Undifferentiated Weight Loss — Viva Defence

The long case — opening statement (SASPOP)

"Mr R is a 68-year-old retired carpenter presenting with a 3-month history of involuntary weight loss of 8 kg (10 per cent of his usual body weight), anorexia, early satiety after small meals, and drenching night sweats. His Tier 1 bloods revealed a microcytic anaemia (haemoglobin 102, MCV 72), an elevated alkaline phosphatase of 320, an elevated LDH of 480, an albumin of 32, and a white cell count of 14.2. His faecal immunochemical test is positive." [1]

The problem list: [1]

1. The significant involuntary weight loss with the multiple red flags for the malignancy — the 10 per cent in 3 months (well above the 5 per cent in 6 months threshold), the anorexia, the early satiety, the night sweats.
2. The iron deficiency anaemia — the microcytic anaemia with the low MCV, the likely iron deficiency from the chronic GI blood loss.
3. The elevated ALP, the elevated LDH, the low albumin, and the elevated white cell count — three of the five Hernandez malignancy prediction score variables, significantly increasing the probability of the malignancy.
4. The positive faecal immunochemical test — confirming the GI bleeding or the mucosal abnormality.
5. The nutritional risk — the significant weight loss and the reduced intake warrant the nutritional assessment and the support. [1]

The integrated management plan

Investigations (the priority): [1]

1. The CT chest, abdomen, and pelvis with the intravenous contrast — to identify the primary tumour (the gastric, the pancreatic, the colorectal), the metastatic disease (the liver, the peritoneum, the nodes), and the staging.
2. The upper GI endoscopy — to identify the oesophageal, the gastric, and the duodenal malignancy, to obtain the biopsy, and to perform the duodenal biopsy for the coeliac disease.
3. The colonoscopy — to identify the colorectal malignancy and to obtain the biopsy.
4. The iron studies and the ferritin — to confirm the iron deficiency.
5. The tumour markers (the CEA, the CA 19-9) — as the adjuncts. [1]

Nutritional support: [1]

The oral nutritional supplements (Fortisip 200 mL, 2 to 3 bottles per day), the food fortification, and the dietitian referral. The goal is the weight stabilisation and the maintenance of the nutritional state during the workup and the treatment. [1]

Symptom control: [1]

The antiemetic for the nausea and the early satiety (the metoclopramide 10 mg three times daily before the meals), the iron replacement for the iron deficiency anaemia (the oral ferrous sulphate 200 mg three times daily). [1]

Communication and the shared decision-making: [1]

The honest discussion with the patient and the family about the concern for the malignancy, the planned investigations, the timeline for the results, and the support available. [1]

The probing questions

Q1: What is the Hernandez clinical prediction score and how do you apply it?

"The Hernandez score is the clinical prediction tool for the malignancy in the patient with the involuntary weight loss without the specific symptoms, derived by Hernandez in 2003 from the cohort of 306 patients [2] [3]. The five variables are: the elevated alkaline phosphatase, the elevated lactate dehydrogenase, the albumin below 40 g per litre, the elevated white blood cell count, and the age above 80 years. The presence of the two or more variables significantly increases the probability of the malignancy and should prompt the CT and the endoscopic evaluation. This patient has the elevated ALP, the elevated LDH, and the low albumin — three of the five variables — placing him in the high-probability group. The score has been validated in some but not all the subsequent studies — the Baicus 2014 study did not confirm it — but it remains a useful framework for the malignancy risk assessment and supports the urgent Tier 2 workup."

Q2: What if the Tier 1 workup had been entirely normal?

"If the Tier 1 workup were completely normal — the normal FBC, the normal biochemistry, the normal TFTs, the normal CRP, the normal CXR, the normal abdominal ultrasound, the negative FIT, the negative coeliac serology — the appropriate strategy would be the 3 to 6 month observation, not the undirected invasive testing. The Metalidis 2008 prospective study of 101 patients showed that the completely normal baseline workup had a 99 per cent negative predictive value for the malignancy at the one-year follow-up [4]. I would re-weigh the patient in 3 months, ask about the new symptoms, and reassure the patient that the normal workup reduces the chance of the cancer to less than 1 per cent over the next year. The Tier 2 investigation (the CT CAP, the endoscopy) would be indicated only if the weight loss continued, the new symptoms developed, or the red flags emerged."

Q3: How does the cancer cachexia differ from the starvation?

"The cancer cachexia is the cytokine-mediated syndrome of the skeletal muscle wasting that cannot be fully reversed by the conventional nutritional support, defined by the Fearon 2011 international consensus as the weight loss greater than 5 per cent, or greater than 2 per cent with the BMI below 20 or the sarcopenia [5]. It differs from the starvation in three ways: first, the cancer cachexia preferentially depletes the lean body mass through the activation of the ubiquitin-proteasome pathway by the tumour cytokines (the TNF-alpha, the IL-1, the IL-6), while the starvation preferentially depletes the fat and spares the muscle until the late stage; second, the cancer cachexia is driven by the inflammatory cytokine cascade and the altered metabolism (the increased resting energy expenditure), while the starvation is driven by the simple calorie deficit with the reduced metabolic rate; third, the cancer cachexia does NOT reverse with the feeding alone, while the starvation reverses with the refeeding. The forced feeding in the refractory cancer cachexia causes the distress (the nausea, the bloating) without the reversal of the wasting, and the management is the treatment of the cancer, the symptom control, and the palliative approach."

The branching scenario — hyperthyroidism with the preserved appetite

Examiner: "Now consider a different patient: a 58-year-old woman with the weight loss of 7 kg over 4 months, but with the preserved appetite — she is eating more than usual. She has the heat intolerance, the palpitations, and a fine tremor. The examination reveals the atrial fibrillation at 96 per minute, the warm moist palms, and a smooth goitre with a soft bruit. What is the diagnosis and the management?" [1]

The candidate's answer: [1]

"This patient has the classic presentation of the hyperthyroidism (the Graves disease): the weight loss WITH THE PRESERVED APPETITE (the key discriminator — the hypermetabolic state), the heat intolerance, the palpitations, the fine tremor, the increased bowel frequency, the warm moist skin, the smooth goitre with the bruit (the increased vascularity of the Graves thyroid), and the atrial fibrillation (the thyroid hormone sensitises the heart to the catecholamines). The diagnosis is confirmed by the thyroid function tests — the TSH will be suppressed (below 0.1 mU per litre) and the free T4 (and the free T3) will be elevated. The TSH receptor antibody is positive in the Graves disease. [1]

The management: the carbimazole 20 to 40 mg orally daily (to block the thyroid hormone synthesis), the beta-blocker (the propranolol 20 to 40 mg three times daily) for the symptom control, and the definitive therapy (the radioiodine or the surgery) after the stabilization. The carbimazole is continued for 12 to 18 months in the Graves disease, with the TSH and the free T4 checked at 4 to 6 weeks and the dose adjusted. The patient is warned about the agranulocytosis (the immediate reporting of the fever and the sore throat) and the hepatotoxicity. [1]

The key teaching point: the weight loss WITH the preserved or the increased appetite points to the hypermetabolic states (the hyperthyroidism, the uncontrolled diabetes) or the malabsorption (the coeliac, the chronic pancreatitis), NOT to the malignancy. The registrar who orders the CT CAP before the TSH in this patient has misdirected the workup." [1]

The branching scenario — Addison disease

Examiner: "Now consider a 72-year-old man with the weight loss of 8 kg over 5 months, the fatigue, the anorexia, the nausea, and the postural dizziness. The examination reveals the blood pressure of 105/70 supine and 88/55 standing, and the prominent pigmentation of the palmar creases and the buccal mucosa. The electrolytes show the sodium of 128 and the potassium of 5.6. What is the diagnosis and the immediate management?" [1]

The candidate's answer: [1]

"This patient has the classic presentation of the primary adrenal insufficiency (the Addison disease): the weight loss, the anorexia, the nausea, the postural hypotension (the mineralocorticoid deficiency causing the sodium wasting and the volume depletion), the characteristic hyperpigmentation of the palmar creases and the buccal mucosa (from the elevated ACTH and the melanocyte-stimulating hormone from the pituitary, driven by the loss of the cortisol negative feedback), and the electrolyte pattern of the hyponatraemia (from the aldosterone deficiency) and the hyperkalaemia (from the aldosterone deficiency). This is the medical emergency — the undiagnosed Addisonian crisis is fatal. [1]

The immediate management:

1. The intravenous hydrocortisone 100 mg stat, then 50 mg every 6 hours (or the continuous infusion).
2. The intravenous fluid resuscitation (the normal saline 1 litre stat, then 1 litre over 4 to 6 hours, with the monitoring of the electrolytes and the fluid balance).
3. The correction of the electrolytes (the hyperkalaemia usually corrects with the hydrocortisone and the fluid; the hypoglycaemia is treated with the dextrose if present).
4. The diagnostic confirmation AFTER the stabilisation — the 9 am cortisol (low), the ACTH (high), and the synacthen stimulation test (the cortisol fails to rise after the 250 microgram synacthen).
5. The search for the cause (the autoimmune — the 21-hydroxylase antibody; the adrenal CT for the infiltrative disease, the haemorrhage, the metastases, the TB). [1]

The long-term management: the hydrocortisone replacement (15 to 25 mg in divided doses), the fludrocortisone (50 to 200 micrograms daily), the MedicAlert bracelet, the sick-day rules (the double the hydrocortisone during the illness, the emergency intramuscular hydrocortisone for the vomiting), and the patient education. [1]

The key teaching point: the weight loss with the fatigue, the postural dizziness, and the hyperpigmentation is the Addison disease until proven otherwise. The registrar who attributes the weight loss to 'just old age' and misses the Addison disease will have the fatal outcome." [1]

The short-case discussion — examination of the cachectic patient

Examiner: "How do you examine the patient who is reported to have lost weight?" [1]

The candidate's answer: [1]

"The examination is systematic and covers the whole body: [1]

1. The general inspection — the cachexia (the temporal wasting, the hollow cheeks, the prominent bones, the loose skin folds from the rapid fat and muscle loss), the pallor (the anaemia), the agility and the functional state. [1]

2. The hands — the clubbing (the malignancy, the IBD, the cirrhosis, the coeliac), the koilonychia (the iron deficiency), the palmar erythema (the chronic liver disease), the pulse (the atrial fibrillation of the hyperthyroidism), and the tremor (the fine rapid tremor of the hyperthyroidism). [1]

3. The mouth and the neck — the oral candidiasis (the immunosuppression, the HIV), the angular cheilitis and the glossitis (the iron, the B12, the folate deficiency), the dental decay and the ill-fitting dentures (the nutritional intake), the goitre (the hyperthyroidism, the Graves disease with the bruit), and the lymphadenopathy (the Virchow node of the gastric cancer, the cervical and the supraclavicular nodes of the lung cancer and the lymphoma, the generalized of the lymphoma). [1]

4. The chest — the crackles (the heart failure, the malignancy), the wheeze (the COPD, the asthma), the apical signs (the TB). [1]

5. The abdomen — the cachexia (the scaphoid abdomen), the hepatomegaly (the metastases, the cirrhosis), the splenomegaly (the lymphoma, the portal hypertension), the palpable mass (the gastric, the colonic, the pancreatic, the ovarian), the ascites (the ovarian cancer, the peritoneal carcinomatosis), and the PR examination (the rectal mass, the prostate, the melaena). [1]

6. The skin — the hyperpigmentation of the Addison disease (the palmar creases, the buccal mucosa, the recent scars), the dermatitis herpetiformis of the coeliac disease, the striae and the thin skin of the Cushing syndrome. [1]

7. The functional and the cognitive assessment — the gait, the balance, the grip strength, the ADLs, the MMSE or the MoCA, and the depression screen (the PHQ-2 or the GDS-15)." [1]

References

1. Gaddey HL, Holder K. Unintentional weight loss in older adults. Am Fam Physician 2014;89(9):718-722. PMID 24784334.
2. Hernández JL, Riancho JA, Matorras P, González-Macías J. Clinical evaluation for cancer in patients with involuntary weight loss without specific symptoms. Am J Med 2003;114(8):631-637. PMID 12798450.
3. Hernández JL, Matorras P, Riancho JA, González-Macías J. Involuntary weight loss without specific symptoms: a clinical prediction score for malignant neoplasm. QJM 2003;96(9):649-655. PMID 12925720.
4. Metalidis C, Knockaert DC, Bobbaers H, Vanderschueren S. Involuntary weight loss. Does a negative baseline evaluation provide adequate reassurance? Eur J Intern Med 2008;19(5):355-359. PMID 18549937.
5. Fearon K, Strasser F, Anker SD, et al. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol 2011;12(5):489-495. PMID 21296615. [1]