2005 ME/CFS Research Forum

ME/CFS RESEARCH FORUM REPORT:
Adelaide Research Network 3 - 4 June 2005
UNIVERSITY OF ADELAIDE

Convenor: Alison Hunter Memorial Foundation

Richard Burnet MBChB FRACP
Senior Endocrinologist
Department of Endocrinology and Metabolism
Royal Adelaide Hosptial Adelaide

Oral presentations

Delayed gastric emptying in Chronic Fatigue Syndrome

Dr Burnet presented his ongoing research with particular reference to to his paper:
"Gastro-intestinal symptoms and gastric emptying studies in Chronic Fatigue Syndrome"
Presented at the International Clinical and Scientific Meeting 2001 Sydney  "ME/CFS:The Medical Practitioners Challenge...informed accurate diagnosis..."

Introduction

Patients with Chronic Fatigue Syndrome (CFS) have many gastro-intestinal (G) symptoms. The commonest of these upper GI symptoms include fullness and bloating after a meal, abdominal distension, nausea, and loss of appetite. Lower GI symptoms include intermittent diarrhoea alternating with constipation, non specific abdominal pain. All of these gut symptoms have usually all been lumped under the umbrella of ‘irritable bowel’. These symptoms can reflect a disturbance in gut motility.

The control of gut motility and gastric emptying is complex, multifactorial and occurs at many differing levels from the gut to the brain. During fasting, human gastric and intestinal motor activity is cyclical. Periods of contractile activity alternate with quiescence. Feeding markedly alters motor activity. After a solid meal antral contractions take place in the stomach, which play an important part in the grinding and propulsion of solid particles. Liquids are emptied primarily by increased intragastric pressure generated by the proximal stomach.

The control of gastric emptying is exerted by electromechanical factors, neurohormonal feedback and at the brain. Disordered mechanisms at any of these points may cause gastric stasis and symptoms. The electrophysiological control at a cellular level is derived from the intrinsic contractile responsiveness of smooth muscle. Neural feedback of gastric emptying is exerted through nerve reflex arcs. Interruption of vagal control may account in part for the post-vagotomy syndrome. Diabetic neuropathy is presumed to be caused in part by interruption of these reflex arcs.

Intestinal hormones, the release of which are triggered by receptors sensitive to acid, osmolality and to the nutrient content of the meal, also control gastric emptying. These include gastric inhibitory polypeptide, cholecystokinin, neurotensin and enteroglucagon. Brain centres are also involved in the regulation of gastric emptying. Emotions such as anxiety or stress retards gastric emptying.

Many reasons have been ascribed to the causation of these symptoms from a disordered diet with either too much carbohydrate, to the wrong carbohydrate, to infestation of the bowel with Candida, bacterial overgrowth, parasites or the presence of toxins. No sustainable proof has been offered for any of these hypotheses to account for all patients with similar symptoms. This paper is an analysis of gut symptoms in patients with CFS and a sub group who had gastric emptying studies for gut symptoms.

Methods

Symptoms Assessment
A standardised questionnaire of GI symptoms was used. Symptoms were divided into upper GI tract of oesophageal: dysphagia, heart burn, acid regurgitation, gastric: anorexia, nausea, early satiety, bloating, abdominal distension. Symptoms which reflect large bowel dysfunction include: frequency of bowel actions, consistency of stools, presence or absence of diarrhoea, intermittent abdominal  pain.

Upper GI symptoms were scored. 0 = none, 1 = mild (symptom could be ignored if patient did not think about it), 2 = moderate (symptom could not be ignored, but did not influence daily activities), 3 = severe, (symptom influenced daily activities).

Gastric Emptying Studies: Measurement of Gastric Emptying

Details of this double isotope test have been previously published.1 The solid meal consisted of 100g of cooked ground beef containing 1–1.5 mCi of in vivo labelled 99mTc-sulfur colloid-chicken liver, and the liquid meal consisted of 150ml of 10% dextrose in water labelled with 0.75–1.0 mCi of 113mIn-Diethylenetriaminepentaacetic acid. The test was performed at 10am (after the patient had fasted from solids from 7pm and from liquids from 12 midnight the previous day. The study was performed in the sitting position with the scintillation camera behind the patient. The patient initially ate the solid meal and then drank the glucose solution. Each study was continued for at least 2 hours. Any medication was discontinued for 24 hours prior to each study.

The normal ranges previously established for this investigation2 were used in this study. For oesophageal emptying the time taken for 95% of the solid bolus to empty from the oesophagus is 7 to 93 seconds. For solids after ingestion of the standard test meal the lag period for food to enter the duodenum is 5 to 65 minutes. The amount of solid food remaining given as a percentage at 100 minutes is 4 to 61%. For liquids a 50% emptying time is 6 to 31 minutes.

Patients: Symptoms

A self-selected group of patients with CFS were given the gut symptom questionnaire either at a local level or over the internet. A discriminating question of the effects of alcohol was used. Those who could tolerate alcohol were removed from the analysis.

A subgroup of patients with gastric symptoms undertook gastric emptying studies. Patients presenting with fatigue as the primary symptom were seen in a dedicated clinic by one physician. All patients with CFS who fulfilled the Fukuda criteria2 and suffered from upper gastrointestinal symptoms of post-prandial fullness, easy satiety, bloating, nausea, or vomiting. Patients who presented with fatigue who did not have gut symptoms but did meet the CFS criteria were also invited to have gastric emptying studies.

The severity of CFS is self-assessed by asking the patient to estimate the percentage reduction in daily living activities compared to their peers. Patients with any other acute, chronic or inter-current medical or psychiatric condition, history of rapid weight change of 5kgs, low BMI, prolonged bed rest, or were taking diuretics of any type, drugs affecting gastric emptying, purgatives, ACE inhibitors, digoxin, and any mineral or vitamin supplement containing potassium, or 'natural' therapies where the constituents were not listed were excluded.

In the sub group who had gastric emptying studies, a morning venous blood sample was obtained and assayed by standard methods for serum sodium, potassium, bicarbonate, calculated osmolality, urea, creatinine, glucose, urate, phosphate, total calcium, ionised calcium, albumin, globulin, total protein, total bilirubin GGT, ALP, ALT, AST, LD, serum magnesium, a complete blood picture, TSH, random cortisol, and anti-nuclear factor, testosterone, DHEAS, B12 and folate, endomysial antibodies, to assess common chronic metabolic causes of fatigue.

Results

The subject who completed the gut questionnaire can be seen in Table 1. 75% of the group were women. There was a mean increase in weight of the CFS group over controls by 11.5kg. The percentage frequency of the specific symptoms are listed in Table 2. Abdominal discomfort and fullness after a small meal occurred in over 80% of CFS subjects, which was present in controls in 35%.

Lower gastrointestinal symptoms are seen in Table 3. The lower bowel is several dysfunctional in CFS with 60% having loose stools and a previously unrecognised symptom of nocturnal diarrhoea reported in one third of subjects. This symptom was not recorded in any of the controls.

Table 1. Characteristics of self-selected CFS subjects completing gut questionnaire
  CFS Controls
N. 183 56
Sex F 138, M 45 F 48, M 8
Age yrs 43.3 ± 13.9 39.8 ± 13.5
Weight kg 86.3 ± 18.5 74.8 ± 27.8
Duration yrs 10.6 ± 7.8  
Severity, % reduction 67.1 ± 21.6  
Smoke % 13.6 17.8


Table 2. Percentage frequency of upper gastric symptoms
  CFS % Controls %
Gastric    
Abdominal discomfort 86 46
Fullness after small meal 78 31
Nausea 76 15
Abdominal pain 73 27
Loss of appetite 58 12
Vomiting 23 4
Oesophageal    
Acid regurgitation 58 38
Heart burn 55 38
Swallowing difficulty 43 12


Table 3. Large bowel symptoms, CFS subjects and controls
Symptoms CFS Controls
BM's/day (mean) 2.5 1.2
Constipation % 20 30
Consistency: Formed % 15 80

Loose %

60 20

Watery %

25 0
Nocturnal diarrhoea % 36 0
Faecal Urgency % 22 16

Gastric emptying studies

A subset of 26 upper G-I symptomatic CFS patients and 6 asymptomatic CFS patients undertook gastric emptying studies. There is a difference in the duration of Chronic Fatigue Syndrome 6.5±4.9 years vs. 5.4±3.7 and estimated severity of CFS 75% vs. 54% between those with and those without symptoms.

The gastric emptying results showed a marked reduction in the emptying of the liquid phase mean 43.7±13.2 (R 6–31 minutes). In the solid phase % remaining at 100 minutes the mean 63.3±13.5 (4–61%) is above the normal range. There is also a marked difference between those with and without symptoms. Those who do not have gastric symptoms having all their values within the normal range.

The individual results for oesophageal emptying are seen in Fig 1. In which 25% of subjects had a delay in emptying. The solid emptying phase is in Fig 2 and there, 50% of subjects had a delay. The liquid phase in Fig 3 with 90% having a delay outside the normal range. In all instances those without G-I symptoms had results in the normal range

Fig 1. Oesophageal emptying time in CFS. Upper G-I symptoms vs those without symptoms.
Figure 1

Fig 2. Solid gastric emptying phase in CFS. Upper G-I symptoms vs those without symptoms.
Figure 2

Fig 3. Liquid gastric emptying phase in CFS. Upper G-I symptoms vs those without symptoms.
Figure 3

Discussion

G-I symptoms are common in patients with CFS. They have never previously been properly analysed. Although this was a small, self-selected sample it gives some idea of the extent of the problem. The patients with symptoms have considerable distress related to their dysfunctional gut. They take numerous differing types of medication to try and relieve the symptoms but usually with little effect. Nocturnal diarrhoea is particularly distressing as it further disrupts an already disturbed sleep pattern. Abdominal pain is considered the most distressing of the symptoms often requiring potent analgesia for relief. The usual explanation for the gut problem is ‘irritable bowel’ and unless specific questions are put to the CFS patient they will not spontaneously discuss these symptoms.

Although this is an observational study utilizing the well-established normal range of the investigation it highlights the presence of gut abnormalities in patients with CFS which have not been previously described. An abnormality in oesophageal, solid or liquid emptying or combinations or these study parameters was found in all patients. There are many known potential causes for abnormal gastric emptying but patients with either other medical illnesses or medications affecting the rate of gastric emptying were excluding from the study.

The major abnormality shown is a delay in the emptying of the liquid phase in 91% of the patients. This is the reversal seen in the other studies of gastric emptying in the group with the well recognised disorder of gastric emptying in diabetic subjects3. There the primary abnormality is a delay in the solid phase of gastric emptying. It has previously been presumed that the abnormality in diabetics was a disorder of autonomic function but latter studies tend to believe that the main disorder is due to fluctuations in blood glucose control. In the elderly there are disorders of gastric emptying and again most of the previous investigations show that the main problem is with solid rather than with liquid emptying a study4 in a group of elderly with a number of neurological defects there is a delay in the liquid rather than the solid phase.

Symptoms and delayed gastric emptying in other studies have not well correlated. There is in this study a good correlation with symptoms. The commonest of these was early satiety, fullness and bloating after eating. There was though a poor correlation with oesophageal symptoms and a disorder of oesophageal emptying.

The significance of these observations indicates that there is an organic basis for the upper gut symptoms in CFS. Although no cause for these findings is apparent in this study, in view of the increased delay in liquid emptying rather than solids it may point to a central rather than a peripheral aetiology. Further studies are needed to confirm these findings. The rest of the gastro-intestinal tract and function should be properly and scientifically investigated and the symptoms not necessarily be ascribed to irritable bowel syndrome.

Dietary advice to improving gastric emptying function with emphasis on small frequent solid meals, reducing fluid intake at the time of eating, and ensuring adequate nutritional needs are met. Fad diets and elimination diets do not appear to have any place in the dietary management of CFS patients.

References

  1. Horowitz M. Harding P.E. Maddox A.F. Wishart J.M. Akkermans L.M. Chatterton B.E. et at Gastric and oesophageal emptying in patients with type 2 diabetes mellitus. Diabetologicia 1989; 32: 151–159.
  2. Fukuda K. Straus S.E. Hickie I Sharpe M.C. Dobbins J.E. Komaroff A. The chronic fatigue syndrome: a comprehensive approach to its definition and study. Ann. Intern. Med. 1994; 121: 953–959.
  3. Horowitz M. Wishart J.M. Jones K. L. Hebbard G.S. Gastric Emptying in Diabetes: an Overview. Diabetic Medicine 1996; 13:S16–S22.
  4. Andrews J.M. Horowitz M. Gastric Function in the Elderly. Clinical Geriatrics 1996; 4: 21–43.

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