Clinical and Diagnostic characteristics of Non-Alcoholic Fatty Liver Disease among Egyptian children and adolescents with type1 diabetes

doi:10.21203/rs.3.rs-2214921/v1

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Research Article

Clinical and Diagnostic characteristics of Non-Alcoholic Fatty Liver Disease among Egyptian children and adolescents with type1 diabetes

https://doi.org/10.21203/rs.3.rs-2214921/v1

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published 21 Mar, 2023

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Background

Type 1 diabetes mellitus (T1DM) patients are at an increased risk for non-alcoholic fatty liver disease (NAFLD). This study aimed to evaluate the clinical criteria associated with the diagnosis of Non Alcoholic Fatty Liver Disease (NAFLD) among T1DM Egyptian children and adolescents.

Methods

74 T1DM patients aged 8–18 y were enrolled in this cross sectional study. Assessments of Clinical status, anthropometric measures, lipid profile, glycated haemoglobin (HbA1c) and liver enzymes were done. Abdominal Ultrasound evaluation of hepatic steatosis was done. Accordingly, patients were divided into two groups (NAFLD & normal liver group) and compared together. Assessment of liver fibrosis using acoustic radiation force impulse elastography (ARFI) was done. Statistical analysis included; independent t-test, Chi square and Fisher’s Exact, Pearson and Spearman tests and Logistic regression models for factors associated with fatty liver were used when appropriate.

Results

in this study; 37 male (50%) & 37 females with mean age 14.3 ± 3.0 y. The mean insulin dose was 1.1 ± 0.4 U/kg & mean disease duration was 6.3 ± 3.0 y. NAFLD was detected in 46 cases while 28 cases had normal liver as diagnosed by abdominal ultrasound. Cases with NAFLD had statistically significant higher BMI-Z scores, waist / hip, waist/ height and sum of skin fold thicknesses compared to those with normal liver (P < 0.05). The mean value of HbA1c % was significantly higher in NAFLD group (P = 0.003). Total cholesterol, triglycerides & LDL serum levels were significantly elevated (p < 0.05), while the HDL level was significantly lower in NAFLD cases (p = 0.001). Although, serum levels of liver enzymes; ALT & AST were significantly higher among cases with NAFLD than in normal liver group (p < 0.05), their means were within normal. Using the ARFI elastography; NAFLD cases exhibited significant fibrosis (F2, 3 &4). BMI, patient age and female gender were among risk factors for NAFLD.

Conclusions

NAFLD represents a serious consequence in type 1 diabetic children and adolescents that deserves attention especially with poor glycemic control. NAFLD has the potential to evolve to fibrosis. BMI, age of patients and female gender were detected as risk factors for NAFLD.

Type1 diabetes

Hepatopathy

Non-alcoholic fatty liver disease (NAFLD)

Anthropometric measures

Acoustic radiation force impulse elastography (ARFI)

Diabetes mellitus type 1 (T1DM), is an autoimmune disease represents a serious, long-term condition with a major impact on the lives. The International Diabetes Federation (IDF) has reported more than 1 million children and adolescents suffer type 1 diabetes [1].

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic hepatopathy among pediatric population and adults. Hepatopathies comprise a varied spectrum of diseases starting from simple steatosis or NAFLD, then non-alcoholic steatohepatitis (NASH), to cirrhosis. NAFLD should be diagnosed only when other causes of hepatic affection are absent [2], [3]. Throughout the last years, NAFLD has represented an apparently medical and financial burden as a result of increase in obesity & diabetes mellitus prevalence [4]. Furthermore, increased mortality caused by liver diseases was attributed to increase in NAFLD cases. High cardiovascular morbidity and mortality was associated with NAFLD; increasing its burden [5]. Putting into consideration, that type 1 diabetes is a lifelong disease with extended duration, the range of NAFLD and its long standing consequences are clinically related to type 1 diabetic cases [6]. Recent studies showed that in type1diabetic patients, there was an increase of about 5-fold in risk of distal symmetric polyneuropathy and 8-fold in risk of Cardio-vascular diseases occurrence associated with NAFLD [7], [8]. Inadequate excretion of triglyceride from the liver by VLD lipoproteins or hyperglycemia stimulates hepatic lipogenesis leading to accumulation of fats in the liver in type 1 diabetes mellitus (T1DM) [9]. Liver biopsy is the ‘‘gold standard’’ for the diagnosis of NAFLD. Nevertheless, it exposes patient to hazards of complications as it is an invasive technique [10]. The European guidelines for managing Non-Alcoholic Fatty Liver endorsed the usage of U/S as the first-line imaging in patients with possible Non-Alcoholic Fatty Liver & Non-Alcoholic Steato-Hepatitis [11]. In adults, its sensitivity is 90% and specificity is 95% for moderate to severe steatosis identification, however its sensitivity is decreased if the amount of liver fat is decreased than 33% [12]. In children, hepatic ultrasound can detect fat with 70–85% sensitivity and 50–60% specificity [13].

Latest information on children have demonstrated worrying relationship among pediatric NAFLD and CVD hazards [14]. Histological characteristics have shown significantly more severe steatosis in pediatric NAFLD in comparison to adults [15]. When the disease progresses to severe fibrotic phase it is called pediatric non-alcoholic steatohepatitis (NASH) [16]. Accordingly, the necessity for precise diagnosis and staging of this disease is of great significance in people with high risk like pediatric diabetic population using non-invasive methods [17].

Pediatric patients with laboratory measures within normal levels, as well those with normal hepatic U/S or slight steatosis, could actually have had a considerable stage of hepatic fibrosis. Acoustic Radiation Force Impulse Imaging (ARFI) is a promising U/S -based technique for assessing hepatic fibrosis and stiffness with diagnostic accuracy comparable to that of Transient elastography (TE) & could be utilized as a non-invasive method to diagnose pediatric NAFLD particularly in subjects where biopsy is not a preferred technique [18], [19]. So far, there is a paucity in paediatric studies examining the association between liver disease and type 1 DM in children and adolescents.

Aim of the study: In this study, we aim to investigate the clinical and diagnostic characteristics distinguishing NAFLD associated with type1 diabetes in a cohort of type 1 diabetic Egyptian children and adolescents; using laboratory examination, ultrasound and liver stiffness measurement; acoustic radiation force imaging [ARFI].

Study design and setting of the study:

- We conducted a cross sectional observational study enrolled 74 patients with type 1 diabetes, aged 8-18 years, and duration of T1DM >2 years who were treated and followed in the National Institute of Diabetes and Endocrine Diseases and recruited to the outpatient clinic in the Medical Research Centre of Excellence in National Research Centre during the period from 2019 to 2021. Cases were further subdivided into two groups: patients with NAFLD and patients without NAFLD.

-Participants:

- Patients’ inclusion criteria included; (8-18)y, confirmed diagnosis of T1DM I according to International Society for Paediatric and Adolescent Diabetes (ISPAD) guidelines [20] & duration of T1DM > than two years.

- Exclusion criteria included; patients who had a known other system affection like central nervous system, respiratory, renal, cardiovascular and congenital diseases or other endocrine disease like thyroid disorders, Mauriac syndrome, history of chronic liver diseases including history suggestive of viral hepatitis A, B, or C infection, genetic disorders, Wilson’s disease, hemochromatosis, and autoimmune hepatitis, and history of use of drugs causing liver function abnormality (hepatotoxic drugs such as tamoxifen, amiodarone, valproate and methotrexate or prednisone).

Assessment of participants’ characteristics:

- All the study cases were subjected to the following; thorough history taking laying stress on; age of onset of diabetes, diabetes duration, diabetes complications, any long term medications other than insulin, diabetic ketoacidosis comas, insulin regimen treatment including; the type and dose of insulin in units (morning and night dose) then the mean of insulin units was taken, glycemic control as indicated by both HbA1C in the last 12 months, frequency of hypoglycemia in the last month (number of times the patient had blood glucose levels ≤70 mg/dL, associated diseases, and hospitalization due to any cause in the last year. In addition to gastrointestinal or hepatic symptoms like abdominal pain, nausea, or vomiting, jaundice, pruritus, visceral pain and abdominal distention. Family history of type 1 or 2 Diabetes, obesity and hypertension was also taken.

- Complete clinical examination was performed stressing on; signs of hepatic affection including; jaundice, spider naevi, tender liver, hepatomegaly, splenomegaly, and ascites.

- Blood pressure was measured according to American Heart Association guidelines; during the patients’ visits to the outpatient clinic, with the use of mercury sphygmomanometer; three consecutive blood pressures were measured for all patients with at least five-minute intervals, in a seated position and through a standard method using an appropriate cuff and sphygmomanometer. Blood pressure (BP) measurements were compared to age-specific percentiles for BP.

- Anthropometric assessment was done as follows; Height and weight were measured. The body mass index (BMI) was calculated as weight (in kilograms) divided by height (in square meters). The standard deviation scores (SDS) of BMI were calculated using the WHO ANTHRO Plus softwares [21]. The waist circumference and hip circumference were measured. Waist /Hip ratio and Waist / Height ratio were calculated.The skinfold thicknesses were measured to the nearest 1.0 mm using Holtain skin fold caliber. They included; triceps, biceps, subscapular, suprailiac and abdominal skin folds. Each measurement was taken as the mean of three consecutive measurements, using standardized equipment and following the recommendations of International Biological programs [22].

-Laboratory and biochemical investigations:

6 milliliters of peripheral venous blood were withdrawn and divided equally into two vacutainers under complete aseptic precautions from fasting subjects (12–14 hours). The blood in one of the vacutainers was anticoagulated with EDTA for CBC and HbA1c assessment, and the blood in the second vacutainer was left to clot at room temperature for 15 min then centrifuged. Sera were then separated, labelled uniquely, and stored for evaluation of the other parameters.
HbA1c was assessed using Labona check hemoglobin A1C analyzer Belglum Korea. In addition, the mean of three readings of glycosylated hemoglobin HbA1c measurements during the last year for each patient was calculated by to be representative of long-term metabolic control and patient was considered with poor glycemic control if >10 % regardless of age.
Fasting blood glucose was assessed using enzymatic colorimetric methods using a Hitachi auto analyzer 704 (Roche Diagnostics. Switzerland) [23].

Diagnosis of pediatric NAFLD using routine noninvasive evaluation included:

1. Biochemical parameters which included; complete lipid profile (serum total cholesterol, triglycerides, HDL, LDL) and liver enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT] were carried out using automated clinical chemistry analyzer (XL-300) Erba Diagnostic Mannheim Germany. HBVs Ag & HCV Ab were done using One Step Diagnostic Rapid test (Cassette) Prechek Bio., INC. (perchek Bio.com) to exclude hepatitis B & C in those patients. Serum Anti smooth muscle antibodies ASMA, Anti-nuclear antibody ANA and anti-liver and kidney microsomal antibodies LKM were measured using ELISA immunoassay to exclude autoimmune hepatitis.

2. Abdominal ultrasonography which is the most commonly used imaging modality because it is relatively inexpensive, widely available to detect fatty liver. A routine liver ultrasound was performed by experienced radiologist. Examinations were performed according to a standardized protocol. US evaluation of hepatic steatosis typically consisted of a qualitative visual assessment of hepatic echogenicity, measurements of the difference between the liver and kidneys in echo amplitude, evaluation of echo penetration into the deep portion of the liver, and determination of the clarity of blood vessel structures in the liver. All US was performed by one of the two radiologists involved in the study who were blinded to the blood test-results and clinical history of patients.

-Measurement of liver fibrosis by Acoustic Radiation Force Impulse elastography (ARFI) was done as follows:

-Acoustic radiation force impulse elastography (ARFI) was performed for all subjects with a Siemens Acuson S3000 Virtual Touch ultrasound system (Siemens AG, Erlangen, Germany) with a 6CI transducer. The principle underlying ARFI elastography is that sharing of the examined tissue induces a strain in the tissues. An acoustic “push” pulse is automatically produced by the ultrasound probe and directed to the side of a region of interest (ROI), which is where the speed of the shear wave is measured. The acoustic “push” pulse generates shear waves that propagate into the tissue, perpendicular to the “push” axis. Detection waves are also generated by the transducer to measure the propagation speed of these shear waves, which increases with fibrosis severity [24]. For each patient, 10 valid ARFI measurements were performed under fasting conditions, with the patient in supine position with the right arm in maximum abduction, by the intercostal approach in the right liver lobe, 1–2 cm under the liver capsule. Minimal scanning pressure was applied, and the patient was asked to stop normal breathing for a moment to minimize breathing motion. The mean of 8–10 valid measurements was calculated and considered indicative of the severity of fibrosis.

Statistical analysis:

The collected data were coded, tabulated, and statistically analyzed using IBM SPSS statistics (Statistical Package for Social Sciences) software version 22.0, IBM Corp., Chicago, USA, 2013. Quantitative normally distributed data were described as mean ± SD (standard deviation) after testing for normality using Shapiro-Wilk test, then compared using independent t-test for normally distributed. While Pearson test was used for correlations of normally distributed data and Spearman correlation for ordinal data. Qualitative data were described as number and percentage and compared using Chi square test and Fisher’s Exact test for variables with small expected numbers. Logistic regression models for factors associated with fatty liver.

- A total of 74 participants with type 1 diabetes mellitus were enrolled in this study where 37 (50%) were females. The mean age of the studied cases was 14.3 ± 3.0 (8-18) year. The mean age of onset of diabetes was 8.0±3.2 while the mean insulin dose/day was 1.1±0.4 U/kg, and the mean disease duration was 6.3±3.0 years. 94.6 % of our cases had history of previous DKA attacks, 64.9% had symptoms of diabetic complications and 68.9% had symptoms of liver affection. Demographic data, clinical characteristics of the total studied cases & comparison according to U/S diagnosis of NAFLD are shown in table (1) & (2).

Table (1) Demographic characteristics among the studied cases and comparison according to presence of NAFLD.

Variables		All cases (N=74)	NAFLD		P-value
Variables		All cases (N=74)	Present (N=46)	Absent (N=28)	P-value
Age (years), Mean±SD		14.3±3.0	15.4±2.3	12.4±3.1	^<0.001*
Gender (n, %)	Male	37 (50.0%)	17 (37.0%)	20 (71.4%)	#0.004*
Gender (n, %)	Female	37 (50.0%)	29 (63.0%)	8 (28.6%)	#0.004*
Family history	Type 2 DM	47 (63.5%)	31 (67.4%)	16 (57.1%)	#0.374
	Obesity	33 (44.6%)	23 (50.0%)	10 (35.7%)	#0.231
	Liver disease	17 (23.0%)	13 (28.3%)	4 (14.3%)	#0.166
	Hypertension	30 (40.5%)	19 (41.3%)	11 (39.3%)	#0.864
	Consanguinity	13 (17.6%)	7 (15.2%)	6 (21.4%)	§0.539

BMI: Body mass index. ^Independent t-test. #Chi square test. §Fishers Exact test. *Significant

Table (2) DM characteristics among the studied cases and comparison according to presence of NAFLD

Variables		All cases (N=74)	NAFLD		P-value
Variables		All cases (N=74)	Present (N=46)	Absent (N=28)	P-value
Age of onset (years), Mean±SD		8.0±3.2	8.7±3.0	6.8±3.2	^0.015*
Duration (years), Mean±SD		6.3±3.0	6.7±3.2	5.6±2.4	^0.110
Insulin dose (unit/kg/ day) Mean±SD		1.1±0.4	1.1±0.4	1.1±0.3	^0.520
History of DKA (n, %)		70 (94.6%)	45 (97.8%)	25 (89.3%)	§0.149
DKA frequency (attack/duration), Mean±SD		0.7±0.6	0.7±0.5	0.6±0.6	^0.458
Complications, (n, %)	total cases with complications	48 (64.9%)	35 (76.1%)	13 (46.4%)	#0.010*
	Lipodystrophy	25 (33.8%)	20 (43.5%)	5 (17.9%)	#0.024*
	Joint affection	25 (33.8%)	19 (41.3%)	6 (21.4%)	#0.080
	Neuropathy	22 (29.7%)	18 (39.1%)	4 (14.3%)	#0.023*
	Nephropathy	7 (9.5%)	6 (13.0%)	1 (3.6%)	§0.242
Symptoms of liver affection, (n, %)	Total cases with symptoms	51 (68.9%)	37 (80.4%)	14 (50.0%)	#0.006*
	Abdominal pain	45 (60.8%)	33 (71.7%)	12 (42.9%)	#0.014*
	Nausea	30 (40.5%)	24 (52.2%)	6 (21.4%)	#0.009*
	Vomiting	24 (32.4%)	19 (41.3%)	5 (17.9%)	#0.037*
	Pruritis	10 (13.5%)	7 (15.2%)	3 (10.7%)	§0.733
	Jaundice	0 (0.0%)	0 (0.0%)	0 (0.0%)	Not applicable

^Independent t-test. #Chi square test. §Fishers Exact test. *Significant (<0.050)

- According to the results of abdominal ultrasound, out of the 74 diabetic children; 46 (62.2 %) had fatty liver (NAFLD) and the rest of them; 28 (37.8%) had normal liver. According to these U/S findings cases were divided into two groups; patients with NAFLD and patients with normal liver then they were compared together.

- This comparison revealed statistically significant difference in age (P< 0.001), the NAFLD group patients were older in age than patients with normal liver (15.4±2.3 vs. 12.4±3.1). Regarding patients gender the number of females (63%) in cases with NAFLD was significantly more than those (28.6%) in the group without NAFLD (p < 0.05) as shown in table (1).

- Concerning the age of onset of diabetes; it was significantly older in cases with NAFLD as compared to cases with normal liver (8.7±3.0 vs. 6.8±3.2) with (p < 0.05). Moreover, cases with NAFLD had significantly more frequent diabetic complications than cases with normal liver (76.1% vs. 46.4%) with (p < 0.05), including; Lipodystrophy & Neuropathy (p < 0.05) for both. Additionally, cases with liver symptoms were significantly greater in NAFLD patients than those among normal liver group (80.4% vs. 50.0%) with (p < 0.05) especially cases with Abdominal pain (71.7% vs. 42.9%) , Nausea (52.2% vs. 21.4%) and Vomiting (41.3% vs. 17.9%) with (p < 0.05) for all. These data are demonstrated in table (2).

- Regarding the anthropometric characteristics; The mean BMI - Z scores ± SD of patients with fatty liver was 0.45±0.77, no patients with fatty liver were wasted while 29 (63%) of them had normal BMI. Among the 28 cases with normal liver U/S, 2 (7.1%) were malnourished (BMI-Z scores ≤ -2.0) while 18 (64.3%) of them had normal BMI (BMI –Z score = 0.0).

- Cases with fatty liver as compared to cases with normal liver significantly had higher mean BMI-Z score, (p = 0.001). There was significant difference in proportions of patients according to different BMI –Z scores grades between NAFLD cases and those with normal liver (p = 0.003) with more frequent BMI Z-score grade = +1.0 (32.6% vs. 7.1%) (p < 0.05). On the other hand, waist/ hip ratio &waist/height ratiowere significantly increased in the NAFLD patients (p = 0.001) who also had significantly higher sum ofskin fold thicknesses than the normal liver group (p < 0.001), table (3).

Table (3): Blood pressure and Anthropometric measurements among the studied cases and comparison according to NAFLD presence

Variables		Total cases (N=74)	NAFLD		P-value
Variables		Total cases (N=74)	Present (N=46)	Absent (N=28)	P-value
SBP (mmHg), Mean±SD		109.9±8.4	109.3±7.4	110.7±9.8	^0.499
DBP (mmHg), Mean±SD		73.2±5.1	73.0±5.1	73.4±5.1	^0.776
BMI Z-score, Mean±SD		0.16±0.95	0.45±0.77	-0.31±1.04	^0.001*
BMI Z-score grades	≤ -2.0	2 (2.7%)	0 (0.0%)	2 (7.1%)	#0.003*
	-1.0	10 (13.5%)	2 (4.3%)	8 (28.6%)
	± 0.0	47 (63.5%)	29 (63.0%)	18 (64.3%)
	+1.0	17 (23.0%)	15 (32.6%)	2 (7.1%)
	≥+2.0	0 (0.0%)	0 (0.0%)	0 (0.0%)
Waist-hip ratio, Mean±SD		0.85±0.06	0.87±0.06	0.82±0.05	^0.001*
Waist-height ratio, Mean±SD		0.46±0.07	0.48±0.07	0.43±0.07	^0.001*
Sum of SFT (mm), Mean±SD		46.3±17.7	53.8±16.4	34.0±12.2	^<0.001*

^Independent t-test. #Chi square test. §Fishers Exact test. *Significant, SBP;systolic blood pressure, DBP; diastolic blood pressure, BMI; body mass index, SFT; skinfold thickness.

- The Laboratory findings were as follows:

- Considering the CBC findings; cases with fatty liver significantly had lower Hemoglobin, RBC count, Hematocrit value compared to cases with normal liver (p = 0.003, 0.037 & 0.005) respectively, while no significant difference between the two groups in the other blood parameters was detected (p > 0.05).

- Regarding the lipid profile, the mean serum concentrations of total cholesterol, triglyceride, and LDL were statistically significantly higher in the NAFLD group compared to the other group (p < 0.001, p = 0.019, p = 0.001, respectively). Nevertheless, HDL serum levels were significantly lower in NAFLD cases (p = 0.001).

- Comparing the glycemic control; FBG levels were significantly higher among the NAFLD group of patients (p = 0.007). While HbA1c % levels measured at the time of the study and themean HbA1c % levels during the last year, a statistically significant difference among the two groups was found (p= 0.001 & 0.003 respectively) being higher in the NAFLD group. The number of cases with HbA1c % levels & means > 10 % measured at the time of the study and during the last year was significantly higher in the NAFLD group (p = 0.014 & 0.002) respectively.

- With respect to the liver enzymes, serum levels of AST & ALTwere significantly higher in NAFLD cases compared to normal liver group (p = 0.019 & 0.015). We considered the level of AST > 35 IU/l was considered abnormal in males and > 31 U/l in females; & ALT > 45 U/l was considered abnormal in males and > 34 U/l in females; 25 IU/l as abnormal in boys and > 22 IU/l in girls; it was detected that the number of cases with elevated AST serum levels was significantly increased in NAFLD patients compared to cases with normal liver ( 19.6% vs. 0.0 %) with ( p = 0.011) while no significant difference was found regarding the number of patients with elevated ALT ( p = 0.285). These findings are shown in table (4).

Table (4): Laboratory findings among the studied cases and comparison according to presence of NAFLD

Variables	Total cases (N=74)	NAFLD		P-value
Variables	Total cases (N=74)	Present (N=46)	Absent (N=28)	P-value
Hemoglobin	13.1±1.4	12.8±1.3	13.7±1.2	^0.003*
RBCs	4.8±0.5	4.7±0.5	4.9±0.4	^0.037*
Hematocrit	38.8±4.1	37.7±4.1	40.5±3.6	^0.005*
MCHC	33.9±0.9	33.9±1.1	34.0±0.5	^0.627
TLC	12.3±5.6	12.0±6.0	12.9±5.0	^0.533
Platelets	354.4±84.9	364.7±86.5	337.5±81.1	^0.184
Cholesterol	148.3±43.2	161.7±45.2	126.4±28.8	^<0.001*
Triglycerides	117.1±74.8	132.9±88.8	91.1±29.6	^0.019*
HDL	52.6±8.6	50.2±7.1	56.7±9.4	^0.001*
LDL	71.1±31.3	80.7±33.4	55.5±19.5	^0.001*
FBG	216.2±75.6	234.5±76.8	186.1±64.1	^0.007*
HbA1c	10.3±2.0	10.9±1.7	9.3±2.0	^0.001*
No. of cases with HbA1c≥10.0	40 (54.1%)	30 (65.2%)	10 (35.7%)	#0.014*
Mean HbA1c / y	10.7±2.0	11.2±1.9	9.9±1.8	^0.003*
No. of cases with mean HbA1c ≥10.0 /y	50 (67.6%)	37 (80.4%)	13 (46.4%)	#0.002*
AST	25.5±18.8	29.5±22.6	19.0±6.1	^0.019*
No. of cases with elevated AST	9 (12.2%)	9 (19.6%)	0 (0.0%)	§0.011*
ALT	14.4±8.5	16.2±10.1	11.3±3.2	^0.015*
No. of cases with elevated ALT	3 (4.1%)	3 (6.5%)	0 (0.0%)	§0.285

^Independent t-test. #Chi square test. §Fishers Exact test. *Significant

- In the context of evaluation of liver fibrosis; Table (5) shows different stages of fibrosis detected by ARFI elastography in comparison to NAFLD diagnosed by hepatic U/S. The majority of type1 diabetic patients had stage 1 (45.9 %), a few had stage 2 (7%) or 3 (5.4%), and one case (1.4%) had stage 4 fibrosis. The proportions of cases with liver Fibrosis detected by ARFI ranging from F2-F4 were significantly more in fatty liver cases than normal liver cases detected by U/S, while the proportion of cases with normal liver (F0) detected by ARFI was significantly higher in cases with U/S normal liver (53.6% vs. 28.3%).

Table (5) Different stages of fibrosis diagnosed by (ARFI) compared to NAFLD diagnosed by abdominal ultrasonography.

Fibrosis by ARFI	All cases (N=74)	NAFLD by US Present (N=46)	NAFLD by US Absent (N=28)	P-value
F0	28 (37.8%)	13 (28.3%)	15 (53.6%)	§0.021*
F1	34 (45.9%)	21 (45.7%)	13 (46.4%)
F2	7 (9.5%)	7 (15.2%)	0 (0.0%)
F3	4 (5.4%)	4 (8.7%)	0 (0.0%)
F4	1 (1.4%)	1 (2.1%)	0 (0.0%)

§Fisher’s Exact test. *Significant (p < 0.05)

- We investigated the factors associated with occurrence of Fatty liver in type 1 diabetic children and adolescents using Logistic regression models and the BMI-Z score ≥ +1.0 and Age ≥ 15 years were significant factors that increased the risk of fatty liver occurrence (p = 0.034 & 0.002) with CI (1.140 – 26.204 & 1.657−9.598) respectively. While being a male was a significant protective factor (p = 0.020) as shown in table (6).

Table (6) Logistic regression models for factors associated with Fatty liver in T1DM children and adolescents

Factors	Β	SE	P	OR (95% CI)
BMI - Z score ≥+1.0	1.699	0.800	0.034*	5.466 (1.140−26.204)
Age ≥ 15 years	1.383	0.448	0.002*	3.988 (1.657−9.598)
Male sex	-0.984	0.422	0.020*	.164−0.854)

β: Regression coefficient, SE: Standard error, OR: Odds ratio, CI: Confidence interval

NAFLD is not common in children below the age 8 years, it usually presents around the age of 12 y [25] and based on the definition of Pediatric NAFLD as chronic hepatic steatosis in children i.e. ≤ 18 years [26]. So the age of our cases was defined as (8–18) y.

The definition of NAFLD necessitates the confirmation of hepatic steatosis, whether by imaging or by histology, with absence of other reasons for secondary fat infiltration of the liver namely; excessive alcohol consumption, administration of drugs inducing steatosis or genetic diseases [25].

In the present study, cases with other causes of chronic liver diseases (hepatic steatosis) such as Wilson disease, Mauriac syndrome, previous infection with viral hepatitis A, B, or C, autoimmune hepatitis, drug-induced hepatitis (e.g. corticosteroids, valproate and antivirals), hereditary diseases, or any additional causes of chronic hepatic diseases were not included from the start of the research as required by international associations for diagnosis of NAFLD [26]; by thorough history taking & laboratory investigations including Anti smooth muscle antibodies ASMA, Anti-nuclear antibody ANA and anti-liver and kidney microsomal antibodies LKM, HBVs Ag & HCV Ab. After exclusion, 74 were included in the study.

We conducted this prospective cross-sectional observational study which aimed to examine 74 T1DM children and adolescents with mean age 14.3 ± 3.0 (8 − 18) years, where 37 (50%) were males.

Whereas, Farhan et al., conducted a study to evaluate fatty liver in fifty T1DM children where 30 (60%) were females with mean age 10.5 ± 4.011 (3–18) years [9].

On the other hand, Ismail et al., demonstrated that of the total 119 participants enrolled in their study 36.6% were boys, and 63.4% were girls aged (6–18) years [27].

In the present study, the mean insulin dose among the total participants was 1.1 ± 0.4 U/kg, and the mean disease duration was 6.3 ± 3.0 years. 94.6% of our cases had history of previous DKA attacks, 64.9% had symptoms of diabetic complications and 68.9% had symptoms of liver affection.

While, Ismail et al., demonstrated that the mean insulin dose/kg/day of the total cases was 1.28 ± 0.63, and the mean duration of diabetes was 5.52 ± 3.23 years [27].

Poor glycemic control was detected in 67.6% of the total included patients in this study; had mean HbA1C > 10% during the last year in comparison to 24% in El-Karaksy et al. study, 61.3% in Al-Hussaini et al. study while (% 64) were reported in Farhan et al., [28, 29, 9].

The mean HbA1c% of our total studied patients at the time of the study was 10.3 ± 2.0 which is more than that detected by Barros et al., which was 8.6% in their study [30]. As a marker of longitudinal metabolic control, it implies general poor metabolic control in our cohort.

The ‘‘gold standard’’ for diagnosis of NAFLD is Liver biopsy. Nonetheless, it is invasive and has the possibility of complications [31]. Ultrasound is the preferred first-choice imaging method in clinical management [10].

Thus in the present study diagnosis of NAFLD was based on abdominal ultrasonographic findings. Our results revealed that among the 74 patients; 46 (62.2%) cases had NAFLD as diagnosed by abdominal ultra sound (US).

According to the results of U/S our study cases were further subdivided into two groups; patients with NAFLD and patients with normal liver; then they were compared together.

Concerning the demographic characteristics, statistically significant difference in age was found (p = 0.015), the NAFLD group patients were older in age than patients with normal liver. (8.7 ± 3.0 vs. 6.8 ± 3.2) y. This disagrees with Barros et al., who found no statistical significant difference in age between the group with altered US liver findings and those with normal liver (p = 0.459) [30].

Regarding patients gender the number of females (63%) in the NAFLD patients was significantly more than those (28.6%) in the group with normal hepatic US. On the other hand the percent of females (63%) with NFLD was more than males (37%) in the same group. While in Farhan et al., study; patients with fatty liver (69.2%) of them were females and in El-Karaksy et al., the female to male ratio was equal. Whereas in Barros et al., study, the female gender represented 75% of the NAFLD group vs. 55.4% in the normal liver group but this was not statistically significant [9, 28, 30].

Moreover, coherent with our results, Samuelsson et al., in their large population study; exihibited a sex difference; girls had poorer metabolic control, i.e., elevated HbA1c concentrations [32]. This could be because girls have poorer metabolic control over the period of adolescence than boys. The variations in hormones might be the influencers among the two genders during this period. Various researches have confirmed that both insulin doses and HbA1c levels were significantly elevated in girls [33, 34].

In the current study, the age of onset of diabetes in cases with NAFLD was significantly higher than in the normal liver patients (P < 0.05). While the duration of diabetes was more in NAFLD cases 6.7 ± 3.2 y vs. 5.6 ± 2.4 in normal liver cases; but this was not statistically significant (p = 0.11).

While in Farahan et al., study, the duration of diabetes in patients with fatty liver was (5.6 ± 3.4) y & in patients with normal liver it was (5.2 ± 3.8). There wasn’t statistical significance correlation with the U/S results; concerning the duration of diabetes which coincides with our findings [9].

In the current study there was no significant difference regarding the insulin dose/ kg/ day between NAFLD cases & those with normal liver (1.1 ± 0.4 vs. 1.1 ± 0.3 U/Kg/Day) (p = 0.520) which in concordance with the results of Barros et al., [30].

On the other hand, this study revealed that, cases with NAFLD had significantly more frequent symptoms of diabetes complications (76.1%).

The NAFLD onset is insidious [35]. Clinically, the majority of children with NAFLD/NASH have general symptoms. A number of them suffer of lethargy, malaise, or ambiguous pain in the abdomen (42%-59%) of cases, particularly in the right upper quadrant, which has been accompanying the further advanced form of NASH [36]. In comparison to this, our study showed that 71.7% of NAFLD patients were complaining of abdominal pain.

NAFLD is accompanied with a myriad of significant co-morbidities, comprising obesity, dyslipidemia, hyperglycemia, and hypertension [37].

However, in the context of Blood pressure only one of our patients had systolic hypertension (150/80) while the difference was insignificant in blood pressure between the two studied groups; whether systolic or diastolic (p = 0.499 & 0.776). This agrees with the results of Barros et al., [30].

In examination of children, body mass index (BMI) is one of the most frequently used indicators in evaluation of obesity and undernourishment [38]. The waist-hip ratio (WHR) permits defining the kind of body contour and site of fat accumulation. Waist to height ratio (WHtR) is used to evaluate the dissemination of abdominal adiposity. In pediatric population with abdominal obesity and an amplified risk of metabolic syndrome, the index value is > 0.5 irrespective of sex [39].

Evaluation of anthropometric measures in diabetic children and adolescents must be done regularly. Approaches for nutritional evaluation are harmless and non-invasive, and the study outcomes may be used by clinicians in individuals with diabetes, assisting in monitoring their metabolic control, that affects the appropriate physical growth of children. Therefore, adjusting the nutritional state is of great importance as a whole, and not only stature and weight individually [34].

In this aspect, the anthropometric assessment in the present study revealed that, cases with NAFLD had higher BMI Z scores, waist / hip, waist/ height and sum of skinfold thicknesses than those with normal liver and the difference was statistically significant (p < 0.05). This is in contrast to the findings of Barros et al., [30].

Moreover, our results revealed that cases with NAFLD had more frequent BMI Z-score grade = + 1.0 (32.6% vs. 7.1%). While, 63% of NAFLD cases had normal mean BMI (Z-score = 0) vs. 64.3% of cases with normal liver. None of our patients had obesity (BMI Z score ≥ + 2.0). On the other hand, in the NAFLD group no cases with malnutrition were detected, whereas, 2 cases (7.1%) with normal liver had malnutrition (BMI Z score ≤ -2.0).

In contrast to our results, Farhan et al., in their study reported; (61.5%) of children with fatty liver had malnutrition while (38.5%) of those children were normal in BMI, in children having normal hepatic findings, (67.6%) were undernourished though (32.4%) had normal BMI [9].

Considering the laboratory findings in our study, comparison between the two groups revealed significant difference in some blood parameters namely, Hb%, RBCs, and hematocrit value while the other CBC parameters didn’t show significant difference.

This is on the contrary to the findings of Farhan et al., which revealed significant difference in platelets count being lesser in patients with fatty liver (P-=0.007), our study detected no significant difference in platelet count between NAFLD and normal liver patients (p = 0.184) [9].

On the other hand, Ismail et al., proved that Platelet count was significantly higher in NAFLD patients [27]. Several ultrasoundbased researches reported this with progression of steatosis [40, 41]. Our study couldn’t detect that.

Increased blood glucose and disorders in lipid metabolism are usually detected in T1DM pediatric patients which predispose them to hazards of CVD. In cases with improper blood glucose control, serum triglycerides and low density lipoproteins values are commonly raised [42].

Regarding the lipid profile, our study revealed that patients with NAFLD showed significantly more serum lipid levels (cholesterol, triglyceride and LDL) (p = 0.001, 0.019 & 0.001) respectively, while there was significant decrease in HDL (p = 0.001), which emphasize that T1DM individuals having NAFLD are highly predisposed to risk of CVD. This agrees with the findings of previous studies [9, 43, 27].

In acceptance with our results, the findings of Barros et al., showed that cases with altered hepatic US findings had significant elevated triglyceride values and lesser HDL than normal liver patients (p = 0.028 & 0.034) respectively. However, Barros et al., in their study; found that there was no significant difference regarding total cholesterol & LDL levels between cases with Abnormal hepatic US findings & normal liver group; both being lower in the 1st group [30]. This is opposite to our results.

Oscillations in blood glucose and insulin levels are significant factors in hepatic steatosis associated with type1 diabetes. HbA1c is a good indicator of metabolic control [44]. Proper metabolic control is necessary not only for adequate growth and development in diabetic children & adolescents, but also for reduction and delay of advancement of present complications [45].

Considering mean HbA1c % levels during the last year in the current study, the mean level of HbA1C of NAFLD patients enrolled in this study was (11.2%±1.9) while for those with normal ultrasound findings it was (9.9%±1.8) with significant difference (P = 0.003) being higher in the NAFLD group. The number of patients with poor glycemic control as indicated by HbA1c% >10 was also significantly higher in the NAFLD group.

Parallel to this is the study of Farhan et al., who reported mean value of HbA1C of diabetic patients with fatty liver (10.69 ± 1.41) whereas in normal U/S cases it was (8.24 ± 2.04) with significant difference (P = 0.021) [9]. However, in El-Karaksy et al. study, the mean value of HbA1C in T1D children having liver affection was (8.1 ± 1.2) while for patients with normal liver was (7.6 ± 1.7) with insignificant difference (P = 0.05) [28].

Additionally, in Ismail et al., study, a statistically significant difference in HbA1c % mean levels, among the studied groups (p < 0.001) being higher in the NAFLD group with mean level = 8.41% ±0.8 [27]. This shows that NAFLD children in our study had more improper glycemic control than the previous studies.

Even though assessment of ALT serum level is usually done as a measure of liver functions, its significance is debatable [46]. The dependence on normal liver enzymes is one of the main causes for missing the diagnosis of NAFLD by general practitioner and diabetologists [47].

In this regards, the current study revealed that AST & ALT were statistically significantly higher in patients with NAFLD (P = 0.019 & 0.015). AST > 35 IU/l was considered abnormal in boys and > 31 U/l in girls; 9 patients only had high level (12.2% of the total cases and they represented only 19.6% of the NAFLD cases). On the other hand ALT > 45 U/l was considered abnormal in boys and > 34 U/l in girls; only 3 patients had increased level (4.1% of the total number of cases and they represented only 6.5% of the NAFLD cases) this agrees with the opinion that normal liver enzymes do not exclude fatty liver [48], and further suggests that serum liver enzymes are good indicators for NAFLD diagnosis, however, ‘‘normal’’ standard levels used for exclusion of NAFLD are needed to be reviewed.

Farhan et al., declared that, there was significant difference of AST level among fatty liver children and cases who don’t have; being elevated in cases with fatty liver (P-value = 0.001) meanwhile, insignificant difference was present concerning ALT levels [9].

However, Ismail et al., in their study found that the mean serum ALT level of the NAFLD cases was at a high normal level & only three female patients had mildly elevated ALT level [27]. In addition, several researches demonstrated that the complete histological picture of NAFLD may be detected in patients with normal ALT levels [49, 50].

In Barros et al., study, there was no significant difference in serum levels of ALT & AST between cases with altered US liver findings and cases with normal liver, with both serum levels being with in normal range in the abnormal hepatic US findings group [30]. Moreover, Singh et al., reported that, in spite of the increased prevalence of NAFLD detected by Hepatic Steatosis Index, the AST and ALT mean levels were normal in their study [12].

Diabetic individuals with NAFLD are highly prone to progress into more severe stage of NAFLD which can lead to liver cirrhosis and finally liver failure [10]. Diabetes had been detected as an independent risk factor for hepatic fibrosis [50].

Ultrasound can assess increase in liver size or diffuse increase in hepatic parenchyma echogenicity however it can’t detect fibrosis. ARFI elastography has the privilege that it is not an invasive technique to evaluate liver fibrosis [27].

Our results support these findings as different stages of liver fibrosis diagnosed by ARFI Fibro-Scan compared to abdominal ultrasonography findings were revealed. Most of our studied type1 diabetic children & adolescents were having grade one fibrosis (n = 34), a few were with grade 2 (n = 7) or 3 (n = 4), & only 1 patient was having grade 4 fibrosis while 28 patients had F0 stage i.e. no fibrosis.

There was a significant difference between proportions in liver affection using ARFI and those diagnosed by US. From the NAFLD free cases diagnosed by US there was liver stiffness (fibrosis) stage F1 in 13 cases (46.4%) indicating that ARFI can detect liver affection more accurately than US.

Moreover, the number of cases with liver Fibrosis detected by ARFI ranging from F2-F4 were significantly higher among cases with fatty liver compared to cases without fatty liver detected by US (p = 0.021). There was a significant difference between proportions in liver affection using ARFI and those diagnosed by US. 53.6% of the NAFLD free cases diagnosed by US had no fibrosis (F0), while no cases with F2, 3 & 4 were detected in this group. Meanwhile, in NAFLD cases, 28.3% had no fibrosis (F0) and only 26% had intermediate and severe form of fibrosis (F2, F3 & F4).

Ismail et al., in their study; stated that, ARFI elastography classification of fibrosis exhibited that 4 children (8.0%) were having liver fibrosis stage 3 and 4 [27]. While in our study; 10.8% of NAFLD cases had stage 3 & 4 liver fibrosis.

Our results disagree with the results of Farhan et al., who stated that there was (73.0%) without fibrosis (F0—F2) in cases with no hepatomegaly and (77%) of NAFLD cases were having intermediate fibrosis and severe fibrosis that encompassed (F2-F3, F3-F4) (P = 0.0001) [9]. However these results were obtained by calculating the NAFLD fibrosis score and not by fibroscan.

Furthermore, a research done by Singh et al., examining 4899 T1D patients aged 18–80 y with suspected NAFLD; showed a prevalence of advanced fibrosis of 22.1% using AST/ALT > 1.4, demonstrating increased risk to develop progressive hepatic affection and its associated complications [12].

In addition, the findings of Barros et al., showed that of the total participants (8.4%) had significant fibrosis (> F2). Whereas, F2 cases were 3.1%, F3 was present in 3.1% & F4 was present in 2.1% as detected by transient elastography (TE) [30].

Multivariate logistic regression was applied to assess risk factors associated with occurrence of NAFLD; BMI-Z score ≥ + 1.0 and Age ≥ 15 years were detected as significant factors associated with increased risk of fatty liver development. While being a male was a significant protective factor.

In Barros et al., study; multivariable logistic regression assessing associated factors with fatty liver using both imaging technique; Gender, age and HbA1c were not associated to steatosis. This is contradicting to our results where we found gender & age as associated risk factors for NAFLD occurrence. However, Barros et al., study revealed that triglycerides were the only risk factor for fatty liver [30]. This could not be detected in our study.

Limitations Of The Study:

Our study has some limitations. First, we diagnosed NAFLD based on ultrasound which is operator-dependent and has a limited sensitivity. Second, ARFI fibroscan; the second technique we used, is not commonly used as first- choice investigation for diagnosis of fatty liver. Thirdly, we did not have histological confirmation of our findings as the gold-standard method; liver biopsy, is invasive and prone to sample mistakes. Another limitation was the small sample size of the study.

As strengths in our study; NAFLD was diagnosed using two methods in this sample of type1 diabetic patients while most of NAFLD studies in type1diabetes used ultrasonography only. In addition, to the best of our knowledge, little previous studies were performed to diagnose steatosis and assess hepatic fibrosis in type1 diabetes children thus this data are represented for Egyptian children.

NAFLD is highly detected among children with type1 diabetes especially in those with poor glycemic control. Despite the NAFLD diagnosis using US, the mean AST and ALT serum levels were within normal range, demonstrating that the traditional clinical determinations of simple steatosis and NASH, based on normal or abnormal liver enzymes values, are unsuitable as they do not exclude fatty liver. NAFLD has the potential to evolve to fibrosis. Ultrasound can detect hepatomegaly and diffuse increase in hepatic parenchyma echogenicity but not fibrosis. ARFI fibro-scan assessment of liver fibrosis in T1DM patients with NAFLD detected the presence of significant fibrosis. BMI, age of patients and female gender were among the risk factors associated with NAFLD. Further prospective studies with larger number of patients are recommended.

ALT Alanine Transaminase
Anti-smooth Muscle Antibodies ASMA
Anti-Liver and Kidney LKM
Microsomal antibodies
Anti-Nuclear Antibodies ANA
ARFI Acoustic Radiation Force Impulse
AST Aspartate Transaminase
BMI Body Mass Index
BP Blood Pressure
CBC Complete blood Count
CVD cardiovascular Disease
DBP Diastolic Blood Pressure
FBG Fasting Blood Glucose
Hb Haemoglobin
HbA1c Glycosylated Haemoglobin
HBVs Ag Hepatitis B Virus Surface Antigen
HCV Ab Hepatitis C Virus Antibodies
HDL High Density Lipoproteins
IDF International Diabetes Federation
ISPAD International Society for Paediatric and Adolescent Diabetes
K Korotkoff sound
LDL low Density Lipoproteins
MCHC Mean Corpuscular Haemoglobin Cocentration
NAFLD Non-Alcoholic Fatty Liver
NASH Non-Alcoholic Steato-Hepatitis
RBCs Red Blood Cells
ROI Region Of Interest
SBP Systolic Blood Pressure
SD Standard Deviation
SKF Skinfold Thickness
SPSS Statistical Package for Social Sciences
T1DM Type1 Diabetes Mellitus
TE Transient Elastography
TLC Total Leucocytic Count
U/S Ultrasound
Vs Versus
WHO World Health Organization
WHR Waist to Hip ratio
WHtR Waist to Height Ratio

Ethics declarations

Ethics approval and consent to participate

Ethical approval was obtained from the Medical Research Ethics Committee of National Research Centre (no: 19/240) according to the “World Medical Association Declaration of Helsinki” in 1995 (as revised in Seoul 2008). Written informed consent was obtained from parents of the children enrolled in the study.

Consent for publication

Not applicable

Availability of data and materials

The datasets used and/or analyzed during this study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

This study was completely funded by the National Research Centre, Egypt. The funder did not interfere in the design of the study and collection, analysis and interpretation of data or in writing the manuscript.

Authors’ contributions

HR: conceptualization and design of the study, anthropometric measures of patients, collecting and entering data, literature search, writing the original draft, preparation, and editing of the final manuscript. ER: methodology: Laboratory investigations. MM: clinical examination of patients, collecting daata MW: clinical examination of patients, collecting data. WM: Methodology; performing Abdominal Ultrasound & ARFI elastography. YE: Methodology; performing Abdominal Ultrasound & ARFI elastography. HH: statistical analysis of data and interpretation and writing the results. MA: clinical examination of patients & collecting data. HR: clinical examination of patients & collecting data.. RE: clinical examination of patients & collecting data. The authors read and approved the final manuscript.

Acknowledgements:

We thank the National Research Centre of Egypt who was the funding sponsor of this study. We also thank the all patients included in the study. We also thank Dr. Yara Hesham Elmeligy; the resident of internal Medicine in the National Institute of Diabetes & Endocrinology, Cairo, Egypt for her assistance.

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No competing interests reported.

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28 Oct, 2022

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Clinical and Diagnostic characteristics of Non-Alcoholic Fatty Liver Disease among Egyptian children and adolescents with type1 diabetes

Status:

Journal Publication

Version 1

Abstract

Background

Methods

Results

Conclusions

Background

Methods

Results

Discussion

Limitations Of The Study:

Conclusions

Abbreviations

Declarations

References

Additional Declarations

Status:

Journal Publication

Version 1