Approach
Due to the high percentage of underlying serious etiologies, all patients who present with unintentional weight loss should receive a thorough history, physical exam, and baseline investigations.[31] Common etiologies reported in case series include cancer, gastrointestinal conditions, and psychiatric conditions, with a significant proportion of cases undiagnosed despite exhaustive workup.
Not all patients present with unintentional weight loss as a chief complaint. Routine weight monitoring over time may detect weight loss. Physicians may not always document unintentional weight loss as a red flag symptom.[80]
Epidemiologic evidence has linked unintentional weight loss to increased risk for cancer and mortality.[18][21][81] However, the optimal strategy to detect cancer or serious disease in patients with unintentional weight loss remains unclear.[81][82]
Unintentional weight loss requires a broad approach to the workup. Figure 1 represents a suggested treatment algorithm; however, the evaluator should remain flexible in their approach.
[Figure caption and citation for the preceding image starts]: Diagnostic algorithm for the workup of unintentional weight lossFrom Christopher J. Wong [Citation ends].
When to initiate a workup
A reasonable starting point to initiate a workup is unintentional weight loss of 5% or more of the patient’s usual body weight within the preceding 6 to 12 months.[1] If measured weights are not available, the physician may use indirect means of assessment (e.g., patient’s self-reported estimate of weight loss, change in clothing size, a friend or relative corroborating the weight loss).[2] Clinical judgment must be used as some patients may not have a witness to their weight loss, access to scales, or the numeracy skills required to estimate their weight loss.
Patients with weight loss over a longer period of time, or those with just under a 5% loss of body weight, but in whom there is a concern for an underlying illness, should be evaluated. In addition, patients in whom intentional weight loss appears to occur too easily, especially if previous attempts at intentional weight loss were unsuccessful, should be evaluated for whether such weight loss was, in hindsight, unintentional, and therefore requires further evaluation.
In some cases, unintentional weight loss may present suddenly (e.g., onset of hypotension, rapidly progressive infection). In these cases, immediate hospital workup may be required.
The decision to initiate a workup should be made in concert with the patient’s wishes. For example, in some cases, an older patient with other serious medical conditions may adopt a palliative approach or a limited workup rather than be subjected to multiple diagnostic tests with consequent risks.
History
A through initial history can lead the clinician to the correct diagnostic pathway.
Age
Consider psychiatric or gastrointestinal conditions, or cancers which have a younger age of onset (e.g., leukemia, lymphoma). Other conditions that are more common in younger patients include multiple sclerosis, amyotrophic lateral sclerosis (ALS), and cystic fibrosis.
Consider cardiovascular conditions or cancer in older patients. These conditions increase in incidence with increasing age. Neurologic conditions such as dementia and Parkinson disease are also more common in older patients.
Social factors
The patient should be asked about abuse, neglect, and access to food. Inadequate food and caloric intake is an important consideration.
Pre-existing medical conditions:
The physician should ascertain whether the patient has pre-existing conditions that have deteriorated, or any other conditions that can result in unintentional weight loss.
Patients with advanced-stage heart failure, COPD, interstitial lung disease, or renal failure may develop a cachexia syndrome with advanced disease[57]
Patients with cystic fibrosis may develop new-onset or worsening gastrointestinal malabsorption
Nonadherence to a gluten-free diet can worsen symptoms of celiac disease
Episodes of mania may arise in patients with bipolar disorder who were previously well-controlled
Gastric bypass surgery may lead to small intestinal bacterial overgrowth
Prior episodes of pancreatitis may lead to exocrine pancreatic insufficiency
Hepatitis B or C infection is often associated with polyarteritis nodosa
Cancer screening status
Status of age-appropriate cancer screening (e.g., cervical, breast, colorectal, lung) should be documented.
Medication adverse effects
Multiple classes of medications have been implicated in causing weight loss as an adverse effect.[71][72][73][74][75][76]
Anticonvulsants (e.g., topiramate, zonisamide)
Antidepressants (e.g., selective serotonin-reuptake inhibitors, bupropion)
Stimulants (e.g., dextroamphetamine)
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 diarrhea
Cholinesterase inhibitors (e.g., donepezil)
Medications that can be misused to cause weight loss
Laxatives
Diuretics
Thyroid hormone
Withdrawal of medications that may have been supporting or maintaining weight may produce weight loss
Pancreatic enzymes
Mirtazapine[77]
Loop diuretics
Treatment of renal disease often includes 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, evaluation for unintentional weight loss should be performed.
Psychiatric history and screening
The patient should be assessed for depression, anxiety, bipolar disorder, exposure to violence and trauma, and eating disorders. Depression and anxiety disorders are prevalent in patients with cancer.[49] Patients are also at increased risk for depression following stroke.[47][48]
Patients who have not been diagnosed with a psychiatric condition previously should be screened for depression and anxiety disorders.[83][84] The Patient Health Questionnaire-9 (PHQ-9) and the Generalized Anxiety Disorder-7 (GAD-7) are useful initial screening tools that are freely available in multiple languages.
Screening for eating disorders should be performed and, if positive, the patient should be evaluated according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, Text Revision (DSM-5-TR) criteria.[45][46] Screening for substance use disorders, including alcohol, prescription opioids, and illicit drugs should be performed.
Risk factors for cancer and infection
Smoking/tobacco use increases risk of lung, head and neck, and bladder cancers. Lung cancer classically occurs in older patients with an extensive smoking history. While cigarette cessation reduces the risk of subsequent lung cancer, the risk does not resolve completely and even past smokers should be assessed for lung cancer in the setting of unintentional weight loss.[82][85] Importantly, lung cancer may also occur in nonsmokers (approximately 10% of cases in the US and up to 25% of cases worldwide).[86][87]
Risk factors for malignancy
Previous radiation exposure: patient may be at risk of thyroid cancer or leukemia
Previous chemotherapy: patients may be at risk for secondary malignancies such as leukemia
Immunosuppression (e.g., HIV infection, medications): increases the risk of squamous cell cancers and lymphoma
Environmental exposures: asbestos exposure increases the risk of lung cancer
Infections: human papillomavirus (HPV), hepatitis B (with or without cirrhosis), hepatitis C (with cirrhosis), or Helicobacter pylori (in stomach cancer) can increase the risk of malignancy
Alcohol use: a common risk factor for head and neck cancers.
Risk factors for infection
HIV: unprotected sex, injection drug use, or transfusions of blood or blood products before adequate testing was introduced or currently in areas without adequate testing
Opportunistic infections: often seen in HIV or with immunosuppressive medications
Parasitic: travel history including travel to regions with endemic gastrointestinal parasites
Tuberculosis: known contacts, homelessness, or incarceration.
Symptoms
Degree of weight loss
It is generally considered that cancers, gastrointestinal illnesses, and severe infections (e.g., HIV) can cause a higher degree of weight loss compared with other conditions. However, many conditions can cause severe weight loss when in the advanced stages. Cancer has been reported to cause particularly rapid weight loss in the elderly, but other studies have not been able to associate the degree or rapidity of weight loss with a particular etiology.[3][7]
Systemic symptoms
Weakness commonly accompanies weight loss. Fever, chills, night sweats may be associated with infection, hematologic malignancies, vasculitides, or rheumatologic conditions. Patients with advanced cardiac, renal, or pulmonary disease can present with a cachexia syndrome (i.e., muscle wasting and weight loss).
Anorexia may be defined as a decrease in or loss of appetite. However, not all patients with unintentional weight loss have anorexia. For example, hyperthyroidism may cause unintentional weight loss and an increase in appetite. Nevertheless, many of the causes of unintended weight loss, such as malignancy, gastrointestinal problems and psychiatric problems, do commonly present with appetite changes. A study of older adults presenting to the emergency department with anorexia found a cause in approximately 80% of cases. The most common causes were infection, gastrointestinal conditions, and cardiovascular disease.[88]
Gastrointestinal symptoms
Dysphagia should prompt evaluation for esophageal, oropharyngeal, or laryngeal cancer, especially in older patients. Abdominal pain may suggest gastrointestinal cancer or peptic ulcer disease, especially if anemia is present. Right upper quadrant pain and jaundice may indicate hepatoma. In pancreatic cancer, abdominal pain may not occur until the cancer is at an advanced stage. May also suggest gastrointestinal conditions such as celiac disease, inflammatory bowel disease, and exocrine pancreatic insufficiency.
Postprandial pain may be due to mesenteric ischemia or peptic ulcer disease. Asymptomatic stenoses of mesenteric arteries have been found in case series.[89] For patients with unintentional weight loss, workup for mesenteric ischemia should be undertaken only with appropriate clinical suspicion.
Patients with Zollinger-Ellison syndrome often present with symptoms of GERD/peptic ulcer disease and commonly have diarrhea.[41] Diarrhea may indicate gastrointestinal conditions such as celiac disease, inflammatory bowel disease, and exocrine pancreatic insufficiency. Carcinoid tumors can cause weight loss due to diarrhea. Other conditions that may cause diarrhea include cystic fibrosis and gastrointestinal infections.
Bloody stools may indicate inflammatory bowel disease or lower gastrointestinal tract malignancy. Black/tarry stools may indicate upper gastrointestinal bleeding. Oily/floating stool is suggestive of malabsorption conditions, such as celiac disease or exocrine pancreatic insufficiency.
Parasitic infections (e.g., amebiasis, giardiasis, cryptosporidiosis, cystoisosporiasis, cyclosporiasis, strongyloidiasis) can cause dysentery/diarrhea.[67]
While peptic ulcer disease may cause weight loss, other causes, including gastric cancer, inflammatory bowel disease, and mesenteric ischemia, should be also considered. Rectal bleeding is common in colorectal cancer.
Genitourinary
Hematuria may be from a medium vessel vasculitis (e.g., polyarteritis nodosa) or a rheumatologic/inflammatory condition if systemic symptoms are also present. Lower urinary tract symptoms may be suggestive for prostate cancer, especially if pelvic or bone pain is also present. Lower pelvic pain may indicate ovarian cancer, especially if abdominal bloating and increased abdominal girth are also present.
Neurologic
Symptoms (e.g., headache, seizures, neuropathy) may suggest a mass lesion or vasculitis.
Endocrinologic
Fatigue, palpitations, anxiousness, and heat intolerance suggest hyperthyroidism. Older patients may not present with typical symptoms, and their presentation may be dominated by unintentional weight loss without other manifestations[59]
Polyuria and polydipsia may indicate diabetes. Type 1 diabetes more commonly presents with weight loss than type 2 diabetes. Chronically poor glycemic control may lead to polyuria, polydipsia, and weight loss in type 1 diabetes. Significant unintentional weight loss in the setting of type 2 diabetes, in the absence of causative medications, may arouse suspicion of a comorbidity such as infection or a pancreatic tumor. Patients may also present suddenly with diabetic ketoacidosis; severe cases may have a decreased level of consciousness due to a hyperosmolar state.
Fatigue, orthostasis, and weakness may indicate adrenal insufficiency.
Pulmonary
Hemoptysis may indicate tuberculosis or lung cancer. Cough may indicate tuberculosis or lung cancer. Mycobacterium avium complex (MAC, also known as mycobacterium avium-intracellulare [MAI]) may produce an indolent syndrome of chronic cough.
Physical exam
The physical exam is the next critical step as the history may not yield a leading diagnosis, despite exhaustive effort.
Vital signs
Tachycardia: may be a sign of hyperthyroidism; however, it is nonspecific and is common to multiple syndromes with volume depletion
Blood pressure: many patients will have low blood pressure; however, high blood pressure or orthostasis in combination with paroxysmal headaches and sweats may suggest pheochromocytoma
Fever: may be a sign of multiple etiologies including infectious, malignant, and inflammatory conditions. A daily spiking fever (with rash and joint pains) is indicative of adult-onset Still disease; however, this disease is rare, and it should be noted that multiple conditions can cause spiking fevers
Mental status
Delirium and altered mental status: may be caused by electrolyte imbalances (e.g., hyponatremia or hypercalcemia can be a feature of multiple conditions, including syndrome of inappropriate antidiuretic hormone [SIADH] and cancer), endocrinopathies (e.g., hyperthyroidism), infections, or CNS vasculitis
Cognitive impairment: should prompt an evaluation for dementia
Systemic
Lymphadenopathy: may indicate malignancy, especially if mass lesions are present and the patient has risk factors for cancer. It may also indicate an infection. Lymphadenopathy may be mediastinal or intra-abdominal; therefore, a negative lymph node exam in a patient with prominent B symptoms (fever, weight loss, night sweats) should not dissuade further workup for lymphoma
Bone or joint pain: may indicate metastatic cancer or a rheumatologic condition
Paraneoplastic syndromes: small cell lung cancer may be associated with a variety of paraneoplastic syndromes including hypercalcemia, Lambert-Eaton myasthenic syndrome, and SIADH
Gastrointestinal
Mass lesions, hepatomegaly, splenomegaly, or ascites: may indicate malignancy
Bruits: may be consistent with mesenteric ischemia but are neither specific nor diagnostic
Genitourinary
Mass lesions: rectal, prostate, or pelvic masses may indicate malignancy
Cardiovascular
Cardiac murmur: new regurgitant murmurs may suggest infective endocarditis
Signs of decompensated heart failure: lung rales, peripheral edema, and elevated jugular venous pressure may indicate heart failure or pericarditis
Pulmonary
Pleural effusion: may indicate malignancy or serositis
Hyperinflation: may be suggestive of COPD or cystic fibrosis
Rales and consolidation: usually a sign of chronic lung disease
Dermatologic
Dermatitis herpetiformis: consistent with a diagnosis of celiac disease[90]
Mass lesions: may indicate skin cancer; however, it does not typically cause unintentional weight loss unless it is metastatic
Janeway lesions or Osler nodes: diagnostic for infective endocarditis
Rash: malar or discoid rash may indicate systemic lupus erythematosus (SLE)
Livedo reticularis: may indicate polyarteritis nodosa
Hyperpigmentation: may be seen with primary adrenal insufficiency
Skin tightening or thickening: common in systemic sclerosis (scleroderma)
Breast exam
Should be performed in the appropriate age groups, or at any age if symptoms suggest a malignancy
Although uncommon, men may develop breast cancer, and breast exam should not be overlooked in male patients who present with unintentional weight loss, especially if other etiologies are not apparent
While breast cancer is more common in patients over 40 years of age, it may rarely present in young patients[91]
Dental exam
Poor dentition: many older patients have decreased oral intake because of poor dentition. Poor dentition may also be a risk factor for infective endocarditis[92]
Laboratory testing
A basic laboratory workup, including a thorough history, physical exam, and baseline investigations, should be performed in cases of significant unintentional weight loss. Even if there is a leading diagnosis after the initial history and physical exam, such a workup is prudent as many patients who present with unintentional weight loss are older and have risk factors for malignancy and cardiovascular disease. For example, an older patient with unintentional weight loss may be diagnosed with depression, but may also have an occult malignancy as a comorbid condition.
The basic initial laboratory workup should include the following:[82]
CBC
Serum electrolytes
Serum glucose
Serum calcium
Blood urea nitrogen/serum creatinine
Urinalysis
LFTs
Serum albumin
Thyroid-stimulating hormone (TSH)
Fecal immunochemical testing
The UK guidelines recommend certain quantitative fecal immunochemical tests (FIT) to guide referral for suspected colorectal cancer in adults:[93][94]
ages 40 years and over with unexplained weight loss and abdominal pain
ages under 50 years with rectal bleeding and unexplained weight loss
ages 50 years and over with unexplained weight loss
Refer to guidelines for an exhaustive list of signs and/or symptoms that may prompt quantitative FIT.[93][94][95][96]
Other tests to consider
HIV serology should be ordered if the patient has risk factors for HIV infection. It is reasonable to complete age and risk-factor appropriate cancer screening (e.g., breast and cervical) if not already done.
Assessment of initial history, exam, and laboratory testing
If a diagnosis is suspected at this stage, then appropriate confirmatory tests should be undertaken. For example, a suspect tumor mass should be biopsied or resected as appropriate; hematologic malignancies may require bone marrow biopsy or lymph node excision.
If there is no diagnosis readily apparent at this stage, it is reasonable to obtain additional testing. While there is no consensus approach, the following laboratory tests should be considered:
Prostate-specific antigen (PSA): in most cases, a patient with prostate cancer who presents with weight loss usually also has urinary symptoms or symptoms of metastatic disease such as bone pain. Even in the absence of these symptoms, if no other cause is found, ordering a PSA level is considered to be reasonable in men.
Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), lactate dehydrogenase (LDH): while nonspecific, an elevated LDH may indicate malignancy, and a markedly elevated ESR or CRP suggests an inflammatory, infectious, or malignant etiology.
Imaging may also be warranted.
Imaging and other diagnostic studies
If a diagnosis is suspected following initial history, exam, and laboratory testing, then appropriate confirmatory imaging studies should be undertaken.
If the initial workup based on history, exam, and laboratory studies is negative, or no diagnosis is readily apparent, imaging should be considered due to the risk of serious diagnoses, such as malignancy, in patients with unintentional weight loss.[97]
Use of clinical judgment and shared decision-making with the patient is vital due to the risks of imaging, including radiation and incidental findings. Some authors have attempted to quantify when to specifically evaluate for malignancy. Using the UK Clinical Practice Research Datalink electronic health records data, they found that cancer was diagnosed in 1.4% of patients after an initial code for involuntary weight loss.[82] Factors increasing the likelihood of cancer included increasing age, male sex, and the presence of symptoms, signs, or abnormal laboratory studies.[82]
Chest x-ray
May reveal a mass on the lung or evidence of other lung lesions, including granulomatosis with polyangiitis, a mediastinal mass, or lymphadenopathy.
Endoscopy
Upper gastrointestinal endoscopy (with biopsy) should be considered in people with unintentional weight loss and the presence of other concerning signs and symptoms, such as anemia, reflux, dyspepsia, and upper abdominal pain, to assess for stomach cancer and esophageal cancer.[93][98][99]
Colonoscopy is indicated for patients with suspected colorectal cancer (unintentional weight loss, anemia, positive fecal immunochemical test (or heme-positive stools) or gross rectal bleeding, abdominal pain, or change in stool caliber). The US guidelines recommend adults <50 years with colorectal bleeding symptoms under colonoscopy or evaluation sufficient to determine a bleeding cause.[95] Refer to guidelines for an exhaustive list of signs and/or symptoms suggestive of colorectal cancer.[93][94][95] A patient with signs of a lower gastrointestinal tract malignancy should be re-evaluated even if the patient has received a prior negative colonoscopy, as a new cancer may arise even before the next interval screening exam.
The yield of endoscopy (esophagogastroduodenoscopy or colonoscopy) is much higher (about 5-fold), in patients with gastrointestinal symptoms compared with those with isolated unintentional weight loss.[100] Therefore its use in undiagnosed cases may be considered, but not necessarily recommended, in all situations.
Consider abdominal ultrasound or chest/abdomen/pelvis computed tomography (CT) for suspected malignancy
A study of 200 patients for whom chest/abdomen/pelvis CT scans were ordered for unintentional weight loss found that 28% of scans identified a highly suspicious finding, 10.5% had indeterminate findings, with the remaining either benign/incidental or normal. The results indicated that a whole body CT scan may be a useful investigation in the diagnostic workup of patients with unexplained weight loss, with diagnostic yield of 33.5%, and high positive and negative predictive values (of 87% and 79% respectively) for all organic etiologies.[101]
For nonmalignant gastrointestinal causes of unintentional weight loss, the CT scan was less helpful; 12 out of 13 patients needed to be diagnosed with endoscopy or other tests.[101]
A subsequent study reported a lower diagnostic yield (12.8%) using chest-abdomen-pelvis CT scans in the diagnosis of unintentional weight loss; the authors noted the difference in populations between the two studies as a possible explanation.[102]
One study that assessed malignancy alone as a diagnostic imaging outcome following CT scan of the abdomen and pelvis (i.e., not including chest imaging) reported a yield of 5.3%, with higher yield associated with ages >60 years, and the presence of other symptoms in addition to weight loss.[103]
Echocardiogram
There is no single test for cardiac cachexia; however, it is reasonable to recheck an echocardiogram, renal function, hematocrit, and thyroid function to assess for other potential causes of weight loss in a patient with heart failure. While inflammatory cytokines are elevated in cardiac cachexia, these are not routinely ordered.
Follow-up
Despite a thorough workup, no diagnosis was found in 11% to 28% of patients in case series.[2][3][4][5][6][7][8][9][27] In one study, which included a more extensive follow-up, a diagnosis was ultimately found in the vast majority of cases.[104] In the largest cohort study, a significant number of patients who were initially undiagnosed were later found to have malignancy either in follow up, or at autopsy.[9]
Close clinical follow-up is, therefore, essential. In cases where a diagnosis is made, and the weight loss continues, the physician should consider the following:
Treatment failure
Incorrect diagnosis
Presence of comorbid disease
For undiagnosed cases, continued follow-up may reveal a diagnosis as new symptoms or signs arise.
Indicators of likely malignancy
A consensus on an optimal approach to rule out malignancy has not been established. Some studies are suggestive, but putative clinical decision scores require further validation.[105][106][107]
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