By: Dr. Wael Thanoon C.A.B.M. College of medicine ,Mosul University. Fat-soluble vitamins By: Dr. Wael Thanoon C.A.B.M. College of medicine ,Mosul University.

Vitamin A Deficiency: Globally, the most important consequence of vitamin A deficiency is blindness. Each year, approximately 500 000 new cases of blindness occur in young children, mostly in Asia. Adults are not usually at risk because liver stores can supply vitamin A when foods containing vitamin A are unavailable.

Xerophthalmia with Bitot’s spots keratomalacia

Early deficiency causes impaired adaptation to the dark (night blindness). Keratinisation of the cornea (xerophthalmia) causes characteristic Bitot's spots, which progresses to keratomalacia, with corneal ulceration, scarring and irreversible blindness. In countries where vitamin A deficiency is endemic, pregnant women should be advised to eat dark green leafy vegetables and yellow fruits (to build up stores of retinol in the fetal liver), and infants should be fed the same.

WHO is giving high priority to prevention in communities where xerophthalmia occurs, with single prophylactic oral doses of 60 mg retinyl palmitate (providing 200 000 U retinol) given to pre-school children. This also reduces mortality from gastroenteritis and respiratory infections.

Toxicity Repeated moderate or high doses of retinol can cause liver damage, hyperostosis and teratogenicity. Women in countries where deficiency is not endemic are therefore advised not to take vitamin A supplements in pregnancy. Retinol intake may also be restricted in those at risk of osteoporosis. Acute overdose leads to nausea and headache, increased intracranial pressure and skin desquamation. Excessive intake of carotene can cause pigmentation of the skin (hypercarotenosis); this gradually fades when intake is reduced.

Vitamin D: The most common cause is lack of sunlight exposure since maintenance of normal levels of vitamin D depends on UV sunlight exposure to catalyse synthesis of cholecalciferol from 7- dehydrocholesterol in the skin . Dietary deficiency can also play a role, but vitamin D occurs in only small quantities in most foods, except oily fish, so the amount present in average diets is insufficient to meet requirements. Lack of cholecalciferol results in reduced hepatic production of 25(OH)D3 and thus reduced renal production of the biologically active metabolite 1,25(OH)2 D3. The lack of 1,25(OH)2 D3 impairs intestinal calcium absorption and lowers serum calcium, which stimulates PTH secretion. This causes phosphate wasting and increased bone resorption in an attempt to maintain serum calcium levels within the normal range, causing progressive demineralisation of bone.

Clinical features of deficiency: Vitamin D deficiency in children causes delayed development, muscle hypotonia, craniotabes (small unossified areas in membranous bones of the skull that yield to finger pressure with a cracking feeling), bossing of the frontal and parietal bones and delayed anterior fontanelle closure, enlargement of epiphyses at the lower end of the radius, and swelling of the rib costochondral junctions ('rickety rosary').

Osteomalacia in adults presents insidiously Osteomalacia in adults presents insidiously. Mild osteomalacia can be asymptomatic or present with fractures and mimic osteoporosis. More severe osteomalacia presents with muscle and bone pain, general malaise and fragility fractures. Proximal muscle weakness is prominent and the patient may walk with a waddling gait and struggle to climb stairs or get out of a chair. There may be bone and muscle tenderness on pressure and focal bone pain can occur due to fissure fractures of the ribs and pelvis.

Investigations The diagnosis can usually be made on a routine biochemical screen with measurement of serum 25(OH)D and PTH. Typically, serum alkaline phosphatase levels are raised, 25(OH)D levels are low or undetectable, and PTH is elevated. Serum calcium and phosphate levels may also be low but normal values do not exclude the diagnosis.

X-rays are normal until advanced disease, when focal radiolucent areas (pseudofracture s or Looser's zones) may be seen in ribs, pelvis and long bones.

Radiographic osteopenia is common and the presence of vertebral crush fractures may cause confusion with osteoporosis. In children, there is thickening and widening of the epiphyseal plate. Radionuclide bone scan can show multiple hot spots in the ribs and pelvis at the site of fractures and the appearance may be mistaken for metastases. Where there is doubt, the diagnosis can be confirmed by bone biopsy, which shows the pathognomonic features of increased thickness and extent of osteoid seams.

Osteomalacia and rickets respond promptly to treatment with ergocalciferol (250-1000 μg daily), showing rapid clinical improvement, an elevation in 25(OH)D and a reduction in PTH. Serum alkaline phosphatase levels sometimes rise initially as mineralisation of bone increases, but eventually fall to within the normal range as the bone disease heals. After 3-4 months, treatment can generally be stopped or the dose of vitamin D reduced to a maintenance level of 10-20 μg cholecalciferol daily, except in patients with underlying disease such as malabsorption, in whom higher doses may be required.

Vitamin D-resistant rickets (VDRR) This term describes osteomalacia and rickets caused by: 1-Inactivating mutations in the 25- hydroxyvitamin D-1-alpha-hydroxylase (CYP27B1) enzyme which converts 25(OH)D to the active metabolite 1,25(OH)2 D3 (type I VDRR) 2-Inactivating mutations in the vitamin D receptor which impair its ability to activate transcription (type II VDRR).

Clinical features are similar to those of infantile rickets and the diagnosis is usually first suspected when the patient fails to respond to vitamin D supplementation. Since both are recessive disorders, consanguinity is common but there may or may not be a positive family history. Biochemical features of type I disease are similar to vitamin D deficiency, except that levels of 25(OH)D are normal. In type II disease, 25(OH)D is normal but PTH and 1,25(OH)2D3 values are raised. Type I can be treated with the active vitamin D metabolites, 1-alpha hydroxyvitamin D (1-2 μg daily orally) or 1,25 dihydroxyvitamin D (0.25-1.5 μg daily orally), with or without calcium supplements, depending upon the patient's diet. Type II VDRR is extremely difficult to treat but sometimes responds partially to very high doses of active vitamin D metabolites and calcium and phosphate supplements

Renal rickets and osteomalacia Osteomalacia and rickets occur in patients with chronic renal failure due to defects in synthesis of renal 1,25(OH)2D3 or due to over- aggressive treatment with oral phosphate binders.

Hypophosphataemic rickets and osteomalacia Rickets and osteomalacia can occur as the result of inherited or acquired defects in renal tubular phosphate reabsorption, and rarely in patients with tumours that secrete phosphaturic substances .

Clinical features and diagnosis The hereditary disorders usually present in childhood with rickets. The diagnosis is made on the basis of the early age at onset and presence of hypophosphataemia with renal phosphate wasting in the absence of vitamin D deficiency. Molecular diagnosis can define the causal mutation. Tumour-induced hypophosphataemic osteomalacia presents with severe, rapidly progessive symptoms in patients with no obvious predisposing factor for osteomalacia. Strenuous efforts should be made to identify the underlying, usually occult tumour. This often requires whole- body MRI or CT.

:Management Treatment is with phosphate supplements (1-4 g daily) and active metabolites of vitamin D (1-alpha hydroxyvitamin D 1-2 μg daily or 1,25 dihydroxyvitamin D 0.25-1.5 μg daily) to promote intestinal calcium and phosphate absorption. The aim is to ameliorate symptoms, restore normal growth, maintain serum phosphate levels within the normal range and normalise alkaline phosphatase levels. Levels of calcium, phosphate and alkaline phosphatase, along with renal function, should be monitored. Tumour-induced osteomalacia can be managed in the same way but surgical excision of the tumour is curative.

Vitamin E: Human deficiency is rare and has only been described in premature infants and in malabsorption. It can cause a mild haemolytic anaemia, ataxia and visual scotomas. Vitamin E intakes are considered safe up to 3200 mg/day (1000-fold greater than recommended intakes). Diets rich in vitamin E are consumed in countries with lower rates of coronary heart disease. However, randomised controlled trials have not demonstrated cardioprotective effects of vitamin E or other antioxidants.

Vitamin K Vitamin K deficiency leads to delayed coagulation and bleeding. In obstructive jaundice, dietary vitamin K is not absorbed and it is essential to administer the vitamin in parenteral form before surgery. Warfarin and related anticoagulants act by antagonising vitamin K. Vitamin K is given routinely to newborn babies to prevent haemorrhagic disease. Symptoms of excess have been reported only in infants, with synthetic preparations linked to haemolysis and liver damage.