Malnutrition and cachexia Flashcards
The pathway of cysteine synthesis
The only part that goes from methionine to cysteine is sulphur group, carbons are totally different
serine gives the carbon skeleton
At first, from methionine we take off the methyl group
then, we add serine, resulting in homocysteine
Serine comes from glucose
Then cysteine can be converted to taurine
Cysteine can be converted to what ( apart beign utilized for protein synthesis)
Can be converted to glutathione, tripeptide, taurine
Functions of taurine
Beta- amino acid
Essential AA for cats
Involved in the development of retina for premature babies
Invovled in muscle metabolism
Not in DNA
Draw the cycle for cysteine synthesis
Critical control point here
Homocysteine- powerful prooxidant
Because the moment it is produced it should be converted back to methionine or converted to cysteine
If higher than very low, can cause oxidative stress
What compound is homocysteine
Technically an AAs , but it is not used in the protein
Enzyme involved in AA metabolism and thus in methione-cysteine circle is
B6-pyrodoxine
Enzymes invovled in transferring methyl groups
Folate and B12
If there is high homocysteine, does it mean that we have problems with high protein intake, because it is their intermediate?
No, problem is in coenzymes
Regulation of methione-cysteine pathway happens in
The liver
If you have not healthy liver-> no breaking down of methionine-> no synthesis of taurine and cysteine
When cysteine can be a conditional essential AAs
Premature infants ( not enough enzymes)
ill liver
Composition of glutathione
gamma-glutamate-cysteine-glycine
What happens with cysteine in solution
It is oxidized to cystine, which is 2 cysteine molecules together and it precipitates
Role of glutathione
Important intracellular redox agent
A substrate for another enzyme that conjugates with electrophiles (toxins, xenobiotics, drugs) and removal of reactive oxygen species
Protection of protein, lipid membranes and DNA (glutathione provides NADH)
Important for immune system function
Another name for tylenol and its metabolisma nd why you should be careful with dosage
acetaminophen or paracetomol
Painkiller and fever reducer
It is conjugated with glutathione to create an intermediate that can be excreted
If too much taken, potentially toxic to the liver, because uses all of glutathione, so no redox status control of liver cells
what drug is given in the case of paracetomol overdose
N-acetylcysteine-> by putting nitrogen cysteine becomes more stable and can be given in liquid form as a drug, so glutathione is saved for redox status
When glutathione status is decreased
During short term and long term fasting
Protein deficiency ->lower synthesis rate
Higher consumption is increased in inflamamtion/infection (burns, AIDS)
How creatine can be an exampel of inter organ colloboration for metabolism
In liver SAM to SAH, so methyl groups is added (can be conjugated with methione to cysteine pathway, because they have this step)
Synthesis of creatinine occurs how
Non-enzymatically from creatine and phosphocreatine
Creatinine levels in urine can be roughly estimated as
As an indicator of muscle mass
Should you consider taking glutathione and creatine
Glutathione-tripeptide-> will not survive in HCl
Increasing creatine pool is probably for power but not for endurance (here you are more limited in oxygen-myoglobin pool)
Increased creatine in muscles-> hydrophilic-> attraction of water-> increased lean body mass, but does not increase power
Can be useful for upregulating myosin synthesis, cytoskeleton, protein and glycogen-> so may be a little anabolic
But a reasonable ergogenic aid for atheletics
What is starvation
The physiological condition created in the body as a consequence of chronic insufficient food intake
2 types of starvation
Can be physiological (coordianted adaptation to reduce nutrient supply-> goal is to prolonging survival)
and pathological (metabolic scenario, where two many compromised functions has occured and now it is a pathology-> disease) will lead to protein-energy malnutrition
The most common aspect of starvation
Protein-energy malnutrition
What was diet of study for starvation
1500 kcal
50 g protein per day (close to RDA, but RDA for adequet energy intake), but if not enough kcal, some AAs are going to be used for energy
for 6 months
Due to what loss the adaptation to starvation occured
loss of a lot of fat (in the end only 1%), lean tissue mass, increased extracellular fluid mass ( because changes in protein metabolism and regulation of water)
Rate of weight change in the end was zero (no fat and muscle less in the end)
What is successul adaptation to starvation
No loss of body substance despite continued food deprivation
Stable body composition must mean cessation of fat loss and cessation of lean tissue loss
What happened to metabolism to reduce the energy expenditure
Reduced resting energy expenditure (reduced mass of metabolically active tissue (basal metabolic rate), reduced energy expenditure per unit active tissue (per kilo of muscle mass), reduced heart rate and muscle tone
Reduced non-resting energy expenditure (reduced work of moving and reduction of voluntary movements)
Why there is a reduced of protein requirement in starvation and what is nitrogen balance
Diminished lean tissue mass
More efficient retention of dietary protein
Lean tissue mass stabalizes despite continued low protein intake
Nitrogen balance at first is going to be negative and then after 6 month it is going to be zero
Benefit and cost of successful adaptation
Benefit: survival
Cost: lean tissue loss, fatigue and inactivity, immunodeficiency, reduced tolerance to stress
Clinical features of PEM
Reduced body weight
Muscle wasting and decreased strength
Reduced respiratory and cardiac muscular capacity
Skin thinning
Decreased metabolic rate
Hypothermia
Apathy
Edema
Immunodeficiency
Draw the scheme how the body is going to adapt to decreased protein and energy intake and how it can be successful and how it can fail
Hypoalbunemia- problems with electrolyte and fluid balance
What is unsuccessful adaptation to malnutrition
Add micronutrient deficient (iron, B1)
Stress (trauma,cancer, inflammation/infection)
And all adaptations before become catastrophic
What happens with resting metabolic rate with starvation and different diseases
what happens with nitrogen excretion starvation vs injury
the 6 causes of muscle atrophy
- Cachexia-cancer, systemic inflammation
- Hormone excess or deficiency
- Old age-sarcopenia
- Protein-energy malnutrition-starvation
- Inactivity-disuse atrophy
- Neuromuscular disease
What can we learn from famine in netherlands
Epigenetics of everyone was affected
But especially pregnant women
Intrauterine growth restricted (IUGR)
This infants had increased chronic disease and even their own babies were affected->Barker hypothesis
What is statistics of child mortality because of femine and how many children are undernourished
5,5 million children under five are dying in 2017
90 million under five are undernourished and underweight
What is 1000 days of opportunity and what can be done
The key time ( from conception to 1000 day of the child)
Support breatfeeding, support women (nutrition and health) and children at the community level, better diets for babies and toddlers, Increased Investment in Children and Families (Paid time off for working parents to care for their newborns), The right foods introduced to babies at the right times, The right knowledge and skills for parents and caregivers to properly nourish young children, Societal investments in the wellbeing of every baby and toddler
What is wasting and what is stunting
Wasting - low weight for height
Stunting-low height for age
What is the disease in children that can be considered as successful and its characteristics (when, onset, what happens, what is weight-for-age, appetite)
Marasmus
Infancy (6 to 18 months of age)
Severe deprivation or impaired absorption of protein, energy, vitamins and minerals
Develops slowly Severe weight loss and muscle wasting, including the heart
Lower than 60% weight-for-age
Anziety and apathy
Good appetite is possible
Skin and bone appearance
Is it easier to treat marasmus or kwashiorkor
Marasmus
What is kwashiorkor (when, what is the prevalence, onset, signs and what happens), weight- for -age , appetite
Unsuccessful adaptation
Older infants and younf children 18 months to 2 years of age ( weaning period vulnerable) , usually the first child when the second is born
5% prevalence in some countries
Inadequate protein and energy intake
Rapid onset
Some muscle wasting, some fat retention
Weight for age (60-80%)
Appetite
Edema and fatty liver
How should you treat kwashiorkor and marasmus
Kwashiorkor - might have infection (respiratory or digestive) or other metabolic stress, electrolyte imbalance. Need to restore electrolyte balance and all other urgence situations, then infection and then nutrition
Marasmus -just gradually refeed
Long term consequences of PEU for children
Decreased development (physical, social, cognitive)
Adult productivity
Reproduction
Potential of the society as a whole
Infections that can occur to PEU children and why they can occur
Lack of antibodies
Nb no longer synthesized-> anemia
Fever
Fluid imbalance (heart failure, possible death)
Infections:
Dysentery
Diarrhea
Pheumonia and other respiratory infections
Urinary tract infections
Measles
Tuberculosis
Parasitic infections
Parasitic infections due to Fe and vitamin A deficiencies
Rehabilitation of PEU children should include
Nutrition must be cautios, slowly increasing protein
Programs should involve the local people
What is edema
Plasma proteins leave leaky blood vessels and move into tissues
Proteins attract water,causing swelling
When pressure is applied to the swollen tissue, it leaves an indentation
Impact of cancer on nutritional status
Presence of tumor (substances secreted by the tumor, demand of the tumor), the host repsonse to those tumor substances and anti-cancer treatment response
All of these influence nutrition status
Consequences of compromised nutrition status in cancer
Reduced intake, altered metabolism-> malnutrition and weight loss-> decreased quality of life, decreased response to treatment, decreased survival
What is cachexia
weakness and wasting of the body due to severe chronic illness
A complex metabolic syndrome associated with
underlying illness and characterized by loss of muscle
with or without loss of fat mass. The prominent
clinical feature is weight loss…
More muscle mass
Secondary effect
What is canadian task force and what is their benefits
Early identification of patients at risk, or experiencing,
malnutrition allows for early intervention
Helps design appropriate nutrition support
Improves patient wellbeing, survival, immune function
and reduced morbidity
Improves response to treatment
what are defficiences particularly common in elderly people
Vitamin D, vitamin C
Draw the scheme how different chronic illnesses increase weight loss and weakness
Insulin resistance because of cortisol
Hypogonadism means diminished functional activity of the gonads—the testes or the ovaries—that may result in diminished production of sex hormones.
Why muscle wasting predicts poor cancer-associated outcomes
↑ fatigue
↑ treatment‐induced toxicity
↓ host response to tumor
↓ performance status
↓ survival
What is sarcopenic-obesity and what outcomes it has
obesity with depleted muscle mass
≈15% of patients with lung or gastro‐intestinal tumors
worse outcomes than obese or sarcopenic patients
Lung or GI tumors that experience cachexia
In what cancers cachexia is more prevalent
Overall prevalence: 50‐80%
Upper gastro‐intestinal cancer
Lung cancer
The key aspect in cachexia is
Weight loss
What is undernutrion, malnutrition, starvation, sarcopenia
Undernutrition: insufficient food intake
Malnutrition: insufficient intake in one or more
nutrients (can also refer to over‐ or undernutrition)-> you cna be overweight and malnourished
Starvation: food deprivation (all nutrients)
Sarcopenia: decreased muscle mass (even in the
absence of weight loss)
What is the dual contribution of metabolic change and reduced food intake in cachexia
On the one hand it is systemic inflammation and catabolic factors(cytokines) - (leading to hyoercatabolism and hypoanabolism) and also primary or secondary anorexia( leading to reduced food intake)
Overall, negative energy and protein balance
What are cytokines
Hormone like substances, secreted by immune cells (lymphocytes,macrophages) or tumor that cause catabolic and proinflammatory effects
They in part are in charge of causing anorexia, acting on the brain-> decreased interest in food, decreased appetite
They also signal muscle cells to increase protein breakdown to increase break down of glucogenic amino acids to make insulin, even when there is no need for extra insulin, but they have insulin resistant stae, so they continue to synthesize insulin
They act locally (paracrine and autocrine) and systemically (endocrine)
In cachexia there hypermetabolism because
As a response to tumor or treatment
What is pyrexia
fever
Compare nutritioal alterations in starvation and cachexia (bodyweight, body cell mass, body fat, caloric intake,TEE,REE,protein synthesis, protein degradation, serum insulin, serum cortisol
Body cell mass (lean mass)
What are stages of cachexia and what are defining features
At what stage should we intervene
precachexia
In cachexia stage what we can measure
cytokines
How the traditional weight loss differs from weight loss in cachexia
Traditional: roughly equal proportions of fat mass and fat-free mass (mainly from skeletal muscle, although we also lose from visclerall tissues like liver and gut)
Cachexia (more muscle break down rather than fat)
Acute phase response in cachexia is a response to
inflammation, infection, injury (surgery)
What are acute-phase proteins
Fibrinogen (increase-> psoitive acute proteins)
And decrease in albumin (negative acute-phase proteins)
Albumins: function
Transport of nutrients around the body, trasnport toxins to the liver
Examples of big three proinflammtory cytokinesTumor
Tumor-necrosis factor alpha (TNF-alpha)
Interleukins 1 and 6 (IL-1, IL-6)
not the big three, but better to know
Interferon gamma (IFN-gamma)
Leukemia inhibitory factor (LIF)
functions of cytokines
decreased appetite and food intake, resulting from both
central and peripheral elements
decreased GI functions: decreased gastric emptying , intestine mobility
decreased blood flow
Inhibit lipoprotein lipase (LPL)
Inhibit growth hormone and IGF‐1 signaling
Induce insulin resistance (IL‐6)
draw a scheme: interaction between inflammation, liver, brain , muscle
What happens to energy expenditure
What happens to energy expenditure in patients with cachexia
Decreased overall expenditure, because of all inflammatory processes
But TEF- 5%, which is the lower bound of normal metabolism
Increased resting metabolic rate (85-90%)
And decreased PAL (physical activity energy ) from 15-30% to 5-10%
What are circulating anabolic and catabolic factors in cachexia
Glucagon and cortsiol promote net catabolism and insulin resistance
Increased mobolization of lipids and increased turnover of fatty acids, Increased lipolysis, FFA, VLDL
Decreased LPL , so overall hypertriglyceridemia (VLDL)
Main fuel for tumors and the outcome from it
Glucose is a fuel for tumors
Tumors produce lactate-> cori cycle (uses more ATP)
Increased gluconeogenesis->increased proteolysis (muscle)
Promotion of insulin resistance
WHat happens with nitrogen balance in cachexia
Negative
Increased basal protein turnover
Increased or no change in muscle proteolysis: provides AA for GNG,
acute‐phase protein synthesis and tumour growth
↓ or ↔ in muscle protein synthesis
↑ hepatic protein synthesis (APPs)
Comparing to starvation, where protein turnover is decreased
intracellular protein degradation pathway that is important
ATP‐dependent ubiquitin‐proteasome pathway
The most important in skeletal muscle proteolysis in
many wasting conditions, including cancer cachexia
describe ubiquitin-proteosome system
Series of three enzymes caleed ligases, its tying several ubiquitin molecules to the protein that is targetted to be degraded and then the protein that is targeted it gets in the proteasome and then ubiquitin recycled again
This pathway is promoted by cortsiol,glucagon and cytokines
Draw the scheme how tumor dusrupt homeostasis in the body with muscle, liver and fat tissue
Liver:Increased urea sythesis, increased lipogenesis because excess of glucose, increased in lypolysis in adipose tissue that will promote hypertriglyceridemia
Cachexia is associated witn mor ethan 50% of ____
Anorexia
An done of the treatmetns of cachexia is to recognize why we have anorexia (cytokines, treatment, lack of appetite, etc.)
What is early satiety
In anorexia, they are full after a few drops
Maybe a result from reduced GI motility, increased gastric emptying time, nervous system dysfunction, morphin related lack of appetite, or metabolic signals of satiety dysregulation
Why there can be nausea and chemosensory abnormalities during cancer
Nausea may occur as:
Side effect of drugs
Abdominal disease, intracranial metastases, metabolic derangements,
GI stasis
Distorsion of taste and smell:
Includes: hypersensitivity to odors and flavors, persistent bad tastes,
phantom smells, food aversions
Apart from treatment, may result from chronic nutritional deficiencies
Clinical diagnosis of cancer cachexia
Weight loss >5% over past 6 months
(in absence of simple starvation)
OR
BMI <20 kg/m2 and any degree of weight loss >2%
OR
Appendicular muscle mass consistent with sarcopenia
(<7.26 kg/m2 in men; <5.45 kg/m2 in women)
and any degree of weight loss >2%
Additional assessment to diagnosis of cachexia
Anorexia or reduced food intake
Questionnaires or <70% of usual food intake
Catabolic drive
serum CRP levels
Muscle mass and strength
DXA, BIA, MAMA, handgrip strength
Functional and psychosocial effects
questionnaires
What are the goals of cachexia treatment
increased Lean body mass (weight stabilisation ?)
Predispose to a better response to radio‐ or
chemo‐therapy
increased Immunocompetence
Symptom management
increased Perception of well‐being
What nutritional counseling should be in case of cachexia
Should be individual
Provide adequate energy and protein (usually 25‐30
kcal/kg/d, 1.2‐1.5 g pro/kg/d) but best to increase usual
intake.
Multi vitamins and minerals, omega‐3 fatty acids (anti-inflammatory)
Adapt dietary strategy according to:
Appetite
Rounds of therapy
Symptoms
Accessible route of feeding (oral, enteral, parenteral)
Encourage physical exercise
For whom enteral nutriton should be applied and to whom parenteral
Enteral
for patients with obstructions, gastric atony or limited
absorptive capacity
Preserves GI architecture, barrier, immune functions and gut permeability
Parental
When enteral route not accessible, but not recommended in advanced
cancer patients receiving chemotherapy
Difficulty of predicting survival is the main challenge for choosing the
right patients for TPN
What are specific AAs that can be given
Leucine stmulates protein synthesis and insulin secretion → may have
anabolic properties
Glutamine & arginine ↑ immune competence, help wound healing :
could be beneficial pre and post‐operatively
Omega 3 should not be given to patients with
Anti-coagulant therapy
What chemical agenst can be given to patients to increase appetite
Progestational agents (megestrol acetate): ↑ appete and
weight gain but not lean mass. Serious side effects: oedema,
thromboembolism.
Corticosteroids: transient increase in appetite and well‐being. Only
for restricted periods (1‐3 weeks). Side effects: insulin resistance,
muscle wasting, osteopenia.
Cannabicoids: dronabinol may have potential but inconsistent
evidence
