Liver diseases: epidemiology, causes, trends and predictions

Abstract

As a highly complex organ with digestive, endocrine, and immune-regulatory functions, the liver is pivotal in maintaining physiological homeostasis through its roles in metabolism, detoxification, and immune response. Various factors including viruses, alcohol, metabolites, toxins, and other pathogenic agents can compromise liver function, leading to acute or chronic injury that may progress to end-stage liver diseases. While sharing common features, liver diseases exhibit distinct pathophysiological, clinical, and therapeutic profiles. Currently, liver diseases contribute to approximately 2 million deaths globally each year, imposing significant economic and social burdens worldwide. However, there is no cure for many kinds of liver diseases, partly due to a lack of thorough understanding of the development of these liver diseases. Therefore, this review provides a comprehensive examination of the epidemiology and characteristics of liver diseases, covering a spectrum from acute and chronic conditions to end-stage manifestations. We also highlight the multifaceted mechanisms underlying the initiation and progression of liver diseases, spanning molecular and cellular levels to organ networks. Additionally, this review offers updates on innovative diagnostic techniques, current treatments, and potential therapeutic targets presently under clinical evaluation. Recent advances in understanding the pathogenesis of liver diseases hold critical implications and translational value for the development of novel therapeutic strategies.

Fig. 1

Worldwide distribution of liver disease prevalence. Prevalence of (a) drug-induced liver injury (DILI), (b) hepatitis B virus infection (HBV), (c) hepatitis C virus infection (HCV), (d) metabolic dysfunction-associated steatotic liver disease (MASLD), (e) alcohol-associated liver disease (ALD), (f) primary sclerosing cholangitis (PSC), (g) liver cirrhosis, and (h) hepatocellular carcinoma (HCC) are displayed

Fig. 2

a Hepatic and extrahepatic manifestations associated with various liver diseases. b Histological progression from normal liver to hepatocellular carcinoma (HCC). Representative hematoxylin and eosin (H&E) stained sections illustrate the stages from normal liver to ballooning degeneration, alcoholic hepatitis, chronic hepatitis, and HCC. Sirius Red staining was used to visualize fibrosis and cirrhosis. Written informed consent was obtained from all patients involved. The study was approved by the Ethical Committee of West China Hospital and registered in the Chinese Clinical Trial Registry (ChiCTR2200063108). Created in BioRender. Yuan, Y. (2024) BioRender.com/o74p618

Fig. 3

RIG-1/MAVS, cGAS/STING, and AMPK signaling in liver diseases. When hepatotropic viruses such as HCV and HBV infect the liver, RIG-1/MAVS and cGAS/STING signaling pathways are activated. Both pathways promote the expression of IFN and other inflammatory cytokines by the phosphorylation of IRF-3/7 and NF-κB, respectively. These cytokines perform essential roles in antiviral defense and liver inflammation. AMPK, serving as an energy sensor, regulates various cellular physiological processes. Upon exposure to excessive energy or ethanol, decreased AMPK activity and fat accumulation are observed in hepatocytes. However, activation of AMPK in the liver decreases lipogenesis and cholesterol synthesis, and cell apoptosis, while promoting fatty acid oxidation, autophagy flux, and mitochondria biogenesis. These effects help attenuate the development of MASLD and ALD. This figure was generated with Adobe Illustrator

Fig. 4

MAPK, PI3K/Akt, and JAK/STAT signaling in liver injury. When liver injury occurs, activated MAPK signaling promotes gluconeogenesis but has bilateral effects on liver lipid metabolism. It enhances liver inflammation by targeting key transcription factors, including activator protein 1 (AP-1) and NF-κB, and promotes HCC and ICC by encouraging tumor cell proliferation and migration. Additionally, MAPK plays a role in antiviral defense by activating the expression of IFN and ISGs. PI3K/Akt signaling promotes liver lipid and glucose metabolism by targeting key transcription factors and enzymes, and similarly promotes liver inflammation and cancer. JAK/STAT signaling is essential for the elimination of hepatotropic viruses through the induction of IFN and ISGs. STAT proteins have bidirectional roles in liver inflammation and cancer. Specifically, STAT1 promotes inflammation, whereas STAT3 exhibits both pro-inflammatory and anti-inflammatory signals. STAT1 prevents HCC development, whereas STAT3 contributes to the liver tumorigenesis. This figure was generated with Adobe Illustrator

Fig. 5

TGF-β and Wnt/β-catenin canonical signaling in liver diseases. Upon liver injury, TGF-β secreted from other liver cell types binds to its receptor TGF-βRII, which subsequently recruits TGF-βRI to synergistically mediate downstream pathways: canonical SMAD-dependent pathway and non-SMAD pathways. In canonical pathway, the SMAD oligomers translocate into the nucleus, where they function as transcription factors, mediating the transcriptional activation. In non-SMAD pathway, PI3K/Akt and MAPK pathways are activated by TGF-βRs. These pathways induce expression of genes, such as α-SMA, Collagens, fibronectin, TIMP-1, LOXL-1, and Kindlin-2, leading to HSC activation, ECM production and stabilization, and cell adhesion. These processes collectively promote liver fibrosis. In a healthy liver, Wnt signaling is typically inactive due to the absence of Wnt-Wnt receptor interactions and the degradation of β-catenin by a protein complex, which includes axis inhibition protein (AXIN), adenomatous polyposis coli (APC), and E3 ubiquitin ligase. During liver oncogenic injury, Wnt proteins bind to Fzd receptor and LRP-5/6 co-receptors, activating the canonical pathway. This activation causes degradation complex to translocate to the cell membrane, preventing the degradation of β-catenin. The β-catenin then enters the nucleus, where it binds with TCF/LEF transcription factors to regulate target gene expression, such as c-Myc, cyclin-D1 and pyruvate kinase M2 (PKM-2). These genes are involved in promoting tumor cell metabolism, proliferation, migration, and metastasis in HCC and ICC. This figure was generated with Adobe Illustrator

Fig. 6

Comprehensive evaluation and therapeutic protocols for acute liver injury. The general diagnostic procedures for acute liver injury encompass etiological screening, identification of liver injury patterns, and assessment of severity. Based on the extent of hepatic damage, appropriate treatment modalities are employed, including causative factor elimination, supportive care administration, utilization of hepatoprotective agents, artificial liver support and liver transplantation. R = (ALT/ULN)/(ALP/ULN). This figure was generated with Adobe Illustrator

Fig. 7

Etiological diagnostic approach for steatotic liver disease. The diagnosis of steatotic liver disease necessitates the integration of medical history (hypertension, T2DM, viral hepatitis, etc.), lifestyle styles (such as alcohol consumption), physical examination (body mass index, blood pressure, etc.), laboratory tests (triglycerides, glycated hemoglobin, ALT, AST, etc.), and pathological examination. This approach is based on expert opinion of the authors and evidence from published data. This figure was generated with Adobe Illustrator

Fig. 8

Strategy for HCC treatment with BCLC staging system. The Barcelona Clinic Liver Cancer (BCLC) staging system categorizes hepatocellular carcinoma into five stages (0/A to D) with varying prognostic significance. The authors have provided a concise summary of the recommended first and second treatment options based on the BCLC stage. ECOG PS, Eastern Cooperative Oncology Group performance status; SBRT, stereotactic body radiation therapy. This figure was generated with Adobe Illustrator