NEET MDS Lessons
General Pathology
Jaundice, or icterus
a. Characterized by yellowness of tissues, including skin, eyes, and mucous membranes.
b. Caused by excess conjugated and/or unconjugated serum bilirubin. (increased levels of bilirubin in the blood)
lcterus is visible when the serum bilirubin exceeds 2 mg/dl. In unconjugated hyperbilirubinemia, bilirubin is not excreted into the urine because of tight protein binding in serum. In conjugated hyperbilirubinemia, small amounts of bilirubin are excreted in the urine because
it is less tightly protein bound.
NOTE: Concentration of bilirubin in blood plasma does not normally exceed 1 mg/dL (>17µmol/L). A concentration higher than 1.8 mg/dL (>30µmol/L) leads to jaundice.
The conjunctiva of the eye are one of the first tissues to change color as bilirubin levels rise in jaundice. This is sometimes referred to as scleral icterus.
c. Types and causes include:
(1) Hepatocellular jaundice—caused by liver diseases such as cirrhosis and hepatitis.
(2) Hemolytic jaundice—caused by hemolytic anemias.
(3) Obstructive jaundice—caused by blockage of the common bile duct either by gallstones (cholelithiasis) or carcinomas involving the head of
the pancreas.
Differential diagnosis
Jaundice is classified into three categories, depending on which part of the physiological mechanism the pathology affects. The three categories are:
Pre-hepatic → The pathology is occurring prior to the liver.
Hepatic → The pathology is located within the liver.
Post-Hepatic → The pathology is located after the conjugation of bilirubin in the liver.
Pre-hepatic
Pre-hepatic jaundice is caused by anything which causes an increased rate of hemolysis (breakdown of red blood cells).
Certain genetic diseases, such as sickle cell anemia, spherocytosis, thalassemia and glucose 6-phosphate dehydrogenase deficiency can lead to increased red cell lysis and therefore hemolytic jaundice.
Commonly, diseases of the kidney, such as hemolytic uremic syndrome, can also lead to coloration. Defects in bilirubin metabolism also
present as jaundice, as in Gilbert's syndrome (a genetic disorder of bilirubin metabolism which can result in mild jaundice, which is found in about 5% of the population) and Crigler-Najjar syndrome.
In jaundice secondary to hemolysis, the increased production of bilirubin, leads to the increased production of urine-urobilinogen. Bilirubin is not usually found in the urine because unconjugated bilirubin is not water-soluble, so, the combination of increased urine-urobilinogen with no bilirubin (since, unconjugated) in urine is suggestive of hemolytic jaundice.
Laboratory findings include:
• Urine: no bilirubin present, urobilinogen > 2 units (i.e., hemolytic anemia causes increased heme metabolism; exception: infants where gut flora has not developed).
• Serum: increased unconjugated bilirubin.
• Kernicterus is associated with increased unconjugated bilirubin.
Hepatocellular
Hepatocellular (hepatic) jaundice can be caused by acute or chronic hepatitis, hepatotoxicity, cirrhosis, drug induced hepatitis and alcoholic liver disease. Cell necrosis reduces the liver's ability to metabolize and excrete bilirubin leading to a buildup of unconjugated bilirubin in the blood.
Laboratory findings depend on the cause of jaundice.
• Urine: Conjugated bilirubin present, urobilirubin > 2 units but variable (except in children). Kernicterus is a condition not associated with increased conjugated bilirubin.
• Plasma protein show characteristic changes.
• Plasma albumin level is low but plasma globulins are raised due to an increased formation of antibodies.
Bilirubin transport across the hepatocyte may be impaired at any point between the uptake of unconjugated bilirubin into the cell and transport of conjugated bilirubin into biliary canaliculi.
Post-hepatic
Post-hepatic jaundice, also called obstructive jaundice, is caused by an interruption to the drainage of bile in the biliary system. The most common causes are gallstones in the common bile duct, and pancreatic cancer in the head of the pancreas. Also, a group of parasites known as "liver flukes" can live in the common bile duct, causing obstructive jaundice. Other causes include strictures of the common bile duct, biliary atresia, cholangiocarcinoma, pancreatitis and pancreatic pseudocysts. A rare cause of obstructive jaundice is Mirizzi's syndrome.
Pathophysiology
When RBCs are damaged, their membranes become fragile and prone to rupture. As each RBC traverses through the reticuloendothelial system, its cell membrane ruptures when its membrane is fragile enough to allow this.
Hemoglobin, are released into the blood. The hemoglobin is phagocytosed by macrophages, and split into its heme and globin portions. The globin portion, a protein, is degraded into amino acids and plays no role in jaundice.
Two reactions then take place with the heme molecule.
The first oxidation reaction is catalyzed by the microsomal enzyme heme oxygenase and results in biliverdin (green color pigment), iron
and carbon monoxide.
The next step is the reduction of biliverdin to a yellow color tetrapyrol pigment called bilirubin by cytosolic enzyme biliverdin reductase.
This bilirubin is "unconjugated," "free" or "indirect" bilirubin. Approximately 4 mg of bilirubin per kg of blood is produced each day.[11] The majority of this bilirubin comes from the breakdown of heme from expired red blood cells in the process just described.
However approximately 20 percent comes from other heme sources, including ineffective erythropoiesis, and the breakdown of other heme-containing proteins, such as muscle myoglobin and cytochromes.
Hepatic events
The unconjugated bilirubin then travels to the liver through the bloodstream. Because bilirubin is not soluble, however, it is transported through the blood bound to serum albumin.
In Liver, it is conjugated with glucuronic acid (to form bilirubin diglucuronide, or just "conjugated bilirubin") to become more water soluble.
The reaction is catalyzed by the enzyme UDP-glucuronyl transferase.
This conjugated bilirubin is excreted from the liver into the biliary and cystic ducts as part of bile. Intestinal bacteria convert the bilirubin into urobilinogen.
Urobilinogen can take two pathways. It can either be further converted into stercobilinogen, which is then oxidized to stercobilin and passed out in the feces, or it can be reabsorbed by the intestinal cells, transported in the blood to the kidneys, and passed out in the urine as the oxidised product urobilin.
Stercobilin and urobilin are the products responsible for the coloration of feces and urine, respectively.
Miscellaneous Bone Tumors
1. Ewing Sarcoma & Primitive Neuroectodermal Tumor (PNET) are primary malignant small round-cell tumors of bone and soft tissue. They are viewed as the same tumor because they share an identical chromosome translocation; they differ only in degree of differentiation. PNETs demonstrate neural differentiation whereas Ewing sarcomas are undifferentiated. After osteosarcomas, they are the second most common pediatric bone sarcomas. Most patients are 10 to 15 years old. The common chromosomal abnormality is a translocation that causes fusion of the EWS gene with a member of the ETS family of transcription factors. The resulting hybrid protein functions as an active transcription factor to stimulate cell proliferation. These translocations are of diagnostic importance since almost all patients with Ewing tumor have t(11;22).
Pathological features
• Ewing sarcoma and PNETs arise in the medullary cavity but eventually invade the cortex and periosteum to produce a soft tissue mass.
• The tumor is tan-white, frequently with foci of hemorrhage and necrosis.
Microscopic features
• There are sheets of uniform small, round cells that are slightly larger than lymphocytes with few mitoses and little intervening stroma.
• The cells have scant glycogen-rich cytoplasm.
• The presence of Homer-Wright rosettes (tumor cells circled about a central fibrillary space) indicates neural differentiation, and hence indicates by definition PNET.
Ewing sarcoma and PNETs typically present as painful enlarging masses in the diaphyses of long tubular bones (especially the femur) and the pelvic flat bones. The tumor may be confused with osteomyelitis because of its association with systemic signs & symptoms of infection. X-rays show a destructive lytic tumor with infiltrative margins and extension into surrounding soft tissues. There is a characteristic periosteal reaction depositing bone in an onionskin fashion.
2. Giant-Cell Tumor of Bone (GCT) is dominated by multinucleated osteoclast-type giant cells, hence the synonym osteoclastoma. GCT is benign but locally aggressive, usually arising in individuals in their 20s to 40s. Current opinion suggests that the giant cell component is likely a reactive macrophage population and the mononuclear cells are neoplastic. Tumors are large and red-brown with frequent cystic degeneration. They are composed of uniform oval mononuclear cells with frequent mitoses, with scattered osteoclast-type giant cells that may contain 30 or more nuclei.
The majority of GCTs arise in the epiphysis of long bones around the knee (distal femur and proximal tibia).
Radiographically, GCTs are large, purely lytic, and eccentric; the overlying cortex is frequently destroyed, producing a bulging soft tissue mass with a thin shell of reactive bone. Although GCTs are benign, roughly 50% recur after simple curettage; some malignant examples (5%) metastasize to the lungs
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.
Adult Respiratory Distress Syndrome
A constellation of pathologic and clinical findings initiated by diffuse injury to alveolar capillaries. This syndrome is associated with a multitude of clinical conditions which primarily damage the lung or secondarily as part of a systemic disorder.
Pathogenesis
There are many types of injuries which lead to the ultimate, common pathway, i.e., damage to the alveolar capillary unit. The initial injury most frequently affects the endothelium, less frequently the alveolar epithelium. Injury produces increased vascular permeability, edema, fibrin-exudation (hyaline membranes). Leukocytes (primarily neutrophils) plays a key role in endothelial damage.
Pathology
Heavy, red lungs showing congestion and edema. The alveoli contain fluid and are lined by hyaline membranes.
Pathophysiology
Severe respiratory insufficiency with dyspnea, cyanosis and hypoxemia refractory to oxygen therapy.
The Specific Immune Response
Definition
The immune response comprises all the phenomenon resulting from specific interaction of cells of the immune-system with antigen. As a consequence of this interaction cells appear that mediate cellular immune response as well cells that synthesis and secrete immunoglobulins
Hence the immune response has 2 components.
1. Cell mediated immunity (CMI).
2:. Humoral immunity (antibodies)
(I) Macrophages. Constituent of the M. P. S. These engulf the antigenic material.
(i) Most of the engulfed antigen is destroyed to' prevent a high dose paralysis of the Immune competent cells.
(ii) Some of it persists in the macrophage, retaining immunogenecity for continued stimulus to the immune system.
(iii)The antigenic information is passed on to effectors cells. There are two proposed mechanisms for this:
(a) As messenger RNA with code for the specific antibody.
(b) As antigen-RNA complexes.
(2) Lymphocytes. There are 2 main classes recognized by surface characteristics.
(A) T-Lymyhocytes (thymus dependant) :- These are responsible for cellular immunity . On exposure to antigen
- They transform to immunoblasts which divide to form the effectors cells.
- They secrete lymphokines These are
- Monocyte migration inhibition factor
- Macrophage activation factor
- Chemotactic factor
- Mitogenic factor
- Transfer factor
- Lymphotoxin which kills target cell
- Interferon.
- Inflammatory factor which increases permeability. .
- Some remain as 1onglived memory cell for a quicker recognition on re-exposure
- They also modify immune response by other lymphocytes in the form of “T – helper cells “ and “T-suppressor” cells
- They are responsible for graft rejection
(B) B-Lymphocytes (Bursa dependent). In birds the Bursa of Fabricious controls
these cells. In man, its role is taken up by," gut associated lymphoid tissue)
(i) They are responsible for antibody synthesis. On stimulation they undergo blastic transformation and then differentiation to plasma cells, the site of immunoglobulin synthesis.
(ii) They also form memory cells. But these are probably short lived.
(C) In addition to T & B lymphocytes, there are some lymphocytes without the surface markers of either of them. These are 'null' cells-the-natural Killer (N,K.) cells and cells responsible for antibody dependent cellular-cytotoxicity.
(3) Plasma cells. These are the effectors cells of humoral immunity. They produce the immunoglobins, which are the effector molecules.
Malignant Diseases of Skin
1. Bowen's disease refers to a carcinoma in situ on sun-exposed skin or on the vulva, glans a penis, or oral mucosa which has an association, in some cases, with a visceral malignancy.
2. Skin cancers associated with ultraviolet light damage include basal cell carcinoma, squamous cell carcinoma, and malignant melanoma.
3. A basal cell carcinoma is the MC malignant tumor of the skin and occurs on sunexposed, hair-bearing surfaces.
- Locally aggressive, infiltrating cancers arising from the basal cell layer of the epidermis and infiltrate the underlying superficial dermis.
- they do not metastasize
- BCC are commonly located on the face on the inner aspect of the nose, around the orbit and the upper lip where they appear as raised nodules containing a central crater with a pearly-colored skin surface and vascular channels.
- microscopically, they have cords of basophilic staining cells originating from the basal cell layer infiltrating the dermis.
- they commonly recur if they are not totally excised, because they are frequently multifocal.
- the basal cell nevus syndrome is an autosomal-dominant disorder characterized by the development of basal cell carcinomas early in life with associated abnormalities of bone, skin, nervous system, eyes, and reproductive system.
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.