1. Pituitary dwarfism (nanism) develops in congenital hypoplasia of the pituitary body or its necrosis in children. General underdevelopment of the organism with preserved proportions is observed.
2. Simmonds’ disease (cerebro-hypophyseal cachexia) is caused by necrosis of pituitary anterior lobe. It may occur after childbirth due to vascular embolism as well as due to syphilis, tuberculosis, and tumor. It manifests by cachexia, inner organ atrophy, and sexual dysfunction.
3. Diabetes insipidus is caused by tumors, inflammation, sclerosis, and trauma of the posterior lobe of pituitary. It manifests itself by increased urine excretion due to deficiency of Antidiuretic hormone.
Diseases of adrenal glands
Adrenal glands consist of cortex and medullar substance. There are 3 zones in the cortex: glomerular zone which produces mineralocorticoids e.g. aldosterone, zona fasciculata which produces glucocorticoids, reticular zone which produces sexual hormones.
The most frequent disease associated with hypoadrenalism is Addison’s disease.
In 1849 Addison described the so-called bronze disease, which develops in bilateral lesion of adrenal cortex with the development of acorticism (absence of hormones) or hypoadrenocorticosis.
The causes of Addison’s disease are divided into two groups:
1. One of them causes primary Addison’s disease (genetic autoimmune disturbances).
2. Secondary Addison’s disease is caused by metastases in the adrenal glands, amyloidosis, hemorrhage, tuberculosis; necrosis due to vascular thrombosis, damage of the pituitary body (decreases ACTH or corticotropin releasing factor).
Morphology
Hyperpigmentation of the skin and mucous membrane due to excessive production of melanin stimulating hormone.
Myocardial atrophy.
Changes of the lumen in the aorta and large vessels.
Hyperplasia of the cells of islets of Langerhans in the pancreas (hypoglycemia).
Gastric mucosa atrophy.
Hyperplasia of thymus and lymphatic peripheral tissue.
The cause of death:
Acute adrenal failure.
Cachexia (suprarenal cachexia)
Cardiovascular insufficiency.
Diseases of theThyroid gland
Two significant functional disorders characterised by distinct clinical syndromes are discribed. There are: hyperthyroidism (thyrotoxicosis) and hypothyroidism (mixedema).
Hyperthyroidism
Hyperthyroidism (thyrotoxicosis) is a hypermetabolic clinical and biochemical state by excess production of thyroid hormones.
Many diseases may cause hyperthyroidism, but three most common causes are:
1. Graves’ disease (diffuse toxic goitre).
2. Toxic multinodular goitre.
3. Toxic adenoma.
Less frequent causes are thyroiditis, metastatic tomors of thyroid, struma ovarii, congenital hyperthyroidism
Goitre
Goitre is defined as thyroid enlargement caused by compensatory hyperplasia and hypertrophy of the follicular epithelium is response to thyroid hormone deficiency.
Goitre is classified according to their morphology and epidemiology, course, functional and clinical peculiarities.
I. According to the morphology goitre may be:
Simple goitre (diffuse nontoxic or colloid goitre).
Nodular goitre (multinodular goitre or adenomatous goitre).
Diffuse nodular (mixed).
II. According to the histology there are 2 types of goitre:
Colloid. Colloid goitre may be macrofollicular and microfollicular as well as mixed type. It consists of follicles. In case of epithelial proliferation the disease is termed proliferating colloid goitre, which is usually nodular.
Parenchymal. Parenchymal goitre is characterized by epithelium proliferation with formation of small follicle-like structures without colloid. In the majority of cases the disease is diffuse.
III. According to the epidemiology goiter is classified into:
Endemic. Endemic goitre develops in the areas with iodine deficiency in the drinking water (the Urals, Siberia, Middle Asia, Switzerland). The thyroid gland has the structure of colloid or parenchymal goitre. The functional activity is decreased. In children, endemic cretinism may develop (physical and mental retardation).
Sporadic. Sporadic goitre manifests in young and old age. This may be colloid; diffuse or mixed. It does not influence the organism as a whole, but it can cause compression of the esophagus, trachea, larynx, etc. with disturbance of their function. This goitre may be the cause of Basedow’s disease.
Graves’ disease
Graves’ disease (or diffuse toxic goiter, Basedow’s disease, primary hyperplasia, exophthalmic goitre)
Diffuse toxic goiter is an autoimmune disease.
Morphology: prismatic epithelium turns into cylindrical, epithelium proliferation with formation of papillae, colloid vacuolization, lymphoid plasmocytic infiltration of the stroma, formation of lymphoid follicles with germ centers are observed.
In the other organs, hypertrophy of the left ventricle of the heart, serous edema and lymphacytic infiltration myocardial interstitial spaces develop (thyrotoxic heart). The outcome is diffuse interstitial sclerosis. In the liver, there is serous edema causing thyrotoxic liver fibrosis. Thymus enlargement causes lymphoid tissue hyperplasia and adrenal hypertrophy. Exophthalmus takes place.
The causes of death are cardiac insufficiency and cachexia.
Hypothyroidism (mixedema)
Hypothyroidism is a hypometabolic clinical state resulting from inadequate production of thyroid hormones of prolonged periods of, or rarely, from resistance of the periferal tissues tj the effects of thyroid hormones. The clinival manifestations of hyperthyroidism are divided to into group:
I. Cretinism or congenital hyperthyroidism.
It produces the clinical syndrome, which occurs a puffy face and enlarged tongue (coarse features), a protuberant abdomen, and delayed physical and mental developmental milestones. The main causes of cretinism are:
Untreated maternal hypothyroidism. This is now rare, due to better prevention, recognition and treatment of maternal hypothyroidism but it is still a problem in some areas of the world where endemic goiter due to dietary iodine deficiency is seen.
Inherited enzyme defect. This produces sporadic cretinism and is due to failure of normal T3 and T4 synthesis.
II. Myxedema
It is the adult hypothyroidism, which is due to reduced metabolic rate. The term “myxedema” connotes non-pitting edema due to accumulation of hydrophilic micopolysaccharides in the ground substence of dermis and others tissues. There is progressive slowing of physical and mental activity, increasing lethargy and sensitivity to cold, puffy face, coarse dry skin, thinning of hair (particularly of the eyebrows), hoarseness and deepening of voice, and various internal abnormalities, particularly heart failure and a predisposition to hyperlipidemia and hypothermic coma.
The main causes of myxedema are:
Surgical ablation of the thyroid gland, which is usually as a result of total thyroidectomy for malignant disease, or aggressive subtotal thyroidectomy for hypothyroid Graves’ disease.
Hashimoto’s thyroiditis.
Some drug e.g. lithium.
Thyroiditis
Thyroiditis is classified into the following types:
1. Hashimoto’s thyroiditis.
2. Infectious thyroiditis.
3. Granulomatous thyroiditis (de Quervain’s thyroiditis or giant cell thyroiditis).
4. Riedel’s thyroiditis (or invasive fibrous thyroiditis, Riedel’ struma).
Hashimoto’s thyroiditis
Hashimoto’s thyroiditis is a destructive autoimmune thyroiditis leading to hypothyroidism.
It is most common in middle age, affecting women more often than men, a good example of organ-specific autoimmune disease.
The following autoantibodies against different thyroid cell antigens are detectable in the sera of most patients:
1. Thyroid microsomal thyroiditis.
2.m Thyroglobulin autoantibodies.
Morphology
Two varieties of Hashimoto’s thyroiditis are seen: classic from (more common), and fibrosing variant (only 10% cases).
Macroscopically, the classic form is characterised by diffuse, symmetric, firm and rubbery enlargement of the thyroid which may weigh 100-300 gm. Sectioned surface is fleshly with accentuation of normal lobulations but with retained normal shape.
Microscopically, the classic form shows the following features:
There is extensive infiltration of the gland by lymphocytes, plasma cells, immunoblasts and macrophages, with formation of lymphoid follicles having germinal centres.
There is decreased number of thyroid follicles, which are generally atrophic and are often devoid of colloid.
The follicular epithelial cells are transformed into their degenerated state termed Hurthle cells (Askanazy cells). These cells have abundant oxyphilic or eosinophilic and granular cytoplasm due to large number of mitochondria and may cantain large nuclei.
There is slight fibrous thickening of the septa separating the thyroid lobules.
Hashimoto thyroids proceed to primary atrophic thyroiditis or lead to carcinoma.
Riedel’s thyroiditis
Riedel’s thyroiditis is characterised by stony-hard thyroid that is densenly adherent to the adjacent structures in the neck.
The etiology is inknown.
Macroscopically, the thyroid gland is contracted, stony-hard, assemetric and adherent to the adjasent structures. Cut section is hard and devoid of lobulations.
Microscopically: extensive fibrocollagenous replacement, atrophy of thyroid tissue, locally scattered lymphocytic infiltration and invasion of the adjusent muscle by the process.
Diabetes mellitus
Diabetes mellitus is a chronic clinical syndrome characterised by hyperglycemia due to deficiency or defective response to insulin.
This is classified into:
1. Spontaneous diabetes mellitus is an independent disease and can be of 2 types:
Type I (insulin- dependent).
Type 2 (insulin-independent).
2. Secondary diabetes may occur in pancreatic diseases, acromegaly, Itsenko-Cushing disease, and complicated genetic syndromes, at administration of some “drugs”.
3. Diabetes of pregnant occurs during pregnancy.
4. Latent (subclinical) diabetes is not evident.
Etiopathogenetic factors:
Genetically determined disturbances of the number and structure of beta-cells.
Environmental factors, which disturb beta-cell nutrition (bacteria, viruses, autoimmune reactions), increase of activity of adrenergetic nervous system.
Risk factors of different kinds of spontaneous diabetes are different.
Pathogenesis
Insulin insufficiency increases blood glucose amount because cellular membranes are closed for glucose - hyperglycemia and glucosuria develop. Considerable amount of sugar is formed from the fats and proteins causing hyperlipidaemia, aceton- and ketonemia.
Morphology
The pancreas is diminished with lipomatosis and sclerosis.
Degeneration and hyalinosis are observed in the islets, some of them are hypertrophic.
The liver is enlarged, glycogen is absent, fat degeneration is observed.
Diabetic macro- and microangiopathy is seen in the vessels.
Macroangiopathy is arterial atherosclerosis.
Microangiopathy is characterized by plasmatic saturation, hyalinosis, and sclerosis with lipohyalin.
Vasculitis takes place.
There is generalized microangiopathy in the kidneys, retina, skeletal muscles, digestive tract mucosa, pancreas, brain, and nerves.
In the kidneys, diabetic glomerulonephritis and glomerulosclerosis develop.
Microscopically proliferation of mesangial cells in response to mesangium clogging with “ballast” metabolic products and immune complexes are observed. Mesangium hyalinosis and glomerulosclerosis take place.
Diabetic glomerulosclerosis may be diffuse and nodular as well as mixed type. Its clinical manifestations are Kimmelstiel-Wilson syndrome (proteinuria, edema, increased arterial pressure).
In the lungs, lipogranulomas consisting of macrophages and gigantic cell of foreign bodies are present in the walls of the arteries.
In the spleen, liver, lymphatic glands: infiltration of brstiomacrophagal system and skin with cell lipids (xantomatosis) develop.
Complications:
Diabetic coma.
Accompanied with macroangiopathy: gangrene of extremities, myocardial infarction.
Diabetic nephropathy (acute and chronic renal failure).
Diabetic retinopathy is a leading cause of blidness.
Infectious sepsis.
The death is caused by coma, diabetic glomerulosclerosis, gangrene.
PRENATAL PATHOLOGY
The period of fetus development beginning with the moment of fertilization to the birth of the child is called Prenatal period.
Duration of the prenatal period is 40 weeks (280 days) or 10 lunar months or 9 calendar’s months.
Fetal pathology, which occurs in this period, is called prenatal pathology.
The case of fetal death before the 14th week of gestation is called abortion that within the period of 14-22 weeks is called late abortion. If the fetus dies on the 22nd week or later (until the delivery or during it), the case is called mortinatality.
The normal and pathologic development and growth can be divided into the following stages:
1. Progenesis is characterised by gametogenesis, i.e.formation and maturation of the gametes. It stage occurs before the fertilization of the ovum. Pathology of gametogenesis is called gametopathy.
2. Development after fertilization is called kymatogenesis. This intrauterine phase can be divided into:
a) Blastogenesis from Day 1 to Day 15 of gestation. Pathology of blastogenesis is called blastopathy.
b) Embryogenesisfrom Day 16 to the end of the 3rd month (75th day). Pathology of embryogenesis is called embryopathy.
c) Fetogenesis from the 4rd month of gestation to delivery (from 76th to 280th day). Pathology of fetogenesis is called fetopathy.
Gametopathy
Gametopathy is an injury of formation and maturation of the gametes during ovo- and spermatogenesis until fertilization.
Gametopathy occurs in gene mutations and chromosomal aberrations. At present about 150 autosomal recessive genetic defects and 200 defects with autosomal dominant inheritance are known. There are also defects connected with sex X chromosome.
Chromosome mutations are called chromosomal aberrations. Virtually all the chromosomal syndromes are characterized by congenital anomalies.
Genetic injuries in origin can be deviled into three groups:
a) Those associated with karyotypic aberrations.
b) These arising in single gene mutations.
c) Those suspected of resulting from multifactorial inheritance, a term that implies the interaction of two or more genes of small effect with environmental factors.
The most frequent is trisomy 21 (Down syndrome) and trisomy 13 (Patau’s syndrome), trisomy 18 (Edward’s syndrome), Klinefelter’s syndrome, Turner’s syndrome.
Down’s syndrome
Down syndrome is the most common of the chromosomal disorders and a major cause of mental retardation.
The risk of the development of Down syndrome increases with maternal age.
It is a disorder associated with autosomes.
Trisomy 21 type – 47XXC2 or 47XXYC1. The majority of cases of Down’s syndrome are due to nondisjunction of maternal meiosis.
Currently more than 80% survive to age 30 or beyond.
The most causes of death are interrcurrent infections or cardiac insufficiency.
Gross appearance:
Short stature.
Muscle hypotonia.
Hyperflexibility of joints and lack of Maro reflex.
Short crooked fifth finger.
Short broad hands with a single simian crease on the palm.
Flat facial profile.
Low-bridged nose.
Dysplastic ears.
Reduced interpupillary distance.
Oblique palpebral fissures.
Epicanthic folds.
Brushfield spots (the iris may be speckled).
The mouth is often open and protruding tongue.
Clinical significances:
Mental retardation is usually severe.
Low intelligence.
May be leukemia.
Patients with Down syndrome have abnormal immune responses that predispose them to serious infections, particularly of the lungs.
Virtually all patients with trisomy 21 older than 40 years of age develop neutropathologic changes characteristic of Alzheimer disease, a form of senile dementia.
Thyroid dysfunction: hyperthyroidism, goiter, and hypothyroidism.
Congenital heart defects.
Gastrointestinal anomalies.
Edward’s syndrome
Trisomy 18E – 47XXE or 47XYE.
May die in the neonatal period, and the majority do not survive beyong 1 year.
Survivors have severe mental retardation and failure to thrive.
Characteristics:
Hypertonicity.
Prominent occiput.
Micrognathia and low-set ears.
Flexion of fingers (index over third).
Short sternum and small pelvis.
Abnormalities of the hips and feet (syndactyly), rocker-bottom feet.
Cardiac defects: patent, ductus arteriosus and interventricular septal defects.
Renal malformations.
Meckel’s diverticulum.
Absence of the corpus callosum and incomplete development of the cerebellum.
Patau’s syndrome
Trisomy 13D – 47XXD or 47XYD occurs at frequency of 1 in 20000 births.
Most children die in the first month, and those who survive have severe mental retardation.
Characteristics:
Microphaly and archinencephaly.
Scalp defect.
Coloboma of the iris.
Microphtalmos.
Anophtalmos.
Cleft palate.
Hair lip.
Polydactyly.
Hemangiomas of the head.
Neck and lower back.
Rocker-bottom feet.
Apneic spells and myoclinic seizures.
Cardiac dextraposition and interventricular septal defect.
Extensive visceral defects: polycystic of kidneys, ectopia of spleen into pancreas; double uterus and vagina.
Turner’s syndrome
It is gonadal dysgenesis (defective second X chromosome – 45 X0).
Somatic anomalies:
Short stature.
Primary amenorrhea.
Webbing of the neck.
Cubitus valgus (an increase in carrying angle of the arm).
Shield – like chest with widely spaced nipples.
Coarctation of the aorta.
Webbing of the digits or of the axillae.
Senile facies.
High-arched palate.
Low-set ears.
Peripheral lymphedema at birth.
Pigmented nevi.
Low posterior hairline.
Uterus, ovarium and fallopian tubes are infantile.
Secondary sex characteristics are absent.
Characteristic laboratory and morphologic findings are:
Negative sex chromatin test.
Ovaries are replaced by white “streaks” of fibrous stroma devoid of follicles.
Reduced levels of ovarian estrogenes.
Increased gonadotropin.
Clinical significans:
It is an important cause of sterility in the female.
Normal intelligence.
Blastopathy
Blastopathies occur during the first 15 days from the moment of fertilization.
The most frequent cause of blastopathy is chromosomal aberration in combination with harmful effect of environmental factors.
Manifestations of blastopathies are different:
a) Superficial or deep implantation of blastocyst (causes defects of development, shape, localization of placenta).
b) Disturbance of embryo orientation (umbilical-cord defects are the most frequent).
c) Empty embryo sacs (blastocytes without an embryo).
d) Double malformations are reduplicated embrional primordial that are either primary or the result of later devision. They may be independent of each other, i.e. they may be connecting only by the placenta or the umbilical cord, or they may be in direct bodily contact. Usually they cannot live.
Double malformations may be free and conjoined:
I. Free double malformations are designated as twins (gemini). They may be identical and fully developed (monosigotes twins), or they may be malformed. Holocardius Acephalus is the most frequent of the free double malformations in which only the trunk and lower extremities are clearly identifiable, while the head is absent.
II. Conjoined double malformations occur:
1. Asymmetric (parasitic) or heteropagus (one of the twins is underdeveloped). Asymmetrical double monsters have one well developed and one rudimentary or hypoplastic twin. The rudimentary twin is always abnormal, and is either externally attached to or internally included in the body of the better-developed sibling (fetus in fetu). Some of the congenital teratomas, especially those in the sacrococcygeal area, are actually asymmetrical monsters. Teratomas are regarded as asymmetric monsters.
2. Symmetric forms or diplopagus represent two equally well developed embrional primordial that are connected to each other by a partial fusion of tissues. They may be:
a) Incomplete individuals result from extensive fusion i.e., there is only an incomplete reduplication of the body axis. This type of malformation includes the dicephalus (to spinal columns but only one pelvis).
b) Completesymmetrical double malformations show a partial fusion between two generally mature fetuses. The important feature is the reduplication of the body axis (head, trunk, or spinal column). It is called cephalopagus, diprosopus (reduplication of the face), craniopagus, thoracopagus, and ischiopagus (“Siamese twins”).
Embryopathy
Embryopathy is a pathology developed within the period of 16 - 75 days and occurs by the development of the congenital malformations.
Congenital malformations are morphologic defects that are present at birth, although they may not become clinically apparent until later in life. The term congenital does not imply or exclude a genetic basis for malformations. It is estimated that about 3% of newborns have a major malformation, defined as a malformation having either cosmetic or functional significance.
Pathologic development is connected with the termination period in which the causative agent acts. Each organ has its own period of teratogenic factor action. This period is called teratogenic termination period.
Causes of the congenital malformations
I. Environmental influences, such as viral infections, drugs, and irradiation, to which the mother was exposed during pregnancy, may induce malformations in the fetus and infant.
TORCH infections are caused by Toxoplasma (T), rubella (R), cytomegalovirus (C), herpes virus (H), and a number of other (O) bacterial and viral agents. The latter include fever, encephalitis, chorioretinitis, hemolytic anemia, hepatosplenomegaly, pneumonitis, myocarditis, and vesicular/hemorrhagic skin lesions. Such infections, occurring early in gestation may also cause chronic sequelae in the child, including growth and mental retardation, cataracts, congenital cardiac anomalies, and bone defects.
A variety of drugs and chemicals have been suspected to be teratogenic. The list includes thalidomide, folate antagonists, androgenic hormones, alcohol, anticonvulsants, warrafin (oral anticoagulant).
Radiation.
II. Genetic factors.
Any congenital defect may manifest as one of the following changes:
Agenesis is the complete absence of an organ pri-mordium.
Aplasia is absence of the organ coupled with persistence of the organ anlage or a rudiment that never developed completely.
Hypoplasia refers to reduce size due to the incomplete development of the organ.
Dysraphic anomalies are defects caused by failure to fuse. Spina bifida is an anomaly in which the spinal canal has not closed completely and the overlaying bone and skin have not fused, thus leaving a midline defect.
Involution failures are defects due to the persistence of embryonic or fetal structures that should involute at certain stages of development.
Division failures are defects caused by incomplete cleavage, when that process depends on the involution and programmed death of cells. Fingers and toes are formed at the distal end of the limb bud through programmed death of cells between the primordia that contain the cartilage. If these cells do not die in a predetermined manner, the fingers will be conjoined or incompletely separated (“syndactyly”).
Atresia refers to defects caused by incomplete formation of a lumen. Many hollow organs originate as strands and cords of cells, the centers of which are programmed to die, thus forming a central cavity or lumen. Atresia of the esophagus is characterized by partial occlusion of the lumen, which was not fully established in embryogenesis.
Dysplasia is a defect caused by abnormal organization of cells into tissues, a situation that results in abnormal histogenesis.
Ectopia or heterotopia is an anomaly in which an organ is outside its normal anatomical site. Thus, ectopic heart is located outside the thorax. Heterotopic parathyroid glands can be located within the thymus in the anterior mediastinum.
Classification of congenital defects
1. According to the character of involvement.
Isolated (one organ).
Systemic (several organs of one system).
Multiple (in different organs and systems).
2. According to localization.
Central nervous system.
Cardiovascular system.
Alimentary tract.
Urinary system, etc.
Central nervous system, and cardiovascular system are most frequently involved because these systems have the longest teratogenic terminal period, from the 18th day to the 50th day.
Malformations of the nervous system
I. Errors of fusion
Craniorachischisis totalis due to failure closure of the neural tube the convexity of the skull is absent and the spine is represented only by it’s bodies with no posterior covering.
Spina bifida occulta due to the failure of closure of the sacral bones (rachischisis):
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