The DDG clinical practice guidelines are updated regularly during the second half
of the calendar year. Please ensure that you read and cite the respective
current version.
Updates To Content And Different Recommendations Compared To The Previous
Year's Version
Change 1: For the screening of non-alcoholic fatty liver disease, reference was
made to the updated S2k guideline on non-alcoholic fatty liver disease of the German
Society for Gastroenterology, Digestive and Metabolic Diseases/Deutschen
Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten
(DGVS) [7 ], the European algorithm of the EASL
Clinical Practice Guidelines [8 ], and a recently
proposed procedure for general practitioners and diabetologists [9 ]
Reason: New recommendation for structured screening for non-alcoholic fatty liver
disease for general practitioners and diabetologists
Supporting reference:
[7 ]
[8 ]
[9 ]
[10 ]
Change 2: New results from pharmacological phase 2 therapy studies are given.
Reason: This provided important new insights into the possible future
pharmacological therapy of non-alcoholic fatty liver disease.
Supporting reference:
[22 ]
[23 ]
[25 ]
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 for the year 2030. At around
70%, the frequency of NAFLD is particularly high in people with obesity
and/or type 1 diabetes [1 ]. However, NAFLD
also occurs in about 7% of thin people and is then primarily of genetic
origin [1 ]. 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 [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 ]. 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 [5 ].
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 are carried out and
drug therapies are evaluated ([Table 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 [4 ]
[6 ].
Table 1 Causes of fatty liver.
Causes
Diagnostics
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
Gliadin antibodies, anti-tissue transglutaminase
Other
E.g., severe malnutrition, hypobetalipoproteinaemia,
lipodystrophy, pronounced chronic inflammatory bowel
diseases
1 Standard drink contains 14 g alcohol.
Screening
In April 2022, the updated S2k guideline on non-alcoholic fatty liver disease of the
German Society for Gastroenterology, Digestive and Metabolic Diseases (DGVS) was
published with the participation of representatives of various medical societies,
including the German Diabetes Society, represented by Michael Roden and Norbert
Stefan [7 ]. It takes the following position for
screening for NAFLD, among others: Screening for NAFLD is not recommended in the
general population. However, a (non-invasive) assessment should be carried out if
risk factors for the development of NASH are present. Screening should therefore be
carried out primarily in people with type 2 diabetes, metabolic syndrome,
overweight/obesity or arterial hypertension. For this purpose, a screening
algorithm has been proposed that includes both steatosis and fibrosis risk, can be
modified according to availability and can be carried out in the general
practitioner’s practice. This algorithm is broadly in line with the European
Algorithm of the European Association for the Study of the Liver (EASL) Clinical
Practice Guidelines [8 ]
[9 ] and a recently proposed procedure for general
practitioners and diabetologists [10 ]. In [Fig. 1 ], we have mapped out the essential steps in
this process.
Fig. 1 Screening algorithm. FIB-4: fibrosis-4 index. Data according to
[7 ]
[9 ]
[10 ].
Diagnosis
Currently, ultrasound, proton magnetic resonance spectroscopy (MRS) and magnetic
resonance imaging (MRI) are used to diagnose NAFLD. 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
([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 transaminases
(glutamate-pyruvate transaminase (GPT)/alanine aminotransferase (ALT),
glutamate oxaloacetate transaminase (GOT)/aspartate aminotransferase (AST)),
special tests can also assist in diagnosing fibrosis stages 3 and 4 [[4, ]
[8 ]
[11 ], [12 ]
although their accuracy seems to be lower, especially in diabetes mellitus [13 ]
.
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 score;
Commercial: ELF, FibroTest, FibroMeter)
Widely available
Inexpensive
Age,
BMI,
Fasting blood glucose,
Diabetes diagnosis,
GOT (AST),
GPT (ALT),
Gamma GT (GGT),
Thrombocytes,
Albumin and
Specific blood markers
Transient elastography
Computer tomography
Radiation exposure
Inferior to MR imaging
Magnetic Resonance (MR) imaging and spectroscopy
MR elastography
NAFLD: non-alcoholic fatty liver disease; BMI: body mass index; GOT (AST): glutamate
oxaloacetate transaminase (aspartate aminotransferase); GPT
(ALT): glutamate-pyruvate transaminase (alanine aminotransferase); GGT: gamma-glutamyl
transferase; MR: magnetic resonance.
From NAFLD to MASLD
Since many years there was a discussion among experts as to whether metabolic risk
factors should replace alcohol consumption as the focus in defining fatty liver
disease [14 ]. This approach is mainly based on the
important finding that the pathogenesis of fatty liver is strongly influenced by
changes in glucose and lipid metabolism [15 ]
[16 ].
In 2023, a multi-society Delphi consensus statement suggested renaming NAFLD to
metabolic dysfunction-associated steatotic liver disease (MASLD) [17 ]. It includes patients with hepatic steatosis
and at least one of five cardiometabolic risk factors. In addition, the term fatty
has been converted into its synonym steatotic, because it was thought that fatty
describes a medical condition that can be stigmatizing for some patients. Thus, the
overarching term for fatty liver disease was changed to steatotic liver diseae
(SLD). In addition, the term metabolic dysfunction-associated steatohepatitis (MASH)
replaced NASH. Furthermore, a new category, outside MASLD, termed metabolic and
alcohol related/associated liver disease (MetALD), was selected to refer to
subjects with metabolic dysfunction-associated steatotic liver disease, who consume
greater amounts of alcohol per week (140-350 g/wk and 210-420 g/wk
for females and males, respectively). If no overt cardiometabolic criteria are
present, other causes should be ruled out. If none are identified, this condition
is
referred to as cryptogenic SLD.
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% [18 ]. 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 [18 ]. In NAFLD,
hepatocellular carcinoma can also develop directly from NAFL without having had NASH
[6 ].
People with NAFLD have a 2–6 times higher risk of type 2 diabetes
and/or cardiovascular disease [19 ]. 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 [6 ], it is of
utmost importance to above all diagnose and prevent 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 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 [4 ].
Table 3 Effects of intervention on NAFLD and diabetes.
Intervention
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: ↑
GLP-1 agonists
Steatosis: ↓↓
Blood glucose: ↓↓
Inflammation: ↓
Insulin resistance: ↓↓
Fibrosis:=
Dyslipidaemia: ↓
Weight: ↓
SGLT-2 inhibitors
Steatosis: ↓
Blood glucose: ↓↓
Inflammation: ?
Insulin resistance: ↓
Fibrosis: ?
Dyslipidaemia:=
Weight: ↓
Bariatric surgery for pronounced obesity or moderate obesity and type 2 diabetes
causes a large 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 ]. Recently, the results of the
SPLENDOR study have been of particular interest. In this study, bariatric surgery
significantly reduced the risk of adverse liver damage and major cardiovascular
events in patients with NASH and obesity compared to nonsurgical treatment [20 ].
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 peroxisome
proliferator-activated receptor (PPAR)-gamma agonist pioglitazone if there are no
associated contraindications (heart failure, history of bladder carcinoma, increased
risk of bone fractures) [4 ]
[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 and SGLT-2 inhibitors (SGLT-2: sodium-dependent glucose
transporter 2) can reduce the liver lipid content and improve NAFLD and type 2
diabetes. In particular, therapy with semaglutide at daily subcutaneous doses of 0.1
mg, 0.2 mg or 0.4 mg showed strong effects on the remission of NASH without
progression of fibrosis in a phase 2 study in people with NASH and liver fibrosis
at
stage F1-F3, compared to placebo [21 ]. However, in
another phase 2 study, semaglutide at the dose of 2.4 mg once weekly showed no
resolution of NASH or improvement in fibrosis compared to placebo in patients with
NASH-associated cirrhosis [22 ]. All other
pharmacological therapies for type 2 diabetes have so far shown no
clinically-relevant effects on the course of NAFLD [4 ].
There are other treatment approaches showing positive effects in current
placebo-controlled phase 2 trials. The pan-PPAR (PPAR alpha, delta and gamma)
agonist lanifibranor showed a marked improvement in NASH and fibrosis in patients
with NASH without cirrhosis [23 ]. The
liver-selective thyroid hormone receptor β-agonist resmetirom showed a
significant improvement in steatosis and, in a subgroup, also a resolution of NASH
in the treatment of patients with NASH and hepatic fibrosis F1-F3 [24 ]. The fibroblast growth factor 21 (FGF21)
analogue pegozafermin also induced NASH resolution and improvement of fibrosis in
patients with NASH and liver fibrosis F2-F3 [25 ].
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.
