South Asian Health in Perspective

Why do highly educated, prosperous middle aged Indian men or women need to worry about health? They now have access to some of the best hospitals, highly qualified physicians, and can literally buy healthcare like a commodity. Surely, there is no cause for concern?

Sadly, there is. Many of the conditions I am going to discuss here are not diseases of poverty, but maladies associated with plenty.

In the two decades between 1990 and 2010, the proportion of deaths worldwide from non-communicable diseases (NCD) rose from 57% to 65%. Fully 80% of these occur in countries like India. And 90% of those deaths affect people below the age of 60.

The 4 biggest killers among NCD are CV disease, Cancer, COPD and Diabetes. Three of those are particularly relevant for Indians.

Of these, the one that towers above the rest is cardiovascular disease- read as a higher risk of MI and stroke. It's sobering to realise that the Indian subcontinent accounts for 25% of the world population but 60% of patients with heart disease.

A recent study (2010-2014), charmingly called the "MASALA study" (Mediators of Atherosclerosis in South Asians Living in America), showed that this cohort has a 4-fold higher risk of ASCVD than the general population. Furthermore, they develop this a decade earlier than others- often even before they have reached their 50s.

But it doesn't end there. They are more likely to require CABG to treat their IHD, and are likely to have poorer outcomes at CABG.

So what's driving this? The fact that Indians have one of the highest rates of Type 2 Diabetes Mellitus (T2DM) does not help. Worldwide, 1 in 11 people suffer from T2DM, i.e. 9%. The Indian government's own figures puts the prevalence at 11.8%. However, the prevalence is almost double in urban areas vis-a-vis rural settings, so that figure is an underestimate for most Indians reading this article.

The worrying thing is that many Indians who develop T2DM or IHD would not be classified as overweight or obese by international consensus definitions. Thus internationally, overweight is BMI>25, while obesity is defined as BMI>30. It has now been suggested by the AHA that we lower this to 23 and 27.5 for people of South Asian origin. Why is that?

The problem appears to be with the distribution of body fat in Indians. We tend to have less of our body weight contributed by muscle and more by fat. However, this fat is distributed around our abdominal organs- so called visceral fat and around our heart, where they contribute to an inflammatory phenotype in the blood vessels. Furthermore, Indians have almost half the brown fat- so called brown adipose tissue, of Caucasians, which is thermogenic and helpful in burning off the calories. Our basal metabolic rate is lower than other ethnicities. It appears that we accumulate fat- in the wrong places- literally, and struggle to burn it off. Thus T2DM and IHD both occur at lower BMI in Indians.

South Asians also have a higher prevalence of hypertension (not more than Blacks), high triglycerides, lower HDL, more LDL cholesterol, and a higher total cholesterol to HDL ratios, again, all at a lower body weight than other groups.

Diet clearly plays a part. Thus the reliance on unrefined bread- naan, etc, high usage of trans fatty acids through Vanaspati, and sources of saturated fats such as ghee and butter don't help. Adoption of Western diets both in India and in those living abroad, with a preference for high fat dairy, pizzas, potatoes and red meat makes for the worst of both worlds. Those who do best have a bicultural diet, adopting the best from both systems, combining a predominantly vegetarian diet with a high consumption of green leafy salads, whole grains, fruits, nuts and seeds, and chicken and fish.

Vegetarianism itself however does not help as this is often accompanied by fried snacks, sweetened beverages, and high fat dairy.

High intensity statins should be prescribed for secondary prevention. Those with T2DM, aged 40-75 and LDL>70 mg/dl should have moderate intensity statins. With other risk factors in addition to T2DM, such as family history of ASCVD, LDL>160, metabolic syndrome, CKD, pre-eclampsia, RA or HIV and South Asian origin, high intensity statins should be used. This means that all Indians aged 40-75 who have T2DM should take high intensity statins.

Primary prevention is based on the estimation of 10-year ASCVD risk through an online calculator, with risk stratified into 3 categories. (<7.5%, 7.5-20%, and >20%). CT calcium scores may be used where doubt exists, such as the intermediate group.

Indians have an unique vulnerability to haemorrhagic stroke. This may be associated with a higher prevalence of hypertension and high salt intake, but there are other, yet undefined factors. Unfortunately, this means that people who need anticoagulation, specifically those with AF and CHADS2 or CHADSVasc score of >1, are often not treated with anticoagulants, despite the availability of DOACs. Instead, aspirin is overprescribed for this group.

Undiagnosed CKD, related to ASCVD, or indeed as a contributor to ASCVD (it cuts both ways) is a further problem. Indians are vulnerable to heat stress nephropathy, found in hot dry areas. This was first described in central America, and therefore began under the rubric of Meso-American nephropathy. It then appeared in Sri Lanka and in Andhra Pradesh, particularly in the Nellore district. It tends to predominate in rural areas and is therefore more common in farmers, with >60% prevalence in villages. It's thought to be related to excessive sweating, coupled with inadequate hydration, with contributions from rhabdomyolysis. The temperature in India has been increasing at the rate of 0.8 degrees Celsius annually in many areas, and it is not unusual to find a wet bulb temp of>35 degree Celsius a few days of the year, a threshold that equates with intolerable heat.

Next to the heart, perhaps the most threatened organ in Indians is the liver. There are 4 prime insults that leads to this risk- alcohol, obesity, Hepatitis B and Hepatitis C.

Alcohol use is common in India across all sections of the society, and is far more common among men. Unfortunately, the Asian liver is also more susceptible to the ravages of alcohol, with increased production of acetaldehyde. Thus, studies in the UK show that Asians, particularly Sikh men, have a higher risk of cirrhosis, compared with White men drinking equivalent amounts of alcohol. Asian women drink much less often, but are exquisitely vulnerable to alcohol induced liver disease.

The chronic viral hepatitides B & C are silent killers in India, as they are in the rest of the world. It is estimated that India has 57 million cases of Chronic Hepatitis B, more than a fifth of the worldwide burden of 257 million cases. The prevalence of Hepatitis C carrier status in the Indian populace is 1-2%, equating with a total case load of 13-26 million cases, out of a worldwide denominator of 140 million cases. As fully 70% of Hepatitis C cases lead to carrier status (55-85%), most subjects are unaware that they have Hepatitis C. The commonest genotype by far in India is Genotype 3, unfortunately also the strain that leads most commonly to liver scarring and hepatocellular cancer. Unlike in the West, chronic Hep C in india is mostly acquired by vertical transmission rather than IVDU or in MSM.

Those born between 1945 and 1965 have a higher risk of chronic Hepatitis C due to a birth cohort effect.

NAFLD, is as expected, common in India, given the high prevalence of correlates such as T2DM, hypertrigyceridaemia, and high BMI. There is very little awareness of this condition and it is particularly damaging in conjunction with Chronic Hepatitis or alcohol.

It would only be appropriate to end with a word on the health of Indian women. They suffer from the lack of a national breast screening programme (contrast that to mammography every 3 years from age 50 in the UK), cervical screening programme (cervical smears from age 25 in the UK), and a general lack of awareness of post menopausal osteoporosis and the role of HRT. There is also very little awareness of the dangers of ovarian cancer and its late presentation.

Fully 800 million Indians are classed as anaemic. Fifty two percent of non pregnant women of reproductive age are anaemic. Iron deficiency anaemia (IDA) is the major aetiology, but other contributors such as poor diet, parasitic infections and haemoglobinopathies also apply. The intake of iron in diet is very low. IDA in turn leads to a higher risk of preterm labour, low birth weight and high infant mortality rate. Infants are at risk of developing IDA after 4 months of age.

However, apart from well known side effects such as fatigue, IDA has a sinister side to it. The microspherocytes that circulate in the blood of such patients are much less deformable, have higher viscosity, and are more likely to clog up capillaries. IDA also increases factor VIII levels & favours platelet aggregation, increasing the risk of both arterial and venous clots.

One large population based study involving over 200,000 patients showed that subjects with IDA were almost 50% more likely to suffer from ischaemic stroke (http://www.ncbi.nlm.nih.gov/pubmed/24349404). There is a well established association between IDA and cerebral venous thrombosis. The pro-coagulant effect of IDA is magnified in subjects who are otherwise predisposed to thrombotic events, such as Congenital Cyanotic Heart Disease and Hereditary Haemorrhagic Telangiectasia. In the former condition, severe polycythaemia is a physiological response to chronic deoxygentation, with haemoglobin levels often above 200g/l. Despite this, venesection is avoided unless symptoms of hyperviscosity such as headache, myalgia, or blurred vision are intolerable and the haematocrit is more than 65%, as the risk of causing IDA is unacceptable.

IDA is also the commonest secondary cause of Restless Legs Syndrome (RLS). This is a disorder where subjects have an unpleasant feelings in their legs in bed or while they are resting, relieved only by moving their legs. The condition affects sleep and many subjects are chronically sleep deprived. While most cases are primary, a significant proportion are iron deficient and respond to iron repletion.

The association of IDA with Restless Legs Syndrome led people to investigate its role in Parkinson's Disease. Reason? RLS responds well to anti-Parkinsonian drugs such as ropinirole. On such chance observations rests progress in Medicine. Sure enough, researchers established an association- IDA is more common in Parkinson's Disease although the association is nowhere as strong as between IDA and RLS. However, the challenge in Parkinson's Disease (PD) is to recognise it when it is not fully established...or even predict it years before the classical motor symptoms of rigidity, bradykinesia and tremor develop. It is now well recognised by neurologists that a constellation of non-motor symptoms- specifically anosmia, constipation, and in particular a strange phenomenon called Rapid-Eye-Movement Sleep Disorder (REM Sleep Disorder) develop in patients destined to suffer from PD up to 5-10 years before the motor symptoms set in. The last of these, REM Sleep Disorder is a fascinating example of corruption of normal physiological processes and deserves an explanation.

Normally, during REM sleep, which principally occurs in the second half of the night, dreams occur frequently, accompanied by a physiological paralysis of skeletal muscles. In REM sleep disorder, the paralysis of skeletal muscles are lost, so that the subject "acts out" his dreams (the disorder is much more common among men) with motor movements such as flailing arms and legs. Such movements can often be quite violent, and in some cases spousal injury has occurred. It has been estimated that REM sleep disorder affects up to half of all patients with PD. It is even more common in other α-synucleopathies such as Multiple System Atrophy and Lewy Body Dementia, affecting around 80% of patients. Thus, strictly speaking, non-motor symptoms are not unusual in PD and Parkinsons plus disorders at all. They are however less appreciated.

Why Do Subjects of Afro-Caribbean Ancestry Have a Higher Mortality from COVID 19 than Caucasians?

The figures are startling. The mortality rate from Covid 19 among black Americans is 2.6 times that of Caucasians.

https://www.apmresearchlab.org/covid/deaths-by-race

In the UK, the figures are even more stark. Blacks are more than 4 times likely to die from COVID than whites.

https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/deaths/articles/coronavirusrelateddeathsbyethnicgroupenglandandwales/2march2020to10april2020

Although in general, Asians and Hispanics do worse than Caucasians as well, the differences are far less pronounced.

What accounts for this difference? There are various possibilities including genetic differences, acquired co-morbidities (diseases) or perhaps the way those co-morbidities are managed by physicians. The last one interests me the most.

Mendelian randomisation is nature's way of demonstrating differences in outcome due to a putative risk factor. For example, subjects with familial hypercholestrolaemia, the commonest autosomal dominant condition in the population, have a higher risk of heart disease and stroke than those without the condition, due to the fact that they have high LDL cholesterol. So far, no such signals have emerged in COVID.

However, differences could be acquired. Black subjects have a higher prevalence of hypertension and obesity than other races. Both of these have emerged as significant risk factors for COVID related mortality.

While the above is undoubtedly true, I believe (I haven't seen this in the medical press yet) that there is another factor- how hypertension is managed in Black subjects. For unknown reasons, Black people with hypertension respond poorly to a class of drugs called ACE inhibitors (yes, it's the same ACE you read about in the context of COVID receptors). In fact, there is evidence to suggest that Black subjects have a higher risk of death from MI (heart attack), stroke and heart failure when treated with ACE inhibitors than when not.

https://www.thecardiologyadvisor.com/home/topics/hypertension/ace-inhibitors-may-not-be-as-effective-in-black-patients/

As a result, ACE inhibitors are used far less often to treat hypertension in Blacks than in other races, and herein, I believe, lies the rub. I have cautioned here in the past against discontinuing ACE inhibitors in hypertensive subjects during the pandemic, as this is likely to lead to harm, an inference that was later confirmed by NEJM.

https://www.nejm.org/doi/full/10.1056/NEJMsr2005760 (free to access)

This is a case of unintended iatrogenic (physician induced) randomisation. If you are obese, and hypertensive, you are more likely to die from COVID 19. However, if you are obese, hypertensive and not taking ACE inhibitors, as in the majority of Black subjects, that risk is far higher.

Hypokalaemia & Hypertension

A relatively common problem in clinical practice is the young subject with hypertension in association with hypokalaemia and metabolic alkalosis. Physicians should resist the temptation of labeling this subset as "Essential Hypertension". A definitive diagnosis can be achieved with a bit of perseverance.

As medicine evolves, new paradigms displace old ones. Primary hyperaldosteronism was thought to be exceedingly rare. Not so. It is now recognised that 10-15% of subjects with hypertension have primary hyperaldosteronism. This is particularly true in young subjects, subjects with a strong family history of hypertension and those with hypokalaemia.

Yet, too much reliability has been placed on the presence of hypokalaemia as a marker of this condition. In fact, less than 50% of subjects with primary hyperaldosteronism have hypokalaemia. The rest are normokalaemic. Therefore it is important to have a high index of suspicion in young subjects, those with a strong family history of early onset hypertension, those with family history of stroke before age 40, and those with refractory hypertension, i.e. subjects whose BP remains uncontrolled despite three anti-hypertensives, including a diuretic.

The assessment should begin by measuring the ratio of plasma aldosterone to plasma renin activity (PRA). A ratio of >30 with an absolute concentration of aldosterone of>415 pmol/l and in particular, a completely suppressed PRA is virtually diagnostic of primary hyperaldosteronism.

The most common cause of this condition is idiopathic adrenal hyperplasia (IHA), causing bilateral hyperplasia of the adrenals, accounting for 65% of cases. Around 30% of cases are due to unilateral adrenal adenomas. The other 5% comprises 3 rare disorders- hereditary hyperaldosteronism types 1,2 and 3.

Type 1 hereditary hyperaldosteronism is a fascinating condition. Also called glucocorticoid remediable aldosteronism (GRA), this rare autosomal dominant condition is due to the fusion of two genes- CYB11B1 and CYB11B2, whereby the enzyme aldosterone synthase comes under the control of ACTH. Thus, aldosterone is made in the zona fasciculata rather than zona glomerulosa and is suppressible by steroid therapy. Half of these subjects have a normal serum potassium.

Type 2 is simply an inherited predisposition to adrenal adenoma or hyperplasia.

What if the plasma renin and aldosterone are both raised? Think of renovascular hypertension, renin secreting tumours, coarctation of aorta and subjects on diuretics.

Then there are those whose plasma renin and aldosterone are both suppressed. These subjects have a non-aldosterone related cause for their hypertension such as hypercortisolism due to Cushing's syndrome, Syndrome of Apparent Mineralocorticoid Excess (SAME), or excessive liquorice intake, certain causes of congenital adrenal hyperplasia such as 11-beta hydroxylase deficiency, deoxycorticosterone secreting tumours and Liddle's syndrome.

Two inherited conditions deserve special mention. SAME is a rare autosomal recessive condition due to inherited deficiency of 11-beta hydroxysteroid dehydrogenase deficiency. This is a renal enzyme that converts cortisol to inactive cortisone. When this enzyme is deficient or inhibited by liquorice, or overwhelmed by excessive production of cortisol, as in Cushing's syndrome (particularly due to ectopic ACTH production from small cell or other tumours), cortisol is freed up to act on the mineralocorticoid receptors and mimic the action of aldosterone. These patients tend to have a very low serum potassium.

The other inherited disorder with suppressed aldosterone and renin levels is Liddle's syndrome. This is an autosomal dominant condition where epithelial sodium channels responsible for reabsorption of tubular sodium at the expense of potassium remain constitutively open due to inability to remove the beta or gamma subunits of these channels. The removal of these channels from the tubular epithelium depends on an uniquitin ligase called Nedd, which is defective in Liddle's patients. Intuitively, direct potassium channel blockers such as amiloride and triamterene work well in the treatment of hypertension in Liddle's syndrome, while aldosterone antagonists such such as spironolactone do not. It's worth remembering that as in GRA, over half of subjects with Liddle's syndrome have normal serum potassium.

In subjects with high aldosterone:PRA ratio, the next test is salt loading to see if the serum aldosterone levels are suppressible. This can be done as an inpatient after infusing IV saline, or as an outpatient, after loading for 3 days with oral salt tablets. Subjects with primary aldosteronism will not suppress their aldosterone levels after salt loading.

Such subjects should then have a CT scan to pick up an adrenal adenoma putatively responsible for the excess aldosterone. If the CT does not show an adenoma, and irrespective of the CT results in subjects over the age of 40, most authorities would recommend that patients should have adrenal vein sampling for aldosterone:cortisol ratio to distinguish functional adenoma from IHA. Subjects under 40 with an obvious adenoma on CT should be directly considered for surgical adrenalectomy. Conversely, those with IHA would benefit from medical management with spironolactone.

Acknowledgement: uptodate.com