Author : Dr Don Rockey Duke University Medical Center Durham
2008-07-28
Cirrhosis : Pathophysiology, diagnosis, and treatment
2008-07-28
Cirrhosis : Pathophysiology, diagnosis, and treatment
OVERVIEW
Cirrhosis
results from chronic and ongoing injury to the liver. The injury
process ultimately leads to extensive scarring, with attendant
impairment in liver function. Although there are multiple causes of
liver injury, the common result - cirrhosis - is associated with
well-known and highly consistent clinical manifestations. Specific
treatment for the underlying disease leading to cirrhosis is available
for some specific diseases. The major complications of cirrhosis
include hepatocellular dysfunction and portal hypertension,
each with associated clinical sequelae. When treatment of the
complications of cirrhosis fails, liver transplantation remains the only
life-prolonging option for patients who are appropriate candidates.
PATHOPHYSIOLOGY
 |
| Cirrhotic liver (top image) with nodules |
Chronic liver injury leads to the clinical-pathologic entity known as cirrhosis. Although
many different diseases can cause cirrhosis, the resultant clinical
feature are identical and related to the development of an extensively
fibrotic and scarred liver. Not surprisingly, the scarred liver is unable to function normally, and clinical disease subsequently ensues. Indeed, cirrhosis is defined as a histologic lesion consisting of bridging fibrosis with regenerative nodules in the setting of clinical evidence chronic liver disease.
The scarring process underlying the development of cirrhosis is caused by activation of effector cells (the classic effector cell is the hepatic stellate cell), which in turn lead to synthesis of large quantities of extracellular matrix - the scar typical of cirrhosis. This “wound healing” process in which activation of effector cells leads to fibrogenesis is complex and involves interplay of a multitude of cells, soluble factors, and the extracellular matrix itself. This wound healing process is similar for various types of liver diseases, and causes essentially the same result, fibrosis and cirrhosis.
The scarring process leads to a variety of problems that become manifest clinically. These clinical manifestations are complications of advanced fibrosis and help define the clinical entity, cirrhosis. Major clinical complications include hepatocellular dysfunction and portal hypertension, each with attendant clinical sequelae. Hepatocellular dysfunction leads to hepatic encephalopathy and liver failure. Portal hypertension causes esophageal or gastric variceal hemorrhage, gastrointestinal bleeding due to portal hypertensive gastropathy, ascites, and the hepatorenal syndrome. It should be noted that not all patients with scarring in the liver develop complications; only patients with a clinical complication are marked for an adverse outcome.
The scarring process underlying the development of cirrhosis is caused by activation of effector cells (the classic effector cell is the hepatic stellate cell), which in turn lead to synthesis of large quantities of extracellular matrix - the scar typical of cirrhosis. This “wound healing” process in which activation of effector cells leads to fibrogenesis is complex and involves interplay of a multitude of cells, soluble factors, and the extracellular matrix itself. This wound healing process is similar for various types of liver diseases, and causes essentially the same result, fibrosis and cirrhosis.
The scarring process leads to a variety of problems that become manifest clinically. These clinical manifestations are complications of advanced fibrosis and help define the clinical entity, cirrhosis. Major clinical complications include hepatocellular dysfunction and portal hypertension, each with attendant clinical sequelae. Hepatocellular dysfunction leads to hepatic encephalopathy and liver failure. Portal hypertension causes esophageal or gastric variceal hemorrhage, gastrointestinal bleeding due to portal hypertensive gastropathy, ascites, and the hepatorenal syndrome. It should be noted that not all patients with scarring in the liver develop complications; only patients with a clinical complication are marked for an adverse outcome.
SPECIFIC CAUSES OF CIRRHOSIS
Liver injury can be caused by a number of processes (see Table 1 and Figure 3), all of which result in fibrogenesis and ultimately cirrhosis. Currently, in the U.S., the most common causes of cirrhosis appear to be hepatitis C and non-alcoholic steatohepatitis (NASH). A
detailed discussion of each of the causes of cirrhosis is beyond the
scope of this review, however, a brief overview of several important
causes of cirrhosis is provided below.
Hepatitis
The most common cause of cirrhosis in the U.S. now is chronic hepatitis C virus (HCV) infection. This viral infection is caused when the virus is transmitted from one person to another, usually via a blood-borne route. Before
the blood pool was readily screened for this virus it was commonly
transmitted via blood transfusion, while currently one of the most
common routes of transmission includes sharing of needles. One
of the most remarkable aspects of HCV infection is that it causes
low-grade infection in the liver over many years (HCV drives the
inflammation – wound healing – scarring process highlighted above), and
it is not unusual for patients to be unaware that they have been
infected with HCV until they present with a clinical complication of
cirrhosis. If detected early, (interferon alpha-based)
treatment is now available, and depending on the HCV genotype, this
therapy may be highly effective.
On
a worldwide basis, chronic hepatitis B virus (HBV) infection is far
more prevalent than HCV infection, but much less common than HCV in the
U.S. An effective vaccine for HBV exists, and thus in
areas where this vaccine is routinely used, the incidence of HBV is
steadily dropping. There have been remarkable strides made
in the effort to treat HBV, and a number of therapies are effective at
reducing viral loads, reducing liver inflammation, and reducing
complications and mortality from this disease.
Alcohol (ethanol)
One
important point (that is often misunderstood) is that while cirrhosis
can certainly be caused by ongoing alcohol consumption, cirrhosis is not always caused by alcohol. Notably, in patients with hepatitis or other types of liver disease, alcohol can accelerate the processes leading to cirrhosis. For
example, concurrent alcohol consumption (even in modest amounts) in the
setting of HCV infection accelerates the course of the disease. An
additional critical feature is that for liver disease to be caused by
alcohol, it generally must be consumed at high levels on a regular
basis. Women appear to be more susceptible than men (for
women, the minimal hepatotoxic dose is ≥ 2 drinks per day for more than
10 years; for men ≥ 3 drinks for more than 10 years). The best treatment for liver disease associated with alcohol is cessation of alcohol.
Biliary cirrhosis
The
term “biliary” connotes involvement of the bile ducts. Several forms
of primary biliary injury may lead to biliary fibrosis and cirrhosis.
Primary biliary cirrhosis (PBC) is (likely) an autoimmune disorder that
afflicts the bile ducts and leads to progressive fibrosis and
cirrhosis. It is most common in women and is associated with several
unique clinical features such as xanthomas (cholesterol deposits), sicca
syndrome (dry eyes and mouth), sever itching, and concomitant
autoimmune disorders (thyroid disease, rheumatoid arthritis, Raynaud’s
phenomenon, CREST syndrome, etc…). While medical treatment may slow the
progression of the disease, especially if begun early, it is not clear
that medical treatment improves long-term survival.
Primary sclerosing cholangitis (PSC), also often considered to be an autoimmune related disease, is also caused by injury to the bile ducts, both within the liver (intrahepatic) and outside it (extrahepatic), leading to bile stasis and wound healing and scarring. Unique features of PSC include that it is predominant in men, and is often associated with inflammatory bowel disease, usually ulcerative colitis.
Secondary biliary cirrhosis is caused by mechanical obstruction of the bile duct, typically after surgery that has inadvertently injured the ductal system.
Treatment of biliary fibrosis and cirrhosis includes ursodeoxycholic acid, a bile acid that has been shown to reduce elevated liver enzyme numbers, but not survival. Itching can be treated with specific drugs such as rifampin or SSRI’s to name a few and bile acid sequesterants (cholestyramine). Antibiotics are given to treat biliary infections (especially with PSC), and vitamin supplements should be given because reduced bile secretion may impair vitamin absorption.
Primary sclerosing cholangitis (PSC), also often considered to be an autoimmune related disease, is also caused by injury to the bile ducts, both within the liver (intrahepatic) and outside it (extrahepatic), leading to bile stasis and wound healing and scarring. Unique features of PSC include that it is predominant in men, and is often associated with inflammatory bowel disease, usually ulcerative colitis.
Secondary biliary cirrhosis is caused by mechanical obstruction of the bile duct, typically after surgery that has inadvertently injured the ductal system.
Treatment of biliary fibrosis and cirrhosis includes ursodeoxycholic acid, a bile acid that has been shown to reduce elevated liver enzyme numbers, but not survival. Itching can be treated with specific drugs such as rifampin or SSRI’s to name a few and bile acid sequesterants (cholestyramine). Antibiotics are given to treat biliary infections (especially with PSC), and vitamin supplements should be given because reduced bile secretion may impair vitamin absorption.
Non-alcoholic steatohepatitis (NASH)
NASH
is on the rise in the U.S. and developing countries where obesity is a
prominent. NASH appears to result from an underlying metabolic syndrome
that in the liver causes fat accumulation in hepatocytes, sometimes
with subsequent inflammation, and ultimately fibrosis. It remains
controversial as to how often fatty liver progress to NASH and then to
cirrhosis, but it appears to occur frequently. The best treatment of
NASH includes weight loss and exercise. As of January 2008, several
medical treatments have been tested in small studies and appear to be
effective at reducing inflammation, and perhaps fibrosis, at least in
the short term.
Cryptogenic cirrhosis
Cryptogenic
cirrhosis refers to cirrhosis that develops in the absence of a clearly
identifiable cause. In this group, it is important to consider and
exclude uncommon diseases such as hemochromatosis, Wilson’s disease,
alpha-1 antitrypsin disease, and others. Cryptogenic cirrhosis makes up
a fairly sizable fraction of all patients with cirrhosis. No specific
therapy is available, though treatment of complications is as for any
type of cirrhosis (see below).
DIAGNOSIS OF CIRRHOSIS
The
diagnosis of cirrhosis requires integration of clinical, laboratory,
radiological and pathological data. Initially, the patient should be
evaluated for symptoms and signs consistent with chronic liver disease
(Table 2). When there is evidence of an underlying etiology consistent
with cirrhosis (i.e. such as known HCV), and the patient has evidence of
a complication of portal hypertension (i.e. such as esophageal
varices), the diagnosis is relatively straightforward. Indeed, in this
setting, once other causes of portal hypertension are excluded, the
diagnosis is essentially established.
Routine diagnostic testing may provide clues to the diagnosis of cirrhosis. For example, portal hypertension leads to splenomegaly, and thus, low platelet counts caused by sequestration of platelets in the spleen. An elevated bilirubin or prothrombin time (PT)/international normalized ratio (INR) or low albumin level are evidence of hepatocyte dysfunction, and thus are typical of cirrhosis. Although, these tests are not specific (or sensitive) by themselves for a diagnosis of cirrhosis, when used in the context of the history and physical findings, they may be helpful diagnostically.
Imaging is often valuable in determining whether the patient has cirrhosis. The liver may appear small or shrunken, nodular, or be associated with collateral venous structures (the latter indicates portal hypertension). The finding of a lesion consistent with a hepatoma in a patient with known underlying liver disease is also highly consistent with cirrhosis. Imaging with endoscopy may demonstrate esophageal varices, a finding consistent with portal hypertension.
In situations where questions persist, other tests may be useful. Non-invasive serum markers of liver fibrosis may help identify patients with cirrhosis. Recently, transient plethysmography has been used to measure liver stiffness, which correlates with the degree of fibrosis, and has been shown to be specific for advanced fibrosis, consistent with a diagnosis of cirrhosis.
In situations where there is question about the diagnosis of cirrhosis, a definitive diagnosis can usually be made with liver biopsy, through a percutaneous, transjugular, or laparoscopic approach. There is a small but significant risk to liver biopsy, and thus it is reserved for specific cases. In patients with suspected cirrhosis, the transjugular approach is often favored since it also allows measurement of the hepatic venous pressure gradient (HVPG), itself a direct measure of portal pressure and portal hypertension. In situations in which the diagnosis is unclear, a hepatologist should be consulted.
Routine diagnostic testing may provide clues to the diagnosis of cirrhosis. For example, portal hypertension leads to splenomegaly, and thus, low platelet counts caused by sequestration of platelets in the spleen. An elevated bilirubin or prothrombin time (PT)/international normalized ratio (INR) or low albumin level are evidence of hepatocyte dysfunction, and thus are typical of cirrhosis. Although, these tests are not specific (or sensitive) by themselves for a diagnosis of cirrhosis, when used in the context of the history and physical findings, they may be helpful diagnostically.
Imaging is often valuable in determining whether the patient has cirrhosis. The liver may appear small or shrunken, nodular, or be associated with collateral venous structures (the latter indicates portal hypertension). The finding of a lesion consistent with a hepatoma in a patient with known underlying liver disease is also highly consistent with cirrhosis. Imaging with endoscopy may demonstrate esophageal varices, a finding consistent with portal hypertension.
In situations where questions persist, other tests may be useful. Non-invasive serum markers of liver fibrosis may help identify patients with cirrhosis. Recently, transient plethysmography has been used to measure liver stiffness, which correlates with the degree of fibrosis, and has been shown to be specific for advanced fibrosis, consistent with a diagnosis of cirrhosis.
In situations where there is question about the diagnosis of cirrhosis, a definitive diagnosis can usually be made with liver biopsy, through a percutaneous, transjugular, or laparoscopic approach. There is a small but significant risk to liver biopsy, and thus it is reserved for specific cases. In patients with suspected cirrhosis, the transjugular approach is often favored since it also allows measurement of the hepatic venous pressure gradient (HVPG), itself a direct measure of portal pressure and portal hypertension. In situations in which the diagnosis is unclear, a hepatologist should be consulted.
COMPLICATIONS OF CIRRHOSIS
The
complications of cirrhosis are often life threatening and among the
most severe in all of medicine. For example, the mortality rate of
patients during the first episode of acute esophageal variceal
hemorrhage was as high as 35% in the 1980’s. This has changed recently
as the introduction of new treatments has improved outcomes.
Nonetheless, variceal hemorrhage is a devastating complication.
Further, the 1-year mortality rate of patients with cirrhotic ascites
approaches 50%. Again, once a patient with extensive scarring develops a
complication, that patient is marked as having cirrhosis, and is marked
as having a poor outcome - underscoring the gravity of the underlying
disease process.
Portal Hypertension
Portal
hypertension is one of the major complications of cirrhosis. The term
portal hypertension connotes the idea that the pressure in the portal
venous system is elevated, analogous to the situation in the arterial
system (essential hypertension). The portal system is normally a
low-pressure system. Portal hypertension occurs if the pressure in this
system exceeds the pressure in the inferior vena cava by more than 5 mm
Hg. Collateral vessels (varices) form as the vascular system attempts to
equalize the pressure between the portal and systemic circulation. The
most common and clinically relevant sites in which collaterals form are
in the esophagus and stomach. Elevated portal pressure results from
increased intrahepatic resistance and/or increased flow through the
portal venous system. Increased resistance probably occurs first and is
followed by an increase in flow. Both increased resistance and flow are
potential therapeutic targets. Although portal hypertension most
commonly results from cirrhosis (which leads to so-called “sinusoidal
portal hypertension”), prehepatic portal hypertension (e.g., caused by
portal or splenic vein thrombosis), and post-hepatic portal hypertension
(caused by cardiac disease or hepatic vein occlusion) must be
considered in all patients. Altered portal hemodynamics contributes not
only to varix formation but also to ascites formation. The mechanism of
ascites formation is not entirely understood but is most likely related
to derangement of the neurohumoral axis that regulates sodium and water
excretion.
Hepatocellular Dysfunction
Hepatocellular
dysfunction leads to 2 major complications – namely hepatic
encephalopathy and outright liver failure. Hepatic encephalopathy
(abnormal brain functioning) is caused by an inability of the liver to
clear toxins from the blood stream. It is not known exactly which
toxins are the cause of encephalopathy, but current dogma is that these
toxins penetrate the blood brain barrier, and affect certain brain
cells. The effect of these toxins on brain cells in turn results in
hepatic encephalopathy. The liver’s key functional cell (known as the
hepatocyte) carries out many other vital functions other than clearing
of toxins. One such function includes synthesis of proteins that the
body uses as building blocks to make tissues such as muscle. Thus,
muscle wasting and weakness is a typical complication of cirrhosis.
Within the liver reside resident macrophages, known as Kupffer cells;
these cells phagocytose bacteria, particularly those that come in to the
body via the intestinal tract. Thus, another problem associated with
progressive liver dysfunction is bacterial infection, in its most severe
form, bacteremia or sepsis. The liver also makes proteins involved in
blood clotting, so that another complication of liver failure is
inability of the body to form blood clots. When liver failure becomes
severe, patients develop overwhelming infection, encephalopathy, or
diffuse coagulation abnormalities, or all of these problems. It should
be noted that patients with cirrhosis might have rapid decompensation,
particularly when they develop infections of other complications such as
variceal hemorrhage.
Decompensation in the patient with known underlying cirrhosis should be distinguished from acute liver failure, the latter of which describes a syndrome associated with rapid decompensation and liver failure in a patient with previously normal liver function.
Decompensation in the patient with known underlying cirrhosis should be distinguished from acute liver failure, the latter of which describes a syndrome associated with rapid decompensation and liver failure in a patient with previously normal liver function.
PRACTICAL APPROACH TO THE PATIENT WITH KNOWN OR SUSPECTED CIRRHOSIS
When
approaching the patient with severe liver scarring and thus possible
cirrhosis, it is important to search for clinical evidence of chronic
liver disease. Clinical signs include those highlighted in Table 2.
However, it is important to emphasize that even in patients with
histologic cirrhosis, these physical signs may not always be present.
Laboratory data, including the prothrombin time (PT)/international
normalized ratio (INR), bilirubin, and albumin are important measures of
liver function. These tests are important components of a
classification scheme known as the Child–Pugh score or Child–Pugh
classification Childs-Pugh classification (Table 3) and therefore are
also used to help assess the severity of the liver disease. These
readily available clinical data allow a rapid assessment of the
patient’s clinical state. Recently, the MELD (model for end-stage liver
disease) scoring system has been used to help assess the severity of
liver disease. This quantitative scoring system calculates a single
number based on the patient’s bilirubin, PT/INR, and creatinine and,
unlike the Child-Pugh score, does not rely on objective assessments.
The cause of cirrhosis should be determined in all patients. An overview of initial evaluation is shown in Figure 4. The differential diagnosis of cirrhosis includes other diseases that may cause portal hypertension or ascites. All patients must have a careful cardiac examination, especially for constrictive pericarditis, because this disease easily can be mistaken for primary hepatic disease with portal hypertension. The nephrotic syndrome also can be misconstrued as cirrhosis. Ultrasound or computed tomography findings can suggest cirrhosis when portal hypertension is present. However, imaging tests are inadequate when an assessment of parenchymal architecture is required.
Once a patient with advanced liver fibrosis or cirrhosis presents with a complication, an assessment should immediately be made as to patient’s the suitability for liver transplantation. This is because the prognosis of the cirrhotic patient in the face of one of the known complications of cirrhosis is generally very poor, and 5-year survival rate with transplantation approaches 70%. Early consultation with an experienced hepatologist is essential.
The cause of cirrhosis should be determined in all patients. An overview of initial evaluation is shown in Figure 4. The differential diagnosis of cirrhosis includes other diseases that may cause portal hypertension or ascites. All patients must have a careful cardiac examination, especially for constrictive pericarditis, because this disease easily can be mistaken for primary hepatic disease with portal hypertension. The nephrotic syndrome also can be misconstrued as cirrhosis. Ultrasound or computed tomography findings can suggest cirrhosis when portal hypertension is present. However, imaging tests are inadequate when an assessment of parenchymal architecture is required.
Once a patient with advanced liver fibrosis or cirrhosis presents with a complication, an assessment should immediately be made as to patient’s the suitability for liver transplantation. This is because the prognosis of the cirrhotic patient in the face of one of the known complications of cirrhosis is generally very poor, and 5-year survival rate with transplantation approaches 70%. Early consultation with an experienced hepatologist is essential.
SPECIFIC COMPLICATIONS IN CIRRHOSIS AND THEIR MANAGEMENT
Varices
Varices
are portosystemic collaterals formed after portal hypertension induced
dilation of preexisting vascular channels. The distal portion of the
esophagus is the most common site for varices, but they can form also in
the stomach or other places in the GI tract. The dilation of
esophageal veins is thought to depend on the presence of a threshold
pressure gradient. The most commonly used measure of pressure is the
hepatic venous pressure gradient (HVPG), defined as the gradient between
the wedged or occluded hepatic vein pressure and the free hepatic vein
pressure (normal, < 5 mm Hg). The commonly stated threshold is an
HPVG of 12 mm Hg; below this threshold varices do not form. The
likelihood of having gastroesophageal varices in patients with cirrhosis
is generally high, although the prevalence of having dangerous varices
is relatively low; the most important variable appears to be the
severity of the underlying liver disease (a general rule of thumb is
that the more severe the liver disease, the larger the varices).
Bleeding occurs in only about one-third of patients with esophageal
varices. Multiple and variable factors therefore play a role in
variceal bleeding. Clinical factors such as continued alcohol use and
poor liver function, as well as endoscopic predictors of bleeding such
as large variceal size and endoscopic “red” signs (e.g., red wale
markings) on varices can be predictive of variceal bleeding. Physical
factors (including elastic properties of the vessel, and intravariceal
and intraluminal pressure), and variceal wall tension play an important
role. It remains a challenge to predict which patients with
esophageal varices will bleed.
Treatment of varices
Treatment of varices
The
treatment of varices depends on the type of varices present and whether
there has been previous variceal hemorrhage, and whether any treatment
has been previously implemented (Table 4). For patients with varices
that have never bled (“primary prophylaxis”), treatment is reserved for
large varices; the best treatment appears to be medical therapy with
beta-blockers. Some patients do not tolerate beta-blockers, and in this
group, variceal banding can be used. In patients with active bleeding,
patients are begun (often empirically) on the somatostatin analogue,
octreotide. Endoscopic therapy is indicated, preferably with variceal
band ligation, as soon as is feasible. When variceal banding is not
technically possible, sclerotherapy is indicated. When bleeding cannot
be stopped, balloon tamponade should be implemented. Balloon tamponade
is almost always successful. After the first episode of bleeding
(“secondary prophylaxis”), beta-blockers and endoscopic obliteration
(preferably with banding) are indicated. In patients with recurrent
bleeding (the risk is greatest soon after the first bleeding episode),
then repeat endoscopic therapy is indicated. However, if patients have
recurrent or ongoing bleeding, then more invasive techniques such as
transjugular intrahepatic portosystemic shunt (TIPS) or shunt surgery
are indicated. These techniques reduce portal pressure and are highly
effective at reducing bleeding; however, they are associated with
specific complications.
Ascites
Ascites
is defined as an abnormal accumulation of fluid in the peritoneal
cavity. In patients with a tense collection of abdominal fluid, the
diagnosis of ascites is straightforward. However, patients with small or
moderate degrees of ascites often present a diagnostic dilemma. If
there is any question as to the presence or absence of ascites,
ultrasound should be performed, as it is extremely reliable, relatively
simple, and inexpensive.
Upon initial presentation, it is important to determine the cause of ascites. Although the majority of patients with ascites will have liver disease and portal hypertension, other causes of ascites must be excluded (Table 5). For this reason, all patients with new-onset ascites should undergo diagnostic paracentesis. Diagnostic paracentesis is performed with a large (16-18 gauge) needle or catheter with or without local anesthesia. Paracentesis can be performed in either the lower quadrant or the midline; the left lower quadrant is probably the safest. In general, the measurement of the ascites fluid albumin level is mandatory in patients undergoing diagnostic paracentesis, and the result is used to measure the serum–ascitic fluid albumin gradient. Diseases with a portal hypertensive basis have a high gradient (>1.1 g/dL); those associated with primary peritoneal disease (e.g., tuberculous peritonitis or carcinomatosis) have a low gradient. It is important to emphasize that a high gradient is present in patients with mixed processes (i.e., portal hypertension and a peritoneal disorder). Ascitic fluid WBC has become the gold standard test for diagnosis of SBP (see below) and therefore is required in all patients in whom this diagnosis is possible. The clinical situation dictates the need for other diagnostic tests (i.e., amylase exclude pancreatic ascites, triglyceride measurements in those with cloudy fluid to exclude chylous ascites, and cytology if malignancy is a possibility).
Treatment of Ascites
The best treatment for cirrhotic ascites is sodium restriction. Sodium intake initially should be restricted to 1,000 mg/d (44 mmol/d). Sodium can be restricted to as low as 250 mg/d; however, patients rarely comply with this degree of sodium restriction, and thus more realistic restriction is often appropriate. Diuretics are used to promote additional sodium loss. Diuresis usually is begun with spironolactone (100 mg/d), and this can be pushed relatively rapidly to a level of 400 mg/day). If spironolactone alone is ineffective, furosemide usually is added (beginning at 20 mg/d). After diuresis has been induced (a target level is 500–1,000 mL/d in those with peripheral edema, and no more than 500 mL/d in those without peripheral edema), sodium restriction and diuretic dose may be tailored to appropriate levels. During therapy, renal function and electrolyte levels must be monitored closely.
Approximately 20% of patients have ascites that is seemingly refractory to sodium restriction and diuretics. Although this is often because of poor compliance, these patients present difficult management problems. Large-volume paracentesis (5–10 L at a time) is effective for short-term removal of fluid, and provides rapid symptomatic relief. Although large-volume paracentesis is generally safe, it is associated with functional changes in hemodynamics and plasma renin activity, and it can be complicated by renal impairment, dilutional hyponatremia, and hepatic encephalopathy. Volume expansion, typically with intravenous albumin, is common, but expensive and the data supporting it are mixed.
Peritoneovenous shunting can be highly effective for treatment of refractory ascites. This intervention leads to increases in glomerular filtration rate and decreased serum aldosterone and plasma renin activity. However, frequent complications, including shunt occlusion, low-grade disseminated intravascular coagulopathy, and sepsis have dampened enthusiasm for this procedure and it is rarely currently performed.
TIPS reduces portal pressure and the amount of ascites in the majority of patients. As above, complications of TIPS may occur (Table 6). Additionally, patients undergoing TIPS require careful follow-up because of the high incidence of shunt stenosis. TIPS should generally be reserved for patients with refractory ascites, and a hepatologist should be involved in all cases prior to this intervention. In patients with ascites, TIPS may be an effective bridge to liver transplantation. TIPS is not recommended in certain patients with advanced liver disease, such as those with elevated bilirubin (greater than 5 mg/dl) or elevated prothrombin time (INR > 2.5).
Spontaneous bacterial peritonitis (SBP)
SBP is defined as infection of preexisting ascitic fluid in the absence of an intra-abdominal primary infection and this complication is an important consideration in all patients with ascites. The clinical presentation of SBP is highly variable. The classic presentation is with fever or abdominal pain. Some patients may be minimally symptomatic, at least initially, and any abrupt clinical change (e.g., worsening encephalopathy) in the patient with liver disease should raise suspicion for SBP. The diagnosis of SBP rests upon analysis of ascitic fluid. A formal diagnosis of SBP is established in the setting of an elevated polymorphonuclear leukocyte (PMN) count (>250 PMNs per cubic millimeter) in the presence of a positive culture for bacteria. Although, a positive ascitic fluid culture is required to make a definitive diagnosis of SBP culture is imperfect because of its low sensitivity and is impractical because of the long lag time before results are known. Thus, the PMN count in ascitic fluid has become used widely for the diagnosis of SBP. The differential diagnosis of SBP is relatively limited; the main alternative diagnosis is secondary peritonitis. An extremely high PMN count (>5,000 per cubic millimeter) should raise the possibility of secondary peritonitis caused by a perforation or other intra-abdominal process. Further diagnostic studies (including abdominal computed tomography scan) are required in this setting.
Treatment of SBP
Without appropriate therapy, the mortality rate of SBP is high and antibiotics are critical. Antibiotics can be tailored to the specific organisms typically isolated from ascitic fluid. Because this process appears to result from translocation of bacteria from bowel to ascitic fluid, the most frequently isolated organisms are gut flora (i.e. the family of enterobactericiae). Gram-positive cocci, including Streptococcus pneumoniae and Enterococcus species, are also common. Anaerobes are rarely isolated.
The best initial antibiotic choice is a third-generation cephalosporin, such as ceftriaxone or cefotaxime. Penicillin–clavulanate combinations also provide excellent coverage with little toxicity. Aminoglycosides must be avoided because of the potential for renal toxicity. Patients usually respond within 48 hours, but if they do not, then other processes should be considered. If specific culture results are available, antibiotic coverage should be changed accordingly. The optimal duration of therapy for SBP is unknown but should be tailored to the individual clinical scenario. Generally, a 5-day course is adequate, some of which may be in the form of oral antibiotics. Selected patients can be treated with short courses of antibiotics and even with outpatient regimens. Intravenous albumin (1.5 mg/kg at the time of diagnosis, followed by 1.0 mg/kg daily) is an expensive intervention but does improve renal function and mortality in patients with SBP, and should be considered.
Chronic oral antibiotic, “suppressive”, therapy should be considered for all patients with ascites, as this intervention reduces the risk of subsequent SBP. Several regimens exist, the best of which appear to be trimethoprim–sulfamethoxazole or ciprofloxacin given as a single daily dose or three times per week.
Hepatic encephalopathy
Hepatic encephalopathy is common in patients with “end-stage” cirrhosis and liver failure. Its diagnosis is based on the presence of specific neurological symptoms and signs in patients with advanced liver disease (Table 7). Importantly, the diagnosis of hepatic encephalopathy also requires exclusion of other causes of altered mental status (i.e., Wernicke–Korsakoff syndrome, hypoglycemia, electrolyte disturbances, ethanol intoxication, central nervous system infection, and structural lesions such as subdural hematoma). Although an ammonia level may be helpful in patients with a previous history of abnormal ammonia levels, this test must be interpreted with caution, as its sensitivity and specificity are imperfect. Reversible predisposing factors, such as gastrointestinal bleeding, infection, increased dietary protein level, use of sedative drugs, and renal failure, also must be identified and corrected in patients with hepatic encephalopathy. In the majority of patients, hepatic encephalopathy results from noncompliance with a prescribed medical regimen. Head computed tomography (to exclude subdural hema¬toma) and lumbar puncture should be considered strongly in patients with atypical symptoms or signs.
Treatment of hepatic encephalopathy
The management of hepatic encephalopathy centers around correction of factors that precipitate or induce the altered mentation as above, and decreasing production of toxins that result from enteric bacterial metabolism of nitrogenous compounds. To remove toxins, dietary protein is restricted and enteric bacteria are killed or their products purged. In patients with mild encephalopathy, dietary protein should be restricted to less than 40 g/d; in those with severe encephalopathy, dietary protein should be eliminated. In patients with severe encephalopathy, treatment entails aggressive lactulose therapy. Lactulose is given at a dose of 30 mL every 2 hours until diarrhea begins. If patients cannot take oral medications because of disorientation, a nasogastric tube is recommended. Once diarrhea occurs, the lactulose schedule should be modified based on response and stool output. Two to four loose stools per day are optimal, and profuse diarrhea should be avoided. Neomycin, a non-absorbable antibiotic, can be added (1–2 g every 6 hours) or may be used as a substitute for lactulose.
Hepatorenal syndrome
The hepatorenal syndrome is a particularly problematic complication of cirrhosis. It is characterized by intense activation of the renin–angiotensin – aldosterone system, with pronounced vasoconstriction of the renal circulation that results in reduction of renal blood flow. There are two types, which are likely to differ mechanistically and require divergent therapies. Type I is characterized by rapidly progressive deterioration in renal function, defined by a doubling of the serum creatinine to a value of more than 2.5 mg/dL or a 50% reduction of creatinine clearance to a level less than 20 mL/min in less than 2 weeks. Type II is characterized by a more moderate and slowly progressive reduction of glomerular filtration rate. The diagnosis of hepatorenal syndrome is established in the patient with rising creatinine and oliguria by documentation of low urinary sodium (<10 mEq/L) in the absence of intravascular volume depletion. Because hypovolemia is often difficult to differentiate from hepatorenal syndrome, a volume challenge of colloid is required, and in some instances central pressure monitoring is indicated. Obstruction and intrinsic renal disease also must be excluded; therefore, ultrasound and examination of the urine sediment are also important.
Upon initial presentation, it is important to determine the cause of ascites. Although the majority of patients with ascites will have liver disease and portal hypertension, other causes of ascites must be excluded (Table 5). For this reason, all patients with new-onset ascites should undergo diagnostic paracentesis. Diagnostic paracentesis is performed with a large (16-18 gauge) needle or catheter with or without local anesthesia. Paracentesis can be performed in either the lower quadrant or the midline; the left lower quadrant is probably the safest. In general, the measurement of the ascites fluid albumin level is mandatory in patients undergoing diagnostic paracentesis, and the result is used to measure the serum–ascitic fluid albumin gradient. Diseases with a portal hypertensive basis have a high gradient (>1.1 g/dL); those associated with primary peritoneal disease (e.g., tuberculous peritonitis or carcinomatosis) have a low gradient. It is important to emphasize that a high gradient is present in patients with mixed processes (i.e., portal hypertension and a peritoneal disorder). Ascitic fluid WBC has become the gold standard test for diagnosis of SBP (see below) and therefore is required in all patients in whom this diagnosis is possible. The clinical situation dictates the need for other diagnostic tests (i.e., amylase exclude pancreatic ascites, triglyceride measurements in those with cloudy fluid to exclude chylous ascites, and cytology if malignancy is a possibility).
Treatment of Ascites
The best treatment for cirrhotic ascites is sodium restriction. Sodium intake initially should be restricted to 1,000 mg/d (44 mmol/d). Sodium can be restricted to as low as 250 mg/d; however, patients rarely comply with this degree of sodium restriction, and thus more realistic restriction is often appropriate. Diuretics are used to promote additional sodium loss. Diuresis usually is begun with spironolactone (100 mg/d), and this can be pushed relatively rapidly to a level of 400 mg/day). If spironolactone alone is ineffective, furosemide usually is added (beginning at 20 mg/d). After diuresis has been induced (a target level is 500–1,000 mL/d in those with peripheral edema, and no more than 500 mL/d in those without peripheral edema), sodium restriction and diuretic dose may be tailored to appropriate levels. During therapy, renal function and electrolyte levels must be monitored closely.
Approximately 20% of patients have ascites that is seemingly refractory to sodium restriction and diuretics. Although this is often because of poor compliance, these patients present difficult management problems. Large-volume paracentesis (5–10 L at a time) is effective for short-term removal of fluid, and provides rapid symptomatic relief. Although large-volume paracentesis is generally safe, it is associated with functional changes in hemodynamics and plasma renin activity, and it can be complicated by renal impairment, dilutional hyponatremia, and hepatic encephalopathy. Volume expansion, typically with intravenous albumin, is common, but expensive and the data supporting it are mixed.
Peritoneovenous shunting can be highly effective for treatment of refractory ascites. This intervention leads to increases in glomerular filtration rate and decreased serum aldosterone and plasma renin activity. However, frequent complications, including shunt occlusion, low-grade disseminated intravascular coagulopathy, and sepsis have dampened enthusiasm for this procedure and it is rarely currently performed.
TIPS reduces portal pressure and the amount of ascites in the majority of patients. As above, complications of TIPS may occur (Table 6). Additionally, patients undergoing TIPS require careful follow-up because of the high incidence of shunt stenosis. TIPS should generally be reserved for patients with refractory ascites, and a hepatologist should be involved in all cases prior to this intervention. In patients with ascites, TIPS may be an effective bridge to liver transplantation. TIPS is not recommended in certain patients with advanced liver disease, such as those with elevated bilirubin (greater than 5 mg/dl) or elevated prothrombin time (INR > 2.5).
Spontaneous bacterial peritonitis (SBP)
SBP is defined as infection of preexisting ascitic fluid in the absence of an intra-abdominal primary infection and this complication is an important consideration in all patients with ascites. The clinical presentation of SBP is highly variable. The classic presentation is with fever or abdominal pain. Some patients may be minimally symptomatic, at least initially, and any abrupt clinical change (e.g., worsening encephalopathy) in the patient with liver disease should raise suspicion for SBP. The diagnosis of SBP rests upon analysis of ascitic fluid. A formal diagnosis of SBP is established in the setting of an elevated polymorphonuclear leukocyte (PMN) count (>250 PMNs per cubic millimeter) in the presence of a positive culture for bacteria. Although, a positive ascitic fluid culture is required to make a definitive diagnosis of SBP culture is imperfect because of its low sensitivity and is impractical because of the long lag time before results are known. Thus, the PMN count in ascitic fluid has become used widely for the diagnosis of SBP. The differential diagnosis of SBP is relatively limited; the main alternative diagnosis is secondary peritonitis. An extremely high PMN count (>5,000 per cubic millimeter) should raise the possibility of secondary peritonitis caused by a perforation or other intra-abdominal process. Further diagnostic studies (including abdominal computed tomography scan) are required in this setting.
Treatment of SBP
Without appropriate therapy, the mortality rate of SBP is high and antibiotics are critical. Antibiotics can be tailored to the specific organisms typically isolated from ascitic fluid. Because this process appears to result from translocation of bacteria from bowel to ascitic fluid, the most frequently isolated organisms are gut flora (i.e. the family of enterobactericiae). Gram-positive cocci, including Streptococcus pneumoniae and Enterococcus species, are also common. Anaerobes are rarely isolated.
The best initial antibiotic choice is a third-generation cephalosporin, such as ceftriaxone or cefotaxime. Penicillin–clavulanate combinations also provide excellent coverage with little toxicity. Aminoglycosides must be avoided because of the potential for renal toxicity. Patients usually respond within 48 hours, but if they do not, then other processes should be considered. If specific culture results are available, antibiotic coverage should be changed accordingly. The optimal duration of therapy for SBP is unknown but should be tailored to the individual clinical scenario. Generally, a 5-day course is adequate, some of which may be in the form of oral antibiotics. Selected patients can be treated with short courses of antibiotics and even with outpatient regimens. Intravenous albumin (1.5 mg/kg at the time of diagnosis, followed by 1.0 mg/kg daily) is an expensive intervention but does improve renal function and mortality in patients with SBP, and should be considered.
Chronic oral antibiotic, “suppressive”, therapy should be considered for all patients with ascites, as this intervention reduces the risk of subsequent SBP. Several regimens exist, the best of which appear to be trimethoprim–sulfamethoxazole or ciprofloxacin given as a single daily dose or three times per week.
Hepatic encephalopathy
Hepatic encephalopathy is common in patients with “end-stage” cirrhosis and liver failure. Its diagnosis is based on the presence of specific neurological symptoms and signs in patients with advanced liver disease (Table 7). Importantly, the diagnosis of hepatic encephalopathy also requires exclusion of other causes of altered mental status (i.e., Wernicke–Korsakoff syndrome, hypoglycemia, electrolyte disturbances, ethanol intoxication, central nervous system infection, and structural lesions such as subdural hematoma). Although an ammonia level may be helpful in patients with a previous history of abnormal ammonia levels, this test must be interpreted with caution, as its sensitivity and specificity are imperfect. Reversible predisposing factors, such as gastrointestinal bleeding, infection, increased dietary protein level, use of sedative drugs, and renal failure, also must be identified and corrected in patients with hepatic encephalopathy. In the majority of patients, hepatic encephalopathy results from noncompliance with a prescribed medical regimen. Head computed tomography (to exclude subdural hema¬toma) and lumbar puncture should be considered strongly in patients with atypical symptoms or signs.
Treatment of hepatic encephalopathy
The management of hepatic encephalopathy centers around correction of factors that precipitate or induce the altered mentation as above, and decreasing production of toxins that result from enteric bacterial metabolism of nitrogenous compounds. To remove toxins, dietary protein is restricted and enteric bacteria are killed or their products purged. In patients with mild encephalopathy, dietary protein should be restricted to less than 40 g/d; in those with severe encephalopathy, dietary protein should be eliminated. In patients with severe encephalopathy, treatment entails aggressive lactulose therapy. Lactulose is given at a dose of 30 mL every 2 hours until diarrhea begins. If patients cannot take oral medications because of disorientation, a nasogastric tube is recommended. Once diarrhea occurs, the lactulose schedule should be modified based on response and stool output. Two to four loose stools per day are optimal, and profuse diarrhea should be avoided. Neomycin, a non-absorbable antibiotic, can be added (1–2 g every 6 hours) or may be used as a substitute for lactulose.
Hepatorenal syndrome
The hepatorenal syndrome is a particularly problematic complication of cirrhosis. It is characterized by intense activation of the renin–angiotensin – aldosterone system, with pronounced vasoconstriction of the renal circulation that results in reduction of renal blood flow. There are two types, which are likely to differ mechanistically and require divergent therapies. Type I is characterized by rapidly progressive deterioration in renal function, defined by a doubling of the serum creatinine to a value of more than 2.5 mg/dL or a 50% reduction of creatinine clearance to a level less than 20 mL/min in less than 2 weeks. Type II is characterized by a more moderate and slowly progressive reduction of glomerular filtration rate. The diagnosis of hepatorenal syndrome is established in the patient with rising creatinine and oliguria by documentation of low urinary sodium (<10 mEq/L) in the absence of intravascular volume depletion. Because hypovolemia is often difficult to differentiate from hepatorenal syndrome, a volume challenge of colloid is required, and in some instances central pressure monitoring is indicated. Obstruction and intrinsic renal disease also must be excluded; therefore, ultrasound and examination of the urine sediment are also important.
Treatment of hepatorenal syndrome
Treatment is generally unsatisfactory, and prognosis is poor. It is imperative to identify and discontinue potentially nephrotoxic compounds. Attention to volume is the most critical aspect of management. Intravascular volume depletion should be reversed if present; volume repletion is often best performed in an intensive care unit setting with central venous pressure monitoring. Medical therapy is generally ineffective, although there are some data indicating that the combination of peripheral vasoconstrictive substances and plasma volume expansion with albumin may result in suppression of vasoconstrictor activity, improvement in glomerular filtration rate, and reversal of the syndrome. Although liver transplantation may be appropriate in some instances, and the 3-year survival approaches 60% at 3 years in patients with hepatorenal syndrome who undergo transplantation, many of these patients have extremely difficult postoperative courses. Hepatology and nephrology input is essential.
MISCELLANEOUS TREATMENTS FOR CIRRHOSIS
The treatment of cirrhosis usually revolves around treatment of complications of cirrhosis. Specific treatment is available for certain specific diseases, and depends in many circumstances on the underlying cause. For example, treatment early in the course of primary biliary cirrhosis (with ursodeoxycholic acid) may improve symptoms and liver tests. Other types of specific treatments are shown in Table 8. Some evidence suggests that advanced fibrosis, and perhaps even clinical cirrhosis may be reversible.
New evidence indicates that patients with cirrhosis likely benefit from a variety of “routine liver health care” type interventions. All patients with cirrhosis should receive vaccination against hepatitis A. If hepatitis B is not the cause of liver disease and the patient is not already immune s/he should also be vaccinated against hepatitis B. Patients with cirrhosis should undergo screening for esophageal varices and for hepatoma.
Liver transplantation is likely the best therapy for cirrhosis in advanced situations. It is reserved for patients who are severely incapacitated or who have had serious complications as highlighted above. A hepatologist should be involved when liver transplantation is being considered. Liver transplantation is meant to extend life, and given the poor prognosis of many patients, clearly meets this goal. Liver transplantation also improves the quality of life for the vast majority of patients in whom it is used. It is critical to emphasize that while liver transplantation is one of the true life-saving maneuvers in all of medicine, it cannot be offered to all patients, and moreover, it brings with it its own set of complications.
Treatment is generally unsatisfactory, and prognosis is poor. It is imperative to identify and discontinue potentially nephrotoxic compounds. Attention to volume is the most critical aspect of management. Intravascular volume depletion should be reversed if present; volume repletion is often best performed in an intensive care unit setting with central venous pressure monitoring. Medical therapy is generally ineffective, although there are some data indicating that the combination of peripheral vasoconstrictive substances and plasma volume expansion with albumin may result in suppression of vasoconstrictor activity, improvement in glomerular filtration rate, and reversal of the syndrome. Although liver transplantation may be appropriate in some instances, and the 3-year survival approaches 60% at 3 years in patients with hepatorenal syndrome who undergo transplantation, many of these patients have extremely difficult postoperative courses. Hepatology and nephrology input is essential.
MISCELLANEOUS TREATMENTS FOR CIRRHOSIS
The treatment of cirrhosis usually revolves around treatment of complications of cirrhosis. Specific treatment is available for certain specific diseases, and depends in many circumstances on the underlying cause. For example, treatment early in the course of primary biliary cirrhosis (with ursodeoxycholic acid) may improve symptoms and liver tests. Other types of specific treatments are shown in Table 8. Some evidence suggests that advanced fibrosis, and perhaps even clinical cirrhosis may be reversible.
New evidence indicates that patients with cirrhosis likely benefit from a variety of “routine liver health care” type interventions. All patients with cirrhosis should receive vaccination against hepatitis A. If hepatitis B is not the cause of liver disease and the patient is not already immune s/he should also be vaccinated against hepatitis B. Patients with cirrhosis should undergo screening for esophageal varices and for hepatoma.
Liver transplantation is likely the best therapy for cirrhosis in advanced situations. It is reserved for patients who are severely incapacitated or who have had serious complications as highlighted above. A hepatologist should be involved when liver transplantation is being considered. Liver transplantation is meant to extend life, and given the poor prognosis of many patients, clearly meets this goal. Liver transplantation also improves the quality of life for the vast majority of patients in whom it is used. It is critical to emphasize that while liver transplantation is one of the true life-saving maneuvers in all of medicine, it cannot be offered to all patients, and moreover, it brings with it its own set of complications.
READING
• Bataller R, Gines P, Guevara M, et al. Hepatorenal syndrome. Semin Liver Dis 1997; 17:233–247.
• Kaplowitz N, ed. Liver and biliary diseases, 2nd ed. Baltimore: Williams and Wilkins, 1996.
• Sanyal AJ, Genning C, Reddy KR, et al. The North American Study for the Treatment of Refractory Ascites. Gastroenterology 2003; 124: 634-641.
• Sharara A, Rockey DC. Esophageal variceal hemorrhage. N Engl J Med 2001;345:669-81.
• Singh N, Gayowski T, Yu VL, et al. Trimethoprim-sulfamethoxazole for the prevention of spontaneous bacterial peritonitis in cirrhosis: a randomized trial. Ann Intern Med 1995;122:595–598.
WEB SITES
The American Association for the Study of Liver Diseases - https://www.aasld.org/eweb/StartPage.aspx
The American Gastroenterological Association - http://www.gastro.org/wmspage.cfm?parm1=2
The National Institute of Diabetes and Digestive and Kidney Diseases - http://digestive.niddk.nih.gov/ddiseases/a-z.asp
The American Liver Foundation - http://www.liverfoundation.org/
Medline - http://www.ncbi.nlm.nih.gov/sites/entrez