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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.