Gall Bladder Disease: Advances in Diagnosis & Management

The biliary system is affected by diverse spectrum of diseases. Abnormalities in bile composition, biliary anatomy or function may cause a biliary disease. Figure 1 depicts the spectrum of benign biliary diseases, however the majority of clinical events are due to gallstones, either in gallbladder or bile duct.¹Dooley JS. Gallstones and Benign Biliary Diseases. Chapter 12. Sherlock’s Diseases of the Liver and Biliary System, Twelfth Edition. Published 2011 by Blackwell Publishing Ltd.  

Gall stones/calculous gall bladder disease: An overview

Gallstones are crystalline deposits in the gallbladder (Figure 2).²Available at: http://emedicine.medscape.com/article/175667-overview. Accessed on 26 feb 2015.   The prevalence of gallstones varies between 5-25%,³Gallstones. BMJ 2014;348:g2669. http://www.bmj.com/content/348/bmj.g 2669   with approximately 6.5% in men and 10.5% in women. The prevalence of gallstones increases with age. By age 70, 15% of men and 24% of women have gallstones, with these numbers increasing to 24% and 35%, respectively, by the age of 90.⁴Duncan CB, Riall TS. Evidence-Based Current Surgical Practice: Calculous Gallbladder Disease. J Gastrointest Surg. 2012 Nov; 16(11): 2011-2025.  

Gallstones are classified earlier as cholesterol stones pigment stones or mixed according to their composition (Table 1), and can only be determined reliably after their removal. Recently, additional types of gallstones have been identified based on their microscopic structure and composition. However, most stones fall under the umbrella of cholesterol (37-86%), pigment (2-27%), calcium (1-17%) or mixed (4-16%).³Gallstones. BMJ 2014;348:g2669. http://www.bmj.com/content/348/bmj.g 2669  

Cholelithiasis (formation of gallstones)

The formation of gallstones (referred to as cholelithiasis) is a complex but slow process that starts with bile. It usually causes no pain or other symptoms. Most gallstones are formed from cholesterol.⁵Available at: http://umm.edu/health/medical/reports/articles/gallstones-andgallbladder-disease. Accessed on 26 Feb 2015.  

Cholesterol stones consist predominantly of cholesterol (51-99%), but also contain other components including calcium carbonate, phosphate, bilirubinate and palmitate, phospholipids, glycoproteins and mucopolysaccharides. The formation of cholesterol gallstones may be due to:¹Dooley JS. Gallstones and Benign Biliary Diseases. Chapter 12. Sherlock’s Diseases of the Liver and Biliary System, Twelfth Edition. Published 2011 by Blackwell Publishing Ltd.  

1. altered composition of hepatic bile,
2. nucleation of cholesterol crystals and
3. impaired gall bladder function.

Altered hepatic bile composition

Bile is 85-95% water, with other components: cholesterol, phospholipids, bile acids, bilirubin, electrolytes and a range of proteins and mucoproteins. Cholesterol is secreted from the canalicular membrane in unilamellar phospholipid vesicles. If there is excess cholesterol or reduced phospholipids and/or bile acid, multilamellar vesicles form and it is from these that there is nucleation of cholesterol crystals and ultimately sludge and stone formation (Figure 3).

Changes in bile acid type also reduce the capacity for cholesterol solubilisation. A higher proportion of deoxycholate is found in gallstone patients.

Cholesterol nucleation

Nucleation of cholesterol monohydrate crystals from multilamellar vesicles is a crucial step in gallstone formation (Figure 3).

Impaired gall bladder function

The gall bladder fills with hepatic bile during fasting, concentrates the bile and contracts in response to a meal, resulting in the passage of bile into the duodenum. The gall bladder must be capable of emptying so as to clear itself of microcrystals, sludge and debris that might initiate stone formation.

The concentration of bile salts, bilirubin and cholesterol, may rise ten fold or more as water and electrolytes are absorbed for the walls of gall bladder. The concentration of these constituents does not, however, rise in parallel and the cholesterol saturation index may decrease with concentration of bile because of the absorption of some cholesterol.

Risk factors of gallstone disease⁶Reshetnyak VI. Concept of the pathogenesis and treatment of cholelithiasis.World J Hepatol 2012 February 27; 4(2): 18-34.  

Gallstone disease is multifactorial. Gender is one of the main risk factor for its development in the general population, as more common in women than in men. Other factors are age, genes and race. Additional factors are obesity, rapid weight loss, glucose intolerance, insulin resistance, high dietary glycaemic load, alcohol use, diabetes mellitus, hypertriglyceridaemia, drugs and pregnancy.

Four major groups of factors contribute to the formation of cholesterol gallstones are (see Figure 4):
(1) those that contribute to cholesterol supersaturation of bile;
(2) those that contribute to cholesterol precipitation and crystallisation core formation;
(3) those that result in impairment of basic gall bladder functions (contraction, absorption, secretion, etc); and (4) those that lead to impairment of the enterohepatic circulation of bile acids.

(1) Factors that contribute to bile cholesterol supersaturation

Age: The rate of gallstone formation increases with each decade, after 20 years of age.

Gender: In reproductive-aged women, the risk of cholelithiasis is 2-3 times higher than that in men. Pregnancies also contribute to formation of stones in the gall bladder, particularly in multiparas (parity 4 or more).

Genetic factors: The risk of gallstone formation is 2-4 times higher in individuals whose relatives suffer from gall stones disease. Mucin, plays an important role in gallstone formation. Several mucin genes (MUC) have been implicated in various diseases and gel-forming mucin genes (MUC2, MUC5AC, MUC5B, and MUC6) were recognised to be the important components of digestive mucus.

Overweight and obesity: Obesity is accompanied by increased synthesis and excretion of cholesterol into bile. At the same time, the amount of produced cholesterol is directly proportional to being overweight. Weight cycling, independent of BMI, may increase the risk of gallstone disease in men.

Diet: A high intake of cholesterol increases its bile level. Refined carbohydrates increase cholesterol saturation of bile while small doses of alcohol have the opposite effect.

Liver and pancreatic diseases: It is stated that subjects with HBsAg and viral hepatitis C have an increased risk for GS formation. Hepatic metabolic dysfunction and bile duct lesions are other possible causes.

Drugs: Oestrogens, prednisolone, cyclosporine, azathioprine, sandostatin, clofibrate, nicotinic acid and a number of other drugs used for long-term increase the risk for gallstone disease. Oral contraceptives increase the incidence of GD in younger women, especially in the early period of their use of oral contraceptives.

Low socioeconomic status and a poor hygiene level are currently stated among the risk factors.

(2) Factors that contribute to cholesterol precipitation and crystallisation core formation

Mucin-glycoprotein gel is one of the most important and

identified pronucleators. Secretory mucins are gel forming and may increase bile viscosity. The biochemical composition of hepatic bile is modified during residence in the gall bladder, contributing to sludge formation.

(3) Factors that lead to impaired gall bladder function (contraction, absorption, secretion)

Gall bladder filling and emptying could be impaired in patients with gallstone disease. Gallstone formation is associated with poorer contractility and larger gallbladder volume.

(4) Factors that lead to impaired enterohepatic circulation of bile acids

Small bowel diseases accompanied by severe malabsorption (gluten enteropathy, Crohn’s disease, etc.) result in impaired bile acid absorption. The rate of stone formation amounts to as high as 26.4% in Crohn’s disease with predominant localisation in the terminal small bowel.

Gallstone disease & associated complications: Clinical symptoms & diagnosis

Gall bladder stones are usually asymptomatic. Over 70% of patients with gallstones are asymptomatic. The risk of developing symptoms or complications related to gallstones is approximately 1 – 4% per year, and around 8-10% of patients with asymptomatic gallstones develop symptoms within 5 years. The most common complications of gallstone disease are biliary colic, acute cholecystitis, common bile duct stones and gallstone pancreatitis. Less common complications include empyema of the gall bladder, liver abscess, gall bladder perforation with bile peritonitis, cholangitis, cholecystoenteric fistula and gallstone ileus.⁴Duncan CB, Riall TS. Evidence-Based Current Surgical Practice: Calculous Gallbladder Disease. J Gastrointest Surg. 2012 Nov; 16(11): 2011-2025.  

Biliary pain

Seventy to 80% of symptomatic patients complain of biliary colic. The pain is characterised as episodic and severe epigastric pain; less commonly, it is located in the right upper quadrant, left upper quadrant, precordium or lower abdomen. The pain generally has a sudden onset, rising in intensity and lasting from 15 minutes to several hours. Pain may be accompanied by radiation to the interscapular region or the right shoulder often with vomiting and diaphoresis. Biliary colic may also present with symptoms of nonspecific dyspepsia such as intolerance of fatty foods, pyrosis, flatulence, aerophagia, sweating, yellowish colour of skin or sclera of the eye and clay-colored stools. These symptoms suggest accompanying complications such as cholangitis and choledocholithiasis.⁷Available at : http://www.hopkinsmedicine.org/gastroenterology_hepatology/_pdfs/pancreas_biliary_tract/gallstone_disease.pdf  

Acute cholecystitis

Acute cholecystitis is an acute inflammation of the gall bladder. It may be due to presence or absence of cholelithiasis.

Acute calculous cholecystitis

In acute calculous cholecystitis (ACC), gallstones are present in over 90% of cases and cause persistent obstruction of the gall bladder outlet because of impaction in the neck of the gall bladder, Hartmann’s pouch or cystic duct.

Obstruction to gall bladder drainage causes an increase in intraluminal pressure, gall bladder distention and wall oedema that may progress to venous and lymphatic obstruction, ischaemia, and necrosis. A number of potential mediators have been identified including cholesterol-supersaturated bile, lysolecithin, phospholipase A and prostaglandins.⁸Yusoff IF, Barkun JS, Barkun AN. Diagnosis and management of cholecystitis and cholangitis. Gastroenterol Clin N Am 2003; 32: 1145-68.  

Clinical features: Pain often occurs late at night or in the early morning, usually in the right upper abdomen or epigastrium and is referred to the angle of the right scapula, to the right shoulder or rarely to the left side. The pain usually rises to a plateau and can last 30-60 min without relief, unlike the short spasm of biliary colic. Attacks may be precipitated by late-night, heavy meals or fatty food.

Distension pain coming in waves is due to the gall bladder contracting to overcome the blocked cystic duct. Peritoneal pain is superficial with skin tenderness, hyperaesthesia and muscular rigidity.¹Dooley JS. Gallstones and Benign Biliary Diseases. Chapter 12. Sherlock’s Diseases of the Liver and Biliary System, Twelfth Edition. Published 2011 by Blackwell Publishing Ltd.  

Clinical examination: Temperature rises with bacterial invasion, and presence of jaundice indicates associated stones in the common bile duct. The gall bladder is usually impalpable; occasionally a tender mass of gall bladder and adherent omentum may be felt, with positive Murphy’s sign.¹Dooley JS. Gallstones and Benign Biliary Diseases. Chapter 12. Sherlock’s Diseases of the Liver and Biliary System, Twelfth Edition. Published 2011 by Blackwell Publishing Ltd.  

Laboratory tests: The leucocyte count may be raised with a moderate increase in polymorphs. In the febrile patient blood cultures may be positive. A plain X-ray is suggested for the patient with acute abdominal pain of uncertain cause, but if acute cholecystitis is suspected scanning is indicated. Only about 10% of gallstones are radio-opaque, compared with 90% of renal calculi.¹Dooley JS. Gallstones and Benign Biliary Diseases. Chapter 12. Sherlock’s Diseases of the Liver and Biliary System, Twelfth Edition. Published 2011 by Blackwell Publishing Ltd.  

Differential diagnosis: Acute cholecystitis is liable to be confused with other causes of sudden pain and tenderness in the right hypochondrium. Below the diaphragm, acute retrocaecal appendicitis, intestinal obstruction, a perforated peptic ulcer or acute pancreatitis may produce similar clinical features. Check for myocardial infarction, as referred pain from muscular and spinal root lesions may cause similar pain.

Radiography: Ultrasound is the test of choice and scintigraphy should be the second option.¹Dooley JS. Gallstones and Benign Biliary Diseases. Chapter 12. Sherlock’s Diseases of the Liver and Biliary System, Twelfth Edition. Published 2011 by Blackwell Publishing Ltd.   (CT and MRI scanning are not indicated as the initial assessment of a patient with suspected acute cholecystitis).

Acute acalculous cholecystitis

Acute acalculous cholecystitis (AAC) is an acute inflammation of the gall bladder in the absence of demonstrable cholelithiasis. AAC accounts for 2-12% of all cases of cholecystitis. AAC most frequently occurs in those who are critically ill from trauma, sepsis or burns. Compared with ACC, AAC tends to have a more complicated course and a higher morbidity and mortality, with mortality rates ranging from 10-50%.⁸Yusoff IF, Barkun JS, Barkun AN. Diagnosis and management of cholecystitis and cholangitis. Gastroenterol Clin N Am 2003; 32: 1145-68.  

Clinical features: Similar as acute calculous cholecystitis with fever, leucocytosis and right upper quadrant pain; but diagnosis is often difficult because of the overall clinical state of the patient who may be intubated, ventilated and receiving narcotic analgesics.

Laboratory tests: Features of cholestasis with a raised bilirubin and alkaline phosphatase suggest AAC.

Imaging: Ultrasound and CT are complementary and useful in showing a thickened gall bladder wall (> 5mm), pericholecystic fluid or subserosal oedema (without ascites), intramural gas or a sloughed mucosal membrane. The sensitivity of ultrasound varies widely between studies (30-100%), while of cholescintigraphy is 60-90% for acalculous cholecystitis, but moving patients to the imaging unit for the time required for scanning may not be practical.¹Dooley JS. Gallstones and Benign Biliary Diseases. Chapter 12. Sherlock’s Diseases of the Liver and Biliary System, Twelfth Edition. Published 2011 by Blackwell Publishing Ltd.  

Choledocholithiasis

Choledocholithiasis (presence of one or more gallstones in the common bile duct), is the most common cause of biliary obstruction. This occurs when a gallstone passes from the gall bladder into the common bile duct, impacting distally in the ampulla of Vater. Obstruction of bile flow by a stone at this critical point may lead to abdominal pain and jaundice. Stagnant bile above an obstructing bile duct stone often becomes infected, and bacteria can spread rapidly back up the ductal system into the liver to produce a life-threatening infection called ascending cholangitis.²Available at: http://emedicine.medscape.com/article/175667-overview. Accessed on 26 feb 2015.  

Patients suspected of having choledocholithiasis are diagnosed with a combination of laboratory tests and imaging studies. The first imaging study obtained is typically a transabdominal ultrasonography (US). When the ultrasound findings are not enough for a diagnosis a magnetic resonance cholangiopancreatography (MRCP) or an endoscopic ultrasound (EUS) should be considered.⁹Magalhaes J, Rosa B, Cotter J. Endoscopic retrograde cholangiopancreat-ography for suspected choledocholithiasis: From guidelines to clinical practice. World J Gastrointest Endosc. 2015 Feb 16; 7(2): 128-134.  

Gallstone pancreatitis

The diagnosis of gallstone pancreatitis should be suspected if the patient has a prior history of biliary colic. Although gallstone pancreatitis is the most common cause of pancreatitis, other aetiologies must be considered, prior to initiating treatment, like moderate to heavy alcohol consumption over a period of years. Other causes include medication, genetic diseases, infectious agents, postoperative states, endoscopic procedure involving pancreatic and bile ducts and other types of injury to pancreas.

Laboratory tests: Documenting an elevated serum amylase and/or lipase is helpful in diagnosing pancreatitis. Serum amylase is elevated in at least 75% of cases of acute pancreatitis and remains elevated for 5-10 days in most patients. However, amylase lacks specificity for pancreatitis because it can be elevated in other disorders. Lipase is more specific for pancreatitis, but both enzymes may be increased in renal failure and various abdominal conditions (e.g., perforated ulcer, mesenteric vascular occlusion and intestinal obstruction). Serum lipase has a longer half life than amylase and therefore tends to remain elevated for longer period of time. Using a cut-off of three times the upper limit of normal, the sensitivity of serum lipase for pancreatitis approaches 90% in patients presenting with abdominal pain. A urine dipstick for trypsinogen-2 has sensitivity and specificity of more than 90% for acute pancreatitis.

Several tests can help differentiate biliary pancreatitis from other causes of pancreatitis, such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase and serum bilirubin are the so-called liver function tests; they should be reviewed before making a confident diagnosis.¹⁰Hazem ZM. Acute Biliary Pancreatitis: Diagnosis and Treatment Saudi J Gastroenterol. 2009 Jul; 15(3): 147-155.  

Gallstone disease: Diagnostic imaging

Imaging modalities that may be useful in the diagnosis of gallbladder stones include the following:

• Abdominal radiography (upright and supine)-Used primarily to exclude other causes of abdominal pain (e.g., intestinal obstruction).
• Ultrasonography-The procedure of choice in suspected gallbladder or biliary disease.
• Endoscopic ultrasonography (EUS)- An accurate and relatively noninvasive means of identifying stones in the distal CBD.
• Laparoscopic ultrasonography-Promising as a potential method for bile duct imaging during laparoscopic cholecystectomy.
• Computed tomography (CT)-More expensive and less sensitive than ultrasonography for detecting gall bladder stones, but superior for demonstrating stones in the distal CBD.
• Magnetic resonance imaging (MRI) with magnetic resonance cholangiopancreatography (MRCP)-Usually reserved for cases in which choledocholithiasis is suspected.
• Scintigraphy-Highly accurate for the diagnosis of cystic duct obstruction.
• Endoscopic retrograde cholangiopancreatography (ERCP)
• Percutaneous transhepatic cholangiography (PTC)

Ultrasonography

The best noninvasive test for detecting gallstones in the gall bladder is abdominal ultrasonography because of its high specificity and sensitivity (90-95%). It is significant for the diagnosis of gallstones greater than 2 mm in diameter. Ultrasonography of the gall bladder should follow a fast of at least eight hours because gallstones are visualised better in a distended, bile-filled gall bladder.¹¹Ahmed A, Cheung RC, Keeffe EB. Management of Gallstones and Their Complications. Am Fam Physician. 2000 Mar 15;61(6):1673-80.  

Ultrasonography is less sensitive for the diagnosis of choledocholithiasis and may document only one half of common bile duct stones. Ultrasound scans may indicate dilatation of intrahepatic or extrahepatic bile ducts, which is highly suggestive of distal obstruction, with a sensitivity of 76 percent.¹¹Ahmed A, Cheung RC, Keeffe EB. Management of Gallstones and Their Complications. Am Fam Physician. 2000 Mar 15;61(6):1673-80.  

Endoscopic ultrasonography

Endoscopic ultrasonography (EUS) is a highly technical, low-risk diagnostic procedure that utilises high-frequency ultrasound during endoscopy to evaluate and diagnose digestive tract disorders. EUS employs a duodenoscope with a distal ultrasound probe and is so advanced that from a position in the stomach or duodenum, the endoscope allows visualisation of the bile ducts, pancreas and adjacent structures (Figure 5).⁷Available at : http://www.hopkinsmedicine.org/gastroenterology_hepatology/_pdfs/pancreas_biliary_tract/gallstone_disease.pdf  

EUS can accurately diagnose the presence or absence of gallstones in the common bile duct but lacks the therapeutic usefulness of ERCP. EUS is more likely to be used when the pretest probability of finding gallstones is low, particularly in high-risk patients. EUS is preferable in this situation because it lacks the potential complications of ERCP.⁷Available at : http://www.hopkinsmedicine.org/gastroenterology_hepatology/_pdfs/pancreas_biliary_tract/gallstone_disease.pdf  

Computed tomography

Detection of calculous disease may employ computed tomography (CT) scanning. CT scans are useful in demonstrating masses and dilated biliary ducts, although they are not as reliable for the diagnosis of calculous disease. Their principle use is detection of the complications of gallstones such as pericholecystic fluid, gas in the gall bladder wall, gall bladder perforations and abscesses. These noninvasive tests may help determine which patients will require urgent surgical intervention.⁷Available at : http://www.hopkinsmedicine.org/gastroenterology_hepatology/_pdfs/pancreas_biliary_tract/gallstone_disease.pdf  

Magnetic resonance imaging and magnetic resonance cholangio-pancreatography

Magnetic resonance imaging (MRI) and magnetic resonance cholangiopancreatography (MRCP) are useful in identifying common bile duct stones and delineating pancreatic and biliary tract anatomy. MRCP can be useful in the evaluation of the pregnant patients with right upper quadrant pain in CBD stones.⁴Duncan CB, Riall TS. Evidence-Based Current Surgical Practice: Calculous Gallbladder Disease. J Gastrointest Surg. 2012 Nov; 16(11): 2011-2025.  

Endoscopic retrograde cholangiopancreatography

Endoscopic retrograde cholangiopancreatography is considered the gold standard in the detection of common bile duct stones, with a sensitivity and specificity approaching 95%.⁴Duncan CB, Riall TS. Evidence-Based Current Surgical Practice: Calculous Gallbladder Disease. J Gastrointest Surg. 2012 Nov; 16(11): 2011-2025.  

Hepatobiliary iminodiacetic acid scan

Hepatobiliary iminodiacetic acid (HIDA) scanning is used for the diagnosis of acute cholecystitis, chronic cholecystitis, acalculous cholecystitis and biliary dyskinesia. After administration of cholecystokinin (CCK), non-visualisation of the gall bladder on HIDA scan is consistent with acute cholecystitis, while visualisation of the gall bladder virtually excludes the diagnosis.

Morphine injection during HIDA scan may distinguish between chronic cholecystitis (visualisation within 20-30 minutes of injection) and acute cholecystitis (persistent nonvisualisation after injection). The “rim sign,” caused by increased pericholecystic hepatic uptake of radioactive tracer, is indicative of gangrenous cholecystitis. After CCK injection, a gall bladder ejection fraction (EF) of less than 40% and reproduction of abdominal pain support the diagnosis of biliary dyskinesia. Keeping this in mind, HIDA scanning is not the primary modality used in the diagnosis of acute calculous cholecystitis and should be reserved for cases in which the diagnosis is unclear or cholecystitis is being ruled out. HIDA scan is indicated when gallstones are not seen on ultrasound and the clinical picture is consistent with cholecystitis.⁴Duncan CB, Riall TS. Evidence-Based Current Surgical Practice: Calculous Gallbladder Disease. J Gastrointest Surg. 2012 Nov; 16(11): 2011-2025.  

Management of gall bladder diseases

The treatment of gallstones depends upon the stage of disease. Guidelines from the American College of Physicians state that in asymptomatic patients, the risks of both surgical and nonsurgical treatments for gallstones outweigh the benefits. Experts suggest a wait-and-see approach, which they have termed expectant management, for these patients.⁵Available at: http://umm.edu/health/medical/reports/articles/gallstones-andgallbladder-disease. Accessed on 26 Feb 2015.  

There are several situations in which cholecystectomy for asymptomatic gallstones should be considered. Patients with porcelain gall bladder and those with gallstones 3 cm in size are at increased risk for cancer and should undergo cholecystectomy.

Prophylactic cholecystectomy has also been advocated in patients with asymptomatic gallstones prior to organ transplant, most commonly heart transplant candidates, due to high rates of symptomatic gallstones and operative morbidity and mortality post-transplant. Pre-transplant laparoscopic cholecystectomy can be performed safely in stable patients, including those awaiting a heart transplant. Patients with chronic haemolytic syndromes, including sickle cell anaemia, should undergo cholecystectomy for asymptomatic gallstones. Historically, prophylactic cholecystectomy was performed in diabetic patients with asymptomatic gallstones to prevent severe biliary and infectious complications experienced by these patients. However, after adjusting for associated comorbidities (renal, vascular, cardiac disease), diabetes has not been shown to be a significant predictor of gallstone complications. Expectant management of asymptomatic gallstones in diabetic patients is now the treatment of choice.

Symptomatic patients may undergo medical or surgical treatments (see Figure 6). ¹¹Ahmed A, Cheung RC, Keeffe EB. Management of Gallstones and Their Complications. Am Fam Physician. 2000 Mar 15;61(6):1673-80.  

Primary care management

According to RCS 2013 Commissioning guide:¹²Available at: https://www.rcseng.ac.uk/healthcare-bodies/docs/publishedguides/gallstones. Accessed on 24 March, 2015  

• Most patients with symptomatic gallstones present with a selflimiting attack of pain that lasts for hours only. This can be controlled successfully in primary care with appropriate analgesia, avoiding the requirement for emergency admission. When pain cannot be managed or if the patient is otherwise unwell (e.g., sepsis), he or she should be referred to hospital as an emergency.
• Further episodes of biliary pain can be prevented in around 30% of patients by adopting a low fat diet. Fat in the stomach releases cholecystokinin, which precipitates gall bladder contraction and might result in biliary pain.

Medical/Non-surgical treatment of gallstones in the gall bladder

Litholytic therapy (dissolution therapy)

Litholytic drugs, such a ursodeoxycholic acid decreases biliary cholesterol secretion as well as cholesterol absorption and increases solubility of cholesterol by the formation of liquid crystals. Ursodeoxycholic acid also prolongs nucleation time.¹Dooley JS. Gallstones and Benign Biliary Diseases. Chapter 12. Sherlock’s Diseases of the Liver and Biliary System, Twelfth Edition. Published 2011 by Blackwell Publishing Ltd.  

Contact litholysis

Contact litholysis is a variant of litholytic therapy. If contact litholysis is used, a substance that dissolves cholesterol stones is injected just into the gall bladder or bile ducts. Only cholesterol stones are prone to dissolution; their size and number are of no fundamental importance. Methyl-tert-butyl ether and propionic ether are used to dissolve stones in the gall bladder and bile ducts, respectively and dissolution occurs within 4-16 h.⁶Reshetnyak VI. Concept of the pathogenesis and treatment of cholelithiasis.World J Hepatol 2012 February 27; 4(2): 18-34.  

Extracorporeal shock-wave lithotripsy

Gall bladder stones can be fragmented by shock waves generated extracorporeally. Here ultrasound is usually used to target stones and oral bile acid therapy is given to dissolve the fragments that are remaining in the gall bladder. However, when pulverisation is achieved bile acid therapy is not necessary. Elderly patients with radiolucent, solitary and < 30mm gallstones are benefited from this technique.¹³ The gall bladder shows bruising and oedema after the shock waves but these are reversible.¹Dooley JS. Gallstones and Benign Biliary Diseases. Chapter 12. Sherlock’s Diseases of the Liver and Biliary System, Twelfth Edition. Published 2011 by Blackwell Publishing Ltd.  

Surgical procedures

Cholecystectomy¹Dooley JS. Gallstones and Benign Biliary Diseases. Chapter 12. Sherlock’s Diseases of the Liver and Biliary System, Twelfth Edition. Published 2011 by Blackwell Publishing Ltd.  ⁴Duncan CB, Riall TS. Evidence-Based Current Surgical Practice: Calculous Gallbladder Disease. J Gastrointest Surg. 2012 Nov; 16(11): 2011-2025.  

Laparoscopic cholecystectomy, introduced in the late 1980s, is the current standard treatment for symptomatic gall bladder stones, and mild and moderate acute cholecystitis, based on superior outcomes compared with open cholecystectomy. Laparoscopic cholecystectomy is performed in over 90% of elective cholecystectomies and 70% of emergent cholecystectomies. Laparoscopic cholecystectomy is associated with shorter hospital stays, faster return to work and lower operative mortality compared to open cholecystectomy. Open cholecystectomy is still required where the laparoscopic approach fails, or is not possible. Thus expertise is still needed for the open operation.

Single-incision laparoscopic cholecystectomy

Single-incision laparoscopic cholecystectomy (SILS) is being increasingly used in an effort to improve postoperative pain and recovery and decrease scarring. Currently, SILS cholecystectomy is being performed in highly selected patients with a BMI less than 40kg/m², symptomatic cholelithiasis without complications of gallstones, and in those with American Society of Anesthesiology (ASA) grade I or II. SILS cholecystectomy is typically not attempted in patients with an umbilical hernia or previous upper abdominal surgery. The operating time for SILS cholecystectomy ranges from 35-180 minutes.⁴Duncan CB, Riall TS. Evidence-Based Current Surgical Practice: Calculous Gallbladder Disease. J Gastrointest Surg. 2012 Nov; 16(11): 2011-2025.  ¹⁴Yeo D, Mackay S, Martin D. Single-incision laparoscopic cholecystectomy with routine intraoperative cholangiography and common bile duct exploration via the umbilical port. Surg Endosc. 2011.  

Natural orifice transluminal endoscopic surgery

Natural orifice transluminal endoscopic surgery (NOTES) is being used with increasing frequency for a variety of surgical procedures, and cholecystectomy is currently the most commonly performed NOTES procedure. Various methods have been used to obtain adequate visualisation and positioning of the trocars during NOTES cholecystectomy. Most commonly the endoscope is inserted transvaginally through a colpotomy, which is later closed with absorbable sutures. One or more trocars may be inserted through an umbilical port to help with the dissection, and transabdominal stay sutures may be placed through the gallbladder wall to aid in retraction and exposure of the triangle of Calot. The gall bladder is removed through the vagina.⁴Duncan CB, Riall TS. Evidence-Based Current Surgical Practice: Calculous Gallbladder Disease. J Gastrointest Surg. 2012 Nov; 16(11): 2011-2025.  

Other procedures⁵Available at: http://umm.edu/health/medical/reports/articles/gallstones-andgallbladder-disease. Accessed on 26 Feb 2015.  

ERCP with endoscopic sphincterotomy: ERCP may be performed before, during or after gall bladder removal. ERCP is often performed after gallstones in the common duct are discovered during cholecystectomy.

Percutaneous cholecystostomy: It is a procedure that may be used in seriously ill patients with severe gall bladder infection who cannot tolerate immediate surgery. It is also the standard treatment for patients with acalculous cholecystitis.

Gall bladder aspiration: The procedure involves removal of fluid while viewing the gall bladder using ultrasound. It does not require leaving a catheter in the abdomen afterward, and may have fewer complications than percutaneous cholecystostomy.

Management of biliary colic/pain in gall bladder disease

Medical therapy of gallbladder colic includes antiemetics and pain control. In mild cholecystitis, in which inflammation is the primary process, prophylactic treatment is considered with antibiotics, while in acute cholecystitis, broad-spectrum antibiotic coverage is used.¹⁵Available at: http://emedicine.medscape.com/article/1950020-overview#a30. Accessed on 24 March, 2015  

Antimicrobial therapy¹⁵Available at: http://emedicine.medscape.com/article/1950020-overview#a30. Accessed on 24 March, 2015  

Guidelines from the Surgical Infection Society and the Infectious Diseases Society of America on the management of intraabdominal infection recommend that antimicrobial therapy be instituted when infection is suspected and the patient has either acute cholecystitis or cholangitis. Antibiotics are also recommended for routine use in patients who are elderly or have diabetes or immunodeficiency and for prophylaxis in patients undergoing cholecystectomy to reduce septic complications even when infection is not suspected.

Anti-inflammatory, analgesics and antiemetic agents¹⁶Available at: http://www.bpac.org.nz/BPJ/2014/June/gallstones.aspx. Accessed on 24 March, 2015   ¹⁷Colli A, Conte D , Valle SD, Sciola V, Fraquelli M. Meta-analysis: NSAIDs for biliary colic. Aliment Pharmacol Ther 2012; 35: 1370-1378.  

Anti-inflammatory and analgesic medications have been reported to be effective in relieving pain from gall bladder distention, caused by the release of prostaglandins. However, appropriate antibiotics need to be given additionally when biliary colic is accompanied with infection.

Even though NSAIDs have been widely used as anti-inflammatory agents for biliary colic relief, they may increase the occurrence of more severe and possibly life threatening adverse events. For example, they may interfere with platelet function and thus increase the risk of spontaneous gastrointestinal bleeding after surgery or ERCP. They may also impair renal function in patients with diabetes, heart failure or hepatic cirrhosis, and at least in the case of chronic use, increase the risk of ischaemic heart disease. Thus, NSAIDS may not be the most appropriate analgesics for some patients with biliary colic. Antispasmodics such as drotaverine can be an effective alternative as it is safer, does not mask the symptoms of acute abdomen, can be safely given prior to diagnosis. If required, it can also be used in combination with an NSAID or opioid.

Nausea is a common symptom in patients with biliary colic, and taking opioids may increase the frequency of nausea and vomiting. Antiemetics, such as metoclopramide, can be prescribed in such patients. Postoperative nausea and vomiting can be controlled by different compounds, such as granisetron, droperidol, metoclopramide and ondansetron.

Drotavarine in the management of biliary colic/pain

Drotaverine, a potent phosphodiesterase 4 (PDE 4) inhibitor, is the first drug of choice in smooth muscle spasm of the biliary system and this treatment may be supplemented with the appropriate antibiotic treatment and/or laparoscopic cholecystectomy, if required.

For rapid relief from spasm and pain, drotaverine should be administered intravenously (IV) or intramuscularly (IM) followed by oral administration for effective maintenance of spasmolysis. In case of cholelithiasis, cholecystitis, cholangitis and cholangiolithiasis, drotaverine treatment should be started immediately and discontinued at the time of any surgical intervention. Those treated conservatively with antibiotics need co-administration of drotaverine until they become symptom free (10-14 days).

Drotaverine has been proved to be effective in several biliary colic states. In one study, efficacy of drotaverine was evaluated in 383 cases of biliary colic. The indications for which the patients had been treated with drotaverine were: cholelithiasis (46.5%), cholecystitis (with or without stones) (30.08%), other dyskinesias (19.3%) and cholangiolithiasis (4.15%). The results showed 86% 18 efficacy of drotaverine in these groups.¹⁸Blasko G. Pharmacology, Mechanism of Action and Clinical Significance of a Conveniet Antispasmodic Agent: Drotaverine. JAMA India-4(2)reprint;59-66.  

Drotaverine scores over other antispasmodics, like hyoscine butyl bromide, as it is devoid of anticholinergic like side-effects, such as dryness of mouth, constipation, blurred vision, etc. It also has the fastest onset of action (12 minutes after oral administration, 2 minutes after IV administration and 5 minutes with IM route). It can also be safely given in patients of glaucoma, hypertension and BPH. It is also safe in pregnancy, lactation and elderly patients. It is safe for long term use and does not mask the symptoms of acute abdomen, thus making diagnosis easier.

Moreover, Drotaverine is available and is used in combination with other agents such as Mefenamic acid, Aceclofenac & Paracetamol whenever spasm, pain & inflammation co-exist.

Conclusion

Gallstone formation is multifactorial. Proper diagnosis is required for its proper management. As the symptomatic patients with gall stones usually present in the emergency with a self-limiting attack of pain lasting hours, this can be controlled successfully in primary care with appropriate analgesia, avoiding the requirement for emergency admission. As studies have shown that early pain control in does not hinder the diagnosis, prescribing analgesics to relief pain in such patient should be the initial approach, followed by diagnostic measures.

Imaging is considered as the central diagnostic procedure in patients with gallstones. Though many newer diagnostic imaging techniques have been invented, ultrasonography is still considered the best. Surgeons use the standard surgical approach ‘Laparoscopic cholecystectomy’ for treating patients with cholecystitis, however open cholecystectomy is still needed in some cases, and because of the comorbidities, this selected patient group has a higher complication rate and mortality. As per NICE guidelines, percutaneous cholecystostomy is considered for the management of gallbladder empyema when surgery is contraindicated at presentation and conservative management is unsuccessful. Laparoscopic cholecystectomy should be reconsidered for people who have had percutaneous cholecystostomy once they are well enough for surgery.

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