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NASH: Advances in Evaluation and Management

Introduction
Rakesh K Tandon, New Delhi
The epidemic of obesity and associated features of metabolic
syndrome including NASH (non-alcoholic steatohepatitis) and
NAFLD (non-alcoholic fatty liver disease) is spreading worldwide; NAFLD and metabolic syndrome which is defined as visceral
thanks to the increasingly sedentary life style! It is estimated that obesity, hypertension, IR or diabetes, and dyslipidemia. Insulin
12-15% of the global population is affected with NAFLD; 50% of resistance and hyperinsulinemia lead to an increased synthesis
diabetics develop NAFLD. It is seen in 57-74% of obese persons of glycogen, lipids and proteins. The exact mechanisms of such
and the prevalence rises to 90% in morbidly obese persons 1,2. actions are not fully understood. However, the prevailing “two
hit” hypothesis constitutes the most widely accepted pathogenetic
Often the terms - NAFLD and NASH - are used loosely. Hence, mechanism for the development of NAFL and NASH. The “first
there is a need for clear definitions. NAFLD means simply fatty hit” is due to the increased influx of free fatty acids into the
infiltration in absence of alcohol abuse, It encompasses a wide liver from visceral adipose tissue via the portal vein. It stimulates
spectrum of conditions associated with accumulation of fat in triglyceride (TG) synthesis in hepatocytes and causes a decrease
the liver, ranging from simple steatosis (NAFL) to steatohepatitis in β-oxidation, which in turn leads to the development of NAFL.
(NASH), advanced fibrosis, cirrhosis and hepatocellular carcinoma The “second hit” includes all mechanisms contributing to the
(HCC). Although NAFL, which is the most common form of development of intrahepatic necroinflammation and fibrosis. It
NAFLD, appears to follow a benign and non-progressive clinical is suggested that NAFL progresses to NASH when adaptive
course, NASH is a potentially serious condition because as many as mechanisms that protect hepatocytes from fatty acid-mediated
25% of patients with the condition may progress to cirrhosis and
experience complications of end-stage liver disease. It is therefore
not surprising that NASH has been shown to be associated with
a high risk of mortality in community population-based studies.
The absolute risk of death from NAFLD is however, low with a
standardized mortality ratio of 1.34 (95% CI 1.003–1.76, P =0.03)
(1). The natural history of NAFLD over a decade is depicted
in figure 1. 3,4

Etiology
The common causes of NAFLD include obesity, type II diabetes
mellitus, hyperlipidemia, medications, insulin resistance and
metabolic syndrome.5 Other conditions that may also lead
to NAFLD include intestinal bypass, malnutrition, starvation,
rapid weight loss, total parenteral nutrition, Wilson’s disease,
galactosemia, fever and systemic diseases.
Drugs that are known to cause fatty liver include glucocorticoids,
synthetic estrogens, aspirin, calcium-channel blockers, tamoxifen,
methotrexate, tetracycline, valproic acid, cocaine, zidovudine,
didianosine, antimony, bleomycin, coumadin and barium salts.

Pathogenesis
The predominant feature of NAFLD is insulin resistance (IR)6.
Insulin resistance is the underlying common feature between Fig. 1 : Natural course of NAFLD over 8-13 years.
 NASH: Advances in Evaluation and Management
lipotoxicity become overwhelmed and rates of hepatocyte
death begin to outstrip mechanisms that normally regenerate
dead hepatocytes. The myofibroblasts generate excessive matrix
and produce factors that stimulate expansion of liver progenitor
populations. The progenitor cells produce chemokines to
attract various kinds of inflammatory cells to the liver. They also
differentiate to replace the dead hepatocytes. The intensity of
these repair responses generally parallels the degree of hepatocyte
death, resulting in variable distortion of the hepatic architecture
with fibrosis, infiltrating immune cells, and regenerating epithelial
nodules.
Evaluation
Patients may either be asymptomatic or present with pain or
discomfort in right hypochondrium , smooth hepatomegaly
and features of underlying diseases (vide supra). Investigations
may reveal raised serum ALT and bright echogenic liver on
ultrasonography.
A number of diseases need be excluded in patients with NAFLD,
namely alcoholic liver diseases, chronic hepatitis B, chronic
hepatitis C, hypothyroidism, autoimmune liver diseases, Wilson’s
diseases and hemochromatosis. Pertinent blood and imaging
tests should therefore be done. Alcoholic steatohepatitis (ASH)
constitutes an important and common differential diagnosis. It
is identified by a history of alcohol consumption (unfortunately
often patients conceal this) and an AST/ALT ratio >2 (in contrast,
ASH and AST/ALT ratio < 1 in NASH).
Histopathology
The definitive diagnosis however, requires a histological
confirmation and hence liver biopsy is considered essential.7,8
Liver histopathology in NASH may show, steatosis, hepatocyte
ballooning degeneration, intrahepatic inflammation, perivenular
and perisinusoidal collagen deposition, Mallory’s hyaline body,
bridging septa and cirrhosis.These changes are graded and staged
as below (see Fig. 2).
Grading of NAFLD
Grade 1 (Mild): Steatosis predominantly macrovesicular involving
33-66% hepatic lobules.
Grade 2 (Moderate): Any degree of steatosis; usually mixed, both
macrovesicular and microvesicular.
Grade 3 (Severe): Mixed steatosis (usually 66%) with florid
steatohepatitis.
Staging of NAFLD
Stage 1: Zone 3 perivenular, perisinusoidal or pericellular focal
or extensive fibrosis.
Stage 2: Stage 1 plus focal or extensive portal fibrosis.
Stage 3: Bridging fibrosis; focal or extensive.
511
Stage 4: Cirrhosis with or without residual perisinusoidal fibrosis.
Noninvasive Markers of NAFLD
Since liver biopsy is an invasive procedure and may be associated
with complications such as bleeding as also with sampling error
ie missing out the disease because of patchy involvement, search
has been on for noninvasive markers of disease severity. Several
such markers have indeed been identified and a few of them have
been validated prospectively. The most important feature of a
diagnostic non-invasive marker is a high sensitivity and specificity,
providing a value as near to 1 of area under the receiver –operating
characterstics curve (ROC). This area ranges between 0.5 (no
prediction) to 1.0 (perfect prediction). Other ideal features
include reproducibility, close correlation with disease severity
and clinical outcomes. Also the results of these markers should
not be influenced by drugs and extrahepatic diseases. Noninvasive
markers for NAFLD can be divided into two broad categories:
1) imaging techniques; and 2) biologically based markers.
Imaging techniques
Fatty deposition and advanced fibrosis/cirrhosis can be easily
demonstrated with ultrasonography, computerized tomography
or magnetic resonance imaging but the difficulty appears in picking
up early fibrosis.
Transient hepatic elastography (TE) is a novel technique has
been developed recently and that is capable of detecting fibrosis in
early stages. 9 It uses an ultrasound transducer probe mounted on
the axis of a vibrator which transmits vibrations of mild amplitude
and low frequency into the tissues via the transducer, thereby
inducing an elastic shear wave that propagates through the tissue.
Pulse-echo ultrasound acquisitions are also performed to track
the propagation of the shear wave and to measure its velocity
which varies according to tissue stiffness. The stiffer the tissue,
the faster the shear wave propagates. The results are expressed
in kilopascals (kPa). Measurements are taken in the right lobe
of the liver through the intercostal spaces with the patient lying
in dorsal decubitus, with the right arm at maximum abduction.
The tip of the transducer probe is covered with coupling gel and
placed on the skin between the ribs at the level of the right lobe
of the liver. The operator, assisted by ultrasound time—motion
images, locates a portion of the liver that is at least 6-cm thick
and free of large vascular structures. Once the measurement area
has been located, the operator presses the probe button to begin
below the skin surface. Acquisitions lacking the correct vibration
profiles or correct follow-up of the vibration propagation are
automatically thrown out by the software. The success rate is
calculated as the ratio of the number of successful measurements
in relation to the total number of acquisitions. The median value
of successful acquisitions is then retained as representative of
liver stiffness and is called the ‘LSM’. Only LSMs obtained with
at least five successful acquisitions and a success rate of at least
50% are considered reliable. The median value of all acquisitions
is considered to represent the liver elastic module for each
 Medicine Update 2010  Vol. 20

patient.Advanced liver fibrosis is defined as a median liver stiffness Table 1 : Direct markers of hepatic fibrosis
greater than 9.5 kPa.Yoneda et al10 recently reported that transient Test Measured marker
elastography documented progressive increase in liver stiffness PICP Procollagen type I carboxy terminal peptide
along the stages of fibrosis and had an excellent sensitivity and PIIINP Procolagen typeIII amino-terminal peptide
specificity in identifying cirrhosis in patients with NAFLD.A major MMPs Matrix metalloproteinase
limitation of the test in patients with NAFLD is presence of obesity TIMPs Tissue inhibitors of mettaloproteinase
wherein a BMI of more than 28 is indepednedntly associated TGF-beta Transforming growth factor beta
with failure of TE examination.Additionally, presence of congestive TGF-alpha Transforming groeth factor alpha
heart failure may influence measurement of liver stiffness.11 PDGF Platelet derived growth factor
HA Hyaluronic acid
SPECT (Single photon emission computed tomography) and in
YKL-40 Chondrex
vivo phosphorus 31 magnetic resonance spectroscopy (MRS) are
other evolving modalities to assess severity of fibrosis in patients Table 2 : Indirect markers of liver fibrosis.
with chronic liver disease. Using minimum spleen pixel count
Test Components
and maximum right hepatic lobe pixel count, SPECT can identify
APRI Aspartate aminotransferase to platelet ratio index
fibrosis in a fairly early stage. However, more experience is needed
AST/ALT ratio Aspartate aminotransferase, alanine aminotransfearse
for wider usage of these techniques in clinical setting.
PGA Index Prothrombin time,gamma-glutamyltransferase,
apolipoprotein A1
Biochemical markers Fibrotest Alpha2 macroglobulin,haptoglobin,gamma-
There are direct and indirect serological markers of fibrosis.They globulin,apolipoprotein A1, gamma-glutamyl
are listed in table1 and 2, respectively 12. transferase, total bilirubin
FibroIndex Platelet count, aspartate aminotransferase,
Using varying combinations of indirect markers scoring systems gamma-globulin
have been developed and evaluated to estimate extent of liver Actitest Alpha2 macroglobulin, haptoglobin, gamma-globulin,
fibrosis and its aggravating factors, steatosis and NASH.These tests apolipoprotein A1, gamma-glutamyl transferase, total
include,FibroTest™, SteatoTest™ and NashTest™, respectively. bilirubin,alanine aminotransferase
TM
FibroMax™ (Biopredictive, Paris, France) is the association of NASH FibroSure Age , gender,Alpha2 macroglobulin, haptoglobin,
these three tests on the same result sheet and provides physicians gamma-globulin, apolipoprotein A1,
with simultaneous and complete estimation of the liver injury gamma-glutamyl transferase, total bilirubin,alanine
associated with NAFLD. Details of these are beyond the scope aminotransferase,aspartate aminotransferase, total
of this write up and hence the reader is referred to a review. 13 cholesterol,glucose,triglycerides
NASH Test Age, gender, height, weight, Alpha2 macroglobulin,
Management haptoglobin, gamma-globulin, apolipoprotein A1,
gamma-glutamyl transferase, total bilirubin,alanine
The mainstay of treatment of NAFLD is aimed at improving aminotransferase,aspartate aminotransferase, total
the underlying peripheral and hepatic insulin resistance. Dietary cholesterol,glucose,triglycerides
change, exercise, weight loss, and pharmacotherapy may all Proteomics Various protein patterns
improve insulin resistance and are thus targets for therapeutic
trials. Additionally, agents that reduce oxidative stress and/or
apoptosis or have cytoprotective properties have been evaluated.
Simultaneously, specific underlying components of the metabolic
syndrome (MS) such as hypertension, diabetes mellitus, or
dyslipidemia should also be treated.

Lifestyle Modifications
Since the main reasons for the dramatic increase in NAFLD
have been increased consumption of refined carbohydrates and
saturated fatty acids along with decreased intake of milk and
mono- and polyunsaturated fatty acids, dietary intervention and
exercise emerge as the first line therapy for this disease. Even
though they lack appeal and are often limited by patient compliance, Fig. 2 : Steatohepatitis progresses to fibrosis / cirrhosis
diet-induced weight loss is associated with physiologic changes
that result in improved insulin sensitivity, reduced adipose tissue with weight loss. However, appropriately powered, prospective,
inflammation and reduced hepatic free fatty acid supply. Two randomized controlled trials of dietary intervention and weight
preliminary studies do show improved serum aminotransferases loss in patients with NASH are lacking, and that is why it is difficult

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 NASH: Advances in Evaluation and Management
to make evidence based recommendations for their use in NAFLD.
A commonsense approach may thus be to aim for a target weight
loss of 7- 10% of the baseline weight in 6-12 months in patients
with a BMI greater than 25; this reduces aminotransferase levels
and diminishes hepatomegaly.14
Weight loss through diet and exercise should be gradual. Rapid
weight loss exceeding 1.6 kg/wk has the potential to worsen
steatohepatitis and cause gallstones.15
Mono and poly-unsaturated fats may potentially improve insulin
resistance and may be beneficial in improving hepatic steatosis.16
Pharmacotherapy
Potential pharmacotherapeutic approaches include therapies
directed at improving insulin resistance, reducing oxidative stress,
decreasing hepatic fibrosis, improving the underlying metabolic
syndrome, or promoting weight loss. Surgical approaches directed
at weight loss have also been investigated.
Metformin
Metformin, commonly used to treat diabetes mellitus, improves
blood glucose levels by decreasing hepatic glucose production
and increasing glucose utilization in peripheral skeletal muscle.17
In the treatment of NAFLD however, it has produced mixed and
generally disappointing results.
Marchesini et al 18 treated 20 biopsy-proven NASH patients
with metformin 500 mg 3 times per day for 4 months.
Significant improvement was noted in insulin resistance and
aminotransferase levels, with 50% of subjects normalizing
their transaminases. Liver volume, as measured by ultrasound,
decreased by 20%. Subsequently, Bugianesi et al19 followed 110
nondiabetic patients with NAFLD over a 12-month period: 55
were treated with metformin 2000 mg daily, 28 with vitamin
E, and 27 with a prescribed diet. Aminotransferases improved
in association with weight loss in all groups with metformin-
treated patients showing the most biochemical improvement in
multivariate analysis. Posttreatment liver biopsy performed on 17
of the metformin-treated group showed statistically significant
changes in liver fat, necroinflammation and fibrosis. . Indeed, a
recent meta-analysis published in Cochrane database showed that
metformin leads to normalization of serum aminotransferases in a
significantly greater proportion of patients compared with dietary
modification (odds ratio: 2.83; 95% CI: 1.27-6.31) and improved
steatosis by imaging (odds ratio: 5.25, 95% CI:1.09-25.21).20
Thiazolidinediones
The thiazolidinediones (TZDs) are another class of diabetic
medications that have been well studied in the treatment of
NASH.These medications include pioglitazone and rosiglitazone,
which act as peroxisomal proliferator activated receptor
agonists leading to increased fatty acid oxidation and decreased
fatty acid synthesis within hepatocytes. The resultant improved
insulin sensitivity in both hepatocytes and skeletal muscle is one
513
mechanism of action that may explain TZD’s usefulness in NASH
patient populations. Several studies have appeared but the latest
of them, FLIRT trial, probably depicts the limited benefit from TZD
treatment of NASH. In this study, 63 patients with NASH were
treated for one year with either rosiglitazone or placebo.21 The
patients receiving rosiglitazone showed a statistically significant
improvement in serum aminotransferases, insulin sensitivity, and
hepatic steatosis, but they did not show an improvement in other
histologic parameters, notably the NAFLD Activity Score (NAS)
or fibrosis.
The side effects of the TZDs may also limit substantially the
usefulness of these medications. They include weight gain, pedal
edema (seen in up to 5% of patients), osteoporosis and an increase
in increase in adverse cardiac events.22
Statins
Although statins appear safe for the treatment of hyperlipidemia in
NAFLD patients, the issue of whether or not they are efficacious in
the treatment of NASH is unclear.Two small pilot trials have shown
improvement of liver enzymes with atorvastatin.23,24 Pravistatin 20
mg given for six months normalized liver enzymes and improved
hepatic inflammation in five patients with NASH.25 Clearly, larger
placebo controlled studies are needed to substantiate these
results.
Cytoprotective Medications
Ursodeoxycholic acid (UDCA) is a common hepatoprotective
agent used and preliminary clinical studies showed some benefit.
However, a large multicenter trial with 107 NASH patients
treated with UDCA or placebo for 2 years.26 Although there
was a significant histological improvement in the posttreatment
biopsies of the UDCA group, comparable findings were present
in the placebo group, with an overall 40% reduction in steatosis
and 21% reduction in fibrosis. This study highlights the need for
large placebo controlled trials to confirm if UDCA does indeed
benefit. UDCA may well be useful in combination with other
treatments and hence that aspect also needs exploration.
Betaine is another medication which increases levels of
S-adenosyl-L-methionine (SAM), a known essential player in
cellular membrane integrity and hepatoprotection, and has been
investigated in the treatment of NASH. One year of treatment
with betaine in 10 NASH patients significantly improved serum
transaminases as well as hepatic steatosis, inflammation, and
fibrosis. 27 However, larger trials are needed to prove the value
of betaine in treating NAFLD.
Antioxidants
A beneficial role of vitamin E in NASH has been long suspected
but not proven. In a recent randomized, placebo-controlled study
a combination of vitamin E and vitamin C was studied in 45
patients with NASH 28. Although serum aminotransferases and
necroinflammation were not improved after 6 months of therapy,
 Medicine Update 2010  Vol. 20
repeat biopsies showed significant improvement in fibrosis scores
between the two groups. This study needs to be replicated and
other antioxidants should be studied.
Weight Loss Promotion
As a part of lifestyle modification, weight loss is expected and that
has shown benefit in NAFLD patients as mentioned above. Thus,
use of medications and surgical interventions to reduce weight
have also been evaluated.
Orlistat
Orlistat is a well recognised and frequently used weight loss
medication. It inhibits gastric and pancreatic lipase, which is
needed to break down triglycerides into free fatty acids and has
been shown to prevent 30% of dietary triglycerides from being
absorbed. Pilot studies with orlistat given for 6 months along with
dietary counselling have shown significant improvement in serum
aminotransferases as well as hepatic steatosis and inflammation. 29
Two subsequent randomized placebo controlled trials
substantiated the above findings and suggested that improvement
in NAFLD patients may occur even with modest weight loss. 30,31
Rimonabant
The endocannabinoid (EC) system is involved in the regulation
of food intake and body weight. In the setting of obesity, the
EC system appears to be upregulated and as such, represents
a novel target for medical therapy of NASH. The EC system
encompasses a network of receptors and their ligands as well
as the enzymes that synthesize and degrade these ligands.32 The
cannabinoid type I (CB1) receptors are found throughout the
body and their activation leads to increased hepatic lipogenesis,
fatty acid synthesis in adipocytes, and decreased adiponectin.
Rimonabant is a selective CB1 receptor antagonist that has
been shown to decrease hepatic lipogenesis and increase
satiety, adiponectin levels, and glucose uptake, thereby improving
insulin levels and lipid profiles.33,34 Two large randomized placebo
controlled multicenter trials have shown the efficacy of this agent
in causing substantial weight loss along with an improvement in
the metabolic profile, particularly the lipid profile (decrease in
low-density lipids and triglycerides) and improvement in insulin
sensitivity with resolution of metabolic syndrome in one-third of
patients. These metabolic benefits appear to exceed what could
be attributed directly to the weight loss and suggest direct effects
of this medication, which may have application in the treatment
of NASH.
Two large multicenter, randomized, placebo controlled trials (one
in diabetic patients and one in nondiabetic patients) are indeed
underway currently to assess any role of this medication in the
treatment of NASH. One potential side effect of the drug that
requires further evaluation is an association with psychiatric
514
problems , particularly depression..
Surgical Interventions
In case medical therapy fails, one has to resort to some form
of bariatric surgery (Roux-en-Y gastric bypass operation or
laparoscopic adjustable band gastroplasty). Numerous studies
using different techniques have demonstrated significant
improvement in steatosis, hepatocellular injury, and fibrosis. In
fact, complete resolution of NASH in as many as 75 to 100%
of cases has been described in some series 35. However, not all
results are so positive, and collective evidence suggests that a
small minority of bariatric surgery patients may develop either
worsening steatohepatitis or mild fibrosis.
Conclusion
Sedentary lifestyle and increased energy intake in the form of
refined carbohydrates have led to a virtual epidemic of NAFLD.
In the subset of these patients with NASH, accumulation of fat in
hepatocytes with subsequent oxidative stress and inflammation
can lead to fibrosis, which may ultimately progress to cirrhosis or
promote the development of HCC.Treatment strategies ranging
from simple lifestyle modifications to pharmacologic agents and
even invasive surgical procedures have shown promise in arresting
the progress of this chronic liver disease. They may however, be
associated with certain complications. That is why prevention is
the best option and that is comprised of ‘healthy life style’ – low
carbohydrate, high fibre diet, regular exercise and a good control
of diabetes, hyperlipidemia, hypertension and hypothyroidism, if
present.
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