The initial differential diagnosis for this patient's right upper quadrant pain included acute gallstone-mediated cholecystitis, acalculous cholecystitis, and congestive hepatopathy. The entity of transient cholecystalgia, fluctuating in real time with volume status, was not initially considered. This led to unnecessary testing for alternative etiologies, plans for cholecystectomy, and significant confusion for the patient and providers when the initial formal RUQ ultrasound did not corroborate the bedside physical exam and point-of-care ultrasound. A brief review of the considered etiologies of RUQ pain and discussion of the appropriate weight we should place on our clinical and imaging diagnostic tests for the gallbladder follows.
Accuracy of gallbladder diagnostics
The right upper quadrant ultrasound is the most commonly used imaging modality in the evaluation of gallbladder disease. The test's accuracy for acute cholecystitis has been debated due to the presence of verification bias [1,2]. A meta-analysis of ultrasound's accuracy for acute cholecystitis found a sensitivity of 94% and specificity of 78%. When the results were adjusted for verification bias, the sensitivity decreased to 88% and specificity increased to 80%. The authors recommended using estimates between the adjusted and unadjusted values. Radionucleotide scanning has better sensitivity (97%) and specificity (90%) for acute cholecystitis .
We rely heavily on these test characteristics of formal ultrasound because our clinical and laboratory testing alone do not have the power to rule in or out the diagnosis of acute cholecystitis. The negative likelihood ratio (LR) of RUQ tenderness is 0.4 (95% confidence interval 0.2 to 1.1), representing the most helpful clinical finding in ruling out acute cholecystitis. However, lack of RUQ tenderness is probably weaker than this for excluding acute cholecystitis when studies are adjusted for verification and spectrum bias. The positive LR of the Murphy sign at 2.8 (0.8 to 8.6) is the most helpful finding for strengthening a diagnosis of acute cholecystitis and appears to be even stronger when the data are adjusted for verification and spectrum bias. Notably, the 95% confidence intervals for both of these likelihood ratios cross 1. The ‘clinical impression’ of cholecystitis, which includes an unspecified combination of history, physical exam, and laboratory findings, results in the best test with an estimated positive LR of 25 to 30 .
In the case of our patient, the presence of gallstones, gallbladder wall thickening, and a positive sonographic Murphy sign has extremely high positive predictive value (98.5%) for a gallbladder requiring surgical intervention . However, she did not require cholecystectomy once the secondary nature of her gallbladder abnormality was confirmed.
Acute acalculous cholecystitis (ACC) remains a menacing diagnosis that carries a mortality rate of at least 30% . Though traditionally associated with critical illness, trauma, burns, and the post-operative period, ACC can occur in a variety of other scenarios. It has been hypothesized that major contributing factors include bile stasis and gallbladder ischemia, followed by secondary infection with enteric pathogens. Bile stasis has been attributed to volume depletion, opioid-induced sphincter of Oddi spasm, gastrointestinal hypomotility, and positive-pressure mechanical ventilation. Gallbladder ischemia may be due to systemic hypotension, possibly exacerbated by increased intraluminal pressure from bile stasis, which together decrease the gallbladder perfusion pressure [5,6]. ACC can occur in the setting of congestive heart failure (CHF), where the gallbladder perfusion pressure presumably suffers due to decreased cardiac output and elevated venous pressures [4,7,8]. Unlike the scenario presented in our case, ACC is typically not transient.
The pathogenesis of ACC involves inflammation and necrosis of the gallbladder in the absence of an obstructing gallstone. Signs and symptoms include fever, anorexia, nausea, vomiting, RUQ or upper abdominal tenderness, and Murphy sign (if the patient is able to communicate pain). Laboratory abnormalities include leukocytosis and elevated alkaline phosphatase, bilirubin, and aminotransferases. Unfortunately, none of these findings are particularly sensitive or specific in the affected patient population, and diagnosis relies heavily on the physician's assessment of the overall clinical picture [2,7].
Ultrasonography is the preferred test for diagnosis due to the typical location of these patients in the intensive care unit; however, the test has a sensitivity ranging from 30% to 100% . Radionucleotide scanning, more cumbersome in sick patients and fraught with false positives, has better sensitivity for ACC with values ranging from 67% to 100%  and a review targeting a sensitivity of 91% . The treatment is surgical, with cholecystectomy or percutaneous cholecystostomy in addition to antibiotic therapy.
Congestive hepatopathy, a common diagnosis in patients with decompensated heart failure and RUQ pain, is a well-established clinical syndrome that can result from any cause of right heart failure. Elevated central venous pressure in congestive heart failure is transmitted to the hepatic veins and to the venules draining hepatic acini, and these increased pressures can result in atrophy of hepatocytes and perisinusoidal edema that impairs diffusion of oxygen and nutrients [10,11].
Patients with hepatic congestion are usually asymptomatic but can present with RUQ pain attributed to stretching of the liver capsule, usually seen during acute exacerbations of congestive heart failure . The most common laboratory abnormalities attributed to congestive hepatopathy in patients with chronic CHF are decreased albumin, elevated serum bilirubin, and elevated alkaline phosphatase . Generally, when abnormalities are present, they are mild: serum bilirubin is typically less than 3 mg/dL, alkaline phosphatase is typically normal or only minimally elevated, and aminotransferases are usually normal and rarely greater than two times the upper limit of normal [14,15]. However, there is some evidence that in more severe congestive heart failure (on the basis of cardiac index ≤1.5 L/min/m2), more significant abnormalities in liver function tests are seen, including aminotransferase elevations >400 U/L . One study found that elevated serum bilirubin was an independent predictor of adverse cardiovascular outcomes and all-cause mortality in patients with chronic CHF .
The typical ultrasound findings in congestive hepatopathy are non-specific and can include a dilated, non-collapsible inferior vena cava, hepatomegaly, ascites, and Doppler waveform abnormalities in the portal veins. The right upper quadrant ultrasound is primarily utilized to rule out other causes of RUQ pain [16,17].
Once identified, management of congestive hepatopathy primarily involves treatment of the underlying heart disease, including careful diuresis and efforts to avoid decreasing cardiac output.
Diffuse gallbladder wall thickening
While heart failure can cause congestive hepatopathy, it is also known to be a cause of diffuse gallbladder wall thickening. This finding is non-specific and can occur in many other states including acute cholecystitis, cirrhosis, hypoalbuminemia, adenomyomatosis, malignancy, hepatitis, pancreatitis, etc. The diffuse wall thickening related to elevated portal and systemic venous pressures such as in cirrhosis and heart failure is typically not thought to cause pain and a positive Murphy sign [18–21]. In our patient, a definite focal Murphy sign was present at the time of the wall thickening (and pain symptoms) and resolved with resolution of wall thickening.