HELLP, Preeclampsia, Antiphospholipid Antibodies and Basic Triplets

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Clotted RBCs in Capillary

Some of my research involves the unique properties of milk and the development of the immune system, so I talk to medical people, lactation researchers and occasionally discuss the control of inflammation involved in ovulation, fertilization, implantation, gestation, labor and lactation.  It is clear to me that there are a few trends in disruption of these pregnancy processes resulting from the modern increase in inflammation and gut-related problems linked with immune tolerance.  Infertility is increasing, because women are becoming more chronically inflamed.  Miscarriages and premature births/low birth weight are increasing, because chronic inflammation enhances labor.  Pre-eclampsia (high blood pressure and protein leaking into the urine) results from chronic inflammation and omega-3 fatty acid depletion.  Now an even scarier form of pre-eclampsia, HELLP (Hemolysis, Elevated Liver enzymes, Low Platelets) is on the rise.  I want to discuss HELLP to put all of these pregnancy-related problems into perspective.

HELLP, Cause and Cure Unknown?

HELLP is an autoimmune disease and I have repeatedly discussed the cause of autoimmune diseases:  1) inflammation, 2) deficiency of Tregs (immune tolerance) and 3) antigen basic triplets (antigen presentation).  When HELLP was recently brought to my attention with a sudden rise in local hospitals, I decided to see if it could be easily explained and cured, just by examining the available medical literature.  Wikipedia indicated that the cause and cure was not known and that was confirmed by local doctors, who just treat the symptoms by early deliveries and long stays for the babies in neonatal intensive care units.  My work was cut out for me.

Autoimmune Disease with Unknown Autoantigen 

An examination of the symptoms, rupture of blood cells (fibrin production), liver damage, clotting (low serum heparin), high blood pressure (capillary apoptosis), proteinuria (low heparan sulfate (HS) to prevent protein loss), pointed to some obvious treatments and the causes.  Infertility is often treated by in vitro fertilization/insemination, supported with aspirin and heparin injections to maintain gestation.  These treatments are consistent with high levels of chronic inflammation that block implantation and stimulate labor.  Infertility is also associated with antiphospholipid antibodies.  A closer look at the antiphospholipid antibodies showed that they were directed against β₂-glycoprotein-I.  So, I expected the β₂-glycoprotein-I protein to be the original target for the antibodies, the initiating antigen, but when I looked up the sequence of that protein, it lacked the expected basic triplet I have found in all  other autoantigens and allergens.  This meant to me that there was a different protein with a related sequence that started the HELLP autoimmune disease.

Attack on P-Selectin Starts Immune Autoimmunity

I checked for other proteins with related sequences and basic triplets (RKR in the carboxy terminal sequence below), and found P-selectin that is produced most abundantly in liver and on the surface of blood cells.  A quick search of the literature showed that P-selectin reacts with anti-phospholipid antibodies and has a pair of basic triplets that enhance immune presentation and make this protein a strong candidate for becoming an autoantigen.  Antibodies against P-selectin will cause clotting as seen in HELLP.

ref|NP_002996.2| P-selectin precursor [Homo sapiens]:

......carboxy terminalGTLLALLRKRFRQKDDGKCPLNPHSHLGTYGVFTNAAFDPSP

Antibiotics and Liver Damage

I suspect that HELLP is caused by a combination of liver damage and prior exposure to antibiotics (or common drugs that have antibiotic activity) that cause gut dysbiosis, i.e. loss of gut bacteria that stimulate development of the suppressive part of the immune system, e.g. deficiency in regulatory T cells, Tregs.  Examples of the type of liver damage that may lead to HELLP are excessive consumption of alcohol (alcoholic fatty liver) or high fructose corn syrup (non-alcoholic fatty liver).

HELLP from Cause to Cure

• Diet and/or infection causes liver inflammation.
• Antibiotics/drugs and/or processed foods lacking prebiotic fiber produce gut dysbiosis.
• Lack of gut bacteria needed for development of the immune system in the gut produces a deficiency of Tregs and dysfunction of immune tolerance.
• Liver inflammation, deficiency of Tregs and availability of antigens with basic triplets leads to antibodies against liver proteins.
• Chronic inflammation leads to decrease in HS production and leaky kidneys/proteinuria.
• Chronic inflammation/liver damage produces fibrin production.
• Fibrin production and low HS enhances clotting and leads to apoptosis/cell death in capillaries.
• Loss of capillaries leads to high blood pressure.
• Cure of HELLP, anti-phospholipid antibodies and pre-ecampsia, involves lowering chronic inflammation (aspirin and heparin treatment) with an Anti-Inflammatory Diet, fixing vitamin D deficiency, increasing omega 3/6 ratio,  and repairing gut dysbiosis to fix immune tolerance.
• Without these interventions, HELLP symptoms will become more severe, especially in subsequent pregnancies and additional autoimmune diseases will develop.

Menstrual Pain is Inflammatory

Inflammation is essential to the menstrual cycle. At key points inflammatory prostaglandins are made from omega-6 arachidonic acid to trigger ovulation and menses, the discharge of the blood-engorged lining of the uterus. Chronic diet-based inflammation can result in disrupted ovulation, infertility due to an inability to suppress an inflammatory response to egg implantation, menstrual pain/cramps and premature birth.

Several studies have shown that reducing diet-based inflammation by eating supplements containing long chain omega-3 oils, e.g. fish oil, decreased menstrual pain and cramps. The reduction in chronic inflammation was associated with decreased production of inflammatory prostaglandins that are the cause of the pain and intense uterine contractions. Normally, the diet would provide a balance of omega-3 and -6 fatty acids, which would yield a mixture of anti-inflammatory and inflammatory prostaglandins, and produce an effective discharge through more moderate uterine contractions.

A more recent evaluation of numerous studies on the impact of omega-3 oils on pain associated with menstruation, arthritis, inflammatory bowel disease, etc., showed a uniform decrease in inflammation and pain. The simple summary is that an inflammatory diet rich in omega-6 vegetable oils leads to pain, suffering and premature aging. A more normal diet with a balance of omega-3 and omega-6 fatty acids leads to health and reduced aging.

Typical symptoms of an inflammatory diet are: menstrual cramps, infertility (gestational problems: preeclampsia, prematurity), joint pain, back pain/sciatica, acne, allergies, asthma, autoimmune diseases. There is increasing evidence that obesity not only produces inflammation, but that an inflammatory diet can lead to obesity. An inflammatory diet, especially if augmented with antibiotics, disrupts the normal gut flora and leads to an inflammatory replacement flora that supports chronic inflammation throughout the body.

Chronic inflammation and much of the damage caused by chronic inflammation is reversible by a shift to an anti-inflammatory diet and lifestyle (described elsewhere on this blog.)

references:
Deutch B. 1995. Menstrual pain in Danish women correlated with low n-3 polyunsaturated fatty acid intake. Eur J Clin Nutr. 49(7):508-16.

Goldberg RJ, Katz J. 2007. A meta-analysis of the analgesic effects of omega-3 polyunsaturated fatty acid supplementation for inflammatory joint pain. Pain 129(1-2):210-23.

Bell RF. 2007. Food and pain: should we be more interested in what our patients eat? Pain. 129(1-2):5-7.