An Adolescent with Obesity that presents with Symptoms of T2DM

Case Report

1. You see a girl (Janet) of 14 years-old with her father in your office for a sore throat that you manage with success. Looking at this girl, you notice that she is obese and that no recent measurement of Body Mass Index (BMI) is included in her file. What should you do as a first step since the main issue at this time is her weight problem?

(a) you ignore the weight problem and discuss only the medical consequences associated with obesity.

(b) you measure her BMI.

(d) you ask permission to discuss with the children and parents of the child’s weight problem and explore changes skills.

Answer: d

Explanations

(a) You ignore the weight problem and discuss only the medical consequences associated with obesity

HCPs can play an important role in the prevention and management of pediatric obesity, because they have long-term relations with obese children/adolescent and their parents. However, most primary HCPs feel ill-prepared to deal with this problem or even they perceive their efforts as inefficient [1]. They also noted obstacles to the proper management of pediatric obesity such as attitude and beliefs perceived by the children/adolescent and their parents, their own attitudes and beliefs concerning the problem of pediatric obesity as well as obstacles related to the clinical practice with this population (lack of time and motivation, inadequate medical equipment, etc.). Even considering these obstacles, ignoring the problem is certainly not the best approach, and it is contrary to what it is recommended in the prevention practice guidelines [2-4].

HCPs often associate obesity with their related medical consequences such as T2DM, HTN, dyslipidemia, CVD, orthopedic and other health problems. Those are certainly very good issues that need to be investigated. However, as a suggested approach since this patient is presenting without any other complaints, it is essential to determine the level of awareness of the children/adolescent and parents to the problem of the child’s weight and then to evaluate their ability to make one or more changes to improve or fix this problem. This process cannot be done without first asking for the permission to discuss the problem with the youth and her parents until you find other obesity-related problems. The best way to approach this patient and her father is by utilising the first A “Ask” of the “6As” model of counselling. For more information on the counselling approach of an obese patient the reader is refer to the “6As” model that is fully described in the article number 4, especially on the “ask” component of the model. The readers are also invited to read the most recent publications and books made by Dr Plourde on this counselling approach to have a complete explanation on the use of this counselling technique [5-8].

(b) You measure her BMI

The measurement of BMI is recommended as a practical measure for the prevention and management of pediatric obesity. It must be taken each year from the age of 2 years to follow the change of child’s weight status and its associated disorders. It can be taken at each visit of regular monitoring or when the patient presents for a specific health problem, as for our patient. The BMI measurement is the method most commonly accepted and used to track obesity in children and adolescent because it is a non-invasive measure. It is also a reliable indicator of body fat and correlates well with the complications associated with obesity [2-4]. Although it is recommended to perform the measurement of BMI in this young girl to evaluate her obesity and health risks, considering that this patient is obese, measuring her BMI is certainly relevant but first you should ask for the permission to discuss the weight problem and raise this issue with tact to avoid creating potential discomfort with the patient and her father. Overweight and obesity highly increase the risk of developing T2DM during childhood. There is also strong evidence that those who are obese during childhood are highly likely to be obese into adulthood and presents the obesity-associated complications [9].

This is certainly an approach that we should look after a discussion with the patient and her father and a more thorough assessment of her condition. Still, this shouldn’t be the first step. Weight loss is not generally recommended for children who are overweight as it may interfere with growth and development [5-8]. The main goal here is to keep Janet from gaining additional weight with hopes that she will grow into her current weight. With healthy eating habits and incorporating exercise, the emphasis should be on Janet’s new healthy lifestyle. Once she is finished growing, if weight loss is a concern, it can then be implemented. But, at this time, the priority is to ask her the permission to discuss her weight problem with her and her father. For more information on what should be included in this step of the counselling please refer to section “Arrange” component of the “6As” model of counselling.

(d) You ask permission to discuss with the children and parents of the child’s weight problem and explore changes skills

The first step and the most important in this case since you note that this patient is obese, is to ask the permission to discuss the problem of weight with the child and her father by asking the following questions or similar questions: “Are you concerned about your child’s weight and the effects of her weight on her health or quality of life? ‘’ Then you suggest the following statement: “Can we have a discussion about the problem of your child’s weight.” These questions can be modified to be adapted to the age and condition of the child [5-8].

The weight problem of a child is a sensitive issue that could embarrass the child and the parents. Therefore, you should proceed without issuing judgment. It is important not to blame or cause feelings of guilt among them. We must limit the medical jargon and use a sensitive and respectful approach. These discussions may provide to family physicians, pediatricians and other HCPs, as well as parents, better identification of personal or family environment factors which act as barriers to change. Talking about the advantages and disadvantages of modifications to the current behaviors can also help parents to reconsider what they can do to help their child [5-8].

2. During the discussion you learned that the patient has non voluntary loss few kg during the past 5 weeks and had more urination than usual during the past 4 days. There was no history of polyphagia, polydipsia or dysuria. But she mentioned that she feels more tired recently that she attributed to her recent episode of sickness including sore throat, cough and some fever. You learned that her mother had gestational diabetes while she was pregnant with Janet. She is now known T2DM since 3 years ago and presently she is on OADs. Janet is the second of three children but her siblings are well. There is a positive family history of T2DM in mother, maternal grandmother, maternal grand aunt, paternal uncle and paternal grandmother. Findings on physical examination were those of an obese adolescent (BMI-32kg/m2) not dehydrated with no evidence of acanthosis nigricans. Systemic examination was essentially normal. The blood pressure was 124/82 which was essentially comparable on subsequent visit. The patient and his parents have a sedentary lifestyle with plenty of time spent in front of the television, playing video games and little or no regular physical activity. Their eating habits are also inadequate; they consume a lot of fatty foods and sugary drinks and junk food. There is also a poor intake of fruits and vegetables. Random blood sugar at presentation was 11.9 mmol/l (N= 3.9 – 5.5 mmol/l), and Urinalysis showed +1 of glucose and absent ketones. A provisional diagnosis of T2DM was made.

What should be the next most important step(s)?

(a) you explain that you will make a full assessment of the problem, including personal and family risk factors associated with her condition.

b) you give advice and information on diets, physical activity and other modes of treatment programs to help parents make an informed decision on the most appropriate method to manage the T2DM problem of their daughter.

(d) assist the child and parents to recognize factors that may resolve the obstacles in the management of the T2DM problem of the child.

(e) explain the necessary follow-up with you, family physician or pediatrician, or other HCPs, according to the needs.

Answer: a

Explanations

a) you explain that you will make a full assessment of the problem, including personal and family risk factors associated with her condition.

It is important to perform a complete history, a general physical examination and appropriate laboratory tests to exclude any complications associated with the adolescent condition to be consistent with the “assess” component of the “6As” model of counselling. The history of the development of the adolescent, including possible delays of growth and weight gain mode must also be evaluated. Psychosocial history of the adolescent looking for a history of depression, eating disorders and the quality of life is also useful because it may indicate the need for a consultation in psychology or psychiatry. The family history of T2DM and associated disorders, including a detailed history of risk factors and complications (see article number 2), must be an integral part of the medical history. The history is complemented by questioning past and present, use of drugs including drugs taken by the mother during pregnancy and lifestyle, physical activity, eating habits, sleep patterns, family dynamics and socio-economic and environmental stress. You complete your assessment by performing a physical examination followed by the laboratory tests recommended (see laboratory testing) and those relevant from the medical history and physical examination. For more information on what should be included in this step of the counselling please refer to the appropriate sections of article number 4.

Pending the confirmation of the T2DM diagnosis by the full assessment (item a), the patient and parents were counseled and placed on dietary control with elimination of SSBs such as juices, soda, reduction of foods with high glycemic index (GI) such as table sugar, ice cream, white bread etc. and increased intake of food with low GI such as pasta, skim milk, sweet potatoes, as well as reducing portion of food and increasing exercise as explained in question 1c. For more information on what should be included in the “Advice” component of the “6As” model of counselling.

As for our patient, the mean age at diagnosis reported for T2DM in youth is 14 years, coinciding with the relative insulin-resistance occurring during puberty, which may precipitate glucose intolerance [10-13]. Although adolescents presenting with diabetes are normally assumed to have T1DM, this may no longer be the case, even if the patient presents in ketoacidosis requiring insulin treatment. In recent studies 5 to 25% of children with T2DM presented with ketoacidosis, and ketonuria was present in a further 33%. The majority of these children are obese, but the severity of the obesity may be mitigated by weight loss prior to presentation [10-13]. These factors may lead to the misclassification of adolescents with T2DM as T1DM, and possibly an under estimation of the current prevalence of this clinical problem. Other pertinent features in the differential diagnosis include a positive family history; the frequency of a first degree relative with T2DM has been reported as ranging from 74 to100%, and the presence of acanthosis nigricans has always been regarded as rare in childhood but when present is strongly associated with obesity and insulin resistance [10-13].

The HCP should pay particular attention to the following points while in presence of an T2DM pediatric patient: 1). both environmental and genetic factors contribute to the etiology of T2DM; 2). a family history of T2DM indicates an increased risk for the disease; 3). the most important preventive measure for an at-risk individual is a healthy lifestyle, including regular exercise, weight management, and a diet low in fats and concentrated sugars and high in fruits and vegetables; 4). small proportion of diabetes mellitus is due to highly penetrant autosomal dominant mutations that result in maturity-onset diabetes of the young (MODY), a form of diabetes mellitus that resembles T2DM and 5). the lifetime risk of T2DM in the general population is about 5%. If a person has a biological relative with T2DM, the risk is increased. When a parent has T2DM, the lifetime risk for offspring is 10-15%. Risk is increased to a lesser degree if only a second-degree relative, such as an aunt, uncle, or grandparent, is affected [10-13].

In general the following are the red flags: i) obesity (as well as body fat distribution, especially central or abdominal body fat adiposity), lack of exercise, and poor dietary habits are all associated with increased risk for T2DM; ii). prevalence of T2DM is higher in some racial and ethnic groups, including African Americans, Native Americans, Hispanic Americans, Asian Americans, and Pacific Islanders; 3). early signs of T2DM include increased thirst, frequent urination, sudden weight loss, blurred vision, and fatigue or irritability as a result of changes in blood sugar levels; 4) history of gestational DM and a high birth weight, and impaired glucose metabolism [10-13].

It is essential to establish the objectives of treatment with the child and the parents. Well family doctors, pediatricians and other HCPs are best placed to determine the best course of action with regard to treatment but it is the patient and his/her parents who must do the work. However, currently, it is difficult to come to a mutual agreement without performing the complete assessment of Janet’s medical condition (item a). In the “mutual agreement” step of the “6As” model of counselling, you should gently mention that the long-term safety is a priority with children and adolescents diagnosed with T2DM and that achieving good glycemic control safely and without delay is a priority for newly diagnosed T2DM individuals [11]. As Janet is young preventing/delaying the onset of diabetes complications through getting optimal glycemic control is particularly important. In adolescents, the onset of T2DM points to a lot of potential complications if the disease is not adequately controlled for long periods of time [14]. An HbA1c as near to normal (< 7%) while minimizing the risk of hypoglycemia is appropriate [12, 15]. There is no need to be aggressive in selecting the general treatment target since Janet seems to have an appropriate family support and she seems highly collaborative; we can consider stronger treatment target if we have strong social and family support, absence of co-morbidities and complications and recent diagnosis [11], but this cannot be decided at this time since the full assessment (item a) of her condition has not been completed. The glycemic target should always be individualised based on a number of factors [11]. The American Diabetes Association has put in place a very nice graphical representation of individual physiologic and patient-centered aspects (https://durobojh7gocg. cloudfront.net/content/diacare/38/1/140/F1.large.jpg) that one should incorporate in the selection of our treatment target that we can then negotiate with the patient [5-8]. For more information on what should be included in this “mutual agreement” component of the “6As” model of counselling. You, Janet and the parents agree on a weight loss of approximately one pound per week for the next few weeks with diet and physical activity has this can have beneficial effects on improving her glycemic control as well as her lipid levels. You also agree on HbA1c (< 7%) glycemic target, but you postpone the final discussion until you complete the full assessment (item a) of her condition to rule out other co-morbidities and complications that could impact the glucose target [11].

(d) assist the child and parents to recognize factors that may re¬solve the obstacles in the management of the T2DM problem of the child.

Family physicians, pediatricians and other HCP must assist the child and parents overcome their barriers to weight and T2DM management as “assist” is another important component of the “6As” model of counseling. Patients and parents should be directed to resources promoting proper management of weight and T2DM. Assist means educate, recommend and support the child and his parents in the performing of their duties. Again a full assessment (item a) should be performed first in order to have a clear clinical picture of the clinical context.

Another approach that you can combine to the “assist” step is working on correcting negative health behaviors. Once families are ready to make a change, you can choose a behavior that children and parents want to change and for which they feel they can achieve successfully. A useful strategy is to help parents change the family environment to break the habit of the child to eat in an unhealthy way or stay sedentary. Parents can implement changes in the family environment so that healthy foods are more easily available and accessible than the unhealthy food which become less accessible and even absent from their environment.

Parents can also make it harder to access sedentary activities by removing the TV in the kitchen or in the bedroom of the child, to get rid of the remote control and put video games in a closet. They can make physical activity more accessible by playing with the children, by going to the park with them. These small changes in the family environment prevent known and unhealthy behaviors and promote the acquisition of new healthier habits. It is important to deliver this message to parents, because even a small change in behavior can make a big difference in the energy ingested or expanded and this can significantly improve the condition of the child [5-8].

(e) explain the necessary follow-up with you, family physician or pediatrician, or other HCPs, according to the needs.

Monitoring is essential to ensure that the medical recommendations can be met more easily. Family doctors, pediatricians and other HCP may need to negotiate with the child and parents the frequency of follow-ups, which will vary according to the condition of the child and the possibilities of family organization. If follow-up with other HCP is recommended, the relevance of this monitoring should be clearly explained to the parents and their agreement must be obtained before it is organized [5-8]. You will have to “arrange” for Janet and her family to be referred for a specialized diabetes nurses who will provide dietary and physical activity advices as well as teaching on self-monitoring of blood-glucose (SMBG), if the diagnosis of T2DM is confirmed after the complete assessment has been performed (item a). As mentioned, a provisional diagnosis of T2DM was made and a series of blood test was requested. For more information on what should be included in the “arrange” component of the “6As” model of counseling.

3. Two weeks after you received the following results. The fasting plasma glucose (FPG) was 12.8 mmol/L (N= 3.9-5.5 mmol/L); HbA1c was 10.2% (4-6%); Ketone body was absent; Tests for insulin antibody and antiglutamic acid decarboxylase (anti-GAD) were negative Cortisol level was normal with a value of 230.6nmol/l (240-418nmol/l), cholesterol level was elevated at 6.9mmol/l (<5.0mmol/l). The electrolyte results were within normal ranges with Sodium 137mmol/ l (128–142mmol/l), Potassium −4.4mmol/l (3.4–4.8 mmol/l), Bicarbonate − 25mmol/l (24–30 mmol/l), Urea−3.3 mmol/l (2.4–6.0mmol/l) and creatinine −75mmol/l (60–120mmol/l); C-Peptide 1.2 mmol/l (0.2-1.0mmoll); ACR 0.88 mg/mmol (<3.5 mg/mmol); eGFR 118 ml/min (90-120 ml/min). The definitive diagnosis was T2DM

What should be the next most important step(s)?

(a) you give advice and information on treatment options to help parents make an informed decision on the most appropriate option to manage the problem of their daughter.

(b) you enter into a mutual agreement on the management goals.

(d) explain the necessary follow-up with a nurse specialised in the treatment of T2DM.

(e) All of the above.

Answer: e

Explanations

(a) you give advice and information on treatment options to help parents make an informed decision on the most appropriate option to manage the problem of their daughter.

In the first follow-up discussion with Janet and her family you should explain the results that she obtained from the blood work (the chemical profile). You explain that based on the results, and the signs and symptoms she presented that she has T2DM. Because of her negative antibodies to GAD [15] and C-Peptide level we can exclude/confirm that she is not having T1DM. When we explained the laboratory results and discuss the diagnosis, we must limit the medical jargon and use a sensitive and respectful approach. You should explain that controlling her blood glucose is a priority for Janet, that the onset of T2DM at an early age point to a risk of multiple medical complications if the disease is not controlled for long periods [14]. However, because of her high C peptide concentration, this implies a certain degree of insulin resistance.

There are four different tests that can be used to diagnose T2DM. The first is the HbA1C test that is greater than 6.5% though there are some question as to how accurate these tests are as HbA1C levels might vary depending upon race/ethnicity. The second test that can permit a diagnosis is a FPG of greater than or equal to 7.0mmol/L. The third is of the two-hour plasma glucose or fasting glucose test which is a diagnosis if greater than or equal to 11.1 mmol/L during an OGTT. The last possible way to diagnose diabetes is by the symptoms – classic symptoms of hyperglycemia or hyperglycemic crisis which is random plasma glucose of greater than or equal to 11.1mmol/L. The standards for pre-diabetes are figured through similar tests but the numbers vary – these numbers are considered “normal but high” [10-13] The reason why Janet’s physician requested an autoantibody test as well as a C-peptide test is to ensure that the T2DM diagnosis is not being confused with T1DM. In obese children, screening guidelines for both T1DM and T2DM are very similar. C-peptide level is based on blood sugar level and is a sign that the body is producing insulin. A low levels or no insulin C-peptide means that the pancreas is producing little or no insulin. Janet’s C-peptide is high at 1.2 mmol/L while her GAD was negative. This means that Janet does in fact have T2DM and it is not being confused with T1DM. Because C-peptide level is high, this shows that her pancreas is still trying to overcompensate for the cells’ inability to take in glucose for energy.

Janet has cholesterol level of 12.8 mmol/L as mentioned earlier. This is high and due to her body’s inability to use blood glucose for energy and possibly a result of her high fat and high sugar diet, as well as her BMI of 31.0 kg/m². Her HbA1c level is an indication specifically of diabetes which was at an elevated level of 10.2% which is a measure of poor long-term blood glucose control. There was also protein and glucose in Janet’s urine which indicate that the kidney’s filtration ability has been altered.

In T1DM, there is a lack of insulin production caused by destruction of β-cells. In T2DM, insulin is produced but the tissues are insulin resistant and the body therefore has an increased need for insulin. To combat this, the pancreas produces more insulin but after too long the pancreas loses the ability to produce insulin at all. This result in T2DM which includes two metabolic defects: first insulin resistance and then insulin deficiency. Insulin resistance in T2DM is caused by a β-cell-receptor defect in which insulin cannot get into the cells and be taken up for fuel and then insulin deficiency which results in fasting hyperglycemia [10-13].

A pediatric patient with T2DM should be tested several times a year for protein in the urine. This is a sign that there is T2DM-related kidney damage as the kidney is allowing protein to escape the body without being absorbed. An extremely high amount of protein may be a sign of kidney disease. Kidney malfunctions and diabetes are related as kidneys are one of the organs that respond to the body’s glucose intolerance. Long-term glucose intolerance can harm the kidney, resulting with protein in the urine [10-13].

i) Potential Option: Lifestyle alone:

Achieving good glycemic control safely and without delay is a priority for newly diagnosed pediatric T2DM individuals [15]. As Janet is young preventing or delaying the onset of T2DM complications through optimal glycemic control is particularly important. In adolescents, the onset of T2DM points to a list of potential complications if the disease is uncontrolled for long periods of time [15]. Lifestyle interventions still form an integral part on any T2DM treatment regimen [15]. They can be considered in isolation for individuals with the glucose target of HbA1c (< 7.5%; 58 mmol/mol) [11]. Since Janet has marked hyperglycemia and even a strict diet and physical activity regimen is unlikely to restore her glycemic control, but would be certainly appropriate to correct her dyslipidemia.

ii) Potential Option selected: Lifestyle + metformin.

Metformin: Decrease HbA1c efficacy: high; hypoglycemic risk: low; Weight effect: Neutral/Loss; Major side effects: GI, Lactic acidosis; Cost: Low.

Choice of pharmacotherapy should aim to preserve β-cell function and improve insulin sensitivity; at present, metformin is the only OAD approved for use in children and adolescents [12, 15]. However Janet is severely hyperglycemic and metformin therapy alongside lifestyle interventions is unlikely to lower her HbA1c to the target level. Metformin would be expected to lower HbA1c by 1-2% leaving Janet with uncontrolled hyperglycemia [15].

iii) Potential Option: Lifestyle + Insulin .

Insulin: Decrease HbA1c efficacy: highest; hypoglycemic risk: high; Weight effect: Gain; Major side effects: hypoglycemia; Cost: variable.

Insulin can be considered alongside LSI from the onset for the treatment of T2DM in children and adolescents [11-12, 15]. For adolescents presenting with an HbA1c > 8% (69 mmol/mol) or severe manifestations of insulin deficiency, insulin is the most effective way to achieve rapid metabolic control [12]. However, Janet is nervous about the perspective of having to inject herself every day and is worried about weight gain since she is already obese. You should explain the benefits of using insulin to lower the risk of diabetes-related complications, that once glycemic control is obtained, it would likely be possible to switch to oral OAD (metformin) in combination with LSI.

(b) you enter into a mutual agreement on the management goals.

Following this discussion, the HCP and Janet decided upon a basal bolus of insulin regimen. Insulin regimens should mimic physiological insulin as closely as possible while achieving optimal glycemic control. Pre-prandial insulin should be divided into 3-4 pre-meal boluses; when regular insulin is being used, the basal: pre-prandial split is typically 30%:70% of the total daily insulin requirements For rapid acting pre-meal bolus, the basal pre-prandial split is typically 50%:50%. This is because regular insulin also provides some basal effects (10-15). The HCP and Janet decided to use rapid acting insulin for pre-meal boluses as it may reduce post prandial hyperglycemia and nocturnal hyperglycemia. Rapid acting insulin can also be taken immediately after food in order to increase flexibility.

During this short medical interview, you noted that one of the primary objectives of the child weight management is to improve her quality of life because she feels uncomfortable to play with the children of her age due to her weight. Therefore, she feels a bit excluded from her group. You also learned that neither the adolescent nor the parents are active physically. However, they do not seem to be very motivated by regular physical activity, despite the fact that this intervention could improve the skills of this young girl for the game and, therefore, have a positive effect on her quality of life. You agree, as a first step, to work on the reduction of sedentary behaviours such a reducing to less than 2 hours per day the time at watching TV or playing video games and gradually adding regular physical activity to promote physical fitness of this girl. You agree also on the importance to replace sedentary activities by low to moderate physical activities that parents and children would go to the convenience store, grocery store or another location nearby, foot or bike to increase in stages, physical activity, rather than taking the car [16].

Involving the entire family is important and ensures that the principle of treatment and the importance of LSI are clearly understood in order to permit appropriate level of support and encouragement from the entire family [13]. Education of the family and friends on the importance of lifestyle choices is essential [15]. Although Janet’s mother has T2DM, therapy is individualized and it is important that Janet’s family understands her individualized needs. In a family with more than one child, parental and sibling education may help prevent further development of T2DM in this family. Throughout the process, it is important to work with parents to verbalize clear and accessible objectives and discuss the steps to follow to achieve them. It is necessary to encourage parents to engage in healthy behaviours with the child/ adolescent and to serve as role models for change, an approach that has proved to be a good predictor of the success of the children in the management of their weight [5-8]. In this approach, the parents who eat vegetables, drink water instead of soft drinks, restrict the size of the portions of meals or snacks and engaged in physical activities with their children are more likely to encourage healthy behaviours in their children, because children learn by examples [5-8].

(d) explain the necessary follow-up with a nurse specialised in the treatment of T2DM.

You explain to the patient that insulin caries a risk of hypoglycemia and that SMBG is an integral part of optimizing Janet’s regimen. You explain that early optimization of blood glucose level will allow her for a rapid transition to oral therapy. For that Janet is advised to aim for the following blood glucose levels [13]: Pre-meal 5-7.2 mmol/L (90-130 mg/dL); Peak postprandial 10 mmol/L (180 mg/dL). You explain to Janet that in order to help her achieve these goals that you will refer her to a nurse specialized in the treatment of T2DM to learn about SMBG. The nurse will educate Janet on how to adjust insulin in response to daily glucose measurements and how to recognize and respond to hypoglycemia.

You explain that insulin is most effective when used in conjunction with an appropriate diet and exercise regimen to increase insulin sensitivity. For Janet the LSI must be specifically tailored to facilitate appropriate weight loss. In addition, to the advice on SMBG and the importance of adhering to the diet and exercise regimen, the diabetes nurses discuss the involvement of Janet’s family in the management of her diabetes. Janet and her family should be educated on SMBG – it is important to teach both Janet and her parents because Janet is young and may need assistance until she gets used to the system. SMBG is recommended with individuals with T2DM because it has been found to be very effective in controlling blood glucose levels. Tests should be done frequently in the beginning until patterns emerge and should be continued to be monitored around meal times, before and after physical activity, and before and after sleep. If Janet becomes ill then she must test her blood glucose every 4 to 6 hours with the same glucose targets as above.

According to the American Association of Diabetes Educators, there are many steps to educating those with diabetes. The first step is healthy eating as mentioned above, followed by being physically active. The nurse should teach Janet and her family members different ways to incorporate physical exercise into their daily routine such as going on family walk, taking more family outings that gets the family out of the home that are inexpensive alternatives to watching television (hiking, swimming, etc.). The nurse should then teach Janet and her family about monitoring and taking her insulin. This would have to be under the supervision of her parents as Janet is just 14 years old. Monitoring would include how to use a SBGM, knowing when to check the numbers and the meanings, the target range, and how to record blood sugar levels. This information should also be kept in Janet’s food journal especially at school. Any medications prescribed by Janet’s HCP should also be included. The nurse should stress the importance to Janet and her parents how important it is to follow this regimen. The next step is problem solving which looks at situations in which Janet may struggle to stick to her new, healthy lifestyle. For example, if there are no options at school for lunch that allow Janet to stick to her new diet or when she goes out with friends. The next step is healthy coping which is about adjustment to this new lifestyle, and the final step is about reducing risk which involves impaired awareness of warning signs of hypoglycemia [17]. For a complete example on problem solving, please consult the Chapter 7 of the book from Dr Plourde [5].

4. Then Janet has returned for her 6 month follow-up and since her diagnosis of T2DM, several insulin adjustments have been made to control her blood glucose level. Janet explain that she is feeling well but finds embarrassing to inject every day especially at school and when she goes out with friends. In addition she has managed very well to lose weight with good adherence to diet and exercise and she no longer feels exclude from the group. She expresses a strong desire to switch to oral therapy. You see that Janet’s journal on her cell phone has been meticulously completed and she has not experienced any problem with postprandial hyperglycemia in the past 3 months. Janet wants to transition from insulin to metformin. Her FPG: 6.7 mmol/L (120 mg/dl); her HbA1c: 6.3% (45 mmol/mol); her BP:120/80 mmHg; and her BMI: 26.7 Kg/m2 as well as a normal lipid profile.

True or False: you explain that she is doing very well on insulin and because of that it is preferable that she stays on insulin.

Response: False

Explanation

Both the risk/benefit ratio and the wish of each individual should be considered when designing treatment regimens. Janet is metabolically stable and is maintaining her blood glucose levels below her glycemic target. She has demonstrated a clear ability to manage her condition. Transitioning from insulin to metformin is therefore a possibility and something that Janet wishes to pursue. The insulin dosage should be tapered gradually to avoid hypoglycemia while steadily introducing metformin [11]. Transition from insulin to metformin can easily be achieved by decreasing insulin dose by 10- 20% each time the metformin dose is increased [11]. You should begin with metformin 250 mg once a day for 3 to 4 days then increase to twice a day if tolerated. Continue to titrate the dose in this manner over 3 to 4 weeks until the maximum dose of 1000 mg twice a day is reached. Meticulous SMBG is integral throughout this process; if the blood glucose reach the impaired range at any time, the taper should be slowed [11].

In conclusion, 3 years have elapsed since Janet was first time diagnosed with T2DM. She managed her T2DM well using metformin plus appropriate eating and regular physical activity. As a consequence, she is much happier and has lost 10 kg. Her FPG: 6.4 mmol/L (115 mg/ dl); her HbA1c: 6.1% (43 mmol/mol); her BP: 116/74 mmHg; and her BMI: 24.6 Kg/m2. The HCP continues to stresses on the importance of LSI to prevent disease progression for her and other member of the family. Now Janet is mostly an adult and if she begins to fail on metformin, she can return on insulin but she will be authorized to get access to a greater variety of OADs to control her T2DM and with the research progress she will eventually be able with the development of pharmacogenetics and pharmacogenomics to get access to personalized treatment.

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Inzucchi SE, Bergenstal RM, Buse JB, et al. (2012) Management of Hyperglycemia in Type 2 Diabetes: A Patient-Centered Approach Position Statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 35: 1364 -1379
Flint A and Arslanian S (2011) Treatment of Type 2 Diabetes in youth. Diabetes Care. 2011; S2:S177-S183Plourde G, Marineau JM. Reducing Sedentary Behaviours in Obese Patients. If they won’t exercise more – try to make them sit less. Parkhurst Exchange.
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Personalised Medicine for the Treatment of T2DM

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Case Report

Introduction

Personalized medicine aims at better targeting therapeutic intervention to the individual by maximizing the benefits and minimizing harms associated with drugs. T2DM is a heterogeneous disease with an important genetic background. The underlying pathogenic mechanisms and the clinical features markedly vary among patients [1-3]. The American Diabetes Association (ADA), the European Association for the Study of Diabetes (EASD) position statement on T2DM management and the American Association of Clinical Endocrinologists (AACE) clearly mention that the choice of T2DM goal therapies of reaching an HbA1c of < 7% for all patients should be replaced by a more patient-individualized approach based on attributes specific to both the patients and the medications themselves [4-6].

Individual drug response may vary due to many factors such as: 1). Individual characteristics of the patient: age, gender, BMI or comorbidities; liver and/or kidney function and others; 2). polymorphisms in genes encoding drug-metabolizing enzymes, transporters, receptors and molecules involved in signal transduction; 3). some specificities of the disease itself such as the known duration of T2DM that may influence the magnitude of the beta-cell defect, its severity as quantified by the increase in HbA1c; 4). the main components of the pathophysiology of the disease, especially the relative contributions of the defect in insulin secretion and insulin resistance; 5) the properties of the OADs especially their specific mode of action tackling the most crucial pathophysiological defects and targeting fasting and/or postprandial hyperglycaemia; and 6). the PKs parameters that may be altered by comorbidities such as renal or hepatic impairment but also by genetic background and polymorphism in enzymes or transporters playing a key role in drug metabolism leading to a true individual drug response [7-8].

However, we are at some point already going for an individualized approach in the treatment of T2DM that is based on our understanding of some of the pathophysiology of the disease such as their risk for hypoglycemia, how long the patients have had the disease, whether they have other important comorbidities, their risk of weight gain and their motivation status. We actually have very good guidelines based on outcome data to suggest how we should individualize treatment targets. Specifically, the ADA has put forward a very interesting graphical representation of individual physiologic and patient-centered patient-centered aspects (https: //durobojh7gocg.cloudfront.net/content/ diacare/38/1/140/F1.large.jpg) that the HCP should incorporate in the selection of our treatment target and in the selection of the appropriate medication. However, a great inter-individual variability exists in the clinical outcomes of glucose-lowering agents, especially for the OADs [7-8]. Therefore, the poor therapeutic outcomes that we often observed with a specific medication may be caused by treating patients without being concern for the individual pharmacogenetic and/or the pharmacogenomic characteristics that might influence the drug response.

Therefore, understanding the basis of this heterogeneity should provide an opportunity for better personalising treatment strategies according to individual patient clinical characteristics and the molecular characteristics of the OADs [9-11]. This case report will discuss both the opportunities and the challenges of personalised medicine and how this new treatment issue may lead to a better individualized treatment of T2DM. Although, the treatment of pediatric T2DM is rather limited to insulin and metformin, if we consider that the mean age that most pediatric patients are diagnosed with T2DM is around 14 years-old, these adolescents will become rapidly adult’s patients and we believe that it is a very good opportunity to introduce this topic within this special issue to better prepare the HPC to this new era of treating T2DM.

Case Report

Joseph is a 16 year-old obese (BMI 32 kg/m2) European- American that came to your office with her mother because he presented symptoms of T2DM. With this limited information what should be the individual characteristics and disease-related biological characteristics you need to consider in the objective of personalising Joseph’s treatment in case he receive the diagnosis of T2DM?

(A) His age;

(B) His gender;

(D) His race/ethnicity;

(E) His markers of insulin secretion (C-peptide);

(F) His markers of disease severity (HbA1c)

(G) His fasting versus postprandial hyperglycaemia;

(H) His markers of insulin resistance (metabolic syndrome);

(I) The presence or not of renal impairment.

(J) The presence or not of liver disease.

(K) All of the above.

Answer: K

Explanations

A) His Age

As mentioned on many occasion in previous articles, the onset of T2DM at an early age points to a glycaemic legacy if the disease is uncontrolled for long periods of time. Many of these patients are obese at diagnosis and also have co-morbidities such as HTN, dyslipidaemia and microalbuminuria at a relatively early age which put them at risk of early CVD. Although LSI may be helpful in the management of many of these co-morbidities, pharmacotherapy with the aim of preserving β-cell function and improving insulin sensitivity should often be added. At present, metformin is the only OAD approved for use in children and adolescent. However, recent data from the Treatment Options for Type 2 Diabetes and Adolescents and Youth (TODAY) study showed that 50% of children and adolescent failed to maintain durable glycaemic control with metformin monotherapy and combination therapy or insulin was often necessary within a few years of diagnosis. Although not discussed in this article, it is possible to suggest the presence of a pharmacogenomic and pharmacogenetic components to explain this relatively poor response to metformin (See below). Therefore, agents that address insulin resistance other than metformin can potentially help to preserve β-cell function (DPP-4 inhibitors and GLP-1 receptor agonists) should be considered given that the disease will progress over many decades. The choice of medication based on Joseph genetic information will be further discussed below.

B) His gender

Differences in gender responses to therapy may be considered when individualizing treatment for people with T2DM as it is an important personal characteristic [7, 12]. For instance, females had smaller decreases in HbA1c and were less likely to reach glycaemic targets despite higher insulin doses and more hypoglycaemic events than males [7]. However, no obvious gender-related differences were reported with OADs so far. Further studies are required to clarify whether or not a gender-related difference clearly exists for OADs. However, for the reasons discussed in previous articles including those related to the puberty; in the context of clinical practice gender should always be considered in personalising treatment.

C) His BMI

When only two classes of OADs were available, metformin was preferred in obese patients while sulphonylureas were considered as a better option in non-obese patients with T2DM. Now metformin is considered as the first-line therapy in all patients with T2DM [8] in the absence of contraindications that include acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma, history of ketoacidosis with or without coma and relevant gastrointestinal symptoms; those patients should rather be treated with insulin [13]. Currently, OADs can be separated according to their effects on body weight: some inducing weight gain (sulphonylureas, glitazones, insulin), others being weight neutral or inducing only mild weight reduction (metformin, DPP-4 inhibitors) and others associated with significant weight loss (SGLT2 inhibitors, glucagon-like peptide-1 or GLP-1 receptor agonists) [7, 14-15]. These differential weight effects may influence HCP’s preferred choice according to patient’s initial body weight and desire of weight change. Considering that our patient is obese, choosing a medication that has a positive effect on weight loss can be a good choice in personalising his treatment.

Therefore, medications in the class of SGLT2 inhibitors or GLP-1 receptor agonist should be considered. However, other clinical and genetic considerations needs to be assessed before deciding which medication should be the best for Joseph. This will be further discussed below.

D) His race/ethnicity

Differing effects of metformin on glycaemic control by race-ethnicity have been reported. For instance, African American individuals appear to have a better glycaemic response to metformin when compared with European Americans [16]. DPP-4 inhibitors exhibit a better glucose-lowering efficacy in Asians than in other ethnic groups. However, the precise underlying mechanisms remain unknown [17] and other research are also needed to further document the impact of race/ethnicity on the choice of the most appropriate OADs to treat their T2DM. The fact that our patient is European American may indicate that his response to metformin may be reduced with time. That is why it is important to note this information in the context on personalising treatment of T2DM.

E) His markers of insulin secretion (C-peptide)

T2DM is an evolving disease characterized by a progressive loss of β-cell function and a decline in insulin secretory capacities, which results in the progression of the disease [7]. Disease progression and interindividual response to OADs varies markedly among patients with T2DM (18). Because some OADs mainly promote insulin secretion while others rather act primarily on insulin sensitivity, the residual insulin secretion should influence the drug-related response regarding improvement of glucose control in patients with T2DM [19- 20]. Therefore, measurement of plasma C-peptide has been suggested of being of clinical utility in the assessment of patients with T2DM [19]. However, there is limited evidence to support the use of C-peptide to predict treatment response in patients with T2DM [21]. Nevertheless, the recent development of incretin-based therapies may somewhat change this approach. Indeed, severe insulin deficiency as evidenced by low plasma C-peptide concentrations predicts a poor to a non-response to GLP-1 receptor agonists [22-23]. Again, this information is particularly relevant when we will have to decide which OADs is the best for our patient. For instance, the patient may have specific gene in favor of specific OADs but without the supporting clinical information the patient is no longer a candidate to receive these medications. Which means that the genetic information should be supported by the clinical information to obtain the best personalised treatment?

F) His markers of disease severity (HbA1c)

The level of HbA1c, used as a validated marker of glucose control during recent weeks, is the main marker use to guide the choice of therapy. Initiation of insulin therapy rather than OADs is recommended in patients with T2DM who present with an initial HbA1c level > 9% (75 mmol/mol) and symptoms related to hyperglycaemia. When the HbA1c is above 8.0–8.5%, the likelihood of achieving glycaemic targets with a single OAD diminishes drastically. These patients may be better candidates for treatment with a combination of OADs as first-line therapy [24], although this is not commonly done yet in clinical practice [25]. Whatever the glucose-lowering agent used, the higher the baseline HbA1c level, the greater the reduction in HbA1c achieved [26]. However, the impact of the increase in baseline HbA1c on the clinical efficacy of a SGLT2 inhibitor is greater than that of a DPP-4 inhibitor [27]. This difference can be explained by the greater amount of glucose removed from the body by SGLT2 inhibitors at the higher plasma glucose concentration. In contrast, high HbA1c may suggest a profound defect in insulin secretion, which may limit the efficacy of DPP-4 inhibitors [28-30]. Thus SGLT2 inhibitors may be preferred to DPP-4 inhibitors in T2DM patients with high initial HbA1c [7, 27]. Knowing the initial HbA1c level is not questionable as it is one of the main characteristic that the HCP should know before initiating T2DM treatment and this has been largely discussed in previous articles. However, it is now evident that this information is essential in the selection of the appropriate OAD not only for the initial treatment of T2DM but also as a second-line treatment; for instance when patients are no longer responding to metformin as in 50% of patients in the TODAY study.

G) His Fasting versus postprandial hyperglycaemia

HbA1c value gives an integrated view of overall glucose control during the last 2–3 months, but does not allow discriminating between preponderant contributions of fasting or postprandial hyperglycaemia [31]. Some OADs are mainly active on fasting hyperglycaemia (metformin, thiazolidinediones, basal insulin) while others are mainly targeting postprandial hyperglycaemia (incretin-based therapies, acarbose, prandial insulin bolus). In a meta-analysis exploring 24- week effects on HbA1c of maximal doses of DPP-4 inhibitors, DPP-4 inhibitors appear to be more effective in patients with mild/moderate fasting hyperglycaemia [32]. Short-acting GLP-1 receptor agonists (i.e. exenatide) mainly target postprandial hyperglycaemia whereas long-acting receptor agonist (i.e. liraglutide) mainly targets fasting hyperglycaemia [33]. Thus, the individual relative contributions of fasting versus postprandial hyperglycaemia may be helpful in choosing the best OAD therapy in patients with T2DM [34, 31]. That is why it is important to get this information in the assessment of each patient with T2DM.

H) His markers of insulin resistance (metabolic syndrome)

Insulin resistance syndrome is linked to abdominal obesity and is usually associated with biological markers of the metabolic syndrome that includes HTN, abdominal obesity, dyslipidemia and dysglycemia. Therefore, the presence of atherogenic dyslipidaemia (hypertriglyceridaemia, low HDL, HTN and abdominal obesity should encourage the prescription of agents that can promote weight loss (SGLT-2 inhibitors, GLP-1 receptor agonists) and/or improve insulin resistance (pioglitazone) [13-15]. NAFLD is rather common in patients with poorly controlled T2DM and metabolic syndrome and could be improved with pioglitazone [35] or liraglutide [36]. Therefore, knowing the presence of the markers of insulin resistance may be helpful in choosing the best OAD therapy in patients with T2DM.

I) The presence or not of renal impairment

As discussed in article number 2, CKD is a frequent complication in patients with T2DM, especially after a long duration of hyperglycaemia, especially when HTN is present. The presence of renal impairment has to be taken into account when selecting both the type and the dose of the OADs in patients with T2DM [12]. More particularly, this is the case for metformin [13], incretin-based therapies (DPP-4 inhibitors and GLP-1 receptor agonists) [16] and SGLT2 inhibitors [37]. The risk of hypoglycaemia is also increased in T2DM patients receiving most sulphonylureas in the presence of renal insufficiency [12]. Again, it is essential to know whether or not we are in presence of renal impairment before choosing the best OAD therapy in patients with T2DM.

J) The presence or not of liver disease

Severe liver disease is much less frequent than CKD in patients with T2DM. If present, it should impose cautious selection of both type and dose of OADs to minimize the risk of adverse drug reactions [38]. However, NAFLD is common in patients with T2DM. Some OADs have proven to be more efficacious to reduce hepatic fat content than others, especially thiazolidinediones (pioglitazone) [35] and GLP-1 receptor agonists (liraglutide) [36]. The presence of a liver disease can easily be found by simply doing a liver profile. This will also permit to screen for the presence of NAFDL. Again, this information is relevant before prescribing the most appropriate medication for a specific patient.

You have completed the investigation and you found that this patient had T2DM. It was then treated with insulin and LSI for few months. After one year with this treatment he was transfer to metformin and LSI. He lost 5 kg of body weight, which means that he is no longer obese but still have difficulties controlling his weight and his blood glucose and had some gastrointestinal intolerance on metformin despite being highly compliant to the HCP and diabetic nurse recommendations. His blood pressure was normal as well as his lipid profile and his liver profile was normal too suggesting the absence of NAFDL and liver diseases. His last HbA1c has increased to 7.8% recently added to his digestive symptoms with metformin consequently he had to return on insulin but does not want to stay on insulin for a long period of time. His C-peptide is at 1.7 mmol/L (0.2-1.0mmoll) suggesting the presence of insulin resistance but not insulin deficiency. His ACR is of 0.88 mg/mmol (<3.5 mg/mmol); and his eGFR is of 118 ml/min (90- 120 ml/min) suggesting the absence of renal impairment. Joseph has no problem with fasting or post prandial hyperglycemia in the past few months as seen on his SBGM. After 6 months, you are planning to change his insulin for a new medication since he is now18 years-old but before that you decided to send him to a research center for a genetic consult in order to determine which medication should be the most appropriate for him. You got the following results from the genetic consult. The patient had OCT1 variants encoded by the gene

SLC22A1; variant alleles in TCF7L2 and IRS-1 genes; the presence of the SLCO1B1*1B (c.388G-c.521T) haplotype; the presence of PPAR- γ. 12Ala carriers; variants of the transcription factor 7- like 2 genes (TCF7L2) and the rs6923761 variant of the GLP-1R gene. Based on this genetic information what should be the treatment of choice?

(A) Biguanides (metformin);

(B) Sulphonylureas;

(D) Thiazolidinediones (TZD) (pioglitazone, rosiglitazone);

(E) Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins);

(F) Glucagon-like peptide-1 (GLP-1) agonist (Liraglutide, Exenatide)

(G) Sodium–glucose cotransporters type 2 (SGLT2) inhibitors (gliflozins)

(H) Only C, D and F are correct

Answer: H

Explanations

A) Biguanides (Metformin)

Metformin has been a cornerstone in T2DM management even if its mechanism of action remains unclear [7]. At the moment, it seems to lower blood glucose through hepatic diminution of glucose production and an increase of peripheral insulin sensitization [39]. Despite its wide and, generally, well tolerated utilisation, according to the TODAY study, 50% of patients are poor responders and up to 63% are experiencing important gastrointestinal adverse reactions [39]. Because of its positive charge, metformin is, most likely, transported by organic action transporters (OCTs); plasma membrane monoamine transporter (PMAT), OCT1 and OCT3 may be responsible for its intestinal absorption, OCT1 and MATE1 for its transport to the liver and biliary excretion, respectively whereas OCT2 seems implicated to its transport to the kidney and MATE1/2 for its secretion [39]. However, some of them were found, by GWAS, to possibly have genetic variants implicated in response variability to OADs [7].

OCT1 encoded by the gene SLC22A1, has been the focus of many studies and results of its variants have been ambiguous about its influence on drug response [7]. Overall, it seems that there is a lower efficacy of metformin with individual having one or more variants associated with reduced function and gastrointestinal intolerance was significantly higher in individual showing reduced function in both alleles [39-40]. OCT2 has been studied mostly in Asian populations and heterozygous GT alleles individuals appear to be associated with better PKs results [39]. As for MATE1 and MATE2, fewer results are available, however, homozygous for minor allele in some variants showed higher and lower, respectively, HbA1c reduction [39]. Also, genetic variants found in OCT1, OCT2 and MATE1 were associated with lower incidence of T2DM or protection effects after metformin treatment [39]. In a large GWAS, ATM gene was linked to better HbA1c reduction for its minor allele but was not found to reduce T2DM progression [60, 84]. Finally, two variants in and around transcription factors gene SP1 were associated with lower HbA1c diminution and lower clearance [39]. Hence, from these equivocal results emphases the need for further studies but also, the important role that genetic profiling could have in metformin treatment, its response and better control over its adverse effects [7]. Therefore, the OCT1 variants encoded by the gene SLC22A1 may at some point explain why this patient became less responsive to metformin therapy and explain his gastrointestinal intolerance. Finally A is not a good answer.

B) Sulphonylureas

Used as first-line and add-on therapy, SUs are known to activate ATP potassium channel in pancreatic β-cell thus leading to a release of glucose-independent insulin. Ten to twenty percent of patient under SU treatment will have a small fasting plasma glucose reduction [39]. Therefore, genetic studies which focused on SU mostly targeted genes that are linked to insulin secretion. Numerous genes and cytochrome P450 (CYP450) were associated to genetic variants that could influence SUs response in T2DM patients [7]. Polymorphisms in CYP enzymes are widely studied, CYP2C9 and CYP2C19 variants have been implicated in T2DM that could altered SU metabolism and response [23, 38, 42]. Asian carriers of a defective allele of CYP2C9 (*3) and CYP2C19 (*3) seems to be particularly affected by SU administration leading to increase PKs parameters whereas Caucasians with affected alleles (*2 or *3), though ambiguous, were associated to higher risk of hypoglycaemia and lower clearance of glucose [23, 38, 42].

ABCC8, KCNJ11, TCF7L2 and IRS-1 are some the genes that were associated to impact SUs response. Two variants in ABCC8, S1369A and E23K, reported higher fasting plasma glucose and HbA1c reductions in Chinese using gliclazide and higher therapy failure associated to K allele when glibenclamide was taken, respectively. As for KCNJ11, results are ambivalent; some studies showed no difference and others implied that K allele was linked to higher HbA1c reduction, lower risk of hypoglycaemia and fasting plasma glucose (39). Variant alleles in TCF7L2 and IRS-1 genes have been associated with treatment failure; first and second SUs treatments for TCF7L2 and secondary treatment for IRS-1 [39, 43-45]. Therefore considering the presence of these variant alleles in TCF7L2 and IRS-1 genes sulphonylureas are not appropriate OADs for Joseph.

C) Meglitinides (repaglinide, nateglinide)

Possible reasons for interindividual variability in response to meglitinides may result from polymorphisms in organic anion transporting polypeptide 1B1 (OATP1B1) gene (SLCO1B1) or the metabolizing enzyme of the CYP family [46]. Nateglinide is metabolised by CYP2C9 whereas repaglinide is metabolised by CYP2C8 [42, 47]. Moderate dose adjustments based on CYP2C9 genotypes may help in reducing interindividual variability in the antihyperglycaemic effects of nateglinide. CYP2C8*3 carriers had higher clearance of repaglinide than carriers of the wild-type genotypes. Although genetic variants in metabolizing enzymes of the CYP family may alter the PK of the medications of the meglitinide family, they do not appear to have major effects on the glucose levels of T2DM patients [7-8, 46].

The SLCO1B1*1B (c.388G-c.521T) haplotype is associated with enhanced hepatic uptake and decreased plasma concentrations of some OATP1B1 substrates. The SLCO1B1 c.521CC genotype has been associated with increased and the SLCO1B1*1B/*1B genotype with decreased exposure to repaglinide. Accordingly, SLCO1B1 genotyping may theoretically help in choosing the optimal starting dose of repaglinide [48]. In Chinese individuals, the SLCO1B1 c.521C allele has been associated with increased plasma concentrations of nateglinide, but the association could not be replicated in Caucasians [48]. Other studies are warranted to examine the association between repaglinide or nateglinide efficacy and safety and different polymorphisms. The presence of the SLCO1B1*1B (c.388G-c.521T) haplotype may have a beneficial effect in the response to meglitinides. Therefore C is a good answer.

D) Thiazolidinediones (TZD) (pioglitazone, rosiglitazone)

CYP2C8 and CYP3A4 are the main enzymes catalyzing the biotransformation of pioglitazone (and troglitazone, a TZD withdrawn because hepatotoxicity), whereas rosiglitazone is metabolized by CYP2C9 and CYP2C8 [42, 49]. SLCO1B1 genotype has had no effect on the PK of rosiglitazone, pioglitazone or their metabolites [48].

The genes coding for CYP2C8 and PPAR (peroxisome proliferator activated receptor)-gamma (γ) are the most extensively studied to date and selected polymorphisms may contribute to respective variability in pioglitazone PK and PDs, which may impact both efficacy and toxicity of the drug [50]. CYP2C8*3 was associated with lower plasma levels of rosiglitazone and hence a reduced therapeutic response but also a lower risk of developing oedema, which suggests that individualised treatment with rosiglitazone on the basis of the CYP2C8 genotype may therefore be possible [51]. However, the studies that looked at the association between CYP polymorphisms and TZD toxicity were inconsistent and generally did not produce statistically significant results. Therefore, it can only be speculated that polymorphisms in TZD-metabolizing enzymes are associated with toxicity [46].

Specific genetic variations in genes involved in the pathways regulated by TZDs could also influence the variability in treatment with these drugs [52]. A first study showed that the Pro12Ala variant in the PPAR- γ gene does not affect the efficacy of pioglitazone in patients with T2DM, suggesting that the glucose-lowering response is independent from pharmacogenetic interactions between PPAR- γ and its ligand pioglitazone [53]. However, in a more recent meta-analysis, which synthesized the currently available data on the PPAR- γ. Pro12Ala polymorphism, PPAR- γ. 12Ala carriers had a more favourable change in fasting blood glucose from baseline as compared to patients with the wild-type Pro12Pro genotype [50]. In a study investigating the influence of the S447X variant in lipoprotein lipase (LPL) gene on the response to therapy with the TZD pioglitazone, the S447X genotype conferred a statistically significant reduction in glucose-lowering response rate to pioglitazone as well as a less favourable lipid lowering response relative to the S447S genotype (54). In a study in Chinese patients with T2DM, the adiponectin gene polymorphism rs2241766 T/G was associated with pioglitazone efficacy [55]. Therefore, pharmacogenomics and pharmacogenetics may be an important tool in drug individualization and therapeutic optimization when prescribing TZDs in patients with T2DM [52]. The presence of PPAR- γ. 12Ala carriers indicates that this drug might be a good choice in the treatment of Joseph’s T2DM. Therefore, D is a good answer.

E) Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins)

DPP-4 inhibitors (gliptins) are increasingly used in the management of patients with T2DM, essentially because of a good safety profile [56]. The liver is not important for the elimination or action of sitagliptin, vildagliptin and saxagliptin [57]. Therefore, SLCO1B1 polymorphism unlikely affects the response to these OADs. ABCB1 polymorphisms (ABCB1 CGC/CGC, CGC/TTT, and TTT/ TTT diplotypes) did not influence sitagliptin PK in healthy volunteers [59]. Cytochrome P450 (P450) enzymes CYP3A4 and CYP3A5 metabolize saxagliptin and 5-hydroxy saxagliptin (M2), its major, active metabolite. Kinetic experiments indicated that the catalytic efficiency for the CYP3A4 was approximately 4-fold higher than that for the CYP3A5. Therefore, it is unlikely that variability in expression levels of CYP3A5 due to genetic polymorphism will impact clearance of saxagliptin [60].

Individuals carrying variants of the transcription factor 7- like 2 gene (TCF7L2) are at increased risk for T2DM and may have diminished pancreatic islet-cell responsiveness to incretins. Linagliptin significantly improved hyperglycaemia in T2DM patients both with and without the TCF7L2 gene diabetes risk alleles, although HbA1c response was significantly reduced in TT compared with CC patients [61]. Thus, diabetes susceptibility genes may be a contributor to the inter-individual variability of treatment response to DPP-4 inhibitors. In a large primary care database recently analyzed to assess the variability in response to a DPP-4 inhibitor, HbA1c reductions were significantly lower with increased T2DM duration, in agreement with a defective insulin secretion [28]. These data are in agreement with previous studies having measured insulin secretion in T2DM patients treated with sitagliptin [29] or vildagliptin [30]. Because this patients is carrying variants of the transcription factor 7- like 2 genes (TCF7L2), he may have diminished pancreatic islet-cell responsiveness to DPP-4 inhibitors (gliptins) is not a good choice for him. Therefore, E is not a good answer. However, we should consider that the genetic studies focusing on the variability of response to DPP-4 inhibitors are scarce and poorly contributive.

F) Glucagon-like peptide-1 (GLP-1) agonist

GLP-1 is an incretin that is known to induce insulin secretion of the β-cells. GLP-1 receptors (GLP-1R) agonists sustain insulin secretion consequently increasing the efficacy in the treatmet of T2DM. Encoded by GLP1R gene, GLP-1R is logically listed as one of the target that could affect treatment’s response. Studies associated to GLP-1R agonist have found that there are three genetic variants that might influence its response. However, still unclear results ensue from these researches [62-64]. T allele of rs3765467 and rs761386 were linked to lower and higher standard deviation in plasma glucose in response to exogenous GLP-1, respectively. The rs6923761 variant has shown an increased response from β-cells. Since this patient is carrying the rs6923761 variant of the GLP-1R gene he may have increased pancreatic β-cells responsiveness to GLP-1. Therefore F is a good response and according to Joseph clinical presentation a GLP- 1 agonist is probably the better choice for him and this is consistent with the most recent Canadian Clinical Practice Guideline http: // guidelines.diabetes.ca/bloodglucoselowering/pharmacologyt2.

G) Sodium–glucose cotransporters type 2 (SGLT2) inhibitors (gliflozins)

SGLT2 inhibitors is a glucose transporter situated in the kidney, it blocks the reabsorption of filtered glucose, leading to glucosuria [7]. The SGLT2 gene (SLC5) has been mapped to chromosome 16 p11.2, and up to 50 different mutations of this gene have been reported in the context of familial renal glucosuria [63]. SLC5A2, a gene implicated in glucose transport, holds a genetic variant, rs9934336, from which the G allele was associated with increased exposure to the drug [64]. SGLT-2 inhibitors are eliminated by uridine diphosphate glucononyltransferases (UGTs) and as for CYPs, they are known to be associated with genetic variant that can alter their function [7]. So far, there have been no definitive studies of patients with T2DM regarding the genetic variants and SNPs associated with response to the SGLT2 inhibitors.

Conclusion

According to the pharmacogenetic assessesment performed on Joseph, we now know that he could have a very good response in his T2DM treatment by using one of the following OADs: Meglitinides (repaglinide, nateglinide); Thiazolidinediones (TZD) (pioglitazone, rosiglitazone); and Glucagon-like peptide-1 (GLP-1) agonist. This information is particularly pertinent for the HCPs in deciding which OAD he will prescribe to Joseph. However, the HCPs cannot only use the information from genotypic markers for selecting and adjusting T2DM therapy and still need to corroborate this information with the clinical information obtained by the clinic and still need to follow the recommendation from clinical practice guidelines Understanding variations in genetics, environment and lifestyle in order to adapt care to each individual is the ultimate objective of precision medicine. As seen in this case report, pharmacogenomics and pharmacogenetics holds a great deal of opportunities toward that goal of personalized care. The cost of personalised medicine should be compensated for by better efficacy, less adverse drug reactions and ultimately less complications associated to T2DM, leading to improved quality of life and increased life expectancy. Eventually, the developments in the field of personalised medicine for T2DM will likely translate, into clinical practices to individualise therapy that will improve both patient outcome and public health.

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Impaired Awareness of Hypoglycaemia in an Obese Woman with Type 2 Diabetes Mellitus

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Case Report

Jane is a 46 year-old obese woman with a 28 year history of type 2 diabetes (T2DM) presented to the clinic following a loss of consciousness the previous day. Her loss of consciousness took place at home and the patient was awake at the time of the incident. This was witnessed by her husband, who administered intramuscular glucagon immediately. After regaining consciousness, the patient consumed a meal consisting of complex carbohydrates. Her blood glucose was not checked at the time of the unconsciousness, but was normal after treatment (glucagon + orange juice). Her T2DM was managed with 32 units of rapid-acting insulin glulisine (Apidra) accompanying each meal and 52 units of long-acting insulin glargine (Lantus) at bedtime. She was also treated with LSI but she was always irregular in the follow-up of her diet and physical activity regimens. She denied having any recent problems with hypoglycaemia and reported that she measured her blood glucose at least once a day and it was ‘always normal’. She is a bus driver and had a traffic accident 2 years ago but she was unable to recall the details. Nobody was injured during the accident which occurred at a very low speed but was witnessed by a client.

What should you ask on medical history?

HCPs should follow the ‘6As model of counselling and assess about the frequency and timing of severe hypoglycaemia, individual awareness of hypoglycemia, hypoglycaemia detected by others, and hypoglycaemia detected only because of monitoring [1-3]. The HCPs should also asses for risk factors for impaired awareness of hypoglycaemia (IAH) (see definition below) that includes age over 50, infrequent self-monitoring of blood glucose (SMBG), duration of diabetes longer than 10 years, glycemic control with glycated hemoglobin (A1C) less than 0.070 (Optimal control is < 0.070, Sub optimal 0.070 – 0.084; inadequate > 0.084) and episodes of hypoglycemia where assistance was required or where there was a loss of consciousness. Then the HCPs assess about drugs used including beta-blockers (non-selective), hypnotics, tranquillisers and alcohol. The HCPs should also assess for the social support including the fear of hypoglycemia, and the impact or anxiety on other family members. He should assess her daily routine for insulin administration, eating patterns, exercise routine, the frequency of SMBG and the distribution of hypoglycemia [1-6].

Finally, the HCP complete the following questionnaire with the patient by asking specific questions related to hypoglycemia according to the Clarke’s questionnaire (5) aims to quantify the degree of IAH. Each response is rated R for ‘reduced awareness’ or A for ‘aware’. A patient who provides four or more R responses is considered to have IAH. The questions are as follows:

1) Do you always have symptoms when your blood sugar is low (A) Do you sometimes have symptoms when your blood sugar is low R.

Response: I do not always have symptoms when my blood sugar is low (1).

2) Have you lost some of the symptoms that used to occur when your blood sugar was low?

Yes (R) No (A);

Response: Yes sometimes (1).

3) In the past six months how often have you had moderate hypoglycemia episodes? (Episodes where you might feel confused, disoriented, or lethargic and were unable to treat yourself)

Never (A) Once or twice (R) Every other month (R) Once a month (R) More than once a month (R)

Response: Yes it happened once or twice (1).

4) In the past year how often have you had severe hypoglycemic episodes?

(Episodes where you were unconscious or had a seizure and needed glucagon or intravenous glucose) Never (A) 1 time (R) 2 times (R) 3 times (R) 5 times (R) 6 times (R) 7 times (R) 8 times (R) 9 times (R) 10 times (R) 11 times (R) 12 or more times (U)

Response: I had one episode last year and one yesterday (1).

5) How often in the last month have you had readings

Never 1 to 3 times 1 time/week 2 to 3 times/week 4 to 5 times/ week Almost daily (R = answer to 5 < answer to 6, A = answer to 6 > answer to 5)

Response: Maybe 1–2 times per week.

6) How often in the last month have you had readings answer to 5)

Response: Maybe 1–2 times per week.

7) How low does your blood sugar need to go before you feel symptoms?

60-69 mg/dl (3.33 – 3.8 mmol/L) (A)

50-59 mg/dl (2.8 – 3.3 mmol/L) (A)

40-49 mg/dl (2.22 – 2.72 mmol/L) (R) < 40 mg/dl (< 2.2 mmol/L) (R)

Response: Between 2.22 – 2.72 mmol/L (1)

8) To what extent can you tell by your symptoms that your blood sugar is low?

Never (R) Rarely (R) Sometimes (R) Often (A) Always (A)

Response: Often.

What is the most likely diagnosis?

The patient scored “5” on the questionnaire, consistent with a diagnosis of IAH. Hypoglycemia is a risk associated with insulin therapy, while impaired awareness has a physiologic basis related to the impact of hypoglycemia on the brain and an impaired response of counter-regulatory mechanisms in the setting of longstanding T1DM and insulin-treated T2DM. In patients with IAH, the ability to perceive the onset of hypoglycaemia becomes diminished or absent. Symptoms are insidious and include difficulty concentrating, confusion, reduced consciousness, coma or seizures before autonomic activation (tremor, sweating, palpitation and nausea) [4]. Impaired awareness of hypoglycaemia is believed to affect approximately 20- 25% of patients with T1DM and up to 10% of insulin-treated T2DM [4]. The condition increases the risk for severe hypoglycaemia by 3 to 6 fold compared to people with normal awareness [4]. It should be differentiated from “hypoglycaemia unawareness” which suggests a rare but total loss of symptomatic response to low glucose [4]. The differential diagnosis also includes a number of rare conditions, including all of the causes of syncope with the two broad categories being cardiac and neurological. The latter would include seizure disorders.

How will you treat this patient?

The key to reversing IAH is by adjusting the glucose target to avoid episodes of hypoglycaemia [4]. In order to achieve this goal, experts recommend frequent SMBG including pre-prandial and nocturnal measurements; avoidance of blood glucose values < 4 mmol/L, readjustment of blood glucose targets upwards (e.g., pre-prandial target 6.0 to 12 mmol/L and bedtime > 8 mmol/L), preventing A1C < 0.060 and inclusion of regular snacks between meals and at bedtime [1- 4]. Helping patients identify subtle cues to their low blood glucose is also recommended [1-4]. While the CDA Clinical Practice Guidelines give some recommendations about hypoglycemia and driving [3], this patient requires special consideration because her job requires that she drives and because she has had both a period of unconsciousness and a motor vehicle accident where IAH was a plausible explanation.

The Case Revisited:

We published a similar case 2 years ago and we resolved the case by decreasing all of his insulin doses by 30% and perform regular SMBG at least four times daily (pre-prandial and at bed time) [7]. Since then, the approach has evolved largely with the use of the ‘6As model of counselling discussed in a previous article of this special issue. But for this specific patient instead of reducing insulin as a target we are now approaching these patients by individualising their glucose target by using the following graphic: graphical representation of individual physiologic and patient-centered aspects
https://durobojh7gocg.cloudfront.net/content/diacare/38/1/140/F1.large.jpg. Therefore, by simply personalising or adjusting her personal glucose target we were able to reduce her insulin doses and correct her IAH. I think that the HCP should now personalise more the treatment of patients with T2DM based on an individual glucose target rather than focusing on treatment target and I think it is the best lesson learn from this case. Because she was injured in a motor vehicle accident for which IAH played a plausible role, we notified the Ontario Ministry of Transportation who then investigated his suitability for driving, according to provincial law [8].

Regular SMBG demonstrated frequent asymptomatic hypoglycaemia requiring further reductions in her insulin dose. With our recommended treatment she was able to avoid hypoglycaemia completely and to reduce his total daily insulin dose by another 20% over a period of three months. Simultaneously, she began regaining warning symptoms when her blood glucose fell into the hypoglycaemic range. She was allowed to drive again with a non-commercial license provided that she does SMBG prior to driving and periodically during every driving exposure [8-10]. Our patient was able to organize a change in her work functions which permitted her to keep her job but not as a bus driver but as a road supervisor without clients. The present case emphasizes the importance of constantly personalising glucose target throughout treatment with insulin. The following points should also be considered [7]:

Structured patient education program about symptoms of hypoglycaemia and hypoglycaemia avoidance, SMBG, the adequate use of insulin; management strategies (carbohydrate intake and insulin dose) for exercise training, alcohol intake and the appropriate selection of food for meals and snacks [2];
Strategies to increase compliance to therapeutic modalities should be emphasized to restore hypoglycaemia awareness and to protect patients from severe hypoglycaemia [1-4].
People with IAH may require psychological counseling to help them modify the management of their diabetes and to address the problems of “low concern” or “denial” regarding hypoglycaemia unawareness often seen in these patients [6].
IAH poses a potential risk to safety, not only when driving, but also when exposed to heights or under water, operating machinery and other activities, and justifies the recommendation to perform SMBG in relation to such activities, even if this may seem inconvenient [1, 3].
Relatives should be taught about IAH and learn on how to administer glucagon (1mg subcutaneously, or intramuscularly) [3].
HCP should always remember to adjust treatment based on personalised glucose target throughout treatment with insulin.

References

Frier BM (2008) How hypoglycaemia can affect the life of a person with diabetes. Diabetes Metab Res Rev 24: 87-92. [crossref]
Choudhary P Amiel SA (2011) Hypoglycaemia: current management and controversies. Postgrad Med J 87: 298-306. [crossref]
Clayton D, Woo V, and Yale JF (2013) Hypoglycemia. Clinical Practice Guidelines. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes 37:S69-71.
Graveling AJ, Frier BM (2010) Impaired awareness of hypoglycaemia: a review. Diabetes Metab 36 Suppl 3: S64-74. [crossref]
Clarke WL, Cox DJ, Gonder-Frederick LA, et al. (1995) Reduced Awareness of Hypoglycemia in Adults with IDDM. A prospective study of hypoglycemia frequency and associated symptoms. Diabetes Care18:517-522.
Rogers HA, de Zoysa N and Amiel A (2012) Patients experience of hypoglycemia unawareness in Type 1 diabetes: are patients appropriately concerned? Diabet Med 29:321-327.
Plourde G, Klein AV2, Dent R2 (2014) Impaired awareness of hypoglycemia in a man with type 1 diabetes. CMAJ 186: 770-771. [crossref]
Begg IS, Yale J-F, Houlden RL, et al. (2003) Canadian Diabetes Association’s Clinical Practice Guidelines for Diabetes and Private and Commercial Driving. Can J Diabetes 27:128-140.
Canadian Medical Association (2012) CMA Driver’s Guide: Determining Medical Fitness to Operate Motor Vehicles. 8th Edition.
Canadian Diabetes Association’s Clinical Practice Guidelines for Diabetes and Private and Commercial Driving. Can J Diabetes 27:128-140

The Specific Impact of Fructose on the Development of Type 2 Diabetes Mellitus in Pediatric Patients

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Abstract

Added fructose in particular i.e., as a constituent of added sucrose or as the main component of high-fructose sweeteners may pose the greatest problem for the development of obesity, T2DM, T2DM-related metabolic abnormalities in pediatric populations and CVD later in life. In contrary, whole foods that contain fructose i.e., fruits and vegetables pose no problem for health and are protective against the above metabolic disorders. Several dietary guidelines appropriately recommend consuming whole foods over foods with added sugars or sugary drinks (SSBs). For instance, in his 2016 Sugar Position Statement, the Canadian Diabetes Association (CDA) recommends reducing free sugar intake to a specific level of 10% of total calories intake i.e., to the level shown to improve glucose tolerance in humans and to decrease the prevalence of T2DM in both adults and pediatric patients. This level is also associated with an improvement of the metabolic complications that often precede and accompany T2DM. Reducing the intake of added sugars and fructose could translate in reduced T2DM-related morbidity and premature mortality. Finally, for our adolescent the recommendation that you as the HCP should give to the parents are no SSBs either fructose or not and to replace these beverages with water, % fruit juice (no added sugar) in limited amount (4 to 6 onces per day), vegetable juice or milk and to limit the intake of free sugar to the CDA recommendations. However, there is no risk to consume the recommended amount of five servings and more of fruits and vegetables per day despite the presence of fructose in these foods.

Introduction

Recent public health interest has focused on fructose as having a unique role in the pathogenesis of cardiometabolic diseases including obesity, T2DM and others [1-2]. However, because we rarely consume fructose in isolation, the major source of fructose in the diet comes from fructose-containing sugars, sucrose and high fructose corn syrup, in sugar-sweetened beverages (SSBs) and foods [2]. The intake of SSBs is now known to be linked to an increased risk of obesity and T2DM in various populations including pediatric population and the risk of developing CVD later in life. The underlying mechanisms is not completely known but include incomplete compensation for liquid calorie, adverse glycemic effects, and increased hepatic metabolism of fructose leading to an increased lipogenesis from the liver which results in a higher production of uric acid, and accumulation of visceral and ectopic fat [2]. In this mini review, with the use of a case report, we summarize the evidence evaluating the impact of added sugars, SSBs, and fructose on the risk of obesity, T2DM, and it’s associated CVD. We also discuss strategies to reduce the intake of fructose-containing sugar in order to answer questions raised by many parents and HCPs dealing with pediatric and adult patients suffering from obesity and T2DM.

Case report

During a subsequent visit, the parents came to the clinic for questions about the diet of her daughter Janet. Because she is obese and recently diagnosed with T2DM, the parents are concerned about the risk of losing control of her T2DM. They said that they should pay attention to the amount of fat, sugars and calories that Janet should ingest every day. On the other hand, they were a little confused regarding sugar: some people say that some sugar are to be avoided, including those added in the juice and food as well as those that are included in the soft drinks. On the other hand, it seems that there are no problems to consume diet drinks since they contains no calories and should be good to help Janet with her weight problem. Among the following, which one would you recommend to the parents?

(a) avoid all foods containing fructose.

(b) there is no risk to eat foods with sugar as long as it’s not fructose.

(d) the use of sweeteners (artificial sugars) is a good choice.

(e) neither is true.

All these answers are wrong.

Answer: e

Explanations

(a) Avoid all foods containing fructose.

Fructose is the most frequent sugar used as sweetener in drinks like soft drinks, and energy drinks which are the single greatest source of calories and added sugars in the US diet, accounting for nearly half of all added sugar intake [3]. Fructose is also found in sucrose or common table sugar, which is a disaccharide composed of one glucose molecule and one fructose molecule linked via an α1–4 glycoside bond, and is obtained from either sugar cane or beets. Fructose and glucose are also both found as naturally occurring monosaccharides that exists in fruit, honey and some vegetables [2].

Sweeteners such as high fructose corn syrup (HFCS), produced from corn starch through industrial processing contain free fructose and free glucose in relatively equal proportions and have progressively replaced use of sugar due to its low cost. The most frequent forms of HFCS contain either 42 % (HFCS-42) or 55 % (HFCS-55) fructose, along with glucose and water. HFCS-55 has the sweetness equivalent of sucrose and is widely used to flavor carbonated soft drinks. HFCS- 42 is somewhat less sweet and is mainly used in processed foods including canned foods (e.g., soups, fruits), cereals, baked goods, desserts, sweetened dairy products, condiments, fruit-flavored noncarbonated beverages, candies, and many fast food items.

Longitudinal data over the past 40 years have shown a close relation between the rise in added sugar and obesity and T2DM epidemics in the US [4]. For now, there is no study in children to answer this question. On the other hand, according to a recent study performed in adults [5] consuming drinks sweetened with fructose and or glucose can increase abdominal fat and the levels of bad cholesterol, i.e., the low-density [LDL-C] cholesterol, two consequences related to an increased risk of CVD [6]. The study in question involved 32 adult subjects overweight or obese who had been asked to consume 25% of their total daily calorie needs by drinking a sweet drink with fructose or glucose, for 10 weeks. The two groups gained substantially the same amount of weight. However, the researchers found that fructose seemed to have more negative effects on the body weight. Indeed, people who drank sweetened drinks with fructose had higher levels of LDL-C, had a lower sensitivity to insulin and the highest rates of abdominal fat, which are known risk factors for CVD [6-7]. This confirms that excessive consumption of fructose, usually from SSBs can be unhealthy.

To ensure to avoid fructose, it is recommended that the consumers take time to read food labels when shopping to see if fructose is part of the ingredients. This will help them avoid fructose. It is also recommended to choose water, 100% fruit juice (no added sugar), vegetable juice or milk rather than the fructose-containing beverages. On the other hand, do not consider fructose as only being a dangerous sugar. Fruits and vegetables are the main natural source of fructose. Most of the fruits contain about 10 g of fructose. If fructose is toxic in high doses, people consuming large quantities of fruits would have undesirable effects, which is not the case. In addition, studies reported an inverse association between fruit consumption and body weight or the metabolic risks discussed above [8].

The absence of adverse effects associated with the consumption of fruits and vegetables in large quantities is related to a slower rate of digestibility for fruits and vegetables compared to drinks and processed foods sweetened with fructose. In addition, the presence of soluble fiber, and the cell structure of fruit and vegetables contribute to reduce the rate of absorption of fructose at the level of the digestive tract. We can add that the content in nutrients and antioxidants from fruits and vegetables protects against the inflammatory effect of fructose at the hepatic level and against the resistance to insulin at the systemic level. In other words, the small amounts of fructose consumed in vegetables and fruits are healthy for the body [8]. Therefore, there is no risk to consume the recommended amount of five servings and more of fruits and vegetables per day despite the presence of fructose in these foods.

The metabolism of fructose differs from that of glucose in two major ways. First, there is nearly complete hepatic extraction of fructose and second, there are different enzymatic reactions in the initial steps of the metabolism of fructose and glucose. Fructose is absorbed from the gut into the portal vein and is metabolized in the liver where it is converted into fructose-1-phosphate by the enzyme fructokinase [2]. Because these processes are not dependent on insulin, fructose is metabolized without requiring insulin secretion and without increasing plasma glucose. Of particular note, unlike glucose, fructose can bypass the main rate limiting step of glycolysis at the level of the enzyme phosphofructokinase, allowing it to act as a substrate for hepatic de novo lipogenesis resulting in an increased production of lipids [2]. The massive uptake and phosphorylation of fructose in the liver can also deplete intracellular ATP leading to an increase in uric acid production, which has been shown to induce metabolic complications [2]. These differences in hepatic metabolism can lead to a variety of different short- and long-term cardiometabolic effects of fructose compared with glucose.

(b) there is no risk to eat foods with sugar as long as it’s not fructose.

There are strong evidences indicating that SSB consumption is associated with an increased risk of T2DM through effects on adiposity and independently through other metabolic effects. A recent meta-analysis of 8 prospective cohort studies evaluating SSB intake and the risk of T2DM was performed (13). This study was based on 310,819 participants and 15,043 cases, individuals in the highest category of SSB intake composed of 1–2 servings per day. These individuals had a 26% greater risk of developing T2DM compared to those in the lowest category (none or less than one serving per month).

A similar association was found in a sub-cohort of 15,374 participants and 11,684 incident cases from the European Prospective Investigation into Cancer and Nutrition (EPIC) study [10] where a one serving per day increase in SSBs was associated with a 22% increased risk of T2DM. A recent meta-analysis of 17 cohort studies found that a one serving per day increase in SSBs was associated with an 18% increased risk of T2DM. Adjusting for BMI reduced this estimate to 13%. Given the similar estimates from studies in the US where HFSC is the primary sweetener and Europe where sucrose is used, there does not appear to be any appreciable difference regarding the impact of sweetener type on risk of T2DM. However, food sources of fructose may make a difference in metabolic effects. Some studies have shown beneficial effects of whole fruit consumption on risk of T2DM [11].

These results indicate that the liquid vs. solid forms of calories from sugars may impact metabolic diseases differently. Fructose in beverages is absorbed more quickly than fructose in whole foods such as fruit and vegetables, which are absorbed more slowly due to their fiber content and slow digestion. As mentioned earlier, the rapid absorption of liquid fructose increases the rate of hepatic extraction of fructose due to an increase in the lipogenesis from the liver which results in a higher production of lipids [2]. This new reality shows that excessive sugar consumption has harmful effects on health beyond his alleged role in obesity. In other words, too much sugar doesn’t just affect growth; it can also make us ill [12-13].

According to a recent study, more the consumption of added sugars is high and steady, more the risk of death from CVD increased [14]. There is also increasing evidence that higher SSB consumption increases CVD risk by contributing to the development of HTN, dyslipidemia, inflammation, coronary heart disease and stroke. In over 88,000 women in the NHS followed for 24 years, it was found that those who consumed 2 servings and more per day of SSBs had a 35% greater risk of CHD (non-fatal myocardial infarction or fatal CHD) compared with infrequent consumers [15]. Additional adjustment for potential mediating factors (including BMI, total energy intake and incident diabetes) attenuated the association, but it remained statistically significant, suggesting that the effect of SSBs may not be entirely mediated by these factors. Similar results were found in the HPFS among 42,883 men [16]. In this study, intake of SSBs was also significantly associated with increased plasma concentrations of inflammatory cytokines [16].

There is also evidence linking intake of SSBs to an increased risk of stroke. Among 84,085 women and 43,371 men in the Harvard cohorts followed for 28 and 22 years respectively, 1 serving and more of SSB per day was associated with 16% increased risk of total stroke compared with none in multivariable adjusted models including BMI [17]. This association was attenuated and no longer statistically significant after adjusting for HTN and T2DM, suggesting that these factors may be mediators. In the multi-ethnic cohort of 2,564 residents in Northern Manhattan followed for a mean of 10 years, daily soft drink consumption was associated with an increased risk of vascular events only in participants free of obesity, T2DM and metabolic syndrome at baseline and adjusted for a number of factors including BMI and HTN [18]. A Japanese cohort of 39,786 men and women followed for 18 years found significant positive associations between SSB intake and total and ischemic stroke in women but not in men in models adjusted for HTN and T2DM [19]. Adjustment for BMI and total energy intake had little effect on estimates, suggesting that these factors are not major mediators.

According to these researchers, we consume too much added sugar. It has been shown that between 2005 and 2010, 70% of adult foods contained at least 10 % of added sugars. Intake of both added sugar and SSBs was associated with an increased risk for CVD mortality in an analysis of NHANES III Linked Morality cohort data [20]. After a median of 14.6 years of follow-up, added sugar intake was associated with a 2-fold greater risk of CVD death comparing extreme quintiles of intake. In contrast, an analysis from the NIH-AARP Diet and Health Study; a prospective cohort of older US adults, found that intake of total fructose but not of added sugar was associated with a modest increase in risk of all-cause mortality in men and women [21]. However, total sugars from beverages, including added sugar were positively associated with risk of all-cause, CVD and other-cause mortality in women while only fructose from beverages was positively associated with risk of all-cause and CVD mortality in men.

In 2015, the WHO released guidelines on the intake of free sugars for adults and children [22]. This guideline strongly recommends to reduce the intake of free sugars throughout the life-course. In both adults and children, it is strongly recommended that the intake of free sugars should not exceed 10% of total energy intake. Further reduction to below 5% of total energy intake is a conditional recommendation. The WHO states that the first 2 recommendations are based on the health risks of free sugars consumption in predisposing those who consume them to overweight and obesity, and dental caries. The third recommendation states that a further reduction of free sugars to below 5% (about 6 teaspoons) of total energy intake per day would provide additional benefits. The limits would apply to all sugars added to food, as well as sugars naturally present in honey, syrups, fruit juices and fruit concentrates.

Another argument going against the fact that not only the fructose is harmful involves the glycemic index (GI). This index is a scale of classification of foods rich in carbohydrates according to the rise in blood sugar compared to a reference element, which is glucose or white bread. Glucose and the most commonly consumed starchy foods have a high GI, while fructose has a low GI. In addition, meta-analyses and systematic reviews have linked diets with high GI in the same undesirable effects as those of fructose, particularly regarding obesity and T2DM [8]. It is wrong to believe that there is no risk to consume foods and drinks with added sugars, as long as it is not fructose.

In other words, there is a real risk to consume added sugar. We cannot repeat enough the importance of taking the time to read food labels when shopping to avoid buying products that contain added sugars. We therefore recommend to this patient and her family to choose foods and drinks that contain no added sugar. It is also recommended to avoid the addition of sugar table in drinks, cereals and to reduce the consumption of processed meals (prepared or frozen) that often contain a lot of added sugar and salt.

To better understand the relationship between the consumption of diet drinks and caloric intake, the researchers looked at almost 24 000 adults of 20 years of age and older and noted the drinks and foods consumed over a period of 24 hours. They found that 11% of adults with a healthy body weight, 19 % of overweight adults and 22 % of obese adults drank diet drinks. The number of calories consumed during that 24 hour period by overweight or obese adults who drank diet drinks was similar in terms of number of calories.

On the other hand, adults with a weight surplus or obese people who drank diet drinks tended to ingest more calories in the form of solid food. Indeed, they have consumed 88 and 194 more calories from solid foods per day, respectively, than similar adult who drank soft drinks. Notably, obese adults who consumed diet drinks ate much more during snacks than those who were exposed to sugary drinks. Those who drank diet drinks consumed 131 calories per day from salty snacks compared to 243 calories from sugary snacks, compared to 107 and 213, respectively, for obese adults who drank sugary drinks.

One of the main reasons for these results is that the consumption of artificial sweeteners present at high doses in diet drinks, is associated with greater activation of the centers of rewards at the brain level, thereby increasing feelings of pleasure a person experiences during the ingestion of sweetened foods [7]. In other words, the consumption of diet drinks artificially sweetened can alter the activity of the receptors responsible for the control of sugar in the brain, causing disturbances in the control of appetite. This results in an increase of food consumption, representing a potential risk of weight gain. Similarly, the increase in the consumption of calories from sweetened snacks rather than salty snacks is compatible with this concept and suggests diet drinks sweetened with natural or artificial sweeteners drinks encourage some form of dependence on sugars [7, 23].

The results of the study from Bleich and colleagues suggest that overweight or obese adults seeking to lose or maintain their weight loss and having already replaced sugary drinks for diet drinks, should look carefully at other solid components of their diet, especially sweet snacks, which would allow them to identify food to change in their diet [23]. Therefore, it is wrong to believe that there is no risk to diet drinks. We do not recommend to totally eliminating diet drinks from the youth diet because they can help control weight due to their low calorie levels especially if they contain no added sugar. However, based on the results presented in the adult, it is also recommended to young people, especially those who are overweight or obese and who drink diet drinks, to become aware of the calories from solid foods, particularly sugary foods, in order to prevent weight gain or facilitate weight loss. It is recommended that patient pay special attention to the choice and content of snacks to ensure that the total and wanted energy intake be respected, even if they consume diet drinks.

It was found that replacement of 1 serving per day of SSBs with one serving of water was associated with 0.49 kg less weight gain over each 4-year period [24]. In the NHS II, substituting water for SSBs was also associated with a significantly lower risk of T2DM [25]. Therefore, this represent a good strategy for our 14 year-old patient, but, unfortunately, I do not think that this strategy will be sustainable at long-term. One hundred percent fruit juice could be perceived as a healthy alternative to SSBs, since juices contain some vitamins and other nutrients. However, fruit juices also contain a relatively high number of calories from natural sugars, with likely greater amounts of fructose. A positive association seems also to exist between the consumption of fruit juice and greater weight gain and T2DM, although some conflicting evidence exists. Nonetheless, based on the current evidence it has been recommended that daily intake of 100 % fruit juices be limited to 4–6 ounces per day [26-28].

(d) the use of sweeteners (artificial sugars) is a good choice

It is often proposed to address the problems associated with the overconsumption of sugar by using artificial sweeteners such as saccharin, acesulfame, aspartame, neotame, stevia (which is a natural plant extract) and others as they contain no calories. On the other hand, these synthetic substances are hundreds to thousands of times sweeter than sucrose and cause an intense feeling of pleasure in the brain with minimal concentrations of artificial sweetener [7]. As suggested by the term “diet”, under which these products are marketed, the food and drinks with artificial sweeteners are supposed to produce a sweet taste comparable to their counterparts containing sugar, but with fewer calories, contributing to weight loss.

Short term clinical trials provide evidence to that effect. For example, an increase in weight and blood pressure and inflammatory markers were observed in obese adults who consumed on average 600 Kcal/d of sucrose, mainly in the form of SSBs, for 10 weeks, compared to a control group using artificial sweeteners [7]. Therefore, it is possible to believe that the use of these artificial sweeteners can have a beneficial effect on weight control. However, the physical mechanisms for maintaining weight are subtle and complex. Now, it is increasingly obvious that the lack of calories from artificial sweeteners would be replaced, over time, with calories from other sources. Thus, this compensation could have an impact on weight control and on health [7]. In addition, increased stimulation of brain receptors by a frequent consumption of these powerful artificial sweeteners can cause taste preferences to sugars which will persist creating an increased tolerance to sugars.

Therefore, people who regularly use these artificial sweeteners can find not sweetened enough some foods such as fruits, vegetables, legumes and other. As these foods have become less attractive, so less consumed, the quality of the diet is reduced, thus contributing to a risk of weight gain. One of the concerns is that the repeated use of these artificial sweeteners can disrupt hormonal ways and neurobehavioral comportments, thus causing a preference for sweet foods, a change in the feeling of hunger, which would affect the control of appetite and, indirectly, the control the weight. Therefore, it is wrong to believe that the use of sweeteners (artificial sugars) is a good choice. Despite the lack of study on the consequences of the sweeteners among young people, it would be preferable that these parents do not give these artificial sweeteners to her 14 year old daughter.

(e) neither is true.

All these answers are false. As discussed by Goran [29-30], children and teens today grow up in a much sweeter nutritional environment than previous generations. A good use of sugary drinks and sugary solids contained in snacks and meals became an important daily task for parents in the education of children and adolescents. Indeed, more than 70% of the foods contain sugar, and the consumption of soft drinks has increased fivefold since 1950.

It is also important to note that the consumption level of sugar is particularly high in vulnerable segments of the population who are more susceptible to obesity, as well as in young people with a low socio-economic status such as ethnic minorities, the obese and other groups. The latest research on this topic has demonstrated a strong link of evidence between the sugar contain in food, particularly fructose and the risk of hepatic steatosis, which has more than doubled in children in the last 10 years [31-32]. Increased consumption of fructose in adolescents was proved to be associated with CVD risks later in life secondary to an increase in abdominal fat [33].

A recent study of Stanhope and his collaborators describes how the metabolism of fructose is associated with a good number of adverse metabolic effects [34]. These effects are likely to be increased during growth and development because fructose promotes differentiation of adipose tissue during growth. In support of this concept, the article of Disse and colleagues shows that children with a disorder of absorption of fructose have lower levels of obesity [35]. Although not definitive, this finding supports the concept of a more damaging effect of fructose on obesity during growth. This concept is also based on the Morgan [36] meta-analysis which shows that the consumption of fructose can contribute to the increase in the prevalence of pediatric obesity, while the limitation of SSBs which include the majority of fructose intake can help to reduce the prevalence of obesity among young people and help to improve their metabolic profile [37].

This imbalance to a greater amount of fructose in the diet has other implications for the growth and development of children and adolescents [29-30]. For example, the consumption of milk, which has declined in favor of SSBs; the milk is now more expensive than SSBs. This has consequences on the daily fructose consumption because milk contains no fructose, while SSBs, is very rich in fructose. For example, a serving of 12 fluid ounces (350 ml) of soft drinks contains 23 g of fructose. Two of these portions would be sufficient to reach 90% of the acceptable level of the daily consumption of fructose for youth, without even taking into account the fructose consumed from other natural sources (fruits and vegetables) and found in the other foods [38].

Despite the diversity of links between increased consumption of SSBs and fructose and obesity among young people, an important conclusion is observed: increased consumption of sugar, particularly fructose, contributes to a profile of altered body fat which would favour an increased risk of metabolic diseases, including T2DM, fatty liver and other [37]. Note a higher level of sugar, especially of dietary fructose induce a metabolic dysfunction, especially among young people who are overweight or obese, compared to young people with normal weight [39]. Youth studies suggest that a reduction in the consumption of SSBs leads to a better weight control among those who are overweight [39].

Despite the mixed conclusions and some gaps in our knowledge about the effects of sugars on obesity and the metabolic risk in pediatric populations, the majority of studies support the current efforts of public health to reduce the total consumption of sugars and fructose in this population [30]. For the reasons given previously, it is a crucial issue among youth because of the underlying effects of added sugar, and fructose on the growth and development of adipose tissue.

The most important is to consider the effects of fructose on the brain and on the appetite control, which are to promote the development of obesity. It is therefore realistic to believe that fructose would have an “obesogenic” effect during the period of development of the youth (30). Since overweight and obesity aggravate the effects of sugar on the metabolic disorders during growth and development, efforts to reduce the sugar consumption should focus on children and adolescents who are overweight or obese. It is also suggested to focus not only on obesity as a consequence, but also as a metabolic risk factor for T2DM and CVD.

From the information above and the lack of clear regulations governing the content in sugar and fructose of several foods and sugary drinks, it seems very justifiable to recommend the absence of SSBs among our young people with overweight or obesity. Remember that, in fruit and vegetables, the fructose is mixed with fibre, vitamins, minerals and enzymes, making it harmless, which justified retaining the current recommendation of five servings of fruits and vegetables per day and no SSBs.

Conclusion

Intake of added sugar, predominantly sucrose and HFCS from SSBs has increased markedly in the US and Canada in the past decades and constitutes the major source of fructose in the diet. In this perspective, and since we rarely consume fructose in isolation, it is logical to measure the potential cardiometabolic effects of fructose by evaluating its associations with SSBs. Although the consumption of SSBs has decreased moderately in recent years, the intake levels remain high in the US and Canadian populations and are increasing rapidly in developing countries.

Based on the available evidence we can conclude that the consumption of SSBs causes excess weight gain and is associated with increased risk of T2DM in adult and pediatric patients. It also increases risk of CVD and other serious health problems later in life. SSBs are thought to promote weight gain in part due to excess calories and incomplete compensation for liquid calories at subsequent meals. These beverages may also increase T2DM and CVD risk independently through an adverse glycemic response and unique metabolic effects of fructose. Short-term mechanistic studies have shown that excess fructose ingestion can result in additional cardiometabolic effects due to increased hepatic de novo lipogenesis, accumulation of visceral adiposity and ectopic fat and production of uric acid [2].

Several public policy and regulatory strategies to reduce intake of SSBs have been in place or are being considered to limit the consumption of SSBs. Implementing and evaluating such policies are important areas for scientists and policymakers. Key areas that warrant future research include examining the effects of different sugars and sugar moieties on health outcomes over a broad range of doses, investigating the health effects of sugar consumed in solid form in comparison to liquid sugar and further elucidating the biological mechanism by which intake of liquid calories induces an incomplete compensatory intake of energy at subsequent meals. There is also a need to identify effective strategies to reduce SSB consumption at the individual and population level. In this regard the Canadian Diabetes Association recommends the following in its Sugar Position Statement for the population and the Government [40].

The Canadian Diabetes Association recommends Canadians:

1. Limit intake of free sugars a to less than 10% of total daily calorie (energy) intake. This is approximately 50g (12 teaspoons) of free sugars consumption per day based on a 2000 calorie diet.

2. Limit intake of sugar sweetened beverages (SSB) and drink water in its place.

3. Promote intake of whole foods and reduce intake of free sugars throughout life for overall health.

The Canadian Diabetes Association recommends that:

1. The Government of Canada introduce a tax on SSBs and use the revenues generated to promote the health of Canadians.

2. The Government of Canada ensures clear nutrition labelling for packaged foods including the amount of free sugars on the Nu-trition Facts Table.

3. Federal, Provincial and Territorial Governments immediately operationalize the World Health Organization (WHO) set of rec-ommendations to prevent the marketing of foods and beverages to children.

4. A Federal, Provincial and Territorial Working Group on Food and Beverage Marketing to Children is convened to develop, im¬plement and monitor policies to restrict food and beverage mar¬keting to children.

5. Federal, Provincial and Territorial governments support im¬proved access to and affordability of nutritious foods in all re¬gions.

6. The Government of Canada implement legislation to require la¬beling of free sugars on menu labels in restaurants so Canadians can make more informed choices about the foods they eat.

7. Recreational events, schools, recreation facilities, and govern¬ment spaces not offer SSBs for purchase.

8. Recreational events, schools, recreation facilities, and govern¬ment spaces provide free water for consumption.

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Is there a definition of Metabolically Healthy Obese Pediatric Patients?

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Letter to the editor

We have clearly explained in the first articles of this special issue that pediatric obesity increases the risk for metabolic diseases, including T2DM, HTN, dyslipidemia and many other chronic disorders. We have also explained that pediatric obesity is associated with the risk of developing cardiovascular disease (CVD) later in life. However, it is also clear that not all obese pediatric patients develop these disorders. Therefore we have a clear evidence that a unique subset of obese pediatric patients who appear to be protected from the development of metabolic disturbances and CVD. In adults, Plourde and Karelis have been able to provide a definition of a subgroup of adult obese patients considered as metabolically healthy obese (MHO) [1].

This definition is now used internationally under the term of (PK definition; Plourde and Karelis definition) and is used to determine the prevalence of MHO vs the prevalence of metabolically unhealthy obese patients (MUHO) [2]. As in adults, identifying obese pediatric patients with this potential protective profile could help us determine which part of the obese pediatric population needs to be only periodically observed and which needs to have early therapeutic interventions [1]. However, as in adults important questions on the MHO profile remain unanswered: do we have consensus on the definition and do they remain metabolically healthy over the course of their lifetime?

Obviously, for the purpose of this article, we will limit our discussion to the adolescent age group i.e., those more at risk of developing T2DM. We limit to this age group for the purpose of being more easily able to compare to the adult population. Also because many questions still remained to be answered having different age group will increase difficulties finding an appropriate definition of MHO. We will not be able to get definitive answers to the questions raised, but we hope that this letter will generate scientific discussion around the topic of pediatric patients with MHO.

Identifying MHO individuals

Adults defined as MHO are characterized for their low metabolic abnormalities such as: insulin resistance (IR), pro-atherogenic lipoprotein profile, pro-inflammatory state, or hypertension. In addition, they present lower visceral, hepatic, muscle fat accumulation and gene expression-encoding markers of adipose cell differentiation [3]. However, it is important to note that MHO individuals may also have multiple intermediate metabolic risk factors that may signal increased risk for T2DM and CVD (3). In general, insulin sensitivity indices and a cluster of metabolic risk factors (i.e. blood pressure, triglycerides, HDL-cholesterol and glycaemia) with specific thresholds are used in the identification of MHO subjects.

As discussed in the review by Plourde and Karelis [1], the complexity of techniques to determine insulin sensitivity and the use of different surrogate indexes to determine metabolic risk factors has led to different definitions of MHO. Therefore, without an expert consensus on the definition of MHO patients, findings and/or conclusions on MHO subjects are difficult to interpret. Accordingly, we considered appropriate to provide simple clinical criteria for the identification of MHO individuals.

We first believed that waist circumference of ≥80 cm for women and ≥94 cm for men should be used to identify adults MHO subjects instead of a BMI of ≥30 kg/m². We then suggested the following metabolic markers with their cut-points: glycemia <5.6 mmol/l, HDL ≥1.3 mmol/l for women and ≥ 1.03 mmol/l for men, triglycerides <1.7 mmol/l, and blood pressure <120/80 mm Hg. The proposed choice of these clinical markers was based from the criteria for the identification of the metabolic syndrome in adults from the International Diabetes Federation [5]. It should be noted that the cut-point for blood pressure was set at <120/80 mmHg since there is evidence to suggest that pre-hypertension may increase the risk of cardiovascular disease [6]. We propose that adults MHO individuals may be identified when all four of the metabolic markers are met. We seek to apply a strict method because our goal is to identify a “true” MHO population which could be different from a non-metabolic syndrome population.

We feel this represents a good first step for a consensus of a standard definition for MHO individuals. We understand that this definition is open to criticism and that the list of criteria could be modified and that the cut-points may be refined. However, according to Truthmaan J et al, (2016) [2], the PK criteria, which define MHO by the fulfilment of all included PK criteria may be more appropriate to determine a “true” MHO. However, in the adolescent age group, it seems that the definition of abdominal obesity is particularly lacking and need to be challenged by the medical and scientific community.

Potential definition for MHO adolescent

In a recent study performed in a district school in Bangladesh they assess the prevalence of obesity and abdominal obesity by means of body mass index (BMI) and waist-to-height ratio (WHtR), respectively, in adolescent girls [7]. Based on age and sex specific BMI percentiles, the students were classified as normal weight (5^th– <85^th percentile), overweight (85^th–<95^th percentiles), and obese (≥95^th percentile). Central obesity was categorized as WHtR ≥ 0.5. Adolescent girls (aged 9–17 years) attending the sixth to twelfth grades (n = 501) in a Bengali medium school participated in the study. The prevalence of obesity and overweight were 23% and 14% among the girls. The prevalence of central obesity was 26%. Around 14% of girls in the normal weight group were centrally obese. Which reinforce the rationale for measuring abdominal obesity in adolescents? There was a significant relationship between WHtR and BMI status (P = 0.0001) [7].

The importance of measuring waist circumference is strongly supported by the results of the 2007–2009 Canadian Measures Health Survey where 2.6% of adults with normal weight, 35.3% of adults with overweight and 93.0% of adults with obesity had waist circumferences suggesting abdominal obesity [8]. Furthermore, although BMI data suggest that 24% of Canadian adults are at high risk for obesity-related illness or death, 37% of Canadian adults are at high risk when waist circumference is taken into consideration [8]. Thus, using both measures increases the threshold for identifying patients at risk for health problems and as mentioned above, adolescent are not different on that aspect [7]. Therefore, the risks for all medical conditions associated with obesity increase with higher BMIs and larger waist circumferences in both adults and adolescent patients [7, 9].

The current International Diabetes Federation definition of metabolic syndrome in pediatric patients recommends the use of WC as a mandatory diagnostic component [10]. Evidence suggested that compared to general obesity, abdominal obesity is associated with greater cardiovascular risks. Recently, the use of BMI as a cardiovascular risk factor has been questioned and WC received increasing attention in clinical practice [10]. Considering the high prevalence of pediatric obesity, we suggest that more attention should be paid to the monitoring aspects of abdominal obesity among children and adolescents and that prevention strategies should be more focused on abdominal obesity [11].

According to the IDF [10, 12], in adolescent ages 10 to 16 years-old, MUHO is defined as: abdominal obesity with the ≥90^th percentile for age and sex (or adult cut-off if lower) as assessed by waist circumference; triglycerides ≥1.7 mmol/L; HDL-cholesterol <1.03 mmol/L; Blood pressure ≥130 mm Hg systolic or ≥85 mm Hg diastolic and Glucose ≥5.6 mmol/L (oral glucose tolerance test recommended) or known T2DM.

For the adolescent aged higher than 16, it is recommended to use the existing criteria for adults. Accordingly, we considered appropriate to provide the same clinical criteria for the identification of adults with MUHO. We first retain the same waist circumference of ≥80 cm for women and ≥94 cm that we used to identify adults MUHO subjects [1]. We then suggest the following metabolic markers with their cut-points: glycemia <5.6 mmol/l, HDL ≥1.3 mmol/l for girls and ≥ 1.03 mmol/l for boys, triglycerides <1.7 mmol/l, and blood pressure <120/80 mm Hg. I believe that, at this point, that this definition is the best definition of MHO especially considering that being obese at a young age and for a longer period of time is associated with a high risk of T2DM and CVD risk factors later in life (see article # 2). However, we do not think that this one is the final definition of pediatric MHO and again we hope that the scientific community will be open to discuss this definition.

Conclusion

As in adults, data on the lifestyle profile of adolescents MHO subjects is rather limited. Indeed, there is evidence to suggest that physical activity levels and the dietary profile of MHO individuals are not similar to MUHO subjects [1]. Thus, currently, it is difficult to elaborate on relevant clinical practice guidelines for both surveillance and treatment of MHO patients. There is no evidence that these subjects are permanently protected from the risk of developing obesity, T2DM and their related comorbidities. Also, adolescent MHO individuals may present other obesity-related comorbidities such as sleep apnea, knee osteoarthritis, poorer body image and many others comorbidities. Moreover, there is no evidence that MHO adolescents could tolerate a further increase of their fat mass, without any consequences on their cardio-metabolic profile as it is well established that worsening of body weight is strongly associated with the deterioration of risk factors for CVD [13]. Therefore, on the basis of this evidence or until future evidence can state otherwise, a prudent attitude would be to regularly monitor cardio-metabolic risk factors in obese adolescent MHO patients (especially elevated triglycerides, glycaemia, HOMA and C-reactive protein as well as low HDL), in order to detect as early as possible a negative evolution of their cardio-metabolic profile as recommended in the Clinical Practice Guidelines for the Management of Obesity [14]. In particular, a special surveillance should be applied to prevent any increase in body weight, and waist circumference (WC) as it was previously concluded that the MHO phenotype may be maintained by promoting lower WC [15]. Furthermore, it seems difficult to prescribe the optimal weight loss program in MHO individuals since the potential benefits of a weight loss treatment are still a matter of debate. Studies assessing the effects of lifestyle interventions, including diet and/or physical activity in MHO have led to divergent results [1]. Thus, we would suggest that prioritization for weight loss treatment may be given to MUHO patients. Achieving permanent weight reduction is a difficult challenge for any obese person and the risk of weight regain is elevated. For this reason, any weight loss program in MHO individuals should be preceded by a careful evaluation of expected resources, costs and benefits. However, for all obese patients including adolescents our public health message should remain the same about promoting good lifestyle habits and prevention of weight gain.

References

Plourde G, Karelis AD (2014) Current issues in the identification and treatment of metabolically healthy but obese individuals. Nutr Metab Cardiovasc Dis 24: 455-459. [crossref]
Truthmann J, Mensink GB, Bosy-Westphal A, et al. (2016) Metabolic Health in Relation to Body Size: Changes in Prevalence over Time between 1997-99 and 2008-11 in Germany. PLoS One 11: e0167159. [crossref]
Karelis AD (2008) Metabolically healthy but obese individuals. Lancet 372: 1281-1283. [crossref]
Manu P, Ionescu-Tirgoviste, C. Tsang, J et al. (2012) Dysmetabolic signals in “Metabolically Healthy”” obesity Obes Res Clin Pract 6:e9–e20
Alberti KG, Zimmet P, Shaw J (2006) Metabolic syndrome–a new world-wide definition. A Consensus Statement from the International Diabetes Federation. Diabet Med 23: 469-480. [crossref]
Huang Y, Wang S, Cai X, Mai W, Hu Y, et al. (2013) Prehypertension and incidence of cardiovascular disease: a meta-analysis. BMC Med 11: 177. [crossref]
Zabeen B, Tayyeb S, Naz F, Ahmed F, Rahman M, et al. (2015) Prevalence of obesity and central obesity among adolescent girls in a district school in Bangladesh. Indian J Endocrinol Metab 19: 649-652. [crossref]
Janssen I, Shields M, Craig CL, Tremblay MS (2011) Prevalence and secular changes in abdominal obesity in Canadian adolescents and adults, 1981 to 2007-2009. Obes Rev 12: 397-405. [crossref]
Plourde G, Prud’homme D (2012) Managing obesity in adults in primary care. CMAJ 184: 1039-1044. [crossref]
Alberti KG, Zimmet P, Shaw J; IDF Epidemiology Task Force Consensus Group (2005) The metabolic syndrome–a new worldwide definition. Lancet 366: 1059-1062. [crossref]
Zhang YX, Zhao JS, Chu ZH (2016) More Attention Should Be Paid to Monitoring of Abdominal Obesity among Children and Adolescents. Ann Nutr Metab 69: 212-214. [crossref]
Zimmet P, Alberti G, Kaufman F, Tajima N, Silink M, et al. (2007) The metabolic syndrome in children and adolescents. Lancet 369: 2059-2061. [crossref]
Berrahmoune H, Herbeth B, Samara A, Marteau JB, Siest G, et al. (2008) Five-year alterations in BMI are associated with clustering of changes in cardiovascular risk factors in a gender-dependant way: the Stanislas study. Int J Obes (Lond) 32: 1279-1288. [crossref]
Lau DC, Douketis JD, Morrison KM, Hramiak IM, Sharma AM, et al. (2007) 2006 Canadian clinical practice guidelines on the management and prevention of obesity in adults and children [summary]. CMAJ 176: S1-13. [crossref]
Appleton SL, Seaborn CJ, Visvanathan R, Hill CL, Gill TK, et al. (2013) Diabetes and cardiovascular disease outcomes in the metabolically healthy obese phenotype: a cohort study. Diabetes Care 36: 2388-2394. [crossref]

Field Deployment of Loop-Mediated Isothermal Amplification for Centralized Mass-Screening of Asymptomatic Malaria in Zanzibar: A Pre-Elimination Setting

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DOI: 10.31038/IMROJ.2017221

Abstract

Background: Molecular tools for detection of low-density asymptomatic Plasmodium infections are needed in malaria elimination efforts. This study reports results from the hitherto largest implementation of loop-mediated isothermal amplification (LAMP) for centralized mass screening of asymptomatic malaria in Zanzibar.

Methods: Healthy individuals present and willing to participate in randomly selected households in 60 villages throughout Zanzibar were screened for malaria by rapid diagnostic tests (RDT). In 50 % of the study households, participants were asked to provide 60 μL of finger-prick blood for additional LAMP screening. LAMP was conducted in two centralized laboratories in Zanzibar, by trained technicians with limited or no previous experience of molecular methods. The LAMP assay was performed with LoopampTM MALARIA Pan/Pf Detection Kit (Eiken Chemical Company, Japan). Samples positive for Plasmodium genus (Pan)-LAMP were re-tested using Plasmodium falciparum-specific LAMP kits.

Results: Paired RDT and LAMP samples were available from 3983 individuals. The prevalence of asymptomatic malaria was 0.5 % (CI 95 % 0.1-0.8) and 1.6 % (CI 95 % 1.1-2.2) by RDT and Pan-LAMP, respectively. LAMP detected 3.4 (CI 95 % 2.2-5.2) times more Plasmodium positive samples than RDT. DNA contamination was experienced, but solved by repetitive decontamination of all equipment and reagents.

Conclusions: LAMP is a simple and sensitive molecular tool, and has potential in active surveillance and mass-screening programmes for detection of low-density asymptomatic malaria in pre-elimination settings. However, in order to deploy LAMP more effectively in field settings, protocols may need to be adapted for processing larger numbers of samples. A higher throughput, affordable closed system would be ideal to avoid contamination.

Keywords

Plasmodium, Malaria, Low-density, Asymptomatic, Loop-mediated isothermal amplification, Mass screening, DNA contamination

Background

Asymptomatic Plasmodium infections are an important reservoir for continued malaria transmission that needs to be addressed in the context of malaria elimination [1]. Detection of asymptomatic infections, which are often sub-patent, i.e., fall beneath the threshold of detection of both microscopy and rapid diagnostic tests (RDT), requires highly sensitive molecular tools. The use of polymerase chain reaction (PCR)-based assays in field settings is, however, limited due to the need for a cold chain, specialized equipment and know-how [2]. Loopmediated
isothermal amplification (LAMP) offers several advantages over PCR in field settings. LAMP requires minimal equipment, has short time-to-result (30 min-1 h), with an analytical sensitivity similar to PCR, and results that can be read by eye using UV fluorescence [3–5].

The Loopamp™ MALARIA Pan/Pf Detection Kit (Eiken Chemical Company, Japan) has been developed as a
field-friendly kit, comprising strips of reaction tubes containing vacuum-dried and temperature-stable reaction
components for either Plasmodium genus (Pan)-specific or Plasmodium falciparum-specific malaria detection. The
kit has been evaluated both in laboratory and field settings [6–8], and was piloted on a small scale in Zanzibar as a health facility-based, point-of-care, diagnostic tool for mass screening and treatment in 2013 [9].

This study reports results from the hitherto largest implementation of LAMP in the field, for scaled-up,
centralized mass screening of asymptomatic malaria in Zanzibar, a pre-elimination setting.

Methods

Study sites and study design

Zanzibar, located 35 km off the coast of mainland Tanzania, consists of two main islands, Unguja and Pemba, with respective populations of approximately 900,000 and 400,000. This study was performed as part of a larger knowledge, attitude, practice, and behavior (KAPB) malaria survey, conducted in Zanzibar April-May 2014. Household visits were carried out in 60 villages in ten districts (six in Unguja and four in Pemba) covering
the whole of Zanzibar. A proportional number of households were sampled from each village to reach a sample
size of 2162 households, powered for the KAPB study. Healthy individuals present and willing to participate in
the randomly selected households were screened for malaria by RDT. In 50 % of study households (in even
house numbers), participants were asked to provide 60 μL of finger-prick blood for additional LAMP screening.
Nexus seven tablet computers were used to conduct questionnaires as part of the KAPB survey. All participants or
guardians provided written informed consent prior to blood sampling. Ethical approvals were obtained from the ethical committees in Zanzibar (ZAMREC/0002/FEBRUARY/014) and the Regional Ethics Committee in Stockholm (2009/387-31).

Training of field enumerators and sample collection

Household visits were conducted by 40 field enumerators in teams of two, together with four field supervisors with prior experience of similar studies. All enumerators attended five days of training for RDT performance, blood sample collection for LAMP, and use of tablet computers. There were 14 teams in Unguja and six teams in Pemba, and each team visited six or seven households per day. RDT screening was conducted with either SD-Bioline Malaria Ag P.f/PanW (Standard Diagnostic, Inc, USA) (used for >90 % of screening) or First ResponseW Malaria Ag Combo (pLDH/HRP2) (Premier Medical Corporation Limited India). Results were recorded on the tablet computer during household visits, and RDT positive indi-viduals were referred to the closest health facility for treat-ment and registration in the Zanzibar malaria surveillance system. In 50 % of study households, 60 μL of finger-prick blood was collected using a plastic capillary tube (Dropstir, Medical Precision Plastics, USA), dispensed into a 1.5-ml pre-labelled sample collection tube containing 60 μL of pre-aliquoted DNA extraction buffer (400 nM NaCl, 40 mM Tris pH 6.5, 0.45 SDS), and mixed by flicking. Blood samples were collected in microtube storage racks with lids and transported at the end of each day to two centralized laboratories, one on each island, where they were stored at 4 °C overnight.

Training of laboratory technicians

Four technicians, two for each laboratory, with limited or no experience of LAMP were trained over three-and-a-half days. Training included a theoretical introduction to LAMP and the LAMP protocol, hands-on practical sessions with malaria positive blood samples diluted to different known concentrations, how to record results on tablet computers, and a half-day field trial with sam-ples collected the same day by the field enumerators.

Screening by LAMP in centralized laboratories

LAMP procedures were similar to the pilot study [9], with some modifications for scale-up of sample sizes. One cen-trifuge, three heat-blocks (1.5-ml block at 95 °C, 0.2-ml block at 65 °C and a 0.2-ml block at 95 °C) and a UV lamp were required in each laboratory. All samples collected in Pemba and half of the samples collected in Unguja (see below) were processed within 24 h of sampling. To reduce the risk of mix-up of samples and contamination, sets of pre-labelled sample collection tubes (containing 60 μL of aliquoted DNA extraction buffer) and pre-labelled DNA dilution tubes (containing 300 μL of aliquoted sterile water) were prepared prior to the start of the study. DNA extraction and the LAMP assays were performed in separ-ate areas to avoid contamination. DNA was extracted by the boil and spin method [10] and 26 μL of the super-natant was transferred to the DNA dilution tubes. The LAMP assay was performed with Loopamp™ MALARIA Pan/Pf Detection Kit (Eiken Chemical Company) as per protocol [10]. Samples positive for Pan-LAMP were retested using P. falciparum-LAMP specific kits. LAMP positive individuals (who were not positive by RDT) were visited by malaria surveillance officers and provided treat-ment within 48 h of sampling where possible.

Freezing of samples

Due to a delay in the shipment of LAMP kits, half of the LAMP samples collected in Unguja (N = 1414) were stored at −20 °C after DNA extraction and dilution, until the remaining reaction tubes arrived five weeks later. Dilution tubes from LAMP-positive samples in Unguja were also stored at −20 °C, for quality control of frozen DNA.

Statistical

Results are reported from individuals for which both RDT and LAMP were conducted (i.e., where paired data are available). Statistical analyses were conducted using Stata/SE 12.1 (StataCorp LP, Texas, USA). The survey de-sign was taken into consideration when calculating 95 % confidence intervals (CI 95 %) for prevalence estimations, using the survey [svy] command in Stata accounting for household and village sampling/stratification. The sensi-tivity and specificity of RDT was calculated using LAMP as the gold standard. McNemar’s test was used to compare the methods. Statistical significance was determined as p < 0.05.

Results

Study population

Participation was high; informed consent was given by 96.9 % of those present at the time of the survey (Fig. 1). Both RDT and LAMP results were available for 3983/4085 (97.5 %) of the individuals willing to participate. The remaining 102 (2.5 %) were excluded from further ana-lysis. The study population consisted of all ages (median: 18 years, range 0–98), with a higher proportion of females (59.0 %). Sample collection was conducted during a total of 19 days with an average of 220 samples processed per day in the two laboratories combined.

Fig.1 Flow chart of study

Prevalence of malaria by RDT and LAMP

The prevalence of asymptomatic malaria was 0.5 % (CI 95 % 0.1-0.8) and 1.6 % (CI 95 % 1.1-2.2) by RDT and Pan-LAMP, respectively (Table 1). Pan-LAMP detected 3.4 (CI 95 % 2.2-5.2) times more Plasmodium positive samples than RDT. Out of the Pan-LAMP positive sam-ples 64.6 % (42/65) were also positive by P. falciparum-LAMP. RDT had a sensitivity of 24.6 % (14.7-36.9) and specificity of 99.9 % (99.7-100.0) when compared to Pan-LAMP. Comparison by McNemar’s test showed a signifi-cant difference between the two methods (p <0.001).

Table 1. Prevalence of malaria detected by RDT and LAMP

	RDT	LAMP
Overall prevalence (%; CI 95 %^a)	0.5; 0.1-0.8 19/3983	1.6; 1.1-2.2 65/3983
Relative proportion positive in:
Only Pan^b (%; CI 95 %)	5.3; 0.0-16.4 1/19	35.4; 23.4-47.4 23/65
Pan + P. falciparum^c (%; CI 95 %)	31.6; 8.5-54.6 6/19	64.6; 52.6-76.6 42/65
Only P. falciparum^d (%; CI 95 %)	63.2; 39.2-87.1 12/19	ND^e

Both RDT brands used for malaria screening are two-band RDTs detecting P. falciparum HRP2 and Pan-Plasmodium LDH simultaneously, although with different detection limits (50–100 parasites/μL for P. falciparum HRP2 and 200–500 parasites/μL for Pan-Plasmodium LDH). In contrast, only the Pan-LAMP positive samples were assessed for P. falciparum during the LAMP screening, with a detection limit of 2–5 parasites/μL for both Pan-Plasmodium
and P. falciparum

^aConfidence intervals for prevalences were calculated using the survey [svy] command in Stata, accounting for household and village sampling/stratification
^bPositive for Plasmodium genus only
^cPositive for Plasmodium and P. falciparum
^dPositive for P. falciparum only
^eND = not determined

Discrepancies in LAMP after freezing of samples

DNA extracted from half of the samples (N = 1414) in Unguja was stored at −20 °C prior to LAMP testing due to a delay in the shipment of LAMP kits. Among these samples, 32 (2.3 %) were positive by Pan-LAMP, out of which 12 was also positive by RDT. However, amongst the frozen samples there were also three RDT positive samples that were found negative by Pan-LAMP. These three samples were positive for P. falciparum HRP2 only, Pan-Plasmodium LDH only, and both P. falcip-arum HRP2 and Pan-Plasmodium LDH, respectively. Among the samples from Unguja that were screened be-fore freezing (N = 1370), 11 (0.8 %) were positive by Pan-LAMP, out of which one was also positive by RDT. The 11 Pan-LAMP positive samples were stored at −20 °C, as a quality control of freezing DNA, however only 7/11 (63.6 %) were positive when re-tested after thawing.

LAMP-amplified DNA contamination

During the study DNA contamination of LAMP arose in the central laboratory in Pemba [see Additional file 1 for flow chart of events]. The contamination resulted from using a heat block with a heated pressurized lid during the 95 °C enzyme inactivation stage, and not allowing the samples to cool to room temperature before removing the strips for recording of results. ‘Fizzing’ was observed around the lid of the LAMP strips resulting in leakage of LAMP-amplified DNA. All equipment and reagents were subjected to repetitive decontamination with 5 % sodium hypochlorite over three days, and moved away from the epicentre of the contamination to a laboratory space avail-able in another building. The final enzyme inactivation step of the protocol [10] was removed as this was thought to be the source of contamination; instead results were read and recorded immediately after the amplification re-action. A negative control was included in each strip of eight reaction tubes, and any Pan-LAMP positive samples were repeated and only recorded as positive if positive in both runs. During the first few days following the contam-ination there were some samples that were considered false positive, but the numbers declined and reached zero within one week after the contamination.

Discussion

This is the hitherto largest reported implementation of LAMP for detection of asymptomatic malaria in a field setting. In order to scale-up the breadth of sampling, LAMP testing was centralized in two laboratories, meaning samples could be collected from all over the islands with fewer resources. The time-to-result was ap-proximately 24 h, compared with three hours in the pilot study where LAMP was used as a health facility-based, point-of-care, diagnostic tool for mass screening and treatment [9].

The results confirm the improved sensitivity of LAMP over RDT, as has been shown previously [3, 9]. The MALARIA Pan/Pf Detection Kit has a detection limit of 2–5 parasites/μL [3, 6], for both Pan-Plasmodium and P. falciparum. This is comparable to PCR, and substantially lower than the detection limits of P. falciparum-specific HRP2 (50–100 parasites/μL) and Pan-Plasmodium LDH (200–500 parasites/μL) in combo RDTs. The proportion of samples detected only by Pan-LAMP (35.4 %) sug-gests the presence of species other than P. falciparum. Similarly, other studies in Zanzibar have shown that up to 40 % of PCR-detectable malaria infections contained non-falciparum species [11, 12]. Non-falciparum infec-tions tend to be of lower parasite densities than P. falcip-arum infections [13], emphasizing the need for more sensitive species-specific methods for non-falciparum Plasmodium detection. The sensitivity (83.8 %) and speci-ficity (99.7 %) of Pan-LAMP, calculated using PCR as the reference standard, was high in the pilot study conducted in Zanzibar [9]. This is similar to previously reported sen-sitivities and specificities [6–8, 14, 15] and, together with the results of this study, suggests malaria LAMP is a use-ful molecular tool sensitive enough for detection of low-density asymptomatic malaria infections in field settings.

Importantly, some discrepancies were shown amongst samples screened following freezing of diluted DNA. RDT false positivity due to recently cleared infections has been well documented when detecting P. falciparum HRP2 [16], although none of the three study participants who were RDT positive/LAMP negative reported receiv-ing malaria treatment within the previous two weeks, and two of the RDTs were positive for Pan-Plasmodium LDH suggesting ongoing infections. The lack of repro-ducibility of results following freezing of samples sug-gests that DNA extracted by simple methods such as boil and spin may not be suitable for long-term storage and should be amplified by LAMP within a short period of time [17]. Alternatively, low reproducibility of PCR for detection of low-density infections has been reported [18] and parasite densities close to the LAMP detection limit could also explain the lack of reproducibility.

The potential risk of contamination with LAMP is large, due to the high efficiency of the reaction, although the risk is reduced when using a closed system [3, 19]. The MAL-ARIA Pan/Pf Detection Kit is manufactured with tubes that cannot be re-opened once closed, in order to avoid contamination with amplified DNA. However, as demon-strated in this study, the exposure of such tubes to high temperatures, as during enzyme inactivation, results in softening of the plastic and leakage of the contents. While removing the inactivation step solved this problem in this case, contaminations have been experienced in other research settings [8, 20] and these issues are important to report. Although MALARIA Pan/Pf Detection Kit is a field-friendly option, three days’ training is not sufficient for dealing with such events. Successful decontamination requires a larger understanding of molecular techniques and rigorous repetitive methods to ensure that the area is free of contamination.

Standard malaria diagnostic tools including microscopy and RDT are not sensitive enough to detect low-density asymptomatic infections [12]. Nucleic acid amplification-based methods provide the, to date, most sensitive and ac-curate tools to detect and identify pathogens [21]. Recently published, highly sensitive quantitative PCR methods state detection limits as low as 0.02 and 0.03 parasites/μL blood [22, 23]. However, these methods lack the field applicability that LAMP offers. Furthermore, the cost of LAMP is estimated to be a tenth of that of conven-tional PCR [15], although the cost of the field friendly kit is still at 5.3 US$ per reaction i.e., considerably more expensive than RDTs [3].

The high cost and risk of contamination may yet limit the implementation LAMP at a point-of-care level, but LAMP will be valuable for research purposes and for evaluating malaria elimination efforts. LAMP may, for ex-ample, be useful in mass/focal screening and treatment (MSAT/FSAT) programmes, for which the deployment of RDTs, perhaps due to their low sensitivity, has had varying results [11, 24]. In any case it will be important to evaluate the impact and cost effectiveness of deploying LAMP, in comparison to the deployment of standard diagnostic tools as well as in comparison to alternative molecular methods.

Conclusions

LAMP is a simple and sensitive molecular tool, and has potential in active surveillance and mass-screening pro-grammes for detection of low-density asymptomatic mal-aria in pre-elimination settings. However, in order to deploy LAMP more effectively in field settings, protocols may need to be adapted for processing larger numbers of samples. A higher throughput, affordable closed system would be ideal to avoid contamination.

Competing interests

IG is an employee of the Foundation for Innovative New Diagnostics (FIND), a co-developer of the Loopamp™ MALARIA Pan/Pf Detection Kit. All other authors declare no competing interest.

Authors’ contributions

MIM, IJG, AM, ASA, AB, and JC conceived and designed the study. UM, MK, BAS, AKA, and JC carried out the training and were responsible for the fieldwork in Zanzibar. UM, BAS and MHN were responsible for the training and conducting of LAMP. UM and JC analysed the data, and drafted the manuscript. All authors read and approved the final manuscript.

Acknowledgments

We would like to thank all participants, staff members, and ZAMEP employees involved in the KAPB survey for their dedicated participation. We would also like to acknowledge Colin Sutherland, Spencer Polly, Michelle Hsiang and Alanna Schwartz for their intellectual input regarding experience of dealing with DNA contamination. This work was supported by Global Fund [Grant number ZAN-809-G07–M, work plan GFRD 8 phase 2 2013]; President’s Malaria Initiative (PMI) [Implementation letter # 45, work plan for FY 2013]; the Swedish Medical Research Council (VR) [grant numbers 2009–3785 and 2013–6594]; the Foundation for Innovative New Diagnostics (FIND) with funds from the German Federal Ministry of Education and Research (BMBF) through the KfW Entwicklungsbank; and the Einhorn foundation. In memoriam of Ali K Abass, a much missed friend and colleague.

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H Pylori Infection as Risk Factor for GIT Bleeding in Haemophilic Patients

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DOI: 10.31038/IMROJ.2016126

Abstract

Background: Helicobacter pyelori is endemic in Egypt and present a main cause of gastrointestinal bleeding.

Aim: Aim of this study is to evaluate the prevalence of Hpylori infection in hemophilic patients, and to assess its impact on gastrointestinal bleeding associated with this infection in such patients.

Methods: We prospectively investigated the prevalence of H. pylori infection in 40 Egyptian patients with hemophilia A, B and von Willebrand syndrome and 20 normal male subjects were included. Every patient and control subject in the study were tested one time for H. pylori stool antigen by ELISA. All patients and control subjects were tested for occult blood using Guaiac-based fecal occult blood test.

Results: Twenty eight out of 40 patients (70%) are H. pylori positive ; and 12 out of 20 control (60%) are H. pylori positive. The odds ratio is ‎‎1.55, 95% CI (0.6162 to 3.9269), ‎Significance level P = 0.3497. Among 28 H.pylori positive patients, 5 patients (17.9 %) tested positive for occult blood. Among the 12 H.pylori positive subjects ‎ in the‎ control group, only one tested positive for occult blood (8.3%). Odds ratio for Occult bleeding in H pylori positive patients and control was 2.39: P= 0.4504. None of the H. pylori negative patients or control subjects had a positive occult blood disease.

Conclusion: Patients with hemophilia, H. pylori should not be considered as an important cause of GI bleeding. The recurrence of the infection and GI bleeding could be prevented with eradication of H. pylori. Screening tests for H. pylori would not be needed in patients with hemophilia in endemic areas.

Keywords

Haemophilia, Hpyelori

Introduction

In Egypt, it is estimated that 5050 people with haemophilia and , 499 with vWD are registered within the six hemophilia treatment centers (www.wfh.org annual report 2013)

More than 50% of the world’s population harbor Helicobacter pylori in their upper gastrointestinal tract. Infection is more prevalent in developing countries, and incidence is decreasing in Western countries. [1]

According to world gastroenterology organization report in 2010, H.pylori incidence in adult Egyptians was 90% (www.worldgastroenterology.org)

It has been hypothesized that the host immunologic response against H. pylori plays a main role in determining gastric mucosal injury, through the release of cytokines and the action of autoantibodies against H1/K1-adenosine triphosphatase of gastric epithelial cells. [2]

Infection with H pylori is the main etiological factor for erosive gastritis and duodenal or gastric peptic ulcers that often complicat with life-threatening bleeding in patients with coagulation disorders. [3]

The Egyptian government provides approximately 38% of healthcare costs of treating haemophilic patients (www.wfh.org annual report 2013). Most hemophilia patients are treated with plasma or cryoprecipitate, resulting in a high risk of transfusing blood-borne diseases like HIV and hepatitis B and C. Factor concentrate is available only in limited quantities, and patients must travel long distances to get it.

There is a contradictory in the previous studies between prevalence of H pyelori and risk of GIT of bleeding, we prospectively investigated the prevalence of H. pylori infection in patients with hemophilia A or B or von Willebrand syndrome and it is impact on risk of bleeding in those patients and compare our results with others’.

Patients and methods

This is a case control study. All participants are adult patients ‎visiting the hematology clinic of kasr Al Aini hospital and ‎the Egyptian society of Hemophilia. The study received research ethical committee approval from Kasr Al Aini ‎medical school and all participants gave written consents. Forty patients with bleeding disorders (mean age 24); categorized as: 30 patients with Hemophilia A, 6 patients with Hemophilia B and 4 patients with VWD. Patients who received triple therapy before or Patients with liver cirrhosis, thrombocytopenia, any platelet or vascular defects or patients with peptic ulcer were excluded. Control group included 20 subjects (mean age 27) of the same socioeconomic level and the same exclusion criteria of the patients included in the study. Each Patient and control subject in the study were tested for H. pylori stool antigen by ELISA, This technique is non-invasive, rapid, easy-to-use, and shows good performance characteristics for diagnosis of H. pylori infections, with sensitivity, specificity, Positive predictive value (PPV),negative predictive value (NPV), and efficiency were 100%, 90.0%, 96.9%, 100%, and 97.6% respectively).[4] All Patients and control subjects were tested for occult blood using guaiac-based fecal occult blood test. [5] All diet and drug precautions were applied before obtaining samples to prevent false positive results as dietary restriction of both hemoglobin and vegetable peroxidase containing substances is essential for valid screening for occult blood.[6]

Statistics

Using SPSS V.16.0 for calculation of the means and z test for comparison between the prevalence of H. pylori infection among ‎Hemophilia A, Hemophilia B and von Willibrand patients and the prevalence of H. pylori infection among the control group to investigate whether there is a ‎difference in prevalence between both groups or not.

Comparison between the odds ratio (OR) of developing occult GI bleeding (indicted by positive guaiac test) among Hemophilia A, Hemophilia B and von Willibrand patients who test positive for H. pylori and the odds ratio of developing occult GI bleeding ‎ among the control group who test positive for H. pylori to investigate whether there is a relation between the possible risk and the outcome.

Results

The patients’ group included 40 male patients (‎30‏‎ patients with Hemophilia A (75%), ‎‏6 patients with Hemophilia B (15%), and 4 patients with VWD (10%)) with age ranged from 12 to 52 years (mean age 24 years).

Twenty eight out of 40 patients (70%) are H. pylori positive; and 12 out of 20 controls (60%) are H. pylori positive. Odds ratio: 1.55 ‎) 95% Confidence Interval: ‎0.6162 to 3.9269‎; P = ‎0.3497)

Among 28 H. pylori positive patients, 5 patients tested positive for occult blood (17.9 %). all patients positive for occult blood were also positive for H. pylori stool antigen. Among the 12 subjects positive for H. pylori in the control group subjects, only one tested positive for occult blood (8.3 %), and he was also H. pylori positive. Odds ratio was 2.3913 (95% Confidence Interval: 0.2485 to 23.0104; P = 0.4504). None of the H. pylori negative patients or control subjects had a positive occult blood disease.

Table 1 and Figure 1 & Figure 2 demonstrate the prevalence of H.pylori and occult bleeding in patients and control.

Figure.1 Prevalence of H.pylori in patients and control Prevalence of occult bleeding in patients and control

Figure1.Prevalence of H.pylori in patients and control Figure2.Prevalence of occult bleeding in patients and control

Table 1. Prevalence of H.pylori and occult bleeding in patients and control

Diagnosis	Occult Blood Positive		Occult blood negative
Diagnosis	H. pylori Positive	H. pylori Negative	H. pylori Positive	H. pylori Negative
Hemophilia A	5	0	15	10
Hemophilia B	0	0	4	2
VWD	0	0	4	0
Total	5	0	23	12

Discussion

The prevalence of H. pylori infection in patients with hemophilia A or B or von ‎Willebrand syndrome was investigated and compared to the prevalence of H. pylori infection in normal control subjects in many studies with variable results. In our study, we didn’t find significant difference between prevalence of H. pylori among hemophilia and VWD patients (70 %) n=40 and its prevalence among normal control subjects (60 %) n=20, the odds ratio is ‎‎1.55, 95% CI (0.6162 to 3.9269), z statistic 0.935, ‎Significance level P = 0.3497).The Prevalence of H. pylori revealed by this study doesn’t differ from the reported prevalence in ‎general population: 72.38% .[7] While the odd ratio of H. pylori infection is about 1.5; It is insignificantly higher for occult ‎bleeding detected by FOBT in absence of history of frank ‎bleeding; Odd ratio is 2.39, 95% Confidence Interval: 0.2485 to ‎‎23.0104, , P= 0.4504. Our case and control were matched for geographic distribution, age, socio economic status and educational level to avoid misleading results as described previously by wang.[8] Our results are also concomitant with Braden et al who found similar prevalence of Helicobacter pylori Infection in seventy patients with haemophilia and WVD and 100 age-related volunteers P value were statistically insignificant.[9] Also Eleftheriadis studied thirty-seven patients with hereditary haemorrahgic diseases and 26 control. ELISA was used to detect IgG, anti-CagA, and IgA antibodies to H. pylori in the serum and saliva. Result of this study revealed that 64.8% of the patients and 65.4% of the controls had H. pylori IgG antibodies in serum (P= 0.1 (. [10] Szczepanik also found that the prevalence of H. pylori infection in hemophilic patients in Poland was comparable to that in patients without coagulation disorders (49.3% vs 39% respectively P = 0.11).[3]

However our results were inconsistent with the study of upper gastrointestinal bleedings in patients with hereditary coagulation disorders in Northwest of Iran. The prevalence of H. pylori infection was investigated by stool antigen test, and serum serologic tests including immunoglobulin G and anti-CagA. Results Among 90 patients (81 men, nine women, mean age 31.30 ±10.72 years), 66 patients with hemophilia A, 10 patients with hemophilia B, six patients with Von Willebrand disease, five patients with platelet function disorders, and three patients with other factor deficiencies were evaluated. About 46.7% of patients in group A, and 23.3% of patients in group B were anti-CagA–positive (P = 0.02), whereas 76.7% of patients in group A and 51.7% of patients in group B had H. pylori immunoglobulin G antibodies (P= 0.02). H. pylori antigen in stool was positive in 76.7% in group A and 55% in group B (P = 0.03). [11]

Our study also found statistically insignificant increased risk of fecal occult ‎bleeding in absence of history of frank ‎bleeding in patients with hemophilia A; Odds ratio was ‎‎2.39, 95% (Confidence Interval: 0.2485 to ‎‎23.0104, z statistic: 0.755, Significance level: ‎P= 0.4504).‎

Though the prevalence of H pylori in Szczepanik et al. study were statistically insignificant however the gastrointestinal bleeding was reported in 46 patients (31.5%) with hemophilia and in two control group patients (2.0%) (P < 0.0001). Gastrointestinal bleeding was significantly more frequent in patients with hemophilia infected with H. pylori (33/46; 71.7%) than in patients with no H. pylori infection (13/46; 28.3%; P = 0.0002). Concluding that Helicobacter pylori infection is a risk factor for duodenal and gastric ulcer bleeding in hemophilia patients. [3]

Eyster et al detected antibodies against H. pylori in 14 (35%) of 40 subjects who had upper gastrointestinal bleeding event compared with 7 (17%) of 41 controls who were closely matched for age and other factors. Bleeding was substantially but not significantly increased (OR: 4.6; 95% CI: 0.3-83.9) with H. pylori seropositivity. [12]

Though Choe studied a group of haemophilic children but his results concluded significant role of H pylori in inducing GIT bleeding. Helicobacter pylori infection was found in four of six (66.7%) patients with GI bleeding (3, duodenal ulcer; 1, H. pylori associated chronic gastritis). The patients with H. pylori infection had an eradication treatment of triple therapy and no recurrence happened. [13]

According to our results screening for H. pylori should be routine work-up for all patients with hemophilia A, and all patients with positive stool antigen test should be treated immediately to prevent gastrointestinal bleeding, and to repeat testing to ensure eradication of the bacteria which may definitely lower the costs as was described by Schulman.[14]

Conclusion

Patients with hemophilia, H. pylori should not be considered as an important cause of GI bleeding. The recurrence of the infection and GI bleeding could be prevented with eradication of H. pylori. Screening tests for H. pylori would not be needed in patients with hemophilia in endemic areas.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent was obtained from all individual participants included in the study.

Authors declare no conflict of interest. Authors declare that the results have not been published previously and are not under submission elsewhere.

References

Brown LM, (2000) Helicobacter pylori: epidemiology and routes of transmission.Epidemiol Rev 22: 283-297. [crossref]
Emilia G, Longo G, Luppi M, Gandini G, Morselli M, et al. (2001) Helicobacter pylori eradication can induce platelet recovery in idiopathic thrombocytopenic purpura. Blood 97:812-4.
Szczepanik AB, Zaleska M, Wiszniewski A, Wislawski S, Misiak A, et al. (2005) Helicobacter pylori infection in patients with haemophilia in Poland: prevalence and risk of upper gastrointestinal bleeding. Haemophilia 11:376-9
Kim PS, Lee JW, Pai SH, Kim YB, Cho JK, et al. (2002) Detection of Helicobacter pylori antigen in stool by enzyme immunoassay. Yonsei Med J 43: 7-13. [crossref]
Green BT, Rockey DC (2004) Gastrointestinal endoscopic evaluation of premenopausal women with iron deficiency anemia. J Clin Gastroenterol 38:104-9
Syed AA, Khatoon BA, Silwadi MF (2001) New reagents for detection of faecal occult blood. J Pharm Biomed Anal 24: 581-586. [crossref]
Mohammad MA, Hussein L, Coward A, Jackson SJ (2007) Prevalence of Helicobacter pylori infection among Egyptian children: impact of social background and effect on growth. Public Health Nutrition 11: 230–236.
Wang F, Meng W, Wang B, Qiao L (2014) Helicobacter pylori-induced gastric inflammation and gastric cancer. Cancer Lett 345: 196-202. [crossref]
Braden B, Wenke A, Karich HJ, Dietrich CF, Scharrer I, et al. (1998) Risk of gastrointestinal bleeding associated with Helicobacter pylori infection in patients with hemophilia or von Willebrand’s syndrome.Helicobacter 3: 184-187. [crossref]
Eleftheriadis N, Makri S, Aggouridaki C, Pithara E, Makris P (2002) Helicobacter pylori infection in upper gastrointestinal bleeding in patients with hereditary hemorrhagic disorders. Eur J Intern Med 13:480-4.
Dolatkhah R, Khoshbaten M, Asvadi Kermani I, Reza Bonyadi M, Ghojazadeh M, et al. (2011) Upper gastrointestinal bleedings in patients with hereditary coagulation disorders in Northwest of Iran: prevalence of Helicobacter pylori infection. Eur J Gastroenterol Hepatol 23:1172-7.
Eyster ME, Asaad SM, Gold BD, Cohn SE, Goedert JJ (2007) Upper gastrointestinal bleeding in haemophiliacs: incidence and relation to use of non-steroidal anti-inflammatory drugs. Haemophilia 13:279-86.
Choe BH, Kim JY, Lee JH, Kim JM, Chu MA, Cho SM (2010) Upper gastrointestinal bleeding in children with haemophilia: a clinical significance of Helicobacter pylori infection. Haemophilia 16:277-80
Schulman S, Rehnberg AS, Hein M, Hegedus O, Lindmarker P, Hellström PM (2003) Helicobacter pylori causes gastrointestinal hemorrhage in patients with congenital bleeding disorders. Thromb Haemost 89:741-6.

Surgical Reduction of Visceral versus Subcutaneous Fat and Effect on Features of the Metabolic Syndrome

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DOI: 10.31038/IMROJ.2016125

Abstract

Background

Obesity results in both health and financial tolls for individuals and society. Despite the great efforts to increase awareness, the obesity epidemic continues at an alarming rate. Subcutaneous fat represents 85% of the fat mass in obese patients, while intra-abdominal fat, including both visceral and retroperitoneal adipose, represent about 15%. Both subcutaneous and visceral fat have a negative effect on individual health and promote metabolic diseases. Logic would thus suggest that adipose tissue removal by liposuction and/or visceral tissue removal could effect an improvement in metabolic diseases such as Type 2 diabetes?

Methods

The scientific literature was searched to illustrate and describe the effect of adipose tissue on metabolism and the effect of its removal on inflammatory and metabolic markers.

Results

Adipose tissue is an endocrine organ and in obesity serves as a source of systemic proinflammatory signals arising from stressed adipocytes and/or infiltrating macrophages. These signals are associated with insulin resistance, dyslipidemia and hypertension (metabolic syndrome). The benefits of fat removal on metabolic syndrome remain controversial.

Conclusion

Visceral and subcutaneous fat is associated with high risk of coronary heart disease, insulin resistance, and other metabolic risk factors. Abdominal lipectomy is a well-known cosmetic procedure and used widely for its benefits on improving body image. However, its benefit on the metabolic disorder remains inconclusive. On the other hand, current evidence would suggest that omentectomy offers no benefit in relation to improvements in systemic inflammation and metabolic control. Removal of visceral adipose tissue in and of itself would thus appear to have limited efficacy as an approach to the treatment of the obesity-related metabolic syndrome.

Key words

Visceral and subcutaneous fat, Liposuction, Omentectomy, Metabolic Syndrome

Introduction

Obesity is defined as a systemic disease that shows excessive and abnormal accumulation of body fat leading to adverse health effects. Obesity has negative effects on health and exerts significant financial tolls on individuals and society. Despite significant efforts to increase awareness, the obesity epidemic continues at an alarming rate [1]. More than 50% of the European population is overweight and up to 30% is obese with prevalence worldwide doubling since 1980 [World Health Organization 2011] [2].

Abdominal obesity is defined as increased visceral fat and trunk subcutaneous fat which leads to increased waist circumference [3]. The contribution of abdominal subcutaneous fat mass and the visceral fat mass to the pathogenesis of metabolic disease is controversial, but it is associated with high risk of coronary heart disease, insulin resistance, and other metabolic risk factors[3, 4].

Subcutaneous fat represents 85% of the fat mass in obese patients, while intra-abdominal fat, including both visceral and retroperitoneal adipose, represent about 15%[5]. Visceral obesity is presumed to predispose individuals to hepatic insulin resistance based on its anatomical site and venous drainage to the liver through the passage of adipocytes products into the portal vein[6-8].

Waist circumference [WC] and waist to hip circumference ratio [WHR] are used to measure abdominal obesity [9, 10], Body mass index [BMI] which equals the ratio of weight in kilograms divided by height in meters squared [kg/m2] is used to measure general obesity [11]. Each of these three parameters can be used to measure the association of obesity and metabolic risk factors, but the combination of the three [BMI, WC, and WHC] appears more useful than the use of BMI alone [12, 13].

Theoretically, WC cut-off results are >88 cm in women and >102 cm in men but actually, it is difficult to apply in all populations due to the marked difference in the average levels of measurement. Asians are characterized by higher morbidity at lower cut-off for WC than other populations [14].

The metabolic effects of visceral and subcutaneous adipose tissue

Although body fat mass distribution is characterized by marked individual variations it can generally be classified into the following four types, a]Abdominal subcutaneous: most of the fat stored subcutaneously around the stomach and chest, b]Lower body: fat storage around the thighs, hip, and buttocks, c] Overall coverage: fat accumulation in the arms, breast, thighs, buttocks, lower back and breast, d] Visceral: fat deposition within visceral cavity surrounding the viscera including stomach, intestine, liver and pancreas [Figure 1] [15].

Figure 1. Types of body fat mass distribution [15]

More specifically, upper body fat distribution and increased visceral fat is more associated with metabolic dysregulation[16-18] than lower body and abdominal subcutaneous fat accumulation [19, 20]. Metabolic disorders associated with subcutaneous and visceral obesity include insulin resistance, type 2 diabetes [21, 22], dyslipidemia [23], and hypertension [24, 25].

Adipose tissue is an endocrine organ producing proinflammatory molecules from adipocytes and/or infiltrating macrophages in patients with high BMI, WC, and WHC [26]. These include tumor necrosis factor-alpha [TNF-α], C-reactive protein [CRP],interleukin-18 [IL-18], and interleukin-6 [IL-6] [27-30]. These cytokines have been linked to impairments in insulin action in liver, muscle, and adipose tissue [31-33].

TNF-α in obesity is increased in both systemic and portal circulation [32], which affects insulin sensitivity within adipocytes and stimulates secretion of IL-6 [34] Also, IL-6 concentration is 50% higher in the portal vein than in the peripheral circulation for patients with high visceral obesity [32].

Leptin and adiponectin expression is higher in subcutaneous fat compared with visceral adipose tissue [35, 36], but cytokine expression such as IL-6, IL-8 appears to be higher in visceral adipose tissue compared with subcutaneous fat [37].

Excess visceral and subcutaneous fat mass are associated with an elevation in postprandial [38] and post-absorptive fatty acid concentration in portal vein and systemic circulations [39]. Chronic exposure of the liver to the high concentration of free fatty acids promotes liver gluconeogenesis facilitating hepatic glucose production, thus providing a continuous source of energy and substrate that tends to raise fasting glycaemia [8, 40]. Increased insulin resistance and reduced fatty acid oxidation increase fat storage and synthesis in the liver [41-43].

Adipose tissue removal surgeries

Liposuction

Liposuction is one of the most common plastic surgeries and aims to remove subcutaneous adipose tissue from different body areas so as to improve body image and create more physical balance [44]. Since its introduction by Illouz 30 years ago, its popularity has rapidly increased, making it the second most common cosmetic surgical procedure in 2012 [313,011 patients] [45]. nearly 400,000 procedures are performed annually in USA [45].

The removal of subcutaneous fat with a blunt cannula attached to a suction generating device was first popularized in Europe in the late 1970s. The procedure of liposuction has undergone many refinements and evolved with improvement in techniques and technology since its introduction by Illouz in 1982 [46-48].

a) Traditional liposuction

Liposuction was first practiced without any preparation of the fat before suctioning it from the subcutaneous tissue and this was called ‘Dry liposuction’ which was associated with a high incidence of hemorrhage and hematoma. Then Illouz developed the wet technique by injecting normal saline, water, and hyaluronidase to create a weak hypotonic solution to destroy the fat cell wall [49]. Hetter added lidocaine and dilute epinephrine to the injected solution [50], then the super wet and tumescent techniques were developed by injecting the standard wetting solution [1 ml of epinephrine and 50ml of 1% xylocaine for each 1 liter of lactated Ringer solution] [51].

The ratio of the volume of wetting solution infused to the volume of fat aspirate is 1:1 in wet technique but 2 or 3:1 in the tumescent. Although, wetting and tumescent techniques are different in this ratio, they both involve infusion of the wetting solution to the point of tissue turgor or a “peau d’orange” of the overlying skin followed by suction of the subcutaneous tissue [51].

b) Ultrasound-assisted liposuction[UAL]

Zocchi is credited for the application of ultrasonic energy in liposuction to allow more selective tissue targeting [52]. It works by having expansion and compression parts of the cycle as a sound wave,which exerting a negative pressure that overcomes molecular forces results in cellular fragmentation with the intracellular content release, which leading to interstitial cavities hence termed as cavitation.Subsequently, a low-power suction can be performed [52, 53]. In this technique, sufficient amount of wetting solution must be used to limit the effect of heat generated by Us probe. Cellular disruption has been confirmed by the homogenous, macroscopically-acellular aspirated fat which contains a high level of adipocyte-specific intracellular glycerol 3-phosphate dehydrogenase isozyme [54]. UAL is highly efficient in removal of fat in fibrous areas such as the upper back, the hypogastrium, and the breast. UAL has been shown to cause less disruption of vasculature than SAL and hence less bruising [55].

c) Power assisted liposuction[PAL]

In the late 1990s, PAL was developed to subside some of UAL side effects. Actually,it is traditional liposuction with a special reciprocating cannula [Figure 2]. It is useful for fibrous rich areas liposuction and easy for the surgeon to use. No heat generation considers its main advantage over PAL [56].

Figure 2. Power assisted liposuction cannula

d) Laser-assisted liposuction [LAL]

LAL is defined as, the simultaneous use of a bare laser fiber as a free beam or a confined beam to lyse, liquefy the fat while simultaneously coagulating small blood vessels at the cannula fat interface. Harness in 1990 described the use of 1064 nm Nd-YAG laser for liposuction with promising results such as minimal incision and skin contraction produced by its photothermal effect [47]. Recently, the use of 1,320-, 1,440- and 2,100-nm wavelengths also have been proposed, with claims of less bleeding, faster healing, and better tissue tightening using laser lipolysis [57-60].

e) Radiofrequency-assisted liposuction [RFAL]

Radiofrequency-assisted liposuction [RFAL] means usage of bipolar radiofrequency energy [similar to that of diathermy] to disrupt the fat cell membrane and facilitate lipolysis with a lesser requirement for suction power [61, 62]. A controlled subdermal thermal injury produced by this energy leads to healing by contraction which produces a secondary effect on skin contraction such as LAL [61].

Omentectomy

Omentectomy [OM] defined as, surgical removal of the whole greater omentum which is a thin fold of abdominal tissue that encases the stomach, large intestine, and other abdominal organs. There are two main types of omentectomy: completely removing the omentum which is called total or supra colic omentectomy and removing a portion of the omentum which refers to partial omentectomy.

The procedure may be performed traditionally or laparoscopically, the traditional approach involves mini-laparotomy with a median supraumbilical incision of 8 to 10 cm to release the omentum from the large gastric curvature while preserving the gastroepiploic artery [63].

Laparoscopic omentectomy technique: Four trocars are used to reach the abdominal cavity at the following positions, under the umbilicus, right lower quadrant, and two at left lower quadrant [63]. After inflation of the abdominal cavity, body and fundus of the stomach are released from the greater omentum and short gastric vessels by harmonic scalpel with remaining of gastroepiploic vessels intact. After detaching the omentum from the transverse colon pulled out through the infra-umbilical incision [64].

Effect of adipose tissue removal on metabolic disease

Liposuction

A study by Giugliano et al, examined the effect of subcutaneous fat suction on insulin resistance and vascular inflammatory markers in 30 obese women by comparing the pre and postoperative [6 months] HOMA [fasting plasma glucose [mmol/l] x fasting serum insulin [mU/ml] divided by 25] as an index of peripheral insulin resistance., High HOMA scores denote low insulin sensitivity. Levels of IL-6, IL-8, TNF-α, CRP and adiponectin were also assessed. Results demonstrated that liposuction was associated with significant decrease in all parameters, except adiponectin, which significantly increased [Table 1] [65]. The risk of cardiovascular death and the incidence of insulin resistance was reduced at follow-up in association with improvements in metabolic and inflammatory markers.

Table 1. Results of Giugliano et al, study [65].

	Baseline	Six months postoperative	P-value
Weight	88	85	<0.001
HOMA	4.1	3.08	<0.05
IL-6 pg/ml	4.1	3.2	<0.05
IL-18 pg/ml	246	219	<0.05
TNF-a pg/ml	5.1	4.1	<0.02
CRP ml/l	2.9	2.4	<0.02
Adiponectin ug/ml	5.1	6.4	<0.02

In a study by Ramos et al, patients underwent abdominoplasty from October 2010 to September 2011. Total cholesterol, high-density lipoprotein [HDL], low-density lipoprotein [LDL], very low-density lipoprotein [VLDL], triglycerides, glucose, insulin, and HOMA index were measured preoperatively and 3 months post-operative. The results showed a significant reduction in triglyceride and LDL and a non-significant trend for improvements in HOMA, cholesterol,glucose, insulin and HDL[Table 2] [66]. The findings of this study were more or less similar to the Swanson study, which included 322 patients and demonstrated a significant reduction in triglycerides only [67].

Table 2. Results of Ramos et al., study [66].

	Baseline	Three months postoperative	P-value
Weight kg	69.1	68.6	0.79
Glucose mg/dl	91.45	90.71	0.81
Insulin Ul/ml	17.11	11.79	0.28
HOMA	3.96	2.58	0.22
Cholesterol mg/dl	224	220	0.84
Triglyceride mg/dl	193	133	0.03
HDL mg/dl	44	49	0.18
VLDL mg/dl	43	39.1	0.55
LDL mg/dl	137	79.61	0.04

In the cohort study of Marfella et al, 20 patients underwent abdominoplasty and 28 patients were exposed to diet, exercise, and behavioral counseling. Authors compared preoperative and 2-month postoperative measurements of triglycerides, insulin, insulin sensitivity, IL-6, TNF-α, and HDL-cholesterol. A significant reduction in triglycerides and insulin and improved insulin sensitivity was observed in both groups, with significant decreases in IL-6 and TNF-α occurring only in abdominoplasty group. There were no changes in HDL-cholesterol during the study period [68]. In a prospective cohort study, 12 obese patients that underwent abdominoplasty were followed up and plasma triglycerides, HDL, cholesterol, and insulin sensitivity measured during the preoperative period and at 50 days postoperative [69]. In difference to other studies in the field, no improvements were observed in any of the parameters studied.

An overall survey of the literature suggests that on balance, besides the cosmetic results of liposuction, a positive impact on lipid profile and other metabolic markers can arise as a secondary benefit of the procedure. However diet, lifestyle, and exercise modification subsequent to liposuction are likely to significantly enhance the magnitude and duration of beneficial effects by preventing new fat deposition [66]. Whether liposuction can be advocated primarily for its metabolic effects remains however rather controversial and there is still an insufficient evidence base to support its use in this context.

Omentectomy

Fabbrini et al, conducted a randomized controlled trial to test the hypothesis of the effect of visceral fat removal on metabolic diseases. Eleven patients underwent laparoscopic combined Roux-en-y [RYGB] with omentectomy, but RYGB alone was performed to the same number. Leptin, blood glucose, HbA1c, insulin, CRP, cholesterol, LDL, HDL, and triglyceride were measured preoperatively, 6 months and 12 months postoperative. Results of comparing pre and postoperative investigations demonstrated that hepatic insulin sensitivity increased 4-fold and skeletal muscle insulin sensitivity approximately doubled at 12 months after surgery in both groups, Critically no significant augmentation of improvements in these parameters was observed in patients undergoing omentectomy. So, metabolic variables improved after RYGB surgery but visceral fat removal has no additive effect on these variables . [70]. However, these data did not preclude the possibility that stand-alone omentectomy could be of metabolic benefit. To examine this, the same trial incorporated a treatment arim in which 10 patients underwent laparoscopic omentectomy alone. Results demonstrated that metabolic variables and minimal model-derived indices of insulin sensitivity, glucose effectiveness, and Beta-cell function did not change significantly 3 months after omentectomy compared with baseline [70].

Lima et al, and Herrera et al, are two prospective randomized trials looking at omentectomy[71, 72]. Both studies randomized patients equally into two groups, patients of the first group underwent RYGB with omentectomy but RYGB alone was performed to patients of the other group. Both studies used blood samples to measure metabolic and inflammatory markers for patients as in the study of Fabbrini and drew the same conclusions, i.e. omentectomy did not confer any additional benefit on top of RYGB.

From the previous studies and trials, it is thus clear that omentectomy does not induce any improvement in the components of metabolic syndrome and inflammatory mediators. Given the constitutive protective function of the omentum in the abdomen, there appears to be no basis for pursuing omentectomy as a viable intervention for metabolic disease.

Conclusion

Theoretically, increased visceral and subcutaneous adiposity are major risk factors for insulin resistance, dyslipidemia, and other metabolic disorders. Abdominal lipectomy is a well-known cosmetic procedure and used widely for its benefits on improving body image. However, its benefit on the metabolic disorder remains controversial. On the other hand, Omentectomy also does not induce any improvement in the components of inflammatory mediators but its effect on metabolic diseases considered an arguable issue. The currently available literature on visceral fat removal and liposuction are characterized by a small number of patients, we need more powerful randomly controlled trials to provide additional evidence. Intriguingly the fact that removal of subcutaneous rather than visceral fat, [at least the omentum] confers metabolic benefits, challenges current orthodoxy regarding the involvement of the two major fat depots in metabolic syndrome.

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Restraint Use in the Management of the Elderly with Dementia in Hospital

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DOI: 10.31038/IMROJ.2016124

Abstract

There is widespread use of physical restraints among the elderly with dementia in residential setting and acute hospitals. Physical restraints are means to limit a person’s freedom of movement. The commonest indications for restraining an elderly are to manage agitated and aggressive elderly at risk of harming themselves or others, reduce falls risk and avoid dislodgement of medical devices. Physical restraints have not been proven to benefit the patients and have been reported to be associated with injuries, falls and deaths. The ethical dilemma associated with restraint use is often conflicting. There are active moves to reduce/ remove physical restraints use in institutions among the elderly with dementia and challenging behaviours. The use of restraints should be considered a last resort when there is imminent danger and where other means of management have failed and patients being restrained should be reviewed regularly to have the restraint removed at the earliest opportunity.

Key words

physical restraints, behavioral and psychological symptoms, dementia, elderly with dementia

Introduction

With the rapid aging population in the world, there is an increasing trend of people living with dementia. Reports have estimated that there will be about 131.5 million people with dementia by 2050. Dementia has a huge economic impact, costing US $818 billion in total worldwide, and it will become a trillion dollar disease by 2018. In many parts of the world, there is a growing awareness of dementia, but a diagnosis of dementia can bring with it stigma and social isolation. Today, it is estimated that 94% of people living with dementia residing in low and middle income countries are cared for at home. These are regions where health and care systems often provide limited or no support to people living with dementia or to their families. [1]

In an acute hospital setting, people with dementia have more than three times hospital stays per year compared to the elderly without dementia. Utilisation of healthcare resources for chronic medical conditions, such as stroke, cancers, diabetes, coronary heart disease is increased among the elderly with dementia. [2]

The elderly patients with dementia in an acute hospital are at high risk of being restrained, especially if they require assistance with their activities of daily living (ADLs) and the most frequently cited reasons for restraint use are for the protection of the patients themselves, and to prevent interference with medical therapies. Physical restraint usage is between 33-68% among the elderly in hospitals. [3]

The elderly with dementia and behavioural symptoms

Dementia is a group of prolonged, debilitating neuropsychiatric disorders which affect the patients and their family for years after diagnosis. The presence of behavioural and psychological symptoms of dementia occurs among 98% of individuals with dementia at some point during their disease progression. Behavioral and Psychological Symptoms of Dementia (BPSD) has been associated with more rapid decline in cognition, greater impairment of ADLs, caregiver burden leading to caregiver burnout, diminished quality of life for caregivers and patients and early institutionalisation. [4-7] The caregiver for a person with dementia has been described as living a 36 hour day by Mace and Rabins, resulting in physical, emotional and mental fatigue. [8]

The spectrum of behavioural abnormalities in BPSD can be divided into behavioural or psychological abnormalities, as shown in (Table 1). Currently, there is no recommended single treatment for BPSD. Clinicians use a combination of drugs such as Cholinesterase inhibitors, anti-depressants, anti-convulsants with mood stabilising properties, antipsychotics, benzodiazepines and N-Methyl-D-aspartate receptor antagonist with varying degree of success. The elderly are more susceptible to side effects of these medications, including anticholinergic side effects with agitation and sedation, extrapyramidal side effects and orthostatic hypotension contributing to fall risk. [9] The non-pharmacological treatment of BPSD with an aim to reduce medication side effects have been studied with music therapy, art therapy, aromatherapy, touch therapy, orientation therapy, physical exercises and tailored activities have been tried with variable success rate due to heterogeneity of the study designs and further research is required. [10]

Table 1. Spectrum of BPSD

Behavioural	Psychological
Agitation-e.g. restless, pacing, disrobing inappropriately.	Mood disorders- anxiety, depression
Aggression-hitting, biting, scratching, pushing, throwing objects, destroying property, tearing items.	Changes in personality
Verbal aggression- cursing, swearing, shouting, screaming	Psychosis- delusions, hallucination
Wandering	Pathological crying
Repetition	Apathy
Sexual disinhibition	Irritability
Urination/ defecation-at inappropriate time and place	Mood lability
Hoarding	Elation

Behavioural symptoms in dementia suggest the presence of underlying unmet needs and must therefore be looked at as means of communication as cognitive abilities decline. The unmet needs include physical causes like medical illness and pain or psycho social and emotional needs. Agitation signifies progression of dementia. At the middle stages of dementia where verbal communication is diminishing, verbally agitated behaviours such as repetitions, cursing or screaming, are common. In severe stages of dementia, physically agitated behaviours predominate because they have lost the abilities to communicate verbally. [11] Agitated behaviours may be a reflection of others’ behaviour where the elderly with dementia does not comprehend or does not want. Agitation is associated with poor outcome for health and general wellbeing. Agitated behaviour places an elderly at risk of harm on themselves, caregivers and often leads to early institutionalisation. Nurses often see an agitated elderly as a challenge and feel helpless to intervene. [12]

Causes of BPSD- Theoretical models

Cohen-Mansfield applied theoretical models to analyse the causes of BPSD. The problematic behaviours in dementia may arise from various causes such as 1.) unmet needs, 2.) behavioural/ learning models and 3.) environmental factors.

Unmet needs among the person with dementia are frequently not obvious to the caregivers. Among some of these include inadequately treated pain, toileting needs, thirst, hunger, sensory deprivation, boredom and loneliness. Use of restraints causes restriction in independence, social isolation and may worsen behaviour. Assisting the person with dementia with proper eye wear and hearing aids, regular toilet rounds, assistance for physical exercise, meaningful activities and meals, providing sensory stimulation like pet therapy, music therapy, social interactions may reduce agitation.

The ABC model of behaviours consists of antecedent events which are the stimuli leading to the behaviour and consequences of the behaviours. The consequences reinforce certain behaviours in response to the antecedents. Many problem behaviours are learned through reinforcements by staff who paid attention when problem behaviours are displayed. To modify the behaviours requires new learning experiences which change the antecedent and behaviour.

The environmental theory suggests that persons with dementia are more vulnerable to environmental stimuli and they have a lower threshold at which their behaviour changes in response. The persons with dementia lose their coping abilities progressively and find the environmental changes increasingly more stressful. The threshold for stress also lowers progressively. When environmental stimuli exceed the stress threshold, they are more likely to show anxiety and inappropriate behaviours. [13]

Cohen-Mansfield suggested that the different models may interact and complement each other. For example, an environmental stimulus (unfamiliar surrounding) may cause an unmet need to surface (getting lost looking for toilets, bedroom) which may account for different behaviours (resulting in pacing, agitation, incontinence, etc) among different people. The different models provide the basis for intervention and the effectiveness of interventions indicates the usefulness of these models.

Indications for Physical restraints

The commonest reasons for restraints use are prevention of falls, protection of medical devices, means to control behaviour like aggression and wandering and to stabilise patient’s position. The traditional management for an agitated elderly is to restrain them either physically or chemically or ignored. [12] A physical restraint is any physical or mechanical method attached or adjacent to the body which restricts one’s freedom or movement or normal access to one’s body. [14] There are various types of physical restraints available, among the commoner ones used in the hospitals and nursing homes include body vest, pelvic vest, limb ties, mittens, lap belts, bed rails and tray tables. The most commonly used restraints are bed rails and belts. The predictors for restraints usage are, poor mobility, cognitive impairment, high physical dependency, organisational characteristics and high fall risk. [15]

Fall prevention and restraints- is there a role?

The elderly with dementia are more likely to be put on physical restraints because of poor memory for recent events, behavioural symptoms, delirium, language dysfunction with impaired abilities to communicate needs. Falls risk increases in dementia due to unsteady gait, poor safety awareness and poor judgement. [16] In a hospital setting, inpatient falls are considered a risk management issue and carries with it guilt, self-blame and possible litigations. There are measures in place in hospitals to reduce falls such as early fall risk assessment with policies for fall precautions and provision of a safe environment. Among some of the data published on nurses’ attitude towards restraint usage among the elderly, most nurses feel negatively towards restraining the elderly. However, they do believe there is a need for restraints mainly to reduce falls. This causes moral conflicts. Generally, when in doubt, most nurses were in favour of restraints. [17]

Staffs frequently have a sense of false security when they put an elderly on restraints to protect them from falls. Physical restraints have not been shown to reduce falls. In fact, restraints like body vests have been associated with higher fall risk and fractures. Tinetti showed that usage of physical restraints resulted in three fold increase likelihood of serious fall-related injures compared to the unrestrained elderly, after adjusting for other factors. [18, 19] Patients being restrained often struggle to get out and in doing so, they often become more agitated with reports of patients getting trapped between mattress and bed rail, some of the patients become more restless and attempt to climb over bed rails resulting in falls from greater height. The struggling also causes fatigue and prolonged restraints imposed immobility causes significant muscular atrophy which is accelerated compared to the younger patients, leading to falls, functional decline and needing longer periods of rehabilitation to restore. Muscle strength reduces by up to 5% a day. Repeated episodes of atrophy and recovery may lead to permanent loss of skeletal muscle mass and strength with disability. [20, 21]

Once a physical restraint has been deemed unnecessary, removal of physical restraints has not been shown to increase falls among nursing home residents. In fact, restraint removal has positive effects on the welfare and independence of the elderly, with changes in behaviour and reductions in the number of antipsychotic prescriptions. [22, 23]

Harm associated with physical restraints

Despite the widespread use of physical restraints in Nursing homes and hospitals, the safety and efficacy have not been well studied. Currently, there is no evidence that restraint prevent falls or secondary injuries. The types of restraint related injuries reported include direct injuries where the physical restraint causes direct physical damage to skin, with skin tear and haematomas being the commonest. Other reported direct injuries include nerve injuries, asphyxiation and sudden death. Sudden deaths occurred among elderly patients with cardiac conditions who struggled to be free of physical restraints. Vests have been associated with asphyxiation leading to death, the mechanisms included patients hanging by vest over bed rails, with vest caught against the neck. Retrospective reviews of death certificates identified deaths associated with restraints use among people in beds or chairs. Bed rails have been associated with getting heads trapped between mattress and bed rails. [24]

Indirect injuries associated with restraint use include increased mortality, falls, longer hospital length of stay, physical deconditioning, contractures, nutritional impairment, pressure ulcers, bowel and urinary incontinence. Patients put on restraints for more than 4 days were at higher risks of developing pressure sores and nosocomial infections. [24]

Apart from physical injuries, restraining the elderly with no or moderate cognitive impairment in a residential setting has been associated with greater decline in cognition. The elderly with severe cognitive impairment seemed to be unaffected. [25] Physical restraints have also been reported to be associated with more unsociable behaviours, depression, fear and regression. [26]

The ethics of using physical restraints

There will be occasions where the patient may be of danger to himself or others around them, and there is a need of using physical restraints to limit harm by restricting patient’s movement. However, sometimes physical restraints are misused in circumstances for staff’s convenience or punishing patient for their bad behaviour.

Autonomy

Respect for autonomy is the belief in individual freedom. The individual has a right to make his/her own decisions and intentionally act upon them, without being coerced or manipulated. The individual also has a right to liberty or self-determination, without controlling influence or interference from others. In people with dementia, there is progressive loss in the decision making capacity. For making a decision on medical treatment, we as healthcare providers need to ensure that the medical information provided is clear and understood. There is capacity to make a decision without coercion or deception. In the cases where the patient has limited decision making capacity, principles of beneficence and non-maleficence outweighs autonomy. [27]

In the situation of treating elderly with behavioural issues and dementia, there is often coercion or deception involved in the behavioural management, like hiding medications in food, putting up seat belts or bed rails when the elderly with dementia are not complying with treatment and yet failed to understand the risk to their own safety if they fail to comply with instructions. The paternalistic view that healthcare professionals are specialists who know best and the patients under their care, in their sick roles are expected to comply. Compliance itself suggests a requirement to yield in the context of cure. The patients are expected to believe their caregivers have the best knowledge, determine the best outcome and act in the patient’s best interest, and often, the interventions are beyond question. Nursing staffs are often faced with the dilemma of weighing the patient’s autonomy and their safety especially when there is a shortage of staff to provide better supervision. In nursing and medical practice, when the expectation is for patient to comply, there may be coercion or deception involved and autonomy is often compromised. [28]

Beneficence and nonmaleficence

In health care, healthcare workers are to act for the patients’ benefits, maximising utility and taking into account risks and cost incurred in doing a procedure or action. Among patients who may have difficulties making decisions, autonomy may be constrained by beneficence. Beneficence is a continuum from preventing or removing harm to doing good or promoting a person’s welfare.

Nonmaleficence in medical ethics means do no harm, remove harm and facilitate good. In the case of physical restraint use among the elderly, there is evidence to show that restraints cause more harm than benefits. [24-26] Since there is no evidence for effectiveness, it is questionable to classify restraint as therapeutic. It is therefore important to ask if restraint use violate the principle of nonmaleficence.

The principle of beneficence to an agitated elderly is rarely absolute where safety is concerned. It is unclear whether restraint actually confers safety to the patients. Instances where immediate safety of patient/ staff is threatened, beneficence is in conflict with autonomy. Other than in those instances where safety is really a legitimate concern, we need to consider the principles of beneficence and nonmaleficence carefully. [29]

The ethical struggle- clinicians left with “dirty hands”

In situations where the patient is at risk of imminent danger to himself or staff, restraining them may be the unavoidable and right thing to do. This may give rise to conflict in professional practice. The argument goes that patient may benefit from restraint and this justifies the risk of harm. This paradox constitutes the philosophical dilemma of dirty hands which essentially means to commit a moral wrong in order to do what is right. Healthcare workers often have to use coercive methods to treat patients with dementia, or getting them to comply with treatment, leaving them with a complex moral stain in order to do “right” for the patients. [30]

Is it possible to have a restraint free environment?

The Federal Drug Authority put forth warnings of safety and alert on vests, limb restraints and bedrails in 1992 and 1995. The legal standard has changed their stand from liability from failure to restrain to one that presumes appropriate care relying on interventions other than restraints.

In the United States, moves to care for the elderly without using restraints include, better tolerance of behavioural symptoms, complete ban of restraints in homes, nurses’ low acceptance for restraint use, improving staff knowledge about restraint hazards, minimising falls risk, understanding and responding to behaviours. Education and leadership of a gerontological trained nurse was helpful in reducing not only restraint use, there was no increase in staff number, psychoactive drug prescription or serious falls-related injuries. [31]

Individualised care plans with psychosocial interventions like anticipation of needs, physiological needs like pain management, planned activities and environmental interventions such as low beds, contoured chairs, based on the individual patient’s needs were also effective in reducing restraint use. The individual’s needs to assist with activities of daily living with walking aids, sensory aids are helpful to determine the changes in functional abilities from baseline. Premorbid toileting habits were adhered to minimise agitation from discomfort. Medical interventions like oxygen tubes or feeding tubes are minimised or disguised to reduce discomfort and distract the patient. Behavioural patterns and psychosocial needs were explored with the family to provide an idea of changes from baseline and to reduces the stresses of environmental changes in causing agitation and restlessness. [32] Environmental modifications like contoured chairs, low beds are safer and more comfortable for the elderly. Bedside alarms and commodes are recommended to reduce injuries and reduce restraint use. [33]

Summary

Physical restraints should be eliminated for the care of elderly with dementia. The risks of harm for physical restraints far outweigh the benefits. Careful, individualised assessment and individualised care plans addresses needs which are often unmet among the elderly with dementia. Education and guidance from a specialist trained nurse has been shown to be successful. A restraint free care environment is possible only if there is support from the organisation.

References

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Obesity and Kidney Disease: Hidden Consequences of the Epidemic

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DOI: 10.31038/EDMJ.2017121

Abstract

Obesity has become a worldwide epidemic, and its prevalence has been projected to grow by 40% in the next decade. This increasing prevalence has implications for the risk of diabetes, cardiovascular disease and also for Chronic Kidney Disease. A high body mass index is one of the strongest risk factors for new-onset Chronic Kidney Disease. In individuals affected by obesity, a compensatory hyperfiltration occurs to meet the heightened metabolic demands of the increased body weight. The increase in intraglomerular pressure can damage the kidneys and raise the risk of developing Chronic Kidney Disease in the long-term. The incidence of obesity-related glomerulopathy has increased ten-fold in recent years. Obesity has also been shown to be a risk factor for nephrolithiasis, and for a number of malignancies including kidney cancer. This year the World Kidney Day promotes education on the harmful consequences of obesity and its association with kidney disease, advocating healthy lifestyle and health policy measures that makes preventive behaviors an affordable option.

Keywords

obesity, chronic kidney disease, nephrolithiasis, kidney cancer, prevention

Abbreviations and Acronyms

Normal weight: BMI 18.5 to 24.9 kg/m²
overweight: BMI 25.0 to 29.9 kg/m²
class I obesity: BMI 30.0 to 34.9 kg/m²
class II obesity: BMI 35.0 to 39.9 kg/m²
class III obesity: BMI ≥40 kg/m²
BMI: body mass index
CKD: chronic kidney disease
DM: diabetes mellitus
eGFR: estimated glomerular filtration rate
ESRD: end stage renal disease
HR: hazard ratio
OR: odds ratio
UACR: urine albumin-creatinine ratio

Introduction

In 2014, over 600 million adults worldwide, 18 years and older, were obese. Obesity is a potent risk factor for the development of kidney disease. It increases the risk of developing major risk factors for Chronic Kidney Disease (CKD), like diabetes and hypertension, and it has a direct impact on the development of CKD and end-stage renal disease (ESRD). In individuals affected by obesity, a (likely) compensatory mechanism of hyperfiltration occurs to meet the heightened metabolic demands of the increased body weight. The increase in intraglomerular pressure can damage the kidney structure and raise the risk of developing CKD in the long-term.

The good news is that obesity, as well as the related CKD, are largely preventable. Education and awareness of the risks of obesity and a healthy lifestyle, including proper nutrition and exercise, can dramatically help in preventing obesity and kidney disease. This article reviews the association of obesity with kidney disease on the occasion of the 2017 World Kidney Day.

Epidemiology of obesity in adults and children

Over the last 3 decades, the prevalence of overweight and obese adults (BMI ≥25 kg/m2) worldwide has increased substantially [1]. In the US, the age-adjusted prevalence of obesity in 2013-2014 was 35% among men and 40.4% among women [2]. The problem of obesity also affects children. In the US in 2011-2014, the prevalence of obesity was 17% and extreme obesity 5.8% among youth 2-19 years of age. The rise in obesity prevalence is also a worldwide concern [3,4] as it is projected to grow by 40% across the globe in the next decade. Low- and middle-income countries are now showing evidence of transitioning from normal weight to overweight and obesity as parts of Europe and the United States did decades ago [5]. This increasing prevalence of obesity has implications for cardiovascular disease (CVD) and also for CKD. A high body mass index (BMI) is one of the strongest risk factors for new-onset CKD [6,7].

Definitions of obesity are most often based on BMI (i.e. weight [kilograms] divided by the square of his or her height [meters]). A BMI between 18.5 and 25 kg/m2 is considered by the World Health Organization (WHO) to be normal weight, a BMI between 25 and 30 kg/m2 as overweight, and a BMI of >30 kg/m2 as obese. Although BMI is easy to calculate, it is a poor estimate of fat mass distribution, as muscular individuals or those with more subcutaneous fat may have a BMI as high as individuals with larger intraabdominal (visceral) fat. The latter type of high BMI is associated with substantially higher risk of metabolic and cardiovascular disease. Alternative parameters to more accurately capture visceral fat include waist circumference (WC) and a waist hip ratio (WHR) of >102 cm and 0.9, respectively, for men and >88 cm and >0.8, respectively, for women. WHR has been shown to be superior to BMI for the correct classification of obesity in CKD.

Association of obesity with CKD and other renal complications

Numerous population based studies have shown an association between measures of obesity and both the development and the progression of CKD (Table 1). Higher BMI is associated with the presence [8] and development [9-11] of proteinuria in individuals without kidney disease. Furthermore, in numerous large population-based studies, higher BMI appears associated with the presence [8,12] and development of low estimated GFR, [9,10,13] with more rapid loss of estimated GFR over time,[14] and with the incidence of ESRD [15-18] Elevated BMI levels, class II obesity and above, have been associated with more rapid progression of CKD in patients with pre-existing CKD [19]. A few studies examining the association of abdominal obesity using WHR or WC with CKD, describe an association between higher girth and albuminuria, [20] decreased GFR [8] or incident ESRD [21] independent of BMI level.

Table 1. Studies examining the association of obesity with various measures of CKD

Study	Patients	Exposure	Outcomes	Results	Comments
Prevention of Renal and Vascular End-Stage Disease (PREVEND) Study⁸	7,676 Dutch individuals without diabetes	Elevated BMI (overweight and obese*), and central fat distribution (waist-hip ratio)	-Presence of urine albumin 30-300 mg/24h -Elevated and diminished GFR	-Obese + central fat: higher risk of albuminuria -Obese +/- central fat: higher risk of elevated GFR -Central fat +/- obesity associated with diminished filtration	Cross sectional analysis
Multinational study of hypertensive outpatients²⁰	20,828 patients from 26 countries	BMI and waist circumference	Prevalence of albuminuria by dip stick	Higher waist circumference associated with albuminuria independent of BMI	Cross sectional analysis
Framingham Multi-Detector Computed Tomography (MDCT) cohort²²	3,099 individuals	Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT)	Prevalence of UACR >25 mg/g in women and >17 mg/g in men	VAT associated with albuminuria in men, but not in women	Cross sectional analysis
CARDIA (Coronary Artery Risk Development in Young Adults) study¹¹	2,354 community-dwelling individuals with normal kidney function aged 28-40 years	-Obesity (BMI >30 kg/m²) -Diet and lifestyle-related factors	Incident microalbuminuria	Obesity (OR 1.9) and unhealthy diet (OR 2.0) associated with incident albuminuria	Low number of events
Hypertension Detection and Follow-Up Program¹⁰	5,897 hypertensive adults	Overweight and obese BMI* vs. normal BMI	Incident CKD (1+ or greater proteinuria on urinalysis and/or an eGFR <60 mL/min/1.73 m²)	Both overweight (OR 1.21) and obesity (OR 1.40) associated with incident CKD	Results unchanged after excluding diabetics
Framingham Offspring Study⁹	2,676 individuals free of CKD stage 3	High vs. normal BMI*	-Incident CKD stage 3 -Incident proteinuria	-Higher BMI not associated with CKD3 after adjustments -Higher BMI associated with increased odds of incident proteinuria	Predominantly white, limited geography
Physicians’ Health Study¹³	11,104 initially healthy men in US	-BMI quintiles -Increase in BMI over time (vs. stable BMI)	Incident eGFR <60 mL/min/1.73 m²	-Higher baseline BMI and increase in BMI over time both associated with higher risk of incident CKD	Exclusively men
Nation-wide US Veterans Administration cohort¹⁴	3,376,187 US veterans with baseline eGFR ≥60 mL/min/1.73 m²	BMI categories from <20 to >50 kg/m²	Rapid decline in kidney function (negative eGFR slope of >5 mL/min/1.73 m²)	BMI >30 kg/m²associated with rapid loss of kidney function	Associations more accentuated in older individuals
Nation-wide population-based study from Sweden¹²	926 Swedes with moderate/advanced CKD compared to 998 controls	BMI ≥25 vs. <25 kg/m²	CKD vs. no CKD	Higher BMI associated with 3x higher risk of CKD	-Risk strongest in diabetics, but also significantly higher in non-diabetics -Cross sectional analysis
Nation-wide population based study in Israel¹⁷	1,194,704 adolescent males and females examined for military service	Elevated BMI (overweight and obesity) vs. normal BMI*	Incident ESRD	Overweight (HR 3.0) and obesity (HR 6.89) associated with higher risk of ESRD	Associations strongest for diabetic ESRD, but also significantly higher for non-diabetic ESRD
The Nord-Trøndelag Health Study (HUNT-1)¹⁵	74,986 Norwegian adults	BMI categories*	Incidence of ESRD or renal death	BMI >30 kg/m² associated with worse outcomes	Associations not present in individuals with BL <120/80 mmHg
Community-based screening in Okinawa, Japan¹⁶	100,753 individuals >20 years old	BMI quartiles	Incidence of ESRD	Higher BMI associated with increased risk of ESRD in men, but not in women	Average BMI lower in Japan compared to Western countries
Nation-wide US Veterans Administration cohort¹⁹	453,946 US veterans with baseline eGFR<60 ml/min per 1.73 m²	BMI categories from <20 to >50 kg/m²	-Incidence of ESRD -Doubling of serum creatinine -Slopes of eGFR	Moderate and severe obesity associated with worse renal outcomes	Associations present but weaker in patients with more advanced CKD
Kaiser Permanente Northern California¹⁸	320,252 adults with and without baseline CKD	Overweight, class I, II and extreme obesity; vs. normal BMI*	Incidence of ESRD	Linearly higher risk of ESRD with higher BMI categories	Associations remained present after adjustment for DM, hypertension and baseline CKD
REGARDS (Reasons for Geographic and Racial Differences in Stroke) Study²¹	30,239 individuals	Elevated waist circumference or BMI	Incidence of ESRD	BMI above normal not associated with ESRD after adjustment for waist circumference -Higher waist circumference associated with ESRD	Association of waist circumference with ESRD became on-significant after adjustment for comorbidities and baseline eGFR and proteinuria

Higher visceral adipose tissue measured by computed tomography has been associated with a higher prevalence of albuminuria in men [22] The observation of a BMI-independent association between abdominal obesity and poorer renal outcomes is also described in relationship with mortality in patients with ESRD [23] and kidney transplant, [24] and suggests a direct role of visceral adiposity. In general, the associations between obesity and poorer renal outcomes persist even after adjustments for possible mediators of obesity’s cardiovascular and metabolic effects, such as high blood pressure and diabetes mellitus, suggesting that obesity may affect kidney function through mechanisms in part unrelated to these complications (vide infra).

The deleterious effect of obesity on the kidneys extends to other complications such as nephrolithiasis and kidney malignancies. Higher BMI is associated with an increased prevalence [25] and incidence [26,27] of nephrolithiasis. Furthermore, weight gain over time, and higher baseline WC were also associated with higher incidence of nephrolithiasis [27] Obesity is associated with various types of malignancies, particularly cancers of the kidneys. In a population-based study of 5.24 million individuals from the UK, a 5 kg/m2 higher BMI was associated with a 25% higher risk of kidney cancers, with 10% of all kidney cancers attributable to excess weight [28] Another large analysis examining the global burden of obesity on malignancies estimated that 17% and 26% of all kidney cancers in men and women, respectively, were attributable to excess weight [29]. The association between obesity and kidney cancers was consistent in both men and women, and across populations from different parts of the world in a meta-analysis that included data from 221 studies (of which 17 examined kidney cancers) [30]. Among the cancers examined in this meta-analysis, kidney cancers had the third highest risk associated with obesity (relative risk per 5 kg/m2 higher BMI: 1.24, 95%CI 1.20-1.28, p<0.0001) [30].

Mechanisms of action underlying the renal effects of obesity

Obesity results in complex metabolic abnormalities which have wide-ranging effects on diseases affecting the kidneys. The exact mechanisms whereby obesity may worsen or cause CKD remain unclear. The fact that most obese individuals never develop CKD, and the distinction of up to as many as 25% of obese individuals as “metabolically healthy” suggests that increased weight alone is not sufficient to induce kidney damage [31] Some of the deleterious renal consequences of obesity may be mediated by downstream comorbid conditions such as diabetes mellitus or hypertension, but there are also effects of adiposity which could impact the kidneys directly, induced by the endocrine activity of the adipose tissue via production of (among others) adiponectin, [32] leptin [33] and resistin [34] (Figure 1). These include the development of inflammation, [35] oxidative stress, [36] abnormal lipid metabolism, [37] activation of the renin-angiotensin-aldosterone system,[38] and increased production of insulin and insulin resistance [39,40].

Figure 1. Putative mechanisms of action whereby obesity causes chronic kidney disease

These various effects result in specific pathologic changes in the kidneys [41] which could underlie the higher risk of CKD seen in observational studies. These include ectopic lipid accumulation [42] and increased deposition of renal sinus fat, [43,44] the development of glomerular hypertension and increased glomerular permeability caused by hyperfiltration-related glomerular filtration barrier injury, [45] and ultimately the development of glomerulomegaly, [46] and focal or segmental glomerulosclerosis [41] (Figure 2). The incidence of the so-called obesity-related glomerulopathy (ORG) has increased ten-fold between 1986 and 2000. [41] Importantly, ORG often presents along with pathophysiologic processes related to other conditions or advanced age, conspiring to result in more accentuated kidney damage in patients with high blood pressure [47] or in the elderly. [14-39].

Figure 2. Obesity-related perihilar focal segmental glomerulosclerosis on a background of glomerulomegaly. Periodic Acid-Schiff stain, original magnification 400x

Obesity is associated with a number of risk factors contributing to the higher incidence and prevalence of nephrolithiasis. Higher body weight is associated with lower urine pH [48] and increased urinary oxalate,[49] uric acid, sodium and phosphate excretion [50] Diets richer in protein and sodium may lead to a more acidic urine and decrease in urinary citrate, also contributing to kidney stone risk. The insulin resistance characteristic of obesity may also predispose to nephrolithiasis [51] through its impact on tubular Na-H exchanger [52] and ammoniagenesis, [53] and the promotion of an acidic milieu [54]. Complicating the picture is the fact that some weight loss therapies result in a worsening, rather than an improvement in the risk for kidney stone formation; e.g. gastric surgery can lead to a substantial increase in enteral oxalate absorption and enhanced risk of nephrolithiasis [55].

The mechanisms behind the increased risk of kidney cancers observed in obese individuals are less well characterized. Insulin resistance, and the consequent chronic hyperinsulinemia and increased production of insulin-like growth factor 1 and numerous complex secondary humoral effects may exert stimulating effects on the growth of various types of tumor cells [56] More recently, the endocrine functions of adipose tissue, [57] its effects on immunity, [58] and the generation of an inflammatory milieu with complex effects on cancers 59, 60] have emerged as additional explanations.

Obesity in patients with advanced kidney disease: The need for a nuanced approach

Considering the above evidence about the overwhelmingly deleterious effects of obesity on various disease processes, it is seemingly counterintuitive that obesity has been consistently associated with lower mortality rates in patients with advanced CKD [19,61] and ESRD [62,63] Similar “paradoxical” associations have also been described in other populations, such as in patients with congestive heart failure [64], chronic obstructive pulmonary disease [65], rheumatoid arthritis, [66] and even in old individuals [67]. It is possible that the seemingly protective effect of a high BMI is the result of the imperfection of BMI as a measure of obesity, as it does not differentiate the effects of adiposity from those of higher non-adipose tissue. Indeed, studies that separated the effects of a higher waist circumference from those of higher BMI showed a reversal of the inverse association with mortality [23,24]. Higher muscle mass has also been shown to explain at least some of the positive effects attributed to elevated BMI [63, 68]. However, there is also evidence to suggest that higher adiposity, especially subcutaneous (non-visceral) fat, may also be associated with better outcomes in ESRD patients [62] Such benefits may indeed be present in patients who have very low short term life expectancy, such as most ESRD patients [69]. Indeed, some studies that examined the association of BMI with time-dependent survival in ESRD have shown a marked contrast between protective short term effects vs. deleterious longer term effects of higher BMI [70]. There are several putative short term benefits that higher body mass could portend, especially to sicker individuals. These include a benefit from the better nutritional status typically seen in obese individuals, and which provides better protein and energy reserves in the face of acute illness, and a higher muscle mass with enhanced antioxidant capacity [63] and lower circulating actin and higher plasma gelsolin levels, [71] which are associated with better outcomes. Other hypothetically beneficial characteristics of obesity include a more stable hemodynamic status with mitigation of stress responses and heightened sympathetic and renin-angiotensin activity [72] increased production of adiponectines [73] and soluble tumor necrosis factor alfa receptors[ 74] by adipose tissue neutralizing the adverse effects of tumor necrosis factor alfa; enhanced binding of circulating endotoxins [75] by the characteristically higher cholesterol levels seen in obesity; and sequestration of uremic toxins by adipose tissue [76].

Potential interventions for management of obesity

Obesity engenders kidney injury via direct mechanisms through deranged synthesis of various adipose tissue cytokines with nephrotoxic potential, as well as indirectly by triggering diabetes and hypertension, i.e. two conditions that rank among the strongest risk factors for CKD. Perhaps due to the survival advantage of obesity in CKD, the prevalence of end stage kidney disease is on the rise both in the USA [77] and in Europe [78]. Strategies for controlling the obesity related CKD epidemic at population level and for countering the evolution of CKD toward kidney failure in obese patients represent the most tantalizing task that today’s health planners, health managers and nephrologists face.

Countering CKD at population level

Calls for public health interventions in the community to prevent and treat CKD at an early stage have been made by major renal associations, including the International Society of Nephrology (ISN), International Federation of the Kidney Foundation (IFKF), the European renal association (ERA-EDTA) and various national societies. In the USA, Healthy People 2020, a program that sets 10-year health targets for health promotion and prevention goals, focuses both on CKD and obesity. Surveys to detect obese patients, particularly those with a high risk of CKD (e.g. hypertensive and/or diabetic obese people) and those receiving suboptimal care to inform these patients of the potential risk for CKD they are exposed to, is the first step towards developing public health interventions. Acquiring evidence that current interventions to reduce CKD risk in the obese are efficacious and deployable, is an urgent priority to set goals and means for risk modification. Appropriate documentation of existing knowledge distilling the risk and the benefits of primary and secondary prevention interventions in obese people, and new trials in this population to fill knowledge gaps (see below) are needed. Finally, surveillance programs that monitor progress on the detection of at-risk individuals and the effectiveness of prevention programs being deployed [79] constitute the third, fundamental element for establishing efficacious CKD prevention plans at population level.

A successful surveillance system for CKD has already been implemented in some places such as the United Kingdom (UK [80]. A campaign to disseminate and apply K-DOQI CKD guidelines in primary care within the UK National Health Service was launched. This progressively increased the adoption of K-DOQI guidelines and, also thanks to specific incentives for UK general physicians to detect CKD, led to an impressive improvement in the detection and care of CKD, i.e. better control of hypertension and increased use of angiotensin-converting enzyme and angiotensin receptor blockers [80]. This system may serve as a platform to improve the prevention of obesity-related CKD. Campaigns aiming at reducing the obesity burden are now at center stage worldwide and are strongly recommended by the WHO and it is expected that these campaigns will reduce the incidence of obesity-related complications, including CKD. However obesity-related goals in obese CKD patients remain vaguely formulated, largely because of the paucity of high-level evidence intervention studies to modify obesity in CKD patients [81].

Prevention of CKD progression in obese people with CKD

Observational studies in metabolically healthy obese subjects show that the obese phenotype unassociated with metabolic abnormalities per se predicts a higher risk for incident CKD [82] suggesting that obesity per se may engender renal dysfunction and kidney damage even without diabetes or hypertension (vide supra). In overweight or obese diabetic patients, a lifestyle intervention including caloric restriction and increased physical activity compared with a standard follow up based on education and support to sustain diabetes treatment reduced the risk for incident CKD by 30%, although it did not affect the incidence of cardiovascular events [83]. Such a protective effect was partly due to reductions in body weight, HbA1c, and systolic BP. No safety concerns regarding kidney-related adverse events were seen [83]. In a recent meta-analysis collating experimental studies in obese CKD patients, interventions aimed at reducing body weight showed coherent reductions in blood pressure, glomerular hyper-filtration and proteinuria [81]. A thorough post-hoc analysis of the REIN study showed that the nephron-protective effect of ACE inhibition in proteinuric CKD patients was maximal in obese CKD patients, but minimal in CKD patients with normal or low BMI [84]. Of note, bariatric surgical intervention have been suggested for selected CKD and ESRD patients including dialysis patients who are waitlisted for kidney transplantation [85-87].

Globally, these experimental findings provide a proof of concept for the usefulness of weight reduction and ACE inhibition interventions in the treatment of CKD in the obese. Studies showing a survival benefit of increased BMI in CKD patients, however, remain to be explained [88]. These findings limit our ability to make strong recommendations about the usefulness and the safety of weight reduction among individuals with more advanced stages of CKD. Lifestyle recommendations to reduce body weight in obese people at risk for CKD and in those with early CKD appear justified, particularly recommendations for the control of diabetes and hypertension. As the independent effect of obesity control on the incidence and progression of CKD is difficult to disentangle from the effects of hypertension and type 2 diabetes, recommendation of weight loss in the minority of metabolically healthy, non-hypertensive obese patients remains unwarranted. These considerations suggest that a therapeutic approach to overweight and obesity in patients with advanced CKD or other significant comorbid conditions has to be pursued carefully, with proper considerations of the expected benefits and potential complications of weight loss over the life span of the individual patient.

Conclusions

The worldwide epidemic of obesity affects the Earth’s population in many ways. Diseases of the kidneys, including CKD, nephrolithiasis and kidney cancers are among the more insidious effects of obesity, but which nonetheless have wide ranging deleterious consequences, ultimately leading to significant excess morbidity and mortality and excess costs to individuals and the entire society. Population-wide interventions to control obesity could have beneficial effects in preventing the development, or delaying the progression of CKD. It is incumbent upon the entire healthcare community to devise long-ranging strategies towards improving the understanding of the links between obesity and kidney diseases, and to determine optimal strategies to stem the tide. The 2017 World Kidney Day is an important opportunity to increase education and awareness to that end.

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