Nonalcoholic fatty liver disease (NAFLD) affects more than 25% of the adult
population worldwide. According to analyses for 2016, Germany ranks third behind
Greece (41%) and Italy (25.4%) in the prevalence of NAFLD
(22.9% of the total population). An increase in the prevalence of NAFLD to
26.4% has been calculated for Germany (2.3) for the year 2030. At around
70%, the frequency of NAFLD is particularly high in people with obesity
and/or type 2 diabetes [2 ]. However, NAFLD
also occurs in about 7% of lean people and is then primarily of genetic
origin [2 ]. In Europe and the USA, NAFLD is now
regarded as the most frequent cause of chronic liver diseases although most people
with NAFLD die from secondary diseases resulting from diabetes or cardiovascular
diseases. Therefore, it is particularly important to test patients with type 2
diabetes for the presence, and especially the degree of severity, of NAFLD, and to
plan therapy accordingly [3 ]
[4 ].
Definition
A fatty liver can have many causes. First, a systematic evaluation is performed, and
if suspected, laboratory tests to confirm specific illnesses or drug therapies are
carried out ([Table 1 ]). If no evidence is found
for these diseases, it is usually because NAFLD is present. There are two types of
NAFLD: Nonalcoholic fatty liver (NAFL) is not associated with any relevant
inflammation or liver fibrosis and affects about 70% of people with NAFLD.
The second type includes nonalcoholic steatohepatitis (NASH), liver fibrosis and
cirrhosis of no specific cause. These represent advanced stages of NAFLD, with NASH
present in about 30% of people with NAFLD. In people with fatty liver and
diabetes, the probability of having NASH is >40% (1,4).
Table 1 Causes of fatty liver.
Causes
Diagnostic
Non-alcoholic fatty liver
Steatosis with none of the causes listed below
Alcohol
>21 standard drinks* per week for men.>14
standard drinks* per week for women
Medication
E.g. glucocorticoids, estrogens, amiodarone, tamoxifen,
tetracycline, methotrexate, valproic acid, antiviral drugs,
perhexiline maleate, chloroquine
Viral hepatitis
Virus serology
Autoimmune hepatitis
Autoimmune serology
Hemochromatosis
Elevated ferritin levels and transferrin saturation in serum
Wilson's disease
Lower levels of caeruloplasmin in serum
Alpha-1-antitrypsin deficiency
Lower alpha-1 antitrypsin levels in serum
Celiac disease
Anti-gliadin antibodies, anti-tissue transglutaminase
Other
E.g. severe malnutrition, hypobetalipoproteinemia, lipodystrophy,
pronounced chronic inflammatory bowel diseases
*1 standard drink contains 14g alcohol.
Diagnostic
NAFL is currently diagnosed by ultrasound examination, proton magnetic resonance
spectroscopy 1H-MRS and MR imaging (MRI) [Fig. 1 ].
The two non-invasive MR methods allow a precise determination of the lipid content
of the liver and are therefore preferred to quantification of the lipid content of
the liver using liver biopsy. The liver biopsy is currently the most suitable method
for diagnosing inflammatory changes, i. e. NASH, as well as for the
diagnosis of liver fibrosis. Ultrasound or MR-based techniques such as FibroScan and
MR elastography (MRE) are quite accurate, but also expensive, non-invasive methods
for diagnosing fibrosis ([Table 2 ]). Tests and
scores based on anthropometric and laboratory chemical parameters are also available
and can be used for risk assessment of NASH and fibrosis. In addition to
aminotransferase (ALT/AST), special tests are available which are primarily
used for diagnosing fibrosis stages 3 and 4 [4 ]
[5 ]
[6 ]
[7 ] although their accuracy seems to
be lower, especially in diabetes mellitus [8 ].
Fig. 1 Diagnostic flow-chart to assess and monitor disease severity in
the presence of suspected NAFLD and metabolic risk factors, according to
[6 ], [rerif].
Table 2 Diagnosis of NAFLD.
Method
Characteristics
Advantages
Disadvantages
Liver biopsy
To date, the reference method for lipid determination
The reference method for the determination of
inflammation and fibrosis
Sonography
Widely available
Inexpensive
Fatty liver index (FLI)
BMI
Waist circumference
Gamma GT
Fasting triglycerides
Widely available
Inexpensive
Indices for fibrosis (non-commercial: NAFLD-FS, FIB-4
Commercial score: ELF, FibroTest, FibroMeter)
Widely available
Inexpensive
Transient Elastography
Computer tomography
Radiation exposure
Inferior to MR imaging
MR imaging and spectroscopy
MR elastography
Risk for Advanced Liver Diseases and Cardiometabolic Diseases in NAFLD
Risk for Advanced Liver Diseases and Cardiometabolic Diseases in NAFLD
In a large meta-analysis of 11 studies it was shown that in people with NAFLD with
fibrosis detected by liver biopsy, over a period of 2145.5 person years, progression
was observed in 33% of people, stabilization in 43% and regression
of fibrosis in 22% [9 ]. Interestingly,
however, the same percentage of people with NAFL or NASH (about 18% each)
without fibrosis in the first liver biopsy have progressed to advanced fibrosis in
the subsequent biopsy [9 ]. In NAFLD, hepatocellular
carcinoma can also develop directly from NAFL without having had NASH [1 ].
People with NAFLD have a 2–6 times higher risk of type 2 diabetes
and/or cardiovascular disease [10 ]. This
risk is particularly high if there is abdominal obesity and especially if there is
insulin resistance. As more people with NAFLD die from complications of diabetes,
including cardiovascular disease [1 ], is of utmost
importance to above all diagnose and prevent diabetes-related and cardiometabolic
diseases as well as advanced liver diseases.
Therapy for NAFLD
First and foremost, in the therapeutic approach and prevention of progression of
NAFLD is a lifestyle modification including a balanced, calorie-reduced diet and an
increase in physical activity ([Table 3 ]). The
effectiveness of lifestyle intervention fundamentally depends on the achieved
reduction in body weight. Weight loss of about 5% results in a 30%
reduction of the liver lipid content. However, to positively influence hepatic
inflammation and fibrosis, weight loss of more than 10% is likely necessary.
For effective NAFLD therapy, revised nutritional mealplans should include a
reduction in fast-digesting carbohydrates, especially of products containing
fructose, and of saturated fatty acids. Endurance and strength training can also be
effective in addition to diet modification [4 ].
Table 3 Effects of intervention on NAFLD and diabetes.
Entervention
Effects on the liver
Systemic effects
Lifestyle
Steatosis: ↓↓↓
Blood glucose: ↓↓
Bariatric surgery
Steatosis: ↓↓↓
Blood glucose: ↓↓↓
Pioglitazone
Steatosis: ↓↓↓
Blood glucose: ↓↓
GLP-1 analogues
Steatosis: ↓↓
Blood glucose: ↓↓
SGLT-2 inhibitors
Steatosis: ↓
Blood glucose: ↓↓
Bariatric surgery for pronounced obesity or moderate obesity and type 2 diabetes
causes a pronounced reduction in the liver lipid content as well as weight loss,
although effects on inflammation and fibrosis of the liver have not yet been
sufficiently investigated [4 ].
So far, no pharmacological therapy has been approved to treat NAFLD. If type 2
diabetes is present, however, drugs can be used to specifically treat diabetes in
order to also treat NAFLD. The joint guidelines of the European Association for the
Study of the Liver (EASL), the European Association for the Study of Diabetes (EASD)
and the European Association for the Study of Obesity (EASO) as well as those of the
American Association for the Study of Liver Diseases recommend the use of
pioglitazone if there are no associated contraindications (heart failure, history
of
bladder carcinoma, increased risk of bone fractures) (4.5). Recent data from studies
with relatively small case numbers indicate that GLP-1 receptor agonists (GLP-1:
glucagon-like peptide 1) such as liraglutide and SGLT-2 inhibitors (SGLT-2:
sodium-dependent glucose transporter 2) can reduce the liver lipid content in NAFLD
and type 2 diabetes. All other pharmacological therapies for type 2 diabetes have
so
far shown no clinically-relevant effects on the course of NAFLD [4 ].
Outlook
The increasing prevalence of NAFLD in the most common metabolic diseases such as
obesity and type 2 diabetes requires targeted screening and careful diagnosis of
liver diseases in these patient groups. Early prevention or therapy of NAFLD will
reduce both the liver-specific as well as the diabetic consequences and
complications. In the future, this will require the full use of all existing
diagnostic possibilities including fibrosis screening on the one hand, and, on the
other hand, the further development of cost-effective and non-invasive or
low-invasive tests. The aim is to reduce the use of liver biopsies for diagnosis
and, above all, to assess the course of NAFLD and the effectiveness of therapies.
At
present, there are still no large studies that have convincingly demonstrated the
effectiveness of new monotherapies or combination therapies of existing drugs.
However, different innovative therapy concepts are already being tested
experimentally and clinically so that specific therapy recommendations for the
increasing number of patients with NAFLD and diabetes can be expected in the near
future.
