Non alcoholic fatty liver

disease
(NAFLD)

Diagnosis and evaluation

Raika Jamali M.D.

Gastroenterologist and hepatologist
Tehran University of Medical Sciences
 Epidemiology
NAFLD is one of the most common liver
disorders in industrialized countries, with
type 2 diabetes, obesity, hyperlipidemia,
and cardiovascular disease being the most
frequently evaluated and cited risk factors
for the presence of NAFLD and accelerated
disease.
 The prevalence of NAFLD has been
increasing along with the rise in obesity
since the term non-alcoholic steatohepatitis
(NASH) was coined by Ludwig in 1980.
Patients with NASH are more likely to have
the metabolic syndrome than are those with
mere steatosis.
 The estimated prevalence in the general
population depends on the type of
screening test and ranges from 2.8% to
46% in unselected populations worldwide.

Ethnic variation in the prevalence of

NAFLD/NASH has been described; several
studies have indicated less common
prevalence in African Americans.
 Risk Score Model for Predicting
Sonographic Non-alcoholic Fatty Liver
Disease in Children and Adolescents
Cross-sectional study was conducted among
962 participants aged 6-18 years in Isfahan,
Iran.

The sonographic findings of 16.8% of

participants were compatible with NAFLD. Age,
sex, body mass index, waist circumference and
serum triglycerides level were diagnosed as
factors associated with NAFLD.

Hosseini SM, et al. Risk Score Model for Predicting Sonographic Non-alcoholic Fatty Liver
Disease in Children and Adolescents. Iran J Pediatr. 2011 21(2):181-7.
 In an autopsy study performed on 896
postmortem subjects at the Forensic Medicine
Center in Tehran who died of acute incidents not
related to hepatic disorders, 2.1% of cases were
found to have NASH upon histological evaluation.

Sotoudehmanesh R,, et al. Silent liver diseases in autopsies from forensic medicine of Tehran. Arch Iran
Med. 2006 Oct;9(4):324-8.
 Non-alcoholic fatty liver disease
prevalence among school-aged children
and adolescents in Iran
966 children aged 718 years in Iran by a cross-
sectional survey in 2007.
Fatty liver was diagnosed by ultrasound in 7.1%
of children. The prevalence of elevated alanine
aminotransferase (ALT) was 1.8%. NAFLD was
significantly more common in the older group.

Alavian SM, et al. . Non-alcoholic fatty liver disease prevalence among school-aged children and
adolescents in Iran and its association with biochemical and anthropometric measures. Liver Int.
2009 Feb;29(2):159-63.
Role of Immune Response
in NASH
 A recent review by Tilg and Moschen
proposed the 'multiple parallel hits'
hypothesis, where inflammation arises as
a consequence of many parallel hits
originating from visceral adipose tissue
and/or gut; according to this hypothesis,
gut-derived bacterial byproducts,
cytokine and adipokine signaling,
endoplasmic reticulum (ER) stress and
innate immunity emerge as key factors in
NASH pathogenesis.
 KCs
KCs represent the largest group of tissue
resident macrophages in the body.

They are able to release pro-

inflammatory cytokines such as IL-1, IL-
6, and TNF which promote the
infiltration of neutrophilic granulocytes
to eliminate bacteria.
 KCs also produce IL-12 and IL-18 which
activate NK cells to produce anti-viral IFN
.
However, following initial activation to
produce pro-inflammatory cytokines, KCs
release IL-10 which down-regulates the
production of TNF , IL-6 and other
cytokines and thereby probably
contributes to the intrahepatic cell
populations capability to induce tolerance.
 Hepatic stellate cells
HSCs, well described for their
participation in hepatic fibrosis and
storage of vitamin A, have been shown
recently to also function as APCs .
They are able to present lipid antigens
to CD1d-restricted T cells, i.e. to NKT
cells.
They are able to present protein
antigens to conventional CD4+ or CD8+
T cells
 Indeed, CD4 T cells can be converted to
induced regulatory T cells (iTregs) by vitamin
A derived retinoic acid and/or TGF .

Moreover, activated HSCs express the

negative co-stimulator PD-L1 .
 NAFLD pathogenesis in
ob/ob mice
Leptin deficiency
Kupffer cell inhibited
activation of
dysfunction Hepatic
stellate cells

Hepatic NKT Increased adipokines

cell depletion (resistin,adiponectin)

inhibited
liver fibrosis Th-1 polarization
Despite Liver injury
increased ROS

Hepatocyte oxidative stress

 Currently, it is widely accepted that
lipopolysaccharide (LPS), a gut
bacteria-derived endotoxin, is
important for the development and
progression of ASH and NASH
through TLR-4 activation and
induction of Kupffer cell activity.
 Oxidative stress may directly activate an
immune response and, subsequently,
drive further inflammation, or may be
the result of inflammation.
Hepatic oxidative stress, lipid
peroxidation and ER stress can directly
activate the inhibitor of NF-B kinase or
JNK to activate transcription of
proinflammatory cytokines.
 The best examples of pattern-
recognition receptors include a group
of Toll-like receptors (TLRs), which
recognizes pathogen-associated
molecular patterns to determine the
presence of pathogens.
 Once pathogens are identified, TLRs
then induce multiple signaling
pathways that regulate the
expression of proinflammatory
cytokines and chemokines to mount
protective responses against
invading pathogens.
 Experimental and clinical data have
demonstrated that levels of
circulating and hepatic LPS are
elevated in both ASH and NASH.
Increased LPS levels in NASH are
likely owing to small intestinal
bacterial overgrowth and alterations
of the intestinal barrier.
 Reportedly, Szabos group has
determined that TLR-2, which
recognizes lipoproteins and
peptidoglycans from gram-positive
bacteria, plays a protective role in
NASH, but has no role in the
pathogenesis of ASH.
 Natural killer (NK) T cells are regulatory T
lymphocytes that are preactivated in situ by
endogenous glycolipids, and are therefore
considered to be innate immune effectors.
NKT cells are present in normal liver and are
relatively depleted in steatosis.
Initial evidence points towards their
fourfold increase in NASH-related cirrhosis,
but there are no data on their numbers in
early-stage NASH.
 The adaptive immune response in NAFLD
involves CD4+ T-helper cells, and although
NASH is not classically considered a Th1-
polarized disease, recent data suggest that
its pathogenesis may be influenced by an
imbalance between a relative excess of
proinflammatory Th1 cytokines (i.e., IFN-)
and a deficiency in anti-inflammatory IL-4
and IL-10 cytokines.

 Emerging evidence also points towards a

functional role of Th17-mediated T-cell
responses in the pathogenesis of NASH.
Th17 cells are a recently described subset of
CD4+ T-helper cells producing the cytokine IL-
17. IL-17 can induce the expression of
neutrophil-attracting chemokines in epithelial
and endothelial cells, but it can also by itself
mobilize and activate neutrophils.
In fatty liver, the characteristic perivenular
infiltration of both neutrophils and lymphocytes
suggests enhanced recruitment via their two
major receptors CXCR1 and CXCR2.
 Circulating, as well as liver and adipose tissue
levels of TNF-, are increased in animal models
of obesity.
This is also true in humans, where TNF- levels
correlate with the degree of insulin resistance.
Furthermore, in humans, acute infusion of TNF-
inhibits insulin-stimulated glucose disposal,and
certain TNF- polymorphisms are associated
with susceptibility to insulin resistance and
NAFLD, supporting the importance of this
cytokine in the interaction among inflammation,
insulin signaling, and fat accumulation.
 Key points
Serum levels of TNF- correlate with
NASH activity however, levels of IL-6
do not.
Low serum levels of adiponectin have
been strongly correlated with NASH.
 The use of pentoxifylline, a known TNF-
inhibitor, has revealed mixed results.
In a small, open-labeled pilot study
evaluating the use of pentoxifylline
(1,600 mg/day) in patients with biopsy-
proven NASH, improvement was
documented in serum transaminase
levels over a 12-month period.
 In 2007, Satapathy et al. reassessed
the use of pentoxifylline in patients
with NASH, but at a dose of 1,200
mg/day over 12 months.
At the end of the study, serum
transaminases and liver histology
(including signs of liver injury,
inflammation, and fibrosis) were
significantly improved.[64]
 Pentoxifylline is a relatively weak and
nonspecific TNF- inhibitor, and thus the
use of more selective TNF- blockers,
such as infliximab and adalimumab, could
potentially be more effective in the
treatment of NAFLD.
Inhibitors targeted at IL-6 may be another
potential target for preventing progression
of steatohepatitis.
A humanized IL-6 receptor antibody,
tocilizumab, has been developed to inhibit
IL-6 binding to its receptor.
 Tocilizumab has been investigated in
clinical trials as a treatment for
rheumatoid arthritis.
In a multicenter, randomized controlled
trial in which patients were treated with
tocilizumab or placebo over 3 months,
tocilizumab significantly reduced disease
activity in rheumatoid arthritis patients. [65,
66]

It is possible that this drug could be

efficacious in NAFLD as well.
 In addition, as it has been established
that hypoadiponectemia is associated
with disease progression, administration
of adiponectin could potentially prevent
development of severe steatohepatitis
in patients with documented steatosis
and mild steatohepatitis.
No human studies of adiponectin
therapy have been performed to date.
 As our understanding of the pathophysiology
of NASH evolves, therapeutic targets for the
treatment of NASH emerge.
One such potential target is NF-B Selective
targeting of NF-B signaling of inflammatory
cells may be crucial in therapy design, as
NF-B may also act as a hepatocellular
survival factor, and its inhibition may
therefore lead to enhanced apoptosis and
compensatory hepatocyte proliferation,
favoring HCC development.
 A second selective target for NASH may be
modulation of the JNK pathway. Selective
blockade of JNK1 may be associated with
improved hepatic steatosis, insulin
resistance and inflammation; however,
blockade of JNK2 may exacerbate
hepatocellular injury.
Alternately, modulation of the gut flora or
inflammatory cytokines may prove
beneficial;[79] however, this has not been
reproduced in human studies. Further work is
needed to evaluate these and other potential
therapeutic targets for NASH.
Signs and symptoms
Asymptomatic in majority of cases
Fatigue (not correlated with liver injury severity)
RUQ pain or discomfort

Hepatomegaly (50%)
Cirrhosis and portal hypertension

Obesity
Hypertension
Cardiovascular or cerebrovascular diseases
PCOD
OSA
Lipodystrophy (in non obese)
 Diagnosis
NAFLD is a diagnosis of exclusion

-Alcoholic Hepatitis
-Drug induced Hepatitis (tamoxifen,
amiodarone)
-Viral Hepatitis
-Autoimmune Hepatitis
-Metabolic (Wilson and Hemochromatosis)
 The most challenging DDX is
alcoholic hepatitis

The histologic picture of both

conditions is similar

Consumption of alcohol less than 10

g/d in women and 20 g/d in men
 NAFLD is considered the hepatic
manifestation of insulin resistance
(metabolic) syndrome

Might be discovered incidentally in a check

up

laboratory investigations alone have

limitations for the diagnosis of NAFLD

Combination of imaging studies is necessary

for the estimation of liver steatosis
 Laboratory
Investigations
~ 80% in normal range

None of the currently used tests are

specific for the diagnosis of NAFLD

Aminotransferase elevation (< 4 times

ULN)

It does not correlate with the severity

of steatosis or fibrosis
 AST/ALT ratio (AAR) > 1 suggesting
cirrhosis

Higher AST , ALT levels and AAR are

associated with NASH

The pattern of aminotrasferase

elevation do not provide a distinction
between simple fatty liver and NASH.
 The differentiation between these
conditions can be made by a
histological approach.

The amount of liver fat can not be

assessed using liver function tests

The degree of fat infiltration might be

diagnosed using a variety of imaging
modalities
 Hyperbilirubinemia, hypoalbominemia
and abnormal prothrombin time are
present in cirrhosis
Hyperglycemia, hypertriglyceridemia,
hypercholestrolemia are related to
metabolic syndrome
HOMA (FIL X FPG / 22.5) is an estimate
of insulin resistance
A correlation between HOMA and
hepatic steatosis is demonstrated
Decreased apolipoprotein B is a rare
cause of familial NAFLD (with normal
LDL and HDL)
 Serum Ferritin elevation (20-50%)
Indicates liver fibrosis not iron overload
Increased transferrin saturation (5-10%)

Hyperuricemia is associated with cirrhosis

related deaths or hospitalizations

Alkaline phosphatase and GGT might be

increased in advanced disease and might
indicate the increased mortality

Autoantibodies might be present at low

titers especially in advanced disease
 Imaging studies

Ultrasonography

- Safe, easy to perform, and acceptable

- First line imaging
- Hyperechogenic liver parenchyma in
contrast to kidney or spleen
- Hepato-renal index
- Spleen longitudinal diameter (might
differentiate between NASH and simple fatty liver)
 Sensitivity is dependent on the degree of
steatosis (decreased in morbid obesity)

Specificity is high (~ 90%)

Can not differentiate steatosis from fibrosis

Contrast enhanced ultrasonography:

- The role of hepatic vein transit times (HVTT)

using a micro bubble contrast agent as a tracer
- Decrease signal intensity in NASH compared
with simple fatty liver due to reduced uptake of
levovist mediated by cell injury
 Doppler ultrasonography

Associated with hepatic parenchyma

perfusion abnormality

Hepatic vein Doppler pattern

Doppler perfusion index (DPI): a ratio

between hepatic arterial blood flow
and total liver blood flow
 Imaging
Patterns OF Fatty
Liver
Fatty liver is a common abnormality among
patients undergoing cross-sectional
imaging of the abdomen.
The image-based diagnosis of fatty liver
usually is straightforward, but fat
accumulation may be manifested with
unusual structural patterns that mimic
neoplastic, inflammatory, or vascular
conditions.
On these occasions, the imaging
appearance of the liver may cause
diagnostic confusion and lead to
unnecessary diagnostic tests and invasive
procedures.
 This Presentation provides a review of
the imaging appearances of fat
accumulation in the liver.
Herein we describe the different
structural patterns of fat accumulation
that may be seen at ultrasonography
(US), computed tomography (CT), and
magnetic resonance (MR) imaging.
We also discuss diagnostic pitfalls and
explain how to distinguish between fat
deposition and more ominous conditions
of the liver.
 Imaging-based
Diagnosis of Fatty Liver

Liver biopsy and histologic analysis is

considered
the diagnostic reference standard for the
Assessment of fatty liver.
However, fatty liver also can be diagnosed with
the use of cross sectional imaging
 Diagnosis at US
The echogenicity of the normal liver equals or minimally exceeds
that of the renal cortex or spleen.

Intrahepatic vessels are sharply demarcated, and posterior

aspect
of the liver are well depicted .

Fatty liver may be diagnosed if liver echogenicity exceeds that of

renal cortex and spleen and there is attenuation of the ultrasound
wave, loss of definition of the diaphragm, and poor delineation of
the intrahepatic architecture.

To avoid false-positive interpretations, fatty liver should not be

considered present if only one or two of these criteria are fulfilled.
Normal appearance of the liver at US. The
echogenicity of the liver is equal to or slightly
Greater than that of the renal cortex (rc).
 Diagnosis at CT
At unenhanced CT, the normal liver has slightly greater attenuation than the spleen
and blood, and intrahepatic vessels are visible as relatively hypoattenuated structures.

Fatty liver can be diagnosed if the attenuation of the liver is at least 10 HU less than
that of
the spleen or if the attenuation of the liver is less than 40 HU.

In severe cases of fatty liver, intrahepatic vessels may appear hyperattenuated

relative to
the fat containing liver tissue. Other CT criteria have been advocated.

At contrast materialenhanced CT, the comparison of liver and spleen attenuation

values is
not as reliable for the diagnosis of fatty liver, because differences between the
appearance
of the liver and that of the spleen depend on timing and technique and because there
is
overlap between normal and abnormal attenuation value Ranges .

Fatty liver can be diagnosed at contrast-enhanced CT if absolute attenuation is less

than 40
HU, but this threshold has limited sensitivity.
Normal appearance
of the liver at unenhanced
CT. The attenuation of the
liver (66 HU) is slightly
higher than that of the
spleen (56 HU), and
intrahepatic vessels (v)
appear hypoattenuated in
Comparison with the liver.
 Diagnosis at MR Imaging
Chemical shift gradient-echo (GRE) imaging with in-phase and opposed-phase
acquisitions is the most
widely used MR imaging technique for the assessment of fatty liver.
The signal intensity of the normal liver parenchyma is similar on inphase and opposed-
phase images ).
Fatty liver may be present if there is a signal intensity loss on opposed-phase images in
comparison with in
Phase images, and the amount of hepatic fat present can be quantified by assessing the
degree of signal
intensity loss.
Fat deposition also can be diagnosed by observing the signal intensity loss of liver on MR
images after the
Application of chemical fat saturation sequences, but this method is less sensitive than is
chemical shift GRE
imaging for the Detection of fatty liver.
On in-phase GRE images or T1- or T2- weighted echo-train spin-echo images, higher than
normal liver signal
intensity is suggestive of fat deposition, but this finding is neither sensitive nor specific
unless the
measurement technique is correctly calibrated.
Proton MR spectroscopy is the most accurate noninvasive method for the assessment of
fatty liver.
However, this method does not generate anatomic images.
. Normal appearance of the liver at MR imaging. Axial
opposed-phase (a) and axial in-phase (b) T1- weighted
GRE images
show similar signal intensity of the liver parenchyma.
 Accuracy for Detection
and Grading of Fat
Deposition
Reported sensitivities and specificities for detection of fatty liver
Deposition are 60%100% and 77%95% for US, 43%95% and 90%
for unenhanced CT, and 81% and 100% for chemical shift GRE MR
imaging.

A US-, CT-, and MR imagingbased diagnosis of fatty liver may be

unreliable in the presence of a liver fat content of less than 30% in wet
weight, although MR techniques that are currently in developmental
stages are likely to be reliable even in the presence of a low liver fat
content.

A few research groups have developed CT and MR techniques that

show promise for use in the quantitative grading of liver fat content
Patterns of Fat Deposition
 Diffuse Deposition

Diffuse fat deposition in the liver is the

most
Frequently encountered pattern.

Liver Involvement usually is homogeneous,

and
The image interpretation is straightforward
if
the rules specified earlier are applied.
Diffuse fat accumulation in the liver at US.
The echogenicity of the liver is greater than that of the
renal cortex (rc). Intrahepatic vessels are not well depicted.
The ultrasound beam is attenuated posteriorly,
and the diaphragm is poorly delineated.
Diffuse fat accumulation in the liver at unenhanced
CT. The attenuation of the liver (15 HU) is
markedly lower than that of the spleen (40 HU). Intrahepatic
vessels (v) also appear hyperattenuated in comparison
with the liver.
Diffuse fat accumulation in the liver at MR imaging.
Axial T1-weighted GRE images show a marked
decrease in the signal intensity of the liver on the opposed
phase image (a), compared with that on the in-phase
image (b).
 Focal Deposition and
Focal Sparing
Slightly less common patterns are focal fat deposition and diffuse fat deposition with focal sparing.

In these patterns, focal fat deposition or focal fat sparing characteristically occurs in specific areas (eg,
adjacent to the
falciform ligament or ligamentum venosum, in the porta hepatis, and in the gallbladder fossa) ; this
distribution is not
yet fully understood but has been attributed to variant venous circulation, such as anomalous gastric
venous drainage.

Focal fat deposition adjacent to insulinoma metastases also has been reported and is thought to be due
to local insulin
effects on hepatocyte triglyceride Synthesis and accumulation.

The diagnosis of focal fat deposition and focal sparing is more difficult than that of homogeneously
diffuse fat
deposition because imaging findings may resemble mass lesions.

Imaging findings suggestive of fatty pseudolesions rather than true masses include the following: fat
content, location
in areas characteristic of fat deposition or sparing, absence of a mass effect on vessels and other liver
structures, a
geographic configuration rather than a round or oval shape, poorly delineated margins, and contrast
enhancement that
is similar to or less than that of the normal liver Involved areas usually are relatively small, but
occasionally there may
be confluent heterogeneous regions of focal deposition and sparing that span large areas of the liver.
Focal fat accumulation in the liver at US.
Transverse image shows, adjacent to the left portal
vein, a geographically shaped area of high echogenicity
that represents accumulation of fat (f) in the falciform
ligament, with posterior acoustic attenuation
(arrows).
Focal fat accumulation in the liver at CT.
Axial contrast-enhanced image obtained during the
portal venous phase shows hypoattenuated regions of
focal fat accumulation adjacent to the falciform and
venous ligaments and in the porta hepatis, with no
evidence
of a mass effect.
. Diffuse fat accumulation with focal sparing at US and CT.
Transverse US image (a) and axial unenhanced
CT image (b) obtained at comparable levels show high
echogenicity and hypoattenuation, respectively,
features indicative of a diffuse accumulation of fat in the liver. Focal
sparing (fs) is manifested as a geographically
shaped area with relative hypoechogenicity in a and
hyperattenuation in b. The focal fatty pseudolesion
exerts no mass effect on the adjacent vessel (v in b).
 Multifocal Deposition
An uncommon pattern is multifocal fat deposition.
In this pattern, multiple fat foci are scattered in atypical locations throughout
the liver.
The foci may be round or oval and closely mimic true nodules.
Correct diagnosis is difficult, especially in patients with a known malignancy,
and requires the
Detection of microscopic fat within the lesion.
For this purpose, chemical shift GRE imaging is more reliable than CT or US.
Other clues indicative of multifocal fat deposition are lack of a mass effect,
stability in size
over time, and contrast enhancement similar to or less than that in the
surrounding liver
parenchyma.
In some cases, the foci of fat deposition have a confluent pattern.
Multifocal fat deposition may be observed within regenerative nodules in some
cirrhotic
patients; in these cases, the foci of fat accumulation correspond to the fat-
containing
regenerative nodules.
Except for fat deposition in regenerative cirrhotic nodules, the pathogenesis of
multifocal fat
Deposition In the liver is unknown.
. Multifocal fat accumulation in the liver at CT and MR
imaging in a 48-year-old woman with breast
cancer. (a) Unenhanced CT image shows multiple
hypoattenuated 1-cm nodules (arrows). (b, c) T1-
weighted GRE
MR images show nodules (arrows) with a signal intensity slightly
higher than that of the normal liver parenchyma on
the in-phase image (b) but with a signal intensity loss on the
opposed-phase image (c). The nodules were mistaken
for metastases at CT but were correctly diagnosed as multifocal
fat accumulation in the liver on the basis of MR findings.
Confluent foci of fat accumulation in the liver at MR
imaging. Axial T1-weighted MR images show a
large irregular region with a loss of signal intensity on the
opposed-phase image (contour outline in b), compared
with the signal intensity on the in-phase image (a). Note
the absence of a mass effect.
 Perivascular Deposition
A perivascular pattern of fat deposition in the liver has
been described
previously.
This pattern is characterized by halos of fat that surround
the hepatic
veins, the portal veins, or both hepatic and portal veins.
The configuration is tramlike or tubular for vessels with a
course in
the imaging plane and ringlike or round for vessels with a
course
perpendicular to the imaging plane.
An unequivocal signal intensity loss on opposed- phase
images in
comparison with that on in-phase images and the lack of a
mass effect
On the surrounded vessels are indicative of the diagnosis.
Perivenous fat accumulation in the liver at CT and MR imaging. (a, b) Axial
unenhanced CT image (a) and axial contrast-enhanced equilibrium phase CT image (b)
show
halos of hypoattenuation (40 HU) that closely surround the hepatic veins (arrows) and that are
more visible on b than on a. The rest of the liver has normal attenuation (63 HU at unenhanced
CT). (c, d) Coronal T1-weighted GRE MR images. Opposed-phase image (c) shows an
unequivocal
signal intensity loss in the regions that surround the hepatic veins (arrows), which appear
slightly hyperintense on the in-phase image (arrows in d). This feature helps confirm the
presence of fat accumulation.
The signal intensity of the normal liver parenchyma (*) in c differs from that in d because of
different window width and level settings.
. Periportal fat accumulation in a patient with a chronic hepatitis B
infection. Axial unenhanced (a) and contrast-enhanced (b) CT images from
the late portal venous phase show no morphologic evidence of cirrhosis.
Partially confluent halos with hypoattenuation (40 HU at unenhanced CT)
indicative of fat deposition closely surround the portal venous segments
(arrows in b), with regions of less marked fat deposition bordering the
Periportal halos and in the periphery of the liver.
 Subcapsular Deposition

In patients with renal failure and insulin-dependent diabetes, insulin

may be
added to the peritoneal dialysate during kidney dialysis.
This route of insulin administration exposes subcapsular hepatocytes to
a
higher concentration of insulin than that to which the remainder of the
liver
is exposed.
Since insulin promotes the esterification of free fatty acids into
triglycerides,
the peritoneal administration of insulin results in a subcapsular pattern
of fat
deposition, which may be manifested as discrete fat nodules or a
confluent
Peripheral region of fat.
A review of the patients clinical history in conjunction with the imaging
findings should facilitate correct diagnosis.
 Differential Diagnosis

The diagnosis of diffuse fat deposition

in the
Liver tends to be straightforward.
The differential diagnosis of other
patterns of fat
deposition is discussed below.
 Primary Lesions and
Hypervascular Metastases
In general, the differentiation of focal or multifocal fat accumulations from
primary
hepatic lesions (eg, hepatocellular carcinoma, hepatic adenoma, and focal
nodular
hyperplasia) or from hypervascular metastases in the liver is not problematic
because
these lesions exert a mass effect, tend to show vivid or heterogeneous
enhancement
after contrast agent administration, and may contain areas of necrosis or
hemorrhage

Infiltrative hepatocellular carcinoma is a notable exception; on CT images, this

tumor
may exert a minimal mass effect, show little evidence of necrosis, show the
same
degree of enhancement as the normal liver parenchyma, and closely resemble
heterogeneous fat deposition.
In our experience, correct diagnosis is usually possible with MR imaging, but the
Correlation of imaging findings with serum biomarkers may be helpful.
. Differentiation of adenoma from fatty
deposition in the liver in a woman with
a long history of oral contraceptive
use. (a, b) Axial opposed-phase (a) and in-
phase (b) T1-weighted GRE images
show diffuse fat deposition
in the liver, indicated by areas with a signal
intensity loss on a in comparison with b.
Two round masses in the
left lobe of the liver (arrows in a) resemble
nodular areas of sparing. (c, d) Three-
dimensional T1-weighted GRE
images obtained before (c) and during (d) the
hepatic arterial phase show
enhancement of the masses (arrows in
c
and d) after the administration of a
gadolinium-based contrast agent. The
rounded shape of the lesions, as well
as
their location, which is atypical for regions of
fatty liver sparing, are important clues
suggestive of tumors. The two
masses remained stable in size for several years
and most likely are adenomas.
Differentiation of hepatocellular carcinoma from fatty deposition in
the liver. Axial unenhanced (a) and
axial contrast-enhanced (b) CT images obtained during the portal
venous phase show a nodular liver contour suggestive
of cirrhosis, as well as large gastric varices (arrowheads in b). In b, the right
lobe of the liver appears hypoattenuated
in comparison with the left lobe, a finding that could be misinterpreted as
evidence of regional fatty liver deposition;
however, the mass effect with bulging of the anterolateral border of the right
liver lobe (arrow), the mosaic
enhancement pattern, and the thrombus (t) in the left main portal vein are
strongly suggestive of an infiltrative malignancy.
This is a case of infiltrative hepatocellular carcinoma.
. Differentiation of metastases from fatty
liver deposition in a woman
undergoing chemotherapy for
breast cancer. Axial unenhanced (a, c) and
contrast-enhanced (b, d) CT images (c
and d at a higher level than a and
b) show diffuse fatty deposition in the
liver and a geographic pseudolesion
at the porta hepatis (arrows in a and
b), a
finding that represents focal sparing. Multiple
round lesions (arrows in c and d), which
are more vividly enhanced
than the liver parenchyma, represent
metastases. If unenhanced CT had not
been performed, the region of focal sparing
on the contrast-enhanced images may have
been mistaken for an enhanced
hypervascular tumor.
 Hypovascular
Metastases and Lymphoma
The differentiation of focal or multifocal fat
Deposition from hypovascular metastases and
Lymphoma in the liver may be difficult.
However, the clinical manifestations and imaging
features such as lesion morphology, location, and
Microscopic fat content usually permit a correct
diagnosis.
Chemical shift GRE imaging may be necessary to
assess the amount of intralesional fat.
 Perfusion Anomalies

Perfusion anomalies may resemble fat

Deposition morphologically but are visible
only
during the arterial and portal venous
phases
after contrast agent administration.
They are not detectable on unenhanced
images
or equilibrium phase images.
. Differentiation of superior vena cava syndrome from fatty liver
deposition. Axial contrast-enhanced CT
images obtained during the arterial phase at the level of the liver (a) and the
upper mediastinum (b) show a hyperattenuated
geographic pseudolesion (white arrow in a) in segment IV, at the anterior
border of the liver, and obstruction
of the superior vena cava by a thoracic mass (arrow in b). With regard to
morphologic features, the pseudolesion
resembles a focal area of fatty liver deposition or sparing, but its marked
enhancement on early phase images helps
confirm that the lesion represents a perfusion abnormalityin this case, one
associated with superior vena cava syndrome.
Note the large systemic collateral veins (arrowheads in a and b) and the
collateral draining vessel in segment
IV (black arrow in a).
. Differentiation of hepatic venous
congestion
(nutmeg liver) from fatty liver deposition.
Axial
contrast-enhanced CT image obtained at the
level of
the liver during the hepatic arterial phase
shows irregular
areas with low attenuation in the nutmeg
pattern,
features that could be mistaken for multifocal
or geographic
fatty liver deposition. However, this pattern
was visible only on arterial phase images and
early portal
venous phase images and not on unenhanced
images
or images obtained in later phases. A
pericardial
effusion also was present. Nutmeg liver is a
perfusion
abnormality that is related to hepatic venous
congestion
from cardiac disease or other causes.
Differentiation of transient hepatic attenuation
difference from fatty liver deposition. Axial unenhanced
CT image (a) and axial contrast-enhanced late
arterial phase (b) and portal venous phase (c) CT images
obtained at the same level in the liver. A wedgeshaped
peripheral hyperattenuated pseudolesion (white
arrows in b) with straight borders appears on the arterial
phase image but not in a or c. The wedgelike shape,
straight borders, peripheral location, and transient enhancement
of the lesion are suggestive of a transient difference
in hepatic attenuation rather than a mass or a fat
deposition abnormality. Note the arterialized flow in a
feeding branch of the portal vein (black arrow in b), a
finding that represents an iatrogenic postbiopsy arteriovenous
fistula.
 Periportal Abnormalities

The US- and CT-based differential diagnosis of periportal fat

deposition
is broad and includes edema, inflammation, hemorrhage, and
Lymphatic dilatation.
Edema, inflammation, and lymphatic dilatation tend to affect the
Portal triads symmetrically.
Hemorrhage characteristically involves the portal triads
asymmetrically
and may be associated with laceration or other signs of injury.
None of these entities are associated with microscopic fat.
Thus, if chemical shift imaging is performed, a signal intensity
loss of
Perivascular tissue on opposed-phase images permits the correct
diagnosis of fat deposition.
. Differentiation of periportal inflammation from fatty liver
deposition. Axial contrast-enhanced CT images
obtained during the portal venous phase (a) and the equilibrium phase
(b). The hypoattenuated halos (arrows)
that surround the portal venous tracts in a could be misinterpreted as
perivascular fat accumulation, but they retain
contrast material and appear hyperattenuated in b. Retention of contrast
material on delayed images is suggestive of
periportal inflammation with transcapillary leakage of the contrast agent into
inflamed periportal tissue; perivascular
fat deposition would not be expected to retain contrast material. The
attenuation of periportal halos should be measured
on unenhanced or delayed phase images, if available, to help differentiate
periportal fat deposition from edema
or inflammation.
Pitfalls
 Fat-containing Primary
Tumors
Hepatic adenomas, hepatocellular carcinomas,
and, rarely, focal nodular hyperplasias may have
microscopic fat content.
Hence, a finding of intralesional fat does not help
exclude these entities, and clinical findings as well
as imaging features such as morphologic structure,
mass effect, and enhancement characteristics must
Be considered .
Differentiation of a fat-containing tumor from fat
deposition in the liver. Coronal T1-
weighted GRE MR images show a large mass (arrows)
with lower signal intensity on the opposed-phase
image (a) than on the in-phase image (b), a
feature indicative of fat. Vivid arterial
enhancement (not
shown), the round rather than geographic shape of the
lesion, and the mass effect are indicative of a
space-occupying lesion rather than fat deposition. The
lesion was an exophytic hepatic adenoma.
 Low-Attenuation Lesions
A threshold attenuation value of less than 40 HU
in the liver at CT is not specific for a finding of fat
deposition.
For example, ischemic or mucinous
metastases or abscesses may manifest low
Attenuation values.
However, a review of the clinical manifestations
and laboratory findings in conjunction with other
CT features should lead to the correct diagnosis. If
necessary, chemical shift GRE imaging can be
performed.
. Differentiation of metastases from fat deposition in the liver. Axial portal
venous phase contrast-enhanced
CT images at the level of the right hepatic vein (rhv) (a) and the pancreatic head (b)
show innumerable hypoattenuated
lesions throughout the liver. Most of the lesions are round or oval, but the largest (m in
b) has a geographic
configuration. Because of their low attenuation (40 HU), the lesions might be mistaken
for multifocal fat
deposition; however, the mass effect of the lesions, which produces bulging of the liver
surface (arrow) and compression
of the right hepatic vein, as well as the multiplicity of lesions, their predominant round
or oval shape, the thrombus
(t in b) in the superior mesenteric vein, and numerous heterogeneous lymph
nodes (n in b), are suggestive of malignancy.
The lesions were identified as hematogenous metastases from pancreatic
adenocarcinoma.
PET scanning using FDG is an imaging
technique that displays glucose uptake by
cells and therefore local metabolic activity.
This metabolic activity can be estimated
noninvasively by a semiquantitative method,
the standardized uptake value (SUV), by
taking into account factors such as the
injected
activity and patient weight (or lean body
mass) and the time after injection.
Regions of interest were placed on liver (large circles) and
spleen (small circles) as well as on mediastinum
(not shown) on both CT (left) and PET (right) to calculate
CT attenuation values and standardized uptake values,
respectively. In this case, mean hepatic attenuation was
13 HU and mean splenic attenuation was 62 HU .
AD, Estimated FF maps by using the four image analysis methods, E, multiecho MR spectra,
and FH, accompanying T2* maps in 18-year-old man with
biopsy-confirmed NAFLD. The ROIs (circles) on imaging and spectroscopic voxel have
been colocalized. The spectroscopic FF was 24.2% in E. Imaging FFs were 21.8%
in A, 24.9% in B, 20.1% in C, and 24.9% in D. The estimated T2* values were 19.2 msec
in F, 28.8 msec in G, and 24.7 msec in H. The triple-echo and multiinterference
methods show higher quantification accuracy than the dual-echo and multiecho
methods. TEecho time.
 CT scan or MRI techniques are expensive
When the steatosis is focal
Evaluation of subcutaneous adipose
tissue
A new MRI technique:
- Proton magnetic resonance spectroscopy
(MRS)
- Measures the fat proton fraction and hepatic
levels (HTGC)
- HTGC > 5% is the diagnostic level for
steatosis
- More accurate than previous modalities for
the diagnosis of NAFLD
 Non of the imaging modalities are
able to differentiate NASH from
simple fatty liver disease

Liver biopsy is the gold standard for

the definite assessment of steatosis,
necroinflammation, and fibrosis
 Liver biopsy
The gold standard for both diagnosis & prognosis
Is not necessary in a typical patient
Liver Bx is indicated in:
- High ferritin with HFE mutations
- Positive autoantibodies
- The use of medications associated with drug induced
liver injury
- Accurate staging of disease in patients with several
risk factors

limitations:
Invasive
Risk of complications
Sampling error
Interobserver variability
 NAFLD activity score
(NAS)
Findings:
Macrovesicular steatosis
Lobular inflammation
Hepatocyte balooning
Perisinusoidal fibrosis
__________________________________________________

Histologic scoring system

Score 5 or greater is consistent with NASH

Score 2 or less is consistent with simple fatty liver

Biomarkers for assessment
of
steatohepatitis and fibrosis
C reactive protein: independent risk factor for the progression of
NAFLD
Plasma Pentraxin 3: risk factor for the progression of
NAFLD
IL6: indicate inflammmatory activity and the degree of fibrosis
TNF : risk factor for the progression of NAFLD
Cytokeratin 18: marker of hepatic appoptosis
Polypeptide specific antigen: released during
appoptosis
Endothelin 1: is a mediator of fibrosis
Adiponectin: is lower in NASH
Oxidative stress biomarkers ? (superoxide desmutase, glutathione
peroxidase, Thioredoxin)
Hyaluronic acid ?
Type 4 collagen 7S domain ?
Laminin ?
Panel of markers/Scoring
systems
Identification of steatosis
NAFLD liver fat score includes:
- Presence of DM
- Fasting serum insulin
- AST
- AST/ALT ratio
Fatty liver index includes:
- BMI
- Waist circumference
- Triglyceride
- GGT
Visceral adiposity index includes:
- BMI
- Waist circumference
- Triglyceride
- HDL
Panel of markers/Scoring
systems
Identification of
inflammation
NASH test includes:
- Total Bilirubin
- GGT
- 2 macroglobulin
- Apolipoprotein A1
- Haptoglobulin
- ALT
HAIR test includes:
- Hypertension
- ALT
- Insulin resistance
Parkler model includes:
- age
- gender
- AST
- BMI
- AST/ALT ratio
- Hyaluronic acid
 Panel of markers/Scoring
systems
AST/ALT Identification
ratio (AAR) of fibrosis
APRI test: uses platelet count and AST
FIB 4 index utilizes age, AST, ALT, and
platelet count
NAFLD fibrosis score includes:
- BMI
- Presence of DM
- Albumin
Fibrotest (BioPredictive) tacking into account:
- GGT
- Haptoglobulin
- Bilirubin
- Apolipoprotein A1
- 2 macroglobulin
Fibro Spect tacking into account:
- Hyaluronic acid
- Tissue inhibited matrix metalloproteinase
- Inhibitor1
- 2 macroglobulin
 Presence of DM (type2), obesity,
hypertension, and aminotrasferase
elevation are markers of fibrosis

The utility of these tests are limited in

cases with advanced fibrosis

The best result for non invasive

staging will be achieved by combining
a clinical/biochemical scoring system
with elastography
 Fibroscan
Transient elastography that evaluates
liver stiffness using pulse-echo
ultrasound
Non invasive
More sensitive than serologic markers
Evaluates a larger part of liver
Main weakness is interference with by
steatosis with wave velocity
Might be unreliable in obese
 In patients with normal ALT and liver
stiffness value <6.0 kPa, no treatment is
required, whereas those with liver
stiffness values >9.0 kPa should be
considered for treatment.
In patients with ALT 1-5x ULN, those
patients with liver stiffness value <7.5
kPa can be observed, whereas those with
value >12.0kPa should be considered for
treatment.
In patients with liver stiffness values
outside these criteria, liver biopsy should
be considered.
 Acoustic radiation force
impulse
(ARFI)
Sonoelastography that evaluates liver
elasticity
Alternative to Fibroscan
Utilizes acoustic waves to interogate the
mechanical stiffness of liver
Can be used during standard US examination
of liver
Diagnosis of significant fibrosis
__________________________________________
Another modality is magnetic resonance
elastography with higher diagnostic
accuracy for fibrosis staging especially in
obese
 Total over night salivary
caffeine assessment test
A marker of systemic caffeine
clearance

It shows liver function in

compensated cirrhosis
 Dynamic breath
tests
C-methacetin breath test (MBT) and
C-octanoate breath test (OBT)
evaluate cytochrome P450 activity
and mitochondrial dysfunction
Both increase oxidative stress that is
implicated in NASH
MBT predict extent of liver fibrosis
OBT distinguish between simple fatty
liver and NASH
Non-alcoholic fatty
liver
disease
the hepatic
consequence
of the
metabolic syndrome
 Causes of Non-Alcoholic Fatty Liver
Disease

Several risk factors increase the likelihood of a person developing NAFLD.

Diabetes

Excess weight and obesity

High levels of fat in the blood (also known as hyperlipidemia)

Abdominal surgery

Taking certain medications such as corticosteroids, antiretrovirals, and

immune-suppressing medications

Medical conditions: Rapid weight loss and malnutrition

There is evidence to suggest the presence of an association between

metabolic syndrome( insulin resistance) and the development of
NAFLD
What
Mets wasis metabolic
originally defined as asyndrome?
cluster of
interconnected factors that directly increase the risk
of:
coronary heart disease (CHD)

other forms of cardiovascular atherosclerotic diseases

(CVD)
diabetes mellitus type 2 (DMT2).
First termed syndrome X in 1988
Insulin resistance syndrome; Syndrome x, dysmetabolic
stroke
syndrome
Its main components are
dyslipidemia

elevation of arterial blood pressure (BP)

dysregulated glucose homeostasis

abdominal obesity

insulin resistance (IR)

Adverse Health Effects of Metabolic
Syndrome
The two major metabolic syndrome health effects are:
type 2 diabetes and cardiovascular disease
Common complications of metabolic syndrome include:

Eye, kidney, cardiovascular, skin, and nerve problems.

Fatty liver - Disease .
Sleep apnea
Chronic kidney disease (CKD)
Polycystic ovarian syndrome (PCOS)

Recent research has also linked age-related memory loss

(dementia) to metabolic syndrome as well as some types of
cancer, such as colon cancer.
 Metabolic syndrome is increasing in prevalence, paralleling
an increasing epidemic of obesity. .
The World Health Organization estimates 25% of adults
world-wide are affected by metabolic syndrome
Epidemiology of Metabolic
syndrome
The prevalence of MetS varies and depends on:

the criteria used in different definition

the composition (sex, age, race and ethnicity) of

In the United States, more than one fourth of the population
the population
meets diagnostic studied
criteria for Mets.
More than 45% of adult Americans over age 50 are affected
.
Approximately one fourth of the adult European population
is
estimated to have mets.

similar prevalence in Latin America.

Asian countries(China, Japan, and Korea): range from 8-13%

in men and 2-18% in women .
 Etiology and
causes
The exact cause of metabolic syndrome is not known.

Many features of the metabolic syndrome are associated

with insulin resistance.

Insulin resistance results from inherited and acquired influences

o Hereditary causes include :

mutations of insulin receptor, glucose transporter, and signaling
proteins, although the common forms are largely unidentified.

o Acquired causes include physical inactivity, diet, medications,

hyperglycemia (glucose toxicity), increased free fatty acids, and the
aging process.
Metabolic Syndrome
Risk Factors
Major Metabolic Syndrome Risk Factors

The major risks for metabolic syndrome include the key features of a

large waist line

abnormal cholesterol levels,

hypertension

high fasting blood glucose

Metabolic Syndrome
Risk Factors
Non-Modifiable Metabolic Syndrome Risk Factors

Non-modifiable risk factors are those you cant change,

including
Age: less than 10 percent of people in their 20s
and 40 percent of people in their 60s
warning signs of metabolic syndrome can
appear in childhood.
Race. Hispanics and Asians seem to be at
greater risk of metabolic syndrome.

Genetic factors :
family history of metabolic syndrome ,DM,PCO
Metabolic Syndrome
Risk Factors
Diseases That Increase Risk of
Developing Metabolic Syndrome

History of diabetes

type 2 diabetes
( 75%of DM)
gestational diabetes

Other diseases

High blood pressure,

Cardiovascular disease(37%,especialy women)
CHD(50%)
Polycystic ovary syndrome
Fatty liver
 Signs
Extra weight around your waist
(central or abdominal obesity)
Diagnostic criteria for
metabolic syndrome
(National Cholesterol Education Programs Adult treatment Panel II(ATPIII))
Diagnostic criteria for
metabolic syndrome
World Health Organization(WHO)
Pathophysiology of the metabolic
syndrome
Molecular mechanisms of insulin action and insulin resistance

Proposed mechanisms center around 3 themes:

effects of mild to moderate hyperglycemia
effects of compensatory hyperinsulinemia
effects of unbalanced pathways of insulin
action
Dysfunctional energy storage and obesity
 Dysfunctional Energy Balance
Triglycerides and fatty acids
(molecules of energy storage and
utilization)

Triglyceride stored physiologically in

small peripheral adipocytes

Energy In > Energy

Out

With obesity, excess triglyceride goes to

hepatocytes (fatty liver),skeletal myocytes,
visceral adipocytes, abnormal large
peripheral adipocytes

Excess triglyceride leads to insulin resistance

in these cells and metabolic syndrome with
increased cardiovascular disease
insulin resistance

Insulin resistance

Compensatory hyper
insulinemia to
maintain euglycemia

Obesity
Dyslipidemia due to high
fatty acid flux

Metabolic syndrome

Increased atherosclerosis and

cardiovascular disease
Pathophysiology of NAFLD
No hepatic processes

Lifestyle
( decreased physical activity and current patterns of food consumption
are Involved in the epidemics of obesity and type 2 diabetes mellitus)

Fat mass
(Increased fat mass is an essential pathophysiologic factor in NASH)

Fat distribution
(increased risk for NASH is associated with central obesity and
increased lipolysis of visceral tissue and an increased supply of
FFAs to the liver )

Insulin resistance

Hepatic processes
 Insulin resistance
Insulin resistance is a state in which a given
concentration of insulin produces a less-than-expected
biological effect.

Insulin resistance has also been arbitrarily defined as the

requirement of 200 or more units of insulin per day to
attain glycemic control and to prevent ketosis.

high levels of insulin in the blood as a marker of

the disease rather than a cause.

It is estimated that 70 to 80 million Americans

have the combination of diseases caused by
insulin resistance or metabolic syndrome.
presentation of insulin resistance
The presentation of insulin resistance depends on the type and stage
of the insulin-resistant state.
Most patients have 1 or more clinical features of the insulin
resistant state.
Many patients do not develop overt diabetes despite extreme
insulin resistance.
Other patients present with cases of severe hyperglycemia that
require large quantities of insulin (>200 units)

Patients may present with the following:

Metabolic syndrome (syndrome X)
patient may be asymptomatic in spite of the presence of some, or
even most, of the components of insulin resistance syndrome

Obesity (most common cause of insulin resistance) or

history or excessive body weight
Type 2 diabetes mellitus
(chronic or acute [during severe decompensation] )

A diagnosis of IGT
 History of biochemical abnormalities: dyslipidemia,
detected during routine screening or workup for a
cardiovascular disease
History of hypertension

Symptoms of coronary artery disease

Symptoms related to other macrovascular disease

(eg, stroke, peripheral vascular disease)

Microvascular angina

Combination of hyperglycemia and virilization

Type A, affects young women, is characterized by severe

hyperinsulinemia, present with obesity and features of
hyperandrogenism.

Polycystic ovary syndrome (PCOS)

Type B syndrome presentation of hypoglycemia

(sweating, tremulousness, irritability, consciousness).
Hypoglycemia results from interaction between
insulinomimetic antibodies and the insulin receptor
 Approach Considerations
In clinical practice, no single laboratory test is used to
diagnose insulin resistance syndrome.

Diagnosis is based on clinical findings corroborated

with laboratory tests.

Individual patients are screened based on the presence

of comorbid conditions.
 WORK UP
Lab Studies :

Routine laboratory measurements in the evaluation of patients

with insulin resistance syndrome include the following:
Plasma glucose level

Fasting insulin level

A measure of the degree of insulin resistance

Insulin resistance
May also be associated with hypoglycemia (autoimmune conditions)

Lipid profile

Electrolyte levels
BUN , creatinine, and uric acid levels)
hyperuricemia is common and is a component of the metabolic syndrome.

Urinanalysis
Microalbuminuria is a marker of endothelial dysfunction
 Homocysteine (H[e])
An elevated level is a risk factor for atherosclerosis,
which predicts macrovascular disease.
are regulated by insulin.

Plasminogen activator inhibitor (PAI)-1

HOMA-IR
fasting glucose (mmol/L) X fasting insulin (U/L) / 22.5).
A value greater than 2 indicates insulin resistance.
 Other Tests:

cardiac tests include echocardiography and stress

testing

A risk-assessment calculator,
based on data from the Framingham Heart Study for estimating
10-year cardiovascular risk, is available. This calculator
estimates the 10-year risk for hard coronary heart disease
outcomes (myocardial infarction and coronary death). The
tool is designed to estimate risk in adults aged 20 years and
older who do not have heart disease or diabetes.

For patients with insulin resistance without overt diabetes,

the metabolic syndrome criteria for cardiovascular risk
stratification are less sensitive than those of the
Framingham Risk Score, which takes into account age, total
cholesterol, tobacco use, HDL-C, and blood pressure, but
not diabetes.
Non-alcoholic fatty liver disease
and metabolic syndrome
Metabolic syndrome is highly prevalent among patients
with NAFLD in multiple populations.

NAFLD can be considered as the hepatic

representation of the Metabolic syndrome

The development of NAFLD is strongly associated with

the metabolic syndrome as reflected by the fact that:

Approximately 90% of the patients with NAFLD have

more than one feature of Mtes

And 33% have 3 or more criteria

With the addition of each of the components of the Mtes to

NFALD increase risk of steatosis
 NAFLD associated with

Obesity (60-95%)

Type2 DM (28-50%)

Dyslipidemia(27-92%)

lipotoxicity plays a predominant role in the pathophysiology

of both entities .

It leads to accumulation of triglycerides in liver as a result of

imbalance among the

Uptake
Synthesis
Export
oxidation of fatty acids
 Developing NASH increase with the severity of obesity.

There is a universal association between NASH and insulin

resistance regardless of body mass index, suggesting that:
Insulin resistance is central pathogenesis of NASH

It is liked to increased oxidative stress and cell death in the liver,

potentiating the development of liver fibrosis and progression to
NASH.
Genetic and environmental factors
associated with
non-alcoholic fatty liver disease
development
and progression
The development of NAFLD is strongly linked to obesity and
insulin resistance.

There are obviously multiple factors determining NAFLD

development and progression:
genetic
environmental

Initial evidence for a genetic component to NAFLD comes from

familial clustering studies
the ethnic variation in NAFLD prevalence

adiponutrin found to be associated with high and low

amounts of hepatic fat in Hispanics and African-Americans.
 important environmental factors that determine risk in NAFLD:
Nutrition
physical activity

Excess food intake and lack of exercise weight gain

progression of liver fibrosis in NAFLD

Specific dietary antagonistic roles in the

development and progression of NAFLD

In view of the role of oxidative stress in NAFLD

pathogenesis several studies have examined antioxidant
supplementation as a therapeutic intervention

additional environmental factor in NAFLD pathogenesis:

Small intestinal bacterial overgrowth
as probiotics could have a beneficial effect.

small human study treatment with antibiotics has been

shown to result in an increase in fasting insulin levels.
 obesity
ENVIROMENTAL
Dietary factors
Food intake
Physical activity Insulin
Gut microflora resistance

NAFLD

Genetic hyperlipidem
Oxidative stress ia
Immune related
Metabolic
inflammatio
n
 Non-alcoholic fatty liver disease
and CVD risk
In the last 5 years NAFLD has emerged as an independent risk
factor for CVD.

Several studies have observed

increased carotid intima-media thickness
carotid plaques in patients with NAFLD,
including children

a systematic review has found that carotid plaques are two

to three times more likely to be observed in patients with
NAFLD

intima-media thickness is strongly associated with NAFLD.

diagnosed by ultrasonography
 increased risk for CVD in NAFLD is independent of
conventional risk factors and components of the metabolic
syndrome.
elevated liver enzymes are also associated
with increased risk for CVD.

As the treatment of NAFLD involves correcting the

same metabolic factors as those involved in CVD, it is
prudent that all patients with NAFLD be evaluated for
early atherosclerosis.

Likewise, patients presenting with the metabolic syndrome or

a high Framingham risk score(118) should be evaluated for
the presence of NAFLD.
Link between Fatty Liver and
Kidney Diseases
Scientists publishing in the "Journal of the American Society
of Nephrology" say the increase in CKD in the United States
is linked to NALFD, especially among diabetics.

People who have a fatty liver condition have a 69 percent

greater risk for CKD than people who don't have fatty liver.

Fatty liver might release substances that promote

inflammation and contribute to kidney damage

liver enzyme that is strongly associated with risk of HTN

seems to be regulated by the distribution of your body fat.
Obesity is a common factor in the diagnosis of both fatty
liver and kidney problems

Treating fatty liver disease will ultimately prevent

progression to chronic kidney disease
 Treatment
The diagnosis and treatment of metabolic
syndrome is public health problem.

The syndrome is associated with an increased morbidity

and mortality mainly due to cardiovascular diseases.

The treatment of patients with NAFLD should include the

identification and treatment of the associated metabolic
abnormalities to ameliorate the cardiovascular risk and to
improve NAFLD.

As the treatment of NAFLD involves correcting

the
same metabolic factors as those involved in
CVD, it is
prudent that all patients with NAFLD be
evaluated for
early atherosclerosis.
Treatment
 Practical recommendations for
lifestyle modification
Exercise goal is 3045 minutes of activities that increase heart rate at
least three times weekly
Walking is a good start for people completely sedentary, but the goal
is to move onto aerobic activities as fitness improves
Vary exercise activities over time
Seek a trainer to guide develop and plan to maintain consistency
Do not think of weight loss as the goal of exercise; the goal of exercise
is to change the bodys metabolism and improve the sense of well-
being
Limit screen time in front of televisions, computers, and video
games
Focus on healthy eating, not dieting
Eat a protein-containing breakfast daily (eg, meat, cheese, eggs,
yoghurt)
Avoid fasting
Eliminate sugar-sweetened beverages (sodas, sweetened tea, and so
forth)
Avoid trans-fats, including foods labeled as trans-fat free but
containing hydrogenated or
partially hydrogenated vegetable oil
 IMPACT OF EXERCISE ON
INSULIN RESISTANCE AND
NASH
Although the theoretical basis is strong, only
limited data are available to support the
recommendation of exercise as an important
lifestyle change for patients with NASH
Visceral adiposity did seem to be a major
determinant of the correlation between fitness or
exercise habits and NAFLD, perhaps because
visceral fat is a major source of fatty acids
delivered to the liver in obesity
The currently available data support
recommending exercise, but it would be
reassuring to have well-conducted trials to
corroborate findings in small and uncontrolled
observational studies
 DEFECTS IN MUSCLE THAT
COULD IMPAIR THE RESPONSE
TO EXERCISE
A number of studies provide evidence that there
may be some people who are not able to build
muscle and increase aerobic exercise
capacity,even with the most earnest attempts to
exercise.
Much of this investigation is now focusing on
mitochondrial biogenesis and function.
Petersen and coworkers evaluated lean, but
insulin-resistant, offspring of diabetics and found
impaired mitochondrial function, raising the
possibility that genetic factors controlling
mitochondrial oxidative phosphorylation and ATP
production predispose to insulin resistance and
the risk of developing diabetes.
 IMPACT OF COMBINED EXERCISE
ANDWEIGHT LOSS ON INSULIN
RESISTANCE,NAFLD, AND NASH
Studies have also shown that losing relatively small
amounts of weight in the range of 5% to 10%
confers significant benefits in terms of NAFLD and
NASH
The prospective cohort study of over 50,000 nurses
that examined risk factors for insulin resistance and
its complications over 6 years demonstrated that
time watching television was strongly associated
with an increased risk of developing diabetes and
walking briskly for 1 hour daily reduced the risk of
developing obesity by 24% and diabetes by 34%
A large population intervention study in Germany
found that exercise and caloric restriction led to
improved liver fat content after 9 months
 SPECIFIC EATING HABITS AND
NASH
Two common food components
deserve special attention: high
fructose corn syrup (HFCS) and
industrial trans-fats.
 HFCS
Soft drinksare typically sweetened with a
solution of 55% fructose, 41% glucose,
and 4% residual complex carbohydrates.
HFCS has desirable properties for its
sweetness, its ease of handling in bulk,
and its cost competitiveness compared
with other sweeteners.Its regular
consumption in large amounts has been
associated with the development of
insulin resistance and NAFLD
 HFCS
At around 40 g of carbohydrate per 12-oz serving, a
typical can of cola contains the amount of sugar in
about 10 sugar cubes.
Such comparisons can be useful in discussing
dietary habits with patients and especially parents of
pediatric patients.
High-dose fructose challenges the liver metabolically
by depleting hepatic energy reserves because of the
rapid first pass uptake of fructose by the liver and
phosphorylation by phosphofructokinase.
Fructose also impairs normal satiety mechanisms, a
response that could be particularly problematic
when soft drinks are consumed with excessively
portioned meals.
 Trans-fats
Industrial trans-fats (ITF) found in partially
hydrogenated vegetable oils (vegetable
shortening) comprise a relatively new addition to
the Western diet
Only a few studies have examined the potential
role of dietary ITF as a cause of liver injury, and
these suggest that ITF could be a significant but
overlooked contributor to the current epidemic of
NASH.
One study reported a rise in mean ALT from 22 U/L
to 97 U/L in just 2 weeks in healthy medical
students who ate at least two meals of fast food
daily
 Trans-fats
Drug Administration labeling standards
allow foods with less than 0.5 g trans-fats
per serving to be labeled as zero trans-
fats, editorialists have pointed out that by
consuming four to five small, industry-
defined, serving sizes of zero trans-fat
food, ITF consumption can easily exceed
the recommended daily limit of 2 g.
Restaurant food also continues to be a
major source of trans-fats, especially at a
number of large national chain restaurants
 PRACTICAL STRATEGIES FOR
ACHIEVING LIFESTYLE MODIFICATIONS
IN PATIENTS WITH NASH
When discussing physical activity with patients, the
discussion should focus on impediments to increasing
physical activity and finding ways for patients to
incorporate exercise into their lives on a regular basis
indefinitely.
It is often helpful to separate the benefits of exercise
from weight loss. Because exercise has its own benefits
in terms of a sense of well-being and improved insulin
responsiveness, being discouraged about lack of weight
loss should not be a reason to quit.
To most, the idea of dieting to achieve weight loss has
many negative connotations because of prior failures
and typically invokes the strongly counterproductive
psychology of denial. Instead of discussing diets and
dieting, the focus needs to be on healthy eating habits,
or the positive side of changes in eating habits
 HCC, diet and metabolic
factors
A diet rich that is in polyunsaturated
fatty acids and, possibly, B-carotene
could reduce the risk of HCC, and
high dietary GL is associated with an
increased risk independently of
cirrhosis or diabetes.
 Diet only interventions
Six using low-to-moderate fat/moderate-to-high
carbohydrate energy restricted diets, one of which
also specifically restricted iron intake
Three groups were given low carbohydrate ketogenic
diets
Two high protein diets
Two studies employed biopsy ,but only one at follow-
up
The other used ALT and AST at follow-up
Three used 1H-MRS ,two used CT ,three
studies relied on ALT and AST .Only two studies had a
Control group ,in one the control group were those
with
low adherence to the protocol
 Diet only interventions
Interventions lasted 16 months and achieved mean body
weight reductions of 414%.
All studies using biopsy or imaging
techniques to estimate IHTAG reported reductions.
The three studies using 1H-MRS reported absolute reductions of 410%
and relative reductions of 4281%.
The only study to do a post intervention biopsy (n = 5) reported reduced
inflammation and
trend towards reduced fibrosis (p = 0.07), as well as the reduction
in steatosis, following a ketogenic diet and a mean weight reduction
of 14%
Five out of seven studies reporting liver enzymes showed reductions and
one showed no change.
The study that found an increase in ALT and AST, but only in women,
suggested
this might have been due to the analysis being done before
weight had stabilised .
Five out of six studies reporting glucose control/insulin sensitivity noted
improvements.
 Exercise only interventions
Two studies published contained exercise only groups
The interventions involved moderate intensity aerobic
activity. Four weeks of stationary cycling three times
per week resulted in a reduction in 1H-MRS measured
IHTAG of 1.8%, relative reduction of 21%, but no
statistically significant change in HOMA relative to
either baseline or control .
Three months of aerobic exercise including brisk
walking/jogging or rhythmic aerobic exercise resulted
in a 47% and 48% reduction in ALT and AST,
Exercise only intervention groups in both studies
maintained their baseline weight suggesting that
weight reduction is not a prerequisite for liver fat or
biomarker reduction.
Exercise combined with diet
Seven studies employed a selection of
behaviour change methods to
decrease energy intake and increase
physical activity/exercise over 312
months ,these studies provided
general physical activity guidelines,
but did not prescribe specific exercise
protocols.
The focus was predominantly on body
weight reduction and
 Discussion
Weight reductions of 414% resulted in statistically
significant relative reductions in IHTAG of 3581%. The
magnitude of change strongly correlated to degree of weight
reduction,
There is also limited evidence that physical activity/exercise
can lead to modest reductions in IHTAG without weight
change.
Low (8001800 kCal/day) and very low-calorie diets
(<800 kCal/day), and/or carbohydrate restriction (2050 g/d)
resulted in the most rapid reductions in body weight and
IHTAG.
The combination of caloric and carbohydrate restriction
resulted in a 30% reduction in IHTAG and equally substantial
improvements in glucose control and insulin sensitivity
within 48 h; a time when weight reduction can only be small
and largely accounted for by glycogen depletion and water
loss
 Weight reduction (dietary change)
1) The first line is Lifestyle modification
Increased physical exercise

Self monitoring of eating and exercise

Behavioral modification is the
Stimulos control techniques
most important
Problem solving
Orlistat

2) Pharmacological treatment Phentermine (FDA) Pharmacotherapy in

the treatment remains
Sibutramine uncertain

3) Surgery
Weight reduction
In the long term
1) Should optimally achieve a 5-10% weight reduction
at which steps of the disease Changing dietary composition

Excessive influx of FFA from endogenous flat

TG deposition in the liver depots
Increased de novo hepatic lipogenesis

Post prandial

Fat
Subtypes of fat (saturated, unsaturated) may be important than their total amount.

Saturated fat intake plasma Glutathione (oxidized glutathione): oxidative stress

Two types of fat are important:
Risk of developing insulin resistance
1) Trans Fatty Acid (TFA): LDL NAFLD
HDL Risk of coronary heart disease
TG
2) Mono unsaturated Fatty Acid (MUFA):
Olive oil
n-9 oleic acid Nuts
Avocado

De novo lipogenesis ( hepatic ch REBP)

Improved insulin resistance
VLDL and fasting plasma triacylglycerol
The flux of FFA s from peripheral adipose tissue back to liver
Release of TG from liver
HDL without adverse effect on LDL
3) Poly unsaturated Fatty Acids (PUFA): omega-3 LFT
Cholestrol

Induce de novo fatty acid synthesis in hepatocytes

Added sugar and soft drink

Sucrose_rich diet hepatic synthesis of TG

NAFLD patients should limit their fructose consumption

Beverages

Cola. Soft drinks: caramel coloring (glycation end products)

>500 soft drink intake = NAFLD

Routinely questions regarding soft drink consumption as part of patient history

Western dietary pattern and fast food

Consumption of fructose, soft drinks, meat, saturated fat

Consumption of fiber, PUFA, fish or omega-3 and vitamins

In one study > twice a week = 4.5 kg extra body weight = two fold greater insulin resistance

In other study: 18 healthy young students with at last 2 fast food meals aday for 4 weeks
11 had elevated ALT at one week

In clinical evaluations of subjects with ALT

Alcohol and soft drink

Questions about
Recent excessive intake of fast food
 Caffeine

Two coffee cup/day =less severe hepatic fibrosis

100mg of caffeine in a cup

Totally:
high energy density and portion size
high fat and saturated fat
high refined carbohydrate
Over flow the FFA to liver
low fiber
high Fructose corn syrup and local inflammation
caramel coloring
red meat
industrially produced trans fatty acids

Physical activity:

upregulation insulin reseptor in muscle

Whole body lipid oxidation

Low long term : walking , swimming or cycling

Even small increment in regular P.A

 21% hepatic TG
3 cycle sessions per week (30-45 min) for 4 weeks 12% visceral adipose
14% plasma FFA
 Aerobic exercise: more extensive effects
Hepatic insulin sensitivity Without weight loss
Resistance exercise Glucose production +
Abdominal fat Unchanged hepatic fat

CDC & AHA > 30 min of moderate intensity all days

OR
Vigorous intensity > 3 times in a week> 20 min
 Potentially therapeutic dietary
supplement

1) Vit E : 300-1000 IU/d

Be carefull : increase risk of hemorrhagic stroke

d with insulin sensitivity & B cell function

 A combination of educational , behavioral and
motivational strategies is required to help
patients achieve life style change.

Multidisciplinary teams including :

dietitians
Psychologists
Physical activity supervisors`
 Therapeutic Strategies
Few effective liver-specific
therapies are available.

Thus, current treatments are

primarily directed towards
cardiovascular risk reduction and
improving the metabolic variables
which contribute to disease
progression
 To achieve optimal control of
obesity,diabetes, hypertensionand
dyslipidaemia,
multidisciplinary approach is ideal, in
which
Hepatologist
Dietitian
Diabetologist
Diabetic specialist nurse can see patients.
It is unlikely that one single
treatment will represent a panacea for
NAFLD; rather the combination of
several modalities of treatment, such
as weight loss
Diet
Exercise
Surgery
pharmacological therapy.
 INDICATIONS FOR TREATMENT

Indications for Pharmacotherapy not been established.

The spectrum of NAFLD covers bland steatosis and

steatohepatitis.

Currently it is believed that only steatohepatitis carries a

significant risk of liver disease progression, while the risk
associated with bland steatosis is largely extrahepatic.

Therefore first-line diet and lifestyle changes should be enforced in

any patient with NAFLD

Pharmacologic therapy specifically aimed at improving the liver

condition is most certainly necessary only in patients with
steatohepatitis
PHARMACOLOGIC TREATMENTS

The need for treatment in NAFLD is

based on the concern for progressive
liver disease
and cirrhosis.
Natural history studies indicate this occurs
in a minority of patients,
the high prevalence of the disease
means an effective treatment could have
major
economic and health benefits.
 Insulin sensitizers

Glitazones
Weight loss agents
Metformin
CB1R blockers
 Thiazolidinediones
(TZDs) function as selective agonists for
peroxisome proliferator activated nuclear
receptor.
Decreasing hepatic fatty acid levels (by
decreasing lipolysis and increasing
-oxidation)
Redistributing fat content from the
liver to peripheral adipose tissue.
Promoting insulin sensitivity by
facilitating preadipocyte differentiation into
insulin-sensitive adipocytes.
 Summary of trials involving
Pioglitazone therapy for NAFLD

Abbreviations: RCT, randomized controlled trial; , improvement; , no

effect .
 Summary of trials involving
Rosiglitazone therapy for
NAFLD

Abbreviations: n/a, not available; RCT, randomized controlled

trial; , improvement; , no effect.
 Discontinuation of TZDs results in
a return to pretreatment NASH
histology and serum
markers, suggesting that TZD
therapy would have to be
maintained indefinitely
for continued treatment
response.22
 TZD therapy, especially with
pioglitazone, seems to be an effective
treatment for NASH
but needs to be given indefinitely and,
given its propensity for weight gain, it
needs further study.
It can be considered one of the preferred
agents in diabetic patients with NASH
 Weight loss agents

Orlistat is a pancreatic and gastric lipase

inhibitor which inhibits the absorption of
up to 30% of dietary triglycerides .
Side effects such as diarrhoea and
bloating
loss of 5% BW correlated with
improvements in insulin sensitivity and
steatosis, whereas a loss of 9% BW was
required for an improvement in overall NAS
Larger studies with longer treatment
durations are required
 Sibutramine is a serotonin and
noradrenaline reuptake inhibitor
Rimonabant, a cannabinoid
receptor antagonist
Were taken off the market.
 Glucagon-Like Peptide-1 (GLP-1) analogues
Exenatide and Liraglutide
Weight loss of 4.8 and 7.2 kg in those taking
1.8 and 3.0 mg liraglutide for (20-week trial)
Liraglutide also reduced blood pressure and
the prevalence of prediabetes
Genetic and pharmacological elevated levels of
GLP-1 in rodent models have been shown to
reduce insulin resistance, liver enzymes
and hepatic steatosis [88,89]. Although
human clinical trials examining the specific
role of GLP-1 analogues in NAFLD patients are
yet to be published,
 Metformin

Metformin, a biguanide, is
traditionally considered first-line
treatment for noninsulin dependent
diabetes.
Because there is a high prevalence
of diabetes in patients with
NAFLD, targeting insulin resistance
with metformin seems like an
appropriate pharmacologic option
 Summary of trials involving
Metformin therapy for NAFLD

Abbreviations: n/a, not available; RCT, randomized controlled trial; , improvement; , no

effect.
 Recent trials continue to provide mixed results.
Omer and colleagues21
compared metformin with rosiglitazone in a
1-year randomized trial of diabetic NASH
patients.
Metformin significantly reduced the waist
circumference and BMI of patients, but no
effect on transaminase levels or NAS. On the
other hand, the combination of
metformin with rosiglitazone significantly
improved transaminase levels and NAS,
suggesting that metformin may have a role in
potentiating TZD effects in NAFLD.
 Metformin may improve insulin
sensitivity in NAFLD, but its effects on
transaminases,
steatosis, inflammation, and fibrosis
remain unclear.
Further trials of longer duration and
larger sample sizes that look at
histologic outcomes are necessary before
metformin can be recommended for use in
NAFLD
 Vitamin E

Vitamin E (-tocopherol) is a naturally

occurring antioxidant. Its effects in
NASH may be secondary to its function as
a
free radical scavenger or its ability to
inhibit cytokines such as transforming
growth factor (TGF-), which plays a role
in hepatic stellate cell activity and
fibrogenesis as shown in rat models
 Summary of trials involving
Vitamin E therapy for NAFLD

effect

Abbreviations: n/a, not available; RCT, randomized controlled trial;

, improvement; , no effect.
 Vitamin E treatment seems to be beneficial
in NASH, but there is a note of caution.
High-dose vitamin E therapy has been
associated with increased mortality in other
studies,31 and most NAFLD trials have used
doses of vitamin E above the current
recommended dose..
It would be prudent until more data emerges
to use vitamin E selectively in NASH patients
with more severe changes on histology.
Combination regimens including vitamin E
cannot currently be recommended.
 Probucol

Probucol is a lipid-lowering agent

with potent antioxidant properties,
allowing it to
function as a free radical
scavenger
 Merat and colleagues40 have
conducted 3 trials of probucol in NAFLD.
In their original pilot study,
500 mg of probucol for 6 months
significantly reduced transaminase
as well as reduced total cholesterol.
However, most of the reduction in
cholesterol was due to a drop in high-
density lipoprotein cholesterol (HDL);
LDL and TG levels did not change
significantly
 Probucol can lower HDL levels and
cardiac arrhythmias have also been
seen.
Therefore, until randomized,controlled
trials show consistent histologic
benefits and no adverse effects,
probucol cannot be recommended
for use in NAFLD.
 Pentoxifylline

Pentoxifylline is a
phosphodiesterase inhibitor,
resulting in decreased activity of
TNF,TGF. Therefore,
pentoxifylline could theoretically
function as an antioxidant,
antifibrotic,and insulin-
sensitizing agent in NAFLD
 Summary of trials involving
Pentoxifylline therapy for
NAFLD

Abbreviations: n/a, not available; RCT, randomized controlled trial; ,

improvement; , no effect
 Pentoxifylline at 1200 mg/d is a
safe and promising potential agent
in NAFLD.
However, until a larger placebo-
controlled study evaluates histologic
end points,
pentoxifylline cannot be
recommended.
 UDCA

UDCA is a secondary bile acid that

plays a role in lipid metabolism by
regulating intestinal cholesterol
uptake.
preventing the formation of
cholesterol gallstones,
UDCA has also been hypothesized to
have anti-apoptotic and anti-
oxidant effects.50,51
 Summary of trials involving
UDCA therapy for NAFLD

Abbreviations: n/a, not available;

 UDCA has not consistently shown any
superiority over placebo in
multiple large trials until convincing
histologic evidence is presented

UDCA cannot be recommended as a

first-line agent for NAFLD.
 Endoscopic Treatment

In comparison with surgery, such as

laparoscopic sleeve gastrectomy,
Intragastric balloon placement is
equally effective in inducing weight loss
and
has less morbidity,
but lacks the ability to maintain weight
loss when the balloon is removed
Spanish study in 714 consecutive patients
demonstrating a decrease in mean BMI
of 6.5 kg/m2 (from 37.6 to 31.1 kg/m2).
 SURGICAL OPTIONS
Bariatric Surgery
In 1991 that the National
Institutes of Health issued a
consensus statement that
bariatric surgery was an
appropriate indication for patients
with a BMI over 40 kg/m2
or 35 kg/m2 with comorbidities
 laparoscopic bariatric surgery such that
it is
among the most common operative
procedures performed in the United States
with more than 200,000 procedures in
2009.6
The most popular is the Roux-en-Y
gastric bypass RYGB, which typically
leads to the greatest and most durable
decrease in BMI.
 Summary of Bariatric surgery
trials for NAFLD

Abbreviations: n/a, not available; , improvement; , no effect

 A recent review and meta-analysis of
15 studies of bariatric surgery in
NAFLD with paired liver biopsy data
determined that the
vast majority of patients had
improvement in steatosis and NASH,
with
resolution seen in 70% and
fibrosis regression in 66%.
 LIVER TRANSPLANTATION
Decompensated liver disease in the
setting of NASH cirrhosis is a relatively
uncommon
finding compared with other common
causes of liver disease such as HCV, but
the sheer scale of the obesity epidemic in
the United States has lead to predictions
that NASH cirrhosis will become the
leading indication for OLT in the next
decade
 According to the United Network of
Organ Sharing, the first adult OLT for
a definitive diagnosis of NASH
cirrhosis took place in 1996 and was
only a tiny fraction of the total adult OLT
performed in that year (0.11%).
Since then, the number of OLTs
performed for NASH cirrhosis has increased
by more than 40-fold in 10 years
 QUASTIONS :

Who should be treated with drug

agents?
What is the best method for the
treatment
of each patient? and
When we can stop the treatment?