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. 

Peutz-Jeghers syndrome
1. Lesions appear as small, melanotic, and freckle-like. They can be found on the skin, oral mucosa, lips, feet, and hands. 
2. May also present with intestinal polyps, which may develop into a gastrointestinal carcinoma. 
3. Genetic transmission: autosomal dominant.

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)

Muscle pathology
1. Myasthenia gravis
a. An autoimmune disease caused by autoantibodies to acetylcholine receptors at the neuromuscular junctions.
b. Characterized by muscle weakness or the inability to maintain long durations of muscle contractions; this worsens during exercise but recovers after rest.
c. Affects various muscle groups, including:
(1) Eyes—diplopia, ptosis.
(2) Neck—dysphagia, problems swallowing or speaking.
(3) Extremities—arms and legs.
d. Treatment: cholinesterase inhibitors(neostigmine), anti-immune therapy.

2. Muscle tumors
a. Rhabdomyoma—benign tumor of skeletal muscle.
b. Leiomyoma
(1) Benign tumor of smooth muscle.
(2) Most common tumor found in women.
(3) Usually affects the uterus, although it can occur anywhere.
c. Rhabdomyosarcoma
(1) Malignant tumor of skeletal muscle.
(2) Most common sarcoma found in children.
(3) Usually affects head and neck region—orbit, nasal cavity, and nasopharynx.

Pneumoconioses—are environmentally related lung diseases that result from chronic inhalation of various substances.

1. Silicosis (stone mason’s disease) 
a. Inhalant: silica dust.
b. Associated with extensive fibrosis of the lungs.
c. Patients have a higher susceptibility to tuberculosis infections.

2. Asbestosis
a. Inhalant: asbestos fibers.
b. Associated with the presence of pleural plaques.
c. Consequences include:
(1) Mesothelioma (malignant mesothelial tumor).
(2) Bronchogenic carcinoma.

3. Anthracosis
a. Inhalant: carbon dust.
b. Usually not as harmful as silicosis or asbestosis.
c. Associated with the presence of macrophages containing carbon.

Causes of disease

The causes of disease Diseases can be caused by either environmental factors, genetic factors or a combination of the two.

A. Environmental factors

Environmental causes of disease are many and are classified into:

 1. Physical agents

 2. Chemicals

 3. Nutritional deficiencies & excesses

 4. Infections & infestations

 5. Immunological factors

 6. Psychogenic factors

 1. Physical agents

These include trauma, radiation, extremes of temperature, and electric power. These agents

apply excess physical energy, in any form, to the body.

2. Chemicals

With the use of an ever-increasing number of chemical agents such as drugs,

3. Nutritional deficiencies and excesses

Nutritional deficiencies may arise as a result of poor supply, interference with absorption, inefficient transport within the body, or defective utilization. It may take the form of deficiency.

4. Infections and infestations

Viruses, bacteria, fungi, protozoa, and metazoa all cause diseases. They may do so by causing cell destruction directly as in virus infections (for example poliomyelitis) or protozoal infections (for example malaria).

5. Immunological factors

A. Hypersensitivity reaction

This is exaggerated immune response to an antigen. For example, bronchial asthma can occur due to exaggerated immune response to the harmless pollen.

B. Immunodeficiency

This is due to deficiency of a component of the immune system which leads to increased susceptibility to different diseases. An example is AIDS.

C. Autoimmunity

This is an abnormal (exaggerated) immune reaction against the self antigens of the host. Therefore, autoimmunity is a hypersensitivity reaction against the self antigens. 4

6. Psychogenic factors

The mental stresses imposed by conditions of life, particularly in technologically advanced

communities, are probably contributory factors in some groups of diseases.

B. Genetic Factors

These are hereditary factors that are inherited genetically from parents.