2 Icahn School of Medicine at Mount Sinai, New York, NY, USA
Background
Acute hepatic failure (AHF) is a rare but life‐threatening critical illness seen most commonly in previously healthy young adults without any pre‐existing liver disease.
Survival rates have improved substantially in recent times, through advances in emergency liver transplantation and acute care management.
Definition of disease
Acute hepatic failure is generally defined as findings of abnormal liver function tests (LFTs) along with an elevated INR >1.5 and signs or symptoms of hepatic encephalopathy (HE), in a patient with no known previous liver disease.
Disease classification
Depending on the time of presentation, hepatic failure can be classified as follows:
Hyperacute (<7 days).
Acute (7–21 days).
Subacute (21 days to 26 weeks).
Chronic (>26 weeks).
Fulminant hepatic failure is a term used to describe rapidly progressing liver failure that develops within 8 days of the onset of symptoms and signs of liver failure.
Incidence/prevalence
In the USA, 2000 cases of AHF occur yearly, accounting for up to 6% of all liver‐related deaths.
The majority of cases are observed in women (67%) with a mean age of 38 years (range 17–79 years).
Etiology
Globally, drug‐induced hepatitis and viral hepatitis are the most common causes of AHF, whereas, in the USA, the most common cause of AHF is acetaminophen toxicity.
The causes of AHF can be categorized as:
Drugs
Acetaminophen (dose dependent); risk is greatest with ingestion staggered over hours or days rather than at a single large dose) Alcohol Recreational drugs (MDMA/ecstasy, cocaine) Toxins (Amanita phalloides, carbon tetrachloride from solvents, herbal supplements (kava, ephedra)) Idiosyncratic drug reaction (typically dose independent unlike acetaminophen); can be caused by several common drugs such as antibiotics, NSAIDs, and anticonvulsants which result in drug‐induced liver injury
Infections
Hepatitis A and E are the major causes of AHF Other viral infections include hepatitis B, cytomegalovirus, herpes simplex, varicella zoster, and adenovirus
Vascular
Acute ischemic hepatocellular injury or hypoxic hepatitis may occur in the setting of shock or respiratory failure Other vascular causes are Budd–Chiari syndrome and portal vein thrombosis
Hepatic failure, whether acute or chronic, leads to a final common pathway that involves reduced clearance of ammonia and lactic acid, reduced gluconeogenesis, and reduced protein synthetic function (Figure 39.1).
Predictive/risk factors for AHF
Chronic alcohol abuse. Malnutrition. Age >40 years and female sex. Chronic use of pain medication. Pregnancy.
Diagnosis
Differential diagnosis of hepatic failure
Differential diagnosis
Features
Wilson’s disease
Neurologic manifestations such as dysarthria, dystonia, tremors, or parkinsonism. Coombs‐negative hemolytic anemia, AST to ALT ratio of >2, normal alkaline phosphatase, elevated serum ceruloplasmin level
Acute severe hepatitis
Presentation may be similar to AHF, but typically lacks features of hepatic encephalopathy
Clinical diagnosis
History
Ingestion history: medication use (prescription/OTC/supplement) with the amount and duration since ingestion, mushroom ingestion, alcohol ingestion.
Travel to endemic region for hepatitis infection.
Sexual exposure history.
History of suicide depression.
History of malignancy, prior liver disease, family history of liver disease.
History of blood transfusion.
For hospitalized patient: history of hypotension/shock, medication used, cardiac function.
Physical examination
Neurologic: asterixis (flapping tremor/reverse myoclonus), mental status changes, altered sleep cycle secondary to HE. Increased ICP can be manifested as Cushing’s triad (systemic hypertension, bradycardia, irregular respirations).
Fetor hepaticus.
Skin: jaundice (common but may be absent in early stages), rash/vascular lesions (from infectious, autoimmune causes), petechiae, ecchymosis.
Eyes: icterus, Keyser–Fleischer rings (in Wilson’s disease), pupillary changes due to HE (varies from hyper‐responsive in grade II/III HE, to slow responsive in grade IV HE, to fixed dilated in brainstem herniation).
Cardiovascular: bounding pulses with wide pulse pressure are suggestive of increased cardiac output. Jugular vein distension and holosystolic murmur of tricuspid regurgitation may be observed in congestive hepatopathy.
GI: abdominal tenderness in right upper quadrant, hepatosplenomegaly, ascites.
Calculated from creatinine, bilirubin, and INR, with correction for sodium, which is used for chronic liver failure.
MELD is also used as a prognostic model to predict short‐term mortality risk and to prioritize patients on the transplant list for acute hepatic failure.
King’s College criteria for acetaminophen toxicity:
Ceruloplasmin level in suspected Wilson’s disease.
List of imaging techniques
Abdominal ultrasound: for diagnosis of cirrhosis, Budd–Chiari syndrome, and other vascular diseases.
CT/MRI/magnetic resonance venography: if malignancy is suspected or ultrasound is negative.
Treatment
Treatment rationale
Grade I hepatic failure can be managed on the medical floors/wards.
HE that progresses to grade II and beyond, typically requires ICU level of care.
Managing the hospitalized patient
Laboratory monitoring
CBC: monitor anemia.
Comprehensive metabolic panel and electrolytes every 6 hours: to monitor creatinine/BUN, serum amylase, lipase, electrolyte imbalance (hypokalemia, hypomagnesemia, hypophosphatemia) along with hypoglycemia.
LFTs (daily): improving liver enzymes could be misleading as it can indicate improving liver function versus loss of hepatic mass.
Coagulation panel: to monitor PT/INR as prognostic factors. Plasma transfusion should be avoided unless there is a compelling indication to do so.
Blood gas analysis: for acid–base disorder (alkalosis more common than acidosis initially).
Ammonia: serum ammonia <75 μg/dL rarely causes HE. Arterial ammonia >100 μg/dL is an independent risk for intracranial hypertension, and >200 μg/dL predicts intracranial hypertension.
General systemic management strategies
Hemodynamic stability:
The goal is a MAP of 75 mmHg or cerebral perfusion pressure (CPP) 50–60 mmHg to avoid cerebral hypoperfusion and anoxia.
For patients who are hypotensive or volume depleted, give fluid resuscitation with NS or 1/2NS + HCO3 if acidotic.
Dextrose for hypoglycemia.
Norepinephrine is the preferred initial vasopressor; the second choice would be vasopressin.
Bleeding management:
With liver failure both pro‐ and anticoagulant factor synthesis are impaired. Bleeding risk is overestimated with conventional tests like PT/INR. Therefore, fibrinogen levels and thromboelastography are better to guide transfusion therapy instead of a simple coagulation panel.
FFP transfusion is not recommended. Transfusion is typically reserved for bleeding episodes or planned procedures (like ICP monitor placement).
Proton pump inhibitors should be given for GI prophylaxis.
Neurologic support:
The goal is to prevent the onset or progression of HE and cerebral edema.
ICP monitoring, avoiding agitation, and maintaining fluid balance are the main goals.
Once intracranial hypertension develops, the definitive therapy is liver transplantation, because cerebral edema is irreversible with medical therapy alone.
Until transplantation can occur, an elevated ICP should be treated with bolus osmotherapy, with repeated doses as needed:
IV hypertonic saline: 30 mL of 23.4% sodium chloride or 200 mL of 3% sodium chloride.
IV mannitol at a dose of 0.5–1.0 g/kg 20% solution.
Temperature goal is hypothermia 32–34°C.
Hyperventilation (which results in vasoconstriction and a reduction in ICP) and barbiturate anesthesia are last resorts if all the above therapy fails.
Lactulose has no proven benefit in HE in acute liver failure.
Infection control:
Patients with compromised liver function are at very high risk of developing infections. Immunization and early treatment of infections is essential.
Renal management:
Renal failure is associated with increased mortality and is most prevalent in elderly patients and patients with acetaminophen toxicity.
If renal replacement therapy is needed, continuous veno‐venous hemofiltration is advised over intermittent dialysis. In most cases, renal function returns to baseline with resolution of liver failure.
Nutritional support:
Patients with acute liver failure are in a catabolic state and require nutritional support. In encephalopathy, enteral protein of 1.0–1.5 g/kg/day is advised.
Specific management
N‐acetyl cysteine: mainly used for acetaminophen toxicity. Can also be used for patients in whom acetaminophen is suspected as a contributing factor or cases where the cause is undetermined.
Liver transplantation: patients who do not recover spontaneously from acute liver failure require liver transplantation as definitive therapy. In the USA, patients with AHF requiring liver transplantation are given highest priority in the transplant list. Scoring systems like MELD and the King’s College Criteria are used to optimize organ allocation.
Steroids: antiviral regimen for the treatment of hepatitis B and acyclovir for the treatment of herpes virus infection are beneficial.
Prognosis
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