Any associated cardiovascular disease. Failure to obtain consent. Contacts and Locations. Information from the National Library of Medicine To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor. Please refer to this study by its ClinicalTrials. More Information. The accuracy of ultrasonography for the evaluation of portal hypertension in patients with cirrhosis: a systematic review.

Korean J Radiol. Epub Feb Hypersplenism: History and current status. Exp Ther Med. Epub Sep 7. Hypersplenism is related to age of onset of liver disease. Ir J Med Sci. Epub Oct Splenomegaly as risk factor of liver cirrhosis. A retrospective cohort study of 2, patients who underwent laparoscopy. In Vivo. Increased apoptosis dependent on caspase-3 activity in polymorphonuclear leukocytes from patients with cirrhosis and ascites. J Hepatol. National Library of Medicine U. National Institutes of Health U.

Department of Health and Human Services. The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. In cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic fibrosis that has resulted in widespread distortion of normal hepatic architecture.

Cirrhosis is characterized by regenerative nodules surrounded by dense However, other potentially reversible factors contribute; they include contractility of sinusoidal lining cells, production of vasoactive substances eg, endothelins, nitric oxide , various systemic mediators of arteriolar resistance, and possibly swelling of hepatocytes.

Over time, portal hypertension Portal Hypertension Portal hypertension is elevated pressure in the portal vein. They may slightly decrease portal vein pressure but can cause complications. Engorged serpentine submucosal vessels varices in the distal esophagus and sometimes in the gastric fundus can rupture, causing sudden, catastrophic gastrointestinal bleeding Varices Varices are dilated veins in the distal esophagus or proximal stomach caused by elevated pressure in the portal venous system, typically from cirrhosis.

They may bleed massively but cause no Gastric mucosal vascular congestion portal hypertensive gastropathy can cause acute or chronic bleeding independent of varices. Visible abdominal wall collaterals are common; veins radiating from the umbilicus caput medusae are much rarer and indicate extensive flow in the umbilical and periumbilical veins. Collaterals around the rectum can cause rectal varices that can bleed.

Portosystemic collaterals shunt blood away from the liver. Thus, less blood reaches the liver when portal flow increases diminished hepatic reserve. In addition, toxic substances from the intestine are shunted directly to the systemic circulation, contributing to portosystemic encephalopathy Portosystemic Encephalopathy Portosystemic encephalopathy is a neuropsychiatric syndrome that can develop in patients with liver disease.

It most often results from high gut protein or acute metabolic stress eg, gastrointestinal Venous congestion within visceral organs due to portal hypertension contributes to ascites via altered Starling forces.

Splenomegaly and hypersplenism Splenomegaly Splenomegaly is abnormal enlargement of the spleen. See also Overview of the Spleen. Splenomegaly is almost always secondary to other disorders. Causes of splenomegaly are myriad, as are the Thrombocytopenia Overview of Platelet Disorders Platelets are cell fragments that function in the clotting system.

Thrombopoietin helps control the number of circulating platelets by stimulating the bone marrow to produce megakaryocytes, Sequelae include opportunistic infections and an increased risk of Hemolysis is defined as premature destruction and hence a shortened RBC life span read more may result.

Portal hypertension is often associated with a hyperdynamic circulation. Mechanisms are complex and seem to involve altered sympathetic tone, production of nitric oxide and other endogenous vasodilators, and enhanced activity of humoral factors eg, glucagon.

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Hepatology 3: — PubMed Google Scholar. Gastroenterology — PubMed Google Scholar. J Gastroenterol Hepatol 1: — Google Scholar. Lymphology 90— PubMed Google Scholar. Price DC Spleen: Nuclear medicine. Recent studies in the field of extracellular microvesicles have provided us with a new paradigm for understanding the crosstalk between the liver and spleen. In a study from Saunderson et al. Considering the extensive involvement of exosomes in the pathogenesis of liver diseases, especially liver fibrosis, a role for liver-derived exosomes in the development of hypersplenism should not be excluded [ 41 , 42 , 43 ].

Further study will be required to elucidate more detailed mechanisms of how the contributions of hepatic injury, inflammation and fibrogenesis may affect splenic homeostasis and contribute to hypersplenism. An association between the liver and spleen has been proposed at least for three major reasons.

Anatomically, both organs are important components of portal circulation. Histologically, the liver and spleen possess similar reticuloendothelial structures, which continuously participate in substance exchange and cellular migration [ 44 ].

Immunologically, both the liver and spleen play essential roles in immune homeostasis as well as pathogen clearance. Thus, the concept of a liver-spleen axis has been proposed as an intersection linking immunity, pathogen clearance and metabolism in various conditions including chronic liver diseases [ 45 ]. Previous studies have unanimously implicated innate and adaptive immune cells in development of liver fibrosis or cirrhosis [ 46 , 47 , 48 , 49 ].

However, direct evidence for the involvement of splenic immune cells or spleen-derived factors has only recently emerged, suggesting that splenic contributions to hepatic fibrogenesis, hepatic immune microenvironment dysregulation and the disruption of liver regeneration may be responsible. In a study by Akahoshi et al. A recent study by Asanoma et al. Overall, the studies from Akahoshi et al. As the largest lymphoid organ in the body, the spleen contains multiple immune cell subsets which are differentially distributed within white and red pulp and marginal zone regions.

B cells are mainly distributed within splenic follicles whilst T cells predominate in the white pulp regions. By contrast, DCs and macrophages are located predominately in the marginal zone MZ and red pulp regions. Immune cell migration between these different regions is necessary for splenic maintenance of immune cell homeostasis, tolerance and pathogen clearance [ 13 , 53 , 54 , 55 ].

Interestingly, the red pulp has been revealed to maintain a reservoir of monocytes capable of rapidly migrating into injured tissues and mediating local inflammatory responses [ 56 ].

Similarly, T lymphocytes and some innate lymphoid cell ILC subsets have also been reported to be capable of splenic extravasation [ 57 , 58 ]. As the liver and spleen are closely associated via the portal vein system, it is more likely for the spleen to exert its influences on the hepatic immune microenvironment by cell migration or the secretion of splenic soluble factors via portal vein blood flow Fig. In a recent study by Yada et al.

Although no splenic monocyte tracing studies have been conducted in the setting of liver fibrosis or cirrhosis, the findings from Yada et al. Diagram of the liver and spleen crosstalk pathways during liver cirrhosis. During liver cirrhosis progression, spleen-derived immune cells and cytokines may travel into the injured liver via portal blood flow.

At the same time, liver cirrhosis also contributes to portal hypertension, which leads to the congestion of the portal system and may give rise to splenomegaly and hypersplenism. Studies focusing on T cells have also shed light in another direction. In a study of Schistosoma japonicum associated liver fibrosis by Romano et al. Splenectomy decreased Treg cell and hepatic fibrogenesis levels, implicating a role for the splenic modulation of the liver via alterations in T cell subsets [ 60 ].

More interestingly, in a whole genome microarray analysis conducted by Burke et al. Another study by Tanabe et al. Although the liver normally possesses a huge regenerative capacity, this capacity is compromised during liver injury or resection, especially in the presence of severe chronic liver injury with marked fibrosis and tissue architecture aberrations [ 62 , 63 ]. Liver regeneration is frequently overwhelmed by fibrogenesis in chronic liver diseases [ 64 ].

During chronic liver injury, hepatic progenitor cells HPCs act as the regenerative source for hepatocyte or cholangiocyte replenishment [ 65 , 66 ]. Liver resident macrophages, also known as KCs, have also been shown to promote the differentiation of progenitor cells through debris engulfment-induced Wnt3a signaling in chronic liver diseases [ 67 , 68 ].

Recently, residential KCs and recruited monocyte-derived macrophages have been both found to play central roles in liver regeneration, most likely through a mechanism involving KC—monocyte crosstalk and the consequent activation of HPCs [ 69 ].

No study has yet to determine, however, whether splenic monocyte-derived macrophages can directly influence KCs or HPCs to alter liver regeneration capacities during chronic liver injury.

Several studies point towards the potential of splenic contributors to impact liver regeneration capacities. Studies from Murata et al. In a study by Ueda et al.

Splenectomy reversed this inhibition and enhanced the regeneration of hepatocytes [ 72 ]. In a separate study by Lee et al. However, more detailed mechanistic pathways remain to be resolved. Recent studies using stem cell therapy in chronic liver diseases have also provided some clues regarding the role of the spleen in hepatic regeneration.

In a study by Iwamoto et al. In a separate study of liver cirrhosis in rats, Tang et al. Further studies, however, will be required to characterize whether and how spleen-derived cells or soluble factors can mediate direct effects on liver-recipient stem cell expansion or hepatic progenitor cell behavior.

Targeting splenic abnormalities may be crucial for the management and treatment of liver cirrhosis due to their multiple pathophysiological associations with cirrhotic disease progression. In the past decades, splenectomy has been utilized to ameliorate the fatal complications of cirrhosis-associated portal hypertension. An alternative to splenectomy, however, is required for many patients with precluding conditions such as thrombocytopenia.

Although such alternatives remain lacking, advances in the field of nanomedicine, especially the usage of nanoparticles for drug delivery and cell targeting, may provide us with novel avenues for targeted therapies. Splenectomy has been traditionally performed to treat liver cirrhosis for the alleviation of portal hypertension. The utility of splenectomy is well accepted and may be especially important for the treatment of fatal complications such as bleeding esophageal or gastric varices.

Apart from its effects on portal hypertension and hypersplenism, splenectomy has also been reported by many groups to be an efficient method for improving liver function and the prognosis of esophageal varices [ 8 , 76 ].

Previous studies have also reported splenectomy to increase the efficacy of liver transplantation and improve the prognosis of hepatocellular carcinoma [ 77 , 78 , 79 ]. A study by Ogawa et al. Although animal studies suggest that splenectomy can ameliorate collagen deposition, improve liver function and regeneration capacity and enhance the therapeutic efficacy of stem cell transplantations [ 6 , 59 , 75 ], many cirrhosis patients present with contraindications which preclude splenectomy.

Thus, it remains critical for us to identify alternative novel and non-surgical methods which can target the spleen for the treatment of liver cirrhosis.

Previous studies suggest that there is potential therapeutic value in targeting splenic mTOR signaling for the amelioration of splenomegaly and hypersplenism. Therapies selectively modulating splenic macrophage or T cell activation may also be useful as these immune cell aberrations have been linked to hepatic immune microenvironment dysregulation and the enhancement of hepatic fibrogenesis. One of the biggest obstacles to these approaches has traditionally been the absence of spleen-selective delivery options for therapeutic agents.

This problem, however, may be circumvented by the use of nanoparticles for novel and targeted drug delivery. In a study of nanoparticle distribution during LPS-induced systemic inflammation in mice, the spleen showed increased retention of carboxylated polystyrene latex bead nanoparticles of different sizes compared to all other organs studied. Nanoparticle retention localized mostly to the splenic marginal zone and red pulp to a lesser extent, with most nanoparticles found to be ingested by splenic macrophages.

This size dependence may be caused by the increased permeability of splenic vessels during inflammatory conditions, and highlights one interesting prospect for the selective targeting of differential splenic regions [ 82 ]. An excellent review of the principles of nanoparticle design can be found elsewhere [ 83 ]. In a recent study by Hu et al. This approach may also be applicable for spleen selective drug targeting as splenic macrophages actively phagocytose red blood cells during hypersplenism and liver cirrhosis [ 84 ].

Research into the targeting of splenic and liver Leishmaniasis infections using nanoparticles may also be of potential strategic use [ 85 , 86 ]. Standardized studies in animal models and pre-clinical trials measuring the efficacies of nanoparticle-based therapeutic agents will also be required for the development of novel spleen-selective therapeutic agents. In addition to nanoparticles, recombinant exosomes may also be useful for splenic targeting given the potentially selective capture of exosomes by splenic macrophages [ 40 , 87 , 88 ].

In addition to nanoparticle-based therapeutic agents, the crosstalk between the spleen and nervous system should also be considered in order to develop a comprehensive spleen-modulating approach for treating liver cirrhosis.

A dense network of sympathetic noradrenergic fibers are closely associated with the splenic artery and branch into the white pulp and consequently T and B cell regions.

Secreted neuropeptides may also directly affect the behaviour of splenic immune cells, and this may also need to be factored when designing spleen modulating therapies [ 89 , 90 ]. Furthermore, the inhibition of liver injury-induced signaling molecules that perturb spleen homeostasis, such as HMGB1 or other DAMPs, may also be beneficial.

Numerous recent findings have greatly amended our understanding of the splenic contributions to liver cirrhosis. In particular, the discovery that the spleen can act as an inflammatory monocyte reservoir provides a new paradigm for understanding the immune-mediated links between the spleen and other organs. Recent studies on the development of splenomegaly and hypersplenism and the roles of spleen-derived cells or soluble factors in liver cirrhosis progression have greatly increased our comprehension of the crosstalk between the liver and spleen.

Splenic characterization in the context of liver cirrhosis will be important for the future management and treatment of liver cirrhosis. New developments in the field of nanomedicine may provide us with improved strategies for targeting the spleen, given its vast reticuloendothelial system and abundant phagocyte distributions Fig. Future studies, however, will be required to characterize the precise mechanistic pathways which mediate spleen and liver crosstalk during disease progression from liver fibrosis to cirrhosis.

This may potentially enable the development of new therapeutic strategies for splenic modulation during the management and treatment of liver cirrhosis, especially in circumstances where the option of splenectomy is precluded. Overall, a comprehensive understanding of the molecular and cellular pathways controlling splenic homeostasis and pathophysiology will be critical for the development of new therapies against liver cirrhosis.

Diagram of the potential usage of nanoparticles for splenic targeting.