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Definition, Etiology, PathogenesisTop
Acute liver failure (ALF) is a sudden-onset, rapid, and potentially reversible deterioration in liver function in patients without prior liver disease that leads to jaundice, hepatic encephalopathy, and coagulopathy. The condition of patients who develop coagulopathy but do not have any alteration to their level of consciousness is defined as acute liver injury.
1) Viral hepatitis: Most commonly hepatitis B (HBV), D (HDV), E (HEV) (especially in pregnancy), A (HAV).
2) Less frequently other viral diseases (cytomegalovirus [CMV], hemorrhagic fever, paramyxovirus, Epstein-Barr virus [EBV], herpes simplex virus [HSV], varicella-zoster virus [VZV], dengue virus).
3) Drugs: Acetaminophen (INN paracetamol; the most common cause of drug-induced acute liver failure), halothane, isoniazid, sulfonamides, ketoconazole, and nitrofurantoin; phenytoin and valproate; statins; nonsteroidal anti-inflammatory drugs (NSAIDs); other (including herbal preparations, eg, Chinese herbal remedies).
4) Toxins: Alpha-amanitin (contained in the Amanita phalloides mushroom), tetrachloromethane, and other substances.
4) Other: Shock; hepatic ischemia; Wilson disease; autoimmune hepatitis; Reye syndrome; sepsis; Budd-Chiari syndrome; portal venous thrombosis; pregnancy associated: acute fatty liver in pregnancy, liver rupture, and HELLP syndrome (hemolysis, elevated liver enzyme [aminotransferase] levels, low platelet levels [thrombocytopenia]).
Massive hepatocyte necrosis leads to impaired metabolic function of the liver, including the neutralization of toxins. Pathogenesis of encephalopathy: see Cirrhosis.
A prerequisite for establishing the diagnosis of ALF is the absence of previous severe fibrosis or cirrhotic chronic liver disease. Specific exceptions are the acute de novo presentation of autoimmune hepatitis and Budd-Chiari syndrome. In these conditions an underlying chronic disease might not have been recognized or diagnosed previously and there should be no clinical or histologic evidence of cirrhosis. Wilson disease is another exception of a chronic liver disease with splenomegaly that may lead to acute presentation. The precipitating event is often a viral infection or, in adolescents, noncompliance with therapy. Nevertheless, these patients are considered as having ALF because they share the poor prognosis and common clinical picture of ALF and present with significant coagulopathy and encephalopathy.
Clinical Features and Natural HistoryTop
1. Signs and symptoms: Early symptoms are generally nonspecific and may include loss of appetite, diarrhea, fever, and rash. Key clinical manifestations:
1) Encephalopathy: The key symptom, may be of varied severity (see Cirrhosis) and dynamics.
2) Jaundice: The presenting symptom in almost all patients. In very rare cases it may develop after the onset of encephalopathy.
3) Symptoms of bleeding disorder (not always present).
4) Hemodynamic instability.
5) Acute kidney injury (hepatorenal syndrome).
6) Ascites (if massive and rapid, suspect Budd-Chiari syndrome).
7) Seizures may occur in some patients (caused by primary brain injury or elevated intracranial pressure).
2. Natural history: The dynamics of ALF may vary. It begins with severe acute liver injury (a 2- to 3-fold increase in serum transaminases, jaundice, and coagulopathy). Depending on the timing of development of hepatic encephalopathy, liver failure may be divided into:
1) Hyperacute: Encephalopathy develops within 1 week from the onset of jaundice. It usually occurs with severe coagulopathy and a significant increase in transaminase activity. Initially there is a small rise in bilirubin. This type is associated with a greater chance of recovery than the subacute form.
2) Acute: Encephalopathy develops between day 8 and 28 from the onset of jaundice.
3) Subacute: Encephalopathy develops between weeks 5 and 12 from the onset of jaundice. Usually severe jaundice with a slight increase in aminotransferases and mild to moderate coagulopathy are seen. Often there is coexisting enlargement of the spleen, ascites, and reduction in liver volume (this may resemble cirrhosis). Once hepatic encephalopathy develops, these patients have a very low chance of survival without definitive treatment.
A fulminant course is not associated with less favorable outcomes (eg, in acetaminophen poisoning). The majority of patients who do not receive appropriate treatment (including urgent liver transplantation) die due to cerebral edema, coma, and multiorgan failure.
When taking a history always remember to inquire about drugs and herbal preparations that have been used by the patient (including over-the-counter agents), previous surgical procedures, history of autoimmune diseases and heart or lung failure, alcohol consumption, presence of malignancy, blood and blood product transfusions, travel to areas endemic for viral hepatitis, consumption of mushrooms, and family history of liver disease.
1. Blood tests:
1) Assessment of disease severity: International normalized ratio (INR), bilirubin, sodium, creatinine (included in the Model for End-Stage Liver Disease and Serum Sodium Concentration [MELDNa] score).
2) Assessment of renal function including urine output, creatinine, and urea.
3) Evaluation of etiology:
a) Acetaminophen level and urine or serum toxicology screen.
b) Virology: Anti-HAV IgM, hepatitis B surface antigen (HBsAg), IgM antibodies to hepatitis B core antigen (anti-HBc IgM), antibodies to HCV, IgM antibodies to HDV, as well as IgM antibodies to HEV when indicated; IgM antibodies to HSV; IgM antibodies to VZV IgM; polymerase chain reaction (PCR) for VZV, EBV, CMV, parvovirus.
c) Autoimmune markers: Antinuclear antibodies (ANAs), smooth muscle antibodies (SMAs), soluble liver antigen/liver-pancreas (SLA/LP) antibodies.
4) Other tests: Complete blood count (CBC); serum levels of other electrolytes (potassium, chloride, calcium, magnesium, phosphate), glucose, albumin, lactate, ammonia; levels of other liver function tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], lactate dehydrogenase [LDH], gamma-glutamyl transferase [GGT]); lipase; antineutrophil cytoplasmic antibodies (ANCAs); arterial blood gases; pregnancy test in women of childbearing age.
Interpretation and ordering of the blood tests: Elevated serum aminotransferase levels are very commonly seen (ALT is more specific for viral etiology; very high values [>2000 IU/L] are typical for toxic or ischemic liver injury). Prolonged prothrombin time (PT) (by >4-6 seconds; INR >1.5) is usually present. Hypoglycemia may occur unexpectedly (regular blood glucose measurements are necessary). Elevated blood ammonia levels have some correlation with the presence and severity of hepatic encephalopathy (ammonia should be measured in arterial blood, if possible). Elevated serum lactate level is an early unfavorable prognostic factor in acetaminophen poisoning. Thrombocytopenia is not uncommon. Other abnormalities depending on the etiology, severity, and complications of liver failure (eg, elevated creatinine levels in patients with renal failure).
2. Imaging studies: Computed tomography (CT) of the abdomen allows recognition of previous cirrhosis and facilitates differentiation between ALF and Budd-Chiari syndrome, hepatic steatosis, and disseminated metastases to the liver. CT of the head is also used to exclude other causes of neurologic symptoms.
3. Electroencephalography (EEG): Triphasic waves (encephalopathy grades 1-3); delta waves (grade 4).
4. Liver biopsy may be useful for determining etiology (eg, Wilson disease, autoimmune hepatitis, fatty liver disease in pregnancy, metastases). In patients with contraindications to percutaneous biopsy (coagulopathy), transjugular biopsy may be an option. Liver biopsy carries a small but relevant risk of serious complications and should be used only in case of diagnostic uncertainty.
Patients should be admitted to the intensive care unit. Watch for hemodynamic, metabolic, fluid and electrolyte, and septic complications. Early transfer to a tertiary care center is important. Optimally the center should be capable of performing liver transplantation.
1. Nutrition therapy: Optimally delivered orally (a nasogastric tube may be needed). Protein ~60 g/d, energy 30 kcal/kg/d; exclude products containing glutamine.
2. N-acetylcysteine: Indicated for use in acetaminophen-induced liver failure, may be also considered for other etiologies of liver failure.
3. Prevention of acute hemorrhagic gastropathy.
4. Antimicrobial and antifungal prophylaxis: In all patients with ALF surveillance cultures should be performed periodically to detect infection as early as possible. There is insufficient evidence to support the routine use of prophylactic antibiotics. However, broad-spectrum antimicrobial agents should be considered in patients with rapidly progressive encephalopathy, hypotension, or systemic inflammatory response syndrome (SIRS) symptoms. The choice of drugs should take into consideration local pathogen resistance profiles.
1. Treatment of hepatic encephalopathy: see Cirrhosis.
2. Prevention of cerebral edema: Elevate the patient’s head and trunk to 30 degrees. In case of seizures, administer phenytoin 10 to 15 mg/kg in a slow IV injection (maximum rate, 50 mg/min) followed by a maintenance dose of 100 mg orally or IV every 6 to 8 hours; do not use phenytoin for seizure prevention. Examine the patient frequently for signs of elevated intracranial pressure. Avoid volume overload, fever, and hypoglycemia, and maintain sodium within a range of 140 to 145 mmol/L.
3. Coagulopathy: Despite elevated INR the risk of bleeding is not markedly increased. Do not transfuse fresh frozen plasma prophylactically. Our practice is to administer vitamin K 5 to 10 mg (orally, subcutaneously, or IV) and repeat if necessary, although this is frequently not effective. Replacement therapy for thrombocytopenia or prolonged INR is recommended only in the setting of hemorrhage or before invasive procedures. If needed, administer fresh frozen plasma 15 mL/kg or alternatively (particularly in case of volume overload) recombinant factor VIIa concentrate. In patients with severe thrombocytopenia (usually <10,000/microL), patients planned for invasive procedures, and patients with bleeding and platelet counts <50,000/microL, administer platelet concentrates. Target a platelet level ≥60,000/microL. If blood transfusion is required, aim for a hemoglobin target >70 g/L.
4. Hemodynamic disturbances and renal failure: Maintain appropriate volume status. Usually start with crystalloids (normal saline, then Ringer lactate). Avoid hyperchloremia as it may worsen renal function. Maintain mean arterial pressure (MAP) at 50 to 60 mm Hg (when necessary, administer vasoconstrictors: epinephrine, norepinephrine, less likely dopamine). Consider (rarely) pulmonary artery catheterization for monitoring. Start renal replacement therapy if required (see Chronic Kidney Disease).
5. Metabolic disturbances: Most biochemical parameters (glucose, sodium, phosphate, potassium, magnesium, calcium) require regular monitoring and correction of abnormalities. Hyponatremia is relatively common; correction of sodium levels, including during resuscitation, should be targeted to maintain sodium at 140 to 145 mmol/L, but rapid changes in sodium levels should be avoided (up to 10 mmol/L per 24 hours or 2 mmol/L per hour). Patients with ALF are particularly prone to hypoglycemia, which may require a continuous IV glucose infusion.
6. Infections: Infections are common (most often pneumonia, followed by urinary tract infection, IV catheter infections, spontaneous bacterial peritonitis, and sepsis from other sources).
2. Mushroom poisoning (mainly Amanita phalloides).
4. Acute fatty liver in pregnancy and HELLP syndrome: Delivery may lead to resolution of liver failure.
5. Ischemic liver injury: Optimize hemodynamic parameters.
Liver transplantation should be considered in patients fulfilling the King’s College criteria or those with ALF and a MELDNa score >30.5. The MELDNa score takes into account the need for dialysis and levels of sodium, bilirubin, INR, and creatinine (available at mdcalc.com).
The King’s College criteria (modified) consider acetaminophen-induced liver injury and other conditions separately:
1) Patients with acetaminophen-induced liver injury:
a) Arterial blood pH <7.3, or arterial lactate >3.0 mmol/L after adequate fluid resuscitation.
b) All of the following within a 24-hour period: grade 3 or 4 encephalopathy, INR >6.5, serum creatinine >3.4 mg/dL (301 micromol/L).
2) Patients with liver injury of nonacetaminophen etiology:
a) INR >6.5 and encephalopathy present (irrespective of grade); or
b) ≥3 of the following criteria fulfilled (with encephalopathy, irrespective of its grade): age <10 years or >40 years, duration of jaundice before the onset of encephalopathy >7 days, INR >3.5, serum bilirubin >18 mg/dL (308 micromol/L), unfavorable etiology (such as non-A non-B viral hepatitis, idiosyncratic drug reaction, halothane-induced hepatitis).
This is most commonly used in patients with hepatic encephalopathy to maintain some metabolic or detoxifying liver functions until liver transplantation or recovery. The techniques include molecular adsorbent recirculating system (MARS) (a combination of albumin dialysis and adsorption), fractionated plasma separation and adsorption (FPSA), and single-pass albumin dialysis (SPAD) combined with continuous venovenous hemodiafiltration (CVVHDF). However, there is no convincing evidence for the effectiveness of these methods and they should only be used in the context of clinical trials.
1. Elevated intracranial pressure and cerebral edema develop in ~30% of patients with grade 3 encephalopathy (see Table 6.2-4) and in 75% to 80% of patients with grade 4 encephalopathy. Brainstem herniation is the most common cause of death in patients with acute liver failure.
Treatment: Position the patient with the head and trunk elevated to 30 degrees, administer IV mannitol 0.5 to 1 g/kg and repeat if necessary, maintain plasma osmolality at 310 to 325 mOsm/kg H2O (monitor the values using a direct method). Intubate patients with grade 3 or 4 encephalopathy. If mannitol is not effective, consider hyperventilation (in patients with impending brain herniation you may reduce partial pressure of carbon dioxide [PaCO2] down to <25 mm Hg; in all other cases maintain PaCO2 at 30 to 35 mm Hg; the effect is short-term); induction of barbiturate coma is used by some, although evidence for improvement in patient-important outcomes is lacking. Glucocorticoids are not effective. Direct intracranial pressure monitoring is suggested by some but remains controversial. The types of catheters and their use vary. Target pressures are 20 to 25 mm Hg.
2. Gastrointestinal bleeding: The source of bleeding may be gastric stress ulcers or esophageal varices. It may be aggravated by coagulopathy.