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A SYSTEMATIC REVIEW OF FOLLOW-UP DISEASE PROGRESSION IN
PATIENTS WITH NON-ALCOHOLIC FATTY LIVER
Khamidоva M.I.
Department of Gospital therapy and EndocrinologyAssistant
Andijan State Medical Institute.
Abstract:
Hepatosteatosis is defined as an excessive accumulation of triglycerides in
hepatocytes. There are 2 main conditions associated with hepatic steatosis: non-alcoholic
fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFFLD). In addition, various
causes are listed in the pathogenesis of hepatic steatosis, such as metabolic, nutritional, drug
(chemotherapy and steroids), and hepatitis C virus (HCV) infection.
1
The natural course of
hepatic steatosis varies depending on the etiology and concomitant conditions such as
inflammation and fibrosis, which can progress to cirrhosis and liver failure. Therefore, it is
important to diagnose and quantify liver steatosis. Liver biopsy is currently the gold
standard for evaluating a patient with suspected liver steatosis.[1] However, there are
potential drawbacks to liver biopsy, such as sampling error, variability in interpretation,
cost, and associated morbidity. Therefore, imaging techniques are commonly used for this
purpose. In this article, we will review the etiology, imaging patterns, and quantification of
hepatic steatosis using traditional and advanced imaging techniques.
Key words:
Hepatosteatosis, metabolic syndrome, NAFLD, metabolically healthy obesity,
ultrasonography
NAFLD is the most common form of hepatic steatosis and affects 30%-40% of men and
15%-20% of women in the general population. This disease is considered a hepatic
manifestation of metabolic syndrome and has a strong association with insulin resistance,
atherosclerosis, obesity, dyslipidemia, and hypertension[3]. Risk factors for NAFLD include
insulin resistance and metabolic syndrome i.e., three or more of the following: obesity,
diabetes mellitus, hypertension, low high-density lipoprotein levels, and high triglyceride
levels. Among these, obesity is the most common risk factor. However, people with normal
div weight (div mass index [BMI; kg/m2 ] Compared to healthy people, patients with
lean NAFLD had higher metabolic syndrome occurrence, diastolic blood pressure,
hemoglobin A1c, and insulin resistance. Additionally, biochemical and hematologic markers,
such as serum ALT, AST, Gamma glutamyl peptidase (γ-GT), and total bilirubin levels,
were higher in patients with lean NAFLD than in healthy participants [1].Although the
prevalence of metabolic syndrome in lean NAFLD was lower than in obese NAFLD, the
impact of lean NAFLD was a stronger risk factor for higher rates of all-cause mortality,
cirrhosis, and HCC than obese NAFLD.reported that patients with lean NAFLD showed
advanced fibrosis stage, higher incidence of metabolic comorbidities, and higher all-cause
mortality than obese NAFLD. Additionally ,that patients with lean NAFLD had a higher risk
for cirrhosis, HCC than obese NAFLD. These results suggest the important role of metabolic
disorders in this population. The etiology of lean NAFLD is assumed to be based on central
obesity and visceral fat Therefore, the BMI-driven approach for NAFLD may need to be
reappraised. BMI does not entirely explain the association between visceral fat and NAFLD.
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Moreover, the relationship between lean NAFLD and metabolic syndrome is still not fully
understood, and more long-term studies are required[2].
Obese patients present with significant variations in metabolic abnormalities, such as
hyperglycemia, hypertension, and dyslipidemia. Recently, these patients have been
classified into different subphenotypes depending on their metabolic health status.
Metabolically healthy obesity (MHO) is a concept derived from clinical observations that
some obese people do not present with common metabolic abnormalites; the implications of
this for the development of NAFLD across its subphenotypes remain vague. In a study that
included 4,432 MHO people, 2,145 patients (48.4%) were presented NAFLD
simultaneously. On the contrary, in 225 patients with NAFLD, 14 (6.2%) were
metabolically healthy. MHO was considered as a risk factor of NAFLD development. [3]As
mentioned earlier, the definition of NAFLD must exclude other causes that can result in
inflammation and fatty changes. The significant amount of alcohol intake that differentiates
NAFLD from alcoholic fatty liver disease ranges from 10 to 40 g (pure alcohol) a day, and
this range varies between studies. The EASL guideline defined the amount of significant
alcohol consumption as ≥210 g in men and ≥140 g in women weekly.3 These criteria were
also applied in the Korean Association for the Study of Liver NAFLD guidelines.4 In the
AASLD guidelines, the standard alcohol drink was defined as 14 g of pure alcohol, and
significant alcohol consumption was defined as more than 21 standard drinks in men and 14
in women per week.[2] Recently, it has been suggested that the term NAFLD does not
reflect the heterogeneous pathogenesis or various courses of fatty liver disease. Furthermore,
the overestimation of the exclusion of alcohol has induced debate about the threshold of
‘significant’ alcohol consumption which is required for the diagnosis of NAFLD. In 2019, a
consensus by 32 experts suggested an alternative terminology, metabolic (dysfunction)-
associated fatty liver disease (MAFLD), to more accurately reflect the pathogenesis of this
disease.[7] The diagnosis of MAFLD is based on the evidence of fat accumulation in the
liver in the presence of one of the following three criteria: overweight/obesity, type 2
diabetes mellitus, and evidence of metabolic dysregulation.[4]
Abdominal imaging studies are often ordered instead of liver biopsy to confirm the clinical
suspicion of NAFLD. This approach is rationalized because it avoids the risks associated
with an invasive procedure. However, the risk of significant bleeding or death from “blind”
percutaneous liver biopsy in patients with incidentally detected liver enzyme elevations is
exceedingly rare, most likely far less than the figures derived from liver biopsy populations
that included patients with conditions that increase biopsy-related morbidity and mortality,
such as coagulopathy or liver tumor. In addition, the potential drawbacks of limiting
diagnostic procedures to noninvasive tests must be considered. Ultrasonography is
commonly used to screen for fatty liver disease. A recent study that correlated radiologic
and histologic diagnoses in 24 healthy volunteers and 28 patients with elevated liver enzyme
values demonstrated that ultrasound detection of fatty infiltration had a sensitivity of 67%, a
specificity of 77%, a positive predictive value of 77%, and a negative predictive value of
67%. Thus, relying on ultrasound to diagnose fatty liver disease gives an incorrect diagnosis
in 25% to 33% of patients. One study found computed tomography (CT) to be inferior to
ultrasound in diagnosing fatty liver, mostly because associated hepatic iron overload
produced a masking effect that decreased the sensitivity of CT scan. However, in another
study, when test objects containing variable amounts of fat were scanned to generate a CT
scan density calibration curve before patients with fatty livers were evaluated, an excellent
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correlation was seen between the hepatic fat content and liver-to-spleen density ratio. Thus
calibrated CT scans might be useful in monitoring hepatic fat content. Proton nuclear
magnetic resonance (NMR) spectroscopy has also been validated as a reliable test for
quantifying liver fat. Hepatic triglyceride content assessed by proton NMR spectroscopy and
by liver biopsy correlate almost perfectly. Thus, the latter approach seems to be the best
noninvasive way for diagnosing and quantifying liver fat. However, the expense of various
imaging modalities is not trivial, and none of these can distinguish simple steatosis from
NASH or “uncomplicated” NASH from NASH with fibrosis. Hepatocellular steatosis is the
hallmark of NAFL, and presence of more than 5% is required for diagnosis.[8] It is
classified into two types: macrovesicular and microvesicular steatosis. Steatosis in NAFLD
is usually macrovesicular; however, microvesicular steatosis may also be present in
approximately 10% of patients with NAFLD.[5] Many previous studies have suggested that
NAFL is a benign disease. Through the several studies performing paired or repeat liver
biopsy, NAFL showed significantly superior overall prognosis, including progression to
cirrhosis rather than NASH.[7] However, the concept that NAFL is a benign disease was
challenged with the accumulation of evidence; it is now regarded as a progressive disease.
Recent data suggest that nearly 25% of the patients with NAFL may develop fibrosis. The
European Association for the Study of the Liver (EASL) Clinical Practice Guidelines
recommend that patients with NAFL without metabolic risk factors should be monitored at
2–3-year intervals considering the low risk of progression.[5] The clinical factors associated
with progression to NASH include hypertension, diabetes or insulin resistance, and low
aspartate aminotransferase/alanine aminotransferase (AST/ ALT) ratio at the time of liver
biopsy.[9] Rapid progression was also often observed with concomitant hepatic injury
related to alcohol, toxin exposure, nutrients, drugs, chronic hepatitis C, or autoimmune liver
disease. Hence, individuals who have inherited the “bad” tendency to have sustained
inflammatory responses might be better off minimizing the consumption of alcohol or foods
that stimulate cellular oxidant production and trigger inflammation or taking medications to
improve their antioxidant/anti-inflammatory defenses, whereas others with “good”
inflammation-control genes can be reassured that they can safely enjoy these pleasures.
References:
1.
Loomba R, Sanyal AJ. The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol.
2013;10:686–90.
2.
Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of
NAFLD development and therapeutic strategies. Nat Med. 2018;24:908–22
3.
Idilman IS, Ozdeniz I, Karcaaltincaba M. Hepatic Steatosis: etiology, patterns, and
quantification. Semin Ultrasound CT MR. 2016;37:501–10.
4.
Molteni M, Gemma S, Rossetti C. The role of toll-like receptor 4 in infectious and
noninfectious inflammation. Mediat Inflamm. 2016;2016:6978936.
5.
Csak T, Velayudham A, Hritz I, Petrasek J, Levin I, Lippai D, et al. Deficiency in
myeloid differentiation factor-2 and toll-like receptor 4 expression attenuates nonalcoholic
steatohepatitis and fibrosis in mice. Am J Physiol Gastrointest Liver Physiol.
2011;300:G433–41.
6.
Hasan ST, Zingg JM, Kwan P, Noble T, Smith D, Meydani M. Curcumin modulation
of high fat diet-induced atherosclerosis and steatohepatosis in LDL receptor deficient mice.
Atherosclerosis. 2014;232:40–51.
Vo
lu
m
e
5,
M
ay
,2
02
5
,
M
ED
IC
AL
SC
IE
N
CE
S.
IM
PA
CT
FA
CT
OR
:7
,8
9
7.
Lee SB, Park GM, Lee JY, Lee BU, Park JH, Kim BG, et al. Association between
non-alcoholic fatty liver disease and subclinical coronary atherosclerosis: an observational
cohort study. J Hepatol 2018;68:1018-1024.
8.
Jang HR, Kang D, Sinn DH, Gu S, Cho SJ, Lee JE, et al. Nonalcoholic fatty liver
disease accelerates kidney function decline in patients with chronic kidney disease: a cohort
study. Sci Rep 2018;8:4718. Erratum in: Sci Rep 2021;11(1):11139.
9.
Lee JY, Kim KM, Lee SG, Yu E, Lim YS, Lee HC, et al. Prevalence and risk
factors of non-alcoholic fatty liver disease in potential living liver donors in Korea: a review
of 589 consecutive liver biopsies in a single center. J Hepatol 2007;47:239-244.
