Menoufia Medical Journal

REVIEW ARTICLE
Year
: 2019  |  Volume : 32  |  Issue : 1  |  Page : 1--7

Platelet-derived growth factor in patients with liver fibrosis


Enas S Essa1, Fikry G Eskander2, Amira Z Badawy1,  
1 Clinical Pathology Department, Faculty of Medicine, Menoufia University, Shebeen El-Kom, Egypt
2 Clinical Pathology Department, Faculty of Medicine, Suez Canal University, Ismailia, Egypt

Correspondence Address:
Amira Z Badawy
Clinical Pathology Department, Faculty of Medicine, Menoufia University, Shebeen El-Kom, Menoufia Governorate
Egypt

Abstract

Objective To asses the changes in platelet-derived growth factor (PDGF) in liver fibrosis. Data sources The data were sourced from the PubMed database from the start of the database to 2017 and from all materials available in the Internet. Study selection The initial search presented 423 articles of which 39 met the inclusion criteria. The articles studied the relation between PDGF and liver fibrosis. Data extraction If the studies did not fulfill the inclusion criteria, they were excluded. Study quality assessment included when ethical approval was obtained, eligibility criteria defined, sufficient information, convenient controls, and known assessment measures. Data synthesis Comparisons were made through structured review with the results tabulated. Findings In total, 39 potentially relevant publications were included. The studies indicate an association between PDGF and liver fibrosis as PDGF increases in patients with hepatic fibrosis and correlates well with the grade of fibrosis. The majority of studies were performed on the effect of PDGF antagonists on liver fibrosis and they found that interference of PDGF pathway leads to reduction of liver fibrosis. Conclusion We found that PDGF levels increase in patients with liver fibrosis and its level correlates well with the stage of fibrosis; thus, PDGF can be used as a potential noninvasive marker for liver fibrosis either alone or in association with other fibrosis markers. Further, antagonizing the pathway of PDGF may offer a promising strategy for the treatment of liver fibrosis.



How to cite this article:
Essa ES, Eskander FG, Badawy AZ. Platelet-derived growth factor in patients with liver fibrosis.Menoufia Med J 2019;32:1-7


How to cite this URL:
Essa ES, Eskander FG, Badawy AZ. Platelet-derived growth factor in patients with liver fibrosis. Menoufia Med J [serial online] 2019 [cited 2019 Aug 26 ];32:1-7
Available from: http://www.mmj.eg.net/text.asp?2019/32/1/1/256117


Full Text



 Introduction



Fibrosis and cirrhosis of the liver are important causes of morbidity and mortality globally and are related to increasing economic and social impact [1]. Liver fibrosis is an outcome of almost all chronic liver diseases, which is either because of chronic viral infection through hepatotropic viruses (especially hepatitis-B and hepatitis-C viruses) or autoimmune injury, in addition to metabolic and toxin-induced injury [2]. Hepatic fibrosis is the final event of chronic liver injury; it is characterized by excessive extracellular matrix deposition that distorts the hepatic architecture by forming fibrotic scars, and the subsequent development of nodules of regenerating hepatocytes leading to liver cirrhosis [3].

To date, percutaneous liver biopsy assessed using histological analysis is still the primary technique for evaluating the severity of liver injury. However, clinically, using this diagnostic technique is limited because of the invasiveness of the process and its associated hazards such as pain, bleeding, and sampling errors. In recent years, there has been growing interest in identifying and describing liver fibrosis using molecular serum markers [4]. For example, the aspartate aminotransferase-to-platelet ratio (APRI) and fibrosis index based on a total of four factors (FIB-4) have been the most commonly used scoring systems; these were initially used to asses patients with persistent hepatitis-C virus infection but a number of research studies have found that APRI and FIB-4 are also suitable markers for detecting liver fibrosis in patients with chronic hepatitis-B (CHB) infection [5]. It has been established that cytokines, growth factors, and other mediators produced locally control the progression from chronic liver injury to fibrosis, cirrhosis, and, lately, tumor formation. Platelet-derived growth factor (PDGF) belongs to a family of growth factors that were previously recognized as key mediators of vascular pathologies [6].

Several studies have been performed over the last two decades to assess the relation between PDGF and liver fibrosis [Table 1] and [Table 2]. They have indicated that PDGF, one of the most potent recognized mitogens, promotes liver fibrosis through activation of hepatic stellate cells (HSCs). Moreover, PDGF is overexpressed in liver tissue during fibrogenesis [15]. Besides, a substantial number of studies on the effect of PDGF antagonists on liver fibrosis have been published [Table 3]. These studies found that usage of PDGF antagonists inhibit liver fibrosis, whereas only one study has found that PDGF expression decreases with advancement of fibrosis [14]. Thus, this review aims to assess the potential changes of PDGF levels in liver fibrosis and evaluate their relation to the grade of fibrosis.{Table 1}{Table 2}{Table 3}

 Patients and Methods



Search strategy

We reviewed papers on the relation between PDGF and liver fibrosis from the PubMed database. We used PDGF and liver fibrosis as search terms. The search was performed in the electronic database from the start of the database to 2017.

Study selection

Each study was independently assessed for the following inclusion criteria:

Posted in peer-reviewed journalsPublished in English languageTargeted on PDGF in liver fibrosis.

We used the latest publication when a study had several publications on certain aspects.

Data extraction

If the studies did not fulfill the above criteria, they were excluded, such as studies on other growth factors, studies about liver fibrosis without assessment of level of PDGF, report without peer-review, studies not within the national research program, letters/comments/editorials/news, and studies not focused on PDGF in liver fibrosis.

The assessed studies 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 [Figure 1].{Figure 1}

US Preventive Services Task Force:

Level I: evidence taken from at least one well-designed randomized controlled trial

Level II-1: evidence came from properly designed controlled trials but without randomization

Level II-2: evidence that was obtained from properly designed cohort or case–control studies, especially, from more than one center or research group

Level II-3: evidence that came from multiple time series with or without an intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence

Level III: opinions of expert committees, based on clinical experience, descriptive studies, or reports of respected authorities.

Quality assessment

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

Data synthesis

A structured systematic review was performed with the results tabulated.

 Results



Study selection and characteristics

In total, 423 potentially relevant publications were identified, and 384 articles were excluded as they did not meet our inclusion criteria [Figure 2]. A total of 39 studies were included in the review as they were deemed eligible by fulfilling the inclusion criteria. The majority of the studies assessed the changes of PDGF in liver fibrosis.{Figure 2}

The relation between platelet-derived growth factor and liver fibrosis was investigated in eight studies

Out of eight studies four of which measured PDGF level in hepatic tissue [Table 1] and four measured it in serum and one study measured it in platelets [Table 2].

Changes in hepatic PDGF according to evidence-based medicine [Table 1].

There are four studies that measured the PDGF level in hepatic tissue, one of which was animal study and three were human studies.

The animal study [Table 1] [12] (which comes in the base of the Evidence Pyramid and provides the least strength of evidence) investigating PDGF in liver fibrosis induced in experimental animals found that PDGF and its receptors are overexpressed in liver fibrosis and they help the progression of fibrosis.

Regarding the three human studies [Table 1], there were two case–control studies with level II-2 or (level B) EBM [8],[10], which reported that hepatitis B virus particles may stimulate HSC proliferation by acting on PDGF-B/platelet-derived growth factor receptor (PDGFR)-β signaling pathway that plays a key role in liver fibrosis and that mRNA expression of PDGF in platelets was remarkably lower in late fibrosis than in early-stage fibrosis, respectively. There was also one purposive nonrandomized study with level II-1 EBM [9], which concluded that PDGF and its receptor mediate the progression of liver fibrosis and highly correlate with the stage of liver fibrosis.

Changes in serum platelet-derived growth factor according to evidence-based medicine [Table 2].

In all, four studies had measured PDGF level in serum, two of which were cohort studies with level II-2 EBM [11],[14], which reported that serum levels of PDGF-BB can predict degree of liver damage and stage of liver fibrosis in CHB and that serum PDGF-BB reduced significantly with advancement of fibrosis in patients with CHB, respectively.

There was also one case–control study with level II-2 EBM [12], which reported that there was significant positive correlation between serum levels of PDGF and degree of liver fibrosis.

There was also one case report [13], which comes in level II-3 EBM, which reported that the PDGF pathway may play a central role in the fibrogenesis of multiple organs in patients with transient myeloproliferative disorder.

Changes in platelet platelet-derived growth factor according to evidence-based medicine [Table 2].

Only one case–control study with level II-2 or (level B) EBM [10] exists, which assessed PDGF in platelets and found that mRNA expression of PDGF in platelets was remarkably lower in late fibrosis than in early-stage fibrosis and that PDGF level is lower in platelets than in hepatic tissue.

The effect of platelet-derived growth factor antagonists on liver fibrosis was investigated in five studies

Out of eight studies four of which were animal studies [16],[17],[18],[19] (which comes in the base of the Evidence Pyramid and provides the least strength of evidence). They all reported that interfering with the PDGF pathway by PDGF antagonists leads to inhibition of liver fibrosis and this provides a promising treatment for liver fibrosis. Of five studies, there was only a mini review [15] (which comes in the second level regarding the pyramid of EBM) which reported that several PDGF antagonists inhibit fibrogenic activation in culture and in some animal models of liver fibrosis and suppression of PDGFR-β signaling with tyrosine kinase inhibitors proved effective in the early stage than in the advanced stage of fibrosis [Table 3].

 Discussion



Liver fibrosis is the unusual accumulation of extracellular matrix (ECM) proteins like collagen, which occurs in the majority of chronic liver diseases. Advanced liver fibrosis leads to cirrhosis, liver-cell failure, and portal hypertension and usually requires liver transplantation [20].

The underlying cellular mechanisms involved in hepatic fibrogenesis basically include the activation of HSCs, which is the principal fibrogenic cell type in the liver. After injury by any of the causes of hepatic fibrosis, HSCs go through a reaction called 'activation', in which quiescent cells transition into proliferative myofibroblasts that have the ability to produce ECM proteins. Hepatocytes and Kupffer cells are involved in the initiation and perpetuation of HSC activation through release of several compounds that cause paracrine stimulation of HSCs, including reactive oxygen species, cytokines, and growth factors [Figure 3]. Activated HSCs respond to these paracrine signals through proliferation, chemotaxis, contractility, release of cytokines and chemokines, deposition of ECM molecules, and loss of retinoids [21]. PDGF plays a central role in most of these responses, especially, in HSC proliferation and chemotaxis.{Figure 3}

Liver biopsy is considered the gold-standard technique for investigating liver fibrosis [4]. Histological examination is useful in recognizing the underlying cause of liver illness and in evaluating the necroinflammatory stage and the degree of fibrosis. Fibrosis stage is assessed using scales such as Metavir (stages I–IV) and Ishak score (stages I–V). Liver biopsy is an invasive process, associated with pain occurring in 40% of patients and major complications in 0.5% of patients [22] in addition to sampling error, especially when the biopsies are too small to be analyzed. Histological examination is vulnerable to intraobserver and interobserver variation and does no longer predict disease progression [23]. Consequently, there is a need for dependable, easy, and noninvasive methods for assessing liver fibrosis. Scores that involve routine laboratory tests, such as platelet count, prothrombin time, aminotransferase levels, and serum levels of acute-phase proteins, have been proposed [24]. Serum levels of proteins that directly associate with hepatic fibrogenesis are also used as alternative markers of liver fibrosis [25], including N-terminal propeptide of type-III collagen, hyaluronic acid, tissue inhibitor of metalloproteinase type-1, and YKL-40. PDGF is one of these proteins that is closely related to liver fibrogenesis and several studies have been carried out to asses its efficacy as a potential marker for liver fibrosis [11].

PDGF is a stimulant and an important regulator for the proliferation, migration, and survival of mesenchymatous cell lineages. According to the distribution of its receptors, it is capable of inducing stimulation or inhibition of the development of these cells. It is also a potent mitogen for fibroblasts and smooth muscle cells [26].

The PDGF family of growth factors includes four different polypeptide chains encoded using the classical PDGF-A and PDGF-B chains, and by the lately discovered PDGF-C and PDGF-D chains. The four PDGF chains assemble into dimers through homodimerization or heterodimerization and five different resultant dimeric isoforms have been observed so far: PDGF-AA PDGF-AB, PDGF-BB, PDGF-CC, and PDGF-DD [27].

PDGF was first discovered and purified from human blood platelets in 1979. It is synthesized and secreted from a wide variety of cells including macrophages, tumor cells, smooth muscle cells, vascular endothelial cells, and fibroblasts [28].

PDGF comprises a series of secretory growth factors that play critical roles in the pathogenesis of liver fibrosis. PDGF activates HSCs and stimulates portal fibroblast proliferation. Besides, it regulates chemotaxis, cell migration, and cell survival [15]. Inside the liver, PDGF levels have been shown to correlate with the incidence of liver fibrosis attributable to different causes [9]. During fibrogenesis, PDGF is secreted by variable cell types as a response to injury, and numerous proinflammatory cytokines control their mitogenic effects through the autocrine release of PDGF. The effect of PDGF is determined through the relative expression of PDGFR-α and PDGFR-β on myofibroblasts. These receptors are stimulated during fibrogenesis, therefore, amplifying biological responses to PDGF isoforms. The effect of PDGF is also mediated by extracellular binding proteins and matrix molecules [29].

Reviewing recent studies about the relation between PDGF and liver fibrosis, we found that serum and hepatic PDGF levels increase in patients with liver fibrosis [Table 1] and [Table 2]. Although the platelet level of PDGF was measured in only one study (case–control study) [10] and it was lower in platelets than in hepatic tissue, the author explains this lower level of PDGF as being consumed by TGFB1 activation.

There was a strong positive correlation between PDGF and fibrosis grade in almost all studies except in one cohort study [14] that had inconsistent results, as it reported that serum PDGF-BB decreased remarkably as fibrosis progressed in patients with CHB. There could be a potential bias in study methodology or in the selection of patients.

Studies in our review that investigated the effect of PDGF antagonists on liver fibrosis [Table 3] had found that inhibition of PDGF pathway leads to reduction of liver fibrosis.

It is recommended that future studies should be carried out to identify the source of PDGF that is elevated during liver fibrosis, and whether it is secreted from hepatic cells, blood platelets, or from platelet pools in the liver.

 Conclusion



This review concluded that PDGF levels increase in patients with liver fibrosis and its level correlates well with fibrosis stage; therefore, PDGF could be used as a potential noninvasive marker for liver fibrosis. Further, antagonizing the pathway of PDGF may offer a promising strategy for the treatment of liver fibrosis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Xu J, Liu X, Koyama Y, Wang P, Lan T, Kim I, et al. The types of hepatic myofibroblasts contributing to liver fibrosis of different etiologies. Front Pharmacol 2015; 5:167.
2Ellis E, Mann D. Clinical evidence for the regression of liver fibrosis. J Hepatol 2012; 56:1171–1180.
3Guo J, Friedman SL. Hepatic fibrogenesis. Semin Liver Dis 2007; 27:413–426.
4El-Saeida GK, El-Sharawya AA, Tahaa HE, Fathya WM, El-Morsy Bedira IS. Assessment of laminin level and its comparison with five liver fibrosis indices in chronic hepatitis B and C patients. Menoufia Med J 2016; 29:354–359.
5Ray Kim W, Berg T, Asselah T, Flisiak R, Fung S, Gordon SC, et al. Evaluation of APRI and FIB-4 scoring systems for non-invasive assessment of hepatic fibrosis in chronic hepatitis B patients. J Hepatol 2016; 64:773–780.
6Paul D, Lipton A, Klinger I. Serum factor requirements of normal and simian virus 40-transformed 3T3 mouse fibroplasts. Proc Natl Acad Sci USA 1971; 68:645–652.
7Kocabayoglu P, Lade A, Lee YA, Dragomir AC, Sun X, Fiel MI, et al. β-PDGF receptor expressed by hepatic stellate cells regulates fibrosis in murine liver injury, but not carcinogenesis. J Hepatol 2015; 63:141-147.
8Bai Q, An J, Wu X, You H, Ma H, Liu T, et al. HBV promotes the proliferation of hepatic stellate cells via the PDGF-B/PDGFR-β signaling pathway in vitro. Int J Mol Med 2012; 30:1443–1450.
9Lou SM, Li YM, Wang KM, Cai WM, Weng HL. Expression of platelet-derived growth factor-BB in liver tissues of patients with chronic hepatitis B. World J Gastroenterol 2004; 10:385–388.
10Tanikawa AA, Grotto RM, Silva GF, Ferrasi AC, Sarnighausen VC, Pardini MI. Platelet-derived growth factor A mRNA in platelets is associated with the degree of hepatic fibrosis in chronic hepatitis C. Rev Soc Bras Med Trop 2017; 50:113–116.
11Diang XC, Ma LN, Li YF, Liu XY, Zhang X, Liu JY, et al. Association between serum platelet-derived growth factor BB and degree of liver damage, fibrosis and hepatitis B e antigen (HBeAg) status in CHB patients. Hepatogastroenterology 2012; 59:2357–2360.
12Talaat RM. Soluble angiogenesis factors in Sera of Egyptian patients with hepatitis C virus infection: correlation with disease severity. Viral Immunol 2010; 23:151–157.
13Ogawa J, Kanegane H, Tsuneyama K, Kanezaki R, Futatani T, Nomura K, et al. Platelet-derived growth factor may be associated with fibrosis in a Down syndrome patient with transient myeloproliferative disorder. Eur J Haematol 2008; 81:58–64.
14Zhou J, Deng Y, Yan L, Zhao H, Wang G China HepB-Related Fibrosis Assessment Research Group. Serum platelet-derived growth factor BB levels: a potential biomarker for the assessment of liver fibrosis in patients with chronic hepatitis B. Int J Infect Dis 2016; 49:94–99.
15Borkham-Kamphorst E, Weiskirchen R The PDGF system and its antagonists in liver fibrosis. Cytokine Growth Factor Rev 2016; 28:53–61.
16Wang X, Wu X, Zhang A, Wang S, Hu C, Chen W, et al. Targeting the PDGF-B/PDGFR-β interface with destruxin A5 to selectively block PDGF-BB/PDGFR-ββ signaling and attenuate liver fibrosis. EBioMedicine 2016; 7:146–156.
17Chen Q, Chen L, Kong D, Shao J, Wu L, Zheng S. Dihydroartemisinin alleviates bile duct ligation-induced liver fibrosis and hepatic stellate cell activation by interfering with the PDGF-βR/ERK signaling pathway. Int Immunopharmacol 2016; 34:250–258.
18Lin X, Kong LN, Huang C, Ma TT, Meng XM, He Y, et al. Hesperetin derivative-7 inhibits PDGF-BB-induced hepatic stellate cell activation and proliferation by targeting Wnt/β-catenin pathway. Int Immunopharmacol 2015; 25:311–320.
19Tsai TH, Shih SC, Ho TC, Ma HI, Liu MY, Chen SL, Tsao YP. Pigment epithelium-derived factor 34-mer peptide prevents liver fibrosis and hepatic stellate cell activation through down-regulation of the PDGF receptor. PLoS One 2014; 9:e95443.
20Bataller R, Brenner DA. Liver fibrosis. J Clin Invest 2005; 115:209–218.
21Friedman SL. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J Biol Chem 2000; 275:2247–2250.
22Thampanitchawong P, Piratvisuth T. Liver biopsy: complications and risk factors. World J Gastroenterol 1999; 5:301–304.
23Regev A, Berho M, Jeffers LJ, Milikowski C, Molina EG, Pyrsopoulos NT, et al. Sampling error and intra-observer variation in liver biopsy in patients with chronic HCV infection. Am J Gastroenterol 2002; 97:2614–2618.
24Forns X, Ampurdanès S, Llovet JM, Aponte J, Quintó L, Martínez-Bauer E, et al. Identification of chronic hepatitis C patients without hepatic fibrosis by a simple predictive model. Hepatology 2002; 36:986–992.
25Fontana RJ, Lok AS. Noninvasive monitoring of patients with chronic hepatitis C. Hepatology 2002; 36:S57–S64.
26Manoranjan SJ, Faizuddin M, Hemalatha M, Ranganath V. The effect of platelet derived growth factor-AB on periodontal ligament fibroblasts: an in vitro study. J Indian Soc Periodontol 2012; 16:49–53.
27Gamal AY, Mailhot JM. The effect of local delivery of PDGF-BB on attachment of human periodontal ligament fibroblasts to periodontitis-affected root surfaces – in vitro. J Clin Periodontol 2000; 27:347–353.
28Ross R. Platelet-derived growth factor. Lancet 1989; 1:1179–1182.
29Bonner JC. Regulation of PDGF and its receptors in fibrotic diseases. Cytokine Growth Factor Rev 2004; 15:255–273.