Dual B-cell receptor pathway blockade was tolerable and efficacious for patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL) who participated in a multicenter phase 1-1b clinical study that added umbralisib to ibrutinib.

The study “is the first successful combination for two drugs targeting the B-cell receptor pathway,” Matthew S. Davids, MD, of the Dana-Farber Cancer Institute in Boston and his colleagues wrote in the Lancet Haematology.

Of the 21 patients with CLL, 90% (n = 19) achieved an overall response (OR), 62% (n = 13) achieved partial response (PR) or PR with lymphocytosis, and 29% (n = 6) achieved complete response (CR). All patients in complete response still had minimal residual disease (MRD) in bone marrow. No CLL patients had progressive disease.

Of the 21 patients with MCL, 67% (n = 14) had an OR, with 19% (n = 4) showing CR and 48% (n = 10) achieving partial response. Three MCL patients (14%) had progressive disease.

Umbralisib is a next-generation phosphoinositide-3-kinase-delta inhibitor that, when added to the Bruton tyrosine kinase inhibitor (BTKi) ibrutinib, offers once-daily oral dosing. The combination affords the possibility of overcoming the resistance that can come with prolonged ibrutinib monotherapy.

A total of 44 patients were enrolled, and 42 patients (21 with CLL and 21 with MCL) received at least one dose of the study drug and were included in the analysis. At enrollment, patients had received a median of two previous therapies.

Diarrhea was the most frequent adverse event, seen in 22 patients (52%), and half of all patients (n = 21) had infections.

Hematologic toxicities included neutropenia, seen in 9 (43%) of the CLL patients and 8 (38%) of the MCL patients; thrombocytopenia, seen in 6 (29%) of the CLL patients and 10 (48%) of the MCL patients; and anemia, seen in 4 (19%) of the CLL and 9 (43%) of the MCL patients. Grade 3 and 4 hematologic toxicities of any type were less common, occurring in less than 20% of patients. One MCL patient developed febrile neutropenia. According to the study investigators, none of the hematologic toxicities were deemed related to the study drugs.

Adverse events did not appear to be dose-dependent for umbralisib, with the maximum tolerated dose not reached in the study, the investigators wrote. For phase 2 trials, the recommended dose of umbralisib is 800 mg given orally once daily in combination with ibrutinib.

“One unanticipated benefit of doublet B-cell receptor pathway inhibition in this study was the ability to continue one drug when a characteristic toxicity required the other drug to be held,” the investigators wrote.

For MCL patients, 67% achieved OR and 19% achieved CR, figures similar to those reported for ibrutinib monotherapy. However, “the 2-year progression-free survival of 49% and overall survival of 58% suggest that patients who made it to 1 year progression-free had few events during the second year on therapy,” the investigators wrote. They also noted that this MCL population was high risk; more than one-quarter of patients had relapsed after prior autologous stem cell transplantation.

The study was limited by small sample size and a short duration of follow-up, so durability of response can’t yet be assessed. Also, neither pharmacokinetics nor resistance mutations were tracked for participants.

Currently, the doublet regimen is designed to be continuous therapy, and although it’s not known whether this regimen would be effective as time-limited therapy, it’s unlikely because 100% of patients who had CR still had detectable minimal residual disease, the investigators noted.

Umbralisib and ibrutinib are also being explored as part of triplet therapy, with the type 2 CD20 antibody ublituximab, for relapsed or refractory B-cell malignancies (NCT02006485).

“These novel drug-based approaches, along with several others in development, hold promise as highly effective and well-tolerated regimens with the potential to substantially improve outcomes for patients with B-cell malignancies,” the investigators wrote.

The study was supported by TG Therapeutics and the Leukemia and Lymphoma Society Therapy Accelerator Program. The authors reported financial relationships with several pharmaceutical companies, including TG Therapeutics.

koakes@mdedge.com

SOURCE: Davids MS et al. Lancet Haemtol. 2019;6:e38-47.

Dual B-cell receptor pathway blockade was tolerable and efficacious for patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL) who participated in a multicenter phase 1-1b clinical study that added umbralisib to ibrutinib.

The study “is the first successful combination for two drugs targeting the B-cell receptor pathway,” Matthew S. Davids, MD, of the Dana-Farber Cancer Institute in Boston and his colleagues wrote in the Lancet Haematology.

Of the 21 patients with CLL, 90% (n = 19) achieved an overall response (OR), 62% (n = 13) achieved partial response (PR) or PR with lymphocytosis, and 29% (n = 6) achieved complete response (CR). All patients in complete response still had minimal residual disease (MRD) in bone marrow. No CLL patients had progressive disease.

Of the 21 patients with MCL, 67% (n = 14) had an OR, with 19% (n = 4) showing CR and 48% (n = 10) achieving partial response. Three MCL patients (14%) had progressive disease.

Umbralisib is a next-generation phosphoinositide-3-kinase-delta inhibitor that, when added to the Bruton tyrosine kinase inhibitor (BTKi) ibrutinib, offers once-daily oral dosing. The combination affords the possibility of overcoming the resistance that can come with prolonged ibrutinib monotherapy.

A total of 44 patients were enrolled, and 42 patients (21 with CLL and 21 with MCL) received at least one dose of the study drug and were included in the analysis. At enrollment, patients had received a median of two previous therapies.

Diarrhea was the most frequent adverse event, seen in 22 patients (52%), and half of all patients (n = 21) had infections.

Hematologic toxicities included neutropenia, seen in 9 (43%) of the CLL patients and 8 (38%) of the MCL patients; thrombocytopenia, seen in 6 (29%) of the CLL patients and 10 (48%) of the MCL patients; and anemia, seen in 4 (19%) of the CLL and 9 (43%) of the MCL patients. Grade 3 and 4 hematologic toxicities of any type were less common, occurring in less than 20% of patients. One MCL patient developed febrile neutropenia. According to the study investigators, none of the hematologic toxicities were deemed related to the study drugs.

Adverse events did not appear to be dose-dependent for umbralisib, with the maximum tolerated dose not reached in the study, the investigators wrote. For phase 2 trials, the recommended dose of umbralisib is 800 mg given orally once daily in combination with ibrutinib.

“One unanticipated benefit of doublet B-cell receptor pathway inhibition in this study was the ability to continue one drug when a characteristic toxicity required the other drug to be held,” the investigators wrote.

For MCL patients, 67% achieved OR and 19% achieved CR, figures similar to those reported for ibrutinib monotherapy. However, “the 2-year progression-free survival of 49% and overall survival of 58% suggest that patients who made it to 1 year progression-free had few events during the second year on therapy,” the investigators wrote. They also noted that this MCL population was high risk; more than one-quarter of patients had relapsed after prior autologous stem cell transplantation.

The study was limited by small sample size and a short duration of follow-up, so durability of response can’t yet be assessed. Also, neither pharmacokinetics nor resistance mutations were tracked for participants.

Currently, the doublet regimen is designed to be continuous therapy, and although it’s not known whether this regimen would be effective as time-limited therapy, it’s unlikely because 100% of patients who had CR still had detectable minimal residual disease, the investigators noted.

Umbralisib and ibrutinib are also being explored as part of triplet therapy, with the type 2 CD20 antibody ublituximab, for relapsed or refractory B-cell malignancies (NCT02006485).

“These novel drug-based approaches, along with several others in development, hold promise as highly effective and well-tolerated regimens with the potential to substantially improve outcomes for patients with B-cell malignancies,” the investigators wrote.

The study was supported by TG Therapeutics and the Leukemia and Lymphoma Society Therapy Accelerator Program. The authors reported financial relationships with several pharmaceutical companies, including TG Therapeutics.

koakes@mdedge.com

SOURCE: Davids MS et al. Lancet Haemtol. 2019;6:e38-47.

Dual B-cell receptor pathway blockade was tolerable and efficacious for patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL) who participated in a multicenter phase 1-1b clinical study that added umbralisib to ibrutinib.

The study “is the first successful combination for two drugs targeting the B-cell receptor pathway,” Matthew S. Davids, MD, of the Dana-Farber Cancer Institute in Boston and his colleagues wrote in the Lancet Haematology.

Of the 21 patients with CLL, 90% (n = 19) achieved an overall response (OR), 62% (n = 13) achieved partial response (PR) or PR with lymphocytosis, and 29% (n = 6) achieved complete response (CR). All patients in complete response still had minimal residual disease (MRD) in bone marrow. No CLL patients had progressive disease.

Of the 21 patients with MCL, 67% (n = 14) had an OR, with 19% (n = 4) showing CR and 48% (n = 10) achieving partial response. Three MCL patients (14%) had progressive disease.

Umbralisib is a next-generation phosphoinositide-3-kinase-delta inhibitor that, when added to the Bruton tyrosine kinase inhibitor (BTKi) ibrutinib, offers once-daily oral dosing. The combination affords the possibility of overcoming the resistance that can come with prolonged ibrutinib monotherapy.

A total of 44 patients were enrolled, and 42 patients (21 with CLL and 21 with MCL) received at least one dose of the study drug and were included in the analysis. At enrollment, patients had received a median of two previous therapies.

Diarrhea was the most frequent adverse event, seen in 22 patients (52%), and half of all patients (n = 21) had infections.

Hematologic toxicities included neutropenia, seen in 9 (43%) of the CLL patients and 8 (38%) of the MCL patients; thrombocytopenia, seen in 6 (29%) of the CLL patients and 10 (48%) of the MCL patients; and anemia, seen in 4 (19%) of the CLL and 9 (43%) of the MCL patients. Grade 3 and 4 hematologic toxicities of any type were less common, occurring in less than 20% of patients. One MCL patient developed febrile neutropenia. According to the study investigators, none of the hematologic toxicities were deemed related to the study drugs.

Adverse events did not appear to be dose-dependent for umbralisib, with the maximum tolerated dose not reached in the study, the investigators wrote. For phase 2 trials, the recommended dose of umbralisib is 800 mg given orally once daily in combination with ibrutinib.

“One unanticipated benefit of doublet B-cell receptor pathway inhibition in this study was the ability to continue one drug when a characteristic toxicity required the other drug to be held,” the investigators wrote.

For MCL patients, 67% achieved OR and 19% achieved CR, figures similar to those reported for ibrutinib monotherapy. However, “the 2-year progression-free survival of 49% and overall survival of 58% suggest that patients who made it to 1 year progression-free had few events during the second year on therapy,” the investigators wrote. They also noted that this MCL population was high risk; more than one-quarter of patients had relapsed after prior autologous stem cell transplantation.

The study was limited by small sample size and a short duration of follow-up, so durability of response can’t yet be assessed. Also, neither pharmacokinetics nor resistance mutations were tracked for participants.

Currently, the doublet regimen is designed to be continuous therapy, and although it’s not known whether this regimen would be effective as time-limited therapy, it’s unlikely because 100% of patients who had CR still had detectable minimal residual disease, the investigators noted.

Umbralisib and ibrutinib are also being explored as part of triplet therapy, with the type 2 CD20 antibody ublituximab, for relapsed or refractory B-cell malignancies (NCT02006485).

“These novel drug-based approaches, along with several others in development, hold promise as highly effective and well-tolerated regimens with the potential to substantially improve outcomes for patients with B-cell malignancies,” the investigators wrote.

The study was supported by TG Therapeutics and the Leukemia and Lymphoma Society Therapy Accelerator Program. The authors reported financial relationships with several pharmaceutical companies, including TG Therapeutics.

koakes@mdedge.com

SOURCE: Davids MS et al. Lancet Haemtol. 2019;6:e38-47.

Benralizumab is safe and effective for the treatment of uncontrolled asthma out to 2 years, according findings of the BORA trial, an extension study of the phase 3 SIROCCO and CALIMA trials. The study follows up and reinforces previously reported 1-year data and was reported by William W. Busse, MD, of University of Wisconsin, Madison, and his colleagues in the Lancet Respiratory Medicine.

Courtesy University of Wisconsin Health System

Benralizumab is a monoclonal antibody that targets interleukin-5 receptor alpha. It causes rapid deletion of eosinophils through cell-mediated cytotoxicity. A 30-mg dose of benralizumab every 8 weeks is approved for severe asthma treatment in Canada, Europe, Japan, the United States, and other countries.

In the second year of treatment, there were no new adverse events associated with depleted eosinophils, and the frequency of opportunistic infections was similar to that observed in the first year.

Eosinophilic inflammation occurs in about half of asthma cases and is associated with greater severity.

The 48-week SIROCCO trial, the 56-week CALIMA trial, and the 28-week ZONDA trial tested the effect of benralizumab 30 mg given every 4 weeks or 8 weeks, combined with high-dosage inhaled steroids and long-acting beta₂-agonists. The 8-week dose of the drug reduced annual exacerbations by 51%, compared with placebo in the SIROCCO trial and by 28% in the CALIMA trial. In the ZONDA trial, benralizumab reduced oral glucocorticoid use by 75%, compared with placebo, and by 25% from baseline.

The BORA extension trial included participants in the previous three trials. In the current report, researchers presented results from the analysis from BORA participants recruited from the SIROCCO and CALIMA trials. Data from participants from all three trials will be reported in the future.

The analysis included 1,576 patients who continued to receive benralizumab after being assigned to the treatment arm in SIROCCO or CALIMA, or who had received placebo were randomized to benralizumab on the 4-week (n = 783; 265 from placebo) or 8-week dose (n = 793; 281 from placebo) schedule.

A total of 166 patients, or about 10% in each group, discontinued treatment. The frequency of any serious adverse event (SAE) ranged between 10% and 11% in all groups. SAEs associated with infections ranged from 1% to 3%, indicating that there were no significant differences in SAE frequencies between those who were originally assigned to placebo and those who originally received benralizumab. That suggests no safety differences between receiving the drug for 1 year or 2 years.

A total of 1,046 subjects had blood eosinophil counts of 300 cells per mcL or greater at baseline; 72% of these patients had no asthma exacerbations during the BORA study. This was true for 74% of patients in the 8-week treatment arm.

The crude asthma exacerbation rate for patients who received benralizumab in SIROCCO or CALIMA was 0.48 in the 4-week arm, compared with placebo (95% confidence interval, 0.42-0.56) and 0.46 in the 8-week arm (95% CI, 0.39-0.53). For patients who started out on placebo, the crude exacerbation rate during BORA was 0.53 in the 4-week group (95% CI, 0.43-0.65) and 0.57 in the 8-week group (95% CI, 0.47-0.68).

Patients who started on benralizumab had similar exacerbation frequencies during year 1 and year 2.

AstraZeneca and Kyowa Hakko Kirin funded the studies. The authors have received fees from AstraZeneca and other pharmaceutical companies, and some are employees of AstraZeneca.

SOURCE: Busse WW et al. Lancet Respir Med. 2019 Jan 1;7(1):46-59.

Benralizumab is safe and effective for the treatment of uncontrolled asthma out to 2 years, according findings of the BORA trial, an extension study of the phase 3 SIROCCO and CALIMA trials. The study follows up and reinforces previously reported 1-year data and was reported by William W. Busse, MD, of University of Wisconsin, Madison, and his colleagues in the Lancet Respiratory Medicine.

Courtesy University of Wisconsin Health System

Benralizumab is a monoclonal antibody that targets interleukin-5 receptor alpha. It causes rapid deletion of eosinophils through cell-mediated cytotoxicity. A 30-mg dose of benralizumab every 8 weeks is approved for severe asthma treatment in Canada, Europe, Japan, the United States, and other countries.

In the second year of treatment, there were no new adverse events associated with depleted eosinophils, and the frequency of opportunistic infections was similar to that observed in the first year.

Eosinophilic inflammation occurs in about half of asthma cases and is associated with greater severity.

The 48-week SIROCCO trial, the 56-week CALIMA trial, and the 28-week ZONDA trial tested the effect of benralizumab 30 mg given every 4 weeks or 8 weeks, combined with high-dosage inhaled steroids and long-acting beta₂-agonists. The 8-week dose of the drug reduced annual exacerbations by 51%, compared with placebo in the SIROCCO trial and by 28% in the CALIMA trial. In the ZONDA trial, benralizumab reduced oral glucocorticoid use by 75%, compared with placebo, and by 25% from baseline.

The BORA extension trial included participants in the previous three trials. In the current report, researchers presented results from the analysis from BORA participants recruited from the SIROCCO and CALIMA trials. Data from participants from all three trials will be reported in the future.

The analysis included 1,576 patients who continued to receive benralizumab after being assigned to the treatment arm in SIROCCO or CALIMA, or who had received placebo were randomized to benralizumab on the 4-week (n = 783; 265 from placebo) or 8-week dose (n = 793; 281 from placebo) schedule.

A total of 166 patients, or about 10% in each group, discontinued treatment. The frequency of any serious adverse event (SAE) ranged between 10% and 11% in all groups. SAEs associated with infections ranged from 1% to 3%, indicating that there were no significant differences in SAE frequencies between those who were originally assigned to placebo and those who originally received benralizumab. That suggests no safety differences between receiving the drug for 1 year or 2 years.

A total of 1,046 subjects had blood eosinophil counts of 300 cells per mcL or greater at baseline; 72% of these patients had no asthma exacerbations during the BORA study. This was true for 74% of patients in the 8-week treatment arm.

The crude asthma exacerbation rate for patients who received benralizumab in SIROCCO or CALIMA was 0.48 in the 4-week arm, compared with placebo (95% confidence interval, 0.42-0.56) and 0.46 in the 8-week arm (95% CI, 0.39-0.53). For patients who started out on placebo, the crude exacerbation rate during BORA was 0.53 in the 4-week group (95% CI, 0.43-0.65) and 0.57 in the 8-week group (95% CI, 0.47-0.68).

Patients who started on benralizumab had similar exacerbation frequencies during year 1 and year 2.

AstraZeneca and Kyowa Hakko Kirin funded the studies. The authors have received fees from AstraZeneca and other pharmaceutical companies, and some are employees of AstraZeneca.

SOURCE: Busse WW et al. Lancet Respir Med. 2019 Jan 1;7(1):46-59.

Benralizumab is safe and effective for the treatment of uncontrolled asthma out to 2 years, according findings of the BORA trial, an extension study of the phase 3 SIROCCO and CALIMA trials. The study follows up and reinforces previously reported 1-year data and was reported by William W. Busse, MD, of University of Wisconsin, Madison, and his colleagues in the Lancet Respiratory Medicine.

Courtesy University of Wisconsin Health System

Benralizumab is a monoclonal antibody that targets interleukin-5 receptor alpha. It causes rapid deletion of eosinophils through cell-mediated cytotoxicity. A 30-mg dose of benralizumab every 8 weeks is approved for severe asthma treatment in Canada, Europe, Japan, the United States, and other countries.

In the second year of treatment, there were no new adverse events associated with depleted eosinophils, and the frequency of opportunistic infections was similar to that observed in the first year.

Eosinophilic inflammation occurs in about half of asthma cases and is associated with greater severity.

The 48-week SIROCCO trial, the 56-week CALIMA trial, and the 28-week ZONDA trial tested the effect of benralizumab 30 mg given every 4 weeks or 8 weeks, combined with high-dosage inhaled steroids and long-acting beta₂-agonists. The 8-week dose of the drug reduced annual exacerbations by 51%, compared with placebo in the SIROCCO trial and by 28% in the CALIMA trial. In the ZONDA trial, benralizumab reduced oral glucocorticoid use by 75%, compared with placebo, and by 25% from baseline.

The BORA extension trial included participants in the previous three trials. In the current report, researchers presented results from the analysis from BORA participants recruited from the SIROCCO and CALIMA trials. Data from participants from all three trials will be reported in the future.

The analysis included 1,576 patients who continued to receive benralizumab after being assigned to the treatment arm in SIROCCO or CALIMA, or who had received placebo were randomized to benralizumab on the 4-week (n = 783; 265 from placebo) or 8-week dose (n = 793; 281 from placebo) schedule.

A total of 166 patients, or about 10% in each group, discontinued treatment. The frequency of any serious adverse event (SAE) ranged between 10% and 11% in all groups. SAEs associated with infections ranged from 1% to 3%, indicating that there were no significant differences in SAE frequencies between those who were originally assigned to placebo and those who originally received benralizumab. That suggests no safety differences between receiving the drug for 1 year or 2 years.

A total of 1,046 subjects had blood eosinophil counts of 300 cells per mcL or greater at baseline; 72% of these patients had no asthma exacerbations during the BORA study. This was true for 74% of patients in the 8-week treatment arm.

The crude asthma exacerbation rate for patients who received benralizumab in SIROCCO or CALIMA was 0.48 in the 4-week arm, compared with placebo (95% confidence interval, 0.42-0.56) and 0.46 in the 8-week arm (95% CI, 0.39-0.53). For patients who started out on placebo, the crude exacerbation rate during BORA was 0.53 in the 4-week group (95% CI, 0.43-0.65) and 0.57 in the 8-week group (95% CI, 0.47-0.68).

Patients who started on benralizumab had similar exacerbation frequencies during year 1 and year 2.

AstraZeneca and Kyowa Hakko Kirin funded the studies. The authors have received fees from AstraZeneca and other pharmaceutical companies, and some are employees of AstraZeneca.

SOURCE: Busse WW et al. Lancet Respir Med. 2019 Jan 1;7(1):46-59.

This week from MDedge Cardiology, a biodegradable polymer shows no long-term benefit in heart stents, appropriate use criteria for imaging in nonvalvular heart disease are released, ACOG updates guidance on hypertension in pregnancy, and more losartan lots are recalled.

Subscribe to Cardiocast wherever you get your podcasts.

Amazon AlexaApple Podcasts

This week from MDedge Cardiology, a biodegradable polymer shows no long-term benefit in heart stents, appropriate use criteria for imaging in nonvalvular heart disease are released, ACOG updates guidance on hypertension in pregnancy, and more losartan lots are recalled.

Subscribe to Cardiocast wherever you get your podcasts.

Amazon AlexaApple Podcasts

This week from MDedge Cardiology, a biodegradable polymer shows no long-term benefit in heart stents, appropriate use criteria for imaging in nonvalvular heart disease are released, ACOG updates guidance on hypertension in pregnancy, and more losartan lots are recalled.

Subscribe to Cardiocast wherever you get your podcasts.

Amazon AlexaApple Podcasts

To the Editor:
A 52-year-old woman with a medical history of migraines and cervicalgia presented with lesions on the right arm, back, and right calf. The patient stated that the lesions began as small papules that had grown over 13 months, with the largest papule on the right forearm. She reported no itching, bleeding, pain, discharge, or other symptoms associated with the lesions. She had a multiple-year history of similar lesions that did not respond to treatment with antifungals, moderate-potency steroids, and other over-the-counter creams. The lesions would resolve spontaneously with scarring and subsequently recur. Prior skin biopsies were inconclusive. The patient did not report any systemic symptoms or a personal or family history of connective tissue diseases.

Physical examination revealed a 4-cm asymmetric, annular, erythematous plaque with central clearing on the right dorsal forearm with defined margins except over the distal aspect (Figure 1). She also had several 1- to 2-cm erythematous, nummular, asymmetric plaques on the right upper arm with well-defined margins. She had several lesions over the central and left sides of the upper back that were similar to the lesions on the upper arm.

Two 4-mm punch biopsies of the right dorsal forearm and left side of the upper back revealed similar histologic features with a predominantly unremarkable epidermis. The dermis revealed a lymphohistiocytic infiltrate with prominent multinucleated giant cells organized into foreign body–type granulomas that extended into the deep dermis and subcutaneous tissue (Figure 2). In the granulomatous areas, there was a near-complete loss of elastic fibers with focal elastophagocytosis highlighted with Verhoeff-van Gieson (elastin) stain (Figure 3). Grocott-Gomori methenamine-silver and Fite stains for microorganisms were negative, and there was an absence of necrobiosis, lipids, and mucin.

The histologic findings of a granulomatous dermatitis with loss of elastic fibers and elastophagocytosis in addition to the patient’s clinical presentation and history were consistent with the diagnosis of annular elastolytic giant cell granuloma (AEGCG). Infectious and other granulomatous diseases including sarcoidosis were ruled out via clinical history, unremarkable laboratory analysis (ie, complete blood cell count, chemistry panel, antinuclear antibody, urinalysis), and a normal chest radiograph. The histologic findings via the various stains were instrumental to the diagnosis. The patient was treated with fluocinonide and subsequently lost to follow-up.

Annular elastolytic giant cell granuloma is an uncommon cutaneous disease that presents with recurring annular plaques with raised erythematous borders and subsequent residual scarring.¹ O’Brien² originally described this condition in 1975 as an actinic granuloma due to similar histologic findings in areas of the patient’s sun-exposed skin. Ragaz and Ackerman³ disputed O’Brien’s² description, claiming granulomatous inflammation was a primary pathologic process and not a consequence to damaged elastotic material. In 1979, Hanke et al⁴ termed the lesions as AEGCG because he did not find a correlation to the sun-exposed areas of the patients and did not see solar elastosis.

Although AEGCG has an unclear pathogenesis, cellular immunologic reactions induced by modified function of elastic fibers’ antigenicity contribute to AEGCG formation.⁵ Therefore, environmental and host factors may play a role in its etiopathogenesis. In one study, 37% of 38 Japanese patients with AEGCG were found to have definitive or latent diabetes mellitus, raising the possible role of diabetes in the structural damage of the elastic fibers.⁶

Patients typically are middle-aged women who present clinically with red or atrophic plaques that have slightly elevated borders. They have centripetal spread with a resulting atrophic center.⁷ Clinically, the differential diagnosis of this condition includes actinic granuloma, granuloma annulare, and granuloma multiforme.⁸

Histologically, AEGCG has a granulomatous component with multinucleated giant cells in the upper and mid dermis. This component typically is distributed peripherally to a central zone that lacks elastic tissue. Elastophagocytosis, a classic finding in AEGCG, is the phagocytosis of elastic fibers that can microscopically be seen in the cytoplasm of histiocytes and multinucleated giant cells. There also is an absence of necrobiosis, lipids, mucin, and a palisading arrangement of the granulomas. These findings distinguish AEGCG from granuloma annulare and necrobiosis lipoidica, the primary histologic differential diagnoses.⁹ In addition, consideration of entities consistently exhibiting elastophagocytosis such as mid-dermal elastolysis, papillary dermal elastolysis, actinic granuloma, and granulomatous slack skin should be considered.^5,10,11

Therapy for AEGCG is broad and includes topical, intralesional, and systemic corticosteroids. Hydroxychloroquine, isotretinoin, clofazimine, dapsone, photochemotherapy, and cyclosporine also have been utilized with varying results. Other reports show improvement with surgical excision, cryotherapy, or cauterization of small lesions.^12-15

To the Editor:
A 52-year-old woman with a medical history of migraines and cervicalgia presented with lesions on the right arm, back, and right calf. The patient stated that the lesions began as small papules that had grown over 13 months, with the largest papule on the right forearm. She reported no itching, bleeding, pain, discharge, or other symptoms associated with the lesions. She had a multiple-year history of similar lesions that did not respond to treatment with antifungals, moderate-potency steroids, and other over-the-counter creams. The lesions would resolve spontaneously with scarring and subsequently recur. Prior skin biopsies were inconclusive. The patient did not report any systemic symptoms or a personal or family history of connective tissue diseases.

Physical examination revealed a 4-cm asymmetric, annular, erythematous plaque with central clearing on the right dorsal forearm with defined margins except over the distal aspect (Figure 1). She also had several 1- to 2-cm erythematous, nummular, asymmetric plaques on the right upper arm with well-defined margins. She had several lesions over the central and left sides of the upper back that were similar to the lesions on the upper arm.

Two 4-mm punch biopsies of the right dorsal forearm and left side of the upper back revealed similar histologic features with a predominantly unremarkable epidermis. The dermis revealed a lymphohistiocytic infiltrate with prominent multinucleated giant cells organized into foreign body–type granulomas that extended into the deep dermis and subcutaneous tissue (Figure 2). In the granulomatous areas, there was a near-complete loss of elastic fibers with focal elastophagocytosis highlighted with Verhoeff-van Gieson (elastin) stain (Figure 3). Grocott-Gomori methenamine-silver and Fite stains for microorganisms were negative, and there was an absence of necrobiosis, lipids, and mucin.

The histologic findings of a granulomatous dermatitis with loss of elastic fibers and elastophagocytosis in addition to the patient’s clinical presentation and history were consistent with the diagnosis of annular elastolytic giant cell granuloma (AEGCG). Infectious and other granulomatous diseases including sarcoidosis were ruled out via clinical history, unremarkable laboratory analysis (ie, complete blood cell count, chemistry panel, antinuclear antibody, urinalysis), and a normal chest radiograph. The histologic findings via the various stains were instrumental to the diagnosis. The patient was treated with fluocinonide and subsequently lost to follow-up.

Annular elastolytic giant cell granuloma is an uncommon cutaneous disease that presents with recurring annular plaques with raised erythematous borders and subsequent residual scarring.¹ O’Brien² originally described this condition in 1975 as an actinic granuloma due to similar histologic findings in areas of the patient’s sun-exposed skin. Ragaz and Ackerman³ disputed O’Brien’s² description, claiming granulomatous inflammation was a primary pathologic process and not a consequence to damaged elastotic material. In 1979, Hanke et al⁴ termed the lesions as AEGCG because he did not find a correlation to the sun-exposed areas of the patients and did not see solar elastosis.

Although AEGCG has an unclear pathogenesis, cellular immunologic reactions induced by modified function of elastic fibers’ antigenicity contribute to AEGCG formation.⁵ Therefore, environmental and host factors may play a role in its etiopathogenesis. In one study, 37% of 38 Japanese patients with AEGCG were found to have definitive or latent diabetes mellitus, raising the possible role of diabetes in the structural damage of the elastic fibers.⁶

Patients typically are middle-aged women who present clinically with red or atrophic plaques that have slightly elevated borders. They have centripetal spread with a resulting atrophic center.⁷ Clinically, the differential diagnosis of this condition includes actinic granuloma, granuloma annulare, and granuloma multiforme.⁸

Histologically, AEGCG has a granulomatous component with multinucleated giant cells in the upper and mid dermis. This component typically is distributed peripherally to a central zone that lacks elastic tissue. Elastophagocytosis, a classic finding in AEGCG, is the phagocytosis of elastic fibers that can microscopically be seen in the cytoplasm of histiocytes and multinucleated giant cells. There also is an absence of necrobiosis, lipids, mucin, and a palisading arrangement of the granulomas. These findings distinguish AEGCG from granuloma annulare and necrobiosis lipoidica, the primary histologic differential diagnoses.⁹ In addition, consideration of entities consistently exhibiting elastophagocytosis such as mid-dermal elastolysis, papillary dermal elastolysis, actinic granuloma, and granulomatous slack skin should be considered.^5,10,11

Therapy for AEGCG is broad and includes topical, intralesional, and systemic corticosteroids. Hydroxychloroquine, isotretinoin, clofazimine, dapsone, photochemotherapy, and cyclosporine also have been utilized with varying results. Other reports show improvement with surgical excision, cryotherapy, or cauterization of small lesions.^12-15

To the Editor:
A 52-year-old woman with a medical history of migraines and cervicalgia presented with lesions on the right arm, back, and right calf. The patient stated that the lesions began as small papules that had grown over 13 months, with the largest papule on the right forearm. She reported no itching, bleeding, pain, discharge, or other symptoms associated with the lesions. She had a multiple-year history of similar lesions that did not respond to treatment with antifungals, moderate-potency steroids, and other over-the-counter creams. The lesions would resolve spontaneously with scarring and subsequently recur. Prior skin biopsies were inconclusive. The patient did not report any systemic symptoms or a personal or family history of connective tissue diseases.

Physical examination revealed a 4-cm asymmetric, annular, erythematous plaque with central clearing on the right dorsal forearm with defined margins except over the distal aspect (Figure 1). She also had several 1- to 2-cm erythematous, nummular, asymmetric plaques on the right upper arm with well-defined margins. She had several lesions over the central and left sides of the upper back that were similar to the lesions on the upper arm.

Two 4-mm punch biopsies of the right dorsal forearm and left side of the upper back revealed similar histologic features with a predominantly unremarkable epidermis. The dermis revealed a lymphohistiocytic infiltrate with prominent multinucleated giant cells organized into foreign body–type granulomas that extended into the deep dermis and subcutaneous tissue (Figure 2). In the granulomatous areas, there was a near-complete loss of elastic fibers with focal elastophagocytosis highlighted with Verhoeff-van Gieson (elastin) stain (Figure 3). Grocott-Gomori methenamine-silver and Fite stains for microorganisms were negative, and there was an absence of necrobiosis, lipids, and mucin.

The histologic findings of a granulomatous dermatitis with loss of elastic fibers and elastophagocytosis in addition to the patient’s clinical presentation and history were consistent with the diagnosis of annular elastolytic giant cell granuloma (AEGCG). Infectious and other granulomatous diseases including sarcoidosis were ruled out via clinical history, unremarkable laboratory analysis (ie, complete blood cell count, chemistry panel, antinuclear antibody, urinalysis), and a normal chest radiograph. The histologic findings via the various stains were instrumental to the diagnosis. The patient was treated with fluocinonide and subsequently lost to follow-up.

Annular elastolytic giant cell granuloma is an uncommon cutaneous disease that presents with recurring annular plaques with raised erythematous borders and subsequent residual scarring.¹ O’Brien² originally described this condition in 1975 as an actinic granuloma due to similar histologic findings in areas of the patient’s sun-exposed skin. Ragaz and Ackerman³ disputed O’Brien’s² description, claiming granulomatous inflammation was a primary pathologic process and not a consequence to damaged elastotic material. In 1979, Hanke et al⁴ termed the lesions as AEGCG because he did not find a correlation to the sun-exposed areas of the patients and did not see solar elastosis.

Although AEGCG has an unclear pathogenesis, cellular immunologic reactions induced by modified function of elastic fibers’ antigenicity contribute to AEGCG formation.⁵ Therefore, environmental and host factors may play a role in its etiopathogenesis. In one study, 37% of 38 Japanese patients with AEGCG were found to have definitive or latent diabetes mellitus, raising the possible role of diabetes in the structural damage of the elastic fibers.⁶

Patients typically are middle-aged women who present clinically with red or atrophic plaques that have slightly elevated borders. They have centripetal spread with a resulting atrophic center.⁷ Clinically, the differential diagnosis of this condition includes actinic granuloma, granuloma annulare, and granuloma multiforme.⁸

Histologically, AEGCG has a granulomatous component with multinucleated giant cells in the upper and mid dermis. This component typically is distributed peripherally to a central zone that lacks elastic tissue. Elastophagocytosis, a classic finding in AEGCG, is the phagocytosis of elastic fibers that can microscopically be seen in the cytoplasm of histiocytes and multinucleated giant cells. There also is an absence of necrobiosis, lipids, mucin, and a palisading arrangement of the granulomas. These findings distinguish AEGCG from granuloma annulare and necrobiosis lipoidica, the primary histologic differential diagnoses.⁹ In addition, consideration of entities consistently exhibiting elastophagocytosis such as mid-dermal elastolysis, papillary dermal elastolysis, actinic granuloma, and granulomatous slack skin should be considered.^5,10,11

Therapy for AEGCG is broad and includes topical, intralesional, and systemic corticosteroids. Hydroxychloroquine, isotretinoin, clofazimine, dapsone, photochemotherapy, and cyclosporine also have been utilized with varying results. Other reports show improvement with surgical excision, cryotherapy, or cauterization of small lesions.^12-15

Advanced fibrosis affected 5.9% of adults with low-normal thyroid function or subclinical hypothyroidism – more than double the prevalence among adults with strict-normal thyroid function (2.8%; P less than .001), according to the results of a large survey study.

Based on these findings, therapy to improve low thyroid function might help prevent advanced fibrosis secondary to nonalcoholic fatty liver disease, wrote Donghee Kim, MD, PhD, of Stanford University (Calif.), together with his associates in Clinical Gastroenterology and Hepatology.

Prior research has linked low-normal thyroid function with obesity, cardiometabolic diseases, and fractures. For this study, Dr. Kim and his coinvestigators analyzed data from 7,259 adults who lacked major etiologies of chronic liver disease and were included in the National Health and Nutrition Examination Survey between 2007 and 2012.

After accounting for demographic, socioeconomic, and clinical variables, the odds of biopsy-confirmed advanced fibrosis were 100% higher in adults with low-normal thyroid function or subclinical hypothyroidism, compared with adults with strict-normal thyroid function (odds ratio, 2.0; 95% confidence interval, 1.2-3.3). The prevalence and odds of advanced fibrosis was similar in each of these two subgroups. Furthermore, low thyroid function remained strongly linked with advanced fibrosis after accounting for insulin resistance using data from fasting subjects (OR, 2.3; 95% CI, 1.2-4.4).

Previously, Dr. Kim and his coinvestigators found a strong link between biopsy-proven advanced fibrosis and low-normal thyroid function or subclinical hypothyroidism among adults in Korea. “These [new] results are consistent with our previous observations in [an] Asian population, and show their generalizability to the Western world across all ethnicities.”

The researchers did not acknowledge external funding sources. They reported having no conflicts of interest.

SOURCE: Kim D et al. Clin Gastroenterol Hepatol. 2018 Nov 17. doi: 10.1016/j.cgh.2018.11.024.

Advanced fibrosis affected 5.9% of adults with low-normal thyroid function or subclinical hypothyroidism – more than double the prevalence among adults with strict-normal thyroid function (2.8%; P less than .001), according to the results of a large survey study.

Based on these findings, therapy to improve low thyroid function might help prevent advanced fibrosis secondary to nonalcoholic fatty liver disease, wrote Donghee Kim, MD, PhD, of Stanford University (Calif.), together with his associates in Clinical Gastroenterology and Hepatology.

Prior research has linked low-normal thyroid function with obesity, cardiometabolic diseases, and fractures. For this study, Dr. Kim and his coinvestigators analyzed data from 7,259 adults who lacked major etiologies of chronic liver disease and were included in the National Health and Nutrition Examination Survey between 2007 and 2012.

After accounting for demographic, socioeconomic, and clinical variables, the odds of biopsy-confirmed advanced fibrosis were 100% higher in adults with low-normal thyroid function or subclinical hypothyroidism, compared with adults with strict-normal thyroid function (odds ratio, 2.0; 95% confidence interval, 1.2-3.3). The prevalence and odds of advanced fibrosis was similar in each of these two subgroups. Furthermore, low thyroid function remained strongly linked with advanced fibrosis after accounting for insulin resistance using data from fasting subjects (OR, 2.3; 95% CI, 1.2-4.4).

Previously, Dr. Kim and his coinvestigators found a strong link between biopsy-proven advanced fibrosis and low-normal thyroid function or subclinical hypothyroidism among adults in Korea. “These [new] results are consistent with our previous observations in [an] Asian population, and show their generalizability to the Western world across all ethnicities.”

The researchers did not acknowledge external funding sources. They reported having no conflicts of interest.

SOURCE: Kim D et al. Clin Gastroenterol Hepatol. 2018 Nov 17. doi: 10.1016/j.cgh.2018.11.024.

Advanced fibrosis affected 5.9% of adults with low-normal thyroid function or subclinical hypothyroidism – more than double the prevalence among adults with strict-normal thyroid function (2.8%; P less than .001), according to the results of a large survey study.

Based on these findings, therapy to improve low thyroid function might help prevent advanced fibrosis secondary to nonalcoholic fatty liver disease, wrote Donghee Kim, MD, PhD, of Stanford University (Calif.), together with his associates in Clinical Gastroenterology and Hepatology.

Prior research has linked low-normal thyroid function with obesity, cardiometabolic diseases, and fractures. For this study, Dr. Kim and his coinvestigators analyzed data from 7,259 adults who lacked major etiologies of chronic liver disease and were included in the National Health and Nutrition Examination Survey between 2007 and 2012.

After accounting for demographic, socioeconomic, and clinical variables, the odds of biopsy-confirmed advanced fibrosis were 100% higher in adults with low-normal thyroid function or subclinical hypothyroidism, compared with adults with strict-normal thyroid function (odds ratio, 2.0; 95% confidence interval, 1.2-3.3). The prevalence and odds of advanced fibrosis was similar in each of these two subgroups. Furthermore, low thyroid function remained strongly linked with advanced fibrosis after accounting for insulin resistance using data from fasting subjects (OR, 2.3; 95% CI, 1.2-4.4).

Previously, Dr. Kim and his coinvestigators found a strong link between biopsy-proven advanced fibrosis and low-normal thyroid function or subclinical hypothyroidism among adults in Korea. “These [new] results are consistent with our previous observations in [an] Asian population, and show their generalizability to the Western world across all ethnicities.”

The researchers did not acknowledge external funding sources. They reported having no conflicts of interest.

SOURCE: Kim D et al. Clin Gastroenterol Hepatol. 2018 Nov 17. doi: 10.1016/j.cgh.2018.11.024.

Patients with acquired thrombotic thrombocytopenic purpura (TTP) who were treated with caplacizumab had faster time to platelet normalization (2.69 days vs. 2.88 days) and were 1.55 times more likely to achieve platelet normalization, compared with placebo, according to results of the double-blind, controlled HERCULES trial published in the New England Journal of Medicine (2019 Jan 9. doi: 10.1056/NEJMoa1806311).

Patients taking caplacizumab also had a 74% lower incidence of a composite outcome that included TTP-related deaths, recurrence of TTP, or a major thromboembolic event.

We covered this story at the annual meeting of the American Society of Hematology before it was published in the journal. Find our coverage at the link below.

lfranki@mdedge.com

Patients with acquired thrombotic thrombocytopenic purpura (TTP) who were treated with caplacizumab had faster time to platelet normalization (2.69 days vs. 2.88 days) and were 1.55 times more likely to achieve platelet normalization, compared with placebo, according to results of the double-blind, controlled HERCULES trial published in the New England Journal of Medicine (2019 Jan 9. doi: 10.1056/NEJMoa1806311).

Patients taking caplacizumab also had a 74% lower incidence of a composite outcome that included TTP-related deaths, recurrence of TTP, or a major thromboembolic event.

We covered this story at the annual meeting of the American Society of Hematology before it was published in the journal. Find our coverage at the link below.

lfranki@mdedge.com

Patients with acquired thrombotic thrombocytopenic purpura (TTP) who were treated with caplacizumab had faster time to platelet normalization (2.69 days vs. 2.88 days) and were 1.55 times more likely to achieve platelet normalization, compared with placebo, according to results of the double-blind, controlled HERCULES trial published in the New England Journal of Medicine (2019 Jan 9. doi: 10.1056/NEJMoa1806311).

Patients taking caplacizumab also had a 74% lower incidence of a composite outcome that included TTP-related deaths, recurrence of TTP, or a major thromboembolic event.

We covered this story at the annual meeting of the American Society of Hematology before it was published in the journal. Find our coverage at the link below.

lfranki@mdedge.com

Just like exposure to secondhand smoke, exposure to secondhand aerosols from e-cigarettes is associated with an increased risk of asthma exacerbations in children, according to a review of the 11,830 kids with asthma in the 2016 Florida Youth Tobacco survey.

diego_cervo/Thinkstock

Every year, the Florida Department of Health surveys public school children aged 11-17 years about various tobacco issues. In 2016, almost 12% of the asthmatic children in the survey said they vaped. Almost half were exposed to secondhand smoke, and a third reported exposure to secondhand vaping aerosols within the past 30 days. Overall, 21% reported an asthma attack in the past 12 months.

Using data from the Florida survey, the investigators crunched the numbers and found that secondhand aerosol exposure increased the odds of an asthma attack by 27%, independent of exposure to secondhand smoke and whether children smoked or vaped themselves (adjusted odds ratio, 1.27; 95% confidence interval, 1.11-1.47).

“Health professionals may wish to counsel asthmatic youth and their families regarding the potential risks of ENDS [electronic nicotine delivery system] use and exposure to ENDS aerosols.” Providers “may also consider including ENDS aerosol exposure as a possible trigger in asthma self-management/action plans and updating asthma home environment assessments to include exposure to ENDS aerosols,” said investigators led by medical student Jennifer Bayly, a research fellow at the National Institute on Minority Health and Health Disparities in Bethesda, Md.

About 4% of adults in the United States and 11% of high school students vape, and almost 10% of U.S. adolescents reported living with an ENDS user in 2014. Given the data, “it is likely that a substantial number of asthmatic youth are exposed,” the investigators said.

The study adds to a growing body of evidence linking e-cigarettes to asthma. There’s moderate evidence for increased cough and wheezing in adolescents who use e-cigarettes, plus an association with e-cigarette use and increased asthma exacerbations. The new study, however, is likely the first to look specifically at secondhand exposure among asthmatic children. Ingredients in vaping aerosols, including flavorings, propylene glycol, and vegetable glycerin, are physiologically active in the lungs, and may be lung irritants.

Overall, about half of the respondents were female, and two-thirds were 11-13 years old. About a third identified as Hispanic, a third as white, and just over a fifth as black. Three-quarters of the sample lived in large or midsized metropolitan areas, and close to two-thirds in stand-alone homes. Participants were considered exposed to secondhand aerosols if they reported that in the past month they were in a room or car with someone who was vaping.

The work was funded by the National Institutes of Health. The investigators had no disclosures.

aotto@mdedge.com

SOURCE: Bayly JE et al. CHEST®. 2018 Oct 22. doi: 10.1016/j.chest.2018.10.005.

Just like exposure to secondhand smoke, exposure to secondhand aerosols from e-cigarettes is associated with an increased risk of asthma exacerbations in children, according to a review of the 11,830 kids with asthma in the 2016 Florida Youth Tobacco survey.

diego_cervo/Thinkstock

Every year, the Florida Department of Health surveys public school children aged 11-17 years about various tobacco issues. In 2016, almost 12% of the asthmatic children in the survey said they vaped. Almost half were exposed to secondhand smoke, and a third reported exposure to secondhand vaping aerosols within the past 30 days. Overall, 21% reported an asthma attack in the past 12 months.

Using data from the Florida survey, the investigators crunched the numbers and found that secondhand aerosol exposure increased the odds of an asthma attack by 27%, independent of exposure to secondhand smoke and whether children smoked or vaped themselves (adjusted odds ratio, 1.27; 95% confidence interval, 1.11-1.47).

“Health professionals may wish to counsel asthmatic youth and their families regarding the potential risks of ENDS [electronic nicotine delivery system] use and exposure to ENDS aerosols.” Providers “may also consider including ENDS aerosol exposure as a possible trigger in asthma self-management/action plans and updating asthma home environment assessments to include exposure to ENDS aerosols,” said investigators led by medical student Jennifer Bayly, a research fellow at the National Institute on Minority Health and Health Disparities in Bethesda, Md.

About 4% of adults in the United States and 11% of high school students vape, and almost 10% of U.S. adolescents reported living with an ENDS user in 2014. Given the data, “it is likely that a substantial number of asthmatic youth are exposed,” the investigators said.

The study adds to a growing body of evidence linking e-cigarettes to asthma. There’s moderate evidence for increased cough and wheezing in adolescents who use e-cigarettes, plus an association with e-cigarette use and increased asthma exacerbations. The new study, however, is likely the first to look specifically at secondhand exposure among asthmatic children. Ingredients in vaping aerosols, including flavorings, propylene glycol, and vegetable glycerin, are physiologically active in the lungs, and may be lung irritants.

Overall, about half of the respondents were female, and two-thirds were 11-13 years old. About a third identified as Hispanic, a third as white, and just over a fifth as black. Three-quarters of the sample lived in large or midsized metropolitan areas, and close to two-thirds in stand-alone homes. Participants were considered exposed to secondhand aerosols if they reported that in the past month they were in a room or car with someone who was vaping.

The work was funded by the National Institutes of Health. The investigators had no disclosures.

aotto@mdedge.com

SOURCE: Bayly JE et al. CHEST®. 2018 Oct 22. doi: 10.1016/j.chest.2018.10.005.

Just like exposure to secondhand smoke, exposure to secondhand aerosols from e-cigarettes is associated with an increased risk of asthma exacerbations in children, according to a review of the 11,830 kids with asthma in the 2016 Florida Youth Tobacco survey.

diego_cervo/Thinkstock

Every year, the Florida Department of Health surveys public school children aged 11-17 years about various tobacco issues. In 2016, almost 12% of the asthmatic children in the survey said they vaped. Almost half were exposed to secondhand smoke, and a third reported exposure to secondhand vaping aerosols within the past 30 days. Overall, 21% reported an asthma attack in the past 12 months.

Using data from the Florida survey, the investigators crunched the numbers and found that secondhand aerosol exposure increased the odds of an asthma attack by 27%, independent of exposure to secondhand smoke and whether children smoked or vaped themselves (adjusted odds ratio, 1.27; 95% confidence interval, 1.11-1.47).

“Health professionals may wish to counsel asthmatic youth and their families regarding the potential risks of ENDS [electronic nicotine delivery system] use and exposure to ENDS aerosols.” Providers “may also consider including ENDS aerosol exposure as a possible trigger in asthma self-management/action plans and updating asthma home environment assessments to include exposure to ENDS aerosols,” said investigators led by medical student Jennifer Bayly, a research fellow at the National Institute on Minority Health and Health Disparities in Bethesda, Md.

About 4% of adults in the United States and 11% of high school students vape, and almost 10% of U.S. adolescents reported living with an ENDS user in 2014. Given the data, “it is likely that a substantial number of asthmatic youth are exposed,” the investigators said.

The study adds to a growing body of evidence linking e-cigarettes to asthma. There’s moderate evidence for increased cough and wheezing in adolescents who use e-cigarettes, plus an association with e-cigarette use and increased asthma exacerbations. The new study, however, is likely the first to look specifically at secondhand exposure among asthmatic children. Ingredients in vaping aerosols, including flavorings, propylene glycol, and vegetable glycerin, are physiologically active in the lungs, and may be lung irritants.

Overall, about half of the respondents were female, and two-thirds were 11-13 years old. About a third identified as Hispanic, a third as white, and just over a fifth as black. Three-quarters of the sample lived in large or midsized metropolitan areas, and close to two-thirds in stand-alone homes. Participants were considered exposed to secondhand aerosols if they reported that in the past month they were in a room or car with someone who was vaping.

The work was funded by the National Institutes of Health. The investigators had no disclosures.

aotto@mdedge.com

SOURCE: Bayly JE et al. CHEST®. 2018 Oct 22. doi: 10.1016/j.chest.2018.10.005.

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. NAFLD also is an independent risk factor for cardiovascular disease, type 2 diabetes mellitus (T2DM), chronic kidney disease, cirrhosis, liver cancer, and all-cause mortality.^1-3 As the leading cause of liver disease in the US and globally, NAFLD is strongly associated with obesity and metabolic syndrome, with the rising prevalence of NAFLD closely mirroring the epidemic of obesity and T2DM.^4,5 The unrelenting increase of NAFLD prevalence has led to a significant rise in associated health care and economic burdens, compounded by the boom in childhood obesity and an aging population. In this review, we will discuss the epidemiology and economic burden of NAFLD in the US and how it affects veteran health.

NAFLD Definition

NAFLD is defined as the presence of > 5% of hepatic steatosis in the absence of excessive alcohol use, steatosis-inducing medication, or other concurrent chronic liver diseases. 

Compared with patients with NAFL, patients with NASH are at a much higher risk of developing fibrosis (scarring of the liver) and cirrhosis (significant scarring with distorted liver architecture). Patients with either NAFL or NASH, with or without advanced fibrosis, also can develop hepatocellular carcinoma (HCC). Severity of liver fibrosis (ie, fibrosis stage) is the most important predictor of liver-associated mortality and all-cause mortality; those with significant fibrosis (≥ F2 stage of fibrosis) are more likely to die of liver disease or to undergo a liver transplant compared with those with earlier stages of disease (ie, stages 0 to F1). Those with advanced scarring or cirrhosis (≥ F3 stage of fibrosis) exhibit an even higher risk of death or liver transplantation.⁶

NAFLD is a slow and often progressive disease. Time to progression between each stage of fibrosis is about 7 years; however, there has been a documented subset of patients with rapid progression to advanced fibrosis.⁷ The risk factors associated with this increased risk of fibrosis progression remain poorly understood.

Prevalence

The prevalence of NAFLD in the US is about 24% to 26%—about 85 million Americans. Up to 20% to 30% of these cases (about 17-25 million Americans) are thought to have NASH (Figure 2). 

Although liver biopsy remains the current gold standard for diagnosis and histopathologic staging of NAFLD, alternatives to liver biopsy include elastography techniques (ie, transient elastography using Fibroscan[Paris, France], shear wave elastography using Supersonic Image Aixplorer [Weston, FL], and magnetic resonance elastography), magnetic resonance spectroscopy, liver enzymes, and noninvasive simple and complex (serologic) scoring systems such as the Fatty Liver Index. Among these, liver enzymes and serologic scores are most likely to underestimate NAFLD disease burden. Transient elastographyis widely used because the test is easy to perform, noninvasive, and reliably estimates the degree of liver fibrosis in patients with NAFLD by measuring the speed of a mechanically induced shear wave using pulse-echo ultrasonic acquisitions in a much larger portion of the tissue (about 100 times more than a liver biopsy core). Transient elastography also can objectively quantify the amount of liver fat by measuring a 3.5 MHz ultrasound coefficient of attenuation or controlled attenuation parameter (CAP). This correlates with the degree of liver fat, and a higher CAP level reflects a greater degree of steatosis.

The largest study of US veterans utilized abnormal (ie, elevated) liver enzymes as the diagnostic criteria and reviewed nearly 10 million veterans who were followed between 2003 and 2011. Investigators reported a NAFLD prevalence of 13.6% in this population and noted an overall increase in NAFLD prevalence from 6.3% in 2003 to 17.6% in 2011, which highlights the continued growth in NAFLD clinical burden.¹⁰ This study, however, is likely to have underestimated the prevalence of NAFLD among veterans because liver enzymes are often normal among those with NAFLD (ie, low sensitivity), and the prevalence of obesity and T2DM are significantly higher in the veteran population vs the general population.

Incidence

There are limited studies on NAFLD incidence. The largest study of US veterans to date used liver enzymes as its diagnostic criteria and reported an annual NAFLD incidence of 2 to 3 per 100 persons (over 9 years from 2003 to 2011).¹⁰ There are a few studies from Asia and Europe, and a recent pooled meta-analysis of these studies reported the incidence of NAFLD in Asia to be 52.3 per 1,000 person-years; the incidence in Western countries was 28 per 1,000 person-years.⁵ These variances may be explained, in part, to disparities in race/background. For example, Hispanics and South Asians (ie, people from Bangladesh, India, or Pakistan) are at higher risk for NAFLD/NASH.¹¹ These findings reinforce the need for further studies to better estimate the true incidence of NAFLD among veterans.

Chronic Liver Disease, Cirrhosis, and Hepatocellular Carcinoma

The prevalence of NASH cirrhosis also has been evaluated using serologic scores, such as aspartate aminotransferase to platelet ratio index (APRI). The National Health and Nutrition Examination Survey (NHANES) database was reviewed, and data for adults in 2 separate periods were analyzed (1999-2002 and 2009-2012) and the prevalence of NASH cirrhosis was noted to have increased 2.5-fold over the period (0.072% vs 0.178%, P < .05).¹¹ Based on data from the HealthCore Integrated Research Database from 2006 to 2014, about 15% of cirrhosis cases were attributed to NAFLD, and about 24% each were attributed to hepatitis C virus (HCV) and alcoholic liver disease.¹² A review of about 60,000 veterans with cirrhosis between 2001 and 2013 revealed a prevalence of NAFLD-related cirrhosis of about 15%, while 48% were attributed to HCV.¹³ In contrast to the continued increase in NAFLD prevalence, the number of patients with HCV-associated liver disease has been in gradual decline since the advent of direct acting antiviral medications in 2011.¹²

Based on data from the United Network for Organ Sharing (UNOS), the number of patients awaiting liver transplant due to NAFLD nearly tripled from 2004 to 2013, and in 2013 NAFLD became the second leading disease among waitlisted patients for liver transplantation.¹⁴ Dynamic Markov modeling predicts that cases of decompensated NASH cirrhosis (ie, liver failure) will rise by 161%, from about 144,000 to 376,000 cases over the next 15 years.⁸ These projections predict that NAFLD will overtake HCV as the leading cause of chronic liver disease among patients awaiting a liver transplant and will pose a significant clinical and economic burden in the coming years.

Aside from cirrhosis due to NAFLD, NAFLD-related HCC has been on the rise and has overtaken HCV-related HCC. UNOS data from 2003 to 2015 have shown a 2-fold decline in liver transplantation for HCV-associated HCC; however, the same period saw a 10-fold increase in liver transplantation for NAFLD-associated HCC.^15,16 This trend in NAFLD-related HCC is expected to grow from 5,000 to 6,000 cases in 2005 to 45,000 cases by 2025.⁹ More surprisingly, studies from the US veteran population have reported that patients with NAFLD-related HCC are less likely to have cirrhosis compared with patients with HCV- or alcohol-related HCC.¹⁷ Among all US veterans who developed HCC in the absence of cirrhosis between 2005 and 2010, NAFLD and metabolic syndrome seemed to be the leading risk factors for development of HCC.¹⁸ These trends raise concern for the rise in noncirrhotic HCC in the NAFLD population and highlight the need to improve current screening guidelines for this subset of patients.

Economic Burden

With such a heavy clinical burden and a projected increase in volume over the next decade, NAFLD is expected to have a similarly exponential impact on the economic burden. A review of 976 Medicare beneficiaries with NAFLD who were hospitalized from January 1, 2010 to December 31, 2010, noted a median annual total payment of about $11,000, with significantly lower payment for patients without cirrhosis compared with those with cirrhosis ($10,146 vs $18,804, P < .01).¹⁹ Another review of 29,528 Medicare beneficiaries with NAFLD who sought outpatient care between 2005 and 2010 saw a rise in mean yearly charges in 2005 of $2,624 ± 3,308 to $3,608 ± 5,132 in 2010 (P < .05).²⁰

To place these costs in perspective, Allen and colleagues reviewed a large national claims database of individuals enrolled with private and Medicare advantage health plans.²¹ Comparing patients with NAFLD with a control matched group with similar metabolic comorbidities the study revealed annual median outpatient care costs of $5,363 for the patients with NAFLD with Medicare advantage plans, which was significantly higher than $4,111 for the control group. Projection models based on similar Medicare beneficiaries estimate a rise in annual US economic burden to $103 billion from direct medical care costs alone and another $188 billion in societal costs related to NAFLD.²² New NASH/antifibrotic therapies are being evaluated in clinical trials and are expected to lead to even higher costs. Given the similarities in the trends of NAFLD prevalence between veterans and the general population, it is anticipated that a similar growth and burden in health care utilization cost will affect the VHA.

Association With Other Chronic Medical Conditions

NAFLD is closely associated with metabolic syndrome (Figure 3). Concurrent diagnosis of NAFLD in patients with existing T2DM is associated with poor glycemic control, progressive diabetic retinopathy, diabetic nephropathy, increased risk of cardiovascular complications, and a 2-fold increase in all-cause mortality.^1-3 

Similar associations have been described between NAFLD and other metabolic conditions such as obesity, hypertension, hypothyroidism, polycystic ovarian syndrome, and chronic kidney disease.³¹ Identifying patients with NAFLD may help with screening for the above metabolic diseases because patients with NAFLD (by comparison with patients with non-NAFLD) are at higher risk for diabetic, cardiovascular, and pulmonary complications and may warrant a more intensive treatment approach.

Conclusion

A leading cause of chronic liver disease and cirrhosis in the US, NAFLD is independently associated with metabolic syndrome and all-cause mortality. The number of veterans with NAFLD is expected to grow significantly over the coming years given the ongoing epidemic of adult and childhood obesity and T2DM. It is associated with many other medical conditions, including cardiovascular disease and complications, incident metabolic diseases, and may progress to liver cirrhosis and cirrhosis associated complications like HCC and liver failure. The current lack of any approved drug treatment for NASH/fibrosis and the shortage of organs for liver transplant emphasize the need for comprehensive primary prevention measures to reduce the future health and economic costs associated with NAFLD.

There is a growing need to address the epidemic of metabolic syndrome, as heralded by the World Health Organization in its 2013 global action plan. To address this multifaceted disease, initial approach should be to improve NAFLD education among veterans, beginning with the primary care teams and extending to specialty care, including hepatologists. Future steps also should include the development of a comprehensive metabolic/NAFLD clinic in all US Department of Veterans Affairs medical centers that integrates multidisciplinary care, point-of-care evaluation (eg, elastography staging of disease), and access to clinical trials, and have NAFLD care/outcome as a key performance target for all providers.

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. NAFLD also is an independent risk factor for cardiovascular disease, type 2 diabetes mellitus (T2DM), chronic kidney disease, cirrhosis, liver cancer, and all-cause mortality.^1-3 As the leading cause of liver disease in the US and globally, NAFLD is strongly associated with obesity and metabolic syndrome, with the rising prevalence of NAFLD closely mirroring the epidemic of obesity and T2DM.^4,5 The unrelenting increase of NAFLD prevalence has led to a significant rise in associated health care and economic burdens, compounded by the boom in childhood obesity and an aging population. In this review, we will discuss the epidemiology and economic burden of NAFLD in the US and how it affects veteran health.

NAFLD Definition

NAFLD is defined as the presence of > 5% of hepatic steatosis in the absence of excessive alcohol use, steatosis-inducing medication, or other concurrent chronic liver diseases. 

Compared with patients with NAFL, patients with NASH are at a much higher risk of developing fibrosis (scarring of the liver) and cirrhosis (significant scarring with distorted liver architecture). Patients with either NAFL or NASH, with or without advanced fibrosis, also can develop hepatocellular carcinoma (HCC). Severity of liver fibrosis (ie, fibrosis stage) is the most important predictor of liver-associated mortality and all-cause mortality; those with significant fibrosis (≥ F2 stage of fibrosis) are more likely to die of liver disease or to undergo a liver transplant compared with those with earlier stages of disease (ie, stages 0 to F1). Those with advanced scarring or cirrhosis (≥ F3 stage of fibrosis) exhibit an even higher risk of death or liver transplantation.⁶

NAFLD is a slow and often progressive disease. Time to progression between each stage of fibrosis is about 7 years; however, there has been a documented subset of patients with rapid progression to advanced fibrosis.⁷ The risk factors associated with this increased risk of fibrosis progression remain poorly understood.

Prevalence

The prevalence of NAFLD in the US is about 24% to 26%—about 85 million Americans. Up to 20% to 30% of these cases (about 17-25 million Americans) are thought to have NASH (Figure 2). 

Although liver biopsy remains the current gold standard for diagnosis and histopathologic staging of NAFLD, alternatives to liver biopsy include elastography techniques (ie, transient elastography using Fibroscan[Paris, France], shear wave elastography using Supersonic Image Aixplorer [Weston, FL], and magnetic resonance elastography), magnetic resonance spectroscopy, liver enzymes, and noninvasive simple and complex (serologic) scoring systems such as the Fatty Liver Index. Among these, liver enzymes and serologic scores are most likely to underestimate NAFLD disease burden. Transient elastographyis widely used because the test is easy to perform, noninvasive, and reliably estimates the degree of liver fibrosis in patients with NAFLD by measuring the speed of a mechanically induced shear wave using pulse-echo ultrasonic acquisitions in a much larger portion of the tissue (about 100 times more than a liver biopsy core). Transient elastography also can objectively quantify the amount of liver fat by measuring a 3.5 MHz ultrasound coefficient of attenuation or controlled attenuation parameter (CAP). This correlates with the degree of liver fat, and a higher CAP level reflects a greater degree of steatosis.

The largest study of US veterans utilized abnormal (ie, elevated) liver enzymes as the diagnostic criteria and reviewed nearly 10 million veterans who were followed between 2003 and 2011. Investigators reported a NAFLD prevalence of 13.6% in this population and noted an overall increase in NAFLD prevalence from 6.3% in 2003 to 17.6% in 2011, which highlights the continued growth in NAFLD clinical burden.¹⁰ This study, however, is likely to have underestimated the prevalence of NAFLD among veterans because liver enzymes are often normal among those with NAFLD (ie, low sensitivity), and the prevalence of obesity and T2DM are significantly higher in the veteran population vs the general population.

Incidence

There are limited studies on NAFLD incidence. The largest study of US veterans to date used liver enzymes as its diagnostic criteria and reported an annual NAFLD incidence of 2 to 3 per 100 persons (over 9 years from 2003 to 2011).¹⁰ There are a few studies from Asia and Europe, and a recent pooled meta-analysis of these studies reported the incidence of NAFLD in Asia to be 52.3 per 1,000 person-years; the incidence in Western countries was 28 per 1,000 person-years.⁵ These variances may be explained, in part, to disparities in race/background. For example, Hispanics and South Asians (ie, people from Bangladesh, India, or Pakistan) are at higher risk for NAFLD/NASH.¹¹ These findings reinforce the need for further studies to better estimate the true incidence of NAFLD among veterans.

Chronic Liver Disease, Cirrhosis, and Hepatocellular Carcinoma

The prevalence of NASH cirrhosis also has been evaluated using serologic scores, such as aspartate aminotransferase to platelet ratio index (APRI). The National Health and Nutrition Examination Survey (NHANES) database was reviewed, and data for adults in 2 separate periods were analyzed (1999-2002 and 2009-2012) and the prevalence of NASH cirrhosis was noted to have increased 2.5-fold over the period (0.072% vs 0.178%, P < .05).¹¹ Based on data from the HealthCore Integrated Research Database from 2006 to 2014, about 15% of cirrhosis cases were attributed to NAFLD, and about 24% each were attributed to hepatitis C virus (HCV) and alcoholic liver disease.¹² A review of about 60,000 veterans with cirrhosis between 2001 and 2013 revealed a prevalence of NAFLD-related cirrhosis of about 15%, while 48% were attributed to HCV.¹³ In contrast to the continued increase in NAFLD prevalence, the number of patients with HCV-associated liver disease has been in gradual decline since the advent of direct acting antiviral medications in 2011.¹²

Based on data from the United Network for Organ Sharing (UNOS), the number of patients awaiting liver transplant due to NAFLD nearly tripled from 2004 to 2013, and in 2013 NAFLD became the second leading disease among waitlisted patients for liver transplantation.¹⁴ Dynamic Markov modeling predicts that cases of decompensated NASH cirrhosis (ie, liver failure) will rise by 161%, from about 144,000 to 376,000 cases over the next 15 years.⁸ These projections predict that NAFLD will overtake HCV as the leading cause of chronic liver disease among patients awaiting a liver transplant and will pose a significant clinical and economic burden in the coming years.

Aside from cirrhosis due to NAFLD, NAFLD-related HCC has been on the rise and has overtaken HCV-related HCC. UNOS data from 2003 to 2015 have shown a 2-fold decline in liver transplantation for HCV-associated HCC; however, the same period saw a 10-fold increase in liver transplantation for NAFLD-associated HCC.^15,16 This trend in NAFLD-related HCC is expected to grow from 5,000 to 6,000 cases in 2005 to 45,000 cases by 2025.⁹ More surprisingly, studies from the US veteran population have reported that patients with NAFLD-related HCC are less likely to have cirrhosis compared with patients with HCV- or alcohol-related HCC.¹⁷ Among all US veterans who developed HCC in the absence of cirrhosis between 2005 and 2010, NAFLD and metabolic syndrome seemed to be the leading risk factors for development of HCC.¹⁸ These trends raise concern for the rise in noncirrhotic HCC in the NAFLD population and highlight the need to improve current screening guidelines for this subset of patients.

Economic Burden

With such a heavy clinical burden and a projected increase in volume over the next decade, NAFLD is expected to have a similarly exponential impact on the economic burden. A review of 976 Medicare beneficiaries with NAFLD who were hospitalized from January 1, 2010 to December 31, 2010, noted a median annual total payment of about $11,000, with significantly lower payment for patients without cirrhosis compared with those with cirrhosis ($10,146 vs $18,804, P < .01).¹⁹ Another review of 29,528 Medicare beneficiaries with NAFLD who sought outpatient care between 2005 and 2010 saw a rise in mean yearly charges in 2005 of $2,624 ± 3,308 to $3,608 ± 5,132 in 2010 (P < .05).²⁰

To place these costs in perspective, Allen and colleagues reviewed a large national claims database of individuals enrolled with private and Medicare advantage health plans.²¹ Comparing patients with NAFLD with a control matched group with similar metabolic comorbidities the study revealed annual median outpatient care costs of $5,363 for the patients with NAFLD with Medicare advantage plans, which was significantly higher than $4,111 for the control group. Projection models based on similar Medicare beneficiaries estimate a rise in annual US economic burden to $103 billion from direct medical care costs alone and another $188 billion in societal costs related to NAFLD.²² New NASH/antifibrotic therapies are being evaluated in clinical trials and are expected to lead to even higher costs. Given the similarities in the trends of NAFLD prevalence between veterans and the general population, it is anticipated that a similar growth and burden in health care utilization cost will affect the VHA.

Association With Other Chronic Medical Conditions

NAFLD is closely associated with metabolic syndrome (Figure 3). Concurrent diagnosis of NAFLD in patients with existing T2DM is associated with poor glycemic control, progressive diabetic retinopathy, diabetic nephropathy, increased risk of cardiovascular complications, and a 2-fold increase in all-cause mortality.^1-3 

Similar associations have been described between NAFLD and other metabolic conditions such as obesity, hypertension, hypothyroidism, polycystic ovarian syndrome, and chronic kidney disease.³¹ Identifying patients with NAFLD may help with screening for the above metabolic diseases because patients with NAFLD (by comparison with patients with non-NAFLD) are at higher risk for diabetic, cardiovascular, and pulmonary complications and may warrant a more intensive treatment approach.

Conclusion

A leading cause of chronic liver disease and cirrhosis in the US, NAFLD is independently associated with metabolic syndrome and all-cause mortality. The number of veterans with NAFLD is expected to grow significantly over the coming years given the ongoing epidemic of adult and childhood obesity and T2DM. It is associated with many other medical conditions, including cardiovascular disease and complications, incident metabolic diseases, and may progress to liver cirrhosis and cirrhosis associated complications like HCC and liver failure. The current lack of any approved drug treatment for NASH/fibrosis and the shortage of organs for liver transplant emphasize the need for comprehensive primary prevention measures to reduce the future health and economic costs associated with NAFLD.

There is a growing need to address the epidemic of metabolic syndrome, as heralded by the World Health Organization in its 2013 global action plan. To address this multifaceted disease, initial approach should be to improve NAFLD education among veterans, beginning with the primary care teams and extending to specialty care, including hepatologists. Future steps also should include the development of a comprehensive metabolic/NAFLD clinic in all US Department of Veterans Affairs medical centers that integrates multidisciplinary care, point-of-care evaluation (eg, elastography staging of disease), and access to clinical trials, and have NAFLD care/outcome as a key performance target for all providers.

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. NAFLD also is an independent risk factor for cardiovascular disease, type 2 diabetes mellitus (T2DM), chronic kidney disease, cirrhosis, liver cancer, and all-cause mortality.^1-3 As the leading cause of liver disease in the US and globally, NAFLD is strongly associated with obesity and metabolic syndrome, with the rising prevalence of NAFLD closely mirroring the epidemic of obesity and T2DM.^4,5 The unrelenting increase of NAFLD prevalence has led to a significant rise in associated health care and economic burdens, compounded by the boom in childhood obesity and an aging population. In this review, we will discuss the epidemiology and economic burden of NAFLD in the US and how it affects veteran health.

NAFLD Definition

NAFLD is defined as the presence of > 5% of hepatic steatosis in the absence of excessive alcohol use, steatosis-inducing medication, or other concurrent chronic liver diseases. 

Compared with patients with NAFL, patients with NASH are at a much higher risk of developing fibrosis (scarring of the liver) and cirrhosis (significant scarring with distorted liver architecture). Patients with either NAFL or NASH, with or without advanced fibrosis, also can develop hepatocellular carcinoma (HCC). Severity of liver fibrosis (ie, fibrosis stage) is the most important predictor of liver-associated mortality and all-cause mortality; those with significant fibrosis (≥ F2 stage of fibrosis) are more likely to die of liver disease or to undergo a liver transplant compared with those with earlier stages of disease (ie, stages 0 to F1). Those with advanced scarring or cirrhosis (≥ F3 stage of fibrosis) exhibit an even higher risk of death or liver transplantation.⁶

NAFLD is a slow and often progressive disease. Time to progression between each stage of fibrosis is about 7 years; however, there has been a documented subset of patients with rapid progression to advanced fibrosis.⁷ The risk factors associated with this increased risk of fibrosis progression remain poorly understood.

Prevalence

The prevalence of NAFLD in the US is about 24% to 26%—about 85 million Americans. Up to 20% to 30% of these cases (about 17-25 million Americans) are thought to have NASH (Figure 2). 

Although liver biopsy remains the current gold standard for diagnosis and histopathologic staging of NAFLD, alternatives to liver biopsy include elastography techniques (ie, transient elastography using Fibroscan[Paris, France], shear wave elastography using Supersonic Image Aixplorer [Weston, FL], and magnetic resonance elastography), magnetic resonance spectroscopy, liver enzymes, and noninvasive simple and complex (serologic) scoring systems such as the Fatty Liver Index. Among these, liver enzymes and serologic scores are most likely to underestimate NAFLD disease burden. Transient elastographyis widely used because the test is easy to perform, noninvasive, and reliably estimates the degree of liver fibrosis in patients with NAFLD by measuring the speed of a mechanically induced shear wave using pulse-echo ultrasonic acquisitions in a much larger portion of the tissue (about 100 times more than a liver biopsy core). Transient elastography also can objectively quantify the amount of liver fat by measuring a 3.5 MHz ultrasound coefficient of attenuation or controlled attenuation parameter (CAP). This correlates with the degree of liver fat, and a higher CAP level reflects a greater degree of steatosis.

The largest study of US veterans utilized abnormal (ie, elevated) liver enzymes as the diagnostic criteria and reviewed nearly 10 million veterans who were followed between 2003 and 2011. Investigators reported a NAFLD prevalence of 13.6% in this population and noted an overall increase in NAFLD prevalence from 6.3% in 2003 to 17.6% in 2011, which highlights the continued growth in NAFLD clinical burden.¹⁰ This study, however, is likely to have underestimated the prevalence of NAFLD among veterans because liver enzymes are often normal among those with NAFLD (ie, low sensitivity), and the prevalence of obesity and T2DM are significantly higher in the veteran population vs the general population.

Incidence

There are limited studies on NAFLD incidence. The largest study of US veterans to date used liver enzymes as its diagnostic criteria and reported an annual NAFLD incidence of 2 to 3 per 100 persons (over 9 years from 2003 to 2011).¹⁰ There are a few studies from Asia and Europe, and a recent pooled meta-analysis of these studies reported the incidence of NAFLD in Asia to be 52.3 per 1,000 person-years; the incidence in Western countries was 28 per 1,000 person-years.⁵ These variances may be explained, in part, to disparities in race/background. For example, Hispanics and South Asians (ie, people from Bangladesh, India, or Pakistan) are at higher risk for NAFLD/NASH.¹¹ These findings reinforce the need for further studies to better estimate the true incidence of NAFLD among veterans.

Chronic Liver Disease, Cirrhosis, and Hepatocellular Carcinoma

The prevalence of NASH cirrhosis also has been evaluated using serologic scores, such as aspartate aminotransferase to platelet ratio index (APRI). The National Health and Nutrition Examination Survey (NHANES) database was reviewed, and data for adults in 2 separate periods were analyzed (1999-2002 and 2009-2012) and the prevalence of NASH cirrhosis was noted to have increased 2.5-fold over the period (0.072% vs 0.178%, P < .05).¹¹ Based on data from the HealthCore Integrated Research Database from 2006 to 2014, about 15% of cirrhosis cases were attributed to NAFLD, and about 24% each were attributed to hepatitis C virus (HCV) and alcoholic liver disease.¹² A review of about 60,000 veterans with cirrhosis between 2001 and 2013 revealed a prevalence of NAFLD-related cirrhosis of about 15%, while 48% were attributed to HCV.¹³ In contrast to the continued increase in NAFLD prevalence, the number of patients with HCV-associated liver disease has been in gradual decline since the advent of direct acting antiviral medications in 2011.¹²

Based on data from the United Network for Organ Sharing (UNOS), the number of patients awaiting liver transplant due to NAFLD nearly tripled from 2004 to 2013, and in 2013 NAFLD became the second leading disease among waitlisted patients for liver transplantation.¹⁴ Dynamic Markov modeling predicts that cases of decompensated NASH cirrhosis (ie, liver failure) will rise by 161%, from about 144,000 to 376,000 cases over the next 15 years.⁸ These projections predict that NAFLD will overtake HCV as the leading cause of chronic liver disease among patients awaiting a liver transplant and will pose a significant clinical and economic burden in the coming years.

Aside from cirrhosis due to NAFLD, NAFLD-related HCC has been on the rise and has overtaken HCV-related HCC. UNOS data from 2003 to 2015 have shown a 2-fold decline in liver transplantation for HCV-associated HCC; however, the same period saw a 10-fold increase in liver transplantation for NAFLD-associated HCC.^15,16 This trend in NAFLD-related HCC is expected to grow from 5,000 to 6,000 cases in 2005 to 45,000 cases by 2025.⁹ More surprisingly, studies from the US veteran population have reported that patients with NAFLD-related HCC are less likely to have cirrhosis compared with patients with HCV- or alcohol-related HCC.¹⁷ Among all US veterans who developed HCC in the absence of cirrhosis between 2005 and 2010, NAFLD and metabolic syndrome seemed to be the leading risk factors for development of HCC.¹⁸ These trends raise concern for the rise in noncirrhotic HCC in the NAFLD population and highlight the need to improve current screening guidelines for this subset of patients.

Economic Burden

With such a heavy clinical burden and a projected increase in volume over the next decade, NAFLD is expected to have a similarly exponential impact on the economic burden. A review of 976 Medicare beneficiaries with NAFLD who were hospitalized from January 1, 2010 to December 31, 2010, noted a median annual total payment of about $11,000, with significantly lower payment for patients without cirrhosis compared with those with cirrhosis ($10,146 vs $18,804, P < .01).¹⁹ Another review of 29,528 Medicare beneficiaries with NAFLD who sought outpatient care between 2005 and 2010 saw a rise in mean yearly charges in 2005 of $2,624 ± 3,308 to $3,608 ± 5,132 in 2010 (P < .05).²⁰

To place these costs in perspective, Allen and colleagues reviewed a large national claims database of individuals enrolled with private and Medicare advantage health plans.²¹ Comparing patients with NAFLD with a control matched group with similar metabolic comorbidities the study revealed annual median outpatient care costs of $5,363 for the patients with NAFLD with Medicare advantage plans, which was significantly higher than $4,111 for the control group. Projection models based on similar Medicare beneficiaries estimate a rise in annual US economic burden to $103 billion from direct medical care costs alone and another $188 billion in societal costs related to NAFLD.²² New NASH/antifibrotic therapies are being evaluated in clinical trials and are expected to lead to even higher costs. Given the similarities in the trends of NAFLD prevalence between veterans and the general population, it is anticipated that a similar growth and burden in health care utilization cost will affect the VHA.

Association With Other Chronic Medical Conditions

NAFLD is closely associated with metabolic syndrome (Figure 3). Concurrent diagnosis of NAFLD in patients with existing T2DM is associated with poor glycemic control, progressive diabetic retinopathy, diabetic nephropathy, increased risk of cardiovascular complications, and a 2-fold increase in all-cause mortality.^1-3 

Similar associations have been described between NAFLD and other metabolic conditions such as obesity, hypertension, hypothyroidism, polycystic ovarian syndrome, and chronic kidney disease.³¹ Identifying patients with NAFLD may help with screening for the above metabolic diseases because patients with NAFLD (by comparison with patients with non-NAFLD) are at higher risk for diabetic, cardiovascular, and pulmonary complications and may warrant a more intensive treatment approach.

Conclusion

A leading cause of chronic liver disease and cirrhosis in the US, NAFLD is independently associated with metabolic syndrome and all-cause mortality. The number of veterans with NAFLD is expected to grow significantly over the coming years given the ongoing epidemic of adult and childhood obesity and T2DM. It is associated with many other medical conditions, including cardiovascular disease and complications, incident metabolic diseases, and may progress to liver cirrhosis and cirrhosis associated complications like HCC and liver failure. The current lack of any approved drug treatment for NASH/fibrosis and the shortage of organs for liver transplant emphasize the need for comprehensive primary prevention measures to reduce the future health and economic costs associated with NAFLD.

There is a growing need to address the epidemic of metabolic syndrome, as heralded by the World Health Organization in its 2013 global action plan. To address this multifaceted disease, initial approach should be to improve NAFLD education among veterans, beginning with the primary care teams and extending to specialty care, including hepatologists. Future steps also should include the development of a comprehensive metabolic/NAFLD clinic in all US Department of Veterans Affairs medical centers that integrates multidisciplinary care, point-of-care evaluation (eg, elastography staging of disease), and access to clinical trials, and have NAFLD care/outcome as a key performance target for all providers.

The Michigan chapter of the Society of Hospital Medicine has named Peter Watson, MD, SFHM, as state Hospitalist of the Year. Dr. Watson is the vice president of care management and outcomes for Health Alliance Plan (HAP) in Detroit. The Michigan chapter cited Dr. Watson’s leadership in hospital medicine and “generosity of spirit” as reasons for his selection.

Dr. Watson oversees nurses, social workers, and support staff while also serving as HAP Midwest Health Plan’s medical director. He’s a founding member of the Michigan SHM chapter, which he formerly represented as president.

Dr. Watson spent 11 years overseeing the Henry Ford Medical Group’s hospitalist program prior to joining HAP, and still works as an attending hospitalist for Henry Ford.

Hyung (Harry) Cho, MD, was named the inaugural chief value officer for NYC Health + Hospitals, which includes 11 hospitals in New York and is the largest public health system in the United States. He will oversee systemwide initiatives in value improvement and the reduction of unnecessary testing and treatment.

Prior to this appointment, Dr. Cho served as an academic hospitalist at Mount Sinai Hospital for 7 years, leading high-value care initiatives. Currently, he is a senior fellow with the Lown Institute in Brookline, Mass., and director of quality improvement implementation for the High Value Practice Academic Alliance.

Nick Fitterman, MD, SFHM, has been promoted to executive director at Huntington (N.Y.) Hospital. Dr. Fitterman has been a long-time physician and administrator at Huntington, serving previously as vice chair of medicine as well as head of hospitalists.

Dr. Fitterman has served as president of SHM’s Long Island chapter.

Previously, Dr. Fitterman was chief resident at the State University of New York at Stony Brook, and he remains an associate professor at Hofstra University, Hempstead, N.Y.

Allen Kachalia, MD, was named director of the Armstrong Institute for Patient Safety and Quality and senior vice president of patient safety and quality for Johns Hopkins Medicine in Baltimore. Dr. Kachalia is a general internist who has been an active academic hospitalist at Brigham and Women’s Hospital in Boston.

Dr. Kachalia will oversee patient safety and quality across all of Hopkins Medicine, with a focus on ending preventable harm, improving outcomes and patient experience, and reducing waste in the system’s delivery of care. He also will guide academic efforts for the Armstrong Institute, formed recently thanks to a $10 million gift.

In addition to his hospitalist work, Dr. Kachalia comes to Hopkins after serving as chief quality officer and vice president of quality and safety at Brigham Health.

Riane Dodge, PA, has been elevated to director of clinical education in physician assistant studies at Clarkson University, Potsdam, N.Y. The veteran physician assistant previously worked as a hospitalist in the Claxton Hepburn Medical Center in Ogdensburg, N.Y. There, she cared for patients in acute rehab, mental health, and on regular medical floors.

Dodge also has a background in urgent care and family medicine, and has experience as an emergency department technician.

BUSINESS MOVES

Surgical Affiliates of Sacramento, a surgical hospitalist provider with expertise in trauma, orthopedic, neurosurgery, and general surgery for hospital systems, has added partnerships with Christus Spohn Hospital South and Christus Spohn Hospital Shoreline in Corpus Christi, Texas.

Surgical Affiliates’ hospitalist system will provide round-the-clock emergency orthopedic surgery service to adult and pediatric patients in the two hospitals. With Surgical Affiliates’ help, Christus Spohn facilities will be able to cover its own patients, as well as those requiring transfer from regional hospitals.

Hospitalist surgeons will handle emergency surgeries and patient surgery consultations. Clinics will be provided at each facility to care for patients after they are discharged.

The Michigan chapter of the Society of Hospital Medicine has named Peter Watson, MD, SFHM, as state Hospitalist of the Year. Dr. Watson is the vice president of care management and outcomes for Health Alliance Plan (HAP) in Detroit. The Michigan chapter cited Dr. Watson’s leadership in hospital medicine and “generosity of spirit” as reasons for his selection.

Dr. Watson oversees nurses, social workers, and support staff while also serving as HAP Midwest Health Plan’s medical director. He’s a founding member of the Michigan SHM chapter, which he formerly represented as president.

Dr. Watson spent 11 years overseeing the Henry Ford Medical Group’s hospitalist program prior to joining HAP, and still works as an attending hospitalist for Henry Ford.

Hyung (Harry) Cho, MD, was named the inaugural chief value officer for NYC Health + Hospitals, which includes 11 hospitals in New York and is the largest public health system in the United States. He will oversee systemwide initiatives in value improvement and the reduction of unnecessary testing and treatment.

Prior to this appointment, Dr. Cho served as an academic hospitalist at Mount Sinai Hospital for 7 years, leading high-value care initiatives. Currently, he is a senior fellow with the Lown Institute in Brookline, Mass., and director of quality improvement implementation for the High Value Practice Academic Alliance.

Nick Fitterman, MD, SFHM, has been promoted to executive director at Huntington (N.Y.) Hospital. Dr. Fitterman has been a long-time physician and administrator at Huntington, serving previously as vice chair of medicine as well as head of hospitalists.

Dr. Fitterman has served as president of SHM’s Long Island chapter.

Previously, Dr. Fitterman was chief resident at the State University of New York at Stony Brook, and he remains an associate professor at Hofstra University, Hempstead, N.Y.

Allen Kachalia, MD, was named director of the Armstrong Institute for Patient Safety and Quality and senior vice president of patient safety and quality for Johns Hopkins Medicine in Baltimore. Dr. Kachalia is a general internist who has been an active academic hospitalist at Brigham and Women’s Hospital in Boston.

Dr. Kachalia will oversee patient safety and quality across all of Hopkins Medicine, with a focus on ending preventable harm, improving outcomes and patient experience, and reducing waste in the system’s delivery of care. He also will guide academic efforts for the Armstrong Institute, formed recently thanks to a $10 million gift.

In addition to his hospitalist work, Dr. Kachalia comes to Hopkins after serving as chief quality officer and vice president of quality and safety at Brigham Health.

Riane Dodge, PA, has been elevated to director of clinical education in physician assistant studies at Clarkson University, Potsdam, N.Y. The veteran physician assistant previously worked as a hospitalist in the Claxton Hepburn Medical Center in Ogdensburg, N.Y. There, she cared for patients in acute rehab, mental health, and on regular medical floors.

Dodge also has a background in urgent care and family medicine, and has experience as an emergency department technician.

BUSINESS MOVES

Surgical Affiliates of Sacramento, a surgical hospitalist provider with expertise in trauma, orthopedic, neurosurgery, and general surgery for hospital systems, has added partnerships with Christus Spohn Hospital South and Christus Spohn Hospital Shoreline in Corpus Christi, Texas.

Surgical Affiliates’ hospitalist system will provide round-the-clock emergency orthopedic surgery service to adult and pediatric patients in the two hospitals. With Surgical Affiliates’ help, Christus Spohn facilities will be able to cover its own patients, as well as those requiring transfer from regional hospitals.

Hospitalist surgeons will handle emergency surgeries and patient surgery consultations. Clinics will be provided at each facility to care for patients after they are discharged.

The Michigan chapter of the Society of Hospital Medicine has named Peter Watson, MD, SFHM, as state Hospitalist of the Year. Dr. Watson is the vice president of care management and outcomes for Health Alliance Plan (HAP) in Detroit. The Michigan chapter cited Dr. Watson’s leadership in hospital medicine and “generosity of spirit” as reasons for his selection.

Dr. Watson oversees nurses, social workers, and support staff while also serving as HAP Midwest Health Plan’s medical director. He’s a founding member of the Michigan SHM chapter, which he formerly represented as president.

Dr. Watson spent 11 years overseeing the Henry Ford Medical Group’s hospitalist program prior to joining HAP, and still works as an attending hospitalist for Henry Ford.

Hyung (Harry) Cho, MD, was named the inaugural chief value officer for NYC Health + Hospitals, which includes 11 hospitals in New York and is the largest public health system in the United States. He will oversee systemwide initiatives in value improvement and the reduction of unnecessary testing and treatment.

Prior to this appointment, Dr. Cho served as an academic hospitalist at Mount Sinai Hospital for 7 years, leading high-value care initiatives. Currently, he is a senior fellow with the Lown Institute in Brookline, Mass., and director of quality improvement implementation for the High Value Practice Academic Alliance.

Nick Fitterman, MD, SFHM, has been promoted to executive director at Huntington (N.Y.) Hospital. Dr. Fitterman has been a long-time physician and administrator at Huntington, serving previously as vice chair of medicine as well as head of hospitalists.

Dr. Fitterman has served as president of SHM’s Long Island chapter.

Previously, Dr. Fitterman was chief resident at the State University of New York at Stony Brook, and he remains an associate professor at Hofstra University, Hempstead, N.Y.

Allen Kachalia, MD, was named director of the Armstrong Institute for Patient Safety and Quality and senior vice president of patient safety and quality for Johns Hopkins Medicine in Baltimore. Dr. Kachalia is a general internist who has been an active academic hospitalist at Brigham and Women’s Hospital in Boston.

Dr. Kachalia will oversee patient safety and quality across all of Hopkins Medicine, with a focus on ending preventable harm, improving outcomes and patient experience, and reducing waste in the system’s delivery of care. He also will guide academic efforts for the Armstrong Institute, formed recently thanks to a $10 million gift.

In addition to his hospitalist work, Dr. Kachalia comes to Hopkins after serving as chief quality officer and vice president of quality and safety at Brigham Health.

Riane Dodge, PA, has been elevated to director of clinical education in physician assistant studies at Clarkson University, Potsdam, N.Y. The veteran physician assistant previously worked as a hospitalist in the Claxton Hepburn Medical Center in Ogdensburg, N.Y. There, she cared for patients in acute rehab, mental health, and on regular medical floors.

Dodge also has a background in urgent care and family medicine, and has experience as an emergency department technician.

BUSINESS MOVES

Surgical Affiliates of Sacramento, a surgical hospitalist provider with expertise in trauma, orthopedic, neurosurgery, and general surgery for hospital systems, has added partnerships with Christus Spohn Hospital South and Christus Spohn Hospital Shoreline in Corpus Christi, Texas.

Surgical Affiliates’ hospitalist system will provide round-the-clock emergency orthopedic surgery service to adult and pediatric patients in the two hospitals. With Surgical Affiliates’ help, Christus Spohn facilities will be able to cover its own patients, as well as those requiring transfer from regional hospitals.

Hospitalist surgeons will handle emergency surgeries and patient surgery consultations. Clinics will be provided at each facility to care for patients after they are discharged.