What to do about the high ALT picked up at the annual review. Dr Michael Yee Consultant in Diabetes and Endocrinology
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1 What to do about the high ALT picked up at the annual review Dr Michael Yee Consultant in Diabetes and Endocrinology
2 Mrs DC
3 HPC
4 PMH Type 2 Diabetes (decades) Regular retinal screening No foot complications/neuropathy No significant nephropathy Obesity Psoriasis Never had methotraxate Hypertension Carpal Tunnel Syndrome
5 DH Aspirin 75mg od Irbesartan 300mg od Doxazosin MR 8mg od Indapamide MR 1.5mg od Amlodipine 10mg od Glimepiride 1mg od (previously 4mg od) Exenatide 10ug bd Simvastatin 40mg od
6 O/E
7 Investigations Na 138 K 4.4 Ur 6.0 Cr 55 ALT 30 AST 25 ggt 24 Bil 12 ALP 65 Alb 40 INR 1.0 HbA1c 7.1 (54) Chol 5.33 HDL 1.06 TG 1.82 WCC 6.0 Hb 14.0 Plts 148
8 Investigations USS (08/07/09): 1.3cm calculus in neck of gallbladder Normal liver parenchyma Normal echotexture and contour CLD screen: Hep B sag Neg Hep C Ab Neg LAA Neg a1at 1.3 Ferritin 8 TSH 1.9
9 Angulo et al. Hepatology 2007
10 Fibroscan 25.1kPa
11 NAFLD Non-Alcoholic Fatty Liver Disease is an increasingly recognised condition that may progress to end-stage liver failure Ludwig in 1980 introduced the term Non-Alcoholic Steatohepatitis Prevalence is increasing worldwide with increasing obesity
12 Prevalence of abnormal LFT s Abnormal LFT s 8% population (NHANES III) An identifiable cause was found in 31% Remainder probably had NAFLD Clark et al Am J Gastroenterol 2003:
13 Prevalence Using traditional upper limits for ALT 3-5% of populations New lower ALT limits (men < 30; women <19) 12-14% Using ultrasound 20% (In obesity and diabetics 60-70%) Prati et al Ann Intern Med 2002: Ruhl et al Gastroenterology 2003:
14 Prevalence of NAFLD in NHANES over All chronic liver disease Hepatitis B Hepatitis C ALD NAFLD Younossi et al. Clin Gastro Hepatol. 2011(9)
15 NORMAL 12-20% STEATOSIS 5-15% NASH 0-12% CIRRHOSIS (Day, Liver Int., 2006)
16 NORMAL 12-20% STEATOSIS Steatosis Genes Oxidative Stress, Cytokine, Endotoxin-related Genes 5-15% NASH GENES Fibrosis Genes 0-12% CIRRHOSIS (Day, Liver Int., 2006)
17 Genotypes PNPLA3 variant I148M TM6FS2 variant E167k
18 NORMAL Diet, Obesity, DM ENVIRONMENT 12-20% STEATOSIS SIBO, Endotoxin, TNFa, ROS 5-15% NASH SIBO, Endotoxin, TNFa, ROS 0-12% CIRRHOSIS (Day, Liver Int., 2006)
19 Environment Fructose Processed foods
20 Obesity Trends* Among U.S. Adults BRFSS, 1985 (*BMI 30, or ~ 30 lbs. overweight for 5 4 person) No Data <10% 10% 14% Source: Behavioral Risk Factor Surveillance System, CDC.
21 Obesity Trends* Among U.S. Adults BRFSS, 1986 (*BMI 30, or ~ 30 lbs. overweight for 5 4 person) No Data <10% 10% 14% Source: Behavioral Risk Factor Surveillance System, CDC.
22 Obesity Trends* Among U.S. Adults BRFSS, 1987 (*BMI 30, or ~ 30 lbs. overweight for 5 4 person) No Data <10% 10% 14% Source: Behavioral Risk Factor Surveillance System, CDC.
23 Obesity Trends* Among U.S. Adults BRFSS, 1988 (*BMI 30, or ~ 30 lbs. overweight for 5 4 person) No Data <10% 10% 14% Source: Behavioral Risk Factor Surveillance System, CDC.
24 Obesity Trends* Among U.S. Adults BRFSS, 1989 (*BMI 30, or ~ 30 lbs. overweight for 5 4 person) No Data <10% 10% 14% Source: Behavioral Risk Factor Surveillance System, CDC.
25 Obesity Trends* Among U.S. Adults BRFSS, 1990 (*BMI 30, or ~ 30 lbs. overweight for 5 4 person) No Data <10% 10% 14% Source: Behavioral Risk Factor Surveillance System, CDC.
26 Obesity Trends* Among U.S. Adults BRFSS, 1991 (*BMI 30, or ~ 30 lbs. overweight for 5 4 person) No Data <10% 10% 14% 15% 19% Source: Behavioral Risk Factor Surveillance System, CDC.
27 Obesity Trends* Among U.S. Adults BRFSS, 1992 (*BMI 30, or ~ 30 lbs. overweight for 5 4 person) No Data <10% 10% 14% 15% 19% Source: Behavioral Risk Factor Surveillance System, CDC.
28 Obesity Trends* Among U.S. Adults BRFSS, 1993 (*BMI 30, or ~ 30 lbs. overweight for 5 4 person) No Data <10% 10% 14% 15% 19% Source: Behavioral Risk Factor Surveillance System, CDC.
29 Obesity Trends* Among U.S. Adults BRFSS, 1994 (*BMI 30, or ~ 30 lbs. overweight for 5 4 person) No Data <10% 10% 14% 15% 19% Source: Behavioral Risk Factor Surveillance System, CDC.
30 Obesity Trends* Among U.S. Adults BRFSS, 1995 (*BMI 30, or ~ 30 lbs. overweight for 5 4 person) No Data <10% 10% 14% 15% 19% Source: Behavioral Risk Factor Surveillance System, CDC.
31 Obesity Trends* Among U.S. Adults BRFSS, 1996 (*BMI 30, or ~ 30 lbs. overweight for 5 4 person) No Data <10% 10% 14% 15% 19% Source: Behavioral Risk Factor Surveillance System, CDC.
32 Obesity Trends* Among U.S. Adults BRFSS, 1997 (*BMI 30, or ~ 30 lbs. overweight for 5 4 person) No Data <10% 10% 14% 15% 19% 20% Source: Behavioral Risk Factor Surveillance System, CDC.
33 Obesity Trends* Among U.S. Adults BRFSS, 1998 (*BMI 30, or ~ 30 lbs. overweight for 5 4 person) No Data <10% 10% 14% 15% 19% 20% Source: Behavioral Risk Factor Surveillance System, CDC.
34 Obesity Trends* Among U.S. Adults BRFSS, 1999 (*BMI 30, or ~ 30 lbs. overweight for 5 4 person) No Data <10% 10% 14% 15% 19% 20% Source: Behavioral Risk Factor Surveillance System, CDC.
35 Obesity Trends* Among U.S. Adults BRFSS, 2000 (*BMI 30, or ~ 30 lbs. overweight for 5 4 person) No Data <10% 10% 14% 15% 19% 20% Source: Behavioral Risk Factor Surveillance System, CDC.
36 Obesity Trends* Among U.S. Adults BRFSS, 2001 (*BMI 30, or ~ 30 lbs. overweight for 5 4 person) No Data <10% 10% 14% 15% 19% 20% 24% 25% Source: Behavioral Risk Factor Surveillance System, CDC.
37 Obesity Trends* Among U.S. Adults BRFSS, 2002 (*BMI 30, or ~ 30 lbs. overweight for 5 4 person) No Data <10% 10% 14% 15% 19% 20% 24% 25% Source: Behavioral Risk Factor Surveillance System, CDC.
38 Obesity Trends* Among U.S. Adults BRFSS, 2003 (*BMI 30, or ~ 30 lbs. overweight for 5 4 person) No Data <10% 10% 14% 15% 19% 20% 24% 25% Source: Behavioral Risk Factor Surveillance System, CDC.
39 Obesity Trends* Among U.S. Adults BRFSS, 2004 (*BMI 30, or ~ 30 lbs. overweight for 5 4 person) No Data <10% 10% 14% 15% 19% 20% 24% 25% Source: Behavioral Risk Factor Surveillance System, CDC.
40 Obesity Trends* Among U.S. Adults BRFSS, 2005 (*BMI 30, or ~ 30 lbs. overweight for 5 4 person) No Data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30% Source: Behavioral Risk Factor Surveillance System, CDC.
41 Obesity Trends* Among U.S. Adults BRFSS, 2006 (*BMI 30, or ~ 30 lbs. overweight for 5 4 person) No Data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30% Source: Behavioral Risk Factor Surveillance System, CDC.
42 Obesity Trends* Among U.S. Adults BRFSS, 2007 (*BMI 30, or ~ 30 lbs. overweight for 5 4 person) No Data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30% Source: Behavioral Risk Factor Surveillance System, CDC.
43 Obesity Trends* Among U.S. Adults BRFSS, 2008 (*BMI 30, or ~ 30 lbs. overweight for 5 4 person) No Data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30% Source: Behavioral Risk Factor Surveillance System, CDC.
44 Obesity Trends* Among U.S. Adults BRFSS, 2009 (*BMI 30, or ~ 30 lbs. overweight for 5 4 person) No Data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30% Source: Behavioral Risk Factor Surveillance System, CDC.
45 Obesity Trends* Among U.S. Adults BRFSS, 2010 (*BMI 30, or ~ 30 lbs. overweight for 5 4 person) No Data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30% Source: Behavioral Risk Factor Surveillance System, CDC.
46 Pathogenesis
47 Clinical features Symptoms Asymptomatic 65% Fatique Right upper quadrant pain Signs Hepatomegaly Acanthosis nigricans Signs of chronic liver disease
48 Biochemistry Usually elevated ALT AST/ALT < 1 GGT variable Platelets Clotting abnormalities
49 Diagnosis
50 Imaging Ultrasound Increased echogenicity to kidney CT Low density to spleen MRI In and Out Phase ECHO MRS Quantative assessment of steatosis No imaging modality can differentiate the different stages of NAFLD Saadeh et al Gastroenterology 2002:
51 Liver Biopsy Confirm diagnosis Staging and Prognosis Management
52 Liver Biopsy Normal and Steatosis
53 Liver Biopsy - Steatohepatitis
54 Liver Biopsy - Fibrosis
55 ALT may not be reliable marker of activity Mofrad et al Hepatology 2003:
56 Percentage (%) Prognosis based on histology Cirrhosis Liver rel Death 5 0 Type 1 Type 2 Type 3 Type 4 Liver Biopsy Matteoni et al Gastroenterology 1999:
57 Survival rates based on liver histology Matteoni et al Gastroenterology 1999:
58 Hepatocellular carcinoma Wong et al, Hepatology 2014 (59)
59 Simple Steatosis (12-40%) NASH (15-25%) Cirrhosis (7%) Hepatic cellular carcinoma
60 Non-Invasive Methods of Staging Age > 45 BMI > 30 AST:ALT ratio > 1 T2DM Obstructive sleep apnoea Angulo et al Hepatology 1999:
61 Non-Invasive Methods of Staging NAFLD Fibrosis score Age, AST/ALT ratio, BMI, platelets, albumin, glycaemia ELF Score Hyaluronic acid, tissue inhibitor of matrix metalloproteinase 1, amino terminal peptide of pro-collagen III Angulo et al Hepatology 2007: Guha et al Hepatology 2008:
62 Non-Invasive Methods of Staging Imaging techniques have limited use in early disease Transient elastography (Fibroscan) BMI < 28 Controlled attenuation parameter (CAP) Foucher et al Eur J Gastroenterol Hepatol 2006:
63 Weight management Lifestyle modification Improvement in LFT s and a few studies shows histological improvement with gradual moderate (10%) wt loss (< 1.6kg/wk) Orlistat Improvements in LFT s and U/S
64 Weight management Bariatric surgery Significant weight loss 60% Early techniques of jejuno ileal bypass were associated with acute liver failure and massive steatosis Newer surgical techniques are associated with histological improvements in liver biopsy
65 Insulin sensitiser Metformin some conflicting evidence regarding benefits on steatosis Thiazolidendione all studies have demonstrated improvements in steatosis in addition to histology. Recent rosiglitazone meta-analysis Stopping treatment leads to recurrence Bugianesi et al Am J Gastro 2005: Belfort et al NEJM 2006:
66 Lipid Lowering Therapy Fibrates Good animal data but limited human data. Improvements have been shown with gemfibrozil, but no significant changes with clofibrate Statins No data on statins Increased CVD risk No evidence of increased hepatoxicity
67 Anti-hypertensive agents Renin-Angiotensin System Lorsartan has been demonstrated to improve liver fibrosis
68 Liver directed treatment Ursodeoxycholic acid promising data on LFT s and histology Anti-oxidants no evidence of benefit from Vitamin C and E Rimonabant in addition to effects from weight loss, inhibition of CB-1 receptor antifibrotic actions TNF α inhibitors (pentoxyfylline) promising results
69 Liver transplant Decompensated cirrhosis 50% have recurrence NASH in 4 years
70 Multidisciplinary clinics 5 year follow up data Percentage Improvement in ALT Normalisation in ALT Reduction in weight (5%) Reduction in weight (10%) Percentage Cobbold et al Frontline Gastro 2013 (4) 263-9
71 Clinical Guidelines
72 Summary NAFLD is increasingly prevalence It can lead to cirrhosis and HCC Treatments are currently limited but likely to increase
73 Specialist Metabolic and Hepatology Clinic Referrals to Dr Michael Yee (Metabolic Medicine Unit) or Dr Pinelopi Manousou (Hepatology Unit) Non-alcoholic and viral hepatitis negative
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