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 Failure2. Low red blood cell (anaemia)3. Lung disease

Lactic Acidosis type B (Do not related to the deficiency of oxygen)

4. Kidney disease5. Liver disease6. 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 -dichloroacetatePDK - pyruvate dehydrogenase kinasePDC- 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,ACETYL-COA IS REGULATOR 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.

CONCLUSIONLactic 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, there’s 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