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.
Post viral (post hepatitic) cirrhosis (15-20%)
Cause:- Viral hepatitis (mostly HBV or HCV)
Acute hepatitis → chronic hepatitis → cirrhosis.
Pathology
Liver is shrunken. Fatty change is absent (except with HCV). Cirrhosis is mixed.
M/E :-
Hepatocytes-show degeneration, necrosis as other types of cirrhosis.
Fibrous septa -They are thick and immature (more cellular and vascular).
- Irregular margins (piece meal necrosis).
- Heavy lymphocytic infiltrate.
Prognosis:- - More rapid course than alcoholic cirrhosis.Hepatocellular carcinoma is more liable to occur
Fanconi’s syndrome
Characterized by the failure of the proximal renal tubules to resorb amino acids, glucose, and phosphates.
May be inherited or acquired.
Clinical manifestations include
glycosuria, hyperphosphaturia, hypophosphatemia, aminoaciduria, and systemic acidosis.
Infections caused by gonorrhea
1. Acute urethritis. Mostly in males. Generally self-limiting. Dysuria and purulent discharge.
2. Endocervical infection. Purulent vaginal discharge, abnormal menses, pelvic pain. Often co-infection with other STD’s. Some women are asymptomatic.
3. Pelvic Inflammatory Disease (PID). Consequence of ascending endocervical infection. Causes salpingitis, endometriosis, bilateral abdominal pain, discharge, fever. May lead to sterility, chronic pain, and ectopic pregnancy because of loss of fallopian cilia.
4. Anorectal inflammation. Mostly in homosexual men. Pain, itching, discharge from anus.
5. Dermatitis/arthritis. Occurs after bacteremia. Skin will have papules on an erythematous base which develop into necrotic pustules. Asymmetric joint pain. These infections are susceptible to penicillin.
6. Neonatal infections. Ophthalmia neonatorum is a conjunctival infection from going through infected vagina. After one year of age, suspect child abuse.
Pyelonephritis
- A bacterial infection that affects the renal tubules, interstitium, and renal pelvis.
- One of the most common renal diseases.
- Usually caused by gram-negative, rod-shaped bacteria that are part of the normal flora of the enteric tract. Most commonly caused by Escherichia coli, followed by Proteus, Klebsiella, and Enterobacter.
- The infecting bacteria are usually from the patient’s own enteric flora an example of an endogenous infection.
- Usually associated with a urinary tract infection (acute pyelonephritis) or involved with another precipitating condition, such as obstruction (chronic pyelonephritis).
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
Parathyroid hormone
Parathyroid hormone (PTH) is a polypeptide (84 amino acid residues) secreted by the chief cells of the parathyroid glands (four glands: two in each of the superior and inferior lobes of the thyroid; total weight 120 mg).
The main action of PTH is to increase serum calcium and decrease serum phosphate.
Its actions are mediated by the bones and kidneys -
In bone, PTH stimulates osteoclastic bone resorption and inhibits osteoblastic bone deposition. The net effect is the release of calcium from bone.
In the kidney, PTH has the following effects:
- Increases calcium reabsorption.
- Decreases phosphate reabsorption.
- Increases 1-hydroxylation of 25-hydroxyvitamin D (i.e. activates vitamin D).
PTH also increases gastrointestinal calcium absorption.