Liver cirrhosis

It is a chronic, progressive diffuse process characterized by 
a. Hepatocellular necrosis           
b. Replacement by fibrosis and inflammation 
c. Hyperplasia of surviving liver cells forming regenerating nodules 
d. Vascular derangement. 

All these changes lead to loss of the normal liver architecture. 

Pathology of cirrhosis
At first the liver is enlarged or of normal size. Late in the disease, it is reduced in size and weight. 
Consistency- Firm. 
Colour -May be yellow (fatty change), red (congestion), green (cholestaisis), or pale gray (recent nodules due to absence of pigment). 

Morphologically  According to the size of these nodules, cirrhosis can be classified
    
    Micronodular (regular) cirrhosis. Small nodules 2-3 mm.in diameter.
    Macronodular (irregular) cirrhosis, nodules up to one cm in diameter.
    Mixed cirrhosis is the end stage of all types of cirrhosis
    
Microscopic picture 

1 Regenerating nodulesn- Proliferated hepatocytes arranged in thick plates and separated by blood sinusoids.  Central vein in abnormal sites (eccentric) - Hepatocytes may be small , large , or binucleated 

2- Fibrosis- It replaces damaged hepatocytes. It develops at certain sites:-
a-perivenular    b -perisinusoidal    c -pericellular  and d -in relation to portal tracts.

- It may be young, cellular and highly vascular or mature with diminished vasculsarity. It encloses groups of hepatocytes, lobules or regenerating nodules.

-As a result of hepatocyte injury and fibrosis, there’s loss of normal liver architecture including the lobular and acinar pattern as well as the liver cell plates 

3- Bile ductular proliferation:- Occurs in the fibrous septa.Focal choestaisis with feathery degeneration of hepatocytes occur at the margins of regenerating nodules. It becomes diffuse terminally.  

4- Inflammatory cells:-   Lymphocytes, macrophages and plasma cells infiltrate the fibrous septa and regenerating nodules 

Etiological classification of cirrhosis

Congenital Occurs at childhood
- congenital syphilis   
  
Hereditary diseases:- 
a. Primary idiopathic haemochromatosis      b. Thalassemia      c. Wilson’s disease      d.α 1-antitrypsin deficien e. glycogen storage disease

Acquired

-Cryptogenic (10-50%).             
-Alcoholic (30-70%)
-Post viral  (15-20%)                
- Biliary cirrhosis (16%) primary or secondary. 

Portal hypertension

 It is elevation of the portal venous pressure (normal 7 m.m Hg). 

 Causes:-
 1- Presinusoidal    
 2- Sinusoidal        
 3- Postsinusoidal
 
Presinusoidal:- 
  a. Massive splenomegaly and increased splenic blood flow.
  b. Portal vein obstruction by thrombosis or outside pressure.
  c. Portal venular obstruction at the portal tracts e.g. by fibrosis, granuloma or chronic hepatitis. 

Sinusoidal:-  
Cirrhosis due to perisinusoidal fibrosis

Postsinusoidal:-  
a.Alcoholic hepatitis leading to perivenular fibrosis.
b. Cirrhosis leading to interference with the blood flow and  to arterio -venous anastomosis resulting in increased venous blood pressure.
c. Veno -occlusive diseases of the liver caused by some drugs & plant toxins. It results in progressive fibrous occlusion of the hepatic venules and vein radicals.
d. Budd- Chiari syndrome: It is hepatic vein thrombosis. 30% of cases have no apparent cause. It produces portal hypertension and hepatomegaly. It is fatal if not treated. 
e. obstruction of major hepatic vein by tumors. 
f. Right sided heart failure and constrictive pericarditis 

Effects of portal hypertension: 

Ascitis
 
It is intraperitoneal accumulation of serous fluid which is a Transudate . It causes abdominal distension.  

Causes

a. Increased hydrostatic pressure` in the portal venous system. 
b. Decreased albumin synthesis in the liver…..decreased colloid osmotic pressure of plasma.
c. Sodium and water retension due to secondary hyperaldosteronism and ADH secretion. 
d. Leakage of hepatic lymph through the hepatic capsule due to hepatic vein obstruction.  

Splenomegaly:-   It results from chronic venous congestion.
- The spleen enlarged with capsular adhesions.
- It shows Gamma Gandi nodules.  - There may be hyperspelenism.  

Porto-Systemic venous anastomosis:-  Present in the following sites Esophageal variesis. Rupture of these vessels is the main cause of death.
Around the umbilicus  “Caput meduci”. Ano-rectal vessels. 
 

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. 

Agranulocytosis. Severe neutropenia with symptoms of infective lesions.

Drugs. are an important cause and the effect may be due to .
-Direct toxic effect.
-Hypersensitivity.

Some of the 'high risk drugs are.
-Amidopyrine.
-Antithyroid drugs.
-Chlorpromazine, mapazine.
-Antimetabolites and other drugs causing pancytopenia.

Bloodpicture:  Neutropenia with toxic granules in neutrophils. Marrow shows decrease in granulocyte precursors with toxic granules in them.

Pemphigoid
1. Ulcerative lesions on the skin and oral mucosa.
2. An autoimmune disease in which patients have autoantibodies against basal cells (desmosome attachment to the basement membrane).
3. Histologically, the entire epithelium appears to separate from the connective tissue. There is no acantholysis.
4. A positive Nikolsky sign is observed.
5. Complications include blindness, due to ocular lesions present in some patients.
6. Treatment: corticosteroids.

Respiratory Viral Diseases

Respiratory viral infections cause acute local and systemic illnesses. The common cold, influenza, pharyngitis, laryngitis (including croup), and tracheobronchitis are common.

An acute, usually afebrile, viral infection of the respiratory tract, with inflammation in any or all airways, including the nose, paranasal sinuses, throat, larynx, and sometimes the trachea and bronchi.

Etiology and Epidemiology

Picornaviruses, especially rhinoviruses and certain echoviruses and coxsackieviruses, cause the common cold. About 30 to 50% of all colds are caused by one of the > 100 serotypes of rhinoviruses.

Symptoms and Signs

Clinical symptoms and signs are nonspecific.

After an incubation period of 24 to 72 h, onset is abrupt, with a burning sensation in the nose or throat, followed by sneezing, rhinorrhea, and malaise.

Characteristically, fever is not present, particularly with a rhinovirus or coronavirus. Pharyngitis usually develops early; laryngitis and tracheobronchitis vary by person and causative agent. Nasal secretions are watery and profuse during the first days, but become more mucoid and purulent.

Cough is usually mild but often lasts into the 2nd wk.