NASH and diabetologists perspective. Dra. Nathalie Carvalho Leite Serviços de Clínica Médica e Hepatologia do HUCFF- UFRJ

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1 NASH and diabetologists perspective Dra. Nathalie Carvalho Leite Serviços de Clínica Médica e Hepatologia do HUCFF- UFRJ

2 Diabetes: the slow-motion disaster Prevalence: 8.5% ou 422 million people worldwide had diabetes (over 18 years) 90% Type 2DM. High Burden: 7th leading cause of death in Major cause of blindness, kidney failure, heart attacks, stroke and lower limb amputation 2014

3 Is insulin resistance the link? NAFLD DM Insulin Resistance

4 Delivery and uptake of FFA Delivery and uptake of FFA Type 2 DM Leite et al. Non-alcoholic fatty liver disease and diabetes: from physiopathological interplay to diagnosisand treatment, World J Gastroenterol Jul 14;20(26):

5 NAFLD-associated hepatic insulin resistance and type 2 diabetes Hyperinsulinemia insulin signaling SREBP-1, ChREBP, LXR lipogenesis DAG + FOXO activation Fatty acids TAG Gluconeogenis glycogenolysis Birkenfeld A.L. and Shulman G.I. Hepatology, 2014.

6 How can type 2 diabetes contribute to Nash Pathogenesis? Cytokines adiponectin TNF,IL6, MCP-1 Inflamation, ROS, fibrogenesis Bile acids FXR/TGR5 Disordered Glucose and energy homeostasis Inflamation LPS TLR4 Advanced glycosylation end-products Inflamation, Inflamation, IR ROS, fibrogenesis insulin levels. iniatilly Lipogenesis fibrogenesis DNA methylation mrnas orchestrate gene expression. fibrogenesis

7 Liver and Diabetes

8 Nafld and risk of future diabetes development ü Over 70% of Nafld patients had IGT or diabetes on standard oral glucose tolerance test (OGTT). (Willner et al. Am J Gastroenterol. 2001; Ortiz-Lopez et al. Diabetes Care. 2012) ü Multi-Ethnic Study of Atherosclerosis üa prospective cohort study of 3153 nondiabetic individuals üincreased risk for incident diabetes in patients with NAFLD üdata adjusted for potential confounding variables üfollow up: 9 years (Shah et al. Atherosclerosis 2015)

9 Nafld and risk of future diabetes development: Systematic review/ Meta-analysis ü 40 studies, including three large community-based cohorts ü Patients with evidence of ultrasonographic and histological NAFLD ü Increased risk for incident diabetes ü follow up from 4 to 10 years. (Musso et al. Ann Med. 2011). ü 20 observational studies, including more than individuals ü Patients diagnosed by abnormal serum liver enzymes ultrasonography ü Increased risk for incident diabetes ü follow up: median period of 5 years. (Ballestri et al. J Gastroenterol Hepatol 2016).

10 Ultrasound prevalence of Nafld in type 2 DM patients 80% 57% 69% 70% 74% Kalra et al 2013 Leite et al 2009 Targer et al 2007 Willians et al % 40% 20% 0%

11 Studies with histopathological evaluation of diabetic patients with Nafld Nash prevalence: Gupte et al 2004 Kemmer et al 2001 Prashanth et al 2009 Leite et al % 80% 60% 40% 20% 87% 64% 63% 78% 0% moderate-to-severe fibrosis: 22 a 60%.

12 ü ü Liver enzymes are not a sensitive marker of NAFLD. In patients with type 2 diabetes and histologically proven NASH, abnormal liver enzymes maybeseen in less than 20% of patients. No diabetes-related parameter was associated with the more severe stages of NAFLD on liver biopsy in our single-centre study. Otherwise, Targer et al has shown an association with microvascular and macrovascular degenerative complications Leite et al. Liver Int Targer G et al. Clin J Am Soc Nephrol2010. Diabetologia 2010 and J Hepatol 2011.

13 Is type 2 DM an independent risk factor for NAFLD progression? üdm was associated with liver fibrosis progression in Nafld patients in some prospective studies with serial liver biopsies. ü DM adds increasing risk of cardiovascular complications, hepatocellular carcinoma and liver-related mortality in Nafld patients. Adams et al Gastroenterology 2005; Ekstedt et al. Hepatology 2006, Brunt et al. 2013) Rafiq et al. Clin Gastroenterol Hepatol. 2009, Targer et al. Diabetes Care. 2007, Stepanova et al. Dig Dis Sci )

14 Noninvasive assessment of liver fibrosis in type 2 DM patients N:392. Results: significant fibrosis (7-10.2kPa) was found in 18.8%, while 13.8% had cirrhosis (F4>/=10.3 kpa).((sporea I et alj Gastrointestin Liver Dis. 2016) N:291. Results: significant fibrosis (>7.9 kpa or >7.2 kpa with XL) was found in 27.5% (Leite NC et al. Liver Int. 2016) N:1918. Results:. Increased LSM ( 9.6 kpa by the M or 9.3 kpa by the XL probe) was 17,7%. (Kwok et al. Gut 2015) N: 100. The prevalence of NAFLD (defined as MRI-PDFF 5%) and advanced fibrosis (defined as MRE 3.6 kpa) was 65% and 7.1%.(Doycheva et al. Aliment Pharmacol Ther 2015)

15 Lessons from Diabetologists: 1. Patients with T2DM should engage in lifestyle management. 2. Treat early and with more stringent glycemic control. 3. Prevention of cardiovascular disease, leading cause of morbidity and mortality in T2DM. Screening for and treatment of modifiable risk factors. Benefit of new antihyperglycemic therapies. 4. Diabetes are heterogeneous diseases in which clinical presentation, disease progression and response to therapy may vary considerably. Hence, a patientcentered approach should be used to guide the choice of pharmacologic agents. 5. Combining will increase the response. Consider a 2 or 3 drug-combination of the six available treatment options.

16 Metformin: It is the first-line therapy for management of T2DM. No histological benefit. Uygun et al.aliment Pharmacol Ther Haukeland et al.scandinavian Journal of Gastroenterology 2009 Shields et al. Ther Adv Gastroenterology Hassan et al. Cancer Lai et al. Am J Gastroenterol 2012 Pioglitazona: Significant improvement in Nash (less with fibrosis) in patients with and without DM. Sanyal et al. N Engl J Med Belfort et al. N Engl J Med Sanyal et al. Clin Gastroenterol Hepatol Aithal et al. Gastroenterology Cusi et al. Gut Liraglutide: Nash without worsening of fibrosis. It apeared to be safe in patients with T2DM. Armstrong et al. Lancet Vitamina E: Benefit in Nas (Nash activity score) without worsening of fibrosis. It apeared to be safe in patients with T2DM. Sanyal et al. N Engl J Med Lavine JE et al. JAMA 2011.

17 Future of Nash therapy PPAR agonists α, β/δ and γ. FXR-bile acid axis/ FGF19 FGF21 GLP-1 receptor agonists SCD-1 inhibitor ACC inhibitor. Effects on glucose and lipid metabolism Inhibitor of apoptosis signal-regulating kinase 1 (ASK1) CCR2/CCR5 antagonist Simtuzumab Anti Gal 3

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20 Receptor de Insulina Liberação de glicose + + Sinalização da insulina Reesterificação de Ác graxo Acil CoA + glicerol fosfato DAG Lipogênese TAG síntese de glicogênio Gliconeogênese

21 Definição: Doença Hepática Gordurosa Não alcoólica (DHGNA) A DHGNA tem como denominador comum a esteatose hepática (> a 5%) Amplo espectro de alterações histológicas: Esteatose; Esteatose com inflamação; Esteatohepatite com diferentes estágios de fibrose e Cirrose É fundamental excluir: ingestão alcoólica diária superior a g nas mulheres e g nos homens outras causas secundárias (corticóides, amiodarona, methotrexate, tamoxifen, ac. valpróico)

22 Prevalência :Doença Hepática Gordurosa NãoAlcoólica Sayener et al. Clin Liv Dis 2016

23 Epidemiologia da Doença Hepática Gordurosa Não Alcoólica na Obesidade A prevalência de esteatose variou de 64% a 97%; a de esteato-hepatite com fibrose, de 25 a 50%; e a de cirrose de 1,7 a 10%. (Dixon et al.,2001. Machado et al Lazo e Clark Mummadi et al.2008) Em crianças obesas, a prevalência de esteatose varia entre 40 a 70% (Bellantani et al., 2010)

24 Epidemiologia da Doença Hepática Gordurosa Não Alcoólica na Síndrome Metabólica 85% dos pacientes com DHGNA têm pelo menos um dos 5 componentes da síndrome metabólica. (Gariani K. et al 2013) 90 cm nos homens e 80 cm nas mulheres (América Central e do Sul) (Alberti et al. Circulation, 2009). Há evidências de maior risco de esteato-hepatite e fibrose em pacientes com critérios e com maior número de componentes da síndrome metabólica. (Marchesini G. et al 2003; Rian M et al, 2005; Kang H. et al. 2006)

25 O papel da Resistência à insulina na fisiopatologia da DHGNA. Expansão adipócitos gdes macrófagos inflamação lipólise Leite et al. Non-alcoholic fatty liver disease and diabetes: from physiopathological interplay to diagnosisand treatment, World J Gastroenterol Jul 14;20(26):

26 Patogênese da Esteatohepatite : The multiparallel hypothesis Lipotoxicidade inflamação stress oxidativo Stress RE Autofagia Recep nucleares Apoptose NASH±Fibrosis Caligiuri A. Molecular Pathogenesis of NASH. Int J Mol Sci. 2016

27 How can type 2 DM can contribute to Nash Pathogenesis? DNA methylation adiponectin TNF, IIL LPS/TLR4 Bile acids/ FXR insulin levels NASH±Fibrosis Adapted from Caligiuri A. Molecular Pathogenesis of NASH. Int J Mol Sci. 2016

28 NAFLD fibrosis score Online calculator Angulo P, Hui JM, Marchesini G et al. The NAFLD fibrosis score A noninvasive system that identifies liver fibrosis in patients with NAFLD Hepatology 2007;45(4): doi: /hep Age (years) BMI (kg/m 2 ) IGF/diabetes AST ALT Platelets (x10 9 /l) Albumin (g/l) Valores < -1,455 associaram-se com a ausência de fibrose avançada. Valores > 0,676 associaram-se com a presença de fibrose avançada. Angulo et al. Hepatology 2007.

29 Técnicas radiológicas com elastografia hepática : Elastografia hepática transitória (Fibroscan) acoplado ao parâmetro de atenuação controlada (CAP) Elastografia acoplada à US: em tempo real (Supersonic Aixplorer), (ARFI) (Ochi H et al, 2012) Elastografia combinada a RNM. (Wong et al. 2010; Lédinghen et al. 2014) (Chen J et al, 2011, Loomba et al, 2014)

30 Diferentes pontos de corte to rule out e rule in estágios de fibrose no Fibroscan Fibroscan Fibroscan Wong et al. Hepatology Cassinoto et al. Hepatology 2016

31 Pacientes com DHGNA (com biópsia) Fibroscan (< 7,9) e Nafld escore (ausência de fibrose) Fibroscan e Nafld intermediários ou discordantes Fibroscan ( 9,6) e Nafld escore (presença de fibrose) Descarta fibrose acentuada Indicada biópsia Confirma fibrose acentuada Petta et al. Liver International 2014

32 Acurácia da Elastografia por Ressonância Magnética (MRE) para detecção da fibrose comparada ao ARFI e Fibroscan Diferenciar F0 de F1 a F4 em obesos, MRE superior ao ARFI (0,85 x 0,63; p<0,001) Loomba et al. Hepatology 2015 Diferenciar F0 de F1 a F4 em obesos, MRE superior ao Fibroscan (0,82 x 0,67; p=0,01) Park et al. Gastroenterology 2017

33 Sumário: 1. O aumento da prevalência das comorbidades associadas à obesidade será responsável por um número crescente de indivíduos com risco de desenvolver doença hepática crônica nas próximas décadas. 2. A cirrose por esteatohepatite é hoje a terceira causa de indicação de transplante hepático (TH) e vem se tornando o principal fator de risco relacionado ao desenvolvimento de carcinoma hepatocelular (CHC). 3. Atenção especial ao risco elevado de eventos cardiovasculares na DHGNA. 4. Além da resistência à insulina, múltiplas vias estão envolvidas na patogênese da DHGNA. 5. Novas técnicas radiológicas baseadas na elastografia vêm sendo estudadas com bons resultados no diagnóstico da fibrose em pacientes com DHGNA

34 Noninvasive assessment of liver fibrosis in type 2 diabetic patients 392 type 2 DM. Results: significant fibrosis (7-10.2kPa) was found in 18.8%, while 13.8% had cirrhosis (F4>/=10.3 kpa).(sporea I et alj Gastrointestin Liver Dis ) 1918 Type 2 DM. The proportion of patients with increased LSM ( 9.6 kpa by the M or 9.3 kpa by the XL probe) was 17,7% (Kwok et al. Gut 2015) 100 consecutively enrolled diabetics. The prevalence of NAFLD (defined as MRI- PDFF 5%) and advanced fibrosis (defined as MRE 3.6 kpa) was 65% and 7.1%, respectively. ( Doycheva et al. Aliment Pharmacol Ther 2015)