Alcohol hangover is linked to oxidative stress and inflammation

1. by
Kevin KF Ng, MD, PhD.
Former Associate Professor of Medicine
Division of Clinical Pharmacology
University of Miami, Miami, FL.,USA
Email: kevinng68@gmail.com
A slide presentation for HealthCare Providers Aug. 2021
NEW EVIDENCE IN 2020 SHOWS
HANGOVER
IS
AN INFLAMMATORY RESPONSE
TO
ALCOHOL CONSUMPTION

2. Presentation Outline
▪ What is alcohol (ethanol) ?
▪ What is an alcohol hangover?
▪ Absorption and metabolism of alcohol
▪ Effects of reactive oxygen species
▪ Necrosis and its damaging sequelae
▪ Evidence of oxidative stress and inflammation
▪ Summary & development of rational remedy

3. The unsolved problem of Alcohol Hangover !
▪ Alcohol hangover has been known for thousands of
years.
▪ There is no specific cure at this time.
▪ Scientific studies show that hangover is an inflammatory
response based on the following evidence::
▪ Alcohol is a foreign chemical which enters every cell in the body.
▪ Acetaldehyde, the breakdown product of alcohol, is a highly reactive
free radical
▪ The free radical causes oxidative stress in the liver, endothelium, etc.
▪ Oxidative stress causes necrosis of cells and tissues.
▪ Necrosis leads to an inflammatory response.
▪ The inflammatory response results in hangover.
▪ The new concept of pathophysiology of hangover will
lead to new treatment strategy.

4. Short history of alcohol (ethanol)
▪ There is evidence of an early alcoholic drink in China
around 7000 B.C.
▪ In India, an alcoholic beverage called sura, distilled from
rice, was in use between 3000 and 2000 B.C.
▪ The Babylonians worshiped a wine goddess as early as
2700 B.C
▪ In the 1600s, alcohol (called “spirits”) was used largely for
medicinal purpose.
▪ In 1920 the US passed a law prohibiting the manufacture,
sale, import and export of intoxicating liquors
▪ In 1933, the prohibition of alcohol was cancelled.
https://www.drugfreeworld.org/drugfacts/alcohol/a-short-history.html

5. What is alcohol?
It is referred to as ethanol (ethyl alcohol) in this presentation.

6. What is a hangover?
▪ Medical term for a hangover is veisalgia which come
from the Norwegian kveis (uneasiness following
debauchery) + the Greek algia (pain).
▪ A hangover refers to a set of symptoms that occur as
a consequence of drinking too much.
▪ Legally, alcohol intoxication is often defined as a
blood alcohol concentration (BAC) of greater than
0.025–0.080%.
https://www.pngitem.com/middle/mRobTw_alcoholic-drink-alcohol-intoxication-computer-icons-alcohol-clipart/

7. The Alcohol Hangover Research Group:
Ten Years of Progress in Research on the
Causes, Consequences, and Treatment of the Alcohol Hangover (2020)
▪ The alcohol hangover is defined as the combination of negative
mental and physical symptoms, which can be experienced after
a single episode of alcohol consumption, starting when blood
alcohol content (BAC) approaches zero.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696633/

8. Published articles on the alcohol hangover.
Number of publications taken from PubMed (2020)
In 2010 (red bar), the Alcohol Hangover Research Group (AHRG) was founded.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696633/

9. Prevalence of Hangover
Adapted from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761819/

10. Symptoms of Alcohol hangover
when blood alcohol concentration (BAC) ≥ 0.08%
https://daniellewoodward.wordpress.com/

11. Measurement of alcohol hangover severity:
development of the Alcohol Hangover Severity Scale (AHSS) 2012
https://link.springer.com/article/10.1007/s00213-012-2866-y

12. ABSORPTION & DISTRIBUTION OF ALCOHOL
CLINICAL EFFECTS OF ALCOHOL CONSUMPTION

13. Absorption of alcohol in the gastrointestinal tract
https://www.mcieast.marines.mil/Staff-Offices/Safety/Alcohol-and-Substance-Abuse/

14. Absorption and degradation of alcohol in the body
Absorption
20%
80%
Degradation
94%
6%
Systemic circulation

15. Length and surface area of blood vessels and
vascular beds in an adult
1% major arteries and veins
99% microscopic capillaries
length: 60,000 miles (100,000 km)
surface area: 0.25 acre (1,000 m2
)
https://www.biology-pages.info/C/Circulation2.html#:~:text=An%20adult%20human%20has%20been,the%20total%20volume%20of%20blood.

16. The glycocalyx is the luminal lining of
vascular endothelium
https://www.youtube.com/watch?v=Sj8NaxnPCg8
glycocalyx

17. Modulation of Endothelial Glycocalyx Structure under
Inflammatory Conditions:
A thin glycocalyx is an indication of dysfunction
https://www.youtube.com/watch?v=Sj8NaxnPCg8
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3997148/

18. Serum ethanol concentration time curves after
oral and intravenous ethanol administration
No significant differences are noted between men and women (1998)
https://gut.bmj.com/content/43/5/612#block-system-main
men (n = 8) women (n = 8

19. How much alcohol is consumed to cause hangover?
▪ The 2010 Alcohol Hangover Research Group consensus paper defined a cutoff
blood alcohol concentration (BAC) of 0.11% as a toxicological threshold indicating
that sufficient alcohol had been consumed to develop a hangover
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019760/

20. Alcohol flush reaction as a result of the accumulation
of acetaldehyde, the first metabolite of alcohol
https://en.wikipedia.org/wiki/Hangover#/media/File:AsianFlushBack.JPG

21. Why does drinking alcohol cause dehydration?
Inhibition of release of antidiuretic hormone (ADH)
https://teachmephysiology.com/urinary-system/regulation/antidiuretic-hormone/

22. Major Effects of Alcohol on the Body

23. Symptoms of varying BAC levels. Additional symptoms may occur.
https://en.wikipedia.org/wiki/Blood_alcohol_content

24. ALCOHOL METABOLISM
FREE RADICALS
OXIDATIVE STRESS

25. Where Alcohol Metabolism Takes Place
▪ 96% of alcohol is metabolized in the body mainly by the liver.
▪ 2% lost through breath, sweat & urine
▪ The brain, pancreas and stomach also metabolize alcohol.
https://pubs.niaaa.nih.gov/publications/aa72/aa72.htm

26. The breakdown of alcohol in the body by enzymes:
Alcohol dehydrogenase (ADH), Catalase, P4502E1 & Aldehyde dehydrogenase (ALDH)
https://pubs.niaaa.nih.gov/publications/aa72/aa72.htm

27. The toxic effects of acetaldehyde
https://pubs.niaaa.nih.gov/publications/aa72/aa72.htm
• Highly reactive
• Toxic chemical
• Carcinogenic
96%
Body weight
modulation
Liver

28. Generation of reactive oxygen species from Alcohol Metabolism
https://pubs.niaaa.nih.gov/publications/aa72/aa72.htm
Reactive oxygen species
(free radicals)

29. How do free radicals damage the cell?
free radical chain reaction
https://www.researchgate.net/figure/Diagram-illustrates-the-free-radical-
chain-reaction-Anthracyclines-produce-free-radicals_fig8_257598984

30. Damaging effect of reactive oxygen species (ROS) on
plasma membrane (glycocalyx, protein, lipids) and DNA
glycocalyx
©DRKEVINKFNG

31. Oxidative stress caused by reactive oxygen species (ROS) on
cell membrane structures and DNA
▪ Damage to endothelial glycocalyx
▪ Damage to membrane proteins:
▪ Enzyme inactivation
▪ Receptor dysfunction
▪ Destruction of protein structure
▪ Damage to membrane lipids:
▪ Chain breakage
▪ Increased membrane fluidity
▪ Damage to DNA/RNA
▪ Strand breakage
©DRKEVINKFNG

32. Effect of oxidative stress on a normal cell:
Apoptosis vs Necrosis
Apoptosis
Necrosis
No inflammation Inflammation

33. WHAT IS NECROSIS?
INFLAMMATORY RESPONSE
FATE OF INFLAMMATORY MEDIATORS

34. What is necrosis?
Necrosis is cellular death associated with inflammatory response
(vasodilation, heat, pain and redness)
Adapted from https://www.news-medical.net/life-sciences/Necroptosis-Process.aspx
Proinflammation
mediators Necrosis
Macrophage
Leukocytes

35. Necrosis and the release of inflammatory mediators
Adapted from https://www.news-medical.net/life-sciences/Necroptosis-Process.aspx
The released chemical mediators include
(1) Cytokines (TNF-α, IL-6)
(2) Chemokines (MCP-10
(3) vasoactive amines (histamine and
serotonin
(4) peptide (bradykinin)
(5) eicosanoids ( thromboxanes,
leukotrienes, and prostaglandins)
(6) Nitric oxide
(7) Free radicals.

36. Actions of inflammatory mediators
Adapted from https://www.semanticscholar.org/paper/Mediators-involved-in-inflammation%3A-
effects-of-500-Jean-Bodinier/7c72c341531faced24f3ace16258fa942d4d3d4f/figure/0

37. Fate of ethanol, acetaldehyde and inflammatory mediators
in the circulation

38. The time course of plasma cytokine levels after an IV bolus
injection of E. coli in Human (2008)
https://www.researchgate.net/figure/Fig-3-The-time-course-of-plasma-
cytokine-levels-after-an-IV-bolus-injection-of-E_fig3_23143372

39. Unanswered questions
1. Could hangover be due to a dysfunction of the pulmonary circulation?
2. Could hangover be due to degradation of glycocalyx on the endothelium?
3. Could hangover be due to a cytokine storm?
pulmonary circulation
endothelium
©DRKEVINKFNG

40. Catabolism of alcohol by enzyme alcohol dehydrogenase (ADH),
Acetaldehyde (ALDH), Catalase & P4502E1
http://www.alcoholeducationforyouth.org/teachers/inv_2/lesson2.pdf
P4502E1

41. Fate of ethanol and its metabolite acetaldehyde in the circulation
▪ Half-life of ethanol: 5-6 hours
▪ Half-life of acetaldehyde 90 sec

42. Comparison of some properties of ethanol and acetaldehyde
©DRKEVINKFNG

43. • FREE RADICALS
• OXIDATIVE STRESS
• NEW CONCEPT OF ALCOHOL HANGOVER

44. How do free radicals damage the cell?
free radical chain reaction
https://www.researchgate.net/figure/Diagram-illustrates-the-free-radical-
chain-reaction-Anthracyclines-produce-free-radicals_fig8_257598984

45. Effect of oxidative stress on red blood cells
Oxidative stress

46. Monocyte- and macrophage-derived substances potentially
affected by alcohol
https://pubs.niaaa.nih.gov/publications/10report/chap04b.pdf

47. New concept of hangover is linked to oxidative stress
and inflammatory process
EVIDENCE
1. The decline in endogenous plasma antioxidants:
▪ glutathione
▪ superoxide dismutase.
2. The increase of
▪ Oxidative stress products: malondialdehyde and 8-isoprostane,
▪ Inflammatory cytokines and chemokines: TNF-α, iL-6, MCP-1
▪ Biomarker of inflammation: C-reactive protein
3. Endothelial dysfunction caused by TNF-α and C-reactive
protein.
4. Partial relief of hangover symptoms by aspirin and non-
steroidal anti-inflammatory drugs.

48. Cytokine Changes following Acute Ethanol Intoxication in
Healthy Men: A Crossover Study (2016)
https://www.hindawi.com/journals/mi/2016/3758590/
iL-1Ra
iL-1β
Monocyte Chemoattractant Protein-1 (MCP-1)
Interleukin-1 Receptor antagonis (iL-1Ra)
Anti-inflammatory
Inflammatory
Inflammatory

49. Increase in saliva cytokine concentrations in individual subject from the
hangover-sensitive group (red markers) and hangover-resistant group (blue markers):
Both interleukin (IL)-6 and IL-10 are significantly increased on the post-alcohol day. (2021)
https://pubmed.ncbi.nlm.nih.gov/33916085/
(inflammatory) (anti-inflammatory)
hangover-sensitive
hangover-resistant

50. TNF-α induced shedding of the endothelial glycocalyx is
prevented by hydrocortisone and antithrombin (2008)
https://link.springer.com/article/10.1007/s00395-008-0749-5

51. C-reactive protein impairs the endothelial glycocalyx
resulting in endothelial dysfunction (2009)
https://academic.oup.com/cardiovascres/article/84/3/479/456186
https://criticalcarethoughtsdotcom.files.wordpress.com/2013/12/glycocalix-pic2.png

52. Markers of oxidative stress and inflammatory responses in the
first four hours after alcohol consumption.(2020)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408936/
endogenous antioxidants
inflammatory markers

53. Summary of oxidative stress and the inflammatory response
during alcohol hangover (2020)
Adapted from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408936/
CRP = C-reactive protein, IL-6 = interleukin-6,
SOD = superoxide dismutase.
TNF-α

54. Summary
▪ Hangover is known to result from excessive alcohol drinking
for thousands of years.
▪ The causative agents were thought to be congeners and
acetaldehyde.
▪ Recent studies show that alcohol hangover is due to
oxidative stress and acute inflammation.
▪ Evidence has shown that hangover caused a reduction of
endogenous antioxidants, an increase in products of
oxidative stress, an increase in cytokines, chemokines and
C-reactive protein.
▪ This new concept of alcohol hangover as an inflammatory
response will lead to new remedy for the relief of hangover
symptoms.

55. ANY QUESTION?
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