Inflammation

Should I treat my patient with community-acquired pneumonia (CAP) with adjunctive corticosteroids?

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

It depends! You should consider ACs in immunocompetent patients with severe bacterial CAP in the absence of concurrent influenza, particularly in patients with a very high inflammatory response (eg, serum C-reactive protein [CRP] >150-200 mg/L). 1-13 In contrast, ACs is NOT recommended for patients with non-severe CAP.

Depending on the study, ACs in severe CAP has been associated with improvement in various patient outcomes, including reduced mortality, need for vasopressor or invasive mechanical ventilation, decrease in ICU stay and decrease in hospital length of stay.1-13 Significantly higher risk of hyperglycemia has been reported in the ACs group without demonstrable increase in the risk of upper GI bleed or hospital-acquired infections.2  

Which definition of severe CAP should we use when considering ACs? Unfortunately, it varies but a commonly cited definition is that proposed by the American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA).9  When determining which patients may benefit from ACs, I favor a broader definition of severe CAP through modification of the ATS/IDSA criteria to include several other criteria used in major trials such as the seminal Community-Acquired Pneumonia Evaluation Corticosteroids (CAPE COD) study criteria and the Pneumonia Severity Index. 1-4   According to this “modified ATS/IDSA criteria”, severe CAP is likely in the presence of either one major criterion OR ≥3 minor criteria as detailed below.

Major criteria (1 needed):1. Septic shock with need for vasopressor; 2. Respiratory failure requiring invasive, non-invasive mechanical ventilation or high-flow nasal cannula; OR 3. Pneumonia severity index class IV or V.  Note: high-flow nasal cannula and PSI IV or V have been added to ATS/IDSA criteria

Minor criteria (3 needed):1. Respiratory rate ≥30/min; 2. Pa02/Fi02 ratio ≤250; 3. Multilobar infiltrates; 4. Confusion/disorientation; 5. BUN≥20 mg/dL; 6. Leukopenia (WBC<4,000/uL); 7. Thrombocytopenia (platelet count < 100,000/uL; 8. Hypothermia (core temp <96.8 ⁰ F, 36 ⁰ C); 9. Hypotension requiring aggressive fluid resuscitation.

In addition, a high inflammatory response based on CRP greater than 150-200 mg/L significantly increases the odds of a favorable outcome (eg, reduced mortality) in CAP when ACs is used.2,3,8 In fact, in a meta-analysis involving data-driven analysis of randomized trials, a significant reduction in mortality with ACs was observed only in those with CRP>204 mg/dL (6.1% vs 13%).8  In a subgroup analysis of CAPE COD study, mortality was significantly reduced only in patients with CRP>150 mg/L (risk difference -7.3 %).2  A 2015 study involving only patients with CRP>150 mg/L and meeting ATS/IDSA criteria for severe CAP or PSI class V, treatment failure (composite deterioration/invasive mechanical ventilation and death within 72 h) was significantly lower in the ACs group (13% vs 31%).3   

Collectively, in the absence of any contraindication to corticosteroids or concurrent influenza, the weight of the evidence supports ACs in select patients with severe CAP, particularly when associated with CRP>150 mg/L.  In contrast, for patients with non-severe CAP and presumed lower level of inflammation, the benefit of ACs may not outweigh its risks and is not recommended, unless there are other indications for their use (eg, COPD exacerbation).  For all other patients, including those without severe CAP but with high CRP levels as above or severe CAP with lower CRP levels, ACs should be considered on a case-by-case basis.

When indicated for severe CAP, based on the inclusion criteria used by various clinical trials, ACs should be started as soon as severe CAP is diagnosed, preferably within 24 h.2,13 As for the choice of ACs regimen, no study has proven the superiority of one particular regime vs others.1  The CAPE COD study used IV hydrocortisone 200 mg/day continuous infusion for 4-8 days with taper over total of 8-14 days.2 Some have suggested methylprednisolone 0.5 mg/kg IV q 12 h or “typical doses” of 40-80 mg/day IV methylprednisolone equivalent for 5-7 days.1,3 Yet others have suggested that hydrocortisone 100 mg IV or methylprednisolone 40 mg IV be given in the emergency department as an initial dose when severe CAP is diagnosed. 11 If IV hydrocortisone is selected, a pragmatic approach using 50 mg every 6 hours, similar to that suggested in the management of septic shock by the 2026 Guidelines by the Surviving Sepsis Campaign14 may also be reasonable.

 

Bonus Pearls:

  1. Did you know that despite ready availability of antibiotics, mortality from CAP in hospitalized patients remains high with nearly 50,000 people dying each year in the U.S. alone? top-pneumonia-facts.pdf
  2. Did you know that in addition to their immune modulating action, experimental studies have shown that corticosteroids may decrease global bacterial burden in lung tissue and lead to less extensive pneumonia in piglets15 and significant reduction in intracellular bacterial survival in human monocytes?16 Who would have guessed?  

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References

  1. Chaudhuri D, Nei AM, Rochwerg B, et al. 2024 Focused update: Guidelines on use of corticosteroids in sepsis, acute respiratory distress syndrome, and community-acquired pneumonia. Crit Care Med 2024;52:e129-33. 2024 Focused Update: Guidelines on Use of… : Critical Care Medicine 
  2. Dequin P.-F, Meziani J.-P, Quenot T, et al. Hydrocortisone in severe community-acquire pneumonia. N Engl J Med 2023; 388: 1931-41. Hydrocortisone in Severe Community-Acquired Pneumonia | New England Journal of Medicine 
  3. Torres A, Sibila O, Ferrer M, et al. Effect of corticosteroids on treatment failure among hospitalized patients with severe community-acquired pneumonia and high inflammatory response: A randomized clinical trial. JAMA 2015;313:677-86 .Effect of corticosteroids on treatment failure among hospitalized patients with severe community-acquired pneumonia and high inflammatory response: a randomized clinical trial – PubMed
  4. Metlay JP, Waterer GW. Time to treat severe community-acquired pneumonia with steroids? N Engl J Med 2023; 388:2001-2. Time to Treat Severe Community-Acquired Pneumonia with Steroids? | New England Journal of Medicine
  5. Pitre Ty, Pauley E, Chaudhuri D, et al. Corticosteroids for adult patients hospitalized with non-viral community-acquired pneumonia: a systematic review and meta-analysis. Intensive Care Medicine 2025; 51:917-29. Corticosteroids for adult patients hospitalised with non-viral community-acquired pneumonia: a systematic review and meta-analysis | Intensive Care Medicine | Springer Nature Link
  6. Soumare A, Kapfer T, Botrel T, et al. Systemic corticosteroids, mortality, and infections in pneumonia and acute respiratory distress syndrome. Ann Intern Med 2026; 179L67-80. Systemic Corticosteroids, Mortality, and Infections in Pneumonia and Acute Respiratory Distress Syndrome : A Systematic Review and Meta-analysis – PubMed
  7. Keisham B, Duhan S, Bajaj D, et al. Steroid therapy in community-acquired pneumonia: an updated systematic review and meta-analysis. Heart & Lung 2026;79:102839. Steroid Therapy in Community-Acquired Pneumonia: An Updated Systematic Review and Meta-Analysis – PubMed
  8. Smit JM, Van Der Zee PA, Stoff SCM, et al. Predicting benefit from adjuvant therapy with corticosteroids in community-acquired pneumonia: a data-driven analysis of randomized trials. Lancet Resp Med 2025;13:221-33. Predicting benefit from adjuvant therapy with corticosteroids in community-acquired pneumonia: a data-driven analysis of randomised trials – The Lancet Respiratory Medicine. 
  9. Jones BE, Ramirez JA, Oren E, et al. Diagnosis and management of community-acquired pneumonia. Am J Resp Crit Care 2026;212:24. Jones BE, Ramirez JA, Oren E, et al. Diagnosis and management of community-acquired pneumonia. Am J Resp Crit Care 2026;212:24. – Search
  10. Reyes LF, Morris AC, Serrano-Mayorga C, et al. Community-acquired pneumonia. Lancet 2025;406:2371-88. Community-acquired pneumonia – The Lancet
  11. Long B, Gottlieb M. 2025 guideline updates for community-acquired pneumonia diagnosis and management. Am J Emerg Med 2026;107:16-20. 2025 guideline updates for community-acquired pneumonia diagnosis and management – EM consulte
  12. Confalonleri M, Urbino R, Potena A, et al. Hydrocortisone infusion for severe community-acquired pneumonia: A preliminary randomized study. Am J Respir Crit Care Med 2005;171:242-8. Hydrocortisone Infusion for Severe Community-acquired Pneumonia | American Journal of Respiratory and Critical Care Medicine | Oxford Academic
  13. Pirracchio R, Venkatesh B, Legrand M. Low-dose corticosteroids for critically ill adults with severe pulmonary infections: A review. JAMA 2024;332:318-328.jama_pirracchio_2024_rv_240011_1721328820.09305 give steroids.pdf
  14. Prescott HC, Antonelli M, Alhazzani W, et al. Surviving Sepsis Campaign: International guidelines for management of sepsis and septic shock 2026. Crit Care Med 2026;54:725-812. Surviving Sepsis Campaign: International… : Critical Care Medicine
  15. Sibila O, Luna CM, Agusti C, et al. Effects of glucocorticoids in ventilated piglets with severe pneumonia. Eur Respir J 2008;32:1037-46. Effects of glucocorticoids in ventilated piglets with severe pneumonia | European Respiratory Society
  16. Meduri GU, Kananagat S, Bronze M, et al. Effects of methylprednisolone on intracellular bacterial growth. Clin Diag Lab Immunol 2001;8:1156-63.Effects of Methylprednisolone on Intracellular Bacterial Growth – PMC

Disclosures/Disclaimers: 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!

Should I treat my patient with community-acquired pneumonia (CAP) with adjunctive corticosteroids?

How should I interpret serum ferritin and transferrin saturation in my patient with anemia?

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

Let’s start with serum ferritin, an iron containing protein that’s considered the most sensitive and specific noninvasive diagnostic test for evaluating total body iron stores (vs. the gold standard—but invasive— iron staining of bone marrow). 1

Although the optimal ferritin threshold to diagnose iron deficiency (ID) varies, compared to bone marrow iron reserves, levels below 15 ug/L are considered 98% specific and 78% sensitive.2 At a higher cut off of less than 45 ug/L, its sensitivity is 85% with a specificity of 92%.3 So if your patient’s ferritin level is less than 45 ug/L—especially less than 15 ug/L—you can be quite confident that they have ID.  

Argument is often made that ferritin levels may be misleadingly high even in the presence of ID because it is an acute phase reactant and its synthesis is expected to increase in a variety of infectious and non-infectious inflammatory conditions. But this argument can only be taken so far, because ferritin synthesis still depends on the presence of cellular iron, such that even in the presence of inflammation, its levels are unlikely to be more 100 ug/L in patients with low iron stores or “absolute ID”.

Absolute ID should be distinguished from “functional” ID which is associated with adequate iron stores but inadequate iron availability to tissues due to cytokine-mediated hepcidin production and macrophage sequestration of iron. 4

This brings us to another key protein, serum transferrin which transports iron to vital tissues, including the bone marrow.  Transferrin saturation (TSat) is not only low (≤20%) in absolute ID but also in functional ID. 1 This is where a combination of serum ferritin and TSat is helpful. A low TSat combined with a normal or high serum ferritin suggests functional ID with the previously discussed caveat that serum ferritin levels may be normal or elevated—but usually less than 100 ug/L)— in patients with absolute ID and concurrent inflammation.

So in your patient with anemia, after reviewing their serum ferritin and TSat, you should have a good idea of whether they have ID and, if so, whether it’s related to an absolute or functional ID. In another post, I will discuss guidelines on the diagnosis and treatment of functional ID.

Bonus Pearl: Did you know that the commonly-cited difference in the threshold for anemia in males vs females (<13.0 g/dL and <12 g/dL, respectively) by WHO may at least in part be related to unrecognized and untreated ID in the female population studies over 50 years ago? 1

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References

  1. Martens KL, DeLoughery TG. Iron deficiency anemia. Ann Intern Med 2026; 179:1-16. Iron Deficiency Anemia | Annals of Internal Medicine
  2. Hallberg L, Bengtsson C, Lapidus L, et al. Screening for iron deficiency: an analysis based on bone marrow examinations and serum ferritin determinations in a population sample of women. Br. J Haematol 199385:787-798. Screening for iron deficiency: an analysis based on bone-marrow examinations and serum ferritin determinations in a population sample of women. – Abstract – Europe PMC
  3. Rockey DC, Altayar O, Falck-Ytter Y, et al. AGA technical review on gastrointestinal evaluation of iron deficiency. Gastroenterology 2020;159:1097-1119. AGA Technical Review on Gastrointestinal Evaluation of Iron Deficiency Anemia – Gastroenterology
  4. Camaschella C, Girelli D. The changing landscape of iron deficiency. Mol Aspects Med 2020;75:100861. The changing landscape of iron deficiency – PubMed

 

Disclosures/Disclaimers: 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!

 

How should I interpret serum ferritin and transferrin saturation in my patient with anemia?

Is my patient with varicose veins at higher risk of venous thromboembolism?

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

Although varicose veins are common and usually not associated with serious health complications, increasing scientific evidence suggests that they are associated with increased risk of subsequent incident deep venous thrombosis (DVT) and pulmonary embolism (PE). 1-3

A 2018 retrospective cohort study involving patients with the diagnosis of varicose veins and controls (>200,000 subjects each) based on claims data from Taiwan found a higher incidence rate of DVT among cases (hazard ratio [HR] 5.3, 95%C.I. 5.1-5.6). Increased risk of DVT with varicose veins was reported in all age groups but decreased with increasing age.  The HR was higher within the first year of the diagnosis of varicose veins. 1

In the same study, the incidence of PE was higher among participants with varicose veins (HR 1.7 95% C.I. 1.5-1.9).  Again, the association did not significantly differ by age.1  Other smaller studies have found similar association between DVT and varicose veins. 2,3

Although these studies at best demonstrate an association (not necessarily a cause and effect relationship) between varicose veins and venous thromboembolism, several possible explanations have been posited. Animal studies have demonstrated higher concentrations of macrophages, monocytes, neutrophils, lymphocytes, and matrix metalloproteinases in venous valves exposed to high pressure for prolonged periods.  The resultant inflammatory state in patients with varicose veins may in turn promote a prothrombotic state contributing to venous thromboembolism. 1,4

Bonus Pearl: Did you know that nearly 1 of 4  adults in the United States have been reported to have varicose veins?

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References

  1. Chang SL, Huang YL, Lee MC, et al. Association of varicose veins with incident venous thromboembolism and peripheral artery disease. JAMA 208;319:807-817. https://jamanetwork.com/journals/jama/fullarticle/2673551
  2. Muller-Buhl U, Leutgeb R, et al. Varicose veins are a risk factor for deep venous thrombosis in general practice patients. Vasa 2012;41:360-65. https://pubmed.ncbi.nlm.nih.gov/22915533/
  3. Engbers MJ, Karasu A, Blom JW, et al. Clinical features of venous insufficiency and the risk of venous thrombosis in older people. Br J Haematol 2015;171:417-23. https://pubmed.ncbi.nlm.nih.gov/26221838/
  4. Riva N, Donadini MP, Ageno W. Epidemiology and pathophysiology of venous thromboembolism: similarities with atherothrombosis and the role of inflammation. Thromb Haemost 2015;113:1176-1183. https://pubmed.ncbi.nlm.nih.gov/25472800/

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 or its affiliate healthcare centers, Mass General Hospital, Harvard Medical School or its affiliated institutions. 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!

Is my patient with varicose veins at higher risk of venous thromboembolism?

Does tuberculosis (TB) increase the risk of cancer?

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

Ample reports in the literature suggest that TB is associated with the development of certain cancers, including lung cancer, lymphoma and urothelial cancers of the genitourinary tract. 1-5

A 2010 literature review including 9 retrospective studies found that several (not all) studies reported a significant association between prior history of TB and lung cancer, with odds ratios as high as 20.5 ( C.I. 8.1-51.8) at 1-5 years following TB.1 One study involving non-smoking women found a lung cancer (mostly adenocarcinoma) prevalence of 18% among those with prior history of TB (O.R. 5.9, CI 1.3-25.9).5 Cases of “pyothorax-associated lymphoma” of the pleural cavity have also been attributed to TB diagnosed as remote as 40 years or greater before the diagnosis of cancer.1

Urinary tuberculosis was associated with the development of urothelial carcinoma (including bladder, ureteral, renal pelvic transitional cell carcinoma) but not renal cell carcinoma in a nationwide cohort study from Taiwan (hazard ratio 3.4, C.I. 2.0-5.7). 2 The mean interval between the index date of TB and the diagnosis of urinary tract cancer was about 5 years in this study.

Several potential mechanisms for TB predisposing to malignancy have been proposed.1,6 Chronic inflammation associated with higher rate of cell turnover may increase the risk of genetic mutation and subsequent malignancy, as observed in other conditions such as gastroesophageal reflux disease and esophageal cancer and inflammatory bowel disease and colon cancer. The ability of Mycobacterium tuberculosis to induce DNA damage, inhibit apoptosis and augment concentrations of leukotrienes, prostaglandins and vascular endothelial growth factors have also been implicated.

And don’t forget that active TB may not only coexist with but may also mimic malignancy (see related pearl on P4P).

 

Bonus Pearl: Did you know that the association of TB with cancer was first described in 1810 by Gaspard Laurent Bayle, a French physician who considered “cavitation cancereuse” as a distinct TB category? 1

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 References

  1. Falagas ME, Kouranos VD, Athanassa Z, et al. Tuberculosis and malignancy. Q J Med 2010;103: 461-87. Doi:10.1093/qjmed/hcq068 https://pubmed.ncbi.nlm.nih.gov/20504861/
  2. Lien YC, Wang JY, Lee MC, et al. Urinary tuberculosis is associated with the development of urothelial carcinoma but not renal cell carcinoma: a nationwide cohort study in Taiwan. B J Cancer 2013;109:2933-2940. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3844900/
  3. Chin SN, Foster T, Char G, et al. Concomitant urothelial cancer and renal tuberculosis. Case Reports in Urology. Volume 2014, Aricle ID 625153. https://www.hindawi.com/journals/criu/2014/625153/
  4. Dobler CC, Cheung K, Nguyen J, et al. Risk of tuberculosis in patients with solid cancers and haematological malignancies: a systematic review and meta-analysis. Eur Respir J 2017;50:1700157. https://doi.org/10.1183/13993003.00157-2017.
  5. Ko YC, Lee CH, Chen MJ, et al. Risk factors for primary lung cancer amng non-smoking women in Taiwan. Int J Epidemiol 1997;26:24-31. https://pubmed.ncbi.nlm.nih.gov/9126500/
  6. Ling S, Chang X, Schultz L, et al. An EGFR-ERK-SOX9 signaling cascade links urothelial development and regeneration to cancer. Cancer Res 2011;71:3812-21. https://pubmed.ncbi.nlm.nih.gov/21512138/ 

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!

Does tuberculosis (TB) increase the risk of cancer?

Is the average body temperature in adults lower than 98.6 ᵒF (37 ᵒC)?

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

Despite the widely-held belief that the normal body temperature is 98.6 ᵒF (37.0 ᵒC), it is becoming increasingly clear that the average body temperature among adults (at least in the U.S.) is actually lower than 98.6 ᵒF (37 ᵒC).

The concept of a single normal body temperature dates way back to the 1800’s, based on measuring axillary temperatures by mercury thermometers. 1 However, a 2001 systematic literature review of 20 studies (1935-1998) of normal body temperature measured in adults found the following mean temperatures: oral 97.5 ᵒF (36.4 ᵒC), rectal 98.4 ᵒF (36.9 ᵒC), tympanic 97.7 ᵒF (36.5 ᵒC), and axillary 97.3 ᵒF (36.3 ᵒC ).  A British study involving >35,000 patients also found a lower mean oral temperature of 97.9 ᵒF (36.6 ᵒC). 2 A 2020 US study of a cohort of >150,000 adults (2007-20017) found a mean oral temperature of 98.1 ᵒF (36.7 ᵒC) in men and 98.2 ᵒF (36.8 ᵒC) in women; these values were lower than that of an earlier cohort (1971-1975). 3

So is the discrepancy between the body temperature in 1800’s and the more recent era due to the differences in measurement techniques or the population? In other words, are we cooling off?

The weight of the evidence suggests that our bodies are cooling!3  The study of an 1860-1940 cohort—presumably using similar thermometer techniques —found a gradual drop in the mean temperature during that period alone. Since axillary temperature (accounting for some of the values in the earlier cohort) is about 1 ᵒC lower than that of oral temperature, the magnitude of the drop in mean temperatures over the past 150 years is likely higher that those reported. 3

Potential explanations for our cooling bodies over the past 2 centuries include reduction in the population level inflammation due to improved standard of living, sanitation, lower incidence of chronic infections. improved dental hygiene, and cooler ambient temperatures. 3

 

Fun Fact: Did you know that in 1851 Carl Wunderlich, a German physician, obtained millions of axillary temperatures from 25,000 patients in Leipzig and thereby established the standard body temperature of 98.6 ᵒF (37 ᵒC)? ᵒ

 

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References

  1. Sund-Levander M, Forsberg C, Wahren LK. Normal oral, rectal, tympanic and axillary body temperature in adult men and women: a systematic literature review. Scan J Caring Sci 2002;16:122-128. https://www.ncbi.nlm.nih.gov/pubmed/12000664
  2. Obermeyer Z, Samra JK, Mullainathan S. Individual differences in normal body temperature: longitudinal big data analysis of patient records. BMJ 2017;359:j5468. https://www.ncbi.nlm.nih.gov/pubmed/29237616
  3. Protsiv M, Ley C, Lankester J, et al. Decreasing human body temperature in the United States since the industrial revolution. Human Biology and Medicine, Jan 7, 2020. DOI: 10.7554/eLife.49555. https://www.researchgate.net/publication/338433061_Decreasing_human_body_temperature_in_the_United_States_since_the_industrial_revolution
Is the average body temperature in adults lower than 98.6 ᵒF (37 ᵒC)?

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

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

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?

How is prealbumin related to albumin?

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

Aside from being synthesized in the liver and serving as a transport protein in the blood, prealbumin (PA) doesn’t really have much in common with albumin. More specifically, PA is not derived from albumin and, in fact, the two proteins are structurally distinct from each other!

So where does PA get its name? PA is the original name for transthyretin (TTR), a transport protein that primarily carries thyroxine (T4) and a protein bound to retinol (vitamin A). The name arose because TTR migrated faster than albumin on gel electrophoresis of human serum.1

Because of its much shorter serum half-life compared to that of albumin ( ~2 days vs ~20 days),2 PA is more sensitive to recent changes in protein synthesis and more accurately reflects recent dietary intake (not necessarily overall nutritional status) than albumin. 3

But, just like albumin, PA may represent a negative acute phase reactant, as its synthesis drops during inflammatory states in favor of acute phase reactants such as C-reactive protein. 4 So be cautious about interpreting low PA levels in patients with active infection, inflammation or trauma.

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Reference

  1. Socolow EL, Woeber KA, Purdy RH, et al. Preparation of I-131-labeled human serum prealbumin and its metabolism in normal and sick patients. J. Clin Invest 1965; 44: 1600-1609. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC292644/
  2. Oppenheimer JH, Surks MI, Bernstein G, and Smith JC. Metabolism of Iodine-131-labeled Thyroxine-Binding Prealbumin in Man. Science 1965; 149: 748-750. https://www.ncbi.nlm.nih.gov/pubmed/14330531
  3. Ingenbleek Y, Young VR. Significance of prealbumin in protein metabolism. Clin Chem Lab Med 2002; 40: 1281-1291. https://www.ncbi.nlm.nih.gov/pubmed/12553432
  4. Shenkin A. Serum prealbumin: is it a marker of nutritional status or of risk of malnutrition? Clin Chem 2006;52:2177 – 2179. http://clinchem.aaccjnls.org/content/52/12/2177

Contributed by Colin Fadzen, Medical Student, Harvard Medical School, Boston, MA.

 

 

How is prealbumin related to albumin?

Why are patients with acute exacerbation of COPD at higher risk of venous thromboembolism (VTE)?

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

Patients admitted to the hospital for acute exacerbation of COPD are generally regarded as being at high risk of venous thromboembolism (VTE) (prevalence 5%-29%), possibly due to the frequent coexistence of other risk factors, such as immobility, history of smoking, and venous stasis.1 The exact mechanism(s) behind this association remains poorly understood, however.

Among patients with moderate-very severe COPD (GOLD criteria stage II-IV),  high BMI, low exercise tolerance, history of pneumothorax, congestive heart failure, and peripheral vascular disease have also been associated with VTE.1

Systemic inflammation has also been implicated in increasing the risk of VTE in patients with COPD. Although the pathophysiology of COPD is largely defined by the local inflammatory response to airway injury, evidence suggests that there is also a systemic inflammatory response in COPD.2,3 This systemic inflammation could in turn contribute to the increased risk of vascular disease, including VTE, coronary artery disease, and cerebrovascular disease.4

Bonus pearl: Did you know that VTE may be 3x more prevalent among patients with COPD exacerbation without known cause (vs those with identifiable cause) and is associated with a 1-year mortality of 61.9%! 5

Contributed by Camilo Campo, Medical Student, Harvard Medical School, Boston, MA.

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References:

  1. Kim V, Goel N, Gangar J, et al. Risk factors for venous thromboembolism in chronic obstructive pulmonary disease. Chronic Obstr Pulm Dis 2014;1: 239-249. https://www.ncbi.nlm.nih.gov/pubmed/25844397
  2. Lankeit M, Held M. Incidence of venous thromboembolism in COPD: linking inflammation and thrombosis? Eur Respir J 2016;47(2):369-73. https://www.ncbi.nlm.nih.gov/pubmed/26828045
  3. Sinden NJ1, Stockley RA. Systemic inflammation and comorbidity in COPD: a result of ‘overspill’ of inflammatory mediators from the lungs? Review of the evidence. Thorax 2010;65:930-6. https://www.ncbi.nlm.nih.gov/pubmed/20627907
  4. King PT. Inflammation in chronic obstructive pulmonary disease and its role in cardiovascular disease and lung cancer. Clinical and Translational Medicine 2015;4:26. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4518022/
  5. Gunen H, Gulbas G, In E, et al. Venous thromboemboli and exacerbations of COPD. Eur Respir J 2010;36:1243-8.  https://www.ncbi.nlm.nih.gov/pubmed/19926740 

 

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 are patients with acute exacerbation of COPD at higher risk of venous thromboembolism (VTE)?

Can my patient develop “anemia of chronic disease” acutely while hospitalized?

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

“Anemia of chronic disease” is better termed anemia of inflammation (AI) which may occur in acute as well as chronic inflammatory states. 1 As such, the view that anemia in the critically ill patients is simply caused by excess phlebotomy is inaccurate. 2 The CRIT study demonstrated that AI in critically ill patients develops even within 30 days, often despite blood transfusions. 3

In addition to the usual causes of AI (eg autoimmune disorders), AI can occur during bacterial, viral or yeast infections and sepsis 4,5.

Recent studies implicate both iron sequestration and impaired erythropoiesis as causes of AI. 1 Inflammation stimulates hepatic production of iron-regulatory peptide, hepcidin, which decreases delivery of iron from macrophages to developing erythrocytes.  Inflammation also causes production of pro-inflammatory cytokine, IL-6, which suppresses erythropoiesis.

Couple of cool studies using injection of heat-killed Brucella abortus in mice as a model of AI, showed dramatic hemoglobin drop by 7 days.6,7. In addition, not only were iron restriction from increase in hepcidin and transient erythropoiesis demonstrated, erythrocyte lifespan was also shortened in these experiments. AI is truly a multifactorial process.

 

References 

  1. Frankel PG. Anemia of inflammation: A review. Med Clin N Ame 2017;101:285-96. https://www.ncbi.nlm.nih.gov/pubmed/28189171
  2. Corwin HL, Krantz SB. Anemia of the critically ill: “Acute” anemia of chronic disease. Crit Care Med 2000;28:3098-99. https://www.ncbi.nlm.nih.gov/pubmed/10966311
  3. Corwin HL, Gettinger A, Pearl RG, et al. The CRIT study: anemia and blood transfusion in the critically ill-current clinical practice in the United states. Crit Care Med 2004;32:39-52. https://www.ncbi.nlm.nih.gov/pubmed/14707558
  4. Gabriel A, Kozek S, Chiari A, et al. High-dose recombinant human erythropoietin stimulates reticulocyte production in patients with multiple organ dysfunction syndrome. J Trauma:Injury, Infection, and Critical Care 1998;44:361-67. https://www.ncbi.nlm.nih.gov/pubmed/9498512
  5. Roy CN. Anemia of inflammation. Hematology Am Soc Hematol Educ Program. 2010;2010:276-80. doi: 10.1182/asheducation-2010.1.276. https://www.ncbi.nlm.nih.gov/pubmed/21239806
  6. Kim A, Fung E, Parikh SG, et al. A mouse model of anemia of inflammation: complex pathogenesis with partial dependence on hepcidin. Blood 2014;123:1129-36. https://www.ncbi.nlm.nih.gov/pubmed/24357728
  7. Gardenghi S, Renaud TM, Meloni A, et al. Distinct roles for hepcidin and interleukin-6 in the recovery from anemia in mice injected with heat-killed Brucella abortus. Blood 2014;123:1137-45. https://www.ncbi.nlm.nih.gov/pubmed/24357729

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Can my patient develop “anemia of chronic disease” acutely while hospitalized?

Does methotrexate reduce the risk of cardiovascular events in patients with rheumatoid arthritis?

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

The weight of the evidence suggests that methotrexate reduces the overall risk of cardiovascular events (CVEs)—including myocardial infarction, congestive heart failure, stroke, and or major adverse cardiac events—in RA patients (RR 0.72, 95% CI 0.57-0.91)1.

Aside from its effect on controlling systemic inflammation, methotrexate has also been shown to increase HDL and reduce total cholesterol/HDL ratio in patients with RA compared with treated non-RA controls2. In vitro, methotrexate appears to activate mechanisms involved in reverse transport of cholesterol out of the cell to the circulation for eventual excretion3. Not surprisingly then, methotrexate has also been reported to decrease atherosclerotic plaque burden measured by carotid artery intima-media thickness2.

We tend to think of RA as a disease that primarily causes arthritis but its effects may extend far beyond the joints. Patients with RA have an increased risk of cardiovascular deaths compared to the general population4, likely due to a variety of factors, including accelerated atherosclerosis secondary to chronic inflammation. At baseline, RA patients also have an unfavorable lipid profile with decreased HDL and higher total cholesterol/HDL ratio.

Fun Final Fact: Did you know that methotrexate is on the WHO Model List of Essential Medicines (April 2015) not only as a cancer drug but for treatment of RA as well5?

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References:

  1. Roubille C, Richer V, Starnino T, McCourt C, McFarlane A, Fleming P, Siu S, Kraft J, Lynde C, Pope J, Gulliver W, Keeling S, Dutz J, Bessette L, Bissonnette R, Haraoui B. The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis. Ann Rheum Dis. 2015;74:480-9. https://www.ncbi.nlm.nih.gov/pubmed/25561362
  2. Georgiadis AN, Voulgari PV, Argyropoulou MI, Alamanos Y, Elisaf M, Tselepis AD, Drosos AA. Early treatment reduces the cardiovascular risk factors in newly diagnosed rheumatoid arthritis patients. Semin Arthritis Rheum 2008;38:13-9. https://www.ncbi.nlm.nih.gov/pubmed/18191989
  3. Reiss AB, Carsons SE, Anwar K, Rao S, Edelman SD, Zhang H, Fernandez P, Cronstein BN, Chan ES. Atheroprotective effects of methotrexate on reverse cholesterol transport proteins and foam cell transformation in human THP-1 monocyte/macrophages. Arthritis Rheum 2008;58:3675-83. https://www.ncbi.nlm.nih.gov/pubmed/19035488
  4. Aviña-Zubieta JA, Choi HK, Sadatsafavi M, Etminan M, Esdaile JM, Lacaille D. Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies. Arthritis Rheum 2008; 59:1690-7. https://www.ncbi.nlm.nih.gov/pubmed/19035419
  5. WHO Model List of Essential Medicines (April 2015). http://www.who.int/medicines/publications/essentialmedicines/en/

 

Contributed by Brian Li, Medical Student, Harvard Medical School

Does methotrexate reduce the risk of cardiovascular events in patients with rheumatoid arthritis?