Biochemistry of Chronic Alcoholism and Liver

Cirrhosis

Reported by:
Soria, Nicole
Talosig, Brenda
Tambal, Nic Junn

Members:
Soria, Nicole
Taaca, Alec
Talosig, Brenda
Tambal, Nic Junn
Tamesis, James
Tanagon, Bianca
Group 9
Alcohol

In chemistry, an alcohol is any organic compound in which a hydroxyl functional group (-OH) is
bound to a carbon atom. An important class is the simple acyclic alcohols, the general formula of which
is CnH2n+1OH. Alcoholic beverages contain the acyclic alcohol ethanol (molecular formula C 2H5OH,
empirical formula C2H6O). Ethanol is volatile, flammable, colorless liquid.

Fig 1. Basic structure for alcohols

The theoretical energy content of alcohol is 7.1 kCal per gram. However, despite having the
second highest energy content, they are considered “naked” since they carry no other nutritional value.

Table 1. Caloric content of different types of alcohol

Alcoholic Drink Amount Calories
Beer Half Liter 184
Lager Half Liter 180
Cider Half Liter 200
Whisky 100ml 220
Gin 100ml 220
Brandy 100ml 220
Rum 100ml 220
Wine Red 100ml 70
Wine White Dry 100ml 65
Wine White Medium 100ml 70
Wine White Sweet 100ml 90
Wine White Sparkling 100ml 74
Champagne 100ml 126

Different alcoholic beverages carry different concentrations of alcoholic. Some beverages range
from less than 0.1%, while others can reach 95%.

Table 2. Alcoholic content of different alcoholic beverages

Alcoholic Beverage Alcoholic content
Fruit juice (naturally occurring) less than 0.1%
Low-alcohol beer 0.0%–1.2%
Kvass 0.05%-1.5%
Cider 2%–8.5%
Beer 2%–12% (most often 4%–6%)
Mead 8%-16%
 Barley wine (strong ale) 8%–15%
Wine 9%–18% (most often 12.5%–14.5%)
Sake (rice wine) 15% (or 18%–20% if not diluted prior to bottling)
Liqueurs 15%–55%
Mezcal, Tequila 32%-60% (usually 40%)
Vodka 32%–80% (usually 40%)
Pure vanilla extract 35%+
Brandy 36%–60%
Rum 37.5%–80%
Gin 40%-50%
Whisky 40%–55% (usually 40% or 43%)
Absinthe 45%–89.9%
Neutral grain spirit 95%
Progressive Effects of Alcohol
BAC (%) Behavior Impairment
0.01–0.029 Average individual appears Subtle effects that can be
normal detected with special tests
0.03–0.059 Mild euphoria Alertness
Sense of well-being Judgment
Relaxation Coordination
Joyousness Concentration
Talkativeness
Decreased inhibition
0.06–0.10 Blunted Feelings Reflexes
Disinhibition Reasoning
Extroversion Depth Perception
Lowered sex drive Distance Acuity
Peripheral Vision
Glare Recovery
0.11–0.20 Over-Expression Reaction Time
Emotional Swings Gross Motor Control
Angriness or Sadness Staggering
Boisterousness Slurred Speech
0.21–0.29 Stupor Severe Motor Impairment
Loss of Understanding Loss of Consciousness
Impaired Sensations Memory Blackout
0.30–0.39 Severe CNS Depression Bladder Function
Unconsciousness Breathing
Death Possible Heart Rate
>0.40 Unconsciousness Breathing
Death Heart Rate

Alcohol has an effect on the gamma-aminobutyric acid system (GABA). GABA is known for its
inhibitory effect on the brain, and could also be responsible for the memory impairment that many
people experience.
 Alcohol primarily acts as a positive allosteric modulator of GABA A. Alcohol binds to several
subtypes of GABAA, but not all. Main subtypes include α1β3γ2, α5β3γ2, α4β3δ and α6β3δ subtypes,
although other subtypes such as α2β3γ2 and α3β3γ2 are also affected. Activation of these receptors
causes most of the effects of alcohol such as relaxation and relief from anxiety, sedation, ataxia and
increase in appetite and lowering of inhibitions which can cause a tendency towards violence in some
people.

Metabolism of Alcohol

Alcohol is completely absorbed by the body in the GIT. However, alcohol cannot be stored in the
body, therefore it must be completely oxidized. Alcohol can only be oxidized in the liver. The first step of
alcohol metabolism is the oxidation of ethanol to acetaldehyde catalyzed by alcohol dehydrogenase
(ADH) containing coenzyme NAD +. Acetaldehyde is further oxidized to acetic acid and finally CO 2 and H2O
through the Kreb’s cycle. Alcohol also is metabolized in the liver by the enzyme cytochrome P450IIE1
(CYP2E1), which may be increased after chronic drinking.
Fig 2. Alcohol metabolism located within the liver

A number of metabolic effects from alcohol are directly linked to the production of an excess of
both NADH and acetaldehyde. Because of the excess NADH and acetaldehyde, a number of pathways
are activated which may consequently block other metabolic pathways. Such pathways include
gluconeogenesis, lipogenesis and the electron transport chain.

Fig 3. Pathways affected by the metabolism of alcohol. Gluconeogenesis and the citric acid cycle are inhibited.
 The conversion of pyruvic acid to lactic acid requires NADH:

Pyruvic Acid + NADH + H+ ---> Lactic Acid + NAD+

Pyruvate is normally used for conversion into glucose by the gluconeogenesis pathway.
However, due to the increased production of NADH, the pyruvic stores of the body are depleted.
Gluconeogenesis is then inhibited by low concentrations of pyruvic acid, resulting in hypoglycemia and
acidosis due to lactic acid build-up.

Excess NADH may be used as a reducing agent in two pathways – one to synthesize glycerol and
the other to synthesize fatty acids. This may lead to initial obesity in heavy drinkers.

NADH can also be directly utilized in the electron transport chain to synthesize ATP as a source
of energy. This reaction has a direct effect on inhibiting the normal oxidation of fats in the fatty acid
spiral and citric acid cycle. The accumulation of fats or acetaldehyde may result in ketosis. Accumulation
of fat in the liver can be alleviated by secreting lipids into the blood stream. The higher lipid levels in the
blood may be responsible for heart attacks.

Diseases associated with Chronic Alcoholism

Wernicke-Korsakoff Encephalopathy

Wernicke encephalopathy is a syndrome characterized by ataxia, ophthalmoplegia, confusion,

and impairment of short-term memory.

It is caused by lesions in the medial thalamic nuclei, mammillary bodies, periaqueductal and
periventricular brainstem nuclei, and superior cerebellar vermis, often resulting from inadequate intake
or absorption of thiamine (Vitamin B1), especially in conjunction with carbohydrate ingestion.
Its most common correlate is prolonged alcohol consumption resulting in thiamine deficiency.
Alcoholics are therefore particularly at risk, but it may also occur with thiamine deficiency states arising
from other causes, particularly in patients with such gastric disorders as carcinoma, chronic gastritis,
Crohn's disease, and repetitive vomiting, particularly after bariatric surgery.
When persistent learning and memory deficits are present, the symptom complex is often called
Wernicke-Korsakoff syndrome

Wernicke-Korsakoff syndrome results from thiamine deficiency. The metabolically active form
of thiamine is thiamine diphosphate which plays a major role as a cofactor or coenzyme in glucose
metabolism. The enzymes which are dependent on thiamine diphosphate are associated with the TCA
Cycle, and catalyse the oxidation of pyruvate, alphaketoglutarate and branched chain amino acids. Thus,
anything that encourages glucose metabolism will exacerbate an existing clinical or sub-clinical thiamine
deficiency
 A deficiency of thiamine (vitamin B-1) is responsible for the symptom complex manifested in
Wernicke-Korsakoff syndrome, and any condition resulting in a poor nutritional state places patients at
risk. Heavy, long-term alcohol use is the most common association with Wernicke-Korsakoff syndrome.
Alcohol interferes with active gastrointestinal transport, and chronic liver disease leads to decreased
activation of thiamine pyrophosphate from thiamine, as well as a decreased capacity of the liver to store
thiamine.

Thiamine is converted to its active form, thiamine pyrophosphate, in neuronal and glial
cells. Thiamine pyrophosphate serves as a cofactor for several enzymes, including transketolase,
pyruvate dehydrogenase, and alpha ketoglutarate, that function in glucose use. The main function of
these enzymes in the brain is lipid (myelin sheath) and carbohydrate metabolism, production of amino
acids, and production of glucose-derived neurotransmitters. Thiamine appears to have a role in axonal
conduction particularly in acetylcholinergic and serotoninergic neurons. A reduction in the function of
these enzymes leads to diffuse impairment in the metabolism of glucose in key regions of the brain
resulting in impaired cellular energy metabolism.

Fatty Liver

Fat (triglycerides) accumulates throughout the hepatocytes for the following reasons:
 Export of fat from the liver is decreased because hepatic fatty acid oxidation and lipoprotein
production decrease.
 Input of fat is increased because the decrease in hepatic fat export increases peripheral lipolysis
and triglyceride synthesis, resulting in hyperlipidemia.

The mechanism of alcohol induced fatty liver involves an above average NADH:NAD ratio caused by
alcohol metabolism by alcohol dehydrogenase and aldehyde dehydrogenase. A higher NADH
concentration induces fatty acid synthesis while decreased NAD level causes decreased fatty acid
oxidation. Consequently, the higher levels of fatty acid signal the hepatocytes to compound it to glycerol
to form triglycerides.

Liver disease in the alcoholic is due not only to malnutrition but also to ethanol's hepatotoxicity
linked to its metabolism by means of the alcohol dehydrogenase and cytochrome P450 2E1 (CYP2E1)
pathways and the resulting production of toxic acetaldehyde. In addition, alcohol dehydrogenase–
mediated ethanol metabolism generates the reduced form of nicotinamide adenine dinucleotide
(NADH), which promotes steatosis or fatty liver by stimulating the synthesis of fatty acids and opposing
their oxidation. Steatosis or Fatty Liver is also promoted by excess dietary lipids and can be attenuated
by their replacement with medium-chain triglycerides. Through reduction of pyruvate, elevated NADH
also increases lactate, which stimulates collagen synthesis in myofibroblasts. Furthermore, CYP2E1
activity is inducible by its substrates, not only ethanol but also fatty acids. Their excess and metabolism
by means of this pathway generate release of free radicals, which cause oxidative stress, with
peroxidation of lipids and membrane damage, including altered enzyme activities. Accordingly, the
intracellular concentration of free fatty acids may become high enough to injure membranes, thereby
contributing to necrosis, inflammation, and progression to fibrosis and cirrhosis.

Liver Cirrhosis
 Liver cirrhosis is a consequence of chronic liver disease characterized by replacement of liver
tissue by fibrosis, scar tissue and regenerative nodules.

Alcohol (ethanol) is readily absorbed from the stomach, but most is absorbed from the small
intestine. Alcohol cannot be stored. A small amount is degraded in transit through the gastric mucosa,
but most is catabolized in the liver, primarily by alcohol dehydrogenase (ADH) but also by cytochrome P-
450 2E1 (CYP2E1) and the microsomal enzyme oxidation system (MEOS).

ADH, a cytoplasmic enzyme, oxidizes alcohol into acetaldehyde. Genetic polymorphisms in ADH
account for some individual differences in blood alcohol levels after the same alcohol intake but not in
susceptibility to alcoholic liver disease.

Acetaldehyde dehydrogenase (ALDH), a mitochondrial enzyme, then oxidizes acetaldehyde to

acetate. Chronic alcohol consumption enhances acetate formation.

These oxidative reactions generate hydrogen, which converts nicotinamide-adenine

dinucleotide (NAD) to its reduced form (NADH), increasing the redox potential (NADH/NAD) in the liver.
The increased redox potential inhibits fatty acid oxidation and gluconeogenesis, promoting fat
accumulation in the liver.

Chronic alcoholism induces the MEOS (mainly in endoplasmic reticulum), increasing its activity.
The main enzyme involved is CYP2E1. When induced, the MEOS pathway can account for 20% of alcohol
metabolism. This pathway generates harmful reactive O 2 species, increasing oxidative stress and
formation of O2-free radicals.

Oxidative damage: Oxidative stress is increased by

 Liver hypermetabolism, caused by alcohol consumption
 Free radical–induced lipid peroxidative damage
 Binding of alcohol oxidation products, such as acetaldehyde, to liver cell proteins, forming
neoantigens and resulting in inflammation
 Accumulation of neutrophils and other WBCs, which are attracted by lipid peroxidative damage
and neoantigens

Pathways Affected by Liver Cirrhosis

 Fig 4. Metabolism of ethanol and acetaldehyde in the hepatoyte

The ADH pathway, which converts alcohol to the toxic substance acetaldehyde in a reaction
that releases hydrogen atoms, is responsible for most of the alcohol breakdown in liver cells.

The major pathway for the metabolism of alcohol is found in the liver and involves the enzyme
alcohol dehydrogenase (ADH).  Alcohol is metabolized to acetaldehyde, a highly reactive and potentially
toxic molecule.  In most circumstances, acetaldehyde is rapidly metabolized by another enzyme,
aldehyde dehydrogenase (ALDH) to acetate.  Because of the rapid enzymatic conversion of acetaldehyde
to acetate, the concentration of acetaldehyde in the cell is typically a thousand-fold lower than that of
alcohol, and the eventual product of this pathway, acetate.  Both alcohol and acetate are found at
millimolar levels following drinking, while acetaldehyde is found at micromolar concentrations.  When
the level of acetaldehyde increases, an individual may experience very dysphoric feelings and the
potential for toxic reactions with various cellular components increases. Conversely, alcohol metabolism
by the ADH pathway also may influence metabolic functions. As mentioned above, ADH-mediated
breakdown of alcohol generates hydrogen atoms in addition to acetaldehyde. These hydrogen atoms
interact with a molecule called nicotinamide adenine dinucleotide, converting it to reduced NAD. NADH,
in turn, participates in many essential biochemical reactions in the cell, and in the process passes on its
hydrogen to other molecules. For proper functioning of the cell, the ratio of NAD to NADH must be
tightly controlled. When alcohol metabolism generates excess amounts of NADH, the cell can no longer
maintain the normal NAD/NADH ratio. This altered NAD/NADH ratio may lead to several metabolic
disorders.

The Microsomal Ethanol Oxidizing System (MEOS) is an alternate pathway of ethanol

metabolism to the oxidation of ethanol via alcohol dehydrogenase.
 After moderate alcohol consumption, most of the ingested alcohol is broken down by the ADH
pathway. After chronic heavy alcohol consumption, the MEOS pathway of alcohol metabolism becomes
more important. This pathway consists of several enzymes located in the liver microsomes - small
spherical structures found in all cells. The MEOS has been investigated extensively because its activity
increases substantially after long-term alcohol consumption and because it is important for the
breakdown and elimination of other foreign molecules from the body. The primary component of the
MEOS is the molecule cytochrome P450, which exists in several variants. The variant most important for
alcohol metabolism is cytochrome P450 2E1 (CYP2E1). Enhanced CYP2E1 activity in response to chronic
alcohol consumption (or other factors) probably contributes to the development of alcoholic liver
disease. Alcoholics commonly suffer from a type of liver disease called steatohepatitis, which is an
inflammation of the liver with concurrent fat accumulation in the liver. Alcohol-induced activation of the
MEOS also contributes to alcoholic liver disease through other mechanisms. For example, alcohol
breakdown by CYP2E1 generates several types of highly reactive oxygen-containing molecules called
reactive oxygen species (ROS). These ROS can damage liver cells by inactivating essential enzymes and
altering the breakdown of fat molecules; higher ROS levels contribute to a condition called oxidative
stress, which can cause liver cell damage.

Clinical Manifestations of Liver Cirrhosis

Hepatic Encephalopathy
Hepatic (portosystemic) encephalopathy represents a potentially reversible decrease in
neuropsychiatric function caused by acute and chronic liver disease, occurring predominantly in patients
with portal hypertension. The onset often is insidious and is characterized by subtle and sometimes
intermittent changes in memory, personality, concentration, and reaction times. Hepatic
encephalopathy is a diagnosis of exclusion; therefore, all other etiologies of altered mental status must
be effectively ruled out.

Increases in the ratio of plasma aromatic amino acids to branched-chain amino acids as a
consequence of hepatic insufficiency also may contribute to encephalopathy.

Precipitants: Although the onset of hepatic encephalopathy may simply reflect worsening of
underlying liver disease, it may also be due to a number of independent factors, each treatable in its
own right. In fact, studies have shown that the majority of cases are due to one (or more) of such
precipitating factors. It is critical, then, that a search for possible precipitants be conducted in patients
with new-onset hepatic encephalopathy, and specific treatment initiated if such a precipitant is
discovered.

Virtually any metabolic disturbance may precipitate hepatic encephalopathy. Common culprits
are hyponatremia (often arising as a result of diuretic treatment or simply as a complication of the
edema typically found in advanced cirrhosis), hypokalemia (again, often as a result of diuretic use),
alkalosis, dehydration, hypoglycemia (a condition to which people with cirrhosis are susceptible), and
renal failure of even mild degree.

Likewise, there are several medications the use of which may bring on hepatic encephalopathy.
These include benzodiazepines (e.g., diazepam, lorazepam), narcotics, and diuretics. Alcohol ingestion,
whether or not it was the cause of the patient's liver disease, may also precipitate hepatic
encephalopathy.

Infection is an important precipitant of hepatic encephalopathy. In some cases, the only clinical
manifestation of the infection is the development of the encephalopathy. In fact, this is a frequent
phenomenon in patients whose ascites has become infected (i.e., spontaneous bacterial peritonitis).
Sometimes, hepatic encephalopathy arises as a result of patient non-compliance with dietary protein
restriction. Indeed, given the general lack of palatability of low-protein diets, non-compliance is
common and, hence, so is its effect to precipitate encephalopathy.

Bleeding into the stomach or small intestine (both of which occur with increased frequency in
people with liver disease and/or portal hypertension) may also lead to hepatic encephalopathy. Blood
contains large quantities of protein in the form of plasma proteins and hemoglobin. Hence, the presence
of blood in the stomach or small intestine represents a protein load which, as a result of bacterial
metabolism in the lumen of the gut, is converted to potentially toxic products such as ammonia.

Certain surgical procedures employed to treat portal hypertension commonly lead to the
development of hepatic encephalopathy. For example, operations to relieve pressure in the portal vein
by connecting it to the splenic vein or other systemic venous vessels have the effect of diverting
incoming intestinal venous blood away from the liver. This means that such ammonia-carrying blood will
not be able to be "purified" by the liver.

Ammonia can cross the blood-brain barrier, where it causes the support cells of the brain
(astrocytes) to swell. The swelling of the brain tissue increases intracranial pressure, and can lead to
coma or death via herniation of the brainstem.

Ascites

Ascites is defined as the pathologic accumulation of fluid in the peritoneal cavity. Approximately
85 percent of patients with ascites have cirrhosis, and the remaining 15 percent have a nonhepatic
cause of fluid retention.

The initial laboratory investigation of ascitic fluid should include a differential leukocyte count, a
total protein level, and a serum-ascites albumin gradient (SAAG). The SAAG is a useful prognosticator of
portal pressure; it is calculated by subtracting the ascitic albumin concentration from the serum albumin
concentration obtained on the same day. If the SAAG is 1.1 g per dL (11 g per L) or greater, there is a
high likelihood of portal hypertension; if it is less than 1.1 g per dL, other causes of ascites should be
explored, including peritoneal carcinomatosis, tuberculous peritonitis, and pancreatic ascites. The ascitic
fluid total protein level typically has been used in defining ascitic fluid as transudative (protein content
less than 2.5 g per dL [25 g per L]) or exudative (protein content of 2.5 g per dL or greater) and to help
identify patients at higher risk of developing spontaneous bacterial peritonitis. However, this method is
flawed because many patients with spontaneous bacterial peritonitis, in which ascitic fluid is infected,
have a low rather than high ascitic fluid total protein level, and many fluid samples from patients with
portal hypertension secondary to heart failure have a high rather than the expected low ascitic fluid
total protein level.

Portal Hypertension and Variceal Bleeding

 Regardless of the etiology of cirrhosis, the development of portal hypertension is nearly
universal and results from an increased resistance to portal flow secondary to scarring, narrowing, and
compression of the hepatic sinusoids due to the deposition of collagen. When the portal pressure
exceeds a certain threshold, it results in the development of varices. Approximately 50 percent of
patients with cirrhosis develop varices, most commonly in the distal 2 to 5 cm of the esophagus. Variceal
hemorrhage is defined as bleeding from an esophageal or gastric varix at the time of endoscopy, or the
presence of large esophageal varices with blood in the stomach and no other recognizable source of
bleeding.

Hyperestrenism

Cirrhosis of liver can also cause hyperesterinism or hyper-estrogenim. Since the liver cannot
inactivate estrogens, there is too much estrogen in the system. This causes gynaecomastia and spider
naevi, and can lead to testicular atrophy and other signs of feminisation.

Bleeding Tendency

One of the effects of a cirrhotic liver is its inability to produce clotting factors, specifically
factors: II, VII, IX and X, which will bring about tendencies of bleeding.

Osteoporosis

Vitamin D regulates calcium and phosphorous in the bones, and it is activated in the liver, but
due to the impairment of the liver, vitamin D remains in its inactive form, bones will not be mineralized
and there will be reduction in their density.

Hypoglycemia

The impaired liver results to a decrease or absence of glycogen stored in the liver due to
decreased in glycogenesis activity, which also occurs in the liver

Treatment and Management of Chronic Alcoholism and Hepatic Encephalopathy

Treatment and Management for Hepatic Encepalopathty

The specific treatment is aimed at elimination/reatment of precipitating factors, and lowering

blood ammonia levels by decreasing the absorption of protein and nitrogenous products from the
intestine

 In the setting of acute GI bleeding, evacuate the blood in the intestine with laxatives to reduce
nitrogen load.
 Exclusion of protein in diet.
 Administration of antibiotics to eliminate intestinal bacterias producing ammonia.
 Liver transplantation could be considered if there would be inadequate response from the
mentioned treatment.
Treatments for Alcoholism

 Admission of having a problem

 Detoxification (drying out)
 Counseling
 Support groups
 Alcoholics Anonymous
 Avoidance of alcohol
 Aversion therapy
 Avoiding friends who abuse alcohol
 Other treatments for any complications
 Vitamin B2 - possibly used if for treatment of vitamin B2 deficiency
 Vitamin B1 - possibly used for related Vitamin B1 deficiency
 Vitamin B6 - possibly used for treatment of vitamin B6 deficiency
 Vitamin B5 - possibly used for treatment of related vitamin B5 deficiency
 Self-help programs, Support group, Counseling, Nutrition, Exercise, Medications - antabuse,
naltrexone, acamprosate, topiramate
 Recognition of the problem
 Detoxification (drying out) as an outpatient in as an inpatient if there is history of delirium
tremens, significant comorbidities or poor social support
 Counseling
 Support groups
 Alcoholics Anonymous
 Avoidance of alcohol related activities
 Aversion therapy
 Avoiding friends who abuse alcohol
 Management of complications of alcoholism - nutritional deficiencies, social issues such as
housing etc.
 Medications - disulfiram, naltrexone, acamprosate, topiramate in combination with a structured
support program
 Aggressive treatment of any psychiatric comorbidities such as anxiety and depression