Hepatic changes in systemic infection

Best Practice & Research Clinical Gastroenterology 27 (2013) 485–495

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Best Practice & Research Clinical Gastroenterology

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Hepatic changes in systemic infection Brijesh Srivastava, MBBS, MRCP, Specialist Registrar, Hepatology 1, Alexander Gimson, FRCP, Consultant Hepatologist * Department of Hepatology, Addenbrookes Hospital, Cambridge, UK

a b s t r a c t Keywords: Extra-hepatic infection Cholestasis Sepsis Hepatic dysfunction

Liver is an integral part of the host-defense mechanism and facilitates clearance of pathogenic organisms in systemic infection by modulating the immunological response. It undergoes several cellular and molecular changes resulting in the release of pro-inflammatory cytokines, which regulate various metabolic and immunological signalling pathways. Some of these changes are pathogen-specific and essential in determining the host response to systemic infection. However, alterations in the immunological homeostasis can adversely affect the liver and lead to hepatic dysfunction. This article focuses on these molecular and immunological changes that occur within the liver in response to extrahepatic systemic infection and its consequences. Ó 2013 Elsevier Ltd. All rights reserved.

Introduction The incidence of sepsis and the occurrence of sepsis-related organ failure in the western world have seen a considerable increase in the last 2–3 decades [1]. Sepsis and extra-hepatic infections account for up to 20% cases of jaundice seen in the hospital [2]. Hyperbilirubinaemia (serum bilirubin >34.2 mmol/l) has been identified as an independent risk factor for mortality in critically ill patients [3]. In the last two decades, liver has emerged as one of the critical organs in determining response to systemic infections

* Corresponding author. Hepatobiliary and Liver Transplantation Unit, Box 210, Addenbrookes Hospital, Hills Road, Cambridge CB2 0QQ, UK. Tel.: 44 01223 586614. E-mail addresses: [email protected] (B. Srivastava), [email protected] (A. Gimson). 1 Hepatobiliary and Liver Transplantation Unit, Box 210, Addenbrookes Hospital, Hills Road, Cambridge CB2 0QQ, UK. Tel.: 44 01223 586614. 1521-6918/$ – see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bpg.2013.06.011

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because of its important role in host-defense mechanism. In addition to its role in key metabolic pathways that are essential for normal physiological functioning, it plays an active role in clearance of systemic endotoxins, bacterial antigens and various other inflammatory proteins released during a systemic inflammatory response, which activates both innate and humoral immune responses [4]. The liver undergoes circulatory changes in sepsis and produces various pro-inflammatory cytokines, acute phase proteins and vasoactive lipids to regulate its effects, some of which adversely effect the functioning of liver cells eventually leading to hepatic dysfunction [4]. Role of liver in host-defense mechanism 60% of the liver cells are constituted by the parenchymal liver cells i.e. hepatocytes. The remaining 40% is made up of the non-parenchymal cells, mainly comprised of sinusoidal endothelial cells (SEC), kupffer cells and the hepatic stellate cells, which line the liver sinusoids [5]. Kupffer cells make up 80–90% of the macrophages of reticuloendothelial system. In addition, the liver contains natural killer (NK) cells and abundant pluripotent haematopoietic stem cells, which are able to differentiate into all types of leucocyte lineage [6,7]. Table 1 lists the metabolic and immunological functions of the liver cells. Hepatocytes and kupffer cells triggered by the pathogen-associated molecular patterns (PAMPs) (e.g. endotoxin), release several pro-inflammatory cytokines and attract neutrophils into the liver which aid in entrapment and clearance of the bacteria and/or bacterial products that enter blood stream [8]. In addition metabolic pathways are modified along with increased synthesis of several acute phase proteins, complement factors, procoagulant and anticoagulant factors. The resultant inflammatory milieu and metabolic change are unfavourable for the pathogenic organisms to sustain and this plays a crucial role in resolution of systemic infection. However, hepatocyte injury can result from the microcirculatory and inflammatory changes as well as bacteria and endotoxin spill over [9]. Thus in sepsis, the liver plays a major role, distinct from other immune organs in modulating the immunological response as well as in removing the pathogenic organisms. However, if it fails to maintain this critical immunological homeostasis, hepatic dysfunction ensues. Hepatic dysfunction in sepsis – clinical significance Jaundice can be seen in up to 1/5th of hospitalized patients with underlying sepsis and/or extrahepatic infections [2]. It can also be seen in patients recovering from severe trauma who develop systemic inflammatory response syndrome. Although any type of systemic infection (viral, bacterial, protozoan) can lead to jaundice, it is most often seen with gram-negative bacterial infection [10]. Intraabdominal infections such as peritonitis, diverticulitis and appendicitis are most commonly associated, although other infections such as pneumonia, infective endocarditis, meningitis and urinary tract infections can also predispose [11]. Typically, jaundice is seen 2–7 days after the onset of bacteraemia [12]. However, bacteraemia is not an essential pre-requisite for development of hepatic dysfunction or cholestasis and up to one third of patients with sepsis can have cholestatic jaundice 1–9 days before the first positive blood culture result [10]. This is often seen in patients with gut-barrier failure (due to sepsis, shock or gut inflammation/infection), which allows bacterial translocation from intestinal

Table 1 Hepatic cellular function. Sinusoidal endothelial cell Kupffer cell

Stellate cells

Controls movement of molecules from sinusoidal flow into the space of Disse. Plays a role in leucocyte adherence, activation and migration. Part of the mononuclear phagocyte system and play a key role in phagocytosis. Activated by endotoxins and other pro-inflammatory cytokines Activates adjacent cells in an autocrine and paracrine loop. Responds to inflammatory mediators released by hepatic parenchymal and non-parenchymal cells. - Plays a key role in hepatic fibrogenesis.

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lumen to the portal circulation (i.e. portal endotoxemia) in the absence of clinically detectable bacteraemia. Hyperbilirubinaemia (75–80% conjugated) is the most common biochemical abnormality with only modest elevation of alkaline phosphatase and serum transaminases. Serum bilirubin is usually between 85 and 170 mmol/l but can go up to >500 mmol/l [10]. Persistent high serum bilirubin is associated with poor prognosis. Other causes of hepatic dysfunction (e.g. drug-induced, parenteral nutrition and ischaemic hepatitis) should be considered and excluded. Hepatic changes in systemic infection The underlying pathophysiology of hepatic dysfunction in the context of systemic infection can be broadly classified into three main categories. Circulatory changes Early hepatic dysfunction occurs due to a combination of both microvascular and macrovascular circulatory changes. In sepsis, leucocytes, platelets, activated kupffer cells and other inflammatory cells flowing through the sinusoids adhere to the activated SEC, cause endothelial cell damage and result in formation of fibrin microthrombi. Sinusoidal occlusion (facilitated by local release of endothelin-1) leads to reduction in sinusoidal blood flow [13]. Nitric oxide (NO), which is synthesized by NO synthase (NOS), plays a critical role in maintaining hepatic microvascular circulatory homeostasis. The two major forms of NOS – endothelial (eNOS) and inducible (iNOS) are mainly found in the liver [14]. In the early phase of sepsis, NO is mainly derived from eNOS and exerts a hepato-protective effect by antagonizing the effect of endothelin-1 and mediating relaxation of sinusoidal vessels [13]. However, during the later stages of sepsis, iNOS is up-regulated in the hepatocytes, SEC and kupffer cells and mediates systemic vasodilatation, hypotension, circulatory collapse and inevitably hepatic hypoperfusion [14]. Both microvascular and macrovascular circulatory changes ultimately lead to hepatocellular necrosis and dysfunction. Cellular and immunological changes: cholestasis of sepsis Cholestasis is the characteristic end result of a cascade of inflammatory and cellular changes within the liver in response to sepsis and clinically manifests as jaundice [10]. Although various other mechanisms (e.g. haemolysis, drug-induced and hepatic ischaemia) can give rise to jaundice, disturbances within the intra-cellular and extra-cellular bile salt transport system in conjunction with changes in the hepatic parenchymal cells as well as the sinusoidal endothelial cells constitute the key underlying pathogenesis of cholestasis of sepsis [4]. The changes that are seen most commonly include either a functional defect at the hepatocellular level or that of bile flow and excretion. Hepatic cellular changes Sinusoids There is sinusoidal dilatation and an increase in the number of inflammatory cells (mainly kupffer cells, platelets, polymorphonuclear and endothelial cells) within the sinusoids. Sinusoidal occlusion results from cell aggregation resulting in sinusoidal hypoperfusion. This leads to dilatation of the space of Disse with structural changes within the SEC, hepatocytic and bile canalicular membranes [4]. The adjacent hepatocytes thus become susceptible to degeneration and apoptotic damage from the inflammatory cells. Kupffer cell Kupffer cells are activated in response to various stimuli, most commonly bacterial endotoxins (LPS), immune complexes and complement factors. The earliest morphological change seen in activated kupffer cells is increased cell size and an increase in the number of intra-cellular lysosomes. The activated kupffer cells work in an autocrine and paracrine fashion with the adjacent cells including hepatic parenchymal cells and stimulates them to secrete various pro-inflammatory cytokines and

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chemical mediators [4]. This facilitates changes within the sinusoids, SEC and ultimately hepatocellular injury. Immunological and molecular changes PAMPs (e.g. endotoxins/lipopolysaccharides) released from the bacteria are the key mediators of local and systemic inflammation. Most of the circulating endotoxin is cleared by kupffer cells, SEC and hepatocytes [15]. Activated kupffer cells and SEC release several pro-inflammatory cytokines including tumour necrosis factor alpha (TNF-a), inter-leukin-1b (IL-1b) and inter-leukin-6 (IL-6) [16]. The cytokines facilitate antigen presentation to the target cells by promoting major histocompatibility complex (MHC) class II expression on the target cells and mediate direct tissue damage via activated neutrophils, T and B cells [17]. These cytokines (predominantly TNF-a) are directly involved in regulating the expression of genes that encode various hepatic acute phase proteins [9] as well as the bile acid transporter genes [18]. The genes encoding the acute phase proteins may be up-regulated or downregulated and results in significant changes in the hepatic metabolic function [9]. Furthermore, the expression of intercellular adhesion molecule-1 (ICAM-1) is up-regulated on the SEC, kupffer cells and hepatocytes along with the up-regulation of its ligand Mac-1 which is expressed on neutrophils, facilitating its migration and adhesion to the liver cells. Activated neutrophils release superoxide free radicals and elastase, which potentiate hepatocellular damage [17]. The bile acid transporter genes on the other hand are down-regulated [10,19]. In several animal models, lipopolysaccharide and proinflammatory cytokines have been shown to inhibit biliary excretion of transport substrates, reduce bile flow and reduce organic anion excretion [20–22]. The affect is seen at both the basolateral membrane and the canalicular membrane with reduced transportation of bile acids (cholate, taurocholate, and chenodeoxycholate) and certain organic anion transporter proteins (OATP) [20]. In humans, use of TNF therapy is also associated with cholestasis [23]. Basolateral and canalicular transporter changes Hepatocellular membrane transporters play a critical role in the uptake and excretion of bile salts. At the basolateral membrane, bile acid uptake from the sinusoids into hepatocytes is facilitated by the sodium-dependent bile salt transporters such as sodium taurocholatecotransporter (NTCP) and organic anion transporters (OATPs). The efflux pumps at the basolateral membrane include: multidrugresistance-associated proteins-3(MRP3) and MRP4 [18]. The canalicular membrane transporters: bile salt export pump (BSEP) and conjugate export pump (MRP2), regulate the excretion of bile acids into the bile duct lumen. Membrane transport studies in endotoxemic rats have shown changes in the maximal transport velocity of bile salts and organic anions [24,25] along with marked down regulation in transcription and protein levels of NTCP and OATP1 at the basolateral membrane [26,27], and BSEP and MRP2 at the canalicular membrane [28,29]. MRP3 and MRP4 are up-regulated in response to cholestasis and facilitate the transport of bile acids back into the systemic circulation [18]. In humans, reduced expression of bile salt transporter systems has been shown on liver biopsy specimens from patients with inflammation-induced cholestasis [30]. Table 2 lists the changes seen in the hepatobiliary transporters in sepsis. Table 2 Hepatocellular transport changes in sepsis. Transporters Basolateral membrane

Canalicular membrane

-

NTCP OATPs MRP3/MRP4 (efflux pump) BSEP MRP2

Transcription/protein levels Down-regulated/reduced Down-regulated/reduced Up-regulated/increased Down-regulated/reduced Down-regulated/reduced

NTCP – sodium taurocholatecotransporter; OATPs – organic anion transporters; MRP3/MRP4 – multidrug-resistance-associated proteins-3/4; BSEP – bile salt export pump; MRP2 – conjugate export pump.

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Bile duct changes Cholangiocytes are able to secrete various pro-inflammatory mediators, cytokines, chemokines and NO in response to systemic infection, which reduce ductal bile acid secretion and facilitates cholangitis [31]. The main cytokines mediating the cholangiocyte changes include interferon-g (IFN-g) and TNF. IFN-g stimulates NO production by cholangiocytes and facilitates lymphocytic infiltration of the bile duct epithelium by promoting MHC class II expression on the cholangiocytes [12]. Furthermore, in animal models, pro-inflammatory cytokines have been shown to inhibit cAMP-dependent chloride and bicarbonate ion transport in cholangiocytes, and impair the biliary epithelial barrier function [32]. Histological changes secondary to bile duct inflammation and secretory failure predominantly include intralobular bilirubinostasis. In more severe cases of sepsis, ductular proliferation with inspissated bile within dilated portal and peri-portal bile ductules has been demonstrated and is referred to as ‘cholangitis lenta’ [33]. Presence of cholangitis lenta is associated with poor prognosis due to an increased risk of mortality. The failure of hepatobiliary transporters results in altered bile flow and excretion and forms the pathophysiological basis of cholestasis of sepsis. Retained bile acids however, can mediate hepatocellular injury via oxidative stress and apoptosis, leading to hepatocyte necrosis [34]. The intricate peri-biliary vascular plexus supplies the intra-hepatic and extra-hepatic bile ducts. Vascular compromise to the biliary tree can lead to secondary sclerosing cholangitis characterized by intra-hepatic and/or extra-hepatic biliary strictures and dilatation on cholangiography [35]. It usually presents late (1–10 months after initial episode of sepsis associated shock) and should be considered in patients who have persistent elevation of alkaline phosphatase and/or serum bilirubin despite resolution of infection. Metabolic changes in sepsis Protein metabolism In sepsis, hepatic uptake of amino acids is increased resulting in increased protein synthesis and urea-genesis. Pro-inflammatory cytokines such as TNF and IL-6 regulate the expression of genes encoding the hepatic acute phase proteins (APPs) [9]. APPs which are up-regulated (positive APPs) include: C-reactive protein (CRP), a-1-antitrypsin, caeruloplasmin and fibrinogen. Down-regulated APPs (negative APPs) include: albumin, transferrin and a-2-macroglobulin. The acute phase protein response can be seen as early as within the first 24 h of onset of sepsis and enhances immune responsiveness and facilitates tissue repair [36]. The procoagulant state of sepsis is potentiated by the hepatic acute phase response, with reduced synthesis of protein C and anti-thrombin and inhibition of protein C via a-1-antitrypsin. Furthermore, synthesis of thrombin-activatable fibrinolytic inhibitor is increased which inhibits fibrinolysis [9]. Glucose metabolism and insulin resistance The normal physiological stress response to sepsis results in the release of neuroendocrine hormones such as cortisol, glucagon, growth factor, epinephrine and norepinephrine. These hormones alter the hepatic and peripheral metabolic homeostasis resulting in hyperglycemia. Hepatic gluconeogenesis is increased and glycogen synthesis is reduced. The latter occurs in response to increased hepatic insulin resistance resulting from altered insulin signalling pathways (mediated by various counter-regulatory hormones) [37]. In severe cases of sepsis, pyruvate production is markedly increased which is then converted to lactate leading to lactic acidosis [38]. Hepatic changes in pathogen-specific systemic infection Histologically, the most common hepatic changes seen in sepsis include bland intra-hepatic cholestasis with kupffer cell hyperplasia and reactive hepatitis with minimal or no evidence of hepatocellular necrosis. Ductular cholestasis with bile duct involvement (cholangitis lenta) and neutrophilic portal tract infiltrates may be seen in severe cases [10]. Hepatic changes that may be seen in response to specific pathogen-associated systemic infection are discussed below.

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Bacterial Gram-negative infections Salmonella typhi Typhoid fever caused by S. typhi frequently affects the liver. Liver manifestation most commonly seen is that of acute hepatitis but some patients can present with cholecystitis or liver abscess. Jaundice is often seen in the second or third week of illness and as many as 55% of patients can have a tender hepatomegaly [39,40]. Histological changes include focal necrosis, peri-portal mononuclear infiltrate and kupffer cell hyperplasia with characteristic typhoid nodules (kupffer cell aggregates). Hepatic damage is mediated by the bacterial endotoxin as well as the cytotoxins released directly by the bacilli which can be seen by indirect immunofluorescence on the liver histology [41]. Shigella Cholestatic hepatitis is the most common hepatic manifestation of enteric infection with Shigella [42]. Histological changes include portal and peri-portal neutrophilic infiltrate, cholestasis and occasionally hepatocyte necrosis. Neisseria gonorrhoeae 30–50% of patients with disseminated gonococcal infection have raised alkaline phosphatase or transaminases with normal or only slightly raised bilirubin [43]. Fitz–Hugh–Curtis syndrome is a syndrome of peri-hepatitis, which can be seen in 12–37% of patients with co-existing pelvic inflammatory disease (mostly due to gonococcal infection) and results from either direct, lymphatic or haematogeneous spread of infection from the pelvis [44]. Adhesions between the liver capsule and abdominal wall may be seen on radiological examination. Legionella pneumophila Pneumonia is the most common clinical manifestation. It is commonly associated with raised alkaline phosphatase and transaminases (45–50%) and raised bilirubin in approximately 20% but jaundice is usually not a feature. Histological changes include microvesicularsteatosis and focal necrosis and the organisms can be seen occasionally. Brucella Hepatic biochemical abnormalities are seen in most infected individuals. Characteristic histological feature is that of multiple non-caseating hepatic granulomas with or without focal peri-portal or perilobular mononuclear cell infiltrate [45]. Organism can be cultured from the liver tissue in some cases. Gram-positive infections Staphylococcus aureus Toxic shock syndrome is caused by the bacterial superantigens secreted by S. aureus and group A streptococci and often involves the liver. Jaundice and raised serum transaminases are commonly present [46]. Histological findings include microabscesses and granulomas. Presence of hyperbilirubinaemia (>34 mmol/l) in patients with S. aureus bacteraemia is associated with an increased risk of mortality [47]. Streptococcus pneumoniae Unlike bland cholestasis seen in most gram-negative infections, hepatic changes in pneumococcal pneumonia typically result from hepatocellular damage. Liver histological changes include patchy hepatocyte necrosis, biliary canalicular dilatation and bilirubinostasis [48]. Mycobacterial infection Hepatic involvement is a recognized complication of mycobacterial infection and is most commonly seen in infection with Mycobacterium tuberculosis. Two distinct clinical entities of liver involvement are

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recognized in tuberculosis (TB): miliary TB and localized hepatic TB (tuberculous hepatitis) [49]. The primary site of infection is usually the lung and infection spreads to the liver via haematogeneous or lymphatic route. Miliary tuberculosis Hepatic involvement is reported in 50–80% (up to 90% on autopsy) of patients with disseminated infection i.e. miliary TB [49]. Patients usually present with non-specific constitutional symptoms such as anorexia, weight loss and lymphadenopathy. Serum transaminases and ALP are usually elevated and hepatomegaly can be seen in up to 50% of cases [50]. Liver biopsy usually shows caseating granulomas, which is diagnostic of TB. It carries a very poor prognosis and is associated with high mortality despite treatment. Localized hepatic tuberculosis This is an uncommon condition and its true incidence and prevalence rates are not known. Hepatomegaly (often tender) is commonly seen and preset in 70–96% of cases. Hyperbilirubinaemia can be seen in 10–50% of cases and occurs due to intra-hepatic cholestasis or extra-hepatic biliary obstruction (e.g. from biliary strictures or lymph nodes). Serum transaminases and ALP are often elevated. Patients may develop multiple liver nodules, tuberculoma or tuberculous liver abscess. Histologically, presence of granulomas with central caseation is diagnostic and present in 70–80% of cases. However, presence of non-caseating granulomas makes distinction from other causes of granulomatous hepatitis difficult (e.g. sarcoidosis). Acid-fast bacilli can be seen in up to 45% of cases. Other non-specific histological features include micro/macrovesicularsteatosis, lymphohistiocytic aggregates, peri-portal fibrosis and nodular regenerative hyperplasia [51]. Spirochetal infections Leptospirosis Leptospirosis is one of the commonest zoonotic infections in the world and is transmitted by contact with infected urine or contaminated water or soil. The disease can present as an anicteric illness (most common) or as severe icteric leptospirosis (Weil’s disease) seen in 5–10% of all cases. The anicteric illness is characterized by the presence of non-specific constitutional symptoms. A small proportion of cases may have mildly elevated serum transaminases and bilirubin along with hepatomegaly. In the severe icteric form of the disease, patients often present with marked jaundice, proteinuria and haemorrhage. In a series of 240 patients with Weil’s disease, jaundice occurred between 1–13 days of onset of illness and lasted between 3–6 weeks in majority of cases with peak bilirubin levels seen during second and third weeks. Serum bilirubin as high as 720 mmol/l was seen [52]. Serum transaminases are usually elevated but do not exceed more than five times the upper limit of normal [53]. Liver histology may show non-specific reactive hepatitis and cholestasis of sepsis but no hepatocellular necrosis. Syphilis Hepatic involvement is a characteristic feature of secondary syphilis and hepatitis is present in 1–50% of cases [54]. Jaundice and tender hepatomegaly are commonly seen. Liver biochemical abnormalities include mild elevations of serum bilirubin and transaminases with a disproportionately high serum alkaline phosphatase (ALP). Histological findings include a mixed inflammatory infiltrate (neutrophils, lymphocytes, eosinophils and plasma cells) with kupffer cell hyperplasia and focal peri-portal and centrilobular necrosis [54,55]. In almost half of the cases, organism can be demonstrated in the liver tissue by silver staining. Hepatic gumma is a characteristic feature of tertiary syphilis, which is now rare. Histologically, gummas are caseating granulomas with central necrosis and a dense fibrous wall with adjacent lymphoplasmacytic infiltrate [56].

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Fungal infections Hepatosplenic candidiasis Disseminated Candida infection is typically seen in immunocompromised patients (usually haematological malignancies and solid organ transplant recipients) and often involves the liver and spleen i.e. hepatosplenic candidiasis (HSC) [57]. The reported incidence of HSC is between 3–29%, but is rapidly declining with routine use of anti-fungal prophylaxis in immunocompromised patients [58]. The immunosuppressed state allows colonization of the gastrointestinal tract by Candida spp. (most commonly Candida albicans) and subsequent gut mucosal injury (e.g. from chemotherapy) facilitates portal fungemia and translocation to the liver [58]. Unsurprisingly, less than 20% of patients with HSC have positive blood cultures and the diagnosis often requires radiological correlation and/or histological confirmation. Fever is the most common presenting symptom and is often associated with right upper quadrant pain and hepatosplenomegaly. Serum ALP is disproportionately elevated (up to ten times the upper limit of normal) with only modest elevation of transaminases [59]. Identification of the fungal hyphae/yeasts on histology is the gold standard for diagnosis of HSC. In addition, granulomatous lesions with central necrosis are often seen along with hepatic microabscesses and moderate to severe inflammatory reaction [58]. Radiologically, magnetic resonance imaging (MRI) is superior to computed tomography or ultrasound and characteristically shows multiple ring-enhancing nodular lesions of varying sizes. Serial imaging allows assessment of response to treatment [59]. Histoplasmosis Infection with Histoplasma capsulatum usually affects the respiratory tract and clinical manifestations can vary from asymptomatic infection to disseminated histoplasmosis. The latter usually involves the liver and is almost always confined to immunocompromised patients (e.g. those with AIDS, solid organ transplant recipients or haematological malignancies). Patients usually present with nonspecific constitutional symptoms and up to 70% have hepatosplenomegaly [60]. Laboratory findings include raised serum ALP and lactate dehydrogenase levels. Liver histology shows granulomatous hepatitis and the organism can be isolated but bone marrow or lymph node biopsy specimens have a much higher yield. Summary In systemic infection, the liver plays a critical role in host-defense and tissue-repair mechanisms. During this process, it undergoes several immunological, molecular and metabolic changes. The proinflammatory cytokines released in response to PAMPs mediate changes in various cellular and signalling pathways locally as well as systemically. Some of these changes facilitate resolution of infection whereas some cause hepatic dysfunction. The functional significance of some of the changes that occur within the liver in response to infection remains obscure and is an area of active scientific research. For example, it is well established that neutrophils migrate to the liver during endotoxemia and sepsis and play a role in mediating hepatocellular damage and clearance of infection, but the mechanism is not fully known. It has only recently been shown that the neutrophils adherent to the SEC in gram-negative sepsis, eliminate circulating bacteria by releasing neutrophil extra-cellular traps (NETs) which capture and eliminate the organism; similar response is seen involving platelet–neutrophil interaction in gram-positive (S. aureus) sepsis [61]. Furthermore, in a recent transcriptomic and metabolomic study, hepatic induction of cholesterol synthesis was identified as a remote pathogen-specific adaptive immune response to pneumococcal pneumonia, by inhibiting pneumolysin (toxin released by S. pneumoniae), which mediates alveolar macrophage necrosis and lung barrier dysfunction, thereby attenuating disease severity and sepsis progression [62]. These data suggest that the liver plays a vital role in a coordinated host-defense mechanism in preventing microbial dissemination and reducing disease severity. One of the most significant metabolic changes in sepsis is that of increased synthesis of APPs. There is emerging evidence that some of these APPs (e.g. fetuin-A, angiopoetin-2 and augmenter of liver regeneration (ALR) protein) mediate host-specific adaptive responses by: facilitating clearance of infection, preventing liver injury or by signalling early inflammation [63–65].

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Cholestasis is a key feature of sepsis but jaundice usually manifests several days after the onset of illness. Failure of hepatobiliary transporter excretory function resulting in retention of bile acids seems to be the most plausible pathological mechanism of cholestasis of sepsis. A recent study has identified impaired biotransformation of bile acids, which is critically dependent on Phosphatidylinositol-3kinases (PI3Ks) activity as an early event in sepsis. Serum levels of conjugated and unconjugated chenodeoxycholic and taurodeoxycholic acid were elevated within the first 24 h of onset of sepsis and strongly correlated with 28-day mortality. In addition, septic PI3Kg / mice were protected against cholestasis and impaired bile acid conjugation [66]. It may thus be possible to identify biomarkers predictive of early hepatic dysfunction and guide therapeutic interventions in a timely fashion. Despite the severity of hepatic dysfunction, cholestasis of sepsis rarely progresses to liver failure, and jaundice often improves after complete resolution of infection. Persistence of jaundice is usually a marker of poor prognosis. Conflict of interest None.

Practice points  In addition to its role in clearance of infection, liver also mediates a well-coordinated immune response in preventing bacterial dissemination and attenuating disease severity.  Certain hepatic changes are specific to the offending pathogen.  Cholestasis of sepsis rarely progresses to liver failure and liver dysfunction often improves after complete resolution of infection.

Research agenda  Functional role of various acute phase proteins released during hepatic dysfunction needs to be better defined.  Role of serum bile acids in determining early liver dysfunction should be further evaluated.

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