Changes in circulatory I-FABP in elderly persons in daily life: a pilot study.

In 2010, 326.202 patients aged 65 years or older underwent surgery in the
Netherlands, which is 25% of all operations executed that year. Since the
elderly population will double in the next years, more and more older patients
will undergo surgery. Older age is associated with increased mortality and
morbidity after surgery. Fifty-one percent of cancer patients of 70 years and
older requiring surgery have a postoperative complication. Also, major surgery
is associated with a significant reduction in physiologic and functional
capacity. A major cause of increased adverse outcomes in elderly patients
undergoing surgery is the high prevalence of malnutrition. In a cohort study
that explored the nutritional state in 4500 elderly (both clinical and in the
general population), 23% was in a state of malnutrition and a further 46% was
at risk to develop malnutrition. The percentage malnourished elderly in
hospitals and geriatric rehabilitation units was even higher. Malnutrition
increases the vulnerability of elderly in general, and is an independent risk
factor impacting on higher complications and increased mortality, length of
hospital stay and costs. Preliminary data of onco-geriatric studies in the UMCG
show a fourfold increased risk for development of postoperative complications
in patients with pre-operative malnutrition. Thus, prevention and treatment of
malnutrition is of major clinical and economical importance. There are multiple
causes of malnutrition in the elderly including decreased smell and taste,
age-related changes in the brain causing a dysregulation of the energy balance,
delayed gastric emptying, spontaneous gastroesophageal reflux and social
factors such as depression and stress. We hypothesize that low grade intestinal
damage, resulting in a decreased uptake of nutrients, is another important
contributor to the malnourished state of many elderly patients.

Intestinal integrity
The bowel harvests the largest immune system of our body. The intestinal wall
is the major barrier between host and environment and the intestinal barrier
plays an important role in health and disease. Recently certain diseases, such
as inflammatory bowel disease and celiac disease, were shown to be associated
with increased intestinal permeability. Therefore, preserving intestinal
integrity forms a potential new target for disease prevention and therapy.
Until now insight in gut barrier integrity and function loss was limited
because of a lack of practical, non-invasive measurement methods; the
measurements were often cumbersome and demanding for the patient. However,
lately there is more interest in serologic biomarkers to determine intestinal
integrity. One of these serologic biomarkers is I-FABP, which is released upon
enterocyte damage.

I-FABP
Fatty acid binding proteins (FABPs) are small cytoplasmic proteins involved in
cellular long-chain fatty acid metabolism and are abundantly expressed in
tissue with an active fatty acid metabolism like heart and liver. After cell
damage, these cellular proteins are released into the interstitium and will
diffuse through endothelial clefts into the circulation and are therefore
sensitive novel biomarkers. Until now 9 different FABP types are known, each
type has a characteristic pattern of tissue distribution. Heart FABP has been
reported the most sensitive marker for myocardial injury. In the bowel, 3
different FABP types are present: intestinal FABP (I-FABP), liver FABP (L-FABP)
and ileal bile ABP (I-BABP). I-FABP is solely present in the entire intestine
and not in other organs, which makes it the most specific FABP subtype to
analyze intestinal damage. I-FABP is present in the cytoplasm of enterocytes on
top of the bowel villi. During normal circumstances, the I-FABP value in plasma
is low to negligible and reflects the physiological turnover rate of
enterocytes. The effect of decreased intestinal perfusion followed by
reperfusion, as studied in a human translational ischemia-reperfusion model,
led to damage on the tip of the villi and increase of I-FABP. Even after a
short period of ischemia, with morphologic hardly noticeable intestinal
ischemic damage, there was a tenfold increase in I-FABP. This emphasizes the
high sensitive nature of I-FABP and indicates that enterocyte membrane
integrity loss alone is sufficient to cause increased plasma I-FABP levels.

I-FABP as a marker for acute intestinal damage has been studied in multiple
patient groups. Patients who underwent open aortic aneurysm repair, during
which the aorta is clamped resulting in temporarily closure of the intestinal
circulation, showed an I-FABP increase during surgery with a peak at the end of
the surgery and a decrease to baseline after the first postoperative day.
Patients who developed intestinal necrosis, a known and severe complication of
open aorta repair, displayed exceptionally high I-FABP levels at the end of
surgery and on the first postoperative day, thus assessment of plasma IFABP
levels enables early identification of patients developing intestinal necrosis
after open aortic repair. Also for trauma patients and neonates suffering from
necrotizing enterocolitis (NEC), high I-FABP values are related to intestinal
ischemia. In otherwise healthy children undergoing spinal fusion surgery
because of scoliosis, plasma I-FABP increased significantly during surgery and
quickly returned back to baseline postoperative. Plasma I-FABP was
significantly negatively correlated with mean arterial pressure. During a
further study it was demonstrated that this increase in I-FABP didn*t occur if
the mean arterial pressure was *60mmHg which indicated that an adequate
intestinal perfusion prevents damage of the enterocytes.

The usefulness of I-FABP as a marker for gut dysfunction was also studied in
healthy individuals and patients with a chronic disease. Young, healthy
volunteers who cycled for one hour showed a significant I-FABP increase,
without any complaints such as nausea or abdominal pain. I-FABP is
significantly elevated during the transient postprandial ischemic episode in
chronic gastro intestinal ischemia patients. COPD patients (mean age 64 years
old) showed a significant I-FABP increase during the performance of activities
of daily living, such as walking, dressing, doing the laundry and cleaning.
This implicates that the impaired gas exchange characteristic for COPD, worsens
during exercise. Patients with moderate to severe COPD are often cachexic which
raises the question if the compromised bowel in these patients contributes to
this malnourished state.

The control group of the fore cited study in COPD patients ,constituting of a
group of healthy volunteers matched for age, sex and BMI, showed no I-FABP
increase during these activities of daily living. The control group in the
study of Mensink et al, consisting of healthy volunteers, showed undetectable
or within normal serum levels of I-FABP before and after a standard test meal
in all healthy participants.

Intestinal atherosclerosis in the elderly
We postulate that occurrence of intestinal damage in elderly under daily
circumstances is associated with atherosclerotic changes in the intestinal
circulation, a condition with a high prevalence in the older population.
Fifteen percent of individuals had at least two stenotic mesenteric arteries as
evaluated in an unselected Finnish autopsy series of 120 cases. The occurrence
of mesenteric artery stenosis was strongly associated with aging. Sixty-seven
per cent of the subjects aged 80 or more presented with mesenteric artery
stenosis, whereas the rate was 6% among those aged less than 40 years.
Mesenteric artery atherosclerosis was strongly associated with atherosclerosis
in coronary arteries and cerebral arteries in the skull base. In the
Netherlands, 21% of men and 11% of women are suffering from a coronary heart
disease as a result of atherosclerosis. Generalized peripheral arterial disease
is also a frequent condition, 7% of women and 10% of men aged 55-59 and 52% of
women and 60% of men aged 85 years or older are affected.

Purpose:
Our hypothesis is that, analogous to the fore cited COPD patients, low grade
intestinal ischemia is present in part of the elderly under daily
circumstances. Atherosclerosis affects blood flow redistribution, thereby
redistribution of the cardiac output during exercise or postprandial, as
appears in the physiological state in healthy individuals, might be compromised
in the elderly. Low mesenteric blood flow subsequently leads to injury of the
cells at the most distal point from the mucosal blood supply, being the mature
enterocytes, evidenced by I-FABP release into the circulation. This disturbed
membrane may reduce the digestive and absorptive capacity of the intestinal
tract and contributes to malnutrition in elderly patients. Before performing
extensive studies in vulnerable onco-geriatric patients, we perform the present
pilot study in elderly persons in the general population.

We will investigate the effect of the combination of moderate physical activity
and a standard meal on the onset of low grade intestinal ischemia. Will will
use the serological biomarker I-FABP to determine the occurrence of low grade
intestinal ischemia.

A minimal invasive study design was set up to obtain a proof of concept in the
general elderly population before performing more extensive experiments in a
vulnerable onco-geriatric patient cohort. This study will be performed in
elderly people aged 75 years and older receiving person-centered and integrated
care and support by Embrace. Thirty volunteers of >75 years will be included.
This study consists of an intake interview and one testing day.

Intake interview: General characteristics of the volunteers are recorded
including gender, medical history and medication. A nutritional assessment
including a short questionnaire (Patient Generated Subjective Global
Assessment; PG-SGA) is taken.

Testing day: Volunteers perform a walking test. No fasting is required before
this test. After the walking test volunteers will eat a standard meal. The
plates are weighed and a picture of the plate is taken before and after the
meal to calculate the ingested macronutrients and calories. A drip is placed in
a vein in the forearm, through which 8 samples of blood are taken in 2,5 hours.
In total, 48ml of blood is taken, constituting <1% of total blood volume. The
drip is removed following the last blood withdrawal.

Burden:
- intake interview, max 1 hour

- drip placement for 2.5 hours. Risk: pain, bleeding

- walking test. No risks involved

- consumption of a standard meal. No risks involved