Gastroenterology and Hepatology Board Review: Pearls of Wisdom, Third Edition
Section VIII HEPATOLOGY
CHAPTER 48. Cirrhosis and Its Complications
Bhupinderjit S. Anand, MD
Cirrhosis refers to a diffuse disease in which the normal architecture of the liver is replaced by abnormal nodules (pseudonodules that lack the lobular arrangement of a normal liver) that are separated by bands of fibrous tissue. In the United States, cirrhosis affects about 3.5 people out of 1000.
True/False: Cirrhosis is an irreversible disease.
False (sort of). Although it has long been held that cirrhosis is irreversible, reversal of cirrhosis has now been documented after treatment of the underlying cause of cirrhosis.
What symptoms commonly occur in cirrhosis?
Patients with cirrhosis frequently experience generalized weakness, fatigue, poor appetite, and weight loss.
What are the most recognized causes of cirrhosis?
There are many causes of cirrhosis. The most recognized causes of cirrhosis include chronic alcohol abuse, viral infections of the liver (especially hepatitis B and C), nonalcoholic fatty liver disease, hereditary hemochromatosis, primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune liver disease.
What classical physical findings may be seen in the cirrhotic patient?
Spider angioma: These consist of a central artery with radiating smaller vessels. Pressure on the artery causes the spider to disappear. When the pressure is released, blood flows back from the artery to the smaller vessels.
Palmar erythema: Erythema of the thenar and hypothenar areas with sparing of the central palms.
Gynecomastia: Enlargement of breasts in men.
Enlargement of liver and spleen.
Asterixis: Flapping motions of the outstretched hands.
What are the common complications of cirrhosis?
Fluid accumulation (edema and ascites), variceal bleeding, spontaneous bacterial peritonitis, hepatic encephalopathy, renal failure (hepatorenal syndrome [HRS]), coagulopathy, hepatocellular carcinoma, and malnutrition.
True/False: Malnutrition is the most prevalent complication of cirrhosis.
True. The prevalence correlates with the severity of the liver disease and the method of nutritional assessment.
What are the causes of malnutrition in chronic liver disease?
Reduced food intake, prescribed diets limited in fat and protein (“liver diets”), maldigestion, malabsorption, and hypermetabolism.
True/False: The evidence supporting branched chain amino acid supplementation in cirrhosis is limited and generally nonsupportive.
What is portal hypertension?
An increase in the pressure in the portal circulation is called portal hypertension. The normal portal pressure is less than 5 mmHg. A portal pressure >12 mmHg is generally considered to constitute clinically significant portal hypertension. Since it is difficult to directly measure the portal pressure, an indirect method is used. This involves measuring the hepatic vein pressure gradient (HVPG), which is the difference between wedged hepatic vein pressure and free hepatic vein pressure. HVPG closely reflects the portal pressure.
At what pressure do esophageal varices form and when do they bleed?
An HVPG >12 mmHg is required for the formation of esophageal varices. Similarly, variceal bleeding occurs only when HVPG is >12 mmHg. The higher the HVPG, the greater is the risk of bleeding. However, there is no absolute level of HVPG that correlates with the risk of bleeding.
True/False: Esophageal varices develop in 25% of patients with alcoholic cirrhosis within 10 years of diagnosis.
False. Nearly 80% patients with alcoholic cirrhosis develop esophageal varices within 10 years of diagnosis. The risk is somewhat less in cirrhosis due to hepatitis C virus infection.
What is the magnitude of the risk of bleeding in a patient with esophageal varices?
Nearly 30% patients with cirrhosis who have large varices experience variceal bleeding, usually within the first year of diagnosis.
How common are recurrent episodes of variceal bleeding?
If left untreated, patients who have experienced an episode of bleeding have a 70% chance of recurrent bleeding within 6 months.
What is the mortality rate of acute variceal bleeding?
Variceal hemorrhage is a serious medical emergency. Each episode of bleeding is associated with about a 30% risk of death.
What are the predictors of increased risk of variceal bleeding?
Factors associated with increased risk of bleeding include large varices, presence of endoscopic stigmata on the varices such as cherry red spots and red wale sign, and advanced liver disease.
What is the treatment of choice for acute variceal bleeding?
First-line treatment consists of combination of endoscopic treatment such as endoscopic variceal ligation (EVL) or sclerotherapy, and vasoactive drugs that reduce the portal pressure. The drug used most commonly is somatostatin or its synthetic analogue, octreotide.
Is there a difference in the results obtained between endoscopic sclerotherapy (EST) and EVL.
EST (injection of a sclerosing agent into varices) and EVL (placing a rubber band on the varices) are designed to obliterate varices. EVL has become the preferred option as it is associated with fewer complications and lower rates of rebleeding, and requires fewer sessions to achieve variceal obliteration.
What drugs are effective in reducing portal pressure?
Portal pressure-reducing drugs are divided into two categories: 1) vasoconstrictors (vasopressin, somatostatin, and beta-blockers) cause splanchnic vasoconstriction and reduce portal blood flow; and 2) vasodilators (nitrates and prazosin) decrease the vascular resistance of the intrahepatic portal vessels.
What is the treatment for patients with acute variceal bleeding who fail first-line (endoscopic/medical) therapy?
About 15% patients continue to bleed despite endoscopic and medical measures. The next line of treatment is the use of the transjugular intrahepatic portosystemic shunt (TIPS) or a surgical shunt. A device to tamponade the varices (eg, Sengstaken–Blakemore and Minnesota tubes) and slow the bleeding may need to be inserted while awaiting these shunt procedures.
What are the two main complications of the TIPS procedure?
The two most important complications are development of hepatic encephalopathy and shunt closure, which may result in variceal rebleeding. With the recent introduction of covered stents, the incidence of shunt closure has decreased substantially.
True/False: Patients with Child’s class C cirrhosis are optimal candidates for shunt surgery.
False. Patients with well-compensated cirrhosis (Child’s class A) are the best candidates for shunt surgery, when appropriate. The distal splenorenal shunt (splenic vein to renal vein) has gained favor since it is associated with a lower risk of hepatic encephalopathy compared to a portocaval shunt.
What is portal hypertensive gastropathy?
This term refers to the development of vascular congestion of the gastric mucosa in patients with portal hypertension. Less frequently, other parts of the gastrointestinal tract may be involved (eg, portal hypertensive colopathy, when the colonic mucosa becomes congested). Portal hypertensive gastropathy may result in chronic blood loss and anemia.
What is the treatment of portal hypertensive gastropathy?
The treatment is to lower the portal pressure with the use of vasoactive agents such as nonselective beta-blockers. If this fails, the TIPS procedure has been shown to be useful and may be considered.
True/False: Varices may form in areas of the gastrointestinal tract other than the esophagus.
True. Varices can develop anywhere in the gastrointestinal tract. After the esophagus, the next most common site is the stomach. Bleeding from extra-esophageal varices is difficult to control by endoscopic means. Initial treatment is with beta-blockers. If unsuccessful, the patients are considered for TIPS, surgical shunt, or liver transplantation.
How can the first episode of variceal hemorrhage be prevented?
Individuals at high risk of bleeding (presence of large varices and advanced liver disease) should be treated with nonselective beta-blockers (eg, propranolol, nadolol, and carvedilol). Those who are unable to tolerate these drugs can be treated with EVL, which is equally effective in the primary prevention of variceal bleeding.
What are the treatment options for patients with recurrent episodes of variceal bleeding?
The best approach is combined treatment with EVL (continued until the varices are completely obliterated) and nonselective beta-blockers. If bleeding recurs despite these measures, TIPS, surgical shunt, or liver transplantation should be considered.
What are the characteristics of ascites in a cirrhotic patient?
The ascitic fluid in cirrhosis has low albumin content and the serum to ascitic fluid albumin gradient (SAAG) is ≥1.1. SAAG value of ≥1.1 is characteristic of portal hypertension but may also be seen in congestive heart failure and myxedema. By contrast, SAAG <1.1 is seen in tuberculous peritonitis, carcinomatosis, pancreatic ascites, and nephrotic syndrome.
Describe the treatment of cirrhotic ascites.
The most important step is to obtain a negative sodium balance. This is achieved by reducing the sodium intake to <88 mmol [2 g]/day. In addition, a combination of the diuretics, spironolactone and furosemide (in a ratio of 100 mg:40 mg, respectively) is given. The maximum doses are 400 mg and 160 mg, respectively.
True/False: Diuretic-refractory ascites and diuretic-resistant ascites refer to the same process.
False. Diuretic-refractory ascites refers to persistent ascites despite sodium restriction and maximal diuretic therapy. Diuretic-resistant ascites refers to the development of diuretic-induced complications, which prevent the use of effective diuretic therapy. The most common complications are renal failure and electrolyte abnormalities.
What are the treatment options for diuretic-refractory and diuretic-resistant ascites?
Treatment options include periodic large-volume paracentesis and TIPS. A less safe and efficacious technique is the placement of a peritoneo-venous shunt (PVS) (eg, Denver shunt), which drains ascitic fluid into the superior vena cava. The PVS is associated with complications such as infection, disseminated intravascular coagulation, congestive heart failure, and shunt thrombosis. All patients with diuretic-refractory and diuretic-resistant ascites should be considered for liver transplantation if otherwise appropriate.
What is spontaneous bacterial peritonitis (SBP)?
Patients with cirrhosis and ascites are prone to develop peritonitis without a precipitating cause such as bowel perforation or inflammation, hence the term “spontaneous.” The diagnosis is made by the presence of an elevated ascitic fluid neutrophil count of ≥250/mm3. A positive ascitic fluid culture is obtained in 90% patients and shows a single bacteria (most commonly Escherichia coli), unlike surgical peritonitis which is polymicrobial.
What is the usual first-line treatment of spontaneous bacterial peritonitis?
The antibiotic of choice is a third-generation cephalosporin (eg, cefotaxime 2 g intravenously every 8 hours) for 5 days.
True/False: Recurrence of SBP is rare.
False. Patients who have experienced an episode of SBP have a 70% probability of a second episode within 1 year. The development of SBP would be another indication for transplant referral in an otherwise acceptable candidate.
True/False: Recurrent episodes of SBP can be prevented.
True. Long-term administration of the antibiotic norfloxacin (400 mg daily), a poorly absorbed antibiotic reduces the risk of recurrent SBP to 20% from 70% in untreated patients. Trimethoprim-sulfamethoxazole has also been shown to be effective. Those with very low ascites albumin levels seem to benefit the most. However, there are concerns regarding the emergence of drug-resistant organisms with such long-term therapy.
HRS is the development of renal failure in patients with advanced liver disease and portal hypertension in the absence of a specific cause for renal failure. Typically, patients have oliguria (urine volume <500 mL/24 h) and low urinary sodium (<10 mEq/L).
Describe the pathogenesis of HRS.
The pathogenetic mechanism is reduction in renal blood flow. Structurally, the kidneys are normal and can recover completely if the liver disease is reversed or after liver transplantation.
What are the different types of HRS.
There are two types of HRS. Type I is an acute process with a twofold increase in creatinine to >2.5mg% over 2 weeks. Type II is associated with a more gradual renal failure over several weeks to months.
True/False: The prognosis of individuals with HRS is poor.
True. The median survival for type I is less than 2 weeks. Survival is longer for patients with type II, but the overall prognosis remains poor.
True/False: Other than liver transplantation, there is no treatment for HRS.
False. Treatment with a combination of midodrine (alpha-1 adrenergic agonist), a systemic vasoconstrictor (7.5–12.5 mg TID), and octreotide (100–200 µg SQ TID) is associated with significant reduction in mortality compared to no treatment.
What is hepatic encephalopathy?
The appearance of neuropsychiatric symptoms (mental confusion, personality change, sleep disturbance, unconscious state, or coma) or signs (asterixis, hyperreflexia, muscular rigidity, and decerebrate posturing) in patients with liver dysfunction in the absence of a specific etiology.
What is subclinical (minimal) hepatic encephalopathy?
Subnormal performance in psychometric tests in the presence of a normal neurological examination. The most commonly performed test is the Reitan trail test in which the time taken by a patient to connect numbers (1 to 25) is determined. Subclinical hepatic encephalopathy is seen in nearly 70% patients with cirrhosis and may be of clinical importance.
True/False: Blood ammonia levels are specific for hepatic encephalopathy.
False. Hepatic encephalopathy is a clinical diagnosis and is not based on any laboratory test. Blood ammonia levels are not diagnostic of hepatic encephalopathy.
What is the treatment of hepatic encephalopathy?
The first step is to treat any precipitating factor (infection, fluid/electrolyte disturbance, drug overdose, renal failure, constipation, or high-protein diet). Classically, treatment has consisted of a low-protein diet and the laxative lactulose, in a dose which results in 2 to 3 bowel movements per day. Recently, rifaximin, a nonabsorbable antibiotic, has been approved for the treatment of hepatic encephalopathy.
• • • SUGGESTED READINGS • • •
Ginès P, Schrier RW. Renal failure in cirrhosis. N Engl J Med. 2009;361:1279-1290.
Runyon BA; AASLD Practice Guidelines Committee. Management of adult patients with ascites due to cirrhosis: an update. Hepatology. 2009;49:2087-2107.
Garcia-Tsao G, Sanyal AJ, Grace ND, et al. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology. 2007;46:922-938.
European Association for the Study of the Liver. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol. 2010;53:397-417.
Toris GT, Bikis CN, Tsourouflis GS, Theocharis SE. Hepatic encephalopathy: an updated approach from pathogenesis to treatment. Med Sci Monit. 2011;17:RA53-RA63.
Verslype C, Cassiman D. Cirrhosis and malnutrition: assessment and management. Acta Gastroenterol Belg. 2010;73:510-513.