Cholangitis is an infection of the biliary tract with the potential to cause significant morbidity and mortality. Many patients with acute cholangitis respond to antibiotic therapy; however, patients with severe or toxic cholangitis may not respond and may require emergency biliary drainage. Jean M. Charcot recognized this illness in 1877 when he described a triad of fever, jaundice, and right upper quadrant pain.[1] In 1959, Reynolds and Dargon described a more severe form of the illness that included the additional components of septic shock and mental confusion, which is referred to as the Reynolds pentad.[1]
Historically, choledocholithiasis was the most common cause of biliary tract obstruction resulting in cholangitis. Over the past 20 years, biliary tract manipulations/interventions and stents have reportedly become more common causes of cholangitis. Hepatobiliary malignancies are a less common cause of biliary tract obstruction and subsequent bile contamination resulting in cholangitis.[2]
The two main causes of cholangitis are common bile duct stones and biliary tract manipulation.[3] In patients with a stent in situ, cholangitis indicates stent block and need for change. Other possible causes of biliary tract obstruction that may lead to infection include strictures, tumors, choledochal/biliary cysts, or sump syndrome. Hepatolithiasis is also a possible cause of cholangitis[4] and is observed more frequently in East Asia. More than 90% of patients with hepatolithiasis have calcium bilirubinate stones, also referred to as brown pigment stones. Worms (eg Ascaris, Clonorchis) in the biliary tract can also cause cholangitis. Cholangitis in patients with a biliary-enteric anastomosis (eg, hepatico-jejunostomy or a bilio-biliary anastomosis) after liver transplant indicates anastomotic stricture.
Cholangitis is reported in all races. One variant, Asian cholangitis (also referred to as Oriental cholangio-hepatitis [OCH] or recurrent pyogenic cholangitis [RPC]), is observed with increased frequency in Southeast Asia.[5]
The condition is reported in both females and males and has no clear predominance in either.
It mostly occurs in adults, with a reported median age at onset of 50-60 years. In neonates, extrahepatic biliary atresia (EHBA) is a cause of cholangitis. In children and young adults, choledochal cyst can cause cholangitis.
The prognosis is usually guarded, although it improves with early antibiotic treatment and appropriate drainage and decompression of biliary tract as needed. Factors reportedly associated with a poor prognosis include old age, female sex, acute renal failure, preexisting cirrhosis, and malignant biliary obstruction.
The mortality rate of acute cholangitis ranges from 5-10%, with a higher mortality rate in patients who require emergency biliary decompression or surgery.
Cholangitis has significant potential for mortality and morbidity, especially if left untreated. Reported mortality rates have been as high as 88% for untreated cholangitis.
Complications include pyogenic liver abscess, cholangiolytic abscess (usually small and multiple) in the liver, longstanding recurrent cholangitis (eg, Asiatic cholangitis), and acute renal failure. Longstanding recurrent cholangitis can cause secondary biliary cirrhosis (SBC), portal hypertension, and liver failure.[6]
A history of choledocholithiasis or recent biliary tract manipulation associated with fever (often with chills and rigors), abdominal (right upper quadrant) pain, and jaundice (the Charcot triad) is highly suggestive of cholangitis. Fever reportedly occurs in nearly 95% of patients with cholangitis. Approximately 90% of patients have right upper quadrant tenderness, and 80% have jaundice.
According to Fujii et al, the 2007 Tokyo guidelines for the diagnosis and treatment of acute cholangitis were mostly acceptable.[7] However, classification into mild or moderate grade using the guidelines could be challenging, so it was necessary for clinicians to carefully distinguish organ dysfunction associated with cholangitis itself from dysfunction associated with the underlying disease in determining the severity of the disease.[7]
Similarly, Nishino et al found that the 2013 Tokyo guidelines for the diagnosis and treatment of acute cholangitis are practical, but they may underestimate some cases that necessitate urgent/early biliary drainage as mild disease.[8] The investigators developed a scoring system that took into consideration the following five predictors, which they indicate may improve identification of patients at high risk of needing urgent/early biliary drainage[8] :
Physical examination may reveal fever, icterus, jaundice, and abdominal tenderness.
Note the following:
Imaging modalities include abdominal ultrasonography and abdominal computed tomography (CT) scanning.[10]
The diagnosis of the cause of cholangitis can be made on magnetic resonance cholangiography (MRC) as it is noninvasive and involves no exposure to radiation, but diagnostic and therapeutic (drainage of the biliary system) modalities include endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography (PTC).
MRC is preferred before ERC or PTC, as it indicates the level of the block (eg, high or low) and the patency of the biliary ductal confluence; this helps in the selection of the therapeutic procedure for drainage of the biliary system (ie, ERC for low blocks and PTC for high blocks with confluence but not patency).
Administration of broad-spectrum intravenous antibiotics and correction of fluid and electrolyte imbalances constitute essential medical care for cholangitis.[11, 12] Patients should take nothing by mouth in the acute stage of cholangitis. Accomplish hydration with intravenous fluids.
Vitamin K or fresh frozen plasma (FFP) may be used for correction of coagulopathy, when needed.
Note the following:
Obtain consultations with the following specialists in a timely manner:
Consider maintenance therapy/antibiotics (ie, sulfamethoxazole and trimethoprim [SMZ-TMP] or a fluoroquinolone) for patients with recurrent cholangitis.
It has been reported that prophylactic antibiotics do not prevent endoscopic retrograde cholangiopancreatography (ERCP)-induced cholangitis significantly in unselected patients, and these agents should not be routinely recommended for this reason.[15]
Endoscopic or percutaneous biliary drainage and decompression have usually replaced surgery as the initial treatment of severe cholangitis. Surgical decompression in the form of T-tube drainage of the common bile duct (CBD) (choledochostomy) is appropriate for patients in whom endoscopic or transhepatic drainage is unsuccessful or unavailable. This can be performed laparoscopically also.
Following adequate biliary drainage and decompression for acute cholangitis with bacteremia, Park et al found no significant differences in the recurrence of acute cholangitis and 30-day mortality between early switch to oral antibiotic therapy and standard 10-day intravenous antibiotic therapy.[16]
Definitive management depends on the underlying cause (eg, removal of CBD stones, resection of tumor, excision of choledochal cyst, percutaneous balloon dilatation, and stenting of anastomotic stricture). Cholangitis, however, must be controlled before the patient undergoes operative intervention. In the case of an unresectable cancer, definitive palliation can be achieved with placement of self-expandable metal stents (SEMS) which remain patent over a long period (eg, plastic stents).
In March 2018, the British Society of Gastroenterology/UK-PBC released guidelines for the treatment and management of primary biliary cholangitis.[17] These guidelines build from previous guidelines from the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD).
Recommend that any patient with persistently elevated cholestatic liver biochemistry (raised alkaline phosphatase [ALP] or gamma-glutamyl transferase [GGT]) without an alternative cause should have autoantibodies checked for anti-mitochondrial (AMA) and anti-nuclear (ANA) reactivity.
The presence of antimitochondrial antibodies (>1 in 40) or highly primary biliary cirrhosis (PBC)-specific antinuclear antibodies, in the appropriate context of cholestatic liver biochemistry, without alternative explanation, is usually sufficient for confidently reaching the diagnosis of PBC.
All patients with PBC should be offered structured life-long follow-up, recognizing that different patients have different disease courses and may require different intensity of follow-up.
Risk assessment should evaluate disease severity and activity at baseline and on treatment. We recommend a combination of serum liver tests (to identify those with an elevated bilirubin, a platelet count < 150, or biochemical disease activity on treatment), imaging (liver ultrasound to identify overt cirrhosis and splenomegaly; transient elastography (to identify increased liver stiffness), recognition of young age at disease onset (< 45 years), and male sex.
To identify those at greatest risk of disease progression, we recommend that all patients have individualized risk stratification using biochemical response indices following 1 year of ursodeoxycholic acid (UDCA) therapy. We suggest that UDCA-treated patients with an ALP >1.67 × upper limit of normal (ULN) and/or elevated bilirubin < 2 × ULN represent a group of high-risk patients in whom there is randomized controlled trial evidence for the addition of second-line therapy.
Recommend oral UDCA at 13–15 mg/kg/day be used as the first-line pharmacotherapy in all patients with PBC. If tolerated, treatment should usually be life-long.
In patients with inadequate response to UDCA (or UDCA intolerance) as defined by ALP >1.67 × ULN and/or elevated bilirubin < 2 × ULN, the addition of obeticholic acid (OCA) has been associated with improvements in biochemical surrogates of disease activity reasonably likely to predict improved outcomes. We therefore recommend, in keeping with the National Institute for Health and Care Excellence (NICE) evaluation of OCA, that the addition of OCA for patients with an inadequate response to UDCA, or intolerant of UDCA, is considered. We recommend dose adjustment in patients with advanced liver disease as per the drug label.
Recommend that all patients be evaluated for the presence of symptoms, particularly fatigue and itch. Clinicians should recognize that severity of symptoms does not correlate with stage of disease.
True overlap with autoimmune hepatitis is probably rare, and we suggest that, when suspected, liver biopsy with expert clinicopathologic review is needed to make the diagnosis and guide treatment.
Recommend that patients with PBC be offered the chance to seek support from patient support groups.
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Possible antibiotic treatments include penicillin derivatives (eg, piperacillin) or a second- or third-generation cephalosporin (eg, ceftazidime) for gram-negative coverage, ampicillin for gram-positive coverage, and metronidazole for anaerobic coverage. Some researchers have reported use of fluoroquinolones (eg, ciprofloxacin, levofloxacin) as effective therapy.
The selection and dosing of appropriate antibiotics and other medications listed below or from another source must be performed by the patient's primary physician and gastroenterologist based on history and clinical presentation.
Clinical Context: Inhibits biosynthesis of cell wall mucopeptides and the stage of active multiplication; has antipseudomonal activity.
Clinical Context: Third-generation cephalosporin with broad-spectrum, gram-negative activity; lower efficacy against gram-positive organisms; higher efficacy against resistant organisms. Arrests bacterial growth by binding to one or more penicillin-binding proteins.
Clinical Context: Bactericidal activity against susceptible organisms.
Clinical Context: Imidazole ring-based antibiotic active against various anaerobic bacteria and protozoa.
Clinical Context: Fluoroquinolone with activity against Pseudomonas species, streptococci, MRSA, Staphylococcus epidermidis, and most gram-negative organisms but no activity against anaerobes. Inhibits bacterial DNA synthesis and, consequently, growth.
Clinical Context: For pseudomonal infections and infections due to multidrug-resistant gram-negative organisms.
Beta lactam and beta lactamase inhibitor (BL + BLI) combinations (eg, ampicillin + sulbactam, amoxicillin + clauvulanic acid, cefoperazone + sulbactam, piperacillin + tazobactam) may be indicated in the presence of extended-spectrum beta lactamase (ESBL)-producing organisms.
Initial empiric antimicrobial therapy must be comprehensive and should cover both aerobic and anaerobic gram-negative organisms.
Clinical Context: Promotes liver synthesis of clotting factors that in turn inhibit warfarin effects.
Clinical Context: Plasma is the fluid compartment of blood containing the soluble clotting factors. Indications for using FFP include bleeding in patients with congenital coagulation defects and multiple coagulation factor deficiencies (severe liver disease).
Vitamin K or fresh frozen plasma (FFP) may be used for correction of coagulopathy when needed.