Wiany of as are familiar with or may have even experienced our faces turning flushed or red after drinking alcohol Yet, most of us are unaware that this symptom is linked to a higher risk of many alcohol-related cancers.
Alcohol consumption is rising in many developing countries. Globally, alcohol causes around three million deaths a year, including over 400,000 from cancer. There is very wrong evidence to indicate that alcohol has a direct causal relationship with cancers of the head, neck oesophagus, liver, colon and breast. In 2007, the International Agency for Research on Cancer from the World Health Organisation concluded that ethanol is carcinogenic to humans. It was classified as a Group 1 carcinogen because there is sufficient evidence to conclude that the consumption of alcoholic beverages causes cancer in humans.
Recent studies have shown a rise in alcohol consumption during the COVID-19 pandemic, especial, among hea, drinkers. The rise became even higher when the lockdown period was prolonged. During the pandemic, alcohol was used by some people as a coping strategy for depression, anxiety, stress or boredom. There was a further rebound in alcohol consumption when COVID-19 restrictions were lifted. Beyond the pandemic, alcohol consumption also general, rises during the seasonal holiday period, such as Christmas, New Year and Chinese New Year, as well as during celebratory events like birthday parties.
GOING RED IN THE FACE
Alcohol for ethanol) is metabolised predominantly in the liver by alcohol dehydrogenase (ADH) to form the toxic substance acetaldehyde (AA). This is in turn quickly metabolised by aldehyde dehydrogenase 2 (ALDH2) to form acetate, a less active byproduct.
A common hereditary enzyme deficiency affecting about 35% of East Asians (especially Chinese) and about 8% of the population is genetic mutation of the ADH and ALDH2 enzymes. In general, two genetic mutations of these enzymes can lead to the toxic accumulation of AA in the blood. The first mutation leads to the loss of metabolic activity by the enzyme ALDH2, while the other results in an increase in the metabolic activity of ADH. The combined effect of these changes is the accumulation of AA – a known carcinogen-to toxic levels.
People with either of these mutations have poor alcohol tolerance. When they drink alcohol, they will exhibit symptoms like redness in the face, tachycardia. nausea and headache. As these mutations are extremely rare in European populations and more common among East Asians, this physiological response of reddening of the face became popularly known as the Asian Flush…Asian Rush” symptoms may be reduced later in life especially if the individual continues to drink alcohol and his/her body adapts to alcohoL However. the damage caused by the accumulation of AA from alcohol consumption remains serious health risk.
ACCUMULARON OF AA
Some individual. are homozygous for ALDH2 (i.e. they can two copies of the mutated gene), which results in dreamily low ALDH2 activity in their livers. For these Indvidual’s, they are unable to tolerate alcohol at all. They develop severe flushing, tachycardia, nausea and headaches upon any alcohol.
Asian Flush - the characteristic redness of the face as part of an alcohol-flushing respon. - can be used as a visible clinical biomarker for ALDH2 deficiency. Clinicians can determine ALDH2 deficiency simply by asking about previous episodes of alcohol-induced flushing.
consumption. Thus, these individuals are unlikely to develop alcoholism due to the severity of their response to alcohol.
On the other hand, there are people who are heterozygous for ALDH2 (i.e., they carry only one copy of the mutated gene).These people have reduced enzyme activity, but they can still tolerate alcohol ingestion. As a result, some of them may become heavy drinkers or alcoholics. These individuals have significantly elevated AA levels in their saliva, even if they only took a moderate dose of alcohol. The AA levels in their saliva can be nine times higher than that in their blood. This suggests that reduced ALDH2 activity in the salivary glands can lead to AA accumulation in the saliva.
Whenever these individuals drink alcohol, they are exposed to extremely high concentrations of AA in their saliva. High levels of AA in the saliva are commonly associated with a marked increase in cancer risk. Beyond reduced ALDH2 activity in 1. salivary gland. AA is also produced from ethanol by bacterial oxidation in the mouth, throat, oesophagus and colon. This is another major source of . in the saliva and, by extension t. oesophagus In fact, AA levels in the saliva can be 10-20 times higher than that in the blood d. to the local formation of AA by oral bacteria. Similarly, bacteria in t. colon are a. able to metabolise ethanol to . Hence, alcohol consumption can a. lead to a higher risk of developing colon and rectal cancer.
AA is highly toxic , mutagenic and carcinogenic interferes with DNA synthesis and repair, and can result in cancer development at various sit. in the body. It induces inflammation and changes in the lining of gut, while enhancing cell injury in the upper airway, oesophagus and colon. When inhaled, AA can cause nose, throat and laryngeal cancer.
OESOPHAGEAL CANCER AND ALCOHOL
Oesophageal cancer (EC) or cancer of the gullet is the 8th most common cancer and the 6th leading cause of cancer death worldwide. It is associated with a very poor prognosis. About half a million new EC cases occur annually worldwide, and 75% of these are in Asia.
In Asia, 90%of EC cases are due to oesophageal squamous cell carcinoma (ESCC). ESCC arises from long-standing irritation ,n (and inflammation) of the oesophageal lining, most commonly due to smoking and chronic alcohol abuse. Men are Mo times more likely to get ESCC than women, and the disease to occur after the age of 50 years. In Singapore. EC is the 10th most frequent cause of cancer death in men.
While alcohol consumption at any level is associated with an increased risk of ESCC, heavy alcohol consumption is associated with a very high risk of ESCC for people who
experience the “Asian Flush”. These ALDH2-deficient individuals are about eight times more likely to develop ESCC from alcohol consumption; the risk can range from 1.3-fold higher for light drinkers to 10-fold higher for heavy drinkers. One study estimated that 539/0 of ESCC might . prevented in the Japanese male population if moderate or heavy drinking ALDH2 deficient individuals were only light drinker.
In addition, several epidemiological studies have reported that the risk of alcohol-associated cancers is significantly elevated in people with low ALDH2 activity. They have 10 times increased risk of developing mouth, throat, upper airway cancer. and ESCC. In addition. they also have a 50-fold higher risk of developing a second cancer at another site of the oesophagus if they continue drinking alcohol. The risk of colon cancer is increased by three times in these individuals.
“Asian Flush” AS A CUNICAL BIOMARKER
“Asian Flush” – the characteristic redness of the face. part of an alcohol-flushing response – can be used as a visible clinical biomarker for ALDH2 deficiency. Clinicians can determine ALDH2 deficiency simply by asking about previous episodes of a,ohol-induced flushing. Those who are identified as ALDH2- deficient should be counselled to reduce or stop alcohol consumption. while high-risk patients should be assessed endoscopi.11y (with a gastroscope, a. the oesophagus should be carefully studied using white light endoscopy and narrow band imaging) for ESCC. Aoyama et al recently used the acetaldehyde breath t.t (A13T) to identity individuals with ALDH2 deficiency with 969/e accuracy. The ABT can detect very Low levels of AA and alcohol even in cases where only very small amounts of alcohol were ingested.
SYNERGISTIC REACTION OF SMOKING AND ALCOHOL
The use of tobacco product, including cigarette, cigar, pipes and chewing tobacco, is a major risk factor for ESCC. The more a person uses tobacco and the longer he/she uses it, the higher his/her cancer risk. Someone who smoke a pack of cigarettes or more a day has at least twice the risk of getting ESCC as compared to a non-smoker. The good news is that this risk does go down for people who quit tobacco.
The Synergistic effect of alcohol and tobacco use on ESCC is interesting. Smoking dramatically increases AA levels in the saliva especially in ALDH2-deficient individual, the reduced risks for the male carriers of these mutated genes who have a reduced capacity to clear salivary AA As such, .d resulted from their lower alcohol consumption worldwide efforts to control the burden of ESCC should focus on individuals who use both alcohol and tobacco.
HIGHER RISKS OF CANCERS AND THE “ASIAN FLUSH”
Both genetic and epigenetic (non-genetic influence on gene expression) mechanisms are involved in alcohol-induced carcinogenesis of the mouth ,throat, stomach, colon, liver and breast aswell as ESCC. However, ALDH2-deficient individuals who are moderate-to-heavy consumers of ethanol have a 10- fold increased risk for ESCC. This makes ALDH2 deficiency the most common hereditary disorder associated with an increased risk of ESCC.
Recent evidence from a large-scale genetic study by the Oxford Population Health Group confirms that alcohol consumption causes cancer directly. The team used DNA samples from approximately 150,000 Chinese participants (60,000 men and 90,000 women), and the participants were followed for about 11 years. During this period, 4,500 men (7.4%) developed cancer.
In the Chinese population, the frequency of mutation was 21% for ALDH2 and 69% for ADH (compared with <0.01% and 4. respectively in European populations). Interestingly men carrying ALDH2 and ADH genetic mutations were strongly linked to reduced alcohol consumption. Men carrying the mutation for ADH drank very little or not at all and they had a 25% lower risk of overall cancer and alcohol-related cancers. On the other hand, men who carried two copies of mutated gene for ALDH2 drank very little alcohol and consequently, had a 149/o lower risk of developing any cancer, and a 31% lower risk of developing alcohol-related cancers
On the flip side, men who carried only one copy of the mutated ALDH2 gene, and who drank regularly and heavily, had a significantly higher risk of cancer of the head, neck and oesophagus. It is a. important to note that men who carried one copy of the mutated gene for ALDH2, and who did not drink or only drank occasionally had no increased cancer risk. In terms of women, only 2./0 of the female sample population drank regularly. The study did not find any increased risk of cancer in women with t. genet, mutations. This further indicates that the reduced risks for the male carriers of these mutated genes had resulted from their lower alcohol consumption.
PREVENTION IS BETTER THAN CURE
Prevention of cancer continues to be one of the most significant public health challenges of the 21st century. It has a key role to play in the fight against cancer. Based on current scientific evidence, at least 40% of all cancer cases could be prevented with effective primary prevention measures (preventing the onset of the disease process), a. further mortality can be reduced through early detection of cancer or precancerous lesion (also known as secondary prevention)
As ALDH2 deficiency is a hereditary disorder and the enzyme functions primarily in the liver. ALDH2 deficiency is an ideal target for the application of a viral-mediated liver-directed gene therapy to prevent cancer. This model has been proven to work in mice models.
Recognizing the “Asian Flush” as a simple biomarker for ALDH2 deficiency can, in turn, reduce the burden of ESCC. We should especially focus on individual who use both alcohol and tobacco. In this way, those who become red in the face from alcohol intake will be able to make necessary lifestyle changes to reduce their risk profile of developing alcohol-related cancers. This is a decision that will help to keep them in the pink of health.