Download Non alcoholic fatty liver disease (NAFLD) Diagnosis and evaluation

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 7–18 years in Iran by a crosssectional 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 TNFɑ 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 γ.
• However, following initial activation to
produce pro-inflammatory cytokines, KCs
release IL-10 which down-regulates the
production of TNFɑ , 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 TGFβ .
• Moreover, activated HSCs express the negative costimulator PD-L1 .
NAFLD pathogenesis in ob/ob mice
Leptin deficiency
Kupffer cell
inhibited activation of
dysfunction
Hepatic stellate cells
Hepatic NKT
cell depletion
Increased adipokines
(resistin,adiponectin)
inhibited liver fibrosis
Despite Liver injury
Th-1 polarization
increased ROS
Hepatocyte oxidative stress
• Currently, it is widely accepted that
lipopolysaccharide (LPS), a gut bacteriaderived 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-κB 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, Szabo’s 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-γ) 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+ Thelper 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-α, are increased in animal models of obesity.
• This is also true in humans, where TNF-α levels
correlate with the degree of insulin resistance.
• Furthermore, in humans, acute infusion of TNF-α
inhibits insulin-stimulated glucose disposal,and certain
TNF-α 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-α 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-α
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-α inhibitor, and thus the use of more
selective TNF-α 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-κB Selective
targeting of NF-κB signaling of inflammatory cells
may be crucial in therapy design, as NF-κB 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.
To avoid such mistakes, radiologists should be aware
of the many imaging manifestations of fatty liver.
• 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 material–enhanced 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 imaging–based 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-yearold 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 patient’s 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) T1weighted 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 contrastenhanced (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 abnormality—in 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 T1weighted 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 contrastenhanced
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.
A–D, Estimated FF maps by using the four image analysis methods, E, multiecho MR spectra, and F–H,
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 α: 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
α2 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
•
•
•
•
Identification of fibrosis
AST/ALT ratio (AAR)
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
α2 macroglobulin
• “Fibro Spect” tacking into account:
-
Hyaluronic acid
Tissue inhibited matrix metalloproteinase
Inhibitor1
α2 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
is defined
metabolic
syndrome?
Mets was
originally
as a 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).
stroke
First termed syndrome X in 1988
Insulin resistance syndrome; Syndrome x, dysmetabolic syndrome
Its main components are
•
•
•
•
•
•
dyslipidemia
elevation of arterial blood pressure (BP)
dysregulated glucose homeostasis
abdominal obesity
insulin resistance (IR)
non-alcoholic fatty liver disease( Recently added to the
syndrome and make its definition even more complex.)
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
the population studied
 In the United States, more than one fourth of the population meets
diagnostic 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 218% in women .
 Iran:25-30%
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 can’t 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 Program’s 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 (µU/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
Gut microflora
Insulin resistance
NAFLD
Genetic
Oxidative stress
Immune related
Metabolic
hyperlipidemia
inflammation
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 30–45 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 body’s 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 wellconducted 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 insulinresistant, 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 1–6 months and achieved mean body
weight reductions of 4–14%.
All studies using biopsy or imaging techniques to estimate IHTAG reported reductions.
• The three studies using 1H-MRS reported absolute reductions of 4–10%
and relative reductions of 42–81%.
• 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 3–12 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 4–14% resulted in statistically significant
relative reductions in IHTAG of 35–81%. 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 (800–1800 kCal/day) and very low-calorie diets
• (<800 kCal/day), and/or carbohydrate restriction (20–50 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
most important
Stimulos control techniques
Problem solving
 Orlistat
2)
Pharmacological treatment
Phentermine
Sibutramine
3)
Surgery
(FDA)
Pharmacotherapy in
the treatment remains uncertain
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 depots
TG deposition in the liver
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):
2)
Mono unsaturated Fatty Acid (MUFA):
 Olive oil
n-9 oleic acid Nuts
Avocado
LDL
HDL
TG
NAFLD
Risk of coronary heart disease
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
3 cycle sessions per week (30-45 min) for 4 weeks
21% hepatic TG
12% visceral adipose
14% plasma FFA
Aerobic exercise: more extensive effects
Hepatic insulin sensitivity
Resistance exercise
Glucose production
Abdominal fat
CDC & AHA
Without weight loss
+
Unchanged hepatic fat
> 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 non–
insulin 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 insulinsensitizing 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?