METAPLASIA

A reversible replacement of one type of adult tissue by another type of tissue. It is usually an adaptive substitution to a. cell type more suited to an environment, often at the cost of specialised function.

(1) Epithelial metaplasia:

• Squamous metaplasia. This is the commoner type of metaplasia and is seen in:
  • Tracheobronchial lining in chronic smokers and in bronchiectasis.
  • In Vitamin A deficiency.
• Columnar metaplasia:
  • Intestinalisation of gastric mucosa in chronic gastritis.

(2) Connective tissue metaplasia:

• Osseous-Metaplasia in :
  • Scars.
  • Myositis ossificans
• Myeloid metaplasia in liver and spleen.

Osteogenesis Imperfecta (OI) (Brittle bone diseases) 

It is a group of hereditary disorders caused by gene mutations that eventuate in defective synthesis of and thus premature degradation of type I collagen. The fundamental abnormality in all forms of OI is too little bone, resulting in extreme susceptibility to fractures. The bones show marked cortical thinning and attenuation of trabeculae. 

Extraskeletal manifestations also occur because type I collagen is a major component of extracellular matrix in other parts of the body. The classic finding of blue sclerae  is attributable to decreased scleral collagen content; this causes a relative transparency that allows the underlying choroid to be seen. Hearing loss can be related to conduction defects in the middle and inner ear bones, and small misshapen teeth are a result of dentin deficiency 

NECROSIS

Definition: Necrosis is defined as the morphologic changes caused by the progressive degradative
action of enzymes on the lethally injured cell.

These changes are due to
I. Autolysis and
2. Heterolysis.

The cellular changes of necrosis i.e. death of circumscribed group of cells in continuity with living tissues are similar to changes in tissues following somatic death, except that in the former, there is leucocytic infiltration in reaction to the dead cells and the lytic
enzymes partly come from the inflammatory cell also. (Heterolysis). Cell death occurs in the normal situation of cell turnover also and this is called apoptosis-single cellular dropout.

Nuclear changes in necrosis

As cytoplasmic changes are a feature of degeneration ,similarly nuclear changes are the hallmark of necrosis. These changes are:
(i) Pyknosis –condensation of chromatin
(ii) Karyorrhexis - fragmentation
(iii) Karyolysis - dissolution

Types of necrosis

(1) Coagulative necrosis: Seen in infarcts. The architectural outlines are maintained though structural details are lost. E.g, myocardial infarct.
(2) Caseous necrosis: A variant of coagulative necrosis seen in tuberculosis. The architecture is destroyed, resulting in an  eosinophilic amorphous debris.
(3) Colliquative (liquifactive). Necrosis seen in Cerebral infarcts and suppurative necrosis.

Gangrenous necrosis: It is the necrosis with superadded putrefaction

May be:
a. dry - coagulative product.
b. Wet - when there is bacterial liquifaction.

Fat necrosis

May be:
a. Traumatic (as in breast and subcutaneous tissue).
b Enzymatic (as in pancreatitis). It shows inflammation of fat with formation of lipophages and giant cells.

This is often followed by deposition of calcium as calcium soaps.

Hyaline necrosis: Seen in skeletal muscles in typhoid and in liver ceIs in some forms of hepatitis.

Fibrinoid necrosis: In hypertension and in immune based diseases.
 

German measles (rubella)
 - sometimes called "three day measles".
 - incubation 14-21 days; infectious 7 days before the rash and 14 days after the onset of the rash.
 - in adults, rubella present with fever, headache, and painful postauricular Lymphadenopathy 1 to 2 days prior to the onset of rash, while in children, the rash is usually the first sign.
 - rash (vasculitis) consists of tiny red to pink macules (not raised) that begins on the head and spreads downwards and disappears over the ensuing 1-3 days; rash tends to become confluent.
 - 1/3rd of young women develop arthritis due to immune-complexes.
 - splenomegaly (50%) 

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. 

DIPHTHERIA

An acute, contagious disease caused by Corynebacterium diphtheriae, characterized by the formation of a fibrinous pseudomembrane, usually on the respiratory mucosa, and by myocardial and neural tissue damage secondary to an exotoxin.

Cutaneous diphtheria (infection of the skin) can occur when any disruption of the integument is colonized by C. diphtheriae. Lacerations, abrasions, ulcers, burns, and other wounds are potential reservoirs of the organism. Skin carriage of C. diphtheriae is also a silent reservoir of infection.

Pathology

C. diphtheriae may produce exotoxins lethal to the adjacent host cells. Occasionally, the primary site is the skin or mucosa elsewhere. The exotoxin, carried by the blood, also damages cells in distant organs, creating pathologic lesions in the respiratory passages, oropharynx, myocardium, nervous system, and kidneys.

The myocardium may show fatty degeneration or fibrosis. Degenerative changes in cranial or peripheral nerves occur chiefly in the motor fibers

In severe cases, anterior horn cells and anterior and posterior nerve roots may show damage proportional to the duration of infection before antitoxin is given. The kidneys may show a reversible interstitial nephritis with extensive cellular infiltration.

The diphtheria bacillus first destroys a layer of superficial epithelium, usually in patches, and the resulting exudate coagulates to form a grayish pseudomembrane containing bacteria, fibrin, leukocytes, and necrotic epithelial cells. However, the areas of bacterial multiplication and toxin absorption are wider and deeper than indicated by the size of the membrane formed in the wake of the spreading infection.