The treatment of patients with overt HE is directed
toward reducing the gut-derived factors that can contrib-
ute to the development of HE72. The AASLD/European
Association for the Study of the Liver (EASL) practice
guidelines recommend treatment with non-absorbable
disaccharides (e.g., lactulose) followed by prophylactic
therapy with non-absorbable disaccharides in combination
with antibiotics (e.g., rifaximin)80. Non-absorbable disac-
charides increase excretion of gut-derived toxins (e.g.,
ammonia) through cathartic effects and by reducing colo-
nic pH81,82. Minimally absorbed antibiotics (e.g., rifaxi-
min) modulate the gut microbiota, including a reduction
in gut-derived toxin production by enteric bacteria.
Patients with a history of HE may benefit from long-term
maintenance therapy to prevent HE recurrence83.
Lactulose and rifaximin are efficacious as long-term
prophylaxis against HE recurrence in patients with
cirrhosis and are recommended for the prevention of HE
recurrence by the AASLD/EASL guidelines79,80,84–87;
however, lactulose therapy for HE prevention is often lim-
ited by gastrointestinal adverse events that can lead to
non-adherence to therapy88. Because rifaximin is minimal-
ly absorbed and has a low risk for the development of
bacterial antibiotic resistance in the clinic, it may not
confer the same risks as those associated with conventional
systemic antibiotics and, therefore, is suitable for long-
term HE management. Given the difficulty in diagnosing
minimal HE, patients might not be treated unless the
Complications associated with cirrhosis Poordad 933
Current Medical Research & Opinion Volume 31, Number 5 May 2015
Table 6. Symptoms, diagnosis, and treatment of patients with HE72–74.
) ligand (pioglitazone), an antiviral
Parameter Characteristics
Symptoms Mild cognitive deficits detectable with
psychometric testing to an increasingly
severe spectrum of neurologic and
neuropsychiatric signs and symptoms
Asterixis
Diagnosis and grading Diagnostic tests for minimal HE
– Neuropsychometric tests: pencil and paper
and computerized tests to evaluate
cognitive functions such as vigilance and
sustained attention, orientation, alertness,
reaction times, and psychomotor speed
Diagnostic tests for overt HE
– Clinical tests: West Haven Criteria (Conn
score), Glasgow Coma scale, HE Scoring
Algorithm, Mini-Mental State Examination
– Neuropsychologic tests: Portosystemic
Encephalopathy Syndrome test, Critical
Clicker Frequency
– Neurophysiological tests
Current treatment Nutritional support (protein intake, zinc
supplementation)
Reduce gut-derived toxin levels
– Non-absorbable disaccharides (lactulose or
lactitol)
– Non-systemic antibiotics (rifaximin)
– Probiotics
HE, hepatic encephalopathy.
Data from Khungar and Poordad72; Prakash et al.73; and Koziarska et al.74.
condition progresses to overt HE. However, several
small studies using probiotics, lactulose, and rifaximin
have suggested that patients with minimal HE achieve
improvement in symptoms and quality-of-life89–91.
Emerging anti-fibrotic therapies
The discovery of the hepatic stellate cells (HSC), the main
fibrogenic cells in the injured liver, has led to understand-
ing of the molecular mechanisms of liver fibrosis92.
Experimental and clinical studies are beginning to demon-
strate that fibrosis is a dynamic process, and that cirrhosis
in its early stages may even be reversible93. In addition,
anti-fibrotic therapies that target the mediators of fibrosis
are being developed for the treatment of liver fibrosis92.
Strategies of anti-fibrotic therapies include elimination of
causes of liver injury, promotion of matrix degradation,
inhibition of HSC activation and proliferation, and stimu-
(pentoxyphilline), peroxisome proliferator-activated
receptor (PPAR
agent (interferon [IFN ]), stem cell transplantation,
angiotensin receptor blocking agents (losartan, candesar-
tan), and Chinese herbal medicine (Fuzheng Huayu)92.
Perhaps the most important arena in liver disease research
in the coming decade will be ameliorating fibrosis and
portal hypertension, as these are the final pathways leading
to mortality.
Additional considerations
The liver is responsible for elimination of bacteria and
other potentially harmful agents (e.g., oral medications)
absorbed by the gastrointestinal tract before they enter
general circulation98. The fibrosis and abnormal liver
architecture observed with cirrhosis impair liver
blood flow, promote formation of intra- and extra-hepatic
portosystemic shunts, and reduce the activity of
hepatocytes98; all of these may subsequently impair
the metabolic capabilities of the liver. In addition,
alterations in the production and secretion of albumin
and bilirubin, both of which regulate drug absorption
and excretion, may be disrupted. Because of these
alterations, drug metabolism and gut flora may be altered
in patients with cirrhosis.
Drugs that undergo intermediate to high hepatic
metabolism via cytochrome P450 detoxification enzymes
may have increased bioavailability in patients with cirrho-
sis due to impaired function of these enzymes. For example,
new antiviral hepatitis C medications such as simeprevir,
which undergoes cytochrome P450 metabolism, have
elevated exposure in patients with cirrhosis, a fact that
may account for their increased toxicity in patients with
advanced disease99. Other medications such as sofosbuvir
(polymerase inhibitor) have shown altered viral kinetics
in patients with cirrhosis99 with and without portal hyper-
tension100, which may be due to the impaired ability to
phosphorylate the drug when hepatic function is disrupted.
Nucleoside analogs that require phosphorylation by
the liver may also behave differently in patients with
decompensated liver disease, as was similarly noted with
the drug entecavir in patients with significant hepatic
impairment101.
Pharmacodynamic properties may also vary in patients
with cirrhosis compared with healthy individuals. For
lation of HSC apoptosis. Although most anti-fibrotic
agents are in pre-clinical stages of development, a few
have been evaluated in the clinic. Anti-fibrotic agents
such as oral PBI-4050, cenicriviroc (dual C-C chemokine
receptor type 2 and 5 [CCR2/CCR5] antagonists), vitamin
D, and caffeine have anti-fibrotic activity in animal
models94–97. Other agents that are in clinical trials
include an anti-tumor necrosis factor (TNF) agent
934 Complications associated with cirrhosis Poordad
example, the effect of -adrenoreceptor antagonists and
diuretics is blunted in patients with cirrhosis, whereas
the impact of analgesics, anxiolytics, and sedatives is
enhanced98. The underlying cause of such differences
varies from drug to drug, but may be related to changes
in drug receptor binding or intrinsic receptor activity98.
Some of the issues of drug metabolism in liver disease
may be related to the shunting of blood into the systemic
www.cmrojournal.com ! 2015 Informa UK Ltd

circulation when significant portal hypertension exists102,
leading to relative hypoxemic environments in oxygen-
poor hepatocytes, with impaired function of energy-
dependent processes.
The role of gut bacteria in cirrhosis and cirrhosis-related
complications has been recently reviewed103,104 and is
briefly mentioned in the sections above. A variety of
chronic liver diseases are associated with increased trans-
location of intestinal bacteria and their components,
impaired mucosal immunity and barrier function, and sys-
temic immune deficiency103. The alterations in intestinal
motility, gastric pH, and bile acid concentration that
are observed in patients with cirrhosis disrupt the normal
gastric acid barrier, allowing infiltration and colonization
of the gastric lining by bacteria104. Patients with cirrhosis
often have excess bacteria levels within the upper
gastrointestinal tract (i.e., SIBO), which has been shown
to correlate with the severity of liver disease and may
contribute to SBP and HE104. The processes by which
inflammation and gut bacteria influence cirrhosis (or
vice versa) are poorly understood103 and represent an
area of ongoing investigation. The so called ‘‘intestinal
microbiome’’ and its relationship to the liver vis-à-vis
the cytokine milieu may have an essential role in multiple
liver diseases.
Conclusions
Cirrhosis and its associated complications cause signifi-
cant morbidity and mortality. Our understanding of the
natural history, pathophysiology, and management of
the complications of cirrhosis has improved dramatically
in recent years. In patients with compensated cirrhosis,
preventing variceal bleeding and other complications
that lead to decompensated cirrhosis is the main focus
of management. Ascites, an indicator of progression to
decompensated cirrhosis, and its associated complica-
tions SBP and HRS are associated with poor prognosis.
Although PPH is a rare complication of cirrhosis, mod-
erate-to-severe PPH can preclude patients as candidates
for liver transplantation. Finally, the development of
HE, a multifactorial neuropsychiatric condition, is a pre-
dictor of mortality in patients with cirrhosis. Substantial
progress has been made to prevent these complications;
however, liver transplantation remains the only curative
option for the underlying condition of chronic liver dis-
ease. The development of anti-fibrotic therapy may
ultimately help in halting or reversing liver fibrosis,
even in patients with decompensated cirrhosis.
However, a deeper understanding of the gut-liver rela-
tionship may also yield some information about the
pathogenesis of many hepatic conditions, including
fatty liver, alcohol-related injury, and cirrhosis.
! 2015 Informa UK Ltd www.cmrojournal.com
Current Medical Research & Opinion Volume 31, Number 5 May 2015
Transparency
Declaration of funding
Funding for editorial support was provided by Salix
Pharmaceuticals, Inc., Raleigh, NC. The author was not provided
funding for development of this review.
Declaration of financial/other relationships
F.F.P. received grant/research support from Abbvie,
Achillion Pharmaceuticals, Anadys Pharmaceuticals, Biolex
Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb,
Genentech, Gilead Sciences, GlaxoSmithKline, GlobeImmune,
Idenix Pharmaceuticals, Idera Pharmaceuticals, Intercept
Pharmaceuticals, Janssen Pharmaceuticals, Inc, Medarex,
Medtronic, Merck, Novartis, Santarus Pharmaceuticals (a
wholly owned subsidiary of Salix Pharmaceuticals, Inc.),
Scynexis Pharmaceuticals, Vertex Pharmaceuticals, and
ZymoGenetics; is a speaker for Gilead, Kadmon, Merck, Onyx/
Bayer, Genentech, GSK, Salix, and Vertex; and a consultant/
advisor for Abbvie, Achillion Pharmaceuticals, Anadys
Pharmaceuticals, Biolex Therapeutics, Boehringer Ingelheim,
Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline,
GlobeImmune, Idenix, Merck, Novartis, Tibotec/Janssen,
Theravance, and Vertex. CMRO Peer Reviewers on this manu-
script have no relevant financial or other relationships to disclose.
Acknowledgments
Technical editorial and medical writing assistance was provided
by Pratibha Hebbar, PhD, Synchrony Medical Communications,
LLC, West Chester, PA.
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