Introduction
Non-alcoholic 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 ]. There is also preliminary
evidence that therapy with checkpoint inhibitors, which is increasingly used in the
context of cancer treatments, may induce NAFLD in lean individuals via subclinical
inflammation of subcutaneous adipose tissue, which leads to, among other things,
significant weight loss [3 ]. 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 [4 ]
[5 ]. New research from the German Diabetes Study
(GDS) indicates that especially the severely insulin-resistant diabetes subtype
(cluster) has a significantly increased prevalence of NAFLD already in the year of
diabetes diagnosis and shows a greater increase in surrogate markers of fibrosis in
the first 5 years [6 ].
Definition and incidence
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 ([Tab. 1 ]). If no evidence is
found for these diseases, it is usually because NAFLD is present. NAFLD includes not
only non-alcoholic fatty liver (simple non-alcoholic steatosis, NAFL), which is not
associated with relevant inflammatory or fibrotic changes in the liver and affects
about 70% of people with NAFLD, but also non-alcoholic steatohepatitis
(NASH), liver fibrosis, and cirrhosis without other aetiologies. These represent
advanced stages of NAFLD, with NASH present in about 30% of people with
NAFLD. People with fatty liver and diabetes are>40% likely to have
NASH [1 ]
[5 ].
Tab. 1 Causes of fatty liver.
Causes
Diagnostic
Non-alcoholic fatty liver
Steatosis with none of the causes listed below
Alcohol
>21 standard drinks 1 per week for men.
>14 standard drinks 1 per week for women
Medication
E.g., glucocorticoids, oestrogens, 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, hypobetalipoproteinaemia,
lipodystrophy, pronounced chronic inflammatory bowel
diseases
1 standard drink contains 14 g alcohol.
Diagnostics
NAFLD 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 Fibro-Scan and MR elastography (MRE) are quite accurate, but also expensive,
non-invasive methods for diagnosing fibrosis ([Tab.
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 (AST), special tests are available which
are primarily used for diagnosing fibrosis stages 3 and 4 [5 ]
[7 ]
[8 ]
[9 ]
although their accuracy seems to be lower, especially in diabetes mellitus [10 ].
Fig. 1 Diagnostic flowchart. NAFDL-FS: nonalcoholic fatty liver
disease fibrosis score; FIB-4: fibrosis-4 index; US/MR: Ultrasound/ Magnetic
resonance. * see European guideline. Data according to [8 ].
Tab. 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)
Widely available
Inexpensive
Indices for fibrosis (non-commercial: NAFLD-FS, FIB-4 Commercial
score: ELF, FibroTest, FibroMeter)
Formulas using the following parameters:
Age,
BMI,
Fasting blood glucose,
Diabetes diagnosis,
Glutamyl oxaloacetic transaminase (Aspartate
aminotransferase),
Glutamyl pyruvic transaminase (Alanine
aminotransferase),
GGT,
Thrombocytes,
Albumin and
Specific blood markers
Widely available
Inexpensive
Transient Elastography
Computer tomography
Radiation exposure
Inferior to MR imaging
Magnetic Resonance (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% [11 ]. 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 [12 ]. 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 [12 ].
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 ([Tab. 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 meal plans 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 [5 ].
Tab. 3 Effects of intervention on NAFLD and
diabetes.
Entervention
Effects on the liver
Systemic effects
Lifestyle
Steatosis: ↓↓↓
Blood glucose: ↓↓
Inflammation: ↓↓
Insulin resistance: ↓↓
Fibrosis: ↓or=
Dyslipidaemia: ↓
Weight: ↓
Bariatric surgery
Steatosis: ↓↓↓
Blood glucose: ↓↓↓
Inflammation: ↓ ?
Insulin resistance: ↓↓↓
Fibrosis: ?
Dyslipidaemia: ↓
Weight: ↓↓↓
Pioglitazone
Steatosis: ↓↓↓
Blood glucose: ↓↓
Inflammation: ↓↓
Insulin resistance: ↓↓↓
Fibrosis: ↓or=
Dyslipidaemia: ↓↓
Weight: ↑
Glucagon-like peptide-1 (GLP-1) analogues
Steatosis: ↓↓
Blood glucose: ↓↓
Inflammation: ↓
Insulin resistance: ↓↓
Fibrosis:=
Dyslipidaemia: ↓
Weight: ↓
Sodium-glucose co-transporter-2 (SGLT2) inhibitors
Steatosis: ↓
Blood glucose: ↓↓
Inflammation: ?
Insulin resistance: ↓
Fibrosis: ?
Dyslipidaemia:=
Weight: ↓
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 [5 ]. However,
recently in the SPLENDOR study, among patients with NASH and obesity, bariatric
surgery was associated with lower risk of adverse liver outcomes and major adverse
cardiovascular events, compared to nonsurgical management [13].
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) [5 ]
[8 ]. Recent data from studies with
relatively small case numbers indicate that GLP-1 receptor agonists (GLP-1:
glucagon-like peptide 1) such as liraglutide (1.8 mg/day) and semaglutide
(at daily doses of either 0.1 mg, 0.2 mg or 0.4 mg) and SGLT-2 inhibitors
(SGLT-2: sodium-dependent glucose transporter 2) can reduce the liver lipid content
and improve NASH 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 [[5 ], 14 ].
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.
This is a translation of the DDG clinical practice guideline
published in Diabetologie 2021; 16 (Suppl 2): S308–S311
DOI 10.1055/a-1581-6360
