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Unsuspected aspect of immune regulation revealed
Immunologists may have discovered an additional role for B cells. Their research suggests the cells participate in the development of regulatory T cells (Tregs).
Until now, the only non-thymic cells known to aid Treg production were dendritic cells, which travel to the thymus to deliver antigens.
The new research, published in the Journal of Immunology, suggests B cells can do the same thing.
B cells were previously thought to specialize only in antibody production. With their newly discovered role, the cells become much more interesting and complex characters, according to the researchers.
The findings mean B cells could have useful applications for treating transplant patients and those with autoimmune disorders.
“Regulatory T cells are critical in the outcome of an immune response, so anything that regulates them becomes very interesting to immunologists,” said study author Shane Grey, PhD, of the Garvan Institute of Medical Research in Darlinghurst, New South Wales, Australia.
“Right now, there are clinical trials around the world looking to expand populations of these cells in patients. Researchers are also working on ways to grow regulatory cells in the laboratory—to infuse into patients as therapy. Our finding suggests it should be possible to set up systems that harness B cells to expand regulatory cells.”
Dr Grey and his colleagues worked with mice genetically modified to express high levels of BAFF, which increases B-cell survival. The higher number of B cells overall allowed researchers to track the activity of B cells in the thymus.
“It has been known for years that some B cells travel to the thymus, but no one has understood why,” said study author Stacey Walters, also of the Garvan Institute of Medical Research.
“Our experiments showed clearly that B cells participated in the creation of regulatory T cells. The more B cells that were in the thymus, the higher the number of regulatory cells generated. That direct correlation raises interesting possibilities. One possibility is using BAFF, a non-toxic substance, to ramp up the B-cell count of patients before transplant procedures.”
Research has suggested that Tregs can reduce the risk of graft-vs-host disease, promote enhanced immune reconstitution, and decrease the incidence of infectious complications in stem cell transplant recipients. And several studies have shown that high levels of Tregs can prevent graft rejection after solid organ transplant. 
Immunologists may have discovered an additional role for B cells. Their research suggests the cells participate in the development of regulatory T cells (Tregs).
Until now, the only non-thymic cells known to aid Treg production were dendritic cells, which travel to the thymus to deliver antigens.
The new research, published in the Journal of Immunology, suggests B cells can do the same thing.
B cells were previously thought to specialize only in antibody production. With their newly discovered role, the cells become much more interesting and complex characters, according to the researchers.
The findings mean B cells could have useful applications for treating transplant patients and those with autoimmune disorders.
“Regulatory T cells are critical in the outcome of an immune response, so anything that regulates them becomes very interesting to immunologists,” said study author Shane Grey, PhD, of the Garvan Institute of Medical Research in Darlinghurst, New South Wales, Australia.
“Right now, there are clinical trials around the world looking to expand populations of these cells in patients. Researchers are also working on ways to grow regulatory cells in the laboratory—to infuse into patients as therapy. Our finding suggests it should be possible to set up systems that harness B cells to expand regulatory cells.”
Dr Grey and his colleagues worked with mice genetically modified to express high levels of BAFF, which increases B-cell survival. The higher number of B cells overall allowed researchers to track the activity of B cells in the thymus.
“It has been known for years that some B cells travel to the thymus, but no one has understood why,” said study author Stacey Walters, also of the Garvan Institute of Medical Research.
“Our experiments showed clearly that B cells participated in the creation of regulatory T cells. The more B cells that were in the thymus, the higher the number of regulatory cells generated. That direct correlation raises interesting possibilities. One possibility is using BAFF, a non-toxic substance, to ramp up the B-cell count of patients before transplant procedures.”
Research has suggested that Tregs can reduce the risk of graft-vs-host disease, promote enhanced immune reconstitution, and decrease the incidence of infectious complications in stem cell transplant recipients. And several studies have shown that high levels of Tregs can prevent graft rejection after solid organ transplant.
Immunologists may have discovered an additional role for B cells. Their research suggests the cells participate in the development of regulatory T cells (Tregs).
Until now, the only non-thymic cells known to aid Treg production were dendritic cells, which travel to the thymus to deliver antigens.
The new research, published in the Journal of Immunology, suggests B cells can do the same thing.
B cells were previously thought to specialize only in antibody production. With their newly discovered role, the cells become much more interesting and complex characters, according to the researchers.
The findings mean B cells could have useful applications for treating transplant patients and those with autoimmune disorders.
“Regulatory T cells are critical in the outcome of an immune response, so anything that regulates them becomes very interesting to immunologists,” said study author Shane Grey, PhD, of the Garvan Institute of Medical Research in Darlinghurst, New South Wales, Australia.
“Right now, there are clinical trials around the world looking to expand populations of these cells in patients. Researchers are also working on ways to grow regulatory cells in the laboratory—to infuse into patients as therapy. Our finding suggests it should be possible to set up systems that harness B cells to expand regulatory cells.”
Dr Grey and his colleagues worked with mice genetically modified to express high levels of BAFF, which increases B-cell survival. The higher number of B cells overall allowed researchers to track the activity of B cells in the thymus.
“It has been known for years that some B cells travel to the thymus, but no one has understood why,” said study author Stacey Walters, also of the Garvan Institute of Medical Research.
“Our experiments showed clearly that B cells participated in the creation of regulatory T cells. The more B cells that were in the thymus, the higher the number of regulatory cells generated. That direct correlation raises interesting possibilities. One possibility is using BAFF, a non-toxic substance, to ramp up the B-cell count of patients before transplant procedures.”
Research has suggested that Tregs can reduce the risk of graft-vs-host disease, promote enhanced immune reconstitution, and decrease the incidence of infectious complications in stem cell transplant recipients. And several studies have shown that high levels of Tregs can prevent graft rejection after solid organ transplant.
Adolescent Obesity and Its Risks: How to Screen and When to Refer
From the Department of Pediatrics, University of Wisconsin, Madison, WI.
Abstract
- Objective: To provide information that will assist clinicians in assessing and addressing risk for obesity-related comorbidities in adolescents.
- Methods: Review of the literature.
- Results: Childhood obesity is a major public health concern. Prevention of obesity or early detection of its health consequences are important responsibilities or opportunities for primary care clinicians. While body mass index (BMI) screening is valuable, insulin resistance and other obesity-related comorbidities can develop even when BMI falls below the 95th percentile threshold for obesity. Detailed history and physical examination can help identify comorbidities and guide diagnostic evaluation. Referral to multidisciplinary clinics specializing in childhood obesity is warranted when obesity is particularly severe, comorbidities are present at baseline, or no improvement is noted after 6 months of intense lifestyle intervention.
- Conclusion: For optimal health outcomes, management of adolescent obesity and associated comorbidities is should be adapted based on an individual’s overall risk rather than BMI alone.
Case Study
Initial Presentation
A 14-year-old Hispanic male presents for a well child check.
History and Physical Examination
The patient and his mother have no complaints or concerns. A comprehensive review of systems is positive for fatigue and snoring but is otherwise unremarkable. Past medical history is unremarkable except for mild intermittent asthma. Family history is positive for type 2 diabetes in paternal grandmother and a maternal uncle and cardiovascular disease and hypertension in multiple extended family members. Both maternal and paternal grandparents are from Mexico.
Vital signs are within normal limits. Height is 160 cm (30th percentile for age), weight is 58.4 kg (75th percentile for age), and body mass index (BMI) is 22.8 kg/m2 (85th percentile for age). Blood pressure is 127/81 mm Hg (95th percentile for age and gender). Physical exam is pertinent for acanthosis nigricans on neck and axilla and nonviolaceous striae on abdomen. Waist circumference is 88 cm (90th percentile for age and ethnicity). Otherwise, physical exam is within normal limits.
• Does this child’s physical examination findings pose a cause for concern?
Yes. A key concept is that while obesity is widespread, the adverse health complications of adiposity and overnutrition affect some children much earlier and more profoundly than others. Some children exhibit adiposity-associated comorbidities even prior to meeting obesity criteria defined by BMI. Careful history and examination can help identify those most at risk for developing adiposity-associated comorbidities, prompting earlier intervention and, when appropriate, subspecialty referral.
Obesity is caused by a complex interplay of genetic, environmental, and metabolic programming, especially early in life, and lifestyle habits [1,2]. The vast majority of obesity is due to excess nutrition leading to energy imbalance, while less than 1% is due to endocrine or syndromic causes [3]. Obesity is defined as excessive body fat and is often estimated indirectly by using a surrogate marker, BMI. Diagnostically, a BMI > 95th percentile for age on sex-specific CDC growth charts is defined as obese, while a BMI from the 85th to 94th percentile is defined as overweight [4]. Using these criteria, the prevalence of childhood obesity more than tripled in the past 3 decades [5], leading to its classification as an epidemic and public health crisis [2]. Today, an estimated 12.5 million American children are obese [5]. For adolescents specifically, the prevalence of obesity is 18.4%, with more than one-third overweight [6].
Childhood obesity is associated with both short- and long-term morbidities including insulin resistance and type 2 diabetes, hypertension, dyslipidemia, asthma, obstructive sleep apnea, psychosocial problems, and decreased quality of life [7,8]. Obese children, particularly older children and adolescents, are more likely become obese adults [2,7]. Obesity in adulthood is associated with both significant morbidity and premature death [9]. Individual characteristics such as lifestyle habits, fitness level, and genetic predisposition influence the likelihood of development of both obesity and associated comorbidities [10].
The burden of obesity and its associated comorbidities are not equally distributed among racial/ethnic and socioeconomic groups. Hispanic and non-Hispanic black children are much more likely to be obese and overweight than non-Hispanic white children [6]. Low socioeconomic status is associated with increased rates of obesity in certain subgroups, including adolescents [2]. In addition, certain ethnic/racial minorities are more likely to develop obesity-associated comorbidities, such as insulin resistance, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD). With regard to insulin resistance and development of type 2 diabetes, the risk is greatest in Native Americans, but there is also increased risk in Hispanic/Latinos, non-Hispanic blacks, and Asian Americans as compared with non-Hispanic whites [11–13]. Collectively, these findings highlight the need for individualized assessment and the importance of obesity prevention and early intervention to improve long-term health outcomes. Primary care providers play a pivotal role in this process of preventing, identifying and treating childhood obesity and associated comorbidities [14]. In the case history, the child’s ethnicity, family history, and borderline overweight BMI indicate a high risk for future obesity-related morbidity and a critical opportunity for prevention intervention.
• What are the initial steps a practitioner can take to address overweight and obesity?
To encourage the development of healthy lifestyles and prevention of obesity, dietary and exercise counseling should be routinely provided as part of anticipatory guidance to all children and families regardless of weight status. It is critical to recognize individuals at high risk for becoming obese starting early in life. Risk factors for obesity in healthy weight children include rapid crossing of BMI percentiles, obese parent(s), maternal history of gestational diabetes during pregnancy, ethnicity, sedentary lifestyle, and excessive caloric intake [2]. Identification of these high-risk individuals can prompt more intensive counseling and early intervention with the goal of preventing the development of obesity and its complications. The use of automated BMI calculation and electronic medical records can facilitate identification of overweight and obesity status when already present and improve counseling rates [15].
Obesity due to excess nutrition is typically associated with linear growth acceleration that occurs subsequent to and to a lesser degree than the percentile shift in weight gain. A declining height velocity associated with obesity, therefore, is concerning and should prompt investigation for endocrine disease such as hypothyroidism, glucocorticoid excess, and growth hormone deficiency. Additional factors that warrant further investigation and/or referral include growth trajectory significantly below genetic potential, developmental delay, and dysmorphic features. A complete physical examination should be performed to evaluate for signs consistent with these conditions (eg, violaceous striae in glucocorticoid excess, microcephaly, and small hands/feet in Prader-Willi syndrome), and signs of obesity-associated comorbidities (eg, acanthosis nigricans). Accurate height, weight, BMI calculation, and blood pressure assessment using an appropriately sized cuff are essential.
While BMI screening is valuable, as noted above it is important to appreciate that insulin resistance (and other obesity-related comorbidities) can develop even when BMI is below the 95th percentile. Detailed history and physical examination can help identify these comorbidities of excess adiposity and guide diagnostic evaluation. Independent risk factors for insulin resistance and the development of type 2 diabetes include family history of diabetes, minority race/ethnicity, elevated waist circumference, and poor fitness level [18–20].
Further History
The patient reports skipping breakfast on most days, eats lunch at school, and snacks on chips and soda after school. Dinner is variable but usually contains carbohydrates and a protein and rarely includes vegetables. Family eats “take-out” about 3 times per week. Patient reports spending 3 hours a day watching television and playing on computer. He had gym last semester but currently reports very limited to no physical activity on most days.
• What are effective ways to raise the issue of obesity during an office visit?
Despite the strong connection of obesity with adverse health outcomes, discussion of obesity in routine office settings can be difficult and is often limited by many factors such as time, training, availability of support services, perceived lack of patient motivation, and low outcome expectations [21,22]. Perhaps most challenging is tactfully handling the stigma associated with obesity, which can make discussion awkward and difficult for patients, parents, and providers. To do this, efforts to choose words that convey a nonjudgmental message while maintaining focus on obesity as a health concern are helpful. For example, terms such as “fat” and “obese” are often perceived as stigmatizing and blaming while using the term “unhealthy weight” is less pejorative and can be motivating [23]. It can also be important to acknowledge and emphasize that some individuals are more susceptible to weight gain and its consequences than others and as a result can tolerate fewer calories without unwanted weight gain and health problems. These approaches shift the focus of the discussion toward the goal of restoring and preserving health rather than changing physical appearance without placing blame on the individual and/or family. Motivational interviewing techniques which can be performed effectively even in short office visits can help to actively engage families, reveal familial perception of obesity and assess readiness to change [2]. Their use may also improve the efficacy of other interventions [24].
Case Continued
The patient and his mother were asked if they had any concerns today, including concerns about future health. Mother expressed worry about the potential for diabetes given their family history. The clinician used this as an opportunity to discuss pertinent factors associated with insulin resistance and type 2 diabetes, including modifiable factors such as diet, fitness level, and weight.
• Should this non-obese adolescent be assessed for obesity comorbidities?
Yes. While there are multiple guidelines available for pediatric screening, all highlight the importance of obtaining individualized risk assessment to guide the extent of diagnostic workup. An Expert Committee comprised of representatives from 15 professional organizations appointed 3 writing groups to review the literature and recommend approaches to prevention, assessment, and treatment. Because effective strategies remain poorly defined, the writing groups used both available evidence and expert opinion to develop the recommendations [2]. In addition to routine blood pressure monitoring and universal lipid screening, the Expert Committee recommends obtaining additional laboratory assessment for obese children (BMI ≥ 95th percentile) including a fasting glucose and ALT/AST levels every 2 years starting at age 10 years. For overweight children (BMI > 85th percentile), the Expert Committee recommends obtaining these studies if additional risk factors are present [2]. The American Diabetes Association (ADA) recommends obtaining diabetes screening in all children classified as overweight (defined as either a BMI > 85th percentile for age and sex, weight for height > 85th percentile, or weight > 120% of ideal for height) once every 3 years beginning at age 10 or at pubertal onset (whichever is earliest) when 2 additional risk factors for diabetes are also present, including: (1) history of type 2 diabetes in a first- or second-degree relative, (2) race/ethnicity with increased risk for diabetes development (eg, Native American, African American, Latino, Asian American), (3) signs of insulin resistance or conditions associated with insulin resistance (eg, small for gestational age, polycystic ovary syndrome, hypertension) and (4) maternal history of gestational diabetes during pregnancy [25]. The ADA recommendations for diabetes screening test include either fasting plasma glucose, HgA1C, or oral glucose tolerance test [25].
With a BMI at the 85th percentile, on initial assessment our patient might be perceived as being at moderate or even low risk for obesity and its associated comorbidities. However, a more careful review has elicited several additional risk factors suggesting more appropriate classification in the high-risk category. First, family history of type 2 diabetes on both sides of his family suggests a degree of genetic predisposition. Second, Hispanic ethnicity is known to be independently associated with insulin resistance, type 2 diabetes, and NAFLD [26]. Moreover, physical exam findings of an elevated waist circumference (90th percentile for age and ethnicity [27]) and acanthosis nigricans are also supportive of insulin resistance. As a result, despite having a BMI at the 85th percentile, this adolescent is at high risk and further evaluation is warranted based on both Expert Committee and ADA guidelines. Detailed discussion of certain risk factors is outlined below.
Pattern of Adipose Tissue Distribution: Utility of BMI and Waist Circumference
BMI is a clinical tool that serves as a surrogate marker of adiposity, but since it does not directly measure body fat it provides a statistical, rather than inherent, description of risk. While it is a relatively specific marker (~95%) with moderately high sensitivity and positive predictive value (~70–80%) at BMI levels > 95th percentile, sensitivity and positive predictive value decrease substantially at lower BMI percentiles (PPV 18% in a sample of overweight children) [28]. Current CDC BMI percentile charts consider age and gender differences but do not take into account sexual maturation level or race/ethnicity, both of which are independently correlated with BMI [29]. That is, children with similar BMIs of the same age and sex may exhibit varying degrees of adiposity and risk attributable to their pubertal stage and/or ethnicity [30]. For example, many studies have demonstrated that at the same BMI percentile, Asian Americans tend to have more adiposity compared with non-Hispanic whites [31], whereas African Americans tend to have more fat-free mass compared with non-Hispanic whites [32]. As a result of these differences, some advocate for adjusting cut-offs for BMI based on ethnicity and/or utilizing alternative measures of adiposity such as waist circumference or waist to hip ratio. However, in order for these latter methods to be useful, standardized methods of measurement and normative reference values must be developed. In summary, though BMI can be a useful screening tool, it is an indirect measure of adiposity and cannot discern adipose distribution. Therefore, it is important to remember that when used alone, BMI may overlook children with high inherent risk for disease.
Abdominal adiposity is associated with increased metabolic risk, including insulin resistance, type 2 diabetes, hypertension, cardiovascular disease, and mortality [33]. Waist circumference, a marker of abdominal/truncal obesity, has been considered as a potential marker in place of or in combination with BMI to identify children with increased metabolic risk. In adults, it is well established that an elevated waist circumference is associated with increased health risk, even among those within a normal-weight BMI category [34], and it is recommended that waist circumference in addition to BMI be used to assess health risk [35]. Many studies have documented similar associations between increased waist circumference and metabolic risk factors in childhood and adolescence [36–38]. Specifically, waist circumference is an independent predictor of both insulin sensitivity and increased visceral adiposity tissue (VAT) in children and adolescents [39]. Waist circumference can provide valuable information beyond BMI alone and may be beneficial in the clinical setting in identifying adolescents at risk for obesity-associated comorbidities.
The use of waist circumference in routine clinical settings is complicated and limited by many factors. First, there is no universal method for waist circumference measurement. For example, the WHO recommends measurement at the midpoint between the superior iliac crest and inferior most rib, while the NIH and NHANES recommend measurement immediately above the iliac crest [40]. Since nationally representative data published by Fernandez et al [27] uses the latter method for waist circumference measurement, we recommend this method to allow for comparison of waist circumference percentile with available data for age, sex, and ethnicity. Second, while absolute waist circumference values are used as cut-offs in adulthood, in childhood use of waist circumference percentiles would be more appropriate to account for expected increases during childhood and changes related to pubertal stage. Unfortunately, a lack of standardized waist circumference percentile charts makes meaningful interpretation of waist circumference difficult. Moreover, even if standardized waist circumference percentile charts were developed, there are currently no accepted standards defining an abnormally elevated waist circumference percentile.
Many studies have identified increased metabolic risk factors associated with a waist circumference at or above the 90th percentile for age [41–43]. Based on these studies, the International Diabetes Federation uses waist circumference > 90th percentile as part of the criteria for metabolic syndrome in adolescents. While this ensures a high degree of specificity, use of waist circumference at the 75th percentile would allow for increased sensitivity. For example, Lee et al found that for insulin resistance use of waist circumference at the 75th percentile compared with the 90th percentile increased sensitivity from 61.3% to 86.1% while decreasing specificity from 91.4% to 71.5% [44]. Thus, for individuals at low risk based on history and clinical findings, a waist circumference threshold at the 90th percentile might be reasonable, while for individuals with additional risk factors for insulin resistance use of a lower waist circumference threshold (such as the 75th percentile) may be beneficial. Finally, since risk for insulin resistance and type 2 diabetes varies by race/ethnicity, which may correspond with visceral fat deposition, utilizing various threshold cut-offs based on race/ethnicity has been proposed by some. However, current data do not support this practice [44]. In summary, though there are many challenges to using waist circumference measurements in routine settings, if performed correctly determination of elevated waist circumference measurement can provide some additional information on an individual’s overall risk for complications of obesity.
Acanthosis Nigricans as an Indicator of Insulin Resistance
Insulin resistance, independent of adiposity, is associated with increased risk for type 2 diabetes, cardiovascular disease, ovarian hyperandrogenism, and certain forms of cancer [45]. Identification of insulin resistance in the clinical setting can lead to appropriate intervention (both lifestyle and, when warranted, pharmacologic) to reduce insulin resistance and improve health outcomes. Several risk factors for insulin resistance have been discussed above. Acanthosis nigricans, which is characterized by thick, velvety hyperpigmentation of the skin in intertriginous areas such as the neck and axilla, is an additional finding that is associated with insulin resistance. Its pathogenesis is felt to be related to activation of the IGF-1 receptor by high levels of circulating insulin [46]. Acanthosis nigricans is independently associated with fasting insulin levels and impaired glucose tolerance [47,48]. In addition to increased insulin resistance, one study found that 1 in 4 youths with acanthosis nigricans demonstrated abnormalities in glucose homeostasis and identified 2 individuals with diabetes who would not have been diagnosed based on fasting glucose levels alone [48]. The presence of acanthosis nigricans should alert the clinician to the likelihood of insulin resistance and prompt further investigation. Of note, the prevalence of acanthosis nigricans is increased among African American and Hispanic patients [49,50].
• What laboratory evaluation is warranted and practical in the office setting?
Laboratory evaluation is warranted when obesity or risk factors for comorbidities of obesity are present. At minimum, this should include lipid screening, liver enzymes (ALT and AST), and fasting glucose as outlined above. This approach, however, fails to identify all individuals with obesity-associated comorbidities. ALT is only moderately sensitive in detecting NAFLD [51], and fasting glucose levels only become abnormal when compensation for the degree of insulin resistance is inadequate to maintain normal fasting glucose homeostasis. As a result, while abnormal results on screening are suggestive of disease, normal results do not necessarily confer its absence. Thus, for high-risk subjects, additional testing and/or referral should be considered.
The hyperinsulinemic euglycemic clamp is the “gold standard” for measuring insulin sensitivity, but it is labor intensive and impractical in routine clinical settings. Alter-native approaches using surrogate markers have commonly been utilized, including fasting insulin and glucose levels and 2-hour oral glucose tolerance test (OGTT). The utility of these approaches in the clinical setting has been limited by several factors, including lack of a universal insulin assay. However, despite these limitations, obtaining fasting insulin in addition to fasting glucose or performing 2-hour OGTT can be useful in providing crude estimates of insulin resistance in certain high-risk subpopulations [52,53]. Recently, the ADA added HgA1C measurement as diagnostic criteria for pre-diabetes (5.7%–6.4%) and diabetes (> 6.5%) [54]. Benefits of HgA1C measurement include reliable measurements in nonfasting conditions and reflection of glucose over time. Studies in pediatric patients have shown the usefulness of HgA1C as a measure of future glucose intolerance or diabetes [55]. When fasting insulin or HgA1C are elevated and/or OGTT is abnormal, this suggests the presence of insulin resistance and need for intervention.
Proposed guideline criteria for the diagnosis of “metabolic syndrome” in adolescents include the following: (1) glucose intolerance, (2) elevated waist circumference or BMI, (3) hypertriglyceridemia, (4) low HDL, and 5) hypertension. There is no universal definition for metabolic syndrome in childhood and adolescence, and cut-off values in each category vary by study group [41–43,56]. When insulin resistance is present, it should alert the clinician to the increased likelihood for metabolic syndrome and NAFLD, and additional screening should be performed accordingly. NAFLD is present in about 25% of all overweight children and is strongly associated with insulin resistance and the metabolic syndrome [57]. Hispanic patients have an increased prevalence of NAFLD compared with patients of other ethnicities [58,59]. Elevated liver transaminases (AST and ALT) are commonly used to screen for NAFLD. However, since these markers are indicative of hepatocellular damage, they may remain within normal limits and correlate poorly with early steatosis [51]. Alternative approaches have been proposed in high-risk populations to detect early steatosis and improve long-term prognosis [60].
Case Continued
The patient underwent laboratory assessment that included fasting glucose and insulin, fasting lipid panel, and ALT. Results were suggestive of insulin resistance and metabolic syndrome and included the following: fasting glucose 108 mg/dL, fasting insulin 65 uIU/mL (reference range 3–25), HgA1C 5.9% (reference range 4.2–5.8), total cholesterol 178 mg/dL, HDL cholesterol 35 mg/dL, LDL cholesterol 110 mg/dL, triglycerides 157 mg/dL, and ALT 40 u/L. Blood pressure, as noted above, is at the 95th percentile for age and height.
• What is the recommended approach to intervention? When is referral warranted?
Staged Obesity Treatment
The initial stage, termed “Prevention Plus,” is similar to obesity prevention strategies and is focused on institution of healthy dietary and activity lifestyle habits tailored to the individual and family. Frequent follow-up and monitoring can be helpful and should be offered to families. Failure to demonstrate progress after 3 to 6 months warrants advancement to Stage 2, “Structured Weight Management,” which includes a planned diet with structured meals and snacks, reduction of screen time to 1 hour or less, 60 minutes of supervised physical activity, use of logs to document diet and activity levels, monthly follow-ups and positive reinforcement for achieving goals. Consultation with a dietician and health psychologist/counseling can be helpful at this level.
If no progress is noted after 3 to 6 months, progression to Stage 3, “Comprehensive Multidisciplinary Intervention,” is recommended. This stage emphasizes the importance of a multidisciplinary team including behavioral counselor, registered dietician and exercise specialist in addition to a medical provider. Current evidence suggests modest improvement of obesity and related comorbidities in adolescents participating in multidisciplinary weight management programs [62,63]. While these interventions can be implemented in community settings, coordination in this setting can be difficult and implementation more commonly involves weight management programs in tertiary care centers. Access to such programs can be limited by geographic accessibility, insurance coverage and physician awareness of available programs/resources [64]. Utilization of technology such as telemedicine visits is one way to overcome limited access [65]. Finally, Stage 4 “Tertiary Care Intervention”, involving discussion of pharmacologic or intensive/surgical weight loss options, can be considered for those who fail to show progression after successful intervention of previous stages.
Specialty Referral
Referral to multidisciplinary clinics specializing in childhood obesity is warranted when obesity is particularly severe, comorbidities are present at baseline, or no improvement is noted after 6 months of intense lifestyle intervention. Insulin resistance evidenced by impaired glucose tolerance (abnormal fasting or 2-hour glucose levels), HgA1C in the pre-diabetes range or higher (> 5.7%), or persistently elevated fasting insulin levels after 3 to 6 months of intensive lifestyle modification should prompt referral for consideration of metformin initiation. Metformin can reduce insulin resistance in children and may reduce progression from impaired glucose tolerance to diabetes [66]. For dyslipidemia related to metabolic syndrome, lifestyle interventions are most likely to be efficacious. Referral to preventative cardiology for consideration of pharmacologic intervention should be considered when severe hypertriglyceridemia is present (> 400 mg/dL) or LDL remains elevated after implementation of healthy lifestyle interventions. Elevations in ALT are highly specific for NAFLD and should prompt referral to gastroenterology. In addition, given the poor sensitivity of ALT for detection of early hepatic steatosis, referral might be considered when ALT is in the high normal ranges, especially in those with increased risk such as Hispanic patients [67]. Finally, when signs of obstructive sleep apnea are present, a sleep study should be performed. In summary, while specialty referral can aid targeted treatment of obesity-related morbidities, the central role of the primary care clinician in anticipating and preventing or minimizing their occurrence remains paramount.
Case Conclusion
The patient was referred to a multidisciplinary obesity clinic where he and his family met with dietician, exercise physiologist, health psychologist, and endocrinologist. Healthy lifestyle modifications with specific goals were instituted, including elimination of all calorie-containing beverages (except daily recommended intake of fat-free milk) and initiation of physical activity for 30 minutes a day 5 days per week. He was started on metformin due to glucose intolerance and increased risk for diabetes. Follow-up occurred at monthly intervals for the first 3 months. Additional goals and lifestyle interventions were implemented at each follow-up. At 6 months’ follow-up, the patient’s height was 164 cm, weight was stable at 58.4 kg and BMI was 21.7 (79th percentile). Blood pressure was slightly improved at 123/80 mm Hg. Repeat labs showed mild but consistent improvement in all areas. Specifically, fasting glucose 100 mg/dL, fasting insulin 40 uIU/mL, HgA1C 5.6%, total cholesterol 162 mg/dL, HDL cholesterol 40 mg/dL, LDL cholesterol 105 mg/dL, triglycerides 140 mg/dL, and ALT 38 u/L. The patient continues to be monitored closely with goal to improve metabolic health and long-term health outcomes.
Summary
Childhood obesity is a major public health concern. The health impact of obesity on children is broad and profound. Since treatment of obesity is often unsuccessful, prevention of obesity or early detection of its health consequences are crucial responsibilities and opportunities for primary care clinicians. While clinical guidelines can be instructive, application of clinical guidelines must be tailored to individual adolescent patients according to accompanying risk factors. This review aims to help clinicians stratify risk based on susceptibility to development of insulin resistance and other morbidities associated with adolescent obesity. While the enormity of the obesity epidemic can appear overwhelming to primary care providers, they remain in the best position to initiate early intervention strategies. Coordinating care between primary care providers and specialty clinics will continue to be an important partnership for the care of those experiencing health-threatening effects of adolescent obesity.
Corresponding author: Aaron L Carrel, MD, University of Wisconsin, 600 Highland Ave, H4-436, Madison, WI 53792.
Financial disclosures: Drs. Seibert and Carrel have received fellowship grants from Genentech.
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33. Cook S. The metabolic syndrome: Antecedent of adult cardiovascular disease in pediatrics. J Pediatr 2004;145:427–30.
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From the Department of Pediatrics, University of Wisconsin, Madison, WI.
Abstract
- Objective: To provide information that will assist clinicians in assessing and addressing risk for obesity-related comorbidities in adolescents.
- Methods: Review of the literature.
- Results: Childhood obesity is a major public health concern. Prevention of obesity or early detection of its health consequences are important responsibilities or opportunities for primary care clinicians. While body mass index (BMI) screening is valuable, insulin resistance and other obesity-related comorbidities can develop even when BMI falls below the 95th percentile threshold for obesity. Detailed history and physical examination can help identify comorbidities and guide diagnostic evaluation. Referral to multidisciplinary clinics specializing in childhood obesity is warranted when obesity is particularly severe, comorbidities are present at baseline, or no improvement is noted after 6 months of intense lifestyle intervention.
- Conclusion: For optimal health outcomes, management of adolescent obesity and associated comorbidities is should be adapted based on an individual’s overall risk rather than BMI alone.
Case Study
Initial Presentation
A 14-year-old Hispanic male presents for a well child check.
History and Physical Examination
The patient and his mother have no complaints or concerns. A comprehensive review of systems is positive for fatigue and snoring but is otherwise unremarkable. Past medical history is unremarkable except for mild intermittent asthma. Family history is positive for type 2 diabetes in paternal grandmother and a maternal uncle and cardiovascular disease and hypertension in multiple extended family members. Both maternal and paternal grandparents are from Mexico.
Vital signs are within normal limits. Height is 160 cm (30th percentile for age), weight is 58.4 kg (75th percentile for age), and body mass index (BMI) is 22.8 kg/m2 (85th percentile for age). Blood pressure is 127/81 mm Hg (95th percentile for age and gender). Physical exam is pertinent for acanthosis nigricans on neck and axilla and nonviolaceous striae on abdomen. Waist circumference is 88 cm (90th percentile for age and ethnicity). Otherwise, physical exam is within normal limits.
• Does this child’s physical examination findings pose a cause for concern?
Yes. A key concept is that while obesity is widespread, the adverse health complications of adiposity and overnutrition affect some children much earlier and more profoundly than others. Some children exhibit adiposity-associated comorbidities even prior to meeting obesity criteria defined by BMI. Careful history and examination can help identify those most at risk for developing adiposity-associated comorbidities, prompting earlier intervention and, when appropriate, subspecialty referral.
Obesity is caused by a complex interplay of genetic, environmental, and metabolic programming, especially early in life, and lifestyle habits [1,2]. The vast majority of obesity is due to excess nutrition leading to energy imbalance, while less than 1% is due to endocrine or syndromic causes [3]. Obesity is defined as excessive body fat and is often estimated indirectly by using a surrogate marker, BMI. Diagnostically, a BMI > 95th percentile for age on sex-specific CDC growth charts is defined as obese, while a BMI from the 85th to 94th percentile is defined as overweight [4]. Using these criteria, the prevalence of childhood obesity more than tripled in the past 3 decades [5], leading to its classification as an epidemic and public health crisis [2]. Today, an estimated 12.5 million American children are obese [5]. For adolescents specifically, the prevalence of obesity is 18.4%, with more than one-third overweight [6].
Childhood obesity is associated with both short- and long-term morbidities including insulin resistance and type 2 diabetes, hypertension, dyslipidemia, asthma, obstructive sleep apnea, psychosocial problems, and decreased quality of life [7,8]. Obese children, particularly older children and adolescents, are more likely become obese adults [2,7]. Obesity in adulthood is associated with both significant morbidity and premature death [9]. Individual characteristics such as lifestyle habits, fitness level, and genetic predisposition influence the likelihood of development of both obesity and associated comorbidities [10].
The burden of obesity and its associated comorbidities are not equally distributed among racial/ethnic and socioeconomic groups. Hispanic and non-Hispanic black children are much more likely to be obese and overweight than non-Hispanic white children [6]. Low socioeconomic status is associated with increased rates of obesity in certain subgroups, including adolescents [2]. In addition, certain ethnic/racial minorities are more likely to develop obesity-associated comorbidities, such as insulin resistance, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD). With regard to insulin resistance and development of type 2 diabetes, the risk is greatest in Native Americans, but there is also increased risk in Hispanic/Latinos, non-Hispanic blacks, and Asian Americans as compared with non-Hispanic whites [11–13]. Collectively, these findings highlight the need for individualized assessment and the importance of obesity prevention and early intervention to improve long-term health outcomes. Primary care providers play a pivotal role in this process of preventing, identifying and treating childhood obesity and associated comorbidities [14]. In the case history, the child’s ethnicity, family history, and borderline overweight BMI indicate a high risk for future obesity-related morbidity and a critical opportunity for prevention intervention.
• What are the initial steps a practitioner can take to address overweight and obesity?
To encourage the development of healthy lifestyles and prevention of obesity, dietary and exercise counseling should be routinely provided as part of anticipatory guidance to all children and families regardless of weight status. It is critical to recognize individuals at high risk for becoming obese starting early in life. Risk factors for obesity in healthy weight children include rapid crossing of BMI percentiles, obese parent(s), maternal history of gestational diabetes during pregnancy, ethnicity, sedentary lifestyle, and excessive caloric intake [2]. Identification of these high-risk individuals can prompt more intensive counseling and early intervention with the goal of preventing the development of obesity and its complications. The use of automated BMI calculation and electronic medical records can facilitate identification of overweight and obesity status when already present and improve counseling rates [15].
Obesity due to excess nutrition is typically associated with linear growth acceleration that occurs subsequent to and to a lesser degree than the percentile shift in weight gain. A declining height velocity associated with obesity, therefore, is concerning and should prompt investigation for endocrine disease such as hypothyroidism, glucocorticoid excess, and growth hormone deficiency. Additional factors that warrant further investigation and/or referral include growth trajectory significantly below genetic potential, developmental delay, and dysmorphic features. A complete physical examination should be performed to evaluate for signs consistent with these conditions (eg, violaceous striae in glucocorticoid excess, microcephaly, and small hands/feet in Prader-Willi syndrome), and signs of obesity-associated comorbidities (eg, acanthosis nigricans). Accurate height, weight, BMI calculation, and blood pressure assessment using an appropriately sized cuff are essential.
While BMI screening is valuable, as noted above it is important to appreciate that insulin resistance (and other obesity-related comorbidities) can develop even when BMI is below the 95th percentile. Detailed history and physical examination can help identify these comorbidities of excess adiposity and guide diagnostic evaluation. Independent risk factors for insulin resistance and the development of type 2 diabetes include family history of diabetes, minority race/ethnicity, elevated waist circumference, and poor fitness level [18–20].
Further History
The patient reports skipping breakfast on most days, eats lunch at school, and snacks on chips and soda after school. Dinner is variable but usually contains carbohydrates and a protein and rarely includes vegetables. Family eats “take-out” about 3 times per week. Patient reports spending 3 hours a day watching television and playing on computer. He had gym last semester but currently reports very limited to no physical activity on most days.
• What are effective ways to raise the issue of obesity during an office visit?
Despite the strong connection of obesity with adverse health outcomes, discussion of obesity in routine office settings can be difficult and is often limited by many factors such as time, training, availability of support services, perceived lack of patient motivation, and low outcome expectations [21,22]. Perhaps most challenging is tactfully handling the stigma associated with obesity, which can make discussion awkward and difficult for patients, parents, and providers. To do this, efforts to choose words that convey a nonjudgmental message while maintaining focus on obesity as a health concern are helpful. For example, terms such as “fat” and “obese” are often perceived as stigmatizing and blaming while using the term “unhealthy weight” is less pejorative and can be motivating [23]. It can also be important to acknowledge and emphasize that some individuals are more susceptible to weight gain and its consequences than others and as a result can tolerate fewer calories without unwanted weight gain and health problems. These approaches shift the focus of the discussion toward the goal of restoring and preserving health rather than changing physical appearance without placing blame on the individual and/or family. Motivational interviewing techniques which can be performed effectively even in short office visits can help to actively engage families, reveal familial perception of obesity and assess readiness to change [2]. Their use may also improve the efficacy of other interventions [24].
Case Continued
The patient and his mother were asked if they had any concerns today, including concerns about future health. Mother expressed worry about the potential for diabetes given their family history. The clinician used this as an opportunity to discuss pertinent factors associated with insulin resistance and type 2 diabetes, including modifiable factors such as diet, fitness level, and weight.
• Should this non-obese adolescent be assessed for obesity comorbidities?
Yes. While there are multiple guidelines available for pediatric screening, all highlight the importance of obtaining individualized risk assessment to guide the extent of diagnostic workup. An Expert Committee comprised of representatives from 15 professional organizations appointed 3 writing groups to review the literature and recommend approaches to prevention, assessment, and treatment. Because effective strategies remain poorly defined, the writing groups used both available evidence and expert opinion to develop the recommendations [2]. In addition to routine blood pressure monitoring and universal lipid screening, the Expert Committee recommends obtaining additional laboratory assessment for obese children (BMI ≥ 95th percentile) including a fasting glucose and ALT/AST levels every 2 years starting at age 10 years. For overweight children (BMI > 85th percentile), the Expert Committee recommends obtaining these studies if additional risk factors are present [2]. The American Diabetes Association (ADA) recommends obtaining diabetes screening in all children classified as overweight (defined as either a BMI > 85th percentile for age and sex, weight for height > 85th percentile, or weight > 120% of ideal for height) once every 3 years beginning at age 10 or at pubertal onset (whichever is earliest) when 2 additional risk factors for diabetes are also present, including: (1) history of type 2 diabetes in a first- or second-degree relative, (2) race/ethnicity with increased risk for diabetes development (eg, Native American, African American, Latino, Asian American), (3) signs of insulin resistance or conditions associated with insulin resistance (eg, small for gestational age, polycystic ovary syndrome, hypertension) and (4) maternal history of gestational diabetes during pregnancy [25]. The ADA recommendations for diabetes screening test include either fasting plasma glucose, HgA1C, or oral glucose tolerance test [25].
With a BMI at the 85th percentile, on initial assessment our patient might be perceived as being at moderate or even low risk for obesity and its associated comorbidities. However, a more careful review has elicited several additional risk factors suggesting more appropriate classification in the high-risk category. First, family history of type 2 diabetes on both sides of his family suggests a degree of genetic predisposition. Second, Hispanic ethnicity is known to be independently associated with insulin resistance, type 2 diabetes, and NAFLD [26]. Moreover, physical exam findings of an elevated waist circumference (90th percentile for age and ethnicity [27]) and acanthosis nigricans are also supportive of insulin resistance. As a result, despite having a BMI at the 85th percentile, this adolescent is at high risk and further evaluation is warranted based on both Expert Committee and ADA guidelines. Detailed discussion of certain risk factors is outlined below.
Pattern of Adipose Tissue Distribution: Utility of BMI and Waist Circumference
BMI is a clinical tool that serves as a surrogate marker of adiposity, but since it does not directly measure body fat it provides a statistical, rather than inherent, description of risk. While it is a relatively specific marker (~95%) with moderately high sensitivity and positive predictive value (~70–80%) at BMI levels > 95th percentile, sensitivity and positive predictive value decrease substantially at lower BMI percentiles (PPV 18% in a sample of overweight children) [28]. Current CDC BMI percentile charts consider age and gender differences but do not take into account sexual maturation level or race/ethnicity, both of which are independently correlated with BMI [29]. That is, children with similar BMIs of the same age and sex may exhibit varying degrees of adiposity and risk attributable to their pubertal stage and/or ethnicity [30]. For example, many studies have demonstrated that at the same BMI percentile, Asian Americans tend to have more adiposity compared with non-Hispanic whites [31], whereas African Americans tend to have more fat-free mass compared with non-Hispanic whites [32]. As a result of these differences, some advocate for adjusting cut-offs for BMI based on ethnicity and/or utilizing alternative measures of adiposity such as waist circumference or waist to hip ratio. However, in order for these latter methods to be useful, standardized methods of measurement and normative reference values must be developed. In summary, though BMI can be a useful screening tool, it is an indirect measure of adiposity and cannot discern adipose distribution. Therefore, it is important to remember that when used alone, BMI may overlook children with high inherent risk for disease.
Abdominal adiposity is associated with increased metabolic risk, including insulin resistance, type 2 diabetes, hypertension, cardiovascular disease, and mortality [33]. Waist circumference, a marker of abdominal/truncal obesity, has been considered as a potential marker in place of or in combination with BMI to identify children with increased metabolic risk. In adults, it is well established that an elevated waist circumference is associated with increased health risk, even among those within a normal-weight BMI category [34], and it is recommended that waist circumference in addition to BMI be used to assess health risk [35]. Many studies have documented similar associations between increased waist circumference and metabolic risk factors in childhood and adolescence [36–38]. Specifically, waist circumference is an independent predictor of both insulin sensitivity and increased visceral adiposity tissue (VAT) in children and adolescents [39]. Waist circumference can provide valuable information beyond BMI alone and may be beneficial in the clinical setting in identifying adolescents at risk for obesity-associated comorbidities.
The use of waist circumference in routine clinical settings is complicated and limited by many factors. First, there is no universal method for waist circumference measurement. For example, the WHO recommends measurement at the midpoint between the superior iliac crest and inferior most rib, while the NIH and NHANES recommend measurement immediately above the iliac crest [40]. Since nationally representative data published by Fernandez et al [27] uses the latter method for waist circumference measurement, we recommend this method to allow for comparison of waist circumference percentile with available data for age, sex, and ethnicity. Second, while absolute waist circumference values are used as cut-offs in adulthood, in childhood use of waist circumference percentiles would be more appropriate to account for expected increases during childhood and changes related to pubertal stage. Unfortunately, a lack of standardized waist circumference percentile charts makes meaningful interpretation of waist circumference difficult. Moreover, even if standardized waist circumference percentile charts were developed, there are currently no accepted standards defining an abnormally elevated waist circumference percentile.
Many studies have identified increased metabolic risk factors associated with a waist circumference at or above the 90th percentile for age [41–43]. Based on these studies, the International Diabetes Federation uses waist circumference > 90th percentile as part of the criteria for metabolic syndrome in adolescents. While this ensures a high degree of specificity, use of waist circumference at the 75th percentile would allow for increased sensitivity. For example, Lee et al found that for insulin resistance use of waist circumference at the 75th percentile compared with the 90th percentile increased sensitivity from 61.3% to 86.1% while decreasing specificity from 91.4% to 71.5% [44]. Thus, for individuals at low risk based on history and clinical findings, a waist circumference threshold at the 90th percentile might be reasonable, while for individuals with additional risk factors for insulin resistance use of a lower waist circumference threshold (such as the 75th percentile) may be beneficial. Finally, since risk for insulin resistance and type 2 diabetes varies by race/ethnicity, which may correspond with visceral fat deposition, utilizing various threshold cut-offs based on race/ethnicity has been proposed by some. However, current data do not support this practice [44]. In summary, though there are many challenges to using waist circumference measurements in routine settings, if performed correctly determination of elevated waist circumference measurement can provide some additional information on an individual’s overall risk for complications of obesity.
Acanthosis Nigricans as an Indicator of Insulin Resistance
Insulin resistance, independent of adiposity, is associated with increased risk for type 2 diabetes, cardiovascular disease, ovarian hyperandrogenism, and certain forms of cancer [45]. Identification of insulin resistance in the clinical setting can lead to appropriate intervention (both lifestyle and, when warranted, pharmacologic) to reduce insulin resistance and improve health outcomes. Several risk factors for insulin resistance have been discussed above. Acanthosis nigricans, which is characterized by thick, velvety hyperpigmentation of the skin in intertriginous areas such as the neck and axilla, is an additional finding that is associated with insulin resistance. Its pathogenesis is felt to be related to activation of the IGF-1 receptor by high levels of circulating insulin [46]. Acanthosis nigricans is independently associated with fasting insulin levels and impaired glucose tolerance [47,48]. In addition to increased insulin resistance, one study found that 1 in 4 youths with acanthosis nigricans demonstrated abnormalities in glucose homeostasis and identified 2 individuals with diabetes who would not have been diagnosed based on fasting glucose levels alone [48]. The presence of acanthosis nigricans should alert the clinician to the likelihood of insulin resistance and prompt further investigation. Of note, the prevalence of acanthosis nigricans is increased among African American and Hispanic patients [49,50].
• What laboratory evaluation is warranted and practical in the office setting?
Laboratory evaluation is warranted when obesity or risk factors for comorbidities of obesity are present. At minimum, this should include lipid screening, liver enzymes (ALT and AST), and fasting glucose as outlined above. This approach, however, fails to identify all individuals with obesity-associated comorbidities. ALT is only moderately sensitive in detecting NAFLD [51], and fasting glucose levels only become abnormal when compensation for the degree of insulin resistance is inadequate to maintain normal fasting glucose homeostasis. As a result, while abnormal results on screening are suggestive of disease, normal results do not necessarily confer its absence. Thus, for high-risk subjects, additional testing and/or referral should be considered.
The hyperinsulinemic euglycemic clamp is the “gold standard” for measuring insulin sensitivity, but it is labor intensive and impractical in routine clinical settings. Alter-native approaches using surrogate markers have commonly been utilized, including fasting insulin and glucose levels and 2-hour oral glucose tolerance test (OGTT). The utility of these approaches in the clinical setting has been limited by several factors, including lack of a universal insulin assay. However, despite these limitations, obtaining fasting insulin in addition to fasting glucose or performing 2-hour OGTT can be useful in providing crude estimates of insulin resistance in certain high-risk subpopulations [52,53]. Recently, the ADA added HgA1C measurement as diagnostic criteria for pre-diabetes (5.7%–6.4%) and diabetes (> 6.5%) [54]. Benefits of HgA1C measurement include reliable measurements in nonfasting conditions and reflection of glucose over time. Studies in pediatric patients have shown the usefulness of HgA1C as a measure of future glucose intolerance or diabetes [55]. When fasting insulin or HgA1C are elevated and/or OGTT is abnormal, this suggests the presence of insulin resistance and need for intervention.
Proposed guideline criteria for the diagnosis of “metabolic syndrome” in adolescents include the following: (1) glucose intolerance, (2) elevated waist circumference or BMI, (3) hypertriglyceridemia, (4) low HDL, and 5) hypertension. There is no universal definition for metabolic syndrome in childhood and adolescence, and cut-off values in each category vary by study group [41–43,56]. When insulin resistance is present, it should alert the clinician to the increased likelihood for metabolic syndrome and NAFLD, and additional screening should be performed accordingly. NAFLD is present in about 25% of all overweight children and is strongly associated with insulin resistance and the metabolic syndrome [57]. Hispanic patients have an increased prevalence of NAFLD compared with patients of other ethnicities [58,59]. Elevated liver transaminases (AST and ALT) are commonly used to screen for NAFLD. However, since these markers are indicative of hepatocellular damage, they may remain within normal limits and correlate poorly with early steatosis [51]. Alternative approaches have been proposed in high-risk populations to detect early steatosis and improve long-term prognosis [60].
Case Continued
The patient underwent laboratory assessment that included fasting glucose and insulin, fasting lipid panel, and ALT. Results were suggestive of insulin resistance and metabolic syndrome and included the following: fasting glucose 108 mg/dL, fasting insulin 65 uIU/mL (reference range 3–25), HgA1C 5.9% (reference range 4.2–5.8), total cholesterol 178 mg/dL, HDL cholesterol 35 mg/dL, LDL cholesterol 110 mg/dL, triglycerides 157 mg/dL, and ALT 40 u/L. Blood pressure, as noted above, is at the 95th percentile for age and height.
• What is the recommended approach to intervention? When is referral warranted?
Staged Obesity Treatment
The initial stage, termed “Prevention Plus,” is similar to obesity prevention strategies and is focused on institution of healthy dietary and activity lifestyle habits tailored to the individual and family. Frequent follow-up and monitoring can be helpful and should be offered to families. Failure to demonstrate progress after 3 to 6 months warrants advancement to Stage 2, “Structured Weight Management,” which includes a planned diet with structured meals and snacks, reduction of screen time to 1 hour or less, 60 minutes of supervised physical activity, use of logs to document diet and activity levels, monthly follow-ups and positive reinforcement for achieving goals. Consultation with a dietician and health psychologist/counseling can be helpful at this level.
If no progress is noted after 3 to 6 months, progression to Stage 3, “Comprehensive Multidisciplinary Intervention,” is recommended. This stage emphasizes the importance of a multidisciplinary team including behavioral counselor, registered dietician and exercise specialist in addition to a medical provider. Current evidence suggests modest improvement of obesity and related comorbidities in adolescents participating in multidisciplinary weight management programs [62,63]. While these interventions can be implemented in community settings, coordination in this setting can be difficult and implementation more commonly involves weight management programs in tertiary care centers. Access to such programs can be limited by geographic accessibility, insurance coverage and physician awareness of available programs/resources [64]. Utilization of technology such as telemedicine visits is one way to overcome limited access [65]. Finally, Stage 4 “Tertiary Care Intervention”, involving discussion of pharmacologic or intensive/surgical weight loss options, can be considered for those who fail to show progression after successful intervention of previous stages.
Specialty Referral
Referral to multidisciplinary clinics specializing in childhood obesity is warranted when obesity is particularly severe, comorbidities are present at baseline, or no improvement is noted after 6 months of intense lifestyle intervention. Insulin resistance evidenced by impaired glucose tolerance (abnormal fasting or 2-hour glucose levels), HgA1C in the pre-diabetes range or higher (> 5.7%), or persistently elevated fasting insulin levels after 3 to 6 months of intensive lifestyle modification should prompt referral for consideration of metformin initiation. Metformin can reduce insulin resistance in children and may reduce progression from impaired glucose tolerance to diabetes [66]. For dyslipidemia related to metabolic syndrome, lifestyle interventions are most likely to be efficacious. Referral to preventative cardiology for consideration of pharmacologic intervention should be considered when severe hypertriglyceridemia is present (> 400 mg/dL) or LDL remains elevated after implementation of healthy lifestyle interventions. Elevations in ALT are highly specific for NAFLD and should prompt referral to gastroenterology. In addition, given the poor sensitivity of ALT for detection of early hepatic steatosis, referral might be considered when ALT is in the high normal ranges, especially in those with increased risk such as Hispanic patients [67]. Finally, when signs of obstructive sleep apnea are present, a sleep study should be performed. In summary, while specialty referral can aid targeted treatment of obesity-related morbidities, the central role of the primary care clinician in anticipating and preventing or minimizing their occurrence remains paramount.
Case Conclusion
The patient was referred to a multidisciplinary obesity clinic where he and his family met with dietician, exercise physiologist, health psychologist, and endocrinologist. Healthy lifestyle modifications with specific goals were instituted, including elimination of all calorie-containing beverages (except daily recommended intake of fat-free milk) and initiation of physical activity for 30 minutes a day 5 days per week. He was started on metformin due to glucose intolerance and increased risk for diabetes. Follow-up occurred at monthly intervals for the first 3 months. Additional goals and lifestyle interventions were implemented at each follow-up. At 6 months’ follow-up, the patient’s height was 164 cm, weight was stable at 58.4 kg and BMI was 21.7 (79th percentile). Blood pressure was slightly improved at 123/80 mm Hg. Repeat labs showed mild but consistent improvement in all areas. Specifically, fasting glucose 100 mg/dL, fasting insulin 40 uIU/mL, HgA1C 5.6%, total cholesterol 162 mg/dL, HDL cholesterol 40 mg/dL, LDL cholesterol 105 mg/dL, triglycerides 140 mg/dL, and ALT 38 u/L. The patient continues to be monitored closely with goal to improve metabolic health and long-term health outcomes.
Summary
Childhood obesity is a major public health concern. The health impact of obesity on children is broad and profound. Since treatment of obesity is often unsuccessful, prevention of obesity or early detection of its health consequences are crucial responsibilities and opportunities for primary care clinicians. While clinical guidelines can be instructive, application of clinical guidelines must be tailored to individual adolescent patients according to accompanying risk factors. This review aims to help clinicians stratify risk based on susceptibility to development of insulin resistance and other morbidities associated with adolescent obesity. While the enormity of the obesity epidemic can appear overwhelming to primary care providers, they remain in the best position to initiate early intervention strategies. Coordinating care between primary care providers and specialty clinics will continue to be an important partnership for the care of those experiencing health-threatening effects of adolescent obesity.
Corresponding author: Aaron L Carrel, MD, University of Wisconsin, 600 Highland Ave, H4-436, Madison, WI 53792.
Financial disclosures: Drs. Seibert and Carrel have received fellowship grants from Genentech.
From the Department of Pediatrics, University of Wisconsin, Madison, WI.
Abstract
- Objective: To provide information that will assist clinicians in assessing and addressing risk for obesity-related comorbidities in adolescents.
- Methods: Review of the literature.
- Results: Childhood obesity is a major public health concern. Prevention of obesity or early detection of its health consequences are important responsibilities or opportunities for primary care clinicians. While body mass index (BMI) screening is valuable, insulin resistance and other obesity-related comorbidities can develop even when BMI falls below the 95th percentile threshold for obesity. Detailed history and physical examination can help identify comorbidities and guide diagnostic evaluation. Referral to multidisciplinary clinics specializing in childhood obesity is warranted when obesity is particularly severe, comorbidities are present at baseline, or no improvement is noted after 6 months of intense lifestyle intervention.
- Conclusion: For optimal health outcomes, management of adolescent obesity and associated comorbidities is should be adapted based on an individual’s overall risk rather than BMI alone.
Case Study
Initial Presentation
A 14-year-old Hispanic male presents for a well child check.
History and Physical Examination
The patient and his mother have no complaints or concerns. A comprehensive review of systems is positive for fatigue and snoring but is otherwise unremarkable. Past medical history is unremarkable except for mild intermittent asthma. Family history is positive for type 2 diabetes in paternal grandmother and a maternal uncle and cardiovascular disease and hypertension in multiple extended family members. Both maternal and paternal grandparents are from Mexico.
Vital signs are within normal limits. Height is 160 cm (30th percentile for age), weight is 58.4 kg (75th percentile for age), and body mass index (BMI) is 22.8 kg/m2 (85th percentile for age). Blood pressure is 127/81 mm Hg (95th percentile for age and gender). Physical exam is pertinent for acanthosis nigricans on neck and axilla and nonviolaceous striae on abdomen. Waist circumference is 88 cm (90th percentile for age and ethnicity). Otherwise, physical exam is within normal limits.
• Does this child’s physical examination findings pose a cause for concern?
Yes. A key concept is that while obesity is widespread, the adverse health complications of adiposity and overnutrition affect some children much earlier and more profoundly than others. Some children exhibit adiposity-associated comorbidities even prior to meeting obesity criteria defined by BMI. Careful history and examination can help identify those most at risk for developing adiposity-associated comorbidities, prompting earlier intervention and, when appropriate, subspecialty referral.
Obesity is caused by a complex interplay of genetic, environmental, and metabolic programming, especially early in life, and lifestyle habits [1,2]. The vast majority of obesity is due to excess nutrition leading to energy imbalance, while less than 1% is due to endocrine or syndromic causes [3]. Obesity is defined as excessive body fat and is often estimated indirectly by using a surrogate marker, BMI. Diagnostically, a BMI > 95th percentile for age on sex-specific CDC growth charts is defined as obese, while a BMI from the 85th to 94th percentile is defined as overweight [4]. Using these criteria, the prevalence of childhood obesity more than tripled in the past 3 decades [5], leading to its classification as an epidemic and public health crisis [2]. Today, an estimated 12.5 million American children are obese [5]. For adolescents specifically, the prevalence of obesity is 18.4%, with more than one-third overweight [6].
Childhood obesity is associated with both short- and long-term morbidities including insulin resistance and type 2 diabetes, hypertension, dyslipidemia, asthma, obstructive sleep apnea, psychosocial problems, and decreased quality of life [7,8]. Obese children, particularly older children and adolescents, are more likely become obese adults [2,7]. Obesity in adulthood is associated with both significant morbidity and premature death [9]. Individual characteristics such as lifestyle habits, fitness level, and genetic predisposition influence the likelihood of development of both obesity and associated comorbidities [10].
The burden of obesity and its associated comorbidities are not equally distributed among racial/ethnic and socioeconomic groups. Hispanic and non-Hispanic black children are much more likely to be obese and overweight than non-Hispanic white children [6]. Low socioeconomic status is associated with increased rates of obesity in certain subgroups, including adolescents [2]. In addition, certain ethnic/racial minorities are more likely to develop obesity-associated comorbidities, such as insulin resistance, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD). With regard to insulin resistance and development of type 2 diabetes, the risk is greatest in Native Americans, but there is also increased risk in Hispanic/Latinos, non-Hispanic blacks, and Asian Americans as compared with non-Hispanic whites [11–13]. Collectively, these findings highlight the need for individualized assessment and the importance of obesity prevention and early intervention to improve long-term health outcomes. Primary care providers play a pivotal role in this process of preventing, identifying and treating childhood obesity and associated comorbidities [14]. In the case history, the child’s ethnicity, family history, and borderline overweight BMI indicate a high risk for future obesity-related morbidity and a critical opportunity for prevention intervention.
• What are the initial steps a practitioner can take to address overweight and obesity?
To encourage the development of healthy lifestyles and prevention of obesity, dietary and exercise counseling should be routinely provided as part of anticipatory guidance to all children and families regardless of weight status. It is critical to recognize individuals at high risk for becoming obese starting early in life. Risk factors for obesity in healthy weight children include rapid crossing of BMI percentiles, obese parent(s), maternal history of gestational diabetes during pregnancy, ethnicity, sedentary lifestyle, and excessive caloric intake [2]. Identification of these high-risk individuals can prompt more intensive counseling and early intervention with the goal of preventing the development of obesity and its complications. The use of automated BMI calculation and electronic medical records can facilitate identification of overweight and obesity status when already present and improve counseling rates [15].
Obesity due to excess nutrition is typically associated with linear growth acceleration that occurs subsequent to and to a lesser degree than the percentile shift in weight gain. A declining height velocity associated with obesity, therefore, is concerning and should prompt investigation for endocrine disease such as hypothyroidism, glucocorticoid excess, and growth hormone deficiency. Additional factors that warrant further investigation and/or referral include growth trajectory significantly below genetic potential, developmental delay, and dysmorphic features. A complete physical examination should be performed to evaluate for signs consistent with these conditions (eg, violaceous striae in glucocorticoid excess, microcephaly, and small hands/feet in Prader-Willi syndrome), and signs of obesity-associated comorbidities (eg, acanthosis nigricans). Accurate height, weight, BMI calculation, and blood pressure assessment using an appropriately sized cuff are essential.
While BMI screening is valuable, as noted above it is important to appreciate that insulin resistance (and other obesity-related comorbidities) can develop even when BMI is below the 95th percentile. Detailed history and physical examination can help identify these comorbidities of excess adiposity and guide diagnostic evaluation. Independent risk factors for insulin resistance and the development of type 2 diabetes include family history of diabetes, minority race/ethnicity, elevated waist circumference, and poor fitness level [18–20].
Further History
The patient reports skipping breakfast on most days, eats lunch at school, and snacks on chips and soda after school. Dinner is variable but usually contains carbohydrates and a protein and rarely includes vegetables. Family eats “take-out” about 3 times per week. Patient reports spending 3 hours a day watching television and playing on computer. He had gym last semester but currently reports very limited to no physical activity on most days.
• What are effective ways to raise the issue of obesity during an office visit?
Despite the strong connection of obesity with adverse health outcomes, discussion of obesity in routine office settings can be difficult and is often limited by many factors such as time, training, availability of support services, perceived lack of patient motivation, and low outcome expectations [21,22]. Perhaps most challenging is tactfully handling the stigma associated with obesity, which can make discussion awkward and difficult for patients, parents, and providers. To do this, efforts to choose words that convey a nonjudgmental message while maintaining focus on obesity as a health concern are helpful. For example, terms such as “fat” and “obese” are often perceived as stigmatizing and blaming while using the term “unhealthy weight” is less pejorative and can be motivating [23]. It can also be important to acknowledge and emphasize that some individuals are more susceptible to weight gain and its consequences than others and as a result can tolerate fewer calories without unwanted weight gain and health problems. These approaches shift the focus of the discussion toward the goal of restoring and preserving health rather than changing physical appearance without placing blame on the individual and/or family. Motivational interviewing techniques which can be performed effectively even in short office visits can help to actively engage families, reveal familial perception of obesity and assess readiness to change [2]. Their use may also improve the efficacy of other interventions [24].
Case Continued
The patient and his mother were asked if they had any concerns today, including concerns about future health. Mother expressed worry about the potential for diabetes given their family history. The clinician used this as an opportunity to discuss pertinent factors associated with insulin resistance and type 2 diabetes, including modifiable factors such as diet, fitness level, and weight.
• Should this non-obese adolescent be assessed for obesity comorbidities?
Yes. While there are multiple guidelines available for pediatric screening, all highlight the importance of obtaining individualized risk assessment to guide the extent of diagnostic workup. An Expert Committee comprised of representatives from 15 professional organizations appointed 3 writing groups to review the literature and recommend approaches to prevention, assessment, and treatment. Because effective strategies remain poorly defined, the writing groups used both available evidence and expert opinion to develop the recommendations [2]. In addition to routine blood pressure monitoring and universal lipid screening, the Expert Committee recommends obtaining additional laboratory assessment for obese children (BMI ≥ 95th percentile) including a fasting glucose and ALT/AST levels every 2 years starting at age 10 years. For overweight children (BMI > 85th percentile), the Expert Committee recommends obtaining these studies if additional risk factors are present [2]. The American Diabetes Association (ADA) recommends obtaining diabetes screening in all children classified as overweight (defined as either a BMI > 85th percentile for age and sex, weight for height > 85th percentile, or weight > 120% of ideal for height) once every 3 years beginning at age 10 or at pubertal onset (whichever is earliest) when 2 additional risk factors for diabetes are also present, including: (1) history of type 2 diabetes in a first- or second-degree relative, (2) race/ethnicity with increased risk for diabetes development (eg, Native American, African American, Latino, Asian American), (3) signs of insulin resistance or conditions associated with insulin resistance (eg, small for gestational age, polycystic ovary syndrome, hypertension) and (4) maternal history of gestational diabetes during pregnancy [25]. The ADA recommendations for diabetes screening test include either fasting plasma glucose, HgA1C, or oral glucose tolerance test [25].
With a BMI at the 85th percentile, on initial assessment our patient might be perceived as being at moderate or even low risk for obesity and its associated comorbidities. However, a more careful review has elicited several additional risk factors suggesting more appropriate classification in the high-risk category. First, family history of type 2 diabetes on both sides of his family suggests a degree of genetic predisposition. Second, Hispanic ethnicity is known to be independently associated with insulin resistance, type 2 diabetes, and NAFLD [26]. Moreover, physical exam findings of an elevated waist circumference (90th percentile for age and ethnicity [27]) and acanthosis nigricans are also supportive of insulin resistance. As a result, despite having a BMI at the 85th percentile, this adolescent is at high risk and further evaluation is warranted based on both Expert Committee and ADA guidelines. Detailed discussion of certain risk factors is outlined below.
Pattern of Adipose Tissue Distribution: Utility of BMI and Waist Circumference
BMI is a clinical tool that serves as a surrogate marker of adiposity, but since it does not directly measure body fat it provides a statistical, rather than inherent, description of risk. While it is a relatively specific marker (~95%) with moderately high sensitivity and positive predictive value (~70–80%) at BMI levels > 95th percentile, sensitivity and positive predictive value decrease substantially at lower BMI percentiles (PPV 18% in a sample of overweight children) [28]. Current CDC BMI percentile charts consider age and gender differences but do not take into account sexual maturation level or race/ethnicity, both of which are independently correlated with BMI [29]. That is, children with similar BMIs of the same age and sex may exhibit varying degrees of adiposity and risk attributable to their pubertal stage and/or ethnicity [30]. For example, many studies have demonstrated that at the same BMI percentile, Asian Americans tend to have more adiposity compared with non-Hispanic whites [31], whereas African Americans tend to have more fat-free mass compared with non-Hispanic whites [32]. As a result of these differences, some advocate for adjusting cut-offs for BMI based on ethnicity and/or utilizing alternative measures of adiposity such as waist circumference or waist to hip ratio. However, in order for these latter methods to be useful, standardized methods of measurement and normative reference values must be developed. In summary, though BMI can be a useful screening tool, it is an indirect measure of adiposity and cannot discern adipose distribution. Therefore, it is important to remember that when used alone, BMI may overlook children with high inherent risk for disease.
Abdominal adiposity is associated with increased metabolic risk, including insulin resistance, type 2 diabetes, hypertension, cardiovascular disease, and mortality [33]. Waist circumference, a marker of abdominal/truncal obesity, has been considered as a potential marker in place of or in combination with BMI to identify children with increased metabolic risk. In adults, it is well established that an elevated waist circumference is associated with increased health risk, even among those within a normal-weight BMI category [34], and it is recommended that waist circumference in addition to BMI be used to assess health risk [35]. Many studies have documented similar associations between increased waist circumference and metabolic risk factors in childhood and adolescence [36–38]. Specifically, waist circumference is an independent predictor of both insulin sensitivity and increased visceral adiposity tissue (VAT) in children and adolescents [39]. Waist circumference can provide valuable information beyond BMI alone and may be beneficial in the clinical setting in identifying adolescents at risk for obesity-associated comorbidities.
The use of waist circumference in routine clinical settings is complicated and limited by many factors. First, there is no universal method for waist circumference measurement. For example, the WHO recommends measurement at the midpoint between the superior iliac crest and inferior most rib, while the NIH and NHANES recommend measurement immediately above the iliac crest [40]. Since nationally representative data published by Fernandez et al [27] uses the latter method for waist circumference measurement, we recommend this method to allow for comparison of waist circumference percentile with available data for age, sex, and ethnicity. Second, while absolute waist circumference values are used as cut-offs in adulthood, in childhood use of waist circumference percentiles would be more appropriate to account for expected increases during childhood and changes related to pubertal stage. Unfortunately, a lack of standardized waist circumference percentile charts makes meaningful interpretation of waist circumference difficult. Moreover, even if standardized waist circumference percentile charts were developed, there are currently no accepted standards defining an abnormally elevated waist circumference percentile.
Many studies have identified increased metabolic risk factors associated with a waist circumference at or above the 90th percentile for age [41–43]. Based on these studies, the International Diabetes Federation uses waist circumference > 90th percentile as part of the criteria for metabolic syndrome in adolescents. While this ensures a high degree of specificity, use of waist circumference at the 75th percentile would allow for increased sensitivity. For example, Lee et al found that for insulin resistance use of waist circumference at the 75th percentile compared with the 90th percentile increased sensitivity from 61.3% to 86.1% while decreasing specificity from 91.4% to 71.5% [44]. Thus, for individuals at low risk based on history and clinical findings, a waist circumference threshold at the 90th percentile might be reasonable, while for individuals with additional risk factors for insulin resistance use of a lower waist circumference threshold (such as the 75th percentile) may be beneficial. Finally, since risk for insulin resistance and type 2 diabetes varies by race/ethnicity, which may correspond with visceral fat deposition, utilizing various threshold cut-offs based on race/ethnicity has been proposed by some. However, current data do not support this practice [44]. In summary, though there are many challenges to using waist circumference measurements in routine settings, if performed correctly determination of elevated waist circumference measurement can provide some additional information on an individual’s overall risk for complications of obesity.
Acanthosis Nigricans as an Indicator of Insulin Resistance
Insulin resistance, independent of adiposity, is associated with increased risk for type 2 diabetes, cardiovascular disease, ovarian hyperandrogenism, and certain forms of cancer [45]. Identification of insulin resistance in the clinical setting can lead to appropriate intervention (both lifestyle and, when warranted, pharmacologic) to reduce insulin resistance and improve health outcomes. Several risk factors for insulin resistance have been discussed above. Acanthosis nigricans, which is characterized by thick, velvety hyperpigmentation of the skin in intertriginous areas such as the neck and axilla, is an additional finding that is associated with insulin resistance. Its pathogenesis is felt to be related to activation of the IGF-1 receptor by high levels of circulating insulin [46]. Acanthosis nigricans is independently associated with fasting insulin levels and impaired glucose tolerance [47,48]. In addition to increased insulin resistance, one study found that 1 in 4 youths with acanthosis nigricans demonstrated abnormalities in glucose homeostasis and identified 2 individuals with diabetes who would not have been diagnosed based on fasting glucose levels alone [48]. The presence of acanthosis nigricans should alert the clinician to the likelihood of insulin resistance and prompt further investigation. Of note, the prevalence of acanthosis nigricans is increased among African American and Hispanic patients [49,50].
• What laboratory evaluation is warranted and practical in the office setting?
Laboratory evaluation is warranted when obesity or risk factors for comorbidities of obesity are present. At minimum, this should include lipid screening, liver enzymes (ALT and AST), and fasting glucose as outlined above. This approach, however, fails to identify all individuals with obesity-associated comorbidities. ALT is only moderately sensitive in detecting NAFLD [51], and fasting glucose levels only become abnormal when compensation for the degree of insulin resistance is inadequate to maintain normal fasting glucose homeostasis. As a result, while abnormal results on screening are suggestive of disease, normal results do not necessarily confer its absence. Thus, for high-risk subjects, additional testing and/or referral should be considered.
The hyperinsulinemic euglycemic clamp is the “gold standard” for measuring insulin sensitivity, but it is labor intensive and impractical in routine clinical settings. Alter-native approaches using surrogate markers have commonly been utilized, including fasting insulin and glucose levels and 2-hour oral glucose tolerance test (OGTT). The utility of these approaches in the clinical setting has been limited by several factors, including lack of a universal insulin assay. However, despite these limitations, obtaining fasting insulin in addition to fasting glucose or performing 2-hour OGTT can be useful in providing crude estimates of insulin resistance in certain high-risk subpopulations [52,53]. Recently, the ADA added HgA1C measurement as diagnostic criteria for pre-diabetes (5.7%–6.4%) and diabetes (> 6.5%) [54]. Benefits of HgA1C measurement include reliable measurements in nonfasting conditions and reflection of glucose over time. Studies in pediatric patients have shown the usefulness of HgA1C as a measure of future glucose intolerance or diabetes [55]. When fasting insulin or HgA1C are elevated and/or OGTT is abnormal, this suggests the presence of insulin resistance and need for intervention.
Proposed guideline criteria for the diagnosis of “metabolic syndrome” in adolescents include the following: (1) glucose intolerance, (2) elevated waist circumference or BMI, (3) hypertriglyceridemia, (4) low HDL, and 5) hypertension. There is no universal definition for metabolic syndrome in childhood and adolescence, and cut-off values in each category vary by study group [41–43,56]. When insulin resistance is present, it should alert the clinician to the increased likelihood for metabolic syndrome and NAFLD, and additional screening should be performed accordingly. NAFLD is present in about 25% of all overweight children and is strongly associated with insulin resistance and the metabolic syndrome [57]. Hispanic patients have an increased prevalence of NAFLD compared with patients of other ethnicities [58,59]. Elevated liver transaminases (AST and ALT) are commonly used to screen for NAFLD. However, since these markers are indicative of hepatocellular damage, they may remain within normal limits and correlate poorly with early steatosis [51]. Alternative approaches have been proposed in high-risk populations to detect early steatosis and improve long-term prognosis [60].
Case Continued
The patient underwent laboratory assessment that included fasting glucose and insulin, fasting lipid panel, and ALT. Results were suggestive of insulin resistance and metabolic syndrome and included the following: fasting glucose 108 mg/dL, fasting insulin 65 uIU/mL (reference range 3–25), HgA1C 5.9% (reference range 4.2–5.8), total cholesterol 178 mg/dL, HDL cholesterol 35 mg/dL, LDL cholesterol 110 mg/dL, triglycerides 157 mg/dL, and ALT 40 u/L. Blood pressure, as noted above, is at the 95th percentile for age and height.
• What is the recommended approach to intervention? When is referral warranted?
Staged Obesity Treatment
The initial stage, termed “Prevention Plus,” is similar to obesity prevention strategies and is focused on institution of healthy dietary and activity lifestyle habits tailored to the individual and family. Frequent follow-up and monitoring can be helpful and should be offered to families. Failure to demonstrate progress after 3 to 6 months warrants advancement to Stage 2, “Structured Weight Management,” which includes a planned diet with structured meals and snacks, reduction of screen time to 1 hour or less, 60 minutes of supervised physical activity, use of logs to document diet and activity levels, monthly follow-ups and positive reinforcement for achieving goals. Consultation with a dietician and health psychologist/counseling can be helpful at this level.
If no progress is noted after 3 to 6 months, progression to Stage 3, “Comprehensive Multidisciplinary Intervention,” is recommended. This stage emphasizes the importance of a multidisciplinary team including behavioral counselor, registered dietician and exercise specialist in addition to a medical provider. Current evidence suggests modest improvement of obesity and related comorbidities in adolescents participating in multidisciplinary weight management programs [62,63]. While these interventions can be implemented in community settings, coordination in this setting can be difficult and implementation more commonly involves weight management programs in tertiary care centers. Access to such programs can be limited by geographic accessibility, insurance coverage and physician awareness of available programs/resources [64]. Utilization of technology such as telemedicine visits is one way to overcome limited access [65]. Finally, Stage 4 “Tertiary Care Intervention”, involving discussion of pharmacologic or intensive/surgical weight loss options, can be considered for those who fail to show progression after successful intervention of previous stages.
Specialty Referral
Referral to multidisciplinary clinics specializing in childhood obesity is warranted when obesity is particularly severe, comorbidities are present at baseline, or no improvement is noted after 6 months of intense lifestyle intervention. Insulin resistance evidenced by impaired glucose tolerance (abnormal fasting or 2-hour glucose levels), HgA1C in the pre-diabetes range or higher (> 5.7%), or persistently elevated fasting insulin levels after 3 to 6 months of intensive lifestyle modification should prompt referral for consideration of metformin initiation. Metformin can reduce insulin resistance in children and may reduce progression from impaired glucose tolerance to diabetes [66]. For dyslipidemia related to metabolic syndrome, lifestyle interventions are most likely to be efficacious. Referral to preventative cardiology for consideration of pharmacologic intervention should be considered when severe hypertriglyceridemia is present (> 400 mg/dL) or LDL remains elevated after implementation of healthy lifestyle interventions. Elevations in ALT are highly specific for NAFLD and should prompt referral to gastroenterology. In addition, given the poor sensitivity of ALT for detection of early hepatic steatosis, referral might be considered when ALT is in the high normal ranges, especially in those with increased risk such as Hispanic patients [67]. Finally, when signs of obstructive sleep apnea are present, a sleep study should be performed. In summary, while specialty referral can aid targeted treatment of obesity-related morbidities, the central role of the primary care clinician in anticipating and preventing or minimizing their occurrence remains paramount.
Case Conclusion
The patient was referred to a multidisciplinary obesity clinic where he and his family met with dietician, exercise physiologist, health psychologist, and endocrinologist. Healthy lifestyle modifications with specific goals were instituted, including elimination of all calorie-containing beverages (except daily recommended intake of fat-free milk) and initiation of physical activity for 30 minutes a day 5 days per week. He was started on metformin due to glucose intolerance and increased risk for diabetes. Follow-up occurred at monthly intervals for the first 3 months. Additional goals and lifestyle interventions were implemented at each follow-up. At 6 months’ follow-up, the patient’s height was 164 cm, weight was stable at 58.4 kg and BMI was 21.7 (79th percentile). Blood pressure was slightly improved at 123/80 mm Hg. Repeat labs showed mild but consistent improvement in all areas. Specifically, fasting glucose 100 mg/dL, fasting insulin 40 uIU/mL, HgA1C 5.6%, total cholesterol 162 mg/dL, HDL cholesterol 40 mg/dL, LDL cholesterol 105 mg/dL, triglycerides 140 mg/dL, and ALT 38 u/L. The patient continues to be monitored closely with goal to improve metabolic health and long-term health outcomes.
Summary
Childhood obesity is a major public health concern. The health impact of obesity on children is broad and profound. Since treatment of obesity is often unsuccessful, prevention of obesity or early detection of its health consequences are crucial responsibilities and opportunities for primary care clinicians. While clinical guidelines can be instructive, application of clinical guidelines must be tailored to individual adolescent patients according to accompanying risk factors. This review aims to help clinicians stratify risk based on susceptibility to development of insulin resistance and other morbidities associated with adolescent obesity. While the enormity of the obesity epidemic can appear overwhelming to primary care providers, they remain in the best position to initiate early intervention strategies. Coordinating care between primary care providers and specialty clinics will continue to be an important partnership for the care of those experiencing health-threatening effects of adolescent obesity.
Corresponding author: Aaron L Carrel, MD, University of Wisconsin, 600 Highland Ave, H4-436, Madison, WI 53792.
Financial disclosures: Drs. Seibert and Carrel have received fellowship grants from Genentech.
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36. Janssen I, Katzmarzyk PT, Srinivasan SR, et al. Combined influence of body mass index and waist circumference on coronary artery disease risk factors among children and adolescents. Pediatrics 2005;115:1623–30.
37. Freedman DS, Serdula MK, Srinivasan SR, Berenson GS. Relation of circumferences and skinfold thicknesses to lipid and insulin concentrations in children and adolescents: the Bogalusa Heart Study. Am J Clin Nutr 1999;69:308–17.
38. Savva SC, Tornaritis M, Savva ME, et al. Waist circumference and waist-to-height ratio are better predictors of cardiovascular disease risk factors in children than body mass index. Int J Obes Rel Metab Disorders 2000;24:1453–8.
39. Lee S, Bacha F, Gungor N, Arslanian SA. Waist circumference is an independent predictor of insulin resistance in black and white youths. J Pediatrics 2006;148:188–94.
40. Wang J, Thornton JC, Bari S, et al. Comparisons of waist circumferences measured at 4 sites. Am J Clin Nutrition 2003;77:379–84.
41. Cook S, Weitzman M, Auinger P, et al. Prevalence of a metabolic syndrome phenotype in adolescents: findings from the third National Health and Nutrition Examination Survey, 1988-1994. Arch Ped Adol Med 2003;157:821–7.
42. Ford ES, Ajani UA, Mokdad AH. The metabolic syndrome and concentrations of C-reactive protein among U.S. youth. Diabetes Care 2005;28:878–81.
43. Cruz ML, Weigensberg MJ, Huang TT, et al. The metabolic syndrome in overweight Hispanic youth and the role of insulin sensitivity. J Clin Endocrin Metab 2004;89:108–13.
44. Lee JM, Davis MM, Woolford SJ, Gurney JG. Waist circumference percentile thresholds for identifying adolescents with insulin resistance in clinical practice. Pediatric Diabetes 2009;10:336–42.
45. Li S, Chen W, Srinivasan SR, et al. Relation of childhood obesity/cardiometabolic phenotypes to adult cardiometabolic profile: the Bogalusa Heart Study. Am J Epidemiol 2012;1:S142–9.
46. Torley D, Bellus GA, Munro CS. Genes, growth factors and acanthosis nigricans. Br J Dermatol 2002;147:1096–101.
47. Mukhtar Q, Cleverley G, Voorhees RE, McGrath JW. Prevalence of acanthosis nigricans and its association with hyperinsulinemia in New Mexico adolescents. J. Adolesc Health 2001;28:372–6.
48. Brickman WJ, Huang J, Silverman BL, Metzger BE. Acanthosis nigricans identifies youth at high risk for metabolic abnormalities. J Pediatrics 2010;156:87–92.
49. Stuart CA, Pate CJ, Peters EJ. Prevalence of acanthosis nigricans in an unselected population. Am J Med 1989;87:269–72.
50. Brickman WJ, Binns HJ, Jovanovic BD, et al. Acanthosis nigricans: a common finding in overweight youth. Pediatr Dermatol 2007;24:601–6.
51. Yang HR, Kim HR, Kim MJ, et al. Noninvasive parameters and hepatic fibrosis scores in children with nonalcoholic fatty liver disease. World J Gastroenterol 2012;18:1525–30.
52. Chiarelli F, Marcovecchio ML. Insulin resistance and obesity in childhood. Eur J Endocrinol 2008;159 Suppl 1:S67–74.
53. Adam TC, Hasson RE, Lane CJ, Goran MI. Fasting indicators of insulin sensitivity: effects of ethnicity and pubertal status. Diabetes Care 2011;34:994–9.
54. Diagnosis and classification of diabetes mellitus. Diabetes Care 2013;36 Suppl 1:S67–74.
55. Nowicka P, Santoro N, Liu H, et al. Utility of hemoglobin A(1c) for diagnosing prediabetes and diabetes in obese children and adolescents. Diabetes Care 2011;34:1306–11.
56. Weiss R, Dziura J, Burgert TS, et al. Obesity and the metabolic syndrome in children and adolescents. N Engl J Med 2004;350:2362–74.
57. Martins C, Pizarro A, Aires L, et al. Fitness and metabolic syndrome in obese fatty liver children. Ann Hum Biol 2013;40:99–101.
58. Taveras EM, Gillman MW, Kleinman KP, et al. Reducing racial/ethnic disparities in childhood obesity: the role of early life risk factors. JAMA Pediatr 2013;167:731–8.
59. Wolfgram PM, Connor EL, Rehm JL, et al. Ethnic differences in the effects of hepatic fat deposition on insulin resistance in non-obese middle school girls. Obesity (Silver Spring) 2014;22:243–8.
60. Sowa JP, Heider D, Bechmann LP, et al. Novel algorithm for non-invasive assessment of fibrosis in NAFLD. PLoS One 2013;8:e62439.
61. Barlow SE. Expert committee recommendations regarding the prevention, assessment, and treatment of child and adolescent overweight and obesity: summary report. Pediatrics 2007;120 Suppl 4:S164–192.
62. Woolford SJ, Sallinen BJ, Clark SJ, Freed GL. Results from a clinical multidisciplinary weight management program. Clin Pediatrics 2011;50:187–91.
63. Savoye M, Shaw M, Dziura J, et al. Effects of a weight management program on body composition and metabolic parameters in overweight children: a randomized controlled trial. JAMA 2007;297:2697–704.
64. Woolford SJ, Clark SJ, Gebremariam A, et al. Physicians’ perspectives on referring obese adolescents to pediatric multidisciplinary weight management programs. Clin Pediatrics 2010;49:871–5.
65. Lipana LS, Bindal D, Nettiksimmons J, Shaikh U. Telemedicine and face-to-face care for pediatric obesity. Telemed J Ehealth 2013;19:806–8.
66. Park MH, Kinra S, Ward KJ, et al. Metformin for obesity in children and adolescents: a systematic review. Diabetes Care 2009;32:1743–5.
67. Urrutia-Rojas X, McConathy W, Willis B, et al. Abnormal glucose metabolism in Hispanic parents of children with acanthosis nigricans. ISRN Endocrinol 2011(Epub 2011 Dec 25.).
1. CDC. Obesity task force report. 2010. Available at www.letsmove.gov/sites/letsmove.gov/files/TaskForce_on_Childhood_Obesity_May2010_FullReport.pdf. Accessed 4 Sept 2013.
2. Barlow SE, AAP Expert Committee. AAP Expert Committee Recommendations regarding prevention, assessment and treatment of child obesity. Pediatrics 2007;120:s164–92.
3. Dietz WH, Robinson TN. Overweight children and adolescents. N Engl J Med 2005;352:2100–9.
4. Centers for Disease Control and Prevention (CDC) 2012; Overweight and obesity. Available at www.cdc.gov/obesity/childhood/basics.html. Accessed 3 Sept 2013.
5. Centers for Disease Control and Prevention (CDC). Prevalence of obesity among children and adolescents: United States, trends 1963–1965 through 2009–2010. Available at www.cdc.gov/nchs/data/hestat/obesity_child_09_10/obesity_child_09_10.pdf.
6. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of obesity and trends in body mass index among US children and adolescents, 1999–2010. JAMA 2012;307:483–90.
7. August GP, Caprio S, Fennoy I, et al; Endocrine Society. Prevention and treatment of pediatric obesity: an endocrine society clinical practice guideline based on expert opinion. J Clin Endocrinol Metab 2008;93:4576–99.
8. Holmes ME, Eisenmann JC, Ekkekakis P, Gentile D. Physical activity, stress, and metabolic risk score in 8- to 18-year-old boys. J Phys Act Health 2008;5:294–307.
9. Peeters A, Barendregt JJ, Willekens F, et al. Obesity in adulthood and its consequences for life expectancy: a life-table analysis. Ann Intern Med 2003;138:24–32.
10. Sharifi M, Marshall G, Marshall R, et al. Accelerating progress in reducing childhood obesity disparities: exploring best practices of positive outliers. J Health Care Poor Underserved 2013;24(2 Suppl):193–9.
11. Cossrow N, Falkner B. Race/ethnic issues in obesity and obesity-related comorbidities. J Clin Endocrinol Metab 2004;89:2590–4.
12. Rosenbaum M, Fennoy I, Accacha S, et al. Racial/ethnic differences in clinical and biochemical type 2 diabetes mellitus risk factors in children. Obesity (Silver Spring) 2013;21:2081–90.
13. NIDDK. National diabetes statistics, 2011. Available at http://diabetes.niddk.nih.gov/dm/pubs/statistics/. Accessed 18 Sept 2013.
14. Janz KF, Butner KL, Pate RR. The role of pediatricians in increasing physical activity in youth. JAMA Pediatr 2013:1–2.
15. Coleman KJ, Hsii AC, Koebnick C, et al. Implementation of clinical practice guidelines for pediatric weight management. J Pediatrics 2012;160:918–22.
16. Ratcliff MB, Jenkins TM, Reiter-Purtill J, et al. Risk-taking behaviors of adolescents with extreme obesity: normative or not? Pediatrics 2011;127:827–34.
17. Goldenring J, Rosen D. Getting into adolescent heads: An essential update. Contemp Pediatr 2004;21:64.
18. Eisenmann JC, Welk GJ, Ihmels M, Dollman J. Fatness, fitness, and cardiovascular disease risk factors in children and adolescents. Med Sci Sports Exerc 2007;39:1251–6.
19. Weiss R, Shaw M, Savoye M, Caprio S. Obesity dynamics and cardiovascular risk factor stability in obese adolescents. Ped Diabetes 2009;10:360–7.
20. Rizzo NS, Ruiz JR, Ortega FB, Sjostrom M. Relationship of physical activity, fitness, and fatness with clustered metabolic risk in children and adolescents: The European Youth Heart Study. J Pediatr 2007;150:388–94.
21. Story MT, Neumark-Stzainer DR, Sherwood NE, et al. Management of child and adolescent obesity: attitudes, barriers, skills, and training needs among health care professionals. Pediatrics 2002;110(1 Pt 2):210–4.
22. Alexander SC, Ostbye T, Pollak KI, et al. Physicians’ beliefs about discussing obesity: results from focus groups. Am J Health Promot 2007;21:498–500.
23. Puhl RM, Peterson JL, Luedicke J. Weight-based victimization: bullying experiences of weight loss treatment-seeking youth. Pediatrics 2013;131:e1–9.
24. Christie D, Channon S. The potential for motivational interviewing to improve outcomes in the management of diabetes and obesity in paediatric and adult populations: a clinical review. Diabetes Obes Metab 2013. Aug 8 [Epub ahead of print].
25. Standards of medical care in diabetes--2010. Diabetes Care 2010;33 Suppl 1:S11–61.
26. Hasson RE, Adam TC, Davis JN, et al. Ethnic differences in insulin action in obese African-American and Latino adolescents. J Clin Endocrinol Metab 2010;95:4048–51.
27. Fernández JR, Redden DT, Pietrobelli A, Allison DB. Waist circumference percentiles in nationally representative samples of African-American, European-American, and Mexican-American children and adolescents. J Pediatrics 2004;145:439–44.
28. Freedman DS, Sherry B. The validity of BMI as an indicator of body fatness and risk among children. Pediatrics 2009;124 Suppl 1:S23–34.
29. Daniels SR, Khoury PR, Morrison JA. The utility of body mass index as a measure of body fatness in children and adolescents: differences by race and gender. Pediatrics 1997;99:804–7.
30. Curtis VA, Carrel AL, Eickhoff JC, Allen DB. Gender and race influence metabolic benefits of fitness in children: a cross-sectional study. Int J Pediatr Endocrinol 2012;2012:4.
31. Nightingale CM, Rudnicka AR, Owen CG, et al. Influence of adiposity on insulin resistance and glycemia markers among U.K. Children of South Asian, black African-Caribbean, and white European origin: child heart and health study in England. Diabetes Care 2013;36:1712–9.
32. Gutin B, Yin Z, Humphries MC, Hoffman WH, et al. Relations of fatness and fitness to fasting insulin in black and white adolescents. J Pediatr 2004;145:737–43.
33. Cook S. The metabolic syndrome: Antecedent of adult cardiovascular disease in pediatrics. J Pediatr 2004;145:427–30.
34. Janssen I, Katzmarzyk PT, Ross R. Body mass index, waist circumference, and health risk: evidence in support of current National Institutes of Health guidelines. Arch Intern Med 2002;162:2074–9.
35. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults. September 1998. NIH Pub No. 98-4083. Available at www.ncbi.nlm.nih.gov/books/NBK2003/pdf/TOC.pdf. Accessed 29 Sept 2013.
36. Janssen I, Katzmarzyk PT, Srinivasan SR, et al. Combined influence of body mass index and waist circumference on coronary artery disease risk factors among children and adolescents. Pediatrics 2005;115:1623–30.
37. Freedman DS, Serdula MK, Srinivasan SR, Berenson GS. Relation of circumferences and skinfold thicknesses to lipid and insulin concentrations in children and adolescents: the Bogalusa Heart Study. Am J Clin Nutr 1999;69:308–17.
38. Savva SC, Tornaritis M, Savva ME, et al. Waist circumference and waist-to-height ratio are better predictors of cardiovascular disease risk factors in children than body mass index. Int J Obes Rel Metab Disorders 2000;24:1453–8.
39. Lee S, Bacha F, Gungor N, Arslanian SA. Waist circumference is an independent predictor of insulin resistance in black and white youths. J Pediatrics 2006;148:188–94.
40. Wang J, Thornton JC, Bari S, et al. Comparisons of waist circumferences measured at 4 sites. Am J Clin Nutrition 2003;77:379–84.
41. Cook S, Weitzman M, Auinger P, et al. Prevalence of a metabolic syndrome phenotype in adolescents: findings from the third National Health and Nutrition Examination Survey, 1988-1994. Arch Ped Adol Med 2003;157:821–7.
42. Ford ES, Ajani UA, Mokdad AH. The metabolic syndrome and concentrations of C-reactive protein among U.S. youth. Diabetes Care 2005;28:878–81.
43. Cruz ML, Weigensberg MJ, Huang TT, et al. The metabolic syndrome in overweight Hispanic youth and the role of insulin sensitivity. J Clin Endocrin Metab 2004;89:108–13.
44. Lee JM, Davis MM, Woolford SJ, Gurney JG. Waist circumference percentile thresholds for identifying adolescents with insulin resistance in clinical practice. Pediatric Diabetes 2009;10:336–42.
45. Li S, Chen W, Srinivasan SR, et al. Relation of childhood obesity/cardiometabolic phenotypes to adult cardiometabolic profile: the Bogalusa Heart Study. Am J Epidemiol 2012;1:S142–9.
46. Torley D, Bellus GA, Munro CS. Genes, growth factors and acanthosis nigricans. Br J Dermatol 2002;147:1096–101.
47. Mukhtar Q, Cleverley G, Voorhees RE, McGrath JW. Prevalence of acanthosis nigricans and its association with hyperinsulinemia in New Mexico adolescents. J. Adolesc Health 2001;28:372–6.
48. Brickman WJ, Huang J, Silverman BL, Metzger BE. Acanthosis nigricans identifies youth at high risk for metabolic abnormalities. J Pediatrics 2010;156:87–92.
49. Stuart CA, Pate CJ, Peters EJ. Prevalence of acanthosis nigricans in an unselected population. Am J Med 1989;87:269–72.
50. Brickman WJ, Binns HJ, Jovanovic BD, et al. Acanthosis nigricans: a common finding in overweight youth. Pediatr Dermatol 2007;24:601–6.
51. Yang HR, Kim HR, Kim MJ, et al. Noninvasive parameters and hepatic fibrosis scores in children with nonalcoholic fatty liver disease. World J Gastroenterol 2012;18:1525–30.
52. Chiarelli F, Marcovecchio ML. Insulin resistance and obesity in childhood. Eur J Endocrinol 2008;159 Suppl 1:S67–74.
53. Adam TC, Hasson RE, Lane CJ, Goran MI. Fasting indicators of insulin sensitivity: effects of ethnicity and pubertal status. Diabetes Care 2011;34:994–9.
54. Diagnosis and classification of diabetes mellitus. Diabetes Care 2013;36 Suppl 1:S67–74.
55. Nowicka P, Santoro N, Liu H, et al. Utility of hemoglobin A(1c) for diagnosing prediabetes and diabetes in obese children and adolescents. Diabetes Care 2011;34:1306–11.
56. Weiss R, Dziura J, Burgert TS, et al. Obesity and the metabolic syndrome in children and adolescents. N Engl J Med 2004;350:2362–74.
57. Martins C, Pizarro A, Aires L, et al. Fitness and metabolic syndrome in obese fatty liver children. Ann Hum Biol 2013;40:99–101.
58. Taveras EM, Gillman MW, Kleinman KP, et al. Reducing racial/ethnic disparities in childhood obesity: the role of early life risk factors. JAMA Pediatr 2013;167:731–8.
59. Wolfgram PM, Connor EL, Rehm JL, et al. Ethnic differences in the effects of hepatic fat deposition on insulin resistance in non-obese middle school girls. Obesity (Silver Spring) 2014;22:243–8.
60. Sowa JP, Heider D, Bechmann LP, et al. Novel algorithm for non-invasive assessment of fibrosis in NAFLD. PLoS One 2013;8:e62439.
61. Barlow SE. Expert committee recommendations regarding the prevention, assessment, and treatment of child and adolescent overweight and obesity: summary report. Pediatrics 2007;120 Suppl 4:S164–192.
62. Woolford SJ, Sallinen BJ, Clark SJ, Freed GL. Results from a clinical multidisciplinary weight management program. Clin Pediatrics 2011;50:187–91.
63. Savoye M, Shaw M, Dziura J, et al. Effects of a weight management program on body composition and metabolic parameters in overweight children: a randomized controlled trial. JAMA 2007;297:2697–704.
64. Woolford SJ, Clark SJ, Gebremariam A, et al. Physicians’ perspectives on referring obese adolescents to pediatric multidisciplinary weight management programs. Clin Pediatrics 2010;49:871–5.
65. Lipana LS, Bindal D, Nettiksimmons J, Shaikh U. Telemedicine and face-to-face care for pediatric obesity. Telemed J Ehealth 2013;19:806–8.
66. Park MH, Kinra S, Ward KJ, et al. Metformin for obesity in children and adolescents: a systematic review. Diabetes Care 2009;32:1743–5.
67. Urrutia-Rojas X, McConathy W, Willis B, et al. Abnormal glucose metabolism in Hispanic parents of children with acanthosis nigricans. ISRN Endocrinol 2011(Epub 2011 Dec 25.).
Mixing meds and supplements to dangerous effect
Credit: CDC
A new study indicates that a fair share of patients may be mixing the herbal supplement St. John’s wort with prescribed medications, which can have dangerous results.
St. John’s wort can reduce the concentration of numerous drugs in the body, including anticoagulants and chemotherapeutic agents. And this can result in impaired effectiveness and treatment failure.
But the supplement can also interact with medications to produce serious adverse events.
“Patients may have a false sense of safety with so-called ‘natural’ treatments like St. John’s wort,” said study author Sarah Taylor, MD, of Wake Forest Baptist Medical Center in Winston-Salem, North Carolina.
“And it is crucial for physicians to know the dangers of ‘natural’ treatments and to communicate the risks to patients effectively.”
Dr Taylor and her colleagues investigated the use of St. John’s wort and reported their findings in The Journal of Alternative and Complementary Medicine.
To determine how often the supplement was being prescribed or taken with other medications, the researchers conducted a retrospective analysis of nationally representative data collected by the National Ambulatory Medical Care Survey from 1993 to 2010.
The team found the use of St. John’s wort in potentially harmful combinations in 28% of the cases reviewed. The drugs involved were warfarin, selective serotonin reuptake inhibitors, benzodiazepines, statins, verapamil, digoxin, and oral contraceptives.
Possible drug interactions include serotonin syndrome (a potentially fatal condition that causes high levels of the chemical serotonin to accumulate in the body), heart disease due to impaired efficacy of blood pressure medications, or unplanned pregnancy due to contraceptive failure, Dr Taylor said.
A key limitation of this study is that only medications recorded by the physician were analyzed. And Dr Taylor said the rate of St. John’s wort interactions may actually be underestimated because the database did not include patients who were using St. John’s wort but did not tell their doctor.
“Labeling requirements for helpful supplements such as St. John’s wort need to provide appropriate cautions and risk information,” Dr Taylor said, adding that France has banned the use of St. John’s wort products, and several other countries, including Japan, the UK, and Canada, are in the process of including drug-herb interaction warnings on St. John’s wort products.
“Doctors also need to be trained to always ask if the patient is taking any supplements, vitamins, minerals or herbs, especially before prescribing any of the common drugs that might interact with St. John’s wort.”
Credit: CDC
A new study indicates that a fair share of patients may be mixing the herbal supplement St. John’s wort with prescribed medications, which can have dangerous results.
St. John’s wort can reduce the concentration of numerous drugs in the body, including anticoagulants and chemotherapeutic agents. And this can result in impaired effectiveness and treatment failure.
But the supplement can also interact with medications to produce serious adverse events.
“Patients may have a false sense of safety with so-called ‘natural’ treatments like St. John’s wort,” said study author Sarah Taylor, MD, of Wake Forest Baptist Medical Center in Winston-Salem, North Carolina.
“And it is crucial for physicians to know the dangers of ‘natural’ treatments and to communicate the risks to patients effectively.”
Dr Taylor and her colleagues investigated the use of St. John’s wort and reported their findings in The Journal of Alternative and Complementary Medicine.
To determine how often the supplement was being prescribed or taken with other medications, the researchers conducted a retrospective analysis of nationally representative data collected by the National Ambulatory Medical Care Survey from 1993 to 2010.
The team found the use of St. John’s wort in potentially harmful combinations in 28% of the cases reviewed. The drugs involved were warfarin, selective serotonin reuptake inhibitors, benzodiazepines, statins, verapamil, digoxin, and oral contraceptives.
Possible drug interactions include serotonin syndrome (a potentially fatal condition that causes high levels of the chemical serotonin to accumulate in the body), heart disease due to impaired efficacy of blood pressure medications, or unplanned pregnancy due to contraceptive failure, Dr Taylor said.
A key limitation of this study is that only medications recorded by the physician were analyzed. And Dr Taylor said the rate of St. John’s wort interactions may actually be underestimated because the database did not include patients who were using St. John’s wort but did not tell their doctor.
“Labeling requirements for helpful supplements such as St. John’s wort need to provide appropriate cautions and risk information,” Dr Taylor said, adding that France has banned the use of St. John’s wort products, and several other countries, including Japan, the UK, and Canada, are in the process of including drug-herb interaction warnings on St. John’s wort products.
“Doctors also need to be trained to always ask if the patient is taking any supplements, vitamins, minerals or herbs, especially before prescribing any of the common drugs that might interact with St. John’s wort.”
Credit: CDC
A new study indicates that a fair share of patients may be mixing the herbal supplement St. John’s wort with prescribed medications, which can have dangerous results.
St. John’s wort can reduce the concentration of numerous drugs in the body, including anticoagulants and chemotherapeutic agents. And this can result in impaired effectiveness and treatment failure.
But the supplement can also interact with medications to produce serious adverse events.
“Patients may have a false sense of safety with so-called ‘natural’ treatments like St. John’s wort,” said study author Sarah Taylor, MD, of Wake Forest Baptist Medical Center in Winston-Salem, North Carolina.
“And it is crucial for physicians to know the dangers of ‘natural’ treatments and to communicate the risks to patients effectively.”
Dr Taylor and her colleagues investigated the use of St. John’s wort and reported their findings in The Journal of Alternative and Complementary Medicine.
To determine how often the supplement was being prescribed or taken with other medications, the researchers conducted a retrospective analysis of nationally representative data collected by the National Ambulatory Medical Care Survey from 1993 to 2010.
The team found the use of St. John’s wort in potentially harmful combinations in 28% of the cases reviewed. The drugs involved were warfarin, selective serotonin reuptake inhibitors, benzodiazepines, statins, verapamil, digoxin, and oral contraceptives.
Possible drug interactions include serotonin syndrome (a potentially fatal condition that causes high levels of the chemical serotonin to accumulate in the body), heart disease due to impaired efficacy of blood pressure medications, or unplanned pregnancy due to contraceptive failure, Dr Taylor said.
A key limitation of this study is that only medications recorded by the physician were analyzed. And Dr Taylor said the rate of St. John’s wort interactions may actually be underestimated because the database did not include patients who were using St. John’s wort but did not tell their doctor.
“Labeling requirements for helpful supplements such as St. John’s wort need to provide appropriate cautions and risk information,” Dr Taylor said, adding that France has banned the use of St. John’s wort products, and several other countries, including Japan, the UK, and Canada, are in the process of including drug-herb interaction warnings on St. John’s wort products.
“Doctors also need to be trained to always ask if the patient is taking any supplements, vitamins, minerals or herbs, especially before prescribing any of the common drugs that might interact with St. John’s wort.”
FISH may help predict survival in ALCL
Researchers have discovered 3 subgroups of ALK-negative anaplastic large-cell lymphoma (ALCL) that have markedly different survival rates, according to a paper published in Blood.
They found that ALCL patients with TP63 rearrangements had a 17% chance of living 5 years beyond diagnosis, compared to 90% of patients who had DUSP22 rearrangements.
A third group of patients, those with neither rearrangement, had a 42% survival rate.
The researchers noted that these subgroups cannot be differentiated by routine pathology but can be identified via fluorescence in situ hybridization (FISH).
“This is the first study to demonstrate unequivocal genetic and clinical heterogeneity among systemic ALK-negative anaplastic large-cell lymphomas,” said study author Andrew L. Feldman, MD, of the Mayo Clinic in Rochester, Minnesota.
“Most strikingly, patients with DUSP22-rearranged ALCL had excellent overall survival rates, while patients with TP63-rearranged ALCL had dismal outcomes and nearly always failed standard therapy.”
Currently, all ALK-negative ALCLs are treated the same, using chemotherapy and, in some institutions, stem cell transplantation. But these new findings make a case for additional testing and possible changes to the standard of care.
“This is a great example of where individualized medicine can make a difference,” Dr Feldman said. “Patients whose chance of surviving is 1 in 6 are receiving the same therapy as patients whose odds are 9 in 10. Developing tests that identify how tumors are different is a critical step toward being able to tailor therapy to each individual patient.”
Therefore, Dr Feldman and his colleagues recommend performing FISH in all patients with ALK-negative ALCL.
To learn more about testing for DUSP22 and TP63:
- 6p25.3 FISH (DUSP22/IRF4): http://www.mayomedicallaboratories.com/test-catalog/Overview/60506
- 3q28 FISH (TP63): http://www.mayomedicallaboratories.com/test-catalog/Overview/70014.
Researchers have discovered 3 subgroups of ALK-negative anaplastic large-cell lymphoma (ALCL) that have markedly different survival rates, according to a paper published in Blood.
They found that ALCL patients with TP63 rearrangements had a 17% chance of living 5 years beyond diagnosis, compared to 90% of patients who had DUSP22 rearrangements.
A third group of patients, those with neither rearrangement, had a 42% survival rate.
The researchers noted that these subgroups cannot be differentiated by routine pathology but can be identified via fluorescence in situ hybridization (FISH).
“This is the first study to demonstrate unequivocal genetic and clinical heterogeneity among systemic ALK-negative anaplastic large-cell lymphomas,” said study author Andrew L. Feldman, MD, of the Mayo Clinic in Rochester, Minnesota.
“Most strikingly, patients with DUSP22-rearranged ALCL had excellent overall survival rates, while patients with TP63-rearranged ALCL had dismal outcomes and nearly always failed standard therapy.”
Currently, all ALK-negative ALCLs are treated the same, using chemotherapy and, in some institutions, stem cell transplantation. But these new findings make a case for additional testing and possible changes to the standard of care.
“This is a great example of where individualized medicine can make a difference,” Dr Feldman said. “Patients whose chance of surviving is 1 in 6 are receiving the same therapy as patients whose odds are 9 in 10. Developing tests that identify how tumors are different is a critical step toward being able to tailor therapy to each individual patient.”
Therefore, Dr Feldman and his colleagues recommend performing FISH in all patients with ALK-negative ALCL.
To learn more about testing for DUSP22 and TP63:
- 6p25.3 FISH (DUSP22/IRF4): http://www.mayomedicallaboratories.com/test-catalog/Overview/60506
- 3q28 FISH (TP63): http://www.mayomedicallaboratories.com/test-catalog/Overview/70014.
Researchers have discovered 3 subgroups of ALK-negative anaplastic large-cell lymphoma (ALCL) that have markedly different survival rates, according to a paper published in Blood.
They found that ALCL patients with TP63 rearrangements had a 17% chance of living 5 years beyond diagnosis, compared to 90% of patients who had DUSP22 rearrangements.
A third group of patients, those with neither rearrangement, had a 42% survival rate.
The researchers noted that these subgroups cannot be differentiated by routine pathology but can be identified via fluorescence in situ hybridization (FISH).
“This is the first study to demonstrate unequivocal genetic and clinical heterogeneity among systemic ALK-negative anaplastic large-cell lymphomas,” said study author Andrew L. Feldman, MD, of the Mayo Clinic in Rochester, Minnesota.
“Most strikingly, patients with DUSP22-rearranged ALCL had excellent overall survival rates, while patients with TP63-rearranged ALCL had dismal outcomes and nearly always failed standard therapy.”
Currently, all ALK-negative ALCLs are treated the same, using chemotherapy and, in some institutions, stem cell transplantation. But these new findings make a case for additional testing and possible changes to the standard of care.
“This is a great example of where individualized medicine can make a difference,” Dr Feldman said. “Patients whose chance of surviving is 1 in 6 are receiving the same therapy as patients whose odds are 9 in 10. Developing tests that identify how tumors are different is a critical step toward being able to tailor therapy to each individual patient.”
Therefore, Dr Feldman and his colleagues recommend performing FISH in all patients with ALK-negative ALCL.
To learn more about testing for DUSP22 and TP63:
- 6p25.3 FISH (DUSP22/IRF4): http://www.mayomedicallaboratories.com/test-catalog/Overview/60506
- 3q28 FISH (TP63): http://www.mayomedicallaboratories.com/test-catalog/Overview/70014.
Mosquitos can sniff out malaria-infected mice
Credit: James Gathany
Scientists have found evidence to suggest that malaria parasites change the body odor of their host to attract hungry mosquitos.
The team observed an increase in mosquito attraction to malaria-infected mice, compared to healthy controls.
And the infected mice exhibited elevations in certain components of their natural scent, which suggests the malaria parasite changes the characteristics of its host’s body odor to make the host more attractive to mosquitos.
These findings appear in Proceedings of the National Academy of Sciences.
The researchers found that mice infected with Plasmodium chabaudii were more attractive to Anopheles stephensi mosquitos than uninfected control mice. And the attraction corresponded to an overall elevation in scent emissions from the infected mice.
However, malaria infection did not appear to trigger the expression of unique scent components. Instead, it seems the malaria pathogens alter the levels of compounds already present in the scent of uninfected mice.
“There appears to be an overall elevation of several compounds that are attractive to mosquitos,” said study author Consuelo De Moraes, PhD, of the Swiss Federal Institute of Technology in Zürich (ETH Zürich).
“Since mosquitos probably don’t benefit from feeding on infected people, it may make sense for the pathogen to exaggerate existing odor cues that the insects are already using for host location,” added study author Mark Mescher, PhD, also of ETH Zürich.
What the researchers found most surprising is the fact that the malaria infection leaves its mark on body odor long-term. Even when infected mice no longer had symptoms, their body odor showed they were carriers of the pathogen.
However, not all stages of disease smelled the same. The team found the scent profile of the acutely ill differed from the profile in mice exhibiting later stages of malaria infection.
Although the findings from this study cannot be directly translated to human malaria, they suggest similar effects might be involved in the attraction of mosquitos to infected people. Drs Mescher and De Moraes are currently investigating this possibility through additional research involving human subjects in Africa.
Credit: James Gathany
Scientists have found evidence to suggest that malaria parasites change the body odor of their host to attract hungry mosquitos.
The team observed an increase in mosquito attraction to malaria-infected mice, compared to healthy controls.
And the infected mice exhibited elevations in certain components of their natural scent, which suggests the malaria parasite changes the characteristics of its host’s body odor to make the host more attractive to mosquitos.
These findings appear in Proceedings of the National Academy of Sciences.
The researchers found that mice infected with Plasmodium chabaudii were more attractive to Anopheles stephensi mosquitos than uninfected control mice. And the attraction corresponded to an overall elevation in scent emissions from the infected mice.
However, malaria infection did not appear to trigger the expression of unique scent components. Instead, it seems the malaria pathogens alter the levels of compounds already present in the scent of uninfected mice.
“There appears to be an overall elevation of several compounds that are attractive to mosquitos,” said study author Consuelo De Moraes, PhD, of the Swiss Federal Institute of Technology in Zürich (ETH Zürich).
“Since mosquitos probably don’t benefit from feeding on infected people, it may make sense for the pathogen to exaggerate existing odor cues that the insects are already using for host location,” added study author Mark Mescher, PhD, also of ETH Zürich.
What the researchers found most surprising is the fact that the malaria infection leaves its mark on body odor long-term. Even when infected mice no longer had symptoms, their body odor showed they were carriers of the pathogen.
However, not all stages of disease smelled the same. The team found the scent profile of the acutely ill differed from the profile in mice exhibiting later stages of malaria infection.
Although the findings from this study cannot be directly translated to human malaria, they suggest similar effects might be involved in the attraction of mosquitos to infected people. Drs Mescher and De Moraes are currently investigating this possibility through additional research involving human subjects in Africa.
Credit: James Gathany
Scientists have found evidence to suggest that malaria parasites change the body odor of their host to attract hungry mosquitos.
The team observed an increase in mosquito attraction to malaria-infected mice, compared to healthy controls.
And the infected mice exhibited elevations in certain components of their natural scent, which suggests the malaria parasite changes the characteristics of its host’s body odor to make the host more attractive to mosquitos.
These findings appear in Proceedings of the National Academy of Sciences.
The researchers found that mice infected with Plasmodium chabaudii were more attractive to Anopheles stephensi mosquitos than uninfected control mice. And the attraction corresponded to an overall elevation in scent emissions from the infected mice.
However, malaria infection did not appear to trigger the expression of unique scent components. Instead, it seems the malaria pathogens alter the levels of compounds already present in the scent of uninfected mice.
“There appears to be an overall elevation of several compounds that are attractive to mosquitos,” said study author Consuelo De Moraes, PhD, of the Swiss Federal Institute of Technology in Zürich (ETH Zürich).
“Since mosquitos probably don’t benefit from feeding on infected people, it may make sense for the pathogen to exaggerate existing odor cues that the insects are already using for host location,” added study author Mark Mescher, PhD, also of ETH Zürich.
What the researchers found most surprising is the fact that the malaria infection leaves its mark on body odor long-term. Even when infected mice no longer had symptoms, their body odor showed they were carriers of the pathogen.
However, not all stages of disease smelled the same. The team found the scent profile of the acutely ill differed from the profile in mice exhibiting later stages of malaria infection.
Although the findings from this study cannot be directly translated to human malaria, they suggest similar effects might be involved in the attraction of mosquitos to infected people. Drs Mescher and De Moraes are currently investigating this possibility through additional research involving human subjects in Africa.
Study validates drug’s efficacy in CLL/SLL
MILAN—Results of the phase 3 RESONATE trial suggest ibrutinib can improve response and survival rates in patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), when compared to ofatumumab.
Ibrutinib conferred these benefits irrespective of baseline clinical characteristics or molecular features, including 17p deletion.
Atrial fibrillation and bleeding-related events were more common with ibrutinib. But the rate of serious adverse events was similar between the treatment arms.
About 86% of patients remained on ibrutinib at last analysis, and roughly 29% of patients initially randomized to ofatumumab crossed over to the ibrutinib arm after disease progression.
“This study undoubtedly confirms that ibrutinib is a very effective agent—as a single-agent—in relapsed CLL patients,” said investigator Peter Hillmen, MD, PhD, of The Leeds Teaching Hospitals in the UK.
Dr Hillmen presented these results at the 19th Congress of the European Hematology Association (EHA) as abstract S693. The RESONATE trial was sponsored by Pharmacyclics and Janssen, the companies developing ibrutinib.
The trial included 391 patients with relapsed or refractory CLL/SLL. They were randomized to receive oral ibrutinib at 420 mg once daily until progression or unacceptable toxicity (n=195) or intravenous ofatumumab at an initial dose of 300 mg, followed by 11 doses of 2000 mg (n=196). Patients in the ofatumumab arm were allowed to cross over to ibrutinib if they progressed (n=57).
The median age in both treatment arms was 67. Overall, roughly 50% of patients had received 3 or more prior therapies, including purine analogs, alkylating agents, and anti-CD20 antibodies. The proportion of patients with del17p was similar between the treatment arms—32% in the ibrutinib arm and 33% in the ofatumumab arm.
Response and survival
At the time of interim analysis, patients’ median time on study was 9.4 months. The best overall response among evaluable patients was 78% in the ibrutinib arm and 11% in the ofatumumab arm, according to an independent review committee.
In addition, ibrutinib significantly prolonged progression-free survival (PFS). The median PFS was 8.1 months in the ofatumumab arm and was not reached in the ibrutinib arm (P<0.0001). The improvement in PFS represents a 78% reduction in the risk of progression or death.
Dr Hillmen noted that PFS favored ibrutinib regardless of baseline characteristics such as refractoriness to purine analogs, del17p, age, gender, Rai stage, bulky disease, number of prior treatments, del11q, B2 microglobulin, and IgVH mutation status.
Ibrutinib significantly prolonged overall survival (OS) as well. The median OS was not reached in either arm, but the hazard ratio was 0.434 (P=0.0049). The improvement in OS represents a 56% reduction in the risk of death in patients treated with ibrutinib.
Adverse events
Dr Hillmen pointed out that the median treatment duration was 8.6 months for ibrutinib and 5.3 months for ofatumumab, and this difference confounds the assessment of side effects.
Nevertheless, nearly all patients in both treatment arms experienced adverse events—99% in the ibrutinib arm and 98% in the ofatumumab arm. Grade 3/4 events occurred in 51% and 39% of patients, respectively.
Atrial fibrillation of any grade was more common in the ibrutinib arm (n=10) than in the ofatumumab arm (n=1), but 5 of the ibrutinib-treated patients had a prior history of atrial fibrillation. Bleeding-related events were also more common with ibrutinib (44% vs 12%), as were diarrhea (48% vs 18%) and arthralgia (17% vs 7%).
Events more common in the ofatumumab arm included infusion-related reactions (28% vs 0%), peripheral sensory neuropathy (13% vs 4%), urticaria (6% vs 1%), night sweats (13% vs 5%), and pruritus (9% vs 4%).
MILAN—Results of the phase 3 RESONATE trial suggest ibrutinib can improve response and survival rates in patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), when compared to ofatumumab.
Ibrutinib conferred these benefits irrespective of baseline clinical characteristics or molecular features, including 17p deletion.
Atrial fibrillation and bleeding-related events were more common with ibrutinib. But the rate of serious adverse events was similar between the treatment arms.
About 86% of patients remained on ibrutinib at last analysis, and roughly 29% of patients initially randomized to ofatumumab crossed over to the ibrutinib arm after disease progression.
“This study undoubtedly confirms that ibrutinib is a very effective agent—as a single-agent—in relapsed CLL patients,” said investigator Peter Hillmen, MD, PhD, of The Leeds Teaching Hospitals in the UK.
Dr Hillmen presented these results at the 19th Congress of the European Hematology Association (EHA) as abstract S693. The RESONATE trial was sponsored by Pharmacyclics and Janssen, the companies developing ibrutinib.
The trial included 391 patients with relapsed or refractory CLL/SLL. They were randomized to receive oral ibrutinib at 420 mg once daily until progression or unacceptable toxicity (n=195) or intravenous ofatumumab at an initial dose of 300 mg, followed by 11 doses of 2000 mg (n=196). Patients in the ofatumumab arm were allowed to cross over to ibrutinib if they progressed (n=57).
The median age in both treatment arms was 67. Overall, roughly 50% of patients had received 3 or more prior therapies, including purine analogs, alkylating agents, and anti-CD20 antibodies. The proportion of patients with del17p was similar between the treatment arms—32% in the ibrutinib arm and 33% in the ofatumumab arm.
Response and survival
At the time of interim analysis, patients’ median time on study was 9.4 months. The best overall response among evaluable patients was 78% in the ibrutinib arm and 11% in the ofatumumab arm, according to an independent review committee.
In addition, ibrutinib significantly prolonged progression-free survival (PFS). The median PFS was 8.1 months in the ofatumumab arm and was not reached in the ibrutinib arm (P<0.0001). The improvement in PFS represents a 78% reduction in the risk of progression or death.
Dr Hillmen noted that PFS favored ibrutinib regardless of baseline characteristics such as refractoriness to purine analogs, del17p, age, gender, Rai stage, bulky disease, number of prior treatments, del11q, B2 microglobulin, and IgVH mutation status.
Ibrutinib significantly prolonged overall survival (OS) as well. The median OS was not reached in either arm, but the hazard ratio was 0.434 (P=0.0049). The improvement in OS represents a 56% reduction in the risk of death in patients treated with ibrutinib.
Adverse events
Dr Hillmen pointed out that the median treatment duration was 8.6 months for ibrutinib and 5.3 months for ofatumumab, and this difference confounds the assessment of side effects.
Nevertheless, nearly all patients in both treatment arms experienced adverse events—99% in the ibrutinib arm and 98% in the ofatumumab arm. Grade 3/4 events occurred in 51% and 39% of patients, respectively.
Atrial fibrillation of any grade was more common in the ibrutinib arm (n=10) than in the ofatumumab arm (n=1), but 5 of the ibrutinib-treated patients had a prior history of atrial fibrillation. Bleeding-related events were also more common with ibrutinib (44% vs 12%), as were diarrhea (48% vs 18%) and arthralgia (17% vs 7%).
Events more common in the ofatumumab arm included infusion-related reactions (28% vs 0%), peripheral sensory neuropathy (13% vs 4%), urticaria (6% vs 1%), night sweats (13% vs 5%), and pruritus (9% vs 4%).
MILAN—Results of the phase 3 RESONATE trial suggest ibrutinib can improve response and survival rates in patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), when compared to ofatumumab.
Ibrutinib conferred these benefits irrespective of baseline clinical characteristics or molecular features, including 17p deletion.
Atrial fibrillation and bleeding-related events were more common with ibrutinib. But the rate of serious adverse events was similar between the treatment arms.
About 86% of patients remained on ibrutinib at last analysis, and roughly 29% of patients initially randomized to ofatumumab crossed over to the ibrutinib arm after disease progression.
“This study undoubtedly confirms that ibrutinib is a very effective agent—as a single-agent—in relapsed CLL patients,” said investigator Peter Hillmen, MD, PhD, of The Leeds Teaching Hospitals in the UK.
Dr Hillmen presented these results at the 19th Congress of the European Hematology Association (EHA) as abstract S693. The RESONATE trial was sponsored by Pharmacyclics and Janssen, the companies developing ibrutinib.
The trial included 391 patients with relapsed or refractory CLL/SLL. They were randomized to receive oral ibrutinib at 420 mg once daily until progression or unacceptable toxicity (n=195) or intravenous ofatumumab at an initial dose of 300 mg, followed by 11 doses of 2000 mg (n=196). Patients in the ofatumumab arm were allowed to cross over to ibrutinib if they progressed (n=57).
The median age in both treatment arms was 67. Overall, roughly 50% of patients had received 3 or more prior therapies, including purine analogs, alkylating agents, and anti-CD20 antibodies. The proportion of patients with del17p was similar between the treatment arms—32% in the ibrutinib arm and 33% in the ofatumumab arm.
Response and survival
At the time of interim analysis, patients’ median time on study was 9.4 months. The best overall response among evaluable patients was 78% in the ibrutinib arm and 11% in the ofatumumab arm, according to an independent review committee.
In addition, ibrutinib significantly prolonged progression-free survival (PFS). The median PFS was 8.1 months in the ofatumumab arm and was not reached in the ibrutinib arm (P<0.0001). The improvement in PFS represents a 78% reduction in the risk of progression or death.
Dr Hillmen noted that PFS favored ibrutinib regardless of baseline characteristics such as refractoriness to purine analogs, del17p, age, gender, Rai stage, bulky disease, number of prior treatments, del11q, B2 microglobulin, and IgVH mutation status.
Ibrutinib significantly prolonged overall survival (OS) as well. The median OS was not reached in either arm, but the hazard ratio was 0.434 (P=0.0049). The improvement in OS represents a 56% reduction in the risk of death in patients treated with ibrutinib.
Adverse events
Dr Hillmen pointed out that the median treatment duration was 8.6 months for ibrutinib and 5.3 months for ofatumumab, and this difference confounds the assessment of side effects.
Nevertheless, nearly all patients in both treatment arms experienced adverse events—99% in the ibrutinib arm and 98% in the ofatumumab arm. Grade 3/4 events occurred in 51% and 39% of patients, respectively.
Atrial fibrillation of any grade was more common in the ibrutinib arm (n=10) than in the ofatumumab arm (n=1), but 5 of the ibrutinib-treated patients had a prior history of atrial fibrillation. Bleeding-related events were also more common with ibrutinib (44% vs 12%), as were diarrhea (48% vs 18%) and arthralgia (17% vs 7%).
Events more common in the ofatumumab arm included infusion-related reactions (28% vs 0%), peripheral sensory neuropathy (13% vs 4%), urticaria (6% vs 1%), night sweats (13% vs 5%), and pruritus (9% vs 4%).
Quality Initiatives Earn Low Marks
More than 70% of people who responded to a survey at The-Hospitalist.org had a negative opinion about how local and national quality initiatives (QI) have impacted their ability to care for hospitalized patients.
Survey respondents were asked to gauge the effectiveness of core measures, Physician Quality Reporting System (PQRS) reporting, and clinical reminders. A combined 38% of respondents said that QI measures produced little benefit for their patients or rarely addressed patients' acute issues. Another 21% of respondents labeled QI measures as "distractions," and 12% said QI measures affected their productivity.
Only 28% of respondents thought that QI have improved inpatient care, just 2% more than those who found "little benefit" to them (26%), indicating that 54% of respondents were nearly evenly split on whether QI measures directly benefit patients.
Felix Aguirre, MD, FHM, vice president of medical affairs for IPC: The Hospitalist Company and a member of SHM's Performance Measurement and Reporting Committee (PMRC), says while certain core measures, such as PQRS reporting, may not address the specific needs of all hospital patients, it does not make them unsuccessful.
"I think measures do improve care, even if it's not for my patients, [then] for the global population of patients," Dr. Aguirre says. "We're not moving the needle quickly by treating my patients; we're moving the needle slowly, but surely, by treating all patients."
PMRC chair Gregory B. Seymann, MD, SFHM, clinical professor and chief of the division of hospital medicine at University of California San Diego Health Sciences, says the variety of QI measures included in the survey may explain the difference in opinions.
"There are multiple different practice arrangements among the general population of hospitalists and thus many different ways an individual respondent might interact with the measures," Dr. Seymann says. TH
Visit our website for more information on quality initiatives.
More than 70% of people who responded to a survey at The-Hospitalist.org had a negative opinion about how local and national quality initiatives (QI) have impacted their ability to care for hospitalized patients.
Survey respondents were asked to gauge the effectiveness of core measures, Physician Quality Reporting System (PQRS) reporting, and clinical reminders. A combined 38% of respondents said that QI measures produced little benefit for their patients or rarely addressed patients' acute issues. Another 21% of respondents labeled QI measures as "distractions," and 12% said QI measures affected their productivity.
Only 28% of respondents thought that QI have improved inpatient care, just 2% more than those who found "little benefit" to them (26%), indicating that 54% of respondents were nearly evenly split on whether QI measures directly benefit patients.
Felix Aguirre, MD, FHM, vice president of medical affairs for IPC: The Hospitalist Company and a member of SHM's Performance Measurement and Reporting Committee (PMRC), says while certain core measures, such as PQRS reporting, may not address the specific needs of all hospital patients, it does not make them unsuccessful.
"I think measures do improve care, even if it's not for my patients, [then] for the global population of patients," Dr. Aguirre says. "We're not moving the needle quickly by treating my patients; we're moving the needle slowly, but surely, by treating all patients."
PMRC chair Gregory B. Seymann, MD, SFHM, clinical professor and chief of the division of hospital medicine at University of California San Diego Health Sciences, says the variety of QI measures included in the survey may explain the difference in opinions.
"There are multiple different practice arrangements among the general population of hospitalists and thus many different ways an individual respondent might interact with the measures," Dr. Seymann says. TH
Visit our website for more information on quality initiatives.
More than 70% of people who responded to a survey at The-Hospitalist.org had a negative opinion about how local and national quality initiatives (QI) have impacted their ability to care for hospitalized patients.
Survey respondents were asked to gauge the effectiveness of core measures, Physician Quality Reporting System (PQRS) reporting, and clinical reminders. A combined 38% of respondents said that QI measures produced little benefit for their patients or rarely addressed patients' acute issues. Another 21% of respondents labeled QI measures as "distractions," and 12% said QI measures affected their productivity.
Only 28% of respondents thought that QI have improved inpatient care, just 2% more than those who found "little benefit" to them (26%), indicating that 54% of respondents were nearly evenly split on whether QI measures directly benefit patients.
Felix Aguirre, MD, FHM, vice president of medical affairs for IPC: The Hospitalist Company and a member of SHM's Performance Measurement and Reporting Committee (PMRC), says while certain core measures, such as PQRS reporting, may not address the specific needs of all hospital patients, it does not make them unsuccessful.
"I think measures do improve care, even if it's not for my patients, [then] for the global population of patients," Dr. Aguirre says. "We're not moving the needle quickly by treating my patients; we're moving the needle slowly, but surely, by treating all patients."
PMRC chair Gregory B. Seymann, MD, SFHM, clinical professor and chief of the division of hospital medicine at University of California San Diego Health Sciences, says the variety of QI measures included in the survey may explain the difference in opinions.
"There are multiple different practice arrangements among the general population of hospitalists and thus many different ways an individual respondent might interact with the measures," Dr. Seymann says. TH
Visit our website for more information on quality initiatives.
Inhaled Corticosteroids Increase Risk of Serious Pneumonia in Patients with COPD
Clinical question: Does the risk of pneumonia vary for different inhaled agents?
Background: Inhaled corticosteroids (ICS) are known to increase the risk of pneumonia in COPD patients; duration, dosage, and various agents, especially fluticasone and budesonide, were investigated.
Study design: Nested, case-control analysis.
Setting: Quebec health insurance database for new users with COPD, 1990–2005, with follow-up through 2007.
Synopsis: Investigators analyzed 163,514 patients, including 20,344 patients with serious pneumonia; current use of ICS was associated with a 69% increase in the rate of serious pneumonia (RR 1.69; 95% CI 1.63-1.75). The increased risk was sustained with long-term use but declined gradually to zero at six months after stopping ICS. The risk of serious pneumonia was higher with fluticasone (RR 2.01; 95% CI 1.93-2.10) than budesonide (RR 1.17; 95% CI 1.09-1.26).
Bottom line: Fluticasone was associated with an increased risk of pneumonia in COPD patients, consistent with earlier clinical trials, but the risk with budesonide was much lower.
Citation: Suissa S, Patenaude V, Lapi F, Ernst P. Inhaled corticosteroids in COPD and the risk of serious pneumonia. Thorax. 2013;68(11):1029-1036.
Clinical question: Does the risk of pneumonia vary for different inhaled agents?
Background: Inhaled corticosteroids (ICS) are known to increase the risk of pneumonia in COPD patients; duration, dosage, and various agents, especially fluticasone and budesonide, were investigated.
Study design: Nested, case-control analysis.
Setting: Quebec health insurance database for new users with COPD, 1990–2005, with follow-up through 2007.
Synopsis: Investigators analyzed 163,514 patients, including 20,344 patients with serious pneumonia; current use of ICS was associated with a 69% increase in the rate of serious pneumonia (RR 1.69; 95% CI 1.63-1.75). The increased risk was sustained with long-term use but declined gradually to zero at six months after stopping ICS. The risk of serious pneumonia was higher with fluticasone (RR 2.01; 95% CI 1.93-2.10) than budesonide (RR 1.17; 95% CI 1.09-1.26).
Bottom line: Fluticasone was associated with an increased risk of pneumonia in COPD patients, consistent with earlier clinical trials, but the risk with budesonide was much lower.
Citation: Suissa S, Patenaude V, Lapi F, Ernst P. Inhaled corticosteroids in COPD and the risk of serious pneumonia. Thorax. 2013;68(11):1029-1036.
Clinical question: Does the risk of pneumonia vary for different inhaled agents?
Background: Inhaled corticosteroids (ICS) are known to increase the risk of pneumonia in COPD patients; duration, dosage, and various agents, especially fluticasone and budesonide, were investigated.
Study design: Nested, case-control analysis.
Setting: Quebec health insurance database for new users with COPD, 1990–2005, with follow-up through 2007.
Synopsis: Investigators analyzed 163,514 patients, including 20,344 patients with serious pneumonia; current use of ICS was associated with a 69% increase in the rate of serious pneumonia (RR 1.69; 95% CI 1.63-1.75). The increased risk was sustained with long-term use but declined gradually to zero at six months after stopping ICS. The risk of serious pneumonia was higher with fluticasone (RR 2.01; 95% CI 1.93-2.10) than budesonide (RR 1.17; 95% CI 1.09-1.26).
Bottom line: Fluticasone was associated with an increased risk of pneumonia in COPD patients, consistent with earlier clinical trials, but the risk with budesonide was much lower.
Citation: Suissa S, Patenaude V, Lapi F, Ernst P. Inhaled corticosteroids in COPD and the risk of serious pneumonia. Thorax. 2013;68(11):1029-1036.
New clinical practice guidelines on pheochromocytomas
CHICAGO – Genetic testing has jumped to the fore in the management of patients diagnosed as having a pheochromocytoma or paraganglioma, according to new clinical practice guidelines released by the Endocrine Society.
Indeed, the new guidelines call for genetic testing to be considered seriously in all patients with a proven pheochromocytoma or paraganglioma (PPGL), Dr. Jacques W. M. Lenders said in presenting highlights of the new guidelines at the joint meeting of the International Congress of Endocrinology and the Endocrine Society.
"We recommend that all patients with PPGLs should be engaged in shared decision making for genetic testing. I don’t say that we should do genetic testing in everybody, but we should consider it and engage the patient in the final decision," said Dr. Lenders, who chaired the practice guidelines task force.
The strong emphasis on genetic testing arises from evidence that roughly one-third of all PPGLs are associated with germline mutations. Moreover, susceptibility mutations are present in 12% of patients with absolutely no suggestion of a positive family history. Some of these mutations – for example, those involving succinate dehydrogenase B (SDHB) – are associated with a high risk of metastasis and unfavorable prognosis. Thus, gene-testing results can have a major impact on patients with PPGL as well as their relatives.
Nonetheless, genetic testing in patients with PPGLs remains controversial.
"I must say, we on the guideline task force spent considerable time on what and how to do it," said Dr. Lenders, who is professor and deputy chair of internal medicine at Radboud University in Nijmegen, the Netherlands.
Since simultaneous testing for all the known culprit genes remains for now too expensive to be cost effective, the guidelines include a clinical feature–driven decisional algorithm designed to establish the priorities for genetic testing in a given patient with proven PPGL.
For example, patients with a metastatic PPGL should be tested for SDHB mutations, while those with a paraganglioma should undergo testing for succinate dehydrogenase mutations, according to the guidelines, published in full in concert with ICE/ENDO 2014 (J. Clin. Endocrinol. Metab. 2014;1915-42).
Dr. Lenders noted that PPGLs are uncommon tumors. It is estimated that 0.1%-1% of patients being treated for hypertension have pheochromocytomas, which are adrenal tumors resulting in excess production of epinephrine and norepinephrine. Symptoms can include paroxysmal severe headache, tachycardia, anxiety, and excessive sweating, along with tough-to-control hypertension.
While pheochromocytomas are typically benign, malignant transformation occurs in up to 17% of cases. And although a complete cure is often possible with timely therapy, the fact is that on average a 3-year delay transpires between symptomatic presentation and diagnosis of PPGL. Also, studies show that failure to appropriately follow up on a positive biochemical test is common in clinical practice; as a consequence, PPGLs are often overdiagnosed. For these reasons, Endocrine Society officials deemed PPGLs a priority area in need of practice guidelines.
In addition to routine consideration of genetic testing, other recommendations include:
• Diagnostic biochemical testing: Initial testing should include measurement of plasma free or urinary fractionated metanephrines, preferably using liquid chromatography with electrochemical or mass spectrometric laboratory methods. Immunoassays, although popular in Europe, haven’t yet been adequately validated. In measuring plasma metanephrines, the blood draw should be done with the patient in supine position, using reference standards established in the same position.
"False-positive test results are a major problem in daily clinical practice, and they outweigh by far the number of true-positive test results. That’s very important to realize," the endocrinologist said.
One common cause of false-positive test results are medications that trigger elevated metanephrine levels, according to guideline panelist Dr. William F. Young Jr., professor of medicine and chair of the department of endocrinology, diabetes, metabolism and nutrition at the Mayo Clinic, Rochester, Minn. The top three offending drugs in his experience are tricyclic antidepressants, antipsychotic agents, and levodopa. The guidelines list others, he added.
• Imaging: Once clear biochemical evidence of a PPGL is established, CT is preferred over MRI in order to locate the tumor because of its superior spatial resolution in the thorax, abdomen, and pelvis. 18F-fluorodeoxyglucose positron emission tomography/CT scanning is preferred over 123I-metaiodobenzylguanidine (MIBG) scintigraphy in patients with known metastatic PPGL. 123I-MIBG is best reserved for functional imaging in patients with metastatic PPGL who are being considered for radiotherapy using 131I-MIBG, in patients with an unusually large primary tumor, and in other special circumstances.
• Perioperative medical management: Preoperative blockade with an alpha-adrenergic–receptor blocker beginning 7-14 days before surgery is recommended together with a high-sodium diet and increased fluid intake as the best means of reducing the risk of perioperative cardiovascular problems.
• Surgery: Minimally invasive adrenalectomy is appropriate for most pheochromocytomas; open resection is best reserved for those tumors which are invasive or greater than 6 cm in size. The guidelines recommend open resection for paragangliomas, although laparoscopic surgery is described as reasonable for those which are small, noninvasive, and favorably located. Partial adrenalectomy is advised for patients with a hereditary pheochromocytoma and in other special circumstances.
• Team approach: Because PPGLs are uncommon, they are best managed by multidisciplinary teams at centers of expertise. That’s particularly important in nonstraightforward cases, such as those involving pregnancy, metastasis, diagnostic uncertainty, or surgical complexity, according to the guideline panelists.
All Endocrine Society clinical practice guidelines are funded by the society without any corporate support. Dr. Lenders reported having no financial conflicts.
CHICAGO – Genetic testing has jumped to the fore in the management of patients diagnosed as having a pheochromocytoma or paraganglioma, according to new clinical practice guidelines released by the Endocrine Society.
Indeed, the new guidelines call for genetic testing to be considered seriously in all patients with a proven pheochromocytoma or paraganglioma (PPGL), Dr. Jacques W. M. Lenders said in presenting highlights of the new guidelines at the joint meeting of the International Congress of Endocrinology and the Endocrine Society.
"We recommend that all patients with PPGLs should be engaged in shared decision making for genetic testing. I don’t say that we should do genetic testing in everybody, but we should consider it and engage the patient in the final decision," said Dr. Lenders, who chaired the practice guidelines task force.
The strong emphasis on genetic testing arises from evidence that roughly one-third of all PPGLs are associated with germline mutations. Moreover, susceptibility mutations are present in 12% of patients with absolutely no suggestion of a positive family history. Some of these mutations – for example, those involving succinate dehydrogenase B (SDHB) – are associated with a high risk of metastasis and unfavorable prognosis. Thus, gene-testing results can have a major impact on patients with PPGL as well as their relatives.
Nonetheless, genetic testing in patients with PPGLs remains controversial.
"I must say, we on the guideline task force spent considerable time on what and how to do it," said Dr. Lenders, who is professor and deputy chair of internal medicine at Radboud University in Nijmegen, the Netherlands.
Since simultaneous testing for all the known culprit genes remains for now too expensive to be cost effective, the guidelines include a clinical feature–driven decisional algorithm designed to establish the priorities for genetic testing in a given patient with proven PPGL.
For example, patients with a metastatic PPGL should be tested for SDHB mutations, while those with a paraganglioma should undergo testing for succinate dehydrogenase mutations, according to the guidelines, published in full in concert with ICE/ENDO 2014 (J. Clin. Endocrinol. Metab. 2014;1915-42).
Dr. Lenders noted that PPGLs are uncommon tumors. It is estimated that 0.1%-1% of patients being treated for hypertension have pheochromocytomas, which are adrenal tumors resulting in excess production of epinephrine and norepinephrine. Symptoms can include paroxysmal severe headache, tachycardia, anxiety, and excessive sweating, along with tough-to-control hypertension.
While pheochromocytomas are typically benign, malignant transformation occurs in up to 17% of cases. And although a complete cure is often possible with timely therapy, the fact is that on average a 3-year delay transpires between symptomatic presentation and diagnosis of PPGL. Also, studies show that failure to appropriately follow up on a positive biochemical test is common in clinical practice; as a consequence, PPGLs are often overdiagnosed. For these reasons, Endocrine Society officials deemed PPGLs a priority area in need of practice guidelines.
In addition to routine consideration of genetic testing, other recommendations include:
• Diagnostic biochemical testing: Initial testing should include measurement of plasma free or urinary fractionated metanephrines, preferably using liquid chromatography with electrochemical or mass spectrometric laboratory methods. Immunoassays, although popular in Europe, haven’t yet been adequately validated. In measuring plasma metanephrines, the blood draw should be done with the patient in supine position, using reference standards established in the same position.
"False-positive test results are a major problem in daily clinical practice, and they outweigh by far the number of true-positive test results. That’s very important to realize," the endocrinologist said.
One common cause of false-positive test results are medications that trigger elevated metanephrine levels, according to guideline panelist Dr. William F. Young Jr., professor of medicine and chair of the department of endocrinology, diabetes, metabolism and nutrition at the Mayo Clinic, Rochester, Minn. The top three offending drugs in his experience are tricyclic antidepressants, antipsychotic agents, and levodopa. The guidelines list others, he added.
• Imaging: Once clear biochemical evidence of a PPGL is established, CT is preferred over MRI in order to locate the tumor because of its superior spatial resolution in the thorax, abdomen, and pelvis. 18F-fluorodeoxyglucose positron emission tomography/CT scanning is preferred over 123I-metaiodobenzylguanidine (MIBG) scintigraphy in patients with known metastatic PPGL. 123I-MIBG is best reserved for functional imaging in patients with metastatic PPGL who are being considered for radiotherapy using 131I-MIBG, in patients with an unusually large primary tumor, and in other special circumstances.
• Perioperative medical management: Preoperative blockade with an alpha-adrenergic–receptor blocker beginning 7-14 days before surgery is recommended together with a high-sodium diet and increased fluid intake as the best means of reducing the risk of perioperative cardiovascular problems.
• Surgery: Minimally invasive adrenalectomy is appropriate for most pheochromocytomas; open resection is best reserved for those tumors which are invasive or greater than 6 cm in size. The guidelines recommend open resection for paragangliomas, although laparoscopic surgery is described as reasonable for those which are small, noninvasive, and favorably located. Partial adrenalectomy is advised for patients with a hereditary pheochromocytoma and in other special circumstances.
• Team approach: Because PPGLs are uncommon, they are best managed by multidisciplinary teams at centers of expertise. That’s particularly important in nonstraightforward cases, such as those involving pregnancy, metastasis, diagnostic uncertainty, or surgical complexity, according to the guideline panelists.
All Endocrine Society clinical practice guidelines are funded by the society without any corporate support. Dr. Lenders reported having no financial conflicts.
CHICAGO – Genetic testing has jumped to the fore in the management of patients diagnosed as having a pheochromocytoma or paraganglioma, according to new clinical practice guidelines released by the Endocrine Society.
Indeed, the new guidelines call for genetic testing to be considered seriously in all patients with a proven pheochromocytoma or paraganglioma (PPGL), Dr. Jacques W. M. Lenders said in presenting highlights of the new guidelines at the joint meeting of the International Congress of Endocrinology and the Endocrine Society.
"We recommend that all patients with PPGLs should be engaged in shared decision making for genetic testing. I don’t say that we should do genetic testing in everybody, but we should consider it and engage the patient in the final decision," said Dr. Lenders, who chaired the practice guidelines task force.
The strong emphasis on genetic testing arises from evidence that roughly one-third of all PPGLs are associated with germline mutations. Moreover, susceptibility mutations are present in 12% of patients with absolutely no suggestion of a positive family history. Some of these mutations – for example, those involving succinate dehydrogenase B (SDHB) – are associated with a high risk of metastasis and unfavorable prognosis. Thus, gene-testing results can have a major impact on patients with PPGL as well as their relatives.
Nonetheless, genetic testing in patients with PPGLs remains controversial.
"I must say, we on the guideline task force spent considerable time on what and how to do it," said Dr. Lenders, who is professor and deputy chair of internal medicine at Radboud University in Nijmegen, the Netherlands.
Since simultaneous testing for all the known culprit genes remains for now too expensive to be cost effective, the guidelines include a clinical feature–driven decisional algorithm designed to establish the priorities for genetic testing in a given patient with proven PPGL.
For example, patients with a metastatic PPGL should be tested for SDHB mutations, while those with a paraganglioma should undergo testing for succinate dehydrogenase mutations, according to the guidelines, published in full in concert with ICE/ENDO 2014 (J. Clin. Endocrinol. Metab. 2014;1915-42).
Dr. Lenders noted that PPGLs are uncommon tumors. It is estimated that 0.1%-1% of patients being treated for hypertension have pheochromocytomas, which are adrenal tumors resulting in excess production of epinephrine and norepinephrine. Symptoms can include paroxysmal severe headache, tachycardia, anxiety, and excessive sweating, along with tough-to-control hypertension.
While pheochromocytomas are typically benign, malignant transformation occurs in up to 17% of cases. And although a complete cure is often possible with timely therapy, the fact is that on average a 3-year delay transpires between symptomatic presentation and diagnosis of PPGL. Also, studies show that failure to appropriately follow up on a positive biochemical test is common in clinical practice; as a consequence, PPGLs are often overdiagnosed. For these reasons, Endocrine Society officials deemed PPGLs a priority area in need of practice guidelines.
In addition to routine consideration of genetic testing, other recommendations include:
• Diagnostic biochemical testing: Initial testing should include measurement of plasma free or urinary fractionated metanephrines, preferably using liquid chromatography with electrochemical or mass spectrometric laboratory methods. Immunoassays, although popular in Europe, haven’t yet been adequately validated. In measuring plasma metanephrines, the blood draw should be done with the patient in supine position, using reference standards established in the same position.
"False-positive test results are a major problem in daily clinical practice, and they outweigh by far the number of true-positive test results. That’s very important to realize," the endocrinologist said.
One common cause of false-positive test results are medications that trigger elevated metanephrine levels, according to guideline panelist Dr. William F. Young Jr., professor of medicine and chair of the department of endocrinology, diabetes, metabolism and nutrition at the Mayo Clinic, Rochester, Minn. The top three offending drugs in his experience are tricyclic antidepressants, antipsychotic agents, and levodopa. The guidelines list others, he added.
• Imaging: Once clear biochemical evidence of a PPGL is established, CT is preferred over MRI in order to locate the tumor because of its superior spatial resolution in the thorax, abdomen, and pelvis. 18F-fluorodeoxyglucose positron emission tomography/CT scanning is preferred over 123I-metaiodobenzylguanidine (MIBG) scintigraphy in patients with known metastatic PPGL. 123I-MIBG is best reserved for functional imaging in patients with metastatic PPGL who are being considered for radiotherapy using 131I-MIBG, in patients with an unusually large primary tumor, and in other special circumstances.
• Perioperative medical management: Preoperative blockade with an alpha-adrenergic–receptor blocker beginning 7-14 days before surgery is recommended together with a high-sodium diet and increased fluid intake as the best means of reducing the risk of perioperative cardiovascular problems.
• Surgery: Minimally invasive adrenalectomy is appropriate for most pheochromocytomas; open resection is best reserved for those tumors which are invasive or greater than 6 cm in size. The guidelines recommend open resection for paragangliomas, although laparoscopic surgery is described as reasonable for those which are small, noninvasive, and favorably located. Partial adrenalectomy is advised for patients with a hereditary pheochromocytoma and in other special circumstances.
• Team approach: Because PPGLs are uncommon, they are best managed by multidisciplinary teams at centers of expertise. That’s particularly important in nonstraightforward cases, such as those involving pregnancy, metastasis, diagnostic uncertainty, or surgical complexity, according to the guideline panelists.
All Endocrine Society clinical practice guidelines are funded by the society without any corporate support. Dr. Lenders reported having no financial conflicts.
AT ICE/ENDO 2014
Frostbite on the Hand of a Homeless Man
To the Editor:
A 58-year-old homeless man presented to the emergency department after being found wandering in the middle of winter in Detroit, Michigan, with altered mental status. A workup for his mental incapacitation uncovered severe electrolyte disturbances, hyperglycemia, and acute renal failure, as well as both alcohol and drug intoxication. After 1 day of admission the patient reported progressive swelling, blistering, and pain in the right hand. The pain was stabbing in nature, worse with movement, and graded 10 of 10 (1=minimal; 10=severe). His medical history was notable for diabetes mellitus with peripheral neuropathy, hypertension, hyperlipidemia, and alcohol and drug abuse. The patient was not taking any medications for these conditions.
Physical examination revealed 2+ moderate pitting edema in all distal extremities, with increased edema of the dorsal aspect of the right hand. The right hand also demonstrated patchy erythema and was warm to touch. The dorsal aspect of the right ring finger had a dusky tip and was studded with several tense blisters (Figure). Vital signs were stable. Based on the patient’s history and physical examination findings, a diagnosis of frostbite was made. Our treatment process involved several modalities including immersion of the affected site in a warm water bath, surgical debridement of blistered sites, tetanus toxoid, penicillin to prevent infection, and oral ibuprofen for pain management. At 3-day follow-up, the patient’s condition substantially improved with a decreased amount of erythema, edema, and pain. All affected sites were successfully preserved with no evidence of focal, motor, or sensory impairment.
Frostbite is a form of localized tissue injury due to extreme cold that most commonly affects the hands and feet, with the greatest incidence occurring in adults aged 30 to 49 years.1,2 Other sites commonly affected include the ears, nose, cheeks, and penis. Frostbite injuries can be categorized into 4 degrees of severity that correlate with the clinical presentation.1,3 Rewarming the affected site is necessary to properly classify the injury, as the initial appearance may be similar among the different degrees of injury. A first-degree injury classically shows a central white plaque with peripheral erythema and is extremely cold to touch. Second-degree injuries display tense blisters filled with clear or milky fluid surrounded by erythema and edema within the first 24 hours. Third-degree injuries are associated with hemorrhagic blisters. Fourth-degree injuries involve complete tissue loss and necrosis.1 Frostbite injuries also may be classified as superficial or deep; the former affects skin and subcutaneous tissue, while the latter affects bones, joints, and tendons.3,4 The superficial form exhibits clear blisters, whereas hemorrhagic blisters demonstrate deep frostbite.
Factors such as the surrounding temperature, length of exposure, and alcohol consumption may exacerbate frostbite injuries.1 Conditions such as atherosclerosis and diabetes mellitus, which can cause neuropathy and peripheral vascular disease, also are potential risks. Psychiatric patients also are at risk for frostbite given the propensity for eccentric behavior as well as the homeless due to inadequate clothing or shelter. Diagnosis often can be made based on medical history and physical examination, though techniques such as radiography, angiography, digital plethysmography, Doppler ultrasonography, and bone scintigraphy (technetium-99) also have been utilized to determine severity and prognosis.2 Differential diagnoses of frostbite are listed in the Table.
Frostbite treatment begins with removal of wet clothing and region protection. Rewarming the site should not begin until refreezing is unlikely to occur and involves placing the injured area in water (temperature, 40°C–42°C) for 15 to 30 minutes to minimize tissue loss.1,2 Analgesics, tetanus toxoid, oral ibuprofen, and benzylpenicillin also are indicated, along with daily hydrotherapy.1,2 White blisters should be debrided, while hemorrhagic blisters should be left intact. Amputation and aggressive debridement typically are delayed until complete ischemia occurs and final demarcation is determined, usually over 1 to 3 months.1 Combination therapy allowed for a positive outcome in our patient.
Frostnip is a mild form of cold injury characterized by localized pain, pallor, and possible numbness.3 Warming the cold area restores the function and sensation with no loss of tissue. Chilblain or pernio refers to a localized cold injury that typically presents as pruritic red-purple papules, macules, plaques, or nodules on the face, anterior tibial surface, or dorsum and tips of the hands and feet.3 The primary cause is repeated exposure to cold, not freezing, temperatures.
Trench foot or cold immersion foot (or hand) is a nonfreezing injury to the hands or feet caused by chronic exposure to wet conditions and temperatures above freezing.3 Painful burning and dysesthesia as well as tissue damage involving edema, blistering, redness, ecchymosis, and ulceration are common. Cellulitis is a bacterial infection of the skin and underlying tissues that can occur anywhere on the body, but the legs are most commonly affected. Typical presentation involves erythema, warmth, swelling, and pain in the infected area.
Although the conditions described above may be considered in the differential diagnosis, physical examination and the patient’s clinical history typically will allow for the distinction of frostbite from these other disease processes.
- Petrone P, Kuncir EJ, Asensio JA. Surgical management and strategies in the treatment of hypothermia and cold injury. Emerg Med Clin North Am. 2003;21:1165-1178.
- Reamy BV. Frostbite: review and current concepts. J Am Board Fam Pract. 1998;11:34-40.
- Jurkovich GJ. Environmental cold-induced injury. Surg Clin North Am. 2007;87:247-267, viii.
- Biem J, Koehncke N, Classen D, et al. Out of the cold: management of hypothermia and frostbite. CMAJ. 2003;168:305-311.
To the Editor:
A 58-year-old homeless man presented to the emergency department after being found wandering in the middle of winter in Detroit, Michigan, with altered mental status. A workup for his mental incapacitation uncovered severe electrolyte disturbances, hyperglycemia, and acute renal failure, as well as both alcohol and drug intoxication. After 1 day of admission the patient reported progressive swelling, blistering, and pain in the right hand. The pain was stabbing in nature, worse with movement, and graded 10 of 10 (1=minimal; 10=severe). His medical history was notable for diabetes mellitus with peripheral neuropathy, hypertension, hyperlipidemia, and alcohol and drug abuse. The patient was not taking any medications for these conditions.
Physical examination revealed 2+ moderate pitting edema in all distal extremities, with increased edema of the dorsal aspect of the right hand. The right hand also demonstrated patchy erythema and was warm to touch. The dorsal aspect of the right ring finger had a dusky tip and was studded with several tense blisters (Figure). Vital signs were stable. Based on the patient’s history and physical examination findings, a diagnosis of frostbite was made. Our treatment process involved several modalities including immersion of the affected site in a warm water bath, surgical debridement of blistered sites, tetanus toxoid, penicillin to prevent infection, and oral ibuprofen for pain management. At 3-day follow-up, the patient’s condition substantially improved with a decreased amount of erythema, edema, and pain. All affected sites were successfully preserved with no evidence of focal, motor, or sensory impairment.
Frostbite is a form of localized tissue injury due to extreme cold that most commonly affects the hands and feet, with the greatest incidence occurring in adults aged 30 to 49 years.1,2 Other sites commonly affected include the ears, nose, cheeks, and penis. Frostbite injuries can be categorized into 4 degrees of severity that correlate with the clinical presentation.1,3 Rewarming the affected site is necessary to properly classify the injury, as the initial appearance may be similar among the different degrees of injury. A first-degree injury classically shows a central white plaque with peripheral erythema and is extremely cold to touch. Second-degree injuries display tense blisters filled with clear or milky fluid surrounded by erythema and edema within the first 24 hours. Third-degree injuries are associated with hemorrhagic blisters. Fourth-degree injuries involve complete tissue loss and necrosis.1 Frostbite injuries also may be classified as superficial or deep; the former affects skin and subcutaneous tissue, while the latter affects bones, joints, and tendons.3,4 The superficial form exhibits clear blisters, whereas hemorrhagic blisters demonstrate deep frostbite.
Factors such as the surrounding temperature, length of exposure, and alcohol consumption may exacerbate frostbite injuries.1 Conditions such as atherosclerosis and diabetes mellitus, which can cause neuropathy and peripheral vascular disease, also are potential risks. Psychiatric patients also are at risk for frostbite given the propensity for eccentric behavior as well as the homeless due to inadequate clothing or shelter. Diagnosis often can be made based on medical history and physical examination, though techniques such as radiography, angiography, digital plethysmography, Doppler ultrasonography, and bone scintigraphy (technetium-99) also have been utilized to determine severity and prognosis.2 Differential diagnoses of frostbite are listed in the Table.
Frostbite treatment begins with removal of wet clothing and region protection. Rewarming the site should not begin until refreezing is unlikely to occur and involves placing the injured area in water (temperature, 40°C–42°C) for 15 to 30 minutes to minimize tissue loss.1,2 Analgesics, tetanus toxoid, oral ibuprofen, and benzylpenicillin also are indicated, along with daily hydrotherapy.1,2 White blisters should be debrided, while hemorrhagic blisters should be left intact. Amputation and aggressive debridement typically are delayed until complete ischemia occurs and final demarcation is determined, usually over 1 to 3 months.1 Combination therapy allowed for a positive outcome in our patient.
Frostnip is a mild form of cold injury characterized by localized pain, pallor, and possible numbness.3 Warming the cold area restores the function and sensation with no loss of tissue. Chilblain or pernio refers to a localized cold injury that typically presents as pruritic red-purple papules, macules, plaques, or nodules on the face, anterior tibial surface, or dorsum and tips of the hands and feet.3 The primary cause is repeated exposure to cold, not freezing, temperatures.
Trench foot or cold immersion foot (or hand) is a nonfreezing injury to the hands or feet caused by chronic exposure to wet conditions and temperatures above freezing.3 Painful burning and dysesthesia as well as tissue damage involving edema, blistering, redness, ecchymosis, and ulceration are common. Cellulitis is a bacterial infection of the skin and underlying tissues that can occur anywhere on the body, but the legs are most commonly affected. Typical presentation involves erythema, warmth, swelling, and pain in the infected area.
Although the conditions described above may be considered in the differential diagnosis, physical examination and the patient’s clinical history typically will allow for the distinction of frostbite from these other disease processes.
To the Editor:
A 58-year-old homeless man presented to the emergency department after being found wandering in the middle of winter in Detroit, Michigan, with altered mental status. A workup for his mental incapacitation uncovered severe electrolyte disturbances, hyperglycemia, and acute renal failure, as well as both alcohol and drug intoxication. After 1 day of admission the patient reported progressive swelling, blistering, and pain in the right hand. The pain was stabbing in nature, worse with movement, and graded 10 of 10 (1=minimal; 10=severe). His medical history was notable for diabetes mellitus with peripheral neuropathy, hypertension, hyperlipidemia, and alcohol and drug abuse. The patient was not taking any medications for these conditions.
Physical examination revealed 2+ moderate pitting edema in all distal extremities, with increased edema of the dorsal aspect of the right hand. The right hand also demonstrated patchy erythema and was warm to touch. The dorsal aspect of the right ring finger had a dusky tip and was studded with several tense blisters (Figure). Vital signs were stable. Based on the patient’s history and physical examination findings, a diagnosis of frostbite was made. Our treatment process involved several modalities including immersion of the affected site in a warm water bath, surgical debridement of blistered sites, tetanus toxoid, penicillin to prevent infection, and oral ibuprofen for pain management. At 3-day follow-up, the patient’s condition substantially improved with a decreased amount of erythema, edema, and pain. All affected sites were successfully preserved with no evidence of focal, motor, or sensory impairment.
Frostbite is a form of localized tissue injury due to extreme cold that most commonly affects the hands and feet, with the greatest incidence occurring in adults aged 30 to 49 years.1,2 Other sites commonly affected include the ears, nose, cheeks, and penis. Frostbite injuries can be categorized into 4 degrees of severity that correlate with the clinical presentation.1,3 Rewarming the affected site is necessary to properly classify the injury, as the initial appearance may be similar among the different degrees of injury. A first-degree injury classically shows a central white plaque with peripheral erythema and is extremely cold to touch. Second-degree injuries display tense blisters filled with clear or milky fluid surrounded by erythema and edema within the first 24 hours. Third-degree injuries are associated with hemorrhagic blisters. Fourth-degree injuries involve complete tissue loss and necrosis.1 Frostbite injuries also may be classified as superficial or deep; the former affects skin and subcutaneous tissue, while the latter affects bones, joints, and tendons.3,4 The superficial form exhibits clear blisters, whereas hemorrhagic blisters demonstrate deep frostbite.
Factors such as the surrounding temperature, length of exposure, and alcohol consumption may exacerbate frostbite injuries.1 Conditions such as atherosclerosis and diabetes mellitus, which can cause neuropathy and peripheral vascular disease, also are potential risks. Psychiatric patients also are at risk for frostbite given the propensity for eccentric behavior as well as the homeless due to inadequate clothing or shelter. Diagnosis often can be made based on medical history and physical examination, though techniques such as radiography, angiography, digital plethysmography, Doppler ultrasonography, and bone scintigraphy (technetium-99) also have been utilized to determine severity and prognosis.2 Differential diagnoses of frostbite are listed in the Table.
Frostbite treatment begins with removal of wet clothing and region protection. Rewarming the site should not begin until refreezing is unlikely to occur and involves placing the injured area in water (temperature, 40°C–42°C) for 15 to 30 minutes to minimize tissue loss.1,2 Analgesics, tetanus toxoid, oral ibuprofen, and benzylpenicillin also are indicated, along with daily hydrotherapy.1,2 White blisters should be debrided, while hemorrhagic blisters should be left intact. Amputation and aggressive debridement typically are delayed until complete ischemia occurs and final demarcation is determined, usually over 1 to 3 months.1 Combination therapy allowed for a positive outcome in our patient.
Frostnip is a mild form of cold injury characterized by localized pain, pallor, and possible numbness.3 Warming the cold area restores the function and sensation with no loss of tissue. Chilblain or pernio refers to a localized cold injury that typically presents as pruritic red-purple papules, macules, plaques, or nodules on the face, anterior tibial surface, or dorsum and tips of the hands and feet.3 The primary cause is repeated exposure to cold, not freezing, temperatures.
Trench foot or cold immersion foot (or hand) is a nonfreezing injury to the hands or feet caused by chronic exposure to wet conditions and temperatures above freezing.3 Painful burning and dysesthesia as well as tissue damage involving edema, blistering, redness, ecchymosis, and ulceration are common. Cellulitis is a bacterial infection of the skin and underlying tissues that can occur anywhere on the body, but the legs are most commonly affected. Typical presentation involves erythema, warmth, swelling, and pain in the infected area.
Although the conditions described above may be considered in the differential diagnosis, physical examination and the patient’s clinical history typically will allow for the distinction of frostbite from these other disease processes.
- Petrone P, Kuncir EJ, Asensio JA. Surgical management and strategies in the treatment of hypothermia and cold injury. Emerg Med Clin North Am. 2003;21:1165-1178.
- Reamy BV. Frostbite: review and current concepts. J Am Board Fam Pract. 1998;11:34-40.
- Jurkovich GJ. Environmental cold-induced injury. Surg Clin North Am. 2007;87:247-267, viii.
- Biem J, Koehncke N, Classen D, et al. Out of the cold: management of hypothermia and frostbite. CMAJ. 2003;168:305-311.
- Petrone P, Kuncir EJ, Asensio JA. Surgical management and strategies in the treatment of hypothermia and cold injury. Emerg Med Clin North Am. 2003;21:1165-1178.
- Reamy BV. Frostbite: review and current concepts. J Am Board Fam Pract. 1998;11:34-40.
- Jurkovich GJ. Environmental cold-induced injury. Surg Clin North Am. 2007;87:247-267, viii.
- Biem J, Koehncke N, Classen D, et al. Out of the cold: management of hypothermia and frostbite. CMAJ. 2003;168:305-311.
