The Growing Economic and Clinical Burden of Nonalcoholic Steatohepatitis (NASH) in the United States

Younossi, Zobair M.; Paik, James; Henry, Linda; Yang, Joe; Fernandes, Gail; Stepanova, Maria; Nader, Fatema

doi:10.1016/j.jceh.2022.12.005

Cited by 24 publications

(14 citation statements)

References 47 publications

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“… 20 In the United States, the number of people with NASH was predicted to reach 19.53 million by 2039. 21 Nowadays, NAFLD/NASH is considered to be greatly driven by altered metabolism, whereby many metabolic factors are involved. 22 To further strengthen the consensus from the field, in June 2023, the European Association for the Study of the Liver (EASL) Congress announced the new nomenclatures MASH (metabolic dysfunction-associated steatohepatitis) and MASLD (metabolic dysfunction-associated steatotic liver disease) to replace NASH and NAFLD, respectively.…”

Section: Clinical Presentation and Diagnosismentioning

confidence: 99%

Oligonucleotide therapies for nonalcoholic steatohepatitis

Li,

Xiong,

Zhang

et al. 2024

Molecular Therapy - Nucleic Acids

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Section: Clinical Presentation and Diagnosismentioning

confidence: 99%

Oligonucleotide therapies for nonalcoholic steatohepatitis

Li,

Xiong,

Zhang

et al. 2024

Molecular Therapy - Nucleic Acids

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“…Numerous economic studies from around the world have found that there is a tremendous economic burden associated with NAFLD and NASH, especially when advanced liver disease is present ( 12 , 59 – 64 ). Additionally, the presence of type 2 diabetes, CVD, and renal impairment can increase costs substantially ( 12 , 61 ).…”

Section: Patient-reported Outcomes Economic Burden and Awarenessmentioning

confidence: 99%

Understanding the Burden of Nonalcoholic Fatty Liver Disease: Time for Action

Younossi,

Henry

2024

Diabetes Spectrum

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The prevalence of nonalcoholic fatty liver disease (NAFLD) in the United States is 38%, having increased by 50% within the past 3 decades. The estimated NAFLD prevalence among people with type 2 diabetes is 55–70%. The presence of type 2 diabetes is associated with a higher likelihood of progression of NAFLD to fibrosis development, liver transplant, and death. Cardiovascular disease is the main cause of mortality among people with NAFLD, and the risk of death is significantly higher in people with both NAFLD and type 2 diabetes. NAFLD carries high patient and economic burdens but low awareness among both the general public and health care providers. This article reviews the epidemiology of NAFLD and discusses the need for appropriate risk stratification, referral for specialty care, management of cardiometabolic risk factors, and treatment of the disease. The authors present a call to action to raise awareness of NAFLD and address its increasing burden in a systematic and efficient manner.

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“…The incidence of nonalcoholic fatty liver disease (NAFLD) is increasing to epidemic levels 1 . Among those with NAFLD, 10% to 30% will progress to nonalcoholic steatohepatitis (NASH), which is characterized by liver injury, hepatic steatosis, necroinflammation, and, most importantly, liver fibrosis due to activation of hepatic stellate cells (HSCs) 2,3 .…”

Section: Introductionmentioning

confidence: 99%

Loss of TIM4-Dependent Efferocytosis in Kupffer Cells Promotes Liver Fibrosis in Nonalcoholic Steatohepatitis

Shi,

Wang,

Gerlach

et al. 2024

Preprint

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Background and aimsHepatocyte apoptosis is a key feature of non-alcoholic steatohepatitis (NASH), but the fate of apoptotic hepatocytes in NASH is poorly understood. Herein we explore the hypothesis that impaired TIM4-mediated clearance of dead hepatocytes by liver macrophages (efferocytosis) is impaired in NASH and drives the progression to liver fibrosis.MethodsKupffer cell (KC)-TIM4 expression and efferocytosis were assayed in normal and NASH liver from humans and diet-induced NASH mice. The engulfment of human and mouse apoptotic hepatocytes by primary human and mouse liver KCs was assayedex vivo. Causation was assessed in NASH mice using anti-TIM4 antibodies, KC-TIM4-knockout, or inducible KC-TIM4 expression, with analyses focused on efferocytosis of apoptotic hepatocytes by liver macrophages and liver fibrosis.ResultsIn human and mouse NASH liver, apoptotic hepatocytes accumulated and was associated with the loss of the KC efferocytosis receptor TIM4. Anti-TIM4 inhibited the engulfment of apoptotic hepatocytes by primary human and mouse liver KCsex vivo, and anti-TIM4 administration to early NASH mice worsened liver macrophage efferocytosis and accelerated the progression to fibrotic NASH. A similar result was obtained by genetically deleting TIM4 in KCs in NASH mice. Most importantly, genetic restoration of macrophage TIM4 in NASH mice enhanced the clearance of apoptotic hepatocytes by liver macrophages and decreased liver fibrosis.ConclusionsThe loss of macrophage TIM4 that occurs during NASH progression impairs the clearance of apoptotic hepatocytes by liver macrophages, which subsequently promotes the progression to fibrotic NASH. This pathogenic sequence of events can be prevented by restoring macrophage TIM4, suggesting that future therapeutic approaches designed to boost TIM4 expression in liver macrophages could represent a novel strategy to prevent fibrotic NASH progression.Lay summaryNonalcoholic steatohepatitis (NASH) is emerging as the leading cause of liver disease, but the processes leading to liver fibrosis in NASH, which determines clinical outcome, are incompletely understood. Our study provides evidence impaired clearance of dead liver cells by liver macrophages in NASH, which is due to loss of a macrophage receptor called TIM4, contributes to liver fibrosis. Knowledge of this process may suggest new ways to bolster the clearance of dead liver cells in NASH and thereby prevent the progression to liver fibrosis and subsequent liver disease.

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The Growing Economic and Clinical Burden of Nonalcoholic Steatohepatitis (NASH) in the United States

Cited by 24 publications

References 47 publications

Oligonucleotide therapies for nonalcoholic steatohepatitis

Oligonucleotide therapies for nonalcoholic steatohepatitis

Understanding the Burden of Nonalcoholic Fatty Liver Disease: Time for Action

Loss of TIM4-Dependent Efferocytosis in Kupffer Cells Promotes Liver Fibrosis in Nonalcoholic Steatohepatitis

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