Clinical Questions

Which Thyroid Antibody Assays Should be Checked in Patients with Thyroid Disease?

April 14, 2010

thyroidMichael Chu MD

Faculty peer reviewed

Case:

A 44-year old female presented to the emergency room with complaints of a lower extremity rash and swelling.  The patient had been in her usual state of health when she presented to her primary care physician with complaints of palpitations, weight loss and insomnia.  Lab tests were performed and she was given a diagnosis of hyperthyroidism.  She was started on propranolol and methimazole, which the patient took intermittently due to intolerance of side effects, which she perceived as the rash and swelling. 

INTRO

Graves’ disease is characterized by the presence of hyperthyroidism, goiter, and sometimes ophthalmopathy and dermopathy.  It is a condition believed to belong to a spectrum of diseases termed autoimmune thyroid diseases, of which Hashimoto’s thyroiditis, postpartum thyroiditis, silent thyroiditis, and atrophic autoimmune thyroiditis belong.  The primary event in autoimmune thyroid diseases is likely T-cell mediated and many of the tissue consequences in both Graves’ and Hashimoto’s disease are caused by specific sub-sets of lymphocytes, lymphokines, as well as antibodies.  The T-cell factors induce the B-cells to produce antibodies: Thyroid Stimulating Immunoglobulins in Graves’ and anti-Thyroglobulin,  anti-thyroid peroxidase, and anti-thyroid symporter in all autoimmune thyroid disorders, as well as TSH-blocking antibodies.  The TSH-blocking antibodies interfere with the ability of native TSH and TSI to up-regulate the TSH receptor.  The net thyroid functional effect is the sum of the trophic and inhibitory factors, anti-enzyme effects, and destructive T-Cell phenomenoa .    For example, in Graves’ disease activation of the thyroid stimulating hormone receptor causes increased production of thyroid hormone leading to hyperthyroidism1, and in Hashimoto’s thyroiditis, anti- anti-thyroid peroxidase antibodies block organification of iodine and may lead to reduced T-4/T-3 levels.  The major thyroid related antigens that are known to have antibodies made against them are the TSH receptor, thyroglobulin, thyroid peroxidase, and the sodium/iodine symporter.2 

In pregnant women, an important issue relates to the immunoglobulins crossing the placenta, which could cause transient neonatal (or fetal) hyper- or hypothyroidism.

Here we will discuss the clinical use of thyroid antibody assays in patients with thyroid diseases.

THYROID STIMULATING HORMONE RECEPTOR ANTIBODY

Antibodies to the Thyroid Stimulating Hormone (TSH) receptor have been found in both Graves’ and Hashimoto’s disease patients, however the stimulating variety of antibodies is specific to Graves’ disease.  TSH receptor antibody assays have been reported to have a specificity of 99.6% with a sensitivity of 98.8% for Graves’ disease.3   TSH receptor antibodies have been used in various roles such as for diagnosis, as a marker of severity and as an aid for choice of treatment for Graves’ disease, however they are not commonly tested for in North America, mostly due to regional differences in practice and cost-effectiveness.4 

THYROID STIMULATING ANTIBODY

Thyroid Stimulating antibody assays measure the ability of IgG to bind to TSH receptor on cells and stimulate adenylate cyclase production.  They are also referred to as thyroid-stimulating immunoglobulin (TSI) assays.  Thyroid stimulating immunoglobulins (TSI) have been detected in 77.8% to 92% of Graves’ patients.5-6   In clinical practice, TSI is not necessary to diagnose Graves’ disease, however it may be used to predict relapse or remission after treatment of Graves’ disease with radioiodine7 or methimazole8, as persistent elevation of TSI correlates with disease activity and remission is normally accompanied by a decrease in activity.

 NOMENCLATURE

Of note, the nomenclature for TSH receptor-antibody assays are known to be inconsistent and confusing.9  Assays that measure binding of TSH to solubilized receptor are referred to as TRAb (thyroid receptor antibody), TBII (TSH-binding inhibitor immunoglobulin), or LATS (long-acting thyroid stimulator).  Assays that measure the ability of IgG to bind to TSH receptor on cells and stimulate adenylate cyclase production are referred to as TSI (thyroid-stimulating immunoglobulin) assays.  LATS was the first anti-TSH assay, is a heterophile antibody, reacting with mouse, not human thyroid, and is of historical interest only.

ANTI- THYROGLOBULIN and ANTI-THYROID PEROXIDASE ANTIBODIES

Thyroglobulin (Tg) is a large glycoprotein that is synthesized by follicular cells in the thyroid gland and secreted into the lumen of the thyroid follicle.  Thyroid peroxidase (TPO) is a key enzyme in the production of thyroid hormone.  TPO catalyzes the iodination of tyrosine residues in thyroglobulin to form monoiodotyrosine that goes on to form diiodotyrosine and ultimately thyroxine.  Antibodies to Tg (anti-Tg) and TPO (anti-TPO) are present in both Hashimoto’s and Graves’ disease patients.

The American Thyroid Association (ATA) guideline statement on treatment of patients with hypothyroidism recommends testing for either anti-TPO or anti-Tg antibodies when autoimmune thyroiditis is suspected as the underlying cause of hypothyroidism and that the anti-TPO antibody test is the more sensitive and specific of the two tests.10 

In patients with subclinical hypothyroidism, painless thyroiditis or postpartum thyroiditis, the presence of anti-TPO antibodies may help predict progression to permanent hypothyroidism.  In patients with subclinical hypothyroidism and positive anti-thyroid antibodies, the ATA states that treatment of hypothyroidism is probably advisable because of the high likelihood of progression to overt hypothyroidism.10  If treatment is deferred, at least yearly evaluation for clinical or biochemical evidence of hypothyroidism is recommended.

In Hashimoto’s patients, anti-TPO and anti-Tg abs have respective prevalence rates of 90-100% and 80-90%.   In Graves’ patients, anti-TPO and anti-Tg abs have respective prevalence rates of 50-70% and 50-80%.11 These antibodies are not specific to these particular diseases. 

CONCLUSIONS

In summary, patients with primary hypothyroidism, anti-TPO and anti-Tg antibodies may be obtained to support the diagnosis of autoimmune thyroiditis, with the former test shown to help predict progression of sub-clinical hypothyroidism to overt hypothyroidism.  In patients with primary hyperthyroidism, a TSI assay may be obtained to support the diagnosis of Graves’ disease and may be followed as a measure of disease activity.  Anti-TPO and anti-Tg antibodies may be present in Graves’ disease patients as an epiphenomenon, but are not causative, in contrast to TSI, which is responsible for the excessive production of T-4/T-3.  In addition,  the TSI, anti-TPO, and TSH blocking antibodies are helpful in predicting the development of transient neonatal Graves’ disease or hypothyroidism in pregnant women with Graves’ disease or Hashimoto’s thyroiditis. 

RESOLUTION OF CASE

The patient was thought to have a drug rash induced by methimazole, which was stopped.  The thyroid stimulating hormone level was 0.004 mIU/mL (normal: 0.35-4.8 mIU/mL), the free T4 level was 3.42 ng/dL (normal: 0.9-1.9 ng/dL).  Thyroglobulin antibodies and Thyroid Peroxidase antibodies were elevated.  A 24-hour radioiodine uptake measurement was elevated and a scan of the thyroid revealed diffuse elevated activity in the thyroid consistent with a diagnosis of Graves’ disease.  The patient subsequently underwent radioiodine treatment of the thyroid gland.

Dr. Chu is a 3rd year resident in internal medicine at NYU Medical Center.

A PRACTICAL OVERVIEW OF THE IMMUNE THYROID DIATHESIS

Commentary by Manfred Blum MD, Professor, NYU Division of Endocrinology

Dr. Michael Chu has presented a classic instance of an allergic reaction to methimazole in a woman with thyrotoxic Graves’ disease and excellently reviewed the pathophysiology of the various thyroid antibodies.  Let me briefly review the etiology, diagnosis and management of patients with the immune thyroid diathesis.

Immune thyroid disease (ITD) is responsible for the vast majority of hypo- and hyperthyroidism in the North America and for a much of euthyroid, thyroid enlargement.  Worldwide, only iodine-deficiency accounts for more thyroid pathology.

ITD is not one disorder.  Rather, there is a spectrum of clinical disorders that occur in a familial setting, most often among women, and frequently associated with other immune-mediated non-thyroid diseases.  The disorders are not fixed and may wax and wane in intensity or evolve from one clinical expression to another, for instance from hyperthyroidism to hypothyroidism.  ITD may be expressed solely in the thyroid, like goiter, have systemic secondary consequences, like myxedema, or primarily affect several organ systems, like Graves’ disease.  The manifestations of ITD are influenced by co-morbidities, past events, environmental factors, and notably local T-lymphocyte phenomena and several immunoglobulins that have unique specificities and impact on thyroid function.  TSI binds to and stimulates the TSH receptor to enhance thyroid hormone levels, anti-TPO antibody interferes with the function of the thyroid peroxidase enzyme to reduce thyroxine production, TSH-blocking antibody impedes TSH and TSI activity at the TSH receptor, also reducing hormone levels, but anti-thyroglobulin antibodies have no known hormonal consequences.  All of the antibodies cross the placenta and affect the fetal and neonatal thyroid for the duration of maternal 7S immunoglobulins in the neonatal circulation.  There are no easily available assessments of the T-lymphocyte factors and their pathophysiology is a subject of ongoing investigation.

The presence of anti-thyroid antibodies in the serum is a label signifying that autoimmune disease is operative and that other illness of this type may be present in the patient or family. The assays offer essential specific diagnostic information about etiology but no insight into thyroid function. The latter requires measurement of TSH.

The following table offers guidelines to common clinical use of anti-thyroid serologic tests.

 

GUIDELINES TO THE USE OF ANTI-THYROID SEROLOGIC TESTS

 

Clinical Condition

Why Do Tests

ATPO

ATg

TSI

CONSIDER Next StepS

Goiter Assess for AITD

X

X

 

If ITD (+), consider presence of other AIDs

Check TSH

Dominant Nodule in Goiter
  • Assess for Hashimoto’s
  • Knowledge helps cytological interpretation of a nodule

X

X

 

If (+) consider other AIDs

If (+) check TSH

  • If TSH is low do RAI Scan
  • If TSH is normal do FNB and Alert Ultrasonographer & Cytologist to diagnosis
Thyrotoxicosis

 

 

Assess for ITD etiology

If positive

 

 

 

If negative

X

X

X

If (+) consider other AIDs

If (+) Graves’

  • Check RAIU To R/O silent thyroiditis
  • Treat as appropriate

 

If (-) R/O TNG or TAN & Rx

Euthyroid Exophthalmos Assess for ITD

If positive

 

 

If negative

X

X

X

 

If (+) Graves’ eye disease & Monitor for hyperthyroidism

If (+) consider other AIDs

If (-) R/O local lesion

Hypothyroidism with high TSH Assess for ITD etiology

X

X

 

If (+) Hashimoto’s & Rx with T-4

If (+) consider other AIs

If (-) R/O other etiology

Hypothyroidism with low TSH  

 

 

 

Evaluate Pituitary
Family history of AI disorders Assess for sub-clinical ITD

X

X

 

If (+) check TSH & thyroid size

If (-) Observe thyroid

Routine Screening No

 

 

 

 

ITD = immune thyroid diseases, AIDs = autoimmune diseases, ATPO = Antithyroid peroxidase antibodies, ATg = Antithyroglobulin antibodies,  TSI = Thyroid stimulating immunoglobulin,  FNB fine needle biopsy of thyroid nodule, Rx = treat

 References

1Adams DD, Fastier FN, Howie JB et al. Stimulation of the human thyroid by infusions of plasma containing LATS protector. J Clin Endocrinol Metab 1974; 39:826.

 2Hadj-Kacem H, Rebuffat S, Mnif-Feki M, Belguith-Maalej S, Ayadi H, Peraldi-Roux S.  Autoimmune thyroid diseases: genetic susceptibility of thyroid-specific genes and thyroid autoantigens contributions.  International Journal of Immunogenetics. 36(2):85-96, 2009 Apr.

 3Costagliola S, Morgenthaler NG, Hoermann R, Badenhoop K, Struck J, Freitag D, Poertl S, Weglohner W, Hollidt JM, Quadbeck B, Dumont JE, Schumm-Draeger PM, Bergmann A, Mann K, Vassart G, Usadel KH.  Second generation assay for thyrotropin receptor antibodies has superior diagnostic sensitivity for Graves’ disease.  J Clin Endocrinol Metab 1999 Jan;84(1):90-7.

 4Orgiazzi J.  Anti-TSH receptor antibodies in clinical practice.  Endocrinol Metab Clin North Am. 2000 Jun;29(2):339-55, vii.

 5Macchia E, Concetti R, Borgoni F, Cetani F, Fenzi GF, Pinchera A.  Assays of TSH-receptor antibodies in 576 patients with various thyroid disorders: their incidence, significance and clinical usefulness.  Autoimmunity. 1989;3(2):103-12.

 6Takasu N, Oshiro C, Akamine H, Komiya I, Nagata A, Sato Y, Yoshimura H, Ito K.  Thyroid-stimulating antibody and TSH-binding inhibitor immunoglobulin in 277 Graves’ patients and in 686 normal subjects.  Journal of Endocrinological Investigation. 20(8):452-61, 1997 Sep.

 7Wortsman J, McConnachie P, Tahara K, Kohn LD. Thyrotropin receptor epitopes recognized by Graves’ autoantibodies developing under immunosuppressive therapy. J Clin Endocrinol Metab. 1998; 83(7):2302-2308.

 8Chiovato L, Fiore E, Vitti P, et al. Outcome of thyroid function in Graves’ patients treated with radioiodine: Role of thyroid-stimulating and thyrotropin-blocking antibodies and of radioiodine-induced thyroid damage. J Clin Endocrinol Metab. 1998; 83:40-46.

 9Lab facets: Thyroid Stimulating Immunoglobulins (TSI).  https://www.labcorp.com/pdf/TSI_Thyroid_Stimulating_Immunoglobulin_LabFacets_1442.pdf.  Accessed 7/13/09.

 10Treatment Guidelines for Patients With Hyperthyroidism and Hypothyroidism.  American Thyroid Association.  1995.  http://www.thyroid.org/professionals/index.html.

 11Davies T.  Pathogenesis of Hashimoto’s Thyroiditis (chronic autoimmune thyroiditis).  Uptodate.com.  Accessed 7/15/09.

When Minutes Matter: Why Do Patients Wait to Seek Treatment Following a Stroke or Heart Attack?

March 3, 2010

stopwatchLaurel Geraghty

Faculty peer reviewed

Both stroke and heart attack require rapid treatment following the onset of symptoms to minimize morbidity and mortality, but few patients seek help in a timely manner.[1] Only about half of patients with acute myocardial infarction (AMI) or stroke arrive to the emergency department within four hours of the onset of symptoms.[1],[2],[3],[4] Every 30-minute delay in treatment following AMI increases one-year mortality by 7.5%, and almost half of the 167,000 annual stroke deaths in this country occur before the patient reaches the hospital.[2],[5] Fibrinolytic therapy (tissue plasminogen activator, or tPA) improves the survival and prognosis of stroke patients if administered within 4.5 hours (ideally, within 90 minutes) of symptom onset, but only 3 to 8.5% of stroke patients receive tPA, partly due to delayed hospital arrival.[2],[5],[6],[7] The response time of medical professionals both inside and outside of the hospital is significantly less important in determining the time to treatment than patient delays in calling for help.[4],[8] So the important question remains: Why do people wait to seek medical attention when experiencing symptoms of a heart attack or stroke?

Indecision and reluctance to seek treatment are key components to the problem.[9] Many patients do not want to believe that they are having a heart attack or stroke, are not convinced that their symptoms are serious, or misattribute their symptoms to a relatively benign condition, such as acid reflux or indigestion.[4],[10] People commonly feel embarrassed about contacting a physician or emergency medical services, particularly if their symptoms occur at night or during the weekend.[4] In one study, nearly two-thirds of patients worried about troubling other people when experiencing symptoms of a stroke.[6],[11] Individuals also wait to contact emergency medical services if they perceive that they are too young to suffer from a heart attack or stroke, if they are responsible for taking care of children or others, or if they do not want to worry family members.[10] Rather than calling for help, many patients attempt to self-treat their illness by lying down or taking an aspirin, wishing or praying for symptoms to disappear, trying to relax, or discussing the symptoms with others, such as a friend, family member, or a primary care physician.[4],[12] These approaches cause significant delays or do not improve hospital arrival times.[4],[12] Ultimately, patients call 911 or present to the emergency room when they begin to feel incapable of comprehending or handling the situation due to a persistent sense of illness, discomfort, or pain.[13]

Only a few factors have been found to reduce the time it takes for patients to call for help. Those who correctly attribute their symptoms to heart attack or stroke, acknowledge that their symptoms are serious, or have feelings of anxiety about their symptoms are most likely to seek medical treatment quickly.[4],[6] Evidence suggests that those who view themselves as worthy of receiving care, or who consider others trustworthy to provide good medical care, are less likely to delay.[14] Among stroke patients, factors associated with reduced time to hospital arrival include severe neurologic impairment, facial droop, language impairment, and the presence of more than one symptom.[6]

Surprisingly, increased awareness of the symptoms and risk factors for heart attack and stroke does not prompt people to seek medical care rapidly.[4],[6],[9] Individuals with a history of AMI actually wait longer to get help than those experiencing their first cardiac event.[4] In addition, a recent study found that patients with AMI do not delay if they have fewer symptoms, but if they have a history of more symptoms, such as increased frequency of angina.[14] Women, blacks, Latinos, older individuals, patients of low socioeconomic status, those with limited education, and people who are untrusting of others are also more likely to stall before enlisting medical help for AMI or stroke, and may therefore face a worse prognosis.[4],[14]

Although over a hundred studies have examined factors contributing to treatment delays after a heart attack or stroke, educational programs geared to the public have so far failed to reduce hospital arrival times.[4],[9],[15] Most efforts have focused on teaching people to recognize the symptoms of acute coronary events and stroke.9 However, recent evidence indicates that patients don’t hesitate to seek medical attention because they are insufficiently fearful or knowledgeable about symptoms, but because they are too fearful of these conditions, suggesting that alternate strategies may be warranted.[9],[14] Some researchers recommend assisted-navigator programs, which educate high-risk individuals about how to seek medical help when experiencing symptoms of AMI or stroke.[14] The use of emergency medical services should be encouraged, since arrival to the emergency department by ambulance is associated with significantly shorter hospital arrival times and decreased treatment times once inside the hospital.[1],[16] The most effective strategy for speeding patient presentation may be multipronged: targeting high-risk patients, tailoring educational programs to different demographics, individuals, and personality types, and addressing common behaviors that contribute to the all-too-common wait-and-see approach.[4]

Laurel Geraghty is a 3rd year medical student at NYU School of Medicine.

 Commentary by Dr. Douglas Bails

The author makes compelling points regarding the poor rates of expedited presentation to the hospital after acute myocardial infarction and stroke. It is not ambulance response times or hospital inefficiency but patient-related factors that contribute the most to the significant delays we are seeing. Most surprisingly, it appears that the poor rates may not be due to poor education or awareness but to excessive fear regarding stroke and MI. Given these patient-related factors, the author’s suggestions for improvement seem to be on the mark: education and behavior modification of high-risk patients.

References

——————————————————————————–

[1]. Frankel M, Hinchey J, Schwamm LH, et al. Prehospital and hospital delays after stroke onset-United States, 2005-2006. MMWR. 2007;56(19);474-478.

[2] Reeves MJ, Arora S, Broderick JP, et al. Acute stroke care in the US; results from 4 pilot prototypes of the Paul Coverdell National Acute Stroke Registry. Stroke. 2005;36(6):1232-1240.

[3] Evenson KR, Foraker RE, Morris DL, Rosamond WD. A comprehensive review of prehospital and in-hospital delay times in acute stroke care. Int J Stroke. 2009;4(3):187-199.

[4] Moser DK, Kimble LP, Alberts MJ, et al. Reducing delay in seeking treatment by patients with acute coronary syndrome and stroke: a scientific statement from the American Heart Association Council on Cardiovascular Nursing and Stroke Council . Circulation. 2006;114(2):168-182.

[5] De Luca G, Suryapranata H, Ottervanger JP, Antman EM. Time delay to treatment and mortality in primary angioplasty for acute myocardial infarction: every minute of delay counts. Circulation. 2004;109(10):1223-1225.

[6] Bouckaert M, Lemmens R, Thijs V. Reducing prehospital delay in acute stroke. Nat Rev Neurol. 2009;5(9):477-483.

 [7] Lansberg MG, Bluhmki E, Thijs VN. Efficacy and safety of tissue plasminogen activator 3 to 4.5 hours after acute ischemic stroke: a metaanalysis. Stroke. 2009;40(7): 2438-2441.

 [8] Dracup K, Moser DK, Eisenberg M, Meischke H, Alonzo AA, Braslow A. Causes of delay in seeking treatment for heart attack symptoms. Soc Sci Med. 1995;40(3):379-392.

 [9] Dracup K. The challenge of reducing prehospital delay in patients with acute coronary syndrome. Circ Cardiovasc Qual Outcomes. 2009;2:144-145.

[10] Heart attack-symptoms. Cleveland Clinic. http://my.clevelandclinic.org/heart/disorders/cad/mi_symptoms.aspx. Copyright 2009 Cleveland Clinic. Accessed October 23, 2009.

[11] Shah M, Makinde KA, Thomas P. Cognitive and behavioral aspects affecting early referral of acute stroke patients to hospital. J Stroke Cerebrovasc Dis. 2007;16(2):71-76.

[12] Zegrean M, Fox-Wasylyshyn SM, El-Masri MM. Alternative coping strategies and decision delay in seeking care for acute myocardial infarction. J Cardiovasc Nurs. 2009;24(2):151-155.

 [13] Nymark C, Mattiasson AC, Henriksson P, Kiessling A. The turning point: from self-regulative illness behavior to care-seeking in patients with an acute myocardial infarction [published online ahead of print Sept. 4, 2009]. J Clin Nurs. 2009;18(23):3358-3365.

[14] Sullivan MD, Ciechanowski PS, Russo JE, et al. Understanding why patients delay seeking care for acute coronary syndromes. Circ Cardiovasc Qual Outcomes. 2009;2:148-154.

[15] Kainth A, Hewitt A, Sowden A, et al. Systematic review of interventions to reduce delay in patients with suspected heart attack. Emerg Med J. 2004;21(4):506-508.

[16] Morris DL, Rosamond W, Madden K, Schultz C, Hamilton S. Prehospital and emergency department delays after acute stroke: the Genentech Stroke Presentation Survey. Stroke. 2000:31(11):2585-2590.

Zinc Cold Remedies: Are They Safe and Effective–Who Nose?

February 11, 2010

Bellevue 1Amanda Benkoff

Faculty peer reviewed

Each year doctors are presented with the dilemma of the common cold. Adults in the U.S. experience an average of 3 colds per year, and children up to 8-10, resulting in over 500 million colds annually.(1) Patients often visit the doctor with cold symptoms requesting antibiotics. Since the etiology of the common cold is viral, antibiotic therapy is ineffective and inappropriate, and only contributes to bacterial antibiotic resistance. More than 200 viruses can cause the common cold, including rhinoviruses, coronaviruses, adenoviruses, respiratory syncytial virus, and parainfluenza viruses.(2) Rhinovirus is the most common culprit.3 Although considered a self-limited benign illness, the common cold is not without complications, including otitis media, sinusitis, and exacerbations of reactive airway diseases.(3) Additionally, the economic impact is far-reaching due to related work absences. Thus, it is clear why patients implore doctors for treatment of this ailment. In more recent years the use of zinc cold remedies has become popular. The question is, are they safe and effective?

The idea of using zinc to control viral disease is not novel. In 1937 zinc sulfate was sprayed intranasally during the poliovirus epidemic in Canada. It was theorized that zinc ions formed a protective coating around olfactory nerves, thereby preventing virus absorption. Unfortunately, this intervention did not alter the attack rate.(4) In more recent years the use of zinc acetate/gluconate lozenges and zinc gluconate nasal spray has become widespread. The basis for therapeutic zinc use is founded on scientific observation over the years. Empirical virology has shown that zinc interferes with rhinoviral coat proteins, thereby preventing viral particle assembly and replication. Mechanistically, it was suggested that zinc ions formed complexes with viral coat proteins.5 Scientific observation has also demonstrated that zinc can alter immune system regulation. By studying the effects of zinc on plasma cytokines, it was determined that patients treated with zinc had reduced levels of intracellular adhesion molecule-1 (ICAM-1). Researchers proposed that zinc ions formed complexes with ICAM-1. This effect is significant because human rhinovirus 14 docks onto somatic cells using ICAM-1; thus, less ICAM-1 results in fewer infected cells.(3) Driessen et al. provided further empirical evidence regarding the immune-regulatory effects of zinc. They demonstrated that in patients with excess zinc, after immune challenge with bacterial endotoxin, there was upregulation of interferon gamma (increased T cell activation) and increased secretion of tumor necrosis factor-alpha and interleukin 1-beta (increased monocyte activation).(6) While much has been revealed regarding the therapeutic actions of zinc, more research is necessary to establish a concrete mechanism for zinc against the common cold.

Regarding the clinical efficacy of zinc, a number of studies have been performed, and the results are inconclusive. One structured review looked at 14 randomized controlled trials (RCTs) evaluating zinc lozenges and nasal sprays/gels. The review created 11 criteria to assess validity of experimental design, and found that only four studies were valid. Of the four studies, three found no therapeutic effect from zinc lozenges or nasal spray, and only one study reported benefit from zinc nasal gel, showing decreased symptom severity and duration with early treatment.(1) In contrast, a second review article looking at 7 double-blind RCTs using zinc gluconate lozenges showed an overall benefit, with decreased cold duration (1-3 days) and symptom severity. This study suggested that 13.3 mg of zinc (the lowest therapeutic dose) should be administered every two hours, with greater efficacy if treated within 24-48 hours of symptom onset. The review also showed astringent taste and nausea as common adverse reactions. Ultimately, it is difficult to judge the overall scientific efficacy of zinc against the common cold due to inconsistent study results. There are many reasons behind this variability, including poor study design (small sample size, artificially-induced vs. natural infection), poor follow-up, sub-therapeutic dosing, and use of additives (mannitol, citric acid, or sorbitol), which have been purported to decrease efficacy by binding to zinc ions.(7)

As for the question of safety, we can again look to 1937 and the use of prophylactic zinc sulfate. Of the 5000 children treated, approximately 10-13% were found to be anosmic months later.(4) This result was further corroborated by an animal study in 1978. Harding et al. showed that mice treated with intranasal zinc sulfate experienced immediate and total anosmia. Up to 80% of the mice were anosmic for 6 weeks, and some still showed changes at 1 year.(4) This result has since been reproduced by McBride et al. in 2003. This study showed that intranasal zinc sulfate produces total disruption of connections from the olfactory epithelium to the olfactory bulb. However, this anosmia was brief, and most mice recovered in 5-30 days.(8)

Of more significance is the safety profile for intranasal zinc gluconate, the key ingredient in nasal sprays/gels, such as Zicam. One study coined the term “zinc-induced anosmia syndrome,” characterized by burning and anosmia. It described a series of patients, all of whom reported sniffing deeply with gel application, followed by anosmia within hours. They reported some degree of recovery over time.(9) Another case series showed that olfaction impairment persisted for up to 2 years, and proposed that the anosmia was potentially permanent. It was hypothesized that zinc cations acted to block the nonspecific cation channel necessary for olfactory receptor cell depolarization, and subsequent transduction of odors to the olfactory bulb. Recent animal studies show that odor detection in mice is affected only at doses ~100 times greater than a single application of Zicam, and even at massive doses the anosmia resolved over time.(10) Despite this, Zicam nasal sprays/gels have been associated with anosmia or hyposmia in over 300 consumers. In June 2009, the FDA discontinued Zicam nasal products, and alerted the public to the possibility of permanent anosmia. This is of particular concern in children, who may not report decreased olfaction and are at increased risk for repeated exposure.(11) The advisory did not concern oral zinc tablets and lozenges.

In conclusion, the evidence for the efficacy of zinc cold remedies remains questionable, and the treatment is not without risk. More valid scientific studies with enhanced methodology are necessary to find conclusive results. The search for effective cold therapies must continue.

Amanda Benkoff is a 4th year student at NYU Medical School.

Peer reviewed by Dr. Robert Holzman, Professor of Medicine, NYU Medical Center

References

1. Caruso TJ, Prober CG, Gwaltney, JM Jr. Treatment of naturally acquired common colds with zinc: a structured review. Clin Infect Dis. 2007;45(5):569-574.
2. Mossad SB, Macknin ML, Medendorp SV, Mason P. Zinc gluconate lozenges for treating the common cold. A randomized, double-blind, placebo-controlled study. Ann Intern Med. 1996;125(2):81-88.
3. Prasad AS, Beck FW, Bao B, Snell D, Fitzgerald JT. Duration and severity of symptoms and levels of plasma interleukin-1 receptor antagonist, soluble tumor necrosis factor receptor, and adhesion molecules in patients with common cold treated with zinc acetate. J Infect Dis. 2008;197(6):795-802.
4. Jafek BW, Linschoten MR, Murrow BW. Anosmia after intranasal zinc gluconate use. Am J Rhinol. 2004;18(3):137-141.
5. Hirt M, Nobel S, Barron E. Zinc nasal gel for the treatment of common cold symptoms: a double-blind, placebo-controlled trial. Ear Nose Throat J. 2000;79(10):778-780, 782.
6. Driessen C, Hirv K, Kirchner H, Rink L. Zinc regulates cytokine induction by superantigens and lipopolysaccharide. Immunology. 1995;84:272-277.
7. Marshall, S. Zinc gluconate and the common cold, review of randomized controlled trials. Can Fam Physician. 1998;44:1037-1042.
8. McBride K, Slotnick B, Margolis FL. Does intranasal application of zinc sulfate produce anosmia in the mouse? An olfactometric and anatomical study. Chem Senses. 2003;28(8):659-670.
9. Alexander TH, Davidson TM. Intranasal zinc and anosmia: the zinc-induced anosmia syndrome. Laryngoscope. 2006;116(2):217-220.
10. Slotnick B, Sanguino A, Husband S, Marquino G, Silberberg A. Olfaction and olfactory epithelium in mice treated with zinc gluconate. Laryngoscope. 2007;117(4):743-749.
11. U.S. Department of Health and Human Services. FDA: Loss of sense of smell with intranasal cold remedies containing zinc. http://www.fda.gov/Drugs/DrugSafety/PublicHealthAdvisories/ucm166059.htm. Accessed September 21, 2009.

Oldies but Goodies: How should you approach a low titer +RPR?

February 5, 2010

Please enjoy a post from the Clinical Correlations Archives, first posted November 28, 2006…

45 year old male with a history of Hepatitis B ( Hep B Surf Ag + but Hep B E Ab+ and E Ag – and DNA viral load was not sent) and syphilis treated in the past. He has RPRs in the past that were 1:1 for years and then negative x 2 a year apart, the last being over two years ago. He had labs drawn last week and had an RPR of 1:4. He does report high-risk unsafe sexual activity (with female prostitutes) over the past two years. He does not recall seeing a chancre and his exam was negative. He has not tested for HIV.

Questions:

1. Would you retreat?

2. Would you retreat if the RPR was 1:2? (should we consider reinfection?)

Commentary By Neal Steigbigel M.D., Professor of Medicine (Infectious Diseases/Immunology)

The RPR antibody (a non-treponemal or reaginic antibody) titer of 1:4 may be associated with:

1) reinfection syphilis (immunity brought about by previous syphilis infection is incomplete)

2) may represent a biological false positve when the titer is less than 1:8 in that this is a reagin antibody which is not specific for syphilis and and can be elevated non-specifically by conditions (particularly liver diseases, especially cirrhosis or HIV infection) that produce non-specific polyclonal increases in various antibodies.

3) persistent mild elevation from his former episode of syphilis, although the fact that it became negative prior to this last determination is somewahat against that possibility.

The patient should have a specific treponemal test performed (such as the MHA-TP test) which is specific for Treponemal infection and usually persists as positive for life. If the latter is positive in this patient that means that he has had syphilis in the past, but 1,2, and 3 above are still the possibilities which cannot be entirely resolved. That is, the patient may have late latent syphilis and if the MHA is positive and there is not documentation that he has been treated for late latent syphilis since his last sexual exposures, I would treat with benzathine penicillin G 2.4 million units im weekly for 3 weeks in the absence of a penicillin allergy. The RPR titer usually becomes negative two years after treatment. If it does not, then again the posibilities are persistent infection, reinfection or false-positive test (most likely the latter).

What would you do if the titer bounced up to 1:2 from 0?

If it fluctuates at low titer (<1:8) after the treatment that is suggested and without signs of disease I would not retreat.

What would you do in a person whose titer never falls below 1:4 and then jumps to 1:16?

That would be unlikely, but would suggest true infection requiring retreatment if the MHA was positive.

Dix-Hallpike Positive, No Red Flags, Now What?

January 23, 2010

dixhallpikeThe Proper Diagnosis and Treatment of Benign Paroxysmal Positional Vertigo

Carly Oboudiyat

Faculty peer reviewed

You finally have the “dizzy” patient whose eyes actually beat torsionally upwards when you do that silly maneuver you have done countless times to no avail. Hallelujah, you think, a positive Dix-Hallpike sign, reassuring you that you have a case of benign paroxysmal positional vertigo (BPPV). But now what? Do you try that other acrobatic maneuver to reposition the canaliths in the posterior canal, or should you give meclizine?

Benign paroxysmal positional vertigo has a lifetime prevalence of 2.4%.[1] It is thought to result from the anomalous position of calcium carbonate otoliths in the inner ear stimulating the ampulla erroneously. The otoliths break off from the macula, and due to its gravitationally privileged position, most commonly end up in the posterior canal becoming canaliths.[2] The movement of the canaliths within the semicircular canal causes stimulation of the ampulla, resulting in central input unidentifiable from actual movement of the head, resulting in vertigo.

BPPV is a diagnosis that can be made by history alone, but is supported by positive exam findings. The patient should describe vertigo provoked by head movements, commonly while lying in bed or standing up from a bent-over position, that lasts 10-30 seconds in the absence of any other neurological symptoms.[2] A positive Dix-Hallpike sign supports the diagnosis and localizes the affected ear. The posterior canal is the most commonly affected canal, and it is this canal that produces upward beating torsional nystagmus upon performing the Dix-Hallpike maneuver. This maneuver also uncovers which ear is the culprit: the nystagmus will be evoked when the affected ear is downwards. When these patients present to the emergency department, 19% undergo imaging studies, constituting a waste of resources.[3]

In a study of 9,472 patients presenting to US emergency departments with the chief complaint of dizziness, 7.4% were diagnosed with a vestibular etiology, either BPPV or acute peripheral vestibular neuropathy.[3] Unfortunately, these patients received very similar treatment despite the very different disease entities. Patients were commonly (58%) prescribed meclizine (trade name Antivert) for BPPV although meclizine does not have utility in this disorder.[3] The treatment guidelines put forth by the American Academy of Neurology in 2008 in fact do not recommend any medication for the treatment of BPPV.[4] Read more »

What is the Role of Drug Therapy in Treating Obesity?

November 19, 2009

800px-feet_on_scaleArlene Chung

Faculty Peer Reviewed

Despite the high prevalence of obesity1 and its associated morbidity2 and mortality 3,4, it represents one of the most difficult chronic conditions to treat. Barriers include a metabolically toxic environment, a history of ill-fated weight-loss regimens, and a general view of obesity as primarily a social, not a medical problem. 5 Deep down, the belief that obesity really is the result of gluttony and sloth probably persists. However, as we learn more about the physiology of energy balance, appetite regulation, and peripheral signaling mechanisms, obesity is increasingly regarded in the same light as other chronic medical conditions, such as hypertension or diabetes, and equally deserving of medical attention.

Theoretically, obesity can be treated in four different ways: (1) reduction of calorie intake through decreased appetite or (2) decreased nutrient absorption, (3) increase in energy expenditure, and (4) direct removal of fat. 6 These targets can be achieved through changes in diet and lifestyle, medication, surgery, or some combination of the above. All overweight and obese patients should follow a reduced-calorie diet and increase their physical activity, whether or not they choose to pursue adjunctive medication or surgery. 7 Medications used for obesity treatment, including those still under development, aim to reduce calorie absorption or decrease appetite.

The FDA has approved two drugs for the induction and long-term maintenance of weight loss. Sibutramine (Meridia) reduces appetite by inhibiting the reuptake of norepinephrine and serotonin in the central nervous system. The other approved medication, orlistat (Xenical, Alli), blocks peripheral absorption of calories in the form of fat by inhibiting pancreatic lipase in the gastrointestinal tract. Both drugs have demonstrated safety and efficacy in inducing weight loss of up to 8-10%. 8,9 However, patients often regain the weight upon discontinuation of the medications and no long-term safety or efficacy data currently exist for either drug beyond two years. Furthermore, undesirable side effects, lack of a dramatic weight-loss response, and the persistence of obesity on an individual and population scale continue to spur the development of other weight-loss treatments.

The selective cannabinoid-1 receptor antagonist rimonabant initially promised to deliver superior results to sibutramine and orlistat, particularly with regard to improvements in HDL, triglycerides, and glucose tolerance. Rimonabant reduces appetite and results in a 4.7 kg weight loss over one year compared to placebo. Although rimonabant initially received approval in Europe, in October 2008 the European Medicines Agency withdrew marketing authorization due to the emergence of anxiety, depression, and suicidality in patients with no prior history of psychiatric illness. The Food and Drug Administration has not approved rimonabant for use in the United States due to similar safety concerns. 10

Lorcaserin, an anorectic selective serotonin 2C receptor agonist, is currently undergoing phase III clinical trials. It differs from the earlier nonselective serotonin agonists, fenfluramine and dexfenfluramine, in that it exerts minimal activity against the serotonin 2B receptors implicated in the pathogenesis of heart valve damage. In a randomized double-blind placebo-controlled study, healthy obese patients receiving 10 mg of lorcaserin twice daily lost an average of 3.1 kg over 12 weeks while maintaining their usual diet and exercise habits. No significant valvular changes were detected by echocardiogram.  The most common adverse effects were headache, nausea, and dizziness. 11

Another medication undergoing phase III trials is cetilistat, which induces weight loss by inhibiting pancreatic lipases and thereby decreasing the absorption of dietary fat. Although it works by a mechanism similar to orlistat, evidence suggests that cetilistat produces fewer gastrointestinal side effects. Participants receiving 60 mg, 120 mg, or 240 mg of cetilistat three times daily, in conjunction with a reduced-calorie diet, lost 3.3 kg, 3.5 kg, and 4.1 kg, respectively, over the course of 12 weeks. Participants on cetilistat did report more adverse effects than participants on placebo, including increased defecation, soft or oily stools, abdominal pain, and flatulence, but these symptoms were generally mild, occurred on only one occasion, and did not appear to be dose-dependent. Fecal incontinence, flatus with discharge, and oily spotting occurred only rarely. 12

Combination medications currently undergoing phase III trials include phentermine plus topiramate (Qnexa) and naltrexone plus bupropion (Contrave).  Phentermine reduces appetite by inhibiting reuptake of norepinephrine, thus suppressing appetite, and has FDA approval for the short-term treatment of obesity. Topiramate is an antiepileptic noted to have weight-loss effects. In a 24-week randomized double-blind placebo-controlled study, the combination of phentermine and topiramate induced 11.4 kg weight loss compared to 5.3 kg and 6.6 kg weight loss for phentermine or topiramate alone.13 The other combination regimen, naltrexone and bupropion, theoretically works by promoting hypothalamic proopiomelanocortin (POMC) activity, thereby reducing appetite and increasing energy expenditure while minimizing autoinhibition by endogenous beta-endorphins. Phase II trials demonstrated that participants receiving either a 16 mg or 32 mg dose of combined naltrexone and bupropion lost approximately 5.4% of their initial body weight over 24 weeks. In comparison, the placebo- treated group lost only 0.8% over the same time period. 14

Despite the significant weight-loss observed in clinical trials, the medications are unlikely to produce such dramatic results in real clinical practice for several reasons. Participants in many of the trials were able to follow a reduced-calorie diet. 8,12-14 Even without specifically prescribed dietary changes, participants may be motivated to initiate changes on their own because of their enrollment in a clinical trial. In contrast, patients offered medication in practice are often unable to sustain a reduced-calorie diet for any length of time. Participants in clinical trials also receive much more frequent follow-up and support for weight-loss efforts compared to the average clinic patient. The high attrition rate15 and lack of long-term follow-up limit the strength of the findings in many of the studies. Most trials specifically excluded patients with pre-existing cardiovascular disease8,9,11-14, but many obese patients in clinical practice already have coronary artery disease, congestive heart failure, or a history of myocardial infarction. As a final note, most insurance companies, including Medicare and Medicaid, do not cover prescription drug costs for weight loss medications, forcing patients to pay as much as $140 per month for the FDA-approved drugs sibutramine and orlistat.

Obesity represents the second leading cause of preventable death in this country4 and an effective treatment has the potential to save millions of lives. Just a 10% reduction in weight has a major beneficial impact on cardiovascular risk factors alone. 16 The currently approved medications and those in phase III trials have demonstrated efficacy in producing weight loss of this magnitude, but obesity and its associated health complications remain widely prevalent in clinical practice. Truly effective treatment strategies will need to target multiple physiologic pathways, in addition to multiple aspects of our social environment.  Hopefully in the near future we will be able to lift this great weight from the shoulders of this country and the rest of the world.

Arlene Chung is a fourth year medical student at NYU School of Medicine and a copy editor for Clinical Correlations.

Peer reviewed by Michelle McMacken, MD Assistant Professor, Division of General Internal Medicine

References

  1. Ogden CL, Carroll MD, Curtin LR, et al. Prevalence of overweight and obesity in the United States, 1999-2004. JAMA. 2006;295(13):1549-1555.
  2. Poirier P, Giles TD, Bray GA, et al. Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the 1997 American Heart Association scientific statement on obesity and heart disease from the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Circulation. 2006;113:898-918.
  3. Allison DB, Fontaine KR, Manson JE, et al. Annual deaths attributable to obesity in the United States. JAMA. 1999; 282(16):1530-1538.
  4. Flegal KM, Graubard BI, Williamson DF, Gail MH. Cause-specific excess deaths associated with underweight, overweight, and obesity. JAMA. 2007;298(17):2028-2037.
  5. Frank, A. Futility and avoidance: Medical professionals in the treatment of obesity. JAMA. 1993;269(16):2132-2133.
  6. Bloom SR, Kuhajda FP, Laher I, et al. The obesity epidemic: pharmacological challenges. Mol Interv. 2008;8(2):82-98.
  7. National Institutes of Health/National, Heart, Lung, and Blood Institute. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults. Am J Clin Nut.1998;68:899-917.
  8. Wirth A, Krause J. Long-term weight loss with sibutramine: a randomized controlled trial. JAMA. 2001;286(11):1331-1339.
  9. Sjostrom L, Rissanen A, Andersen T, et al. Randomized placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. Lancet. 1998;352(9123):167-172.
  10. Idelevich E, Kirch W, Schindler C. Current pharmacotherapeutic concepts for the treatment of obesity in adults. Ther Adv Cardiovasc Dis. 2009;3(1)75-90.
  11. Smith SR, Prosser WA, Donahue DJ, et al. Lorcaserin (APD356), a selective 5-HT(2C) agonist, reduces body weight in obese men and women. Obesity (Silver Spring). 2009;17(3):494-503.
  12. Kopelman P, Bryson A, Hickling R, et al. Cetilistat (ATL-962), a novel lipase inhibitor: a 12-week randomized, placebo-controlled study of weight reduction in obese patients. Int J Obes. 2007;31:494-499.
  13. Gadde KM, Kolotkin RL, Peterson CA, Day WW. Changes in weight and quality of life in obese adults treated with topiramate plus phentermine. North American Association for the Study of Obesity: The Obesity Society Annual Scientific Meeting, 2007. Poster presentation.
  14. Greenway FL, Fujioka K, Gupta AK, et al. A double-blind, placebo-, bupropion- and naltrexone-controlled study of the efficacy and safety of three doses of naltrexone-bupropion SR combination therapy in obesity: Effects on total and visceral adipose tissue and CV risk markers. North American Association for the Study of Obesity: The Obesity Society Annual Scientific Meeting, 2007. Poster presentation.
  15. Rucker D, Padwal R, Li SK, et al. Long term pharmacotherapy for obesity and overweight: updated meta-analysis. BMJ. 2007;335:1194-1199.
  16. Pi-Sunyer FX. A review of long-term studies evaluating the efficacy of weight loss in ameliorating disorders associated with obesity. Clin Ther. 1996;18(6):1006-1035.

    How Does Alcohol Cause Cardiomyopathy?

    November 4, 2009

    alcoholCharles Levine

    Faculty peer reviewed

    Excessive consumption of ethanol (EtOH) has many deleterious effects on the human body. The heart is a target of damage from EtOH consumption, as chronic consumption of EtOH leads to decreased cardiac function and structural heart disease, including dilated cardiomyopathy.(1) The exact mechanism by which EtOH exerts its deleterious effects on the heart remains poorly understood and is an area of active research. This report will focus on some of the proposed mechanisms and some recent advances in the understanding of the pathogenesis of EtOH-induced cardiomyopathy.

    The pathogenesis of alcoholic cardiomyopathy is likely multifactorial, and current evidence suggests a role for decreased excitation/contraction coupling, oxidative damage, and membrane destabilization in cardiac myocytes. However, the key initiating event is not known. Several theories have been put forth to explain the underlying pathogenesis of alcoholic cardiomyopathy. Two of the leading theories will be reviewed here.

    The idea that apoptosis underlies the myocardial damage observed in alcoholic cardiomyopathy was first proposed in 2000 by Chen et al, based on the observation that several markers of apoptosis were observed to be elevated in many cardiac diseases.(2-4) A more recent study looked at the post-mortem hearts of 20 long-standing alcoholics and compared them to non-alcoholic controls and hearts from patients with hypertension but not alcoholism. Histological staining for apoptosis using terminal deoxynucleotidyl transferase d-UTP nick-end labeling (TUNEL), as well as staining for several markers of apoptosis, including Bcl-2 and activated caspase-3, revealed a significantly elevated level of apoptosis in the alcoholic and hypertensive hearts, as compared to control hearts.(5) The authors concluded that alcohol mediates its deleterious effects on the heart via induction of apoptosis. These studies failed, however, to identify any mechanistic connection between EtOH exposure and myocyte death.

    Another theory has been termed the acetaldehyde toxicity theory by Cai et al.(6) The theory is based on the observation, made several decades ago in rats, that acute EtOH exposure can decrease cardiac contractility.(7) It was hypothesized then that the long-term effects of EtOH exposure on cardiac contractility could result from either chronic exposure to EtOH itself or from exposure to a toxic metabolite of EtOH, possibly acetaldehyde, which is metabolized from EtOH in the liver by the enzymes alcohol dehydrogenase and P450IIE1.(8)

    To elucidate the exact effects of acetaldehyde on various cellular and physiological processes, Li and Ren recently conducted an elegant study using transgenic mice. These mice express a transgene coding for the human enzyme alcohol dehydrogenase.(9) By feeding these mice high levels of ethanol, they were able to simulate the high serum levels of acetaldehyde observed in human chronic alcoholics. The authors fed EtOH to transgenic and non-transgenic littermate control mice and analyzed these mice for insulin signaling in the heart, oxidative and endoplasmic reticulum (ER) stress in the heart, and overall cardiac function. Any differences between the two groups could then be attributed to increased exposure to acetaldehyde.

    Interestingly, the authors found significant differences between the two groups of mice in all of the processes they tested. It had been known previously that chronic EtOH ingestion leads to impaired glucose tolerance and to cerebral dysfunction secondary to reduced insulin-receptor signaling. It was not clear, however, whether these effects were at all related to EtOH induced cardiomyopathy. This study provided evidence that these effects do indeed contribute to the pathogenesis of alcoholic cardiomyopathy. Chronic alcohol feeding led to glucose intolerance, dampened cardiac glucose uptake, cardiac hypertrophy, and contractile dysfunction in control mice. These effects were significantly exaggerated by the alcohol dehydrogenase transgene. Thus, acetaldehyde exposure directly mediates the toxicity of EtOH on the heart and may underlie the pathogenesis of alcohol-induced cardiomyopathy.

    Although the above study did not directly address the role of acetaldehyde in the ER and oxidative stress, previous studies from Ren’s lab showed that acetaldehyde and ethanol both induced the generation of reactive oxygen species and resultant apoptosis in human cardiac myocytes.(10) This finding provides more evidence for the acetaldehyde toxicity theory, and in addition, explains some of the findings of Chen et al, mentioned above, that apoptosis underlies the pathogenesis of alcoholic cardiomyopathy. Thus, both theories of the pathogenesis of alcoholic cardiomyopathy can be seen as complementary, with the acetaldehyde toxicity theory underlying the ultimate apoptosis that may contribute significantly to cardiac dysfunction.

    These studies provide a compelling explanation for the pathogenesis of alcoholic cardiomyopathy, but they do not offer an explanation for the reversibility of the disease observed clinically with EtOH abstinence. Several studies have demonstrated that even as little as 10 weeks of abstinence can improve cardiac function significantly in patients with alcoholic cardiomyopathy. (11-13) Given that the final cardiac insult from EtOH results in apoptosis, and that the cardiomyopathy can be reversible, perhaps myocyte regeneration from adult stem cells may play a significant role in restoration of cardiac function following abstinence from EtOH. This finding itself could be extremely exciting in the context of harnessing this reparative potential for the treatment of other cardiac diseases as well.

    Charles Levine is a 4th year medical student at NYU School of Medicine.

    Peer reviewed by Robert Donnino MD, NYU Division of Cardiology

    References
    1. McKenna CJ, Codd MB, McCann HJ, Sugrue DD. Alcohol consumption and idiopathic dilated cardiomyopathy: a case control study. Am Heart J. 1998;135(5 Pt 1):833-837.
    2. Chen DB, Wang L, Wang PH. Insulin-like growth factor I retards apoptotic signaling induced by ethanol in cardiomyocytes. Life Sci. 2000;67(14):1683-1693.
    3. Piano MR. Alcoholic cardiomyopathy: incidence, clinical characteristics, and pathophysiology. Chest. 2002;121(5):1638-1650.
    4. Djoussé L, Gaziano JM. Alcohol consumption and heart failure: a systematic review. Curr Atheroscler Rep. 2008;10(2):117-120.
    5. Fernández-Solà J, Fatjó, Sacanella E, et al. Evidence of apoptosis in alcoholic cardiomyopathy. Hum Pathol. 2006;37(8):1100-1110.
    6. Cai L. Alcoholic cardiomyopathy: Acetaldehyde, insulin insensitization and ER stress. J Mol Cell Cardiol. 2008;44(6):979-982.
    7. Rubin E, Urbano-Marquez A. Alcoholic cardiomyopathy. Alcohol Clin Exp Res. 1994; 18(1):111-114.
    8. Oyama T, Isse T, Kagawa N, et al. Tissue-distribution of aldehyde dehydrogenase 2 and effects of the ALDH2 gene-disruption on the expression of enzymes involved in alcohol metabolism. Front Biosci. 2005;10:951-960.
    9. Li SY, Gilbert SA, Li Q, Ren J. Aldehyde dehydrogenase-2 (ALDH2) ameliorates chronic alcohol ingestion-induced myocardial insulin resistance and endoplasmic reticulum stress. J Mol Cell Cardiol. 2009;47(2):247-255.
    10. Guo R, Ma H, Gao F, Zhong L, Ren J. Metallothionein alleviates oxidative stress-induced endoplasmic reticulum stress and myocardial dysfunction. J Mol Cell Cardiol. 2009.
    11. Masani F, Kato H, Sasagawa Y. [An echocardiographic study of alcoholic cardiomyopathy after total abstinence]. J Cardiol. 1990;20(3):627-634.
    12. Agatston AS, Snow ME, Samet P. Regression of severe alcoholic cardiomyopathy after abstinence of 10 weeks. Alcohol Clin Exp Res. 1986;10(4):386-387.
    13. Renault A, Mansourati J, Genet L, Blanc JJ. [Dilated cardiomyopathies in severe cardiac failure in chronic alcoholics: clinical course after complete withdrawal]. Rev Med Interne. 1993;14(10):942.

    How to interpret troponins in renal disease?

    October 21, 2009

    pbb_protein_tnnc1_imageIvan Saraiva MD

    Case: A 68-year-old man, with a history of stable angina and end-stage renal disease treated by hemodialysis for the past three years, presents to the hospital with leg swelling and shortness of breath. He also complains of intermittent chest pain unrelated to exertion. Physical exam reveals bilateral pitting lower extremity edema, pulmonary crackles, and an elevated jugular venous pressure. Initial electrocardiogram is notable for some nonspecific repolarization abnormalities. Troponin I levels drawn at 0, 6, and 12 hours after initial presentation are 0.03-ng/mL, 0.12-ng/mL, and 0.09-ng/mL, respectively. How should this patient be further evaluated and treated?

    Many clinicians debate the usefulness of troponin and other biomarkers in patients with impaired renal function for several reasons. Often, patients admitted for non-cardiac problems will have incidentally elevated troponins. On the other hand, patients in heart failure may have positive troponins for any number of reasons, whether due to an acute ischemic myocardial insult or as a consequence of a chronic fluid-overloaded state. Some clinicians even question whether or not elevated troponins represent myocardial injury at all. In each of these cases, concomitant renal disease only further complicates the clinical picture.

    Troponin (Tn) subtypes T, I, and C exist together as a protein complex bound to actin thin filaments in both skeletal and cardiac muscle. This complex regulates muscle contraction and relaxation via its interaction with actin and calcium ions released from the sarcoplasmic reticulum of the muscle cells. TnT and TnI have different isoforms in cardiac and striated muscle, which allows laboratory assays that can identify troponins specifically released from injured myocytes in the heart.

    Several studies have explored the significance of elevated troponins in patients with concomitant renal disease [1-10]. Up to 80% of patients with low glomerular filtration rates (GFR), and in the absence of acute coronary syndromes or congestive heart failure, have positive values for TnT, regardless of whether or not they receive dialysis treatment. On the other hand, one large study that included more than 700 patients found the prevalence of TnI to be only 0.4-6% depending on the cut-off value chosen [3]. These results suggest that a positive TnT may represent a common and benign incidental finding in patients with impaired renal function, whereas a positive TnI occurs only in the setting of an acute coronary event. However, other studies have demonstrated consistent associations between elevated TnT and hard endpoints such as death and myocardial infarction [2,3,5,6]. Therefore, although chronic kidney disease appears to be nonspecifically associated with positive TnT values, the absolute TnT level may serve as a useful prognostic marker.

    The etiology of the increased TnT in renal disease remains unclear. Recently, a few small, but well-designed, studies have attempted to clarify the association. Askoy et al. studied TnT levels in 62 patients with non-ischemic congestive heart failure. Elevated TnT values were associated with a low ejection fraction, severity of heart failure (NYHA class), and low GFR in the initial univariate analysis. However, after adjustment by regression analysis, only a low GFR remained significantly associated with a positive TnT [1]. Going in the same line of thought, Tsutamoto et al. performed a very elegant study measuring the transcardiac TnT gradient by measuring levels in both the aortic root and coronary sinus [10]. They classified 258 patients with congestive heart failure as having either normal or low GFR. Despite the finding of markedly elevated levels of TnT in the patients with low GFR compared to the patients with normal renal function, the transcardiac gradient appeared similar between the two groups. They concluded that the elevated TnT observed in patients with a low GFR occurs as a result of accumulation rather than increased myocardial injury.

    In conclusion, evidence suggests that the kidneys clear TnT and thus baseline levels may indeed rise in the setting of a low GFR. Conversely, it appears that elevated TnI values represent myocardial injury in both patients with low GFR and other populations. Keep in mind however that several mechanisms of non-ischemic myocardial injury occur in the setting of renal disease, including fibrotic and infiltrative processes. These may independently result in an elevated TnI even in the absence of an acute ischemic myocardial insult [11]. Despite these conclusions, elevated TnT and TnI remain specific for heart disease and should never be treated as meaningless.

    Based on the above discussion, the management of our case patient should proceed as follows. The differential diagnosis for his presentation must account for a fluid-overloaded state, chest discomfort, and positive TnI values. The patient may have suffered an acute coronary event, exacerbation of a chronic heart failure state, or worsening of his renal function leading to fluid-overload. All of these etiologies may account for his elevated troponin. Notably, this case used the values of TnI, the biomarker assumed to be less commonly accumulated in the setting of chronically impaired renal function. Thus, his positive TnI can be more confidently interpreted as specific for an acute myocardial injury. Furthermore, the patient’s TnI displays a peak followed by a downward trend, which increases the likelihood of an acute event and less likely represents a chronically elevated troponin due to renal disease alone.

    Dr. Saraiva is a 2nd year internal medicine resident at NYU Medical Center.

    Faculty peer reviewed by Robert Roswell MD, NYU Division of Cardiology

    References:
    1. Aksoy N, Ozer O, Sari I, Sucu M, Aksoy M, Geyikli I. Contribution of renal function impairment to unexplained troponin T elevations in congestive heart failure. Ren Fail 2009, 31(4):272-7.
    2. Ammann P, Maggiorini M, Bertel O, Haenseler E, Joller-Jemelka HI, Oechslin E, Minder EI, Rickli H, Fehr T. Troponin as a risk factor for mortality in critically ill patients without acute coronary syndromes. J Am Coll Cardiol 2003, 41(11):2004-9.
    3. Apple FS, Murakami MM, Pearce LA, Herzog CA. Predictive value of cardiac troponin I and T for subsequent death in end-stage renal disease. Circulation 2002, 106:2941-5.
    4. Aviles RJ, Askari AT, Lindahl B, Wallentin L, Jia G, Ohman EM, Mahaffrey KW, Newby LK, Califf RM, Simoons ML, Topol EJ, Lauer MS. Troponin T levels in patients with acute coronary syndromes, with or without renal dysfunction. N Engl J Med 2002, 346(26):2047-52.
    5. deFilippi C, Wasserman S, Rosanio S, Tiblier E, Sperger H, Tocchi M, Christenson R, Uretsky B, Smiley M, Gold J, Muniz H, Badalamenti J, Herzog C, Henrich W. Cardiac troponin T and C-reactive protein for predicting prognosis, coronary atherosclerosis, and cardiomyopathy in patients undergoing long-term hemodialysis. JAMA 2003, 290:353-9.
    6. Frankel WL, Herold DA, Ziegler TW, Fitzgerald RL. Cardiac troponin T is elevated in asymptomatic patients with chronic renal failure. Am J Clin Pathol 1996, 106(1):118-23.
    7. Jacobs LH, de Kerkhof JV, Mingels AM, Keijnen VW, der Sande FM, Wodzig WK, Kooman JP, van Dieijen-Visser MP. Haemodialysis patients longitudinally assessed by highly sensitive cardiac troponin T and commencial cardiac troponin T and cardiac troponin I assays. Ann Clin Biochem 2009, 46:283-90.
    8. Mongeon F-P, Dorais M, Lorier JL, Froment D, Letendre E, Rinfret S. Effect of hemodialysis, coronary artery disease and diabetes on cardiac troponin T: a prospective survery over one year. Open cardiovasc med j 2009, 3:69-77.
    9. Sutidze M, Kajrishvili M, Tsimakuridze M, Khachapuridze N, Sulakvelidze M. Factors associated with increased serum levels of specific markers of myocardial injury – cardiac troponins T and I in chronic haemodialysis patients. Georgian Med News 2009, 169:39-43.
    10. Tsutamoto T, Kawahara C, Yamaji M, Nishiyama K, Fujii M, Yamamoto T, Horie M. Relationship between renal function and serum cardiac troponin T in patients with chronic heart failure. Eur J Heart Fail 2009, 11(7):653-8.
    11. Schietinger BJ, Brammer GM, Wang H, Christopher JM, Kwon KW, Mangrum AJ, Mangrum JM, Kramer CM. Patterns of later gadolinium enhancement in chronic hemodialysis patients. J Am Coll Cardiol Img 2008, 1(4):450-6.

    What is Wellens’ Syndrome?

    October 7, 2009

    Erin Ducharme MD

    Faculty peer reviewed

    Wellens’ syndrome refers to a pattern of ECG signs occurring during chest-pain free periods in patients with unstable angina, heralding critical, proximal left anterior descending artery (LAD) stenosis [1,2]. The eponym honors Dr. Hein J.J. Wellens who first described this ECG phenomenon in 1982. Wellens and colleagues identified a subgroup of patients with unstable angina who demonstrated a pattern of inverted precordial T-waves which strongly correlated with early large anterior myocardial infarction (MI) and a poor prognosis [1,2]. In fact, seventy-five percent of these patients who were treated conservatively progressed to develop an extensive anterior MI despite receiving standard medical care. The investigators went on to show that the majority of these patients had severe promixal left anterior descending (LAD) disease.

    Characteristics of Wellens’ Syndrome

    • Recent history of chest pain
    • Little or no elevation of cardiac enzymes
    • No precordial Q waves or loss of R waves
    • Symmetric, deep TWI or biphasic T waves in V2-V5 or V6 during pain free periods (see Figure 1)
    • Minimal (<1mm), if any, ST elevations

    The warning T-wave changes of Wellens’ are not uncommon in patients with unstable angina. In the original study, 18% of angina patients exhibited symmetric, deep TWI or biphasic T waves in V2-V5 or V6. The prognostic importance of these T wave changes was demonstrated in a subsequent study which found that sensitivity and specificity of an anterior TWI of 2 mm or greater indicating a significant LAD obstruction was 69% and 89% respectively, with a positive predictive value of 86% [3].

    Interestingly, the pattern of ECG changes seen in Wellens’ has been described in patients without chest pain. During episodes of chest pain the ECG can transiently show positivization of T waves or pseudonormalization, or – more likely – ST depressions or ST elevations.  Clearly, the not-uncommon warning sign of Wellens’ is a critically important ECG finding for physicians to recognize and intervene upon. The recommended treatment for such patients is an early invasive approach, either with cardiac catheterization with angioplasty or coronary artery bypass surgery.

    Today, Dr. Wellens serves as Chairman of the Scientific Council of the Interuniversity Cardiological Institute of the Netherlands. Previously he was the founder and head of the department of cardiology at the University Hospital Maastricht from 1977 until 2000. Throughout his career he has written more than 680 international scientific publications and 14 books on cardiology. Other notable achievements include early work on programmed electrical cardiac stimulation in patients with Wolff-Parkinson-White and the demonstration that such stimulations, when appropriately timed allowed creation of cardiac arrhythmias and subsequent study of the effects of antiarrythmic pharmaceuticals on the mechanism of these dysrhythmias. His extensive work in electrophysiology formed the foundation for innovative surgical and pacing approaches in the treatment of cardiac arrhythmias.

    wellens2

     

     

     

     

     

    Figure 1: Biphasic T waves can be seen in leads V1, V2, with inverted T waves in V3-V6. (Image taken with permission from http://www.ems1.com)

    Reviewed by Robert Donnino MD, NYU Division of Cardiology

    References
    1. de Zwaan C, Bär FW, Wellens HJ. Characteristic electrocardiographic pattern indicating a critical stenosis in left anterior descending coronary artery in patients admitted because of impending myocardial infarction. Am Heart J 1982, 103:730-6.
    2. de Zwaan C, Bär FW, Janssen JH, Cheriex EC, Dassen WR, Brugada P, Penn OC, Wellens HJ. Angiographic and clinical characteristics of patients with unstable angina showing an ECG pattern indicating critical narrowing of the proximal LAD coronary artery. Am Heart J 1989, 117:657-65.
    3. Haines DE, Raabe DS, Gundel WD, Wackers FJ. Anatomic and prognostic significance of new T-wave inversion in unstable angina. Am J Cardiol 1983, 52:14-8.

    When Should You Obtain a Renal Biopsy? Indications, Risks, Follow-up and Value

    September 30, 2009

    kidneybiopsyFrederick Gandolfo MD

    Faculty peer reviewed

    At a recent conference on renal transplantation, the importance of early renal biopsy for the diagnosis of acute rejection was emphasized. As busy practitioners of general internal medicine, we rarely have the opportunity to learn the details of a subspecialty procedure such as renal biopsy. However, knowing the details of these procedures is important in providing care for these specific patients. What are the indications, risks, and follow-up care required for the renal biopsy patient? In the native kidney patient, is the renal biopsy an underutilized test?

    Renal biopsy is indicated for a myriad of conditions. Renal biopsy should be considered in patients with acute kidney injury after clinical history and physical, lab, and imaging exams fail to diagnose the etiology of the renal insult (1). However, the more specific indications for biopsy are largely a matter of expert opinion. In patients with preserved renal function a commonly accepted indication for biopsy is microhematuria that is associated with greater than 1 g/day of proteinuria. In acute renal failure it is accepted to biopsy when a glomerular lesion is suspected; however experts vary in the appropriate timing of the biopsy. Most experts advocate biopsy immediately or after one week of non-recovery, although some wait up to one month. In chronic kidney disease, most experts would biopsy patients with preserved renal size, except in the USA where small renal size was not a deterrent to biopsy. Almost all experts will biopsy patients with chronic renal insufficiency and nephrotic range proteinuria (2). Also in chronic kidney disease, renal biopsy can confirm the diagnosis by differentiating chronic from acute kidney disease, guide treatment, and provide prognostic information (3). In fact, in a study by Haas et al., renal biopsy results for over one-thousand elderly patients were examined and compared to pre-biopsy clinical diagnoses for the etiology of renal disease. It was found that the pre and post biopsy results only agreed 67% of the time, and that the biopsy provided a diagnosis over 90% of the time (4). This suggests that renal biopsy is an underutilized and important procedure in diagnosing both acute and chronic kidney disease.

    Like most invasive procedures in internal medicine, renal biopsy technique has evolved over the years in favor of better patient safety. What used to be a blind manual procedure is now one that is often done under real-time ultrasound guidance and always with a spring-loaded biopsy gun. This has been shown to result in less complications and higher yield of adequate renal tissue for pathologic examination. An interventional radiology transjugular approach is also available in the case of a patient at a very high risk of bleeding (5).

    Although the safety of renal biopsy is improving with better technique, the procedure is not without risks. The most common risks are bleeding complications, including hematuria and perinephric or retroperitoneal hematoma. These complications are serious (as defined by requiring blood transfusion, surgical intervention, or other invasive procedures such as angiography and embolization to control bleeding) in less than 1 % or up to 6 % of patients undergoing biopsy, depending on the study. Since almost all of these complications become evident in the first 8-24 hours after biopsy, some authors have recommended that patients should be observed for at least this amount of time before returning home after the procedure. A 24 hour period of observation is more ideal, with measurement of a post-biopsy hematocrit the next day (5, 6). However, in practice, patients are usually observed for about 4-6 hours, and the hematocrit is only checked in cases of suspected bleeding. This allows renal biopsy to be done in the outpatient setting.

    The clinical predictors associated with increased risk of bleeding identified in one recent prospective cohort study of 471 patients using modern biopsy technique were female sex, increased baseline PTT, and younger age (7). As with all procedures, the number of passes and the gauge of the biopsy needle are also correlated with the bleeding risk. Some relative contraindications to renal biopsy are uncontrolled hypertension, solitary kidney, hydronephrosis, renal infection, severe anemia, pregnancy, and renal artery aneurysm (5). These factors should be taken into consideration when assessing your individual patient for renal biopsy. Another question that is often raised in the era of drug-eluting coronary stents is the need to stop antiplatelet therapy for a particular procedure. A recently published retrospective study compared patients undergoing elective renal biopsies while on antiplatelet therapy (aspirin and/or clopidigrel) with those that discontinued antiplatelet therapy 5 days prior to biopsy (8). An increase in minor bleeding was seen in the antiplatelet group, but there was no increase in major bleeding, defined as requiring blood transfusion or intervention. Although the event rate was low in the study, and therefore a much larger study would be needed to demonstrate any differences that may exist in the endpoints, it does suggest that renal biopsy while on antiplatelet therapy may be safe in selected patients. This must be weighed against the risk of stopping aspirin and plavix in your individual patient. In practice, renal biopsy on antiplatelet agents is usually reserved for emergent situations, such as acute glomerulonephritis or suspected renal transplant rejection.

    Dr. Gandolfo is a 3rd year internal medicine resident at NYU Medical Center.

    Faculty peer and commentary below by Alexander Gilbert, M.D. ,Clinical Assistant Professor of Medicine , Division of Neprhology, New York University Medical Center

    In his review of renal biopsy indications and technique, Dr. Gandolfo discusses the vital role that renal biopsy plays in evaluation of medical renal disease. While the diagnosis of tubular or interstitial disease is often accomplished without need for invasive procedures, the nature of glomerular damage means that while laboratory testing can be helpful and suggestive, renal biopsy remains the “gold-standard” for diagnosing glomerular diseases. As the therapies available for renal disease have diversified, accurate diagnosis of renal disease has become increasingly important. Moreover, the knowledge of specific pathology enables nephrologists to specifically stage and classify the renal disease allowing less toxic or more specific therapies to be used. In addition, with modern processing methods, initial results from a biopsy may be available within 6 hours, faster than most laboratory testing.

    In the transplant population, the value of the renal biopsy is even greater. As an example, transplant patients are susceptible to viral nephropathies (treated with a reduction in their immune suppression) and acute rejection (treated with an increase in immune suppression). These conditions, with their diametrically opposed treatments, present identically and are increasingly refractory to treatment when there are delays in diagnosis. As a result, biopsy is often the initial diagnostic test done in the renal transplant patient. Indeed, routine or “protocol” biopsies are being increasingly used in order to make the earliest possible diagnosis of renal pathology.

    With the increasing incidence of renal disease, and the rising numbers of kidney transplant recipients, it is of growing importance to be familiar with the risks and benefits of renal biopsy. In his review, Dr. Gandolfo mentions some of the contra-indications to biopsy. It is critical to know when any of these complicating factors are present, but it is also important to realize that none of these are absolute contraindications to biopsy, especially in cases where a rapidly progressive renal disease such as acute rejection or necrotizing crescentic glomerulonephritis are suspected. With new technologies including real-time ultrasound guidance, automatic biopsy needles, and close post-procedure follow-up, renal biopsy can be done as a very safe and effective outpatient procedure for managing renal disease.

    1. Saxena R, Toto R. Brenner and Rector’s The Kidney. 8th ed. Philadelphia: Saunders; c2007. Chapter 22, Approach to the patient with kidney disease; p. 710.
    2. Fuiano G, Mazza G, Comi N, et al. Current indications for renal biopsy: a questionnaire based survey. Am J Kidney Dis. 2000 Mar;35(3): 448-457.
    3. Saxena R, Toto RD. Brenner and Rector’s The Kidney. 8th ed. Philadelphia: Saunders; c2007. Chapter 22, Approach to the patient with kidney disease; p. 713.
    4. Haas M, Spargo B, Wit E, et al. Etiologies and outcome of acute renal insufficiency in older adults: a renal biopsy study of 259 cases. Am J Kidney Dis. 2000 Mar 35(3):433-47.
    5. Maya I, Allon M, Saddekni S, et al. Brenner and Rector’s The Kidney. 8th ed. Philadelphia: Saunders; c2007. Chapter 28, Interventional nephrology; p. 936.
    6. Whittier W, Korbet S. Timing of complications in percutaneous renal biopsy. J Am Soc Nephrol. 2004 Jan;15(1):142-7.
    7. Manno C, Strippoli G, Arnesano L, et al. Predictors of bleeding complications in percutaneous ultrasound-guided renal biopsy. Kidney Int. 2004 Oct;66:1570-1577.
    8. Mackinnon B, Fraser E, Simpson K, et al. Is it necessary to stop antiplatelet agents before a native renal biopsy? Nephrol Dial Transplant. 2008 Nov;23(11):3566-70.

    Can you offer a liver transplant to a patient with HIV?

    August 28, 2009

    120px-bellevue_hospital_ambulance2c_new_york_times2c_1895Faculty Peer Reviewed

    Uzma Sarwar MD

    Coincident with greater use of highly active antiretroviral therapy (HAART), chronic liver disease has become one of the leading causes of death amongst HIV patients. This reflects the high prevalence of chronic liver diseases in the HIV-infected; almost a third of HIV-seropositive patients are afflicted with liver disease, predominantly as a result of hepatitis B and/or hepatitis C co-infection. Given their increased life-span, many HIV-infected patients now progress to end-stage liver disease, where they used to succumb to the effects of HIV prior to death due to liver disease, in the pre-HAART era. Liver transplantation is commonly considered for treatment of end-stage liver disease among the HIV seronegative population, but the situation is not as clear-cut for patients infected with HIV.

    In the past, HIV was considered an absolute contraindication to liver transplant due to the infecteds’ overall poor prognosis and their inability to continue immunosuppressive therapy post transplant. The winds have now shifted and liver transplantation is now considered possible in this population. However, only 26 centers in the United States consider HIV-positive patients for liver transplant. Preliminary reports on the safety and efficacy of transplant in HIV positive patients are encouraging, having revealed that carefully selecting HIV-infected patients to receive solid organ transplants results in low rejection rates, few opportunistic infections and survival rates comparable to non HIV-seropositive patients. An outcome study of nineteen HIV patients conducted in 2002 by Roland, et al. at UCSF is particularly salient. In this study, transplanted patients, whose baseline CD4 cell count was 280 and whose plasma viral load was between undetectable and 115,000, experienced a low graft rejection rate of 21% after 300 days post-transplant. Another retrospective analysis of 15 HIV-infected patients (baseline CD4 cell count >100 and plasma viral load between undetectable and 141,000) who underwent transplant from 1999 to 2006 at the University of Miami, showed similar survival rates when compared with 857 HIV-uninfected patients, after 38 months median follow-up. However the HIV patients did have a higher rate of infectious complications.It should be noted that these studies did not specifically examine patients who underwent liver transplantation, but all HIV patients receiving solid organ transplants. Therefore, it is necessary for studies to specifically examine outcomes of liver transplantation in the HIV-infected population. Further, studies comparing long-term survival between transplanted HIV-infected and uninfected patients have yet to be reported.

    In addition to the traditional criteria used for transplant eligibility, HIV patients have  stricter inclusion criteria for consideration and enrollment. Some of the prominent criteria that have been utilized in previous studies are included  below.

    Inclusion Criteria:
    Life expectancy greater than 5 years
    CD4 cell count greater than 200 for over 6 months pre-transplant
    Adherence to stable HAART regimen
    Absence of any AIDS defining illness
    Plasma viral load less than 50 copies/ml

    Exclusion Criteria:
    Presence of any cancer diagnosis
    Any untreated chronic illness (included tuberculosis)
    Greater than 3 classes of viral resistance
    Persistent HIV viremia
    Any non-compliance with HAART

    To conclude, with careful and stringent selection criteria, HIV-infected patients may be considered for liver transplantation. They appear to have similar short-term survival post-transplant as do HIV-uninfected patients, although more studies are needed to evaluate their long-term prognosis.

    Dr. Sarwar is a third year internal medicine resident at NYU Medical Center.

    Reviewed by Michael Poles MD, Associate Editor, Clinical Correlations, Assistant Professor of Medicine, NYU Division of Gastroenterology 

    References
    1. Kozei, margaretJ, Peters, Marion G, Viral Hepatitis in HIV infection, NEJM 2007; 356:1445-54
    2. Sulkowski MS et al, Rapid fibrosis progression among HIV/Hep C virus co-infected adults, AIDS 2007;16:2209-16
    3. Merchante N et al, Survival and prognostic factors of HIV infected patients with HCV related end stage liver disease, AIDS 2006;20:49-57
    4. Hadler, SC, Judson, FN, O’Malley PM et al, Outcome of hepatitis B virus infection in homosexual men and its relation to prior HIV infection
    5. Thio et al, HIV-1, HBV and risk of liver related mortality in the Multicenter Cohort study. Lancet 2002;360:1921-6
    6. Roland et al, Solid organ transplantation in HIV infected patients in potent anti-retroviral therapy era. Topics in HIV medicine;12:73-6
    7. Schreibman Ian et al, Outcomes after orthotropic liver transplantation in fifteen HIV infected patients. Transplantation 2007; 84:697-704
    8. Powderly, William, Antiretroviral therapy in patients with hepatitis and HIV: weighing the risks and benefits, CID 2004;38:109-113
    9. Vennarecci,G et al, Transplantation in HIV positive patients. Transplantation Proceedings 2007;39:1936-38
    10. Sanchez-Conde M, Berenguer, J, Miralles, P et al, Liver biopsy findings for HIV infected patients with chronic hepatitis C and persistently normal levels of alanine aminotransferases, Clin Infect Dis 2006; 43:640-4
    11. Uptodate.com
    12. Harrison’s Manual of Internal Medicine, 16th edition

    Why is Syphilis Still Sensitive to Penicillin?

    July 30, 2009

    382px-syphilis_is_a_dangerous_disease.pngSam Rougas MD

    Faculty Peer Reviewed

    It seems that every week a new article in a major newspaper is reporting what most infectious disease physicians have been preaching for several years. Antibiotic resistance is rapidly spreading. Infections such as Methicillin Resistant Staphylococcal Aureus, Extremely Drug Resistant Tuberculosis, and Vancomycin Resistant Enterococcus have journeyed from the intensive care units to the locker rooms of the National Football League. That being said, some bacteria have strangely and until recently inexplicably behaved. Syphilis, a disease caused by the spirochete Treponema Pallidum, though first reported in Europe around the 15th century has likely been in North America since the dawn of mankind. Its rapid spread in Europe began shortly after Christopher Columbus returned from the new world[1] and remained unabated until it was first noted that Penicillin (PCN) could cure the disease[2]. However, since that time, syphilis, once the great pox, is now at the bottom of most differentials. How is it then, that one of our oldest diseases remains sensitive to our first antibiotic?Penicillin resistance to staphylococcal species was reported as early as 1946 and multiple cases were noted worldwide before the turn of the decade[3]. Literally within ten years of the existence of PCN there was resistance among staph species; however, after 50 years, PCN resistant syphilis is a worthy of a case report. In practically every case, the infection was cured with increasing the dose or duration of therapy or with another beta-lactam antibiotic[4,5]. One tempting explanation is that spirochetes are incapable of developing PCN resistance; however, that is not true. Brachyspira Pilosicoli, in intestinal spirochete has shown PCN resistance[6]. A second thought is that Syphilis is incapable of developing antibiotic resistance at all, though this too has not been shown to be true. Case reports of azithromycin resistance in T. Pallidum became increasingly common at the beginning of this century. Gene sequencing of these species mapped out the mutation leading to the macrolide resistant phenotype[7]. Obviously the mechanism of action of a macrolide antibiotic is different from a beta lactam as is the resistance profile. However, it does show that syphilis is capable of developing resistance to at least one class of antibiotic.

    The classic teaching is that beta lactam antibiotics function at the level of the cell wall via binding to penicillin binding proteins (PBPs). Once bound, the beta lactams are able to interfere with the production of specific peptidoglycans critical for cell wall structure. Once these peptides are eliminated the cell wall ruptures and the bacteria dies. Resistance occurs when bacteria either via an innate mutation or via DNA exchange acquire the ability to produce beta lactamase, an enzyme cabable of cleaving the antibiotic rendering it useless. In syphilis the mechanism of action is thought to be the same, but resistance has never developed. This may be a direct consequence of one of the more recently discovered PBPs called Tp47[8]. Tp47 functions as both a PBP and a beta lactamase. However, it may paradoxically be responsible for the persistence of PCN sensitivity in syphilis. The binding of the beta lactam component of PCN to Tp47 results in hydrolysis of the beta-lactam bond of the antibiotic. However, in the process of this reaction several byproducts are created. The thought is that these byproducts have a higher affinity for Tp47 than the beta lactam itself[9]. Thus as a consequence of PCN being broken down, products are released which make it more difficult for the beta-lactamase to bind the antibiotic.

    While this is one current theory behind the exquisite sensitivity of syphilis to PCN, it is clearly not cause for celebration. Cases of syphilis are increasing world-wide10 as the medical community has been unable to eradicate this disease. As the number of cases increase, so too does the potential for antibiotic resistance. Theoretically a mutation in Tp47 may alter the protective byproducts upon which the sensitivity of syphilis to PCN depends. Such a mutation would likely result in the end of the gravy train that has been the treatment of syphilis.

     
    1. Rose M. Origins of Syphilis. Archeology 1997; Volume 50 Number 1
    2. Mahoney J, Arnold R, Harris A. Penicillin treatment of early syphilis; a preliminary report. Vener Dis Inform 1943; 24:355-357
    3. Shanson DC, Review Article: Antibiotic-resistant staphylococcus aureus. Journal of Hospital Infection (1981) 2: 11-36
    4. Cnossen W, Niekus H, Nielsen et al. Ceftriaxone treatment of penicillin resistant neurosyphilis in alcoholic patients. J. Neurol. Neurosurg. Psychiatry 1995; 59; 194-195
    5. Stockli H, Current aspects of neurosyphilis: therapy resistant cases with high-dosage penicillin? Schweiz Rundsch Med Prax. 1992 Dec 1; 81(49):1473-80
    6. Mortimer-Jones S, Phillips N, Ram Naresh T et al. Penicllin resistance in the intestinal spirochaete Brachyspira pilosicoli associated with OXA-136 and OXA-137, two new variants of the class D Beta-Lacatmase OXA-63. Journal of Medical Microbiology 2006; 57 1122-1128
    7. Katz K, Klausner J. Current Opinion in Infectious Disease 2008, 21:83-91
    8. Deka R, Machius M, Norgard M et al. Crystal Structure of the 47-kDa Lipoprotein of Treponemal Pallidum Reveals a Novel Pencillin-Binding Protein. The Journal of Biological Chemistry 2002. 277:44: 41857-41864
    9. Cha J, Ishiwata A, Mobashery S. A Novel B-Lactamase Activity from a Penicllin-binding Protein of Treponema pallidum and Why Syphilis Is Still Treatable With Penicllin. The Journal of Biological Chemistry 2004. 279: 15: 14917-14921
    10. Gerbose A, Rawley J, Heymann D, et al. Global prevalence and incidence estimates of selected curable STDs. Sex Transm Infections 1998; 74: 512-516

    Faculty Peer Reviewed with commentary by Meagan O’brien MD, NYU Division of Infectious Diseases and Immunology 

    While it is true that Treponema Pallidum remains highly susceptible to Penicillin and has developed resistance to Azithromycin through an A–>G mutation at position 2058 of the 23S rRNA gene of T. pallidum, which confers resistance by precluding macrolide binding to the bacterial 50S ribosomal subunit, of which 23S rRNA is a structural component, the mechanisms of retained Penicillin sensitivity are not fully understood[7]. The discovery of Tp47 as a dual PBP and Beta-lactamase is interesting and important, but more studies would be needed to attribute this mechanism to the persistence of Treponema Pallidum sensitivity to Penicillin. Luckily, we do not have many clinical isolates to test this theorized mechanism. One key clinical point to remember is that eradication of the infection depends not only on the invading organism, but also upon the host defense system. In our HIV+ immunocompromized patient population, we routinely are concerned about treatment failure in syphilis infection due not to penicillin drug resistance but to dysfunctional host responses. A body of evidence now exists supporting the recommendation that if an HIV+ patient has a CD4 T-cell count ≤350 cell/uL and a blood RPR titer ≥ 1:32 with latent syphilis or syphilis of unknown duration, a lumbar puncture should be performed to rule out neurosyphilis, and if positive, that intravenous penicillin should be given instead of IM Benzathine Penicillin[11-14]. Additionally, after treating late or latent syphilis, a fall in RPR titer by 1:4 needs to be observed over 12 months or the patient should be evaluated for treatment failure or neurosyphilis, with the understanding that the CNS may be a more privelidged site for Treponema survival in the face of IM Benzathine Pencillin.

    11. Marra, C.M., C.L. Maxwell, S.L. Smith, et al., Cerebrospinal fluid abnormalities in patients with syphilis: association with clinical and laboratory features. J Infect Dis, 2004. 189(3): p. 369-76.

    12. Marra, C.M., C.L. Maxwell, L. Tantalo, et al., Normalization of cerebrospinal fluid abnormalities after neurosyphilis therapy: does HIV status matter? Clin Infect Dis, 2004. 38(7): p. 1001-6.

    13. Ghanem KG, Moore RD, Rompalo AM, Erbelding EJ, Zenilman JM, Gebo KA. Lumbar puncture in HIV-infected patients with syphilis and no neurologic symptoms.
    Clin Infect Dis. 2009 Mar 15;48(6):816-21.

    14. Ghanem KG, Moore RD, Rompalo AM, Erbelding EJ, Zenilman JM, Gebo KA. Neurosyphilis in a clinical cohort of HIV-1-infected patients. AIDS. 2008 Jun 19;22(10):1145-51.