Tuesday, December 29, 2015

Inflammatory markers and endometriosis

What can I say? It's complicated.

Endometriosis is an inflammatory disease, so a lot of people have questions about blood tests that look at inflammation. Let's look at what inflammatory markers are and specifically at CRP:

"Serum proteins that are produced in response to inflammation can be referred to as inflammatory markers. These proteins are mainly produced by the liver in response to stress and can also be called acute phase reactants. Pro-inflammatory cytokines such as IL-1, IL-6, and TNF-alpha induce synthesis of some acute phase reactants that include CRP, fibrinogen and haptoglobin. Other proteins, like albumin, are not sensitive to inflammatory cytokines for increased synthesis; instead chronic stress (inflammation) results in a lower synthesis rate with resultant decreased serum concentrations. The inflammatory markers are not diagnostic of inflammation, but reflect abnormalities that are seen in autoimmune diseases, infections, malignancies and other illnesses.

C-reactive protein (CRP)

"C-reactive protein (CRP/CRP-high sensitivity) was discovered and named for its reactivity to the C polysaccharide in the cell wall of S. pneumoniae. CRP, an innate immune protein, helps opsonize pathogens for phagocytosis and activates the complement system. CRP production is under the control of IL-1, IL-6, and TNF-alpha. Changes in serum CRP concentration change more quickly than ESR and therefore CRP may be a better reflection of current inflammation. Unlike the ESR, CRP is a fairly stable serum protein whose measurement is not time-sensitive and is not affected by other serum components. The magnitude of inflammation directly relates to the concentration of CRP. Levels < 0.2 mg/dl are considered normal, while those >1.0 mg/dL are suggestive off inflammation and/or infection. More recently, the use of high sensitivity CRP has been utilized. This test may better quantify lower levels of inflammation and has been important in evaluating cardiac disease and other inflammatory states.2, 3" http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2832720/?report=reader      

So what does this have to do with endometriosis?

Endometriosis is an inflammatory disease, so one might expect the markers to be high. But not necessarily in blood tests:
There was no significant difference between the CRP serum level in patients with endometriosis and infertile women without endometriosis. There was a significant difference in peritoneal level of CRP between case and control groups (p < 0.05).


The findings suggested that measurement of this marker in patients’ serum or plasma cannot be used to diagnose endometriosis. It is further recommended that a combination of different markers might be helpful in this regard that could be studied in future."
So we may not see an increase in the blood test but there is a difference in the peritoneal samples:
"Compared to the control group, the CRP level of the peritoneal fluid were higher in patients with endometriosis (p<0.05). Pelvic endometriosis is a chronic inflammatory disease that is in association with a general inflammatory response in the peritoneal cavity.[,] This disease is known to have an immunological background.[] Macrophage constitutes 82- 99% of the all the cell population of peritoneal fluid.[] Literature has repeatedly reported an increase of total peritoneal fluid cell numbers, cell concentration and macrophages in endometriosis patients in compare to the control.[] The study of Dunselman et al. also confirmed that there is an increase in the number and concentration of peritoneal cells in patients with endometriosis as compared to the control group.[]" http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3696960/
While we're on the subject, let's discuss CA-125 levels:
It's a test that looks at markers for certain cancers, but if your doctor orders it and it's high, don't let it scare you. "...many noncancerous conditions can increase the CA 125 level.
Many different conditions can cause an increase in CA 125, including normal conditions, such as menstruation, and noncancerous conditions, such as uterine fibroids." http://www.mayoclinic.org/tests-procedures/ca-125-test/basics/definition/prc-20009524 It can also be high in people with endometriosis: "Studies published since continue to demonstrate a correlation between raised CA125 levels and endometriosis (Abrao et al., 1999; Somigliana et al., 2004; Agic et al., 2008; Seeber et al., 2008), and some imply a correlation with stage of disease (Chen et al., 1998; Amaral et al., 2006; Martinez et al., 2007; Rosa e Silva et al., 2007). One study has indicated that CA125 may be more accurate at diagnosing women with later stages of disease, in concordance with the review by Mol (Maiorana et al., 2007)." http://humupd.oxfordjournals.org/content/16/6/651.full 

Remember, all these tests might be a mere indication of endometriosis, but they are very nonspecific. The only way to accurately diagnose endometriosis is through surgery.

Mast cells:

"Mast cells may contribute to the development of pain and hyperalgesia in endometriosis
October 2006
The presence of increased activated and degranulating mast cells in deeply infiltrating endometriosis, which are the most painful lesions, and the close histological relationship between mast cells and nerves strongly suggest that mast cells could contribute to the development of pain and hyperalgesia in endometriosis, possibly by a direct effect on nerve structures.

Researchers set out to detect and quantify mast cells in peritoneal, ovarian, and deep infiltrating endometriosis and to study the relationship between mast cells and nerves in endometriosis.

Excision of endometriosis from different anatomical locations was undertaken in 69 women, who were undergoing laparoscopic excision of endometriosis for pain. Thirty-seven biopsies of normal tissue were obtained from women without endometriosis.
The women with deeply infiltrating lesions had significantly higher preoperative pain scores than women with peritoneal or ovarian endometriosis. Mast cells and degranulating mast cells are significantly more abundant in endometriotic lesions than in non-affected tissues. Deep infiltrating lesions show a significantly higher number of mast cells, activated mast cells, and mast cells located <25 mum from nerves than peritoneal and ovarian lesions. The authors found significantly more degranulating mast cells in deep infiltrating lesions than in peritoneal lesions.
Anaf V, Chapron C, El Nakadi I, De Moor V, Simonart T, Noel JC. Pain, mast cells, and nerves in peritoneal, ovarian, and deep infiltrating endometriosis. Fertil Steril 2006;86(5):1336-43"

For a lot more on peripheral biomarkers of endometriosis see: http://humupd.oxfordjournals.org/content/16/6/651.full

  "Endometriotic lesion removal significantly alters the inflammatory profile both locally and systemically in women with endometriosis. Our findings indicate that ectopic lesions are the major drivers of systemic inflammation in endometriosis." http://www.ncbi.nlm.nih.gov/pubmed/26698677