Herbal Therapeutic Approaches for Metabolic Dysfunction-Associated Steatotic Liver Disease

Steatotic liver disease (MASLD) is a loose clinical term that is employed to describe a continuum of

liver diseases that includes the abnormal build-up of fat in liver cells in connection with metabolic dysfunction. Hepatic steatosis is defined as the process of triglycerides in the hepatocyte, which may be observed with the help of imaging method and confirmed by means of histologic research. MASLD is among the most prevalent chronic liver diseases in the world and is strongly linked with the metabolic diseases including obesity, type 2 diabetes mellitus, dyslipidemia, hypertension and insulin resistance. The disease is covered by a variety of conditions which run a continuum of simple hepatic steatosis to more serious complications of steatohepatitis, fibrosis, cirrhosis and finally hepatocellular carcinoma [1,2]. The growing incidence of MASLD has been one of the consequences of the escalating cases of obesity and metabolic syndrome in the world as well as in both developed and developing nations.

The idea behind the MASLD and its name have developed during a number of decades. Historically, the fatty liver disease was initially identified in the 19th century after pathologists noticed fatty infiltration in the liver of people who consume alcohol excessively. Fatty liver had been divided into alcohol-related liver injury as well as fatty liver over many years. Nevertheless, towards the end of the 20th century, clinicians started diagnosing patients who developed fatty liver changes even though they did not consume alcohol in large amounts or at all. In 1980, Ludwig and others defined a phenomenon called nonalcoholic steatohepatitis (NASH) as the state where hepatic steatosis was accompanied by inflammation and hepatocellular in the non-alcoholic drinkers. This spawned the more comprehensive nonalcoholic fatty liver disease (NAFLD) which encompassed both simple steatosis and nonalcoholic steatohepatitis. The diagnosis of NAFLD was mainly based on the absence of other liver disease causes, particularly, the intake of alcohol in large amounts. In the long run, the shortcomings of this nomenclature came into the limelight since it was deemed scientifically weak and even perplexing to describe a disease in terms of what it is not. Also, the word fatty was thought to be having negative stigma to the patients.

In order to overcome these limitations, some new terminology was suggested by experts, which is more likely to reflect the underlying pathophysiological mechanisms of the disease. In 2020, Eslam and colleagues coined the term of metabolic dysfunction-associated fatty liver disease (MAFLD). This definition focused on the hepatic steatosis presence along with the metabolic risk factors like obesity, type 2 diabetes mellitus, or other metabolic disorders. The MAFLD concept changed the paradigm of excluding alcohol intake to metabolic dysfunction as the main cause of liver disease. Later on, the nomenclature was further improved by an international consensus which included the term metabolic dysfunction–related steatotic liver disease (MASLD). MASLD has been included as one of the subtypes of the broader term steatotic liver disease (SLD), which encompasses a number of conditions that lead to the accumulation of hepatic fats. The new classification offers a more realistic and comprehensive approach to the diagnosis of fatty liver diseases and studying them and indicates the accumulating knowledge about the metabolic processes of hepatic steatosis.

MASLD is the pathological process of the liver that can go through the mildest fat deposition to the most serious liver damage. The most basic one is the isolated hepatic steatosis, whereby the liver cells are filled with fat with minimal inflammation or fibrosis. Although simple steatosis may not cause any further disease over many years, in some people, simple steatosis can develop into a more aggressive disease, called metabolic dysfunction-associated steatohepatitis (MASH). The liver pathology of MASH is a hepatic steatosis and inflammation, hepatocellular injury, and different extents of fibrosis. Prolonged inflammation and fibrotic alteration can eventually result into progressive fibrosis and cirrhosis, characterized by scarring of liver tissue extensively and liver dysfunction. Cirrhosis has a great role in causing hepatocellular carcinoma, the most widespread primary liver cancer. Thus, MASLD is a disease with many stages of development, and it is critical to detect it and manage it early.

MASLD is caused by a number of metabolic and environmental factors. Insulin resistance, which facilitates the deposition of fatty acids in liver is the most significant underlying mechanism. Overconsumption of calories and lack of exercise in people with obesity or possessing a metabolic syndrome result in more adipose tissue lipolysis and increased levels of circulating free fatty acids. These fatty acids are taken to the liver, which transforms to triglycerides and is stored in hepatocytes [3,4]. Also, greater de novo lipogenesis hepatic accumulation and the inability to oxidize fatty acids are additional contributors to lipid build-up. Oxidative stress, mitochondrial dysfunction, and cytokine release play a role in hepatocellular injury and steatohepatitis development of simple steatosis. The genetic predisposition, changes in the gut microbiota, as well as the impact of the diet and hormones, are also important in the development and progression of diseases.

Clinical manifestations of MASLD are subtle or not present especially at the initial stages of the disease. A lot of people do not show any symptoms and are accidentally diagnosed when a routine medical checkup was done or when an imaging procedure was conducted due to other causes. The symptoms are usually nonspecific when they happen and could consist of fatigue, weakness, and feeling of discomfort or fullness in the upper right quadrant of the abdomen. Other patients can have mild hepatomegaly or enlargement of the liver that is felt during the physical examination. With the further development of the disease to the advanced fibrosis or the cirrhosis, more serious symptoms can emerge. These can be jaundice, swelling in the abdomen by ascites, easy bruising, confusion by hepatic encephalopathy and general weakness. Portal hypertension, gastrointestinal bleeding, liver failure are complications that may arise in the progression in the advanced stages.

MASLD diagnosis is made through a complex of the clinical examination, lab tests, radiography, and occasionally liver biopsy. The initial diagnosis requires the detection of the existence of hepatic steatosis, through imaging systems that may include ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI). The most frequently used imaging method as the first one is ultrasound due to its noninvasive nature, universal availability and the fact that it is not a very expensive method. It is able to detect moderate and severe fat in the liver but it could be weak when it comes to the detection of mild steatosis. MRI and some special methods like the proton density fat fraction (MRI-PDFF) are more precise to determine the hepatic fat content and are typically applied in the research sphere or special clinics.

The laboratory tests are also significant in the assessment of MASLD. Detection of slightly higher liver enzymes, especially liver alanine aminotransferase (ALT) and aspartate aminotransferase (AST) may be observed in blood tests. But the normal liver enzyme levels do not rule out the occurrence of MASLD since there are also patients whose liver is not damaged severely but yet they have normal enzyme levels. Further lab tests can consist of lipid profile evaluation, fasting glucose, glycated hemoglobin (HbA1c), and indicators of insulin resistance to assess risk factors of related metabolic disorders. Simple noninvasive scoring systems like the Fibrosis-4 (FIB-4) index and NAFLD fibrosis score can usually be used to estimate the risk of progressive liver fibrosis in relation to the routine clinical parameters.

Imaging techniques that have been shown to measure liver stiffness, including transient elastography (FibroScan), can be used to measure the presence and extent of fibrosis in some scenarios. Those are noninvasive methods of liver biopsy, which gain popularity in clinical practice. Although noninvasive diagnostic methods have advanced, liver biopsy is still considered the gold standard in the confirmation of the diagnosis of steatohepatitis and the stage of liver fibrosis. The important characteristics that can be observed through the histological analysis of liver tissue include macrovesicular steatosis, hepatocellular ballooning, lobular inflammation and fibrotic changes. Nonetheless, liver biopsy is very invasive and may come with complications hence it is usually done on some selected cases when the diagnosis is not clear or when it is necessary to have proper staging of the disease.

Over the past decades, the global burden of MASLD has grown tremendously with the escalating levels of obesity, sedentary lifestyles and the occurrence of metabolic disorders. Epidemiological researches have estimated that MASLD has a prevalence of about a quarter-third of adult population all over the world. Its occurrence is quite high in patients with type 2 diabetes mellitus and obesity, and over 50% of these patients have signs of hepatic steatosis. MASLD is also being identified in children and adolescents, which is partly the role of the increasing prevalence of childhood obesity. The disease does not only cause liver related morbidity and mortality, but also raises chances of cardiovascular disease, which is still the leading cause of death among the victims.

To conclude, steatotic liver disease associated with metabolic dysfunction is a multifactorial and complicated issue in relation to excessive fat deposition in the liver in relation to metabolic dysfunction. The development of previous names like NAFLD into the current MASLD classification is a positive sign of a better comprehension of the metabolic causes behind the disease and attempts to offer a more straightforward and mechanistic model of diagnosis and studies. There is a broad range of pathological stages involved in MASLD with presence of simple steatosis up to hepatocellular carcinoma as a result of fibrosis, steatohepatitis, cirrhosis and steatosis. In spite of the fact that the disease is not accompanied with many symptoms in its initial stages, gradual liver damage may result in severe complications. Clinical evaluation, laboratory tests, and imaging studies should therefore be carried out at an early stage so that the disease can be managed and prevented. Since the number of patients with metabolic disorders has become increasingly high worldwide, MASLD is likely to remain a significant concern of healthcare systems and a significant subject of current medical studies.

CAUSES AND RISK FACTORS:

The picture demonstrates the key risk factors that can take part in the development of Metabolic Dysfunction associated Steatotic Liver Disease (MASLD) and how interplaying metabolic, genetic and environmental factors can result in liver injury. MASLD is a multifaceted metabolic disease that is related to the accumulation of fat in the liver cells which may eventually result in inflammation, fibrosis and severe liver complications without proper management. Genetic predisposition is also one of the key factors in MASLD development. Certain genetic mutations that include PNPLA3, TM6SF2, and HSD17B13 are identified to play a role in determining the intensity of lipid metabolism and fat build-up in the liver. These genes have the capability to modify the hepatic fat storage, lipid transport and inflammatory response and this renders some people more vulnerable to developing MASLD despite having no major lifestyle-related risk factors. Genetic susceptibility thus is very important in influencing the severity and development of the disease in various people. One more significant factor that contributes to the process of MASLD is Type 2 diabetes mellitus that is strongly correlated with insulin resistance and metabolic imbalance. Hyperinsulinemia and long-term hyperglycemia are the factors that make the liver increase hepatic lipid synthesis and decrease lipid oxidation, which leads to excessive fat accumulating in the liver. These metabolic alterations may also stimulate a number of molecular pathways including transforming growth factor beta (TGF- β) and connective tissue growth factor (CTGF), which stimulate liver inflammation and fibrosis. Also, NOX2 and TIMP3 as enzymes mediate oxidative stress and deactivate protective factors like Sirt1 and TIMP3, which worsen liver damage [5,6]. Therefore, patients with Type 2 diabetes are much more exposed to the risk of developing MASLD and developing the disease at a high rate. Another significant risk factor of MASLD is visceral obesity. Abdominal fat in excess is metabolically active and condenses different pro-inflammatory cytokines and adipokines that interfere with the normal metabolism. High concentrations of the inflammatory mediators and hormones like leptin favor insulin resistance and improve lipid buildup in the liver. Simultaneously, changes in adiponectin levels upset the defensive metabolic processes which, as a rule, maintain the metabolism of glucose and lipids. Such an unbalance of pro-inflammatory and protective signals provides a metabolic environment, which supports hepatic steatosis, inflammation, and fibrosis. This means that people having central obesity are highly susceptible to the development of MASLD and associated metabolic issues. The diet and lifestyle are also important factors that contribute to the occurrence of MASLD. Diets characterized by excessive intake of saturated fatty acids (SFAs), processed foods, and alcohol intake are major causes of metabolic imbalances, which influence the condition of the liver. The consumption of high-fat diets may trigger toll-like receptors (TLRs), which cause the rise of inflammatory signals and oxidative stress in the liver. Such dietary habits can also disrupt autophagy, which is a protective mechanism of the cell that gets rid of damaged organelles (and surplus lipid droplets). Decreased autophagy is thus capable of advancing lipid collection and dysfunction of the hepatocytes. Prolonged exposure to these food elements can also elevate the likelihood of tumorigenesis and developed liver diseases. The other crucial aspect that is indicated in the diagram is gut dysbiosis, which is described as an excess of intestinal microbiota. The gut-liver axis is important in ensuring metabolic and immune homeostasis. The disturbance of the gut microbial community may elevate intestinal permeability through which bacterial elements and toxins may enter the bloodstream and reach the liver. It is called bacterial translocation and causes inflammatory reactions and the release of cytokines like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-A). Also, gut dysbiosis has the potential to disrupt intestinal nuclear receptors like FXR that mediate bile acid metabolism and lipid homeostasis. The combination of these changes leads to inflammation of the liver, metabolic dysfunction and evolution of the disease in the MASLD. In general, the pathogenesis and pathophysiology of MASLD are the combination of a number of factors such as genetic predisposition, metabolic diseases such as Type 2 diabetes, visceral obesity, unhealthy dietary habits, and intestinal microbiome disruptions. All these mechanisms contribute to fat deposition in the liver, inflammation and oxidative stress, and fibrosis eventually leading to the development of serious liver complications [7]. These risk factors are important to understand in order to come up with efficient preventive and therapeutic measures that would help in controlling the abnormalities of their metabolism, lifestyle, and keep the gut healthy. These contributing factors can be identified and managed early and this will go a long way in the prevention of the further development of the disease and this will also be able to enhance the long-term liver health outcomes. The risk factors are presented in Fig. 1.1.

 

 

Fig. 1.1- Risk factors of MASLD

 

 

Fig. 1.2- Complications of MASLD

 

 

Fig. 1.3- Pathogenesis of MASLD

 

 

Fig. 1.4- Classification of drugs used in MASLD

 

 

Fig. 1.5 - Ayurvedic remedies for MASLD

CONCLUSION

Metabolic Dysfunction -Associated Steatotic Liver Disease (MASLD) has become one of the most widespread chronic hepatitis diseases in the world, because of the progressive rise in obesity, unhealthy lifestyles, and metabolic diseases like type 2 diabetes mellitus, dyslipidemia and insulin resistance. The disease is a continuous spectrum of hepatic steatosis to metabolic dysfunction related steatohepatitis (MASH), fibrosis, cirrhosis, and hepatocellular carcinoma. The mechanism behind the complicated pathogenesis of MASLD is multifactorial and interrelated and includes insulin resistance, disturbances in lipid metabolism, oxidative stress, inflammation, genetic vulnerability, gut-liver axis changes. Even though MASLD may go unnoticed at the initial stages of its development, its progressive development may cause serious hepatic and extrahepatic complications, including cardiovascular disease, chronic kidney disease, and metabolic syndrome. Clinical assessment, laboratory studies, and imaging research are vital in the early diagnosis of the disease and prevention of its progression and better patient outcome. Treatment of MASLD is based on a holistic and multidisciplinary approach to treatment that includes lifestyle change, metabolic risk management, medication therapy, and supportive care. Also, non-modern systems like Ayurveda offer promising herbal treatments with hepatoprotective, antioxidant, and anti-inflammatory effects that can be used to supplement the conventional approach to treatment. Thus, earlier diagnosis, raise of awareness and combination of therapeutic strategies are also vital to the successful management of MASLD and its increasing health pandemic.

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