Etiological classification of ascites according to the serum-ascites albumin gradient value.
\r\n\tThe most phenomena of colloids in the surrounding ecosystem appear in the blue color of the sky, which due to the scattering of light by colloidal particles in the air, and this phenomenon is named Tyndall effect. Also, seawater seems blue due to scattering of light by the colloidal particle present in seawater. In our body, blood is a colloidal solution. Some examples in our daily life include milk, cream, gelatin, colored glass, butter, jelly, and river mud. Colloids are useful for human health, commercial, and industrial use. Colloids and colloidal systems are essential and play a significant role in our life. Important applications of colloids are in medicines, sewage disposal, purification of water, cleansing action of soap, the formation of the delta, industry, mining, smoke precipitation, photography, electroplating, artificial rain, agriculture, the rubber industry, and others.
\r\n\r\n\tThis book aims to gather recent researches by outstanding experts in the field of colloids (chemistry, physics, biology, medicine, nanotechnology, pharmacology, and others), which include colloid synthesis, modification, and application.
",isbn:"978-1-83962-979-2",printIsbn:"978-1-83962-969-3",pdfIsbn:"978-1-83962-980-8",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"55025219ea1a8b915ec8aa4b9f497a8d",bookSignature:"Prof. Mohamed Nageeb Rashed",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10505.jpg",keywords:"Colloids, Biotechnology, Industry, Colloidal Systems, Human Health, Nutrition, Intravenous Therapy, Pharmacology, Drugs, Wastewater Treatment, Nanocolloids, Green Nanocolloids",numberOfDownloads:410,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"June 30th 2020",dateEndSecondStepPublish:"July 21st 2020",dateEndThirdStepPublish:"September 19th 2020",dateEndFourthStepPublish:"December 8th 2020",dateEndFifthStepPublish:"February 6th 2021",remainingDaysToSecondStep:"6 months",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:"Professor of analytical and environmental chemistry, member of several national and international societies, and winner of the Egyptian State Award for Environmental Researches.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"63465",title:"Prof.",name:"Mohamed Nageeb",middleName:null,surname:"Rashed",slug:"mohamed-nageeb-rashed",fullName:"Mohamed Nageeb Rashed",profilePictureURL:"https://mts.intechopen.com/storage/users/63465/images/system/63465.gif",biography:"Prof. Mohamed Nageeb Rashed is a professor of analytical and environmental chemistry, a previous vice-dean for environmental affairs, Faculty of Science, Aswan University, Egypt. In 1989 he received his Ph.D. in analytical environmental chemistry from Assiut University, Egypt. His research interest has been analytical and environmental chemistry with special emphasis on soil and water pollution monitoring, control and treatment; bioindicators for water pollution monitoring; wastewater impact; advanced oxidation treatment; photocatalysis, nanocatalyst, nanocomposite and adsorption techniques in water and wastewater treatment. Prof. Rashed supervised several M.Sc. and Ph.D. thesis in the field of pollution, analytical and environmental chemistry. He participated as an invited speaker in 30 international conferences worldwide. Prof.Rashed acts as editor-in-chief and an editorial board member in several international journals (30) in the fields of chemistry and environment. His society membership includes several national and international societies. Prof.Rashed was awarded the Egyptian State Award for Environmental Researches for the year 2001, and enrolled among Top 2% Scientists Around the World from Stanford University, USA, 2020.",institutionString:"Aswan University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"3",institution:{name:"Aswan University",institutionURL:null,country:{name:"Egypt"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"8",title:"Chemistry",slug:"chemistry"}],chapters:[{id:"74126",title:"A Simple and “Green” Technique to Synthesize Metal Nanocolloids by Ultrashort Light Pulses",slug:"a-simple-and-green-technique-to-synthesize-metal-nanocolloids-by-ultrashort-light-pulses",totalDownloads:53,totalCrossrefCites:0,authors:[null]},{id:"73791",title:"Gemini Imidazolinium Surfactants: A Versatile Class of Molecules",slug:"gemini-imidazolinium-surfactants-a-versatile-class-of-molecules",totalDownloads:25,totalCrossrefCites:0,authors:[null]},{id:"74505",title:"Optimization of Biogenic Synthesis of Colloidal Metal Nanoparticles",slug:"optimization-of-biogenic-synthesis-of-colloidal-metal-nanoparticles",totalDownloads:97,totalCrossrefCites:0,authors:[null]},{id:"74609",title:"Magnetic Iron Oxide Colloids for Environmental Applications",slug:"magnetic-iron-oxide-colloids-for-environmental-applications",totalDownloads:54,totalCrossrefCites:0,authors:[null]},{id:"73859",title:"Colloidal Stability of Cellulose Suspensions",slug:"colloidal-stability-of-cellulose-suspensions",totalDownloads:55,totalCrossrefCites:0,authors:[null]},{id:"73574",title:"Structure and Dynamics of Aqueous Dispersions",slug:"structure-and-dynamics-of-aqueous-dispersions",totalDownloads:101,totalCrossrefCites:0,authors:[null]},{id:"72963",title:"Aerogels Utilization in Electrochemical Capacitors",slug:"aerogels-utilization-in-electrochemical-capacitors",totalDownloads:32,totalCrossrefCites:0,authors:[{id:"271773",title:"Dr.",name:"Ranganatha",surname:"S",slug:"ranganatha-s",fullName:"Ranganatha S"}]}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"205697",firstName:"Kristina",lastName:"Kardum Cvitan",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/205697/images/5186_n.jpg",email:"kristina.k@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"56674",title:"Ascites: Treatment, Complications, and Prognosis",doi:"10.5772/intechopen.70384",slug:"ascites-treatment-complications-and-prognosis",body:'Decompensated cirrhosis is the end stage of chronic liver disease of any etiology. It has a wide range of different clinical manifestations that are secondary to portal hypertension and/or liver insufficiency. Ascites is the most frequent decompensation, and it is usually the first manifestation of the disease in the majority of the patients [1]. Ascites is the accumulation of liquid inside of the peritoneal cavity, and it is developed in 60% of patients with compensated cirrhosis within 10 years during the natural course of their liver disease [1]. Hippocrates of Kos described ascites a long time ago (ca. 460–ca. 310 BC), and its treatment with large paracentesis was already performed since the ancient Greek physicians. It is still a very common problem in patients with liver cirrhosis, malignancy, or cardiovascular disease today. As in Western Europe and the United States of America, liver cirrhosis is the main cause of ascites (75–85%), and we will focus on this disease [2, 3].
The development of ascites is the consequence of the action of several complex mechanisms secondary to severe portal hypertension (i.e., hepatic venous pressure gradient (HVPG) >12 mm Hg) giving place to an impairment of hepatic, circulatory, and renal function. Portal hypertension induces the activation of the endogenous vasoactive systems, which prevent the renal excretion of an adequate amount of sodium, leading to a positive sodium balance [4]. Large evidence suggests that renal sodium retention in patients with cirrhosis is secondary to arterial splanchnic vasodilation. This causes a decrease in effective arterial blood volume with activation of arterial and cardiopulmonary volume receptors, and homeostatic activation of vasoconstrictor and sodium retaining systems (i.e., renin-angiotensin-aldosterone, vasopressin, and the sympathetic nervous systems). Renal sodium retention leads to expansion of the extracellular fluid volume and increases intestinal capillary pressure. The latter is further increased due to both portal hypertension and splanchnic arterial vasodilatation, which also disrupts the intestinal capillary permeability, and thereby contributes to the accumulation of fluid in the abdominal cavity [5]. In addition, certain polymorphisms of the aquaporin-1 gene could predispose to water retention [6].
The development of ascites is associated with a poor prognosis and impaired quality of life in patients with cirrhosis [7]. The probability of survival at 1 and 5 years after decompensation by ascites is about 50 and 20%, respectively [8]. Because of the poor survival, and other complications that will be explained later, patients with ascites should generally be considered for referral for liver transplantation [3].
The first step in the management of every patient with a new-onset ascites is to reveal its underlying cause. A thorough history and physical examination will help narrow the differential diagnosis and reveal factors that might have been implicated in the development of ascites (e.g., nonsteroidal anti-inflammatory drugs (NSAIDs)). Risk factors for liver disease such as alcohol abuse, metabolic syndrome, or family history of hemochromatosis should be sought. Patients should also be questioned about past history of cancer, heart failure, renal disease, or tuberculosis as they may all be responsible for the development of ascites [3].
The main complaint of patients with ascites is an increase in abdominal girth, often accompanied by lower-extremity edema. Other common manifestations include dyspnea due to increasing abdominal distension and/or accompanying pleural effusions, abdominal pain, anorexia, nausea, and fatigue [9]. The accuracy of the physical examination to detect ascites is highly dependent on the amount of ascites and on the physical constitution of the patient. Accordingly, patients must have approximately 1500 mL of fluid for ascites to be detected reliably by physical examination and the presence of obesity greatly reduces its diagnostic accuracy [3]. Several signs support the presence of ascites such as the shifting dullness, fluid wave, and puddle signs. The former has 83% sensitivity and 56% specificity in detecting ascites. It is also less cumbersome and performs better than the latter two [3, 10]. The clinician should also look for other physical signs that suggest the presence of a liver disease (e.g., spider angiomas, Dupuytren contracture, palmar erythema, gynecomastia, parotid gland enlargement, or testicular atrophy) or an extrahepatic disease (e.g. jugular venous distension related to heart failure) as the cause of ascites.
The essential investigations that should follow the anamnesis and physical examination to confirm the cause of ascites include an abdominal ultrasound (to screen for morphologic evidence of cirrhosis and portal hypertension, tumors, portal vein thrombosis, and hepatic vein thrombosis), laboratory assessment of liver function, renal function, serum and urine electrolytes, and abdominal paracentesis. The latter is compulsory in order to confirm the cause of the ascites and to rule out complications such as spontaneous bacterial peritonitis (SBP). Thus, it should always be performed in a new episode of ascites grades 2 or 3, in patients hospitalized for any complication of the disease or because of worsening of ascites [2, 11]. It is a safe procedure, even in patients with prolonged prothrombin time and low platelets. Indeed, the policy of some physicians to give blood products (fresh frozen plasma and/or platelets) routinely in these patients is not data-supported [3]. Growing evidence from the last two decades has demonstrated that most patients with liver cirrhosis remain in a tenous but balanced state of hemostasis [12]. Accordingly, in a study of 1100 large volume paracentesis, there were no hemorrhagic complications despite no prophylactic correction of platelet counts as low as 19,000 cells/mm3 (54% < 50,000) and of prolonged international normalized ratios for prothrombin time as high as 8.7 (75% > 1.5 and 26.5% > 2.0) [13]. The most common site for paracentesis is the left lower quadrant of the abdominal wall (3 cm cephalad and 3 cm medial to the anterior superior iliac spine), as in this location the wall is thinner and with a larger pool of fluid than the midline. Visible collateral must be avoided, and in patients with obesity or loculated ascites, an ecoguided paracentesis is commonly needed [3].
The analysis of the ascitic fluid includes cell count and differential, culture, biochemical analysis, and cytology. Current guidelines recommend to routinely perform only cell count and differential, ascitic fluid protein and albumin, and note the gross appearance of the fluid (i.e., water-clear, bilious, purulent, bloody, or chylous) [2, 3]. The former enables to discard SBP or suspect the presence of other type of infection (e.g., high lymphocyte count in patients with tuberculosis). Albumin measurement on the same day in serum and ascitic fluid allows the calculation of the serum-ascites albumin gradient (SAAG), which properly differentiates ascites due to portal hypertension from ascites due to other causes. If the SAAG is greater than or equal to 1.1 g/dL, ascites is ascribed to portal hypertension with an approximate 97% accuracy [14]. Importantly, SAAG accuracy is not influenced by fluid infusion and diuretic use and also remains greater or equal to 1.1 g/dL in patients with both portal hypertension and a second cause for ascites formation [3]. Measurement of SAAG is, therefore, of utmost importance in patients with new-onset ascites, but its repeated measurement is usually not needed in other scenarios (e.g., worsening or refractory ascites) [3]. Table 1 shows the etiological classification of ascites according to the SAAG value. Further ascitic testing should be done depending on clinical judgment [3]. In patients in whom a peritoneal carcinomatosis is suspected, an ascitic fluid cytology must be performed, as it has a sensitivity as high as 96.7% if three samples from different paracentesis procedures are analyzed [15]. Bacterial culture is mandatory if infection is suspected. Cultures should be done in aerobic and anaerobic blood cultures inoculated (10 mL) at the bedside to increase their profitability (80% by this method). The utility of lactate dehydrogenase and glucose determination in ascitic fluid to assist in differentiating spontaneous from secondary bacterial peritonitis is supported by limited data and the European Association for the Study of the Liver (EASL) does not recommend its performance [2]. On the contrary, an ascitic fluid carcinoembryonic antigen >5 ng/mL or ascitic fluid alkaline phosphatase >240 units/L has been shown to be accurate in detecting gut perforation into ascitic fluid [16]. Other tests, such as amylase, triglycerides, and polymerase chain reaction (PCR) and culture for mycobacteria should be done only when there is a clinical suspicion of pancreatic disease, chylous ascites, and tuberculosis, respectively. Finally, it is worth mentioning that serum cancer antigen 125 levels are increased in patients with ascites of any cause. Therefore, its measurement is not recommended to guide the differential diagnosis [3].
SAAG | Diseases | Diagnosis |
---|---|---|
≥1.1 | Liver cirrhosis | Compatible image test and biopsy, known etiology of liver disease, HVPG > 10 mm Hg, liver stiffness >15 Kpa, proteins in ascites <2.5 g/L |
Budd-Chiari syndrome | Imaging test, proteins in ascites >2.5 g/L | |
Sinusoidal obstruction syndrome | Appropriate clinical context (e.g. hemotopoietic stem cell transplantation), proteins in ascites >2.5 g/L | |
Portal thrombosis | Imaging test, usually associated with a clinical trigger such as variceal bleeding | |
Right heart failure | Right heart failure confirmed by echocardiogram, serum BNP >364 pg/mL, dilated suprahepatic veins, proteins in ascites >2.5 g/L | |
Acute liver failure | Appropriate clinical context | |
Massive liver metastases | Imaging test, proteins in ascites <2.5 g/L | |
Myxedema | Clinical and laboratory findings of severe hypothyroidism | |
“Mixed” ascites* | Imaging or other test according to clinical suspicion | |
<1.1 | Peritoneal carcinomatosis | Positive citology, proteins in ascites >2.5 g/L, WBC >500 with PMNs<250, image test to find primary tumor (most frequent ovarian, gastric, and pancreatic origin) |
Peritoneal tuberculosis | WBC > 500 with PMNs<250 and predominance of lymphocytes, proteins in ascites >2.5 g/L, ADA >40 UI/L, positive culture or PCR, peritoneal biopsy | |
Pancreatic ascitis | Ascitic amylase level usually >2000 UI/L, protein concentration in ascites variable, but normally >2.5 g/L, PMN > 250, imaging test to diagnose the underlying disease | |
Bilious ascites | Elevated ascitic bilirubin levels and higher than serum, imaging test to diagnose the underlying disease | |
Chylous ascites | Ascitic triglyceride level >110–200 mg/dL or higher than serum, imaging test to diagnose the underlying disease | |
Nephrotic syndrome | Appropriate clinical context, proteins in ascites <2.5 g/L | |
Protein-losing enteropathy | Diarrhea and other clinical symptoms due to the underlying disease, proteins in ascites <2.5 g/L | |
Serositis related to connective tissue diseases | Rare manifestación of systemic lupus erythematosus, polyarteritis nodosa and Schölein-Henoch purpura. Appropriate clinical context | |
Intestinal ischemia or obstruction | Imaging test |
Etiological classification of ascites according to the serum-ascites albumin gradient value.
Patients with cirrhosis and other cause (one or more) of ascites formation. Abbreviations: SAAG: serum-ascites albumin gradient; HVPG: hepatic venous pressure gradient; WCC: white blood cell; PMN: polymorphonuclear leukocyte; ADA: adenosine deaminase; PCR: polymerase chain reaction.
Current guidelines follow the classification of ascites from the International Ascites Club, which divides patients into three groups on the basis of a quantitative criterion. Each group is also linked to a specific treatment strategy (see Table 2) [3, 17]. Accordingly, only patients with ascites grade 2 or more should be treated, and they can be treated as outpatients unless they have other complications [2]. The aim of the treatment of ascites is to induce negative sodium balance by reducing sodium intake and increasing sodium excretion by the administration of diuretics.
Severity and definition | Treatment and strategy |
---|---|
Grade 1 or mild Diagnosed exclusively by ultrasonography. | No treatment is necessary. |
Grade 2 or moderate Clinically evident. | Dietary sodium restriction and diuretics. (first spironolactone 50–100 mg/day to reach weight loss: 300–500 mg/day, if needed, add furosemide 20–40 mg/day and increase both every 7 days up to 400 and 160 mg/day, respectively) |
Grade 3 or large Clinically evident or tense. | Large-volume paracentesis plus albumin 8 g/L of ascites removed in first place and later dietary sodium restriction (90 mmol/day) and diuretics. |
Ascites classification and treatment [17].
In approximately 10–20% of patients with cirrhosis and ascites, we can obtain a negative sodium balance only by reducing dietary sodium intake, particularly in those presenting with their first episode of ascites [18]. No predictive factors of response to low sodium diet have been detected. Although the level of dietary restriction should be applied according to the baseline urinary sodium excretion, a moderate restriction of salt intake is generally recommended (intake of sodium of 80–120 mmol/day, which corresponds to 4.6–6.9 g of salt/day). This is generally equivalent to a no-added salt diet with avoidance of preprepared meals. A more severe reduction in dietary sodium content is considered unnecessary and even potentially deleterious since it may impair nutritional status [2, 3]. Fluid restriction is not necessary unless patients have hypovolemic hyponatremia (serum sodium <130 mEq/L together with ascites and/or edema). Fluid loss and weight change are directly related to sodium balance in these patients. It is sodium restriction, not fluid restriction, which results in weight loss, as fluid follows sodium passively [2].
Evidence demonstrates that renal sodium retention is mainly due to increased proximal as well as distal tubular sodium reabsorption rather than due to a decrease of filtered sodium load [2, 19]. The increased reabsorption of sodium along the distal tubule is mostly related to hyperaldosteronism. As previously mentioned, patients with ascites grade 2 require diuretic treatment if there is no contraindication. The goal of treatment is to achieve an average weight loss of no more than 500 g/day in patients without peripheral edema and no more than 800–1000 g/day in those with peripheral edema.
The efficacy of diuretic therapy in the control of ascites is approximately 90% in patients without renal dysfunction [2, 19]. The diuretics most frequently used are aldosterone antagonists, mainly spironolactone, which selectively antagonizes the sodium-retaining effects of aldosterone in the renal collecting tubules, and loop diuretics, especially furosemide, that inhibit the Na + −K + –2Cl – cotransporter in the loop of Henle. It has been extensively debated whether both types of diuretics should be combined from the beginning or use aldosterone antagonists in a stepwise increase every 7 days with furosemide added only in patients not responding to high doses of aldosterone antagonists. It can be concluded that a diuretic regime based on the combination of aldosterone antagonists and furosemide is the most adequate approach for patients with recurrent ascites but not for patients with a first episode of ascites. These latter patients respond well to spironolactone 50–100 mg/day [2]. Those with recurrent episodes of ascites or peripheral edema should receive a combination of spironolactone 100 mg/day with furosemide 40 mg/day [2, 19]. If there is no response, adherence to a low sodium-diet and diuretic treatment should be confirmed through a good anamnesis and a 24-hour urine sodium excretion measurement. An ascites that is not controlled despite a natriuresis greater than 80–110 mmol/day suggests a nonadherence to a low-sodium diet [3]. Given that full-day collections are cumbersome, the measurement of urine creatinine helps determine if the collection of the 24-hour specimen has been complete. Men with cirrhosis should excrete more than 15 mg of creatinine/kg of body weight per day, and women should excrete more than 10 mg/kg/day. Less creatinine is indicative of an incomplete collection [3]. A random “spot” urine sample is also useful to assess natriuresis and is the preferable test to adjust diuretic treatment in certain scenarios such as the emergency unit. A sodium concentration that is greater than the potassium concentration correlates well with a 24-hour sodium excretion. When the urine sodium/potassium ratio is >1, the patient should be responding to the treatment. The higher the ratio, the greater the urine sodium excretion [20]. In compliant patients with poorly controlled ascites, diuretics may then be increased every 7 days by doubling doses (1:1 ratio) to a maximal dose of spironolactone (400 mg/day) and a maximal dose of furosemide (160 mg/day). Unfortunately, diuretics can also have side effects and cause fluid and electrolytes balance disturbances such as hyponatremia, dehydration, renal impairment, hyperkalemia, or hypokalemia and subsequently, hepatic encephalopathy. For all these reasons, patients should be closely followed after the onset of diuretic treatment. Thus, a clinical evaluation and measurements of serum and urine electrolytes must be performed within the first 2 weeks after starting or modifying their dose. When any of the abovementioned side effects appear, diuretics should be stopped or their dose reduced. A particular side effect of spironolactone is tender gynecomastia and muscle cramps in some patients. Amiloride, a diuretic acting in the collecting duct, is less effective than aldosterone antagonists and should be used only in those patients who develop severe side effects with aldosterone antagonists [2].
Treatment of the underlying disease whenever possible is of great importance as dramatic responses have been described after alcohol abstinence, antiviral, and immunosuppressive therapies in patients with alcoholic, viral and autoimmune liver diseases, respectively [3]. Nutritional therapy can ameliorate nutritional status in cirrhotic patients, reduce infection rates, and decrease perioperative morbidity [11]. Some drugs must be avoided or use with caution in patients with ascites such as NSAID due to the high risk of developing further sodium retention, hyponatremia, and renal failure. In a recent case control study, 37% of the NSAIDs-associated acute kidney injury (AKI) cases were severe and persistent with a very poor short-term outcome [21]. Interestingly, Metamizol use was more common in patients with persistent AKI than in those with transient AKI, and therefore, this drug should also be used with caution. Likewise, angiotensin converting enzyme inhibitors, angiotensin II antagonists, or a1-adrenergic receptor blockers should generally not be used in patients with ascites because of increased risk of renal impairment [2]. Bed rest was previously recommended on the basis that the upright posture could aggravate the already elevated plasma renin levels of patients with liver cirrhosis and ascites. However, it is no longer advocated as there is insufficient evidence to support its use as part of ascites treatment [2]. There is an ongoing debate about the use of nonselective betablockers in patients with refractory ascites. The current guidelines from the American Association for the Study of Liver Diseases recommend to avoid high doses of these drugs (over 160 mg/day of propranolol or over 80 mg/day of nadolol), and in patients with concomitant severe circulatory dysfunction [i.e., systolic blood pressure <90 mm Hg, serum sodium <130 mEq/L, or hepatorenal syndrome (HRS)], their dose should be decreased or the drug temporarily held [22]. Finally, in unblinded randomized clinical trials (RCTs), the long-term albumin infusion (25 gweekly for one year and 25 g every two weeks thereafter) improved survival in patients with new onset ascites [23]. However, further studies are needed before this treatment can be advocated [3].
Despite the fact that patients with ascites constitute a heterogeneous population with different prognosis depending on the degree of liver insufficiency and circulatory dysfunction, the development of ascites is an ominous sign. The probability of survival at one and five years after the diagnosis of ascites is approximately 50 and 20%, respectively, and long-term survival of more than 10 years is very rare [8]. In addition, mortality rises up to 80% within 6–12 months in patients who also develop kidney failure [1]. Patients with cirrhosis and ascites are also at high risk for other life-threatening complications of liver disease, including refractory ascites, SBP, respiratory distress, worsening of nutritional status, hyponatremia, or HRS. Accordingly, current guidelines recommend that every patient with ascites should be generally considered for referral for liver transplantation, especially when quality of life is impaired due to refractory ascites, or in the presence of SBE and HRS [2, 3]. Since 2002, the model of end-stage liver disease (MELD) score is used for patient priority in liver transplantation. However, MELD does not reflect the impact of some complications (the so-called Exceptions to MELD score) such as refractory ascites. Indeed, in some patients with this complication the latter score does not accurately reflect their poor prognosis (median survival is approximately 6 months) and their prioritization in the list should be assessed [24].
A nonnegligible number of patients with ascites (10%) develop refractory ascites due to severe sodium retention that cannot be mobilized pharmacologically either because there is no response to high diuretic dose (resistant ascites) or because side effects appear with the use of diuretics (intractable ascites). The term “recurrent ascites” defines an ascites that requires more than three admissions per year because of reaccumulation of ascites [25]. In these patients other therapeutical approaches must be used.
Current guidelines recommend LVP as the first-line treatment in patients with refractory ascites, unless it is loculated [2, 3]. In order to minimize the number of paracentesis (LVP is usually performed every 2–4 weeks), total paracentesis is preferred and diuretic therapy can be maintained if the urine sodium is >30 mmol/day. It is a safe procedure with a complicate rate similar to diagnostic paracentesis, and it can be performed in the outpatient setting [2, 3]. LVP is defined as a volume above 5 L. Although Kao et al. arbitrarily selected this threshold in 1985 based upon the volume required to “adequately decompress the distended abdomen,” the intra-individual neurohormonal changes induced by the removal of different ascitic volumes have not been examined [26, 27]. These neurohormonal changes reflect the physiopathological background of the main complication of LP, i.e., postparacentesis circulatory dysfunction (PPCD). Indeed, the removal of large volumes of ascites fluid can further decline the effective circulating volume by causing a significant drop in peripheral vascular resistance by mechanisms not fully elucidated. This hemodynamic derangement is demonstrated by a pronounced reactivation of renin-angiotensin-aldosterone and sympathetic nervous systems that can persist for months. An increase in plasma renin activity of 50% or greater is usually used to define PPCD [27, 28]. Although frequently asymptomatic, PPCD has been associated with significant detrimental effects such as re-accumulation of ascites, development of HRS and dilutional hyponatremia, and shortened survival [2]. It was first demonstrated in the 1980s that adjunctive albumin infusion can prevent PPCD occurrence and since the early 1990s, less costly alternatives to albumin have been sought, such as artificial colloid volume expanders and vasoconstrictors [28]. Despite initial uncertain results, a meta-analysis of 17 trials with a total 1225 patients demonstrated that albumin infusion after LVP is more effective than other plasma expanders (i.e., hypertonic saline, hydroxyethyl starch, and dextran-70, polygeline) for the prevention of PPCD and showed a trend to increased survival. The rate of PPCD was 73% after paracentesis without any re-expansion, 38% when combined with an infusion of dextran or gelatin solutions and only 15–17% when taps were combined with albumin administration. Doses of albumin infusion ranged between 5 and 10 g of albumin per liter of fluid removed [28]. Current guidelines recommend 8 g/L as this has been the dose most commonly used [2, 3]. It is usually administered during or after the paracentesis. Whether lower doses could be used is currently debated as one study comparing doses of 4 vs. 8 g/L showed similar efficacy in preventing PPCD and renal impairment [29]. When less than 5 L of ascites are removed, artificial plasma expanders, saline, and albumin are equally effective [2]. The latter meta-analysis also compared albumin with vasoconstrictors (i.e., midodrine, norepinephrine, and terlipressin). The results were more variable in this subgroup (OR from 0.30 to 5.54) due to the small size of the five included trials and therefore, no definitive conclusions can be made [28]. Further studies that target survival as the primary end-point in patients with truly refractory ascites are needed to fully demonstrate whether albumin or vasoconstrictors can improve survival.
Another treatment option for patients with refractory ascites is transjugular intrahepatic portosystemic shunt (TIPS). It is a procedure in which an intrahepatic stent is inserted between the hepatic and portal veins with intent for portal decompression to avoid the recurrence of ascites [30]. The optimal portal pressure gradient (PPG) that needs to be obtained to adequately control ascites is not clear, but might be lower than the well-validated 12 mm Hg threshold for the prevention of rebleeding from esophageal varices [30]. Most of randomized clinical trials (RCTs) aimed to reduce PPG below 12 mm Hg by dilating 10-mm diameter stents to 6–8 mm with subsequent calibration up to 10 mm, depending on post-PPG and clinical response [31–34]. By this approach, marked reductions in PPG are avoided, which may be associated with an increased risk of hepatic encephalopathy and liver failure. Until today, seven RCT [31–37] and six meta-analysis [38–43] have assessed the efficacy and safety of TIPS in patients with refractory and recurrent ascites. They have consistently demonstrated that TIPS is effective in the management of this complication, but is associated with higher risk of hepatic encephalopathy compared to LVP. Thus, about 64% (range of 38–84%) had their ascites controlled (although its resolution was slow and most patients required continued administration of diuretics and salt restriction), and hepatic encephalopathy occurred in approximately 51% of patients (39% severe) treated with TIPS. This latter complication is known to increase the rate of mortality and hospitalization and to significantly affect the quality of life [30]. TIPS dysfunction due to pseudointimal hyperplasia within the parenchymal tract or within the outflow hepatic vein was another major drawback in these studies. Indeed, a significant proportion of patients (from 30 to 87%) needed TIPS revision due to malfunction. It must be emphasized that all, but one clinical trial [34], used bare stents instead of the politetrafluoroethylene-covered stents that are used today. These covered-stents have greatly improved shunt patency rates and have also reduced the incidence of hepatic encephalopathy after TIPS placement [30]. There is great controversy over the survival benefit of TIPS in refractory ascites. At the time current guidelines were published, studies had not convincingly proved that TIPS improved survival compared to repeated LVP, and consequently, it was left as a second-line therapy that had to be considered in patients with very frequent requirement of LVP or with loculated ascites [2, 3]. Among the five trials that had been published at that time, transplant-free survival was significantly improved in two (in one of them only in the multivariate analysis) [33, 36], decreased in one (probably due to technical disability) [35], and not affected in the other two [31, 37]. These discrepancies among studies were likely due to patient selection and data analysis biases. These RCTs excluded patients with advanced liver disease (as defined by serum bilirubin > 5–6 mg/dL, INR > 2, current or chronic HE > 2 by West-Heaven scale), and renal failure (as defined by serum creatinine >3 mg/dL) and thus, only 48% (median, 21–77%) of the screened patients could be included in the RCTs. Meta-analysis also contributed to this controversy. Four conventional meta-analysis did not show any benefit in survival [38–41], whereas a meta-analysis of individual patient data from four RCT showed a significant improvement in transplant-free survival at 1 and 2 years between TIPS and LVP (63 and 49% vs. 53 and 35%, p = 0.035) [42]. After the publication of the current guidelines, two RCT [32, 34] and another meta-analysis [43] have been published and concluded that TIPS is more effective in controlling ascites than repeated LVP and improved transplant-free survival in these patients. The RCT of Narahara et al. included 60 patients with refractory ascites treated with bare metal TIPS or LVP. The selection criteria were stricter than the previous RCT and included patients with better preserved renal and hepatic function [32]. The last RCT was recently published and included patients with recurrent ascites treated with covered-stents or LVP with inclusion criteria similar to the former RCT [34]. It can be concluded that pending further RCT with covered stents, TIPS can be recommended in patients with refractory ascites and preserved liver function (Child–Pugh score <13, MELD score <18, bilirubin <5 mg/dL, platelet count >75,000, serum sodium >130 mEq/L), aged <70, no previous episodes of hepatic encephalopathy, and neither central or large hepatocellular carcinoma nor cardiopulmonary disease [19]. In fact, some authors and scientific associations recommend TIPS as the primary therapy for refractory ascites [44–46].
The alfapump is a subcutaneous battery-operated pump to move ascites from the peritoneum to the urinary bladder. One catheter connects the pump to the peritoneal cavity, and another connects it to the urinary bladder. Every 5–10 min small volumes of ascites (generally 5–10 mL) are pumped into the urinary bladder, ranging the daily volume that can be removed between 500 mL and 2.5 L. In order to improve patient’s comfort it is deactivated at night. The pump battery is charged via a charging device (Smart Charger, Sequana Medical AG, Zürich, Switzerland) that is placed over the area of the pump twice daily during no more than 20 min. It is at this time when pump function parameters (e.g., volumen transported, pressures in the bladder and abdominal cavity) are automatically transmitted to the charger. This information is forwarded to a central databank and communicated, if needed, to the treating physician, who can remotely program the system to the patient’s needs or contact the patient because of possible technical issues. The current price of the device is 22,500 Euros [47].
The alfapump was conceived as an alternative treatment for refractory ascites, especially in those patients who are not candidates for TIPS [47, 48]. This system also requires a good selection process, in which issues such as compliance of the patient, nutritional status, previous abdominal surgery, urinary outlet obstruction, or local skin infections should be carefully evaluated before its implantation [47]. An initial multicenter, prospective, uncontrolled study (PIONEER) evaluated its safety and efficacy in 40 patients over a period of 6 months. It showed that the pump removed 90% of the ascites and reduced the median number of LVP, but with a significant rate of complications mainly due to infections and catheter dislodgement [49]. However, the number of complications was reduced along the study after including some changes recommended by the data safety monitoring board (i.e., antibiotic prophylaxis with norfloxacin, strict avoidance of NSAID, and the intravenous administration of albumin if ascites was aspired during the surgical intervention) [47]. A recent RCT compared the safety and efficacy of the alfapump system in comparison with LVP in 58 cirrhotic patients with refractory ascites over a 6-month period [48]. The alfapump was more effective reducing and, in many cases, eliminating (more than 50%) the need for paracentesis. It also improved the quality of life and nutritional status of the patients. Survival was similar in both groups, despite the occurrence of more adverse events (96.3 vs. 77.4%, p = 0.057), which were also more frequently severe (85.2% vs. 45.2%, p = 0.002) in the group treated with alfapump. Adverse events consisted predominantly of AKI in the immediate post-operative period, and re-intervention for pump-related issues. Device deficiencies accounted for seven re-interventions, which are an improvement compared to the results of the PIONEER study and may reflect the continual technological improvements to the alfapump system since commercialization in 2011. After the postoperative period (>7 days), the incidence of AKI and hyponatremia was similar in both groups, but more of these events required hospitalization in the alfapump group. The underlying mechanism for this renal dysfunction and hyponatremia remains unclear. In a recent prospective study that included ten patients with refractory ascites treated with the alfapump system, a marked activation of endogenous vasoconstrictor systems and impairment of kidney function after the device insertion was observed. This finding led the authors to hypothesize that treatment with alfapump might impair effective arterial blood volume mimicking a postparacentesis circulatory dysfunction syndrome and suggested a potential role of albumin in counteracting these effects [50]. Supporting this hypothesis, the authors of the RCT observed an increase in plasma renin activity at 3 months. Finally, total median cost (including implantation procedure and device, scheduled visits, lab test, medications and treatment of adverse events) was significantly higher in the alfapump group (£36970 vs. £12660, p < 0.0001). The difference was primarily due to the statistically higher cost of implantation procedure and adverse effects [48]. It can be concluded that further refinements in patient selection, patient care algorithms (including regular albumin administration), and modifications in device design are needed before the alfapump can become a truly alternative treatment for patients with refractory ascites.
Vaptans are V2 vasopressin receptor antagonists acting on the kidney and promoting solute-free water diuresis. In patients with cirrhosis, they have been studied in the setting of dilutional hyponatremia (see below section 6) and ascites. In patients with both uncomplicated and refractory ascites, satavaptan did not have a clinical benefit in controlling ascites and even increased mortality, which was related with known complications of liver cirrhosis [51, 52]. Consequently, the drug was withdrawn from development. Tolvaptan has also been used in patients with liver cirrhosis and refractory ascites. Most of the data come from observational studies in which tolvaptan seemed to improve control of ascites [53–57]. Two RCT also showed that tolvaptan was more effective than placebo for the treatment of ascites-related clinical symptoms. However, in both trials, the drug was given for only 7 days and the follow-up period was no longer than 3 weeks [58, 59]. Both issues are of great concern, given that its efficacy is lost after the discontinuation of the drug [60] and that a black-box warning by the Food and Drug Administration determined that tolvaptan should not be used for longer than 30 days, and limited its use in patients with underlying liver disease. The latter warning came from an increased risk of liver injury in a recent large clinical trial evaluating tolvaptan for a new use in patients with autosomal dominant polycystic kidney disease [61]. Therefore, the use of vaptans in cirrhotic patients with uncomplicated or refractory ascites cannot be recommended at present and required further RCT with a longer follow-up [3, 11].
Since arterial splanchnic vasodilation plays a major role in the pathogenesis of ascites formation, the use of vasoconstrictors has been evaluated in the treatment of patients with refractory or recurrent ascites. In two preliminary studies both the acute and 7-day administration of Midodrine, an alfa-1-adrenergic agonist, in nonazotemic cirrhotic patients with ascites improved systemic hemodynamics and sodium excretion [62, 63]. Similarly, in another study, the addition of midodrine corrected the deleterious effects on renal function of octreotide and improved systemic hemodynamics [64]. The first study evaluating its effect on patients with refractory or recurrent ascites was a RCT in which 40 patients were randomized to oral midodrine (7.5 mg every 8 h) plus standard medical therapy (sodium restriction plus diuretics) or to standard medical therapy alone. Midodrine significantly improved systemic hemodynamics without significant complications and was superior for the control of ascites at 3 months, but not at 1 and 6 months after therapy. Moreover, the mortality rate in the standard medical therapy group was significantly higher than that in the midodrine group (p < 0.046) [65]. A recent pilot study evaluated the efficacy and safety of midodrine in combination with tolvaptan in 50 cirrhotic patients with refractory or recurrent ascites. Their combination controlled ascites significantly better than standard diuretic treatment alone and more rapidly than midodrine alone [66].
Clonidine, a centrally acting α2-agonist and sympatholytic agent, has also been evaluated as an adjunct treatment in patients with cirrhosis and refractory ascites. In two pilot studies, its addition to spironolactone increased natriuresis and body weight loss more efficiently than spironolactone alone in patients with cirrhosis and ascites and activated sympathetic nervous system [67, 68]. Years later, the same group performed a first RCT that included patients with cirrhosis, ascites, and a plasma norepinephrine level of >300 pg/mL. Oral clonidine (0.075 mg b.i.d.) led to an earlier duretic response and was associated with fewer diuretic requirements and complications [69]. A later RCT using the same dose of clonidine for 3 months evaluated its efficacy in 270 patients with refractory ascites. The response rate to the association of clonidine and diuretics was 55–60%. The highest efficacy was obtained in patients who had high serum levels of norepinephine and the presence of two specific polymorphisms of the G-protein and α2-adrenergic receptor gene [70]. The efficacy of the combination of clonidine and midrodine was evaluated in a RCT that included 60 patients with refractory and recurrent ascites. Their combination controlled ascites significantly better than standard diuretic treatment alone over a 1-month period, but was not superior to midodrine or clonidine alone [71].
Finally, there is very limited data available with terlipressin. In a small RCT that included 15 patients with nonrefractory ascites and 8 with refractory ascites without HRS, 2 mg of intravenous terlipressin improved renal function and natriuresis in both types of ascites. However, a clinical effect on weight or abdominal girth was not recorded [72]. In a prospective study in which 26 patients with refractory ascites without HRS were treated with maximum diuretic treatment plus albumin and terlipressin, complete and partial response were observed in 62 and 23% of the patients, respectively [73].
With the available evidence, the American Association for the Study of Liver Diseases recommends that the use of oral midodrine should be considered in patients with refractory ascites [3]. On the other hand, the European Association for the Study of the Liver considers that larger RCT with longer follow-up are needed before these drugs can be routinely recommended in the management of these patients [2]. The authors of this chapter are in agreement with this last recommendation.
Figure 1 depicts the pathophysiological rationale for the treatment of patients with ascites and other related complications.
Physiopathology and treatment of patients with ascites and other related complications. Splanchnic vasodilatation driven by portal hypertension leads to an arterial underfilling that is counteracted by the activation of antinatriuretic and vasoconstrictor factors (RAAS, SNS, and AVP) that may lead to development of ascites, dilutional hyponatremia, and hepatorenal syndrome. Current therapies act at different levels of this pathophysiological cascade. Abbreviations: TIPS: transjugular intrahepatic portosystemic shunt; RAAS: renin-angotensin-aldosterone system; sympathetic nervous system; AVP: arginine vasopressin.
Compared to general population, patients with cirrhosis have an increased risk of developing bacterial infections and sepsis, for this reason, SBP has a remarkable importance. SBP is a common infection of ascitic fluid developed in patients in the absence of an intra-abdominal genesis of infection. SBP was described for the first-time long time ago, approximately in the 1970s by Harold Conn [74], who pointed out the high in-hospital mortality in patients with this complication. The mechanisms leading to SBP include bacterial translocation, the reduced gut motility giving place to intestinal bacterial overgrowth, altered structure, and function of the intestinal mucosal barrier, and shortage in local immune response systems [75]. Patients with cirrhosis and SBP frequently develop an exaggerated inflammatory response with a severe impairment in renal, cardiovascular, or other organs functions. This syndrome is called acute or chronic liver failure and implies a high rate of hospital mortality [76].
SBP is the most frequent bacterial infection in hospitalized patients with cirrhosis [77]. It occurs in approximately 15–30% of hospitalized patients. Approximately 70% of the episodes of SBP is present when patients are admitted to the hospital, and the rest, 30%, is acquired during hospitalization [78]. The clinical manifestations in patients with SBP are usually symptoms such as abdominal pain, diarrhea, fever, chills, and hepatic encephalopathy, but in approximately 25% of cases of SBP, there are no apparent symptoms. Subclinical manifestations could occur as, for example, deterioration in renal function without other cause or development of tense and refractory ascites in a patient previously responsive to diuretics.
The prognosis in patients with SBP is very poor. The mortality during hospitalization is still remarkably high (20–40%) and is due to other complications that could appear because of the advanced liver disease. The most determinant prognostic factor in patients with SBP is the development of HRS [79]. The development of type-1 HRS and the poor short-term prognosis in these patients mostly depends on the degree of liver and renal impairment at diagnosis of SBP. There are several related-factors to an increased risk of type 1 HRS in patients with SBP; serum bilirubin levels ≥4 mg/dL, serum creatinine levels ≥1 mg/dL, and BUN ≥30 mg/dL [80–83]. In addition, SBP may trigger severe life-threatening complications, as for example, renal impairment, gastrointestinal bleeding, and deterioration of hepatic insufficiency, which are responsible for the associated high mortality.
The importance of an early diagnosis and the use of an adequate treatment are crucial in the survival. As previously mentioned, its diagnosis requires a polymorphonuclear leukocyte count greater than 250 cells/mm3 [2]. The most common organisms isolated in SBP are Escherichia coli, Klebsiella pneumoniae, and Streptococcus pneumoniae [19]. The organism responsible for the infection is isolated in 60–70% of the cases. The remaining cases without the isolation of the organism are considered to have a culture-negative SBP and are treated in the same way as those with a positive culture. In the diagnostic procedure of SBP, must be a differentiation between SBP and secondary peritonitis. Secondary peritonitis is defined because it follows a primary abdominal infection such as gallbladder infection, diverticulitis, or gut perforation. Patients’ general conditions rapidly deteriorates in those with secondary peritonitis, for this reason, the diagnosis must be quick, and can be confirmed by a laboratory workup, showing at least two of the following conditions: low glucose concentration levels in ascitic fluid (<50 mg/mL), ascites lactate dehydrogenase higher than serum lactate dehydrogenase, and finally, ascites concentration of proteins >1.5 g/dL. Other typical characteristics in secondary peritonitis are positive cultures with different bacteria, very high count of neutrophils in blood and ascitic fluid. When these conditions appear, a CT scan is recommended to localize the source of the infection [84, 85].
Current guidelines recommend the onset of the empirical treatment immediately after the diagnosis of the infection, and it should be performed with broad-spectrum antibiotics such as a third-generation cephalosporin [2, 3]. Until the last 10 years, the use of third-generation cephalosporins has been shown to be highly effective in the treatment of SBP. Gram-negative bacteria (particularly enterobacteriaceae) were responsible for the majority of the episodes of SBP [86]. However, the etiology and epidemiology in patients with cirrhosis and SBP have changed in the last years, and the efficacy of the third-generation cephalosporins as well as that of alternative therapies such as amoxicillin-clavulanic or quinolones has decreased [78]. It has been speculated that prophylaxis with norfloxacin and invasive procedures could have caused these changes [87].
Patients with nosocomial SBP have a high incidence of multidrug resistant (MDR) bacteria and have a poor response to third-generation cephalosporin in up to 25–66% of cases [78, 88]. Patients with an ineffective first-line treatment for SBP have been associated with very poor survival [86]. A group of experts suggested in 2014 a modification of the current guidelines in patients with nosocomial SBP by using a broader-spectrum of antibiotics, but it was not until last year, when a randomized controlled trial of 32 patients in Padua compared different antibiotic treatment of nosocomial SBP. Patients were randomized to receive meropenem plus daptomycin vs. cetazidime. After 48 hours of treatment, a paracentesis was performed and if the neutrophil count of the ascitic fluid decreased less than 25% compared to pretreatment value, it was considered a treatment failure. The main outcome was the resolution of SBP after 7 days of treatment. The arm with the combination of meropenem plus daptomycin was markedly more effective than the arm of only the third-generation cephalosporin (87 vs. 25%, respectively) with a p value of <0.001. In the study, 90-day transplant-free survival was also evaluated without significantly different values between both arms of treatment, and the last important issue to be described of the study, in the multivariate analysis of 90-day transplant-free survival. The independent predictive factors or survival were ineffective response to first-line treatment (hazard ratio: 20.6; p < 0.01), development of AKI throughout the hospitalization (HR: 23.2; p < 0.01), and baseline mean arterial pressure (HR: 0.92; p < 0.01) [89].
Different broad-spectrum of antibiotics have been proposed, but carbapenems should be used in order to widely cover the spectrum of Gram-negative MDR bacteria. Regarding Gram-positive bacteria, linezolid, lipo, or glycopeptides should be used, but there are some concerns about the high risk of nephrotoxicity and the high rate of vancomycin-resistant enterococci in patients with cirrhosis and nosocomial infections treated with glycopeptides. Duration of therapy should be a minimum of 5–7 days. In patients who develop renal impairment, it is recommended to use intravenous albumin (1.5 g/kg at diagnosis, followed by 1 g/kg on day 3) along with ceftriaxone [90]. The SBP resolution rate ranges between 70 and 90%. Despite the resolution of the infection, patients recovering from an episode of SBP should be considered as potential candidates for liver transplantation.
In patients who have had one episode of SBP, the recurrence rate within 1 year is 70% [91]. Long-term norfloxacin administration (400 mg/day p.o) decreases the recurrence within the first year after SBP from 68% in the placebo group to 20% in the treated group. Therefore, with these results, all patients with a previous episode of SBP should be treated with norfloxacin indefinitely until liver transplantation, death, or resolution of ascites [90, 92].
Prevention of SBP should always be considered especially in high-risk patients, including those with acute gastrointestinal hemorrhage, low ascitic fluid protein concentration (<10–15 g/L), survivors of a previous episode of SBP, and advanced cirrhosis [2]. A RCT showed that the administration of primary prophylaxis with norfloxacin in patients with low protein ascites (<15 g/L), advanced liver disease (Child Pugh score ≥9, serum bilirubin ≥ 3 mg/dL), or deterioration of kidney function (serum creatinine ≥1.2 mg/dL or serum sodium <130 mEq/L) significantly reduce several complications such as 1 year probability of developing SBP (from 61 to 7%), HRS (from 41 to 28%), and improved 3-month survival (from 62 to 94%) [83]. In addition, Soriano et al. demonstrated that intestinal decontamination with norfloxacin was useful to prevent SBP in hospitalized patients with low ascitic fluid protein levels (23 vs. 0%) [91]. Although prophylaxis strategies are beneficial in several aspects, long-term administration of antibiotics leads to the emergence of MDR bacteria as previously explained. However, due to the problem of antibiotic resistance, clinical judgment must guide the use of antibiotic prophylaxis [93]. Rifaximin has been recently proposed as a possible alternative treatment in prophylaxis of SBP. A case control study published many years ago showed that rifaximin was beneficial in the prevention of SBP in patients with hepatic encephalopathy [94]. Since then two studies have compared the efficacy of rifaximin vs. conventional prophylaxis (i.e., norfloxacin) and have provided contradictory results. In a prospective study including patients with and without previous SBP, rifaximin did not lead to a reduction of SBP occurrence in hospitalized patients with advanced liver disease, despite a greater proportion of patients with previous SBP in the norfloxacin group (89 vs. 15%, p < 0.001) [95]. Conversely, in a RCT including 260 patients with ascites and a previous episode of SBP, rifaximin was more effective than norfloxacin in reducing the recurrence of SBP (3.9% vs. 14.1%; p = 0.04) and even improved survival (13.7% vs. 24.4%; p = 0.044) during an 18 month of follow-up [96].
Furthermore, ascites is very often complicated by a disability of solute-free water excretion. In this setting, the antinatriuretic pathway involves the oversecretion of arginine vasopressin (AVP) that enhances the function of the vasopressin 2 (V2) receptors in the renal distal collecting tubules, inhibiting solute-free water excretion [97]. In this scenario, the AVP production is increased, and there is a lack of clearance of AVP due to cirrhosis itself. In addition, V2 is excessively bound by AVP, triggering more free water retention in kidney tubules by the creation of more aquaporin-2 channels to retain more water. Therefore, these patients cannot remove enough water and results in worsening serum dilution and hypoosmolarity [98]. All this mechanism gives place to dilutional hyponatremia, which is the commonest form of hyponatremia in patients with cirrhosis.
In patients hospitalized with cirrhosis and ascites, the prevalence of hyponatremia, defined by sodium <135 mEq/L, is about 22%, which rises to 49% if the cut-off point is 130 mEq/L. The presence of hyponatremia implies a poor prognosis. It has been demonstrated that hyponatremia is an independent predictive factor to have an increased morbidity and mortality and has been added to the MELD score (Sodium-MELD) for liver donor allocation in the United States [99]. When there is a decrease of 1 unit of sodium below 135 mEq/L, the mortality risk increases by over 10% in patients who are in the list for liver transplant [100]. In addition, it has been demonstrated that hyponatremia is a common event in patients with cirrhosis that may lead to hepatic encephalopathy, with implies a significant decline in quality of life and increased neurological complications throughout liver transplantation. Several transplant centers require correction of hyponatremia prior to liver transplantation, but there is no standard algorithm.
There are several types of hyponatremia. On the one hand, hypervolemic or dilutional hyponatremia as explained previously, and on the other hand, hypovolemic hyponatremia, which is usually secondary to excessive fluid losses from the kidney (overdiuresis secondary to diuretic treatment) or from gastrointestinal tract due to diarrhea. If there is an evidence of dehydration or prerenal azotemia, the treatment in these patients consists in solving the cause with fluid volume expansion replacement. Otherwise, if there is a hypervolemic hyponatremia in the setting of volume overload, it is much more difficult to correct the hyponatremia and for patients to tolerate properly the correction. The therapy consists mainly in water restriction and the increase of free water renal excretion. Daily dietary fluid restriction is recommended to 1.5 L, particularly when the serum sodium is below 130 mEq/L. The main drawback of this strategy is the poor patient’s compliance and low response. Another point in the treatment is the diuretic adjustment or withdrawal if it is required.
A study of 997 patients with cirrhosis and ascites demonstrated that serum sodium is less than or equal to 120 mmol/L in only 1.2% of patients and less than or equal to 125 mmol/L in only 5.7% [101]. Attempts to rapidly correct hyponatremia in this setting with hypertonic saline can lead to more complications than the hyponatremia itself [2]. Fluid restriction (i.e., 1–1.5 L of water per day) is seldom effective in improving hyponatremia, but prevents a further decrease in sodium levels [2, 3].
There are other strategies under investigation such as increasing the effective arterial blood volume with intravenous albumin with or without vasoconstrictors as, for example, midodrine. These studies are nonrandomized, and there is a need of further studies before their incorporation into clinical practice [102]. Another interesting treatment option for dilutional hyponatremia is the use of vaptans. They induce the release of solute-free water into urine and improve hyponatremia in patients with cirrhosis [103, 104]. Vaptans result useful and effective in improving sodium levels in 45–82% of patients with dilutional hyponatremia. However, the effect is short and goes back to baseline hyponatremia after the withdrawal of the drug, and they do not improve survival. The side effects of this drug are dehydration, thirst, AKI, and overcorrection of sodium levels. Experts in the issue recommend the use of vaptans for a short period of time in patients with hyponatremia below 125 mEq/L who are hospitalized waiting for a liver transplant. Although they have been approved by the Food and Drug Administration and the European Medication Agency for the management of hypervolemic hyponatremia, their widespread use in cirrhosis warrants further long-term studies [2].
Finally, the last important complication related with ascites is the development of a harmful event such as HRS. HRS is a late manifestation of extreme circulatory dysfunction with a marked vasoconstriction of the kidney arteries trying to compensate splanchnic vasodilatation secondary to portal hypertension. HRS usually appears in patients with cirrhosis and advance stage of liver dysfunction, and it is always accompanied by ascites and usually hyponatremia [105].
HRS may appear with or without precipitating factors, and there are several predictive factors for the development of HRS. The development of bacterial infections, particularly SBP, is the most important risk factor for HRS (30%) [106]. Other important causes include infections, hypovolemia, paracentesis, and bleeding and nephrotoxic medication. HRS is a potentially reversible functional renal impairment in patients with cirrhosis. It may be rapidly progressive (type I HRS) or may develop gradually (type II HRS), which is usually associated with refractory ascites [106]. HRS is diagnosed with clinical and analytical data and its definition has been updated recently. Since the first definition of HRS type 1 in 1994, there have been slight changes, the last one being in 2015 in the revised consensus recommendations of the International Club of Ascites (ICA) [93]. This last change has been made adopting the concept of AKI originally developed in general critically ill patients and has removed the high cut-off value of serum creatinine (2.5 mg/dL or 220 μmol/L) to start pharmacological treatment with vasoconstrictors. HRS type 1 is defined when AKI stage 2 or more is fulfilled with the rest of HRS criteria (see Table 3) [80]. In this way, vasoconstrictors and albumin can be administrated earlier and thus potentially achieving a better efficacy. Although this new definition could have benefits in the efficacy, there is still a lack of biomarkers to differentiate between HRS and parenchymal kidney disease such as acute tubular necrosis. The adequate differentiation could select patients with a real functional damage to start the correct treatment as soon as possible. Recently, there are several urine biomarkers under study, trying to help in this hard work.
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Hepatorenal syndrome criteria [93].
The prognosis of HRS remains poor, with an average median survival time of nearly 3 months. High MELD scores and type 1 HRS are associated with very poor prognosis. Median survival of patients with untreated type 1 HRS is approximately 1 month [107]. Current guidelines from the European Association for the Study of the Liver emphasize the early detection and treatment of HRS and give priority to liver transplantation [2].
Diuretics should be removed and albumin expansion (1 g/kg) for 48 hours must be administrated if there is no contraindication. If there is no response and the rest of HRS criteria are fulfilled, these patients should be admitted to an intensive care unit. Fluid balance, arterial pressure, vital signs, and central venous pressure are ideally required to prevent volume overload. Current standard treatment involves the use of vasoconstrictors therapy: Terlipressin (1 mg/4–6 hours intravenous bolus) with albumin (20–40 g/day) should be considered as the first-line treatment, and if not available, norepinephrine is a valid alternative. A recent study demonstrated that the administration of terlipressin in continuous infusion instead of boluses had the same rate of response and less side effects [108]. Seventy-eight patients were randomly assigned to receive either continuous intravenous infusion (2 mg/day) or intravenous boluses (0.5 mg/4 h), and if there was no response, the dose was progressively increased to a final dose of 12 mg/day in both groups. The rate of side effects was lower in the infusion than in the boluses (35.29 vs. 62.16%, respectively, p < 0.025). The rate of HRS reversal (total and partial) was not significantly different in both groups (76.47 vs. 64.85%). This standard treatment with vasoconstrictor and albumin is effective in 40–50% approximately, although in the last study explained previously it was about 70%. The recurrence of HRS after stopping the vasoconstrictor is about 40%. There are a few studies assessing independent predictive factors of response to terlipressin, and these studies showed a relationship between the improvement in systemic hemodynamics and the effectiveness of treatment. In a study performed in Barcelona, patients with an increase in mean arterial pressure (MAP) of at least 5 mm Hg at day 3 after the beginning of terlipressin, had a higher rate of response. In addition to the improvement in hemodynamics, the degree of liver dysfunction, evaluated with bilirubin greater than 10 mg/dL, was related to a poor response to terlipressin [109]. Another study performed in United States showed that baseline serum creatinine before the beginning of terlipressin predicted the resolution of HRS, and with this information they suggested that an earlier start of treatment would be more effective [110].
A recent RCT compared norepinephrine with terlipressin and demonstrated that reversal of HRS was similar to terlipressin (43 vs. 39%, respectively). Furthermore, there was no statistical difference in survival in both arms: 39% in norepinephrine group and 48% in terlipressin group (p = 0.461) [111]. In addition, a recent meta-analysis of 152 patients suggested that norepinephrine is also an effective option for the treatment of HRS as good as terlipressin, when is used in combination with albumin [112].
Other therapeutic option is the combination of midodrine and octreotide plus albumin. This therapeutic option has been used widely in countries where terlipressin is not available. A RCT has demonstrated a worse response rate in patients treated with midodrine and octreotide compared to the arm treated with terlipressin (5 vs. 56%, respectively. p < 0.001). Ninety-day survival was also lower in the midodrine and octreotide group (29 vs. 56%, p < 0.06) [113].
To summarize all these data, although norepinephrine requires an intensive care unit for its use, it is an effective alternative to terlipressin for the treatment of HRS. On the other side, the combination of midodrine and octreotide is not an effective treatment.
Transjugular intrahepatic portosystemic shunt (TIPS) may be considered as a second-line therapy, although there is weak evidence to support its use in this complication [2]. TIPS is usually contraindicated in patients with HRS because the syndrome appears in the setting of advanced liver dysfunction. Few small trials have shown renal function improvement and a decrease in renin, aldosterone, and norepinephrine levels after the TIPS insertion [114, 115]. However, data is not strong enough to recommend its use in clinical practice.
Renal replacement therapy is recommended in guidelines when everything fails, but implies an even worse prognosis [2, 3, 107]. In clinical practice, it is used in patients awaiting liver transplantation, whose renal function did not respond to vasoconstrictor treatment.
Liver support with molecular adsorbent recirculating system (MARS) has been used in studies with small sample size in patients who did not respond to standard treatment and it was not effective in changing systemic hemodynamics and kidney function [116]. Only one trial showed a decrease in serum creatinine and bilirubin levels in the arm treated with MARS in comparison to hemodialysis arm [117].
All these invasive treatments are controversially recommended to use in patients without the possibility of liver transplantation and should only be assessed in patients awaiting liver transplant.
As previously, HRS can be avoided in several situations. The first situation that HRS could be avoided is in large volume paracentesis (LVP). We must give 6-8g of albumin/liter of ascites removed. This action will prevent worsening of circulatory dysfunction, and second, renal impairment, in addition, it also improves survival [2].
The second situation to prevent HRS is in the scenario of SBP. It could be prevented with primary prophylaxis with norfloxacin. Fernandez et al. showed that norfloxacin administration reduced the development of HRS (28 vs. 41%, p < 0.001) and 3-month mortality (94 vs. 62%, p = 0.003). In addition, norfloxacin administration reduced the 1-year probability of developing a SBP (7 vs. 61%, p < 0.001) compared to placebo [83]. Therefore, primary prophylaxis with norfloxacin has an outstanding impact in the clinical course of patients with cirrhosis, reduces the incidence of SBP, delays de development of HRS, and improves survival. This effect is probably secondary to the reduction of bacterial products in the gut, and hence reducing bacterial translocation.
As explained previously, SBP can trigger a kidney failure, which implies a fatal prognosis. In this situation, the utilization of intravenous albumin infusion may improve the effect on circulatory dysfunction in this setting. The study in the Hospital Clinic of Barcelona showed a better 3-month-survival (41 vs. 22%, p = 0.03) and lower incidence of kidney failure in patients treated with albumin. (10 vs. 33%, p = 0.002). There are ongoing studies, and others done previously recommending the use of albumin expansion in patients with other infections different from SBP, but there is no enough evidence to recommend it in the current guidelines [118].
Highlights
Gut dysbiosis, inflammation, and increased intestinal permeability are synergistically contributed to the pathogenesis of hepatocellular carcinoma.
Previous studies in animal models suggest that targeting the gut-liver axis can inhibit HCC development.
Targeting the gut-liver axis with probiotics, antibiotics, FMT, TLR4 antagonists, FXR agonists, and natural compounds could be the promising strategies for HCC prevention.
Hepatocellular carcinoma (HCC) is a heterogeneous type of tumor that is likely to develop on the background of an inflammatory milieu in patients with advanced liver disease. It is the third leading cause of cancer death globally and is more prevalent in men than in women [1]. Over the past two decades, there is increasing evidence from studies suggesting a causal link between gut microbiota in the progression of HCC. Normal commensal gut microbiota acts as an important source of energy and is pivotal to host metabolism and innate immunity [2]. Not unsurprisingly therefore, alteration to gut microbial composition has been linked to the promotion of chronic inflammatory bowel disease (IBD) via local effects. However, activation of such inflammatory effects can have a broader response across all organ beds such as the liver, kidney, brain, heart, and the hematopoietic system and have been strongly associated with carcinogenesis [3]. Anatomical considerations provide us with a logical understanding on why gut microbiosis may have such an impact on disease development, especially in the liver. Since the liver is anatomically connected to the intestine via the portal vein, it is the first organ to receive nutrient-rich blood and also the first target of gut microbiota. Furthermore, the liver can elicit an inflammatory response through microbe-associated molecular patterns (MAMPs) and pattern recognition receptors (PRRs). Though translocation of gut microbiota from the intestinal lumen to the systemic circulation is counterchecked by multilayer intestinal epithelium, any change in its integrity can initiate inflammation and contribute to fibrosis and thus chronic liver disease (CLD) progression and thus a precursor to HCC development, which is itself usually only seen in the context of cirrhosis, the most advanced form of CLD [4]. In this chapter, we summarize the available literature on the key role of gut microbiome in HCC pathogenesis and novel therapeutic approaches developed to target these processes.
\nThe gut microbiota resides in the gastrointestinal (GI) tract. The human gut harbors complex and diverse microbial community of 100 trillion microorganisms with more than 2000 distinct species of bacteria, in addition to fungi protozoans and viruses. These microorganisms are collectively called gut microbiota, which comprises of commensals, beneficial microbiota, and opportunistic pathogens residing in what is a complex and dense microenvironment. Immediately after birth commensal bacteria colonize the intestine and predominantly comprise Proteobacteria, Lactobacillus, and Actinobacteria, but as we mature into adults Bacteroidetes and Firmicutes species predominate [5]. The composition of microbiota also varies from the small intestine to the distal colon, due largely to the effects of nutrient availability, intestinal pH, and motility. Moreover the overall composition of the microbial community in the gut is further individualized by any alteration in our diet, age, lifestyle, disease, and also medication exposure [6]. A symbiotic relationship exists between gut microbiota and the human host, which are critical to our maintenance of health. For example, gut microbiota are involved in the metabolism of bile acids, synthesis of vitamins, digestion of complex polysaccharides, and production of short-chain fatty acids (SCFAs) [2]. SCFAs are a vital source of energy for enterocytes, which are integral in maintaining gut barrier integrity. In addition, gut microbiota are also involved in the development of local and innate immunity providing defense against not only the pathogenic invasion but also systemic infection [7]. Experimental studies from rodents and humans have demonstrated that the gut microbiota is involved in the progression of HCC by increasing LPS-mediated pro-inflammatory microenvironment in the liver.
\nGut microbiota are known to influence multiple extraintestinal organs; however the importance of the gut-liver axis has understandably received greater attention in recent years. The gut and liver share anatomy from the embryonic phase, with bidirectional interaction through the portal vein. The symbiotic relationship between the gut microbiota and the liver is modulated by the nutrition, immune, metabolic, and neuroendocrine crosstalk between them and thus shapes human health and disease [8]. Functionally, gut and liver coordination influences our physiology. The liver receives 70% of the blood supply from the gut via the portal circulation. The nutrient-rich blood from the gut is effectively processed by the liver and delivered to systemic circulation for normal body growth. In turn, the liver synthesizes bile acids (BAs) and other mediators, like IgA, which influence intestinal microbial composition and barrier integrity, thereby maintaining intestinal homeostasis [8]. Bile acids are involved in energy homeostasis by regulating the metabolism of glucose and lipids and also help in conjugation and detoxification process as well as maintenance of intact intestinal epithelia. Bile acids also regulate microbial composition via antimicrobial peptides production; in turn, microbiota influences the bile acid pool in the intestine as they are involved in secondary bile acid production [9]. IgA secreted from the liver and intestine prevents growth and invasion of pathogenic bacteria to maintain normal gut-liver homeostasis [7]. In normal physiological conditions, translocation of gut bacteria and their metabolites is tightly regulated by the intestinal epithelial barrier, and if any reaches the liver, it is eliminated by hepatic Kupffer cells. Any breach in barrier integrity resulting from intestinal inflammation allows microbiota to pass through the portal vein to potentially trigger hepatic immune cells to enact an inflammatory response (from hepatic stellate cells and Kupffer cells), which may result in necrotic inflammation and hepatic fibrosis contributing to worsening fibrosis and thus liver disease progression [10]. Accumulating evidence suggests gut dysbiosis, bacterial endotoxin, and increased intestinal permeability are hallmark features of CLD and positively correlate with disease severity. These factors play a crucial role in the pathogenesis of not only CLD but have also been shown to promote HCC through various mechanisms (Figure 1).
\nAn overview of homeostatic and impaired gut-liver axis in HCC progression. (A) In homeostatic condition gut lumen contains normal gut flora which is restricted by tightly closed intestinal epithelial cells to prevent its translocation to the liver. (B) Increased bacterial overgrowth in gut lumen and increased intestinal permeability promotes HCC progression through binding of LPS to toll-like receptor 4 (TLR4) which are present on Kupffer cells, hepatocytes, and HSC to elicit the release of pro-inflammatory cytokines and activation of proliferative and anti-apoptotic signals. Prebiotics, probiotics, synbiotics, FMT, and polyphenols can be used to restore eubiosis, while the use of antibiotics can potentially eliminate pathogenic bacteria and endotoxin release. FXR agonists can attenuate intestinal permeability and prevent bacterial translocation. TLR4 antagonists prevent binding of LPS to TLR4 and suppress cancer-promoting signals.
Dysbiosis defines any change in the typical gut microbial composition found in health. Several lines of evidence suggest that gut bacterial dysbiosis is a pathogenic factor in the progression of HCC whatever the trigger for CLD (e.g., alcohol, nonalcoholic steatohepatitis (NASH), viral hepatitis, etc.). The role of gut dysbiosis in the propagation of progressive CLD is likely triggered by the formation of microbial metabolites such as LPS, bacterial DNA, and deoxycholic acid, which causes chronic inflammation in the portal circulation and thus the liver. In cirrhotic patients overgrowth of the pathogenic bacteria such as Enterobacteriaceae, Veillonellaceae, and Streptococcaceae and decreased Lachnospiraceae have been observed to correlate with the child-turcotte-pugh (CTP) score, clinically used to assess the severity of cirrhosis [11]. Moreover, in cirrhotic patients studies have found an increase in both the oral and gut levels of the same microbial species suggesting invasion from the mouth to intestine [12]. It is therefore postulated oral bacterial overgrowth may have a profound effect on intestinal bacterial communities and thus CLD pathogenesis and HCC development. This concept is supported by a recent study that showed a high level of oral microbiota Oribacterium and Fusobacterium in HCC patients [13]. The alteration in gut microbiota composition in HCC is summarized in Table 1.
\nAuthors | \nSample type | \nChanges in fecal microbiota composition | \nClinical implication in HCC | \n
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Ren et al. [14] | \nFeces | \nKlebsiella i | \n\n
| \n
Ponziani et al. [15] | \nFeces | \nBacteroides ↑ Ruminococcaceae ↑ Enterococcus ↑ Phascolarctobacterium ↑ Oscillospira ↑ Bifidobacterium ↓ Blautia ↓ | \n\n
| \n
Grat et al. [16] | \nFeces | \nEscherichia coli ↑ | \n\n
| \n
Huang et al. [18] | \nHCC liver biopsy | \nHelicobacter pylori ↑ | \n\n
| \n
Zhang et al. [19] | \nFeces | \nEscherichia coli ↑ Atopobium cluster ↓ Prevotella ↓ Bacteroides ↑ Lactobacillus spp. ↑ Bifidobacterium spp. ↑ Enterococcus spp. ↓ | \n\n
| \n
Yoshimoto et al. [38] | \nFeces | \nClostridium cluster XI and XIVa ↑ | \n\n
| \n
Gut microbiota dysbiosis in HCC.
Microbial gene signatures that relate to energy production, nickel/iron transport, and amino acid transport appear to be altered in HCC patients when compared to healthy controls [13]. Moreover, when compared to cirrhotic patients, fecal samples from HCC patients have shown increased growth of phylum Actinobacteria and 13 genera including Gemmiger and Parabacteroides [14]. They also found a decrease in butyrate-producing bacteria and an increase in LPS-producing bacteria in HCC patients when compared to healthy controls [14]. A study conducted by Ponziani et al. in NAFLD-related HCC showed increased fecal Bacteroides and Ruminococcaceae, whereas reduced Akkermansia and Bifidobacterium were negatively correlated with intestinal inflammatory marker fecal calprotectin level [15]. This study also showed increased intestinal permeability in these patients accompanied by an increase in plasma level of IL8, IL13, CCL3, CCL4, and CCL5, showing the evidence that alteration in gut microbiota profile is associated with systemic inflammation that may contribute to HCC pathogenesis [15]. In another study, E. coli growth in fecal samples was significantly elevated in HCC patients compared to matched cirrhotic patients [16]. Interestingly, inoculation of AFB1 and/or Helicobacter hepaticus in Helicobacter-free C3H/HeN mice was associated with HCC progression [17]. This observation may suggest that neither direct bacterial translocation nor hepatocyte injury is necessary for HCC development. In clinical studies utilizing liver HCC tumor biopsy tissue, some authors report the presence of Helicobacter ssp. DNA, whereas other investigators failed to correlate the presence of Helicobacter ssp. DNA with HCC progression [18]. In DEN-treated rats, fecal and cecal samples show an increase of pathogenic bacterial species like E. coli, Atopobium, Collinsella, Eggerthella, and Corynebacterium; in contrast there was a decline in the numbers of beneficial bacteria like Lactobacillus spp., Bifidobacterium spp., and Enterococcus spp. [19]. Although the exact mechanism by which gut microbiota promotes HCC has not been firmly established, studies in murine models indicated LPS-TLR4 axis plays a crucial role in the progression of HCC [19, 20]. Zhang et al. suggest that gut dysbiosis merely promotes HCC by increasing LPS levels and that conversely probiotics may suppresses tumor growth [19]. Similarly, Dapito et al. propose that gut microbiota only has a role in the promotion of HCC rather than its initiation [20]. The ability of pathogenic bacteria to disrupt TJs protein thereby increasing intestinal permeability has also been postulated as another mechanism by which microbiota may promote CLD and HCC [21]. However further preclinical and clinical studies are needed to establish the causal link between gut microbiota and HCC progression and to further delineate the molecular mechanisms involved.
\nHCC is arising in an inflammatory environment of the CLD, and therefore, neutralizing inflammation with anti-inflammatory agents may reduce the incidence and recurrence of HCC. Much attention has been focused on the potential involvement of the toll-like receptors (TLR) signaling pathway in the development of liver inflammation and associated HCC progression. Gut-derived endotoxin initiates the innate immune system such as TLRs, which recognize bacterial products and are predominantly expressed throughout the gut-liver axis. In addition, TLR4 plays a central role through LPS (a component of Gram-negative bacteria)-induced hepatic inflammation, while TLR 2 senses component of Gram-positive bacteria such as peptidoglycan [22]. In this context, Yu et al. identified that increased activation of the TLR 4-LPS axis correlated with intestinal permeability in DEN-induced acute liver failure (ALF), which directly regulates pro-survival molecules and enhances hepatocyte proliferation [23]. Interestingly, in mice models the use of antibiotics and/or TLR4 genetic ablation prevented tumor growth and multiplicity [19, 23]. Dapito et al. showed a close link between gut microbiota and LPS-TLR 4 axis in HCC progression in a chimeric mice model [20]. This study also showed in DEN-CCl4 treated mice (with histological CLD) that low-dose LPS treatment triggered TLR4 activation and increased rate of tumor formation, whereas gut sterilization prevented HCC progression rather than regression of the established tumor [20]. Taken together these studies would therefore suggest that gut microbiota may not have a role in HCC initiation but may instead have a tumor-promoting effect through TLRs signaling pathways [20].
\nIn respect of HCC promotion, multiple downstream targets of the LPS-TLR4 axis have been identified in both in vitro and in vivo studies. HSCs, Kupffer cells, and hepatocytes show TLR4 expression and thus are sensitive to LPS challenge [24]. Dapito et al. showed that TLR4 activation in HSCs, hepatocytes, and non-bone-marrow-derived resident cells promotes hepatocarcinogenesis by upregulating epiregulin (hepatomitogen) and inhibiting cleaved caspase 3 via NF-κB activation [20]. Moreover, Yu et al. showed hepatic Kupffer cells as the chief target for LPS-induced TLR4 activation by increasing pro-inflammatory cytokines such as TNF-α and IL-6 production [23]. Similarly, in vitro studies have shown evidence of LPS-TLR4-promoted HCC cell proliferation via NF-κB, MAPK, and STAT3 mediated signaling pathways [24]. LPS-TLR4 has also been shown to promote epithelial-to-mesenchymal transition (EMT) in HCC by upregulating NF-κB- and JNK/MAPK-mediated expression, while NF-κB and JNK/MAPK signaling blockade inhibited EMT occurrence [25]. Similarly, LPS-TLR4 axis is also known to enhance angiogenesis in HCC mice model via production of pro-angiogenic factors by HSCs in tumor stroma [26]. However further studies incorporating TLR4 deletion are needed to better understand its role in hepatocyte proliferation and distinguish paracrine signaling from HSCs and Kupffer cells in HCC progression.
\nCommensals and opportunistic pathogens are kept in check within the intestinal lumen by a single layer of intestinal epithelial cells (IEC) which spans almost 400 m2 in surface area [27]. The gut barrier is highly dynamic in nature in which IEC is capable of self-renewal every 4–7 days with constant changes in intestinal luminal content. IEC are predominantly composed of absorptive enterocytes, which have metabolic and digestive functions. It also has secretory functions enacted by cell types such as enteroendocrine, goblet, and paneth cells which are specialized for maintaining digestive, immune, and epithelial barrier function [27]. Enteroendocrine cells connect the central and enteric neuroendocrine system via the secretion of various digestive hormones like gastrin, cholecystokinin, incretin, etc. The highly glycosylated mucins secreted by goblet cells form the first line of defense against microbial invasion and when compromised may predispose to disease as is evident in Mucin 2-deficient mice which are susceptible to colitis and inflammation-induced colorectal cancer [28, 29]. The intestinal barrier function is further strengthened by antimicrobial peptides (AMPs) including defensin, cathelicidin, and lysozyme [27]. These AMPs disrupt bacterial cell membranes and prevent adherence to gut mucosa.
\nApart from IEC, the gut barrier is primarily maintained by tight junction (TJs) components (e.g., claudin, occludin, zonula occludens, and other junctional adhesion molecules (JAMs)) preserving intact epithelia which in turn regulate the paracellular movement of solutes, water, and other nutrients while restricting the entry of bacteria from the lumen to systemic circulation [30]. The mechanism of increased intestinal permeability is poorly understood. Growing evidence suggests that inflammation and TJ protein disruption are two of the key players driving increased intestinal permeability. In our previous study, we found increased systemic ZO-1 level in HCC patients reflecting increased intestinal permeability [31]. Moreover, plasma ZO-1 level was positively correlated with the inflammatory marker hs-CRP and with disease severity, suggesting inflammation drives intestinal permeability associated with HCC progression [31]. Bacterial overgrowth leads to increased production of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β, which is mainly mediated through the TLR4-NF-kB signaling pathway, thereby promoting intestinal inflammation and HCC progression [19]. These pro-inflammatory cytokines have a direct effect on TJ proteins like claudin and ZO-1, leading to enhance intestinal permeability [32]. Furthermore, in both in vivo and in vitro models, LPS dose dependently increases intestinal permeability via upregulating TLR4-mediated CD14 expression in enterocytes [33]. Similarly, NLRP6-deficient mice show altered microbiota and enhanced colonic inflammation through the chemokine (C-C motif) ligand CCL5 [34]. This results in increased intestinal permeability to microbial products and thus increases hepatic inflammation and progression from NAFLD to NASH [34]. Moreover, enteric pathogens such as Escherichia coli and Clostridium difficile are increased in CLD and are capable of increased intestinal permeability by modulating TJ integrity [11, 21].
\nBile acids are another key player for maintaining gut barrier function by promoting intestinal epithelial cell proliferation and microbiota composition [35]. There is clear evidence that bile acids have both direct antimicrobial effect and an indirect effect through FXR-induced AMPs and thus control growth and adhesion of intestinal bacteria. In fact, decreased bile acids pool in the intestine is associated with bacterial overgrowth and inflammation [36]. The study by Kakiyama et al. showed that cirrhosis reduced bile acids entering the intestine causing bacterial dysbiosis by reducing beneficial bacteria such as Gram-positive Blautia and Ruminococcaceae and increasing pathogenic bacteria like Enterobacteriaceae [37]. In a NASH-induced CLD/HCC mouse model, increased Gram-positive Clostridium clusters (XI and XVIa) were positively correlated with increased serum deoxycholic acid (DCA) [38]. Notably, Clostridium clusters are capable of synthesis of secondary bile acid DCA via 7α-dehydroxylation of primary bile acids. DCA is a DNA-damaging agent and a known pro-carcinogen shown to affect various cancer signaling pathways. In this context, a study by Yoshimoto et al. revealed DCA activates a senescent-associated secretory phenotype in HSCs, thereby producing various pro-inflammatory and pro-tumorigenic factors promoting HCC development in mice, while antibiotic treatment and/or blocking DCA production prevented HCC development [38]. Similarly, in a HCC mouse model induced by steatohepatitis-inducing high-fat diet (STHD-01), increased hepatic and fecal bile acids concentrations were observed [39]. In this model, DCA activated mTOR and promoted HCC development. However, following antibiotic treatment, there was a decrease in HCC progression suggesting an interrelationship between BA metabolism, gut microbiota, and HCC development [39].
\nBile acids maintain homeostatic IEC proliferation via EGFR- and FXR-dependent pathways, which helps the continuous regeneration of enterocytes and maintain intact epithelia [40]. Several studies demonstrate that the intestinal bile acid pool also regulates TJ protein distribution and expression. In Caco-2 cell monolayers, incubation with dihydroxy bile acids decreased transepithelial resistance (TER) and was accompanied by increased phosphorylation and redistribution of occludin [41]. In human colonic biopsies, DCA induces Cr-EDTA permeability altering TER and increasing translocation of E. coli. Several in vivo studies have also elucidated the role of bile acids in the regulation of TJ permeability [42]. In HFD mice increased intestinal bile acid pool was associated with increased intestinal permeability with decreased expression of TJ proteins ZO-2 and JAM-A [43]. Similarly, in bile duct ligated (BDL) rats where intestinal BA delivery was prevented, there was increased bacterial translocation and increased intestinal permeability with decreased expression of claudin-1 and occludin. Conversely, the above effects were ameliorated by FXR activation [44]. These studies highlighted the protective role of FXR in the maintenance of intestinal barrier integrity; however, it is unclear whether these effects were from direct activation of FXR on TJ proteins or indirect effects from altered mucosal immune cells. In addition to FXR, another bile acid receptor TGR5 also modulates barrier permeability and TJ protein expression. In TGR5 null mice, increased intestinal permeability due to alteration of TJ protein expression develops colitis [45]. Therefore, the quantity and composition of BA pool in the intestine represent an important factor in the regulation of gut microbial community and gut barrier integrity.
\nTraditionally, HCC is cured based on the available treatment options such as surgical treatment, chemotherapy, and local ablation therapy; however, patients are facing many problems including the poor hepatic reserve [46]. Furthermore, the possible therapeutic interventions targeting the gut-liver axis in HCC are summarized in Table 2.
\nAuthors | \nIntervention class | \nMedication | \nDesired effect in HCC | \n
---|---|---|---|
Zong et al. [53] | \nPrebiotics | \nLactulose | \n\n
| \n
Zhang et al. [19] | \nProbiotics | \nVSL#3 | \n\n
| \n
El-Nezami et al. [63] | \nProbiotics | \nLactobacillus rhamnosus LC 705 and Propionibacterium freudenreichii subsp. shermani | \n\n
| \n
Li et al. [46] | \nProbiotics | \nProhep | \n\n
| \n
Kumar et al. [62] | \nProbiotics | \nCombination of probiotic fermented milk and chlorophyllin | \n\n
| \n
Yoshimoto et al. [38] | \nAntibiotics | \n4Abx (ampicillin, metronidazole, vancomycin, neomycin) | \n\n
| \n
Abdel-Hamid et al. [67] | \nAntibiotics | \nClarithromycin and azithromycin | \n\n
| \n
Dapito et al. [20] | \nAntibiotics | \nRifaximin | \n\n
| \n
Nguyen et al. [93] | \nTLR4 antagonists | \nTAK-242 | \n\n
| \n
Nkontchou et al. [117] | \nNonselective β-blockers | \nPropranolol | \n\n
| \n
Chang et al. [118] | \nNonselective β-blockers | \nPropranolol | \n\n
| \n
Bishayee et al. [121] | \nNatural compound | \nResveratrol | \n\n
| \n
Ji et al. [124] | \nNatural compound | \nQuercetin | \n\n
| \n
Teng et al. [125] | \nNatural compound | \nCurcumin | \n\n
| \n
Therapeutic intervention targeting the gut-liver axis in HCC.
Prebiotics are non-absorbant and nondigestible food ingredients which promote growth or activity of beneficial bacteria like Bifidobacteria and Lactobacilli and inhibit the growth of potentially pathogenic bacteria [47]. Currently, prebiotics like lactulose, lactitol, fructo-oligosaccharides, and galacto-oligosaccharides are commercially available [48]. Synthetic disaccharides like lactulose and lactitol are extensively used for the treatment of hepatic encephalopathy in CLD patients as ammonia detoxifying agents [48]. Also, these disaccharides are metabolized by colonic bacteria to produce lactic acid and acetic acid due to which pH in the gut lumen is decreased [49]. Low pH enhances the growth of non-urease-producing lactobacilli and inhibits pathogenic urease-producing bacteria [50]. Chen et al. showed that in chronic viral hepatitis patients, lactitol administration significantly decreased plasma endotoxin levels and increased the growth of beneficial Lactobacilli and Bifidobacteria species [51]. In contrast, Bajaj et al. reported lactulose administration in patients with HE did not improve dysbiosis and increased growth of Gram-negative bacteria such as Enterobacteriaceae and Bacteroidaceae [52]. This indicates the pattern of gut microbiota abundance is the major determinants of disease severity [52]. In HCC patients administration of lactulose (30 mL/day) for 14 days significantly reduced ALT and bilirubin levels, while antioxidant enzyme SOD, anti-inflammatory markers IFN-γ and IL-4, and blood cells CD4(+)/CD8(+) were found to be increased suggesting its ability to reduce inflammation and restore oxidation/antioxidant system imbalance [53]. Similarly in partial hepatectomized rats, administration of lactulose induces liver regeneration by inducing hydrogen and abrogating oxidative stress (heme oxygenase-1, SOD-2) and inflammation (IL-6 and TNF-α) [54]. Moreover, mixed diets of galacto-oligosaccharides and fructo-oligosaccharides to infants were increased the growth of Bifidobacterium; however, this formulation has not been tried in patients with liver disease [55].
\nProbiotics are live microorganisms which when administered in adequate amounts confer a health benefit for the host [56]. Probiotic supplementation was also shown to restore intestinal dysbiosis in CLD patients [48]. Furthermore, mice treated with probiotic such as VSL#3 significantly reduces Clostridium spp. and modified gut microbiota [57]. In cirrhotic patients, VSL#3 supplementation for nearly 6 months was shown to reduce the risk of hospitalization and improved CTP and MELD score [58]. Similarly, in NASH-associated obese children, treatment with VSL#3 over the period of 4 months reduces fatty liver and improved lipid profile and insulin sensitivity [59]. The other probiotics such as Lactobacillus salivarius LI01 and Pediococcus pentosaceus LI05 reduced inflammation, protected the intestinal barrier, prevented bacterial translocation, restored eubiosis, and attenuated hepatic fibrosis in CCl4-induced cirrhotic rats [60]. Similarly, Lactobacillus GG (LGG) supplemented with standard diet in cirrhosis patients show significantly reduced blood endotoxemia and TNF-α, thereby restoring eubiosis [61]. However, in HCC, probiotic usage is meager, and only a few studies have identified the therapeutic potential. VSL#3 (contains three strains of Bifidobacteria, four strains of Lactobacilli, and one strain of Streptococcus thermophilus) treatment to DEN-induced rat hepatocarcinogenesis has shown to attenuate HCC progression, reduce tumor number and multiplicity, ameliorate hepatic and intestinal inflammation, and thus restore gut dysbiosis [19]. Li et al. identified that subcutaneous administration of Prohep (a novel probiotic mixture of Lactobacillus rhamnosus GG, Escherichia coli Nissle 1917, and heat-inactivated VSL#3) reduced the tumor size and HCC growth [46]. Prohep improves beneficial bacteria such as Prevotella and Oscillibacter and control tissue inflammation as evidenced by decreased T helper 17 cells in the gut, thereby attenuating the progression of HCC [46]. Moreover, in aflatoxin B1-induced HCC rats, treatment with probiotic fermented milk and chlorophyllin significantly reduced tumor incidence by decreasing the expression of cyclin D1, bcl-2, and c-myc proto-oncogenes [62]. Similarly, aflatoxin-induced HCC patients treated with dietary supplementation of probiotics (using viable Lactobacillus rhamnosus LC 705 and Propionibacterium freudenreichii subsp. shermani) decreased the urinary excretion of aflatoxin-DNA adduct (AFB-N7 guanine) and improved HCC [63]. Thus, probiotic supplementation could be beneficial to cirrhotic patients with the potential to progress to HCC.
\nSynbiotics are combined form of prebiotics and probiotics, which contains four fermentable fibers (symbiotic 2000) and four freeze-dried non-urease-producing lactic acid bacteria. Synbiotic administration to cirrhotic patients results in decreased plasma endotoxin and ammonia levels and increased fecal Lactobacillus spp. [64]. Interestingly 50% of these patients have improved child-turcotte-pugh score compared to placebo [64]. Moreover, in NAFLD patients synbiotic supplementation has shown to have beneficial effects by improving lipid profile, glucose homeostasis, hepatic marker enzymes, and inflammatory markers [65]. Synbiotic (FloraGuard) administration also has a protective role in alcohol-induced liver injury in rats [66]. In addition, the synbiotic treatment restored ethanol-induced intestinal permeability and increased the growth of beneficial bacteria Bifidobacterium spp. and Lactobacillus spp. [66]. Currently, studies are lacking for the use of synbiotics in chronic liver diseases or HCC prevention.
\nSeveral studies have postulated that antibiotic treatment may cause gut microbiota dysbiosis. It may represent effective strategies to prevent the tumor-promoting gut microbiota, its metabolites DCA, and pro-inflammatory signal inducer LPS which all have a role in the progression of CLD and HCC. In DEN-CCl4- and DMBA-HFD-induced HCC mice model, the oral antibiotics ampicillin, metronidazole, neomycin, and vancomycin significantly reduced the tumor number and size [20, 38]. In addition, this antibiotic combination also reduced the liver fibrosis and improved liver histology in cirrhosis. Moreover, the effectiveness of antibiotics administration was enhanced when given at late-stage HCC in mice rather than earlier stage [20]. In another study conducted in DEN-induced HCC rats, clarithromycin and azithromycin suppressed HCC progression through extrinsic and intrinsic apoptotic pathways, whereas erythromycin aggravated HCC and did not show antitumorigenic effect [67]. Vancomycin is an antibiotic used to treat a bacterial infection, which effectively prevented the mouse model of HCC; however, long-term administration to CLD patients develops potential side effects [38]. Many studies have concluded that norfloxacin and rifaximin treatments to cirrhotic patients have beneficial effects [68]. In a double-blind placebo-controlled clinical trial, long-term oral administration of norfloxacin to cirrhotic patients markedly reduces Gram-negative bacteria in the fecal matters and lowers the spontaneous bacterial peritonitis (SBP) [69]. Furthermore, CCl4-induced cirrhotic animals showed decreased SBP and inflammation following norfloxacin treatment [70]. Norfloxacin was identified as a promising antibiotic in regulating gut microbiota overgrowth and prevention of BT in both cirrhotic humans and rodents; indeed its effect on HCC patients remains unidentified. Rifaximin is a broad spectrum oral antibiotic having potential bactericidal activity against aerobic and anaerobic Gram-negative bacteria [71]. It is an excellent choice of drug to cure HE in advanced cirrhotic patients [72]. The study conducted by Vlachogiannakos et al. showed treatment with rifaximin for 4 weeks significantly decreased portal pressure and LPS levels in decompensated cirrhotic patients [73]. Long-term treatment with rifaximin reduces SBP occurrence, variceal bleeding, HRS, and HE with an overall improvement in survival rate in cirrhotic patients [74]. Similarly, in murine DEN-CCl4-induced HCC mouse model, rifaximin treatment was shown to ameliorate HCC progression [20]. Although rifaximin is clinically used for prevention of HE and other complications in cirrhotic patients, its role in HCC prevention in humans is further warranted.
\nFecal microbiota transplantation is currently being used for the treatment of Clostridium difficile infection [75]. The enteric dysbiosis was restored to normal gut flora following FMT from healthy donor to Clostridium difficile-infected patients [75]. Moreover, in mice with gut dysbiosis induced by antibiotics and chemotherapy, treatments were reversed by FMT [76]. In experimental cirrhosis with hepatic encephalopathy, FMT improves liver function and HE grade by limiting inflammation and improving tight junction integrity [77]. In this context, Bajaj et al. reported that FMT in cirrhotic patients with recurrent HE improves cognition, restores dysbiosis, and improves MELD score compared to standard care in those patients [78]. A number of clinical trials are ongoing in patients with NASH and cirrhosis for the efficacy of FMT [79, 80]. Vrieze et al. reported in patients with severe metabolic syndrome that treatment with FMT from a healthy donor improves liver biochemistry, peripheral insulin resistance, and restoration of eubiosis [81]. Furthermore, in alcoholic hepatitis patients, FMT treatment significantly reduced liver disease severity and HE occurrence [82]. FMT recipients also showed an increase in beneficial bacteria like Actinobacteria and Bifidobacterium longum and decrease in Pseudomonas and E. coli with an increase in bile secretion [82]. Collectively these findings indicated that FMT may restore gut dysbiosis and reduce complications in cirrhotic patients and thus attenuate HCC development. However, scarce literature supporting the beneficial effect of FMT and long-term study is needed to prove permanent colonization in altered gut microbiota environment in cirrhotic patients. Moreover, there is a chance of inducing viral infection and transmission of other pathogens through FMT which may have deleterious effect and immunosuppression in advanced liver disease patients [83, 84].
\nNumerous studies have shown that LPS-TLR4 is a key inflammatory pathway in the progression of CLD and has a tumor-promoting effect on HCC [20, 23, 85]. Therefore blocking this pathway might represent a promising treatment approach in controlling cirrhosis and HCC progression. Several TLR4 antagonists have been developed toward controlling LPS-activated TLR4-mediated inflammatory responses which include polymyxin B [86], glycolipids interfering CD14-LPS interaction [87], eritoran [88], resatorvid (TAK242) [89], and thalidomide [90]. In BDL-induced cirrhotic rats, intravenous administration of TAK-242 significantly reduces plasma transaminases and inflammatory cytokines [91]. It also ameliorates acetaminophen-induced acute liver failure [92]. Similarly, in transgenic HCC mice (HepPten−), TAK-242 treatment for 28 days significantly reduced tumor burden and ameliorated HCC progression [93]. Eritoran tetrasodium protects against liver ischemia/reperfusion injury by inhibiting inflammatory response induced by high-mobility group box protein B1 (HMGB1) [94]. Similarly in D-galactosamine- and LPS-induced acute liver failure, treatment with eritoran significantly reduces inflammation and hepatic marker enzymes [95]. Eritoran treatment also decreases proliferation and induces apoptosis in tumor cells in a chemically induced mouse model of colorectal carcinoma [96]. Although resatorvid and eritoran showed the beneficial effect in improving the survival of murine sepsis model, it failed to do so in patients with severe sepsis [97]. Several TLRs have been upregulated in HCC [98]. In addition, TLRs are also abundantly expressed on immune cells which recognize various pathogens such as HBV which upon activation induces an innate immune response [99]. All the TLRs are activated by two independent pathways: MyD88-dependent (except TLR3) and MyD88-independent (TLR3 and TLR4) pathway [100]. Activation of TLR3-TRIF signaling pathway leads to apoptotic activity independently and, in turn, also activates IRF3 transcription factor to produce interferons [100]. TLR3 agonist BM-06 (synthetic dsRNA) significantly inhibited HCC cell proliferation, increased apoptosis, and decreased cell invasion and migration with increased antiviral IFN level [101]. Activation of TLR9 leads to phosphorylation of NF-κB with increased production of pro-inflammatory cytokine TNF-α, IL-6, and IL-10 [102]. Mohamed et al. showed that inhibition of TLR7 and TLR9 with antagonist IRS-954 or chloroquine significantly reduces HCC cell proliferation, angiogenesis with increased apoptosis [103]. This was further supported by tumor xenograft and DEN-induced rat HCC model in which chloroquine treatment reduces HCC incidence [103]. Although growing evidence shows TLRs as an important mediator of HCC progression, the molecular mechanism for disease progression is not completely understood. Therefore, further research needs to be done for the use of TLR agonist or antagonist as a drug target for HCC prevention since TLRs are also involved in both cancer-promoting mechanism and immune-modulator which is responsible for an innate immune response against tumor cells and HBV and HCV infection [99, 104, 105, 106].
\nBacterial overgrowth due to impaired gut motility has been reported in cirrhotic patients [107]. Cisapride, a prokinetic drug, has shown beneficial effects not only by regulating intestinal motility but also inhibiting bacterial overgrowth and preventing bacterial translocation in both rodent models and liver cirrhotic patients [108, 109]. Cisapride in combination with norfloxacin significantly reduces the incidence of SBP in high-risk cirrhotic patients [110]. Although the mechanism of impaired gastrointestinal motility in cirrhotic patients is unclear, increased adrenergic activity may be responsible for the altered motility.
\nNonselective β-blockers are prevalently used in decompensated chronic liver disease patients to reduce morbidity and mortality. It is used as bleeding prophylaxis in cirrhotic patients with esophageal varices. NSBB also antagonizes β-adrenoceptors. The β-adrenergic receptor pathway is involved in maintaining normal physiological functions. The catecholamines such as epinephrine and norepinephrine are the key ligands for β-adrenoceptors (β1 and β2). Furthermore, increased expression of β-adrenoceptors was observed in HCC cell membranes compared to healthy liver cells; however, the mechanisms remain unclear [111]. Catecholamines exhibit pro-carcinogenic effects in gastric, pancreatic, and breast cancer, which is antagonized by NSBB. Its beneficial effects to reduce the risk of HCC have also been identified by the very recent observational and experimental trials [112]. Moreover, in ovarian and breast cancer patients, NSBB treatment was shown to reduce cancer formation and growth. In cirrhotic patients, increased catecholamines results in disease severity, and thus, NSBB treatment may be potent to inhibit carcinogenesis in cirrhosis [113]. A recent study by Leithead et al. showed NSBB is safe and may confer benefit in patients with ascites complicating the end-stage liver disease [114]. In addition, Reiberger et al. observed that NSBB treatment ameliorates intestinal permeability and reduces BT in cirrhotic patients [115]. In a recent study, Wang et al. showed propranolol induces apoptosis and suppresses proliferation of liver cancer cells [116]. Of note, long-term treatment with propranolol in patients with HCV-related cirrhosis reduces the incidence of HCC [117]. Similarly, in patients with unresectable/metastatic HCC cohort, propranolol treatment significantly reduces mortality risk and improved overall survival suggesting β-blockers might be another therapeutic approach in HCC prevention [118].
\nTreatment with natural compounds and food ingredients like polyphenols represents another therapeutic approach in the restoration of eubiosis, modulation of gut microbiota, reduction of inflammation, prevention of cirrhosis, and thus the progression of HCC. Many experimental data have shown evidence that flavonoids are proficient to alter gut microbial composition and restoration of eubiosis in chronic liver diseases. Proanthocyanidin improves beneficial microbiota Bacteroides such as Lactobacillus spp. and Bifidobacterium spp. composition and reduces intestinal inflammation and oxidative damage, thereby attenuating experimental colon cancer. Resveratrol, a flavonoid, is shown to modulate intestinal microbiota with a profound increase in Bifidobacterium spp. and Lactobacillus spp. and reduce systemic and colonic inflammation in rats [119]. Resveratrol also shown to have anticancer activity in HCC cell lines; inhibit proliferation, viability, invasion, and metastasis; and induce apoptosis [120]. Its anticancer property was also studied in DEN-induced hepatocarcinogenesis [121]. We found resveratrol treatment to cirrhotic mice attenuated systemic inflammation and ammonia levels and altered neuronal TJ proteins, thereby preventing secondary complications such as HE in cirrhosis [122]. Quercetin, a bioactive flavonoid, was shown to inhibit human HCC cell proliferation, migration, and invasion and trigger apoptosis both in vivo and in vitro [123]. Its profound antitumor effect was also shown in xenograft and DEN-induced HCC rodent models [124]. Curcumin, a powerful antioxidant, has a wide range of bioactive properties. Previous studies have shown evidence that curcumin has HCC chemoprevention in preclinical models as well as patients with HCC [125, 126]. Moreover, nimbolide from the leaf of the neem tree (Azadirachta indica) is another potential natural compound having antioxidant, anti-inflammatory, antibacterial, antiviral, and anticancer properties [127]. In vitro study in HCC cell line (HepG2) shows that nimbolide induces cell apoptosis by abrogating NF-κB and Wnt signaling pathway [128]. Currently, our lab is focusing on anticancer effects of nimbolide and its molecular mechanisms in an experimental hepatocarcinogenesis. Of note, these natural compounds have a wide variety of biological activities on gut microbiota and may preserve gut barrier integrity, microbial metabolites, TJ integrity, and mucosal immunology. Indeed, further human studies are warranted to see the effect of natural compounds on gut microbial modulation and prevention of HCC.
\nGut epithelial barrier acts as a fence for translocation of gut microbiota and its metabolite into the systemic circulation which is the major driving factor for CLD progression and HCC development [129]. Therefore, primarily targeting or restoring the gut epithelial barrier is an interesting therapeutic approach in HCC pathogenesis. Compelling evidence has shown that targeting gut microbiota (restoring eubiosis) directly or receptor-mediated pharmacological intervention using TLR4 antagonist or FXR agonist might improve epithelial barrier function [130, 131]. FXR is a BA receptor which is widely expressed throughout the gut-liver axis. Decreased BA is associated with intestinal bacterial overgrowth, increased gut permeability, and bacterial translocation in rodents [38]. FXR controls hepatic inflammation, promotes liver regeneration, and suppresses HCC formation mainly through enterokine FGF19 [132]. FXR null mice have an intestinal barrier dysfunction and high occurrence of HCC, whereas reactivation of FXR inhibited HCC through FGF15-cyp7a1 axis [133]. In this context, FXR agonist obeticholic acid (OCA) prevents gut barrier dysfunction and BT in cholestatic rats [131]. Furthermore, in CCl4-induced cirrhotic rats, OCA treatment significantly reduces BT and inhibits intestinal inflammation by restoring intestinal TJ proteins such as ZO-1 and occludin and antimicrobial peptides [134]. OCA treatment also improves hepatic inflammation and decreased portal pressure in BDL cirrhotic rats [135]. Consequently, OCA treatment may prevent HCC by limiting intestinal inflammation and improving gut barrier dysfunction in advanced liver disease.
\nIncreased TNF-α production in mesenteric lymph nodes by monocyte is the major factor responsible for increased intestinal permeability in cirrhosis and HCC [19, 136]. TNF-α decreases ZO-1 expression through NF-κB and MLCK activation [137]. TNF-α also downregulated occludin expression in Caco-2 enterocyte by targeting PI3k/Akt signaling [138]. In BDL rats, treatment with infliximab (IFX, a monoclonal antibody against TNF) significantly reduced portal pressure and attenuated inflammation [139]. Therefore modulating intestinal TJs protein with anti-TNF-α therapy may restore intestinal integrity. However, due to the immunosuppressive activity of TNF inhibitors, it may lead to systemic infection in cirrhosis patients. Hence, detailed knowledge for local inhibition is required for improvement in gut barrier dysfunction without affecting innate immune response.
\nRetinoic acid can modulate TJs proteins. In a mice model of colitis characterized by gut permeability, treatment with retinoic acid enhances barrier function by upregulating TJs proteins claudin-1, claudin-4, and ZO-1 [140]. However, the effect of retinoic acid in the preservation of intestinal integrity has not been tested in cirrhosis and HCC. Modulation of the epithelial barrier with probiotics seems to be beneficial. In this regard, Zhang et al. showed probiotics VSL#3 (combination of S. thermophilus, four Lactobacillus species, and three Bifidobacterium species) treatment restores intestinal permeability and dysbiosis and prevented HCC progression in rats [19]. Similarly, probiotics like E. coli Nissle1971 (ECN) was also shown to enhance intestinal TJs integrity by upregulating ZO-1 expression in the mouse model of DSS-induced colitis [141].
\nIn addition, treatment with red wine polyphenol promoted barrier function by significantly increasing mRNA expression of TJ proteins occludin, claudin-5, and ZO-1 in cytokine-stimulated HT-29 colon epithelial cells [142]. Resveratrol also preserves TJ barrier integrity and diminishes intestinal permeability by upregulating occludin, ZO-1, and claudin-1expression and thus abrogating intestinal inflammation and oxidative stress both in vivo and in vitro [143]. Similarly in NAFLD mice model, treatment with resveratrol enhances barrier function by increasing mRNA expression of TJ proteins ZO-1, occludin, and claudin-1 in the intestinal mucosa [144]. Curcumin also modulates intestinal barrier integrity and attenuates paracellular permeability and organization of TJs [145]. Thus, targeting TJ proteins, which maintain intact intestinal epithelia, is another area of therapeutic approach for the control of intestinal permeability in cirrhosis and HCC.
\nHCC is the end-stage liver disease, which mostly develops on the background of cirrhosis. As discussed above, the gut-liver axis plays a significant role in the progression of CLD and ultimately HCC and would be a potentially significant therapeutic target in the prevention of HCC. There have been several preclinical and human studies demonstrating an association between gut dysbiosis and HCC progression. However, from the animal studies, it is unclear whether gut microbiota initiates HCC or acts with other precipitating factors like chronic inflammation in the progression of HCC. Modulation of gut dysbiosis with prebiotics and probiotics, FMT, or preventing bacterial overgrowth with antibiotics may therefore prevent HCC. Moreover, in cirrhotic patients these interventions appeared to prevent secondary complications and improved survival. We may therefore speculate that the above interventions might prevent HCC development in high-risk cirrhotic patients. Moreover, we should consider trialing these therapies in HCC patients with unresectable tumors, which might improve survival time and secondary complications. Furthermore interventions that restore intestinal barrier integrity may prevent gut BT and may consider another line of therapy in HCC.
\nIn conclusion, there is growing evidence to suggest gut microbiota may play a significant role in the progression of CLD and thus HCC, which is likely to involve multiple pathways ranging from gut dysbiosis, endotoxemia, inflammation, loss of TJ integrity, and intestinal permeability. It is therefore suggested that the use of agents that have the potential to target microbial dysbiosis and restore intestinal epithelial barrier integrity may prevent bacterial translocation and ultimately delay HCC progression. However, whether bacterial overgrowth and/or intestinal permeability act independently or synergistically as causal pathogenic factors to influence the inflammatory milieu so closely associated with HCC progression remains unclear. Further research is therefore warranted to better understand the molecular pathways involved and guide the development of novel therapeutic interventions that can be taken to clinical trial to limit CLD/HCC progression through the targeting of dysbiosis and its effect on inflammation and intestinal permeability.
\nThe authors declare that they have no conflict of interest.
\nALT | alanine transaminase |
AMPs | antimicrobial peptides |
AST | aspartate transaminase |
BAs | bile acids |
BDL | bile duct ligation |
CCL | chemokine ligand |
CCl4 | carbon tetrachloride |
CD | cluster of differentiation |
CLD | chronic liver disease |
CTP | child-turcotte-pugh |
DCA | deoxycholic acid |
DEN | diethylnitrosamine |
DMBA | 2,4-dimethoxybenzaldehyde |
ERK | extracellular signal-regulated kinase |
FMT | fecal microbiota transplantation |
HCC | hepatocellular carcinoma |
HFD | high-fat diet |
HSCs | hepatic stellate cells |
IBD | inflammatory bowel disease |
IEC | intestinal epithelial cell |
IL | interleukin |
JNK | c-Jun N-terminal kinase |
LBP | lipopolysaccharide binding protein |
LPS | lipopolysaccharides |
MAMPs | microbe-associated molecular patterns |
MAPK | mitogen-activated protein kinase |
MELD | model for end-stage liver disease |
NAFLD | nonalcoholic fatty liver disease |
NASH | nonalcoholic steatohepatitis |
NF-κB | nuclear factor kappa-light-chain-enhancer of activated B cells |
NLRP | nucleotide-binding oligomerization domain, leucine-rich repeat- and pyrin domain-containing |
NSBB | nonselective beta-blockers |
OCA | obeticholic acid |
PRRs | pattern recognition receptor |
SCFAs | short-chain fatty acids |
STHD | steatohepatitis-inducing high-fat diet |
TB | total bilirubin |
TGR5 | takeda G-protein-coupled receptor 5 |
TLR | toll-like receptors |
TNF-α | tumor necrosis factor alpha |
TJs | tight junctions |
WHO | World Health Organization |
ZO | zonula occluden |
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\\n\\nIf you are interested in publishing your book with IntechOpen, please submit your book proposal by completing the Publishing Proposal Form.
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\n\n*The price does not include Value-Added Tax (VAT). Residents of European Union countries need to add VAT based on the specific rate applied in their country of residence. Institutions and companies registered as VAT taxable entities in their own EU member state will not pay VAT by providing us with their VAT registration number. This is made possible by the EU reverse charge method.
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\n\nIntechOpen has collaborated with Enago, through its sister brand, Ulatus, which is one of the world’s leading providers of book translation services. The services are designed to convey the essence of your work to readers from across the globe in a language they understand. Enago’s expert translators incorporate cultural nuances in translations to make the content relevant for local audiences while retaining the original meaning and style. Enago translators are equipped to handle all complex and multiple overlapping themes encompassed in a single book and their high degree of linguistic and subject expertise enables them to deliver a superior quality output.
\n\nIntechOpen Authors that wish to use this service will receive a 20% discount on all translation services. To find out more information or obtain a quote, please visit: https://www.enago.com/intech.
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\n\nFor a complete overview of all publishing process steps and descriptions, go to How Open Access Publishing Works.
\n\nSEND YOUR PROPOSAL
\n\nIf you are interested in publishing your book with IntechOpen, please submit your book proposal by completing the Publishing Proposal Form.
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