The Journal of Family Practice

Like many physicians, I struggle with looking at my patients while they are talking and getting the stories that they tell me transcribed as accurately and completely as possible. After I read the article, “EHR use and patient satisfaction: What we learned” by Farber, et al, (J Fam Pract. 2015;64:687-696), I was struck by something.

Of the 126 patients chosen for the research, the educational level breakdown included 75% with at least some college education and 28% with postgraduate education. A study performed by the National Center for Veterans Analysis and Statistics published in 2015 has different statistics.¹ Although a similar percentage had at least some college education, only 10.5% of the men and 12.4% of the women had postgraduate education.

In my practice, most of my patients who have worked with computers empathize with the amount of time that I spend looking at the screen. Those with less education are less agreeable. Since the patients were picked by their physicians to take part in the study, I wonder if there was an unconscious bias present.

Holly Leeds, MD
Auburn, Calif

1. National Center for Veterans Analysis and Statistics. Profile of Veterans: 2013. US Department of Veterans Affairs Web site. Available at: http://www.va.gov/vetdata/docs/SpecialReports/Profile_of_Veterans_2013.pdf. Accessed March 21, 2016.

Author's response:
Dr. Leeds brings up an interesting issue. It is possible that there is an unconscious bias on the part of physicians who participated in this study. Although the demographics are fairly similar to those that she cites, the veterans in our study were somewhat more educated.

If less well-educated subjects participated, this would make the data more impressive, in terms of less satisfaction with physicians who more readily focus their eyes on computer screens rather than on their patients. The fact that we did find this association is important for physicians who use EHR systems.

Neil J. Farber, MD, FACP
San Diego, Calif

Like many physicians, I struggle with looking at my patients while they are talking and getting the stories that they tell me transcribed as accurately and completely as possible. After I read the article, “EHR use and patient satisfaction: What we learned” by Farber, et al, (J Fam Pract. 2015;64:687-696), I was struck by something.

Of the 126 patients chosen for the research, the educational level breakdown included 75% with at least some college education and 28% with postgraduate education. A study performed by the National Center for Veterans Analysis and Statistics published in 2015 has different statistics.¹ Although a similar percentage had at least some college education, only 10.5% of the men and 12.4% of the women had postgraduate education.

In my practice, most of my patients who have worked with computers empathize with the amount of time that I spend looking at the screen. Those with less education are less agreeable. Since the patients were picked by their physicians to take part in the study, I wonder if there was an unconscious bias present.

Holly Leeds, MD
Auburn, Calif

1. National Center for Veterans Analysis and Statistics. Profile of Veterans: 2013. US Department of Veterans Affairs Web site. Available at: http://www.va.gov/vetdata/docs/SpecialReports/Profile_of_Veterans_2013.pdf. Accessed March 21, 2016.

Author's response:
Dr. Leeds brings up an interesting issue. It is possible that there is an unconscious bias on the part of physicians who participated in this study. Although the demographics are fairly similar to those that she cites, the veterans in our study were somewhat more educated.

If less well-educated subjects participated, this would make the data more impressive, in terms of less satisfaction with physicians who more readily focus their eyes on computer screens rather than on their patients. The fact that we did find this association is important for physicians who use EHR systems.

Neil J. Farber, MD, FACP
San Diego, Calif

Like many physicians, I struggle with looking at my patients while they are talking and getting the stories that they tell me transcribed as accurately and completely as possible. After I read the article, “EHR use and patient satisfaction: What we learned” by Farber, et al, (J Fam Pract. 2015;64:687-696), I was struck by something.

Of the 126 patients chosen for the research, the educational level breakdown included 75% with at least some college education and 28% with postgraduate education. A study performed by the National Center for Veterans Analysis and Statistics published in 2015 has different statistics.¹ Although a similar percentage had at least some college education, only 10.5% of the men and 12.4% of the women had postgraduate education.

In my practice, most of my patients who have worked with computers empathize with the amount of time that I spend looking at the screen. Those with less education are less agreeable. Since the patients were picked by their physicians to take part in the study, I wonder if there was an unconscious bias present.

Holly Leeds, MD
Auburn, Calif

1. National Center for Veterans Analysis and Statistics. Profile of Veterans: 2013. US Department of Veterans Affairs Web site. Available at: http://www.va.gov/vetdata/docs/SpecialReports/Profile_of_Veterans_2013.pdf. Accessed March 21, 2016.

Author's response:
Dr. Leeds brings up an interesting issue. It is possible that there is an unconscious bias on the part of physicians who participated in this study. Although the demographics are fairly similar to those that she cites, the veterans in our study were somewhat more educated.

If less well-educated subjects participated, this would make the data more impressive, in terms of less satisfaction with physicians who more readily focus their eyes on computer screens rather than on their patients. The fact that we did find this association is important for physicians who use EHR systems.

Neil J. Farber, MD, FACP
San Diego, Calif

CASE › A 39-year-old Hispanic man with a body mass index (BMI) of 35 kg/m², type 2 diabetes mellitus (T2DM), and hypertension is referred for evaluation of abnormal liver function tests (LFTs) and fatty liver on ultrasound. He is taking metformin and lisinopril, and a patient alcohol screening survey is negative. LFT results reveal the following: alanine aminotransferase (ALT) 27 IU/dL; aspartate aminotransferase (AST) 43 IU/dL; albumin 4.2 g/dL; gamma glutamyl transferase 22 u/L; alkaline phosphatase 51 IU/L; and total bilirubin 0.3 mg/dL. Lactate dehydrogenase and prothrombin time are normal.

Results of his liver screen are as follows: hepatitis B surface antigen, hepatitis C antibody, antimitochondrial antibody, and anti-smooth muscle antibody are negative, and iron, transferrin saturation, and ceruloplasmin are in normal range. Antinuclear antibody (1:20 dilution) is weakly positive, and alpha-1 antitrypsin (264 mg/dL) and serum ferritin (300 ng/mL) are mildly increased.

The patient undergoes a liver biopsy that shows grade 2 steatosis, grade 1 lobular inflammation, few ballooned hepatocytes, and stage 1 fibrosis. Based on these clinical findings, he is given a diagnosis of non-alcoholic fatty liver disease (NAFLD).

NAFLD is the most frequent cause of chronic liver disease both in the United States and globally.¹ In fact, a number of long-term epidemiologic studies report that nearly one-third of the US population has the disease.² The spectrum of NAFLD ranges from simple steatosis to non-alcoholic steatohepatitis (NASH) to cirrhosis. Of patients with NAFLD, 10% to 30% have the more severe form—NASH—and about 10% of those with NASH progress to cirrhosis and other liver-related complications.³

People with NAFLD consume no alcohol, or only a modest amount (ie, weekly intake <140 g in women and <210 g in men). Typically, they are asymptomatic with normal or mildly abnormal LFTs discovered as part of a preventive health screening. In patients with simple hepatic steatosis alone, serum ALT levels are higher than serum AST levels. (In contrast, patients with alcoholic liver injury and NASH with progressive fibrosis have higher serum AST than ALT levels.) A serum hepatitis panel and liver screen are negative for other explanations of chronic liver disease.

NAFLD is strongly associated with obesity, insulin resistance/T2DM, and hyperlipidemia, all of which are components of metabolic syndrome. Obesity, particularly central obesity, is highly predictive of hepatic steatosis and disease progression.⁴ T2DM occurs 5 to 9 times more frequently in people with NAFLD than in the general population,⁵ and, conversely, nearly 66% of patients with T2DM have NAFLD.^6,7 Furthermore, nearly 70% of patients with T2DM develop fatty liver and its consequences, including NASH, fibrosis, cirrhosis, and hepatocellular carcinoma.^5,7

4 therapeutic strategies. Based on our current understanding of the pathogenesis of NAFLD, there are 4 main therapeutic avenues: lifestyle modification, liver-directed pharmacotherapy, management of metabolic syndrome, and surveillance of the complications of cirrhosis. The review that follows explores the evidence to date for each.

Take steps to reduce weight and increase physical activity

The primary objective with NAFLD is to right the imbalance between calorie intake and utilization so as to reverse the obesity and insulin resistance underlying the disease.

Target carbohydrates. Current data clearly suggest that energy intake is significantly higher in patients with NAFLD than in those without the disease.⁸ Thus, reducing dietary carbohydrate and overall energy intake is beneficial to preventing and halting the progression of liver damage. Increased intake of high fructose corn syrup may be at least partially to blame; research has linked the substance to the occurrence of obesity, metabolic syndrome, and NAFLD.⁹

The optimal diet to treat NAFLD is not known because of the difficulties inherent to performing well-designed dietary intervention trials and ensuring long-term compliance. At least one study reported that a Mediterranean diet helped reduce hepatic steatosis and improve insulin sensitivity in nondiabetic individuals.¹⁰ Generally, patients should avoid saturated fats, simple carbohydrates, and sweetened drinks, and they should be instructed to restrict calories to cause weight loss of about .5 kg to 1 kg per week until the target weight is achieved.¹¹

Current observational studies indicate that prudent calorie restriction combined with increased physical activity is the best strategy for achieving and sustaining optimum body weight; severe calorie restriction is likely to cause skeletal muscle loss that can aggravate NAFLD.

Encourage exercise. Aerobic exercise improves skeletal muscle insulin sensitivity—the primary underlying mechanism that causes NAFLD.¹² Although the optimum duration and intensity of exercise is not known, several randomized controlled trials (RCTs) found that moderately intense training, high-intensity training, and/or resistance training improved hepatic steatosis and insulin resistance, but an effect on ALT was inconsistent.¹³ (None of these studies included histology as an outcome measure.)

Given the multitude of benefits of aerobic exercise, there is no question that patients with NAFLD should try to increase their physical activity and incorporate exercise into their daily routine.

Hold off on pharmacologic weight loss. Orlistat, an enteric lipase inhibitor, causes malabsorption of dietary fat, which leads to weight loss. Although one study demonstrated that orlistat improves ALT and steatosis in patients with NAFLD, a subsequent RCT concluded that orlistat with caloric restriction and vitamin E (800 IU/d) did not enhance weight loss over caloric restriction and vitamin E alone.¹⁴ Additionally, in patients with weight loss >9% of body weight, histologic improvement occurred independent of orlistat.¹⁴ Therefore, orlistat is not currently recommended for weight loss in patients with NAFLD.

Keep bariatric surgery on your radar. Bariatric-metabolic surgery provides the most reliable method for achieving sustained weight loss in morbidly obese individuals with NAFLD. Commonly used surgical procedures are associated with reduced steatosis and lobular inflammatory changes, but reports are conflicting regarding fibrosis.¹⁵

The majority of published data indicate that bariatric surgery improves the histologic and metabolic changes associated with NAFLD and has potential as a treatment option for patients with morbid obesity and NAFLD. However, the timing and type of surgery that is most effective, and whether bariatric surgery can cure the disease, remain unanswered questions. Long-term follow-up and RCTs are needed to address these issues. As a result, no definitive recommendations regarding bariatric surgery as a treatment for NAFLD can be made at this time.¹⁵

Liver-directed pharmacotherapy: Evidence is lacking for many agents

Lifestyle modification remains the mainstay of therapy for NAFLD because of its efficacy and lack of adverse effects. But low compliance rates often make pharmacotherapy necessary to reduce the health burden related to NAFLD. Despite the success rate of pharmacologic agents that focus on insulin resistance and lipid metabolism and that have antioxidant properties, the long-term safety and efficacy of many of these agents is largely unknown. Furthermore, the FDA has not approved any pharmacologic agents specifically for the treatment of NAFLD. Here’s what we know:

Vitamin E. Five RCTs have evaluated the antioxidant vitamin E in patients with NASH. The best study published to date found that 96 weeks of therapy with 800 IU/d vitamin E was associated with a 42% improvement in hepatic histology, compared with 19% improvement in the placebo group.¹⁶ Vitamin E was also associated with improved serum ALT.

Although vitamin E seems to be a promising agent for the treatment of NASH, concerns exist about its long-term safety because of an increased risk of all-cause mortality and hemorrhagic stroke.¹⁷ In addition, because the optimal dose and duration of treatment is unknown and because studies have not evaluated the supplement in patients who have diabetes and NASH, vitamin E is not currently considered to be a standard therapy for NASH.

Insulin sensitizers. Because insulin resistance is believed to be the underlying mechanism for the development and progression of NAFLD, a compelling rationale exists for the use of insulin sensitizers in the management of the disease. Metformin, an activator of adenosine monophosphate-activated protein kinase, and the thiazolidinediones (pioglitazone and rosiglitazone) are the most extensively studied agents in clinical trials. A number of studies looking at the effects of metformin on NAFLD found that liver function, steatosis, and insulin sensitivity improved;¹⁸ however, a recent meta-analysis found that metformin failed to improve liver histology.¹⁹

Similarly, although clinical trials have shown that thiazolidinediones improve liver enzymes, inflammatory markers, and hepatic steatosis, questions surround their long-term safety.²⁰ The largest placebo-controlled trial on this issue to date—PIVENS (pioglitazone vs vitamin E vs placebo)—found that pioglitazone was beneficial in improving hepatic histology.¹⁶ However, the well-recognized adverse effects of pioglitazone (eg, upper respiratory tract infection, edema, and hypoglycemia) may temper its utility.

Clinical trials involving newer antidiabetic agents, such as dipeptidyl peptidase-4 (DPP4) inhibitors and glucagon-like peptide-1 (GLP1) analogues, indicate that such agents improve insulin resistance, steatosis, and inflammation.²¹ However, these drugs are not considered to be routine therapy because of limited data and the lack of long-term benefits.

Bile acid regulatory agents. Ursodeoxycholic acid (UDCA), a bile acid with antiapoptotic and cytoprotective properties, is used as a hepatoprotectant in NAFLD. Although early studies showed no significant differences in LFT results between UDCA-treated and untreated groups, recent RCTs indicate that UDCA improves ALT and serum fibrosis.^22,23 The FLINT trial, a recent multicenter RCT involving obeticholic acid, found that UDCA was associated with improvement in histologic outcomes, although long-term benefits and safety—especially with regard to worsening hyperlipidemia—are questionable.²⁴

Pentoxifylline. Researchers have evaluated pentoxifylline, a hepatoprotectant with anti-tumor necrosis factor effect, in the treatment of NAFLD.²⁵ In fact, pooled results from 5 well-designed studies indicate that pentoxifylline significantly reduces ALT and AST and improves steatosis, lobular inflammation, and fibrosis.²⁶ Although these data suggest that pentoxifylline holds promise as a therapeutic option, the lack of large multicenter studies and FDA approval temper its utility in the management of NASH at this time.

Cholesterol-lowering agents. Statins inhibit hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase in the liver and have anti-inflammatory and anti-fibrogenic properties. They have been used in patients with NAFLD, primarily because of their cardiovascular benefit. Two RCTs with high risk of bias and a small number of participants found statin therapy to be associated with improved serum transaminases and ultrasound findings; however, liver biopsies were not performed in either of these studies.²⁷

While the data suggest that pentoxifylline holds promise as a therapeutic option, the lack of large studies and FDA approval temper its utility in the management of non-alcoholic steatohepatitis.

Lowering cholesterol using an absorption inhibitor, such as ezetimibe, was associated with improvement in liver histology in a single RCT.²⁸ Even though statins are not considered to be a treatment for NAFLD, they can be used to safely lower plasma cholesterol in patients with the disease.

Renin-angiotensin system (RAS) inhibitors. Research in animals indicates that activation of the renin-angiotensin system contributes to the pathogenesis of NAFLD, but data on the benefits of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in patients with NAFLD are limited, conflicting, and derived largely from retrospective²⁹ and pilot prospective studies.

Based on currently published literature, RAS inhibitors are not considered an NAFLD treatment. However, because cardiovascular disease is a major cause of death in patients with NAFLD, the renal and cardiovascular protection offered by these agents likely lowers mortality in patients with the disease.

Probiotics. The use of probiotics in the treatment of NAFLD is based on the premise that alterations in intestinal microbes and the inflammatory response may improve the disease. Three RCTs involving different formulations of probiotics, synbiotics, or placebo, showed improvement in serum liver markers and insulin resistance, but did not include histologic outcome measures.³⁰ Furthermore, the long-term consequences of altered gut flora are presently unknown. As such, the available evidence does not support the use of probiotics for the treatment of NAFLD.

Polyunsaturated fatty acids (PUFA). Clearly, omega-3 fatty acids have beneficial effects on cardiometabolic risk factors and positively impact lipid metabolism and insulin sensitivity. In addition, a few studies have reported improvement in non-histologic outcome measures of NAFLD, but 2 high-quality RCTs found no benefit of fish oil-based PUFA on histology.^31,32 Thus, current evidence does not support recommending PUFA supplementation for the treatment of NAFLD.

Chinese herbal medicines. At least 56 trials have looked at 75 different Chinese herbal medicines in varying formulations, dosages, routes of administration, and durations of treatment, using various controlled interventions.³³ No trial reported primary outcomes, such as hepatic-related mortality, morbidity, or health care quality of life. Although a large number of the trials reported some positive effects on various biochemical or radiologic measures, the high risk of bias and the limited number of trials testing individual herbal medicines leave efficacy and safety open to question. As such, no Chinese herbal medicines are regarded as treatment for NAFLD at this time.

Target components of metabolic syndrome

Management of the components of metabolic syndrome remains one of the safest and most effective ways to manage NAFLD. Therefore, screening for and treating T2DM, hypertension, and dyslipidemia are priorities. Although obstructive sleep apnea (OSA) is not part of metabolic syndrome, the condition frequently coexists with metabolic syndrome because both entities have obesity as a risk factor.

T2DM. Screen all patients with NAFLD for T2DM and vice-versa because, as noted earlier, patients with diabetes have more severe and progressive NAFLD, and a high proportion of patients with NAFLD have T2DM.^5,6 Although research has not shown metformin to improve histology in NASH, metformin is recommended as a first-line agent for the treatment of T2DM because it aids in weight loss and lowers diabetes-related mortality.³⁴

Pioglitazone is considered a second-line agent. Despite its beneficial effects on insulin sensitivity and hepatic histology, there are concerns about the adverse effects of thiazolidinediones. GLP1 analogues, which improve liver enzymes and reduce hepatic steatosis, are considered third-line agents.

Hypertension. Because approximately 70% of patients with NAFLD have hypertension,³⁵ it is imperative to screen patients for the condition. If blood pressure is >140/90 mm Hg, patients should be managed according to hypertension guidelines. ACE inhibitors or ARBs are recommended as first-line therapy, since blocking the renin-angiotensin system potentially reduces hepatic fibrosis,³⁶ and ARBs may lower transaminases and improve insulin sensitivity in NAFLD.

Dyslipidemia. Treatment of dyslipidemia is essential to lowering cardiovascular mortality in patients with NAFLD. Even though elevated transaminases occur with NAFLD, this should not preclude starting therapy to lower triglycerides to <150 mg/dL and total cholesterol to <200 mg/dL.

OSA. Because of the high prevalence of OSA in patients with NAFLD, physicians should have a high index of suspicion and screen this population for sleep disorders. OSA is associated with an increased risk of NAFLD and advanced fibrosis in NASH.³⁷ Treatment of OSA improves quality of life and controls blood pressure in patients with NAFLD, but it’s currently unclear whether targeting sleep disorders can slow the progression of fibrosis in NAFLD.

Concentrate on the complications of cirrhosis

Patients with NASH cirrhosis, like those with cirrhosis of other etiologies, are at risk for complications, including hepatic encephalopathy, ascites, hepatorenal syndrome, and esophageal variceal hemorrhage. Surveillance to detect these include an annual liver ultrasound, an alpha-fetoprotein test every 6 months, esophagogastroduodenoscopy for varices, and an assessment for liver transplantation. For more on these complications, see, “Cirrhosis complications: Keeping them under control,” J Fam Pract. 2015;64:338-342. NAFLD-associated cirrhosis is the third most frequent indication for liver transplantation in the United States and may become the most frequent indication in the next decade.³⁸

CASE ›  Because the patient’s liver biopsy showed early NASH, we recommended that he aggressively pursue lifestyle modification, including regular physical activity and dietary changes. Additionally, we discussed optimization of glycemic control and continued use of lisinopril for control of hypertension. On follow-up 6 months later, he had lost weight and his BMI was 32 kg/m². In addition, his transaminase levels had improved, but they had not normalized.

We recommended that he continue the same measures, with follow-up every 6 months to ensure compliance with lifestyle modifications and with diabetes and hypertension control.

CORRESPONDENCE
Jaividhya Dasarathy, MD, Metro Health Medical Center, 2500 Metro Health Drive, Cleveland, OH 44109; jdasarathy@metrohealth.org.

CASE › A 39-year-old Hispanic man with a body mass index (BMI) of 35 kg/m², type 2 diabetes mellitus (T2DM), and hypertension is referred for evaluation of abnormal liver function tests (LFTs) and fatty liver on ultrasound. He is taking metformin and lisinopril, and a patient alcohol screening survey is negative. LFT results reveal the following: alanine aminotransferase (ALT) 27 IU/dL; aspartate aminotransferase (AST) 43 IU/dL; albumin 4.2 g/dL; gamma glutamyl transferase 22 u/L; alkaline phosphatase 51 IU/L; and total bilirubin 0.3 mg/dL. Lactate dehydrogenase and prothrombin time are normal.

Results of his liver screen are as follows: hepatitis B surface antigen, hepatitis C antibody, antimitochondrial antibody, and anti-smooth muscle antibody are negative, and iron, transferrin saturation, and ceruloplasmin are in normal range. Antinuclear antibody (1:20 dilution) is weakly positive, and alpha-1 antitrypsin (264 mg/dL) and serum ferritin (300 ng/mL) are mildly increased.

The patient undergoes a liver biopsy that shows grade 2 steatosis, grade 1 lobular inflammation, few ballooned hepatocytes, and stage 1 fibrosis. Based on these clinical findings, he is given a diagnosis of non-alcoholic fatty liver disease (NAFLD).

NAFLD is the most frequent cause of chronic liver disease both in the United States and globally.¹ In fact, a number of long-term epidemiologic studies report that nearly one-third of the US population has the disease.² The spectrum of NAFLD ranges from simple steatosis to non-alcoholic steatohepatitis (NASH) to cirrhosis. Of patients with NAFLD, 10% to 30% have the more severe form—NASH—and about 10% of those with NASH progress to cirrhosis and other liver-related complications.³

People with NAFLD consume no alcohol, or only a modest amount (ie, weekly intake <140 g in women and <210 g in men). Typically, they are asymptomatic with normal or mildly abnormal LFTs discovered as part of a preventive health screening. In patients with simple hepatic steatosis alone, serum ALT levels are higher than serum AST levels. (In contrast, patients with alcoholic liver injury and NASH with progressive fibrosis have higher serum AST than ALT levels.) A serum hepatitis panel and liver screen are negative for other explanations of chronic liver disease.

NAFLD is strongly associated with obesity, insulin resistance/T2DM, and hyperlipidemia, all of which are components of metabolic syndrome. Obesity, particularly central obesity, is highly predictive of hepatic steatosis and disease progression.⁴ T2DM occurs 5 to 9 times more frequently in people with NAFLD than in the general population,⁵ and, conversely, nearly 66% of patients with T2DM have NAFLD.^6,7 Furthermore, nearly 70% of patients with T2DM develop fatty liver and its consequences, including NASH, fibrosis, cirrhosis, and hepatocellular carcinoma.^5,7

4 therapeutic strategies. Based on our current understanding of the pathogenesis of NAFLD, there are 4 main therapeutic avenues: lifestyle modification, liver-directed pharmacotherapy, management of metabolic syndrome, and surveillance of the complications of cirrhosis. The review that follows explores the evidence to date for each.

Take steps to reduce weight and increase physical activity

The primary objective with NAFLD is to right the imbalance between calorie intake and utilization so as to reverse the obesity and insulin resistance underlying the disease.

Target carbohydrates. Current data clearly suggest that energy intake is significantly higher in patients with NAFLD than in those without the disease.⁸ Thus, reducing dietary carbohydrate and overall energy intake is beneficial to preventing and halting the progression of liver damage. Increased intake of high fructose corn syrup may be at least partially to blame; research has linked the substance to the occurrence of obesity, metabolic syndrome, and NAFLD.⁹

The optimal diet to treat NAFLD is not known because of the difficulties inherent to performing well-designed dietary intervention trials and ensuring long-term compliance. At least one study reported that a Mediterranean diet helped reduce hepatic steatosis and improve insulin sensitivity in nondiabetic individuals.¹⁰ Generally, patients should avoid saturated fats, simple carbohydrates, and sweetened drinks, and they should be instructed to restrict calories to cause weight loss of about .5 kg to 1 kg per week until the target weight is achieved.¹¹

Current observational studies indicate that prudent calorie restriction combined with increased physical activity is the best strategy for achieving and sustaining optimum body weight; severe calorie restriction is likely to cause skeletal muscle loss that can aggravate NAFLD.

Encourage exercise. Aerobic exercise improves skeletal muscle insulin sensitivity—the primary underlying mechanism that causes NAFLD.¹² Although the optimum duration and intensity of exercise is not known, several randomized controlled trials (RCTs) found that moderately intense training, high-intensity training, and/or resistance training improved hepatic steatosis and insulin resistance, but an effect on ALT was inconsistent.¹³ (None of these studies included histology as an outcome measure.)

Given the multitude of benefits of aerobic exercise, there is no question that patients with NAFLD should try to increase their physical activity and incorporate exercise into their daily routine.

Hold off on pharmacologic weight loss. Orlistat, an enteric lipase inhibitor, causes malabsorption of dietary fat, which leads to weight loss. Although one study demonstrated that orlistat improves ALT and steatosis in patients with NAFLD, a subsequent RCT concluded that orlistat with caloric restriction and vitamin E (800 IU/d) did not enhance weight loss over caloric restriction and vitamin E alone.¹⁴ Additionally, in patients with weight loss >9% of body weight, histologic improvement occurred independent of orlistat.¹⁴ Therefore, orlistat is not currently recommended for weight loss in patients with NAFLD.

Keep bariatric surgery on your radar. Bariatric-metabolic surgery provides the most reliable method for achieving sustained weight loss in morbidly obese individuals with NAFLD. Commonly used surgical procedures are associated with reduced steatosis and lobular inflammatory changes, but reports are conflicting regarding fibrosis.¹⁵

The majority of published data indicate that bariatric surgery improves the histologic and metabolic changes associated with NAFLD and has potential as a treatment option for patients with morbid obesity and NAFLD. However, the timing and type of surgery that is most effective, and whether bariatric surgery can cure the disease, remain unanswered questions. Long-term follow-up and RCTs are needed to address these issues. As a result, no definitive recommendations regarding bariatric surgery as a treatment for NAFLD can be made at this time.¹⁵

Liver-directed pharmacotherapy: Evidence is lacking for many agents

Lifestyle modification remains the mainstay of therapy for NAFLD because of its efficacy and lack of adverse effects. But low compliance rates often make pharmacotherapy necessary to reduce the health burden related to NAFLD. Despite the success rate of pharmacologic agents that focus on insulin resistance and lipid metabolism and that have antioxidant properties, the long-term safety and efficacy of many of these agents is largely unknown. Furthermore, the FDA has not approved any pharmacologic agents specifically for the treatment of NAFLD. Here’s what we know:

Vitamin E. Five RCTs have evaluated the antioxidant vitamin E in patients with NASH. The best study published to date found that 96 weeks of therapy with 800 IU/d vitamin E was associated with a 42% improvement in hepatic histology, compared with 19% improvement in the placebo group.¹⁶ Vitamin E was also associated with improved serum ALT.

Although vitamin E seems to be a promising agent for the treatment of NASH, concerns exist about its long-term safety because of an increased risk of all-cause mortality and hemorrhagic stroke.¹⁷ In addition, because the optimal dose and duration of treatment is unknown and because studies have not evaluated the supplement in patients who have diabetes and NASH, vitamin E is not currently considered to be a standard therapy for NASH.

Insulin sensitizers. Because insulin resistance is believed to be the underlying mechanism for the development and progression of NAFLD, a compelling rationale exists for the use of insulin sensitizers in the management of the disease. Metformin, an activator of adenosine monophosphate-activated protein kinase, and the thiazolidinediones (pioglitazone and rosiglitazone) are the most extensively studied agents in clinical trials. A number of studies looking at the effects of metformin on NAFLD found that liver function, steatosis, and insulin sensitivity improved;¹⁸ however, a recent meta-analysis found that metformin failed to improve liver histology.¹⁹

Similarly, although clinical trials have shown that thiazolidinediones improve liver enzymes, inflammatory markers, and hepatic steatosis, questions surround their long-term safety.²⁰ The largest placebo-controlled trial on this issue to date—PIVENS (pioglitazone vs vitamin E vs placebo)—found that pioglitazone was beneficial in improving hepatic histology.¹⁶ However, the well-recognized adverse effects of pioglitazone (eg, upper respiratory tract infection, edema, and hypoglycemia) may temper its utility.

Clinical trials involving newer antidiabetic agents, such as dipeptidyl peptidase-4 (DPP4) inhibitors and glucagon-like peptide-1 (GLP1) analogues, indicate that such agents improve insulin resistance, steatosis, and inflammation.²¹ However, these drugs are not considered to be routine therapy because of limited data and the lack of long-term benefits.

Bile acid regulatory agents. Ursodeoxycholic acid (UDCA), a bile acid with antiapoptotic and cytoprotective properties, is used as a hepatoprotectant in NAFLD. Although early studies showed no significant differences in LFT results between UDCA-treated and untreated groups, recent RCTs indicate that UDCA improves ALT and serum fibrosis.^22,23 The FLINT trial, a recent multicenter RCT involving obeticholic acid, found that UDCA was associated with improvement in histologic outcomes, although long-term benefits and safety—especially with regard to worsening hyperlipidemia—are questionable.²⁴

Pentoxifylline. Researchers have evaluated pentoxifylline, a hepatoprotectant with anti-tumor necrosis factor effect, in the treatment of NAFLD.²⁵ In fact, pooled results from 5 well-designed studies indicate that pentoxifylline significantly reduces ALT and AST and improves steatosis, lobular inflammation, and fibrosis.²⁶ Although these data suggest that pentoxifylline holds promise as a therapeutic option, the lack of large multicenter studies and FDA approval temper its utility in the management of NASH at this time.

Cholesterol-lowering agents. Statins inhibit hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase in the liver and have anti-inflammatory and anti-fibrogenic properties. They have been used in patients with NAFLD, primarily because of their cardiovascular benefit. Two RCTs with high risk of bias and a small number of participants found statin therapy to be associated with improved serum transaminases and ultrasound findings; however, liver biopsies were not performed in either of these studies.²⁷

While the data suggest that pentoxifylline holds promise as a therapeutic option, the lack of large studies and FDA approval temper its utility in the management of non-alcoholic steatohepatitis.

Lowering cholesterol using an absorption inhibitor, such as ezetimibe, was associated with improvement in liver histology in a single RCT.²⁸ Even though statins are not considered to be a treatment for NAFLD, they can be used to safely lower plasma cholesterol in patients with the disease.

Renin-angiotensin system (RAS) inhibitors. Research in animals indicates that activation of the renin-angiotensin system contributes to the pathogenesis of NAFLD, but data on the benefits of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in patients with NAFLD are limited, conflicting, and derived largely from retrospective²⁹ and pilot prospective studies.

Based on currently published literature, RAS inhibitors are not considered an NAFLD treatment. However, because cardiovascular disease is a major cause of death in patients with NAFLD, the renal and cardiovascular protection offered by these agents likely lowers mortality in patients with the disease.

Probiotics. The use of probiotics in the treatment of NAFLD is based on the premise that alterations in intestinal microbes and the inflammatory response may improve the disease. Three RCTs involving different formulations of probiotics, synbiotics, or placebo, showed improvement in serum liver markers and insulin resistance, but did not include histologic outcome measures.³⁰ Furthermore, the long-term consequences of altered gut flora are presently unknown. As such, the available evidence does not support the use of probiotics for the treatment of NAFLD.

Polyunsaturated fatty acids (PUFA). Clearly, omega-3 fatty acids have beneficial effects on cardiometabolic risk factors and positively impact lipid metabolism and insulin sensitivity. In addition, a few studies have reported improvement in non-histologic outcome measures of NAFLD, but 2 high-quality RCTs found no benefit of fish oil-based PUFA on histology.^31,32 Thus, current evidence does not support recommending PUFA supplementation for the treatment of NAFLD.

Chinese herbal medicines. At least 56 trials have looked at 75 different Chinese herbal medicines in varying formulations, dosages, routes of administration, and durations of treatment, using various controlled interventions.³³ No trial reported primary outcomes, such as hepatic-related mortality, morbidity, or health care quality of life. Although a large number of the trials reported some positive effects on various biochemical or radiologic measures, the high risk of bias and the limited number of trials testing individual herbal medicines leave efficacy and safety open to question. As such, no Chinese herbal medicines are regarded as treatment for NAFLD at this time.

Target components of metabolic syndrome

Management of the components of metabolic syndrome remains one of the safest and most effective ways to manage NAFLD. Therefore, screening for and treating T2DM, hypertension, and dyslipidemia are priorities. Although obstructive sleep apnea (OSA) is not part of metabolic syndrome, the condition frequently coexists with metabolic syndrome because both entities have obesity as a risk factor.

T2DM. Screen all patients with NAFLD for T2DM and vice-versa because, as noted earlier, patients with diabetes have more severe and progressive NAFLD, and a high proportion of patients with NAFLD have T2DM.^5,6 Although research has not shown metformin to improve histology in NASH, metformin is recommended as a first-line agent for the treatment of T2DM because it aids in weight loss and lowers diabetes-related mortality.³⁴

Pioglitazone is considered a second-line agent. Despite its beneficial effects on insulin sensitivity and hepatic histology, there are concerns about the adverse effects of thiazolidinediones. GLP1 analogues, which improve liver enzymes and reduce hepatic steatosis, are considered third-line agents.

Hypertension. Because approximately 70% of patients with NAFLD have hypertension,³⁵ it is imperative to screen patients for the condition. If blood pressure is >140/90 mm Hg, patients should be managed according to hypertension guidelines. ACE inhibitors or ARBs are recommended as first-line therapy, since blocking the renin-angiotensin system potentially reduces hepatic fibrosis,³⁶ and ARBs may lower transaminases and improve insulin sensitivity in NAFLD.

Dyslipidemia. Treatment of dyslipidemia is essential to lowering cardiovascular mortality in patients with NAFLD. Even though elevated transaminases occur with NAFLD, this should not preclude starting therapy to lower triglycerides to <150 mg/dL and total cholesterol to <200 mg/dL.

OSA. Because of the high prevalence of OSA in patients with NAFLD, physicians should have a high index of suspicion and screen this population for sleep disorders. OSA is associated with an increased risk of NAFLD and advanced fibrosis in NASH.³⁷ Treatment of OSA improves quality of life and controls blood pressure in patients with NAFLD, but it’s currently unclear whether targeting sleep disorders can slow the progression of fibrosis in NAFLD.

Concentrate on the complications of cirrhosis

Patients with NASH cirrhosis, like those with cirrhosis of other etiologies, are at risk for complications, including hepatic encephalopathy, ascites, hepatorenal syndrome, and esophageal variceal hemorrhage. Surveillance to detect these include an annual liver ultrasound, an alpha-fetoprotein test every 6 months, esophagogastroduodenoscopy for varices, and an assessment for liver transplantation. For more on these complications, see, “Cirrhosis complications: Keeping them under control,” J Fam Pract. 2015;64:338-342. NAFLD-associated cirrhosis is the third most frequent indication for liver transplantation in the United States and may become the most frequent indication in the next decade.³⁸

CASE ›  Because the patient’s liver biopsy showed early NASH, we recommended that he aggressively pursue lifestyle modification, including regular physical activity and dietary changes. Additionally, we discussed optimization of glycemic control and continued use of lisinopril for control of hypertension. On follow-up 6 months later, he had lost weight and his BMI was 32 kg/m². In addition, his transaminase levels had improved, but they had not normalized.

We recommended that he continue the same measures, with follow-up every 6 months to ensure compliance with lifestyle modifications and with diabetes and hypertension control.

CORRESPONDENCE
Jaividhya Dasarathy, MD, Metro Health Medical Center, 2500 Metro Health Drive, Cleveland, OH 44109; jdasarathy@metrohealth.org.

CASE › A 39-year-old Hispanic man with a body mass index (BMI) of 35 kg/m², type 2 diabetes mellitus (T2DM), and hypertension is referred for evaluation of abnormal liver function tests (LFTs) and fatty liver on ultrasound. He is taking metformin and lisinopril, and a patient alcohol screening survey is negative. LFT results reveal the following: alanine aminotransferase (ALT) 27 IU/dL; aspartate aminotransferase (AST) 43 IU/dL; albumin 4.2 g/dL; gamma glutamyl transferase 22 u/L; alkaline phosphatase 51 IU/L; and total bilirubin 0.3 mg/dL. Lactate dehydrogenase and prothrombin time are normal.

Results of his liver screen are as follows: hepatitis B surface antigen, hepatitis C antibody, antimitochondrial antibody, and anti-smooth muscle antibody are negative, and iron, transferrin saturation, and ceruloplasmin are in normal range. Antinuclear antibody (1:20 dilution) is weakly positive, and alpha-1 antitrypsin (264 mg/dL) and serum ferritin (300 ng/mL) are mildly increased.

The patient undergoes a liver biopsy that shows grade 2 steatosis, grade 1 lobular inflammation, few ballooned hepatocytes, and stage 1 fibrosis. Based on these clinical findings, he is given a diagnosis of non-alcoholic fatty liver disease (NAFLD).

NAFLD is the most frequent cause of chronic liver disease both in the United States and globally.¹ In fact, a number of long-term epidemiologic studies report that nearly one-third of the US population has the disease.² The spectrum of NAFLD ranges from simple steatosis to non-alcoholic steatohepatitis (NASH) to cirrhosis. Of patients with NAFLD, 10% to 30% have the more severe form—NASH—and about 10% of those with NASH progress to cirrhosis and other liver-related complications.³

People with NAFLD consume no alcohol, or only a modest amount (ie, weekly intake <140 g in women and <210 g in men). Typically, they are asymptomatic with normal or mildly abnormal LFTs discovered as part of a preventive health screening. In patients with simple hepatic steatosis alone, serum ALT levels are higher than serum AST levels. (In contrast, patients with alcoholic liver injury and NASH with progressive fibrosis have higher serum AST than ALT levels.) A serum hepatitis panel and liver screen are negative for other explanations of chronic liver disease.

NAFLD is strongly associated with obesity, insulin resistance/T2DM, and hyperlipidemia, all of which are components of metabolic syndrome. Obesity, particularly central obesity, is highly predictive of hepatic steatosis and disease progression.⁴ T2DM occurs 5 to 9 times more frequently in people with NAFLD than in the general population,⁵ and, conversely, nearly 66% of patients with T2DM have NAFLD.^6,7 Furthermore, nearly 70% of patients with T2DM develop fatty liver and its consequences, including NASH, fibrosis, cirrhosis, and hepatocellular carcinoma.^5,7

4 therapeutic strategies. Based on our current understanding of the pathogenesis of NAFLD, there are 4 main therapeutic avenues: lifestyle modification, liver-directed pharmacotherapy, management of metabolic syndrome, and surveillance of the complications of cirrhosis. The review that follows explores the evidence to date for each.

Take steps to reduce weight and increase physical activity

The primary objective with NAFLD is to right the imbalance between calorie intake and utilization so as to reverse the obesity and insulin resistance underlying the disease.

Target carbohydrates. Current data clearly suggest that energy intake is significantly higher in patients with NAFLD than in those without the disease.⁸ Thus, reducing dietary carbohydrate and overall energy intake is beneficial to preventing and halting the progression of liver damage. Increased intake of high fructose corn syrup may be at least partially to blame; research has linked the substance to the occurrence of obesity, metabolic syndrome, and NAFLD.⁹

The optimal diet to treat NAFLD is not known because of the difficulties inherent to performing well-designed dietary intervention trials and ensuring long-term compliance. At least one study reported that a Mediterranean diet helped reduce hepatic steatosis and improve insulin sensitivity in nondiabetic individuals.¹⁰ Generally, patients should avoid saturated fats, simple carbohydrates, and sweetened drinks, and they should be instructed to restrict calories to cause weight loss of about .5 kg to 1 kg per week until the target weight is achieved.¹¹

Current observational studies indicate that prudent calorie restriction combined with increased physical activity is the best strategy for achieving and sustaining optimum body weight; severe calorie restriction is likely to cause skeletal muscle loss that can aggravate NAFLD.

Encourage exercise. Aerobic exercise improves skeletal muscle insulin sensitivity—the primary underlying mechanism that causes NAFLD.¹² Although the optimum duration and intensity of exercise is not known, several randomized controlled trials (RCTs) found that moderately intense training, high-intensity training, and/or resistance training improved hepatic steatosis and insulin resistance, but an effect on ALT was inconsistent.¹³ (None of these studies included histology as an outcome measure.)

Given the multitude of benefits of aerobic exercise, there is no question that patients with NAFLD should try to increase their physical activity and incorporate exercise into their daily routine.

Hold off on pharmacologic weight loss. Orlistat, an enteric lipase inhibitor, causes malabsorption of dietary fat, which leads to weight loss. Although one study demonstrated that orlistat improves ALT and steatosis in patients with NAFLD, a subsequent RCT concluded that orlistat with caloric restriction and vitamin E (800 IU/d) did not enhance weight loss over caloric restriction and vitamin E alone.¹⁴ Additionally, in patients with weight loss >9% of body weight, histologic improvement occurred independent of orlistat.¹⁴ Therefore, orlistat is not currently recommended for weight loss in patients with NAFLD.

Keep bariatric surgery on your radar. Bariatric-metabolic surgery provides the most reliable method for achieving sustained weight loss in morbidly obese individuals with NAFLD. Commonly used surgical procedures are associated with reduced steatosis and lobular inflammatory changes, but reports are conflicting regarding fibrosis.¹⁵

The majority of published data indicate that bariatric surgery improves the histologic and metabolic changes associated with NAFLD and has potential as a treatment option for patients with morbid obesity and NAFLD. However, the timing and type of surgery that is most effective, and whether bariatric surgery can cure the disease, remain unanswered questions. Long-term follow-up and RCTs are needed to address these issues. As a result, no definitive recommendations regarding bariatric surgery as a treatment for NAFLD can be made at this time.¹⁵

Liver-directed pharmacotherapy: Evidence is lacking for many agents

Lifestyle modification remains the mainstay of therapy for NAFLD because of its efficacy and lack of adverse effects. But low compliance rates often make pharmacotherapy necessary to reduce the health burden related to NAFLD. Despite the success rate of pharmacologic agents that focus on insulin resistance and lipid metabolism and that have antioxidant properties, the long-term safety and efficacy of many of these agents is largely unknown. Furthermore, the FDA has not approved any pharmacologic agents specifically for the treatment of NAFLD. Here’s what we know:

Vitamin E. Five RCTs have evaluated the antioxidant vitamin E in patients with NASH. The best study published to date found that 96 weeks of therapy with 800 IU/d vitamin E was associated with a 42% improvement in hepatic histology, compared with 19% improvement in the placebo group.¹⁶ Vitamin E was also associated with improved serum ALT.

Although vitamin E seems to be a promising agent for the treatment of NASH, concerns exist about its long-term safety because of an increased risk of all-cause mortality and hemorrhagic stroke.¹⁷ In addition, because the optimal dose and duration of treatment is unknown and because studies have not evaluated the supplement in patients who have diabetes and NASH, vitamin E is not currently considered to be a standard therapy for NASH.

Insulin sensitizers. Because insulin resistance is believed to be the underlying mechanism for the development and progression of NAFLD, a compelling rationale exists for the use of insulin sensitizers in the management of the disease. Metformin, an activator of adenosine monophosphate-activated protein kinase, and the thiazolidinediones (pioglitazone and rosiglitazone) are the most extensively studied agents in clinical trials. A number of studies looking at the effects of metformin on NAFLD found that liver function, steatosis, and insulin sensitivity improved;¹⁸ however, a recent meta-analysis found that metformin failed to improve liver histology.¹⁹

Similarly, although clinical trials have shown that thiazolidinediones improve liver enzymes, inflammatory markers, and hepatic steatosis, questions surround their long-term safety.²⁰ The largest placebo-controlled trial on this issue to date—PIVENS (pioglitazone vs vitamin E vs placebo)—found that pioglitazone was beneficial in improving hepatic histology.¹⁶ However, the well-recognized adverse effects of pioglitazone (eg, upper respiratory tract infection, edema, and hypoglycemia) may temper its utility.

Clinical trials involving newer antidiabetic agents, such as dipeptidyl peptidase-4 (DPP4) inhibitors and glucagon-like peptide-1 (GLP1) analogues, indicate that such agents improve insulin resistance, steatosis, and inflammation.²¹ However, these drugs are not considered to be routine therapy because of limited data and the lack of long-term benefits.

Bile acid regulatory agents. Ursodeoxycholic acid (UDCA), a bile acid with antiapoptotic and cytoprotective properties, is used as a hepatoprotectant in NAFLD. Although early studies showed no significant differences in LFT results between UDCA-treated and untreated groups, recent RCTs indicate that UDCA improves ALT and serum fibrosis.^22,23 The FLINT trial, a recent multicenter RCT involving obeticholic acid, found that UDCA was associated with improvement in histologic outcomes, although long-term benefits and safety—especially with regard to worsening hyperlipidemia—are questionable.²⁴

Pentoxifylline. Researchers have evaluated pentoxifylline, a hepatoprotectant with anti-tumor necrosis factor effect, in the treatment of NAFLD.²⁵ In fact, pooled results from 5 well-designed studies indicate that pentoxifylline significantly reduces ALT and AST and improves steatosis, lobular inflammation, and fibrosis.²⁶ Although these data suggest that pentoxifylline holds promise as a therapeutic option, the lack of large multicenter studies and FDA approval temper its utility in the management of NASH at this time.

Cholesterol-lowering agents. Statins inhibit hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase in the liver and have anti-inflammatory and anti-fibrogenic properties. They have been used in patients with NAFLD, primarily because of their cardiovascular benefit. Two RCTs with high risk of bias and a small number of participants found statin therapy to be associated with improved serum transaminases and ultrasound findings; however, liver biopsies were not performed in either of these studies.²⁷

While the data suggest that pentoxifylline holds promise as a therapeutic option, the lack of large studies and FDA approval temper its utility in the management of non-alcoholic steatohepatitis.

Lowering cholesterol using an absorption inhibitor, such as ezetimibe, was associated with improvement in liver histology in a single RCT.²⁸ Even though statins are not considered to be a treatment for NAFLD, they can be used to safely lower plasma cholesterol in patients with the disease.

Renin-angiotensin system (RAS) inhibitors. Research in animals indicates that activation of the renin-angiotensin system contributes to the pathogenesis of NAFLD, but data on the benefits of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in patients with NAFLD are limited, conflicting, and derived largely from retrospective²⁹ and pilot prospective studies.

Based on currently published literature, RAS inhibitors are not considered an NAFLD treatment. However, because cardiovascular disease is a major cause of death in patients with NAFLD, the renal and cardiovascular protection offered by these agents likely lowers mortality in patients with the disease.

Probiotics. The use of probiotics in the treatment of NAFLD is based on the premise that alterations in intestinal microbes and the inflammatory response may improve the disease. Three RCTs involving different formulations of probiotics, synbiotics, or placebo, showed improvement in serum liver markers and insulin resistance, but did not include histologic outcome measures.³⁰ Furthermore, the long-term consequences of altered gut flora are presently unknown. As such, the available evidence does not support the use of probiotics for the treatment of NAFLD.

Polyunsaturated fatty acids (PUFA). Clearly, omega-3 fatty acids have beneficial effects on cardiometabolic risk factors and positively impact lipid metabolism and insulin sensitivity. In addition, a few studies have reported improvement in non-histologic outcome measures of NAFLD, but 2 high-quality RCTs found no benefit of fish oil-based PUFA on histology.^31,32 Thus, current evidence does not support recommending PUFA supplementation for the treatment of NAFLD.

Chinese herbal medicines. At least 56 trials have looked at 75 different Chinese herbal medicines in varying formulations, dosages, routes of administration, and durations of treatment, using various controlled interventions.³³ No trial reported primary outcomes, such as hepatic-related mortality, morbidity, or health care quality of life. Although a large number of the trials reported some positive effects on various biochemical or radiologic measures, the high risk of bias and the limited number of trials testing individual herbal medicines leave efficacy and safety open to question. As such, no Chinese herbal medicines are regarded as treatment for NAFLD at this time.

Target components of metabolic syndrome

Management of the components of metabolic syndrome remains one of the safest and most effective ways to manage NAFLD. Therefore, screening for and treating T2DM, hypertension, and dyslipidemia are priorities. Although obstructive sleep apnea (OSA) is not part of metabolic syndrome, the condition frequently coexists with metabolic syndrome because both entities have obesity as a risk factor.

T2DM. Screen all patients with NAFLD for T2DM and vice-versa because, as noted earlier, patients with diabetes have more severe and progressive NAFLD, and a high proportion of patients with NAFLD have T2DM.^5,6 Although research has not shown metformin to improve histology in NASH, metformin is recommended as a first-line agent for the treatment of T2DM because it aids in weight loss and lowers diabetes-related mortality.³⁴

Pioglitazone is considered a second-line agent. Despite its beneficial effects on insulin sensitivity and hepatic histology, there are concerns about the adverse effects of thiazolidinediones. GLP1 analogues, which improve liver enzymes and reduce hepatic steatosis, are considered third-line agents.

Hypertension. Because approximately 70% of patients with NAFLD have hypertension,³⁵ it is imperative to screen patients for the condition. If blood pressure is >140/90 mm Hg, patients should be managed according to hypertension guidelines. ACE inhibitors or ARBs are recommended as first-line therapy, since blocking the renin-angiotensin system potentially reduces hepatic fibrosis,³⁶ and ARBs may lower transaminases and improve insulin sensitivity in NAFLD.

Dyslipidemia. Treatment of dyslipidemia is essential to lowering cardiovascular mortality in patients with NAFLD. Even though elevated transaminases occur with NAFLD, this should not preclude starting therapy to lower triglycerides to <150 mg/dL and total cholesterol to <200 mg/dL.

OSA. Because of the high prevalence of OSA in patients with NAFLD, physicians should have a high index of suspicion and screen this population for sleep disorders. OSA is associated with an increased risk of NAFLD and advanced fibrosis in NASH.³⁷ Treatment of OSA improves quality of life and controls blood pressure in patients with NAFLD, but it’s currently unclear whether targeting sleep disorders can slow the progression of fibrosis in NAFLD.

Concentrate on the complications of cirrhosis

Patients with NASH cirrhosis, like those with cirrhosis of other etiologies, are at risk for complications, including hepatic encephalopathy, ascites, hepatorenal syndrome, and esophageal variceal hemorrhage. Surveillance to detect these include an annual liver ultrasound, an alpha-fetoprotein test every 6 months, esophagogastroduodenoscopy for varices, and an assessment for liver transplantation. For more on these complications, see, “Cirrhosis complications: Keeping them under control,” J Fam Pract. 2015;64:338-342. NAFLD-associated cirrhosis is the third most frequent indication for liver transplantation in the United States and may become the most frequent indication in the next decade.³⁸

CASE ›  Because the patient’s liver biopsy showed early NASH, we recommended that he aggressively pursue lifestyle modification, including regular physical activity and dietary changes. Additionally, we discussed optimization of glycemic control and continued use of lisinopril for control of hypertension. On follow-up 6 months later, he had lost weight and his BMI was 32 kg/m². In addition, his transaminase levels had improved, but they had not normalized.

We recommended that he continue the same measures, with follow-up every 6 months to ensure compliance with lifestyle modifications and with diabetes and hypertension control.

CORRESPONDENCE
Jaividhya Dasarathy, MD, Metro Health Medical Center, 2500 Metro Health Drive, Cleveland, OH 44109; jdasarathy@metrohealth.org.

Editor’s Note: This is the third installment of a five-part monthly series that will discuss the pathologic, genomic, and health system factors that contribute to the racial survival disparity in breast cancer. The series, which is adapted from an article that originally appeared in CA: A Cancer Journal for Clinicians¹, a journal of the American Cancer Society, will also review exciting and innovative interventions to close the survival gap. This month’s column reviews patterns of care – the second element in the perfect storm.

Mammography

Despite advances in breast cancer imaging technology, the mainstay of breast cancer screening has remained mammography. Chu et al.² found that African American women have less early-stage disease in every age group for each hormone receptor status, and this raises the concern that mammography screening might be inadequate in this population. Although historically, African American women used mammography less than did white women, this difference has fortunately disappeared with time.³ According to results from the 2010 National Health Interview Survey, among women who were 40 years or older, 50.6% of non-Hispanic African Americans and 51.5% of non-Hispanic whites reported having had a mammogram within the past year.⁴

Although mammography uptake may be similar between these groups, there are still differences both in quality and in follow-up of abnormal imaging results. A study of mammography capacity and quality in a large urban setting found that the facilities that served predominantly minority women were more likely to be public institutions (31% vs. 0%) and less likely to be academic (27% vs. 71%), less likely to have digital mammography (18% vs. 71%), and less likely to have dedicated breast imaging specialists reading the films (23% vs. 87%). The authors concluded that the mammography process was broken, with quality differences in the manner in which the centers provided care and reported results.⁵

The accompanying graphic illustrates the disparities seen in breast cancer mammography and care for women in underserved communities on Chicago’s South Side. As the figure demonstrates, there are fewer mammography centers on the city’s South Side, with the concentration of breast cancer imaging and treatment resources localized in the more affluent communities of central and northern Chicago. A total of 300,000 women who were eligible for screening went unscreened because of improper management of resources.

Highlighting the importance of location in breast cancer care, Gehlert et al.⁶ asserted that ensuring that inner-city health facilities have up-to-date, well-maintained equipment and that mammographers have access to continuing training and opportunities for consultation should help reduce breast cancer mortality in African Americans.

With respect to follow-up of abnormal imaging results, a large retrospective cohort study of 6,722 women with abnormal mammogram results seen at a New York academic medical center from January 2002 through December 2002 found longer times to diagnostic follow-up for African American versus white women. The median number of days to diagnostic follow-up was 20 for African American patients versus 14 for white patients. In addition, racial disparities remained significant after the researchers controlled for age, Breast Imaging Reporting and Data System (BI-RADS) category, insurance status, provider practice location, and median household income. More important, in women with a BI-RADS classification of 4 or 5 – signifying a lesion seen on mammography that is either suspicious for or highly suggestive of malignancy, respectively – the median number of days to follow-up among those without same-day additional imaging was 26 for African Americans and 14 for whites (P < .05).⁷

Delays in treatment

A cascade of delays also has been documented in breast cancer care for African American women. Silber et al.⁸ investigated factors associated with differences in breast cancer outcomes in a large population-based study using Surveillance, Epidemiology, and End Results (SEER)-Medicare data. The mean time from diagnosis to treatment was 29.2 days for African Americans versus 22.5 days for whites (P < .001). The authors also found that African Americans were more likely to have very-long treatment delays. At least 6% of African Americans did not initiate treatment within the first 3 months of diagnosis, whereas only 3% of whites failed to start treatment (P < .001). Gwyn et al.⁹ also found potentially clinically significant treatment delays more often for African American women than for white women. The time from medical consultation to the initiation of treatment was longer than 3 months for 22.4% of African American women versus 14.3% of white women. Three months was chosen as a clinically significant time period, because Richards et al.¹⁰ demonstrated that a delay ≥ to 3 months affects survival. Thus, delays in the diagnosis and treatment of African American women are factors that worsen the survival gap.

Misuse of treatment

Once treatment is initiated, African Americans often receive inappropriate therapy, studies have demonstrated. In a prospective analysis of 957 patients in 101 oncology practices, Griggs et al.¹¹ found more frequent use of non–guideline concordant adjuvant chemotherapy regimens in African American women. In a univariate analysis, African American patients were more likely than were whites to receive a nonstandard regimen (19% vs. 11%; P = .047). Although we will discuss further in this column whether guidelines based on clinical trials are appropriate for African American patients, the study demonstrates that these women are not uniformly receiving standard-of-care treatment.

Underuse of treatment

In addition to misuse of treatment, studies also have examined undertreatment of African American patients with breast cancer. One study investigated chemotherapy administration among African American patients with stage I-III breast cancer at 10 different treatment sites. Compared with white patients, African Americans received a lower dose proportion (actual vs. expected dose) and lower relative dose intensity.

The authors found that between-group differences in biological and medical characteristics, such as tolerance of therapy, comorbidities, and leukocyte counts, did not explain these variations in treatment. In fact, despite the association between lower leukocyte counts and African American ethnicity, there was no evidence that white blood cell levels accounted for the difference in dose proportion or relative dose intensity. Significantly, the authors discovered that more African Americans had chemotherapy dose reductions in the first cycle of treatment, perhaps indicating physician assumptions regarding African American patients’ ability to tolerate chemotherapy.¹²

Silber et al.⁸ also examined differences in the administration of chemotherapy between white and African American breast cancer patients. The authors found that 3.7% of African Americans received both an anthracycline and a taxane; that figure rose to 5.0% among whites who were matched to African Americans at presentation.

Bickell et al.¹³ explored further racial disparity in the underuse of adjuvant breast cancer treatment. The researchers examined the medical records of 677 women treated surgically for stage I or II breast cancer. The study defined underuse as omissions of radiotherapy after breast-conserving surgery, adjuvant chemotherapy after resection of hormone receptor–negative tumors ≥ 1 cm, or hormonal therapy for receptor-positive tumors ≥ 1 cm. Underuse of appropriate adjuvant treatment was found in 34% of African American patients versus 16% of white patients (P less than .001). There were racial disparities present in all three adjuvant therapies assessed.

Hormonal therapy has been shown effective in clinical trials for preventing breast cancer recurrence and death in women with early-stage breast cancer.¹⁴ The study by Bickell et al.¹³ documented underuse of this treatment in African American patients. Partridge et al.¹⁵ conducted the largest study of oral antineoplastic use outside of a clinical trial setting. Their study consisted of 2,378 primary breast cancer patients enrolled in New Jersey’s Medicaid or pharmaceutical assistance program; the main outcome was the number of days covered by filled tamoxifen prescriptions in the first year of therapy. The study found that nonwhite patients had significantly lower adherence rates than did whites. Although further investigation is needed to determine the drivers of this nonadherence in African American patients, medication cost has been proposed as a significant factor leading to underuse of these agents. Streeter et al.¹⁶ analyzed a nationally representative pharmacy claims database for oral antineoplastics and calculated abandonment rates for the initial claim. Not surprisingly, high cost sharing and low incomes were associated with a higher abandonment rate (P < .05). Despite being an important component of health equity research, treatment adherence has been identified by the Association of American Medical Colleges as a critically underrepresented area of disparities-focused health services research.¹⁷ More attention to this area is needed to understand the underuse of hormonal therapies in African American breast cancer patients.

The treatment strategies that have been shown to be delayed, underused, or misused in African American patients in the aforementioned studies have improved disease-free and overall survival in large randomized trials. Furthermore, diminished total dose and dose intensity of adjuvant chemotherapy both have been associated with lower breast cancer survival rates.^18,19 These quality-of-care failures in breast cancer treatment for minority patients are thought to partially explain the survival disparity between African Americans and whites. It has been proposed that patients in both groups derive a similar benefit from systemic therapy when it is administered in accordance with their clinical and pathologic presentation,²⁰ but that assumption becomes more nuanced when the clinical trial experience is reviewed.

Clinical trial experience

Dignam²⁰ examined survival by race in several National Surgical Adjuvant Breast and Bowel Project trials. He found that the benefit from systemic adjuvant therapy for reductions in disease recurrence and mortality was comparable between African American and white patients. His survey of trials consistently indicated equivalent disease-free survival, but a mortality deficit for African Americans also was found consistently. Among African Americans, the excess risk of mortality was 21% for those who were lymph node–negative and 17% for those who were lymph node–positive. The excess mortality risk was thought to be attributable to greater mortality from noncancer causes among African American patients rather than a failure of African Americans to respond to breast cancer treatment.

In contrast to Dignam’s findings²⁰, Hershman et al.²¹ assessed the association between race and treatment discontinuation/delay, white blood cell counts, and survival in women enrolled in the Southwest Oncology Group adjuvant breast cancer trials. The study found that African American women were significantly more likely to experience treatment discontinuation/delay than were white women (87% vs. 81%, respectively; P = .04). These delays were not accounted for by toxicities, which were experienced in similar proportions by race. African American women also were more likely to miss appointments (19% vs. 9%; P = .0002); perhaps, as Hassett and Griggs²² speculated, this finding speaks to economic barriers, including the inability to arrange alternate child care, miss work, or afford transportation to the clinic. Despite these barriers to care for African American patients, they still received the same mean relative dose intensity (87% vs. 86%).

In their survival analysis, Hershman et al.²¹ controlled for treatment-related factors such as dose reductions and delays, body surface area, baseline white blood cell counts, and other predictors of survival and still found that African Americans had worse disease-free and overall survival than did white women. The authors concluded that the study was “unable to demonstrate that any factor related to treatment quality or delivery contributed to racial differences in survival between the groups.”²¹ The study thus established two important findings related to the disparity gap. First, even in the controlled setting of a clinical trial, African American patients faced barriers to optimal treatment,²² and second, despite attempts to control for treatment quality and delivery, African American women still had worse outcomes. These findings suggest that tumor biology and genomics remain important.

In next month’s installment, we will discuss interventions aimed at closing the racial survival disparity in breast cancer. Eliminating racial disparities in cancer mortality through effective interventions has become an increasingly important imperative in federal, state, and community health care programs.

Other installments of this column can be found in the Related Content box.

1. Daly B, Olopade OI. A perfect storm: How tumor biology, genomics, and health care delivery patterns collide to create a racial survival disparity in breast cancer and proposed interventions for change. CA Cancer J Clin. 2015 May-Jun;65(3):221-38.

2. Chu KC, Lamar CA, Freeman HP. Racial disparities in breast carcinoma survival rates: Separating factors that affect diagnosis from factors that affect treatment. Cancer. 2003 Jun;97(11):2853-60.

3. DeLancey JO, Thun MJ, Jemal A, Ward EM. Recent trends in black-white disparities in cancer mortality. Cancer Epidemiol Biomarkers Prev. 2008 Nov;17(11):2908-12.

4. DeSantis C, Naishadham D, Jemal A. Cancer statistics for African Americans, 2013. CA Cancer J Clin. 2013 Nov;63(3):151-66.

5. Ansell D, Grabler P, Whitman S, et al. A community effort to reduce the black/white breast cancer mortality disparity in Chicago. Cancer Causes Control. 2009 Nov;20(9):1681-8.

6. Gehlert S, Sohmer D, Sacks T, Mininger C, McClintock M, Olopade O. Targeting health disparities: a model linking upstream determinants to downstream interventions. Health Aff (Millwood). 2008 Mar-Apr;27(2):339-49.

7. Press R, Carrasquillo O, Sciacca RR, Giardina EG. Racial/ethnic disparities in time to follow-up after an abnormal mammogram. J Womens Health (Larchmt). 2008 Jul;17(6):923-30.

8. Silber JH, Rosenbaum PR, Clark AS, et al. Characteristics associated with differences in survival among black and white women with breast cancer. JAMA. 2013 Jul;310(4):389-397.

9. Gwyn K, Bondy ML, Cohen DS, et al. Racial differences in diagnosis, treatment, and clinical delays in a population-based study of patients with newly diagnosed breast carcinoma. Cancer. 2004 Apr;100(8):1595-604.

10. Richards MA, Westcombe AM, Love SB, Littlejohns P, Ramirez AJ. Influence of delay on survival in patients with breast cancer: a systematic review. Lancet. 1999 Apr 3;353(9159):1119-26.

11. Griggs JJ, Culakova E, Sorbero ME, et al. Social and racial differences in selection of breast cancer adjuvant chemotherapy regimens. J Clin Oncol. 2007 Jun 20;25(18):2522-7.

12. Griggs JJ, Sorbero ME, Stark AT, Heininger SE, Dick AW. Racial disparity in the dose and dose intensity of breast cancer adjuvant chemotherapy. Breast Cancer Res Treat. 2003 Sep;81(1):21-31.

13. Bickell NA, Wang JJ, Oluwole S, et al. Missed opportunities: racial disparities in adjuvant breast cancer treatment. J Clin Oncol. 2006 Mar 20;24(9):1357-62.
14. Fisher B, Costantino J, Redmond C, et al. A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med. 1989 Feb 23;320(8):479-84.

15. Partridge AH, Wang PS, Winer EP, Avorn J. Nonadherence to adjuvant tamoxifen therapy in women with primary breast cancer. J Clin Oncol. 2003 Feb 15;21(4):602-6.

16. Streeter SB, Schwartzberg L, Husain N, Johnsrud M. Patient and plan characteristics affecting abandonment of oral oncolytic prescriptions. J Oncol Pract. 2011 Jul;7(3 Suppl):46s-51s.

17. Alberti PM KN, Sutton K, Johnson BH, Holve E. The state of health equity research: closing knowledge gaps to address inequities. ©2014 Association of American Medical Colleges. May not be reproduced or distributed without prior permission.

18. Wood WC, Budman DR, Korzun AH, et al. Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med. 1994 May 5;330(18):1253-9.

19. Budman DR, Berry DA, Cirrincione CT, et al. Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. The Cancer and Leukemia Group B. J Natl Cancer Inst. 1998 Aug 19;90(16):1205-11.

20. Dignam JJ. Efficacy of systemic adjuvant therapy for breast cancer in African-American and Caucasian women. J Natl Cancer Inst Monogr. 2001(30):36-43.

21. Hershman DL, Unger JM, Barlow WE, et al. Treatment quality and outcomes of African American versus white breast cancer patients: retrospective analysis of Southwest Oncology studies S8814/S8897. J Clin Oncol. 2009 May;27(13):2157-62.

22. Hassett MJ, Griggs JJ. Disparities in breast cancer adjuvant chemotherapy: moving beyond yes or no. J Clin Oncol. 2009 May 1;27(13):2120-1.

Bobby Daly, MD, MBA, is the chief fellow in the section of hematology/oncology at the University of Chicago Medicine. His clinical focus is breast and thoracic oncology, and his research focus is health services. Specifically, Dr. Daly researches disparities in oncology care delivery, oncology health care utilization, aggressive end-of-life oncology care, and oncology payment models. He received his MD and MBA from Harvard Medical School and Harvard Business School, both in Boston, and a BA in Economics and History from Stanford (Calif.) University. He was the recipient of the Dean’s Award at Harvard Medical and Business Schools.

Olufunmilayo Olopade, MD, FACP, OON, is the Walter L. Palmer Distinguished Service Professor of Medicine and Human Genetics, and director, Center for Global Health at the University of Chicago. She is adopting emerging high throughput genomic and informatics strategies to identify genetic and nongenetic risk factors for breast cancer in order to implement precision health care in diverse populations. This innovative approach has the potential to improve the quality of care and reduce costs while saving more lives.

Disclosures: Dr. Olopade serves on the Medical Advisory Board for CancerIQ. Dr. Daly serves as a director of Quadrant Holdings Corporation and receives compensation from this entity. Frontline Medical Communications is a subsidiary of Quadrant Holdings Corporation.

Published in conjunction with Susan G. Komen®.

Editor’s Note: This is the third installment of a five-part monthly series that will discuss the pathologic, genomic, and health system factors that contribute to the racial survival disparity in breast cancer. The series, which is adapted from an article that originally appeared in CA: A Cancer Journal for Clinicians¹, a journal of the American Cancer Society, will also review exciting and innovative interventions to close the survival gap. This month’s column reviews patterns of care – the second element in the perfect storm.

Mammography

Despite advances in breast cancer imaging technology, the mainstay of breast cancer screening has remained mammography. Chu et al.² found that African American women have less early-stage disease in every age group for each hormone receptor status, and this raises the concern that mammography screening might be inadequate in this population. Although historically, African American women used mammography less than did white women, this difference has fortunately disappeared with time.³ According to results from the 2010 National Health Interview Survey, among women who were 40 years or older, 50.6% of non-Hispanic African Americans and 51.5% of non-Hispanic whites reported having had a mammogram within the past year.⁴

Although mammography uptake may be similar between these groups, there are still differences both in quality and in follow-up of abnormal imaging results. A study of mammography capacity and quality in a large urban setting found that the facilities that served predominantly minority women were more likely to be public institutions (31% vs. 0%) and less likely to be academic (27% vs. 71%), less likely to have digital mammography (18% vs. 71%), and less likely to have dedicated breast imaging specialists reading the films (23% vs. 87%). The authors concluded that the mammography process was broken, with quality differences in the manner in which the centers provided care and reported results.⁵

The accompanying graphic illustrates the disparities seen in breast cancer mammography and care for women in underserved communities on Chicago’s South Side. As the figure demonstrates, there are fewer mammography centers on the city’s South Side, with the concentration of breast cancer imaging and treatment resources localized in the more affluent communities of central and northern Chicago. A total of 300,000 women who were eligible for screening went unscreened because of improper management of resources.

Highlighting the importance of location in breast cancer care, Gehlert et al.⁶ asserted that ensuring that inner-city health facilities have up-to-date, well-maintained equipment and that mammographers have access to continuing training and opportunities for consultation should help reduce breast cancer mortality in African Americans.

With respect to follow-up of abnormal imaging results, a large retrospective cohort study of 6,722 women with abnormal mammogram results seen at a New York academic medical center from January 2002 through December 2002 found longer times to diagnostic follow-up for African American versus white women. The median number of days to diagnostic follow-up was 20 for African American patients versus 14 for white patients. In addition, racial disparities remained significant after the researchers controlled for age, Breast Imaging Reporting and Data System (BI-RADS) category, insurance status, provider practice location, and median household income. More important, in women with a BI-RADS classification of 4 or 5 – signifying a lesion seen on mammography that is either suspicious for or highly suggestive of malignancy, respectively – the median number of days to follow-up among those without same-day additional imaging was 26 for African Americans and 14 for whites (P < .05).⁷

Delays in treatment

A cascade of delays also has been documented in breast cancer care for African American women. Silber et al.⁸ investigated factors associated with differences in breast cancer outcomes in a large population-based study using Surveillance, Epidemiology, and End Results (SEER)-Medicare data. The mean time from diagnosis to treatment was 29.2 days for African Americans versus 22.5 days for whites (P < .001). The authors also found that African Americans were more likely to have very-long treatment delays. At least 6% of African Americans did not initiate treatment within the first 3 months of diagnosis, whereas only 3% of whites failed to start treatment (P < .001). Gwyn et al.⁹ also found potentially clinically significant treatment delays more often for African American women than for white women. The time from medical consultation to the initiation of treatment was longer than 3 months for 22.4% of African American women versus 14.3% of white women. Three months was chosen as a clinically significant time period, because Richards et al.¹⁰ demonstrated that a delay ≥ to 3 months affects survival. Thus, delays in the diagnosis and treatment of African American women are factors that worsen the survival gap.

Misuse of treatment

Once treatment is initiated, African Americans often receive inappropriate therapy, studies have demonstrated. In a prospective analysis of 957 patients in 101 oncology practices, Griggs et al.¹¹ found more frequent use of non–guideline concordant adjuvant chemotherapy regimens in African American women. In a univariate analysis, African American patients were more likely than were whites to receive a nonstandard regimen (19% vs. 11%; P = .047). Although we will discuss further in this column whether guidelines based on clinical trials are appropriate for African American patients, the study demonstrates that these women are not uniformly receiving standard-of-care treatment.

Underuse of treatment

In addition to misuse of treatment, studies also have examined undertreatment of African American patients with breast cancer. One study investigated chemotherapy administration among African American patients with stage I-III breast cancer at 10 different treatment sites. Compared with white patients, African Americans received a lower dose proportion (actual vs. expected dose) and lower relative dose intensity.

The authors found that between-group differences in biological and medical characteristics, such as tolerance of therapy, comorbidities, and leukocyte counts, did not explain these variations in treatment. In fact, despite the association between lower leukocyte counts and African American ethnicity, there was no evidence that white blood cell levels accounted for the difference in dose proportion or relative dose intensity. Significantly, the authors discovered that more African Americans had chemotherapy dose reductions in the first cycle of treatment, perhaps indicating physician assumptions regarding African American patients’ ability to tolerate chemotherapy.¹²

Silber et al.⁸ also examined differences in the administration of chemotherapy between white and African American breast cancer patients. The authors found that 3.7% of African Americans received both an anthracycline and a taxane; that figure rose to 5.0% among whites who were matched to African Americans at presentation.

Bickell et al.¹³ explored further racial disparity in the underuse of adjuvant breast cancer treatment. The researchers examined the medical records of 677 women treated surgically for stage I or II breast cancer. The study defined underuse as omissions of radiotherapy after breast-conserving surgery, adjuvant chemotherapy after resection of hormone receptor–negative tumors ≥ 1 cm, or hormonal therapy for receptor-positive tumors ≥ 1 cm. Underuse of appropriate adjuvant treatment was found in 34% of African American patients versus 16% of white patients (P less than .001). There were racial disparities present in all three adjuvant therapies assessed.

Hormonal therapy has been shown effective in clinical trials for preventing breast cancer recurrence and death in women with early-stage breast cancer.¹⁴ The study by Bickell et al.¹³ documented underuse of this treatment in African American patients. Partridge et al.¹⁵ conducted the largest study of oral antineoplastic use outside of a clinical trial setting. Their study consisted of 2,378 primary breast cancer patients enrolled in New Jersey’s Medicaid or pharmaceutical assistance program; the main outcome was the number of days covered by filled tamoxifen prescriptions in the first year of therapy. The study found that nonwhite patients had significantly lower adherence rates than did whites. Although further investigation is needed to determine the drivers of this nonadherence in African American patients, medication cost has been proposed as a significant factor leading to underuse of these agents. Streeter et al.¹⁶ analyzed a nationally representative pharmacy claims database for oral antineoplastics and calculated abandonment rates for the initial claim. Not surprisingly, high cost sharing and low incomes were associated with a higher abandonment rate (P < .05). Despite being an important component of health equity research, treatment adherence has been identified by the Association of American Medical Colleges as a critically underrepresented area of disparities-focused health services research.¹⁷ More attention to this area is needed to understand the underuse of hormonal therapies in African American breast cancer patients.

The treatment strategies that have been shown to be delayed, underused, or misused in African American patients in the aforementioned studies have improved disease-free and overall survival in large randomized trials. Furthermore, diminished total dose and dose intensity of adjuvant chemotherapy both have been associated with lower breast cancer survival rates.^18,19 These quality-of-care failures in breast cancer treatment for minority patients are thought to partially explain the survival disparity between African Americans and whites. It has been proposed that patients in both groups derive a similar benefit from systemic therapy when it is administered in accordance with their clinical and pathologic presentation,²⁰ but that assumption becomes more nuanced when the clinical trial experience is reviewed.

Clinical trial experience

Dignam²⁰ examined survival by race in several National Surgical Adjuvant Breast and Bowel Project trials. He found that the benefit from systemic adjuvant therapy for reductions in disease recurrence and mortality was comparable between African American and white patients. His survey of trials consistently indicated equivalent disease-free survival, but a mortality deficit for African Americans also was found consistently. Among African Americans, the excess risk of mortality was 21% for those who were lymph node–negative and 17% for those who were lymph node–positive. The excess mortality risk was thought to be attributable to greater mortality from noncancer causes among African American patients rather than a failure of African Americans to respond to breast cancer treatment.

In contrast to Dignam’s findings²⁰, Hershman et al.²¹ assessed the association between race and treatment discontinuation/delay, white blood cell counts, and survival in women enrolled in the Southwest Oncology Group adjuvant breast cancer trials. The study found that African American women were significantly more likely to experience treatment discontinuation/delay than were white women (87% vs. 81%, respectively; P = .04). These delays were not accounted for by toxicities, which were experienced in similar proportions by race. African American women also were more likely to miss appointments (19% vs. 9%; P = .0002); perhaps, as Hassett and Griggs²² speculated, this finding speaks to economic barriers, including the inability to arrange alternate child care, miss work, or afford transportation to the clinic. Despite these barriers to care for African American patients, they still received the same mean relative dose intensity (87% vs. 86%).

In their survival analysis, Hershman et al.²¹ controlled for treatment-related factors such as dose reductions and delays, body surface area, baseline white blood cell counts, and other predictors of survival and still found that African Americans had worse disease-free and overall survival than did white women. The authors concluded that the study was “unable to demonstrate that any factor related to treatment quality or delivery contributed to racial differences in survival between the groups.”²¹ The study thus established two important findings related to the disparity gap. First, even in the controlled setting of a clinical trial, African American patients faced barriers to optimal treatment,²² and second, despite attempts to control for treatment quality and delivery, African American women still had worse outcomes. These findings suggest that tumor biology and genomics remain important.

In next month’s installment, we will discuss interventions aimed at closing the racial survival disparity in breast cancer. Eliminating racial disparities in cancer mortality through effective interventions has become an increasingly important imperative in federal, state, and community health care programs.

Other installments of this column can be found in the Related Content box.

1. Daly B, Olopade OI. A perfect storm: How tumor biology, genomics, and health care delivery patterns collide to create a racial survival disparity in breast cancer and proposed interventions for change. CA Cancer J Clin. 2015 May-Jun;65(3):221-38.

2. Chu KC, Lamar CA, Freeman HP. Racial disparities in breast carcinoma survival rates: Separating factors that affect diagnosis from factors that affect treatment. Cancer. 2003 Jun;97(11):2853-60.

3. DeLancey JO, Thun MJ, Jemal A, Ward EM. Recent trends in black-white disparities in cancer mortality. Cancer Epidemiol Biomarkers Prev. 2008 Nov;17(11):2908-12.

4. DeSantis C, Naishadham D, Jemal A. Cancer statistics for African Americans, 2013. CA Cancer J Clin. 2013 Nov;63(3):151-66.

5. Ansell D, Grabler P, Whitman S, et al. A community effort to reduce the black/white breast cancer mortality disparity in Chicago. Cancer Causes Control. 2009 Nov;20(9):1681-8.

6. Gehlert S, Sohmer D, Sacks T, Mininger C, McClintock M, Olopade O. Targeting health disparities: a model linking upstream determinants to downstream interventions. Health Aff (Millwood). 2008 Mar-Apr;27(2):339-49.

7. Press R, Carrasquillo O, Sciacca RR, Giardina EG. Racial/ethnic disparities in time to follow-up after an abnormal mammogram. J Womens Health (Larchmt). 2008 Jul;17(6):923-30.

8. Silber JH, Rosenbaum PR, Clark AS, et al. Characteristics associated with differences in survival among black and white women with breast cancer. JAMA. 2013 Jul;310(4):389-397.

9. Gwyn K, Bondy ML, Cohen DS, et al. Racial differences in diagnosis, treatment, and clinical delays in a population-based study of patients with newly diagnosed breast carcinoma. Cancer. 2004 Apr;100(8):1595-604.

10. Richards MA, Westcombe AM, Love SB, Littlejohns P, Ramirez AJ. Influence of delay on survival in patients with breast cancer: a systematic review. Lancet. 1999 Apr 3;353(9159):1119-26.

11. Griggs JJ, Culakova E, Sorbero ME, et al. Social and racial differences in selection of breast cancer adjuvant chemotherapy regimens. J Clin Oncol. 2007 Jun 20;25(18):2522-7.

12. Griggs JJ, Sorbero ME, Stark AT, Heininger SE, Dick AW. Racial disparity in the dose and dose intensity of breast cancer adjuvant chemotherapy. Breast Cancer Res Treat. 2003 Sep;81(1):21-31.

13. Bickell NA, Wang JJ, Oluwole S, et al. Missed opportunities: racial disparities in adjuvant breast cancer treatment. J Clin Oncol. 2006 Mar 20;24(9):1357-62.
14. Fisher B, Costantino J, Redmond C, et al. A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med. 1989 Feb 23;320(8):479-84.

15. Partridge AH, Wang PS, Winer EP, Avorn J. Nonadherence to adjuvant tamoxifen therapy in women with primary breast cancer. J Clin Oncol. 2003 Feb 15;21(4):602-6.

16. Streeter SB, Schwartzberg L, Husain N, Johnsrud M. Patient and plan characteristics affecting abandonment of oral oncolytic prescriptions. J Oncol Pract. 2011 Jul;7(3 Suppl):46s-51s.

17. Alberti PM KN, Sutton K, Johnson BH, Holve E. The state of health equity research: closing knowledge gaps to address inequities. ©2014 Association of American Medical Colleges. May not be reproduced or distributed without prior permission.

18. Wood WC, Budman DR, Korzun AH, et al. Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med. 1994 May 5;330(18):1253-9.

19. Budman DR, Berry DA, Cirrincione CT, et al. Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. The Cancer and Leukemia Group B. J Natl Cancer Inst. 1998 Aug 19;90(16):1205-11.

20. Dignam JJ. Efficacy of systemic adjuvant therapy for breast cancer in African-American and Caucasian women. J Natl Cancer Inst Monogr. 2001(30):36-43.

21. Hershman DL, Unger JM, Barlow WE, et al. Treatment quality and outcomes of African American versus white breast cancer patients: retrospective analysis of Southwest Oncology studies S8814/S8897. J Clin Oncol. 2009 May;27(13):2157-62.

22. Hassett MJ, Griggs JJ. Disparities in breast cancer adjuvant chemotherapy: moving beyond yes or no. J Clin Oncol. 2009 May 1;27(13):2120-1.

Bobby Daly, MD, MBA, is the chief fellow in the section of hematology/oncology at the University of Chicago Medicine. His clinical focus is breast and thoracic oncology, and his research focus is health services. Specifically, Dr. Daly researches disparities in oncology care delivery, oncology health care utilization, aggressive end-of-life oncology care, and oncology payment models. He received his MD and MBA from Harvard Medical School and Harvard Business School, both in Boston, and a BA in Economics and History from Stanford (Calif.) University. He was the recipient of the Dean’s Award at Harvard Medical and Business Schools.

Olufunmilayo Olopade, MD, FACP, OON, is the Walter L. Palmer Distinguished Service Professor of Medicine and Human Genetics, and director, Center for Global Health at the University of Chicago. She is adopting emerging high throughput genomic and informatics strategies to identify genetic and nongenetic risk factors for breast cancer in order to implement precision health care in diverse populations. This innovative approach has the potential to improve the quality of care and reduce costs while saving more lives.

Disclosures: Dr. Olopade serves on the Medical Advisory Board for CancerIQ. Dr. Daly serves as a director of Quadrant Holdings Corporation and receives compensation from this entity. Frontline Medical Communications is a subsidiary of Quadrant Holdings Corporation.

Published in conjunction with Susan G. Komen®.

Editor’s Note: This is the third installment of a five-part monthly series that will discuss the pathologic, genomic, and health system factors that contribute to the racial survival disparity in breast cancer. The series, which is adapted from an article that originally appeared in CA: A Cancer Journal for Clinicians¹, a journal of the American Cancer Society, will also review exciting and innovative interventions to close the survival gap. This month’s column reviews patterns of care – the second element in the perfect storm.

Mammography

Despite advances in breast cancer imaging technology, the mainstay of breast cancer screening has remained mammography. Chu et al.² found that African American women have less early-stage disease in every age group for each hormone receptor status, and this raises the concern that mammography screening might be inadequate in this population. Although historically, African American women used mammography less than did white women, this difference has fortunately disappeared with time.³ According to results from the 2010 National Health Interview Survey, among women who were 40 years or older, 50.6% of non-Hispanic African Americans and 51.5% of non-Hispanic whites reported having had a mammogram within the past year.⁴

Although mammography uptake may be similar between these groups, there are still differences both in quality and in follow-up of abnormal imaging results. A study of mammography capacity and quality in a large urban setting found that the facilities that served predominantly minority women were more likely to be public institutions (31% vs. 0%) and less likely to be academic (27% vs. 71%), less likely to have digital mammography (18% vs. 71%), and less likely to have dedicated breast imaging specialists reading the films (23% vs. 87%). The authors concluded that the mammography process was broken, with quality differences in the manner in which the centers provided care and reported results.⁵

The accompanying graphic illustrates the disparities seen in breast cancer mammography and care for women in underserved communities on Chicago’s South Side. As the figure demonstrates, there are fewer mammography centers on the city’s South Side, with the concentration of breast cancer imaging and treatment resources localized in the more affluent communities of central and northern Chicago. A total of 300,000 women who were eligible for screening went unscreened because of improper management of resources.

Highlighting the importance of location in breast cancer care, Gehlert et al.⁶ asserted that ensuring that inner-city health facilities have up-to-date, well-maintained equipment and that mammographers have access to continuing training and opportunities for consultation should help reduce breast cancer mortality in African Americans.

With respect to follow-up of abnormal imaging results, a large retrospective cohort study of 6,722 women with abnormal mammogram results seen at a New York academic medical center from January 2002 through December 2002 found longer times to diagnostic follow-up for African American versus white women. The median number of days to diagnostic follow-up was 20 for African American patients versus 14 for white patients. In addition, racial disparities remained significant after the researchers controlled for age, Breast Imaging Reporting and Data System (BI-RADS) category, insurance status, provider practice location, and median household income. More important, in women with a BI-RADS classification of 4 or 5 – signifying a lesion seen on mammography that is either suspicious for or highly suggestive of malignancy, respectively – the median number of days to follow-up among those without same-day additional imaging was 26 for African Americans and 14 for whites (P < .05).⁷

Delays in treatment

A cascade of delays also has been documented in breast cancer care for African American women. Silber et al.⁸ investigated factors associated with differences in breast cancer outcomes in a large population-based study using Surveillance, Epidemiology, and End Results (SEER)-Medicare data. The mean time from diagnosis to treatment was 29.2 days for African Americans versus 22.5 days for whites (P < .001). The authors also found that African Americans were more likely to have very-long treatment delays. At least 6% of African Americans did not initiate treatment within the first 3 months of diagnosis, whereas only 3% of whites failed to start treatment (P < .001). Gwyn et al.⁹ also found potentially clinically significant treatment delays more often for African American women than for white women. The time from medical consultation to the initiation of treatment was longer than 3 months for 22.4% of African American women versus 14.3% of white women. Three months was chosen as a clinically significant time period, because Richards et al.¹⁰ demonstrated that a delay ≥ to 3 months affects survival. Thus, delays in the diagnosis and treatment of African American women are factors that worsen the survival gap.

Misuse of treatment

Once treatment is initiated, African Americans often receive inappropriate therapy, studies have demonstrated. In a prospective analysis of 957 patients in 101 oncology practices, Griggs et al.¹¹ found more frequent use of non–guideline concordant adjuvant chemotherapy regimens in African American women. In a univariate analysis, African American patients were more likely than were whites to receive a nonstandard regimen (19% vs. 11%; P = .047). Although we will discuss further in this column whether guidelines based on clinical trials are appropriate for African American patients, the study demonstrates that these women are not uniformly receiving standard-of-care treatment.

Underuse of treatment

In addition to misuse of treatment, studies also have examined undertreatment of African American patients with breast cancer. One study investigated chemotherapy administration among African American patients with stage I-III breast cancer at 10 different treatment sites. Compared with white patients, African Americans received a lower dose proportion (actual vs. expected dose) and lower relative dose intensity.

The authors found that between-group differences in biological and medical characteristics, such as tolerance of therapy, comorbidities, and leukocyte counts, did not explain these variations in treatment. In fact, despite the association between lower leukocyte counts and African American ethnicity, there was no evidence that white blood cell levels accounted for the difference in dose proportion or relative dose intensity. Significantly, the authors discovered that more African Americans had chemotherapy dose reductions in the first cycle of treatment, perhaps indicating physician assumptions regarding African American patients’ ability to tolerate chemotherapy.¹²

Silber et al.⁸ also examined differences in the administration of chemotherapy between white and African American breast cancer patients. The authors found that 3.7% of African Americans received both an anthracycline and a taxane; that figure rose to 5.0% among whites who were matched to African Americans at presentation.

Bickell et al.¹³ explored further racial disparity in the underuse of adjuvant breast cancer treatment. The researchers examined the medical records of 677 women treated surgically for stage I or II breast cancer. The study defined underuse as omissions of radiotherapy after breast-conserving surgery, adjuvant chemotherapy after resection of hormone receptor–negative tumors ≥ 1 cm, or hormonal therapy for receptor-positive tumors ≥ 1 cm. Underuse of appropriate adjuvant treatment was found in 34% of African American patients versus 16% of white patients (P less than .001). There were racial disparities present in all three adjuvant therapies assessed.

Hormonal therapy has been shown effective in clinical trials for preventing breast cancer recurrence and death in women with early-stage breast cancer.¹⁴ The study by Bickell et al.¹³ documented underuse of this treatment in African American patients. Partridge et al.¹⁵ conducted the largest study of oral antineoplastic use outside of a clinical trial setting. Their study consisted of 2,378 primary breast cancer patients enrolled in New Jersey’s Medicaid or pharmaceutical assistance program; the main outcome was the number of days covered by filled tamoxifen prescriptions in the first year of therapy. The study found that nonwhite patients had significantly lower adherence rates than did whites. Although further investigation is needed to determine the drivers of this nonadherence in African American patients, medication cost has been proposed as a significant factor leading to underuse of these agents. Streeter et al.¹⁶ analyzed a nationally representative pharmacy claims database for oral antineoplastics and calculated abandonment rates for the initial claim. Not surprisingly, high cost sharing and low incomes were associated with a higher abandonment rate (P < .05). Despite being an important component of health equity research, treatment adherence has been identified by the Association of American Medical Colleges as a critically underrepresented area of disparities-focused health services research.¹⁷ More attention to this area is needed to understand the underuse of hormonal therapies in African American breast cancer patients.

The treatment strategies that have been shown to be delayed, underused, or misused in African American patients in the aforementioned studies have improved disease-free and overall survival in large randomized trials. Furthermore, diminished total dose and dose intensity of adjuvant chemotherapy both have been associated with lower breast cancer survival rates.^18,19 These quality-of-care failures in breast cancer treatment for minority patients are thought to partially explain the survival disparity between African Americans and whites. It has been proposed that patients in both groups derive a similar benefit from systemic therapy when it is administered in accordance with their clinical and pathologic presentation,²⁰ but that assumption becomes more nuanced when the clinical trial experience is reviewed.

Clinical trial experience

Dignam²⁰ examined survival by race in several National Surgical Adjuvant Breast and Bowel Project trials. He found that the benefit from systemic adjuvant therapy for reductions in disease recurrence and mortality was comparable between African American and white patients. His survey of trials consistently indicated equivalent disease-free survival, but a mortality deficit for African Americans also was found consistently. Among African Americans, the excess risk of mortality was 21% for those who were lymph node–negative and 17% for those who were lymph node–positive. The excess mortality risk was thought to be attributable to greater mortality from noncancer causes among African American patients rather than a failure of African Americans to respond to breast cancer treatment.

In contrast to Dignam’s findings²⁰, Hershman et al.²¹ assessed the association between race and treatment discontinuation/delay, white blood cell counts, and survival in women enrolled in the Southwest Oncology Group adjuvant breast cancer trials. The study found that African American women were significantly more likely to experience treatment discontinuation/delay than were white women (87% vs. 81%, respectively; P = .04). These delays were not accounted for by toxicities, which were experienced in similar proportions by race. African American women also were more likely to miss appointments (19% vs. 9%; P = .0002); perhaps, as Hassett and Griggs²² speculated, this finding speaks to economic barriers, including the inability to arrange alternate child care, miss work, or afford transportation to the clinic. Despite these barriers to care for African American patients, they still received the same mean relative dose intensity (87% vs. 86%).

In their survival analysis, Hershman et al.²¹ controlled for treatment-related factors such as dose reductions and delays, body surface area, baseline white blood cell counts, and other predictors of survival and still found that African Americans had worse disease-free and overall survival than did white women. The authors concluded that the study was “unable to demonstrate that any factor related to treatment quality or delivery contributed to racial differences in survival between the groups.”²¹ The study thus established two important findings related to the disparity gap. First, even in the controlled setting of a clinical trial, African American patients faced barriers to optimal treatment,²² and second, despite attempts to control for treatment quality and delivery, African American women still had worse outcomes. These findings suggest that tumor biology and genomics remain important.

In next month’s installment, we will discuss interventions aimed at closing the racial survival disparity in breast cancer. Eliminating racial disparities in cancer mortality through effective interventions has become an increasingly important imperative in federal, state, and community health care programs.

Other installments of this column can be found in the Related Content box.

1. Daly B, Olopade OI. A perfect storm: How tumor biology, genomics, and health care delivery patterns collide to create a racial survival disparity in breast cancer and proposed interventions for change. CA Cancer J Clin. 2015 May-Jun;65(3):221-38.

2. Chu KC, Lamar CA, Freeman HP. Racial disparities in breast carcinoma survival rates: Separating factors that affect diagnosis from factors that affect treatment. Cancer. 2003 Jun;97(11):2853-60.

3. DeLancey JO, Thun MJ, Jemal A, Ward EM. Recent trends in black-white disparities in cancer mortality. Cancer Epidemiol Biomarkers Prev. 2008 Nov;17(11):2908-12.

4. DeSantis C, Naishadham D, Jemal A. Cancer statistics for African Americans, 2013. CA Cancer J Clin. 2013 Nov;63(3):151-66.

5. Ansell D, Grabler P, Whitman S, et al. A community effort to reduce the black/white breast cancer mortality disparity in Chicago. Cancer Causes Control. 2009 Nov;20(9):1681-8.

6. Gehlert S, Sohmer D, Sacks T, Mininger C, McClintock M, Olopade O. Targeting health disparities: a model linking upstream determinants to downstream interventions. Health Aff (Millwood). 2008 Mar-Apr;27(2):339-49.

7. Press R, Carrasquillo O, Sciacca RR, Giardina EG. Racial/ethnic disparities in time to follow-up after an abnormal mammogram. J Womens Health (Larchmt). 2008 Jul;17(6):923-30.

8. Silber JH, Rosenbaum PR, Clark AS, et al. Characteristics associated with differences in survival among black and white women with breast cancer. JAMA. 2013 Jul;310(4):389-397.

9. Gwyn K, Bondy ML, Cohen DS, et al. Racial differences in diagnosis, treatment, and clinical delays in a population-based study of patients with newly diagnosed breast carcinoma. Cancer. 2004 Apr;100(8):1595-604.

10. Richards MA, Westcombe AM, Love SB, Littlejohns P, Ramirez AJ. Influence of delay on survival in patients with breast cancer: a systematic review. Lancet. 1999 Apr 3;353(9159):1119-26.

11. Griggs JJ, Culakova E, Sorbero ME, et al. Social and racial differences in selection of breast cancer adjuvant chemotherapy regimens. J Clin Oncol. 2007 Jun 20;25(18):2522-7.

12. Griggs JJ, Sorbero ME, Stark AT, Heininger SE, Dick AW. Racial disparity in the dose and dose intensity of breast cancer adjuvant chemotherapy. Breast Cancer Res Treat. 2003 Sep;81(1):21-31.

13. Bickell NA, Wang JJ, Oluwole S, et al. Missed opportunities: racial disparities in adjuvant breast cancer treatment. J Clin Oncol. 2006 Mar 20;24(9):1357-62.
14. Fisher B, Costantino J, Redmond C, et al. A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med. 1989 Feb 23;320(8):479-84.

15. Partridge AH, Wang PS, Winer EP, Avorn J. Nonadherence to adjuvant tamoxifen therapy in women with primary breast cancer. J Clin Oncol. 2003 Feb 15;21(4):602-6.

16. Streeter SB, Schwartzberg L, Husain N, Johnsrud M. Patient and plan characteristics affecting abandonment of oral oncolytic prescriptions. J Oncol Pract. 2011 Jul;7(3 Suppl):46s-51s.

17. Alberti PM KN, Sutton K, Johnson BH, Holve E. The state of health equity research: closing knowledge gaps to address inequities. ©2014 Association of American Medical Colleges. May not be reproduced or distributed without prior permission.

18. Wood WC, Budman DR, Korzun AH, et al. Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med. 1994 May 5;330(18):1253-9.

19. Budman DR, Berry DA, Cirrincione CT, et al. Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. The Cancer and Leukemia Group B. J Natl Cancer Inst. 1998 Aug 19;90(16):1205-11.

20. Dignam JJ. Efficacy of systemic adjuvant therapy for breast cancer in African-American and Caucasian women. J Natl Cancer Inst Monogr. 2001(30):36-43.

21. Hershman DL, Unger JM, Barlow WE, et al. Treatment quality and outcomes of African American versus white breast cancer patients: retrospective analysis of Southwest Oncology studies S8814/S8897. J Clin Oncol. 2009 May;27(13):2157-62.

22. Hassett MJ, Griggs JJ. Disparities in breast cancer adjuvant chemotherapy: moving beyond yes or no. J Clin Oncol. 2009 May 1;27(13):2120-1.

Bobby Daly, MD, MBA, is the chief fellow in the section of hematology/oncology at the University of Chicago Medicine. His clinical focus is breast and thoracic oncology, and his research focus is health services. Specifically, Dr. Daly researches disparities in oncology care delivery, oncology health care utilization, aggressive end-of-life oncology care, and oncology payment models. He received his MD and MBA from Harvard Medical School and Harvard Business School, both in Boston, and a BA in Economics and History from Stanford (Calif.) University. He was the recipient of the Dean’s Award at Harvard Medical and Business Schools.

Olufunmilayo Olopade, MD, FACP, OON, is the Walter L. Palmer Distinguished Service Professor of Medicine and Human Genetics, and director, Center for Global Health at the University of Chicago. She is adopting emerging high throughput genomic and informatics strategies to identify genetic and nongenetic risk factors for breast cancer in order to implement precision health care in diverse populations. This innovative approach has the potential to improve the quality of care and reduce costs while saving more lives.

Disclosures: Dr. Olopade serves on the Medical Advisory Board for CancerIQ. Dr. Daly serves as a director of Quadrant Holdings Corporation and receives compensation from this entity. Frontline Medical Communications is a subsidiary of Quadrant Holdings Corporation.

Published in conjunction with Susan G. Komen®.

The ED physician suspected necrotizing fasciitis (NF) and immediately called for a surgical consult. This patient had type II NF, which can be caused by common skin organisms, such as Streptococcus pyogenes and Staphylococcus aureus.

Surgical debridement is the primary therapeutic modality. If the first debridement occurs within 24 hours of the onset of symptoms, there is a significantly improved chance of survival. Extensive, definitive debridement should be the goal with the first surgery. This may require amputation of an extremity to control the disease. Surgical debridement is repeated until all infected devitalized tissue is removed.

Antibiotics are the main adjunctive therapy to surgery. Broad-spectrum empiric antibiotics should be started immediately when NF is suspected and should include coverage of Gram-positive, Gram-negative, and anaerobic organisms. Antimicrobial therapy must be directed at the known or suspected pathogens and used in appropriate doses until repeated operative procedures are no longer needed. Empiric vancomycin should be considered while awaiting culture results to cover for the increasing incidence of methicillin-resistant Staphylococcus aureus (MRSA). Aggressive fluid resuscitation is often necessary because of massive capillary leak syndrome.

In this case, the patient was started on empiric broad-spectrum intravenous antibiotics to cover Gram-positive, Gram-negative, and anaerobic organisms. The surgical team then rapidly admitted the patient to the operating room (OR) for debridement. From the OR, she was transferred to the surgical intensive care unit where she received ongoing supportive and postoperative care. The intraoperative tissue cultures grew out MRSA.

The patient in this case was fortunate. She survived because of the speed with which she received a proper diagnosis and treatment.

Photo courtesy of Michael Babcock, MD. Text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R, Franklin J. Necrotizing fasciitis. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:702-706.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com

The ED physician suspected necrotizing fasciitis (NF) and immediately called for a surgical consult. This patient had type II NF, which can be caused by common skin organisms, such as Streptococcus pyogenes and Staphylococcus aureus.

Surgical debridement is the primary therapeutic modality. If the first debridement occurs within 24 hours of the onset of symptoms, there is a significantly improved chance of survival. Extensive, definitive debridement should be the goal with the first surgery. This may require amputation of an extremity to control the disease. Surgical debridement is repeated until all infected devitalized tissue is removed.

Antibiotics are the main adjunctive therapy to surgery. Broad-spectrum empiric antibiotics should be started immediately when NF is suspected and should include coverage of Gram-positive, Gram-negative, and anaerobic organisms. Antimicrobial therapy must be directed at the known or suspected pathogens and used in appropriate doses until repeated operative procedures are no longer needed. Empiric vancomycin should be considered while awaiting culture results to cover for the increasing incidence of methicillin-resistant Staphylococcus aureus (MRSA). Aggressive fluid resuscitation is often necessary because of massive capillary leak syndrome.

In this case, the patient was started on empiric broad-spectrum intravenous antibiotics to cover Gram-positive, Gram-negative, and anaerobic organisms. The surgical team then rapidly admitted the patient to the operating room (OR) for debridement. From the OR, she was transferred to the surgical intensive care unit where she received ongoing supportive and postoperative care. The intraoperative tissue cultures grew out MRSA.

The patient in this case was fortunate. She survived because of the speed with which she received a proper diagnosis and treatment.

Photo courtesy of Michael Babcock, MD. Text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R, Franklin J. Necrotizing fasciitis. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:702-706.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com

The ED physician suspected necrotizing fasciitis (NF) and immediately called for a surgical consult. This patient had type II NF, which can be caused by common skin organisms, such as Streptococcus pyogenes and Staphylococcus aureus.

Surgical debridement is the primary therapeutic modality. If the first debridement occurs within 24 hours of the onset of symptoms, there is a significantly improved chance of survival. Extensive, definitive debridement should be the goal with the first surgery. This may require amputation of an extremity to control the disease. Surgical debridement is repeated until all infected devitalized tissue is removed.

Antibiotics are the main adjunctive therapy to surgery. Broad-spectrum empiric antibiotics should be started immediately when NF is suspected and should include coverage of Gram-positive, Gram-negative, and anaerobic organisms. Antimicrobial therapy must be directed at the known or suspected pathogens and used in appropriate doses until repeated operative procedures are no longer needed. Empiric vancomycin should be considered while awaiting culture results to cover for the increasing incidence of methicillin-resistant Staphylococcus aureus (MRSA). Aggressive fluid resuscitation is often necessary because of massive capillary leak syndrome.

In this case, the patient was started on empiric broad-spectrum intravenous antibiotics to cover Gram-positive, Gram-negative, and anaerobic organisms. The surgical team then rapidly admitted the patient to the operating room (OR) for debridement. From the OR, she was transferred to the surgical intensive care unit where she received ongoing supportive and postoperative care. The intraoperative tissue cultures grew out MRSA.

The patient in this case was fortunate. She survived because of the speed with which she received a proper diagnosis and treatment.

Photo courtesy of Michael Babcock, MD. Text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R, Franklin J. Necrotizing fasciitis. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:702-706.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com

The ED physician suspected necrotizing fasciitis (NF), a rapidly progressive infection of the deep fascia with necrosis of the subcutaneous tissues. It usually occurs after surgery or trauma. Patients have erythema and pain disproportionate to the physical findings.

This patient had type I NF, a polymicrobial infection with aerobic and anaerobic bacteria. It is frequently caused by enteric Gram-negative pathogens including Enterobacteriaceae organisms and Bacteroides. It can also occur with Gram-positive organisms such as non–group A streptococci and Peptostreptococcus.

Risk factors for type I NF include diabetes, severe peripheral vascular disease, obesity, alcoholism, cirrhosis, intravenous drug use, decubitus ulcers, poor nutritional status, surgery, and penetrating trauma. Early recognition based on signs and symptoms is potentially lifesaving. Although lab tests and imaging studies can confirm one’s clinical impression, rapid treatment with antibiotics and surgery are crucial to improving survival.

The patient in this case was taken to the operating room for debridement of her NF. Broad-spectrum antibiotics were started, but the infection continued to quickly advance. The patient died the following day. Her wound culture later grew Escherichia coli, Proteus vulgaris, Corynebacterium, Enterococcus, Staphylococcus sp., and Peptostreptococcus.


Adapted from: Dufel S, Martino M. Simple cellulitis or a more serious infection? J Fam Pract. 2006;55:396-400.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com

The ED physician suspected necrotizing fasciitis (NF), a rapidly progressive infection of the deep fascia with necrosis of the subcutaneous tissues. It usually occurs after surgery or trauma. Patients have erythema and pain disproportionate to the physical findings.

This patient had type I NF, a polymicrobial infection with aerobic and anaerobic bacteria. It is frequently caused by enteric Gram-negative pathogens including Enterobacteriaceae organisms and Bacteroides. It can also occur with Gram-positive organisms such as non–group A streptococci and Peptostreptococcus.

Risk factors for type I NF include diabetes, severe peripheral vascular disease, obesity, alcoholism, cirrhosis, intravenous drug use, decubitus ulcers, poor nutritional status, surgery, and penetrating trauma. Early recognition based on signs and symptoms is potentially lifesaving. Although lab tests and imaging studies can confirm one’s clinical impression, rapid treatment with antibiotics and surgery are crucial to improving survival.

The patient in this case was taken to the operating room for debridement of her NF. Broad-spectrum antibiotics were started, but the infection continued to quickly advance. The patient died the following day. Her wound culture later grew Escherichia coli, Proteus vulgaris, Corynebacterium, Enterococcus, Staphylococcus sp., and Peptostreptococcus.


Adapted from: Dufel S, Martino M. Simple cellulitis or a more serious infection? J Fam Pract. 2006;55:396-400.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com

The ED physician suspected necrotizing fasciitis (NF), a rapidly progressive infection of the deep fascia with necrosis of the subcutaneous tissues. It usually occurs after surgery or trauma. Patients have erythema and pain disproportionate to the physical findings.

This patient had type I NF, a polymicrobial infection with aerobic and anaerobic bacteria. It is frequently caused by enteric Gram-negative pathogens including Enterobacteriaceae organisms and Bacteroides. It can also occur with Gram-positive organisms such as non–group A streptococci and Peptostreptococcus.

Risk factors for type I NF include diabetes, severe peripheral vascular disease, obesity, alcoholism, cirrhosis, intravenous drug use, decubitus ulcers, poor nutritional status, surgery, and penetrating trauma. Early recognition based on signs and symptoms is potentially lifesaving. Although lab tests and imaging studies can confirm one’s clinical impression, rapid treatment with antibiotics and surgery are crucial to improving survival.

The patient in this case was taken to the operating room for debridement of her NF. Broad-spectrum antibiotics were started, but the infection continued to quickly advance. The patient died the following day. Her wound culture later grew Escherichia coli, Proteus vulgaris, Corynebacterium, Enterococcus, Staphylococcus sp., and Peptostreptococcus.


Adapted from: Dufel S, Martino M. Simple cellulitis or a more serious infection? J Fam Pract. 2006;55:396-400.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com

The physician recognized that his patient had a neck abscess that was likely related to a dental abscess (odontogenic abscess). The patient’s alcoholism most likely weakened his ability to fight the infection, causing it to become potentially life-threatening. Risk factors for abscess formation include intravenous drug abuse, alcoholism, homelessness, dental disease, contact sports, and incarceration.

The physician transferred the patient to the local emergency department for hospitalization under the care of the ear, nose, and throat (ENT) service. The ENT physicians drained the abscess in the operating room without any complications. They cultured the abscess and started the patient on appropriate antibiotics, including penicillin G for dental aerobes and anaerobes.

The hospital team observed the patient for signs of alcohol withdrawal, but there were no complications because the patient hadn’t been drinking for the 5 days prior to hospitalization. Social Services was consulted and the patient was discharged to a respite bed in a local shelter that also had an alcohol and drug rehabilitation program. Arrangements were made for dental work in a charity dental clinic.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R. Abscess. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill;2013:698-701.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com