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Liver Failure 

Liver Failure
Chapter:
Liver Failure
Author(s):

Sameer D. Saini

, and Akbar K. Waljee

DOI:
10.1093/med/9780190862800.003.0035
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date: 18 September 2020

  1. A. Introduction

    1. a. Acute hepatitis is acute inflammation of the liver. It is most often caused by alcohol or a virus, but it may be due to several other etiologies, including nonalcoholic fatty liver disease (NAFLD), medications, toxins, or autoimmune disease. Acute hepatitis may be self-limited, or it may progress to acute liver failure or chronic hepatitis.

    2. b. Acute liver failure is defined by the presence of encephalopathy and coagulopathy (international normalized ratio [INR] >1.5) associated with acute hepatic disease. It is often classified as hyperacute, acute, or subacute, and as fulminant or subfulminant, depending on the interval between the onset of jaundice and encephalopathy.

    3. c. Chronic hepatitis is chronic inflammation of the liver (>3–6 months) as evidenced by elevated aminotransaminases or histologic findings. It may be caused by acute hepatitis, alcohol, viral infections, NAFLD, autoimmune disease, medications, Wilson’s disease, α‎1-antitrypsin deficiency, or celiac disease.

    4. d. End-stage liver disease (ESLD) includes compensated and decompensated cirrhosis, depending on the presence of major complications. Cirrhosis is the end result of chronic hepatitis (i.e., chronic hepatocellular injury) and pathologically represents the occurrence of fibrosis and formation of regenerative nodules. The term “chronic liver failure” is related to the concept of ESLD but is no longer an accurate term and should not be used in clinical parlance.

      Hot Key

      Acute hepatitis is not the same as acute liver failure. But acute hepatitis can cause acute liver failure.

  2. B. Clinical Manifestations of Liver Failure

    1. a. Acute liver failure is characterized by the rapid development (within days) of coagulopathy, jaundice, altered mental status, and often nonspecific symptoms (e.g., nausea, malaise). Acute liver failure often occurs in patients without preexisting liver disease.

      1. i. Central nervous system (CNS) signs

        1. 1. Altered mental status. Encephalopathy produces an alteration in mental status that ranges from mild confusion (West Haven grade I or II encephalopathy) to stupor or coma (grade III or IV). Likely etiologies include cerebral edema (especially in fulminant liver failure) and portosystemic shunting of toxins (especially in subfulminant liver disease and ESLD). Other causes of altered mental status include hypoglycemia, sepsis, fever, and hypotension that may contribute to, be a manifestation of, or occur in the setting of acute liver failure. Patients may also present with agitation and delusions; however, these more dramatic symptoms are uncommon in ESLD. Unlike ESLD, acute liver failure may not be clinically obvious; it is therefore important to have a high suspicion for liver failure in all patients with altered mental status.

        2. 2. Cerebral edema accompanies hepatic encephalopathy in most acute liver failure patients with grade IV encephalopathy (coma). Significant cerebral edema can lead to brain herniation and is a common cause of death in patients with acute liver failure. Cushing’s reflex (hypertension and bradycardia), abnormal pupillary reflexes, oculomotor nerve palsy (“down and out” eye position), and increased muscle tone progressing to decerebrate posturing are signs of increased cerebral edema. Cerebral edema occurs more commonly with fulminant liver failure, whereas renal failure and ascites are more often associated with a subfulminant course.

        3. 3. Asterixis is frequently noted on examination in patients with acute liver failure. If a patient cannot cooperate by raising their hands, gently dorsiflex the hands to elicit asterixis. Occasionally, asterixis may also be observed in the tongue of otherwise altered patients.

      2. ii. Hematologic signs. Elevation of the prothrombin time (PT) is universally present and may be accompanied by an elevated partial thromboplastin time (PTT). Thrombocytopenia may also occur.

      3. iii. Cardiovascular signs may include hypovolemia, a decrease in systemic vascular resistance associated with hypotension, and an increase in cardiac output. Because these findings are not specific and may also indicate sepsis, infection should be considered and ruled out in all patients with acute mental status changes.

      4. iv. Metabolic changes

        1. 1. Hypoglycemia may aggravate the alteration in mental status. Patients with profound liver injury can develop refractory hypoglycemia. Blood glucose levels should be monitored frequently.

        2. 2. Hypokalemia can result from respiratory alkalosis induced by liver failure.

        3. 3. Hyponatremia and hypophosphatemia may also occur.

        4. 4. Metabolic acidosis may be caused by increased intracellular lactate production and decreased hepatic lactate uptake.

      5. v. Complications

        1. 1. Hemorrhage. Thrombocytopenia is a strong risk factor for gastrointestinal or other bleeding.

        2. 2. Infections. Defects in neutrophil function and in humoral and cell-mediated immunity may result in bacterial or fungal infections. Early use of broad-spectrum antibiotics is encouraged in patients with acute liver failure, evidence of infection, or clinical decompensation.

        3. 3. Renal failure is an ominous complication.

          • a. Hepatorenal syndrome (type I [acute] and type II [chronic]) should be considered in patients with severe liver disease, declining renal function (including azotemia and oliguria), and prerenal physiology (i.e., a low urinary sodium level). Hepatorenal syndrome is likely caused by portal hypertension, which induces vasodilator factors that act primarily on the splanchnic circulation. It is distinguished from hypovolemia by the patient’s failure to respond to a fluid challenge. Hepatorenal syndrome must also be distinguished (on the basis of clinical criteria) from other causes of kidney failure associated with prerenal physiology (see Chapter 37).

          • b. Acute tubular necrosis may also occur in the setting of acute liver failure.

        1. 4. Hepatopulmonary syndrome consists of the triad of (1) liver disease leading to (2) intrapulmonary vascular dilation, which causes intrapulmonary shunting of blood and leads to (3) impaired oxygenation. Typically, patients have more symptoms when they are sitting up as opposed to lying down (i.e., they are platypneic) because sitting up increases blood flow to the lower lobes where more shunting occurs. This complication is most commonly seen in ESLD.

      6. b. ESLD can occur in the setting of compensated and decompensated cirrhosis, which can be differentiated by the presence of complications. Patients with the following signs more than likely have decompensated cirrhosis: ascites, variceal hemorrhage, spontaneous bacterial peritonitis (SBP), hepatocellular carcinoma (HCC), hepatorenal syndrome, and hepatopulmonary syndrome. Note that a patient with only asymptomatic varices (i.e., without hemorrhage) would be considered to have compensated cirrhosis.

  3. C. Causes of Liver Failure

    1. a. Acute liver failure

      1. i. Infection

        1. 1. Viral hepatitis is one of the most common causes of acute liver failure (along with acetaminophen toxicity).

          • a. Hepatitis A is a rare cause of fulminant hepatitis in developed countries and never produces chronic disease. However, globally, this is one of the most common causes of acute liver failure, along with hepatitis E.

          • b. Hepatitis B causes fulminant liver failure in approximately 1% of infected patients.

          • c. Hepatitis C typically causes only chronic disease, unless coinfected with hepatitis B. Hepatitis C is now the most common cause of infectious hepatitis in the United States.

          • d. Hepatitis D causes coinfection or superinfection only in the presence of hepatitis B surface antigen and may account for more than 50% of cases of fulminant disease caused by hepatitis B. It is more common in developing countries.

          • e. Hepatitis E is likely the most common cause of acute hepatitis globally; the mortality rate is high among pregnant women.

          • f. Epstein-Barr virus, cytomegalovirus (CMV), and herpesvirus occasionally cause acute liver failure. Liver failure from these infections is more common in immunocompromised patients.

      1. ii. Drugs and toxins

        1. 1. Drugs

          • a. Direct hepatotoxicity

            • i. Acetaminophen overdose. Alcoholic and malnourished patients have a higher risk for hepatotoxicity as a result of acetaminophen overdose. At least 50% of cases of acetaminophen hepatotoxicity are not related to overdose attempts, but rather represent inadvertent overdoses in the setting of treatment.

              Hot Key

              Remember the “rule of 140s” when confronted with the possibility of acetaminophen overdose: the approximate toxic dose is 140 mg/kg, a blood level that exceeds 140 μ‎g/mL 4 hours after ingestion may be toxic, and the first dose of acetylcysteine (the antidote) is 140 mg/kg orally or by nasogastric tube (followed by 70 mg/kg every 4 hours for 17 doses).

            • ii. Heavy metals, phosphorus, vitamin A, valproic acid, and tetracyclines may also be directly hepatotoxic.

          • b. Idiosyncratic reactions may also result in acute liver failure. Isoniazid, halothane, phenytoin, and sulfonamides are but a few of the drugs that can cause idiosyncratic hepatotoxicity.

          • c. Toxins. Amanita phalloides (the death-cap mushroom) and carbon tetrachloride (found in industrial cleaning solvents) can both produce acute liver failure.

      2. iii. Cardiovascular disorders

        1. 1. Inadequate arterial supply as a result of cardiac pathology (e.g., cardiac arrest, myocardial infarction, cardiomyopathy), infiltrating malignancies, or sepsis may cause liver failure.

        2. 2. Venous obstruction

          • a. Venoocclusive disease. Intrahepatic obstruction of the hepatic venules may be associated with bone marrow transplantation, chemotherapy, or oral contraceptive use.

          • b. Inferior vena cava obstruction or hepatic vein obstruction (i.e., Budd-Chiari syndrome) often results from thrombosis associated with a myeloproliferative disorder or hypercoagulable state or from direct tumor invasion.

      3. iv. Inherited metabolic disorders. Wilson’s disease usually presents in younger patients (20–40 years of age) and may result in acute or ESLD.

      4. v. Miscellaneous causes

        1. 1. Pregnancy. Both acute fatty liver and the HELLP (Hemolysis, Elevated Liver enzymes, Low Platelets) syndrome may complicate pregnancy and predispose or directly lead to acute liver failure.

        2. 2. Reye’s syndrome. Children younger than 15 years are more likely to develop Reye’s syndrome than adults. It is usually associated with viral illness and concomitant salicylate use.

    2. b. ESLD

      1. i. Infections, including viral hepatitis (primarily hepatitis B and C), schistosomiasis, and toxoplasmosis.

      2. ii. Drugs and toxins. Alcoholism is one of the most common causes of cirrhosis in the United States.

      3. iii. Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease globally. It is divided into two categories:

        1. 1. Nonalcoholic fatty liver (NAFL) consists of hepatic steatosis and absent or mild inflammation.

        2. 2. Nonalcoholic steatohepatitis (NASH) consists of hepatic steatosis with hepatocellular injury. Livers of patients with NASH may or may not show fibrosis on liver biopsy.

          Hot Key

          NAFLD and nonalcoholic steatohepatitis are not synonymous. NAFLD is divided into the two categories of NASH and NAFL.

      4. iv. Vascular abnormalities (e.g., as a result of cardiac failure, tumors, or venous obstruction).

      5. v. Inherited metabolic disorders, including Wilson’s disease, hemochromatosis, α‎1-antitrypsin deficiency, and glycogen storage disease.

      6. vi. Miscellaneous causes

        1. 1. Primary biliary cirrhosis. Women between the ages of 40 and 60 years are most often affected. Intense pruritus with a cholestatic liver function test picture (i.e., significantly elevated serum alkaline phosphatase with minimal if any elevation of aspartate aminotransferase [AST] and alanine transaminase [ALT]) is common. The presence of antimitochondrial antibody in this clinical and laboratory setting is diagnostic and found in 95% of cases.

        2. 2. Secondary biliary cirrhosis may result from stones or strictures causing chronic biliary tract obstruction.

        3. 3. Autoimmune hepatitis is most common in young women. Patients may have other manifestations of autoimmunity; antinuclear and anti–smooth muscle antibodies are found in 20%–40% and 60%–80% of patients, respectively.

  4. D. Approach to the Patient

    1. a. Patient history. A thorough history is critical if drug or toxin exposure is thought to be the cause of liver failure. Vascular disorders may also be suggested by the history (e.g., right upper quadrant pain may imply Budd-Chiari syndrome; weight loss may suggest an intra-abdominal malignancy). Patients need to be specifically asked about over-the-counter and complementary medications. St. John’s wort (often used for depression) is an example of one over-the-counter medication associated with liver failure.

    2. b. Laboratory tests

      1. i. General tests. The following tests are usually performed to evaluate liver function and screen for associated metabolic or hematologic derangements and complications (e.g., bleeding, infection, or renal failure):

        1. 1. Complete blood count (CBC) with differential and platelets

        2. 2. Electrolyte panel with blood urea nitrogen (BUN), creatinine, and glucose levels

        3. 3. Evaluation of PT and PTT

        4. 4. Liver tests (i.e., AST, ALT), alkaline phosphatase, total bilirubin)

      2. ii. Specific tests can be used to help determine the etiology:

        1. 1. Hepatitis serologies, including hepatitis A and C antibodies, hepatitis B surface antigen, and hepatitis B surface and core antibodies, are often ordered.

        2. 2. Acetaminophen level. An acetaminophen level should be obtained in all patients with signs of acute liver failure. Salicylate levels and toxicology screen are also commonly performed.

        3. 3. Serum ceruloplasmin. Wilson’s disease should be considered in patients younger than 50 years who have acute or ESLD. A low serum ceruloplasmin level suggests Wilson’s disease; other findings include a high urinary copper level or the presence of Kayser-Fleischer rings on slit-lamp examination. The diagnosis is confirmed by liver biopsy.

        4. 4. Transferrin saturation and ferritin levels are high in patients with hemochromatosis, which is an inherited cause of ESLD. These levels may be artificially elevated in acute liver injury because they often respond as acute-phase reactants.

        5. 5. α‎1-Antitrypsin level. Deficiency may result in ESLD.

        6. 6. Antibody tests. Antinuclear, anti–smooth muscle, and antimitochondrial antibodies may be studied to evaluate the possibility of autoimmune hepatitis or primary biliary cirrhosis.

      3. iii. Liver biopsy or imaging studies may be performed when the diagnosis is still in question.

  5. E. Treatment

    1. a. Acute liver failure

      1. i. Acetaminophen overdose should be treated with N-acetylcysteine. Early treatment is desirable, and empiric therapy may be indicated when a toxic dose is suspected. Patients may benefit even when the ingestion occurred as many as 36 hours before therapy.

      2. ii. Mushroom poisoning may be treated with penicillin, silybin, or both.

      3. iii. Pregnancy-related liver failure is often resolved by delivery of the baby.

      4. iv. Patients with acute hepatitis B can be treated with antiviral therapy.

    2. b. ESLD is usually not reversible. However, if it is identified and certain treatments are administered early in the disease, the progression may be slowed. Specific strategies include:

      1. i. All patients with ESLD should abstain from alcohol.

      2. ii. NAFLD may respond to weight loss and increased physical activity.

      3. iii. Hemochromatosis may be treated with phlebotomy or deferoxamine chelation therapy.

      4. iv. Wilson’s disease may be treated with penicillamine chelation therapy.

      5. v. Autoimmune hepatitis is sensitive to steroid therapy, which should be initiated promptly after the diagnosis is confirmed.

      6. vi. Chronic hepatitis B or C may be treated with antiviral therapy.

    3. c. Prevent or treat complications

      1. i. Infections, such as SBP, must be treated aggressively. A third-generation cephalosporin is often the initial therapy and is administered for at least 5 days. Following therapy, norfloxacin prophylaxis may be used to decrease the rate of recurrent SBP. Every attempt should be made to avoid potentially nephrotoxic drugs (such as gentamicin) in patients with liver disease because these may promote development of hepatorenal syndrome, which can be life-threatening. Patients should be given hepatitis A and B immunizations if not already immune.

      2. ii. Hemorrhage

        1. 1. Patients who are not actively bleeding are usually administered vitamin K subcutaneously in case vitamin deficiency is partially responsible for the coagulopathy.

        2. 2. Fresh-frozen plasma and blood products may be required for patients with active bleeding (see Chapter 66).

      3. iii. Bleeding esophageal varices

        1. 1. Treatment

          • a. Pharmacologic treatment includes intravenous administration of octreotide. Although intravenous proton pump inhibitors are often given to patients with upper gastrointestinal bleeding, they do not affect outcomes for patients with variceal bleeds.

          • b. Band ligation and injection sclerotherapy by upper endoscopy are effective procedures but may not be technically feasible in all patients.

          • c. Transjugular intrahepatic portosystemic shunting (TIPS) or surgical shunting may be used for refractory bleeding.

        2. 2. Prophylaxis of variceal bleeding. Propranolol (20–80 mg orally twice daily) or another noncardioselective β‎-blocker is often given to patients who are stable after a variceal bleed (usually days later) and to those with very large varices.

      4. iv. Ascites and edema are often treated with a sodium-restricted diet and diuretics.

        1. 1. The primary method of treating ascites in patients with ESLD is sodium restriction. Patients should ingest fewer than 2 g of sodium per day. Fluid does not need to be limited except in patients with significant hyponatremia. In up to 80% of patients, ascites can be completely controlled with sodium restriction alone.

        2. 2. Spironolactone. The initial dose is often 100 mg orally once daily; this amount should be increased by 100 mg/day every few days while following serum and urine electrolytes. Spironolactone will take several days before maximal benefit occurs, and thus treatment should not be abandoned without an adequate trial.

        3. 3. Furosemide may also be added to the regimen to increase diuresis after initiating spironolactone. In hospital practice, both spironolactone and furosemide are often started together to help reduce volume. However, careful monitoring of volume status and electrolytes is required when initiating both treatments.

        4. 4. Large-volume paracentesis is often necessary for patients with massive ascites whose condition is refractory to medical therapy or otherwise symptomatic despite pharmacologic treatment. Intravenous albumin is often given just before large-volume paracentesis to maintain the intravascular volume (especially in patients without peripheral edema).

        5. 5. TIPS is being increasingly used for patients with refractory ascites. However, TIPS may worsen hepatic encephalopathy.

      5. v. Hepatic encephalopathy may be precipitated by medication noncompliance, infections, overly aggressive diuresis, electrolyte abnormalities, gastrointestinal bleeding, or drugs (e.g., sedative-hypnotics, narcotics). The inciting factor leading to the condition must always be identified and addressed to prevent recurrent episodes. Management usually involves identifying and treating precipitating factors and administering lactulose (usually 30 mL three times daily orally or by nasogastric tube, titrated to maintain three loose stools per day). In patients with acute liver failure, cerebral edema may occur and can be treated with mannitol (usually 0.3–0.4 g/kg body weight) or hyperventilation. Lactulose is typically not given in acute liver failure.

        Hot Key

        Intracerebral hemorrhage is possible in patients with coagulopathy and altered mental status. These patients may benefit from further radiographic evaluation (e.g., computed tomography).

      6. vi. Hepatorenal syndrome. Midodrine, low-dose dopamine, and calcium channel blockers are still sometimes tried. Patients should be urgently evaluated for liver transplantation.

      7. vii. Metabolic derangements

        1. 1. Hypoglycemia may require intravenous administration of a 10% glucose solution.

        2. 2. Hypokalemia and hypophosphatemia may require electrolyte replacement.

        3. 3. Hyponatremia may require free water restriction.

    4. d. When to consider liver transplantation. Liver transplantation may be considered in patients with acute liver failure or ESLD when specific criteria are met.

      1. i. In the acute setting, liver transplantation is usually indicated when a variety of prognostic factors (e.g., age, etiology, grade of encephalopathy, bilirubin, PT; several criteria have been developed to score these factors) suggest a poor chance of survival with organ replacement. Because safe transport to a specialized facility is easier when patients have low-grade encephalopathy, a liver transplantation referral should be considered as soon as possible after a diagnosis of acute liver failure.

      2. ii. Patients with ESLD should be evaluated for liver transplantation when they first develop evidence of decompensated cirrhosis or HCC.

      3. iii. The 5-year survival rate after liver transplantation for cirrhosis is greater than 75%.

Suggested Further Readings

Bernal W, Wendon J. Acute liver failure. N Engl J Med 2013;369:2525–34.Find this resource:

Graham BB, Kaul DR, Saint S, Janssen WJ. Kiss of death. N Engl J Med 2009;360:2564–8.Find this resource:

Rinella ME. Nonalcoholic fatty liver disease: a systematic review. JAMA 2015;313:2263–73.Find this resource:

Wijdicks EF. Hepatic Encephalopathy. N Engl J Med 2016;375:1660–70.Find this resource: