Non Alcoholic Fatty Liver Disease (NAFLD) :A New Epidemic?

Dr Pascale Anglade, MDConsultant Gastroenterologist and Hepatologist

Diagnostic and Therapeutic Endoscopy Center (DTEC)Lagos, Nigeria

The Case of Mr A.

Mr A. 36 yo man who was told that his liver “looked fatty” on ultrasound a year ago. He is now concerned about the implications for his health but stresses the fact that he feels completely fine.

He underwent a medical work up about a year prior because he had suffered from bloating and gas. Symptoms have resolved since

PMHx: None PSHx: None All: NKDA Meds: None FHx: NC

SHx: EtOH 2-4 beers a week; No drugs, +Tob 6-10 cigs a day

The Case of Mr A.

PE: BP 130/84 HR 86 Wt 90kg Ht: 1m69 BMI: 31.5 Obese pleasant man NAD No icterus or jaundice Abd: Soft NABS, NT, no HSM, no ascites

AST:30 ALT : 42 Alk phos: 62 Tbili: 1.4 Plts: 252k INR: 1.0

Total cholesterol: 220 HDL cholesterol: 40

TG: 190 Gluc: 89

Mr. A’s ultrasound

Normal liver Fatty liver

Summary: 36 yo man with ultrasound showing fatty liver. Asymptomatic. Slightly elevated ALT. High total cholesterol, low HDL and high TG.

Diagnosis?

Summary: Mr. A.

Case of Mrs. M.

Patient sent by primary care physician for suspicion of ascites.

52 yo woman with long standing poorly controlled DM 2, HTN, hypercholesterolemia who noticed abdominal swelling over past 2 weeks. SOB, legs swelling

PMHx: DM2 (HgA1c: 9.5%), HTN, Hypercholesterolemia

PSHx: 2 c-sections All: NKDA

SHx: No ETOH, no drugs, no tob

Meds: merformin, lisinopril, asa, lipitor

Case of Mrs. M.

PE: BP 109/65 HR 60 Wt: 72kg Ht: 1m58 BMI: 30 Obese woman, moderately dyspneic No jaundice or icterus Cor: Reg S1S2 Lungs: Good air mvt bilat, clear Abd: protuberant, tense, fluid wave, +BS. Prominent veins. Ext: 2+ pitting edema bilat; no clubbing Skin: spider angiomas

Labs: INR 1.8 AST 48 ALT 42 Alk phos 160 Plts 62,000 Hgb 10.5 AFP: 2.8

Mrs. M’s CT scan

Normal liver

Fatty liver

Case of Mrs. M.

Parecentesis: consistent with portal hypertension with a SAAG (serum albumin ascites gradient) of 1.3

Further labs: Neg viral serologies; low titer ANA

Diagnosis?

Fatty Liver Disease. The Basics.

Fatty liver = Steatosis= accumulation of fat in the liver

Many different etiologies Alcohol Autoimmune hepatitis Inherited liver diseases Medications Acute fatty liver of pregnancy

NAFLD: Steatosis In the absence of other causes

NAFLD. A worldwide epidemic?

Prevalence of NAFLD General adult population worldwide: 10% to 24% Obese population: 57.5% to 74% NAFLD is the cause of 90% of all cases of elevated liver

function test (LFT) results in patients after exclusion of other causes

NAFLD: has become one of the most common reason for referral to hepatologist in western world

NAFLD is the hepatic manifestation of the metabolic syndrome

P. Angulo, “Medical progress: nonalcoholic fatty liver disease,” The New England Journal of Medicine, vol. 346, no. 16, pp. 1221–1231, 200Dallas heart NHANES III

Metabolic Syndrome

Group of risk factors that tend to occur together and increase the risk for CAD, strokes and DM 2. HTN Elevated fasting blood glucose Central pattern of obesity Low HDL cholesterol Triglycerides = or >150 mg/dL

Worldwide increase in the prevalence of obesity Estimated that close to 50 million individuals have

the metabolic syndrome in the US Developing countries…

Metabolic Syndrome in Nigeria

Assess the prevalence of metabolic syndrome in a Nigerian rural community.

132 participants from three rural towns in southwestern Nigeria

Assessed: Anthropometric variables Fasting blood glucose Triglyceride Total and HDL cholesterol Blood pressure

Adegoke OA et al., Metab Syndr Relat Disord. 2010 Feb;8(1):59-62.Prevalence of metabolic syndrome in a rural community in Nigeria.

Metabolic Syndrome in Nigeria

Ages: men 58.6; women 46.1

Overall prevalence of metabolic syndrome: 12.1%. No significant difference between men and women Prevalence of abdominal obesity: higher in women(16.9%

and 7.3%) Men: higher mean serum level of triglyceride (P < 0.05).

High prevalence of metabolic syndrome in this study.

Small study but possibly important implications for the health-care sector.

Adegoke OA et al., Metab Syndr Relat Disord. 2010 Feb;8(1):59-62.Prevalence of metabolic syndrome in a rural community in Nigeria.

Metabolic Syndrome in Nigeria

2000 healthy adults ages 18 to 64 in rural Southwest Nigeria; 56% women, 44% men

Variables measured: BP BMI Waist circumference Blood sugar Serum lipids Tobacco use Dietary habits

Oladapo OO et al, Cardiovasc J Afr. 2010 Jan-Feb;21(1):26-31.A prevalence of cardiometabolic risk factors among a rural Yoruba south-western Nigerian population: a population-based survey

Metabolic Syndrome in Nigeria

Results: 20.8% hypertension 2.5% diabetes 1.9% hypertriglyceridemia 3.9% general obesity

14.7% abdominal obesity 43.1% low HDL

High prevalence of cardiometabolic risk factors in this rural population

Oladapo OO et al, Cardiovasc J Afr. 2010 Jan-Feb;21(1):26-31.A prevalence of cardiometabolic risk factors among a rural Yoruba south-western Nigerian population: a population-based survey

NAFLD in Nigeria

Study conducted in endo clinic @ LASUTH

Determine prevalence of NAFLD in DM pts vs non diabetic pts

Ascertain other contributing factors

Compare the occurrence of the metabolic syndrome in subjects with and without NAFLD

Onyekwere C. Et al, Ann Hepatol. 2011 Apr-Jun;10(2):119-24.Non-alcoholic fatty liver disease and the metabolic syndrome in an urban hospital serving an African community.

NAFLD in Nigeria

150 pts 106 were diabetics vs 44 non-diabetics The overall prevalence of NAFLD was 8.7%.

DM cases 9.5% vs control subjects 4.5% not statistically (p = 0.2).

The mean body mass index (BMI) of diabetic and non-diabetic patients was similar (31 vs. 30 kg/m(2)).

The prevalence of the metabolic syndrome was higher in the subjects with NAFLD than in those without fatty liver disease but this difference was not statistically significant (p = 0.8).

Onyekwere C. Et al, Ann Hepatol. 2011 Apr-Jun;10(2):119-24.Non-alcoholic fatty liver disease and the metabolic syndrome in an urban hospital serving an African community.

Spectrum of Disease

Non alcoholic fatty liver: Fat accumulation in vacuoles

Non alcoholic steatohepatitis: + inflammation, ballooning degeneration

of hepatocytes, pericellular fibrosis

Cirrhosis: Regenerative nodules and fibrosis

20-30% over 5-10 yrs

HCC

3% over 10 yrs

Pathophysiology of NAFLD

Insulin resistanceIncreased serum free fatty acids

FFA transported into hepatocytes

Increased hepatic

lipogenesis

Exceeds liver oxidation and

export mechanisms

Hepatic steatosis

NASH?

Apoptosis

Making the Diagnosis of NAFLD

Eliminate other causes of liver disease Medications (amiodarone, steroids, tamoxifen) Viral EtOH Autoimmune liver disease

ANA, ASMA, LKM can be positive but at low titers Liver biopsy may be needed

Iron overload: Elevated ferritin levels 50% of pts with NASH No increase in concentration of hepatic iron

Wilson’s disease Alpha 1 antitrypsin deficiency

No single biochemical marker can confirm a dx of NAFLD

Making the Diagnosis of NASH

Patient’s symptoms

Labs results

Imaging studies

Panels of tests non invasive histologic assessment has been able to

predict advanced fibrosis and cirrhosis but less able to determine NASH.

None will make the crucialdistinction between steatosis and steatohepatitis

Diagnostic Panels of markers

Goal to facilitate the non-invasive assessment of NAFLD and differentiation between different stages of disease.

Based on a number of laboratory measurements in combination with clinical parameters (age, sex and BMI). The BARD score is a scoring system designed to identify

NAFLD patients with a low risk of advanced disease. It combines three variables of BMI, AST/ALT ratio (AAR) and the presence of diabetes into a weighted sum. AST/plt ratio index (APRI) FIB-4 NAFLD fibrosis score

To Biopsy or not to Biopsy?

Only test to distinguish NAFL from NASH

Invasive, risks

Sampling variability since fibrosis is not uniform

Inter observer discordance since there is subjectivity involved

Score (steatosis + ballooning+ fibrosis) vs pattern recognition?

“Imperfect” gold standard

Treatment Options

TARGET TREATMENT

OBESITY WEIGHT LOSS

*DIET +/- EXERCISE

*PHARM AGENTS

- ORLISTAT

*INVASIVE OPTIONS

INSULIN RESISTANCE INSULIN SENTIZING AGENTS

*METFORMIN

*THIAZOLIDINEDIONES (TZD)

DYSLIPIDEMIA STATINS

OXIDATIVE STRESS ANTIOXIDANTS

*VITAMIN E

* SILYMARIN

Is there any evidence of use of orlistat?

50 overweight Biopsy-proven NASH

Randomized to: 1400 kcal/day diet plus 800 IU vitamin E daily with orlistat

x 36 weeks 1400 kcal/day diet plus 800 IU vitamin E x 36 weeks.

Weight loss of 9% or more of body weight, NOT treatment with orlistat, resulted in improvement of steatosis, ballooning, inflammation on repeat biopsy

Harrison, S.A., Fecht, W., Brunt, E.M. and Neuschwander-Tetri, B.A. (2009) Orlistat for overweight subjects with nonalcoholic steatohepatitis: a randomized, prospective trial. Hepatology 49: 80-86

Bariatric surgery

Meta-analysis of bariatric surgery

766 paired liver biopsies from 15 studies

Improvement Steatosis in 91.6% of patients Steatohepatitis in 81.3% Fibrosis in 65.5% Complete NASH resolution in 69.5%

Mummadi, R.R., Kasturi, K.S., Chennareddygari, S. and Sood, G.K. (2008) Effect of bariatric surgery on nonalcoholic fatty liver disease: systematic review and meta-analysis. Clin Gastroenterol Hepato 6: 1396-1402

Invasive Weight Loss Management: Intra Gastric Balloon

Prospective intervention study

131 patients, mean BMI 43

Placement of balloon x 6 months

Follow average 21 months

Results: 91 responders ie BMI decrease by 3.5kg/m(2) or more- severe liver steatosis decreased from 52% to 4%

Forlano R et al, Gastrointest Endosc. 2010 May;71(6):927-33.Effect of the BioEnterics intragastric balloon on weight, insulin resistance, and liver steatosis in obese patients.

Pioglitazone and Vitamin E

Randomized multi center study

247 adults with NASH and without DM Pioglitazone 30 mg qd (80 subjects) Vitamin 800 IU qd (84 subjects) Placebo (83 subjects)

96 weeks

Primary outcome: improvement in histologic features of NASH comparing pre and post treatment liver biopsies (using composite of standardized scores for steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis).

Sanyal A.J et Al; N Engl J Med. 2010 May 6; 362(18): 1675–1685S

Pioglitazone, Vitamin E

Vitamin E compared with placebo significantly higher rate of improvement in nonalcoholic

steatohepatitis (43% vs. 19%, P = 0.001)

Pioglitazone therapy with placebo did not reach the prespecified 0.025 level of significance

for the primary outcome (34% vs. 19%, P = 0.04) But reductions in steatosis, inflammation, and

hepatocellular ballooning, as well as with improvements in insulin resistance and liver- enzyme levels

Problem with weight gain May be good option for pts with NASH and DM II

Sanyal A.J et Al; N Engl J Med. 2010 May 6; 362(18): 1675–1685S

Metformin

Randomized, double blind, placebo-controlled trial 48 patients with biopsy-proven NAFLD 6 months of metformin vs placebo

No significant improvement in steatosis (by histological or CT evaluation), transaminase levels

Significant improvements in metformin cohort of: body weight total cholesterol LDL glucose, HbA1c

Haukeland, J.W.et al(2004) Metformin in patients with non-alcoholic fatty liver disease: a randomized, controlled trial. Scand J Gastroenterol 44: 853-860.

Are statins safe and do they work?

Concern about hepatotoxic effects statins

Efficacy and safety of lipid-lowering agents for NAFLD/NASH by reviewing reports of human studies from 1980 to 2011.

Compelling evidence that statins are safe and efficacious in patients with NAFLD/NASH Some agents can induce a reduction in the extent of the

hepatic steatosis.

Need RCT to establish a suitable lipid-lowering treatment for hyperlipidemic patients with NAFLD/NASH nonhyperlipidemic patients with NAFLD/NASH with a high

risk for cardiovascular disease.Nseir W et al; Dig Dis Sci. 2012 Mar 15. Lipid-Lowering Agents in Nonalcoholic Fatty Liver Disease and Steatohepatitis: Human Studies.

Remember Mr. A. ?

36 yo man with ultrasound showing fatty liver. Asymptomatic. Slightly elevated ALT. High total cholesterol, low HDL and high TG.

I recommended weight loss, tobacco cessation.

Liver biopsy?

Medications? Statin Metformin Vitamin E Pioglitazone

Algorithm

What about Mrs. M. ?

Presented to the ER with hematemesis and melena, change in mental status.

BP 80/50 HR 98 sat 98% Obtunded, jaundiced, icteric Abd: distented, +BS, +ascites

Labs: Hgb 6.5 Pls : 50k INR: 1.8

Intubated, transfused 2u pRBCs, vit k, given IV antibiotics

Emergency EGD…

Listed for liver transplant in July 2011 and succesfully transplanted in November 2011

Take home points

Fatty liver is a spectrum in diseases

EtOH abstinence

Critical distinction between steatosis and NASH

NASH should result into a very aggressive approach towards the risk factors associated metabolic syndrome

All patients meeting criteria for metabolic syndrome should be assessed for NAFLD

Nigeria: Shift to chronic diseases? Need for more awareness