Cachexia
Encyclopedia
Cachexia or wasting syndrome is loss of weight
Weight loss
Weight loss, in the context of medicine, health or physical fitness, is a reduction of the total body mass, due to a mean loss of fluid, body fat or adipose tissue and/or lean mass, namely bone mineral deposits, muscle, tendon and other connective tissue...

, muscle atrophy
Muscle atrophy
Muscle atrophy, or disuse atrophy, is defined as a decrease in the mass of the muscle; it can be a partial or complete wasting away of muscle. When a muscle atrophies, this leads to muscle weakness, since the ability to exert force is related to mass...

, fatigue, weakness, and significant loss of appetite
Anorexia (symptom)
Anorexia is the decreased sensation of appetite...

 in someone who is not actively trying to lose weight. The formal definition of cachexia is the loss of body mass that cannot be reversed nutritionally: Even if the affected patient eats more calories, lean body mass will be lost, indicating there is a fundamental pathology in place.

Cachexia is seen in patients with cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...

, AIDS
AIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...

, chronic obstructive lung disease, congestive heart failure
Congestive heart failure
Heart failure often called congestive heart failure is generally defined as the inability of the heart to supply sufficient blood flow to meet the needs of the body. Heart failure can cause a number of symptoms including shortness of breath, leg swelling, and exercise intolerance. The condition...

, tuberculosis
Tuberculosis
Tuberculosis, MTB, or TB is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs but can also affect other parts of the body...

, familial amyloid polyneuropathy
Familial amyloid neuropathy
The familial amyloid neuropathies are a rare group of autosomal dominant neuropathies of autonomic and peripheral nerves....

, mercury poisoning
Mercury poisoning
Mercury poisoning is a disease caused by exposure to mercury or its compounds. Mercury is a heavy metal occurring in several forms, all of which can produce toxic effects in high enough doses...

 (acrodynia) and hormonal deficiency.

It is a positive risk factor for death, meaning that if the patient has cachexia, the chance of death from the underlying condition is increased dramatically. It can be a sign of various underlying disorders; when a patient presents with cachexia, a doctor will generally consider the possibility of cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...

, metabolic acidosis
Metabolic acidosis
In medicine, metabolic acidosis is a condition that occurs when the body produces too much acid or when the kidneys are not removing enough acid from the body. If unchecked, metabolic acidosis leads to acidemia, i.e., blood pH is low due to increased production of hydrogen by the body or the...

 (from decreased protein synthesis and increased protein catabolism
Catabolism
Catabolism is the set of metabolic pathways that break down molecules into smaller units and release energy. In catabolism, large molecules such as polysaccharides, lipids, nucleic acids and proteins are broken down into smaller units such as monosaccharides, fatty acids, nucleotides, and amino...

), certain infectious disease
Infectious disease
Infectious diseases, also known as communicable diseases, contagious diseases or transmissible diseases comprise clinically evident illness resulting from the infection, presence and growth of pathogenic biological agents in an individual host organism...

s (e.g., tuberculosis
Tuberculosis
Tuberculosis, MTB, or TB is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs but can also affect other parts of the body...

, AIDS
AIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...

), chronic pancreatitis, and some autoimmune disorders, or addiction to amphetamine
Amphetamine
Amphetamine or amfetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat,...

s. Cachexia physically weakens patients to a state of immobility stemming from loss of appetite, asthenia, and anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...

, and response to standard treatment is usually poor.

Disease settings

Cachexia is often seen in end-stage cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...

, and in that context is called "cancer cachexia."

It was also prevalent in HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...

 patients before the advent of highly active anti-retroviral therapy (HAART) for that condition; now it is seen less frequently in those countries where such treatment is available. It is this characteristic that prompted a common African name for AIDS, "slim disease".

In patients with congestive heart failure
Congestive heart failure
Heart failure often called congestive heart failure is generally defined as the inability of the heart to supply sufficient blood flow to meet the needs of the body. Heart failure can cause a number of symptoms including shortness of breath, leg swelling, and exercise intolerance. The condition...

, there is also a cachectic syndrome. Also, a cachexia co-morbidity is seen in patients that have any of the range of illnesses classified as "COPD
Chronic obstructive pulmonary disease
Chronic obstructive pulmonary disease , also known as chronic obstructive lung disease , chronic obstructive airway disease , chronic airflow limitation and chronic obstructive respiratory disease , is the co-occurrence of chronic bronchitis and emphysema, a pair of commonly co-existing diseases...

" (chronic obstructive pulmonary disease), particularly emphysema. Some severe cases of schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...

 can present this condition where it is named vesanic cachexia (from vesania, a Latin term for insanity).

It also can be observed in such parasitic
Parasitism
Parasitism is a type of symbiotic relationship between organisms of different species where one organism, the parasite, benefits at the expense of the other, the host. Traditionally parasite referred to organisms with lifestages that needed more than one host . These are now called macroparasites...

 diseases
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...

 as african trypanosomiasis (Sleeping sickness).

In each of these settings there is full-body wasting
Wasting
In medicine, wasting refers to the process by which a debilitating disease causes muscle and fat tissue to "waste" away. Wasting is sometimes referred to as "acute malnutrition" because it is believed that episodes of wasting have a short duration, in contrast to stunting, which is regarded as...

, which hits the skeletal muscle
Skeletal muscle
Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth muscle...

 especially hard, resulting in muscle atrophy
Muscle atrophy
Muscle atrophy, or disuse atrophy, is defined as a decrease in the mass of the muscle; it can be a partial or complete wasting away of muscle. When a muscle atrophies, this leads to muscle weakness, since the ability to exert force is related to mass...

 and great muscle loss. However, when presenting comorbidly with malabsorbtion syndrome, (as seen, for example, in Crohn's Disease or Celiac Disease) simply consuming more food is not sufficient to reverse wasting and the malabsorbtion must be treated before the patient will be able to stabilize body mass.

Mechanism

The exact mechanism in which these diseases cause cachexia is poorly understood, but there is probably a role for inflammatory
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...

 cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...

s such as tumor necrosis factor-alpha (TNF-α), which is also nicknamed cachexin (also spelled cachectin) for this reason, Interferon gamma
Interferon
Interferons are proteins made and released by host cells in response to the presence of pathogens—such as viruses, bacteria, or parasites—or tumor cells. They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.IFNs belong to...

 (IFNγ), and Interleukin 6
Interleukin 6
Interleukin-6 is a protein that in humans is encoded by the IL6 gene.IL-6 is an interleukin that acts as both a pro-inflammatory and anti-inflammatory cytokine. It is secreted by T cells and macrophages to stimulate immune response, e.g. during infection and after trauma, especially burns or other...

 (IL-6), as well as the tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...

-secreted proteolysis
Proteolysis
Proteolysis is the directed degradation of proteins by cellular enzymes called proteases or by intramolecular digestion.-Purposes:Proteolysis is used by the cell for several purposes...

 inducing factor (PIF).

Related malnutrition syndromes are kwashiorkor
Kwashiorkor
Kwashiorkor is an acute form of childhood protein-energy malnutrition characterized by edema, irritability, anorexia, ulcerating dermatoses, and an enlarged liver with fatty infiltrates. The presence of edema caused by poor nutrition defines kwashiorkor...

 and marasmus
Marasmus
Marasmus is a form of severe protein-energy malnutrition characterized by energy deficiency.A child with marasmus looks emaciated. Body weight may be reduced to less than 80% of the average weight that corresponds to the height . Marasmus occurrence increases prior to age 1, whereas kwashiorkor...

, although these do not always have an underlying causative illness; they are most often symptomatic of severe malnutrition
Malnutrition
Malnutrition is the condition that results from taking an unbalanced diet in which certain nutrients are lacking, in excess , or in the wrong proportions....

.

Those suffering from the eating disorder anorexia nervosa appear to have high plasma levels of ghrelin
Ghrelin
Ghrelin is a 28 amino acid peptide and hormone that is produced mainly by P/D1 cells lining the fundus of the human stomach and epsilon cells of the pancreas that stimulates hunger. Ghrelin levels increase before meals and decrease after meals. It is considered the counterpart of the hormone...

. Ghrelin levels are also high in patients who have cancer-induced cachexia.

Treatment

Currently, there are widely accepted drugs to treat cachexia and there are no FDA-approved drugs to treat cancer cachexia.

Cachexia may be treated by steroid
Steroid
A steroid is a type of organic compound that contains a characteristic arrangement of four cycloalkane rings that are joined to each other. Examples of steroids include the dietary fat cholesterol, the sex hormones estradiol and testosterone, and the anti-inflammatory drug dexamethasone.The core...

s such as corticosteroid
Corticosteroid
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte...

s or drugs that mimic progesterone
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...

, which increase appetite, may reverse weight loss but have no evidence of reversing muscle loss. Medical marijuana has been allowed for the treatment of cachexia in some US states such as Nevada, Michigan, Washington, Oregon, California, Colorado, New Mexico, and Arizona.

Omega-3 fatty acids

A 2007 systematic review
Systematic review
A systematic review is a literature review focused on a research question that tries to identify, appraise, select and synthesize all high quality research evidence relevant to that question. Systematic reviews of high-quality randomized controlled trials are crucial to evidence-based medicine...

 of n-3 fatty acids and cachexia found seventeen studies, eight of which were high-quality. It concluded that there was evidence that oral n-3 fatty acid
Omega-3 fatty acid
N−3 fatty acids are essential unsaturated fatty acids with a double bond starting after the third carbon atom from the end of the carbon chain....

 supplements benefit cancer patients, improving appetite, weight and quality of life
Quality of life
The term quality of life is used to evaluate the general well-being of individuals and societies. The term is used in a wide range of contexts, including the fields of international development, healthcare, and politics. Quality of life should not be confused with the concept of standard of...

.
A 2009 trial found that a supplement of eicosapentaenoic acid
Eicosapentaenoic acid
Eicosapentaenoic acid is an omega-3 fatty acid. In physiological literature, it is given the name 20:5. It also has the trivial name timnodonic acid...

 helped cancer patients retain muscle mass.

Drugs in development

Three Phase 2 clinical presentations occurred at ASCO 2010 with the following results:
ALD518
ALD518
BMS-945429 is an aglycosylated, humanized monoclonal antibody against interleukin-6. It is an investigational drug for cancer and rheumatoid arthritis due to its anti-inflammatory properties....

 is a humanized anti-IL-6
Anti-IL-6
Anti-interleukin-6 agents are a recent class of therapeutics.Interleukin-6 is relevant to many inflammatory diseases and many cancers. Hence anti-IL-6 agents have been sought....

 antibody. In testing, 124 patients with advanced NSCLC were randomized to one of four treatment groups (~30/group). Researchers concluded that ALD518 given to patients with NSCLC was safe and well tolerated. ALD518 improved the lung symptom score, reversed fatigue, and there was less loss of LBM (-0.19 kg on ALD518 vs. -1.50 kg on placebo).

GTx-024 is a Selective Adrenergic Receptor Modulator (SARM). In testing, 159 patients with either non-small cell lung cancer, colorectal cancer, non-Hodgkin's lymphoma, chronic lymphocytic leukemia or breast cancer were randomized to oral GTx-024 (3 mg or 1 mg) or placebo daily for 16 weeks. As a result, a statistically significant increase in lean body mass (LBM) was observed in both treatment groups compared to baseline (1 mg, P=0.001; 3 mg, P=0.045).

VT-122 is a co-administration of propranolol and etodolac
Etodolac
Etodolac: Etodolac belongs to a class of drugs called nonsteroidal anti-inflammatory drugs . Other members of this class include aspirin, ibuprofen , naproxen , indomethacin , nabumetone and numerous others. These drugs are used for the management of mild to moderate pain, fever, and inflammation...

. In testing, 37 patients with advanced NSCLC were randomized to one of three treatment groups (~12/group). Researchers observed a statistically significant difference in the proportion of subjects who responded with an improvement of ≥ 5% in LBM at Week 12 (Group A, control, n = 0/12; Group B, low dose VT-122, n = 7/12 p = 0.0191; Group C, high dose VT-122, n = 5/12, p = 0.0174). No patient in Group A gained any lean body mass. An increasing trend in improvement was seen at Weeks 6 and 9 for Group B and C.

The world's leading scientists gathered at the 5th annual meeting of the Society on Cachexia and Wasting Disorders in Barcelona December 5–8, 2009 to present data on various molecules in development. Kung et al. report highlights from the 5th Cachexia Conference held in December 2009 in Barcelona, Spain. Novel therapeutic approaches shown here include type 4 melanocortin receptor antagonist SNT 207979, an IL-6 antagonism ALD518, the appetite promoting synthetic ghrelin SUN11031, the soluble myostatin decoy receptor ActRIIB-Fc, the fast skeletal muscle troponin activating substance CK-2017357, the anti-catabolic/anabolic transforming agent MT-102, the anti-inflammatory agent celecoxib
Celecoxib
Celecoxib INN is a sulfa non-steroidal anti-inflammatory drug and selective COX-2 inhibitor used in the treatment of osteoarthritis, rheumatoid arthritis, acute pain, painful menstruation and menstrual symptoms, and to reduce numbers of colon and rectum polyps in patients with familial...

, testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...

 supplementation and vitamin D
Vitamin D
Vitamin D is a group of fat-soluble secosteroids. In humans, vitamin D is unique both because it functions as a prohormone and because the body can synthesize it when sun exposure is adequate ....

.
Two of the presenting companies were Cytokinetics and Ohr Pharmaceutical. Cytokinetics' molecule acts as a skeletal muscle activator by making certain proteins more sensitive to calcium. Potential treatment for diseases and conditions associated with aging, muscle wasting or neuromuscular dysfunction. Ohr Pharmaceutical's drug, OHR/AVR118, modulates pro-inflammatory chemokine
Chemokine
Chemokines are a family of small cytokines, or proteins secreted by cells. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines...

 and cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...

 synthesis, including TNF-alpha.

Other preclinical work

In a study published 2010, researchers demonstrated a link between cachexia and activin and myostatin
Myostatin
Myostatin is a secreted TGF beta protein family member that inhibits muscle differentiation and growth. Myostatin is produced primarily in skeletal muscle cells, circulates in the blood and acts on muscle tissue, by binding a cell-bound receptor called the activin type II receptor...

 activity, and successfully reversed the effects in mice, by inhibiting that activity through treatment with a soluble version of the ActRIIB receptor (sActRIIB).

Prevalence

According to the 2007 AHRQ National Inpatient sample, there were a projected 129,164 hospital encounters in the United States where cachexia was listed as at least one of up to 14 listed diagnosis codes, based on a sample of 26,325 unweighted encounters. The CDC National Ambulatory Medical Care Survey (NAMCS), a sample of U.S. outpatient visits listed 0 visits where cachexia was listed as one of up to three recorded diagnoses treated during the visit, out of a sample of 32,778 unweighted visits.

External links

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