NAFLD Flashcards
what are primary causes of NAFLD?
obesity
T2DM
hyperlipidaemia
insulin resistance
what are secondary causes of NAFLD?
drugs/toxins
surgical procedures
inborn errors
HCV
weight gain/ rapid weight loss
what are signs and symptoms of NAFLD?
77% asymptomatic
RUQ pain
fatigue
hepatosplenomegaly
what findings would there be in NAFLD?
abnormal ALT/GGT
bright spots of liver US
negative liver screen
features of obesity/insulin resistance/ T2DM
therapeutic response to wt loss
liver biopsy
what lab findings could be seen in NAFLD?
AST/ALT <1 ( if > 1 indicates advanced fibrosis
ALP and GGT raised 2-3X normal limit
serum bilirubin and albumin normal
how is NASH diagnosed?
liver biopsy shows steatosis, hepatocyte ballooning and lobular inflammation
what can lipids induce in NAFLD?
hepatic immune response and inflammation
how does insulin resistance contribute to hepatic steatosis?
1) increased lipolysis of TAGs in adipose tissue and release of fatty acids from adipose tissue
2) enhances de novo lipogenesis
3) increases gluconeogenesis and diminishes glycogen synthesis in the liver
describe dysbiosis
an unhealthy, calorie dense, fibre-poor diet results in changes in the intestinal microbiota (dysbiosis)
this may lead to alterations in short chain fatty acids
can increase ethanol, incretin and metabolite production
all these products then gain access to the liver and multiple pro inflammatory pathways are activated to promote HCC
describe mitochondrial dysfucntion
Excessive and dysregulated reactive oxygen species (ROS) production within the mitochondrial matrix may damage constituent structures including mitochondrial membrane, mitochondrialDNA (mtDNA) and may induce pro-apoptotic pathways including mitochondrial autophagy/ mitophagy
describe NLRP3
NLRP3 inflammasome and/or NLRP3 inflammasome activation has been shown in innate immune cells
Also demonstrated in hepatocytes, hepatic stellate cells, endothelial cells, and myofibroblasts
gene expression of NLRP3 inflammasome components, pro-IL-18, and pro-IL-1βwas markedly increased in the liver of NASH patients
what is Nrf2?
a key antioxidant in the NAFLD inflammatory process
describe the role of visceral ectopic fat in NAFLD
Visceral ectopic fat accumulation, which often occurs with inflammation and type 2 diabetes, causes resistance to insulin action and hepatic necro-inflammation.
Stimulates Kupffer cell activation with secondary activation of hepatic stellate cells and increased production of collagen matrix and progression of liver disease.
Progression of liver disease over an ill-defined period of time causes advanced liver fibrosis, cirrhosis and, in some cases, hepatocellular carcinoma.
what does NAFL show on liver biopsy?
Steatosis alone plus ONE of lobular or portal inflammation OR ballooning
what does NASH show on liver biopsy?
NASH requires
Steatosis AND
Lobular or portal inflammation AND
Ballooning
what is oxidative stress?
An imbalance between oxidants and antioxidants in favour of the oxidants, leading to a disruption of redox signalling and control and/or molecular damage.
what are reactive oxygen species?
In biology there are many oxidants with different properties, abundance and reactivities that are referred to as ‘reactive oxygen species’. These are all elevated during most instances of oxidative stress.
derived from incomplete reduction of 02
e.g. superoxide, hydrogen peroxide, hydroxyl radical
where is the major source of ROS?
mitochondria (also ER, plasma membrane, cytoplasm. peroxisomes, microscomes)
how are ROS produced by mitochondria?
incomplete oxidative phosphorylation
production of ROS is primarily by complex 3 and involves the action of coenzyme Q, coenzyme Q is reduced to form an unstable intermediate that can give rise to superoxide.
how can oxidative stress be caused?
increased ROS
antioxidant depletion or inhibition
what is the response to oxidative stress?
The antioxidant transcription factor Nrf2 is normally constitutively repressed by the ubiquitin ligase substrate adaptor Keap1
Cells can adapt to oxidative stress, by increasing the activity of transcription factor Nrf2, through a mechanism in which Keap1 acts as a redox sensor
High levels of oxidative stress that are sufficient to overwhelmNrf2-based adaptation can trigger inflammation and apoptosis
how are ROS toxic to cells?
ROS are toxic to cells because they can damage macromolecules directly.
they can produce reactive aldehydes, which in turn can produce a secondary wave of damage
what regulates redox signalling?
transcription factor Nrf2
what do ROS do to insulin signalling?
Reactive oxygen species promote insulin signalling
