©2005 by Alan Cocchetto, NCF Medical Director

 

Research work completed by Dr. Yoshitsugi Hokama, from the Department of Pathology at the John A. Burns School of Medicine at the University of Hawaii, has demonstrated the destruction of red blood cells in in-vitro testing in the presence of the ciguatera epitope. Previous research had found this epitope in the sera of over 95% of CFIDS/ME patients tested. Dr. Hokama's research, discussed in this article, was fully funded via the National CFIDS Foundation's (NCF) Research Grant Program.

 

"Since Dr. Hokama had previously published on ciguatera toxin and its effect on red blood cells, we knew we had to pursue this" stated Gail Kansky, President of the NCF. "Ciguatera toxin kills red blood cells. Now we needed to know if the ciguatera epitope could produce the same damage. This was very important in light of a variety of red cell defects that have been previously found in these patients" said Kansky.

 

As stated, Dr. Hokama has discovered that the ciguatera epitope kills red blood cells.  Furthermore, he has found that this epitope does its destruction, just like ciguatera toxin, via the red cell sodium/potassium pump, known formally as the Na+/K+ ATPase enzyme that is located on the red blood cell surface. Why is this important? Though Dr. Hokama's initial research has demonstrated these results in-vitro, the NCF has confirmed these results in-vivo through patient bone marrow biopsy reports from PWC/ME's that had previously tested positive for the ciguatera epitope. In addition, the NCF found a specific red cell enzyme that could be measured by a diagnostic assay to provide additional insight into this disease process. As you will learn, these results have important implications to PWC/ME's worldwide.

 

The NCF had learned that the red cell sodium/potassium pump, altered by the ciguatera epitope, directly affects an important enzyme present in the red blood cell. That enzyme is known as phosphoglycerate kinase. Phosphoglycerate kinase is involved in glycolysis reactions. Glycolysis is the pathway by which glucose is converted to pyruvate. Furthermore, phosphoglycerate kinase also assists in the conversion of ADP to ATP.

 

However, the NCF found additional medical information regarding the sodium/potassium pump and phosphoglycerate kinase with respect to red blood cell function. A scientific research study, completed several years ago, modelled the effects of modulation of the sodium/potassium pump on the red blood cell. This model described all reactions of glycolysis, adenylate metabolism, ionic balance and osmotic regulation of the cell volume. An incease in cell volume to some critical value was considered to be the natural criterion for red blood cell destruction. Normal red blood cells are discoid and their surface area-to-volume ratio is high. The discoid shape of red blood cells ensures optimal rheological characteristics of these cells. As the red cell membrane is inextensible, its shape must be maintained by mechanisms stabilizing the cell volume. The red cell volume is kept almost constant owing to operation of transport sodium/potassium pump which utilizes energy produced in glycolysis. If transport sodium/potassium pump and/or glycolytic enzymes are abnormal, the volume and rheological characteristics of red cells will also be abnormal. This results in sequestration from the circulation or even osmotic lysis. It is likely that the cells with greater deviations are sequestered from the circulation. Thus, in general, metabolic impairments and cell death may result from any significant change, whether increase or decrease, in the activity of a particular enzyme and in this case, the activity of the red cell sodium/potassium pump and the red cell enzyme phosphoglycerate kinase.

 

As mentioned earlier, the NCF received bone marrow biopsy reports from several patients who tested positive for the ciguatera epitope. These reports indicated that there was destruction of red blood cells in the periphery taking place along with sequestration of these cells occurring in organs. As expected, the bone marrow was trying to compensate for the overall loss of these cells!

 

Dr. David S. Bell, along with the late Dr. H. P. David Streeten, had previously reported on the low red blood cell volume that occurs in CFS/ME patients. Likewise, Dr. L. O. Simpson had previously reported on altered red blood cell rheology in patients. The NCF believes that this research, done by Dr. Hokama and his colleagues, greatly aids to confirm the disease mechanism by which these very alterations to the red blood cell are taking place. Furthermore, because Dr. Hokama's research confirmed the destruction of red blood cells by the ciguatera epitope, the NCF firmly believes this mechanism is critically important to the disease process.

 

Likewise, since the ciguatera epitope appears capable of destroying red blood cells in the periphery and through our knowledge of this epitope's interaction with the red cell sodium/
potassium pump, the ciguatera epitope certainly appears capable of modulating the red cell enzyme phosphoglycerate kinase. Alterations of phosphoglycerate kinase can, for example, cause hemolytic anemia. Equally important is the fact that this modulation can produce alterations to red cell rheology and act to create a condition of low red cell volume due to sequestration of these cells (primarily in the liver and spleen). You may recall that PWC/ME patients have often noted pain in the area of the liver and spleen. We wonder whether or not this could be due to the sequestration of red cells? To reiterate, the NCF's research to date points to sequestration of red blood cells as the mechanism directly responsible for reductions in blood volume. In addition, the NCF has verified that alterations are occurring in red cell phosphoglycerate kinase through an assay test that was used at the Mayo Clinic.

 

The NCF hopes all PWC/ME patients and their physicians begin to see additional importance of the ciguatera epitope and its implications in the disease process. Please help us help you by continuing to donate to the NCF's Research Grant Program!

 

References:
1. Chronic phase lipids in sera of chronic fatigue syndrome (CFS), chronic ciguatera fish poisoning
(CCFP), hepatitis B, and cancer with antigenic epitope resembling ciguatoxin, as assessed with
MAb-CTX; Hokama Y, Uto GA, Palafox NA, Enlander D, Jordan E, Cocchetto A;
J Clin Lab Anal. 2003; 17(4): 132-9
2. Evidence for palytoxin as one of the sheep erythrocyte lytic factors in crude extracts of ciguateric
and non-ciguateric reef fish tissue; Wachi KM, Hokama Y, Haga LS, Shiraki A, Takenaka WE,
Bignami GS, Levine L; J Nat Toxins. 2000 May; 9(2):139-46
3. Interaction of palytoxin with red cells: structure-function studies; Tosteson MT, Scriven DR,
Bharadwaj AK, Kishi Y, Tosteson DC; Toxicon. 1995 Jun; 33(6): 799-807
4. The role of membrane phosphoglycerate kinase in the control of glycolytic rate by active cation
transport in human red blood cells; Parker JC, Hoffman JF; J Gen Physiol. 1967 Mar;
50(4): 893-916
5. Deficiencies of glycolytic enzymes as a possible cause of hemolytic anemia; Martinov MV,
Plotnikov AG, Vitvitsky VM, Ataullakhanov FI; Biochim Biophys Acta. 2000 Mar 6;
1474(1): 75-87
6. Circulating blood volume in Chronic Fatigue Syndrome; Streeten DHP, Bell DS; J Chronic
Fatigue Syndrome 1998; 4(1)
7. The role of nondiscocytic erythrocytes in the pathogenesis of Myalgic Encephalomyelitis / Chronic
Fatigue Syndrome; Simpson LO; The clinical and scientific basis of Myalgic Encephalomyelitis /
Chronic Fatigue Syndrome; Nightingale Research Foundation 1992; 65: 597-605