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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 7  |  Issue : 1  |  Page : 14-23

Nonalcoholic fatty liver disease in prediabetes – Predisposing and protective factors


Department of Medicine, Father Muller Medical College, Mangalore, Karnataka, India

Date of Submission25-Sep-2020
Date of Decision21-Nov-2020
Date of Acceptance25-Nov-2020
Date of Web Publication02-Jul-2021

Correspondence Address:
Smitha Bhat
Department of Medicine, Father Muller Medical College, Mangalore - 575 002, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrsm.jcrsm_64_20

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  Abstract 


Introduction: Nonalcoholic fatty liver disease (NAFLD) is increasing worldwide with a prevalence ranging from 5% to 28% in India. It is a common cause of chronic liver disease and can lead to complications including cirrhosis and portal hypertension. NAFLD and insulin-resistant states such as obesity, type 2 diabetes, and prediabetes are interlinked. We studied the role of diet, dyslipidemia, and glycemia in the genesis of NAFLD in patients with prediabetes.
Methods: This case–control study was done in 86 prediabetic subjects availing the services of a medical college hospital. Cases of NAFLD were diagnosed and categorized by severity by ultrasonogram. Symptoms, demographic profile, dietary history by 24 h recall method, anthropometry, liver function tests, lipid profile, and blood glucose were recorded.
Results: Cases of NAFLD were found to have higher fat consumption and lower carbohydrate and protein in their diet. Fatigue and right hypochondriac pain were common symptoms among the cases, and their mean body mass index (27.2 kg/m2) was higher. When compared with prediabetic controls, cases of NAFLD had higher mean systolic and diastolic blood pressures, as well as impaired lipid profile and postprandial hyperglycemia.
Conclusion: Obesity, dyslipidemia, and specific dietary patterns predispose patients with prediabetes to develop NAFLD. Additionally, postprandial hyperglycemia is associated with NAFLD. Thus, targeting postprandial hyperglycemia in patients with prediabetes may retard the development of NAFLD.

Keywords: Diet, dyslipidemia, glycemic control, nonalcoholic fatty liver disease, obesity, prediabetes


How to cite this article:
Miranda J, Bhat S. Nonalcoholic fatty liver disease in prediabetes – Predisposing and protective factors. J Curr Res Sci Med 2021;7:14-23

How to cite this URL:
Miranda J, Bhat S. Nonalcoholic fatty liver disease in prediabetes – Predisposing and protective factors. J Curr Res Sci Med [serial online] 2021 [cited 2021 Nov 27];7:14-23. Available from: https://www.jcrsmed.org/text.asp?2021/7/1/14/320506




  Introduction Top


Nonalcoholic fatty liver disease (NAFLD) is emerging as an important cause of chronic liver disease in India, with a prevalence ranging from 9% to 32%.[1] It is more common in obese individuals and those with diabetes.[2] NAFLD can progress from steatosis to steatohepatitis and finally to cirrhosis. Detection at an early stage can help in preventing the progression of NAFLD to more severe forms.[2]

NAFLD is said to be the hepatic manifestation of metabolic syndrome and is thus strongly associated with the presence of Type 2 diabetes mellitus (T2DM).[3] However, the association between NAFLD and prediabetes is less clear, though some research shows progressive hepatic fibrosis in prediabetes as well.[4] Insulin resistance was common in patients of NAFLD. A study showed that NAFLD was associated not only with T2DM but also with prediabetes.[5] Whether NAFLD is a cause or consequence of diabetes still remains a matter of debate.

Dietary intervention plays a major role in the management of prediabetes and diabetes mellitus. Because insulin resistance and oxidative stress are implicated in the pathogenesis of NAFLD, a low carbohydrate, antioxidant-rich diet may conceivably reduce the risk of NAFLD as well.[6] The relation between NAFLD and diet has been studied. A low glycemic index, low saturated fat, high fiber, high mono-unsaturated fatty acid diet has been found to be beneficial in patients with NAFLD.[7] In contrast to this, it was shown that patients consuming a carbohydrate-rich and low fat diet had a higher degree of hepatic inflammation, suggesting an insulin resistance mediated link between diet and liver injury.[8]

Although the predisposing factors for patients with diabetes to develop NAFLD have been studied, Indian data regarding the influence of dietary factors in the development of NAFLD in patients with prediabetes are scanty. We aimed to find the predisposing factors for patients with prediabetes to develop NAFLD.

Objectives of the study

  1. To find if an association exists between diet and NAFLD in subjects with prediabetes


  2. To find if an association exists between specific biochemical parameters and NAFLD in subjects with prediabetes.



  Materials and Methods Top


This study was a case–control study conducted on patients with prediabetes availing the outpatient and inpatient services of a medical college hospital in South India. It was conducted for a period of seventeen months after ethical clearance was obtained from the Institutional Ethical Committee. Written informed consent was obtained from the 86 subjects who satisfied the inclusion and exclusion criteria; 43 subjects with prediabetes and NAFLD were taken as cases and 43 with prediabetes without NAFLD were taken as controls.

Inclusion criteria

  1. Subjects in the age group of 18–65 years with impaired fasting glucose or impaired glucose tolerance or hemoglobin A1c (HbA1c) between 5.6 and 6.4% and NAFLD as defined by sonographic criteria were recruited as cases
  2. Subjects with prediabetes and without NAFLD were recruited as controls.


Exclusion criteria

  1. Pregnancy
  2. Known cases of hepatitis B and C
  3. Alcohol consumption(>20 g/day in females and 30 g/day in males)
  4. Intake of steroids, tamoxifen, amiodarone, antitubercular therapy, valproic acid, methotrexate, and other known hepatotoxic drugs
  5. Known cases of diabetes mellitus on treatment
  6. Patients previously diagnosed to have chronic liver disease.


The subjects were interviewed and examined, and data were entered as per proforma. Diet history was obtained using 24 h recall method, and calorie and nutrient intake was measured using standard nutritive values of Indian foods. Height, body weight, waist circumference, and waist-to-hip ratio were measured using standard methods. Body mass index (BMI) was calculated as weight divided by height (in meters) squared (kg/m2). Waist circumference was measured as the smallest girth between the costal cartilage and the iliac crests at minimal inspiration. Two measurements were taken and the mean of the two was taken as the waist circumference. Acanthosis nigricans and skin tags were taken as markers of insulin resistance. Asian guidelines were used to define obesity (overweight-BMI >23); at risk for obesity (BMI 23–24.9); obesity Grade I (BMI 25–29.9) and obesity Grade II (BMI >30). Blood pressure (BP) was measured in the right arm in the supine position to the nearest 2 mmHg using a diamond sphygmomanometer with a standard adult cuff. Hypertension was diagnosed using the 8th report of the Joint National Committee on prevention, detection, evaluation, and treatment of high BP in adults. Fasting and postprandial blood sugar (PPBS) levels were measured using the spectrophotometric method, with Cobas e501. HbA1c was measured using the immuno-turbidometric method with Cobas e601, and patients diagnosed as prediabetes according to the American Diabetes Association (ADA) 2015 guidelines. Subjects underwent a transabdominal ultrasound using a 3–5 MHz frequency curvilinear probe (C5-1 Philips IU22) to define liver echotexture. Sonogram was performed by a radiologist who was masked to all clinical and biochemical characteristics of the subjects.

NAFLD, if the present was classified according to severity based on standard criteria:[9]

  1. Grade 1 (mild steatosis) – Defined as slightly increased liver echogenicity with normal vessels and absent posterior attenuation
  2. Grade 2 (moderate steatosis) – Defined as moderately increased liver echogenicity with partial dimming of vessels and early posterior attenuation
  3. Grade 3 (severe steatosis) – Defined as diffusely increased liver echogenicity with the absence of visible vessels and heavy posterior attenuation.


Hepatic enzyme levels (aspartate transaminase [AST], alanine transaminase [ALT]) were measured with Cobas e 601 using kinetic enzymatic method, total protein was measured using Biuret method, serum albumin using Bromocresol green (BCG) dye-binding method, and bilirubin levels using the diazo photometric method with Cobas e 501.

Estimation of serum lipid profile (total cholesterol using cholesterol oxidase/peroxidase method, serum triglyceride using enzymatic kinetic, glycerol phosphate method, high-density lipoprotein (HDL) cholesterol using direct method polymer/detergent) was done with Cobas e 501.

All the statistical data were analyzed using Statistical Package for the Social Sciences version. 20 (SPSS Inc., Chicago, IL, USA). Descriptive statistics were expressed as mean + standard deviation. Inferential statistics were computed using Chi-square test and student “t”-test.


  Results Top


Forty-three cases of prediabetes with NAFLD and 43 Controls of prediabetes without NAFLD were included for analysis. Cases of Grade 2 and 3 NAFLD were combined in one group for analysis.

There was no significant age difference between cases and controls. The mean age of cases was 51.75 years and that of controls was 51.88 years [Figure 1].
Figure 1: Percentage of females in the case–control group

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Females outnumbered males both among cases and controls – 69.8% of controls and 65.11% cases of fatty liver [Figure 2].
Figure 2: Dietary preferences among the cases and controls

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Effect of diet

The association between diet and development of NAFLD was not straightforward. Nonvegetarians were more common in the control (90.7% of controls consumed meat) rather than the case group, however, when they did develop NAFLD, it tended to be more severe (100% of Grade 2/3 NAFLD consumed meat) [Figure 3].
Figure 3: Comparison of mean systolic blood pressure among case and controls

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Controls had a higher carbohydrate consumption, however, among cases, higher carbohydrate consumption (more than 55% of total calories) was associated with more severe disease [Figure 4] (58.5% of Grade 2/3 as opposed to 55.64%of Grade 1]. The protein composition of diet appeared to be protective, with controls having a mean dietary protein percentage of 20.91%, Grade 1 cases consuming 18.32% protein, and Grade 2/3 with 14.32% [Figure 5].
Figure 4: Mean diastolic blood pressure in the case–control group

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Figure 5: Comparison of mean fasting blood sugar among cases and controls

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Mean dietary fat percentage was highest among cases (21.81% of total calories) [Figure 6].
Figure 6: Mean postprandial blood sugar in case–control group

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Clinical features

All cases of severe disease complained of fatigue [Figure 7]. Right hypochondriac pain was seen in 50% of cases with mild disease, and 40% of cases with severe disease [Figure 8]. Dyspepsia was more common among controls [Figure 9].
Figure 7: Comparison of mean HbA1C levels among cases and controls

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Figure 8: Mean AST levels in the case–control group

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Figure 9: Mean ALT levels in the case–control group

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Acanthosis was noted in 44.2% and skin tags in 64% of subjects with prediabetes [Figure 10] However, more cases than controls had acanthosis nigricans (55.81% of cases). Skin tags were also more common in cases (60.5% of controls and 71.1% of cases) [Figure 11]
Figure 10: Dyslipidemia in cases and controls

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Figure 11: Mean triglyceride levels (mg/dl) among cases and controls

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More than 50% of cases were overweight and had a higher BMI when compared to controls [Table 1]. The disease severity correlated with the increasing weight and waist circumference [Figure 12]. Controls weighed the least at a mean of 64.2 kg [Figure 13]. Waist hip ratio was highest in cases with mild disease at 1.2 and least in patients with severe disease.
Table 1: Mean BMI among cases and controls

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Figure 12: Mean VLDL levels (mg/dl) in cases and controls

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Figure 13: Weight in Kgs

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Mean systolic and diastolic BP was higher among cases. A higher mean diastolic BP was seen in more severe cases [Figure 14] and [Figure 15].
Figure 14: Systolic BP

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Figure 15: Diastolic BP

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Parameters of diet, age, and anthropometry are summarized in [Table 2].
Table 2: Dietary and demographic variables

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Blood sugars

The mean fasting, postprandial sugars, and HbA1c values were higher among cases, and more so among severe cases [Figure 16[, [Figure 17] [Figure 18]. There was also a statistically significant correlation of postprandial hyperglycemia with NAFLD.
Figure 16: Fasting Blood Sugar

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Figure 17: HbA1C

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Figure 18: Post prandial blood sugar

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Hepatic function

Mean total protein and albumin values were lower among cases [Figure 19] and [Figure 20]. Mean globulin values were found to be higher among cases with mild disease [Figure 21]. Although not statistically significant, AST, ALT, and ALP values tended to be higher in cases [Figure 22] and [Figure 23].
Figure 19: Serum albumin

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Figure 20: Total protein

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Figure 21: Serum globulin

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Figure 22: ALT levels

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Figure 23: AST levels

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Lipid profile

Dyslipidemia was higher among cases [Figure 24]. Mean values of triglycerides and very low-density lipoproteins (VLDL) were higher among cases. VLDL levels also correlated with the severity of the disease. Sixty percent of cases had metabolic syndrome [Table 3].
Table 3: Metabolic syndrome in cases and controls

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Figure 24: Presence of dyslipidemia

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  Discussion Top


We found that middle-aged women had a higher prevalence of NAFLD – almost twice the prevalence in males. Unlike in our study, research in Japan showed a higher prevalence of NAFLD in males, in whom the prevalence declined in the 6th and 7th decades.[10] While NAFLD can affect any age group, its prevalence increases with age and it is more common and more severe in the elderly. The complications (hepatocellular carcinoma, cirrhosis) and extra-hepatic manifestations (cardiovascular disease) also increase with age.[11] Research has shown that the greatest effect of age, independent of weight gain, is seen in premenopausal women.[12]

The effect of gender on NAFLD is yet to be fully understood. Although NAFLD is more prevalent in males, lean NAFLD is more common in females.[13] Gender differences in NAFLD may be influenced by lifestyle, sex hormones, insulin resistance, and obesity. However, not all studies show a significant difference in insulin resistance or obesity between male and female patients with NAFLD.[14]

Fatigue and right hypochondriac pain were the most common complaints among cases, and dyspepsia was more common among the controls. In contrast to these results, other studies found that NAFLD is usually asymptomatic.[15] Some patients may manifest with vague symptoms such as fatigue and abdominal discomfort, or rarely, anxiety, upper abdominal pain, and dyspepsia.[16] However, it must be kept in mind that many of the above symptoms may be nonspecific and unrelated to NAFLD per se.

Though both cases and controls did have a sedentary lifestyle (as assessed by history), the odds of cases of NAFLD having a sedentary lifestyle was higher. This point has been corroborated by other studies which also show that physical activity has a protective effect against NAFLD and that this effect increases with the frequency and intensity of exercise.[17] Additionally, populations with higher levels of physical activity have a lower prevalence of NAFLD.[18]

The odds of prediabetes with NAFLD being vegetarian was slightly higher. However, among cases, nonvegetarians had more severe disease. Prior research has also shown contradictory results with some studies showing that a vegetarian diet is not protective against NAFLD[19] while others show that consumption of nonvegetarian diet is a risk factor for its development.[20] However, unlike these studies which include patients with diabetes as well, our subjects were limited to those with prediabetes.

We found that cases of NAFLD when compared to controls, consumed a higher amount of fat.[21] A higher percentage of total calories consumed in the form of protein appeared to be protective, with severe cases consuming the least amount of protein. Other studies show a similar result, with diets rich in protein tending to reverse NAFLD.[22]

Interestingly, we found that controls, when compared to cases, had higher carbohydrate content in their diet. Researchers in Sweden had results similar to ours where, surprisingly, a high carbohydrate diet was protective. They found that patients with higher carbohydrate consumption had a markedly lower grade of steatosis.[23] This study showed that it was not just the quality of macronutrients consumed, but the quantity as well, which influenced the development of NAFLD – finding that a hypocaloric diet reduces visceral adiposity, increased lipid accumulation, and progression to NAFLD.[23]

We found that most cases were overweight. Additionally, increasing abdominal obesity was linked to a more severe disease. One researcher states that among the anthropometric measurements SAD i.e., Sagittal Abdominal Diameter was one of the better predictors of NAFLD.[24] A study done in the US shows that NAFLD is strongly linked with obesity, with almost 76% of patients being obese.[25] It is not the absolute BMI alone, but also the quantum of BMI increase which predicts the onset of NAFLD.[26]

Systolic and diastolic BPs readings were higher among cases. Additionally, severe cases had a higher diastolic BP. This result has been corroborated by other studies as well.[27]

Mean fasting blood sugars, PPBS and glycosylated hemoglobin values were higher in cases of NAFLD and we found a statistically significant correlation between increasing PPBS and NAFLD. In 168 patients in Japan, Impaired Glucose Tolerance (IGT) was found to be a better predictor of NAFLD than HbA1C.[28] The authors hypothesized that postprandial hyperinsulinemia rather than postprandial glucose foretells NAFLD.[29] However, a Chinese study found that IFG was a better predictor than IGT and HbA1C of NAFLD.[30]

Cases of NAFLD had higher values of AST and ALT when compared to controls. It has been found that mild to moderate elevation in serum transaminases is the commonest laboratory abnormality found in patients with symptomatic NAFLD.[31] In patients with elevated triglycerides, obesity, age more than 45 years, or those with type 2 diabetes, an AST/ALT ratio of more than 1 could be an indicator of advanced fibrosis.[32] Weight loss of more than 7%–10% was associated with improvement in transaminases.[33]

The pattern of dyslipidemia usually associated with NAFLD is an increase in triglycerides and low-density lipoproteins (LDL) cholesterol and a decrease in HDL cholesterol. Though 77.75% of all our subjects had dyslipidemia, it was more common in cases than controls. We found that Mean total cholesterol, LDL cholesterol, and HDL cholesterol were higher among controls whereas triglycerides and VLDL were higher among cases [Figure 25], [Figure 26], [Figure 27], [Figure 28], [Figure 29]. An Indian study showed that patients with NAFLD had a significantly higher percentage of body fat, total cholesterol, and triglycerides.[34] However, the association between obesity, dyslipidemia, and NAFLD is not invariable, with some research showing that 29% of the patients with biopsy proven NAFLD were nonobese, nondiabetic, and had a normal lipid profile.[35] Hence, yet unknown factors may be implicated in the pathogenesis of NAFLD.
Figure 25: Total cholesterol

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Figure 26: LDL Cholesterol

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Figure 27: HDL Cholesterol

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Figure 28: Triglycerides

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Figure 29: VLDL Cholesterol

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Unsurprisingly, we found that metabolic syndrome was more common in cases than controls. In fact, NAFLD is often considered the fifth component of the metabolic syndrome. This result was also seen in a study in Italy where approximately 90% of patients with NAFLD had more than one feature of metabolic syndrome and 33% of them had all the components.[36] The presence of metabolic syndrome predicts higher risk for the development of NAFLD in women more than men.[37] In patients with metabolic syndrome and NAFLD, good metabolic control was recommended, but rarely effective in reversing NAFLD, though tighter glycemic control has also been found to ameliorate fibrosis.[38]

This study was limited by the fact that dietary history was mainly based on recall method with its inherent inaccuracies. Though we relied on sonography to diagnose NAFLD and not the gold standard of liver biopsy, we ensured that all sonograms were performed by one experienced radiologist.

Many of the predisposing factors for NAFLD are seen in prediabetes viz. obesity and metabolic syndrome. We aimed to find which factors in subjects with prediabetes predispose them to develop NAFLD. In spite of the limitations of the study, an important result emerges - in subjects with prediabetes, postprandial hyperglycemia may be a predictor of NAFLD.

This might be a focus for intervention in the future.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12], [Figure 13], [Figure 14], [Figure 15], [Figure 16], [Figure 17], [Figure 18], [Figure 19], [Figure 20], [Figure 21], [Figure 22], [Figure 23], [Figure 24], [Figure 25], [Figure 26], [Figure 27], [Figure 28], [Figure 29]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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