In the structure of chronic liver diseases, the most common are non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), and viral hepatitis B and C. Alcoholic disease has no geographical boundaries. All over the world, people continue to drink alcohol, causing irreparable harm to their health. It is believed that drinking more than 80 g of ethanol per day (1 liter of wine, about 3.6 liters of beer, and approximately 250 g of strong alcoholic beverages) can lead to clinically obvious liver disease in men. In women, this dose is 2-4 times less. However, the risk of developing alcoholic liver disease is associated with a much smaller dose, namely, with the consumption of 30 g of ethanol per day. In ALD, the most common manifestation of liver damage is fatty liver disease (FLD); a pathology caused by a violation of lipid metabolism in the hepatocyte, leading to the accumulation of fat in the liver.

Liver, Non-alcoholic fatty liver disease, Alcoholic liver disease, Ethanol, Hepatocytes, Hepatitis.

FLD is divided into minor, moderate, and severe according to the degree of fatty infiltration. More precise gradation: 1+ – less than 25%, 2+ – 25-50%, 3+ – 50-75%, and 4+ – 75% or more of hepatocytes contain fat. The gallbladder is not frozen. Excellent reduction of alcohol intake without the influence of other hepatotoxic factors leads to complete morphological normalization of the hepatocyte. With continued alcoholization, the next stage of the progression of alcoholic liver damage is alcoholic hepatitis, when microscopic examination of the liver reveals necrosis of hepatocytes. Alcoholic hepatitis is considered a precursor to alcoholic cirrhosis.[1-4] Approximately 18 to 25% of alcoholics are infected with the hepatitis C virus (HCV). In alcoholics with liver disease, the frequency of HCV infection is higher, more than 40%. The combination of alcohol with HCV significantly accelerates the progression of liver disease, approximately 8-10 times. Like HCV, the hepatitis B virus (HBV) accelerates the rate of development of the disease. Epidemiological data reflect a higher mortality rate of alcoholics in combination with HBV infection.[5-7]

In a 1980 study of the liver of individuals who did not abuse alcohol, some studies discovered a histological picture identical to alcoholic hepatitis. The dynamics of this etiologic variant of liver pathology, called “non-alcoholic fatty liver disease” (NAFLD), is similar to alcoholic: NAFLD (non-alcoholic steatosis) – non-alcoholic steatohepatitis (NASH) – liver cirrhosis. Liver steatosis is a descriptive term characterizing the excessive accumulation of triglycerides (TG) in the cytoplasm of hepatocytes (more than 5% of the liver mass). NASH is a chronic diffuse liver disease, the morphological equivalent of which is steatosis, necroinflammatory changes in liver tissue with the formation of successive stages of liver fibrosis (LF).

The criteria for the diagnosis of NAFLD are:

• Puncture biopsy data: Fatty liver disease or inflammatory changes, symptoms similar to alcoholic hepatitis.
• Absence of alcohol consumption in hepatotoxic doses.
• Absence of other liver pathology.

The greatest risk of developing NAFLD is wives of women in the age category of 40-60 years with signs of MS.[8,9] In accordance with the stages of pathogenesis, primary and secondary NAFLD. In primary NAFLD, when the etiologic factors are obesity, type 2 diabetes mellitus (DM), dys/hyper-lipidemia, high levels of TG, lipoproteins, and free fatty acids (FFA) are found in the blood and liver. Accumulation of FFA in the liver contributes to high levels of insulin in the blood. Hyperinsulinism, which accompanies obesity, type 2 DM, and multiple sclerosis (MS), is a pathogenetic factor, since insulin stimulates the synthesis of FFA, TG, and reduces beta-oxidation of FFA and evacuation of lipids from the liver.[10] The list of diseases and situations in which “secondary” NAFLD and NASH occur is very wide and includes malabsorption syndrome, especially during obesity surgeries, intensive weight loss, long-term, unbalanced parenteral nutrition, and storage diseases. Drugs, the use of which is very often accompanied by the development of NASH, have also been identified: amiodarone, glucocorticosteroids, tetracycline, non-steroidal anti-inflammatory drugs (NSAIDs), methotrexate, synthetic estrogens, and tamoxifen.[11] Since NAFLD is closely associated with insulin resistance and MS, the majority (up to 70%) of patients have dyslipidemia, expressed in hypertriglyceridemia (HTG) and a decrease in the level of antiatherogenic high-density lipoproteins (HDL). Dyslipidemia is an important major risk factor for atherosclerotic vascular diseases, so its correction is of relevance for patients with NAFLD. It is known that most lipid-lowering drugs used in clinical practice (statins, fibrates, and nicotinic acid) have potential hepatotoxic effects. Therefore, until recently, the use of statins in patients with NAFLD was not recommended for patients with liver damage or elevated transaminases.[12]

One of the well-known side effects of statins is increased liver function enzymes (in particular, alanine and aspartate aminotransferases (ALT and AST)). Asymptomatic increases in aminotransferase levels usually occur in the first few months of treatment and are reversible. ALT, AST levels may return to normal after stopping statin treatment, with dose reduction, or spontaneously with the same statin dose. There have been concerns about whether the increase in aminotransferase levels is SVID E-statehood hepatotoxicity because of taking statins or the liver’s reaction to a decrease in cholesterol levels, which is typical for all lipid-lowering drugs.[13]

There is now evidence that statins are well tolerated in patients with chronic liver diseases with elevated liver enzymes, such as NAFLD, primary biliary tract infection, cirrhosis, and chronic hepatitis C. One of the major studies that played an important role in this issue was a study by Chalasani N, published in 2004. Observation of 4024 study participants, divided into three groups, was conducted from 01.01.1998 to 31.06.2002. The first group – 342 patients with elevated levels of ALT, AST, and taking statins. The second group – 1437 patients with levels of ALT, AST within normal limits, taking statins. The third group – 2245 patients with elevated levels of ALT and AST not taking statins. The effect of statin use was assessed 6 months after the date of their prescription by the frequency of occurrence of weak and significant increases in transaminase levels. For the first group, these indicators were 4.7% and 0.6%, for the second group – 1.9% and 0.2%, for the third group – 6.4% and 0.4%, respectively. At the end of the study, it was concluded that the use of statins in patients with initially elevated transaminase levels is not associated with an increased risk of hepatotoxicity.[14]

In 2005, the results of a study conducted in the United States were published, which involved 1,000 healthy people with elevated levels of calcium in the walls of the coronary arteries. Daily intake included either a combination of atorvastatin 20 mg, vitamin C 1 g, vitamin E 1000 IU, or placebo for an average of 3.6 years. At baseline, all patients had low-density lipoprotein (LDL) levels between 2.3 and 4.5 mmol/L, and transaminase levels were elevated to no more than 1.5-fold. Of the 455 patients who underwent CT scanning at both baseline and endpoint, 80 were found to have NAFLD. At endpoint CT, the proportion of patients with NAFLD in the atorvastatin, vitamin C, and vitamin E group was significantly lower than in the placebo group (37% versus 78% after two years). The study concluded that in patients with NAFLD and mild transaminase elevation, aminase the positive effect of taking statins on cardiovascular diseases outweighs the risk of developing hepatotoxicity. However, to confirm the ability of statins to interrupt the progression of NAFLD, larger long-term studies are needed.[15]

Evidence of the safety and efficacy of statins in patients with chronic liver disease was demonstrated in a clinical trial of pravastatin in 2006. A multicenter, randomized, double-blind, placebo-controlled study of 326 patients with chronic liver disease, including 64% with NAFLD and 23% with hepatitis C, was conducted for 36 weeks. Patients were divided into two groups. In the first, patients received a placebo, and in the second, pravastatin at a dose of 80 mg. As a result, in the group of patients taking the statin, the increase in ALT levels was 7.5%, and in the group receiving a placebo, 12.5%. Thus, a high dose of pravastatin (80 mg), used for hypercholesterolemia in patients with chronic liver disease, significantly reduced LDL, total cholesterol, and triglyceride levels compared with placebo, and was also safe and well tolerated.[16]

In 2006, the results of the Dallas study were published in a heart study, the purpose of which was to determine the presence of a relationship between statin use, triglyceride levels, and ALT. It involved 2,264 patients who were divided into two groups. In the first group, the study participants did not take lipid-lowering drugs (n = 2,124), and in the second, they took statins (n = 140). As a result of the study, no association was found between statin use and an increased incidence of steatosis (38% vs. 34%) or an increase in ALT levels (15% vs. 13%), and it was confirmed that the incidence of increased ALT levels in patients with steatosis (n = 638) taking statins was no greater than in the group of patients who did not take statins. These findings may serve as a basis for prescribing statins to patients with liver steatosis.[16]

In 2010, the results of the randomized, prospective, open-label Greek atorvastatin and coronary heart disease evaluation (GREACE) study, which involved 1,600 patients aged up to 75 years, suffering from coronary heart disease and having a triglyceride level of less than 10.3 mmol/L and LDL more than 2.58 mmol/L. Patients were randomly divided into two groups. The first group included patients who were taking their usual therapy (only 30% of them received lipid-lowering drugs) and normalizing their lifestyle. Patients of the second group took a dose of 10 to 80 mg to reduce the LDL level below 2.58 mmol/L. Dosage adjustment was made every six months for 3 years. In this case, the AST and ALT levels were measured at the beginning of the study, after six weeks, and every six months. At the beginning of the study, an increase in the AST and ALT levels of no more than three times was observed in 437 of 1600 patients. Alcoholic hepatitis, viral hepatitis B and C, Wilson’s disease and autoimmune hepatitis were excluded from patients participating in the study. The primary endpoint was the occurrence of any cardiovascular event, including myocardial infarction, unstable angina, stroke, or revascularization. The relative risk of such an event was calculated for 437 patients with elevated transaminase levels and patients with normal ALT and AST levels. An additional endpoint was an increase in AST, ALT, and the appearance of other signs of liver injury. Cardiovascular events occurred in 10% (22/227) of patients with transaminase elevation in the statin group and in 30% (63/210) of patients with ALT and AST elevation in the non-statin group. In the group – Among patients taking atorvastatin, there were 3.2 cases per 100 patient-years compared with 10 cases per 100 patient-years in the group of patients not taking statins. The risk of cardiovascular events in patients with NAFLD decreased by 68%, while in patients without transaminase elevation, it decreased by 39%. In patients with NAFLD taking statins, there was a decrease in AST levels of 35%, ALT by 47%. And in patients with NAFLD who did not take statins, the ALT and AST levels increased by 12%. In addition, in the group of patients taking statins, by the end of the study, ALT, AST, and gamma-glutamyl transferase (GGT) levels were within normal limits in 89%. Only 10 patients out of 880 taking statins had an increase in transaminase levels by more than three times. In 3 out of 10 patients, as a result of adjusting the statin dose, ALT and AST decreased to normal. And in 7 (<1%) patients, dose adjustment was not effective, because of which statin therapy was discontinued.[16]

Based on the results of all studies devoted to the effect of statins on the liver in patients with NAFLD, it can be concluded that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-Co-A) reductase inhibitors, despite their potential hepatotoxicity, are not only not contraindicated in individuals with elevated levels of ALT, AST (except in cases of an increase in transaminases by three or more times), but are also a necessary component of therapy to reduce the incidence of cardiovascular events, the level of liver enzymes with minimal side effects.

For a long time, statins have remained the drugs of choice among lipid-lowering agents used to correct dyslipidemia in atherosclerotic vascular diseases. However, for many years, the question of the possibility, and most importantly, the effectiveness and safety of using statins in people with non-alcoholic fatty liver disease has remained open. Dozens of studies have been conducted to determine the risk-benefit ratio of using statins in this category of patients. According to the results of the latest large clinical placebo and controlled studies on this issue, the use of statins is not only possible but also a necessary and safe means of reducing cardiovascular risk.

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Corresponding Author:
Ruzikulova Munira Shukhrat kizi
Department of Dentistry and Maxillofacial Surgery
Tashkent Medical Academy, Uzbekistan
Email: munira_9898@list.ru

Co-Author:
Ibragimova Malika Khudaiberganovna
Department of Dentistry
Tashkent State Dental Institute, Uzbekistan

All authors contributed to the conceptualization, investigation, and data curation by acquiring and critically reviewing the selected articles. They were collectively involved in the writing – original draft preparation, and writing – review & editing to refine the manuscript. Additionally, all authors participated in the supervision of the work, ensuring accuracy and completeness. The final manuscript was approved by all named authors for submission to the journal.

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https://doi.org/10.63096/medtigo30622466

Ruzikulova MS kizi, Ibragimova MK. A Literature review on Fatty Liver Disease. medtigo J Med. 2024;2(4):e30622466. doi:10.63096/medtigo30622466 Crossref