Various Disease States and Ghrelin
Ghrelin and Cushings Syndrome:
Ghrelin levels have been found to be low correlating with fat mass in Cushing’s patients . Five patients with Cushing's syndrome were compared to 8 lean controls who ingested 30 mg prednisolone for 5 days. Cushing's syndrome patients had a low Ghrelin level which increased post pituitary surgery associated with reduction in BMI. In the healthy controls, prednisolone treatment reduced Ghrelin levels by 18% (too short to assess weight gain; calorie intake?). Eur J Endocrinol. 2004 Jul;151(1):113-7. Ghrelin though unlikely to be the driving force for obesity in Cushing's, is still likely to be dysregulated by hypercortisolism in the long term? Ghrelin stimulated GH release has been shown to be significantly impaired in ten patients with active Cushing's disease, while Ghrelin's effect on ACTH release is exaggerated with higher cortisol responses compared to 10 age and sex matched controls. Neuroendocrinology. 2002 Dec;76(6):390-6
Ghrelin and Hypogonadism:
The testis has Ghrelin receptors and also produces Ghrelin. Ghrelin levels in hypogonadal men are lower when compared with weight-matched eugonadal men. Testosterone replacement restores Ghrelin levels in hypogonadal men. J Clin Endocrinol Metab. 2003 Sep;88(9):4139-43 The effect of androgens on Ghrelin may be through peptide synthesis regulation or through leptin which has been shown to decrease after therapy with testosterone. J Clin Endocrinol Metab 82:2510–2513
Ghrelin and Prader-Willi Syndrome
Prader-Willi syndrome (PWS) is a genetic disorder characterized by mild mental retardation, short stature, abnormal body composition, muscular hypotonia and distinctive behavioural features and associated with increased cardiovascular mortality. PWS arises from a lack of expression of paternally inherited imprinted genes on chromosome 15q11-q13. Patients with Prader-Willi syndrome (PWS) are hyperphagic and obese. While Leptin levels are high in keeping with the increased BMI of these patients, Growth Horm IGF Res. 2003 Dec;13(6):322-7 Ghrelin levels tend to be very high (3-4 fold higher levels than normals). J Clin Endocrinol Metab. 2002 Dec;87(12):5461-4. Growth hormone deficiency is common in PWS despite a characteristically high Ghrelin levels in this disease group. Despite this high Ghrelin levels, gastric emptying in prader-willi syndrome is not hastened. J Clin Endocrinol Metab. 2005 Jun;90(6):3367-70 A Ghrelin resistance at the hypothalamic level is possible due to a local defect. Horm Res. 2004;62(1):49-54. The Ghrelin levels in PWS patients tends to be non-suppressed by food, although food-induced suppression is preserved in the earlier stages of PWS. Horm Metab Res. 2004 Mar;36(3):164-9. despite higher levels of Ghrelin in the fasted state, J Clin Endocrinol Metab. 2003 Jan;88(1):174-8. suggesting a progressive dysregulation of Ghrelin with time. Interestingly, Ghrelin suppression with somatostatin did not reduce appetite J Clin Endocrinol Metab. 2004 Aug;89(8):4162-5. although suppression of other anorexigenic hormones by somatostatin might have confused issues.
Ghrelin and PCOS:
Women with the polycystic ovary syndrome (PCOS) have even lower Ghrelin levels than predicted by their obese phenotype. J Clin Endocrinol Metab 87:5625–5629 Ghrelin levels in this population have been shown to negatively correlate with androgen levels. Treatment with anti androgens increases Ghrelin levels in PCOS, independent of changes in BMI/fat and insulin sensitivity.
Ghrelin and Thyrotoxicosis:
Circulating Ghrelin levels were measured in nine hyperthyroid patients before and after medical treatment and compared with those in eight healthy control subjects. All participants were studied in the postabsorptive state and during a 3-h euglycemic hyperinsulinemic clamp. Before treatment the patients had 3- to 5-fold elevations of T (3), and during treatment the patients gained 5 kg of body weight. Ghrelin levels were decreased in hyperthyroidism both in the fasting state (hyperthyroid, 1080 +/- 195 pg/ml; euthyroid, 1480 +/- 215 pg/ml; P = 0.03) and during clamp (hyperthyroid, 833 +/- 150 pg/ml; euthyroid, 1210 +/- 180 pg/m; P = 0.02). After treatment, Ghrelin levels did not differ from those in control subjects. In all three study groups the clamp significantly reduced Ghrelin levels compared with fasting levels. J Clin Endocrinol Metab. 2003 Feb;88(2):853-7 In conclusion, Ghrelin levels are reduced in hyperthyroidism and become normalized by medical antithyroid treatment. Hyperinsulinaemia suppresses Ghrelin regardless of thyroid status. Ghrelin is not a primary stimulator of appetite and food intake in hyperthyroidism, and the mechanisms underlying the suppressive effect of hyperthyroidism on Ghrelin secretion remain unclear.
P S: This is interesting, because you would expect Ghrelin to be high in thyrotoxicosis due to the lower fat mass or weight loss, but this is a contradiction of Ghrelin tracking fat mass. Or is it because there is more of lean body mass loss rather than fat? (Leptin was also low in thyrotoxic patients suggesting that thyroid hormones may override fat mass signals). Rat studies have shown similar effect of induced hypothyroidism and thyrotoxicosis on Ghrelin mRNA expression in stomach and in circulation. Is it worth studying the acute effects of T4 on Ghrelin in the short term during initiation of thyroxine treatment to assess rapidity for restoration of Ghrelin response to meals? Is it worth studying the response of Ghrelin to food intake in patients with hypothyroidism to assess for lack of suppression in this group?
Studying Motor neuron disease patients who have muscle wasting diseases could clarify this further? or in those with anabolic steroid administration and increase in muscle mass? Anabolic steroids increase muscle rather than fat and how does this correlate with Ghrelin rises? One would not expect Ghrelin suppression as it is the fat mass that provides feedback for Ghrelin secretion.
Ghrelin and Hypothyroidism
Hypothyroidism induced in adult male Sprague-Dawley resulted in an increase in gastric ghrelin mRNA levels with associated increase in circulating plasma Ghrelin levels. Eur J Endocrinol. 2002 Jul;147(1):159-63
Ghrelin and Anorexia nervosa.
In pathologically lean people with anorexia nervosa, Ghrelin levels are raised as the fat mass is low, and fails to suppress with food, suggesting chronic dysregulation resulting in lack of response to food induced responses. J Clin Endocrinol Metab. 2003 Apr;88(4):1678-82. Despite this high baseline levels of Ghrelin, suppression by food is preserved. Psychoneuroendocrinology. 2005 Jul;30(6):577-81. Weight gain in anorexia nervosa patients returns Ghrelin to normal levels. The Growth hormone response to Ghrelin is impaired in patients with anorexia nervosa, although stimulation of ACTH, Prolactin and insulin by exogenous Ghrelin is normal. Abnormalities of sex hormones and IGF1 are well recognised in anorexia nervosa . A 6 month study involving 78 women with anorexia nervosa demonstrated that administration of estrogen and recombinant IGF1 separately increased Ghrelin levels with no significant changes in weight, calorie intake or Growth Hormone levels. . J Clin Endocrinol Metab. 2004 Aug;89(8):3988-93. Does pathologically low fat mass on a chronic basis produce tertiary hyper-ghrelinaemia resulting in dysregulation?
Ghrelin levels are raised in bulimia nervosa patients despite normal BMI. In contrast to anorexic women, the growth hormone response as well as that of ACTH and Prolactin to Ghrelin is preserved in bulimia nervosa patients.
Cancer and Cardiac cachectic states are also associated with high Ghrelin levels suggesting Ghrelin resistance in these states. Circulation. 2001 Oct 23;104(17):2034-8. Ghrelin injected intracerebroventricularly has shown only modest effects on increasing food intake in anorexic rats with prostate cancer.Endocrinology. 2001 Aug;142(8):3292-301 The effects of exogenous Ghrelin in these scenarios await clarification.
Ghrelin and Cardiac Failure:
Ghrelin can inhibit apoptosis of cardiomyocytes and endothelial cells. J Cell Biol. 2002 Dec 23;159(6):1029-37 Ghrelin receptors have been shown to be increased within atherosclerotic coronary arteries. An endothelin antagonistic action of Ghrelin has been postulated, Br J Pharmacol. 2002 Aug;136(8):1146-52with vasodilation mediated via IGF-1 and probably partly through nitric oxide synthesis stimulation. Ghrelin infusion in healthy subjects decreases afterload and decreases blood pressure (reduction of MAP by -12 mmHg by 10mcg/kg Ghrelin). Am J Physiol Regul Integr Comp Physiol. 2001 May;280(5):R1483-7Blood pressure is reduced without reflex tachycardia. J Clin Endocrinol Metab. 2001 Dec;86(12):5854-9
Ghrelin infusion in rats with cardiac failure inhibited Left ventricular enlargement and increased LV fractional shortening. Circulation. 2001 Sep 18;104(12):1430-5. Administration of Ghrelin intravenously to 10 heart failure patients for 3 weeks improved left ventricular function, exercise capacity, and muscle wasting compared to 8 controls with heart failure. Circulation. 2004 Nov 29 The vasodilatory and sympathetic-inhibitory actions of Ghrelin resulting in lower plasma nor epinephrine levels might be responsible for these beneficial effects. Ghrelin (but not desacetyl Ghrelin or MK 0677) can be cardio-protective in rats following ischemic injury. Basic Res Cardiol. 2003 Nov;98(6):401-5.
Ghrelin and Pregnancy:
Ghrelin may have a role in the development of pregnancy induced hypertension. Patients with PIH have high levels of Ghrelin. Hypertension. 2002 Mar 1;39(3):781-4 Ghrelin may well play a counter regulatory role in this situation via its vasodilatory properties.
Ghrelin and Cystic fibrosis
Cystic fibrosis is a protein catabolic state with significant effects on carbohydrate metabolism and intestinal function. Ghrelin levels in these patients would be expected to be influenced by a combination of a hypercatabolic state, low fat mass, lower postprandial insulin levels, and intestinal function. Ghrelin status and regulation in cystic fibrosis patients has not been studied to date.
Cyproheptadine, a 5-HT(2) receptor antagonists has been shown to improve appetite in cystic fibrosis patients.Pediatr Pulmonol. 2004 Aug;38(2):129-34 The intrinsic anticholinergic property of cyproheptadine has been shown to produce a blunting effect on the GH response to Hexarelin, but not the latter's action on Prolactin and ACTH stimulation. J Endocrinol Invest. 1998 Nov;21(10):673-9. Ghrelin is an even more potent stimulator of GH release than hexarelin, with greater stimulatory effect on Prolactin and ACTH production. J Clin Endocrinol Metab. 2001 Mar;86(3):1169-74. Ghrelin secretion has been demonstrated to be under cholinergic control using cholinergic agonist as pyridostigmine and muscarinic antagonist as pirenzipine. J Clin Endocrinol Metab. 2004 May;89(5):2429-33. Cholinergic stimulation in that study resulted in increased Ghrelin while anticholinergic treatment decreased Ghrelin levels. Nonspecific cholinergic blockade with atropine in another study showed decreased Ghrelin release, and also decreased GH responses to Ghrelin. J Clin Endocrinol Metab. 2004 Sep;89(9):4729-33. Another study assessing the effect of cholinergic pathway on Ghrelin effects found that Ghrelin's endocrine effects, namely GH, PRL and ACTH releasing actions, were not modified by cholinergic agonists or antagonists( pirenzipine in this instance) Clin Endocrinol (Oxf). 2003 Jan;58(1):92-8. The effect of an agent with intrinsic anticholinergic activity and appetite increasing characteristics as cyproheptadine, on Ghrelin levels in patients with cystic fibrosis and low appetite levels would be interesting to assess. Assessment would have to target adult cystic fibrosis patients as Ghrelin levels in prepubertal lean healthy children, though similar to adult levels in the fasting state, do not suppress normally with food. J Clin Endocrinol Metab. 2004 Apr;89(4):1662-5.
Intestinal motility in cystic fibrosis patients has been shown to be slow Arch Dis Child 1999;80:149-152. which has been suggested to be a function of disordered gut hormonal secretion or regulation. Dig Dis Sci 1992;37:187-192. Intestinal motility has clinical significance while treating with pancreatic enzymes to improve fat malabsorption. Ghrelin has been shown to increase intestinal motility through cholinergic mechanisms in rats, with demonstration of Ghrelin receptors in the intestinal neuromuscular tissue of the rat. Regul Pept. 2004 Sep 15;121(1-3):25-30. While small intestinal transit is accelerated, Ghrelin has no effect on colonic motility. Gastric emptying has been shown to be high in patients with Cystic fibrosis J Pediatr Gastroenterol Nutr. 1997 Nov;25(5):492-8. although studies have been contradicting with variations based on isotope and food material/tablets used. Arch Dis Child. 1999 Feb;80(2):149-52. Ghrelin in fact, with its structural relation to motilin, has been shown to stimulate gastric emptying in a dose dependent manner. Regul Pept. 2004 Aug 15;120(1-3):23-32. Ghrelin also increases gastric acid secretion. Biochem Biophys Res Commun. 2000 Oct 5;276(3):905-8.
An insulin synthesis inhibiting action has been attributed to cyproheptadine. Toxicol Sci. 2004 Jun;79(2):258-65. Epub 2004 Mar 31. Ghrelin also decreases insulin levels with production of hyperglycaemia. Cystic fibrosis patients have an insulin secretory defect due to pancreatic endocrine dysfunction secondary to diffuse exocrine damage. (Do diabetic patients have higher Ghrelin?) The low fat mass in cystic fibrosis patients would be expected to result in higher Ghrelin levels. A previous study showed no dysregulation in leptin in cystic fibrosis patients (Endocr Res. 1998 May;24(2):247-57.),with lean patients showing leptin levels corresponding to their body fat status. Another more recent study has demonstrated raised leptin levels in cystic fibrosis patients probably mediated by inflammatory cytokines. Acta Paediatr. 2004 Sep;93(9):1185-91.
Fat mass has been shown to be similar in CF patients and controls with DEXA, with hidden fat free mass depletion correlating with disease severity despite normal BMI. Chest. 2003 Dec;124(6):2220-8 Ghrelin levels correlate with fat mass and hence apparently fat depleted CF patients might not have the raised Ghrelin levels expected from their clinically lean body habitus.
GH treatment has been shown to significantly improve weight and linear growth in young patients with CF. J Am Coll Nutr. 1998 Oct;17(5):419-24. Ghrelin is a potent GH releasing secretagogue, with greater potency than GHRH itself.
Ghrelin has been shown to be abnormally high in untreated Coeliac disease patients with lowering of levels on treatment. Am J Gastroenterol. 2003 Nov;98(11):2474-8.Ghrelin levels correlated with the severity of the intestinal mucosal lesions, with lowering of levels with administration of probiotics. Intestinal inflammation is a major feature of cystic fibrosis Aliment Pharmacol Ther. 2004 Oct 1;20(7):813-9. The degree of Ghrelin elevation would thus be higher than expected in adults who have not received probiotics and significant active ongoing disease. A dysregulation of Ghrelin due to central and peripheral mechanisms is thus possible.
Cystic fibrosis patients have a recognised hepatic insulin resistance. Diabetes. 1999 May;48(5):1082-7.But their insulin response is lower due to associated beta cell secretory defects. Ghrelin levels are regulated by insulin levels and inversely correlate with insulin resistance albeit this has been demonstrated only in the "healthy" obese. J Clin Endocrinol Metab. 2004 Apr;89(4):1630-5.
Multiple factors including decreased absorption of fat-soluble vitamins, specifically vitamin D and K, altered sex hormone production, chronic inflammation, a lack of physical activity, steroid treatment and an intrinsic hyper-resorptive bone physiology result in poor mineralisation of bones in patients with Cystic Fibrosis. Up to 75% of adult patients with CF have been shown to have osteopenia or osteoporosis.
Inflammatory States:
Nutrients, Gut hormones, metabolic factors and neuropeptides have been evaluated for their influence on Ghrelin levels. Is there a substance secreted by fat that might regulate Ghrelin secretion? (TNF α or CRP) Obesity is being increasingly thought of as an inflammatory condition like atherosclerosis with CRP levels correlating with fat mass. A study to correlate CRP and Ghrelin in the obese pre and post weight loss would be informative. Is Ghrelin raised in other inflammatory states is a question that this hypothesis begs. It has been shown that rheumatoid patients had significantly lower plasma Ghrelin levels than healthy controls (RA = 24.54 +/- 2.57 pg/ml vs. 39.01 +/- 4.47 pg/ml of healthy controls; P = 0.0041).Rheumatology (Oxford). 2004 Mar;43(3):306-10 Ghrelin levels in the rats with adjuvant induced arthritis correlated with weight changes: i.e. an initial weight loss with low Ghrelin levels followed by gain in weight and normalisation of Ghrelin.
Ghrelin and Intestinal Diseases:
Ghrelin has been shown to be abnormally high in untreated Coeliac disease patients with lowering of levels on treatment. Am J Gastroenterol. 2003 Nov;98(11):2474-8.Ghrelin level in a pernicious anaemia patient was found to be low.
Ghrelin and Tumours:
Ghrelin's usual action seems to be cell proliferation inhibition, Endocrine. 2001 Feb;14(1):87-93 although a stimulatory effect has been demonstrated on prostate cancer derived cell lines. J Endocrinol. 2002 Mar;172(3):R7-11 Human tumours (breast, thyroid, prostate, pituitary carcinomas) have been shown to have Ghrelin specific binding sites. Ghrelin expression by tumours and ghrelin's influence on tumours may be determined by the size and type of tumour developmentClin Endocrinol (Oxf). 2001 Jun;54(6):759-68 or the degree of differentiation of the tumour. J Clin Endocrinol Metab. 2001 Apr;86(4):1738-45
Neuroendocrine tumour of the stomach secreting Ghrelin has been described. Total Ghrelin levels of 2100 microg/L with active Ghrelin levels of 28 mcg/L were demonstrated in a malignant gastric neuroendocrine tumour. Treatment of the tumour had no effect on Ghrelin levels. J Clin Endocrinol Metab. 2004 Aug;89(8):3739-44 A patient with malignant nonfunctioning pancreatic tumor had circulating Ghrelin levels of 12,000 pM with even the peritoneal metastatic lesions showed an intense, focal cytoplasmic positivity for Ghrelin on histochemistry. J Clin Endocrinol Metab. 2003 Jul;88(7):3117-20 Ghrelin production has also been demonstrated in thyroid cells and medullary thyroid carcinoma cell lines. J Clin Endocrinol Metab. 2001 Oct;86(10):4984-90
Ghrelin and Osteoporosis:
Although Growth hormone therapy in GH- deficient humans increases BMD, the role of the growth hormone secretagogue (Ghrelin) in maintenance of normal BMD is less clear. Ghrelin is thought to have a protective effect on bone. A 10-week study in rats undergoing varying degrees of gastric fundic resection demonstrated that the degree of osteopenia developing in the calvaria was proportional to the extent of resection. A 70% gastric fundus resection was needed to produce osteopenia. Ghrelin levels were proportional to the degree of fundus resection. Scand J Gastroenterol. 2002 Apr;37(4):437-43
Ghrelin levels have been found to be low correlating with fat mass in Cushing’s patients . Five patients with Cushing's syndrome were compared to 8 lean controls who ingested 30 mg prednisolone for 5 days. Cushing's syndrome patients had a low Ghrelin level which increased post pituitary surgery associated with reduction in BMI. In the healthy controls, prednisolone treatment reduced Ghrelin levels by 18% (too short to assess weight gain; calorie intake?). Eur J Endocrinol. 2004 Jul;151(1):113-7. Ghrelin though unlikely to be the driving force for obesity in Cushing's, is still likely to be dysregulated by hypercortisolism in the long term? Ghrelin stimulated GH release has been shown to be significantly impaired in ten patients with active Cushing's disease, while Ghrelin's effect on ACTH release is exaggerated with higher cortisol responses compared to 10 age and sex matched controls. Neuroendocrinology. 2002 Dec;76(6):390-6
Ghrelin and Hypogonadism:
The testis has Ghrelin receptors and also produces Ghrelin. Ghrelin levels in hypogonadal men are lower when compared with weight-matched eugonadal men. Testosterone replacement restores Ghrelin levels in hypogonadal men. J Clin Endocrinol Metab. 2003 Sep;88(9):4139-43 The effect of androgens on Ghrelin may be through peptide synthesis regulation or through leptin which has been shown to decrease after therapy with testosterone. J Clin Endocrinol Metab 82:2510–2513
Ghrelin and Prader-Willi Syndrome
Prader-Willi syndrome (PWS) is a genetic disorder characterized by mild mental retardation, short stature, abnormal body composition, muscular hypotonia and distinctive behavioural features and associated with increased cardiovascular mortality. PWS arises from a lack of expression of paternally inherited imprinted genes on chromosome 15q11-q13. Patients with Prader-Willi syndrome (PWS) are hyperphagic and obese. While Leptin levels are high in keeping with the increased BMI of these patients, Growth Horm IGF Res. 2003 Dec;13(6):322-7 Ghrelin levels tend to be very high (3-4 fold higher levels than normals). J Clin Endocrinol Metab. 2002 Dec;87(12):5461-4. Growth hormone deficiency is common in PWS despite a characteristically high Ghrelin levels in this disease group. Despite this high Ghrelin levels, gastric emptying in prader-willi syndrome is not hastened. J Clin Endocrinol Metab. 2005 Jun;90(6):3367-70 A Ghrelin resistance at the hypothalamic level is possible due to a local defect. Horm Res. 2004;62(1):49-54. The Ghrelin levels in PWS patients tends to be non-suppressed by food, although food-induced suppression is preserved in the earlier stages of PWS. Horm Metab Res. 2004 Mar;36(3):164-9. despite higher levels of Ghrelin in the fasted state, J Clin Endocrinol Metab. 2003 Jan;88(1):174-8. suggesting a progressive dysregulation of Ghrelin with time. Interestingly, Ghrelin suppression with somatostatin did not reduce appetite J Clin Endocrinol Metab. 2004 Aug;89(8):4162-5. although suppression of other anorexigenic hormones by somatostatin might have confused issues.
Ghrelin and PCOS:
Women with the polycystic ovary syndrome (PCOS) have even lower Ghrelin levels than predicted by their obese phenotype. J Clin Endocrinol Metab 87:5625–5629 Ghrelin levels in this population have been shown to negatively correlate with androgen levels. Treatment with anti androgens increases Ghrelin levels in PCOS, independent of changes in BMI/fat and insulin sensitivity.
Ghrelin and Thyrotoxicosis:
Circulating Ghrelin levels were measured in nine hyperthyroid patients before and after medical treatment and compared with those in eight healthy control subjects. All participants were studied in the postabsorptive state and during a 3-h euglycemic hyperinsulinemic clamp. Before treatment the patients had 3- to 5-fold elevations of T (3), and during treatment the patients gained 5 kg of body weight. Ghrelin levels were decreased in hyperthyroidism both in the fasting state (hyperthyroid, 1080 +/- 195 pg/ml; euthyroid, 1480 +/- 215 pg/ml; P = 0.03) and during clamp (hyperthyroid, 833 +/- 150 pg/ml; euthyroid, 1210 +/- 180 pg/m; P = 0.02). After treatment, Ghrelin levels did not differ from those in control subjects. In all three study groups the clamp significantly reduced Ghrelin levels compared with fasting levels. J Clin Endocrinol Metab. 2003 Feb;88(2):853-7 In conclusion, Ghrelin levels are reduced in hyperthyroidism and become normalized by medical antithyroid treatment. Hyperinsulinaemia suppresses Ghrelin regardless of thyroid status. Ghrelin is not a primary stimulator of appetite and food intake in hyperthyroidism, and the mechanisms underlying the suppressive effect of hyperthyroidism on Ghrelin secretion remain unclear.
P S: This is interesting, because you would expect Ghrelin to be high in thyrotoxicosis due to the lower fat mass or weight loss, but this is a contradiction of Ghrelin tracking fat mass. Or is it because there is more of lean body mass loss rather than fat? (Leptin was also low in thyrotoxic patients suggesting that thyroid hormones may override fat mass signals). Rat studies have shown similar effect of induced hypothyroidism and thyrotoxicosis on Ghrelin mRNA expression in stomach and in circulation. Is it worth studying the acute effects of T4 on Ghrelin in the short term during initiation of thyroxine treatment to assess rapidity for restoration of Ghrelin response to meals? Is it worth studying the response of Ghrelin to food intake in patients with hypothyroidism to assess for lack of suppression in this group?
Studying Motor neuron disease patients who have muscle wasting diseases could clarify this further? or in those with anabolic steroid administration and increase in muscle mass? Anabolic steroids increase muscle rather than fat and how does this correlate with Ghrelin rises? One would not expect Ghrelin suppression as it is the fat mass that provides feedback for Ghrelin secretion.
Ghrelin and Hypothyroidism
Hypothyroidism induced in adult male Sprague-Dawley resulted in an increase in gastric ghrelin mRNA levels with associated increase in circulating plasma Ghrelin levels. Eur J Endocrinol. 2002 Jul;147(1):159-63
Ghrelin and Anorexia nervosa.
In pathologically lean people with anorexia nervosa, Ghrelin levels are raised as the fat mass is low, and fails to suppress with food, suggesting chronic dysregulation resulting in lack of response to food induced responses. J Clin Endocrinol Metab. 2003 Apr;88(4):1678-82. Despite this high baseline levels of Ghrelin, suppression by food is preserved. Psychoneuroendocrinology. 2005 Jul;30(6):577-81. Weight gain in anorexia nervosa patients returns Ghrelin to normal levels. The Growth hormone response to Ghrelin is impaired in patients with anorexia nervosa, although stimulation of ACTH, Prolactin and insulin by exogenous Ghrelin is normal. Abnormalities of sex hormones and IGF1 are well recognised in anorexia nervosa . A 6 month study involving 78 women with anorexia nervosa demonstrated that administration of estrogen and recombinant IGF1 separately increased Ghrelin levels with no significant changes in weight, calorie intake or Growth Hormone levels. . J Clin Endocrinol Metab. 2004 Aug;89(8):3988-93. Does pathologically low fat mass on a chronic basis produce tertiary hyper-ghrelinaemia resulting in dysregulation?
Ghrelin levels are raised in bulimia nervosa patients despite normal BMI. In contrast to anorexic women, the growth hormone response as well as that of ACTH and Prolactin to Ghrelin is preserved in bulimia nervosa patients.
Cancer and Cardiac cachectic states are also associated with high Ghrelin levels suggesting Ghrelin resistance in these states. Circulation. 2001 Oct 23;104(17):2034-8. Ghrelin injected intracerebroventricularly has shown only modest effects on increasing food intake in anorexic rats with prostate cancer.Endocrinology. 2001 Aug;142(8):3292-301 The effects of exogenous Ghrelin in these scenarios await clarification.
Ghrelin and Cardiac Failure:
Ghrelin can inhibit apoptosis of cardiomyocytes and endothelial cells. J Cell Biol. 2002 Dec 23;159(6):1029-37 Ghrelin receptors have been shown to be increased within atherosclerotic coronary arteries. An endothelin antagonistic action of Ghrelin has been postulated, Br J Pharmacol. 2002 Aug;136(8):1146-52with vasodilation mediated via IGF-1 and probably partly through nitric oxide synthesis stimulation. Ghrelin infusion in healthy subjects decreases afterload and decreases blood pressure (reduction of MAP by -12 mmHg by 10mcg/kg Ghrelin). Am J Physiol Regul Integr Comp Physiol. 2001 May;280(5):R1483-7Blood pressure is reduced without reflex tachycardia. J Clin Endocrinol Metab. 2001 Dec;86(12):5854-9
Ghrelin infusion in rats with cardiac failure inhibited Left ventricular enlargement and increased LV fractional shortening. Circulation. 2001 Sep 18;104(12):1430-5. Administration of Ghrelin intravenously to 10 heart failure patients for 3 weeks improved left ventricular function, exercise capacity, and muscle wasting compared to 8 controls with heart failure. Circulation. 2004 Nov 29 The vasodilatory and sympathetic-inhibitory actions of Ghrelin resulting in lower plasma nor epinephrine levels might be responsible for these beneficial effects. Ghrelin (but not desacetyl Ghrelin or MK 0677) can be cardio-protective in rats following ischemic injury. Basic Res Cardiol. 2003 Nov;98(6):401-5.
Ghrelin and Pregnancy:
Ghrelin may have a role in the development of pregnancy induced hypertension. Patients with PIH have high levels of Ghrelin. Hypertension. 2002 Mar 1;39(3):781-4 Ghrelin may well play a counter regulatory role in this situation via its vasodilatory properties.
Ghrelin and Cystic fibrosis
Cystic fibrosis is a protein catabolic state with significant effects on carbohydrate metabolism and intestinal function. Ghrelin levels in these patients would be expected to be influenced by a combination of a hypercatabolic state, low fat mass, lower postprandial insulin levels, and intestinal function. Ghrelin status and regulation in cystic fibrosis patients has not been studied to date.
Cyproheptadine, a 5-HT(2) receptor antagonists has been shown to improve appetite in cystic fibrosis patients.Pediatr Pulmonol. 2004 Aug;38(2):129-34 The intrinsic anticholinergic property of cyproheptadine has been shown to produce a blunting effect on the GH response to Hexarelin, but not the latter's action on Prolactin and ACTH stimulation. J Endocrinol Invest. 1998 Nov;21(10):673-9. Ghrelin is an even more potent stimulator of GH release than hexarelin, with greater stimulatory effect on Prolactin and ACTH production. J Clin Endocrinol Metab. 2001 Mar;86(3):1169-74. Ghrelin secretion has been demonstrated to be under cholinergic control using cholinergic agonist as pyridostigmine and muscarinic antagonist as pirenzipine. J Clin Endocrinol Metab. 2004 May;89(5):2429-33. Cholinergic stimulation in that study resulted in increased Ghrelin while anticholinergic treatment decreased Ghrelin levels. Nonspecific cholinergic blockade with atropine in another study showed decreased Ghrelin release, and also decreased GH responses to Ghrelin. J Clin Endocrinol Metab. 2004 Sep;89(9):4729-33. Another study assessing the effect of cholinergic pathway on Ghrelin effects found that Ghrelin's endocrine effects, namely GH, PRL and ACTH releasing actions, were not modified by cholinergic agonists or antagonists( pirenzipine in this instance) Clin Endocrinol (Oxf). 2003 Jan;58(1):92-8. The effect of an agent with intrinsic anticholinergic activity and appetite increasing characteristics as cyproheptadine, on Ghrelin levels in patients with cystic fibrosis and low appetite levels would be interesting to assess. Assessment would have to target adult cystic fibrosis patients as Ghrelin levels in prepubertal lean healthy children, though similar to adult levels in the fasting state, do not suppress normally with food. J Clin Endocrinol Metab. 2004 Apr;89(4):1662-5.
Intestinal motility in cystic fibrosis patients has been shown to be slow Arch Dis Child 1999;80:149-152. which has been suggested to be a function of disordered gut hormonal secretion or regulation. Dig Dis Sci 1992;37:187-192. Intestinal motility has clinical significance while treating with pancreatic enzymes to improve fat malabsorption. Ghrelin has been shown to increase intestinal motility through cholinergic mechanisms in rats, with demonstration of Ghrelin receptors in the intestinal neuromuscular tissue of the rat. Regul Pept. 2004 Sep 15;121(1-3):25-30. While small intestinal transit is accelerated, Ghrelin has no effect on colonic motility. Gastric emptying has been shown to be high in patients with Cystic fibrosis J Pediatr Gastroenterol Nutr. 1997 Nov;25(5):492-8. although studies have been contradicting with variations based on isotope and food material/tablets used. Arch Dis Child. 1999 Feb;80(2):149-52. Ghrelin in fact, with its structural relation to motilin, has been shown to stimulate gastric emptying in a dose dependent manner. Regul Pept. 2004 Aug 15;120(1-3):23-32. Ghrelin also increases gastric acid secretion. Biochem Biophys Res Commun. 2000 Oct 5;276(3):905-8.
An insulin synthesis inhibiting action has been attributed to cyproheptadine. Toxicol Sci. 2004 Jun;79(2):258-65. Epub 2004 Mar 31. Ghrelin also decreases insulin levels with production of hyperglycaemia. Cystic fibrosis patients have an insulin secretory defect due to pancreatic endocrine dysfunction secondary to diffuse exocrine damage. (Do diabetic patients have higher Ghrelin?) The low fat mass in cystic fibrosis patients would be expected to result in higher Ghrelin levels. A previous study showed no dysregulation in leptin in cystic fibrosis patients (Endocr Res. 1998 May;24(2):247-57.),with lean patients showing leptin levels corresponding to their body fat status. Another more recent study has demonstrated raised leptin levels in cystic fibrosis patients probably mediated by inflammatory cytokines. Acta Paediatr. 2004 Sep;93(9):1185-91.
Fat mass has been shown to be similar in CF patients and controls with DEXA, with hidden fat free mass depletion correlating with disease severity despite normal BMI. Chest. 2003 Dec;124(6):2220-8 Ghrelin levels correlate with fat mass and hence apparently fat depleted CF patients might not have the raised Ghrelin levels expected from their clinically lean body habitus.
GH treatment has been shown to significantly improve weight and linear growth in young patients with CF. J Am Coll Nutr. 1998 Oct;17(5):419-24. Ghrelin is a potent GH releasing secretagogue, with greater potency than GHRH itself.
Ghrelin has been shown to be abnormally high in untreated Coeliac disease patients with lowering of levels on treatment. Am J Gastroenterol. 2003 Nov;98(11):2474-8.Ghrelin levels correlated with the severity of the intestinal mucosal lesions, with lowering of levels with administration of probiotics. Intestinal inflammation is a major feature of cystic fibrosis Aliment Pharmacol Ther. 2004 Oct 1;20(7):813-9. The degree of Ghrelin elevation would thus be higher than expected in adults who have not received probiotics and significant active ongoing disease. A dysregulation of Ghrelin due to central and peripheral mechanisms is thus possible.
Cystic fibrosis patients have a recognised hepatic insulin resistance. Diabetes. 1999 May;48(5):1082-7.But their insulin response is lower due to associated beta cell secretory defects. Ghrelin levels are regulated by insulin levels and inversely correlate with insulin resistance albeit this has been demonstrated only in the "healthy" obese. J Clin Endocrinol Metab. 2004 Apr;89(4):1630-5.
Multiple factors including decreased absorption of fat-soluble vitamins, specifically vitamin D and K, altered sex hormone production, chronic inflammation, a lack of physical activity, steroid treatment and an intrinsic hyper-resorptive bone physiology result in poor mineralisation of bones in patients with Cystic Fibrosis. Up to 75% of adult patients with CF have been shown to have osteopenia or osteoporosis.
Inflammatory States:
Nutrients, Gut hormones, metabolic factors and neuropeptides have been evaluated for their influence on Ghrelin levels. Is there a substance secreted by fat that might regulate Ghrelin secretion? (TNF α or CRP) Obesity is being increasingly thought of as an inflammatory condition like atherosclerosis with CRP levels correlating with fat mass. A study to correlate CRP and Ghrelin in the obese pre and post weight loss would be informative. Is Ghrelin raised in other inflammatory states is a question that this hypothesis begs. It has been shown that rheumatoid patients had significantly lower plasma Ghrelin levels than healthy controls (RA = 24.54 +/- 2.57 pg/ml vs. 39.01 +/- 4.47 pg/ml of healthy controls; P = 0.0041).Rheumatology (Oxford). 2004 Mar;43(3):306-10 Ghrelin levels in the rats with adjuvant induced arthritis correlated with weight changes: i.e. an initial weight loss with low Ghrelin levels followed by gain in weight and normalisation of Ghrelin.
Ghrelin and Intestinal Diseases:
Ghrelin has been shown to be abnormally high in untreated Coeliac disease patients with lowering of levels on treatment. Am J Gastroenterol. 2003 Nov;98(11):2474-8.Ghrelin level in a pernicious anaemia patient was found to be low.
Ghrelin and Tumours:
Ghrelin's usual action seems to be cell proliferation inhibition, Endocrine. 2001 Feb;14(1):87-93 although a stimulatory effect has been demonstrated on prostate cancer derived cell lines. J Endocrinol. 2002 Mar;172(3):R7-11 Human tumours (breast, thyroid, prostate, pituitary carcinomas) have been shown to have Ghrelin specific binding sites. Ghrelin expression by tumours and ghrelin's influence on tumours may be determined by the size and type of tumour developmentClin Endocrinol (Oxf). 2001 Jun;54(6):759-68 or the degree of differentiation of the tumour. J Clin Endocrinol Metab. 2001 Apr;86(4):1738-45
Neuroendocrine tumour of the stomach secreting Ghrelin has been described. Total Ghrelin levels of 2100 microg/L with active Ghrelin levels of 28 mcg/L were demonstrated in a malignant gastric neuroendocrine tumour. Treatment of the tumour had no effect on Ghrelin levels. J Clin Endocrinol Metab. 2004 Aug;89(8):3739-44 A patient with malignant nonfunctioning pancreatic tumor had circulating Ghrelin levels of 12,000 pM with even the peritoneal metastatic lesions showed an intense, focal cytoplasmic positivity for Ghrelin on histochemistry. J Clin Endocrinol Metab. 2003 Jul;88(7):3117-20 Ghrelin production has also been demonstrated in thyroid cells and medullary thyroid carcinoma cell lines. J Clin Endocrinol Metab. 2001 Oct;86(10):4984-90
Ghrelin and Osteoporosis:
Although Growth hormone therapy in GH- deficient humans increases BMD, the role of the growth hormone secretagogue (Ghrelin) in maintenance of normal BMD is less clear. Ghrelin is thought to have a protective effect on bone. A 10-week study in rats undergoing varying degrees of gastric fundic resection demonstrated that the degree of osteopenia developing in the calvaria was proportional to the extent of resection. A 70% gastric fundus resection was needed to produce osteopenia. Ghrelin levels were proportional to the degree of fundus resection. Scand J Gastroenterol. 2002 Apr;37(4):437-43