The big “C” and Auto immunity

Cancer has become such a prevalent phenomenon that it even has its own television show! It is the second most common leading cause of death, accounting for 7.6 million deaths in 2008 and projected to continue to an estimated 13.1 million deaths by 2030 2(WHO, 2013). But what does cancer actually entail?

On a basic molecular level it seems quite simple, a genetic mutation.
In normal tissue, the rate of cell division and the rate of cell loss are balanced to maintain. The rate of cell division is controlled by genes. Although, these genes may be activated in response to stimuli such as growth factors, which then promote cell division. In a similar fashion, cell division may be inhibited by repressor genes such as p53 gene (Martini & Nath, 2009). Other genes involved in normal embryonic development, to control cell turnover such as Ras is involved in cell-signalling pathways in the receptor tyrosine kinase pathway, and is also involved in the underlying mechanism of cancer; uncontrolled and excessive cell proliferation leading to enlarged tissue. However this cannot result in tumour formation by itself and requires mutation of p53 gene to result in tumour formation (Albertus, Johnson & Lewis, 2002).

The p53 gene is involved in cell-cycle control by preventing DNA replication of damaged cells. In addition to restricting cell division, this tumour suppressor gene allows cells to undergo apoptosis which is a normal physiological response that damaged cells may undertake as a protective measure to the body. Furthermore, p53 is involved in a mechanism that prohibits cell division to occur until its damaged DNA is repaired (Albertus et al., 2002).

Therefore, cell division may occur unchecked and cells may escape apoptosis thus spread to the rest of the body, moreover cells continue to proliferate with a corrupted genome. A consequence of these results in abnormalities in the chromosomes resulting in more DNA damage in successive cell divisions and widespread of havoc as depicted in figure 1. Therefore mutations of this p53 gene are critical in the persistence of cancer and unresponsiveness to treatment (Albertus et al., 2002).

However, as statistics and personal experiences of having loved ones who have battled and eventually succumbed to cancer, the effects of cancer are not simple at all. Cancer behaves as a parasite and competes with normal tissue for metabolic needs (Rippey, 1994). Sometimes, the tumours remain localised and are referred to as benign and may be removed although, it can displace adjacent tissue causing functional impairment of tissue and destruction. In malignant tumours, which are more invasive and rapidly growing they may infiltrate blood vessels reaching the blood stream and spread throughout the body (Underwood & Cross, 2009). Once cancer spreads it poses greater threat and makes treatment even more difficult.

Auto immune diseases
Auto immune diseases are similar to cancers in that they both represent a disturbed physiological function and have a genetic basis. However in auto immune disease it results from an auto immune response against a self- antigen which leads to tissue damage (Underwood & Cross, 2009).

As mentioned above, the cell-signalling pathways in the receptor tyrosine kinase pathway involved in cancer is also related to the regulation of the immune response. Tyrosine Kinase controls the JAK-STAT pathway which is hyper-activated in many auto immune diseases including rheumatoid arthritis and Crohn’s disease. In multiple sclerosis another kinase enzyme, Tyrosine Kinase 3 is involved in the maturation of dendritic cells which is disrupted in this disease (Sareum, 2013).

In conclusion, these modules focused upon the molecular occurrences at a more in-depth level as opposed to the level of detail covered in medical biosciences and medical microbiology. Cancer is definitely an important disease given that it is one of leading causes of mortality globally and considering the destruction inflicted upon the body as well as pain and emotional turmoil cancer patients undergo.

References

Martini, F.H. & Nath, J.L. (2009). Fundamentals of anatomy and physiology. USA: Pearson Benjamin Cummings
Rippey, J.J. (1994). General pathology. Johannesburg: Witswatersrand University Press.
Underwood, J.C.E. & Cross, S.S. (2009). General and systematic pathology. (5th ed.). China: Churchill-Livingstone.
Alberts, B., Johnson, A. and Lewis, J. (2002). Molecular Biology of the Cell. (4th ed.). New York: Garland Science. Retrieved, April 21, 2013 from:
http://www.ncbi.nlm.nih.gov/books/NBK26902/
Sareum. Drug Discovery – Cancer & Auto-Immune Disease Drug Programmes. Retrieved, April 21, 2013 from:
http://www.sareum.co.uk/cancer.php
WHO. Cancer. Retrieved, April 21, 2013 from:
http://www.who.int/mediacentre/factsheets/fs297/en/

The central roles of inflammation and repair in health and disease

Inflammation can be described as the local physiological response to tissue injury that is usually a manifestation of disease. Inflammation is generally classed according to its time course; as either acute inflammation which is the initial and brief tissue responses to the injury or chronic inflammation which is the succeeding and often extended tissue response that follows the initial reaction.1 Inflammation plays a central role in preserving health as well as contributing to disease.

Inflammation in health

The quintessential characteristics of inflammation are: redness, heat, swelling, pain and loss of function. These signs are related to the vascular changes including; vascular dilation, exudation of fluid from vessels into tissues, release of chemical mediators of inflammation, and increased tissue tension and pressure. The purpose of inflammation is to offset the effect of the injury by diluting toxins, sealing it off or destroying it by phagocytosis. 2
A common case of an inflammatory response which most people have experienced and can relate to is that of a mosquito bite. The cardinal signs of inflammation, as well as pruritus (an annoying itch), is usually noted. This response is brought about by the infection of human body with the mosquito’s saliva which is detected by mast cells that then release mediators of inflammation and result in bacterial removal.3 This example reflects the central role of inflammation as part of the body’s defence system to protect the body against infection.
This process is depicted in figure 15:

figure 1

Although inflammation acts a means of defence against the tissue injury, it may however also serve as a contributing factor to the development of disease.

Inflammation in disease

Acute inflammation can progress to chronic inflammation if the injurious substance persists while attempts at healing occur. This could have implications on the health of the body.2 A painful condition commonly experienced by older people is rheumatoid arthritis.4 In this disease; undesired and unnecessary inflammatory reactions form the basis of the disease.2 Chronic inflammation can result in breakdown of cartilage, bone and ligaments contributing to the deformity of joints.4
In the case of tissue injury that necessitates inflammation, this inflammatory response may have served to protect the body. Whereas, an inappropriate inflammatory response that exceeds the body’s need may pose greater harm.
Furthermore is the case of an abscess formation in the brain (suppurative inflammation2). This may have occurred as a result of the body’s attempt to seclude pus to a confined area and thereby prevent further spread of infection. However, this may then act as a space-occupying lesion that could compress vital surrounding structures and result in disease.1

Healing and repair

Inflammation is generally followed by other tissue changes that occur in healing such as regeneration of destroyed cells and repair by proliferation of fibrous tissue. The way in which healing occurs depends on the type of cell damaged as well as the extent of the damage. This ultimately affects the extent to which restoration of the damaged tissue can occur .2
Figure 2 illustrates the two main processes of healing6:

figure 2

A personal life experience of having burnt my hand on a heater as a toddler comes to mind as this chapter on healing and repair explains the pale, irregular and slightly raised fibrous appearance of the scar still twenty years later, and why it will never return completely to its normal appearance.

The process of healing may happen in various ways: Resolution occurs when the tissue is returned to normal structural and functional capabilities; which requires the preservation of the underlying tissue framework. Regeneration pertains to proliferation of parenchymal cells with some loss of normal architecture. Whereas organisation occurs when lost tissue is replaced with granulation tissue and fibrous repair. Regeneration and organisation may occur simultaneously, although if the underlying framework has been destroyed, the architecture may not be restored,2 as in the case of my burn scar.
Furthermore, the process of healing and repair, which is aimed at restoring function to the body, may also result in disease of the human body. This is seen in the case of severe hepatitis showing massive liver necrosis, in which regeneration and fibrous scarring occurs resulting in functional impairment of the liver2.

Conclusion

Prior to studying general pathology I had not realised how much of illness and disease actually result from the attempt of the body to defend and heal itself. Although these mechanisms serve its purpose of protecting and preserving health to a certain extent, I find it quite strange and ironic to think that these exact mechanisms of protecting result in disease too.
Inflammation is described (particularly in microbiology) as the body’s defence system, although it may contribute to pathogenesis as it might occur as an unwanted effect, as described in rheumatoid arthritis. Similarly, healing and repair attempts to restore the body to its normal capacity; however it may result in impaired function as seen in fibrous liver scarring. Essentially, the mechanisms of inflammation and healing offer the body greater benefit than potential harm.

References
1 J.C.E. Underwood and S.S. Cross, General and systematic pathology, Churchill-Livingstone, China, 2009

2 J.J. Rippey, General pathology, Witswatersrand University Press, Johannesburg, 1994

3 C. E. Demeure, K. Brahimi, F. Hacini, F. Marchand, R. Pe´ronet, M. Huerre, P. St.-Mezard, J.F Nicolas, P. Brey, G. Delespesse and S. Me´cheri, The Journal of Immunology., 2005, 174: 3932–3940.
(accessed 6 April 2013).

4 W. Shiel, What is rheumatoid arthritis, , 2012 (accessed 6 April 2013).

Images retrieved from:
5 http://www.studyblue.com
6 http://www.kmle.co.kr

Normal and abnormal fluid distribution and function

The human body mass comprises about 55-60% of water (Rippey, 1994). Thus water is a vital component of the body and forms the primary constituent of blood plasma, maintains fluid-electrolyte balances between cells and thus ensures cell function as well as maintains body temperature and excretion of toxic substances and pH balance (IvyRose, 2013). The body needs to maintain its fluid balance by various compensatory mechanisms such as thirst and excretory mechanisms via hormonal regulation (Rippey, 1994).

functions of water in the body

If this balance is disrupted and disparities such as excess or insufficiency of flow of fluid occurs in measures that are beyond the control and regulatory powers of the body, disease may manifest, often as consequence of the body’s attempt at restoration. The following conditions could arise as result of the body failing to overcome the imbalance or some trauma or in attempt thereof:
Oedema may manifest in cases of excessive accumulation of extracellular fluid in the interstitial spaces (Rippey, 1994), as seen in obstructive hydrocephalus which pertains to the condition of enlarged ventricles due to the accumulation of cerebrospinal fluid (CSF). This generally results from blockage of normal CSF flow through the ventricles. The danger of such condition is the delicate brain matter compressing against hard cranium which could result in cell and tissue death (Zillmer, Spiers & Culbertson, 2008). This illustrates the importance of homeostasis and synergy within the various body systems to ensure fluid and electrolyte balance.
Other conditions related to oedema are hyperaemia and congestion which describe abnormal flow of blood within blood vessels and thus an increase in blood in certain areas. In the case of hyperaemia which refers to increased blood flow and reddening to a particular area. This can be manifested by an inflammatory response in the attempt of body to increase blood flow to a specific area (Rippey, 1994), however if this response persists beyond the extent of inflammation, it could create an imbalance in blood flow and potentially lead to cellular/tissue damage.
Whereas, in congestion blood flow is reduced and congestion occurs due to a venous blockage and can lead to an increased level of deoxygenated blood buildup in the vessel. In severe cases, congestion could give rise to oedema by the escape of circulatory fluid to tissues, anoxia by decreased blood flow bringing oxygen or haemorrhage may result by escape of red cells (Rippey, 1994).
Haemorrhage which pertains to the escape of blood from vessels could arise by injury to blood vessels. The body responds to blood loss by compensatory mechanisms including the selective peripheral vasoconstriction to maintain blood pressure with the now decreased blood volume and an increased heart rate to ensure the supply to vital organs is maintained (Rippey, 1994). However, if the damage exceeds the body’s capacity to compensate for the effects, shock may ensue. Shock may entail pooling of blood contributing to congestion and oedema in lungs, metabolic lactic acidosis and anoxia due to ischaemia which gives rise cellular and tissue death and leads to an infarction (Rippey, 1994).
Furthermore, illustrating how the body’s attempt at regulating the imbalance and striving toward homeostasis could contribute to the disease process in the case of overwhelming trauma/imbalance can be seen in the example of thrombus formation which can occur as a result of the body’s attempt to fill a ruptured vessel and thus recompense the damaged vessel. Depending on the magnitude of the damage, increased platelet aggregation and fibrin precipitation in producing a larger thrombus may result in an occlusion and subsequently a decreased blood flow through the vessel. Similarly, an embolus which is an abnormal form of undissolved material that was transported via circulation to other areas of the body may cause vessel occlusion (Rippey, 1994). This could result in ishaemia and hypoxia or anoxia, depending on the extent of the blockage (Zillmer et al., 2008). As a consequence of this physiological compensatory mechanism, ischaemia and subsequent infarction may result. In terms of the region this could have serious medical consequences; it may be a stroke occurring in the cerebral artery or myocardial infarction in coronary artery (Rippey, 1994).
Thrombosis may also occur in haemostasis and congestion given the restricted removal of clotting factors and lack of admission of anticoagulants to the area. Thrombosis may also contribute to hyperaemia and congestion by creating an occlusion and hence build-up of blood within the vessel (Rippey, 1994).

thrombosis

Thus severe pathological outcomes might occur as result of the body’s physiological response to various stressors and imbalance and in such other areas in the body may be affected or conditions of homeostasis worsened. Similarly, a normal physiological response could give rise to pathological effects if there is no inhibition of the physiological process when it is no longer needed

References:
IvyRose, (2013). Structure and Functions of Blood Tissue. Retrieved March, 24, 2013 from:
http://www.ivy-rose.co.uk/HumanBody/Tissue/Tissue_Blood-Tissue.php
Rippey, J.J. (1994). General pathology. Johannesburg: Witswatersrand University Press.
Zillmer, E. A., Spiers, M. V., & Culbertson, W. C., (2008). Principles of neuropsychology. (2nd ed.). USA: Wadsworth
http://catalog.nucleusinc.com/enlargeexhibit.php?ID=11858
http://www.mayoclinic.com/health/medical/IM00594
http://www.strokecare.co.uk/Stroke%20Explained/what-is-stroke

The abnormal deposition of material in tissues

The abnormal deposition of materials in various soft tissues as seen in the anomalies of: Amyloidosis, Calcification, Pigmentation and Jaundice reflect the importance of maintaining balance and homeostasis in the human body. These conditions highlight the importance of synergy of all the body’s systems to constantly adapt and maintain complete homeostasis. Furthermore, it reflects the importance that every basic structure in the body, albeit seemingly simple, plays in maintaining harmony of the entire body as dysfunction in any such area impacts upon other systems thus causing a ripple effect.

In the case of amyloidosis which pertains to the unusual deposition of immunoglobulins leads to an excess of light-chain fragments that in turn account abnormal protein structures in soft tissue and walls of small blood vessels, a disturbance in the synthesis for the occurrence of AL amyloidosis (Rippey, 1994). Amyloid deposits commonly occur in the kidney, heart, liver and gastro intestinal tract (Attaelmannan & Levinson, 2000). As such, restrictive cardiomyopathy which is characterised by stiffness of the myocardium and linked to heart failure, could arise as a consequence of amyloid deposits in vital organs (Nihoyannopoulos & Dawson, 2009).

Similarly, serious and possibly fatal consequences could arise in the deposition of such amyloids in kidneys resulting in ischaemia, tissue death and eventually renal failure. Likewise in calcification which relates to deposition of calcium salts in unusual tissues, heterotrophic calcification could occur in elastic arteries and in kidneys leading to renal failure (Rippey, 1994).

Whereas dystrophic calcification pertains to the calcification of dead and degenerating tissue, and may be illustrative of an immune response and the body’s attempt to preserve health of the rest of the body by isolating the necrotic tissue to avoid putrefaction and further invasion of foreign organisms to the rest of the body (Hall, 2012).
Another case of accumulation of a pigmented substance, bilirubin, in tissues and interstitial fluid of the body is referred to as jaundice. This condition may not necessarily be a serious pathological state as it is commonly seen in new-born babies due to their initial lack of the enzyme glucuronyl transferase. However, should these levels of bilirubin elevate to a certain level it could lead to kernicterus, the reach of bilirubin in the brain causing irreversible neural defects (Rippey, 1994).
In a similar fashion, tissue deposits could also be seen in hemosiderosis, which is a form of pigmentation affecting various organs by excess of hemosiderin. The excess accumulation of iron leads to hemosiderin deposition and pigmentation in parenchymal cells of the liver which leads to destruction and fibrous replacement as well as its deposition in endocrine organs like the pancreas that lead to dysfunction subsequently diabetes (Rippey, 1994). Thus demonstrating the importance of each system and how tissue deposition relates to its destruction and the development of other diseases.

In terms of the importance of various systems working together; the lack of an enzyme could result in substance accumulation and this could affect various essential organs and lead to serious consequences or death.The common ground of these conditions is the alteration of tissue structure and hence functions due to excessive product accumulation normally present in minute amounts including calcium, amyloid and pigments like heamosiderin and lipofuscin (Underwood & Cross, 2009). An excess of a particular substance either as result of accumulation of substances due to excess formation or insufficient removal as in jaundice results in the presentation of these conditions and hence its importance as contributing to the disease process as in bronze diabetes by pancreatic cell destruction as seen in haemosiderosis (Rippey, 1994). Moreover, these conditions may occur as an attempt of the body to avoid further harm to the body as seen in dystrophic calcification (Hall, 2012). However depending on the regions affected and degree of calcification, this could also form part of disease process and lead to other conditions such as ischaemia and eventually tissue death and destruction.

References:

Attaelmannan, M. & Levinson, S. S. (2000). Understanding and identifying monoclonal gammopathies. Retrieved March, 01, 2013, from: http://www.clinchem.org/content/46/8/1230.full#sec-8

Hall, M. J. (2012). What is dystrophic calcification. Retrieved March, 03, 2013, from: http://www.wisegeek.com/what-is-dystrophic-calcification.htm

Nihoyannopoulos, P. & Dawson, D. (2009). Restrictive cardiomyopathies. Retrieved March, 01, 2013, from: http://intl-ejechocard.oxfordjournals.org/content/10/8/iii23.full

Rippey, J.J. (1994). General pathology. Johannesburg: Witswatersrand University Press.

Underwood, J.C.E. & Cross, S.S. (2009). General and systematic pathology. (5th ed.). China: Churchill-Livingstone.

The role of cells in health and disease

The cell is the most basic unit of life; it is micro in size, usually about 0.1mm in diameter. (Martini & Nath, 2009). Despite its tiny size, its importance in the existence of an organism is invaluable. The cells functions include cellular respiration, protein synthesis as well as maintaining ionic and osmotic balance; tasks that are vital to the operation of the organism.  Cells function to maintain tissue and subsequently organ structure and function, by maintaining homeostasis primarily at a cellular level (Martini & Nath, 2009). Any disruption in the internal or external environment of the organism, however minor, places stress on cells and would thus require effort by the cells to restore homeostasis as any disruption to this equilibrium could predispose the organism to disease (Kahn, 2007).                                     

There are various methods of adaptation by which cells respond to various stressors, such methods include hypertrophy and hypotrophy which relate to changes in cell size. Furthermore, cellular adaptation could include changes in cell number such as hyperplasia and hypoplasia. These adaptation strategies as seen in the case of increased muscle size with continuous exercise/strain (hypertrophy) as well as glandular proliferation of breasts during pregnancy (hyperplasia) illustrate the remarkable and continuous work of cells to adapt to an ever-changing environment (Kahn, 2007). 

These forms of cellular adaptation reflect ‘normal’ physiological responses to stress and mild injury and are often reversible. However in cases of more severe cellular injury; this could lead to irreversible cell injury and eventually cell death should the cells’ adaptive capacity be exceeded (Rippey, 1994). Furthermore, the cells’ adaptability and extent of injury depends on the type of cell (also related to cell location) as well as the duration and type of injury sustained. Injury to the cells include: trauma, thermal injury, poisons, infectious organisms, ischemia, and ionising radiation (Underwood & Cross, 2009). This could detrimentally impact upon the normal functioning of the cell thus leading to infiltrations and cellular degenerations (Rippey, 1994).

The most common mechanisms by which the cells respond to cell injury are hydropic change and fatty change (Underwood & Cross, 2009). Such changes in the cells affect the morphological appearances of tissue and hence the functioning of the organ itself. The progression of such changes as seen in the cellular responses to injury, and subsequent dysfunction generally forms the basis of the emanating disease, as can be seen in the case of liver cirrhosis, and will eventually lead to cell death (Rippey, 1994).                    

Cell death may have occurred by apoptosis which can be described as the programmed death of individual cells that generally occur as a ‘normal’ physiological response.  In contrast; necrosis occurs and is associated with a pathological response and refers to the morphological changes that occur in the cell after cell death (Rippey, 1994), and is also used to describe cell death occurring as a result of bioenergetic dysfunction and loss of cell membrane integrity (Underwood & Cross, 2009). Both forms of cell death have their relevance as seen in the apoptotic death of endometrial cells with menstruation. Whereas in the case of necrosis; many forms exist depending on the region affected as well as type of cell injury (Rippey, 1994).

Gangrene could result with putrefaction of dead cells and surrounding tissue by anaerobic saprophytic organisms commonly Clostridial organisms and could require amputation to prevent further damage to the rest of the body and fatality. Necrosis and moreover gangrene illustrates the importance of the functioning of a tiny cell, how severe adversity and dysfunction in this minute structure could escalate and result in the destruction of entire organs and possibly organisms.

In conclusion; these modules illustrated the enormous effort cells undergo to maintain homeostasis and health. The manifestation of disease and clinical signs and symptoms only emerge after the much of cells’ attempt to maintain homeostasis and ensure survival (Rippey, 1994). In contrast to medical microbiological modules, the role of the foreign organism is often highlighted, whereas the cells’ role in attempt to combat the effects of micro-organism seems underplayed. Thus any adversity affecting the cell, if too severe to be overcome by cellular adaptation and cellular responses could result in cell death and necrosis and may affect the entire organism. 

 

References:

Khan, M.A. (2007). Cellular adaptations to disease/cell injury and death.

Retrieved February, 17, 2013, from Tufts University website: http://ocw.tufts.edu/data/51/551831.pdf

Martini, F.H. & Nath, J.L. (2009). Fundamentals of anatomy and physiology. USA:  Pearson Benjamin Cummings

Rippey, J.J. (1994). General pathology. Johannesburg: Witswatersrand University Press.

Underwood, J.C.E. & Cross, S.S. (2009). General and systematic pathology. (5^th ed.).          China: Churchill-Livingstone.

Images links:

Extracted from: http://www.beyond1.com/7Minutes.php

Extracted from: http://ocw.tufts.edu/Content/51/lecturenotes/551831/552077

Extracted from http://www.cell-bio.com/bbs/data/k5/cell_death02.jpg

Personal Biography

Wi’ahm Petersen

I am a Natural Medicine student interested in Unani tibb, I became interested in Unani tibb when I attended the opening of a local Unani tibb clinic and learnt about their philosophies and practices. I have keen interest in natural medicine and its methodology of facilitating nature in healing processes. General pathology seems interesting in providing an understanding of the human body and its mechanisms of manifesting illness in its attempt to restore the body to balance and re-establish health. Apart from natural medicine, interests and hobbies include fashion, arts and crafts and culinary arts.