Cirrhosis is a condition of the liver that results from long-term damage to liver cells. In cirrhosis, bands of fibrosis (internal scarring) develop, leaving nodules of regenerating cells that are inadequately supplied with blood. Liver function is gradually impaired; the liver no longer effectively removes toxic substances from the blood. The distortion and fibrosis also lead to portal portal hypertension (abnormally high blood pressure in the veins leading from the intestines and spleen to the liver).
The most common cause of cirrhosis is excessive alcohol consumption. Another possible cause is one of the forms of chronic hepatitis (inflammation of the liver). Other causes, which are rare, include disorders of the bile ducts; haemochromatosis, in which increased iron absorption occurs; Wilson’s disease (an increase in copper absorption); cystic fibrosis, which causes obstruction of the bile ducts with mucus; and heart failure.
Symptoms and complications
Cirrhosis may go unrecognized until symptoms such as mild jaundice, oedema (an accumulation of fluid in body tissues) and vomiting of blood develop. There may be enlargement of the liver and spleen. Men may experience loss of body hair and enlargement of the breasts due to an imbalance in sex hormones caused by liver failure. Complications of cirrhosis include ascites (an accumulation of fluid in the abdominal cavity), oesophageal varices (enlarged veins within the oesophagus wall), and hepatoma (liver cancer). Cirrhosis may also cause toxins to build up in the brain, producing symptoms such as confusion and coma (hepatic encephalopathy).
Treatment is focused on slowing the rate at which liver cells are being damaged, if possible by treating the cause. Any complications will also be treated. In some cases, however, the cirrhosis progresses and a liver transplant may need to be considered.
Cirrhosis in detail - technical
Essentials of Diagnosis
- End result of injury that leads to both fibrosis and nodular regeneration.
- May be reversible if cause is removed.
- The clinical features result from hepatic cell dysfunction, portosystemic shunting, and portal hypertension.
Cirrhosis, the twelfth leading cause of death in the United States, is the end result of hepatocellular injury that leads to both fibrosis and nodular regeneration throughout the liver. Causes include chronic viral hepatitis, alcohol, drug toxicity, autoimmune and metabolic liver diseases, and miscellaneous disorders. In patients at increased risk for liver injury (eg, heavy alcohol use, obesity, iron overload), higher coffee and tea consumption has been reported to reduce the risk of cirrhosis. Hospitalization rates for cirrhosis and portal hypertension are rising in the United States.
The most common histologic classification divides cirrhosis into micronodular, macronodular, and mixed forms. These are descriptive terms rather than separate diseases, and each form may be seen in the same patient at different stages of the disease. In micronodular cirrhosis—typical of alcoholic liver disease (Laennec cirrhosis)—the regenerating nodules are no larger than the original lobules, ie, approximately 1 mm in diameter or less.
Macronodular cirrhosis is characterized by larger nodules, which can measure several centimeters in diameter and may contain central veins. This form corresponds more or less to postnecrotic (posthepatitic) cirrhosis but does not necessarily follow episodes of massive necrosis and stromal collapse.
Symptoms and Signs
The clinical features of cirrhosis result from hepatic cell dysfunction, portosystemic shunting, and portal hypertension.
Patients may have no symptoms for long periods. The onset of symptoms may be insidious or, less often, abrupt. Weakness, fatigability, disturbed sleep, muscle cramps, and weight loss are common. In advanced cirrhosis, anorexia is usually present and may be extreme, with associated nausea and occasional vomiting. Abdominal pain may be present and is related either to hepatic enlargement and stretching of Glisson capsule or to the presence of ascites. Menstrual abnormalities (usually amenorrhea), impotence, loss of libido, sterility, and gynecomastia in men may occur. Hematemesis is the presenting symptom in 15–25%.
In 70% of cases, the liver is enlarged, palpable, and firm if not hard and has a sharp or nodular edge; the left lobe may predominate. Skin manifestations consist of spider nevi (invariably on the upper half of the body), palmar erythema (mottled redness of the thenar and hypothenar eminences), and Dupuytren contractures. Evidence of vitamin deficiencies (glossitis and cheilosis) is common. Weight loss, wasting, and the appearance of chronic illness are present. Jaundice—usually not an initial sign—is mild at first, increasing in severity during the later stages of the disease.
Ascites, pleural effusions, peripheral edema, and ecchymoses are late findings. Encephalopathy characterized by day–night reversal, asterixis, tremor, dysarthria, delirium, drowsiness, and ultimately coma also occurs late except when precipitated by an acute hepatocellular insult or an episode of gastrointestinal bleeding. Fever may be a presenting symptom in up to 35% of patients and usually reflects associated alcoholic hepatitis, spontaneous bacterial peritonitis, or intercurrent infection. Splenomegaly is present in 35–50% of cases. The superficial veins of the abdomen and thorax are dilated, reflecting the intrahepatic obstruction to portal blood flow, as do rectal varices. The veins fill from below when compressed.
Laboratory abnormalities are either absent or minimal in early or compensated cirrhosis. Anemia, a frequent finding, is often macrocytic; causes include suppression of erythropoiesis by alcohol as well as folate deficiency, hemolysis, hypersplenism, and occult or overt blood loss from the gastrointestinal tract. The white blood cell count may be low, reflecting hypersplenism, or high, suggesting infection; thrombocytopenia is secondary to alcoholic marrow suppression, sepsis, folate deficiency, or splenic sequestration. Prolongation of the prothrombin time may result from reduced levels of clotting factors (except factor VIII). However, bleeding risk correlates poorly with results of conventional coagulation parameters.
Blood chemistries reflect hepatocellular injury and dysfunction, manifested by modest elevations of AST and alkaline phosphatase and progressive elevation of the bilirubin. Serum albumin is low; -globulin is increased and may be as high as in autoimmune hepatitis. The risk of diabetes mellitus is increased in patients with cirrhosis, particularly when associated with HCV infection, alcoholism, hemochromatosis, and NAFLD. Vitamin D deficiency has been reported in as many as 91% of patients with cirrhosis.
Patients with alcoholic cirrhosis may have elevated serum cardiac troponin I and brain natriuretic peptide levels. Blunted cardiac inotropic and chronotropic responses to exercise, stress, and drugs, as well as reduced ventricular function ("cirrhotic cardiomyopathy") and prolongation of the QT interval, are common in cirrhosis of all causes, but overt heart failure is rare in the absence of alcoholism. Relative adrenal insufficiency appears to be common in patients with advanced cirrhosis, even in the absence of sepsis.
Liver biopsy may show inactive cirrhosis (fibrosis with regenerative nodules) with no specific features to suggest the underlying cause. Alternatively, there may be additional features of alcoholic liver disease, chronic hepatitis, NASH, or other specific causes of cirrhosis. Combinations of routine blood tests (eg, AST, platelet count), including a commercially available panel of five tests called FibroSure, and serum markers of hepatic fibrosis (eg, hyaluronic acid, amino-terminal propeptide of type III collagen, tissue inhibitor of matrix metalloproteinase 1) are under study as alternatives to liver biopsy for the diagnosis or exclusion of cirrhosis. In persons with chronic hepatitis C, a low FibroSure score reliably excludes advanced fibrosis, a high score reliably predicts advanced fibrosis, and intermediate scores are inconclusive.
Ultrasound is helpful for assessing liver size and detecting ascites or hepatic nodules, including small hepatocellular carcinomas. Together with a Doppler study, it may establish patency of the splenic, portal, and hepatic veins. Hepatic nodules are characterized further by contrast-enhanced CT scan or MRI. Nodules suspicious for malignancy may be biopsied under ultrasound or CT guidance.
Esophagogastroduodenoscopy confirms the presence of varices and detects specific causes of bleeding in the esophagus, stomach, and proximal duodenum. Liver biopsy may be performed by laparoscopy or, in patients with coagulopathy and ascites, by a transjugular approach. In selected cases, wedged hepatic vein pressure measurement may establish the presence and cause of portal hypertension. Transient elastography, which uses ultrasonography to determine liver stiffness, is under study as a noninvasive test for cirrhosis and portal hypertension.
The most common causes of cirrhosis are chronic hepatitis C and B and alcohol. Many cases of cirrhosis are "cryptogenic," in which unrecognized NAFLD may play a role. Mutations in the keratin 8 gene have been associated with some cases of cryptogenic cirrhosis. Hemochromatosis is the most commonly identified genetic disorder that causes cirrhosis. Other metabolic diseases that may lead to cirrhosis include Wilson disease and 1-antiprotease (1-antitrypsin) deficiency. Primary biliary cirrhosis occurs more frequently in women than men. Secondary biliary cirrhosis may result from chronic biliary obstruction due to a stone, stricture, or neoplasm. Congestive heart failure and constrictive pericarditis may lead to hepatic fibrosis ("cardiac cirrhosis") complicated by ascites and may be mistaken for other causes of cirrhosis. Hereditary hemorrhagic telangiectasia can lead to portal hypertension because of portosystemic shunting and nodular transformation of the liver.
Upper gastrointestinal tract bleeding may occur from varices, portal hypertensive gastropathy, or gastroduodenal ulcer. Varices may also result from portal vein thrombosis. Liver failure may be precipitated by alcoholism, surgery, and infection. The risk of carcinoma of the liver is increased greatly in patients with cirrhosis. Hepatic Kupffer cell (reticuloendothelial) dysfunction and decreased opsonic activity lead to an increased risk of systemic infection. Osteoporosis occurs in 12–55% of patients with cirrhosis.
The most important principle of treatment is abstinence from alcohol. The diet should be palatable, with adequate calories (25–35 kcal/kg body weight per day in those with compensated cirrhosis and 35–40 kcal/kg/d in those with malnutrition) and protein (1–1.2 g/kg/d in those with compensated cirrhosis and 1.5 g/kg/d in those with malnutrition) and, if there is fluid retention, sodium restriction. In the presence of hepatic encephalopathy, protein intake should be reduced to 60–80 g/d. The benefit of using specialized supplements containing branched-chain amino acids to prevent or treat hepatic encephalopathy or delay progressive liver failure is uncertain. Vitamin supplementation is desirable. Patients with cirrhosis should receive the HAV, HBV, and pneumococcal vaccines and a yearly influenza vaccine.
Treatment of Complications
Ascites and oedema
Diagnostic paracentesis is indicated for new ascites. It is rarely associated with serious complications such as bleeding, infection, or bowel perforation even in patients with severe coagulopathy. In addition to a cell count and culture, the ascitic albumin level should be determined; a serum-ascites albumin gradient (serum albumin minus ascitic albumin) 1.1 suggests portal hypertension. An elevated ascitic adenosine deaminase level is suggestive of tuberculous peritonitis, but the sensitivity of the test is reduced in patients with portal hypertension. Occasionally, cirrhotic ascites is chylous (rich in triglycerides); other causes of chylous ascites are malignancy, tuberculosis, and recent abdominal surgery or trauma.
Ascites in patients with cirrhosis results from portal hypertension (increased hydrostatic pressure); hypoalbuminemia (decreased oncotic pressure); peripheral vasodilation, perhaps mediated by endotoxin-induced release of nitric oxide from splanchnic and systemic vasculature, with resulting increases in renin and angiotensin levels and sodium retention by the kidneys; impaired liver inactivation of aldosterone; and increased aldosterone secretion secondary to increased renin production (see illustration). Free water excretion is also impaired in cirrhosis, and hyponatremia may develop.
In all patients with cirrhotic ascites, dietary sodium intake may initially be restricted to 2000 mg/d; the intake of sodium may be liberalized slightly after diuresis ensues. In some patients, there is a rapid diminution of ascites on bed rest and dietary sodium restriction alone. In individuals with ascites, the urinary excretion of sodium is usually less than 10 mEq/L. Restriction of fluid intake (800–1000 mL/d) is required for patients with hyponatremia (serum sodium < 125 mEq/L). Treatment of severe hyponatremia with vasopressin receptor antagonists is under study.
Spironolactone, generally in combination with furosemide, should be used in patients who do not respond to salt restriction. An initial trial of furosemide 80 mg intravenously demonstrating a rise in urine sodium to 750 mmol in 8 hours may predict response to diuretic therapy. The dose of spironolactone is initially 100 mg orally daily and may be increased by 100 mg every 3–5 days (up to a maximal conventional daily dose of 400 mg/d, although higher doses have been used) until diuresis is achieved, typically preceded by a rise in the urinary sodium concentration. Monitoring for hyperkalemia is important. In patients who cannot tolerate spironolactone because of side effects, such as painful gynecomastia, amiloride (another potassium-sparing diuretic) may be used in a dose of 5–10 mg orally daily. Diuresis is augmented by the addition of a loop diuretic such as furosemide. This potent diuretic, however, will maintain its effect even with a falling glomerular filtration rate, with resultant prerenal azotemia. The dose of oral furosemide ranges from 40 mg/d to 160 mg/d, and the drug should be administered while monitoring blood pressure, urinary output, mental status, and serum electrolytes, especially potassium.
n patients with massive ascites and respiratory compromise, ascites refractory to diuretics, or intolerable diuretic side effects, large-volume paracentesis (4–6 L) is effective. Intravenous albumin concomitantly at a dosage of 10 g/L of ascites fluid removed protects the intravascular volume, although the usefulness of this practice is debated. Moreover, use of albumin adds considerable expense. Large-volume paracentesis can be repeated daily until ascites is largely resolved and may decrease the need for hospitalization. If possible, diuretics should be continued in the hope of preventing recurrent ascites.
Transjugular intrahepatic portosystemic shunt (TIPS)
TIPS is an effective treatment of variceal bleeding refractory to standard therapy (eg, endoscopic band ligation or sclerotherapy) and has shown benefit in the treatment of severe refractory ascites. The technique involves insertion of an expandable metal stent between a branch of the hepatic vein and portal vein over a catheter inserted via the internal jugular vein. Increased renal sodium excretion and control of ascites refractory to diuretics can be achieved in about 75% of selected cases. The success rate is lower in patients with underlying renal insufficiency. TIPS appears to be the treatment of choice for refractory hepatic hydrothorax (translocation of ascites across the diaphragm to the pleural space); video-assisted thoracoscopy with pleurodesis using talc may be effective when TIPS is contraindicated.
Complications of TIPS include hepatic encephalopathy in 20–30% of cases, infection, shunt stenosis in up to 60% of cases, and shunt occlusion in up to 30% of cases. Long-term patency usually requires periodic shunt revisions. In most cases, patency can be maintained by balloon dilation, local thrombolysis, or placement of an additional stent. TIPS is particularly useful in patients who require short-term control of variceal bleeding or ascites until liver transplantation can be performed. In patients with refractory ascites, TIPS results in lower rates of ascites recurrence and hepatorenal syndrome but a higher rate of hepatic encephalopathy than occurs with repeated large-volume paracentesis; a benefit in survival has been demonstrated in one study and a recent meta-analysis. Renal insufficiency, refractory encephalopathy, and hyperbilirubinemia are associated with mortality after TIPS.
Peritoneovenous shunts are sometimes placed in patients with malignant ascites but are no longer used for refractory cirrhotic ascites because of a considerable complication rate: disseminated intravascular coagulation in 65% of patients (25% symptomatic; 5% severe), bacterial infections in 4–8%, congestive heart failure in 2–4%, and variceal bleeding from sudden expansion of intravascular volume. TIPS is now preferred for refractory ascites.
Spontaneous bacterial peritonitis
Spontaneous bacterial peritonitis is heralded by abdominal pain, increasing ascites, fever, and progressive encephalopathy in a patient with cirrhotic ascites; symptoms are typically mild. Paracentesis reveals an ascitic fluid with, most commonly, a total white cell count of up to 500 cells/mcL with a high percentage of polymorphonuclear cells (PMNs) (> 250/mcL) and a protein concentration of 1 g/dL or less, corresponding to decreased ascitic opsonic activity. Rapid diagnosis of bacterial peritonitis can be made with a high degree of specificity with rapid reagent strips ("dipsticks") that detect leukocyte esterase in ascitic fluid. Cultures of ascites give the highest yield—80–90% positive—using blood culture bottles inoculated at the bedside.
Common isolates are Escherichia coli and pneumococci. (Gram-positive cocci are the most common isolates in patients who have undergone invasive procedures such as central venous line placement.) Anaerobes are rare. Pending culture results, if there are 250 or more PMN/mcL, intravenous antibiotic therapy should be initiated with cefotaxime, 2 g every 8–12 hours for at least 5 days. Ceftriaxone and amoxicillin-clavulanic acid are alternatives. Oral ofloxacin, 400 mg twice daily, or a 2-day course of intravenous ciprofloxacin, 200 mg twice daily, followed by oral ciprofloxacin, 500 mg twice daily for 5 days, may be effective in selected patients. Supplemental administration of intravenous albumin appears to reduce mortality. Response to therapy can be documented, if necessary, by a decrease in the PMN count of at least 50% on repeat paracentesis 48 hours after initiation of therapy.
The overall mortality rate is high—up to 30% during hospitalization and up to 70% by 1 year. Patients with cirrhosis and septic shock have a high frequency of relative adrenal insufficiency, which if present requires administration of hydrocortisone. In survivors of bacterial peritonitis, the risk of recurrent peritonitis may be decreased by long-term norfloxacin, 400 mg orally daily (although in recurrence the causative organism is often resistant to quinolones). In high-risk cirrhotic patients (eg, those with ascitic protein < 1.5 g/dL, serum bilirubin > 3.0 mg/dL, acute variceal bleeding), the risk of peritonitis, hepatorenal syndrome, and mortality for at least 1 year may be reduced by prophylactic norfloxacin, ciprofloxacin (500 mg orally twice a day), trimethoprim-sulfamethoxazole (one double-strength tablet five times a week), or intravenous ceftriaxone (1 g per day for 7 days in patients with variceal bleeding).
Hepatorenal syndrome occurs in up to 10% of patients with advanced cirrhosis and ascites and is characterized by azotemia (serum creatinine > 1.5 mg/dL) in the absence of parenchymal kidney disease or shock and by failure of renal function to improve following 2 days of diuretic withdrawal and volume expansion with albumin, 1 g/kg up to a maximum of 100 g/d. Oliguria, hyponatremia, and low urinary sodium are typical features. Hepatorenal syndrome is diagnosed only when other causes of renal failure (including prerenal azotemia and acute tubular necrosis) have been excluded.
Type I hepatorenal syndrome is characterized by doubling of the serum creatinine to a level greater than 2.5 mg/dL or by halving of the creatinine clearance to less than 20 mL/min in less than 2 weeks.
Type II hepatorenal syndrome is more slowly progressive and chronic. The pathogenesis involves intense renal vasoconstriction, possibly because of impaired synthesis of renal vasodilators such as prostaglandin E2 and decreased total renal blood flow; histologically, the kidneys are normal. An acute decrease in cardiac output is often the precipitating event. Improvement may follow intravenous infusion of albumin in combination with one of the following vasoconstrictors for 7–14 days: intravenous vasopressin or ornipressin (but with a high rate of ischemic side effects); intravenous ornipressin plus dopamine; intravenous terlipressin (a long-acting vasopressin analog not available in the United States); intravenous norepinephrine; or oral midodrine, an -adrenergic drug, plus the somatostatin analog octreotide, subcutaneously or intravenously.
Prolongation of survival has been associated with use of the molecular adsorbent recirculating system (MARS), a modified dialysis method that selectively removes albumin-bound substances. Improvement and sometimes normalization of renal function may also follow placement of a TIPS. Liver transplantation is the treatment of choice, but many patients die before a donor liver can be obtained. Mortality correlates with the MELD score and presence of a systemic inflammatory response.
Hepatic encephalopathy is a state of disordered central nervous system function resulting from failure of the liver to detoxify noxious agents of gut origin because of hepatocellular dysfunction and portosystemic shunting. The clinical spectrum ranges from day–night reversal and mild intellectual impairment to coma. Patients with minimal hepatic encephalopathy have no recognizable clinical symptoms but demonstrate mild cognitive and psychomotor deficits and attention deficit on standardized tests and an increased rate of traffic accidents.
The stages of overt encephalopathy are (1) mild confusion, (2) drowsiness, (3) stupor, and (4) coma. Ammonia is the most readily identified and measurable toxin but is not solely responsible for the disturbed mental status. Other pathogenic factors may include increased brain glutamine levels, production of false neurotransmitters, increased sensitivity of central nervous system neurons to the inhibitory neurotransmitter -aminobutyric acid (GABA), increased circulating levels of endogenous benzodiazepines, decreased activity of urea-cycle enzymes due to zinc deficiency, decreased brain levels of myoinositol, deposition of manganese in the basal ganglia, and swelling of astrocytes in the brain. Bleeding into the intestinal tract may significantly increase the amount of protein in the bowel and precipitate encephalopathy.
Other precipitants include constipation, alkalosis, and potassium deficiency induced by diuretics, opioids, hypnotics, and sedatives; medications containing ammonium or amino compounds; paracentesis with attendant hypovolemia; hepatic or systemic infection; and portosystemic shunts (including TIPS). The diagnosis is based primarily on detection of characteristic symptoms and signs, including asterixis. The role of neuroimaging studies (eg, cerebral positron emission tomography, magnetic resonance spectroscopy) in the diagnosis of hepatic encephalopathy is evolving.
Dietary protein should be withheld during acute episodes if the patient cannot eat. When the patient resumes oral intake, protein intake should be 60–80 g/d as tolerated; vegetable protein is better tolerated than meat protein. Gastrointestinal bleeding should be controlled and blood purged from the gastrointestinal tract. This can be accomplished with 120 mL of magnesium citrate by mouth or nasogastric tube every 3–4 hours until the stool is free of gross blood, or by administration of lactulose. The value of treating patients with minimal hepatic encephalopathy is uncertain.
Lactulose, a nonabsorbable synthetic disaccharide syrup, is digested by bacteria in the colon to short-chain fatty acids, resulting in acidification of colon contents. This acidification favors the formation of ammonium ion in the NH4+ NH3 + H+ equation; NH4+ is not absorbable, whereas NH3 is absorbable and thought to be neurotoxic. Lactulose also leads to a change in bowel flora so that fewer ammonia-forming organisms are present. When given orally, the initial dose of lactulose for acute hepatic encephalopathy is 30 mL three or four times daily. The dose should then be titrated so that two or three soft stools per day are produced. When rectal use is indicated because of the patient's inability to take medicines orally, the dose is 300 mL of lactulose in 700 mL of saline or sorbitol as a retention enema for 30–60 minutes; it may be repeated every 4–6 hours. Lactilol is a less sweet disaccharide alternative available as a powder in some countries.
The ammonia-producing intestinal flora may also be controlled with an oral antibiotic. Traditionally, neomycin sulfate, 0.5–1 g orally every 6 or 12 hours for 7 days, has been used, but side effects (including diarrhea, malabsorption, superinfection, ototoxicity, and nephrotoxicity) are frequent, especially after prolonged use. Increasingly, the nonabsorbable agent rifaximin, 400 mg orally three times daily, is preferred. Other antibiotics shown to have benefit are vancomycin, 1 g orally twice daily, and metronidazole, 250 mg orally three times daily. Patients who do not respond to lactulose alone may improve with a course of an antibiotic in addition to lactulose.
Opioids and sedatives metabolized or excreted by the liver are avoided. If agitation is marked, oxazepam, 10–30 mg, which is not metabolized by the liver, may be given cautiously by mouth or by nasogastric tube. Zinc deficiency should be corrected, if present, with oral zinc sulfate, 600 mg/d in divided doses. Sodium benzoate, 5 g orally twice daily, and ornithine aspartate, 9 g orally three times daily, may lower blood ammonia levels, but there is less experience with these drugs than with lactulose.
The benzodiazepine competitive antagonist flumazenil is effective in about 30% of patients with severe hepatic encephalopathy, but the drug is short-acting and intravenous administration is required. Use of special dietary supplements enriched with branched-chain amino acids is usually unnecessary except in occasional patients who are intolerant of standard protein supplements. Treatment with acarbose (an -glucosidase inhibitor) and L-carnitine (an essential factor in the mitochrondrial transport of long-chain fatty acids) is under study; other therapies being evaluated include modulating the gut flora with prebiotic and probiotic agents and the use of extracorporeal albumin dialysis (MARS).
For iron deficiency anemia, ferrous sulfate, 0.3-g enteric-coated tablets, one tablet orally three times daily after meals, is effective. Folic acid, 1 mg/d orally, is indicated in the treatment of macrocytic anemia associated with alcoholism. Transfusions with packed red blood cells may be necessary to replace blood loss.
Severe hypoprothrombinemia may be treated with vitamin K (eg, phytonadione, 5 mg orally or subcutaneously daily). This treatment is ineffective when synthesis of coagulation factors is impaired because of severe hepatic disease. In such cases, correcting the prolonged prothrombin time requires large volumes of fresh frozen plasma: Blood Disorders). Because the effect is transient, plasma infusions are not indicated except for active bleeding or before an invasive procedure. Use of recombinant activated factor VII may be an alternative, but it is expensive and poses a 1–2% risk of thrombotic complications. Eltrombopag, an oral thrombopoietin-receptor agonist, has shown promise in patients with cirrhosis and severe thrombocytopenia.
Hemorrhage from oesophageal varices
Shortness of breath in patients with cirrhosis may result from pulmonary restriction and atelectasis caused by massive ascites. The hepatopulmonary syndrome is the triad of chronic liver disease, an increased alveolar–arterial gradient while the patient is breathing room air, and intrapulmonary vascular dilations or arteriovenous communications that result in a right-to-left intrapulmonary shunt and occurs in 4–29% of patients with cirrhosis. The syndrome is presumed to result from failure of the diseased liver to clear circulating pulmonary vasodilators.
Patients often have greater dyspnea (platypnea) and arterial deoxygenation (orthodeoxia) in the upright than in the recumbent position. The diagnosis should be suspected in a cirrhotic patient with a pulse oximetry level 96%. Contrast-enhanced echocardiography is a sensitive screening test for detecting pulmonary vascular dilations, whereas macroaggregated albumin lung perfusion scanning is more specific and is used to confirm the diagnosis. High-resolution CT may be useful for detecting dilated pulmonary vessels that may be amenable to embolization in patients who respond poorly to supplemental oxygen and is under study. Medical therapy has been disappointing; however, intravenous methylene blue and oral garlic powder may improve oxygenation in patients by inhibiting nitric oxide-induced vasodilation.
The syndrome may reverse with liver transplantation, although postoperative mortality is increased in patients with a preoperative arterial oxygen tension < 50 mm Hg or with substantial intrapulmonary shunting. TIPS may provide palliation in patients with hepatopulmonary syndrome awaiting transplantation. Liver transplantation is contraindicated in patients with moderate to severe pulmonary hypertension (mean pulmonary pressure > 35 mm Hg). Pulmonary hypertension occurs in 0.7% of patients with cirrhosis and is thought to result from an excess of circulating vasoconstrictors, particularly endothelin-1. In cases confirmed by right-sided heart catheterization, treatment with epoprostenol or bosentan may reduce pulmonary hypertension and thereby facilitate liver transplantation; -blockers worsen exercise capacity and are contraindicated.