Prof. Dr. Muhammad Shoaib Shafi

MBBS, FCPS (Pak) FACP FRCP ( Ireland, Edin, London , Glasgow)Professor of Medicine, BBH, Rawalpindi

Defining NAFLD

o A liver biopsy showing moderate to gross macrovesicular fatty change with or without inflammation (lobular or portal), Mallory bodies, fibrosis, or cirrhosis.

o Negligible alcohol consumption (less than 40 g of ethanol per week) • History obtained by three physicians independently. • Random blood assays for ethanol should be

negative.• If performed, desialylated transferrin in serum

should also be negative.o Absence of serologic evidence of hepatitis B or

hepatitis C.

NAFLD—Spectrum of Disease

Steatosis

Steatohepatitis (NASH)

NASH with Fibrosis

Cirrhosis

NAFLD

NAFLD—Why Study it?

o Prevalence of NAFLD 13-18% and that of NASH specifically 2-3% (1.2-9%)

o Is the leading cause of cryptogenic cirrhosis

o Is a disease of all sexes, ethnicities, and age groups (peak 40-59)

o Occurs more frequently in females (65 to 83%)

Spectrum of NAFLDo Simple hepatic steatosis (NAFLD) is most frequent,

usually benign, and asymptomatic

o 10% have or develop liver injury and necroinflammation which is nonalcoholic steatohepatitis (NASH) and up to 20% of NASH subjects may progress to more advanced liver disease

o Cirrhosis may occur in ~ 30% of NASH patients and some may develop hepatocellular carcinoma (increased 2-3 fold in T2DM)

Browning JD et al. Hepatology 2004;40:1387 Powell EA et al. Ann Int Med 2005;143:753

Global Prevalence of NAFLD: US

3%

14%

7%

16% 16%

34%

76%

0%

10%

20%

30%

40%

50%

60%

70%

80%

China (1) India (2) Japan(3) Italy (4) Korea (5) Korea (5) Italy (4)

LEAN

OVT

OBSALL

1) Shen L, et al. World J of Gastroenterology 2003; 9:1106.2) Singh S, et al. Tropical Gastroenterology 2004; 25:76.3) Omagari Ket al. J of Gastroenterology and Hepatology 2002; 17:1098.4) Bellentani S, et al.. Ann Int Medicine 2000; 132:112.5) Kim H, et al. Arch Int Medicine 2004; 164:2169.

By 2020

NAFLD—Risk Factors

Acquired Metabolic Disorders in 38%

ObesityDiabetes Mellitus

Hypertriglyceridemia

Total Parenteral Nutrition ,Rapid weight loss, Acute starvation

SurgeryJejunoileal Bypass

Extensive Small Bowel Loss

Medications

Corticosteroids; Estrogens

Amiodarone

Methotrexate; Tamoxifen

Diltiazem; Nifedipine

Occupational ExposuresOthers

Organic SolventsWilson's dis,Abetalipoproteinemia Jejunal

diverticulosis

Risk factors: Emerging association

o Polycystic ovary syndromeo Hypothyroidismo Obstructive sleep apneao Hypopituitarismo Hypogonadismo Pancreatic-duodenal resection

Risk factor: Bacteria overgrowth

o Grieco, et al. Hepatology 2009• 35 pts with NAFLD bx confirmed• 27 pts with celiac disease• 24 healthy individuals• Those with FLD had increased intestinal permeability

and increased small bowel bacterial overgrowtho Compare, et al Nutrition Metabolism &

Cardiovascular Disease Feb 2012• Liver is 1st line of defense against gut-derived antigens• Levels of bacterial lipopolysaccharide (component of

GN bacteria) are increased in the circulation in several types of chronic liver disease

• Can modulation of gut microbia represent a new way to treat/prevent NAFLD????

Insulin resistance

Fatty acids

Steatosis

Lipid peroxidation

NASH

NAFLD—Pathogenesis

First HitSecond Hit

Hepatic iron, leptin, anti-oxidant deficiencies, and intestinal bacteria

NAFLD—Pathogenesiso Triglyceride accumulation o Insulin resistance

o Lipid Peroxidation and Hepatic Lipotoxicity

o Cytokine Activation and Fibrosis

o Adiponectin and Leptin (Adipocytokines)

o Abnormal Lipoprotein Metabolism

NAFLD—Symptoms

0 10 20 30 40 50 60 70

Prevalence (%)

Asymptomatic

Fatigue

RUQ pain

Edema

Pruritus

GI bleeding

Ascites

NAFLD—Exam Findings

0 5 10 15 20 25 30 35 40

Prevalence (%)

Normal

Hepatomegaly

Edema

Jaundice

Splenomegaly

Ascites

Algorithm for evaluating NAFLD

Accidental discovery Screen those with risk factors

AST or AST Symptomatic liver disease elevated normal

r/o other causes of liver disease

monitor ongoing alcohol

yes no Abstain Imaging study Echogenic US or fat on CT May need biopsy

NAFLD: DX and Imagingo Liver biopsy is the “gold standard” for diagnosis (?when

to Bx)o US: sensitivity 60-99% specificity 84-95%

o 100% sensitive in detecting >33% fat on biopsy o Imaging generally underestimates presence of

steatosiso No imaging modality allows staging of NAFLDo CT scanning reveals low density hepatic parenchyma

with occasional focal areas which may be misread as masses. MRI can differentiate masses and may allow a more quantitative assessment of fatty infiltration of liver

o No reliable serum markers have been found to stage NAFLD

Joy D, et al. Eur J Gastroenterol Hepatol 2003; 539. Saadeh S, Younossi Z, et al. Gastroenterology 2002;123:745

Scatarige JC et al. J Ultrasound Med 1984;3:914.

Liver biopsy

o Incidental finding on imagery with normal enzymes: no biopsy indicated, monitor.

o Presence of metabolic syndrome and persistently elevated biochemistries may benefit from liver biopsy

o Patients with biopsy proven NASH cirrhosis should be screened routinely for esophageal varices and HCC

NAFLD fibrosis score

http://nafldscore.com

AgeBMIHyperglycemiaPlatelet count

AlbuminASTALT

NAFLD fibrosis score

o < -1.455: predictor of absence of significant fibrosis (F0-F2 fibrosis)

o ≤ -1.455 to ≤ 0.675: indeterminate score

o > 0.675: predictor of presence of significant fibrosis (F3-F4 fibrosis)

NAFLD—Histological Spectrum

Macrovesicular Steatosis

Lobular Inflammation

Fibrosis

Cirrhosis

Tim

e

Pro

gre

ssio

n

Liver biopsy in NASH, Indications

o Peripheral stigmata of chronic liver disease

o Splenomegaly

o Cytopenia

o Abnormal iron studies

o Diabetes and/or significant obesity in an individual over the age of 45

Predictors of More Severe Histology in NASH

o Age >40–50 y o Female gendero Degree of obesity or steatosiso Hypertensiono Diabetes or insulin resistanceo Hypertriglyceridemiao Elevated ALT,AST, γ-GT levelo AST:ALT transaminase ratio >1o Elevated immunoglobulin A level

Panel of markers/Scoring systems

Identification of steatosiso “NAFLD liver fat score” includes:

- Presence of DM - Fasting serum insulin- AST- AST/ALT ratio

o “Fatty liver index” includes:- BMI- Waist circumference- Triglyceride- GGT

o “Visceral adiposity index” includes:- BMI- Waist circumference- Triglyceride- HDL

Panel of markers/Scoring systems Identification of inflammationo “NASH test” includes:

- Total Bilirubin- GGT- α2 macroglobulin- Apolipoprotein A1- Haptoglobulin- ALT

o “HAIR test” includes:- Hypertension- ALT- Insulin resistance

o ‘Parkler model” includes:- age- gender- AST- BMI- AST/ALT ratio- Hyaluronic acid

Panel of markers/Scoring systemsIdentification of fibrosis

o AST/ALT ratio (AAR)o APRI test: uses platelet count and ASTo “FIB 4 index” utilizes age, AST, ALT, and platelet count o “NAFLD fibrosis score” includes:

- BMI- Presence of DM- Albumin

o “Fibrotest” (BioPredictive) tacking into account:- GGT- Haptoglobulin- Bilirubin- Apolipoprotein A1- α2 macroglobulin

o “Fibro Spect” tacking into account:- Hyaluronic acid- Tissue inhibited matrix metalloproteinase- Inhibitor1- α2 macroglobulin

o Presence of DM (type2), obesity, hypertension, and aminotrasferase elevation are markers of fibrosis

o The utility of these tests are limited in cases with advanced fibrosis

o The best result for non invasive staging will be achieved by combining a clinical/biochemical scoring system with elastography

Biomarkers for assessment of steatohepatitis and fibrosis

o C reactive protein: independent risk factor for the progression of NAFLD

o Plasma Pentraxin 3: risk factor for the progression of NAFLDo IL6: indicate inflammmatory activity and the degree of

fibrosiso TNF α: risk factor for the progression of NAFLDo Cytokeratin 18: marker of hepatic appoptosiso Polypeptide specific antigen: released during appoptosiso Endothelin 1: is a mediator of fibrosiso Adiponectin: is lower in NASHo Oxidative stress biomarkers ? (superoxide desmutase,

glutathione peroxidase, Thioredoxin)o Hyaluronic acid ?o Type 4 collagen 7S domain ?o Laminin ?

Fibroscan

o Transient elastography that evaluates liver stiffness using pulse-echo ultrasound

o Non invasiveo More sensitive than serologic markerso Evaluates a larger part of livero Main weakness is interference with by steatosis

with wave velocityo Might be unreliable in obese

Acoustic radiation force impulse(ARFI)

o Sonoelastography that evaluates liver elasticityo Alternative to Fibroscano Utilizes acoustic waves to interogate the

mechanical stiffness of livero Can be used during standard US examination of

livero Diagnosis of significant fibrosiso Another modality is magnetic resonance

elastography with higher diagnostic accuracy for fibrosis staging especially in obese

Insulin resistance

Fatty acids

Steatosis

Lipid peroxidation

NASH

CytoprotectantsInsulin Sensitizers

Antihyperlipidemics

First Hit Second Hit

Weight Loss

Diet/Exercise

Antioxidants

How to Treat?

Lifestyle Interventionso Weight loss by lower caloric intake and increased

physical exercise led to improvement in biopsy.

o 9.3% weight loss: improvement in steatosis, necrosis, and inflammation; not fibrosis

o 3-5% weight loss improves steatosis but more is needed to improve inflammation

o Alcohol consumption: o heavy intake should be avoidedo light intake (<1/day) may have benefits**, may

not*** * Promrat, et al. Hepatology 2010 ** Dunn, et al. Hepatology 2008** Gunji. et al. Am J Gastro 2009** Moriya, et al. Alim Pharm Ther 2011***Ruhl , et al. Clin Gastro Hepatol 2005

Insulin sensitizing agentso Metformin

• reduction in IR and enzymes, • no improvement in histology

o Thiazolidinediones• Rosiglitazone : improved enzymes and

steatosis, but not inflammation• Pioglitazone: +weight gain, but improvement in

hepatocellular injury Uygun, et al Aliment

Pharm Ther 2004 Nair, et al Aliment Pharm

Ther 2004 Ratziu, et al Gastroenterology 2008 Sanyal, et al NE J Med 2010

PIVENS Study

o Pioglitazone , Vitamin E, placeboo 96 weekso Adults

• with NASH• without DM, cirrhosis, Hep C, heart failure• limited alcohol intake over previous 5 years

o Randomized trial• Pio group: 80• Vit E group: 84• Placebo: 83

Sanyal et al, New England J of

Medicine 2010

PIVEN Conclusions

Vitamin E was superior to placebo in adults with NASH and without DM

Pioglitazone may have a role in treating patients with biopsy-proven NASH, however long term safety and efficacy has not been established

Sanyal et al, New EnglJ of Med 2010

AASLD recommendations:

o Pio can be used to treat certain patients with biopsy-proven NASH who do not have DM but long term safety and efficacy has not been established

o Vitamin E 800 IU/day improves liver histology in NASH pts• Not recommended to treat NASH in those with other

chronic liver diseases, diabetics, those with NASH cirrhosis or cryptogenic cirrhosis, NAFLD without biopsy

Vitamin E: other concerns

o Meta-analysis including 136,000 participants found taking Vitamin E supplements > 400 IU/day had a higher risk of all cause mortality

o Vitamin E > 400 IU/day increases risk of prostate cancer in relatively healthy men

Miller et al Annals of Internal

Medicine 2005 Klein, et al, JAMA 2011

AASLD Recommendation on Statins

“Given lack of evidence that patients with NAFLD and NASH are at increased risk for serious drug-induced liver injury from statins, they can be used to treat dyslipidemia in patients with NAFLD and NASH.”

Bariatric surgeryo No RCTso Cochrane review 2010: lack of RCTs prevents

definitive assessment of risks/benefitso Prospective study

381 adults with severe obesity, fibrosis score<3 Clinical, metabolic, liver biopsy comparisons at 1 year

and 5 years Significant improvement in steatosis, ballooning,

resolution of probable/definite NASH at 1 and 5 years Small but significant increase of fibrosis score at 5

years (96% had improvement)

Mathurin et al Gastroenterology 2009

AASLD Pediatric Recommendations

o Intensive lifestyle behavior modification, including dietitian consultation, is first line treatment

o Metformin 500mg BID offers no benefit

o Vitamin E 800 IU/d offers histological benefit but confirmatory studies are needed before it can be recommended in clinical use.