Diagnosis and Prognosis of NAFLD: History
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Contributor:
Joel Yeh Siang Chen
,
Damien Chua
,
Carissa Odelia Lim
,
Wan Xi Ho
,
Nguan Soon Tan

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, occurring in both obese and lean patients. It can lead to life-threatening liver diseases and nonhepatic complications, such as cirrhosis and cardiovascular diseases, that burden public health and the health care system. While liver biopsies are the gold-standard in diagnosing NAFLD, it is highly invasive. Hence, several non-invasive methods are developed to diagnose various stages of disease progression and predict NAFLD-related morbidity and mortality. 

  • NAFLD
  • NASH
  • NAFLD diagnostics
  • therapeutics
  • NAFLD clinical management

1. Introduction

1.1. Prevalence of NAFLD

In the past 20 years, nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease and one of the biggest contributors to cirrhosis. NAFLD prevalence worldwide is at 30%, increasing in tandem with well-established risk factors such as type 2 diabetes (T2DM) and obesity [1]. The Middle East (32%) and South America (30%) have the highest prevalence, followed by Asia (27%), with a disproportionately higher incidence found in the younger population <45 years old [2]. BMI is strongly associated with metabolic conditions such as NAFLD and is commonly used as a disease predictor. In correlation with a higher NAFLD prevalence, Caucasians report a higher mean BMI than South Asians [3]. However, studies have shown that South Asians face a higher risk of NAFLD than their Western and Arabian counterparts at the same BMI. In South Asia, 63.5% of NAFLD patients were identified to have NASH, higher than that in South America (27%) [4]. Previously thought to affect mainly Western countries [5], NAFLD prevalence is also rising at an alarming rate in Asia, especially in China [2]. Researchers are still investigating how Asians have an increased risk of weight-related issues at lower BMIs, with explanations such as higher central adiposity, insulin resistance, genetic predisposition, and carbohydrate-rich diets [6]. In the face of each ethnicity’s unique factors contributing to NAFLD development, it is important to dwell deeper into how these heterogeneous factors may affect therapeutic development in today’s translational NAFLD scene.

1.2. Pathogenesis of NAFLD

There are various theories surrounding NAFLD pathogenesis, with the most prevalent two theories being the “two hits hypothesis” and “multiple hits hypothesis” [7]. The “two hits hypothesis,” now obsolete, describes the first hit (high-fat diets, obesity, sedentary lifestyle, and insulin resistance) to cause hepatic steatosis, predisposing the liver to a second hit that triggers hepatic inflammation, ballooning, and fibrosis. On the other hand, the “multiple hits hypothesis” is now regarded as the more accurate theory delineating the mechanism of NAFLD progression and consists of multiple factors working in tandem to develop NAFLD.
NAFL. NAFLD consists of nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). NAFL is characterized by hepatic steatosis without hepatocyte inflammation or ballooning, while NASH is characterized by hepatic steatosis with hepatocyte inflammation or ballooning. In NAFL, fat accumulates in the liver in the absence of excessive alcohol consumption, infections, and autoimmune diseases [2]. The largest contributor to hepatic fat is adipose-derived circulating free fatty acids (FFAs) (59%), which are stored as triglycerides (TGs), the predominant fat found in the livers of NAFLD patients. Hypertriglyceridemia is commonly found in patients with poorly controlled T2DM, obesity, and sedentary lifestyles, heavily predisposing them to NAFL development due to lipotoxicity [8]. Insulin resistance is a key factor in intrahepatic fat accumulation, increasing FFA levels for hepatic accumulation and intrahepatic de novo lipogenesis and promoting adipose tissue dysfunction, which reduces adiponectin secretion while increasing proinflammatory cytokine release [2]. The second largest contributor of hepatic fat is de novo lipogenesis from non-lipid precursors, mainly glucose and fructose. Diets high in sugar combined with sedentary lifestyles put patients at high risk [9]. Interestingly, TG accumulation may not be as hepatotoxic as people think and could be a defensive mechanism in response to excess FFA levels. A study has shown that triacylglycerol (TAG) accumulation acts to protect the liver from hepatotoxic FFA and does not directly cause liver injury, hence occurring as an epiphenomenon separate from liver injury [10].
First-degree relatives of NAFLD patients have three times the risk of developing NAFLD compared to the general population, pointing to a genetic component in NAFL development [11]. The most common genetic variant identified is PNPLA3 I148M. Loss of function of PNPLA3 reduces TG turnover, leading to TG accumulation in the liver and promoting fibrosis via hepatic stellate cell activation. Reduced expression of PNPLA3 I148M was observed to reduce liver damage. Another common genetic variant is TM6SF2 E167K. Loss of function of TM6SF2 encourages steatosis by preventing the exportation of TG via VLDL. Notably, NAFLD has a high degree of gene-environment interaction, as evidenced by obesity significantly amplifying the risk of NAFLD in genetically predisposed patients.
NASH. While it was previously thought that NAFL must precede NASH, studies have shown that NASH itself can be an initial liver lesion. Twenty-five percent of NAFL patients still progress to NASH within three years, with lipotoxicity from excess fats causing hepatocyte inflammation, ballooning, and fibrosis [12]. In NASH, the body enters a proinflammatory state from intrahepatic fat-induced lipotoxicity. High levels of proinflammatory cytokines, such as TNF-α, IL, DAMPs, and PAMPs, are released. Kupffer cells and neutrophils are also activated, exacerbating hepatocyte injury. In NASH patients, increased lipid burden is mirrored by increased mitochondrial activity, which in turn leads to mitochondrial exhaustion. Mitochondria are responsible for the β-oxidation of FFAs, ATP synthesis, and ROS production [13]. Hence, lipotoxicity-induced mitochondrial dysregulation results in enhanced hepatotoxic ROS and increased mitochondrial sensitivity to TNF-α.
A study showed that transplantation of gut microbiota from lean patients increased insulin sensitivity in obese patients [14]. This suggests the presence of “obese microbiota” and “lean microbiota”, which have different capacities in absorbing fats in the gastrointestinal tract. NAFLD patients were also found to have compositional differences and larger volumes of microbiota with a higher prevalence of small intestine bacterial overgrowth (SIBO) (77%) than healthy individuals. SIBO leads to increased intestinal permeability, proinflammatory cytokines, and dysregulated bile acid metabolism. Bile acids activate the farnesoid X receptor (FXR), which is responsible for lipogenesis and VLDL export, linking bile acid metabolism to NAFLD development. However, variables are difficult to control due to different diets, lifestyles, as well as antibiotic and microbiota exposure; hence, the results are not the most conclusive.
NAFLD patients with NASH, fibrosis, or associated T2DM are at high risk of NAFLD progression and must be identified early to prevent complications. Hepatic complications include cirrhosis, leading to hepatocellular carcinoma (>50% mortality), and hepatic emergencies, such as esophageal variceal bleeding (15% mortality) [15]. Patients are also at risk of nonhepatic complications, including cardiovascular diseases (40% mortality), T2DM and chronic kidney disease [16].
Cirrhosis and hepatocellular carcinoma (HCC). Approximately 40% of NASH patients develop fibrosis, which is double the fibrosis progression rate compared to NAFL [2]. Patients with NAFLD with fibrosis are at higher risk of adverse outcomes, such as cirrhosis and HCC [17]. Constant inflammation and regeneration of the hepatocyte, along with added stress from dysfunctional fibrosed hepatocytes, predisposes to neoplastic formation in the liver. Even without cirrhosis, 50% of HCC cases are associated with NAFLD [18]. One UK study discovered that cases of HCC secondary to NAFLD increased by 10-fold within the last decade [2].

1.3. Risk Factors for NAFLD

In a global study, T2DM and obesity were found in 22.5% and 51% of NAFLD patients, respectively [2]. Furthermore, NAFLD prevalence is almost double that in T2DM and obese patients compared to the general population. The bidirectional relationship between T2DM and NAFLD also means that either condition will lead to the other, which is clearly an important risk factor to address.
While obesity is a risk factor for NAFLD, it is unlikely to be the main driver of fibrosis progression after NAFLD onset. Lean NAFLD patients with BMI <25 are found more commonly in Asia (19%) than in South America (7%). Furthermore, lean NAFLD exhibits worse insulin resistance, dyslipidemia, and hypertension than the general population but has better cardio-metabolic risk than obese NAFLD [2]. A study has shown that lean NAFLD patients have accelerated fibrosis progression over 20 years compared to obese NAFLD patients, but this remains controversial [19]. with both lean and obese NAFLD exhibiting worse insulin resistance than the general population, insulin resistance may be an important driver in NAFLD progression. Other endocrine risk factors for NAFLD include hypogonadism, glucocorticoid excess, hypothyroidism, menopause, and growth hormone deficiency [2].

2. Diagnosis and Prognosis of NAFLD

After more than 10 years of active investigations, alternatives to liver biopsy for staging chronic liver diseases have revealed both their strength and weakness. Liver biopsies predict disease progression, while noninvasive markers predict NAFLD diagnosis and NAFLD-related morbidity and mortality. This implies that risk stratification of NAFLD patients can be carried out purely by noninvasive markers, with high-risk patients undergoing recommended biopsies, while low-risk patients continue with noninvasive markers only. Moving forward, using a combination of biomarkers with imaging techniques may yield the most accurate diagnostic capabilities via noninvasive measures.

2.1. Noninvasive Methods for NAFLD

Although hepatic steatosis was initially defined as a diagnostic histological feature for NAFLD diagnosis, recent years saw the emergence and clinical adoption of various noninvasive diagnostics through MRI-proton density fat fraction (MRI PDFF), magnetic resonance spectroscopy (MRS), and computed tomography (CT). Early detection of NAFLD is key to effective treatments and better management of the disease. There is an increasing reliance on noninvasive methods to diagnose and stage NAFLD. Not only are these methods more relevant in detecting early-stage asymptomatic NAFLD, but they also have better risk-benefit ratios than invasive methods.
MRI PDFF. Hepatic steatosis is heavily associated with chronic liver disease, especially in the earlier stages of NAFLD. In addition to histological changes, steatosis severity has been found to be linked to the development of fibrosis and NASH progression [20]. Currently, MRI-proton density fat fraction (MRI PDFF) is the most accurate noninvasive quantifier of hepatic steatosis reduction in clinical trials. A 2-point improvement in NAS can be identified by MRI-PDFF via a 30% reduction in hepatic fat content [21]. Hence, the drug responses of NAFLD patients with simple steatosis or NASH without fibrosis can be accessed via hepatic fat content measurements by MRI PDFF [22]. MRI PDFF is advantageous, as it performs whole liver mapping to determine hepatic fat content compared to magnetic resonance spectroscopy, which only covers a selected area of the liver. However, MRI-PDFF is user dependent, with variable performance based on technical skills, and cost expensive.
MRS. MRS is the mainstay imaging modality for grading hepatic steatosis in clinical trials, as it is not affected by concomitant liver conditions, iron deposition, or fibrosis, unlike other noninvasive methods. It can detect, grade, and quantify hepatic fat with high sensitivity and specificity. However, MRS is also user-dependent and expensive. NAFLD is usually defined as >5% hepatic fat content measured by MRS. This value, however, is almost the same as the absolute hepatic fat reduction cutoff (>5%) and can restrict the reported proportion of patients undergoing hepatic fat reduction, especially for those with hepatic fat slightly above 5%. NASH patients typically also have at least 20% hepatic fat content along with inflammation, which can be used as another surrogate marker of hepatic fat reduction [23]. Hepatic fat reduction as a predictor of histological improvement in NASH is a highly contested topic. According to studies, a decrease in at least 5% absolute liver fat content or 30% relative liver fat content measured by MRI-related methods is required for overall histological improvement [24][25].
CT. CT measures hepatic steatosis via radiation attenuation, with higher sensitivity and specificity for more advanced NAFLD [26]. However, ionizing radiation in CT limits its usage in at-risk populations, such as children and pregnant women. The main limitation of imaging techniques such as MRI-PDFF and CT, when compared to biopsies or biomarkers, is the inability to determine if the steatosis is reactive to infectious or inflammatory conditions, such as hepatitis or alcohol-induced or secondary to metabolic syndrome.
Biomarkers. AST and ALT are the most closely associated biochemical markers with hepatocellular injury and can be used to predict overall NAFLD severity and mortality. The FLINT trial demonstrated how ALT reduction in at least 17 IU/L is associated with histological improvements. However, the nonspecific nature of these liver enzymes makes it difficult to diagnose NAFLD in asymptomatic patients. For example, despite the almost universal reliance on transaminase levels in real-life practice, liver enzyme levels are not considered useful for diagnosing NASH. Most patients have normal transaminase levels, but this does not rule out histologically advanced disease. Finding biomarkers that can identify patients at high risk of NAFLD and quantifying the severity of the disease will prove very useful in both clinical trials and practice.
Homeostatic model assessment of insulin resistance (HOMA-IR). HOMA-IR is an affordable, noninvasive diagnostic method for NAFLD in T2DM patients. It is calculated using the following formula: [plasma glucose (mg/dL) ∗ plasma insulin (μU/mL)]/405. A study concluded that HOMA-IR is independently associated with NAFLD in T2DM patients, with decent sensitivity (66%) and high specificity (93%) and rivaling imaging techniques [27]. The main limitation of utilizing HOMA-IR lies in only evaluating the patient’s insulin sensitivity [28]. In individuals with nondiabetic glucose intolerance, fasting glucose and insulin concentrations are highly correlated positively. When a patient’s glucose tolerance deteriorates into a diabetic state, insulin concentrations start to decline and exhibit an inverse relationship to glucose rather than a positive relationship [29]. Under such conditions, HOMA-IR underestimates insulin resistance-associated NAFLD.

2.2. Noninvasive Methods for NAFLD with Fibrosis

Fibrosis is a strong predictor of NAFLD patient morbidity and mortality. Given the nonlinear progression of fibrosis, fibrosis must be regularly reassessed over time. However, repeated biopsies pose a significant risk to the patient, and the patient will also be unwilling to return for follow-up. Noninvasive measures that can perform at the same level, if not better than liver biopsies, will be key in the risk stratification and management of NAFLD patients.
FibroScan (transient elastography). FibroScan is a form of ultrasound. Ultrasound is used to look for hepatic steatosis, with decent sensitivity and specificity. It produces a low-frequency wave and correlates the wave velocity to liver stiffness, measuring the extent of liver steatosis and fibrosis [30]. Compared to noninvasive biomarkers such as the AST to platelet ratio index (APRI), FibroScan is significantly more accurate in predicting all-cause mortality in NAFLD patients [31]. However, the measurement of liver stiffness in FibroScan may be inaccurate depending on inter-operator differences, abdominal adiposity, or the size of the intercostal space. There is also variability in cutoff liver stiffness measurement values, but no studies to date have specifically addressed this clinical predicament [32]. FibroScan is not as effective in obese individuals, which make up a large proportion of NAFLD patients.
Biomarkers. Studies have shown that Fibrosis 4 (FIB-4), NAFLD fibrosis score (NFS), and APRI have limited ability to predict fibrosis progression but are on par or even better than liver biopsies in predicting liver-related morbidity [31]. The FIB-4 index and NFS are both the most accurate in predicting all-cause mortality, while NFS has the best prognostic accuracy for fibrosis progression, especially at advanced stages beyond F3. Other predictors of fibrosis include BAAT score, BARD score, Fibrometer, HAIR algorithm, and extracellular matrix turnover markers such as the European Liver Fibrosis test (ELF), hyaluronic acid, P3NP, and T1MP1 [33]. Currently, the best fibrosis predictors are hyaluronic acid, P3NP, and T1MPI for detecting F1 and F3, and fibrometer for F2.

2.3. Invasive Methods for NASH

Liver biopsy. Liver histology via biopsy remains the “imperfect” gold standard diagnostic tool for NAFLD. Histological staging scores include NAS and SAF (steatosis, activity, fibrosis), which are commonly used as primary and secondary outcomes in clinical trials. NAS is a measure of disease progression and is not the same as the clinical diagnosis of definite steatohepatitis. Each scoring has its own criteria (Table 1 and Table 2). However, there are many downsides to an overreliance on biopsies, not only in clinical research but also in clinical practice. The invasive procedure has a risk of rare but life-threatening complications and is not ideal for monitoring patients over time. It is a costly procedure that may require the additional cost and time of an interventional radiologist. Patients are also concerned about the invasive nature of the biopsy and the potential for pain, discomfort, and complications. Thus, the number of patients with NASH is underdiagnosed. Finally, a biopsy analyses 1/50,000 of the liver, and interpretation may differ between pathologists; therefore, serial biopsies may provide inconsistent findings.
Table 1. NAFLD Activity Score (NAS) and Fibrosis Score. Adapted from [34].
NAFLD Activity Score    
Score Steatosis Lobular
Inflammation		 Ballooning
Degeneration
0 <5% None None
1 5–33% <2 foci/20× field Few
2 >33–66% 2–4 foci/20× field Many
3 >60% >4 foci/20× field  
Fibrosis Score    
Stage Histological Findings
1a mild pericellular fibrosis (only seen on connective tissue stain)
1b moderate pericellular fibrosis (readily seen on H&E)
1c portal/periportal fibrosis without pericellular fibrosis
2 pericelluar and portal/periportal fibrosis
3 bridging fibrosis
4 cirrhosis
NASH resolution is defined by three criteria: ballooning = 0, inflammation = 0 or 1, and no worsening of fibrosis.
Table 2. Steatosis, Activity, and Fibrosis (SAF) score. Adapted from [35].
SAF (Steatosis, Activity, Fibrosis) Score
Score Steatosis  
0 <5%  
1 5–33%  
2 >33–66%  
3 >60%  
Activity Score Lobular
Inflammation (LI)		 Ballooning Degeneration (BD)
A0–4 0 none none
(LI + BD) 1 <2 foci/20× field hepatocytes with rounded shape and pale cytoplasm usually reticulated. size is quite similar to normal hepatocytes.
  2 >2 foci/20× field hepatocytes with rounded shape and pale cytoplasm usually reticulated. some cells are twice the size of normal hepatocytes.
Fibrosis Histological Findings
1a mild pericellular fibrosis (only seen on connective tissue stain)
1b moderate pericellular fibrosis (readily seen on H&E)
1c portal/periportal fibrosis without pericellular fibrosis
2 pericelluar and portal/periportal fibrosis
3 bridging fibrosis
4 cirrhosis

This entry is adapted from the peer-reviewed paper 10.3390/ijms24010158

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