Professional Documents
Culture Documents
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.
CHAPTER 90 Hepatobiliary Infections Page 25 of 47
Infectious Diseases of the Dog and Cat, 3rd Edition
Supportive Therapy
B-Vitamins 2 ml/liter fluid
therapy
IV Each fluid
allocation
Low
Vitamin K
1
0.51.5 mg/kg SC
12
e
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
Pruritus
f
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 20
min before
effect, lasts only
2 hr
IV 1 time
treatment
Also use as
pretreatment
for blood
donor to
increase vWF
& Factor VIII
High dose may
augment 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.
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CHAPTER 90 Hepatobiliary Infections Page 26 of 47
Infectious Diseases of the Dog and Cat, 3rd Edition
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, Staphylococcus spp., -hemolytic Streptococcus, Klebsiella, Acinetobacter, Citrobacter
freundi, Pseudomonas, Actinomyces, Clostridium perfringens, Clostridium spp., and Bacteroides.
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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CHAPTER 90 Hepatobiliary Infections Page 27 of 47
Infectious Diseases of the Dog and Cat, 3rd Edition
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 cholangitis form 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 K
1
are 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 heterogenous
multifocal 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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CHAPTER 90 Hepatobiliary Infections Page 28 of 47
Infectious Diseases of the Dog and Cat, 3rd Edition
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 antibiotic
therapy 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 3
weeks) 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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CHAPTER 90 Hepatobiliary Infections Page 29 of 47
Infectious Diseases of the Dog and Cat, 3rd Edition
(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 B
12
is 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 B
12
deficiency, possibly lending to both
glutathione deficiency and inadequacy of l-carnitine, dependent on adequate methylation reactions
(influenced by SAMe availability and vitamin B
12
). 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 dysmotility, septicemia, or ascending bacterial invasion of the biliary structures.
22
Acute cholecystitis can be experimentally created by introducing pepsin, activated proteolytic pancreatic
enzymes, neutrophils, or bacteria into the bile duct.
65,158
Such spontaneous reflux of initiating agents up the
shared bile duct may occur in the cat, especially considering ductal pressure changes invoked by the vomiting
reflex. Cholelithiasis and choledocholithiasis may each be associated with septic and nonseptic cholangitis,
cholecystitis, and choledochocystitis (gallbladder and duct inflammation) in both dogs and cats.
92
In dogs, old,
small- to medium-sized breed females are more commonly afflicted with cholelithiasis, especially if an
underlying disorder of lipid metabolism exists (e.g., hereditary defect of lipoprotein metabolism,
hypothyroidism). Bile stasis, biliary inflammation and infection, altered bile composition (increased cholesterol
or bilirubin concentrations), or biliary mucosal irregularity associated with neoplasia or cystic mucinous
hyperplasia can promote biliary lithiasis or gallbladder mucocele formation. The slow, insidious onset of duct
occlusion by choleliths or slow-growing neoplasia augments development of biliary infection. E. coli is a
common isolate from biliary tissue and bile in animals with cholecystitis. Aerobic bacterial culture results of
bile from dogs with gallbladder mucoceles have been positive
10
; however, microscopic abnormalities did not
suggest primary biliary tract infection, and bacterial colonization may likely be secondary to biliary stasis.
Chronic cholecystitis also has been associated with Salmonella (dogs) and Pasteurella (cats). Acute
cholecystitis has been reported in dogs with Campylobacter (likely Helicobacter) infections (see Chapter 39).
Although still controversial, the pathologic role of Helicobacter in certain forms of biliary tree disease in
humans and animal models is expanding.
102
Most diagnoses are based on PCR detection of Helicobacter DNA,
and whether this represents enterohepatic circulation of DNA in bile, transient colonization, or colonization
with pathogenicity remains arguable.
102
Given that conditions such as biliary infection, cystic duct occlusion,
EHBDO, and acute cholecystitis are known to decrease bile pH significantly, markedly, researchers have
suggested that Helicobacter spp. may opportunistically appear in patients with more primary hepatobiliary
disorders.
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CHAPTER 90 Hepatobiliary Infections Page 30 of 47
Infectious Diseases of the Dog and Cat, 3rd Edition
In human and in experimental animal models, the general belief holds that bacteria play an important role in the
formation of pigment gallstones. Glucuronidases produced by certain Enterobacteriaceae can deconjugate
bilirubin diglucuronide, resulting in precipitation of calcium bilirubinate, which may culminate in stone
formation.
170
Other organisms may interact with bile through production of hydrolyzing enzymes, perpetuated
inflammation (foreign body effect), and provision of nucleating proteins such as immunoglobulins or debris
derived from bacteria, mucus, or cells that can act as a nucleation nidus.
Clinical Signs
Infections involving the bile ducts and gallbladder generate clinical signs of infection and EHBDO. These
signs include fever, anorexia, vomiting, abdominal tenderness, hepatomegaly, jaundice, and (with EHBDO)
acholic feces and bleeding tendencies. Clinical signs can be persistent, intermittent, or episodic.
Diagnosis
Cholecystitis is frequently associated with clinicopathologic abnormalities typical of EHBDO and severe
CCHS in cats. A nonregenerative anemia attributable to chronic inflammation may develop. A strongly
regenerative anemia may reflect substantial enteric hemorrhage derived from gastroduodenal ulcers
associated with gastroduodenal vascular ectasia, portal hypertensive gastroenteropathy compromising
mucosal perfusion and repair, and co-existent IBD. Portal hypertension derives from biliary cirrhosis, which
is a predictable sequela to complete EHBDO after 6 weeks. A marked leukocytosis with a left shift is
common. Liver enzyme activities, especially ALP and -GT, are markedly increased (5 to 10 times reference
values). Severe cholestasis is common, with hyperbilirubinemia reaching as much as 20 times reference
values. Serum concentrations of total cholesterol usually increase two to four times reference values in
complete EHBDO. Prolonged coagulation times may develop as a result of vitamin K
1
depletion or DIC.
Lack of an enterohepatic circulation of vitamins B
12
and K
1
(and possibly folate) are seemingly more
problematic for cats. Septic bile peritonitis may prevail if the biliary system ruptures subsequent to
necrotizing cholecystitis. Abdominocentesis yielding yellowish-orange fluid containing bile with or without
bacteria indicates the need for abdominal lavage and surgical intervention. Abdominal radiographs may
disclose the presence of abdominal effusion and, in exceptional cases, radiodense mineralized choleliths
(Fig. 90-5). Although many choleliths are radiopaque in cats and dogs, a considerable subset of cats have
radiodense choleliths identifiable on good quality survey abdominal radiographs.
90.15.4.1
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CHAPTER 90 Hepatobiliary Infections Page 31 of 47
Infectious Diseases of the Dog and Cat, 3rd Edition
Fig 90-5 Radiograph showing radiodense choledocholithiasis within the
intrahepatic biliary tree in a mature cat that 2 years previously
underwent cholecystotomy for cholelith removal. Chronic
cholangitis, biliary infection, and sludged bile were contributing
causes of cholelith development.
US images provide important diagnostic information, revealing changes consistent with EHBDO as early as
72 hours of onset. Initial changes include thickening and distention of biliary structures, obstruction-induced
tortuosity of the common duct, and choleliths, reflecting acoustic shadows in the gallbladder (Fig.
90-6).
121,176
Choleliths within the common or cystic ducts are less easily imaged because of adjacent enteric
gas. Care must be taken to avoid confusion caused by commonly visualized gallbladder bile sludge or
sediment observed in anorectic patients. Gravitational mobility can be used to evaluate bile fluidity. The
kiwi fruit sign indicative of a biliary mucocele also may be disclosed (Fig. 90-7). A bi- or trilaminar
appearance of the gallbladder wall associated with a heterogenous or kiwi fruit sign suggests a biliary
mucocele associated with necrotizing cholecystitis and a need for emergency cholecystectomy, biliary
diversion, common duct repair, or any combination of these measures (Fig. 90-8). US evaluation may also
disclose pericholecystic effusion and guide accurate needle sampling for cytologic and culture analyses.
Cholecystocentesis
Diagnostic sampling of bile may be useful in certain cases in which infection of the biliary tree or
cholecystitis is considered possible.
177,147
This procedure is ill advised in the presence of suspected EHBDO
90.15.4.3
CHAPTER 90 Hepatobiliary Infections Page 32 of 47
Infectious Diseases of the Dog and Cat, 3rd Edition
or US changes indicative of necrotizing cholecystitis. Sampling of bile can be safely achieved by US
guidance using a transhepatic approach. The transhepatic approach provides some degree of compression on
the site of gallbladder puncture limiting bile extravasation. Nevertheless, sampling should be completed with
the intent of removing as much liquid bile as possible to reduce subsequent leakage. Sampling by US
guidance is done using a 22-gauge spinal needle, a 3-way valve, extension tubing, syringe, and receptacle;
sterile tubes for collecting culture specimens should be available. Penetration of the gallbladder is
accomplished using a rapid thrusting motion rather than slow-dull pressure because the latter technique may
induce a vasovagal response that can lead to pathologic bradycardia, hypotension, and asystole (see later
discussion under Cholecystitis). During exploratory laparotomy or laparoscopy, direct gallbladder puncture
for bile collection should also be completed with the intent of emptying the gallbladder to reduce
postsampling leakage. US evaluation of the biliary tree 24 to 48 hours after nonsurgical transhepatic
sampling is advised to monitor for the presence or extent of focal bile accumulation, especially if biliary
sepsis is found on cytologic evaluation of the aspirated bile.
Fig 90-6 Ultrasonographic image showing a mineralized cholelith with
acoustic shadowing in a cat with suppurative CCHS (GB, gallbladder;
CBD, distended common bile duct; ST, stone).
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Infectious Diseases of the Dog and Cat, 3rd Edition
Fig 90-7 Ultrasonographic image showing the kiwi fruit sign, consistent with
the presence of a biliary mucocele. A biliary mucocele is composed
of thick tenacious mucous and biliary debris entrapped in a
dysfunctional gallbladder. This phenomenon can lead to necrotizing
cholecystitis complicated by infection.
Fig 90-8 Ultrasonographic image of the gallbladder in a dog with necrotizing
cholecystitis. Notice the laminar appearance of the gallbladder wall
(arrows), consistent with edema and tissue necrosis, obvious on
histologic section.
CHAPTER 90 Hepatobiliary Infections Page 34 of 47
Infectious Diseases of the Dog and Cat, 3rd Edition
Therapy
Treatment of septic cholecystitis includes prolonged administration of antibiotics effective against involved
aerobic and anaerobic bacteria. Selection of antibiotics that achieve good systemic concentration is
important. Laparotomy is necessary to confirm the diagnosis, to identify etiologic factors, and to perform
cholecystectomy or biliary diversion, or both (e.g., biliary decompression, provision of an alternate route of
bile drainage, cholecystoenterostomy, choledochoenterostomy). The need for cholecystectomy is determined
by the surgeon and is advised when even a small portion of the gallbladder wall appears devitalized or when
neoplasia is suspected. Emergency laparotomy is essential if biliary rupture or septic bile peritonitis is
detected. Management of bile peritonitis is discussed later. Hydrocholeresis in conjunction with appropriate
antibiotics is used on a long-term basis to diminish bile stasis, after biliary obstruction is resolved. See
General Treatment Considerations.
Fig 90-9 Radiograph demonstrating emphysematous cholecystitis observed in
a dog with diabetes mellitus (arrows denote gas in gallbladder).
Emphysematous Cholecystitis
Emphysematous cholecystitis is an uncommon and life-threatening condition diagnosed in dogs with and
without diabetes mellitus.
18,73,104,105
Diagnosis in the cat is rare. The most commonly recognized precipitating
factor is cystic duct obstruction. Ischemia of the gallbladder wall as a result of tense gallbladder distention
potentiates an environment conducive to invasion by gas-producing anaerobes. Accessed bacteria can
proliferate in the gallbladder wall and spread within adjacent tissues or shared microvasculature. Left untreated,
90.15.4.4
90.15.5
CHAPTER 90 Hepatobiliary Infections Page 35 of 47
Infectious Diseases of the Dog and Cat, 3rd Edition
the gallbladder may rupture and organisms spill into the abdominal cavity, leading to pneumoperitoneum and
septic peritonitis (Fig. 90-9).
Clinical Findings
Clinical signs associated with emphysematous cholecystitis include abdominal tenderness, fever, jaundice,
anorexia, and vomiting. Neutrophilic leukocytosis with a left shift and toxic changes; hyperbilirubinemia;
increased serum ALP, -GT, ALT, and AST activities; and prerenal azotemia are common. A tympanic
abdomen may follow gallbladder rupture. Initial radiographic features may consist only of poorly defined gas
infiltrates in the gallbladder wall. Over time, this activity may expand to fill the gallbladder lumen and
progressively involve pericholecystic tissues. A sufficient volume of gas for radiographic detection usually
accumulates within a few days of overt clinical signs; radiography, however, is insensitive for an early
pivotal diagnosis. US may disclose small amounts of gas in the gallbladder wall as an echogenic line. Large
amounts of gas may prevent visualization of the gallbladder wall, casting a distinct acoustic shadow.
Unfortunately, US may not clearly differentiate whether gas localizes to the gallbladder wall or extends into
the surrounding tissue.
92
Rarely, small amounts of gas may be detected within intrahepatic bile ducts.
Conditions other than emphysematous cholecystitis compromising US visualization of the gallbladder
include the presence of a porcelain gallbladder (mineralized wall), a contracted gallbladder filled with
choleliths, and duodenal ileus (gas-filled intestines that may be overcome by intercostal positioning of the
probe or imaging of patient in standing posture). The most common bacteria isolated from humans and dogs
with emphysematous cholecystitis are Clostridium spp. (Fig. 90-10).
Therapy
Management of emphysematous cholecystitis involves cholecystectomy combined with prolonged
administration of antibiotics effective against anaerobes, but even then, the prognosis is poor. Only rarely
have patients with emphysematous cholecystitis survived without surgical intervention. Medical and surgical
treatment for septic peritonitis is usually needed.
Bile Peritonitis
Bile peritonitis is a serious complication of biliary tree infection, inflammation, ischemia, or trauma. The
toxicity of bile on tissues and hypovolemic shock associated with the pooling of fluid in the peritoneal cavity
are responsible for most clinical signs. Pleural effusion of a similar composition may also accumulate.
8
Bacterial contamination of biliary ascites may spontaneously develop and is the usual cause of death.
19,22,124
Bile-induced permeability changes in the intestinal wall promote passage of enteric flora into the peritoneal
effusion. Anaerobic organisms (Clostridium spp.) have also been shown to spontaneously invade
experimentally created biliary ascites in dogs.
Clinical Findings
Animals with bile peritonitis usually have histories of anorexia, vomiting, abdominal tenderness and
distention, fever, and lethargy. Most patients are overtly jaundiced. However, some animals with aseptic bile
peritonitis can be relatively free of clinical signs because of omental and adhesion loculation of spilled bile.
Animals with septic peritonitis may develop emphysematous peritonitis subsequent to growth of
gas-producing bacteria; this condition may progress, causing a tense and tympanic abdomen (see Fig. 90-3).
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90.15.5.2
90.15.6
90.15.6.1
CHAPTER 90 Hepatobiliary Infections Page 36 of 47
Infectious Diseases of the Dog and Cat, 3rd Edition
Fig 90-10 A, Sporulating Clostridium spp. found in the abdominal effusion. B,
Free spores (arrows) from a dog with an emphysematous hepatic
abscess, pneumoperitoneum, and septic peritonitis (Wright-Giemsa,
680). Same dog as that shown in Fig. 90-3.
Diagnosis
Hematologic abnormalities typically include a left-shifted neutrophilic leukocytosis with toxic changes.
Some patients have a degenerative left-shifted leukon, representing systemic sepsis and peritoneal leukocyte
migration. However, some patients with walled-off abdominal infection show no hematologic features.
Biochemical abnormalities typically reflect the underlying disease process involving biliary structures.
Increased serum activities of liver enzymes and moderate to severe hyperbilirubinemia are typical.
Hypercholesterolemia develops if EHBDO precedes biliary tree rupture. Progressive hypoalbuminemia
reflects sequestration of a protein-rich abdominal effusion. Prerenal azotemia reflects systemic volume
contraction and reduced renal perfusion and may indicate endotoxemia. Prolonged hypovolemia or
hypotension may provoke acute renal failure.
Abdominal radiography typically discloses a diffuse loss of visceral detail. Careful evaluation for free
abdominal gas or gas within the biliary structures is essential because anaerobic bacterial infection is
indicated. Cholangiography or cholescintigraphic studies are rarely indicated. Cholangiography may not
delineate the site of biliary rupture because of competition between iodinated imaging agents and bilirubin,
as well as reduced flow within the biliary tree. Cholescintigraphy using an iminodiacetic analog can provide
a noninvasive method of documenting the site of bile leakage, but this too lacks practicality, can be done
only in selected centers, and does not reliably indicate the anatomic site of bile leakage.
98
Abdominocentesis reveals a yellowish-orange or golden-green effusion. Cytologic evaluation usually
discloses a modified or exudative effusion with many neutrophils, macrophages, erythrocytes, and variable
numbers of bilirubin crystals (Fig. 90-11). Given that yellow discoloration of effusion is expected in a
jaundiced animal, effusion color alone cannot be used as definitive evidence of bile peritonitis. The presence
of bile crystals and a very high fluid bilirubin concentration in relation to serum are useful in confirming
the diagnosis. The presence of bacteria is confirmed using a Wright-Giemsa's or new methylene blue stain.
Thereafter, Gram stain elucidates bacterial morphology and the presence of sporulated anaerobes, which can
greatly facilitate initial antimicrobial selection. Aerobic and anaerobic cultures of abdominal effusion should
929
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be collected and immediately submitted when bile peritonitis is suspected, irrespective of whether bacteria
have been observed. Antimicrobial therapy is indicated when this diagnosis is considered probable.
Fig 90-11 Photomicrograph showing cytologic features of an abdominal
effusion observed in a dog with septic bile peritonitis. Neutrophils,
macrophages, erythrocytes, intracytoplasmic large Gram stain
positive rod-form bacteria, and golden bilirubin crystals were
observed (Wright-Giemsa, 680).
Therapy
Surgical intervention is indicated whenever bile peritonitis is suspected. The presence of sepsis makes the
situation urgent. Before general anesthesia and laparotomy, the patient must receive aggressive supportive
care, including colloid administration to reinstate deficient oncotic pressure, vitamin K
1
to ensure its
repletion, blood-component therapy to correct acute symptomatic bleeding tendencies, and IV antimicrobials
targeting enteric aerobes and anaerobes derived from transmural enteric translocation. Whether colonic
lavage with nonabsorbable antimicrobials should be routinely enacted remains controversial. Experimental
and clinical evidence in humans suggests that this procedure may reduce enteric bacterial translocation that
predisposes the patient to endotoxemia and septicemia. Neomycin given at 22 mg/kg as a retention (high)
enema may be used up to every 8 hours. At surgery, visual inspection of visceral structures usually reveals
the site of biliary rupture and provides information essential for an appropriate operative approach. If the
gallbladder appears inflamed or devitalized, a cholecystectomy is necessary. If a portion of the common bile
duct is damaged, a biliary diversion such as a cholecystoduodenostomy or cholecystojejunostomy may be
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needed. If the cystic duct is damaged, cholecystectomy is usually done; alternatively, placement of a T tube,
or choledochoenterostomy, may be implemented. A careful and systematic inspection of the biliary tree with
appraisal of its patency and bile fluidity is essential. Choleliths or mass lesions, as well as inspissated bile or
biliary mucoceles, must be removed. Biliary mucoceles are firm conglomerations of bile that lead to
necrotizing cholecystitis (more common in hyperlipidemic dogs such as Shetland sheepdogs and Schnauzers
with hereditary hyperlipidemia); these are associated with a unique kiwi fruit appearance on abdominal US;
these also require cholecystectomy (see Fig. 90-7). Biopsy specimens optimally should be collected from
adjacent and distant portions of the hepatic parenchyma, as well as from representative portions of the
diseased biliary system. Parenchymal samples collected from tissues located distal to the biliary structures
clarify the presence of diffuse and preexisting hepatobiliary disease. Samples should be evaluated for
cytologic and histopathologic features and submitted for both aerobic and anaerobic bacterial culture. During
surgical manipulations, remaining vigilant for an induced vasovagal crisis derived from iatrogenic pressure
on main biliary structures is important. Vasovagal crisis is characterized by hypotension, bradycardia, and
asystole, and correction requires elimination of vagal stimulation (relief of biliary tree pressure or
manipulation) and administration of atropine. A similar response may be noted during cholecystocentesis
when slow penetration of the gallbladder occurs before needle puncture.
Peritoneal sepsis may be apparent at laparotomy by discovery of a notable fetid odor when the abdomen is
first opened. Before abdominal closure, peritoneal lavage with sterile saline is recommended in all cases of
bile peritonitis to diminish chemical peritonitis and to remove bacterial organisms mechanically. Appropriate
antibiotics should be continued for 4 to 6 weeks postoperatively. Repeated administration of blood
components or synthetic colloids may be necessary to correct for bleeding tendencies and to maintain plasma
oncotic pressure during surgery and during the immediate postoperative interval because of prodigious loss
of plasma proteins and fluid into the abdominal cavity. In cases in which surgery is delayed, abdominal
lavage should be aseptically performed to assist in eliminating bile (causing chemical peritonitis) and
infectious organisms.
General Treatment Considerations
Supportive Care
Fluids, Electrolytes, Oncotic Support, and Blood Component Therapy
Initial management of the animal with hepatobiliary infection involves provision of fluid therapy and
correction of electrolyte abnormalities. Polyionic crystalloid fluids are given to correct dehydration
deficits, to cover contemporary losses, and to provide for maintenance needs. A commercially available
colloid (hetastarch, Hespan [Bristol Myers Squibb, New York, N.Y.], or generic) may be used to
reinstate colloid oncotic pressure; however, its use may promote bleeding tendencies because of effects on
platelet aggregation. The author prefers using hetastarch rather than dextran-70 in veterinary patients with
liver disease (subjectively, fewer complications with bleeding tendencies). Blood-component therapy may
be essential during the first several days in treating patients with chronic EHBDO or severe diffuse
parenchymal cholestasis, as well as intraoperatively in patients undergoing surgical resolution of bile
peritonitis and cholecystectomy. If present, hypoglycemia is ameliorated with fluids supplemented to a
2.5% or 5.0% dextrose concentration, as necessary. If hypoalbuminemia, hepatic insufficiency, ascites, or
a tendency for sodium retention exists, attention must be given to avoid sodium loading (use solutions
with lowest sodium content, or prepare a mixed solution combining 5.0% dextrose in water mixed 1:1 v/v
with a balanced polyionic fluid). Judicious supplementation with potassium chloride (use the conventional
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sliding scale for potassium administration) is important, as well as monitoring serum phosphate and
administration of potassium phosphate if serum phosphate is less than 2.0 mg/dl (using a constant rate
infusion, provide 0.02 to 0.06 mmol/kg/hr). Close monitoring to ensure repletion of potassium and
phosphate is important because subnormal electrolyte concentrations can have dire metabolic and
physiologic complications in the patient with liver disease. Low potassium can promote
hyperammonemia, anorexia, weakness, enteric ileus, and hyposthenuria that can aggravate electrolyte
wasting. Hypophosphatemia can lead to metabolic encephalopathy, anorexia, vomiting, diarrhea,
weakness, ataxia, hemolysis, rhabdomyolysis, and bleeding tendencies (platelet dysfunction). Careful
sequential monitoring of electrolytes is important to avoid over-supplementation with either electrolyte.
Potassium should never be given IV at a rate exceeding 0.5 mEq/kg/hour.
Bleeding Tendencies
Vitamin K
1
should be administered by subcutaneous injection in patients with jaundice, whether caused
by EHBDO or chronic diffuse cholestasis and whether patients are displaying bleeding tendencies.
Vitamin K supplementation has particular relevance in patients with overt bleeding or prolonged
coagulation times (see Table 90-5). Coagulation assessments include a thorough physical assessment for
bleeding tendencies (including careful inspection of retina, oral cavity, prepuce and penis, vulvar mucosa,
as well as more easily inspected cutaneous surfaces), bench coagulation tests (prothrombin time and
activated partial thromboplastin time assessments), and a buccal mucosal bleeding time (longer than 5
minutes is abnormal). Unfortunately, routinely evaluated clotting tests are relatively insensitive for
detecting clinically relevant bleeding tendencies. The author prefers using the PIVKA (proteins invoked
by vitamin K antagonism) clotting test to most routinely performed bench assessments because PIVKA
clotting times have higher sensitivity for detecting compromised clotting.
26,27
Increased PIVKA clotting
times appear to develop rapidly in cholestatic liver disorders treated with long-term oral antimicrobials,
possibly because of synergistic influences, including suppression of enteric microbial vitamin K synthesis,
impaired enteric vitamin uptake (caused by lack of sufficient alimentary bile), and compromised hepatic
rejuvenation of active vitamin K. Cats appear to have increased risk.
25
Bleeding tendencies may be recognized before or appear only during invasive procedures (surgery, tru cut
needle biopsy, catheterizations). Treatment requires initiating fresh, compatible blood transfusion and may
benefit from administration of synthetic vasopressin (desmopressin, DDAVP [Aventis, Bridgewater,
N.J.], or generic; 1 to 5 g/kg, subcutaneously, 30 minutes before tissue injury, a one-time-only therapy).
Fresh whole blood rather than stored frozen plasma is usually better for patients with compromised liver
function because of the possibility that thrombocytopenia or acquired thrombopathia may contribute to
bleeding tendencies and because ammonia may accumulate in stored blood products. Pretreatment of a
blood donor with DDAVP may augment von Willebrand's factor concentration in the collected product.
Although DDAVP has been observed to reduce pathologic hemorrhage in humans and companion animals
with severe liver disease, the mechanism remains ill defined and is clearly more complex than simple
elaboration of von Willebrand's factor from vascular endothelium and increasing factor VIII.
91,110
Nutritional Support
Nutritional support of the patient with hepatobiliary infections requires provision of a nutritionally and
calorically adequate diet. These animals should not be initially placed on a protein-restricted diet unless
overt signs of hepatic encephalopathy or hyperammonemia (ammonium biurate crystalluria) exist.
Avoiding a negative nitrogen balance is important in the patient with hepatobiliary disease and sepsis
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because this precaution protects tissues from catabolism, provides nitrogen for tissue regeneration and
repair, and protects cats from developing hepatic lipidosis. Anorexia is managed whenever possible using
enteric modes of feeding (e.g., nasogastric, esophageal, or gastric intubation). The use of appetite
stimulants cannot be endorsed (e.g., benzodiazepines, cyproheptadine) because these drugs are
inconsistent in effect and are generally unreliable in establishing adequate energy intake. Furthermore, in
the circumstance of hepatic insufficiency, benzodiazepines are contraindicated.
Although enteral feeding was found to enhance SIBO in dogs with EHBDO, the prerequisite for
correction of biliary tree occlusion in patients makes this complication less important.
34,35
In patients with
uncorrectable biliary occlusion (e.g., cats with intrahepatic ductopenia caused by chronic CCHS), chronic
antimicrobial therapy may assist in protecting the patient against the complications induced by SIBO. Use
of ursodeoxycholate will not solve this problem because this bile acid has limited physiologic influence on
nutrient assimilation compared with the natural primary bile acids. Patients with active pancreatitis may
require enteral feeding via a weighted jejunostomy tube or temporary support with total parenteral
alimentation (TPN). Use of partial parenteral nutrition (PPN) or TPN may be necessary if vomiting is
persistent despite administration of metoclopramide (0.2 to 0.4 mg/kg, subcutaneously or intramuscularly,
every 8 hours or IV constant-infusion drip of 0.01 to 0.02 mg/kg/hr) or ondansetron (0.1 to 1.0 mg/kg
every 12 to 24 hours). Although PPN can be given through a peripherally placed long-line catheter, its use
is restricted to a 5- to 7-day interval. This interval may importantly limit the extent of lean body mass
catabolism during the initial treatment phase. However, after the first week, transition to an enteral
feeding method is recommended. TPN requires placement of a committed central catheter, is costly,
requires close monitoring, increases the risk of iatrogenic hemorrhage and septicemia, and may result in
enteric changes permissive to transmural microbial translocation. Therefore other modes of nutritional
support are more practical, are associated with fewer iatrogenic effects, and are advised.
Caloric intake should achieve at least 70 to 90 Kcal/kg/day optimal body weight in cats and for dogs
should at least meet values for resting energy requirements (99 body weight [kg],
0.67
70 body weight
[kg]
0.75
or 30 + weight [kg] + 70 body weight [kg]). Although adding an illness factor (a constant that
estimates energy needs above resting energy requirements) is commonly recommended, these factors have
been empirically devised (1.2 to 1.6 times resting energy requirements for illness).
Vitamins, Antioxidants, and Conditionally Essential Nutrients
Water-soluble vitamins should be provided at a doubled conventional daily dose, whether the patient is
eating or not, because they are necessary for intermediary metabolism. Antioxidants in the form of
vitamin E and thiol donors (N-acetylcysteine, 140 mg/kg IV; dilute 10% solution 1:1 in saline, administer
through a 0.2 mm filter; subsequent dosing at 70 mg/kg IV up to every 6 hours; or S-adenosylmethionine
20 mg/kg enteric-coated tablets on an empty stomach, orally, once a day) may be advantageous. This
dosage has not been proven but is supported by disease modeling. Furthermore, research shows that
spontaneous necroinflammatory and cholestatic liver disease in the dog and cat are associated with a risk
of low hepatic glutathione (GSH) concentrations. (GSH is the major intracellular thiol antioxidant with
pivotal importance in the liver, which provides GSH precursors for use elsewhere in the body.)
28
Supplementation with L-carnitine has been shown to facilitate hepatocellular regenerations in the
circumstance of severe hepatotoxicity; in this capacity, increased facilitation of fatty acid oxidation may
assist in cell recovery and repair.
29
Comparable studies in the dog and cat have not been undertaken,
although L-carnitine has been proven to increase the metabolic utilization of fatty acids for energy
production in healthy cats.
25
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Antibiotics
Antibiotics for hepatobiliary infections should possess relevant activity against enteric organisms commonly
cultured from liver tissue and bile (see Tables 90-1 to 90-6).*.
Culture and susceptibility of involved organisms remains the best measure for correct antibiotic selection.
Cytologic evaluation of each sampled tissue and bile may importantly contribute to identification of
infectious agents because a positive culture result may be denied by prior antibiotic therapy or mechanistic
factors interfering in organism growth in vitro. Using a simple Wright-Giemsa's staining procedure,
infectious organisms that are difficult to visualize on routinely prepared histologic specimens may be readily
apparent. Bacterial morphology, including Gram stain characteristics, assists in selecting the initial course of
antimicrobial therapy (seeTables 90-2 to 90-4)..
Satisfactory and clinically effective biliary excretion of many antibiotics is achieved in an unobstructed
biliary system.
163,164
Although selection of an antimicrobial having good penetration into the biliary tract
seems logical (Table 90-6),
145,170
the achieved systemic activity may be most important. Preventing
bacteremic dissemination from the biliary tree to the systemic circulation requires that serum antimicrobial
concentrations achieve effective plasma levels against involved microorganisms, especially aerobes.
Antibiotics with good serum but poor biliary concentrations have proven efficacy in this scenario, preventing
both systemic dispersal and infection of surgical wounds. Use of antibiotics achieving lower relative serum
and yet good biliary levels may not afford comparable protection.
90
Such drugs may not achieve effective
concentrations in bile in the face of cholestasis, particularly considering that the minimum inhibitory
concentration of an antibiotic for a particular microorganism may be many fold higher in bile versus serum.
Although antibiotic prophylaxis cannot likely prevent bacterial invasion in the face of bile stasis, antibiotics
protecting against systemic infection are essential before surgical manipulations in which bacteremia, local
trauma, and infection are unavoidable.
163
Although antibiotics administered during EHBDO do not attain
therapeutic concentrations in bile because of the cessation of bile flow, it has been proven in animal models
and humans with EHBDO that achieving a critical therapeutic plasma concentrations of an effective
antimicrobial before surgical manipulations protects against septicemia and endotoxemia. To eradicate
biliary tree infection in EHBDO successfully, bile flow must be reinstated by removing the obstruction or by
creating a biliary-enteric anastomosis. This augments removal of infectious organisms by the responsive
choleresis concurrent with delivery of the antimicrobial into the biliary compartment. Immunocompromised
patients and those with uncorrectable diffuse disease involving the intrahepatic biliary tree (e.g., certain cats
with cholangitis causing destruction of small to medium sized bile ducts) will maintain a chronic
predisposition for hepatobiliary infection.
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Table 90-6 Achieved Biliary Concentrations of Certain Antimicrobial Agent in
the Absence of Major Bile Duct Occlusion
a,3,107
ANTIMICROBIAL AGENT RATIO OF ANTIBIOTIC BILE/SERUM
Aminoglycosides
Amikacin 0.3
Gentamicin 0.30.6
Kanamycin 1
Streptomycin 0.43.0
Cephalosporins
Cefazolin (first generation) 0.33.0
Cephalothin (first generation) 2.2
Cefoxitin (second generation) 2.8
Ceftriaxone (third generation) 25
Penicillins
Natural Penicillin
Penicillin G 5.0
Penicillinase resistant
Oxacillin >1.0
Nafcillin >100
Aminopenicillins
Ampicillin 1.030
Amoxicillin 130
Amoxicillin, clavulanate 130
Antipseudomonal Penicillins
Piperacillin 1060
Mezlocillin 1060
Ticarcillin NA
Imipenem Minor
Tetracyclines
Tetracycline 232
Doxycycline 232
Miscellaneous
Chloramphenicol 0.21
Clindamycin 2.53
Ciprofloxacin 2.84.5
Erythromycin 825
Metronidazole 1
Trimethoprim/sulfonamide 12/0.40.7
Vancomycin 0.5
a Data derived from experimental literature and from work in human beings.
In the absence of culture and susceptibility, or morphologic features of involved organisms, antimicrobial
treatments should cover aerobic and anaerobic enteric opportunists. A combination of drugs is required.
-lactamaseresistant penicillin, clindamycin, or metronidazole is given IV as a good first-choice antibiotic
for anaerobic organisms. The dose of clindamycin and metronidazole is adjusted for cholestasis and severe
hepatic dysfunction; see later discussion. One of these drugs is used in combination with either an
aminoglycoside or a fluorinated quinolone (e.g., enrofloxacin, orbifloxacin) to achieve efficacy against
aerobic gram-negative organisms. Aminoglycosides should not be given until the patient's hydration status
and prerenal azotemia are corrected. Aminoglycoside nephrotoxicity should be monitored by examining
urine sediment for granular casts on at least an alternate-day schedule.
CHAPTER 90 Hepatobiliary Infections Page 43 of 47
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Antibiotics that require extensive hepatobiliary activation, biotransformation, or excretion or those that have
been associated with adverse effects on the hepatobiliary system are considered poor first-choice selections
when liver function is compromised. These drugs include hetacillin, tetracycline, doxycycline, lincomycin,
erythromycin, sulfonamides, trimethoprim-sulfonamide, and chloramphenicol. Severe jaundice argues
against using antibiotics excreted predominantly in bile and that undergo enterohepatic circulation; examples
include chloramphenicol, erythromycin, doxycycline, rifampin, clindamycin, and nafcillin. Use of such drugs
in the face of reduced liver function, especially overt jaundice, necessitates reduction of conventional dosing
usually by as much as 50% (Table 90-7).
3,9
Consultation with a comprehensive pharmaceutical reference is
recommended before adjusting drug doses.
4,146
Tetracyclines are best avoided unless specific therapy is
indicated (e.g., rickettsial infections, clearing leptospirosis) because of their inhibitory influence on egress of
triglycerides from the hepatocyte (promotes hepatic lipid accumulation in all species studied) and because
tetracyclines have experimentally induced hepatic encephalopathy in dogs with portosystemic shunts. When
circumstances warrant using contraindicated drugs, Table 90-6 should be consulted for cases in which
recommendations have been derived from multiple references pertinent to humans, considering the lack of
information for animals.
Table 90-7 Influence of Hepatic Disease on Disposition of Selected
Antimicrobials in Humans with Severe Hepatic Disease,
Insufficiency
3, 9
ANTIBACTERIALS PLASMA CLEARANCE VOLUME OF DISTRIBUTIONHALF-LIFE
Amikacin 200% No change
Ampicillin No change 46%200% 30%45%
Carbenicillin 90%
Cefoperazone 040% 150% 200%
Cefotaxime 30%40% Increased
Chloramphenicol 65%70% 20% 130%150%
Clindamycin 25%60% 40% 15%40%
Erythromycin 30% 50% 60%65%
Gentamicin No change 85%
Metronidazole No change No change 40%150%
Mezlocillin 50% 170%
Norfloxacin No change No change
Pefloxacin 70% 20% 255%
Vancomycin 70% No change 130%
Prophylactic treatment with a best-guess antimicrobial combination is recommended for biliary obstruction
and known or suspected bacterial infection, both before and during surgery. Given that this approach
diminishes the ability to culture involved organisms from surgical specimens, presurgical hepatic-bile
aspiration and preparation of bile and tissue imprints for cytologic evaluation (including Gram staining)
becomes imperative. Antibiotic administration is necessary until biliary tree obstruction and cholestasis have
been eliminated (e.g., when EHBDO or specific infection of the biliary tree has been resolved) or may be
continued as part of chronic medical therapy.
Bacterial enteric translocation is known to be reduced by long-term administration of antibiotics suppressing
aerobic intestinal flora. In humans, fluorinated quinolones are used most often for this purpose in cirrhosis.
Predisposition to enteric bacterial translocation during surgery (e.g., cholestasis, chronic liver disease) is also
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diminished in humans by orally administered neomycin, fluoroquinolones, polymyxin B, or tobramycin. This
effect has not been studied in veterinary patients.
* References: 3, 4, 9, 50, 145, 146, 160, 161
References: 3, 4, 9, 24, 50, 145, 146
Probiotics And Nondigestible Carbohydrates
An alternative nonantibiotic approach, microbial interference therapy, is receiving greater attention in human
medicine owing to the increasing appearance of antibiotic-resistant enteric microorganisms. Such therapy
involves maintaining or restoring health by introducing live nonpathogenic microorganisms from a probiotic to
ostensibly stabilize the balance of intestinal flora. This concept is based on experimental work indicating that
certain probiotics can reduce intestinal bacterial overgrowth, improve local immunologic host defenses,
increase enteric and splanchnic neutrophil phagocytic function, inhibit enterovirulence of natural gut microbes,
and reduce enteric bacterial translocation (modeled in rodents). Consequently, probiotics are claimed to reduce
the risk of spontaneous infection in patients with chronic liver disease associated with portal hypertension,
ascites, and cholestasis.
Bacteria considered host beneficial include bifidobacteria, eubacteria, and lactobacilli; and when these are
combined with a fermented carbohydrate, they are referred to as liver probiotics. Whether they provide a
reliable benefit remains controversial. Lactobacilli are considered an integral part of normal enteric
microecology and have received the greatest investigation. These organisms have been capitalized on for their
demonstrated effects on local enteric flora, immune response, and host metabolism. Adherence of lactobacilli to
enterocyte receptors can induce expression of genes coding for variants of intestinal mucins that inhibit
adherence of enteropathogens (e.g., E. coli).
105
They also produce antimicrobial effects through production of
bacteriocin and metabolic end products, demonstrated in animals and humans. However, an important point to
recognize is that different lactic acid bacterial strains have very different probiotic effects such that results
obtained with a single strain cannot be universally expected for all others. Although use of probiotics to reduce
opportunistic gram-negative and anaerobic enteric microorganisms is widely proposed, benefits remain
controversial, and a risk of probiotic organisms achieving opportunistic hepatic or systemic infections
exists.
136,148
Experimental evidence and limited information in humans with liver disease suggest that certain probiotics may
have a prophylactic and therapeutic effect on hepatic encephalopathy and predisposition of patients with acute
hepatic failure or necrosis to endotoxemia or sepsis. They also may beneficially modulate enteric inflammation
co-existent with liver disease. Nondigestible carbohydrates that serve as fermentable microbial energy
substrates are commonly used to ameliorate clinical signs of hepatic encephalopathy. These substances
encourage bacterial nitrogen fixation, acidify the colonic lumen, modulate mucosal and microbial protease
activity, and produce a cathartic effect (from osmotic solute production) useful for controlling SIBO and
eliminating enteric toxins and ammonia, contributing to hepatic encephalopathy. They may also ameliorate
endotoxemia through modifying the enteric microbial ecosystem, reducing the enteric bacterial pool size, or
through a direct antiendotoxic effect.
37,103,149
In this regard, lactulose is the prototype nondigestible
carbohydrate.
45
Oral or rectal administration of lactulose has been proposed as an alternative means of
modulating bowel flora, which may reduce postoperative sepsis. Probiotics combining the benefit of a poorly
digested carbohydrate (by the mammalian host) and a beneficial microbial organism also are available. Many of
these probiotics likely provide a variety of effects, but none have proven efficacy.
37
Based on experimental
work, combined administration of a probiotic and antioxidants may significantly alter pathologic changes,
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encouraging enteric bacterial translocation, by altering the concentration of enterobacteria and enterococci in
the lower bowel, reducing peroxidative bowel wall damage, and reducing endotoxin translocation. Increased
intestinal oxidative damage and bacterial translocation are observed in rats with prehepatic portal hypertension
and EHBDO. Oxidative bowel damage is associated with slow enteric transit time in several experimental
models and has been implicated as a cause of SIBO in cirrhotic humans.
30,130
Proclivity for enteric bacterial
translocation (using this model) is reduced with a variety of antioxidants, including vitamin C, vitamin E,
allopurinol (50 mg/kg twice weekly), and glutamine (1 gm/kg per day) as a means of promoting enterocyte
metabolism and cell size.
32,150,151
Surgery
Laparotomy may be required to alleviate the source of hepatobiliary sepsis. Surgical intervention becomes
imperative when hepatobiliary abscesses cannot be effectively managed by US-guided drainage and
antimicrobial therapy and in the circumstances of septic peritonitis, bile peritonitis, or major bile duct
occlusion. Hepatic or bile aspirate or biopsy is the only definitive method of confirming an infectious
process. Biopsy of the liver and involved biliary structures is required for definitive diagnosis of underlying
disease. At surgery, the abdominal viscera should be inspected for a primary disease process. Mesenteric and
hepatic lymph nodes should be visualized and biopsy specimens taken for histologic evaluation and culture,
especially if a primary diagnosis remains uncertain. Liver specimens from one or more sites should be
sampled to ascertain disease local to the obvious disease process and to determine whether diffuse liver
disease preceded or evolved from the current condition. If entire lobes of liver appear involved in an abscess
or appear necrotic, they should be resected. Infarcted or devitalized areas should be manipulated minimally
before resection. Venous outflow from such tissue should be ligated as early in resection as possible to avoid
systemic dispersal of noxious substances (e.g., endotoxin, bacterial products, infectious organisms). The
biliary tract should be evaluated for patency by gentle compression of the gallbladder and bile fluidity and
flow determined. The gallbladder and major bile ducts should be carefully palpated for choleliths,
intraluminal or mural masses, and sludged bile. If abnormalities are detected, a cholecystotomy should be
done, a biopsy of the gallbladder taken, and any abnormalities inspected and removed. Biliary mucocele
requires gallbladder resection and removal of tenacious bile from the cystic and major bile ducts.
Extrahepatic bile ducts should be flushed with sterile saline using a soft catheter to remove choleliths and
sludged bile, taking care to avoid peritoneal contamination. In some cases, sludged bile may require
mechanical removal using forceps or a curette. Cholecystectomy is necessary if the gallbladder wall appears
devitalized or involves a suspected neoplasm.
Samples of tissue and bile should be cultured for aerobic and anaerobic organisms. Bile for culture and
cytology should be collected by fine-needle (22-gauge) aspiration into a syringe. The needle should enter the
gallbladder at an oblique angle to reduce postaspiration bile leakage. Using a large syringe and aspirating the
entire volume of bile minimizes postaspiration bile leakage. If cholecystitis or cholangitis is suspected,
biopsy and culture of a portion of the gallbladder wall and liver increases the chance of identifying the
infectious agent. Choleliths also should be submitted for culture.
Cytologic smears should be made from each tissue biopsied and from bile to permit morphologic
characterization of infectious agents and to achieve early recognition of neoplasia. Strict attention must be
paid to the methods of handling and transporting specimens for anaerobic bacterial cultures (see Chapter 33).
Gram staining of tissue and bile imprints guides selection of initial antibacterial therapy. Cytologic
evaluation serves as an important quality control indicator of transport and culture procedures. If organisms
are identified on smears made at surgery and yet are not grown, transport or culture methods were probably
inadequate unless antimicrobial therapy is a complicating factor. If trematode infection is possible, bile and
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Infectious Diseases of the Dog and Cat, 3rd Edition
feces should be examined cytologically for trematode eggs. Hepatic tissue should always be submitted for
routine histologic evaluation, and the pathologist should be prompted to examine tissues for infectious agents
with special stains.
Hydrocholeresis
After establishing patency of the biliary tract, hydrocholeresis can improve bile flow in patients with
resolved extrahepatic cholestasis, cholelithiasis, or inspissated bile. Hydrocholeresis also improves
mechanical removal of infectious organisms involved in diffuse septic cholangitis. Resolution of bile stasis
assists in clearing biliary infection and reduces the potential for further stone formation. Ursodeoxycholic
acid (see Table 90-5) is used as a long-term therapeutic agent in patients with persistent cholestatic liver
injury. Choleresis is provided in conjunction with maintaining adequate patient hydration, which optimizes
the hydrocholeretic response. In addition to choleresis, ursodeoxycholic acid also provides a large number of
advantageous effects beneficial to chronic cholestatic and necroinflammatory liver disorders (i.e., it has
immunomodulatory, cytoprotective effects for the hepatocyte and biliary epithelium, a choleretic influence,
antiendotoxic, antioxidant, and antifibrotic effects, and importantly, attenuates accumulation of
membranocytolytic bile acids in bile, hepatic tissue, and plasma).
Suggested Readings
*
* See the CD-ROM for a complete list of references.
147. Savary-Bataille, KC, Bunch, SE, Spaulding, KA, et al.: Percutaneous ultrasound-guided
cholecystocentesis in healthy cats. J Vet Intern Med. 17(3), 2003, 298303.
177. Vrs, K, Sterczer, A, Manczur, E, et al.: Percutaneous ultrasound-guided cholecystocentesis in
dogs. Acta Vet Hung. 50(4), 2002, 385393.
Uncited references
39. Cole, TL, Center, SA, Flood, SN, et al.: Diagnostic comparison of needle and wedge biopsy
specimens of the liver in dogs and cats. J Am Vet Med Assoc. 220, 2002, 14831490.
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