Metabolic dysfunction-associated steatotic liver disease (MASLD) is a continuum of hepatic pathological manifestations of the metabolic syndrome. Pathogenesis is not clearly understood despite recent progress, but Kupffer cells and bone marrow-derived macrophages (BMDMs) have a fundamental role. In this review, the multiple pathophysiological aspects of MASLD are presented, including genetics, insulin resistance, lipotoxicity, and inflammation. The participation of innate and adaptive immunity, as well as the implications of the recently described trained immunity, is presented. The interplay of the liver with the gut microbiota is also analyzed. A recent adipocentric theory and the various mechanisms of hepatocyte death are also described. The fundamental role of Kupffer cells and other liver macrophages is discussed in detail, including their extreme phenotypic plasticity in both the normal and the MASLD liver. The functional differentiation between pro-inflammatory and anti-inflammatory subpopulations and their protective or detrimental involvement is further described, including the participation of Kupffer cells and BMDMs in all aspects of MASLD pathogenesis. The role of macrophages in the development of advanced MASLD, including fibrosis and hepatocellular carcinoma, is analyzed and the lack of explanation for the transition from MASLD to MASH is recognized. Finally, current modalities of drug treatment are briefly presented and the effects of different drugs on macrophage polarization and functions are discussed.

Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection remain a world health problem leading to fibrosis and cirrhosis. Liver damage is primarily mediated by the innate and adaptive immune responses since HBV and HCV are not directly cytotoxic. Kupffer cells and liver-recruited macrophages are heavily implicated in both viral elimination and progression of the disease. HBV and HCV proteins polarize macrophages into either an M1 pro-inflammatory phenotype, promoting hepatocyte damage or into an M2 immunosuppressive phenotype, leading to viral persistence and fibrogenesis via cytokines such as interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β). In this review a brief overview of the heterogeneity of liver macrophages in health and during chronic viral infection is presented. Recognition of viruses by macrophages and the modulation of macrophages by viral proteins in the pathogenesis of liver inflammation and injury are discussed in detail. Most importantly, the mechanisms that HBV and HCV are using to manipulate macrophages and escape elimination are also presented. The role of macrophages in the evolution of acute-on-chronic liver failure is analyzed. Finally, a concise presentation of the emerging, but not yet clinically used, therapeutic strategies targeting macrophages to control chronic HBV infection and restore the dysregulated immune response is discussed. In conclusion, this integrated review of liver macrophage implication summarizes the pathophysiology and pathogenesis of HBV and HCV including acute-on-chronic- liver failure and viral cirrhosis.

Background. Somatostatin and its synthetic analog octreotide are suppressive hormones that have been used in the treatment of variceal bleeding or bleeding from portal hypertensive gastropathy. They are also used in the treatment of some cancers, including hepatocellular carcinoma (HCC). Experimental evidence reported that they have potentially useful effects on liver inflammation and fibrosis, acting on Kupffer cells (KCs) and hepatic stellate cells (HSCs). However, clinical data is missing. Therefore, the effect of somatostatin and octreotide was studied on several fibrosis mediators in patients with compensated cirrhosis. Patients and Methods. Fifty-eight patients with HCV-related compensated cirrhosis treated with either somatostatin or octreotide for bleeding from portal gastropathy were compared with twenty-nine healthy controls matched for age and sex. Serum levels of three metalloproteases (MMP1, MMP2 and MMP9) and their inhibitors, TIMP1 and TIMP2, were measured. Additional fibrosis and inflammation mediators—such as nitric oxide (NO), TNFα, soluble ICAM-1, and the CC chemokines RANTES (CCL5) and MIP1a (CCL3)—were also measured. Results. Serum levels of MMP1, MMP2, MMP9 and TIMP1 were significantly decreased in cirrhosis (p < 0.01). TIMP2 levels were increased (p < 0.01). RANTES levels were also significantly decreased (p < 0.01), but NO, TNFα, MIP1a and sICAM-1 were significantly increased (p < 0.01). Administration of somatostatin had no effect on MMP2 or MMP9 but significantly decreased all other mediators. Octreotide had similar but milder effects, but it had no effects on MIP1a and sICAM-1 were demonstrated. Conclusions. Somatostatin and octreotide modulate factors implicated in the progression of fibrosis in the short term. Whether they could be used in the long term as treatment for liver diseases with progressive fibrosis or in cases with intense inflammatory reactions, such as alcoholic hepatitis, requires further investigation.

Growth factors play a significant role in the immunopathogenesis of liver diseases, especially liver cirrhosis and hepatocellular carcinoma (HCC). The somatostatin analog octreotide has been used as treatment in advanced HCC, based on its anti-neoplastic effects in vitro. Therefore, the effect of somatostatin and octreotide was studied on several growth factors in patients with HCC. Nineteen patients with advanced HCC were treated with octreotide and compared with thirty-seven patients with viral cirrhosis (19 decompensated) treated with intravenous somatostatin for severe bleeding from portal gastropathy. Five growth factors, namely Gastrin, Insulin-like growth factor 1 (IGF 1), Hepatocyte growth factor (HGF), Stem cell factor (SCF) and Vascular endothelial growth factor (VEGF) were measured in serum before and after treatment with specific commercially available ELISAs. Seventeen healthy individuals and nineteen patients with chronic viral hepatitis C (CAH) were used as pre-treatment controls. Eighteen patients with advanced Primary Biliary Cholangitis (stage III and IV) before and after Ursodeoxycholic acid (UDCA) treatment were also studied. Pre-treatment levels of Gastrin were significantly increased in HCC, cirrhosis and PBC but not in CAH. Levels were significantly reduced by octreotide or somatostatin but also by UDCA in PBC. By contrast, IGF1 showed a mirror image being significantly reduced in HCC, cirrhosis and PBC, but not in CAH. Post-treatment levels were reduced in all groups, but not in PBC. Levels of HGF were significantly increased in HCC and cirrhosis but not in CAH and PBC. They were further increased in HCC after treatment. SCF increased only in HCC and was reduced after octreotide but not after somatostatin treatment. VEGF was reduced in cirrhosis and CAH but not in PBC. It was not significantly increased in HCC, but it was reduced by octreotide and was increased after UDCA. In this retrospective observational study, somatostatin and its analog octreotide have a significant effect on several growth factors involved in HCC pathogenesis.