L15 - Alcohol Flashcards
Hepatic stellate cells
Fat containing myofibroblasts.
Myofibroblasts
- contractile cell, contraction stimulated by endothelin-1
Increase in platelet derived growth factor will activate hepatic stellate cells into myofibroblasts
Steatosis
Accumulation of fat in hepatocytes
Cholestasis
Decrease in bile flow due to impaired secretion by hepatocytes or to obstruction of bile flow.
Substances normally excreted in bile are retained e.g. billirubin
Hepatocyte integrity measured by:
Serum
- aspartate aminotransferase AST
- alanine aminotransferase ALT
- lactate dehydrogenase LDH
Function of Kupffer cell and lymphocytes
Release cytokines and chemokines which moldulate the expression of genes in stellate cells that are involved in fibrogenesis.
e.g. TGF-b
Cirrhosis
Diffuse transformation of entire liver into regenerative parenchymal nodule surrounded by fibrous bands and variable degrees of vascular shunting.
Impaired oestrogen metabolism and consequent hypereoestrogenemia in male patients with chronic liver failure can lead to:
Palmar erythema
- reflection of local vasodilation
Spider naevi
- central pulsating dilated arteriole from which small vessels radiate
Gynecomastia
Hypogonadism
Describe portal hypertension in liver
Increased resistance to portal blood flow.
- alteration in sinusoidal endothelial cells that contribute to the intrahepatic vasoconstriction; associated with portal hypertension
What other factors can cause vasoconstriction
- decreased nitric oxide
- increased endothelin-1
- angiotensinogen
Four major clinical clinical consequences of portal hypertension
- Ascites: accumulation excess fluid in peritoneal cavity
- Formation of portosystemic venous shunt
- Congestive splenomegaly
- Hepatic encephalopathy
Morphology of hepatic steatosis
- lipid droplets accumulate in hepatocytes
- lipid begins as small droplets
coalesce into large one which distend the hepatocyte - nucleus pushed aside
Describe alcoholic (steato-) hepatitis
Hepatocyte swelling and necrosis
- accumulation fat, water and proteins which are normally exported
Inflammation induces production and accumulation of ECM (collagen) from Hepatic stellate cells.
Mallory Denk bodies
- clumped eosinophil material in ballooned hepatocyte
Steatofibres
Alcoholic steatofibrosis
- fibrosis begin with sclerosis of central vein
Why are females more susceptible to hepatic injury
LPS - lipopolysaccharide
- oestrogen increases gut permeability to endotoxins
- increased expression of LPS receptor CD14 in Kuppfer cell.
- predisposes to increase production of pro-inflam cytokines and chemo kines
Hepatocellular steatosis occurs because
- normal substrates shunted away from catabolism to lipid biosynthesis, hence increase in reduced NADH
- impaired assembly and secretion of lipoproteins
- increased peripheral catabolism of fat, releasing free fatty acids into circulation
What does the alcohol metabolite acetylaldehyde induce
- lipid peroxidation
- protein adduct formation
Disrupts cytoskeleton and membrane function.
Patients resistant to insulin
- increase in visceral adipose tissue
- decrease in adiponectin (lipid hormone)
- increase in inflammatory cytokines TNF-a , IL-6
Autophagy
Body’s way of cleaning out damaged cells
Diminished autophagy contributes to
- mitochondrial injury
- formation of Mallory Denk bodies
- Kupffer cell production of TNF-a, TGF-R
- activates stellate cell
- deposition of scar tissue
Haemochromatosis
- caused by excessive iron absorption
- iron deposited in parenchyma in organs such as liver, pancreas, heart joint and endocrine organs
Ethanol oxidation results in increased ratio of…
NADH to NAD+
- inhibits oxidation of lactate to pyruvate
- pyruvate susbtrate for hepatic gluconeogenesis
- hence risk of hypoglycemia
- NAD+ needed as a co-factor,
Describe the NADH/NAD+ shift
When NADH increases
- inhibits beta oxidation of fatty acids
- promotes triglyceride synthesis
- excess of triglyceride deposited in liver
- secreted into plasma as VLDL
Chronic alcohol consumption has what effect on proteasome activity
Decreases proteasome activity.
Can de-regulate hepatocyte signalling by inhibiting Janus Kinase signal transduer and activation of transcriptor JAK-STAT (acute phase response fo antiviral defence)
Accumulation of protein in liver –> enlargement
Increased secretion of chemokine IL8 and monocyte chemo-attractant protein 1 by hepatocytes leads to…
Leads to liver infiltration by neutrophils.
Describe speed of ingestion of alcohol
Slowly absorbed from stomach.
Rapidly absorbed from the small intestine.
Which enzymes metabolise the ethanol consumed?
- Alcohol dehydrogenase ADH
- Mitochondrial acetylaldehyde dehydrogenase ALDH
First step in the metabolism of alcohol?
Oxidation of ethanol to acetylaldehyde catalysed by ADH.
Uses NAD+ and reuslts in generation of reduced NADH.
Acetylaldehyde - acetate
- also requires NAD+
- results in reduced NADH
Why might alcohol consumption cause tachycardia and increase in BP?
- stimulation of the hypothalamus
- increased release of sympathetomimetic amines and pituitary adrenal hormones.
What happens to the acetate produced?
Further oxidized to CO2 and H20. Example of mitochondrial extrahepatic oxidation.
Acetate entering the citric acid cycle generates even more NADH.
Describe how metabolism of alcohol is faster in heavy drinkers?
- high blood acetate levels
- brings the microsomal ethanol oxidising system into play
- dependent on liver enzyme cytochrome P450IIE1 , which may increased after chronic drinking
Why does drinking alcohol warm people up for a short time?
Rapid NADH production from alcohol.
Increases energy availability and body temperature.
Describe how excess NADH can lead to acidosis?
- Pyruvic acid —NADH— lactic acid
- low [pyruvic acid] results in inhibition of hepatic gluconeogenesis.
- Glucose production reduced.
- Hypoglycaemia risk
- Over production of lactic acid blocks uric acid excretion by the kidneys.
Effects of excess NADH?
- Inhibition of lipolysis and increases lipogenesis.
- Accumulated fatty acids, converted into ketones and lipids.
- Heavy drinkers tend to be overweight.
Summarise how alcohol damages the GI tract?
- Inflammation of tongue, stomach, pancreas, liver and intestines.
- Breakdown products lead to fat deposition, fibrosis and scarring of the liver.
- Impaired digestion and absorption of food.
- Diarrhoea
Describe effects of alcohol on pancreas?
- Stimulation of CCK and secretin release from duodenum
- Changes in pancreatic blood flow and secretion
- Generation of free radicals from ethanol metabolism leading to necrosis.
How might non-oxidative metabolism lead to pancreatitis?
Non-oxidation metabolism of alcohol via carboxylesterase.
Results in fatty acid ethyl esters forming.
Results in calcium spike overload, mitochondrial dysfunction, necrosis –> Pancreatitis
Will oxidative metabolism lead to pancreatitis?
Oxidative metabolism
- alcohol dehydrogenase
- cytochrome P450
Acetate
No calcium spikes.
No pancreatitis.
Summarise signs of necrosis
- Jaundice
- Fluid in belly (ascites)
- vomitting blood (haemetemesis)
- confusion (hepatic encephalopathy)
- spider naevi
- gynaecomastia (reduction in testosterone production)
Oesophageal varices
Abnormal dilation of veins due to increase in portal vein pressure.
Effect of alcohol on brain
- alcohol increases dopamine release to cause euphoria
- inhibits glutamate receptor function.
- potentiates GABA-A receptor function
- increases release of serotonin (5HT)
5HT plays major role in
Sleep-wakefullness cycle, mood and emotion
GABA
Major inhibitory neurotransmitter in brain.
Receptor sub types.
a5 - memory impairing effects
a2,a3 - relaxation and pleasure mediating effects
a1 - sedation, anaesthesia and unsteadiness
Describe production of No in a cirrhotic liver?
Normally NO vasodilator synthesised by sinusoidal endothelial cells.
Production of NO decreased. in cirrhotic liver. Intraheptatic vasoconstriction occurs in CL and accounts for some increased intrahepatic resistance.
