Acute and Chronic Liver Failure

Article Author:
Niraj Shah
Article Author:
Omar Mousa
Article Editor:
Savio John
6/24/2020 2:33:57 PM
PubMed Link:
Acute and Chronic Liver Failure


Acute on chronic liver failure (ACLF) is a clinical syndrome of sudden hepatic decompensation observed in patients with pre-existing chronic liver disease and is associated with one or more extrahepatic organ failures and increased mortality.[1][2][3][4]

No matter the etiology of chronic liver injury, when a clinician follows the natural history of the liver injury, the initial uncomplicated chronic liver disease leads to cirrhosis and later, the decompensation of liver functions with ascites, jaundice, portal hypertension with variceal bleeding, and hepatic encephalopathy. Type-A ACLF is acute worsening of liver function in a patient with chronic liver disease. Type-B ACLF is when this acute decompensation occurs in patients with cirrhosis, while type-C ACLF is acute worsening of liver functions in decompensated cirrhotics.


The etiology of ACLF would be a precipitating event on a pre-existing liver condition. Hepatic causes include alcohol-related injury, drug-induced liver injury, viral hepatitis (A, B, C, D, and E), hypoxic injury or liver surgeries including a transjugular intrahepatic portosystemic shunt (TIPS) placement. Extra-hepatic causes mainly consist of bacterial infections and major surgery. An estimated 40% to 50% of patients are labeled to have an unrecognized precipitating event leading to ACLF.[5][6][7]

The precipitating event has a geographical variation, similar to the etiology of acute liver failure. While acute alcohol injury and bacterial infections are the most common precipitating factor of ACLF in the west; reactivation of chronic hepatitis B, acute hepatitis A, and E infection, along with acute alcohol injury and bacterial infections are most common in Asia.


 Recent trends in morbidity and mortality indicate patients with acute of chronic liver failure to constitute 5% of all hospitalizations for cirrhosis. When compared to the most common causes of hospitalization in the United States, the healthcare burden per patient is much higher in patients with ACLF. The mean cost of hospitalization for patients with ACLF is three times more than the cost of patients hospitalized with cirrhosis, and five times more than the cost of patients hospitalized with congestive heart failure   The estimated mortality rates in patients with ACLF has decreased from 65% in 2001 to 50% in 2011. The current worldwide mortality rates as per the European Association for the Study of Liver-Chronic-Liver Failure (EASL-CLIF consortium) is at 30% to 50%. While the mortality rates in the United States, as per the North-American Consortium for the Study of End-Stage Liver Disease (NACSELD) in infected decompensated patients was 27%, 49%, 64% and 77% with 1, 2, 3 or 4 organ failures, respectively.[8][9][8]

Patients discharged following admission for ACLF has a very high 30-day readmission rate of approximately 30%.


The pathophysiology is based on the understanding that an acute precipitating event in a patient with the chronic liver condition would injure hepatocytes leading to the accumulation of a cascade of inflammatory cytokines, resulting in further hepatic injury in the presence of failure of hepatocyte regeneration. The resulting compromise in immune function and liver decompensation leads to further susceptibility to infections, multi-organ failure, and death.

Systemic inflammation with elevated leukocytosis, cytokines, and chemokines including IL-6, IL8 are observed in patients with ACLF. This is something that is usually absent in cirrhotics with ACLF.

Bacteria-induced pathogen-associated molecular patterns (PAMPS) and virulence factors activate transcription factors required for encoding cytokines in the inflammatory cascade. Endogenous inducers of inflammation, obtained as a result of denaturation of hepatocytes, called damage-associated molecular patterns (DAMPs) are also responsible for activating inflammatory cascades cooperating with Toll-like receptors (TLRs). The resulting immunopathology is responsible for tissue and organ damage, leading to organ failure.

History and Physical

A detailed history delineates possible precipitating factors for the acute hepatic decompensation. The following information should be obtained from the patient's chart, the patient, or the family:

  1. A known chronic liver condition, the degree of fibrosis or cirrhosis
  2. Any known history of hepatic decompensation
  3. Any concomitant relevant chronic health conditions
  4. The timeline of symptoms the patient presented with regarding systemic features, fluid overload, gastrointestinal bleeding, abdominal pain, altered mental status
  5. Toxic habits or high-risk behavior
  6. Any recent change in medications or recent ingestion of hepatotoxins including herbal products and sedatives/analgesics
  7. Any recent history of travel
  8. Any recent surgeries, including a TIPS procedure

Physical exam findings of hypotension, altered mental status, fever (with infectious etiology), right upper quadrant discomfort, pain, and tenderness, with nausea and features of jaundice and fluid overload, may be included.


Patients will have features of acute hepatic decompensation. Also, prolonged INR greater than or equal to 1.5, often elevated bilirubin and aminotransferases, thrombocytopenia with anemia, hypoglycemia, elevated ammonia and features of acute renal injury (with elevated serum creatinine), and dyselectrolytemia (hypokalemia, hypophosphatemia) are common.[10][11][12][13]

Any imaging to support the clinical examination findings and to ascertain infection or any organ involvement or organ failure may be required. Imaging of the abdomen, pelvis, brain, and chest should be considered. Abdominal imaging to determine the presence of features of portal hypertension, hepatocellular carcinoma, vascular thrombosis, lymph nodes, and spleen is vital. Abdominal sonogram with Doppler could be considered in patients with concomitant renal injury and vascular thrombosis. Brain imaging (CT or an MRI) is helpful to rule out organic etiology of altered mental status while chest imaging will help rule out pulmonary edema or pneumonia.

Based on the severity of ACLF, it is stratified into 3 grades.

Grade-1 ACLF is defined as: 

  • Single renal failure
  • Single liver, coagulation, circulatory, or lung failure that is associated with a serum creatinine level of 1.5 to 1.9 mg/dl and/or hepatic encephalopathy grade 1 or grade 2
  • A single brain failure with a serum creatinine level of 1.5 to 1.9 mg/dl

Grade 2 ACLF is diagnosed when there are 2 organ failures of any combination.

Grade 3 ACLF is diagnosed when there are three or more organ failures of any combination. 

Grading ACLF helps clinicians assess the prognosis, the usefulness of which has been validated in various studies.

Treatment / Management

The management of ACLF consists of prevention of precipitating factors leading to acute hepatic decompensation, supportive care, and earliest initiation of specific therapy, prevention, and management of complications. It also includes determining prognosis and the need for liver support including possible liver transplantation. All patients should be hospitalized preferably at a center which has facilities and expertise for a liver transplant.[14][15]

Prevention of Precipitating Factors Leading to Acute Hepatic Decompensation

  1. To have a high degree of suspicion, evaluate and treat any infection as early as possible.
  2. Attain sustained viral suppression of HBV and HCV
  3. Intravenous administration of albumin in patients with diagnosed spontaneous bacterial peritonitis to prevent accelerated renal dysfunction characterized by hepatorenal physiology. Intravenous albumin has no proven benefit in other bacterial infections
  4. Prophylactic antibiotics for low ascetic albumin
  5. In patients with severe acute alcoholic hepatitis, early initiation of both Pentoxifylline or a combination of prednisolone and intravenous N-acetylcysteine has shown to reduce the incidence of type-1 hepatorenal syndrome.
  6. In patients with severe sepsis, a combination of granulocyte colony-stimulating factor (C-CSF) and Darbepoetin has shown to have improved 1-year survival in decompensated cirrhotics.

Supportive Care

  1. Access hemodynamic stability and the need for intravenous fluids and maintenance of acid-base levels and normal electrolytes. Vasopressors are indicated to maintain a mean arterial pressure of greater than or equal to 75 mm Hg to ensure adequate renal and cerebral perfusion.
  2. Monitor hematocrit for any bleeding, as the patients have coagulopathy and poor platelet functions. Blood products of platelets and fresh frozen plasma for coagulopathy is only indicated in patients with active bleeding or before an invasive procedure. Patients should be empirically started on proton pump inhibitors for prophylaxis of gastrointestinal bleed.
  3. Monitor hepatic encephalopathy and protect airway (aspiration risk) should the patient show signs of worsening encephalopathy. This patient should be intubated and should be on a protocol to avoid cerebral edema.
  4. Adequate nutrition with 1.0 to 1.5 gm of protein per kilogram per day should be administered
  5. Monitor for hypoglycemia and maintain blood glucose between 160 to 200.
  6. Discontinue all home medications except the ones we identify essential to continue.

Specific Treatment when Etiology is Known        

  1. Patients with hepatitis A and E associated ACLF should receive supportive care as no specific anti-virals are known to be effective.
  2. Patients with acute or reactivation of hepatitis C should receive appropriate anti-virals based on prior treatment administered
  3. Patients with acute or reactivation of hepatitis B should receive nucleos(t)ide analogues.
  4. Patients with acute decompensation in known Wilson’s disease or development of hepatic vein thrombosis as the etiology for ACLF should be considered for a liver transplant.

Management of Complications

Every attempt should be made to avoid the development of multi-organ dysfunction.

Renal Failure: It may occur due to hypovolemia, acute tubular necrosis or hepatorenal syndrome. Vasopressor therapy with norepinephrine or dopamine is indicated in severe hypotension. Renal-replacement may be considered a bridge for a possible liver transplant. Continuous renal replacement therapy is preferred to hemodialysis in critically ill patients.

Sepsis, including aspiration pneumonia and fever, should be covered with broad-spectrum antibiotics. Surveillance cultures of blood, sputum, and urine should be obtained in all patients with ALF.

Metabolic Disorders:  Hypoglycemia occurs due to impaired glycogen production and gluconeogenesis, and will need continuous infusions of 10% 20% glucose. Hypophosphatemia occurring due to ATP consumption in the setting of hepatocyte necrosis requires aggressive repletion. Alkalosis in ALF is due to hyperventilation, and acidosis with a pH less than 7.3 portends 95% mortality in acetaminophen overdose if the patient does not undergo a liver transplant. Hypoxemia may occur due to aspiration, acute respiratory distress syndrome, or pulmonary hemorrhage. Patients with encephalopathy greater than grade 2 should undergo endotracheal intubation for airway protection. Seizure-like activity may be treated with phenytoin or benzodiazepines.

Cerebral Edema: The most common cause of death in ALF is cerebral edema which leads to intracranial hypertension, ischemic brain injury and herniation. Patients with arterial ammonia levels higher than 200 micromoles per liter are at an increased risk for intracranial hypertension. Triggers for cerebral edema include hypoxia, systemic hypotension, decreased cerebral perfusion pressure (CPP) and astrocyte swelling which occurs due to increased ammonia levels and glutamine production in the brain. Abnormal pupillary reflexes, muscular rigidity and decerebrate posturing when present indicate the onset of intracranial hypertension. Measures to keep the intracranial pressure (ICP) below 25 mm Hg and CPP above 50 mm Hg, if an ICP monitoring device is placed, should be undertaken. Such measures include elevation of the head end of the bed to 30 degrees, avoiding unnecessary stimulation such as suctioning of the oropharynx and background noise, endotracheal intubation, and sedation in a patient with grade 3 encephalopathy and above, prompt initiation of vasopressor therapy and renal replacement therapy, hyperventilation, and intravenous mannitol therapy.

Encephalopathy:  Encephalopathy is a key feature of ALF. CT of the head should be done in patients with grade 3 encephalopathy and above to assess for intracranial bleeding and cerebral edema.

Coagulopathy: Like encephalopathy, coagulopathy is also a defining feature of ALF.  Bleeding events are rare despite the presence of severe coagulopathy. Hence routine correction of coagulopathy is not recommended unless in the setting of overt bleeding or before invasive procedures. Transfusions of platelets, plasma, and cryoprecipitate, may be given if indicated. Recombinant factor VII an administration can cause thrombus; parenteral vitamin-K therapy (slow intravenous infusion) may be considered if a nutritional deficiency is suspected or in cases of prolonged cholestasis.

Liver Support and Transplantation

The grading of ACLF and the progress of hospital stay helps physicians ascertain whether a particular patient is likely to improve or not, and hence need a liver transplant. Though a liver transplant is the only defined definitive treatment for ACLF, no guidelines exist regarding selection criteria. Also, infection rules out almost half of the patients to receive a liver transplant. Out of half of the patients with ACLF which get listed for a liver transplant, only 10% to 25% receive a transplant, while 50% to 75% die while on the waiting list.

Extracorporeal liver-assist devices have been used in clinical trials in patients with ACLF and are a potential treatment. The aim with extracorporeal liver-assist devices is to target for detoxification and restore synthetic functions. Tumor hepatocyte, also known as the porcine hepatocyte line. Vital therapies ELAD and Alliqua HepatAssist 2000 systems are the only available bioartificial liver support systems available. Recent multicenter trials, however, have not shown to increase survival rates.


The chronic liver failure (CLIF) organ failure score can be used to predict mortality of patients with ACLF. The score is directly proportional to the number of organ failures, with a CLIF score of more than 64 always requiring an immediate consideration for liver transplantation. The etiology of the precipitating factor leading to ACLF does not alter the prognosis. The most common etiology of ACLF is infection and patients with infections are delisted from the liver transplant list and ultimately have a poorer outcome. Patients with respiratory failure have the worst outcomes.

ACLF is a dynamic syndrome, which may improve, worsen or have a mild protracted course giving us an opportunity to evaluate for a possible liver transplant.

Pearls and Other Issues

At present clinicians do not have a consensus on the definition of ACLF. Also, we do not have a satisfactory understanding of the pathophysiology, the use of prognostic scoring system and guidelines to the management of ACLF. Subsequent studies to better understand ACLF is vital. In future, we should be able to accurately determine appropriate interventions and management strategies to help us ascertain the best approach to divert our resources based on cost-effective, evidence-based medicine.

Enhancing Healthcare Team Outcomes

ACLF is a serious disease with very high morbidity and mortality. It is best managed by an interprofessional team that includes a specialty trained nurse, internist, liver specialist, neurologist, transplant surgeon, intensivist, pathologist, infectious disease expert, and a radiologist. To date, the treatment is symptomatic and geared towards the control of the primary disorder causing liver problems. The outlook for most patients is guarded. While liver transplant can help prolong life, the procedure is also associated with serious complications that are life-threatening.[5][16] (Level V)


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