ALCOHOLISM, FATTY LIVER & LIVER CIRRHOSIS

BIOCHEMISTRY CONFERENCE
SECOND SEMESTER- SCHOOL YEAR 2015-2016
MEDICINE 1B-1 GROUP 6

REPORTERS:
Ching, Arkanel
Co, Marc Christian
Collado, Jodeeym

MEMBERS:
Clarito, Hermily Claire
Chuan, Lizette
Cipriano, Alvin
Objectives
At the end of the conference, the students should
be able to:
• Define Alcoholism.
• Discuss how the human body metabolized
alcohol.
• Enumerate the metabolites accumulated in
alcohol ingestion and the metabolic pathways
that are affected.
• Discuss causes of inebriation after alcohol
ingestion.
• Discuss the development of hypoglycemia.
• Discuss Wernicke-korsakoff encephalopathy.
Objectives
• Discuss the causes of fatty liver in chronic
alcoholism.
• Discuss the mechanisms involved in the production
of liver cirrhosis in chronic alcoholism.
• Enumerate the metabolic pathways are affected as
a result of liver damage in liver cirrhosis.
• Discuss the mechanisms involved in the
development of the clinical manifestations seen in
liver cirrhosis.
• Discuss the mechanisms behind the development
of hepatic coma in liver cirrhosis.
• Discuss the management of hepatic
encephalopathy.
 Outline
I. Alcoholism VIII. Clinical Manifestation In Liver
i. Alcohol Cirrhosis
ii. Ethanol IX. Development of Hepatic Coma in
II. Alcohol Metabolism Liver Cirrhosis
i. Alcohol Dehydrogenase X. Management of Hepatic
Encephalopathy
ii. Catalase
iii. CYP2E1
iv. Acetaldehyde Dehydrogenase
III. Metabolites And Affected Pathway
IV. Alcohol Inebriation
V. Wernicke-korsakoff Encephalopathy
VI. Mechanisms Involve In Liver Cirrhosis
VII. Pathway Affected In Liver Cirrhosis
i. ADH Pathway
ii. Microsomal Ethanol Oxidizing
System
ALCOHOLISM
• (WHO) It refers to chronic continual drinking
or periodic consumption of alcohol which is
characterized by impaired control over
drinking, frequent episodes of intoxication
and pre-occupation with alcohol and the use
of alcohol despite adverse consequences.
ALCOHOLS
• A large group of organic compounds.
• Derived from hydrocarbons containing one or
more (-OH) group.
ETHANOL
• Also known as Ethyl alcohol.
• Molecular formula (C2H5OH).
• Main ingredient in alcoholic beverages.
– Beer
– Wines
– Spirits
ALCOHOL METABOLISM

Ref: Alcohol Research and Health V. 29 No. 4

METABOLITES ACCUMULATED IN
EXCESSIVE ALCOHOL INGESTION
• NADH
• NAD+

AFFECTED METABOLIC PATHWAY

• GLUCONEOGENESIS
• LIPOGENESIS
• ELECTRON TRANSPORT CHAIN
GLUCONEOGENESIS
• NADH inhibits Gluconeogenesis.
• Preventing the oxidation of lactate to
pyruvate.
• May lead to Hypoglycemia and Lactic Acidosis.
GLUCONEOGENESIS
(↑) Increase
Alcohol Intake

(↑) Increase
NADH/NAD+

(↑) Increase
Lactate

(↓) Decrease
Glucose

HYPOGLYCEMIA
LIPOGENESIS
• The synthesis of Fatty Acid and their esterification
to glycerol to form Triacylglycerol.
• Impaired Fatty Acid oxidation and increased
lipogenesis is due to changes in NADH/NAD+
redox potential.
• Oxidation of ethanol by Alcohol Dehydrogenase
leads to excess production of NADH which
competes with reducing equivalents from other
substrate.
LIPOGENESIS
• It inhibits their oxidation and cause increased
esterification of Fatty Acid to form
Triacyglycerol resulting to Fatty Liver.
• Increased NADH/NAD+ ratios causes increased
Lactate/ Pyruvate resulting to
HYPERLACTICACEDEMIA.
ELECTRON TRANSPORT CHAIN
• Cytochrome P450- dependent Microsomal
Ethanol Oxidizing System (MEOS)
• This system increases activity in chronic
alcoholism.
• Many cytochrome P450 enzymes are induced
by substrate which give rise to tolerance.
• Ethanol can inhibit cytochrome P450 system.
• MEOS is utilized when ethanol is high.
INEBRIATION/ ACUTE INTOXICATION
• (WHO) A condition that follows the
administration of a psychoactive substances
and results in disturbances in the level of
consciousness, cognition, perception,
judgment, affect on behavior, or other
psychophysiological function.
Ref: http://awareawakealive.org/educate/blood-alcohol-content
INEBRIATION/ ACUTE INTOXICATION
(↑) Increase Alcohol
Intake

(↑) Increase GABA

(-) Slow signal flow to

brain

(↓) Decrease Mental

and Physical Activities
Wernicke Encephalopathy
 Ataxia
Ophthalmoplegia
Confusion
Impairment of short-term memory

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, especially in conjunction
with carbohydrate ingestion.
Its most common correlate is prolonged alcohol
consumption resulting in thiamine deficiency.

When persistent learning and memory deficits

are present, the symptom complex is often called
Wernicke-Korsakoff syndrome
 Wernicke-Korsakoff syndrome
 deficiency of thiamine (vitamin B-1)
 poor nutritional state
 heavy, long-term alcohol use

Alcohol interferes with active gastrointestinal

transport, and chronic liver disease leads to
decreased activation of thiamine pyrophosphate
from thiamine

decreased capacity of the liver to store thiamine

Thiamine pyrophosphate
• neuronal and glial cells
• cofactor for several enzymes, including
transketolase, pyruvate dehydrogenase, and
alpha ketoglutarate, that function in glucose
use:
• lipid (myelin sheath) and carbohydrate
metabolism
• production of amino acids
• production of glucose-derived
neurotransmitters

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
Normal Liver
Alcoholic Fatty Liver
 Fatty Liver
Fat (triglycerides) accumulates throughout the
hepatocytes for the following reasons:

1.Export of fat from the liver is decreased

because hepatic fatty acid oxidation and
lipoprotein production decrease
2.Input of fat is increased because the decrease
in hepatic fat export increases peripheral
lipolysis and triglyceride synthesis, resulting in
hyperlipidemia
• alcohol induced fatty liver involves an above
average NADH:NAD ratio caused by alcohol
metabolism by alcohol dehydrogenase and
aldehyde dehydrogenase

• higher levels of fatty acid signals the

hepatocytes to compound it to glycerol to
form triglycerides
Cirrhotic Liver
 LIVER CIRRHOSIS
- a consequence of chronic liver disease
- replacement of liver tissue by fibrosis, scar tissue
and regenerative nodules

ALCOHOL
absorbed in stomach, most in small intestine
cannot be stored
 small amount 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)
Alcohol produces toxin by product known to be acetaldehyde
that causes damage to the structure and function of
mitochondria in human body cells particularly the liver. Once
the liver become inflamed due to acetaldehyde the kupfer cell
will be activated because kupfer cell is responsible for
inflammation, then the kupfer cell will send signal to cytokines
that will activate the stellate cell. The stellate cell will now
produce fibrin scar that will replace the fluid space.
 Pathways Affected by Liver Cirrhosis
• ADH pathway
• Microsomal Ethanol Oxidizing System
 ADH pathway
converts alcohol to the toxic substance
acetaldehyde in a reaction that releases
hydrogen atoms

 responsible for most of the alcohol

breakdown in liver cells
ADH pathway
MEOS(Microsomal Ethanol Oxidizing System)
Clinical manifestation in liver cirrhosis
Clinical manifestation in liver cirrhosis
• Portal hypertension
• Gastroesophageal varices
• Ascites
• Jaundice
• Coagulopathy
• Hepatorenal syndrome
• Splenomegaly
• Hypoalbuminea or Peripheral edema
• Hepatic encephalopathy
 Clinical manifestation in liver
cirrhosis
• PORTAL
HYPERTENSION
• GASTROESOPHAGEAL
VARICES
 Clinical manifestation in liver
cirrhosis
• JAUNDICE
• ASCITES
• EDEMA
 Clinical manifestation in liver
cirrhosis
• SPLEENOMEGALY
• COAGULOPATHY
• HEPATORENAL SYNDROME
• HEPATIC ENCEPHALOPATHY
Mechanism of hepatic coma in liver
cirrhosis
Mechanism of hepatic coma in liver
cirrhosis

Stage 1 (Mild Hepatic encephalopathy)

Mood fluctuation Sleep-wake reversal Forgetfulness

Stage 2 ( Moderate Hepatic encephalopathy)

Disorrientation Confusion Asterixis Lethargy Aberrant behavior Apraxia

Stage 3 (Severe Hepatic encephalopathy)

Hyperventilation Stuporous but noisy When awake, they become abusive

Stage 4 (Comatose stage)

Fetor hepaticus( musty ,sweet breath odor) Coma

 Management Hepatic
encephalopathy
• Rule out other cause of Hepatic
encephalopathy
• Identify precipitating cause of HE
• Initiate treatment
– Cathartics
– Antibiotics
– Increasing ammonia metabolism
 Management Hepatic
encephalopathy
Cathartics
– Lactulose (beta-galactosidofructose)
• Non-absorbable disaccharides
• Inhibits intestinal ammonia production
• Dosage: 30mL, 2x a day
• Overdosage can cause:
– Ileus
– Severe diarrhea
– Electrolyte disturbance
– hypovolemia
 Management Hepatic
encephalopathy
Antibiotics
• To decrease the colonic concentration of
ammoniagenic bacteria
– Neomycin
– Rifamixin
– Metronidazole
– Oral vancomycin
– Paromomycin
– Oral quinolones
 Management Hepatic
encephalopathy
Increase ammonia clearance

– L-ornithine L-aspartate (LOLA)

• It is a stable salt of 2 constituent amino acids
• L-ornithine stimulate the urea cycle, resulting loss of
ammonia
• L-ornithine and L-aspartate are substrates for
glutamate transaminase.
 Management Hepatic
encephalopathy
Increase ammonia clearance

– Zinc
• Improve hyperammonemia by increasing the activity
of ornithine transcarbamylase, an enzyme in the
urea cycle. Increase in ureagenesis results in loss of
ammonia ions.

– L-carnithine
– Sodium benzoate, sodium phenylbutyrate
Most current therapies are designed to treat hyperammonemia that is a hallmark
of most cases in hepatic encephalopathy.
SUMMARY
• Alcoholism is chronic continual drinking of alcohol which is
characterized by impaired control over drinking.
• Alcohols are derived from hydrocarbons containing one or more (-
OH) group.
• Ethanol is main ingredient of alcoholic drinks.
• Alcohol metabolism takes place in Cytosol (Alcohol DH),
Microsomes (CYP2E1), Peroxisomes (Catalase), and Acetaldehyde
DH (Mitochondria).
• Wermicke’s encephalopathy is a paralysis of the muscles within or
surrounding the eyes.Inabilty to coordinate voluntary muscular
movements.
• Fatty liver is a accumulation of triaglycerides in hepatocytes.
• Liver cirrhosis is a replacement of liver tissue by fibrosis, scar tissue
and regenerative nodules.
References
Rodwell, V.M., Bender, D.A., Botham, K.M., Kennely, P.J., Weil., P.A. Haper’s Illustrated
Biochemistry 30th Ed. (2015). Mc graw Hill.

Puri D. Medical Biochemistry 2nd Ed. (2006) Elsevier.

Zakari S. Overvie: How Is Alcohol Metabolize by the Body?. In Alcohol Research and
Health Vol. 29 No. 4. (2006) pp. 245-255.

Kumar, V. Abbas, A., Asster, J. Robbins and Cotran’s Pathologic Basis of Disease 9th
Ed.(2015) Elsevier.

www.who.int

www.emedicinehealth.com

http://awareawakealive.org/educate/blood-alcohol-content