Non-alcoholic fatty liver disease pathophysiology

The pathogenesis of MASLD is multifactorial. The exact pathogenesis of NAFLD is not fully understood but is believed due to the interaction of multiple factors such as obesity, Insulin resistance, and metabolic syndrome. Hepatic steatosis develops due to increased hepatic uptake of free fatty acids, increased de novo hepatic lipogenesis, decreased hepatic fatty acid oxidation, and reduced hepatic export of triglycerides into very low-density lipoproteins. Systemic insulin resistance promotes adipose tissue lipolysis and hepatic de novo lipogenesis, thereby increasing hepatic lipid accumulation. Progression from isolated steatosis to MASH is associated with lipotoxicity, in which accumulation of triglycerides, free cholesterol, saturated fatty acids, and ceramides contributes to hepatic inflammation, cellular dysfunction, and cell death. Metabolic factors, diet, genetic susceptibility, adipose tissue inflammation, and the gut microbiome may also contribute to disease progression. Dietary factors, including high intake of glucose, fructose, saturated fats, and processed foods, may promote low-grade inflammation in the liver and extrahepatic organs. Excess adipose tissue contributes to systemic inflammation through increased release of proinflammatory cytokines and recruitment and activation of immune cells, particularly macrophages.^[1]

Pathogenesis of non-alcoholic liver disease was previously explained by 2 hit hypothesis. The first hit is steatosis. The second hit is controversial and is likely cause changes that leads from hepatic steatosis to hepatic inflammation and fibrosis by way of lipid peroxidation. The older two-hit hypothesis should be regarded as historical background. Current evidence supports a broader multifactorial model in which insulin resistance, lipotoxicity, diet, adipose tissue inflammation, genetics, and gut microbiome-related pathways act together to promote progression from steatosis to MASH and fibrosis.

The exact pathogenesis of NAFLD is not fully understood but is believed due to the interaction of multiple factors.

Pathogenesis of non-alcoholic liver disease can be summarized by 2 hit hypothesis. According to 2 hit hypothesis:

• The first hit results in increased fat accumulation especially triglycerides within the hepatocyte and increases the risk of liver injury.
• On the second hit inflammatory cytokines causes mitochondrial dysfunction and oxidative stress which in turn lead to steatohepatitis and/or fibrosis.^[2]

• Free fatty acids (FFA) play very crucial role in damaging the liver indirectly by either undergoing β-oxidation or are esterified with glycerol to form triglycerides, leading to hepatic fat accumulation.^[3][4][5]
• By upregulating TNF-alpha expression via lysosomal pathway, free fatty acids make the liver susceptible to oxidative stress.^[6]

• Oxidative stress inhibits the replication process in the mature hepatocytes.
• Inhibition of hepatocyte replication results in the proliferation of progenitor cell population which can also differentiates into hepatocyte-like cells.
• Progenitor cells along with hepatocyte-like cells are responsible for fibrosis and carcinogenesis in non alcoholic fatty liver.^[2]

• Obese patients who underwent jejuno-ileal bypass surgery has the risk of developing bacterial endotoxins in the portal circulation due to small intestinal deformity.
• Increase in small bowel bacterial overgrowth due to decreased gastric motility.
• Bacterial toxins released by this bacteria overgrowth stimulate an elevation of intra-hepatic levels of pro-inflammatory cytokines, such as tumor necrosis factor-alpha.
• Expression of TNF-alpha begins the cascade of events making liver susceptible for free radical injury.

• Adiponectin is an anti-atherogenic, insulin sensitizing cytokine whose secretion is decreased in obesity.^{[10][11][12][13]}
• There is an inverse relationship between circulating concentrations of adiponectin and tumor necrosis factor.
• Any conditions that cause low production of adiponectin ( consuming high amounts of poly unsaturated fatty acids) results in production of TNF alpha.

• Alteration of purinergic metabolism is another important pathway responsible for development of non-alcoholic liver disease.
• Adenosine receptor A2A is a major factor in the pathogenesis of cirrhosis.
• CD39 is the dominant vascular ectonucleotidase in the liver that hydrolyzes extracellular ATP and ADP to AMP which can then be converted to adenosine via ecto-5’-nucleotidase/CD73.^[15]
• Alterations in purinergic signaling induced by altered CD39 mutation have major impacts upon hepatic metabolism, repair mechanisms, regeneration and associated immune responses.
• Adenosine forms a supportive link in the cell’s cascade healing response to inflammation.
  • Adenosine suppresses inflammation by enhancing fibrosis.
• CD39 deletion shifts the local population of cytokines to produce TNF alpha.

• Fibroblast growth factor 21 (FGF21) is an important metabolic regulator of glucose and lipid metabolism.
• FGF21 moderates or induces the hepatic response to a fasting state by gluconeogenesis, fatty acid oxidation, and ketogenesis.
• Moreover, it is a crucial component of the hepatic lipid oxidation machinery, as proliferator-activated receptor activation.
• FGF21 is responsible for normal blood glucose, insulin, and lipid levels in normal individuals.
• Low levels of FGF21 are closely associated with the obesity, insulin resistance, type two diabetes mellitus and hyperlipidemia.

• Most patients have associated features of the metabolic syndrome including obesity, diabetes mellitus type 2, hyperlipidemia (hypertriglyceridemia), and hypertension
• MASLD is a multisystem metabolic disease associated with cardiovascular disease, chronic kidney disease, heart failure, atrial fibrillation, incident type 2 diabetes, and certain extrahepatic cancers, particularly gastrointestinal, breast, and gynecologic cancers.
• Patients may suffer from complications of obesity such as obstructive sleep apnea , orthopedic complications, and polycystic ovary syndrome.

On microscopic histopathological analysis, characteristic findings of the non-alcoholic liver disease include:

• Macrovesicular steatosis

• Predominant lobular inflammation in form of spotty necrosis in cases where steatosis is associated with inflammation.

• Ballooning degeneration (hallmark of steatohepatitis)
  • Characterized by cellular swelling, rarefaction of the hepatocytic cytoplasm and clumped strands of intermediate filaments.
• Mallory-Denk bodies (MDB)
• Fibrosis
• Perivenular and pericellular (peri-sinusoidal) fibrosis.

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