Cite this asOccurrence, diagnosis and management of hepatic fibrosis and cirrhosis: An updated literature review. Arch Hepat Res 5(1): 022-026. DOI: 10.17352/ahr.000023
Background: Hepatic fibrosis and cirrhosis, characterized with significant morbidity and mortality, have always been worldwide health care problems.
Objective: This manuscript is aimed at providing a research progress overview of hepatic fibrosis and cirrhosis.
Method: Online search for articles published in years from 2009 to 2019 with “hepatic fibrosis”, “cirrhosis”, “therapy”, “liver disease” and “hepatitis” as keywords. The adopted database involves PubMed, MIDLINE, Google Scholar, CNKI and EMBASE.
Result: This review summarizes the latest findings about pathogenesis, diagnosis and therapies of hepatic fibrosis and cirrhosis, and describes their application prospect and future research directions, providing references to some extent for fellow academics.
Liver possesses specific regeneration ability, which usually allowes its reconstruction after acute injuries and moderate diseases. In chronic injuries, however, the liver usually unable to repair itself effectively, with fibrosis being the main complication in this process . Hepatic fibrosis may further develop to liver cirrhosis, liver cancer and other serious complications. The pathological basis of hepatic fibrosis is now considered to be abnormal accumulation of extracellular matrix in liver tissue [2,3].
Liver cirrhosis is an end stage of liver fibrosis, which is characterized by fibrotic septa separated regenerative nodules [4,5]. Liver cirrhosis killed 1.2million people worldwide each year, ranking as 10th cause of death in developed countries . Deformation of liver tissue caused by cirrhosis often leads to related serious consequences, such as intravenous bleeding, portal hypertension and ascites [7,8]. Clinically, complications of cirrhosis include loss of liver function, esophagus varicose veins, ascites with spontaneous bacterial peritonitis, hepatic encephalopathy, hepato-pulmonary syndrome, hepato-renal syndrome and hepatic encephalopathy and hepatocellular carcinoma [9,10].
At present, major limitations of hepatic fibrosis treatment are accurate & non-invasive diagnosis and delaying the course of development [11,12]. In recent years, many studies focus on hepatic fibrosis and cirrhosis have been conducted, expanding our cognitive territory. The purpose of this review is to integrate the current research progress by searching the existing database of Chinese and Western databases, and to provide suggestions for future research.
Various types of chronic injury may lead to liver fibrosis, such as auto-immune destruction of hepatocytes, metabolic diseases, alcohol abuse, congenital abnormalities, drugs and viral hepatitis [13,14]. Since alcoholism is an important death-leading factor among patients with cirrhosis and liver cancers, the association between alcohol and mortality of patients with hepatopathy is obvious [15,16]. In addition, alcohol intake can lead to ascites formation and venous bleeding, according to Peter Jepsen, which further intensify the related complications of liver fibrosis . Possible explanation of association between alcohol intake and chronic liver injury is alcohol potentiation of other hepatotoxins present in the environment at subtoxic levels, according to Hall . Besides, alcohol intake often leads to a rapid increase of portal pressure, which is a common complication of cirrhosis . According to the report, liver fibrosis and cirrhosis is also associated with immune dysfunction in various types, justifying liver cirrhosis being descripted as a common immunodeficiency syndrome . Nearly 35% of patients with liver cirrhosis appear infections with a variety of sources, accounted for 50% of all fatal results [21,22].
The production of cirrhosis involves three main mechanisms, which are cell death, abnormal matrix deposition (fibrosis) and vascular recombination . Extracellular matrixes accumulation in hepatic fibrosis and cirrhosis is resulted by the activation of fibroblasts and obtaining myo-fibroblastic phenotype . For example, Hepatitis drives activation of precursor cells, such as hepatic stellate cells, generating muscle fibroblasts and leading to liver fibrosis [25,26]. It has always been a tough task to develop anti-fibrotic therapies since the associated signal pathways are complex, which make it difficult to identify and modulate the specific targets . Thus, it is essential to figure out the molecular mechanisms underlying the gradual progress of liver fibrosis, which is necessary for developing specific and efficient treatments targeting the cells those are responsible for hepatitis fibrosis and cirrhosis.
Recently, infiltration of immune cells is found to be responsible for the progression of hepatitis fibrosis. Karlmark found that inflammatory Gr1(+) monocytes, which infiltrated into the injured liver via CCR2-dependent bone marrow egress, promoted the progression of hepatitis fibrosis . Therefore, Gr1(+) monocytes may provide an interesting new target for antifibrotic therapies. Besides, Han found that HIF1 mediated PTEN/NF-kBp65 pathway played an important role in the development of nonalcoholic fatty liver disease induced by high fat-diet-and its deterioration into liver fibrosis . Which mains that HIF1 could be targeted for the therapy of fibrosis lesions in liver. In addition, Ma studied a single-nucleotide polymorphism in DNA sequence (rs6834314) and its nearest gene (HSD17B13) to identify their associations with nonalcoholic fatty liver disease. and to characterize the role of HSD17B13 in of of nonalcoholic fatty liver disease She reported that HSD17B13 plays an important functional role in pathogenesis and histological features of nonalcoholic fatty liver disease by way of its enzymatic activity . Thus, HSD17B13 may become a valuable target for gene therapy.
Liver cirrhosis is characterized normal liver architecture converting into abnormal nodules surrounding by circular fibrosis . This chronic progressive clinical disease always leads to liver cell failure accompanied with portal hypertension, which is benefit to the occurrence of hepatocellular carcinoma . Defining the pathological stage of the hepatic fibrosis is essential for therapy choice and prognosis . At present, liver biopsy is still the gold standard for judgment of fibrosis progression [34,35]. Although biopsy is generally accurate in diagnosing of cirrhosis, long-term follow-up in patients with chronic liver disease is always inevitable , which brings considerable operating difficulties and great pain to the patients. Therefore, it would be desirable to develop a repeatedly available and non-invasive method for the assessment of hepatic fibrosis . For example imaging techniques and non-invasive serological tests, which have been suggested as trustworthy parameters . Here, the most recent information from papers about helpful non-invasive methods in defining hepatic fibrosis is described.
Diagnostic imaging technology involves numbers of devices and techniques to evaluate hepatic fibrosis and cirrhosis, for instance, ultrasound Doppler, contrast enhanced ultrasound and elastography [34,39]. Ultrasound is widely used as the basic imaging check but is inadequate to be an accurate method for estimating disease severity . Besides, many of the diagnostic imaging technologies do not permit investigation or grading of pre-cirrhotic liver disease . Recently, Kirubakaran described a technique for distinguishing the cirrhotic liver from the normal liver by adaptive ultrasound rather than ultrasound images with Hybrid Coupled Dictionary Pairs on Longitudinal Domain . This cirrhosis prediction policy helps to modify the results of traditional ultrasound images with the accuracy of 99.82%, helping to supervise the patient health precisely. However, these techniques have a universal limitation that only very small liver volume can be measured at once, which means potentially uncomprehensive result, and the accuracy of this measurement is very dependent on the professionality of operators . In this case, biomarkers same to be a reliable auxiliary reference to effectively increase diagnostic accuracy.
Serum markers diagnostic techniques are less invasive and theoretically free of complications, providing a cost-effective alternative to liver biopsy testing. Serum markers are divided into direct and indirect markers, which can be used alone or combined to produce compound fractions for diagnosis and evaluation of fibrosis lesions . For instance, The hepatic metabolism ability of patients with cirrhosis is reduced and can be measured by galactose elimination capacity test, which is a strong prediction of mortality . Although blood markers and methods have been proposed for non-invasive assessment of hepatitis fibrosis, international guidelines do not recommend their use due to unsatisfactory accuracy and incomplete verification . Hardy lately uncovered dynamic epigenetic markers of fibrosis measurable in patients’ serum, PPAR hypermethylation, that may be useful in non-invasive diagnosis and staging of fibrosis in chronic liver disease patients . Besides, Nonalcoholic Fatty Liver Disease Fibrosis Score (NFS) and Transient Elastography (TE) have been recommended to diagnose advanced fibrosis [47,48]. In addition, the union of the M30 biomarker with NFS or TE allows a more dependable identification in patients with progressed nonalcoholic fatty liver disease according to Liebig .
Hepatic Venous Pressure Gradient (HVPG) measurement is a useful approach in the administration of portal hypertension in liver cirrhosis . Despite of detecting and classifying the severity of portal hypertension, HVPG measurement also provide reliable prognostic information on the danger of complications, disease advances, and survival . However not all patients are HVPG responders, and there is still no accurate non-invasive biomarker to identify. Fortunately, Reverter recently found in univariate analysis that eighteen metabolites were related to the HVPG response, and integration of two metabolites made a contribution in identifying HVPG responders .
Valuable Non-invasive scoring system has been established such as NFS that is mentioned above. Augustinho reported that Quick Sequential Organ Failure Score was linked to survival independently, it appears to be an effective way to determine the severity of infection and identify hepatic fibrosis patients with low sensitivity . In multivariate analysis, Zhao found that cirrhosis on transient elastography was relevant to ages, aspartate aminotransferase, and platelet count, but not to alanine aminotransferase . These indexes form the components of the modified Aspartate Aminotransferase To Platelet Ratio Index Sscore, which is favorable in predicting cirrhosis in hepatitis C virus population .
With the development of biomedical research, diagnosis methods of hepatic fibrosis and cirrhosis evolve into multi-level and multi-angle accompanied with statistical analysis methods. Diagnostic technique is gradually ameliorating towards more safe, non-invasive, more comfortable and high repeatability.
Hepatic fibrosis is usually invertible, however, liver cirrhosis is generally nonreversible . Therefore, delaying the fibrosis process and avoiding the occurrence of cirrhosis is the main goal of clinical treatment [56,57]. In the treatment of hepatic fibrosis, etiology, complications and fibrosis nidus are the main therapeutic objectives [58-60]. The most effective and ideal treatment is to cure the underlying causes of fibrosis lesions before it develops into cirrhosis .
Unfortunately, the current treatment of the causes of chronic liver damage can only delay the development of fibrosis. According to the report, sustaining contact with pro-inflammatory irritation accelerates the pathological process of liver failure . Thus, immune modulation therapies are promising methods for treating hepatic fibrosis, such as blockers of inflammatory signaling pathways [63,64]. Xu found dietary Fisetin intervention could suppress metabolic disorder and hepatic function loss. The mechanism of action involved down-regulating TNF-α/RIPK3 signaling-associated hepatic inflammation and balancing lipid metabolism-related gene expression, and then inhibiting lipid accumulation and steatohepatitis . IL-1Ra, secreted exclusively from tonsil-derived mesenchymal stem cells, has been found to defuse the activation of myoblasts to myofibroblast . Conditioned medium from tonsil-derived MSCs display anti-inflammatory and anti-fibrotic effects in the CCl4-injured mouse liver via the endogenous production of IL-1Ra according to Kim .
Evidence suggests that Ephrins and its receptors are possible molecular regulations of hepatic fibrosis, promoting fibrotic development in many organs . Therefore, treatment options aiming at Ephrin signaling pathway may be new ways for fibro-therapy . Hepatic fibrosis established in animal model can be degraded by drugs targeting the bioactivities of fibrous hepatic stellate cells, this suggests that the established fibrosis could be reversed and even cured . Verbeke reported that Farnesoid-X receptor agonist obeticholic acid demonstrated preventive and treating effects accompanied with decreased hepatic stellate cell activation on hepatic inflammation and fibrosis in cirrhotic animal model . At present, drugs targeting at the signaling pathway stoking fibrosis are still the most effective and direct strategies for liver fibrosis and cirrhosis treatment. With the insight of fibrosis pathogenesis, new targeted drugs or can fundamentally blocking the occurrence of fibrosis lesions.
Some phytochemicals have shown hepatoprotective effects. Solanum nigrum has been used as therapy for different kinds of ailments associated with gastroenterology and hepatology. Moreover, solanum nigrum was an valuable hepatoprotective reagent on account for its effect of modifying the protein and energy in the liver tissue according to Krithika .
As for cell therapy, Duman reported that bone marrow-mesenchymal stem cells might inhibit hepatic fibrosis with expanded intrahepatic natural killer cells on common bile duct ligated rat model. Thus, marrow-mesenchymal stem cells therapy seems to be promising candidate for treatment of end-stage liver diseases .
Fibrosis, the main histopathological change of chronic liver injury, develops into cirrhosis once deteriorates, which often leads to serious complications and considerable mortality. Liver biopsy is the most reliable method for evaluating hepatic fibrosis at present. Nevertheless, it still has many drawbacks and cannot give a precise judgment. Early diagnosis of hepatic fibrosis helps to take early intervention timely, avoiding irreversible cirrhosis and other fatal complications, improving prognosis. In addition, it can be treated by anti-inflammation and anti-fibrosis medications. It is urgent to understand pathogenesis and develop more accurate diagnostic methods, as well as exploit new therapies and drugs. Over all, the present and coming information will promote innovation of diagnosis and optimum therapy, thus improving prognosis of hepatic fibrosis, reducing complications and improving cure rate.
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