Endoscopic Management of Variceal Haemorrhage

Endoscopic Management of Variceal Haemorrhage

One of the most important complications of portal hypertension, in the setting of liver cirrhosis or of non-cirrhotic portal hypertension, is upper gastrointestinal bleeding from ruptured gastroesophageal varices and portal hypertensive gastropathy. The management of the acute variceal bleeding is a multidisciplinary process that includes the initial assessment of the patient, effective resuscitation, timely diagnosis, control of bleeding and prevention of early rebleeding and complications such as infection, hepatorenal syndrome, or hepatic encephalopathy. Antibiotic prophylaxis, conservative targets for blood transfusions and combination therapy with vasoactive drugs and endoscopic treatments are the first-line measures in the management of acute variceal bleeding; transjugular intrahepatic portosystemic shunts should be proposed early to high-risk patients or as a rescue therapy for those who fail first-line treatment.

Portal hypertension, as a complication of liver cirrhosis or in the setting of non-cirrhotic portal hypertension, leads to different complications ranging from the development of varices to upper gastrointestinal bleeding from ruptured gastroesophageal varices and portal hypertensive gastropathy, to ascites, hepatorenal syndrome and hepatic encephalopathy[1]. Portal hypertension is defined as an increase in the portal venous pressure above the normal values of 1-5 mmHg. Nowadays we dont usually measure directly the portal pressure but estimate it using the hepatic venous pressure gradient (HVPG), measured as the difference between the wedged (portal vein) and the free hepatic venous pressures (inferior vena cava). The HVPG value of 10 mmHg is used to define clinically significant portal hypertension, the level of portal pressure above which complications can arise[2-5].
    The prevalence of varices in cirrhotic patients ranges from 30 to 60%, according to the presence of decompensation[6] and prospective studies have shown that more than 90% of patients will develop esophageal varices during their lifetime (Figure 1). The expected incidence of newly developed varices is about 5% per year[7,8]. Once varices develop their rate of progression in size is 5-30% per year according to the study population and follow-up endoscopic schedule[8-12]. The main prognostic factors associated to progression of small to large varices are decompensated cirrhosis (Child B/C), alcoholic etiology of cirrhosis, HVPG and the presence of red wale markings on the esophageal varices at the time of baseline endoscopy[9,11,13].

Acute variceal bleeding in patients with cirrhosis indicates decompensation and a high-risk of death[6]. The annual rate of bleeding, in absence of treatment, is 10%-15%[14,15]. The most important predictors are variceal size[8,10,16], presence of red signs on varices[17,18], and severity of liver dysfunction defined by the Child-Pugh classification[15]. These risk indicators have been combined in the North Italian Endoscopy Club (NIEC) index, which allows the classification of patients into different groups with a predicted 1-year bleeding risk ranging between 6 and 60%. The risk of bleeding is very low (1%-2%) in patients without varices at the first examination, and increases to 5% per year in those with small varices, and to 15% per year in those with medium or large varices at diagnosis. Another important determinant of variceal bleeding is the degree of portal pressure: variceal bleeding only occurs if the HVPG reaches a threshold value of 12 mmHg, if the HVPG is reduced below 12 mmHg or by more than 20% of the baseline levels the risk of bleeding is substantially reduced[19].
    In patients with cirrhosis, ruptured esophageal varices cause approximately 70% of all upper digestive bleeding[20] and are the second most common cause of mortality for cirrhotic patients[21]. Mortality from variceal bleeding has greatly decreased during the last decades to the current rates of 6-12%[6,10,22-24]. Causes of bleeding related death (i.e. any death occurring within 6 weeks from hospital admission for variceal bleeding)[25] are uncontrolled bleeding in 4-8% of cases[26-28], rebleeding and infection, renal failure, hepatic encephalopathy (these are also prognostic indicators of morbidity and mortality after the first bleeding)[29]. Other factors independently associated with a higher mortality are severe liver dysfunction,  HVPG >20 mmHg and active bleeding at endoscopy[30,31].

The management of the acute variceal bleeding is a multidisciplinary process[25] that includes the initial assessment of the patient, effective resuscitation, timely diagnosis, control of bleeding, and prevention of early rebleeding and complications such as infection, hepatorenal syndrome, or hepatic encephalopathy. Blood volume restitution should be performed to maintain hemodynamic stability; packed red blood cells should be transfused conservatively aiming at hemoglobin levels between 7-8 g/dL[25,32] avoiding over transfusion which could be the cause of rebleeding[33,34]. Transfusion policy, however, should also consider the presence of co-morbidities, age, hemodynamic status and ongoing bleeding. Definitive recommendations regarding management of coagulopathy and thrombocytopenia cannot be made on the basis of currently available data[25]Antibiotic prophylaxis should be instituted from admission. It should consist of oral quinolones for most patients considering intravenous ceftriazone in patients with advanced cirrhosis, in hospital settings with high prevalence of quinolone-resistant bacterial infections and in patients on previous quinolone prophylaxis[25,35,36]. Vasoactive drugs (terlipressin, somatostatin, octreotide, vapreotide) should be started as soon as possible, even before endoscopy[37]. Vasoactive drugs used in combination with endoscopic therapy allow a better control of hemorrhage than drug therapy or endoscopy alone[38]. No significant differences have been found in several studies between different vasoactive drugs in the control of the index bleeding and in the prevention of recurrence. Terlipressin is the only vasoactive drug that has a positive effect on survival[14]. In clinical practice the choice of the vasoactive drug is based on its availability and on its cost. Vasoactive drugs therapy should be prolonged for 2-5 days according to control of bleeding and can be stopped after 24 hours free from bleeding. A post hoc analysis of a trial suggested that with higher dose of somatostatin (500 g/h) control of bleeding and better survival can be achieved in significantly higher proportion of patients[39], but this finding has never been confirmed in other trials.
    Endotracheal intubation may be needed in selected cases[37]Balloon tamponade can also be used as a bridge therapy to obtain temporary hemostasis (maximum 24 hours)[40]. Recently preliminary studies have shown that the placement of self-expanding metallic stents as an alternative to balloon tamponade for the control of refractory variceal hemorrhage may be beneficial[41,42] but these findings must be confirmed in other trials before their use can be introduced in clinical practice.
    Emergency EGD may be at the same time diagnostic and therapeutic. When it is performed early, 39-44% of patients present with active bleeding, 33-44% with signs of recent bleeding (clots or white nipple on varices)[43] and 12-28% have no sign of active or recent hemorrhage[28].

Endoscopic treatment of EV may be performed by endoscopic sclerotherapy (ES) and endoscopic variceal ligation (EVL).

Endoscopic Sclerotherapy (ES)
ES, first described in 1939 by Crafford and Frenckner[44] is currently performed using flexible catheters with a short needle tip (23 or 25 gauge). Different sclerosant agents (e.g. sodium morrhuate, podidocanol, ethanolamine, alcohol, and sodium tetradecyl sulphate) have been used in controlled trials[45] and nowadays the most commonly used agents are ethanolamine oleate (5%) or polidocanol (1%-2%) in Europe, and sodium morrhuate (5%) in the United States[46,47]. The injection of the sclerosant agent may be performed into the variceal lumen (intravariceal) or adjacent to it (paravariceal) inducing thrombosis of the vessel and inflammation of the surrounding tissues[48,49] leading to fibrosis and resulting in variceal obliteration[50]. Paravariceal injection forms a fibrotic layer around varices while intravariceal injection, directly induces variceal thrombosis. Injection of sclerosant should be first made immediately below the bleeding point (1-3 mL) and then in the remaining varices near the bleeding one (2-3 mL injections). The total amount of sclerosant per session is usually 10-15 mL. Both intravariceal and paravariceal injections have been associated with good outcomes[51] and no differences have been found with different sclerosants[52], the volume injected, or frequency of sessions[53].
    Compared to EVL, ES is easier to use since it does not require to withdraw and reinsert the endoscope.
    Complications of ES are more frequent than those of EVL[47,54-60]. The complications can be classified as local: esophageal ulcers, ulcer bleeding, and esophageal stricture; cardiovascular and respiratory: pleural effusion, acute respiratory distress syndrome, and pericarditis; and systemic: fever, bacteremia, spontaneous bacterial peritonitis, distant embolism or abscess[61]. Frequent minor complications that do not require treatment occur within the first 24-48 hours: retrosternal chest pain, low grade fever, dysphagia, asymptomatic pleural effusions, nonspecific chest radiographic changes[48]. Esophageal ulcers occur in up to 90% of patients and may cause bleeding in 20% of patients[59,62]. They should be prevented and treated with proton pump inhibitors; the efficacy of sucralfate in treating these ulcers and preventing rebleeding is not clear[63]. Bacteremia may occur in up to 35% of patients and may be responsible for the development of abscesses and spontaneous bacterial peritonitis[64,65]. Less frequent complications are esophageal stenoses (2-10% of cases) and esophageal perforation[48]. Death for post-ES complications may occur in 2% of patients[66].
    In a Cochrane meta-analysis ES was not shown to be superior to the vasoactive drug therapy for the control of bleeding, rebleeding, and mortality[67].

Endoscopic Variceal Ligation (EVL).
Endoscopic Variceal Ligation (EVL). The first reports of EVL appeared in 1988 by Stiegmann et al[68]. While ES used chemical action to obliterate varices, EVL causes a mechanical strangulation with rubber bands that induces thrombosis with ischemic necrosis of the mucosa. EVL consists in placing rubber rings on esophageal varices after sucking them into a plastic cylinder attached to the tip of the endoscope[69,70](Figure 2). In the beginning single-shot ligators were used, requiring the use of an overtube with all the complications of its use; nowadays multiple-shot (4-10 bands) devices are commonly used and the procedure is simpler and faster[46]. During an emergency EGD the bleeding varix is identified; the endoscope is then removed from the patient and the banding device is loaded. The endoscope is then reinserted into the esophagus up to the gastroesophageal junction to identify the varices. Then the tip of the endoscope is oriented toward the varix and a continuous suction is applied until the varix fills the cap. At this moment the band can be fired[70]. The bands should be placed on the varix at the point of bleeding or starting from the gastroesophageal junction in a helical fashion[48] for 6-8 cm within the palisade and perforating zones[61]. The rubber bands on the ligated varix detach in 1-10 days leaving shallow esophageal ulcers and smaller esophageal varices. The ulcers generated by EVL are bigger and shallower than those of ES and heal more rapidly[61,71]. The scars that may be generated by EVL ulcers[72], make subsequent redevelopment of varices more difficult. After band ligation patients should start with liquids at room temperature for the first 12 h and then take soft foods gradually. A recent trial has shown that proton pump inhibitor therapy is associated with smaller ulcers but the total number and the symptoms were not different[73]. Varices are considered eradicated when they have either disappeared or cannot be sucked and banded by the ligator[46]. Variceal eradication is obtained in about 90% of patients with up to 4 banding sessions[46] but recurrence is not uncommon[74].

A meta-analysis of 7 randomized controlled trials (RCTs) showed that there is a tendency toward benefit of EVL compared to ES in terms of control of bleeding, recurrent bleeding, side effects, need for fewer endoscopic treatments, and survival[60]. Therefore, EVL has become the treatment of choice for variceal bleeding but ES can be used when EVL is technically difficult[25,37].
    Compared to ES, EVL has a higher frequency of recurrent varices[75-77] but they can be treated with repeated EVL[77].
    Minor complications of EVL, that respond well to oral analgesia and antacids, include chest pain and transient dysphagia. Serious, but rare, complications include massive bleeding from untimely sloughing of bands, esophageal perforation (mostly for the use of overtube), esophageal strictures[78] and bacteremia[79] even if with a lower frequency than with ES[80]. Finally, there are reports that EVL may cause worsening of and/or appearance of PHG[81].

Vasoactive drugs and endoscopic therapy
Vasoactive drugs and endoscopic therapy. Combination of vasoactive drugs plus EVL/ES is the standard of care for variceal bleeding[25,37]. In fact, a meta-analysis of 8 trials demonstrated that combined therapy (endoscopic plus vasoactive drugs) compared to endoscopic therapy alone (ES or EVL) improved control of bleeding and 5-day hemostasis without differences in severe side effects or mortality[38].

EVL plus ES
EVL plus ES. Some studies have been performed on the combination of EVL and ES in order to achieve variceal eradication more quickly and thus reduce the likelihood of rebleeding[39]and the incidence of recurrent varices[82]. A meta-analysis of 7 RCTs by Singh et al showed that combination therapy had no advantage over EVL alone in the control of bleeding varices, prevention of rebleeding or reducing mortality[83] with a significant increase in esophageal strictures.

Current guidelines define treatment failure a failure to control acute variceal bleeding within 24 hours, or failure to prevent clinically significant rebleeding or death within 5 days of treatment[25]. Approximately 10-15% of patients have a risk of treatment failure[28,37]. Child-Pugh class, shock at admission, presence of portal vein thrombosis, active bleeding at endoscopy, and elevated HVPG >20mmHg have been shown to be predictive of treatment failure[28,31]. A second attempt at endoscopic therapy can be tried, possibly changing the endoscopic technique[25,84] but if this is unsuccessful a more aggressive approach by shunt therapy (TIPS or surgical) may be needed[25,37] (Figure 3). Indeed, a recent trial showed a significant reduction in treatment failures and in mortality by early use of TIPS (within 72 hours after admission) in patients with active variceal bleeding and in Child-Pugh class B cirrhosis or class C disease[85].

Bleeding from gastric varices (GV) is less frequent but more severe than bleeding from EV[20]. The treatment of GV is more difficult than that of EV because of the torrential blood outflow and their treatment modality depends on their location in the stomach and relation with EV. The Sarin classification is most widely used[20,25]. Gastroesophageal varices type 1 (GOV1) are an extension of esophageal varices along the lesser curvature of the stomach and have the same behavior of EV as far as haemostasis and rebleeding is concerned and therefore should be treated as EV[86]. Gastroesophageal varices type 2 (GOV2) located in the fundus of the stomach have been treated with different endoscopic techniques including ES, EVL, obliteration with glue and thrombin injection.

ES was shown to be ineffective and with a high rate of complications[87], possibly because the high volume of blood flowing through GV may wash away the sclerosant.

Gastric varices obliteration
Gastric varices obliteration consist in the injection of a tissue adhesive (polymers of cyanoacrylate) into a varix; the tissue adhesive upon contact with blood immediately polymerizes obliterating the varix. Complications of this procedure are rare but may be severe (with a mortality rate 0.5%): rebleeding due to extrusion of the glue cast (4.4%), sepsis (1.3%), pulmonary, cerebral, or splenic emboli (0.7%), gastric ulcer formation (0.1%) and mesenteric hematoma associated with hemoperitoneum and bacterial peritonitis (0.1%)[88]. Gastric varices obliteration is effective for acute fundal GV bleeding as it allows a better control of bleeding and reduces the rate of rebleeding [87,89-93] in comparison with alternative treatments. In the United States cyanoacrilate use is not approved by the Food and Drug Administration.

EVL was shown to be similar to cyanoacrylate in controlling active bleeding but with higher rebleeding rate[89]. Therefore, EVL is recommended as an alternative option, where tissue adhesives are not available[37].

Intravariceal thrombin injection
Intravariceal thrombin injection was useful in achieving initial hemostasis in GV bleeding without significant side effects in preliminary studies[87,94-96] but further evidence is needed before its use could be recommended in clinical practice.
    In case of treatment failure of pharmacological and endoscopic therapy TIPS should be considered, sometimes associated with coil embolization of GV[37].
    The actual recommendation for the treatment of GV is to use tissue adhesive (e.g. N-butyl-cyanoacrylate) for acute bleeding from isolated gastric varices (IGV) and gastroesophageal varices type 2 (GOV2) that extend beyond the cardia; in acute bleeding from gastroesophageal varices type 1 (GOV1) EVL or tissue adhesive can be used[25,37].

Portal hypertension may be responsible not only for the development and/or bleeding of esophageal and gastric varices but also of varices in other sites, e.g. in the duodenum, rectum and peristomal. Ectopic variceal bleeding is rare (less than 5% of portal-hypertensive related bleeding episodes) but mostly occurs from duodenal varices. No formal recommendation on their optimal treatment can be made because no clinical trials have been made. To date they are treated like EV or GV and the preferred treatment depends mainly on local expertise and location of the varices[97-99].

ES was shown to be effective in controlling bleeding from duodenal[100,101], rectal[102,103], and stomal varices[104,105].

Ectopic varices obliteration
Ectopic varices obliteration. Cyanoacrylate glue injection has been successfully used to obliterate bleeding duodenal[106,107], jejunal[108], and rectal varices[109].

EVL for bleeding duodenal varices is challenging because of limited visibility from the banding hood. It may be useful for temporary hemostasis but rebleeding is a problem[110,111]. However, several cases of successful treatment of rectal varices using EVL have been reported[112,113].

Blood transfusion should be aimed at hemoglobin levels between 7-8 g/dL.
    Definitive recommendations regarding management of coagulopathy and thrombocytopenia cannot be made on the basis of currently available data.
    Antibiotic prophylaxis should be instituted from admission, oral quinolones for most patients considering intravenous ceftriaxone in patients with advanced cirrhosis, in hospital settings with high prevalence of quinolone-resistant bacterial infections and in patients on previous quinolone prophylaxis.
    Vasoactive drugs (terlipressin, somatostatin, octreotide, vapreotide) should be started as soon as possible, even before endoscopy, and should be maintained for 2-5 days according to control of bleeding and can be stopped after 24 hours free from bleeding.
    Vasoactive drugs should be used in combination with endoscopic therapy.
    Emergency EGD may be at the same time diagnostic and therapeutic.
    Esophageal variceal bleeding may be treated by endoscopic variceal ligation or endoscopic sclerotherapy.
    Gastric variceal bleeding: Gastroesophageal varices type 1 (GOV1) should be treated as esophageal varices; Gastroesophageal varices type 2 (GOV2) should be treated with different endoscopic techniques including ES, EVL, obliteration with glue and thrombin injection.
    Ectopic variceal bleeding: No formal recommendation on their optimal treatment can be made because no clinical trials have been made. To date they are treated like EV or GV and the preferred treatment depends mainly on local expertise and location of the varices.
    TIPS should be used as an early treatment for high-risk patients or as a rescue therapy for patients who do not respond to endoscopic and drug therapy.

Lindsay Jarrett is climbing her way to beating Alpha-1

Lindsay Jarrett is climbing her way to beating Alpha-1

C/O: http://www.sundaypost.com/news-views/lindsay-jarrett-is-climbing-her-way-to-beating-alpha-1-1.887007

A BATTLING woman given a year to live seven years ago is still going strong – thanks to her love of mountaineering.

Expert climber Lindsay Jarrett was in the prime of her life when she received a shock diagnosis that would change her life forever.

Specialists diagnosed the 44-year-old with Alpha-1, a rare condition which means she is only able to use 20% of her lung capacity.

She was told she would die without an urgent organ transplant.

Yet courageous Lindsay is still going strong today – so much so she’s preparing to stand in next May’s Scottish Parliament elections – and credits her love of the mountains with helping her defy medical opinion.

The mum-of-five, whose children all share the genetic condition, has been through some terrifying lows since the fateful day she was told she could die.

But she insists the thrilling high she experiences when she stands at the summit of a cloud-skimming mountain is enough to power her will to live.

“I would be dead by now if I didn’t climb,” said the adrenaline junkie, who has to battle up cliffs with the aid of a specially adapted oxygen tank due to her cruel condition.

“I treat my body like a machine, but I love the mountains. What I do gives me a positive mindset that keeps me going.”

Experts believe keeping physically fit and having a passion are crucial and can aid patients suffering from a wide variety of conditions.

Now Lindsay, a former police officer, is seeking out a fresh thrill as a candidate for Solidarity in the Holyrood elections.

Explaining why she is now following a political career, she said: “I want to leave Scotland a better place for my children.

“It will be possible that they will be disabled later on and will have needs. This is about their future.”

Lindsay, however, must juggle her political aspirations with an on-going wait for a lung transplant.

She removed herself from the donor register last year – to climb and raise awareness of her condition.

However, doctors have since told her it may be too risky to put her back on the transplant waiting list.

They are worried Lindsay who, on top of her lung condition, also suffers from a number of severe allergies, could have a dangerous reaction to surgical instruments – or even rubber gloves.

There is a risk she could be thrown into anaphylactic shock – an extreme and potentially deadly reaction – during the operation.

“They have said I may never be able to have a transplant because my allergies could lead to anaphylaxis,” she said.

“If they go to operate, it could be the instruments or the rubber gloves or something else will put me into shock.

“I could be allergic to anything or everything.”

Lindsay now faces an agonising wait for test results to be analysed by an immunologist to find out what she is allergic to. Only then will she be considered for a transplant.

She said: “The surgeons say they will not risk it unless they have expert advice saying it will not kill me.”

And even if she is accepted for surgery, doctors will have to make a decision on whether she is strong enough.

“It is a waiting game,” said Lindsay, mum to Ciara, 21, Jemma, 19, Mia, 11, Rory, eight and Findlay, seven. “It could be a week, it could be a year. There is no way of telling.”

Last year, and with an oxygen pack strapped to her back, she scaled some of the highest peaks in Scotland, England and Wales.

Now the Lochaber Mountain Rescue Team have built a special buggy to help take her off-road to peaks she’d never have been able to access in the past.

Lindsay, who started climbing aged seven, said: “My consultant, Dr Brian Tregaskis, who is also their doctor, made a promise to my dad that he would look after me.

“My dad, Fred, died of cancer in 2003, aged 63.

“The mountain rescue boys visited me in hospital recently and said they had bought me a contraption they called a ‘stroller’.

“It will help me get off-road and keep strong in order to maximise the lung capacity I have left.”

Lindsay made headlines by climbing up the dangerous, craggy face of Edinburgh Castle to unfurl a Yes banner at the height of the independence referendum debate.

The stunt won the staunch indie campaigner a great deal of publicity and she was invited to speak at rallies and was chosen as the Solidarity Highlands and Islands coordinator.

Asked about her chances of taking a seat at Holyrood next year, Lindsay replied: “We’ll just have to wait and see.”

But she admitted she would love to “shake up” politics, adding: “There are too many career politicians and we have a real and dire need for real people.

“As a mum and a disabled person, I have experienced what vulnerable people are living through and have the passion and guts to fight for what is right.”

Last night Dr Tregaskis described Lindsay as an “inspiration.”

Gastroenterology & Hepatology: Open Access

Gastroenterology & Hepatology: Open Access

Gastroenterology & Hepatology: Open Access (GHOA) is an internationally acclaimed and peer reviewed multi - disciplinary Open Access Journal which aims to provide information on diagnosis, treatment and preventive measures of gastrointestinal diseases. 

This journal includes major clinical examinations and investigations which can play a major role in the treatment of the gastrointestinal diseases. The scope of journal includes but is not confined to therapeutic and diagnostic aspects of gastroenterology and the specific intestinal diseases.

In GHOA, Authors can submit reviews, articles, editorials and rapid communications in the field of gastroenterology which has been a major breakthrough. 
Email: gh@medcraveonline.orggh@medcraveonline.us

Immune Dysfunction and Infections in Patients With Cirrhosis

Immune Dysfunction and Infections in Patients With Cirrhosis


Patients with cirrhosis are immunocompromised and susceptible to infections. Although detection and treatment of spontaneous bacterial peritonitis (SBP) have improved, overall survival rates have not increased greatly in recent decades—infection still increases mortality 4-fold among patients with cirrhosis. Hospitalized patients with cirrhosis have the highest risk of developing infections, especially patients with gastrointestinal (GI) hemorrhage. Bacterial infections occur in 32% to 34% of patients with cirrhosis who are admitted to the hospital and 45% of patients with GI hemorrhage. These rates are much higher than the overall rate of infection in hospitalized patients (5%–7%). The most common are SBP (25% of infections), urinary tract infection (20%), and pneumonia (15%). Bacterial overgrowth and transloca-tion from the GI tract are important steps in the pathogenesis of SBP and bacteremia—these processes increase levels of en-dotoxins and cytokines that induce the inflammatory response and can lead to septic shock, multiorgan dysfunction, and death. A number of other bacterial and fungal pathogens are more common and virulent in patients with cirrhosis than in the overall population. We review the pathogenesis of infections in these patients, along with diagnostic and management strategies.


Cirrhosis is considered an immunocompromised state that leads to a variety of infections, which then account for an approximate 30% mortality.[1] Apart from early recognition and better treatment of spontaneous bacterial peritonitis (SBP) leading to better survival, there has been little improvement in overall survival rates in recent decades: infections still account for a 4-fold increase in mortality among patients with cirrhosis.[2] Hospitalized patients with cirrhosis are at the highest risk of developing infection, especially in those with gastrointestinal (GI) hemorrhage. Bacterial infections occur in 32% to 34% of admitted patients with cirrhosis[3] and in 45% of those with GI hemorrhage.[4] These rates are drastically higher than the usual 5% to 7% overall rate of infection in hospitalized patients.[1] The most common infections are SBP (25% of infections), urinary tract infection (UTI) (20%), and pneumonia (15%).[3] Bacterial overgrowth and translocation from the GI tract are important steps in the pathogenesis of SBP and bacteremia.[5]'[6] This pathogenic process leads to increased levels of endotoxins and cytokines that trigger an excessive inflammatory host response, a cause for septic shock, multiorgan dysfunction, and death.
Pathogens such as Mycobacterium tuberculosis, Clostridium difficile, Cryptococcus neoformans, Vibrio vulnificus, Yersinia enteroco-litica, and Listeria monocytogenes, are more common and virulent in patients with cirrhosis than in the general population. Because of the high morbidity and mortality of infections in cirrhosis, prevention, early diagnosis, and proper management of these infections are necessary to improve survival.

State of Immune Dysfunction in Cirrhosis

Cirrhosis-associated immune dysfunction syndrome (CAIDS) is a multifactorial state of systemic immune dysfunction (Figure 1), which decreases their ability to clear cytokines, bacteria, and endotoxins from circulation. The liver contains 90% of the reticuloendothelial (RE) cells,[7] such as Kupffer and sinusoidal endothelial cells, that are central to clearing bacteria. When radiolabeled E. coli and P. aeruginosa were injected intravenously, 70% and 96% of their populations, respectively, were found in the liver only 10 minutes later.[8] Porto-systemic shunting, whereby blood is increasingly directed away from the liver, and reduced RE cells in patients with cirrhosis, allow less bacteria and endotoxins to be cleared by the liver from circulation.[1,7]
Figure 1.
Cirrhosis-associated immune dysfunction syndrome (CAIDS).
Monocyte spreading, chemotaxis, bacterial phagocytosis, and bacterial killing are significantly reduced in cirrhosis compared with controls. Patients with acute decompensated liver cirrhosis have reduced expression of the antigen presenting HLA-DR molecules on monocytes.[9] This may also result in decreased monocyte activation and cytokine secretion.
In addition to RE system dysfunction, patients with cirrhosis have decreased neutrophil mobilization and phagocytic activity, a phenomenon that correlates with severity of liver disease.[10,11] The decreased phagocytic activity in cirrhosis has been attributed to reduced activity of tuftsin,[12] and phospholipase C.[13,14] In addition, it has been suggested that hyperammonemia and hyponatremia function synergistically to affect neutrophil cell volume and impair phagocytosis.[15] Neutropema, typically a result of hypersplenism in cirrhosis, is further exacerbated by shortened neutrophil survival via apoptosis.[16]The Fas/Fas li-gand has been implicated in the regulation of apoptosis in neutrophils,[17] but it is unclear how decreased levels of Fas in cirrhosis impact this mechanism.[16]
The decreased phagocytic activity of the innate immune response is confounded by decreased bactericidal and opsonization capacity. Patients with cirrhosis have much lower levels of immunoglobulins IgM, IgG, and IgA in ascitic fluid.[18] Further, C3, C4, and CH50 concentrations are significantly lower in both serum and ascitic fluid, thus leading to diminished bactericidal activity.[18,19]
Additional aspects of immunodeficiency are complicated by factors such as malnutrition, immunosuppressive medications, and alcohol intake.[20,21] Chronic and acute alcohol consumption are associated with a decrease in T cells, B cells, natural killer cells, monocytes, and an increase in proinflammatory cytokines.[22,23]

Bacterial Translocation

Bacterial translocation is the migration of bacteria or bacterial products from the intestinal lumen to mesenteric lymph nodes (Figure 2).[24] Bacterial translocation is known to be increased in cirrhosis and has been pathogenetically linked to the development of SBP.[5,6] It has also been implicated as a cause of recurrent SBP.[25] Patients with cirrhosis have slowed intestinal motility, which leads to intestinal bacterial overgrowth.[26] This overgrowth, along with portosystemic shunting, enables perpetuation of bacteria and can lead to bacteremia. Further oxidative damage from increased endotoxins, proinflammatory cytokines, and nitric oxide (NO) alter the structure and permeability of intestinal mucosa in cirrhosis.[24]In conjunction with the decreased local and impaired systemic immune function in cirrhosis, decreased gut motility and increased permeability facilitate the spread of intestinal bacteria to extraintestinal sites and predispose patients with cirrhosis to infections.
Figure 2.
Pathogenesis of SBP

Sirs, Sepsis, and Cirrhosis

Systemic inflammatory response syndrome (SIRS) is not uncommon in cirrhosis, and sepsis is defined as SIRS in the presence of confirmed bacterial infection (Figure 3).[1,2,11,27,30] Bacterial derived toxins, such as peptidoglycans from gram-positive bacteria or lipopolysaccharides from gram-negative bacteria, bind to Toll-like receptors which initiate a cascade of cell signaling. Toll-like receptors trigger either nuclear factor fxB or mitogen activated protein kinase, which in turn stimulate the release of NO and proinflammatory cytokines tumor necrosis factor (TNF)-a, interleukin (IL)-6, and IL-1.[31] In SIRS, anti-inflammatory cytokines (IL-10, IL-4, IL-13, prostaglandin E2) are unable to balance the proinflammatory cytokines, also known as a "cytokine storm," resulting in excessive inflammation.[1,32]
Figure 3.
Consequences of sepsis in cirrhosis.
SIRS and cirrhosis are interlinked determinants of survival outcomes. The severity of liver disease determines the development of SIRS, while SIRS leads to variceal bleeding, hepatic encephalopathy, and adversely affects survival.[33] Certain aspects of cirrhosis can exacerbate SIRS and complicate its diagnosis. Patients with cirrhosis have higher levels of circulating endotoxins that inversely correlate with hepatic deterioration.[34] After lipopolysaccharide challenge, those with cirrhosis had higher proinflammatory cytokine levels than those without, particularly TNF-a and IL-6.[35,36] Protein C and high density hpopro-tein, protective anti-inflammatory, and antiapoptotic factors are thought to be reduced in cirrhosis.[37]NO, whose metabolite concentrations are correlated with those of endotoxins, is increased in cirrhosis and is known to contribute to the oxidative stress and worsening vasodilatation of sepsis.[38,39]Complications of cirrhosis may mask themselves as symptoms of SIRS. For example, hypersplenism may reduce white blood cell count, hyperdynamic circulation may elevate heart rate, and hepatic encephalopathy may cause hyperventilation.[31] However, these indicators appear to be more exaggerated in patients with cirrhosis. The release of large amounts of cytokines in sepsis intensifies this hyperdynamic state and serves as the link between bacterial infection and renal failure. Renal failure following SBP-related and non-SBP-related bacteremia has been observed in 1 third of patients with cirrhosis and ascites.[28,30] Altered hemodynamics and widespread inflammation lead to impaired tissue oxygenation, cell necrosis, and apoptosis, and ultimately organ failure. When organ function can no longer sustain homeostasis without intervention, the patient isdeemed to have multiple organ dysfunction syndrome, a common result of cirrhosis and severe sepsis.
Relative adrenal insufficiency is common in patients with septic shock and is associated with hemodynamic instability, renal failure, and increased mortality.[40] It is diagnosed in approximately 70% of septic shock patients with cirrhosis and is believed to be linked to their impaired cortisol synthesis and decreased high density lipoprotein levels.[41,42] The use of hydro-cortisone in patients with septic shock remains controversial,[41,43,44] however, a recent randomized trial found its use to be associated with an increase in shock relapse and GI bleeding.[45]

Infections in Cirrhosis

Gastrointestinal Bleeding-associated Infections and Prophylaxis

GI bleeding is associated with an increased incidence of infection, and approximately 17% to 45% of cases lead to an episode of SBP or bacteremia.[46] Conversely, the presence of infection has been found to increase the risk of early bleeding.[47,48] Goulis et al[49] hypothesize that bacterial endotoxins stimulate hepatic stellate cell contraction and endothelial NO production, which then increase sinusoidal pressure and inhibit platelet aggregation, respectively.
Patients who present with acute episodes of GI bleeding require short-term antibiotic prophylaxis regardless of the presence of ascites. Most infections are caused by gram-negative bacteria and are preventable with selective decontamination by quinolones.[50] Long-term SBP prophylaxis with norfloxacin has resulted in quinolone-resistant gram-negative bacteria and an increased prevalence of gram-positive bacteria.[3] Therefore, third-generation cephalosporins, which target both gram-negative and gram-positive bacteria, are preferred prophylactic strategies. In patients with advanced cirrhosis, 1 g of intravenous (IV) ceftriaxone for 7 days after bleeding was found to be more effective in preventing bacterial infections than oral norfloxacin.[51]Prospective randomized trials and a recent Cochrane Database review found antibiotic prophylaxis to significantly reduce rates of infection, rebleeding, and mortality.[5254] Based upon the "endotoxin-induced sinusoidal pressure" hypothesis,[49] antibiotic decontamination may lower the risk of rebleeding via reduction of endotoxin levels and subsequent portal pressure. Nonselective beta blockers, commonly used to lower portal hypertension and prevent initial variceal hemorrhage, can also serve to decrease bacterial translocation during an acute hemorrhage. A recent meta-analysis[55] found evidence that beta blockers increase gut motihty and reduce translocation, thereby reducing the incidence of infection. A study by Che-larescu et al[56] in the postsurgical setting found propranolol to reduce infections from 42% to 15%. However, the use of beta blockers in patients with refractory ascites may limit the compensatory increase in cardiac output and increase vulnerability to complications such as septic shock and renal failure.[57,58]
Prokinetic agents may also reduce dysmotility and bacterial translocation. Prophylaxis with norfloxacin and cisapride was found to significantly reduce the rate of SBP compared with norfloxacin alone.[59]There is some evidence to suggest that the use of probiotics promotes the growth of gram-positive bacteria at the expense of gram-negative bacteria,[60] but it has yet to been shown to benefit patients with cirrhosis.[61,62] Given the increasingly negative implication of gram-positive bacteria in infections, replacing gram-negative bacterial populations may be of little use.

Spontaneous Bacterial Peritonitis: Diagnosis, Treatment, and Prevention

The prevalence of SBP in patients with cirrhosis and ascites admitted to the hospital ranges between 10% and 30%; approximately half of cases are present at the time of hospital-ization and half develop during the hospitalization.[63] The in-hospital mortality rate from SBP is approximately 32%.[64] The majority of these infections are caused by E. coli, Klebsiella spp., other Enterobacteriaceae, P. aeruginosa, enterococci, and streptococci (Table I).[65] The current recommendation is to perform a diagnostic paracentesis in all patients with ascites at the time of hospital admission and in those who manifest symptoms of peritoneal infection, systemic signs of infection, hepatic en-cephalopathy, or rapid impairment in renal function while hospitalized.[63,66] The diagnosis cutoff of SBP is a polymorphonuclear (PMN) count of 250 cells/mm3 while the highest specificity is reached at 500 cells/mm3.[63]
Up to 65% of patients with clinical evidence of SBP and increased ascites have negative cultures,[67] but inoculation of 10 mL of ascitic fluid in aerobic and anaerobic culture bottles at the bedside has improved sensitivity to approximately 80%.[68] Recent applications of culture-independent methods have attempted to improve screening outcomes. Several types of leukocyte esterase reagent strips have been evaluated in the diagnosis of SBP and have demonstrated sensitivity and specificity ranging between 45% and 100% and 81% to 100%, respectively.[69] A recent study demonstrated an esterase strip calibrated to an ascitic fluid PMN count >250 cells/mm3 to be a good bedside screening tool.[70]Preliminary application of molecular analysis to identify bacterial DNA has yielded promising results that may replace culture techniques in the future.[71,72]
Bacterascites and secondary peritonitis are unique conditions of SBP that require specific guidelines for identification and therapy. It is identified by a positive ascitic fluid culture and an ascitic PMN <250 cells/mm3 The differentiation between SBP and secondary peritonitis, le, bacterial peritonitis caused by perforation or acute inflammation of organs, can be quite difficult. Secondary peritonitis, though only accounting for 4.5% of all peritonitis cases in cirrhosis,[73] should be suspected in any of the following situations: (1) lack of a response to antibiotic therapy; (2) 2 or more organisms isolated (particularly anaerobes or fungi; (3) the presence of at least 2 of the following in ascitic fluid: glucose <50 mg/dL, protein >1 g/dL, lactic dehydrogenase greater than normal serum levels.[63] With intestinal perforation, secondary peritonitis may also be suspected if chorioembryonic antigen >5 ng/mL or alkaline phosphatase >240 U/L.[74] After diagnosis of a cause of secondary peritonitis with a radiological study such as magnetic resonance imaging or computed tomography scan, patients should receive antibiotic therapy and undergo surgical evaluation.[63,66,73,75] Because it is often a monobacterial infection with an associated white blood cell response, SBP is defined as culture positive. However, a variant of it called culture-negative neutrocytic ascites can be encountered and has similar clinical outcomes (Figure 4).[66,74,76–79]
Figure 4.
Ascites infection algorithm
The current standard for treatment of SBP is with a minimal dose of 2 g of intravenous cefotaxime every 12 hours for 5 days.[80,81] In those with clinical improvement, a repeat of paracentesis is not necessary to assess for resolution of SBP. Equally effective alternative therapies include cephalosporins (ceftriaxone, ceftazidime, ceftizoxime), amoxicillin-clavulamc acid, and quinolones (ciprofloxacin, ofloxacin, levofloxacin) for beta-lac-tam hypersensitive patients.[31]>[63,82] When clinical signs of infection have improved, replacing IV cephalosponn with oral ciprofloxacin to complete the course of therapy may be more cost-effective.[83] Patients taking quinolones as prophylaxis should be aware of treatment failure because of antibiotic resistance or enterococcal infection. If clinical improvement and a sufficient drop in neutrophil count in ascites (<25% of initial value) are not observed by day 3 of treatment, a switch of antibiotic therapy should be considered while the patient is evaluated for secondary peritonitis.
Renal impairment develops in approximately 1 third of all SBP patients and is a strong predictor of mortality during hospitalization.[27] The activation of the cytokine cascade and NO production in cirrhosis and SBP negatively impact renal function.[28,84] The use
of intravenous albumin (1.5 g/kg body weight within 6 hours of SBP diagnosis followed by 1 g/kg body weight on day 3) in conjunction with cefotaxime was found to reduce the incidence of renal impairment from 33% to 10% and mortality from 29% to 10%.[28] Albumin increases mean arterial volume, binds TNF-a and NO to counteract the inflammatory response of infection, and removes toxins from circulation.[84–86] These infusions are most effective in patients with baseline creatinine >1.0 mg/dL and total bilirubin >4.0 mg/dL.[28,87] A recent pilot study by Cartier et al[88] suggests polygeline (Gelafundin 4%; B Braun Medical AG, Cnssier, Switzerland), a cheaper plasma expander, as a reasonable alternative to albumin.
When treated effectively, recovery from SBP is seen in approximately 90% of patients and 30-day survival is in at least 80%.[63] For patients who fail treatment, hospital mortality ranges from 50% to 80%.[89] The rapid deterioration of liver function in SBP patients makes for generally poor long-term prognosis after an episode of SBP. Franca et al[90] found the 1-year survival rate to be 28.5%. The recent shift in microbial etiology of SBP toward cefotaxime-resistant strains may complicate survival by delaying infection resolution.
Patients recovering from an episode of SBP should be given antibiotic prophylaxis. In those without antibiotic prophylaxis, the rate of recurrence of SBP is 43% at 6 months, 69% at 1 year, and 74% at 2 years after the initial episode.[91] Gines et al[92] found that 400 mg per day oral norfloxacin reduced recurrence of SBP from 68% to 20%. The use of 500 mg ciprofloxacin per day, rather than the 750 mg once per week dosage previously suggested,[93] is known to be effective.[94] Intermittent dosing of prophylactic antibiotics may select resistant flora, therefore daily dosing is preferred. For patients intolerant to quinolones, daily double-strength oral trimethoprim/sulfamethoxazole is an effective alternative.[95,96] The current time scale for long-term prophylaxis is indefinite.
Patients with advanced cirrhosis and low protein ascites may be candidates for primary prophylaxis against SBP.[97] In a randomized controlled trial,[98] patients with low protein ascites levels (<1.5 g/dL) with advanced liver failure or impaired renal function who received norfloxacin prophylaxis had a significantly decreased probability of SBP, hepatorenal syndrome, and mortality.

Other Infections in Cirrhosis

Urinary Tract Infection

UTI occurs in approximately 15% to 20% of hospitalized patients with cirrhosis; it is twice as frequent in patients with cirrhosis compared with matched controls.[3,99] Women have a 4 times higher rate of bacteriuria than men.[99] Gram-negative bacilli, such as E. coli and Klebsiella spp., are the primary causative agents. Notably, bacteriuria is not associated with an increased risk of sepsis, SBP, or other infections often seen in patients with cirrhosis.[99] Although more frequent among those with cirrhosis, UTI does not consistently correlate with the severity of liver disease and is more strongly associated with gender and diabetes.[99–101] The high incidence of UTI in cirrhosis remains unexplained. Bercoff et al[102] cite the increased bladder postvoid residual volume as an explanation, however, this finding was not supported in a subsequent study.[99] Treatment of UTI with quinolones is effective in approximately 95% of cases.[99]


Pneumonia is the third leading cause of infections in patients with cirrhosis.[1,50] Pulmonary clearance of pneumococci was significantly decreased in a rat model of cirrhosis, most likely as a result of decreased complement levels.[103] Community-acquired pneumonia (CAP) is most often caused by S. pneu-moniae and H. influenza.[104]S. aureus, M. pneumoniae, M. catarrha-lis, C. pneumoniae, Klebsiella spp., and Legionella spp. have also been implicated as causes of CAP. The risk of bacteremia in CAP is increased in patients with cirrhosis.[105]Further, procedures such as tracheal intubation and esophageal tamponade put patients with cirrhosis at risk of hospital-acquired pneumonia.[106] In the presence of comorbidities such as cirrhosis, treatment is ideal with IV beta-lactam plus macrolide or IV antipneumococcal quinolones.[104] Pneumococcal vaccination is recommended in patients with cirrhosis.[104,107]

Soft Tissue Infections

Chronic edema and increased bacterial translocation predispose patients with cirrhosis to soft tissue infections, which constitute approximately 11% of infections.[108] Both gram-positive (S. aureus, group AStreptococci) and gram-negative bacteria Klebsiella spp., Aeromonas spp., V. vulnificus) are common causes of soft tissue infections. Cellulitis is the most frequently observed skin infection in patients with cirrhosis and has a recurrence rate of 20%.[109] Necrotizing fasciitis, a rare but severe form of soft tissue infection, is predominantly caused by gram-negative bacilli.[110] Unlike the general population, necrotizing fasciitis in those with cirrhosis rarely develops from an obvious portal of entry in the extremities, thereby suggesting a potential pathway of bacterial translocation and bacteremia leading to soft tissue infections.[110,111] Broad spectrum antibiotic treatment is necessary for proper management of soft tissue infections, and surgical intervention for deep infections may be needed.


Approximately 10% of infectious endocarditis (IE) cases have cirrhosis as an underlying condition.[112]IE is a concern for hospitalized patients with cirrhosis because of the increased risk of bacteremia associated with invasive procedures (transjugular intra-hepatic portosystemic shunt, upper endoscopy, etc). Valve disorders are present in approximately 60% of patients with cirrhosis who have IE.[112] Gram-positive bacteria such S. aureus, j3-hemolytic streptococci (S. agalactiae, S. pyogenes), and enterococci (E. faecalis, E. faecium) are the most commonly isolated organisms.[112,113] Depending on the organism, a minimum of 4 weeks of antibiotic therapy is recommended.[114] Patients with advanced liver cirrhosis have high surgical mortality rates;[115] therefore surgical management of IE is reserved for selected patients who do not respond to medical therapy.


The incidence and virulence of Mycobacterium tuberculosis infections are increased in patients with cirrhosis.[116] In a cohort of tuberculosis (TB) patients with liver cirrhosis in Denmark, the 30-day case fatality rate was 27.3% and the 1-year case fatality rate was 47.7%.[116] TB patients with liver cirrhosis show extrapulmonary involvement,[117] such as TB peritonitis, more frequently. Compared with SBP, TB peritonitis is present in less advanced cirrhosis and is characterized by lower white blood cell count in ascites, higher proportion of mononuclear leukocytes, higher protein concentration, and higher levels of adenosine deaminase activity in ascites.[118] Though adenosine deaminase level analysis is useful in the detection of TB peritonitis in patients without cirrhosis, the presence of cirrhosis reduces its sensitivity to 30%.[119] Laparoscopic biopsies provide definitive diagnosis of TB peritonitis by revealing multiple whitish nodules scattered over the peritoneum.[118,120] Patients with TB and cirrhosis respond well to anti-TB therapy, however they face a greater risk of hepatotoxicity.[117]
Clostridium difficileClostridium difficile is an increasingly prevalent hospital-acquired infection that affects patients with cirrhosis. A recent study of over 80,000 patients with cirrhosis found patients with C.difficile-associated disease to have higher mortality and longer length of stay than those without infection.[121] Antibiotics and proton pump inhibitors were independently associated with C. difficileinfection. Thus it is recommended that antibiotic prophylaxis be limited to patients at highest risk of developing SBP and that proton pump inhibitors be used selectively.[122]

Drug-Resistant Infections

Nosocomial infections account for a significant proportion of infections in patients with cirrhosis and an increasing number of these infections are caused by antibiotic-resistant and gram-positive pathogens. Approximately 37% to 64% of bacterial infections, either nosocomial or in the context of antibiotic intervention in an outpatient setting, have been found to be multidrug-resistant.[3,123,124] Gram-negative isolates in SBP, such as E. coli and K. pneumoniae, are being encountered with increasing rates of resistance.[125] Gram-positive pathogens are increasingly common in patients with cirrhosis.[125] Methi-cillin-resistant S. aureus has been noted to account for 24.8% of nosocomial SBP.[125]E. faecalis and E. faecium have been isolated in nearly 10% to 24% of infections in the setting of cirrhosis and are associated with 25% mortality rate.[3,125,126] Approximately a third of enterococcal bacteremia cases demonstrate vancomycin resistance and are associated with twice the mortality rate of nonresistant strains.[127,128]

Fungal Infections

Cirrhosis increases susceptibility to Cryptococcus neofor-mans, an encapsulated fungus that is typically associated with human immunodeficiency virus-infected patients.[129,130] Liver cirrhosis is an underlying condition in approximately a third of non-human immunodeficiency virus cryptococcaemia cases and is a stronger independent predictor of 30-day mortality than in those with acquired immunodeficiency syndrome.[131] Though uncommon, C. neoformans may infect ascites and cause spontaneous cryptococcal peritonitis. Unlike SBP, spontaneous cryptococcal peritonitis presents itself with an elevation in lymphocyte count and, because of late detection, has a very high mortality rate (~70%).[132]The pathogenesis of cryptococcal peritonitis may be via direct percutaneous inoculation during para-centesis, GI bleeding, or bacterial translocation.[130,133]Candida infections can also be encountered particularly in patients with primary sclerosing cholangitis (PSC). Candida species have been identified in 44% of bile samples in PSC patients, particularly those with dominant strictures.[134,135] A high prevalence of biliary candidiasis exists, however, the effect of antifungal therapies on treatment outcomes for recurrent cholangitis remains unknown.

Specific Liver Disease-related Infections

Iron overload state impairs cell-mediated response and enhances growth of various pathogens such asE. coli, Vibrio spp., and Listeria monocytogenes.[136] Recent evidence suggests that decreased levels of hepcidin, an iron-regulator hormone with antimicrobial activity, serve as the link between liver disease and these infections.[137] Patients with hemochromatosis face a 30-fold greater risk of acquiring V. vulnfficus, a bacterium acquired through ingestion of contaminated raw oysters.[138]V. vulnificussepticemia has a 50% to 60% case mortality rate in patients with liver disease and 7% to 22% mortality for localized wound infection.[138,139] Yersinia enterocolitica and Yersinia pseudotuberculo-sis, 2 gram-negative bacilli transmitted zoonotically, infect via systemic or portal vein bacteremia to cause hepatic abscesses with up to a 56% mortality rate.[140–142]
PSC is a risk factor for ascending cholangitis, which is associated with up to a 16% mortality rate.[143,144] Generally, ascending cholangitis is relatively uncommon unless the biliary tree has been manipulated by endoscopic retrograde cholangio-pancreotography. The most common infections after endoscopic retrograde cholangiopancreotography are caused by gram-negative bacteria such as E. coli, Klebsiella spp., and Entero-bacter spp.[143,144] However, if cholangitis occurs without any intervention, the presence of stones, dominant strictures, or chol-angiocarcinoma should be considered. In a study of explanted livers with PSC, bacteria were isolated in approximately 60% of cases.[145] The most common bacteria isolated were alpha-hemo-lytic streptococci, enterococci, and staphylococci. Though the etiology of PSC is largely unknown, bacterial infection of the bile ducts with dominant stenoses has been implicated in the progression of the disease.


Patients with cirrhosis are in a multifactorial lmmuno-comprormsed state which predisposes them to a higher risk of infection. Bacterial infections, particularly SBP and bacteremia, are an important cause of morbidity and mortality in these patients. Gram-negative enteric bacteria appear to be the most common causative organisms. However, other unusualbacteria, and fungi are also frequently observed and more virulent in patients with cirrhosis relative to those without liver disease. Moreover, these pathogens can present with various clinical syndromes that may be difficult to recognize. The relationship between immune dysfunction and infection in cirrhosis has been extensively investigated. Bacterialtranslocation appears to be an important step, which accounts for the increased levels of endotoxins, cytokines, and NO; these play a critical role in the development of an excessive inflammatory response and hyperdynamic circulatory state of cirrhosis. As hepatic function deteriorates and portal hypertension progresses, overt infection is more likely to develop and subsequently can evolve to sepsis, leading to consequences such as septic shock, multiorgan failure, and death.
Early diagnosis and proper management of infections in patients with cirrhosis are necessary. Generally, intravenous third generation cephalosponns are recommended as empiric antibiotic therapy for most cases of SBP and bacteremia. However, the risk of resistant organisms and unusual pathogens should be kept in mind, especially in patients with cirrhosis who are receiving quinolone prophylaxis or have hemochroma-tosis as an etiology of liver disease. Auxiliary therapy with intravenous albumin can significantly reduce morbidity and mortality in SBP patients who are at high risk of developing renal failure. The importance of preventive strategies cannot be underscored. Patients with cirrhosis admitted with GI hemorrhage benefit from short-term antibiotic prophylaxis, whereas long-term oral prophylaxis is recommended in those who have recovered from SBP. Despite recent advances in understanding of the mechanisms of infection in patients with cirrhosis, the outcomes of those patients with severe infections still remain poor. Further studies into mechanisms, diagnostic approaches, and potential preventive strategies are needed to improve the management of infections in patients with cirrhosis.