Biliary Disease

by Dan O’Brien

Introduction

The biliary system can be defined as the organs and ducts that create, transport and store bile and eventually release it into the duodenum. The system includes the bile ducts both inside and outside the liver, the gallbladder, and the biliary sphincter. The biliary disease is the result of altered bile composition, biliary anatomy or function. Bile, a complex mixture of bile acids and salts, phospholipids, pigments water, and electrolytes, is produced by the liver, channeled to the gallbladder where it is concentrated and stored. When a meal is eaten, bile is released into the duodenum through the sphincter of Oddi to emulsify and promote the absorption of fats and fat-soluble vitamins. Also, waste products, including bilirubin, are eliminated. Enterohepatic circulation allows a majority of bile salts to be reabsorbed from the terminal ileum and be transported back to the liver for recycling.

The most common form of the biliary disease is gallstone disease. Gallstones affect 10%-15% of the adult population. They are composed of cholesterol stones, pigmented or bilirubin-based stones or a mixture of both. There are regional variations on which predominate. Pigmented stones are more common in Asia and cholesterol stones predominate in the West. The vast majority of patients with gallstones remain asymptomatic, and they are often discovered incidentally on diagnostic imaging for other indications. Gallstone disease is responsible for less than two-percent of surgical deaths recorded and those who die to tend to be elderly and those with significant co-morbidities. However, even though there is only a 1% to 4% per year chance of developing symptoms or complications, given the incidence of gallstones in the general population it is a common complaint in the emergency department.

Case Presentation

A 35-year-old woman presents to the emergency department with right upper quadrant pain of two hours duration. She awoke several hours after eating a large meal. Based on increasing pain and nausea she presents for evaluation. She denies vomiting, fever or dysuria. Her past history is notable for diet-controlled type II diabetes, dyslipidemia, and essential hypertension. Her BMI is 33. Her only medication is lisinopril 10 mg daily. She has never had surgery. Her social history is unremarkable. She neither drinks alcohol nor uses tobacco. She has begun to diet and reports recent weight loss.

Her temperature is 37ºC, blood pressure: 110/70 mmHg, pulse: 90 beats per minute. Physical exam reveals an overweight female in mild distress secondary to right upper quadrant pain. She cannot find a position of comfort and describes the pain as similar to labor pains. Pertinent exam findings include: chest exam normal, cardiac exam normal, abdominal exam demonstrates normal bowel sounds and no rebound in any quadrant. She has guarding to inspiration with palpation over the gallbladder (positive Murphy’s sign). Rectal exam normal, stool is hemoccult negative for blood. Pertinent lab values: glucose 110 mg/dl, alkaline phosphatase 120 U/L, alanine aminotransferase (ALT) 25 U/L, aspartate aminotransferase (AST) 25 U/L, gamma glutamyl transferase (GGT) 20 U/L, direct bilirubin 0.1 mg/dL, total bilirubin 0.5 mg/dL, lipase 20 U/L.

The emergency physician performs a focused right upper quadrant ultrasound and finds gallstones without associated gallbladder wall thickening or pericholecystic fluid. In addition, the patient has a “sonographic Murphy sign”: there is maximal abdominal tenderness when the ultrasound probe is pressed over the visualized gallbladder.

An IV was established, and the patient received an isotonic fluid bolus. In addition, ketorolac 30 mg IV and ondansetron 4 mg IV were administered. Over the course of an hour symptoms resolved. Absent evidence of gallbladder inflammation or infection, she was discharged from the emergency department and referred to a general surgeon for elective cholecystectomy. She was advised that her pain might return but if it is prolonged, is associated with fever or jaundice she is to return to the emergency department.

Critical Bedside Actions and General Approach

Abdominal pain is a common complaint in the emergency department and can be challenging to diagnose. Presenting illnesses may range from benign self-limited diseases to true surgical emergencies. The priority is to assess the stability of the patient. Use history, the likelihood of disease, vital signs, and the physical exam to assist in determining whether a patient may have a serious illness or surgical emergency. For example, a sudden onset of tearing pain radiating to the back in an older patient with a history of hypertension may suggest a dissecting abdominal aortic aneurysm, but the colicky pain associated with abdominal distention may suggest bowel obstruction. Fever, protracted vomiting, syncope or gastrointestinal blood loss should all raise the suspicion of serious illness. In addition, it is important to exclude pregnancy and its complications in any woman of childbearing years who presents with abdominal pain. In this case, the patient had classic biliary colic and documented gallstones. The pain was due to crystals or a small stone passing and or blocking the cystic duct. Based on the resolution of pain, the absence of abnormalities on ultrasound exam such as pericholecystic fluid or wall thickening, and normal laboratory values it would be safe to discharge this patient for elective cholecystectomy. During the course of the management, it is very important to differentiate critical situations from uncomplicated gallbladder disease. In addition, the physicians should think early pain medication to comfort the patient.

Differential Diagnosis

Pain in the right upper quadrant can be of biliary origin including cholelithiasis: gallstones without inflammation, cholecystitis: inflammation or infection of the gallbladder wall, or cholangitis: inflammation or infection of the biliary ducts. Pancreatitis independent of, or as a consequence of gallstone obstruction of the common biliary duct, choledocholithiasis, may present in a similar fashion as well. Hepatitis, gastritis, dyspepsia, peptic ulcer disease are other potential gastrointestinal causes of right upper quadrant pain. Appendicitis, especially in pregnant patients may present with symptoms of right upper quadrant pain. Non-abdominal diseases such as pneumonia or pleurisy on the right lung may present with right upper quadrant pain.

History and Physical Examination Hints

“A 35-year-old woman presents to the emergency department with right upper quadrant pain of two hours duration. She awoke several hours after eating a large meal. Based on increasing pain and nausea she presents for evaluation. She denies vomiting, fever or dysuria.Her past history is notable for diet-controlled type II diabetes, dyslipidemia, and essential hypertension. Her BMI is 33. Her only medication is lisinopril 10 mg daily. She has never had surgery. Her social history is unremarkable. She neither drinks alcohol nor uses tobacco. She has begun to diet and reports recent weight loss.”

Gallstones are two to three times more common in women, especially during childbearing years. The risk of also gallstones increases with age. Obesity or Body Mass Index (BMI) greater than 30 is associated with increased gallstone formation. Type II diabetes is associated with obesity, hyperlipidemia, and gallbladder hypomotility. Diabetic patients are at increased risk for pancreatitis as well. Diets low in fiber and high in carbohydrates and fat have been associated with gallstone formation. This may, in part, explain regional differences in gallstone formation.

“Her temperature is 37ºC, blood pressure: 110/70 mmHg, pulse: 90 betas per minute. Physical exam reveals an overweight female in mild distress secondary to right upper quadrant pain. She cannot find a position of comfort and describes the pain as similar to labor pains. Pertinent exam findings include: chest exam normal, cardiac exam normal, abdominal exam demonstrates normal bowel sounds and no rebound in any quadrant. She has guarding to inspiration with palpation over the gallbladder (positive Murphy’s sign). Rectal exam normal, stool is hemoccult negative for blood.”

Patients with biliary colic have moderate to severe right upper quadrant colicky pain without peritoneal signs. Although described as colic, the pain may be more constant as it is caused by an obstruction of bile flow with subsequent distention. Patients may appear restless and unable to find a comfortable position. Murphy’s sign (the sudden cessation of a deep inspiration when the inflamed gallbladder descends and reaches the examiners’ fingers palpating the right subcostal area) is 65% sensitive and 87% specific for acute cholecystitis. Fever is not typical, and jaundice is rarely seen unless there is obstruction of the common bile duct from choledocholithiasis or extrinsic compression due to mass or inflammation.

Emergency and Diagnostic Tests and Interpretations

Laboratory Tests

“Pertinent lab values: glucose 110 mg/dL, alkaline phosphatase 120 U/L, alanine aminotransferase (ALT) 25 U/L, aspartate aminotransferase (AST) 25 U/L, gamma glutamyl transferase (GGT) 20 U/L, direct bilirubin 0.1 mg/dL, total bilirubin 0.5 mg/dL, lipase 20 U/L.”

Alkaline phosphatase (ALP) is synthesized by the bile duct epithelial cells. Its production is stimulated by bile duct obstruction and is elevated in a majority of patients with cholestasis. However, isoenzymes are found in the liver, bone, placenta, small bowel and leukocytes; it is therefore not specific for the biliary tract.

Bilirubin is a breakdown product of heme. Unconjugated bilirubin is hydrophobic and is transported in the blood bound to albumin. It is taken up by the hepatocyte, conjugated, and actively secreted into the biliary tract. Cholestasis may elevate serum bilirubin.

The aminotransferases; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are found in the liver, cardiac and skeletal muscle, and cerebral nerve cells. Levels of these enzymes are typically only mildly elevated but may be markedly increased in cholangitis. ALT may briefly spike during acute obstruction, but it usually is not elevated unless there is secondary liver parenchymal damage. An AST level greater than the ALT level suggests alcoholic liver disease, cirrhosis or metastatic disease.
Gamma-glutamyl transpeptidase (GGT) is a membrane-bound peptidase that hydrolyzes peptides to amino acids and smaller peptides. Although serum activity is primarily from the liver, it is found in the renal proximal tubule, pancreas, and intestine. Its circulating half-life is usually 7-10 days but may increase to 28 days in alcohol-associated liver disease. The cholestatic disease may elevate GGT significantly. A complete white blood cell count, serum electrolytes, glucose renal function studies, and urinalysis, may assist in diagnosis and management.

Imaging Modalities

“The emergency physician performs a focused right upper quadrant ultrasound and finds gallstones without associated gallbladder wall thickening or pericholecystic fluid. In addition, the patient has a “sonographic Murphy sign”: there is maximal abdominal tenderness when the ultrasound probe is pressed over the visualized gallbladder.”

Plain radiography is often not helpful in assessing biliary stones as most do not contain enough calcium to be visible on plain x-ray. Plain imaging may be useful to identify gas in the biliary tree or evidence of intestinal obstruction.

X-ray shows relatively normal findings in a RUQ and abdominal pain patient. The CT scan of the same patient is shown below. It revealed cholecystitis.

Ultrasound imaging of the right upper quadrant is the principal study used to evaluate biliary-type pain and detect gallbladder disease and biliary dilatation.

There are several sonographic criteria for acute cholecystitis;

the presence of gallstones,
thickened gallbladder wall,
pericholecystic fluid,
sonographic Murphy’s sign,
common duct dilatation.

In acute cholecystitis, gallstones are present in 95-99% of cases. Emergency physicians, performing focused, limited bedside ultrasound and taking into account the context of the patient’s history and clinical picture have documented a sensitivity of 90-96%, a specificity of 88-96% as well as a positive predictive value of 88-99% and a negative predictive value of 73-96% for cholecystitis.

CT imaging is not nearly as helpful as the right upper quadrant ultrasound in evaluating the biliary system for evidence of cholecystitis. Gallstone sensitivity is about 75%, and common duct stones may be missed. It may be helpful to reveal complications of cholecystitis such as gangrenous or emphysematous cholecystitis as well as to exclude other pathologies in the abdomen.

Emergency Treatment Options

“An IV was established, and the patient received an isotonic fluid bolus. In addition ketorolac, 30 mg IV and ondansetron 4 mg IV were administered. Over the course of an hour symptoms resolved. Absent evidence of gallbladder inflammation or infection she was discharged from the emergency department and referred to a general surgeon for elective cholecystectomy. She was advised that her pain might return but if it is prolonged, is associated with fever or jaundice she is to return to the emergency department.”

Asymptomatic gallstones do not require any treatment. Most remain asymptomatic for years after diagnosis. About 1-2% may become symptomatic annually.

Biliary colic or biliary pain typically has a definitive onset with a duration ranging from 15 minutes to up to four hours. Antiemetics and nonsteroidal anti-inflammatory drugs (NSAIDs) are first-line therapies. In fact, studies suggest that NSAIDs have similar efficacy as opioids with fewer complications. Opioids may be used to control pain. Although there were historical concerns about morphine causing greater sphincter of Oddi spasm relative to other opioids, all opioids to some degree increase sphincter of Oddi pressure and biliary pressure. If a patient’s pain is resolving and controlled with oral agents, they may be discharged and referred to a general surgeon for consideration of elective laparoscopic cholecystectomy.

Acute cholecystitis is best managed in the hospital with surgical consultation. Early laparoscopic cholecystectomy is often the treatment of choice. Patients should be given nothing by mouth. About 20% of patients develop gallbladder or biliary duct infection. Appropriate antibiotics regimens include second- and third-generation cephalosporins, carbapenems, ß-lactam/ß-lactamase inhibitor combinations or a combination of metronidazole and a fluoroquinolone. Most patients will improve over 24 to 72 hours before surgical intervention.

Cholangitis, an infection of the bile duct, is a life-threatening disease that requires aggressive resuscitation, timely antibiotics, and early drainage via either endoscopic retrograde cholangiopancreatography (ERCP) guided sphincterotomy or stent placement or percutaneous drainage to stabilize the patient prior to definitive surgery.

Pediatric, Geriatric, Pregnant Patient and Other Considerations

None other than mentioned above.

Disposition Decisions

Admission

Patients with suspected cholecystitis or cholangitis should be admitted to the hospital. For suspected cholangitis, emergency consultation, and if need be, transfer to a facility that can emergently establish biliary drainage either via ERCP-guided sphincterotomy or percutaneous stenting.

Discharge

Patients with biliary colic may be discharged once their symptoms have resolved with follow up with a general surgeon. They should be informed that there may be symptom recurrence and should be instructed to return if they experience prolonged pain, fever or jaundice.

Referral

Asymptomatic gallstones need not be referred to a general surgeon. The patient should be informed of their findings and instructed to follow up with their primary care physician.

References and Further Reading

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RL Bree. Further observations on the usefulness of the sonographic Murphy sign in the evaluation of suspected acute cholecystitis. J Clin Ultrasound. 1995 Mar-Apr;23(3):169-72
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Tsai CJ, Leitzmann MF, Willett WC, et al. Glycemic load, glycemic index, and carbohydrate intake in relation to risk of cholecystectomy in women. Gastroenterology 129: 105-112, 2005
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