Thyroid surgery. Patients should be rendered euthyroid with antithyroid drugs before operation.

Potassium iodide, 60 mg 3 times daily orally, is often added for 2 weeks before surgery to inhibit thyroid hormone release and reduce the size and vascularity of the gland, making surgery technically easier.

‘subtotal’ thyroidectomy is performed, in which a portionof one lobe of the thyroid is left in situ, with the aim of rendering the patient euthyroid post-operatively. While complications of surgery are rare and 80% of patients are euthyroid, 15% are permanently hypothyroid and 5% remain thyrotoxic.,

many endocrine surgeons now opt to perform a ‘near total’ thyroidectomy, leaving behind only a small portionof gland adjacent to the recurrent laryngeal nerves. This strategy invariably results in permanent hypothyroidismand is probably associated with a higher risk

Radioactive iodine. 131I 131I is administered orally as a single dose400 MBq (10 mCi) is given orally.

, and is trapped and organified in the thyroid Although 131I decays within a few weeks, it has long-lasting inhibitory effects on survival and replication of follicular cells. This regimen is effective in

75% of patients within 4–12 weeks.

During the lag period, symptoms can be controlled by a β-blocker or, in more severe cases, by carbimazole. However, reduces the efficacy of 131I therapy because it prevents organification of 131I in the gland, and so should be carbimazole avoided until 48 hours after radio-iodine administration.

If thyrotoxicosis persists after 6 months, a further dose of 131I can be given.

The disadvantage of 131I treatment 1 hypothyroidism. 2 131I isusually avoided in patients with Graves’ ophthalmopathy It can be administered with caution in those with mild or ‘burnt-out’ eye disease, when it is customary to cover the treatment with a 6-week tapering course of oral prednisolone. 3 In women of reproductive age, pregnancy must be excluded before administration of 131I and avoided for 6 months there after; men are also advised against fathering children for 6 months after receiving 131I

.

The majority of patients require no treatment other than reassurance. Smoking cessation should be activelyMethylcellulose eye drops and gel counter

the gritty discomfort of dry eyes, and tinted glasses orside shields attached to spectacle frames reduce theexcessive lacrimation triggered by sun or wind. Inpatients with mild Graves’ ophthalmopathy,

oral selenium(100 μg twice daily for 6 months) improvesquality of life, reduces ocular involvement and slowsprogression of disease; the mechanism of action is notknown but may relate to an antioxidant effect More severe inflammatory episodes are treated

with glucocorticoids (e.g. daily oral prednisolone orpulsed IV methylprednisolone) and sometimes

orbitalradiotherapy. There is also an increasing trend to useimmunosuppressant therapies, such as ciclosporin, incombination with glucocorticoids.

Pretibial myxoedemaThis infiltrative dermopathy occurs in fewer than 10% of patients with Graves’ disease and has similar pathologicalfeatures as occur in the orbit. It takes the form of raised pink-coloured or purplish plaques on the anterioraspect of the leg, extending on to the dorsum of the foot The lesions may be itchy and the skin may havea ‘peau d’orange’ appearance with growth of coarse hair; less commonly, the face and arms are affected.Treatment is rarely required, but in severe cases topical glucocorticoids may be helpful.

Thyrotoxicosis in pregnancyThe coexistence of pregnancy and thyrotoxicosis is unusual, as anovulatory cycles are common in thyrotoxicpatients and autoimmune disease tends to remitduring pregnancy, when the maternal immune responseis suppressed. Thyroid function tests must be interpretedin the knowledge that thyroid-binding globulin, and hence total T4 and T3 levels, are increased in pregnancyand that TSH reference ranges may be lower (seea fully suppressed TSH with elevatedfree thyroid hormone levels indicates thyrotoxicosis.The thyrotoxicosis is almost always caused by Graves’ disease. Both mother and fetus must be considered,since maternal thyroid hormones, TRAb and antithyroiddrugs can all cross the placenta to some degree, exposingthe fetus to the risks of thyrotoxicosis, iatrogenic hypothyroidism and goitre. Poorly controlled maternalthyrotoxicosis can result in fetal tachycardia, retardation, prematurity, stillbirth and possibly even congenital malformations. Antithyroid drugs are the treatment of choice for thyrotoxicosis in pregnancy. Carbimazole has beenassociated with rare cases of embryopathy, particularly skin defect known as aplasia cutis, and should be

a

HypothyroidismHypothyroidism is a common condition with variouscauses (but autoimmune disease(Hashimoto’s thyroiditis) and thyroid failure following131I or surgical treatment of thyrotoxicosis account for over 90% of cases, except in areas where iodine deficiency is endemic. Women are affected approximately six times more frequently than men

Features of hypothyroidism

consequence of prolonged hypothyroidism is the infiltration of many body tissuesby the mucopolysaccharides, hyaluronic acid and chondroitin sulphate, resulting in a low-pitched voice, poorhearing, slurred speech due to a large tongue, and compressionof the median nerve at the wrist (carpal tunnel syndrome).

Infiltration of the dermis gives rise to nonpitting oedema (myxoedema), which is most marked inthe skin of the hands, feet and eyelidsThe resultantperiorbital puffiness is often striking and may be combined with facial pallor due to vasoconstriction andanaemia, or a lemon-yellow tint to the skin caused bycarotenaemia, along with purplish lips and malar flush. Most cases of hypothyroidism are not clinically obvious,. maintained so that the diagnosis is not overlooked inindividuals complaining of non-specific symptoms suchas tiredness, weight gain, depression or carpal tunnel

Hashimoto’s thyroiditisHashimoto’s thyroiditis is characterised by destructive lymphoid infiltration of the thyroid, leading to a varying degree of fibrosis and thyroid enlargement.

There is an increased risk of thyroid lymphoma although this is exceedingly rare.

The autoimmune hypothyroidism is confusing. Some authorities reserve the term ‘Hashimoto’s thyroiditis’ for patients with positive antithyroid peroxidase autoantibodies and a firm goitre who may or may notbe hypothyroid, and use the term ‘spontaneous atrophic hypothyroidism’ for hypothyroid patients without agoitre in whom TSH receptor-blocking antibodies may be more important than antiperoxidase antibodies.However, these syndromes can both be considered asvariants of the same underlying disease process.

Hashimoto’s thyroiditis increases in incidence with age and affects approximately 3.5 per 1000 women and 0.8 per 1000 men each year. Many present with a small or moderately sized diffuse goitre, firm or rubbery in consistency. The goitre may be soft, however, and impossible to differentiate from. Around 25%of patients are hypothyroid at presentation. In the

Antithyroid peroxidase antibodies are present in the serum in more than 90% ofpatients with Hashimoto’s thyroiditis. In those under

Sub acute(de Quervain’s)thyroiditis

In its classical painful form, sub acute thyroiditis is a transient inflammation of the thyroid gland occurring There is pain in the region of the thyroid that may radiate to the angle of the jaw and the ears, and is made worse by swallowing, coughing and movement of the neck. The thyroid is usually palpably enlarged and tender. Systemic upset is common. Affected patients are usually females aged 20–40 years.. The condition can also be precipitated by drugs, including interferon-α and lithium.also after infection with. with damage to follicular cells and impaired

synthesisCoxsackie, mumps or adenovirusesof new thyroid hormones. As a result, T4 and T3 levels are raised for 4–6 weeks until the pre-formed colloid is depleted. Thereafter, there is usually a period of hypothyroidism of variable severity before the follicular cells recover and normal thyroid function is restored within 4–6 is suppressed. Low-titre thyroid autoantibodies appear transiently in the serum, and the erythrocyte sedimentationrate (ESR) is usually raised.

High-titre autoantibodie ssuggest an underlying autoimmune pathology and greater risk of recurrence and ultimate progression to hypothyroidism.

The pain and systemic upset usually respond tosimple measures such as non-steroidal anti-inflammatorydrugs (NSAIDs). Occasionally, however, it may benecessary to prescribe prednisolone 40 mg daily for3–4 weeks. The thyrotoxicosis is mild and treatmentwith a β-blocker is usually adequate. Antithyroid drugsare of no benefit because thyroid hormone synthesisis impaired rather than enhanced. Careful monitoringof thyroid function and symptoms is required so that

Management

Treatment is with levothyroxine replacement. It is customaryto start with a low dose of 50 μg per day for3 weeks, increasing thereafter to 100 μg per day for afurther 3 weeks and finally to a maintenance dose of100–150 μg per day.

In younger patients, it is safe toinitiate levothyroxine at a higher dose to allow a more rapid normalisation of thyroid hormone levels. Levothyroxine has a half-life of 7 days so it should always be taken as a single daily dose and at least 6 weeks should pass before repeatingthyroid function tests and adjusting the dose, usually

by 25 μg per day. Patients feel better within 2–3 weeks.Reduction in weight and periorbital puffiness occursquickly, but the restoration of skin and hair texture may take 3–6 months It is important to measure thyroid function every1–2 years

Levothyroxine replacement in ischaemic heart disease

exacerbation of myocardial ischaemia, infarction and sudden death are recognised complications of levothyroxine replacement, even using doses as low as 25 μgper day. In replacement should be introduced at low dose and increased very slowly under specialistsupervision. It has been suggested that T3 has an advantage over T4, since T3 has a shorter half-life and anyadverse effect will reverse more quickly, but the moredistinct peak in hormone levels after each dose of T3 isa disadvantage. Coronary angioplasty or bypass surgerymay be required if angina is exacerbated by levothyroxine

.

Myxoedema comadepressed level of consciousness,usually in an elderly patient who appears myxoedematous. Body temperature may be as low as 25°C, convulsionsare not uncommon and cerebrospinal fluid (CSF) pressure and protein content are raised. The mortalityrate is 50% and survival depends on early recognitionand treatment of hypothyroidism and other factorscontributing to the altered consciousness level, as medication, cardiac failure, pneumonia, dilutionalhyponatraemia and respiratory failure.

Myxoedema coma is a medical emergency and treatmentmust begin before biochemical confirmation of thediagnosis. Suspected cases should be treated with anintravenous injection of 20 μg triiodothyronine, followedby further injections of 20 μg 3 times daily unti lthere is sustained clinical improvement. In survivors,there is a rise in body temperature within 24 hours

after 48–72 hours, it is usually possible to switch patientsto oral levothyroxine in a dose of 50 μg daily. Unlessit is apparent that the patient has primary hypothyroidism, the thyroid failure should also be assumed to be secondary to hypothalamic or pituitary diseaseand treatment given with hydrocortisone 100 mg IM3 times daily, pending the results of T4, TSH and cortisolmeasurement (p. 787). Other measures include slowrewarming (p. 105), cautious use of intravenous fluids,broad-spectrum antibiotics and high-flow oxygen. Occasionally,assisted ventilation may be necessary

Hypothyroidism in pregnancyMost pregnant women with primary hypothyroidismrequire an increase in the dose of levothyroxine ofapproximately 25–50 μg daily to maintain normal TSH levels. This may reflect increased metabolism of thyroxineby the placenta and increased serum thyroxinebindingglobulin during pregnancy, resulting in an increase in the total thyroid hormone pool to maintain the same free T4 and T3 concentrations. Inadequate maternal T4 therapy may be associated with impaired cognitive development in an unborn child and so women are usually advised to increase their daily levothyroxine dose by 25 μg when pregnancy is confirmed. Serum TSHand free T4 should be measured during each trimester and the dose of levothyroxine adjusted to maintain a normal TSH

Subclinical hypothyroidismSerum TSH is raised, and serum T3 and T4 lower end of the reference range. This may persist for many years, although there is a risk ofprogression to overt thyroid failure, particularly ifantibodies to thyroid peroxidase are present or if theTSH rises above 10 mU/L. Levothyroxine should be given in a dose sufficient to restore the serum TSH concentration

Subclinical thyrotoxicosisSerum TSH is decrease , and serum T3 and T4 are at the upper end of the reference range. This combinationin older patients with multinodular goitre. increased risk atrial fibrillation and osteoporosis, mild thyrotoxicosis and require therapy, usually with 131I. Otherwise, annual review is essential, as the conversion rate to overt thyrotoxicosis5% each year.

Non-thyroidal illness (‘sick euthyroidism’)

This typically presents with a low serum TSH, raised T4and normal or low T3

,.These abnormalities are caused by1 decreased peripheral conversion of T4 to T3, 2 altered levels of binding proteins and their affinity for thyroid hormones, 3 reduced secretion of TSH. During convalescence, serum

Symptoms of hypothyroidism with normal thyroid function tests

The classic symptoms of hypothyroidism are, by theirvery nature, non-specific There is a widedifferential diagnosis for symptoms such as ‘fatigue’, weight gain’ and ‘low mood’. As has been noted,outside the context of pituitary and hypothalamicdisease, serum TSH is an excellent measure of an individual’sthyroid hormone status. However, some individualsbelieve that they have hypothyroidism despitenormal serum TSH concentrations. There are a large number of websites which claim that serum TSH is nota good measure of thyroid hormone status and suggestthat other factors, such as abnormalities of T4 to T3 conversion,may lead to low tissue levels of active thyroidhormones. Such websites often advocate a variety oftests of thyroid function of dubious scientific validity, including measurement of serum reverse T3, 24-hoururine T3, basal body temperature, skin iodine absorption, and levels of selenium in blood and urine. Individualswho believe they have hypothyroidism, despitenormal conventional tests of thyroid function, can bedifficult to manage. They require reassurance that theirsymptoms are being taken seriously and that organicdisease has been carefully considered; if their symptomspersist, then referral to a team specialising in medicallyunexplained symptoms should be considered.

‘

Iodine-induced thyroid dysfunctionIodine has complex effects on thyroid function. Ver yhigh concentrations of iodine inhibit thyroid hormone release and this forms the rationale for iodine treatmen tof thyroid storm and prior to thyroid surgery for thyrotoxicosis . Iodine administration initially enhances, but then inhibits, iodination of tyrosine and thyroid hormone synthesis

The resulting effect of iodine on thyroid function varies according to whether the patient has an

iodine-deficient diet or underlying thyroid disease. In iodine-deficient parts of the world, transient thyrotoxicosis may be precipitated by prophylactic iodinisation programmes.

In iodine-sufficient areas, thyrotoxicosis can be precipitated by radiographic contrast medium or expectorants in individuals who have underlying thyroid disease predisposing to thyrotoxicosis, such as multinodular goiter or Graves’ disease in remission.

Induction of thyrotoxicosis by iodine is called the Jod–Basedow effect. Chronic excess iodine administration can, however, result in hypothyroidism. Increased iodine within the thyroid gland down-regulates iodine trapping,

AmiodaroneThe anti-arrhythmic agent amiodarone has a structurethat is analogous to that of T4 and contains

huge amounts of iodine; a 200 mg dose contains 75 mg iodine, compared with a daily dietary requirement of

just 125 μg. Amiodarone also has a cytotoxic effect on thyroid follicular cells and inhibits conversion of T4 toT3. Most patients receiving amiodarone have normal thyroid function, but up to 20% develop hypothyroidism

or thyrotoxicosis and so thyroid function should be monitored regularly. The ratio of T4:T3 is elevated andTSH provides the best indicator of thyroid function. The thyrotoxicosis can be classified as either:• type I: iodine-induced excess thyroid hormone synthesis in patients with an underlying thyroid

disorder, such as nodular goitre or latent Graves’ disease treatment Antithyroid drugs may be effective inpatients with the type I form, but are ineffective in typeII thyrotoxicosis.

• type II: thyroiditis due to a direct cytotoxic effect if amiodarone administration results in a transientThyrotoxicosis treatment

Prednisolone is beneficial in the type II

THE PARATHYROID GLANDSTHE PARATHYROID GLANDSTHE PARATHYROID GLANDS

Parathyroid hormone (PTH)

More than 99% of total body calcium is in bone. Prolonged exposure of bone to high levels of PTH is associated with increased osteoclastic activity and new bone formation, but the net effect is to cause bone loss with mobilisation of calcium into the extracellular

50% of total calcium is bound to organic ions, such as citrate or phosphate, and to proteins, especially albumin. 50% of total calcium is freeAccordingly, if the serum albumin level is reduced, total calcium concentrations should be ‘corrected’ by adjustingthe value for calcium upwards by 0.02 mmol/L(0.4 mg/dL) for each 1 g/L reduction in albumin below40 g/L. If albumin concentrations are significantly low, as in severe acute illness and other chronic illness suchas liver cirrhosis, this correction is less accurate and measurement of ionised calcium is needed.

Calcitonin is secreted from the parafollicular C cells of the thyroid gland. Although it is a useful tumour marker in medullary carcinoma of thyroid andcan be given therapeutically in Paget’s disease of bone

HypercalcaemiaHypercalcaemia is one of the most common biochemical abnormalities and is often detected during

routine biochemical analysis in asymptomatic patients. However, it can present with chronic symptoms, as described below,

and occasionally as an acute emergency with severe hypercalcaemia and dehydration.

Causes of hypercalcaemia are listed in Of these, primary hyperparathyroidism and malignant

hypercalcaemia are by far the most common. Familial hypocalciuric hypercalcaemia (FHH) is a rare but important

cause that needs differentiation from primary hyperparathyroidism (HPT). Lithium may cause hyperparathyroidismby reducing the sensitivity of the calcium-sensing receptor.

Clinical assessment 50% of patients with primary hyperparathyroidismare asymptomatic while others have nonspecificsymptoms such as fatigue, depression and generalised aches and pains. Some present with renal calculi 5% of first stone formers, 15% of recurrent stone formershaveHypertension is a common feature of hyperparathyroidism. Parathyroidtumours are almost never palpable.

1 High plasmaphosphate and alkaline phosphatase accompanied by renal impairment suggest tertiary hyperparathyroidism.

2 nephrocalcinosis and renaltubular impairment

3 Patients with FHH can present with a similar biochemical picture to primary hyperparathyroidism but typically have low urinary calcium excretion (a ratio of urinary calcium clearance to creatinine clearance of < 0.01). The diagnosis of FHH can be confirmed by screening family members for hypercalcaemia and/or a mutation in the gene encoding the calcium-sensing receptor.

4 If PTH is low and no other cause is apparent, then malignancy with or without bony metastases is likely PTH-related peptide

management1 Patients should initially be treated with intravenous 0.9% saline to improve renal function and increaseurinary calcium excretion. This alone often results in clinical improvement

2 Intravenous bisphosphonates should be given to inhibit bone resorption. serum calcium levels to normal within 5 days The duration of action is up to 4 weeks and repeated therapy can be given at 3–4-weekly intervals

3Calcitonin acts rapidly to increase calcium excretion and to reduce bone resorption and can be combined

with fluid and bisphosphonate therapy for the first 24–48 hours in patients with life-threatening hypercalcaemia.

The prevalence of primary hyperparathyroidism is about 1 in 800 and it is 2–3 times more common inwomen than men; 90% of patients are over 50 years of age. It also occurs in the familial MEN syndromes

Clinical and radiological featuresThe clinical presentation of primary hyperparathyroidism is bone disease is now rare due to earlier diagnosis and treatment.

Osteitis fibrosa results from increased bone resorption by osteoclasts with fibrous replacement in thelacunae. This may present as bone pain and tenderness, fracture and deformity.

Chondrocalcinosis can occur due to deposition of calcium pyrophosphate crystals within articular cartilage. It typically affects the menisci at the knees and can result in secondary degenerative arthritis or predispose to attacks of acute pseudogout

Skeletal X-rays are usually normal in mild primary hyperparathyroidism, but in patients with advanced disease characteristic changes are observed. In the early stages there is demineralisation, with subperiostealerosions and terminal resorption in the phalanges.

A ‘pepper-pot’ appearance may be seen on lateral X-rays of the skull.

In nephrocalcinosis, scattered opacities may be visible within the renal outline.

There may be soft tissue calcification in arterial walls and hands and in the cornea.

Investigations

The diagnosis can be confirmed by finding a raised PTH level in the presence of hypercalcaemia, provided thatFHH is excluded .

Parathyroid scanning by 99mTcsestamibi scintigraphy and/or ultrasound, in an attempt to localise an adenoma and allow a targetedresection. However, negative imaging does not excludethe diagnosis.

Surgery is usually indicated for individuals aged less than 50 years, with clear-cut symptoms or documented complications (such as peptic ulceration, renal stones, renal impairment or osteoporosis), and (in asymptomaticpatients) significant hypercalcaemia (corrected serum calcium > 2.85 mmol/L (> 11.4 mg/dL)).

Patients who are treated conservatively without surgery should have calcium biochemistry and renal function checkedannually and bone density monitored periodically. They should be encouraged to maintain a high oral fluidintake to avoid renal stones

.

Familial hypocalciuric hypercalcaemia

This autosomal dominant disorder is caused by an inactivating mutation in one of the alleles of the calcium sensing receptor gene which reduces the ability of the parathyroid gland to ‘sense’ ionised calcium concentrations.As a result, higher than normal calcium levels are required to suppress PTH secretion. The typical presentationis with mild hypercalcaemia with PTH concentrations that are ‘inappropriately’ at the upper end of the reference range or are slightly elevated

. Calcium-sensing receptors in the renal tubules are also affected and thisleads to increased renal tubular reabsorption of calcium and hypocalciuria.

The hypercalcaemia of FHH is always asymptomatic and complications do not occur. The main risk of FHH is of the patient being subjected to an unnecessary(and ineffective) parathyroidectomy if misdiagnosed as having primary hyperparathyroidism.

Testing of family members for hypercalcaemia is helpful in confirming the diagnosis and it is also possible to performgenetic testing. No treatment is necessary.

Hypocalcaemia may also develop as a result of magnesium depletion and should be considered in patientswith malabsorption, on diuretic or proton pump inhibitor therapy, and/or with a history of alcohol excess.

Magnesium deficiency causes hypocalcaemia by impairing the ability of the parathyroid glands to secrete PTH(resulting in PTH concentrations that are low or inappropriately in the reference range) and may also impairthe actions of PTH on bone and kidney

Clinical assessmentMild hypocalcaemia is often asymptomatic but, with more profound reductions in serum calcium, tetany canoccur. This is characterised by muscle spasms due to increased excitability of peripheral nerves.Children are more liable to develop tetany than adults and present with a characteristic triad of carpopedal spasm {the hands adopt a characteristic position with flexion of the metacarpophalangeal joints}

, stridor caused by spasm of the glottis.and convulsions, although one or more of these may be found independently of the others.frequent. Stridor is Adults can also develop carpopedal spasm in association with tingling of the hands and feet and around the

Trousseau’s sign; inflation of a sphygmomanometer cuff on the upper arm to more than the systolic blood pressurefollowed by carpal spasm within 3 minutes.is Less specificis Chvostek’s sign, tapping over the branches of the facial nerve as they emerge from the parotid gland produces twitching of the facial muscles.

Hypocalcaemia can cause papilloedema and prolongation of the ECG QT interval, which may predisposeto ventricular arrhythmias. Prolonged hypocalcaemia and hyperphosphataemia (as in hypoparathyroidism)may cause calcification of the basal ganglia, grand mal epilepsy, psychosis and cataracts. Hypocalcaemia associatedwith hypophosphataemia, as in vitamin D deficiency, causes rickets in children and osteomalacia inAdults

Pseudohypoparathyroidism

In this disorder, the individual is functionally hypoparathyroid, but instead of PTH deficiency there is tissue resistance to the effects of PTH, such that PTH concentrations are markedly elevated. The PTH receptor itself is normal, but there are defective post-receptor mechanisms due to mutations at the GNAS1 locus. There are several subtypes, but in the most common form (type 1a) features include short stature, short 4th metacarpals and metatarsals, rounded face, obesity and subcutaneous calcification (Albright's hereditary osteodystrophy, AHO).

The term 'pseudo-pseudohypoparathyroidism' is used to describe patients with AHO in whom serum calcium and PTH concentrations are normal. The inheritance of these disorders is an example of genetic imprinting (p. 49); inheritance of the defective allele from a mother with pseudohypoparathyroidism results in pseudohypoparathyroidism in the offspring, but inheritance from the father results in pseudo-pseudohypoparathyroidism.

Some clinical features are more common in ectopic ACTH syndrome. Unlike pituitary tumours secreting ACTH, ectopic tumours have no residual negative feedback sensitivity to cortisol, and both ACTH and cortisol levels are usually higher than with other causes.

Very high ACTH levels are associated with marked pigmentation .

high cortisol levels overcome the barrier of 11β-HSD2 in the kidney and cause hypokalaemic alkalosis. Hypokalaemia aggravates both myopathy

hyperglycaemia (by inhibiting insulin secretion). When the tumour secreting ACTH is malignant, then the onset is usually rapid and may be associated with cachexia. For these reasons, the classical features of Cushing's syndrome are less common in ectopic ACTH syndrome, and if present suggest that a less aggressive tumour (e.g. bronchial carcinoid) is

responsible .

In Cushing's disease, the pituitary tumour is usually a microadenoma (< 10 mm in diameter); hence other features of a pituitary macroadenoma (hypopituitarism, visual failure or disconnection hyperprolactinaemia

Management Untreated Cushing's syndrome has a 50% 5-year mortality. Most patients are treated surgically with medical therapy given for a few weeks prior to operation. A number of drugs are used to inhibit corticosteroid biosynthesis, including metyrapone and ketoconazole. The dose of these agents is best titrated against 24-hour urine free cortisol. Cushing's disease

Trans-sphenoidal surgery with selective removal of the adenoma is the treatment of choice. Experienced

surgeons can identify microadenomas which were not detected by MRI and cure about 80% of patients. If the operation is unsuccessful, then bilateral adrenalectomy is an alternative.

If bilateral adrenalectomy is used in patients with pituitary-dependent Cushing's syndrome, then there is a risk that the pituitary tumour will grow in the absence of the negative feedback suppression previously provided by elevated cortisol

levels. This can result in Nelson's syndrome, with an aggressive pituitary macroadenoma and very high ACTH levels causing pigmentation. Nelson's syndrome can be prevented by pituitary irradiation.

Adrenal tumours Adrenal adenomas are removed by laparoscopy or a loin incision. Surgery offers the only prospect of cure for

adrenocortical carcinomas, but in general prognosis is poor with high rates of recurrence even in patients with localised disease at presentation. Although often used, there is little evidence that radiotherapy, chemotherapy or the adrenolytic drug mitotane improves recurrence rates or survival.

Ectopic ACTH syndrome Localised tumours such as bronchial carcinoid should be removed surgically. In patients with incurable malignancy it is important to reduce the severity of the Cushing's syndrome using medical therapy

Management of glucocorticoid withdrawal All glucocorticoid therapy, even if inhaled or applied topically, can suppress the HPA axis. In practice, this is only likely to result in a crisis due to adrenal insufficiency on withdrawal of

treatment if glucocorticoids have been administered orally or systemically for longer than 3 weeks, if repeated courses have been prescribed within the previous year, or if the dose is

higher than the equivalent of 7.5 mg prednisolone per day.

Once the dose of glucocorticoid is reduced to a minimum (e.g. 4 mg prednisolone or 0.5 mg dexamethasone per day), then measure plasma cortisol at 0900 hrs before the next dose. If this is

detectable, then perform an ACTH stimulation test to confirm that glucocorticoids can be withdrawn completely.

Even once glucocorticoids have been successfully withdrawn, short-term replacement therapy is often advised during significant intercurrent illness occurring in subsequent months, as the HPA axis may not be able to respond fully to severe stress. Adrenal insufficiency

Assessment of glucocorticoids

Random plasma cortisol is usually low in patients with adrenal insufficiency, but it may be within

the normal range, Random measurement of plasma cortisol cannot therefore be used to

confirm or refute the diagnosis, unless the value is high (> 460 nmol/L (> 17 μg/dL)) .

Assessment of mineralocorticoids

Assessment of mineralocorticoidsMineralocorticoid secretion in patients with suspected Addison's disease cannot be adequately assessed by electrolyte measurements since hyponatraemia occurs in both aldosterone and cortisol deficiency (see Box 20.45 and p. 435). Hyperkalaemia is common, but not universal, in aldosterone deficiency. Plasma renin activity and aldosterone should be measured in the supine position. In mineralocorticoid deficiency, plasma renin activity is high, with plasma aldosterone being either low or

in the lower part of the normal range .

Assessment of adrenal androgens

Assessment of adrenal androgens This is not necessary in men because testosterone

from the testes is the principal androgen. In women, dehydroepiandrosterone (DHEA) and androstenedione may be measured in a random specimen of blood,

though levels are highest in the morning .

Hydrocortisone (cortisol) is the drug of choice. In someone who, hydrocortisone should be given by mouth,10- 15 mg on waking and 5 mg at around 1800 hrs.. weight gain usually indicates over-replacement, whilst persistent lethargy or hyperpigmentation may be due to an inadequate dose. Measurement of plasma cortisol levels is unhelpful,

These are physiological replacement doses which should not cause Cushingoid side-effects.

Androgen replacement DHEA (approximately 50 mg/day) is sometimes given to women with primary adrenal insufficiency. Some trials have suggested that DHEA increases libido and sense of well-being, but complications include acne and hirsutism.

I

incidental adrenal mass It is not uncommon for a mass in the adrenal gland to be identified on a CT or MRI scan of the abdomen that has been

performed for another indication. Such lesions are known as adrenal 'incidentalomas'. They are

present in up to 10% of adults and the prevalence increases with age.

Eighty-five per cent of adrenal incidentalomas are non-functioning adrenal adenomas. The remainder includes functional tumours of the adrenal cortex (secreting cortisol, aldosterone or androgens), phaeochromocytomas, primary and secondary carcinomas, hamartomas and other rare disorders including granulomatous infiltrations.

Clinical assessment and investigations There are two key questions to be resolved: is the lesion secreting hormones, and is it benign or malignant? Patients with an adrenal incidentaloma are usually asymptomatic.

Investigations should include a 24-hour urine collection for metanephrines and urine free cortisol and,

in women, measurement of serum testosterone, DHEA and androstenedione

Patients with hypertension should be investigated for mineralocorticoid excess as described below. CT and MRI are equally effective in assessing the malignant potential of an adrenal mass, using the following parameters:

Size. The larger the lesion, the greater the malignant potential. Around 90% of adrenocortical carcinomas are > 4 cm in diameter, but specificity is poor since only approximately 25% of such lesions are malignant.

Configuration. Homogeneous and smooth lesions are more likely to be benign. Adenomas are usually lipid-rich

Management Functional lesions and tumours > 5 cm in diameter should be removed by laparoscopic adrenalectomy. In patients with radiologically benign, non-functioning lesions < 5 cm in diameter, surgery is only required if serial imaging suggests tumour growth.

Primary hyperaldosteronism

as 10% of people with hypertension. Indications to test for mineralocorticoid excess in hypertensive patients include hypokalaemia (including hypokalaemia induced by thiazide diuretics), poor control of blood pressure with conventional therapy, a family history of early-onset hypertension, or presentation at a young age. It is important to differentiate primary hyperaldosteronism, caused by an intrinsic abnormality of the adrenal glands resulting in aldosterone excess, from secondary hyperaldosteronism, which is usually a consequence of enhanced activity of renin in response to inadequate renal perfusion and hypotension. Most individuals with

primary hyperaldosteronism have bilateral adrenal hyperplasia (idiopathic hyperaldosteronism), while only a minority have an aldosterone-producing adenoma (APA; Conn's syndrome).

Clinical features Individuals with primary hyperaldosteronism are usually asymptomatic, but they may have features of sodium retention or potassium loss. Sodium retention may cause oedema, while hypokalaemia may causes muscle weakness (or even paralysis, especially in Chinese), polyuria (secondary to renal tubular damage which produces nephrogenic diabetes insipidus)

tetany (because of associated metabolic alkalosis and low ionised calcium).

Blood pressure is elevated but accelerated phase hypertension is rare.

Management Mineralocorticoid receptor antagonists are valuable in treating both hypokalaemia and hypertension in all forms of mineralocorticoid excess. Up to 20% of males develop gynaecomastia on spironolactone. Eplerenone or amiloride (10-40 mg/day), which blocks the epithelial sodium channel regulated by aldosterone, is an alternative.

Phaeochromocytoma and paraganglioma These are rare neuro-endocrine tumours that may secrete catecholamines (adrenaline/epinephrine, noradrenaline/norepinephrine) and are responsible for less than 0.1% of cases of hypertension. Approximately 80% of these tumours occur in the adrenal medulla (phaeochromocytomas), while 20% arise elsewhere in the body in sympathetic ganglia (paragangliomas). Most are benign but approximately 15% show malignant . Around 25% of phaeochromocytomas are associated with inherited disorders, including neurofibromatosis , von Hippel-Lindau syndrome and MEN type 2 Paragangliomas are particularly associated with mutations in the succinate dehydrogenase B, C and D genes.

Investigations Excessive secretion of catecholamines can be confirmed by measuring metabolites in plasma and/or urine (metanephrine and normetanephrine). There is a high 'false positive' rate as misleading metanephrine

concentrations may be seen in stressed patients (during acute illness or following vigorous exercise or severe pain) and following ingestion of some drugs such as tricyclic antidepressants.

this reason, a repeat sample should usually be requested if elevated levels are found, although as a rule the higher the concentration of metanephrines, the more likely the diagnosis of phaeochromocytoma/paraganglioma.

Serum chromogranin A is often elevated and may be a useful tumour marker in patients with non-secretory tumours and/or metastatic disease.

Genetic testing should be considered in individuals with other features of a genetic syndrome, with a family history of phaeochromocytoma/paraganglioma and in those presenting under the age of 50 years.

Localisation Phaeochromocytomas are usually identified by abdominal CT or MRI . Localisation of paragangliomas may be more difficult. Scintigraphy using meta-iodobenzyl guanidine (MIBG) can be useful, particularly if combined with CT.

Medical therapy is required to prepare the patient for surgery, preferably for a minimum of 6 weeks to allow restoration of normal plasma volume.

The most useful drug in the face of very high circulating catecholamines is the α-blocker phenoxybenzamine (10-20 mg orally 6-8-hourly) because it is a non-competitive antagonist, unlike prazosin or doxazosin. If α-blockade produces a marked tachycardia, then a β-blocker (e.g. propranolol) or combined α- and β-antagonist (e.g. labetalol) can be added. On no account should the β-antagonist be given before the α-antagonist, as it may cause a paradoxical rise in blood pressure due to unopposed α-mediated vasoconstriction.

During surgery sodium nitroprusside and the short-acting α-antagonist phentolamine are useful in controlling hypertensive episodes which may result from anaesthetic induction or tumour mobilization

Post-operative hypotension may occur and require volume expansion and, very occasionally, noradrenaline (norepinephrine) infusion. This is uncommon if the patient has been prepared adequately with phenoxybenzamine.

Nutrients the diet can be classified into ‘macronutrients’,which are eaten in relatively large amounts toprovide fuel for energy, and ‘micronutrients’ (e.g. vitaminsand minerals), which do not contribute to energy balance but are required in small amounts because they are not synthesised in the body.

Energy intake is determined by the ‘macronutrient’content of food. Carbohydrates, fat, protein and alcoholprovide fuel for oxidation in the mitochondria to generateenergy (as adenosine triphosphate (ATP). Theenergy provided by each of these elements differs:• carbohydrates (16 kJ/g)• fat (37 kJ/g)• protein (17 kJ/g)• alcohol (29 kJ/g).

Vitamins are organic substances with key roles in certainmetabolic pathways, and are categorised into those thatare fat-soluble (vitamins A, D, E and K) and those thatare water-soluble (vitamins of the B complex group andvitamin C).

saad

Vitamin A (retinol)Pre-formed retinol is found only in foods of animalorigin. Vitamin A can also be derived from carotenes,which are present in green and coloured vegetables and some fruits. Carotenes provide most of the totalvitamin A in the UK, and constitute the only supply invegans. Retinol is converted to several other importantmolecules:

• 11-cis retinaldehyde is part of the photoreceptor complex in rods of the retina.• Retinoic acid induces differentiation of epithelialcells by binding to specific nuclear receptors, whichinduce responsive genes. In vitamin A deficiency,mucus-secreting cells are replaced by keratinproducingcells.• Retinoids are necessary for normal growth, fetaldevelopment, fertility, haematopoiesis and immunefunction.

Globally, the most important consequence ofvitamin A deficiency is irreversible blindness in youngchildren. Asia is most notably affected and the problemis being addressed through widespread vitamin Asupplementation programmes. Adults are not usually atrisk because liver stores can supply vitamin A whenfoods containing vitamin A are unavailable.

Early deficiency causes impaired adaptation to thedark (night blindness). Keratinisation of the cornea(xerophthalmia) gives rise to characteristic Bitot’s spots, and progresses to keratomalacia, with corneal ulceration,scarring and irreversible blindness ). Incountries where vitamin A deficiency is endemic, pregnantwomen should be advised to eat dark-green, leafyvegetables and yellow fruits (to build up stores of retinolin the fetal liver), and infants should be fed the same.WHO is according high priority to prevention in communitieswhere xerophthalmia occurs, giving singleprophylactic oral doses of 60 mg retinyl palmitate (providing200 000 U retinol) to pre-school children. Thisalso reduces mortality from gastroenteritis and respiratoryinfections.

Repeated moderate or high doses of retinol can causeliver damage, hyperostosis and teratogenicity. Womenin countries where deficiency is not endemic are thereforeadvised not to take vitamin A supplements in pregnancy.Retinol intake may also be restricted in those atrisk of osteoporosis. Acute overdose leads to nausea andheadache, increased intracranial pressure and skin desquamation.Excessive intake of carotene can cause pigmentationof the skin (hypercarotenosis); this graduallyfades when intake is reduced.

The natural form of vitamin D, cholecalciferol or vitaminD3, is formed in the skin by the action of UV light on7-dehydrocholesterol, a metabolite of cholesterol. Fewfoods contain vitamin D naturally and skin exposure tosunlight is the main source. Moving away from theequator, the intensity of UV light decreases, so that ata latitude above 50° (including northern Europe),

vitamin D is not synthesised in winter, and even above30° there is seasonal variation. The body store accumulatedduring the summer is consumed during the winter. Vitamin D is converted in the liver to 25-hydroxy vitaminD (25(OH)D), which is further hydroxylated in thekidneys to 1,25-dihydroxy-vitamin D (1,25 (OH)2D), theactive form of the vitamin 1,25(OH)2D activates specific intracellular receptorswhich influence calcium metabolism, bone mineralisationand tissue differentiation. The synthetic form, ergocalciferol, or vitamin D2, is considered to be less potentthan the endogenous D3.

The effects of vitamin D deficiency (calcium deficiency,rickets and osteomalacia) are described on An analogue of vitamin D (calcipotriol) is used fortreatment of skin conditions such as psoriasis. Excessivedoses of cholecalciferol, ergocalciferol or the hydroxylatedmetabolites cause hypercalcaemia

-Vitamihasn E αtocopherol. many direct metabolicactions:• It prevents oxidation of polyunsaturated fatty acidsin cell membranes by free radicals.1 helps maintain cell membrane structure.2 DNA synthesis and cell signalling.3 anti-inflammatory and immunesystems.

Human deficiency is rare and has only been describedin premature infants and in malabsorption. It cancause a mild haemolytic anaemia, ataxia and scotomas. visual

Vitamin K is supplied in the diet mainly as vitamin K1

Gla(phylloquinone) in the UK, or as vitamin K2 (menaquinone)from fermented products in parts of Asia. VitaminK2 is also synthesised by bacteria in the colon. VitaminK is a co-factor for carboxylation reactions: in particular,the production of γ-carboxyglutamate (gla).

residues are found in four of the coagulation factor proteins(II, VII, IX and X; , conferring their capacityto bind to phospholipid surfaces in the presence ofcalcium. Other important gla proteins are osteocalcinand matrix gla protein, which are important in bonemineralisation

Vitamin K deficiency leads to delayed coagulationand bleeding. In obstructive jaundice, dietary vitamin Kis not absorbed and it is essential to administer thevitamin in parenteral form before surgery.

Warfarin andrelated anticoagulants act by antagonisingvitamin K. Vitamin K is given routinely to newbornbabies to prevent haemorrhagic disease. Symptoms ofexcess have been reported only in infants, with syntheticpreparations linked to haemolysis and liver damage

Water-soluble vitamins

Thiamin (vitamin B1 )Thiamin is widely distributed in foods of both vegetableand animal origin. Thiamin pyrophosphate (TPP) isa co-factor for enzyme reactions involved in themetabolism of macronutrients (carbohydrate, fat andalcohol), including• decarboxylation of pyruvate to acetyl-co-enzyme A,which bridges between glycolysis and thetricarboxylic acid (Krebs) cycle• transketolase activity in the hexose monophosphateshunt pathway• decarboxylation of α-ketoglutarate to succinate inthe Krebs cycle.

In thiamin deficiency, cells cannot metabolise glucoseaerobically to generate energy as ATP. Neuronal cellsare most vulnerable, since they depend almost exclusivelyon glucose for energy requirements. Impaired glucose oxidation also causes an accumulation ofpyruvic and lactic acids, which produce vasodilatationand increased cardiac output.

Deficiency – beri-beri

In the developed world, thiamin deficiency is mainlyencountered in chronic alcoholics. Poor diet, impairedabsorption, storage and phosphorylation of thiamin inthe liver, and the increased requirements for thiamin to metabolise ethanol all contribute. In the developingworld, deficiency usually arises as a consequence of adiet based on polished rice. The body has very limitedstores of thiamin, so deficiency is manifest after only 1month on a thiamin-free diet. There are two forms of thedisease in adults:

• Dry (or neurological) beri-beri manifests with chronicperipheral neuropathy and with wrist and/or footdrop, and may cause Korsakoff’s psychosis andWernicke’s encephalopathy• Wet (or cardiac) beri-beri causes generalised oedemadue to biventricular heart failure with pulmonarycongestion.In dry beri-beri, response to thiamin administrationis not uniformly good. However, multivitamin therapyseems to produce some improvement, suggestingthat other vitamin deficiencies may be involved.Wernicke’s encephalopathy and wet beri-beri shouldbe treated without delay with intravenous vitamin Band C mixture (‘Pabrinex’, Korsakoff’s psychosis is irreversible and does not respond to thiamin

A rare but important effect of chronic alcohol misuseis the Wernicke–Korsakoff syndrome. This organic braindisorder results from damage to the mamillary bodies,dorsomedial nuclei of the thalamus and adjacent areasof periventricular grey matter caused by a deficiency ofthiamin (vitamin B1), which most commonly resultsfrom long-standing heavy drinking and an inadequatediet. It can also arise from malabsorption or even protractedvomiting. Without prompt treatment (see below),the acute presentation of Wernicke’s encephalopathy(nystagmus, ophthalmoplegia, ataxia and confusion)can progress to the irreversible deficits of Korsakoff’ssyndrome (severe short-term memory deficits andconfabulation, and also reduced red blood cell transketolase).In those who die in the acute stage, microscopicexamination of the brain shows hyperaemia,petechial haemorrhages and astrocytic prolifera

Riboflavin (vitamin B2 )Riboflavin is required for the flavin co-factors involvedin oxidation–reduction reactions. It is widely distributedin animal and vegetable foods. Levels are low in staplecereals but germination increases its content. It isdestroyed under alkaline conditions by heat and byexposure to sunlight.Deficiency is rare in developed countries. It mainlyaffects the tongue and lips and manifests as glossitis,angular stomatitis and cheilosis. The genitals may beaffected, as well as the skin areas rich in sebaceousglands, causing nasolabial or facial dyssebacea. Rapid

Niacin (vitamin B3 )Niacin encompasses nicotinic acid and nicotinamide. Nicotinamide is an essential part of the two pyridinenucleotides, nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate(NADP), which play a key role as hydrogen acceptors and donors for many enzymes. Niacin can be synthesisedin the body in limited amounts from the aminoacid tryptophan.Deficiency – pellagraPellagra was formerly endemic among poor people whosubsisted chiefly on maize, which contains niacytin, a

form of niacin that the body is unable to utilise. Pellagracan develop in only 8 weeks in individuals eating dietsthat are very deficient in niacin and tryptophanremains a problem in parts of Africa, and is occasionallyseen in alcoholics and in patients with chronic smallintestinal disease in developed countries.

Pellagra canoccur in Hartnup’s disease, a genetic disorder characterisedby impaired absorption of several amino acids, including tryptophan. It is also seen occasionally in carcinoid syndrome , when tryptophan is consumedin the excessive production of 5-hydroxytryptamine(5-HT). Pellagra has been called the disease of thethree D

• Dermatitis. Characteristically, there is erythemaresembling severe sunburn, appearingsymmetrically over the parts of the body exposed to sunlight, particularly the limbs and especiallyon the neck, but not the face (Casal’s necklace,

The skin lesions may progress tovesiculation, cracking, exudation and secondaryinfection.

• Diarrhoea. This is often associated with anorexia, nausea, glossitis and dysphagia, reflecting thepresence of a non-infective inflammation thatextends throughout the gastrointestinal tract.

• Dementia. In severe deficiency, delirium occursacutely and dementia develops in chronic cases.

ToxicityExcessive intakes of niacin may lead to reversiblehepatotoxicity. Nicotinic acid is a lipid-lowering agent,but at doses above 200 mg a day gives rise to vasodilatorysymptoms (‘flushing’ and/orhypotension)

Pyridoxine (vitamin B6 )Pyridoxine, pyridoxal and pyridoxamine are differentforms of vitamin B6 that undergo phosphorylation toproduce pyridoxal 5-phosphate (PLP). PLP is theco-factor for a large number of enzymes involved in themetabolism of amino acids. Vitamin B6 is available inmost foods.

Deficiency is rare, although certain drugs, such asisoniazid and penicillamine, act as chemical antagoniststo pyridoxine.Pyridoxine administration is effectivein isoniazid-induced peripheral neuropathy and somecases of sideroblastic anaemia.

Large doses of vitaminB6 have an antiemetic effect in radiotherapy-induced nausea

. Although vitamin B6 supplements have become popular in the treatment of nausea in pregnancy, carpaltunnel syndrome and premenstrual syndrome, there is no convincing evidence of benefit. Very high doses ofvitamin B6 taken for several months can cause a

sensorypolyneuropathy.

BiotinBiotin is a co-enzyme in the synthesis of fatty acids, isoleucine and valine and is also involved in gluconeogenesis.

Deficiency results from consuming very largequantities of raw egg whites (> 30% energy intake)because the avidin they contain binds to and inactivatesbiotin in the intestine. It may also be seen after longperiods of total parenteral nutrition. The clinical featuresof deficiency include scaly dermatitis, alopecia andparaesthesia.

Folate (folic acid) Folates exist in many forms. The main circulating formis 5-methyltetrahydrofolate. Folic acid is the stable synthetic form. Folate works as a methyl donor for cellular methylationand protein synthesis. It is directly involved in DNAand RNA synthesis, and requirements increase during embryonic development

Folate deficiency may cause three major birth defects

(spina bifida, anencephaly and encephalocele) resultingfrom imperfect closure of the neural tube, which takesplace 3–4 weeks after conception.

Departmentof Health advises that women who have experienced apregnancy affected by a neural tube defect should take5 mg of folic acid daily from before conception andthroughout the first trimester All

women planning a pregnancy are advised to include good sources of folate in their diet, and to take folate supplements throughout the first trimester. Liver is the richest source of folate but an alternative source (e.g. leafy vegetables) is advised in early pregnancy because of the high vitamin A content of liver

Folate deficiency also has been associated with heart disease, dementia and cancer.. There are now concerns that this may contribute to the increased incidence of colon cancer through promotion of the growth of polyps.

Hydroxycobalamin (vitamin B12 )Vitamin B12 is a co-factor in folate co-enzyme recyclingand nerve myelination. Vitamin B12 and folate are particularlyimportant in DNA synthesis in red blood cells

The haematological disorders (macrocytic ormegaloblastic anaemias) due to their deficiency are discussedon . Vitamin B12, but not folate, is needed for the integrity of myelin, so that vitamin B12deficiency is also associated with neurological disease

Neurological consequences of vitamin B12

deficiency. In older people and chronic alcoholics, vitamin B12

deficiencyarises from insufficient intake and/or frommalabsorption. Several drugs, including neomycin, canrender vitamin B12 inactive. Adequate intake of folatemaintains erythropoiesis and there is a concern that fortification of foods with folate may mask underlyingvitamin B12 deficiency. In severe deficiency there is insidious, diffuse and uneven demyelination. It may be clinically manifest as peripheral neuropathy or spinalcord degeneration

affecting both posterior and lateral columns (‘subacute combined degeneration of the spinal cord’ or there may be cerebral manifestations(resembling dementia) or optic atrophy. Vitamin B12therapy improves symptoms in most cases

.

The average daily diet contains 5–30 μg of vitamin B12,mainly in meat, fish, eggs and milk – well in excess ofthe 1 μg daily requirement. In the stomach, gastricenzymes release vitamin B12 from food and at gastric pHit binds to a carrier protein termed R protein. The gastricparietal cells produce intrinsic factor, a vitamin B12-binding protein which optimally binds vitamin B12 at pH8. As gastric emptying occurs, pancreatic secretion raisesthe pH and vitamin B12 released from the diet switchesfrom the R protein to intrinsic factor. Bile also containsvitamin B12 which is available for reabsorption in theintestine. The vitamin B12–intrinsic factor complex bindsto specific receptors in the terminal ileum, and vitaminB12 is actively transported by the enterocytes to plasma

where it binds to transcobalamin II, a transport proteinproduced by the liver, which carries it to the tissues forutilisation. The liver stores enough vitamin B12 for3 years and this, together with the enterohepatic circulation,.Blood levels of vitamin B12 provide a reasonable indicationof tissue stores and are usually diagnostic of deficiency. Levels of cobalamins fall in normal pregnancy.Reference ranges vary between laboratories but levelsbelow 150 ng/L are common and, in the last trimester,. Spuriouslylow B12 values occur in women using the oralcontraceptive pill and in patients with myeloma,.