Moving beyond the metabolic syndrome: syndrome Z in Indian subcontinent: a case report and review of literature

INTRODUCTION

The metabolic syndrome (syndrome X or insulin resistance syndrome) consists of a constellation of metabolic abnormalities including central obesity, hypertriglyceridemia, low levels of high density lipoprotein (HDL) cholesterol, hyperglycemia and hypertension.¹ The diagnosis of OSA can be made when the AHI is >5 in a patient with excessive daytime sleepiness.² The combination of OSA and metabolic syndrome has been referred to as “syndrome Z”. There is paucity of information on the exact prevalence of syndrome Z in the Indian subcontinent community and the factors associated with it.³ Although, in India a community based survey had reported the prevalence of OSA as 9.3% and that of obstructive sleep apnea syndrome (OSAS) as 2.8%.⁴ These figures are similar to those reported in the western population.⁵ The past few decades have seen a growing recognition of the presence of various types of metabolic dysfunction in subjects with OSA, which have further highlighted the association of metabolic syndrome and OSA.⁶ Obstructive sleep apnea (OSA) has been linked to increased cardiovascular morbidity and mortality from both coronary heart disease and stroke.⁷ Sleep disorders are common among the general population.^7,8 Sleep related breathing disorders (SRBD) can impair academic and occupational performance, cause work-related and road accidents, and disturb mood and social adjustment disrupting personal life and relationships. Also, sleep-related breathing disorders may lead to or exacerbate serious medical, neurological and psychiatric problems.⁹ This clearly signifies the personal, social and economic impact of syndrome Z on human society. Still only a few studies in India have studied the prevalence of syndrome Z which clearly underscores the unmet need of research in this direction. Hence, we report here a case of syndrome Z to put a spotlight on this severe systemic disease with appalling health effects.

CASE REPORT

A 45 year old female presented to us with a history of excessive day time sleepiness since 4 years which was associated with habitual loud snoring and excessive weight gain in the recent past. This all led to impaired concentration, decreased sleep latency and eventually had severely affected her quality of life. She was a diagnosed case of hypothyroidism and systemic hypertension since 10 years and 5 years respectively and was on regular medication since then. In past, she had also underwent endoscopic sinus surgery and cholecystectomy in the year 1998 and 1993 respectively. On examination, she was obese with body mass index (BMI) of 39.26 (obesity class II), height of 148 cm and weight of 86 kg. Her waist circumference was 117 cm, hip circumference was 121 cm, neck circumference was 36 cm and neck length was 7 cm. Her waist to hip ratio was 0.967. Her blood pressure was 160/90 mm Hg, respiratory rate was 18 cycles/ minute with a pulse rate of 82 beats/minute.

On investigation, her hemoglobin was 9.3 gm%, fasting blood sugar (FBS) was 130 mg% and post prandial (PP) blood sugar was 287 mg%. Fasting lipid profile showed total cholesterol of 241 mg%, HDL of 32 mg%, LDL of 166 mg%, VLDL of 43 mg% and triglyceride of 213 mg%. Her HbA1c was 7.38 mg% and serum TSH was 3.2 mIU/L while her arterial blood gas analysis was within normal limits.

Overnight polysomnography study with 319 minutes of sleep recording showed apnea index 1.1, hypopnea index 6.2 and total apnea hypopnea index (AHI) of 7.3/hr of sleep which was suggestive of mild obstructive sleep apnea, while AHI individually for NREM and REM was 6.4/hr and 21.0/hr respectively with CPAP titration of 8 cm of water. Modified Berlin Questionnaire reflected high risk while Epworth Sleepiness Score (ESS) was 17/24. She also had metabolic syndrome according to NCEP ATP criteria. She was thus diagnosed with OSA along with metabolic syndrome hence fulfilling the criteria for syndrome Z.

Subsequently, apart from the supportive and symptomatic care the patient was started on metformin to benefit the insulin resistance, statin, was put on CPAP in the night during the course of admission (was not affordable enough to buy a portable CPAP machine for use at home), the medications for patient’s chronic diseases were continued and she was counselled regarding various options available for weight reduction. She principally agreed to undergo bariatric surgery and was thereby transferred under the care of a bariatric surgeon. The patient is yet to come in follow-up.

REVIEW OF LITERATURE AND DISCUSSION

Agrawal et al in their study had showed that the prevalence of metabolic syndrome was four times higher in patients of OSA than controls and the prevalence increased with increasing severity of OSA.¹⁰ Therefore, patients with metabolic syndrome should be investigated for OSA and vice versa, as early detection and correction of these conditions may result in significant decrease in morbidity and mortality. Mishra et al had also earlier reported that the development and presentation of sleep disordered breathing and its frequent association with metabolic syndrome and type 2 diabetes reflect that the underlying pathophysiologies are certainly linked and treating one disorder ameliorates the symptoms of the related conditions.¹¹ Hasan et al had also concluded that the obstructive sleep apnea syndrome is strongly associated with the metabolic syndrome, hypothyroidism, and recent or current smoking.¹² Khot et al reported that the prevalence of syndrome Z is high in T2DM, and increases with age and duration of diabetes. Hypertension is an independent risk factor.¹³ Syndrome Z has a positive correlation with BMI, hypertriglyceridemia, and increased waist circumference. Iyer also found evidence favoring a possible role of sleep disorders as risk factors for metabolic abnormalities and concluded that there is a close relationship between sleep, circadian rhythm, obesity, insulin resistance, hypertension and cardiovascular disorders which needs to be dissected and managed and also suggested a causal role of OSA in development of metabolic syndrome and eventually their compounded adverse effects on human health.¹⁴ Thus, all these studies highlight the severity and adverse effects of syndrome Z as a systemic disease and therefore call for instituting aggressive measures for preventing and treating syndrome Z at an early stage.

Soneja et al in a large placebo controlled, double blind, randomized, crossover study with a longer duration of follow-up observed that the metabolic abnormalities are responsive to CPAP therapy.¹⁵ The same was reiterated by Sharma et al who found that 3 months of CPAP therapy lowers blood pressure and partially reverses metabolic abnormalities.¹⁶ Hence, as was done in this case CPAP therapy should be recommended in all patients with syndrome Z more so in patients who can afford portable machines to administer home based CPAP therapy.

Dubey et al in their study had validated polysomnography as a valuable tool to access non symptomatic sleep disordered breathing at an early stage in patients with metabolic syndromes.¹⁷ Iyer et al also observed that the association of sleep disorders with obesity and metabolic syndrome demands sleep history to be recorded and polysomnography performed in these patients.¹⁸ Diagnosis of sleep disordered breathing will pave the way for better management and possibly reversal of metabolic errors. Pandharipande et al in line with these findings suggested therefore that every patient with the metabolic syndrome should be screened for OSA, at the very least by taking a sleep history and using the Epworth sleepiness scale.¹⁹ If results are positive, a diagnostic sleep study should be performed. In fact the metabolic syndrome itself could serve as a marker of OSA as these two syndromes often go hand in hand in the form of syndrome Z. Based on our experience in this case we too strongly recommend the same for early identification and better management of syndrome Z.

Ravindran et al while reporting a case of syndrome Z had also emphasized upon the significant correlation of syndrome Z with CAD and the need for early diagnosis and treatment of this condition to prevent cardiovascular morbidity and mortality.²⁰ We also by means of this case report intend to sensitize the medical community regarding the magnitude of the syndrome Z epidemic and the urgent need to institute public health measures in this regard.

CONCLUSION

To conclude we can say that by means of the above reported case we want to lay stress on the dire consequences of syndrome Z so that further prospective and interventional studies, with adequate sample sizes and longer follow-up, rigorous control for confounding factors and ideally, randomization and control for any therapeutic intervention, can be encouraged to estimate the exact incidence & prevalence and explore the other not yet identified ill health effects of syndrome Z in order to initiate goal directed community health measures to curb this rising epidemic.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: Not required

REFERENCES

1. 1. Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J. Harrison's principles of internal medicine. 19th ed. New York: McGraw-Hill; 2015.
2. 2. Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. The Report of an American Academy of Sleep Medicine Task Force. Sleep. 1999;22(5):667-89.
3. 3. Sharma SK, Reddy EV, Sharma A, Kadhiravan T, Mishra HK, Sreenivas V, Mishra HK, Lakshmy R. Prevalence and risk factors of syndrome Z in urban Indians. Sleep Med. 2010;11(6):562-8.
4. 4. Reddy EV, Kadhiravan T, Mishra HK, Sreenivas V, Handa KK, Sinha S, et al. Prevalence and risk factors of obstructive sleep apnea among middle-aged urban Indians: A community-based study. Sleep Med. 2009;10:913–8.
5. 5. Lam JC, Sharma SK, Lam B. Obstructive sleep apnoea: Definitions, epidemiology and natural history. Indian J Med Res. 2010;131:165–70.
6. 6. Wilcox I, McNamara SG, Collins FL, Grunstein RR, Sullivan CE. ‘‘Syndrome Z’’: the interaction of sleep apnoea, vascular risk factors and heart disease. Thorax. 1998;53:25–8.
7. 7. Peppard PE, Young T, Barnet JH, Palta M, Hagen EW, Hla KM. Increased prevalence of sleepdisordered breathing in adults. Am J Epidemiol. 2013;177(9):1006-14.
8. 8. Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep apnea: a population health perspective. Am J Respir Crit Care Med. 2002;165(9):1217-39.
9. 9. Goldbart AD. Sleep medicine. Curr Opin Pediatr. 2015;27(3):329-33.
10. 10. Agrawal S, Sharma SK, Sreenivas V, Lakshmy R. Prevalence of metabolic syndrome in a north Indian hospital-based population with obstructive sleep apnoea. Indian J Med Res. 2011;134:639-44.
11. 11. Mishra B, Mishra B. Acute onset sleep apnea with severe transient hyperglycemia in young adult: the diagnostic dilemma and management controversy. Int J Res Med Sci. 2013;1:168-72.
12. 12. Hasan A, Uzma N, Swamy T, Shoba A, Kumar B. Correlation of clinical profiles with obstructive sleep apnea and metabolic syndrome. Sleep Breathing. 2011;16(1):111-6.
13. 13. Khot R, Sinha N, Joshi R, Wankhade N. Prevalence and Clinical Profile of Syndrome Z in Type 2 Diabetes Mellitus. Vidarbha J Internal Med. 2017;23:6-12.
14. 14. Iyer S. Sleep and Type 2 Diabetes Mellitus- Clinical Implications. JAPI. 2012;60:42-7.
15. 15. Soneja M, Singh V. Metabolic abnormalities in obstructive sleep apnea: A double whammy. Lung India. 2012;29:107-8.
16. 16. Sharma SK, Agrawal S, Damodaran D, Sreenivas V, Kadhiravan T, Lakshmy R. CPAP for the Metabolic Syndrome in Patients with Obstructive Sleep Apnea. N Engl J Med. 2011;365:2277-86.
17. 17. Dubey AP, Rajput AK, Suhag V, Sharma D, Kandpal A, Keisham R. Prevalence of obstructive sleep apnoea in metabolic syndrome. Int J Adv Med. 2017;4:722-7.
18. 18. Iyer S, Iyer R. Sleep and obesity in the causation of metabolic syndrome. Int J Diab Dev Ctries. 2006;26(2):63-9.
19. 19. Pandharipande M, Manohar T, Joshi P. Metabolic syndrome and Obsructive sleep apnea - Syndrome Z. Vidarbha J Internal Med. 2017;23:4-5.
20. 20. Ravindran C, Arun P, Harilakshmanan P. Calicut Medical J. 2007;5(1):1.