NEET MDS Lessons
General Pathology
Osteoporosis
is characterized by increased porosity of the skeleton resulting from reduced bone mass. The disorder may be localized to a certain bone (s), as in disuse osteoporosis of a limb, or generalized involving the entire skeleton. Generalized osteoporosis may be primary, or secondary
Primary generalized osteoporosis
• Postmenopausal
• Senile
Secondary generalized osteoporosis
A. Endocrine disorders
• Hyperparathyroidism
• Hypo or hyperthyroidism
• Others
B. Neoplasia
• Multiple myeloma
• Carcinomatosis
C. Gastrointestinal disorders
• Malnutrition & malabsorption
• Vit D & C deficiency
• Hepatic insufficiency
D. Drugs
• Corticosteroids
• Anticoagulants
• Chemotherapy
• Alcohol
E. Miscellaneous
• osteogenesis imperfecta
• immobilization
• pulmonary disease
Senile and postmenopausal osteoporosis are the most common forms. In the fourth decade in both sexes, bone resorption begins to overrun bone deposition. Such losses generally occur in areas containing abundant cancelloues bone such as the vertebrae & femoral neck. The postmenopausal state accelerates the rate of loss; that is why females are more susceptible to osteoporosis and its complications.
Gross features
• Because of bone loss, the bony trabeculae are thinner and more widely separated than usual. This leads to obvious porosity of otherwise spongy cancellous bones
Microscopic features
• There is thinning of the trabeculae and widening of Haversian canals.
• The mineral content of the thinned bone is normal, and thus there is no alteration in the ratio of minerals to protein matrix
Etiology & Pathogenesis
• Osteoporosis involves an imbalance of bone formation, bone resorption, & regulation of osteoclast activation. It occurs when the balance tilts in favor of resorption.
• Osteoclasts (as macrophages) bear receptors (called RANK receptors) that when stimulated activate the nuclear factor (NFκB) transcriptional pathway. RANK ligand synthesized by bone stromal cells and osteoblasts activates RANK. RANK activation converts macrophages into bone-crunching osteoclasts and is therefore a major stimulus for bone resorption.
• Osteoprotegerin (OPG) is a receptor secreted by osteoblasts and stromal cells, which can bind RANK ligand and by doing so makes the ligand unavailable to activate RANK, thus limiting osteoclast bone-resorbing activity.
• Dysregulation of RANK, RANK ligand, and OPG interactions seems to be a major contributor in the pathogenesis of osteoporosis. Such dysregulation can occur for a variety of reasons, including aging and estrogen deficiency.
• Influence of age: with increasing age, osteoblasts synthetic activity of bone matrix progressively diminished in the face of fully active osteoclasts.
• The hypoestrogenic effects: the decline in estrogen levels associated with menopause correlates with an annual decline of as much as 2% of cortical bone and 9% of cancellous bone. The hypoestrogenic effects are attributable in part to augmented cytokine production (especially interleukin-1 and TNF). These translate into increased RANK-RANK ligand activity and diminished OPG.
• Physical activity: reduced physical activity increases bone loss. This effect is obvious in an immobilized limb, but also occurs diffusely with decreased physical activity in older individuals.
• Genetic factors: these influence vitamin D receptors efficiency, calcium uptake, or PTH synthesis and responses.
• Calcium nutritional insufficiency: the majority of adolescent girls (but not boys) have insufficient dietary intake of calcium. As a result, they do not achieve the maximal peak bone mass, and are therefore likely to develop clinically significant osteoporosis at an earlier age.
• Secondary causes of osteoporosis: these include prolonged glucocorticoid therapy (increases bone resorption and reduce bone synthesis.)
The clinical outcome of osteoporosis depends on which bones are involved. Thoracic and lumbar vertebral fractures are extremely common, and produce loss of height and various deformities, including kyphoscoliosis that can compromise respiratory function. Pulmonary embolism and pneumonia are common complications of fractures of the femoral neck, pelvis, or spine.
Asthma
Asthma is
(1) An obstructive lung disease characterized by narrowing of the airways.
Inflammation of the airways is a major component of asthma.
(2) Common symptoms are dyspnea, wheezing on expiration, and coughing.
(3) Two types:
(a) Extrinsic (allergic, atopic) asthma
(i) An atopic allergy caused by a type I immediate hypersensitivity immune reaction to an allergen.
(ii) Seen in children, adults.
(b) Intrinsic (nonallergic) asthma
(i) Not caused by an allergic reaction.
(ii) Mostly seen in adults.
The disorder is a chronic inflammatory condition in which the airways develop increased responsiveness to various stimuli, characterized by bronchial hyper-responsiveness, inflammation, increased mucus production, and intermittent airway obstruction.
Signs and symptoms
- The clinical hallmarks of an attack are shortness of breath (dyspnea) and wheezing
- A cough—sometimes producing clear sputum—may also be present
- The onset is often sudden; there is a "sense of constriction" in the chest, breathing becomes difficult, and wheezing occurs
- Signs of an asthmatic episode are wheezing, rapid breathing (tachypnea), prolonged expiration, a rapid heart rate (tachycardia), rhonchous lung sounds (audible through a stethoscope), and over-inflation of the chest.
- During very severe attacks asthma sufferer can turn blue due to lack of oxygen , can experience chest pain or even loss of consciousness, may lead to respiratory arrest and death
Pathophysiology
Bronchoconstriction : asthma is the result of an abnormal immune response in the bronchial airways. The airways of asthmatics are "hypersensitive" to certain triggers, also known as stimuli, these stimuli include allergens, medications , air pollution, early child hood infection, exercise, emotional stress
Bronchial inflammation asthma resulting from an immune response to inhaled allergens—are the best understood of the causal factors. In both asthmatics and non-asthmatics, inhaled allergens that find their way to the inner airways are ingested by a type of cell known as antigen presenting cells These activate an humoral immune response. The humoral immune system produces antibodies against the inhaled allergen. Later, when an asthmatic inhales the same allergen, these antibodies "recognize" it and activate a humoral response. Inflammation results: chemicals are produced that cause the airways to constrict and release more mucus, and the cell-mediated arm of the immune system is activated. The inflammatory response is responsible for the clinical manifestations of an asthma attack
Symptomatic Treatment
Episodes of wheeze and shortness of breath generally respond to inhaled bronchodilators which work by relaxing the smooth muscle in the walls of the bronchi., More severe episodes may need short courses of inhaled, oral, or intravenous steroids which suppress inflammation and reduce the swelling of the lining of the airway.
Bronchodilators (usually inhaled)
Short-acting selective beta2-adrenoceptor agonists(salbutamol, terbutaline)
less selective adrenergic agonists, such as inhaled epinephrine and ephedrine tablets
Antimuscarinics
Systemic steroids
Oxygen to alleviate the hypoxia that is the result of extreme asthma attacks.
If chronic acid indigestion ( GERD) is part of the attack, it is necessary to treat it as well or it will restart the inflammatory process
Preventive Treatment
most effective preventive medication are
Inhaled corticosteroids
Long-acting beta2-adrenoceptor agonists
Leukotriene modifiers
Mast cell stabilizers
Methylxanthines (theophylline and aminophylline),
Antihistamines, often used to treat allergic symptoms
Diseases from Str. pyogenes (Group A strep)
1. Streptococcal pharyngitis. Most frequent Group A infection. Throat has gray-white exudate. Infection may become systemic into blood, sinuses, jugular vein, meninges. In less than a week the M-protein and capsule production decrease, and transmission declines.
2. Skin infections, such as impetigo. Especially in children. Different M-proteins than in pharyngitis. Skin infections associated with edema and red streaking (characteristic).
3. Necrotizing fasciitis/myositis. Infection of deeper tissue advances despite antibiotics.
4. Scarlet fever. Caused by phage-associated erythrogenic toxin-producing strains. Toxins cause cardiac, renal, and other systemic failures. Rash is very red with a sand-papery feel and shedding of superficial skin.
5. Toxic Shock Syndrome. Parallels the toxic shock caused by TSST-carrying Staph. aureus.
6. Non-suppurative, post-infection diseases.
Rheumatic fever (myocarditis, cardiac valve disease, polyarthralgia, rashes. Occurs two weeks after a pharyngeal infection)
Glomerulonephritis (Occurs two weeks after pharyngeal or skin infections. Often due to immunologic reaction to M-protein type 12)
Malnutrition
A. Marasmus - calorie malnutrition
A child with marasmus suffers growth retardation and loss of muscle. The loss of muscle mass results from catabolism and depletion of the somatic protein compartment.
With such losses of muscle and subcutaneous fat, the extremities are emaciated; by comparison, the head appears too large for the body. Anemia and manifestations of multivitamin deficiencies are present, and there is evidence of immune deficiency, particularly of T cell-mediated immunity.
B. Kwashiorkor - protein malnutrition - importance of protein quality as well as quantity
Marked protein deprivation is associated with severe loss of the visceral protein compartment, and the resultant hypoalbuminemia gives rise to generalized, or dependent, edema.
The weight of children with severe kwashiorkor is typically 60% to 80% of normal.
However, the true loss of weight is masked by the increased fluid retention (edema).
Children with kwashiorkor have characteristic skin lesions, with alternating zones of hyperpigmentation, areas of desquamation, and hypopigmentation, giving a "flaky paint" appearance.
Hair changes include overall loss of color or alternating bands of pale and darker hair, straightening, line texture, and loss of firm attachment to the scalp.
An enlarged, fatty liver (resulting from reduced synthesis of carrier proteins) and a tendency to develop early apathy, listlessness, and loss of appetite.
The bone marrow in both kwashiorkor and marasmus may be hypoplastic, mainly because of decreased numbers of red cell precursors. How much of this derangement is due to a deficiency of protein and folates or to reduced synthesis of transferrin and ceruloplasmin is uncertain. Thus, anemia is usually present, most often hypochromic microcytic anemia, but a concurrent deficiency of folates may lead to a mixed microcytic-macrocytic anemia.
C. Most cases of severe malnutrition are a combination of A and B usually characterized by:
• Failure of growth
• Behavioral changes
• Edema (kwashiorkor)
• Dermatosis
• Changes in hair
• Loss of appetite
• Liver enlargement
• Anemia
• Osteoporosis
ADRENAL INSUFFICIENCY
Adrenocortical hypofunction is either primary (adrenocrtical) or secondary (ACTH deficiency). Primary insufficiency is divided into acute & chronic.
Acute Adrenocortical Insufficiency occurs most commonly in the following clinical settings
- massive adrenal hemorrhage including Waterhouse-Friderichsen syndrome
- Sudden withdrawal of long-term corticosteroid therapy
- Stress in those with chronic adrenal insufficiency
Massive adrenal hemorrhage may destroy the adrenal cortex sufficiently to cause acute adrenocortical
insufficiency. This condition may occur
1. in patients maintained on anticoagulant therapy
2. in postoperative patients who develop DIC
3. during pregnancy
4. in patients suffering from overwhelming sepsis (Waterhouse-Friderichsen syndrome)
Waterhouse-Friderichsen syndrome is a catastrophic syndrome classically associated with Neisseria meningitidis septicemia but can also be caused by other organisms, including Pseudomonas species, pneumococci & Haemophilus influenzae. The pathogenesis of the syndrome remains unclear, but probably involves endotoxin-induced vascular injury with associated DIC.
Chronic adrenocortical insufficiency (Addison disease) results from progressive destruction of the adrenal cortex. More than 90% of all cases are attributable to one of four disorders:
1. autoimmune adrenalitis (the most common cause; 70% of cases)
2. tuberculosis &fungal infections
3. AIDS
4. Metastatic cancers
In such primary diseases, there is hyperpigmentation of the skin oral mucosa due to high levels of MSH (associated with high levels of ACTH).
Autoimmune adrenalitis is due to autoimmune destruction of steroid-producing cells. It is either isolated associated other autoimmune diseases, such as Hashimoto disease, pernicious anemia, etc.
Infections, particularly tuberculous and fungal
Tuberculous adrenalitis, which once was responsible for as many as 90% of cases of Addison disease, has become less common with the advent of antituberculous therapy. When present, tuberculous adrenalitis is usually associated with active infection elsewhere, particularly the lungs and genitourinary tract. Among fungi, disseminated infections caused by Histoplasma capsulatum is the main cause.
AIDS patients are at risk for developing adrenal insufficiency from several infectious (cytomegalovirus, Mycobacterium avium-intracellulare) and noninfectious (Kaposi sarcoma) complications.
Metastatic neoplasms: the adrenals are a fairly common site for metastases in persons with disseminated carcinomas. Although adrenal function is preserved in most such patients, the metastatic growths sometimes destroy sufficient adrenal cortex to produce a degree of adrenal insufficiency. Carcinomas of the lung and breast are the major primary sources.
Secondary Adrenocortical Insufficiency
Any disorder of the hypothalamus and pituitary, such as metastatic cancer, infection, infarction, or irradiation, that reduces the output of ACTH leads to a syndrome of hypoadrenalism having many similarities to Addison disease. In such secondary disease, the hyperpigmentation of primary Addison disease is lacking because melanotropic hormone levels are low.
Secondary adrenocortical insufficiency is characterized by low serum ACTH and a prompt rise in plasma cortisol levels in response to ACTH administration.
Pathological features of adrenocortical deficiency
- The appearance of the adrenal glands varies with the cause of the insufficiency.
- In secondary hypoadrenalism the adrenals are reduced to small, uniform, thin rim of atrophic yellow cortex that surrounds a central, intact medulla. Histologically, there is atrophy of cortical cells with loss of cytoplasmic lipid, particularly in the zonae fasciculata and reticularis.
- In primary autoimmune adrenalitis there is also atrophy of the cortex associated with a variable lymphoid infiltrate that may extend into the subjacent medulla. The medulla is otherwise normal.
- In tuberculosis or fungal diseases there is granulomatous inflammatory reaction. Demonstration of the responsible organism may require the use of special stains.
- With metastatic carcinoma, the adrenals are enlarged and their normal architecture is obscured by the infiltrating neoplasm.
Acanthosis nigricans is a pigmented skin lesion commonly present in the axilla which is a phenotypic marker for an insulin-receptor abnormality as well as a marker for adenocarcinoma, most commonly of gastric origin.
Pulmonary Hypertension
Sustained elevation of mean pulmonary arterial pressure.
Pathogenesis
Elevated pressure, through endothelial cell dysfunction, produces structural changes in the pulmonary vasculature. These changes ultimately decrease pulmonary blood flow and stress the heart to the point of failure. Based on etiology, pulmonary hypertension is divided into two categories.
Primary (idiopathic): The cause is unknown.
Secondary: The hypertension is secondary to a variety of conditions which increase pulmonary blood flow or increase resistance to blood flow. Example: Interstitial fibrosis.
Pathology
The changes involve large and small pulmonary blood vessels and range from mild to severe. The major changes include atherosclerosis, striking medial hypertrophy and intimal fibrosis of small arteries and arterioles, and plexogenic arteriopathy. Refer to Figure 15-7 in your textbook.
Pathophysiology
Dyspnea and fatigue eventually give way to irreversible respiratory insufficiency, cyanosis and cor pulmonale.