Cancer

tumblr_m8i0x4P2ob1qg1up7o1_500This blog post considers the modules relating to cancer from the recommended text book General Pathology by J.J. Rippey and how engagement with this material has changed my previous understanding of the disease. I explore how cancer is such a simple concept on a molecular basis and yet there is a high complexity to individual cancers making many of them very difficult to treat. I also briefly look into some of the molecular similarities between the pathogenesis of auto-immunity and cancer.

Before engaging with these modules my preconceived understanding of cancer was limited in that I didn’t really know much about the pathophysiology of cancer. I knew that cancerous tumours were due to abnormal cell growth and that these cells had the ability to spread in the body. I had a feeling for how complicated and difficult it was to treat cancer but had no clear understanding as to why.

I believe that in some way I thought that cancer was somehow something alien to the body even though I rationally knew that it came from within. But now, I see how intimately it is bound to the body, how it is a completely natural progression within the body when there is a loss of growth regulation, how the tumour cells are striving to survive with the same tenacity as physiologically normal cells. While reading in preparation for this blog there were certain things that jumped out for me in particular as they are new to me. One of these is that neoplasms seem to behave as parasites! “Tumour cells do not grow in isolation, but require a supporting connective tissue framework, which is not in itself tumourous” (Rippey, 1994: 244). They secrete growth factors that promote angiogenesis, attract and stimulate formation and penetration of vessels, lymphatics and nerves – creating this framework, that comes from the host, to support their nutritional and metabolic needs. (Rippey, 1994)(Leisegang, 2012) In doing so, they compete with normal cells and tissues. (Leisegang, 2012) This shows that all tumours have two basic components – the parenchyma cells of the neoplasm which dictates biological behaviour of the tumour, and the supporting framework that is derived from the host and is not neoplastic (this is crucial to the growth of tumours). (Leisegang, 2012) Another aspect of cancer pathophysiology that was new to me is that not all cancer cells are able to metastasise, that there are several stages necessary for metastasis to occur and for a tumour cell to be able to do this it must have certain attributes. (Rippey, 1994) This process is shown in the video below. (MechanismsMedicine, 2012)

 

molecular basisOn a molecular basis, cancer is such a simple concept. The diagram to the left, from our carcinogenesis module notes, is a simplified scheme of the molecular basis of cancer formation and clearly demonstrates this concept. (Leisegang, 2012: 6) Yet individual cancers are highly complex and many are difficult to treat. Why is this the case? The slides below show how cancer starts with multiple mutations involving many genes in cellular DNA; and how the mutations occur not only in the oncogenes, tumour suppressor genes and DNA repair genes but also in quite a few others, as can be seen below. (National Cancer Institute, 2013) Due to the build-up of mutations in these genes being a random and haphazard process, an individual evolution in response to the body’s selective pressures, cancers are actually extremely diverse diseases as every patient’s cancer is unique! (Evans, 2012) Also, ‘cancer cells adapt and evolve in response to treatment’, rendering drugs less effective over time in two ways – compensation and evolution. (Evans, 2012) They can compensate by working around the biological systems that are blocked by cancer treatment, and they can evolve if mutant daughter cancer cells resistant to the cancer treatment spontaneously come about. (Evans, 2012)

cancer49

cancer50

In reading the modules on auto-immunity I noticed that there were some molecular similarities between the pathogenesis of cancer and auto-immunity in that they both share very similar environmental factors as aetiologies for their initiation as well as a genetic predisposition not being enough of a trigger, they both need the environmental factors to trigger an autoimmune response or tumour development. The environmental factors I refer to above are hormones (oestrogen sensitivity), drugs (comparable mechanisms to molecular mimicry), UV radiation (can damage DNA and modify self-antigens) and infection (not as clearly implicated in auto-immunity as cancer but may be able to form immunogenic units that bypass T-cell tolerance). (Leisegang, 2012) There is even a very interesting review linking lymphocytes and cancer cells called The cancer stem cell: Evidence for its origin as an injured autoreactive T Cell – it is definitely worth a read! (It can be found here)

Cancer-CellIn conclusion, the study of these modules on cancer and auto-immunity has deepened my understanding of cancer and cleared up some murky areas in my perception of the pathophysiology of cancer. I now see why, due to their bewildering genetic variety, individual cancers are so difficult to treat; and that there are some interesting similarities between the pathogenesis of cancer and auto-immunity.

 
References

Evan, G., 2012. Expert Opinion: why are some cancers so difficult to treat? Cancer Research UK Science Update Blog, [blog] 26 January. Available at: <http://scienceblog.cancerresearchuk.org/2012/01/26/expert-opinion-why-are-some-cancers-so-difficult-to-treat/&gt; [Accessed 19 April 2013].

Leisegang, K., 2012. Tumours and their Classification, NAT311 General Pathology. University of the Western Cape, unpublished.

MechanismsMedicine, 2012. Introduction to Cancer Biology (Part 3): Tissue Invasion and Metastasis. Available at: <http://www.youtube.com/watch?v=bdWRZd19swg&gt; [Accessed 19 April 2013].

National Cancer Institute, 2013. Understanding Cancer Series. [online] Available at: <http://www.cancer.gov/cancertopics/understandingcancer/cancer/AllPages&gt; [Accessed 19 April 2013].

Rippey, J.J., 1994. General Pathology. Johannesburg: Witwatersrand University Press.

Inflammation, Infection and Repair

inflammation_cartoon
The reflections on the central role of inflammation in both human health and human disease in this blog post considers the chapters ‘Acute Inflammation’, ‘Classification of Inflammation’, ‘Chronic Inflammation’, ‘Healing and Repair’, and ‘Infection and some Infectious Diseases’ in the prescribed textbook General Pathology by J.J. Rippey. This post explores the physiology of inflammation in different pathological situations, namely injury due to various aetiologies and infection, and its role in healing leading to human health as well as its role in human disease and how it contributes to the overall pathology.

In reading the relatively simple and concise definition of inflammation as “the reaction of vascularised living tissue to local injury” (Rippey, 1994: 125) I felt that it doesn’t quite convey the vast impact that inflammation has on the human body! It is a process that we can experience almost constantly in different forms due to the many injuries that a body can experience over a lifetime, ranging from very minor to very severe. For every injury that our bodies experience inflammation follows, it is the initial response of the body – the almost daily minor mechanical injuries of little bumps leading to small bruises and minor cuts in the skin from accidents in the kitchen or garden, as well as exposure to the many infective microbes on a daily basis that our body deals with without our conscious knowledge, will mean that some part of our body is in one stage of inflammation or another almost constantly. Acute inflammation is a linear progression of events in response to a stimulus and is pertinent to the examples just mentioned. (Leisegang, 2012) It is also pertinent to my own seasonal run-in with inflammation – in the winter, due to the cold weather and not having the greatest peripheral circulation, I experience the discomfort of mild chilblains in some of my toes. These chilblains display the cardinal signs of inflammation of rubor (redness), calor (heat), tumor (swelling) and dolor (pain), as well as functiolaesa (loss of function) as it is sore to walk on them! (Martini & Nath, 2009) The stimulus for this inflammation is an idiopathic abnormal vascular response to cold causing slight tissue injury. (Raza, 2006) The chemical composition of the interstitial fluid is altered because of the cold changes and damaged cells release prostaglandins, proteins and potassium ions. (Martini & Nath, 2009) This in turn triggers the inflammation process, which is ‘designed to neutralise the injurious agent in some way’ (Rippey, 1994) and to remove the consequences of the injury, such as any necrotic cells (AFP785, 2009) and to facilitate healing. I’m not going to go into the process of the inflammatory response itself as it is covered very well in the video below. (Khanacademy, 2010)

So far I have been looking into acute inflammation with my mild winter chilblains as an example. I want to take this example further by looking into classification of inflammation. This is done taking into consideration the duration of the inflammation, the nature of the inflammatory exudate, and the site of the inflammation. (Rippey, 1994) In reflecting on what I have been taught I would classify the inflammation I experience each winter as acute in duration, with very mild serous exudation, and with the anatomical site of perniosis. “Inflammation, although a response to a stimulus, may contribute to the overall pathology” (Leisegang, 2012: 16). Acute inflammation may go on to develop into chronic inflammation for many different reasons – chronic inflammation is a circular progression of the inflammatory response which is prolonged and where ‘destruction and inflammation are proceeding at the same time as attempts at healing’. (Rippey, 1994) The differences between acute and chronic inflammation at tissue level can be seen in the diagram below. An example of chronic inflammation is osteomyelitis, where the inflammatory response to the infected bone causes swelling which leads to ischaemia and necrosis because of the unyielding nature of the bone. The dead bone prevents draining of pus, delays healing and leads to a chronic inflammatory situation needing medical treatment. This is demonstrated in the lower diagram.

acute vs chronic

osteomyelitis

local_inflammationIn the past month our household has been hit by the recent seasonal virus, a rather nasty cold that started with a sore throat. This has been the result of an infection with a parasitic micro-organism termed a pathogen which probably gained access to my family members’ bodies via direct spread through inhalation and then overcame the body’s defence mechanisms. The portal of entry was probably the epithelium of the throat due to the first symptom of the cold. The pathogen was then able to multiply and cause tissue damage leading to local inflammation and later accompanied by the systemic effects of inflammation being malaise, increased body temperature and decreased appetite. (Rippey, 1994) Luckily, the immune system of my family members worked well and without the need to take medication the ultimate result of this experience was recovery! The diagram above shows how the body’s immune system in conjunction with the inflammatory process worked to fight off the infection. In reflecting on this chapter in the textbook I remembered when I had tick-bite fever a few years ago. I was walking a wilderness trail in Hluhluwe-iMfolozi National Park when, unknowingly, I was bitten by a tick and infected with Rickettsia conorii. The first I knew of this was a week later when I had an unusual and persistent headache, stiff neck, and a swollen, blackish, crusted eschar on my upper thigh. Luckily the tick-bite fever was diagnosed and treated before the maculopapular rash appeared! (Rippey, 1994)

After the inflammatory response comes healing and repair. The video above clearly shows the process of wound healing and repair. I have personally been able to witness this over the past month on a macroscopic level as my partner healed from a hernia operation. His surgical wounds healed by first intention, a process that will take about six weeks to complete. Being a month into this process I think he is at the point where the collagen fibres have been laid down, probably the type-I fibres at this point, and the scar is contracting slowly to increase tensile strength. The diagram below shows the process of healing by first intention. (Rippey, 1994: 160)  I have spent many happy hours explaining this all to him 🙂 I’m not entirely sure how much he has enjoyed the experience though!

wound healing
In conclusion, by reflecting on the physiology of inflammation in different pathological situations – namely injury due to cold, infection and mechanical injury due to surgical wounds, also in the pathophysiology that occurs during chronic inflammation – I feel I have come to understand the central role that inflammation plays in human health and human disease.

 
References

AFP785, 2009. Pathlogy: Acute Inflammation. Available at: <http://www.youtube.com/watch?v=3oUxDsZp71Y&gt; [Accessed on 7 April 2013].

Elcheguevarra, 2012. Wound Healing – Integumentary System 3D. Available at: <http://www.youtube.com/watch?v=iXfM13u3mp8&gt; [Accessed on 7 April 2013].

Khanacademy, 2010. Inflammatory Response. Available at: <http://www.youtube.com/watch?v=FXSuEIMrPQk&gt; [Accessed on 7 April 2013].

Leisegang, K., 2012. Module Descriptor: general pathology NAT311. University of the Western Cape, unpublished.

Martini, F.H. and Nath, J.L., 2009. Fundamentals of Anatomy and Physiology. 8th ed. San Francisco: Pearson Benjamin Cummings.

Raza, N., 2006. Chilblains at Abbottabad, a moderately cold weather station. Journal of Ayub Medical College, 18(3), pg25-28. [online] Available at: <www.ayubmed.edu.pk/JAMC/PAST/18-3/06Naeemraza.pdf> [Accessed on 7 April 2013].

Rippey, J.J., 1994. General Pathology. Johannesburg: Witwatersrand University Press.

Normal and Abnormal Fluid Distribution and Function

nerve endThe reflections on the broad role of fluid in health and disease in this blog post considers the chapters ‘Fluid and Electrolyte Balance’, ‘Oedema’, ‘Hyperaemia and Congestion’, ‘Haemorrhage’, ‘Shock’, ‘Thrombosis and Embolism’, and ‘Ischaemia and Infarction’ in the prescribed textbook General Pathology by J.J. Rippey. This post explores the role of fluid in health and disease, the concept that mechanisms of human disease are the same as the mechanisms of physiological homeostasis, and further examples of the body constantly striving to survive.

I believe the role of fluid in health and disease can be partly summed up by the golden rule of normal and abnormal fluid distribution and function that is in our notes and was discussed in class: ‘a fluid that is meant to move in the body, that does not move, will make the patient susceptible to infection and/or fibrosis’. (Leisegang, 2012) It is a place for me to start with this large subject matter! I think this rule is particularly true for the pathological concept of congestion where there is reduced venous drainage – blood flow is slowed (the fluid that is meant to move in the body) and there is a build up of deoxygenated haemoglobin. As a chronic or severe condition this can lead to oedema because of an increase in hydrostatic pressure, or haemorrhage because of increased permeability of the vessel wall due to anoxia – both of these are also examples of abnormal fluid distribution that will be looked at further. (Rippey, 1994) In researching congestion I found the truly excellent video below, it describes how congestive heart failure affects the rest of the body and beautifully illustrates what I was reflecting on above.

 

nutmeg liver cardiac cirrhosisWith chronic congestion, eventually the organs will show anoxic degeneration, particularly the liver, spleen and lungs. To the left is a macroscopic image of what is called ‘nutmeg liver’ where on the cut surface of the liver the central veins appear red and are surrounded by uncongested liver, yellowish-brown in colour and may show fatty change. (Rippey, 1994) To the right is a microscopic image of a liver with diffuse fibrosis called ‘cardiac cirrhosis’, this is a progression from ‘nutmeg liver’ and shows how chronic hindered blood flow can lead to fibrosis.

pulmonary oedemaIn considering the golden rule mentioned above I thought that it could also be true that when fluid moves in the body, into areas it shouldn’t move into or in volumes it shouldn’t move in, it will also make the patient susceptible to infection and/or fibrosis. The pathological concept of oedema is an example of this, the excessive accumulation of extracellular fluid in the interstitial tissue spaces. (Rippey, 1994) The mechanisms of fluid movement in oedema are physiologically normal but the amount of fluid that moves is pathological. It is natural that extracellular fluid can move into and out of the interstitial and intravascular compartments through the strictly controlled balance of hydrostatic pressure and colloid osmotic pressure – it is a fluid in the body that moves – but when it moves too much oedema will develop. (Rippey, 1994) For example, due to a pathological aetiology such as left-sided heart failure there is peripheral vasoconstriction and a shift of blood to the lungs leading to increased hydrostatic pressure in the pulmonary vessels and the pushing of fluid into the alveolar wall. When lymph drainage fails the fluid is pushed further, into the alveolar space causing transudate oedema. (Rippey, 1994) Soon, the alveolar capillaries become hypoxic leading to increased capillary permeability allowing proteins to escape with the fluid and causing exudate oedema. In this state the lungs are very prone to infection. (Rippey, 1994) And yet the body had to push the fluid out of the vascular system and into the lungs because the hydrostatic pressure in the lung vessels had increased so much. The image above is of “a piece of lung tissue where the alveoli are partly full of oedematous fluid, which is seen as pink staining. There are also red blood cells and some macrophages can be seen. The capillaries of the alveolar septums are dilated and congestive. Also, some typical features of pneumonia can be seen. 40x magnification, HE-staining.” (Solunetti, 2006)

shock Cardiogenic Shock Complicating Acute Myocardial InfarctionI have understood the concept that mechanisms of human disease are the same as the mechanisms of physiological homeostasis to mean that it is possible that when faced with an imbalance in homeostasis the body’s physiological tools/mechanisms for correcting the imbalance may cause a, or worsen the already present, pathological circumstance. I started to understand the implications of this concept when I was studying the pathological concept of shock. A specific example of this is cardiogenic shock with the aetiology of extensive myocardial infarction, or even massive pulmonary embolism, leading to low cardiac output and stroke volume with peripheral pooling of blood. The resulting poor perfusion causes metabolic acidosis and the body’s normal physiological mechanism to deal with metabolic acidosis is dilatation of small vessels to increase blood flow to the area – there is loss of tone and arteriolar vasoconstriction. Unfortunately, this has the effect of causing inadequate venous return and loss of effective circulating volume thus worsening the shock state! (Rippey, 1994) The diagram above shows the aetiologies and consequences of shock. The diagram below that outlines how cardiogenic shock complicates acute myocardial infarction.

I thought that another example of this concept is the formation of a thrombus and/or embolus. Normal thrombus formation is vital to maintain haemostasis if a vessel becomes damaged. The normal physiological mechanisms used in this process can also cause a pathological thrombus if the body is unable to fibrinolyse it and it prevents blood flow within the vessel it is trying to repair, or if it separates from the vessel wall entering circulation as an embolus to impact somewhere else in the circulation, causing a blockage and leading to ischaemia and infarction if it is not dissolved by fibrinolysis fast enough. (Rippey, 1994) Below is a video describing the process of deep vein thrombus formation.

 

blood loss mechanismsThe body always strives to survive, is always actively trying to maintain homeostasis and survival even in the most challenging circumstances. While tackling this subject matter this became clear to me again, particularly when studying the pathological concept of haemorrhage. I found it amazing how much blood can be lost by the body and it will still recover! Importantly, this depends on the amount of blood lost, the speed with which it is lost and the site of haemorrhage (it is far more serious in the brain than if from peripheral circulation). (Rippey, 1994) However, a sudden loss of 20% of blood can be coped with by the body’s compensatory mechanisms! A sudden loss of about 40% will result in death, but if this same amount is lost over 24 hours or so the body will also be able to compensate. The reasons for this are the body’s different mechanisms that it can use in response to blood loss and these are outlined in the diagram above. (Rippey, 1994:91) Another example of the body striving to survive, that I find incredible, is when the body recovers from an infarct. An infarct is caused by complete ischaemia leading to ischaemic necrosis and depending on its severity and site of occurrence infarction is often fatal. But if the infarction does not lead to a major heart attack or stroke then the body is able to recover – it reacts to infarction as it does to any large area of necrotic tissue. (Rippey, 1994) It is remarkable to me how the body can cope with a relatively large area of an organ becoming necrotic, how it can heal, given time, and continue to function. The diagrams below show this process. (Rippey, 1994:119-120)

infarction 1infarction 2

infarction 3

In conclusion, my experience of reading the chapters mentioned at the beginning of the post has been very interesting for me – seeing how the concept that mechanisms of human disease are the same as the mechanisms of physiological homoeostasis  and yet more amazing examples of the body’s ability to survive.  Absorbing and engaging with the subject matter not as separate bits of knowledge to be learned but as a larger concept of fluid in health and disease has been a process and a challenge, as each of these blog posts has been so far, and rewarding in that at the end I realise the information contained here is now firmly in my mind, has been thought about and actively tackled with rather than passively memorised.

 

References

ASKVisualScience, 2010. 3D Medical Animation Congestive Heart Failure. Available at: <http://www.youtube.com/watch?feature=player_embedded&v=3YddwXPWVSc> [Accessed 21 March 2013].

BupaHealth, 2008. How deep vein thrombosis (DVT) forms. Available at: <http://www.youtube.com/watch?feature=player_embedded&v=CETfozL0cQg> [Accessed 21 March 2013].

Leisegang, K., 2012. Hyperaemia and Congestion, NAT311 General Pathology. University of the Western Cape, unpublished.

Rippey, J.J., 1994. General Pathology. Johannesburg: Witwatersrand University Press.

Solunetti, 2006. Pulmonary Edema (OEDEMA Pulmonum) 40x. [online] Available at: <http://www.solunetti.fi/en/patologia/keuhkoodeema_40x/&gt; [Accessed 21 March 2013].

The Abnormal Deposition of Material in Tissues

capillaryThe deposition of material in tissues ranges from being completely physiologically normal and healthy (ie. melanin deposition in the skin protecting against UV damage) to being abnormal and pathological (ie. amyloidosis, calcification, abnormal pigmentation, jaundice, etc.). In this blog post I will focus on the abnormal deposition of material in tissues, briefly describing the different processes, identifying their basic common ground and how in general, it seems to me, the deposition of material seems to be a possible response, or mode of action, of the body to try to safely store material when faced with high levels of it in the blood.

Amyloid is an abnormal protein material that consists of a number of chemically different proteins that are all fibrillar and arranged in ß-pleated sheets, it is believed that it is this physio-chemical characteristic that accounts for amyloid behaviour in the body. (Rippey, 1994) The table below clearly outlines the different types of amyloid, their associated diseases and sites of deposition.

Table - amyloid

Amyloid deposits itself in the extracellular space of various organs and tissues and eventually hinders their function, even though amyloid itself is inert and does not cause an inflammatory response. For example, by restricting movement of the cardiac muscle, causing ischaemia by the narrowing of blood vessels (Kyle, 2001), causing proteinuria by increasing glomerular permeability, and causing atrophy and destruction in organs by increasing pressure on parenchymal cells. (Rippey, 1994) The protein pieces that form amyloid share in common becoming insoluble in water and are not proteolysed to be reused or excreted – they aggregate to form plaques and are deposited instead.  This fact jumped out at me when I read this chapter and it was the first clue I had in considering the common ground between the materials discussed in this post.  The video below demonstrates this process with regards to Alzheimer’s disease as a result of amyloid deposition in the brain. (Alzheimer’s Disease Education & Referral Centre, 2010)

intervertebral disc calcification

calcific aoric stenosis 3

When calcium is deposited in tissues other than the bones and teeth, where it is normally found, it is termed heterotropic calcification, of which there are two main types. Dystropic calcification occurs when there is no calcium metabolism abnormality and there is a deposition of calcium salts in degenerate or dead tissue such as areas of caseous necrosis and fat necrosis, around dead parasites, in thrombi forming phleboliths, in scar tissue and in tumours. (Rippey, 1994) Metastatic calcification occurs when there is a disturbance in calcium metabolism and there is usually hypercalcaemia. There are high serum levels of calcium and the calcium salts are deposited in tissues such as renal tubules, stomach wall, joints, lung alveoli, artery walls and the cornea instead of being excreted. It can also lead to the formation of calculi in hollow organs or ducts such as the pelvis, ureter or bladder of the urinary tract, or the gall bladder. (Rippey, 1994) Two common causes of hypercalcaemia are malignancy and hyperparathyroidism,less common causes are vitamin D intoxication, familial hypocalciuric hypercalcaemia and sarcoidosis. (Waters, 2009) In this case the body’s normal paths of deposition and excretion of calcium are blocked by pathological hormone signals and so it must deposit the calcium extracellularly to try and lower calcium levels in the blood – in a very general way this seemed similar to amyloid deposition to me and was my second clue. The images above, to the left shows dystrophic calcification of the aortic valve with stenosis, and to the right shows intervertebral disc calcification.

melanocytePigmentation in the human body takes many forms. Exogenous pigments such as dust will cause a blackening of the lungs due to inhaled carbon particles accumulating in the macrophages there. Endogenous pigments such as melanin, a brown pigment produced by melanocytes, gives natural colour to our skin, iris and hair; and lipofuscin, a golden brown pigment thought to be created by free radical injury and lipid peroxidation of cell membranes and so result from cell injury and death in a tissue, particularly found in the heart. (Rippey, 1994)  The video below shows lipofuscin accumulation within the retinal pigment epithelium.  The image above shows melanin formation within a melanocyte and its transferral to a keratinocyte. Particularly evident in everyday life are the pigments derived from haemoglobin breakdown, nearly all of which can be seen in a bruise. The escape of red blood cells into tissues after the damaging act causes the initial redish-blue colour, followed by the formation of biliverdin causing a greenish colour, then yellow with the formation of bilirubin, and finally only haemosiderin is left causing a brownish black colour, until this is also absorbed by the body. (Rippey, 1994) 

idiopathic pulmonary haemosiderosis

Haemosiderosis is abnormal deposition of haemosiderin, storing iron, in organs and tissues of the body. This is caused by an iron overload of the body as the body does not have a method of excreting iron to manage iron levels – this is seen particularly in haemochromatosis. (Rippey, 1994) The image to the right is a histological sample of idiopathic pulmonary haemosiderosis, showing haemosiderin-laden macrophages in the alveolar spaces and was my third clue.

bilirubin metabolism diagramJaundice is the accumulation of bilirubin in tissues and interstitial fluid of the body due to high levels of total serum bilirubin – it is a sign of many different diseases and is not a disease itself. (Rippey, 1994) The diagram to the right outlines bilirubin metabolism. (Aras, 2012)  If jaundice is due to an accumulation of unconjugated bilirubin it could be because of an overproduction of bilirubin due to excessive haemolysis, decreased hepatic uptake due to viral hepatitis, or decreased bilirubin conjugation due to a hereditary lack of glucuronyl transferase. (Rippey, 1994) If jaundice is due to an accumulation of conjugated bilirubin it could be because of extrahepatic biliary obstruction due to gallstones, impaired canalicular bile flow due to viral hepatitis, or decreased cellular secretion of conjugated bilirubin due to hereditary conditions. (Rippey, 1994) Jaundice is reversible except, under certain circumstances, high levels of total serum bilirubin may be toxic to the central nervous system of healthy term newborns and may cause neurologic impairment. (Provisional Committee for Quality Improvement and Subcommittee on Hyperbilirubinemia, 1994) This occurs when all the albumin in the body has been used to bind to the excessive levels of unconjugated bilirubin and there is not enough – the excess bilirubin can then penetrate the blood-brain barrier, be deposited in the extracellular brain tissue, staining the tissue and causing damage to the neurons. (Rippey, 1994)  This was my final clue!

For myself, the abnormal deposition of material in tissues mentioned above seem to share the common ground of the material starting out as part of normal physiological processes in the body. Then, due to various aetiologies there develops abnormally high levels of the material in the blood and the body is unable to metabolise or excrete the substance sufficiently, or not at all, and so the next option for the body is to deposit the material out of the way, so to say, in the various body tissues and extracellular spaces in order for it not to hinder normal functioning too much. However, over time the build up of abnormal material deposition becomes too much for the body to cope with and pathological symptoms occur. I think it is important to understand these pathological processes within the larger concept of learning about human disease because they are nearly all irreversible, are often not clinically visible until the deposition has built up to significant levels within the body and mostly because they are all important signs of a deeper pathological aetiology that would need to be investigated.

References

Alzheimer’s Disease Education & Referral Centre, 2010. Inside the Brain: Unraveling the Mystery of Alzheimer’s Disease. Available at: <http://www.youtube.com/watch?NR=1&feature=endscreen&v=NjgBnx1jVIU> [Accessed 1 March 2013].

Aras, H., 2012. All About Jaundice. [online] Slide Share. Available at: <http://www.slideshare.net/ozhenaras/all-about-jaundice> [Accessed 1 March 2013]. Slide 5.

[Dystrophic calcification of the aortic valve] n.d. [image online] Available at: <http://quizlet.com/13172006/pathology-test-1-w-pics-flash-cards/> [Accessed 1 March 2013].

HDEngineering, 2012. SPECTRALIS BluePeak – Blue Laser Autofluorescence – Lipofuscin Accumulation Over Time. Available at: <http://www.youtube.com/watch?v=M-oZh6U_GZk> [Accessed 1 March 2013].

[Idiopathic pulmonary haemosiderosis] n.d. [image online] Available at: <http://www.brown.edu/Courses/Digital_Path/systemic_path/pulmonary/iph.html> [Accessed 1 March 2013].

[Intervertebral disc calcification] 2010. [image online] Available at: <http://radiologyinthai.blogspot.com/2010/08/intervertebral-disc-calcification.html> [Accessed 1 March 2013].

Kyle, R.A., 2001. Amyloidosis: a convoluted story. British Journal of Haematology, 114, pg 529-538.

Provisional Committee for Quality Improvement and Subcommittee on Hyperbilirubinemia, 1994. Practice Parameter: Management of Hyperbilirubinemia in the Healthy Term New Born. Pediactrics, 94(4), pg 558-565.

Rippey, J.J., 1994. General Pathology. Johannesburg: Witwatersrand University Press.

Waters, M., 2009. Hypercalcaemia. InnovAiT: The Royal College of General Practitioners Journal for Associates in Training, 2(12), pg 698-701.

Cell physiology, pathophysiology and the relationship to all human disease

biography photo 3

This blog post is a reflection on the modules ‘The Normal Cell’, ‘Cell Injury’ and ‘Cell Death and Necrosis – Gangrene’, from the prescribed text book General Pathology by J.J. Rippey, focussing on the role of the cell in health and disease. Having studied normal cell physiology in the last two years it was good to do a recap of the anatomy of the cell, its organelles and their functions. I will not go into those details here but have included a diagram of a model cell.

Model CellA brief summary of the concepts of the cell theory are that cells are the basic building units of all plants and animals, they are the smallest units that perform all physiological functions vital to life, that all cells come from preexisting cells through the process of division, and that at the cellular level each cell maintains homeostasis. (Martini & Nath, 2009) The role of the cell in health and disease is central as “homeostasis at the level of the tissue, organ, organ system, and organism reflects the combined and coordinated actions of many cells” (Marini & Nath, 2009: 67) and disease can be very broadly defined as an inbalance in homeostasis.

There are many possible aetiologies for cell injury and these include vital substrate deficiency, and physical, chemical or biological insults. (Cobb, et al., 1996) The original injury is a biochemical one and will disrupt or depress, even stop, vital functions of the cell such as energy production by damage to mitochondria, protein synthesis by damage to the endoplasmic reticulum, disruption of the ionic and osmotic steady state by damage to the cell membrane, disruption of reproduction by damage to the nucleus, and generation of reactive oxygen species. (Rippey, 1994) In response to mild and slightly severe injury the cell can adapt so as to restore homeostasis, to protect the cell from further injury (Cobb, et al., 1996) and eventually recover but very severe injury will result in irreversible changes and cell death (Rippey, 1994). Adaptive changes of the cell in response to damage are atrophy, hypertrophy, hyperplasia, and metaplasia. (Badizadegan, 2003) Lets consider hypertrophy. Hypertrophic degeneration of a cell is caused by infiltrations such as water, fat, protein and glycogen. (Rippey, 1994) Cloudy swelling is the accumulation of water in a cell, first as granules and then as vacuoles, and is reversible. Hydropic degeneration is extreme water accumulation, when the vacuoles have coalesced, it may be reversible but usually leads to cell rupture and death. (Rippey, 1994) Fatty change is the accumulation of fat within a cell, first as liposomes close to the endoplasmic reticulum and then as fat vacuoles, it is a more severe form of cell damage even though in its earlier stages it is still reversible. (Rippey, 1994) Hyaline droplets, Russell bodies and Mallory’s hyaline are examples of protein accumulation within a cell. They have an homogenous glassy eosinophilic appearance and indicate very severe injury to a cell and a precursor to cell death. (Rippey, 1994) Glycogen infiltration does not lead to cell death nor functional damage, however it does lead to vacuoles in the cytoplasm and nucleus when there is an excessive accumulation. (Rippey, 1994)

“Cell death is valuable for the organism because it removes terminally injured or unwanted cells that utilise valuable substrates and nutrients.” (Cobb, et al., 1996: 3) Necrosis is the morphological changes – such as cytoplasmic swelling, swelling of the endoplasmic reticulum and mitochondria, blebbing of the plasma membrane, dissolution of chromatin, and loss of membrane integrity (Cobb, et al., 1996) – which occur after cell death in a living body. (Rippey, 1994) Apoptosis is programmed cell death and is manifested by cytoplasmic shrinkage, nuclear chromatin shrinkage and eventually larger plasma membrane buds. (Cobb, et al., 1996) The debris resulting from both types of cell death are engulfed by phagocytic cells. Necrotic debris acts as an irritant to the adjacent living tissue which triggers inflammation, this is called the vital response. Apoptosis does not trigger inflammation. (Rippey, 1994)

There are different types of necrosis. Coagulative necrosis is when the cell becomes an eosinophilic opaque mass with loss of the nucleus, this usually occurs in an infarct of the kidney, prostate, heart, spleen and lung. (Rippey, 1994) Colliquative necrosis is complete destruction of a cell due to total enzymatic dissolution, this usually occurs in a brain infarct. (Rippey, 1994) Suppurative necrosis is a form of colliquative necrosis due to bacterial infection, causing pus formation. Casseous necrosis is associated with tuberculosis, it is when there is a total loss of cell detail due to the cell becoming a mass of amorphous fat and protein. Gummatous necrosis is similar to casseous necrosis but is associated with syphilis. (Rippey, 1994) Fat necrosis is either the enzymatic breakdown of true fat in tissues surrounding the pancreas (enzymatic fat necrosis) or the release of neutral fat from a cell causing inflammation and eventually scarring (traumatic fat necrosis). (Rippey, 1994) Gangrenous necrosis is necrotic tissue that has been invaded by saprophytic putrefactive organisms from the gut or soil, it can only occur in living tissue and, due the presence of oedema in gangrenous tissue, is called moist gangrene. (Rippey, 1994)

CellsMy concept of disease changed after studying the modules above in that I didn’t realise how much our bodies are able to withstand before consciously experiencing disease, how much injury a cell can withstand before it becomes irreversible and leads to cell death. The adaptation that occurs at the deepest levels of the body is astounding, the continual striving for homeostasis by each cell despite damage, resulting in either recovery or cell death and the vital reaction.  Also, that the cell’s reaction to injury may contribute to the disease process itself, it seems paradoxical yet by understanding the mechanisms of cellular response to injury it makes sense too.

References

Badizadegan, K., 2003. Cell injury, adaptation and death, HST.035 Principle and Practice of Human Pathology. Harvard-MIT Division of Health Sciences and Technology, unpublished.

Cobb, J.P., Hotchkiss, R.F., Karl, I.E. and Buchman, T.G., 1996. Mechanisms of cell injury and death. British Journal of Anaesthesia, 77: 3-10.

Martini, F.H. and Nath, J.L., 2009. Fundamentals of Anatomy and Physiology. 8th ed. San Francisco: Pearson Benjamin Cummings.

Rippey, J.J., 1994. General Pathology. Johannesburg: Witwatersrand University Press.

Coming soon…

biography photo 2Upcoming blog posts:

Cell physiology, pathophysiology and the relationship to all human disease – 18th February 2013

The abnormal deposition of material in tissues – 4 March 2013

Normal and abnormal fluid distribution and function – 25 March 2013

Inflammation, infection and repair – 8 April 2013

Cancer – 22 April 2013