By:Nader Al-assadi Taiz university Definition of weight loss: Clinically important weight loss is defined as the loss of 10 pounds (4.5 kg) or >5% of one’s body weight over a period of 6–12 months. Weight loss can be divided into 2 categories: involuntary or voluntary. -1 Involuntary weight loss is a manifestation of cachexia associated with many disease states. 2- Voluntary weight loss, in the form of healthy dieting, is common among men and women. However, signifcant voluntary weight loss can herald a psychiatric illness such as an eating disorder, particularly among women. K E Y T E R M S: Anorexia Loss of the desire to eat. Anorexia nervosa4 Intense fear of gaining weight and refusal to maintain weight at or above a minimally appropriate weight for height and age. Bulimia nervosa4 Recurrent episodes of binge eating followed by recurrent compensatory behavior to prevent weight gain (ie, laxative abuse and self-induced vomiting). Cachexia General muscle and/or fat wasting with malnutrition usually associated with chronic disease. Involuntary weight loss The unintended loss of weight; sometimes not reported by the patient and only noted upon chart review. Malnutrition Poor nutrition due to inadequate or unbalanced intake of nutrients or their impaired utilization. Voluntary weight loss The conscious effort to lose weight; frequently not a complaint among those with eating disorders.

1. Weight loss
assadi
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By:Nader Al
INTRODUCTION
Definition of weight loss:
Clinically important weight loss is defined as the loss of 10 pounds (4.5 kg)
or >5% of one’s body weight over a period of 6–12 months.
Weight loss can be divided into 2 categories: involuntary or voluntary.
-
1 Involuntary weight loss is a manifestation of cachexia associated with many disease states.
2- Voluntary weight loss, in the form of healthy dieting, is common among men and women.
However, signifcant voluntary weight loss can herald a psychiatric illness such as an eating
disorder, particularly among women.
K E Y T E R M S:
Anorexia Loss of the desire to eat.
Anorexia nervosa4 Intense fear of gaining weight and refusal to maintain weight at or
above a minimally appropriate weight for height and age.
Bulimia nervosa4 Recurrent episodes of binge eating followed by recurrent compensatory
behavior to prevent weight gain (ie, laxative abuse and self-induced vomiting).
Cachexia General muscle and/or fat wasting with malnutrition usually associated with
chronic disease.
Involuntary weight loss The unintended loss of weight; sometimes not reported by the
patient and only noted upon chart review.
Malnutrition Poor nutrition due to inadequate or unbalanced intake of nutrients or their
impaired utilization.
Voluntary weight loss The conscious effort to lose weight; frequently not a complaint
among those with eating disorders.
Physiology of Weight Regulation
Concept of Energy Homeostasis
Fat is the primary form of energy storage in the human body.
.According to the first law of thermodynamics, the amount of energy stored is equal to
the difference between energy intake and energy expenditure.
Under normal conditions, homeostatic mechanisms maintain the difference between energy intake
and energy expenditure close to zero.

2. A very small imbalance in those mechanisms over a long period of time can result in large
cumulative effects, leading to a major change in weight.
In order to keep a perfect balance between energy intake and expenditure, homeostatic
mechanisms rely on neural signals that emanate from adipose tissue and from endocrine,
neurological, and GI systems and are integrated by the CNS .
The CNS subsequently sends signals to multiple organs in the periphery in order to control energy
intake and expenditure and maintain energy homeostasis over long periods of time.
Role of the Central Nervous System
Eating in humans is thought to follow a dual model: “Reflexive eating,” which represents
automatic impulses to overeat in anticipation of a coming food shortage, and “reflective eating,”
which incorporates a cognitive dimension involving social expectations of body shape and long-
term health goals . Reflexive eating is repre-ented by the brainstem and the arcuate nucleus.
 Two populations of neurons are responsible for the regulation of food intake in
the arcuate nucleus:
 one expressing neuropeptide Y (NPY) and agouti- related peptide (AgRP), which when activated
leads to an orexigenic response and reduced energy expenditure.
o NPY is one part of the pancreatic polypeptide family, which includes two other hormones:
pancreatic polypeptide (PP) and peptide YY (PYY). NPY is present in large quantities in
the hypothalamus and is one of the most potent orexigenic factors [9]. Among NPY recep-
tors, the Y5 receptors have been implicated as important media-tors of the feeding effect
and the Y5 receptors antagonists have been involved in recent weight-loss studies
 the other containing pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated
transcript (CART), in which increased activity results in an increase in energy expenditure and a
decrease in food intake .
 The brain cortex seems to play a role in the regulation of food intake and represents “reflec- tive
eating”.

The right prefrontal cortex (PFC) has been specifi- cally involved in the cognitive inhibition of food
intake.
Role of Adipose Tissue
Insulin and leptin are adiposity signals that play an important role
in the physiology of weight regulation.
 Insulin receptors are widely present in the CNS. Insulin levels have been shown to correlate with
body adiposity. Increases in food intake and adiposity can result from hypothalamic defects in
insulin signaling .Insulin may also act outside the hypothalamus in the ventral tegmental area to
suppress some aspects of feeding.
 Adiponectin and resistin are two other peptides produced by
adipocytes. Low levels of the former are associated with insulin resistance, dyslipidemia, and
atherosclerosis, whereas low levels of the latter have pro inflammatory effects and have also been
impli-cated in insulin resistance .
 Circulating levels of leptin, an adipocyte-derived hormone, reflect the adipose tissue mass, as well
as recent nutritional status. The action of leptin in the CNS results in a decrease in food intake

3. and an increase in energy expenditure through the inhibition of NPY/AgRP neurons and activation
of POMC neurons .
Most obese humans have elevated serum leptin levels, which suggests leptin resistance may be
important in human obesity. Manipulating leptin resistance may provide an interesting target for
obesity treatment. Recent research suggests that reduced responsiveness to leptin may result from
a reduction in the POMC neuronal population and subsequent reactive gliosis in the hypothalamus
in response to a high-fat diet.
Role of the GI Tract
The GI tract elicits neural and endocrine signals that play a major role in food intake regulation. The
interaction of GI hormones with the brain constitutes the gut–brain axis, which has been extensively studied
in the past decade.
 Role of the Stomach in Food Intake Regulation:
 Gastric Distension
Gastric distension has been shown in multiple studies to serve as a signal for satiety. Instillation of a volume
load in the stomach leadsto distension of gastric wall, which in turn induces satiety regardless
of the nature of the load: in rats, studies have shown that equivalent volumes of saline or different nutrient
solutions produce equivalent reductions in food intake.
 Ghrelin
 Ghrelin is a peptide predominantly produced by the stomach. Its secretion is increased by fasting
and in response to weight loss and is decreased by food intake. Ghrelin is the only known circulat-
ing appetite stimulant. It stimulates appetite by acting on arcuate nucleus NPY/AgRP neurons and
may also inhibit POMC neurons]. There is evidence that the vagus nerve is required to mediate its
orexigenic effect.
 Ghrelin plays a role in meal initiation, as demonstrated by a pre-meal surge in plasma ghrelin levels
in humans and animals. It also appears to participate in long-term energy homeostasis, as
suggested by its fluctuation in response to body weight variations It has been shown to play a role
in stress-induced food reward behavior by acting on the ventral tegmental area of the brain.
 Role of the Pancreas and Small Intestine in Food Intake Regulation
 Cholecystokinin
Cholecystokinin (CCK) is the prototypical satiety hormone, pro- duced by cells in the duodenum and jejunum.
It is produced in response to the presence of nutrients within the gut lumen, specif- ically fat and protein.
The satiating effect of CCK is mediated through paracrine interaction with sensory fibers of the vagus nerve.
It inhibits food intake by reducing meal size and duration CCK has a short half-life, which makes it a very
short-term modulator of appetite.

4.  Peptide Tyrosine Tyrosine and Pancreatic
Polypeptide PYY is secreted by enteroendocrine L-cells, mainly in the distal portion of the GI tract. It is
released following meals (acting as a meal terminator) and is suppressed by fasting: exactly opposite to the
pat-tern seen with ghrelin .
Increased levels of PYY are thought to play a role in the early weight loss observed after gastric bypass
surgery .
PP is secreted in response to a meal, in proportion to the caloric load, and has been shown to reduce
appetite and food intake . It is mainly produced in the endocrine pancreas, but also in the exocrine pancreas,
colon, and rectum.
 Glucagon-
GLP-1 and oxyntomodulin derive from the post-translational processing of proglucagon, which is expressed
in the gut, pancreas, and brain. GLP-1 is secreted by enteroendocrine L-cells in the distal small bowel in
response to direct nutrient stimulation in the distal small intestine, as well as indirect neurohumoral
stimulation in proximal regions of the small intestine.
The actions of GLP-1 include inhibition of gastric emptying, stimulation of insulinrelease, inhibition of
glucagon release, and inhibition of appetite Furthermore, the effects of GLP-1 on weight and satiety are
thought to be mediated in part by the presence of GLP-1 receptors in the CNS.
Oxyntomodulin is also secreted in the distal small intestine. It binds to the GLP-1 receptor, but with a lower
affinity. It has been shown to decrease energy intake and, moreover, increase energy expenditure.
Role of Gut Microbiota in the Developmentof Obesity:
Recent evidence indicates that the commensal and symbiotic microbes that populate the gut (the gut
microbiota) play a role in the development of obesity and insulin resistance. Several mechanisms are
involved in this process, including increased energy extraction from diet, an effect on energy expenditure,
and an effect on fat stor- age .
Conclusion
The physiology of weight regulation involves intricate interactions between the brain and the gut.
Tremendous progress has been made in our understanding of the different components of the gut–brain
axis and extensive research is underway to create agents targeting these components in order to
accomplish significant and lasting weight reduction.

5. ■PHYSIOLOGY OF WEIGHT REGULATION WITH AGING:
 Among healthy aging people, total body weight peaks in the sixth decade of life and generally
remains stable until the ninth decade, after which it gradually falls.
 In contrast, lean body mass (fat-free mass) begins to decline at a rate of 0.3 kg per year in the
third decade, and the rate of decline increases further beginning at age 60 in men and age 65 in
women.
 These changes in lean body mass largely reflect the age-dependent decline in growth hormone
secretion and, consequently, circulating levels of insulin-like growth factor type I (IGF-I) that occur
with normal aging. Loss of sex steroids, at menopause in women and more gradually with aging
in men, also contributes to these changes in body composition.
 In the healthy elderly, an increase in fat tissue balances the loss in lean body mass until very old
age, when loss of both fat and skeletal muscle occurs.
 Age-dependent changes also occur at the cellular level.

6.  Telomeres shorten, and body cell mass—the fat-free portion of cells—declines steadily with aging.
 Between ages 20 and 80, mean energy intake is reduced by up to 1200 kcal/d in men and 800 kcal/d
in women.
 Decreased hunger is a reflection of reduced physical activity and loss of lean body mass,
producing lower demand for calories and food intake.
 Several important age-associated physiologic changes also predispose elderly persons to weight
loss, such as declining chemosensory function (smell and taste), reduced efficiency of
chewing, slowed gastric emptying, and alterations in the neuroendocrine axis, including
changes in levels of leptin, cholecystokinin, neuropeptide Y, and other hormones and peptides.
 These changes are associated with early satiety and a decline in both appetite and the hedonistic
appreciation of food. Collectively, they contribute to the “anorexia of aging.
CAUSES OF UNINTENTIONAL WEIGHT LOSS:
Most causes of UWL belong to one of four categories: (1) malignant neoplasms, (2) chronic inflammatory
or infectious diseases, (3) metabolic disorders (e.g., hyperthyroidism and diabetes), or (4) psychiatric
disorders.
 In older persons the most common causes of weight loss are depression, cancer, and benign GI
disease. Lung and GI cancers are the most common malignancies in pts. presenting with weight
loss.
 The most common malignant causes of UWL are gastrointestinal, hepatobiliary, hematologic,
lung, breast, genitourinary, ovarian, and prostate.
 In younger individuals, diabetes mellitus, hyperthyroidism, anorexia nervosa, and infection,
especially with HIV, should be considered.
 People with no known cause of weight loss generally have a better prognosis than do those with
known causes, particularly when the source is neoplastic.

7.  In addition to malignancies, gastrointestinal causes are among the most prominent causes of UWL..
 Cardiovascular and pulmonary diseases cause UWL through increased metabolic demand and
decreased appetite and caloric intake.
 Repeated surgeries may lead to weight loss because of reduced caloric intake and increased
metabolic demands resulting from a systemic inflammatory response
 . Uremia produces nausea, anorexia, and vomiting.
 Connective tissue diseases may increase metabolic demand and disrupt nutritional balance.
 As the incidence of diabetes mellitus increases with aging, the associated glucosuria can
contribute to weight loss.
 Hyperthyroidism in the elderly may have less prominent sympathomimeticfeatures and may
present as “apathetic hyperthyroidism” or T3 toxicosis
 .Neurologic injuries such as stroke, quadriplegia, and multiple sclerosis may lead to visceral and
autonomic dysfunction that can impair caloric intake. Dysphagia from these neurologic insults is a
common mechanism
 . Functional disability that compromises activities of daily living (ADLs) is a common cause of
undernutrition in the elderly.
 Visual impairment from ophthalmic or central nervous system disor-ders such as a tremor can limit
the ability of people to prepare and eat meals
 Isolation and depression are significant causes of UWL that may manifest as an inability to care for
oneself, including nutritional needs. A cytokine-mediated inflammatory metabolic cascade can be
both a cause of and a manifestation of depression. Bereavement can be a cause of UWL and, when
present, is often more pronounced in men. More intense forms of mental illness such as paranoid
disorders may lead to delusions about food and cause weight loss.
 Alcoholism can be a significant source of weight loss and malnutrition
 .Elderly persons living in poverty may have to choose whether to purchase food or use the money
for other expenses including medications.
ASSESSMENT:
 The four major manifestations of UWL are (1) anorexia (loss of appetite), (2) sarcopenia (loss of
muscle mass), (3) cachexia (a syndrome that combines weight loss, loss of muscle and adipose
tissue, anorexia, and weakness), and (4) dehydration.
 .Initial assessment includes a comprehensive history and physical examination :
 Before extensive evaluation is undertaken, it is important to confirm that weight loss has occurred
(up to 50% of claims of weight loss cannot be substantiated). In the absence of documentation,
changes in belt notch size or the fit of clothing may help to determine loss of weight.
 The history should include questions about fever, pain, shortness of breath or cough, palpitations,
and evidence of neurologic disease.
 A history of GI symptoms should be obtained, including difficulty eating, dysgeusia,
dysphagia, anorexia, nausea, and change in bowel habits. Travel history, use of cigarettes,
alcohol, and all medications should be reviewed, and pts should be questioned about previous
illness or surgery as well as diseases in family members.
 Risk factors for HIV should be assessed. Signs of depression, evidence of dementia, and social
factors, including isolation, loneliness, and financial issues that might affect food intake, should
be considered.

8. 
 Physical examination should begin with weight determination and documentation of vital signs.
The skin should be examined for pallor, jaundice, turgor, surgical scars, and stigmata of systemic
disease. Evaluation for oral thrush, dental disease, thyroid gland enlargement, and adenopathy
and for respiratory, cardiac, or abdominal abnormalities should be performed. All men should have

9. a rectal exami-nation, including the prostate; all women should have a pelvic examination; and
both should have testing of the stool for occult blood.
 Neurologic examination should include mental status assessment and screening for depression.
 Initial laboratory evaluation is shown in Table, with appropriate treatment based on the underlying
cause of the weight loss. If an etiology of weight loss is not found, careful clinical follow-up, rather
than persistent undirected testing, is reason-able. The absence of abnormal laboratory tests is a
favorable prognostic sign.
a complete blood count, tests of liver enzyme levels, C-reactive protein, erythrocyte sedimentation rate,
renal function studies, thyroid function tests, chest radiography, and an abdominal ultrasound . Age, sex,
and risk factor–specific cancer screening tests, such as mam-mography and colonoscopy, should be
performed)
TREATMENT
WEIGHT LOSS Treatment of weight loss should be directed at correcting the underlying
physical cause or social circumstance. In specific situations, nutritional supplements and
medications (megestrol acetate, dronabinol, or growth hormone) may be effective for
stimulating appetite or increasing weight.

10. :

12. The 5 most severe consequences of extreme weight-loss
1. Loss of muscle mass
When you lose weight, it’s not just fat that you lose but muscle as well. A loss in
muscle mass often comes with decreasing metabolism rate, which further destabilises the
fat-to-muscle ratio. Weaker muscles translate to more inconvenience in day-to-day
activities like carrying heavy groceries or climbing the stairs. Even if the number on the
weighing scale ends up looking nicer, your quality of life may not be as rosy.
2. Imbalance of electrolytes
Many of our bodily functions are regulated by naturally occurring elements. Any
imbalance to the proportion of these elements could be potentially dangerous and may
cause conditions such as seizures and arrhythmia (irregular heartbeats). Electrolytes in
particular are critical to cellular function and integrity. If the latter were to break down, it
wouldn't be long before the rest of the body follows suit.
3. Nutritional deficiencies
Extreme weight-loss deprives your body of the essential nutrients that are
necessary for healthy function. Furthermore, deficiencies in certain nutrients like vitamin
D and calcium can lead to an increased risk of developing certain health conditions or
predispose you to injury. One such example of a disease associated with nutritional
deficiency is anaemia, which is characterised by feelings of weakness and fainting spells
and can occur when you your intake of iron is insufficient.
4. Gallstones
When gallstones form, severe pain is experienced along with indigestion. They are
formed when digestive juices in the gallbladder aren’t released because of a lack of food
to digest. These juices then harden inside the gallbladder and can block the opening,
causing indigestion which leads to further pain and discomfort.
5. Drastic drop in energy levels
Consuming insufficient calories or expending too many of them will definitely lead
to adverse effects on your energy levels. Apart from feeling physically tired, your cognitive
functions may take a hit as well as your productivity. Your mood can also be affected –
drastic weight-loss is often accompanied with constant feelings of irritation.
Reference :
harrison's 20th edition.
The Patient History - An Evidence-Based Approach to Differential Diagnosis, 2nd
Edition.
louis Chaptini1 and Steven Peikin2
1Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT,
USA2Division of Gastroenterology and Liver Diseases, Cooper Medical School at Rowan
University, Camden, NJ, USA.