Cachexia

Cachexia is a devastating syndrome that causes severe weight loss and muscle wasting in people with serious illnesses like cancer, heart disease, and chronic lung conditions. This condition affects millions of people worldwide and can significantly impact quality of life, treatment outcomes, and survival.

Table of contents

• What is Cachexia
• Causes and Associated Conditions
• Who is Affected
• Symptoms and Signs
• Stages of Cachexia
• How Cachexia Develops
• Diagnosis
• Treatment Approaches
• Impact on Quality of Life and Prognosis

What is Cachexia

Cachexia is a complicated metabolic syndrome (a group of related symptoms caused by changes in how the body processes nutrients) that occurs as a result of serious underlying illnesses. The name “cachexia” comes from Greek words meaning “bad body” or “poor physical state,” which describes how dramatically this condition can change a person’s appearance and overall health^[7].

The hallmark of cachexia is the loss of muscle mass, with or without the loss of fat tissue. This weight loss cannot be fully reversed simply by eating more food or receiving standard nutritional support^[1][3]. Unlike weight loss from dieting or starvation, cachexia involves a persistent increase in the body’s basal metabolic rate (the amount of energy your body needs at rest) that is not balanced by increased food intake^[1].

Cachexia is often accompanied by loss of appetite (called anorexia), an inflammatory process throughout the body, resistance to insulin, and increased breakdown of proteins^[1]. This condition is sometimes referred to as “wasting syndrome” or “cancer anorexia cachexia” when it occurs in cancer patients^[6][4].

Causes and Associated Conditions

The major cause of cachexia is an excess of substances called cytokines (proteins in the immune system that help regulate how the body responds to disease and infection). Other factors that contribute to cachexia include deficiencies in testosterone and insulin-like growth factor-I, excess of a protein called myostatin, and too much of hormones called glucocorticoids^[1].

Cachexia is most commonly associated with cancer, but it also occurs with other chronic diseases^[1][3]. The conditions that can cause cachexia include:

• Cancer (especially advanced stages)
• Chronic obstructive pulmonary disease (COPD)
• Chronic heart failure
• Chronic kidney disease
• AIDS and other chronic infectious diseases
• Chronic inflammatory diseases
• Alzheimer’s disease
• Dementia

In cancer patients, cachexia is most common in those with pancreatic cancer and lung cancer, but it also frequently occurs in people with colorectal (colon) cancer, kidney cancer, stomach cancer, and melanoma^[8][13].

Who is Affected

Cachexia is estimated to affect approximately 9 million people worldwide^[7]. In cancer patients, the overall prevalence of cachexia ranges from 40% at the time of cancer diagnosis to 70% in advanced disease^[1]. Cachexia is estimated to occur in up to 80% of people with advanced cancer, depending on the cancer type and how well they respond to cancer treatment^[8].

The condition affects almost 90% of people living with pancreatic cancer and half of patients with advanced lung cancer^[10][15]. In 20% to 25% of patients with advanced solid tumors, cachexia is considered the primary cause of death, in addition to being a significant comorbidity that reduces median survival by up to 30%^[1]. Cachexia is thought to directly cause up to 30% of cancer deaths, often because of heart or respiratory failure related to muscle loss^[8].

As many as 75% of patients with cancer have significant unexplained weight loss six months before they are diagnosed, but this important clue is often missed^[10].

Symptoms and Signs

The most significant symptom of cachexia is losing more than 10% of your total body weight, including muscle mass and fat, over the past six to 12 months^[13]. This is weight loss that happens when you are not trying to lose weight, even though you may be eating high-calorie meals^[7].

Other symptoms include:

• Loss of appetite: In cachexia-related anorexia, you don’t feel hungry and lose interest in eating at all. This is different from the eating disorder anorexia nervosa^[7][6].
• Muscle loss or wasting: Your muscle mass decreases, so your muscles appear smaller and are not as strong. Healthcare providers may call this muscle atrophy^[7][13].
• Fatigue and weakness: Cachexia can make you feel exhausted and too tired to manage daily tasks. You may feel like you don’t have the strength to move around as you normally would^[7][13].
• Having no sense of taste or taste changes^[6]
• Electrolyte levels in your blood being too high or too low^[6]
• Anemia (low red blood cell count)^[6][13]
• Weakened immune system, making it harder to fight off infections^[6][13]

History from patients frequently includes a report of significant weight loss associated with lack of appetite^[1]. The physical and mental toll of cachexia can be severe. Many people find that everyday activities like taking a bath, going to the grocery store, or meeting a friend for coffee become extremely difficult or impossible^[8].

Stages of Cachexia

Cachexia has three clinically relevant stages^[5][6]:

Precachexia: This is the early stage where clinical and metabolic signs first appear, such as anorexia and impaired glucose tolerance. Weight loss in this stage is 5% or less of body weight. Patients may also experience having no sense of taste^[5][6][16].

Cachexia: This stage is diagnosed in patients with weight reduction of more than 5%, or a weight loss of over 2% in individuals who are already depleted based on their current body weight and height (with a body mass index below 20 kg/m² if under 65 years old, or below 22 kg/m² if over 65)^[5][16].

Refractory cachexia: This is the advanced stage characterized by cancer that is unresponsive to treatment. Once a patient reaches this stage, life expectancy is less than 3 months, and the primary focus of care becomes reducing symptoms and patient distress^[5][16].

Not all patients with cancer will have all three stages of cachexia. The risk of cachexia getting worse can depend on many factors, including cancer type and stage, how much food you are eating, how much inflammation you have in your body, how inactive you are, whether cancer treatment is working, and whether you have had surgery and are healing properly^[6].

How Cachexia Develops

Cachexia happens when there is a disconnect between energy demand (your metabolism) and energy supply (food). This disconnect often occurs because you are very sick with a chronic medical condition like cancer or heart disease^[7].

When you are very sick, your metabolism speeds up as your immune system reacts to the disease, creating an ongoing demand for more energy from the food you eat. At the same time, the same condition that speeds up your metabolism may affect your appetite. Without an adequate energy supply from food, your body uses your muscles and fat to get more energy, so you lose muscle mass and weight^[7][13].

Specific factors involved in how cachexia develops include:

Too many cytokines: Cytokines manage how and when your immune cells react to intruders like viruses. In cachexia, extra cytokines cause inflammation that makes you lose fat and muscle^[7][13].

System-wide inflammation: Cancer and other chronic diseases cause inflammation throughout the body that can lead to loss of fat and muscle. Inflammatory mediators such as tumor necrosis factor and interleukins induce anorexia while increasing glucagon, cortisol, and catecholamines, producing a catabolic (breaking down tissues), hypermetabolic state^[1][7].

Hormonal changes: Hormonal anabolic mediators (substances that help build tissues) such as growth hormone, insulin-like growth factor-1, testosterone, and ghrelin are reduced in cachexia^[1].

Insulin resistance: This is when your muscles and fat don’t react to insulin as they should. Insulin resistance in cachexia may increase muscle loss^[7].

Increased protein turnover: Protein turnover refers to the way new proteins replace older proteins in your cells through protein degradation (breaking down proteins). In cachexia, proteins in your cells break down too quickly to be replaced with new proteins, leading to muscle loss^[7].

Digestive factors resulting in poor food intake include changes in taste, nausea, difficulty swallowing, mouth sores, and constipation. Tumor-mediated factors have been identified that activate the breakdown of proteins and fats^[1].

Diagnosis

A healthcare provider may suspect you have cachexia if you have lost 5% or more of your weight within the past six to 12 months without trying to lose weight^[7][13]. The diagnosis requires consideration of your medical history, current body weight and height, and the presence of an underlying chronic illness.

Anyone who is losing weight unexpectedly should immediately seek the care of a health provider to investigate it further^[10]. Healthcare providers can only help if they know what is going on, so it is important to talk to your doctor if you believe you are experiencing cachexia^[15].

Treatment Approaches

Healthcare providers cannot cure cachexia at this time. Right now, the only treatment for cachexia involves managing the underlying condition and taking steps to improve nutrition^[7]. Treatment focuses on boosting the amount of food that you eat, with special emphasis on high-protein, high-calorie foods^[13].

Early nutritional intervention and multidisciplinary care are essential to ensure sufficient nutritional requirements and minimize factors that make it hard for the body to build muscle. Preventive care that minimizes deterioration of nutritional status and loss of skeletal muscle mass is required for the effective treatment of cachexia^[11].

Nutritional approaches: Treatment can include eating small meals with lots of protein, and working with a dietitian or nutritionist^[6][13]. However, conventional nutritional support alone cannot entirely reverse cachexia^[3].

Medications: Steroids have traditionally been used for cachexia drug therapy, but their effects are limited^[11]. Currently, there are no FDA-approved drugs specifically for cancer cachexia, though this represents a huge unmet need^[8][10].

Researchers are investigating medications that may keep cachexia symptoms from getting worse^[7]. At least one drug, anamorelin hydrochloride, has been shown in large studies to help people with cancer cachexia maintain lean muscle mass, which is critical for daily functioning and the ability to tolerate cancer treatments. This medication was the first drug to be approved for treating cachexia in some countries^[8][11].

Several experimental drugs that showed remarkable effects against cachexia in mice are now being tested in human studies. A drug called ponsegromab, which blocks a hormone known as GDF-15 that regulates appetite and body weight, showed promising results in a randomized phase 2 clinical trial. The drug improved many aspects of cachexia and its symptoms, with minimal side effects^[12].

Exercise and physical therapy: Researchers have launched clinical trials to test exercise-based treatments for cancer cachexia^[8].

The number of researchers studying cancer-related cachexia is growing, bringing with them new information about how this wasting syndrome develops and clinical trials testing new treatments^[8].

Impact on Quality of Life and Prognosis

Cachexia has been identified as a negative outcome of cancer and other chronic diseases, leading to reduced physical function, tolerance to treatment, and survival rates^[5][9]. The condition can be life-threatening. It affects quality of life and may affect your ability to receive cancer treatment^[7][13].

Cachexia not only has a dramatic impact on patient quality of life, but is also associated with poor responses to chemotherapy and decreased survival^[9]. Body muscle and fat are important for healing and recovery from treatment. People with cachexia may not tolerate cancer treatments well^[6]. There is also an increased risk of side effects from chemotherapy treatments in cancer patients who suffer from cachexia^[16].

Significantly shorter survival in advanced cancer patients with cachexia has been identified relative to those without cachexia^[1]. More than 25% of cancer-related deaths can be attributed to cachexia^[10].

The mental health impact of cachexia is also significant. The physical toll of cachexia can give way to worry, stress, anxiety, and mental anguish^[8]. Cachexia causes distress and anxiety, as people often don’t look the same when they have cachexia, which can be upsetting to patients and their caregivers^[6]. For the family and loved ones of a person experiencing cachexia, witnessing this physical and mental decline can leave them feeling helpless and confused^[8].

A cachexia diagnosis often means that the end of life is near^[7]. The weakness results in part from decreases in size and number of muscle fibers and reduced blood flow to muscles^[1].