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.
Lysosomal (lipid) storage diseases
- Genetic transmission: autosomal recessive.
- This group of diseases is characterized by a deficiency of a particular lysosomal enzyme. This results in an accumulation of the metabolite, which would have otherwise been degraded by the presence of normal levels of this specific enzyme.
Diseases include:
Gaucher’s disease
(1) Deficient enzyme: glucocerebrosidase.
(2) Metabolite that accumulates: glucocerebroside.
(3) Important cells affected: macrophages.
Tay-Sachs disease
(1) Deficient enzyme: hexosaminidase A.
(2) Metabolite that accumulates: GM2 ganglioside.
(3) Important cells affected: neurons.
(4) Symptoms include motor and mental deterioration, blindness, and dementia.
(5) Common in the Ashkenazi Jews.
Niemann-Pick disease
(1) Deficient enzyme: sphingomyelinase.
(2) Metabolite that accumulates: sphingomyelin.
(3) Important cells affected: neurons.
Huntington’s disease
a. Causes dementia.
b. Genetic transmission: autosomal dominant.
c. Characterized by the degeneration of striatal neurons, affecting cortical and basal ganglia function.
d. Clinically, the disease affects both movement and cognition and is ultimately fatal.
Leukaemias
Uncontrolled proliferation of leukocyte precursors (may be with associated red cell and platelet series proliferation).
Factors which may playa causal role are.
- Viral
- Radiation.
- Genetic.
Classification
1. Acule leukaemia:
a. Lymphocytic (lymphoblastic).
b. Myelocytic and promyelocytic (myeloblastic).
c. Monocytic.
d. Myelomonocytic.
e. Undifferentiated (Stem cell).
2. Chronic leukaemia:
a. Lymphocytic
b. Myelocytic
3. Miscellaneous:
a. Erythroleukaemia (De Guglielmo's disease).
b. Eosinophilic leukaemia.
c. Megakaryocytic leukaemia.
Neuroblastoma and Related Neoplasms
Neuroblastoma is the second most common solid malignancy of childhood after brain tumors, accounting for up to10% of all pediatric neoplasms. They are most common during the first 5 years of life. Neuroblastomas may occur anywhere along the sympathetic nervous system and occasionally within the brain. Most neuroblastomas are sporadic. Spontaneous regression and spontaneous- or therapy-induced maturation are their unique features.
Gross features
- The adrenal medulla is the commonest site of neuroblastomas. The remainder occur along the sympathetic chain, mostly in the paravertebral region of the abdomen and posterior mediastinum.
- They range in size from minute nodules to large masses weighing more than 1 kg.
- Some tumors are delineated by a fibrous pseudo-capsule, but others invade surrounding structures, including the kidneys, renal vein, vena cava, and the aorta.
- Sectioning shows soft, gray-tan, brain-like tissue. Areas of necrosis, cystic softening, and hemorrhage may be present in large tumors.
Microscopic features
- Neuroblastomas are composed of small, primitive-appearing neuroblasts with dark nuclei & scant cytoplasm, g rowing in solid sheets.
- The background consists of light pinkish fibrillary material corresponding to neuritic processes of the primitive cells.
- Typically, rosettes can be found in which the tumor cells are concentrically arranged about a central space filled with the fibrillary neurites.
- Supporting features include include immunochemical detection of neuron-specific enolase and ultrastructural demonstration of small, membrane-bound, cytoplasmic catecholamine-containing secretory granules.
- Some neoplasms show signs of maturation, either spontaneous or therapy-induced. Larger ganglion-like cells having more abundant cytoplasm with large vesicular nuclei and prominent nucleoli may be found in tumors admixed with primitive neuroblasts (ganglioneuroblastoma). Further maturation leads to tumors containing many mature ganglion-like cells in the absence of residual neuroblasts (ganglioneuroma).
Many factors influence prognosis, but the most important are the stage of the tumor and the age of the patient. Children below 1 year of age have a much more favorable outlook than do older children at a comparable stage of disease.
Miscroscopic features are also an independent prognostic factor; evidence of gangliocytic differentiation is indicative of a "favorable" histology. Amplification of the MYCN oncogene in neuroblastomas is a molecular event that has profound impact on prognosis. The greater the number of copies, the worse is the prognosis. MYCN amplification is currently the most important genetic abnormality used in risk stratification of neuroblastic tumors.
About 90% of neuroblastomas produce catecholamines (as pheochromocytomas), which are an important diagnostic feature (i.e., elevated blood levels of catecholamines and elevated urine levels of catecholamine metabolites such as vanillylmandelic acid [VMA] and homovanillic acid [HVA]).
Glycogen storage diseases (glycogenoses)
1. Genetic transmission: autosomal recessive.
2. This group of diseases is characterized by a deficiency of a particular enzyme involved in either glycogen production or degradative pathways.
Diseases include:
on Gierke disease (type I)
(a) Deficient enzyme: glucose-6-phosphatase.
(b) Major organ affected by the buildup of glycogen: liver.
Pompe disease (type II)
(1) Deficient enzyme: α-glucosidase(acid maltase).
(2) Major organ affected by the buildup of glycogen: heart.
Cori disease (type III)
(1) Deficient enzyme: debranching enzyme (amylo-1,6-glucosidase).
(2) Organs affected by the buildup of glycogen: varies between the heart, liver, or skeletal muscle.
Brancher glycogenosis (type IV)
(1) Deficient enzyme: branching enzyme.
(2) Organs affected by the buildup of glycogen: liver, heart, skeletal muscle, and brain.
McArdle syndrome (type V)
(1) Deficient enzyme: muscle phosphorylase.
(2) Major organ affected by the buildup of glycogen: skeletal muscle.
Biliary cirrhosis(16%)
It is due diffuse chronic cholestaisis (obstruction of the biliary flow) leading to damage and scarring all over the liver. Two types are known
1. Primary biliary cirrhosis and
2. Secondary biliary cirrhosis.
Primary biliary cirrhosis
It is destructive chronic inflammation of intrahepatic bile ductules and small ducts leading to micronodular cirrhosis.
-Typically affects middle aged women.
- Patients present with fatigue, pruritis and eventually, jaundice.
Cause:- Autoimmune. Patients have autoantibodies directed against mitochondrial enzymes (AMA).
Pathology:-
Liver is enlarged, dark green in color (cholestaisis). Cirrhosis is micronodular.
M/E :-
- Early, portal tracts show lymphocytes and plasma cell infiltrate the bile ducts and destroy them.
- Granulomatous inflammation surrounding the damaged and inflamed bile ducts is the hallmark of (PBC).
- Cholestatic changes such as bile ductular proliferation, periportal Mallory’s hyaline and increased copper in periportal hepatocytes.
- In the end stage disease, micro nodular cirrhosis occurs and the inflammatory changes subside
Secondary biliary cirrhosis:-
It is extra hepatic (surgical) cholestaisis due to prolonged extra hepatic major bile duct obstruction.
Causes - Obstruction of hepatic or common bile duct by:
- Congenital biliary atresia.
- Pressure by enlarged LN or tumor * Biliary stones.
- Carcinoma of the bile duct, ampulla of Vater or pancreatic head
Effects of obstruction:-
Complete obstruction leads to back pressure all over the biliary tract
- damage by inspessated bile
- inflammation and scarring.
Incomplete obstruction leads to acute suppurative cholangitis and cholangiolitis.