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CHRONIC FATIGUE SYNDROME CONFERENCE SYDNEY Feb 12-13'98

This was available on http://203.21.141.7/mall/cfs/meeting/INDEX.HTM

FULL TEXT OF POSTER CASE REPORTS: CFS ASSOCIATED WITH INSULIN RESISTANCE By Allen E. Gale, Consultant Physician (Allergy), PO Box 401, Hindmarsh, 5007 SA.  Email to: allenegale@ozemail.com.au

 Case No 1. H.O’D. Caucasian male, aged 52 years gives a 20 year history of multiple food allergies associated with intractable weight gain, depression, fatigue, malaise, spatial co-ordination, memory difficulty with lack of concentration, mental cloudiness, alcoholism, food addiction, symptoms of hypoglycaemia, intestinal disorders, arthritis, hypertension, obesity and irritable bowel syndrome. Because of the failure of doctors, specialists and others to solve his health problems, he read widely. For years he had controlled his weight at normal levels and was free of symptoms only if he restricted carbohydrates. He stated that "one piece of pizza would wipe me out mentally for almost 2 days in 1980 with my weight at 185 pounds" (84 kilos, 180 cms. predicted weight 61-85K.). Because of depression he was placed on Zoloft (Sertraline Hydrochloride) but his weight then ballooned to 240 pounds (109K). At one stage it appeared to him that his health problems were due to multiple food allergies. He found that proteins of plant and marine origin were the most frequent culprits as well as cow’s milk. He also wondered if his diagnosis was "leaky gut syndrome" as the cause of his gastrointestinal symptoms which he described as a "crippling illness". In 1994 his problem with his gut reached such a level that he wrote in one letter "GI Doctors can find nothing wrong with my GI tract. I can only eat a few vegetables and meat. I have lived on this diet for years now with vitamin supplements, however my intestinal tract seems to become more permeable each year. The list of foods I seem to be sensitive to are too numerous to be believable as food allergy"

 In June 1996 he sought help from an endocrine specialist and in his letter to the doctor complained that he had "symptoms of fatigue, spatial disorientation, mental confusion, (depression like symptoms) for years until by trial and error I came to an all meat/fat/leafy vegetable diet that minimised the symptoms. I survived on this diet for 15 years. However I would binge on simple carbohydrate type foods and alcohol many weekends when work hours were over and I did not need to be sharp. When I binged, I noticed that my sleep came quickly, I would wake up sweaty, and my calf muscles cramped easily. The sleep would last only 4 hours and I would be wide awake and mentally active, but then about 2-3 hours later, I would start co-ordination/depression/fatigue/mental confusion symptoms that would last for almost 2 days. Two years ago, I began taking Zoloft to cut back on the weekend binges. Within months, I felt better than I ever did in my life only to find myself gaining weight as I resumed a normal diet of carbohydrate on a daily basis. Four months ago I entered alcohol rehab as my drinking and eating binges became more uncontrollable and a daily problem. My blood pressure and weight rose to the same unacceptable levels (150/100;104 K) they had been before the protein diet. But I was still feeling very sharp mentally. I am an Air Force Reserve Pilot and High School Chemistry teacher. I need to get my blood pressure and weight down to pass my annual physical".

 Numerous investigations and treatments were performed over the years until on December 23 1996, a 2 hour glucose tolerance test was performed with concurrent insulin levels. The values in that test were:-

 fasting glucose 114 (6.4) insulin 18

following the glucose drink:-

at 30 minutes glucose 212 (11.7) insulin 118

at 1 hour glucose 228 (12.6) insulin 167

at 2 hours glucose 157 (8.0) insulin 76.

Following the glucose/insulin tolerance test a diagnosis of impaired glucose tolerance associated with hyperinsulinaemia due to insulin resistance was made. He was advised to follow an "insulin aware diet", exercise regularly and achieve an ideal weight. A second endocrine specialist has now diagnosed him as diabetic on the basis of the 2 hour glucose levels above 200 (11.0).

The above formerly on:-  http://commodore.perry.pps.pgh.pa.us/~odonnell/irhoo.html

CASE: No 2. T.S. UR 3916. Caucasian female aged 38 years with extreme weakness and fatigue. The symptoms had included bloating, constipation, urticarial rashes and food intolerance. She had been seen by numerous doctors and was referred for assistance in understanding her various food intolerances. Her extreme weakness had been diagnosed as spinal muscular atrophy and labelled "Welander-Kugelburg syndrome". She was 160 cms in height and weighed 41 kilos (predicted 51-64 K). She was extremely weak with marked muscle wasting of her limbs, was unable to stand unaided and came to my rooms in a wheelchair. Urine examination revealed the presence of moderate ketones and discussion of her diet for that day revealed that she had eaten rice cakes, mushrooms, steamed broccoli, brussel sprouts and leek. She had "dabbled with a vegetarian diet as a teenager" and used to drink copious amounts of cordial and eat lots of potato and bread. She was never in the habit of regular exercise. Her father had hypertension and cardiac disease. She was on the pill for severe dysmenorrhoea. She went to work as a clerical officer 2 days each week.

 A 2 hour glucose and insulin tolerance test revealed glucose levels approaching

impaired with elevation of the 2 hour insulin level, the levels being:-

fasting glucose 3.7, insulin 5

following the glucose drink:-

at 1 hour glucose 6.4, insulin 35

at 2 hours glucose 7.7, insulin 76.

Other routine laboratory tests performed at the initial consultation and subsequently by a Gynaecologist are as attached (Appendix 2). It is interesting that her cholesterol was elevated although she was on a Vegan diet. The reason for the ketonuria was explained to her and she agreed to abandon her Vegan diet and began following an "insulin aware diet" and began graduated exercise on an exercise bike. One of the reasons she gave for not eating was that as soon as she ate she would put on a kilogram of weight and it all seemed to be on her belly. There was a slow and steady improvement and six months after commencing management based on diet and exercise alone, she reported that she was "eating better and felt hugely better".

DISCUSSION

Whilst the existence of hyperinsulinemia and insulin resistance (IR) are now well documented in the scientific literature, the value of insulin assays remains controversial, and in the opinion of some, should never be performed! owehHowHowever However performance of a 2hour standard glucose tolerance test with concurrent insulin levels (GTT/INS) provides both clinician and patient with an understanding of the pathophysiology of this fascinating, ubiquitous but neglected syndrome. In 1986, Reaven stated that at first blush it may appear outlandish to suggest an association between hypertension, hypertriglyceridemia and hyperinsulinemia. Similarly the association between polycystic ovary disease and angina, or muscle cramps night sweats and CFS appears bizarre until the diverse clinical manifestations of IR are appreciated. However the results of GTT/INS studies and the response to treatment in my clinical practice has revealed that the diagnosis of *SyndromeX/CHAOS/IR/Metabolic Syndrome may be made in the majority of cases entirely on clinical grounds, and is supported in most by abnormalities in the GTT/INS test. It has been stated that insulin is a primitive and "dangerous peptide" and it is inevitable that the body has developed several counter-regulatory and backup mechanisms to control it. Age, sex, inheritance, medication, plant estrogens and steroids, stress, intercurrent and chronic infection, menstrual cycle in women, diet, exercise, sexual activity ; the list grows daily; have all been documented to impinge on the endocrine/insulin balance. To overcome these variables the insulin and glucose clamp procedures have been developed; but these remain as research tools.

All of the diverse and bizarre clinical features in the above cases may be traced to the metabolic changes associated with insulin resistance. It is significant that both of these patients had been told that their problem was related to diet. The first had been instructed to lose weight and the second to eliminate various foods. However neither understood the mechanisms involved. Whilst a diagnosis of insulin resistance/metabolic syndrome can be made entirely on clinical grounds, success in management of these patients has come through helping the patient understand the pathophysiology of insulin resistance which has led to hypertension, obesity and finally diabetes as in the first case; and to muscle weakness, abdominal adiposity and elevated cholesterol in the second case. It is also relevant that both cases experienced altered gastrointestinal motility. ("Hyperinsulinaemia per se has effects similar to hyperglycaemia on the stomach and small bowel …." Anon 1995). The muscular atrophy in the second case could be explained on the basis of "metabolic myopathy" (Table 23-25). Is the apparent adverse effect of Sertraline in the first case due to the interference with serotonin metabolism?

The pathophysiology of NIDDM in many cases may be clearly demonstrated to progress from normal glucose and insulin levels through initially Phase I with elevated insulin levels, Phase II with impaired glucose tolerance and markedly elevated insulin levels through to Phase III with markedly elevated glucose levels and insulin levels which may be elevated or falling. (Harrison 1995). However many diabetics classified as "non insulin dependent" require insulin therapy. It has been proposed that with the soon to be available sensitive Immunoassay Kits to detect islet cell antibodies to GAD, a new classification will be forthcoming relating to cause and independent of therapy. To retain the acronyms Type I could aptly be termed "Immune-Dependent Diabetes Mellitus" (IDDM) and Type II "Non-Immune-Dependent Diabetes Mellitus (NIDDM).

(Current medical diagnosis 1997). Insulin resistance syndrome (Syndrome X, Chaos) with its wellknown association of hyperglycaemia, hyperinsulinaemia, lipidemia which lead to coronary artery disease and stroke, may result from a genetic defect reducing insulin resistance. This genetic defect may be latent but is expressed normally in the teenage years and in pregnancy in response to drugs - notably cortisone but also infection or stress.

Is Harrison’s concept of phases I, II & III outdated? The debate appears to continue as to whether insulin resistance precedes or is a sequel to obesity; in either case insulin resistance is then compounded by obesity as the fat cells themselves are capable of producing a protein - PC-1 which in itself is capable of inducing insulin resistance. The insulin resistance which initially develops in response to drugs, stress, infection, puberty or pregnancy, would appear to be a receptor defect. Once obesity has become established insulin resistance is then perpetuated by a post receptor defect associated with the production of PC-1. The development of a preceptor defect due to production of insulin antibodies and associated with HAIR-AN syndrome would appear to be relatively uncommon.

Management proves to be intractable in many cases, but the patient must be encouraged to follow an "insulin aware diet" based on the insulin index of foods (Holt et al 1996). Furthermore the sufferer must be encouraged to exercise regularly. This presents a problem as many with chronic fatigue find the slightest exertion completely debilitating. A graduated programme of rehabilitation beginning, preferably with an exercise bike, has been tried in many cases with success. It is relevant to encourage the patient to exercise in the light of the findings of Brown et al (1997). In their study of African-American women with hypertension, moderate obesity but no evidence of diabetes, daily exercise sessions of 50 minutes for one week increased insulin sensitivity by 58% on average and 5 of the 12 women were no longer insulin resistant. The conclusion of that research lead to the observation that "most people become discouraged because they can’t see any overt signs of improvement, but these results are evidence that early on you are doing some good".

 Anon 1995. J.Int.Med.1995:237:403.

 Table 23-25. Muscular Dystrophies and Myotonies of Childhood in Current Paediatric Diagnosis and Treatment 1997 on StatRef! on CD ROM.

 Current Medical Diagnosis and Treatment - 36th edition 1997 Chapter on diabetes mellitus and hypoglycemia by John H. Karam M.D.

 Harrison’s Textbook of Medicine 1995 on CD ROM.

 Holt, SHA, Brand Miller, J.C., Petocz, P. "An Insulin Index of Common Foods". Abstract in proceedings of the Nutrition Society of Australia (1996) 20. Page 175.

 Brown, M.D., et al Improvement of Insulin Sensitivity by Short Term Exercise Training in Hypertensive African American Women. Hypertension 1997 December 1:30 (6):1549-1553.

 *Syndrome X or Microvascular Angina. Typical exertional or stress-induced angina occurring in the absence of angiograghically documented epicardial coronary artery disease is defined as syndrome X.

CHAOS. Coronary artery disease, hypertension, atherosclerosis, obesity, and stroke).

From:- Stein Internal Medicine -4th ed.[1994] on Stat Ref! on CD ROM

 "Insulin resistance syndrome(syndrome X, CHAOS). Investigators have speculated that the well-known association of hyperglycemia, hyperinsulinemia, dyslipidemia and hypertension, which lead to coronary artery disease and stroke, may result from a genetic defect producing insulin resistance, particularly when obesity aggravates the degree of insulin resistance."

From:- Current Medical Diagnosis & Treatment 38th Ed [1997] on StatRef! on CD ROM

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