Liver disease

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?  

FA Manian MD, MPH, , , , , , , , , , , , , Leave a comment

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?  

Why do we often prescribe ceftriaxone in preference to fluoroquinolones for prophylaxis of infections in patients with cirrhosis and upper GI bleed?

FA Manian MD, MPH, , , , , , , , , , , Leave a comment

Preference of ceftriaxone over fluoroquinolones (FQs) for prophylaxis of infection in patients with cirrhosis and upper GI bleed (UGIB) can often be traced back to a small 2006 Spanish randomized controlled trial (RCT)1 which found a significantly lower rate of proved or possible bacterial infection and lower rate of fermentative Gram-negative bacilli infection in the ceftriaxone group (vs norfloxacin) over a 10-day period (11% vs 33% and 0% vs 11%, respectively). There was no significant difference in the incidence of proved bacterial infection (spontaneous bacterial peritonitis or bacteremia, P=0.07) or 10-day mortality between the 2 groups.   

It’s worth emphasizing that the primary impetus for this study was evaluation of the efficacy of ceftriaxone in patients with cirrhosis and UGIB in a setting where FQ Gram-negative bacilli was thought to be highly prevalent. Parenthetically, a similar RCT performed where the prevalence of FQ resistance was considered low failed to find a significant difference in breakthrough bacterial infection, rebleeding or mortality when ceftriaxone was compared to IV ciprofloxacin.2

Another caveat of the 2006 study was that an IV antibiotic (ceftriaxone) was compared to a oral antibiotic (norfloxacin) which, in the setting of active UGIB, may be problematic.

Despite these limitations, its favorable safety profile compared to FQs coupled with its ease of administration has often made ceftriaxone the drug of choice for prophylaxis of infections in patients with cirrhosis and UGIB. The 2016 Practice Guidance by the American Association for the Study of Liver Diseases considers ceftriaxone as the first choice in patients with advanced cirrhosis, on FQ prophylaxis, and in hospital settings with high prevalence of FQ resistant bacterial infection.3

Bonus Pearl: Did you know that the prevalence of FQ resistant in Enterobacteriaceae may be as high as 30% in certain regions of U.S. and >50% in certain regions of the world? 4

Also see related 2 P4P pearls (1, 2) on the association of UGIB bleed with infections in patients with cirrhosis.

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References

  1. Fernandez J, Del Arbol LR, Gomez C, et al. Norfloxacin vs ceftriaxone in the prophylaxis of infections in patients with advanced cirrhosis and hemorrhage. Gastroenterol 2006;131:1049-1056. https://pubmed.ncbi.nlm.nih.gov/17030175/
  2. Pittayanon R, Reknimir R, Kullavanijaya P, et al. Intravenous ciprofloxacin vs ceftriaxone for the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding:A randomized controlled trial. Thai J Gastroenterol 2016;17:24-30. http://www.thaigastro.com/books.php?act=content&content_id=476&book_id=61
  3. Garcia-Tsao G, Abraldes JG, Berzigotti A, et al. Portal hypertensive bleeding in cirrhosis:risk stratification, diagnosis and management: 2016 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology 2017;65:310-335. https://pubmed.ncbi.nlm.nih.gov/27786365/
  4. Spellberg B, Doi Y. The rise of fluoroquinolone-resistant Escherichia coli in the community:scarier than we thought. J Infect Dis 2015;212:1853-1855. https://pubmed.ncbi.nlm.nih.gov/25969562/

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!

Why do we often prescribe ceftriaxone in preference to fluoroquinolones for prophylaxis of infections in patients with cirrhosis and upper GI bleed?

Why are antibiotics routinely administered in patients with cirrhosis and upper gastrointestinal (GI) bleed?

FA Manian MD, MPH, , , , , , , , , , , , , , , , , , 1 Comment

Antibiotic prophylaxis in patients with cirrhosis and upper gastrointestinal bleed (UGIB) reduce bacterial infections, all-cause mortality, bacterial infection, mortality, rebleeding events and hospitalization.1

A 2011 Cochrane meta-analysis involving 12 trials comparing antibiotic prophylaxis to no prophylaxis or placebo found reduction in bacterial infection (RR 0.35, 95% C.I., 0.26-0.47) and overall mortality (RR 0.79, 95% C.I. 0.63-0.98). It also found a significant reduction in rebleeding and days of hospitalization, based on more limited data. Trials in this meta-analysis involved a variety of antibiotics, including norfloxacin, ciprofloxacin, cefazolin, cefotaxime, ceftriaxone and ampicillin-sulbactam. 1

So why is ceftriaxone the often-favored bacterial prophylaxis in UGIB? First, infections in cirrhotic patients often originate from bacterial translocation through the GI tract with aerobic gram-negative GI flora expected to be susceptible to ceftriaxone.2 Second, the emerging quinolone resistance among aerobic Gram-negative bacteria 2 and frequent use of ciprofloxacin for prophylaxis against spontaneous bacterial peritonitis have made use of ceftriaxone in this setting more desirable than quinolones.

Of note, a 2006 study involving patients with advanced cirrhosis (Child Pugh B or C) and GI hemorrhage receiving either norfloxacin or ceftriaxone for 7 days found a significantly lower risk of suspected or proven infections (11% vs 33%) and bacteremia or spontaneous bacterial peritonitis (2% vs 12%) in the ceftriaxone group; there was no difference in hospital mortality. 3 Although the overall prevalence of quinolone-resistant gram-negatives was unknown, 6 of 7 gram-negative bacilli isolated in the norfloxacin group were quinolone resistant.

Bonus Pearl: Did you know that 30-40% of cirrhotic patients presenting with UGIB will develop a bacterial infection within a week of their admission? 1

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References

  1. Chavez-Tapia NC, Barrientos-Gutierrez T, Tellez-Avila F, et al. Meta-analysis: antibiotic prophylaxis for cirrhotic patients with upper gastrointestinal bleeding-an updated Cochrane review. Aliment Pharmacol Ther 2011;34:509-518. https://onlinelibrary.wiley.com/doi/epdf/10.1111/j.1365-2036.2011.04746.x
  2. Mallet M, Rudler M, Thabut D. Variceal bleeding in cirrhotic patients. Gastroenterology Reports 2017;5:185-192. https://academic.oup.com/gastro/article/5/3/185/4002779
  3. Fernandez J, del Arbo LR, Gomez C, et al. Norfloxacin vs ceftriaxone in the prophylaxis of infections in patients with advanced cirrhosis and hemorrhage. Gastroenterology 2006;131:1049-1056. https://www.sciencedirect.com/science/article/abs/pii/S0016508506015356

 

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its 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!

Why are antibiotics routinely administered in patients with cirrhosis and upper gastrointestinal (GI) bleed?

How does iron overload increase the risk of infection?

FA Manian MD, MPH, , , , , , , , , , , , , , , , , , , , , , , , Leave a comment

Iron overload, either primary (eg, hereditary hemochromatosis) or secondary (eg, hemolysis/frequent transfusion states), may increase the risk of infections through at least 2 mechanisms: 1. Enhancement of the virulence of the pathogen; and 2. Interference with the body’s normal defense system.1-7

Excess iron has been reported to enhance the growth of numerous organisms, ranging from bacteria (eg, Yersinia, Shigella, Vibrio, Listeria, Legionella, Ehrlichia, many other Gram-negative bacteria, staphylococci, streptococci), mycobacteria, fungi (eg, Aspergillus, Rhizopus/Mucor, Cryptococcus, Pneumocystis), protozoa (eg, Entamaeba, Plasmodium, Toxoplasma) and viruses (HIV, hepatitis B/C, cytomegalovirus, parvovirus). 1-7

In addition to enhancing the growth of many pathogens, excess iron may also inhibit macrophage and lymphocyte function and neutrophil chemotaxis .1,2 Iron loading of macrophages results in the inhibition of interferon-gamma mediated pathways and loss of their ability to kill intracellular pathogens such as Legionella, Listeria and Ehrlichia. 2

Not surprisingly, there are numerous reports in the literature of infections in hemochromatosis, including Listeria monocytogenes meningitis, E. Coli septic shock, Yersinia enterocolitica sepsis/liver abscess, Vibrio vulnificus shock (attributed to ingestion of raw oysters) and mucormycosis causing periorbital cellulitis. 2

Bonus pearl: Did you know that the ascitic fluid of patients with cirrhosis has low transferrin levels compared to those with malignancy, potentially enhancing bacterial growth and increasing their susceptibility to spontaneous bacterial peritonitis? 8

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 References

  1. Weinberg ED, Weinberg GA. The role of iron in infection. Curr Opin Infect Dis 1995;8:164-69. https://journals.lww.com/co-infectiousdiseases/abstract/1995/06000/the_role_of_iron_in_infection.4.aspx
  2. Khan FA, Fisher MA, Khakoo RA. Association of hemochromatosis with infectious diseases: expanding spectrum. Intern J Infect Dis 2007;11:482-87. https://www.sciencedirect.com/science/article/pii/S1201971207000811
  3. Thwaites PA, Woods ML. Sepsis and siderosis, Yersinia enterocolitica and hereditary haemochromatosis. BMJ Case Rep 2017. Doi:10.11336/bvr-206-218185. https://casereports.bmj.com/content/2017/bcr-2016-218185
  4. Weinberg ED. Iron loading and disease surveillance. Emerg Infect Dis 1999;5:346-52. https://wwwnc.cdc.gov/eid/article/5/3/99-0305-t3
  5. Matthaiou EI, Sass G, Stevens DA, et al. Iron: an essential nutrient for Aspergillus fumigatus and a fulcrum for pathogenesis. Curr Opin Infect Dis 2018;31:506-11. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6579532/
  6. Alexander J, Limaye AP, Ko CW, et al. Association of hepatic iron overload with invasive fungal infection in liver transplant recipients. Liver Transpl 12:1799-1804. https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/lt.20827
  7. Schmidt SM. The role of iron in viral infections. Front Biosci (Landmark Ed) 2020;25:893-911. https://pubmed.ncbi.nlm.nih.gov/31585922/
  8. Romero A, Perez-Aurellao JL, Gonzalez-Villaron L et al. Effect of transferrin concentration on bacterial growth in human ascetic fluid from cirrhotic and neoplastic patients. J Clin Invest 1993;23:699-705. https://onlinelibrary.wiley.com/doi/epdf/10.1111/j.1365-2362.1993.tb01289.x

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its 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!

How does iron overload increase the risk of infection?

How often is the liver affected by Covid-19?

FA Manian MD, MPH, , , , , , , , , , , , , Leave a comment

Abnormal liver enzymes in patients with Covid-19 are common, particularly in those with severe disease.

 
Elevated levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have been reported in 14-53% of patients in several case series. More severe cases appear to have a higher prevalence of AST elevation (1). As some cases also have elevated creatine kinase (CK), the relative contribution of muscles to these enzyme abnormalities is unclear (2).

 
A small study involving ICU patients with Covid-19 reported a prevalence of elevated AST of 62% compared to 25% in non-ICU patients (3). Other studies have confirmed lower incidence of AST abnormality among patients with mild or subclinical disease (4,5).

 
Although much of the published reports of liver injury in Covid-19 have revolved around AST and ALT abnormalities, gamma-glutamyl transferase (GGT) may also be elevated. GGT was abnormal in 54% of patients with Covid-19 during their hospitalization with alkaline phosphatase elevation reported in ~2.0% (1, unpublished reports). Elevation of total bilirubin has also been reported occasionally (1).

 
Although the exact mechanism(s) of Covid-19-related is unclear, direct viral infection of liver cells is one possibility as viremia has been documented in some cases (1). Of interest, a related coronavirus, SARS-CoV-1 has been shown to infect liver tissue and cholangiocytes may express ACE2 receptors, a prime target for Covid-19 virus (1,6,7, unpublished reports).

 

Despite these observations, to date, viral inclusions have not been demonstrated in the liver. Other possible causes of liver injury in Covid-19 include innate immune dysregulation, cytokine storm, hypoxia and drugs (1,2).

 

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References
1. Zhang C, Shi L, Wang FS. Liver injury in COVID-19:management and challenges. Lancet Gastroenterol Hepatol 2020; March 4. https://doi.org/10.1016/S2468-1253(20)30057-1
2. Bangash MN, Patel J, Parekh D. COVID-19 and the liver: little cause for concern. Lancet Gastroenterol Hepatol 2020;March 20. https://doi.org/10.1016/52468-1253(20)30084-4
3. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497-506. https://pubmed.ncbi.nlm.nih.gov/31986264/
4. Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of 2019 novel coronavirus infection in China. N Engl J Med 2020;published online Feb 28. DOI:10.1056/NEJMoa2003032
5. Shi H, Han X, Jiang N, et al. Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study. Lancet Infect Dis 2020; published onlineFeb 24. DOI:10.1016/S1473-3099(20)30086-4 (lancet 8)
6. Chai X, Hu L, Zhang Y, et al. Specific ACE2 expression in cholangiocytes may cause liver damage after 209-nCoV infection. bioRxiv 2020;published online Feb 4. https://doi.org/10.1101/2020.02.03.931766.
7. Xu Z, Shi L, Wang Y, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020; published online Feb 18. DOI:10.1016/S2213-2600(20)30076-X

 

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its 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!

 

How often is the liver affected by Covid-19?

When should I consider steroids in my patient with alcoholic hepatitis?

FA Manian MD, MPH, , , , , , , , , , Leave a comment

The short answer is not very often! In the treatment of alcoholic hepatitis (AH), steroids are reserved for a narrow group of patients only, with a 2018 meta-analysis finding a reduction in short-term mortality (average 36%) at 28 days but not at 6 months.1

The most studied scoring system to help clinicians decide whether a patient should get steroids is the Maddrey’s Discriminant Function (MDF), which is based on the prothrombin and total bilirubin. A score of ≥32 indicates severe disease and potential response to steroids, while a score <32 indicates mild to moderate disease, for which the risk of steroids (e.g. infection, worsening ulcer disease/bleeding, and glucose intolerance) may outweigh any potential benefit.

However, even with a score ≥32, the likelihood of patient adherence to 28 days of steroid therapy, risk of infection and other steroid-related complications should be carefully considered in individual patients. It’s also important to note that a 2008 meta-analysis showed that patients with a very high MDF score of >54 actually had higher mortality rates with steroid therapy, possibly related to the lack of response in very advanced disease as well as high infection risk.2

Many clinicians also use the Lille’s score to help determine whether a patient is a responder after 7 days of initial therapy. A score >0.45 (calculated based on bilirubin levels at day 0 and 7 and other initial labs and age) indicates poor response and that steroids may be stopped due to its risks.3

Based on the result of a small retrospective study, Glasgow Alcoholic Hepatitis (GAH) score has also been suggested as a means of further defining patients with a MDF ≥32 who may potentially benefit from steroids (ie, score ≥9).4

Bonus pearl: Did you know that pentoxifylline, a tumor necrosis factor (TNF), has generally not been found to be effective in the treatment of AH?5,6

Contributed by Tom Wang, MD, Mass General Hospital, Boston, MA.

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References

  1. Louvet A, et al. “Corticosteroids reduce risk of death within 28 days for patients with severe alcoholic hepatitis, compared with pentoxifylline or Placebo—a meta-analysis of individual data from controlled trials.” Gastroenterology 2018; 155: 458-468. https://www.sciencedirect.com/science/article/abs/pii/S0016508518344950
  2. Rambaldi A, et al. “Systematic review: glucocorticosteroids for alcoholic hepatitis–a Cochrane Hepato‐Biliary Group systematic review with meta‐analyses and trial sequential analyses of randomized clinical trials.” Alimentary pharmacology & therapeutics 2008; 27: 1167-1178. https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2036.2008.03685.x
  3. Louvet A, et al. “The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids.” Hepatology 2007; 45: 1348-1354. https://www.ncbi.nlm.nih.gov/pubmed/17518367
  4. Forrest EH, et al. “Analysis of factors predictive of mortality in alcoholic hepatitis and derivation and validation of the Glasgow alcoholic hepatitis score.” Gut 2005; 54: 1174-1179. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1774903/
  5. Thursz MR, et al. “Prednisolone or pentoxifylline for alcoholic hepatitis.” N Engl J Med 2015; 372: 1619-1628. https://www.nejm.org/doi/full/10.1056/NEJMoa1412278
  6. Parker R. “Systematic review: pentoxifylline for the treatment of severe alcoholic hepatitis.” Alimentary Pharm Therapeutics 2018; 37: 845-854. https://onlinelibrary.wiley.com/doi/10.1111/apt.12279

 

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its 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!

When should I consider steroids in my patient with alcoholic hepatitis?

Why can’t my patient with alcohol-related liver disease be placed on the liver transplant list for at least 6 months after his last drink?

FA Manian MD, MPH, , , , , , , , Leave a comment

Although many centers impose a 6-month sobriety rule before patients can be listed for liver transplant, this rule has been increasingly challenged based on the results of more recent studies and ethical issues. 1-10

The argument for enforcing a 6-month sobriety rule is in part based on earlier studies (often small and/or single center) that reported an association between less than 6 months of sobriety before liver transplantation and relapse.5-6 Another frequently cited reason for postponing liver transplantation is to allow the liver enough time to recover from adverse effect of recent alcohol consumption before assessing the need for transplantation.6

Arguments against the 6-month sobriety rule include the very limited life-expectancy (often 3 months or less) of patients with severe alcohol-related liver disease who do not respond to medical therapy and increasing number of studies supporting earlier transplantation particularly in selected patients (eg, severe acute alcoholic hepatitis [SAAH], acute-on-chronic liver failure [ACLF]).1,7,9,10,

Further supporting a less stringent transplantation rule are a low rate (about 4%) of death or graft loss in alcohol-related liver disease patients who experience a relapse and lack of significant differences in survival between non-relapsers, occasional drinkers and problem drinkers.1 A 2019 multicenter, prospective study in the U.S. also found that early liver transplant for alcohol-related  liver disease was associated with comparable patient and graft survival as those without alcohol-related liver disease at 5 years post-transplant but increased risk of death at 10 years. 10

Bonus Pearl: Did you know that alcohol-related liver disease is now the most common diagnosis among patients undergoing liver transplantation in the U.S.? 10

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References

  1. Obed A, Stern S, Jarrad A, et al. Six month abstinence rule for liver transplantation in severe alcoholic liver disease patients. W J Gastroenterol 2015; 21:4423-26. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4394109/
  2. Bramstedt KA, Jabbour N. When alcohol abstinence criteria create ethical dilemmas for the liver transplant team. J Med Ethics 2006;32:263-65. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2579412/
  3. Kollmann D, Rashoul-Rockenschaub S, Steiner I, et al. Good outcome after liver transplantation for ALD without a 6 months abstinence rule prior to transplantation including post-tranplantation CDT monitoring for alcohol relapse assement— a retrospective study. Transplant International 2016;29:559-67. https://onlinelibrary.wiley.com/doi/epdf/10.1111/tri.12756
  4. Osorio RW, Ascher NL, Avery M, et al. Predicting recidivism after orthoptic liver transplantation for alcoholic liver disease. Hepatoloty 1994;20:105-110. https://aasldpubs.onlinelibrary.wiley.com/doi/epdf/10.1002/hep.1840200117
  5. Carbonneau M, Jensen LA, Bain VG. Alcohol use while on the liver transplant waiting list: a single-center experience. Liver Transplantation 2010;16:91-97. https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/lt.21957
  6. Harnanan A. Challenging the “six-month sober” rule for liver transplants in Canada. McGill Journal of Law and Health. Dec 12, 2019. https://mjlh.mcgill.ca/2019/12/12/challenging-the-six-month-sober-rule-for-liver-transplants-in-canada/
  7. Lee BP, Mehta N, Platt L, et al. Outcomes of early liver transplantation for patients with severe alcoholic hepatitis. Gastroenterology 2018;155:422-430.e1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460480/
  8. Rice JP, Lee BP. Early liver transplantation for alcohol-associated liver disease: need for engagement and education of all stakeholders. Hepatol Communications 2019;3: 1019-21. https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep4.1385
  9. Lee BP, Vittinghoff E, Pletcher MJ, et al. Medicaid policy and liver transplant for alcohol-related liver disease. Hepatology; November 8, 2019 https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.31027
  10. Lee BP, Vittinghoff E, Dodge JL, et al. National trends and long-term outcomes of liver transplant for alcohol-associated liver disease in the United States. JAMA Intern Med 2019;179:340-48. https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2720757?widget=personalizedcontent&previousarticle=2720750

Contributed in part by Nneka Ufere, MD, GI Division, Massachusetts General Hospital, Boston, MA

Why can’t my patient with alcohol-related liver disease be placed on the liver transplant list for at least 6 months after his last drink?

Can the elevation of AST and ALT in my patient with rhabdomyolysis be related to the muscle injury itself?

FA Manian MD, MPH, , , , , , , , , , , , , , , , , , , , , Leave a comment

Yes! Elevated serum AST and ALT in the setting of rhabdomyolysis is not uncommon and, at least in some cases, appears to be related to the skeletal muscle injury itself.1,2

In a study of 16 patients considered to have significant muscle necrosis due to extreme exercise, polymyositis or seizures without evidence of liver disease (eg, viral hepatitis, exposure to hepatotoxic drugs, heart failure, biliary tract disease, recent hypotension) AST and, to lesser degree, ALT was elevated. For extreme exercise, the median AST and ALT concentrations were 2,466 IU/L and 497 U/L, respectively, while for seizures these levels were 1,448 U/L and 383 U/L respectively.1  

Another study reported AST elevation (>40 U/L) in 93.1% of patients with rhabdomyolysis and ALT elevation (>40 U/L) in 75.0% of patients with serum creatine kinase ≥1000 U/L. 2  Further supporting a skeletal muscle origin for AST elevation was the finding that AST concentrations fell in parallel with CK drop during the first 6 days of hospitalization for rhabdomyolysis. It was posited that ALT concentrations dropped slower because of its longer serum half-life (47 hours vs 17 hours for AST).2 Despite these findings, concurrent liver injury as an additional source of AST or ALT elevation cannot be excluded.

Elevation of AST and ALT with muscle injury should not come as a surprise. AST is found in heart and skeletal muscle among many other organs. Even ALT which is considered more specific to liver is found in organs such as skeletal muscle, heart and kidney, though at lower concentrations.3

Bonus Pearl: Did you know that the first description of rhabdomyolysis in the literature involved English victims of crush injuries during World War II?2

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References

  1. Nathwani RA, Pais S, Reynolds TB, et al. Serum alanine aminotransferase in skeletal muscle diseases. Hepatology 2005;41:380-82. https://www.ncbi.nlm.nih.gov/pubmed/15660433
  2. Weibrecht K, Dayno M, Darling C, et al. Liver aminotransferases are elevated with rhabdomyolysis in the absence of significant liver injury. J Med Toxicol 2010;6:294-300. https://link.springer.com/article/10.1007%2Fs13181-010-0075-9
  3. Giannini EG, Testa R, Savarino V. Liver enzyme alteration: a guidance for clinicians. CMAJ2005;172:367-79. Giannini EG, Testa R, Savarino V. Liver enzyme alteration: a guidance for clinicians. CMAJ 2005;172:367-79. https://www.ncbi.nlm.nih.gov/pubmed/15684121
Can the elevation of AST and ALT in my patient with rhabdomyolysis be related to the muscle injury itself?

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

FA Manian MD, MPH, , , , , , , , , , , , , , , , , , , Leave a comment

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 patient with jaundice complains of abdominal fullness. How useful is the history or physical exam when assessing for ascites?

FA Manian MD, MPH, , , , , , , , , , Leave a comment

Even in the age of ultrasound, history and physical exam can be useful in assessing for ascites.

History is a good place to start. Of all the questions we often ask when we suspect ascites (eg, increasing abdominal girth, weight gain and ankle swelling), lack of report of ankle swelling is probably the most helpful in excluding ascites (negative likelihood ratio [LR-], 0.1 in a study involving men), followed by no increase in abdominal girth (LR-, 0.17). Conversely, patient reported ankle swelling or increasing abdominal girth may be helpful in suspecting ascites (LR+ 4.12 and 2.8, respectively). 1

Of the various physical signs and maneuvers, absence of peripheral edema is highly associated with the lack of ascites, followed by lack of shifting dullness or fluid wave (LR-, 0.2, 0.3, 0.4, respectively). The presence of a fluid wave may be the most helpful in suspecting ascites, followed by peripheral edema, and shifting dullness (LR+ 6.0, 3.8, 2.7, respectively). 1  Relatively high sensitivities have been reported for shifting dullness (83-88%), while relatively high specificities have been reported for the fluid wave test (82-90%).2,3 An elevated INR may also improve the positive predictive value of shifting dullness and fluid waves.4

So if you don’t get a history of ankle edema and find no evidence of peripheral edema or shifting dullness on exam, the likelihood of ascites is pretty low. On the other hand, if you find a positive fluid wave, you can be pretty sure that the patient has ascites.

Of course, the actual likelihood of detecting ascites also depends on several other factors, including your pre-test probability and the volume of the ascites in the abdominal cavity, with at least ~500 ml of ascites necessary before it can be detected on exam (vs ~100 ml for ultrasound). 2,5

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References

  1. Williams JW, Simetl DL. Does this patient have ascites? How to divine fluid in the abdomen. JAMA 1992;267: 2645-48. https://jamanetwork.com/journals/jama/fullarticle/397285
  2. Cattau EL, Benjamin SB, Knuff TE, et al The accuracy of the physical examination in the diagnosis of suspected ascites. JAMA 1982;247:1164-66. https://www.ncbi.nlm.nih.gov/pubmed/7057606
  3. Cummings S, Papadakis M, Melnick J, et al. The predictive value of physical examinations for ascites. West J Med 1985;142:633-36. https://www.ncbi.nlm.nih.gov/pubmed/3892916
  4. Fitzgerald FT. Physical diagnosis versus modern technology. A review. West J Med 1990;152:377-82. https://www.ncbi.nlm.nih.gov/pubmed/2190412
  5. CDC. Assessment for ascites. https://www.cdc.gov/dengue/training/cme/ccm/Assess%20for%20Ascites_F.pdf. Accessed November 13, 2019.
My patient with jaundice complains of abdominal fullness. How useful is the history or physical exam when assessing for ascites?