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Een vrij groot artikel van W.M. Wiersinga (Departement Endocrinologie AMC Amsterdam)


Adult Hypothyroidism
Last Updated: December 12, 2013

Wilmar M. Wiersinga, M.D.
Department of Endocrinology F5-171 Academic Medical Center Meibergdreef 9 NL-1105 AZ
Amsterdam, The Netherlands Tel: 011-31-20-566-6071 Fax: 011-31-20-566-4440


9.1 HISTORICAL

9.2 DEFINITION AND EPIDEMIOLOGY OF HYPOTHYROIDISM

9.2.1. GRADES OF HYPOTHYROIDISM

Figure 9-1.
Individual and median values of thyroid function tests in patients with various grades of hypothyroidism.
Discontinuous horizontal lines represent upper limit (TSH) and lower limit (FT4,T3) of the normal reference ranges. (Reproduced with permission) (2)

Table 9-1. Grades of hypothyroidism


9.2.2. EPIDEMIOLOGY OF HYPOTHYROIDISM

Table 9-2. Prevalence and incidence of thyroid antibodies and hypothyroidism in the Whickham survey (8,9).

Figure 9-2. Logit probability (log odds) for the development of hypothyroidism as a function of TSH values at first survey during a 20-year follow-up of 912 women in the Whickham Survey. (Reproduced with permission)(9).


9.3 CAUSES OF HYPOTHYROIDISM

Table 9-3. Causes of hypothyroidism
1. Central (hypothalamic/pituitary) hypothyroidism
1. Loss of functional tissue
2. Functional defects in TSH biosynthesis and release

2. Primary (thyroidal) hypothyroidism
1. Loss of functional thyroid tissue
2. Functional defects in thyroid hormone biosynthesis and release

3. "Peripheral" (extrathyroidal) hypothyroidism
1. Consumptive hypothyroidism (massive infantile hemangioma)
2. Mutations in genes encoding for MCT8, SECISBP2, TRα or TRβ
(thyroid hormone resistance)

9.3.1. CENTRAL HYPOTHYROIDISM

9.3.2 CHRONIC AUTOIMMUNE THYROIDITIS

9.3.3 REVERSIBLE AUTOIMMUNE HYPOTHYROIDISM

9.3.4 POSTOPERATIVE AND POSTRADIATION HYPOTHYROIDISM

9.3.5 INFILTRATIVE AND INFECTIOUS DISEASES

9.3.6 CONGENITAL HYPOTHYROIDISM

9.3.7 IODINE DEFICIENCY AND IODINE EXCESS

9.3.8 DRUG-INDUCED HYPOTHYROIDISM

9.3.9. CONSUMPTIVE HYPOTHYROIDISM (MASSIVE INFANTILE HEMANGIOMA


9.4 PATHOLOGY OF HYPOTHYROIDISM


9.5 SYSTEMIC MANIFESTATIONS OF HYPOTHYROIDISM

9.5.1 ENERGY AND NUTRIENT METABOLISM
Energy metabolism.
Protein metabolism.
Carbohydrate metabolism
Lipid metabolism.

Table 9-4. Changes in serum lipids in hypothyroidism
Total cholesterol increase
LDL-cholesterol increase
HDL2-cholesterol modest increase
HDL3-cholesterol no change
Triglycerides no change or modest increase


9.5.2 FACIES AND INTEGUMENT

Figure 9-3. (A) The classic torpid facies of severe myxedema in a man.
The face appears puffy, and the eyelids are edematous. The skin is thickened and dry. (B)
The facies in pituitary myxedema is often characterized by skin of normal thickness, covered by fine wrinkles.
Puffiness is usually less than in primary myxedema. The eyelids are often edematous.
The palpebral fissure may be narrwowed because of blepharoptosis, due to diminished tone of the sympathetic nervous fibers to Müller's levator palpebral superious muscle and is the opposite of the lid retraction seen in thyrotoxicosis.
The modest measurable exophthalmos seen in some patients with myxedema is presumably related to
accumulation of the same mucous edema in the orbit as is seen elsewhere.
It is not progressive and carries no threat to vision, as in the ophthalmopathy of Graves' disease.
The tongue is usually large, occasionally to the point of clumsiness.
Sometimes a patient will complain of this problem.
Sometimes it is smooth, as in pernicious anemia (of course, pernicious anemia may coexist).
Patients do not usually complain of soreness of the tongue, as they may in pernicious anemia.
When anemia is marked, the tongue may be pale, but more often it is red, in contrast to the pallid face.


9.5.3 NERVOUS SYSTEM

Table 9-5. Neurologic and psychiatric manifestations of hypothyroidism.
NEUROLOGIC SYMPTOMS AND SIGNS
- Headache
- Paresthesias
- Carpal tunnel syndrome
- Cerebellar ataxia
- Deafness: nerve or conduction type
- Vertigo or tinnitus
- Delayed relaxation of deep tendon reflexes
- Sleep apnea
- EEG: low-amplitude theta and delta waves
- Prolonged evoked potentials
- CSF: elevated protein concentration
COGNITIVE FUNCTIONS
- Reduced attention span
- Memory deficits
- Calculation difficulties
PSYCHIATRIC SYNDROMES
- Myxedema madness (akinetic or agitated schizoid or affective psychoses)
- Depression

Neurologic symptoms and signs
Mental Symptoms
Psychiatric syndromes.


9.5.4 CARDIOVASCULAR SYSTEM
Table 9-8. Cardiovascular manifestations of hypothyroidism
Pathophysiology
• reduced myocardial contractility
• low cardiac output
• increased peripheral vascular resistance
• decreased blood volume
• increased capillary permeability
Symptoms
• dyspnea
• decreased exercise tolerance
• angina
Signs
• low pulse rate
• diastolic hypertension
• cardiomegaly
• pericardial effusion
• peripheral (non)pitting edema
• low voltage ECG with conduction disturbances and nonspecific ST-T changes
• prolonged systolic time intervals

Systemic changes.
Cardiomegaly.
Pericardial effusion.
Electrocardiogram.
Atherosclerosis.
Angina pectoris.


9.5.5 RESPIRATORY SYSTEM

9.5.6 MUSCULOSKELETAL SYSTEM

Table 9-7. Manifestations of hypothyroidism in the musculoskeletal system.
Clinical Symptoms and Signs
• Myalgia, muscle weakness, stiffness, cramps, fatigue
• Delayed reflex relaxation (e.g. prolonged Achilles tendon reflex relaxation time)
• Arthralgias, joint stiffness, joint effusions
• Carpal tunnel syndrome
Delayed linear bone growth in children
Laboratory
• Normal ionized calcium, phosphate, and bone density
• Increased serum PTH and 1,25 (OH)2-vitamin D3, normal 25-OH vitamin D3
• Reduced urine calcium, hydroxyproline, serum alkaline phosphatase, osteocalcin, and IGF-1
• Epiphyseal dysgenesis or delayed ossification in children
Joints.
Bones.

9.5.7 GASTROINTESTINAL SYSTEM
Table 9-8. Gastrointestinal manifestations of hypothyroidism.
Symptoms
anorexia
gaseous distention
constipation
Signs
prolonged gastric emptying
prolonged intestinal transit time
slowed intestinal absorption
rarely ileus or ascites
gallbladder hypotonia
elevated liver enzymes and CEA


9.5.8 RENAL FUNCTION, WATER AND ELECTROLYTES


9.5.9 REPRODUCTIVE FUNCTION
Male gonads and reproduction
Female gonads and reproduction


9.5.10 ENDOCRINE SYSTEM


9.5.11 HEMATOPOIETIC SYSTEM


9.6 COURSE OF THE DISEASE


9.7 DIAGNOSIS OF HYPOTHYROIDISM


9.7.1 CLINICAL EVALUATION (STAGE 1A)

Table 9-10. Incidence of symptoms and signs in hypothyroidism

Table 9-11 Accuracy of 12 symptoms and signs in the diagnosis of primary Hypothyroidism

Figure 9-4. Assessment of hypothyroidism by a clinical score, composed of 12 symptoms and signs as
listed in Table 3 (Reproduced with persmission(4)).


9.7.2 LABORATORY EVALUATION (STAGE 1B)

Figure 9-5. Flow-diagram for the biochemical diagnosis of hypothyroidism


1. TSH normal.
Euthyroidism is almost certain, as primary hypothyroidism is excluded.
However, two conditions will not be recognized. The first is the existence of central hypothyroidism.
As isolated TSH deficiency is very rare, clinical examination of the patient will usually provide sufficient clues (symptoms and signs of a pituitary mass, of hypopituitarism, or of overproduction of pituitary hormones) to warrant further evaluation by a FT4 assay.
The second is thyroid hormone resistance due to TRα mutations;
this recently discovered and probably rare disease is characterized by low normal to slightyly low FT4 and
high normal to slightly high T3 13,14 .

2. TSH elevated, FT4 decreases.
This classical combination of test results indicates primary hypothyroidism.
Test results are sometimes due to central hypothyroidism or nonthyroidal illness when TSH is slightly elevated (5-15 mU/l).

3. TSH elevated, FT4 normal.
Test results indicate most often subclinical hypothyroidism, sometimes nonthyroidal illness.

4. TSH elevated, FT4 increased.
A rarely encountered combination of test results, indicating either thyroid hormone resistance due to mutations in TRβ or TSH producing pituitary adenoma.

5. TSH decreased, FT4 decreased.
Central hypothyroidism accounts for these test results, which, however, also can be observed in severe nonthyroidal illness and after recently instituted treatment for thyrotoxicosis (131I, surgery, antithyroid drugs) or recent discontinuation of excessive thyroid hormone medication.

6. TSH decreased, FT4 increased or normal.
Hypothyroidism is excluded.
Results indicate overt thyrotoxicosis or subclinical hyperthyroidism respectively.


The reference interval of serum TSH is about 0.4-4.0 mU/L.
However, the lower normal limit is lower in pregnancy, and the upper normal limit increases with advancing age, reaching levels of 6.3 mU/L at the age of ≥80 yr 16. .
Serum T3 should not be done for the diagnosis of hypothyroidism 12


9.7.3 NOSOLOGICAL DIAGNOSIS (STAGE 2)

Table 9-12. Reversible causes of hypothyroidism


9.8 TREATMENT OF HYPOTHYROIDISM

9.8.1 PHARMACOLOGY OF THYROID HORMONE REPLACEMENT PREPARATIONS
Levothyroxine.
Liothyronine.
Desiccated thyroid.
Combinations of T3 and T4.

9.8.2 REPLACEMENT WITH THYROXINE

Figure 9-6. Relationship between the optimal daily dose of levothyroxine sodium and the mean pretreatment serum TSH concentration in patients with primary hypothyroidism.
Simple linear regressions are shown for two subgroups calculated according to the daily dose of L-T4 divided at the median dose of 125 μg;
the intercept of these two correlation lines occurs at the TSH concentration of 36 mU/l. (Reproduced with permission)

Figure 9-7. Frequency distribution curves of serum FT4, FT3 and FT3/FT4 ratio in 1,811 athyreotic patients under levothyroxine replacement. Shaded areas indicate normal range (2.5 and 97.5 percentiles) as calculated from 3,875 controls, with vertical lines indicating the median (reproduced with permission)

9.8.3 SITUATIONS REQUIRING DOSE ADJUSTMENT

Table 9-13. Conditions requiring adjustment of the replacement dose of thyroxine for hypothyroidism

9.8.4 INTERFERENCE WITH CO-EXISTENT CONDITIONS
Hypocortisolemia.
Ischemic heart disease
Drugs.
Growth hormone deficiency
Chronic renal failure


9.9 MYXEDEMA COMA

Table 9-14. Recommendations for the treatment of myxedema coma.


9.10 SUBCLINICAL HYPOTHYROIDISM

9.10.1 DIAGNOSIS AND ETIOLOGY

9.10.2 NATURAL HISTORY

9.10.3 SYSTEMIC MANIFESTATIONS

Table 9-15. Abnormalities reported in some but not all studies on subclinical hypothyroidism.

9.10.4. ASSOCIATIONS WITH CARDIOVASCULAR MORBIDITY AND MORTALITY

9.10.5. TREATMENT

OP BLADZIJDE 73
Figure 9-7. Algoritm for the individual management of subclinical hypothyroidism.(TPO-Ab =
thyroid peroxidase antibodies; risk factors = cardiovascular risk factors).

Table 9-16. Summary of data on subclinical hypothyroidism.


9.11 SCREENING FOR HYPOTHYROIDISM

Table 9-17. Indications for screening for hypothyroidism. (Reproduced with permission)


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