|
Clinical Cirrhosis: The Spectrum of Danger
Cirrhosis is no stranger in the emergency department, but the effects of this disease on the body are so extensive that treating it can seem like breaking new ground. This article will help you manage this devastating problem.
By Nicole Watring, MD, and Sandra Deane, MD
Cirrhosis is the end stage of all chronic liver disease. It kills about 26,000 people every year in the United States, making it the 12th leading cause of death overall and the 8th leading cause of death in men. But although cirrhosis is widespread, managing it still poses a challenge to emergency physicians because the disease affects every body system. It not only causes a range of unique diseases, but also makes treating common diseases more difficult.
Most cases of cirrhosis are preventable, with alcohol and viral infections causing the majority of cases (see graph below). Nonalcoholic fatty liver disease may develop as a result of obesity, diabetes, hypertriglyceridemia, or profound weight loss after jejunoileal bypass surgery. Mortality rates in alcoholic liver disease are higher than those in other causes
of cirrhosis.
| Leading Causes of Cirrhosis in the United States |
 |
NAFLD= nonalcoholic fatty liver disease
Source: Heidelbaugh JJ and Bruderly M (see Suggested Reading)
|
|
In this article, we will explain the effects of cirrhosis on the body and the physiologic principles to consider when treating patients with cirrhosis. We will also discuss special treatment options for cirrhotic patients who have common diseases and present an overview of seven unique complications of cirrhosis.
HOW CIRRHOSIS DEVELOPS
Cirrhosis is a progressive liver fibrosis with nodular regeneration and distortion of hepatic architecture. This distorted architecture causes resistance to portal flow that leads to portal hypertension. As a result, blood is shunted away from the liver. The body’s attempt to compensate leads to local production of vasodilators, like nitric oxide, that induce splanchnic arterial vasodilation and collateral vein formation, causing blood to be diverted to the systemic circulation and development of a hyperdynamic circulatory system.
Splanchnic vasodilation is the most important factor in the development of ascites. Eventually, vasodilation becomes so severe that the effective circulating blood volume decreases and arterial pressure drops. This leads to activation of the sympathetic nervous and renin-
angiotensin-aldosterone systems, resulting in sodium and fluid retention. Also, the combination of splanchnic arterial vasodilation and portal hypertension alters intestinal capillary permeability and pressure, facilitating the accumulation of retained fluid within the abdominal cavity and further increasing fluid retention.
CLINICAL PROFILE
About 40% of patients with cirrhosis are asymptomatic. This is because 80% to 90% of the liver parenchyma must be destroyed before the clinical manifestations of liver failure and cirrhosis develop. Once ascites or gastrointestinal bleeding develops, cirrhosis is considered decompensated. Half of all patients with cirrhosis and ascites will die within two years if they do not receive an orthotopic liver transplant.
Physical examination findings in the skin of patients with cirrhosis include caput medusae (abdominal wall collateral vessels), jaundice, palmar erythema, and vascular spiders. Dupuytren’s contracture and finger clubbing may develop. Men may present with gynecomastia and testicular atrophy. Hepatomegaly, splenomegaly, or ascites may be discovered on abdominal examination, depending on how far the disease has progressed. Asterixis (flapping tremor of the hands) may be present in cases of hepatic encephalopathy.
Abdominal ultrasonography is the first-line radiographic study for diagnosing cirrhosis, and adding Doppler studies can also assess vascular status. Therapy consists of sodium restriction (2000 mg per day), diuretics (spironolactone, furosemide), and abstention from alcohol. Fluid restriction is unnecessary unless serum sodium is less than 125 mEq/L, although it may help control ascites and minimize the amount of diuretic required.
COMMON COMPLICATIONS
Cirrhosis is an immunocompromised state. As more and more damage is done to the liver, its synthetic function begins to decline. This leads to a qualitative dysfunction of macrophages, neutrophils, and the reticuloendothelial system and, due to decreased synthesis of complement, reduced opsonization capacity of the ascitic fluid and defective chemotaxis.
This problem is compounded by increased sympathetic tone, causing a decrease in gut motility. This in turn promotes bacterial stasis and overgrowth, which leads to an overpopulation of enteric gram-negative bacteria. Intestinal submucosal edema from portal hypertension increases intestinal capillary permeability and compromises the protective integrity of the mucosal barrier, promoting translocation of these gram-negative bacteria and their associated endotoxins from the intestinal lumen. The above problems—combined with the failure of antibacterial defense mechanisms to efficiently clear translocating microorganisms and toxins from the blood—often have disastrous results in the body, including sepsis.
Another common problem associated with cirrhosis is malnutrition due to anorexia, poor diet, malabsorption, and an altered metabolic state. Malnutrition also increases the risk of infection. Bleeding can occur secondary to decreased production of clotting factors (except factor VIII), causing an increase in prothrombin time. Portal hypertension also leads to thrombocytopenia secondary to hypersplenism.
In addition, patients with cirrhosis are prone to hypoglycemia due to decreased hepatic glycogen storage. A chronic hypersympathetic state leads to desensitization of sympathetic receptors, blunting cardiac chronotropic and inotropic reactions to physiologic stresses. Autonomic neuropathy also contributes to chronotropic incompetence. Dilutional hyponatremia results from expanded extracellular fluid volume.
SPECIAL TREATMENT CONSIDERATIONS
Because of the unusual physiologic mechanisms of their disease, patients with cirrhosis do not respond to traditional therapies for common problems. Early goal-directed therapy, intensive insulin therapy, and other sepsis treatments have been shown to decrease mortality in the general population but have not been tried on patients with cirrhosis.
Hypotension from sepsis or other causes of shock may be refractory to catecholamine administration in patients with cirrhosis because of sympathetic desensitization. Preliminary evidence shows that vasopressin may improve refractory shock in these patients. Terlipressin (a vasopressin analogue) has been extremely beneficial in treating hepatorenal syndrome (HRS) and has shown great promise in treating acute liver injury with hypotension and severe lactic acidosis resistant to volume expansion, as well as catecholamine-resistant septic shock. This drug is still in phase III clinical trials in the United States, however.
Marked adrenal insufficiency almost always occurs in patients with cirrhosis and severe sepsis and can lead to circulatory collapse. Steroids should be considered early in the course of therapy—100 mg of IV hydrocortisone every six hours is sufficient. An alternative is 4 mg of IV dexamethasone, which does not interfere with subsequent adrenal testing. In addition, septic patients with cirrhosis are more prone to developing disseminated intravascular coagulopathy (DIC) than the general population, so early vigilant monitoring is suggested. Distinguishing DIC from hepatic coagulopathy can be difficult because fibrinogen levels may be low, high, or normal in cirrhosis. Fibrin split products and D-dimer levels are also elevated in patients with advanced cirrhosis. Early monitoring for trends in these laboratory values may help differentiate DIC from hepatic coagulopathy.
Some drugs should be avoided in patients with cirrhosis. Nonsteroidal anti-inflammatory drugs cause a decrease in renal perfusion by blocking the cyclooxygenase-derived vasodilator prostaglandins that protect renal perfusion in patients with ascites. In addition, iodinated contrast agents given for computed tomography or other imaging studies may cause renal vasoconstriction when administered intravascularly. Nitrovasodilators or substances inhibiting angiotensin II action may be used to treat portal hypertension, but they shunt blood away from the kidneys and may induce renal dysfunction in patients with cirrhosis and ascites. They should not be used by emergency physicians because they may precipitate HRS or prerenal failure.
Finally, 33% to 46% of patients with cirrhosis have gallstones, a higher incidence than in the general population. Keep this in mind, especially when patients present with abdominal pain. Traditional laboratory results, such as liver function tests, may not be helpful in delineating this diagnosis. If gallstones are strongly suspected, an abdominal ultrasound should be performed.
VARICEAL BLEEDING:
MOST FEARED COMPLICATION
Variceal bleeding is one of seven unique complications that may occur with cirrhosis. The others are spontaneous bacterial peritonitis, hepatic encephalopathy, HRS, cirrhotic cardiomyopathy, hepatopulmonary syndrome, and portopulmonary hypertension.
Patients can lose massive amounts of blood rapidly with variceal bleeding, making it the cirrhosis complication physicians fear most. The situation is further complicated by impaired platelet function and coagulopathy. About 50% of patients with cirrhosis develop varices; the complication is present in 30% to 40% of patients with compensated cirrhosis and in 60% of those with ascites. Patients with numerous visible vascular spiders are at increased risk for variceal hemorrhage, with the rate of variceal bleeding at 10% to 30% per year.
Once varices have been identified, prophylaxis with 40 mg of oral propranolol twice a day is recommended. If propranolol is contraindicated or not tolerated, 20 mg of oral isosorbid mononitrate twice a day may be used, but patients must be monitored closely for renal failure. Beta blockers should never be started during acute bleeding in patients with cirrhosis.
Approximately 10% to 20% of cirrhotic patients with portal hypertensive bleeding have hypovolemic shock at admission but variceal bleeding stops spontaneously in about half of them. Even so, 5% to 8% of patients die within 48 hours, and the six-week mortality rate is 20%. In addition, 30% to 40% will rebleed within six weeks. The highest risk for rebleeding is during the first five days after the initial bleed, and early rebleeding increases the mortality rate.
When patients present to the emergency department with variceal bleeding, the mainstays of therapy are correcting hypovolemia, achieving hemostasis, and preventing complications. Upper gastrointestinal hemorrhage from esophageal varices may be massive, and patients may have trouble protecting their airway. If airway compromise seems likely, early intubation is recommended. A minimum of two large-bore peripheral intravenous lines should be placed. Maintain hematocrit levels between 25% and 30%, and administer plasma expanders, such as normal saline or albumin, to prevent HRS. Also administer a somatostatin bolus of 250 µg followed by an infusion of 250 µg every hour for the next five days, or an octreotide bolus of 100 µg followed by 50 µg every hour for the next five days. Consider giving recombinant factor VII if bleeding is still uncontrolled.
There is no mortality benefit in using both medical and endoscopic management for an initial bleed. Each of these therapies reduces the risk of rebleeding by 40% to 50%. Endoscopy is a reasonable choice for the first rebleed, but surgical placement of a transjugular intrahepatic portosystemic shunt (TIPS) must be strongly considered. About 70% of TIPS catheters obstruct within one year.
There is a significant decrease in mortality when antibiotics are implemented early in the course of variceal hemorrhage, so prophylaxis with norfloxacin should begin as soon as possible.
SPONTANEOUS BACTERIAL PERITONITIS
Because cirrhosis is an immunocompromised state, infections are a common and serious complication. Bacterial infection can trigger variceal rebleeding, which predisposes the patient to bacterial infection with gut-derived flora, setting up a vicious circle of bleeding and infection. Half of patients with cirrhosis that are admitted with gastrointestinal hemorrhage will develop infection. The mortality rate from sepsis is more than 20 times higher in patients with cirrhosis than in the general population.
The most common bacterial infection in cirrhosis is spontaneous bacterial peritonitis (SBP) at 25%, followed by urinary tract infection (20%); pneumonia, including spontaneous bacterial empyema (15%); and bacteremia (12%). Bacteria that translocate from the intestine, such as gram-negative members of the Enterobacteriaceae family (Escherichia coli and Klebsiella species), enterococci, and streptococci, are the most effective at bacterial translocation and the most common culprits in SBP and urinary tract infection. Gram-positive bacteria like Streptococcus pneumoniae predominate in pneumonia, and Staphylococcus aureus—especially methicillin-resistant S. aureus (MRSA)—are often found in procedure-associated bacteremia. Overall, the number of infections caused by gram-negative bacteria equals the number caused by gram-positive bacteria. Gram-positive bacterial infections are often acquired nosocomially during procedures.
Spontaneous bacterial peritonitis is an infection of the ascitic fluid, generally with a single bacterial species, in the absence of any other primary abdominal source for infection. It usually presents with signs of peritoneal irritation, pain, nausea, vomiting, and changes in gastrointestinal motility (diarrhea or ileus), but it may be subclinical. Up to 50% of patients who have community-acquired SBP are asymptomatic. The incidence of SBP in patients with ascites is 10% per year, and mortality rates are now only 15% to 20%, compared to 80% in the 1970s.
About 30% of patients with SBP will develop renal failure, the most important predictor of in-hospital mortality associated with this infection. Mortality reaches 50% in the presence of renal failure, as opposed to only 6% in its absence. If patients recover from SBP, the one-year mortality rate is still 30% to 80%, with a median survival time of nine months. The risk of one-year recurrence is 40% to 70%.
Escherichia coli and Klebsiella are isolated in 70% of culture-positive community-acquired SPB cases. Aerobic gram-positive organisms like Staphylococcus and Streptococcus account for most of the remaining cases. An exception to this rule is nosocomial SBP, in which gram-positive organisms account for 70% of isolates. A causative organism is not identified 30% to 50% of the time.
USE OF DIAGNOSTIC PARACENTESIS
Any patient with ascites of cirrhosis who is admitted to the hospital, regardless of whether he has symptoms of SBP, must have a diagnostic paracentesis done. Approximately 1500 ml of ascites must be present before dullness is detected on physical examination, but routine ultrasonography can detect as little as 50 ml and also may aid in procedural guidance. Since half of community-acquired cases are asymptomatic, and this infection has such devastating consequences, it must be excluded in every patient.
To test for SPB, inoculate 10 ml of ascitic fluid into a blood culture bottle and also draw separate and simultaneous blood cultures. The following studies should be ordered on the ascitic fluid: cell count with differential, culture in blood culture bottles, and albumin and total protein levels. An ascitic neutrophil count greater than 250/µl is diagnostic for SBP. A serum-ascites albumin gradient should also be calculated using this formula: serum albumin level – ascites albumin level = serum-ascites albumin gradient.
If the serum-ascites albumin gradient is greater than 1.1 g/dl, portal hypertension is likely. If the total protein level is less than 2.5 g/dl, it is considered transudative; a level greater than 2.5 g/dl is exudative. A post-paracentesis albumin infusion is unnecessary for a single paracentesis of less than four liters, but for large-volume paracentesis, an albumin infusion of 8 to 10 grams for every liter removed can be considered.
Panculture every patient and start empiric antibiotic treatment immediately after diagnostic paracentesis. Chest films should also be obtained. A third-generation cephalosporin (1 g of IV cefotaxime every 12 hours or 2 g of IV ceftriaxone every 24 hours) or amoxicillin and clavulanate is the treatment of choice. Treatment should continue for at least five days, preferably eight days. In uncomplicated SBP, oral quinolones (400 mg of norfloxacin or ciprofloxacin twice a day) are a suitable alternative as long as the local prevalence of quinolone resistance to gram-negative bacteria remains low.
Patients who survive an episode of SBP should receive short-term prophylaxis with norfloxacin or trimethoprim-sulfamethoxazole twice daily for seven days. Patients who develop SBP while on chronic norfloxacin prophylaxis have an increased likelihood of developing quinolone-resistant gram-negative bacteria and are also susceptible to gram-positive coccal infection, including MRSA.
The diminished effective circulatory volume present in SBP may lead to renal dysfunction. The most common independent baseline predictors of death in SBP are a blood urea nitrogen level above 30 mg/dl or a creatinine level over 1 mg/dl, which are markers of renal dysfunction. Patients who develop renal dysfunction during active infection have the highest mortality rates, so those at increased risk for renal dysfunction require adjunctive albumin therapy as a preventive measure. The albumin dose of 1.5 g/kg is very costly, so limit its use to patients who already have some renal dysfunction. Procedures such as large-volume paracentesis or medications such as diuretics that deplete the intravascular volume should be discontinued to avoid prerenal failure.
RISK OF HEPATIC ENCEPHALOPATHY
Approximately 10% to 50% of patients with cirrhosis will experience an episode of overt hepatic encephalopathy at some point in their illness. Cirrhosis causes many disordered brain pathways, including those of glutamine, monoamine, serotonin, opiates, and catecholamines. Encephalopathy associated with acute fulminant liver failure carries a 70% to 80% mortality and quickly progresses to seizures, coma, and decerebrate rigidity that leads to hypoxia and cerebral herniation secondary to cerebral edema. More commonly, patients present with milder symptoms of chronic encephalopathy, triggered by precipitating factors such as infection, electrolyte disturbances, constipation, and gastrointestinal bleeding, which are reversible in most cases. The one-year mortality rate after overt hepatic encephalopathy is 60%; the three-year mortality rate climbs to 85%.
Ammonia is produced primarily in the intestine from the uptake of glutamine. Glutaminase in the intestinal wall converts glutamine to glutamate and ammonia. Glutaminase activity increases in cirrhosis, causing an increase in ammonia levels. Astrocytes, the main site of ammonia detoxification, use ammonia to convert glutamate back to glutamine. Increased ammonia leads to an increase in glutamine levels within astrocytes. This causes an osmotic imbalance that leads to cell swelling and brain edema.
This glial edema, along with elevated ammonia levels, potentiates the effects of gamma-amino butyric acid, the main inhibitory neurotransmitter in the central nervous system. After edema, inflammation develops and the resultant increase in cerebral blood flow plays a synergistic role with all of the mechanisms described above (multiple-hit hypothesis). In addition, blood-brain barrier permeability and the cerebral metabolic rate for ammonia increases two to three times in patients with cirrhosis. This elevated cerebral volume causes an additional increase in intracranial pressure that further promotes osmotic movement of water across the blood-brain barrier. Malignant hypertension precedes death and can only be treated with a liver transplant. Plasma ammonia levels greater than 150 U are associated with brain herniation, but there is no linear relationship between the arterial ammonia level and hepatic encephalopathy grade.
In acute liver failure, brain herniation and death can occur from rapid deterioration in level of consciousness and increased intracranial pressure. Coma may result in severe forms of acute and chronic liver failure. Improved outcomes result from early specialist intensive care, treatment of precipitating factors such as variceal bleeds, and the judicious use of liver transplants.
Chronic hepatic encephalopathy, also known as subclinical hepatic encephalopathy, presents with extrapyramidal signs, psychomotor dysfunction, increased reaction time, and less severe cognitive deficits, such as impaired memory and visual perception, sensory abnormalities, and poor concentration. Verbal ability is generally spared. Progression to hepatic encephalopathy is characterized by severe cognitive, psychiatric, and motor disturbances. Initially, patients develop sleep abnormalities, mood and personality changes, and a shortened attention span, followed by deterioration to anxiety and depression with subsequent motor incoordination and asterixis. Finally, patients lapse into a coma.
Other relatively common central nervous system disorders encountered in cirrhosis are osmotic demyelination disorders like pseudobulbar palsy, impaired responsiveness, and rapidly evolving paraparesis or quadriparesis. Some less common problems include acquired hepatocerebral degeneration and hepatic myelopathy. Hepatocerebral degeneration presents with irreversible dementia, dysarthria, ataxia, intention tremor, and choreoathetosis. Hepatic myelopathy is characterized by spastic paraparesis with minimal sensory involvement.
DIAGNOSING AND TREATING
HEPATIC ENCEPHALOPATHY
To establish a diagnosis of hepatic encephalopathy, there must be a history or clinical evidence of liver disease with or without precipitating factors. The most common causes of hepatic encephalopathy are constipation, electrolyte and acid-base imbalance (especially low serum potassium and sodium), infection, gastrointestinal bleeding, and portosystemic shunts. Insertion of a shunt in patients with uncontrolled variceal bleeding or intractable ascites may induce hepatic encephalopathy, especially within the first few months after placement. Less common causes that may also trigger hepatic encephalopathy include sedatives or tranquilizers, vascular occlusion (hepatic vein or portal vein thrombosis), and hepatocellular carcinoma transformation.
When a patient presents to the emergency department with suspected hepatic encephalopathy, obtain pancultures to look for infection and get a basic metabolic panel to check for electrolyte disturbances or other precipitating factors. Try to take a thorough history, asking questions that target a cause for precipitating factors. Getting an accurate history from the patient may be difficult, so whenever possible, obtain a more detailed history from friends or family members.
The most important facet of treatment is correction or removal of the underlying precipitant, such as hypovolemia, electrolyte imbalance, hypoxia, constipation, gastrointestinal bleeding, metabolic derangement, infections, and sedatives and tranquilizers. Adjunctive therapy consists of reducing ammonia generation and increasing its detoxification. The most common methods to lower ammonia are purgatives, such as lactulose and antibiotics. Although lactulose is more effective than a placebo in improving hepatic encephalopathy, it has no effect on mortality. And while antibiotics are better at improving hepatic encephalopathy grade and lowering ammonia levels than lactulose, they also have no proven mortality benefit.
Protein restriction has traditionally been used, but sound evidence to support this hypothesis is lacking and dietary restrictions may further exacerbate malnutrition. Tight glycemic control using insulin is imperative. Typically, hepatic encephalopathy is reversible with therapy. Induced moderate hypothermia for the treatment of uncontrolled intracranial pressure has shown promise in initial trials to decrease intracranial pressure, increase cerebral or coronary blood flow, and reduce arterial ammonia and cerebral ammonia uptake.
HEPATORENAL SYNDROME
In patients with cirrhosis, acute renal failure (ARF) is almost always due to either prerenal failure or tubular necrosis. In ARF, there is a rapid decline in the glomerular filtration rate (GFR), alterations of extracellular fluid volume and electrolyte and acid-base homeostasis, and retention of nitrogenous waste from protein metabolism. Acute renal failure is diagnosed when serum creatinine increases by more than 50% from the baseline value, to above 1.5 mg/dl in patients without previous renal impairment.
Prerenal failure usually occurs in patients with decompensated cirrhosis. Increased intra-abdominal pressure from tense ascites leads to a baseline decrease in renal perfusion, making the kidneys more susceptible to insults. In addition, patients already have significant circulatory dysfunction characterized by low arterial pressure with resultant renal vasoconstriction and decreased renal blood flow. However, they have no reduction or only a mild reduction in GFR. The causes of prerenal failure induce another insult to renal blood flow and in turn cause a marked decline in GFR. If prerenal failure is present, patients generally have low urine sodium (less than 20 mmol/L) and elevated urine osmolality (greater than 500 mOsm/kg).
Renal hypoperfusion is responsible for more than 90% of cirrhosis-associated ARF. The three main causes of prerenal failure are true hypovolemia (from hemorrhage or gastrointestinal or renal fluid losses), sepsis, and type 1 HRS. Other less common causes are administration of nonsteroidal anti-inflammatory drugs or intravascular radiocontrast agents. Prerenal failure may be rapidly reversible if the underlying cause is identified and corrected.
Diuretic treatment used to mobilize ascites, glycosuria resulting in renal fluid losses, and septic shock all may lead to prerenal failure. Septic shock and subsequent renal impairment occur in 10% of patients with SBP. Fluid replacement is used to treat prerenal failure that is not caused by HRS and, by definition, it is reversible after restoration of blood flow, whereas HRS is not. In patients with intestinal or renal fluid losses, crystalloids are administered and diuretics stopped.
Increased renal vasoconstriction and a relative decline in cardiac output (due to decreased cardiac preload) are two main mechanisms of renal failure in patients with HRS. Portal hypertension leads to vasodilation of the splanchnic arterial bed, causing a decrease in cardiac afterload. Consequently, cardiac and sympathetic output increase. Eventually there comes a point where the heart is no longer able to compensate, which leads to arterial hypotension. Baroreceptors detect this decrease in blood pressure and cause a marked increase in sympathetic output, activation of the renin-angiotensin-aldosterone system, and antidiuretic hormone levels. Salt and water retention are a result of this compensation, and HRS develops from ensuing vasoconstriction. This is known as the HRS peripheral vasodilation hypothesis.
TWO TYPES OF HEPATORENAL SYNDROME
There are two types of HRS. Type 1 is acute and rapidly progressive, with serum creatinine levels greater than 2.5 mg/dl; type 2 is a milder, more chronic form. Five major criteria are required to diagnose HRS (see box below). The syndrome is associated with severe oliguria, urinary sodium retention, and dilutional hyponatremia. It may develop spontaneously or simultaneously with systemic bacterial infections—in particular SBP—where bacterial by-products like endotoxin stimulate production of tumor necrosis factor-alpha, leading to a further increase in splanchnic vasodilation and a decrease in cardiac afterload. At the onset of SBP, 20% to 40% of patients have renal impairment without shock. About 30% of those admitted for bacterial infection develop type 1 HRS during hospitalization. Approximately 25% of patients with severe acute alcoholic hepatitis will develop type 1 HRS. One in 10 patients treated with large-volume paracentesis without albumin support will develop type 1 HRS, as will 5% of patients hospitalized for upper gastrointestinal hemorrhage.
 |
Without treatment, the median survival time of patients with type 1 HRS is less than two weeks, and virtually all patients die within 8 to 10 weeks after the onset of renal failure. Patients with type 2 HRS have a longer median survival time of approximately six months. In patients with type 1 HRS who have a low short-term survival rate, liver transplant is the ideal treatment. Systemic vasoconstrictor therapy with norepinephrine (combined with albumin and furosemide) or midodrine (combined with octreotide and albumin) may improve renal function in type 1 HRS patients waiting for a transplant. Insertion of a TIPS may also improve renal function in these patients.
Acute tubular necrosis (ATN) is caused by ischemic or toxic injury, including all causes of prerenal azotemia. In patients with cirrhosis, ATN is mainly due to an ischemic insult on the renal tubules. Aminoglycoside antibiotics are the most common cause of toxic tubular necrosis in patients with cirrhosis. Patients have high urine sodium (above 40 mmol/L) and low urine osmolality (below 350 mOsm/kg). Unlike patients with type 1 HRS, those with ATN do not have improved renal function following administration of a vasoconstrictor combined with intravenous human albumin. The only treatment for ATN is the prevention and elimination of precipitants, such as discontinuing nephrotoxins, avoiding radiocontrast agents, treating hyperkalemia and metabolic acidosis, providing sufficient nutritional support, preventing and treating portal hypertensive bleeding, and preventing and treating bacterial infections.
Other causes of renal failure must be excluded. The existence of arterial hypertension (an unexpected finding in patients with cirrhosis) suggests glomerulonephritis. Purpura, arthralgias, weakness, Raynaud’s syndrome, or leg ulcers suggest cryoglobulinemia.
Renal replacement therapy is indicated for cirrhotic patients just as for patients in the general population, when signs or symptoms of uremia are present (pericardial rub or effusion, hiccups, changes in mental status), and in the management of volume overload, hyperkalemia, or acidosis that is refractory to the usual treatment.
CIRRHOTIC CARDIOMYOPATHY
Cirrhosis is associated with increased cardiac output, decreased arterial pressure, and decreased total peripheral resistance. Cardiac output and contractility are normal or increased at rest, but abnormal in the presence of pharmacologic, physiologic, or surgical stressors. All of these abnormalities are termed “cirrhotic cardiomyopathy.”
Beta-adrenergic receptor signaling pathways, intracellular calcium kinetics, and humoral factors—such as endogenous cannabinoids, nitric oxide, and carbon monoxide—are all impaired or altered in cirrhotic cardiomyopathy. This leads to an electromechanical dyssynchrony and causes ventricular contractile dysfunction. In addition, diastolic relaxation is impaired secondary to stiffening and hypertrophy of the left ventricle. This results in attenuated systolic and diastolic function in the presence of stressors like eating, exercise, body position changes, intravascular volume alterations, insertion of TIPS, liver transplant, infection (especially SBP), major surgery, and hemorrhage. Prolongation of the QT interval as a result of abnormal myocardial repolarization puts patients at higher risk for torsades de pointes and other ventricular arrhythmias.
It is important to note that TIPS insertion, which is used as therapy for refractory ascites or gastrointestinal hemorrhage, can place a significant amount of stress on the heart as it redirects portal blood into the systemic circulation. It may precipitate overt heart failure in a few patients.
In overt congestive heart failure, treatment is similar to that of noncirrhotic patients, but there are a few important cautions. Patients with cirrhosis have very low arterial pressures, so they have a poor tolerance for many drugs that reduce preload or afterload. In particular, angiotensin-converting enzyme inhibitors may cause a precipitous fall in blood pressure. Also, many cardiovascular drugs have relatively little effect due to desensitization. These include dobutamine, epinephrine, and nitrovasodilators. Cardiac glycosides also seem to be ineffective in improving contractility, although this has not been adequately studied. The mainstays of therapy are bed rest and oxygen supplementation.
LAST TWO UNIQUE COMPLICATIONS
The last two unique complications of cirrhosis that we will discuss are hepatopulmonary syndrome and portopulmonary hypertension.
Hepatopulmonary syndrome. This complication results in hypoxemia through pulmonary microvasculature vasodilation (due to elevated nitric oxide levels) and intrapulmonary arteriovenous shunting. These phenomena result in ventilation-perfusion mismatch. Patients will complain of the subtle onset of progressive dyspnea or orthodeoxia-platypnea (dyspnea and deoxygenation accompanying a change from a recumbent position to sitting or standing). Physical examination may show signs of hypoxia, including cyanosis and clubbing.
Mortality can be as high as 41% at 2.5 years after the onset of dyspnea. No therapies have been successful in treating it, but indomethacin is used based on the principle of inhibiting prostaglandins, which play important roles in vasodilation. This drug must be used with caution to avoid precipitating HRS, and it should not be given by emergency physicians. Liver transplant is the only successful long-term treatment.
Portopulmonary hypertension. The complication of portopulmonary hypertension is characterized by an elevated mean pulmonary artery wedge pressure, increased pulmonary vascular resistance, and normal wedge pressure in the setting of underlying portal hypertension. Patients may present with dyspnea on exertion, fatigue, orthopnea, syncope, chest pain, or hemoptysis. Echocardiography or right-heart catheterization must be done to provide a definitive diagnosis.
Trials may be initiated with short-acting vasodilators (calcium channel blockers, beta blockers, nitrates, and nitric oxide) to assess responsiveness. However, response is variable and, once again, caution should be advised so as not to precipitate HRS. There are reports of persistence and even progression of cirrhosis after a liver transplant, but many patients slowly improve
after the transplant.
Suggested Reading
Ardizzone G, et al.: Neurological complications of liver cirrhosis and orthotopic liver transplant. Transplantation Proc 38(3):789, 2006.
Cardenas A and Ginés P: Management of complications of cirrhosis in patients awaiting liver transplantation. J Hepatol 42 Suppl(1):S124, 2005.
de Franchis R and Dell’Era A: Non-invasive diagnosis of cirrhosis and the natural history of its complications. Best Pract Res Clin Gastroenterol 21(1):3, 2007.
Garcia-Tsao G: Bacterial infections in cirrhosis: treatment and prophylaxis. J Hepatol 42 Suppl(1):S85, 2005.
Ghassemi S and Garcia-Tsao G: Prevention and treatment of infections in patients with cirrhosis. Best Pract Res Clin Gastroenterol 21(1):77, 2007.
Ginés P, et al.: Management of cirrhosis and ascites. N Engl J Med 350(16):1646, 2004.
Heidelbaugh JJ and Bruderly M: Cirrhosis and chronic liver failure: part I. Diagnosis and evaluation. Am Fam Physician 74(5):756, 2006.
Heidelbaugh JJ and Sherbondy M: Cirrhosis and chronic liver failure: part II. Complications and treatment. Am Fam Physician 74(5):767, 2006.
Ho JK and Yoshida E: The extrahepatic consequences of cirrhosis. MedGenMed 8(1):59, 2006.
Lee RF, et al.: Cardiac dysfunction in cirrhosis. Best Pract Res Clin Gastroenterol 21(1):125, 2007.
Moreau R and Lebrec D: Diagnosis and treatment of acute renal failure in patients with cirrhosis. Best Pract Res Clin Gastroenterol 21(1):111, 2007.
National Digestive Diseases Information Clearinghouse: Cirrhosis of the liver. NDDIC Web site, 2003. Available at: http://digestive.niddk.nih.gov/ddiseases/pubs/cirrhosis. Accessed October 31, 2007.
Riordan SM and Williams R: The intestinal flora and bacterial infection in cirrhosis. J Hepatol 45(5):744, 2006.
Thalheimer U, et al.: Infection, coagulation, and variceal bleeding in cirrhosis. Gut 54(4):556, 2005.
Wright G and Jalan R: Management of hepatic encephalopathy in patients with cirrhosis. Best Pract Res Clin Gastroenterol 21(1):95, 2007.
Zambruni A, et al.: Cardiac electrophysiological abnormalities in patients with cirrhosis. J Hepatol 44(5):994, 2006.
|
|
