Abstract
Background and aims
Nonalcoholic fatty liver disease (NAFLD) is hepatic steatosis that is require the exclusion of certain etiologies, including drug usage or alcoholic consumption. Conversely, metabolic dysfunction-associated fatty liver disease (MAFLD) needs not to. In this study, we aimed to examine whether MAFLD is more easily diagnosed than NAFLD in liver transplant (LT) recipients with abnormal liver function.
Methods
In this cross-sectional study, LT recipients with abnormal liver function were investigated for the prevalence of MAFLD and NAFLD.
Results
We recruited 57 LT recipients with abnormal liver function at a referral hospital. Among these patients, the prevalence of MAFLD and NAFLD was 37.8% and 11.1%, respectively. 17 patients showed hepatic steatosis, with an average NAFLD activity score of 3.5 and a fibrosis score of 1.0. Compared with non-MAFLD patients, MAFLD patients had a significant difference in fasting blood glucose levels (p = 0.009). Among 17 MAFLD patients, 12 were overweight and four were diagnosed with diabetes mellitus. The majority of MAFLD diagnoses were based on body mass index (70.6%) and diabetes mellitus history (23.5%), biomarkers that are easily obtained. At 6, 12, 24, and 36 months after LT, MAFLD patients had higher levels of fasting blood glucose (6 months: p = 0.004, 12 months: p = 0.038) and higher trend of body mass index value and plasma triglyceride level but no significance.
Conclusions
MAFLD was more easily diagnosed in LT recipients with abnormal liver function and higher in prevalence than NAFLD. A larger sample size research is required to validate these conclusions.
Keywords: Metabolic dysfunction-associated fatty liver disease, Nonalcoholic fatty liver disease, Prevalence, Recipient, Fasting blood glucose
1. Introduction
Nonalcoholic fatty liver disease (NAFLD) is a form of hepatic steatosis and is associated with a spectrum of metabolic changes [1]. A diagnosis of NAFLD requires the exclusion of other causes of steatosis [2,3], such as drug usage or alcohol consumption. In clinical practice, however, this is difficult because it is challenging to exclude secondary mild hepatic steatosis. The limitations of NAFLD have thus become apparent in both research and in clinical practice. For this reason, the term metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed as a more appropriate diagnosis [4,5]. Liver transplant (LT) recipients have a high prevalence of metabolic syndrome, and some LT recipients with hepatic steatosis and abnormal liver function may not be diagnosed with NAFLD [6]. In these cases, a diagnosis of MAFLD may be easier when observing metabolic dysfunctions in recipients with complex etiologies. To date, studies looking at MAFLD in LT recipients with abnormal liver function are limited. We therefore recruited LT recipients with abnormal liver function that had liver biopsies at our hospital and examined the prevalence of MAFLD and NAFLD.
2. Materials and methods
2.1. Study design and patients
This cross-sectional study enrolled adult LT patients who had a liver biopsy that were admitted to a referral hospital from April 1, 2015 to March 1, 2019. Patients enrolled in the study were between 18 and 70 years old, had abnormal liver function, and had undergone a liver biopsy. We focused on patients with abnormal liver function that had an explicit cause. Donor-related steatosis will typically improve during the first two or three months following liver transplantation [7], and so patients who had undergone a liver biopsy within three months of their liver transplantation were excluded. Patients with tumors were also excluded.
This was a retrospective study. The study protocol was reviewed and approved by the Committee of Ethics at our hospital. All procedures followed the Declaration of Helsinki.
2.2. Diagnostic criteria
NAFLD is defined as the presence of more than 5% hepatic steatosis, confirmed via liver histology. NAFLD diagnosis in this study furthermore required the exclusion of both secondary causes and a daily alcohol consumption of ≥30 g for men and ≥20 g for women. NAFLD was not diagnosed in patients with mild hepatic steatosis (5%–10%) that was not detected by ultrasound, nor accompanied by another explicit etiology of abnormal liver function, because it is difficult to exclude secondary hepatic steatosis. MAFLD was diagnosed based on hepatic steatosis detected by liver histology and required at least one of the following criteria to be met: (1) a body mass index (BMI) ≥ 23 kg/m2; (2) type 2 diabetes; (3) at least two of the following metabolic risk abnormalities: blood pressure ≥130/85 mmHg; plasma triglyceride (TG) levels ≥1.70 mmol/L; plasma high-density lipoprotein (HDL) cholesterol levels <1.0 mmol/L for men or < 1.3 mmol/L for women; prediabetes (characterized by fasting blood glucose (FBG) levels of 5.6–6.9 mmol/L or glycosylated hemoglobin A1c levels of 5.7%–6.4%); or plasma high sensitivity C-reactive protein (CRP) levels >2 mg/L [4]. Overweight is defined as a BMI ≥23 kg/m2.
2.3. Data collection
We collected clinical and laboratory data at the time of the liver biopsy and recorded the patients’ complete medical history. Demographic variables were obtained from hospital electronic medical records, including age, sex, history of hypertension and diabetes mellitus (DM), and BMI (calculated as weight (kg)/height (m2)). Levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBil), cholesterol, TG, HDL, low-density lipoprotein (LDL), FBG, CRP, albumin (ALB), and lactic dehydrogenase were recorded. An abdominal ultrasound was used to detect steatosis.
2.4. Liver histology
The collected liver biopsies measured at least 15 mm when extended or had more than 10 fully portal tracts. The diagnoses of MAFLD and NAFLD required ≥5% hepatic steatosis. The NAFLD activity score (NAS) was recorded as the sum of the scores for steatosis (0–3), lobular inflammation (0–3), and ballooning (0–2). Fibrosis was measured on a scale of 0–4 [8]. Steatosis was graded on a scale of 0–3 scale: a score of 0 indicating the absence of steatosis or steatosis in <5% of the hepatocytes; a score of 1 indicating that steatosis is present in ≤33% of the hepatocytes; a score of 2 indicating that steatosis is found in 33%–66% of the hepatocytes; and a score of 3 indicating that steatosis is present in >66% of the hepatocytes.
2.5. Statistical analysis
Continuous variables are given as either a mean ± standard deviation (SD) or a median with the interquartile range (IQR). Categorical variables are described as frequency rates or percentages. Differences between MAFLD and non-MAFLD were compared using a t-test or a Mann–Whitney test. Proportions for categorical variables were compared using the χ2 test. A p value of <0.05 was considered statistically significant. All statistical analyses were performed using SPSS 25.0 software.
3. Results
3.1. The profiles of the 45 LT recipients with abnormal liver function
We recruited 57 consecutively biopsied LT recipients with abnormal liver function from April 1, 2015 to March 1, 2019. We excluded 12 of these recipients due to the liver biopsy being performed within 3 months of their LT. In total therefore, this study looked at 45 patients (Fig. 1).
Fig. 1.
Flow chart of LT patients with abnormal liver function. We recruited 57 LT recipients who underwent a liver biopsy. 12 patients were excluded for having a liver biopsy within three months after liver transplantation. In total, 45 LT recipients met the inclusion criteria, among which 17 were diagnosed with MAFLD. LT: liver transplant; NAFLD: Nonalcoholic fatty liver disease; MAFLD: Metabolic dysfunction-associated with fatty liver disease.
Among these 45 patients, seven (15.6%) were female and 38 (84.4%) were male. The median age was 45 (IQR: 38, 54). The LTs were performed due to chronic hepatitis B (CHB) infection (n = 16, 35.6%), alcoholic disease (n = 14, 31.1%), or other reasons (n = 15, 33.3%). All recipients took tacrolimus and mycophenolate mofetil but did not take sirolimus or cyclosporine. The median dose of tacrolimus was 4.0 (2.0, 4.0) mg/day, and the median trough concentration of tacrolimus was 7.6 (4.8, 8.8) ng/mL. The median time between liver transplantation and liver biopsy was 12.33 (6.23, 16.03) months. Other median values were as follows: TBil was 22.8 (16.4, 54.6) μmol/L; direct bilirubin was 10.4 (7.1, 41.4) μmol/L; ALT was 109 (72, 243) U/L; and AST was 83 (39, 139) U/L (Table 1). The median donor steatosis was 0.0% (0.0%, 20.0%).
Table 1.
Variables of 45 consecutive biopsied liver transplant recipients.
| Variables | Total (n = 45) |
|---|---|
| Gender | |
| Male | 38 (84.40%) |
| Female | 7 (15.60%) |
| Age (yrs) | 45.00 (38.00,54.00) |
| BMI(kg/m2) | 23.40 ± 0.63 |
| WBC (×109/L) | 4.11 (2.81, 4.80) |
| Hemoglobin (g/L) | 134.30 ± 3.47 |
| Platelet (×109/L) | 130.00 (79.00,162.00) |
| Albumin (g/L) | 40.38 ± 0.81 |
| TBIL (umol/L) | 22.80 (16.40, 54.60) |
| ALT (U/L) | 109.00 (72.00, 243.00) |
| AST (U/L) | 83.00 (39.00,139.00) |
| FBG (mmol/L) | 5.500 (4.85, 6.32) |
| Cholesterol (mmol/L) | 3.83 (3.30,4.76) |
| Triglyceride (mmol/L) | 1.39 (1.06, 1.82) |
| HDL (mmol/L) | 0.98 (0.76, 1.32) |
| LDL (mmol/L) | 2.64 (2.11, 3.30) |
| CRP (mg/L) | 1.53 (0.65, 3.95) |
| Creatine (umol/L) | 78.50 (69.50, 95.50) |
| Tacrolimus∗ (ng/mL) | 6.68 ± 0.59 |
Abbreviation: BMI, body mass index; WBC, white blood cell; TBil, total bilirubin; ALT, alanine transaminase; AST, aspartate aminotransferase; FBG, fasting blood glucose; HDL, high-density lipoprotein; LDL, low-density lipoprotein; CRP, c-reactive protein; ∗Tacrolimus, Tacrolimus trough concentration.
3.2. The differences in etiology of abnormal liver function between MAFLD and non-MAFLD
Among the 45 study participants, 17 patients presented with steatosis and were diagnosed with MAFLD (37.78%). Five of these patients (11.11%) were also diagnosed with NAFLD. The remaining 12 patients had mild hepatic steatosis (steatosis graded 1: 5%–10%) that was not detected by an abdominal ultrasound and presented with an explicit cause of abnormal liver function and were not diagnosed with NAFLD. The 17 patients with MAFLD had an average NAFLD activity score (NAS) of 3.5 and an average fibrosis score of 1.0. The five patients diagnosed with NAFLD had an average NAS score of 4.5 and an average fibrosis score of 1.0. The causes of liver injury in the 45 LT recipients were acute cellular rejection (ACR) (n = 13, 28.9%), bile duct injury (n = 12, 26.7%), NAFLD (n = 5, 11.11%), CHB (n = 3, 6.7%), or another cause (n = 12, 26.7%). The prevalence of co-existing diseases was significantly different (p = 0.033) between patients with and without MAFLD.
Of the patients with MAFLD, five (29.4%) were also diagnosed with NAFLD, two (11.8%) with CHB, five (29.4%) with bile duct injury, three (17.6%) with ACR, and two were diagnosed with another disease.
3.3. Clinical characteristics of MAFLD and NAFLD in recipients with abnormal liver function
Compared with non-MAFLD patients, MAFLD patients had significantly higher FBG levels (p = 0.009). However, we observed no differences in the prevalence of DM (p = 0.452), BMI (p = 0.314), TG levels (p = 0.223), CRP levels (p = 0.368), TBil levels (p = 0.237), ALT levels (p = 0.194), AST levels (p = 0.153) (Table 2), or donor steatosis (p = 0.535).
Tables 2.
Differences between MAFLD and non-MAFLD patients
| Variables | No MAFLD10 (n = 28) | MAFLD (n = 17) | p |
|---|---|---|---|
| Gender | 0.693 | ||
| Male | 23 (82.10%) | 15 (88.20%) | |
| Female | 5 (17.90%) | 2 (11.80%) | |
| Age (yrs) | 46.88 ± 1.79 | 45.00 (38.00,55.00) | 0.787 |
| BMI (kg/m2) | 23.19 (19.51,25.14) | 24.40 (22.79,26.23) | 0.314 |
| WBC (×109/L) | 4.31 (2.58,4.80) | 3.78 (3.08,4.85) | 0.981 |
| Hemoglobin (g/L) | 124.50 (117.00,143.00) | 139.82 ± 6.95 | 0.085 |
| Platelet (×109/L) | 132.00 (81.50,156.00) | 127.00 (79.00,172.00) | 0.888 |
| Albumin (g/L) | 39.86 ± 1.08 | 41.24 ± 1.23 | 0.418 |
| TBIL (umol/L) | 24.90 (17.65,61.45) | 20.80 (14.30,30.90) | 0.237 |
| ALT (U/L) | 123.50 (79.50,254.00) | 81.00 (55.00,139.00) | 0.194 |
| AST (U/L) | 99.50 (52.50,152.00) | 55.00 (35.00,114.00) | 0.153 |
| FBG (mmol/L) | 5.10 (4.65,6.10) | 6.00 (5.80,6.93) | 0.009 |
| Cholesterol (mmol/L) | 3.78 (3.28,5.00) | 4.0 (3.58,4.59) | 0.727 |
| Triglyceride (mmol/L) | 1.40 (0.80,1.77) | 1.32 (1.18,1.72) | 0.223 |
| HDL (mmol/L) | 1.19 ± 0.13 | 1.12 ± 0.16 | 0.972 |
| LDL (mmol/L) | 2.59 ± 1.23 | 2.45 (1.69,3.09) | 0.949 |
| CRP (mg/L) | 1.57 (0.5,4.3) | 2.20 (0.95,3.65) | 0.368 |
| Creatine (umol/L) | 79.00 (69.00,97.00) | 78.00 (71.00,94.00) | 0.916 |
| Tacrolimus∗ (ng/mL) | 6.88 ± 0.53 | 7.26 ± 0.79 | 0.686 |
Abbreviation: BMI, body mass index; WBC, white blood cell; TBil, total bilirubin; ALT, alanine transaminase; AST, aspartate aminotransferase; FBG, fasting blood glucose; HDL, high-density lipoprotein; LDL, low-density lipoprotein; CRP, c-reactive protein; ∗Tacrolimus, Tacrolimus trough concentration; MAFLD, metabolic dysfunction-associated fatty liver disease.
Compared with non-NAFLD patients, NAFLD patients had significantly higher ALB (p = 0.008). However, we observed no differences in FBG levels (p = 0.202), the prevalence of DM (p = 0.629), BMI (p = 0.636), TG levels (p = 0.293), CRP levels (p = 0.446), TBil levels (p = 0.296), ALT levels (p = 0.118), or AST levels (p = 0.148).
Compared with NAFLD patients, the patients with MAFLD but without NAFLD showed statistically lower NAS scores (p < 0.001) and a low trend of ALT level (74.0 U/L versus 97 U/L, p = 0.195), however, the difference was not statistically significant.
3.4. The components of MAFLD
Among the 17 patients diagnosed with MAFLD, 12 were overweight (70.6%), four were diagnosed with DM (23.5%; two of these patients were also overweight), and three patients met the metabolic risk abnormalities criteria. Most of the MAFLD diagnoses were based on BMI and DM, biomarkers that were easily obtained.
3.5. Dynamic metabolic abnormalities within MAFLD patients after LT
Three years after the liver transplantation, patients with MAFLD had a higher BMI, and greater levels of FBG and TG compared with patients not diagnosed with MAFLD. Follow-up testing was performed at 6, 12, 24, and 36 months after the liver transplantation, and showed that MAFLD patients consistently had higher levels of FBG (6 months, p = 0.004; 12 months, p = 0.038) compared with patients without MAFLD, regardless of the levels of ALT, AST, and TBil. Patients with MAFLD also showed higher BMI values; however, these differences were not statistically significant (see Fig. 2).
Fig. 2.
The dynamic changes of (A) BMI, (B) FBG, (C) TG, and (D) ALT levels between MAFLD and non-MAFLD patients at 6 months, 12 months, 24 months, and 36 months after liver transplantation. During three years following liver transplantation, MAFLD patients consistently showed higher BMI values, FBG levels, and TG levels, regardless of changes in ALT levels. BMI: body mass index; FBG: fasting blood glucose; TG: triglyceride; ALT: alanine aminotransferase; MAFLD: metabolic dysfunction-associated with fatty liver disease.
4. Discussion
A diagnosis of NAFLD is based on hepatic steatosis and requires the exclusion of certain causes of steatosis, such as drug usage or alcohol consumption. A diagnosis of MAFLD, however, is not dependent on deciphering the etiology of steatosis. In this study, the prevalence of MAFLD among patients that received a LT was 37.8%, while the prevalence of NAFLD was 11.1%. Some of the study patients with MAFLD had co-existing diseases, including bile duct injury and NAFLD. The patients with MAFLD also showed significantly higher FBG levels compared with patients without MAFLD. Three years after the liver transplantation, patients with MAFLD had consistently higher FBG levels, higher trend of BMI values, and higher trend of TG levels compared with patients without MAFLD. The majority of MAFLD diagnoses were based on a high BMI (70.6%) and a history of DM (23.5%). The diagnosis of MAFLD was easy in recipients with abnormal liver function, especially those with mild hepatic steatosis.
MAFLD was more easily diagnosed than NAFLD in LT recipients with abnormal liver function. Among the 17 patients diagnosed with hepatic steatoses, five were diagnosed with NAFLD. The remaining 12 patients showed mild hepatic steatosis (steatosis graded 1: 5%–10%), and with a clear cause of abnormal liver function. In these cases, it was not possible to rule out secondary steatosis. However, the 17 patients with hepatic steatoses were all diagnosed with MAFLD. Therefore, MAFLD was better at identifying patients with metabolic risk.
LT recipients have a higher risk of metabolic dysfunction. Many LT recipients presented with metabolic syndrome [[9], [10], [11]]. This condition has a global prevalence of 39%–58% [12], and is associated with increased cardiovascular and cerebrovascular risk [13]. In our study, 27 out of the total 45 patients had a BMI of more than 23 kg/m2, while 22 patients had prediabetes or DM. In these cases, MAFLD was easily diagnosed from the available data [14]. Within the same population, however, most of the cases of hepatic steatosis were not diagnosed with NAFLD [[15], [16], [17]]. In addition, we observed that LT recipients with MAFLD are more easily diagnosed with further metabolic dysfunctions compared with LT recipients with NAFLD.
Hepatic steatosis changes over time. Donor-related steatosis often improves following a liver transplantation, and so the impact of donor-related steatosis is typically reduced within 2 or 3 months following liver transplantation. For this reason, this study excluded patients that were diagnosed with steatosis within 3 months of the liver transplantation [7]. We observed no significant differences in donor-related steatosis between patients with and without MAFLD. However, we did observe some long-term differences in metabolic risks between the two groups. Patients with MAFLD had higher FBG levels, BMI values, and TG levels when assessed 36 months after their LT, regardless of their ALT levels. These data suggest that MAFLD patients are a population at high risk of developing long-term metabolic risks.
When diagnosed via abdominal ultrasound, only 5 out of 17 patients in this study were diagnosed with steatosis, while the majority of the LT recipients (12 out of 17) showed no steatosis. Abdominal ultrasounds are only able to detect cases with hepatic fat contents greater than 30% [18], meaning that mild hepatic steatoses are often undiagnosed.
This study has certain limitations, including a modest sample size. However, LT recipients with abnormal liver function often have a high prevalence of metabolic disorders and hepatic steatosis, which can be attributed to different complex etiologies. In this study, we have examined the prevalence and characteristics of both MAFLD and NAFLD in patients with abnormal liver function. We have demonstrated new evidence to suggest that the criteria for MAFLD diagnosis may be more useful in LT recipients than NAFLD diagnosis.
In conclusion, LT recipients with abnormal liver function have a high prevalence of MAFLD. These patients often present with co-existing diseases when NAFLD is not established, meaning that the extent of hepatic steatosis may be underestimated. In contrast, MAFLD appears to be more easily diagnosed in these patients. A larger sample size and further research is required to confirm these conclusions.
Author contributions
Design and Critical Review - Hongling Liu, Yinjie Gao; Writing Manuscript and Analysis - Dali Zhang, Hongbo Wang; Data Collection and Interpretation - Danni Feng, Xi He, Yanling Sun; Supervision - Zhenwen Liu.
Acknowledgement
None
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Data available statement
All original data are available upon reasonable request to the corresponding authors.
Funding
This work was supported by the Beijing Funding Project [Z161100000116058] and the 302 Military Hospital Project [YNKT2014006].
Ethics statement
This study was approved by the Committee of Ethics of Fifth Medical Center of the Chinese People's Liberation Army General Hospital. All procedures followed the Declaration of Helsinki.
Informed consent
Informed consent was obtained from all patients.
Contributor Information
Yinjie Gao, Email: gaoyj302@163.com.
Hongling Liu, Email: lhl7125@sina.com.
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