CK;

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54% of patients with Covid-19 during their hospitalization with alkaline phosphatase elevation reported in ~2.0% (1, unpublished reports).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shown to infect liver tissue and cholangiocytes may express ACE2 receptors, a prime target for Covid-19 virus (1,6,7, unpublished reports).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

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?

Why is my diabetic patient complaining of arm pain and localized edema for couple of weeks without an obvious cause?

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

Aside from the usual suspects associated with a painful extremity (eg, trauma, deep venous thrombosis and soft tissue infections), think of spontaneous diabetic myonecrosis (DMN), also known as diabetic muscle infarction (1-3).

DMN is characterized by abrupt onset of painful swelling of the affected muscle, most often of the lower extremities, but also occasionally upper extremities. DMN occurs in patients with longstanding DM whose blood glucose control has deteriorated over time, often with nephropathy, retinopathy and/or neuropathy (1-3).

Couple of things to remember when considering DMN in your differential of a painful extremity. First, except for localized edema and tenderness over the involved muscle, the exam may be unremarkable. Specifically, there is no erythema or signs of compartment syndrome and fever is absent in the great majority of patients (~90%) (2). Even white blood cell count and creatine kinase (CK) are usually normal. The reason for normal CK at presentation is not clear but CK might have already peaked by the time of patient presentation (3). In contrast, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are usually elevated (>80%) (1).

MRI (without contrast in patients with renal insufficiency) is the imaging of choice with muscle enlargement and edema with hyperintense signal on T2-weighted images and other changes, including perifascial, perimuscular and or subcutaneous edema (1-3). Muscle biopsy is not currently recommended because of its adverse impact on time to symptomatic improvement. Non-surgical therapy, with rest, analgesia and glycemic control is usually recommended (1-3).

 
Though its exact cause is still unclear, atherosclerosis, diabetic microangiopathy, vasculitis with thrombosis and ischemia-reperfusion injury have been posited as potential precipitants for DMN. The role of anti-phospholipid syndrome, particularly in patients with type I DM, is unclear (1,2).

 
Bonus pearl: Did you know that symptoms of DMN may last for weeks with at least one-third of patients having a recurrence in the same muscle or elsewhere (1)?

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Reference
1. Horton WB, Taylor JS, Ragland TJ, et al. Diabetic muscle infarction: a systematic review. BMJ Open Diabetes Research and Care 2015;3:e000082.
2. Trujillo-Santos AJ. Diabetic muscle infarction. An underdiagnosed complication of long-standing diabetes. Diabetes Care 2003;26:211-15.
3. Diabetes muscle infarction in end-stage renal disease:A scoping review on epidemiology, diagnosis and treatment. World J Nephrol 2018;7:58-64.

Why is my diabetic patient complaining of arm pain and localized edema for couple of weeks without an obvious cause?

How can I distinguish serotonin syndrome from neuroleptic malignant syndrome in my patient with fever and mental status changes?

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

Although there is often an overlap between the clinical presentation of serotonin syndrome (SS) and neuromuscular malignant syndrome (NMS), start out with the physical exam. The presence of hyperreflexia, tremors, clonus, hyperactive bowel sounds, and dilated pupils should make you think of SS, whereas hyporeflexia, “lead-pipe” rigidity in all muscle groups, normal pupils, and normal or decreased bowels sounds suggest NMS in the proper context.1-3 The most sensitive and specific sign of SS is clonus.1

Aside from physical exam findings, symptom onset in relation to the implicated drug may also be important. Onset of symptoms within 12-24 h of the initiation or change of an implicated drug suggests SS, whereas a more delayed onset (often 1-3 days) is more supportive of NMS.1-3  SS also tends to resolve within a few days after discontinuation of the offending agent, while NMS usually takes 9-14 days to resolve. 1-3 Although both SS and NMS can be associated with leukocytosis, elevated CK and low serum iron levels are more common in NMS.2

SS is caused by excess serotonin due to a variety of mechanisms—therefore medications— including inhibition of serotonin uptake ( eg, serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, metoclopramide, ondansetron), inhibition of serotonin metabolism (seen with monoamine oxidase inhibitors , including linezolid, methylene blue), increased serotonin release (eg stimulants, including amphetamines, cocaine), and activation of serotonin receptors (eg, lithium), among others. 2

As for medications that can cause NMS, look for neuroleptic agents (eg, haloperidol, olanzapine, quetiapine, risperidone), as well as antiemeics, such as metoclopramide and promethazine.2

 

Bonus Pearl: Did you know that several supplements/herbal products have been associated with serotonin syndrome, including L-tryptophan, St. John’s wort and ginseng?1

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References

  1. Bienvenu OJ, Neufeld K, Needham DM. Treatment of four psychiatric emergencies in the intensive care unit. Crit Care Med 2012;40: 2662-70. https://insights.ovid.com/crossref?an=00003246-201209000-00017
  2. Turner AAH, Kim JJ, McCarron RM, et al. Differentiating serotonin syndrome and neuroleptic malignant syndrome. Current Psychiatry 2019;18: 36. https://www.mdedge.com/psychiatry/article/193418/schizophrenia-other-psychotic-disorders/differentiating-serotonin-syndrome
  3. Dosi R, Ambaliya A, Joshi H, et al. Serotonin syndrome versus neuroleptic malignant syndrome: a challenging clinical quandary. BMJ Case Rep 2014. Doi:10.1136/bcr-2014-204154. https://casereports.bmj.com/content/2014/bcr-2014-204154

 

How can I distinguish serotonin syndrome from neuroleptic malignant syndrome in my patient with fever and mental status changes?

My patient with sepsis and bacteremia has an extremely high serum Creatine kinase (CK) level. Can his infection be causing rhabdomyolysis?

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

 Absolutely! Although trauma, toxins, exertion, and medications are often listed as common causes of rhabdomyolysis, infectious etiologies should not be overlooked as they may account for 5% to 30% or more of rhabdomyolysis cases (1,2).

Rhabdomyolysis tends to be associated with a variety of infections, often severe, involving the respiratory tract, as well as urinary tract, heart and meninges, and may be caused by a long list of pathogens (1).  Among bacterial causes, Legionella sp. (“classic” pathogen associated with rhabdomyolysis), Streptococcus sp. (including S. pneumoniae), Salmonella sp, Staphylococcus aureus, Francisella tularensis have been cited frequently (3).  Some series have reported a preponderance of aerobic gram-negatives such as Klebsiella sp., Pseudomonas sp. and E. coli  (1,2).   Among viral etiologies, influenza virus, human immunodeficiency virus, and coxsackievirus are commonly cited (2,3).  Fungal and protozoal infections (eg, malaria) may also be associated with rhabdomyolysis (5).

So how might sepsis cause rhabdomyolysis? Several potential mechanisms have been implicated, including tissue hypoxemia due to sepsis, direct muscle invasion by pathogens (eg, S. aureus, streptococci, Salmonella sp.), toxin generation (eg, Legionella), cytokine-mediated muscle cell toxicity (eg, aerobic gram-negatives) as well as muscle ischemia due to shock (1,5).

Bonus Pearl: Did you know that among patients with HIV infection, infections are the most common cause (39%) of rhabdomyolysis (6)? 

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References

1. Kumar AA, Bhaskar E, Shantha GPS, et al. Rhabdomyolysis in community acquired bacterial sepsis—A retrospective cohort study. PLoS ONE 2009;e7182. Doi:10.1371/journa.pone.0007182. https://www.ncbi.nlm.nih.gov/pubmed/19787056.

2. Blanco JR, Zabaza M, Sacedo J, et al. Rhabdomyolysis of infectious and noninfectious causes. South Med J 2002;95:542-44. https://www.ncbi.nlm.nih.gov/pubmed/12005014

3. Singh U, Scheld WM. Infectious etiologies of rhabdomyolysis:three case reports and review. Clin Infect Dis 1996;22:642-9. https://www.ncbi.nlm.nih.gov/pubmed/8729203

4. Shih CC, Hii HP, Tsao CM, et al. Therapeutic effects of procainamide on endotoxin-induced rhabdomyolysis in rats. PLOS ONE 2016. Doi:10.1371/journal.pone.0150319. https://www.ncbi.nlm.nih.gov/pubmed/26918767

5. Khan FY. Rhabdomyolysis: a review of the literature. NJM 2009;67:272-83. http://www.njmonline.nl/getpdf.php?id=842

6. Koubar SH, Estrella MM, Warrier R, et al. Rhabdomyolysis in an HIV cohort: epidemiology, causes and outcomes. BMC Nephrology 2017;18:242. DOI 10.1186/s12882-017-0656-9. https://bmcnephrol.biomedcentral.com/track/pdf/10.1186/s12882-017-0656-9

My patient with sepsis and bacteremia has an extremely high serum Creatine kinase (CK) level. Can his infection be causing rhabdomyolysis?

Is there a connection between cirrhosis and elevated CK or rhabdomyolysis?

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

Besides the usual causes of rhabdomyolysis such as trauma, drugs, alcohol, sepsis, etc…, cirrhotic patients may also have what some have called “hepatic myopathy”.  

One study involving 99 patients with cirrhosis and myopathy (all with elevated serum myoglobin) found “infections” as the most common cause (47%),  followed by “idiopathic” (27%) sources as well as ETOH, herbal medicine, and trauma-related causes (<10% each) (1).  Whether this is truly an entity  or just a non-causal association is unclear.

Another study reported that ~60% of rhabdomyolysis cases in cirrhosis had no apparent cause (2), with mortality among patient with cirrhosis and rhabdomyolysis significantly higher than that of controls without cirrhosis (27.5% vs 14.5%).

So perhaps we should lower our threshold for checking serum CK in our patients with cirrhosis and weakness.

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Reference

1. Lee O-J, Yoon J-H, Lee E-J, et al. Acute myopathy associated with liver cirrhosis. World J Gastroenterol 2006;12:2254-2258.  https://www.ncbi.nlm.nih.gov/pubmed/16610032 .

2. Baek JE, Park DJ, Kim HJ, et al. The clinical characteristics of rhabdomyolysis in patients with liver cirrhosis. J Clin Gastroenterol 2007;41:317-21.

 

Is there a connection between cirrhosis and elevated CK or rhabdomyolysis?