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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 31  |  Issue : 3  |  Page : 911-915

Dipeptidy l peptidase 4 enzyme in chronic hepatitis C


1 Department of Internal Medicine, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
3 Department of Internal Medicine, Ministry of Health, Al-Sinbillaween, Dakahlia, Egypt

Date of Submission18-Jan-2017
Date of Acceptance11-Mar-2017
Date of Web Publication31-Dec-2018

Correspondence Address:
Basem M El Sayed El Khyary
Mustafa Kamel Street, Al-Sinbillaween, Dakahlia Governorate
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_66_17

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  Abstract 


Objective
The objective of this study was to assess the role of serum dipeptidyl peptidase 4 (DPP-4) in patients with diabetes mellitus (DM) and in chronic hepatitis C infection patients.
Methods
Our data sources were Medline databases (PubMed, Medscape, and Science Direct; EMF Portal). Articles with values of serum DPP-4 in patients with DM and in chronic hepatitis C patients from Medline databases were selected. We used the following search terms: DPP4/DM/HCV/GLP1/insulin resistance/fatty liver/antiviral drugs. The initial search presented nine articles, of which five met inclusion criteria. The articles studied the value of serum DPP-4 in patients with DM and in chronic hepatitis C patients. If the studies did not fulfill inclusion criteria, they were excluded. Study quality assessment included whether ethics approval was gained, eligibility criteria were specified, appropriate controls were used, and whether adequate information and defined assessment measures were provided. Comparisons were made by a structured review with the results tabulated.
Results
In total, nine potentially relevant publications were included. Some studies indicated that the serum DPP-4 activity was not increased in type 2 diabetes, provided that patients with liver disease were intentionally excluded, whereas similar to our findings several studies support increased DPP-4 activity in type 2 diabetes patients. However, the cause for the increase in DPP-4 activity in diabetic patients remains unclear.
Conclusion
Serum DPP-4 activity in patients with chronic hepatitis C virus strongly suggests that serum DPP-4 is a novel biomarker of chronic hepatitis C virus, irrespective of the presence of DM.

Keywords: diabetes mellitus, dipeptidyl peptidase 4 enzyme, hepatitis C virus


How to cite this article:
Shaaban MA, Dawood AA, Helwa MA, El Sayed El Khyary BM. Dipeptidy l peptidase 4 enzyme in chronic hepatitis C. Menoufia Med J 2018;31:911-5

How to cite this URL:
Shaaban MA, Dawood AA, Helwa MA, El Sayed El Khyary BM. Dipeptidy l peptidase 4 enzyme in chronic hepatitis C. Menoufia Med J [serial online] 2018 [cited 2019 Jun 19];31:911-5. Available from: http://www.mmj.eg.net/text.asp?2018/31/3/911/248759




  Introduction Top


Hepatitis C virus (HCV) infection is a major public health problem, which currently affects over 200 million people, with an estimated prevalence of 2.2% globally[1]. Egypt has the highest prevalence rate of HCV in the world, making it the most challenging health problem facing the country. Studies show that 14.7% of the Egyptian population carry HCV antibodies[2] and 9.8% have an active infection[3].

Diabetes mellitus (DM) is a metabolic disorder resulting from a defect in insulin secretion and/or insulin action, which results in hyperglycemia with disturbances in carbohydrate, fat, and protein metabolism. The incidence of DM has increased dramatically in recent decades, predominantly because of changes in lifestyle, an increase in the prevalence of obesity, and longevity. Current projections estimate that the number of people with DM will nearly double by 2025[4]. Both diabetes and HCV infection are severe health problems worldwide, especially in developing countries[5].

A range of extrahepatic manifestations such as arthralgia, thyroiditis, and diabetes are linked with HCV infections. It has been shown that patients infected with HCV have more glucose intolerance than the general population[6].

The mechanism of the pathogenesis of diabetes in patients with HCV infection remains unclear, although it has been implicated that insulin resistance plays an important role and is related to fibrosis score[7].

Dipeptidyl peptidase 4 (DPP-4) is a membrane-associated peptidase, also known as CD26. DPP-4 has widespread organ distribution throughout the body, and exerts pleiotropic effects through its peptidase activity. A representative target peptide is glucagon-like peptide-1, and inactivation of glucagon-like peptide-1 results in the development of glucose intolerance/DM and hepatic steatosis. In addition to its peptidase activity, DPP-4 is known to be associated with immune stimulation, binding to and degradation of extracellular matrix, resistance to anticancer agents, and lipid accumulation. The liver expresses DPP-4 to a high degree, and recent accumulating data suggest that DPP-4 is involved in the development of various chronic liver diseases (CLDs) such as HCV infection, non alcoholic fatty liver disease (NAFLD), and hepatocellular carcinoma[8].


  Methods Top


Search strategy

We reviewed articles on the values of serum DPP-4 in patients with DM and chronic hepatitis C from Medline databases (PubMed, Medscape, and Science Direct) and also materials available on the internet. We used the following search terms: DPP4/DM/HCV/GLP1/insulin resistance/fatty liver/antiviral drugs. In addition, we examined references from specialist databases such as EMF Portal (http://www.emf-portal.de). The search was performed in electronic databases from 2001 to 2016.

Study selection

All studies were independently assessed for inclusion. They were included if they fulfilled the following criteria:

  • Published in English language
  • Published in peer-reviewed journals
  • Discussed the value of serum DPP-4 in patients with DM and in chronic hepatitis C infection patients
  • If a study had several publications on certain aspects, we used the latest publication giving the most relevant data.


Data extraction

If the studies did not fulfill the above-mentioned criteria, they were excluded. Reports without peer-review, not within national research programs, letters/comments/editorials/news, and studies not focused on values of serum DPP-4 in patients with DM and in chronic hepatitis C patients were also excluded.

The analyzed publications were evaluated according to evidence-based medicine (EBM) criteria using the classification of the US Preventive Services Task Force and UK National Health Service protocol for EBM in addition to the Evidence Pyramid.

US Preventive Services Task Force:

  • Level I: evidence obtained from at least one properly designed, randomized controlled trial
  • Level II-1: evidence obtained from well-designed controlled trials without randomization
  • Level II-2: evidence obtained from well-designed cohort or case–control analytical studies, preferably from more than one center or research group
  • Level II-3: evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence
  • Level III: opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.


Quality assessment

The quality of all the studies was assessed. Important factors included study design, attainment of ethics approval, evidence of a power calculation, specified eligibility criteria, appropriate controls, and adequate information and specified assessment measures. It was expected that confounding factors would be reported and controlled for and appropriate data analysis would be carried out in addition to an explanation of missing data.

Data synthesis

A structured systematic review was performed with the results tabulated.


  Results Top


Study selection and characteristics

The initial search presented nine articles, of which five met inclusion criteria. The articles studied the value of serum DPP-4 in patients with DM and in chronic hepatitis C infection patients. The studies were analyzed with respect to the study design using the classification of the US Preventive Services Task Force and UK National Health Service protocol for EBM.

Concerning baseline general characteristics, there was no significant difference between the four groups regarding age and sex (P > 0.05). Regarding laboratory findings, there were significant differences between the four groups regarding hemoglobin, platelet count, serum albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and glycated hemoglobin (HbA1c) (P < 0.05), whereas there was no significant difference between the four groups regarding white blood cell, total bilirubin, and serum creatinine (P > 0.05).

DPP-4 levels showed highly significant differences among group 1 (1675 ± 245.8 ng/ml), group 2 (2107.8 ± 557.6 ng/ml), group 3 (4475 ± 467.2 ng/ml), and group 4 (12 760 ± 3733 ng/ml) (P < 0.001) [Figure 1]). A correlation study between DPP-4 and other parameters in the studied groups revealed a significant direct correlation between DPP-4 and ALT and AST in group 2 and group 4. On the other hand, there was significant inverse correlation between DPP-4 and platelet count in group 2 [Figure 2],[Figure 3],[Figure 4],[Figure 5],[Figure 6].
Figure 1: Comparison between the four groups regarding dipeptidyl peptidase 4 (DPP-4).

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Figure 2: Correlation between platelets and dipeptidyl peptidase 4 (DPP-4) in group 2.

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Figure 3: Correlation between alanine aminotransferase (ALT) and dipeptidyl peptidase 4 (DPP-4) in group 2.

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Figure 4: Correlation between aspartate aminotransferase (AST) and dipeptidyl peptidase 4 (DPP-4) in group 2.

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Figure 5: Correlation between alanine aminotransferase (ALT) and dipeptidyl peptidase 4 (DPP-4) in group 4.

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Figure 6: Correlation between aspartate aminotransferase (AST) and dipeptidyl peptidase 4 (DPP-4) in group 4.

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  Discussion Top


Concerning hematological tests in this study and by comparing the 4 groups using analysis of variances, there was a significant difference between the four groups regarding platelet counts (P < 0.05). Mohamed et al.[9] found significant decreased mean platelet counts among patients with chronic HCV compared with healthy patients (P < 0.0001). França et al.[10] and his associates explained that, as there are various theories about thrombocytopenia in CLDs, portal hypertension, hypersplenism, and bone marrow suppression are factors associated with thrombocytopenia in patients with chronic hepatitis C.

There was a significant difference between the four groups regarding ALT and AST (P < 0.05). This was in agreement with the study by Sleisenger and Fordtran[11] who reported that these tests will usually indicate the type of liver injury, whether hepatocellular or cholestatic, but cannot be expected to differentiate one form of hepatitis from another or to determine whether cholestasis is intrahepatic or extrahepatic.

HbA1c is formed when hemoglobin binds with glucose. HbA1c has been able to accurately measure average plasma glucose concentrations over a period of 8–12 weeks[12]. In the present study, there was a significant difference between the four groups regarding HbA1c (P < 0.05), which increased among diabetic patients.

DPP-4 level was significantly different in group 1 (1675 ± 245.8 ng/ml), group 2 (2107.8 ± 557.6 ng/ml), group 3 (4475 ± 467.2 ng/ml), and group 4 (12 760 ± 3733 ng/ml) (P < 0.001). Patients with HCV infection show increased serum DPP-4 expressions in hepatocytes, and HCV infection is known to be associated with increased DPP-4 expressions in the ileum, liver, and serum[8]. Serum DPP-4 activity was not increased in type 2 diabetes mellitus (T2DM), provided that patients with liver disease were intentionally excluded[13].

Similar to our findings, there are several studies that support increased DPP-IV activity in T2DM patients[14],[15]; however, the cause for the increase in DPP-IV activity in diabetic patients remains unclear. Pala et al.[16] indicated that human glomerular endothelial cells that are exposed to high concentrations of glucose promote the biosynthesis of DPP-IV in vitro. Later on, another study by Pala et al.[17] reported that DPP-IV activation was not induced in control, T2DM patients, or patients with impaired glucose tolerance according to oral glucose loading. Similarly, a study by Ryskjær et al.[18] indicated that DPP-IV activity was increased in T2DM patients.

Higher serum DPP-4 activity was found in CHC patients (in the serum, bile canaliculi, hepatocytes, and hepatic stellate cells), a disease known to be associated with DM and insulin resistance. The serum DPP-4 showed correlation with liver tests (ALT, γ-glutamyl transferase, and alkaline phosphatase) in NAFLD and other CLD cases, and the excess was of hepatic origin. It is hypothesized that in NAFLD the DPP-4 enzymatic activity is increased, which might contribute to the development of T2DM and metabolic deterioration[13].

There was no correlation between DPP-4 and HbA1c. Firneisz et al.[13] could neither confirm the correlation between serum DPP-4 and HbA1C values nor between serum DPP-4 and fasting plasma glucose, which have been reported in earlier studies on T2DM patients with smaller sample sizes[18]. Thus, it was thought that the increment in serum DPP-4 activity reported earlier in patients with T2DM by others might also be due to the uncounted or unrecognized liver disease[14].


  Conclusion Top


The review showed that there is a significant association between HCV infection and T2DM. However, it remains unclear whether HCV infection is a risk factor for diabetes or vice versa. DPP-4 activity was not increased in diabetic patients, provided that patients with liver disease were intentionally excluded. The high serum DPP-4 activities in patients with chronic HCV infection were correlated with liver tests but not with HbA1C, supporting that the excess is of hepatic origin and it might contribute to the speed up of metabolic deterioration. The correlation among ALT, AST, and serum DPP-4 activity in patients with chronic HCV strongly suggests that serum DPP-4 activity should be considered as a novel liver disease biomarker.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Bostan, N, Mahmood, T. An overview about hepatitis C: a devastating virus. Crit Rev Microbiol 2010; 36:91–133.  Back to cited text no. 1
    
2.
Esmat, G. Hepatitis C in the eastern Mediterranean region. East Mediterr Health J 2013; 19:587–588.  Back to cited text no. 2
    
3.
El-Zanaty F, Way A. Egypt demographic and health survey 2008. Egyptian: Ministry of Health. Cairo: El-Zanaty and Associates and Macro International; 2009.  Back to cited text no. 3
    
4.
Arinzon Z, Shabat S, Shuval I, Peisakh A, Berner Y. Prevalence of diabetes mellitus in elderly patients received enteral nutrition long-term care service. Arch Gerontol Geriatr 2008; 47:383–893.  Back to cited text no. 4
    
5.
Waheed Y, Safi SZ, Qadri I. Role of potash alum in hepatitis c virus transmission at barber's shop. Virol J 2001; 8:211.  Back to cited text no. 5
    
6.
Safi SZ, Qvist R, Kumar S, Batumalaie K, Ismail IS. Molecular mechanisms of diabetic retinopathy, general preventive strategies, and novel therapeutic targets. Bio Med Res Int 2014; 2014:801269.  Back to cited text no. 6
    
7.
Sanzone AM, Begue RE. Hepatitis C and arthritis: an update. Infect Dis Clin North Am 2006; 20:877–889.  Back to cited text no. 7
    
8.
Itou M, Kawaguchi T, Taniguchi E, Sata M. Dipeptidyl peptidase-4: a key player in chronic liver disease. World J Gastroenterol 2013; 19:2298–2306.  Back to cited text no. 8
    
9.
Mohamed WS, Serwah AHA, Elnemr GM, Mohamed FS. Some platelet parameters in patients with HCV-associated chronic liver diseases. Sch J App Med Sci 2016; 4(5C):1632–1639.  Back to cited text no. 9
    
10.
França AV, Elias JJ, Lima BL, Martinelli AL, Carrilho FJ. Diagnosis, staging and treatment of hepatocellular carcinoma. Braz J Med Biol Res 2004; 37;1689–1705.  Back to cited text no. 10
    
11.
Sleisenger MF, Fordtran BF. Hepatic tumors and cysts gastrointestinal and liver disease. Vol. 2. 6th ed. Philadelphia: W.B. Saunders; 2002:pp. 1577–1579.  Back to cited text no. 11
    
12.
International Expert Committee. International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care 2009; 32:1327–1334.  Back to cited text no. 12
    
13.
Firneisz G, Varga T, Lengyel G, Fehér J, Ghyczy D, Wichmann B, et al. Serum dipeptidyl peptidase-4 activity in insulin resistant patients with non-alcoholic fatty liver disease: a novel liver disease biomarker. PLoS One 2010; 5:e12226.  Back to cited text no. 13
    
14.
Mannucci E, Pala L, Ciani S, Bardini G, Pezzatini A, Sposato I, et al. Hyperglycaemia increases dipeptidyl peptidase IV activity in diabetes mellitus. Diabetologia 2005; 48:1168–1172.  Back to cited text no. 14
    
15.
Fadini GP, Albiero M, Menegazzo L, de Kreutzenberg SV, Avogaro A. The increased dipeptidyl peptidase-4 activity is not counteracted by optimized glucose control in type 2 diabetes, but is lower in metformin-treated patients. Diabetes Obes Metab 2012; 14:518–522.  Back to cited text no. 15
    
16.
Pala L, Mannucci E, Pezzatini A, Ciani S, Sardi J, Raimondi L, et al. Dipeptidyl peptidase-IV expression and activity in human glomerular endothelial cells. Biochem Biophys Res Commun 2003; 310:28–31.  Back to cited text no. 16
    
17.
Pala L, Ciani S, Dicembrini I, Bardini G, Cresci B, Pezzatini A, et al. Relationship between GLP-1 levels and dipeptidyl peptidase-4 activity in different glucose tolerance conditions. Diabetic Med 2010; 27:691–695.  Back to cited text no. 17
    
18.
Ryskjær J, Deacon CF, Carr RD, Krarup T, Madsbad S, Holst J, et al. Plasma dipeptidyl peptidase-IV activity in patients with type-2 diabetes mellitus correlates positively with HbAlc levels, but is not acutely affected by food intake. Eur J Endocrinol 2006; 155:485–493.  Back to cited text no. 18
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]



 

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