Water-Soluble Vitamin B1 → B7😊😍

Water-Soluble Vitamin Deficiencies

Excretion and Storage

• Easily excreted in urine – minimal storage in the body.

• Exceptions:
• B12 stored in liver for 3–4 years
• B9 (Folate) stored for 3–4 months

• Note: Vitamin C deficiency → defective collagen due to ↓ lysyl hydroxylase.

Vitamin B1 (Thiamine)

Thiamine Dependent Enzymes → ABPT

1. Alpha ketoglutarate dehydrogenase complex.

2. Branched Chain Ketoacid Dehydrogenase:
• Ketoacid → Not amino acid
• Maple Syrup Urine Disease.
• Enzyme deficient: Branched chain Alpha-ketoacid dehydrogenase
• Autosomal recessive
• Boxing, cyclic movements and seizures in new-born
• Amino Acids: Leucine, Isoleucine, Valine
• Urine odor:
• Maple syrup or Burnt sugar
• Diagnostic tests are employed:
• FeCl3 test +ve
• DNPH test +ve
• Ketone bodies in urine
• Treatment:
• Restrict Valine, Leucine, Isoleucine in diet
• (Branched chain AA)
• Branch → VaLI
• Thiamine supplementation.
• Mnemonic Miss u di (MSUD )- Batch (Branch) mate valli
• Maple () tree has Branches () and VALi () → got in Cycle (Cyclical movements)

3. Pyruvate Dehydrogenase (PDH):
• Involved in aerobic glucose utilisation.
• In Thiamine deficiency, PDH is inactive.
• Pyruvate converts to Lactate, causing Lactic acidosis.
• Lactic acidosis contributes to Wet beriberi.
• It has a vasodilatory effect.
• Causes arteriolar dilatation and venoconstriction.
• This can lead to:
• Hypotension.
• Tachycardia.
• Increased hydrostatic pressure in capillaries, causing:
• Oedema.
• High output cardiac failure.

4. Transketolase of HMP shunt:
• RBC Transketolase activity
• diagnostic marker for suspected Thiamine deficiency.

Pyruvate Dehydrogenase Complex

Deficiency Causes

• Polishing of rice

• Alcohol use disorder

• Andhra Pradesh population

• Chronic fasting

• Malabsorption, malnutrition, diarrhea, vomiting

Sources:

• Gingelly seeds (richest)

• Rice, chappathi, wheat

Prevention:

• Parboiling of polished rice

• Intake of Thiamine-rich foods (e.g., gingelly seeds)

Dry beriberi:

• D/t ⛔ of PDH → ↓ Aerobic glycolysis in Nerves → Nerves are the most affected
• Polyneuropathy,
• symmetric muscle wasting,
• neurological features
• irritability,
• weakness of lower limbs,
• diminished DTRs
• peripheral neuropathy

Wet beriberi:

• D/t ⛔ PDH → ↓ PDH → Pyruvate cannot enter Krebs cycle → Excess Pyruvate shunted to Lactate → Lactic acidosis → vasodilatory effect
• Causes arteriolar dilatation and venoconstriction.
• This can lead to:
• Hypotension.
• Tachycardia.
• High output cardiac failure.
• Oedema.
• cardiovascular symptoms,
• cardiac edema,
• dilated cardiomyopathy,
• Peripheral edema,
• Pulmonary edema

Infantile Beri Beri:

• In infants of breast-feeding mothers who are thiamine deficient

Alcohol and Thiamine Deficiency

• Alcohol cause ↓↓ Thiamine and Magnesium absorption

• Thiamine ⇏ Thiamine Pyrophosphate (active form)
• by Thiamine Kinase.
• Requires Magnesium.

• This leads to a functional deficiency of Thiamine.

Alcohol is a High Energy

• In a high energy state, an individual may not feel hungry and may skip meals.

• Skipping meals can lead to micronutrient deficiencies.

• Alcohol is considered a source of "empty calories".
• It provides excess energy without sufficient micronutrients.

Biochemical Test

• Erythrocyte transketolase activity

• Urinary thiamine excretion

Q. A person has a history of alcoholism for 20 years. He avoids alcohol for 2 days and presents with agitation, global confusion, disorientation, hallucination, fever, high BP, diaphoresis and autonomic hyperactivity. The most common cause is:

• Chronic alcoholism is associated with Wernicke's encephalopathy.
• Presents with Global confusion, Ophthalmoplegia, and Ataxia (GOA).

• The question specifies alcohol withdrawal for 2 days.
• This commonly causes Delirium tremens.

• Pancreatitis will not cause autonomic hyperactivity, disorientation, or hallucinations.

• Wernicke's encephalopathy does not typically present with autonomic hyperactivity, diaphoresis, or high blood pressure.

• Korsakoff syndrome primarily presents with Amnesia and is a chronic manifestation.

Delirium Tremens

Vitamin B2 (Riboflavin)

• A/w Circumcorneal vascularisation → earliest sign

Function

• 12 SAGE - Features similar to 12
• Succinate DH
• Acyl CoA DH
• Glutathione reductase
• ETC

• AKA Warburg yellow enzyme

• Component of flavins FAD and FMN as cofactors in redox reactions

• Present in flavoproteins

• Active forms:
• FAD (Acyl CoADH, Succinate DH)
• FMN (Complex I ETC)

• Coenzyme for glutathione reductase

• Heat stable

Clinical Features:

• Magenta red tongue



• Also called Geographical tongue / Glossitis
• Tongue becomes shiny, pink and devoid of papillae.

• Angular stomatitis (most specific)

• Oral ulcers.

Differential Tongue Signs

• Angular stomatitis & cheilosis

• Fissures in lips

• Corneal vascularization (difficulty in vision, lacrimation)

• Seborrheic dermatitis along nasolabial folds

• Photophobia

• Normocytic anemia (differentiate from B12)

• Pharyngitis, stomatitis

Biochemical Tests

• Erythrocyte glutathione reductase activity

• Urinary riboflavin

• Urinary excretion less than 10% of intake over 24 hours indicates deficiency

• Cofactor-induced increase of 20% above basal levels indicates deficiency

Treatment

• Children: 3–10 mg oral riboflavin daily for several weeks

• Infants: 1 mg daily

Vitamin B3 (Niacin)

• Tryptophan is converted to Niacin in steps:
• Tryptophan -> Formylkynurenine (by Tryptophan pyrrolase).
• Formylkynurenine -> Kynurenine (by Formyltransferase).
• Tetrahydrofolate → N10 formyl Tetrahydrofolate,
• entering the one-carbon pool.
• Kynurenine -> 3-OH Kynurenine (by Hydroxylase).
• 3-OH Kynurenine -> 3-OH Anthranilic Acid (by Kynureninase, dependent on B6).
• 3-OH Anthranilic Acid -> Quinolinate (non-enzyme catalysed).
• Quinolinate -> Niacin Mono Nucleotide (by QPRTASE).
• Niacin Mono Nucleotide -> Niacin Adenine Dinucleotide (NAD).

Synthesis

• Requires tryptophan
• (60 mg tryptophan → 1 mg niacin)

• Requires vitamins B2 and B6

Causes of Pellagra

• Drug causing Pellagra:
• Isoniazid:
• Induces B6 deficiency → ↓ Niacin → pellagra
• Azathioprine, 6-MP, 5-FU:
• Inhibit tryptophan → ⛔ niacin conversion → Pellagra

• Dietary deficiency:
• Of Niacin.
• Of Tryptophan (A/w Maize-based diets).

• Tryptophan malabsorption:
• e.g., Hartnup's disease.
• Affecting transport of Neutral amino acids
• Obermeyer test

• Tryptophan diversion:
• e.g., Carcinoid syndrome,
• (Tryptophan is used for Serotonin synthesis)

• B6 deficiency:
• B6 is crucial for Kynureninase.
• In B6 deficiency, Kynureninase is inactive.
• Kynurenine converts to Xanthurinic acid,
• Measured in urine to diagnose B6 deficiency.

• Leucine Pellagra:
• Leucine inhibits Quinolinate Phospho Ribosyl Transferase.
• Common in Sorghum-based diets (rich in Leucine).

• Folate deficiency ?

Deficiency Manifestations (Pellagra)

• B3 → 3D
• Diarrhea
• Dementia (also hallucinations)
• Dermatitis (photosensitivity),
• C3/C4 dermatome

NOTE: 4 Ds of Glucogonoma

• Death

• Depression

• Delirium

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• Diabetes Mellitus (DM).

• Dermatitis (Necrolytic migratory rash)
• Hyperglycemic cutaneous syndrome/ Necrolytic Erythema Migrans

• Deep Vein Thrombosis (DVT).

• Depression.

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"Broad collar" rash (Cassal’s necklace),

• Subacute eczema

• On photoexposed areas (V-area of neck, dorsum of hands)

• Hyperkeratotic, lichenified, eczematous patches

• Neck: Castle's Necklace

Treatment

• High-protein diet

• Niacin or Nicotinamide.

Preventive food:

• GroundNUTs

• Mnemonic: N (Niacin) doesnt like M (Maize & Sorghum), likes N (Nuts)

Toxicity of Niacin

• PG mediated flushing
• pretreatment: aspirin, laropiprant

• Hyperuricemia

• Glucose intolerance

• Cystoid macular edema

• Gastric irritation

• Fulminant hepatitis

Q. A person presents with diarrhoea, dementia and dermatitis. What is the probable cause?

• The triad of Diarrhoea, Dementia, and Dermatitis is characteristic of Pellagra.
• Caused by Niacin (B3) deficiency.
• Other options
• Cystinuria:
• Due to a defect in a neutral amino acid transporter in the PCT.
• Leads to decreased reabsorption of Cysteine, Ornithine, Lysine, Arginine (COLA)
• Only Sister → Urge to Lie
• Neutral COLA
• These amino acids are excreted in urine.
• Cysteine vs Cystine
• Cysteine → has a Cys-SH group.
• Two cysteine molecules → condense → form Cystine (disulfide bridge).
• Excess Cysteine forms insoluble Cystine
• Cystine is insoluble in urine.
• Accumulates in renal tubules.
• Leads to renal stones (cystine stones).
• Obstructive uropathy.


• Cystinuria in Urine detected with
• sodium cyanide nitroprusside test
• proton nuclear magnetic resonance spectroscopy
• Alkaptonuria:
• Caused by a defect in Homogentisate oxidase.
• Leads to accumulation of homogentisic acid.
• Turns urine black on standing (Black urine disease).
• Can cause ochronosis.
• Porphyria:
• Presents with neuropsychiatric manifestations or photosensitivity, or both.
• Not typically the 3 D's.

Q. A patient presents to the OPD with complaints of diarrhoea. The patient was later diagnosed with dementia and photosensitive dermatitis in sun -exposed areas. Which Vitamin deficiency is responsible for this condition?

• The presentation of diarrhoea, dementia, and photosensitive dermatitis indicates Pellagra.

• Pellagra is caused by Niacin deficiency (Vitamin B3).

Vitamin B5 (Pantothenic Acid)

Function

• Present in
• CoA (Acetyl CoA and Succinyl CoA)
• Acyl carrier protein (Fatty Acid synthase complex)

• Required by Pyruvate dehydrogenase complex

• Important for blood cell production

• Converts protein and carbohydrates into energy

• Increases glutathione levels, protects cells from peroxidative damage

Deficiency Manifestations

• Gopalan's burning foot syndrome/nutritional melalgia

• Adrenal insufficiency

• Dermatitis

• Enteritis

• Alopecia

Vitamin B6 (Pyridoxine)

Q. A known patient of Tuberculosis on INH for six months presents with tingling sensation and paraesthesia. Deficiency of which of the following vitamins is the most probable cause

• INH (Isoniazid) is a drug for Tuberculosis.

• It is known to cause B6 deficiency.

• B6 deficiency causes neurological manifestations like tingling and paraesthesia.

Active Form

• Pyridoxal phosphate (PLP)

Coenzyme role in:

• Mnemonic:
• Pyramidil → Trans person

• "Trans (Transamination) Decent (Decarboxylation) Sulphur (Transulfuration) Try (Tryptophan metabolism) Hema (Heme metabolism) Glysis (Glycogenolysis)"

Required for

• niacin synthesis from tryptophan

• metabolism of sulphur-containing amino acids

• Mnemonic:
• Xanthade periods () il (Xanthinuria) Seized (Seizure)

Diagnostic steps for Some similar conditions

Citrulline Levels High	ㅤ
↳ Citrullinemia	ㅤ
↳ Arginosuccinate aciduria	ㅤ
Citrulline level Low	ㅤ
↳ Type 1 Hyperammonemia	Enzyme: CPS 1 • XLR • ↑ Ammonia, glutamate, glutamine • Normal Orotic acid & Uracil Symptoms when ↑ Protein intake • Lethargy, Confusion, coma • Vomiting, Hyperventilation
Citrulline Level Normal + Hyperornithinemia	ㅤ
↳ HHH Syndrome • Hyperornithinemia →→→→→→→→→ • Hyperammonemia →→→→→→→→→ • Homocitrullinuria →→→→→→→→→→	Enzyme: Mitochondrial ornithine transporter (ORNT1) • ↑ Ornithine • ↑ Ammonia • ↑ Homocitrulline (d/t CP reacting with lysine). Treatment • Protein restriction • Ammonia-scavenging (sodium benzoate, phenylbutyrate) • Arginine or citrulline supplementation ↳ to improve urea cycle flux
↳ Gyrate Atrophy of Choroid and Retina	Enzyme: OAT deficiency • AR • OAT deficiency→ ⛔ breakdown of Ornithine • Source: From Arginine • Ornithine is toxic to Retinal Pigment Epithelium (RPE) • Progressive chorioretinal degeneration ↳ night blindness, visual loss Treatment • Low-arginine diet • B6 supplementation Arni (Ornithine) kk avlde Kannu (RPE) kandapo Urge (Arginine) ayi → Glued (GLutamate) ayi
Citrulline Level Normal + Hyperornithinemia + Orotic Aciduria	ㅤ
↳ Type 2 Hyperammonemia	Enzyme: OTC • (m/c UCD) • AR • ↑Ammonia, glutamate, glutamine • ↑↑ Orotic acid & Uracil ⇒ Orotic aciduria • Accumulation of ornithine Symptoms • Type 1 + Hepatomegaly
Just Orotic Aciduria	ㅤ
Hereditary orotic aciduria	Enzyme: UMP synthase deficiency • AR • ↑ Orotic acid in urine • Megaloblastic anemia unresponsive to B12/folate • Normal ammonia (differentiates from OTC deficiency). Symptoms • Failure to thrive • Growth retardation • Developmental delay Treatment • Uridine supplementation ↳ provides UMP, bypasses block, decreases orotic acid
Allopurinol	ㅤ

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Screening for IEM

• IOC / Gold standard: Tandem Mass Spectrometry:
• Blood spot

• Gas Chromatography - Mass Spectrometry:
• Fresh Urine

• High Performance Liquid chromatography/Electrophoresis:
• Plasma, urine

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• Blood pH
• ↑/Normal: UCD
• ↓: Organic aciduria

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• Acylation therapy / AMMONIA SCAVENGERS
• Phenyl butyrate (prodrug)
• Phenyl acetate + Glutamine → Phenyl acetyl glutamine (excreted)
• Mnemonic: But → Glut
• Sodium benzoate + Glycine → Benzoyl glycine/hippurate (excreted)
• (via Glycine synthase)
• Mnemonic: Benz → Glazing
• Glycine requires NH₃ + CO₂ + 1 Carbon group

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Key differentiator in exams:

• Hyperornithinemia → think urea cycle defects or retinal disease.

• Orotic aciduria → think megaloblastic anemia + orotic acid in urine + normal ammonia.

• OTC deficiency: Hyperammonemia, no anemia.

Glutamate → GABA pathway

• Enzyme: Glutamate decarboxylase (GAD) – B6 dependent

• Interseting reaction bcz
• Glutamate = excitatory neurotransmitter
• GABA = inhibitory neurotransmitter

• B6 deficiency:
• ↑ Glutamate, ↓ GABA → seizures

Neonatal seizures:

• Causes: Hypocalcemia, Hypoglycemia

• Initial treatment: Calcium gluconate

• If unresponsive → give B6 injection (Glutamate → GABA conversion restored)

ALA Synthase & Anemia

• ALA Synthase (Heme synthesis) is B6 dependent
• Reaction: Glycine + Succinyl CoA → (ALA synthase) → ALA
• Requires Pyridoxal phosphate

• Deficiency:
• ALA synthase not functional → ↓ Heme synthesis → Sideroblastic Anemia

• Treatment: Anemia responds to B6 administration

Kynureninase & Niacin

• Kynureninase (B6 dependent)

• Converts Tryptophan → Niacin

• B6 deficiency:
• Impaired conversion → Niacin deficiency → Pellagra

• Kynureninase → Xanthuric acid excretion in urine → used for diagnosis of B6 deficiency

• Tryptophan load test → Measure Xanthuric acid

Treatment

• For sideroblastic anemia

• High doses for Xanthurenic aciduria

• 10–50 mg/day for INH patients (prevents peripheral neuropathy)

• 100 mg IM for refractory seizures

• For isoniazid toxicity induced seizures:
• IV pyridoxine, 1 g for 1 g isoniazid (max 5 g)

Toxicity

• Sensory neuropathy

Vitamin H/B7 (Biotin)

Function

• Coenzyme for Carboxylation reaction

Deficiency Causes

• Raw egg consumption (avidin inhibits biotin)

• Long-term antibiotic use

Deficiency Manifestations

• Relatively rare

• Fatigue on Moderate exercise

• Dermatitis

• Enteritis

• Alopecia

• Depression, hallucinations

• Scaling, seborrheic dermatitis & erythematous rash

• Perioral eruptions

• Reduced nail growth

• Hypoglycemia due to decreased carboxylase activity

• Thinning of hair and scaling of scalp

Biochemical Tests

• Urinary biotin concentration

• Serum & urine propionic acid level

• ↓Activity of biotin-dependent enzymes in lymphocyte

Associated Disorders

• Multiple carboxylase deficiency
• Global developmental delay
• intellectual disability
• Skin and hair
• D/t biotin
• Alopecia
• dermatitis
• Tom cat urine odour
• Treatment:
• Biotin

• Biotinidase deficiency

• Leiner's disease:
• ↓ Biotin linked to complement 5a deficiency

Q. A 4 years old child presents with mental retardation, Charley chaplin gait, ectopia lentis. Plasma homocysteine, methionine level was raised, plasma cysteine is markedly reduced. There is increased excretion of Homocysteine, Methionine in urine. The diagnosis is:

• Clinical features and biochemical findings are characteristic of Type 1 Homocystinuria.
• Clinical: Mental retardation, Charlie Chaplin gait, ectopia lentis.
• Biochemical: Raised homocysteine and methionine, reduced cysteine.

• This is caused by Cystathionine Beta synthase deficiency.

Q. Sideroblastic anemia is treated using which of the following?

• Anaemia caused by ALA synthase deficiency can be treated by B6 administration.
• ALA synthase is a B6-dependent enzyme.

Q. A pair of 19 year old female identical twins was referred to our hospital with progressive visual loss. They exhibited bilateral chorioretinal atrophy. Based on these observations and biochemical findings, the patients were diagnosed with gyrate atrophy of the choroid and the retina. Which is true about this disorder?

• Gyrate atrophy is caused by a defect of Ornithine aminotransferase.

• This leads to elevated Ornithine levels, which are toxic to the RPE.

• The disorder responds to:
• PLP (active form of B6) supplementation.
• Ornithine-restricted diets.
• Arginine-restricted diets.

Q. A woman with complaints of pain, tingling sensation, and numbness of the foot has a history of taking vitamin supplements. Which of the following is responsible for this patient's condition?

• The symptoms of neuropathy (pain, tingling, numbness) in a patient taking vitamin supplements suggest Hypervitaminosis B6.

• Excessive intake of B6 can cause neurological manifestations.

Vitamin C (Ascorbic Acid / Antiscorbutic factor)

Source

• Synthesized from glucose
• via Uronic acid pathway
• Absent in humans & higher primates
• d/t lack of L-gulonolactone oxidase

Functions

1. Collagen synthesis
• triple helix formation via prolyl & lysyl hydroxylases

2. Iron absorption
• reduces Fe³⁺ → Fe²⁺ for intestinal absorption

3. Tyrosine metabolism
• PHPP hydroxylase

4. Tryptophan metabolism
• hydroxylation reactions

5. Bile acid synthesis
• requires 7α hydroxylase

6. Steroid hormone synthesis

7. Cholesterol synthesis
• Functions 3 – 7 → Cofactor functions

Deficiency

• Causes anemia

Scurvy (clinical features)

• Bleeding gums

• Anemia (peripheral smear)

• Scorbutic rosary
• Beaded appearance at costochondral junction
• Angulated, tender (vs. Rachitic rosary → round, non-tender)