M2C: Disorders of Fructose and Galactose Metabolism

Disorders of Fructose and Galactose Metabolism

- Occur when an enzyme in the fructose or galactose pathways is deficient
- Autosomal recessive disorders
- Leads to excess fructose or galactose in the body

How do we test for Disorders of Fructose and Galactose Metabolism?

- Urin tests
- Patients with these disorders will show a negative urine dipstick test result because the test is specific for the monosaccharide glucose.
- However, a special urine test for inborn errors of carbohydrate metabolism can detect the presence of a reducing sugar (ie, something that is not glucose).

How do we ingest fructose?

Through foods like fruits, honey, and sucrose (scientific name for table sugar; chemically it is a disaccharide of fructose and glucose)

How does fructose first enter liver cells?

Through the GLUT-5 transporter (which works via facilitated diffusion)

Glyceraldehyde-3-P process through glycolysis image

What are the two main fructose metabolism disorders to know?

- Hereditary fructose intolerance (aldolase B deficiency) and
- Essential fructosuria (fructokinase deficiency)

What step in fructose metabolism does fructokinase catalyze?

Conversion of fructose to fructose-1-P

Describe the pathophysiology of hereditary fructose intolerance

Deficiency in aldolase B causes accumulation of fructose-1-P and depletion of phosphate and ATP; this leads to decreased gluconeogenesis and glycogenolysis in the liver.

What can Hereditary Fructose Intolerance cause (clinical aspects)?

- Hypoglycemia,
- Vomiting, and
- Liver problems (such as hepatomegaly, jaundice, and even cirrhosis)
- Fruit intolerance

What symptoms do babies with Hereditary Fructose Intolerance usually exhibit?

- Failure to thrive,
- Seizures,
- Gastrointestinal (GI) upset, and
- Hepatomegaly after eating fructose-containing foods.

Hepatomegaly

Enlargement of the liver

Cirrhosis

A chronic liver disease characterized by scarring with loss of normal hepatic architecture and areas of ineffective regeneration

Why can Hereditary Fructose Intolerance cause hypoglycemia?

Fructose-1-P competitively inhibits glycogen phosphorylase (the first step in glycogenolysis)

Essential fructosuria

- A deficiency of fructokinase (the enzyme that catalyzes the first step of fructose metabolism)
- A rare but benign condition, (considered by some to be a "non-disease" because the body can still metabolize fructose using hexokinase, allowing for entry into the glycolytic pathway)
- Fructose may be present in the blood or urine if the patient consumes a lot of it; otherwise, most patients are completely asymptomatic
- Requires no treatment

Mnemonic for Essential fructosuria

Fructokinase is kinder (a milder disease than aldolase B deficiency, ie, hereditary fructose intolerance)

How do we treat Fructose Metabolism Disorders?

By removing fructose from the diet

What types of sugars should be avoided in patients with fructose metabolism disorders?

Fructose, sucrose, and sorbitol

Galactose metabolism image

How does Galactose enter the cell?

Through SGLT1 (the same sodium-dependent transporter used to take up glucose)

What are the two main galactose metabolism disorders to know?

- Classical galactosemia (GALT deficiency) and
- Galactokinase deficiency

What enzyme is deficient in classical galactosemia?

Galactose-1-phosphate uridylyltransferase (GALT)

Describe the pathophysiology of classical galactosemia

- Galactose metabolism is stuck at the galactose-1-P step.
- Galactose-1-P accumulates and depletes the cell of ATP and causes phosphate trapping, which impairs gluconeogenesis and glycogenolysis.
- Leads to build up of galactose

Mnemonic for hereditary fructose intolerance vs. classical galactosemia

Fructose is to Aldolase B as Galactose is to UridylylTransferase: FABGUT

When is classical galactosemia typically diagnosed?

Infancy (usually in the first few days of life after breastfeeding)

What are the clinical aspects of classical galactosemia?

- Hepatomegaly
- Jaundice
- Cirrhosis
- Failure to thrive in neonate after breastfeeding.
- Infantile cataracts from galactitol osmotic damage.
- Increased risk for E coli sepsis.

What occurs is galactokinase deficiency?

Galactose accumulates due to a deficiency of Galactokinase

What is the only clinical manifestation of galactokinase deficiency?

- Cataracts in childhood or young adulthood
- Elevated galactose in blood.
- May present with failure to track objects or to develop a social smile.

Mnemonic for galactokinase deficiency

Galactokinase is kinder (a milder disease than GALT deficiency, ie, classical galactosemia)

How do we treat Galactose Metabolism Disorders?

- Eliminate galactose-containing foods (primarily dairy products)
- Patients with classical galactosemia must follow a more strict diet (drink lactose-free soy-based infant formulas as babies)