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Cirrhosis represents the final common histologic pathway for a wide variety of
chronic liver diseases. The term cirrhosis was first introduced by Laennec in Granulomatous disease - Eg, sarcoidosis
1826. It is derived from the Greek term scirrhus and refers to the orange or Type IV glycogen storage disease
tawny surface of the liver seen at autopsy. Drug-induced liver disease - Eg, methotrexate, alpha methyldopa,
Cirrhosis is defined histologically as a diffuse hepatic process characterized by amiodarone
fibrosis and the conversion of normal liver architecture into structurally Venous outflow obstruction - Eg, Budd-Chiari syndrome, veno-
abnormal nodules. The progression of liver injury to cirrhosis may occur over occlusive disease
weeks to years. Indeed, patients with hepatitis C may have chronic hepatitis for
as long as 40 years before progressing to cirrhosis. Chronic right-sided heart failure
Many forms of liver injury are marked by fibrosis, which is defined as an excess Tricuspid regurgitation
deposition of the components of the extracellular matrix (ie, collagens, Epidemiology
glycoproteins, proteoglycans) in the liver. This response to liver injury
potentially is reversible. By contrast, in most patients, cirrhosis is not a reversible United States data
process.
In addition to fibrosis, the complications of cirrhosis include, but are not limited Chronic liver disease and cirrhosis result in about 35,000 deaths each year in the
to, portal hypertension, ascites, hepatorenal syndrome, and hepatic United States. Cirrhosis is the ninth leading cause of death in the United States
encephalopathy. and is responsible for 1.2% of all US deaths. Many patients die from the disease
Often a poor correlation exists between the histologic findings in cirrhosis and in their fifth or sixth decade of life.
the clinical picture. Some patients with cirrhosis are completely asymptomatic Each year, 2000 additional deaths are attributed to fulminant hepatic
and have a reasonably normal life expectancy. Other individuals have a failure (FHF). FHF may be caused viral hepatitis (eg, hepatitis A and B), drugs
multitude of the most severe symptoms of end-stage liver disease and have a (eg, acetaminophen), toxins (eg, Amanita phalloides, the yellow death-cap
limited chance for survival. Common signs and symptoms may stem from mushroom), autoimmune hepatitis, Wilson disease, or a variety of less common
decreased hepatic synthetic function (eg, coagulopathy), decreased detoxification etiologies. Cryptogenic causes are responsible for one third of fulminant cases.
capabilities of the liver (eg, hepatic encephalopathy), or portal hypertension (eg, Patients with the syndrome of FHF have a 50-80% mortality rate unless they are
variceal bleeding). salvaged by liver transplantation.
In August 2012, the Centers for Disease Control and Prevention (CDC) International data
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 Worldwide, cirrhosis is the 14th most common cause of death, but in Europe, it
born between 1945 and 1965, who account for approximately three fourths of all is the 4th most common cause of death. [5]
chronic HCV infections in the United States—without prior ascertainment of Hepatic Fibrosis
HCV risk (see Recommendations for the Identification of Chronic Hepatitis C The development of hepatic fibrosis reflects an alteration in the normally
Virus Infection Among Persons Born During 1945–1965). [2] One-time HCV balanced processes of extracellular matrix production and degradation. [6] The
testing in this population could identify nearly 808,600 additional people with extracellular matrix, the normal scaffolding for hepatocytes, is composed of
chronic infection. All individuals identified with HCV should be screened and/or collagens (especially types I, III, and V), glycoproteins, and proteoglycans.
managed for alcohol abuse, followed by referral to preventative and/or treatment Stellate cells, located in the perisinusoidal space, are essential for the production
services, as appropriate. of extracellular matrix. Stellate cells, which were once known as Ito cells,
For patient education information, see the Mental Health Center, as well lipocytes, or perisinusoidal cells, may become activated into collagen-forming
as Alcoholism. cells by a variety of paracrine factors. Such factors may be released by
Etiology hepatocytes, Kupffer cells, and sinusoidal endothelium following liver injury. As
Alcoholic liver disease once was considered to be the predominant source of an example, increased levels of the cytokine transforming growth factor beta1
cirrhosis in the United States, but hepatitis C has emerged as the nation's leading (TGF-beta1) are observed in patients with chronic hepatitis C and those with
cause of chronic hepatitis and cirrhosis. cirrhosis. TGF-beta1, in turn, stimulates activated stellate cells to produce type I
Many cases of cryptogenic cirrhosis appear to have resulted from nonalcoholic collagen.
fatty liver disease (NAFLD). When cases of cryptogenic cirrhosis are reviewed, In a study that evaluated serum cytokine levels between healthy patients, those
many patients have 1 or more of the classic risk factors for NAFLD: obesity, with stable cirrhosis, and patients with decompensated cirrhosis with and without
diabetes, and hypertriglyceridemia. [3] It is postulated that steatosis may regress in development of acute-on-chronic liver failure (ACLF), Dirchwolf et al found the
some patients as hepatic fibrosis progresses, making the histologic diagnosis of presence of distinct cytokine phenotypes was associated with cirrhosis
NAFLD difficult. Flavinoids have been reported to have positive effects on key severity. [7]Relative to the healthy patients, those with cirrhosis had elevated
pathophysiologic pathways in NAFLD (eg, lipid metabolism, insulin resistance, levels of proinflammatory cytokines (interleukin [IL]-6, -7, -8, -10, and -12, and
inflammation, oxidative stress) and may hold future potential for inclusion in tumor necrosis factor-alpha [TNF-α]) and chemoattractant elements. Leukocyte
NAFLD treatment. [4] count was positively correlated with disease severity across the scoring systems
Up to one third of Americans have NAFLD. About 2-3% of Americans have used, levels of IL-6 and IL-8 had positive correlation with Model for End-Stage
nonalcoholic steatohepatitis (NASH), in which fat deposition in the hepatocyte is Liver Disease (MELD) score, and IL-6 alone had a positive correlation with
complicated by liver inflammation and fibrosis. It is estimated that 10% of chronic liver failure-sequential organ failure assessment (Clif-SOFA) score at
patients with NASH will ultimately develop cirrhosis. NAFLD and NASH are day 7 (but a negative correlation with IL-2 at admission). [7]
anticipated to have a major impact on the United States' public health Increased collagen deposition in the space of Disse (the space between
infrastructure. hepatocytes and sinusoids) and the diminution of the size of endothelial fenestrae
The most common causes of cirrhosis in the United States include the following: lead to the capillarization of sinusoids. Activated stellate cells also have
Hepatitis C (26%) contractile properties. Capillarization and constriction of sinusoids by stellate
Alcoholic liver disease (21%) cells contribute to the development of portal hypertension.
Future drug strategies to prevent fibrosis may focus on reducing hepatic
Hepatitis C plus alcoholic liver disease (15%) inflammation, inhibiting stellate cell activation, inhibiting the fibrogenic
Cryptogenic causes (18%) - Many cases actually are due to NAFLD activities of stellate cells, and stimulating matrix degradation.
Hepatitis B - May be coincident with hepatitis D (15%) Portal Hypertension
Miscellaneous (5%) Causes
Miscellaneous causes of chronic liver disease and cirrhosis include the
following: The normal liver has the ability to accommodate large changes in portal blood
Autoimmune hepatitis flow without appreciable alterations in portal pressure. Portal
Primary biliary cirrhosis hypertension results from a combination of increased portal venous inflow and
increased resistance to portal blood flow.
Secondary biliary cirrhosis - Associated with chronic extrahepatic bile Patients with cirrhosis demonstrate increased splanchnic arterial flow and,
duct obstruction accordingly, increased splanchnic venous inflow into the liver. Increased
Primary sclerosing cholangitis splanchnic arterial flow is explained partly by decreased peripheral vascular
Hemochromatosis resistance and increased cardiac output in the patient with cirrhosis. Nitric oxide
appears to be the major driving force for this phenomenon. [8]
Wilson disease
Furthermore, evidence for splanchnic vasodilation exists. Putative splanchnic carcinoma and lower albumin levels, whereas in decompensated patients, they
vasodilators include glucagon, vasoactive intestinal peptide, substance P, were elevated bilirubin levels and overt ascites. [10]
prostacyclin, bile acids, tumor necrosis factor-alpha (TNF-alpha), and nitric
oxide. Measurement
Increased resistance across the sinusoidal vascular bed of the liver is caused by
fixed factors and dynamic factors. Two thirds of intrahepatic vascular resistance Widespread use of the transjugular intrahepatic portosystemic shunt (TIPS)
can be explained by fixed changes in the hepatic architecture. Such changes procedure in the 1990s for the management of variceal bleeding led to a
include the formation of regenerating nodules and, after the production of resurgence of clinicians' interest in measuring portal pressure. During
collagen by activated stellate cells, deposition of the collagen within the space of angiography, a catheter may be placed selectively via either the transjugular or
Disse. transfemoral route into the hepatic vein. In the healthy patient, free hepatic vein
Dynamic factors account for one third of intrahepatic vascular resistance. Stellate pressure (FHVP) is equal to inferior vena cava pressure. FHVP is used as an
cells serve as contractile cells for adjacent hepatic endothelial cells. The nitric internal zero reference point.
oxide produced by the endothelial cells, in turn, controls the relative degree of Wedged hepatic venous pressure (WHVP) is measured by inflating a balloon at
vasodilation or vasoconstriction produced by the stellate cells. In cirrhosis, the catheter tip, thus occluding a hepatic vein branch. Measurement of the
decreased local production of nitric oxide by endothelial cells permits stellate WHVP provides a close approximation of portal pressure. The WHVP actually is
cell contraction, with resulting vasoconstriction of the hepatic sinusoid. (This slightly lower than the portal pressure because of some dissipation of pressure in
contrasts with the peripheral circulation, where there are high circulating levels the sinusoidal bed. The WHVP and portal pressure are elevated in patients with
of nitric oxide in cirrhosis.) Increased local levels of vasoconstricting chemicals, sinusoidal portal hypertension, as is observed in cirrhosis.
such as endothelin, may also contribute to sinusoidal vasoconstriction.
Complications
The portal hypertension of cirrhosis is caused by the disruption of hepatic
sinusoids. However, portal hypertension may be observed in a variety of The hepatic venous pressure gradient (HVPG) is defined as the difference in
noncirrhotic conditions. pressure between the portal vein and the inferior vena cava. Thus, the HVPG is
Prehepatic causes equal to the WHVP value minus the FHVP value (ie, HVPG = WHVP - FHVP).
Prehepatic causes include splenic vein thrombosis and portal vein thrombosis. The normal HVPG is 3-6 mm Hg.
These conditions commonly are associated with hypercoagulable states and with Portal hypertension is defined as a sustained elevation of portal pressure above
malignancy (eg, pancreatic cancer). In a retrospective study (2002-2014) of 66 normal. An HVPG of 8 mm Hg is believed to be the threshold above which
patients with cirrhosis and portal vein thrombosis, Chen et al reported that ascites potentially can develop. An HVPG of 12 mm Hg is the threshold for the
warfarin anticoagulation may potentially safely and effectively resolve cases of potential formation of varices. High portal pressures may predispose patients to
more advanced portal vein thrombosis. [9] However, they did not observe any an increased risk of variceal hemorrhage. [11]
benefit of anticoagulation on decompensation or mortality. Levels of albumin Ascites
were significant predictors of decompensated disease at 1 year. [9] Ascites, which is an accumulation of excessive fluid within the peritoneal cavity,
Intrahepatic causes can be a complication of either hepatic or nonhepatic disease. The 4 most
Intrahepatic causes of portal hypertension are divided into presinusoidal, common causes of ascites in North America and Europe are cirrhosis, neoplasm,
sinusoidal, and postsinusoidal conditions. The classic sinusoidal cause of portal congestive heart failure, and tuberculous peritonitis.
hypertension is cirrhosis. In the past, ascites was classified as being a transudate or an exudate. In
The classic form of presinusoidal portal hypertension is caused by the deposition transudative ascites, fluid was said to cross the liver capsule because of an
of Schistosoma oocytes in presinusoidal portal venules, with the subsequent imbalance in Starling forces. In general, ascites protein would be less than 2.5
development of granulomata and portal fibrosis. Schistosomiasis is the most g/dL in this form of ascites. A classic cause of transudative ascites would be
common noncirrhotic cause of variceal bleeding worldwide. Schistosoma portal hypertension secondary to cirrhosis and congestive heart failure.
mansoniinfection is described in Puerto Rico, Central and South America, the In exudative ascites, fluid was said to weep from an inflamed or tumor-laden
Middle East, and Africa. S japonicum is described in the Far East. S peritoneum. In general, ascites protein in exudative ascites would be greater than
hematobium, observed in the Middle East and Africa, can produce portal fibrosis 2.5 g/dL. Causes of the condition would include peritoneal carcinomatosis and
but more commonly is associated with urinary tract deposition of eggs. tuberculous peritonitis.
The classic postsinusoidal condition is an entity known as veno-occlusive
disease. Obliteration of the terminal hepatic venules may result from ingestion of Nonperitoneal causes
pyrrolizidine alkaloids in Comfrey tea or Jamaican bush tea or following the
high-dose chemotherapy that precedes bone marrow transplantation. Attributing ascites to diseases of nonperitoneal or peritoneal origin is more
Posthepatic causes useful. Thanks to the work of Bruce Runyon, the serum-ascites albumin gradient
Posthepatic causes of portal hypertension may include chronic right-sided heart (SAAG) has come into common clinical use for differentiating these conditions.
failure and tricuspid regurgitation and obstructing lesions of the hepatic veins Nonperitoneal diseases produce ascites with a SAAG greater than 1.1 g/dL. (See
and inferior vena cava. The latter conditions, and the symptoms they produce, Table 1, below.) [12]
are termed Budd-Chiari syndrome. Predisposing conditions include Table 1. Nonperitoneal Causes of Ascites [13] (Open Table in a new window)
hypercoagulable states, tumor invasion into the hepatic vein or inferior vena
cava, and membranous obstruction of the inferior vena cava. Inferior vena cava Causes of Nonperitoneal
Examples
webs are observed most commonly in South and East Asia and are postulated to Ascites
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 Cirrhosis
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 Fulminant hepatic failure
produce ascites and varices. Intrahepatic portal
Hepatic vein patency is checked most readily by performing abdominal hypertension
ultrasonography, with Doppler examination of the hepatic vessels. Abdominal
computed tomography (CT) scanning with intravenous (IV) contrast, abdominal Veno-occlusive disease
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 Hepatic vein obstruction (ie, Budd-Chiari
was baseline higher model for end-stage liver disease (MELD) score; moreover, syndrome)
Extrahepatic portal
signficant prognostic factors for developing cirrhosis included higher alanine hypertension
transaminase levels, lower albumin levels, and lower mean velocity in the portal
trunk. [10] For compensated patients, significant predictors were hepatocellular
Congestive heart failure Tuberculous peritonitis
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
Vasculitis
Biliary ascites Henoch-Schönlein purpura
Chylous ascites, caused by obstruction of the thoracic duct or cisterna chyli, most
The role of portal hypertension in the pathogenesis of cirrhotic ascites
often is due to malignancy (eg, lymphoma) but occasionally is observed
postoperatively and following radiation injury. Chylous ascites also may be The formation of ascites in cirrhosis depends on the presence of unfavorable
observed in the setting of cirrhosis. The triglyceride concentration of the ascites Starling forces within the hepatic sinusoid and on some degree of renal
is greater than 110 mg/dL and greater than that observed in plasma. Patients dysfunction. Patients with cirrhosis are observed to have increased hepatic
should be placed on a low-fat diet that is supplemented with medium-chain lymphatic flow.
triglycerides. Treatment with diuretics and large-volume paracentesis may be Fluid and plasma proteins diffuse freely across the highly permeable sinusoidal
required. 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
Peritoneal causes
liver.
Peritoneal diseases produce ascites with a SAAG of less than 1.1 g/dL. (See Because the trans-sinusoidal oncotic gradient is approximately zero, the
Table 2, below.) increased sinusoidal pressure that develops in portal hypertension increases the
Table 2. Peritoneal Causes of Ascites [13] (Open Table in a new window) amount of fluid entering the space of Disse. When the increased hepatic lymph
production observed in portal hypertension exceeds the ability of the cisterna
Causes of chyli and thoracic duct to clear the lymph, fluid crosses into the liver
Examples interstitium. Fluid may then extravasate across the liver capsule into the
Peritoneal Ascites
peritoneal cavity.
Peritoneovenous shunts Hepatorenal syndrome progression may be slow (type II) or rapid (type
I). [33] Type I disease frequently is accompanied by rapidly progressive liver
LeVeen shunts and Denver shunts are devices that permit the return of ascites failure. Hemodialysis offers temporary support for such patients. These
fluid and proteins to the intravascular space. Plastic tubing inserted individuals are salvaged only by performance of liver transplantation. Exceptions
subcutaneously under local anesthesia connects the peritoneal cavity to the to this rule are the patients with fulminant hepatic failure (FHF) or severe
internal jugular vein or subclavian vein via a pumping chamber. These devices alcoholic hepatitis who spontaneously recover liver and kidney function. In type
are successful at relieving ascites and reversing protein loss in some patients. II hepatorenal syndrome, patients may have stable or slowly progressive renal
However, shunts may clot and require replacement in 30% of patients. insufficiency. Many such patients develop ascites that is resistant to management
Serious complications are observed in at least 10% of the recipients of these with diuretics.
devices, including peritoneal infection, sepsis, disseminated intravascular
coagulation, congestive heart failure, and death. The author considers Diagnosis
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- Hepatorenal syndrome is diagnosed when a creatinine clearance rate of less than
volume paracentesis procedures may actually outweigh the safety of 40 mL/min is present or when a serum creatinine level of greater than 1.5 mg/dL,
peritoneovenous shunt placement. 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.
Portosystemic shunts and transjugular intrahepatic portosystemic shunts 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 Grade 4 - Coma, with or without response to painful stimuli
occurs following the infusion of at least 1.5 L of a plasma expander. Patients with mild and moderate hepatic encephalopathy demonstrate decreased
short-term memory and concentration on mental status testing. Findings on
Treatment
physical examination include asterixis and fetor hepaticus.
Nephrotoxic medications, including aminoglycoside antibiotics, should be
Laboratory abnormalities
avoided in patients with cirrhosis. Patients with early hepatorenal syndrome may
be salvaged by aggressive expansion of intravascular volume with albumin and An elevated arterial or free venous serum ammonia level is the classic laboratory
fresh frozen plasma and by avoidance of diuretics. The use of renal-dose abnormality reported in patients with hepatic encephalopathy. This finding may
dopamine is not effective. aid in the assignment of a correct diagnosis to a patient with cirrhosis who
A number of investigators have employed systemic vasoconstrictors in an presents with altered mental status.
attempt to reverse the effects of nitric oxide on peripheral arterial vasodilation. In However, serial ammonia measurements are inferior to clinical assessment in
Europe, administration of IV terlipressin (an analog of vasopressin not available gauging improvement or deterioration in patients under therapy for hepatic
in the United States) improved renal dysfunction in patients with hepatorenal encephalopathy. No utility exists for checking the ammonia level in a patient
syndrome.[34, 35] with cirrhosis who does not have hepatic encephalopathy.
A combination of midodrine (an oral alpha agonist), subcutaneous octreotide, Some patients with hepatic encephalopathy have the classic, but nonspecific,
and albumin infusion has also been demonstrated to improve renal function in electroencephalogram (EEG) changes of high-amplitude low-frequency waves
small cohorts of patients with hepatorenal syndrome. [36] and triphasic waves. Electroencephalography may be helpful in the initial
Hepatic Encephalopathy workup of a patient with cirrhosis and altered mental status, when ruling out
Hepatic encephalopathy, a syndrome observed in some patients with cirrhosis, is seizure activity may be necessary.
marked by personality changes, intellectual impairment, and a depressed level of CT scan and MRI studies of the brain may be important in ruling out intracranial
consciousness. The diversion of portal blood into the systemic circulation lesions when the diagnosis of hepatic encephalopathy is in question.
appears to be a prerequisite for the syndrome. Indeed, hepatic encephalopathy
may develop in patients without cirrhosis who undergo portocaval shunt surgery. Common precipitants
Pathogenesis Some patients with a history of hepatic encephalopathy have normal mental
status when under medical therapy. Others have chronic memory impairment in
A number of theories have been postulated to explain the pathogenesis of hepatic spite of medical management. Both groups of patients are subject to episodes of
encephalopathy in patients with cirrhosis. Patients may have altered brain energy worsened encephalopathy. Common precipitants of hyperammonemia and
metabolism and increased permeability of the blood-brain barrier. The latter may worsening mental status are as follows:
facilitate the passage of neurotoxins into the brain. Putative neurotoxins include
short-chain fatty acids, mercaptans, false neurotransmitters (eg, tyramine, Diuretic therapy
octopamine, beta phenylethanolamines), ammonia, and gamma-aminobutyric Hypovolemia
acid (GABA). Renal failure
Ammonia hypothesis GI bleeding
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 Infection
conversion to urea and glutamine. In liver disease or portosystemic shunting, Constipation
portal blood ammonia is not converted efficiently to urea. Increased levels of Dietary protein overload is an infrequent cause of worsening encephalopathy.
ammonia may enter the systemic circulation because of portosystemic shunting. Medications, notably opiates, benzodiazepines, antidepressants, and
Ammonia has multiple neurotoxic effects, including alteration of the transit of antipsychotic agents, also may worsen encephalopathic symptoms.
amino acids, water, and electrolytes across the neuronal membrane. Ammonia
also can inhibit the generation of excitatory and inhibitory postsynaptic Differential diagnosis
potentials. Therapeutic strategies to reduce serum ammonia levels tend to
improve hepatic encephalopathy. However, approximately 10% of patients with Conditions to consider in the differential diagnosis of encephalopathy include the
significant encephalopathy have normal serum ammonia levels. Furthermore, following:
many patients with cirrhosis have elevated ammonia levels without evidence of Intracranial lesions - Eg, subdural hematoma, intracranial bleeding,
encephalopathy. cerebrovascular accident, tumor, abscess
Gamma-aminobutyric acid hypothesis Infections - Eg, meningitis, encephalitis, abscess
GABA is a neuroinhibitory substance produced in the GI tract. It was postulated
Metabolic encephalopathy - Eg, hypoglycemia, electrolyte imbalance,
that GABA crosses the extrapermeable blood-brain barriers of patients with
anoxia, hypercarbia, uremia
cirrhosis and then interacts with supersensitive postsynaptic GABA
receptors. [37] This would lead to the generation of inhibitory postsynaptic Hyperammonemia from other causes - Eg, secondary to
potentials. Clinically, this interaction was believed to produce the symptoms of ureterosigmoidostomy, inherited urea cycle disorders
hepatic encephalopathy. Subsequent work has suggested that brain GABA levels Toxic encephalopathy due to alcohol - Eg, acute intoxication, alcohol
are not increased in patients with cirrhosis. withdrawal, Wernicke encephalopathy
However, brain levels of neurosteroids are increased in patients with Toxic encephalopathy due to drugs - Eg, sedative-hypnotics,
cirrhosis. [38]They are capable of binding to their receptor within the neuronal antidepressants, antipsychotic agents, salicylates
GABA receptor complex and can increase inhibitory neurotransmission. Some
investigators currently contend that neurosteroids may play a key role in hepatic Organic brain syndrome
encephalopathy. [39] Postseizure encephalopathy
Clinical features Management
The symptoms of hepatic encephalopathy may range from mild to severe and Nonhepatic causes of altered mental function must be excluded in patients with
may be observed in as many as 70% of patients with cirrhosis. Symptoms are cirrhosis who have worsening mental function. A check of the blood ammonia
graded on the following scale: level may be helpful in such patients. Medications that depress central nervous
system (CNS) function, especially benzodiazepines, should be avoided.
Grade 0 - Subclinical; normal mental status but minimal changes in
memory, concentration, intellectual function, coordination Precipitants of hepatic encephalopathy should be corrected (eg, hypovolemia,
metabolic disturbances, GI bleeding, infection, constipation).
Grade 1 - Mild confusion, euphoria or depression, decreased attention, Lactulose
slowing of ability to perform mental tasks, irritability, disorder of sleep Lactulose is helpful in patients with an acute onset of severe encephalopathy
pattern (ie, inverted sleep cycle) symptoms and in patients with milder, chronic symptoms. This nonabsorbable
Grade 2 - Drowsiness, lethargy, gross deficits in ability to perform disaccharide stimulates the passage of ammonia from tissues into the gut lumen
mental tasks, obvious personality changes, inappropriate behavior, and inhibits intestinal ammonia production. Initial lactulose dosing is 30 mL
intermittent disorientation (usually with regard to time) orally once or twice daily. Dosing is increased until the patient has 2-4 loose
Grade 3 - Somnolent, but arousable state; inability to perform mental stools per day. Dosing should be reduced if the patient complains of diarrhea,
tasks; disorientation with regard to time and place; marked confusion; abdominal cramping, or bloating.
amnesia; occasional fits of rage; speech is present but incomprehensible
Higher doses of lactulose may be administered via either a nasogastric or rectal Hematologic manifestations
tube to hospitalized patients with severe encephalopathy. Other cathartics,
including colonic lavage solutions that contain polyethylene glycol (PEG) (eg, Anemia may result from folate deficiency, hemolysis, or
Go-Lytely), also may be effective in patients with severe encephalopathy. hypersplenism. [45]Thrombocytopenia usually is secondary to hypersplenism and
In a study, Sharma et al concluded that the use of lactulose effectively prevents decreased levels of thrombopoietin. Coagulopathy results from decreased hepatic
hepatic encephalopathy recurrence in cirrhosis. Patients with cirrhosis recovering production of coagulation factors. If cholestasis is present, decreased micelle
from hepatic encephalopathy were randomized to receive lactulose (n = 61) or entry into the small intestine leads to decreased vitamin K absorption, with
placebo (n = 64). Over a median follow-up of 14 months, 12 patients (19.6%) in resulting reduction in hepatic production of factors II, VII, IX, and X. Patients
the lactulose group developed hepatic encephalopathy, compared with 30 with cirrhosis also may experience fibrinolysis and disseminated intravascular
patients (46.8%) in the placebo group. [40] coagulation.
Antibiotics
Neomycin and other antibiotics (eg, metronidazole, oral vancomycin, Pulmonary and cardiac manifestations
paromomycin, oral quinolones) serve as second-line agents. They work by
Patients with cirrhosis may have impaired pulmonary function. Pleural effusions
decreasing the colonic concentration of ammoniagenic bacteria. Neomycin
and the diaphragmatic elevation caused by massive ascites may alter ventilation-
dosing is 250-1000 mg orally 2-4 times daily. Treatment with neomycin may be
perfusion relations. Interstitial edema or dilated precapillary pulmonary vessels
complicated by ototoxicity and nephrotoxicity.
may reduce pulmonary diffusing capacity.
Rifaximin (Xifaxan) is a nonabsorbable antibiotic that received FDA approval in
Patients also may have hepatopulmonary syndrome (HPS). In this condition,
2004 for the treatment of travelers' diarrhea and was given approval in 2010 for
pulmonary arteriovenous anastomoses result in arteriovenous shunting. HPS is a
the reduction of recurrent hepatic encephalopathy. This drug was also approved
potentially progressive and life-threatening complication of cirrhosis. Classic
in May 2015 for the treatment of diarrhea-predominant irritable bowel syndrome
HPS is marked by the symptom of platypnea and the finding of orthodeoxia, but
(IBS-D). Data from Europe suggest that rifaximin can decrease colonic levels of
the syndrome must be considered in any patient with cirrhosis who has evidence
ammoniagenic bacteria, with resulting improvement in the symptoms of hepatic
of oxygen desaturation.
encephalopathy.
HPS is detected most readily by echocardiographic visualization of late-
A double-blind, placebo-controlled trial, indicated that rifaximin can prevent the
appearing bubbles in the left atrium following the injection of agitated saline.
occurrence hepatic encephalopathy. In the study, 299 patients whose recurrent
Patients can receive a diagnosis of HPS when their PaO2 is less than 70 mm Hg.
hepatic encephalopathy was in remission received either rifaximin 550 mg or
Some cases of HPS may be corrected by liver transplantation. In fact, a patient's
placebo twice daily. Each group also received lactulose. Breakthrough episodes
course to liver transplantation may be expedited when his or her PaO 2 is less than
of hepatic encephalopathy occurred in 22% of patients treated with rifaximin and
60 mm Hg.
in 46% of patients who were given placebo, while hepatic encephalopathy –
Portopulmonary hypertension (PPHTN) is observed in up to 6% of patients with
related hospitalization occurred in 14% of rifaximin patients and in 23% of
cirrhosis. Its etiology is unknown. PPHTN is defined as the presence of a mean
placebo patients.[41] Rifaximin also appeared to be more effective than lactulose
pulmonary artery pressure of greater than 25 mm Hg in the setting of a normal
in trials that compared the 2 drugs head-to-head. [42]
pulmonary capillary wedge pressure.
Other drugs
Routine Doppler echocardiography is performed as part of the regular workup in
Other chemicals capable of decreasing blood ammonia levels are L-ornithine L-
many liver transplant programs to rule out the interval development of PPHTN in
aspartate (available in Europe) and sodium benzoate. [43]
patients on the transplant waiting list. Indeed, the presence of a mean pulmonary
Protein restriction
pressure of greater than 35 mm Hg significantly increases the risks of liver
Low-protein diets were recommended routinely in the past for patients with
transplant surgery. Patients who develop severe PPHTN may require aggressive
cirrhosis. High levels of aromatic amino acids contained in animal proteins were
medical therapy in an effort to stabilize pulmonary artery pressures and to
believed to lead to increased blood levels of the false neurotransmitters tyramine
decrease their chance of perioperative mortality.
and octopamine, with resultant worsening of encephalopathic symptoms. In this
author's experience, the vast majority of patients can tolerate a protein-rich diet Hepatocellular carcinoma and cholangiocarcinoma
(>1.2 g/kg daily) that includes well-cooked chicken, fish, vegetable protein, and,
if needed, protein supplements. Hepatocellular carcinoma (HCC) ultimately arises in 10-25% of patients with
Protein restriction is rarely necessary in patients with symptoms of chronic cirrhosis in the United States. It typically occurs in about of 3% of patients per
encephalopathy. Many patients with cirrhosis have protein-calorie malnutrition year, when the etiology of cirrhosis is hepatitis B, hepatitis C, or alcohol. It
at baseline; the routine restriction of dietary protein intake increases their risk for develops more commonly in patients with underlying hereditary
worsening malnutrition. hemochromatosis or alpha-1 antitrypsin deficiency. HCC is observed less
In the author's opinion, protein restriction is infrequently valuable in patients commonly in primary biliary cirrhosis and is a rare complication of Wilson
with an acute flare-up of symptoms of hepatic encephalopathy. One study disease.
randomized hospitalized patients with hepatic encephalopathy to receive either a Hepatobiliary scintigraphy may improve radioembolization treatment planning in
normal-protein diet or a low-protein diet, in addition to standard treatment HCC patients when clinical and laboratory findings may not be
measures, and found no difference between the 2 groups in outcomes for hepatic sufficient. [46] This imaging modality may aid in estimating liver function reserve
encephalopathy. [44] and its segmental distribution, particularly in those with underlying cirrhosis.
Other Manifestations of Cirrhosis Cholangiocarcinoma occurs in approximately 10% of patients with primary
All chronic liver diseases that progress to cirrhosis have in common the sclerosing cholangitis. Early diagnosis of HCC is critical because it is potentially
histologic features of hepatic fibrosis and nodular regeneration. However, the curable through either liver resection or liver transplant.
patients' signs and symptoms may vary, depending on the underlying etiology of
the disease. Other diseases
As an example, patients with end-stage liver disease caused by hepatitis C may
develop profound muscle wasting, marked ascites, and severe hepatic Other conditions that appear with increased incidence in patients with cirrhosis
encephalopathy, with only mild jaundice. In contrast, patients with end-stage include peptic ulcer disease, diabetes, and gallstones.
primary biliary cirrhosis may be deeply icteric, with no evidence of muscle Assessment of the Severity of Cirrhosis
wasting. These patients may complain of extreme fatigue and pruritus and have For many years, the most common prognostic tool used in patients with cirrhosis
no complications of portal hypertension. In both cases, medical management is was the Child-Turcotte-Pugh (CTP) system. Child and Turcotte first introduced
focused on the relief of symptoms. Liver transplantation should be considered as their scoring system in 1964 as a means of predicting the operative mortality
a potential therapeutic option, given the inexorable course of most cases of end- associated with portocaval shunt surgery. Pugh's revised system in 1973
stage liver disease. substituted albumin for the less specific variable of nutritional
Many patients with cirrhosis experience fatigue, anorexia, weight loss, and status. [47] Subsequent revisions have used the International Normalized Ratio
muscle wasting. Cutaneous manifestations of cirrhosis include jaundice, spider (INR) in addition to prothrombin time.
angiomata, skin telangiectasias (termed "paper money skin" by Dame Sheila Epidemiologic work shows that the CTP score may predict life expectancy in
Sherlock), palmar erythema, white nails, disappearance of lunulae, and finger patients with advanced cirrhosis. A CTP score of 10 or greater is associated with
clubbing, especially in the setting of hepatopulmonary syndrome. a 50% chance of death within 1 year. (See Table 4, below.)
Patients with cirrhosis may experience increased conversion of androgenic Table 4. Child-Turcotte-Pugh Scoring System for Cirrhosis (Open Table in a
steroids into estrogens in skin, adipose tissue, muscle, and bone. Males may new window)
develop gynecomastia and impotence. Loss of axillary and pubic hair is noted in
men and women. Hyperestrogenemia also may explain spider angiomata and Clinical Variable 1 Point 2 Points 3 Points
palmar erythema.
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.
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