NEET MDS Lessons
General Pathology
DIABETES MELLITUS
a group of metabolic disorders sharing the common underlying characteristic of hyperglycemia.
Diabetes is an important disease because
1. It is common (affects 7% of the population).
2. It increases the risk of atherosclerotic coronary artery and cerebrovascular diseases.
3. It is a leading cause of
a. Chronic renal failure
b. Adult-onset blindness
c. Non traumatic lower extremity amputations (due to gangrene)
Classification
Diabetes is divided into two broad classes:
1. Type1 diabetes (10%): characterized by an absolute deficiency of insulin secretion caused by pancreatic βcell destruction, usually as a result of an autoimmune attack.
2. Type2 diabetes (80%): caused by a combination of peripheral resistance to insulin action and an inadequate secretion of insulin from the pancreatic β cells in response to elevated blood glucose levels.
The long-term complications in kidneys, eyes, nerves, and blood vessels are the same in both types.
Pathogenesis
Type 1 diabetes is an autoimmune disease and as in all such diseases, genetic susceptibility and environmental influences play important roles in the pathogenesis. The islet destruction is caused primarily by T lymphocytes reacting against immunologic epitopes on the insulin hormone located within β-cell; this results in a reduction of β-cell mass. The reactive T cells include CD4+ T cells of the TH1 subset, which cause tissue injury by activating macrophages, and CD8+ cytotoxic T lymphocytes; these directly kill β cells and also secrete cytokines that activate further macrophages. The islets show cellular necrosis and lymphocytic infiltration (insulitis). Autoantibodies against a variety of β-cell antigens, including insulin are also detected in the blood and may also contribute to islet damage.
Type 2 Diabetes Mellitus: the pathogenesis remains unsettled. Environmental influences, such as inactive life style and dietary habits that eventuates in obesity, clearly have a role. Nevertheless, genetic factors are even more important than in type 1 diabetes. Among first-degree relatives with type 2 diabetes the risk of developing the disease is 20% to 40%, as compared with 5% in the general population.
The two metabolic defects that characterize type 2 diabetes are 1. A decreased ability of peripheral tissues to respond to insulin (insulin resistance) and 2. β-cell dysfunction manifested as inadequate insulin secretion in the face of hyperglycemia. In most cases, insulin resistance is the primary event and is followed by increasing degrees of β-cell dysfunction.
Morphology of Diabetes and Its Late Complications
The important morphologic changes are related to the many late systemic complications of diabetes and thus are likely to be found in arteries (macrovascular disease), basement membranes of small vessels (microangiopathy), kidneys (diabetic nephropathy), retina (retinopathy), and nerves (neuropathy). These changes are seen in both type 1 and type 2 diabetes.
The changes are divided into pancreatic & extrapancreatic
A. Pancreatic changes are inconstant and are more commonly associated with type 1 than with type 2 diabetes.
One or more of the following alterations may be present.
1. Reduction in the number and size of islets
2. Leukocytic infiltration of the islets (insulitis) principally byT lymphocytes.
3. Amyloid replacement of islets; which is seen in advanced stages
B. Extrapancreatic changes
1. Diabetic macrovascular disease is reflected as accelerated atherosclerosis affecting the aorta and other large and medium-sized arteries including the coronaries. Myocardial infarction is the most common cause of death in diabetics. Gangrene of the lower limbs due to advanced vascular disease, is about 100 times more common in diabetics than in the general population.
2. Hyaline arteriolosclerosis
is the vascular lesion associated with hypertension. It is both more prevalent and more severe in diabetics than in nondiabetics, but it is not specific for diabetes and may be seen in elderly nondiabetics without hypertension.
3. Diabetic microangiopathy
is one of the most consistent morphologic features of diabetes, which reflected morphologically as diffuse thickening of basement membranes. The thickening is most evident in the capillaries of the retina, renal glomeruli, and peripheral nerves. The thickened capillary basement membranes are associated with leakiness to plasma proteins. The microangiopathy underlies the development of diabetic nephropathy, retinopathy, and some forms of neuropathy.
4. Diabetic Nephropathy: renal failure is second only to myocardial infarction as a cause of death from diabetes.
Three lesions encountered are:
1. Glomerular lesions
2. Renal vascular lesions, principally arteriolosclerosis; and
3. Pyelonephritis, including necrotizing papillitis.
Glomerular lesions: these include
a. diffuse glomerular capillary basement membrane thickening
b. diffuse glomerular sclerosis : diffuse increase in mesangial matrix; always associated with the above.
c. nodular glomerulosclerosis (Kimmelstiel-Wilson lesion) refers to a rounded deposits of a laminated matrix situated in the periphery of the glomerulus
Pyelonephritis: both acute and chronic pyelonephritis are more common & more severe
Ocular Complications of Diabetes: Visual impairment up to total blindness may occur in long-standing diabetes. The ocular involvement may take the form of
a. retinopathy
b. cataract formation
c. glaucoma
In both forms of long-standing diabetes, cardiovascular events such as myocardial infarction, renal vascular insufficiency, and cerebrovascular accidents are the most common causes of mortality. Diabetic nephropathy is a leading cause of end-stage renal disease. By 20 years after diagnosis, more than 75% of type 1 diabetics and about 20% of type 2 diabetics with overt renal disease will develop end-stage renal disease, requiring dialysis or renal transplantation.
Diabetics are plagued by an enhanced susceptibility to infections of the skin, as well as to tuberculosis,
pneumonia, and pyelonephritis. Such infections cause the deaths of about 5% of diabetics.
Aneurysm
An aneurysm is a localized abnormal dilation of a blood vessel or the heart
Types:
1. True aneurysm - it involves all three layers of the arterial wall (intima, media, and adventitia) or the attenuated wall of the heart.
e.g. Atherosclerotic, syphilitic, and congenital aneurysms, and ventricular aneurysms that follow transmural myocardial infarctions.
2 False aneurysm
(also called pseudo-aneurysm) is a breach in the vascular wall leading to an extravascular hematoma that freely communicates with the intravascular space ("pulsating hematoma").
E.g. ventricular ruptures after MI that are contained by a pericardial adhesion
E.g. a leak at the junction of a vascular graft with a natural artery.
Aneurysms are classified by macroscopic shape and size
Saccular aneurysms
spherical outpouchings (involving only a portion of the vessel wall, and often contain thrombi.
Fusiform aneurysms
diffuse, circumferential dilation of a long vascular segment;
they vary in diameter and length and can involve extensive portions of the aortic arch, abdominal aorta, or even the iliacs.
Aortic Aneurysm
The two most important causes are:
1- atherosclerosis : the most common cause
It causes thinning and weakening of the media. The intimal plaques compress the underlying media and also compromise nutrient and waste diffusion from the vascular lumen into the arterial wall. The media consequently undergoes degeneration and necrosis, thus allowing the dilation of the vessel
2- cystic medial degeneration of the arterial media. E.g. Marfan syndrome.
3- Other causes include: trauma, congenital defects (e.g., berry aneurysms), infections (mycotic aneurysms), systemic diseases, such as vasculitis.
Mycotic Aneurysm :
Infection of a major artery that weakens its wall is called a mycotic aneurysm
possible complications: thrombosis and rupture.
It can originate from:
(1) embolization of a septic thrombus, usually as a complication of infective endocarditis
(2) extension of an adjacent suppurative process;
(3) circulating organisms directly infecting the arterial wall
Mycotic AAAs are atherosclerotic lesions infected by lodging of circulating microorganisms in the wall
- e.g. bacteremia from a primary Salmonella gastroenteritis.
Abdominal Aortic Aneurysm
Atherosclerotic aneurysms occur most frequently in the abdominal aorta ,the common iliac arteries, the arch, and descending parts of the thoracic aorta can also be involved
Pathogenesis
AAA occurs more frequently in men and rarely develops before age 50.
Atherosclerosis is a major cause of AAA
hereditary defects in structural components of the aorta (e.g., defective fibrillin production in Marfan disease affects elastic tissue synthesis)
Morphology :
Usually positioned below the renal arteries and above the bifurcation of the aorta
AAA can be saccular or fusiform
as large as 15 cm in diameter, and as long as 25 cm.
Microscopically: atherosclerosis with destruction and thinning of the underlying aortic media
the aneurysm frequently contains a laminated mural thrombus
Syphilitic Aneurysm
Caused by The spirochetes T. pallidum
Tertiary stage of syphilis can cause obliterative endarteritis of the involve small vessels in any part of the body, including the vasa vasorum of the aorta
This results in ischemic medial injury, leading to aneurysmal dilation of the aorta and aortic annulus, and eventually valvular insufficiency.
valvular insufficiency and massive volume overload lead to hypertrophy of the left ventricle. The greatly enlarged hearts are sometimes called "cor bovinum" (cow's heart).
CLINICAL CONSEQUENCES
1. Rupture → massive potentially fatal hemorrhage
2. Obstruction of downstream vessel → tissue ischemic injury
3. Embolism → from atheroma or mural thrombus
4. Impingement and compression on an adjacent structure
5. Presentation as an abdominal mass
Viral meningitis
1. Can be caused by many different viruses, including cytomegalovirus, herpes virus, rabies, and HIV.
2. CSF fluid from a spinal tap differs from that seen in a bacterial infection. It shows mononuclear cells, higher levels of protein, and normal levels of glucose.
TOXOPLASMOSIS
Infection with Toxoplasma gondii, causing a spectrum of manifestations ranging from asymptomatic benign lymphadenopathy to life-threatening CNS disease, chorioretinitis, and mental retardation.
Symptomatic infections may present in several ways
Acute toxoplasmosis may mimic infectious mononucleosis with lymphadenopathy, fever, malaise, myalgia, hepatosplenomegaly, and pharyngitis. Atypical lymphocytosis, mild anemia, leukopenia, and slightly abnormal liver function tests are common. The syndrome may persist for weeks or months but is almost always self-limited.
A severe disseminated form characterized by pneumonitis, myocarditis, meningoencephalitis, polymyositis, diffuse maculopapular rash, high fevers, chills, and prostration. Acute fulminating disease is uncommon.
Congenital toxoplasmosis usually results from a primary (and often asymptomatic) acute infection acquired by the mother during pregnancy. The risk of transplacental infection increases from 15% to 30 to 60% for maternal infections acquired in the 1st, 2nd, or 3rd trimester of gestation, respectively
Alzheimer’s disease
a. The most common cause of dementia in older people.
b. Characterized by degeneration of neurons in the cerebral cortex.
c. Histologic findings include amyloid plaques and neurofibrillary tangles.
d. Clinically, the disease takes years to develop and results in the loss of cognition, memory, and the ability to ommunicate. Motor problems, contractures, and paralysis are some of the symptoms at the terminal stage.
Growth and spread of tumours
Growth in excess of normal is a feature of all tumours but extension to tissue away from the site of origin is a feature of malignant tumours.
Modes of spread of malignant tumours
- local, invasion. This is a feature of all malignant tumors and takes place along tissue spaces and facial planes
o Lymphatic spread. Most often seen in carcinomas. This can be in the form of
o Lymphatic permeation: Where the cells extend along the lymphatics as a solid core
o Lymphatic embolisation: Where a group of tumour cells break off and get carried to the draining mode
-Vascular spread : This is a common and early mode of spread for sarcomas but certain carcinomas like renal cell carcinoma and chorio carcinoma have a predilection to early vascular spread.
Vascular spread is most often due .to invasion of venous channels and can be by permeation or embolisation.
Lungs, liver, bones and brain are the common sites for vascular metastasis but
different tumours have different organ preference for metastasis, e.g. : Bronchogenic carcinoma often spreads to liver and adrenals.
-Body cavities and natural passages
o Gastrointestinal carcinomas spread to ovaries (Krukenberg’s tomour)
Acne vulgaris is a chronic inflammatory disorder usually present in the late teenage years characterized by comedones, papules, nodules, and cysts.
- subdivided into obstructive type with closed comedones (whiteheads) and open comedones (blackheads) and the inflammatory type consisting of papules, pustules, nodules, cysts and scars.
- pathogenesis of inflammatory acne relates to blockage of the hair follicle with keratin and sebaceous secretions, which are acted upon by Propionibacterium acnes (anaerobe) that causes the release of irritating fatty acids resulting in an inflammatory response.
- pathogenesis of the obstructive type (comedones) is related to plugging of the outlet of a hair follicle by keratin debris.
- chocolate, shellfish, nuts iodized salt do not aggravate acne.
- obstructive type is best treated with benzoyl peroxide and triretnoin (vitamin A acid)
- treatment of inflammatory type is the above plus antibiotics (topical and/or systemic; erythromycin, tetracycline, clindamycin).