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“...once a pathological process has started ‘one damn thing leads to
another’” (Spector, W.G. 1989). Discuss this statement with reference to
named examples.
The human body is not a culmination of several organs working separately to different ends; it is
made up of systems, connected by their function and their objectives. It could therefore be
considered inevitable that a part of the body when diseased, as a result of multiple connections and
multiple effects that part has on other parts of the body, will have a knock on effect, and manifest in
at least one other.
The inheritance of a faulty gene could be considered the starting point for the “pathological
process”. Considering an inherited gene mutation is present at the very beginning of foetal
development, it means it is very possible that it will manifest systemically. For this reason, inherited
diseases are a good example of the progression from one disease to another. Depending on the size
of the gene affected, and its role, the number of different phenotypic pathologies can vary greatly
from disease to disease. A genetic disease that exhibits many different phenotypes is known as
pleiotropic (Carter, G.W 2013, et al). An example of a pleiotropic genetic disease is Down’s
syndrome. It is associated with a high predisposition to many diseases, including blood disorders,
bowel abnormalities, dementias and thyroid dysfunctions. Specifically, an example is a high
prevalence of myeloid leukaemia carrying the 10-20 fold increase in its potential to develop
(Crispino, J.D 2011 et al). Trisomy 21 is associated with the development of mutations in the GATA1
gene. This results in a faulty GATA1 protein, which is a transcription factor essential for erethroid
and megakaryocytic differentiation. An N-terminal truncation of the GATA1 protein (Bennet, P 2008
et al) results in an alteration in translation capacity and therefore can result in uncontrolled
proliferation of megakaryocytes, resulting in leukaemia. (Taub, J.W 2012 et al) Another impediment
of Down syndrome is the potential development of congenital heart disease (CHD). In a study in
South India undertaken in 2013, 63.4% of 418 Down syndrome patients were suffering from CHD.
(Anilkumar, A 2012 et al) A common complication of CHD due to altered heart anatomy, is
Pulmonary arterial hypertension (PAH) (Beghatti, M 2013 et al) which is defined as a mean arterial
pressure of more than 25mmHg (Farber, H.W 2004 et al). PAH, if unrelieved, may lead to right
ventricular pressure overload, leading to dysfunction, right heart failure and eventually premature
death (Coeytaux, R.R 2013 et al) Treatments to prevent the progression of CHD, include surgery and
cardiac care, allowing the repair of congenital heart defects in infancy. (Beghatti, M 2013 et al) Heart
transplant is also increasingly considered a treatment option. (Canter, C.E 2011 et al) Treatment
development is an ongoing pursuit. Prior to 1989, when Spector made his statement, less treatment
was likely to have been available, or at least surgeries carried higher risks and treatments were in a
more primitive state. Survival from 1981 to 1985 showed rates for 1-year, 3-year, and 5-year of
68%, 48%, and 34% respectively. (Abman, S.H 2004 et al) It has been stated in a study from 2004,
that over the past decade, treatment options that have become available have changed the course
of the disease. (Abman, S.H 2004 et al) In respect to Spector’s statement, if it is to be interpreted as
a certainty, then his statement is not always true. As mentioned, only 63.4% of Down syndrome
patients were seen to be suffering from CHD (Anilkumar, A 2012 et al) and with the development
treatment for PAH, it is likely that the number of people progressing further into the flow of disease
development from CHD to PAH to death, will reduce. However the number of people developing
PAH from CHD ever become 0? Will Spector’s statement in regards to this particular disease
development ever be completely untrue?
There can be various interpretations of Spector’s words. Did he mean that one disease very often
leads to the acquisition of another, or that an individual disease or syndrome spreads to other
organs and systems. Could it be said, therefore, that metastatic cancers are an example of one thing
leading to another, or is it just a progression of a single disease. By definition, metastatic cancer is a
spreading of one type of cancer i.e. Of a single to another area. For example: if a lung cancer was to
metastasise to the liver, then that cancerous mass in the liver would be formed of the same type of
cancer cells. It would therefore be referred to as metastatic lung cancer rather than liver cancer. The
difference being it would have a very different local affect. It is therefore arguable that metastatic
cancer is not one thing leading to another but merely enlargement and progression of one disease.
The relevance of metastatic cancer to Spector’s statement is dependent on what it was he meant.
Nonetheless, metastatic cancer is a highly discussed disease progression due to its extreme
prevalence, high mortality rates and its ability to reside in any part of the body formed by
proliferating cells. It is considered by the public as a disease that “spreads” and that once
metastasized, is more aggressive and less treatable. An example of a cancer with ability to
metastasize is renal cell carcinoma (RCC). RCC is responsible for over 80% of kidney cancers
(Katsube, K.I 20013 et al) and around 30% of them metastasise. In the kidney an over-expression of
metalloproteinases in RCC, results in digestion on the main components of the basement membrane
and extracellular matrix. (Katsube, K.I 20013 et al) It metastasizes most commonly to bone, leading
to increased osteoclastic activity (Katsube, K.I 20013 et al) This metastatic ability is partly due the
expression of the receptor activator of nuclear factor kB ligand (RANKL) (Katsube, K.I 20013 et al).
Perhaps more worryingly, RCC has the ability to metastasise to the pancreas. Metastatic pancreatic
cancer makes up for only 2% of pancreatic cancers as a whole. (Furukawa, J 2012 et al) The majority
of these are from RCC (Furukawa, J 2012 et al j). This is an example of a disease developing into
something worse. According to the SEER cancer reviews (2013), Renal Cell Carcinoma carries an
average 5 year survival probability of 71.8%, whereas pancreatic cancer has a likelihood of surviving
5 years, of only 6%. Cancer metastasis supports Spector’s statement, as once a cancer has become
malignant to the point at which it can metastasize, it is likely it will continue to do so unless treated,
and the prognosis can worsen.
A recurring suggestion throughout the previous discussion, is that diseases progress when not
treated. For many of these, we have developed the medical technology and knowledge to be able to
treat them. However treatment is not the finite answer. In some cases, treatment, though
preventing the spread and progression of disease in one respect, can result in the acquisition of
another, at least through side effects predisposing a patient to other diseases. We therefore
contribute to the knock on effect ourselves, in trying to prevent it. A highly discussed example of
this is chemotherapy in the treatment of cancers. Cancers prevalence and association with poor
prognosis and high suffering, means that treatment is in high demand, and despite sometimes
debilitating side effects, patients and families continue to make decisions to use chemotherapy. An
example of this is the treatment of testicular cancer. In a study to determine the presence and
extent of long term side effects, patients with testicular cancer who had been successfully treated
using various chemical agents, including Cisplatin, Bleomycin and Vinblastine, underwent clinical and
technological investigations. Amongst many changes, patients exhibited alterations in hormone
levels, low serum magnesium or phosphate levels, and elevated cholesterol levels. (Awollersheim, H
2007 et al) Elevated cholesterol levels are associated with atherosclerosis, a thickening of arterial
walls and the formation of plaques, which if untreated, leads to coronary thrombosis and eventually
myocardial infarction. (Falk, E 1985)
Infectious diseases, particularly those that target the immune system directly, mean a preoccupation
and depletion of immune cells. This can result in opportunistic infections, and is again an example of
the knock on effect of pathology. A prime example of direct targeting of the immune system by
human pathogens, is the Human Immunodeficiency Virus, or HIV. The HIV virus is a retro-virus which
infects CD4 T-Helper cells, and macrophages. Viral replication within the cell, results in their eventual
destruction and depletion. Tuberculosis, bacterial infection of the lungs, is caused by the bacteria
Myobacterium tuberculosis. The tissue response to Tubercule bacilli, is to form granuloma: a
compact collection of macrophages. This is as a result of the inability of phagocytes to digest the
bacilli, post-engulfing, attributable to the ability of the bacterium to inhibit lysosome-phagosome
fusion. The infection can lie dormant, within these granulomas, until a co-infection such as HIV is
present, where a reduction in immune system capabilities arises. Both TB and HIV impact the
pathogenesis of one another. (Bador, M.K 2013 et al.) A trend appearing in the argument supporting
Spector’s statement, is the suggestion that all these diseases “if left untreated” would go on to cause
further and potentially more life threatening complications. In the case of HIV and many other
infectious diseases, the antibiotic treatments are becoming redundant as a result of resistance, and
options for replacements are running out. HIV resistance in the UK was shown to have increased
markedly from 1996 to 2003 (Cane, P 2005 et al) due to its high mutation rates.
There is an argument to suggest that those organs that are most vital, are those that have a major
role in supplying the rest of the body with the energy to function: The heart and lungs. It therefore
could be proposed that pathologies relating to these organs are the ones that would have the most
widespread affect. (However it is not to say that the remaining are not vital). An example in support
of this, is the extremely systemic manifestation of chronic obstructive pulmonary disease (COPD).
Respiratory tract obstruction in this disease results in an inhibition of gas exchange and henceforth
has a profound effect on cardiac function. The huge inflammatory response associated with COPD
may result in inflammatory mediators “spilling over” into the circulation. This can lead to skeletal
muscle wasting, cachexia, ischaemic heart disease, heart failure, osteoporosis, normocytic anaemia,
lung cancer, depression and diabetes. (Barnes, P J 2009 et al) These pathologies are all varied in their
location and their symptoms, and many, particularly diabetes, are diseases which themselves, have
huge systemic consequences. It is therefore suggestive that heart and lung pathologies may result in
the largest knock on effect.
Unexpectedly, it is sometime the case, that pathologies of one organ can have a serious and direct
effect on another organ that is not commonly associated with it. Existing data have been considered
sufficient to suggest that severe psoriasis, a skin condition, should be widely recognised as a
potential risk factor for cardiovascular disease. (Alexandroff, A B 2009 et al) These two organs would
often be considered very loosely related, and this example is evidence to suggest that Spector’s
statement is true in that a pathology can lead to another, even crossing system boundaries generally
considered present. In addition, the skin, though the largest organ, and certainly considered vital, is
only really perceived to play a part in homeostasis and in first defence. Its protective nature also
implies that pathologies related to it cannot pass the through the barrier and have an effect on other
parts of the body. This example suggests otherwise and implies the irrelevance of the perceived
importance of an organ in the development and spread of disease.
There is no doubt that Spector’s statement is true in many cases, as has been discussed. Pathologies
can, and do progress and spread to other parts of the body, they predispose patients to other
diseases and can be the direct cause of the development of other diseases. They can act in a knockon effect motion, where a chain of events can be triggered by one simple pathology, infectious or
non-infections, and can result in something more or less serious. They manifest systemically, having
profound effects on organs considered distantly related to their origin. Above, it has been suggested
that what Spector’s statement made in 1989, is more or less true dependant on the location of the
manifestation; meaning the supposed importance of the organ correlates with the extent of the
pathological consequences. However it has also been shown that this may not be the case, in the
example of skin and its effect on the likelihood of contraction of cardiovascular disease (Alexandroff,
A B 2009 et al). These chains can be halted by the application of treatments, meaning that in some
instances, Spector’s statement is becoming less true. However other treatments mean that despite
the prevention of one disease, it becomes more likely that another will develop. We, as humans,
have become as a causative entity in the progression of pathology to pathology. It could be said that
treatments mean that Spector’s statement is becoming less true as medical knowledge increases,
but a good question to pose in light of this discussion is: will it ever become untrue? The answer is
likely no. That is because where other organisms are involved, we can never totally find the cure for
all diseases. It is not just our medical knowledge that is evolving, but human pathogens also, and
that is out of our control. It is also because we have to make sacrifices in treatments, we have to
accept side effects that may have a pathogenic effect on an entirely different part of the body,
meaning rather than preventing the progression of pathogenesis, we are merely causing a diversion
towards a pathology that is deemed less likely to result in mortality.
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