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 Table of Contents  
Year : 2018  |  Volume : 2  |  Issue : 1  |  Page : 20-25

The role of adiponectin, insulin resistance, and vitamin D as predictors of transformation of fatty liver to hepatocellular carcinoma

1 Department of Internal Medicine, Faculty of Medicine, Al Azhar University, Cairo, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, El Monofeya University, El Monofeya, Egypt
3 Department of Internal Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt

Date of Submission01-Apr-2018
Date of Acceptance20-May-2018
Date of Web Publication12-Jul-2018

Correspondence Address:
Walaa S.M Ibrahim
Assistant Specialist Internal Medicine El Mataryia Teaching Hospital, Cairo
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/sjamf.sjamf_10_18

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Introduction Hepatocellular carcinoma (HCC) is considered the fifth most common cancer in the world and is responsible for 5% of all malignant tumors in humans. Most HCC cases are related to chronic hepatitis C virus (HCV) infection, chronic hepatitis B (HBV) infection, and alcohol abuse. Approximately 15–50% of HCC cases were classified as idiopathic, suggesting that other risk factors are responsible for its rising incidence. Recent studies have suggested that nonalcoholic fatty liver disease (NAFLD) can be associated with these ‘idiopathic’ cases.
Aim The aim of the study was to evaluate the levels of both serum 25(OH)VD and adiponectin, as well as homeostatic model assessment insulin resistance as predictors of transformation of NAFLD to HCC among patients with NAFLD, HCV, HBV positive patients and HCC patients.
Patients and Methods This is a case–control study which was conducted on 100 patients at the Internal Medicine Department in ElMataryia Teaching Hospital. They were classified into 20 patients with NAFLD, 20 patients with HBV positive, 20 patients with HCV positive, and 20 patients with HCC, in addition to 20 age-matched and sex-matched healthy participants,. Full medical history, clinical examination, and laboratory investigations including complete blood count, alanine transaminase, aspartate transaminase, prothrombin time, international normalized ratio, fasting blood sugar, glycated hemoglobin, homeostatic model assessment insulin resistance, hepatitis B antigen, hepatitis B antibody, serum vitamin D, and serum adiponectin, abdominal ultrasound were done. Statistical analysis using SPSS was done.
Results The level of adiponectin showed a decrease in NAFLD cases (2 μg/ml), but there was an increase in HBV (18 μg/ml), HCV (10.5 μg/ml), and HCC (13 μg/ml) in comparison to the control group (3.75 μg/ml). Further, the cut-off points for adiponectin to detect HCC in NAFLD was found to be greater than 3.2, with a sensitivity of 100% and specificity of 100%.
Conclusion Serum adiponectin is an excellent marker to predict the transformation of NAFLD to HCC.

Keywords: adiponectin, hepatocellular carcinoma, insulin resistance, nonalcoholic fatty liver

How to cite this article:
Mohammed AK, AbdelRehem FS, Hendy OM, Mohammed ER, Ibrahim WS. The role of adiponectin, insulin resistance, and vitamin D as predictors of transformation of fatty liver to hepatocellular carcinoma. Sci J Al-Azhar Med Fac Girls 2018;2:20-5

How to cite this URL:
Mohammed AK, AbdelRehem FS, Hendy OM, Mohammed ER, Ibrahim WS. The role of adiponectin, insulin resistance, and vitamin D as predictors of transformation of fatty liver to hepatocellular carcinoma. Sci J Al-Azhar Med Fac Girls [serial online] 2018 [cited 2019 Mar 22];2:20-5. Available from: http://www.sjamf.eg.net/text.asp?2018/2/1/20/236467

  Introduction Top

Fatty liver (steatosis) is the result of an imbalance in the triglyceride metabolism and characterized by accumulation of lipid within the hepatocytes. It affects up to 30% of the population in industrialized countries and is becoming more prevalent in the developing world with the rise in living standards and change in dietary habits. Although most individuals with this condition do not develop any serious liver disease, it is associated with an increased annual incidence of hepatocellular carcinoma (HCC). Several studies have found that patients suffering from cirrhosis preceded by fatty liver are at risk of developing HCC equal to those who develop cirrhosis related to hepatitis C virus (HCV) [1].

The definition of nonalcoholic fatty liver requires evidence of hepatic steatosis by imaging or histology and no causes for secondary hepatic fat accumulation like alcohol [2]. Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of diseases ranging from simple steatosis to nonalcoholic steatohepatitis and cirrhosis [3].

The prevalence of NAFLD has risen rapidly in parallel to the dramatic rise in levels of obesity and diabetes mellitus II. NAFLD is strongly associated with hepatic and adipose tissue insulin resistance (IR) as well as reduced whole-body insulin sensitivity [4].

IR is defined as decreased sensitivity or responsiveness to metabolic actions of insulin such as inhibition of hepatic glucose production. IR is a key factor in the pathogenesis of NAFLD, which is being considered as the hepatic component of IR or metabolic syndrome [5].

Patients with NAFLD have lower adiponectin levels compared with normal people, which may act as a predictor of transformation to HCC [6].

ADP is an amino acid protein which accounts for 0.01% of total plasma proteins; it is mainly secreted from the adipose tissue, and it modulates a number of metabolic processes, including glucose regulation and fatty acid oxidation. ADP has antiatherogenic, antidiabetic, and anti-inflammatory properties. ADP plays a role in the suppression of the metabolic actions that may result in type II diabetes, obesity, and NAFLD [7].

Vitamin D has a significant immunomodulatory action and is an important mediator of innate and adaptive immune system, The active form of vitamin D1, 25(OH)2D3, has been shown to exert an antitumor activities, including anti proliferation, anti-inflammation, antiangiogenesis proapoptosis, prodifferentiation, and inhibiting cancer cell invasion. This means that decreased level of vitamin D in NAFLD might have a role in the proliferation of malignant cells and could rise the possibility of developing HCC [8].

HCC is usually asymptomatic in the early stages and tends to be invasive, and most patients are presented with incurable diseases at the time of detection which makes its early diagnosis critical for good prognosis; hence, the aim of the work was to evaluate serum adiponectin, serum vitamin D, and homeostatic model assessment insulin resistance (HOMA-IR) to predict HCC among NAFLD.

  Patients and methods Top


This study was conducted on 100 participants classified into five groups: group 1 included 20 patients with NAFLD; group 2 included 20 patients with positive hepatitis B virus (HBV); group 3 included 20 patients with positive HCV; group 4 included 20 patients with HCC; group 5 included 20 healthy normal participants (age and sex matched).

All participants were selected from the outpatient clinic of Internal Medicine and Inpatient Medicine Departments of Elmatariya Teaching Hospital; all are Egyptians, their age ranged from 30 to 55 years. The study was conducted in the period from June 2016 to June 2017.

All participants enrolled in the study were subjected to full history taking, full clinical examination including BMI and laboratory tests including (complete blood count, liver function tests: serum glutamate pyruvate transaminase and serum glutamic oxaloacetic transaminase, serum albumin, prothrombin time, and international normalized ratio). viral screening for hepatitis B antigen and hepatitis C antibody, fasting blood sugar, and glycated hemoglobin, serum adiponectin, serum vitamin D, IR (HOMA-IR) and abdominal ultrasound.

An informed consent was taken from the patients and controls which are approved by the ethics committee of Al Azhar University.

  Methods Top

Specimen collection: 7 ml of venous blood was obtained from each patient and from controls with a sterile syringe drawn without anticoagulant, allowed to stand for 2 h at room temperature, and then centrifuged at 3000 rpm for 10 min. The sera samples were collected and each was divided into two aliquots, one for routine laboratory investigations and the other aliquots were stored at −20°C till the time of use, avoiding repeated freezing/thawing.

Serum vitamin D was measured using the enzyme-linked immunosorbent assay technique; serum adiponectin was measured using the enzyme-linked immunosorbent assay technique, fasting serum insulin, and HOMA-index for the calculation of IR, through the following Matthews formula: HOMA-IR=[FPG (mg/dl)×fasting insulin (µIU/l)]/405.

Statistical analysis

The statistical presentation and analysis of the results of our study was conducted using SPSS (SPSS Inc., Chicago, Illinios, USA); χ2-test was used to compare qualitative variables between groups. Unpaired t-test was used to compare quantitative variables in parametric data (SD<50% mean). Mann–Whitney test was used instead of unpaired t-test in nonparametric data (SD>50%mean). One-way analysis of variance test was used to compare more than two groups as regards quantitative variables (least significant difference). Spearman’s correlation coefficient test was used to rank variables versus each other positively or inversely. Power of significance was evaluated as follows: A P value of greater than or equal to 0.05 was considered insignificant. A P value of less than 0.05 was considered significant and a P value less than 0.01was considered highly significant.

  Results Top

All demographic and anthropometric measures are tabulated, as shown in [Table 1]; the detailed laboratory data are shown in [Table 2].
Table 1 Comparison between control group and patients group regarding demographic and anthropometric measures

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Table 2 Comparison between control group and patients group regarding laboratory data

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The study showed that there was a significant decrease in adiponectin level in NAFLD with median and interquartile (IQ) range (2 μg/ml) compared with the control (3.75 μg/ml). The level of adiponectin was increased in HBV (18 μg/ml), HCV (10.5 μg/ml), and HCC (13 μg/ml) compared with the control group.

The study showed a significant decrease in vitamin D level in patients with NAFLD (median IQ range: 10 ng/ml), HBV (8.75 ng/ml), HCV (10.5 ng/ml) compared with the control group. There was a more significant decrease in the level of vitamin D in HCC (5 ng/ml) compared with controls.

We have found that there was a statistically significant difference between all patients groups and the control group regarding HOMA-IR (P<0.00). Also there was a statistically significant difference between NAFLD and HCV (P<0.02), but no statistically significant difference between NAFLD and HBV (P>0.76), and NAFLD and HCC (P>0.06) regarding HOMA-IR ([Table 3]).
Table 3 Comparison between patients subgroup regarding insulin (homeostatic model assessment insulin resistance), adiponectin, vitamin D

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Receiver operating characteristic curve between the HCC group and the NAFLD group was done to detect the best marker that predicts HCC among NAFLD; adiponectin was the excellent predictor for HCC among NAFLD with a sensitivity of 100%, specificity of 100% at the best cut-off point (>3.2 mg/ml), followed by vitamin D sensitivity of 85%, specificity of 95% at the best cut-off point (≤6 ng/ml), and lastly HOMA-IR with a sensitivity of 95% and specificity of 35% ([Figure 1], [Table 4]).
Figure 1 Receiver operating characteristic curve for hepatocellular carcinoma group vs. nonalcoholic fatty liver disease group.

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Table 4 Receiver operating characteristic curve between hepatocellular carcinoma group and nonalcoholic fatty liver disease group

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[Table 1] shows a statistically significant difference between the control group and patients group regarding weight and BMI, whereas no statistically significant difference was found between the two studied groups regarding sex and height.

[Table 2] shows a statistically significant difference between the control group and patients group regarding all laboratory data.

There was a statically significant difference between all patient subgroups and the control group regarding IR (HOMA-IR), adiponectin, and vitamin D levels.

  Discussion Top

NAFLD is rapidly becoming the most common liver condition which implicated in rising HCC incidence, independently or in synergy with cirrhosis. There are multiple postulated mechanisms for the development of HCC in NAFLD.
  1. Hepatic steatosis mainly causes 1-oxidative (via increased reactive oxygen species and carcinogenic metabolites of lipid peroxidation such as trans­4­hydroxy­nonenal).
  2. inflammatory (upregulation of tumor necrosis factor-α, interleukin-6).
  3. Apoptotic and hormonal changes. Also there is increase in hepatic inflammation and apoptosis through downstream modulation of pathways as mitogen­active protein kinase and phosphatidyl-inositol­3 kinase.
  4. Also one of important mechanisms implicated in HCC from NAFLD is decrease in adiponectin levels with subsequent loss of its antiangiogenic and anti-inflammatory effects [9].

NAFLD is extremely frequent among diabetic and obese patients. The risk of HCC was found to be increased among diabetic and obese patients even without HBV or HCV infection. Both obesity and diabetes were associated with IR and elevated insulin-like growth factor, which stimulate cell growth and may promote cancer cells proliferation and apoptosis which increase the risk of HCC by threefold [9].

The present study showed that there was a significant decrease in adiponectin level in patients with NAFLD but on the other hand the level increased in HBV positive patients (18 μg/ml), HCV positive patients (10.5 μg/ml), and HCC patients (13 μg/ml) compared to control group. This result showed an agreement with Mohamed et al. [10], their study was carried out to evaluate the role of adiponectin, in NAFLD Egyptian patients, they found that plasma adiponectin were significally lower in NAFLD patients than control (3.05±2.65 vs. 10.52±3.35 μg/ml), this mean that high level of adiponectin is a protective against fatty liver and the lower adiponectin level related to higher grade of inflammation suggesting that adiponectin deficiency is an important risk factor for development of liver injury and could accelerate tumor formation in NAFLD. Also our result is in agreement with that reported by Adolph et al. [11] who suggested that advanced liver diseases are associated with increased serum adiponectin levels, they found that cirrhotic and noncirrhotic HCC patients demonstrated more increase in serum levels of adiponectin, and high adiponectin serum levels might predict the consecutive development of HCC and higher plasma levels of adiponectin could predict poor HCC survival among patients without liver transplantation, and they explained this by the ability of adiponectin to increase apoptosis of HCC cells through activation of caspase-3, and increased phosphorylation of c-Jun N-terminal kinase. Inhibition of c-Jun N-terminal kinase-phosphorylation prevented this apoptotic effect of adiponectin.

The present study showed that there was a significant decrease in vitamin D level in patients with NAFLD (median IQ range: 10 ng/ml), HBV (median IQ range: 8.75 ng/ml), HCV (median IQ range:10.5 ng/ml) patients compared to control and there was more significant decrease in the level of vitamin D in HCC patients (median IQ range: 5 ng/ml) compared to control. This result showed an agreements with Cordeiro et al. [12]. The results of this study showed that the lowest serum vitamin D concentrations were found in steatohepatitis diagnosed by liver biopsy, and there was more decreases in more histologically severe stages of the disease, suggesting that vitamin D may play a role in the development and progression of liver disease, partly via inhibition of vitamin D anti-inflammatory and immunomodulatory properties.Also we have found that there is no statistically significant difference in IR (HOMA-IR) level in NAFLD patients compared to the control group (P=0.110), and this showed an agreement with results recorded by Signh et al. [13] who had reported that IR could not be detected in 45.53% of the 336 NAFLD patients they had studied. Although age, sex, BMI, and transaminase levels were comparable, significantly higher proportion of patients in non-IR group were nonobese, which mean that NAFLD is probably a heterogeneous disease and IR is not the sole factor responsible for NAFLD, and NAFLD may not be associated with IR especially in nonobese lacking criteria of metabolic syndrome.

In view of the expected possible changes in the pattern of chronic hepatic diseases in Egypt after the ‘National Plan for HCV Prevention and Eradication’, NAFLD with its serious complication HCC, might dominate the picture in the future, especially with the obvious increasing rise of the incidence and prevalence of both obesity and type 2 diabetes among the Egyptians as a result of changing life style and eating habits.

The results in our study might add to the protocol of both prediction and early detection of this serious condition.

  Conclusion Top

We recommend to take NAFLD seriously, as it is emerging as the most common liver disorder in the industrialized countries leading to HCC. Finding a simple noninvasive measures for follow-up patients with NAFLD, using the previous three markers [adiponectin, serum vitamin D, and IR (HOMA-IR)] might give a hope to early detection of HCC in NAFLD patients. Adiponectin level shows an excellent sensitivity and specificity followed by vitamin D then IR (HOMA-IR). Our study adds to the increasing evidence that HCC can occur in patients even with noncirrhotic NAFLD and those who are nonobese.

The main value of our study is that it might add to the protocol of both prediction and early detection HCC in patients with NAFLD, the emerging common chronic liver disease after eradication of HCV in Egypt.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

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Vernon G, Baranova A, Younossi ZM. The epidemiology and natural history or NAFLD. Aliment Pharmacol Ther 2012 34:274–285.  Back to cited text no. 2
Ounossi ZM, Stepanova M, Afendy M, Fang Y, Younossi Y, Mir H et al. Change in prevalence of the most common causes of chronic liver diseases in the united states from1988 to 2008. Clin Gastroentrol Hepatol 2013; 9:524–530.  Back to cited text no. 3
Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K et al. The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 2012; 55:2005–2023.  Back to cited text no. 4
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Bastard JP, Maachi M, Lagathu C, Kim MJ, Caron M, Vidal H et al. Recent advances in the relationship between obesity, inflammation, and insulin resistance. Eur Cytokine Netw 2013; 17:4–12.  Back to cited text no. 6
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Mohamed AA, Shousha W, Shaker O et al. Role of serum adiponectin, IL-6, and hs-CRP in non-alcoholic fatty liver Egyptian patients. Int J Bioche Res Rev 2014; 4: 493–504.  Back to cited text no. 10
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Cordeiro A, Pereira S, Saboya CJ et al. Relationship between nonalcoholic fatty liver disease and vitamin D nutritional status in extreme obesity. Can J Gastroenterol Hepatol 2017; 2017: 9456897.  Back to cited text no. 12
Singh SP, Misra B, Kar SK, Panigrahi MK, Misra D, Bhuyan P et al. Nonalcoholic fatty liver disease (NAFLD) without insulin resistance: is it different? Clin Res Hepatol Gastroenterol. 2015; 39:482–488.  Back to cited text no. 13


  [Figure 1]

  [Table 1], [Table 2], [Table 3], [Table 4]


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