Aetiology
The aetiology of unintentional weight loss comprises a broad range of clinical conditions. Nearly every organ system or disease classification has a syndrome that may result in unintentional weight loss. As a diagnostic challenge, it resembles fever of unknown origin in its breadth. The most important considerations for initial work-up are to detect an underlying malignancy that could have improved outcomes if identified early, and other conditions of high morbidity and mortality. In most case series, the aetiology remains unidentified in a small percentage of cases despite exhaustive work-up. For these patients, ongoing follow-up is required.
Malignant
Cancer is a common cause of unintentional weight loss in published case series (i.e., 6% to 36% of patients).[1][9]
Risk factors for malignancy include age, exposure to radiation, previous chemotherapy, immunosuppression and smoking. Examples of organ-specific risk factors include a history of colon polyps, leading to an increased risk of colorectal cancer, and hepatitis B infection increasing the risk of hepatocellular carcinoma.
In the most difficult cases there may be no risk factors or examination findings other than unintentional weight loss.
In a population-based sample in the US, cancer was associated with unintentional weight loss to a greater degree than other chronic illnesses.[32]
Weight loss in non-specialist settings, such as primary care, has been associated with a wide range of cancers, including prostate, colorectal, lung, gastro-oesophageal, pancreatic, non-Hodgkin’s lymphoma, ovarian, multiple myeloma, renal tract, and biliary tree.[33][34]
Solid tumours
Solid tumours are more likely to present with weight loss than other cancers. Gastrointestinal, lung, and head and neck cancers (e.g., laryngeal, oropharyngeal) are associated with significant weight loss.[35][36] Bladder cancer and brain tumours have been implicated; weight loss at presentation is not common with primary brain tumours such as glioblastoma.
Haematological malignancies
Weight loss can occur in haematological malignancies (e.g., leukaemia, lymphoma, multiple myeloma). Chronic leukaemia is more likely to present with weight loss compared with acute leukaemia, and chronic lymphocytic leukaemia and lymphoma more commonly present with weight loss compared with chronic myeloid leukaemia. In acute leukaemia, the weight loss may occur over a shorter time period. Multiple myeloma is more common in older patients.[37]
Metastatic and advanced disease
Certain cancers do not typically present with weight loss unless they are either metastatic or at an advanced stage. These include breast, ovarian, cervical, endometrial, and prostate cancer. Endometrial and cervical cancer more commonly present with local symptoms.
Weight loss at time of diagnosis may not reliably predict advanced stage disease; in one study, more than 50% of patients with weight loss as a presenting symptom were diagnosed with cancer at stages other than stage IV.[38]
Neuroendocrine tumours
Neuroendocrine tumours (e.g., carcinoid tumours, gastrinoma from Zollinger-Ellison syndrome, VIPoma) are rare entities and may cause weight loss due to their hormonal effects (or the presence of diarrhoea). However, only 3% of neuroendocrine tumours present with weight loss.[39][40] Zollinger-Ellison syndrome arises from a gastrinoma and over-secretion of gastrin, and is associated with multiple endocrine neoplasia type 1. In one case series, 17% of patients with Zollinger-Ellison syndrome presented with unintentional weight loss.[41]
Gastrointestinal (non-malignant)
Non-malignant gastrointestinal conditions are a common cause of unintentional weight loss in published case series (i.e., 6% to 22% of patients).[1][9] A variety of conditions can lead to chronic diarrhoea and weight loss.
Coeliac disease: a common cause; however, it is important to establish the diagnosis and rule out other causes of weight loss.
Exocrine pancreatic insufficiency: may be due to prior episodes of pancreatitis or cystic fibrosis. Extensive disease may result in endocrine pancreatic insufficiency and type 1 diabetes. Unintentional weight loss usually only occurs in severe cases.
Inflammatory bowel disease: typically presents in younger patients, but there is a second peak in the sixth decade. Crohn's disease may present in a myriad of ways and does not always have all of the typical findings.
Ischaemic bowel disease: cardiovascular disease may present as mesenteric ischaemia, typically in older patients. Weight loss may be severe.[42] Superior mesenteric artery and coeliac artery stenoses may be more likely to precipitate weight loss[43]
Peptic ulcer disease: pain and nausea can result in decreased oral intake resulting in weight loss. Consider inflammatory bowel disease and gastric cancer if the patient has symptoms of peptic ulcer disease and severe weight loss.
Oesophageal webs/rings/diverticula, chronic hepatitis, gastroparesis, small intestinal bacterial overgrowth, and post-surgical complications may rarely cause unintentional weight loss.
Irritable bowel syndrome (IBS) is common but does not usually cause significant weight loss. Patients with coeliac disease or inflammatory bowel disease may have comorbid IBS, and a diagnosis of IBS should not preclude suspicion for these conditions should weight loss be present. Microscopic colitis does not typically result in severe weight loss.
Severe oropharyngeal disorders, such as stomatitis, and dental problems (particularly in older people) can also result in decreased oral intake and subsequent weight loss.[9]
Median arcuate ligament syndrome is a rare and debated diagnosis in which the median arcuate ligament compresses the coeliac artery, leading to epigastric pain, nausea, vomiting, and unintentional weight loss. Symptoms are typically postprandial. Consensus criteria are lacking.[44]
Psychiatric
Psychiatric illnesses commonly present with weight change; bipolar disorder, schizophrenia, anxiety disorders and depressive episodes have been associated with unintentional weight loss.[9][31] Weight changes can be variable, and significant unintentional weight loss can occur. In published series of patients presenting with unintentional weight loss, psychiatric or psychosocial causes (variously defined) were found in 9% to 33% of cases.[1][9]
Weight change is considered common in anxiety disorders, although its prevalence is not well studied, and it is not currently part of the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, Text Revision (DSM-5-TR) or International Classification of Diseases (ICD) criteria for generalised anxiety disorder.[45][46]
In patients with medical comorbidities, some of the somatic symptoms of depression (e.g., fatigue, psychomotor slowing, weight loss) may overlap with medical illnesses. Further complicating this symptom overlap is the comorbid pathology of depression and serious medical conditions. Patients are at increased risk for depression following stroke and myocardial infarction, and both depression and anxiety disorders are prevalent in patients with cancer.[47][48][49]
Eating disorders such as anorexia nervosa and bulimia nervosa present with weight loss, and often the history is not forthcoming as to the patient’s distorted body perception and fear of weight gain. Depression, anxiety, and obsessive compulsive disorder are common comorbidities.
Substance use disorders, when severe, may result in weight loss due to inadequate attention paid to nourishment in the setting of time and resources spent toward the addiction. Progressive loss of functioning and societal networks may further lead to undernourishment. Comorbid depression and anxiety are common and may contribute to barriers to treatment.
Neurological
Neurological conditions frequently present with unintentional weight loss.
Advanced dementia may present with weight loss owing to decreased executive function, apathy, decreased taste, and decreased swallowing and chewing function. One case control study of outpatients aged ≥60 years with unintentional weight loss reported that the weight loss was attributed to dementia in 14% of cases.[50]
Neuromuscular disorders may impair the patient’s ability to eat. In multiple sclerosis (MS), weight loss may occur due to global weakness, diminished ability to self-feed, and decreased control of swallowing function with progressive disease. Fatigue and depression are common in MS and may also contribute to weight loss. In amyotrophic lateral sclerosis, weight loss may occur from muscle atrophy and an impaired ability to eat. In Parkinson's disease, weight loss may occur as a consequence of impaired oropharyngeal function, decreased ability to self-feed, or cognitive impairment.
Prion disease should also be considered in the differential, although weight loss is not common.
Cardiovascular
Unintentional weight loss can occur in patients with cardiovascular disease.
While patients with heart failure frequently present with weight gain due to volume overload, in cases of advanced heart failure, a syndrome of cardiac cachexia may develop.[12] Both unintentional weight loss and cardiac cachexia are predictors of mortality in patients with chronic heart failure.[51][52]
Valvular heart disease may lead to weight loss through heart failure and cardiac cachexia; pericardial disease may rarely lead to a cachexia syndrome.
Patients who have suffered a stroke may lose weight from the direct effects of the stroke on oropharyngeal muscles, or from a diminished ability to self-feed due to arm or hand weakness. Additionally, post-stroke depression is common and associated with weight loss.[53]
Pulmonary (non-malignant)
End-stage chronic obstructive pulmonary disease (COPD) may result in cachexia due to increased work of breathing and neurohormonal changes, and is associated with increased mortality.[54] While COPD is the best-studied model of cachexia in pulmonary disease, other severe chronic lung disease (e.g., interstitial lung disease) may also result in weight loss due to increased work of breathing and a similar cachectic process.
Patients with chronic respiratory disease who present with unintentional weight loss should not be assumed to have a pulmonary cachexia syndrome, as COPD and lung cancer have smoking as a common aetiological agent. Therefore, patients with COPD and unintentional weight loss should still be evaluated for lung cancer. Only 25% of patients with COPD will develop cachexia, and those with less severe COPD who present with unintentional weight loss should still be assessed for other potential aetiologies.[54]
Cystic fibrosis generally presents in childhood, and a multitude of factors lead to unintentional weight loss, including gastrointestinal malabsorption, malnutrition, increased metabolic rate due to respiratory disease, and cystic fibrosis-related diabetes.[55][56]
Renal
Although renal failure typically leads to weight gain due to diminished renal excretion and consequent volume retention, end-stage renal disease can result in a syndrome of renal cachexia.[57]
Patients with renal disease are often on loop diuretics to maintain volume status. Unintentional weight loss should be distinguished from this intended weight loss. If a patient has greater weight loss than expected, or suffers weight loss despite a stable dose of diuretic, then evaluation for unintentional weight loss should be performed.
Vasculitides may also present with unintentional weight loss. Polyarteritis nodosa and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides, such as microscopic polyangiitis, frequently have renal involvement.
Endocrinological
In patients with new-onset type 1 diabetes, weight loss is due to polyuria and insulin deficiency. Ketosis, if present, compounds the weight loss because of decreased appetite. Type 2 diabetes less frequently presents with weight loss due to polyuria.
Hyperthyroidism may present with a myriad of symptoms, including weight loss.[58] Older patients may not present with typical symptoms, and the presentation may be dominated by unintentional weight loss without other manifestations.[59]
Adrenal insufficiency presented with weight loss in 25% of patients in one case series.[60] Aetiologies of primary adrenal failure include metastatic tumours, tuberculosis, and autoimmune endocrinopathies. With the commonplace use of corticosteroids, tertiary adrenal insufficiency should be considered in patients with a history of glucocorticoid exposure, although it less commonly causes significant weight loss.
Hypopituitarism may manifest in multiple endocrine axes. However, while hypothyroidism, hypogonadism, and growth hormone deficiency may cause transformation of body mass with reduction in muscle, they do not typically cause severe weight loss. Secondary adrenal insufficiency (adrenal hypofunction due to a lack of adrenocorticotropic hormone) may cause weight loss but usually not as severe as in primary adrenal insufficiency.
Phaeochromocytoma is a rare entity that may cause weight loss due to hormonal effects. It may be part of multiple endocrine neoplasia type 2.
Rheumatological/inflammatory
Rheumatological conditions frequently present with unintentional weight loss as a component of systemic inflammation. Rheumatoid arthritis, systemic lupus erythematosus, and mixed connective tissue disorders can all cause unintentional weight loss. Sarcoidosis is an inflammatory disorder characterised by non-caseating granulomas. While it frequently involves the lungs, eyes, and skin, nearly any organ system can be involved and systemic symptoms include weight loss.[61]
Vasculitides may also present with unintentional weight loss. Polyarteritis nodosa, and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides such as microscopic polyangiitis, frequently have renal involvement. Polyarteritis nodosa can also cause vasculitis of the mesenteric arteries, and is often associated with hepatitis B and C. Autoimmune conditions that involve the respiratory tract, such as granulomatosis with polyangiitis, often present with anorexia and weight loss.[62]
While many rheumatological disorders can have systemic features, including weight loss, several can cause weight loss as a consequence of direct gastrointestinal tract involvement (e.g., systemic sclerosis/scleroderma).
Infectious diseases
Any severe infection can result in temporary weight loss. This topic considers only infections that may result in a more chronic or subacute weight loss where the weight loss itself may be a prominent feature of the presentation.
HIV infection may cause severe cachexia as one of its manifestations due to either the virus itself, or the presence of opportunistic infections. While tuberculosis frequently presents with weight loss, HIV-positive patients with tuberculosis may experience particularly severe weight loss.[63][64][65] HIV-positive patients with low CD4+ cell counts are at particular risk for disseminated mycobacterium avium complex (MAC, also known as mycobacterium avium-intracellulare [MAI]) that can result in profound weight loss.[66]
Many infectious conditions can cause a chronic or subacute diarrhoea and weight loss, including parasitic infections (e.g., amoebiasis, giardiasis, cryptosporidiosis, cystoisosporiasis, cyclosporiasis, strongyloidiasis). In immunosuppressed patients, including those with HIV and solid organ transplant recipients, opportunistic infections (e.g., amoebiasis, cytomegalovirus, cryptosporidiosis) can cause profound weight loss.[67]
Disseminated histoplasmosis presents with constitutional symptoms, including weight loss, in more than 85% of cases in both HIV-positive and HIV-negative patients.[68] Dissemination is more common in the immunosuppressed patient.
Infective endocarditis has a variable presentation depending on the infecting organism, host factors, and the presence of prosthetic cardiac valves and implanted cardiac devices. While it can present suddenly with acute heart failure, it may also present subacutely with weight loss. While many patients have risk factors such as prosthetic valves and devices or injection drug use, some have no obvious risk factors at all, highlighting the need to consider this condition. Other valvular heart disease may lead to weight loss through heart failure and cardiac cachexia.
Coronavirus disease 2019 has been associated with unintentional weight loss.[69] For a subset of patients, a more prolonged weight loss (1 month after symptom onset) has been reported.[69][70]
Infections that rarely cause unintentional weight loss include Whipple's disease and cat-scratch disease (Bartonella henselae infection).
Medication-related
Multiple classes of medications have been implicated in causing weight loss as an adverse effect. Any new medication associated temporally with the occurrence of unintentional weight loss should be scrutinised carefully. Medications include:[71][72][73][74][75][76]
Anticonvulsants (e.g., topiramate, zonisamide)
Antidepressants (e.g., selective serotonin-reuptake inhibitors, bupropion)
Stimulants (e.g., dexamfetamine)
Diabetes medications (e.g., metformin, glucagon-like peptide-1 receptor agonists, sodium-glucose co-transporter 2 inhibitors), although weight loss with these drugs may be considered beneficial in some patients
Antibiotics, and other medications that cause diarrhoea
Cholinesterase inhibitors (e.g., donepezil)
Some medications may be misused to cause weight loss, including laxatives, diuretics, and thyroid hormone. In these cases, the patient’s weight loss may be noticed by the clinician or the patient’s close contacts, but the history may not be forthcoming.
Withdrawal of medications that may have been supporting or maintaining weight may produce weight loss, for example discontinuation of pancreatic enzymes or mirtazapine.[77]
Social factors
Inadequate food and caloric intake is an important consideration. This can be due to poverty or inadequate resources. In older people, fewer social interactions during meals can all contribute to decreased oral intake. Patients may not readily report inadequate access to food to their physician, and access to food and types of food should be investigated as part of the history. Unintentional weight loss from inadequate access to food is not associated with the neurohormonal changes of cachexia syndromes, and is readily reversed with restoring appropriate caloric intake.
Exposure to violence, traumatic stress, and other forms of abuse has been associated with both weight gain, and weight loss and may not be initially disclosed to the treating physician.[78]
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