What is the connection between cirrhosis and adrenal insufficiency (AI)?

The prevalence of AI in patients with liver disease varies widely (30-60%). However, there is no consensus on how to define AI in such patients, nor is the methodology for its evaluation standardized. 

A common criticism is the frequent reliance on total, not free, serum cortisol in cirrhosis which may overestimate the prevalence of AI because cortisol is bound to corticosteroid binding globulin and albumin, commonly found at lower concentrations in cirrhosis. However, even when based on measuring free cortisol, AI is found in 12%-29% of clinically stable cirrhotic patients. 1

 Secondary AI due to hypothalamic-pituitary dysfunction has also been reported in Child-Pugh class A, B, and C patients (42%, 69%, and 80%, respectively). 2

The mechanism of AI in cirrhosis is unclear, but low serum cholesterol in cirrhosis leading to lack of substrate for steroidogenesis, and increased levels of circulating endotoxin and pro-inflammatory cytokines impairing the hypothalamic-pituitary-adrenal axis have been postulated. 1

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References

  1. Fede G, Spadaro L, Purrello F. Review: adrenal insufficiency in liver disease. J Liver 2014;3:1. https://www.ncbi.nlm.nih.gov/pubmed/22234976
  2. Zietz, B, Lock, G, Plach, B, et al. Dysfunction of the hypothalamic-pituitary-glandular axes and relation to Child-Pugh classification in male patients with alcoholic and virus-related cirrhosis. Eur J Gastroenterol Hepatology 2003;15:495-501. https://www.ncbi.nlm.nih.gov/pubmed/12702906
What is the connection between cirrhosis and adrenal insufficiency (AI)?

Should my patient with chronic obstructive pulmonary disease (COPD) who emigrated from Latin America over 20 years ago undergo testing for Strongyloides infection (SI)?

Worldwide prevalence of SI may be as high as 100 million people, with an increasing number seen in developed countries among immigrants (including those from Latin America), refugees, and travelers. “Autoinfection” by Strongyloides allows it to complete its life cycle between the GI tract and the lung without leaving the host, and is often associated with chronic asymptomatic infection in the immunocompetent persons1.

Immunocompromised patients, however, particularly those treated with corticosteroids (including systemic courses as short as 6 days, or local injection)  are at increased risk of developing an accelerated form of autoinfection due to SI, also known as  hyperinfection syndrome (HIS)1,2.  HIS has been reported as late as 64 years after leaving an endemic  area!1.   When Strongyloides larvae disseminate away from the lung or GI tract into other organs (e.g. brain) the mortality rate may approach 100%, if untreated.

Due to the potential complications associated with untreated SI, particularly in the immunocompromised , routine screening of anyone with a potential Strongyloides-exposure history (irrespective of symptoms or years since exposure) has been advocated1,3.  In our patient with COPD, screening for asymptomatic SI by a highly sensitive test (eg serology) should be considered (as early as possible if corticosteroids are being considered for treatment of his COPD).  Some have also advocated empiric treatment with ivermectin in “at risk patients” in whom testing is not feasible or practical1,4.

 

References

  1. Mejia R, Nutman TB. Screening, prevention, and treatment for hyperinfection syndrome and disseminated infections caused by Strongyloides stercoralis. Curr Opin Infect Dis 2012;25:458-463.
  2. Keiser PB, Nutman TB. Strongyloides stercoralis in the immunocompromised population. Clin Microbiol Rev 2004;17:208-217.
  3. CDC. Strongyloides. http://www.cdc.gov/parsites/strongyloides/helath_professionals/ , accessed September 20, 2016.
  4. Santiago M, Leitão B. Prevention of strongyloides hyperinfection syndrome: a rheumatologic point of view. Eur J Intern Med 2009;20:744-748.
Should my patient with chronic obstructive pulmonary disease (COPD) who emigrated from Latin America over 20 years ago undergo testing for Strongyloides infection (SI)?

What is the significance of Howell-Jolly bodies in the peripheral smear of my patient with a spleen who presents with pneumonia?

Howell-Jolly bodies (HJBs, Figure) are often indicative of asplenia (either post-splenectomy or congenital absence) or hyposplenism associated with a variety of conditions, including  sickle cell disease, autoimmune disorders, celiac disease, inflammatory bowel disease (particularly ulcerative colitis), HIV, cirrhosis, primary pulmonary hypertension, splenic irradiation, amyloidosis, sarcoidosis, bone marrow transplantation, and high-dose corticosteroid therapy1-4.

Patients with pneumonia and HJBs on peripheral smear may be hyposplenic and at risk of potentially serious infections, predominantly caused by encapsulated bacteria eg, Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis3.  Such patients should be immunized against these organisms, including sequential receipt of both conjugated and polysaccharide pneumococcal vaccines3,5.

HJBs are nuclear remnants in circulating mature red blood cells which are usually pitted by the spleen under normal physiological conditions. 

Final Fun Pearl:  Did you know that  HJBs were named after Henry Howell, an American physiologist who pioneered the use of heparin as an anti-coagulant and Justin Jolly, a French hematologist who was among the first to film mitotic activity in cells?

howelljollymgh

Figure. Howell-Jolly body in an RBC. Photo courtesy of Michael S. Abers, MD

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References

  1. Di Sabatino, A, Carsetti R, Corazza G. Post-splenectomy and hyposplenic states. Lancet 2011;378:86–97. https://www.ncbi.nlm.nih.gov/pubmed/21474172
  2. Brousse, V, Buffet P, Rees D. The spleen and sickle cell disease: the sick(led) spleen. Br J Haematol 2014;166: 165–176. https://www.ncbi.nlm.nih.gov/pubmed/24862308
  3. Mathew H, Dittus C, Malek A, Negroiu A. Howell-Jolly bodies on peripheral smear leading to the diagnosis of congenital hyposplenism in a patient with septic shock. Clin Case Rep 2015;3:714-717. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4551333
  4. Ryan FP, Smart RC, Holdsworth CD, et al. Hyposplenism in inflammatory bowel disease 1978;19:50-55. https://www.ncbi.nlm.nih.gov/pubmed/624506
  5. Kuchar E, Miśkiewicz K , Karlikowska M. A review of guidance on immunization in persons with defective or deficient splenic function. Br J Haematol 2015; 171:683-94.  http://onlinelibrary.wiley.com/doi/10.1111/bjh.13660/full

Contributed by Katarzyna Orlewska, Medical Student, Warszawski Uniwersytet Medyczny, Poland

What is the significance of Howell-Jolly bodies in the peripheral smear of my patient with a spleen who presents with pneumonia?

Should corticosteroids (CS) be routinely considered in the treatment of hospitalized patients with community-acquired pneumonia (CAP)?

A recent systematic review on the subject concluded that for hospitalized adults with CAP, systemic CS may reduce mortality by about ~3% (primarily in severe CAP), mechanical ventilation need by ~5%, and hospital stay by ~1 day (1). But determining who might benefit the most and at what CS dosage regimen without undue risk of side effects (e.g. hyperglycemia) may be tricky.  

A randomized control trial of patients with CAP on prednisone 50 mg daily x 7d (vs placebo) showed a significant shorter time to clinical stability (3 vs 4.4 d) and higher in-hospital hyperglycemia in the CS group (2).; this study was not powered to detect significant difference in mortality, however.  Less treatment failure with adjunctive CS but without impact on mortality was recently reported in a small study involving patients with serum CRP >150 mg/L (i.e. high inflammatory state) (3).

Fortunately, a multicenter trial (ESCAPe, Extended Steroid in CAP) is currently underway. In the meantime, before considering CS, we need to be confident of the diagnosis and severity of CAP, its potential adverse effects in individual patients, and the appropriateness of the antibiotic (s) on board.

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References

1. Siemieniuk RAC, Meade MO, Alonso-Coello P, et al. Corticosteroid therapy for patients hospitalized with community-acquired pneumonia: a systematic review and meta-analysis. Ann Intern Med 2015;165:519-528. https://www.ncbi.nlm.nih.gov/pubmed/26258555

2. Blum CA, Nigro N, Briel M. Adjunct prednisone therapy for patients with community-acquired pneumonia: a multi-centre, double-blind randomized, placebo-controlled trial. Lancet 2015;385:1511-1518. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)62447-8/abstract

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. https://www.ncbi.nlm.nih.gov/pubmed/25688779

 

Should corticosteroids (CS) be routinely considered in the treatment of hospitalized patients with community-acquired pneumonia (CAP)?

Does corticosteroid therapy impact the results of interferon-gamma (IG) release assays—IGRAs— in patients screened for latent tuberculosis?

There is relative dearth of data addressing this very important issue. A decreased IG response after mitogen stimulation during treatment with oral prednisolone has been reported (1).

In a study of patients with autoimmune disorders, 27% of patients on daily prednisolone dose of 10 mg or more had indeterminate QuantiFeron Gold In-Tube test compared to 1% of patients not taking prednisolone (1).

A meta-analysis of the performance of IGRAs (including T-SPOT.TB) concluded that these assays were negatively affected by immunosuppressive therapy (2). So, until more data becomes available, caution is advised in interpreting lack of positive test or indeterminate results of IGRAs in patients on corticosteroid therapy.

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References

1. Belard E, Semb S, Ruhwald M, et al. Prednisolone treatment affects the performance of the QuantiFERON Gold In-Tube test and the Tuberculin skin test in patients with autoimmune disorders screened for latent tuberculosis infection. Inflamm Bowel Dis 2011;17:2340-2349. https://academic.oup.com/ibdjournal/article/17/11/2340/4631016

2. Shahidi N, Fu Y-T, Qian H, et al. Performance of interferon-gamma release assays in patients with inflammatory bowel disease: a systematic review and meta-analysis. Inflamm Bowel Dis 2012;18:2034-2042. https://www.researchgate.net/publication/265093409_Performance_of_Interferon-gamma_Release_Assay_for_Tuberculosis_Screening_in_Inflammatory_Bowel_Disease_Patients

Does corticosteroid therapy impact the results of interferon-gamma (IG) release assays—IGRAs— in patients screened for latent tuberculosis?