Calling a stage-based treatment model for chronic liver diseases in China mainland

China is regarded as the “leader in liver diseases” because that one-fifth of the population was affected by some forms of liver diseases in this developing country. In addition to common infectious liver diseases (such as viral hepatitis and parasitic liver diseases), non-infectious liver diseases such as fatty liver diseases (FLD), drug-induced liver injury (DILI), alcoholic liver diseases (ALD), autoimmune liver diseases (AILD), vessel-related liver diseases, genetic metabolic liver diseases and liver masses are present. In recent years, an increasing number of liver diseases have been reported in special populations, including childhood liver diseases, pregnancy-related liver diseases and liver transplant-associated diseases and so on. Absence of characteristic symptoms and signs coupled with a lack of medical knowledge, patients with chronic liver diseases seek medical treatment without a reliable model, which resulted to the chaotic consult medical status in China mainland. This article aims to describe the current seek medical status of chronic liver diseases and discuss a stage-based consulting medical model for chronic liver diseases in China mainland, which would contribute to make rational use of limited medical resources and help to address National Health China 2030 strategy initiated by the Chinese government.     

Acute liver failure as the initial manifestation of acute leukaemia.

BACKGROUND/AIMS: Haematological malignancies seldom cause clinically significant liver disease. Acute liver failure as the initial manifestation of acute leukaemia is very rare and carries a very poor prognosis. METHODS/RESULTS: Three cases of acute liver failure secondary to acute leukaemia are described. Each case presented initially as acute liver failure of uncertain cause. Specific treatment for the leukaemia was instituted; however, all three patients died as a consequence of the liver failure. We describe the clinical course and relevant investigations of these patients and discuss possible mechanisms of acute liver failure in this setting. CONCLUSION: Acute leukaemia presenting as acute liver failure has a very poor prognosis. Although a rare cause of acute liver failure, it should be considered in any patient presenting with acute liver failure with prodromal symptoms and a raised peripheral white cell count, lactate dehydrogenase and uric acid.     

Focal spared area in fatty liver mimicking a tumor

A focal fatty liver change may be associated with several conditions related to diffuse hepatic steatosis, such as a diffuse fatty liver change. Using ultrasonography, the focal fatty liver change appears more frequently as hyperechoic and less frequently as hypoechoic areas in the liver. We report a rare case of a focal fatty liver change in which an area was spared in fatty liver. The patient was a 42-year-old man. Abdominal ultrasonography showed focal hypoechogenicity with an irregular margin in S8 within a bright liver. Abdominal computed tomography and enhanced computed tomography showed a high-density mass in S8 of the right lobe. A microscopic examination of the specimens from the liver biopsy from the hypoechoic region revealed normal hepatic parenchymal cells, while tissue samples from the surrounding liver had a high fat deposition.     

The role of liver biopsy in the management of patients with liver disease.

The role of liver biopsy in the diagnosis and management of liver disease is a controversial issue even among hepatologists. Although most causes of elevated liver enzymes can be determined, or at least suspected, on the basis of a careful history and laboratory tests, histological assessment remains the gold standard for most liver diseases. Histological evaluation can either confirm or refute clinical diagnoses and can provide information about the severity and stage of disease. Occasionally, the liver biopsy also provides an additional diagnosis. The spectrum of nonalcoholic fatty liver disease accounts for a substantial proportion of cases of chronically elevated liver enzymes and can be reliably diagnosed only by liver biopsy. Prognostic information can be obtained in patients with this disorder, as well as in those with alcoholic liver disease and viral hepatitis, and liver biopsy can be used as a guide to their management.     

枯否氏细胞在肝损伤中的作用研究进展

枯否氏细胞在肝脏组织中起重要的保护屏障作用。在内毒素血症相关肝损伤中,枯否氏细胞与模式相关分子受体如Toll样受体结合,主要产生促炎细胞因子及其它化学分子,进而加速肝损伤的进程,而在药物性（如对乙酰氨基酚）肝损伤中,枯否氏细胞能分泌抗炎因子,促进肝脏血管生成,从而起保护作用。本文就近年来内毒素血症相关肝损伤和药物性肝损伤研究进展,对枯否氏细胞在肝脏损伤中的重要作用加以介绍。     

Liver and aging

In conclusion, available data are not sufficient to conclude that ageper se compromises liver functions in general as long as subjects maintain their health. This does not mean, however, that livers in the elderly can always function as efficiently as those in the young. In many situations, where the physical condition of the subjects is impaired, the liver in the elderly will respond to these stresses more sensitively, its function may decline more drastically and the recovery of reduced function may also be slower. In other words, if clinicians find evidence of liver malfunction in the elderly with no obvious liver diseases, (e.g., lower albumin, increase in ICG test, etc.), they should suspect latent morbidity in the patient and be ready for the possible impairment for other liver functions such as drug metabolism and detoxification. In other words, the aging of the liver is not a disease, and the aging liver maintains its sound functions. However, aged liver can be a factor in the reduction of liver functions, if unfavorable conditions like morbidities accompany it. This can occur in any patient with malnutrition and/or infection and, therefore, aging can be regarded as a latent liver disease factor in countries or communities where malnutrition and infections are prevalent. In this sense, the aging liver must be regarded as a potentially diseased liver, with no specific nomenclature.     

Hemostasis in liver resection surgery

Although patients with liver tumors are considered as challenging by hepatic surgeons, advances in liver resection procedures mean that virtually no liver tumor should be considered as unresectable. Newer techniques, such as in situ hypothermic perfusion, the “ante situm technique,” and ex vivo liver resection have been recently introduced. The aim of these techniques is to provide a bloodless field and a prolonged and more precise dissection. The use of recombinant factor VIIa (rFVIIa), a hemostatic agent previously developed for bleed management in patients with hemophilia and inhibitors, has recently been investigated as a means of reducing red blood cell transfusion requirements during major liver surgery. This paper reviews details of this clinical trial, as well as current and future methods to manage hemostasis during liver resection surgery.     

Hepatic tumorigenesis in acute hepatic failure

We report on a 59-year-old woman and a 31-year-old man with no previous medical history of liver disease presenting with acute liver failure probably caused by drug toxicity. High urgency liver transplantation was performed 30 and 51 days after the onset of symptoms, respectively. Histomorphological evaluation of the explanted livers revealed incidental dysplastic nodules and hepatocellular carcinoma of up to 8 mm in diameter. Up to now only a few cases of metastatic liver disease and even fewer cases of primary liver cancer presenting as acute liver failure have been described. Our cases indicate hepatic tumorigenesis not as a cause of hepatic failure but either as an event taking place in parallel or as a process being induced by progressive liver failure.     

Erhöhte Leberwerte: Was tun?

Elevated liver enzymes are a frequent clinical finding with variable significance. The indication for further diagnostic work-up depends on the clinical presentation as well as on the extent and duration of liver enzyme elevation. It is important to recognize that liver enzymes within the normal range do not exclude liver disease, while healthy individuals can present with elevated liver enzymes. Blood chemistry analyses are very valuable as screening tests for liver diseases. They allow a differentiation between liver cell damage (ALT and AST elevated), cholestasis (alkaline phosphatase, bilirubin and y-GT elevated) and liver dysfunction (prolonged INR, albumin and cholinesterase reduced). If the laboratory values indicate any signs of liver disease, further diagnostic procedures are required. These should determine the etiology of the liver disease to allow a specific treatment and in addition provide information about progress and prognosis of the disease.     

Evaluation of liver fibrosis: a concise review

The diagnosis of liver fibrosis has traditionally relied on liver biopsy. However, recent studies have suggested that there can be up to a 33 % error in the diagnosis of cirrhosis. In this article, we review the current status of liver biopsy as a gold standard for the diagnosis of liver fibrosis and discuss the radiological and serum tests that have been proposed as potential adjuncts or alternatives to biopsies. Indirect markers of liver fibrosis which reflect alterations in liver function and or inflammation are discussed as well as more direct markers of liver fibrosis. The limitations of utilization of these markers for both cross-sectional diagnosis of fibrosis and monitoring disease progression or regression are discussed.     

不同阶段慢性乙型肝炎患者外周血单个核细胞中NF-κB/iNOS的表达及免疫状态

目的研究核因子-κB(NF-κB)/诱导型一氧化氮合成酶(iNOS)在不同阶段慢性乙型肝炎患者外周血单个核细胞(PBMC)中的表达,比较各阶段自然杀伤细胞及T、B淋巴细胞的变化情况。方法纳入福建医科大学附属南平第一医院2017年10月-2019年1月慢性乙型肝炎相关疾病患者,按照疾病不同阶段分4组:肝炎组、肝衰竭组、肝硬化组、肝癌组,每组各20例;另选取10例健康志愿者作为对照组。采用流式细胞仪检测5组外周血总淋巴细胞计数和淋巴细胞亚群计数;采用Western Blot检测PBMC中NF-κB、iNOS蛋白的表达水平;硝酸还原酶法和ELISA法检测血清中NO、IL-6水平。多组间比较采用单因素方差分析,进一步两两比较采用LSD-t检验。结果与对照组比较,肝炎组、肝衰竭组、肝癌组、肝硬化组总淋巴细胞计数水平均明显下降(P值均<0.05);与肝炎组比较,肝衰竭组、肝癌组、肝硬化组总淋巴细胞计数水平均明显下降(P值均<0.05)。肝衰竭组、肝癌组、肝硬化组CD3+明显下降,分别与对照组、肝炎组比较差异均有统计学意义(P值均<0.05);肝衰竭组、肝癌组、肝硬化组与肝炎组CD4+比较明显下降(P<0.05);肝衰竭组与肝癌组、肝硬化组、对照组CD8+比较明显升高(P值均<0.05);肝衰竭组较对照组、肝炎组、肝硬化组、肝癌组CD4+/CD8+明显降低(P值均<0.05);肝衰竭组、肝硬化组CD3-CD19+明显升高,分别与肝炎组、对照组比较差异均有统计学意义(P值均<0.05);肝衰竭组、肝癌组CD16+CD56+明显下降,分别与肝炎组、对照组比较差异均有统计学意义(P值均<0.05)。肝硬化组、肝衰竭组、肝癌组NF-κB、iNOS蛋白表达水平均明显增高,分别与肝炎组、对照组比较差异均有统计学意义(P值均<0.05)。与对照组比较,肝衰竭组、肝癌组、肝硬化组和肝炎组的NO和IL-6水平均明显升高(P值均<0.05)。结论不同阶段HBV感染者免疫状态存在一定差异性,NF-κB-iNOS-NO可能参与HBV相关疾病的免疫反应。     

Liver contains heparin-binding growth factors as the major growth factor for cultured fibroblasts.

The presence of heparin-binding growth factors in liver was investigated by measuring the DNA synthesis stimulatory activity of liver extracts using quiescent fibroblasts as target cells. It was found that cytosolic fractions of mouse, rat and human liver, as well as isolated rat hepatocytes, contain a large amount of growth stimulatory activity. Most liver cytosolic activity is due to heparin-binding growth factors, because greater than 90% of the activity bound to a heparin affinity column in the presence of 0.8 mol/L NaCl, and was quantitatively eluted with 2 mol/L NaCl. Purification of these factors from both mouse and rat liver indicated the presence of both heparin-binding growth factor-1 and 2 in liver extracts. The level of the heparin-binding growth factors, as estimated from the biological activity, is approximately 1 microgram/gm mouse liver and 0.1 microgram/gm rat and human liver. Heparin-binding growth factor-1-like factors were 10 times as abundant as heparin-binding growth factor-2-like factors. These data indicate that the cytosolic fractions of mouse, rat and human liver contain heparin-binding growth factors as the primary growth factor for fibroblasts, and heparin binding growth factor-1-like molecules account for most of the cytosolic activity in both mouse and rat liver.     

Orthotopic liver transplantation and the cytosolic estrogen-androgen receptor status of the liver: the influence of the sex of the donor

Mammalian liver is known to contain cytosolic receptors for both estrogens and androgens. Furthermore, certain mammalian hepatic functions are known to display a sexual dimorphism. However, in clinical liver transplantation, the sex of the donor is not taken into consideration in selection of the donor. In this study, the effect of liver transplantation on the estrogen and androgen receptor content of the liver was determined. Adult male and female rats were subjected to orthotopic liver transplantation, using donors from both the same and the opposite sex as the recipient. The animals were killed on the tenth postoperative day, and the livers were assayed to determine their cytosolic estrogen and androgen receptor content. Transplantation of a liver from a male donor into a male recipient, from a male donor into female recipient and from a female donor into a male recipient produced similar changes in the number of cytosolic estrogen and androgen receptors in hepatic cytosol. In all three situations, the estrogen receptor content in the cytosol of the transplanted liver was the same as that found in an unoperated male liver, and the cytosolic content of the androgen receptor was the same as that of an unoperated female liver. After transplantation of the liver from a female donor into a female recipient, the estrogen and androgen receptor content in the cytosol of the transplanted liver was the same as that of an unoperated female.(ABSTRACT TRUNCATED AT 250 WORDS)     

Liver regeneration and tumour stimulation: implications of the renin–angiotensin system

Liver resection is the most effective treatment for primary liver tumours and metastasis to the liver, and remains the only potentially long‐term curative therapy for patients with colorectal cancer (CRC) liver metastases. Nevertheless, there is a significant incidence of tumour recurrence following liver resection. Cellular and molecular changes resulting from resection and the subsequent liver regeneration process may influence the kinetics of tumour growth, contributing to recurrence. Although commonly associated with the systemic homeostasis of blood pressure, fluid and electrolyte, the renin–angiotensin system (RAS) has recently been shown to play a role in regulating cell proliferation, apoptosis and angiogenesis in local organs as well as in malignancies. An electronic search of the English literature on the role of the RAS in liver regeneration and tumourigenesis was performed using PubMed, with additional relevant articles sourced from reference lists. Studies have shown that the blockade of the RAS pathway stimulates liver regeneration and inhibits tumour progression. An understanding of the role of RAS in liver regeneration and tumourigenesis may enable alternative strategies to improve patient outcome and survival after liver resection. This review will discuss the role of the RAS in liver regeneration and in tumour recurrence post‐liver resection. The potential of the RAS as a novel therapeutic target for CRC liver metastases patients undergoing liver resection will be outlined.     

Staging of liver fibrosis or cirrhosis: The role of hepatic venous pressure gradient measurement

Liver fibrosis is a common histological change of chronic liver injury and it is closely related with portalhypertension which is hemodynamic complication of chronic liver disease. Currently, liver fibrosis has been known as a reversible dynamic process in previous literatures. Although liver biopsy is a gold standard for assessing the stage of liver fibrosis, it may not completely represent the stage of liver fibrosis because of sampling error or semi-quantative measurement. Recent evidences suggested that histologic, clinical, hemodynamic, and biologic features are closely associated in patients with chronic liver disease. Hepatic venous pressure gradient(HVPG) measurement has been known as a modality to evaluate the portal pressure. The HVPG measurement has been used clinically for fibrosis diagnosis, risk stratification, preoperative screening for liver resection, monitoring the efficacy of medical treatments, and assessing the prognosis of liver fibrosis. Therefore, the HVPG measurement can be used to monitor areas the chronic liver disease but also other important areas of chronic liver disease.     

Drug-induced autoimmune hepatitis: A minireview

Drug-induced autoimmune hepatitis (DIAIH) is a specific phenotype of drug-induced liver injury that may lead to the devastating outcome of acute liver failure requiring liver transplantation. Drugs implicated in DIAIH include antimicrobials such as nitrofurantoin and minocycline, non-steroidal anti-inflammatory drugs, statins as well as anti-tumor necrosis agents. The clinical features of drug-induced liver injury are indistinguishable from idiopathic autoimmune hepatitis (AIH) as both may have positive AIH-related autoantibodies, elevated immunoglobulin G, as well as similar histopathological findings. In patients who show no clinical improvement, or there is progressive liver injury despite cessation of the suspected drug, a liver biopsy should be considered, whereby the presence of advance fibrosis on histology favors the diagnosis of idiopathic AIH. Empirical treatment with corticosteroids may be required in patients with non-resolving liver injury. A typical clinical scenario supportive of DIAIH includes a history of drug exposure with spontaneous resolution of liver injury after drug withdrawal and the absence of relapse after rapid steroid taper. In this article we report two cases of DIAIH secondary to Sorafenib and Atorvastatin along with a review of currently available literature. Early identification and treatment often lead to a favorable outcome in DIAIH.     

Liver disease in menopause

There are numerous physiologic and biochemical changes in menopause that can affect the function of the liver and mediate the development of liver disease. Menopause represents a state of growing estrogen deficiency, and this loss of estrogen in the setting of physiologic aging increases the likelihood of mitochondrial dysfunction, cellular senescence, declining immune responses to injury, and disarray in the balance between antioxidant formation and oxidative stress. The sum effect of these changes can contribute to increased susceptibility to development of significant liver pathology, particularly nonalcoholic fatty liver disease and hepatocellular carcinoma, as well as accelerated progression of fibrosis in liver diseases, as has been particularly demonstrated in hepatitis C virus liver disease. Recognition of the unique nature of these mediating factors should raise suspicion for liver disease in perimenopausal and menopausal women and offer an opportunity for implementation of aggressive treatment measures so as to avoid progression of liver disease to cirrhosis, liver cancer and liver failure.     

Acute liver failure as the initial manifestation of acute leukaemia

Abstract: Background/Aims: Haematological malignancies seldom cause clinically significant liver disease. Acute liver failure as the initial manifestation of acute leukaemia is very rare and carries a very poor prognosis. Methods/Results: Three cases of acute liver failure secondary to acute leukaemia are described. Each case presented initially as acute liver failure of uncertain cause. Specific treatment for the leukaemia was instituted; however, all three patients died as a consequence of the liver failure. We describe the clinical course and relevant investigations of these patients and discuss possible mechanisms of acute liver failure in this setting. Conclusion: Acute leukaemia presenting as acute liver failure has a very poor prognosis. Although a rare cause of acute liver failure, it should be considered in any patient presenting with acute liver failure with prodromal symptoms and a raised peripheral white cell count, lactate dehydrogenase and uric acid.     

Ischaemia reperfusion injury in liver transplantation: Cellular and molecular mechanisms

Liver disease causing end organ failure is a growing cause of mortality. In most cases, the only therapy is liver transplantation. However, liver transplantation is a complex undertaking and its success is dependent on a number of factors. In particular, liver transplantation is subject to the risks of ischaemia‐reperfusion injury (IRI). Liver IRI has significant effects on the function of a liver after transplantation. The cellular and molecular mechanisms governing IRI in liver transplantation are numerous. They involve multiple cells types such as liver sinusoidal endothelial cells, hepatocytes, Kupffer cells, neutrophils and platelets acting via an interconnected network of molecular pathways such as activation of toll‐like receptor signalling, alterations in micro‐RNA expression, production of ROS, regulation of autophagy and activation of hypoxia‐inducible factors. Interestingly, the cellular and molecular events in liver IRI can be correlated with clinical risk factors for IRI in liver transplantation such as donor organ steatosis, ischaemic times, donor age, and donor and recipient coagulopathy. Thus, understanding the relationship of the clinical risk factors for liver IRI to the cellular and molecular mechanisms that govern it is critical to higher levels of success after liver transplantation. This in turn will help in the discovery of therapeutics for IRI in liver transplantation – a process that will lead to improved outcomes for patients suffering from end‐stage liver disease.     

Benign focal liver lesions: The role of magnetic resonance imaging

Liver lesions are common findings in radiologists’ daily routine. They are a complex category of pathology that range from solitary benign lesions to primary liver cancer and liver metastases. Benign focal liver lesions can arise from different liver cell types: Epithelial (hepatocytes and biliary cells) and nonepithelial (mesenchymal cells). Liver magnetic resonance imaging (MRI) is a fundamental radiological method in these patients as it allows with its multiparametric approach optimal non-invasive tissue characterization. Furthermore, advanced liver MRI techniques such as diffusion-weighted imaging and hepatobiliary contrast agents have improved the detection of focal liver lesions and can be highly effective in differentiating pseudotumor from tumors, as well as benign from malignant lesions, and can also be used for differential diagnosis. Although histological examination can be useful in making a definitive diagnosis, MRI is an important modality in the diagnosis of liver lesions with a significant impact on patient care. This aim of this review is to provide a comprehensive overview of benign liver lesions on MRI.