VITAMIN B COMPLEX DISORDERS

Vitamin B complex is a heterogeneous but closely linked group of water-soluble vitamins, all being important constituents of various enzyme systems. As many vitamins of this group share common source and inter-related metabolism, multiple vitamin B complex deficiencies are more common than isolated disorders.

Table 6.15 presents a synopsis of important functions, dietary requirements, sources and deficiency states for different members of this group, though the exact role of some of them is not yet well established.

Thiamine (B1) deficiency is an essential coenzyme for acetylcholine synthesis and oxidative utilization of glucose in Krebs cycle, also involves in synthesis of nucleic acids and fatty acids.

Thiamine deficiency in India is predominantly seen among rice-eating population of costal Andhra Pradesh, though the incidence has substantially markedly declined in recent years.

Etiology: RDA for thiamine is 0.2-2.2 mg#8725;day. Although widely distributed in dietary sources, thiamine is a water-soluble and heat-labile vitamin, mainly present in outer-coating of grains. Consequently, its deficiency is endemic areas is predominantly associated with:

(a) use of milled and polished rice as staple cereal, and

(b) vigorous washing and prolonged boiling with excessive water during cooking.

TABLE 6.15: Vitamin B complex at a glance

RDA: Recommended dietary allowance; BF: Breastfeeding; TPN: Total parenteral nutrition; CHO: Carbohydrate; P: Protein

Other causes include: (a) breastfeeding by thiamine­deficient mothers, and (b) total parenteral nutrition.

Clinical spectrum of thiamine deficiency is extremely wide, ranging from non-specific manifestations to well-defined syndromes, e.g. beriberi and Wernicke's encephalopathy.

• Beriberi, may be classified as: (i) dry beriberi, (ii) wet or cardiac beriberi, and (iii) infantile beriberi. These cases present with:

± General features, e.g. mental changes (irritability, apathy) failure to thrive and gastrointestinal upsets like anorexia, nausea and vomiting.

± Dry beriberi with predominant neurological mani­festations, e.g. peripheral neuritis (paresthesia, hyporeflexia, calf pains), ocular signs (ptosis/optic atrophy) and hoarseness/ aphonia due to laryngeal nerve paralysis (characteristic).

- Wet or cardiac beriberi with predominant cardiac manifestations, e.g. CCF with edema, cardiomegaly and pericardial effusion.

- Infantile beriberi presents at 2-4 months of age with vomiting, peripheral neuropathy and puffiness, in breastfed infants of thiamine-deficient mothers.

• Wernicke's encephalopathy is a rare manifestation of thiamine deficiency in severe undernutrition or unsupplemented parenteral nutrition, presenting with irritability, ataxia, ophthalmoplegia and altered sensorium.

• Non-specific manifestations are more common in endemic as well as non-endemic regions than well- defined beriberi, presenting with anorexia, mild calf tenderness and absence of ankle/knee jerk.

Diagnosis is best established by clinical response to thiamine administration, though biochemical tests, e.g. low RBC transketolase levels or elevated urinary glyoxalate excretion indicate subclinical deficiency.

Management includes oral or parenteral thiamine administration (5-10 mg/day) for at least 6 week, followed by low-dose oral supplements (0.5-1.5 mg/ day) and proper diet. Mothers of infantile beriberi, even if asymptomatic, should be treated with oral thiamine (50 mg/day).

Riboflavin (B₂) deficiency is a cofactor for various enzymes involved in cellular oxidation, energy metabolism and erythropoiesis. Riboflavin deficiency is rarely isolated, usually a part of multivitamin deficiency in sick children.

Etiology: RDA for Riboflavin is 0.5-3.0 mg/day. Deficient dietary intake or malabsorptive disorders, e.g. chronic diarrhea are most important causes of riboflavin deficiency, though sub-clinical deficiency may occur in newborns on phototherapy (destroys riboflavin) or during drug therapy, e.g. phenothiazines (interfere with its metabolism).

Clinically these cases present with:

• Oral signs: For example, angular stomatitis, cheilosis, glossitis

• Ocular signs: For example, keratitis, conjunktivitis.

• Others: For example, neuromotor dysfunction, poor wound healing or normocytic normochromic anemia.

Diagnosis is clinical, though subclinical deficiency may be detected by decreased urinary riboflavin excretion (lt;30 mg/day) or low glutathione reductase content in RBCs.

Treatment includes PO riboflavin (3-10 mg/day) till disappearance of signs, followed by adequate dietary intake and treatment of primary cause. Severe or non- responsive cases may need intramuscular riboflavin (2 mg TDS) in early stages.

Niacin (B₃) deficiency (Pellagra) is a component of two important glycolytic enzymes—nicotinamide adenine dinucleotide (NAD) and NAD phosphate, as well as a regulator of DNA synthesis and repair. Nutritionally, it is available as:

• Preformed niacin or nicotinic acid, mainly in non­vegetarian foods, e.g. meat and fish; or

• Synthesized from its precursor—tryptophan, mainly present in milk and eggs (60 mg tryptophan yields ~ 1 mg of niacin).

Cereals and vegetarian diet are poor sources of free niacin as well as tryptophan.

Etiology: RDA for niacin is 2-22 mg/day. Niacin deficiency is prevalent in maize-eating populations, dueto high leucine content in maize that interferes with endogenous conversion of typtophan into niacin (aminoacid imbalance). However in India, it is mainly seen in jowar-eating population of Telangana, due to same reason.

Clinically, Pellagra, the prototype manifestation of niacin deficiency, presents with a triad of 3 D's, as follows:

• Dermatitis, i.e. photosensitive rashes on exposed parts of body, often described as pellagrous glove (hands), boot (legs), necklace (neck), etc. Chronic cases may develop vesicobullous, weeping, desquamating or hyperpigmented lesions.

• Chronic Diarrhea with/without vomiting.

• Dementia with depression, dizziness, disorientation, delirium and burning sensation/numbness (paresthesia).

Diagnosis rests on clinical triad, dietary history and response to niacin therapy. Reduced urinary excretion of N-methyl nicotinamide (a metabolite) has been used as an indicator of subclinical deficiency.

Treatment includes oral niacin supplementation (50-300 mg/day). IV niacin (100 mg) may be given in severe cases, though it lead to an unpleasant sensation of local heat and flushing, and rarely the cholestatic jaundice. Avoidance of sun-exposure, soothing topical agents over skin lesions and treatment of co-existing vitamin deficiencies is also necessary.

Vitamin (B₆) deficiency includes three compounds— pyridoxal, pyridoxine and pyridoxamine, each convertible to pyridoxal phosphate—a co-factor for many neuroenzymes, e.g. GABA, apart from other functions. Consequently, seizures and peripheral neuropathies are most common manifestations of pyridoxine deficiency. Etiology: RDA for pyridoxine is 0.1-3.0 mg/day. Pyridoxine deficiency is rarely dietary, due to adequate vitamin content in milk and cereals. It is mainly caused by: (a) chronic diarrhea and malabsorptive states,

(b) treatment with pyridoxine-antagonists, e.g. INH, penicillamine, etc. and (c) dependency states, due to

genetically abnormal structure/function of vitamin B₆ dependent enzymes.

Important dependency states include pyridoxine­dependent seizures, anemia and homocystinuria.

Clinically, these cases present with one or more of following four features: (a) peripheral neuritis, (b) seizures, (c) microcytic hypochromic anemia, and (d) dermatitis with cheilosis, glossitis and seborrhea around eyes, nose and mouth.

Pyridoxine-related seizures include:

• Deficiency seizures due to dietary deficiency in formula-fed children. These seizures are typically generalized and present in infancy, beyond neonatal period.

• Dependency seizures due to: (i) genetic defects in pyridoxine-dependent enzymes, or (ii) mega pyri­doxine therapy in pregnant mothers for hyperemesis gravidarum.

Diagnosis must be suspected after exclusion of other causes for seizures and anemia. In a suspected case, 100 mg pyridoxine is given intramuscularly, preferably with concomitant EEG recording. Immediate control of seizures and EEG abnormality suggests pyridoxine deficiency/dependency.

Tryptophan loading test, a biochemical test, to differen­tiate between pyridoxine deficiency and dependency states, involves loading with 100 mg/kg of tryptophan that leads to increased urinary excretion of xanthurenic acid in deficiency states. This test is normal in dependency states.

Treatment: Pyridoxine-deficiency seizures are treated with IM pyridoxine (100 mg), followed by adequate dietary intake and treatment of primary cause. Pyridoxine-dependent seizures need long-term daily therapy (PO 10-100 mg or IM 2-5 mg).

Folic acid deficiency (pteroylglutamic acid) is essential for normal DNA synthesis and hence, folic acid deficiency mainly affects rapidly dividing cells, e.g. bone marrow (megaloblastic anemia) or in fetus (neuronal tube defects). In natural diet, folic acid exists as folates. Etiology: Folic acid deficiency is rarely dietary due to miniscule daily requirements (25-350 #956;g#8725;day), usually caused by: (a) malabsorption states, e.g. fish tapeworm infestations, (b) increased requirements, e.g. in pregnancy and hemolytic anemia, and (c) anti-folate drugs, e.g. methotrexate, pyrimethamine. Goat and camel milk are poor sources of folic acid.

Clinically, these cases present with four important manifestations: (a) megaloblastic anemia, (b) chronic diarrhea, (c) neurological manifestations, e.g. tremors and developmental regression, and (d) skin hyper­pigmentation, specially on knuckles and thigh. Severe deficiency may also be associated with thrombotic epi­sodes and atherosclerosis, due to altered homocysteine metabolism.

Diagnosis depends on peripheral smear (megaloblastic anemia), supported by low RBC/serum folate levels (normal: 5-20 ng#8725;ml). FIGLU test, i.e. urinary excretion of formiminoglutamic acid after loading dose of histidine, may detect subclinical deficiency.

Treatment: Folic acid deficiency is treated with PO or parenteral folic acid (1-5 mg#8725; day) for 3-4 weeks, along with concomitant vitamin B₁₂ supplementation and elimination of offending drug, if applicable.

Folic acid deficiency in pregnancy is an important cause of neural tube defects in fetus, which can be easily prevented by Routine folic acid supplementation with 400 #956;g#8725;day to all pregnant mothers or 5 mg/day to all mothers with previously affected child (recurrence) from 1 month before to 3 months after the conception (Ch 18.10.1).

Also see Chapter 19.4.2 for folic acid deficiency anemia. Cobalamin (B₁₂) Deficiency is a cobalt-containing vitamin, essential for nucleic acid metabolism and myelin formation (Cyanocobalamin is the therapeutic preparation, used to treat vitamin B₁₂ deficiency).

Widely present in animal sources, vitamin B₁₂ is absent in plant foods, but may be endogenously synthesized by colonic bacteria. Vitamin B₁₂ absorption requires hydrolysis by gastric acid and combination with a specific protein in stomach—intrinsic factor of castle (IFc). This B₁₂-IFc complex attaches to specific receptor sites in terminal ileum, where B₁₂ component is absorbed, transported in bound form with a plasma protein- transcobalamin and stored in tissues, bound to another protein-transcobalamin I.

Etiology: RDA for vitamin B₁₂ is 1.0-2.5 #956;g#8725;day. Vitamin B₁₂ deficiency is rarely dietary, due to extremely low requirements, usually caused by congenital or acquired defects in its absorption, e.g. (a) congenital IFc deficiency or juvenile pernicious anemia, (b) malabsorption disorders,

(c) imerslund syndrome, i.e. IFc-B₁₂ receptor deficiency, and

(d) congenital transcobalamin deficiency.

Clinically, vitamin B₁₂ deficiency presents with a triad of: (a) megaloblastic anemia, (b) glossitis, and (c) signs of demyelination, e.g. ataxia, paresthesia, hypo/ hyperreflexia (subacute combined degeneration of cord).

Diagnosis is usually based on:

• Megaloblastic anemia on smear that does not respond to folic acid therapy, supported by

• Low serum vitamin B₁₂ levels (lt;100 pg#8725;ml)

• Methylmalonic aciduria (gt;3.5 mg#8725;day).

Schilling test is used to confirm vitamin B₁₂ deficiency as well as to differentiate between IFc deficiency and malabsorption defects (Ch 19.4.2).

Treatment: Oral vitamin B₁₂ therapy is unreliable due to defective absorption, though may be given as 500-1000 #956;g/ day for 3 months, in cases without neurological signs.

Cases with neurological signs should be treated with parenteral Vitamin B₁₂ (IV/IM) 250-1000 #956;g#8725;day for 2 weeks, then weekly for next 2-3 months, and then monthly doses till correction of anemia. Lower range of dose (0.2 mg) may be used in infants and young children. Life-long therapy is required if cause is untreatable, e.g. juvenile pernicious anemia or malabsorption disorders. Prevention with prophylactic Vitamin B₁₂ is advised in cases with malabsorptive states.

Biotin deficiency: Role of biotin as an important co­factor of various carboxylase enzymes in carbohydrate/ fat metabolism is being increasingly recognized in recent years.

Etiology: Biotin deficiency is rarely dietary, as it is also synthesized by intestinal bacteria. Important causes include: (a) excessive consumption of raw egg-white, which is rich in Avidin—a biotin-binding protein, (b) unsupplemented formula or parenteral feeding, and

(c) genetic biotinidase deficiency an enzyme required to recycle biotin (dependency state).

Clinically, it presents with: (a) skin lesions, e.g. exfoliative dermatitis and alopecia, (b) GIT manifestations, e.g. anorexia and glossitis, and (c) neurological manifestations, e.g. extreme lassitude and muscle pains. Genetic defects may also present with Rett syndrome.

Diagnosis depends on dietary history, clinical features, organic aciduria and response to biotin therapy. A filter-paper spot test is available to screen newborns for biotinidase deficiency, testing increased excretion of 3-hydroxyisovaleric acid in urine.

Treatment includes PO or IM Biotin therapy with 2-5 mg/day for 3 weeks, though higher doses (10 mg#8725; day) are required for dependency states.

6.3