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For Primary Care| Differential diagnosis

Unintended Weight Loss: What's the Diagnosis?

Dr Sonya Jey Explains the Importance of Considering and Excluding Sinister Causes of Unintentional Weight Loss and Explores Some Clinical Scenarios in Which Unintentional Weight Loss is a Feature 

Read This Article to Learn More About:
  • when and why causes of unintentional weight loss should be explored
  • possible causes of unintentional weight loss
  • aspects to consider in the diagnosis and management of conditions where unintentional weight loss may feature.

Weight loss is an important symptom, regardless of the cause, and there are several sinister underlying pathologies that need to be considered. It is important to proactively enquire about weight loss in the consultation as it is easily forgotten by patient and clinician alike. Unintentional weight loss of more than 5% in 6–12 months needs to be explored.

Causes of unintentional weight loss are many and varied, and include:

  • mental health conditions such as depression, anxiety, eating disorders, and obsessive compulsive disorder
  • cognitive decline as with dementia
  • loss of appetite
  • dental problems
  • neuromuscular/rheumatological disease
  • chronic inflammatory conditions
  • endocrinological disease such as type 1 diabetes, hyperthyroidism, and Addison’s
  • chronic cardiac, respiratory, renal and liver disease
  • malignancy
  • gastrointestinal disease resulting in malabsorptive and high energy states (coeliac disease, inflammatory bowel disease, chronic pancreatitis), any condition resulting in vomiting/diarrhoea/difficulty swallowing
  • bacterial, viral, or parasitic infections
  • toxins (alcohol or illicit drug use, iatrogenic).

Case 1

A 54-year-old Caucasian woman, who is generally healthy and goes to the gym on a regular basis, has recently been severely stressed with a relationship issue that impacts her mood, appetite, and outlook. She is slim. Her bloods from earlier in the year noted a borderline glycated haemoglobin (HbA1c). She was counselled regarding her high risk of diabetes and referred to the diabetic education programme. She engaged with this service well and has been stringent in following the diet suggested. She remarks that her diet has always been good and she loves very long walks.

One evening, she presents to the surgery appearing cachectic and slightly frantic about her home stressors. As usual, this becomes the main theme of the consultation but she also mentions some unilateral breast pain. The GP remarks on her appearance, to which she responds, ‘It’s all the stress, I can’t eat.’ Her current weight is 20% lower than it was 1 year ago. Her breast examination notes a small area of nodularity but no overt mass, with normal skin, nipples, and no axillary lymphadenopathy. She is referred to the breast clinic on a 2-week wait pathway and for repeat blood tests. Three days later the HbA1c result is received. It is 130 mmol/mol. She has normal thyroid function and normal early-morning cortisol. The patient is brought back to clinic that same day. Further history suggests symptoms of diuresis and urine testing notes ketonuria. The capillary blood glucose is 28 mmol/l. She is admitted to hospital.


The patient is assessed by the admitting team and diabetic ketoacidosis is confirmed.


She is started on intravenous fluids and insulin. While she is an inpatient, she is assessed by the breast team and reassured. Her computed tomography chest-abdomen-pelvis (CTCAP) is normal, reducing the likelihood of intra-abdominal/pancreatic malignancy.

She is commenced on insulin aspart and insulin glargine and referred to the diabetes clinic on discharge; here it is found that her anti-islet antibodies and her antibodies to glutamic acid decarboxylase (anti-GAD antibodies) are positive, suggesting that she has late-onset type 1 diabetes.


The patient’s HbA1c slowly responded and she gained weight. For recommendations on management of type 1 diabetes, refer to NICE Guideline (NG) 17 on Type 1 diabetes in adults: diagnosis and management.1 NICE states that patients presenting with type 1 diabetes in adulthood usually have at least one of the following:1

  • ketosis
  • rapid weight loss
  • age of onset below 50 years
  • body mass index (BMI) below 25 kg/m2
  • personal and/or family history of autoimmune disease.

NICE however also reminds us not to discount a diagnosis of type 1 diabetes if an adult presents with a BMI of 25 kg/m2 or above, or is aged 50 or above, as in the case example here.1

Case 2

A 58-year-old man presents with a 2-week history of dry cough, mildly hoarse voice, and very slightly elevated temperature. He is a non-smoker and generally fit with no past medical history. His heart rate is slightly elevated at 92 beats per minute (bpm) and a regular rhythm. He suspects he has had a viral infection but wants his chest checked. There are no other coryzal symptoms, chest examination is unremarkable, and a plan to monitor is made. He presents a week later suggesting the same symptoms but says he is now aware of palpitations. He appears a little agitated. He has a mild tremor of the hands and when he is weighed, it is found that he has lost weight. Weight loss is not his presenting complaint. His voice seems more hoarse. Neck examination is normal as is chest examination. Heart rate is 100 bpm regular and oxygen saturation 100% on air. Blood tests are requested and the patient is referred on a head and neck 2-week wait pathway, given the persistent hoarse voice and weight loss.


The following results were obtained from blood tests:

  • thyroid-stimulating hormone (TSH): <0.05 mU/l
  • thyroxine (T4): high
  • tri-iodothyronine (T3): elevated
  • full blood count (FBC) and liver function tests (LFTs): normal.

The patient was diagnosed with hyperthyroidism.


Propranolol was initiated to ease the symptoms.

After a telephone discussion with an on-call endocrinologist, carbimazole was commenced with monitoring of thyroid function tests (TFTs) while the patient awaited an outpatient endocrinology appointment. He was given safety-netting information about sore throat, mouth ulcers, febrile or non-specific illness, bruising, or malaise. Further guidance can be found in NICE Clinical Knowledge Summary on Hyperthyroidism.2


The man was adequately treated for hyperthyroidism; his TFTs returned to normal and remained normal. His symptoms completely resolved, his weight returned to baseline, and he no longer required carbimazole.

Case 3

A 40-year-old woman presents with ongoing weight loss, chronic diarrhoea, and chronic central abdominal discomfort that gets worse after meals. She has a history of recurrent acute pancreatitis secondary to a past history of alcohol abuse. She has already undergone several abdominal ultrasound and computed tomography (CT) scans that have confirmed chronic pancreatitis. In addition to chronic pancreatitis, she has a stoma bag from an ileostomy following resection of ischaemic bowel 5 years ago. Her BMI is <17 kg/m2.


The patient is referred to a dietitian in a specialist unit for management of chronic pancreatitis.


She is started on nutritional supplements and pancreatic enzyme replacement therapy (PERT) and continues this alongside a very cautiously constructed diet plan.

Chronic pancreatitis is a chronic inflammatory condition of the pancreas leading to permanent injury, which affects endocrine and exocrine functions.3 Endocrine dysfunction can lead to diabetes.4

Pancreatic enzyme insufficiency causes malabsorption of carbohydrates, proteins, fat and thereby, fat-soluble vitamins A, D, E, and K. Steatorrhoea develops when >90% of the enzyme output is lost. Osteoporosis/osteopenia occurs in 60% of people with pancreatic enzyme insufficiency.4

NICE recommends referral to a ‘specialist pancreatic centre to identify when advice from a specialist dietitian is needed, including advice on food, supplements and long-term pancreatic enzyme replacement therapy, and when to start these interventions.’3

The principles for treatment are to achieve sufficient pancreatic enzyme levels in the duodenum for digestion by using pancreatic enzyme replacement therapy (PERT). The most commonly used product is pancreatin, which is taken with meals and at smaller doses with snacks.4

Response to treatment is measured by symptom response, that is, improvement of steatorrhoea and weight gain as well as levels of fat-soluble vitamin levels (A, D, E, and K).4


The patient no longer has chronic loose stool, still experiences infrequent central abdominal pain, and over a period of 2 years has put on weight. Her BMI is now 21.5 kg/m2.

Case 4

An 18-year-old man presents with tiredness, weight loss, a few episodes of rectal bleeding noted in the pan, and looser stools. On examination he is pale; a set of observations are normal. His abdomen is mildly tender. Blood pressure is low but normal for him. He weighs 50 kg. The patient is reviewed a few days later. He continued to experience rectal bleeds and more frequent bowel habit. On examination his heart rate is 120 bpm, temperature 37.4°C.


Results of primary investigations were as follows:

  • bloods:
    • haemoglobin (Hb) 82 g/l
    • mean corpuscular volume (MCV) 70 fl
    • ferritin 6 mcg/l
    • white cell count (WCC) 15.8 × 109/l
    • platelet count 653 × 109/l
    • erythrocyte sedimentation rate (ESR) 38 mm/hour
  • faecal calprotectin >4500 mcg/g.

Inflammatory bowel disease was suspected; however given the severity of the patient’s presentation, he was admitted to hospital, received a blood transfusion, and was commenced on steroids.

He was followed up by gastroenterology and underwent a flexisigmoidoscopy, which noted mild inflammation to 25 cm from the anal verge, erosions, and increased granularity.

Histology was in keeping with moderate active chronic inflammation with crypt architectural changes in keeping with ulcerative colitis.


The patient was started on oral mesalazine 2.4 g taken daily in divided doses, and 1 g daily by foam enema.

Patients with suspected inflammatory bowel disease need prompt referral to outpatient gastroenterology for investigation, confirmation of diagnosis, and early chronic management. Assessment of the severity of presentation/flare informs as to the urgency of action required (see Table 1).5 More guidance about assessing severity, including a table with Truelove and Witts’ criteria for adults and another with criteria for children, can be found in NICE Guideline 130 on Ulcerative colitis5 (see and associated NICE flowchart In this young man’s case, he required urgent admission and, thereafter, follow up in the outpatient setting.

The challenge in inflammatory bowel disease is rapid diagnosis, inducing remission, and then maintaining it. Drugs commonly used to induce remission include topical or oral aminosalicylates and topical or oral corticosteroids. Less often, ciclosporin and infliximab are used—see section 1.2 in NG130 on inducing remission in people with ulcerative colitis and the NICE BNF treatment summary for ulcerative colitis.5,6

To maintain remission, secondary care initiates topical or oral aminosalicylates, mercaptopurine, or azathioprine.5,6

In the older patient who presents with lower GI symptoms and unintentional weight loss, consider malignancy (see Box 1). NICE is due to publish an updated guideline on colorectal cancer in January 2020.9

Box 1: NICE Referral Pathway for Colorectal Cancer7,8
  • Refer adults using a suspected cancer pathway referral (for an appointment within 2 weeks) for colorectal cancer if
    • they are aged 40 and over with unexplained weight loss and abdominal pain or
    • they are aged 50 and over with unexplained rectal bleeding or
    • they are aged 60 and over with:
      • iron-deficiency anaemia or
      • changes in their bowel habit, or
      • tests show occult blood in their faeces.
  • Consider a suspected cancer pathway referral (for an appointment within 2 weeks) for colorectal cancer in adults with a rectal or abdominal mass.
  • Consider a suspected cancer pathway referral (for an appointment within 2 weeks) for colorectal cancer in adults aged under 50 with rectal bleeding and any of the following unexplained symptoms or findings:
    • abdominal pain
    • change in bowel habit
    • weight loss
    • iron-deficiency anaemia.
  • Offer faecal immunochemical tests (FIT) to guide referral for suspected colorectal cancer for people without rectal bleeding who have unexplained symptoms but do not meet the criteria for a suspected cancer pathway referral outlined in NICE’s guideline [NG12] on suspected cancer (recommendations 1.3.1 to 1.3.3).

Adapted from: NICE. Suspected cancer. NICE Guideline 12. NICE, 2015 (last updated 2017). Available at: and Quantitative faecal immunochemical tests to guide referral for colorectal cancer in primary care. NICE Diagnostics guidance 30. NICE, 2017. Available at:


Outcomes for the patient were positive in terms of the resolution of his symptoms and results of investigations 6 months after referral and initiation of treatment. His weight increased to 58 kg and blood test results were as follows:

  • Hb 145 g/l
  • WCC 7.7 × 109/l
  • ESR 5 mm/hour
  • C-reactive protein 1.2 mg/l
  • ferritin 17 mcg/l
  • faecal calprotectin 450 mcg/g.                                                                                                                                           

Case 5

A 58-year-old man, who is a current smoker and has a past medical history of asthma–chronic obstructive pulmonary disease (COPD) overlap syndrome, presents to the out-of-hours service with a cough and green sputum. On examination, he has a fever and crepitations. He is diagnosed with a lower respiratory tract infection and prescribed amoxicillin 500 mg three times per day.

What he does not divulge is a worsening of his asthma, that the cough has been intermittent but present most days over the last 1–2 months, and that his clothes are too big.

On follow up, the man’s symptoms are no better so a second antibiotic is commenced and a chest X-ray requested; this shows shadowing in the left upper zone. A repeat chest X-ray is recommended in 2 weeks’ time. The patient does not attend for chest X-ray until 4 weeks later, by which time he has lost a further 1 kg in weight, become breathless, and developed a hoarse voice. The shadow persists on the repeat chest X-ray and he is referred on a 2-week wait lung cancer pathway.

He has a very poor forced expiratory volume in one second (FEV1) and transfer factor of the lung for carbon monoxide (TLCO).


Following a chest computed tomography (CT) scan, staging CT, and bronchoscopy, the definitive diagnosis is squamous cell carcinoma of the left upper lobe, compression of the left recurrent laryngeal nerve, and nodal spread.


A multidisciplinary team meeting was followed by a meeting of the oncologist, clinical nurse specialist, patient, and his family. The decision was to consider palliative radiotherapy, which the patient underwent. He was referred to palliative care services and received nutrition supplements from dietetics. He received help from a speech therapist in the community for his hoarseness. A do not attempt resuscitation (DNAR) form had been discussed and signed.


The patient sadly succumbed to his disease and died less than 3 months later.

See Table 1 for a summary of NICE guidance on weight loss with specific features and recommendations for referrals and/or investigations for possible cancers. Refer to the full guideline for further details.7

Table 1: Weight Loss: Recommendations Organised by Symptom and Findings of Primary Care Investigations (NICE Guideline 12 on Suspected Cancer: Recognition and Referral)7

Symptom and Specific Features Possible Cancer Recommendation
Weight loss (unexplained) Several, including colorectal, gastro‑oesophageal, lung, prostate, pancreatic or urological cancer Carry out an assessment for additional symptoms, signs or findings that may help to clarify which cancer is most likely.Offer urgent investigation or a suspected cancer pathway referral (for an appointment within 2 weeks) [1.13.2]
Weight loss (unexplained) with abdominal pain, 40 and over Colorectal Refer adults using a suspected cancer pathway referral (for an appointment within 2 weeks) [1.3.1]
Weight loss (unexplained) with rectal bleeding in adults under 50 Colorectal Consider a suspected cancer pathway referral (for an appointment within 2 weeks) [1.3.3]
Weight loss (unexplained) without rectal bleeding, and criteria for a suspected cancer pathway referral not met Colorectal See diagnostics guidance on quantitative faecal immunochemical tests to guide referral for colorectal cancer in primary care [NICE Diagnostics guidance 308]
Weight loss (unexplained), 40 and over, ever smoked Lung or mesothelioma Offer an urgent chest X‑ray (to be performed within 2 weeks) [1.1.2] [1.1.5]
Weight loss (unexplained), 40 and over, exposed to asbestos Mesothelioma Offer an urgent chest X‑ray (to be performed within 2 weeks) [1.1.5]
Weight loss with cough or fatigue or shortness of breath or chest pain or appetite loss (unexplained), 40 and over, never smoked Lung or mesothelioma Offer an urgent chest X‑ray (to be performed within 2 weeks) [1.1.2] [1.1.5]
Weight loss with unexplained splenomegaly in adults Non‑Hodgkin’s lymphoma Consider a suspected cancer pathway referral (for an appointment within 2 weeks). When considering referral, take into account any associated symptoms [1.10.8]
Weight loss with unexplained lymphadenopathy in adultsA Hodgkin’s lymphoma or non‑Hodgkin’s lymphoma Consider a suspected cancer pathway referral (for an appointment within 2 weeks). When considering referral, take into account any associated symptoms [1.10.8] [1.10.10]
Weight loss with upper abdominal pain or reflux or dyspepsia, 55 and over Oesophageal or stomach Offer urgent direct access upper gastrointestinal endoscopy (to be performed within 2 weeks) [1.2.1] [1.2.7]
Weight loss (unexplained) in womenB Ovarian     Consider carrying out tests in primary care [1.5.3]

Measure serum CA125 in primary care [1.5.6]

See primary care investigations for information on tests for ovarian cancer [p.66 of full guideline pdf]

Weight loss with diarrhoea or back pain or abdominal pain or nausea or vomiting or constipation or new‑onset diabetes, 60 and over Pancreatic Consider an urgent direct access CT scan (to be performed within 2 weeks), or an urgent ultrasound scan if CT is not available [1.2.5]
Weight loss with raised platelet count or nausea or vomiting, 55 and over Oesophageal or stomach Consider non-urgent direct access upper gastrointestinal endoscopy [1.2.3] [1.2.9]
The recommendations … are displayed … in order of urgency of the action needed, to make sure that most urgent actions are not missed. Where there are several recommendations relating to the same cancer these have been grouped for ease of reference. Occasionally the same symptom may suggest more than one cancer site. In such instances the recommendations are displayed together and the GP should use their clinical judgement to decide on the most appropriate action. [See the full guideline for further information.]

A Separate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. However, in practice young people (aged 16–24) may be referred using either an adult or children’s pathway depending on their age and local arrangements.

B The recommendations for ovarian cancer apply to women aged 18 and over.

© NICE 2015. Suspected cancer: recognition and referral. Available from: All rights reserved. Subject to Notice of rights. NICE guidance is prepared for the National Health Service in England. All NICE guidance is subject to regular review and may be updated or withdrawn. NICE accepts no responsibility for the use of its content in this product/publication. See for further details.

Case 6

An 86-year-old woman is losing weight; she has lost 6% of her body weight in 1 year. She has multimorbidity and an orthopaedic source of hip pain. She has been intolerant of certain opioids and has contraindications to the use of anti-inflammatories. She is unsuitable for anaesthesia and sedation and unable to mobilise despite all efforts to relieve pain by her GP. On further questioning, she opens up to the GP about how she struggles to cope with the pain and her resultant low mood.


The natural (expected) rate of loss in total body weight after the age of 70 years is 0.1 to 0.2 kg per year. Therefore, substantial weight changes (i.e. >5% weight loss in a 6–12 month period) should not be attributed to normal anorexia of ageing.10 In some patients, use of opioids and other commonly used regular medication may result in nausea or a loss in appetite.10

This patient’s weight loss is likely to be linked to her loss of appetite, which may be a result of the treatment she is taking for her chronic pain, or the related psychological impact of her chronic condition.


It is important to consider the psychological effects of chronic pain, especially in older people, who are less likely to recognise depressed mood. Depression can lead to a loss of appetite or loss of motivation to buy and prepare meals.11

A randomised controlled trial noted that people with chronic pain and moderate depression benefited in terms of mood, pain severity, and disability after a period of antidepressant use.12 From this, the Scottish Intercollegiate Guidelines Network (SIGN) concluded that depression is a common co-morbidity with chronic pain, and antidepressant therapy should be considered in those who have chronic pain with moderate depression. It also concluded that:13

  • referral to a pain management programme should be considered for patients with chronic pain
  • cognitive behavioural therapy should be considered for the treatment of patients with chronic pain.

Psychotropics can cause adverse reactions in older people so it is important to use caution when prescribing and follow the relevant guidance.14,15


The patient opted against any form of hip surgery and wished only for analgesia. She experienced reduced mobility, stiffness, reduced muscle bulk, some dependent oedema, and loss of appetite. The palliative and chronic care teams became involved. The patient’s oral and cutaneous-application analgesics were tailored and up-titrated, and interventions involving physiotherapy, occupational therapy, and adaptations in the home were introduced. The patient’s appetite increased slightly. Physiotherapy was too demanding for the patient despite best efforts by the pain team to optimise analgesia. It was only after the addition of an antidepressant that the patient’s appetite improved and resulted in some weight gain. It has been suggested that mirtazapine causes some weight gain and so may be the psychotropic therapy of choice in older people with depression who are losing weight due to their low mood.10,16


Unintentional weight loss is an important symptom and the cause must be identified. Presentations are very rarely ‘textbook’ in real-life general practice. As with the examples above, each patient presenting with weight loss has several potential causes for it and commonly, the causes can have an additive effect. It is not enough to assume the aetiology is psychological or physiological. If the weight loss is significant, red flags must be enquired about and sinister causes actively excluded.

Dr Sonya Jey

Locum GP, West London