Is higher body mass index correlated with worse clinical outcomes in acute liver failure?

Abstract

Krishnan et al’s article is a comprehensive and vigorous retrospective cohort study regarding the association between obesity and clinical outcomes in acute liver failure (ALF). Among patients with ALF in the United States, mean body mass index (BMI) was significantly greater in those who underwent liver transplantation or who died than among survivors, although acetaminophen induced ALF was the most common etiology. A high BMI was associated with renal failure and high grades of hepatic encephalopathy. The prevalence of obesity and its related fatty liver diseases, such as metabolic dysfunction-associated fatty liver disease/ metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis, has increased worldwide. Obesity is related to increased serum cytokines and immune abnormalities. These findings may explain why ALF in patients with high BMI is associated with worse clinical outcomes. Further studies are needed to determine the associations among BMI, ALF and acute-on-chronic liver failure.

Key Words: Obesity; Fatty liver; Body mass index; Acute-on-chronic liver failure; Acute liver failure; Acetaminophen

Core Tip: Association between obesity and clinical outcomes in acute liver failure (ALF) was recently shown by Krishnan et al. Kaplan-Meier analysis revealed a significant difference in mortality between overweight and obese patients and patients with normal body mass index (BMI). Overweight and obese patients with ALF had a 2.20-fold and 2.04-fold increased risk of liver transplantation/death, respectively. A higher BMI was associated with acute kidney injury and higher grades of hepatic encephalopathy. Further studies are needed to determine the distribution of BMI among patients with acute severe hepatitis, including ALF and acute-on-chronic liver failure.

TO THE EDITOR

We have read with great interest, the article by Krishnan et al[1]. Whether obesity is associated with the severity of acute hepatitis has been previously examined[2,3]. Kanda et al[2] retrospectively analyzed the body mass index (BMI) in patients with severe acute hepatitis [n = 38; mean age: 43.7 years; 52.6% male (hepatitis A virus, n = 9; hepatitis B virus, n = 11; hepatitis C virus, n = 0; drug-induced hepatitis, n = 3; unknown etiology, n = 15)] and in those with non-severe acute hepatitis [n = 31; mean age: 43.4 years; 64.5% male (hepatitis A virus, n = 7; hepatitis B virus, n = 4; hepatitis C virus, n = 3; drug-induced hepatitis, n = 3; unknown etiology, n = 14)] in Japan, where factors other than acetaminophen toxicity are major causes of severe acute hepatitis. They consisted of 69 Asian patients, mostly Japanese, between January 1995 to December 2001. Severe acute hepatitis is defined as acute hepatitis and a plasma prothrombin level of < 40% with or without hepatic encephalopathy within 24 weeks of onset[2]. Patients with previous chronic hepatitis or alcoholic liver diseases were excluded from this study[2]. Although there were no other differences between the groups, 2 (5.3%) of the 38 patients with severe obesity (BMI > 35 kg/m²) were found only in the severe acute hepatitis group, suggesting that severe obesity may be one of the risk factors for severe acute hepatitis[2].

Rutherford et al[3] examined the influence of high BMI on outcomes in patients with acute liver failure (ALF). They prospectively enrolled 782 adult patients with ALF, and they examined 573 BMI-recorded patients with ALF between January 1, 1998 to December 31, 2004 in the United States, where acetaminophen is a major cause of severe acute hepatitis. All patients included in that study had, by definition, an international normalized ratio > 1.5, evidence of hepatic encephalopathy and an illness of less than 26 weeks with no history of chronic liver disease[3].

Mean BMI for patients who underwent liver transplantation or died (n = 318; mean age: 39.8 years; 66.7% female; 71.9% white; BMI: 28.8 ± 8.3 kg/m²; acetaminophen, 31.1%; drug-induced liver injury, 15.4%; viral hepatitis, 12.6%; indeterminate, 19.5%; autoimmune hepatitis, 9.1%; acute fatty liver of pregnancy, 0.3%; Wilson disease, 3.8%; and other, 8.2%) was significantly greater than that of spontaneous survivors (n = 255; mean age: 38.7 years; 65.5% female; 82.1% white; BMI: 26.6 ± 7.1 kg/m²; acetaminophen, 64.7%; drug-induced liver injury, 5.5%; viral hepatitis, 9.8%; indeterminate, 9.4%; autoimmune hepatitis, 2.4%; acute fatty liver of pregnancy, 1.2%; Wilson disease, 0% and other, 7.1%; P = 0.0001).

Compared with that of adult Americans in the NHANES III database (30.4%), 167 (29.1%) adult patients with ALF were obese (P = 0.542). Obese patients (BMI ≥ 30 kg/m², 67.1%) underwent liver transplantation or died more often than nonobese patients did (BMI < 30 kg/m², 50.7%; P = 0.0004). Severely obese patients (BMI ≥ 35 kg/m²) with ALF underwent liver transplantation or died more often than those with a BMI < 35 kg/m² (odds ratio = 1.93, 95% confidence interval: 1.02-3.62; P = 0.042)[3].

Krishnan et al[1] included 196 consecutive patients in the United States in the Johns Hopkins Health System between January 1, 2000 to May 1, 2020. ALF was diagnosed based on the American Association for the Study of Liver Diseases guidelines[4]. Mean BMI was significantly greater among patients who underwent liver transplantation or died than survivors (26.6 kg/m²vs 29.7 kg/m²; P = 0.008). This retrospective analysis revealed that the median age was 43.5 (30-56.5) years, with 63.3% female and 59.7% Caucasian. In terms of ALF, 45.4% were due to acetaminophen toxicity, 10.7% to drug-related hepatitis, 8.7% to viral hepatitis, and 35.2% were due to other etiologies[1].

Kaplan-Meier analysis revealed a significant difference in mortality between overweight (BMI: 25.0-29.9 kg/m²) and obese patients (BMI ≥ 35 kg/m²) compared with patients with a normal BMI (BMI: 18.5-24.9 kg/m²)[1]. Overweight or obese patients with ALF had a 2.20-fold or 2.04-fold increased risk of liver transplantation/death, respectively[1]. A higher BMI was related to acute kidney injury and higher grades of hepatic encephalopathy. More attention should be given to preventing complications, including hepatic encephalopathy and renal dysfunction, in overweight or obese patients with ALF. Overweight patients are more susceptible to acute-on-chronic liver failure (ACLF)[5]. ALF and ACLF, which are fatal severe liver diseases without transplantation, have emerged as critical global health challenges and exhibit rapid progression and high short-term mortality[6-8]. The prevalence of obesity and its related liver diseases, such as metabolic dysfunction-associated fatty liver disease/metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis, has increased worldwide[9]. Immune dysregulation, including abnormal cytokine secretion, caused by obesity is observed[10,11]. We should also examine BMI’s association with the severity of acute hepatitis, including ALF and ACLF, caused by nonacetaminophen etiologies, such as viruses, autoimmune or drugs, including immune checkpoint inhibitors. In conclusion, further studies in addition to the recent data by Krishnan et al[1] are needed to determine the distribution of BMI among patients with ALF and ACLF.