- Email: [email protected]
How to Approach a Patient With Nonalcoholic Fatty Liver Disease
Accepted Manuscript How to approach a patient with non-alcoholic fatty liver disease Herbert Tilg
PII: DOI: Reference:
S0016-5085(17)35801-8 10.1053/j.gastro.2017.06.016 YGAST 61251
To appear in:
Gastroenterology
Please cite this article as: Tilg H, How to approach a patient with non-alcoholic fatty liver disease, Gastroenterology (2017), doi: 10.1053/j.gastro.2017.06.016. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
How to approach a patient with non-alcoholic
RI PT
fatty liver disease
M AN U
Herbert Tilg
SC
Running Title: NAFLD and clinical management
Department of Internal Medicine I, Gastroenterology, Hepatology & Endocrinology, Medical University Innsbruck, Austria
TE D
Corresponding author:
Herbert Tilg, M.D., Department of Internal Medicine I, Gastroenterology, Hepatology & Endocrinology, Medical University Innsbruck, Innsbruck, Austria
EP
Phone: +43 512 504 23539, Fax: +43 512 504 23538
AC C
E-mail: [email protected]
ACCEPTED MANUSCRIPT 2
Non-alcoholic fatty liver disease (NAFLD) has evolved as the most common liver disease world-wide. NAFLD covers a disease spectrum, ranging from simple
RI PT
steatosis in the absence of inflammation to non-alcoholic steatohepatitis (NASH), liver cirrhosis and hepatocellular carcinoma (HCC). Prevalence of NAFLD is high and might reach up to 30% in certain populations such as US Americans or
SC
Asians mostly paralleling rates of obesity and type 2 diabetes (T2D).1 The number of patients with NAFLD that have NASH is unclear, but exceeds >10% of
M AN U
the overall NAFLD population. A definite diagnosis of NASH is important as inflammation and/or fibrosis dictate the long-term prognosis of this disease which might ultimately require liver transplantation. Whereas liver-related long-term complications are mainly seen in patients presenting with definite NASH, NAFLD has in general a high rate of extrahepatic complications dominated by
TE D
cardiovascular complications, chronic kidney disease, T2D and various cancers.2 Although no established treatment for NASH currently exists, several treatments
EP
such as peroxisome proliferator-activated receptor (PPAR)γ agonists, vitamin E or glucagon-like peptide (GLP)-1 agonists, have demonstrated some clinical
AC C
efficacy in the past years. As a substantial proportion of patients die of liver disease, there exists an urgent need for effective NASH therapies.3 An intimate knowledge of this topic is therefore crucial for many medical disciplines.
ACCEPTED MANUSCRIPT 3
When to suspect NAFLD?
RI PT
Most NAFLD patients are obese with or without T2D, consume rather unhealthy diets and practice a sedentary lifestyle lacking physical activity and exercise. Insulin resistance has been characterized as one of the hallmarks of NAFLD.4
SC
Assessment of HOMA-IR is a useful surrogate for insulin resistance in NAFLD but only in subjects without T2D. Patients with metabolic syndrome and or certain
M AN U
metabolic risk factors such as obesity and/or arterial hypertension should be evaluated towards the presence of NAFLD. In addition, patients with T2D should undergo repeatedly a careful liver investigation to diagnose highly prevalent
TE D
NAFLD (in more than > 50% of T2D patients).5
As concordant presence of NAFLD and alcoholic liver disease is frequent, assessment of alcohol intake is mandatory. In all individuals with persistently
EP
elevated liver enzymes (e.g. primarily elevated ALT, γGT), NAFLD has to be considered (Figure 1). In addition, in all subjects with proven liver steatosis e.g.
AC C
as observed during ultrasonography, a thorough assessment towards metabolic syndrome/T2D is expected. This holds also true for subjects with liver steatosis and normal liver enzymes as NAFLD is frequently present under such circumstances. A genetic testing for common variants (e.g. PNPLA3 I148M or TM6SF2) is currently not recommended in daily practice. NASH patients with hypertension need special attention as they exhibit a more progressive disease.
ACCEPTED MANUSCRIPT 4
Other chronic liver diseases have to be ruled out especially if typically associated
How to assess steatosis and fibrosis?
RI PT
with liver steatosis such as Wilson´s disease.
SC
Physicians have to make a judgement of relevance and stage of liver disease in NAFLD.6 Adequate assessment of fibrosis is the most important task in the
M AN U
management of NAFLD patients. This is derived from the fact that many studies have now demonstrated that fibrosis is the key long-term determinant risk factor for development of liver cirrhosis and further liver complications such as HCC.1 Risk of liver related mortality increases exponentially with increase in fibrosis
TE D
stage as shown by a recent systemic review and meta-analysis.7 For this analysis, 5 adult NAFLD cohort studies reporting fibrosis stage-specific mortality including 1,495 patients were analyzed. Liver biopsy still reflects the state-of-the
EP
art procedure to assess stage of liver disease including degree of inflammation and fibrosis.8 Invasive nature of this procedure and the current lack of
AC C
established therapies for NAFLD has obviously limited its use in daily clinical practice.
Assessment of steatosis. Ultrasonography reflects the preferred diagnostic procedure for imaging of NAFLD as it is widely available and cheaper than more advanced technologies such as magnetic resonance imaging (MRI). Besides
ACCEPTED MANUSCRIPT 5
classical ultrasonography, ultrasound-based controlled attenuation parameter (CAP) provides a standardized non-invasive measure of hepatic steatosis, is now
RI PT
widely available and despite its limitations especially in case of high body mass index its use should be recommended.9 The best quantitative assessment of liver fat is obtained by using 1H-MR spectroscopy (MRS), which is, however, not
SC
generally available, expensive and used mainly for clinical studies.
M AN U
Assessment of fibrosis. Monitoring of fibrosis would be ideally performed repeatedly in high-risk patients e.g. with T2D and for this purpose certain biomarkers would be highly valuable. Several serum markers such as NAFLD fibrosis score (NFS), fibrosis 4 calculator (FIB-4), Enhanced Liver Fibrosis (ELF)
TE D
and FibroTest® have been shown to predict both cardiovascular and liver-related mortality. All these tests are especially useful in identifying more advanced disease (>F3). In addition, the negative predictive values for excluding advanced
EP
fibrosis are higher and therefore these tests are indeed useful in clinical practice. Whereas transient elastography (TE) is currently the most common technique
AC C
used to define fibrosis stage of NAFLD patients, this technique is accompanied by certain shortcomings such as difficulty of proper assessment and interpretation in the very obese population. Furthermore, large clinical series have shown that up to 20% of investigations produce unreliable results even when using the XL probe again especially in obese subjects.10 Obviously, the combination of biomarkers/scores and TE might add additional diagnostic
ACCEPTED MANUSCRIPT 6
accuracy and reflect the preferred clinical strategy. Magnetic resonance elastography (MRE) has recently appeared as the most accurate method to
RI PT
assess stage of fibrosis.11 In a prospective, cross-sectional study MRE was significantly more accurate than TE in identification of liver fibrosis (stage 1 or more), using biopsy analysis as the standard. Interestingly, MRI-based proton
SC
density fat fraction was also more accurate than CAP in detecting all grades of steatosis in patients with NAFLD.11 Availability and financial issues might,
M AN U
however, limit the use of MR-based assessment considering the enormous number of NAFLD patients (Figure 1). Further studies are needed to define exact roles for TE/CAP and MRE in NAFLD management in various health care
TE D
systems.
How to treat patients with NAFLD?
EP
Non-pharmacological interventions. Physicians treating NAFLD patients have to urge their patients to practice lifestyle changes including weight loss and
AC C
exercise. Weight loss, independent of other strategies, improves various features of this disease and weight reduction of 7-10% body weight has been shown to improve liver histology.12,13 Most dramatic improvements of liver pathology have been observed by bariatric surgery as NASH disappeared in > 80% and fibrosis was significantly reduced in > 30% of patients.14,15 The evidence that particular diets are able to improve liver disease in NAFLD beyond weight loss is sparse.
ACCEPTED MANUSCRIPT 7
Interestingly, a recent study in T2D showed that diets high in animal or plant protein reduced liver fat independent from weight loss, improved insulin 16
Moderate (brisk walking
RI PT
resistance and liver histology associated with NASH.
for 150 minutes per week for 12 months) or vigorous moderate exercise (jogging for 150 minutes per week at 65-80% of maximum heart rate for 6 months and
SC
brisk walking 150 minutes per week at 45-55% of maximum heart rate for another 6 months) was able to reduce intrahepatic triglyceride content (as
M AN U
assessed by magnetic resonance spectroscopy) at 6 and 12 months, and this effect was mainly mediated by weight loss.17 Although profound weight loss (around 10%) improves liver histology including liver fibrosis, this effect is significantly less in case of advanced NASH. Intensified therapy for associated
TE D
arterial hypertension, T2D and hyperlipidemia including use of statins is highly recommended to reduce the increased risk for cardiovascular diseases in NAFLD
EP
patients.
Pharmacotherapy
for
NAFLD.
Although
there
are
still
no
approved
AC C
pharmacological therapies available for the medical management of NAFLD despite urgent need, certain treatments such as thiazolidinediones i.e. PPARγ agonists, drugs which potently decrease liver fat content have been demonstrated to be effective for the treatment of NASH.18,19 In the largest trial of PPARγ agonists to date, NASH patients without T2D received pioglitazone 30 mg/day for 96 weeks and treatment was associated with histological
ACCEPTED MANUSCRIPT 8
improvement in 34% of patients compared with 19% of controls.18 A recently reported long-term pioglitazone study (45 mg/day up to 3 years) also resulted in
RI PT
improvement of histologic scores including fibrosis score19 Despite this fact acceptance of this therapy in clinical practice is unfortunately low because of certain side effects including weight gain. Vitamin E, a potent anti-oxidant, has 18
Vitamin E used at a dose of 800
SC
been studied in multiple clinical studies.
IU/day for 96 weeks was more effective than placebo resulting in resolution of
M AN U
NASH in 36%, however, without affecting fibrosis. Despite these interesting data for Vitamin E, there exists some concern regarding its long-term safety20 and its use has to take into account a critical risk/benefit evaluation. GLP-1 agonists are approved for the treatment of T2D and the LEAN study investigating only 52 subjects showed histological resolution of NASH without worsening of fibrosis,
TE D
the primary end point, in 39% of subjects.21 Liraglutide resulted as expected in weight loss which might have contributed to observed effects. Several of these
EP
therapies i.e. PPARγ agonists and GLP-1 agonists reflect established therapies in the management of T2D highlighting the crucial importance of insulin
AC C
resistance in NAFLD. Therefore some of these therapies, despite lack of approval, might be used in highly selected high-risk patients with NASH. Several other randomized controlled trials which cannot be discussed here have been performed in the last years with certain efficacy regarding improvement of liver histology such as elafibrinor, a dual PPARα/δ agonist.
22
Numerous clinical trials
targeting metabolic pathways, oxidative stress/inflammation, gut microbiota and
ACCEPTED MANUSCRIPT 9
fibrosis are currently underway providing hopefully in the near future new and effective therapeutics (Figure 2). There remains, however, an urgent need to
RI PT
develop methods to identify the populations at risk of disease progression and validate endpoints that reflect clinically relevant changes in this population.23
SC
Follow-up of diagnosed NAFLD patients
M AN U
Liver complications. At least 10% of NAFLD patients present with NASH and this group reflects the high-risk patient group developing advanced chronic liver disease, liver cirrhosis and HCC. It is also this patient group which finally needs liver transplantation and in the United States - NAFLD is close becoming number
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1 indication for orthotopic liver transplantation. Similar trends have also been observed in other countries. As NAFLD patients exhibit a considerably enhanced risk for HCC, especially also in the non-cirrhotic stage, special awareness into
EP
this direction is needed.24 Despite this risk, broadly accepted HCC screening strategies have so far not been implemented in the long-term care of NAFLD
AC C
patients.
Extrahepatic and systemic complications. NAFLD reflects a prototypic systemic disorder and as it is highly associated with metabolic syndrome and insulin resistance, it is expected that cardiovascular complications are common and the leading cause of death in this population.25 Therefore, diagnosis of NAFLD,
ACCEPTED MANUSCRIPT 10
implicates a life-long search for potentially associated cardiovascular disorders,
RI PT
chronic kidney disease, T2D and malignancies such as colonic neoplasia.
Conclusions
SC
In the past years, substantial progress has been made in the understanding of the pathophysiology of NAFLD suggesting that multiple parallel hits are needed
M AN U
for the evolution of NASH.26 Awareness for NAFLD is needed in many medical disciplines especially by general practitioners, hepatologists and diabetologists reflecting the key physician groups taking care of these patients. As NAFLD constitutes a clinical syndrome with various clinical features it is essential for
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physicians to consider these patients in a rather holistic manner. Search for cofeatures such as arterial hypertension, diabetes, and sleep apnea are key clinical prerequisites. Only a broad awareness in the medical community in the future will
EP
allow proper diagnosis and hopefully effective management and treatment of this
AC C
epidemic disorder in the future.
ACCEPTED MANUSCRIPT 11
Figure Legends
RI PT
Figure 1: NAFLD: Diagnostic algorithm in the general population (A) and in type 2 diabetes patients (B).
Diagnostic steps (from non-invasive towards invasive) are dependent on severity
SC
of disease. Abbreviations: CAP, controlled attenuation parameter; HDL, highdensity lipoproteins; IR, insulin resistance; MRE, magnetic resonance
T2D, type 2 diabetes.
M AN U
elastography; MS, metabolic syndrome; OGTT, oral glucose tolerance testing;
Figure 2: Multiple hits drive the pathogenesis of NAFLD and define
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potential treatment targets.
A simplified illustration and examples of involved pathways are illustrated in the Figure. All these pathways have been or are currently studied in numerous
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clinical trials (> Phase II studies). 1) Lipotoxicity: drugs either suppress de novo lipogenesis (e.g. aramchol, a conjugate of cholic and arachidic acid, or selective
AC C
inhibitors of acetyl-CoA-carboxylase) or increase lipid export from the liver (e.g. PPARγ agonists such as pioglitazone). 2) Insulin resistance: hepatic/systemic insulin resistance is improved by various drugs such as PPARα/γ/δ agonists (e.g. pioglitazone, elafibrinor) or GI hormones such as GLP-1 analogues (e.g. liraglutide) or FGF19/FGF21 analogues. Induction of the potent anti-inflammatory adipokine adiponectin is one of the key functions of PPARγ agonists. 3) Oxidative
ACCEPTED MANUSCRIPT 12
stress: affected by Vitamin E 4) Inflammation/apoptosis: as inflammation commonly precedes fibrosis effective targeting of inflammation is of crucial
RI PT
importance in this disease. Currently, inhibitors of apoptosis signal-regulating kinase 1 (ASK1) or an oral antagonist of CCR2/5, chemokine receptors for MCP1 and RANTES are tested in phase III studies. 5) Fibrosis: reduction of fibrosis
SC
reflects the main goal in treatment. Galectin-3 plays a key role in fibrosis development (Galectin-3 inhibitors currently tested). 6) Farnesoid X receptor
M AN U
(FXR) agonists negatively regulate bile acid synthesis, decrease hepatic lipogenesis and gluconeogenesis and improve peripheral insulin sensitivity thereby critically affecting various NAFLD pathways. Several FXR agonists e.g. obeticholic acid have been tested in clinical trials. 7) Bile acids: Blocking
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enterohepatic circulation of bile acids e.g. bei inhibiting the ileal apical sodiumdependent bile acid transporter (ASBT) by sevelamer. 8) Gut microbiota: targeted by anti- or probiotics and fecal microbial transfer (FMT). Several of the
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here discussed potential NAFLD drugs are able to affect various treatment targets (e.g hepatic fat content and insulin resistance) thereby acting in a
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pleiotropic manner. Considering its complex pathophysiology it appears likely that a combination therapy might be the future treatment approach in NASH patients.
ACCEPTED MANUSCRIPT 13
1.
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References Rinella, M. E. Nonalcoholic fatty liver disease: a systematic review. JAMA
2015;313:2263-73.
Targher, G. Non-alcoholic fatty liver disease as driving force in coronary heart
SC
2.
disease? Gut 2017;66:213-4.
Lassailly, G., Caiazzo, R., Pattou, F., et al. Perspectives on Treatment for
M AN U
3.
Nonalcoholic Steatohepatitis. Gastroenterology 2016;150:1835-48. 4.
Marchesini, G., Brizi, M., Morselli-Labate, A. M., et al. Association of
nonalcoholic fatty liver disease with insulin resistance. Am J Med 1999;107:450-5. EASL-EASD-EASO Clinical Practice Guidelines for the management of non-
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5.
alcoholic fatty liver disease. J Hepatol 2016;64:1388-402. 6.
Bedossa, P., Patel, K. Biopsy and Noninvasive Methods to Assess Progression of
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Nonalcoholic Fatty Liver Disease. Gastroenterology 2016;150:1811-22 e4. Dulai, P. S., Singh, S., Patel, J., et al. Increased risk of mortality by fibrosis stage
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7.
in nonalcoholic fatty liver disease: Systematic review and meta-analysis. Hepatology 2017. 8.
Brunt, E. M., Kleiner, D. E. Challenges in the hepatic histopathology in non-
alcoholic fatty liver disease. Gut 2017.
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9.
Karlas, T., Petroff, D., Sasso, M., et al. Individual patient data meta-analysis of
controlled attenuation parameter (CAP) technology for assessing steatosis. J Hepatol
10.
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2016. Wong, V. W., Vergniol, J., Wong, G. L., et al. Liver stiffness measurement using
XL probe in patients with nonalcoholic fatty liver disease. Am J Gastroenterol
11.
SC
2012;107:1862-71.
Park, C. C., Nguyen, P., Hernandez, C., et al. Magnetic Resonance Elastography
vs Transient Elastography in Detection of Fibrosis and Noninvasive Measurement of
M AN U
Steatosis in Patients With Biopsy-Proven Nonalcoholic Fatty Liver Disease. Gastroenterology 2017;152:598-607 e2. 12.
Promrat, K., Kleiner, D. E., Niemeier, H. M., et al. Randomized controlled trial
testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology
13.
TE D
2010;51:121-9.
Ratziu, V. Non-pharmacological interventions in non-alcoholic fatty liver disease
patients. Liver Int 2017;37 Suppl 1:90-6.
Klein, S., Mittendorfer, B., Eagon, J. C., et al. Gastric bypass surgery improves
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14.
metabolic and hepatic abnormalities associated with nonalcoholic fatty liver disease.
AC C
Gastroenterology 2006;130:1564-72. 15.
Lassailly, G., Caiazzo, R., Buob, D., et al. Bariatric Surgery Reduces Features of
Nonalcoholic
Steatohepatitis
2015;149:379-88; quiz e15-6.
in
Morbidly
Obese
Patients.
Gastroenterology
ACCEPTED MANUSCRIPT 15
16.
Markova, M., Pivovarova, O., Hornemann, S., et al. Isocaloric Diets High in
Animal or Plant Protein Reduce Liver Fat and Inflammation in Individuals With Type 2
17.
RI PT
Diabetes. Gastroenterology 2017;152:571-85 e8. Zhang, H. J., He, J., Pan, L. L., et al. Effects of Moderate and Vigorous Exercise
on Nonalcoholic Fatty Liver Disease: A Randomized Clinical Trial. JAMA Intern Med
18.
SC
2016;176:1074-82.
Sanyal, A. J., Chalasani, N., Kowdley, K. V., et al. Pioglitazone, vitamin E, or
19.
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placebo for nonalcoholic steatohepatitis. N Engl J Med 2010;362:1675-85. Cusi, K., Orsak, B., Bril, F., et al. Long-Term Pioglitazone Treatment for Patients
With Nonalcoholic Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus: A Randomized Trial. Ann Intern Med 2016;165:305-15. 20.
Miller, E. R., 3rd, Pastor-Barriuso, R., Dalal, D., et al. Meta-analysis: high-dosage
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vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2005;142:37-46. 21.
Armstrong, M. J., Gaunt, P., Aithal, G. P., et al. Liraglutide safety and efficacy in
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patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind,
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randomised, placebo-controlled phase 2 study. Lancet 2016;387:679-90. 22.
Ratziu, V., Harrison, S. A., Francque, S., et al. Elafibranor, an Agonist of the
Peroxisome Proliferator-Activated Receptor-alpha and -delta, Induces Resolution of Nonalcoholic
Steatohepatitis
Without
Fibrosis
Worsening.
Gastroenterology
2016;150:1147-59 e5. 23.
Sanyal, A. J., Friedman, S. L., McCullough, A. J., et al. Challenges and
opportunities in drug and biomarker development for nonalcoholic steatohepatitis:
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findings and recommendations from an American Association for the Study of Liver Diseases-U.S.
Food
and
Drug
Administration
Joint
Workshop.
Hepatology
24.
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2015;61:1392-405. Zoller, H., Tilg, H. Nonalcoholic fatty liver disease and hepatocellular carcinoma.
Metabolism 2016;65:1151-60.
Adams, L. A., Anstee, Q. M., Tilg, H., et al. Non-alcoholic fatty liver disease and
SC
25.
its relationship with cardiovascular disease and other extrahepatic diseases. Gut 2017. Tilg, H., Moschen, A. R. Evolution of inflammation in nonalcoholic fatty liver
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26.
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disease: the multiple parallel hits hypothesis. Hepatology 2010;52:1836-46.
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SC
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ACCEPTED MANUSCRIPT
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EP
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M AN U
SC
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ACCEPTED MANUSCRIPT
PII: DOI: Reference:
S0016-5085(17)35801-8 10.1053/j.gastro.2017.06.016 YGAST 61251
To appear in:
Gastroenterology
Please cite this article as: Tilg H, How to approach a patient with non-alcoholic fatty liver disease, Gastroenterology (2017), doi: 10.1053/j.gastro.2017.06.016. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
How to approach a patient with non-alcoholic
RI PT
fatty liver disease
M AN U
Herbert Tilg
SC
Running Title: NAFLD and clinical management
Department of Internal Medicine I, Gastroenterology, Hepatology & Endocrinology, Medical University Innsbruck, Austria
TE D
Corresponding author:
Herbert Tilg, M.D., Department of Internal Medicine I, Gastroenterology, Hepatology & Endocrinology, Medical University Innsbruck, Innsbruck, Austria
EP
Phone: +43 512 504 23539, Fax: +43 512 504 23538
AC C
E-mail: [email protected]
ACCEPTED MANUSCRIPT 2
Non-alcoholic fatty liver disease (NAFLD) has evolved as the most common liver disease world-wide. NAFLD covers a disease spectrum, ranging from simple
RI PT
steatosis in the absence of inflammation to non-alcoholic steatohepatitis (NASH), liver cirrhosis and hepatocellular carcinoma (HCC). Prevalence of NAFLD is high and might reach up to 30% in certain populations such as US Americans or
SC
Asians mostly paralleling rates of obesity and type 2 diabetes (T2D).1 The number of patients with NAFLD that have NASH is unclear, but exceeds >10% of
M AN U
the overall NAFLD population. A definite diagnosis of NASH is important as inflammation and/or fibrosis dictate the long-term prognosis of this disease which might ultimately require liver transplantation. Whereas liver-related long-term complications are mainly seen in patients presenting with definite NASH, NAFLD has in general a high rate of extrahepatic complications dominated by
TE D
cardiovascular complications, chronic kidney disease, T2D and various cancers.2 Although no established treatment for NASH currently exists, several treatments
EP
such as peroxisome proliferator-activated receptor (PPAR)γ agonists, vitamin E or glucagon-like peptide (GLP)-1 agonists, have demonstrated some clinical
AC C
efficacy in the past years. As a substantial proportion of patients die of liver disease, there exists an urgent need for effective NASH therapies.3 An intimate knowledge of this topic is therefore crucial for many medical disciplines.
ACCEPTED MANUSCRIPT 3
When to suspect NAFLD?
RI PT
Most NAFLD patients are obese with or without T2D, consume rather unhealthy diets and practice a sedentary lifestyle lacking physical activity and exercise. Insulin resistance has been characterized as one of the hallmarks of NAFLD.4
SC
Assessment of HOMA-IR is a useful surrogate for insulin resistance in NAFLD but only in subjects without T2D. Patients with metabolic syndrome and or certain
M AN U
metabolic risk factors such as obesity and/or arterial hypertension should be evaluated towards the presence of NAFLD. In addition, patients with T2D should undergo repeatedly a careful liver investigation to diagnose highly prevalent
TE D
NAFLD (in more than > 50% of T2D patients).5
As concordant presence of NAFLD and alcoholic liver disease is frequent, assessment of alcohol intake is mandatory. In all individuals with persistently
EP
elevated liver enzymes (e.g. primarily elevated ALT, γGT), NAFLD has to be considered (Figure 1). In addition, in all subjects with proven liver steatosis e.g.
AC C
as observed during ultrasonography, a thorough assessment towards metabolic syndrome/T2D is expected. This holds also true for subjects with liver steatosis and normal liver enzymes as NAFLD is frequently present under such circumstances. A genetic testing for common variants (e.g. PNPLA3 I148M or TM6SF2) is currently not recommended in daily practice. NASH patients with hypertension need special attention as they exhibit a more progressive disease.
ACCEPTED MANUSCRIPT 4
Other chronic liver diseases have to be ruled out especially if typically associated
How to assess steatosis and fibrosis?
RI PT
with liver steatosis such as Wilson´s disease.
SC
Physicians have to make a judgement of relevance and stage of liver disease in NAFLD.6 Adequate assessment of fibrosis is the most important task in the
M AN U
management of NAFLD patients. This is derived from the fact that many studies have now demonstrated that fibrosis is the key long-term determinant risk factor for development of liver cirrhosis and further liver complications such as HCC.1 Risk of liver related mortality increases exponentially with increase in fibrosis
TE D
stage as shown by a recent systemic review and meta-analysis.7 For this analysis, 5 adult NAFLD cohort studies reporting fibrosis stage-specific mortality including 1,495 patients were analyzed. Liver biopsy still reflects the state-of-the
EP
art procedure to assess stage of liver disease including degree of inflammation and fibrosis.8 Invasive nature of this procedure and the current lack of
AC C
established therapies for NAFLD has obviously limited its use in daily clinical practice.
Assessment of steatosis. Ultrasonography reflects the preferred diagnostic procedure for imaging of NAFLD as it is widely available and cheaper than more advanced technologies such as magnetic resonance imaging (MRI). Besides
ACCEPTED MANUSCRIPT 5
classical ultrasonography, ultrasound-based controlled attenuation parameter (CAP) provides a standardized non-invasive measure of hepatic steatosis, is now
RI PT
widely available and despite its limitations especially in case of high body mass index its use should be recommended.9 The best quantitative assessment of liver fat is obtained by using 1H-MR spectroscopy (MRS), which is, however, not
SC
generally available, expensive and used mainly for clinical studies.
M AN U
Assessment of fibrosis. Monitoring of fibrosis would be ideally performed repeatedly in high-risk patients e.g. with T2D and for this purpose certain biomarkers would be highly valuable. Several serum markers such as NAFLD fibrosis score (NFS), fibrosis 4 calculator (FIB-4), Enhanced Liver Fibrosis (ELF)
TE D
and FibroTest® have been shown to predict both cardiovascular and liver-related mortality. All these tests are especially useful in identifying more advanced disease (>F3). In addition, the negative predictive values for excluding advanced
EP
fibrosis are higher and therefore these tests are indeed useful in clinical practice. Whereas transient elastography (TE) is currently the most common technique
AC C
used to define fibrosis stage of NAFLD patients, this technique is accompanied by certain shortcomings such as difficulty of proper assessment and interpretation in the very obese population. Furthermore, large clinical series have shown that up to 20% of investigations produce unreliable results even when using the XL probe again especially in obese subjects.10 Obviously, the combination of biomarkers/scores and TE might add additional diagnostic
ACCEPTED MANUSCRIPT 6
accuracy and reflect the preferred clinical strategy. Magnetic resonance elastography (MRE) has recently appeared as the most accurate method to
RI PT
assess stage of fibrosis.11 In a prospective, cross-sectional study MRE was significantly more accurate than TE in identification of liver fibrosis (stage 1 or more), using biopsy analysis as the standard. Interestingly, MRI-based proton
SC
density fat fraction was also more accurate than CAP in detecting all grades of steatosis in patients with NAFLD.11 Availability and financial issues might,
M AN U
however, limit the use of MR-based assessment considering the enormous number of NAFLD patients (Figure 1). Further studies are needed to define exact roles for TE/CAP and MRE in NAFLD management in various health care
TE D
systems.
How to treat patients with NAFLD?
EP
Non-pharmacological interventions. Physicians treating NAFLD patients have to urge their patients to practice lifestyle changes including weight loss and
AC C
exercise. Weight loss, independent of other strategies, improves various features of this disease and weight reduction of 7-10% body weight has been shown to improve liver histology.12,13 Most dramatic improvements of liver pathology have been observed by bariatric surgery as NASH disappeared in > 80% and fibrosis was significantly reduced in > 30% of patients.14,15 The evidence that particular diets are able to improve liver disease in NAFLD beyond weight loss is sparse.
ACCEPTED MANUSCRIPT 7
Interestingly, a recent study in T2D showed that diets high in animal or plant protein reduced liver fat independent from weight loss, improved insulin 16
Moderate (brisk walking
RI PT
resistance and liver histology associated with NASH.
for 150 minutes per week for 12 months) or vigorous moderate exercise (jogging for 150 minutes per week at 65-80% of maximum heart rate for 6 months and
SC
brisk walking 150 minutes per week at 45-55% of maximum heart rate for another 6 months) was able to reduce intrahepatic triglyceride content (as
M AN U
assessed by magnetic resonance spectroscopy) at 6 and 12 months, and this effect was mainly mediated by weight loss.17 Although profound weight loss (around 10%) improves liver histology including liver fibrosis, this effect is significantly less in case of advanced NASH. Intensified therapy for associated
TE D
arterial hypertension, T2D and hyperlipidemia including use of statins is highly recommended to reduce the increased risk for cardiovascular diseases in NAFLD
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patients.
Pharmacotherapy
for
NAFLD.
Although
there
are
still
no
approved
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pharmacological therapies available for the medical management of NAFLD despite urgent need, certain treatments such as thiazolidinediones i.e. PPARγ agonists, drugs which potently decrease liver fat content have been demonstrated to be effective for the treatment of NASH.18,19 In the largest trial of PPARγ agonists to date, NASH patients without T2D received pioglitazone 30 mg/day for 96 weeks and treatment was associated with histological
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improvement in 34% of patients compared with 19% of controls.18 A recently reported long-term pioglitazone study (45 mg/day up to 3 years) also resulted in
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improvement of histologic scores including fibrosis score19 Despite this fact acceptance of this therapy in clinical practice is unfortunately low because of certain side effects including weight gain. Vitamin E, a potent anti-oxidant, has 18
Vitamin E used at a dose of 800
SC
been studied in multiple clinical studies.
IU/day for 96 weeks was more effective than placebo resulting in resolution of
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NASH in 36%, however, without affecting fibrosis. Despite these interesting data for Vitamin E, there exists some concern regarding its long-term safety20 and its use has to take into account a critical risk/benefit evaluation. GLP-1 agonists are approved for the treatment of T2D and the LEAN study investigating only 52 subjects showed histological resolution of NASH without worsening of fibrosis,
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the primary end point, in 39% of subjects.21 Liraglutide resulted as expected in weight loss which might have contributed to observed effects. Several of these
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therapies i.e. PPARγ agonists and GLP-1 agonists reflect established therapies in the management of T2D highlighting the crucial importance of insulin
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resistance in NAFLD. Therefore some of these therapies, despite lack of approval, might be used in highly selected high-risk patients with NASH. Several other randomized controlled trials which cannot be discussed here have been performed in the last years with certain efficacy regarding improvement of liver histology such as elafibrinor, a dual PPARα/δ agonist.
22
Numerous clinical trials
targeting metabolic pathways, oxidative stress/inflammation, gut microbiota and
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fibrosis are currently underway providing hopefully in the near future new and effective therapeutics (Figure 2). There remains, however, an urgent need to
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develop methods to identify the populations at risk of disease progression and validate endpoints that reflect clinically relevant changes in this population.23
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Follow-up of diagnosed NAFLD patients
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Liver complications. At least 10% of NAFLD patients present with NASH and this group reflects the high-risk patient group developing advanced chronic liver disease, liver cirrhosis and HCC. It is also this patient group which finally needs liver transplantation and in the United States - NAFLD is close becoming number
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1 indication for orthotopic liver transplantation. Similar trends have also been observed in other countries. As NAFLD patients exhibit a considerably enhanced risk for HCC, especially also in the non-cirrhotic stage, special awareness into
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this direction is needed.24 Despite this risk, broadly accepted HCC screening strategies have so far not been implemented in the long-term care of NAFLD
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patients.
Extrahepatic and systemic complications. NAFLD reflects a prototypic systemic disorder and as it is highly associated with metabolic syndrome and insulin resistance, it is expected that cardiovascular complications are common and the leading cause of death in this population.25 Therefore, diagnosis of NAFLD,
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implicates a life-long search for potentially associated cardiovascular disorders,
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chronic kidney disease, T2D and malignancies such as colonic neoplasia.
Conclusions
SC
In the past years, substantial progress has been made in the understanding of the pathophysiology of NAFLD suggesting that multiple parallel hits are needed
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for the evolution of NASH.26 Awareness for NAFLD is needed in many medical disciplines especially by general practitioners, hepatologists and diabetologists reflecting the key physician groups taking care of these patients. As NAFLD constitutes a clinical syndrome with various clinical features it is essential for
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physicians to consider these patients in a rather holistic manner. Search for cofeatures such as arterial hypertension, diabetes, and sleep apnea are key clinical prerequisites. Only a broad awareness in the medical community in the future will
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allow proper diagnosis and hopefully effective management and treatment of this
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epidemic disorder in the future.
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Figure Legends
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Figure 1: NAFLD: Diagnostic algorithm in the general population (A) and in type 2 diabetes patients (B).
Diagnostic steps (from non-invasive towards invasive) are dependent on severity
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of disease. Abbreviations: CAP, controlled attenuation parameter; HDL, highdensity lipoproteins; IR, insulin resistance; MRE, magnetic resonance
T2D, type 2 diabetes.
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elastography; MS, metabolic syndrome; OGTT, oral glucose tolerance testing;
Figure 2: Multiple hits drive the pathogenesis of NAFLD and define
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potential treatment targets.
A simplified illustration and examples of involved pathways are illustrated in the Figure. All these pathways have been or are currently studied in numerous
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clinical trials (> Phase II studies). 1) Lipotoxicity: drugs either suppress de novo lipogenesis (e.g. aramchol, a conjugate of cholic and arachidic acid, or selective
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inhibitors of acetyl-CoA-carboxylase) or increase lipid export from the liver (e.g. PPARγ agonists such as pioglitazone). 2) Insulin resistance: hepatic/systemic insulin resistance is improved by various drugs such as PPARα/γ/δ agonists (e.g. pioglitazone, elafibrinor) or GI hormones such as GLP-1 analogues (e.g. liraglutide) or FGF19/FGF21 analogues. Induction of the potent anti-inflammatory adipokine adiponectin is one of the key functions of PPARγ agonists. 3) Oxidative
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stress: affected by Vitamin E 4) Inflammation/apoptosis: as inflammation commonly precedes fibrosis effective targeting of inflammation is of crucial
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importance in this disease. Currently, inhibitors of apoptosis signal-regulating kinase 1 (ASK1) or an oral antagonist of CCR2/5, chemokine receptors for MCP1 and RANTES are tested in phase III studies. 5) Fibrosis: reduction of fibrosis
SC
reflects the main goal in treatment. Galectin-3 plays a key role in fibrosis development (Galectin-3 inhibitors currently tested). 6) Farnesoid X receptor
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(FXR) agonists negatively regulate bile acid synthesis, decrease hepatic lipogenesis and gluconeogenesis and improve peripheral insulin sensitivity thereby critically affecting various NAFLD pathways. Several FXR agonists e.g. obeticholic acid have been tested in clinical trials. 7) Bile acids: Blocking
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enterohepatic circulation of bile acids e.g. bei inhibiting the ileal apical sodiumdependent bile acid transporter (ASBT) by sevelamer. 8) Gut microbiota: targeted by anti- or probiotics and fecal microbial transfer (FMT). Several of the
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here discussed potential NAFLD drugs are able to affect various treatment targets (e.g hepatic fat content and insulin resistance) thereby acting in a
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pleiotropic manner. Considering its complex pathophysiology it appears likely that a combination therapy might be the future treatment approach in NASH patients.
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1.
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