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?

My elderly patient with abdominal pain has a negative Murphy’s sign on physical exam. How accurate is Murphy’s sign in diagnosing cholecystitis?

Not as accurate as we might like! In fact, no single clinical finding has been found to carry sufficient weight in ruling in or excluding cholecystitis and Murphy’s sign (inability to take a deep breath due to pain upon palpation of the right upper quadrant) is no exception. 1

A meta-analysis of patients with Murphy’s sign reported a sensitivity of 65% and a specificity of 87% (positive LR 2.8, negative LR 0.4, with 95% C.I. including 1.0 in both). 1,2  However, among the elderly (mean age 79 y), the sensitivity may be a slow as 48% 2 and in patients with gangrenous cholecystitis as low as 33%.3  

In contrast, Murphy’ s sign elicited at the time of ultrasound of the gallbladder (ie,“sonographic Murphy’s) is generally thought to very sensitive  (>90%) for acute cholecystitis;3,4 1 study reported a sensitivity of 63%, however (specificity 94%).5  Remember that altered mental status may also mask sonographic Murphy’s sign. 

Indirect fist percussion of the liver has been suggested by some authors as a more sensitive alternative to Murphy’s sign (100% vs 80%) in a small series of patients with cholecystitis.2

Bonus pearl: Did you know that another technique originally described by the famed American surgeon, John Murphy, to diagnose acute cholecystitis consisted of the “hammer stroke maneuver” in which percussion of the right midsubcostal region with the bent middle finger of the left hand was performed using the right hand to strike the dorsum of the left hand with hammer-like blows? 6

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  1. Trowbridge RL, Rutkowski NK, Shojania KG. Does this patient have acute cholecystitis. JAMA 2003;289:80-86.
  2. Ueda T, Ishida E. Indirect fist percussion of the liver is a more sensitive technique for detecting hepatobiliary infections than Murphy’s sign. Current Gerontol Geriat Res, Volume 2015, Article ID 431638.
  3. Simeone JF, Brink JA, Mueller PR, et al. The sonographic diagnosis of acute gangrenous cholecystitis. The importance of the Murphy sign. AJR 1989;152:289-90.
  4. O’Connor OJ, Maher MM. Imaging of cholecystitis. AJR 2011;196:W36774.
  5. Rallis PW, Lapin SA, Quinn MF, et al. Prospective evaluation of the sonographic Murphy sign in suspected acute cholecystitis. J Clin Ultrasound 1982;10:113-5.
  6. Salati SA, al Kadi A. Murphy’s sign of cholecystitis-a brief revisit. Journal of Signs and Symptoms 2012;1:53-6.’s_sign_of_cholecystitis-_a_brief_revisit



My elderly patient with abdominal pain has a negative Murphy’s sign on physical exam. How accurate is Murphy’s sign in diagnosing cholecystitis?

When should surgery be considered in my hospitalized patient with divertculitis?

Severe diffuse abdominal pain, fever, tachycardia, leukocytosis or other signs of sepsis and diffuse peritonitis indicative of free perforation requires emergent surgery. Urgent surgery should be considered when your patient fails to improve (eg, abdominal pain or the inability to tolerate enteral nutrition, bowel obstruction, or infection-related ileus) despite medical therapy or percutaneous drainage. 1,2

Lower threshold for surgical intervention is also needed in transplant patients, patients on chronic corticosteroid therapy, other immunosuppressed patients and those with chronic renal failure or collagen-vascular disease because these patients have a significantly greater risk of recurrent, complicated diverticulitis requiring emergency surgery. Overall, up to 20% of patients with acute diverticulitis undergo surgery during the same hospitalization.2

For patients with recurrent uncomplicated diverticulitis, decision regarding future elective surgery should be individualized. Although older guidelines recommended surgery after 2 attacks of uncomplicated diverticulitis, more recent guidelines place less emphasis on the number of episodes and stress the importance of considering the severity of the attacks, chronic or lingering symptoms, inability to exclude carcinoma, overall medical condition of the patient, risks of surgery, and the impact of diverticulitis on the patient’s lifestyle.1,2

Of interest, a decision analysis model suggests that elective resection after a fourth episode may be as safe as earlier resection.3



  1. Young-Fadok TM. Diverticulitis. N Eng J Med 2018;397:1635-42
  2. Feingold D, Steele SM, Lee S, et al. Practice parameters for the treatment of sigmoid diverticulitis. Dis Colon Rectum 2014;57:284-94.
  3. Salem L, Veenstra DL, Sullivan SD, et al. The timing of elective colectomy in diverticulitis: A decision analysis. J Am Coll Surg 2004;199:904-12.

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When should surgery be considered in my hospitalized patient with divertculitis?

Is it possible to have acute pancreatitis with normal serum lipase?

Yes! Although an elevated serum lipase has a negative predictive value of 94%-100% for acute pancreatitis (1), there are ample reports in the literature of patients with CT findings of pancreatitis in the presence of abdominal symptoms but with normal serum lipase and/or amylase (2,3).

A case series and review of literature of acute pancreatitis with normal lipase and amylase failed to reveal any specific risk factors for such observation (2). More specifically, the etiologies of acute pancreatitis in the reported cases have varied, including drug-induced, cholelithiasis, alcohol, hypertriglyceridemia, and postoperative causes.

But what accounts for this phenomenon? Many cases have been associated with the first bout of pancreatitis without evidence of pancreatic calcifications which makes the possibility of a “burned-out” pancreas without sufficient acinar cells to release lipase as a frequent cause unlikely. Other potential explanations for normal lipase in acute pancreatitis have included measurement of serum lipase at a very early phase of the disease before significant destruction of acinar cells has occurred (increases in 3-6 h, peaks at 24 h [4]) and more rapid renal clearance of serum lipase due to tubular dysfunction (2).

Of note, unlike amylase, lipase is totally reabsorbed by renal tubules under normal conditions (5). Thus, it’s conceivable that even a reversible tubular dysfunction may lead to increased clearance of serum lipase and potentially lower its levels.
1. Ko K, Tello LC, Salt J. Acute pancreatitis with normal amylase and lipase. The Medicine Forum. 2011;11 Article 4.
2. Singh A, Shrestha M. Acute pancreatitis with normal amylase and lipase-an ED dilemma. Am J Emerg Med 2016;940.e5-940.e7.
3. Limon O, Sahin E, Kantar FU, et al. A rare entity in ED: normal lipase level in acute pancreatitis. Turk J Emerg Med 2016;16:32-34.
4. Shah AM, Eddi R, Kothari ST, et al. Acute pancreatitis with normal serum lipase: a case series. J Pancreas (Online) 2010 July 5;11:369-72. PDF
5. Lott JA, Lu CJ. Lipase isoforms and amylase isoenzymes: assays and application in the diagnosis of acute pancreatitis. Clin Chem 1991;37:361-68.
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Is it possible to have acute pancreatitis with normal serum lipase?

Should I be concerned about the umbilical hernia in my patient with cirrhosis and ascites?

Although umbilical hernia in patients with cirrhosis and ascites is common and often “expected” (a rate of 20% during the course of their disease), it can be associated with significant risk of complications such as incarceration, ascites drainage, peritonitis, and spontaneous rupture or evisceration from necrosis of overlying skin.1,2

A 2007 retrospective study involving patients with cirrhosis and umbilical hernia reported a complication rate of 77% and related mortality of 15% among those managed conservatively (mean period of observation ~ 5 years); MELD score could not predict failure of conservative management (median 22 in complicated vs 24 in uncomplicated).3

Because the risk of death with hernia repair in urgent settings is 7x higher than for elective hernia repair in cirrhotic patients, there has been increasing interest in elective repair in patients with well-compensated cirrhosis.3 Interestingly, the reported surgical complication rates among patients with well-compensated cirrhosis appear similar to those in noncirrhotic patients.3 If the patient is expected to undergo liver transplantation in the near future, elective hernia repair can be postponed and managed concomitantly.

Bonus pearl: Did you know that spontaneous umbilical hernia rupture is also known as “Flood syndrome” (should be easy to remember!), first described by Frank B Flood, a surgical resident back in 1961? 4


  1. Marsman HA, Heisterkamp J, Halm JA, et al. Management in patients with liver cirrhosis and an umbilical hernia. Surgery 2007;142:372-5.
  2. Coelho, JCU, Claus CMP, Campos ACL, et al. Umbilical hernia in patients with liver cirrhosis: a surgical challenge. World J Gastrointest Surg 2016;8:476-82.
  3. Martens P, Laleman W. Umbilical hernia in a patient with cirrhosis. Cleveland Clin J Med 2015;82: 404-5.
  4. Nguyen ET, Tudtud-Hans LA. Flood syndrome: spontaneous umbilical hernia rupture leaking ascitic fluid-a case report. Perm J 2017;21:16-152. 

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Should I be concerned about the umbilical hernia in my patient with cirrhosis and ascites?

Should I consider octreotide in my patient with non-variceal upper GI bleed?

Octreotide is routinely used in the treatment of variceal bleeding due to its vasoconstrictive effects on the splanchnic vasculature.1 In non-variceal upper GI bleed (NVUGB), however, the evidence for routine use of octreotide is hard to come by with an international consensus panel recommending its use only on a case-by-case basis in patients with very active bleeding while awaiting endoscopy or surgery.2,3

These recommendations are based on the failure of several randomized controlled trials in demonstrating the superiority of octreotide in NVUGB over placebo, either alone or with ranitidine, except in a small subset of patients with actively oozing ulcers.4-6 Although a meta-analysis has suggested that octreotide may reduce the risk of continued bleeding in NVUGB,7 the validity of some of the included studies has been questioned.8

On the other hand, octreotide decreases gastric mucosal blood flow and inhibits acid and pepsin secretion, which may potentially benefit patients who are actively bleeding.9

Final fun fact: Did you know that octreotide may be effective in the treatment of chylothorax?



  1. Avgerinos A, Armonis A, Raptis S. Somatostatin and octreotide in the management of acute variceal hemorrhage. Hepatogastroenterology 1995;42:145-50.
  2. Barkun AN, Barrdou M, Kulpers EJ, et al. International concensus recommendations on the management of patients with nonvariceal upper gastrointestinal bleeding. Ann Intern Med 2010;152:101-113.
  3. Barkun A, Bardou M, Marshall JK, Nonvariceal Upper GIBCCG Consensus Conference Group. Consensus recommendations for managing patients with nonvariceal upper gastrointestinal bleeding. Ann Intern Med 2003;139:843–857.
  4. Nikolopoulou VN, Thomopoulos KC, Katsakoulis EC, et al. The effect of octreotide as an adjunct treatment in active nonvariceal upper gastrointestinal bleeding. J Clin Gastroenterol 2004;38:243-7.
  5. Archimandritis A, Tsirantonaki M, Tryphonos M, et al. Ranitidine versus ranitidine plus octreotide in the treatment of acute non-variceal upper gastrointestinal bleeding: a prospective randomized study. Curr Med Res Opin. 2000;16(3):178-83.
  6. Okan A, Simsek I, Akpinar H, et al. Somatostatin and ranitidine in the treatment of non-variceal upper gastrointestinal bleeding: a prospective, randomized, double-blind, controlled study. Hepatogastroenterology 2000;47:1325-7.
  7. Imperiale TF, Birgisson S. Somatostatin or octreotide compared with H2 antagonists and placebo in the management of acute nonvariceal upper gastrointestinal hemorrhage: a meta-analysis. Ann Intern Med 1997;127:1062–1071.
  8. Palmer KR. Non-variceal upper gastrointestinal haemorrhage: guidelines. Gut. 2002;51 (Suppl 4): iv1–iv6.
  9. Sgouros SN, Bergele C, Viazis N, et al. Somatostatin and its analogues in peptic ulcer bleeding: facts and pathophysiological aspects. Dig Liver Dis. 2006;38:143-8.


Contributed byAlice Choi, Medical Student, Harvard Medical School


Should I consider octreotide in my patient with non-variceal upper GI bleed?

Is measurement of amylase and lipase useful in patients with renal insufficiency suspected of pancreatitis?

Depends on how high the serum levels are! Although the clearance of both amylase and lipase appears to be impaired in patients with significant renal insufficiency (eg,  creatinine clearance <50ml/min), serum levels greater than 2-4 times the upper limits of normal for these enzymes are still considered suggestive of pancreatitis in these patients1-3.

Interestingly, in hemodialysis patients, elevation of lipase may also be due to the lipolytic effect of heparin during this procedure.  That’s why obtaining serum lipase levels before, not after,  hemodialysis has been recommended4

Also fascinating is that most of the elevation of serum amylase in patients with significant renal insufficiency appears to be related to the elevation of salivary, not pancreatic, isoenzyme of amylase4.

Final fun fact: Did you know that at one time the diagnosis of pancreatitis was based on the activity of serum on starch (for amylase) and olive oil (for lipase)? 5


  1. Levitt MD, Rapoport M, Cooperband SR. The renal clearance of amylase in renal insufficiency, acute pancreatitis, and macroamylasemia. Ann Intern Med 1969;71:920-25.
  2. Collen MJ, Ansher AF, Chapman AB, et al. Serum amylase in patients with renal insufficiency and renal failure. Am J Gastroenterol 1990;85:1377-80.
  3. Royce VL, Jensen DM, Corwin HL. Pancreatic enzymes in chronic renal failure. Arch Intern Med 1987;147:537-39.
  4. Vaziri ND, Change D, Malekpour A, et al. Pancreatic enzymes in patients with end-stage renal disease maintained on hemodialysis. Am J Gastroenterol 1988;83:410-12.
  5. Editorial. Pancreatic enzymes. N Engl J Med 1963;268:901-2.
Is measurement of amylase and lipase useful in patients with renal insufficiency suspected of pancreatitis?

How should I interpret a positive result for serum cryoglobulins?

Cryoglobulins (CGs) are immunoglobulins that precipitate in the blood under cold conditions (<37◦ C) and redissolve upon warming1.  The term “cryoglobulinemia” is commonly used to describe patients with a systemic inflammatory syndrome that is often associated with small-to-medium vessel vasculitis due to cryoglobulin-containing immune complexes. Although some patients with cryoglobulinemia may be asymptomatic, most present with a range of diseases characterized by fatigue, arthralgia, skin rashes or necrosis, purpura, neuropathy, bowel wall ischemia and/or glomerulonephritis and kidney failure.

Wintrobe and Buell are credited for first describing cryglobulinemia in 1933 when assessing a patient who ultimately was found to have multiple myeloma2. Since then the spectrum of diseases associated with CG has expanded to also include seemingly disparate conditions such as hepatitis C, autoimmune disorders and monoclonal gammopathy of undetermined significance (MGUS).  A commonly cited classification scheme for CG is shown (Table)3.   It should be emphasized that some CGs may not fit neatly into this scheme.

In our patient, the positive CG serum test should be interpreted in the clinical context in which it was obtained while searching for risk factors as well as signs and symptoms that may be associated with cryoglobulinemia.


Table. Classification of cryoglobulinemia

Category Description Examples
Type I Isolated monoclonal immunoglobulin, either IgM or IgG (less commonly IgA or free immunoglobulin light chains Multiple myeloma, Waldenström’s macroglobulinemia, monoclonal gammopathy of undetermined significance (MGUS)
Type II Mixture of monoclonal IgM and polyclonal IgG Hepatitis C, HIV, other viral infections
Type III Polyclonal mixture IgM and IgG Autoimmune disorders, hepatitis C


  1. Takada S, Shimizu T, Hadano Y, et al. Cryoglobulinemia (review). Mol Med Rep 2012;6:3-8
  2. Wintrobe MM, Buell MV. Hyperproteinemia associated with multiple myeloma. Bull Johns Hopkins Hosp 52: 156-165, 1933
  3. Brouet JC, Clauvel JP, Danon F, et al. Biological and clinical significance of cryoglobulins. Am J Med 1974; 57:775-88.


Contributed by Kirstin Scott, Medical Student, Harvard Medical School

How should I interpret a positive result for serum cryoglobulins?

My 35 year old patient with chronic alcoholism blames benign prostatic hypertrophy for his difficulty voiding. Could his bladder dysfunction be related to his alcoholism?

Several case reports in the literature have stressed the association of bladder dysfunction (BD) with chronic alcohol abuse1,2.  Although some cases may be associated with concurrent thiamine deficiency (with its attendant neuropathy), other cases of BD do not appear to be. The mechanism of BD in this setting may be related to the toxic effect of alcohol on peripheral, autonomic and/or central nervous systems2,3.

Binge drinking may also be associated with urinary retention, with spontaneous atraumatic urinary bladder rupture having been reported on several occasions4. Lastly, alcohol withdrawal alone may precipitate urinary retention5.  

Unfortunately, many cases of abdominal pain due to urinary retention in the setting of alcohol abuse or withdrawal may be mistakenly attributed to ascites or other causes5.  High index of suspicion for BD is essential to minimize its complications.

In our patient, given the low prevalence of benign prostatic hypertrophy in men less than 40 years of age, urinary retention due to alcohol-related BD is more likely.



  1. Yuan R, Carcciolo VJ, Kulaga M. Chronic abdominal distension secondary to urinary retention in a patient with alcoholism. JAMA 2002;287;318-19.
  2. Sheremata WA, Sherwin I. Alcoholic myelopathy with spastic urinary bladder. Dis Nerv Syst 1972;33:136-139.
  3. Mellion M, Gilchrist JM, De La Monte S. Alcohol-related peripheral neuropathy: nutritional, toxic or both? Muscle Nerve 2011;43:309-16.
  4. Muneer M, Abdelrahman H, El-Menyar A, et al. Spontaneous atraumatic urinary bladder rupture secondary to alcohol intoxication: a case report and review of literature. Am J Case Rep 2015;16:778-81.
  5. Iga J-I, Taniguchi T, Ohmori T. Acute abdominal distension secondary to urinary retention in a patient after alcohol withdrawal. Alcohol Alcoholism 2005;40:86-87.
My 35 year old patient with chronic alcoholism blames benign prostatic hypertrophy for his difficulty voiding. Could his bladder dysfunction be related to his alcoholism?

“In my patient with abdominal pain, what physical exam finding can help differentiate abdominal wall from intra-abdominal sources of pain?”

Carnett’s sign (described by a surgeon, J.B. Carnett, in 1926) is a physical exam finding that helps differentiate abdominal wall or psychogenic pain from intra-abdominal sources of pain.

The test is considered positive when, upon locating the tender abdominal spot, the patient’s pain worsens on tensing of the abdominal wall muscles by lifting the head and shoulders from the bed or by raising both legs with straight knees. Conversely, if the pain decreases with this maneuver, an intra-abdominal source is more likely1,2. Sensitivity of 85%, specificity of 97%, positive likelihood ratio of 2.6 and negative likelihood ratio of 0.2 have been reported in various studies. 3,4

A positive Carnett’s sign should broaden the differential of abdominal pain to include: hernias, irritation of intercostal nerve roots, rectus sheath hematomas, myofascial pain, anterior cutaneous nerve entrapment (latter also discussed in another pearl) and psychogenic pain. In the appropriate clinical setting,  local corticosteroids or anesthetic injections, or the application of hot or cold packs may be therapeutic. 2,5

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  1. Carnett JB. Intercostal neuralgia as a cause of abdominal pain and tenderness. J Surg Gynecol Obstet 1926; 42:625-632.
  2. Bundrick JB, Litin SC. Clinical pearls in general internal medicine.  Mayo Clin Proceedings 2011;86: 70–74.
  3. Takada T, Ikusaka M, Ohira Y, et al. Diagnostic usefulness of Carnett’s test in psychogenic abdominal pain. Intern Med 2011;50:213-17.
  4. Kamboj Ak, Hoverten P, Oxentenko AS. Chronic abdominal wall pain: a common yet overlooked etiology of chronic abdominal pain. Mayo Clin Proc 2019;94:139-44.
  5. Suleiman S , Johnston DE.  The abdominal wall: an overlooked source of pain. Am Fam Physician 2001; 64: 431-8.

Contributed in part by Brad Lander MD, Mass General Hospital, Boston, MA.


“In my patient with abdominal pain, what physical exam finding can help differentiate abdominal wall from intra-abdominal sources of pain?”