emedicine.medscape.

com

Cirrhosis
Updated: Oct 15, 2020
Author: David C Wolf, MD, FACP, FACG, AGAF, FAASLD; Chief Editor: BS Anand, MD

Practice Essentials
Cirrhosis is defined histologically as a diffuse hepatic process characterized by fibrosis
and conversion of the normal liver architecture into structurally abnormal nodules. The
progression of liver injury to cirrhosis may occur over several weeks to years.

Signs and symptoms

Some patients with cirrhosis are completely asymptomatic and have a reasonably
normal life expectancy. Other individuals have a multitude of the most severe symptoms
of end-stage liver disease and a limited chance for survival. Common signs and
symptoms may stem from decreased hepatic synthetic function (eg, coagulopathy),
portal hypertension (eg, variceal bleeding), or decreased detoxification capabilities of
the liver (eg, hepatic encephalopathy).

Portal hypertension

Portal hypertension can have prehepatic, intrahepatic, or posthepatic causes. Budd-

Chiari syndrome, a posthepatic cause, is characterized by the following symptoms:

Hepatomegaly

Abdominal pain

Ascites

Ascites is suggested by the following findings on physical examination:

Abdominal distention

Bulging flanks

Shifting dullness

Elicitation of a "puddle sign" in patients in the knee-elbow position

Hepatic encephalopathy
The symptoms of hepatic encephalopathy may range from mild to severe and may be
observed in as many as 70% of patients with cirrhosis. Symptoms are graded on the
following scale:

Grade 0 - Subclinical; normal mental status but minimal changes in memory,

concentration, intellectual function, coordination

Grade 1 - Mild confusion, euphoria or depression, decreased attention, slowing

of ability to perform mental tasks, irritability, disorder of sleep pattern (ie, inverted
sleep cycle)

Grade 2 - Drowsiness, lethargy, gross deficits in ability to perform mental tasks,

obvious personality changes, inappropriate behavior, intermittent disorientation
(usually with regard to time)

Grade 3 - Somnolent, but arousable state; inability to perform mental tasks;

disorientation with regard to time and place; marked confusion; amnesia;
occasional fits of rage; speech is present but incomprehensible

Grade 4 - Coma, with or without response to painful stimuli

Findings on physical examination in hepatic encephalopathy include asterixis and fetor

hepaticus.

Additional signs and symptoms

Many patients with cirrhosis experience fatigue, anorexia, weight loss, and muscle
wasting. Cutaneous manifestations of cirrhosis include jaundice, spider angiomata, skin
telangiectasias ("paper money skin"), palmar erythema, white nails, disappearance of
lunulae, and finger clubbing, especially in the setting of hepatopulmonary syndrome.

Diagnosis

Hepatorenal syndrome

Hepatorenal syndrome is diagnosed when a creatinine clearance rate of less than 40

mL/min is present or when a serum creatinine level of greater than 1.5 mg/dL, a urine
volume of less than 500 mL/day, and a urine sodium level of less than 10 mEq/L are
present.[1] Urine osmolality is greater than plasma osmolality.

Portal hypertension

During angiography, a catheter is placed selectively via either the transjugular or

transfemoral route into the hepatic vein to measure portal pressure.

Hepatic encephalopathy

An elevated arterial or free venous serum ammonia level is the classic laboratory
abnormality reported in patients with hepatic encephalopathy.
Electroencephalography may be helpful in the initial workup of a patient with cirrhosis
and altered mental status, when ruling out seizure activity may be necessary.

Computed tomography (CT) scanning and MRI studies of the brain may be important in
ruling out intracranial lesions when the diagnosis of hepatic encephalopathy is in
question.

Ascites

Paracentesis is essential in determining whether ascites is caused by portal

hypertension or by another process.

Management

Specific medical therapies may be applied to many liver diseases in an effort to diminish
symptoms and to prevent or forestall the development of cirrhosis. Examples of such
treatments include the following:

Prednisone and azathioprine - For autoimmune hepatitis

Interferon and other antiviral agents - For hepatitis B and C

Phlebotomy - For hemochromatosis

Ursodeoxycholic acid and obeticholic acid - For primary biliary cholangitis

Trientine and zinc - For Wilson disease

Once cirrhosis develops, treatment is aimed at the management of complications as

they arise. Examples include the following:

Hepatorenal syndrome - Kidney function usually recovers when patients with

cirrhosis and hepatorenal syndrome undergo liver transplantation; patients with
early hepatorenal syndrome may be salvaged by aggressive expansion of
intravascular volume with albumin and fresh frozen plasma and by the
avoidance of diuretics

Hepatic encephalopathy - Pharmacologic treatment includes the administration

of lactulose and antibiotics

Ascites - Treatment can include sodium restriction and the use of diuretics,
large-volume paracentesis, and shunts (peritoneovenous, portosystemic,
transjugular intrahepatic portosystemic)

Liver transplantation

Patients should be referred for consideration for liver transplantation after the first signs
of hepatic decompensation.

Overview
Cirrhosis represents the final common histologic pathway for a wide variety of chronic
liver diseases. The term cirrhosis was first introduced by Laennec in 1826. It is derived
from the Greek term scirrhus and refers to the orange-brown or tawny surface of the
liver seen at autopsy.

Cirrhosis is defined histologically as a diffuse hepatic process characterized by fibrosis

and the conversion of normal liver architecture into structurally abnormal nodules. The
progression of liver injury to cirrhosis may occur over weeks to years. Indeed, patients
with hepatitis C may have chronic hepatitis for as long as 40 years before progressing
to cirrhosis.

Many forms of liver injury are marked by fibrosis, which is defined as an excess
deposition of the components of the extracellular matrix (ie, collagens, glycoproteins,
proteoglycans) in the liver. This response to liver injury potentially is reversible. By
contrast, in most patients, cirrhosis is not a reversible process.

In addition to fibrosis, the complications of cirrhosis include, but are not limited to, portal
hypertension, ascites, hepatorenal syndrome, and hepatic encephalopathy.

Often a poor correlation exists between the histologic findings in cirrhosis and the
clinical picture. Some patients with cirrhosis are completely asymptomatic and have a
reasonably normal life expectancy. Other individuals have a multitude of the most
severe symptoms of end-stage liver disease and have a limited chance for survival.
Common signs and symptoms may stem from decreased hepatic synthetic function (eg,
coagulopathy), decreased detoxification capabilities of the liver (eg, hepatic
encephalopathy), or portal hypertension (eg, variceal bleeding).

In August 2012, the Centers for Disease Control and Prevention (CDC) expanded their
existing, risk-based testing guidelines to recommend a 1-time blood test for hepatitis C
virus (HCV) infection in baby boomers—the generation born between 1945 and 1965,
who account for approximately three fourths of all chronic HCV infections in the United
States—without prior ascertainment of HCV risk (see Recommendations for the
Identification of Chronic Hepatitis C Virus Infection Among Persons Born During 1945–
1965).[2] One-time HCV testing in this population could identify nearly 808,600
additional people with chronic infection. All individuals identified with HCV should be
screened and/or managed for alcohol abuse, followed by referral to preventative and/or
treatment services, as appropriate.

For patient education information, see the Mental Health Center, as well as Alcoholism.

Etiology
Alcoholic liver disease once was considered to be the predominant source of cirrhosis
in the United States, but hepatitis C has emerged as the nation's leading cause of
chronic hepatitis and cirrhosis.

Many cases of cryptogenic cirrhosis appear to have resulted from nonalcoholic fatty
liver disease (NAFLD). When cases of cryptogenic cirrhosis are reviewed, many
patients have one or more of the classic risk factors for NAFLD: obesity, diabetes, and
hypertriglyceridemia.[3] It is postulated that steatosis may regress in some patients as
hepatic fibrosis progresses, making the histologic diagnosis of NAFLD difficult.
Flavinoids have been reported to have positive effects on key pathophysiologic
pathways in NAFLD (eg, lipid metabolism, insulin resistance, inflammation, oxidative
stress) and may hold future potential for inclusion in NAFLD treatment.[4]

Up to one third of Americans have NAFLD. About 2-3% of Americans have nonalcoholic
steatohepatitis (NASH), in which fat deposition in the hepatocyte is complicated by liver
inflammation and fibrosis. It is estimated that 10% of patients with NASH will ultimately
develop cirrhosis. NAFLD and NASH are anticipated to have a major impact on the
United States' public health infrastructure.

The most common causes of cirrhosis in the United States include the following:

Hepatitis C (26%)

Alcoholic liver disease (21%)

Hepatitis C plus alcoholic liver disease (15%)

Cryptogenic causes (18%) - Many cases actually are due to NAFLD

Hepatitis B - May be coincident with hepatitis D (15%)

Miscellaneous (5%)

Miscellaneous causes of chronic liver disease and cirrhosis include the following:

Autoimmune hepatitis

Primary biliary cholangitis

Secondary biliary cirrhosis - Associated with chronic extrahepatic bile duct

obstruction

Primary sclerosing cholangitis

Hemochromatosis

Wilson disease

Alpha-1 antitrypsin deficiency

Granulomatous disease - Eg, sarcoidosis

Type IV glycogen storage disease

Drug-induced liver disease - Eg, methotrexate, alpha methyldopa, amiodarone

Venous outflow obstruction - Eg, Budd-Chiari syndrome, veno-occlusive disease

Chronic right-sided heart failure

 Tricuspid regurgitation

Epidemiology
United States data

Chronic liver disease and cirrhosis result in about 35,000 deaths each year in the
United States. Cirrhosis is the ninth leading cause of death in the United States and is
responsible for 1.2% of all US deaths. Many patients die from the disease in their fifth or
sixth decade of life. The incidence of nonalcoholic fatty liver disease (NAFLD) and
nonalcoholic steatohepatitis (NASH) is expected to rise, leading to an increased
incidence of cirrhosis.[5]

Each year, 2000 additional deaths are attributed to fulminant hepatic failure (FHF). FHF
may be caused viral hepatitis (eg, hepatitis A and B), drugs (eg, acetaminophen), toxins
(eg, Amanita phalloides, the yellow death-cap mushroom), autoimmune hepatitis,
Wilson disease, or a variety of less common etiologies. Cryptogenic causes are
responsible for one third of fulminant cases. Patients with the syndrome of FHF have a
50-80% mortality rate unless they are salvaged by liver transplantation.

International data

Worldwide, cirrhosis is the 14th most common cause of death, but in Europe, it is the
4th most common cause of death.[6]

The estimated worldwide prevalence of NAFLD is 25.2%.[7]

Hepatic Fibrosis
The development of hepatic fibrosis reflects an alteration in the normally balanced
processes of extracellular matrix production and degradation.[8] The extracellular
matrix, the normal scaffolding for hepatocytes, is composed of collagens (especially
types I, III, and V), glycoproteins, and proteoglycans.

Stellate cells, located in the perisinusoidal space, are essential for the production of
extracellular matrix. Stellate cells, which were once known as Ito cells, lipocytes, or
perisinusoidal cells, may become activated into collagen-forming cells by a variety of
paracrine factors. Such factors may be released by hepatocytes, Kupffer cells, and
sinusoidal endothelium following liver injury. As an example, increased levels of the
cytokine transforming growth factor beta1 (TGF-beta1) are observed in patients with
chronic hepatitis C and those with cirrhosis. TGF-beta1, in turn, stimulates activated
stellate cells to produce type I collagen.

In a study that evaluated serum cytokine levels between healthy patients, those with
stable cirrhosis, and patients with decompensated cirrhosis with and without the
development of acute-on-chronic liver failure (ACLF), Dirchwolf et al found the presence
of distinct cytokine phenotypes was associated with cirrhosis severity.[9] Relative to the
healthy patients, those with cirrhosis had elevated levels of proinflammatory cytokines
(interleukin [IL]-6, -7, -8, -10, and -12, and tumor necrosis factor-alpha [TNF-α]) and
chemoattractant elements. Leukocyte count was positively correlated with disease
severity across the scoring systems used, levels of IL-6 and IL-8 had positive
correlation with Model for End-Stage Liver Disease (MELD) score, and IL-6 alone had a
positive correlation with chronic liver failure-sequential organ failure assessment (Clif-
SOFA) score at day 7 (but a negative correlation with IL-2 at admission).[9]

Increased collagen deposition in the space of Disse (the space between hepatocytes
and sinusoids) and the diminution of the size of endothelial fenestrae lead to the
capillarization of sinusoids. Activated stellate cells also have contractile properties.
Capillarization and constriction of sinusoids by stellate cells contribute to the
development of portal hypertension.

Future drug strategies to prevent fibrosis may focus on reducing hepatic inflammation,
inhibiting stellate cell activation, inhibiting the fibrogenic activities of stellate cells, and
stimulating matrix degradation.

Portal Hypertension
Causes

The normal liver has the ability to accommodate large changes in portal blood flow
without appreciable alterations in portal pressure. Portal hypertension results from a
combination of increased portal venous inflow and increased resistance to portal blood
flow.

Patients with cirrhosis demonstrate increased splanchnic arterial flow and, accordingly,
increased splanchnic venous inflow into the liver. Increased splanchnic arterial flow is
explained partly by decreased peripheral vascular resistance and increased cardiac
output in the patient with cirrhosis. Nitric oxide appears to be the major driving force for
this phenomenon.[10]

Furthermore, evidence for splanchnic vasodilation exists. Putative splanchnic

vasodilators include glucagon, vasoactive intestinal peptide, substance P, prostacyclin,
bile acids, tumor necrosis factor-alpha (TNF-alpha), and nitric oxide.

Increased resistance across the sinusoidal vascular bed of the liver is caused by fixed
factors and dynamic factors. Two thirds of intrahepatic vascular resistance can be
explained by fixed changes in the hepatic architecture. Such changes include the
formation of regenerating nodules and, after the production of collagen by activated
stellate cells, deposition of the collagen within the space of Disse.

Dynamic factors account for one third of intrahepatic vascular resistance. Stellate cells
serve as contractile cells for adjacent hepatic endothelial cells. The nitric oxide
produced by the endothelial cells, in turn, controls the relative degree of vasodilation or
vasoconstriction produced by the stellate cells. In cirrhosis, decreased local production
of nitric oxide by endothelial cells permits stellate cell contraction, with resulting
vasoconstriction of the hepatic sinusoid. (This contrasts with the peripheral circulation,
where there are high circulating levels of nitric oxide in cirrhosis.) Increased local levels
of vasoconstricting chemicals, such as endothelin, may also contribute to sinusoidal
vasoconstriction.

The portal hypertension of cirrhosis is caused by the disruption of hepatic sinusoids.

However, portal hypertension may be observed in a variety of noncirrhotic conditions.

Prehepatic causes

Prehepatic causes include splenic vein thrombosis and portal vein thrombosis. These
conditions commonly are associated with hypercoagulable states and with malignancy
(eg, pancreatic cancer). In a retrospective study (2002-2014) of 66 patients with
cirrhosis and portal vein thrombosis, Chen et al reported that warfarin anticoagulation
may potentially safely and effectively resolve cases of more advanced portal vein
thrombosis.[11] However, they did not observe any benefit of anticoagulation on
decompensation or mortality. Levels of albumin were significant predictors of
decompensated disease at 1 year.[11]

Intrahepatic causes

Intrahepatic causes of portal hypertension are divided into presinusoidal, sinusoidal,

and postsinusoidal conditions. The classic sinusoidal cause of portal hypertension is
cirrhosis.

The classic form of presinusoidal portal hypertension is caused by the deposition of

Schistosoma oocytes in presinusoidal portal venules, with the subsequent development
of granulomata and portal fibrosis. Schistosomiasis is the most common noncirrhotic
cause of variceal bleeding worldwide. Schistosoma mansoni infection is described in
Puerto Rico, Central and South America, the Middle East, and Africa. S japonicum is
described in the Far East. S hematobium, observed in the Middle East and Africa, can
produce portal fibrosis but more commonly is associated with urinary tract deposition of
eggs.

The classic postsinusoidal condition is an entity known as veno-occlusive disease.

Obliteration of the terminal hepatic venules may result from ingestion of pyrrolizidine
alkaloids in Comfrey tea or Jamaican bush tea or following the high-dose chemotherapy
that precedes bone marrow transplantation.

Posthepatic causes

Posthepatic causes of portal hypertension may include chronic right-sided heart failure
and tricuspid regurgitation and obstructing lesions of the hepatic veins and inferior vena
cava. The latter conditions, and the symptoms they produce, are termed Budd-Chiari
syndrome. Predisposing conditions include hypercoagulable states, tumor invasion into
the hepatic vein or inferior vena cava, and membranous obstruction of the inferior vena
cava. Inferior vena cava webs are observed most commonly in South and East Asia
and are postulated to be due to nutritional factors.

Symptoms of Budd-Chiari syndrome are attributed to decreased outflow of blood from

the liver, with resulting hepatic congestion and portal hypertension. These symptoms
include hepatomegaly, abdominal pain, and ascites. Cirrhosis ensues only later in the
course of disease. Differentiating Budd-Chiari syndrome from cirrhosis by history or
physical examination may be difficult. Thus, Budd-Chiari syndrome must be included in
the differential diagnosis of conditions that produce ascites and varices.

Hepatic vein patency is checked most readily by performing abdominal ultrasonography,

with Doppler examination of the hepatic vessels. Abdominal computed tomography (CT)
scanning with intravenous (IV) contrast, abdominal magnetic resonance imaging (MRI),
and visceral angiography also may provide information regarding the patency of hepatic
vessels.

Kondo et al have reported that portal hemodynamics on Doppler ultrasonography may

provide noninvasive prognostic implications for decompensation and long-term
outcomes in patients with cirrhosis.[12] In their retrospective study of 236 cirrhotic
patients (compensated, n = 110; decompensated, n = 126) (mean follow-up, 33.2 mo), a
significant predictor for the presence of decompensation was baseline higher model for
end-stage liver disease (MELD) score; moreover, significant prognostic factors for
developing cirrhosis included higher alanine transaminase levels, lower albumin levels,
and lower mean velocity in the portal trunk.[12] For compensated patients, significant
predictors were hepatocellular carcinoma and lower albumin levels, whereas in
decompensated patients, they were elevated bilirubin levels and overt ascites.[12]

Measurement

AASLD recommendations

The 2016 American Association for the study of Liver Diseases (AASLD) provides the
following guidance for noninvasive testing for the diagnosis of clinically significant portal
hypertension (CSPH)[13] :

Hepatic venous pressure gradient (HVPG) measurement is the gold-standard

method to assess the presence of CSPH, defined as an HVPG of at least 10 mm
Hg.
CSPH can be identified by noninvasive tests: Liver stiffness above 20-25 kPa,
alone or combined with platelet count and spleen size. The presence of
portosystemic collaterals on imaging studies is sufficient to diagnose CSPH.
By definition, patients with gastroesophageal varices as demonstrated by
endoscopy have CSPH.

Widespread use of the transjugular intrahepatic portosystemic shunt (TIPS) procedure

in the 1990s for the management of variceal bleeding led to a resurgence of clinicians'
interest in measuring portal pressure. During angiography, a catheter may be placed
selectively via either the transjugular or transfemoral route into the hepatic vein. In the
healthy patient, free hepatic vein pressure (FHVP) is equal to inferior vena cava
pressure. FHVP is used as an internal zero reference point.

Wedged hepatic venous pressure (WHVP) is measured by inflating a balloon at the

catheter tip, thus occluding a hepatic vein branch. Measurement of the WHVP provides
a close approximation of portal pressure. The WHVP actually is slightly lower than the
portal pressure because of some dissipation of pressure in the sinusoidal bed. The
WHVP and portal pressure are elevated in patients with sinusoidal portal hypertension,
as is observed in cirrhosis.

Complications

The HVPG is defined as the difference in pressure between the portal vein and the
inferior vena cava. Thus, the HVPG is equal to the WHVP value minus the FHVP value
(ie, HVPG = WHVP - FHVP). The normal HVPG is 3-6 mm Hg.

Portal hypertension is defined as a sustained elevation of portal pressure above normal.

An HVPG of 8 mm Hg is believed to be the threshold above which ascites potentially
can develop. An HVPG of 12 mm Hg is the threshold for the potential formation of
varices. High portal pressures may predispose patients to an increased risk of variceal
hemorrhage.[14]

AASLD recommendations

The AASLD recommends the following for noninvasive testing for the diagnosis of
gastroesophageal varices[13] :

Patients with a liver stiffness below 20 kPa and a platelet count over 150,000/μL
have a very low probability (< 5%) of having high-risk varices, and
esophagogastroduodenoscopy (EGD) can be circumvented.
In patients who do not meet these criteria, screening endoscopy for the
diagnosis of gastroesophageal varices is recommended when the diagnosis of
cirrhosis is made.

Ascites
Ascites, which is an accumulation of excessive fluid within the peritoneal cavity, can be
a complication of either hepatic or nonhepatic disease. The four most common causes
of ascites in North America and Europe are cirrhosis, neoplasm, congestive heart
failure, and tuberculous peritonitis.

In the past, ascites was classified as being a transudate or an exudate. In transudative

ascites, fluid was said to cross the liver capsule because of an imbalance in Starling
forces. In general, ascites protein would be less than 2.5 g/dL in this form of ascites. A
classic cause of transudative ascites would be portal hypertension secondary to
cirrhosis and congestive heart failure.

In exudative ascites, fluid was said to weep from an inflamed or tumor-laden

peritoneum. In general, ascites protein in exudative ascites would be greater than 2.5
g/dL. Causes of the condition would include peritoneal carcinomatosis and tuberculous
peritonitis.

Nonperitoneal causes

Attributing ascites to diseases of nonperitoneal or peritoneal origin is more useful.

Thanks to the work of Bruce Runyon, the serum-ascites albumin gradient (SAAG) has
come into common clinical use for differentiating these conditions. Nonperitoneal
diseases produce ascites with a SAAG greater than 1.1 g/dL. (See Table 1, below.)[15]

Table 1. Nonperitoneal Causes of Ascites [16] (Open Table in a new window)

Causes of Nonperitoneal
Examples
Ascites

Cirrhosis
Intrahepatic portal
Fulminant hepatic failure
hypertension
Veno-occlusive disease

Hepatic vein obstruction (ie, Budd-Chiari

Extrahepatic portal syndrome)
hypertension
Congestive heart failure

Nephrotic syndrome
Hypoalbuminemia
Protein-losing enteropathy, Malnutrition

Myxedema

Ovarian tumors
Miscellaneous disorders
Pancreatic ascites

Biliary ascites

Secondary to malignancy

Chylous Secondary to trauma

Secondary to portal hypertension

Chylous ascites, caused by obstruction of the thoracic duct or cisterna chyli, most often
is due to malignancy (eg, lymphoma) but occasionally is observed postoperatively and
following radiation injury. Chylous ascites also may be observed in the setting of
cirrhosis. The triglyceride concentration of the ascites is greater than 110 mg/dL and
greater than that observed in plasma. Patients should be placed on a low-fat diet that is
supplemented with medium-chain triglycerides. Treatment with diuretics and large-
volume paracentesis may be required.

Peritoneal causes

Peritoneal diseases produce ascites with a SAAG of less than 1.1 g/dL. (See Table 2,
below.)

Table 2. Peritoneal Causes of Ascites [16] (Open Table in a new window)

Causes of Peritoneal
Examples
Ascites

Primary peritoneal mesothelioma

Malignant ascites
Secondary peritoneal carcinomatosis

Tuberculous peritonitis

Fungal and parasitic infections (eg, Candida,

Histoplasma, Cryptococcus, Schistosoma mansoni,

Granulomatous
Strongyloides, Entamoeba histolytica)
peritonitis
Sarcoidosis

Foreign bodies (ie, talc, cotton, wood fibers, starch, and

barium)

Systemic lupus erythematosus

Vasculitis
Henoch-Schönlein purpura
 Eosinophilic gastroenteritis
Miscellaneous
Whipple disease
disorders
Endometriosis

The role of portal hypertension in the pathogenesis of cirrhotic

ascites

The formation of ascites in cirrhosis depends on the presence of unfavorable Starling

forces within the hepatic sinusoid and on some degree of renal dysfunction. Patients
with cirrhosis are observed to have increased hepatic lymphatic flow.

Fluid and plasma proteins diffuse freely across the highly permeable sinusoidal
endothelium into the space of Disse. Fluid in the space of Disse, in turn, enters the
lymphatic channels that run within the portal and central venous areas of the liver.

Because the trans-sinusoidal oncotic gradient is approximately zero, the increased

sinusoidal pressure that develops in portal hypertension increases the amount of fluid
entering the space of Disse. When the increased hepatic lymph production observed in
portal hypertension exceeds the ability of the cisterna chyli and thoracic duct to clear
the lymph, fluid crosses into the liver interstitium. Fluid may then extravasate across the
liver capsule into the peritoneal cavity.

The role of renal dysfunction in the pathogenesis of cirrhotic ascites

Patients with cirrhosis experience sodium retention, impaired free-water excretion, and
intravascular volume overload. These abnormalities may occur even in the setting of a
normal glomerular filtration rate. They are, to some extent, due to increased levels of
renin and aldosterone.

The peripheral arterial vasodilation hypothesis states that splanchnic arterial

vasodilation, driven by high nitric oxide levels, leads to intravascular underfilling. This
causes stimulation of the renin-angiotensin system and the sympathetic nervous
system and results in antidiuretic hormone release. These events are followed by an
increase in sodium and water retention and in plasma volume, as well as by the
overflow of fluid into the peritoneal cavity.

Clinical features of ascites

Ascites is suggested by the presence of the following findings upon physical

examination:

Abdominal distention

Bulging flanks
 Shifting dullness

Elicitation of a "puddle sign" with patients in the knee-elbow position

A fluid wave may be elicited in patients with massive tense ascites. However, physical
examination findings are much less sensitive than abdominal ultrasonography, which
can detect as little as 30 mL of fluid. Furthermore, ultrasonography with Doppler can
help to assess the patency of hepatic vessels.

Factors associated with worsening of ascites include excess fluid or salt intake,
malignancy, venous occlusion (eg, Budd-Chiari syndrome), progressive liver disease,
and spontaneous bacterial peritonitis (SBP).

Spontaneous bacterial peritonitis

SBP is observed in 15-26% of patients hospitalized with ascites. The syndrome arises
most commonly in patients whose low-protein ascites (< 1 g/dL) contains low levels of
complement, resulting in decreased opsonic activity. SBP appears to be caused by the
translocation of gastrointestinal (GI) tract bacteria across the gut wall and also by the
hematogenous spread of bacteria. The most common causative organisms are
Escherichia coli, Streptococcus pneumoniae, Klebsiella species, and other gram-
negative enteric organisms.[17]

Classic SBP is diagnosed by the presence of neutrocytosis, which is defined as greater

than 250 polymorphonuclear cells (PMNs) per mm3 of ascites, in the setting of a
positive ascites culture. Culture-negative neutrocytic ascites is observed more
commonly. Both conditions represent serious infections that carry a 20-30% mortality
rate.

The most commonly used regimen in the treatment of SBP is a 5-day course of
cefotaxime at 1-2g intravenously every 8 hours.[18] Alternatives include oral ofloxacin
and other IV antibiotics with activity against gram-negative enteric organisms. Many
authorities advise repeat paracentesis in 48-72 hours to document a decrease in the
ascites PMN count to less than 250 cells/mm3 to ensure efficacy of therapy.

Once SBP develops, patients have a 70% chance of redeveloping the condition within 1
year. Prophylactic antibiotic therapy can reduce the recurrence rate of SBP to 20%.
Some of the regimens used in the prophylaxis of SBP include norfloxacin at 400 mg
orally every day[19] and trimethoprim-sulfamethoxazole at 1 double-strength tablet 5
days per week.[20]

Therapy with norfloxacin at 400 mg orally twice per day for 7 days can reduce serious
bacterial infection in patients with cirrhosis who have GI bleeding. One study noted that
the 37% incidence of serious bacterial infection was reduced to 10% when treatment
with norfloxacin was instituted.[21] Furthermore, it can be argued that all patients with
low-protein ascites should undergo prophylactic therapy (eg, with norfloxacin 400 mg
daily PO) at the time of hospital admission, given the high incidence of hospital-
acquired SBP.[22]

Hernias
Umbilical and inguinal hernias are common in patients with moderate and massive
ascites. The use of an elastic abdominal binder may protect the skin overlying a
protruding umbilical hernia from maceration and may help to prevent rupture and
subsequent infection. Timely, large-volume paracentesis also may help to prevent this
disastrous complication.

Umbilical hernias should not undergo elective repair unless patients are significantly
symptomatic or their hernias are irreducible. As with all other surgeries in patients with
cirrhosis, herniorrhaphy carries multiple potential risks, such as intraoperative bleeding,
postoperative infection, and liver failure, because of anesthesia-induced reductions in
hepatic blood flow. However, these risks become acceptable in patients with severe
symptoms from their hernia. Urgent surgery is necessary in the patient whose hernia
has been complicated by bowel incarceration.

Other complications of massive ascites

Patients with massive ascites may experience abdominal discomfort, depressed

appetite, and decreased oral intake. Diaphragmatic elevation may lead to symptoms of
dyspnea. Pleural effusions may result from the passage of ascitic fluid across channels
in the diaphragm.

Paracentesis in the diagnosis of ascites

Paracentesis is essential in determining whether ascites is caused by portal

hypertension or by another process. Ascites studies also are used to rule out infection
and malignancy. Paracentesis should be performed in all patients with either new onset
of ascites or worsening ascites. Paracentesis also should be performed when SBP is
suggested by the presence of abdominal pain, fever, leukocytosis, or worsening hepatic
encephalopathy. Some argue that paracentesis should be performed in all patients with
cirrhosis who have ascites at the time of hospitalization, given the significant possibility
of asymptomatic SBP. (See Table 3, below.)

Table 3. Ascites Tests (Open Table in a new window)

Routine Optional Special

Glucose (minimal
Cell count Cytology
use)

Lactate
Albumin Tuberculosis smear and culture
dehydrogenase
 Culture Gram stain Triglycerides (to rule out chylous ascites)

Total Bilirubin (to rule out biliary leak when

protein clinically suspected)

Amylase (to rule out pancreatic duct leak

when clinically suspected)

Ascitic fluid with more than 250 PMNs/mm3 defines neutrocytic ascites and SBP. Many
cases of ascites fluid with more than 1000 PMNs/mm3 (and certainly >5000
PMNs/mm3) are associated with appendicitis or a perforated viscus with resulting
bacterial peritonitis. Appropriate radiologic studies must be performed in such patients
to rule out surgical causes of peritonitis.

Lymphocyte-predominant ascites raises concerns about the possibility of underlying

malignancy or tuberculosis. Similarly, grossly bloody ascites may be observed in
malignancy and tuberculosis. (Bloody ascites is seen infrequently in uncomplicated
cirrhosis.) A common clinical dilemma is how to interpret the ascites PMN count in the
setting of bloody ascites. This author recommends subtraction of 1 PMN for every 250
red blood cells (RBCs) in ascites to ascertain a corrected PMN count.

The yield of ascites culture studies may be increased by directly inoculating 10 mL of

ascetic fluid into aerobic and anaerobic culture bottles at the patient's bedside.[23]

Medical treatment of ascites

Therapy for ascites should be tailored to the patient's needs. Some patients with mild
ascites respond to sodium restriction or diuretics taken once or twice per week. Other
patients require aggressive diuretic therapy, careful monitoring of electrolytes, and
occasional hospitalization to facilitate even more intensive diuresis.

The development of massive ascites that is refractory to medical therapy has dire
prognostic implications, with only 50% of patients surviving 6 months.[24]

Sodium restriction

Salt restriction is the first line of therapy. In general, patients begin with a diet containing
less than 2000 mg of sodium daily. Some patients with refractory ascites require a diet
containing less than 500 mg of sodium daily. However, ensuring that patients do not
construct diets that might place them at risk for calorie and protein malnutrition is
important. Indeed, the benefit of commercially available liquid nutritional supplements
(which often contain moderate amounts of sodium) often exceeds the risk of slightly
increasing the patient's salt intake.

Diuretics

Diuretics should be considered the second line of therapy. Spironolactone (Aldactone)

blocks the aldosterone receptor at the distal tubule. It is dosed at 50-300 mg once daily.
Although the drug has a relatively short half-life, its blockade of the aldosterone
receptor lasts for at least 24 hours. Adverse effects of spironolactone include
hyperkalemia, gynecomastia, and lactation. Other potassium-sparing diuretics,
including amiloride and triamterene, may be used as alternative agents, especially in
patients complaining of gynecomastia.

Furosemide (Lasix) may be used as a solo agent or in combination with spironolactone.

The drug blocks sodium reuptake in the loop of Henle. It is dosed at 40-240 mg daily in
1-2 divided doses. Patients infrequently need potassium repletion when furosemide is
dosed in combination with spironolactone. An Italian study by Angeli et al found
sequential dosing with a potassium-sparing diuretic plus furosemide to be superior for
patients with moderate ascites without renal failure when compared with potassium-
sparing diuretic monotherapy.[25]

Aggressive diuretic therapy in hospitalized patients with massive ascites can safely
induce a weight loss of 0.5-1kg daily, provided that patients undergo careful monitoring
of renal function. Diuretic therapy should be held in the event of electrolyte
disturbances, azotemia, or induction of hepatic encephalopathy.

Albumin

Thus far, evidence-based medicine has not firmly supported the use of albumin as an
aid to diuresis in a patient with cirrhosis who is hospitalized. The author's anecdotal
experience suggests that albumin may increase the efficacy and safety of diuretics. The
author's practice in hospitalized patients who are hypoalbuminemic is to administer IV
furosemide following IV infusion of albumin at 25g twice daily, in addition to providing
ongoing therapy with spironolactone. One article supported the use of chronic albumin
infusions to achieve diuresis in patients with diuretic-resistant ascites.[26]

Albumin infusion may protect against the development of renal insufficiency in patients
with SBP. Patients receiving cefotaxime and albumin at 1 g/kg daily experienced a lower
risk of renal failure and a lower in-hospital mortality rate than patients treated with
cefotaxime and conventional fluid management.[27]

V2 receptor antagonists

Vasopressin V2 receptor antagonists are a class of agents with the potential to increase
free-water excretion, improve diuresis, and decrease the need for paracentesis.
However, no such agent has received US Food and Drug Administration (FDA)
approval for this indication.
Tolvaptan (Samsca, Otsuka Pharmaceutical Co; Tokyo, Japan) is an oral V2 receptor
antagonist; it received FDA approval in 2009 only for the management of hyponatremia.
A black box warning cautions against treatment initiation in outpatients. Furthermore, it
may be associated with an increased incidence of GI bleeding in patients with cirrhosis.
The author advises against its use for ascites management at this time.

Large-volume paracentesis

Aggressive diuretic therapy is ineffective in controlling ascites in approximately 5-10%

of patients. Such patients with massive ascites may need to undergo large-volume
paracentesis to obtain relief from symptoms of abdominal discomfort, anorexia, or
dyspnea. The procedure also may help to reduce the risk of umbilical hernia rupture.

Large-volume paracentesis was first used in ancient times. It fell out of favor from the
1950s through the 1980s with the advent of diuretic therapy and following a handful of
case reports describing paracentesis-induced azotemia. In 1987, Gines and colleagues
demonstrated that large-volume paracentesis could be performed with minimal or no
impact on renal function.[28] This and other studies showed that 5-15 L of ascites could
be removed safely at one time.

Large-volume paracentesis is thought to be safe in patients with peripheral edema and

in patients not currently treated with diuretics. Debate exists whether colloid infusions
(eg, with 5-10g of albumin per 1L of ascites removed) are necessary to prevent
intravascular volume depletion in patients who are receiving ongoing diuretic therapy or
in patients with mild or moderate, underlying renal insufficiency.

Peritoneovenous shunts

LeVeen shunts and Denver shunts are devices that permit the return of ascites fluid and
proteins to the intravascular space. Plastic tubing inserted subcutaneously under local
anesthesia connects the peritoneal cavity to the internal jugular vein or subclavian vein
via a pumping chamber. These devices are successful at relieving ascites and reversing
protein loss in some patients. However, shunts may clot and require replacement in
30% of patients.

Serious complications are observed in at least 10% of the recipients of these devices,
including peritoneal infection, sepsis, disseminated intravascular coagulation,
congestive heart failure, and death. The author considers peritoneovenous shunts to be
a last resort for patients with refractory ascites who are not candidates for TIPS or liver
transplantation. The safety of repeat large-volume paracentesis procedures may
actually outweigh the safety of peritoneovenous shunt placement.

Portosystemic shunts and transjugular intrahepatic portosystemic

shunts

The prime indication for portocaval shunt surgery is the management of refractory
variceal bleeding. Since 1945, however, the medical field has recognized that
portocaval shunts, by decompressing the hepatic sinusoid, may improve ascites. The
performance of a side-to-side portocaval shunt for ascites management must be
weighed against the approximate 5% mortality rate associated with this surgery and the
chance (as high as 30%) of inducing hepatic encephalopathy.

A TIPS is an effective tool in managing massive ascites in some patients. Ideally, TIPS
placement produces a decrease in sinusoidal pressure and in plasma renin and
aldosterone levels, with subsequent improved urinary sodium excretion. In one study,
74% of patients with refractory ascites achieved complete remission of ascites within 3
months of TIPS placement.[29] Typically, about one half of appropriately selected
patients undergoing TIPS achieve significant relief of ascites.

Multiple studies have demonstrated that TIPS is superior to large-volume paracentesis

when it comes to the control of ascites.[30] One meta-analysis of individual patient data
demonstrated an improvement in transplant-free life expectancy in patients whose
massive ascites was treated with a TIPS, as opposed to large-volume paracentesis.[31]
However, the creation of a TIPS has the potential to worsen preexisting hepatic
encephalopathy and exacerbate liver dysfunction in patients with severe, underlying
liver failure.[32]

Both a pre-TIPS bilirubin level of greater than 3 mg/dL and a pre-TIPS Model for End-
Stage Liver Disease (MELD) score of greater than 18 (see the MELD Score calculator)
are associated with an increased mortality rate when a TIPS is created for the
management of ascites.[33, 34] In the author's opinion, TIPS use should be reserved
for patients with Child Class B cirrhosis or patients with Child Class C cirrhosis without
severe coagulopathy or encephalopathy.

In the 1990s, shunt stenosis was observed in one half of cases within 1 year of TIPS
placement, necessitating angiographic revision. Although the advent of coated stents
appears to have reduced the incidence of shunt stenosis, patients must still be willing to
return to the hospital for Doppler and angiographic follow-up of TIPS patency.

Liver transplantation

Patients with massive ascites have 1-year survival rate of less than 50%. Liver
transplantation should be considered as a potential means of salvaging the patient prior
to the onset of intractable liver failure or hepatorenal syndrome.

Hepatorenal Syndrome
This syndrome represents a continuum of renal dysfunction that may be observed in
patients with a combination of cirrhosis and ascites. Hepatorenal syndrome is caused
by the vasoconstriction of large and small renal arteries and the impaired renal
perfusion that results.[35]

The syndrome may represent an imbalance between renal vasoconstrictors and

vasodilators. Plasma levels of a number of vasoconstricting substances—including
angiotensin, antidiuretic hormone, and norepinephrine—are elevated in patients with
cirrhosis. Renal perfusion appears to be protected by vasodilators, including
prostaglandins E2 and I2 and atrial natriuretic factor.
Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin synthesis. They
may potentiate renal vasoconstriction, with a resulting drop in glomerular filtration. Thus,
the use of NSAIDs is contraindicated in patients with decompensated cirrhosis.

Most patients with hepatorenal syndrome are noted to have minimal histologic changes
in the kidneys. Kidney function usually recovers when patients with cirrhosis and
hepatorenal syndrome undergo liver transplantation. In fact, a kidney donated by a
patient dying from hepatorenal syndrome functions normally when transplanted into a
renal transplant recipient.

Types of hepatorenal syndrome

Hepatorenal syndrome progression may be slow (type II) or rapid (type I).[36] Type I
disease frequently is accompanied by rapidly progressive liver failure. Hemodialysis
offers temporary support for such patients. These individuals are salvaged only by
performance of liver transplantation. Exceptions to this rule are the patients with
fulminant hepatic failure (FHF) or severe alcoholic hepatitis who spontaneously recover
liver and kidney function. In type II hepatorenal syndrome, patients may have stable or
slowly progressive renal insufficiency. Many such patients develop ascites that is
resistant to management with diuretics.

Diagnosis

Hepatorenal syndrome is diagnosed when a creatinine clearance rate of less than 40

mL/min is present or when a serum creatinine level of greater than 1.5 mg/dL, a urine
volume of less than 500 mL/day, and a urine sodium level of less than 10 mEq/L are
present.[1] Urine osmolality is greater than plasma osmolality.

In hepatorenal syndrome, renal dysfunction cannot be explained by preexisting kidney

disease, prerenal azotemia, the use of diuretics, or exposure to nephrotoxins. Clinically,
the diagnosis may be reached if the central venous pressure is determined to be normal
or if no improvement in renal function occurs following the infusion of at least 1.5 L of a
plasma expander.

Treatment

Nephrotoxic medications, including aminoglycoside antibiotics, should be avoided in

patients with cirrhosis. Patients with early hepatorenal syndrome may be salvaged by
aggressive expansion of intravascular volume with albumin and fresh frozen plasma
and by avoidance of diuretics. The use of renal-dose dopamine is not effective.

A number of investigators have employed systemic vasoconstrictors in an attempt to

reverse the effects of nitric oxide on peripheral arterial vasodilation. In Europe,
administration of IV terlipressin (an analog of vasopressin not available in the United
States) improved renal dysfunction in patients with hepatorenal syndrome.[37, 38]

A combination of midodrine (an oral alpha agonist), subcutaneous octreotide, and

albumin infusion has also been demonstrated to improve renal function in small cohorts
of patients with hepatorenal syndrome.[39]
Hepatic Encephalopathy
Hepatic encephalopathy, a syndrome observed in some patients with cirrhosis, is
marked by personality changes, intellectual impairment, and a depressed level of
consciousness. The diversion of portal blood into the systemic circulation appears to be
a prerequisite for the syndrome. Indeed, hepatic encephalopathy may develop in
patients without cirrhosis who undergo portocaval shunt surgery.

Pathogenesis

A number of theories have been postulated to explain the pathogenesis of hepatic

encephalopathy in patients with cirrhosis. Patients may have altered brain energy
metabolism and increased permeability of the blood-brain barrier. The latter may
facilitate the passage of neurotoxins into the brain. Putative neurotoxins include short-
chain fatty acids, mercaptans, false neurotransmitters (eg, tyramine, octopamine, beta
phenylethanolamines), ammonia, and gamma-aminobutyric acid (GABA).

Ammonia hypothesis

Ammonia is produced in the GI tract by bacterial degradation of amines, amino acids,

purines, and urea. Normally, ammonia is detoxified in the liver by conversion to urea
and glutamine. In liver disease or portosystemic shunting, portal blood ammonia is not
converted efficiently to urea. Increased levels of ammonia may enter the systemic
circulation because of portosystemic shunting.

Ammonia has multiple neurotoxic effects, including alteration of the transit of amino
acids, water, and electrolytes across the neuronal membrane. Ammonia also can inhibit
the generation of excitatory and inhibitory postsynaptic potentials. Therapeutic
strategies to reduce serum ammonia levels tend to improve hepatic encephalopathy.
However, approximately 10% of patients with significant encephalopathy have normal
serum ammonia levels. Furthermore, many patients with cirrhosis have elevated
ammonia levels without evidence of encephalopathy.

Gamma-aminobutyric acid hypothesis

GABA is a neuroinhibitory substance produced in the GI tract. It was postulated that

GABA crosses the extrapermeable blood-brain barriers of patients with cirrhosis and
then interacts with supersensitive postsynaptic GABA receptors.[40] This would lead to
the generation of inhibitory postsynaptic potentials. Clinically, this interaction was
believed to produce the symptoms of hepatic encephalopathy. Subsequent work has
suggested that brain GABA levels are not increased in patients with cirrhosis.

However, brain levels of neurosteroids are increased in patients with cirrhosis.[41] They
are capable of binding to their receptor within the neuronal GABA receptor complex and
can increase inhibitory neurotransmission. Some investigators currently contend that
neurosteroids may play a key role in hepatic encephalopathy.[42]

Clinical features
The symptoms of hepatic encephalopathy may range from mild to severe and may be
observed in as many as 70% of patients with cirrhosis. Symptoms are graded on the
following scale:

Grade 0 - Subclinical; normal mental status but minimal changes in memory,

concentration, intellectual function, coordination

Grade 1 - Mild confusion, euphoria or depression, decreased attention, slowing

of ability to perform mental tasks, irritability, disorder of sleep pattern (ie, inverted
sleep cycle)

Grade 2 - Drowsiness, lethargy, gross deficits in ability to perform mental tasks,

obvious personality changes, inappropriate behavior, intermittent disorientation
(usually with regard to time)

Grade 3 - Somnolent, but arousable state; inability to perform mental tasks;

disorientation with regard to time and place; marked confusion; amnesia;
occasional fits of rage; speech is present but incomprehensible

Grade 4 - Coma, with or without response to painful stimuli

Patients with mild and moderate hepatic encephalopathy demonstrate decreased short-
term memory and concentration on mental status testing. Findings on physical
examination include asterixis and fetor hepaticus.

Laboratory abnormalities

An elevated arterial or free venous serum ammonia level is the classic laboratory
abnormality reported in patients with hepatic encephalopathy. This finding may aid in
the assignment of a correct diagnosis to a patient with cirrhosis who presents with
altered mental status.

However, serial ammonia measurements are inferior to clinical assessment in gauging

improvement or deterioration in patients under therapy for hepatic encephalopathy. No
utility exists for checking the ammonia level in a patient with cirrhosis who does not
have hepatic encephalopathy.

Some patients with hepatic encephalopathy have the classic, but nonspecific,
electroencephalogram (EEG) changes of high-amplitude low-frequency waves and
triphasic waves. Electroencephalography may be helpful in the initial workup of a
patient with cirrhosis and altered mental status, when ruling out seizure activity may be
necessary.

CT scan and MRI studies of the brain may be important in ruling out intracranial lesions
when the diagnosis of hepatic encephalopathy is in question.

Common precipitants

Some patients with a history of hepatic encephalopathy have normal mental status
when under medical therapy. Others have chronic memory impairment in spite of
medical management. Both groups of patients are subject to episodes of worsened
encephalopathy. Common precipitants of hyperammonemia and worsening mental
status are as follows:

Diuretic therapy

Hypovolemia

Renal failure

GI bleeding

Infection

Constipation

Dietary protein overload is an infrequent cause of worsening encephalopathy.

Medications, notably opiates, benzodiazepines, antidepressants, and antipsychotic
agents, also may worsen encephalopathic symptoms.

Differential diagnosis

Conditions to consider in the differential diagnosis of encephalopathy include the

following:

Intracranial lesions - Eg, subdural hematoma, intracranial bleeding,

cerebrovascular accident, tumor, abscess

Infections - Eg, meningitis, encephalitis, abscess

Metabolic encephalopathy - Eg, hypoglycemia, electrolyte imbalance, anoxia,

hypercarbia, uremia

Hyperammonemia from other causes - Eg, secondary to ureterosigmoidostomy,

inherited urea cycle disorders

Toxic encephalopathy due to alcohol - Eg, acute intoxication, alcohol withdrawal,

Wernicke encephalopathy

Toxic encephalopathy due to drugs - Eg, sedative-hypnotics, antidepressants,

antipsychotic agents, salicylates

Organic brain syndrome

Postseizure encephalopathy

Management

Nonhepatic causes of altered mental function must be excluded in patients with

cirrhosis who have worsening mental function. A check of the blood ammonia level may
be helpful in such patients. Medications that depress central nervous system (CNS)
function, especially benzodiazepines, should be avoided. Precipitants of hepatic
encephalopathy should be corrected (eg, hypovolemia, metabolic disturbances, GI
bleeding, infection, constipation).

Lactulose

Lactulose is helpful in patients with an acute onset of severe encephalopathy symptoms

and in patients with milder, chronic symptoms. This nonabsorbable disaccharide
stimulates the passage of ammonia from tissues into the gut lumen and inhibits
intestinal ammonia production. Initial lactulose dosing is 30 mL orally once or twice
daily. Dosing is increased until the patient has 2-4 loose stools per day. Dosing should
be reduced if the patient complains of diarrhea, abdominal cramping, or bloating.

Higher doses of lactulose may be administered via either a nasogastric or rectal tube to
hospitalized patients with severe encephalopathy. Other cathartics, including colonic
lavage solutions that contain polyethylene glycol (PEG) (eg, Go-Lytely), also may be
effective in patients with severe encephalopathy.

In a study, Sharma et al concluded that the use of lactulose effectively prevents hepatic
encephalopathy recurrence in cirrhosis. Patients with cirrhosis recovering from hepatic
encephalopathy were randomized to receive lactulose (n = 61) or placebo (n = 64).
Over a median follow-up of 14 months, 12 patients (19.6%) in the lactulose group
developed hepatic encephalopathy, compared with 30 patients (46.8%) in the placebo
group.[43]

Antibiotics

Neomycin and other antibiotics (eg, metronidazole, oral vancomycin, paromomycin, oral
quinolones) serve as second-line agents. They work by decreasing the colonic
concentration of ammoniagenic bacteria. Neomycin dosing is 250-1000 mg orally 2-4
times daily. Treatment with neomycin may be complicated by ototoxicity and
nephrotoxicity.

Rifaximin (Xifaxan) is a nonabsorbable antibiotic that received FDA approval in 2004 for
the treatment of travelers' diarrhea and was given approval in 2010 for the reduction of
recurrent hepatic encephalopathy. This drug was also approved in May 2015 for the
treatment of diarrhea-predominant irritable bowel syndrome (IBS-D). Data from Europe
suggest that rifaximin can decrease colonic levels of ammoniagenic bacteria, with
resulting improvement in the symptoms of hepatic encephalopathy.

A double-blind, placebo-controlled trial, indicated that rifaximin can prevent the

occurrence hepatic encephalopathy. In the study, 299 patients whose recurrent hepatic
encephalopathy was in remission received either rifaximin 550 mg or placebo twice
daily. Each group also received lactulose. Breakthrough episodes of hepatic
encephalopathy occurred in 22% of patients treated with rifaximin and in 46% of
patients who were given placebo, while hepatic encephalopathy – related
hospitalization occurred in 14% of rifaximin patients and in 23% of placebo patients.[44]
Rifaximin also appeared to be more effective than lactulose in trials that compared the 2
drugs head-to-head.[45]

Other drugs
Other chemicals capable of decreasing blood ammonia levels are L-ornithine L-
aspartate (available in Europe) and sodium benzoate.[46]

Protein restriction

Low-protein diets were recommended routinely in the past for patients with cirrhosis.
High levels of aromatic amino acids contained in animal proteins were believed to lead
to increased blood levels of the false neurotransmitters tyramine and octopamine, with
resultant worsening of encephalopathic symptoms. In this author's experience, the vast
majority of patients can tolerate a protein-rich diet (>1.2 g/kg daily) that includes well-
cooked chicken, fish, vegetable protein, and, if needed, protein supplements.

Protein restriction is rarely necessary in patients with symptoms of chronic

encephalopathy. Many patients with cirrhosis have protein-calorie malnutrition at
baseline; the routine restriction of dietary protein intake increases their risk for
worsening malnutrition.

In the author's opinion, protein restriction is infrequently valuable in patients with an

acute flare-up of symptoms of hepatic encephalopathy. One study randomized
hospitalized patients with hepatic encephalopathy to receive either a normal-protein diet
or a low-protein diet, in addition to standard treatment measures, and found no
difference between the 2 groups in outcomes for hepatic encephalopathy.[47]

Other Manifestations of Cirrhosis

All chronic liver diseases that progress to cirrhosis have in common the histologic
features of hepatic fibrosis and nodular regeneration. However, the patients' signs and
symptoms may vary, depending on the underlying etiology of the disease.

As an example, patients with end-stage liver disease caused by hepatitis C may

develop profound muscle wasting, marked ascites, and severe hepatic encephalopathy,
with only mild jaundice. In contrast, patients with end-stage primary biliary cirrhosis may
be deeply icteric, with no evidence of muscle wasting. These patients may complain of
extreme fatigue and pruritus and have no complications of portal hypertension. In both
cases, medical management is focused on the relief of symptoms. Liver transplantation
should be considered as a potential therapeutic option, given the inexorable course of
most cases of end-stage liver disease.

Many patients with cirrhosis experience fatigue, anorexia, weight loss, and muscle
wasting. Cutaneous manifestations of cirrhosis include jaundice, spider angiomata, skin
telangiectasias (termed "paper money skin" by Dame Sheila Sherlock), palmar
erythema, white nails, disappearance of lunulae, and finger clubbing, especially in the
setting of hepatopulmonary syndrome.

Patients with cirrhosis may experience increased conversion of androgenic steroids into
estrogens in skin, adipose tissue, muscle, and bone. Males may develop gynecomastia
and impotence. Loss of axillary and pubic hair is noted in men and women.
Hyperestrogenemia also may explain spider angiomata and palmar erythema.
Hematologic manifestations

Anemia may result from folate deficiency, hemolysis, or hypersplenism.[48]

Thrombocytopenia usually is secondary to hypersplenism and decreased levels of
thrombopoietin. Coagulopathy results from decreased hepatic production of coagulation
factors. If cholestasis is present, decreased micelle entry into the small intestine leads
to decreased vitamin K absorption, with resulting reduction in hepatic production of
factors II, VII, IX, and X. Patients with cirrhosis also may experience fibrinolysis and
disseminated intravascular coagulation.

The oral thrombopoietin receptor agonist (TPO-RA) avatrombopag (Doptelet) was

approved by the FDA in May 2018 for adults with thrombocytopenia secondary to
chronic liver disease who are scheduled to undergo a procedure.[49]

Approval was based on the ADAPT-1 and ADAPT-2 clinical trials (N=435). The trials
investigated the use of avatrombopag at two doses, 40 and 60 mg. The doses were
selected on the basis of baseline platelet count and were administered orally over 5
consecutive days. Patients underwent their procedure 5 to 8 days after receiving the
last dose. At both doses tested, a higher proportion of patients who received
avatrombopag demonstrated an increase in platelet count compared with patients who
received placebo. The primary endpoint was the proportion of patients not requiring
platelet transfusions or rescue procedures for bleeding up to 7 days following the
procedure. Patients who received avatrombopag met the primary endpoint
65.6%-68.6% relative to 22.9%-33.3% who received placebo. Patients who received
avatrombopag 40 mg met the primary endpoint 87.9%-88.1% compared with
38.2%-33.3% who received placebo.[50]

A second TPO-RA, lusutrombopag (Mulpleta) was approved in July 2018 for treatment
of thrombocytopenia in adults with chronic liver disease who are scheduled to undergo
a procedure.[51] Approval was based on an international, randomized trial (N=215). The
study met its primary efficacy endpoint: 64.8% of patients in the lusutrombopag group
required no platelet transfusion and no rescue therapy for bleeding, compared with 29%
in placebo group (P< 0.0001).[52]

Pulmonary and cardiac manifestations

Patients with cirrhosis may have impaired pulmonary function. Pleural effusions and the
diaphragmatic elevation caused by massive ascites may alter ventilation-perfusion
relations. Interstitial edema or dilated precapillary pulmonary vessels may reduce
pulmonary diffusing capacity.

Patients also may have hepatopulmonary syndrome (HPS). In this condition, pulmonary
arteriovenous anastomoses result in arteriovenous shunting. HPS is a potentially
progressive and life-threatening complication of cirrhosis. Classic HPS is marked by the
symptom of platypnea (shortness of breath relieved when lying down and worsened
when sitting or standing), and the finding of orthodeoxia (decrease in the arterial oxygen
tension when the patient moves from a supine to an upright position), but the syndrome
must be considered in any patient with cirrhosis who has evidence of oxygen
desaturation.
HPS is detected most readily by echocardiographic visualization of late-appearing
bubbles in the left atrium following the injection of agitated saline. Patients can receive
a diagnosis of HPS when their PaO2 is less than 70 mm Hg. Some cases of HPS may
be corrected by liver transplantation. In fact, a patient's course to liver transplantation
may be expedited when his or her PaO2 is less than 60 mm Hg.

Portopulmonary hypertension (PPHTN) is observed in up to 6% of patients with

cirrhosis. Its etiology is unknown. PPHTN is defined as the presence of a mean
pulmonary artery pressure of greater than 25 mm Hg in the setting of a normal
pulmonary capillary wedge pressure.

Routine Doppler echocardiography is performed as part of the regular workup in many

liver transplant programs to rule out the interval development of PPHTN in patients on
the transplant waiting list. Indeed, the presence of a mean pulmonary pressure of
greater than 35 mm Hg significantly increases the risks of liver transplant surgery.
Patients who develop severe PPHTN may require aggressive medical therapy in an
effort to stabilize pulmonary artery pressures and to decrease their chance of
perioperative mortality.

Hepatocellular carcinoma and cholangiocarcinoma

Hepatocellular carcinoma (HCC) ultimately arises in 10-25% of patients with cirrhosis in

the United States. It typically occurs in about of 3% of patients per year, when the
etiology of cirrhosis is hepatitis B, hepatitis C, or alcohol. It develops more commonly in
patients with underlying hereditary hemochromatosis or alpha-1 antitrypsin deficiency.
HCC is observed less commonly in primary biliary cholangitis and is a rare complication
of Wilson disease.

Hepatobiliary scintigraphy may improve radioembolization treatment planning in HCC

patients when clinical and laboratory findings may not be sufficient.[53] This imaging
modality may aid in estimating liver function reserve and its segmental distribution,
particularly in those with underlying cirrhosis.

Cholangiocarcinoma occurs in approximately 10% of patients with primary sclerosing

cholangitis. Early diagnosis of HCC is critical because it is potentially curable through
either liver resection or liver transplant.

Other diseases

Other conditions that appear with increased incidence in patients with cirrhosis include
peptic ulcer disease, diabetes, and gallstones.

Assessment of the Severity of Cirrhosis

For many years, the most common prognostic tool used in patients with cirrhosis was
the Child-Turcotte-Pugh (CTP) system. Child and Turcotte first introduced their scoring
system in 1964 as a means of predicting the operative mortality associated with
portocaval shunt surgery. Pugh's revised system in 1973 substituted albumin for the
less specific variable of nutritional status.[54] Subsequent revisions have used the
International Normalized Ratio (INR) in addition to prothrombin time.

Epidemiologic work shows that the CTP score may predict life expectancy in patients
with advanced cirrhosis. A CTP score of 10 or greater is associated with a 50% chance
of death within 1 year. (See Table 4, below.)

Table 4. Child-Turcotte-Pugh Scoring System for Cirrhosis (Open Table in a new

window)

Clinical Variable 1 Point 2 Points 3 Points

Encephalopathy None Grade 1-2 Grade 3-4

Moderate or
Ascites Absent Slight
large

Bilirubin (mg/dL) <2 2-3 >3

Bilirubin in PBC* or PSC**

<4 4-10 10
(mg/dL)

Albumin (g/dL) >3.5 2.8-3.5 < 2.8

Prothrombin time(seconds < 4 s or INR 4-6 s or INR >6 s or INR

prolonged or INR) < 1.7 1.7-2.3 >2.3

*PBC = Primary biliary cholangitis

**PSC = Primary sclerosing cholangitis

 Child Class A = 5-6 points, Child Class B = 7-9 points, Child Class C = 10-15
points

Since 2002, liver transplant programs in the United States have used the Model for
End-Stage Liver Disease (MELD) scoring system to assess the relative severity of
patients' liver disease. Patients may receive a MELD score of 6-40 points (see the
MELD Score calculator). The 3-month mortality statistics are associated with the
following MELD scores[55] :

MELD score of less than 9 - 2.9% mortality

MELD score of 10-19 - 7.7% mortality

MELD score of 20-29 - 23.5% mortality

MELD score of 30-39 - 60% mortality

MELD score of greater than 40 - 81% mortality

Pharmacologic Treatment
Specific medical therapies may be applied to many liver diseases in an effort to diminish
symptoms and to prevent or forestall the development of cirrhosis. Examples include
prednisone and azathioprine for autoimmune hepatitis, interferon and other antiviral
agents for hepatitis B and C,[56] phlebotomy for hemochromatosis, ursodeoxycholic
acid for primary biliary cholangitis, and trientine and zinc for Wilson disease.

In a retrospective meta-analysis of studies evaluating the efficacy of antiviral therapies

for decompensated hepatitis B cirrhosis, Zhao et al concluded that patients on effective
antiviral therapy have significantly improved Child-Turcotte-Pugh scores, suggesting
that decompensated hepatitis B cirrhosis can be recompensated. However, data are
limited, long-term studies are lacking, and further investigation is warranted.[57]

These therapies become progressively less effective if chronic liver disease evolves into
cirrhosis. Once cirrhosis develops, treatment is aimed at the management of
complications as they arise. Certainly variceal bleeding, ascites, and hepatic
encephalopathy are among the most serious complications experienced by patients
with cirrhosis. However, attention also must be paid to patients' chronic constitutional
complaints.

According to an analysis of data from the TURQUOISE-II study, presented in October

2014 at the Annual Scientific Meeting of the American College of Gastroenterology
(ACG), treatment with the combination of the protease inhibitor ABT-450 boosted with
ritonavir, the NS5A inhibitor ombitasvir, and the non-nucleoside polymerase inhibitor
dasabuvir plus ribavirin (3D + RBV) improved measures of liver function at 12 weeks in
hepatitis C patients with cirrhosis.[58]
Highly significant improvements from baseline were seen at 12 weeks for the liver
enzymes alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl
transferase.[58] Among patients with elevated transaminase levels at baseline, levels
normalized after 12 weeks in 70-90% of cases. Highly significant improvements were
also observed in conjugated bilirubin and albumin levels and in prothrombin time at 12
weeks.

Zinc deficiency

Zinc deficiency commonly is observed in patients with cirrhosis. Treatment with zinc
sulfate at 220 mg orally twice daily may improve dysgeusia and can stimulate appetite.
Furthermore, zinc is effective in the treatment of muscle cramps and is adjunctive
therapy for hepatic encephalopathy.

Pruritus

Pruritus is a common complaint in cholestatic liver diseases (eg, primary biliary

cholangitis) and in noncholestatic chronic liver diseases (eg, hepatitis C). Although
increased serum bile acid levels once were thought to be the cause of pruritus,
endogenous opioids are more likely to be the culprit pruritogen. Mild itching complaints
may respond to treatment with antihistamines and topical ammonium lactate.

Cholestyramine is the mainstay of therapy for the pruritus of liver disease. To avoid
compromising GI absorption, care should be taken to avoid coadministration of this
organic anion binder with any other medication.

Other medications that may provide relief against pruritus in addition to antihistamines
(eg, diphenhydramine, hydroxyzine) and ammonium lactate 12% skin cream (Lac-
Hydrin), include ursodeoxycholic acid, doxepin, and rifampin. Naltrexone may be
effective but is often poorly tolerated. Gabapentin is an unreliable therapy. Patients with
severe pruritus may require institution of ultraviolet light therapy or plasmapheresis.

Hypogonadism

Some male patients suffer from hypogonadism. Patients with severe symptoms may
undergo therapy with topical testosterone preparations, although their safety and
efficacy is not well studied. Similarly, the utility and safety of growth hormone therapy
remains unclear.

Osteoporosis

Patients with cirrhosis may develop osteoporosis. Supplementation with calcium and
vitamin D is important in patients at high risk for osteoporosis, especially patients with
chronic cholestasis or primary biliary cholangitis and patients receiving corticosteroids
for autoimmune hepatitis. The finding on bone densitometry studies of decreased bone
mineralization may prompt the institution of therapy with an aminobisphosphonate (eg,
alendronate sodium).

Vaccination
Patients with chronic liver disease should receive vaccination to protect them against
hepatitis A. Other protective measures include vaccination against influenza and
pneumococci.

Drug hepatotoxicity in the patient with cirrhosis

The institution of any new medical therapy warrants the performance of more frequent
liver chemistries; patients with liver disease can ill afford to have drug-induced liver
disease superimposed on their condition. Medications associated with drug-induced
liver disease include the following:

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Isoniazid

Valproic acid

Erythromycin

Amoxicillin-clavulanate

Ketoconazole

Chlorpromazine

Ezetimibe

Statins

Hepatic 3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors are frequently

associated with mild elevations of alanine aminotransferase (ALT) levels. However,
severe hepatotoxicity is reported infrequently.[59] The literature suggests that statins
can be used safely in most patients with chronic liver disease.[60] Certainly, liver
chemistries should be followed frequently after the initiation of therapy.

In a retrospective cohort study (1988-2011) evaluating mortality in cirrhotic patients on

statins (n = 81) compared to those not on statins (n = 162), Kumar and colleagues did
not find an association between increased mortality and statin use, but they did note
statin use may delay decompensation.[61]

In a study of the effects of statins in 58 patients with primary biliary cholangitis, Rajab
and Kaplan concluded that statin use is safe in patients with this condition.[62]
Individuals in the study were on statins for a median period of 41 months, with ALT
levels measured every 3 months. The authors found that these levels did not increase,
being slightly elevated when statin treatment began and normal by the last follow-up
analysis. Patients did not complain of muscle pain or weakness, and serum cholesterol
levels fell by 30%.

Analgesics
The use of analgesics in patients with cirrhosis can be problematic. Although high-dose
acetaminophen is a well-known hepatotoxin, most hepatologists permit the use of
acetaminophen in patients with cirrhosis at doses of up to 2000 mg daily.

NSAID use may predispose patients with cirrhosis to GI bleeding. Patients with
decompensated cirrhosis are at risk for NSAID-induced renal insufficiency, presumably
because of prostaglandin inhibition and worsening of renal blood flow. Opiate
analgesics are not contraindicated but must be used with caution in patients with
preexisting hepatic encephalopathy on account of the drugs' potential to worsen
underlying mental function.

Other drugs

Aminoglycoside antibiotics are considered obligate nephrotoxins in patients with

cirrhosis and should be avoided. Low-dose estrogens and progesterone appear to be
safe in the setting of liver disease.

A review by Lewis and Stine provided recommendations on the safe use of medications
in patients with cirrhosis, including the following[63, 64] :

Lower medication doses should generally be used, particularly in patients with

significant liver dysfunction

Proton-pump inhibitors and histamine-2 blockers should be used only for valid
indications, since they may lead to serious infections in patients with cirrhosis

Nutrition and Exercise

Many patients complain of anorexia, which may be compounded by the direct
compression of ascites on the GI tract. Care should be taken to ensure that patients
receive adequate calories and protein in their diets. Patients frequently benefit from the
addition of commonly available liquid and powdered nutritional supplements to the diet.
Only rarely are patients not able to tolerate proteins in the form of chicken, fish,
vegetables, and nutritional supplements. Institution of a low-protein diet out of concern
that hepatic encephalopathy may develop places the patient at risk for profound muscle
wasting.

The 2010 practice guidelines for alcoholic liver disease published by the American
Association for the Study of Liver Diseases and the American College of
Gastroenterology recommend aggressive treatment of protein calorie malnutrition in
patients with alcoholic cirrhosis. Multiple feedings per day, including breakfast and a
snack at night, are specified.[65]

Regular exercise, including walking and even swimming, should be encouraged in

patients with cirrhosis, to prevent these patients from slipping into a vicious cycle of
inactivity and muscle wasting. Debilitated patients frequently benefit from a formal
exercise program supervised by a physical therapist.
Surgical Risks
Surgery and general anesthesia carry increased risks in the patient with cirrhosis.
Anesthesia reduces cardiac output, induces splanchnic vasodilation, and causes a 30-
50% reduction in hepatic blood flow. This places the cirrhotic liver at additional risk for
decompensation.

Surgery is said to be safe in the setting of mild chronic hepatitis. Its risk in patients with
severe chronic hepatitis is unknown. Patients with well-compensated cirrhosis have
increased, but acceptable, morbidity and mortality risks. Care should be taken to avoid
postoperative infection, fluid overload, unnecessary sedatives and analgesics, and
potentially hepatotoxic and nephrotoxic drugs (eg, aminoglycoside antibiotics).

In the prelaparoscopic era, a study of nonshunt abdominal surgeries demonstrated a

10% mortality rate for patients with Child Class A cirrhosis, as opposed to a 30%
mortality rate for patients with Child Class B cirrhosis and a 75% mortality rate for
patients with Child Class C cirrhosis.[66] Although cholecystectomy was among the
riskier surgeries noted, several reports have described the successful performance of
laparoscopic cholecystectomy in patients with Child Class A or B cirrhosis.[67]

Studies have used the MELD score as a tool in predicting postoperative outcomes in
abdominal surgery (see the MELD Score calculator). In one study, a preoperative MELD
score of greater than 14 was a better predictor of postoperative death than Child Class
C status.[68]

In a study of patients with cirrhosis who underwent major digestive, orthopedic, or

cardiovascular surgery, the preoperative MELD scores and their associated 30-day
postoperative mortality rates were as follows[69] :

MELD score of 7 or less - 5.7% mortality

MELD score of 8-11 - 10.3% mortality

MELD score of 12-15 - 25.4% mortality

MELD score of 16-20 - 44% mortality

MELD score of 21-25 - 53.8% mortality

MELD score of greater than 26 - 90% mortality

The benefits and the risks of surgery should be carefully weighed before advising the
patient with cirrhosis to undergo surgery.

Liver Transplantation
Liver transplantation has emerged as an important strategy in the management of
patients with decompensated cirrhosis. Patients should be referred for consideration of
liver transplantation after the first signs of hepatic decompensation.
Advances in surgical technique, organ preservation, and immunosuppression have
resulted in dramatic improvements in postoperative survival. In the early 1980s, the
percentage of patients surviving 1 year and 5 years after liver transplant were only 70%
and 15%, respectively. Now, patients can anticipate a 1-year survival rate of 85-90%
and a 5-year survival rate of higher than 70%. Quality of life after liver transplant is good
or excellent in most cases.

Contraindications to transplant

Contraindications for liver transplantation include severe cardiovascular or pulmonary

disease, active drug or alcohol abuse, malignancy outside the liver, sepsis, or
psychosocial problems that might jeopardize patients' abilities to follow their medical
regimens after transplant.

According to the 2010 guidelines for alcoholic liver disease from the American
Association for the Study of Liver Diseases, patients whose end-stage liver disease is
alcohol related should be considered as candidates for transplantation after a medical
and psychosocial evaluation that includes formal assessment of the probability of long-
term abstinence.[65]

In a retrospective nationwide Danish study (1990-2013) that evaluated the cumulative

incidence of heavy drinking in 156 recipients of liver transplants for alcoholic liver
disease, Askgaard et al found that predictors of posttransplantation heavy drinking
included younger age, being retired, and not having a lifetime diagnosis of alcohol
dependence.[70]

The presence of the human immunodeficiency virus (HIV) in the bloodstream also is a
contraindication to transplant. However, successful liver transplantations are now being
performed in patients with no detectable HIV viral load due to antiretroviral therapy.[71]
Additional clinical studies are required before liver transplantation can be offered
routinely to such patients.

Organ allocation

Approximately 6500 liver transplants are performed in the United States each year. An
increasing number of lives are being saved every year by transplant. However, the
number of diagnosed cases of cirrhosis is rising, fueled in part by the hepatitis C
epidemic and by the growing number of cases of nonalcoholic fatty liver disease
(NAFLD). This has resulted in a dramatic increase in the number of patients listed as
candidates for liver transplantation.

Approximately 12-15% of patients listed as candidates die while waiting because of the
relatively static number of organ donations. Strategies to improve the current donor
organ shortage include programs to increase public awareness of the importance of
organ donation, increased use of living donor liver transplantation for pediatric and adult
recipients, organ donation after cardiac death, and the use of extended criteria donors
(ECDs).

An ECD "deviates in some aspect from the ideal donor." One example of an ECD organ
is the hepatitis C-infected liver with minimal fibrosis that is transplanted into a hepatitis
C-infected recipient. Such transplants have been performed successfully for a number
of years. Other examples of ECDs include donors older than 70 years and donors with
relatively minimal fatty livers.

The need for a more efficient and equitable system of organ allocation resulted in
dramatic changes in United States organ allocation policy in 2002.[72] Previously,
patients who were accepted as liver transplant candidates with 7-9 CTP points (Child
Class B) received low priority on the transplant waiting list maintained by the United
Network for Organ Sharing (UNOS). Patients with 10 or more CTP points (Child Class
C) received a higher priority. Emergent liver transplantation at UNOS status 1 was
reserved primarily for noncirrhotic patients suffering from fulminant hepatic failure.

Since 2002, livers from deceased donors (ie, cadaveric organs) have been allocated to
cirrhotic patients using the MELD scoring system and the Pediatric End-Stage Liver
Disease (PELD) scoring system[55] (see the MELD Score calculator and the PELD
Score calculator).

In the MELD scoring system for adults, a patient receives a score based on the
following formula:

MELD score = 0.957 x Loge (creatinine mg/dL) + 0.378 x Loge (bilirubin mg/dL) + 1.120
x Loge (INR) + 0.643

As an example, a cirrhotic patient with a creatinine level of 1.9 mg/dL, a bilirubin level of
4.2 mg/dL, and an INR of 1.2 would receive the following score:

MELD score = (0.957 x Loge 1.9) + (0.378 x Loge 4.2) + (1.120 x Loge 1.2) + 0.643 =
2.039

That value is then multiplied by 10 to give the patient a risk score of 20. Patients' MELD
scores are recalculated every time they undergo laboratory testing. Patients can be
assigned a maximum MELD score of 40 points.

The PELD system uses a somewhat different formula: PELD score = 0.480 x Loge
(total bilirubin mg/dL) + 1.857 x Loge (INR) - 0.687 x Loge (albumin g/dL) + 0.436 if the
patient is younger than 1 year + 0.667 if the patient has growth failure (< 2 standard
deviations). This value is multiplied by 10 to give a final risk score.

Within any region of the country, a donor organ in a particular ABO blood group is
allocated to the cirrhotic patient within the same blood group who has the highest MELD
or PELD score. Special rules have been developed to address potentially life-
threatening liver disease complications, such as hepatocellular carcinoma and
hepatopulmonary syndrome. Patients with these conditions, as well as other
exceptional cases, can receive a higher MELD or PELD score than that calculated from
creatinine, bilirubin, and INR alone.

The timing of the transplant surgery for patients on the transplant waiting list is a key
issue. Typically, it is believed that the risks of the transplant may exceed the benefits
when the MELD score is less than 15. However, when the MELD score is greater than
15, the benefits of the transplant typically exceed the risks.[73] Needless to say, there
can be many exceptions to this so-called rule.
Living donor liver transplantation

The advent of living donor liver transplantation (LDLT) has introduced a new variable
into any discussion of the timing of transplantation. LDLT has the potential to make liver
transplantation an elective procedure not only for the cirrhotic patient with significant
complications but also for the cirrhotic patient with a poor quality of life.

LDLT became a reality for pediatric recipients in 1988 and for adult recipients a decade
later. The procedure arose from advances in surgical technique and a worsening
shortage of deceased donor organs. In LDLT, up to 60% of a healthy volunteer donor's
liver can be surgically resected and transplanted into the abdomen of a recipient. Graft
survival in LDLT recipients is on par with that seen in the recipients of deceased donor
organs.

However, LDLT has its limitations. The most obvious problem is the low, but real, risk of
serious operative complications for the healthy volunteer liver donor. It is estimated that
about 0.4% of the more than 3000 healthy liver donors worldwide over the last decade
have died as a consequence of their surgery. Thus, transplant programs must maximize
donor safety. They must also ensure that the benefits of LDLT to the potential recipient
offset the risks to the donor.

Furthermore, not every potential recipient is sufficiently stable to undergo safe and
effective LDLT. Indeed, the recipient's risk of posttransplant mortality increases when his
or her MELD score is greater than 25. In the author's opinion, LDLT should not be
performed in such recipients.

Liver donation after cardiac death

The shortage of donor organs has spurred interest in the use of liver allografts from
non–heart beating donors (NHBDs). Typically, an NHBD is an individual who has
sustained irreversible neurologic damage but whose clinical condition does not meet
formal brain death criteria. Knowing this, a prospective donor's family will give consent
for withdrawal of care and for organ donation. The donor is then brought to the
operating room, with the anticipation that withdrawal of ventilator support will result in
the cessation of the patient's cardiopulmonary function. Once death is declared, organ
procurement surgery can proceed.

In contrast to the organ procured from a heart-beating donor (HBD), the allograft
obtained from an NHBD may be subject to considerable warm ischemia time before it is
perfused with the cold preservative solution.

A review comparing the results of liver transplantation using allografts from 144 NHBDs
and 26,856 HBDs over an 8-year period found better outcomes in HBD transplant
recipients.[74] One- and 3-year graft survival rates were 70% and 63%, respectively,
with organs from NHBDs, as opposed to 80% and 72%, respectively, with organs from
HBDs. Higher rates of primary nonfunction and retransplantation were seen in the
recipients of allografts from NHBDs.

Other authors have described a higher incidence of hepatic artery stenosis, hepatic
abscesses, and bilomas in the recipients of allografts from NHBDs.[75] It is possible
that improved results will be seen by limiting donor age, by minimizing donor warm
ischemia time, and by not attempting to transplant livers from NHBDs into recipients
who are severely ill.

The future of liver transplantation

Exciting new technical advances also may help to improve patients' chances of survival.
In the future, expanded use of hepatocyte transplantation may occur. In this therapy, a
splenic artery catheter is used to deliver billions of cryopreserved hepatocytes into the
spleen of a patient who has end-stage liver disease. The patient then undergoes routine
immunosuppression. This strategy has been employed successfully in a small number
of patients with cirrhosis and fulminant hepatic failure (FHF) who were not candidates
for liver transplant surgery.

Bioartificial livers may see increased application in the care of patients with FHF and,
perhaps, cirrhosis. The two most studied devices are composed of semipermeable
capillary hollow fiber membranes enclosed in a plastic shell. Either human C3A
hepatoma cells or pig hepatocytes are attached to the exterior surface of the
membranes as blood from the patient is pumped through the device. Intracranial
pressure and hepatic encephalopathy improved in some patients with FHF who were
assisted with these devices. However, currently available bioartificial livers have not yet
fulfilled the goals of biotransforming and removing toxins while supplying the patient
with clotting factors and growth factors.

Xenotransplantation may come into use during the next decade. To date, all attempts at
xenotransplantation in humans have suffered from severe, early humoral or late cellular
rejection and have resulted in patient death. Advances in genetic engineering may lead
to the development of swine as an organ donor because its livers are more likely to
undergo graft acceptance when transplanted into humans. Once this obstacle is
overcome, a determination can be made as to whether a swine liver is an effective
substitute for a human liver.

Most importantly, the medical world awaits the development of medical therapies that
forestall the development of hepatic fibrosis long before patients develop cirrhosis and
its complications.

Patient Monitoring
Patients with cirrhosis should undergo routine follow-up monitoring of their complete
blood count, renal and liver chemistries, and prothrombin time. The author's policy is to
monitor stable patients 3-4 times per year.

Surveillance of esophageal varices

The author performs routine diagnostic endoscopy to determine whether the patient has
asymptomatic esophageal varices. Follow-up endoscopy is performed in 2 years if
varices are not present. If varices are present, treatment is initiated with a nonselective
beta blocker (eg, propranolol, nadolol), aiming for a 25% reduction in heart rate. Such
therapy offers effective primary prophylaxis against new onset of variceal bleeding.[76]
Patients with large esophageal varices should undergo prophylactic endoscopic
variceal ligation.

Surveillance for hepatocellular carcinoma

The incidence of hepatocellular carcinoma (HCC) has risen in the United States. The
practice guidelines of the American Association for the Study of Liver Diseases
recommend that patients with cirrhosis undergo surveillance for HCC with
ultrasonography every 6 months.[77] The discovery of a liver nodule should prompt the
performance of a 4-phase CT scan or an MRI scan (ie, unenhanced, arterial, venous,
and delayed phases). Lesions that enhance in the arterial phase and exhibit "washout"
in the delayed phases are highly suggestive of HCC.

Many authors contend that the combination of arterial enhancement and washout on CT
scanning or MRI offers greater diagnostic power for HCC than does guided liver biopsy.
[78, 79] Indeed, guided liver biopsies have a 20-30% false negative rate in making the
diagnosis of HCC. Current guidelines support the use of CT scanning and MRI in
confirming the presence of HCC. Biopsy is not required in order to define a lesion as
HCC.[77] However, CT scanning or ultrasonographically guided liver biopsy may be
useful when a nodule’s enhancement characteristics are not typical for HCC.

Patients with a diagnosis of HCC and no evidence of extrahepatic disease, as

determined by chest and abdominal CT scans and by bone scan, should be offered
curative therapy. Commonly, this therapy entails liver resection surgery for patients with
Child Class A cirrhosis and an accelerated course to liver transplantation for patients
with Child Class B or C cirrhosis.

Patients who are awaiting liver transplantation are often offered minimally invasive
therapies in an effort to keep tumors from spreading. These therapies include
percutaneous injection therapy with ethanol, radiofrequency and microwave thermal
ablation, chemoembolization, intensity-modulated radiation therapy, and
radioembolization.

AASLD Treatment Recommendations

The 2016 American Association for the Study of Liver Diseases (AASLD) practice
guidelines include, but are not limited to, the information outlined below.[13]

Cirrhosis

For individuals with compensated cirrhosis and mild portal hypertension, the AASLD
provides the following guidance[13] :

The treatment goal is to prevent the development of clinically significant portal

hypertension (CSPH)/decompensation and, perhaps, even to achieve regression
of cirrhosis.
Elimination of the etiologic agent is the current mainstay of therapy.
Drugs that act on portal flow, such as nonselective beta-blockers, will be mostly
ineffective in this substage, given that the hyperdynamic circulatory state is not
 fully developed.

For individuals with compensated cirrhosis and CSPH but without gastroesophageal
varices, the AASLD recommends the following[13] :

The goal of treatment should be to prevent clinical decompensation (ie, it is no

longer the objective to prevent varices).
No evidence exists at present to recommend the use of nonselective beta-
blockers to prevent the formation of varices.

In patients with compensated cirrhosis and gastroesophageal varices, AASLD

recommendations include the following[13] :

Nonselective beta-blockers are the recommended therapy for patients with high-
risk small esophageal varices (ie, primary prevention in patients with small
esophageal varices).
Either traditional nonselective beta-blockers (eg, propranolol, nadolol),
carvedilol, or endoscopic variceal ligation (EVL) is recommended for the
prevention of first variceal hemorrhage (VH) (primary prophylaxis) in patients
with medium or large varices.
Treatment selection should be based on patient preference and characteristics.
Patients on nonselective beta-blockers or carvedilol for primary prophylaxis do
not require monitoring with serial esophagogastroduodenoscopy (EGD).
Not recommended in this setting: The combination therapy of nonselective
beta-blockers plus EVL
Not recommended in the prevention of first VH: Transjugular intrahepatic
portosystemic shunt (TIPS) placement

Variceal bleeding

For patients who present with acute esophageal VH, the AASLD guidelines indicate the
following[13] :

Conservative transfusion of packed red blood cell (PRBC): Starting to transfuse

when the hemoglobin reaches a threshold of around 7 g/dL, with the goal of
maintaining it between 7 and 9 g/dL.
Short-term (maximum 7 days) antibiotic prophylaxis should be instituted in any
patient with cirrhosis and gastrointestinal hemorrhage.
Intravenous (IV) ceftriaxone 1 g/24 h is the antibiotic of choice and should be
used for a maximum of 7 days (consider discontinuing when hemorrhage has
resolved and vasoactive drugs discontinued).
Vasoactive drugs (somatostatin or its analogue, octreotide; vasopressin or its
analogue, terlipressin) should be initiated as soon as VH is suspected.
EGD should be performed within 12 hours of admission and once the patient is
hemodynamically stable.
If a variceal source is confirmed/suspected, EVL should be performed.
In patients at high risk of failure or rebleeding (Child-Turcotte-Pugh [CTP] class
C cirrhosis or CTP class B with active bleeding on endoscopy) who have no
contraindications for TIPS, an “early” (preemptive) TIPS within 72 hours from
EGD/EVL may benefit selected patients.
 For patients in whom an early TIPS is not performed, IV vasoactive drugs should
be continued for 2-5 days and nonselective beta-blockers initiated once
vasoactive drugs are discontinued. Rescue TIPS is indicated in these patients if
hemorrhage cannot be controlled or if bleeding recurs despite the use of
vasoactive drugs plus EVL.
In patients in whom TIPS is performed successfully, IV vasoactive drugs can be
discontinued.

For individuals who have recovered from an episode of acute esophageal VH, the
AASLD recommends the following[13] :

First-line therapy in the prevention of rebleeding: The combination of

nonselective beta-blockers plus EVL
Patients who have had successful placement of a TIPS during the acute episode
do not require nonselective beta-blockers or EVL.
TIPS is the recommended rescue therapy in patients who experience recurrent
hemorrhage despite the use of combination therapy nonselective beta-blockers
plus EVL.

EASL Recommendations
In 2018, the European Association for the Study of the Liver (EASL) released updated
guidelines for the management of decompensated cirrhosis[80] and hepatocellular
carcinoma (HCC),[81] as outlined below.

Cirrhosis

In patients with decompensated cirrhosis, the etiologic factor, should be removed,

particularly alcohol consumption and hepatitis B or C virus infection, as this strategy is
associated with decreased risk of decompensation and increased survival.

Strategies based on targeting abnormalities in the gut-liver axis by antibiotic

administration (ie, rifaximin), improving the disturbed systemic circulatory function (ie,
long-term albumin administration), decreasing the inflammatory state (ie, statins), and
reducing portal hypertension (ie, beta blockers) have shown potential benefit to
decrease cirrhosis progression in patients with decompensated cirrhosis.

A diagnostic paracentesis is recommended in all patients with new-onset grade 2 or 3

ascites, or in those hospitalized for worsening of ascites or any complication of
cirrhosis.

Neutrophil count and culture of ascitic fluid culture (bedside inoculation of blood culture
bottles with 10 mL fluid each) should be performed to exclude bacterial peritonitis. A
neutrophil count above 250 cells/µL is required to diagnose spontaneous bacterial
peritonitis (SBP).

Ascitic total protein concentration should be performed to identify patients at higher risk
of developing SBP.
The serum ascites albumin gradient (SAAG) should be calculated when the cause of
ascites is not immediately evident, and/or when conditions other than cirrhosis are
suspected.

Cytology should be performed to differentiate malignancy-related from non-malignant

ascites.

Since the development of grade 2 or 3 ascites in patients with cirrhosis is associated

with reduced survival, liver transplantation (LT) should be considered as a potential
treatment option.

A moderate restriction of sodium intake (80–120 mmol/day, corresponding to 4.6–6.9 g

of salt) is recommended in patients with moderate, uncomplicated ascites. This is
generally equivalent to a no-added-salt diet with avoidance of pre-prepared meals.
Adequate nutritional education of patients on how to manage dietary sodium is also
recommended.

Diets with a very low sodium content (< 40 mmol/day) should be avoided, as they favor
diuretic-induced complications and can endanger a patient’s nutritional status.

Patients with the first episode of grade 2 (moderate) ascites should receive an anti-
mineralocorticoid drug alone, starting at 100 mg/day with stepwise increases every
72 hr (in 100 mg steps) to a maximum of 400 mg/day if there is no response to lower
doses.

In patients who do not respond to anti-mineralocorticoids, as defined by a body weight

reduction of less than 2 kg/wk, or in patients who develop hyperkalemia, furosemide
should be added at an increasing stepwise dose from 40 mg/day to a maximum of
160 mg/day (in 40 mg steps).

Patients with long-standing or recurrent ascites should be treated with a combination of

an anti-mineralocorticoid drug and furosemide, the dose of which should be increased
sequentially according to the response.

Torasemide can be given in patients exhibiting a weak response to furosemide.

During diuretic therapy, a maximum weight loss of 0.5 kg/day in patients without edema
and 1 kg/day in patients with edema is recommended.

Once ascites has largely resolved, the dose of diuretics should be reduced to the lowest
effective dose.

In patients presenting with gastrointestinal (GI) hemorrhage, renal impairment, hepatic

encephalopathy, hyponatremia, or alterations in serum potassium concentration, these
abnormalities should be corrected before starting diuretic therapy. In these patients,
cautious initiation of diuretic therapy and frequent clinical and biochemical assessments
should be performed. Diuretic therapy is generally not recommended in patients with
persistent overt hepatic encephalopathy.

Diuretics should be discontinued if severe hyponatremia (serum sodium concentration <

125 mmol/L), acute kidney injury (AKI), worsening hepatic encephalopathy, or
incapacitating muscle cramps develop.

Furosemide should be stopped if severe hypokalemia occurs (< 3 mmol/L). Anti-

mineralocorticoids should be stopped if severe hyperkalemia occurs (>6 mmol/L).

Albumin infusion or baclofen administration (10 mg/day, with a weekly increase of

10 mg/day up to 30 mg/day) is recommended in patients with muscle cramps.

Large volume paracentesis (LVP) is the first-line therapy in patients with large ascites
(grade 3 ascites), which should be completely removed in a single session. LVP should
be followed with plasma volume expansion to prevent post-paracentesis circulatory
dysfunction (PPCD).

In patients undergoing LVP greater than 5 L of ascites, plasma volume expansion

should be performed by infusing albumin (8 g/L of ascites removed), as it is more
effective than other plasma expanders, which are not recommended for this setting

In patients undergoing LVP less than 5 L of ascites, the risk of developing PPCD is low.
However, it is generally agreed that these patients should still be treated with albumin
because of concerns about use of alternative plasma expanders.

Non-steroidal anti-inflammatory drugs should not be used in patients with ascites

because of the high risk of developing further sodium retention, hyponatremia, and AKI.

Repeated LVP plus albumin (8 g/L of ascites removed) is recommended as first-line

treatment for refractory ascites.

Diuretics should be discontinued in patients with refractory ascites who do not excrete
>30 mmol/day of sodium under diuretic treatment.

Antibiotic prophylaxis is recommended in cirrhotic patients with acute GI bleeding

because it reduces the incidence of infections and improves control of bleeding and
survival. Treatment should be initiated on presentation of bleeding and continued for up
to 7 days. Ceftriaxone (1 g/24 hr) is the first choice in patients with decompensated
cirrhosis, those already on quinolone prophylaxis, and in hospital settings with high
prevalence of quinolone-resistant bacterial infections. Oral quinolones (norfloxacin
400 mg bid) should be used in the remaining patients.

Hepatocellular carcinoma

Vaccination against hepatitis B reduces the risk of HCC and is recommended for all
newborns and high-risk groups.

In patients with chronic hepatitis, antiviral therapies leading to sustained hepatitis B

virus (HBV) suppression in chronic hepatitis B and viral eradication in hepatitis C are
recommended, since they have been shown to prevent progression to cirrhosis and
HCC development.

Once cirrhosis is established, antiviral therapy is beneficial in preventing cirrhosis

progression and decompensation. Furthermore, successful antiviral therapy reduces
but does not eliminate the risk of HCC development. Antiviral therapies should follow
the EASL guidelines for the management of chronic hepatitis B and C infection.

Coffee consumption has been shown to decrease the risk of HCC in patients with
chronic liver disease. In these patients, coffee consumption should be encouraged.

Diagnosis of HCC in cirrhotic patients should be based on non-invasive criteria and/or

pathology.

In noncirrhotic patients, diagnosis of HCC should be confirmed by pathology.

Noninvasive criteria can only be applied to cirrhotic patients for nodule(s) ≥1 cm, in light
of the high pre-test probability and are based on imaging techniques obtained by
multiphasic computed tomography (CT), dynamic contrast-enhanced magnetic
resonance imaging (MRI), or contrast-enhanced ultrasound (CEUS). Diagnosis is based
on the identification of the typical hallmarks of HCC, which differ according to imaging
techniques or contrast agents (arterial phase hyperenhancement [APHE]) with washout
in the portal venous or delayed phases on CT and MRI using extracellular contrast
agents or gadobenate dimeglumine, APHE with washout in the portal venous phase on
MRI using gadoxetic acid, APHE with late-onset (>60 s) washout of mild intensity on
CEUS).

Because of their higher sensitivity and the analysis of the whole liver, CT scanning or
MRI should be used first.

Fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan is not

recommended for early diagnosis of HCC because of the high rate of false-negative
cases.

In patients at high risk of developing HCC, nodule(s) less than 1 cm in diameter

detected by ultrasound should be followed at ≤4-month intervals in the first year. If there
is no increase in the size or number of nodules, surveillance could be returned to the
usual 6-month interval thereafter.

In cirrhotic patients, diagnosis of HCC for nodules of ≥1 cm in diameter can be achieved

with non-invasive criteria and/or biopsy-proven pathologic confirmation.

Repeated bioptic sampling is recommended in cases of inconclusive histologic or

discordant findings, or in cases of growth or change in the enhancement pattern
identified during follow-up, but with imaging still not diagnostic for HCC.

Staging systems for clinical decision making in HCC should include tumor burden, liver
function, and performance status.

Multiphasic contrast-enhanced CT scanning or MRI is recommended for assessment of

response after resection, loco-regional, or systemic therapies.

Perioperative mortality of liver resection (LR) in cirrhotic patients should be less than
3%.
LR is recommended for single HCC of any size and in particular for tumors >2 cm, when
hepatic function is preserved, and when sufficient remnant liver volume is maintained.

Tumor vascular invasion and extrahepatic metastases are an absolute contraindication

for liver transplantation in HCC.

Thermal ablation with radiofrequency is the standard of care for patients with BCLC
(Barcelona Clinic Liver Cancer) 0 and A tumors not suitable for surgery. Thermal
ablation in single tumors 2 to 3 cm in size is an alternative to surgical resection based
on technical factors (location of the tumor) and hepatic and extrahepatic patient
conditions.

In patients with very early stage HCC (BCLC-0), radiofrequency ablation in favorable
locations can be adopted as first-line therapy even in surgical patients.

Ethanol injection is an option in some cases where thermal ablation is not technically
feasible, especially in tumors < 2 cm.

Sorafenib is the standard first-line systemic therapy for HCC. It is indicated for patients
with well-preserved liver function (Child-Pugh A) and with advanced tumors (BCLC–C)
or earlier stage tumors progressing upon or unsuitable for loco-regional therapies.

Lenvatinib has been shown to be non-inferior to sorafenib and is also recommended in

first-line therapy for HCC given its approval. It is indicated for patients with well-
preserved liver function (Child-Pugh A class), with good performance status, and with
advanced tumors – BCLC-C without main portal vein invasion or tumors progressing
upon or unsuitable for loco-regional therapies.

Regorafenib is recommended as second-line treatment for patients tolerating and

progressing on sorafenib and with well-preserved liver function (Child-Pugh A class)
and good performance status. Recently, cabozantinib has shown survival benefits
versus placebo in this setting.

Questions & Answers

Overview

What is the correlation between cirrhosis and chronic liver disease?

How is cirrhosis defined histologically?

What is the liver fibrosis?

What are the complications of cirrhosis?

How might the clinical presentation of cirrhosis vary among patients?

What are the CDC risk-based testing guidelines for hepatitis C virus (HCV) infection?

What are characteristics of Budd-Chiari syndrome in patients with cirrhosis?