Vitamin deficiencies

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Vitamin deficiencies

Vitamin deficiencies are a significant cause of neurologic disease in developing countries and in certain high-risk groups in developed countries (i.e. chronic alcoholics, patients with gastrointestinal diseases, and patients receiving long-term parenteral nutrition with inadequate vitamin supplementation). They can also result from lifestyle factors such as vegetarianism or from a wide variety of medical and psychiatric conditions. Evidence of the importance of vitamins for the wellbeing and normal function of the brain derives from data showing neurologic and psychologic dysfunction in vitamin deficiency states, and in inherited defects of vitamin metabolism. Vitamin deficiencies (particularly of B vitamins) are frequent in the elderly and may contribute to loss of cognitive function. Vitamin deficiencies have effects on the functional and structural integrity of the nervous system that are diverse and highly dependent on the degree of maturity of the system. For the pathologist there are significant difficulties in differentiating between changes that are specific and those that are secondary or non-specific. It is generally acknowledged that maternal nutritional status can affect the development of a number of organ systems in the infant including the brain.

Dietary deficiency of folate, vitamin B6 and B12 results in a significant increase of homocysteine levels, which has been shown to be a risk factor for developing Alzheimer’s disease (AD). Vitamin deficiencies can also affect the early development of the brain.

THIAMINE DEFICIENCY AND WERNICKE’S ENCEPHALOPATHY

MACROSCOPIC APPEARANCES

Lesions are usually discernible in the mamillary bodies (Fig. 21.1), but may also involve other parts of the hypothalamus, the medial thalamic nuclei, the floor of the third ventricle, the periaqueductal region (Fig. 21.1), the colliculi (Fig. 21.1), the nuclei in the pontomedullary tegmentum (Fig. 21.1) (particularly the dorsal motor nuclei of the vagus), the inferior olives, and the cerebral cortex. Typically, the involved regions are slightly shrunken and show brown discoloration due to hemosiderin deposition, and there may be petechial hemorrhages. The periventricular and periaqueductal lesions often spare a slender strip of subependymal tissue. In some patients, particularly those with previously treated disease, the mamillary bodies may be only mildly discolored and the brain may appear macroscopically normal.

image WERNICKE’S ENCEPHALOPATHY

MICROSCOPIC APPEARANCES

Acute lesions are edematous with relative preservation of neurons, variable necrosis of intervening tissue (Fig. 21.2), and loss of myelinated fibers. Capillaries may appear strikingly prominent due to endothelial hyperplasia and cuffing by macrophages (Fig. 21.2), but this is not a constant feature. There may be petechial hemorrhages and hemosiderin-laden macrophages (Fig. 21.3). Astrocytes show reactive changes.

Chronic lesions usually appear gliotic and slightly spongiotic, with mild loss of neurons, depletion of myelinated fibers, and scattered hemosiderin-laden macrophages and astrocytes (Figs 21.4, 21.5).

The histologic changes in Wernicke’s encephalopathy and Wernicke–Korsakoff syndrome are essentially identical. Studies suggest that Korsakoff’s psychosis occurs in those patients who have lesions involving the medial dorsal (or possibly other medial thalamic) nuclei (Fig. 21.6).

image WERNICKE’S ENCEPHALOPATHY

image This usually manifests acutely with gaze palsies and ataxia, which rapidly respond to thiamine administration.

image Apathy and clouding of consciousness (acute confusion/delirium) may form part of the initial presentation, though these symptoms often develop later if the encephalopathy is left untreated for more than a few days.

image Wernicke’s encephalopathy is sometimes associated with Korsakoff’s psychosis, which is characterized by retrograde and anterograde amnesia (i.e. impaired recall of events before the onset of illness and of new information), and confabulation. This does not respond to thiamine and is usually irreversible. The combination of Korsakoff’s psychosis with Wernicke’s encephalopathy is known as Wernicke–Korsakoff syndrome.

image Post-translationally modified variants of transketolase with a reduced affinity for thiamine pyrophosphate have been described in some chronic alcoholics with Wernicke–Korsakoff syndrome.

NICOTINIC ACID DEFICIENCY AND PELLAGRA

MACROSCOPIC AND MICROSCOPIC APPEARANCES

The brain and spinal cord appear macroscopically normal. Histologic changes in the CNS occur predominantly in the later stages of pellagra. Betz cells and neurons in the pontine and cerebellar dentate nuclei show striking chromatolysis without associated microglial or astrocytic changes (Fig. 21.7). Other neurons in the brain stem and the anterior horn cells of the spinal cord (Fig. 21.7) may also be affected. Symmetric degeneration of the dorsal columns, especially the gracile funiculi, and, to a lesser extent, of the corticospinal tracts, has been observed.

image NICOTINIC ACID DEFICIENCY AND PELLAGRA

Pellagra is caused by a deficiency of nicotinic acid or its amino acid precursor (i.e. tryptophan). Although fortification of bread and cereals with niacin has greatly reduced its prevalence, pellagra still occurs in developing countries where the primary source of calories is unfortified maize. Other causes include:

image PELLAGRA

The classic clinical triad of dermatitis, diarrhea, and dementia is often present only in part. The range of manifestations includes the following:

PYRIDOXINE (VITAMIN B6)

Pyridoxine is present in most foods, and nutritional deficiency is rare. A functional deficiency can occur in patients receiving isoniazid or other pyridoxine antagonists (see Chapter 25).

image PYRIDOXINE DEFICIENCY

VITAMIN B12 (COBALAMIN) DEFICIENCY AND SUBACUTE COMBINED DEGENERATION (SACD)

MICROSCOPIC APPEARANCES

Early lesions consist of spongy vacuolation and degeneration of myelin sheaths in the thoracic region, initially in the posterior columns and later in the corticospinal and spinocerebellar tracts in the lateral columns (Figs 21.8, 21.9). The lesions are approximately symmetric. The disease is not a system degeneration in the sense of involving specific nuclei and their related pathways, and the extent of individual lesions in cross-sections through the cord does not necessarily correspond to that of specific fiber tracts. As the disease progresses myelin breakdown is followed by axonal degeneration, macrophage infiltration, and astrocytic gliosis (Figs 21.8, 21.9). The severity of the lesions usually diminishes towards the cervical and lumbar regions, but these show changes of secondary ascending and descending tract degeneration. In severe cases the anterior columns are also involved (Fig. 21.9). Rarely, the lesions extend rostrally into the medulla.

The cerebral white matter and optic nerves may contain small, often perivascular, foci of demyelination or fiber degeneration with an accumulation of lipid-laden macrophages (Fig. 21.9). Rarely, the cerebral lesions are extensive.

image VITAMIN B12 DEFICIENCY

image VITAMIN B12 DEFICIENCY

Vitamin B12 deficiency can cause SACD of the spinal cord, and peripheral neuropathy, as well as megaloblastic anemia, glossitis, and gastrointestinal disturbances. Vitamin B12 is present only in animal foods such as meat, dairy products, and yeasts, is released during gastric digestion, and must bind to intrinsic factor (a glycoprotein produced by gastric parietal cells) before it can be absorbed in the distal ileum.

SACD is believed to result from defective methylation of myelin basic protein and other CNS proteins. The synthesis of the methyl donor (i.e. S-adenosylmethionine) is wholly dependent on methionine synthase (at least in the CNS), which is itself dependent on vitamin B12.

Vitamin B12 deficiency is usually due to autoimmune atrophic gastritis resulting in inadequate production of intrinsic factor by the gastric parietal cells in patients with pernicious anemia.

VITAMIN A DEFICIENCY AND INTOXICATION

Vitamin A is the precursor of the light-sensitive retinal pigment rhodopsin. It is ingested in animal tissues or synthesized from carotenoids in fruits and vegetables.

image FOLIC ACID DEFICIENCY

image Folic acid is present in many foods, but particularly leafy vegetables, legumes, yeasts, and liver. It is a cofactor of enzymes involved in nucleotide synthesis and methylation. N5-methyltetrahydrofolate donates a methyl group to the vitamin B12-dependent enzyme, methionine synthase, for the conversion of homocysteine to methionine.

image Folic acid deficiency is usually due to malnutrition or malabsorption.

image Several drugs, including phenytoin, primidone, phenobarbitone, estrogens, alcohol, methotrexate, trimethoprim, and triamterene, are folate antagonists and can produce signs of deficiency, particularly when associated with other predisposing factors.

image Rare inborn errors of folate metabolism (e.g. an inherited defect of folate transport across the intestine and the blood–brain barrier, methylenetetrahydrofolate reductase deficiency, methionine synthase deficiency, and glutamate formiminotransferase-cyclodeaminase deficiency) cause severe disease of the CNS from an early age.

Vitamin A deficiency usually results from intestinal malabsorption with steatorrhea, though inadequate dietary intake is another cause, particularly in developing countries. It causes dryness and hyperkeratosis of the skin, night blindness, and corneal keratinization. Increased intracranial pressure has been reported as a rare manifestation of deficiency in infancy.

Vitamin A toxicity usually results from taking excessive vitamin supplements. It causes liver disease and brain swelling, leading to the symptoms and signs of raised intracranial pressure.

image FOLIC ACID DEFICIENCY

image Although most of the clinical effects of folic acid deficiency are related to the development of megaloblastic anemia, patients occasionally also develop neurologic disease.

image Peripheral nerve and myelopathic disturbances can occur that are similar to those associated with vitamin B12 deficiency (i.e. paresthesiae, sensory impairment, and weakness predominantly involving the lower limbs), but unresponsive to vitamin B12 administration.

image Confusion and cognitive impairment have been reported.

image The rare inborn errors of folate metabolism (see previous box) result in varying degrees of megaloblastic anemia, mental and physical retardation, extrapyramidal disorders, and seizures.

image Folate deficiency has been associated with abnormal fetal development, particularly neural tube defects. Administration of supplementary folate to pregnant women (even those with normal serum folate levels) who have already had a child with a neural tube defect probably reduces the risk that a similar defect will affect the fetus in the uterus.

VITAMIN D

Most vitamin D is synthesized in the skin, through the action of ultraviolet light on 7-dehydrocholesterol, but it is also obtained through dietary ingestion of food such as oily fish, eggs, liver or foods fortified by the addition of vitamin D (e.g. margarine and breakfast cereals). The inactive vitamin is hydroxylated in the liver and then activated by conversion to calcitriol in the proximal renal tubules.

Vitamin D is necessary for normal brain development and also has immunomodulatory activity. Deficiency usually results primarily from low exposure to sunlight although dietary deficiency is often a contributory factor. Gestational deficiency or excessive ingestion of vitamin D during pregnancy can both affect brain development, although there are no neuropathological data from human studies. In later life, vitamin D deficiency can cause myopathy and has been associated with an increased risk of neuropsychiatric disorders, Parkinson’s disease, Alzheimer’s disease and multiple sclerosis. Manifestations of vitamin D toxicity include hypercalcemia, muscle weakness, headache and irritability.

VITAMIN E (α-TOCOPHEROL)

MACROSCOPIC AND MICROSCOPIC APPEARANCES

The brain and spinal cord appear macroscopically normal. Histology reveals swelling and degeneration of the distal part of longer axons in peripheral nerves and the posterior spinal, spinocerebellar, and corticospinal tracts (see Chapter 25). Axonal swellings are particularly prominent in the gracile and, to a lesser extent, cuneate funiculi and nuclei (Fig. 21.10), but may also be seen in other brain stem nuclei and in the basal ganglia. The axons show dystrophic ultrastructural changes, with accumulation of filaments, membranes, tubules, degenerate mitochondria, and osmiophilic debris.

Neuronal loss may be evident in the dorsal root ganglia and occasionally in the brain stem sensory and oculomotor nuclei, the anterior spinal horn, and Clarke’s column. There may be prominent neuronal lipofuscinosis.

image VITAMIN E (α-TOCOPHEROL)

image Vitamin E is present in vegetable oils and leafy vegetables, and its absorption depends on normal biliary, pancreatic, and small intestinal function.

image Vitamin E is transported to the liver in chylomicrons, and in the systemic circulation in very-low-density and low-density lipoproteins. Its incorporation into lipoproteins in the liver depends on the presence of functional α-tocopherol transfer protein, which is a 278-amino acid protein encoded on chromosome 8.

image Vitamin E is an important biologic antioxidant and as such prevents phospholipid peroxidation in biologic membranes. Deficiency causes neurologic disease and acanthocytosis (i.e. spiny deformity of red blood cells, resulting in their having a diminished lifespan, Fig. 21.10) and is most commonly due to malabsorption associated with liver or pancreatic disease.

image Cystic fibrosis is an important cause of vitamin E deficiency in children.

image Two inherited metabolic disorders that are due to lack of circulating α-tocopherol, leading to inadequate protection against oxidative damage are:

image INTESTINAL ABSORPTION OF FAT-SOLUBLE VITAMINS, INCLUDING VITAMINS A, D, AND E

image VITAMIN E DEFICIENCY

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