Download Epidemiology of Cachexia

Chapter 1.4
Epidemiology of Cachexia
Giovanni Mantovani, Clelia Madeddu
Introduction
The interrelationships between clinical diseases
and malnutrition have long been recognised.
Malnutrition due to starvation, disease or injury is
a very common phenomenon, even in current
times. Our predecessors in medicine were more
familiar with clinical malnutrition than we are,
since observation and physical examination played
a much greater role in diagnosis in the past.
Century-old textbooks provide detailed descriptions of physical changes that occur with malnutrition. Classic studies document the complex
adaptations that occur in response to starvation as
well as the metabolic alterations associated with
stress and trauma.
The rationale that effective treatment of malnutrition may have clinical benefit has led to
renewed interest in applying the tools of clinical
nutrition. As such, caregivers may need to reac-
quaint themselves with the topic of clinical nutrition while investigators continue to make advances
in those fields that are relevant in the current
health care environment [1].
Malnutrition means ‘badly nourished’ but it is
more than a measure of what we eat, or fail to eat.
Clinically, malnutrition is characterised by inadequate intake of protein, energy and micronutrients, and by frequent infections or disease.
Although often an invisible phenomenon, malnutrition casts long shadows, affecting close to 800
million people – 20% of all people in the developing world (Fig. 1) [2].
Although the greatest number of people worldwide are affected by iron deficiency and anaemia,
protein-energy malnutrition (PEM) has by far the
most lethal consequences, accounting for almost
half of all premature deaths from nutrition-related
diseases. Also, although trends differ (for example,
iodine-deficiency disorder is rapidly declining
Estimates of malnutrion-related disease
2000
1500
1000
500
0
anaemia
IDD
Obesity
PEM
population affected (millions)
VAD
IUGR
Fig. 1. Dimensions of malnutrition:
casting long shadows of disability and
death (Adapted from [2]). IDD, iodinedeficiency disorders; PEM, proteinenergy manutrition; VAD, vitamin A
deficiency; IUGR, intrauterine growth
retardation
40
Giovanni Mantovani, Clelia Madeddu
while obesity is rapidly increasing), the overall
dimension of malnutrition gives serious cause for
concern [2].
The Spectrum of Malnutrition
Hunger and malnutrition remain among the most
devastating problems facing the majority of the
world’s poor and needy, and continue to dominate
the health of the world’s poorest nations.
Nearly 30% of humanity – infants, children,
adolescents, adults and older persons in the developing world – are currently suffering from one or
more of the multiple forms of malnutrition. This
remains a continuing travesty of the recognised
fundamental human right to adequate food and
nutrition, and freedom from hunger and malnutrition, particularly in a world that has both the
resources and knowledge to end this catastrophe.
The tragic consequences of malnutrition include
death, disability, stunted mental and physical
growth and as a result, retarded national socioeconomic development. Some 49% of the 10.7 million
deaths each year among children aged under 5 in
the developing world are associated with malnutrition. Iron-deficiency anaemia affects 2 billion people, especially women and children. Iodine deficiency is the greatest single preventable cause of
brain damage and mental retardation worldwide:
740 million are affected. PEM affects 150 million
children aged under 5. Intrauterine growth retardation affects 30 million per year (23.8% of all
births).Vitamin A deficiency remains the single
greatest preventable cause of needless childhood
blindness, with 2.8 million children aged under 5
affected. At the same time, especially in rapidly
industrialising and industrialised countries, a
massive global epidemic of obesity is emerging in
children, adolescents and adults, so that more than
half the adult population is affected in some countries, with consequent increasing death rates from
heart disease, hypertension, stroke and diabetes.
Diet is also a major causative factor in the problems of post-menopausal women and in many
types of cancer [2].
Other important nutrition issues affecting
large population groups include:
– Only 35% of infants are exclusively breast-fed
between 0 and 4 months of age
– Poor complementary feeding practices are very
widespread – a major cause of childhood malnutrition
– Scurvy, beriberi and rickets occur in badly
deprived and refugee populations
– Folate deficiency in women of child-bearing
age and adolescent girls, causing three quarters
of the cases of anaemia and neural tube defects
– Zinc deficiency in deprived populations, contributing to growth retardation, diarrhoea,
immune deficiency, skin lesions
– Selenium deficiency, widespread in China and
the Russian Federation, causing Keshan disease
and Kashin-Beck disease.
Protein-Energy Malnutrition
Protein-energy malnutrition is by far the most
lethal form of malnutrition. Children are its most
visible victims. Malnutrition, ‘the silent emergency’, is an accomplice in at least half of the 10.4
million child deaths each year. These young lives
are prematurely, and needlessly, lost.
First recognised in the twentieth century, the
full impact of PEM has been revealed only in
recent decades. Infants and young children are
most susceptible to PEM’s characteristic growth
impairment because of their high energy and protein needs and their vulnerability to infection.
Globally, children who are poorly nourished suffer
up to 160 days of illness each year. Malnutrition
magnifies the effect of every disease. PEM affects
every fourth child worldwide: 150 million (26.7%)
are underweight while 182 million (32.5%) are
stunted. Geographically, more than 70% of PEM
children live in Asia, 26% in Africa and 4% in Latin
America and the Caribbean. Their plight may well
have begun even before birth with a malnourished
mother [2].
Clinical Relevance of Cachexia
Cachexia is one of the most visible and devastating
consequences of human disease, seen in several
1.4 Epidemiology of Cachexia
chronic diseases, including cancer, acquired
immunodeficiency syndrome (AIDS), thyrotoxicosis, chronic heart failure and rheumatoid arthritis.
In malignant cancer and AIDS, cachexia is known
to be a sign of very poor prognosis [3].
Cancer Cachexia
Owing to the difficulties in clearly defining and
diagnosing cancer anorexia, its prevalence is yet to
be precisely assessed [4]. Based on different diagnostic tools, anorexia has been detected at the
point of cancer diagnosis in 13–55% of patients
[5]. Nevertheless, consistent evidence suggests that
approximately 50% of cancer patients report
abnormalities of eating behaviour at the time of
first diagnosis [6] and prevalence in terminally ill
cancer patients is even higher, at approximately
65% [7]. The incidence of weight loss upon diagnosis varies greatly according to the tumour site
(Table 1) [8]. In less aggressive forms of Hodgkin’s
lymphoma, acute non-lymphocytic leukaemia, and
in breast cancer, the frequency of weight loss is
30–40%. More aggressive forms of non-Hodgkin’s
lymphoma, colon cancer and other cancers are
associated with a frequency of weight loss between
50 and 60% [9–11]. Patients with pancreatic or
gastric cancer have the highest frequency of
weight loss at over 80%. The onset of
anorexia–cachexia significantly influences the
clinical course of the disease, and most antitumour
Table 1. Incidence of weight loss in cancers of different
sites. (Adapted from [8])
Tumour site
Incidence of weight loss (%)
Pancreas
83
Gastric
83
Oesophagus
79
Head and neck
72
Colorectal
55–60
Lung
50–66
Prostate
Breast
General cancer population
56
10–35
63
therapies actually exacerbate anorexia and worsen
body weight loss. As a consequence, the higher
prevalence
and
greater
severity
of
anorexia–cachexia syndrome in advanced cancer
patients is mostly due to iatrogenic causes. The
presence of early satiety at any stage of the disease
can significantly increase the risk of death by 30%.
Similarly, the extent of body weight loss negatively
influences survival not only per se, but also by
delaying initiation and/or completion of aggressive antitumour therapy [12].
Cachexia in Chronic Heart Failure
There is considerable disagreement as to the percentage of heart failure patients who develop
cachexia and how this should be defined and
measured. Carr et al. reported that up to 50% of
patients with chronic heart failure suffered from
some form of malnutrition [13]. Anker and Coats
reported that up to 15% of patients attending their
chronic heart failure clinic developed cachexia
during the clinical course of the disease [14].
Roubenoff et al. observed that loss of more than
40% of lean body tissue would cause death [15].
Cardiac cachexia also occurs in childhood, related
to malnutrition and/or malabsorption diseases
such as kwashiorkor or marasmus [3].
Cachexia and Infectious Diseases
Malnutrition, particularly that related to micronutrients (vitamins, trace minerals, essential amino
acids, polyunsaturated fatty acids), is certainly one
of the most easily preventable causes of death and
disability. The 1995 World Health Organization
(WHO) bulletin shows population-attributable
risk for child deaths in 52 developing countries
due to interaction between malnutrition and infectious disorders [16].
Malnutrition is a common complication of HIV
infection and plays a significant and independent
role in its morbidity and mortality. Malnutrition was
one of the earliest complications of AIDS to be recognised and has been one of the most common initial
AIDS-defining diagnoses to be reported to public
health authorities [1]. The earliest studies of nutritional status in AIDS patients, performed between
41
42
Giovanni Mantovani, Clelia Madeddu
1981 and 1983, were determined in hospitalised patients [17]. Weight loss to an average of 80% of ideal weight was found in this population. Evidence of
protein deficiency was documented by demonstrating deficiencies in serum proteins (transferrin, albumin), haemoglobin, and by muscle wasting (midarm
circumference). Several other studies also reported
a high prevalence of severe weight loss in AIDS patients at the time of hospital admission.
The results of formal nutritional assessments
in HIV infection, using high-precision techniques,
were first reported in 1985 [18]. In a cross-sectional study, body cell mass as total body potassium
content, fat content, and body water volumes (total
body water, intracellular water and extracellular
water), were measured in hospitalised, clinically ill
AIDS patients and compared to results in normal
controls. The AIDS patients averaged 82% of ideal
body weight. However, the body cell mass was
depleted disproportionately and was only 68% as
compared to control. The magnitude of depletion
of body cell mass was striking, since the body fat
content was not severely depressed, at least in male
subjects. The women studied had equivalent depletion of body cell mass as men, but were much
more depleted of fat. This finding was confirmed
in later studies performed in the USA and Africa
[19, 20]. Other studies have concentrated on the
body’s protein status and have demonstrated that
malnutrition is accompanied by depletion of
nitrogen, which is directly related to protein content. Approximately one half of the weight difference between HIV-infected and control men could
be ascribed to differences in skeletal muscle mass.
The cross-sectional studies described above
have provided the field with a point of reference
for over a decade. However, it is important to note
that these studies were performed in the prezidovudine era, at which time the treatment of
many complications of HIV disease was rudimentary. These reports document the natural history
of untreated HIV infection and AIDS. While the
findings may still reflect the nutritional consequences of HIV infection in much of the world,
they may be less accurate in the USA, Europe and
Australia. More recent studies have shown a relatively greater loss of fat than early studies, and
lesser depletion of body cell mass [1].
Other studies have demonstrated that depletion
of body cell mass may precede the progression to
AIDS, suggesting that cause of the depletion may be
related to the underlying HIV infection, rather than
to an opportunistic infection [21]. Clinical stability
is associated with nutritional stability [22].
Weight loss can be episodic and related to an acute
event, often a specific disease complication [23].
Malnutrition in children is manifested as
growth failure; a decrease in the rate of increase in
linear height [24].
Most opportunistic infections and many lymphomas in AIDS patients are accompanied by cachexia. In such patients, weight loss is rapid (3–5 pounds
per week or 5% per month). While the metabolic
rate is extremely elevated, food intake is diminished.
There is often extreme weakness and lethargy.
Cachexia in Chronic Kidney Disease
Many reports indicate that in patients with advanced
chronic kidney disease (CKD) and those on dialysis
there is a high prevalence of PEM, up to 40% or more,
and a strong association between malnutrition and
greater morbidity and mortality [25]. CKD patients
not only have a high prevalence of malnutrition, but
also a higher occurrence rate of inflammatory processes. Many conditions leading to malnutrition and wasting may also cause inflammation. Oxidative stress
may be a major underlying cause for both conditions
[26]. Since both malnutrition and inflammation are
strongly associated with each other and can change
many nutritional measures and clinical outcomes in
the same direction, and because the relative contributions of measures of these two conditions to each other and to poor outcomes in CKD patients are not yet
well defined, the term ‘malnutrition–inflammation
complex syndrome’ (MICS) has been suggested to denote the important contribution of both of these conditions to end-stage renal disease outcome [25]. The
MICS may also be defined as the ‘malnutrition–inflammation–cachexia syndrome’ to indicate better the
presence of the wasting syndrome pointed out recently. However, unlike cancer cachexia, the wasting
syndrome in CKD usually does not lead to immediate death from the direct consequences of malnutrition, but acts over time to promote atherosclerotic
cardiovascular disease [27].
1.4 Epidemiology of Cachexia
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