Hepatitis;

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in 54% of patients with Covid-19 during their hospitalization with alkaline phosphatase elevation reported in ~2.0% (1, unpublished reports).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shown to infect liver tissue and cholangiocytes may express ACE2 receptors, a prime target for Covid-19 virus (1,6,7, unpublished reports).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?

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

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

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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References
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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1358029/pdf/annsurg00170-0061.pdf
2. Huffman JL, Schenker S. Acute acalculous cholecystitis: A review. Clin Gastroenterol Hepatol 2010;8:15-22. https://www.cghjournal.org/article/S1542-3565(09)00880-5/pdf
3. Hakala T, Nuutinene PJO, Ruokonen ET, et al. Microangiopathy in acute acalculous cholecystitis Br J Surg 1997;84:1249-52. https://bjssjournals.onlinelibrary.wiley.com/doi/abs/10.1046/j.1365-2168.1997.02775.x?sid=nlm%3Apubmed
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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4941110/
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. https://journals.lww.com/pidj/pages/articleviewer.aspx?year=2018&issue=02000&article=00020&type=Fulltext  
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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3784234/pdf/CRIM.ID2013-407182.pdf
7. Simoes AS, Marinhas A, Coelho P, et al. Acalculous acute cholecystitis during the course of an enteroviral infection. BMJ Case Rep 2013;12. https://casereports.bmj.com/content/12/4/e228306
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. https://jitc.biomedcentral.com/articles/10.1186/s40425-019-0604-2

 

 

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

My patient with erythema multiforme has tested positive for Mycoplasma pneumoniae IgM antibody. Does this mean she has an acute M. pneumonia infection as the cause of her acute illness?

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

Not necessarily! Although detection of IgM in the serum of patients has proven valuable in diagnosing many infections during their early phase, particularly before IgG is detected, less well known is that false-positive IgM results are not uncommon. 1

More specific to M. pneumoniae IgM, false-positive results have been reported in 10-80% of patients without a clinical diagnosis of acute M. pneumoniae infection 2-4 and 3-15% of blood donors. 4

False-positive IgM results may also occur when testing for other infectious agents, such as the agent of Lyme disease (Borrelia burgdorferi), arboviruses (eg, Zika virus), and herpes simplex, Epstein-Barr, cytomegalovirus, hepatitis A and measles viruses. 1,5  

Reports of false positive IgM results include a patient with congestive heart failure and mildly elevated liver enzymes who had a false-positive hepatitis IgM which led to unnecessary public health investigation and exclusion from an adult day care center. 1 Another patient with sulfa rash had a false-positive measles IgM antibody resulting in callback of >100 patients and healthcare providers for testing!5

There are many potential mechanisms for false-positive IgM results, including polyclonal B cell activation, “vigorous immune response”, cross-reactive antibodies, autoimmune disease, subclinical reactivation of latent viruses, influenza vaccination, overreading weakly reactive results, and persistence of antibodies long after the resolution of the acute disease. 1,2

In our patient, a significant rise in M. pneumoniae IgG between acute and convalescent samples several weeks apart may be more helpful in diagnosing an acute infection accounting for her erythema multiforme.

 

References

  1. Landry ML. Immunoglobulin M for acute infection: true or false? Clin Vac Immunol 2016;23:540-5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4933779/
  2. Csango PA, Pedersen JE, Hess RD. Comparison of four Mycoplasma pneumoniae IgM-, IgG- and IgA-specific enzyme immunoassays in blood donors and patients. Clin Micro Infect 2004;10:1089-1104. https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(14)63853-2/pdf
  3. Thacker WL, Talkington DF. Analysis of complement fixation and commercial enzyme immunoassays for detection of antibodies to Mycoplasma pneumoniae in human serum. Clin Diag Lab Immunol 2000;7:778-80. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC95955/
  4. Ryuta U, Juri O, Inoue Y, et al. Rapid detection of Mycoplasma pneumoniae IgM antibodies using immunoCard Mycoplasma kit compared with complement fixation (CF) tests and clinical application. European Respiratory Journal 2012; 40: P 2466 (Abstract). https://erj.ersjournals.com/content/40/Suppl_56/P2466 
  5. Woods CR. False-positive results for immunoglobulin M serologic results: explanations and examples. J Ped Infect Dis Soc 2013;2:87-90. https://www.ncbi.nlm.nih.gov/pubmed/26619450

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My patient with erythema multiforme has tested positive for Mycoplasma pneumoniae IgM antibody. Does this mean she has an acute M. pneumonia infection as the cause of her acute illness?

Should my patient with suspected alcoholic hepatitis undergo liver biopsy?

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

Although a characteristic clinical history and biochemical pattern of liver injury can strongly suggest the diagnosis of alcoholic hepatitis (AH), a definitive diagnosis is confirmed with liver biopsy only. In fact, in 30% of patients clinically diagnosed as having AH, a liver biopsy may lead to an alternative diagnosis.1Understandably, many physicians are reluctant to proceed with biopsy in this fragile patient population given the associated risks, notably bleeding. For this reason, most patients with AH are clinically diagnosed without a liver biopsy. However, there are certain instances in which a biopsy can be helpful, including when:2

  • Diagnosis of AH is in doubt
  • Suspicion for another disease process that may be contributing in parallel to AH is high
  • Obtaining prognostic data or identification of advanced hepatic fibrosis or cirrhosis in AH is desired

Thus, liver biopsy findings may influence short- and long-term management in AH. For these reasons, the European Association for the Study of the Liver recommends consideration of a liver biopsy in patients with AH.3 To minimize the bleeding risk, the transjugular approach is preferred.

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References

  1. Mookerjee RP, Lackner C, Stauber R, et al. The role of liver biopsy in the diagnosis and prognosis of patients with acute deterioration of alcoholic cirrhosis. J Hepatol 2011; 55:1103-1111 Link
  2. Altamirano J, Miquel R, Katoonizadeh A, et al. A histologic scoring system for prognosis of patients with alcoholic hepatitis. Gastroenterology 2014;146: 1231-1239. PDF
  3. European Association for the Study of Liver. EASL clinical practical guidelines: management of alcoholic liver disease. J Hepatol 2012; 57:399-420. PDF

Contributed by Jay Luther, MD, Gastrointestinal Unit, Mass General Hospital, Boston, MA.

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!

 

Should my patient with suspected alcoholic hepatitis undergo liver biopsy?