Beta-Thalassemia Major

DISCOVERY OF HEMOGLOBIN

1. Hemoglobin was discovered by Hünefeld in 1840.
2. Hemoglobin (Hb) is an iron-containing oxygen-transport metalloprotein in the red blood cells (rbc's) of all vertebrates (with the exception of the fish family Channichthyidae) as well as the tissues of some invertebrates.
3. Hemoglobin has the formula C2952H4664O832N812S8Fe4. 
4. Each hemoglobin molecule has 4 iron (Fe) atoms.
5. The role of hemoglobin in the blood was elucidated by French physiologist Claude Bernard.
6. Hemoglobin carries oxygen in the blood from the respiratory organs (lungs or gills) to the rest of the body (ie. the tissues). 
7. Hemoglobin is red because it contains heme, which is a bright cherry red molecule.
8. Hemoglobin is a bright cherry red molecule which can undergo oxygenation and deoxygenation reactions.
9. Hemoglobin's reversible oxygenation was described a few years later (1851-1859) by Felix Hoppe-Seyler.
10. Presence of oxygenated hemoglobin gives blood a bright red colour and the smell of fresh blood as present in hospital corridors.
11. Presence of deoxygenated hemoglobin gives blood a dark red-brown colour and this blood stinks of dead bodies (corpses) if left to stand at room temperature.
12. Cells and tissues require oxygen for aerobic glycolysis. Complete biological oxidation produces energy (ATP), carbon dioxide (CO2) and water (H2O).
13. Hemoglobin + CO2 = carbaminohemoglobin. Carbaminohemoglobin carries carbon dioxide
14. Hemoglobin is also found outside red blood cells and their progenitor lines. 
15. Other cells that contain hemoglobin include the A9 dopaminergic neurons in the substantia nigra, macrophages, alveolar cells, and mesangial cells in the kidney. In these tissues, hemoglobin has a non-oxygen-carrying function as an antioxidant and a regulator of iron metabolism.
16. In 1959, Max Perutz determined the molecular structure of hemoglobin by X-ray crystallography.

HEMOGLOBIN GENES AND HEME & HEMOGLOBIN SYNTHESES

Hemoglobin forms in the developing rbc (reticulocytes) in the bone marrow (BM).

Steps in heme & hemoglobin synthesis:

1. Glycine + succinyl-CoA = delta-aminolevulinic acid (d-ALA)
2. d-ALA exits into cytoplasm
3. d-ALA is reacted upon by enzymes
4. forms protoporphyrin
5. protoporphyrin re-enters mitochondria
6. Iron (Fe) is added to protoporphyrin
7. forms heme
8. Globin is made at ribosomes of rbc's and involves 2 chromosomes. Alpha globin chains are made by Chromosome 16. Beta globin chains are made by Chromosome 11.
9. Heme + Globin = Hemoglobin
10. Lead (Pb) is an inhibitor of heme and hemoglobin synthesis

HEMOGLOBIN STRUCTURE AND FUNCTION

1. Hemoglobin helps to carry oxygen to body tissues.
2. Hemoglobin helps to carry carbon dioxide for disposal by the lungs.
3. Rbc's contain hemoglobin.
4. The level of hemglobin in blood varies for males and females.
5. Males perform more physical activities and have higher hemoglobin levels in blood.
6. Females perform less physical activities and have lower hemoglobin levels in blood.
7. Hemoglobin has a quaternary structure characteristic of many multi-subunit globular proteins.
8. There are 4 types of globin chains: alpha (a), beta (b), delta (d) and gamma (g)
9. Hemoglobin consists of 4 subunits: 2 alpha globins + 2 beta/delta/gamma globins
10. Fetal hemoglobin is Hb F.
11. Adult hemoglobins are Hb A1 and Hb A2
12. Hb A1 = a2 b2 (alpha2 beta2)
13. Hb A2 = a2 d2 (alpha2 delta2)
14. Hb F = a2 g2 (alpha2 gamma2)
15. Hemoglobin can be saturated with oxygen molecules (oxyhemoglobin), or desaturated with oxygen molecules (deoxyhemoglobin).

POSTNATAL GENETICS:
(1) GLOBIN CHAINS IN HEMOGLOBINS
(2) HEMOGLOBIN VARIANTS

1. A globin chain is a polypeptide.
2. The amino acid sequence of a globin chain is determined by DNA sequences called genes.
3. There are 4 globin chains: alpha (a), beta (b), delta (d) and gamma (g)
4. Different globin chains are synthesized at different times during fetal development and till adult stage.
5. There is more than one hemoglobin gene.
6. The main form of hemoglobin present in adult man is hemoglobin A (HbA).
7. In humans, hemoglobin A is coded for by the genes, HBA1, HBA2, and HBB.
8. Hemoglobin contains 2 alpha globin chains and 2 beta, 2 delta or 2 gamma globin chains
9. Thus, many configurations of globin chains are possible:
10. Hb A1 = a2 b2 (alpha2 beta2) (heterotetramer, α2β2)
11. Hb A2 = a2 d2 (alpha2 delta2)
12. Hb F = a2 g2 (alpha2 gamma2) (HbF, α2γ2)
13. Fetal hemoglobin is Hb F.
14. Adult hemoglobins are Hb A1 and Hb A2
15. Normal hemoglobin types found in adults are; 

• Hemoglobin A (Hb A), which is 95-98% of hemoglobin found in adults, 
• Hemoglobin A2 (Hb A2), which is 2-3% of hemoglobin found in adults, and 
• Hemoglobin F (Hb F), which is found in adults up to 2.5%. It  is the primary hemoglobin that is produced by the fetus during pregnancy.

     16. In the embryo:

• Hb Gower 1 (ζ₂ε₂)
• Hb Gower 2 (α₂ε₂)
• Hemoglobin Portland I (ζ₂γ₂)
• Hemoglobin Portland II (ζ₂β₂).

     17. In the fetus: Hemoglobin F (α₂γ₂) 

      18. After birth:

• Hemoglobin A (α₂β₂) – The most common with a normal amount over 95%.
• Hemoglobin A2 (α₂δ₂) – δ chain synthesis begins late in the third trimester and, in adults, it has a normal range of 1.5–3.5%.
• Hemoglobin F (α₂γ₂) – In adults Hemoglobin F is restricted to a limited population of red cells called F-cells. However, the level of Hb F can be elevated in persons with sickle-cell disease and beta-thalassemia.

    19. Variant forms that cause disease:

• Hemoglobin D-Punjab – (α₂β^D₂) – A variant form of hemoglobin.
• Hemoglobin H (β₄) – A variant form of hemoglobin, formed by a tetramer of β chains, which may be present in variants of α thalassemia.
• Hemoglobin Barts (γ₄) – A variant form of hemoglobin, formed by a tetramer of γ chains, which may be present in variants of α thalassemia.
• Hemoglobin S (α₂β^S₂) – A variant form of hemoglobin found in people with sickle cell disease. There is a variation in the β-chain gene, causing a change in the properties of hemoglobin, which results in sickling of red blood cells.
• Hemoglobin C (α₂β^C₂) – Another variant due to a variation in the β-chain gene. This variant causes a mild chronic hemolytic anemia.
• Hemoglobin E (α₂β^E₂) – Another variant due to a variation in the β-chain gene. This variant causes a mild chronic hemolytic anemia.
• Hemoglobin AS – A heterozygous form causing sickle cell trait (SCT) with one adult gene and one sickle cell disease gene
• Hemoglobin SC disease – A compound heterozygous form with one sickle gene and another encoding Hemoglobin C. Hemoglobin Hopkins-2 - A variant form of hemoglobin that is sometimes viewed in combination with Hemoglobin S to produce sickle cell disease.

      20. List of known hemoglobin variants

• Hb Kansas
• Hb S
• Hb C
• Hb E
• Hb D-Punjab
• Hb O-Arab
• Hb G-Philadelphia
• Hb Hasharon
• Hb Lepore
• Hb M
• Hb F
• Hb Hope
• Hb Pisa
• Hb J
• Hb N-Baltimore

HEMOGLOBIN F (Hb F)

1. Fetal hemoglobin (HbF, α2γ2) is found in the developing fetus, and binds oxygen with greater affinity than adult hemoglobin A.
2. Hemoglobin F (Hb F) is the primary hemoglobin that is produced by the fetus during pregnancy.
3. The levels can be normal to increased in beta thalassemia. 
4. Hemoglobin F frequently increases in individuals with sickle cell anemia and sickle cell-beta thalassemia. 
5. Individuals with sickle cell and increase of Hb F have a milder case of the disease. 
6. There are situations where the Hb F is increased. This rare condition is called Hereditary Persistence of Fetal Hemoglobin (HPFH).
7. HPFH is a group of disorders where the Hemoglobin F is increased without signs or clinical features of thalassemia. 
8. Some different ethnic groups have different mutations that cause HPFH. 
9. Hb F can also be increase by acquired conditions that involve the red blood cells. 
10. Elevated Hemoglobin F levels are also associated with Leukemia and myeloproliferative disorders.

HEMOGLOBIN H

1. Hemoglobin H (Hb H) increases the affinity for oxygen. 
2. Hb H holds onto the oxygen instead of releasing it into tissue and cells. 
3. Hb H usually occurs in some alpha thalassemia and is composed of four beta globin (protein) chains (beta tetramer, β4). 
4. This variant is usually produced in response to a severe shortage of alpha chains, and usually cause beta chains to function abnormally.

HEMOGLOBINOPATHY VS THALASSEMIA

1. Hemoglobinopathy is a hereditary condition involving an abnormality in the structure of hemoglobin.
2. Mutations in the genes for the hemoglobin protein in a species result in hemoglobin variants. Many of these mutant forms of hemoglobin cause no disease. Some of these mutant forms of hemoglobin, however, cause a group of hereditary diseases termed the hemoglobinopathies. The best known hemoglobinopathy is sickle-cell disease (SCD).
3. Hemoglobin variants are a part of the normal embryonic and fetal development. They may also be pathologic mutant forms of hemoglobin in a population, caused by variations in genetics. Some well-known hemoglobin variants, such as sickle-cell anemia (SCA), are responsible for diseases and are considered hemoglobinopathies. Other variants cause no detectable pathology, and are thus considered non-pathological variants.
4. Thalassemia is a reduced or no production of a or b globin chain. The a and b globin chains have normal structures.

HEMOGLOBIN CONTENT OF ERYTHROCYTES

1. Hemoglobin carries oxygen to tissues.
2. Hemoglobin carries carbon dioxide back to the lungs for expulsion (expiration).
3. Hemoglobin is not synthesized (made) in red blood cells (erythrocytes).
4. Hemoglobin synthesis occurs in nucleated reticulocytes.
5. Hemoglobin synthesis is regulated (controlled).
6. Erythrocytes have a half-life of 120 days (ie they survive approximately 120 days before they are cleared from the blood circulation).
7. When old erythrocytes are removed and broken down, hemoglobin in them too is broken down (degraded).
8. New hemoglobin will need to be synthesized to replace that lost.
9. If hemoglobin synthesis is slowed (or lags behind), there will be either insufficient hemoglobin, lack of hemoglobin or defective hemoglobin in the erythrocytes.

THALASSEMIAS

1. Thalassemias are a group of genetic blood disorders 
2. Thalassemias are inherited blood disorders
3. Thalassemia patients make normal globin chains, but at reduced rates
4. These blood disorders have defective production of hemoglobin
5. The thalassemias are autosomal recessive disorders which result in reduced production of one or more of the subunits of hemoglobin
6. There are 2 forms of thalassemia: alpha- and beta-thalassemia
7. There are two forms of beta-thalassemia: thalassemia minor and thalassemia major (also called Cooley's anemia)

ALPHA-THALASSEMIA

1. Reduced production of alpha globin chains
2. Results from gene deletion
3. Alpha-thalassemias have reduced production of alpha-globin chains to make new hemoglobin
4. The resulting hemoglobin molecule has either 1 or no alpha-globin chain; 
5. The resulting hemoglobin configuration can be b2 or ab2, which are defective hemoglobins.
6. Hemoglobin with b2 configuration occurs in alpha-thalassemia major.
7. Hemoglobin with ab2 configuration occurs in alpha-thalassemia minor.

ALPHA THALASSEMIA GENE DELETION

1. The alpha globin gene is present on Chromosome 16.
2. Alpha thalassemia results from gene deletion.
3. ONE alpha globin gene deletion is asymptomatic.
4. TWO alpha globin gene deletions, can be either from the same chromosome (cis deletion) or from different chromosomes (trans deletion)
5. Cis deletion is worse than trans deletion. 
6. Inheritance of cis deletion from both parents by the offspring is dangerous as it results in severe alpha thalassemia (no alpha globin chain).
7. THREE alpha gene deletions results in Hb H, with b2 dimer and b4 tetramer.
8. FOUR alpha gene deletions results in Hb Bart's, with g4 tetramer.

TREATMENT OF ALPHA THALASSEMIA

1. alpha carrier and Hb H don't need treatment as they are fine.

BETA THALASSEMIA

1. Reduced or no production of beta globin chains
2. It is genetically determined
3. The beta globin gene is located on a chromosome 11 (ie an autosome, not a sex chromosome, not X or Y)
4. Two copies are derived in the child, one from the father, and one from the mother
5. Each chromosome has an allele for beta globin
6. Each allele codes for beta globin chain, one from the father, one from the mother
7. Beta thalassemia also occurs as a result of gene mutation 

BETA THALASSEMIA GENE MUTATIONS

1. There are 2 types of beta globin gene mutations: B+ and B0
2. In B+ gene mutation, the gene is capable of producing beta globin chain even though at reduced rate; there is some production of beta globin chain
3. In B0 mutation, the gene is incapable of producing beta globin chain; there is no production of beta globin chain
4. Possible genetic combinations are thus: B+B+, B+B0, B0B+, and B0B0
5.         B+B+ = produce beta globin chain .... beta thalassemia major
6.         B+B0 or B0B+  = produce beta globin chain ... beta thalassemia minor
7.         B0B0 = do not produce beta globin chain .... beta thalassemia major

BETA-THALASSEMIA MAJOR & MINOR

1. Beta-thalassemias are of 2 types - thalassemia major and thalassemia minor
2. Thalassemia major is also called Cooley's anemia
3. Production of beta-globin chain of hemoglobin is reduced or none
4. The resulting hemoglobin molecule has either a2 or a2b, which are hemoglobins with reduced beta globin or no beta globin
5. Hemoglobin with a2 configuration occurs in beta-thalassemia major.
6. Hemoglobin with a2b configuration occurs in beta-thalassemia minor.
7. Beta thalassemia minor is a2BB+ with mild anemia and increased Rbc count
8. Beta thalassemia major is a2B+B+ or a2B0B0 with severe anemia and increased Rbc count
9. In B0B0, there is no beta globin production; there will be excess alpha globin chains
10. When there is no beta globin production, and there is excess alpha globins, 4 alpha globin chains combine to form an alpha globin tetramer, which in turn forms ineffective hemoglobin. This results in ineffective erythropoiesis.

THE BONE MARROW

1. When rbc count is low, the bone marrow compensates by producing more rbc's.
2. Rbc's with alpha globin tetramers (a4) are abnormal and are destroyed while still in the bone marrow.
3. Any rbc's with alpha globin tetramers (a4) that escaped from the bone marrow and are released into the circulation, are trapped by the endothelial system (eg  spleen) and are destroyed, thus removing them from the systemic circulation ... leading to anaemia.
4. Any rbc's containing alpha4 tetramer will be destroyed ... leading to anaemia.
5. When the body senses a rapid reduction in rbc count, it tries to make more rbc's in the bone marrow.
6. The bone marrow will become hyperactive in order to make rbc's.
7. The bone marrow is now hyperactive ... trying to make a lot of new rbc's even though beta globin synthesis is reduced.
8. When the bone marrow is active and increasing its mass (expanding), it compresses the cortex, thus thinning the cortex.
9. The thick cortex gives bone strength. Once the cortex is thinner, bone strength is reduced and the bones are weakened, and can possibly lead to pathological fracture. This can happen in thalassemia patients. The body will try to produce rbc's using all the bone marrow in the body.
10. Normally after birth, erythropoiesis is limited to a few bones - bone marrow of the central bones - of the skull, ribs, vertebra and a few long bones, ribs. However, in beta thalasemia with anemia, almost all bones with bone marrow will try to make rbc's.
11. As a result, when the bone marrow cavity expands rapidly to produce more rbc's in the skull and the cortex thins, the skull marrow will crack, giving a hair-on-end or crew cut appearance. Expansion of the bone marrow of the face will give a chipmunk appearance. These are findings in thalassemia patients.

VIRAL INFECTIONS IN THALASSEMIA PATIENTS

1. Parvovirus P19 infection halts rbc production for 1-2 weeks in normal healthy persons, as we have a large reserve of rbc's.
2. However, in beta thalassemia major patients, Parvovirus P19 infection is dangerous. They hardly have any rbc reserve and need all the rbc's in the bone marrow.

GEOGRAPHIC ORIGIN OF THE THALASSEMIAS

1. The Indians are classified as Caucasanoids. They are Aryans of Italian and Greek origins. Thus, they inherit beta-thalassemia from their Mediterranean ancestors.
2. The Malays of Indian heritage also inherit beta-thalassemia from their Indian Mediterranean ancestors. Beta-thalassemia is common among this Malay population in Malaysia.

THALASSEMIA COMMON CLINICAL FEATURES

1. Anaemia
2. Manifestation of increased hemopoiesis in face and skull
3. Extramedullary hemopoiesis in liver and spleen results in nucleated rbc's
4. Hepatosplenomegaly

BETA-THALASSEMIA MAJOR SYMPTOMS

1. fatigue, weakness, or shortness of breath
2. a pale appearance (pallor) or a yellow color to the skin (jaundice)
3. irritability
4. deformities of the facial bones
5. slow growth (retarded growth, short for stature)
6. a swollen abdomen
7. dark urine

INVESTIGATIONS OF THALASSEMIA

1. Microscopy
2. Skull radiography
3. Hemoglobin

MICROSCOPY OF ERYTHROCYTES IN THALASSEMIA

1. The microscope is the best way to examine erythrocyte appearances.
2. Erythrocytes with insufficient or deficient hemoglobin will not look normal when examined under the microscope.
3. Microscopic findings are diagnostic.
4. Pale erythrocytes point to anemia.
5. "Mexican hats" or target cells (or targets) point to thalassemia.
6. Small erythrocytes (microcytic) point to iron deficiency - microcytic anemia.
7. Big pale erythrocytes (macrocytic) point to vitamin B deficiency - macrocytic anemia.
8. Spiky erythrocytes (echinocytes) have spike-like projections on their surfaces.
9. Spindle-shaped erythrocytes
10. Sickle-shaped erythrocytes occur in sickle cell anemia (SCA)
11. Extramedullary hemopoiesis (occurs in liver and spleen) will lead to nucleated rbc's.
12. Liver and spleen are not equipped to make rbs'c. So these organs will make immature nucleated rbc's which are seen in the circulation.
13. Microcytic hypochromic anaemia
14. Normal rbc's are round biconcave discs, with 2/3 red due to hemoglobin and 1/3 pale due to less hemogloin
15. Target cells are seen thalassemia. Target cells lack tensile strength and rbc biconcavity has blebs (outgrowths) and are filled with hemoglobin. The rbc's now look like target cells, like bull's eye

TREATMENT OF BETA THALASSEMIA

1. Blood transfusion. Blood transfusion bags contain iron (Fe); 1 bag = 250 mg iron. When we transfuse patients at 4 weeks interval, we also supply them with extra iron (blood > rbc > Hb > rbc's are degraded in 120 days and free iron is released). Iron has no specific way for excretion. So iron is deposited in tissues, leading to hemosiderosis or hemochromatosis. So, iron overload results. A lot of problems thus result.
2. Iron chelation therapy

External links

Hemoglobin
https://en.wikipedia.org/wiki/Hemoglobin
https://youtu.be/M4cKGWP12w4

HBB
https://en.wikipedia.org/wiki/HBB

Hemoglobin variants
https://en.wikipedia.org/wiki/Hemoglobin_variants

Hemoglobinopathies
https://youtu.be/89feCoBXRGE

Thalassemia

https://www.medicinenet.com/beta_thalassemia/article.htm
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2943116/pdf/JBB2010-706872.pdf
http://www.tandfonline.com/doi/full/10.1080/00313020600922538?scroll=top&needAccess=true

Theodora Lam and Brenda S.A. Yeoh. 2004. Negotiating ‘home’ and ‘national identity’: Chinese-Malaysian transmigrants in Singapore
http://onlinelibrary.wiley.com/doi/10.1111/j.1467-8373.2004.00235.x/full

Videos - Thalassemia

https://youtu.be/39tW_o3SqDM
https://youtu.be/uowfqUc4ems
https://youtu.be/M4cKGWP12w4

Malaysia Statistics 2017

MALAYSIA

Geographic coordinates: 3 10 N, 101 42 E

Time difference: UTC+8 (13 hours ahead of Washington, DC)

National anthem: Negaraku (My Country/My Nation)

Population: 31,381,992 (July 2017 est.)

Ethnic groups:

• Malay 50.1%
• Chinese 22.6%
• Indigenous 11.8%
• Indian 6.7%
• Other 0.7%
• Non-citizens 8.2% (2010 est.)

East Malaysia indegenous languages: Iban and Kadazan most widely spoken

0-14 years: 27.83% (male 4,493,084/female 4,238,991)

Literacy (defined as age 15 and over can read and write):
total population: 94.6%
male: 96.2%
female: 93.2% (2015 est.)

School life expectancy (primary to tertiary education):
total: 13 years
male: 12 years
female: 13 years (2015)

Population below poverty line: 3.8% (2009 est.)
lowest 10%: 1.8%
highest 10%: 34.7%

Distribution of family income (Gini index):
49.2% (1997); 46.2% (2009)

The proverbial case where the richest 20% have 80% of all income (see Pareto principle) would lead to an income Gini coefficient of at least 60%.
An often cited case that 1% of all the world's population owns 50% of all wealth, means a wealth Gini coefficient of at least 49%. - Wikipedia

Electricity access:
population without electricity: 100,000
electrification (total population): 99.5%
electrification (urban areas): 99.8%
electrification (rural areas): 98.7% (2013)

Telephones (mobile cellular): 43,912,600

Internet users (total): 24,384,952
% of population: 78.8% (July 2016 est.) ... Internet penetration 78.8%

Airports: 114

Source:

CIA > World Factbook > Malaysia
https://www.cia.gov/library/publications/the-world-factbook/geos/my.html

Gini
https://en.wikipedia.org/wiki/Gini_coefficient

Malay Women
Khalidah Khalid Ali.  The Role of Malay Women in the Malaysian Workforce and its Impact on the Consciousness of Ethics and Integrity. Global Business and Management Research: An International Journal, Vol. 6, No. 4 (2014). https://www.gbmr.ioksp.com/pdf/vol.%206%20no.%204/v6n4-9.pdf

Tuberculous meningitis

KEYWORDS
Mycobacterium tuberculosis; antitubercular agents; case management; public health.


A. DISEASE BACKGROUND & PRESENTATION

===================

I. TUBERCULOSIS (TB)

====================

TB: Tuberculosis
BCG: Bacille Calmette-Guerrin
MDR-TB: Multidrug-resistant TB
XDR-TB: Extensively drug-resistant TB
DOT: Directly Observed Therapy

Tuberculosis (TB) is an ancient disease that is still present in many parts of the world today. It is endemic in 33 third world countries and absent in first world nations.

BCG, or bacille Calmette-Guerin, is a vaccine for tuberculosis. Many foreign-born persons have been BCG-vaccinated. BCG is used in many countries with a high prevalence of TB to prevent childhood tuberculous meningitis and miliary disease.

Malaysians must take the BCG vaccination when they first report for primary school at age 7 years. However, BCG does not provide full protection against TB. When BCG-vaccinated adults work in the hospital environment later on in life, some do acquire TB from their workplaces.

Some countries such the USA and Australia do not provide BCG vaccination as part of childhood immunization unless requested. Families who travel with unborns, newborns, babies, and young children from TB-rife countries travelling to first world nations may be safe at their destination. However, families with unborns, newborns, babies and young children from first world nations travelling to third world countries may possibly expose their family members to TB.

Today, we have an added health problem of TB coming from 3 populations - travellers and globe trotters, domestic helpers or maids, and foreign labourers. People ill with TB can infect up to 10-15 other people through close contact over the course of a year. TB is spread by airborne particles (which are moist droplets) via coughs, sneezing, speaking, singing, screaming and yelling. TB is spread through air and not by contact (touching) with the infected person.

Even though Malaysia has a good health monitoring system, TB seems to make a comeback. It was MDR-TB then, and now XDR-TB that we have to worry about now.

TYPES OF TB

There 2 types of TB, one of which is not easily detected because it is latent, and the other is obvious as it is active.

• Latent TB - the bacteria remain in the body in an inactive state. There are no symptoms visible. The carrier (person) seems normal. This type of TB is not contagious. However, the TB microorganism can become active, and thus become infectious.
• Active TB - the bacteria cause visible symptoms. This type of TB is infectious and can be transmitted to others.

SYMPTOMS OF TB

TB may be mild for many months before it progresses and cause more severe manifestations. Symptoms of TB include:

• Chills
• Fatigue
• Fever
• Loss of weight (LOW, weight loss)
• Loss of appetite (LOA)
• Night sweats

TB usually occurs in the lungs. TB of the lungs is called pulmonary TB (PTB). If TB is in the lungs (pulmonary), symptoms may include:

• Coughing for longer than 3 weeks
• Hemoptysis (coughing up blood)
• Chest pain

EXTRA-PULMONARY TB (EPTB)

Tuberculosis can involve virtually any organ or tissue in the body. TB can occur at sites outside the lungs, and thus is referred to as extra-pulmonary TB. These sites can be bones, brain, liver, kidneys, and heart.

• Bone - TB infecting the bones can lead to spinal pain and joint destruction
• Brain - TB infecting the brain can cause meningitis, which manifests as tonic clonic seizures
• Liver and kidneys - TB infecting the liver and kidneys can impair their waste filtration functions and lead to blood in the urine (refer Urine FEME)
• Heart - TB infecting the heart (tuberculous pericarditis) can impair the heart's ability to pump blood, resulting in a condition called cardiac tamponade that can be fatal (end-points are cardiac tamponade, mortality and constrictive pericarditis). 

CHEMOTHERAPY FOR EXTRAPULMONARY TB

Chemotherapy for extrapulmonary tuberculosis is initiated with INH, RIF, PZA, and EMB in an initial 2-month phase. After 2 months of 4-drug therapy, for extrapulmonary tuberculosis known or
presumed to be caused by susceptible strains, PZA and EMB may be discontinued, and INH and RIF continued during a continuation phase. Increasing evidence, including randomized controlled trials (RCTs), suggests that 6–9 month INH and RIF-containing regimens are effective for the majority of extrapulmonary sites of disease. The exception is tuberculous meningitis where the optimal duration of therapy has not been established through randomized controlled trials, but most experts and society
guidelines prescribe 12 months of treatment associated with prolonged wound discharge and scarring. Of note, the majority of lymphatic cases of mycobacterial disease in US children are caused by non tuberculous mycobacteria.

TREATMENT OF TB

Antituberculosis drugs are taken for 6 months, and there are associated risks. Non compliance (non adherence) with such a long-term antituberculosis course gives rise to MDR-TB. Follow DOT guidelines to ensure TB patients comply with taking the 6-month course of antituberculosis drugs.

The intensive phase of TB treatment consists of 4 drugs (INH, RIF, PZA, EMB):

• Ethambutol (EMB)
• Isoniazid (INH)
• Pyrazinamide (PZA)
• Rifampin (RIF)

First-line drugs

1. Isoniazid
2. Rifampin
3. Rifabutin
4. Rifapentine
5. Pyrazinamide
6. Ethambutol

Second-line drugs

1. Cycloserine
2. Ethionamide
3. Streptomycin
4. Amikacin/kanamycin
5. Capreomycin
6. Para-amino salicylic acid
7. Levofloxacin
8. Moxifloxacin

==========================

II. TUBERCULOUS MENINGITIS

==========================

BRAIN ANATOMY

The brain is protected by 3 layers of membrane, collectively known as meninges. The 3 membranes are the dura mater, arachnoid, and pia mater. They enclose the brain and spinal cord. Cerebrospinal fluid (CSF) fills the spaces between the membranes and cushions the brain.

MENINGITIS VS ENCEPHALITIS

Infection of the meninges by Mycobacterium tuberculosis can cause fever and seizures. Infected patients are immediately warded in the ICU and are closely monitored till they recover, if at all. Recovery is often a long process (1-2 years). Some patients may be able to recover fully, while others can only partially recover, and others die.

CHEMOTHERAPY FOR TUBERCULOUS MENINGITIS

Chemotherapy for tuberculous meningitis is initiated with INH, RIF, PZA, and EMB in an initial 2-month phase. After 2 months of 4-drug therapy, for meningitis known or presumed to be caused by susceptible strains, PZA and EMB may be discontinued, and INH and RIF continued for an additional 7–10 months, although the optimal duration of chemotherapy is not defined. Based on expert opinion, repeated lumbar punctures should be considered to monitor changes in cerebrospinal fluid cell count, glucose, and protein, especially early in the course of therapy.

In children with tuberculous meningitis, the American Academy of Pediatrics (AAP) lists an initial 4-drug regimen composed of INH, RIF, PZA, and ethionamide, if possible, or an aminoglycoside,
followed by 7–10 months of INH and RIF as the preferred regimen. There are no data from controlled trials to guide the selection of EMB vs an injectable or ethionamide as the fourth drug for tuberculosis meningitis. Most societies and experts recommend the use of either an injectable or EMB. For adults, based on expert opinion, our guideline committee prefers using EMB as the fourth drug in the regimen for tuberculous meningitis.

ADJUNCTIVE CORTICOSTEROID THERAPY

The role of adjunctive corticosteroid therapy in the treatment of tuberculous meningitis has been reported by numerous studies and an updated systematic review found a mortality benefit from the use of adjuvant corticosteroids. Therefore, we recommend adjunctive corticosteroid therapy with dexamethasone or prednisolone tapered over 6–8 weeks for patients with tuberculous meningitis.

===========

III. EPILEPSY

===========

A&E: Accident & Emergency Department

Synonyms:
 Seizure(s)
 Epileptic seizure(s)
 Fit(s)
 Electric ictus
 Malay terms - tarik; nyetok; guling; rasuk; gila babi

Epilepsy may develop as a result of a brain injury, tumour, stroke, prior infection or birth defect (genetic origin).

TB infecting the brain meninges and causing meningitis is common nowadays. Patients have a characteristic fall pattern and wriggle on the floor as if struck by a lightning bolt. Some have a slight saliva output while some have a foamy mouth. The seizure may last 5 minutes or longer - and for which it becomes a medical emergency, and the patient needs to be rushed to A&E at the nearest hospital.

WHAT IS EPILEPSY?
WHAT ARE THE SYMPTOMS?

Epilepsy is a group of neurological diseases characterized by recurrent seizures.

HOW DOES SEIZURE MANIFEST?

Depending on which part of the brain is affected, a seizure may manifest as follows:

Loss of awareness
Unusual behaviours
Unusual sensations
Uncontrollable movements
Loss of consciousness

TYPES OF SEIZURES and PART OF BRAIN AFFECTED

If the abnormal electrical surge happens within a limited area of the brain, it causes PARTIAL or FOCAL seizures.
If the entire brain is involved, GENERALIZED seizures will result.

Partial seizures subdivide further to:
- Simple partial
- Complex partial

Generalized seizures subdivide further to:
- Absence seizures
- Tonic seizures 
- Atonic seizures or drop attacks
- Clonic seizures
- Myoclonic seizures

MOST COMMON SEIZURE

The most common and also most dramatic are tonic-clonic seizures, also known as convulsive seizures, which are combinations of muscle stiffening and jerking. This type is what most people relate to when they think of a seizure. It also involves sudden loss of consciousness and sometimes loss of bladder control. A tonic-clonic seizure that lasts longer than 5 minutes requires immediate medical treatment.

GENERALIZED SEIZURES OF GENETIC ORIGIN

Generalized seizures that start in childhood are likely to involve genetic factors. Epilepsy due to a single gene mutation is rare. More often, an interaction of multiple genes and environmental factors is responsible. Hundreds genes have been implicated. Examples include genes encoding for GABA receptors – major components of the inhibitory circuit, and ion channels. Many genetic disorders that cause brain abnormalities or metabolic conditions have epilepsy as a primary symptom. The cause of epilepsy is unknown in about half of cases.

CAUSES OF EPILEPSY

Epilepsy may develop as a result of the following:

1. Brain injury (trauma or fall)
2. Tumour
3. Stroke
4. Previous infection 
5. Birth defect 

Babies with too much warm clothing on may suffer from seizures.
Seizures in children are caused by birth traumas, infections, congenital abnormalies, and high fevers.
Seizures in adults are caused by head injuries, infections, alcohol, stimulant drugs, side effects of medications.
Seizures in the elderly are caused by brain tumours and strokes.
Chemical causes of seizure are low blood sugar, low blood oxygen, low blood sodium, and low blood calcium.

PATHOPHYSIOLOGY OF SEIZURES

HOW DO SEIZURES HAPPEN?
WHY DO THEY HAPPEN?
PATHOPHYSIOLOGY (MECHANISM) OF EPILEPSY

NORMAL BRAIN ACTIVITY

The brain is a complex network of billions of neurons. Neurons can be excitatory or inhibitory. Excitatory neurons stimulate others to fire action potentials and transmit electrical messages, while inhibitory neurons SUPPRESS this process, preventing EXCESSIVE firing. A balance between excitation and inhibition is essential for normal brain functions.

BRAIN ACTIVITY IN EPILEPSY

Seizures happen as a result of a sudden surge in the brain’s electrical activities. In epilepsy, there is an UP-regulation of excitation and/or DOWN-regulation of inhibition, causing lots of neurons to fire SYNCHRONOUSLY at the same time.

DIAGNOSIS OF TYPE OF SEIZURE

Diagnosis is based on:

(i) Observation of symptoms
(ii) Medical history
(iii) An electroencephalogram (EEG) - to look for abnormal brain waves.
(iv) Genetic testing maybe helpful when genetic factors are suspected.

TREATMENT

There is no cure for epilepsy, but various treatments are available to control seizures.

TRADITIONAL CURE

The traditional cure used by the Malay community is freshly crushed onion. The patients lies down on a cooling pandanus mat. One big Bombay onion is coarsely pounded to yield coarsely ground juicy onion paste which is applied directly to the forehead and left to dry. A small wet towel maybe placed to avoid onion paste falling onto the eyes. The onion paste is removed when semi- or partially dry. A fresh onion paste can be re-applied if necessary, but normally one application is sufficient to cure seizure completely. This traditional method seems to work well in children whose eyeballs roll up and only the sclerae can be seen. It seems to work with children up to age 4 years, and does not recurr for 55+ years. No drugs are required when treated in this traditional manner.

TREATMENT OF EPILEPSY

The hospital provides 2 modes of treatment - dietary and drug therapies. Both are useful to control seizures. These will halt seizures and kill off M. tuberculosis.

(1) DRUG THERAPY

Medication successfully controls seizures for about 70% of cases. Many anti-epileptic drugs are available which target sodium channels, GABA receptors, and other components involved in neuronal transmission. Different medicines help with different types of seizures. Patients may need to try several drugs to find the most suitable regime for their cases.

Anticonvulsants: Phenytoin, lamotrigine

(2) DIET THERAPY

Dietary therapy: ketogenic diet has been shown to reduce or prevent seizures in many children whose seizures could not be controlled with medication. Ketogenic diet is a special high-fat, low-carbohydrate diet that must be prescribed and followed strictly. With this diet, the body uses fat as the major source of energy instead of carbohydrates. The reason why this helps control epilepsy is unclear.

Ketogenic diet reduces seizures.
Ketogenic diet is high-fat and low-carb.
When living on ketogenic diet, the body derives its energy from fat and not carbohydrates..
Ketone bodies are preferred substrates for brain energy; it utilizes ketone bodies more efficiently than glucose.
Ketone bodies are acidic as well as a cleansing agent that may cleanse the brain of unncessary firing.
The brain has a more calming effect when on ketogenic diet as occurs in strict fasting (eg Ramadan fasting).

(3) NERVE STIMULATION

Nerve stimulation therapies such as vagus nerve stimulation in which a device placed under the skin is programmed to stimulate the vagus nerve at a certain rate. The device acts as a pacemaker for the brain. The underlying mechanism is poorly understood but it has been shown to reduce seizures significantly.

(4) SURGERY

Finally, a surgery may be performed to remove part of the brain that causes seizure. This is usually done when tests show that seizures are originated from a small area that does not have any vital function.

====================
B. PATHOPHYSIOLOGY

• Coughing 3 weeks or longer, sometimes with mucus or blood - PTB
• Chills, fever & night sweats - bacterial infection
• LOW, LOA & fatigue - bacterial infection
• Tonic clonic seizures - meningitis

====================
C. DIFFERENTIAL DIAGNOSIS

Differential Diagnoses of TB:

1. Actinomycosis
2. Aspergillosis
3. Bronchiectasis
4. Constrictive Pericarditis
5. Fungal Pneumonia
6. Histoplasmosis
7. Lung Abscess
8. Nocardiosis
9. Non-Small Cell Lung Cancer
10. Pott Disease

Tuberculosis (TB) can masquerade as other infectious and disease processes, eg, congenital TB can mimic congenital syphilis or cytomegalovirus (CMV) infection.

Conditions with a presentation that may resemble pulmonary TB (PTB) (1-11) and can be included in the differential diagnosis of extrapulmonary TB include the following (1-22):

1. Blastomycosis
2. Tularemia
3. Actinomycosis
4. Mycobacterium avium-intracellulare infection
5. M chelonae infection
6. M fortuitum infection
7. M gordonae infection
8. M kansasii infection
9. M marinum infection
10. M xenopi infection
11. Squamous cell carcinoma
12. Hidradenitis suppurativa
13. Eosinophilic granuloma
14. Endemic syphilis
15. Erythema induratum (nodular vasculitis)
16. Erythema nodosum
17. Leishmaniasis
18. Leprosy
19. Cat scratch disease
20. Syphilis
21. Syringoma
22. Rheumatoid arthritis

Dermatologic differential diagnosis

Diagnosis of skin infection with M tuberculosis involves the following:

1. Differentiate primary-inoculation TB from ulceroglandular complexes and mycobacterioses
2. Differentiate TB verrucosa cutis from diseases such as North American blastomycosis, chromoblastomycosis, iododerma and bromoderma, chronic vegetative pyoderma, verruca vulgaris, verrucous carcinoma, verrucous atypical mycobacterial infection, and verrucous lupus vulgaris
3. Differentiate miliary TB of the skin (which appears as small, noncharacteristic, erythematous, papular or purpuric lesions) from drug reactions
4. Differentiate scrofuloderma from suppurative lymphadenitis with sinus-tract formation, such as blastomycosis or coccidioidomycosis
5. Differentiate TB cutis orificialis from glossitis, apotheosis, and deep fungal infections
6. Differentiate lupus vulgaris from lupoid rosacea, deep fungal or atypical mycobacterial infection, chronic granulomatous disease, granulomatous rosacea, and Wegener granulomatosis
7. Differentiate erythema induratum from nodular panniculitides (eg, Weber-Christian disease) and nodular vasculitides (eg, syphilitic gumma, nodular pernio)
8. Differentiate papulonecrotic tuberculid from other papulonecrotic entities, such as leukocytoclastic vasculitis, lymphomatoid papulosis, papular eczema, and prurigo simplex with neurotic excoriation
9. Differentiate lichen scrofulosorum from keratosis spinulosa, lichenoid sarcoid, and lichenoid secondary syphilis

=================
D. INVESTIGATIONS

TB is diagnosed by skin tests, blood tests, x-rays, and other tests.

1. Radiology - Chest radiograph; Brain and spine imaging - Imaging techniques: X-ray, CT-scan, MRI. Monitoring brain activity pattern: EEG. An EEG may also help in differentiating between partial and generalized seizures. EEG and MRI/CT-scan are tools to monitor the brain in unconscious patients.
2. Chemical Pathology - CSF Biochemistry - CSF protein (increased due to active infection), CSF glucose (reduced due to active infection); Renal function tests (RFT)
3. Microbiology - Tuberculin skin test; sputum test; Gram stain (Gram-); Ziehl-Neelsen stain for AFB; C&S - susceptibility and dose; Molecular techniques - DOT immunobinding assay for TB Ab
4. Hematology - Coagulation profile
5. Pathology - Autopsy: if brain death occurs
6. Genome - Genetic studies: Causes of lowered immunity - HIV/AIDS, coinfection (PCR)
7. Community Medicine - social and community studies; carrier status of family members
8. Ophthalmology - Visual acuity and red-green color perception testing

(1) RADIOLOGY

Imaging techniques are X-ray, CT-scan, and MRI.

1. Chest radiograph
2. Brain and spine imaging  

(2) MEDICINE, ANAESTHESIOLOGY & ANATOMY

SPINAL TAP

A spinal tap is performed to obtain CSF. The spinal tap is of 3 types, each puncture giving different characteristics for the CSF harvested. Lumbar puncture is the usual one performed to obtain CSF. There are risks associated with spinal tap.

1. Lumbar puncture
2. Cisternal puncture
3. Ventricular puncture

At HUSM, the CSF is collected into a sterile 20-ml vial with a yellow screw cap and sent for CSF Biochemistry.

(3) CHEMICAL PATHOLOGY

In the Chemical Pathology laboratory, a CSF specimen may show up as often as once every 2 days (ie about 10 CSF specimens per month). These samples can come from both pediatric as well as adults patients.

CSF and serum are analysed for various analytes. For CSF Biochemistry, there are 2 major analytes that are measured - ie CSF protein and CSF glucose. These tests are done on an automated chemistry analyser. CSF protein is elevated in tuberculous meningitis while CSF glucose is reduced.

Serum samples are obtained from blood specimens and are analysed for Renal Function Tests (RFT) and Liver Function Tests (LFT). All these chemistries are categorised as STAT and their analyses are performed ASAP. They are performed on automated chemistry analysers and the turnaround time (TAT) for these tests are less than an hour.

Patients with TB who are receiving pyrazinamide (PZA) should undergo baseline and periodic serum uric acid assessments.

1. CSF >> For CSF Biochemistry >> CSF protein & CSF glucose. Other analytes are included as required.
2. BLOOD >> SERUM >> Renal Function Tests (RFT) are performed to detect kidney involvement if any. RFT includes Sodium, Potassium, Chloride, and Creatinine.
3. BLOOD >> SERUM >> Liver Function Tests (LFT). LFT is performed to detect liver involvement, if any. LFT includes AST, ALT, Bilirubin, and ALP. Other causes of abnormal LFT should be excluded, if any (see HIV).*
4. BLOOD >> SERUM >> Uric acid.

(4) MICROBIOLOGY

PPD: purified protein derivative
IGRA: interferon-gamma release assay
DNA: deoxyribonucleic acid
rRNA: ribosomal RNA
PCR: polymerase chain reaction
PCR-RFLP: polymerase chain reaction-restriction fragment length polymorphism
NAAT: Nucleic Acid Amplification Tests
MODS: Microscopic-observation drug susceptibility (MODS) assay
TLA: thin-layer agar (TLA) assay

For Microbiology tests, CSF, sputum and bacterial isolates are tested when available. Sputum is the main specimen for PTB. Sputum is used for Culture and TB Drug Susceptibility Testing. However, in extra-PTB, and when there is no sputum, and other means of testing are tried.

Since conventional Microbiology techniques are time-consuming (3 weeks to 1 month), more recent/newer test methodologies are constantly being developed. These deploy molecular techniques (eg PCR, PCR-RFLP) and use either DNA or rRNA of the mycobacterium as samples. Some of these new/recent tests which have been developed are NAAT, MODS and TLA assays. These assays are less time-consuming and turnaround time (TAT) for results are shorter (about 2 weeks).

For CSF Microbiology, detection of the mycobacterium is done by the Microbiology lab and involves the following tests:

1. Skin on left forearm >> Mantoux tuberculin skin test using PPD. For detecting latent TB and previous exposure to TB or BCG. Noticeable bump (induration) larger than 5 mm/10 mm/ 15 mm diameter are positive Mantoux. The diameter is marked with a ballpoint pen as 2 black dots and the distance between the 2 dots is measured in mm.

An itchy red bump measuring 15mm indicates a positive Mantoux test.
The ballpoint pen outline is the size of a 50 sen coin.

1. Blood >> Serum >> An in vitro blood test based on IGRA with antigens specific for M tuberculosis can also be used to screen for latent TB infection and offers certain advantages over tuberculin skin testing. 
2. Sputum >> Mycobacterial culture and sensitivity (C&S) is done to plate out and isolate M. tuberculosis. MTB is isolated and identified. Its susceptibility to INH, RIF, PZA, EMB is determined.
3. Sputum >> An automated molecular test that uses sputum samples for the detection of M tuberculosis and resistance to rifampin has been developed.
4. Sputum >> Gram stain: Gram negative (Gram- pink rods)
5. Sputum >> Culture for acid-fast bacilli (AFB) and smear microscopy. M. tuberculosis is spread on a microscope slide and stained with Ziehl-Neelsen stain. M. tuberculosis are Gram- rods which appear as bright pink bullets under the microscope.
6. Sputum >> TB Drug susceptibility testing.  DNA sequencing analysis (PCR-RFLP) is a rapid and useful method for detecting drug-resistant TB.
7. Bacterial isolate >> Nucleic Acid Amplification Tests (NAAT): DNA probes specific for mycobacterial rRNA identify species of clinically significant isolates after recovery. In tissue, PCR amplification techniques can be used to detect M tuberculosis-specific DNA sequences and thus, small numbers of mycobacteria in clinical specimens.
8. Sputum >> TB Drug susceptibility testing >> Microscopic-observation drug susceptibility (MODS) and thin-layer agar (TLA) assays are inexpensive, rapid alternatives to conventional and molecular methods of TB drug susceptibility testing.
9. Blood >> Serum >> Hepatitis B and C screen

*Culture-Negative Pulmonary Tuberculosis in Adults
Failure to isolate M. tuberculosis from appropriately collected sputum specimens in persons who, because of clinical or radiographic findings, are suspected of having pulmonary tuberculosis (PTB) does not exclude a diagnosis of active tuberculosis. Some causes of failure to isolate organisms include low bacillary populations, inadequate sputum specimens, temporal variations in the number of expelled bacilli, overgrowth of cultures with other microorganisms, and errors in specimen processing


(5) IMMUNOLOGY

IRIS: immune reconstitution inflammatory syndrome
ART: antiretroviral therapy

HIV serology testing

*HIV/AIDS

1. Patients with HIV infection and tuberculosis are at increased risk of developing paradoxical worsening of symptoms, signs, or clinical manifestations of tuberculosis after beginning antituberculosis and antiretroviral treatments. 
2. These reactions presumably develop as a consequence of reconstitution of immune responsiveness brought about by ART, and are designated as the immune reconstitution inflammatory syndrome (IRIS). 
3. Tuberculosis IRIS has been noted to be more common in participants with earlier ART initiation and CD4+ cell counts less than 50 cells per microlitre.
4. Signs of IRIS may include high fevers, worsening respiratory symptoms, increase in size and inflammation of involved lymph nodes, new lymphadenopathy, expanding central nervous system lesions, worsening of pulmonary parenchymal infiltrations, new or increasing pleural effusions, and development of intra-abdominal or retroperitoneal abscesses .

(6) HEMATOLOGY

Anticoagulants: Warfarin

Monitoring blood coagulation is necessary.

1. Prothrombin time (PTT) 
2. Platelet count
3. Complete blood cell (CBC) count

*(7) PATHOLOGY & PHARMACOLOGY

1. Viral hepatitis (hepatitis A, B, and C in all patients; Epstein-Barr virus, cytomegalovirus, and herpes simplex in immunosuppressed patients)
2. Biliary tract disease
3. Other hepatotoxic drugs (eg, acetaminophen, acetaminophen-containing multiagent preparations, lipid-lowering agents, other drugs)
4. Select herbal and dietary supplements

(8) SOCIAL/COMMUNITY MEDICINE and PSYCHOLOGY

1. Weight
2. Vision assessment 
3. Diabetes screen
4. Alcohol
5. HIV/AIDS

Psychotropic drugs

1. Nortriptyline
2. Haloperidol, quetiapine
3. Benzodiazepines (eg diazepam, triazolam), zolpiderm, buspirone

(9) OPHTHALMOLOGY

Patients with TB who are receiving long-term ethambutol (EMB) therapy should undergo baseline and periodic visual acuity and red-green color perception testing. The latter can be performed with a standard test, such as the Ishihara test for color blindness.

========
E. DIAGNOSIS

A positive TB skin test or TB blood test only tells that a person has been infected with TB bacteria. It does not tell whether the person has latent TB infection (LTBI) or has progressed to TB disease. Other tests, such as a chest x-ray (CXR) and a sample of sputum, are needed to see whether the person has TB disease.

Tuberculous meningitis  (TBM)

==========
F. TREATMENT AND MANAGEMENT

Refer to sections above on Treatment for TB and Treatment for Seizures.

1. Isolation of TB patients (wards and ICU) are necessary to avoid further transmission
2. In patients with tuberculous meningitis, dexamethasone added to routine 4-drug therapy reduces complications.
3. DOT is necessary to ensure patients take their medications for 6 or 9 months
4. Monitoring the desired and adverse effects of the drugs is necessary

Monitoring

Patients diagnosed with active TB should undergo sputum analysis for Mycobacterium tuberculosis weekly until sputum conversion is documented. Monitoring for toxicity includes baseline and periodic liver enzymes (AST, ALT, ALP), complete blood cell (CBC) count, and serum creatinine.

========
G. MERCI

Medical (M)
An epileptic patient needs help when unconscioous or sub-conscious or when falling.
Falling and hitting the head may cause further injury to the H&N region.

Empathy (E)
An epileptic patient needs comforting, help and care during a seizure and post-seizure.

Rights and Respect (R)
Epileptic patients have the same rights and must be respected just like you and me.

Communication (C)
Talking to the patient pre- and post-seizure must be gentle and soothing so as not to create depression (blues) and more harm.
There are instances when epileptic patient must not drive. Seeing to patient compliance is very important.

Insight (I)
Timing and recording the characteristics of each seizure are important.
The duration between seizures is important to know.
Keeping a close watch on epileptic patient is important.
Seeing to that epileptic patient takes his/her medicine is important.

-------------

External links:

TB
https://www.medicalnewstoday.com/articles/8856.php
https://medlineplus.gov/tuberculosis.html

Epilepsy
https://youtu.be/L0XqL2I35n8

Epilepsy (animation)
https://youtu.be/e_Eb32Eq_fw

Causes of epilepsy
https://youtu.be/6NcqQkKjqTI

Epiletic seizure
https://youtu.be/MRZY2a2jnuw

Tonic-clonic (grand mal) seizure
https://youtu.be/c6vKvKuhHXI

Tonic-clonic seizure
https://youtu.be/FBEj9H42fa4

Pharmacology of Epilepsy
https://youtu.be/GMyCWup1Xqo

Antiepileptics
https://youtu.be/c-Cf1xkKofg

TB Workup
http://emedicine.medscape.com/

TB Differential Diagnosis
http://emedicine.medscape.com/article/230802-differential

TB Diagnosis
https://www.cdc.gov/tb/publications/factsheets/testing/diagnosis.htm

CSF Analysis
http://emedicine.medscape.com/article/2093316-overview

CSF Meningitis
http://www.globalrph.com/cerebrospinal_fluid.htm

NAAT
http://emedicine.medscape.com/

Drug susceptibility testing
http://emedicine.medscape.com/

BCG
https://www.cdc.gov/tb/publications/factsheets/prevention/BCG.htm

AFB
https://labtestsonline.org/understanding/analytes/afb-culture/tab/test
http://emedicine.medscape.com/

Neuropathology
http://neuropathology-web.org/chapter14/chapter14CSF.html

CXR
https://www.nhlbi.nih.gov/health/health-topics/topics/cxray
http://emedicine.medscape.com/

TB Treatment
http://emedicine.medscape.com/article/230802-treatment

TB Drugs
http://emedicine.medscape.com/article/230802-medication

MERCI
https://www.healthline.com/health/csf-total-protein#overview1

DOT
http://www.health.state.mn.us/divs/idepc/diseases/tb/lph/dot.html

TB Elimination
https://www.cdc.gov/tb/publications/factsheets/testing/diagnosis.pdf

Sickle-Cell Anaemia (SCA)

Sickle-cell anaemia (SCA) on YouTube:
A Child Prodigy, a Painful Disease, and a Life-Changing Treatment | National Geographic
https://youtu.be/SpzjD1ctCyY

Caesar Sant's Facebook
https://www.facebook.com/Caesar-Sant-592087044136325/

Crowd funding for Caesar Sant's bone transplant
https://www.gofundme.com/You-can-help-Caesar-Sant

Ethical issues involved:

1. Was the second daughter (Helen) a sacrificial bone marrow transplant (BMT) donor for her SCA inflicted elder brother Caesar Sant?
2. Is it ethical to say a sibling is born for the purpose of donation of her body parts (eg bone marrow) for the benefit of others (eg her elder sib)?
3. Why is the cost of a bone transplant in the case of SCA an expensive affair?
4. What will happen to the SCA patient if the funds cannot meet the target (cost of operation)?
5. Is crowd-funding a reliable source of funding for SCA treatment for SCA patients?
6. Can the bone marrow transplant be done at a much cheaper cost elsewhere?
7. Where are the hospitals in the world that can avail their resources to support a BMT for a chikd like Caesar?
8. Can the child's nationality, his family history of SCA and his genetic inheritance of SCA be made public?
9. What is the SCA child's right to fair and affordable treatment?
10. What type of genetic counselling can be given to the family members? First-degree relatives? How far need counselling go - up to what level do doctors need to provide counselling?

LIPID MAPS

LIPID MAPS is a useful website for finding references. It offers basic PowerPoints for helping students learn about Lipids (the other 2 topics in first-year Biochemistry are Carbohydrates and Proteins). It is useful for self-study and guided self-learning (GSL). LIPID MAPS is operated by the University of California based in San Diego campus (UCSD).


LIPID Metabolites and Pathways Strategy (LIPID MAPS)
Lipidomics Gateway
Tutorials and lectures on lipids
http://lipidmaps.org/resources/tutorials/lipid_tutorial.html#L


LIPID MAPS
University of California, San Diego
9500 Gilman Drive, MC 0601
La Jolla, CA 92093-0601
E-mail info@lipidmaps.org
Webmaster@lipidmaps.org.

Endogenous Pathway of Lipoprotein Metabolism (June 2017)

In an integrated curriculum, which our Medical School deploys, temporal distribution of related topics can be an issue which may seriously affect students' learning. This problem can go unnoticed by both lecturers and students. It is a worry when scheduling related topics far apart. They would be close together in a conventional curriculum.


Let me give you an example of what I mean.

1. The topic Exogenous Pathway of Lipoprotein Metabolism was covered in two ways - guided self-learning (GSL5) and a class lecture. However, these two inputs were spaced far apart on the time-table.
2. The GSL5 module was made available to students at the e-learning portal on 19 Sept 2016
3. The lecture Lipoprotein Metabolism was delivered in the lecture hall on 1 March 2017
4. Time difference between GSL5 and the lipoprotein lecture was 4.5 months
5. A semester exam was conducted on 19 June 2017 (7.5 months after GSL5 and 2.5 months after lecture

Module:
CELL AND TISSUE
COURSE (GMT 101)
PHASE I MD 2016/2017
GUIDED SELF-LEARNING (GSL) ON
STRUCTURE AND FUNCTION OF LIPIDS
Prepared by
PROF. FARIDAH ABDUL RASHID
DEPARTMENT OF CHEMICAL PATHOLOGY
SCHOOL OF MEDICAL SCIENCES
KUBANG KERIAN, KELANTAN
Updated on
22 August 2016
------
Medical Doctor (MD) Programme Phase I
Academic Session 2016/2017
Cell & Tissue Course (GMT 101)
Week 2
GSL 5: Structure and Function of Carbohydrates, Lipids, Amino Acids
and Nucleic Acids (Biomolecules) ... uploaded at e-learning portal
KNSS, IZA, FAR
19 Sept 2016
Contents:
PLASMA LIPOPROTEINS AND LIPOPROTEIN METABOLISM (pages 28-35)
ENDOGENOUS PATHWAY (page 32)
-----------
Phase I
Year 1 Sem 2
MEDICAL DOCTOR (MD) PROGRAMME PHASE I (YEAR 1)
Academic Session 2016/2017
CVS Course (GMT 107)
Week 3
Lecture
Lipoprotein Metabolism
1 March 2017

Even though the lecture on Lipoprotein Metabolism was given late in first year (Sem 2), in the CVS Course (GMT 107), it should not be an excuse for students who are unable to connect with or recall earlier topics (Learning Issues, LI, or Learning Objects, LO).

Students may not be able to recall or connect that the same topic and essay questions have appeared earlier - in the self-learning module or guided self-learning (GSL), in their first week of Medical School (Sem 1, Cell & Tissue Course (GMT 101).

This shows that students often do not revise, re-study or check back on what they have learned very early in their medical course. There is a gap and topics early in their medical studies may have been forgotten altogether. However, they only need to revise, re-study or check back. They may not be able to connect past topics if they did not re-check, revise or re-study the topics that they have learned many months before to exam.

There are 3 possible essay questions concerning the topic Lipoprotein Metabolism. Any of these 3 essay questions can pop up on any exam - Term and Professional. Therefore, students should be aware that there are these 3 options. They should be prepared, rather than not be aware and be unprepared or go blank during exam.

For June 2017 exam, though a large number of students passed (77/124 or 62%), I am quite disappointed that quite a large number of students (47/124 or 38%) still failed a repeat essay question on lipoprotein metabolism, which have been made available to students in their first week of Medical School since 2014 (and earlier). What a shame!

The essay question below was taken directly from the GSL, that was made available online at the e-learning portal on 19 Sept 2016, to all incoming first-year medical students. Students either saw it but overlooked it, or took it seriously, studied and attempted to answer it! There is no excuse for failing this essay question.


Essay
Describe the endogenous pathway of lipoprotein metabolism. (10 marks)


Proposed Model Answer

(i) Diagram

Is a diagram required?
No and it is not necessary.
A diagram is not required since it is not specifically asked.
However, you can draw a labelled diagram or flowchart if it helps and guides you to answer the question.
Refer to any diagram on "endogenous pathway of lipoprotein metabolism" in any textbook or Google it.

(ii) Text

	Any 10 Statements pertaining to the following, or other statements relevant to the topic.	Max. 10 Marks
1.	Endogenous pathway happens all the time.	1
2.	It involves VLDL-LDL metabolism or “LDL cascade” and LDL receptor-mediated uptake in liver.	1
	Synthesis of VLDL:
3.	The liver synthesizes VLDL. Hepatocytes release nascent VLDL into the Space of Disse àVLDL enter sinusoids à VLDL enter systemic circulation.	1
	VLDL have several fates:
4.	a)      VLDL transport triglycerides from liver to peripheral tissues for utilization.	1
5.	b)      When VLDL reach vascular/capillary beds, they undergo hydrolysis (lipolysis) by LPL where their triglycerides contents are hydrolysed to free fatty acids (FFAs) and glycerol.	1
6.	c)      VLDL remnants are taken up by liver via LDL (B,E) receptors.	1
7.	d)     The VLDL are reduced in size (but increased density) and are converted into VLDL remnants and IDL, as a result of lipoprotein lipase (LPL) activity, hydrolysis or delipidation, which requires apolipoprotein C-II as cofactor.	1
	Unesterified FFAs have several fates:
8.	a)      During lipolysis, some FFA can be carried by plasma albumin and dispersed in plasma for delivery to other cells. Not much of this happens.	1
9.	b)      Normally, FFA can enter underlying adipocytes by simple diffusion. Inside the adipocytes, the FFA are re-esterified to form triglycerides (TG) once more. Adipocytes store TG until required (as an energy source during fasting or starvation). A majority of FFA are stored in adipocytes following lipolysis.	1
10.	c)      In times of starvation, when blood glucose is low and glycogen reserves are low, triglycerides stored in adipose tissues are hydrolysed by hormone sensitive lipase (HSL) and the FFAs are released from adipose tissue. FFAs then attach to circulating albumin and are brought to liver for beta-oxidation, for continued energy supply.	1
	IDL have several fates:
11.	a)      IDL can be converted into LDL by LPL in blood (intravascular).	1
12.	b)      IDL can be taken up by hepatic receptors.	1
13.	c)      IDL can be converted into LDL by hepatic lipase (HTGL) in liver.	1
	LDL have several fates:
14.	a)      Normally, LDL are taken up by hepatic LDL (B,E) receptors. The contents of LDL are broken down into FC, CE, PL, TG/ DG/ MG/ FFA and amino acids. These are kept within the hepatocytes or recycled for use by other cells. Hepatic contents of FC and CE are regulated by acyl cholesterol acyltransferase (ACAT). Few things can happen if cholesterol is low, specifically in the cell or in the blood. If there is low cellular FC, stored cholesterol (as cholesteryl ester, CE) is broken down to free cholesterol (FC) by ACAT. If there is low plasma FC, the liver cell makes more FC via increased HMG-CoA reductase activity. The 2 enzymes, ACAT and HMG-CoA reductase, are sensitive to cellular and blood cholesterol levels, and combined, they regulate cholesterol levels in cells and blood.	1
15.	b)      LDL can also deliver its contents directly to cells, eg adrenal glands, for synthesis of steroid hormones.	1
16.	c)      Under abnormal levels of LDL in the blood (eg hyperlipidaemia), LDL can be taken up by the scavenger receptors present on extrahepatic tissues (EHT).	1
17.	d)     LDL apoB-100 will be oxidized due to the prolonged presence of LDL in blood. Also, the LDL particle is now smaller and apoB-100 is unstable at this stage. ApoB-100 becomes easily oxidised. Oxidised apoB-100 has higher affinity for macrophages. Thus, oxidised LDL will be taken up by macrophages in EHT.	1
18.	e)      Macrophages contain scavenger receptors on their surface. Macrophages are present on blood vessel walls. Oxidised LDL will attach to the receptors and be internalised by macrophages.	1
19.	f)       The oxidised LDL are hydrolysed into component cholesterol, fatty acids, glycerol and amino acids, which are stored within the macrophages.	1
20.	g)      This uptake of oxidised LDL is unregulated (ie, uncontrolled). The macrophages take up as much LDL as they can until they stop functioning and die - becoming foam cells.	1

OUTCOMES

Students' English proficiency

1. Some can write well
2. A few cannot write correct English sentences and seemed to struggle
3. Not knowing how to properly use some words in sentences makes it difficult to comprehend what students are writing or trying to convey. Use of certain words seem difficult for students: constituent, composition, comprise, compose; retained, remained, degrade, bind, combine, uptake, consumed, utilised, undergo, etc
4. Understanding of reciprocal relationships - lipoprotein density increases as size decreases
5. Practice will make essay writing perfect, but there is lack of written assignments in first-year Medical School.
6. There may be greater underlying problems such as learning the relevant science subjects in Bahasa Malaysia in primary and secondary schools. Subjects such as Biology, Chemistry, Physics, may have been taught in Bahasa. They should be taught in English if students have to master English at university level, and especially in a medical course.
7. Students have tried their best to answer in English.

Students' answering difficulties

1. No schema or outline to use to answer the question
2. Careless writing 
3. Haphazard writing 
4. Don't know how & where to begin
5. No proper writing style
6. Page improperly utilised
7. Considerable amount of scribbling at edges
8. Diagrams in pencil and not ink 
9. Thinking and writing at full speed 
10. No knowledge to even write anything
11. Blank or stuck
12. Unexpected essay question
13. No time to check answers

Students' handwriting

• Handwriting was terrible for a majority of the scripts.
• Most handwriting were tiny and had to be read close-up.
• 1 script was intelligible (hard to read and comprehend)

Students' creativity

• Abbreviations for VLDL, IDL and LDL were various and incorrect
• Swapped functions of VLDL and HDL
• New abbreviations were created! ILDL, LDLL, LPLL, CDL, etc. 
• New terminologies were created! Empty HDL
• Mixed up abbreviations! ADH instead of ADP.

Diagrams drawn by students

• Interesting diagrams, but some were incomplete
• There were 11 little diagrams of sorts. Some were weird.
• There were 2 big flowcharts that filled the entire page and were easy to follow.
• There was a tiny pathway that looked like the Intrinsic Pathway for Clotting Factors; could be a Physics answer or something, but not E = mc2.

PROBLEMS FACED BY STUDENTS
23 students scored 0 marks (18.5%)

Breakdown of problems faced by students who scored 0 marks:

• 8 students handed in empty answer scripts (completely no answer; nothing written).
• 7 students answered wrongly on Chylomicron Metabolism* 
•    *Chylomicron Metabolism is Exogenous pathway of lipoprotein metabolism.
• 5 students answered on Lipid Digestion (2) / Micelles and Chylomicron / Lipid Digestion and Chylomicron / Stomach Functions and Chylomicron
• 1 student answered on Cholesterol Synthesis
• 1 student answered on Ketogenesis
• 1 student drew a pathway that looked like the Intrinsic Pathway for Clotting Factors, without any text.

FOCUS of this essay question

Since this essay question is specifically about VLDL-IDL-LDL metabolism or endogenous pathway, any answer on chylomicron metabolism or exogenous pathway will be incorrect. Since HDL metabolism is not asked, there is no need to touch on HDL metabolism, except its associated role in the endogenous pathway.

Other answers such as stomach contents and functions, lipid digestion (formation of micelles, enzymic digesiton of lipids), lipid absorption, formation of chylomicron in enterocytes, passage of chylomicron from lacteals via lymphatics to liver are all irrelevant.

Other processes in the liver such as cholesterol synthesis and ketogenesis are irrelevant as this question is specific and focused on the metabolism of lipoproteins containing apo B-100.


FALSE Statements

1. This VLDL is major transported [transporter?] of phospholipid [F]. VLDL then could send the phospholipid to cell for cell integrity or to the cell that uses it for the production of energy [F].[VLDL is the major transporter of endogenous triglycerides ... from adipose tissues. Phospholipid is not used to generate energy.]
2. Endogenous pathway of lipoprotein metabolism is for metabolism of chylomicrons [F].

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IRRELEVANT Answers

The essay question specifically asked about endogenous pathway (VLDL-IDL-LDL metabolism), which occurs all the time in the body, whether we are fasting or not. There is no need to write about other topics. There is no need to write about carbohydrate metabolism (polysaccharide digestion, glucose and rbc metabolism). There is no need to write about GIT (stomach contents and functions). There is no need to write about lipid digestion and absorption. Stay focussed on the topic.

(a) Glucose & rbc metabolism

1. Glucose is converted into pyruvate which will form the cholesterol.
2. When rbc is damaged, or aged, lipoprotein will metabolised to be store into the body as a source of heat, membrane fluidity.

(b) Lipid digestion and absorption 

1. So lipoprotein metabolism functions to break down lipid and protein to their respective basic units for better absorption.
2. Lipid is broken down to its simplest form which are fatty acids and 3 glycerols with the help of ADH for energy.
3. Lipid will enter lacteals (specialised lymph in the villi) to be utilised by the body again (as chylomicra).

(c) Carbohydrate digestion 

1. From complex polysaccharide, it is broken down into disaccharide by removal of water. Then disscharide is broken down to amino acids which is the simplest form of protein.

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Student Answers on

ENDOGENOUS PATHWAY OF LIPOPROTEIN METABOLISM

[F] = False statement

[?] = examiner's query

(a) Students' understanding of the different lipoprotein pathways

1. There are 2 pathway(s) involved in lipoprotein mechanism which are through endogenous pathway and exogenous pathway
2. Endogenous pathway is about VLDL
3. Endogenous pathway of lipoprotein is when it is synthesis from cholesterol inside the liver.
4. Endogenous Pathway is occur within circulation. Endogenous Pathway of lipoprotein metabolism consist of VLDL-LDL metabolism, LDL metabolism and LDL-mediated receptor (uptake).

(b) Ambiguous statements written by students

1. Lipoprotein metabolism occur in liver. It is combination of lipid and protein.[Abstract writing!]
2. Cholesterol is transported from the GIT to the liver in both estercifed [esterified] and free form in the liver. [Meaning?]
3. Cholesterol under go oxidation estirification and compannded with protiens Apo proteins to form lipoproteins which are sent to the bloodstream as VLDL. [Meaning?]

(c) Lipoprotein structure

1. Lipid basic structure and triglyceride and fatty acids
2. For proteins, its amino acids
3. Cholesterol combines with apolipoprotein
4. Cholesterol, apolipoprotein, phospholipid and triglyceride will form VLDL and also empty HDL
5. Lipoprotein is constituent of both lipid and protein.
6. Triglyceride has about 60% in VLDL [This is better written as VLDL contains approximately 60% triglycerides.]
7. VLDL has Apo B-100 molecule [This is better written as Each VLDL has an apo B-100 molecule.]
8. IDL is high in cholesterol

(d) Classes of lipoproteins

1. There are 2 lipoprotein(s) that (are) present in (the) body which are high density lipoprotein (HDL) and low density lipoprotein (LDL). [F] [There are 4 major classes of lipoproteins.]
2. The last one is HDL

(e) Function of lipoproteins

1. LDL is described as bad cholesterol
2. LDL is major transporter of cholesterol. It send the cholesterol (to) the cell of adipose and liver to be stored.
3. HDL is described as good cholesterol
4. The function of HDL is to transport excess cholesterol to the liver to be metabolised. The HDL is the could be recycle for the next  use.

(f) Lipoprotein conversions

1. In lipoprotein metabolism, chylomicron is converted into very low density lipoprotein (VLDL) [F]. VLDL in then convert into intermediate low density lipoprotein (ILDL) [F]. ILDL will form low density lipoprotein (LDL) which then converted into high density lipoprotein (HDL) [F].
2. Chylomicron will bind to Apo E and C to become high density lipoprotein [F]. Then it become  intermediate density lipoprotein, low density lipoprotein and very low density lipoprotein [F]. 
3. After the VLDL will converted into IDL or LDL
4. Triglyceride in VLDL is further dehydrolysed leads to conversion of VLDL to IDL.
5. Very low density lipoprotein (VLDL) is degraded by IDL [F]. [VLDL is degraded by LPL to IDL.] Then, forming Low density lipoprotein (LDL) and exocytosed [endocytosed?] either via (scavenger) receptor-mediated or via hepatic (receptors). Then, LDL is taken up to the hepatocytes [taken up by hepatocytes?]. LDL converted to free cholesterol in liver.

(g) Lipoprotein movements

1. Lipid (from circulation) will flow into the liver to (be) metabolised.
2. VLDL will transport cholesterol from tissue to liver for excretion and HDL will transport cholesterol from liver to tissue [F]. [What does VLDL transport?]
3. When it enters the blood circulation, VLDL attaches to Apo C and Apo E
4. Upon entering the circulation, Apo CII activates lipoprotein lipase (LPL). Lipoprotein lipase hydrolyses triglyceride into free fatty acid and glycerol
5. IDL is taken up by the hepatic cells. This is because hepatic cell recognise Apo E on IDL. Apo C and Apo E is retained from IDL [retained with IDL?]. IDL is hydrolysed [to what?]

(h) Products of lipoprotein hydrolysis by LPL

1. Free fatty acid is used for energy, milk lactating
2. Glycerol is needed in glucogenesis and gluconeogenesis

(i) Lipoprotein uptake

1. Macrophages engulfing lipoprotein becomes foam cell

(j) Depth of students' understanding of the topic asked

1. LDL is low density lipoprotein which collects cholesterol from liver to body
2. HDL is good cholesterol which collects cholesterol from body to the liver
3. Liver will produce VLDL with attachment of Apolipoprotein B-100 which is produced by hepatocyte
4. VLDL will combine with Apo E and Apo CII
5. CII will activate lipoprotein lipase to breakdown triglyceride into fatty acid and glycerol
6. Fatty acid can be used in synthesis of lipid, energy storage, production of milk fat in mammary gland
7. The breakdown of triglyceride reduce the VLDL into IDL (VLDL remnant)
8. IDL will transport into the hepatocyte by binding of Apo E on the surface of liver (LDL receptor)
9. IDL will also degrade into LDL with the help of HTL (hepato ... lipase) [HTL or HTGL is hepatic triglyceride lipase.]
10. LDL is more dense and reduce in size [Meaning?] [LDL is smaller and denser than IDL.]
11. It contain more cholesteryl ester
12. LDL can enter the liver by binding of Apo B-100 at the LDL receptor. [Meaning?] [Where is apo B-100 located?] [LDL apo B-100 binds to LDL receptors present on hepatocytes. OR LDL binds to LDL receptors via its apo B-100.]

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CORRECT answers attempted by students (10 marks)
Text only. Associated diagrams are not included here.

Example 1

1. VLDL (very low density lipoprotein) is synthesized in the liver and consist of triglycerides and Apo B-100. [F] [VLDL contains 4 lipid classes and apo B-100.]
2. Then, VLDL is goes out of the liver into blood circulation.
3. Inside the circulation, it receives two apolipoprotein from HDL which is apo C and apo E.
4. Then, VLDL is hydrolysed by lipoprotein lipase which hydrolyse the triglycerides in(to) fatty acids and monoglycerides.
5. This make VLDL size and density decrease [F].[VLDL size is reduced, but its density increases after lipolysis by LPL.]
6. Before transported back into liver, apo C return back to HDL and VLDL remnants diffuse into liver by lipoprotein receptor and by endocytosis. [Diffuse into liver or taken up by liver?]
7. The VLDL remnants become IDL but IDL does not remain for a long time before it converted into LDL (low density lipoprotein). [IDL exists transiently in blood.]

Example 2

1. VLDL (very light density lipoprotein) is form(ed) endogenously in liver. 
2. It consist(s) of free amino acid, cholesterol, cholesteryl ester, phospholipid, triacylglycerol and apo B-100. [VLDL cannot contain free amino acids! Apo B-100 is a large protein!]
3. It is released into circulation.
4. It then take up apo C and apo E from HDL (High density lipoprotein).
5. Apo C will activate Lipoprotein lipase in cappilary epithelium to break down triacylglycerol in VLDL into fatty acid and glycerol. [It should be capillary endothelium.]
6. Now VLDL decrease in volume increase in density and now convert to IDL (intermediate density lipoprotein).
7. IDL bind to lipoprotein receptor at hepatocyte  via apo E through endocytosis. [IDL are internalized by endocytosis.]
8. In the hepatocyte, triacylglycerol in IDL (undergo) further break down by hepatic lipase.
9. Now the compound is increase in density and rich in cholesterol.
10. It is now LDL (low density lipoprotein).
11. It will (be) released by the hepatocyte.
12. After that LDL (is) either absorb(ed) by the liver or posthepatic tissues to (be) further metabolize(d).

Example 3

1. In the lipoprotein metabolism, it consist the exogenous pathway, endogenous pathway and the reverse metabolism pathway. [F] [There is no such thing as reverse metabolism pathway! There is reverse cholesterol transport.]
2. During the endogenous pathway it is started in the liver.
3. From the very low density lipoprotein (VLDL) which is present inside our body will produce in the liver, 
4. It is function to bring the cholesterol to the tissue cell for storage.
5. When it enter the circulation it will undergo lypolysis and converted into the Intermediate density lipoprotein (IDL). 
6. This IDL is appear in the blood just for a while. [Transient]
7. Next the IDL will undergo the lipolysis and then being the low density lipoprotein (LDL).
8. This LDL will deposit into our tissue.
9. Plus the LDL is very anthrogenic [atherogenic], thus LDL will lead into the formation of the atherosclerotic plaque and lead to other disease.
10. This plaque prone to forming more at the abdominal aorta than the thoracic aorta.
11. This LDL that deposit inside the tissue will be taken up back into the liver via the high density lipoprotein (HDL) during the reverse lipoprotein pathway. [Reverse cholesterol transport]
12. The LDL serve as the bad cholesterol inside our body.
13. {Diagram}

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WRONG answers attempted by students (0 marks)

Example 1

1. Chylomicrons are found in intestinal mucosa from dietary lipid. 
2. During the endogenous pathway, high density lipoprotein (HDL) serves as reservoir for apo-C and apo E. [F] [Chylomicron metabolism is exogenous pathway.]
3. The apo-C and apo-E will bind to chylomicrons.
4. As chylomicrons enters the blood circulatory system, lipoprotein lipase (LPL) will hydrolyse the triglycerides into free fatty acid and glycerol.
5. As the triglycerides are broken down, the size of chylomicrons decreases, becomes smaller but its density increases.
6. The Apo-I in chylomicrons will restore back to high density lipoprotein before reaching liver  while the apo-E will stay with the chylomicrons. [Which apolipoproteins go where?]
7. The remnants of chylomicrons reach liver, and will be metabolized as source of energy, heat energy. [F] [What do chylomicron remnants contain?]

Example 2

1. Endogenous pathway of lipoprotein metabolism begins with the absorption of chylomicrons. [F]
2. The chylomicron binds with Apo B-II. [F] [There is no such thing as Apo B-II.]
3. The chylomicron then travels through the lymphatic system while being metabolised by lipoprotein lipase .
4. After a few stages of digestion, the chylomicron enters the liver.

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WRONG answers mixed with correct answers

Example 1 (2 marks)

1. Endogenous pathway.
2. The lipoprotein is transported as VLDL. [1 mark]
3. Then, it changes into LDL. [1 mark]
4. The LDL form chylomicron. [F]
5. Chylomicron is absorb(ed) by lacteal. [irrelevant]
6. Then it moves into blood. [irrelevant]

Example 2 (4 marks)

1. When dietary lipids and cholesterol enter intestine, they (are) converted to tryglyceride, monoglyceride  and fatty acids by intestinal lipase. [The correct spelling is triglyceride.]
2. They are absorbed into intestinal cells which (are) then converted into tryglyceride by golgi apparatus [Golgi apparatus].
3. Tryglyceride, cholesterol will be bind forming chylomicrons (CM). 
4. Chylomicrons are too big to enter blood vessels so it will enter lacteals which then enter blood vessels.
5. CM are utilised by lipase that (are) present in blood vessels forming smaller lipids to be transported to muscle cells for energy and to liver for storage,
6. CM are then transported to liver.
7. Cholesterol will bind to Apo B to form very low density lipoprotein (VLDL). [1 mark]
8. VLDL will be transported in blood vessels where it  (is) utilised by tissues converting it to Intermediate density lipoprotein (IDL). [1 mark]
9. IDL (is) transported to liver forming Low density lipoprotein (LDL). [1 mark]
10. LDL is then again circulated in blood to be utilised by tissues for energy. [1 mark]

End