Liver Research – Open Journal

Background
Earlier, we reviewed different methods of treating non-alcoholic fatty acid liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), concentrated on organokines liberated by adipose tissue (AT) and liver (adipoklines and hepatokines), adipokines in obesity with heart failure (HF), and myokines like irisin in exercise in obesity, and thought they might work as diagnostic and therapeutic targets in NAFLD and NASH with hepatocellular carcinoma (HCC). These are believed to be biological markers that can anticipate the robustness of NAFLD from NAFLD to HCC.
Methods
We conducted a narrative review utilizing search engines PubMed, Google Scholar; Web of Science; Embasee; Cochrane Library utilizing the MeSH terms “NAFLD”; “NASH”; “Organokines”; “Adipokines”; “Hepatokines”; “Myokines”; “Osteokines”; “Stellakines”; “Fructose”; “Gut Microbiota”; “Insulin resistance (IR)”; “Crosstalk of organokines”; “Obesity”; “T2D” from last 10-years till date in 2023.
Results
We found a total of 750 articles, out of which we selected 95 for this review. No meta-analysis has been done.
Conclusion
As acknowledged earlier, NAFLD possesses the characteristics of simple steatosis, while NASH progresses to hepatic steatosis, lobular inflammation, and an escalated diameter of hepatocytes (ballooning of hepatocytes) with or without fibrosis in 20% of cases of NAFLD. Usually, it is correlated with metabolic diseases like obesity, type 2 diabetes mellitus (T2DM), and metabolic syndrome (MetS); hence, the liberation of organokines gets manipulated in a way that might aid in the etiopathogenesis or propagation of disease. We observed that insulin resistance (IR), oxidative stress (OS), mitochondrial impairment, fructose, and gut microbiota reflected factors taking part in the development and propagation of NASH. Alterations in various organokines (inclusive of adipokines, hepatokines, myokines, osteokines, and a newer one, stellakines) produced by hepatic stellate cells (HSCs) were further seen to directly or indirectly aid in the exacerbation and propagation of disease or cause dysfunctional homeostasis. Moreover, we discuss the role of stellakines in detail, and targeting silymarin might give us an efficacious drug for the early treatment of NAFLD or NASH.

Background: Population aging is coupled with an increased morbidity rate of chronic diseases, and the lesions are mostly related to the liver, joints, and adipose tissues. Chronic diseases not only influence personal health but also increase national health and medical expenses. Non-alcoholic fatty liver disease (NAFLD) is the most familiar chronic liver disease (CLD) in the world. It will cause liver fibrosis or death without treatment, but there is no certified drug for treatment. According to many studies, artichoke (Cynara scolymus L.) extract, Kenponashi (Hoveniadulcis thunberg) extract, sanghuangporus sanghuang (Phellinuslinteus) extract, fructus schisandrae (Schisandra chinensis) extract, sesame (Sesamum indicum) extract, vitamin B complex and vitamin E have potential in resisting inflammation and liver fibrosis, but this novel combination for improving hepatic injury has not been studied or discussed in practice.
Objective: This experiment discussed the effect of an artichoke compound (AHC) formula containing artichoke extract, Kenponashi extract, sanghuangporus sanghuang extract, fructus schisandrae extract, sesame extract, vitamin B complex and vitamin E on improving the chronic hepatitis of rats induced by carbon tetrachloride(CCl4).
Design: A total of 50 six-week-old male Wistar rats were divided into five groups for use in the experiment, including the control group and four experimental groups (CCl4). The CCl4 groups were given carboxymethylcellulose (CMC) or AHC (318, 636 and 1,590 mg/kg, represented by AHC-L, AHC-M, and AHC-H, respectively). All rats were fed AHC for one week at first. Starting from the second week, the control group was fed olive oil (0.2 ml/100 g) per os, while the experimental group was fed with CCl4 20% twice per week for eight-weeks. During the experimental period, CMC or AHC was given to the rats once per day. All rats were sacrificed in the ninth-week to analyze their body weight, food intake, body fat content, serum biochemical value and liver lipids.
Results: The results showed that the final spleen weight of the CCl4+AHC-H group was significantly lower than that of the CCl4 +CMC group; the AST concentration in the plasma of the CCl4+AHC-L, M and H groups was significantly lower than that of the CCl4+CMC group; the ALT concentration in the plasma of the CCl4+AHC-H group was significantly lower than that of the CCl4+CMC group; the triglyceride and cholesterol concentrations in the plasma of the CCl4+AHC-L, M and H groups were significantly lower than that of the CCl4+CMC group; the GSH concentration in the livers of the CCl4+AHC-L and H groups was significantly higher than that of the CCl4+CMC group; the hepatic fibrosis of the CCl4+AHC-L, M and H groups were significantly lower than that of the CCl4+CMC group (p<0.05).
Conclusion: AHC could reduce the ALT and AST values of rat plasma induced by CCl4, increase the antioxidant GSH content in the liver, and reduce the degree of hepatic fibrosis. It has the potential to be a natural and mild plant extract dietary supplement. Its long-term administration effect on the human body should be observed in the future.

Aim
In Africa’s malaria-endemic regions, artesunate/amodiaquine (A/A) and artemether/lumefantrine (A/L) are the antimalarial medications that are most frequently prescribed. Antimalarial medications could be overused if they are self-prescribed based on symptoms rather than a parasitological diagnosis. This investigation looked at potential cytotoxic and oxidative stress effects following three dosage treatments spaced 24 h apart.
Method
Artesunate (50 μM and 100 μM), Amodiaquine (1 μM and 10 μM), Artemether (200 μM and 400 μM), and Lumefantrine (200 μM and 400 μM) were administered to HepG2-derived VL-17A for up to 72 h.
Result
With a downward trend from 24 h to 48 h to 72 h, the study findings showed that repeated administration of these medications greatly reduced cell viability. Additionally, for artemether 200 μM treatment, the reactive oxygen species (ROS) levels increased after 24 h and 48 h but considerably decreased after 72 h. The ROS levels in artesunate, amodiaquine, artemether 400 μM, and lumefantrine were also noticeably lower after 72 h.
Conclusion
The results of this experiment show that repeated applications of anti-malaria drugs, A/L and A/A to HepG2 liver cells reduced their viability in a manner that was consistent. These findings have significant implications for those who use antimalarial medications as a preventative measure without a diagnosis of parasite infection.

It is well known that acute liver failure (ALF) in children is rare but potentially a life-threatening disorder. Its true incidence in the pediatric population is undetermined but is responsible for 10-15% of all pediatric liver transplantations. 1 Unlike adults, a specific cause of pediatric ALF is not identified in almost half of the cases, 2 and the etiology is classified as indeterminate in 18-47% of all patients. 1 The etiology is important because the survival rate and need for liver transplantation vary depending on the diagnosis. Spontaneous recovery is better in children with toxic etiology and worst for those with indeterminate or other causes. 1,2 There is no specific treatment for most ALF cases, and the mainstay of medical care is to minimize complications and to limit additional morbidity. 3 ALF can be associated with rapidly progressive multiorgan failure and high mortality rates. One of the leading causes of death is cerebral edema and intracranial hypertension (ICH), responsible for about 20-25% of all deaths. 3 From that perspective, it is desirable to develop new therapies/technologies for diagnostic investigation and interventions. The use of transcranial Doppler (TCD) is an important component in the assessment of cerebral edema, which should be monitored. Some centers use invasive intracranial pressure (ICP) monitoring; however, non-invasive monitoring of cerebral arterial flow is becoming a useful tool to identify ICH. 1 Two relevant articles 4,5 tried to demonstrate the usefulness of TCD to characterize the cerebral hemodynamics patterns in patients diagnosed with ALF. TCD is becoming an important tool since there is no risk of complications like bleeding or infection, which can occur in the use of invasive ICP monitoring. 4,6 The complication risk is around 20%, and there are limited therapeutic options for ICH, 6 which should be taken into consideration to indicate invasive procedures. Besides that, Aggarwal et al 6 studied whether TCD waveform features could be used to differentiate ALF patients with respect to ICP or cerebral perfusion pressure (CPP) levels. They concluded that TCD could provide information about the dynamic state of the intracranial circulation and perfusion with clinical complications. Another issue is the use of continuous renal replacement therapy (CRRT) on pediatric ALF. 7 As mentioned before, the pediatric ALF is a dramatic clinical syndrome in which children has rapid deterioration of hepatic function and can evolve to multiorgan failure and cere-bral edema. As found by Deep et al 7 patients who benefited most from CRRT were those with toxic cause unlike the patients with metabolic causes. Therefore, clinicians should be careful in the selection of patients who underwent CRRT, as the cause of pediatric ALF is determinant for prognosis. That is important to consider because of the possible complications related to CRRT. Santiago et al 8 found in their study that CRRT-complications are common in children and some are potentially serious, the majority were problems of venous catheterization, hypotension on connection to CRRT, electrolytes disturbances and clinically significant hemorrhage. Probably this can be diminished by ultrasound-guided catheter placement, as well as the choice to use prostacyclin instead of regional citrate anticoagulation, and standardized service practices. 9 Despite these two useful tools, another relevant resource to be used by intensivists is the ammonia level. It is well known that the ammonia level is an independent risk factor for the development of severe hepatic encephalopathy and ICH. Bernal et al 10 demonstrated that

Iron (Fe) and copper (Cu) overloads in rats showed a dose and time dependent metal accumulation in liver with its associated toxicity. The increased contents of the transition metals markedly enhanced the endogenous free-radical mediated processes of phospholipid peroxidation. In vivo liver chemiluminescence showed an increased production of 1 O 2 , and a consumption of reduced glutathione (GSH), the main intracellular antioxidant. Results fit with a Haber-Weiss type molecular mechanism in which Fe or Cu and endogenously produced O 2-and H 2 O 2 , yield HO • that initiates free-radical mediated phospholipid peroxidation and protein oxidation.

During almost half of century period, in the Department of Surgery of Portal Hypertension and Pancreatoduodenal Zone of the JSC "Republican Specialized Center of Surgery (named after Academician V. Vakhidov"), portosystemic shunting (PSSh in the traditional variant) was performed on 925 patients suffering with portal hypertension (PH). Results and competitive prospects of PSSh in patients with PH are represented in this article. In accordance with literature data, as well as our own experience, competitive prospects of traditional PSSh, endoscopic methods and transjugular intrahepatic portosystemic shunting (TIPS), in patients with portal hypertension, were defined. For patients with functional class A and B (Child-Pugh), and in the absence of liver transplantation prospects, central partial or selective PSSh, can be considered as competitive alternative.

Introduction of Direct Acting Antivirals (DAA) to Hepatitis C Virus (HCV) treatment armamentarium has offered a great boost to the providers' confidence to safely and effectively treat HCV infection in the majority of patients. However, the cost of these medications is high and thus access is poor. Medicaid insurance providers have devised stringent eligibility criteria to approve the cost of DAA for its members. We reviewed the criteria among various Medicaid agencies from States of Ohio and Pennsylvania and noticed similarities and differences among them. The prerequisite process demanding clinical, laboratory, radiologic or histologic documentation is quite cumbersome and sometimes confusing. In certain aspects the eligibility requirements for DAA are not in concordance with the clinical evidence provided by the recently updated guidelines. We have addressed the dilemma most of the providers face while planning HCV treatment for the Medicaid insured patients in regards to the needed testing, clinical documentation and liver fibrosis assessment, along with the clinical implications of such requirements. While HCV remains a major public health issue, variable State Medicaid policies may lead to disparity in access to the emerging DAA with subsequent healthcare outcomes. These gaps may compromise long term efforts of the public health HCV initiatives.

Non-alcoholic fatty liver disease (NAFLD) is an emerging epidemic in light of its two predisposing factors, a surge in both obesity and diabetes rates with reports of between 70-80% of obese individuals in Western countries. The disease progression of NAFLD remains elusive but is generally attributed to insulin resistance, lipid metabolism dysfunction, altered immune response to name a few. Potential therapeutic strategies should target one or some of these pathological events in the liver, however currently no specific therapies for NAFLD exist. Thus novel therapeutic approaches to manage the chronic liver disease epidemic are becoming essential. In this review we discuss the evidence supporting the role of bile acid activated Farnesoid X Receptor (FXR) in promoting lipid oxidation, reducing inflammation and fibrosis in the liver. We also examine the potential of FXR agonists, as an attractive class of drugs for the safe and effective treatment of NAFLD.

Clinicians are always in search of a less invasive method of diagnosing and assessing a patient. Patients with liver cirrhosis are no exception. Liver cirrhosis is the end stage of many liver pathologies and knowledge of the onset and stage of liver cirrhosis is important to the clinician as it dictates the treatments on offer. This has become increasingly important in viral hepatitis, as it determines level and timing of anti-viral therapy. Furthermore, onset of cirrhosis would alert the physician to screen for varices and hepatocellular carcinoma. To date the gold standard for diagnosing and staging liver cirrhosis is percutaneous liver biopsy. This is expensive and carries a significant complication rate and a small mortality rate. There could also be sampling error and it only shows if the area targeted has the cirrhotic changes, and does not give the picture of the entire liver. There have been attempts at non-invasive tests like the Fi-brotest and ultrasound based elastography. There are at least two methods of ultrasound based elastography. Deformation elastography depends on the constant pressure/stress applied to the organ and shear wave elastography in which a shear wave is applied and propagation measured. These measures are at best qualitative and has a disadvantage of being operator dependent and subjects who have small livers or prominent fat cover may be difficult to assess. 1 Magnetic Resonance Elastography (MRE) was first described in 1995. Since then the technique has been refined and applied to the liver. The technique uses propagating mechanical shear waves. The waves propagate more quickly in stiffer tissue. Wave propagation depends on wavelength, so the stiffer the tissue, the lower frequency (longer wavelength) is required to propagate the wave a given distance. A wave generator is applied to the liver at a frequency range of between 20-200 Hz. Imaging is done in one or more breathe holds and wave images taken. Special software generates elastograms that quantitatively display the tissue stiffness which can be displayed numerically or as colour-coded overlay on the Magnetic Resonance Imaging (MRI) images. (Figure 1) Figure1: Normal liver is pictured on the left and the cirrhotic liver on the right. The top image is the MRI scan, the second row show the shear wave signal and the third, the integrated shear stiffness in kPa, colour coded as shown.

Background: Hepatic Myelopathy (HM) is a rare complication of chronic liver disease usually associated with extensive portosystemic shunt of blood, which has been created surgically or has occurred spontaneously, causing progressive spastic paraparesis. Some single cases or short clinical reports describing patients suffering from HM have been published worldwide, but are often scattered. Material and method: One additional case of HM with typical symptoms was presented, and a retrospective survey of the literature in a manner of comprehensive review was undertaken. Results: 46 case reports with 98 patients of HM including ours have been eligibly selected. General information on all cases was summarized. Detailed analysis of the clinical characteristics of HM patients was undertaken. Conclusion: Liver cirrhosis caused by hepatitis B infection and alcoholism is the most frequent causes of HM. Portosystemic shunt which resulted in chronic exposure to toxic substances bypassing the liver play an important role in the pathogenesis. The pathology study consistently disclosed a selective and symmetrical severe loss of myelin in both lateral pyramidal tracts. The predominant neurologic abnormality of HM is the progressive spasticity and weakness in the lower extremities. A typical manifestations, such as triparesis or quadriparesis, sensory deficit, urinary or bladder incontinence and non-pyramidal manifestations such as dysarthria, tremor and ataxia can also occur, which render the disorder more complicated to be diagnosed. Plasma ammonia concentrations were frequently found to be elevated. MEP provides evidence of the early diagnosis of HM and assesses different degrees of neurological involvement. The spinal cord MRI imaging shows no abnormality. Abnormalities of brain magnetic resonance combined with syndrome of brain dysfunction, hepatocerebral degeneration should be taken into consideration. Appending case studies suggest that liver transplantation is a promising therapeutic strategy.

Non-alcoholic fatty liver disease (NAFLD) and Non-alcoholic steatohepatitis (NASH)
are associated with cardiovascular events and Metabolic Syndrome (MetS). NAFLD is considered to be a hepatic manifestation of MetS and has become an important public health issue
because of its high prevalence. It is currently being considered an independent Cardiovascular
disease (CVD) risk factor. In this clinical review, we will briefly review the mechanisms linking
NAFLD to the complement system, endothelial dysfunction and the atherosclerosis.

Drug-induced liver injury (DILI) accounts for approximately 10 percent of all cases of acute hepatitis. The patterns of acute injury include any form of hepatic injury, but the most common problems are cholestasis, hepatocellular damage, or a mixed type. DILI is often reversible, and discontinuation of the offending agent usually results in a complete recovery; however, some cases may lead to chronic liver injury, cirrhosis, and even death. Temozolomide (TMZ) is an alkylating, anti-neoplastic agent used for the treatment of refractory anaplastic astrocytoma, newly-diagnosed Glioblastoma multiforme (GBM) and metastatic melanoma. Levetiracetam (LEV) is an established second-generation antiepileptic drug and is most commonly approved as adjunctive treatment of partial-onset seizures with or without secondary generalization. When administered separately each of these drugs is considered to be relatively safe and only few cases of severe liver injury can be found throughout the literature; however, LEV and TMZ are commonly used together in the treatment of brain malignancies. We report three patients who presented with jaundice during treatment with TMZ and LEV, and propose a mechanism for liver sensitization by LEV for TMZ-induced injury.

The unique dual circulation of the liver confers relative protection against ischemic injury; however, low oxygen tension in the microcirculation (sinusoidal blood of the hepatic acinus) may render hepatocytes in zone 3 relatively vulnerable to ischemic injury and necrosis. Severe congestive heart failure is associated with two distinct forms of liver dysfunction under the umbrella term “cardiac hepatopathy”. The two entities include: jaundice related to passive
congestion (congestive hepatopathy from backward cardiac failure) and acute hepatocellular necrosis caused by impaired hepatic perfusion (hypoxic hepatitis from forward cardiac failure). This article provides a comprehensive, up-to-date review on the topic and focuses on the epidemiology, pathology, pathogenesis, clinical manifestations, diagnostic testing and treatment strategies pertaining to liver disease in circulatory failure.

Hepatocellular carcinoma (HCC), one of the most frequent neoplasms worldwide, causes more than 700,000 deaths per year, and is the third cause of cancer-related mortality. HCC occurs after years of damage to hepatocytes with inflammatory conditions due to Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) infection resulting in chronic hepatitis and/
or cirrhosis.