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and all-cause mortality in patients with adrenal incidentalomas. They stratifi ed individuals according to the degree of subclinical cortisol hypersecretion and the presence or not of a worsening phenotype. However, they did not stratify risk in patients according to baseline characteristics or include healthy controls matched for age, sex, and BMI. Their fi ndings support the importance of long-term hormonal follow-up for clinical management of all patients with adrenal incidentalomas. Furthermore, clinical monitoring of cardiometabolic risks seems to be important in these patients, particularly in those with subclinical Cushing’s syndrome and intermediate phenotype adrenal incidentalomas, for whom medical or surgical intervention could be needed.

Long-term prospective studies are needed to assess the frequency of new cardiovascular events and mortality in patients with adrenal incidentalomas, stratifi ed according to the degree of subclinical hormone hypersecretion at baseline, compared with controls matched for age, sex, and BMI.

*Rosario Pivonello, Maria Cristina De Martino, Annamaria ColaoDipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II, Naples, Italyrosario.pivonello@unina.it

Targeting non-alcoholic fatty liver disease through 11-βHSD1 inhibition

Published OnlineFebruary 17, 2014

http://dx.doi.org/10.1016/S2213-8587(14)70028-2

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With the epidemic surge of obesity and diabetes worldwide, excessive liver fat is becoming increasingly common. Although for most patients fatty liver is a benign condition, a sizeable proportion develop non-alcoholic steatohepatitis—a progressive disorder associated with liver-related mortality, cirrhosis, and liver cancer.1 In patients who do not successfully implement diet and lifestyle changes, pharmacotherapy that aims t o prevent liver disease progression is necessary, yet few pharmacological agents have been tested within well-designed development programmes.

Most patients with non-alcoholic steatohepatitis are insulin resistant and have increased adipose tissue mass. This expansion triggers uncontrolled lipolysis from visceral adipose tissue, which results in increased delivery of fatty acids to the liver, de-novo hepatic lipogenesis

stimulated by hyperinsulinaemia, and deregulated hepatic glucose production.1 In itself, esterifi ed fat does not damage the liver; however, lipotoxic intermediates trigger the hepatic infl ammation, cell injury, and fi brosis that characterise non-alcoholic steatohepatitis. Cellular toxicity of free cholesterol, endotoxinaemia, hypoxia, and altered innate immunity also contribute to liver damage.

The agents used up to now within well designed clinical trials tested two distinct approaches: a broad, non-specifi c antioxidant (vitamin E)2 and insulin sensitisers—such as glitazones2—with predominantly extrahepatic actions. Glitazones restore adipose tissue insulin sensitivity, expandability, adiponectin secretion and, only as a consequence of these eff ects, reduce liver fat and associated lipotoxic species. Both agents were moderately eff ective, although large, confi rmatory trials are lacking.

We declare that we have no confl icts of interest.

1 Terzolo M, Stigliano A, Chiodini I, et al. AME position statement on adrenal incidentaloma. Eur J Endocrinol 2011; 164: 851–70.

2 Young WF Jr. The incidentally discovered adrenal mass. N Engl J Med 2007; 356: 601–10.

3 Baudin E, Leboulleux S, Al Ghuzlan A, et al. Therapeutic management of advanced adrenocortical carcinoma: what do we know in 2011? Horm Cancer 2011; 2: 363–71.

4 Pivonello R, De Martino MC, De Leo M, Lombardi G, Colao A. Cushing’s syndrome. Endocrinol Metab Clin North Am 2008; 37: 135–49.

5 Graversen D, Vestergaard P, Stochholm K, Gravholt CH, Jorgensen JO. Mortality in Cushing’s syndrome: a systematic review and meta-analysis. Eur J Intern Med 2012; 23: 278–82.

6 Peppa M, Koliaki C, Raptis SA. Adrenal incidentalomas and cardiometabolic morbidity: an emerging association with serious clinical implications. J Intern Med 2010; 268: 555–66.

7 Tauchmanova L, Rossi R, Biondi B, et al. Patients with subclinical Cushing’s syndrome due to adrenal adenoma have increased cardiovascular risk. J Clin Endocrinol Metab 2002; 87: 4872–78.

8 Di Dalmazi G, Vicennati V, Rinaldi E, et al. Progressively increased patterns of subclinical cortisol hypersecretion in adrenal incidentalomas diff erently predict major metabolic and cardiovascular outcomes: a large cross-sectional study. Eur J Endocrinol 2012; 166: 669–77.

9 Barzon L, Sonino N, Fallo F, Palu G, Boscaro M. Prevalence and natural history of adrenal incidentalomas. Eur J Endocrinol 2003; 149: 273–85.

10 Di Dalmazi G, Vicennati V, Garelli S, et al. Cardiovascular events and mortality in patients with non-secreting adrenal incidentalomas and subclinical Cushing’s syndrome: a 15-year retrospective study. Lancet Diabetes Endocrinol 2014; published online Jan 29. http://dx.doi.org/10.1016/S2213-8587(13)70211-0.

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In The Lancet Diabetes & Endocrinology, Norbert Stefan and colleagues3 report results of a trial testing an innovative approach for treating patients with fatty liver: inhibiting 11-β hydroxysteroid dehydrogenase type 1 (11-βHSD1, also known as HSD11B1) activity with a drug targeting both the liver and adipose tissue. 11-βHSD1 is an enzyme that promotes tissue-specifi c conversion of inactive cortisone into active cortisol, independent of circulating cortisol concentrations.4 Because 11-βHSD1 is highly expressed in both adipose tissue and liver, and the drug has a nanomolar inhibitory concentration, the assumption is that potent eff ects will be triggered in the two key tissues involved in the pathogenesis of non-alcoholic steatohepatitis without upsetting compensatory mechanisms of the hypothalmic-pituitary-adrenal (HPA) axis. But what data, if any, point to a role of 11-βHSD1 and cortisol metabolism in the pathophysiology of non-alcoholic steatohepatitis?

Much evidence shows that glucocorticosteroids drive adipogenesis, lipid storage, and lipolysis in adipose tissue, whereas they increase insulin-stimulated lipogenesis and enhance hepatic glucose output in the liver.4 Consequently, patients with Cushing’s syndrome, for example, exhibit insulin resistance, steatosis, dyslipidaemia, atherosclerosis, and hyperglycaemia or type 2 diabetes. Genetic deletion or pharmacological inhibition of 11-βHSD1 provides metabolic protection from diet-induced obesity, steatosis, glucose intolerance, and insulin resistance—inducing a safer adipose tissue distribution.5,6 Overexpression of 11-βHSD1 has opposite eff ects, further suggesting that this enzyme plays a key part in regulation of global metabolic homoeostasis.

Stefan and colleagues used RO5093151, a selective inhibitor of human 11-βHSD1, to study the eff ect of 11-βHSD1 inhibition in patients with non-alcoholic fatty liver disease. Overweight, insulin-resistant, non-diabetic patients with excess liver fat (diagnosed by magnetic resonance spectroscopy) were randomised to receive either the active compound (400 mg daily, n=35) or placebo (n=39) for a 12 week period. The primary endpoint—change in mean liver fat content—was met (RO5093151 group 16·75% [SD 8·67] at baseline, 14·28% [8·89] at 12 weeks vs placebo group 18·53% [10·00] at baseline, 18·46% [10·78] at 12 weeks; absolute diff erence in changes −2·57% [95% CI −4·64 to −0·49], p=0·02). Total body fat was also signifi cantly

reduced in the active group compared with the control group (absolute diff erence in changes −2139 mL [95% CI −3003 to −1276], p<0·0001). These eff ects were achieved after only a short period of treatment, but longer treatment might result in further improvement. Importantly, the drug was safe and well tolerated: the authors showed the absence of any signs of adrenal insuffi ciency, and although they showed an increase in androgens in the active group, these stayed within the normal range in most patients (four patients had above normal increases in testosterone). These results are encouraging, were this drug to be developed as a treatment for obesity. As a treatment for non-alcoholic steatohepatitis, the story looks diff erent.

Three important caveats need to be discussed. First, contrary to expectations from preclinical data and clinical trials of same-class compounds in a population with diabetes,7 RO5093151 did not improve systemic or hepatic insulin resistance, nor did it reduce hepatic glucose production. This fi nding is problematic because even if body fat and visceral adipose tissue are reduced, an improvement of steatohepatitis might not be achieved without an insulin sensitising or a direct hepatoprotective eff ect. Also, patients in the RO5093151 group lost weight (mean 1·9 kg [SD 2·11]), whereas those in the placebo group gained weight (0·34 kg [2·04]). It is unclear to what extent weight-loss alone might explain the benefi cial eff ects on ectopic fat, and also whether changes in diet or physical activity—rather than drug intake—could explain the diff erence between groups. Second, from a hepatological perspective, the results of this trial are merely a proof-of-principle of the mode of action of 11-βHSD1 rather than a straightforward, preliminary demonstration of effi cacy of this class of compounds in non-alcoholic steatohepatitis. Overall, the magnitude of the anti-steatogenic eff ect was rather low and only 20% (seven of 35) of patients in the active group had normalisation of liver fat. The small reduction in alanine aminotransferase (ALT) identifi ed in the active group (baseline median 40·88 U/L [range 11·46−82·50] vs 12 weeks 32·08 U/L [16·04−98·54]) is not predictive of improvement in infl ammation or liver cell injury, especially in this setting, because patients were not selected on the basis of histological confi rmation of steatohepatitis. Patients with isolated steatosis can have increased ALT that declines after reduction in fat content, and patients with non-alcoholic steatohepatitis can have

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ALT reduction when liver fat content is reduced, even without improvement in hepatic infl ammation.8 Finally, although patients with non-alcoholic steatohepatitis can have increased urinary free cortisol, data for increased 11-βHSD1 hepatic expression is confl icting,9,10

thus questioning the relevance of this protein as a therapeutic target.

Stefan and colleagues’ carefully conducted trial shows benefi cial eff ects of 11-βHSD1 inhibition on body and liver fat in overweight, insulin-resistant patients with liver steatosis. Unfortunately, data suggestive of effi cacy in patients with non-alcoholic steatohepatitis cannot be inferred from this report and need to be obtained from future, liver-oriented trials with relevant histological endpoints.

Vlad RatziuUniversité Pierre et Marie Curie, Hospital Pitié Salpêtrière, Paris 75013, France; and INSERM U938, Paris, Francevlad.ratziu@upmc.fr

I have acted as a consultant for Abbott, Enterome, GalMed, Genfi t, Gilead, Intercept, and Roche-Gene ntech.

1 Cusi K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Gastroenterology 2012; 142: 711– 25.e6.

Defi nition and management of radioactive iodine-refractory diff erentiated thyroid cancer

Published OnlineJanuary 30, 2014

http://dx.doi.org/10.1016/S2213-8587(13)70215-8

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For some patients with metastatic disease from diff erentiated thyroid cancer, remarkable results can be achieved with eradication of tumour cells through radioactive iodine (131I) uptake. However, even after an adequate stimulation by thyroid-stimulating hormone and in the absence of excess iodine, only two thirds of patients with metastases show substantial radioactive iodine uptake, and only 42% of them achieve a cure.1 Patients who are not responsive to radioactive iodine treatment have a life expectancy of 3–5 years and represent a group for whom there is a clear unmet medical need.1 Development in this area is hampered by an absence of consensus regarding the defi nition of radioactive iodine-refractory diff erentiated thyroid cancer. Therefore, in September, 2012, an expert panel met to propose a working defi nition and treatment algorithm.

Most patients with radioactive iodine-refractory diff erentiated thyroid cancer fall into four categories.

1) Patients with metastatic disease that does not take up radioactive iodine at the time of initial treatment. For these patients there is no evidence that treatment with radioactive iodine provides benefi t. This group includes patients with structurally evident disease with no radioactive iodine uptake on a diagnostic whole-body scan; in such patients uptake, when present on post-therapy scans, will not be suffi cient to induce benefi t.2 2) Patients whose tumours lose the ability to take up radioactive iodine after previous evidence of uptake. This often occurs in patients with multiple large metastases and is due to the eradication of diff erentiated cells that take up radioactive iodine but not of poorly diff erentiated cells that do not take up radioactive iodine. 3) Patients with radioactive iodine uptake retained in some lesions but not in others. This is frequently seen in patients with multiple large metastases, as shown by 124I studies on PET scan,3 and

2 Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010; 362: 1675–85.

3 Stefan N, Ramsauer M, Jordan P, et al. Inhibition of 11β-HSD1 with RO5093151 for non-alcoholic fatty liver disease: a multicentre, randomised, double blind, placebo-controlled trial. Lancet Diabetes Endocrinol 2014; published online Feb 17. http://dx.doi.org/10.1016/S2213-8587(13)70170-0.

4 Gathercole LL, Lavery GG, Morgan SA, et al. 11beta-hydroxysteroid dehydrogenase 1: translational and therapeutic aspects. Endocr Rev 2013; 34: 5 25–55.

5 Morton NM, Holmes MC, Fievet C, et al. Improved lipid and lipoprotein profi le, hepatic insulin sensitivity, and glucose tolerance in 11beta-hydroxysteroid dehydrogenase type 1 null mice. J Biol Chem 2001; 276: 4129 3–300.

6 Li G, Hernandez-Ono A, Crooke RM, Graham MJ, Ginsberg HN. Eff ects of antisense-mediated inhibition of 11beta-hydroxysteroid dehydrogenase type 1 on hepatic lipid metabolism. J Lipid Res 2011; 52: 9 71–81.

7 Rosenstock J, Banarer S, Fonseca VA, et al. The 11-beta-hydroxysteroid dehydrogenase type 1 inhibitor INCB13739 improves hyperglycemia in patients with type 2 diabetes inadequately controlled by metformin monotherapy. Diabetes Care 2010; 33: 15 16–22.

8 Ratziu V, Giral P, Jacqueminet S, et al. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) trial. Gastroenterology 2008; 135: 1 00–10.

9 Konopelska S, Kienitz T, Hughes B, et al. Hepatic 11beta-HSD1 mRNA expression in fatty liver and nonalcoholic steatohepatitis. Clin Endocrinol (Oxf) 2009; 70: 5 54–60.

10 Westerbacka J, Yki-Jarvinen H, Vehkavaara S, et al. Body fat distribution and cortisol metabolism in healthy men: enhanced 5beta-reductase and lower cortisol/cortisone metabolite ratios in men with fatty liver. J Clin Endocrinol Metab 2003; 88: 4924–31.