- Causes of ACLF
- Evaluation of ACLF
- Questions & discussion
- This is defined roughly as the new onset of ascites, hepatic encephalopathy, gastrointestinal hemorrhage, or hepatorenal syndrome in a patient with cirrhosis.
- Organ failure may or may not occur.
- Patients may or may not require hospital admission.
acute-on-chronic liver failure (ACLF)
- ACLF refers to the most severe subset of patients with acutely decompensated cirrhosis, who are at higher risk of short-term mortality.
- There is disagreement about the precise definition of ACLF. Regardless, the crux of the definition involves failure of two or more nonhepatic organs (e.g., renal failure, severe encephalopathy, respiratory failure, shock, or severe coagulation abnormalities) in combination with worsened hepatic function.
- ACLF is essentially decompensated cirrhosis causing multiorgan failure.
underlying hepatorenal physiology + inflammatory triggers
- Cirrhosis causes systemic vasodilation, with reflex vasoconstriction of the renal vasculature (sometimes referred to as “hepatorenal physiology;” more on this here).
- Chronic vasodilation renders patients vulnerable to any hemodynamic insult. Additional sources of inflammation may promote further vasodilation, leading to profound vasodilation and hypoperfusion. Overall, this process has several parallels to septic shock.
- Sepsis itself is a common source of inflammation and thus a common trigger of ACLF.
- Sterile inflammation may also trigger ACLF (e.g., alcoholic hepatitis, or translocation of bacterial lipopolysaccharide from the gut).
common causes of ACLF
- Infection (including spontaneous bacterial peritonitis, urosepsis, pneumonia, and cellulitis).
- Hemorrhage (e.g., variceal bleeding, portal gastropathy, peptic ulceration)
- Thrombosis (e.g., portal vein thrombosis, hepatic vein thrombosis a.k.a. Budd-Chiari syndrome)
- Hepatic insult:
- Alcoholic hepatitis (very common cause of ACLF).
- Drug-induced liver injury (especially acetaminophen toxicity).
- Viral infection: acquisition of new viral infection or flare of chronic viral hepatitis.
- Biliary obstruction.
- Hemodynamic abnormalities:
- Hypovolemia (e.g., due to excess diuretic or poor PO intake).
- Hypervolemia (e.g., due to cirrhosis with volume retention).
- Pulmonary hypertension (typically portopulmonary hypertension caused by cirrhosis).
- Medications (e.g., antihypertensives, vasodilators, nephrotoxins).
- Iatrogenic (e.g., hepatic resection, ablation of hepatocellular carcinoma, abdominal surgery).
evaluation of ACLF
- Focus on alcohol use and other potential hepatotoxic drugs (especially acetaminophen), herbal medications, or dietary supplements.
- Evaluate volume status (e.g., history of fluid intake, edema, diarrhea, and weight changes).
- Evaluate for recent changes in diuretic or hemodynamic medications (e.g., beta-blocker escalation).
- Review recent procedures or other iatrogenic exposures (e.g., inhalational anesthetics can injure the liver or use of chemotherapeutic agents in patients with chronic hepatitis).
- Electrolytes, including magnesium and phosphate.
- Liver function tests.
- Coagulation tests.
- Complete blood count.
- Infection is the most common cause of ACLF. Cirrhotic patients may not mount a fever, so there should be a very low threshold for an infection workup (e.g., blood cultures, urinalysis with culture PRN, chest X-ray).
- Acetaminophen level.
- Depending on exposure history, investigation may be warranted to exclude acute superimposed viral hepatitis.
- Echocardiography at bedside to evaluate hemodynamics.
- Formal RUQ ultrasonography with Doppler, to evaluate for portal or hepatic vein thrombosis.
- Chest X-ray, if there is any concern regarding infection or respiratory failure.
- Paracentesis if a substantial volume ascites is present, to exclude spontaneous bacterial peritonitis.
- (More on paracentesis to exclude spontaneous bacterial peritonitis here.)
management of inciting cause
- If a cause of decompensation is discovered, it should be immediately addressed.
- Whether or not a cause is found, aggressive multiorgan support should be provided as outlined in the next section. This aims at treatment or prevention of common problems encountered in ACLF (e.g., hepatic encephalopathy, malnutrition, infection, and hepatorenal syndrome).
nonspecific management – cirrhosis support package
- If hypovolemic, 5% albumin might be a preferred fluid.(31394283, 33205036, 32058375) The recent ATTIRE trial demonstrated that administration of albumin to target an albumin level >3 g/dL was nonbeneficial – this demonstrates that fluids should be titrated to optimize hemodynamics, rather than albumin levels.(33657293)
- Consider targeting a high Bp (e.g., MAP>80 mm) if hepatorenal syndrome is probable.
- There may be a relatively low threshold for stress-dose steroids to treat shock or alcoholic hepatitis, given a high prevalence of relative adrenal insufficiency in advanced cirrhosis.(31589973, 31977332, 17058239)
- There should be a low threshold to discontinue antihypertensives and diuretics.
- Continue midodrine if the patient is on it chronically.
- Avoid constipation, with an extremely low threshold to initiate lactulose as the cathartic agent of choice.
- Stress ulcer prophylaxis should be considered, even in non-intubated patients (e.g., patients who are on steroid and have a history of gastrointestinal hemorrhage).
- GI hemorrhage should be suspected and treatment initiated early (e.g., in patients with falling hemoglobin). More on the management of GI bleeding here.
- Consider prednisolone for alcoholic hepatitis (more on this here).
- HBV: Consult with infectious diseases and/or hepatology, consider immediate therapy.
- In severe alcoholism:
- If poor baseline oral intake, gradually advance diet while following phosphate for evidence of refeeding syndrome.
- Thiamine 100 mg IV daily for most patients. High-dose thiamine (500 mg IV q8hr) if altered mental status with possible Wernicke's encephalopathy.
- Vitamin B6 (pyridoxine) supplementation might be considered, which may reduce the risk of seizure.
- Full nutritional support should generally be provided to most patients (i.e., protein should not be restricted).
- Daily multivitamin.
- Avoid nephrotoxins.
- Treat electrolyte abnormalities (especially hypokalemia or sodium abnormalities, if they seem to be contributing to encephalopathy).
- Treat acute kidney injury early (defined as a creatinine rise by 0.3 mg/dL, or 1.5 times baseline):
- Consider empiric therapy for hepatorenal syndrome, including albumin and vasopressors (more on this here).
- Consider therapeutic paracentesis, if the patient has tense ascites (with 8 grams/liter of 20% albumin replacement).
- Empiric antibiotics may be indicated in gastrointestinal hemorrhage, suspected septic shock, or a known site of infection (e.g., pneumonia).
- If the INR is elevated:
- DVT prophylaxis is still indicated (when in doubt, thromboelastography may help clarify whether there is true enzymatic hypocoagulation).
- Consider 10 mg vitamin K intravenously (to exclude vitamin K deficiency and thereby promote accurate prognostication).
- Avoid hypoglycemia (the liver's ability to release glucose is often impaired).
- Follow glucose levels, especially if patients are NPO.
- Don't aggressively control hyperglycemia.
- Hepatic encephalopathy (full chapter here).
- There should be a very low threshold to initiate lactulose +/- rifaximin for delirium (in addition to investigating and treating any additional contributory factors; more on delirium here).
- For intubated patients with hepatic encephalopathy and ACLF, whole-bowel lavage with polyethylene glycol may be considered (to expedite management of encephalopathy and reduce bacterial translocation).(25243839, 30234645, 28316761)
- Avoid sedatives & deliriogenic medications.
- Avoid empiric diagnosis and subsequent aggressive therapy for “alcohol withdrawal.” Delirious patients often have hepatic encephalopathy or multifactorial ICU delirium, rather than alcohol withdrawal; benzodiazepines or barbiturates will only exacerbate these conditions.
transplantation vs. palliation
- Consider candidacy for liver transplantation and discuss with a liver transplant service or center if this is a possibility.
- If not a candidate for transplantation, consider palliative care consultation.
Follow us on iTunes
questions & discussion
To keep this page small and fast, questions & discussion about this post can be found on another page here.
- Failure to aggressively address all of the failing organs involved in ACLF (the key to treatment is often prompt and simultaneous support of multiple organ systems). In particular, if renal dysfunction occurs, this should be rapidly managed (often in a fashion similar to hepatorenal syndrome).
- Excluding the possibility of infection based on a lack of fever (patients with advanced cirrhosis may fail to mount a fever).
- 17058239 Fernández J, Escorsell A, Zabalza M, et al. Adrenal insufficiency in patients with cirrhosis and septic shock: Effect of treatment with hydrocortisone on survival. Hepatology. 2006 Nov;44(5):1288-95. doi: 10.1002/hep.21352 [PubMed]
- 25243839 Rahimi RS, Singal AG, Cuthbert JA, Rockey DC. Lactulose vs polyethylene glycol 3350–electrolyte solution for treatment of overt hepatic encephalopathy: the HELP randomized clinical trial. JAMA Intern Med. 2014 Nov;174(11):1727-33. doi: 10.1001/jamainternmed.2014.4746 [PubMed]
- 28316761 Naderian M, Akbari H, Saeedi M, Sohrabpour AA. Polyethylene Glycol and Lactulose versus Lactulose Alone in the Treatment of Hepatic Encephalopathy in Patients with Cirrhosis: A Non-Inferiority Randomized Controlled Trial. Middle East J Dig Dis. 2017 Jan;9(1):12-19. doi: 10.15171/mejdd.2016.46 [PubMed]
- 30234645 Shehata HH, Elfert AA, Abdin AA, Soliman SM, Elkhouly RA, Hawash NI, Soliman HH. Randomized controlled trial of polyethylene glycol versus lactulose for the treatment of overt hepatic encephalopathy. Eur J Gastroenterol Hepatol. 2018 Dec;30(12):1476-1481. doi: 10.1097/MEG.0000000000001267 [PubMed]
- 31394283 Fernández J, Angeli P, Trebicka J, et al. Efficacy of Albumin Treatment for Patients with Cirrhosis and Infections Unrelated to Spontaneous Bacterial Peritonitis. Clin Gastroenterol Hepatol. 2020 Apr;18(4):963-973.e14. doi: 10.1016/j.cgh.2019.07.055 [PubMed]
- 31589973 Piano S, Favaretto E, Tonon M, et al. Including Relative Adrenal Insufficiency in Definition and Classification of Acute-on-Chronic Liver Failure. Clin Gastroenterol Hepatol. 2020 May;18(5):1188-1196.e3. doi: 10.1016/j.cgh.2019.09.035 [PubMed]
- 31977332 MacDonald AJ, Olson J, Karvellas CJ. Critical care considerations in the management of acute-on-chronic liver failure. Curr Opin Crit Care. 2020 Apr;26(2):171-179. doi: 10.1097/MCC.0000000000000698 [PubMed]
- 32039351 Dong V, Karvellas CJ. Acute-on-chronic liver failure: Objective admission and support criteria in the intensive care unit. JHEP Rep. 2019 Mar 18;1(1):44-52. doi: 10.1016/j.jhepr.2019.02.005 [PubMed]
- 32058375 Nanchal R, Subramanian R, Karvellas CJ, et al. Guidelines for the Management of Adult Acute and Acute-on-Chronic Liver Failure in the ICU: Cardiovascular, Endocrine, Hematologic, Pulmonary and Renal Considerations: Executive Summary. Crit Care Med. 2020 Mar;48(3):415-419. doi: 10.1097/CCM.0000000000004193 [PubMed]
- 32459924 Arroyo V, Moreau R, Jalan R. Acute-on-Chronic Liver Failure. N Engl J Med. 2020 May 28;382(22):2137-2145. doi: 10.1056/NEJMra1914900 [PubMed]
- 32620286 Aday A, O'Leary JG. Acute on Chronic Liver Failure: Definition and Implications. Clin Liver Dis. 2020 Aug;24(3):521-534. doi: 10.1016/j.cld.2020.04.004 [PubMed]
- 33101624 Amin A, Mookerjee RP. Acute-on-chronic liver failure: definition, prognosis and management. Frontline Gastroenterol. 2019 Nov 25;11(6):458-467. doi: 10.1136/flgastro-2018-101103 [PubMed]
- 33205036 Zaccherini G, Weiss E, Moreau R. Acute-on-chronic liver failure: Definitions, pathophysiology and principles of treatment. JHEP Rep. 2020 Sep 2;3(1):100176. doi: 10.1016/j.jhepr.2020.100176 [PubMed]
- 33657293 China L, Freemantle N, Forrest E, Kallis Y, Ryder SD, Wright G, Portal AJ, Becares Salles N, Gilroy DW, O'Brien A; ATTIRE Trial Investigators. A Randomized Trial of Albumin Infusions in Hospitalized Patients with Cirrhosis. N Engl J Med. 2021 Mar 4;384(9):808-817. doi: 10.1056/NEJMoa2022166 [PubMed]