87 Nonalcoholic Fatty Liver Disease

Dawn M. Torres, Stephen A. Harrison

CHAPTER OUTLINE the diagnostic criteria used to establish the diagnosis (i.e., liver bio-
chemical test levels, imaging study results, or liver biopsy findings).
EPIDEMIOLOGY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1354 Because the majority of patients with NAFLD are asymptomatic,
DEFINITIONS AND ASSOCIATIONS. . . . . . . . . . . . . . . . . . 1355 the prevalence of NAFLD in the USA and globally is not completely
PATHOGENESIS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1356 defined, although a meta-analysis in 2016 suggested a global preva-
lence of 25%.4 The first estimates of the prevalence of NASH came
Hepatic Steatosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1356 from autopsy studies, in which steatohepatitis was found in 18.5% of
Steatohepatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1356 markedly obese and 2.7% of lean persons.5 Advanced hepatic fibro-
CLINICAL FEATURES AND DIAGNOSIS. . . . . . . . . . . . . . . 1358 sis was seen in 13.8% of markedly obese persons compared with
Liver Biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1359 6.6% of lean persons. High rates of NAFLD and NASH among the
Imaging to Detect Fibrosis. . . . . . . . . . . . . . . . . . . . . . . 1359 obese were subsequently confirmed in a study of patients undergo-
Laboratory Tests for Fibrosis. . . . . . . . . . . . . . . . . . . . . 1360 ing bariatric surgery, in whom the frequency of NAFLD and NASH
Focal Fatty Liver . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1361 was reported to be as high as 91% and 37%, respectively.6
The Dallas Heart Study used magnetic resonance spectros-
NATURAL HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1361 copy in more than 2200 adults to identify a 31% frequency of
CLINICAL ASSOCIATIONS . . . . . . . . . . . . . . . . . . . . . . . . 1362 fatty liver disease in a cohort of asymptomatic persons.7,8 Sub-
sequent population-based cohort studies from China, Japan, and
TREATMENT. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1362 Korea using US have reported NAFLD prevalence rates ranging
Lifestyle Modification . . . . . . . . . . . . . . . . . . . . . . . . . . 1362 from 10% to 24%.9-11 The largest study using US paired with
Bariatric Surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1364 hepatic histology evaluated a cohort of asymptomatic middle-
Pharmacotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1364 aged persons from San Antonio, Texas and revealed a 46% preva-
LT. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1365 lence rate of NAFLD and a 12.2% prevalence rate of NASH.12
Most cases of NAFLD are discovered in middle age during
the fourth to sixth decades of life, although NAFLD has also been
described with increasing frequency in children and adolescents,
The global obesity epidemic has dramatically increased the preva- in whom the frequency of overweight and obese persons has been
lence of NAFLD and made it the leading cause of chronic liver reported to be 30% of the population.13 The prevalence of pedi-
disease in Western nations. NAFLD is considered the hepatic mani- atric NAFLD cases has risen accordingly, with a meta-analysis
festation of the metabolic syndrome and shares a strong association demonstrating a pooled mean prevalence rate for NAFLD in the
with type 2 diabetes mellitus, obstructive sleep apnea (OSA), and general pediatric population of 7.6%; in a pediatric obesity clinic,
cardiovascular disease. Although cardiovascular disease is the lead- the frequency is as high as 34.2%.14
ing cause of death in patients with NAFLD, the subset of patients Most relevant studies have reported NAFLD to be more com-
who meet histopathologic criteria for NASH are those at greatest mon in men than women and describe a later peaking prevalence
risk of liver-related morbidity and mortality. Ludwig and colleagues in women than men, including a propensity for more advanced
coined the term NASH in 1980 to describe a cohort of middle-aged disease in postmenopausal women,15 suggesting a relationship
patients with elevated serum liver enzyme levels who had evidence with sex hormones and menopause.16 NAFLD (and specifically
of alcohol-associated hepatitis on biopsy specimens in the absence of NASH) is often associated with diabetes mellitus, with an associ-
alcohol consumption.1 Subsequent study led to the proposed “2-hit” ated 60% to 76% prevalence rate for NAFLD and a 22% preva-
hypothesis in which a sequential progression from isolated fatty liver lence rate for NASH.17 This finding is not surprising because
(IFL) to NASH involved the initial “hit” of hepatic steatosis followed NAFLD is considered to be the hepatic manifestation of the met-
by a second “hit” of oxidative stress resulting in liver injury.2 It was abolic syndrome as defined by the presence of 3 or more of the
subsequently recognized that patients who have steatohepatitis on following: abdominal obesity, hypertriglyceridemia, low HDL
a liver biopsy specimen are at greatest risk for progression to cir- levels, hypertension, and elevated fasting plasma glucose levels.18
rhosis compared with those who have IFL. Correspondingly, our The role of ethnicity is evolving. Early evidence from the
understanding of the pathogenesis of NAFLD has evolved from the Dallas Heart Study suggested that ethnicity was important, with
2-hit hypothesis. NASH is expected to become the most common Hispanics showing the highest prevalence of NAFLD (45%),
cause of cirrhosis and the leading indication for LT in the USA in compared with 33% in Caucasians and 24% in African Ameri-
the 2020s. As a major public health concern, an understanding of its cans. Similar findings were reported by Williams and colleagues,
epidemiology and pathogenesis is paramount to facilitate our ability with a 58.3% prevalence rate for NAFLD in Hispanics, com-
to effectively diagnose and treat patients with NAFLD and NASH. pared with 44% in Caucasians and 35% in African Americans.
The reason for these trends appears multifactorial. A study by the
EPIDEMIOLOGY NASH Clinical Research Network found Hispanics with NASH
to be younger, less active, and consuming a diet higher in carbo-
The rise of NAFLD has paralleled the rising rates of obesity. In hydrates when compared with Caucasians.19 A systematic review
2016, 39% of adults in the USA qualified as overweight, and another and meta-analysis confirmed that the prevalence of NAFLD is
13% were obese (see Chapter 7). These figures are triple the rate highest among Hispanics, followed by Caucasians and then Afri-
of obesity described in 1975.3 Prevalence estimates vary widely can Americans, with similar proportions of liver fibrosis in the 3
depending on the information available in a given population and ethnic groups.20
1354
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Fig. 87.1 Histologic features of isolated fatty liver. The characteristic
feature is diffuse macrovesicular steatosis without significant necro-
inflammation or fibrosis. Glycogenated nuclei are common (H&E).
(Courtesy Dr. Gregory Y. Lauwers, Boston, MA.)
Lifestyle is important, and increased consumption of high-
fructose corn syrup and sugar-containing sodas, coupled with
a sedentary lifestyle, has been associated with higher rates of
NAFLD, and specifically NASH. Genetic influences on the devel-
opment of NAFLD may prove to be equally important. Single
nucleotide polymorphisms (SNPs) from specific genes have been
found to be associated with an increased risk of NAFLD. The
first of these SNPs to be identified was in the patatin-like phos-
pholipase domain-containing protein-3 (PNPLA3) gene located
on chromosome 22q13 and known to encode adiponutrin, a 481-
amino acid protein that mediates triacylglycerol synthesis.21 The
allelic variant rs738409 results in a change from isoleucine to
methionine at position 148 (I148M) and has been shown to be
associated with increased hepatic steatosis as well as inflamma-
tion.22 This variant was more common in Hispanics followed by
Caucasians and African Americans and may explain the higher
rates of NASH seen in Hispanic populations. Subsequent study
has confirmed the association of the I148M SNP with hepatic
steatosis, NASH, and even fibrosis with a meta-analysis demon-
strating an odds ratio (OR) of 3.26 (95% confidence interval (CI)
CI, 2.14 to 4.95) for NASH and 3.25 (95% CI, 2.86 to 3.70) for
hepatic fibrosis for persons with the I148M SNP.23
More recently, the membrane bound O-acyltransferase
domain containing 7 (MBOAT7) locus has been shown to be
associated with hepatic steatosis, steatohepatitis,24 and, poten-
tially, the development of HCC.25 Numerous other genetic poly-
morphisms have been studied, including those encoding proteins
involved in VLDL secretion (apolipoprotein B, apoB; transmem-
brane 6 superfamily 2, TM6SF2), de novo lipogenesis regulation
(glucokinase regulatory protein, GCKR; Krüppel-like factor 6,
KLF6), the innate immune system (interferon lambda 3, IFNL3),
and mitochondrial oxidation (superoxide dismutase 2, SOD2).26
Ongoing research will provide a better understanding of the
complex interplay between genetic and host factors that promote
the development of hepatic steatosis and steatohepatitis.
DEFINITIONS AND ASSOCIATIONS
Macrovesicular fat accumulation in more than 5% of hepato-
cytes is the defining feature of NAFLD. As mentioned earlier,
IFL compromises the majority of patients with NAFLD and is
defined by hepatic steatosis in the absence of significant necro-
inflammation or fibrosis (Fig. 87.1). Hepatocyte ballooning
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CHAPTER 87 Nonalcoholic Fatty Liver Disease 1355
87
Fig. 87.2 Histologic features of NASH. Diffuse or perivenular macrove-
sicular steatosis is present. Lobular inflammation consists of neutro-
phils, lymphocytes, and other mononuclear cells. Hepatocyte balloon-
ing and necrosis of varied degrees are hallmark features. Glycogenated
nuclei are present. Mallory bodies, which may be small, sparse, and
inconspicuous, are seen (H&E). (Courtesy Dr. Gregory Y. Lauwers,
Boston, MA.)
degeneration and lobular inflammation of a mixed inflamma-
tory cell infiltrate is required to meet criteria for NASH, and
Mallory-Denk (or Mallory) bodies, iron deposition, ductular
reaction, megamitochondria, periodic acid-Schiff-diastase-
resistant Kupffer cells, and vacuolated nuclei in periportal
hepatocytes may also be seen (Fig. 87.2).27 Fibrosis, if present,
is predominantly perisinusoidal and pericellular (“chicken-wire
fibrosis”) in acinar zone 3 (see Chapter 71), although it may
extend to portal and periportal regions with disease progres-
sion (Box 87.1). Alcohol-associated steatosis and steatohepatitis
(alcohol-associated hepatitis) are histologically indistinguish-
able from IFL and NASH (see Chapter 86), although expert
pathologists describe more fibro-occlusive venous lesions and
bile stasis in alcohol-associated steatohepatitis.28 Pediatric
NAFLD is a somewhat distinct histologic entity marked by
portal-based chronic inflammation and fibrosis with less fre-
quent findings of hepatocyte ballooning and Mallory-Denk
bodies.29
To reach consensus on the pathologic classification of NASH,
the Pathology Committee of the National Institutes of Health
NASH Clinical Research Network proposed a scoring system
incorporating 14 histologic features in 2005.30 The NAFLD
activity score (NAS) combines the unweighted sum of scores for
steatosis, lobular inflammation, and hepatocellular ballooning on
a scale of 0 to 8 (Table 87.1). A score of 0 to 2 is most suggestive
of “not-NASH,” and a score of 5 or greater suggests that NASH is
present. Although the NAS is primarily a research tool and NASH
is not defined by an absolute score, NAS provides a framework to
accurately detect changes in disease activity with therapy.
Other conditions may promote hepatic steatosis and should
be considered (Box 87.2). TPN, rapid weight loss, or starva-
tion can lead to hepatic steatosis. Similarly, surgeries that lead
to rapid and extreme intestinal malabsorption and weight loss,
such as extensive small bowel resection, biliopancreatic diver-
sion, or jejunoileal bypass, have been associated with hepatic
steatosis. Medications such as amiodarone, valproic acid, meth-
otrexate, tamoxifen, glucocorticoids, certain antiretrovirals,
and tetracyclines have also been implicated, as have systemic
conditions such as Wilson disease, abetalipoproteinemia, and
lipodystrophy.
1356 PART IX Liver

(FFA). Normally, FFA is supplied to the liver through intestinal

BOX 87.1 Histologic Features of NAFLD absorption (in the form of chylomicron remnants) or from lipoly-
sis of adipose tissue, where FFA is stored as TG. In the liver,
OBSERVED IN ALL OR MOST CASES FFA is oxidized by mitochondria, esterified into TG, synthesized
Macrovesicular steatosis into phospholipids and cholesteryl esters, and secreted from the
Diffuse or centrilobular steatosis; degree may correlate with BMI liver as VLDL (see Chapter 72). Fatty acid metabolism is under
Parenchymal inflammation tight regulatory control by catecholamines, glucagon, growth
Polymorphonuclear neutrophils, lymphocytes, other mononuclear hormone, and insulin. Hepatic TG accumulation occurs when
cells fatty acid metabolism shifts to favor net lipogenesis, rather than
Hepatocyte necrosis lipolysis. This shift occurs when the amount of FFA supplied to
Ballooning hepatocyte degeneration the liver from the intestine or adipose tissue exceeds the amount
OBSERVED WITH VARIED FREQUENCIES needed for mitochondrial oxidation, phospholipid synthesis, and
synthesis of cholesteryl esters. TG also accumulate in the liver
Perivenular, perisinusoidal, or periportal fibrosis (37%-84%),
when synthesis of lipoprotein decreases or export of lipids from
moderate to severe in 15%-50%; most prevalent in zone 3
the liver is impeded.
(perivenular)
Insulin resistance from excessive accumulation of FFA is
Cirrhosis (7%-16% on index biopsy specimen)
thought to be a primary factor in the development of steatosis in
Mallory bodies
most patients with NAFLD. Impairment of insulin signaling in
Glycogenated nuclei
adipose tissue and the liver, along with increased dietary fat and
Lipogranulomas
de novo lipogenesis, contributes to hepatic steatosis in NAFLD.31
Stainable hepatic iron
Dietary fructose is delivered directly via the portal vein to the
liver, where it activates carbohydrate response element binding
protein and sterol regulatory element binding protein-1 (SREBP)
TABLE 87.1 NAFLD Activity Score to promote de novo lipogenesis.32
The excess and dysfunctional visceral adipose tissue seen in
Steatosis (%)
NAFLD further promotes insulin hypersecretion secondary to
5 1 insulin resistance. The increased secretion of specific proinflam-
5-33 2 matory cytokines, such as leptin, TNF-α, IL-6, resistin, and plas-
33-66 3
minogen activator inhibitor-1, has been described, along with
Ballooning decreased secretion of the anti-inflammatory cytokine adiponec-
None 0 tin. Serum adiponectin levels are reduced in obesity, insulin resis-
Few 1 tance, diabetes mellitus, and the metabolic syndrome.33 Higher
Many 2 leptin and lower adiponectin levels have been associated with
Lobular Inflammation liver inflammation and fibrosis.34
Mild 1 Research into the pathogenesis of NAFLD has addressed the
Moderate 2 role of bile acids (BAs) and their nuclear hormone receptors as
Severe 3 vital regulators of energy homeostasis during carbohydrate and
Total Score lipid metabolism in hepatic and extrahepatic tissues (see Chapter
0-2 Likely not NASH
64). BAs absorbed from the distal ileum bind to these nuclear
3-4 Intermediate hormone receptors. The most studied nuclear hormone receptor
5-8 Likely NASH is the farnesoid X receptor (FXR), which has been identified as
the master regulator of BA synthesis. Activation of FXR has been
shown to decrease de novo lipogenesis, impair VLDL synthesis
and assembly, and increase β-oxidation of FFA.35 Other nuclear
PATHOGENESIS hormone receptors such as G-protein‒coupled bile acid recep-
The “2-hit hypothesis” proposed by Day and colleagues in tor (TGR-5), sphingosine 1 receptor 2, and pregnane X receptor
1988 (see earlier) has provided a framework for our cur- (PXR, NR1I2) also appear to be important and may offer future
rent understanding of the increasingly complicated pathway therapeutic targets.36
to hepatic steatosis, steatohepatitis, and fibrosis. The 2-hit
hypothesis states that dysregulation of fatty acid metabolism Steatohepatitis
leads to steatosis, which is associated with several cellular adap-
tations and altered signaling pathways that render hepatocytes Although insulin resistance and hyperinsulinemia are clearly piv-
vulnerable to a second hit. The second insult may be 1 or more otal to the development of steatosis, consensus is lacking on the
environmental or genetic perturbations that cause hepatocyte subsequent insults that lead to steatohepatitis and fibrosis in some
necrosis and inflammation. In a minority of cases, incompletely patients. Isolated steatosis may be considered to be an adaptive
defined factors activate a fibrogenic cascade that leads eventu- mechanism designed to mitigate the effects of long chain satu-
ally to cirrhosis. In light of the variety of conditions that have rated fatty acids in the liver. If the protective processes are over-
been associated with NAFLD, it is not surprising that no single whelmed or faulty, lipotoxicity can develop, potentially activating
mechanism has been identified and that numerous interacting numerous signaling pathways resulting in hepatocyte apoptosis
and nonlinear pathways, influenced by a variety of environmen- and stellate cell activation. The precise signaling pathways are
tal and genetic factors, promote hepatic steatosis, steatohepa- still being uncovered, but several key pathways have been defined.
titis, and fibrosis. Cellular homeostasis, communication, and regulation involve
lipids, which are an essential part of cell structure. Increased
levels of FFA can be directly toxic to hepatocytes through a
Hepatic Steatosis number of mechanisms. An excess of specific FFA, including
Hepatic steatosis is the hallmark histologic feature of NAFLD palmitic acid, cholesterol, lysophosphatidylcholine, and cerami-
and the net result of excessive accumulation of free fatty acid des, is particularly harmful to intracellular organelles.37 These
toxic lipids promote oxidative and endoplasmic reticulum stress,

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 CHAPTER 87 Nonalcoholic Fatty Liver Disease 1357

BOX 87.2 Causes of Fatty Liver Disease 87

ACQUIRED METABOLIC DISORDERS METALS
Diabetes mellitus Antimony
Dyslipidemia Barium salts
Kwashiorkor and marasmus Chromates
Obesity Mercury
Starvation Phosphorus
CYTOTOXIC AND CYTOSTATIC DRUGS Rare earths of low atomic number
Thallium compounds
L-Asparaginase
Uranium compounds
Azacytidine
Bleomycin INBORN ERRORS OF METABOLISM
Cisplatin Abetalipoproteinemia
5-Fluorouracil Familial hepatosteatosis
Methotrexate Galactosemia
Tetracycline* Glycogen storage disease
OTHER DRUGS AND TOXINS Hereditary fructose intolerance
Homocystinuria
Amiodarone
Systemic carnitine deficiency
Antiretroviral therapy (didanosine, stavudine, zidovudine)
Tyrosinemia
Camphor
Weber-Christian syndrome
Chloroform
Wilson disease
Cocaine
Ethanol SURGICAL PROCEDURES
Ethyl bromide Biliopancreatic diversion
Estrogens Extensive small bowel resection
Glucocorticoids Jejunoileal bypass
Griseofulvin MISCELLANEOUS CONDITIONS
Lycopodium serratum (Jin bu huan, herbal supplement)
IBD
Nifedipine
Industrial exposure to petrochemicals
Nitrofurantoin
Jejunal diverticulosis with SIBO
NSAIDs (buprofen, indomethacin, piroxicam, sulindac)
Partial lipodystrophy
Tamoxifen
TPN
Valproic acid
  
*Tetracycline is cytotoxic by virtue of inhibiting mitochondrial β-oxidation.

modify mitochondrial function, and induce autophagy, leading
to activation of hepatic stellate cells and fibrosis.38 Autophagy is
another housekeeping process within hepatocytes that involves
autodigestion of unwanted proteins and organelles (see Chapter
72). Lipotoxicity in hepatocytes has also been shown to increase
the inflammatory response through the release of cell-derived
extracellular vesicles, which are bioactive molecules that appear
to activate hepatic stellate cells and promote fibrinogenesis in
NASH.39
The hedgehog signaling pathway, an important part of the
liver’s usual synchronized response to wound healing, is another
area of dysregulation involved in the pathogenesis of NAFLD.
Lipotoxicity activates the hedgehog pathway, thereby promoting
portal inflammation, hepatocellular ballooning, and hepatic fibro-
sis.40 Activation of the hedgehog signaling pathway leads to the
conversion of quiescent hepatic stellate cells to myofibroblasts,
which in turn produce chemoattractants for natural killer cells.41
Natural killer cells are responsible for secreting profibrotic cyto-
kines that further activate myofibroblasts. The stage of hepatic
fibrosis (see later, and Chapter 74) has been directly correlated
with the degree of hedgehog pathway activation in patients with
NASH,42 and mouse model studies have demonstrated that inhi-
bition of the hedgehog pathway can reverse liver fibrosis.43
The role of the intestinal microbiota in the development of
NAFLD is becoming increasingly appreciated with enhanced
understanding of the close relationship between the GI tract and
the liver. Organisms (mostly bacteria) in the GI tract contrib-
ute to digestion and act as important modulators of the immune
system (see Chapter 3). Dysbiosis is defined as an imbalance
between protective and harmful bacteria and can lead to altered
intestinal permeability and perturbations in immunity.44 Data
also suggest the existence of a distinct gut microbiota in patients
with NASH.45 SIBO in the setting of a surgical jejunoileal bypass
or duodenal switch procedure (performed in the past to treat obe-
sity) has been associated with the development of NASH, the risk
of which is reduced with antibiotics or even eliminated with revi-
sion of the surgical procedure.46,47
Obesity and fructose consumption have been linked to gut-
derived endotoxin in humans.48,49 Yang and colleagues dem-
onstrated that ob/ob mice with steatosis are highly vulnerable
to endotoxin-induced hepatocyte damage, and NASH rapidly
develops in these animals after exposure to low doses of bac-
terial lipopolysaccharide (LPS).50 The net result of increased
endotoxin, particularly from Gram-negative bacteria, is an acti-
vation of Kupffer cells via toll-like receptor 4, which in turn
up-regulates several inflammatory pathways, including activa-
tion of Jun N-terminal kinase and nuclear factor kappa B, and
releases pro-inflammatory cytokines such as TNF-α and IL-1β.
Follow-up studies of mice deficient in the LPS binding protein,
compared with wild-type mice fed high-fructose, high-fat diets
have supported the critical role of LPS in the development of
NAFLD.51
Any 1 of the putative mechanisms discussed is unlikely to
explain the pathogenesis of NAFLD in all affected patients. The
precise interplay among various mechanisms remains to be eluci-
dated. Our present understanding of the pathogenesis of NASH

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1358 PART IX Liver

Fig. 87.3 Mechanism of action of pharmacologic treatments for NAFLD and NASH. The sites of action of
available and experimental agents (some of which are discussed in the text) with metabolic, anti-inflammatory,
and antifibrotic effects are shown. ACC, Acetyl-CoA carboxylase; AOC, amine oxidase, copper containing;
DNL, de novo lipogenesis; ER, endoplasmic reticulum; FFA, free fatty acids; FGF, fibroblast growth factor; FXR,
farnesoid X receptor; IL, interleukin; JNK, Jun N-terminal kinases; LPS, lipopolysaccharide; PPAR, peroxi-
some proliferator-activated receptor; ROS, reactive oxygen species; SIM, simtuzumab; SHP, small heterodimer
partner; SREBP, sterol regulatory element binding proteins; TLR, toll like receptor; TR, thyroid receptor; UPR,
unfolded protein response. (From Konerman MA, Jones JC, Harrison SA. Pharmacotherapy for NASH: current
and emerging. J Hepatol 2018;68:362-75.)

is summarized in Fig. 87.3, with an emphasis on pathways with
therapeutic targets under investigation.
CLINICAL FEATURES AND DIAGNOSIS
The clinical and laboratory features of NAFLD are summarized
in Table 87.2. NAFLD is usually discovered incidentally because
of elevated liver biochemical test levels or an incidental finding
of hepatic steatosis on imaging. Most patients with NAFLD are
asymptomatic, but some may describe vague RUQ pain, fatigue,
and malaise. Hepatomegaly is commonly seen but is often dif-
ficult to appreciate on physical examination because of obesity.
Stigmata of chronic liver disease, such as splenomegaly, spider
telangiectasias, and ascites, are limited to patients with NASH
cirrhosis (see Chapter 74). To establish a diagnosis of NAFLD,
alcohol-associated liver disease must be excluded, and the diag-
nosis of NAFLD should be entertained only in the absence of
significant alcohol use (consumption of less than 20 to 40 g of
alcohol per day in most clinical studies). In patients with meta-
bolic risk factors and significant alcohol use, it is impossible to
determine which factor is paramount, and both can be assumed
to be the cause of the liver disease.
In metabolic fatty liver disease, mild-to-moderate (1.5- to
4-fold) elevations of the serum AST or ALT level, or both, is
common, although levels seldom exceed 10 times the upper limit
of normal. The serum ALT level usually is greater than the AST
level, in contrast with the pattern in alcohol-associated, in which
the AST level is typically at least 2-fold higher than the ALT
level. A large retrospective study of patients with NAFLD dem-
onstrated a mean serum ALT level of 83 and AST level of 63
IU/mL.52 The alkaline phosphatase and GGTP levels may be
elevated, but the serum bilirubin level, prothrombin time, and
serum albumin level typically are normal, except in patients with
NAFLD-associated cirrhosis.
Up to one fourth of patients with NAFLD may have ANA
in low titers (<1:320), although their presence does not impact
the patient’s clinical presentation or outcomes.53 Laboratory
tests for other chronic liver diseases are negative. NAFLD can
exist in concert with HCV, although HCV infection (particu-
larly genotype 3 HCV) itself can promote hepatic steatosis (see
Chapter 80). Serum and hepatic iron levels may be elevated in
patients with NAFLD. In particular, the serum ferritin level may
be elevated in 20% to 50% of patients with NAFLD and may
be a marker of more advanced disease. A serum ferritin greater
than 1.5 times the upper limit of normal has been independently
associated with a higher NAS in a study of 628 adult patients
with NAFLD,54 although the frequency of genetic hemochroma-
tosis is not increased in patients with NAFLD, who demonstrate

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TABLE 87.2 Clinical and Laboratory Features of NAFLD
Symptoms Signs
Common
None (48%-100% of patients) Hepatomegaly
Uncommon
Vague RUQ pain Splenomegaly
Fatigue Spider telangiectases
Malaise Palmar erythema
Ascites
A B
Fig. 87.4 Imaging studies of fatty liver. A, US demonstrating increased echogenicity. B, T1-weighted MRI
demonstrating a “bright” liver. (Courtesy Dr. Mukesh Harisinghani, Boston, MA.)
predominantly Kupffer cell (secondary) iron overload on liver
biopsy specimens.55 Clinical and laboratory findings do not cor-
relate with the histologic severity of NAFLD, and the entire
histologic spectrum of NAFLD, including cirrhosis, can be seen
in patients with normal or near-normal serum aminotransferase
levels.56
Imaging studies are often obtained during the evaluation of
unexplained liver biochemical test abnormalities or suspected
NAFLD. Hepatic US may reveal a “bright” liver of increased
echogenicity, consistent with hepatic steatosis (Fig. 87.4). Fatty
liver also can be documented by abdominal CT (a fatty liver is
lower in density than the spleen), or by MRI (fat appears bright
on T1-weighted imaging). Areas of relative sparing of fat may
be seen. CT and MRI are excellent at detecting steatosis, with
areas under the receiver operating curve (AUROC) of 0.90 and
greater,57 whereas US is good at detecting steatosis, particularly
if the hepatic fat content is greater than 20%. Traditional cross-
sectional imaging is also useful for evaluating hepatic masses and
may describe findings of portal hypertension in advanced disease
(see Chapter 74). These modalities cannot confirm the presence
of or determine the severity of NASH.
Liver Biopsy
Although the diagnosis of NAFLD is relatively easy to make
when there is hepatic steatosis on cross-sectional imaging and
other chronic liver diseases have been excluded, a liver biopsy is
still required to identify patients with NASH. The reality is that
most patients with NAFLD do not undergo a liver biopsy. Liver
biopsy is an invasive procedure associated with rare but severe
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CHAPTER 87 Nonalcoholic Fatty Liver Disease 1359
87
Laboratory Features
2- to 4-fold elevation of serum ALT and AST levels
AST/ALT ratio <1 in most patients
Serum alkaline phosphatase level is slightly elevated in one third of patients
Normal serum bilirubin and serum albumin levels and prothrombin time
Elevated serum ferritin level
Low-titer (<1:320) ANA
complications, including hemorrhage and even death, and under-
taking liver biopsies in 20% to 30% of the general population is
not feasible. The ability to differentiate NASH from IFL is criti-
cal because those with NASH are at risk for progression to cir-
rhosis. The ideal approach would be to select patients for whom
liver biopsy might influence management with a more aggressive
treatment strategy, participation in clinical trials, or screening for
HCC in the setting of cirrhosis. Advanced imaging techniques as
well as laboratory tests and scoring systems have been studied as
either a means to identify high-risk patients who should undergo
liver biopsy or as potential noninvasive markers of either steato-
hepatitis or fibrosis (Fig. 87.5).
Imaging to Detect Fibrosis
New imaging techniques have been more successful in identifying
hepatic fibrosis than in detecting necroinflammation. The most
studied and widely available is the US-based technology of vibra-
tion-controlled transient elastography (VCTE or FibroScan),
which uses a low-amplitude shear wave that propagates through
the liver parenchyma (see Chapters 74 and 80). The speed of the
wave correlates with liver stiffness. Advantages of this noninvasive
technique include its ease of use and patient acceptance. Variable
cutoff values for liver stiffness have been used for identifying
advanced fibrosis, and one study demonstrated an AUROC of
0.93 with a cutoff score of 9.9 kPa, although 27% of participants
had unreliable results with the usual M probe.58 An XL probe
was developed to improve accuracy in the setting of obesity and
has improved reliability.59 A prospective study has demonstrated
that VCTE accurately distinguishes low from advanced stages
1360 PART IX Liver

Elevated serum aminotransferase levels,

hepatomegaly, and/or fatty liver on imaging

Exclude excessive alcohol use and other forms of

liver disease by history and laboratory tests

Fig. 87.5 Diagnostic approach to patients

Noninvasive risk stratification with clinical scoring system
(BARD, AST/ALT ratio, NAFLD fibrosis score, FIB-4)
Low risk Intermediate or high risk
Manage metabolic syndrome VCTE, MRI, or other method to evaluate
for fibrosis
Annual follow-up for reassessment
VCTE > 8.5 kilopascals,MRE > 3.1 kilopascals,
or other test result suggestive
of significant fibrosis
Consider liver biopsy to stage the disease and
assess the risk of progression
with suspected NAFLD. The diagnosis of
NAFLD is based on clinical and histologic
criteria. Most patients are evaluated because
of elevated serum aminotransferase levels
and/or hepatomegaly. The diagnosis of
NAFLD should be considered when exces-
sive alcohol use is absent and laboratory test
results exclude other causes of liver disease.
Imaging studies may demonstrate fatty liver.
Noninvasive risk stratification is appropri-
ate to determine who is at the greater risk
of advanced fibrosis and should be referred
for immediate liver biopsy. Liver biopsy is
the standard means of diagnosis and the
only test that can reliably differentiate simple
steatosis from NASH, although noninvasive
methods for assessing fibrosis are being
used increasingly. BARD, BMI, AST/ALT ratio,
diabetes mellitus; FIB-4, Fibrosis-4 (plate-
let count, age, AST, ALT); MRE, magnetic
resonance elastography; VCTE, vibration-
controlled transient elastography.

of fibrosis but is less accurate in distinguishing intermediate
stages of fibrosis or the presence of NASH.60 Other noninvasive
modalities to assess liver stiffness include acoustic radiation force
impulse elastography and supersonic sheer imaging. Acoustic
radiation force impulse elastography measures the velocity of
short-duration, high-intensity acoustic pushing pulses in the
liver. One large study of 291 patients with NAFLD in which all 3
ultrasound-based modalities were compared found similarly high
AUROCs for detection of F2, F3, and F4 fibrosis.61
Magnetic resonance elastography (MRE) combines MRI
with elastography and is accurate for staging NAFLD fibrosis.
MRE has proved excellent for staging liver fibrosis in patients
with NAFLD and is superior to VCTE.62-64 Disadvantages to
MRE include a comparatively higher cost and limited availability
because of the specific MRI software and hardware required.
Laboratory Tests for Fibrosis
Simple, noninvasive, and quantitative laboratory tests have been
developed to estimate the presence of steatohepatitis or hepatic
fibrosis. The most studied single marker for identifying NASH
is cytokeratin (CK)-18, a marker of apoptosis,65,66 but this test is
not commercially available and does not appear to have enough
sensitivity and specificity to be used alone as a predictive marker
for NASH.
Clinical scoring systems have also been investigated for their
ability to predict either NASH or advanced fibrosis. These
systems use clinical or laboratory variables ranging from read-
ily available tests such as serum liver enzyme levels and plate-
let count to surrogate markers of necroinflammation or fibrosis,
such as apolipoprotein A-1 or tissue inhibitor of metalloprotein-
ase 1 (TIMP-1).
The major clinical scoring systems studied in NAFLD include
the FibroTest (FibroSure); FibroMeter; NAFLD fibrosis score;
Fibrosis-4 (FIB-4); AST-to-platelet ratio (APRI); BARD (BMI,
AST/ALT ratio, diabetes mellitus); Enhanced Liver Fibrosis
(ELF) score (TIMP-1, amino-terminal propeptide of type III
procollagen [PIIINP], hyaluronic acid); NashTest; and the AST/
ALT ratio. Comparison of the accuracy of these tests in terms
of positive and negative predictive values generally has dem-
onstrated that the more complicated and expensive tests (e.g.,
FibroTest, ELF) do not outperform the more readily obtained
basic laboratory tests that can be calculated during an office visit.
These tests are best at predicting absent or advanced fibrosis and
are less helpful for distinguishing intermediate stages of fibrosis.67
The NAFLD fibrosis score is perhaps the most commonly used
clinical scoring algorithm and incorporates age, BMI, hypergly-
cemia, AST/ALT ratio, platelet count, and serum albumin level
(http://gihep.com/calculators/hepatology/nafld-fibrosis-score/).68
A low cutoff value for this score has been shown to have a high
negative predictive value of 88% to 93%, and a high cutoff value
has shown a good positive predictive value of 82% to 90%. This
leaves 1 in 4 patients as having an indeterminate result; for this
group, a liver biopsy would be required for accurate staging. A
study investigating the utility of US or the NAFLD fibrosis score
in the National Health and Nutrition Examination Survey, 1988-
1994 cohort, has suggested that the NAFLD fibrosis score may
predict increased mortality along with advanced fibrosis.69 The
FIB-4 index is also available online (http://gihep.com/calculator
s/hepatology/fibrosis-4-score) and uses platelet count, age, AST,
and ALT to predict presence or absence of advanced fibrosis with
reasonable accuracy, as reported in a study of Veteran Affairs
patients with an AUROC of 0.62 to 0.80.70 Both scoring systems
have a 20% to 35% false-positive rate in older populations, a limi-
tation in patients who are 65 years of age or older.71 These scor-
ing systems are useful adjuncts in clinical practice for stratifying
risk within the large cohort of NAFLD patients. The AST/ALT
ratio alone can be used as a “stand-alone” test, with the implication

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 CHAPTER 87 Nonalcoholic Fatty Liver Disease 1361

BOX 87.3 Risk Factors for Advanced* NAFLD 87

CLINICAL
Older age (>50 yr)
Obesity
Diabetes mellitus/insulin resistance
Ethnicity (Hispanic)
Hypertension
LABORATORY
AST/ALT ratio approaching 1
Serum ALT level > twice the upper limit of normal
Serum AST level > 40 U/L
HISTOLOGIC
Necroinflammatory activity (hepatocyte ballooning, necrosis)
Stainable iron
Fibrosis
  
*NASH and advanced fibrosis.
Fig. 87.6 Focal fatty liver. Focal fatty liver (arrow) on CT. The charac-
teristic features are the nonspherical shape, absence of a mass effect,
and CT attenuation values consistent with those of soft tissue. US and
of more advanced fibrosis as the value approaches 1 in patients MRI also may confirm the diagnosis of focal fatty liver. (Courtesy Dr.
with NAFLD. Box 87.3 lists the common risk factors for advanced Mukesh Harisinghani, Boston, MA.)
fibrosis in NAFLD.

Focal Fatty Liver
In contrast to NAFLD, which is a diffuse parenchymal process,
focal fatty liver is a localized or patchy process that simulates a
space-occupying lesion in the liver on imaging studies. This con-
dition has been recognized increasingly in adults and children as
a result of the improved sensitivity of abdominal imaging. Focal
fatty liver has characteristic patterns on CT: usually a nonspheri-
cal shape, absence of mass effect, and CT attenuation values con-
sistent with those of soft tissue.72 The density of focal fatty liver is
close to that of water, unlike that of liver metastases, which have a
density that is closer to that of hepatocytes. US and MRI can help
confirm a diagnosis of focal fatty liver (Fig. 87.6). A presumptive
diagnosis of focal fatty liver should not be made when a mass
effect, areas of mixed hypo- and hyperechogenicity, an irregular
shape, or a history of malignancy is present. In such cases, ultra-
sound-guided fine-needle biopsy is recommended. No evidence
exists to suggest that the pathogenesis of focal fatty liver is similar
to that of NAFLD. In fact, the pathogenesis of focal fatty liver is
uncertain and may involve altered venous blood flow to the liver,
tissue hypoxia, or intestinal malabsorption of lipoprotein. In the
absence of accompanying liver disease, the lesion often regresses.
No specific treatment is necessary.
NATURAL HISTORY
The natural history of NAFLD is determined in large part by the
histopathology of the liver at baseline, which identifies patients
with NASH and quantifies the amount of hepatic fibrosis. The
prognosis in patients with IFL in the absence of hepatocyte
necrosis and fibrosis is clearly more favorable, with a low poten-
tial for histologic or clinical progression.73 Patients with NAFLD
have been shown to have increased overall mortality compared
with matched controls without NAFLD,74 and the increased
liver-related mortality is confined to patients with NASH.75,76
Fibrosis appears to be the single most important predictor of dis-
ease-specific mortality, as shown in a cohort study of 229 patients
with biopsy-proven NAFLD followed for up to 33 years in whom
a fibrosis stage of 3 to 4, irrespective of the NAS, had an increased
mortality with a hazard ratio of 3.3 (confidence interval [CI], 2.27
to 4.76).77 There is substantial variability in the rate of fibrosis
NAFLD
80% 20%
Isolated NASH
fatty liver
~11% over 15 yr
Cirrhosis
~31% over 8 yr ~7% over 6.5 yr
Decompensation HCC
Fig. 87.7 Natural history of NAFLD, including isolated fatty liver (IFL)
and NASH. IFL rarely if ever progresses to cirrhosis and is not as-
sociated with an increased risk of death compared with the general
population. NASH is associated with an increased risk of death due
to cardiovascular disease, malignancy, and cirrhosis and its compli-
cations. Progression of fibrosis in NASH is associated with diabetes
mellitus, severe insulin resistance, higher BMI, weight gain >5 kg,
cigarette smoking, and rising serum aminotransferase levels. (Adapted
from Torres DM, Williams CD, Harrison SA. Features, diagnosis and
treatment of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol
2012;10:837-58.)
progression, and no clinical or laboratory data appear to reliably
predict the disease course. A meta-analysis of 11 cohort studies
has suggested annual fibrosis progression rates, from a baseline
of stage 0, of 0.07 stages for IFL compared with 0.14 stages for
NASH.78 This translates into progression of 1 stage over 14.3
years in patients with IFL and 7.1 years in patients with NASH. A
reasonable estimate is that ∼11% of patients with NASH progress
to cirrhosis over a 15- to 20-year period (Fig. 87.7).79
NAFLD and alcoholic hepatitis are similar histologically but
differ substantially in clinical outcomes. The 5-year survival rate
of patients with alcohol-associated hepatitis is only 50% to 75%
because of the large proportion of patients (>50%) in whom cir-
rhosis and its complications develop (see Chapter 86). One study
has shown that the long-term survival of patients with NASH is

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1362 PART IX Liver
significantly better than that of patients with alcohol-associated
hepatitis.80
In patients in whom NAFLD-associated cirrhosis develops,
the outcome may be similar to that for other causes of cirrho-
sis. NAFLD is the likely cause of most cases of cryptogenic cir-
rhosis,81 is the second most common indication for LT,82 and is
expected to become the leading indication for LT in the 2020s
(see Chapter 97).83
In concert with rising rates of NASH cirrhosis, rates of
NAFLD-related HCC are increasing, with one study showing a
9% annual increase84 and another suggesting that ∼7% of patients
with NASH cirrhosis will progress to HCC over 6.5 years of fol-
low-up.85 Reports of HCC developing in noncirrhotic patients
with NASH86 pose a difficult diagnostic dilemma, because it may
not be feasible to survey such a large population for HCC (see
Chapters 74 and 97).
CLINICAL ASSOCIATIONS
As noted earlier, the metabolic syndrome and diabetes mellitus
are associated with NAFLD. Other conditions, including cardio-
vascular disease, OSA, vitamin D deficiency, colonic adenomas,
hypothyroidism, chronic kidney disease, and polycystic ovarian
syndrome have also been associated with NAFLD. Cardiovascular
disease has been shown to be the primary cause of death in this
population. Although this is not surprising given the association of
NAFLD with the metabolic syndrome, evidence points to NAFLD
as an independent risk factor for cardiovascular disease with an OR
of 2.05 (95% CI, 1.81 to 2.31).95 In 5121 asymptomatic individuals,
NAFLD was an independent risk factor for subclinical coronary
atherosclerosis as detected by coronary CT angiography.96
OSA is common in the general population with an estimated
frequency of 1% to 4% and higher rates (25% to 35%) in obese
populations. Chronic intermittent hypoxia was associated with
a high NAS and increased hepatic fibrosis in a cohort of mor-
bidly obese patients undergoing bariatric surgery.97 One study
has demonstrated that obese patients with OSA have a greater
than 90% frequency of NAFLD and that 50% of patients with
NAFLD have symptoms suggestive of OSA.98
Vitamin D deficiency has been related to increased endo-
toxin exposure (see earlier), and the recognition of its widespread
prevalence parallels that of NAFLD. The coexistence of NAFLD
and vitamin D deficiency appears to go beyond a simple associa-
tion because vitamin D deficiency is found in populations with
NAFLD independent of age, gender, and serum TG and glu-
cose levels,99 although a meta-analysis has suggested that vita-
min D deficiency is not associated with the histologic severity
of NAFLD.100 There are no prospective studies to suggest vita-
min D replacement may improve NAFLD or NASH, but it has
become common to check vitamin D levels and replete vitamin D
as necessary in patients with NAFLD.
Several retrospective and prospective studies have also sug-
gested a relationship between NAFLD and colonic adenomas.101
One population-based study in Korea102 and one prospective
study in China103 showed higher frequencies of colonic adeno-
mas, as well as of advanced neoplasia such as cancer, high-grade
dysplasia, or villous histology, in persons with NAFLD. A study of
26,540 patients undergoing first-time colonoscopy and same-day
abdominal US demonstrated higher rates of advanced colorectal
neoplasia in patients with NAFLD compared with patients with-
out NAFLD (OR 1.2; 95% CI, 0.99 to 1.47).104
NAFLD has been reported to be associated with chronic kidney
disease. A large meta-analysis demonstrated that NAFLD is asso-
ciated with a 40% increase in incident chronic kidney disease.105
Similarly, in a cohort of middle-aged patients without chronic kid-
ney disease assessed for NAFLD via the NAFLD fibrosis score and
US,106 the risk of developing chronic kidney disease was greater in
patients with NAFLD and increased with a greater NFS.
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TREATMENT
The optimal therapy for NAFLD has not been established,
although there is general consensus that treatment efforts should
be targeted to patients with NASH, particularly with fibrosis.
Each of the histologic or surrogate end points that have been used
in treatment trials have limitations. Histologic improvement in
steatosis, inflammation, and fibrosis is the ultimate goal of treat-
ment, but a single drug is unlikely to produce all these effects.
As fibrosis worsens, steatosis and inflammation often improve;
therefore, NASH and fibrosis must be assessed separately. As
discussed earlier, the NAS has been the most accepted scoring
system for quantifying histologic improvement, and a 2-point
improvement in the NAS, with 1 of the points coming from a
reduction in hepatocyte ballooning, has been thought to indicate
a successful intervention.107 Improvement in fibrosis (which is not
part of the NAS) has become a primary end point of newer trials,
although inclusion of this end point has lengthened the duration
of treatment trials from 6 to 12 months to multiple years. Most
trials with histologic end points target either a 2-point improve-
ment in the NAS with stable fibrosis or improvement in fibrosis
with a stable NAS.
Although still the gold standard, liver biopsy is invasive and
subject to interobserver variability as well as sampling error (see
earlier). Therefore, interest has increased in biomarkers as poten-
tial surrogate end points for clinical treatment trials. Noninvasive
markers of hepatic fibrosis, such as VCTE and MRE, are often
used in clinical treatment trials. Controlled attenuation parame-
ter software may be added on to VCTE to quantify steatosis. Bio-
chemical markers such as CK-18 and scoring systems including
the ELF and NAFLD fibrosis scores have also been used. Treat-
ment trials using clinical end points are difficult but can be done
when the trial is long in duration and focused on patients with
end-stage liver disease, in whom outcomes such as variceal bleed-
ing or encephalopathy can occur. Changes in portal venous pres-
sure can be evaluated using directed measurement of the hepatic
venous pressure gradient, particularly in clinical treatment trials
focused on reducing fibrosis (see Chapter 92).
Historically, the treatment of NAFLD has consisted of weight
loss, removal of offending drugs and toxins, and control of associ-
ated metabolic disorders, including diabetes mellitus and hyper-
lipidemia. Treatment strategies are now grouped into lifestyle
modification, surgical interventions for weight loss, and pharma-
cotherapy (Table 87.3).
Lifestyle Modification
Lifestyle modification is often divided into a reduction in calories
with a goal of weight loss, macronutrient modification, and physi-
cal activity, including aerobic and resistance activity. Most studies
of calorie restriction include an exercise component, making it
difficult to assess which approach is the most beneficial.
Nutritional counseling and caloric restriction leading to
weight loss have been shown to improve hepatic histology in sev-
eral randomized controlled trials. One large prospective trial of
261 patients followed for 12 months demonstrated that all fea-
tures of NASH improved with weight loss of at least 10%, and
fibrosis stabilized or improved with weight loss of at least 5%.108
Similarly, a meta-analysis of 8 randomized controlled trials sug-
gested a weight loss of at least 5% resulted in improvement in
hepatic steatosis, and weight loss of at least 7% improved the
NAS.109 Optimal approaches to obtain these weight loss goals
remain undefined, and the ability to sustain weight loss over time
is limited to a small minority of patients.
The merits of specific diets such as the Mediterranean or low-
carbohydrate diets have not been well studied in patients with
NASH. Although some data suggest that the Mediterranean diet
may improve hepatic steatosis,110 there is no evidence to favor
 CHAPTER 87 Nonalcoholic Fatty Liver Disease 1363

TABLE 87.3 Current and Future Treatment Options for NAFLD

87
Modality Effect Comment(s)
Dietary Advice
Weight loss 5%-10% Improves most features of NASH Difficult to sustain
Moderate caloric restriction with goal 500-750
kcal fewer per day
Eliminate or reduce SFAs, high fructose corn High consumption risk factor for NASH and Prospective trials lacking
syrup ↑ fibrosis
Consider omega-3 fatty acid replacement Decreases hepatic steatosis improves serum Lack of histologic improvement in NAFLD/NASH
triglycerides Useful for hypertriglyceridemia
Consider regular coffee consumption, 2-3 cups Decreased risk of fibrosis Optimal amount unclear
per day
Exercise Advice
Aerobic and/or resistance training 3-4 times per Improves insulin resistance Best results when leads to weight loss
wk with the goal of 400 kcal expended
Bariatric Surgery
Sleeve gastrectomy, RYGB, LABG Improves or resolves NASH in 60%-80% cases as Use only when failed lifestyle modification and
well as fibrosis comorbid conditions justify risk of surgery
Pharmacotherapy (Current)
Vitamin E 800 IU daily Improves NASH but modestly; no fibrosis benefit Useful in nondiabetic populations
? Prostate cancer risk
Pioglitazone 30-45 mg daily Improves NASH, possible fibrosis improvement Side effect profile is often prohibitive (e.g., weight
gain, osteoporosis, edema, congestive heart
failure)
Not FDA approved for NASH
Incretin mimetics (exenatide and liraglutide) Improve insulin resistance, promote weight loss, GI side effects
modest histologic improvement in small trials Ongoing trial with semaglutide
Pentoxifylline Possible NASH and fibrosis improvement Small pilot trials
Statins Does not improve NASH histology Safe in NAFLD and reduces risk of cardiovascular
disease
Ezetimibe Modest improvement in pilot trial Safe in NAFLD and can be used for hyperlipidemia
but not as NAFLD/NASH therapy
Pharmacotherapy (Future)
FXR agonists: Improves NASH histology Side effects: pruritus, increased LDL, lowered HDL
Obeticholic acid
Aldafermin Ongoing phase 2 studies Side effects: diarrhea, nausea, diabetes mellitus
Antifibrotics: Ongoing phase 2 and phase 3 studies Promising but more data needed
Cenicriviroc, emricasan, selonsertib, GR-MD-02
PPAR-α/δ agonist: Relatively modest efficacy Side effects: ↑ serum creatinine
Elafibranor
  
FXR, farnesoid X receptor; LAGB, laparoscopic adjustable gastric banding; PPAR, peroxisome proliferator-activated receptor; RYGB, Roux-en-Y gastric
bypass; SFA, saturated fatty acid.
  

one approach over a general reduction of caloric intake. Limit-
ing saturated fatty acids and high-fructose corn syrup may also
be beneficial, because diets high in saturated fatty acids and
fructose have been associated with NASH.111 A large retrospec-
tive study has even shown a correlation between daily fructose
consumption and higher fibrosis stage, although no prospective
trials have demonstrated histologic improvement with fructose
restriction.112
Omega-3 fatty acids are approved in the USA to treat hyper-
triglyceridemia and have been investigated as a potential therapy
for NAFLD. A meta-analysis of 9 studies of 355 patients dem-
onstrated that omega-3 supplementation improved hepatic ste-
atosis, although no histologic data were available.113 Reduction
in steatosis occurred in the absence of weight loss with a median
daily omega-3 supplement dose of 4 g. Other trials have failed
to show benefit with omega-3 supplementation in NAFLD and
NASH.114,115 Omega-3 supplementation requires further study
as a treatment for NAFLD or NASH but can be considered for
the treatment of hypertriglyceridemia in these patients.
A relationship between caffeinated coffee intake and chronic
liver disease has been observed, and large retrospective studies
have demonstrated a protective effect of coffee in alcoholic liver
disease116 as well as chronic hepatitis C117 (see Chapters 74, 80,
and 86). Preliminary studies suggest that this relationship holds
true for patients with NAFLD as well, in whom coffee intake has
been associated with lower stages of hepatic fibrosis.118,119 This
benefit has been seen with 2 to 3 cups of caffeinated coffee daily
and does not appear to carry over to other caffeinated beverages,
decaffeinated coffee, or espresso.120
Patients with NASH are more sedentary and have less cardio-
vascular fitness compared with untrained sedentary controls.121
Physical activity is another lifestyle intervention that can be rec-
ommended in concert with nutritional counseling or as mono-
therapy. Moderate and vigorous physical activity have been
shown to be effective in reducing intrahepatic TG content in a
12-month treatment trial, although the improvement appeared to
be mediated largely by weight loss.122 Smaller trials and a meta-
analysis have suggested that weight reduction is not required to

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1364 PART IX Liver
improve intrahepatic TG content.123-125 The response of NASH
to exercise is less certain, with analysis from a large retrospec-
tive cohort of biopsy-proved patients with NASH demonstrating
that moderate intensity exercise (3.0 to 5.9 metabolic equivalents)
did not improve the severity of NASH or fibrosis.126 Vigorous
activity (≥6 metabolic equivalents) did improve NASH histology,
and fibrosis improved with doubling of vigorous activity. Prac-
tice guidelines by the AASLD in 2018 recommended exercise
in concert with caloric reduction, with the net goal of sustained
weight loss over time.83 Specific recommendations on the type
and intensity of exercise have not been made.
Although lifestyle modification appears beneficial for NAFLD,
no single particular lifestyle intervention can be recommended,
and no one approach is likely to be suitable for all patients.127
Adequate weight loss of 5% to 10% is difficult to achieve and even
more difficult to sustain over time. The AASLD practice guide-
lines83 and 2012 tri-society practice guidelines128 both recom-
mend a hypocaloric diet in conjunction with increased physical
activity with weight loss goal of 7% to 10% but omit specific rec-
ommendations on the composition of the diet or type of exercise.
Bariatric Surgery
Bariatric surgery leads to substantial weight loss that results in
improved metabolic parameters and hepatic histology in patients
with NAFLD, according to numerous large retrospective and pro-
spective cohort studies (see Chapter 8).128,129 In one study of 109
patients with NASH who underwent follow-up liver biopsy one year
after bariatric surgery, 85% of patients had resolution of NASH, and
33% had improvement in fibrosis.130 Initial concerns that fibrosis
would worsen with rapid weight loss were unfounded, as demon-
strated in a meta-analysis in which fibrosis improved by 11.9% from
baseline after bariatric surgery.131 Although bariatric surgery is not
recommended as a treatment for NASH, the abundant positive
data in its favor suggest that surgical weight loss is a viable option
for patients with comorbid conditions that would warrant the sur-
gery for other reasons. Patients with NASH cirrhosis are at poten-
tially higher risk for surgical complications, although some centers
have demonstrated encouraging results with sleeve gastrectomy in
patients with Child-Pugh class A cirrhosis (see Chapter 8).132
Pharmacotherapy
A myriad of pharmacologic approaches has been investigated for
the treatment of NAFLD and may be grouped into the broad
categories of weight loss medications, insulin sensitizers, antioxi-
dants, and cytoprotective or antifibrotic agents.
Weight Loss Medications
A limited number of medical therapies are available for weight loss,
and even fewer have been studied in patients with NAFLD (see
Chapter 7). The most studied to date is orlistat, a reversible inhibi-
tor of pancreatic and gastric lipase. This medication promotes mod-
est weight loss through intestinal fat malabsorption and is available
by prescription (Xenical, Roche) as well as in a lower-dose over-
the-counter version (Alli, GlaxoSmithKline). Pilot trials were ini-
tially promising, but subsequent larger randomized controlled trials
demonstrated similar weight loss between patients receiving orlistat
and those receiving placebo.133,134 A weight loss of 9% was shown
to be the threshold required to produce histologic improvement
in steatosis and necroinflammation regardless of treatment arm.
Case reports of cholelithiasis, cholestasis, and, rarely, hepatic injury
prompted the FDA to issue a post-marketing warning for orlistat
in 2009. These observations, combined with only modest weight
loss effect and side effects of oily stools and potential malabsorption
of other medications, have limited the utility of this drug. Other
weight loss agents, including phentermine, lorcaserin, and phenter-
mine/topiramate, have not been studied in patients with NAFLD.
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Antioxidants
Medications that reduce the generation of reactive oxygen spe-
cies in the liver to minimize oxidative stress are another potential
avenue for therapy. The most studied antioxidant, vitamin E, an
inexpensive yet potent antioxidant, has been examined as an agent
for the treatment of NAFLD in adult and pediatric studies. In
most adult and pediatric studies, vitamin E was well tolerated,
improved serum aminotransferase levels, reduced hepatic ste-
atosis, and, in nondiabetic populations, improved steatohepati-
tis but not fibrosis.135,136 Some concerns have been raised about
the use of vitamin E in diabetic patients due to cardiovascular
risk, and vitamin E is not recommended in diabetic patients with
NAFLD.137 A reported increase in all-cause mortality in a meta-
analysis138 was refuted by a larger, more comprehensive study.139
Despite lingering questions about a modest increase in prostate
cancer rates,140 therapy with vitamin E can be considered in non-
diabetic patients with NASH, as recommended by the AASLD.83
Diabetic Medications
The association between hyperinsulinemic insulin resistance
and NAFLD provides a logical target for treatment. Metformin,
thiazolidinediones (TZDs), and incretin mimetics are all dia-
betic medications that have been investigated in the treatment of
NASH. Metformin, a biguanide that reduces hyperinsulinemia
and improves hepatic insulin sensitivity, reduces hepatomeg-
aly and hepatic steatosis in ob/ob mice141 but results in human
NAFLD have been less impressive.142,143 The use of metformin is
currently not recommended as a therapy for NAFLD or NASH.
TZDs are potent peroxisome proliferator-activated receptor
(PPAR)-γ agonists, a nuclear receptor that is expressed in adipose
tissue, muscle, and liver. In adipocytes, PPAR-γ promotes cell
differentiation and decreases lipolysis and FFA release. TZDs
improve insulin resistance by increasing glucose disposal in mus-
cle and decreasing hepatic glucose output. The TZDs rosigli-
tazone and pioglitazone have been investigated in several large,
well-designed, randomized controlled trials, in which treatment
was well tolerated and associated with improved insulin resis-
tance, normalization of liver biochemical test levels, and histo-
logic improvement in most patients.141,144,145 Pioglitazone has
become the primary agent available, because rosiglitazone use
is now limited because of an FDA warning that the frequency
of coronary events is increased. A meta-analysis has confirmed
that treatment with pioglitazone results in a significant benefit in
reducing hepatic fibrosis in patients with NASH with or without
diabetes mellitus.146 Drawbacks to TZD therapy include an aver-
age weight gain of 5 to 10 pounds over 1 to 3 years of therapy,
as well as increased bone loss147 and possibly increased rates of
bladder cancer.148 Continued treatment appears to be necessary
because subsequent studies have demonstrated recurrent NASH
after discontinuation of therapy.149 Fortunately, long-term
treatment with pioglitazone for NASH was reported to be safe,
effective, and well tolerated in both prediabetics and diabetics
in a study of 101 patients followed for 36 months.150 The 2018
AASLD practice guidelines recommend pioglitazone as a therapy
for patients with biopsy-proven NASH after a discussion with the
patient of the risks and benefits of therapy.83
Incretin mimetics are another class of diabetic medications
that have been less studied in NASH populations but have shown
preliminary promise. Exenatide and liraglutide are glucagon-like
protein-1 receptor (GLP-1) agonists that improve insulin sensi-
tivity and serum glucose levels and promote modest weight loss.
Exenatide has shown promise in animal models,151 as have human
pilot trials.152,153 A randomized controlled trial of 52 patients in
which liraglutide was compared with placebo showed signifi-
cant histologic improvement, including resolution in NASH, in
39% treated with liraglutide compared with 9% in those treated
with placebo.154 A phase 2b trial with another GLP-1 agonist

(semaglutide) is ongoing.155 GI side effects, including nausea and
diarrhea, may contribute to the weight loss seen with these medi-
cations, and results from larger studies are awaited.
Cytoprotective Agents
Cytoprotective agents are thought to prevent apoptosis and
down-regulate the inflammatory cascade. UDCA, a cytopro-
tective agent, showed promise in smaller trials in patients with
NASH,156,157 although the largest placebo-controlled trial dem-
onstrated equal improvement with UDCA and placebo.158 UDCA
is not currently recommended for the treatment of NAFLD or
NASH.
Pentoxifylline (PTX) is a cytoprotective agent that has also
been studied in patients with NASH and that has been shown to
inhibit proinflammatory cytokines (including TNF-α), leading to
a reduced production of reactive oxygen species.159 Two pilot tri-
als, as well as a randomized controlled trial, have shown varying
degrees of histologic improvement as well as improvements in
liver biochemical test levels and insulin resistance.160,161 Another
small open-label study demonstrated improvement in the NAS
but not in fibrosis with PTX for 1 year and lifestyle modification
compared with lifestyle modification alone.162 Further study is
required to determine whether PTX therapy is an appropriate
primary NASH therapy.
Lipid-Lowering Agents
Because patients with NASH often have co-existing hyperlip-
idemia, the use of lipid-lowering agents in NAFLD has been
studied as a potential duel-target therapy to address both condi-
tions. The most commonly prescribed agents for hyperlipidemia
are statins, which inhibit 3-hydroxy-3-methylglutaryl-coenzyme
A (HMG-CoA) reductase, a primary enzyme in cholesterol bio-
synthesis (see Chapter 64). Statins have shown modest benefit in
pilot NASH treatment trials.163,164 Larger trials without the sur-
rogate end points of liver enzyme levels or improved hepatic ste-
atosis have also suggested a benefit and demonstrated improved
cardiovascular outcomes with therapy.165,166 Statins can be rec-
ommended to treat concomitant hyperlipidemia in patients with
NASH, but further study is needed before statins can be recom-
mended as primary therapy for NASH.
Ezetimibe is another lipid-lowering agent that has shown ben-
efit in improving hepatic histology in animal models,167 as well as
in 1 pilot trial in 24 patients with NAFLD.168 Again, more evi-
dence is necessary before ezetimibe can be recommended as pri-
mary therapy for NAFLD. An expert panel recommended use of
statins, alone or in combination with ezetimibe or pioglitazone,
as a treatment for NAFLD and NASH pending forthcoming ran-
domized clinical trials.169
Other Therapies
Angiotensin-receptor blockers (ARBs) are used routinely for
the treatment of hypertension, heart failure, and chronic kid-
ney disease—conditions that may be found in association with
NAFLD. In animal models, ARBs have been shown to inhibit
hepatic stellate cell activity, leading to a reduction in hepatic
fibrosis in obese mice.170 One pilot trial suggested a similar ben-
efit in humans, but a larger randomized controlled trial using
losartan in addition to rosiglitazone failed to produce any addi-
tional histologic benefit beyond that seen with rosiglitazone
alone.171 Additional study is necessary to determine if ARBs are
efficacious for NASH.
The importance of bile acid synthesis and transport in the
pathogenesis of NAFLD, as discussed earlier, suggests novel
targets for potential treatments (see Chapter 64). The nuclear
hormone receptor FXR receptor is a master “conductor” that
modulates lipid and glucose homeostasis. The FXR agonist
obeticholic acid has shown promise as a treatment for NASH,
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CHAPTER 87 Nonalcoholic Fatty Liver Disease 1365
with results from the large randomized controlled trial (the
FLINT trial) demonstrating improved metabolic parameters and 87
liver histology.172 Side effects, including pruritus, increased LDL
levels, and lowered HDL levels led to a larger phase 3 study, in
progress, to clarify the severity of these effects.
The antifibrotic agents are potential therapies and are
undergoing intense investigation. Targeting fibrosis is appeal-
ing because of the direct link between fibrosis and outcomes,
although using fibrosis as a primary study end point often results
in studies of long duration because it may take ∼7 years per stage
of fibrosis progression in the absence of an intervention (see ear-
lier).173 Numerous antifibrotic agents have been or are currently
under study, including emricisan, selonsertib, aldafermin, and
GF-MD-02. Although selonsertib was shown to improve fibro-
sis without worsening of the NAS in a phase 2 study, subsequent
phase 3 studies failed to confirm its antifibrotic effect.174 Alda-
fermin demonstrated significant increases in fibrosis improve-
ment and resolution of NASH compared with placebo in a phase
2 trial.
Other novel therapeutic approaches may be derived from
advances in our understanding of the pathogenesis of NASH.
Alterations in gut flora and SIBO are thought to contribute to
NASH and may provide a novel outlet for therapy. Elafibranor
is a dual PPAR-α/δ dual agonist and has beneficial effects on
glucose and lipid homeostasis. In a large published randomized
controlled trial, treatment with elafibranor led to resolution of
NASH without worsening of fibrosis in an intention-to-treat
analysis and had a good side effect profile.175 Potential effects on
the serum creatinine level with this medication and a relatively
modest effect (19% improvement) necessitate that further study
be undertaken.
Most NASH treatment trials have involved single agents that
usually target pathways that lead to inflammation or fibrosis.
Combination therapies could approach multiple different targets
and improve efficacy. A few phase 2 trials have begun using this
approach in the hope that combination therapy will provide equal
or greater efficacy than each agent alone would.
In summary, present therapies for NAFLD rely heavily on
lifestyle interventions that, when successful and sustained, can
produce significant histology and biochemical benefits. Treat-
ment of concomitant metabolic disease such as diabetes mel-
litus or hyperlipidemia may produce modest improvements in
hepatic histology as well, although not enough to warrant their
use as primary therapy for NASH. Pioglitazone and vitamin E
can be considered in specific target populations. Bariatric sur-
gery is an option for obese patients with NASH and comorbid
conditions.
LT
As described earlier, NASH cirrhosis is the second most com-
mon indication for LT and is expected to become the lead-
ing indication for LT in the 2020s.87 Comorbid conditions
limit eligibility for transplantation, and although the 30-day
transplant mortality is higher for NASH cirrhosis, 1- to
3-year mortality rates are similar to those for other indica-
tions for LT.88-90 Cardiovascular disease is found frequently
in patients with NASH, and adequate preoperative cardiac
risk stratification is important. Van Wagner and colleagues
demonstrated an increased rate of cardiovascular events in
NASH cirrhotics undergoing LT, particularly in the peri-
operative period, compared with patients with alcohol-asso-
ciated cirrhosis, with an OR of 4.12 (95 CI, 1.91 to 8.90).91
The majority of patients have recurrent steatosis 5 years after
LT, although only 5% have been reported to develop recur-
rent cirrhosis within that time.92Hepatic steatosis in donor
grafts is an entirely different consideration that is increasingly
common and is found in one third to one half of potential
1366 PART IX Liver

liver and cadaveric liver transplant donors.93 Transplanted
steatotic livers have been associated with primary graft non-
function and poorer overall outcomes (see Chapter 97).94
Grafts with less than 30% steatosis are acceptable for use, and
those with greater than 60% fat are generally considered unac-
ceptable. Those with intermediate grades of steatosis (30% to
60%) are evaluated on a case-by-case and center-dependent
basis. Liver biopsy and consultation with an expert pathologist
prior to harvesting the organ can be useful for determining
donor acceptability.
Full references for this chapter can be found on www.expertconsult.com.

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