Lactic

acidosis
explain about the condition
and how DCA could treat it.

CASE FOR LACTIC ACIDOSIS

Lactic acidosis is a physiological condition characterized by low pH in body tissues
and blood (acidosis) accompanied by the buildup of lactate, especially L-lactate,
and is considered a distinct form of metabolic acidosis. Lactic acidosis is
characterized by lactate levels >5 mmol/L and serum pH <7.35.
In a Young Biochemist Association Forum, you are invited to explain about the
condition and how DCA could treat it.

Lactic Acidosis type A(Production of energy without using oxygen)

1. Congestive Heart Failure
2. Low red blood cell (anaemia)
3. Lung disease
Lactic Acidosis type B (Do not related to the deficiency of oxygen)
4. Kidney disease
5. Liver disease
6. Leukimia

Symptoms

Shallow breathing

Muscle pain that may later lead to cramping

Unusual tiredness, sleepiness or weakness

Decreased appetite

Abdominal pain

irregular heart rate

How Lactic acidosis can form ?

Lactic acidosis form by the following:

1. activity of the pyruvate dehydrogenase complex

-

Why PDC can be decreased by low oxygen level?

Pyruvate Dehydrogenase Complex (PDC) is a complex that irreversible oxidation pyruvate to

acetyl-CoA.To convert to acetyl-Coa,its required oxygen

PDC within mitochondrial matrix

The activity of the pyruvate dehydrogenase complex decrease due to the low concentration of
oxygen.

If the oxygen available is insufficient(hypoxia) ,thus the pyruvate will convert into lactate catalyse
by the lactate dehydrogenase in an anaerobic respiration instead of the acetyl-CoA.

This process known as anaerobic respiration.

Thus, it cause the activity of the pyruvate dehydrogenase complex is lower

Pyruvate + NADH + H+ <=> Lactate + NAD+

2. The formation of lactate from the pyruvate (Lactic Acidosis)

PDC kinase cause the inactivation of PDC,inhibiting pyruvate oxidation. Persistent glycolysis
without pyruvate oxidation leads to accumulation of lactate.

Mutations of subunits of the PDC system cause damage of the activity of the enzyme complex
are likely to lead to lactate accumulation

Inability to oxidise carbohydrate completely caused by the consequence of dysfunctional

PDC result in reducing equivalents of NADH

The consequent rise in the intramitochondrial NADH/NAD ratio inhibits PDC activity that
cause pyruvate oxidation decreases, and pyruvate is converted to lactate, resulting in an
increased lactate

Cases of Lactic Acidosis

Congestive heart failure(CHF)
Heart can no longer pump blood efficiently. Cause blood and fluid to back up in the
body.
Heart have two chamber.Blood back up from the right side of heart cause the swelling
of the legs and ankles.If from left side cause the shortness of breath and coughing.
Symptom of the heart failure are caused from the blood backing up on both right and
left side of the heart.
It can cause the damage of heart muscle which is damage the valve within the heart
because heart is forced to beat much more strongly than normal.

How DCA can treat Lactic Acidosis ?

Lactic acidosis can be treated by DCA (dichloroacetate)
DCA will affect PDC by :
- activity of pyruvate dehydrogenase complex is affected by dichloroacetate?

DCA -dichloroacetate
PDK - pyruvate dehydrogenase kinase
PDC- pyruvate dehyrogenase complex
PDH- pyruvate dehydrogenase

Pyruvate dehydrogenase is the enzyme that will catalyse the oxidative decarboxylation of
pyruvate to acetyl CoA
PDH complex can be existed in two forms: Phosphorylated & dephosphorylated

PDH complex is activated when it is dephosphorylated by pyruvate dehydrogenase phosphatase

PDH complex is deactivated when it is phosphorylated by pyruvate dehydrogenase kinase

DCA is a compound that lowers blood lactate levels.

DCA act as an inhibitor of PDK

PDC activity is increased by DCA by inhibit the PDK

when PDK is inhibit the PDC will be in active form

when PDC is in its active form, pyruvate can be converted to Acetyl CoA

Formation of lactate is inhibit

NADH, ATP,
ACETYLCOA IS
REGULATO
R FOR
SYSTEM

DCA WILL
INHIBIT
PDH
KINASE
INCREASE
PDH
ACTIVITY

Treatment for Lactic Acidosis

Treatment is directed towards correcting the underlying cause of lactic acidosis and
optimizing tissue oxygen delivered by cardiopulmonary support.
Chemotherapy
Drink lots of water.It helps get rid of any excess acid.
Eat a balanced diet includes fruits,vegetables,meats and whole grains
get plenty of sleep at night
Discuss and get the advice from the doctors

The principles of management of

patient with LA :

Diagnose and correct the underlying condition *if possible

Restore adequate tissue O2 delivery *esp restore adequate perfusion

Avoid sodium bicarbonate *except Possibly for treatment of associated severe

hyperkalaemia

# When the circulation is restored, the liver can metabolise the circulating
lactate. If lactic acidosis is severe and the cause cannot be corrected, the
mortality can be quite high.

CONCLUSION
Lactic Acidosis : occurs in association with a wide variety of underlying processes
and may represent a well-tolerated, physiologic event or a life-threatening,
pathologic condition. Overall, theres 2 type of LA : A & B
Lactic acidosis is classified based upon oxygen supply to the tissues. Type A is
that clearly associated with clinically evident hypoperfusion or hypoxia, and type B
includes all other forms, those in which there is no evidence of tissue anoxia.
Lactic acidosis is often diagnosed during the evaluation of an anion gap
acidosis. Treatment is directed toward identification and correction of the
underlying disorder and restitution of normal acid-base equilibrium. (This is the
basic therapeutic goals in treatment of LA)

CONCLUSION
Dichloroacetate (DCA) is an experimental drug that increases the activity of
pyruvate dehydrogenase, and this promotes the oxidation of glucose,
pyruvate, and lactate and thus reduces blood lactate levels. Since oxygen is
required for this metabolic process, DCA has no role in treatment of type A
lactic acidosis. Its role in therapy for type B lactic acidosis may be limited by
the increased ketosis and neurologic complications that occur with its use.
The fact that so many experimental therapies have been tried in lactic
acidosis reflects the poor outcome of this disorder with the use of
current treatment. The mortality of patients with type A lactic acidosis is
approximately 80 percent; with type B it is 50 to 80 percent. Earlier
recognition and correction of the underlying disorder responsible for the
lactic acidosis is the best hope for reduction of this high mortality