Cachexia-Anorexia Syndrome

Cachexia is a severe, multifactorial condition characterised by significant loss of skeletal muscle mass and adipose tissue. When significant anorexia accompanies it, the combination is called the anorexia-cachexia syndrome.

The point that matters clinically is that this is not simply reduced intake. Metabolic dysregulation, systemic inflammation and alimentary tract dysfunction combine to make conventional nutritional support ineffective at reversing the condition.

Where it occurs

Cachexia occurs in cancer, heart and renal failure, COPD, HIV and other chronic infections, and advanced autoimmune disease.

• Advanced malignancy — 50-80% of patients, highest in pancreatic, stomach and oesophageal cancer
• End-stage heart and renal failure — 5-15%, annual mortality 20-30%
• Advanced COPD — similar prevalence, annual mortality 10-15%

Breast cancer, sarcomas and haematological malignancies are less commonly affected. Nearly 20% of cancer deaths are due to cachexia and its sequelae.

Mechanism

Key mediators are pro-inflammatory cytokines — TNF-alpha, IL-6, IL-1beta — together with proteolysis-inducing factor and lipid-mobilising factor. These increase catabolism, muscle wasting and lipolysis while inhibiting muscle protein synthesis.

Cachexia is associated with excessive resting energy expenditure, driven by heightened sympathetic activity and cytokine production. Hypothalamic inflammation blunts appetite. Chronic inflammation causes growth-hormone resistance and low IGF-1, and low testosterone adds to muscle loss. Protein turnover continues even when energy and protein intake would be adequate in a healthy person.

Alimentary tract dysfunction compounds it: altered taste and smell, obstructing tumours, pancreatic insufficiency and malabsorption, delayed gastric emptying and early satiety, and the mucositis, nausea and xerostomia of chemotherapy and radiotherapy.

Distinguishing it

• Starvation — loss of fat and lean mass without the inflammation or metabolic disturbance, and it recovers with adequate nutrition
• Anorexia nervosa — severe weight loss without the muscle wasting and metabolic abnormalities of cachexia
• Sarcopenia — age-related muscle loss without inflammation or significant weight loss. Most people with cachexia are sarcopenic; most with sarcopenia do not have cachexia

Management

No medical intervention completely reverses cachexia, and care must be individualised.

Nutrition

Nutritional attention helps most earlier in the disease trajectory. Prompt assessment and support in pre-cachexia can improve nutritional status and wellbeing, and ESPEN advises early nutritional risk screening in cancer patients.

Practical advice: frequent small meals and snacks, calorie-dense foods, adequate hydration, and a standard multivitamin. Room-temperature or sour foods can be more palatable where taste is altered. Involve a dietitian, and steer patients away from unproven or extreme diets.

Artificial nutrition does not reverse advanced cachexia. No evidence supports routine enteral tube feeding or parenteral nutrition. ASCO advises against routine total parenteral nutrition given the lack of demonstrated benefit and the risk of catheter-related and abdominal infection; short-term TPN has a place in specific situations such as bowel obstruction, but has not been shown to improve quality of life or prolong survival.

Exercise

Moderate resistance and aerobic training is recommended by ESPEN and ESMO to maintain muscle mass and physical function. Exercise is safe in cancer patients and improves muscle strength, bone health and quality of life while reducing depression, fatigue and distress. Resistance training preserves lean mass better than aerobic work. Fatigue, bone pain, weakness and low mood are real barriers, so individualise and supervise.

Drugs

Corticosteroids such as dexamethasone improve appetite in the short term, but immunosuppression, osteoporosis, fluid retention and hypertension limit chronic use. Any weight gained is fat and fluid, not muscle.

Progesterone analogues (megestrol acetate, medroxyprogesterone) stimulate appetite and may increase fat mass, but megestrol carries fluid retention, thromboembolism and an increased risk of death.

Low-dose olanzapine increases appetite and weight with minimal adverse effects, and its antiemetic properties help chemotherapy-induced nausea. Mirtazapine is useful where depression drives the anorexia, though evidence is weaker.

Not recommended: cannabinoids (no better than placebo or megestrol for appetite, weight or quality of life), cyproheptadine (no weight gain in adults, though it may help children), and NSAIDs outside trials. Metoclopramide treats nausea and gastroparesis but does nothing for the metabolic disturbance. Anamorelin, enobosarm, thalidomide and myostatin inhibitors remain investigational.

Check eTG or AMH before prescribing any of these.

Symptom control and communication

Treat the individual symptom components — early satiety, nausea and vomiting, constipation, malabsorption, pain, depression — and support physical and occupational function alongside.

Help the patient and family adjust expectations around poor appetite and inevitable weight loss. This is one of the most emotionally significant symptoms for families, who often perceive reduced eating as hastening death, when in fact it is usually the dying process causing the reduced intake, not the reverse.