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Hypothyroidism anaemia

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					Hypothyroidism
PATHOPHYSIOLOGY
Underactivity of the thyroid may be primary, from disease of the thyroid, or secondary to hypothalamic–
pituitary disease (reduced TSH drive) (Table 16.23). It is one of the most common endocrine conditions
with a UK prevalence of 1.4% in women, but under 0.1% in men.




Causes of primary hypothyroidism
Atrophic (autoimmune) hypothyroidism
This is the most common cause of hypothyroidism and is associated with microsomal autoantibodies
leading to lymphoid infiltration of the gland and eventual atrophy and fibrosis. It is six times more common
in females and the incidence increases with age. The condition is associated with other autoimmune disease
such as pernicious anaemia. In some instances the condition shows intermittent hypothyroidism with
recovery. In some cases antibodies which block the TSH receptor may be involved in the aetiology.
Hashimoto’s thyroiditis
This form of autoimmune thyroiditis, again more common in women and most common in late middle age,
produces atrophic changes with regeneration, leading to goitre formation. The gland is usually firm and
rubbery but may range from soft to hard. Thyroid microsomal antibodies are again present, often in very
high titres (>1:100 000). Patients may be hypothyroid or euthyroid, though they may go through an initial
toxic phase, ‘Hashi toxicity’. Thyroxine therapy may shrink the goitre even when the patient is not
hypothyroid, though this may take a long time.
Postpartum thyroiditis
This is usually a transient phenomenon observed following pregnancy and may involve hyperthyroidism,
hypothyroidism or the two sequentially. It is believed to result from the modifications to the immune
system necessary in pregnancy, and histologically is a lymphocytic thyroiditis. The process is normally
self-limiting, but when conventional antibodies are found there is a high chance of this proceeding to
permanent hypothyroidism.
Iodine deficiency
In mountainous areas (the Alps, Himalayas, South America, Central Africa) dietary iodine deficiency still
exists, in some areas as ‘endemic goitre’ where goitre, occasionally massive, is common. The patients may
be euthyroid or hypothyroid depending on the severity of iodine deficiency. The mechanism is thought to
be borderline hypothyroidism leading to TSH stimulation and thyroid enlargement in the face of continuing
iodine deficiency.
Dyshormonogenesis
This rare condition is due to genetic defects in the synthesis of thyroid hormones; patients develop
hypothyroidism with a goitre. One particular familial form is associated with sensorineural deafness
(Pendred’s syndrome).

CLINICAL FEATURES
See Fig 16.20
Hypothyroidism may produce many symptoms. The classic picture of the slow, dry-haired, thick-skinned,
deep-voiced patient with weight gain, cold intolerance, bradycardia and constipation makes the diagnosis
easy. The term ‘myxoedema’ refers to the accumulation of mucopolysaccharide in subcutaneous tissues.
Milder symptoms are, however, more common and many cases are detected on biochemical screening.
Special difficulties in diagnosis may arise in certain circumstances:
•Children with hypothyroidism may not show classic features but often have a slow growth velocity, poor
school performance and sometimes arrest of pubertal development.
•Young women with hypothyroidism may not show obvious signs. Hypothyroidism should be excluded in
all patients with oligomenorrhoea/amenorrhoea, menorrhagia, infertility or hyperprolactinaemia.
•The elderly show many clinical features that are difficult to differentiate from normal ageing.
The signs of hypothyroidism. Bold type indicates signs of greater discriminant value


INVESTIGATION OF PRIMARY HYPOTHYROIDISM
Serum TSH is the investigation of choice; a high TSH level confirms primary hypothyroidism. A low total
or free serum T4 level confirms the hypothyroid state and is especially important if there is any evidence of
hypothalamic and pituitary disease, when TSH may be low or normal.
Thyroid and other organ-specific antibodies may be present. Other abnormalities include the following:
•anaemia, which is usually normochromic and normocytic in type but may be macrocytic (sometimes this
is due to associated pernicious anaemia) or microcytic (in women, due to menorrhagia)
•increased aspartate transferase levels, from muscle and/or liver
•increased creatine kinase levels
• hypercholesterolaemia
•hyponatraemia due to an increase in ADH and impaired free water clearance.


TREATMENT
Replacement therapy with T4 is given for life. The starting dose will depend upon the severity of the
deficiency and on the age and fitness of the patient, especially cardiac performance. In the young and fit,
100 µg daily is suitable, while 50 mg daily is more appropriate for the small, old or frail. T 3 offers no
significant advantage over T4.
Patients with ischaemic heart disease require even lower initial doses, especially if the hypothyroidism is
severe and longstanding. Most physicians would then begin with 25 µg daily and perform serial ECGs,
increasing the dose at 3–4 week intervals if angina does not occur or worsen and the ECG does not
deteriorate. Some, however, would use T3 beginning with 2.5 µg 8-hourly, doubling the dose every 48
hours up to 10 µg thrice daily. If progress is satisfactory, T 4 (100 µg daily) is then started and T 3 is
discontinued five days later.
Adequacy of replacement should be assessed clinically and by thyroid function tests (TSH and possibly T 4)
after at least six weeks on a steady dose; the aim is to restore TSH to well within the normal range. If serum
TSH remains high, the dose of T 4 should be increased in 25–50 µg increments and the tests repeated six
weeks later. This stepwise progression should be continued until TSH becomes normal, though some
physicians believe that complete well-being is only restored in some patients when the T 4 is high-normal
and the TSH is slightly suppressed. The usual maintenance dose is 100–150 µg given as a single daily dose;
over-replacement may increase the risk of atrial fibrillation in those aged over 60. An annual thyroid
function test is recommended.
Clinical improvement on T4 may not begin for two weeks or more, even though it is quicker on T 3, and full
resolution of symptoms may take six months. The importance of lifelong therapy must be emphasized and
the possibility of other autoimmune endocrine disease developing, especially Addison’s disease, should be
considered. During pregnancy about a 50 µg increase in T 4 dosage is often needed to maintain normal TSH
levels, probably because of the increased TBG levels.


Borderline hypothyroidism or ‘compensated euthyroidism’
Patients are frequently seen with low-normal serum T4 levels and slightly raised TSH levels. Sometimes
this follows surgery or radioactive iodine therapy when it can reasonably be seen as ‘compensatory’.
Treatment with thyroxine is now normally recommended where the TSH is consistently above 10 mU L–1,
or when possible symptoms, thyroid antibodies or lipid abnormalities are present. Where the TSH is only
marginally raised, the tests should be repeated 3–6 months later. Conversion to overt hypothyroidism is
more common in men or when microsomal antibodies are present.


Myxoedema coma
Although very rare, severe hypothyroidism, especially in the elderly, may present with confusion or even
coma.
Hypothermia is often present and the patient may have severe cardiac failure, hypoventilation,
hypoglycaemia and hyponatraemia.
The mortality was previously at least 50% and patients require full intensive care. Optimal treatment is
controversial and data lacking; most physicians would advise T 3 orally or intravenously in doses of 2.5–5
µg every eight hours, then increasing as above. Large intravenous doses should not be used. Additional
measures, though unproven, should include:
• oxygen (by ventilation if necessary)
• monitoring of cardiac output and pressures via a Swan–Ganz catheter
• gradual rewarming
• hydrocortisone 100 mg i.v. 8-hourly
• dextrose infusion to prevent hypoglycaemia.


‘Myxoedema madness’
Depression is common in hypothyroidism but occasionally with severe hypothyroidism in the elderly the
patient may become frankly demented or psychotic, sometimes with striking delusions. This may occur
shortly after starting T4 replacement.


Screening for hypothyroidism
The incidence of congenital hypothyroidism is approximately 1 in 3500 births. Untreated, severe
hypothyroidism leads to permanent neurological and intellectual damage (‘cretinism’). Routine screening
of the newborn using a blood-spot, as in the Guthrie test, to detect a high TSH level as an indicator of
primary hypothyroidism is efficient; cretinism is prevented if T 4 is started within the first few months of
life.
Screening of elderly patients for thyroid dysfunction is controversial and not currently recommended.
However, patients who have undergone thyroid surgery or received radioiodine should have regular thyroid
function tests, as should those receiving lithium or amiodarone therapy.