Nov 24, 2025 PDF Available

Topic Overview

Hexose Monophosphate (HMP) Shunt Pathway

The HMP shunt is an alternative metabolic route for glucose. Its role is not to produce ATP, but to generate NADPH and pentose sugars, both essential for biosynthesis and antioxidant protection.

1. Purpose of the Pathway

A. Production of NADPH

NADPH is required for:

Fatty acid synthesis
Cholesterol and steroid hormone synthesis
Regeneration of reduced glutathione
Detoxification reactions in liver (cytochrome P450 system)

B. Production of Ribose-5-Phosphate

This pentose sugar is required for:

DNA & RNA synthesis
ATP, NAD⁺, FAD, CoA synthesis

2. Tissues With High Activity

The pathway is most active in tissues that require NADPH or nucleotide precursors.

Liver
Adipose tissue
Adrenal cortex
Mammary gland
Thyroid
Red blood cells (primary defense against oxidative damage)

3. Phases of the Pathway

The HMP shunt consists of two distinct phases.

A. Oxidative Phase (Irreversible)

This phase oxidizes glucose-6-phosphate, producing NADPH, releasing CO₂, and forming ribulose-5-phosphate.

Step 1: Formation of 6-phosphogluconolactone

Enzyme: Glucose-6-phosphate dehydrogenase (G6PD)
NADP⁺ → NADPH
This is the rate-limiting and most regulated step.

Step 2: Formation of 6-phosphogluconate

Lactonase enzyme opens the ring of 6-phosphogluconolactone.

Step 3: Formation of Ribulose-5-Phosphate and CO₂

Enzyme: 6-phosphogluconate dehydrogenase
Produces another NADPH
Removes carbon-1 of glucose as CO₂

B. Non-Oxidative Phase (Reversible)

This phase interconverts 3-, 4-, 5-, 6-, and 7-carbon sugars to supply either:

Ribose-5-phosphate for nucleotide synthesis
Fructose-6-phosphate & glyceraldehyde-3-phosphate for glycolysis
Glucose-6-phosphate to restart the cycle

1. First Transketolase Reaction

Converts xylulose-5-P and ribose-5-P into:
- Glyceraldehyde-3-phosphate (3C)
- Sedoheptulose-7-phosphate (7C)
Cofactor required: Thiamine (TPP)

2. Transaldolase Reaction

Sedoheptulose-7-P donates a 3-carbon unit to glyceraldehyde-3-P to form:

Fructose-6-phosphate (6C)
Erythrose-4-phosphate (4C)

3. Second Transketolase Reaction

Xylulose-5-P donates 2 carbons to erythrose-4-P to form:

Fructose-6-phosphate
Glyceraldehyde-3-phosphate

4. Regeneration of Glucose-6-Phosphate

Glyceraldehyde-3-phosphate molecules combine to form fructose-6-phosphate → converted back to glucose-6-phosphate.

4. Carbon Rearrangement Summary

Process	Explanation
6 glucose molecules enter	Total 36 carbons
6 carbons removed as CO₂	One carbon from each glucose (oxidative phase)
12 NADPH produced	Two per glucose oxidized
30 carbons rearranged	Converted into pentoses
5 glucose molecules regenerated	Non-oxidative recycling

One whole glucose is “sacrificed” to produce NADPH.

5. Regulation of the Pathway

A. NADP⁺ / NADPH ratio is the primary regulator

High NADP⁺ → pathway accelerates
High NADPH → pathway slows down

B. Hormonal Control

Insulin increases activity by inducing G6PD
More active in the fed state

6. Clinical Significance: G6PD Deficiency

RBCs rely solely on the HMP shunt for NADPH because they lack mitochondria.
When G6PD is deficient:

Triggers of hemolysis:

Fava beans (favism)
Sulfonamides
Antimalarial drugs
Nitrofurantoin
Infections

Consequences:

Oxidative injury to hemoglobin → Heinz bodies
RBC membrane fragility → hemolysis
Jaundice
Dark urine
Increased methemoglobin levels

Evolutionary note:

Low glutathione levels impair malaria parasite survival → partial protection against malaria.

7. Physiological Roles of the Pathway

A. Source of NADPH

Needed for fatty acid synthesis, cholesterol synthesis, steroidogenesis
Required for reduction of oxidized glutathione → protects RBCs

B. Source of Ribose-5-Phosphate

Needed for nucleotides and nucleic acids

C. Supports Detoxification

NADPH provides reducing power for cytochrome P450 enzymes

D. Protects Against Oxidative Stress

Especially vital in RBCs

8. Integrated Importance

The HMP shunt does not make ATP, but it supplies the cell with reducing power (NADPH) and pentose sugars, making it crucial for:

Anabolic processes
Antioxidant defense
Rapidly dividing cells
Hormone-producing tissues

Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency

G6PD deficiency is the most common inherited enzyme defect in the world.
It directly affects the HMP shunt pathway, especially the oxidative phase, where G6PD is the rate-limiting enzyme.

1. Why G6PD Is Important

A. Produces NADPH

G6PD is the enzyme that starts the oxidative phase of the HMP pathway.
NADPH is needed to:

Keep glutathione in reduced form (GSH)
Protect RBC membranes and hemoglobin from oxidative injury
Neutralize harmful oxidants (H₂O₂, free radicals)

B. Especially important in RBCs

RBCs have no mitochondria
Their only source of NADPH is the HMP shunt
Without NADPH, glutathione becomes oxidized and useless
RBCs cannot repair oxidative damage → hemolysis

This is why the deficiency mainly causes hemolytic anemia.

2. Genetic Features

X-linked recessive disorder
Affects males more commonly
Females can be carriers or symptomatic (lyonization)

Prevalence:

Very common in Africa, Middle East, India, Mediterranean countries
The distribution overlaps with malarial endemic areas

3. Protective Effect Against Malaria

Plasmodium species (malaria parasites) need reduced glutathione to survive.
In G6PD deficiency:

Less GSH is available
Parasites grow poorly
Provides partial resistance to malaria
(This is why the mutation persists in these populations.)

4. What Triggers Hemolysis?

People with G6PD deficiency are usually normal until exposed to oxidative stress.

Major triggers:

A. Foods

Fava beans → “Favism”

B. Drugs

Sulfonamides
Antimalarials (e.g., primaquine, chloroquine)
Nitrofurantoin
Dapsone
High-dose aspirin

C. Infections

Most common trigger
Infection produces free radicals → RBC damage

D. Chemicals

Naphthalene (mothballs)

Even mild oxidative stress can destroy RBCs in severe deficiency.

5. What Happens Inside the RBC? (Pathogenesis)

Step-wise process:

Oxidative stress increases in the blood
G6PD-deficient RBC cannot produce enough NADPH
Glutathione becomes oxidized and inactive
Oxidants attack hemoglobin → Heinz body formation
Heinz bodies attach to RBC membrane
The spleen removes these cells → bite cells / blister cells
Sudden fall in RBC count → acute hemolysis

6. Clinical Features

A. Symptoms of hemolysis

Sudden fatigue
Pallor
Jaundice
Dark brown/cola-colored urine
Back and abdominal pain (due to hemolysis)

B. Neonatal jaundice

Can be severe
May require phototherapy or exchange transfusion

C. Hemolytic crisis can occur within hours after exposure to a trigger.

7. Laboratory Findings

Hemolytic anemia
Increased reticulocyte count
Increased serum bilirubin
Low haptoglobin
Heinz bodies on supravital stain
Bite cells on peripheral smear
Enzyme assay: low G6PD levels (done in stable phase, not during acute hemolysis)

8. Management

A. Avoid triggers

Avoid fava beans
Avoid sulfa drugs, antimalarials, nitrofurantoin
Avoid naphthalene balls

B. Treat hemolysis

Stop the offending drug
Hydration
Treat infection
Blood transfusion if severe

C. Neonatal care

Phototherapy
Exchange transfusion when required

There is no cure, but good avoidance and counseling prevent most episodes.

9. Key High-Yield Points for Exams

X-linked recessive
RBCs are especially vulnerable → no mitochondria
Only source of NADPH is HMP shunt
Triggers include fava beans, sulfa drugs, antimalarials, infections
Causes Heinz bodies & bite cells
Provides resistance to malaria
Enzyme levels must be tested after the hemolytic episode, not during

Glucuronic Acid Pathway (Uronic Acid Pathway)

The glucuronic acid pathway is a minor route of glucose metabolism.
Its main purpose is to produce UDP-glucuronic acid, a highly active form of glucuronic acid that the body uses for detoxification and biosynthesis.

1. Purpose of the Glucuronic Acid Pathway

A. Detoxification (Glucuronidation)

UDP-glucuronic acid attaches to toxic substances and makes them:

More water-soluble
Easier to excrete through urine or bile

This is essential for:

Drug metabolism
Bilirubin conjugation
Steroid hormone inactivation

B. Synthesis Functions

UDP-glucuronic acid is needed for:

Glycosaminoglycans (GAGs) such as:
- Hyaluronic acid
- Chondroitin sulfate
- Heparan sulfate
Proteoglycan formation (connective tissue strength)

2. Steps of the Pathway (Simplified)

The pathway starts from glucose and moves through a series of steps to produce UDP-glucuronic acid.

Step 1: Conversion to UDP-glucose

Glucose → Glucose-6-phosphate → Glucose-1-phosphate → UDP-glucose

This prepares glucose for activation.

Step 2: Oxidation

UDP-glucose is oxidized to UDP-glucuronic acid.

This is the active form used for conjugation and synthesis.

Step 3: Further metabolism

UDP-glucuronic acid can enter two pathways:

Used directly for detoxification
Converted further into L-gulonate → L-gulonolactone

Human Limitation

Humans lack the enzyme L-gulonolactone oxidase, so the pathway cannot produce vitamin C.
Therefore, ascorbic acid is an essential vitamin in humans.

(Animals that have this enzyme make their own vitamin C.)

3. Biological Importance

⭐ A. Bilirubin Conjugation

Bilirubin is toxic and water-insoluble.
Liver attaches two molecules of glucuronic acid → forms bilirubin diglucuronide, which is:

Water-soluble
Excreted through bile

This prevents jaundice.

⭐ B. Conjugation of Steroids and Drugs

Glucuronic acid attaches to:

Steroid hormones (estrogen, cortisol)
Drugs (paracetamol, morphine, chloramphenicol)
Environmental toxins

This increases their solubility and speeds excretion.

⭐ C. Synthesis of Glycosaminoglycans (GAGs)

GAGs form the gel-like matrix of connective tissue, skin, cartilage, and joints.

UDP-glucuronic acid is required for:

Hyaluronic acid
Chondroitin sulfate
Dermatan sulfate
Heparan sulfate

These provide:

Lubrication
Shock absorption
Cell adhesion
Structural strength

4. Clinical Correlations

A. Neonatal jaundice

Low activity of bilirubin-conjugating enzymes in newborns → accumulation of unconjugated bilirubin.

Glucuronidation is essential to prevent:

Kernicterus
Severe hyperbilirubinemia

B. Drug toxicity

In conditions where glucuronidation is impaired, drugs accumulate and become toxic.

C. Vitamin C deficiency (Scurvy)

Because humans cannot synthesize vitamin C from this pathway:

Vitamin C must be taken through diet
Deficiency leads to scurvy (bleeding gums, poor wound healing)

5. Essential Pentosuria (Related Condition)

A rare, benign inborn error where L-xylulose (a sugar from this pathway) appears in urine.

Features:

Autosomal recessive
No symptoms
Urine tests falsely appear “sugar-positive”
No treatment needed

(This is often asked as a short note.)

6. Key Points to Remember

Produces UDP-glucuronic acid
Essential for detoxification, bilirubin conjugation, and GAG synthesis
Humans cannot synthesize vitamin C due to missing enzyme
Impairment can worsen drug toxicity and jaundice
Essential pentosuria is related but benign

Essential Pentosuria

Essential pentosuria is a rare, harmless, inherited metabolic condition involving the glucuronic acid pathway.

1. Cause

Deficiency of the enzyme L-xylulose reductase
L-xylulose (a sugar from the glucuronic acid pathway) cannot be converted further
Result → L-xylulose is excreted in urine

2. Inheritance

Autosomal recessive

3. Clinical significance

Completely benign
No symptoms
No complications
Found incidentally

4. Laboratory finding

Urine tests positive for “reducing sugar”, but:
- It is not glucose
- Therefore blood sugar levels are normal
- Important differential diagnosis for diabetes

5. Treatment

No treatment required

Polyol Pathway

The polyol pathway converts glucose ↔ fructose using two steps.

1. Steps of the Polyol Pathway

Step 1: Glucose → Sorbitol

Enzyme: Aldose reductase
Requires NADPH

Step 2: Sorbitol → Fructose

Enzyme: Sorbitol dehydrogenase
Occurs mainly in liver, ovaries, and seminal vesicles

2. Why the Polyol Pathway Becomes Important

Some tissues have aldose reductase but very little sorbitol dehydrogenase:

Lens of eye
Retina
Kidney
Peripheral nerves

In these tissues:

Sorbitol accumulates
Sorbitol draws water → osmotic damage

This is a major mechanism of diabetic complications.

3. Clinical importance (High-Yield)

A. Diabetic Cataract

Excess glucose → sorbitol → water enters lens → swelling → opacity

B. Diabetic Neuropathy

Sorbitol accumulation damages nerve axons

C. Diabetic Retinopathy

Osmotic stress injures retinal cells

D. Diabetic Nephropathy

Sorbitol accumulation in kidney cells triggers injury

Fructose Metabolism

Fructose is metabolized primarily in the liver, and bypasses the major regulatory step of glycolysis.

1. Steps of Fructose Metabolism

Step 1: Fructose → Fructose-1-phosphate

Enzyme: Fructokinase
Uses ATP
Rapid phosphorylation (not regulated by insulin)

Step 2: Fructose-1-phosphate → DHAP + Glyceraldehyde

Enzyme: Aldolase B

Step 3:

Glyceraldehyde → Glyceraldehyde-3-phosphate
Enters glycolysis or lipogenesis

Clinical relevance of fructose metabolism

Rapid metabolism may increase lipogenesis → raise triglycerides
Excess fructose intake associated with fatty liver

Hereditary Fructose Intolerance (HFI)

A severe, potentially fatal disorder of fructose metabolism.

1. Cause

Deficiency of Aldolase B
Fructose-1-phosphate accumulates in the liver
This traps phosphate, blocks ATP production

2. Consequences

Severe fall in blood glucose
Inhibition of:
- Glycogenolysis
- Gluconeogenesis
Leads to profound hypoglycemia

3. Symptoms

Appear when fructose, sucrose, or sorbitol is introduced in diet (weaning phase).

Vomiting
Sweating
Lethargy
Seizures
Hypoglycemia
Jaundice
Hepatomegaly
Failure to thrive

4. Dangerous complications

Liver failure
Renal failure
Death (if untreated)

5. Diagnosis

History of symptoms after fructose/sucrose intake
Hypoglycemia
Liver dysfunction
Genetic testing for Aldolase B mutation

6. Treatment

Strict lifelong avoidance of:
- Fructose
- Sucrose
- Sorbitol
With avoidance → normal life

Fructosuria (Essential Fructosuria)

A mild, benign condition involving fructose metabolism.

1. Cause

Deficiency of fructokinase
Fructose is not phosphorylated
It stays in free form → excreted in urine

2. Clinical features

Completely asymptomatic
No hypoglycemia
No liver enlargement
No toxicity
Incidental finding

3. Lab findings

Fructose appears in urine
Urine reducing test positive
Blood glucose normal
Distinguishes it from diabetes and HFI

4. Treatment

No treatment needed
Dietary restriction unnecessary

Quickest Exam Revision

Essential pentosuria → L-xylulose in urine, benign

Polyol pathway → sorbitol accumulation → diabetic complications

Fructose metabolism → via fructokinase & Aldolase B

Hereditary fructose intolerance → Aldolase B deficiency → severe hypoglycemia

Fructosuria → Fructokinase deficiency → harmless

Galactose Metabolism

Galactose comes mainly from lactose in milk.
When lactose is digested in the intestine, it splits into:

Glucose
Galactose

Galactose is transported to the liver, where it is converted into glucose.

1. Steps of Galactose Metabolism

The pathway converts galactose → glucose-1-phosphate → glucose.

Step 1: Galactose → Galactose-1-phosphate

Enzyme: Galactokinase (GALK)
Requires ATP
Traps galactose inside hepatocytes

Step 2: Galactose-1-phosphate + UDP-glucose → UDP-galactose + Glucose-1-phosphate

Enzyme: Galactose-1-phosphate uridyl transferase (GALT)
This is the most important step
Creates the activated form UDP-galactose

Step 3: UDP-galactose → UDP-glucose

Enzyme: UDP-galactose 4-epimerase (GALE)
Allows UDP-glucose to be reused
This completes the Leloir pathway

Step 4: Glucose-1-phosphate → Glucose-6-phosphate

Enters glycolysis or glycogen synthesis

2. Uses of UDP-Galactose

UDP-galactose is essential for synthesizing:

Lactose (in mammary gland during lactation)
Glycoproteins
Glycolipids
Proteoglycans

Thus, galactose metabolism supports both energy production and structural functions.

3. Importance of Efficient Galactose Metabolism

If any step is blocked:

Galactose and its metabolites accumulate
These are toxic, especially in infants
This leads to the disorder known as galactosemia

Galactosemia

Galactosemia refers to a group of inherited enzyme deficiencies in the galactose metabolic pathway.
Accumulated metabolites cause toxicity in liver, brain, and kidney.

There are three types, depending on the enzyme deficiency:

Classic Galactosemia (Type I) – GALT deficiency
Galactokinase Deficiency (Type II)
Epimerase Deficiency (Type III)

1. Classic Galactosemia (Type I)

Most severe and most important for exams

A. Cause

Deficiency of Galactose-1-phosphate uridyl transferase (GALT)
Galactose-1-phosphate accumulates in tissues → highly toxic

B. Pathogenesis

Accumulating metabolites include:

Galactose-1-phosphate
Galactose
Galactitol (from polyol pathway: galactose → galactitol)

These cause:

Liver injury
Kidney tubular damage
Brain dysfunction
Lens damage (cataract)

C. Clinical Features (Infants present after milk feeding begins)

Early signs:

Vomiting
Diarrhea
Poor feeding
Lethargy
Jaundice
Hepatomegaly

Severe features:

Hypoglycemia
Failure to thrive
Bleeding tendencies
Sepsis (commonly E. coli)
Cataract
Progressive liver failure

D. Complications

Liver cirrhosis
Intellectual disability
Kidney damage
Ovarian failure in females
Death if untreated

E. Investigations

Reducing substances in urine (but not glucose)
Elevated galactose-1-phosphate levels
Positive newborn screening test
Confirmed by GALT enzyme assay

F. Treatment

Immediate and lifelong removal of galactose & lactose from diet
Switch to lactose-free formula (soy-based)
Treat complications like sepsis and liver dysfunction

G. Prognosis

Early treatment prevents life-threatening complications
Some long-term issues may persist (speech delay, learning difficulties)

2. Galactokinase Deficiency (Type II)

Much milder

A. Cause

Defective galactokinase (GALK)
Galactose cannot be phosphorylated
Excess galactose → polyol pathway → galactitol

B. Clinical feature

Infantile cataracts (main finding)
No liver damage
No kidney damage
Normal growth otherwise

C. Treatment

Remove galactose/lactose from diet
Prevents cataract progression

3. Epimerase Deficiency (Type III)

Two forms:

Benign form: only RBC/WBC affected
Severe form: resembles classic galactosemia

Features

Ranging from symptomless to liver damage and developmental delay
Managed similarly to GALT deficiency in severe cases

High-Yield Differences (Easy Recall)

Classic Galactosemia (GALT deficiency)
→ Most severe
→ Liver failure + kidney damage + sepsis
→ Cataract also possible
→ Treat immediately

Galactokinase deficiency (GALK)
→ Only cataracts
→ No liver or brain involvement

Epimerase deficiency
→ Mild or severe
→ Severe form mimics classic galactosemia

Ultra-Short Exam Summary

Galactose metabolism converts galactose to glucose via GALK → GALT → GALE.
Classic galactosemia = GALT deficiency, life-threatening.
Galactokinase deficiency = cataracts only, benign.
Remove lactose/galactose from diet in all symptomatic types.

Metabolism of Alcohol (Ethanol Metabolism)

Alcohol is mainly metabolized in the liver, through two major pathways.
The end goal is to convert ethanol → acetate → energy.

1. Primary Pathway: Alcohol Dehydrogenase (ADH pathway)

Step 1 — Ethanol → Acetaldehyde

Enzyme: Alcohol dehydrogenase (ADH)
Location: Cytosol
Requires NAD⁺ → produces NADH

This step controls how fast alcohol is metabolized.

Step 2 — Acetaldehyde → Acetate

Enzyme: Aldehyde dehydrogenase (ALDH)
Location: Mitochondria
Also produces NADH

Acetaldehyde is highly toxic and responsible for:

Facial flushing
Hangover symptoms
Vomiting
Heart palpitations

People with ALDH2 deficiency (common in East Asians) have intense flushing after drinking.

Step 3 — Acetate → Acetyl-CoA

Enzyme: Acetyl-CoA synthetase
Acetyl-CoA enters:
- TCA cycle
- Ketone body pathway
- Fatty acid synthesis

2. Microsomal Ethanol-Oxidizing System (MEOS)

A secondary pathway used during:

Chronic alcohol consumption
High alcohol levels
Liver hypertrophy in alcoholics

Features:

Location: Smooth endoplasmic reticulum
Enzyme system: Cytochrome P450 2E1 (CYP2E1)
Uses NADPH and oxygen
Produces free radicals
↑ Contributes to oxidative liver injury in alcoholics.

3. Catalase Pathway

Minor pathway (5–10%)
Uses hydrogen peroxide
Occurs in peroxisomes
Not clinically significant

4. Clinical Effects of Alcohol Metabolism

A. High NADH/NAD⁺ Ratio

Excess NADH from ADH + ALDH leads to:

Lactic acidosis (pyruvate converted to lactate)
Hypoglycemia (blocks gluconeogenesis)
Fatty liver (triglyceride accumulation)
Ketoacidosis

B. Acetaldehyde Toxicity

Liver inflammation
Mitochondrial damage
Protein adducts → immune reactions

C. Chronic alcohol intake

Hepatic steatosis → hepatitis → cirrhosis
Induced CYP2E1 affects drug metabolism (paracetamol becomes toxic)

5. Summary

Ethanol → Acetaldehyde → Acetate → Acetyl-CoA
Main pathway = ADH; Chronic use activates MEOS; High NADH causes hypoglycemia + fatty liver.

Amino Sugars

Amino sugars are monosaccharides in which an –OH group is replaced by an –NH₂ group.
They are essential components of:

Glycoproteins
Glycolipids
Proteoglycans
Cartilage
Basement membranes

1. Common Amino Sugars

A. Glucosamine

Derived from fructose-6-phosphate
Important in:
- Chitin
- Hyaluronic acid
- Heparan sulfate

B. Galactosamine

Part of:
- Chondroitin sulfate
- Dermatan sulfate

C. N-Acetylated forms

N-acetylglucosamine (NAG)
N-acetylgalactosamine (NAGal)
These form:
Mucins
GAGs
Blood group substances

2. Biological Roles of Amino Sugars

Provide strength and flexibility to connective tissues
Form part of cell surface receptors
Help in cell adhesion
Needed for joint lubrication and cartilage resilience

3. Clinical Note

Glucosamine supplements are often used for osteoarthritis, though evidence varies.

Glycoproteins

Glycoproteins are proteins with oligosaccharide chains (glycans) attached to them.
They are found on:

Cell surfaces
Serum proteins
Hormones
Immunoglobulins
Secretions (mucus, saliva)

1. Structure of Glycoproteins

A. Protein backbone

Forms the structural part.

B. Carbohydrate portion

Attached by:

N-linkage (to asparagine)
O-linkage (to serine/threonine)

Carbohydrates usually contain:

Glucose
Galactose
Mannose
Fucose
N-acetylglucosamine
N-acetylgalactosamine
Sialic acid (NANA)

2. Functions of Glycoproteins

A. Cell Recognition & Adhesion

Blood group antigens (A, B, O types)
Cell–cell interaction
Immune cell binding

B. Immune System

Antibodies (IgG, IgM, IgA) are glycoproteins
Complement proteins

C. Hormones & Receptors

Examples:

FSH, LH, TSH
Receptor proteins

D. Mucosal Protection

Mucins are glycoproteins that:

Lubricate surfaces
Protect against pathogens

E. Enzyme Stability

Carbohydrate chains protect proteins from degradation.

3. Clinical Importance of Glycoproteins

A. Congenital Disorders of Glycosylation

Cause:

Developmental delay
Liver problems
Neuropathy

B. Blood Group Substances

A, B antigens = terminal sugars in glycoproteins
Determined by glycosyltransferase activity

C. Viral Attachment

Viruses (influenza, HIV) recognize sugar chains on host glycoproteins to enter cells.

4. Summary

Amino sugars form the building blocks.
Glycoproteins perform cell recognition, immunity, hormone activity, and protection.

Blood Group Substances (ABO Blood Group System)

Blood group substances are carbohydrate-rich glycoproteins and glycolipids found on the surface of red blood cells.
The terminal sugars determine whether a person is A, B, AB, or O.

1. Basic Structure of Blood Group Antigens

All RBCs begin with a common H-antigen backbone.
This is made up of:

Fucose
Galactose
N-acetylglucosamine
Other linked sugars

What differentiates the groups?

Specific glycosyltransferase enzymes add terminal sugars:

A Group

Enzyme adds N-acetylgalactosamine
Forms A antigen

B Group

Enzyme adds Galactose
Forms B antigen

AB Group

Both enzymes work
A and B antigens present together

O Group

Enzyme is inactive
No additional sugar added
Only H antigen is present

Exam point:
O group is not “empty”—it carries the basic H-antigen.

2. Location of Blood Group Substances

Antigens are found on:

Red blood cells
Epithelial cells
Secretions (saliva, gastric juice—if the person is a “secretor”)

They are part of cell membrane glycoproteins and glycolipids.

3. Antibodies in ABO System

Antibodies (isohemagglutinins):

Are IgM type
Naturally present due to exposure to gut bacterial antigens
Do not cross placenta (important in pregnancy questions)

Blood Group	Antigen on RBC	Antibody in Plasma
A	A antigen	Anti-B
B	B antigen	Anti-A
AB	A + B	None
O	H antigen	Anti-A & Anti-B

4. Clinical Importance

A. Blood transfusion compatibility

Incorrect transfusion causes acute hemolytic transfusion reaction
Fever, chills, hemoglobinuria, renal failure

B. Blood group & organs

Organ transplantation requires ABO matching
Mismatch → rapid rejection

C. Bombay blood group (hh phenotype)

Extremely rare
No H antigen → cannot form A or B antigens
They have anti-H antibodies
Can receive blood only from another Bombay individual

(Highly important MCQ topic)

5. Summary

Blood group substances are glycoproteins/glycolipids.
Terminal sugar determines blood group.
Antibodies are IgM.
Bombay group lacks H antigen.

Mucopolysaccharidoses (MPS)

MPS are a group of lysosomal storage disorders caused by deficiency of enzymes required to degrade glycosaminoglycans (GAGs).

GAGs accumulate in:

Liver
Spleen
Joints
Heart valves
Brain
Skeleton

Leading to progressive multi-system disease.

1. What are Glycosaminoglycans (GAGs)?

Long chains of repeating sugar units:

Amino sugar (N-acetylglucosamine or N-acetylgalactosamine)
Uronic acid (glucuronic acid or iduronic acid)

Types of GAGs:

Heparan sulfate
Dermatan sulfate
Keratan sulfate
Chondroitin sulfate
Hyaluronic acid

These form the structural material of connective tissue, cartilage, cornea, joints, and skin.

2. Why MPS Occur

Each MPS type is due to deficiency of a specific lysosomal enzyme needed to break down GAGs.
Without the enzyme:

GAGs accumulate in lysosomes
Cells enlarge and malfunction
Tissues become thickened
Progressive organ damage occurs

3. General Clinical Features of MPS

Common features across multiple types:

A. Facial changes

Coarse facial features (“gargoyle-like facies”)
Broad nose, thick lips, large tongue

B. Skeletal abnormalities (Dysostosis multiplex)

Short stature
Joint stiffness
Enlarged skull
Spinal deformities

C. Organ involvement

Hepatosplenomegaly
Cardiac valve disease

D. Eye involvement

Corneal clouding (in some types)

E. Neurological issues

Developmental delay (in many types)
Behavior disturbances

F. Urinary GAGs increased

Diagnostic feature

4. Major Types of MPS (Exam-Oriented)

1. Hurler Syndrome (MPS I H)

Enzyme: α-L-iduronidase deficiency
Accumulation: Dermatan sulfate + heparan sulfate
Features:
- Severe mental retardation
- Corneal clouding
- Hepatosplenomegaly
- Skeletal deformities
- Early death if untreated

2. Hunter Syndrome (MPS II)

Enzyme: Iduronate sulfatase deficiency
X-linked recessive (only MPS that is X-linked)
No corneal clouding
Similar features to Hurler but milder

3. Sanfilippo Syndrome (MPS III)

Four enzyme defects (A–D)
Predominantly severe CNS involvement
Mild somatic features

4. Morquio Syndrome (MPS IV)

Enzyme: N-acetylgalactosamine-6-sulfatase or β-galactosidase
Severe skeletal deformities
Normal intelligence
Corneal clouding present

5. Maroteaux–Lamy Syndrome (MPS VI)

Enzyme: Aryl sulfatase B deficiency
Normal intelligence
Skeletal + cardiac involvement

6. Sly Syndrome (MPS VII)

Enzyme: β-glucuronidase deficiency
Hepatosplenomegaly
Developmental delay
Skeletal abnormalities

5. Diagnosis

Increased urinary GAGs
Specific enzyme assays (blood, fibroblasts)
Genetic testing
Imaging showing dysostosis multiplex

6. Treatment

A. Enzyme Replacement Therapy (ERT)

Available for:

MPS I
MPS II
MPS IVA
MPS VI

B. Bone Marrow Transplantation

Helps in Hurler syndrome (MPS I) if done early.

C. Supportive therapy

Physiotherapy
Cardiac monitoring
Eye care
Surgical procedures for skeletal and airway issues

7. Quick Revision Table (Concept-Based)

Hurler (MPS I) → α-L-iduronidase → Corneal clouding → Severe
Hunter (MPS II) → Iduronate sulfatase → No corneal clouding → X-linked
Sanfilippo (MPS III) → CNS dominant → Mild somatic signs
Morquio (MPS IV) → Skeletal abnormalities → Normal intelligence
Maroteaux–Lamy (VI) → Aryl sulfatase B → No CNS issues
Sly (VII) → β-glucuronidase → Variable severity

Inborn Errors Associated With Carbohydrate Metabolism

These disorders occur when specific enzymes in carbohydrate pathways are missing or defective.
As a result, intermediate sugars accumulate, becoming toxic to organs such as the liver, kidney, brain, lens, and muscle.

For easy study, they can be grouped under:

Glycogen Storage Disorders (GSDs)
Fructose Metabolism Disorders
Galactose Metabolism Disorders
Pentose/Glucuronic Acid Pathway Disorders
Disorders of Pyruvate Lactate Metabolism

Below is a clean, structured explanation of all major conditions.

1. Glycogen Storage Disorders (GSDs)

These arise from defects in enzymes handling glycogen breakdown or synthesis.

A. Von Gierke Disease (Type I)

Enzyme defect: Glucose-6-phosphatase
Liver cannot release glucose
Features:
- Severe fasting hypoglycemia
- Lactic acidosis
- Hyperuricemia
- Hyperlipidemia
- Enlarged liver (hepatomegaly)

B. Pompe Disease (Type II)

Enzyme: Lysosomal acid maltase (α-1,4-glucosidase)
GSD affecting muscle + heart
Features:
- Hypotonia
- Cardiomegaly
- Early death (infantile form)

C. Cori Disease (Type III)

Enzyme: Debranching enzyme deficiency
Features similar to GSD I but milder

D. Andersen Disease (Type IV)

Enzyme: Branching enzyme deficiency
Abnormal glycogen → liver cirrhosis

E. McArdle Disease (Type V)

Enzyme: Muscle glycogen phosphorylase
Features:
- Muscle cramps
- Myoglobinuria after exercise
- “Second wind phenomenon”

F. Hers Disease (Type VI)

Enzyme: Liver glycogen phosphorylase
Mild hypoglycemia + hepatomegaly

2. Disorders of Fructose Metabolism

A. Essential Fructosuria

Enzyme: Fructokinase deficiency
Benign
Fructose appears in urine
No hypoglycemia

B. Hereditary Fructose Intolerance

Enzyme: Aldolase B deficiency
Fructose-1-phosphate accumulates
Features:
- Severe hypoglycemia
- Vomiting
- Lethargy
- Liver failure
Triggered after feeding fructose/sucrose
Requires strict fructose-free diet

3. Disorders of Galactose Metabolism

A. Classic Galactosemia (Type I)

Enzyme: Galactose-1-phosphate uridyl transferase (GALT)
Galactose-1-phosphate accumulates
Features:
- Jaundice
- Cataracts
- Vomiting
- Liver failure
- E. coli sepsis
Requires lifelong lactose-free diet

B. Galactokinase Deficiency (Type II)

Cataracts due to galactitol buildup
No liver damage

C. Epimerase Deficiency (Type III)

Mild or severe depending on form
Severe form resembles GALT deficiency

4. Pentose & Glucuronic Acid Pathway Disorders

A. G6PD Deficiency

Enzyme: Glucose-6-phosphate dehydrogenase
RBCs cannot make NADPH → oxidative damage
Triggers:
- Fava beans
- Sulfa drugs
- Antimalarials
- Infections
Features:
- Hemolysis
- Jaundice
- Dark urine

B. Essential Pentosuria

Enzyme: L-xylulose reductase deficiency
L-xylulose in urine
Benign, no clinical symptoms

5. Disorders of Pyruvate & Lactate Metabolism

A. Pyruvate Dehydrogenase Deficiency

Pyruvate cannot enter TCA cycle
Converts to lactate → lactic acidosis
Features:
- Severe neurological problems
- Developmental delay
Treatment: ketogenic diet (bypass carbohydrates)

B. Pyruvate Carboxylase Deficiency

Impaired gluconeogenesis
Hypoglycemia
Lactic acidosis
Ketosis

6. Disorders of Glycolysis (Rare but Classic for Exams)

A. Hexokinase Deficiency

Affects RBCs → hemolytic anemia

B. Phosphofructokinase Deficiency (Tarui Disease)

Affects muscle glycolysis
Exercise intolerance + myoglobinuria

C. Pyruvate Kinase Deficiency

Most common glycolytic enzyme defect causing chronic hemolytic anemia
RBCs produce less ATP → membrane damage

7. Disorders of Glucose Transport

GLUT1 Deficiency Syndrome

Impaired glucose transport to brain
Features:
- Seizures
- Developmental delay
CSF glucose low
Treatment: ketogenic diet (ketones become alternate fuel)

8. Integrated Summary (Fast Revision)

GSDs → storage problems in liver/muscle
Fructose intolerance → aldolase B defect → severe hypoglycemia
Essential fructosuria → harmless
Galactosemia → GALT defect → liver failure + cataract
G6PD deficiency → hemolysis under oxidative stress
Pyruvate disorders → lactic acidosis + neurological issues
GLUT1 defect → low CSF glucose

⭐ Important Points to Remember

(Directly grounded on PDF content)

1. Polyol Pathway

Aldose reductase converts glucose → sorbitol, sorbitol dehydrogenase converts sorbitol → fructose.
Sorbitol gets trapped inside tissues like lens → causes osmotic damage → cataract.
(PDF reference: sorbitol accumulation in lens and cataract formation)
Polyol pathway is active in brain, fructose is present in CSF.
Pathway is inactive in liver.

2. Essential Pentosuria

Due to L-xylulose reductase or xylitol dehydrogenase deficiency.
L-xylulose appears in urine → positive Benedict’s test.
Harmless, but must be differentiated from diabetes.

3. Fructose Metabolism

Fructokinase phosphorylates fructose at 1st carbon.
Fructose metabolism bypasses PFK, therefore increases glycolytic flux → more lipogenesis & ↑ triglycerides.
Fructose rapidly increases fatty acid synthesis and raises LDL.
Fructose metabolism depletes ATP, increases AMP breakdown → ↑ uric acid levels.

4. Hereditary Fructose Intolerance (HFI)

Caused by deficiency of Aldolase B.
Fructose-1-phosphate accumulation → inhibits glycogen phosphorylase → hypoglycemia.
Symptoms: vomiting, failure to thrive, jaundice, hepatomegaly; fatal if untreated.
Removing fructose from diet relieves symptoms immediately.

5. Fructosuria

Caused by fructokinase deficiency.
Benign; fructose simply appears in urine (reducing sugar positive).

6. Galactose Metabolism

Galactose is converted to UDP-galactose through galactokinase and GALT.
UDP-galactose is needed for: lactose, GAGs, cerebrosides, glycolipids, and glycoproteins.
Galactose tolerance test assesses liver function because galactose is metabolized mainly in the liver.

7. Galactosemia

Galactose-1-phosphate accumulation → cataracts (galactitol), jaundice, liver dysfunction.
(PDF figure reference: Clinical features of galactosemia)

⭐ Frequently Asked Questions (FAQs)

(Crafted from the concepts that appear in the PDF and common exam patterns)

Q1. Why does sorbitol cause cataracts in diabetes?

Because in hyperglycemia, more glucose enters the polyol pathway.
Sorbitol builds up in the lens (cannot diffuse out) → draws water → lens opacity.
(As shown: sorbitol accumulation damages lens)

Q2. Why is essential pentosuria not harmful?

Because L-xylulose accumulation does not damage tissues; only causes positive sugar test in urine.

Q3. Why is fructose harmful in diabetes even though it doesn't require insulin?

Fructose bypasses PFK → rapidly increases glycolysis → increases:

Fatty acid synthesis
Triglycerides
LDL
(All shown to be harmful and atherogenic)

Q4. Why does hereditary fructose intolerance cause severe hypoglycemia?

Fructose-1-phosphate accumulates and inhibits glycogen phosphorylase → prevents glycogen breakdown.
Also blocks gluconeogenesis.

Q5. How to differentiate Hereditary Fructose Intolerance from Fructosuria?

HFI: Aldolase B deficiency → vomiting, jaundice, hepatomegaly
Fructosuria: Fructokinase deficiency → benign → only fructose in urine

Q6. Why do infants with galactosemia develop cataracts?

Because unmetabolized galactose is converted to galactitol (via aldose reductase), which accumulates in lens causing osmotic swelling.
(Cataract feature shown in galactosemia clinical figure)

Q7. Why is galactose tolerance test used for liver function?

Galactose is metabolized almost exclusively in the liver; impaired metabolism suggests hepatic dysfunction.

Q8. Why is fructose found in semen?

Because fructose is produced via the polyol pathway and acts as a major energy source for sperm.

Q9. Which pathway is active in brain but inactive in liver?

Polyol pathway → produces fructose in CSF, but liver does NOT use this pathway.

Q10. Which reducing sugars in urine indicate what disorder?

Fructose → fructosuria (benign) or HFI
L-xylulose → essential pentosuria
(Both give positive Benedict's test)

⭐ Clinical Points From the Chapter

1. Sorbitol-Induced Cataract (Polyol Pathway)

In hyperglycemia, excess glucose enters the polyol pathway → converted to sorbitol.
Sorbitol cannot diffuse out of the lens → accumulates → osmotic swelling → cataract formation.
Same mechanism applies to galactitol in galactosemia.

2. Fructose as a Marker in Semen (Male Infertility Evaluation)

Fructose is present in seminal plasma; provides energy for sperm.
If fructose absent in semen, it suggests obstruction after seminal vesicles.
If fructose present, obstruction is before seminal vesicles.

3. Fructose & Cardiometabolic Risk

High fructose intake increases:
- Fatty acid synthesis
- Serum triglycerides
- LDL cholesterol
Increases atherogenic risk and worsens diabetic dyslipidemia.

4. Fructose → Hyperuricemia

Fructokinase rapidly uses ATP → intracellular ATP drops → AMP broken down → uric acid rises.
Link: fructose overload may contribute to gout.

5. Hereditary Fructose Intolerance → Severe Hypoglycemia

Aldolase B defect → fructose-1-phosphate accumulates.
This inhibits glycogen phosphorylase → glycogen cannot break down → hypoglycemia.
Presents in infants when fructose / sucrose is introduced.

6. Jaundice & Liver Failure in HFI

Accumulated F-1-P is hepatotoxic → jaundice, vomiting, hepatomegaly, failure to thrive.

7. Fructosuria → Benign Condition

Fructokinase deficiency → fructose spills in urine.
No hypoglycemia or liver damage; only positive reducing sugar tests.

8. Essential Pentosuria → False Positive Sugar Test

L-xylulose excreted in urine → positive Benedict’s test.
Must differentiate from diabetes mellitus.

9. Galactosemia → Cataract + Liver Failure

Galactose → galactitol (polyol pathway) → cataracts.
Galactose-1-phosphate accumulation causes:
- Hepatomegaly
- Failure to thrive
- Vomiting
- Jaundice
Severe cases lead to death if untreated.

10. Galactose Tolerance Test as a Liver Function Test

Galactose is metabolized almost exclusively by liver.
Delayed clearance of galactose → indicates hepatic impairment.

11. Polyol Pathway Active in Brain

Fructose appears in CSF because the pathway is active in brain.
Clinical implication: sorbitol accumulation may contribute to neurotoxicity in uncontrolled diabetes.

⭐ Clinical Problem Scenarios (Exam Pattern)

These mimic real MBBS exam/viva style “clinical problem” questions.

Problem 1: Child with Vomiting After Weaning

A 6-month-old infant develops vomiting, sweating, jaundice, and lethargy after starting fruit juices.

Diagnosis: Hereditary Fructose Intolerance
Cause: Aldolase B deficiency
Mechanism: F-1-P inhibits glycogenolysis → severe hypoglycemia.
(Reference: HFI features)

Problem 2: Infantile Cataract Without Liver Symptoms

A newborn with clear liver tests but dense cataracts.

Diagnosis: Galactokinase deficiency
Mechanism: Galactose → galactitol in lens → osmotic swelling.

Problem 3: Reducing Sugar Positive but Blood Glucose Normal

Urine shows positive Benedict’s test; fasting glucose normal.

Possibilities:

Essential pentosuria (L-xylulose)
Fructosuria (fructose)
Differentiation:
No systemic symptoms
Both benign
(Reference: pentosuria lines)

Problem 4: Diabetic Patient Developing Early Cataracts

High glucose → high sorbitol in lens → osmotic injury.

Diagnosis: Diabetic cataract due to polyol pathway.
(Reference: sorbitol leads to cataract)

Problem 5: Male Infertility Evaluation

Semen sample tested for fructose:

Fructose present → obstruction is before seminal vesicles
Fructose absent → obstruction after seminal vesicles
(Reference: fructose in semen)

Problem 6: Hyperuricemia after High-Fructose Diet

High fructose → ATP depletion → excess AMP → increased uric acid.

Clinical relevance: fructose may worsen gout or cause acute hyperuricemia.
(Reference ATP depletion → uric acid increase)

Problem 7: Liver Function Assessment Using Sugar

If galactose blood levels remain high after ingestion → liver cannot metabolize it.

Interpretation: hepatic impairment.
(Reference: Galactose tolerance test)

⭐ MCQs: Minor Metabolic Pathways of Carbohydrates

1. Sorbitol accumulation in the lens is mainly responsible for which condition?

A. Wilson disease
B. Diabetic cataract
C. Galactosemia liver failure
D. Wernicke encephalopathy

Answer: B. Diabetic cataract
Explanation: Polyol pathway → sorbitol trapped in lens → osmotic damage → cataract.

2. Essential pentosuria is due to deficiency of which enzyme?

A. Aldolase B
B. Fructokinase
C. L-xylulose reductase
D. G6PD

Answer: C. L-xylulose reductase
Explanation: Leads to L-xylulose in urine → benign condition.

3. Which statement correctly explains fructose metabolism in liver?

A. It depends on insulin
B. It bypasses PFK
C. It increases ATP level
D. It reduces lipogenesis

Answer: B. It bypasses PFK
Explanation: Leads to ↑ glycolysis flux → ↑ lipogenesis & ↑ TAG.

4. High fructose intake increases uric acid because:

A. Fructose inhibits AMP deaminase
B. Fructose depletes ATP rapidly
C. Fructose increases gluconeogenesis
D. Fructose blocks ketone body production

Answer: B. Fructose depletes ATP rapidly
Explanation: Low ATP → AMP breakdown → ↑ uric acid.

5. A 6-month-old baby develops jaundice, vomiting, hepatomegaly after taking fruit juice. Most likely enzyme deficiency:

A. Galactokinase
B. Aldolase B
C. Fructokinase
D. Epimerase

Answer: B. Aldolase B
Explanation: Hereditary fructose intolerance; F-1-P accumulation.

6. Presence of fructose in semen is an indicator of:

A. Testicular failure
B. Prostate carcinoma
C. Seminal vesicle function
D. Epididymal obstruction

Answer: C. Seminal vesicle function
Explanation: Fructose is secreted by seminal vesicles.

7. Infantile cataracts without liver involvement is seen in:

A. Classic galactosemia
B. Galactokinase deficiency
C. HFI
D. Fructosuria

Answer: B. Galactokinase deficiency
Explanation: Due to galactitol accumulation.

8. A benign condition with positive Benedict’s test but normal blood glucose:

A. HFI
B. Von Gierke disease
C. Essential pentosuria
D. Classic galactosemia

Answer: C. Essential pentosuria
Explanation: L-xylulose appears in urine; harmless.

9. Which pathway is active in brain but inactive in liver?

A. Galactose metabolism
B. Polyol pathway
C. Glycogenolysis
D. Gluconeogenesis

Answer: B. Polyol pathway
Explanation: Fructose found in CSF as pathway is active in brain but not liver.

10. Fructose is rapidly utilized in normal individuals because:

A. It enters pentose phosphate pathway
B. Fructokinase is inhibited by insulin
C. It bypasses glucokinase and PFK bottlenecks
D. It needs no phosphorylation

Answer: C. It bypasses glucokinase and PFK bottlenecks
Explanation: Hence rapid utilization.

11. Which enzyme deficiency leads to accumulation of galactose-1-phosphate?

A. Galactokinase
B. Galactose-1-phosphate uridyl transferase
C. Epimerase
D. Aldolase B

Answer: B. Galactose-1-phosphate uridyl transferase (GALT)
Explanation: Classic galactosemia (severe).

12. Which condition shows fructose in urine but is completely harmless?

A. HFI
B. Fructosuria
C. Galactosemia
D. Pentosuria

Answer: B. Fructosuria
Explanation: Fructokinase deficiency; benign.

13. Which metabolic disorder causes severe hypoglycemia due to inhibition of glycogen phosphorylase?

A. Essential pentosuria
B. Fructosuria
C. HFI
D. Galactokinase deficiency

Answer: C. HFI
Explanation: F-1-P blocks glycogen breakdown.

14. Which sugar is found in large quantity in seminal fluid?

A. Glucose
B. Galactose
C. Fructose
D. Mannose

Answer: C. Fructose
Explanation: Energy for sperm; secreted by seminal vesicles.

15. A diabetic patient develops early cataracts. The most likely accumulated substance is:

A. Mannitol
B. Sorbitol
C. Ribitol
D. Inositol

Answer: B. Sorbitol
Explanation: Sorbitol builds up in lens → osmotic damage → cataract.

⭐ Viva Voce Questions – Minor Metabolic Pathways of Carbohydrates

1. What is the polyol pathway?

It is an alternative pathway where glucose is converted to sorbitol by aldose reductase, and sorbitol is converted to fructose by sorbitol dehydrogenase.

2. Why does sorbitol accumulate in the lens?

The lens lacks sorbitol dehydrogenase.
Sorbitol cannot exit the lens → causes osmotic swelling → cataract.

(Shown in PDF lines about sorbitol causing cataract)

3. In which tissues is the polyol pathway active?

Lens
Retina
Kidney
Peripheral nerves
Brain (fructose found in CSF)

(Polyol pathway active in brain and not in liver)

4. Why is fructose commonly found in seminal plasma?

Because seminal vesicles secrete fructose, which is the major energy source for sperm.

5. Which reducing sugar is detected in essential pentosuria?

L-xylulose appears in urine due to deficiency of L-xylulose reductase.

6. Is essential pentosuria dangerous?

No. It is a benign condition but gives a positive Benedict’s test, which may be confused with diabetes.

7. What is the first step in fructose metabolism?

Phosphorylation by fructokinase at carbon-1 to form fructose-1-phosphate.

8. Why is fructose metabolism rapid?

Because it bypasses phosphofructokinase (PFK), the rate-limiting step of glycolysis.

9. Why does fructose increase lipogenesis?

Rapid fructolysis produces:

Dihydroxyacetone phosphate
Glyceraldehyde
These increase triglyceride and fatty acid synthesis.

10. Why does high fructose intake raise uric acid levels?

Fructokinase consumes ATP rapidly → ATP depletion → AMP breakdown → hyperuricemia.

11. What is the enzyme defect in hereditary fructose intolerance?

Aldolase B deficiency.

12. Why does hereditary fructose intolerance cause hypoglycemia?

Accumulated fructose-1-phosphate inhibits:

Glycogen phosphorylase
Gluconeogenesis

This leads to severe fasting hypoglycemia.

13. How does hereditary fructose intolerance present clinically?

Infant presents with:

Vomiting
Jaundice
Hepatomegaly
Hypoglycemia
Symptoms start after fructose/sucrose ingestion.

14. What is essential fructosuria?

Benign disorder due to fructokinase deficiency.
Fructose appears in urine but no hypoglycemia or liver damage.

15. What is galactosemia?

Inherited defect of galactose metabolism, most commonly GALT deficiency, leading to accumulation of galactose-1-phosphate.

16. Why do infants with galactosemia develop cataracts?

Galactose is converted to galactitol, which accumulates in the lens → osmotic damage → cataract.

17. What are the main clinical features of classic galactosemia?

Jaundice
Hepatomegaly
Cataracts
Vomiting
Failure to thrive
Risk of E. coli sepsis

18. What is galactokinase deficiency?

A mild form of galactosemia presenting mainly with infantile cataracts without liver involvement.

19. Why is the galactose tolerance test used as a liver function test?

Because galactose is metabolized almost exclusively in the liver.
Delayed clearance indicates hepatic damage.

20. Name a benign inborn error detected by a reducing sugar test but without systemic symptoms.

Essential pentosuria or fructosuria.

21. Why does fructose appear in urine in fructosuria?

Due to fructokinase deficiency, so fructose remains unphosphorylated and spills into urine.

22. Which pathway is active in brain but not in liver?

Polyol pathway.

23. What sugar accumulates in semen if seminal vesicles are functioning normally?

Fructose.

24. What distinguishes HFI from fructosuria clinically?

HFI → hypoglycemia + jaundice + hepatomegaly
Fructosuria → asymptomatic

25. What is the toxic metabolite in classic galactosemia?

Galactose-1-phosphate.

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