Endoscopic investigations (both upper and lower) are recommended immediately after history, physical examination, chest radiography, abdominal ultrasonography and standard laboratory tests in patients with IWL [2
], because gastrointestinal cancer is always feared, although its frequency is about 10% in patients with IWL [5
]. In our study on 290 patients, 148 patients (51%) were investigated using upper endoscopy, and 140 patients (48%) had colonoscopy, while the frequency of gastric and colorectal cancer was only 2.8% and 4.5%, respectively.
Generally, the sensitivity of anaemia for the diagnosis of gastrointestinal cancer is only about 50% [6
], but theoretically it should be more sensitive in IWL, as more advanced tumours are usually diagnosed in these patients [15
]. On the other hand, ferritin should be more sensitive in the diagnosis of iron deficiency states, therefore in the diagnosis of gastrointestinal cancer as the cause of weight loss.
Ferritin was assessed in a few studies for the diagnosis of gastrointestinal cancer, and revealed that 10% of 143 patients with a ferritin less than 50 mcg/L had gastrointestinal cancer [16
]; in two patients without anaemia, a low ferritin (<18 mcg/L) actually lead to the discovery of colon cancer [17
]; and in 414 patients referred for colonoscopy because of anaemia, a ferritin higher than 100 mcg/L excluded colorectal cancer [18
]. However, in a retrospective study on 359 consecutive elderly inpatients referred to colonoscopy because of symptoms suggesting colorectal cancer, ferritin was not useful in the diagnosis [19
In the current study, we examined the usefulness of ferritin in the diagnosis of gastrointestinal/colorectal cancer in patients with IWL, and we found that ferritin was a better test than serum iron, MCV, haemoglobin, and RDW, as it had the biggest AUC, and it was the only test associated with gastrointestinal and colorectal cancer in multivariable analysis.
Ferritin ≥ 100 mcg/L could exclude colon cancer, because it had good sensitivity and negative likelihood ratio, and a very high negative predictive value. The main weakness of the study is the low prevalence of colon cancer in this series of patients with IWL, possibly overestimating the negative predictive value of ferritin ≥ 100 mcg/L, and leading to a relatively large confidence interval for the sensitivity.
The cut-off value of 50 mcg/L for ferritin is useless, because the test looses sensitivity, without a decisive gain in specificity, while anaemia is, as expected, a little more sensitive for gastrointestinal cancer in these patients with IWL than in other patients, but not sensitive enough to rule out the disease.
Ferritin < 100 mcg/L was less sensitive for gastrointestinal cancer, because of two false negative gastric cancers, the third false negative being a rectal cancer. Upon this results, one could speculate that ferritin might be very sensitive only for colon cancer, whose main feature is iron deficiency anaemia, and not for the extremities of the digestive tract (stomach and rectum), which are, anyway, easier to explore by upper endoscopy and rectoscopy (Additional file 2
Ferritin as a diagnostic test performed much better than haemoglobin both in terms of AUC and sensitivity. Using ferritin in place of haemoglobin, 6 additional patients without anaemia were diagnosed with cancer (1 with caecum cancer, 2 with stomach cancer, 2 with rectal cancer, and one with sigmoid cancer) (Table ).
Ferritin, ESR, CRP, ALAT and alcoholism*in patients with gastrointestinal cancer
The fact that ferritin was not associated with gastrointestinal/colon cancer in patients without anaemia was unexpected. This finding could be explained, in our opinion, by the low statistical power (only 7 and 5 patients without anaemia had gastrointestinal and colon cancer, respectively), and by the fact that, in this population with IWL, ferritin was more homogenous in patients without anaemia, who generally did not have an organic disease, while being more frequently elevated in patients with anaemia of chronic disease, or low in patients with iron deficiency anaemia due to gastrointestinal cancer [24
As it is known, ferritin increases in inflammation and alcohol consumption, which means that, if adjusted for inflammation, this test could have become even better as sensitivity (with fewer false negatives), and therefore for ruling out the disease. However, there are no guidelines concerning this adjustment: one source suggests that inflammation augments the serum ferritin threefold, and therefore its value should be divided by three [9
], without any research study as reference, while a meta-analysis showed that inflammation augments the value of ferritin with about 40% [25
], but it is based mainly on studies on children with acute inflammation. Nowhere is stated from what level of inflammation one should adjust, and if adjustment should be the same for a CRP of 10 as for a CRP of 80 mg/L. This eventual adjustment could have changed the classification of only 3 patients with ferritin higher than 100mcg/L who tested false negatives (two with stomach cancer and one with rectal cancer (Table ), but it is probably that the patient with stomach cancer and ferritin of 500 mcg/L would have been a false negative regardless of any such adjustment, because even if divided by three, the value still would have been higher than 100 mcg/L.
Because IWL can have multiple causes, it is difficult, expansive and frequently useless to settle a standardized investigation protocol [2
]. We decided to let the investigators decide the diagnostic approach in every patient, depending on clinical and biological diagnostic clues. In order to avoid misclassification concerning the final diagnosis (gastrointestinal cancer or not) for patients who did not have both upper and lower digestive endoscopy, after leaving the hospital the patients were followed up for six months, therefore our diagnostic study had a valuable reference standard. Only 11 (3.8%) patients did not have endoscopy and were lost to follow-up after leaving the hospital, of which only 4 had not a certain cause for their weight loss. All patients had ferritin measured.