NEET MDS Lessons
General Pathology
Hyperparathyroidism
Abnormally high levels of parathyroid hormone (PTH) cause hypercalcemia. This can result from either primary or secondary causes. Primary hyperparathyroidism is caused usually by a parathyroid adenoma, which is associated with autonomous PTH secretion. Secondary hyperparathyroidism, on the other hand, can occur in the setting of chronic renal failure. In either situation, the presence of excessive amounts of this hormone leads to significant skeletal changes related to a persistently exuberant osteoclast activity that is associated with increased bone resorption and calcium mobilization. The entire skeleton is affected. PTH is directly responsible for the bone changes seen in primary hyperparathyroidism, but in secondary hyperparathyroidism additional influences also contribute. In chronic renal failure there is inadequate 1,25- (OH)2-D synthesis that ultimately affects gastrointestinal calcium absorption. The hyperphosphatemia of renal
failure also suppresses renal α1-hydroxylase, which further impair vitamin D synthesis; all these eventuate in hypocalcemia, which stimulates excessive secretion of PTH by the parathyroid glands, & hence elevation in PTH serum levels.
Gross features
• There is increased osteoclastic activity, with bone resorption. Cortical and trabecular bone are lost and replaced by loose connective tissue.
• Bone resorption is especially pronounced in the subperiosteal regions and produces characteristic radiographic changes, best seen along the radial aspect of the middle phalanges of the second and third fingers.
Microscopical features
• There is increased numbers of osteoclasts and accompanying erosion of bone surfaces.
• The marrow space contains increased amounts of loose fibrovascular tissue.
• Hemosiderin deposits are present, reflecting episodes of hemorrhage resulting from microfractures of the weakened bone.
• In some instances, collections of osteoclasts, reactive giant cells, and hemorrhagic debris form a distinct mass, termed "brown tumor of hyperparathyroidism". Cystic change is common in such lesions (hence the name osteitis fibrosa cystica). Patients with hyperparathyroidism have reduced bone mass, and hence are increasingly susceptible to fractures and bone deformities.
Connective tissue diseases
Marfan’s syndrome
a. Genetic transmission: autosomal dominant.
b. Characterized by a defective microfibril glycoprotein, fibrillin.
c. Clinical findings include tall stature, joints that can be hyperextended, and cardiovascular defects, including mitral valve prolapse and dilation of the ascending aorta.
Ehlers-Danlos syndrome
a. Genetic transmission: autosomal dominant or recessive.
b. This group of diseases is characterized by defects in collagen.
c. Clinical findings include hypermobile joints and highly stretchable skin. The skin also bruises easily. Oral findings include Gorlin’s sign and possible temporomandibular joint (TMJ) subluxation.
The oral mucosa may also appear more fragile and vulnerable to trauma.
Neutrophilia
Causes
-Pyogenic infections.
-Haemorrhage and trauma.
-Malignancies.
-Infarction.
-Myelo proliferative disorders.
Autoimmune Diseases
These are a group of disease where antibodies (or CMI) are produced against self antigens, causing disease process.
Normally one's immune competent cells do not react against one's own tissues. This is due to self tolerance acquired during embryogenesis. Any antigen encountered at that stage is recognized as self and the clone of cells capable of forming the corresponding antibody is suppressed.
Mechanism of autoimmunity
(1) Alteration of antigen
-Physicochemical denaturation by UV light, drugs etc. e.g. SLE.
- Native protein may turn antigenic when a foreign hapten combines with it, e.g. Haemolytic anemia with Alpha methyl dopa.
(2) Cross reaction: Antibody produced against foreign antigen may cross react with native protein because of partial similarity e.g. Rheumatic fever.
(3) Exposure of sequestered antigens: Antigens not normally exposed to immune competent cells are not accepted as self as tolerance has not been developed to them. e.g. thyroglobulin, lens protein, sperms.
(4) Breakdown of tolerance :
Emergence of forbidden clones (due to neoplasia of immune system as in lymphomas and lymphocytic leukaemia)
Loss of suppressor T cells as in old age and CMI defects
Autoimmunity may be
Organ specific.
Non organ specific (multisystemic)
I. Organ specific
(1) Hemolytic anaemia:
Warm or cold antibodies (active at 37° C or at colder temperature)
They may lyse the RBC by complement activation or coat them and make them vulnerable to phagocytosis
(2) Hashimoto's thyroiditis:
Antibodies to thyroglobulin and microsomal antigens.
Cell mediated immunity.
Leads to chronic. destructive thyroiditis.
(3) Pernicious anemia
Antibodies to gastric parietal cells and to intrinsic factor.
2. Non organ specific.
Lesions are seen in more than one system but principally affect blood vessels and
connective tissue (collagen diseases).
1. Systemic lupus erythematosus (SLE). Antibodies to varied antigens are seen. Hence it is possible that there is abnormal reactivity of the immune system in self recognition.
Antibodies have been demonstrated against:
Nuclear material (antinuclear I antibodies) including DNA. nucleoprotein etc. Anti nuclear antibodies are demonstrated by LE cell test.
Cytoplasmic organelles- mitochondria, rib osomes, Iysosomes.
Blood constituents like RBC, WBC. platelets, coagulation factors.
Mechanism. Immune complexes of body proteins and auto antibodies deposit in various
organs and cause damage as in type III hypersensitivity
Organs involved
Skin- basal dissolution and collagen degeneration with fibrinoid vasculitis.
Heart- pancarditis.
Kidneys- glomerulonephritis of focal, diffuse or membranous type
Joints- arthritis.
Spleen- perisplenitis and vascular thickening (onion skin).
Lymph nodes- focal necrosis and follicular hyperplasia.
Vasculitis in other organs like liver, central or peripheral nervous system etc,
2. Polyarteritis nodosa. Remittant .disseminated necrotising vasculitis of small and medium sized arteries
Mechanism :- Not definitely known. Proposed immune reaction to exogenous or auto antigens
Lesion : Focal panarteritis- a segment of vessel is involved. There is fibrinoid necrosis
with initially acute and later chronic inflammatory cells. This may result in haemorrhage
and aneurysm.
Organs involved. No organ or tissue is exempt but commonly involved organs are :
- Kidneys.
- Heart.
- Spleen.
- GIT
3. Rheumatoid arthritis. A disease primarily of females in young adult life.
Antibodies
- Rheumatoid factor (An IgM antibody to self IgG)
- Antinuclear antibodies in 20% patients.
Lesions
- Arthritis which may progress on to a crippling deformity.
- Arteritis in various organs- heart, GIT, muscles.
- Pleuritis and fibrosing alveolitis.
- Amyloidosis is an important complication.
4. Sjogren's Syndrome. This is constituted by
- Kerato conjunctivitis sicca
-Xerostomia
-Rheumatoid arthritis.
Antibodies
- Rheumatoid factor
- Antinuclear factors (70%).
- Other antibodies like antithyroid, complement fixing Ab etc
- Functional defects in lymphocytes. There is a higher incidence of lymphoma
5. Scleroderma (Progressive systemic sclerosis)
Inflammation and progressive sclerosis of connective tissue of skin and viscera.
Antibodies
- Antinuclear antibodies.
- Rheumatoid factor. .
- Defect is cell mediated.
lesions
Skin- depigmentation, sclerotic atrophy followed by cakinosis-claw fingers and mask face.
Joints-synovitis with fibrosis
Muscles- myositis.
GIT- diffuse fibrous replacement of muscularis resulting in hypomotility and malabsorption
Kidneys changes as in SLE and necrotising vasculitis.
Lungs – fibrosing alveolitis.
Vasculitis in any organ or tissue.
6.Wegener’s granulomatosis. A complex of:
Necrotising lesions in upper respiratory tract.
Disseminated necrotising vasculitis.
Focal or diffuse glomerulitis.
Mechanism. Not known. It is classed with autoimmune diseases because of the vasculitis resembling other immune based disorders.
Erythema multiforme is a hypersensitivity reaction to an infection (Mycoplasma), drugs or various autoimmune diseases.
- probable immunologic disease
- lesions vary from erythematous macules, papules, or vesicles.
- papular lesions frequently look like a target with a pale central area.
- extensive erythema multiforme in children is called Stevens-Johnson syndrome, where there is extensive skin and mucous membrane involvement with fever and respiratory symptoms.
Systemic Candidiasis (Candidosis; Moniliasis)
Invasive infections caused by Candida sp, most often C. albicans, manifested by fungemia, endocarditis, meningitis, and/or focal lesions in liver, spleen, kidneys, bone, skin, and subcutaneous or other tissues.
Infections due to Candida sp account for about 80% of all major systemic fungal infections.
Symptoms and Signs
Esophagitis is most often manifested by dysphagia. Symptoms of respiratory tract infections are nonspecific, such as cough. Vaginal infections cause itching, burning, and discharge. Candidemia usually causes fever, but other symptoms are typically nonspecific. Sometimes, a syndrome develops resembling bacterial sepsis, with a fulminating course that may include shock, oliguria, renal shutdown, and disseminated intravascular coagulation.
Hematogenous endophthalmitis starts as white retinal plaques that can cause blindness as destructive inflammation progresses, extending to opacify the vitreous and causing potentially irreversible scarring. Most often, there are no symptoms in early stages of Candida endophthalmitis. If treatment is not begun before symptoms appear, significant or even total loss of vision is likely to occur in the affected eye. In neutropenic patients, eye involvement is more often manifested by retinal hemorrhages; papulonodular, erythematous, and vasculitic skin lesions may also develop.
Metastatic Tumors
These are the most common malignant tumor of bone. Certain tumors exhibit a distinct skeletal prediliction. In adults more than 75% of skeletal metastases originate from cancers of the prostate, breast, kidney, and lung. In children, neuroblastoma, Wilms' tumor, osteosarcoma, Ewing sarcoma, and rhabdomyosarcoma are the common sources of bony metastases. Most metastases involve the axial skeleton (vertebral column, pelvis, ribs, skull, sternum), proximal femur, and humerus. The radiologic appearance of metastases can be purely osteolytic, purely osteoblastic, or mixed osteolytic-osteoblastic (majority of cases). In lytic lesions (e.g., kidney& lung), the metastatic cells secrete substances such as prostaglandins, interleukins, etc. that stimulate osteoclastic bone resorption; the tumor cells themselves do not directly resorb bone. Similarly, metastases that elicit a blastic response (e.g., prostate adenocarcinoma) do so by stimulating osteoblastic bone formation.