2001 – Page 6 – American ME and CFS Society

Familial corticosteroid-binding globulin deficiency due to a novel null mutation: association with fatigue and relative hypotension

Abstract:

Corticosteroid-binding globulin is a 383-amino acid glycoprotein that serves a hormone transport role and may have functions related to the stress response and inflammation. We describe a 39-member Italian-Australian family with a novel complete loss of function (null) mutation of the corticosteroid-binding globulin gene. A second, previously described, mutation (Lyon) segregated independently in the same kindred. The novel exon 2 mutation led to a premature termination codon corresponding to residue -12 of the procorticosteroid-binding globulin molecule (c.121G–>A).

Among 32 family members there were 3 null homozygotes, 19 null heterozygotes, 2 compound heterozygotes, 3 Lyon heterozygotes, and 5 individuals without corticosteroid-binding globulin mutations. Plasma immunoreactive corticosteroid-binding globulin was undetectable in null homozygotes, and mean corticosteroid-binding globulin levels were reduced by approximately 50% at 18.7 +/- 1.3 microg/ml (reference range, 30-52 microg/ml) in null heterozygotes. Morning total plasma cortisol levels were less than 1.8 microg/dl in homozygotes and were positively correlated to the plasma corticosteroid-binding globulin level in heterozygotes. Homozygotes and heterozygote null mutation subjects had a high prevalence of hypotension and fatigue.

Among 19 adults with the null mutation, the systolic blood pressure z-score was 12.1 +/- 3.5; 11 of 19 subjects (54%) had a systolic blood pressure below the third percentile. The mean diastolic blood pressure z-score was 18.1 +/- 3.4; 8 of 19 subjects (42%) had a diastolic blood pressure z-score below 10.

Idiopathic chronic fatigue was present in 12 of 14 adult null heterozygote subjects (86%) and in 2 of 3 null homozygotes. Five cases met the Centers for Disease Control criteria for chronic fatigue syndrome. Fatigue questionnaires revealed scores of 25.1 +/- 2.5 in 18 adults with the mutation vs. 4.2 +/- 1.5 in 23 healthy controls (P < 0.0001).

Compound heterozygosity for both mutations resulted in plasma cortisol levels comparable to those in null homozygotes. Abnormal corticosteroid-binding globulin concentrations or binding affinity may lead to the misdiagnosis of isolated ACTH deficiency. The mechanism of the association between fatigue and relative hypotension is not established by these studies. As idiopathic fatigue disorders are associated with relatively low plasma cortisol, abnormalities of corticosteroid-binding globulin may be pathogenic.

Source: Torpy DJ, Bachmann AW, Grice JE, Fitzgerald SP, Phillips PJ, Whitworth JA, Jackson RV. Familial corticosteroid-binding globulin deficiency due to a novel null mutation: association with fatigue and relative hypotension. J Clin Endocrinol Metab. 2001 Aug;86(8):3692-700. http://www.ncbi.nlm.nih.gov/pubmed/11502797

Hypothalamo-pituitary-adrenal axis dysfunction in chronic fatigue syndrome, and the effects of low-dose hydrocortisone therapy

Abstract:

These neuroendocrine studies were part of a series of studies testing the hypotheses that 1) there may be reduced activity of the hypothalamic-pituitary-adrenal axis in chronic fatigue syndrome and 2) low-dose augmentation with hydrocortisone therapy would improve the core symptoms.

We measured ACTH and cortisol responses to human CRH, the insulin stress test, and D-fenfluramine in 37 medication-free patients with CDC-defined chronic fatigue syndrome but no comorbid psychiatric disorders and 28 healthy controls. We also measured 24-h urinary free cortisol in both groups. All patients (n = 37) had a pituitary challenge test (human CRH) and a hypothalamic challenge test [either the insulin stress test (n = 16) or D-fenfluramine (n = 21)].

Baseline cortisol concentrations were significantly raised in the chronic fatigue syndrome group for the human CRH test only. Baseline ACTH concentrations did not differ between groups for any test. ACTH responses to human CRH, the insulin stress test, and D- fenfluramine were similar for patient and control groups. Cortisol responses to the insulin stress test did not differ between groups, but there was a trend for cortisol responses both to human CRH and D-fenfluramine to be lower in the chronic fatigue syndrome group. These differences were significant when ACTH responses were controlled. Urinary free cortisol levels were lower in the chronic fatigue syndrome group compared with the healthy group.

These results indicate that ACTH responses to pituitary and hypothalamic challenges are intact in chronic fatigue syndrome and do not support previous findings of reduced central responses in hypothalamic-pituitary-adrenal axis function or the hypothesis of abnormal CRH secretion in chronic fatigue syndrome. These data further suggest that the hypocortisolism found in chronic fatigue syndrome may be secondary to reduced adrenal gland output.

Thirty-two patients were treated with a low-dose hydrocortisone regime in a double-blind, placebo-controlled cross-over design, with 28 days on each treatment. They underwent repeated 24-h urinary free cortisol collections, a human CRH test, and an insulin stress test after both active and placebo arms of treatment. Looking at all subjects, 24-h urinary free cortisol was higher after active compared with placebo treatments, but 0900-h cortisol levels and the ACTH and cortisol responses to human CRH and the insulin stress test did not differ.

However, a differential effect was seen in those patients who responded to active treatment (defined as a reduction in fatigue score to the median population level or less). In this group, there was a significant increase in the cortisol response to human CRH, which reversed the previously observed blunted responses seen in these patients.

We conclude that the improvement in fatigue seen in some patients with chronic fatigue syndrome during hydrocortisone treatment is accompanied by a reversal of the blunted cortisol responses to human CRH.

Source: Cleare AJ, Miell J, Heap E, Sookdeo S, Young L, Malhi GS, O’Keane V. Hypothalamo-pituitary-adrenal axis dysfunction in chronic fatigue syndrome, and the effects of low-dose hydrocortisone therapy. J Clin Endocrinol Metab. 2001 Aug;86(8):3545-54. http://www.ncbi.nlm.nih.gov/pubmed/11502777

Autoantibodies to a 68/48 kDa protein in chronic fatigue syndrome and primary fibromyalgia: a possible marker for hypersomnia and cognitive disorders

Abstract:

OBJECTIVE: To identify antinuclear antibodies (ANA) specific for chronic fatigue syndrome (CFS), and in related conditions such as fibromyalgia (FM) or psychiatric disorders.

METHODS: One hundred and fourteen CFS patients and 125 primary and secondary FM patients were selected based on criteria advocated by the Centers for Disease Control and Prevention and by the American College of Rheumatology, respectively. As controls, healthy subjects and patients with either various psychiatric disorders or diffuse connective tissue diseases were included. Autoantibodies were examined by immunoblot utilizing HeLa cell extracts as the antigen.

RESULTS: Autoantibodies to a 68/48 kDa protein were present in 13.2 and 15.6% of patients with CFS and primary FM, respectively. In addition, autoantibodies to a 45 kDa protein were found in 37.1 and 21.6% of the patients with secondary FM and psychiatric disorders, respectively. Meanwhile, these two autoantibodies were not found at all in connective tissue disease patients without FM, nor in healthy subjects (P<0.05). As a group, the anti-68/48 kDa-positive CFS patients presented more frequently with hypersomnia (P<0.005), short-term amnesia (P<0.07) or difficulty in concentration (P<0.05) than those CFS patients without the antibodies.

CONCLUSIONS: The presence of the anti-68/48 kDa protein antibodies in a portion of both CFS and primary FM patients suggests the existence of a common immunological background. These antibodies may find utility as possible markers for a clinicoserological subset of CFS/FM patients with hypersomnia and cognitive complaints.

Source: Nishikai M, Tomomatsu S, Hankins RW, Takagi S, Miyachi K, Kosaka S, Akiya K. Autoantibodies to a 68/48 kDa protein in chronic fatigue syndrome and primary fibromyalgia: a possible marker for hypersomnia and cognitive disorders. Rheumatology (Oxford). 2001 Jul;40(7):806-10. http://rheumatology.oxfordjournals.org/content/40/7/806.long (Full article)

Serum concentrations of some metals and steroids in patients with chronic fatigue syndrome with reference to neurological and cognitive abnormalities

Abstract:

Chronic fatigue syndrome is defined by the Atlanta Centers for Disease Control (Atlanta, GA, USA) as debilitating fatigue lasting for longer than 6 months. Symptoms include disturbances of cognition. Certain factors have in the past been shown to influence cognition, including metals such as aluminum, iron, and zinc; and steroids such as dehydroepiandrosterone.

In the present study, concentrations of these factors were determined in the serum and plasma of patients and their age- and gender-matched healthy controls (10 women and 5 men in each group). In addition, copper, dehydroepiandrosterone sulphate, cortisol, cholesterol, hemoglobin, ferritin and transferrin concentrations, as well as transferrin genetic subtypes were determined in both groups.

The results indicate that patients had significantly increased serum aluminum and decreased iron compared to controls. In the females, serum iron and dehydroepiandrosterone sulphate were significantly decreased and correlated. Total cholesterol was significantly increased, and significantly negatively correlated with dehydroepiandrosterone sulphate. There were no differences in zinc, copper, cortisol, hemoglobin, transferrin and ferritin concentrations, or in transferrin genetic subtypes.

Source: van Rensburg SJ, Potocnik FC, Kiss T, Hugo F, van Zijl P, Mansvelt E, Carstens ME, Theodorou P, Hurly PR, Emsley RA, Taljaard JJ. Serum concentrations of some metals and steroids in patients with chronic fatigue syndrome with reference to neurological and cognitive abnormalities. Brain Res Bull. 2001 May 15;55(2):319-25. http://www.ncbi.nlm.nih.gov/pubmed/11470334

Frequency of attendance in general practice and symptoms before development of chronic fatigue syndrome: a case-control study

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) research has concentrated on infective, immunological, and psychological causes. Illness behaviour has received less attention, with most research studying CFS patients after diagnosis. Our previous study on the records of an insurance company showed a highly significant increase in illness reporting before development of CFS.

AIM: To investigate the number and type of general practitioner (GP) consultations by patients with CFS for 15 years before they develop their condition.

DESIGN OF STUDY: Case-control study in 11 general practices in Devon.

SETTING: Forty-nine patients with CFS (satisfying the Centers for Disease Control criteria), 49 age, sex, and general practice matched controls, and 37 patients with multiple sclerosis (MS) were identified from the general practices’ computerised databases.

METHOD: The number of general practice consultations and symptoms recorded in three five-year periods (quinquennia) were counted before development of the patients’ condition.

RESULTS: The median number of consultations was significantly higher for CFS patients than that of matched controls in each of the quinquennia: ratios for first quinquennium = 1.88, P = 0.01; second quinquennium = 1.70, P = 0.005; last quinquennium = 2.25, P < 0.001. More CFS patients than controls attended for 13 of the 18 symptoms studied. Significant increases were found for upper respiratory tract infection (P < 0.001), lethargy (P < 0.001), and vertigo (P = 0.02). Similar results were found for CFS patients when compared with MS.

CONCLUSIONS: CFS patients consulted their GP more frequently in the 15 years before development of their condition, for a wide variety of complaints. Several possibilities may explain these findings. The results support the hypothesis that behavioural factors have a role in the aetiology of CFS.

Comment in:

Chronic fatigue syndrome. [Br J Gen Pract. 2001]

Source: Hamilton WT, Hall GH, Round AP. Frequency of attendance in general practice and symptoms before development of chronic fatigue syndrome: a case-control study. Br J Gen Pract. 2001 Jul;51(468):553-8. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1314047/ (Full article)

Chronic fatigue syndrome: neurological findings may be related to blood–brain barrier permeability

Abstract:

Despite volumes of international research, the etiology of chronic fatigue syndrome (CFS) remains elusive. There is, however, considerable evidence that CFS is a disorder involving the central nervous system (CNS).

It is our hypothesis that altered permeability of the blood-brain barrier (BBB) may contribute to ongoing signs and symptoms found in CFS. To support this hypothesis we have examined agents that can increase the blood-brain barrier permeability (BBBP) and those that may be involved in CFS.

The factors which can compromise the normal BBBP in CFS include viruses, cytokines, 5-hydroxytryptamine, peroxynitrite, nitric oxide, stress, glutathione depletion, essential fatty acid deficiency, and N-methyl-D-aspartate overactivity. It is possible that breakdown of normal BBBP leads to CNS cellular dysfunction and disruptions of neuronal transmission in CFS. Abnormal changes in BBBP have been linked to a number of disorders involving the CNS; based on review of the literature we conclude that the BBB integrity in CFS warrants investigation.

Source: Bested AC, Saunders PR, Logan AC. Chronic fatigue syndrome: neurological findings may be related to blood–brain barrier permeability. Med Hypotheses. 2001 Aug;57(2):231-7. http://www.ncbi.nlm.nih.gov/pubmed/11461179

Common etiology of posttraumatic stress disorder, fibromyalgia, chronic fatigue syndrome and multiple chemical sensitivity via elevated nitric oxide/peroxynitrite

Abstract:

Three types of overlap occur among the disease states chronic fatigue syndrome (CFS), fibromyalgia (FM), multiple chemical sensitivity (MCS) and posttraumatic stress disorder (PTSD). They share common symptoms. Many patients meet the criteria for diagnosis for two or more of these disorders and each disorder appears to be often induced by a relatively short-term stress which is followed by a chronic pathology, suggesting that the stress may act by inducing a self-perpetuating vicious cycle. Such a vicious cycle mechanism has been proposed to explain the etiology of CFS and MCS, based on elevated levels of nitric oxide and its potent oxidant product, peroxynitrite.

Six positive feedback loops were proposed to act such that when peroxynitrite levels are elevated, they may remain elevated. The biochemistry involved is not highly tissue-specific, so that variation in symptoms may be explained by a variation in nitric oxide/peroxynitrite tissue distribution. The evidence for the same biochemical mechanism in the etiology of PTSD and FM is discussed here, and while less extensive than in the case of CFS and MCS, it is nevertheless suggestive. Evidence supporting the role of elevated nitric oxide/peroxynitrite in these four disease states is summarized, including induction of nitric oxide by common apparent inducers of these disease states, markers of elevated nitric oxide/peroxynitrite in patients and evidence for an inductive role of elevated nitric oxide in animal models.

This theory appears to be the first to provide a mechanistic explanation for the multiple overlaps of these disease states and it also explains the origin of many of their common symptoms and similarity to both Gulf War syndrome and chronic sequelae of carbon monoxide toxicity. This theory suggests multiple studies that should be performed to further test this proposed mechanism. If this mechanism proves central to the etiology of these four conditions, it may also be involved in other conditions of currently obscure etiology and criteria are suggested for identifying such conditions.

Comment in: Nitric oxide and the etiology of chronic fatigue syndrome: giving credit where credit is due. [Med Hypotheses. 2005]

Source: Pall ML. Common etiology of posttraumatic stress disorder, fibromyalgia, chronic fatigue syndrome and multiple chemical sensitivity via elevated nitric oxide/peroxynitrite. Med Hypotheses. 2001 Aug;57(2):139-45. http://www.ncbi.nlm.nih.gov/pubmed/11461161

Chronic fatigue in general practice

Comment on: Chronic fatigue in general practice: is counselling as good as cognitive behaviour therapy? A UK randomised trial. [Br J Gen Pract. 2001]

Ridsdale and colleagues are to be congratulated on performing a randomised controlled trial of different treatments for chronic fatigue. However, their data do not substantiate their conclusions.

The trial was set up to demonstrate that cognitive behavioural therapy was better than counselling for patients seen in general practice with fatigue symptoms. No difference in the main outcome measures was found between the intervention and control groups. This has been interpreted as showing that the two treatments are equivalent. The sample size required for, and analysis of, equivalence studies are different than those required for trials designed to show differences,2 not least the requirement that equivalence be defined before the trial starts. This trial was not designed to show equivalence. Thus, although the results for the main outcome measures are similar they should not be reported as being equivalent. Without a definition of equivalence, calculating the study’s power to show equivalence is not possible. Also, part of the conclusions depend on a sub-group analysis which, while acknowledged as being underpowered, is given more weight than is justified. If equivalence is defined as six points on the fatigue score then, in this subgroup, the trial only has a power of 36% to show equivalence based on a 95% confidence interval. With a more conservative definition of equivalence even the main study lacks power.

You can read the rest of this comment here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1313987/pdf/11458490.pdf

Source: Underwood M, Eldridge S. Chronic fatigue in general practice. Br J Gen Pract. 2001 Apr;51(465):317-8. http://www.ncbi.nlm.nih.gov/pubmed/11458490

Cognitive behaviour therapy and chronic fatigue syndrome

Comment on: Chronic fatigue in general practice: is counselling as good as cognitive behaviour therapy? A UK randomised trial. [Br J Gen Pract. 2001]

Ridsdale and colleagues state that there is evidence that cognitive behaviour therapy (CBT) is effective for patients with chronic fatigue syndrome (CFS), but fail to point out that such evidence derives only from studies performed in the United Kingdom, where CFS is diagnosed on the basis of the Oxford criteria. There is no evidence that CBT is beneficial to patients fulfilling the Australian criteria for CFS or the American ones, namely, the original criteria of the Centers for Disease Control.

You can read the rest of this comment here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1313986/pdf/11458489.pdf

Source: Baschetti R. Cognitive behaviour therapy and chronic fatigue syndrome. Br J Gen Pract. 2001 Apr;51(465):316-7. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1313986/ (Full comment)

Plasma leptin in chronic fatigue syndrome and a placebo-controlled study of the effects of low-dose hydrocortisone on leptin secretion

Abstract:

OBJECTIVE: Previous studies have suggested that chronic fatigue syndrome (CFS) is associated with changes in appetite and weight, and also with mild hypocortisolism. Because both of these features may be related to leptin metabolism, we undertook a study of leptin in CFS.

DESIGN: (i) A comparison of morning leptin concentration in patients with CFS and controls and (ii) a randomized, placebo-controlled crossover study of the effects of hydrocortisone on leptin levels in CFS.

PATIENTS: Thirty-two medication free patients with CFS but not comorbid depression or anxiety. Thirty-two age, gender, weight, body mass index and menstrual cycle matched volunteer subjects acted as controls.

MEASUREMENTS: We measured basal 0900 h plasma leptin levels in patients and controls. All 32 patients were taking part in a randomized, placebo-controlled crossover trial of low dose (5 or 10 mg) hydrocortisone as a potential therapy for CFS. We measured plasma leptin after 28 days treatment with hydrocortisone and after 28 days treatment with placebo.

RESULTS: At baseline, there was no significant difference in plasma leptin between patients [mean 13.8, median 7.4, interquartile range (IQR) 18.0 ng/ml] and controls (mean 10.2, median 5.5, IQR 11.3 ng/ml). Hydrocortisone treatment, for both doses combined, caused a significant increase in leptin levels compared to placebo. When the two doses were analysed separately, only 10 mg was associated with a significant effect on leptin levels. We also compared the hydrocortisone induced increase in leptin between those who were deemed treatment-responders and those deemed nonresponders. Responders showed a significantly greater hydrocortisone-induced rise in leptin than nonresponders. This association between a clinical response to hydrocortisone and a greater rise in leptin levels may indicate a greater biological effect of hydrocortisone in these subjects, perhaps due to increased glucocorticoid receptor sensitivity, which may be present in some patients with CFS.

CONCLUSIONS: We conclude that, while we found no evidence of alterations in leptin levels in CFS, low dose hydrocortisone therapy caused increases in plasma leptin levels, with this biological response being more marked in those CFS subjects who showed a positive therapeutic response to hydrocortisone therapy. Increases in plasma leptin levels following low dose hydrocortisone therapy may be a marker of pretreatment physiological hypocortisolism and of response to therapy.

Source: Cleare AJ, O’Keane V, Miell J. Plasma leptin in chronic fatigue syndrome and a placebo-controlled study of the effects of low-dose hydrocortisone on leptin secretion. Clin Endocrinol (Oxf). 2001 Jul;55(1):113-9. http://www.ncbi.nlm.nih.gov/pubmed/11453960