Have you ever spared a thought for the little magic green pouch that's tucked underneath the liver? It might seem small, but when it throws a tantrum, it usually causes a mess big enough that, if left untreated, the patient may end up dying in front of the attending physician. The gallbladder, the less affectionate name, is the storage and concentration point of bile (this is a common misconception - bile is produced by the liver and stored in the gallbladder). Bile is a key ingredient in the emulsification of fat, leading to an increase in the aggregated surface areas of fatty molecules, thereby leading to a rise in efficacy in their enzymatic digestion by lipases in the duodenum.
Diagram illustrating the anatomy of the gallbladder and associated structures. The neck of the gallbladder is also known as the 'infundibulum'. This diagram is extracted from: https://www.ehealthstar.com/wp-content/uploads/2014/12/Gallbladder-Anatomy-15.jpg.
However, the gallbladder is only one of the trickiest organs in the upper abdomen. The annoying thing for every patient is, he or she presents with symptoms rather than clear indications of which organ wreaking havoc in the body. More often than not, the very vague but crucial symptom is the chief complaint - very severe tummy pain. Sometimes, they may be apt enough to point you to the direction of the upper tummy, narrowing thus the cumbersome list of differential diagnoses. It can be the gallbladder getting jealous, or the pancreas projecting a volley of insults, or the stomach demanding attention. Luckily, when an organ throws a tantrum, we can tease out who's being naughty by assessing the symptoms associated with the abdominal pain. Then, once we have a vague idea of who to tackle, we move on to the reasons behind the mischief. Is it infection? Is it inflammation? Is it, god forbid, a malignancy? Needless to say, medicine is never purely academic. It is also about being practical at crucial moments. If the patient is seriously unwell, we need to sort out our priorities as well. Sort the patient out, stabilise the vitals and assess the problem while the first two are being executed.
Diagram illustrating the anatomy of the pancreatic biliary drainage system (extracted from: https://www.earthslab.com/wp-content/uploads/2017/03/031717_1534_Pancreas8.jpg)
Diagram illustrating the anatomy of the biliary tree (the pancreas is omitted; it has to be noted, however, that there are two pancreatic ducts, as shown in the diagram above: the major and minor pancreatic ducts) (extracted from: https://media.springernature.com/lw785/springer-static/image/chp:10.1007/978-1-4939-1884-3_5/MediaObjects/303228_1_En_5_Fig1_HTML.jpg)
In this article, I illustrate the diagnostic conundrums that arise when dealing with a patient with upper abdominal pain. I also introduce and elaborate on the different gadgets (quite like the ones in Xiaolin Showdown on Cartoon Network) used by physicians when attempting to explore the issue in greater profundity. They are our lovely imaging partners - CT and Ultrasound.
Theodore** is an adult man who presents to the A&E with acute abdominal pain. He looks unwell and sickly upon admission. Luckily, he remains conscious - by that, I mean his GCS score (Glasgow Coma Scale) is 15 / 15, and responsive to questions. He is well-oriented. He is also slightly feverish upon admission (37.9 degrees Celsius). He is brought in after experiencing serious abdominal pain for five consecutive hours and has vomited two times already, due to the pain. As usual, let's draw up a list of the patient's characteristics as obtained by history-taking.
Patient Profile:
34 Year Old Male, previously healthy who presents with acute abdominal pain for the previous 5 hours; sedentary lifestyle assumed since he works as a solicitor in the City.
Chief Complain(s) and Features:
(a) Abdominal Pain: mainly over the upper abdomen, radiating to the back in the past thirty minutes; spontaneous, acute onset; it is persistent (for the past five hours) and progressive; the pain has not occurred before (i.e. no past episodes) and is excruciating in nature; it is graded 10/10 on the Visual Analogue scale (pain severity scale); debilitating to the extent that the patient cannot perform any normal daily activities; it is relieved (albeit slightly) by leaning forward, with knees bent, and exacerbated by coughing or talking (which involves exertion of further pressure in the abdominal cavity);
(b) Vomiting: two known episodes of vomiting, which has started with the pain. It has to be stressed that there are no episodes prior to the pain; normal consistency and colour of the vomit, as described by the patient (importantly, there is no blood visible); 1 cup of vomit per episode (roughly);
The patient, at this stage, might also be dehydrated, even though it doesn't seem like it at this stage. However, we still have to be careful since the abdominal pain is so severe that the patient may have neglected things other than the pain. Dehydration will be examined during physical examination.
Any vomiting presented is NOT associated, in terms of pathogenesis, with the abdominal pain. They are simply results of the same phenomenon (that we postulate at this stage) - inflammation somewhere in the tummy. The chemicals produced in the process, such as Substance P, Histamine and calcitonin gene-related peptide (CGRP), increase the sensation of pain and trigger vomiting by stimulating a place called the Chemoreceptor Trigger Zone in the medulla oblongata.
Associated Features: No constitutional symptoms, no anaemic symptoms; no change of bowel habit, such as diarrhoea and constipation; no blood in stool (haematochezia); no urinary symptoms, including dysuria and haematuria; other systems are fine (the detailed review of systems is done at a later stage, when we've sorted the patient out).
Past Medical History: Diagnosed gonococcal disease a few weeks ago, fully recovered; medical history otherwise unremarkable;
Past Surgical History: Unremarkable.
Drug History: occasional use of cannabis, no known drug allergies; no chronic medication taken.
Family History: Mother diagnosed primary biliary cholangitis, otherwise unremarkable;
Infectious History: Unremarkable, including no recent travel history;
Dietary History: In non-specific terms, ordering takeaways every day of the week and not eating enough vegetables and fruit; upon prompting- patient confesses that he frequently feeds on snacks like crisps and chocolate, as well as burgers and fries.
Social History: Non-smoker, regular drinker (2 cans of beer per day, sometimes 1 bottle of whisky, especially over the weekend) (Current public health guidelines state that one should not drink more than 14 units per week [4]); living alone, feeling regularly depressed due to occupation and the fact that he works long hours.
At this stage, we also suspect that the patient has alcohol dependency. Due to several mentions of suicide by the patient during the consultation, we also recommend psychiatric referral. Suicidal ideation is a serious affair and we need to make sure that the patient receives prompt support regarding his mental health, in addition to treatment of his current organic issues.
Due to the fact that the patient has had gonococcal disease, we also decide to ask about his sexual history, just to gain a clearer and more comprehensive picture of his overall health.
Sexual History: Single, sexually active. The patient states that he has had ten sexual partners over the past month. Sexual intercourse is mostly unprotected until he was diagnosed gonococcal disease and treated accordingly. He then reverts back to unprotected sex. The patient is also heterosexual - this is not a political question. Men who have sex with men have higher risk in contracting HIV, HPV and a wide array of cancers (See my article: HPV - not just a shorthand for cervical cancer).
With all the information gathered, we move on to the physical examination. At the meantime, regarding the patient's current health status, we have administered pethidine (opioid) to control the pain and anti-emetics to control the vomiting.
Physical Examination:
The following are performed accordingly:
General Examination;
Abdominal Examination.
In case I haven't mentioned them earlier, the patient's vitals are:
(a) Blood pressure - 123 / 82 mmHg (slightly hypertensive);
(b) Heart rate: 111 beats per minute (tachypnoeic, where the normal range is 60-100 beats per minute);
(c) Respiratory rate: 25 breaths per minute (higher than the normal range of 12-20 breaths per minute);
(d) Urinalysis - normal;
(e) Normal urinary output (also a sign against dehydration).
General Examination Findings:
Patient conscious and oriented, but distracted immensely by the pain;
Slight tinge of yellow over the sclera, suggestive of mild jaundice;
No pallor; the patient is also not dehydrated (i.e. no dry mucous membranes, capillary refill time normal at < 2 seconds, no decreased skin turgor);
No finger clubbing; no stigmata of chronic liver disease (this umbrella term encompass telangiectasia, palmar erythema, hepatic flap, caput medusa and so forth), no peripheral oedema;
No abnormalities in the lymph node examination (cervical);
No scratch marks or bruising (Both of which are very important. The former are hallmark signs of severe cholestasis, a condition characterised by bile duct obstruction and the retention of bile in the biliary tree; the scratch marks come from pruritus. The latter is indicative of impairment in coagulative function, which is related to an underlying liver condition).
Picture showing a patient with mild scleral jaundice (bilateral, naturally). There is no jaundice of the skin, which requires a higher corresponding concentration of conjugated bilirubin. This picture is extracted from: http://4.bp.blogspot.com/_1NJkyVMFbuA/S2EO_io6JRI/AAAAAAAACVw/29k2W1KRv58/s320/500-1a.jpg.
Abdominal Examination Findings:
Upon general inspection, there is no asymmetry, overlying skin changes, masses or scars;
Severe non-specific upper abdominal tenderness upon superficial palpation; deep palpation cannot be performed due to the intensity of the pain;
No abdominal guarding or increased muscle tone (abdominal) (excluding peritonitis);
The pain radiates to the back. Other abdominal regions are not affected;
Liver and Spleen examination (both palpation and percussion) cannot be performed due to the intense pain endured;
Kidneys cannot be ballotted, but this can be wrong since the back pain is rather intense and the patient refuses to move more than necessary;
No ascites (crucial to rule out peritonitis);
Bowel sounds present and normal;
No abnormalities regarding the aortic and renal pulses, as well as liver pulsation.
Diagram showing the nine abdominal regions to be palpated in abdominal examination (some clinicians go for 4 quadrants, but I think it's better to be more meticulous here) (Extracted from: https://www.ligastrohealth.com/hs-fs/hubfs/Blog/AdobeStock_75455616.jpeg?width=600&name=AdobeStock_75455616.jpeg)
Clinical Pictures showing respectively Cullen's Sign (A) (periumbilical bruising) and Grey Turner's Sign (B) (flank bruising). Both are signs of haemorrhagic pancreatitis (a very severe form of disease). Both signs are absent in this patient. This clinical picture is extracted from: https://i2.wp.com/www.60secondem.com/wp-content/uploads/2016/02/Cullens-sign-and-Grey-turners-sign-60secondEM.png?resize=618%2C396.
Differential Diagnoses:
Notwithstanding the constraints posed to the utility of our clinical examination by the abdominal pain, we are able to draw up a list of differential diagnoses:
Acute Pancreatitis (Most Likely);
Acute Cholecystitis;
Acute Cholangitis;
Gallstones (not very likely to be in isolation since the patient's condition is of acute and spontaneous onset; unlike gallstones, the abdominal pain is also persistent in nature, rather than episodic);
Peptic Ulcer Disease (not very likely);
Malignancy (at the end of the list since the patient's condition has an acute, spontaneous onset; the reason why we've kept it on the list is because the acute event may be precipitated by an underlying malignancy. This especially rings true in acute pancreatitis);
Bowel diseases, such as diverticulitis (ruled out due to no blood in stool and no change in bowel habit).
Acute Pancreatitis naturally means the inflammation of the pancreas and is a disease which carries high morbidity and mortality. It presents with acute abdominal pain over the upper regions, with subsequent radiation to the back since the pancreas is located in the retroperitoneum (the posterior section of the peritoneal cavity). It can be caused by the following aetiologies, summarised by the helpful mnemonic 'Get Smashed':
- Gallstones;
- Ethanol (basically alcohol);
- Trauma (this refers to both surgical trauma and blunt trauma);
- Steroids;
- Mumps;
- Autoimmune Disease (however, autoimmune pancreatitis usually has a relapsing-remitting or chronically persistent natural course; there are two major types of disease: IgG4-mediated, and non-IgG4-mediated (or idiopathic). Due to the chronicity of most cases, there is higher risk of pancreatic carcinogenesis);
- Scorpion Toxin (weird but true);
- Hypercalcaemia;
- ERCP (Endoscopic Retrograde Cholangiopancreatography; this is an iatrogenic injury);
- Drugs and Toxins (these include azathioprine and NSAIDs).
Acute pancreatitis does not require any antibiotics usually, but depending on local guidelines, antibiotics may still be administered for prophylaxis. This means the antibiotics are there to pre-empt any infections that may arise.
We think that, judging by the patient's dietary and drinking habits, as well as the characteristics of the condition, acute pancreatitis is the most likely condition and gallstones can be one of the triggers.
Acute Cholecystitis and Cholangitis are both diseases of the biliary tree. They refer to the inflammation of, respectively, the gallbladder and the bile ducts. Acute cholecystitis arises from increased pressure within the gallbladder and excessive contraction of the structure. This can be traced back to the obstruction of the cystic duct or the infundibulum of the gallbladder, leading to a compensatory increase in contractile force. This is the principal cause for the pain felt over the upper abdomen, specifically the right upper quadrant. As bile is sterile (at least in most cases), acute cholecystitis is not usually suppurative (pus-involving). Acute cholangitis involves the blockade of the common bile duct and is clinically more debilitating.
Acute cholecystitis presents clinically with a little something called the 'Murphy's Sign'. During liver palpation, we inevitably palpate for the gallbladder which is tucked behind the liver. At that point, if the patient ceases breathing (because of pain) and that the same phenomenon is not observed on the left upper quadrant, then bingo- the patient is positive for the Murphy's Sign. Moreover, the eponymous sign is used to describe the same phenomenon during an ultrasound examination.
Diagram illustrating how the Murphy's Sign is examined (extracted from: https://healthandwillness.org/wp-content/uploads/2020/07/murphey-sign.jpg)
Acute cholangitis is naturally more sinister. Its manifestations can be summarised by Charcot's Triad, which is a constellation of three symptoms: jaundice, abdominal pain and fever. The 'stronger' version is called Reynold Pentad, which has five symptoms - two in addition to the three in Charcot's Triad: hypotension and mental state changes. Acute cholangitis has a high chance of leading on to septic shock and must be treaded cautiously. Bacteraemia, where bacteria are present in the blood thus being capable of widespread infection, is present in 25 to 40 per cent of all cases. Having said so, Charcot's Triad is present in no more than 72 per cent of all patients with acute cholangitis. Reynold Pentad is extremely rare, amounting to 3.5 to 7.7 per cent of all cases.
Gallstone disease does cause upper abdominal pain (to be more specific: the right upper quadrant). This can overlap with a whole bunch of liver stuff, such as acute hepatitis and hepatocellular carcinoma (provided that the liver capsule is affected). However, the pain is usually episodic and much milder. The pain originates from the friction between gallbladder epithelium and the stones, which is generated whenever the gallbladder contracts. The gallbladder mainly contracts more under the influence of a sneaky hormone called Cholecystokinin, which is basically there to inform the digestive system that there is a lot of food in the system waiting to be digested. As bile helps with fat digestion (emulsification of fat, leading to increased surface area for more efficacious enzymatic activity in the duodenum), the gallbladder as the storage point pumps the bile out to the duodenum.
Figure showing Bouveret's Syndrome, which is a complication of chronic gallstone formation. As we can see, the gallstone is perilously close to the duodenum. Due to chronic rubbing and damage to the gallbladder epithelium, there is inflammation and erosion over the region. This can lead to fistula formation, which basically means a hollow tract is constructed between the gallbladder and the duodenum. As the gallbladder travels to the duodenum and obstructs it, it can cause gastric outlet obstruction. (diagram extracted from: http://www.casereports.in/articles/5/1/Management-Options-of-Bouverets-Syndrome.html)
Diagram showing a gallstone at the infundibulum of the gallbladder. Owing to its massive size, the bulging of the neck also leads to the obstruction of the common hepatic duct. This leads to symptoms similar to acute cholangitis, since the main difference between this scenario and acute cholangitis is essentially the site of obstruction. This is called Mirizzi Syndrome and is also a complication of chronic gallstone formation. (Diagram extracted from Teach Me Surgery).
Classification of Mirizzi Syndrome according to the severity and location of fistula formation. This is known as the Csendes Classification. As the gallstone creeps further out from the infundibulum of the gallbladder, the intense frictional forces at play prompt inflammation. Such processes blur the boundaries between the bile ducts and the gallbladder. In Stage V, you can see the formation of fistulas between the gallbladder, common bile duct and the duodenum. (Operating under Creative Common Licence) (Extracted from: https://www.researchgate.net/figure/Outline-representation-of-the-new-classification-of-Csendes-to-Mirizzi-syndrome-1_fig1_265342764
Investigations:
We are moving in the direction of acute pancreatitis and gallstones. However, other differentials are still born in mind since we don't have enough information in hand to entirely rule them out. The following investigations are performed which can hopefully aid our clinical decision-making process. IV Fluids are administered to the patient.
Routine Blood Tests: Full Blood Count, Coagulation Profile (important here- we want to see if the patient's condition has deteriorated. Most crucially, sepsis may manifest in the form of impaired coagulability), U&E (urea and electrolytes), Liver and Renal Function Tests, C-Reactive Protein (CRP), Erythrocyte Sedimentary Rate (ESR) [both being inflammatory markers], Group & Save and Crossmatching;
Special Tests: Serum Amylase and Serum Lipase (both being sensitive and specific for acute pancreatitis);
Ultrasound (for gallstones) (done after CT);
Computed Tomography (CT) of the Abdomen.
There is a CT Severity Index, also known as the Balthazar Score, for determining the severity of acute pancreatitis.
CT Scan of the Abdomen showing Acute Pancreatitis (blurred contours of the pancreas due to extensive inflammation; extensive fat stranding indicated by increased density of the fat relative to the water; peri-pancreatic oedema) (diagram extracted from Radiopaedia).
Ultrasound scan showing gallstones resting on the gallbladder epithelium. Note the posterior shadowing (the long lines of shadows that emanate from the shiny pebbles), which confirms that the masses are made of solid and do not contain liquid. Other typical ultrasound findings may include the thickening of the gallbladder epithelium to above 2 mm, enlargement of the gallbladder to above 4 cm x 10 cm, as well as the sonographic Murphy's Sign. The diagram is extracted from: https://www.ehealthstar.com/wp-content/uploads/2015/03/Gallstones-ultrasound.jpg.
Notable Results from Investigations:
Leucocytosis, Slight Anaemia; coagulation function normal (for now);
Slightly lowered calcium levels in serum;
Raised inflammatory markers, High Urea, High Creatinine;
High AST, ALP and GGT (Liver Function Tests) (this shows a cholecystic picture, meaning that there is some extent of biliary obstruction);
Serum Amylase and Lipase raised (3 times above normal);
CT Abdomen shows typical findings of acute pancreatitis, with no complications such as pseudocysts or walled-off necrosis;
Ultrasound discovers gallstones in the gallbladder and the right hepatic duct.
Ultrasound findings may not be entirely accurate, since some stones cannot be detected by ultrasound in virtue of their composition.
As a side note, the DeRitis Ratio is calculated from the formula: AST/ALT. AST and ALT are both liver enzymes whose interactions point us to more likely liver pathologies. Where the DeRitis Ratio exceeds 2, it is likely to be alcoholic liver disease.
Diagnosis: Acute Pancreatitis.
Symptomatic treatment has already been administered at the early stage of admission. Now, we are planning our definitive treatment strategy. Obviously, the first thing to do is to remove the gallstones and make sure the patient's condition does not deteriorate - especially looking out for sepsis. Acute pancreatitis, if not caused by gallstones, is self-limiting and will get better once the initial storm is over. However, with gallstones, we need to carry out a procedure called ERCP. The procedure does not only remove gallstones, but also allows us to install a stent to make sure the diameter of the bile duct is wide enough to facilitate their removal. An adjunct procedure called endoscopic sphincterectomy can be executed as well, resulting in higher efficacy in gallstone removal.
As for nutrition, oral intake is fine as long as it is tolerated. Given that the vomiting is improved upon the administration of anti-emetics, we think it is sensible to restart oral nutrition. [15]
However, in the long-term (we're talking about within the coming two weeks), cholecystectomy (surgical removal of the gallbladder) has to be done to avoid recurrence. We also advise the patient to cut back on the alcohol (and possibly the drugs). Since the patient has suicidal ideation and exhibits signs of clinical depression, we've solicited help from the psychiatrists in the other wing. After all, patient care is all about working together as a team.
[13]
Illustration of Laparoscopic Cholecystectomy which is one of the most widely-used surgical techniques in treating gallbladder disease. Refer to [2] for the comparison of different surgical modalities currently available and other methods for achieving effective biliary drainage if the patient is not eligible for surgery. This diagram is extracted from JAMA, on URL: https://jamanetwork.com/data/journals/jama/936979/m_jpg180008fa.png.
So, here we have it. Gallstones and gallbladder tantrums do not only manifest in the form of gallbladder diseases. The tantrum can have far-reaching consequences. The pancreas can be affected. If improperly treated, this can escalate rapidly. The patient can experience septic shock and die in a few hours. Never forget the gallbladder and the pancreas if the patient presents with severe upper abdominal pain.
*Cover Image courtesy of The Awkward Yeti project.
**This patient is fake as I've written the entire case study to demonstrate the line of clinical reasoning adopted in diagnosing and treating patients with upper abdominal pain.
References and Further Reading:
[1] Forsmark C, Swaroop Vege S, Wilcox C. Acute Pancreatitis. New England Journal of Medicine. 2016;375(20):1972-1981. doi:10.1056/nejmra1505202.
[2] Baron T, Grimm I, Swanstrom L. Interventional Approaches to Gallbladder Disease. New England Journal of Medicine. 2015;373(4):357-365. doi:10.1056/nejmra1411372.
(discussing the new approaches to gallbladder disease, with in-depth discussion and comparisons between surgical removal of the gallbladder and bile drainage - ultimately, it depends on the patient's overall status, the severity of the gallbladder condition, as well as locally available technology and expertise)
[3] Esparza Monzavi C, Peters X, Spaggiari M. Cholecystocolonic fistula: A rare case report of Mirizzi syndrome. Int J Surg Case Rep. 2019;63:97-100. doi:10.1016/j.ijscr.2019.09.023.
[4] Alcohol units. NHS. https://www.nhs.uk/live-well/alcohol-support/calculating-alcohol-units/. Published 2020. Accessed December 14, 2020.
[5] Beyer G, Habtezion A, Werner J, Lerch M, Mayerle J. Chronic pancreatitis. The Lancet. 2020;396(10249):499-512. doi:10.1016/s0140-6736(20)31318-0.
[6] Kimura Y, Takada T, Kawarada Y, et al. Definitions, pathophysiology, and epidemiology of acute cholangitis and cholecystitis: Tokyo Guidelines. J Hepatobiliary Pancreat Surg. 2007;14(1):15-26. doi:10.1007/s00534-006-1152-y.
[7] Wada K, Takada T, Kawarada Y, et al. Diagnostic criteria and severity assessment of acute cholangitis: Tokyo Guidelines. J Hepatobiliary Pancreat Surg. 2007;14(1):52-58. doi:10.1007/s00534-006-1156-7.
[8] Mohammad Alizadeh AH. Cholangitis: diagnosis, treatment and prognosis. J Clin Transl Hepatol. 2017 Dec 28. 5 (4):404-13.
[9] Balthazar EJ, Freeny PC, vanSonnenberg E. Imaging and intervention in acute pancreatitis. Radiology. 1994;193(2):297-306. doi:10.1148/radiology.193.2.7972730.
[10] Wu BU, Bakker OJ, Papachristou GI, et al. Blood Urea Nitrogen in the Early Assessment of Acute Pancreatitis: An International Validation Study. Arch Intern Med. 2011;171(7):669–676. doi:10.1001/archinternmed.2011.126.
(established that blood urea nitrogen can be a surrogate marker for predicting acute severe pancreatitis)
[11] Brink JA, Simeone JF, Mueller PR, Saini S, Tung GA, Spell NO, Ferrucci JT. Routine sonographic techniques fail to quantify gallstone size and number: a retrospective study of 111 surgically proved cases. American Journal of Roentgenology. 1989;153: 505. 10.2214/ajr.153.3.503 http://www.ajronline.org/doi/pdf/10.2214/ajr.153.3.503.
[12] Raman SR, Moradi D, Samaan BM, et al. The degree of gallbladder wall thickness and its impact on outcomes after laparoscopic cholecystectomy. Surg Endosc. 2012;26(11):3174-3179. doi:10.1007/s00464-012-2310-8.
[13] Fogel E, Sherman S. ERCP for Gallstone Pancreatitis. New England Journal of Medicine. 2014;370(2):150-157. doi:10.1056/nejmct1208450.
[14] Kingsnorth A, O'Reilly D. Acute pancreatitis. BMJ. 2006;332(7549):1072-1076. doi:10.1136/bmj.332.7549.1072.
[15] Horibe M, Nishizawa T, Suzuki H, et al. Timing of oral refeeding in acute pancreatitis: A systematic review and meta-analysis. United European Gastroenterol J. 2016;4(6):725-732. doi:10.1177/2050640615612368.