- File Under cirrhosis
Author: David C Wolf, MD, FACP, FACG, AGAF, Medical Director of Liver Transplantation, Westchester Medical Center, Professor of Clinical Medicine, Division of Gastroenterology and Hepatobiliary Diseases, Department of Medicine, New York Medical College
Contributor Information and Disclosures
Updated: Jun 28, 2010
Definition, Epidemiology, and Etiology of Cirrhosis
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 is used to describe the orange or tawny surface of the liver seen at autopsy.
Many forms of liver injury are marked by fibrosis. Fibrosis is defined as an excess deposition of the components of extracellular matrix (ie, collagens, glycoproteins, proteoglycans) within the liver. This response to liver injury potentially is reversible. In contrast, in most patients, cirrhosis is not a reversible process.
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.
Often a poor correlation exists between histologic findings 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).
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, and 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.
Alcoholic liver disease once was considered to be the predominant cause of cirrhosis in the United States. Hepatitis C has emerged as the nation's leading cause of both chronic hepatitis and cirrhosis.
Many cases of cryptogenic cirrhosis appear to have resulted from nonalcoholic fatty liver disease (NAFLD). When cases of cryptogenic cirrhosis are reviewed, many patients have one or more of the classical risk factors for NAFLD: obesity, diabetes, and hypertriglyceridemia.1 It is postulated that steatosis may regress in some patients as hepatic fibrosis progresses, making the histologic diagnosis of NAFLD difficult.
Up to one third of Americans have NAFLD. About 2-3% of Americans have nonalcoholic steatohepatitis (NASH), where 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 over the next decade.
Most common causes of cirrhosis in the United States
Hepatitis C (26%)
Alcoholic liver disease (21%)
Hepatitis C plus alcoholic liver disease (15%)
Cryptogenic causes (18%)
Hepatitis B, which may be coincident with hepatitis D (15%)
Miscellaneous causes of chronic liver disease and cirrhosis
Primary biliary cirrhosis
Secondary biliary cirrhosis (associated with chronic extrahepatic bile duct obstruction)
Primary sclerosing cholangitis
Alpha-1 antitrypsin deficiency
Granulomatous disease (eg, sarcoidosis)
Type IV glycogen storage disease
Drug-induced liver disease (eg, methotrexate, alpha methyldopa, amiodarone)
Venous outflow obstruction (eg, Budd-Chiari syndrome, veno-occlusive disease)
Chronic right-sided heart failure
Pathophysiology of Hepatic Fibrosis
The development of hepatic fibrosis reflects an alteration in the normally balanced processes of extracellular matrix production and degradation.2 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.
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. Both 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.
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.3 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 both fixed factors and dynamic factors. Two thirds of intrahepatic vascular resistance is explained by fixed changes in the hepatic architecture. Such changes include the formation of regenerating nodules and the production of collagen by activated stellate cells. Collagen, in turn, is deposited 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, like 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 include splenic vein thrombosis and portal vein thrombosis. These conditions commonly are associated with hypercoagulable states and with malignancy (eg, pancreatic cancer).
Intrahepatic causes of portal hypertension are divided into presinusoidal, sinusoidal, and postsinusoidal conditions.
The classic form of presinusoidal disease is caused by the deposition of Schistosoma oocytes in presinusoidal portal venules, with the subsequent development of granulomata and portal fibrosis. Schistosomiasis is the most common noncirrhotic cause of variceal bleeding worldwide. Schistosoma mansoni infection is described in Puerto Rico, Central and South America, the Middle East, and Africa. Schistosoma japonicum is described in the Far East. Schistosoma 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 sinusoidal cause of portal hypertension is cirrhosis.
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 and following the high-dose chemotherapy that precedes bone marrow transplantation.
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. These 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 only ensues 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 an abdominal ultrasound with Doppler examination of the hepatic vessels. Abdominal CT scan with intravenous contrast, abdominal MRI, and visceral angiography also may provide information regarding the patency of hepatic vessels.
Measurement of portal hypertension
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 (PP). The WHVP actually is slightly lower than the PP because of some dissipation of pressure in the sinusoidal bed. The WHVP and PP both are elevated in patients with sinusoidal portal hypertension, as is observed in cirrhosis.
Consequences of portal hypertension
Hepatic venous pressure gradient (HVPG) is defined as the difference in pressure between the portal vein and the inferior vena cava. Thus, HVPG is equal to the WHVP value minus the FHVP value (ie, HVPG=WHVP-FHVP). Normal HVPG is defined as 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.4
Ascites is defined as an accumulation of excessive fluid within the peritoneal cavity and may be a complication of both hepatic and nonhepatic diseases. 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 was less than 2.5 g/dL. Classic causes of transudative ascites are portal hypertension secondary to cirrhosis and congestive heart failure.
Table 1. Nonperitoneal Causes of Ascites5
Cause of Nonperitoneal Ascites Examples
Intrahepatic portal hypertension Cirrhosis
Fulminant hepatic failure
Extrahepatic portal hypertension
Hepatic vein obstruction (ie, Budd-Chiari syndrome)
Congestive heart failure
Protein-losing enteropathy Malnutrition
Chylous Secondary to malignancy
Secondary to trauma
Secondary to portal hypertension
In exudative ascites, fluid was said to weep from an inflamed or tumor-laden peritoneum. In general, ascites protein was greater than 2.5 g/dL. Examples included peritoneal carcinomatosis and tuberculous peritonitis.
Table 2. Peritoneal Causes of Ascites5
Causes of Peritoneal Ascites Examples
Malignant ascites Primary peritoneal mesothelioma
Secondary peritoneal carcinomatosis
Granulomatous peritonitis Tuberculous peritonitis
Fungal and parasitic infections (eg, Candida,
Histoplasma, Cryptococcus, Schistosoma mansoni,
Strongyloides, Entamoeba histolytica)
Foreign bodies (ie, talc, cotton and wood fibers,
Systemic lupus erythematosus
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).6
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 ascites triglyceride concentration is greater than 110 mg/dL. In addition, ascites triglyceride concentrations are greater than those observed in plasma. Patients should be placed on a low-fat diet, which is supplemented by medium-chain triglycerides. Treatment with diuretics and large-volume paracentesis may be required. Peritoneal diseases produce ascites with a SAAG of less than 1.1 g/dL (see Table 2).
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 transsinusoidal oncotic gradient is approximately zero, the increased sinusoidal pressure that develops in portal hypertension increases the amount of fluid entering the space of Disse. When the increased hepatic lymph production observed in portal hypertension exceeds the ability of the cisterna chyli and thoracic duct to clear the lymph, fluid crosses into the liver interstitium. Fluid may then extravasate across the liver capsule into the peritoneal cavity.
The role of renal dysfunction in the pathogenesis of cirrhotic ascites
Patients with cirrhosis experience sodium retention, impaired free water excretion, and intravascular volume overload. These abnormalities may occur even in the setting of a normal glomerular filtration rate. To some extent, these abnormalities are 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 leads to stimulation of the renin-angiotensin system and the sympathetic nervous system and to antidiuretic hormone release. These events are followed by an increase in sodium and water retention, by an increase in plasma volume, and by the overflow of ascites into the peritoneal cavity.
This syndrome represents a continuum of renal dysfunction that may be observed in patients with cirrhosis and is caused by the vasoconstriction of large and small renal arteries and the impaired renal perfusion that results.7 The syndrome may represent an imbalance between renal vasoconstrictors and vasodilators. Plasma levels of a number of vasoconstricting substances are elevated in patients with cirrhosis and include angiotensin, antidiuretic hormone, and norepinephrine. 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 histological 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.
Hepatorenal syndrome progression may be slow (type II) or rapid (type I).8 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 FHF or severe alcoholic hepatitis who spontaneously recover both 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.
Hepatorenal syndrome is diagnosed when a creatinine clearance less than 40 mL/min is present or when a serum creatinine greater than 1.5 mg/dL, urine volume less than 500 mL/d, and urine sodium less than 10 mEq/L are present.9 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 central venous pressure is determined to be normal or if no improvement of renal function occurs following the infusion of at least 1.5 L of a plasma expander.
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. Administration of oral prostaglandins may be beneficial, but this point is controversial. 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 intravenous terlipressin (an analog of vasopressin not available in the United States) improved the renal dysfunction of patients with hepatorenal syndrome. A combination of midodrine (an oral alpha agonist), subcutaneous octreotide, and albumin infusion also improved renal function in a small series of patients with hepatorenal syndrome.
Clinical features of ascites
Ascites is suggested by the presence of a number of findings upon physical examination, which are abdominal distention, bulging flanks, shifting dullness, and elicitation of a "puddle sign" in 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 performing abdominal ultrasonography, which can detect as little as 30 mL of fluid. Furthermore, ultrasound with Doppler can help 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>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 RBCs in ascites to ascertain a corrected PMN count.
The yield of ascites culture studies may be increased by directly inoculating 10 mL of ascites into aerobic and anaerobic culture bottles at the patient's bedside.16
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.17
Salt restriction is the first line of therapy. In general, patients begin with a diet containing less than 2000 mg sodium per day. Some patients with refractory ascites require a diet containing less than 500 mg sodium per day. 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 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 per day. 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 per day 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.18
Aggressive diuretic therapy in hospitalized patients with massive ascites can safely induce a 0.5- to 1-kg weight loss per day, providing 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. Thus far, evidence-based medicine has not firmly supported the use of albumin as an aid to diuresis in the 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 intravenous furosemide following intravenous infusion of albumin at 25 g twice per day, in addition to ongoing therapy with spironolactone. One article supported the use of chronic albumin infusions to achieve diuresis in patients with diuretic-resistant ascites.19
Albumin infusion may protect against the development of renal insufficiency in patients with SBP. Patients receiving cefotaxime and albumin at 1 g/kg/day experienced a lower risk of renal failure and a lower in-hospital mortality rate than patients treated with cefotaxime and conventional fluid management.20
Satavaptan, a vasopressin V2 receptor antagonist, is a promising new investigational agent that may improve diuresis and decrease the need for paracentesis in patients with diuretic-refractory ascites.21
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 receive relief from symptoms of abdominal discomfort, anorexia, or dyspnea. The procedure also may help 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.22 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 5-10 g albumin per 1 L 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.
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, serious complications are observed in 10% of the recipients of these devices. Complications include peritoneal infection, sepsis, disseminated intravascular coagulation, and congestive heart failure. Shunts may clot and require replacement in an additional 30% of patients. However, peritoneovenous shunts may be a reasonable form of therapy for patients with refractory ascites who are not candidates for TIPS or liver transplantation.
Portosystemic shunts and transjugular intrahepatic portosystemic shunts
The prime indication for portocaval shunt surgery is the management of refractory variceal bleeding. However, since 1945, 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.
TIPS is an effective tool in managing massive ascites in some patients. Ideally, TIPS placement produces a decrease in sinusoidal pressure and a decrease 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.23 Multiple studies have demonstrated that TIPS is superior to large volume paracentesis when it comes to the control of ascites.24 However, creation of TIPS has the potential to worsen preexisting hepatic encephalopathy and exacerbate liver dysfunction in patients with severe underlying liver failure.25 Indeed, it remains unclear whether or not TIPS increases transplant-free life expectancy in patients undergoing treatment for massive ascites.
A pre-TIPS bilirubin of less than 3 mg/dL is associated with an increased mortality rate when TIPS is created for the management of ascites.26 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 in the 2000s appears to be reducing the incidence of shunt stenosis, patients must still be willing to return to the hospital for Doppler and angiographic follow-up of TIPS patency.
Patients with massive ascites have a less than 50% 1-year survival rate. Liver transplantation should be considered as a potential means of salvaging the patient prior to the onset of intractable liver failure or hepatorenal syndrome.
Hepatic encephalopathy is a syndrome observed in some patients with cirrhosis that 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 who do not have cirrhosis who undergo portocaval shunt surgery.
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, and beta-phenylethanolamines), ammonia, and gamma-aminobutyric acid (GABA).
The 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 altering the transit of amino acids, water, and electrolytes across the neuronal membrane. Ammonia also can inhibit the generation of both 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.
The gamma-aminobutyric acid hypothesis
GABA is a neuroinhibitory substance produced in the GI tract. It was postulated that GABA crossed the extrapermeable blood-brain barriers of patients with cirrhosis and then interacted with supersensitive postsynaptic GABA receptors.27 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.
Brain levels of neurosteroids are increased in patients with cirrhosis.28 They are capable of binding to their receptor within the neuronal GABA receptor complex and can increase inhibitory neurotransmission. Today, some investigators contend that neurosteroids may play a key role in hepatic encephalopathy.29
Clinical features of hepatic encephalopathy
The symptoms of hepatic encephalopathy may range from mild to severe and may be observed in as many as 70% of patients with cirrhosis. Symptoms are graded on the following scale:
Grade 0 - Subclinical; normal mental status, but minimal changes in memory, concentration, intellectual function, coordination
Grade 1 - Mild confusion, euphoria or depression, decreased attention, slowing of ability to perform mental tasks, irritability, disorder of sleep pattern (ie, inverted sleep cycle)
Grade 2 - Drowsiness, lethargy, gross deficits in ability to perform mental tasks, obvious personality changes, inappropriate behavior, intermittent disorientation (usually for time)
Grade 3 - Somnolent but arousable, unable to perform mental tasks, disorientation 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 upon physical examination include asterixis and fetor hepaticus.
Laboratory abnormalities in hepatic encephalopathy
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. EEG 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 of hepatic encephalopathy
Some patients with a history of hepatic encephalopathy may 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 diuretic therapy, renal failure, GI bleeding, infection, and constipation. Dietary protein overload is an infrequent cause of worsening encephalopathy. Medications, notably opiates, benzodiazepines, antidepressants, and antipsychotic agents, also may worsen encephalopathy symptoms.
Differential diagnosis for hepatic encephalopathy
Conditions 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
Management of hepatic encephalopathy
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 CNS function, especially benzodiazepines, should be avoided. Precipitants of hepatic encephalopathy should be corrected (eg, metabolic disturbances, GI bleeding, infection, constipation).
Lactulose is helpful in patients with the 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 tube 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.
Sharma et al studied whether lactulose prevented recurrence of hepatic encephalopathy.30 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 (P = 0.001).30 The authors concluded that use of lactulose effectively prevents hepatic encephalopathy recurrence in cirrhosis.
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, Salix Pharmaceuticals, Inc, Morrisville, NC) is a nonabsorbable antibiotic that received approval by the US Food and Drug Administration (FDA) in 2004 for the treatment of travelers' diarrhea. Experience in Europe over the last 2 decades suggests that rifaximin can decrease colonic levels of ammoniagenic bacteria, with resulting improvement in hepatic encephalopathy symptoms. Typical rifaximin dosing in European hepatic encephalopathy trials was two 200 mg tablets taken orally 3 times daily. Work is being done to determine if lower doses of the medication can effectively treat hepatic encephalopathy. One meta-analysis suggested that rifaximin may be more effective than lactulose in the treatment of hepatic encephalopathy.31
Other chemicals capable of decreasing blood ammonia levels are L-ornithine L-aspartate (available in Europe) and sodium benzoate.32
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 resulting worsening of encephalopathy symptoms. In this author's experience, the vast majority of patients can tolerate a protein-rich diet (>1.2 g/kg/d) including well-cooked chicken, fish, vegetable protein, and, if needed, protein supplements.
Protein restriction is rarely necessary in patients with chronic encephalopathy symptoms. 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 of hepatic encephalopathy symptoms. 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. There was no difference in hepatic encephalopathy outcome in the two treatment groups.33
Other Manifestations of Cirrhosis; Assessment of Severity of Cirrhosis
All chronic liver diseases that progress to cirrhosis have in common the histologic features of hepatic fibrosis and nodular regeneration. However, patients' signs and symptoms may vary depending on the underlying etiology of liver disease. As an example, patients with end-stage liver disease caused by hepatitis C might develop profound muscle wasting, marked ascites, and severe hepatic encephalopathy, with only mild jaundice. In contrast, patients with end-stage primary biliary cirrhosis might 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 both men and women. Hyperestrogenemia also may explain spider angiomata and palmar erythema.
Anemia may result from folate deficiency, hemolysis, or hypersplenism.34 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, patients may receive an expedited course to liver transplantation when their PaO2 is less than 60 mm Hg.
Portopulmonary hypertension (PPHTN) is observed in up to 6% of patients with cirrhosis. Its etiology is unknown. PPHTN is defined as the presence of a mean pulmonary artery pressure of greater than 25 mm Hg in the setting of a normal pulmonary capillary wedge pressure. Routine Doppler echocardiography is performed as part of 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) occurs in 10-25% of patients with cirrhosis in the United States and most often is associated with hemochromatosis, alpha-1 antitrypsin deficiency, hepatitis B, hepatitis C, and alcoholic cirrhosis. HCC is observed less commonly in primary biliary cirrhosis and is a rare complication of Wilson disease. Cholangiocarcinoma occurs in approximately 10% of patients with primary sclerosing cholangitis.
Other diseases associated with cirrhosis
Other conditions that appear with increased incidence in patients with cirrhosis include peptic ulcer disease, diabetes, and gallstones.
Assessment of the severity of cirrhosis
The most common tool for gauging prognosis in cirrhosis is 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.35 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.
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 severities of patients' liver diseases (see Liver Transplantation). Patients may receive a MELD score of 6-40 points.
The 3-month mortality statistics are associated with the following MELD scores: 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; and MELD score of greater than 40, 81% mortality.36
Table 4. Child-Turcotte-Pugh Scoring System for Cirrhosis (Child Class A=5-6 points, Child Class B=7-9 points, Child Class C=10-15 points)
Clinical variable 1 point 2 points 3 points
Encephalopathy None Stages 1-2 Stages 3-4
Ascites Absent Slight Moderate
Bilirubin (mg/dL) <2>3
Bilirubin in PBC or PSC (mg/dL) <4>3.5 2.8-3.5 <2.8>6 s or INR >2.3
Clinical variable 1 point 2 points 3 points
Encephalopathy None Stages 1-2 Stages 3-4
Ascites Absent Slight Moderate
Bilirubin (mg/dL) <2>3
Bilirubin in PBC or PSC (mg/dL) <4>3.5 2.8-3.5 <2.8>6 s or INR >2.3
Treatment of Cirrhosis
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, 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.
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 can patients not tolerate proteins in the form of chicken, fish, vegetables, and nutritional supplements. Institution of a low-protein diet in the fear that hepatic encephalopathy might develop places the patient at risk for the development of profound muscle wasting.
Zinc deficiency commonly is observed in patients with cirrhosis. Treatment with zinc sulfate at 220 mg orally twice daily may improve dysgeusia and can stimulate appetite. Furthermore, zinc is effective in the treatment of muscle cramps and is adjunctive therapy for hepatic encephalopathy.
Pruritus is a common complaint in both cholestatic liver diseases (eg, primary biliary 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 pruritogens. Mild itching complaints may respond to treatment with antihistamines.
Cholestyramine is the mainstay of therapy for the pruritus of liver disease. Care should be taken to avoid coadministration of this organic anion binder with any other medication, to avoid compromising GI absorption. Other medications that may provide relief against pruritus include ursodeoxycholic acid, ammonium lactate 12% skin cream (Lac-Hydrin, Westwood-Squibb Pharmaceuticals, Inc, Princeton, NJ), naltrexone (an opioid antagonist), rifampin, gabapentin, and ondansetron. Patients with severe pruritus may require institution of ultraviolet light therapy or plasmapheresis.
Some male patients suffer from hypogonadism. Patients with severe symptoms may undergo therapy with topical testosterone preparations, although their safety and efficacy is not well studied. Similarly, the utility and safety of growth hormone therapy remains unclear.
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, patients with primary biliary cirrhosis, and patients receiving corticosteroids for autoimmune hepatitis. The discovery of decreased bone mineralization upon bone densitometry studies also may prompt institution of therapy with an aminobisphosphonate (eg, alendronate sodium).
Regular exercise, including walking and even swimming, should be encouraged in patients with cirrhosis, lest the patient slip into a vicious cycle of inactivity and muscle wasting. Debilitated patients frequently benefit from formal exercise programs supervised by a physical therapist. Patients with chronic liver disease should receive vaccination to protect them against hepatitis A. Other protective measures include vaccination against hepatitis B, pneumococci, and influenza.
Drug hepatotoxicity in the patient with cirrhosis
The institution of any new medical therapy warrants the performance of more frequent liver chemistries. Indeed, 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 NSAIDs, isoniazid, valproic acid, erythromycin, amoxicillin/clavulanate, ketoconazole, chlorpromazine and ezetimibe.
Hepatic 3-methylglutaryl coenzyme A (HMG Co-A) reductase inhibitors are frequently associated with mild elevations of alanine aminotransferase (ALT) levels. However, severe hepatotoxicity is reported infrequently.37 The literature suggests that statins can be used safely in most patients with chronic liver disease.38 Certainly, liver chemistries should be followed frequently after the initiation of therapy.
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.39 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%.
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 up to 2000 mg/d. 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 their potential to worsen underlying mental function.
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.
Surgery in the patient with cirrhosis
Surgery and general anesthesia carry increased risks in the patient with cirrhosis. Anesthesia reduces cardiac output, induces splanchnic vasodilation, and causes a 30- to 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 an increased but acceptable risk of morbidity and mortality. 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.40 Although cholecystectomy was among the riskier surgeries noted, several reports have described the successful performance of laparoscopic cholecystectomy in patients with Child Class A and B cirrhosis.41
Studies have used the MELD score as a tool in predicting the postoperative outcome. In one study, a preoperative MELD score of greater than 14 was a better predictor of postoperative death than Child Class C status.42 In another study, the preoperative MELD scores and their associated 30-day postoperative mortality rates were as follows: MELD score of 0-7, 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.43 The benefits and the risks of surgery should be carefully weighed before advising the patient with cirrhosis to undergo surgery.
Monitoring the patient with cirrhosis
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. 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 the new onset of variceal bleeding.44 Patients intolerant of beta-blockers should undergo prophylactic endoscopic variceal ligation.
This author encourages the screening of patients to rule out the interval development of HCC. The author's practice is to perform abdominal ultrasonography and alpha-fetoprotein testing twice yearly, although the clinical utility and cost-effectiveness of this strategy remains controversial. In the past, clinical suspicion for HCC mandated the performance of a confirmatory biopsy, by either ultrasound or CT guidance. However, guided biopsy is accompanied by a significant false-negative rate. Biopsy may be complicated either by hemorrhage or by the tracking of tumor cells in the needle tract.
Increasingly, patients with clinical diagnoses of cirrhosis and HCC are monitored in the setting of liver transplant programs. Many hepatologists and surgeons now rely on noninvasive testing when it comes to making a diagnosis of HCC. In most transplant programs, the presence of a suspicious lesion on both triple-phase CT scan and MRI or the combination of a suspicious finding on radiologic study and an alpha-fetoprotein (AFP) level of greater than 400 ng/mL is believed to have the same or an even greater diagnostic power than guided liver biopsy.45,46
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 and C cirrhosis. Patients who await 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 thermal ablation, and chemoembolization.47
For excellent patient education resources, visit eMedicine's Mental Health and Behavior Center. Also, see eMedicine's patient education article Alcoholism.
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 over the last 2 decades. 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 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. The presence of 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.48 Additional clinical study is required before liver transplantation can be offered routinely to such patients.
Approximately 6500 liver transplants are performed in the United States each year. An increasing number of lives are saved each 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 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 (ECD).
In ECD, the donor "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 an HCV-infected recipient. Such transplants have been performed successfully for a number of years. Other examples of extended criteria donors include donors older than 70 years, donors with relatively fatty livers, and donors infected with HTLV-I or HTLV-II.
The need for a more efficient and equitable system of organ allocation resulted in dramatic changes in United States organ allocation policy in 2002.49 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 the 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.36
In the MELD scoring system for adults, a patient receives a score based upon 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 of 1.9 mg/dL, a bilirubin of 4.2 mg/dL, and an INR of 1.2 receives 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 may 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.50 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 both 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 needful 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
[#LiverDonation]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 and 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 cold preservation solution.
One review compared the results of liver transplantation using allografts from 144 NHBDs and 26,856 HBDs over an 8-year period.51 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 [P = 0.003 and P = 0.012]. Higher rates of primary nonfunction and retransplantation were seen in the recipients of allografts from NHBDs.
Other authors have described a higher rate of hepatic artery stenosis, hepatic abscesses, and bilomas in the recipients of allografts from NHBDs.52 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 FHF who were not candidates for liver transplant surgery.
Bioartificial livers may see increased application in the care of patients with FHF and, perhaps, cirrhosis. The two most studied devices are comprised 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 of the 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 fruition 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 whose livers are more likely to undergo graft acceptance when transplanted into humans. Once this obstacle is overcome, a determination may be made 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.