Annals of Medicine and Surgery 50 (2020) 41–48

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Review

Work up of fatty liver by primary care physicians, review T

a,∗ b b
Rishi Rikhi , Tavankit Singh , Jamak Modaresi Esfeh
a
Cleveland Clinic, Department of Internal Medicine, 9500 Euclid Avenue, Cleveland, OH, 44195, USA
b
Cleveland Clinic, Department of Gastroenterology, Hepatology & Nutrition, 9500 Euclid Avenue, Cleveland, OH, 44195, USA

ARTICLE INFO ABSTRACT

Keywords: Nonalcoholic fatty liver disease (NAFLD) is an overarching term that refers to abnormal deposition of lipids in
NAFLD the liver and is used to describe the spectrum of disease ranging from hepatic steatosis to nonalcoholic stea-
Primary health care tohepatitis to cirrhosis. NAFLD is the most common cause of chronic liver disease and the second most common
cause of cirrhosis. Although the pathophysiology is not completely understood, there is a strong link between
NAFLD and metabolic syndrome. This review focuses on the workup of NAFLD in the primary care setting, from
differential diagnoses to assessing fibrosis via predictive models that use commonly used laboratory values,
biomarkers, and imaging. The purpose of this review article is to provide a set of screening and diagnostic tools
for all primary care physicians in order to better manage patients with NAFLD.

1. Introduction 2. What is nonalcoholic fatty liver disease?

Chronic liver disease (CLD) is the 12th leading cause of death in the NAFLD is an overarching term that refers to abnormal deposition of
United States (US) [1]. The most common cause of CLD not just in the lipids in the liver and is used to describe the spectrum of disease ran-
US, but worldwide is nonalcoholic fatty liver disease (NAFLD) [2–4]. ging from hepatic steatosis to nonalcoholic steatohepatitis (NASH) to
NAFLD is currently the second most common etiology of cirrhosis in cirrhosis [11]. By definition, a diagnosis of NAFLD cannot be made in
patients undergoing liver transplantation [5] and is projected to be- an individual with other etiologies of fatty liver disease (discussed
come the leading cause of liver transplant by 2020 [6,7]. The increase below) or in patients with excessive alcohol intake, described as 20 g
in prevalence of NAFLD, examined by the National Health and Nutri- and 10 g a day for men and women, respectively [11]. For reference, 12
tion Examination Surveys from 1988 to 2008 illustrating that NAFLD as ounces of beer, 5 ounces of wine, and 1.5 ounces of 80 proof liquor are
a cause of CLD rose from 46.8% in 1988 to 75.1% in 2008 parallels the all equal to 14 g of alcohol [12]. Simple steatosis (SS) refers to excessive
rise in prevalence of obesity, diabetes mellitus and hypertension during lipid deposition in > 5% hepatocytes without hepatocellular injury
the same time period [4]. In addition to hypertension, diabetes and [11,13]. While the course of SS is relatively benign [14], approximately
obesity; hypertriglyceridemia and low levels of high-density lipoprotein 20% of individuals with SS will progress to the more aggressive variant
cholesterol (HDL) have also been found to be risk factors for the de- of NAFLD-called NASH, which includes the presence of steatosis, lob-
velopment of NAFLD [8]. ular inflammation and hepatocellular injury [15]. Hepatocellular injury
Several of the above risk factors for NAFLD are chronic conditions is characterized by hepatocyte ballooning, a term used to describe he-
managed by primary care providers (PCPs) [9]. Thus, PCPs usually are patocytes that have lost their sharp angles and have a non-vacuolar
the ones who have the opportunity to diagnose patients with NAFLD cytoplasm [16]. Progressive inflammation leads to activation of stellate
and manage it initially [9]. Yet, surveys have found that 33% of PCPs cells in the liver which deposit collagen in the hepatic lobules. This
underestimated the prevalence of NAFLD [9], 69% did not identify process is known as fibrosis and fibrosis is staged 0–4 depending on the
NAFLD as a clinically important condition and 53% were un- extent and distribution (Table 1) [17]. Approximately 20% of patients
comfortable with the management of NAFLD [9]. Hence, there is an with NASH and 38% patient with NASH and fibrosis develop cirrhosis
urgent need to educate PCPs on the epidemiology and work up of this [18]. Unfortunately, to date, we do not have any tool to predict which
very common disease in order to provide more effective care for pa- patients with NAFLD will progress to cirrhosis.
tients with NAFLD. This review article provides an overview of NAFLD
and the recommended workup in the primary care setting.

∗
Corresponding author.
E-mail addresses: rikhir@[Link] (R. Rikhi), SINGHT4@[Link] (T. Singh), modarej@[Link] (J. Modaresi Esfeh).

[Link]
Received 2 September 2019; Received in revised form 17 December 2019; Accepted 3 January 2020
2049-0801/ © 2020 The Authors. Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd. This is an open access article under the CC BY license
([Link]
R. Rikhi, et al. Annals of Medicine and Surgery 50 (2020) 41–48

Abbreviations HU Hounsfield units

HELLP Hemolysis, elevated liver enzymes, low platelet count
NAFLD Nonalcoholic fatty liver disease AASLD The American Association for Study of Liver Disease
US United States FIB-4 Fibrosis-4 index
CLD Chronic liver disease VCTE Vibration controlled transient elastography
HDL High-density lipoprotein cholesterol NFS NAFLD fibrosis score
PCPs Primary care providers BMI Body mass index
NASH Nonalcoholic steatohepatitis ELF Enhanced Liver Fibrosis
SS Simple steatosis TIMP-1 Metalloproteinases
VLDL Very low-density lipoprotein PIIINP Propeptide of procollagen type III
JNK Jun N terminal kinase VCTE Vibration-controlled transient elastography
PNPLA3 Patatin-like phospholipase 3 MRE Magnetic resonance elastography
TM6SF2 Transmembrane 6 superfamily member 2 MRI Magnetic resonance imaging
AST Aspartate aminotransferase AGA American Gastroenterology Association
ALT Alanine transaminase

3. How does NAFLD develop? exact definitions for each of these conditions varies based on the or-
ganization or society [24]. The International Diabetes Federation
The pathophysiology of NAFLD is complex and not fully understood. guidelines from 2005 are commonly used in practice (Table 2) [24].
One of the leading theories is the “two-hit” hypothesis (Fig. 1). Here, the Patients with increased waist circumference, fasting glucose, blood
first hit leads to hepatic steatosis and the second hit results in steatohe- pressure, and triglycerides have a 4.9-fold, 2.1-fold, 1.8-fold, and 1.6-
patitis and hepatocellular injury. The liver allows for lipid homeostasis fold greater risk of NAFLD, respectively [19]. The prevalence of NAFLD
and this balance can be offset in obesity or in individuals with a dietary varies from 45% to 75% in diabetics and over 50% in patients with
intake high in saturated fatty acids and fructose, leading to increased hypertension [23]. The prevalence of NAFLD in obese patients is
fatty acid deposition in the liver, resulting in hepatic steatosis. Studies 80–90% and approximately 90% in patients with hyperlipidemia [25].
have found abdominal obesity (measured by waist circumference) to be While most patients with NAFLD have metabolic syndrome, seminal
more strongly associated with NAFLD, as visceral fat has higher rates of research has focused on a population of patients who are not obese but
lipolysis, leading to increased delivery of fatty acids to the liver [19]. have NAFLD [26]. Often, these cases, commonly referred to as “lean
Another factor that leads to increased uptake of free fatty acids and tri- NAFLD” are overlooked as they do not fit the typical NAFLD pre-
glycerides in the liver is insulin resistance [13]. Insulin normally sup- sentation [26]. Lean NAFLD illustrates the complexity of NAFLD pa-
presses hepatic production of very low-density lipoprotein (VLDL), which thophysiology and underscores the interplay between genetics and
is rich in triglycerides; thus, insulin resistance leads to hypertriglycer- metabolic syndrome in the development of NAFLD [26]. While limited
idemia [19]. Additionally, the higher amount of VLDL in the bloodstream information exists on the why patients with normal body weights de-
leads to decreased HDL [19]. Hormones, such as adiponectin, leptin, and velop NAFLD, research has shown that lean NAFLD is more prevalent
resistin regulate insulin activity and aberrant expression of these hor- among the Asian population [26]. Additionally, patients with lean
mones further leads to the development of NAFLD [20,21]. NAFLD still have higher amounts of abdominal fatty tissue, although
Hepatic inflammation is thought to occur from lipotoxicity and mi- their overall body weight is normal [26].
tochondrial dysfunction [22]. Mitochondrial dysfunction includes struc- There is also a strong genetic component associated with the de-
tural and functional changes, which impairs fat homeostasis leading to velopment of NAFLD with Latin Americans carrying the highest burden
increased inflammation and lipid-derived toxic metabolites [22]. Lipo- of NAFLD, and African Americans the lowest [27,28]. A prospective
toxicity occurs from saturated fatty acids that activate the Jun N terminal study of 320 individuals in the outpatient setting found the prevalence
kinase (JNK) pathway, resulting in hepatocyte death [22]. The excess of NAFLD to be 58.3% in Hispanics, 44.4% in Caucasians, and 35.1% in
fatty acids from lipolysis leads to increased acid oxidation, resulting in African Americans [29].
mitochondrial dysfunction [22]. The resulting inflammation leads to To further understand the genetic risk associated with NAFLD, re-
activation of Kupffer cells, which release cytokines that further damage search on polymorphisms in regulatory proteins involved in hepatic
hepatocytes [22]. The inflammatory process converts hepatic stellate lipid metabolism and insulin signaling is currently underway [13].
cells to myofibroblasts, resulting in hepatic fibrosis [22]. Patatin-like phospholipase 3 (PNPLA3) and transmembrane 6 super-
family member 2 (TM6SF2) are two well characterized genes involved
in the pathogenesis of NAFLD [22]. PNPLA3 encodes adiponutrin, a
4. Risk factors for NAFLD protein that aids in triglyceride metabolism and TM6SF2 encodes
TM6SF2 protein that aids in secretion of VLDL from the liver [22].
There is a strong association between NAFLD and metabolic syn- Polymorphisms of PNPLA3 and TM6SF2 are associated with increased
drome [19,23]. This syndrome is defined as having three of the fol- hepatic triglyceride accumulation and hepatic steatosis [22].
lowing conditions: diabetes mellitus, low HDL, hypertriglyceridemia, In addition to risk factors mentioned above, there are also un-
hypertension, and increased abdominal waist circumference [19]. The common causes of NAFLD [30]. There are several disorders of lipid
metabolism that lead to NAFLD: abetalipoproteinemia, familial hypo-
Table 1 betalipoproteinemia, familial combined hyperlipidemia, glycogen sto-
NASH stages of fibrosis.
rage disease, Weber-Christian disease, and congenital lipodystrophy
Fibrosis Stage [30]. Certain nutritional causes, including total parenteral nutrition,
surgical weight loss, and starvation can lead to NAFLD as well [30].
F 0 No fibrosis
F 1 Perisinusoidal or periportal fibrosis
Long term total parenteral nutrition results in a depletion of carnitine
F 2 Perisinusoidal and portal/periportal fibrosis and choline, key players in fatty acid transport and lipid storage,
F 3 Bridging fibrosis leading to steatosis [30]. Surgical weight loss leads to an increase in
F 4 Cirrhosis free fatty acids and starvation results in protein depletion, including

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R. Rikhi, et al. Annals of Medicine and Surgery 50 (2020) 41–48

Fig. 1. Pathogenesis of NAFLD using 2 hit hypothesis.

apolipoprotein synthesis, both leading to NAFLD [30]. Lastly, several might be equal to or higher than ALT. The degree of elevation of AST
medications have been shown to promote NAFLD, including amio- and ALT does not correlate with the quantity of hepatic fat deposition
darone, tamoxifen, methotrexate, corticosteroids, and highly active or severity of fibrosis. Despite having NAFLD, some patients can have
antiretroviral therapy [30]. normal AST/ALT levels. In fact, patients with normal ALT values can
exhibit the full spectrum of NAFLD [31]. Neither AST nor ALT are a
reflection of synthetic function of the liver. As a matter of fact, “liver
5. Clinical presentation and diagnostic modalities function tests” is a misnomer, as liver enzymes are not a reflection of
liver function, but rather, hepatocyte integrity [34]. The blood work
Patients with NAFLD may present to their PCP with complaints of that can show synthetic function of the liver include albumin, INR, and
fatigue and right upper quadrant pain; however, many will not have bilirubin [34]. These laboratory values are a measure of synthetic liver
any symptoms, although the majority will be overweight [31]. Eva- function and can be normal in patients with NAFLD [11].
luation of liver enzymes is helpful, as NAFLD is the most common cause Patients who have an incidental finding of hepatic steatosis on
of chronically elevated liver enzymes [32]. Aspartate aminotransferase imaging should be evaluated for NAFLD [11]. While screening for
(AST), found in hepatocellular mitochondria, and alanine transaminase NAFLD in high-risk groups is not recommended, right upper quadrant
(ALT), found in hepatocellular cytosol, are released during times of ultrasound or abdominal CT images may be ordered in patients for
liver injury [33]. Patients with NAFLD typically have an ALT level that other reasons; and subsequently, NAFLD may be incidentally diagnosed
is higher than AST except in patients with advanced fibrosis where AST

Table 2
The international diabetes federation guidelines 2005.
Waist Circumference > 80 cm in women and < 90 cm in men

Lipid Dysregulation Triglycerides > 150, HDL-C < 40 in men and < 50 in women
Hypertension Systolic > 130 mm Hg, Diastolic > 85, or patient on hypertension medications
Hyperglycemia Glucose over 100 mg/dL or diabetic

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R. Rikhi, et al. Annals of Medicine and Surgery 50 (2020) 41–48

[11]. Approximately 11% of individuals who have thoracic or abdom- screening [11]
inal imaging for non-liver related reasons would have incidental find- • There should be a high index of suspicion for NAFLD and NASH in
ings of hepatic steatosis [11]. Ultrasound is a noninvasive imaging patients with type 2 diabetes. Clinical decision aids such as NAFLD fi-
modality used to view the echogenicity of the liver parenchyma (Fig. 2) brosis score or fibrosis-4 index (FIB-4) or vibration controlled transient
[35]. The deposition of fat in the liver increases the echogenicity elastography (VCTE) can be used to identify those at low or high risk for
(Fig. 2) [35]. Normally, the echogenicity of the liver, spleen, and renal advanced fibrosis (bridging fibrosis or cirrhosis) [11]
cortex are similar [36]. Therefore, using the spleen and renal cortex as a
comparison, increased echogenicity of the liver can be assessed with
ultrasound (Fig. 2) [36]. CT imaging uses Hounsfield units (HU) to 8. Management of NAFLD
measure attenuation of organs and vasculature [36]. The liver normally
has increased attenuation compared to the spleen and intrahepatic Given that the degree of fibrosis is linked to long term outcomes and
vasculature [36]. Fatty liver causes decreased attenuation; thus, if the mortality in NAFLD patients [41], one of the first steps to do after di-
liver is 10 HU less than the spleen or if the liver has a total attenuation agnosing a patient with NAFLD is to assess the stage of fibrosis. While
less than 40 HU, fatty liver is suspected [36]. Ultrasound and non- liver biopsy remains the gold standard test for establishing the stage of
contrast enhanced CT imaging are useful modalities for detecting fatty fibrosis, in order to avoid an invasive procedure that carries a risk of
liver in patients with moderate to severe cases of hepatic steatosis; pain and bleeding, a number of prediction models that use demographic
however, they are not effective at detecting milder cases [36]. In fact, variables and laboratory values have been developed (Tables 4–6). In
once fatty liver has been detected by US imaging, more than 20% of the addition, over the last few years, imaging techniques like transient
liver is fat content [37]. elastography and magnetic resonance elastography have been devel-
oped to replace or serve as an adjunct to the prediction models to es-
6. Differentials timate the fibrosis stage.

In order for a diagnosis of NAFLD to be made, other causes of liver

disease must be excluded first, including viral hepatitis, autoimmune
hepatitis, Wilson disease, hemochromatosis, alpha-1 antitrypsin defi-
ciency, and alcoholic liver disease [11]. The patient's clinical picture of
diabetes mellitus, obesity, and dyslipidemia can help to narrow the
differential diagnoses [11]. Also, alcoholic liver disease must be ruled
out by assessing the patient's history of alcohol use [11]. If NAFLD is
still likely, other causes of hepatic steatosis must be investigated
(Table 3) [11]. Patients on parental nutrition or malnourished may
develop macrovesicular steatosis [11]. Wilson disease, hepatitis C in-
fection, lipodystrophy, and abetalipoproteinemia can all cause macro-
vesicular steatosis [11]. Patients who are pregnant may develop acute
fatty liver of pregnancy or HELLP (hemolysis, elevated liver enzymes,
low platelet count) syndrome, leading to microvesicular steatosis [11].
Additionally, Reye's syndrome and genetic metabolic diseases can lead
to microvesicular steatosis [11]. Iron studies can be useful in differ-
entiating hemochromatosis, but serum ferritin may be elevated in
NAFLD patients as well [11]. When elevated in NAFLD patients, the
ferritin and transferrin saturation are only mildly elevated. Approxi-
mately 21% of NAFLD patients will have high antibody titers (anti-
nuclear antibodies > 1:160 and anti-smooth muscle antibodies >
1:40); yet, positive antibodies and higher titer values are not associated
with advanced disease progression [11]. Specific lab tests should be
ordered by PCPs based on the clinical presentation of the patient, family
history, and patient's pretest probability [38].

7. Screening

The data regarding screening individuals with risk factors for

NAFLD is conflicting [11]. There is a lack of information on the effec-
tiveness of screening tests, such as ultrasound imaging or biochemical
studies, as well as diagnostic tests and treatment. Recent studies have
suggested that routine screening in high risk groups, such as patients
with diabetes mellitus or a family history of NASH, is not cost effective
and should not be done in the primary care setting [39,40]. The
American Association for Study of Liver Disease (AASLD) guidelines
currently do not recommend routine screening for NAFLD, even in
patients with risk factors and also do not recommend screening family
members of NAFLD patients [11].

• Routine Screening for NAFLD in high-risk groups attending primary care, Fig. 2. Ultrasonographic evidence of hepatic steatosis. The blue arrow high-
lights the increased echogenicity of the liver. (For interpretation of the refer-
diabetes, or obesity clinics is not advised at this time because of un-
certainties surrounding diagnostic tests and treatment options, along with ences to colour in this figure legend, the reader is referred to the Web version of
lack of knowledge related to long-term benefits and cost-effectiveness of this article.)

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R. Rikhi, et al. Annals of Medicine and Surgery 50 (2020) 41–48

Table 3 of fibrosis risk stratification tools found that NFS was the most cost
Differentials of NAFLD. effective in the primary care setting [44]. NFS is 90% accurate in de-
Condition Clinical History tecting the absence or presence of fibrosis [43].
Another tool for hepatic fibrosis assessment is the FIB-4 index that
Alcoholic liver disease Alcohol consumption: uses platelet count, patient's age, AST, and ALT to predict fibrosis [45].
• > 20 g a day for men
•
The FIB-4 score was originally used to estimate fibrosis stage in patients
> 10 g a day for women
Medication induced fatty liver Elevation of AST and ALT will coincide with
with hepatitis C virus infection but was subsequently validated for
disease medication use. NAFLD patients too [46]. FIB-4 values less than 1.6 have a 93.2% ne-
• Common medications include: gative predictive value and values greater than 3.6 have a 90.8% positive
• Lipid lowering agents (mipomersen and
lomitapide)
predictive value for detecting cirrhosis [47]. Both NFS and Fib-4 have

• Antiarrhythmics (amiodarone)
Immunosuppressive agents (methotrexate,
been validated by several studies, including McPherson et al., and can be
used in NAFLD patients to predict hepatic fibrosis (Tables 4 and 6) [48].
tamoxifen, and corticosteroids) FibroSURE, Hepascore, and Enhanced Liver Fibrosis (ELF) score are
• Antiepileptics (sodium valproate) three serum studies that measure direct biomarkers of fibrosis to predict
• Antiretrovirals
•
hepatic fibrosis in NAFLD (Tables 5 and 6) [49]. FibroSURE uses ALT,
Starvation Clinical history of BMI < 18.5
• Unintentional weight loss
α2‐macroglobulin, apolipoprotein A1, γ‐glutamyl transferase, hap-
• Poor oral intake toglobin, total bilirubin, age, and gender [49]. Hepascore uses
Parenteral nutrition • Current use of parenteral nutrition α2‐macroglobulin, hyaluronic acid, γ‐glutamyl transpeptidase, total
• History of recent use of parenteral nutrition bilirubin, age, and gender [50]. The ELF scoring system uses hyaluronic
Hepatitis C • History of intravenous drug use
• History of risky sexual practices
acid, tissue inhibitors of metalloproteinases (TIMP-1), and amino-
• Lab tests supporting Hepatitis C infection terminal propeptide of procollagen type III (PIIINP) in order to predict
Acute fatty liver of pregnancy • 3rd trimester pregnancy or early
postpartum
fibrosis [51]. These tests are expensive as they include special labora-
tory testing, which is not routinely done when evaluating patients with
• Right upper quadrant pain
•
CLD whereas the NAFLD fibrosis score and FIB-4 score use the la-
Jaundice
• Febrile
boratory values that are routinely done in CLD patients.
• Nausea and anorexia
HELLP syndrome • 3rd trimester pregnancy 9.1. Non-invasive imaging
• Headaches and visual disturbances
• Nausea and vomiting
• Abdominal pain
Measurement of liver stiffness via vibration-controlled transient
Reye's Syndrome • Children elastography (VCTE) is a useful noninvasive ultrasound-based tool to
• Use of aspirin assess for liver fibrosis in patients with NAFLD (Table 6) [52]. VCTE is
• Recent viral infection not capable of diagnosing NASH, but rather, can be used to estimate the
• Seizures
Abetalipoproteinemia • Diagnosed early in life
degree of fibrosis [53]. VCTE works by using ultrasonic waves to detect
• Failure to thrive liver stiffness, which has a high correlation with hepatic fibrosis [52].
• Neurological symptoms Using VCTE, a cut of value of 10.3 kPa has a 99% negative predictive
• Acanthocytosis value and 46% positive predictive value for cirrhosis [53]. This modality
• Foul smelling stools
•
previously had limitations as the probe was unable to measure adequate
Wilson Disease Younger than 55 years of age
• Psychiatric symptoms
depths [52]. In patients with a BMI greater than 30 kg/m2 have a VCTE
• Kayser-Fleischer rings failure rate of 22%–25% [53]. Advancements in the field have allowed
Hemochromatosis • Skin pigmentation for the XL probe, which is currently being studied as a method to over-
• Diabetes come adiposity interference [53]. Other factors that can limit the validity
• Cardiomegaly
of VCTE are hepatic congestion from heart failure and cholestasis [53].
Additionally, patients must fast 3 h prior to testing [53]. Lastly, similar to
most ultrasound-based imaging, VCTE is operator dependent and re-
9. Prediction models based on demographic variables and/or
quires an experienced technician [53]. However, a novel numerical
laboratory values
measurement, controlled attenuation parameter (CAP), allows for the
quantification of ultrasound attenuation, correlating to the degree of
The prediction models typically differentiate between presence of
steatosis; and thus, limiting operator variability [54,55].
advanced fibrosis (stage 3–4 fibrosis) and absence of advanced fibrosis
Magnetic resonance elastography (MRE) is an imaging modality that
(i.e. presence of stage 0–2 fibrosis) [42]. The NAFLD fibrosis score
combines magnetic resonance imaging (MRI) with mechanical waves to
(NFS) uses age, body mass index (BMI), presence of diabetes, AST, ALT,
measure liver stiffness (Table 6) [56]. The mechanical waves are generated
platelets, and albumin [43]. This model uses a score of less than
by a vibratory source and when they come into contact with the liver, they
−1.455 (negative predictive value 88% in validation group) to re-
generate a wavelength based on liver stiffness [57]. MRI sequence then
present stages F0–F2 and a score of greater than 0.675 (positive pre-
creates wave images and algorithms are then used for quantitative assess-
dictive value of 82% in validation group) to represent stages F3–F4
ment of liver stiffness. Since Liver fibrosis does not occur as a homogenous
(Tables 4 and 6) [43]. A recent study evaluating the cost-effectiveness
process, especially early in its course, an advantage of MRE is that it creates

Table 4
Non-invasive blood tests—serum calculators.
NFS Score Meaning Sensitivity Specificity PPV NPV

< -1.455 Absence of significant fibrosis 82% 77% 56% 93%

> 0.675 Presence of significant fibrosis 51% 98% 90% 85%
FIB-4
< 1.3 Absence of significant fibrosis 74% 71% 43% 90%
> 2.67 Presence of advanced fibrosis 33% 98% 80% 83%

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Table 5
Non-invasive blood tests—serum biomarker tests.
FibroSURE Score Meaning Sensitivity Specificity PPV NPV

> 0.3 Detection of bridging fibrosis or cirrhosis 92% 71% 33% 98%
> 0.7 Detection of bridging fibrosis or cirrhosis 25% 97% 60% 89%
Hepascore
> 0.5–0.55 Detection of significant fibrosis 70% 79% 78% 71%
ELF
> 9.8 Severe fibrosis 86.7% 92.5% 72% 97%

Table 6
Assessment of fibrosis.
Non-Invasive Blood Tests
NAFLD fibrosis score (NFS) Age, body mass index (BMI), presence of diabetes, AST, ALT, platelets, and albumin
Fib-4 index Platelet count, patient's age, AST, and ALT
FibroSURE ALT, α2‐macroglobulin, apolipoprotein A1, γ‐glutamyl transferase, haptoglobin, total bilirubin, age, and gender
Hepascore α2‐macroglobulin, hyaluronic acid, γ‐glutamyl transpeptidase, total bilirubin, age, and gender
Enhanced Liver Fibrosis (ELF) Hyaluronic acid, tissue inhibitors of metalloproteinases (TIMP-1), and amino-terminal propeptide of procollagen type III
(PIIINP)
Non-Invasive Imaging
Vibration-controlled transient elastography (VCTE) Ultrasonic waves to detect liver stiffness
Magnetic resonance elastography (MRE) Magnetic resonance imaging (MRI) with mechanical waves to measure liver stiffness
Invasive
Liver Biopsy Percutaneous liver biopsy and transvenous liver biopsy

a spatial map of the liver, allowing for detection of heterogenous fibrosis. with NAFLD are not at an increased risk of hepatotoxicity from statins,
Compared to VCTE, MRE is advantageous in that it has less operator de- and thus, statins can be used in patients with comorbid hyperlipidemia,
pendence and is not affected by obesity [57]. Compared to the prediction as long as patients do not have decompensated cirrhosis [11].
models, VCTE and MRE have shown to be more accurate in predicting stage While limited treatment options directly addressing liver disease are
of fibrosis [58]. While the AASLD guidelines do not make any comment on available, several studies have investigated promising therapies that
preferential usage of prediction models or imaging modalities to predict target inflammation, lipid metabolism, or fibrosis (Table 7). Vitamin E
fibrosis stage [11], the American Gastroenterology Association (AGA) and pentoxifylline are two agents that have shown to reduce in-
guidelines state that there is not enough data to support use of one modality flammation in patients with NASH. The Pioglitazone versus Vitamin E
over the other [59]. versus Placebo for the Treatment of Nondiabetic Patients with NASH
(PIVENS) trial showed that vitamin E significantly reduced ALT and
9.2. Liver biopsy AST levels, hepatic steatosis, and lobular inflammation [64]. It is re-
commended that patients with NASH without diabetes be prescribed
Liver biopsy is the gold standard for assessing liver histology 800 IU/day of Vitamin E for stage 2 fibrosis or higher [11,64]. Pen-
(Table 6) [60]. There are two main methods of obtaining a liver biopsy: toxifylline is a methylxanthine derivative that reduces inflammation
percutaneous liver biopsy and transvenous liver biopsy [61]. Transve- and may have hepatoprotective effects [65]. In a randomized placebo
nous liver biopsy is indicated in cases of severe coagulation abnorm- trial, pentoxifylline was shown to significantly reduce steatosis and
alities, ascites, morbid obesity, atrophic liver, prior failed percutaneous lobular inflammation in patients with NASH [65].
biopsy, and for pressure measurements [61]. It is contraindicated to Agents currently being studied that target lipid metabolism in pa-
proceed with transvenous liver biopsy in the following conditions: right tients with NASH are Liraglutide (glucagon-like peptide-1 analogue),
internal jugular vein thrombosis, hepatic vein thrombosis, hydatid Obeticholic acid (farnesoid X nuclear receptor activator), and Elafibranor
cysts, and cholangitis [61]. Some of potential complications of liver (peroxisome proliferator-activated receptor agonist) [66]. Liraglutide is
biopsy include bleeding, hemoperitoneum, and fistula formation [61]. commonly used for treatment in diabetes [67]. In the liraglutide safety
Further, there is sampling error with liver biopsy, as a liver biopsy only and efficacy in patients with non-alcoholic steatohepatitis (LEAN) trial,
represents 1/50,000 of the liver parenchyma [60]. To reduce sampling liraglutide resulted in histological resolution of NASH [67]. Obeticholic
error, it is recommended that at least one core biopsy be obtained and a
16-gauge needle, 2–3 cm in length, be used [11]. Further, two separate
Table 7
readings of a sample by one pathologist has been shown to improve
Treatment.
diagnostic yield compared to only one reading [62].
Therapy Mechanism
10. Treatment
Weight loss and Exercise Reduce hepatic steatosis
Treat comorbid conditions (obesity, diabetes, Reduce hepatic steatosis
Treatment of NAFLD involves lifestyle modifications, treatment of dyslipidemia)
comorbid medical conditions, as well as treatment of liver disease itself Limit heavy alcohol use Decrease inflammation
Vitamin E (antioxidant) Decrease inflammation
[11]. Patients with NAFLD should be advised to lose weight through a
Pentoxifylline (methylxanthine derivative) Decrease inflammation
combination of calorie reduction and exercise, as this has been shown to Liraglutide (glucagon-like peptide-1 analogue) Target lipid metabolism
reduce hepatic steatosis [11]. Additionally, NAFLD patients should be Obeticholic acid (farnesoid X nuclear receptor Target lipid metabolism
encouraged to limit heavy alcohol consumption, as more than 1.5 drinks activator)
(1 drink is defined as 12 ounces of beer, 5 ounces of wine, or 1.5 ounces Elafibranor (peroxisome proliferator-activated Target lipid metabolism
receptor agonist)
of liquor) a day has been shown to increase mortality in patient with
Cenicriviroc (dual antagonist of C–C motif chemokine Antifibrotic
NAFLD [11,63]. Patients with comorbid diabetes and hyperlipidemia receptor types 2 and 5)
should be managed appropriately [11]. Studies have found that patients

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R. Rikhi, et al. Annals of Medicine and Surgery 50 (2020) 41–48

acid leads to activation of farnesoid X nuclear receptor, leading to de- Consent

creased triglyceride levels. The Farnesoid X nuclear receptor ligand
obeticholic acid for non-cirrhotic NASH (FLINT) trial showed that obe- The paper is a review that did not involve patients or volunteers;
ticholic acid improved histological features in patients with NASH [68]. thus, ethical approval and informed written consent was not necessary.
Elafibranor promotes fatty acid catabolism, which has been shown to
improve dyslipidemia [66]. Currently, Elafibranor is being compared to Declaration of competing interest
placebo in the RESOLVE-IT phase 3 clinical study [66].
Cenicriviroc is a dual antagonist of C–C motif chemokine receptor The authors have no conflicts of interest.
types 2 and 5 that has been shown to have antifibrotic properties by
decreasing inflammation and collagen production at the site of liver Acknowledgements
injury [66,69]. The Efficacy and Safety Study of Cenicriviroc for the
Treatment of Nonalcoholic Steatohepatitis in Adult Participants with The authors would like to thank Mr. Jaret M Karnuta M.S. for
Liver Fibrosis (CENTAUR) phase 2 study showed that subjects treated helping create Fig. 1.
with Cenicriviroc had double the improvement in fibrosis compared to
placebo [69]. Although promising, larger studies are still needed for the References
above mentioned therapies.
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