Should I consider acute acalculous cholecystitis in my elderly ambulatory patient admitted with right upper quadrant pain?

Short answer: Yes! Although we usually associate acute acalculous cholecystitis (AAC) with critically ill patients (eg, with sepsis, trauma, shock, major burns) in ICUs, AAC is not as rare as we might think in ambulatory patients. In fact, a 7 year study of AAC involving multiple centers reported that AAC among outpatients was increasing in prevalence and accounted for 77% of all cases (1)!

Although the pathophysiology of ACC is not fully understood, bile stasis and ischemia of the gallbladder either due to microvascular or macrovascular pathology have been implicated as potential causes (2). One study found that 72% of outpatients who developed ACC had atherosclerotic disease associated with hypertension, coronary, peripheral or cerebral vascular disease, diabetes or congestive heart failure (1). Interestingly, in contrast to calculous cholecystitis, “multiple arterial occlusions” have been observed on pathological examination of the gallbladder in at least some patients with ACC and accordingly a name change to “acute ischemic cholecystitis” has been proposed (3).

AAC can also complicate acute mesenteric ischemia and may herald critical ischemia and mesenteric infarction (3). The fact that cystic artery is a terminal branch artery probably doesn’t help and leaves the gallbladder more vulnerable to ischemia when arterial blood flow is compromised irrespective of the cause (4).

Of course, besides vascular ischemia there are numerous other causes of ACC, including infectious (eg, viral hepatitis, cytomegalovirus, Epstein-Barr virus, Salmonella, brucellosis, malaria, Rickettsia and enteroviruses), as well as many non-infectious causes such as vasculitides and, more recently, check-point inhibitor toxicity (1,5-8).

Bonus Pearl: Did you know that in contrast to cholecystitis associated with gallstones (where females and 4th and 5th decade age groups predominate), ACC in ambulatory patients is generally more common among males and older age groups (mean age 65 y) (1)?


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1. Savoca PE, Longo WE, Zucker KA, et al. The increasing prevalence of acalculous cholecystitis in outpatients: Result of a 7-year study. Ann Surg 1990;211: 433-37.
2. Huffman JL, Schenker S. Acute acalculous cholecystitis: A review. Clin Gastroenterol Hepatol 2010;8:15-22.
3. Hakala T, Nuutinene PJO, Ruokonen ET, et al. Microangiopathy in acute acalculous cholecystitis Br J Surg 1997;84:1249-52.
4. Melo R, Pedro LM, Silvestre L, et al. Acute acalculous cholecystitis as a rare manifestation of chronic mesenteric ischemia. A case report. Int J Surg Case Rep 2016;25:207-11.
5. Aguilera-Alonso D, Median EVL, Del Rosal T, et al. Acalculous cholecystitis in a pediatric patient with Plasmodium falciparum infection: A case report and literature review. Ped Infect Dis J 2018;37: e43-e45.  
6. Kaya S, Eskazan AE, Ay N, et al. Acute acalculous cholecystitis due to viral hepatitis A. Case Rep Infect Dis 2013;Article ID 407182.
7. Simoes AS, Marinhas A, Coelho P, et al. Acalculous acute cholecystitis during the course of an enteroviral infection. BMJ Case Rep 2013;12.
8. Abu-Sbeih H, Tran CN, Ge PS, et al. Case series of cancer patients who developed cholecystitis related to immune checkpoint inhibitor treatment. J ImmunoTherapy of Cancer 2019;7:118.



Should I consider acute acalculous cholecystitis in my elderly ambulatory patient admitted with right upper quadrant pain?

Why are patients with acute exacerbation of COPD at higher risk of venous thromboembolism (VTE)?

Patients admitted to the hospital for acute exacerbation of COPD are generally regarded as being at high risk of venous thromboembolism (VTE) (prevalence 5%-29%), possibly due to the frequent coexistence of other risk factors, such as immobility, history of smoking, and venous stasis.1 The exact mechanism(s) behind this association remains poorly understood, however.

Among patients with moderate-very severe COPD (GOLD criteria stage II-IV),  high BMI, low exercise tolerance, history of pneumothorax, congestive heart failure, and peripheral vascular disease have also been associated with VTE.1

Systemic inflammation has also been implicated in increasing the risk of VTE in patients with COPD. Although the pathophysiology of COPD is largely defined by the local inflammatory response to airway injury, evidence suggests that there is also a systemic inflammatory response in COPD.2,3 This systemic inflammation could in turn contribute to the increased risk of vascular disease, including VTE, coronary artery disease, and cerebrovascular disease.4

Bonus pearl: Did you know that VTE may be 3x more prevalent among patients with COPD exacerbation without known cause (vs those with identifiable cause) and is associated with a 1-year mortality of 61.9%! 5


  1. Kim V, Goel N, Gangar J, et al. Risk factors for venous thromboembolism in chronic obstructive pulmonary disease. Chronic Obstr Pulm Dis 2014;1: 239-249.
  2. Lankeit M, Held M. Incidence of venous thromboembolism in COPD: linking inflammation and thrombosis? Eur Respir J 2016;47(2):369-73.
  3. Sinden NJ1, Stockley RA. Systemic inflammation and comorbidity in COPD: a result of ‘overspill’ of inflammatory mediators from the lungs? Review of the evidence. Thorax 2010;65:930-6.
  4. King PT. Inflammation in chronic obstructive pulmonary disease and its role in cardiovascular disease and lung cancer. Clinical and Translational Medicine 2015;4:26.
  5. Gunen H, Gulbas G, In E, et al. Venous thromboemboli and exacerbations of COPD. Eur Respir J 2010;36:1243-8. 

Contributed by Camilo Campo, Medical Student, Harvard Medical School, Boston, MA.

Why are patients with acute exacerbation of COPD at higher risk of venous thromboembolism (VTE)?

How does hyperventilation cause coronary vasospasm?

Hyperventilation may be an important cause of coronary vasospasm and chest pain. 1 The mechanism likely revolves around the competition between the effects of hydrogen and calcium ions on the smooth muscle of coronary arteries. 2

Respiratory alkalosis induced by hyperventilation causes a reduction of hydrogen ions which, under physiologic conditions, compete with calcium ion, an important trigger for arterial smooth muscle contraction. Lower hydrogen ion concentrations tips the balance in favor of calcium’s effects on transmembrane channels and myofibrillar ATP-ase of the smooth muscle and causes vasoconstriction.2

In fact, hyperventilation has been used to reproduce coronary spasm during angiography in patients with non-obstructive coronary artery disease and angina symptoms.The efficacy of hyperventilation in inducing an alkalotic state during this test is verified by obtaining an arterial blood gas after 6-minutes of hyperventilation.  A basic Tris-buffer to enhance alkalotic provocation was also used in earlier studies. 2

In addition to producing spasm and angina, hyperventilation-induced alkalosis has been associated with frank transmural myocardial infarction and ischemia-related arrhythmias such as ventricular tachycardia. 2,4,5

So in the appropriate context, hyperventilation may not be so benign!


  1. Freeman LJ, Nixon PGF. Chest pain and the hyperventilation syndrome-some aetiologic considerations. Postgrad Med J 1985;61:957-61.
  2. Yasue HM, Nagao S, Omote A, et al. Coronary arterial spasm and Prinzmetal’s variant form of angina induced by hyperventilation and Tris-buffer infusion. Circulation 1978;58:56-62.
  3. Zaya M, Mehta PK, Merz NB, etal. Provocative testing for coronary reactivity and spasm. J Am Coll Cardiol 2014; 63:103-9.
  4. Magarian GJ, Jones S, Calverley T. Hyperventilation testing for coronary vasospasm: induction of spontaneous ventricular tachycardia in association with transmural ischemia without obstructive coronary disease. 1990; 120:1447-49.
  5. Chelmowski MK, Keelan MH. Hyperventilation and myocardial infarction. Chest 1988;93:1095-96.

Contributed by Ramya Chitra Mosarla, Medical Student, Harvard Medical School

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How does hyperventilation cause coronary vasospasm?

What is the significance of the diagonal ear lobe crease or “Frank’s sign”?

Frank’s sign, also known as diagonal earlobe crease (DELC), has often been considered a sign of coronary artery disease (CAD), originally described in patients 60 years of age or younger in 1973 (1). Since then, the majority of clinical, angiographic, and postmortem reports seem to support the association of this physical finding (see figure) with atherosclerotic coronary disease (2,3). In addition, it may be associated with peripheral vascular disease (4) as well as cerebrovascular disease (5).

In a study of hospitalized patients, there was a significant association between DELC and cardiovascular events with a sensitivity of 43% and specificity of 70% (3).

Although the mechanism for this association is unclear, microvascular disease involving the middle ear lobe end-artery territory has been implicated (6).  Free radical oxidative stress activation of the metalloproteinases that break down type 1 collagen has also been suggested (7).

It is fair to conclude, however, that the value of this sign as a screening tool for CAD has not been firmly established and its utility in clinical practice remains uncertain, particularly in those older than 60 years of age or those with diabetes (6).



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1. Frank ST. Aural sign of coronary-artery disease. N Engl J Med 1973;289:327-8.

2. Friedlander AH, Lopez-Lopez J, Velasco-Ortega E. Diagonal ear lobe crease and atherosclerosis: a review of the medical literature and dental implications. Med Oral Patol Oral Cir Bucal 2012;1:e153-9. 

3. Rodriguez-Lopez C. Garlito-Diaz H, Madronero-Mariscal R, et al. Earlobe crease shapes and cardiovascular events. Am J Cardiol 2015;116:286-93.

4. Korkmaz L, Agac MT, Acar Z, et al. Earlobe crease may provide predictive information on asymptomatic peripheral arterial disease in patients clinically ree of atherosclertotic vascular disase. Angiology  2014;65:303-7.

5. Celik S, Erdogan T, Gedikli O, et al. Earlobe crease is associated with carotid intima-media thickness in subjects free of clinical cardiovascular disease. Atherosclerosis 2007;192:428-31.

6. Shoenfeld Y, Mor R, Weinberger A, et al. Diagonal earl lobe crease and coronary risk factors. J Am Geriatr Soc 1980;28:184-7.

7.  Fabijanic D, Culic V. Diagonal ear lobe crease and coronary artery disease. Am J Cardiol 2012;110:1385-6. 

Contributed in part by Kathryn Dinh, Medical Student, Harvard Medical School, Boston, MA.

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis or its affiliate healthcare centers. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you


What is the significance of the diagonal ear lobe crease or “Frank’s sign”?