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20. Pathophysiology of alcohol effects

Alcohol (ethanol) is the second most used psychoactive stimulant in the world after caffeine. The consumption is high and rising. This makes it important to know the harmful effects of alcohol on the body.

As alcoholism can be regarded as a disease, we can look at the etiology. There are both environmental and genetic factors involve that predispose a person to alcoholism. Social studies have determined that there are two different types of alcoholics.

Characteristic Type I (environmental type) Type II (genetic type)
Etiology Mostly environmental factors Mostly genetic factors
Gender Both genders Mostly males
Start of alcohol problem After 25 years Before 25 years
Situation of alcohol consumption Rarely and mostly in company of others Frequently and mostly alone
Alcohol induces aggressive behaviour? Rarely Frequently
Feels guilty after consumption? Frequently Rarely
Type of dependence Psychological Physiological

Metabolism

The absorption of alcohol starts already in the stomach but finishes in the small intestine. The metabolism begins in the GI mucosa by the use of alcohol dehydrogenase in the mucosal cells. Alcohol is further metabolised in the liver and pancreas, and the metabolites are excreted by the kidney and the lungs. The breakdown is normally 8-10 g/h but can be increased to 12-16 g/h in regular drinkers.

The metabolism pathway of alcohol is like this: ethanol -> acetaldehyde -> acetate -> acetyl-CoA

The conversion of ethanol into acetaldehyde occurs with alcohol dehydrogenase in the mucosa, and with the three enzymes alcohol dehydrogenase (ADH), CYP2E1 and peroxisomal catalase in the liver. ADH is the most important and has NAD+ as a cofactor, which is converted into NADH. NAD+ is quickly depleted and must be regenerated from NADH, and it is this regeneration that is the rate-limiting step of ethanol metabolism.

The conversion of acetaldehyde into acetate is by acetaldehyde dehydrogenase (ALDH). This enzyme is present in lower amount in Asians and in chronic alcoholics.

Consequences of consumption

The consequences of alcohol consumption on the body are plentiful. They derive 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

NADH is converted back into NAD+ by the use of lactate dehydrogenase, which converts pyruvate into lactate. The accumulating lactate may cause lactic acidosis. Blood glucose is converted into pyruvate to continue to provide pyruvate for the lactate dehydrogenase. The depletion of pyruvate, which is essential for gluconeogenesis, means that the liver is unable to increase blood sugar levels during fasting, causing hypoglycaemia.

High NADH/NAD+ ratio and high levels of acetyl-CoA stimulate fatty acid synthesis, causing fat to accumulate in the liver and the production of lipoproteins to be increased. This can cause steatosis and hyperlipoproteinaemia, respectively.

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

Chronic alcohol consumption increases the metabolism of testosterone into female sex hormones, which causes femininization. This can cause gynecomastia and hypogonadism.

H2O2 and free radicals, both dangerous, are produced by several mechanisms after alcohol consumption. CYP2E1 produces H2O2 during biotransformation of ethanol, while increased NADH/NAD+ ratio increases free radical production. Xanthine oxidase also produces H2O2.

Because both alcohol and some drugs are metabolized by the same cytochrome P450 enzymes can they interact. Acute alcohol consumption competes with the biotransformation of other drugs metabolized by CYP2E1 like paracetamol and halothane. Chronic alcohol consumption induces CYP2E1 which decreases the half-life of drugs that are biotransformed by the same enzyme.

Alcohol limits the production of vasopressin (ADH). This may contribute to dehydration.

1 gram of ethanol provides 30 kJ of energy, however these calories are “empty calories” (meaning that they provide energy but no nutrients). Moderate amounts of alcohol cause weight gain while chronic severe alcohol consumption can cause cachexia if liver damage occurs.

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. There are other mechanisms involved as well.

Foetal alcohol syndrome (FAS) is a condition of the foetus caused by maternal alcohol consumption during the pregnancy. Growth retardation, microcephaly, craniofacial malformation and cognitive and behavioural disorders are common. Patients with FAS have a characteristic face morphology including small eye openings, smooth philtrum and thin upper lip.

Several laboratory parameters are influenced by chronic alcohol consumption, like:

  • Gamma glutamyltransferase (GGT) increases
  • Mean corpuscular volume (MCV) increases
  • HDL3 increases
  • Phosphatidyl ethanol (PEth) increases

In addition may other liver function tests like AST and ALT increase 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 include:

  • Osteoporosis
  • Muscle breakdown
  • Vitamin deficiency
    • Vitamin A – due to transformation of hepatic stellate (Ito) cells into myofibroblasts
    • Vitamin D – due to deficiency in liver function
    • Vitamin B’s – due to increased need and decreased intake
  • Deficiency of 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 cold thermoregulation
  • CNS effects
    • Decreased response time
    • Encephalopathy
    • Cerebral atrophy
    • Dementia
    • Neuropathy
    • Withdrawal

“Good" effects of alcohol

Alcohol use has a complex association with health. Globally is alcohol use the seventh leading risk factor for deaths and decreased lifespan. Everyone knows it’s bad for you but for some time have there been reports that small amounts of alcohol have some protective cardiovascular effects. While this may indeed be true did a large 2016 study conclude that the cancer-inducing effects of alcohol far outweigh the potential cardiovascular benefits.

The study found that the level of alcohol consumption that minimized harmful health effects was 0 (zero) drinks per week. In other words is there no level of regular alcohol consumption that is beneficial for overall health.