NAFLD ppt Dr Suresh Gorka

1. NAFLD
DR SURESH GORKA

2. Definition
• NAFLD is characterised by excessive hepatic fat accumulation, associated
with insulin resistance (IR), and defined by the presence of steatosis in
>5% of hepatocytes according to histological analysis or
by a proton density fat fraction >5.6% assessed by proton magnetic
resonance spectroscopy (1H-MRS) or quantitative fat/water selective
magnetic resonance imaging (MRI).

3. Spectrum of NAFLD

4. STEATOSIS is the presence of lipid within the cytoplasm of hepatocytes, the
criteria for which is defined in the literature as being either hepatic lipid
levels above the 95th percentile for healthy individuals (about >55 mg/g
liver), greater than 5% of the liver’s weight, or found in greater than 5% of
hepatocytes histologically.
NASH is defined as steatosis in the presence of hepatocyte damage,
inflammation and/or subsequent scarring and replacement of the tissue
with type 1 collagen.
K Hassan et al, World J Gastroenterol 2014

5. EPIDEMIOLOGY
• Prevalence: 2.8 – 46%
Hispanics highest 45%
Indian
• Age: 4-6th decade
• Sex: M>F

6. Multi-hit hypothesis

7. Risk Factors

8. Natural History

9. • Compared with HCV cirrhosis, the incidence and
prevalence of HCC are less,
NASH cirrhotic - 2.6%–2.7%/year, compared with
HCV cirrhotic- 4%– 4.7%/year
• Causes of death:
• Cardiovascular > Malignancy > Liver related

10. Presentation
ANA 25%
Ferritin 20-50%
Clinical and laboratory finding do not correlate with the histologic severity of NASH

11. • ALT/ AST are normal in >50%
• GGT elevation may be associated with advanced
fibrosis

12. Clinical associations
50%
71%
20%
85%

13. NASH scoring system in morbid obesity

14. DIAGNOSIS
• Diagnosis of NAFLD requires hepatic steatosis
by imaging or histology and the exclusion of
both secondary causes and of a daily alcohol
consumption >30 g for men and >20 g for
women
• Definitive diagnosis of NASH requires a liver
biopsy, is the only procedure that reliably
differentiates NAFL from NASH

16. Fibrosis Scores
• Surrogate markers of fibrosis (NFS, FIB-4, ELF or
FibroTest, etc.) should be calculated for every
NAFLD patient, in order to rule out significant
fibrosis (F2).

19. Transient elastography (TE) also k/a
(Fibroscan)
 measures stiffness in kilopascals by introducing low
frequency vibrations to the tissue and measuring the
propagation of the energy.
 If significant fibrosis cannot be ruled out by fibrosis
scores, patients should be referred for fibroscan
 better for cirrhosis (F4) than for advanced fibrosis
(F3).

20. • Has higher rate of false-positive than false-
negative results and higher NPV than PPV, hence the
ability to diagnose bridging fibrosis or cirrhosis is
insufficient for clinical decision making.
• Limitation - Obesity
success rate 75% in obese patients v/s 97% in
patients with a BMI below 30 kg/m. The XL probe
should be used in these patients to reduce the
failure rate, which remains high (35%).

21. Biomarkers
• Cytokeratin-18 fragments (CK-18), generated during
cell death (M65 fragment) or apoptosis (M30
fragment) have modest accuracy for the diagnosis of
NASH with sensitivity of 66% and specificity of 82%.
• The M65 ELISA test was superior to the M30 ELISA at
differentiating NAFLD from NASH, with a sensitivity
and specificity of 100% and 80%, respectively.

22. • Fibrosis score, Transient elastography as well as
Biomarkers help in
 identification of cases at low risk of advanced
fibrosis/cirrhosis
 might confer additional diagnostic accuracy and
might save a number of diagnostic liver biopsies
 Monitoring of fibrosis progression in clinical practice
may rely although this strategy requires validation

23. • The identification of advanced fibrosis or cirrhosis by
fibrosis scores/ biomarkers and/or elastography is
less accurate and needs to be confirmed by liver
biopsy, according to the clinical context.

24. Imagings
• Ultrasonography (US)
 sensitivity ranging from 60% to 94% and a specificity
of 66% to 95%
 lower sensitivities are frequently observed in patients
with mild disease
 Limitations- interobserver variability, difficulty in obese
patients

25. • CT without contrast
 useful modality for assessing the presence and
amount of steatosis, with a sensitivity ranging from
82% to 95% and a specificity approaching 100%
 One of three findings is diagnostic of steatosis on CT:
absolute hepatic attenuation of less than 40 HU,
a hepatic attenuation value <10 HU compared with the spleen or
a liver to spleen attenuation ratio <1

26. Limitations
• expensive, expose patient to ionizing
radiation and can provide less accurate results
in patients with underlying liver disease

27. • Magnetic resonance spectroscopy (MRS)
 most sensitive and specific imaging modality, with
both values being greater than 90% in most studies
and near 100% accuracy
 compare adjacent tissues by their differing hydrogen
content, by this able to calculate the fraction of the
liver composed of fat, so called fat fraction is said to
be abnormal when it is greater than 5.56%

28.  Like CT, MRS has a high cost and also exposes
patients to radiation (albeit a lower amount than CT)

29. Liver biopsy
• Remains gold-standard for diagnosis of NASH.
• Only means of distinguishing NAFLD and
NASH.

30. • NAFL encompasses:
a) steatosis alone,
b) steatosis with lobular or portal inflammation,
without ballooning, or
c) steatosis with ballooning but without inflammation.
• NASH requires the joint presence of steatosis, ballooning
and lobular inflammation.
• Other histological features can be seen in NASH, but are
not necessary for the diagnosis: portal inflammation,
polymorphonuclear infiltrates, Mallory-Denk bodies,
apoptotic bodies, clear vacuolated nuclei, microvacuolar
steatosis and megamitochondria. Perisinusoidal fibrosis is
also frequent, but not part of the diagnostic criteria

31. • In children:
• Portal inflammation is a frequent feature,
Hepatocellular ballooning and Mallory-Denk bodies
are only sporadically observed, and potential for
severe liver-related complications later in life.
. Long term outcome poor.

32. NASH histological scoring system

33. Other tests
• Stool test
 Loomba & team found that advanced NAFLD tend to
have more Proteobacteria and fewer Firmicutes in
their stool that with early stages NAFLD.

34. • HOMA-IR (Homeostatic model assessment)
• provides a surrogate estimate of IR in
persons without diabetes.
• HOMA-IR is of limited use for NAFLD diagnosis in
patients with metabolic risk factors.

35. • It could confirm altered insulin sensitivity, thereby favouring a
diagnosis of IR-associated NAFLD in cases of diagnostic
uncertainty (e.g., US-defined steatosis with normal body
weight)
• During follow-up, HOMA-IR might help identify patients at risk
of NASH or fibrosis progression in selected cases.
• Improvement of HOMA-IR during weight loss may indicate
metabolic improvement that could be beneficial for NAFLD.

37. Survival rate

38. Treatment

40. Insulin sensitizers
• Thiazolidinediones (TZDs)
• Include Pioglitazone (30 or 45mg) & Rosiglitazone
• MOA- PPAR-agonists to improve IR in skeletal muscle,
adipose tissue, and the liver. Also exert anti-
inflammatory effects
• Boettcher et al performed a meta-analysis of 4
randomized controlled trials (3 with pioglitazone and 1
with rosiglitazone), and although improvement in
steatosis, necroinflammation, and ballooning were
indeed found, no improvement in fibrosis was seen.

41. • Recent evidence linking Rosiglitazone to increased
rates of myocardial infarction have essentially
removed this agent as a treatment choice.

42. • Metformin
• MOA- improves insulin sensitivity by decreasing
hepatic gluconeogenesis and limiting triacylglycerol
production.
• It promotes modest weight loss rather than the
weight gain seen with TZD therapy
• Metformin is not indicated as monotherapy in
NASH patients but may be useful in diabetic NASH.

43. • Incretin-Based Therapies
• Glucagon like peptide-1 (GLP-1) is a naturally
existing incretin hormone with a potent blood-
glucose reducing action only during hyperglycemia
since it induces insulin secretion and reduces
glucagon secretion in a glucose dependent
manner.

44. • In Ohki et al study, that included 126 patients with
NAFLD & T2DM, the aspartate aminotransferase to
platelet ratio index (APRI) was significantly
improved in the liraglutide group and pioglitazone
group but not in the sitagliptin group.
• Armstrong et al showed a significant histological
benefit in 52 patients with biopsy-proven NASH,
treated with liraglutide 1.8 mg per day for 48 weeks.
NASH resolution occurred in 39% of patients
treated with liraglutide compared to 9% with
placebo, and less patients treated with liraglutide
experienced worsening of fibrosis.

45. Antioxidants
• It reduces the generation of reactive oxygen species
in the liver & inhibit the activation of inflammatory
cytokines involved in steatohepatitis.
• Vitamin E, Vitamin C, and Betaine.

46. • Vitamin E (alfa-tocopherol)
• In the large PIVENS trial, 247 subjects were randomized
to receive alfa-tocopherol 800 IU/day versus
Pioglitazone 30mg/day versus Placebo over 96 weeks.
• There was a significant improvement of hepatocellular
ballooning and steatosis, without significant
improvement in fibrosis score.
• However, vitamin E use is associated with adverse
effects, including risk hemorrhagic stroke, bladder
cancer and prostate cancer.
NEJM 362: 1675-1685, 2010

47. • The positive results seen with adults and Vitamin E
may not extend to pediatric NAFLD, where Vitamin E
was not superior to placebo in the treatment of
NASH, although ballooning was significantly
improved.

48. • Betaine
• is another antioxidant that increases S-
adenosylmethionine levels and has been shown to
decrease hepatic steatosis in animal models.
• Only one randomized controlled trial exists to date
that compared betaine with placebo. This study
suggested only steatosis improvement with therapy.
Until more data are available, this agent cannot be
recommended for the treatment of NASH.

49. Cytoprotective agents
• These agents prevent apoptosis and down-regulate
the inflammatory cascade, mechanisms thought
central in the pathogenesis of NASH.
• Ursodeoxycholic acid (UDCA)
• Pentoxifylline (PTX)

50. • Ursodeoxycholic acid (UDCA)
• One larger randomized controlled trial of 147
patients treated with placebo or UDCA 23–28
mg/kg/d that found only improvement
gamma-glutamyltransferase and lobular
inflammation but no overall significant improvement
in histology.

51. • Pentoxifylline (PTX)
• is another cytoprotective agent that has been shown to
have anti-inflammatory properties via inhibition of
proinflammatory cytokines including TNF-alfa, reduced
production of oxygen free radicals and anti-
fibrotic. Fibrosis improvement was not statistically
significant, although 35% of patients in the
PTX group showed improvement in fibrosis vs 15% in
the placebo group

52. • Zein et al, administered pentoxifyllin (1200 mg/d)
for 12 mt, improved histological features of NASH
(steatosis, lobular inflammation, and fibrosis)
compared to placebo.
• Baniasadi et al suggest that pentoxifyllin
administration does not significantly help in the
treatment of patients with NASH.

53. • A meta-analysis carried out by Du Juan et al showed
that pentoxifyllin therapy improved liver function and
histological changes in patients with NAFLD/NASH.

54. Lipid-lowering medications
• Statins
• inhibit enzyme essential to cholesterol
biosynthesis, 3-hydroxy-3-methylglutaryl-coenzyme
A reductase.

55. • In a randomized controlled trial, Atorvastatin (20
mg/d) combined with Antioxidants (vitamin C and E)
was effective in reducing the risk of hepatic steatosis
by 71% after 4 years of active therapy in individuals
with NAFLD at baseline.
• Although some studies have reported decreased
serum aminotransferases or a reduction in steatosis
evidenced by imaging methods, most studies have
shown no evidence of liver histology improvement.

56. • Until histologic data are available, statin
therapy may be recommended for treatment of
concomitant hyperlipidemia but not as a primary
NAFLD therapy.

57. • Ezetimibe
• is another lipid-lowering medication that has shown
some early promise in the treatment of NASH.
• A recent study by Park et al showed similar
improvement in hepatic steatosis, necro-
inflammation, and metabolic parameters in
45 NAFLD patients treated for 24 months with
ezetimibe, although there was no significant change
in fibrosis.

58. • Confirmation in larger placebo-controlled trials is
required, but the use of ezetimibe in NASH patients
with concomitant hyperlipidemia is reasonable

59. Newer drugs
• Angiotension receptor blockers
• Probiotic
• Obeticholic acid
• PPAR agonist
• Anti-apoptotic
Caspase inhibitor
(GS-9450, Emricasan)
Chemokine receptor type 2 & 5 antagonists
(Cenicriviroc)
• Anti-fibrotic agents MCA against LOXL2
(Simtuzumab)

60. Angiotensin converting enzyme inhibitors (ACE-I) and
angiotensin receptor blockers (ARBs)
• ACE-I and ARBs induced
• vasodilation increases the delivery of glucose and insulin
to insulin-sensitive tissues and improves blood flow in the
pancreas, promoting insulin secretion.
• The beneficial effects of ARBs on insulin resistance could
also be related to the selective stimulation of peroxisome
proliferator-activated receptors γ (PPAR-γ).

61. • Furthermore, clinical trials have showed the ability of
renin-angiotensin system (RAS) inhibition to prevent
new-onset of diabetes mellitus.
• A meta-analysis by Al-Mallah et al including 100.848
patients, reported that there was a 20% reduction in
the incidence of new onset T2DM with the use of ACE-I
and ARBs.
• Despite the encouraging evidence from
animal studies, data from human studies about the use
of ACE-I and ARBs in NAFLD/NASH, are limited and
contradictory.
Cardiol J. 010;17(5):448-56

62. Probiotic
• modulating effect on the gut flora could influence
the gut-liver axis.
• Several studies have suggested the important role of
gut-derived bacterial products in the pathogenesis
of steatosis, inflammation and fibrosis, all NASH
- associated features.

63. • A recent meta-analysis that included 134
patients with NAFLD/NASH from 14 randomised
controlled trials (RCTs), showed probiotic therapy
significantly decreased liver aminotransferases,
total-cholesterol level, TNF-α and improve insulin
resistance in NAFLD patients. Of the four RCTs
included in this meta-analysis, the studied
probiotics included Lactobacillus,
Bifidobacterium and Streptococcus (VSL#3).

64. • One study in obese mice has shown that treatment
with the probiotic VSL#3 resulted in improved liver
histology and decreased ALT levels.
• Two small trials in humans have been performed and
demonstrate improved markers of oxidative stress
and improved liver enzymes. Histopathologic end
points are currently lacking, and thus probiotics
cannot be routinely recommended to treat NAFLD at
this time, although further study is indicated.

65. Farnesoid X receptor agonists
• Obeticholic acid (OCA)
• Farnesoid X receptor (FXR), regulator of bile acid
synthesis, and, more recently, as a regulator of the
gut-liver axis in the fed state.
• Activation of FXR improves hepatic steatosis,
inflammation and fibrogenesis in NAFLD.

66. • Obeticholic acid (OCA) is a synthetic farnesoid X
receptor (FXR) agonist, and in animal models of
NAFLD/NASH, has been shown to increase hepatic
insulin sensitivity and reduce gluconeogenesis, with
amelioration of hepatic steatosis.
• In the recently published FLINT clinical trial in 2015,
Neuschwander-Tetri et al. studied NASH patients
treated with OCA (25mg/d) versus placebo for 72 wk
and showed improvement of histological hepatic
steatosis, inflammation, and fibrosis in OCA group, but
its long-term benefits and safety need further
clarification.

67. Dual PPARα and PPARγ agonists
• Saroglitazar,
a potent PPARα agonist and moderate PPARγ agonist
• In the 1-year extension of the Phase III randomized
multicentre PRESS V trial, which compared saroglitazar with
pioglitazone in patients with diabetic dyslipidaemia,
saroglitazar was associated with significant improvements in
lipid and glycaemic parameters, but was not associated with
weight gain, peripheral odema or any other adverse event.

68. • Currently approved by the Drug Controller General of India
(DCGI) for diabetic dyslipidaemia, saroglitazar also improved
symptoms in a diet-induced experimental model of NASH and
improved liver disease markers in patients with diabetes and
NAFLD. A small Phase IIa single-arm clinical trial (PRESS VIII)
using saroglitazar to treat patients with biopsy-proven NASH
has been completed (Clinical Trials Registry India identifier:
CTRI/2010/091/000108). Larger and longer randomized
clinical trials with clinical outcomes are needed to assess the
long-term safety and efficacy of saroglitazar

69. ANTIAPOPTOTIC
• Caspase inhibition
• GS-9450, Emricasan
• A Phase 2 randomized, placebo-controlled study
investigating the safety, tolerability, and activity of
multiple oral doses of GS-9450 was performed in
124 patients with NASH. Study design included five
parallel treatment groups: placebo or GS-9450 1mg,
5 mg, 10mg, or 40mg administered orally once daily
for 4 weeks.

70. • Subject entered a 4-week follow-up period the result
showed significant decreases in alanine amino-
transferase (ALT) levels and smaller nonstatistically
significant reductions in aspartataminotransferase
(AST) and CK-18 fragments in patients with NASH.
• This finding suggests that reducing apoptosis may be
a valuable therapeutic strategy in patients with
NASH.

71. • Emricasan (IDN-6556)
• is an irreversible pancaspase protease inhibitor
that is orally administered. In animal models, hepatic
fibrosis and liver damage were reduced by
Emricasan.
• In a double- blind, placebo-controlled,
study that included 105 patients treated with
Emricasan for 14 days, significantly reduced ALT and
AST levels were observed

72. • Dual inhibitor of CCR2 and CCR5,
• Cenicriviroc, an immunomodulator evaluated for the
treatment of NASH. Cenicriviroc is primarily
metabolized by the liver.
• In a phase 1 study of safety in patients with mild and
moderate hepatic impairment (Child-Pugh A or B),
patients received cenicriviroc 150 mg orally once
daily for 14 days. Cenicriviroc concentrations were
not affected by mild hepatic impairment, but were
increased by moderate impairment. Cenicriviroc was
safe and well tolerated

73. • A phase II study is currently evaluating
cenicriviroc in noncirrhotic patients with NASH
and liver fibrosis.

74. ANTI-FIBROTIC
• Lysyl oxidase–like-2 (LOXL2)
Simtuzumab
• LOXL2 is an extracellular matrix enzyme that causes
crosslinkage of type 1 collagen and elastin, leading to
remodeling of the extracellular matrix and promoting
fibrosis.
• Simtuzumab is a humanized antifibrotic monoclonal
antibody (immunoglobulin G4) against LOXL2.

75. • Simtuzumab was well tolerated at doses up to 10
mg/kg.
• Current multicenter clinical trials are examining the
safety and efficacy of simtuzumab in patients with
cirrhosis and advance fibrosis with NASH.

76. Bariatric Surgery
• In patients unresponsive to lifestyle changes and
pharmacotherapy, bariatric surgery is an option
• A recent cohort study with 1-year follow-up
confirmed that bariatric surgery-associated weight
loss cleared NASH in 85% of patients and improved
fibrosis in 34%, although the possible benefits
should be balanced against peri-/postoperative
complications.

77. • No solid data on the comparative effects of different
bariatric procedures on liver fat are available
• Recommendations
• By improving obesity and diabetes, bariatric
(metabolic) surgery reduces liver fat and is likely to
reduce NASH progression; prospective data have
shown an improvement in all histological lesions of
NASH, including fibrosis

78. Liver Transplantation
• NASH is now the third most common indication for liver
transplantation (behind hepatitis C and alcoholic liver disease)
in the United States and is expected to become the number
one indication within the next 8 –15 years.
• Steatosis is currently detected in approximately one-third to
one-half of potential living and cadaveric liver transplant
donors.
• Livers with less than 30% steatosis are considered optimal,
whereas severely steatotic livers with >60% fat are not
typically used. Livers with intermediate quantities of steatosis
from 30%– 60% may be assessed for use on a case-by-case
basis.

79. • Transplanted steatotic livers are associated with primary graft
nonfunction, poor initial function, and poorer outcomes in
general.
• NASH cirrhosis has been linked to increased 30-day transplant
mortality, but generally survival at 1 and 3 years after
transplant is similar to other indications for transplant.
•
• Unfortunately, recurrent NAFLD in patients who undergo
transplantation for NASH or cryptogenic cirrhosis is high,
occurring in 30% of patients by 1 year and the majority of
patients within 5 years.

80. • Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver
disease in the world, affecting up to 30% of the adult population and 70–
80% of individuals who are obese and diabetic
• NASH is now the third most common indication for liver transplantation
(behind hepatitis C and alcoholic liver disease) in the United States and is
expected to become the number one indication by 2020.
• NAFLD is 2nd leading indication for HCC-related transplantation in the USA.
• There are currently no approved pharmacological therapies for NASH.

81. Thank You