1
NON-ALCOHOLIC FATTY LIVER DISEASE: AN EMERGING DRIVING
FORCE IN CKD
Giovanni Targher
1
and Christopher D. Byrne
2,3
1
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University
and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
2
Nutrition and Metabolism, Faculty of Medicine, University of Southampton, Southampton,
UK
3
Southampton National Institute for Health Research Biomedical Research Centre,
University Hospital Southampton, UK
Word count: Abstract: 193 words; Text 7,205 (excluding title page, abstract, figure
legends, references, key points and tables); Tables=1; Figures=5; References=142
Address for correspondence:
Prof. Giovanni Targher
Section of Endocrinology, Diabetes and Metabolism
Department of Medicine
University and Azienda Ospedaliera Universitaria Integrata of Verona
Piazzale Stefani, 1
37126 Verona, Italy
Phone: +39-0458123110
E-mail: giovanni.targher@univr.it
2
Abbreviations:
AGE, advanced glycation end-products
AMPK, adenosine monophosphate-activated protein kinase
Ask-1, apoptosis signal-regulating kinase 1 (Ask-1 is also known as mitogen-activated protein
kinase 5)
CETP, cholesterol ester transfer protein
CCL2, chemokine (C-C motif) ligand 2 (CCL2 is also referred to as monocyte chemoattractant
protein 1 (MCP1))
CCR, chemokine receptor
FGF, fibroblast growth factor
FXR, farnesoid X receptor
GLP-1, glucagon like peptide 1
IL-6, interleukin 6
JNK, C-Jun-N-terminal kinase
LPS, lipopolysaccharide
mTOR, mechanistic target of rapamycin/ mammalian target of rapamycin
NEFA, non-esterified fatty acids
NF-kB, nuclear factor-kB
Nrf 2, nuclear factor (erythroid-derived 2)-like 2
PPAR, peroxisome activated proliferated receptor
PAI-1, plasminogen activator inhibitor-1
PUFA, polyunsaturated fatty acids
PYY, peptide YY (PYY is also known as peptide tyrosine or pancreatic peptide YY 3-36)
ROS, reactive oxygen species
SCFA, short chain fatty acids
SREBP, sterol regulatory element binding protein
TGF-β, transforming growth factor-β
TMA, trimethylamine
TMAO, trimethylamine oxide
TNF-α, tumour necrosis factor-α
3
1. ABSTRACT
Non-alcoholic fatty liver disease (NAFLD) is a lipid-related liver condition that may
progress over time to increase the risk of cirrhosis, end-stage liver disease and
hepatocellular carcinoma. The prevalence of NAFLD is increasing rapidly due to the global
epidemic of obesity and type 2 diabetes mellitus (T2DM), and it has been predicted that
NAFLD will become the most important indication for liver transplantation over the next
decade. It is now increasingly clear that NAFLD not only affects the liver but also affects
risk of developing other extra-hepatic diseases that have a considerable impact on health
care resources. These extra-hepatic diseases include T2DM, cardiovascular disease and
chronic kidney disease (CKD), and the “cross talk” between each affected organ or tissue
with these diseases has the potential to further harm function and worsen patient
outcomes. The aim of this review article is to discuss the diagnostic tests for confirming
NAFLD, the epidemiology linking NAFLD to CKD, and the pathogenic mechanisms
underpinning the link between NAFLD and CKD. This review will also discuss potential
treatments for NAFLD as well as a pragmatic algorithm for case finding and diagnosing the
severity of NAFLD, in patients with CKD.
4
2. INTRODUCTION
Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver
disease in high-income countries, affecting up to one third of the general adult population
1-
3
. In addition, NAFLD is now the third most common indication for liver transplantation in
the United States and is on a trajectory to become the most common
4
. Similarly, NAFLD is
also the most rapidly growing indication for simultaneous liver kidney transplantation with
poor renal outcomes
5
.
Over the last 15 years, it has become increasingly evident that NAFLD is associated not
only with liver-related mortality and morbidity, but there is now growing evidence that
NAFLD is a multisystem disease that affects multiple extra-hepatic organ systems,
including the cardiovascular system
6
. In recent years, recognition of the importance of
NAFLD and its strong relationship with the metabolic syndrome has stimulated
considerable interest in its putative prognostic impact on the risk of chronic kidney disease
(CKD)
7
. CKD is a disease that causes high morbidity, mortality, and health care costs
across the globe
8
. CKD is becoming increasingly common and in the United States, for
example, more than 10% of the adult population (about 26 million people) and more than
25% of individuals older than 65 years have CKD
9
.
NAFLD and CKD share multiple risk factors (abdominal obesity, insulin resistance,
atherogenic dyslipidemia, hypertension and dysglycemia) and mechanistic pathways in
their pathogenesis
7,10,11
. The existence of mechanistic pathways linking the liver and
kidneys is also supported by the presence of the hepato-renal syndrome, which may
develop in cirrhotic patients with portal hypertension.
Here, we review the accumulating body of clinical and experimental evidence supporting
the existence of a link between NAFLD and CKD. We discuss the diagnostic tests for
confirming NAFLD, the epidemiology linking NAFLD to CKD, and the pathogenic
mechanisms underpinning the link between NAFLD and CKD. We also discuss potential
treatments for NAFLD and an algorithm for case finding and diagnosing the severity of
NAFLD in patients with CKD.
3. DIAGNOSIS AND EPIDEMIOLOGY OF NAFLD
3.1. Diagnosis
5
NAFLD is a clinico-pathological spectrum of liver diseases that encompasses simple fatty
infiltration in more than 5% of hepatocytes (simple steatosis), fatty infiltration plus
inflammation (non-alcoholic steatohepatitis, NASH), advanced fibrosis and, ultimately,
cirrhosis that may progress to hepatocellular carcinoma
1,3
.
Diagnosis of NAFLD is based on the following criteria: (1) hepatic steatosis on either
imaging or histology, (2) no excessive alcohol consumption (a threshold of 20 g/day for
women and 30 g/day for men is conventionally adopted), and (3) no competing causes for
hepatic steatosis (e.g., virus, drugs, iron overload, autoimmunity)
1,3
. Liver biopsy remains
the reference standard for diagnosing NASH and staging fibrosis in patients with NAFLD.
However, this procedure is invasive, potentially risky, patient-unfriendly, and subject to
sampling error; therefore, liver biopsy is not suitable for patient monitoring or for diagnosis
in large cohorts of individuals
1,3
.
Liver ultrasonography is the recommended first-line imaging modality for detecting NAFLD
in clinical practice
1,3
. On ultrasonography, hepatic steatosis produces a typical diffuse
increase in echogenicity (the so-called “bright liver”). Ultrasonography has a good
diagnostic accuracy to detect the presence of mild and moderate-to-severe hepatic
steatosis, demonstrating a sensitivity and specificity, respectively, of approximately 85%
and 95% (when liver fat infiltration is at least 20-30%)
12
. Moreover, ultrasonography is
relatively inexpensive and may help clinicians to exclude other causes of liver disease and
identify any early signs of cirrhosis or portal hypertension. To date, T1-weighted dual-echo
magnetic resonance imaging and proton magnetic resonance spectroscopy have the best
diagnostic accuracy in defining hepatic steatosis. Proton magnetic resonance
spectroscopy enables quantitative assessment of hepatic triglyceride content, has
excellent reproducibility and sensitivity, but is resource intensive and cannot reliably
discriminate simple steatosis from NASH
1,3
.
Most patients with NAFLD have no symptoms or clinical signs of liver disease at the time
of diagnosis, although some patients report fatigue and a sensation of fullness or
abdominal discomfort; moderate hepatomegaly may be the only physical finding in most
patients. A large part of patients with NAFLD display the typical features of metabolic
syndrome (i.e., abdominal obesity, atherogenic dyslipidemia, hypertension, insulin
resistance, glucose intolerance or type 2 diabetes mellitus [T2DM])
1,3
. The presence of
mildly to moderately elevated levels of serum liver enzymes (serum aminotransferases
