nill

1. Abnormalities In
Carbohydrate Metabolism
By: Ibrahim Bangura, MD.

2. Contents
• Introduction
• Disorders of glucose metabolism
• Disorders of fructose metabolism
• Disorder of galactose metabolism
• Conclusion

3. Introduction
• Carbohydrates are widely distributed in plants and animals
• Major source of energy
• If there is any defect in carbohydrate metabolism, there will be clinical
consequences and may even lead to death
• Inborn error may occur in metabolism of all biomolecules
• Errors occur due to defective enzyme
• The effected enzyme may be absent or deficient

4. • The defect occur due to mutation in coding gene of the enzyme
• If the enzyme
 totally inactive ; the reaction will not occur (absent enzyme)
 Decreased activity ; the reaction velocity will decrease (deficient enzyme)
• When an enzyme of a metabolic pathway is absent or deficient, the
entire pathway become abnormal.
• Such abnormalities can occur in carbohydrate metabolism.

5. Disorders Of Glucose Metabolism
• Pyruvate kinase deficiency
• Pyruvate dehydrogenase deficiency
• Muscle phosphofructokinase deficiency
• Glucose 6 phosphate dehydrogenase deficiency
• Essential pentosuria
• Glycogen storage diseases

6. Pyruvate kinase deficiency
• Autosomal recessive disease
• The most common enzyme defect in glycolytic pathway

7. • Almost all individuals with PK deficiency have mutant enzyme
• The enzyme may show
Abnormal response to the activator Fructose 1,6-bisphosphate
Abnormal Km or Vmax for substrate or coenzyme
Altered enzyme activity
Amountof enzyme decrease

8. • 90% of energy in RBC comes from glycolysis
• ATP is needed for maintenance of membrane structure
• Defect in PK reduced rate of glycolysis decreased ATP production
• alterations in RBC membrane phagocytosed by the RE system
hemolytic anaemia.
• Symptoms due to hemolytic anaemia, splenomegaly, hepatomegaly
• Treatment include blood transfusion, splenectomy.

9. • The effect is restricted to RBC
• Hepatic PK is encoded by the same gene as the RBC isozyme.
• Liver cells show no effect because they have mitochondria and can
generate ATP by oxidative phosphorylation
• Individuals with heterozygous for PK deficiency have resistance to the
most severe forms of malaria

10. Pyruvate Dehydrogenase
Deficiency
• Most common cause of congenital lactic acidosis
• The PDH complex is a protein aggregate containing three enzymes
 pyruvate dehydrogenase (E1)
dihydrolipoyl transacetylase (E2), and
dihydrolipoyl dehydrogenase (E3)
• E1 thiamine pyrophosphate (TPP)
• E2 lipoic acid and CoA
• E3 flavin adenine dinucleotide (FAD) and nicotinamide adenine
dinucleotide (NAD+)

11. Oxidative decarboxylation
of pyruvate

12. • Pyruvate is decarboxylated by
PDH
forming hydroxyethyl TDP
• Reacts with oxidized lipoamide
group of
E2 forming acetyl lipoamide
• Reacts with coenzyme A forming
acetyl CoA
• Reduced lipoamide is oxidized by
FAD which is bound to E3
• FADH2 is then oxidized back to
FAD by NAD

14. • Symptoms
varies
Neurodegeneration
muscle spasticity
in the neonatal onset form, early death
• Treatment
 dietary restriction of carbohydrate
 supplementation with thiamine

15. • Deficiencies of thiamine or niacin can cause serious central nervous
system problems. This is because brain cells are unable to produce
sufficient ATP (via the TCA cycle) if the PDH complex is inactive.
• Wernicke-Korsakoff, an encephalopathy-psychosis syndrome due to
thiamine deficiency, may be seen with alcohol abuse.
• Arsenic and mercury ions react with the SH group of the lipoic acid
and inhibit the PDH

16. Muscle Phosphofructokinase
Deficiency
• Rare
• The exercise capacity of the muscle is low
• Symptoms worsen after carbohydrate rich diet
• Provide lipid as alternative fuel
• Work capacity is improved when blood FFA or ketone bodies level are
increased

17. Hexose
monophosphate
shunt
• Found in liver, lactating
mammary gland,
adipocyte, adrenal
cortex, RBC
• Irreversible oxidative
reactions
• Reversible non-
oxidative reactions
• Provide NADPH,
ribose 5 phosphate

18. Glucose 6 phosphate
dehydrogenase deficiency
• Common in Mediterranean and Afro Caribbean people
• 400 million people carries mutated gene
• caused by point mutation
• many mutant enzymes show
decreased catalytic activity
decreased stability, or
an alteration of binding affinity for NADP +, NADPH, or glucose 6-phosphate
• The severity of the disease usually correlates with the amount of
residual enzyme activity in the patient’s RBC.

19. • Present on X
chromosome
• q28locus
• • Mainly affect males

20. Uses of NADPH
• Reductive synthesis
• Reduction of H2O2
• Cytochrome P450 monooxygenase system
• Phagocytosis
• Synthesis of NO

21. Reduction of H2O2
• Hydrogen peroxide (H2O2) is one of a family of reactive oxygen species
(ROS) that are formed from the partial reduction of molecular oxygen.
• These compounds are formed continuously as byproducts of aerobic
metabolism.
• When the level of antioxidants is diminished, oxidative stress will occur.
• The highly reactive oxygen intermediates can cause damage to DNA,
proteins, and unsaturatedlipids and can lead to cell death.
• The cell has several protective mechanisms that minimize the toxic
potential of these compounds.

22. Pathways of glucose 6-phosphate metabolism
in the erythrocyte

23. Role of G6PD in RBC
• Defect in G6PD NADPH reduce
• Decrease level of reduced glutathione
Decrease in cellular detoxification of free radicals and peroxides
Heinz bodies
Oxidation of sulfhydryl groups of proteins, including Hb
Oxidation of membrane protein
• RBC membrane become rigid and nondeformable
• Destroyed by RE cells

24. Precipitating factors in G6PD deficiency
• Most individuals do not show symptoms
• Present neonatal jaundice
• Develop hemolytic anaemia if they are exposed to
• Oxidant drugs (A=antibiotic, A=antimalarial, A=antipyretics)
• Favism (the hemolytic effect of ingesting fava beans is not seen in all
individuals with G6PD deficiency, but all patients with favism have G6PD
deficiency)
• Infections (the inflammatory response to infection generate free radicals in
macrophage which can diffuse into RBC causing oxidative damage )

25. Essential
pentosuria
• Rare benign
hereditary
condition
• Deficiency of
xylulose reductase
• No clinical
consequence
except pentosuria
which can give
false positive
benedict test

26. Glycogen Storage Disease
• Generic term to describe A group of inherited disorders
• Autosomal recessive disorder
• Caused by deficiency of enzymes of glycogen metabolism in both liver
and muscle
• Characterized by deposition of an abnormal type or quantity of
glycogen in tissues or failure to mobilize glycogen
• Lead to liver damage and muscle weakness
• Sometimes , early death

27. Glycogen
• Storage form of glucose
• Present in
Liver maintain blood glucose level
Muscle server as a fuel reserve during muscle exercise

30. Lysosomal degradation of glycogen
• A small amount of glycogen is continuously degraded by the
lysosomal enzyme, glycosidase
• Purpose is unknown
• Deficiency of this enzyme accumulation of glycogen in
lysosome Pompe disease

32. Disorders of fructose metabolism
• Essential fructosuria
• Hereditary fructose intolerance

34. Essential fructosuria
• Fructokinase deficiency
• Benign
• Autosomal recessive
• Fructose accumulate in urine

35. Hereditary fructose intolerance
• Aldolase B deficiency
• Severe clinical condition
• Symptoms begin when the baby is exposed to sucrose or fructose diet
• Fructose 1P trapped in the cell drop in Pi level
rises AMP degraded in the absence of Pi
gluconeogenesis decrease
decrease protein synthesis
ATP falls, AMP
hyperuricaemia
severe hypoglycaemia
decrease CF and
• Hepatic ATP falls
• Hepatic ATP falls
essential proteins
Treatment
• Rapid detection and removal of sucrose and fructose in the diet

36. Disorder of galactose metabolism
• Galactosemia

38. Classic galactosemia
• Uridyltransferase deficiency
• Autosomal recessive disorder
• Accumulation of Gal 1-P liver
damage, severe mental
retardation, ovarian failure and
cataracts
• Therapy rapid diagnosis and
removal of lactose from the diet
Galcactokinase deficiency
• Galcactokinase deficiency
• Rare autosomal recessive
disorder
• Benign condition
• Causes elevation of galactose in
blood and urine
• Causes galactitol accumulation if
galactose is present in the diet

39. Diabetes Mellitus
• Not one disease, but rather is a heterogeneous group of
multifactorial, polygenic syndromes characterized by an elevated
fasting blood glucose (FBG) caused by a relative or absolute deficiency
in insulin.
• Diabetes is the leading cause of adult blindness and amputation and a
major cause of renal failure, nerve damage, heart attacks, and
strokes.
• Two types
type 1 formerly called insulin-dependent diabetes mellitus and
type 2 formerly called noninsulin-dependent diabetes mellitus

40. Type 1 DM
• Characterized by an absolute deficiency of insulin caused by an
autoimmune attack on the β cells of the pancreas
• Over a period of years, this autoimmune attack on the β cells leads to
gradual depletion of the β-cell population
• Symptoms appear abruptly when 90% of the β cells have been
destroyed
• At this point, the pancreas fails to respond adequately to ingestion of
glucose, and insulin therapy is required

41. Metabolic changes in Type I DM
• Affect liver, muscle and adipocyte
• Hyperglycaemia
increased hepatic production of glucose via gluconeogenesis
Decreased peripheral utilization (muscle and adipose tissue have the insulinsensitive
glucose transporter GLUT-4
• Ketoacidosis
Increased mobilization of fatty acids (FAs) from adipose tissue
Accelerated hepatic β-oxidation which lead to Increased synthesis of ketone bodies
• Hypertriacylglycerolemia
fatty acids triacylglycerol (TAG), which is packaged and secreted in VLDLs
Decreased lipoprotein lipase
Increased chylomicron and VLDL

42. Type II DM
• Common
• Due to insulin resistance
• Obesity usually present
• Frequently age 37
• Symptoms develop gradually

43. Metabolic changes in Type II DM
• Result of insulin resistance on liver, muscle and adipose tissue
• Hyperglycaemia
increased hepatic production of glucose, combined with diminished
peripheral use
• Hypertriacylglycerolemia
chylomicron and VLDL levels are elevated

44. • The long-standing elevation of blood glucose is associated with the
chronic complications of diabetes including
 atherosclerosis (macrovascular)
 retinopathy, nephropathy, and neuropathy (microvascular)
• Both fructose and sorbitol are found in the lens in increased
concentration in DM diabetic cataract
• The sorbitol pathway (not in liver) is responsible for fructose
formation from glucose and increases in activity in tissues that are
not insulin sensitive

45. Conclusion
• Defects in carbohydrate metabolism not only affect the carbohydrate
metabolic pathways but also other metabolic pathways
•Some diseases are fatal, so early detection and adequate treatment is
required.

46. Thank You
Reading Assignment:Read on Lipid Metabolism
Next Topic: ABNORMALITIES IN LIPID METABOLISM