Secondary Logo

Journal Logo

THE RED SECTION: GUIDELINES IN PRACTICE

Acute-on-Chronic Liver Failure

Bajaj, Jasmohan S. MD1; Wong, Florence MD2; Kamath, Patrick S. MD3; Lai, Jennifer C. MD4; O'Leary, Jacqueline G. MD5

Author Information
The American Journal of Gastroenterology: June 2022 - Volume 117 - Issue 6 - p 831-834
doi: 10.14309/ajg.0000000000001748
  • Free

The recently published ACG guideline on acute-on-chronic liver failure (ACLF) illustrates the major burden on patients and healthcare systems (1). ACLF is distinct from other entities (Table 1) and is defined as “a potentially reversible condition in patients with chronic liver disease with or without cirrhosis that is associated with the potential for organ failure and mortality within 3 months in the absence of treatment of the underlying liver disease, liver support, or liver transplantation.” We illustrate the importance of this entity using a case-based vignette and highlight.

T1
Table 1.:
Differentiation between acute liver failure, decompensated cirrhosis, and ACLF
T2
Table 2.:
Recommendations highlighted in this case report
T3
Table 3.:
Key concept statements highlighted in this case report

Case 1

A 59-year-old man presented to the emergency department (ER) by his wife for new-onset confusion and increased abdominal girth. Medical history was notable for uncontrolled diabetes, obesity, and social alcohol use. On examination, he was afebrile, alert, and oriented only to place. Abdominal examination revealed a fluid wave. He had not sought outpatient care for 3 years, although he underwent emergency surgery for a strangulated inguinal hernia 6 weeks ago. At hospital discharge, a proton pump inhibitor was initiated for “prophylaxis.” Notable admission laboratory test results included serum creatinine 1.3 mg/dL, bilirubin 2 mg/dL, albumin 3.1 g/dL, international normalized ratio (INR) 1.4, white blood cell (WBC) count 7,000/mL, and platelet count 105 × 109/L.

The demographics of cirrhosis are changing with the obesity epidemic and COVID-19 pandemic leading to high rates of nonalcoholic fatty liver disease and alcohol-related liver disease (2). This patient likely progressed from chronic liver disease to cirrhosis without follow-up, and the final event that pushed him into decompensation was surgery. In the ER, a high index of suspicion is needed to ensure that hepatic encephalopathy (HE) is in the differential diagnosis of confusion because that may be the first sign of decompensation in nonalcoholic fatty liver disease cirrhosis (3). The low platelet count and albumin and high INR and bilirubin also indicate this diagnosis. If cirrhosis is not accurately diagnosed, then downstream complications such as HE, ascites, and resultant infections may also be delayed or missed.

The patient had been in the ER for 8 hours and was finally admitted with diagnoses of cirrhosis, ascites, and HE. He was started on lactulose with some improvement in mental status but still had asterixis the next morning. Fourteen hours after initial presentation, a diagnostic paracentesis showed spontaneous bacterial peritonitis (SBP). His serum creatinine and WBC count had increased to 1.8 mg/dL and 8,600/mL, respectively. The urinalysis was bland, and the renal sonogram was normal. He was started on IV ceftriaxone 2 g daily and IV 25% salt-poor albumin.

Almost 40% of patients admitted with complications of cirrhosis have or acquire infection during hospitalization. Proton pump inhibitor use is associated with an increased risk of infection (4). Infection may not be obvious because patients with cirrhosis may not develop fever or leukocytosis. The most common infection in patients with cirrhosis is SBP, and infection is the most common precipitant of ACLF (5). Therefore, all patients with cirrhosis who present to the ER require a full infectious workup, including a diagnostic paracentesis in patients with ascites, even in the absence of fever and leukocytosis. Delayed diagnostic paracentesis almost triples the risk for in-hospital mortality (6). Because early treatment with antibiotics in patients with cirrhosis and infection improves mortality and every hour counts, the diagnostic evaluation and antibiotic therapy should always be initiated in the ER.

The patient met the criteria for stage 1 acute kidney injury (AKI) because his serum creatinine had increased by ≥0.3 mg/dL within 48 hours. The bland urinalysis and normal sized kidneys on ultrasound may have indicated that the patient had prerenal azotemia that may be responsive to fluid challenge. Diuretics must be held, and nephrotoxic drugs, such as nonsteroidal anti-inflammatory drugs, must be avoided (7). Because the patient had underlying chronic kidney disease, with a baseline serum creatinine of 1.3 mg/dL, the AKI was more likely to progress (8), and therefore, it was imperative that the infection be controlled and intravascular volume be replaced promptly.

The patient continued to be disoriented despite ceftriaxone therapy for 48 hours, and he developed shortness of breath. The serum creatinine was then 3.0 mg/dL, sodium 130 mEq/L, bilirubin 3.5 mg/dL, and INR 1.8. A repeat tap showed a <25% reduction in polymorphonuclears (PMNs). Blood and ascitic fluid cultures from the ER were negative. IV norepinephrine was initiated (because terlipressin was not currently available in the United States). Antibiotics were escalated to meropenem and vancomycin because the ascites PMNs had not decreased by ≥25%.

When choosing first-line antibiotics, the etiology of the infection, mode of acquisition, severity of illness, and local resistance patterns are all important. Despite this patient having a healthcare-associated infection (because he was admitted the past month), he inappropriately received community-acquired SBP antibiotic therapy. Piperacillin-tazobactam is preferred for healthcare-associated SBP with meropenem recommended in geographic regions where multidrug resistant (MDR) gram-negative infections are common. Although repeat paracentesis is not mandatory in patients appropriately responding, it is essential in those not responding after 48 hours or those listed for transplant. Our patient's worsening clinical condition and inadequate decrease in ascitic fluid PMN count document nonresponse and mandate broadening antibiotic coverage. MDR infections in cirrhosis are rising and are an independent risk factor for ACLF. Nonresponse to first-line antibiotic therapy increases the risk for AKI and death (9).

In the interim, the patient's AKI had progressed to at least stage 2 (>doubling of the initial serum creatinine) and he fulfilled all criteria for HRS-AKI; he needed to be started on a vasoconstrictor (10). The most widely used vasoconstrictor for HRS-AKI outside the United States is terlipressin. Terlipressin vasoconstricts the splanchnic vessels and lowers the portal pressure. It also increases the mean arterial pressure (MAP) and, therefore, the renal perfusion pressure (11). When terlipressin is not available, oral midodrine at doses of 7.5–12.5 mg 3 times daily with octreotide (100 to 200 μg subcutaneously 3 times daily) is used. Norepinephrine as a continuous intravenous infusion at a starting dose of 0.5 mg/hr and increased every 4 hours by 0.5 mg/hr to a maximum of 3 mg/hr, with the goal of increasing the MAP ≥10 mm Hg and/or the urine output to >50 mL per hour for at least 4 hours, has been proven superior to midodrine and octreotide but necessitates intensive care unit (ICU) care (12,13).

Although stable the previous evening, the patient was found the following morning to be tachypneic and hypoxic (SpO2: 91%). Chest x-ray revealed a new right lower lobe infiltrate. He was then obtunded and anuric with a MAP of 45 mm Hg. He was transferred to the ICU with a serum creatinine of 4.8 mg/dL and a WBC count of 15,000/mL. Discussions regarding intubation, renal replacement therapy (RRT), and pressor support were undertaken with his wife.

The patient required endotracheal intubation and met the criteria for ACLF with respiratory, circulatory, brain, and renal failures (14,15). The abrupt clinical decline despite optimal treatment of bacterial infection prompted consideration of a superimposed nosocomial MDR bacterial or fungal infection. Repeat cultures with 1,3‐β-D-Glucan testing in serum and addition of antifungal coverage were then indicated. Clearly, the patient's HRS-AKI was not responding to the combination of the vasoconstrictor and albumin, and he had multiorgan failure. The decision whether to start RRT needs to be assessed on a case-by-case basis. In general, RRT for HRS-AKI serves only as a bridge to transplant. Currently, the patient had almost certain mortality in the absence of liver transplantation.

Because then he required organ support to maintain perfusion, oxygenation, and was obtunded, the wife was counseled regarding his poor prognosis, and rapid progression toward this stage made him a suboptimal candidate for liver transplantation.

Early counseling of patients and their family members to provide an insight into the disease process and prognosis is essential. In this case, the situation was even more challenging because this was a new diagnosis of cirrhosis and the patient himself was obtunded. The ICU, hepatology team, and family would benefit from guidance from the palliative care service if available, especially using the NACSELD-ACLF score, which is associated with futility (16–18). This is because liver transplant candidacy depends on multiple factors. Multiorgan failure and the presence of untreated extrahepatic infection, especially fungal infection, argue against proceeding (19). If infection is controlled with decreasing vasopressor support and MELD-Na and the patient is not intubated, this could tilt the balance in favor of proceeding with listing. Regardless, early involvement of palliative care is needed.

Ultimately, our patient died without liver transplant. This case report illustrates several missed opportunities (Table 4 and Figure 1) for intervention that could have potentially avoided progression to ACLF and improved outcome.

T4
Table 4.:
Missed opportunities to prevent progression to ACLF in this case report
F1
Figure 1.:
Missed opportunities for intervention (marked with yellow star) that could have potentially avoided progression to ACLF and improved outcome.

CONFLICTS OF INTEREST

Guarantor of the article: Jasmohan S. Bajaj, MD.

Specific author contributions: All authors contributed equally.

Financial support: None to report.

Potential competing interests: None to report.

REFERENCES

1. Bajaj JS, O'Leary JG, Lai JC, et al. Acute-on-chronic liver failure clinical guidelines. Am J Gastroenterol 2022;117:225–52.
2. Baki JA, Tapper EB. Contemporary epidemiology of cirrhosis. Curr Treat Options Gastroenterol 2019;17:244–53.
3. Sanyal AJ, Van Natta ML, Clark J, et al. Prospective study of outcomes in adults with nonalcoholic fatty liver disease. N Engl J Med 2021;385:1559–69.
4. Wong F, Piano S, Singh V, et al. Clinical features and evolution of bacterial infection-related acute-on-chronic liver failure. J Hepatol 2021;74:330–9.
5. Bajaj JS, Kamath PS, Reddy KR. The evolving challenge of infections in cirrhosis. N Engl J Med 2021;384:2317–30.
6. Kim JJ, Tsukamoto MM, Mathur AK, et al. Delayed paracentesis is associated with increased in-hospital mortality in patients with spontaneous bacterial peritonitis. Am J Gastroenterol 2014;109:1436–42.
7. Wong F, Angeli P. New diagnostic criteria and management of acute kidney injury. J Hepatol 2017;66:860–1.
8. Wong F, Reddy KR, O'Leary JG, et al. Impact of chronic kidney disease on outcomes in cirrhosis. Liver Transpl 2019;25:870–80.
9. Piano S, Singh V, Caraceni P, et al. Epidemiology and effects of bacterial infections in patients with cirrhosis worldwide. Gastroenterology 2019;156:1368–80 e10.
10. Angeli P, Gines P, Wong F, et al. Diagnosis and management of acute kidney injury in patients with cirrhosis: Revised consensus recommendations of the International Club of Ascites. Gut 2015;64:531–7.
11. Wong F, Pappas SC, Curry MP, et al. Terlipressin plus albumin for the treatment of type 1 hepatorenal syndrome. N Engl J Med 2021;384:818–28.
12. El-Desoki Mahmoud EI, Abdelaziz DH, Abd-Elsalam S, et al. Norepinephrine is more effective than midodrine/octreotide in patients with hepatorenal syndrome-acute kidney injury: A randomized controlled trial. Front Pharmacol 2021;12:675948.
13. Wang H, Liu A, Bo W, et al. Terlipressin in the treatment of hepatorenal syndrome: A systematic review and meta-analysis. Medicine (Baltimore) 2018;97:e0431.
14. O'Leary JG, Reddy KR, Garcia-Tsao G, et al. NACSELD acute-on-chronic liver failure (NACSELD-ACLF) score predicts 30-day survival in hospitalized patients with cirrhosis. Hepatology 2018;67:2367–74.
15. Moreau R, Jalan R, Gines P, et al. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology 20131437;144:1426–37, 1437.e1–9.
16. Rogal S, Hansen L, Patel A, et al. AASLD practice guidance: Palliative care and symptom-based management in decompensated cirrhosis. Hepatology Published online February 1, 2022 (doi: 10.1002/hep.32378.).
17. Wong F, Reddy KR, Tandon P, et al. The prediction of in-hospital mortality in decompensated cirrhosis with acute-on-chronic liver failure. Liver Transpl 2022;25:570–80.
18. Cao Z, Liu Y, Cai M, et al. The use of NACSELD and EASL-CLIF Classification Systems of ACLF in the prediction of prognosis in hospitalized patients with cirrhosis. Am J Gastroenterol 2020;115:2026–35.
19. Sundaram V, Jalan R, Wu T, et al. Factors associated with survival of patients with severe acute-on-chronic liver failure before and after liver transplantation. Gastroenterology 2019;156:1381–91.e3.
© 2022 by The American College of Gastroenterology