Introduction
Liver fibrosis, a condition characterized by the excessive accumulation of extracellular matrix components, is more than just a liver issue. It has far-reaching implications, particularly in the context of metabolic dysfunction-associated steatotic liver disease (SLD). This article delves into the intricate relationship between liver fibrosis and various microvascular and macrovascular complications, especially in individuals with diabetes.
Steatotic Liver Disease and Accelerated Micro-Macro-Angiopathy
Steatotic liver disease (SLD), often resulting from metabolic dysfunction, is known by various terms such as nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and metabolic dysfunction-associated fatty liver disease (MAFLD). These conditions are strongly linked to accelerated macrovascular disease, with the risk increasing alongside the severity of liver fibrosis. Proper management of SLD could potentially prevent cardiovascular conditions.
In diabetes, the retinal neurovascular unit is typically dysfunctional, leading to varying clinical manifestations of microvascular disease. It is crucial to determine whether SLD and its fibrosis progression are risk factors for microangiopathy, including chronic kidney disease (CKD), retinopathy, and neuropathy.
The Study by Dr. Li and Colleagues
In a recent issue of Annals of Hepatology, Dr. Li and colleagues reported on their cross-sectional research involving 5413 participants from the NHANES 2005-2008 database. They found that retinopathy, categorized into four levels of severity based on retinal imaging, was an independent predictor of significant hepatic fibrosis among individuals with type 2 diabetes.
These findings align with another study published in Annals of Hepatology, which evaluated 2389 participants from primary care practices. This study found that complications of type 2 diabetes, such as diabetic nephropathy, retinopathy, or neuropathy, were associated with the stage of liver fibrosis, irrespective of hemoglobin A1c levels.
What Do These Studies Teach Us?
First, the association between advanced stages of liver fibrosis and the risk of diabetic retinopathy (DR) occurs regardless of the non-invasive technique used to assess steatosis. Liver stiffness measurement, a non-invasive tool, has been found effective in ruling out clinically significant portal hypertension in over 95% of patients. Various biomarkers, including the AST to ALT ratio, APRI, FIB-4, and others, are accurate in ruling out advanced liver fibrosis and correlate with cardiovascular risk scores in patients with chronic liver disease.
The Role of the Liver
Second, these associations occur irrespective of the duration of diabetes and the degree of metabolic compensation, supporting the notion that the liver plays a major pathogenic role in the «hepato-retinal» axis. Although the underlying mechanisms are not fully understood, genetic factors may play a role in the development of eye-kidney-liver complications in predisposed individuals with diabetes.
The Role of Hepatic Fibrosis
Third, liver fibrosis, aimed at limiting tissue integrity by circumscribing offending agents, results from persistent liver injury due to various insults, including chronic viral hepatitis, toxic injury from alcohol consumption, and metabolic dysfunction. When liver fibrosis becomes dysfunctional due to prolonged inflammation, it compromises liver regeneration and function, leading to portal hypertension, cirrhosis, and hepatocellular carcinoma.
The association between liver fibrosis and DR may result from common factors such as insulin resistance, metabolic dysfunction, increased oxidative stress, and sterile metabolic inflammation. The steatotic and chronically inflamed liver, particularly in NASH and MASH, could amplify systemic insulin resistance and subclinical low-grade chronic inflammation, damaging the retinal microvasculature.
Clinical Implications
One of the most challenging aspects of clinical practice is encouraging multidisciplinary collaboration. Hepatologists should be aware of the risk of DR and refer patients with advanced dysmetabolic SLD to ophthalmologists. Similarly, ophthalmologists and diabetologists should refer patients with DR for hepatological assessment.
Conclusion and Research Agenda
Individuals with NAFLD/NASH, MAFLD/MASLD, and concurrent DR are likely to have CKD, diabetic neuropathy, and increased cardiovascular risk in the context of advanced liver fibrosis. Prompt recognition of this syndromic picture by dedicated clinicians will trigger comprehensive multi-organ assessment. Strategies targeting advanced liver fibrosis among at-risk groups play a crucial role.
From a therapeutic perspective, patients with advanced liver fibrosis in the setting of diabetes may benefit from various marketed drugs and those in the pipeline, including pioglitazone, GLP-1 receptor antagonists, SGLT2 inhibitors, fibroblast growth factor analogues, and others. Further studies should explore the role of serum levels of mac-2 binding protein and galectin 1 as biomarkers of systemic fibrosing disease and potential targets for selective anti-fibrotic pharmacological intervention.
References
- Chen L, Tao X, Zeng M, Mi Y, Xu L. Clinical and histological features under different nomenclatures of fatty liver disease: NAFLD, MAFLD, MASLD and MetALD. J Hepatol 2023.
- Lonardo A, Ballestri S, Mantovani A, Targher G, Bril F. Endpoints in NASH clinical trials: are we blind in one eye? Metabolites 2024.
- Lee CH, Lui DT, Lam KS. Non-alcoholic fatty liver disease and type 2 diabetes: an update. J Diabetes Investig 2022.
- Platek AE, Szymanska A. Metabolic dysfunction-associated steatotic liver disease as a cardiovascular risk factor. Clin Exp Hepatol 2023.
- Stefan N, Lonardo A, Targher G. Role of steatotic liver disease in prediction and prevention of cardiometabolic diseases. Nat Rev Gastroenterol Hepatol 2023.