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Diabetes > NAFLD > Flashcards

NAFLD Flashcards

1
Q

what are primary causes of NAFLD?

A

obesity
T2DM
hyperlipidaemia
insulin resistance

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2
Q

what are secondary causes of NAFLD?

A

drugs/toxins
surgical procedures
inborn errors
HCV
weight gain/ rapid weight loss

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3
Q

what are signs and symptoms of NAFLD?

A

77% asymptomatic
RUQ pain
fatigue
hepatosplenomegaly

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4
Q

what findings would there be in NAFLD?

A

abnormal ALT/GGT
bright spots of liver US
negative liver screen
features of obesity/insulin resistance/ T2DM
therapeutic response to wt loss
liver biopsy

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5
Q

what lab findings could be seen in NAFLD?

A

AST/ALT <1 ( if > 1 indicates advanced fibrosis
ALP and GGT raised 2-3X normal limit
serum bilirubin and albumin normal

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6
Q

how is NASH diagnosed?

A

liver biopsy shows steatosis, hepatocyte ballooning and lobular inflammation

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7
Q

what can lipids induce in NAFLD?

A

hepatic immune response and inflammation

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8
Q

how does insulin resistance contribute to hepatic steatosis?

A

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

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9
Q

describe dysbiosis

A

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

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10
Q

describe mitochondrial dysfucntion

A

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

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11
Q

describe NLRP3

A

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

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12
Q

what is Nrf2?

A

a key antioxidant in the NAFLD inflammatory process

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13
Q

describe the role of visceral ectopic fat in NAFLD

A

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.

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14
Q

what does NAFL show on liver biopsy?

A

Steatosis alone plus ONE of lobular or portal inflammation OR ballooning

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15
Q

what does NASH show on liver biopsy?

A

NASH requires
Steatosis AND
Lobular or portal inflammation AND
Ballooning

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16
Q

what is oxidative stress?

A

An imbalance between oxidants and antioxidants in favour of the oxidants, leading to a disruption of redox signalling and control and/or molecular damage.

17
Q

what are reactive oxygen species?

A

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

18
Q

where is the major source of ROS?

A

mitochondria (also ER, plasma membrane, cytoplasm. peroxisomes, microscomes)

19
Q

how are ROS produced by mitochondria?

A

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.

20
Q

how can oxidative stress be caused?

A

increased ROS

antioxidant depletion or inhibition

21
Q

what is the response to oxidative stress?

A

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

22
Q

how are ROS toxic to cells?

A

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

23
Q

what regulates redox signalling?

A

transcription factor Nrf2

24
Q

what do ROS do to insulin signalling?

A

Reactive oxygen species promote insulin signalling

25
Q

What happens in ER stress?

A

Endoplasmic reticulum (ER) stress arises when misfolded or unfolded proteins accumulate within the lumen of the ER, and it triggers the unfolded protein response (UPR)

This initiates adaptive processes that counter ER stress

The unfolded protein response entails recognition by BiP of misfolded protein, which then allows activation of three arms, or pathways, with IRE1⍺ controlling lipid biosynthesis

ER stress stimulates inflammation via activation of IRE1 and TRAF

During protein folding ROS are formed as a by product, which may produce oxidative stress and contribute to apoptosis

26
Q

what does triggering of ER stress lead to?

A

Triggering of ER stress during NASH exacerbates both steatosis and inflammation

Excessive ER stress that cannot be resolved promotes apoptosis via activation of PERK-ATF4-CHOP (also called ’irremediable’ ER stress)

27
Q

how does obesity contribute to ER stress?

A

Overnutrition triggers both ER stress and Oxidative stress. Crosstalk exists between ER stress and oxidative stress during progression of NASH

Overconsumption of fructose is a risk factor for NASH

28
Q

what does Nrf2 do?

A

Nrf2 suppresses multiple steps in the development of insulin resistance, NASH and liver cirrhosis

Nrf2 activity decreases throughout progression of NASH into liver cirrhosis, suggesting this may be necessary for advanced liver disease

29
Q

what are lifestyle changes to be made in NAFLD?

A

energy restriction, fructose intake, daily alochol intake, macronutrient compostion, physical activity

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