Reversible hypertension following coeliac disease treatment: the role of moderate hyperhomocysteinaemia and vascular endothelial dysfunction

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1 (2002) 16, Nature Publishing Group All rights reserved /02 $ ORIGINAL ARTICLE Reversible hypertension following coeliac disease treatment: the role of moderate hyperhomocysteinaemia and vascular endothelial dysfunction PO Lim 1,2,5, N Tzemos 1, CAJ Farquharson 2, JE Anderson 1, P Deegan 3, RS MacWalter 4, AD Struthers 2 and TM MacDonald 1 1 Hypertension Research Centre, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK; 2 Cardiovascular Research Group, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK; 3 Directorate of Biochemical Medicine, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK; 4 Stroke Studies Centre, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK; 5 Department of Cardiology, Wales Heart Research Institute, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, U Kingdom The vascular endothelium maintains a relatively vasodilated state via the release of nitric oxide (NO), a process that could be disrupted by hyperhomocysteinaemia. Since endothelial dysfunction is associated with increased systemic vascular resistance that is the hallmark of sustained arterial hypertension, we hypothesised that in patients with both hypertension and coeliac disease with hyperhomocysteinaemia (via malabsorption of essential cofactors), treatment of the latter disease could improve blood pressure (BP) control. A single patient with proven sustained hypertension and newly-diagnosed coeliac disease had baseline and post-treatment BP and endothelial function assessed by ambulatory BP monitoring (ABPM) and brachial artery forearm occlusion plethysmography respectively. This 49 year-old woman had uncomplicated sustained hypertension proven on repeated ABPM carried out 6 weeks apart (daytime mean 151/92 mm Hg and 155/95 mm Hg), and sub-clinical coeliac disease (gluten-sensitive enteropathy). Initial assessments revealed raised homocysteine levels with low normal vitamin B 12 level. It was likely that she had impaired absorption of essential cofactors for normal homocysteine metabolism. She adhered to a gluten-free diet and was give oral iron, folate and B 6 supplementations as well as B 12 injections for 3 months. Her BP had improved by 6 months and normalised by 15 months (daytime ABPM mean 128/80 mm Hg). There was parallel restoration of normal endothelial function with normalisation of her homocysteine levels. These observations suggest that sub-clinical coeliac disease related hyperhomocysteinaemia might cause endothelial dysfunction, potentially giving rise to a reversible form of hypertension. In addition, this case study supports the notion that irrespective of aetiology, endothelial dysfunction may be the precursor of hypertension. This highlights the need to resolve co-existing vascular risk factors in patients with hypertension. (2002) 16, DOI: /sj/jhh/ Keywords: nitric oxide; hyperhomocysteinaemia; coeliac disease; endothelial dysfunction Introduction The serendipitous observation of Furchgott and Zawadzki 1 in 1980 that an intact endothelium is essential for a normal vasodilatory response to acetylcholine (ACh) has revolutionised vascular Correspondence: Dr PO Lim, British Heart Foundation Clinical Lecturer in Cardiology, Department of Cardiology, Wales Heart Research Institute, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, UK. limpo cf.ac.uk Received 14 January 2002; revised and accepted 16 January 2002 biology. This led to the discovery that the vascular endothelium releases nitric oxide (NO) continuously to regulate the vascular tone favouring a vasodilated state. Loss of this NO-driven vasodilatory control or endothelial dysfunction hence causes vasoconstriction that increases the vascular resistance. Hypertension is one common vascular disease that is primarily due to an unexplained rise in systemic vascular resistance, and it is also associated with endothelial dysfunction. At present, there is controversy whether endothelial dysfunction in hypertension initiates the disease process, or it is

2 412 simply an epiphenomenon. Interestingly, normotensive offsprings of hypertensive parents who are more at risk of developing hypertension in the future have been reported to have impaired endothelial function. 2,3 This finding would support the notion that endothelial dysfunction precedes hypertension, although there are as yet no direct longitudinal follow-up data to show that normotensive young individuals with worse endothelial dysfunction are more likely to develop hypertension over time. More recently, vitamin C, a potent antioxidant which reduces endothelial dysfunction has been reported to lower blood pressure (BP) significantly in hypertensives 4 suggesting that to some extent, endothelial dysfunction maintains hypertension. At least in rats, endothelial dysfunction produced experimentally initiates the hypertensive disease process. 5,6 The vascular endothelium is exceedingly sensitive to risk factors for vascular diseases such as smoking, 7 hypercholestrolaemia, 8 hyperglycaemia 9 and hyperhomocysteinaemia. 10 These factors which cause endothelial dysfunction through diverse mechanisms are also commonly found clustered within many hypertensive individuals. 11 Thus, the primacy of endothelial dysfunction in causing hypertension in human potentially can be elucidated by finding a disease model whereby BP is lowered by reversing endothelial dysfunction. Here we report an extended case study of a patient confirmed to have mild and uncomplicated hypertension who was incidentally diagnosed to have sub-clinical coeliac disease. Coeliac disease is a readily reversible malabsorption syndrome that is associated with relative folate and vitamin B 12 deficiency. These are essential cofactors needed for homocysteine metabolism, the lack of which cause an elevation in homocysteine level that in turn impairs the vascular endothelial function. It has been shown that even borderline high homocysteine levels are associated with vascular diseases. 12 Methods Patient A 49-year old woman who was a sedentary life-long non-smoker with 1-year history of hypertension was referred for assessment in our specialist hypertension clinic. She was incidentally found to have untreated coeliac disease. She was asymptomatic other than a long-standing vague feeling of fatigue. She had previous back surgery, right kidney pyloroplasty for ureteric obstruction and had two unevenful pregnancies, but one of her daughters has spina bifida occulta. Fully informed written consent was obtained from this patient prior to her taking part in this unique observational study, which involved brachial artery endothelial function assessment (see below), a technique that we have considerable experience in and had been approved for use in hypertensives in our department by the Tayside medical ethics committee. Blood pressure measurements BP was measured in triplicate by trained hypertension research nurses using a standard mercury sphygmomanometer at 1-min intervals after a seated rest of 2 min. The mean of these three readings was used to define clinic BP. Ambulatory BP monitoring (ABPM) (Spacelabs 90207, Redmond, WA, USA) was done on an active day. The device was programmed to measure BP every 15 min during daytime from to The following spurious readings were discarded by editing software; systolic BP diastolic BP, diastolic BP 160 or 40 mm Hg and systolic BP 260 mm Hg or 50 mm Hg. Normotension was defined as a daytime mean ABPM of 135/85 mm Hg. 13 Brachial artery endothelial function assessment The vascular endothelial function was assessed using differential forearm venous occlusion plethysmography by CAJF/NT who were blinded to other measurements in a temperature-controlled room (24 ± 0.5 C). The methodology of this technique has previously been described elsewhere. 14 The forearm blood flow measurements (ml/100 ml/min) were performed after each of the three 5-min incremental dosages of the following agents infused intraarterially into the non-dominant brachial artery: acetylcholine (ACh, 25, 50, and 100 nmol/min), sodium nitroprusside (SNP, 4.2, 12.6, and 37.8 pmol/min) and n-monomethyl-l-arginine (L-NMMA, 1, 2, and 4 mol/min). The responses to these agents were expressed as the percentage difference in forearm blood flows between the infused and control arms ( FBF) whilst ensuring that the baseline blood flows were the same in both arms at the beginning of each infusion. Each infusate tested different aspects of the vascular function, ACh, endothelium-dependant vasodilatation or stimulated NO release, SNP, endothelium-independant vasodilatation and L-NNMA, endothelium-dependant vasoconstriction or basal nitric oxide production respectively. Results Our patient was of slim build, and had a normal body mass index of 22 kg m 2. Physical examination revealed no hypertension-induced target-organ damage, and her seated clinic BP was 166/92 mm Hg. ABPM was 151/92 mm Hg (normal daytime mean 135/85 mm Hg) (Figure 1). A repeat ABPM 6 weeks later was 155/94 mm Hg confirming reproducible sustained hypertension. Plasma electrolytes and glucose were normal, haemoglobin was 11.4 g/dl, serum ferritin 6 g (reference range ), folate 7 ug/l (1.8 14), vitamin B ng/l ( ), fasting total cholesterol 5.33 mmol/l and

3 413 Figure 1 Ambulatory blood pressure monitoring. total homocysteine levels were 16 mol/l ( 15, fasting), 25 (2 h) and 31 (4 h) following a 6-g methionine load. Echocardiography detected no cardiac hypertrophy. Anti-endomesial antibody was positive and a distal duodenal biopsy showed sub-total villous atrophy consistent with the diagnosis of coeliac disease. Brachial artery vascular endothelial function was assessed using forearm differential occlusion plethysmography (Figure 2). Since coeliac disease is a form gluten-sensitive enteropathy, standard gluten-free dietary advice was offered following the baseline investigations. She was also treated with oral ferrous sulphate 200 mg three times daily, folate 5 mg daily and B 6 50 mg daily for 3 months, and weekly intramuscular injection of vitamin B g for the first 4 weeks followed by monthly injection for the next 2 months. At 3 months follow up, repeat anti-endomesial antibody was negative suggesting dietary compliance and therefore resolution of her gluten enteropathy. She was now folate (14.6 ug/l) and vitamin B 12 (1727 ng/l) replete. At 6 months, clinic BP was 148/92 mm Hg and a repeat ABPM was 145/89 mm Hg, suggesting some improvement in BP control. Clinic BP at 15 months was 140/86 mm Hg and ABPM was, 128/80 mm Hg which is normotensive. Her general well-being was subjectively improved. Total homocysteine levels were now 9 mol/l ( 15, fasting), 18 (2 h) and 23 (4 h) following a 6-g methionine load, and serum total cholesterol, 4.98 mmol/l, folate 6.3 g/l and vitamin B ng/l. Her vascular endothelial function improved as evidenced by an increase in both basal NO release (assessed using L-NMMA) and stimulated NO release (assessed using ACh) to normal levels. While the response to SNP, an NO-independent direct vasodilator was unaltered. This was associated with a cure of her hypertension. Her initially raised homocysteine level fell to well within the laboratory normal range and interestingly, the response to methionine load was blunted at 15 months indicating improved homocysteine metabolic control. These changes were achieved by dietary manipulation alone. Figure 2 Brachial artery endothelial function.

4 414 Discussion This is an observational rather than a mechanistic study. Although this report on a single patient does not provide conclusive proof that endothelial dysfunction underlies the hypertensive disease process, we believe that in this case, treatment of coeliac disease was associated with reduction in homocysteine levels with parallel normalisation of endothelial function and cure of hypertension. However, this chain of events is only a theoretical possibility. This patient was kick-started with vitamin supplementations for the first 3 months as she commenced treatment with gluten-free diet. It is likely that resumption of normal gastrointestinal absorption allowed her to replenish her stocks of co-factors necessary for normal vascular endothelial function. Importantly, this patient was not obese at baseline hence her hypertension was not weight related. Similarly, gluten-free food products are not low in salt content thus the changes that we observed were unlikely to be related to reduced salt intake although we did not formally measure salt intake. It is well known that experimental hyperhomocysteinaemia in man causes endothelial dysfunction with increased vascular resistance via an oxidative stress process that reduces NO bioavailability. 15 It is now realised that even moderate elevations in homocysteine levels ( 10 umol/l) are associated with hypertension 16 and death from coronary artery disease. 17 In a report by Nygard and colleagues 17 who followed up 587 patients with coronary artery disease over a median period of 4.6 years, subjects with a homocysteine level 15 mol/l had a death rate 6.5 times that of those with a homocysteine level 10 umol/l. Our patient s fasting homocysteine level was thus moderately elevated at baseline but fell by 44% to within normal ranges at 15 months follow-up when her coeliac disease was treated with diet alone, having stopped her vitamin supplementations for 1 year previously. More recently, there is evidence to suggest that a reduction in a folate-derived co-factor tetrahydrobiopterin causes uncoupling of NO synthase leading to paradoxical NO synthase-mediated formation of superoxide anions and hydrogen peroxide. 18 These reactive agents are detrimental to endothelial function. Hence supplementation with folate alone could to some extent improve endothelial function independently of homocysteine lowering. 19 However in this case, the serum folate at baseline and at 15 months were not different suggesting that other cofactors essential for homocysteine metabolism that we did not measure might be more important. Two important implications from this unique case study can be drawn. Firstly, this patient had subclinical coeliac disease, in that, apart from a vague sense of tiredness, she was asymptomatic. She had no history of weight loss or altered bowel habits. Hence, under normal clinical circumstances, coeliac disease would not feature as a probable diagnosis. Notably, she has a daughter with neural tube defect, well known to be associated with folate deficiency. 20 It is conceivable that her folate requirements increased during her pregnancy, and this demand was not met due to malabsorption secondary to her sub-clinical coeliac disease. Coeliac disease was previously thought to be relatively rare. However, since the diagnosis can now be more easily made by detecting endomesial antibody, a much higher prevalence of about one in 200 in the general population has been uncovered. 21 In view of this, we can speculate that there may be many more patients with hypertension secondary to coeliac disease who have a potentially reversible form of hypertension. Indeed, it may be sensible to look out for this disorder in hypertensive patients with low or normal body mass index. The second implication of this report is that human hypertension can potentially be directly caused by endothelial dysfunction per se, afinding that has been confirmed in animals. Whether the converse is also true is similarly controversial. There is in vitro experimental data to show that endothelial function in gluteal resistance vessels is affected by increased intravascular pressure. 22 In clinical studies however, BP-lowering with drug treatment is not usually associated with an improvement in endothelial function. 23 It should be borne in mind that high BP is not a disease in itself but an expression of the underlying vascular state given that the cardiac function is intact. Hence, avoiding factors that cause endothelial dysfunction can reduce the risk of vascular diseases and the development of future hypertension. Similarly, the management of hypertension should perhaps be extended to include a study of whether adverse endothelial factors are present, reversal of which may help BP control. This is likely to be more effective prior to the onset of structural vascular target-organ damage. Acknowledgement We especially wish to thank the patient who was the subject of this paper for her magnanimity in participating actively with us in testing out a scientific hypothesis. References 1 Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980; 288: Taddei S, Salvetti A. Pathogenetic factors in hypertension. Endothelial factors. Clin Exp Hypertens 1996; 18: McAllister AS et al. Basal nitric oxide production is impaired in offspring of patients with essential hypertension. Clin Sci (Colch). 1999; 97: Duffy SJ et al. Treatment of hypertension with ascorbic acid. Lancet. 1999; 354: Ribeiro MO et al. Chronic inhibition of nitric oxide synthesis. A new model of arterial hypertension. Hypertension 1992; 20:

5 6 Baylis C, Mitruka B, Deng A. Chronic blockade of nitric oxide synthesis in the rat produces systemic hypertension and glomerular damage. J Clin Invest 1992; 90: Celermajer DS et al. Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults. Circulation 1993; 88: Vogel RA. Cholesterol lowering and endothelial function. Am J Med 1999; 107: Shige H et al. Endothelium-dependent flow-mediated vasodilation in the postprandial state in type 2 diabetes mellitus. Am J Cardiol 1999; 84: Tawakol A et al. Hyperhomocyst(e)inemia is associated with impaired endothelium-dependent vasodilation in humans. Circulation 1997; 95: Kannel WB. Fifty years of Framingham Study contributions to understanding hypertension. J Hum Hypertens 2000; 14: Hankey GJ, Eikelboom JW. Homocysteine and vascular disease. Lancet 1999; 354: O Brien E et al. Use and interpretation of ambulatory blood pressure monitoring: recommendations of the British hypertension society. BMJ 2000; 320: Butler R, Morris AD, Burchell B, Struthers AD. DD angiotensin-converting enzyme gene polymorphism is associated with endothelial dysfunction in normal humans. Hypertension 1999; 33: Kanani PM et al. Role of oxidant stress in endothelial dysfunction produced by experimental hyperhomocyst(e)inemia in humans. Circulation 1999; 100: Sutton-Tyrrell K, Bostom A, Selhub J, Zeigler-Johnson C. High homocysteine levels are independently related to isolated systolic hypertension in older adults. Circulation 1997; 96: Nygard O et al. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl JMed1997; 337: Katusic ZS. Vascular endothelial dysfunction: does tetrahydrobiopterin play a role? Am J Physiol Heart Circ Physiol 2001; 281: H981 H Doshi SN et al. Folate improves endothelial function in coronary artery disease: an effect mediated by reduction of intracellular superoxide? Arterioscler Thromb Vasc Biol 2001; 21: Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. MRC Vitamin Study Research Group. Lancet 1991; 338: Feighery C. Fortnightly review: coeliac disease. BMJ 1999; 319: Paniagua OA, Bryant MB, Panza JA. Transient hypertension directly impairs endothelium-dependent vasodilation of the human microvasculature. Hypertension 2000; 36: Tzemos N, Lim PO, MacDonald TM. Nebivolol reverses endothelial dysfunction in essential hypertension: a randomized, double-blind, crossover study. Circulation 2001; 104:

How well do office and exercise blood pressures predict sustained hypertension? A Dundee Step Test Study

(2000) 14, 429 433 2000 Macmillan Publishers Ltd All rights reserved 0950-9240/00 $15.00 www.nature.com/jhh ORIGINAL ARTICLE How well do office and exercise blood pressures predict sustained hypertension?