My patient with choledocholithiasis presents with acute abdominal pain, bile duct dilatation and markedly elevated serum aminotransferases (AST and ALT).  Can her markedly elevated AST and ALT levels be caused by cholelithiasis with bile duct obstruction?  

Although markedly increased serum alanine transaminase (ALT) and aspartate transaminase (AST) are often considered a marker for severe hepatocellular injury or necrosis (particularly when levels exceed 1000 IU/L), occasionally such elevations may also be due to isolated acute biliary duct obstruction caused by choledocholithiasis.1  

In one case series, patients  diagnosed with choledocholithiasis were found to have transient elevations in their AST/ALT (>1000 units/L) directly proportional to the degree of common bile duct dilation in the absence of any hepatocellular disease on imaging. These levels were found to rapidly fall following intervention with endoscopic retrograde cholangiopancreatography (ERCP). 2   Intriguingly, the authors of this study suggest that patients who present with severe abdominal pain associated with an acute and markedly elevated serum aminotransferase levels, are more likely to have acute biliary obstruction than hepatocellular disease.3  Several other case series have also shown similar elevations of serum aminotransferases in choledocholithiasis, with some levels reaching >2000 IU/L.4  

Several hypotheses have been proposed to explain this phenomenon, including pressure-induced damage of hepatocytes and bile salt-induced hepatocyte injury in the setting of acute biliary duct obstruction.2 Of interest, some have proposed that the gallbladder may minimize elevations in serum aminotransferases by protecting the liver from rapid increases in biliary duct pressure.  In fact, more robust elevations in aminotransferases in choledocholithiasis have been observed in those who have had cholecystectomy.4  

So even though choledocholithiasis is traditionally associated with a “cholestatic” pattern of enzyme elevations—with elevated alkaline-phosphatase, and gamma-glutamyl transferase (GGT) levels 1,3—when associated with bile duct obstruction, it  can also be associated with markedly elevated ALT and AST.  

Bonus Pearl: Did you know that when assessing for choledocholithiasis, magnetic resonance cholangiopancreatography (MRCP) is more sensitive than ultrasound (81% vs 18-74 %).4,5,6  

Contributed by Connor S. Shaw, D.O., Mercy Hospital, St. Louis, Missouri

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References  

  1. Feldman, Mark, et al. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management. Elsevier, 2021.  
  2. Tetangco, Eula Plana, et al. “Markedly Elevated Liver Enzymes in Choledocholithiasis in the Absence of Hepatocellular Disease.” Journal of Investigative Medicine High Impact Case Reports, vol. 4, no. 2, 2016, p. 232470961665109., https://doi.org/10.1177/2324709616651092. 
  3. De Angelis C, Marietti M, Bruno M, Pellicano R, Rizzetto M. Endoscopic ultrasound in common bile duct dilatation with normal liver enzymes. World J Gastrointest Endosc. 2015 Jul 10;7(8):799-805. doi: 10.4253/v7.i8.799. PMID: 26191344; PMCID: PMC4501970.
  4. Agahi, A., and A. McNair. “Choledocholithiasis Presenting with Very High Transaminase Level.” Case Reports, vol. 2012, no. nov22 2, 2012, https://doi.org/10.1136/bcr-2012-007268.
  5. Makmun, Dadang, et al. “Sensitivity and Specificity of Magnetic Resonance Cholangiopancreatography versus Endoscopic Ultrasonography against Endoscopic Retrograde Cholangiopancreatography in Diagnosing Choledocholithiasis: The Indonesian Experience.” Clinical Endoscopy, vol. 50, no. 5, 2017, pp. 486–490., https://doi.org/10.5946/ce.2016.159.
  6. Ferri, João Victor, et al. “Níveis Elevados De Transaminases Em Um Caso De Coledocolitíase: A Importância Do Reconhecimento Deste Padrão.” Revista De Medicina, vol. 96, no. 2, 2017, p. 131., https://doi.org/10.11606/issn.1679-9836.v96i2p131-133.   

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, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their affiliate academic healthcare centers, or its contributors. 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!

 

My patient with choledocholithiasis presents with acute abdominal pain, bile duct dilatation and markedly elevated serum aminotransferases (AST and ALT).  Can her markedly elevated AST and ALT levels be caused by cholelithiasis with bile duct obstruction?  

What’s causing an isolated GGT elevation in my patient with an abnormal alkaline phosphatase on her routine admission lab?

Although serum gamma-glutamyl transpeptidase or GGT is a very sensitive test for liver disease, especially of biliary origin, it’s by no means a very specific test. Besides the liver, GGT is found in the kidneys, pancreas, prostate, heart, brain, and seminal vesicles but not in bone (1-4).

 
Obesity, alcohol consumption and drugs are common causes of GGT elevation (2). As early as 1960s, elevated GGT was reported in such seemingly disparate conditions as diabetes mellitus, congestive heart failure, myocardial infarction, nephrotic syndrome and renal neoplasm (3). Nonalcoholic steatohepatitis, viral hepatitis, biliary obstruction, COPD, liver metastasis, drug-induced liver injury can all cause GGT elevation (1-4).

 
An isolated GGT does not necessarily indicate serious or progressive liver disease. That’s one reason it’s often not included in routine “liver panel” lab tests (1).

What to do when GGT is high but other liver panel tests such as ALT, AST, albumin, and bilirubin are normal? If your patient is at risk of acquired liver disease, then further workup may be necessary (eg, hepatitis B and C screening tests). Alcohol consumption should be queried. Don’t forget conditions associated with iron overload. If your patient is obese, diabetic or has elevated both lipids, an ultrasound of the liver to look for fatty liver should be considered. In the absence of risk factors, symptoms, or physical exam suggestive of liver disease, isolated GGT elevation should not require further investigation (1).

 
One good thing that may come out of finding an isolated elevated GGT is to encourage your patient to curb alcohol consumption or lose weight when indicated. But don’t rely on a normal GGT to rule out heavy alcohol consumption as it may miss 70% to 80% of cases (6)! 

 
Bonus Pearl: Did you know that GGT activity is thought to increase in alcohol use due to its role in maintaining intracellular glutathione, an anti-oxidant, at adequate levels to protect cells from oxidative stress caused by alcohol?

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References

1. Carey WD. How should a patient with an isolated GGT elevation be evaluated? Clev Clin J Med 2000;67:315-16. https://www.ncbi.nlm.nih.gov/pubmed/10832186
2. Newsome PN, Cramb R, Davison SM, et al. Guidelines on the management of abnormal liver blood tests. Gut 2018;67:6-19. https://gut.bmj.com/content/gutjnl/67/1/6.full.pdf
3. Whitfield JB, Pounder RE, Neale G, et al. Serum gamma-glutamyl transpeptidase activity in liver disease. Gut 1972;13:702-8. https://www.ncbi.nlm.nih.gov/pubmed/4404786
4. Tekin O, Uraldi C, Isik B, et al. Clinical importance of gamma glutamyltransferase in the Ankara-Pursaklar region of Turkey. Medscape General Medicine 2004;6(1):e16. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1140713/
5. Van Beek JHDA, de Moor MHM, Geels LM, et al. The association of alcohol intake with gamma-glutamyl transferase (GGT) levels:evidence for correlated genetic effects. Drug Alcohol Depend 2014;134:99-105. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3909645/

6. Bertholet N, Winter MR, Cheng DM, et al. How accurate are blood (or breath) tests for identifying self-reported heavy drinking among people with alcohol dependence? Alcohol and Alcoholism 2014;49:423-29. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4060735/pdf/agu016.pdf

What’s causing an isolated GGT elevation in my patient with an abnormal alkaline phosphatase on her routine admission lab?

My middle-aged patient with a history of mediastinal irradiation for Hodgkin’s lymphoma in his 20s now has moderate aortic regurgitation. Could his valvular disease be related to the radiation he received over 20 years ago?

Absolutely! Mediastinal irradiation is associated with several cardiac complications, including coronary artery disease, pericarditis, systolic or diastolic dysfunction and valvular disease. Valvular disease may occur in 2-37% of patients after mediastinal irradiation, is dose-dependent, and generally does not manifest until 10-20 years after the radiation exposure.1 Since mediastinal irradiation is common in young adults diagnosed with Hodgkin’s lymphoma, these complications may be seen in early middle-age or later.

Valvular retraction is usually the first radiation-induced valvular change, and most commonly leads to mitral and aortic valve regurgitation.2 This retraction tends to occur within 10 years of the radiation therapy, followed by fibrosis and calcification of the valves after 20 years.

Although the pathophysiology of radiation-induced valvular disease is not entirely understood, activation of fibrogenic growth factors (eg, tissue growth factor β1 and myofibroblasts) which promote the synthesis of collagen has been postulated.1 Additionally, irradiation of aortic interstitial cells has been shown to cause transformation to an osteogenic phenotype that produces bone morphogenic protein 2, osteopontin and alkaline phosphatase, all important factors in bone formation and possibly valvular calcification.3

Since radiation-induced heart disease is the most common cause of non-malignant morbidity and mortality in patients who have undergone mediastinal irradiation, some have recommended screening of asymptomatic patients for valvular disease every 5 years by echocardiography beginning 10 years after radiation therapy. 2  If an abnormality is found, the screening frequency should increase to every 2-3  years,  if the valvular abnormality is mild, or annually if the abnormality is moderate. For severe valvular abnormalities, the patients should be considered for valve replacement.

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References

    1. Gujral DM, Lloyd G, Bhattacharyya S. Radiation-induced valvular heart disease. Heart 2016;102:269–276. https://heart.bmj.com/content/heartjnl/102/4/269.full.pdf
    2. Cuomo JR, Sharma GK, Conger PD, Weintraub NL. Novel concepts in radiation-induced cardiovascular disease. World J Cardiol. 2016; 8 (9):504-519. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5039353/
    3. Nadlonek NA, Weyant MJ, Yu JA, et al. Radiation induces osteogenesis in human aortic valve interstitial cells. J Thorac Cardiovasc Surg 2012;144:1466–70. doi:10.1016/j.jtcvs.2012.08.041 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3665422/

Contributed by Rachel Wallwork, MD, Mass General Hospital, Boston, MA

 

My middle-aged patient with a history of mediastinal irradiation for Hodgkin’s lymphoma in his 20s now has moderate aortic regurgitation. Could his valvular disease be related to the radiation he received over 20 years ago?