Nonalcoholic Fatty Liver Disease

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Nonalcoholic fatty liver disease (NAFLD) is a hyponym of wide-ranging liver conditions that can affect persons who drink little or no alcohol. As the name denotes, nonalcoholic fatty liver disease is mainly associated with excessive amounts of fat stored in liver cells; moreover, NAFLD is also characterized by type 2 diabetes and insulin resistance (Mantovani 457). The excessive accumulation of fat in the liver can result in hepatic inflammation and progressive scarring thus ultimately leading to nonalcoholic steatohepatitis (NASH) and even a perpetual liver impairment (cirrhosis). Hence, for this reason, there has been an increased urgency to meticulously examine patients for risks factors consorted with NAFLD and NASH by means of biomarkers. This study aims to provide a systematic review of the evolving biomarkers of NAFLD and NASH, and also apply the medical implication and diagnostic concerns of biomarkers to emphasize sentinel physiognomies of the disease.

Certainly, it must go without saying that examining the history of biomarkers in this disease is vital as it can help provide a possible extrapolative or problem-solving indicator for disease progression, manifestation, or even considering both factors concurrently. For quite a number of years, the most commonly used biomarkers for this disease has been Serum biomarkers including triglycerides, total cholesterol, insulin resistance and C-peptide (Murai, Takebe and Nagasawa ). However, in present times, there has been emerging biomarkers including free fatty acids, ghrelin, leptin, apolipoprotein A1 and apolipoprotein B etcetera (Hajmohammadi, Heydari and Nimrouzi 45). These newly-integrated biomarkers have the potential to supplement the valuable findings of the outmoded biomarkers. It should be noted that dated biomarkers used interludes that took into consideration variances of sex and ethnicity as essential basis for determining the scientific practicality of biomarkers to diagnose and treat conditions.

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This is an original research that uses sources from an online search engine namely PubMed. The main search terms used for this study include nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, along with the title of every biomarker mentioned in the paper. The sources used are within the timeframe of the previous 5-6 years, and so this research work uses articles indexed between 2014 and 2019. The publications are then read separately and only information needed for this report is drawn from them. Importantly, to be worthy of inclusion, this study only discussed biomarkers with relevant characteristics such as simplicity, accuracy, availability, verifiability, and budget-friendly and so on. Furthermore, a dependable marker was considered to have the capacity to provide practitioners with accurate substantiation, indicate an advanced diagnostic command to diversify the phases of NALPD. On the other hand, with regards to exclusion criteria, the biomarkers that are unqualified for this study are those that have very low sensitivity and specificity and unable to diagnose the complexity of phases of this disease. It is worth noting, as well, that animal models or cell culture models were excluded from this study.


Diagnosis of NAFLD is of great significance for the reason that the condition ought to be controlled before it advances to more life-threatening phases. According to Valeria et al., diagnosis at a premature stage makes it easier to thwart the disease aggravation through the application of simple techniques including advising patients to adopt a healthier diet and be more physically active (1299). Nonetheless, the progressive stages of the disease, as in the case of NASH, should also be diagnosed soon enough due to its likelihood to advance into cirrhosis. For inpatients believed to have cirrhosis, further diagnostic procedures can be applied including probing the possibility of hepatocellular carcinoma progression as well as checking for bleeding esophageal (Men and Zhang). Overall, it is vital for medical practitioners to first examine the simple steatosis and steatohepatitis before screening for the progressive phases of the disease such as cirrhosis and fibrosis.

Currently, liver biopsy is widely considered as the best standard of diagnosing nonalcoholic fatty liver; however, this technique has its limitations. One of the limitations is that it may perhaps expose patients to severe complications. Moreover, it must go without saying that liver biopsy is costly and the process can also be jeopardized by sampling error. Without a doubt, these challenges have led to the need to apply and invent more noninvasive techniques of diagnosis of the different stages of NAFLD. Hence, in the sequel, this section assesses major discoveries by various individuals for the diagnosis and prediction of different stages of NAFLD.

Hepatic Markers

In their study, Cai and Sebastiani indicated that in excess of 60 transamination reactions are present in liver, where only the transaminases of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) have medical importance (23). The medical field typically uses these two markers as indicators of hepatic damages; as well, the two markers have proven to have a substantial connection with steatohepatitis. For instance, Chen et al. study has indicated that increased levels of aminotransferases and diabetes from patients suffering with NAFLD can be regarded as dependable predictors of moderate to extreme fibrosis (1). It must also be stated that alkaline phosphate (ALKP) is another important marker relating to hepatic steatohepatitis. Accordingly, the subsequent subsections review how both hepatic transaminase, ALT and AST, play a role in the diagnosis of steatohepatitis as well as the significance of ALKP in diagnosis of this disease.


For the case of ALT, asymptomatic rise of transaminases level has been observed in many people, where it has been reported contrarily in diverse populaces. As for example, the prevalence of asymptomatic increase of ALT stands at 7.3% in the US, 21.27% in Scotland, and 15.24% in Spain. It is worth noting that one-third of persons who show an increased level of serum transaminases in their initial test have turned out to exhibit ordinary level of enzyme in subsequent tests. Some of the major predictors of increasing ALT level in persons can also be exhibited by features such us high body mass index, high waist circumference, the level of alcohol consumption and so on. ALT level has also been shown to have a positive association with the presence of several signs and symptoms of metabolic syndrome. Serum ALT level has been recognized to have an affirmative association with plasma fasting glucose, serum triglyceride, and serum dehydroepiandrosterone sulfate (Choi, Lee and Park). Conversely, serum ALT level has exhibited an undesirable connection with serum high-density lipoprotein and hemoglobin.

According to certain studies, NASH is considered to be the most predominant cause of constant rises in serum ALT amongst the asymptomatic blood donors. In addition, Di et al. proved that several persons who undergo ultrasound examination have been diagnosed with steatohepatitis together with asymptomatic rise in transaminases level. One more study indicated that severe fibrosis can be distinctly predictable by ALT along with other indices including diabetes and serum ferritin. While other studies have also recognized the association of steatohepatitis with increased level of ALT, they have gone as far as including ALT in a section of some steatohepatitis diagnostic panels such as FIB4 index, BAAT score, FibroTest, NashTest and the rest. On the contrary, other studies have claimed that patients suffering from NAFLD do exhibit normal levels of ALT. For instance, the Dallas Heart Study organization examined the US population where they revealed that a staggering 79% of adults with fatty liver had normal aminotransferase level.

One of the limitations of ALT is that there is no consensus on maximum value or optimal concentration of ALT since a broad value range between 26 and 66 IU/L is still used in varying studies. For the BAAT score, Rath et al. indicated in their study that a standard range of ALT is ranges between 1 and 19 and also used both BAAT and APRI score of 0% and 29% respectively in their research. As for example, one study that used a cutoff values of 19 and 30 for men and women respectively, when screening fibrosis in patients suffering from NAFLD, revealed outcomes of 99% and 8% sensitivity and specificity correspondingly. Then again, the cutoff value of 40 U/L normally used in medicine exhibited 86% and 32% sensitivity and specificity respectively. While considering a reduction of ALT level within this reference range can be vital towards increasing sensitivity, Pournik O et al. have rejected this notion as it only leads to increased inaccuracies of labeling several asymptomatic persons as patients (116). Hence, these researchers claim that there are no efficient values with adequate sensitivity to incorporate ALT as a reliable screening test for diagnosing steatohepatitis amongst persons with fatty liver. All the same, this reiview sides with several research works that have proven that this enzyme is the best individual marker for detecting infiltration in the liver.


AST is one more hepatic transaminase, dissimilar to the previously discussed ALT, which also contributes immensely towards the diagnosis of steatohepatitis. Reports have it that 3.6% of the US population has an asymptomatic upsurge in AST. Furthermore, it is a proven fact that this hepatic index is closely associated with BMI as well as metabolic syndrome. It is also notable that Asian studies have established that AST is a reliable marker for advanced levels of fibrosis particularly when it is twice more than the standard value. A number of diagnostic panels, for example NAFLD Fibrosis Score, FIB4 index, and NashTest, have used this marker. For instance, Okamura et al. used the Fib4 index in patients believed to be suffering from NASH (1-2). Besides, Choi et al. also revealed that the most used tests for this marker is the AST to ALT ratio and the AST to platelet ratio indexes which are created using this enzyme. The AST to ALT ratio is frequently used in medicine as a dependable predictor index for severe hepatic fibrosis as well as liver damages caused by drugs (Lee BM 1815). Moreover, the ratio is applicable to a number of panels including ScoreBARD and NAFLD Fibrosis Score. On the other hand, the AST to platelet ratio index (APRI) is considered by Pereyra D et al. as a noninvasive index for examining hepatic fibrosis in patients suffering from NAFLD (791). In fact, several studies have preferred the APRI over the AST to ALT ratio whenever diagnosing severe hepatic fibrosis.

ALKP has also been included in studies that relate to hepatic fibrosis as it plays a role in determining the degree of hepatic fibrosis in patients suffering from steatohepatitis. Reports have it that increased serum level of ALKP is normally witnessed in patients suffering from NASH unlike in persons without the disease. Hence, it can be established that an increased level of ALKP is a reliable predictor of hepatic fibrosis in NASH patients. Some studies have also demonstrated that even at a standard range, a higher ALKP can still determine the presence of hepatic fibrosis. Therefore, this marker can be used by physicians for the reason that it is self-reliant as it regularly attempts to exhibit a higher sensitivity.

Inflammatory Markers


Thrombocytopenia, which is a condition developed due to having platelets counts less than 150,000 from the normal counts of 150,000-450,000, can also be used in the diagnosis of severity of hepatic diseases. For patients suffering with NAFLD, conducting platelet count is important since platelets also act as independent predictors for the diagnosis of hepatic fibrosis. Scientists have proven that platelet counts of less than 150,000 can be considered as a reliable predictor for advanced stages of hepatic fibrosis. As an illustration, a study conducted on patients with fatty liver from nine hepatology centers located in Japan revealed a reduction in platelet count corresponds with the increase in the severity of hepatic fibrosis. It must also be noted that mean platelet volume (MPV) has an important correlation with NASH; for instance, the severity of NASH is determined by increased values of MPV after fine-tuning of the variables. Therefore, in any case, platelet count is simple, cheap and accurate method and should be considered as a suitable biomarker for diagnosis of advanced fibrosis in patients.

Based on several studies pertaining to C-reactive protein (CRP), it can be established that this index can be considered as potential biomarker for diagnosing steatohapititis in the foreseeable future. These studies regard CRP as an independent predictor for NAFLD due to the proven fact that a rise in serum level of CRP serves as a warning sign for the progression of NAFLD. Besides the regular procedure of measuring of the quantity of CRP, evaluating values of high-sensitivity CRP (hs-CRP) has been devised as an alternative technique. With this technique, it is possible to detect even the minutest levels of inflammation. Hence, hs-CRP can be seen as an effective diagnostic tool that can classify of steatohepatitis, and also determine the degree of fibrosis among patients. However, this marker has its limitations as some factors, such as alcohol consumption, race, or gender, have varying effects on serum concentration. One more limitation is that there is a lack of standard cutoff value for hs-CRP particularly in diagnosis of NASH. In spite of all these, CRP is still in contention to develop as a resilient predictor of steatohepatitis.

Some studies have proven that also TNF-? takes part in the development of NAFLD. It is worth noting that TNF-? possess pro-inflammatory effects and can trigger destructive pathogenic routes through diminishing HDL-cholesterol while at the same time snowballing the activeness of cholesterol genes as well as quashing cholesterol exclusion. Moreover, TNF-? also activates the synthesis of hepatic fatty acids which has an effect on pathogenesis of hepatic fibrosis. TNF-? is generally considered imperative in the development of fatty liver disease and has been demonstrated in some studies that counterbalancing TNF-? goings-on can help lessen the severity of NAFLD. It can also be determined that TNF-? takes part in supervisory role for iron that increases ion in the liver of patients suffering from fatty liver disease. An illustration of this is based on the interleukin-6 (IL-6) which is highlighted in the subsequent section.

IL-6 is a cytokine that plays a significant role in the physiological process of the multifaceted aspects of NAFLD in humans. This cytokine is believed to stimulate the liver which results to the production of other critical phase proteins such as CRP in the liver. Just as the above-mentioned TNF-?, serum level of IL-6 can actuate an increased level of resistance to insulin. Furthermore, IL-6 also triggers hepatic lipogenesis which is connected to resistance to insulin together with obesity. With this in mind, it can be concluded that this cytokine definitely has a strong connection with NAFLD. To point out, in one particular study, Bhatt SP et al. revealed that high serum level of IL-6 is associated with obstructive sleep apnea which is one of the risk factors of NAFLD.

Structural Markers

Due to the fact that several studies have revealed that apoptosis plays a significant role in hepatic damage happening in progressive phases of NAFLD, it is more appropriate to use the hepatocyte apoptosis markers for the diagnosis of NAFLD (Sharma G). With this in mind, Cytokeratin-18 (CK-18) comes into play in the apoptosis process when it is fragmented by hepatocytes and caspase 3 that causes cell death in this process (Bratoeva K 350). During apoptosis process, fragments of CK-18 are directed into the blood stream thus this makes the blood level of CK-18 to have strong connection with hepatic fibrosis. Markedly, this substance has been found to be considerably higher in patients suffering from NASH. One major study that proved the usefulness of CK-18 in diagnosis of steatohepatitis is when a research was done concerning the clinical utility of a number of serum markers including CK-18 and hyaluronic acid. In this particular research, it was established that CK-18 is the only reliable biomarker amongst other serum markers. Indeed, this study also indicated that CK-18 has a greater predictive value for the diagnosis of steatohepatitis.

Collagen 7s is another diagnostic marker that plays a significant role in the diagnosis of steatohepatitis, and also has a close connection with the progression of fatty liver. This marker is has higher positive predictive value for diagnosing steatohepatitis as well as severe fibrosis (Lin B). Chan et al. made major contributions to this marker in a study that based its analysis on the symptoms of liver stiffness in the stages of hepatic fibrosis in patients suffering from NAFLD (1542). The study revealed that liver stiffness has a close association with serum level of collagen 7s particularly type IV. Hence, this shows that this marker can be considered as an important diagnosis tool for both severe fibrosis and steatohepatitis and can also be used as an independent predictor of NAFLD.

Hyaluronic acid, secreted by mesenchymal cells, can be used as a reliable predictor for severity of fibrosis. Studies have pointed out that an increased serum level of hyaluronic acid is an indicator of potentially having steatohepatitis. As well, higher serum level of hyaluronic acid has also been discovered in patients suffering with cirrhosis. It must also be said that hyaluronic acid is considered as a useful diagnostic tool for patients suffering with hepatic fibrosis as it can measure the slightest levels of fibrosis. For instance, unlike other markers such as platelets that drop in stage 4 of hepatic fibrosis, hyaluronic acid can rise in both stages 3 and 4 thus making it capable of detecting fibrosis in earlier stages. Li et al. established that the reliability of this diagnostic tool is an analysis that revealed progression of fibrosis corresponds with rise of serum level of hyaluronic acid (404-409). However, some studies have shown the limitations of this marker and established that it is not suitable for diagnosing fibrosis as it usually fails to show a correlation with progression of this disease. Considering all factors, this report sees serum level of hyaluronic acid as a reliable predictor of the presence of fibrosis and steatohepatitis in patients.


While some of the presented markers, such as CK-18 and hyaluronic acid, have indicated encouraging outcomes, they are still not yet reliable to be used as independent markers for the diagnosis of NAFLD. Nonetheless, this gives room for more development of reliable biomarkers in future studies so as to ensure that conditions necessary for a more desirable marker are fulfilled. These necessary conditions include factors such as accuracy, simplicity, accessibility, verifiability, budget-friendly and the like. This study also recommends the use of markers with higher sensitivity as well as considering the specificity when diagnosing patients believed to have NAFLD. Finally, owing to the fact that every marker presented in this study has limitations, it is advisable to use these markers in tandem so as to come up with more reliable diagnosis outcomes.”

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Nonalcoholic Fatty Liver Disease. (2021, May 24). Retrieved from