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.
Joint pathology
1. Rheumatoid arthritis
a. Cause is autoimmune in nature.
b. More common in women aged 20 to 50.
c. Characterized by inflammation of the synovial membrane. Granulation tissue, known as pannus, will form in the synovium and expand over the articular cartilage. This causes the destruction of the underlying cartilage and results in fibrotic changes and ankylosis.
Scarring, contracture, and deformity of the joints may occur.
d. Clinical symptoms include swollen joints. It can affect any joint in the body.
2. Osteoarthritis
a. Most common arthritis.
b. Cause is unknown.
c. Higher incidence in women, usually after age 50.
d. Characterized by degeneration of the articular cartilage and the formation of osteophytes (bony spurs) at the margins of affected areas.
Clinical signs and symptoms include:
(1) Stiff and painful joints affecting joints in the hand (phalangeal joints) and weight-bearing joints.
(2) Heberden’s nodes—nodules at the distal interphalangeal joint.
(3) Bocard’s nodes—nodules at the proximal interphalangeal joint.
Eczematous Dermatitis
Eczematous dermatitis includes a large category of skin lesions characterized by severe pruritus and distinctive gross and microscopic features.
- type I hypersensitivity is involved with atopic dermatitis in patients who have an allergic history.
- type IV hypersensitivity is involved in contact dermatitis (poison ivy).
- acute eczematous dermatitis is characterized by a weeping, pruritic rash, while a chronic eczematous dermatitis presents with dry, scaly, plaque-like thickening of the skin, a process called lichenification.
Megaloblastic anaemia
Metabolism: B12(cyanocobalamin) is a coenzyme in DNA synthesis and for maintenance of nervous system. Daily requirement 2 micro grams. Absorption in terminal ileum in the presence gastric intrinsic factor. It is stored in liver mainly-
Folic acid (Pteroylglutamic acid) is needed for DNA synthesis.. Daily requirement 100 micro grams. Absorption in duodenum and jejunum
Causes of deficiency .-
- Nutritional deficiency-
- Malabsorption syndrome.
- Pernicious anaemia (B12).
- Gastrectomy (B12).
- Fish tapeworm infestation (B12).
- Pregnancy and puerperium (Folic acid mainly).
- Myeloproliferative disorders (Folic acid).
- Malignancies (Folic acid).
- Drug induced (Folic-acid)
Features:
(i) Megaloblastic anaemia.
(ii) Glossitis.
(iii) Subacute combined degeneration (in B12deficiency).
Blood picture :
- Macrocytic normochromic anaemia.
- Anisocytosis and poikilocytosis with Howell-Jolly bodies and basophilic stippling.
- Occasional megalo blasts may be-seen.
- Neutropenia with hypersegmented neutrophills and macropolycytes.
- Thrombocytopenia.
- Increased MVC and MCH with normal or decreased MCHC.
Bone marrow:
- Megaloblasts are seen. They are larger with a more open stippled chromatin. The nuclear maturation lags behind. the cytoplasmic maturation. Maturation arrest is seen (more of early forms).
- Immature cells of granulocyte series are also larger.
-Giant stab forms (giant metamyelocytes).
ANAEMIA
Definition. Reduction of the hemoglobin level below the normal for the age and sex of the patient
Classification
1. Blood loss anaemia:
- Acute.
- Chronic (results in iron deficiency).
2. Deficiency anaemia:
- Iron deficiency.
- Megaloblastic anaemia-BI2 and Folic acid deficiency.
- Protein deficiency.
- Scurvy-Vitamin C deficiency.
3. Marrow dysfunction:
- Aplastic anaemia.
- Marrow infiltration.
- Liver failure.
- Renal failure.
- Collagen diseases.
4 Increased destruction (Heamolysis)
- Due to corpuscular defects.
- Due to extra corpuscular defects
IMMUNITY AND RESISTANCE TO INFECTION
Body's resistance to infection depends upon:
I. Defence mechanisms at surfaces and portals of entry.
II. Nonspecific or innate immunity
Ill. Specific immune response.
I. Surface Defence Mechanisms
1. Skin:
(i) Mechanical barrier of keratin and desquamation.
(ii) Resident commensal organisms
(iii)Acidity of sweat.
(iv) Unsaturated fatty acids of sebum
2. Oropharyngeal
(i)Resident flora
(ii) Saliva, rich in lysozyme, mucin and Immunoglobulins (lgA).
3. Gastrointestinal tract.-
(i) Gastric HCI
(ii) Commensal organisms in Intestine
(iii) Bile salts
(iv) IgA.
(v) Diarrhoeal expulsion of irritants.
4. Respiratory tract:
(i) Trapping in turbinates
(ii) Mucus trapping
(iii) Expulsion by coughing and sneezing.
(iv) Ciliary propulsion.
(V) Lysozymes and antibodies in secretion.
(vi) Phagocytosis by alveolar macrophages.
5. Urinary tract:
(i) Flushing action.
(ii) Acidity
(iii) Phagocytosis by urothelial cells.
6. Vagina.-
(i) Desquamation.
(ii) Acid barrier.
(iii) Doderlein's bacilli (Lactobacilli)
7. Conjunctiva:
Lysozymes and IgA in tears
II. Nonspecific or Innate Immunity
1. Genetic factors
- Species: Guinea pig is very susceptible to tuberculosis.
- Race: Negroes are more susceptible to tuberculosis than whites
- Sickle cells (HbS-a genetic determined Haemoglobinopathy resistant to Malarial parasite.
2. Age Extremes of age are more susceptible.
3. Hormonal status. Low resistance in:
- Diabetes Mellitus.
- Increased corticosteroid levels.
- Hypothyroidism
4. Phagocytosis. Infections can Occur in :
- Qualitative or quantitative defects in neutrophils and monocytes.
- Diseases of mononuclear phagocytic system (Reticuloendothelial cells-RES).
- Overload blockade of RES.
5. Humoral factors
- Lysozyme.
- Opsonins.
- Complement
- Interferon (antiviral agent secreted by cells infected by virus)
III. 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.
Cholangitis
Cholangitis is inflammation of the bile ducts.
1. It is usually associated with biliary duct obstruction by gallstones or carcinoma, which leads to infection with enteric organisms. This results in purulent exudation within the bile ducts and bile stasis.
2. Clinically, cholangitis presents with jaundice, fever, chills. leukocytosis, and right upper quadrant pain