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Gastroenterol Clin North Am. Author manuscript; available in PMC 2017 December 01.
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Published in final edited form as:

Gastroenterol Clin North Am. 2016 December ; 45(4): 639–652. doi:10.1016/j.gtc.2016.07.003.

Non-alcoholic fatty liver disease: Pathophysiology and

management
Rotonya M. Carr, MD, Amanke Oranu, MD, and Vandana Khungar, MD, MSc
University of Pennsylvania, Division of Gastroenterology and Hepatology

Abstract/Summary
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NAFLD is an important cause of morbidity and mortality worldwide both because of

cardiovascular, hepatic and oncologic sequelae as well as because it is rapidly becoming the
leading cause of end stage liver disease and liver transplant. With a prevalence of 30% in the US, it
has reached epidemic proportions. While the metabolic syndrome is a common risk factor, there
are differences among racial and ethnic groups, suggesting the complex interaction between
hormonal, nutritional and genetic factors at play in disease pathogenesis. The clinical syndrome of
NAFLD spans from bland steatosis to steatohepatitis which can progress to fibrosis and cirrhosis.
The pathogenesis including roles of hormones, nutritional and intestinal dysbiosis, insulin
resistance, lipotoxicity, and hepatic inflammation, and genes are examined. Non-invasive testing
and liver biopsy indications are reviewed. Approved and investigational therapies for NAFLD and
NASH are outlined in this review of a disease that is currently an area of great interest to the
hepatology community.
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Keywords
Non-alcoholic fatty liver disease; NASH; obesity; hepatic steatosis; NASH therapeutics; lipid
droplet; perilipins

INTRODUCTION
Non-alcoholic fatty liver disease (NAFLD) is a clinical diagnosis that includes the presence
of 5% or more hepatic steatosis as determined by liver imaging or biopsy in the absence of
secondary causes of hepatic fat accumulation (Table 1). NAFLD spans the spectrum of
simple steatosis or non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH)
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which is defined histologically as hepatic steatosis, hepatic inflammation, and hepatocellular

ballooning with or without fibrosis. NASH can progress to cirrhosis and hepatocellular
carcinoma.1

Corresponding author: Rotonya M. Carr, 421 Curie Boulevard, 907 Biomedical Research Building, [email protected],
215-573-3933.
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Current estimates are that NAFLD affects 30% of the United States (US) population; 32% of
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the Middle East population; 30% of the South American population; 27% of Asian
populations (highest in East Asians); 24% of the European population; and 13% of the
African population.2–4 In the US, men are disproportionately affected.5 Hispanic Americans
have a higher prevalence of NAFLD compared with Caucasians; while African-Americans
have the lowest prevalence among all racial and ethnic groups in the US.6 Among the
Hispanic population, those of Mexican heritage have the highest prevalence while
Dominican Republicans have the lowest prevalence.7, 8 The etiology of this racial and ethnic
disparity is likely multi-factorial and includes contributions from genetic, behavioral and
socio-economic factors.9

NAFLD prevalence parallels that of the obesity epidemic and in the US is expected to
become the leading cause of end stage liver disease by 2020.10 Like patients who suffer
from obesity, patients with NAFLD have a higher risk of diabetes, cardiovascular disease
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and carcinoma.11 Indeed, the metabolic syndrome (defined as the presence of three or more
of fasting glucose ≥ 100 mg/dL, blood pressure ≥ 130/85, triglycerides ≥ 150 mg/dL, HDL-
C < 40 mg/dL in men or < 50 mg/dL in women, waist circumference >40 inches in men or
35 inches in women12 (and if Asian American >35 in men or >32 in women13)) is common
in NAFLD patients. Consequently, NAFLD is often considered its hepatic manifestation14
(although this has recently been challenged).15

PATHOGENESIS
NAFLD is a metabolic disorder, and its pathogenesis involves the complex interaction
among hormonal, nutritional and genetic factors (Figure 1).
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Role of hormones
The majority of patients with NAFLD suffer from obesity resulting from an imbalance
between high energy intake (overnutrition) and energy expenditure. Overnutrition of both
high fat foods and sugars has been linked with activating opioid and dopamine receptors in
the nucleus accumbens,16, 17 an area of the brain responsible for the development of
cravings. In addition, the macronutrient fructose increases cerebral blood flow to areas of the
brain responsible for motivation and reward, failing to reduce satiety when compared with
glucose.18 Although these pathways have not been examined specifically in NAFLD, it is
conceivable that they contribute to obesity in NAFLD patients as well. Concomitant with the
activation of reward centers in response to certain macronutrients is the systemic reduction
of gut-derived hormones that promote satiety (eg. glucagon-like peptide 1 (GLP-1))18, 19 and
increase of gut-derived hormones that stimulate hunger (eg. ghrelin).19 These changes are
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associated with an increase in circulating triglyceride levels19 and thus are implicated in
NAFLD pathogenesis.

In addition to gut-derived hormones, the adipose-derived hormones leptin and adiponectin

are suspected to play a role in NAFLD pathogenesis. Leptin primarily acts centrally to
reduce food intake and increase energy expenditure.20 Adiponectin increases hepatic insulin
sensitivity and reduces body fat.21 Leptin levels are elevated in NAFLD patients suggesting

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a possible contribution of leptin resistance22; while adiponectin levels are low and
independently predict risk of NASH in obese patients.23
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The systemic effects of hormones on both lipid and glucose homeostasis have inspired
clinical studies investigating their efficacy in NASH patients. For example, NASH resolved
in 39% of patients who received the GLP1 agonist liraglutide compared with 9% of patients
who received placebo. Liraglutide also reduced fibrosis progression24 demonstrating that
hormones may be exploited to influence NAFLD risk and severity.

Role of nutrition and intestinal dysbiosis

One common link among the aforementioned hormones is their regulation by nutritional
status. However, because of the inherent challenges of human nutrition studies, the degree to
which specific macronutrients increase NAFLD susceptibility is unknown. High saturated
fat, low fiber and carbohydrate-rich diets have all been associated with NAFLD risk,25–28
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but little direct evidence exists in humans. Data from pre-clinical studies demonstrate that
diets high in sucrose and fructose are steatogenic, perhaps through their promotion of
intestinal dysbiosis or dysregulation of key lipid metabolic pathways and hormones.29 In
support of these data are studies demonstrating that high fructose diet30 and high soda intake
(and therefore consumption of high fructose corn syrup)31 increase risk of NAFLD in
humans. Such studies, however, are based on dietary intake surveys and are unable to make
direct connections between nutrient intake and NAFLD.

Microbiota are primary nutrient sensors within the gastrointestinal tract, and diet modulates
gut bacterial composition in NAFLD patients.32 Emerging evidence demonstrates that
NASH patients have disrupted gut epithelial tight junctions through which bacteria gain
access to the systemic circulation and release inflammatory cytokines to promote hepatic
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steatosis and inflammation.33, 34 Investigations regarding how specific macronutrients

promote these disruptions are needed to inform dietary recommendations for NAFLD
patients.

Role of insulin resistance, lipotoxicity, and hepatic inflammation

Both hyperinsulinemia and insulin resistance are central to NAFLD pathophysiology.35
Under normal conditions, pancreatic beta cells secrete insulin primarily in response to
circulating glucose levels. Insulin acts on several metabolic tissues, including adipose tissue
to promote esterification of fatty acids and storage into lipid droplets while inhibiting the
opposing process of lipolysis. In hepatocytes, insulin has three primary actions: to promote
glycogen storage, inhibit gluconeogenesis and activate key regulators of de novo lipogenesis.
In NAFLD patients, the development of insulin resistance results in 1) increased adipocyte
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lipolysis and high circulating free fatty acids available for subsequent hepatic uptake, 2)
reduced hepatic glycogen storage and 3) and increased gluconeogenesis. Perhaps in response
to systemic insulin resistance (or preceding the development of insulin resistance36),
hyperinsulinemia develops which augments hepatic de novo lipogenesis pathways. The net
effect is increased intra-hepatic lipid accumulation (steatosis) and accentuated triglyceride
secretion in the form of very-low density lipoprotein. The increased lipid load circulates to

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adipose tissue, thus compounding the already reduced ability of adipocytes to store these
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lipids in lipid droplets.

In hepatocytes, the inability to accommodate neutral lipids within lipid droplets exposes
cells to lipotoxic bioactive lipids. Lipotoxicity further impairs insulin signaling, causes
oxidative damage, and promotes inflammation and fibrosis through a number of
mechanisms.37 These downstream effects are thought to be responsible for progression from
NAFL to NASH and development of fibrosis and hepatocellular carcinoma in NAFLD
patients.

Role of Genes
Perhaps the most compelling evidence for genetic contributions to NAFLD is the
observation by Makkonen, et al. that among monozygotic Finnish twins, liver fat and serum
alanine aminotransferase (ALT) vary independently of obesity and alcohol use38. These
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early genetic studies have been bolstered by results from present day genome-wide
association studies (GWAS) which have implicated several genetic polymorphisms
associated with NAFLD risk and severity (Table 2). The earliest and most widely reported
association is the patatin-like phospholipase domain-containing 3 (PNPLA3) gene, a protein
with both triacylglyerol lipase and acylglycerol transacylase activity.39, 40 The single
nucleotide polymorphism (SNP) I148M (isoleucine to methione at position 148) of PNPLA3
has been associated with both NAFLD risk and severity in adults41–43 and children44. This
so-called “G” allele is found most commonly among Hispanics and least frequently among
African-Americans42, the demographic groups with the highest and lowest risk of NAFLD
in the US population, respectively. Among Hispanics, Mexican-Americans have the highest
prevalence of the “G” allele.45 Conversely, a serine to isoleucine change in codon 453
appears to be protective of hepatic steatosis and is more commonly seen in African-
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Americans.42 Whether PNPLA3 per se is involved pathogenically in NAFLD is still unclear

owing partially to inconsistencies in cell culture and in vivo genetic models.46–48

GWAS studies have identified several additional loci associated with NAFLD, namely
neurocan (NCAN), glucokinase regulator (GCKR), lysophospholipase like 1 (LYPLAL1),
transmembrane 6-superfamily member 2 (TM6SF2) and protein phosphatase 1 regulatory
subunit 3B (PPP1R3B)45, 49. Like PNPLA3 polymorphisms, these genes have differential
associations with ethnic groups50 and together are estimated to account for as much as 28%
of the variation in hepatic steatosis as measured by CT scan.49 A summary of these genes is
included in Table 2. The functional significance of all of these genes has not been fully
determined in NAFLD patients, thus highlighting some of the challenges inherent in
extrapolating GWAS data to clinical care and demonstrating the limitations of using these
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tools in whole population screens.

DIAGNOSIS AND STAGING

Non-invasive tests
Diagnosis of NAFLD is based on a combination of clinical factors and liver imaging.
Clinical assessment involves a detailed alcohol consumption history, examination of

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personal and family metabolic risk factors, medication history (including supplements) and
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serologic testing. A summary of our approach to initial evaluation is outlined in Table 3.

Liver enzymes are not a component of NAFLD diagnostic criteria, as up to 60% of

NAFLD patients with normal ALT can have NASH or advanced fibrosis, and 53%
of NAFLD patients with elevated ALT do not have NASH or advanced
fibrosis51, 52.

Despite using the standard assessments, diagnosis of NAFLD remains challenging in some
patients as high serum autoantibodies, high ferritin, and low ceruloplasmin can be seen in
the absence of concomitant chronic liver disease. As many as 20% of NAFLD patients may
have abnormal autoantibody titers.53–55 Abnormal results of serologic tests in the context of
additional clinical features which support alternative diagnoses should be evaluated further
and may require liver biopsy.
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Clinical history and serologic testing are combined with radiologic findings (ultrasound, CT
or MRI) to make the diagnosis of NAFLD in the majority of patients. Notably, most patients
diagnosed with NAFLD are initially suspected because of an incidental radiologic finding of
hepatic steatosis. The presence of at least 30% hepatic steatosis is optimal to visualize
hepatic steatosis by these common radiology tools56 although there is wide inter- and intra-
observer variability.57 None of the standard radiologic modalities can detect the presence of
steatohepatitis or early fibrosis.57

The inability of standard radiology protocols to detect advanced stages of NAFLD has
spurred research in other non-invasive strategies to stage NAFLD severity. Serologic tests
and biomarker panels, ultrasound transient elastography (TE), and MRI elastography (MRE)
can be used to stage NAFLD. Cytokeratin-18 (CK-18) is a hepatocyte intermediate filament
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that is cleaved by caspases during apoptosis whose serum levels are elevated in NASH
patients.58 Although this test discriminates NAFL from NASH, CK-18 is not commercially
available in the US, thus limiting its practical use. Unlike discrimination of NASH, several
modalities are available for the non-invasive assessment of fibrosis in NAFLD patients. The
most validated biomarker panel is the NAFLD Fibrosis Score (NFS)1 which calculates
probability of advanced fibrosis based on readily available clinical data: age, BMI, AST,
ALT, platelets, albumin, and presence or absence of impaired fasting glucose. A low cutoff
score −1.455 excludes advanced fibrosis (negative predictive value of 93%), while a high
cutoff score 0.676 suggests advanced fibrosis (positive predictive value 90%).59

Both TE and MRE measure liver stiffness. TE performs less well in obese patients with a
failure rate of up to 16%60 and overestimates fibrosis in patients with significant steatosis or
inflammation.61 An extra large (XL) probe for TE was designed for use in overweight and
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obese patients however median liver stiffness measurements were on average lower with the
XL probe compared with the standard M probe.62 To date, these differences have not
resulted in a new scoring system with use of this probe limiting interpretation of XL probe-
derived results. MRE performs better than TE for fibrosis assessment63 but the expense of
this technology limits widespread adoption.

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Liver biopsy
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Due to the limitations of non-invasive testing in NAFLD patients, liver biopsy remains the
gold standard for NAFLD staging. Nevertheless, the prevalence of NAFLD, relatively low
likelihood of progressive disease in the majority of patients, dearth of treatment options, risk
of biopsy, and the uncertain cost effectiveness of invasive testing, preclude liver biopsy from
being recommended in all patients. Current guidelines limit liver biopsy to those patients
who have an uncertain diagnosis or who are likely to have advanced disease based on non-
invasive assessment modalities described above.1 Consensus guidelines recommend use of a
transjugular approach for patients who are morbidly obese with an obscured flank site. To
reduce risk of bleeding, guidelines recommend the following:64

• Hold anti-platelets from several days to 10 days prior

• Hold warfarin at least 5 days prior

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• Hold heparin products 12–24 hours prior

• Weigh above against risk of thrombotic event

Although there is no formal recommendation regarding the use of vitamin E prior to liver
biopsy, vitamin E in high doses does have anticoagulant properties65 and consideration may
be made to hold this prior to liver biopsy.

The range of NAFLD histology includes simple steatosis, steatohepatitis, fibrosis and
cirrhosis. Of these, fibrosis is the histologic feature that best predicts NAFLD mortality.66
Steatosis results from hepatocellular accumulation of cytoplasmic macrovesicular lipid
droplets that displace the nucleus. Lipid droplets are cores of primarily neutral lipids
(triglycerides) surrounded by a single phospholipid membrane. The membrane is comprised
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of lipid droplet proteins and metabolically active enzymes. The predominant hepatocellular
lipid droplet proteins are members of the perilipin family of proteins. Perlipin 2 and Perilipin
3 are expressed in NAFL whereas Perilipin 1 is de novo expressed in steatohepatitis.67–70

The recent NASH Clinical Research Network pathologic scoring system is based on the
original Brunt histologic criteria but expands the fibrosis stages to delineate pattern of
fibrosis.71 Even with expert pathology examination, challenges remain with staging NAFLD
patients. Because a standard needle biopsy sample approximates only 1/50000 of the mass
of the liver,64 liver biopsy specimens are highly variable.72 This underscores the need for
providers to be judicious in recommending liver biopsy for the management of NAFLD
patients.

MANAGEMENT
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Mortality from NAFLD is due to cardiometabolic disease (12.7%), non-HCC malignancy

(8.1%), and liver disease (including HCC) (6.9%).11 Eighteen-year liver-related mortality is
greater in NASH compared with non-NASH patients (17.5% versus 2.7%, respectively).11
The risk of mortality from cardiometabolic and oncologic disease in NAFLD patients
requires that special attention be paid to both metabolic and cancer risk factors. Namely,
assessment and management of obesity, hyperlipidemia (notwithstanding institution of

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statins which improve mortality in NASH cirrhotics66), insulin resistance and diabetes is
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recommended for all patients. In addition, patients are advised to undergo standard cancer
screening examinations according to their age, gender and family history. In our practice, we
additionally co-manage patients with primary care, cardiology, endocrinology, and nutrition
(Figure 2).

In addition to surveillance of risk factors for mortality, all patients should be placed on an
appropriate dietary and exercise regimen to promote weight loss of at least 5% for those with
NAFL or 7–9% for those with NASH. Such lifestyle modification improves transaminases
and liver histology73 and also reverses fibrosis.74 In fact, 90% of patients who achieve ≥10%
weight loss have complete NASH resolution.74

The finding of advanced fibrosis or cirrhosis on liver biopsy in a NAFLD patient necessitates
screening for complications of cirrhosis and referral to hepatology if a referral has not
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already been made. In addition to standard dietary recommendations, we recommend

complete alcohol abstinence for patients with advanced NAFLD. All patients with advanced
fibrosis and cirrhosis require both endoscopic variceal screening and radiologic surveillance
for hepatocellular carcinoma (HCC) every 6 months. There may be an increased risk of
HCC even in the absence of cirrhosis in NAFLD. Among patients with metabolic syndrome
and no other etiology of chronic liver disease 65.5% of patients with HCC had no or mild
fibrosis; and patients diagnosed with cryptogenic cirrhosis without apparent metabolic
syndrome developed HCC in non-fibrotic livers more commonly than in fibrotic livers (75%
versus 25%).75 Further studies are warranted to determine the feasibility and utility of earlier
HCC screening in NAFLD patients.

Approved pharmacologic therapy and investigational agents

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Only two therapies are currently recommended for use in NASH patients, Pioglitazone and
vitamin E. In both diabetic76 and non-diabetic patients77, treatment with pioglitazone (30–
45mg daily) improves NASH compared with placebo.77 Treatment, however, is associated
with significant weight gain. Vitamin E was investigated in the PIVENs trial, a randomized
control trial examining the benefit of pioglitazone or vitamin E versus placebo in non-
diabetic NASH patients. Patients treated with 800 IU of vitamin E daily for 96 weeks
demonstrated reduced steatosis and inflammation.77 The use of vitamin E is reserved for
biopsy-proven NASH in non-diabetic patients.

Investigational therapies
Over the past several years, there has been a surge in NAFLD therapeutic trials. Among the
investigational agents is a new class of farnesoid X receptor (FXR) agonists. FXR agonists
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regulate both glucose and lipid homeostasis. Obeticholic acid is the first drug in this class
under investigation for NASH.78 A recent randomized, double-blinded placebo-controlled
trial of non-diabetic NASH patients demonstrated improvement in histologic NASH in 45%
of patients who received obeticholic acid versus 21% of placebo patients. In addition,
patients who received obeticholic acid had improvement of fibrosis compared with
placebo.79 There was a lack of improvement in insulin sensitivity and dyslipidemia that

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developed in patients who took obeticholic acid, and a Phase III trial is currently
underway.80
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The PPARα/δ agent elafibrinor has also recently been studied in NASH. Compared with
placebo, elafibranor improved liver enzymes and serum lipids. In an intention-to-treat
analysis of the primary endpoint, elafibranor failed to resolve NASH; however, using a
modified endpoint, elafibranor resolved NASH without fibrosis worsening (20% versus
11%). This medication caused a reversible increase in serum creatinine and, as a result,
requires further investigation.81

Besides pharmacotherapy, several studies have demonstrated the effectiveness of obesity

surgery for NASH demonstrating up to 85% NASH resolution one year after surgery.82
Although there are now several anti-obesity endoscopic procedures under investigation,83
none have been evaluated for the primary indication of NASH. However, it is conceivable
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that there would be improvements in NASH histology if similar weight loss is achieved with
these procedures.

Regardless of the modality, the management of NAFLD patients requires interventions that
work systemically to integrate hepatic and extra-hepatic signals. Such therapies must
incorporate lifestyle changes to impact cardiovascular endpoints and accomplish weight
reduction as weight loss of 7–10% is currently the only therapy that achieves NASH
resolution in a majority of patients.

SUMMARY/DISCUSSION
NAFLD is an important cause of morbidity and mortality worldwide both because of
cardiovascular and oncologic sequelae as well as because it is rapidly becoming the leading
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cause of end stage liver disease and liver transplant. With a prevalence of 30% in the US it
has reached epidemic proportions. While the metabolic syndrome is a common risk factor,
there are differences among racial and ethnic groups, suggesting the complex interaction
between hormonal, nutritional and genetic factors at play in disease pathogenesis.
Furthermore, these biologic factors likely intersect with socioeconomic forces that
ultimately influence one’s susceptibility to NAFLD and likelihood of progression to
advanced stages.

The complexity of NAFLD pathogenesis mirrors that of its management in that successful
care of NAFLD patients requires a multi-system, integrated approach. Close attention must
be paid to overall metabolic health in addition to hepatic health. Providers should assess and
manage risk factors aggressively and estimate risk of fibrosis at presentation and
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longitudinally. Hepatology referral can be made at any stage but especially at the stage
where fibrosis is suspected. The arena of treatment options is an area ripe for innovation as
few currently approved treatments exist. Regression of NASH and fibrosis is possible with
weight loss, however, we anticipate that adjunctive pharmacologic and non-pharmacologic
therapies may be available for the care of NAFLD patients in the future.

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Acknowledgments
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Disclosures and Funding Sources Research support from Intercept (RMC); NIH/NIAAA K08-AA021424, Robert
Wood Johnson Foundation, Harold Amos Medical Faculty Development Award, 7158, IDOM DRC Pilot Award
P30 DK019525 (RMC); NIH/NIDDK T32 DK007066 (AO). This work was supported in part by NIH P30-
DK050306 and its core facilities and its pilot grant program.

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Key Points
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• Non-alcoholic fatty liver disease (NAFLD) is a systemic disease

• NAFLD pathogenesis involves hormonal, nutritional and genetic

factors

• NAFLD mortality is due to cardiovascular disease, cancer and hepatic

disease

• Patients with NAFLD should be risk stratified at diagnosis and

longitudinally for the presence and degree of fibrosis and referred if
advanced disease is suspected

• The cornerstone of NAFLD management is 7–9% weight loss and

management of cardiovascular, oncologic, and hepatic risk factors.
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Figure 1.
Pathogenesis of NAFLD.
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Figure 2.
Strategies to reduce cardiovascular, oncologic and hepatic mortality in NAFLD patients.
Rx=pharmacologic
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Table 1

Known causes of secondary hepatic steatosis

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Macrovesicular steatosis Microvesicular steatosis

Excessive alcohol consumption Reye's syndrome

Viral infection- Hepatitis C Viral infection- Delta hepatitis

Wilson's disease HELLP syndrome

Autoimmune hepatitis Acute fatty liver of pregnancy

Parenteral nutrition Medications (eg. valproate, tetracycline,

anti-retroviral)

Medications (eg. amiodarone, Genetic anomalies and inborn errors of

methotrexate, tamoxifen, corticosteroids, metabolism*
anti-retrovirals)

Starvation – Kwashiorkor Jamaican vomiting sickness

Lipodystrophy
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Abetalipoproteinemia

*
(Lecithin–cholesterol acyltransferase [LCAT] deficiency, urea cycle defects, cholesterol ester storage diseases, defects of fatty acid beta oxidation,
lysosomal acid lipase deficiency and Alpers syndrome)
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Table 2

Genetic polymorphisms associated with NAFLD

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Gene Function of gene NAFLD association

polymorphism
Patatin-like Triacylglyerol lipase, Increases NAFLD risk and severity;
phospholipase acylglycerol highest prevalence in Hispanic-
domain-containing transacylase Americans (highest in Mexican-
3 (PNPLA3) Americans)42, 45, 49, 50
(I148M)

PNPLA3 (S453I) Triacylglyerol lipase, Reduces NAFLD risk and severity;

acylglycerol highest prevalence in African-
transacylase Americans42

Neurocan (NCAN) Cell adhesion Hepatic steatosis, liver inflammation

molecule and fibrosis45, 49, 84

Glucokinase Glucokinase inhibitor Hepatic steatosis, increased ALT45, 49

regulatory protein
(GCKR)
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Transmembrane 6- Unknown Increased ALT, AST and hepatic fat,

superfamily small effect size85
member 2
(TM6SF2) (E167K)

Protein Hepatic glycogen Hepatic steatosis45, 49, 50

phosphatase 1 synthesis
regulatory subunit
3B (PPP1R3B)
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Table 3

Initial Evaluation of a Patient with Suspected NAFLD

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History Physical Exam Serology

Patterns of weight loss and weight Blood pressure, weight, Hepatic and basic metabolic
gain; anti-obesity interventions height (calculate BMI) panel (for creatinine)

Dietary and exercise patterns Distribution of obesity CBC

Alcohol intake Stigmata of insulin resistance INR

(eg. acanthosis nigricans)

Use of parenteral nutrition Stigmata of Fasting lipids

hypertriglyceridemia (eg.
xanthomas)

Fertility history, menstrual history Stigmata of chronic liver Fasting glucose, insulin
disease (eg. icterus, jaundice, (calculate HOMA-IR), HbA1C
ascites, spider angiomata,
palmar erythema)

Risk factors for viral hepatitis Stigmata of primary Hepatitis C virus antibody
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endocrine disorder

History of autoimmune diseases or Stigmata of autoimmune ANA and iron panel

suggestive symptoms disease (eg. skin rashes, joint
findings)

Review of steatogenic medications Other* (eg. additional

autoantibody titers,
ceruloplasmin, alpha 1
antitrypsin, lysosomal acid
lipase activity)

Family history of liver disease,

obesity, diabetes, hyperlipidemia,
cardiovascular disease, cancer

*
These tests can be individualized based on patient risk factors
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