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?

How is prealbumin related to albumin?

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.

 

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

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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)?

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

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 

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

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?

“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?

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?

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?

What is the mechanism of anemia of chronic disease in my patient with rheumatoid arthritis?

Anemia of chronic disease (ACD)—or more aptly “anemia of inflammation”— is the second most common cause of anemia after iron deficiency and is associated with numerous acute or chronic conditions (eg, infection, cancer, autoimmune diseases, chronic organ rejection, and chronic kidney disease)1.

The hallmark of ACD is disturbances in iron homeostasis which result in increased uptake and retention of iron within cells of the reticuloendothelial system, with its attendant diversion of iron from the circulation and reduced availability for erythropoiesis1. More specifically, pathogens, cancer cells, or even the body’s own immune system stimulate CD3+ T cells and macrophages to produce a variety of cytokines, (eg, interferon-ɤ, TNF-α, IL-1, IL-6, and IL-10) which in turn increase iron storage within macrophages through induction of expression of ferritin, transferrin and divalent metal transporter 1.

In addition to increased macrophage storage of iron, ACD is also associated with IL-6-induced synthesis of hepcidin, a peptide secreted by the liver that decreases iron absorption from the duodenum and its release from macrophages2. TNF-α and interferon-ɤ also contribute to ACD by inhibiting the production of erythropoietin by the kidney.  Finally, the life span of RBCs is adversely impacted in AKD due to their reduced deformability and increased adherence to the endothelium in inflammatory states3.

Of interest, it is often postulated that by limiting access to iron through inflammation, the body hinders the growth of pathogens by depriving them of this important mineral2.

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References

  1. Weiss, G and Goodnough, L. Anemia of chronic disease. N Engl J Med 2005; 352; 1011-23. http://www.med.unc.edu/medclerk/medselect/files/anemia2.pdf
  2. D’Angelo, G. Role of hepcidin in the pathophysiology and diagnosis of anemia. Blood Res 2013; 48(1): 10-15. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3624997/pdf/br-48-10.pdf                                                                                                                                  
  3. Straat M, van Bruggen R, de Korte D, et al. Red blood cell clearance in inflammation. Transfus Med Hemother 2012;39:353-60. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3678279/pdf/tmh-0039-0353.pdf

 

Contributed by Amir Hossein Ameri, Medical Student, Harvard Medical School

                     

What is the mechanism of anemia of chronic disease in my patient with rheumatoid arthritis?

How exactly do urinary tract infections (UTIs) cause delirium in my elderly patients?

 UTIs are often considered in the differential diagnosis of causes of delirium in the elderly. Though largely speculative, 2 possible pathophysiologic basis for this association are suggested:1-3

  •  Direct brain insult (eg, in the setting of sepsis/hypotension)
  • Indirect aberrant stress response, involving cytokines/inflammatory pathways,  hypothalamic-pituitary-adrenal [HPA] axis and sympathetic nervous system (SNS). One or both pathways can interact with the neurotransmitter and intracellular signal transduction systems underlying delirium in the brain, which may already be impaired in the elderly due to age-related or other pathologic changes.

The indirect aberrant stress pathway suggests that not only pain and discomfort (eg from dysuria) can contribute to delirium but UTI-associated circulating cytokines may also cause delirium.  Indeed, a large study of older adults undergoing elective surgery found a significant association between delirium postoperatively (postop day 2) and serum proinflammatory cytokine levels such as IL-6. 4  

The corollary is that bacteriuria is unlikely to be associated with delirium in the absence of significant systemic inflammatory response, pain or discomfort.

 

References

1.Trzepacz P, van der Mast R. The neuropathophysiology of delirium. In Lindesay J,  Rockwood K, Macdonald A (Eds.). Delirium in old age, pp. 51–90. Oxford University Press, Oxford , 2002.

2.Flacker JM, Lipsitz LA. Neural mechanisms of delirium: current hypotheses and evolving concepts. J Gerontol A Biol Sci Med Sci. 1999; 54: B239–B246 https://www.ncbi.nlm.nih.gov/pubmed/10411009

3. Maclullich AM, Ferguson KJ, Miller T, de Rooij SE, Cunningham C. Unravelling the pathophysiology of delirium: a focus on the role of aberrant stress responses. J Psychosom Res. 2008;65:229–38. https://www.ncbi.nlm.nih.gov/pubmed/18707945

4. Vasunilashom SM, Ngo L, Inouye SK, et al. Cytokines and postoperative delirium in older patients undergoing major elective surgery. J Gerontol A Biol Sci Med Sci 2015;70:1289-95. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4817082/pdf/glv083.pdf

Contributed by Henrietta Afari MD, Mass General Hospital, Boston, MA

How exactly do urinary tract infections (UTIs) cause delirium in my elderly patients?

Why has my hospitalized patient with head and neck cancer developed thrombocytosis few days following surgery?

An acute rise in platelet count is not uncommon among hospitalized patients and may be related to several factors, including “tissue damage” from a surgical procedure, infection, and acute blood loss1.  Postoperative thrombocytosis is thought to be related to increased platelet production as well as redistribution of platelets from the splenic platelet pool to the general circulation1.  Increased levels of megakaryocytic growth factors such as thrombopoietin, and pro-or anti-inflammatory cytokines such as interleukin (IL)-1, 3, 6, or 11 may also stimulate megakaryopoeisis in the setting of inflammation2.

Less well known is that enoxaparin (Lovenox), an anticoagulant commonly used for prevention of thromboembolic events in hospitalized patients, may also cause reactive thrombocytosis, usually within the first 2 weeks of therapy and resolving 2 weeks following its discontinuation3

Although malignancy is also associated with secondary thrombocytosis, given its acute nature in our patient, it is less likely to be playing a role.

 

References

  1. . Griesshammer M, Bangerter M, Sauer T, et al. Aetiology and clinical significance of thrombocytosis: analysis of 732 patients with an elevated platelet count. J Intern Med 1999;245:295-300. https://www.ncbi.nlm.nih.gov/pubmed/10205592
  2. Kulnigg-Dabsch S, Schmid W, Howaldt S, et al. Iron deficiency generates secondary thrombocytosis and platelet activation in IBD: the randomized, controlled thromboVIT trial. Inflamm Bowel Dis 2013;published online, DOI10.1097/MIB.0b013e318281f4db. https://www.ncbi.nlm.nih.gov/pubmed/23644823
  3. Hummel MC, Morse BC, Hayes LE. Reactive thrombocytosis associated with enoxaparin. Pharmacotherapy 2006;26:1667-1670. https://www.ncbi.nlm.nih.gov/pubmed/17064215

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Why has my hospitalized patient with head and neck cancer developed thrombocytosis few days following surgery?

Is there a seasonal variation in the incidence of cardiovascular (CV) events or venous thromboembolism (VTE)?

Seasonal variation, primarily characterized by a winter peak, has been reported for acute CV events, such as acute myocardial infarction (AMI) and sudden death, aortic rupture or dissection, and ischemic or hemorrhagic stroke, and VTE (1). A meta-analysis involving patients with VTE, primarily with a diagnosis of pulmonary embolism, revealed a 20% absolute increase in the incidence of VTE during January (1).  

Potential physiological mechanisms for these observations include increased sympathetic activity, decreased loss of fluids and sodium, increase in LDL cholesterol, increase in serum fibrinogen levels and other coagulation markers and C-reactive protein, and lower vitamin D levels due to shorter daylight hours during winter months (1,2).  At least in the case of AMI in the U.S., the higher incidence in winter is not affected by climate (2).  

Respiratory virus infections as a cause of acute inflammation leading to  CV or VTE events is another intriguing explanation (3). Indeed, influenza vaccination has been associated with reduction in hospitalization for cardiac disease and stroke among the elderly (4) and, in patients with cardiovascular disease, a reduction in death due to combined cardiovascular disease events such as heart attacks and strokes (5).

 

 

References

  1. Dentali F, Ageno W, Rancan E, et al. Seasonal and monthly variability in the incidence of venous thromboembolism. A systematic review and a meta-analysis of the literature. Thromb Haemost 2011;106:439-447. https://www.ncbi.nlm.nih.gov/pubmed/21725580
  2. Spencer FA, Goldberg RJ, Becker RC, et al. Seasonal distribution of acute myocardial infarction in the Second National Registry of Myocardial Infarction. J Am Coll Cardiol 1998;31:1226-33.h ttps://www.ncbi.nlm.nih.gov/pubmed/9581712
  3. Woodhouse PR, Khaw KT, Plummer M, et al. Seasonal variations of plasma fibrinogen and factor VII activity in the elderly: winter infections and death from cardiovascular disease. Lancet 1994;343:435-39.  https://www.ncbi.nlm.nih.gov/pubmed/7508540
  4. Nichol KL, Nordin J, Mulloly J, et al. Influenza vaccination and reduction in hospitalization for cardiac disease and stroke among the elderly. N Engl J Med 2003; 348:1322-1332. http://www.nejm.org/doi/full/10.1056/NEJMoa025028
  5. Clar C, Oseni Z, Flowers N, et al. Cochrane Database of Systematic Reviews 2015. DOI: 10.1002/14651858.CD005050.pub3h ttp://www.cochrane.org/CD005050/VASC_flu-vaccines-for-preventing-cardiovascular-disease  

 

 

 

 

Is there a seasonal variation in the incidence of cardiovascular (CV) events or venous thromboembolism (VTE)?