CIRRHOSIS  Alpha-1 antitrypsin deficiency
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 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 1 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 cirrhosis
 Secondary biliary cirrhosis - Associated with chronic extrahepatic bile
duct obstruction
 Primary sclerosing cholangitis
 Hemochromatosis
 Wilson disease
 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.
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. [5]
Hepatic Fibrosis
The development of hepatic fibrosis reflects an alteration in the normally
balanced processes of extracellular matrix production and degradation. [6] 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
development of acute-on-chronic liver failure (ACLF), Dirchwolf et al found the
presence of distinct cytokine phenotypes was associated with cirrhosis
severity. [7]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). [7]
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. [8]
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. [9] 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. [9]
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
mansoniinfection 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. [10] In their retrospective study of 236
cirrhotic patients (compensated, n = 110; decompensated, n = 126) (mean
followup, 33.2 mo), a significant predictor for the presence of decompensation
was baseline higher model for end-stage liver disease (MELD) score; moreover,
signficant prognostic factors for developing cirrhosis included higher alanine
transaminase levels, lower albumin levels, and lower mean velocity in the portal
trunk. [10] For compensated patients, significant predictors were hepatocellular
carcinoma and lower albumin levels, whereas in decompensated patients, they
were elevated bilirubin levels and overt ascites. [10]
Measurement
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 hepatic venous pressure gradient (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. [11]
Ascites
Ascites, which is an accumulation of excessive fluid within the peritoneal cavity,
can be a complication of either hepatic or nonhepatic disease. The 4 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.) [12]
Table 1. Nonperitoneal Causes of Ascites [13] (Open Table in a new window)
Causes of Nonperitoneal
Examples
Ascites
Cirrhosis
Fulminant hepatic failure
Intrahepatic portal
hypertension
Veno-occlusive disease
Hepatic vein obstruction (ie, Budd-Chiari
syndrome)
Extrahepatic portal
hypertension
 Congestive heart failure Tuberculous peritonitis

Fungal and parasitic infections (eg, Candida,

Nephrotic syndrome
Histoplasma, Cryptococcus, Schistosoma
mansoni, Strongyloides, Entamoeba histolytica)
Hypoalbuminemia Granulomatous
Protein-losing enteropathy, Malnutrition
peritonitis

Sarcoidosis

Myxedema
Foreign bodies (ie, talc, cotton, wood fibers, starch,
and barium)

Ovarian tumors

Miscellaneous disorders Systemic lupus erythematosus

Pancreatic ascites

Vasculitis
Biliary ascites Henoch-Schönlein purpura

Secondary to malignancy Eosinophilic gastroenteritis

Secondary to trauma Whipple disease

Miscellaneous
Chylous disorders

Secondary to portal hypertension Endometriosis

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 [13] (Open Table in a new window)
Causes of
Examples
Peritoneal Ascites
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

Primary peritoneal mesothelioma
Malignant ascites
Secondary peritoneal carcinomatosis
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. [14]
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. [15] 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 [16] and trimethoprim-sulfamethoxazole at
1 double-strength tablet 5 days per week. [17]
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. [18] 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. [19]
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
Triglycerides (to rule out chylous
Culture Gram stain
ascites)
Total Bilirubin (to rule out biliary leak
protein when 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.[20]
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. [21]
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. [22]
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. [23]
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. [24]
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. [25] 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. [26] 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. [27] 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. [28] 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. [29]
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. [30, 31] 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. [32]
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). [33] 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.[34, 35]
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. [36]
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. [37] 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. [38]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. [39]
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. [40]
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.[41] Rifaximin also appeared to be more effective than lactulose
in trials that compared the 2 drugs head-to-head. [42]
Other drugs
Other chemicals capable of decreasing blood ammonia levels are L-ornithine L-
aspartate (available in Europe) and sodium benzoate. [43]
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. [44]
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. [45]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.
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 and the finding of orthodeoxia, 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 PaO 2 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 cirrhosis 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. [46] 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. [47] 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
 glutamyl transferase. [50] Among patients with elevated transaminase levels at
Grade baseline, levels normalized after 12 weeks in 70-90% of cases. Highly significant
Encephalopathy None Grade 3-4 improvements were also observed in conjugated bilirubin and albumin levels and
1-2
in prothrombin time at 12 weeks.

Zinc deficiency
Moderate
Ascites Absent Slight
or large 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
Bilirubin (mg/dL) <2 2-3 >3 cramps and is adjunctive therapy for hepatic encephalopathy.

Pruritus
Bilirubin in PBC* or Pruritus is a common complaint in cholestatic liver diseases (eg, primary biliary
<4 4-10 10
PSC** (mg/dL) cirrhosis) 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
Albumin (g/dL) >3.5 2.8-3.5 < 2.8 complaints may respond to treatment with antihistamines and topical ammonium
lactate.
Cholestyramine is the mainstay of therapy for the pruritus of liver disease. To
< 4 s or 4-6 s or avoid compromising GI absorption, care should be taken to avoid
Prothrombin time(seconds >6 s or coadministration of this organic anion binder with any other medication.
INR < INR
prolonged or INR) INR >2.3 Other medications that may provide relief against pruritus in addition to
1.7 1.7-2.3
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
*PBC = Primary biliary unreliable therapy. Patients with severe pruritus may require institution of
cirrhosis ultraviolet light therapy or plasmapheresis.

Hypogonadism

**PSC = Primary Some male patients suffer from hypogonadism. Patients with severe symptoms
sclerosing cholangitis 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.

Child Class A = 5-6 Osteoporosis

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 [48] :
 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, [49] phlebotomy for
hemochromatosis, ursodeoxycholic acid for primary biliary cirrhosis, and
trientine and zinc for Wilson disease.
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. [50]
Highly significant improvements from baseline were seen at 12 weeks for the
liver enzymes alanine aminotransferase, aspartate aminotransferase, and gamma-
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 cirrhosis and patients
receiving corticosteroids for autoimmune hepatitis. The discovery 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. [51] The literature
suggests that statins can be used safely in most patients with chronic liver
disease. [52]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. [53]
In a study of the effects of statins in 58 patients with primary biliary cirrhosis,
Rajab and Kaplan concluded that statin use is safe in patients with this
condition. [54]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 develop 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 [55, 56] :
 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. [57]
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. [58] 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. [59]
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. [60]
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 [61] :
 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. [57]
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. [62]
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. [63] 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. [64] 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 [48] (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. [65]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. [66] 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. [67] 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 2 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. [68] 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. [69] 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. [70, 71] 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. [69] 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.