Hypothyroidism can affect all organ systems. The presence and severity of clinical manifesta- tions are usually dependent on the degree of hor- mone defi ciency. Two mechanisms explain most of the symptoms and signs: the generalized slow- ing of metabolic processes and the accumulation of glycosaminoglycans in the interstitial space of many tissues [ 99 ]. To simplify the discussion the authors decided to group the clinical features in organ systems.
Skin and Appendages
A mucinous nonpitting edema known as myx- edema can be found around the eyes given a puffy or moonlike appearance, on the dorsum of the hands and feet, and in the supraclavicular fossa. This is explained by the accumulation of hyaluronic acid and other glycosaminoglycans in the dermis. The secretions of the sweat and seba-
ceous glands are reduced, leading to dryness of the skin. The skin is pale and cool as a result of cutaneous vasoconstriction and/or anemia. Some patients may have hypercarotenemia, which gives the skin a yellow tint. Wounds heal slowly. Easy bruising can also occur due to an increase in capillary fragility [ 14 , 100 ].
Head and body hair is dry and brittle, lacks shine, and tends to fall out. Hair may be lost from the lateral margins of the eyebrows (Queen Anne’s sign), although this is not a spe- cifi c feature. Eyebrows can totally disappear. The nails are thickened, brittle and grow slowly (Fig. 7.3 ).
Cardiovascular
The cardiac output is decreased due to a reduc- tion in both stroke volume and heart rate, which can explain the symptoms of reduced exercise tolerance and dyspnea. Peripheral vascular resis- tance is increased. These hemodynamic altera-
tions cause narrowing of pulse pressure, diastolic hypertension (10–25 % of patients) and a decrease in blood fl ow to organs [ 101 , 102 ]. In most tissues, the reduction in blood fl ow is pro- portional to the decrease in oxygen consumption and therefore angina is an infrequent symptom [ 103 ]. When present it is usually explained by an underlying coronary heart disease (CHD). Serum levels of homocysteine [ 104 , 105 ] and creatine kinase (CK) [ 106 ] may be increased in hypothy- roidism. Dyslipidemia can be found in more than 90 % of patients, usually presenting as elevations of total and low-density lipoprotein (LDL) cho- lesterol [ 107 ]. These fi ndings may contribute to an increased risk of atherosclerosis.
An electrocardiogram can show sinus brady- cardia, low voltage, prolongation of the PR interval, alterations of the ST segment, pro- longed QT interval and fl attened or inverted T waves [ 14 , 100 ]. Torsade de pointes can rarely occur [ 108 ]. Echocardiographic evaluation may reveal pericardial effusion [ 109 ], asymmetric septal hypertrophy or other abnormalities
a b
Fig. 7.3 Features of a patient with severe hypothyroid- ism. ( a ) Clinical presentation with marked periorbital myxedema, dry and cool skin and fatigue. ( b ) Signifi cant
improvement of signs and symptoms of hypothyroidism 3 months after the introduction of levothyroxine
[ 110 ]. Rarely, patients can develop congestive heart failure [ 111 ].
Respiratory
Pleural effusions can be present and may contribute to dyspnea [ 100 ]. In severe hypothyroidism, alveo- lar hypoventilation and carbon dioxide retention may occur, contributing to the development of myx- edema coma [ 112 , 113 ]. Obstructive sleep apnea is common as a result of macroglossia [ 114 , 115 ].
Gastrointestinal
Appetite is usually reduced (anorexia). Modest weight gain can occur due to the decreased meta- bolic rate and retention of fl uid in tissues. Contrary to popular belief, hypothyroidism is not related to an increase of fat and obesity [ 116 ]. Dysphagia or heartburn may be due to disordered esophageal motility, whereas dyspepsia, nausea or vomiting are related to delayed gastric emptying [ 117 ]. Decreased gut motility and decreased food intake result in constipation [ 118 ]. The latter may lead to fecal impaction, megacolon and ileus [ 119 ]. The rate of intestinal absorption is decreased and intestinal transit time is prolonged [ 120 ]. Ascites is rarely found [ 121]. Gallbladder motility is decreased in hypothyroid patients [ 122 ].
In addition, measurements of serum aspartate aminotransferase, lactate dehydrogenase [ 123 ] and carcinoembryonic antigen [ 124 ] may be ele- vated, and pernicious anemia can be present. Celiac disease is also associated with hypothy- roidism [ 125 ].
Neurologic
Thyroid hormones are crucial for the develop- ment of the central nervous system. Congenital hypothyroidism is related to severe and irrevers- ible neurologic abnormalities if left untreated. It can be associated with hypoplasia of cortical neurons, retarded myelination, and altered cell migration and differentiation [ 126 , 127 ].
Manifestations include mental retardation, impaired motor development such as tremor, rigidity and spasticity of the trunk and proximal extremities, and also strabismus and sensorineu- ral hearing loss [ 128 ].
Hypothyroidism occurring in adult life is characterized by less severe neurologic manifes- tations. Headaches can be identifi ed in 30 % of hypothyroid patients [ 129 ]. Carpal tunnel syn- drome is present in 29–38 % of cases due to compression of the median nerve by deposits of glycosaminoglycans [ 130 , 131]. Body move- ments are slow and cerebellar ataxia may be identifi ed [ 132]. The occurrence of delayed relaxation of deep tendon refl exes may be related to peripheral neuropathy [ 133 ]. Hearing loss, vertigo and tinnitus are frequent [ 134 ]. The voice is husky (hoarseness), low-pitched, and coarse.
The speech is slow and slurred [ 100 ]. These changes are caused by myxedematous infi ltration of the tongue and larynx. Loss of initiative, mem- ory and calculation defects, reduced attention span and poor concentration may be present. Irritability is decreased and apathy can occur. Psychiatric disorders are common and usually manifest as depression. However, some patients may present with psychosis and hallucinations (myxedema madness) [ 135]. An association between Alzheimer’s disease and hypothyroid- ism was reported but an etiologic relationship has not been established [ 136 , 137 ]. Lethargy and somnolence are sometimes found and epileptic seizures have been reported. The patient can evolve to myxedema coma. The pathogenesis of cognitive dysfunction in hypothyroidism is unknown. It may be related to a decrease in cere- bral blood fl ow and a reduction in glucose metab- olism [ 138 ].
Hashimoto’s encephalopathy is a rare mani- festation of HT [ 139 ]. Patients most often have an acute or subacute onset of confusion with alteration of consciousness and other neurologic signs, such as seizures, myoclonus, tremor, hyperrefl exia and psychosis [ 139 , 140 ]. The diagnosis is usually performed by the presence of these clinical manifestations in patients with ele- vated thyroid antibodies [ 141 ].
Musculoskeletal
Thyroid hormones are essential for normal growth and skeletal development. Thyroid hormone defi - ciency in infants results in growth failure and dwarfi sm in which the limbs are disproportion- ately short in relation to the trunk. Epiphyseal dysgenesis is a typical fi nding that can be identi- fi ed in radiologic exams. Ossifi cation centers appear late and bone age is retarded in relation to chronologic age [ 142]. Delayed closure of the fontanelles is also found. In older children hypo- thyroidism can cause short stature [ 143 ].
Adults may complain of arthralgias, joint stiffness and effusions [ 144]. Muscular symp- toms can be identifi ed in about 80 % of patients, namely muscle weakness and cramps [ 130 ]. Rarely, a combination of generalized muscular hypertrophy and weakness may be found, which is referred as Kocher-Debre-Semelaigne syn- drome in children [ 145 , 146 ] and Hofmann’s syn- drome in adults [ 147 ].
CK levels are sometimes high and patients may develop rhabdomyolysis [ 148 ]. Serum cal- cium levels are usually normal but may be ele- vated [ 149 ]. Serum phosphorus concentration is normal. Urinary excretion of calcium is decreased.
Renal
Renal blood fl ow is decreased due to the reduc- tion of cardiac output and blood volume. The glo- merular fi ltration rate is also low [ 150 ]. Other effects of hypothyroidism include impaired sodium reabsorption and renal ability to dilute urine. As a result, increased serum creatinine and hyponatremia can occur [ 151 ].
Hematopoietic
The red blood cell mass is decreased. Mild anemia may be found in one-third of patients [ 152 ], and it is usually normocytic and normochromic. Less commonly, a macrocytic form in the context of pernicious anemia or folate defi ciency may occur [ 153 ]. Menorrhagia and the defective absorption
of iron resulting from achlorhydria can contribute to a microcytic and hypochromic anemia.
White blood cell and platelet counts are usu- ally normal. Hypothyroid patients have a higher risk of bleeding mainly due to acquired von Willebrand’s syndrome [ 154 , 155 ]. Some symp- toms such as epistaxis, gum bleeding, menorrha- gia and easy bruising may be present.
Endocrine
In primary hypothyroidism the increase in TSH levels stimulates the thyroid gland and results in the development of a goiter. Untreated primary hypothyroidism can also cause hyperplasia of the thyrotrophs and pituitary gland enlargement [ 156 ], which may result in hypopituitarism and visual fi eld defects [ 157 , 158 ]. About 39–63 % of patients have increased serum prolactin levels due to the increased TRH secretion. Galactorrhea may develop [ 159 , 160 ]. Growth hormone secre- tion is decreased in hypothyroidism [ 161 ]. Serum aldosterone and cortisol levels are often normal in hypothyroid patients but the turnover rates are decreased. Plasma renin activity is also reduced [ 162 ]. Individuals may have an elevated plasma noradrenaline level, whereas the adrenaline con- centration is usually normal [ 163 ]. A decreased adrenergic response is often found [ 164 ].
Reproductive
Thyroid hormones infl uence sexual development and reproductive function. Untreated infantile hypothyroidism results in sexual immaturity, whereas juvenile hypothyroidism causes a delay in the onset of puberty. However, it may also induce precocious puberty, which can be explained by the action of elevated levels of TSH on the follicle-stimulating hormone receptor [ 165 ].
In adult women, hypothyroidism may be asso- ciated with diminished libido and failure of ovu- lation [ 166]. Irregular menstrual cycles are present in more than 20 % of women, especially oligomenorrhea and menorrhagia [ 167 ]. Fertility
may be reduced and both miscarriage and adverse neonatal outcomes can occur [ 168 ]. However, most women with untreated hypothyroidism have uneventful pregnancies and give birth to normal infants [ 169 ]. Hypothyroidism in adult men may cause decreased libido, erectile dysfunction, delayed ejaculation and defects in spermatogen- esis [ 170 , 171 ].
Energy Metabolism
Energy metabolism is decreased in hypothyroid- ism contributing to a lower energy expenditure, oxygen consumption and utilization of substrates. Both the synthesis and the degradation of protein are decreased, but nitrogen balance is usually positive. Permeability of capillaries to protein is increased, which explains the high levels of pro- tein in effusions [ 14 ].
Hypothyroidism is usually associated with normal plasma glucose levels, whereas plasma insulin can be increased [ 172 ]. A lower glucose uptake in muscles and adipose tissue was reported [ 173 ]. In patients with preexisting diabetes mel- litus who develop hypothyroidism, insulin requirements may be reduced possibly due to the decreased insulin degradation [ 174 ].
Both the synthesis and the degradation of lipid are reduced in hypothyroidism. As previously noted, hypothyroidism is associated with dyslip- idemia usually presenting as elevations of total and LDL cholesterol [ 107 ].