DISCUSSION
obesity, cirrhosis, fibrosis, NASH, HCC, fatty liver disease, T2D, hyperinsulinemia, hepatitis, Metabolic dysfunction, metabolic dysfunction, steatohepatitis, NAFLD, hyperglucagonemia, metabolic disturbances, cirrhosis, impaired liver function, overweight, glucogenic dysregulation, steatosis
OBESITY, STEATOSIS, OBESE, ALCOHOLIC LIVER DISEASE, CIRRHOSIS, IMPAIRED GLUCOSE TOLERANCE, HYPERINSULINEMIA, FIBROSIS, INSULIN RESISTANCE, METABOLIC DISTURBANCE, HYPERINSULINEMIA, INSULIN RESISTANCE, HEPATITIS, INSULIN SENSITIVITY, STEATOHEPATITIS
In this study, we investigated fasting and postprandial metabolic and hormonal disturbances in a cohort of well‐characterized patients with NAFLD and cirrhosis, as well as normal weight, metabolic healthy young adults, both women, and men. Our patients with NAFLD and cirrhosis were overweight or obese and could be classified as having MAFLD.The main findings were that patients with NAFLD and patients with cirrhosis exhibit the following: (1) hyperinsulinemia, hyperglucagonemia, and impaired glucose tolerance due to decreased insulin sensitivity, (2) exaggeration of these metabolic disturbances postprandially, and 3. increased levels of FGF‐21, indicating potential metabolic stress.Firstly, our NAFLD and cirrhosis patients presented with significant metabolic dysfunction at baseline. We found pronounced metabolic disturbances in these groups, although the NAFLD cohort consisted of patients with fatty liver disease without T2D, and in cirrhosis. History of T2D was present in two patients allocated to fasting, therefore unlikely influencing postprandial results. However, as the groups were not matched on age and BMI, the present findings may reflect impaired glucose homeostasis (present in the cirrhosis group) and or overweight in the NAFLD group. Metabolic dysfunction in our cohort was most augmented in patients with cirrhosis. Metabolic dysfunction presented as hyperinsulinemia, insulin resistance assessed by HOMA‐IR, decreased hepatic insulin extraction, and hyperglucagonemia as sign of glucagon resistance.Hyperinsulinemia and insulin resistance were previously found in patients with fatty liver disease without T2D and non‐alcoholic steatohepatitis (NASH) without obesity (Sanyal et al., In cirrhosis, impaired liver function has been found to contribute to the development of hyperinsulinemia and insulin resistance (Armandi et al., We found increased concentrations of glucagon in both NAFLD and cirrhosis patients. Glucagon dysregulation and hyperglucagonemia were previously associated with pre‐diabetes and T2D (Demant et al., Secondly, we found an exaggerated postprandial metabolic response after the meal intervention in both patients with NAFLD and cirrhosis. The test meal revealed increased postprandial glucose, insulin, and C‐peptide concentrations, and decreased hepatic insulin extraction and glucagon insulin ratio.One study demonstrated insulin resistance after an oral glucose tolerance test (OGTT) in non‐diabetic patients with NASH (Pagano et al., Thirdly, patients with NAFLD and cirrhosis had high levels of FGF21. Compared with healthy, FGF21 concentrations were more than twice as high in patients with NAFLD and even higher in cirrhosis, although the difference between NAFLD and cirrhosis was not statistically significant. We found a positive correlation between FGF21 concentrations to age, fasting glucose, waist circumference, and BMI. Previous studies reported FGF21 to be associated with age (Hanks et al., Genetics account for approximately half of the interindividual variation in the risk of fatty liver disease. We investigated the genotypes of PNPLA3, TM6SF2, and HSD17B13 in our study cohort. For each of the three variants, individuals that are homozygous for the risk increasing alleles have at least twice the risk of developing fibrosis, cirrhosis and HCC compared to those without risk alleles. One patient with cirrhosis was homozygous for the risk increasing allele of PNPLA3 (I148M) while the distribution of the other genotypes for PNPLA3 was very similar between groups. PNPLA3 is strongly associated with hepatic fat content and liver enzymes and is the strongest common genetic risk factor for fatty liver disease (Romeo et al., Our study has limitations typically seen in pilot studies. Firstly, the study population was small. This reduced the statistical power of our results, and several differences observed between the study groups did not reach statistical significance. The small study population was mainly due to the pilot character of this new study design, and more participants should be included in future trials. Secondly, our healthy control group was not matched for BMI and age. NAFLD and cirrhosis patients were significantly older than healthy, and obesity was present in 60%. It is difficult to assess how much our results are driven by obesity or age alone. Therefore, it might be of interest to include an additional control group of older, obese without fatty liver disease in future studies.In our study, we could demonstrate that a meal intervention can reveal otherwise hidden metabolic changes. These findings suggest the need for future studies to focus more on the postprandial state instead of fasting conditions. Many studies use an OGTT to measure the metabolic response in different patient groups, but this may not be the most suitable intervention to assess physiological postprandial changes. Instead, we used a standardized meal containing carbohydrates, proteins, and fat in physiological amounts to assess metabolic changes under real‐life conditions.Most patients with cirrhosis were obese and classified as MAFLD, although the etiology of cirrhosis in our cohort consisted mainly of alcoholic liver disease, apart from one patient with hepatitis B. Hence, our study population was relatively homogenous and presented with similar degrees of glucogenic dysregulation after the meal. With MAFLD cirrhosis currently on the rise, we expect a change in the “typical cirrhotic patient,” with more patients with cirrhosis and obesity in the future. Therefore, it is of great importance to study this specific patient group.Lastly, patients diagnosed with simple steatosis without fibrosis and NASH are often not followed‐up by a specialist. Here, we showed that patients with mostly mild MAFLD showed surprisingly pronounced metabolic disturbances and insulin resistance after a test meal, suggesting that more research needs to be conducted in this patient group. Insulin resistance is a major player in the development and progression of NASH, fibrosis, and, of course, T2D. Therefore, we suggest that patients with MAFLD should be assessed metabolically in a postprandial state rather than fasted to detect impaired glucose tolerance and pre‐diabetes and might profit from regular follow‐up to prevent progression to T2D, NASH, and fibrosis.