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In general, where do toxins/toxic agent that cells are exposed to come from?

- external
- GI tract e.g. alcohol
- lung
- skin

ultimately all flow into the bloodstream where they get distributed very rapidly throughout the body - in essence to every single cell in the body that has a capillary supply.


How can metabolism affect toxicity?

Depending on which chemical and which organ is involved the metabolism/the normal metabolic function of those tissues will determine how toxic a particular substance will be


How can storage affect toxicity?

- in the longer term storage of toxins can allow them to exert their effects for longer periods
- otherwise how quickly they can be excreted thereby diminishing the length of time they can exert their effects


What are some examples of recreational and medicinal toxins?

- ethanol
- recreational drugs
- tobacco smoke
- cocaine
- heroin
- amphetamine
- therapeutic drugs
- oral contraceptives
- aspirin
- paracetamol


What happens to a xenobiotic in the body that is non-toxic?

Can undergo a number of different reaction steps:
phase I reaction possibilities:
- hydrolysis
- reduction
- oxidation
--> produces a primary metabolite

Phase II reactions (require further enzyme activity):
- glucuronidation
- sulfation
- methylation
- conjugation
--> produces secondary metabolite

- eliminated by normal body processes e.g. urine, bile or feces


What happens to a xenobiotic in the body that is toxic?

- the compound itself initially may not have a strong toxic effect but the metabolites it produces can
- changes from the primary product to a more toxic product can occur
- ways that the toxic metabolite is dealt with either allowing the cells that are exposed to these metabolites to be repaired or longer term effects that reduce the cytotoxicity

reactive metabolite
effects on cellular molecules (enzymes, receptors, membranes, DNA)
>> molecular and cellular repair
Toxicity (short- and long-term effects)


For how long has the effect of alcohol on the liver been known?

Quite a long time
Known in ancient India
300 years ago: english physician named 'schirrous' liver in those who consume large amounts if 'spiritious liquors'

Organs (stomach, liver, heart, kidneys, brain) known to change from their normal state to very recognisably different (even macroscopically).
Psychological changes associated with alcoholism


What are the three major types of pathophyisiology changes that occur in the liver because of alcohol?

1. fatty liver
2. alcoholic hepatitis (hepatitis = general damage to the liver, causes severe inflammation)
3. cirrhosis (irreversible damage to liver, remodels into a non-functional tissue that cannot do any of the things that a normal liver can do in terms of metabolism, detoxification etc)


What is feature of alcohol is important in causing this pathophysiology?

- nature/type of alcohol not important
- daily dose of alcohol IS important


What are the widespread organs affected by alcohol?

- skin
- heart
- pancreas
- bowel
- immune system
- female/male reproductive system
- kidneys
- liver
- stomach
- brain


How can chemicals become toxic?

- some act directly - covalent binding
- some metabolised to toxic metabolic by-products
- many form free radicals --> membrane damage


What constitutes 10 gm of ethanol?

- 1 pot of beer
- 1 glass of wine
- 1 shot spirits


What can prolonged use induce?

- changes to mitochondrial/microsomal functions
- up-regulates expression of metabolising enzymes


What causes the pathology in alcohol consumption?

Ethanol may have a small role but it certainly seems to be the metabolites that have the biggest impact on the liver


What are the consequences of chronic alcohol use?

small to moderate consumption
- increases insulin sensitivity
- lower risk of diabetes

- atrophy
- reduce the number of silent infarcts
- decrease the risk of dementia

- increases HDL
- decreases thrombosis
- reduces fibrinogen
- increases fibrinolysis
- reduces artery spasm from stress
- increases coronary blood flow

- higher bone mineral density

Effects linked with both small and large consumption
- reduced risk of rheumatoid arthritis

- reduced the risk of developing gallstones

- reduced risk of developing kidney stones

Large consumption
- impaired development
- wernicke-korsakoff syndrome
-- vision changes
-- ataxia
-- impaired memory
- psychological
-- cravings
-- irritability
-- antisociality
-- depression
-- anxiety
-- panic
-- psychosis
-- hallucinations
-- delusions
-- sleep disorders

mouth, trachea and esophagus
- cancer

- anaemia

- alcoholic cardiomyopathy

- cirrhosis
- hepatitis

- chronic gastritis

- pancreatitis

peripheral tissues
- increased risk of type 2 diabetes


What are the major diseases due to chronic alcohol abuse?

Increased incidence of:
- cancer (alcohol NOT a direct carcinogen) of the oesophagus, larynx, breast, liver
- peptic ulcer in the stomach
- abscess in the lung
- tissue remodelling in the liver: fatty liver syndrome, cirrhosis, hepatitis


What are some of the positive effects of moderate alcohol consumption?

Blood vessels: decreases atherosclerosis, decreased AMI
Blood: inhibits platelet aggregation, decreased thrombosis
Gall bladder: decreased risk of stones
Bone: decreased osteoporosis


How is alcohol metabolised?

After ethanol ingestion:
(GIT = stomach and small intestine):
- absorbed directly via GIT --> blood (minutes)
- metabolised --> some gastric mucosa, mostly liver
- excreted unchanged (5-10%) --> air, sweat and urine/amount proportional to blood


What are the metabolic pathways in the metabolism of alcohol?

1. cytochrome P450 enzymes (CYP2E1) = microsomal ethanol oxidising system - a member of the cytochrome P450 oxidase system, is involved in the metabolism of xenobiotics in the body - enriched on smooth endoplasmic reticulum (=microsomes) in LIVER cells

2. alcohol dehydrogenase (ADH) - cytosol in GASTRIC mucosal epithelial cells and liver cells ( [ADH] women < [ADH] men)

3. catalase - in peroxisomes - in liver cells

Chronic alcohol drinkers - metabolise at higher rate: 5-10x up-regulation of P450


What are the final products of all three metabolic pathways?

Acetaldehyde and acetic acid
Acetaldehyde is a very toxic substance compared to alcohol on its own


What are the effects of ethanol oxidation?

- Acetaldehyde produces acute effects of ethanol
-- evidence: oral cancers
-- genetic variants: varying metabolic efficiency
- Excess of NADH over NAD stimulates lipid biosynthesis
- production of reactive oxygen species (ROS) - CYP2E1 - membrane breakdown, liver cell injury and possibly DNA damage


What are the effects of alcohol on the CNS?

- powerful depressant
- inhibitory control centres depressed - releases excitatory pathways
-- cortex (higher order functions; behaviour, decision making) first then the limbic system (emotions, memory: can change personalities)
-- cerebellum (motor control)
-- lower brain stem (respiration/BP: may stop breathing/become unconscious)

Party syndrome = euphoria, disordered cognitive and motor function. Occurs at 0.020 - 0.030 gm/dl from 1 or 2 drinks - onset is rapid


At what levels do the acute effects of alcohol occur?

- legal intoxication @ 0.05 gm/dl (australia)
- narcosis @ 0.1gm/dl
- coma/fatal respiratory arrest @ 0.3-0.4 gm/dl
- chronic alcohol drinkers - tolerate much more: e.g. 0.7-0.8gm/dl


What are the acute effects of alcohol on the liver?

- fatty liver
- small (microvesicular) lipid droplets in hepatocytes
- reversible


What are the acute effects of alcohol on the stomach?

- acute gastritis: acute, transient mucosal inflammatory process + haemorrhage &/or sloughing of mucosa


What is alcoholism?

- alcoholism is difficult to define
- different susceptibilities
- regular intake of alcohol enough to injure socially, psychologically or physically


What is one effect of chronic intake of alcohol?

- metabolic derangement: accumulation of triglyceride in liver, heart, muscle and kidney


What are the risk factors for serious liver damage in heavy drinkers?

- polymorphisms in EtOH - metabolising genes
- obesity
- exposure to other hepatotoxins (high doses of analgesics, antibiotics)
- infection with hepatitis C


How does alcohol affect fat metabolism?

1. fatty acids (FA) from diet to liver cell in cytoplasm - increased
2. acetate to FA - increased
3. FA to ketone bodies (toxic) - increased
4. FA to triglycerides (TG) (bad, float around in blood) - increased
5. TGs linked to apoproteins (proteins that absorb TGs) - decreased (more free FAs/lipids)
6. lipoproteins - transported - decreased


How does alcohol exposure affect the liver?

Exposure can lead to steatosis (fatty change and perivenular fibrosis), however this is reversible and can go back to normal after a period of abstinence.
Severe exposure can lead to hepatitis (liver cell necrosis, inflammation, mallory bodies, fatty change), which again can be reversed through abstinence, though to a lesser degree, after a certain number of incidents damage becomes more and more permanent.
Continued exposure after reaching steatosis or repeated attacks of sever exposure leading to hepatitis can cause the irreversible disease state: cirrhosis (fibrosis, hyperplastic nodules)


What is the structure-function of the liver?

- liver is made up of units called liver lobules - 10s of cells across, stacked together
- very regular structure - hexagonal with blood vessels and ducts
- blood enters the lobules through branches of the portal vein and hepatic artery, then flows through small channels called sinusoids that are lined with primary liver cells (i.e. hepatocytes)
- the hepatocytes remove toxic substances, including alcohol, from the blood, which then exits the lobule through the central vein (i.e. the hepatic venule)
- toxins are removed via the bile duct to the gall bladder


What is the structure of a liver lobule?

- terminal hepatic (=central) vein (THV)
- cords of liver cells
- sinusoids = gaps between liver cells
- portal triad/tract = hepatic arter, portal vein, bile duct
- delicate connective tissue - holds structure into this shape, very important for the function of the liver lobule

- has various zones


What is the histology of fatty liver?

- reversible
- all heavy drinkers
- chronic alcoholics lose a lot of the underlying ECM, which is quite important in the development of disease
- changes in cell - fat accumulates
-- increased FA synthesis
-- decreased mitochondrial oxidation of FA
-- increased production of triglycerides
-- impaired release of lipoproteins

- you see lots of white circles - spongy in appearance - lipid droplets
- fribrosis/fibrotic tissue between lobules


What is the pathogenesis and histopathology of alcoholic hepatitis?

- ethanol and metabolites directly hepatotoxic
- inflammatory and necrotising disease
- significant mortality

Recognised by:
- characterised by necrosis of hepatocytes, cytoplasmic hyaline inclusions (Mallory bodies - intermediate filaments = cytokeratin, pink stain), infiltrate of neutrophils, perivenular fibrosis
- produces fever, liver tenderness, jaundice
- liver droplets

In inflamed liver:
- glutathione (antioxidant) - levels drop enormously lowering protection of hepatocytes + mitochondrial injury (metabolism decrease) + cytokines from Kupffer cells (mPhis) (resident macrophages in liver, produce molecules that amplify inflammatory response)

- loss of structure of hepatocytes and sinusoids
- infiltration of immune cells
- mallory bodies


What is Cirrhosis?

- occurs in 10-15% of chronic alcoholic users
- necrosis + inflammation + fibrosis + regeneration = cirrhosis
- finite number of times you can regenerate damaged tissue
- irreversible scarring --> ^ portal hypertension
- liver failure


What is the pathogenesis of cirrhosis?

- fatty liver/hepatitis not always precursor
- induction of P450 --> toxic products + O2 radicals
- microtubular and mitochondrial function affected
- [acetaldehyde+protein] complexes - disrupt membranes and cytoskeleton
- new disease epitopes - activate immune response --> repeated cycles of inflammation and regeneration


What does the cirrhotic liver look like?

- characteristic diffuse nodules on the surface reflects the processes of nodular regeneration and scarring
- the greenish tint of some nodules is due to bile stasis
- microscopic view shows nodules of varying sizes entrapped in blue-staining fibrous tissue (masson trichrome stains fibrous tissue blue)
- hepatic car cinoma can develop


How does liver fibrosis occur?

Stellate cell activation and liver fibrosis:
- Kupffer cell activation leads to secretion of multiple cytokines
- Platelet-derived growth factor (PDGF) and tumor necrosis factor (TNF) activate stellate cells, and contraction of the activated stellate cells is stimulated by endothelin-1 (ET-1)
- fibrogenesis is stimulated by transforming growth factor Beta (TGF-Beta)
- chemotaxis of activated stellate cells to areas of injury is promoted by PDGF and monocyte chemotactic protein-1 (MCP-1)

- stellate cells differentiate into fibroblasts which lay down all the fibrotic tissue that ultimately causes the change in liver structure.

Bridging necrosis (and fibrosis) occurs in chronic and acute hepatitis - web-like connection between central vein and ducts on the edge. Microscopic view shows nodules of varying sizes entrapped in blue-staining fibrous tissue


What are some other diseases due to alcohol?

- stomach: acute erosive gastritis
- pancreas: acute pancreatitis --> effects on insulin production
- CNS - chronic exposure: wernicke syndrome (brain stem - neurological disorder)
- pregnancy - foetal alcohol system
- liver cancer: abnormal liver cell activation
-- In this rat experimental model chronic alcohol intake causes cancer
-- it appears that cell growth signalling pathways are chronically activated and together with changes in the metabolic enzyme CYP2E1
- remember one of the alcohol breakdown pathways which generate ROS --> lead to the development of liver cancer


What are the effects of alcohol on pulmonary immunity?

- chronic EtOH consumption increases the severity of the influenza virus infections
- reduces ability of immune system