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193 Del Med J, July 2011, Vol 83 No 7 Medical Society of Delaware Officers and Trustees 2010-2011 InsTrucTIOns TO AuThOrs The Delaware Medical Journal (DMJ) is owned and published by the Medical Society of Delaware as a medium of commu- nication, education, and expression for its members, and also for others striving for excellence in medical practice. Articles in the DMJ are intended to be scientific and educational and are not intended to reflect standards of medical care. All material published is under copyright. On receipt of material submitted for publication, a suitable release form will be sent for signature by all authors. Scientific articles on medical matters are especially welcomed, including case reports, clinical experiences, observations, and information on matters relevant to medical practice. Other material may also be accepted if the editorial staff deems it of interest to DMJ readers. All submissions should include a brief summary and a brief (one to two sentence) biographical sketch of all authors. It is highly recommended that authors familiarize themselves with DMJ style before submitting manuscripts for consider- ation. Material for publication should be submitted on disk or CD in Microsoft Word format, PC compatible. Text-only material (without graphs, charts, or photographs) may also be submit- ted electronically via e-mail. The ideal manuscript length is 750 to 5,000 words with up to 12 references, each keyed with superscripts in the text in the order cited. The format should follow that used in the Index Medicus. Authors are responsible for the accuracy of the citations. Graphs, charts, and black-and-white glossy photographs are accepted if important to the understanding of the text, but should not exceed five pieces. Original hard copies of each chart, graph, and photograph are required. Electronic copies of each graph, chart or photo should also be submitted. Most graphic formats are acceptable. Photos imbedded in Word documents and Power Point slides are not acceptable. Photos of patients should generally be taken in a way that obscures the patient’s identity. Photos in which a patient’s face must be clearly seen, however, must be accompanied by signed release forms. All manuscripts are reviewed by the editor, and all scientific articles are then sent for peer review by members of the Edi- torial Board and/or other appropriate physicians. The usual processing time to publication is two to four months, though in some circumstances this may be longer or shorter. All materials should be submitted to: Delaware Medical Jour- nal, The Medical Society of Delaware, 900 Prides Crossing, Newark, Delaware 19713 or e-mailed to [email protected]. OFFICERS DAVID M. BErcAW, M.D. – PRESIDENT rAnDEEP s. KAhLOn, M.D. – PRESIDENT-ELECT sTEPhEn J. KushnEr, D.O. – VICE PRESIDENT KEVIn P. shEAhAn, M.D. – SECRETARY JOsEPh F. hAcKEr III, M.D. – TREASURER rOBErT L. MEcKELnBurG, M.D. – SPEAKER OF THE HOUSE WILLIAM h. DuncAn, M.D. VICE SPEAKER OF THE HOUSE nIchOLAs O. BIAsOTTO, D.O. – PAST PRESIDENT TRUSTEES Kent County JACQUELINE J. CHRISTMAN, M.D. New Castle County JOHN DECARLI, D.O KRISTINE B. DIEHL, M.D. JAMES M. GILL, M.D., MPH JOHN J. GOODILL, M.D. DOROTHY M. MOORE, M.D. Sussex County MARK J. BOYTIM, M.D. Council on Medical Specialties CHRISTOPHER L. BALDI, D.O. CEDRIC T. BARNES, D.O. CHRISTIAN M. COLETTI, M.D. ELLIOTT H. LEITMAN, M.D. BHASKAR S. PALEKAR, M.D. ESTELLE H. WHITNEY, M.D. AMA Delegate KELLY S. ESCHBACH, M.D. DELPAC Representative JOSEPH P. OLEKSZYK, D.O. Legislative Chair JOSEPH F. HACKER III, M.D. Young Physicians Section Representative NANCY FAN, M.D. Resident & Fellow Section Representative ROI ALTIT, M.D. EDITORIAL STAFF Editor-in-Chief, Delaware Medical Journal PETER V. ROCCA, M.D. EXECUTIVE STAFF MARK A. MEISTER, SR. – EXECUTIVE DIRECTOR

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193Del Med J, July 2011, Vol 83 No 7

Medical Society of DelawareOfficers and Trustees

2010-2011InsTrucTIOns TO AuThOrs

The Delaware Medical Journal (DMJ) is owned and published by the Medical Society of Delaware as a medium of commu-nication, education, and expression for its members, and also for others striving for excellence in medical practice. Articles in the DMJ are intended to be scientific and educational and are not intended to reflect standards of medical care. All material published is under copyright. On receipt of material submitted for publication, a suitable release form will be sent for signature by all authors.

Scientific articles on medical matters are especially welcomed, including case reports, clinical experiences, observations, and information on matters relevant to medical practice. Other material may also be accepted if the editorial staff deems it of interest to DMJ readers. All submissions should include a brief summary and a brief (one to two sentence) biographical sketch of all authors.

It is highly recommended that authors familiarize themselves with DMJ style before submitting manuscripts for consider-ation.

Material for publication should be submitted on disk or CD in Microsoft Word format, PC compatible. Text-only material (without graphs, charts, or photographs) may also be submit-ted electronically via e-mail. The ideal manuscript length is 750 to 5,000 words with up to 12 references, each keyed with superscripts in the text in the order cited. The format should follow that used in the Index Medicus. Authors are responsible for the accuracy of the citations.

Graphs, charts, and black-and-white glossy photographs are accepted if important to the understanding of the text, but should not exceed five pieces. Original hard copies of each chart, graph, and photograph are required. Electronic copies of each graph, chart or photo should also be submitted. Most graphic formats are acceptable. Photos imbedded in Word documents and Power Point slides are not acceptable.

Photos of patients should generally be taken in a way that obscures the patient’s identity. Photos in which a patient’s face must be clearly seen, however, must be accompanied by signed release forms.

All manuscripts are reviewed by the editor, and all scientific articles are then sent for peer review by members of the Edi-torial Board and/or other appropriate physicians. The usual processing time to publication is two to four months, though in some circumstances this may be longer or shorter.

All materials should be submitted to: Delaware Medical Jour-nal, The Medical Society of Delaware, 900 Prides Crossing, Newark, Delaware 19713 or e-mailed to [email protected].

OFFICERS

DAVID M. BErcAW, M.D. – PRESIDENTrAnDEEP s. KAhLOn, M.D. – PRESIDENT-ELECTsTEPhEn J. KushnEr, D.O. – VICE PRESIDENTKEVIn P. shEAhAn, M.D. – SECRETARYJOsEPh F. hAcKEr III, M.D. – TREASURERrOBErT L. MEcKELnBurG, M.D. – SPEAKER OF THE HOUSEWILLIAM h. DuncAn, M.D. – VICE SPEAKER OF THE HOUSEnIchOLAs O. BIAsOTTO, D.O. – PAST PRESIDENT

TRUSTEES

Kent CountyJACQUELINE J. CHRISTMAN, M.D.

New Castle CountyJOHN DECARLI, D.OKRISTINE B. DIEHL, M.D.JAMES M. GILL, M.D., MPHJOHN J. GOODILL, M.D.DOROTHY M. MOORE, M.D.

Sussex CountyMARK J. BOYTIM, M.D.

Council on Medical SpecialtiesCHRISTOPHER L. BALDI, D.O.CEDRIC T. BARNES, D.O.CHRISTIAN M. COLETTI, M.D.ELLIOTT H. LEITMAN, M.D.BHASKAR S. PALEKAR, M.D.ESTELLE H. WHITNEY, M.D.

AMA DelegateKELLY S. ESCHBACH, M.D.

DELPAC RepresentativeJOSEPH P. OLEKSZYK, D.O.

Legislative ChairJOSEPH F. HACKER III, M.D.

Young Physicians Section RepresentativeNANCY FAN, M.D.

Resident & Fellow Section RepresentativeROI ALTIT, M.D.

EDITORIAL STAFF

Editor-in-Chief, Delaware Medical JournalPETER V. ROCCA, M.D.

EXECUTIVE STAFFMARK A. MEISTER, SR. – EXECUTIVE DIRECTOR

C O N T E N T S

ISSN 0011-7781

DELAWAREMEDICALJOURNALOfficial Publicationof the Medical Society of Delaware

900 Prides CrossingNewark, Delaware 19713

Editor-in-ChiefPeter V. Rocca, M.D.

Editorial Board MembersJoseph A. Lieberman III, M.D., MPHBrian W. Little, M.D., Ph.D.E. Wayne Martz, M.D. (Editor Emeritus)Michael R. Zaragoza, M.D.

Publication andEditorial CommitteeEvan H. Crain, M.D.Andrew J. Doorey, M.D.Steven L. Edell, D.O.Gerard J. Fulda, M.D.Galicano F. Inguito, M.D.Rebecca Jaffe, M.D.Nancy Kim, M.D.James F. Lally, M.D.Joseph A. Lieberman III, M.D., MPHBrian W. Little, M.D., Ph.D.E. Wayne Martz, M.D.Gregory A. Masters, M.D.Hiep C. Nguyen, M.D.Leo W. Raisis, M.D.Peter V. Rocca, M.D.Anthony C. Sciscione, D.O.Udayan K. Shah, M.D.Kevin P. Sheahan, M.D.Sonya N. Tuerff, M.D.Michael R. Zaragoza, M.D.

Former EditorsRobert B. Flinn, M.D. Bernadine Z. Paulshock, M.D.G. Stephen DeCherney, M.D., MPHE. Wayne Martz, M.D.

VOLUME 83 JULY 2011 NUMBER 7

The Delaware Medical Journal (ISSN 0011-7781, USPS 152140) is published monthly by the Medical Society of Delaware at 900 Prides Crossing, Newark, DE 19713. Periodicals postage paid at Newark, Delaware, 19711 and additional entry offices. Copyright 2010 by the Medical Society of Delaware. Indexed in "Hospital Litera-ture Index" and "Index Medicus." Available through University Microfilms. The Delaware Medical Journal does not hold itself responsible for statements made by any contributor or advertiser. Annual subscription rates are $30 for domestic and $45 for overseas. Single copies are $2.50. Advertising copy is accepted, subject to the approval of the Publication and Editorial Committee of the Medical Society of Delaware. For information about advertising, call the Journal office at (302) 366-1400. POSTMASTER: Address changes to 900 Prides Crossing, Newark, DE 19713.

On the Cover: “West Madrid Sky VII” by George Martz, 8 x 8, oil on canvas, Station Gallery, Greenville, Del.

197 PRESIDENT'S PAGE "A Modest Proposal" for Restructuring the Medical Society of Delaware David M. Bercaw, M.D.

201 NATIONAL CANCER INSTITUTE CLINICAL TRIAL OF THE MONTH

203 SCIENTIFIC ARTICLE Methemoglobinemia: A Systematic Review of the Pathophysiology,

Detection and Treatment John Ashurst, D.O. and Megan Wasson, D.O. 211 CASE STUDY Licorice: A Patient's Shocking Presentation Mohammed Kaleel, Vinay Hosmane, M.D., Manish Garg, M.D., FACP, and Wasif A. Qureshi, M.D., FACC, FSCAI 217 NEWSMAKERS

219 OBITUARY

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197

PRESIDENT'S PAGE

“A Modest Proposal” for Restructuring the Medical Society of Delaware

David M. Bercaw, M.D.

MSD President David M. Bercaw, M.D., is Vice Chair of the Christiana Care Health System Department of Family and Com-munity Medicine and practices at the Family Medicine Center in Wilmington, Delaware.

"I profess, in the sincerity of my heart, that I have not the least personal interest in endeavoring to promote this necessary work, having no other motive than the public good of my country."

– Jonathan Swift, A Modest Proposal, 1729

In 2006 and 2007, in response to diminished membership engagement – especially at the county medical society level – the MSD House of Delegates adopted resolutions which established a Task Force to Study Governance & Activities of the County Medical Societies. The Task Force has met several times over these past years and its most recent proposal has now been accepted by the MSD Board of Trustees. It is planned for the proposal to be presented for a vote at the upcoming MSD House of Delegates in October. Acceptance of the Task Force’s proposal would pave the way for the most sweeping overhaul of MSD’s governance structure in its 222-year history. So how did this all come about?

The diminishing level of membership engage-ment in the county medical societies has been evident for years. Fewer members are stepping up into leadership roles, especially in Kent and Sussex Counties. Membership participation in the New Castle County Medical Society, while more robust, has still diminished significantly over the years. Multiple surveys demonstrated that physician members were mostly interested in social events and in continuing medical education. Under Delaware Law, the county societies are no longer permitted to participate in peer review and professional conduct processes, both of which had been duties established for the county medical societies under MSD Bylaws. Despite declining interest, the financial costs and administrative burdens of running the county societies have continued to escalate. It is time for a change.

The proposal from the Task Force would be to eliminate county medical societies as corpo-rate structures with its officers and bylaws. The creation of less formal “districts” throughout the state, without corporate structure, but based upon smaller geographic areas would be developed. Examples of geographic districts could include:

Del Med J, July 2011, Vol 83 No 7

President's Page

l Eastern Sussex Countyl Western Sussex Countyl Milford areal Dover areal Middletown areal Christiana/Newark areal City of Wilmington/North Wilmington

areal Hockessin/Pike Creek area

MSD would assume responsibility for all programming, CME, social events, and other func-tions which were formerly conducted by the county societies. The districts, however, would serve as smaller, more cohesive member groupings which should result in improved member recruitment, leadership development, and grassroots engage-ment. Local leaders within each district would be identified to advise MSD on member engagement, leadership development, and advocacy issues.

Such sweeping changes can be accompanied by a more efficient and streamlined MSD gover-nance in order to more effectively represent the needs of the membership [refer to charts on the next page]. The House of Delegates (which meets once each year and is currently comprised of 378 Delegates and Alternate Delegates) would be re-placed by a Council (approximately 60 members who would meet at least twice yearly). Proposed members of the Council would include: l Members of the Executive Board, (15)

comprised of:s Officers (6)s AMA Representative (1)

166

s MSD Section Representatives (3)s At-Large Representatives (4)s Legislative Committee Representative

(1)l District Representatives (approximately 16

to 18 – two from each district)l Specialty societies (approximately 25 – one

from each American Board of Medical Special-ties-recognized organization in Delaware)

l Practice type (8)

Having been involved in MSD leadership throughout the entire tenure of the Task Force, I have witnessed the process unfold and have taken part in the debates and deliberations of such a sweeping proposal. With tongue in cheek and a nod to Jonathan Swift, I fully support the “cannibalization” of the current county medical society system and the revamping, streamlining, and modernization of our entire MSD governance structure.

The MSD website, www.medicalsocietyofdel-aware.org homepage contains a link to the full report: “A Proposal for Reorganizing the County Medical Society Structure and MSD Governance Structure.” Feel free to respond to MSD leadership via the link within the proposal. We look forward to hearing your thoughts.

David M. Bercaw, M.D.President, Medical Society of Delaware

Del Med J, July 2011, Vol 83 No 7

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199

Del Med J, July 2011, Vol 83 No 7

NATIONAL CANCER INSTITUTE CLINICAL TRIAL OF THE MONTH

CTSU S0777: A Randomized Phase III Trial of CC-5-13 (lenalidomide, NSD-

703813) and Low Dose Dexamethasone (LLD) versus Bortezomib (PS-341, NSC-681239), Lenalidomide, and Low Dose Dexametha-sone (BLLD) for Induction, in Patients with Previously Untreated Multiple Myeloma without Intent for Immediate Autologous Stem Cell Transplant

The Objectives of the Trial are:Primary Objective:

• The primary objective of this study is to compare progression-free survival (PFS) in patients with newly diagnosed myeloma treated with lenalidomide plus low dose dexamethasone versus bortezomib plus lenalidomide and low dose dexamethasone.

Secondary Objectives:• Assess response using the new international response criteria.• To bank specimens for future translational medicine research.• Follow patients to assess overall survival and other long-term outcomes stratified by intent to

transplant at progression.

Eligibility:• Patients must have newly diagnosed multiple myeloma.• Patients must have received no prior chemotherapy for this disease.• Patients must have a Performance Status of 0 – 3.

Treatment:Arm 1 – LLD: 6 cycles, each 28 days Dexamethasone 40 mg/day PO days 1, 8, 15, 22 Lenalidomide 25 mg/day PO Daily at bedtime; days 1-21 Aspirin 325 mg/day PO Continuous

Arm 2 – BLLD: 8 cycles each 21 days Dexamethasone 20 mg/day PO days 1, 2, 4, 5, 8, 9, 11, 12 Lenalidomide 25 mg/day PO Daily at bedtime; days 1-14 Bortezomib 1.3 mg/m2 IVP days 1, 4, 8, 11 Aspirin 325 mg/day PO Continuous

HSV prophylaxis per institutional standard.

For information regarding this clinical trial or if you would like to have the list of open protocols e-mailed to you,

please call the Cancer Research Office at (302) 623-4450 or e-mail [email protected].

201

Del Med J, July 2011, Vol 83 No 7

Scientific Article

Abstract

Methemoglobin is the oxidized form of hemoglobin which does not bind to oxygen efficiently. An increased level of methemo-globin can be attributed to congenital enzymatic defects, alterations in the hemoglobin molecule, or as a result of medica-tions and toxins. The main clinical characteristic of the disease include cyanosis which is unresponsive to oxygen therapy and blood that is chocolate color when drawn. Co-oximetry is the gold standard for diagnosis but arterial blood gas paired with pulse oximetry and serum methemoglobin levels can confirm the diagnosis clinically. Treatment is aimed at removal of the offending agent, if medication induced, and is directed at aggressive oxygen therapy and treatment with the antidote, methylene blue.

Key words: Hypoxia, Congenital Methemoglobinemia, Drug-Induced Methemoglobinemia, Methylene Blue

1. John Ashurst, D.O. is an Emergency Physician at Lehigh Valley Health Network in Allentown, Penn.

2. Megan Wasson, D.O. is a Resident in the Department of Obstetrics and Gynecology at Christiana Care Health System in Wilmington, Del.

203

SCIENTIFIC ARTICLE

Methemoglobinemia: A Systematic Review of thePathophysiology, Detection, and Treatment

John Ashurst, D.O.1 and Megan Wasson, D.O.2

INTRODUCTION

Methemoglobinemia is a clinical syndrome caused by either an increase of methemoglobin in the blood due to congenital changes in hemoglobin synthesis and metabolism or an acute adverse drug reaction. Methemoglobin is an oxidized form of hemoglobin in which the original ferrous atom is oxidized to a ferric atom. The ferric atom then causes an allosteric change in the heme portion of the oxidized hemoglobin molecule causing an increase in its oxygen affinity but a functional decrease in its oxygen binding capacity.1 Physi-ologically, the newly formed methemoglobin shifts the oxygen dissociation curve of the oxidized he-moglobin to the left which hinders the release of oxygen in tissue.1 Not only is the tissue hypoxia due to a leftward shift of the oxygen saturation curve but can also be related to the reduction of free hemoglobin to transport oxygen to the tis-sues (a relative anemia).1 Clinically these two

mechanisms will produce central cyanosis which is unresponsive to oxygen therapy.1

The prevalence of the syndrome is difficult to determine due to the mild nature of many cases but must be within the differential of any patient with preoperative cyanosis, beginning a new medication, and any child living in an agricultural region. In this article, the pathophysiology, diag-nosis, and management of hereditary and acquired methemoglobinemia will be discussed.

GENETIC DEFECT

Hereditary methemoglobinemia is a reces-sively inherited disorder which is attributed to the deficiency of the enzyme nicotinamide adenine dinucleotide (NADH) cytochrome b5 reductase.1-5 Erythrocytes convert harmful methemoglobin into useful hemoglobin through their inherent cytochrome b5 reccutase pathway.1-5 However, the gene regulating the synthesis of NADH cytochrome b5 reductase has been localized to chromosome 22q13qter which has been noted to be involved in over 40 genetic mutations.1-5 Due to these mutations, hereditary methemoglobinemia

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has been classified into two subtypes, erythrocyte (type I) and generalized (type II).1-5

In the type I form, only mature erythrocytes are affected due to a deficiency of the soluble form of the enzyme.1-5 Currently, type I is found worldwide but has been noted to be endemic in several population groups including the Atha-basca and Navajo Native Americans in the United States and the Yakutusk in Siberia. Homozygous individuals present with a methemoglobin level varying between 10 percent and 35 percent.1 Due to the relatively low levels of methemoglo-bin present in the blood, patients present with central cyanosis and polycythemia while other symptoms of methemoglobinemia present only when the percentage exceeds 50 percent.1-5 Cur-rently, the life expectancy of these individuals is not lower than the general population and potential pregnancies have not been complicated due to the disorder.1

Patients with the heterozygous form of hereditary type I methemoglobinemia typically have a cytochrome b5 reductase deficiency of approximately 50 percent as compared to the general population.1,5 Although there is an altered level of activity of the enzyme, it is sufficient in maintaining methemoglobin levels around one percent.1,5 However, conditions in which the body is placed under significant oxidative stress may induce an attack of acute or chronic methemoglobinemia.

Hereditary type II methemoglobinemia is classified as a deficiency of the membrane bound form of cytochrome b5 reductase. Research has shown that type II methemoglobinemia occurs in all tissue types (including fibroblasts, lympho-cytes, and cells from the central nervous system) because the enzyme deficiency is located in the outer mitochondrial membrane and the endoplas-mic reticulum of all somatic cells.1-5 Currently type II is sporadic worldwide and presents with severe mental retardation, neurological impair-ment, and developmental abnormalities.1-5 Due to the severe nature of the neurological impair-ment which is unresponsive to methylene blue therapy, the life expectancy of the patients is severely diminished.1-5

Although two types of hereditary methemo-globinemia have been attributed to an enzyme defect, a third subtype has been distinguished

as hemoglobin M and is attributed to abnormal variants of the hemoglobin molecule.1,6-8 In the majority of the cases, tyrosine replaces either the proximal or distal histidine in the alpha or beta chain of hemoglobin causing the formation of an iron-phenolate complex.1,6 This aberrant complex results in a diminished capacity of reducing the ferric form of iron into its divalent form of ferrous, ultimately leading to methemoglobinemia.1,6-8

Those patients affected with the alpha chain deficiency present with cyanosis at birth while those with the aberrant beta chain present with cyanosis later in life due to the conversion of fetal hemoglobin to adult hemoglobin.1,6-8 Hemoglobin M is inherited autosomal dominantly and does not affect the life expectancy of the affected individual.1

DRUG INDUCED

Although several congenital forms of meth-emoglobinemia have been established, by far the most common cause is due to an acute drug reaction (Table 1).1,8-20 Over the years, numerous case reports have established that either the ingestion of or the exposure to skin and or mu-cous membranes can lead to an adverse reaction which causes methemoglobinemia.1,8-20 Most of the medications directly oxidize hemoglobin to methemoglobin, while others indirectly oxidize hemoglobin to methemoglobin by reducing free oxygen to a superoxide free radical.1,8-20

A major predisposition to the acquisition of drug induced methemoglobinemia would be the concurrent use of a hemoglobin oxidizing medica-tion and having glucose 6 phosphate dehydroge-nase (G6PD) deficiency. The nicotinamide adenine dinucleotide phosphate (NADPH) pathway, a second enzymatic system which reduces meth-emoglobin to hemoglobin, is directly dependent on both the activity of glutlathione and glucose-6-phosphate dehydronease.17,21 However in those with a deficiency of G6PD, inherent levels of methemoglobin can not be efficiently reduced and an additive effect will be seen in the presence of increased hemoglobin oxidation.17,21

A second population group which must be closely monitored when given hemoglobin oxidiz-ing agents would be those with liver cirrhosis.22

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Acetanilid Alloxan Aniline Arsine Benzene derivatives Benzocaine Bivalent copper Bismuth subnitrate Bupivacaine hydrochloride Chlorates Chloroquine Chromates Clofazimine Dapsone Dimethyl sulfoxide Dinitrophenol Exhaust fumes Ferricyanide Flutamide Hydroxylamine Lidocaine hydrochloride Metoclopramide hydrochloride Methylene blue Naphthalene Nitrates Nitric oxide Nitrites Nitrofuran Nitroglycerin Sodium nitroprusside Paraquat Phenacetin Phenazopyridine hydrochloride Phenol Phenytoin Prilocaine hydrochloride Primaquine phosphate Rifampin Silver nitrate Sodium valproate Sulfasalazine Sulfonamides Trinitrotoluene

Table 1: Drugs and toxins that can cause methemoglobinemia

The red blood cells in those with cirrhosis are already under severe oxidative stress, especially in those where bleed-ing complications have arisen.22

Due to this, any increase in

oxidative stress may lead to methemoglobinemia.22

Although patients with ac-quired methemoglobinemia due to toxin exposure can be severely ill when diagnosed, with appro-priate treatment a full recovery is possible. Strict outpatient follow-up is recommended for those with acquired methemo-globinemia upon discharge from the hospital to ensure no recur-rence of the disease process.

CLINICAL MANIFESTATIONS

The clinical manifestations of methemoglobinemia are di-rectly related to the reduction in oxygen carrying capacity of hemoglobin which leads to hypoxia.1,8-12 Although the physi-ologic levels of methemoglobin range between 1-2 percent, when concentrations reach 10-15 percent central cyanosis is noted as well as a general grayish color of the skin.1,12-16 As levels reach 30 - 40 percent neurologic and cardiovascular symptoms are noted (headache, fatigue, tachycardia, weakness, and dizziness).1,14-20 Levels of 60 percent typically result in leth-argy, convulsions, and coma.1,8-20

Some research has shown that the lethal level of methemoglobin is 70 percent, but survival has been reported when the meth-emoglobin concentration has reached 81 percent.1,8-20

However, many patients with lifelong methemoglobine-mia are usually asymptomatic at relatively high levels. Although these patients can withstand these levels, patients exposed to drugs and toxins who abruptly develop the same concentra-

tion of methemoglobin may be severely symptomatic. Due to this, it has been proposed that not only the amount of meth-emoglobin in the blood but also the rapidity of methemoglobin formation will lead to a patient’s symptoms.1,8-20

A higher level of suspicion must be used when a patient has a co-morbidity. Patients with glucose 6 phosphate de-hydrogenase deficiency have an increased risk of oxidation of hemoglobin to methemoglo-bin.21,23 Also, a form of idiopathic methemoglobinemia can occur in association with systemic aci-dosis in infants.24,25 Typically, this will occur in the first six months of life and is associated with dehydration and diar-rhea.24,25 The disease process is exacerbated by the lower levels of functioning methemoglobin reductase enzyme found in infant’s blood.24,25

DIAGNOSIS ANDMONITORING

Methemoglobinemia should be suspected in patients with central cyanosis and low oxygen saturations which are unre-sponsive to oxygen therapy.1,9-20 Currently in the clinical setting, arterial blood gas analysis paired with oxygen saturation by pulse oximitry and serum methemoblin levels are now considered the definitive mea-sures to make a diagnosis.1,9-20 However in an emergency set-ting, the presence of chocolate brown blood that does not turn red when exposed to atmo-spheric oxygen and a positive family history is indicative of methemoglobinemia.1,9-20,26

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Typically in methemoglobinemia, arterial blood gas (ABG) will reveal a normal to elevated PO2 with low oxyhemoglobin saturation.1,9-20 Al-though arterial blood gasses (ABGs) are used in aiding in the diagnosis, new research has shown that ABGs should not be the sole diagnostic tool to assess the oxygen carrying capacity of meth-emoglobinemia.26,27 Currently, the conventional analyzers used for ABGs use a mathematical relationship for determining the value of he-moglobin saturation which is based solely upon the standard hemoglobin dissociation curve.26,27 Thus, in critically ill individuals or those with congenital methemoglobinemia the parameters that the machine sets will inaccurately measure the amount of saturated hemoglobin.26,27

A low oxyhemoglobin detected by pulse oximetry can be pathognomonic for methemoglo-binemia. Although pulse oximetry is one crucial tool in the diagnosis, it may also overestimate the true amount of saturated hemoglobin in the blood.7,8 A pulse oximeter is based on the fact that light absorption of both saturated hemo-globin and reduced hemoglobin will occur at the wavelengths of 660 nm and 940 nm.1,7,8,20,26,28-30 At these wave lengths, red and infrared light is absorbed in a 1-to-1 ratio.7 However, meth-emoglobin has two distinct peaks of absorption which lie at 630 nm and 960 nm.1,7,8,20,26,28-30 Due to the increasing levels of methemoglobin in the blood, the pulse oximeter will be insensitive to hypoxemia and would overestimate the degree of oxygen saturation. Further research has shown that when methemoglobin levels reach 30 percent or greater, oxygen saturation detected by a pulse oximeter would plateau at 85 percent and would be unchanged with oxygen therapy.7,8,20,26,28-30

Although in a clinical setting arterial blood gas paired with pulse oximetry and a serum methemoglobin level will aid in the diagnosis of methemoglobinemia, in the research setting several other means for detection exist.20,26,28-30 The definitive means for detecting methemoglobin-emia is by the use of a pulse co-oximeter. A pulse co-oxemeter is an oversimplified spectrophotom-eter that measures the light absorbance of four different wavelengths in the blood.20,26,28-30 Due to the increased differentiation of wave lengths, a co-oximeter can distinctly measure the levels of hemoglobin, carboxyhemoglobin, oxyhemoglobin and methemoglobin in the blood.20,26,28-30 Further-

more, the newer versions of co-oximeters can also detect sulfhemoglobin.20,26,28-30 However, due to the cost of these machines very few laboratories currently have them in use. Unfortunately, the presence of lipemic specimens and methylene blue in the blood will lead to elevated levels of methemoglobin.20,26,28-30 Thus, this method is not a reliable tool for following the trend of methem-globin in a treated patient.20,26,28-30

In those patients where sulfhemoglobin of the blood is suspected, the potassium cyanide test may aid in the diagnosis of methemoglobinemia.1,26,31 The methemoglobin in the blood will react with the cyanide to form cyanomethemoglobin.1,26,31 When a drop of this blood is placed on a swatch of white paper it will appear bright red.1,26,31 However, since sulfhemoglobin does not react with cyanide, there would be no change in color.1,26,31

TREATMENT

Currently there is no cure for hereditary meth-emoglobinemia and these patients should avoid oxidizing medications at all costs.1-5 However, treatment can be aimed at the cosmetic defects (blue skin) of the disorder. It has been shown that 300 to 600 mg of ascorbic acid given three times a day orally is helpful in diminishing skin dis-coloration.2,3 Unfortunately, long term high dose management with ascorbic acid may result in the formation of sodium oxalate kidney stones.32

Treatment of patients with drug induced methemoglobinemia should be guided by the severity of the symptoms initially. Secondly, treat-ment should be aimed at decreasing the amount of methemoglobin found in the blood.

When the patient’s symptomology is mild, treatment consists of removal of the offending agent as well as administration of high flow oxygen, observation, and serial evaluation with a co-oximeter.1,8-20 Typically, after removing the offending agent for 36 hours, the patient’s meth-emoglobin level will return to baseline. Research has shown that hyperoxic pulmonary ventilation can further accelerate the degradation of meth-emoglobin concentrations in those exposed to a lethal toxic ingestion.33

When significant symptoms (dizziness, confusion, seizure, somnolence, headache etc.) are present methelyene blue in association

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with the aforementioned treatments should be conducted.1,8-20 Methylene blue is a thiazine dye which possesses dose-dependent antiseptic and oxidizing properties.1,8-20,34 Intravenously, methyl-ene blue is oxidized into leukomethylene blue by accepting an electron from NADPH in the pres-ence of NADPH-methemoglobin reductase.1,8-20,34

Leukomethylene blue then acts as an artificial electron acceptor to methemoglobin resulting in its conversion back to hemoglobin.1,8-21,34

The methylene blue dose is 1-2 mg/kg admin-istered as a 1 percent solution over a five minute interval and should not exceed 7 mg/kg, because this agent in itself can be toxic and cause dyspnea, chest pain, and hemolysis.1,9-20 This dose may be repeated again at 1 mg/kg every 30 minutes as necessary. 9-20 However, additional studies have shown that supplementing the methylene blue with activated charcoal will result in a lower dose of methylene blue being required to trigger a reversal of methemoglobinemia symptoms.36

Furthermore, IV dextrose should be given in conjunction with methylene blue.1,20 Dextrose is necessary to form NADPH through the hexose monophosphate shunt, which is crucial for meth-ylene blue to be effective.1,20

Additionally, patients who have G6PD deficiency will not respond to methylene blue therapy.1,20 Patients with G6PD deficiency will not produce sufficient NADPH to reduce methylene blue to leukomethylene blue in the blood.1,20 Due to this, the relatively large doses of methylene blue used in treatment may result in higher lev-els of methylene blue rather than the oxidized leukomethylene blue. This then will result in hemolysis and a paradoxical methemoglobinemia in these patients.1,20 Current research has shown that the electron acceptor N-acetyl-cysteine can be used in these cases.1,35

Moreover, methylene blue therapy has not been FDA approved for the use in the pediatric population. Due to this, infants with idiopathic methemoglobinemia caused by metabolic acido-sis should be treated with intravenous hydra-tion and bicarbonate to reverse the acidosis.24,25 Furthermore, intravenous hydration should be accomplished by the use of 5 percent dextrose in water due to the increased need of NADPH for methemoglobin to be cleared.24,25 New research has also shown that methylene blue given in-traosseously will effectively lower the amount of

methemoglobin in the blood.37 For those who fail original therapy with

methylene blue or those who are severely symp-tomatic, exchange transfusion or hyperbaric oxygen therapy may be considered.1,38 Hyperbaric oxygen therapy will increase the amount of dis-solved oxygen in the blood and will also bring the amount of carbon dioxide to the minimal limit that still allows metabolism to occur.33 Therefore, with hyperbaric oxygen therapy one can maintain oxygenation until exchange transfusion can be assembled.

Further experimental research has shown that the use of cimetdine and ketoconazole can be used in the long-term management of decreasing methemoglobin levels in those with an enzyme deficiency or those who need to be on oxidizing medications for long term management of chronic illnesses.39,40

CONCLUSION

Currently, methemoglobinemia is a syndrome with many unknowns. Prevalence, modes of diagnosis, treatments, and many of the causes have yet to been discovered. However, a high clinical suspicion must be maintained in all cases of severe cyanosis which is unresponsive to ag-gressive oxygen therapy. Once the diagnosis is made, aggressive treatment with methlyene blue should be initiated, as well as clinical observation of a downward trend of methemoglobin levels in the blood.

REFERENCES

1. Rehman HU. Methemoglobinemia: Evidence based case review. West J Med. 2001;175:193-196.

2. Percy M, Gillespie M, Savage G, Hughes A, McMullin M, Lappin T. Familial idiopathic methemoglobinemia revisited: Original cases reveal 2 novel mutations in NADH – cytochrome b5 reductase. Blood. 2002;100: 3447-3449.

3. Ewenczyk C, Leroux A, Roubergue A, et al. Recessive hereditary methaemoglobinaemia, type II: Delineation of the clinical spectrum. Brain. 2008;131:760-761.

4. Percy M, Lappin T. Recessive congenital methaemo-globinaemia: Cytochrome b5 reductase deficiency. Br J Haematol. 2008;141:298-308.

5. Dekker J, Eppink M, van Zwieten R, et al. Seven new mutations in the nicotinamide adenine dinculeotide reduced cytochrome b5 reductase gene leading to meth-

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emoglobinemia type I. Blood. 2001;97:1106-1114.6. America A, Fairbanks V, Yanik G, et al. Identification of

the molecular genetic defect of patients with methemo-globin M-Kankakee (M-Iwate), alpha 87 (F8) His →Tyr: Evidence for an electrostatic model of alpha M hemoglobin assembly. Blood. 1999;94:1825-1826.

7. Stucke A, Riess M, Connolly L. Hemoglobin M (Mil-waukee) affects arterial oxygen saturation and makes pulse oximetry unreliable. Anesthesiology. 2006;104: 887-888.

8. Da-Silva S, Sajan I, Underwood J. Congenital Methemo-globinemia: A rare cause of cyanosis in the newborn – A case report. Pediatrics. 2003;112:158-161.

9. Turner M, Karlis V, Glickman R. The recognition, physiology, and treatment of medication-induced meth-emoglobinemia: A case report. Anesth Prog. 2007;54: 115-117.

10. Sener O, Doganci L, Safali M, Besibellioglu B, Bulucu F, Pahsa A. Severe dapsone hypersensitivity syndrome: A case report. J Investig Allergol Clin Immunol. 2006;16: 268-270.

11. Mayo W, Leighton K, Robertson B, Ruedy J. Intraoperative cyanosis: A case of dapsone induced methemoglobinemia. Can J Anaesth. 1987;34:79-82.

12. Hansen D, Challoner K, Smith D. Dapsone intoxication: two case reports. J Emerg Med. 1994;12:347-351.

13. Falkenhahn M, Kannan S, O’Kane M. Unexplained acute severe methaemoglobinaemia in a young adult. Br J Anaesth. 2001;87:802-803.

14. Bayard M, Farrow J, Tudiver F. Acute methemoglobin-emia after endoscopy. J Am Board Fam Pract. 2004;17: 227-229.

15. Birchem S. Benzocaine induced methemoglobinemia dur-ing transesophageal echocardriography. J Am Osteopath Assoc. 2005;105:381-384.

16. Ash-Bernal R, Wise R, Wright S. Acquired Methemo-globinemia: A retrospective series of 138 cases at two teaching hospitals. Medicine (Baltimore). 2004;83:265 -273.

17. Hall D, Moses M, Weaver J, Yanich J, Voyles J, Reed D. Dental anesthesia management of methemoglobinemia-susceptible patients: A case report and review of literature. Anesth Prog. 2004;51:24-27.

18. Wilburn-Goo D, Lloyd L. When patients become cyanotic: Acquired methemoglobinemia. J Am Dent Assoc. 1999; 130:826-831.

19. Ashurst J, Wasson M, Hauger W, Fritz W. Pathopysiologic mechanisms, diagnosis and management of dapsone-induced methemoglobinemia. J Am Osteopath Assoc. 2010;10:19-20.

20. Abu-Laban R, Zed P, Purssell R, Evans K. Severe meth-emoglobinemia from topical anesthetic spray: A case report, discussion and qualitative systematic review. Can J Emerg Med. 2001;3:51-56.

21. Jaffe E. The reduction of methemoglobin in erythrocytes of a patient with congenital methemoglobinemia, subjects with erthryocyte glucose 6 phosphate dehydrogenase deficiency and normal individuals. Blood. 1963;21:561- 572.

22. Geetha A, Lakshmi Priya MD, Jeyachristy SA, Surendran R. Level of oxidative stress in the red blood cells of patients with liver cirrhosis. Indian J Med Res. 2007;126:204-210.

23. Swissa M, Shaked Y, Garty M. Severe methemoglobin-emia and syncope in a patient with glucose 6 phosphate dehydrogenase deficiency. Isr Med Assoc J. 2007;9:684-685.

24. Hanukoglu A and Danon P. Endogenous methemoglo-binemia associated with diarrheal disease in infancy. J Pediatr Gastroenterol Nutr. 1996;23: 1-7.

25. Jolly G, Monico E, McDevitt B. Methemoglobinemia in an infant: A case report and review of the literature. Pediatr Emerg Care. 1995;11:294-297.

26. Haymond S, Cariappa R, Eby C, Scott M. Laboratory assessment of oxygenation in methemoglobinemia. Clin Chem. 2005;112:158-161.

27. Salyer J, Chatburn R, Dolcini D. Measures vs. calculated oxygen saturation in a population of pediatric intensive care patients. Respir Care. 1989;34:342-348.

28. Tremper K, Barker S. Pulse oximetry. Anesthesiology. 1989;70:98-108.

29. Koning M, Dolinski S. A 74-year-old woman with desatu-ration following surgery: Co-Oximetry is the first step in making the diagnosis of dyshemoglobinemia. Chest. 2003;123:613-616.

30. Barker S, Curry J, Redford D, Morgan S. Measurement of carboxyhemoglobin and methemoglobin by pulse oxi-metry: A human volunteer study. Anesthesiology. 2006: 105;892-897.

31. Noor M, Beutler E. Acquired sulfhemoglobinemia: An underreported diagnosis? West J Med. 1998;169:386- 389.

32. Massey L, Liebman M, Kynast-Gales S. Ascorbate in-creases human oxaluria and kidney stone risk. J Nutr. 2005;135:1673-1677.

33. Lindenmann J, Matzi V, Kaufmann P, Krisper P, Maier A, Porubsky C, Smolle-Juettner F. Hyperbaric oxygen-ation in the treatment of life-threatening isobutyl nitrite induced methemoglobinemia: A case report. Inhal Toxicol. 2006;18:1047-1049.

34. Metz E, Balcerzak S, Sagone A. Mechanisms of methylene blue stimulation of the hexose monophosphate shunt in erythrocytes. J Clin Invest. 1976;58:797-802.

35. Liu X, Spolarics Z. Methemoglobin is a potent activator of endothelial cells by stimulating IL-6 and IL-8 prodcution and E-selectin membrane expression. Am J Physiol Cell Physiol. 2003;285:1036-1046.

36. Chung S, Hwant T, Choi S, Kim S, Lee H. Acute dapsone intoxication: The dosage of activated charcoal and meth-ylene blue. J Korean Soc Emerg Med. 1997;8:277-282.

37. Herman M, Chyka P, Butler A, Rieger S. Methylene blue by intraosseous infusion for methemoglobinemia. Ann Emerg Med. 1999;33:111-113.

38. Bhat P, Sisler I, Collier A. Exchange transfusion as treat-ment for rasburicase induced methemoglobinemia in a glucose 6 phosphate dehydrogenase deficient patient. Pediatr Blood Cancer. 2008;51:568.

39. Coleman M, Rhodes L, Scott A, et al. The use of cimetidine to reduce dapsone-dependent methemoglobinemia in dermatitis herpetiformis patients. Br J Clin Pharmacol. 1992;34:244-249.

40. Tingle M, Coleman M, Park B. An investigation of the role of metabolism in dapsone induced methaemoglobinemia using a two compartment in vitro test system. Br J Clin Pharmacol. 1990;30:829 -838.

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1. Mohammed Kaleel, MSIV is a graduate of Saba University School of Medicine and is entering residency at Hartford Hospital, Hartford, Conn.

2. Vinay Hosmane, M.D., is Board Certified in Internal Medicine, Cardiology, and Echocardiography and practices with Alfieri Cardiology in Newark, Del.

3. Manish Garg, M.D., FACP is Board Certified in Nephrology and Internal Medicine and is Managing Partner of Neephrol-ogy Consultants in Wilmington, Del.

4. Wasif A. Qureshi, M.D., FACC, FSCAI is the Associate medi-cal Director of the Cardiac Catheterization Lab at Christiana Care Health System in Newark, Del. and is an Interventional Cardiologist and Peripheral Endovascular Specialist for Delaware Cardiovascular Associates in Wilmington, Del.

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CASE STUDY

Licorice: A Patient’s Shocking Presentation Mohammed Kaleel, MSIV,1 Vinay Hosmane, M.D.,2 Manish Garg, M.D., FACP3

and Wasif A. Qureshi, M.D., FACC, FSCAI4

Chronic licorice ingestion is a known, albeit rare, cause of pseudoaldosteronism. Pseudoal-dosteronism should be suspected in patients presenting with alkalosis and uncorrectable hypokalemia, particularly when a low plasma aldosterone level can distinguish the syndrome from primary aldosteronism. History and physi-cal should be thorough enough to evaluate for all possible etiologies, including licorice ingestion.

CASE REPORT

A 38-year old male presented to the Emer-gency Department after his Automatic Implant-able Cardioverter Defibrillator (AICD) began firing the previous night, where it was found to have a delivered a total of six shocks. His signifi-cant past medical history included nonischemic cardiomyopathy with a left ventricular ejection fraction of 10 to 15 percent and Congestive Heart Failure (CHF) stage 3. He also had a past his-tory of anoxic encephalopathy due to pulseless electrical activity several years prior, for which he received his AICD placement.

On presentation, he was found to have a serum potassium of 2.1 and was found to be alkalotic. He had no prior history of electrolyte abnormali-ties or alkalosis. He was also noted to be severely dehydrated, with a Blood Urea Nitrogen (BUN) of 103 and creatinine of 2.7. His current medications included the loop diuretic Bumetanide. Therefore,

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diuretic overdose was suspected as the most likely etiology of his hypokalemia. He was given 4g IV of Potassium and Magnesium. His AICD continued to deliver several more shocks, due to ventricular fibrillation, by the time he was admitted to the ICU. Repeat labs in the ICU showed a potassium level of 2.3. He was further given 40 mEq of both K-Dur and K-Phos per oral. Further lab studies overnight still showed no improvement and he was further dosed with 200 mEq of K-Dur per oral. Several hours later, his potassium had improved marginally to 2.6. Nephrology was consulted and a history was elucidated of recent, heavy licorice ingestion.

His potassium levels that night were finally found to be elevated at an acceptable value of 4.0. As the effects of his licorice ingestion began to wear off and his potassium levels stabilized, no further treatment was necessary. He was then strongly advised to avoid further licorice ingestion.

DISCUSSION

Mineralocorticoid excess can be caused by a wide range of different diseases that present with

similar findings. These diseases include primary and secondary hyperaldosteronism, apparent mineralocorticoid excess syndrome, ectopic ACTH syndrome, licorice ingestion, carbenoloxone treatment, and, rarely, Liddle syndrome. The primary findings in these patients are hyper-tension, hypokalemia, and metabolic alkalosis. As treatment varies significantly based on the underlying disease, it is important to work-up patients presenting with these symptoms.

When evaluating the underlying etiology, plasma renin activity and plasma aldosterone levels are useful initial tests to help differentiate the various causes (Figure 1). When aldosterone is elevated, the cause can be narrowed down to primary or secondary hyperaldosteronism. These two causes can be further differentiated from each other by renin levels. In the presence of elevated aldosterone, low renin levels indicate primary hyperaldosteronism and high levels indicate secondary hyperaldosteronism. Furthermore, when aldosterone and renin levels are both low, the other mineralocorticoid excess syndromes are suspected.

Mineralocorticoid excess syndromes share in common an increased urinary cortisol to

Ectopic ACTHSyndrome

CarbenoloxoneIngestion

AME Syndrome

Primary Adlosteronism Increased UrinaryCortisol:Cortisone Ratio

SecondaryHyperaldosteronism

Renin: LowAldosterone: High

Renin: LowAldosterone: Low

Renin: HighAldosterone: High

Plasma Renin Activity andPlasma Aldosterone

Hypertension, Hypokalemia,Metabolic Alkalosis

Licorice Ingestion

Figure 1. Evaluating a Patient with hypertension, Kypokalemia, and Metabolic Alkalosis

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cortisone ratio. In normal subjects, this ratio is between 0.3 to 0.5, as most of the physiologically active cortisol is converted to inactive cortisone by 11-beta-hydroxysteroid dehydrogenase type 2 (11-beta-HSD2).1 Thus, there is typically a higher urine concentration of inactive cortisone than there is of cortisol. However, when the enzyme 11-beta-HSD2 is not functioning, physiologi-cally active cortisol remains unconverted. Active cortisol is then able to bind to mineralocorticoid receptors with the same affinity as aldosterone, causing a similar phenotypic presentation to hyperaldosteronism. Moreover, the inability to convert cortisol to cortisone results in a higher urinary cortisol to cortisone ratio.2

Apparent mineralocorticoid excess (AME) syndrome is a congenital deficiency of 11-beta-HSD2 that is oftentimes transmitted as an autosomal recessive trait. Due to the congenital deficiency of this enzyme, patients suffering from AME syndrome often present with juvenile hypertension.3 Ectopic ACTH syndrome results in the production of excess cortisol and leads to mineralocorticoid excess through two suggested mechanisms. The excess cortisol can result in mineralocorticoid excess by either exceeding the metabolic capacity of 11-beta-HSD2 or by actu-ally inhibiting the enzyme with high circulating levels of cortisol.4, 5 Licorice and carbenoloxone exert their mineralocorticoid effects by acting to inhibit 11-beta-HSD2.

Licorice has been used for over a millennium as an herbal supplement, a natural sweetener, and as a mouth freshener. Earlier this century, it was found to have some beneficial effects in treating duodenal ulcers by Revers et al. This led to the formulation of the drug carbenoloxone, which is a synthetic derivative of licorice’s active ingredient. In 1946, Revers first documented the adverse mineralocorticoid effects of licorice inges-tion during the treatment of his patients.6 These effects have been strongly documented as common adverse effects of carbenoloxone, a drug currently licensed for use in the UK and Europe.2

Licorice contains a compound called glycyr-rhizin (GL), responsible for the sweet taste, that is metabolized to the steroid glycyrrhetinic acid (GA) by Beta-D-glucoronidase.7 GA then acts to competitively inhibit 11-beta-HSD2 and reduce its gene expression.8 This results in the hyper-

mineralocorticoid state observed with licorice ingestion, as 11-beta-HSD2 is no longer available to convert circulating cortisol.

While there is still speculation over which patients are more at risk than others for being susceptible to adverse effects, a few documented trials on licorice gives us a general consensus on its effects on normal subjects. The most popular study, performed in 1977 by Epstein et al, evalu-ated the effects of 100g to 200g of licorice daily on healthy subjects.9 The subjects were followed for one to four weeks and were observed for variations in blood pressure, body weight, plasma renin activity, aldosterone, angiotensin II, and electrolytes. The study was prematurely stopped in 43 percent of the patients because of adverse effects of hypokalemia and edema. Another 28 percent developed transient generalized edema but continued the study. All of his subjects showed signs of significant mineralocorticoidism in the forms of hypokalemia, sodium retention, and weight gain. The study demonstrated the consid-erable effects in healthy subjects of consuming a relatively small amount of 100 to 200g/day, in the form of just two or four confectionery twists respectively.

A study on licorice and GA by Van Gelderen et al in 2000 attempted to find a safe level of GA consumption at which no adverse effects were produced.10 Healthy female volunteers were selected to consume 0, 1, 2, and 4 mg of GA per kg of body weight for 12 weeks. It was found that effects were observed in patients receiving 4mg/kg but were essentially absent in patients receiving 2mg/kg or less daily, which led to his conclusion that 2mg/kg could be established as the safe daily level of consumption.

It has more recently been demonstrated that there is a direct linear dose-response relationship with licorice-induced rises in blood pressure. This was demonstrated in a 2001 study by Sigurjons-dottir et al.11 Once again, healthy subjects were selected and they consumed between 50 and 200 g/day for two to four weeks. The study found a systolic blood pressure increase of 3.1 to 14.4 mmHg with a strong dose-response relationship. The response was evident with doses as low as 50 g/day, with maximal effects observed after only two weeks of consumption. This study highlighted both the strength of the dose-response relation-

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ship as well as the acuity of the response with relatively low levels of daily consumption.

In an effort to discover a susceptibility factor for some patients to have more severe adverse ef-fects than others with similar amounts of licorice consumption, a recent 2010 study by Miettinen et al studied 30 volunteers with documented licorice-induced hypertension.12 The objective of the study was to determine whether these patients suffering adverse effects from licorice ingestion had any variations of the gene encod-ing 11-beta-HSD2, and thus rendering them more susceptible than the general population to licorice’s effects. All patients’ DNA samples were taken and screened for any genetic varia-tions. No significant variations were found and the study suggested this does not represent a likely cause of susceptibility for most patients. However, variants of epithelial sodium channel subunits were found at a much higher incidence in the patient population with licorice-induced hypertension, suggesting this may lead to an increased susceptibility in some patients.

Mineralocorticoid excess has been known to result in a wide range of symptoms. The most common symptoms of mineralocorticoidism re-sulting from licorice use are hypertension and hypokalemia.13,14 However, a variety of presen-tations due to licorice consumption have been reported in the literature. Two such patients developed hypertensive encephalopathy as their initial presentation of mineralocorticoid excess resulting from licorice ingestion.15 There have been reports of patients presenting with fatigue, weakness, rhabdomyolysis, and even paralysis, who were discovered to have an underlying diag-nosis of licorice-induced mineralocorticoidism.16-18 Furthermore, a few other reports describe car-diovascular complaints as a result of prolonged licorice ingestion. Crean et al reported on a pa-tient who developed cardiac arrest due to licorice use.19 Two other case reports documented cases of licorice causing ventricular fibrillation and ventricular tachycardia in their patients.20,21

Although it is fairly common for patients to present with both hypertension and an incidental finding of hypokalemia, it is important for the clinician to keep possible syndromes in mind. This is especially important when considering uncorrectable hypokalemia or any of the other

symptoms described above. Tools that can aid in the diagnosis include a urinary cortisol/cortisone ratio.1 While the normal ratio is 0.3 to 0.5, the ratio in mineralocorticoid excess reaches as high as 18 in adults.22, 23 Urinary GA can also be measured, with normal values typically being less than 5 micrograms. However, for clinical practice, these diagnostic tests may not be practical. Thus, the most reasonable method of diagnosis is through a thorough history and physical exam.

If the history reveals heavy licorice use in a patient with compatible symptoms, simply ask them to remove licorice from their diet and observe them. This serves as both the diagnosis and treatment of the patient. In cases of severe or symptomatic hypokalemia, as in our case, cor-rection is required through high dose potassium supplementation.

If the patient does not respond after sev-eral weeks of licorice removal from the diet, it is imperative to work the patient up for other causes of mineralocorticoid excess. Leitolf et al recently described a patient who presented with hypertension and hypokalemia and reported a history of heavy licorice consumption.24 Despite removing licorice from his diet, he continued to present with hypertension and hypokalemia. Further workup uncovered an adrenal adenoma for which the patient received an adrenalectomy. This highlights the importance of following up to ensure that removal of licorice from the diet corrects the symptoms.

It is also important for the clinician to educate patients on safe levels of licorice for prevention of symptoms. The European Union recommends 100mg/day as the upper limit for ingestion of glyzyrrhizin, which is equivalent to the GA found in about 60-70g of licorice.13 However, as Van Gelder demonstrated, the mg of licorice per kg of body weight is a more accurate gauge of safety levels. Stoving et al recently reported on an anorexic patient who developed symptoms of mineralocorticoidism with only 20g of licorice use per day.25 It is particularly vital to educate pa-tients on the potential harmful effects when they inquire about its benefits as an herbal remedy. Patients currently use licorice as a treatment for peptic ulcers, as a cough suppressant, and as an expectorant. Licorice fluid extracts contain approximately 10 to 20 percent glycyrrhizin and

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typical doses of 2 to 4 mL deliver 200 to 800mg. Powdered licorice root is 4 to 9 percent glycyr-rhizin and daily doses of 1 to 4g contain about 40 to 360 mg of glycyrrhizin.13 Thus, it is necessary to advise patients on safe levels of these products.

CONCLUSION

This case demonstrates the value of a thor-ough history in the clinical evaluation of a patient presenting with symptoms of mineralocorticoid excess. Despite leading to potentially life-threat-ening complications, mineralocorticoid excess due to licorice use can be easily remedied with licorice cessation and potassium supplementation if the diagnosis is made in a timely manner. Thus, it is crucial for the clinician to keep licorice in mind as a possible cause of mineralocorticoid excess and investigate it thoroughly.

REFERENCES

1. Mantero F, Palermo M, Petrelli MD, Tedde R, Stewart PM, Shackleton CH. Apparent mineralocorticoid excess: Type I and type II. Steroids. 1996;61:193-196.

2. Quinkler M, Stewart PM. Hypertension and the cortisol-cortisone shuttle. J Clin Endocrinol Metab. 2003;88:2384-2392.

3. Palermo M, Quinkler M, Stewart PM. Apparent min-eralocorticoid excess syndrome: An overview. Arq Bras Endocrinol Metabol. 2004;48:687-696.

4. Ulick S, Wang JZ, Blumenfeld JD, Pickering TG. Cortisol inactivation overload: A mechanism of mineralocorticoid hypertension in the ectopic adrenocorticotropin syndrome. J Clin Endocrinol Metab. 1992;74:963-967.

5. Walker BR, Campbell JC, Fraser R, Stewart PM, Edwards CR. Mineralocorticoid excess and inhibition of 11 beta-hydroxysteroid dehydrogenase in patients with ectopic ACTH syndrome. Clin Endocrinol (Oxf).1992;37:483-492.

6. Revers FE. [Not Available]. Ned Tijdschr Geneeskd. 1946;90:135-137.

7. van Rossum TG, Vulto AG, de Man RA, Brouwer JT, Schalm SW. Review article: Glycyrrhizin as a potential treatment for chronic hepatitis C. Aliment Pharmacol Ther. 1998;12:199-205.

8. van Uum SH. Liquorice and hypertension. Neth J Med. 2005;63:119-120.

9. Epstein MT, Espiner EA, Donald RA, Hughes H. Effect of eating liquorice on the renin-angiotensin aldosterone axis in normal subjects. Br Med J. 1977;1:488-490.

10. van Gelderen CE, Bijlsma JA, van Dokkum W, Savelkoul TJ. Glycyrrhizic acid:The assessment of a no effect level. Hum Exp Toxicol. 2000;19:434-439.

11. Sigurjonsdottir HA, Franzson L, Manhem K, Ragnarsson J, Sigurdsson G, Wallerstedt S. Liquorice-induced rise in blood pressure: A linear dose-response relationship. J Hum Hypertens. 2001;15:549-552.

12. Miettinen HE, Piippo K, Hannila-Handelberg T, et al. Licorice-induced hypertension and common variants of genes regulating renal sodium reabsorption. Ann Med. 2010;42:465-474.

13. Murphy SC, Agger S, Rainey PM. Too much of a good thing: A woman with hypertension and hypokalemia. Clin Chem. 2009;55:2093-2096.

14. Yamamoto T, Hatanaka M, Matsuda J, et al. [Clinical characteristics of five elderly patients with severe hy-pokalemia induced by glycyrrhizin derivatives]. Nippon Jinzo Gakkai Shi. 2010;52:80-85.

15. Russo S, Mastropasqua M, Mosetti MA, Persegani C, Paggi A. Low doses of liquorice can induce hypertension encephalopathy. Am J Nephrol. 2000;20:145-148.

16. van den Bosch AE, van der Klooster JM, Zuidgeest DM, Ouwendijk RJ, Dees A. Severe hypokalaemic paralysis and rhabdomyolysis due to ingestion of liquorice. Neth J Med. 2005;63:146-148.

17. Templin C, Westhoff-Bleck M, Ghadri JR. Hypokalemic paralysis with rhabdomyolysis and arterial hyperten-sion caused by liquorice ingestion. Clin Res Cardiol. 2009;98:130-132.

18. Pant P, Nadimpalli L, Singh M, Cheng JC. A case of severe hypokalemic paralysis and hypertension. Lico-rice-induced hypokalemic paralysis. Am J Kidney Dis. 2010;55:A35-37.

19. Crean AM, Abdel-Rahman SE, Greenwood JP. A sweet tooth as the root cause of cardiac arrest. Can J Cardiol. 2009;25:e357-358.

20. Gerritsen KG, Meulenbelt J, Spiering W, Kema IP, Demir A, van Driel VJ. An unusual cause of ventricular fibril-lation. Lancet. 2009;373:1144.

21. Eriksson JW, Carlberg B, Hillorn V. Life-threatening ventricular tachycardia due to liquorice-induced hypoka-laemia. J Intern Med. 1999;245:307-310.

22. Palermo M, Shackleton CH, Mantero F, Stewart PM. Urinary free cortisone and the assessment of 11 beta-hydroxysteroid dehydrogenase activity in man. Clin Endocrinol (Oxf). 1996;45:605-611.

23. Palermo M, Delitala G, Mantero F, Stewart PM, Shack-leton CH. Congenital deficiency of 11beta-hydroxysteroid dehydrogenase (apparent mineralocorticoid excess syn-drome): Diagnostic value of urinary free cortisol and cortisone. J Endocrinol Invest. 2001;24:17-23.

24. Leitolf H, Dixit KC, Higham CE, Brabant G. Licorice – or more? Exp Clin Endocrinol Diabetes. 2010;118:250-253.

25. Stoving RK, Lingqvist LE, Bonde RK, et al. Is glycyr-rhizin sensitivity increased in anorexia nervosa and should licorice be avoided? Case report and review of the literature. Nutrition. Aug 24 2010.

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MSD Member News

MSD MembersNEWSMAKERS

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Mehdi Balakhani, DDS, M.D., FACS was selected to serve on the Government Af-fairs Committee of the Ameri-can Society of Plastic and Reconstructive Surgery. Dr. Balakhani practices Plastic Surgery in Newark.

Daniel J. Meara, M.D., DMD was selected to serve on the Research Education Committee for the American Cleft Palate-Craniofacial Associa-tion. Dr. Meara practices in the Department of Oral and Maxillofacial Surgery at Christiana Care.

William S. Weintraub, M.D. ,FACC was awarded the American College of Cardiology's 2011 Distinguished Service Award at the Col-lege's Annual Scientific Session in April. The award is in recognition of Dr. Weintraub's numer-ous contributions to medicine and the delivery of health care. He is the John H. Ammon Chair of Cardiology at Christiana Care and Director of the Christiana Care Center for Outcomes Research.

Rafael Zaragoza, M.D. and Venerando Maximo, M.D. led the 16th Annual Operation We Care Medical Mission to the Philippines. The project is an international project of the Dover Rotary Club. The 2011 mission was co-sponsored by the Gallipolis, Ohio Rotary Club and included 24 physicians. The team performed 97 major and 70 minor surgical procedures.

HospitalsAlfred I. duPont Hospital for Children was ranked in eight of ten specialty areas among the best in the nation in the 2011-2012 edition of Best Children's Hospitals by U.S. News & World Reports. The hospital was ranked:l 7th in Orthopedics;l 17th in Gastroenterology;l 24th in Pulmonology;

l 29th in Urology;l 33rd in Cardiology and Heart Surgery;l 41st in Neonatology;l 44th in Nephrology; andl 50th in Diabetes and Endocrinology.

The Bayhealth Wound Care Center has earned the Center of Distinction Award from Diversified Clinical Services for the second year in a row. The award recognizes wound care facilities with high patient satisfaction rates, exceptional healing results, and outstanding clinical outcomes for wound care management and related services.

Beebe Medical Center has received the Ameri-can Heart Association/American Stroke Associa-tion's Get With the Guidelines Stroke Gold Plus Quality Achievement Award in recognition of the Medical Center's commitment and success in implementing excellent care for stroke patients.

Christian Care's Department of Family and Community Medicine has received recognition for patient-centered, highly coordinated care and use of long-term, patient-doctor relation-ships from the National Committee for Quality Assurance (NCQA). The Department's Family Medicine Center has sites at Foulk Road and the Wilmington Hospital Annex. It is the first practice in Delaware and one of 2,189 in the nation to achieve designation as a Physician Practice Connections Patient-Centered Medical Home from NCQA.

The cardiac surgery programs at Christiana Care Health Systems's Center for Heart and Vascular Health and Beebe Medical Center have earned the highest quality ranking from the Society of Thoracic Surgeons for the second consecutive year. Only 13.5 percent of 968 hos-pitals in the Society's cardiac surgery database received the three-star rating for 2010.

Nanticoke Health Services has been named to the 2011 Becker's Hospital Review list of Best Places to Work in Healthcare. Those selected provide a work environment that promotes team-work, professional development, and quality patient care.

Del Med J, July 2011, Vol 83 No 7

Obituary

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OBITUARY

Lawrence Martin Baker III, M.D.

Michael R. Zaragoza, M.D.

LAWRENCE M. BAKER III, M.D.

Dr. Lawrence M. Baker died May 25, 2011, in Chestertown, Maryland, at the age of 85. He practiced general and thoracic surgery at Kent General Hospital, now Bayhealth, in Dover from 1957-1993. After his retirement from medicine, he eventually moved to Chestertown with his wife Margot in 2000.

Dr. Baker was born July 8, 1925, in Frank-lin, Pennsylvania, and grew up in Coraopolis, Pennsylvania, outside of Pittsburgh. He served in the U.S. Army from 1943-1946 and spent time in Saipan in the Pacific in preparation for the expected invasion of Japan. Upon discharge from the military, he attended Harvard College and then received his medical degree from Har-vard Medical School in 1951. He completed his internship at the Geisinger Memorial Hospital, Danville, Pennsylvania, in 1952, followed by his surgical residency at the Hospital of the University of Pennsylvania from 1952-1957.

He initially joined Dr. Henry Wilson as part of the first General Surgery practice in Dover. He later partnered with Dr. Arthur Zimmerman and Dr. Bruce Bolasny during his 37 year career in the area. A respected member of the medical staff and Dover community, Dr. Baker was a fel-low of the American College of Surgeons, and a diplomate of the American Board of Surgery and the National Board of Medical Examiners. He served as Chief of the Department of Surgery at Kent General and was a long-standing member of the Applications Committee for the American College of Surgeons.

Dr. Baker is survived by his wife of 62 years, Margaret (Margot) Holliday Hoon Baker; four daughters, Christine Brockmeyer of Pittsburgh, Pennsylvania, Nancy Coffin of Greenwich, Con-necticut, Marianne Kitchell of Seattle, Washing-ton, and Barbara A. Baker, M.D. of Pewaukee, Wisconsin.; nine grandchildren and two great grandchildren; and his sister Elizabeth Kuci of Signal Mountain, Tennessee. He was preceded in death by his sister, Jean Marie Baker.Michael R. Zaragoza, M.D., is a Urologist who practices in

Dover, Del., and a member of the Delaware Medical Journal Editorial Board.