Acalculous Biliary Pain, Acute Acalculous Cholecystitis, Cholesterolosis, Adenomyomatosis, and Gallbladder Polyps

Although gallstones and their complications account for most cholecystectomies, a consistent 15% of these operations are performed in patients without gallstones. In these patients, the majority of cholecystectomies are performed as treatment for 1 of 2 distinct clinical syndromes: acalculous biliary pain and acalculous cholecystitis. As shown in Table 67.1 , acalculous biliary pain is generally a disorder of young, predominantly female, ambulatory patients and mimics calculous biliary pain. Acute acalculous cholecystitis is typically a disease of immobilized and critically ill older men with coexisting vascular disease. Because the clinical features and prognosis of these 2 entities are quite different, they are considered separately in this chapter. Three typically asymptomatic conditions of the gallbladder—cholesterolosis, adenomyomatosis, and gallbladder polyps—are also reviewed.

TABLE 67.1

Comparison of Acalculous Biliary Pain and Acute Acalculous Cholecystitis

	Acalculous Biliary Pain	Acute Acalculous Cholecystitis
Epidemiology	Female preponderance (80%) Young to middle-aged ambulatory patient Risk factors are similar to those for cholelithiasis (i.e., obesity and multiparity)	Male preponderance (80%) A critically ill older adult patient in an ICU Risk factors are preexisting atherosclerosis, recent surgery, and hemodynamic instability
Clinical features	Episodic RUQ or epigastric pain identical to calculous biliary pain Physical findings are usually normal Laboratory findings are usually normal	Unexplained sepsis with few localizing signs; rapid progression to gangrene and perforation Physical examination may show fever; RUQ tenderness is present in only 25% Leukocytosis and hyperamylasemia may be present
Diagnostic tests	US shows no stones and usually a normal gallbladder Stimulated cholescintigraphy using CCK to measure the GBEF may identify patients who are likely to improve after cholecystectomy	See Table 67.2
Treatment	Elective cholecystectomy may be considered for patients with classic biliary pain or a GBEF <35% and persistent symptoms not suggestive of underlying functional GI disease	Urgent cholecystostomy or emergency cholecystectomy for gangrene or perforation
Prognosis	Good; attacks resolve spontaneously or with cholecystectomy	Poor; mortality rate of 10%-50% related to underlying comorbid diseases

GBEF , gallbladder ejection fraction.

Acalculous Biliary Pain

Definition and Clinical Features

Biliary pain (or biliary “colic”) is typically characterized by intense epigastric or right upper quadrant pain that starts suddenly, rises in intensity over a 15-minute period, and continues at a steady plateau for 30 minutes or more before slowly subsiding. The localization of pain to the right hypochondrium or radiation to the right shoulder is the most specific finding for a biliary tract origin. The attacks of pain are frequently precipitated by ingestion of a meal and may be accompanied by restlessness, nausea, or vomiting. Between attacks, the physical findings are usually normal, with the possible exception of residual upper abdominal tenderness.

When a patient presents with such a history and US confirms the presence of gallstones, the management is straightforward—namely, elective cholecystectomy (or rarely an attempt at medical dissolution of the stones; see Chapter 65 and 66 ). In comparison, the management of acalculous biliary pain represents a significant challenge. Patients with acalculous biliary pain have clinical features and biliary-type pain similar to those of patients with cholelithiasis, but a normal gallbladder on US and normal serum levels of liver and pancreatic enzymes. Acalculous biliary pain may stem from a spectrum of overlapping disorders, including chronic acalculous cholecystitis and gallbladder dysmotility (biliary dyskinesia), which share symptomatology but differ in the pathologic findings of the resected gallbladder. In patients with acalculous biliary pain, symptomatic improvement following cholecystectomy is variable.

Epidemiology and Pathophysiology

US-negative biliary pain is common in population studies, with reported frequencies of approximately 7% in men and 20% among women. Acalculous biliary pain is predominantly a disorder of young women. In one series of more than 100 patients, 83% were female, and the mean age was approximately 30 years.

The cause of the acalculous biliary pain syndrome is not known, but indirect evidence suggests that several different etiologies may culminate in the same clinical presentation. Stimulated duodenal bile from patients with acalculous biliary pain is more dilute with respect to both bile acids and phospholipids than bile from patients with gallstones or from control women without biliary symptoms. The low bile acid concentration may be related to the sluggish or incomplete gallbladder contraction that has been observed in patients with acalculous biliary pain. The lower molar percentage of phospholipids supports the hypothesis that biliary phospholipids are hydrolyzed to free fatty acids, which incite inflammation.

The striking preponderance of young, fertile women among patients with acalculous biliary pain closely parallels the epidemiology of cholelithiasis, suggesting that the 2 conditions have similar risk factors. Some studies have shown that up to half of patients with acalculous biliary pain actually have microscopic cholelithiasis in resected gallbladder specimens, indicating that the original US was falsely negative. Several studies have shown that a subset of patients with acalculous biliary pain have histologic evidence of cholesterolosis in their resected gallbladders (see later). Although usually an incidental pathologic finding, cholesterolosis of the gallbladder may, in some patients, disrupt normal gallbladder contraction and result in biliary pain. In other patients, the resected gallbladder demonstrates significant inflammation, characteristic of chronic acalculous cholecystitis.

Finally, acalculous biliary pain is listed as a functional GI disorder by a multinational working committee of GI investigators (Rome IV classification [see Chapter 122 ]), with the implication that a pathologic lesion is not required for the diagnosis. In patients with a histologically normal gallbladder, a lack of coordination between gallbladder contraction and sphincter of Oddi relaxation or gallbladder dysmotility (also called functional gallbladder disorder) may cause biliary pain (see Chapter 63 ). The strong link between acalculous biliary pain and other functional bowel disorders suggests that visceral hypersensitivity may be a common cause of biliary pain in patients with a normal gallbladder.

Diagnosis and Treatment

As described earlier, the symptoms of acalculous biliary pain may be indistinguishable from those of cholelithiasis. A careful review of the patient’s complaints should confirm that the symptoms are genuinely suggestive of biliary pain rather than dyspepsia, heartburn, cramping abdominal pain, or flatulence. If the symptoms are consistent with biliary pain, a detailed review of the US results with a radiologist is warranted. Although gallstones greater than 2 mm are unlikely to be missed (the sensitivity of US for detecting stones exceeds 95%), other US evidence of gallbladder disease may be overlooked if the primary focus is to exclude stones. In patients with typical biliary symptoms and a negative US result, further assessment of the biliary tract with EUS, MRCP, or secretin-enhanced MRCP may be of benefit. Patients with adenomyomatosis of the gallbladder or small cholesterol polyps may have biliary pain that is relieved by cholecystectomy (see later). Determining when and in whom to pursue cholecystectomy for patients with biliary pain and a normal US result presents a challenge (see Chapter 63 ).

Stimulated Cholescintigraphy

A recommended, although still controversial, approach to determining which patients with acalculous biliary pain are likely to benefit from cholecystectomy involves calculation of a gallbladder ejection fraction (GBEF) using cholescintigraphy (see also Chapter 63 ). An IV-administered radiolabeled hepatobiliary agent (e.g., ^99m Tc-diisopropyl iminodiacetic acid) is concentrated in the gallbladder, and a computer-assisted gamma camera measures activity before and after stimulation of gallbladder contraction with a slow IV infusion of CCK over 30 minutes. The GBEF is defined as the change in activity divided by the baseline activity. Studies in healthy volunteers have shown that normal GBEF averages 75% and virtually always exceeds 35%. Fatty meal cholescintigraphy is a less costly alternative to the CCK-stimulated test and uses oral fat intake (typically half-and-half milk) to stimulate gallbladder contraction physiologically; normal values for GBEF tend to be lower than those for CCK-stimulated cholescintigraphy.

Fewer than one half of patients with acalculous biliary pain have a depressed GBEF, but most of those who do have a depressed GBEF continue to have symptoms when followed for as long as 3 years. If cholecystectomy is performed in these patients, histologic evidence of chronic cholecystitis is found in approximately 90%, cystic duct narrowing in 80%, and cholesterolosis in 30%. Long-term symptom relief following cholecystectomy may occur in more than 50% of patients with an abnormal GBEF ; however, up to 50% of patients managed without surgery also experience symptom relief. In one study of patients with a GBEF less than 35% and atypical symptoms, 30% experienced spontaneous resolution of symptoms, whereas 57% of those with persistent symptoms experienced symptom resolution following cholecystectomy. In the single randomized, controlled trial of cholecystectomy as treatment for biliary pain in patients with a depressed GBEF, all 11 patients who underwent cholecystectomy reported resolution of their symptoms over an average follow-up period of 54 months. The 10 patients in the group randomized to no surgery continued to experience symptoms.

Patients with acalculous biliary pain and a normal GBEF also have a variable, although generally benign, course. Some are found to have a nonbiliary cause of the symptoms, and in others the pain resolves with time. Cholecystectomy has not typically been recommended for patients with acalculous pain and a normal GBEF, although the frequency of symptom relief following cholecystectomy in this population may be equivalent to that of patients with a depressed GBEF who undergo cholecystectomy. As a result, although the GBEF is used commonly to evaluate patients with acalculous biliary-type pain, it is not a reliable predictor of the response to cholecystectomy. As a general rule, typical biliary pain tends to resolve more reliably following cholecystectomy than do atypical symptoms such as bloating or dyspepsia. This observation raises the question as to whether surgery should be recommended based on symptoms, without scintigraphy, and suggests a period of observation or medical management before a decision to operate is made, to allow the possibility that the symptoms will resolve.

As stimulated cholescintigraphy has been used earlier in the evaluation of patients with biliary pain (sometimes immediately after US fails to demonstrate gallstones), patients with nonbiliary or self-limiting diseases have not been weeded out, and the positive predictive value of the test has declined. A low GBEF is not specific for functional gallbladder disease and can occur in asymptomatic, healthy persons, those with IBS, and persons taking medications that affect GI motility, including calcium channel blockers, oral contraceptives, and H2RAs. The test should be used when there is a high pretest probability of gallbladder-related symptoms and after other diagnoses have been ruled out. Experts recommend that patients with biliary pain and normal US undergo serum liver biochemical testing, pancreatic enzyme measurement, and upper endoscopy to exclude other causes of the symptoms. If these tests fail to provide an alternative explanation, the patient should be observed for several months to allow the possibility of spontaneous resolution of symptoms before undergoing cholescintigraphy. In patients with atypical symptoms or other functional GI complaints, treatment of visceral hypersensitivity should be considered (see Chapters 12, 14, 22, and Chapter 122 ).

An apparent consequence of the diagnostic uncertainty associated with acalculous biliary pain is a dramatic increase in the rate of cholecystectomy for acalculous biliary pain, particularly in young and insured persons and since the advent of laparoscopic surgery. The rate of cholecystectomy for gallstone disease has declined in the same population.

Acute Acalculous Cholecystitis

Definition

Acute acalculous cholecystitis is acute inflammation of the gallbladder in the absence of stones. Acute cholecystitis resulting from calculi is discussed in Chapter 65 . The term acalculous cholecystitis has been questioned as incorrectly suggesting that the disease is simply cholecystitis without stones. Instead, the term necrotizing cholecystitis has been proposed to reflect the distinct etiology, pathology, and prognosis of the disease.

Epidemiology

Acute acalculous cholecystitis accounts for 5% to 10% of cholecystectomies performed in the USA. In fact, of the cholecystectomies performed in postoperative or hospitalized patients recovering from trauma or burns, more than half are for acalculous disease. In one series, acalculous cholecystitis occurred in 0.19% of surgical ICU admissions and accounted for 14% of all cases of acute cholecystitis.

Less commonly, acute acalculous cholecystitis may occur in the absence of antecedent trauma or stress, especially in children, older adult patients with coexisting vascular disease, bone marrow transplant recipients, patients receiving chemotherapy, and patients with AIDS. In some cases, specific infectious causes can be identified, such as Salmonella spp., Staphylococcus aureus , CMV, Zika virus in immuno-compromised patients, and EBV in children. Systemic vasculitides such as polyarteritis nodosa, SLE, Henoch-Schönlein purpura, and eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) may manifest as acute acalculous cholecystitis caused by ischemic injury to the gallbladder. Several cases of acute acalculous cholecystitis have been observed during alemtuzumab therapy for multiple sclerosis. Finally, acute acalculous cholecystitis has been recognized increasingly in otherwise healthy people without any risk factors. As a group, patients with acute acalculous cholecystitis are more likely to be old men, in contrast to patients with cholecystitis caused by calculi, cases of which cluster in younger women.

Pathogenesis

Most cases of acute acalculous cholecystitis occur in the setting of prolonged fasting, immobility, and hemodynamic instability. The gallbladder epithelium, although normally a robust tissue, is exposed continuously to one of the most noxious agents in the body: a concentrated solution of bile acid detergents. In the course of a normal day, the gallbladder empties the concentrated bile several times and is replenished with dilute (and presumably less noxious) hepatic bile. With prolonged fasting, the gallbladder is not stimulated by CCK to empty, and concentrated bile stagnates in the gallbladder lumen. In addition, the gallbladder epithelium has relatively high metabolic energy requirements in order to absorb electrolytes and water from the bile. Therefore, in an immobile, fasting patient with splanchnic vasoconstriction (often resulting from septic shock in a patient in an ICU), ischemic and chemical injury to the gallbladder epithelium may occur. A study that compared the microcirculation of gallbladders removed for gallstone disease with those removed for acute acalculous cholecystitis showed that the capillaries barely filled in gallbladders associated with acalculous cholecystitis, indicating that disturbed microcirculation and ischemia may play an important role in its pathogenesis.

Inappropriate activation of factor XII (demonstrated to initiate gallbladder inflammation in animals) and local release of prostaglandins in the gallbladder wall have also been implicated in the tissue injury associated with acalculous cholecystitis. In animal models, tissue destruction can be attenuated by inhibiting prostaglandin synthesis with indomethacin. Expression of tight junction proteins in the gallbladder epithelium of patients with acute acalculous cholecystitis differs from that in patients with calculous cholecystitis, perhaps reflecting the role of increased gallbladder wall permeability in the systemic inflammatory response. Infection of the gallbladder mucosa with bacteria, usually Gram-negative enteric organisms and anaerobes, is thought to be a secondary event in acute acalculous cholecystitis, following rather than causing the initial injury.

One postulated explanation for the rising incidence of acute acalculous cholecystitis, particularly in younger patients, is obesity and the accompanying increase in gallbladder wall fat, which has been demonstrated to interfere with gallbladder emptying in animal models. In one study, 16 patients with acute acalculous cholecystitis had significantly more gallbladder wall fat than normal subjects without cholecystitis.

Clinical Features

The clinical features of acute acalculous cholecystitis often differ from those of acute cholecystitis caused by stone disease. Although RUQ pain, fever, localized tenderness overlying the gallbladder, and leukocytosis may be evident in classic presentations, such as those of younger outpatients, some or all of these features are commonly lacking in older adult postoperative patients. Symptoms or signs referable to the RUQ are initially absent in 75% of cases. Unexplained fever, hypotension, leukocytosis, or hyperamylasemia may be the only clue that something is amiss.

Compared with the clinical course of typical calculous cholecystitis, that of acute acalculous cholecystitis is more fulminant. By the time the diagnosis has been made, at least half of the patients have experienced a complication of cholecystitis, such as gangrene or a confined perforation of the gallbladder. Empyema of the gallbladder and ascending cholangitis may further complicate cases in which bacterial superinfection of the gallbladder has occurred. Because the disease often occurs in debilitated patients and complications occur rapidly, the mortality rate of acute acalculous cholecystitis is high, ranging from 10% to 50%, as compared with a 1% mortality rate in patients with calculous cholecystitis. Such high mortality rates have led some investigators to propose that empirical cholecystostomy be considered in gravely ill patients in the ICU in whom no source of sepsis can be found.

Diagnosis

The rapid development of complications in acute acalculous cholecystitis makes early diagnosis critical for avoiding excessive mortality. Unfortunately, the lack of specific clinical findings that point to the gallbladder, combined with a confusing clinical picture related to antecedent surgery or trauma, makes early diagnosis difficult. For older adult patients at risk, a high index of suspicion for biliary tract sepsis is the best hope for early recognition and treatment. Table 67.2 delineates several diagnostic criteria for acute acalculous cholecystitis.

TABLE 67.2

Diagnostic Criteria for Acute Acalculous Cholecystitis

Technique	Findings
Clinical evaluation	RUQ tenderness, if present, supports the diagnosis but is lacking in 75% of cases
	Unexplained fever, hypotension, leukocytosis, or hyperamylasemia is frequently the only finding
US	Thickened gallbladder wall (>4 mm) in the absence of ascites and hypoalbuminemia (serum albumin <3.2 g/dL)
	Sonographic Murphy’s sign (maximum tenderness over the US-localized gallbladder)
	Pericholecystic fluid collection
	Bedside availability is a major advantage
CT	Thickened gallbladder wall (>4 mm) in the absence of ascites and hypoalbuminemia
	Pericholecystic fluid, subserosal edema (in the absence of ascites), intramural gas, or sloughed mucosa
	The best test for excluding other intra-abdominal diseases but requires moving the patient to a scanner
Hepatobiliary scintigraphy	Nonvisualization of the gallbladder with normal excretion of radionuclide into the bile duct and duodenum indicates a positive result for acute cholecystitis
	Results in critically ill, immobilized patients may be falsely positive because of viscous bile
	Better at excluding than confirming acute cholecystitis

US

In the evaluation of patients with suspected acute acalculous cholecystitis, US offers the distinct advantage of being widely available and easily transportable to the bedside. Three US findings indicative of gallbladder disease are a (1) thickened gallbladder wall (defined as > 4 mm) in the absence of ascites or hypoalbuminemia, (2) sonographic Murphy’s sign (defined as maximum tenderness over the US-localized gallbladder), and (3) pericholecystic fluid collection. A thickened gallbladder wall ( Fig. 67.1 ) is not specific for cholecystitis but in the proper clinical setting is suggestive of gallbladder involvement and should prompt further evaluation. A sonographic Murphy’s sign is operator dependent and requires a cooperative patient but, when present, is a reliable indicator of gallbladder inflammation. A pericholecystic fluid collection indicates advanced disease. Sensitivity rates of US for detecting acute acalculous cholecystitis have been reported to range from 67% to 92%, with a specificity of more than 90%.

Fig. 67.1, US demonstrating thickening of the gallbladder wall to 17 mm ( denoted by asterisks ) characteristic of acute acalculous cholecystitis. Point tenderness was noted when the transducer was pressed onto the abdomen over the gallbladder (sonographic Murphy’s sign). The diagnosis was confirmed at surgery.

Investigators have proposed a US scoring system to improve the diagnostic accuracy of US in critically ill patients. Two points are given for distention of the gallbladder or thickening of the gallbladder wall, and one point each is given for “striated” thickening (alternating hypoechoic and hyperechoic layers) of the gallbladder wall, sludge, and pericholecystic fluid. Scores of 6 or higher accurately predict acalculous cholecystitis.

One group evaluated the routine use of US for early detection of acalculous cholecystitis in the ICU. In a group of 53 mechanically ventilated patients, 3 men were diagnosed with acute acalculous cholecystitis by US findings and clinical features; however, gallbladder abnormalities were also detected in 30% of patients without acalculous cholecystitis. US should be performed in patients with a high pretest probability of acute acalculous cholecystitis.

CT

CT findings suggestive of cholecystitis are similar to US findings and include gallbladder wall thickening (>4 mm), pericholecystic fluid, subserosal edema (in the absence of ascites), intramural gas, and sloughed gallbladder mucosa. The sensitivity and specificity of these findings for predicting acute acalculous cholecystitis at surgery exceed 95%. CT is also superior to US in detecting disease elsewhere in the abdomen that could be the cause of a patient’s fever or abdominal pain. An obvious disadvantage of CT is that it cannot be performed at the bedside, which is necessary in many critically ill patients. Several investigators have emphasized that CT is complementary to US and may detect gallbladder disease in high-risk patients with normal US findings.

Hepatobiliary scintigraphy

Hepatobiliary scintigraphy may be useful for excluding cystic duct obstruction in patients with clinical features suggestive of acute cholecystitis. Under normal conditions, IV-administered radionuclide is taken up by the liver, secreted into bile, concentrated in the gallbladder (where it produces a “hot spot” on a scan), and emptied into the duodenum. A positive scan result for cystic duct obstruction is defined as failure of filling of the gallbladder despite the normal passage of radionuclide into the duodenum. In suspected calculous cholecystitis, the pathogenesis of which involves obstruction of the cystic duct by a stone, filling of the gallbladder on scintigraphy virtually excludes cholecystitis as the cause of the patient’s symptoms.

Hepatobiliary scintigraphy is less precise in acute acalculous cholecystitis. Gallbladder and cystic wall edema can cause an obstructive picture similar to that of calculous cholecystitis on scintigraphy. Patients with acute acalculous cholecystitis have often fasted for prolonged periods, a state that can result in concentrated, viscous bile that flows poorly through the cystic duct and causes a false-positive hepatobiliary scan result. Most patients with acute acalculous cholecystitis (in contrast to those with calculi) do not have an obstructed cystic duct; hence, hepatobiliary scans can be falsely negative as well. The sensitivity of the test may exceed 90%, but the lack of specificity in fasted, critically ill patients limits the usefulness of the test primarily to excluding acute acalculous cholecystitis rather than confirming the diagnosis. A study in which US and cholescintigraphy were performed in critically ill patients found cholescintigraphy to be useful for the early diagnosis of acute acalculous cholecystitis, whereas US alone did not permit an early decision regarding the need for surgery.

In an effort to improve the accuracy of biliary scintigraphy, investigators have proposed the use of morphine-augmented cholescintigraphy , in which morphine sulfate is administered IV (0.05 to 0.1 mg/kg) to increase resistance to the flow of bile through the sphincter of Oddi and, hence, “force fill” the gallbladder if the cystic duct is patent to reduce the likelihood of a false positive result. Although this test may exclude cholecystitis as a cause of sepsis, it is difficult to perform in critically ill patients.

Treatment

In light of the rapid progression of acute acalculous cholecystitis to gangrene and perforation, early recognition and intervention are required. Supportive medical care should include restoration of hemodynamic stability as well as antibiotic coverage for Gram-negative enteric organisms and anaerobes if biliary tract infection is suspected.

Surgical Cholecystectomy and Cholecystostomy

In the past, the definitive therapeutic approach to acute acalculous cholecystitis was emergency laparotomy and cholecystectomy (see Chapter 66 ). Subsequently, laparoscopic cholecystectomy became the standard surgical approach, but more recently radiographically guided percutaneous cholecystostomy has been used more frequently because patients are often too unstable to tolerate anesthesia and surgery. If necessary, definitive cholecystectomy can be undertaken after cholecystotomy when the patient is stable.

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