Minimizing peri-operative complications in RYGB is important because morbidly obese patients have significant operative risks, many related to associated co-morbidities. Iron status is a potentially important factor influencing these co-morbidities. We found that increased serum iron and transferrin saturation measured pre-operatively were associated with post-operative complications and that increased serum ferritin, as well as iron and transferrin saturation, were associated with major complications. Pre-operatively increased serum transferrin saturation was also associated with wound complications following open RYGB and transferrin saturation and ferritin with prolonged lengths of stay. The presence of 2 or more HFE mutations was associated with overall complications as well as wound complications in open RYGB. No differences were found in complication rates between those with stainable liver iron and those without histological evidence of hepatic iron overload. Stratifying by gender and diabetes also revealed several other associations of higher iron status in patients with complications.
The relationship between iron status and complications may be due oxidative stress. Iron is the most abundant transition metal in the human body and is an essential element for life . It is potentially toxic because of its ability to generate toxic free radicals and resulting cellular injury from oxidative stress . As a protective measure, iron is sequestered in proteins, particularly ferritin and transferrin. Iron-catalyzed generation of oxidative stress has been implicated in many clinical disorders, including wound healing and infection. In wounds there is a low pH, a partial ischemic state, and an excess of free radicals . Under these conditions, iron may be released from storage, thereby making it available to catalyze further tissue damage. Our findings that serum iron and transferrin saturation were increased in patients with complications, particularly wound complications, is consistent with the availability of increased iron that could play a role in the pathogenesis of complications. We found only a higher level of ferritin in patients with major complications. Ferritin is also an acute phase response protein and may be a marker for a sub-clinical inflammatory state pre-disposing to major complications in open RYGB and not reflecting differences in iron status.
Iron may also be deleterious if present in insufficient amounts. It is required for the hydroxylation of proline and lysine required in collagen synthesis, thus iron deficiency may collagen production and delay wound healing . A reduction in oxygen carrying capacity with iron deficiency may also affect wound healing. Iron levels need to be in an optimal range, neither deficiency not elevated, in order for optimum physiological responses to surgical procedures.
Consistent with the results for serum iron parameters, we found that patients carrying 2 or more HFE gene mutations had a two-fold higher rate of overall complications, though each individual mutation did not reach statistical significance. The HFE C282Y mutation has been associated with venous leg ulceration  suggesting that HFE genotype may affect wound complications and healing. Patients with HFE gene mutations absorb increased amounts of dietary iron that is characteristically reflected as an elevation of transferrin saturation . The HFE C282Y and H63D mutations cause increased iron absorption whether in a homozygous, i.e., C282Y/C282Y or H62D/H62D, or compound heterozygous configuration, i.e., C282Y/H63D. However, the biochemical expression of HFE mutations is variable. In a study of over 200 C282Y homozygotes, a total of 28% of male C282Y homozygotes had evidence of iron-overload-related disease . In contrast, the prevalence of iron-overload-related disease was only 1% in female C282Y homozygotes, which may be due to a lower iron burden and/or other modifying effects. In our population, about 80% of the patients were female, thus the clinical expression of mutations may be under-represented.
Despite the association of complications with serum iron indices, the presence of stainable iron in the liver was not associated with post-operative RYGB complications. The liver serves as a major storage depot for total body iron. Total body iron stores are generally proportional to serum ferritin, although the correlation is not very strong . In the absence of HFE mutations, the levels of serum iron and transferrin saturation may not be indicative of increased iron absorption and increased iron stores, thus stainable liver iron may not be expected to predict the same outcomes as serum iron and transferrin saturation.
A higher rate of wound complications, defined as superficial and deep surgical site infections and dehiscence, was found in patients undergoing open RYGB versus those who had laparoscopic RYGB. This is similar to reports in the literature of wound problems occurring in about 10-20% of patients following open RYGB [19, 28]. A majority of the complications in RYGB were considered minor, whereas in laparoscopic RYGB approximately equal numbers of major and minor complications were seen.
Obesity is a known risk factor for several types of complications in other surgeries. For example, overall postoperative complications have been associated with BMI in patients with non-perforated appendicitis . Increased BMI has also been associated with increased wound complications in both minimally invasive and open rectal surgery [30, 31]. Percent body fat calculated by bioelectrical impedance analysis has been associated with a 5-fold increased risk of surgical site infections after elective surgery . However, BMI may not affect complication rates for all types of operations. Although total laparoscopic hysterectomy for obese patients required significantly longer to complete and was associated with a higher risk of significant blood loss, major and minor complications, hospital readmission, and reoperation were not different .
There are several limitations to our study. The only operation studied was RYGB. The findings do not apply to other types of bariatric surgeries, such as the laparoscopic band procedure. The relative number of men enrolled in the study was much lower than the number of women, so limited statistical power exists to determine whether the associations found for female patients are truly not present in males. Follow-up studies with larger numbers of male patients will be required. The numbers of C282Y and H63D homozygotes was also relatively low and thus not sufficiently powered to determine whether these genotypes were associated with differences in complication rates. A much larger sample size will be required given the low rates of these mutations. Our population also consisted of only Caucasian patients. Whether iron status in patients of other races/ethnicities is associated with post-RYGB complications will need to be determined in other studies. We also did not address independent effects of other variables on complications, such as blood glucose levels and BMI.