Acute on chronic liver failure (ACLF) is a clinical syndrome of sudden hepatic decompensation observed in patients with pre-existing chronic liver disease and associated with one or more extrahepatic organ failures and increased mortality.
Regardless of the etiology of chronic liver injury, when a clinician follows the natural history of liver injury, the initial uncomplicated chronic liver disease leads to cirrhosis and, later, the decompensation of liver function with ascites, jaundice, portal hypertension with variceal bleeding, and hepatic encephalopathy. Type-A ACLF is an 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 function in decompensated cirrhotics.
The etiology of ACLF would be related to a precipitating event in the context of 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 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 as having an unrecognized precipitating event culminating in ACLF.
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 that patients with acute of chronic liver failure comprise 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 rate in patients with ACLF has decreased from 65% in 2001 to 50% in 2011. The current worldwide mortality rate as per the European Association for the Study of Liver-Chronic-Liver Failure (EASL-CLIF consortium) is 30% to 50%. 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 were 27%, 49%, 64% and 77% with 1, 2, 3 or 4 organ failures, respectively.
Patients discharged following admission for ACLF have a 30-day readmission rate of approximately 30%.
The pathophysiology is based on the understanding that an acute precipitating event in a patient with a chronic liver condition that injures hepatocytes, leads to the accumulation of a cascade of inflammatory cytokines, and results 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 and IL-8) are observed in patients with ACLF. This is usually absent in cirrhotic patients with ACLF.
Bacteria-induced pathogen-associated molecular patterns (PAMPS) and virulence factors activate transcription factors are 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). This immunopathology is responsible for tissue, organ damage and, ultimately, organ failure.
A detailed history delineates possible precipitating factors for the acute hepatic decompensation. The following information should be obtained from the patient's chart, patient, or family:
Physical exam findings may include hypotension, altered mental status, jaundice, fever (with possible infectious etiology), right upper quadrant discomfort, pain, and tenderness, with associated nausea, and signs of fluid overload.
Patients will have features of acute hepatic decompensation. Also common are prolonged INR greater than or equal to 1.5, often elevated bilirubin and aminotransferases, thrombocytopenia with anemia, hypoglycemia, elevated ammonia, features of acute renal injury (with elevated serum creatinine), and abnormal electrolytes (hypokalemia, hypophosphatemia).
Any imaging to support the clinical examination findings and ascertain infection or any organ involvement or organ failure may be required. Imaging of the brain, chest, abdomen, and pelvis 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 MRI) is helpful to rule out organic etiology of altered mental status, while chest imaging will help rule out pulmonary edema or pneumonia.
Grading ACLF helps clinicians assess the prognosis, the usefulness of which has been validated in various studies. ACLF is stratified into 3 grades based on its severity:
Grade-1 ACLF is defined as:
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.
The management of ACLF consists of the prevention of precipitating factors leading to acute hepatic decompensation, supportive care, and early initiation of specific therapy, prevention, and management of complications. It also includes determining the prognosis and the need for liver support including possible liver transplantation. All patients should be hospitalized preferably at a center that has facilities and expertise for a liver transplant.
Prevention of Precipitating Factors Leading to Acute Hepatic Decompensation
Specific Treatment when Etiology is Known
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 from aspiration pneumonia): Address it with broad-spectrum antibiotic coverage. Obtain surveillance cultures of the blood, sputum, and urine in all patients with ALF.
Metabolic Disorders: Hypoglycemia occurs due to impaired glycogen production and gluconeogenesis, and requires continuous infusions of 10% or 20% glucose. Hypophosphatemia due to ATP consumption in the setting of hepatocyte necrosis necessitates aggressive repletion. Alkalosis in ALF is due to hyperventilation, and acidemia with a pH below 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 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 thrombosis; 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 subsequently need a liver transplant. Though a liver transplant is the only definitive treatment for ACLF, no guidelines exist regarding selection criteria. Also, infection disqualifies almost half of patients from receiving a liver transplant. Out of half of the patients with ACLF who are awaiting a liver transplant, only 10% to 25% receive it, while 50% to 75% die in wait.
Extracorporeal liver-assist devices have been used in clinical trials in patients with ACLF and are a potential treatment. Extracorporeal liver-assist devices aim to target 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 in patients with ACLF. The score is directly proportional to the number of organ failures. A CLIF score above 64 always requires immediate consideration of 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 de-listed from the liver transplant list and ultimately have poorer outcomes. Patients with respiratory failure have the worst outcomes.
ACLF is a dynamic syndrome, which may improve, worsen, or have a mild protracted course, allowing us the opportunity for a possible liver transplant.
At present clinicians do not have a consensus on the definition of ACLF. Also, we do not have a satisfactory understanding of the pathophysiology, use of prognostic scoring system, or universal guidelines on the management of ACLF. Subsequent studies to better understand ACLF are vital. In the future, we should be able to accurately determine appropriate interventions and management strategies to help clinicians ascertain the best approach to divert resources based on cost-effective and evidence-based medicine.
ACLF is a serious disease with significant morbidity and mortality. It is best managed by an interprofessional team that includes a specialty-trained nurse, internist, liver specialist, neurologist, transplant surgeon, radiologist, pathologist, infectious disease expert, and an intensivist. 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 life-threatening complications. (Level V)
|||Praktiknjo M,Clees C,Pigliacelli A,Fischer S,Jansen C,Lehmann J,Pohlmann A,Lattanzi B,Krabbe VK,Strassburg CP,Arroyo V,Merli M,Meyer C,Trebicka J, Sarcopenia Is Associated With Development of Acute-on-Chronic Liver Failure in Decompensated Liver Cirrhosis Receiving Transjugular Intrahepatic Portosystemic Shunt. Clinical and translational gastroenterology. 2019 Mar 29; [PubMed PMID: 30939488]|
|||Cai JJ,Wang K,Jiang HQ,Han T, Characteristics, Risk Factors, and Adverse Outcomes of Hyperkalemia in Acute-on-Chronic Liver Failure Patients. BioMed research international. 2019; [PubMed PMID: 30937312]|
|||Wilde B,Katsounas A, Immune Dysfunction and Albumin-Related Immunity in Liver Cirrhosis. Mediators of inflammation. 2019; [PubMed PMID: 30930689]|
|||Patil V,Jain M,Venkataraman J, Paracentesis-induced acute kidney injury in decompensated cirrhosis - prevalence and predictors. Clinical and experimental hepatology. 2019 Mar; [PubMed PMID: 30915407]|
|||Rahim MN,Liberal R,Miquel R,Heaton ND,Heneghan MA, Acute severe autoimmune hepatitis - Corticosteroids or liver transplantation? Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 2019 Mar 22; [PubMed PMID: 30900368]|
|||Lopes D,Samant H, Hepatic Failure 2019 Jan; [PubMed PMID: 30855815]|
|||Thongprayoon C,Kaewput W,Thamcharoen N,Bathini T,Watthanasuntorn K,Lertjitbanjong P,Sharma K,Salim SA,Ungprasert P,Wijarnpreecha K,Kröner PT,Aeddula NR,Mao MA,Cheungpasitporn W, Incidence and Impact of Acute Kidney Injury after Liver Transplantation: A Meta-Analysis. Journal of clinical medicine. 2019 Mar 17; [PubMed PMID: 30884912]|
|||Avolio AW,Gaspari R,Teofili L,Bianco G,Spinazzola G,Soave PM,Paiano G,Francesconi AG,Arcangeli A,Nicolotti N,Antonelli M, Postoperative respiratory failure in liver transplantation: Risk factors and effect on prognosis. PloS one. 2019; [PubMed PMID: 30742650]|
|||de Mattos ÂZ,de Mattos AA, Acute-on-chronic liver failure - conceptual divergences. Hepatology (Baltimore, Md.). 2019 Mar 12; [PubMed PMID: 30864173]|
|||Artzner T,Michard B,Besch C,Levesque E,Faitot F, Liver transplantation for critically ill cirrhotic patients: Overview and pragmatic proposals. World journal of gastroenterology. 2018 Dec 14; [PubMed PMID: 30581269]|
|||[Guidelines for the diagnosis and management of hepatic encephalopathy in cirrhosis]. Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology. 2018 Oct 20; [PubMed PMID: 30481878]|
|||Steve RJ,Gnanadurai FJ,Anantharam R,Jeyaseelan V,Zachariah UG,Goel A,Chundamannil EE,Abraham P, Expanded diagnostic approach to hepatitis E virus detection in patients with acute-on-chronic liver failure: A pilot study. Indian journal of medical microbiology. 2018 Jul-Sep; [PubMed PMID: 30429393]|
|||Hernández-Gea V,Procopet B,Giráldez Á,Amitrano L,Villanueva C,Thabut D,Ibañez-Samaniego L,Silva-Junior G,Martinez J,Genescà J,Bureau C,Trebicka J,Llop E,Laleman W,Palazon JM,Castellote J,Rodrigues S,Gluud LL,Noronha Ferreira C,Barcelo R,Cañete N,Rodríguez M,Ferlitsch A,Mundi JL,Gronbaek H,Hernández-Guerra M,Sassatelli R,Dell'Era A,Senzolo M,Abraldes JG,Romero-Gómez M,Zipprich A,Casas M,Masnou H,Primignani M,Krag A,Nevens F,Calleja JL,Jansen C,Robic MA,Conejo I,Catalina MV,Albillos A,Rudler M,Alvarado E,Guardascione MA,Tantau M,Bosch J,Torres F,Garcia-Pagán JC, Preemptive-TIPS Improves Outcome in High-Risk Variceal Bleeding: An Observational Study. Hepatology (Baltimore, Md.). 2019 Jan; [PubMed PMID: 30014519]|
|||Raices M,Czerwonko ME,Ardiles V,Boldrini G,D'Agostino D,Marcó Del Pont J,Pekolj J,Mattera J,Brandi C,Ciardullo M,de Santibañes E,de Santibañes M, Short- and Long-Term Outcomes After Live-Donor Transplantation with Hyper-Reduced Liver Grafts in Low-Weight Pediatric Recipients. Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract. 2019 Mar 18; [PubMed PMID: 30887299]|
|||Lum EL,Cardenas A,Martin P,Bunnapradist S, Current Status of Simultaneous Liver Kidney Transplantation in the United States. Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 2019 Mar 12; [PubMed PMID: 30861294]|
|||Thuluvath PJ,Thuluvath AJ,Savva Y,Zhang T, Karnofsky Performance Status Following Liver Transplantation in Patients With Multiple Organ Failures and Probable Acute on Chronic Liver Failure. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2019 Mar 15; [PubMed PMID: 30885883]|