90 Hepatobiliary Infections

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Infectious Diseases of the Dog and Cat, 3rd Edition

CHAPTER 90 Hepatobiliary Infections

Sharon A. Center

ANTIBACTERIAL DEFENSE

Bacteriologic studies of portal vein blood of the mature dog have shown that alimentary flora commonly circulates

to the liver.22,24

Although unproven, the suspicion is that this activity also occurs in the cat. Enteric organisms

delivered to the liver in the healthy animal are extracted by the hepatic Kupffer cells and either killed or excreted

in bile. Liver disorders associated with ischemic injury, impaired hepatic artery perfusion, reduced macrophage

function, and cholestasis can be complicated by infections derived from this normal enteric flora.16

SUSCEPTIBILITY TO INFECTION

Given the dual blood supply and strategic location of the liver, its exposure to substances derived from thesplanchnic and systemic circulations is considerable (e.g., gut-derived par-ticulate debris, toxins, microorganisms,

immunoreactive substances). The hepatic Kupffer cells (hepatobiliary macrophages) play an essential role in the

innate immune response to bacteria and their by-products entering from the portal system. These cells also protect

against systemic bacteremia by cleansing blood delivered through the hepatic artery. Hepatoprotection against

systemic toxicity and infections can become compromised when the liver is injured in a variety of ways. The

integrity of the hepatic reticuloendothelial system (RES), which influences systemic susceptibility to enteric

bacterial translocation (i.e., is associated with hemorrhagic and endotoxic shock, trauma, and bowel ischemia), is

compromised in chronic liver disease, portal hypertension, portosystemic shunting, and cholestasis.120

Consequently, patients with liver disease have increased risk for hepatic infection with or without polysystemic

complications. In addition, the expansive sinusoidal endothelium of the liver provides a site for invasion by

vasculotropic organisms.

Substantial host-dependent differences exist in hepatic clearance of blood-borne particulates. In dogs, 60% to 90%

of hematogenously borne bacteria and particulates are removed by the liver and spleen, giving them an inherent

propensity for hepatobiliary infections.40,180

Comparatively, the cat appears to target pulmonary macrophages

preferentially. Failure of hepatic Kupffer cells to function properly can shift the burden of RES function to other

organs, such as the spleen, lungs, and lymph nodes, as has been shown in dogs with chronic liver disease

associated with acquired portosystemic shunting and in dogs with congenital portosystemic vascular anomalies

(PSVA).78,95

Humans with cirrhosis have an increased incidence of bacterial infections; similar data is unavailable

for the dog and cat. Current belief asserts that the predominant perfusion of hepatic sinusoids with portal venous

blood, a low-flow low-pressure system, rather than arterial blood, facilitates efficient bacterial removal by the RES

because slower flow permits greater opportunity for phagocytosis.85,140

Given that hepatic arterial perfusion

compensatively increases when portal flow is compromised (for example, chronic liver disease with portal

hypertension and portosystemic shunting or PSVA or hepatofugal circulation), change in sinusoidal blood flow

may thwart efficient phagocytosis.

ENDOTOXIN

Endotoxin, or lipopolysaccharide (LPS), is derived from enteric microorganisms and is a normal constituent in

portal venous blood. These glycolipids represent a portion of the outer bacterial cell membrane of gram-negative

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bacteria and are largely derived from organisms colonizing the colon.162

Normally, hepatic Kupffer cells

efficiently clear endotoxin such that the liver attenuates systemic exposure. Endotoxin extraction is enabled by

high-affinity LPS receptors on Kupffer cells and LPS-binding glycoproteins on hepatocytes that facilitate transfer

to Kupffer cell receptors. On exposure to endotoxin, Kupffer cell activation initiates a series of signals eventuating

in production of proinflammatory cytokines. Consequently, increased hepatic exposure to endotoxin can

exacerbate ongoing liver injury and produce changes in liver enzymes reflecting inflammation.

Certain changes in liver function or perfusion can increase hepatic and systemic exposure to endotoxin. In fact,

endotoxemia in the absence of overt sepsis is a common finding in cirrhotic humans. Although higher levels of

endotoxemia are associated with hepatic failure, hepatic encephalopathy, and death, it is unclear whether

detectable systemic endotoxin levels reflect normal exposure left unchecked by the dysfunctional liver, relevant

systemic abnormalities, increased enteric uptake (i.e., enhanced enteric endotoxin translocation), or if they play a

causal role in liver disease or merely represent an epiphenomenon. Because enteric bile acids bind and inactivate

endotoxin, patients with extrahepatic bile duct occlusion (EHBDO) or severe cholestasis having impaired

enterohepatic bile acid circulation may experience increased enteric endotoxin uptake and hepatic exposure.155

Dogs with experimentally induced chronic liver disease (chronic administration of dimethylnitrosamine) with

acquired portosystemic shunts develop measurable portal, hepatic, and caudal vena caval venous endotoxemia.79

Dogs with PSVA (n = 10), medically stable at the time of laparotomy for vascular ligation, also had detectible

endotoxemia in portal and peripheral venous samples (mean SD, 28.0 16.9 versus 19.6 7.0; median [range],

20 [12 to 40] versus 17 [8 to 30]). In the PSVA dogs, shunt ligation attenuated peripheral endotoxemia at

postoperative sampling (at 5 to 13 months).135

Small patient numbers precluded achieving significant differences

(p = 0.06, six dogs studied postoperatively). These observations in clinically relevant conditions suggest that

systemic endotoxemia is a real phenomenon in dogs and, by inference, suggest increased systemic exposure to

enteric microbes and their by-products in the circumstance of hepatofugal circulation. However, systemic response

to endotoxemia, the presence of bacteremia, or evidence of altered oxygen utilization in portal blood have not

been shown in dogs with PSVA.169

ROLE OF KUPFFER CELLS

Hepatic Kupffer cells comprise the largest compartment of tissue macrophages in the body, representing 80% to

90% of the total fixed macrophages and approximately 35% of the nonparenchymal liver cells.70

Residing mainly

within the lumen of the hepatic sinusoids and adherent to endothelial cells by long cytoplasmic processes, Kupffer

cells are most numerous in the periportal area where they offer first-line defense against bacteria, endotoxin, and

microbial debris entering from the alimentary canal.57

Kupffer cells possess both FCand C3receptors and

phagocytize a wide variety of opsonized and nonopsonized particulates.100

Similar to other mononuclear

phagocytes, Kupffer cells also have the capacity to function as antigen-presenting cells, for induction of T

lymphocytes, and on activation, can release superoxide radicals, hydrogen peroxide, nitric oxide, hydrolytic

enzymes, and eicosanoids (prostaglandins and leukotrienes), which can aid in antigen destruction. They also

release a large number of different immunoregulatory and inflammatory cytokines, including interleukin (IL)-1,

IL-6, tumor necrosis factor (TNF)-, platelet-activating factor, transforming growth factor-(TGF-), and

interferon (IFN)-. A heterogenous population of Kupffer cells resides in different lobular zones. Cells associated

with the portal triad (zone 1) are larger, more phagocytic, and generate greater amounts of TNF-, IL-1,

prostaglandin E, and lysosomal enzymes. Smaller cells are associated with zone 3 where more nitric oxide and

superoxide are produced; these exhibit greater cytotoxic activity to certain stimuli and are more easily activated.52

Nitric oxide released by Kupffer cells mediates a wide variety of physiologic events, including (but not restricted

to) vasodilation, neutrophil chemotaxis, and adhesion of neutrophils to vascular endothelium in response to

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bacteria or endotoxin.70

As potent inducers of inflammatory cytokines, Kupffer cells are implicated in the

pathologic events leading to liver injury.162

Inflammatory mediator release from Kupffer cells is enhanced after

primingby endotoxin exposure in reactivehepatobiliary processes. Later, during the course of infection, other

cells including hepatocytes, T lymphocytes, and immigrating phagocytes (monocytes and neutrophils) contributecytokines to the inflammatory process. Certain bacteria undergo initial physical attachment to Kupffer cell surface

receptors (macrophage scavenger receptors) and are subsequently cleared from the sinusoidal circulation. These

receptors have a high affinity for a broad range of polyanionic ligands, including lipoteichoic acid, a component of

gram-positive bacteria.52,131

However, some organisms are not efficiently cleared by Kupffer cells (e.g.,

Pseudomonas aeruginosa, Morganella morganii, and Serratia marcescens) caused by cell surface composition or

increased hydrophobicity, or both.69

ROLE OF NEUTROPHILS

Routine, uneventful removal of bacteria, endotoxin, and particulate and antigenic debris acquired from the portal

venous circulation occurs in part in collaboration with infiltrating neutrophils. Immigrating neutrophils contribute

an early bactericidal influence important for bacterial pathogen clearance.69While providing this ancillarydefensive role, neutrophil participation also may impart self-injury. Neutrophil accumulation in hepatic sinusoids,

a distinguishing feature of endotoxemia and sepsis, fosters the production, release, and accumulation of toxic

metabolic products and degradative enzymes (reactive oxygen intermediates and proteolytic enzymes) from

themselves, as well as from neighboring Kupffer cells. This involvement of neutrophils in response to endotoxin

exposure confuses histologic interpretation of hepatobiliary lesions, erroneously suggesting in some cases the

actual presence of an infectious organism. This response may contribute to the lesion characterized as reactive

hepatitis, commonly described in liver biopsies from veterinary patients with inflammatory bowel disease (IBD).

Neutrophil associated tissue injury is normally limited by neutrophil apoptosis and phagocytosis by hepatic

Kupffer cells on infection control or toxin elimination. Dysregulation of these mechanisms can propagate chronic

liver injury and inflammation.

BILE: PROTECTION FROM INFECTION

Hepatobiliary production of bile and IgA contribute importantly to the health of the biliary and gastrointestinal

(GI) systems. Secretory IgA (S-IgA) is the major immunoglobulin in bile; IgG and IgM are present in much

smaller amounts. IgA binds to a secretory component, made in the liver, forming an S-IgA complex, which assists

in maintaining mucosal integrity by binding infectious agents (e.g., bacteria, viruses). Bile and IgA both influence

enteric bacterial populations (type, number of organisms, and enterocyte adherence). Normal physiologic

choleresis (bile flow) routinely cleanses biliary pathways. The normal biliary-entero-bacterial cycle permits rapid

elimination of bacteria achieving entrance to the biliary tree, and local IgA production protects against epithelial

invasion.20,154

Bile salts contribute an antibacterial influence synergistic with IgA binding, limiting enteric and

biliary bacterial translocation. Normally, tight junctions between hepatocytes resist bacterial entry into canalicular

bile. Along with the high competence of the extrahepatic biliary structures, normal pressure differentials in the

biliary system limit retrograde access of enteric organisms to the hepatobiliary system. However, development of

EHBDO or substantial cholestasis of any cause can interrupt these mechanisms, increasing host susceptibility to

infection.154

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BACTERIAL FLORA OF THE HEPATOBILIARY SYSTEM

The sterility of the portal venous circulation, hepatic tissue, and bile in health has been investigated for more than

50 years. Although older studies suggest that liver tissue is commonly contaminated, especially with Clostridium

spp., more recent work is contradictive.38,49

In the absence of biliary tree obstruction or choleliths, gallbladder and

bile are now thought to be normally sterile.155

Improved methods of collecting samples (reducing

cross-contamination) has been suggested to explain disparate observations.

Normally, enteric organisms delivered to the liver are extracted and killed by neutrophils and hepatic Kupffer

cells. Remaining organisms are thought to be excreted in bile. Clearly, even in normal animals, portal venous

translocation of large bacterial inocula result in hepatic sinusoidal bacterial exposure and bacterobilia.162

In the

diseased liver (e.g., perfusion abnormalities, impaired macrophage function, cholestasis), survival of infectious

agents may be permissively affected by loss of normal protective mechanisms already discussed.20

Consequently,

diseases of the biliary tract and liver may be complicated by the presence of pathogenic bacteria (in bile

[bacteriobilia] or liver tissue) as a secondary phenomenon. Positive bacterial culture results from liver tissue andbile from animals with chronic liver disease in the author's hospital supports this contention.

CIRCUMSTANCES INCREASING THE RISK OF HEPATOBILIARY INFECTION

The liver plays a key role in providing protective responses during gram-negative sepsis. Consequently, a variety

of liver diseases place the host at increased risk for infection. Enhanced pathogenicity of gram-negative sepsis has

been demonstrated in experimental cirrhosis in animal models.77

An important point to acknowledge is that

bacterial organisms commonly found in bile, gallbladder, or liver tissue, in disease, are nearly always enteric in

origin. Greatest risks for infection and postoperative sepsis exist for EHBDO and chronic liver disease associated

with portal hypertension, compromised hepatic perfusion or Kupffer cell function, or both, and conditions

promoting enteric bacterial translocation.

Along with reduced mechanical cleansing of the biliary tree, impaired biliary IgA production or delivery,

enhanced translocation of gut flora into the splanchnic circulation, impaired Kupffer cell activation and

phagocytosis, reduced humoral immunity, compromised neutrophil rolling, migration, or adherence in

hypertensive splanchnic vasculature (but not in hepatic sinusoids), disruption of tight junctions between

hepatocytes, and increased access to hepatic lymph, each facilitate infection.*Cholestasis also imposes an

immunosuppressive effect by reducing in vitro lymphocyte transformation testing. This activity relates to high

plasma, tissue, and bile concentrations of dihydroxy bile acids.155

* References: 47, 88, 133, 138, 139, 141, 143, 165, 167, 172, 174.

INFLUENCE OF CHOLESTASIS ON HEPATOBILIARY INFECTIONS

Any disorder invoking cholestasis can compromise protective mechanisms normally derived from bile and normal

choleresis. EHBDO provokes numerous changes facilitating hepatobiliary and systemic bacterial infection.

Animal models of EHBDO, including dogs and cats, convincingly demonstrate that impaired enteric bile flow

favors small intestinal bacterial overgrowth (SIBO) and enteric-bacterial translocation.34

Cessation of enteric bile

delivery (bile salts and s-IgAs) curtails the normally suppressive influence of bile salts on the endogenous

bacterial population and s-IgA on bacterial mucosal adherence. Defective RES function, altered sinusoidal fenestra

in the area of the peribiliary plexus (permitting greater access to bacterial organisms), reduced enteric mucosal

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integrity, and impaired endotoxin clearance or inactivation augment the opportunity for enteric bacterial and

endotoxin translocation to mesenteric lymph nodes, liver, and the systemic circulation. Given that the liver is

metabolically compromised in cholestasis and the RES dysfunctional, a heightened risk of hepatobiliary infection

is achieved. In this circumstance, development of cholangitis by any route (ascending, hematogenous, or

lymphatic) is favored.155

Inadequate RES function and liberalized portal bacteremia increases the risk for systemic

bacteremia and endotoxemia.128

Although biliary decompression ameliorates jaundice, chronic damage to the

biliary tree causing functional changes reverse slowly, and certain functionality is never fully restored. Immune

dysfunction in cholestatic liver injury derives from inadequate or inappropriate antigen processing by the RES,

cytokine production by Kupffer cells, or abnormal Kupffer-hepatocyte interactions. Chronic down regulation of

Kupffer cell vigilance against endotoxin increases risk for endotoxemia during episodes of heightened exposure

(e.g., hemorrhagic gastroenteritis). Hepatofugal portal circulation reduces hepatic delivery and extraction of

substances in the portal splanchnic vasculature, causing increased systemic exposure to immune complexes,

enteric bacteria, and antigens. Impaired bacterial opsonization reduces appropriate macrophage bacterial clearance

and heightens risk of infection. Dysregulation of inflammatory cascades, crucial to wound healing, may increase

postoperative complications, including wound dehiscence and infections that compromise surgical recovery.155

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Table 90-1 Organisms Associated with Suppurative or Pyogranulomatous

Hepatobiliary Inflammation and Abscesses in Dogs and Catsa

Aerobic Cultures (Positive Cultures: n = 108) Anaerobic Cultures (Positive Cultures: n = 49)a



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n= 5 eacha

Escherichia coli

Streptococcusgroup D enterococci

Staphylococcus aureus

Staphylococcus intermedius

Enterococcus

Staphylococcus epidermidis

Enterobacter aerogenes

Streptococcus-hemolytic

n=3 or 4 eacha

Pseudomonas aeruginosa

Enterobacter agglomerans

Citrobacter freundii

n= 2 eacha

Acinetobacter calcoacetius

Pasteurella multocida

Pseudomonas fluorescens

Nocardia

Klebsiella pneumoniae

Bacillusspp.

Serratia marcesens

n= 1 eacha

hemolytic

Streptococcus

Bordetella bronchiseptica

Campylobacter jejuni

Candidasp.

Enterococcus hermanniensis

Lactobacillussp.

n ==6 eacha

Clostridium perfringens, Clostridiumsp.

Propionibacterium acnes

Bacteroides melaninogenicus

n=3 eacha

Actinomyces

Peptostreptococcus

n= 1 eacha

Corynebacteriumspp.

Fusobacterium

Anaerobic streptococci

Bacillus

Additional Microbes Reported Elsewhere (Case Reports)

Bacillus piliformis

Francisella tularensis

Listeria monocytogenes

Eugenic fermenter-4 bacilli(/L1)

Other noncultured infectious agents proven based onantibody titers, histopathology, or molecular testing (or

any combination) and response to treatment)

Leptospiraserovarsa

Borreliaburgdorferia

Ehrlichiasp.a

Rickettsia rickettsiia

Toxoplasmaa

Babesiasp.

Trematodes (cats)a(/L1)



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Moraxella phenylpyruvica

Morganella morgani

Proteussp.

Pseudomonas fluorescens

Salmonella

a In order from most to least common. Data acquired from case records, 19852001, Companion Animal

Hospital, College of Veterinary Medicine, Cornell University, Ithaca, N.Y.

Experimental models have clarified the significance of enteric portal bacteremia. Infusion of 105to 10

7bacteria

into the splenic vein of normal cats results in a significant reduction in bile flow and the appearance of bacteria in

bile within 30 minutes. However, in the presence of EHBDO, modest bacterial inocula (103) cause bacterobilia

within the same time frame. Bacteria enter sinusoidal blood where some are phagocytized (Kupffer cells and

neutrophils), but ultimately, viable organisms enter bile.167

Although mechanical obstruction of the biliary tree

clearly augments bacteriobilia, also apparent is that any cause of cholestasis may impart this influence. Given that

hematogenously dispersed gram-negative organisms impart a cholestatic response in both dogs and cats, this

activity likely augments their risk for hepatic infection. This phenomenon may explain why bacterial organisms

are unexpectedly cultured from liver tissue and bile in animals with illnesses thought not to be primarily bacterial

in origin (Table 90-1).

TRANSMURAL PASSAGE OF ENTERIC ORGANISMS

The idea that translocation of bacteria and endotoxin from the GI tract may initiate or exacerbate infection has

been increasingly accepted as the so-called gut hypothesis of sepsis and multiple organ failure.45

Increased

vulnerability of the jaundiced host to gut-barrier breakdown and bacterial translocation has been confirmed by

many experimental studies and is strongly supported by clinical observations in veterinary patients. Diseases

involving the biliary tract especially thwart protective mechanisms, leading to bacteriobilia.164

Study of dogs undergoing routine ovariohysterectomy proves that enteric bacterial translocation occurs even in

normal dogs.37

In this study, bacteria was verified in 52% of 26 dogs by positive results of culture of a single

mesenteric lymph node; the number of bacteria cultured varied from 50 to 105organism/g of tissue. Organisms

isolated, in decreasing prevalence, wereEscherichia coli(n = 6),Bacillus(n = 5), nonhemolytic Streptococcus(n

= 4), Salmonella(n = 3), coagulase-negative Staphylococcus(n = 2),Enterococcus(n = 2), and one each with

Staphylococcus intermedius, Clostridium sordelli,Micrococcusspp.,Pseudomonasspp.,Lactobacillusspp., and

Propionibacterium acnes. However, no bacteria were isolated from a single portal blood specimen.42

Translocated enteric bacteria and endotoxin invoke Kupffer cytokine secretion, neutrophil chemotaxis, vascular

adhesion, and degranulation, as well as proinflammatory changes in sinusoidal endothelial cells and hepatic

stellate cells (the source of connective tissue in chronic liver disease), leading to fibrosis. Tissue injury derivesfrom products of activated Kupffer cells and neutrophils, including reactive oxygen species, cytokines, and

proteases, along with reactions involving complement and coagulation system activation. Gut-derived bacteria or

endotoxin may provoke development of the sepsis syndrome in the absence of clinically proven microbiologic

infection. Although compromised gut-barrier function is believed to be relevant to sepsis in the jaundiced patient,

correlation of plasma endotoxin concentrations with morbidity and immunosuppression is inconsistent and quite

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variable as a result of differences in regional blood sample collection, methods employed to detect endotoxin,

units of expression, and inconsistent use of endotoxin standards and expression units.67,138

Enteric translocation of bacteria and subsequent hepatobiliary invasion is enhanced in the presence of (1) bowel

disease (direct mucosal injury), (2) altered gut flora with gram-negative microbial overgrowth (SIBO), (3) portal

hypertension, (4) splanchnic hypoperfusion, (5) hepatofugal portal circulation, proven in dogs with acquired and

congenital portal shunting, (6) local or systemic immunosuppression, including impaired macrophage function, (7)

altered gut motility (slow transit time documented in cirrhosis), and (8) absence of enteric bile (bile acids, IgA,

mechanical cleansing function of bile in the biliary tree). In human and animal models with chronic liver disease,

reduced enteric transit rate has been shown to increase the risk of SIBO and enteric bacterial translocation.134

Contributing factors include portal hypertension, acquired varices, gastroduodenal vascular ectasia associated with

portal hypertensive gastroenteropathy, and oxidative damage in the bowel (with or without coexistent

IBD).30,151,182

An increased propensity for enteric translocation of bacteria in EHBDO has been proven in dogs

and cats.29,167

The clinical impact of cholestasis on enteric translocation is exemplified in humans in whom

postoperative infectious complications following EHBDO decompression are reduced by preoperative internal

biliary drainage.

106,175

BACTERIOBILIA

Bacteriobilia may be clinically silent until biliary obstruction leads to systemic sepsis by biliary-venous reflux.

Increased pressure in the biliary system (at least 25 cm water), causing retrograde flow of bile (regurgitation) into

hepatic sinusoids is a proven prerequisite for infection. The importance of mechanical disruption of bile flow is

well exemplified by the long-term follow-up of humans with choledochoduodenostomy in which retrograde

invasion of the biliary tree by bacteria is the rule. These patients do not develop septic cholangitis as long as

mechanical obstruction to bile flow is avoided. Furthermore, clinical and experimental evidence suggests that

infection is most likely when obstruction is incomplete or intermittent and is seemingly potentiated by the

presence of a foreign body such as a cholelith.48

Once enteric organisms gain access to bile, they may dehydroxylate and deconjugate bile acids, generating

membranocytolytic forms (e.g., chenodeoxycholate yielding lithocholate) capable of provoking cholestasis,

oxidant cell injury, immunotargeting of biliary epithelium or hepatocytes, and cell death by cytolytic necrosis or

apoptosis. This activity is thought to greatly facilitate tissue injury in cats with cholangiohepatitis.

Unfortunately, the bacterial flora in bile is not accurately represented by detection of systemic bacteremia or

urinary tract organisms. Anaerobic bacteria are infrequently found in blood, as compared with bile, andE. coliis

found far more commonly in bile. Consequently, no easy and practical screening method exists for detecting

bacteriobilia. Despite many experimental studies of bacterial translocation that show compelling evidence

supporting this infectious pathomechanism, exactly which clinical patients besides those with EHBDO have

greatest risk has not been clearly defined in either human or veterinary patients.

Cytologic evaluation of bile with a Wright-Giemsa's stain discloses a rich blue amorphous material. Identification

of multilobular nuclear remnants (released from degenerating neutrophils) may be the only evidence of

inflammation. However, with sepsis, bacterial organisms are commonly seen, sometimes in the absence of

well-defined inflammatory cells.

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RISKS INCREASING POSTOPERATIVE SEPSIS

Given that mechanical resolution of EHBDO allows acute mobilization of sequesteredbacteria, a sudden

appearance of bacteria in bile is realized. Failure to provide adequate antibiotic coverage during this transition

increases risk of postoperative infection and sepsis in patients with biliary tree infection and EHBDO undergoing

surgical investigation and correction. An important point to remember is that surgical trauma augments the risk

imposed by reduced gut-barrier function in patients with cholestasis or severe hepatobiliary dysfunction.46,132

Presurgical internal drainage of the biliary tree in humans with EHBDO has been shown to reduce postoperative

septic complications. Modifying the enteric microbial population with antibiotics (e.g., fluoroquinolones,

neomycin, tobramycin) or using certain probiotics (Lactobacilli combined with antioxidants) also has reduced

septic complications in humans and animal models with cholestatic liver disease. Treatment of cirrhotic humans

with ciprofloxacin reduces spontaneous bacterial infections with enteric organisms.142

Restoration of

biliary-enteric communication improves RES function and restores protective mechanisms lost to cholestasis,

reducing the risk of systemic and biliary tree infection.155

INNOCENT BYSTANDER EFFECTS ON THE HEPATOBILIARY SYSTEM

Despite the immense potential for exposure of the liver to infectious organisms, increased liver enzyme activity

and hepatic dysfunction in infectious disease more commonly reflect secondary effects of systemic infection rather

than specific hepatic involvement.116,123

Pyrexia, anoxia, nutritional deficits, released toxins, and inflammatory

mediators each contribute to clinicopathologic abnormalities. Innocent bystander injury from pathologic

conditions initiated elsewhere in the body can lead to inappropriate diagnostic emphasis on the hepatobiliary

system. Occasionally, a self-perpetuating form of chronic active hepatitis may develop as a complication of

infection with bacterial or viral agents. Examples include chronic hepatitis in dogs after infection with

leptospirosis or canine adenovirus-1.13,64

An emerging role ofHelicobacterspp. in humans with cholestatic liver

disease, cholecystitis, and neoplasia of the biliary tree suggests that a relationship may also exist between this

organism and liver disease.58,102,121

Isolation ofHelicobacter canisfrom a single dog with multifocal necrotizing

hepatitis has been reported; organisms were observed using a silver stain at the periphery of necrotizing lesions.59

Bacteria were concentrated between adjacent hepatocytes in bile canaliculi and observed in the lumen of bile

ducts. Organisms were cultured and phenotypically and molecularly identified as being different fromH. canis.

Detection ofHelicobacterDNA using polymerase chain reaction (PCR) and amplicon sequencing from archived

formalin-fixed liver tissue from 2 out of 29 cats with cholangiohepatitis and a cat with PSVA included in a control

group was reported in a scientific abstract.71

Based on comparisons to published sequence homology,H.

nemestrinaeH. pyloriand a combination ofH. nemestrinaeH. pylori, andH. felisH. cinaediiin the two cats

with cholangiohepatits andH. bilisin the PSVA cat were identified. In no case were organisms identified by silver

stains or immunocytochemistry.

SYSTEMIC INFECTIONS

Sepsis and Endotoxemia

Hepatic dysfunction and cholestatic liver injury have been documented in people and in numerous animal

models as a result of systemic bacterial infection and endotoxemia.49

Intrahepatic cholestasis induced by severe

extrahepatic bacterial infection has been experimentally modeled in dogs and cats and observed clinically in 916

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these species.167,171

Response of the liver to systemic infection has been studied in dogs experimentally infused

with endotoxin or live gram-negative bacteria, or both.55,72-74

Acute morphologic changes include dilation and

congestion of sinusoids and hepatic veins, central (zone 3) and midzonal (zone 2) hepatocellular necrosis, fatty

or vacuolar degeneration (not glycogen associated), acute diffuse influx of inflammatory cells (neutrophils andmonocytes), and microabscess formation. Kupffer cell hyperplasia is occasionally described, and canalicular

stasis (microscopically evident bile plugs) has also been described with chronicity. Considerable

hepatocellular dysfunction can cause a shift to anaerobic metabolism, impair gluconeogenesis, and mobilize

lipid from adipose stores. In dogs, acutely increased serum triglyceride, nonesterified fatty acids, and

cholesterol concentrations reflect a metabolic shift to fatty acid oxidation.72

If this activity also occurs in cats,

peripheral fat mobilization might augment development of hepatic lipidosis. In fatty liver modeled in the

choline-deficient rat, impaired RES function increases host susceptibility to endotoxemia.122

Although it is not

known if this is also true in cats with hepatic lipidosis, the common occurrence of a more primary disease

causing anorexia and subsequently the lipidosis syndrome warrants consideration that IBD or constipation

might potentiate endotoxemia in these patients.

Logically, animals with compromised liver function or cholestasis experiencing gastroenteric hemorrhage have

an increased risk for endotoxemia, as is shown in humans. These patients should be treated with broad-spectrum

antimicrobials appropriate for enteric opportunists. Unfortunately, a risk exists that aggressive antimicrobial

treatment for gram-negative organisms may intensify endotoxin release and related clinical signs (as suggested

by some in vitro and in vivo work). This risk relates to the type of antibiotic action and whether the microbial

cell wall remains intact.41,81,83

For -lactam antibiotics, endotoxin-enhancing properties relate to the affinity of

the penicillin-binding proteins (PBP) in the bacterial cell wall. Antibiotics with highest affinity for these

proteins (PBP-2) initiate bacterial transformation to rounded spheroplast forms without cell lysis or endotoxin

release. Antibiotics with highest affinity for the penicillin-binding proteins (PBP-3) convert bacteria to

long-filament forms, with substantial endotoxin release. Antibiotics with high affinity for both receptors have

an intermediate effect. In addition to endotoxin-induced hepatic injury, patients with obstructive jaundice,

cirrhosis, or following extensive hepatic mass excision have greater susceptibility to endotoxemia caused by

impaired Kupffer cell function and hepatic perfusion and greater enteric microbial translocation.

Tick-Borne Diseases

Ticks transmit a variety of organisms, including protozoal, bacterial, and rickettsial organisms. The most

common agents encountered in dogs that may have clinical evidence of liver involvement (increased liver

enzymes and less consistently hyperbilirubinemia) includeEhrlichiasp.,Rickettsia rickettsiiandBorrelia.

Pathomechanisms of rickettsial agents easily explain their apparent hepatic involvement in systemic

infection because these organisms may infect either hepatocytes or endothelial cells. Considering the

extensive endothelial network in the liver, organisms with endothelial tropism may involve the liver as an

innocent bystander. In humans, hepatic involvement in ehrlichial infection occurs in over 80% of patients

causing mild transient increases in transaminase activity.51

Rarely, cholestasis and liver failure may occur,

but in most cases, signs of liver injury resolve with appropriate antimicrobial therapy. A similar phenomenon

may also occur in dogs. Liver injury is related to proliferation of organisms in hepatocytes and bystimulation of immunologic and nonspecific inflammatory mechanisms. In humans, lesions vary from focal

hepatic necrosis to granulomas and cholestatic hepatitis associated with a mixed portal infiltrate, sinusoidal

lymphoid cell infiltrate, and reactive Kupffer cells.51,118

VasculotropicRickettsiasuch as the organism

causing Rocky Mountain spotted fever can involve hepatic endothelium, leading to mild or moderate

increases in hepatic transaminase activity, hepatocellular apoptosis, and less commonly, cholestasis. In

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humans, cholestasis often reflects pancreatic infection and vasculitis, leading to common bile duct

entrapment.178,181

Hemolysis also may contribute to hyperbilirubinemia.181

Similar effects likely occur in

dogs but have not been well characterized. Systemic borrelial infections in humans, early in the course of

disease, can also be associated with clinical evidence of hepatic infection (high liver enzyme activity). In

dogs, this association has also been observed clinically and confirmed by liver biopsy in two ill dogs (several

weeks of illness) observed by the author. Histologic lesions were consistent with lobular dissecting hepatitis

in one dog and a mixed multifocal inflammatory reaction causing focal pyogranulomas in the other.

Experimental work withBorreliasuggests that organisms are rapidly extracted by Kupffer cells following

systemic dispersal and killed by nonopsonic phagocytosis (in vivo and in vitro).144

Considering the

complicated immunopathogenesis ofBorreliainfections, aberrant immune response, humoral immune

activity, cytokines, and cell-mediated immune events likely invoke liver injury.80

Experimental work with

theBorreliasuggests direct hepatic invasion by the spirochete in conjunction with cellular and humoral

immunologic mechanisms.181

Leptospirosis

During the last 15 years, retrospective clinical reports of leptospirosis in dogs in North America and

additional reports from other continents have been published, owing to increased disease recognition and

diagnostic surveillance (see Chapter 44). A retrospective report of cases managed in the author's hospital

documented hepatic involvement in 22 out of 36 (61%) dogs based on increased liver enzyme activity.12

Approximately 17% became hyperbilirubinemic, although some of these dogs had evidence of

microangiopathic anemia as a complicating factor. Increased serum alkaline phosphatase (ALP) activity was

most common (60% of dogs with high liver enzymes) and was evident either on initial blood work or

developed after initiation of treatment (antimicrobial therapy). High transaminase activity in some dogs

reflected muscle injury, substantiated by concurrently high creatine kinase activity. Rise in liver enzyme

activities and evidence of cholestasis during the first week of treatment is thought to reflect hepatocellular or

vascular injury derived from released bacterial toxins or immunologic responses. An association between

infection withL. pomonaand high liver enzymes has been appreciated. Other retrospective and experimental

studies of leptospiral infection in dogs confirm that increased ALP activity is the most common indicator of

hepatic involvement.*Evidence of liver injury in the absence of renal involvement seems uncommon but

may occur. Hepatic lesions in a small number of necropsied dogs were characterized by marked hepatic

venous and sinusoidal congestion, severe perivenous edema, and a predominantly neutrophilic multifocal

inflammatory reaction. Association between leptospiral infection and chronic hepatitis also has been

recognized.13

* References: 12, 76, 86, 89, 137.

Clinical Findings of Hepatobiliary Involvement in Infectious Disorders

Hepatomegaly, splenomegaly, fever, icterus, and lethargy are common clinical signs. The hemogram may

depict a leukopenia, degenerative left shift, and nonregenerative anemia. Markers of an acute phase response

including hyperglobulinemia and hyperfibrinogenemia, a negative acute phase response of

hypoalbuminemia, and hypoglycemia may develop rapidly. These changes are accompanied by variable

increases in the serum activity of liver enzymes, notably alanine aminotransferase (ALT) and aspartate

aminotransferase (AST). In the dog, ALP activity consistently increases after several days, and

hyperbilirubinemia occurs in dogs and cats after 36 to 48 hours. Certain bacterial organisms can directly

induce jaundice without causing substantial hepatic injury; however, generally, the development of jaundice

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portends a poorer prognosis. Disseminated intravascular coagulation (DIC), acute renal failure, and

myocardial dysfunction may develop in terminal cases.

Therapy

The cornerstone of treatment is the provision of adequate fluid therapy, including colloids, parenteral

antibiotics effective against involved organisms, glucose supplementation in the event of hypoglycemia

caused by the sepsis syndrome or hepatic failure, and identification and correction of associated conditions

(see Endotoxemia, Chapter 38). Widespread interest in and documentation shows that oxidant and

perioxidative injury is an important pathomechanism in necroinflammatory. Cholestatic liver disease, as well

as in infectious disease, and the recent documentation of antioxidant depletion in companion animals with

spontaneous liver diseases warrant provision of adequate nutritional and vitamin support and antioxidant

supplementation.28

Maintaining a positive nitrogen balance is important for cell repair and hepatic

regeneration. Antioxidant supplementation in the form of thiol donors, that is, nutritionally as cystine,

cysteine, or methionine or by supplementation with N-acetylcysteine or S-adenosylmethionine (SAMe),

along with -tocopherol (vitamin E) for biomembrane protection, is recommended.28

SPECIFIC HEPATOBILIARY INFECTIONS

Bacterial infections restricted to the hepatobiliary system are relatively uncommon. These infections may assume

the form of multifocal microabscess formation, diffuse suppurative cholangitis-cholangiohepatitis, cholecystitis,

choledochitis, ill-defined hepatic inflammation (as is the case in chronic hepatitis), or they may be associated with

discrete, focal suppuration, and necrosis involving large abscesses. Conditions predisposing the patient to

hepatobiliary infections are summarized in Table 90-2.

Pyogenic Abscess

Unifocal pyogenic hepatic abscesses are rare but may develop consequent to a significant number of disorders

(see Table 90-2).*Most common causes include trauma, extension of sepsis from adjacent viscera or the

peritoneal cavity, hematogenous distribution, ascending biliary tract infection, or ischemia associated with liver

lobe torsion or a neoplastic mass that has outgrown its blood supply. In humans, dental infection is an important

occult cause commonly overlooked; this also may be true in animals. Patients with solitary abscesses may have

no discernible underlying or predisposing condition, whereas those with multiple abscesses usually have some

other disease in the abdominal cavity or disorder producing bacteremia. Because of the dynamics of the portal

circulation delivering splanchnic blood first to the right liver lobes, focal abscess formation is most common on

that side in humans. Despite observation that portal blood also first disseminates here in dogs, lateralization to

the right side does not appear to occur in this species. Lethal hepatic abscesses derived from omphalogenic

infections have been reported in neonates in which Staphylococcusappears to be the most common isolate.75

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Table 90-2 Conditions Predisposing to Hepatobiliary Infectionsa

Obstructed Bile Flow

Extrahepatic bile duct occlusion

Disease of the gall bladder:

Dysmotility

Cholelithiasis

Cystic duct occlusion

Cholecystic neoplasia

Parenchymal cholestasis

Destruction of intrahepatic bile ducts: ductopenia (e.g., certain cats with chronic cholangitis,

cholangiohepatitis)

Microcholelithiasis (intrahepatic bile ducts)

Pancreatitis

Impaired Hepatic Perfusion +/- Oxidant Injury

Chronic necroinflammatory liver disease: chronic hepatitis, chronic cholangiohepatitis

Cirrhosis

Copper storage hepatopathy

Acquired portosystemic shunting

Congenital portosystemic shunting

Liver lobe torsion



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Hepatic neoplasia

Primary: development of a necrotic center

Hepatocellular carcinoma, hepatoma

Metastatic:

Lymphosarcoma, adenocarcinoma, malignant histiocytosis

Portal venous thrombosis

Pancreatitis

Trauma: automobile accident, bite wounds, penetrating wounds

Compromised Immunocompetence

Hyperadrenocorticism

Diabetes mellitus

Severe hypothyroidism

FIV, FeLV infection

Treatment with immunomodulatory drugs: glucocorticoids, azathioprine, methotrexate, chemotherapy

Amyloidosis

Increased Translocation of Enteric Organisms

Inflammatory bowel disease

Enteric neoplasia: lymphosarcoma, adenocarcinoma

Chronic liver disease

Extrahepatic bile duct occlusion



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17/47


* References: 16, 54, 73, 75, 94, 104, 114, 153.

Diagnosis

Most patients develop a neutrophilic leukocytosis inconsistently associated with a left shift, toxic

neutrophils, and monocytosis. Some patients become thrombocytopenic (severe to mild) and demonstrate a

nonregenerative anemia. Increased serum ALT (1.1 to 50 times high normal), AST (1.1 to 18 times high

normal), and ALP (1.2 to 21 times high normal) activities and hyperglobulinemia are common.

Hyperfibrinogenemia with an associated hyperglobulinemia represents an acute-phase response.

Hyperbilirubinemia is inconsistent and usually mild. The sepsis syndrome is exhibited by hypoglycemia and

high lactate concentrations.55

Studies in dogs confirm that lactic acidosis derives from increased splanchnic

lactate production and reduced hepatic lactate extraction.33

Gram-negative bacterial abscess formation often

evokes laboratory features of endotoxemia. Septic peritonitis follows abscess rupture. Blood cultures are

more likely to be positive in patients with multiple abscesses and rarely disclose anaerobic organisms.

Ultrasound (US) provides the best chance for early diagnosis of unifocal hepatic abscess formation and is

capable of disclosing focal lesions that are 0.5 cm or larger. In humans, US is considered the diagnostic

modality of choice because of high utility in both detecting and serially monitoring lesions. US imaging also

may disclose evidence of multiple miliaryabscesses overlooked by more sophisticated imaging modalities

(e.g., computerized tomography [CT], contrast-enhanced imaging).171

US appearance of hepatic abscesses is

variable and may appear as anechoic masses having irregular margins, as lesions with a well defined rim, or

it may contain variable and complex internal echoes (Figs. 90-1and 90-2,AandB). The presence of a

gas-associated anechoic (fluid) compartment highly suggests infection; gas appears echogenic with or

without acoustic shadowing depending on its amount and distribution. Overall echogenic patterns associated

with hepatic abscesses have been described as (1) hypoechoic lesions, consistent with liquefaction necrosis,

(2) heteroechoic lesions, reflecting an irregular hyperechoic abscess rim surrounding a liquefied hypoechoic

center, or (3) hyperechoic lesions, representing a highly cellular cellulitis or pyogranulomatous reaction,

caseation, dystrophic mineralization, or an emphysematous foci.82,114

Rarely, a target lesion similar in

appearance to hepatic neoplasia (especially carcinoma) may be observed. An important rule-out diagnosis is

fluid collection in benign cystic structures; these are comparatively free of internal echoes and are associated

with well-defined walls, usually generating excellent sonographic transmission. Unfortunately, US images of

hepatobiliary abscesses may be compromised by intestinal ileus in which enteric gas compromises the

imaging window. Plain radiographs usually have limited value in diagnosing hepatic abscess formation.

Exceptionally, radiographs may disclose loculated hepatic gas, free abdominal gas, focal mineralization,

mass lesions, or reduced peritoneal detail, reflecting peritonitis or effusion, or both (Fig. 90-3). Miliary

abscess formation cannot be distinguished from other multifocal hepatic parenchymal lesions based on US or

radiographic imaging. Thoracic radiographs may reveal evidence of pneumonia, reflecting increased

pulmonary exposure to infectious organisms. The presence of sternal lymph node enlargement may signal

abdominal inflammation or infection because this lymphatic pathway drains the abdominal structures.

Although blood and urine cultures may identify causal organisms, these cultures are unreliable. More direct

diagnostic sampling is achieved by lesion aspiration. Cytologic examination of aspirated material should be

initially completed using a modified Wright-Giemsa's stain (Diff Quik). Identified microorganisms are

subsequently characterized by Gram staining. Although exceedingly useful, diagnostic and therapeutic

abscess aspiration is associated with a risk of peritoneal contamination, requiring forethought as to the need

for emergency laparotomy. Anaerobic and aerobic cultures of abscess contents should always be submitted.

Polymicrobial infections nearly always involve an anaerobic organism; approximately 50% of solitary

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hepatic abscesses in dogs appear to be polymicrobial. Because anaerobes are difficult to culture, they should

be suspected and treated when cytologic evaluation discloses a polymicrobial population. Furthermore,

therapy should continue even if no organisms are cultured or only a few aerobic organisms are grown. When

causal factors remain illusive, hepatic biopsy may be indicated in a search for underlying neoplasia or other

primary hepatic processes permissive to infection.

Fig 90-1 Ultrasonographic image of a hepatic abscess showing a hyperechoic

rim and heterogenous interior echogenicity (between arrows). The

image reflects solid or complex mass structure associated with

hemorrhagic, cellular, or edematous fluid or caseation. The gross

appearance of this abscess is shown in Fig. 90-2, Aand B.

Fig 90-2 Gross appearance of the hepatic abscess demonstrated in Fig. 90-1

A, Lesion on surface of the liver. B, Lesion on cut surface. A

polymicrobial infection was proved to involve Bacteroides.



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Fig 90-3 Radiograph demonstrating pneumoperitoneum associated with

emphysematous hepatic abscesses (arrows)and pneumoperitoneum

from a mature dog. Central necrosis of a large hepatic adenoma wasthe underlying disease. A clostridial organism was suspected based

on Gram stain characteristics and was subsequently confirmed by

anaerobic bacterial culture.

Therapy

Successful management of multifocal microabscess formation in 60% of treated human cases is

accomplished when only intravenous (IV) antibiotics are used.117

Successful outcome usually requires early

diagnosis, aggressive abscess drainage (needle-catheter or surgical drainage), lobectomy, or any combination

of these, and long-term administration (minimum of 6 to 8 weeks) of an appropriate antibiotic. Needle or

catheter drainage procedures have received increased attention as a therapeutic option for successful

management of single (or few) abscesses owing to the wide availability and high sensitivity of US

imaging.36,114,153

Aspiration using an 18-gauge needle (superficial abscess) or 22-gauge spinal needle (deep

abscess) or via a drainage catheter placed by guide-wire technique may be performed with the intent of

removing all liquefied suppuration (large syringe, three-way valve, and collection reservoir prepared in

anticipation). Flushing the abscess cavity with sterile saline is recommended if physically possible after

evacuation. Reappraisal for potential peritoneal contamination by US imaging is recommended within 24 to

48 hours. Response to therapy is monitored with serial US images, body temperature, and measurement of

90.15.1.3



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liver enzymes. In human medicine, bedside US imaging and abscess drainage (n = 886 cases) by the

managing clinician have been proven to be advantageous and safe.36

Aspiration drainage by

clinician-operated US technique met or exceeded information and treatments afforded by imaging specialists

or alternative imaging modalities (e.g., fluoroscopy, CT imaging).

36

US-guided abscess aspiration as a primary mode of abscess treatment has been successfully applied to

veterinary patients. This approach is recommended for several reasons: (1) as a method of confirming the

diagnosis, (2) to provide time for patient stabilization before surgical exploration for liver lobe resection, and

(3) because it is successful as a solitary means of therapy in a subset of patients. Major factors arguing

against this technique include unsafe access (i.e., abscess immediately adjacent to large vascular structures in

the porta hepatis or main biliary structures) and lesion depth exceeding aspiration needle length. When

aspirating a suspected hepatic abscess, the clinician must always anticipate a need for immediate surgical

intervention in the event of abscess rupture into the peritoneal cavity. Given that primary hepatic tumors

comprise an important underlying cause of hepatic abscess formation in older dogs, these lesions must

always be considered. Unfortunately, although these lesions require resection, they may not be diagnosed

until tissue is resected and examined histologically.

The duration of antimicrobial treatment remains empirical, being based objectively on perceived patient

response. In humans, certain organisms (e.g.,Actinomyces) are routinely treated for a minimum of 3

months.156

Because polymicrobial infections involving anaerobes are relatively common, antibiotics

effective against both aerobic and anaerobic organisms should be initially administered. Anaerobes may act

synergistically with other pathogens, altering the course of infection and the prevalence of other pathogens

caused by microniche modification. In this circumstance, infection control and bacterial eradication may

become more difficult, requiring a longer course of treatment. Anaerobes can enhance virulence of other

bacteria by inhibiting phagocytosis (i.e., impairing opsonization, neutrophil chemotaxis) and by locally

interfering with the efficacy of antibacterial therapy.102,154,155

Bacteroides fragilisis one of the worst

offenders, producing -lactamases, which can overwhelm the function of -lactamase inhibitors.106

Good initial therapy for hepatic abscess formation is achieved with a combination of a penicillin and afluoroquinolone or an aminoglycoside. Metronidazole or clindamycin can be substituted for penicillin to

provide an anaerobic spectrum (see Therapy sections and Tables 90-3, 90-4, and 90-5). Fluoroquinolones

provide broader gram-positive coverage compared with aminoglycosides and are thought to have better

penetration across an abscess wall. First-generation cephalosporins, potentiated sulfonamides, and

aminoglycosides are uniformly ineffective against anaerobes.

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Table 90-3 Guidelines for Selection of Initial Antimicrobials for Anaerobic

Hepatobiliary Infections Based on Gram Stain Characteristics3, 9, 45

GRAM-NEGATIVE RODS

(NON-SPORE-FORMING)

GRAM-POSITIVE

RODS

(SPORE-FORMING)

GRAM-POSITIVE RODS

(NON-SPORE FORMING)

GRAM-POSITIVE

COCCI

ANTIMICROBIAL Bacteroides Clostridium PropionibacteriumActinomycesPeptostreptococcus

Penicillin G +++ +++ +++ +++Penicillin and -lactamaseinhibitor

to ++ +++ +++ +++ +++

Ticarcillin +++ +++ +++ +++ +++

Imipenem +++ +++ +++ ++ +++

Cephalosporins

Cephalothin

(first

generation)

+++ ++

Cefoxitin

(secondgeneration)

to ++ to +++ to++ to ++ +++

Cefotaxime

(third

generation)

to +++ to ++ to ++ +++

Metronidazole +++ +++ +++ ++ to +++Clindamycin ++ to +++ +++ +++ ++ +++

Chloramphenicol +++ +++ +++ ++ +++

Tetracycline to + to ++ to ++ Doxycycline to + to ++ to +++ Fluoroquinolones to ++ NA to ++

Aminoglycosidesa

Trimethoprim-sulfonamideb NA NA

Vancomycin +++ +++ ++ +++NA,Not available; , not effective; +, slight efficacy; ++, effective; +++, very effective.

a Aminoglycosides require transport enzyme systems to gain entrance to the interior of the bacteria;

these are lacking in anaerobes.

b Sulfonamides are usually not effective despite in vitro sensitivity testing results. Tissue necrosis

and suppuration commonly associated with anaerobic infections result in competitive inhibition of

sulfonamide activity.

Treatment of hepatic microabscesses requires extensive supportive care and long-term administration of a

tailored antibiotic regimen specifically targeting involved pathogens along with identification and

management of the underlying cause. Disseminated sepsis should initiate a search for an underlying

condition compromising immune defense (see Table 90-2).

Granulomatous Hepatitis

Granulomatous hepatic inflammation is an uncommon diagnosis characterized by multiple discrete, sharply

defined nodular infiltrates consisting of macrophage aggregates (and sometimes epithelioid cells) surrounded by

or intermixed with (or both) lymphocytes and plasma cells. Lesions may be focal, multifocal, or diffuse.

Underlying causes include metazoal (e.g., schistosomiasis, dirofilariasis), fungal (e.g., histoplasmosis,

paecilomycosis), protozoal (e.g., visceral leishmaniasis, toxoplasmosis), bacterial (e.g., infections with

mycobacteria,Nocardia, Bartonella, Brucella, Borrelia, Propionibacterium acnes), and viral (e.g., feline

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coronavirus [feline infectious peritonitis virus] infections; visceral larval migrans (Toxocara migration);and

noninfectious disorders (drug reactions, lymphangiectasia, histiocytosis or histiocytic neoplasia,

lymphosarcoma, and immune-mediated inflammation). These disorders may be associated with a positive

antinuclear antibody test.26

Causal factors have remained elusive in at least 50% of cases; however, with

increased molecular surveillance for infectious origins, more definitive diagnoses are anticipated.

Table 90-4 Guidelines for Selection of Initial Antimicrobials for Aerobic

Hepatobiliary Infections Based on Gram Stain

Characteristics3,4,9,50,145,146

GRAM-POSITIVE COCCI GRAM-NEGATIVE RODS

VARIABLE Staph. Strep. Enteroc. E . coli Past . Enterob. Pseud.a Kleb.

Penicillin G to + +++ to ++b +++

Penicillin and -lactamaseinhibitor

+ to +++ +++ to ++b to ++b +++

Extended-Spectrum Penicillin

Ticarcillin to + +++ ++b to ++b +++ +++b to +++b Ticarcillin and -lactamaseinhibitor

to +++ +++ ++b to ++b +++ +++b to +++b to+++

b

Imipenem/cilastatin to +++ +++ +++ +++b +++ +++b +++c +++b

Cephalosporins

Cephalothin (first

generation)

to + +++ ++ +++ +++

Cefoxitin (second

generation)

to + +++ ++ +++ to ++ +++

Cefotaxime (third

generation)

to ++ +++ +++ +++ +++ to ++ +++

Metronidazole Clindamycin to +++ ++ Chloramphenicol to + +++ +++ +++ to ++ to ++ to

+++

Tetracycline NA ++ to - to ++ Doxycycline to +++ +++ to ++ Fluoroquinolones to + to + to + +++ +++ +++ ++c +++

Aminoglycosidesd to + to + +++ +++ +++ NA +++

Trimethoprim-sulfonamideeto + to + to + to +++ NA ++ +++

Vancomycin to +++ +++ +++ Staph., Staphylococcus; Strep., Streptococcus; Enteroc., Enterococcus; E. coli, Escherichia coli; Past., Pasteurella; Enterob.,

Enterobacter; Pseud., Pseudomonas; Kleb., Klebsiella; NA,data not available; , not effective; +, slight efficacy; ++,effective; +++, very effective.

a Pseudomonasmay require parenteral third-generation cephalosporins, antipseudomonal penicillins:

ticarcillin, carbenicillin, ticarcillin clavulanate, or lastly, a fluoroquinolone.

b Synergistic with aminoglycosides.

c Not used forPseudomonas fluorescensinfections.

d Aminoglycosides require transport enzyme systems to gain entrance to the interior of the bacteria;

these are lacking in anaerobes.



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e Sulfonamides are usually not effective despite in vitro susceptibility testing results. Tissue necrosis

and suppuration commonly associated with anaerobic infections result in competitive inhibition of

sulfonamide activity.

Clinical signs may remain vague. In patients with diffuse hepatic involvement, signs may involve profound

hepatomegaly, causing discomfort, icterus, and (later) ascites. Laboratory features include hyperbilirubinemia,

high serum ALP, and more variable transaminase activity. In patients with diffuse severe parenchymal

involvement, hepatic failure is indicated by subnormal cholesterol and urea concentrations and prolonged

coagulation times. Although hepatomegaly is associated with severe diffuse parenchymal involvement, chronic

disease may lead to a reduced liver size. Change in hepatic size is usually evident radiographically. The US

image may appear normal or disclose a diffusely or irregularly hyperechoic hepatic parenchyma and regional

hypoechogenicity. Splenomegaly and mesenteric lymphadenopathy are common, followed later by peritoneal

effusion. Histopathologic lesions vary in zonal distribution, severity, and cell involvement, depending on the

underlying cause.31

Infectious causes require specific targeted therapy. In idiopathic cases in which an immune-mediated

mechanism is surmised, lesions may abate with glucocorticoid or other immunosuppressive therapies (e.g.,azathioprine, cyclosporin, methotrexate). However, immunosuppression requires vigilant monitoring for

opportunistic pathogenicity of undetected infectious agents. Molecular techniques for detecting infectious

causes has been widely used and applied successfully in human medicine. Recently, PCR analysis detected

Bartonellaspp. infection from two dogs with hepatic disease, one with blatant pyogranulomatous inflammation

and the other unexpectedly (Doberman pinscher with chronic hepatitis used as a disease control).63

HepatosplenicBartonellainfection in humans is thought to be widely under-diagnosed when it is associated

with multinodular lesions involving either bacillary angiomatosis or peliosis hepatica (the latter lesion has been

reported in an infected dog) or a necrotizing granulomatous reaction.43,93,129

Feline Hepatobiliary Infections

Cholangitis-Cholangiohepatitis

The cholangitis-cholangiohepatitis syndrome (CCHS) is the most common necroinflammatory hepatobiliary

disorder of the domestic cat.24,61,87

Inflammation involving intrahepatic bile ducts (cholangitis) is frequently

associated with chronic interstitial pancreatitis possibly because of the anatomic proximity of these tissues

(anatomic fusion of the common bile and pancreatic ducts), because of shared epitopes on epithelial cells of

these ductular structures, or because of a common, as of yet unidentified, infectious organism. Concurrent

presence of IBD and interstitial nephritis is also clinically recognized. Cholangiohepatitis as a classification

exists when cholangitis extends to involve surrounding hepatic parenchyma. CCHS may be suppurative or

nonsuppurative; cats with suppurative disease are more acutely and severely ill. Although some researchers

have postulated that suppurative inflammation may progress to nonsuppurative disease, this has not been

confirmed. CCHS has been detected in cats infected with a variety of agents, including trematodes,

Toxoplasma(see Chapter 80), an organism resemblingHepatozoon canis(see Chapter 74), gram-negativeintestinal bacteria, Clostridium piliforme, formerlyBacillus piliformis(see Chapter 39) (Fig. 90-4),

Bartonella(experimentally), and recently,HelicobacterDNA found in archived formalin-fixed tissue from

two cats.71

Given that a general unifying infectious cause of CCHS has not been discovered, most cats are

classified as having idiopathic disease if infectious agents are not identified cytologically or cultured from

liver and bile samplings. Although infectious agents may initiate inflammation, the process appears to

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involve chronic and self-perpetuating immunologic and oxidative tissue injury. However, some cats with

nonsuppurative CCHS have had positive bacterial cultures from liver tissue and bile.



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Table 90-5 Dosages of Drugs for Treatment of Hepatobiliary Infections and

Modifications for Hepatic Insufficiency or Jaundice

DRUGa

DOSEb ROUTE INTERVAL

(HOURS)

TOXICITY WITH

ACCUMULATIONc

STANDARD LIVER-IMPAIRED

Antimicrobials

Penicillin G 20,00040,000

U/kg

IV, IM, SC 4 Low

Amoxicillin-clavulanate 1020 mg/kg PO 12 Low

Ticarcillin 1525 mg/kg

over 15 min

then CRI

IV, IM, SC IV loading

then CRI or

discrete

dosing at 68

Low

7.515 mg/kg/hr

or 4080 mg/kg

IV, IM, SC IV loading

then CRI or

discretedosing at 68

Low

Imipenem 510 mg/kg IV/IM 68 Low

Cephalosporins

1st generation 1030 mg/kg PO, IV, IM, SC 8 Low

2nd generation 1020 mg/kg IM, IV 8 Low

Ceftazidine 3050 mg/kg IV 812 Low

Metronidazole 15 mg/kg 7.5 mg/kg PO 12 Neurotoxic

Clindamycin 1016 mg/kg 5 mg/kg SC 24 Anorexia,

vomiting, diarrhea

510 mg/kg 5 mg/kg PO 12 Anorexia,

vomiting, diarrhea

Chloramphenicol (rarely indicated) D: 2550 mg/kg 1225 mg/kg PO, IV, IM, SC 8 Myelosuppression

C: 1622 mg/kg 811 mg/kg PO, IV, IM, SC 8 Myelosuppression

Tetracycline 1020 mg/kg PO 8 Potential

hepatotoxic

Doxycycline 2.55 mg/kg PO 12 Low

Enrofloxacin D: 2.55 mg/kg d PO, IM, SC 12 Drug interactions,

seizures

C: 2.5 mg/kg/day d PO, IM, SC 24 Drug interactions,

seizures

Gentamicin 68 mg/kg IV, IM, SC 24 Nephrotoxic,

ototoxic;

therapeutic

monitoring

Amikacin 1015 mg/kg IV, IM, SC 24 Nephrotoxic,

ototoxic;

therapeutic

monitoring

Trimethoprim-sulfonamide 30 mg/kg 15 mg/kg PO, SC 1224 Cholestasis,

immune complex

disease

Vancomycin 1520 mg/kg IV (slowly

over 3060

min)

812 Nephrotoxic,

painful IM;

therapeutic

monitoring

recommended

esp. cats.



26/47

Infectious Diseases of the Dog and Cat, 3rd EditionSupportive Therapy

B-Vitamins 2 ml/liter fluid

therapy

IV Each fluid

allocation

Low

Vitamin K1 0.51.5 mg/kg SC 12e Anaphylaxis if IV,

hemolysis if too

great a dose:

heinz bodies

Vitamin C (avoid if high liver tissue

Cu or Fe concentrations in biopsy)

100500 mg total PO, IV 24 Low, may

augment hepatic

oxidative injury

associated with

transition metals

(Cu & Fe)

Vitamin E 1015 U/kg PO 24 Low

Ursodeoxycholic acid 7.5 mg/kg PO 12 Pruritusf

Crystalloids 66 ml/kg IV, SC 24 Edema,

hypertension

Hetastarch D: 1020 mg/kg IV 24 Hypertension

C: 1015 mg/kg IV 24 Hypertension

Desmopressin acetate DDAVP 15 g/kg 20min beforeeffect, lasts only

2 hr

IV 1 timetreatment

Also use as

pretreatment

for blood

donor to

increase vWF

& Factor VIII

High dose mayaugment water

retention and

aggravate edema

or ascites, rarely a

problem

CRI, Constant rate infusion; D, dog; C, cat; DDAVP, deoxy-d-arginine vasopressin; vWF, vonWillebrand's factor

a For further information on antimicrobial drugs, see Drug Formulary, Appendix 8.

b Dose per administration at specified interval.

c For additional information on toxicity, see Drug Formulary, Appendix 8.

d Data on dose reduction not established.

e Use for 13 doses, then dose every 710 days. Too frequent administration or too high a dose will

cause Heinz body hemolytic anemia in cats.

f Avoid use until complete biliary obstruction is relieved.

Suppurative Cholangitis

Suppurative cholangitis occurs least commonly.*Most cats are middle aged or younger, predominantly

male, and have only a short duration of clinical illness (under 5 days). Fewer than 50% of patients have

hepatomegaly, and most are jaundiced, febrile, lethargic, dehydrated, and exhibit abdominal pain. Vomiting

or diarrhea occurs in approximately 50% of cases. 924

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Fig 90-4 Photomicrograph of hepatic tissue from a cat with suppurative

cholangiohepatitis. Even though the suppurative nature of the

inflammation is recognizable, infectious organisms could not be seen(H and E stain, 600). Bacterial organisms were clearly evident on an

impression cytologic imprint.

Most cats with suppurative CCHS have underlying disorders of the biliary system, causing bile stasis

(cholestasis), including EHBDO, cholelithiasis, cholecystitis, choledochitis, or periductal pancreatic and

biliary duct fibrosis derived from ascending infection, pancreatitis, trematode infection, immune-mediated

mechanisms (presumed) or congenital biliary tract malformation (polycystic liver disease). Inflammatory

bowel disease is a common concurrent problem and is thought to contribute to infection. Culture of tissue,

bile, and choleliths have disclosed infections with, in descending order of frequency,Enterococcus, E. coli,

Enterobacter, Staphylococcusspp., -hemolytic Streptococcus, Klebsiella, Acinetobacter, Citrobacter

freundi, Pseudomonas, Actinomyces, Clostridium perfringens, Clostridiumspp., andBacteroides.

Unfortunately, a positive result on bacterial culture does not define a causal relationship because cholestasis

predisposes to infection by opportunists translocated from enteric flora, ascending the biliary tree, or

hematogenously dispersed. Most cats have intermittent vomiting and diarrhea, which circumstantially may

coincide with portal bacteremia or reflux of enteric flora into biliary or pancreatic ducts.

Suppurative cholangitis is characterized by a neutrophilic infiltrate around and within intrahepatic bile ducts

and associated periductal edema, hepatocellular cholestasis (canalicular bile plugs), and eventually, with

chronicity of greater than several weeks, a circumferential periportal fibrolamellar mantel.

* References: 22, 24, 55, 61, 79, 84.

Nonsuppurative Cholangitis

Nonsuppurative cholangitis is the most common form of CCHS, occurring in middle-aged to older cats. This

form of disease is associated with variable clinical signs and slow, insidious progression. No sex or breed

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predisposition has been found, feline leukemia or feline immunodeficiency virus infection is not a

predisposing factor, most cats are ill for more than 3 weeks, and many are ill for greater than 2 months or for

several years. Intermittent anorexia, vomiting and diarrhea, weight loss, cyclic fever, hepatomegaly, and

jaundice occur in 70% of cats. Most cats are not consistently lethargic, and chronic disease may lead to

polyphagia, apparently associated with maldigestion induced by impaired bile flow and chronic IBD.

Common concurrent chronic disorders include IBD, fibrosing pancreatitis, and cholecystitis. In some cats, a

history of EHBDO or prior suppurative CCHS exists, which may have initiated the disease process

(presumably). However, in some cats, chronic CCHS is the only identified disorder. Importantly, some of

these cats develop hepatobiliary infections possibly as a consequence of immunosuppressive therapy or

overlooked primary infectious origins. Some of these cats progress to develop biliary tree neoplasia

(adenocarcinoma).

Retrospective and prospective evaluation of affected cats in the author's hospital suggests several different

histologic categories included in the morphologic description of nonsuppurative CCHS: (1)

lymphoplasmacytic cholangitis, (2) lymphocytic cholangitis, (3) lymphoproliferative disease(low-grade

lymphosarcoma confined to the liver), and (4) a sclerosing cholangitisform associated with destruction of

small to medium sized bile ducts.

22,24

Discussion of each subset is beyond the scope of this chapter.Histologically, nonsuppurative inflammation is characterized by bile duct hyperplasia, periportal and

periductal fibrosis, lymphoid or lymphoplasmacytic aggregates in the portal triads, and (with chronicity)

biliary cirrhosis. Duct destruction in certain cats leads to ductopenia or a sclerosing cholangitis category

characterized by obliteration of small and medium-sized bile ducts proven by application of an epithelial

specific immunocytokeratin stain. The least common type of portal inflammation in cats is characterized by

portal lymphocytic or lymphoplasmacytic infiltrates lacking an apparent involvement of bile ducts; these are

more appropriately described by the term lymphocytic portal hepatitis.61

Clinical Laboratory Findings

Suppurative cholangitis is usually associated with a moderate-to-severe neutrophilic leukocytosis, which may

be accompanied by a left shift with or without toxic changes. Nonsuppurative cholangitis may be associated

with a mild nonregenerative anemia, normal leukogram, neutrophilic leukocytosis, or lymphocytosis.

Variable magnitudes of increased serum activities of ALT, AST, ALP, and -glutamyltransferase (-GT)

develop, depending on the duration and degree of tissue inflammation and cholestasis. Hyperglobulinemia

and prerenal azotemia are common on initial presentation of overtly ill animals. Hyperbilirubinemia is more

consistent in cats with nonsuppurative cholangitis and has an insidious onset and cyclic nature. In the

anicteric cat, detection of bilirubinuria is a sensitive measure of impending hyperbilirubinemia. Measurement

of serum bile acids can also detect cholestasis before overt hyperbilirubinemia. Abnormal coagulation test

results and bleeding tendencies responsive to vitamin K1are observed in severe CCHS accompanied by

anorexia of several days duration, EHBDO, or intrahepatic ductopenia. Radiography is fairly unrewarding,

although dystrophic mineralization is sometimes observed in cats with chronic intrahepatic bile duct

inflammation and infection, when radiodense choleliths exist, or when unexpected hepatomegaly is

confirmed. Hepatic US may fail to disclose altered liver echogenicity, may reflect diffuse hyperechogenicity

(a result either from fibrosis, inflammation, or development of hepatic lipidosis), or disclose a heterogenousmultifocal pattern. Mineralization of intrahepatic bile ducts is rarely observed. Thickening of biliary

structures and evidence of EHBDO may be found. Abdominal effusion is rare in cats with CCHS unless

suppurative inflammation and infection exist or severe portal hypertension caused by extensive periportal

fibrosis has developed.

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Therapy

Surgical exploration is necessary for definitive diagnosis of necroinflammatory hepatobiliary disorders in the

cat because it allows visual and mechanical inspection of the biliary tree, sampling of multiple tissues

(biopsy of liver, gut, pancreas, and mesenteric lymph nodes), and collection of samples (tissue, bile) for

aerobic and anaerobic bacterial culture. If the common bile duct is occluded, a biliary diversion can be

implemented or inspissated bile removed. Hydrocholeresis can be used to improve bile flow postoperatively

in these cats through administration of ursodeoxycholic acid. Surgical biopsies provide better intestinal

samples as compared with endoscopically retrieved samples and have the advantage of permitting biopsy of

jejunum and ileum in addition to duodenum and stomach, as well as safe pancreatic sampling, bile

aspiration, and collection of liver biopsies from several different liver areas in a short period. Biopsy of

several liver lobes is recommended because differential liver lobe involvement has been shown in patients

with high liver enzymes (i.e., minimal involvement in one liver lobe with concurrent severe involvement in

another).

A therapeutic strategy is formulated after examination of the liver and bile for sepsis. Aggressive antibiotictherapy is implemented if infection is suspected while aerobic and anaerobic bacterial culture results are

pending. Hepatic tissue should be submitted for routine histologic evaluation and reviewed for infectious

agents with special stains or immunohistochemistry or subjected to PCR-amplification techniques for

unusual organisms. If flukes are considered a possibility, feces should be examined preoperatively and bile

collected intraoperatively for trematode egg detection.

Management of CCHS requires long-term supportive care, including fluid therapy, nutritional support by

feeding appliance if necessary (esophagostomy or gastrostomy is preferred in most cases) with a balanced

feline ration, supplemental water-soluble vitamins (two times normal dosing), antibiotics tailored to the

involved infectious organisms, ursodeoxycholic acid for its immunomodulatory-antifibrotic-choleretic and

hepatoprotective effects, and, in cases of nonsuppurative CCHS in which no infectious agent has been

detected, immunomodulation (antiinflammatory doses of prednisolone are customary).22,24

Suppurative

cholangitis should be treated with antibiotics for at least 6 to 8 weeks. Periodic reevaluation (every 2 to 3weeks) using physical assessment, hemogram, liver enzyme activities, and bilirubin concentration, is used to

monitor patient response. Assessments are based on patient physical status, including body weight and

condition, absence of fever, resolution of leukocytosis and jaundice, and reduced liver enzyme activities.

Reevaluation of a liver biopsy is desirable but often cannot be justified. In some cases, an US-guided hepatic

and bile aspiration permits reevaluation of infection (cytology and cultures). Aspiration of hepatic

parenchyma may also disclose developing hepatic lipidosis and initiate further metabolic and nutritional

supportive efforts and restriction of glucocorticoids. Some cats with nonsuppurative CCHS appear to be

glucocorticoid intolerant, developing hepatic lipid vacuolation or becoming diabetic.

Cats with nonsuppurative cholangitis should be prophylactically treated with antibiotics for possible

infectious causes until culture results, antibody titers, cytology of impression smears, and histopathology rule

out an infectious cause or decrease it from consideration. If peribiliary fibrosis is observed and culture and

titer results deny infectious agents, prednisolone is given initially at a dose of 2.0 to 4.0 mg/kg, orally, once

per day. This dose is tapered after the first 1 to 4 weeks depending on patient drug tolerance and clinical

response. Chronic administration of antiinflammatory and chemotherapeutic drugs is necessary to control

severe nonsuppurative CCHS. Given that hepatic glutathione concentrations have been shown to be low in

cats with CCHS, antioxidants are now routinely recommended in the form of (1) S-adenosylmethionine

(Denosyl-SD4 [Nutramax Laboratories, Inc., Edgewood, Md.] 200 mg/cat per day) and (2) -tocopherol

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(vitamin E; 10 IU/kg/day), along with a daily source of water-soluble vitamins because deficiency of certain

B vitamins can limit important metabolic pathways that may facilitate antioxidant function and development

of hepatic lipidosis. The adequacy of vitamin B12is appraised in all cats with CCHS because this vitamin

undergoes enterohepatic circulation and is known to be seriously compromised in cats with substantial gut

disease (infiltrative disease such as lymphoma or severe IBD and enteric lamina propria fibrosis). An

important subset of cats with hepatic lipidosis exhibits vitamin B12deficiency, possibly lending to both

glutathione deficiency and inadequacy of l-carnitine, dependent on adequate methylation reactions

(influenced by SAMe availability and vitamin B12). In cats with the sclerosing CCHS form of disease,

methotrexate is used by the author at a total dose of 0.4 mg, given every 8 hours per day once weekly, along

with folinic acid (folate) at 0.25 mg/kg and the other medications described previously.22,24

Most of these

cats also receive chronic low-dose metronidazole (7.5 mg/kg, orally, every 12 hours) for its

immunomodulatory effect useful in managing IBD (typically a coexistent problem), as well as its excellent

protection against anaerobic bacterial organisms that may opportunistically complicate the illness.

Cholecystitis and Extrahepatic Bile Duct Occlusion

Septic inflammation of the bile ducts and gallbladder can develop in dogs and cats as a distinct entity.56

With

chronicity, many of these patients eventually develop EHBDO or a ruptured biliary tree (bile peritonitis). Bile

peritonitis is discussed in another section. Although the pathogenesis of acute cholecystitis is not clearly

understood, a variety of associated causes are implicated, including any disorder causing obstruction of the

biliary tree, gallbladder dysmotilit

90 Hepatobiliary Infections

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