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

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. 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?

Should I routinely treat my patients with acute COPD exacerbation with antibiotics?

The answer is “NO”! With an estimated 20% to 50% of acute chronic obstructive pulmonary disease (COPD) exacerbations attributed to noninfectious factors (1,2), routine inclusion of antibiotics in the treatment of this condition is not only unnecessary but potentially harmful.

 
Although the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommends the use of antibiotics in patients who have dyspnea, increased sputum volume, and increased sputum purulence—or at least 2 of these 3 criteria when sputum purulence is one of them (3)—, these recommendations are not based on robust evidence and have not been widely corroborated (2,4-6).

 
That’s why the findings of a 2019 New England Journal of Medicine study (PACE) supporting the use of serum C-reactive protein (CRP) as an adjunctive test in COPD exacerbation is particularly welcome (1). In this multicenter randomized controlled trial performed in the U.K., the following CRP guidelines (arrived from prior studies) were provided to primary care clinicians to be used as part of their decision making in determining which patients with COPD exacerbation may not need antibiotic therapy:
• CRP less than 20 mg/L: Antibiotics unlikely to be beneficial
• CRP 20-40 mg/L: Antibiotics may be beneficial, mainly if purulent sputum is present
• CRP greater than 40 mg/L: Antibiotics likely to be beneficial

 
Adoption of these guidelines resulted in significantlly fewer patients being placed on antibiotics without evidence of harm over a 4-week follow-up period (1).  Despite its inherent limitations (eg, single country, outpatient setting), CRP testing may be a step in the right direction in curbing unnecessary use of antibiotics in COPD exacerbation.  

 

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References
1. Butler CC, Gillespie D, White P, et al. C-reactive protein testing to guide antibiotic prescribing for COPD exacerbations. N Engl J Med 2019;381:111-20. https://www.ncbi.nlm.nih.gov/pubmed/31291514
2. Llor C, Moragas A, Hernandez S, et al. Efficacy of antibiotic therapy for acute exacerbations of mild to moderate chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012;186:716-23. https://www.ncbi.nlm.nih.gov/pubmed/22923662
3. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. GOLD, 2019 (http://www.goldcopd.org).
4. Brett AS, Al-Hasan MN. COPD exacerbations—A target for antibiotic stewardship. N Engl J Med 2018;381:174-75. https://www.ncbi.nlm.nih.gov/pubmed/31291521
5. Miravitlles M, Moragas A, Hernandez S, et al. Is it possible to identify exacerbations of mild to moderate COPD that do not require antibiotic treatment? Chest 2013;144:1571-7. https://www.ncbi.nlm.nih.gov/pubmed/23807094
6. Van Vezen P, Ter Riet G, Bresser P, et al. Doxycycline for outpatient-treated acute exacerbations of COPD: a randomized double-blind placebo-controlled trial. Lancet Respir Med 2017;5:492-9. https://www.ncbi.nlm.nih.gov/pubmed/28483402

Should I routinely treat my patients with acute COPD exacerbation with antibiotics?

My patient with cirrhosis now has an upper gastrointestinal bleed (UGIB) with hepatic encephalopathy (HE). What’s the connection between UGIB and HE?

Hepatic encephalopathy (HE) may be precipitated by a variety of factors including infection, hypovolemia, electrolyte imbalance (eg, hyponatremia, hypokalemia), metabolic alkalosis, sedatives, and of course UGIB. 1-3

Ammonia is often considered to play a central role in the the pathogenesis of HE, particularly when associated with UGIB. The ammoniagenic potential of UGIB is primarily attributed to the presence of hemoglobin protein in the intestinal tract. One-half of the ammoniagenesis originates from amino acid metabolism (mainly glutamine) in the mucosa of the small bowel, while the other half is due to the splitting of urea by the resident bacteria in the colon (eg, Proteus spp., Enterobacteriaceae, and anerobes).1,2

A large protein load in the GI tract, as occurs in UGIB, may result in hyperammonemia in patients with cirrhosis due to the limited capacity of the liver to convert ammonia to urea through the urea cycle as well as by the shunting of blood around hepatic sinusoids. Recent studies, however, also implicate the kidneys as an important source of ammonia in this setting, further compounding HE.3

It’s important to stress that ammonia is not likely to be the only mediator of HE. Enhanced production of cytokines due to infection or other inflammatory states, neurosteroids, endogenous benzodiazepines, and other bacterial byproducts may also play an important role in precipitating HE.2,4-6  So stay tuned!

Bonus pearl: Did you know that proinflammatory cytokines tumor necrosis factor-alpha and inerleukin-6 increase ammonia permeability across central nervous system-derived endothelial cells? 7

 

References

  1. Olde Damink SWM, Jalan R, Deutz NEP, et al. The kidney plays a major role in the hyperammonemia seen after simulated or actual GI bleeding in patients with cirrhosis. Hepatology 2003;37:1277-85.
  2. Frederick RT. Current concepts in the pathophysiology and management of hepatic encephalopathy. Gastroenterol Hepatol 2011;7:222-233.
  3. Tapper EB, Jiang ZG, Patwardhan VR. Refining the ammonia hypothesis: a physiology-driven approach to the treatment of hepatic encephalopathy. Mayo Clin Proc 2015;90:646-58.
  4. Shawcross DL, Davies NA, Williams R, et al. Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis. J Hepatol 2004;40:247-254.
  5. Shawcross DL, Sharifi Y, Canavan JB, et al. Infection and systemic inflammation, not ammonia, are associated with grade ¾ hepatic encephalopathy, but not mortality in controls. J Hepatol 2011;54:640-49.
  6. Shawcross D, Jalan R. The pathophysiologic basis of hepatic encephalopathy: central role for ammonia and inflammation.Cell Mol Life Sci 2005;62:2295-2304.
  7. Duchini A, Govindarajan S, Santucci M, et al. Effects of tumor necrosis factor-alpha and interleukin-6 on fluid-phase permeability and ammonia diffusion in CNS-derived endothelial cells. J Investig Med 1996;44:474-82.

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My patient with cirrhosis now has an upper gastrointestinal bleed (UGIB) with hepatic encephalopathy (HE). What’s the connection between UGIB and HE?

Why is my hospitalized patient with alcohol withdrawal syndrome so thrombocytopenic?

Although thrombocytopenia associated with chronic alcoholism may be related to complications of cirrhosis (eg, platelet sequestration in spleen due to portal hypertension, poor platelet production, and increased platelet destruction) (1), it may also occur in the absence of cirrhosis due to the direct toxic effect of alcohol on platelet production and survival (2).

 
In a prospective study of patients ingesting the equivalent of a fifth or more daily of 86 proof whiskey admitted for treatment of alcohol withdrawal—without evidence of severe liver disease, infection or sepsis— 81% had initial platelet counts below 150,000/µl, with about one-third having platelet counts below 100,000 µl (as low as 24,000/ul) (3).
In most patients, 2-3 days elapsed before the platelet count began to rise significantly, peaking 5-18 days after admission. Others have also reported that platelet counts rise within 5-7 days and normalize in a few weeks after alcohol withdrawal (1); bleeding complications have been uncommon in this setting.
Perhaps even more intriguing is the report of the association between thrombocytopenia in early alcohol withdrawal and the development of delirium tremens or seizures (sensitivity and specificity ~ 70%, positive predictive value less than 10% but with a negative predictive value of 99%) (4)! In fact, the authors suggested that, if their findings are corroborated, a normal platelet count could potentially be used to identify patients at low risk of alcohol withdrawal syndrome and therefore outpatient therapy. 

References
1. Mitchell O, Feldman D, Diakow M, et al. The pathophysiology of thrombocytopenia in chronic liver disease. Hepatic Medicine: Evidence and Research 2016;8 39-50. https://www.dovepress.com/the-pathophysiology-of-thrombocytopenia-in-chronic-liver-disease-peer-reviewed-article-HMER

2. Cowan DH. Effect of alcoholism on hemostasis. Semin Hematol 1980;17:137-47. https://www.ncbi.nlm.nih.gov/pubmed/6990498

3. Cowan DH, Hines JD. Thrombocytopenia of severe alcoholism. Ann Intern Med 1971;74:37-43. http://annals.org/aim/article-abstract/685069/thrombocytopenia-severe-alcoholism.

4. Berggren U, Falke C, Berglund KJ, et al. Thrombocytopenia in early alcohol withdrawal is associated with development of delirium tremens or seizures. Alcohol & Alcoholism 2009;44:382-86. https://www.ncbi.nlm.nih.gov/pubmed/19293148

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Why is my hospitalized patient with alcohol withdrawal syndrome so thrombocytopenic?

What is the evidence for iron deficiency causing pica?

Pica refers to the compulsive craving and persistent consumption of substances not fit as food such as ice (pagophagia) and soil (geophagia). Several reports have implicated iron deficiency as a cause of pica, with resolution of symptoms following treatment of iron deficiency (1).

In a recent study involving blood donors , pica (particularly pagophagia) was nearly 3 times as likely among donors with iron deficiency  compared to iron-replete donors (11%  vs 4%, respectively, P<0.0001).  In the same study, donors with pica reported a marked reduction in their pica by day 5-8 of iron therapy. 

It has been suggested that cerebral tissue function may be adversely impacted by a deficiency in Fe-containing enzymes (e.g. cytochrome c reductase) resulting in behavioral disorders, such as hyperactivity and pica (2).  

Of interest, cats can be induced to swallow inedible objects when certain points in the hypothalamic area high in iron content are stimulated (3).

References

  1. Bryant BJ, Yau YY, Arceo SM, et al. Ascertainment of iron deficiency and depletion in blood donors through screening questions for pica and restless legs syndrome. Transfusion 2013;53:1637-1644. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3691288
  2. Osman YM, Wali YA, Osman OM. Craving for ice and iron-deficiency anemia: a case series from Oman. Pediatric Hematol Oncol 2005; 22:127-131. https://www.ncbi.nlm.nih.gov/pubmed/15804997
  3. Von Bonsdorff B. Pica: a hypothesis.. British J Haematol 1977;35:476-477.  https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2141.1977.tb00611.x

 

Contributed by S.J. Lee,  Medical Student, Harvard Medical School, Boston, MA

What is the evidence for iron deficiency causing pica?