Obesity and Liver Decompensation

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Abbreviations

ACLF

acute‐on‐chronic liver failure

BMI

body mass index

ESLD

end‐stage liver disease

IL

interleukin

LT

liver transplantation

UNOS

United Network for Organ Sharing

Along with the growing epidemic of obesity, the prevalence of obesity is rapidly increasing among patients with end‐stage liver disease (ESLD) in the United States. The proportion of obese patients among liver transplant recipients increased from 20% between 1988 and 1996 to 33% between 2001 and 2011.1 Obesity presents challenges before and after liver transplantation (LT) because of high rates of comorbidities and unique challenges with perioperative and postoperative care (Fig. 1).1 Obesity itself can cause nonalcoholic steatohepatitis, leading to ESLD, hepatocellular carcinoma, and death, and there is increasing evidence of a deleterious effect of obesity on preexisting chronic liver disease caused by hepatitis C, hepatitis B, or alcohol‐related liver disease.2 Multiple studies have found obesity to be associated with significant morbidity and mortality among patients with ESLD. In addition to increased liver transplant wait‐list mortality, obesity has also been identified to be an independent risk factor for liver decompensation and infection in cirrhosis, as well as acute‐on‐chronic liver failure (ACLF).2, 3, 4, 5 Therefore, proper understanding and management of this high‐risk population of patients with ESLD is essential to improve clinical outcomes.

Figure 1.

Conceptual diagram of the pretransplant, peritransplant, and posttransplant challenges in the obese patient with liver transplant.

Proposed Physiology

Acute liver decompensation is defined by acute development of one or more major complications of liver disease (i.e., ascites, hepatic encephalopathy, gastrointestinal hemorrhage, bacterial infection), and can be further complicated by organ failures and high short‐term mortality in a syndrome referred to as ACLF.6 Acute liver decompensation, especially in the form of ACLF, is characterized to be a state of excessive systemic inflammation and immune dysregulation. Studies looking at molecular profiles in patients with ACLF have shown markedly increased levels of circulating proinflammatory cytokines and chemokines.7 An association between obesity and increased risk for acute decompensation and ACLF is that obesity is also a state of systemic inflammation. Human adipocytes express many proinflammatory cytokines/chemokines that induce inflammation and activate CD4⁺ T cells independent of macrophages, and the inflammatory cells infiltrating the obese adipose tissue also release cytokines, including tumor necrosis factor‐α, interleukin (IL)‐1, IL‐6, adiponectin, and resistin, which act on immune cells to promote local and generalized inflammation.8 Therefore, obese patients have a greater reservoir of inflammatory cytokines compared with nonobese patients, which increases their risk for acute decompensation and ACLF via systemic inflammatory response.

Obesity and Outcomes

The pathophysiological association between obesity and liver decompensation translates into adverse patient outcomes in the clinical setting. In 2011, Berzigotti et al.2 found that the proportion of patients with compensated cirrhosis who suffered clinical decompensation increased with increasing baseline body mass index (BMI) (Fig. 2). This was the first study that exhibited a deleterious role of obesity on the natural history of compensated cirrhosis of all causative factors, independent of portal pressure and liver function.2 A recent United Network for Organ Sharing (UNOS) registry study evaluating LT wait‐list mortality in obese patients showed significantly higher wait‐list mortality for LT candidates with BMI of 40 kg/m² or greater as compared with those with a BMI less than 30 kg/m², with a higher cumulative incidence of wait‐list mortality at 1 and 3 years.3 Bacterial infection is the leading cause of acute decompensation and mortality in patients with ESLD. Retrospective studies of large patient databases also show that obesity is independently associated with increased risk for infection among patients with ESLD,4 as well as increased in‐hospital mortality among critically ill patients with ESLD.9 A recent study of UNOS and Nationwide Inpatient Sample registries also identified class III obesity (BMI ≥ 40) to be an independent risk factor for the development of ACLF.5 In addition, morbidly obese patients with ESLD are also at a paradoxically higher risk for sarcopenia, which is a significant risk factor for increased mortality on the liver transplant wait list.10 It is thought that an obesity‐associated increase in proinflammatory cytokines leads to increased skeletal muscle catabolism and contributes to development of sarcopenia.11 Furthermore, obesity is also associated with undesirable perioperative outcomes, including longer intraoperative time during transplantation, higher rates of wound infection, wound dehiscence, biliary complications, and perioperative respiratory failure.1

Figure 2.

(A) Proportion of patients experiencing first clinical decompensation according to BMI group. Obesity was associated with a significantly higher proportion of clinical decompensation in a median follow‐up of 59 months. (B) Probability of first clinical decompensation of cirrhosis according to BMI group. As shown, obese patients had the highest probability of decompensation, and patients with a normal BMI had the lowest probability of decompensation, with overweight patients having an intermediate probability. Differences among groups were statistically significant (log‐rank 7.60; P = 0.022).

Assessment of Obesity

It must be emphasized that solely relying on BMI alone to manage obesity in patients with ESLD may not be ideal. It is difficult to correctly define and categorize obesity based on BMI alone in patients with ESLD because of their variable volume status, which can significantly affect their BMI.1 Studies have shown that correcting BMI for ascites moved 11% to 20% of patients into lower BMI classes.12 Even after correcting for volume status, BMI alone may not be an accurate predictor of risks because it does not account for the distribution of fat deposition and presence of sarcopenia. A study of 384 LT recipients found that visceral adiposity, but not peripheral adiposity, was associated with increased mortality after LT, particularly among patients with sarcopenia.13 Given the challenges of BMI in accurately assessing obesity and obesity‐related risk factors, a comprehensive assessment including frailty, sarcopenia, and visceral adiposity should be advocated to predict outcomes in obese patients with cirrhosis.1

Obesity Management

Given the clear association between obesity and poor outcomes in patients with ESLD, weight reduction should be a common goal in morbidly obese patients with compensated cirrhosis. Lifestyle interventions alone can lead to effective weight loss if implemented in the right settings. One prospective cohort study on patients with median BMI of 40 kg/m² showed that an intensive weight loss program without bariatric surgery led to 84% success in achievement of target BMI less than 35 kg/m².14 For those with compensated cirrhosis who are unable to reach an acceptable weight via lifestyle modifications alone, bariatric surgery such as sleeve gastrectomy can be a viable and effective option. In contrast, for morbidly obese patients with decompensated cirrhosis, weight loss via either lifestyle modifications or bariatric surgery is not recommended, because these patients are at high risk for sarcopenia, frailty, and malnutrition, which may be worsened by reduction in calorie/nutrition intake.1 Patients with decompensated cirrhosis should maintain caloric intake with higher‐protein, nutrient‐rich foods and engage in frequent low‐impact exercise to prevent catabolism and preserve muscle mass.

Conclusion

Obesity is a state of systemic inflammation and immune dysregulation associated with adverse clinical outcomes in patients with ESLD, including acute decompensation, increased wait‐list mortality, and perioperative complications. A careful, individualized approach to weight loss and nutrition optimization according to the patient’s degree of hepatic decompensation is essential for management of these high‐risk patients.