MUDr. Dana Maňasková


Vyhledávání na medicinman.cz
 

Patofyziologie

Adiponectin

  • Is involved in NAFLD pathology
  • By affecting insulin resistance (Ishtiaq et al., 2019)
  • Changes in fat mass may lead to a decline in adipokine production
  • Impeding adipokine production can impact liver metabolism and hepatic insulin sensitivity (Stern et al., 2016).
  • adiponectin levels are significantly lower in patients with NAFLD than in healthy controls (Ebrahimi et al., 2018).
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC9007706/

Ferritin

  • Multivariate analysis identified hsCRP and liver fat content as independent predictors of serum ferritin in the pediatric male patients.
  • Our data indicate that serum ferritin in male adolescents with obesity is mainly determined by liver fat content and inflammation but not by body iron status.
  • pubmed.ncbi.nlm.nih.gov/32625166/
  • Hyperferritinemia in patients with nonalcoholic fatty liver disease
  • Relationship between ferritin elevated serum levels and NAFLD/NASH with and without fibrosis and insulin resistance.
Raffaelle K Barros 1, Helma Pinchemel Cotrim 1, Carla H Daltro 1, Yanaihara A Oliveira 1, PMID: 28489136 DOI: 10.1590/1806-9282.63.03.284

  • Hyperferritinemia, iron overload, and multiple metabolic alterations identify patients at risk for nonalcoholic steatohepatitis
  • Increased ferritin with normal transferrin saturation
    • Frequently found in patients with hepatic steatosis
    • Reflects iron overload only in those patients in whom it persists despite an appropriate diet
  • Simultaneous disorder of iron and glucose and/or lipid metabolism
    • In most of the cases associated with insulin resistance
    • Responsible for persistent hyperferritinemia and identifies patients at risk for NASH.
S Fargion 1, M Mattioli, A L Fracanzani, M Sampietro, D Tavazzi, P Fociani, E Taioli, L Valenti, G Fiorelli, PMID: 11513189 DOI: 10.1111/j.1572-0241.2001.04052.x

  • Increased susceptibility to nonalcoholic fatty liver disease in heterozygotes for the mutation responsible for hereditary hemochromatosis.
Valenti L, Dongiovanni P, Fracanzani AL, Santorelli G, Fatta E, Bertelli C, Taioli E, Fiorelli G, Fargion S., Dig Liver Dis. 2003 Mar;35(3):172-8. doi: 10.1016/s1590-8658(03)00025-2.

  • Ferritin as a key risk factor for nonalcoholic fatty liver disease in children with obesity
  • Adjusted ORs were
    • 3.298 (95% CI:1.326-8.204),
    • 7.322 (95% CI:2.725-19.574) across the ferritin concentration tertiles after adjustment for confounders.
  • Ferritin was shown to be the best predictor for NAFLD with sensitivity and specificity of 60.0% and 77.9%
Junfeng Zhang 1 2, Jiajia Cao 1 2, Hui Xu 1 2, Guanping Dong 2 3, Ke Huang 2 3, Wei Wu 2 3, Jingjing Ye 2 4, Junfen Fu 2 3, PMID: 33249617 PMCID: PMC7891541 DOI: 10.1002/jcla.23602

  • Metabolic hyperferritinaemia
    • Alterations in iron metabolism
    • Facilitate iron accumulation in the body
    • Associated with an increased risk of cardiometabolic and liver diseases
  • Genetic variants that modulate iron homeostasis and tissue levels of iron
    • Main determinants of serum levels of ferritin in individuals with metabolic dysfunction
    • Hypothesis that iron accumulation might be implicated in the pathogenesis of insulin resistance and the related organ damage
  • no clear evidence of a benefit for iron depletion therapy
  • pubmed.ncbi.nlm.nih.gov/36805052/

Heme oxygenase 1

  • Alleviates nonalcoholic steatohepatitis by suppressing hepatic ferroptosis
Xiwei Yuan 1, Lu Li 1, Ying Zhang 1, Rong Ai 1, Dongdong Li 1, Yao Dou 1, Mengmeng Hou 1, Dandan Zhao 1, Suxian Zhao 1, Yuemin Nan 2, PMID: 37422643 PMCID: PMC10329355 DOI: 10.1186/s12944-023-01855-7
  • Heme oxygenase 1 (HO-1) - effect on ferroptosis
    • Form of programmed cell death
    • May play an effect on nonalcoholic steatohepatitis (NASH)

Hepatocyte conditional HO-1 knockout (HO-1HEPKO) C57BL/6J mice fed a high-fat diet (HFD)

  • Wild-type mice were fed either a normal diet or a HFD
  • In mice, HFD caused lipid accumulation, inflammation, fibrosis, and lipid peroxidation,
    • Aggravated by HO-1HEPKO
  • In vivo results, HO-1 knockdown
    • Upregulated reactive oxygen species accumulation, lipid peroxidation, and iron overload in AML12 and HepG2 cells
  • HO-1 knockdown
    • Reduced the GSH and SOD levels
      • In contrast to HO-1 overexpression in vitro
  • NF-kappaB signaling pathway was associated with ferroptosis in NASH models
    • Consistent with the liver histopathology results of NASH patients.
  • pubmed.ncbi.nlm.nih.gov/37422643/

Most patients with NAFLD have associated




  • NAFLD affects the antilipolytic action of insulin
    • Promotes the production of excess free fatty acids (FFAs)
    • Increasing the delivery of FFAs to the liver and de novo lipogenesis
    • Developing secondary insulin resistance
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC7698421/
  • Pathogenesis of NAFLD was described by the two-hit hypothesis
    • Insulin resistance leads to hepatic steatosis
    • Oxidative stress leads to steatohepatitis and fibrosis
  • Crucial role of oxidative stress in the progression of NAFLD to more advanced stages
    • Is related to the production of reactive oxygen species
    • Consequence of excess fatty acids in hepatic cells with energy depletion
  • Later, this theory was expanded into the multi-hits hypothesis
    • NAFLD pathogenesis, many hits may act in parallel,
    • Especially factors derived from gut and adipose tissue
      • Resulting in endoplasmic stress, oxidative stress, and hepatocyte apoptosis
  • NAFLD affects the antilipolytic action of insulin
    • Promotes the production of excess free fatty acids (FFAs)
      • Increasing the delivery of FFAs to the liver and de novo lipogenesis,
        • Developing secondary insulin resistance

Lipid accumulation in hepatocytes

  • Lipid accumulation in the form of triglycerides (TGs) is the first step
    • In the development of NAFLD
    • Represents the “first hit”
  • Lipid peroxidation
    • Due to oxidative stress in the context of lipid-loaded hepatocytes
    • Induces inflammation and necrosis,
    • Representing the “second hit”
  • Alone TG accumulation in the form of LDs does not result in cellular injury and inflammation
    • Occurs in parallel with the generation of fatty acid metabolites
      • Associated with lipotoxic hepatocellular injury
        • Resulting in endoplasmic reticulum stress, inflammation, apoptosis, and necrosis
  • www.jhep-reports.eu/article/S2589-5559(21)00041-0/fulltext
  • Histologically is characterised by inflammation
    • With or without fibrosis
  • 40% of patients with NAFLD
    • Develop fibrosis
      • Progression of which is usually faster in patients with NASH
  • 5–18% of the patients with NASH develop cirrhosis
  • 38% of patients with NASH and fibrosis develop cirrhosis
  • Patients with NASH and either fibrosis or cirrhosis
    • Are at an increased risk of hepatocellular carcinoma.
  • www.jhep-reports.eu/article/S2589-5559(21)00041-0/fulltext
  • Lipid accumulation exacerbate the fragility of the liver
    • When exposed to ischaemia-reperfusion injury
      • Could explain why the transplantation of steatotic livers results in worse outcomes.
  • Pak taky budou mnohem hůř snášet různá imunosupresiva...

Plasminogen activator inhibitor type 1 (PAI-1)

  • The most thrombophilic factor reported,
  • Significantly increases with exposure to non-oxidized low-density lipoprotein (LDL)
  • Directly related to hepatic steatosis
  • Resulting in a procoagulant state and contributing to atherosclerotic injury
  • Patients with NAFLD have a higher rate of major cardiovascular (CV) events (30% vs 8%)
  • NAFLD is associated with increased production of proinflammatory cytokines
    • IL-6
    • High-sensitivity C-reactive protein (Hs-CRP),
    • mitochondrial dysfunction eliciting reactive oxygen species (ROS)
    • Stress biomarkers
    • Fibroblast growth factors (FGFs)
      • Increase the risk of CV and liver-related mortality
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC10415861/

Liver disease with extensive inflammation and a high degree of steatosis

  • Often progresses to more severe forms of the disease
  • Hepatocyte ballooning and necrosis of varying degrees
    • Often present at this stage
  • Liver cell death and inflammatory responses lead to the activation of hepatic stellate cells
    • Pivotal role in hepatic fibrosis
  • Extent of fibrosis varies widely
  • Perisinusoidal fibrosis is most common
    • Especially in adults
    • Predominates in zone 3 around the terminal hepatic veins
  • Progression to cirrhosis
    • May be influenced by the amount of fat and degree of steatohepatitis
    • By a variety of other sensitizing factors
  • en.wikipedia.org/wiki/Fatty_liver_disease

Non-alcoholic fatty liver disease (NAFLD)

  • Several forms of liver disorders
    • fat disposition in hepatocytes - simple steatosis
      • Mild to the severe stage non-alcoholic steatohepatitis (NASH)
        • Cirhosis
  • pubmed.ncbi.nlm.nih.gov/35164140/

Sirtuin 1 (SIRT1)

  • Member of the nicotine adenine dinucleotide (NAD+)-dependent enzyme family
  • Roles in glucose and lipid metabolism (Ye et al., 2017)
  • Involved in beta-oxidation, oxidative stress, inflammation, insulin secretion, and sensitivity (Kosgei et al., 2020)
  • SIRT1 facilitates fatty acid beta-oxidation
    • Through peroxisome proliferator-activated receptor-gamma coactivator 1-alpha
  • Inhibits de novo lipogenesis
    • Alterations in pathways involving SIRT1 can potentially lead to metabolic disorders, including NAFLD (Stacchiotti et al., 2019).
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC9007706/


O úroveň výše

Poslední aktualizace: 30. 11. 2023 1:41:13