18. Pathophysiology of alcohol effects

Alcohol as a stimulant?

Ethanol is the second most used psychoactive stimulant in the world, after caffeine.

- Consumption is high and rising - therefore important to be aware of its harmful effects on the body

Alcoholism?

A disease in which a person has a physical and psychological dependence on alcohol

- There are both environmental and genetic factors involved that predispose a person to alcoholism

- Social studies have determined two different types of alcoholics

Type 1 alcoholism?

Type 1 (environmental type)

- Mostly environmental factors

- Affects both genders

- Starts after 25 years of age

- Drinks rarely and mostly in the company of others

- Rarely aggressive

- Frequently feels guilty after consumption

- Psychological dependence

Tyoe II alcoholism?

Type II (genetic type)

- Mostly genetic factors

- Affects mostly males

- Problems usually start before the age of 25

- Consumes alcohol frequently and mostly alone

- Frequently becomes aggressive

- Rarely feels guilty after consumption

- Is a physiological dependence

Metabolism of alcohol?

Starts in the stomach, but finishes in the small intestines

- GI mucosa uses alcohol dehydrogenase - further it is metabolized in the liver and pancreas

= The metabolites are excreted by the kidneys and the lungs

What is the breakdown time of alcohol?

Normally 8-10g/h

Can be increased to 12-16g/h in regular drinkers

The metabolism pathway of alcohol?

ethanol -> acetaldehyde -> acetate -> acetyl-CoA

The conversion of ethanol to acetaldehyde occurs with alcohol dehydrogenase in the mucosa, then further in the liver:

- Alcohol dehydrogenase - Has NAD+ as a cofactor, which is converted to NADH. NAD+ is quickly depleted and must be regenerated from NADH, -> this is the rate-limiting step of ethanol metabolism

- CYP2E1

- Peroxisomal catalase

Conversion of acetaldehyde into acetate?

By the enzyme acetaldehyde dehydrogenase

- Is present in lower amounts in asians and chronic alcoholics

What factors does the consequences of alcohol derive from?

There are several consequences from alcohol consumption, deriving from one of two factors:

- Acetaldehyde is toxic to the body

- The increased NADH/NAD+ ratio produces a redox state similar to hypoxia called pseudohypoxia

Explain the NADH/NAD+ relationship and metabolism in alcoholism

NADH is converted back to NAD+ by lactate dehydrogenase, also converting pyruvate to lactate

= Accumulation of lactate -> lactic acidosis

Glucose from blood is converted to pyruvate to continue to provide pyruvate for the lactate dehydrogenase (trying to get rid of the large NADH amounts)

= The depletion of pyruvate, which is essential for gluconeogenesis, means that the liver is unable to increase blood sugar levels during fasting, causing hypoglycemia

What does the high NADH/NAD+ ratio and high levels of Acetyl-CoA cause?

(The high acetyl-CoA levels are from the breakdown of ethanol)

Stimulates fatty acid synthesis -> causing fat to accumulate in the liver & the production of lipoproteins to be increased

= Steatosis hepatis

= Hyperlipoproteinaemia

Also, NADH accumulation increases breakdown of ATP into uric acid by xanthine oxidase -> may predispose to an acute attack of gout

Hormonal changes in alcoholism?

Chronic alcohol consumption increases the metabolism of testosterone into female sex hormones -> causes feminization

- Gynecomastia: development of breast tissue

- Hypogonadism

Free radicals/ROS in chronic alcohol abuse?

- CYP2E1 produces H2O2 (a ROS) during biotransformation of ethanol

- Increased NADH/NAD+ ratio increases free radical production

- Xanthine oxidase produces H2O2

Are dangerous to the cells of the body

Alcohol consumption and breakdown of drugs (e.g. paracetamol, halothane)?

Both alcohol and some drugs are metabolized my the same cytochrome P450 enzymes

- Acute alcohol consumption competes with the biotransformation of other drugs that are metabolized by CYP2E1 like paracetamol and halothane.

= The half-time of drugs are decreased when they are biotransformed by the same enzyme as alcohol

Alcohol and dehydration?

Alcohol limits the production of ADH -> may contribute to dehydration

Alcohol and weight gain?

1g alcohol = 30kJ of energy

- Empty calories

• Moderate amounts of alcohol cause weight gain

• Chronic severe alcohol consumption can cause cachexia if liver damage occurs

Alcohol and cancer?

Alcohol is carcinogenic, especially locally:

- Oral cavity

- Pharynx

- GI tract

- Liver

Acetaldehyde itself is a mutagen and carcinogen

- Induction of CYP2E1 is associated with oxidative stress and conversion of procarcinogens into carcinogens

(other mechanisms are involved as well)

Foetal alcohol syndrome?

A condition of the fetus caused by maternal alcohol consumption during pregnancy

- Growth retardation

- Microcephaly

- Craniofacial malformation (small eye openings, smooth philtrum & thin upper lip)

- Cognitive & behavioral disorders

What parameters are influenced by chronic alcohol consumption?

• ↑ Gamma glutamyltransferase (GGT)

• ↑ Mean corpuscular volume (MCV)

• ↑ HDL3

• ↑ Phosphatidyl ethanol (PEth)

• AST and ALT may be increased (if the alcohol consumption has led to liver damage)

  • In alcohol-induced liver damage is the AST/ALT ratio increased up to 2:1 or greater

Other effects of chronic alcohol consumption?

Osteoporosis

Muscle breakdown

Vitamin deficiency

- Vit A: as Ito cells are transformed to myofibroblasts

- Vit D: deficiency in liver function

- Vit B's: due to increased need and decreased intake

Deficiency in antioxidants - due to increased free radical production

Acute or chronic pancreatitis

Peptic ulcer

Steatosis and hepatitis

Dilatative cardiomyopathy - direct effect of alcohol and acetaldehyde

Increased level of stress hormones

Depression of bone marrow

Suppresses both warm and col thermoregulation

CNS effects

- Decreased response time

- Encephalopathy

- Cerebral atrophy

- Dementia

- Neuropathy

- Withdrawal

Worldwide; where is alcohol located on the leading cause of death?

Globally is alcohol use the 7th leading risk factor for deaths & decreased life span

Are there any "good" effects of alcohol?

Not really

- Some studies show that small amounts of alcohol can have protective cardiovascular effects

Even though this is true, another study showed that the cancer-inducing effects of alcohol far outweighs the potential CV benefits

The level of alcohol consumption that minimize harmful health effects are zero drinks per week = there is no level that is beneficial for overall health