Interesting Cases

Metformin Overdose Causes Severe Lactic Acidosis

Lactic Acidosis is a common cause of metabolic acidosis.  Metabolic acidosis has several effects on human physiology, the most serious of which is the lowering of the ventricular fibrillation threshold of the heart.  Lactic acidosis in popular literature is connected to excessive exercise, but there are other causes for lactic acidosis including dehydration, starvation, severe anemia, diabetic ketoacidosis, and other conditions.  The paper that follows is a case study published in a 2012 issue of J. Med having to do with an overdose of Metformin, an oral hypoglycemic agent used to treat Type II diabetics.  It is a very interesting toxicology case.

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Metformin Overdose Causes Severe Lactic Acidosis

Lactic Acidosis is a common cause of metabolic acidosis.  Metabolic acidosis has several effects on human physiology, the most serious of which is the lowering of the ventricular fibrillation threshold of the heart.  Lactic acidosis in popular literature is connected to excessive exercise, but there are other causes for lactic acidosis including dehydration, starvation, severe anemia, diabetic ketoacidosis, and other conditions.  The paper that follows is a case study published in a 2012 issue of J. Med having to do with an overdose of Metformin, an oral hypoglycemic agent used to treat Type II diabetics.  It is a very interesting toxicology case.

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A 13 year old boy Sick for 3 Months



A 13-Year-Old Boy With a 3-Month History of Malaise


A missed diagnosis that allowed for severe progression of a disease that in its early stages is amenable to treatment.  An illustrative example of medical malpractice prevention.




A 13-year-old boy presents to the emergency department (ED) with a history of epigastric pain, vomiting, malaise, polyuria, and a 12-pound weight loss during the past 3 months. The parents report no history of hematuria, hematemesis, fever, chills, or any other associated symptoms, prior surgeries, or medical problems. The patient has previously been seen by his pediatrician and is undergoing a workup. An upper gastroendoscopy performed at a nearby hospital 2 weeks ago had revealed chronic gastritis with erosive changes in the antral region. Triple treatment for Helicobacter pylori, however, did not lead to any improvement. Abdominal ultrasonography also performed at that time showed mild nephrocalcinosis. The parents have brought the patient to the ED today because his pain and vomiting are worsening.

On physical examination, the child is thin and mildly ill-appearing. His temperature is 98.6°F (37.0°C), his pulse has a regular rhythm, with a rate of 80 bpm, and his blood pressure is 120/70 mm Hg. The patient's respirations are regular and unlabored at 14 breaths/min. The child is in mild distress secondary to his epigastric discomfort. The examination of the head and neck is normal except that the oropharynx appears slightly dry. He has no dysmorphic facial features. His lungs are clear to auscultation, and normal respiratory effort is noted. The S1 and S2 heart sounds are normal, and no murmurs are detected. The abdomen is soft but tender to deep palpation in the epigastric region. The patient's extremities show no edema and there is brisk capillary refill. His skin is clear except for in the gluteal region, where a nodular eczematous lesion is present.



Routine laboratory tests reveal a normal complete blood count and normal values for sodium, potassium, chloride, bicarbonate, and magnesium. The patient's blood urea nitrogen (BUN) and serum creatinine values are elevated (22.4 mg/dL [8 mmol/L] and 1.8 mg/dL [160 mmol/L], respectively). The calcium level is elevated at 14.4 mg/dL (3.6 mmol/L), which is confirmed with an ionized calcium level of 7.2 mg/dL (1.8 mmol/L). The phosphorus level is low at 5.0 mg/dL (1.6 mmol/L). The hepatic aminotransferase levels are slightly elevated as well; the aspartate aminotransferase (AST) level is measured at 61 Units/L, the alanine aminotransferase (ALT) is 201 Units/L, and the bilirubin is 0.7 mg/dL (12 μmol/L). A chest radiograph (see Figure 2) is obtained.





The patient is hospitalized. During the hospital course, additional laboratory tests are performed. The thyroid hormone levels are in the normal range, but the parathyroid hormone level is low at 10.91 pg/mL (10.91 ng/L; normal range, 15-65 pg/mL). Vitamin D metabolites are not measured. The serum angiotensin-converting enzyme (ACE) level is normal at 32.7 Units/L (547.7 nkat/L; normal range, 12-42 Units/L). The results of a purified protein derivative test are negative.

A urinalysis performed on several occasions shows a specific gravity of 1.003 and a pH of 5, with normal urinary sediment. Urinary cultures are negative. On several occasions, there is marked hypercalciuria, with a level of 14 mg/kg and a urinary calcium:creatinine ratio (mmol/mmol) ranging from 2.5 to 3.5. There is no glycosuria or aminoaciduria.

Ultrasonography is performed. The parathyroid glands appear normal. Renal ultrasonography confirms mild nephrocalcinosis around the renal calices. A renal biopsy is performed. The specimen exhibits tubulointerstitial nephritis associated with tubular calcium deposits (see Figure 3). There is also interstitial infiltration by mononuclear cells, interstitial fibrosis, tubular necrosis, and atrophy. Dystrophic calcifications are present in some of the tubules. Negative results are obtained for IgA, IgG, IgM, and C3 on immunofluorescent analysis. Immunohistochemical analysis reveals inflammatory cellular substrate CD 68, macrophages, and lymphoid population. No glomerular abnormalities are evident.

The clinical picture of this patient was dominated by nonspecific constitutional symptoms, such as fatigue, malaise, vomiting, abdominal cramps, and weight loss. He had no history of maculopapular rashes, erythema nodosum, arthritis, chronic lymphocytopenia, hepatomegaly, splenomegaly, lymphadenopathy, or uveitis. He also did not have any coughing or exertional dyspnea. The child did have vomiting and polyuria, which were caused by his hypercalcemia. The renal biopsy specimen exhibited acute tubulointerstitial nephritis associated with tubular calcium deposits without glomerular abnormalities. In addition, the chest radiograph demonstrated combined hilar lymphadenopathy and reticulonodular interstitial infiltrates in the upper lung zone (see Figure 2). The chest radiograph findings, when considered along with the hypercalcemia, rash, and renal biopsy results, were consistent with stage 2 radiographic sarcoidosis.


Hypercalcemia associated with hypercalciuria and nephrocalcinosis are rare in childhood and may have many causes.  The most common cause is iatrogenic. This is followed by idiopathic infantile hypercalcemia (IIH) in its mild or severe form (Williams syndrome). Intoxication with vitamin D is a rare cause of clinically manifested hypercalcemia, but it is associated with significant morbidity. 

Measurement of an intact parathyroid hormone (PTH) level at the time of hypercalcemia is pivotal in narrowing the differential diagnosis. If the PTH level is high, the child must be thoroughly investigated for the cause of hyperparathyroidism and may require urgent surgical intervention. If the PTH level is low (as it was in this patient), additional calciotropic hormones may be assayed if appropriate testing is available. Identifying the abnormal calciotropic hormone might allow for the diagnosis of the specific cause, elucidation of the mechanism for the hypercalcemia, and optimal treatment.

Sarcoidosis is a multisystem disorder characterized by an increased cellular immune response to an unknown antigen and the formation of noncaseating granulomas in affected tissues. Although the lungs and lymph nodes are the predominant sites affected by sarcoidosis (75-90%), other organs, such as the eyes, bone marrow, kidneys, liver, and spleen, may also be involved. Cases of extrapulmonary sarcoidosis affecting the kidneys are rare; most such cases present with nephrocalcinosis or nephrolithiasis (3.6%). Renal failure is an extremely uncommon manifestation.

Hypercalcemia in sarcoidosis is uncommon, only occurring in approximately 10% of cases. It is usually caused by the autonomous production of 1,25-dihydroxyvitamin D (calcitriol) by macrophages within the granuloma. These macrophages can convert 25-hydroxyvitamin D, produced by the liver, into calcitriol by possessing the 1alpha-hydroxylase enzyme. Calcitriol then travels to the intestinal cells and promotes luminal absorption of calcium and phosphate into the circulation. Hypercalcemia is accompanied by hypercalciuria and, eventually, nephrocalcinosis (as seen in this case). Hypercalcemia may also eventually cause renal failure both by causing dehydration and by inducing renal vasoconstriction, thereby reducing the glomerular filtration rate. Systemic corticosteroids can be used to treat hypercalcemia associated with sarcoidosis because they inhibit the production of calcitriol within the macrophages.

The true incidence and prevalence in children are unknown because of the rarity of the disease and the small number of reported cases in childhood. Most reported childhood cases have occurred in patients aged 13-15 years, but the disease has also been reported in very young children. Two distinct forms of childhood sarcoidosis appear to exist. Older children usually present with a multisystem disease similar to the adult manifestation, with frequent lymphadenopathy and pulmonary involvement. They also show generalized signs and symptoms, such as fever and malaise. In contrast, early-onset childhood sarcoidosis is a unique form of the disease characterized by the triad of rash, uveitis, and arthritis, usually in patients who are younger than 4 years of age.

Pulmonary disease and abnormal findings on chest radiography are more common in children with sarcoidosis who are aged 8- 15 years; these findings occur in 94-100% of patients in that age group compared with 22% in those who are younger than 4 years of age. Bilateral hilar adenopathy is the most common finding on chest radiography in children, and it occurs in almost all cases. It is typically symmetrical, although it may appear unilateral in rare instances. Pulmonary parenchymal involvement is common and predominantly appears radiographically as an interstitial pattern; however, nodular, alveolar, and fibrotic patterns have also been described. Other uncommon manifestations include pleural effusion, pneumothorax, pleural thickening, calcification, atelectasis, and cor pulmonale. Nearly half of all children with sarcoidosis demonstrate restrictive lung disease on static and dynamic pulmonary function tests, including a reduction in total lung capacity, forced vital capacity, functional residual capacity, and transfer factor. These changes are believed to be secondary to early alveolitis progressing to fibrosis. An obstructive ventilatory pattern has been reported in approximately 15% of children with sarcoidosis. Airway obstruction may be secondary to airway hyperactivity, intrabronchial sarcoid granuloma, hilar or mediastinal lymph node compression of the airways, or bronchiectasis.

The serum ACE level is increased in 30-80% of patients with sarcoidosis and may be a surrogate marker of the total granuloma burden. False-positive findings are noted in fewer than 20% of patients with other pulmonary disorders; however, the serum



ACE level may be normal in patients with active disease.


About 40-70% of children with sarcoidosis have palpable peripheral lymph glands. The lymph nodes typically are firm, nontender, discrete, and freely movable. They do not ulcerate and do not form draining sinuses. The most frequently involved glands are the cervical, axillary, epitrochlear, and inguinal glands. In the neck, the posterior triangle nodes are affected more commonly than the nodes in the anterior triangle. The enlarged peripheral lymph nodes are the most accessible tissue for biopsy, providing a high diagnostic yield.

Hepatosplenomegaly occurs in up to 43% of children with sarcoidosis at some point in their clinical course; however, clinically significant hepatic dysfunction is rare. Mild elevation in biochemical liver function test values is common (as it was in this patient), but severe liver involvement is unusual in children.

Ocular involvement is extremely common in children with sarcoidosis, and a complete ophthalmologic evaluation, including a slit-lamp examination, is crucial (particularly in young children). Any part of the eye or orbit may be affected. Anterior uveitis (also known as iritis or iridocyclitis) is the most frequently observed lesion, occurring in about 58-90% of early-onset sarcoidoses, as compared with 24-54% of sarcoidosis cases in older children. Sarcoid-associated uveitis can be acute or chronic and may vary from an isolated iridocyclitis to a bilateral panuveitis syndrome. If left untreated, the disease may result in synechiae, corneal opacities, glaucoma, and, eventually, blindness. Conjunctival granulomas are the second most common ocular manifestation in sarcoidosis. Other forms of ocular lesions include interstitial keratitis, band keratopathy (from calcium deposition), dacryocystitis, retinal vasculitis, lacrimal gland enlargement, choroiditis, and orbital infiltration, which may result in proptosis.

Cutaneous involvement occurs in about 24-40% of older children with sarcoidosis and in 77% of young children with sarcoidosis. A variety of cutaneous eruptions are frequently found on the face, but the trunk, extremities, and buttocks may also be involved. Skin lesions of sarcoidosis may include macules, papules, nodules, hyperpigmented lesions, hypopigmented lesions, ulcers, subcutaneous tumors, and erythema nodosum. Rarely, "scar sarcoidosis", the infiltration of old scars with granuloma, may present in children.

Renal involvement is not well characterized in published series of childhood sarcoidosis. Actually, only 32 isolated cases of sarcoidosis with renal involvement have been reported in children since 1941. Histopathologic studies have revealed epithelioid granuloma formation, interstitial infiltration by mononuclear cells, interstitial fibrosis, tubulitis, tubular atrophy, mesangial hyperplasia, glomerular fibrosis, membranous nephropathy, and vascular involvement.

The treatment of sarcoidosis remains controversial. Corticosteroids remain the cornerstone of therapy, but immunosuppressive, cytotoxic, and immunomodulatory agents have emerged as viable therapeutic options for patients who do not respond to or experience adverse effects from corticosteroids. Published data most extensively documents treatment with methotrexate, but favorable responses have been noted with leflunomide, azathioprine, and antimalarial and antimicrobial agents, as well as with tumor necrosis factor–alpha inhibitors. The dosage and the duration of corticosteroid therapy must often be individualized. The treatment is continued until the clinical manifestations of the disease resolve or show significant improvement.

The patient in this case received prednisone, 1.5 mg/kg per day for 1 month, with gradual tapering of the dose over the following 4-5 months. Hypercalcemia and renal failure reversed completely, as did the pulmonary changes seen on radiography (see Figure 4). No recurrence was observed at a 1-year follow-up. Renal nephrocalcinosis persisted, however, despite symptomatic and biochemical improvement. During the corticosteroid therapy, measurement of the urinary beta-2-microglobulin concentration by sodium dodecyl sulfate polyacrylamide gel electrophoresis proved a valuable monitoring tool for assessing the recovery of the tubular impairment.



This patient is a rare case of sarcoidosis presenting with acute renal failure and hypercalcemia as the initial manifestations. Sarcoidosis should be considered in the differential diagnosis of hypercalcemia and renal failure, either occurring singly or in combination. Corticosteroids are useful for treatment and can lead to the reversal of hypercalcemia and renal failure and the resolution of pulmonary lesions. Renal nephrocalcinosis may persist despite symptomatic and biochemical improvement.



The bottom line is that when a physician does not find the underlying cause of a continuing or worsening condition, the most appropriate next step is referral to a higher level of care, such as in a University setting.  This is best for the patient and will help avert litigation.

This case is from a recent Medscape Issue.

Review Article on Marijuana

The following is a recent review of the literature regarding marijuana.  Printed in the J. Am. Board Fam. Med., and copied in Medscape, it describes the medical uses of marijuana and its derivatives, and reviews the medical-legal aspects of this drug's usage.

Cannabis and Its Derivatives

Lawrence Leung, MBBChir, MFM(Clin)

Posted: 08/30/2011; J Am Board Fam Med. 2011;24(4):452-462. © 2011 American Board of Family Medicine

Abstract and Introduction


Background: Use of cannabis is often an under-reported activity in our society. Despite legal restriction, cannabis is often used to relieve chronic and neuropathic pain, and it carries psychotropic and physical adverse effects with a propensity for addiction. This article aims to update the current knowledge and evidence of using cannabis and its derivatives with a view to the sociolegal context and perspectives for future research.
Methods: Cannabis use can be traced back to ancient cultures and still continues in our present society despite legal curtailment. The active ingredient, Δ9-tetrahydrocannabinol, accounts for both the physical and psychotropic effects of cannabis. Though clinical trials demonstrate benefits in alleviating chronic and neuropathic pain, there is also significant potential physical and psychotropic side-effects of cannabis. Recent laboratory data highlight synergistic interactions between cannabinoid and opioid receptors, with potential reduction of drug-seeking behavior and opiate sparing effects. Legal rulings also have changed in certain American states, which may lead to wider use of cannabis among eligible persons.
Conclusions: Family physicians need to be cognizant of such changing landscapes with a practical knowledge on the pros and cons of medical marijuana, the legal implications of its use, and possible developments in the future.

Case 1


You are a family physician in Ontario, Canada. A 54-year-old man suffering from multiple sclerosis came to your office asking for a prescription for medical marijuana to control his pain. He was taking continuous-release morphine, gabapentin, and lamotrigine, but this combination was still insufficient. He visited Florida a few times, where he smoked cannabis, which helped tremendously to reduce the neuropathic pain and detach his mind from it. He would like to continue using cannabis but is worried about the legal implications and the purity of sample he may obtain on the street.

Suggested Management

The evidence of various forms of cannabis (smoked, oral, and oromucosal spray) for treating neuropathic pain caused by multiple sclerosis should be discussed against the known harms and challenges of usage. Sativex (legally available form of cannabis in Canada; GW Pharmaceuticals, Salisbury, Wiltshire, UK) could be recommended as a first-line treatment. If the patient still decided to pursue a smoked or oral extract of cannabis, referral should be made to recognized specialists in Quebec for a full assessment of eligibility of patient's use and possession of medical marijuana. Close monitoring of the patient would be necessary.

Case 2


You are a family physician in the state of California. A 65-year-old male veteran came to your office as a new patient. He had a history of chronic leg pain caused by a shrapnel injury he suffered during the Vietnam War in 1968. Since the 1970s, he has been treated at the local veterans hospital under a pain management program, but control has been unsatisfactory. When asked if he used any recreational drugs, including marijuana, he evaded your question and said he needed to stay on the pain program. You suspected he was using marijuana for his chronic pain.

Suggested Management

The patient should be informed of the new directive from the Veterans Health Administration regarding veterans' use of marijuana and be reassured that he would not be denied his pain management services at the veterans hospital on that basis. He also should be encouraged to discuss his marijuana use with you so that you can monitor his progress. Liaising with an addiction medicine specialist can be helpful to ensure the best follow-up of this patient.

Cannabis, also known as marijuana, refers to the preparation 53 from the plant belonging to the family Cannabaceae, the genusCannabis, and the species Cannabis sativa, which possess psychoactive effects. The flowering tops, leaves, and stalks of the mature female plant are commonly used as the herbal form of cannabis, but sometimes the resinous extract of compressed herb is also used and is called "hash." Archaeologists have identified fibers from cannabis stems in specimens dating back to 4000 BC, and its incorporation into textiles and paper was found in the tombs of the Chinese Han dynasty (~100 BC).[1] The first record of cannabis as a medicine can be found in the oldest Chinese pharmacopeia, Shen Nong Ben Cao Jing, written in the Eastern Han Dynasty (AD 25 to AD 220), which was indicated for rheumatic pain, malaria, constipation, and disorders of the female reproductive system.[2] Though the cannabis leaf and stem is rarely used nowadays in Chinese herbal medicine, cannabis seeds, which contain very few psychoactive ingredients, are still commonly prescribed for their laxative effects.[2]Smoking cannabis is often an under-reported behavior in our society, with a reported prevalence from the World Health Organization of 3.9% among the global population aged 15 to 64 years.[3] There are more than 70 psychoactive compounds called "cannabinoids" that have been identified in cannabis,[4] among which Δ9- tetrahydrocannabinol (THC) accounts for most of the psychological and physical effects, and its content is often used as a measure of sample potency. We now know that THC acts on 2 types of cannabinoid receptors: CB1 and CB2. CB1 receptors are mainly found in the brain, peripheral nerves, and autonomic nervous system,[5] whereas CB2 receptors are found both in the neurons and immune cells.[6] THC exerts its effects primarily via CB1 receptors.

The Laws Regarding Cannabis

In the United States, cannabis is an illicit drug either to possess or trade. Since the inception of the Controlled Substance Act in 1970, the US Federal Law penalizes any act of possessing, dispensing, and prescribing marijuana. Enforcement of prohibition carries an annual price tag of up to $7.7 billion in the United States alone.[7] However, since 1996 the situation has been changing rapidly—14 states (California, Alaska, Oregon, Washington, Maine, Hawaii, Colorado, Nevada, Vermont, Montana, Rhode Island, New Mexico, Michigan, and New Jersey) already have amended their state laws to allow the use of marijuana by persons with debilitating medical conditions as certified by licensed physicians.[8,9] The impact has been significant: a recent study in Washington estimated that per annum, up to 2000 licensed physicians have prescribed medical cannabis;[10] in California, more than 350,000 patients already possess a physician's recommendation to use cannabis.[11] Nevertheless, among these 14 states, there is substantial variation in the regulation of the quality control, prescription limit, patient registry, and dispensing outlets. For example, in Oregon and Washington, it is legal to possess up to 24 ounces of marijuana, but in Nevada, Montana, and Alaska, the legal limit is only 1 ounce.[8] Cannabis is currently schedule I; additional research would be facilitated if the drug were reclassified to schedule II.[8] From a public health standpoint, there is some evidence that decriminalization of cannabis could free up law enforcement resources to curtail other trafficking activities without leading to increased cannabis abuses.[12] Overall, however, the US Federal law remains unchanged regarding the penal stance toward marijuana, creating various ambiguities and difficulties. For those veterans who are permitted to use medical marijuana by law of their state, these difficulties have been lessened. This has posed an administrative dilemma for those veterans who are allowed to use; the Department of Veterans Affairs issued a directive in July 2010 that permits veterans to continue their use of medical marijuana in states where it is legal without losing their medical benefits from Veterans Affairs.[13]

Recent news from USA Today [14] reports that the US federal government has issued warning letters to several states that have approved the use of medical marijuana with an implication that anyone involved in the growth, operation, or legal regulation of medical marijuana will be subjected to prosecution. These states include Washington, California, Montana, and Rode Island. This was coupled by recent large-scale raids at marijuana growing operations in Montana. Despite reassurance from Eric Holder, US Attorney General, that the penal policy is directed at those who violate both deferral and state laws, this unexpected siren from the federal government has been heard loud and clear, leading Governor Chris Gregoire, of the state of Washington, to abort a proposal to create licensed marijuana dispensaries and Governor Chris Christie, of the state of New Jersey, to postpone plans for marijuana operators.

In Canada, it is also illegal to trade or possess 104 marijuana according to provincial and government laws. However, access to marijuana for medical use is possible under Health Canada's Marijuana Medical Access Regulations, which came into force on July 30, 2001.[14] The regulations clearly outline 2 categories of persons who can apply to possess for an authorization to possess marijuana for medical purposes. Category 1 refers to people with end-of-life care; seizures from epilepsy; severe pain and/or persistent muscle spasms caused by multiple sclerosis, spinal cord diseases, or spinal cord injury; severe pain; cachexia; anorexia; weight loss and/or severe nausea from cancer or HIV/AIDS infection. A medical declaration from a licensed medical practitioner is required. Category 2 refers to people who have debilitating symptom(s) of medical condition(s), other than those described in category 1, which have failed conventional medical treatment. An assessment by a designated specialist is necessary along with a medical declaration from a licensed medical practitioner.

Under the regulations, the maximum amount of marijuana that can be possessed by any authorized user is a 30-day total of daily requirement. Health Canada sources its supply of dried marijuana and seeds from Prairie Plant Systems Incorporated (Saskatoon, Saskatchewan, Canada), a company that specializes in the growing, harvesting, and processing of plants for pharmaceutical products and research. Alternatively, authorized marijuana users can apply for a permit to produce and grow their own supply provided they meet specific and detailed criteria.

The Harms of Cannabis

Physical and Psychiatric Effects

Among naive users, cannabis smoking often leads to adverse effects. Physical symptoms include increased heart rate and fluctuations in blood pressure;[15] psychomotor sequelae include euphoria, anxiety, psychomotor retardation, and impairment of cognition and memory.[16] The estimated lethal dose for humans is between 15 g and 70 g.[3] When compared with cigarette smoke, cannabis contains a similar array of detrimental and carcinogenic compounds, some of which are present even at higher concentrations.[17] Among chronic users, population studies have associated cannabis use with decreased pulmonary function, chronic obstructive airway diseases, and pulmonary infections,[18] although data may be confounded by concomitant tobacco smoking and other social factors. In vitro and in vivo animal studies have demonstrated mutagenic effects of cannabis smoke, and precancerous pulmonary pathology as seen in tobacco smokers has been described in cannabis users.[19] Nevertheless, there is still inconsistency from the published literature regarding an increased risk for upper respiratory tract cancer caused by cannabis smoking.[3,18] Various reports have associated cannabis with cardiac arrhythmias,[20,21] coronary insufficiency[22–24]and myocardial infarction.[25,26] A retrospective cross-sectional study revealed a 4.8-times increased risk of developing myocardial infarction within the first hour after smoking cannabis. Earlier data from population studies[27,28] and meta-analysis[29] have associated cannabis smoking with low birth weight,[29] which is maybe confounded by cigarette smoking and socioeconomic status and is not supported by more recent studies.[30,31] Finally, the controversial link of cannabis use and psychosis has found more support in recent publications.[32–34]

Dependence and Abuse

Cannabis is recognized as a substance with a high potential for dependence, which occurs in 1 out of 10 people who have ever used cannabis. It leads to behaviors of preoccupation, compulsion, reinforcement, and withdrawal after chronic use.[35] An Australian survey found that symptoms of cannabis withdrawal satisfied the diagnostic criteria of both International Classification of Diseases 10 and Diagnostic and Statistical Manual of Mental Disorders IV for substance dependence, which included sleep disturbance, anorexia, irritability, dysphoria, lethargy, and cravings.[36] In the United States, cannabis is now ranked among alcohol and tobacco as one of the most common substances of among adolescents.[37] There is also ample evidence indicating that regular use of cannabis predicts subsequent psychosocial problems and abuse behavior of other addictive substances. A review of cohort studies by McLaren et al[38] supported a causal link between cannabis use and psychosis. A recent 10-year follow-up study of adolescents in Australia who used cannabis occasionally were found to be at higher risks of drug abuse and educational problems.[39] However, several issues have been identified in the published literature about cannabis, which have limited our understanding on the adverse effects of cannabis: (1) lack of consensus on the definition and classification of different types of cannabis users (heavy, regular, occasional, and nonusers); (2) variable quality of studies regarding design, effect sizes, and control of confounding factors; and (3) the polarization of the approach to either studying nonusers versus light/infrequent users or, infrequent/light/nondependent users versus frequent/heavy/dependent users.[40]

New Kids on the Block

Recently, synthetic analogues of marijuana, known generically as "spice" or "K2," have gained rapid popularity among youths in the Unites States and Europe. Marketed as an incense or herbal blend, the exact constituents of spice has been a myth, and its place of origin is often unclear. Despite sharing similar psychotropic effects as genuine cannabis, spice cannot be reliably tested by drug screens and poses a technical problem for the law enforcement; hence it is capable of evading legal scrutiny among most states in America. A report from the Drug Enforcement Administration of the US Department of Justice in June 2010 had divulged the possible constituents of spice (or K2), which included HU-210, JWH-018, JWH-073 and CP-47,497,[41] all of which were synthetic cannabinoids legally endorsed for scientific research. This was echoed by a recent research publication that identified a synthetic cannabinoid in commercially obtained spice, JWH-018, which activated CB1.[42]

Analgesic Potential and Synergism With Opioids

Despite legal curtailment, cannabis is still used by 10% to 15% of patients with multiple sclerosis[43] and noncancer types of chronic pain[44] for both analgesia and psychological detachment. Various well-designed, randomized, placebo-controlled trials have shown that smoked cannabis can relieve peripheral,[45] posttraumatic,[46] and HIV-induced[47,48] neuropathic pain. Evidence has been accumulating from molecular and cell-signaling studies that suggest that the opioids and cannabinoid systems can interact synergistically to enhance analgesic effects.[49] Animal studies have shown that topical cannabinoid enhances the action of topical morphine,[50] an effect that is preserved in a morphine-tolerant state.[51] Moreover, cannabinoids are increasingly being recognized in animal models for their potential sparing effects with opioids[52] of neuropathic pain and arthritic pain.[53] Although similar effects have not been translated to human studies, Robert et al[54] found a synergistic affective analgesia between Δ9-THC and morphine in experimentally induced pain in human volunteers.

Evidence From Clinical Studies

To review the latest evidence of cannabis use and its derivatives, a literature search was conducted from the MEDLINE, EMBASE, PsycINFO, and Cochrane Database of Systematic Reviews from their inception dates to 30 November 2010, using the following keywords: "cannabis," "marijuana," "Δ9-tetrahydrocannabinol," "clinical trial," "benefits," and "side effects." Relevant articles were selected and their quality of evidence was rated according to the Strength of Recommendations Taxonomy (SORT),[56] with recommendations rated as A, B, or C. The results are summarized in Table 1. In brief, the efficacy of smoked cannabis has been studied for Gilles de la Tourette syndrome, glaucoma, and pain, with good evidence for clinical benefits in HIV-induced neuropathic pain. Oral extract of cannabis has better evidence of relieving self-reported symptoms of spasticity caused by multiple sclerosis. Finally, the oromucosal form of cannabis extract (Sativex, GW Pharmaceuticals) is efficacious for peripheral and central neuropathic pain, especially that caused by multiple sclerosis.

Table 1. Clinical Studies of Cannabis and Its Derivatives with SORT Level of Recommendation56

AgentCondition IndicatedForm of deliveryNature of StudyPatients (n)Outcome MeasuresOutcomeSORT Level of RecommendationReference
Cannabis Gilles de la Tourette Syndrome Smoking Case report 3 Self-reported frequency of motor tics 50% to 70% remission C Sandyk et al57
Cannabis Gilles de la Tourette Syndrome Smoking Case report 1 Self-reported symptoms 100% remission C Hemming et al58
Cannabis Glaucoma Smoking single dose Double-blinded cross-over placebo-controlled RCT 18 Intraocular pressure Significant reduction B Merritt et al59
Cannabis Neuropathic pain in HIV patient Smoking 5 days a week for 2 weeks Prospective placebo-controlled RCT 28 Pain intensity using Descriptor Differential Scale Improvement in pain (P = .016) A Ellis et al49
Cannabis Sensory neuropathic pain in HIV patient Smoking 3 times a day for 5 days Double-blinded cross-over placebo-controlled RCT 50 Chronic pain ratings Reduction of pain by 34% (P = .03) A Abrams et al48
Cannabis Capsaicin-induced pain in volunteers Smoking single dose at various concentrations Double-blinded cross-over placebo-controlled RCT 15 Pain scores and McGill Pain Questionnaire Pain reduction at medium dose within a certain time frame only B Wallace et al60
Cannabis Acute inflammatory pain in volunteers Single oral dose of encapsulate extract Double-blinded cross-over placebo-controlled RCT 18 Threshold to heat and electricity in areas with UV-induced sunburnt No effect on pain thresholds B Kraft et al61
Cannabis Spasticity due to multiple sclerosis Escalating dose of oral encapsulate extract Double-blinded cross-over placebo-controlled RCT 50 Spasms frequency and mobility Improvement in spasms frequency (P= .013) and mobility (P = .01) A Vaney et al62
Cannabis Spasticity caused by multiple sclerosis Titrating oral dose of cannabis extract Double-blinded placebo-controlled RCT 327 Ashworth score and self-reported spasticity Improvement of self-report ratings of pain and spasticity (P= .003) A Zajicek et al63
Δ9-THC Gilles de la Tourette Syndrome Single oral dose Cross-over placebo-controlled RCT 12 TSSL, STSS, YGTSS scores Significant reduction in TSSL score (P = .015), nil for STSS and YGTSS A Müller-Vahl et al64
Δ9-THC Gilles de la Tourette Syndrome Daily oral dose for 6 weeks Placebo-controlled RCT 24 TSSL,TS-CGI, STSS; YGTSS Significant reduction in TSSL score using ANOVA (P = .037), nil for TS-CGI, STSS, YGTSS A Müller-Vahl et al65
Δ9-THC Spasticity caused by multiple sclerosis Escalating dose for 5 days Double-blinded cross-over placebo-controlled RCT 13 Subjective rating and objective measure of spasticity Significant in both scores A Ungerleider et al66
Δ9-THC Spasticity due to multiple sclerosis Titrating oral dose of Δ9-THC Double-blinded placebo-controlled RCT 330 Ashworth score and self-reported spasticity Improvement of self-report ratings of pain and spasticity (P= .003) A Zajicek et al63
Δ9-THC Postoperative pain Single oral dose on postoperative day 2 Double-blinded placebo-controlled RCT 40 Summed pain intensity difference 6 hours after administration No significant difference B Buggy et al67
Δ9-THC Refractory neuropathic pain Titrating oral dose Open label pilot 8 Neuropathic pain score and quality of life No apparent effect C Attal et al68
Δ9-THC Glioblastoma multiforme Daily intracranial tumour injection up to 64 days Phase I cohort pilot study 9 Safety of intracranial route of administration Intracranial route seems to be safe and may slow down tumour growth C Guzman et al69
Dronabinol (synthetic Δ9-THC) Alzheimer's disease Twice-daily oral dose for 6 weeks Double-blinded cross-over placebo-controlled RCT 15 Body weight, triceps skin fold, disturbed behavior, affect A trend of improvement reported but no significance quoted B Volicer et al70
Dronabinol (synthetic Δ9-THC) Alzheimer's disease Daily oral dose for 2 weeks Open label pilot 6 Nocturnal motor activity score and Neuropsychiatric Inventory Significant improvement in both (P = .028 and P = 0027) C Walther et al71
Dronabinol (synthetic Δ9-THC) Anorexia and weight loss in AIDS Twice-daily oral dose for 6 weeks Placebo-controlled RCT 139 VAS for appetite, mood, and nausea Significant change in appetite (38%; P = .015); mood (10%; P = .06); and nausea (20%; P = .05) A Beal et al72
Nabilone Spasticity caused by spinal cord injury Twice-daily oral dose for 4 weeks Double-blinded cross-over placebo-controlled RCT 12 Ashworth Scale, Total Ashworth Score Significant reduction, P= .003 and 0.001 respectively A Pooyania et al73
Nabilone Pain caused by fibromyalgia Oral dose for 4 weeks Double-blinded placebo-controlled RCT 40 VAS and Fibromyalgia impact questionnaire Significant reduction in both scores (P < .02) A Skrabek et al74
Sativex (extract of cannabis containing Δ9-THC and cannabidiol) Peripheral neuropathic pain Self-titrating dose of oromucosal spray for 5 weeks Double-blinded placebo-controlled RCT 125 Various pain intensity scores Significant reduction, (P= .001 to P= .04) A Nurmikko et al75
Sativex (extract of cannabis containing Δ9-THC and cannabidiol) Intractable neurogenic symptoms Self-titrating dose of oromucosal spray for 2 weeks Double-blinded cross-over placebo-controlled RCT 20 Self-report symptoms and adverse effects Significant relief in pain with certain domains reaching significance of P < .05 A Wade et al76
Sativex (extract of cannabis containing Δ9-THC and cannabidiol) Central pain in multiple sclerosis Self-titrating dose of oromucosal spray for 4 weeks Double-blinded placebo-controlled RCT 66 11-point scale for pain and sleep disturbance Significant reduction of pain (P = .005) and sleep disturbance (P = .003) A Rog et al77
Sativex (extract of cannabis containing Δ9-THC and cannabidiol) Bladder dysfunction in multiple sclerosis Single daily dose for 8 weeks Open label pilot study 15 Occurrence of urinary incontinence, frequency, nocturia Significant reduction in all 3 domains (P< .05) A Brady et al78

RCT, randomized controlled trial; UV, ultraviolet; TSSL,; STSS,; YGTSS,; TS-CGI, ANOVA, analysis of variance; VAS, Visual Analog Scale; THC, tetrahydrolcannabinol.

The Challenges of using Cannabis

Despite the evidence of benefits in certain conditions, the use of medical marijuana within a legal jurisdiction still faces a number of challenges:

  • Method of Delivery and Quality Control. Smoking raw cannabis remains the most common and easiest route of delivery, but the actual amount of cannabinoids deliverable to the alveolar space varies considerably depending on the individual's techniques of inhalation/exhalation, the percentage of aeroingestion, and the individual's functional lung capacity. Without prior training, it could be difficult for a family physician in daily practice to advise an eligible patient on the proper techniques of administration and quality control of prescription regarding medical marijuana. The content of THC in cannabis may vary remarkably according by geographic origin,[56] the parts of plant being used (buds versus stem and seeds), the methods of storage, and the techniques of cultivation.[79] There are 2 main strains used in medical marijuana: the Sativa and the Indica. The Sativa plant is usually taller with longer leaves that grow better outdoors, whereas the Indica plant is more bushy with shorter leaves that thrive better indoors. Although both strains exist in pure forms, various combinations of the 2 strains are packaged as medical marijuana, which may result in variable therapeutic and side effects. Health Canada's policy of adopting a centralized source of medical marijuana from an approved plantation is a good way to assure quality; however, it is still technically difficult to endorse it globally for all licensed users and growers. As a prescription, standardization and titration of dose efficacy remain a challenge for medical marijuana.
  • Adequate Monitoring and Prevention of Addiction. As with other substances of abuse, cannabis may lead to varying adverse effects and addiction potential among different individuals. Before facilitating an eligible person to receive medical marijuana, family physicians should possess the knowledge and skills to screen for addiction potential. During the course of treatment, close surveillance of the patient to prevent addiction and adverse effects, in collaboration with a specialist when necessary, remains a top priority. In Canada and in those American states where it is legal to use medical marijuana, more training and educational resources should be made available for the practicing family physician to enhance their competence in approaching cannabis.
  • Contaminants in Cannabis. Studies have reported an alarming level of biological contaminants in cannabis, which includeAspergillus fungus[80,81] and bacteria,[82] potentially leading to fulminant pneumonia, especially among the immunosuppressed.[83] Nonbiological contaminants also have been found, which include heavy metals from soil like aluminum[84] and cadmium, the latter of which seems to be absorbed by the cannabis plant in particularly high concentrations.[85] Organophosphate pesticides are other nonbiological contaminants that are found less in cannabis cultivated outdoors than indoors.[36] Finally, tiny glass beads or sand have been found in street samples of cannabis, which were added for weight to boost profits and can cause damage to the oral mucosa and lungs.[86]
  • Contamination by Cannabis. Secondary inhalation of cannabis fumes released by primary smokers is a theoretical but negligible threat, as shown by a study of airborne particulates in urban Spain[87] and another study of passive exposure to cannabis smoke in a Netherlands coffee shop.[88] More research in this area is warranted from the perspective of public health.

The Controversy Remains

In 1969, an article published in the New England Journal of Medicine quoted from the Wootton Report that cannabis is "a potent drug, having as wide a capacity as alcohol to alter mood, judgment, and functional ability, and admitted that it is a dangerous drug in that sense, but in terms of physical harmfulness much less dangerous than opiates, amphetamines, and barbiturates and also less dangerous than alcohol."[89] Since then, scientific and clinical data have helped us understand the mechanisms of actions of cannabis and its derived compounds for treating chronic and neuropathic pain, highlighting the potential analgesic synergism with opioids and the potential of an opiate sparing effect in clinical settings. In particular, animal studies have recently shown that cannabidiol (CBD), a nonpsychoactive constituent of marijuana, is capable of decreasing self-administration and drug-seeking behavior caused by heroin,[90] in addition to other anti-inflammatory antipsychotic and neuroprotective effects.[91,92] Another observational study of the ratio of CBD:THC from street cannabis samples suggests that a higher CBD content reduced reinforcing behavior and attention bias to marijuana. Further directions of research include a better understanding of the mechanisms of action of CBD and its interplay with THC, plus bioengineering a safer marijuana strain that contains the appropriate composition of CBD and THC for optimal therapeutic effects with the least adverse profile and addictive potential. Thus, important issues of dosage standardization, quality control, adverse effects profiling, and prevention of addiction could be resolved. Until then, family physicians in North America and Canada continue to face the under-reported use of cannabis in our society and its risks of abuse.


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Post-Surgical Dyspnea in a 52 year old man

A 52-year-old man with a history of hypertension presents for an elective subtotal colectomy for colon cancer. A recent workup identified a partially obstructing mass at the patient's splenic flexure. As an outpatient, he underwent a colonoscopy with a biopsy of the mass which revealed a moderately differentiated adenocarcinoma. At the time of admission, he denied any symptoms of constipation, diarrhea, abdominal pain, weight loss, or hematochezia. He has no history of heavy alcohol intake, tobacco use, or illicit drug use. He does not have a family history of malignancy. He undergoes a successful subtotal colectomy and ileocolic anastomosis, without any signs of complication. His immediate postoperative state is stable, but on postoperative day 5 he develops sudden-onset shortness of breath. He denies having any chest pain, palpitations, nausea, or diaphoresis.

On physical examination, his blood pressure is 132/74 mm Hg; his pulse is regular, with a rate of 105beats/min, and his respiratory rate is 30 breaths/min. His temperature is 98.7°F and his oxygen saturation is 90% on room air, which improves to 96% on 3 L of oxygen via nasal cannula. He is in mild respiratory distress but is able to speak in full sentences. He is not using the accessory muscles of respiration. The examination of his head and neck is normal. He has mildly decreased breath sounds at his right lung base. His heart examination demonstrates a normal S1 and S2 without murmurs or gallops. His abdomen is soft, nontender, and mildly distended with good bowel sounds; a midline incision scar is clean and nontender. He has palpable peripheral arterial pulses in his upper and lower extremities. The patient did not have edema or tenderness in the lower extremities.

The laboratory analyses, including a complete blood cell count and basic metabolic panel, are normal. An arterial blood gas on room air demonstrates a pH of 7.45, a pCO2 of 32 mm Hg, and a pO2 of 62 mm Hg, with an oxygen saturation of 93%. A chest x-ray reveals bibasilar subsegmental atelectasis. He is encouraged to perform incentive spirometry; however, his oxygen saturation deteriorates progressively and rapidly. On postoperative day 6 his hypoxemia is refractory to oxygen via a non-rebreather mask and he is intubated for hypoxemic respiratory distress and impending respiratory arrest. He is transferred to the ICU. His ECG shows an S1Q3T3 pattern and sinus tachycardia.

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Tachycardia in a 61 year old

An interesting case recently appeared in MedScape involving the sudden onset of a rapid heartrate in a woman.

A 61-year-old woman presents to the emergency department (ED) after being referred from her primary care provider's (PCP) office for evaluation of tachycardia. She had been seen by her PCP for routine placement of a purified protein derivative (PPD) tuberculin skin test and was incidentally noted to have a pulse of 160 beats/min. The patient currently denies any specific complaints other than occasional palpitations. On review of her systems, however, she notes having night sweats; a 110-lb (50-kg) weight loss over the preceding 12 months; and 2-3 months of anxiety, diarrhea, and occasional diplopia. She denies having any fever, chills, chest pain, dyspnea, or swelling in her extremities. She has a medical history of an unspecified thyroid problem. She does not take any daily medications and has no medication allergies. She has a 50-pack-year smoking history, with occasional alcohol consumption. She had been homeless for a time, but is currently living in an apartment.

On examination, the patient is awake and fully oriented. She is diaphoretic but in no apparent distress. Her temperature is 97.0°F (36.1°C); her pulse is 160 beats/min; her respiratory rate is 24 breaths/min, with an oxygen saturation of 98%; and her blood pressure is 190/117 mm Hg. She has bilateral exophthalmos with exotropia of the right eye. Her visual acuity and extraocular movements are intact. The neck examination reveals a diffuse, nontender goiter, without nodules or thyroid bruits. The heart is tachycardic, intermittently irregular, and without murmurs. The lungs are clear to auscultation bilaterally. The abdomen is nondistended, soft, and nontender, with no palpable masses. There is no edema of the extremities. The neurologic examination reveals normal mentation, intact cranial nerves, intact motor strength and sensation, and normal reflexes. No tremor is noted.

The initial laboratory studies reveal her complete blood cell count, electrolytes, renal function, and cardiac marker findings are all within normal limits. A plain chest x-ray is interpreted as normal (not pictured). An ECG is obtained which shows sinus tachycardia.

This patient's ECG showed atrial fibrillation with a rapid ventricular response, which is a possible cardiac manifestation of thyrotoxicosis. No ischemic changes were noted despite her rapid heart rate. Her laboratory studies confirmed the suspected diagnosis, with findings of a markedly depressed thyroid-stimulating hormone (TSH) level of 0.006 mIU/L (normal range, 0.5-5.0 mIU/L) and elevated triiodothyronine (T3) and thyroxine (T4) concentrations of 632 ng/dL (9.73 nmol/L) and 23.7 ug/dL (305.02 nmol/L), respectively (normal ranges, T3: 70-170 ng/dL; T4: 5-11 ug/dL).

Thyrotoxicosis refers to an elevated concentration of thyroid hormone as well as the related clinical manifestations. This is differentiated from thyroid storm, a life-threatening manifestation of thyrotoxicosis in which a markedly hypermetabolic state is present. Hyperthyroidism most commonly results from uncontrolled Graves disease, in which autoantibodies to the TSH receptor are produced. This leads to excessive thyroid hormone production from the thyroid gland and a reflexive inhibition of TSH release from the pituitary gland. Other etiologies can include a solitary thyroid adenoma, toxic multinodular goiter, hypersecretory thyroid carcinoma, thyrotropin-secreting pituitary adenoma, struma ovarii, and iodine or amiodarone administration. A precipitating event, such as surgery, trauma, myocardial infarction, pulmonary embolism, diabetic ketoacidosis, childbirth, severe infection, discontinuation of antithyroid medication, or thyroid surgery on a patient with uncontrolled hyperthyroidism, is often needed to push a patient with hyperthyroidism into thyroid storm.[1,2]

The incidence of hyperthyroidism in the United States is 0.05%-1.3%, most of which remains undiagnosed. Approximately 1%-2% of these patients will progress to thyroid storm at some point. The prevalence is slightly higher in women compared with men and in white and Hispanic populations compared with black populations. Thyroid storm is most common in the third to sixth decades of life, although it can occur at any age.[1]

Thyroid storm is a clinical diagnosis and, considering the acuity of this life-threatening condition, patients with thyrotoxicosis should be treated empirically when the diagnosis is suspected. Symptoms of thyrotoxicosis include weight loss, palpitations, hair loss, diplopia, chest pain, oligomenorrhea, or confusion. The physical examination reveals a hypermetabolic state, with abnormalities involving multiple organ systems. These findings commonly include hyperpyrexia, tachycardia, tachypnea, and hypertension. Other findings may include fine tremor, exophthalmos, ophthalmoplegia, pretibial edema, congestive heart failure, thyromegaly, thyroid bruit, and hyperreflexia.[3] Laboratory studies show a low TSH level and elevated T3 and T4 concentrations. TSH is the most precise indicator of thyroid function because of the very high sensitivity of the thyroid-pituitary feedback loop, and current assays are able to detect levels of 0.02 mIU/L or less. As such, a normal TSH level largely excludes significant thyroid disease. Other laboratory findings seen in thyrotoxicosis may include hyperglycemia, hypercalcemia, leukocytosis, and elevated liver enzymes.[2] Further testing may be indicated as part of a search for the precipitating cause of clinical decompensation, such as infection, myocardial infarction, or diabetic ketoacidosis. Electrocardiography most often reveals sinus tachycardia or atrial fibrillation. Although thyroid storm requires more rapid and aggressive therapy than thyrotoxicosis, differentiating between the 2 can sometimes be difficult, as it was in this patient. Burch and Wartofsky developed a scoring system to assist in making this distinction that takes into account thermoregulatory dysfunction, central nervous system effects, gastrointestinal dysfunction, the degree of tachycardia, the extent of congestive heart failure, the presence of atrial fibrillation, and the presence or absence of a precipitating event.[4]

Cardiac complications from thyrotoxicosis include arrhythmias, congestive heart failure, and pulmonary hypertension. The most common arrhythmia in thyrotoxicosis is sinus tachycardia; however, atrial fibrillation occurs in 10%-20% of patients with thyrotoxicosis, most often in patients who are older than 60 years of age. Risk factors for atrial fibrillation in these patients include male sex, increasing age, coronary heart disease, heart failure, and structural heart or valvular disease. Congestive heart failure in thyrotoxicosis is predominantly caused by either persistent tachyarrhythmias (tachycardia-induced cardiomyopathy) or uncontrolled hypertension as a consequence of thyrotoxicosis. Systolic dysfunction can occur as a consequence of the persistent cardiac arrhythmias, but it usually resolves once the hyperthyroid state is treated. Pulmonary hypertension can also occur in thyrotoxicosis, either as a result of a primary effect of thyroid hormone on pulmonary arteriolar resistance vessels, decompensated left heart failure, or via increased pulmonary arterial blood flow (high-output).[1]

The differential diagnosis for thyrotoxicosis and thyroid storm may include anxiety, congestive heart failure, heat exhaustion or heatstroke, factitious disorder, neuroleptic malignant syndrome, panic disorder, septic shock, serotonin syndrome, anticholinergic or sympathomimetic toxicity, and alcohol or benzodiazepine withdrawal syndromes.[5] Because infection is a common trigger for thyroid storm, an initial misdiagnosis of sepsis is not uncommon because of similar characteristics, such as tachycardia, fever, and altered mental status.

Management of thyrotoxicosis consists of a 5-pronged, ordered approach, targeting each step in the biosynthetic pathway of thyroid hormone and its activity on target tissues. Treatment begins with administration of propylthiouracil (PTU) or methimazole, both of which act by inhibiting new hormone synthesis. PTU has the added effect of decreasing peripheral T4 to T3 conversion. Beta-blockers are then used to inhibit target activity of thyroid hormone. Propranolol is the preferred agent because it also blocks peripheral conversion of T4. When cardioselective agents are preferred, atenolol or metoprolol may be used. At least 1 hour after administration of PTU or methimazole, the patient may be given iodide to inhibit further thyroid hormone release. It is imperative that iodine be given only after synthesis of new hormone is blocked because iodide administration can have the undesired effect of increasing new hormone synthesis. Potassium iodide or Lugol solution of iodine is recommended. Peripheral conversion of T4 to T3 is blocked, as noted above, and dexamethasone may be used as well. Further treatment is supportive and may include acetaminophen for fever and hydrocortisone if the patient is hypotensive as a result of adrenal insufficiency. Salicylates are contraindicated because they displace bound thyroid hormone in the blood.[2,3]

With regard to the management of cardiac symptoms related to thyrotoxicosis, treatment is focused on reducing adrenergic drive to the heart and restoring normal cardiac rhythm. As mentioned above, beta blockers are very effective for rapid hemodynamic improvement. Either propranolol or metoprolol given intravenously can be used to improve heart rate control either in sinus tachycardia or atrial fibrillation. In severe cases, a continuous infusion of esmolol may be required for rate control. Amiodarone should be avoided when treating atrial fibrillation from thyrotoxicosis because of its high iodine content, which may induce or exacerbate thyroid storm.

If a patient is hemodynamically unstable from atrial fibrillation, direct current cardioversion should be used. If symptoms of pulmonary congestion appear, diuretics may be used. Other drugs for heart failure (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and/or aldosterone receptor antagonists) are reasonable agents in patients who have depressed left ventricular systolic function. Anticoagulation is recommended for patients in atrial fibrillation secondary to thyrotoxicosis. The 2006 American College of Cardiology/American Heart Association/European Society of Cardiology (ACC/AHA/ESC) guidelines recommend anticoagulation with warfarin to an international normalized ratio of 2.0-3.0 until the patient is euthyroid, after which recommendations and risk stratification are the same as those for atrial fibrillation without thyrotoxicosis.[3] Of note, PTU, methimazole, and iodide solutions are all classified as pregnancy class D and, as such, should not be used in pregnancy.

This patient's clinical presentation bordered between thyrotoxicosis and thyroid storm, and she was hemodynamically stable. She was immediately treated with propranolol and PTU and was admitted to a monitored bed in the medical service. Because her clinical condition improved and she remained stable, the admitting team chose to forgo further therapy with iodine and steroids. Her atrial fibrillation resolved within 12 hours, but an echocardiogram revealed cardiomyopathy with a left ventricular ejection fraction of 45% that was attributed to her long-standing hyperthyroidism. A diagnosis of Graves disease was made. She was continued on methimazole and metoprolol, and anticoagulation was initiated. Five months later, the patient was still taking methimazole. Her thyroid function had normalized, her cardiomyopathy had reversed, and her anticoagulation was discontinued, because atrial fibrillation did not recur. Incidentally, she was ruled out for tuberculosis during her admission with 3 induced sputum samples.



  1. Schraga ED. Hyperthyroidism, thyroid storm, and Graves disease. eMedicine from WebMD: Emergency Medicine. Last updated April 23, 2010. Available at: Accessed January 28, 2011.
  2. Nayak B, Burman K. Thyrotoxicosis and thyroid storm. Endocrinol Metab Clin North Am. 2006;35:663-686. Abstract
  3. Fuster V, Rydén LE, Cannom DS, et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines; European Society of Cardiology Committee for Practice Guidelines; European Heart Rhythm Association; Heart Rhythm Society. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006;114:e257-354. Abstract
  4. Burch HB, Wartofsky L. Life-threatening thyrotoxicosis. Thyroid storm. Endocrinol Metab Clin North Am. 1993;22:263-277. Abstract
  5. Pimentel L, Hansen KN. Thyroid disease in the emergency department: a clinical and laboratory review. J Emerg Med. 2005;28:201-209. Abstract

Dyspnea on Exertion in a 40 year old man

A 40-year-old man presents to the emergency department with a 5-day history of progressively worsening breathlessness on exertion and mild, general flulike symptoms. He also complains about night sweats and an intermittent low-grade fever, both of which started about 2 weeks ago.  This interesting case was actually misdiagnosed as early pneumonia caused by influenza.  The patient was treated with anti-influenza medication and was discharged home.  He returned two days later in a worsened condition.  Read more about this condition and how it was diagnosed.

Read more ...

Unexplained Shortness of Breath in a 48 year old Man

Case History:

A 48-year-old man with no significant past medical history presents to the emergency department (ED) with a long-standing history of dyspnea (shortness of breath) that has been persistently worsening for the past two years. According to the patient, the dyspnea is worse on exertion and is associated with decreased exercise tolerance. There are no associated chest pains, palpitations, dizziness, or syncope. The patient denies any associated cough, hemoptysis, fever, or weight loss. Upon initial presentation to his primary care physician (PCP) at the time of symptom onset, a cardiac stress test and pulmonary function testing were within normal limits; however, his symptoms have persisted and have actually worsening over the prior two weeks. He has been prescribed zolpidem (sleeping medication), as needed, by his PCP, who labeled his condition secondary to anxiety. The shortness of breath has progressively gotten worse, so much so that the patient can no longer exercise, or even walk, without becoming short of breath. The patient is an active tennis player and has no family history of heart disease. He does not take any medications or herbal supplements, and he has no known drug or food allergies. There is no history of smoking, alcohol abuse, or illicit drug use.

In the emergency room, the physician has access to his medical records and notes his physician's evaluation.  He obtains the history as above.

Physical examination reveals an alert and oriented male with a regular pulse of 92 bpm, blood pressure of 135/85 mm Hg, respiratory rate of 20 breaths/min, a temperature of 98.6°F (37.0°C), and an O2 saturation of 98% on room air. The neck is supple and without any jugular venous distention, lymphadenopathy, tracheal deviation, or thyroid nodules. Cardiac examination reveals a normal S1, fixed split S2, and a prominent P2, but no audible murmurs, rubs or gallops are noted. The chest examination shows bilateral equal air entry, without any wheezes, rhonchi, or rales. The abdomen is soft, nontender and nondistended, without any evidence of organomegaly. No lower extremity edema, cyanosis, or clubbing is seen. The peripheral arterial pulses are palpable. The neurologic examination is normal.

Laboratory investigations, including a complete blood count, comprehensive metabolic panel, B-type natriuretic peptide (BNP), and troponin are within normal limits. A stool guaiac test is negative. An ECG shows a S1Q3T3 pattern with a right bundle branch block.

The patient is discharged home with instructions to see his primary care physician in a few days.

The following day, the patient awakes and he is acutely dyspneic at rest such that he cannot speak.  His wife calls 911 and he is returned to the ER.  On route to the hospital he is given 100% high flow oxygen, but his oxygen saturation vacillates between 90% and 96%.  His blood pressure is 90/54, and he is noted to be tachypneic with a respiratory rate of 26.  On arrival to the ER, he is noted to be hemodynamically unstable.  A stat arterial blood gas on room air shows a pH of 7.48, a partial carbon dioxide pressure (pCO2) of 31 mm Hg, and a partial oxygen pressure (pO2) of 70 mm Hg. Stat portable chest radiography shows clear lung fields with prominent central pulmonary arteries. A 12-lead electrocardiogram (ECG) shows tall R waves in V1, inverted T waves in leads V1 to V4, II, II, and aVF. A stat computed tomography (CT) angiogram of the chest is obtained. The axial image of the chest CT angiogram demonstrated a constellation of findings suggestive of both chronic and acute pulmonary thromboemboli.

Upon completion of the study, the patient suddenly codes and undergoes cardiopulmonary resuscitation also with the administration of clot busting medication and anti-coagulants. He is successfully resuscitated and has additional work-up.

Further testing included a duplex ultrasound scan of the lower extremities, which revealed a bilateral calf deep vein thrombosis; a ventilation/perfusion scan, which showed several mismatched perfusion defects of the posterior segment of the right and anterior segments of the left upper lobes (read as high probability for pulmonary embolism); and an elevated factor VIII assay. Echocardiography showed a high pulmonary systolic pressure of 82 mm Hg, right ventricular hypertrophy, and reduced right ventricular function. A subsequent right heart catheterization confirmed the diagnosis of pulmonary hypertension, with an elevated mean pulmonary artery pressure of 52 mm Hg and pulmonary vascular resistance of 12.3 Wood units.

Unfortunately, he does not regain consciousness and neurologic testing reveals that he has minimal brain function ostensibly from an anoxic/hypoxic injury.  He stays in the ICU for several weeks and then is transferred in a vegetative state to a skilled nursing facility.  He dies from complications two months later.

Analysis and Discussion:

A patient may provide a history that is consistent with chronic or acute pulmonary emboli, but diagnostic delays can occur when the physician does not work through all the testing that is necessary to make the diagnosis. Patients who have chronic thromboembolic disease (CTEPH) usually complain of exertional dyspnea and a gradual decrease in exercise tolerance over months to years. Other symptoms that may be reported include a nonproductive cough, hemoptysis, pleuritic chest pain, and presyncope/syncope. Findings on physical examination in patients with chronic thromboembolic disease reflect the degree of pulmonary vascular disease on presentation. Physical signs attributable to this condition may be subtle or absent in the absence of right-sided heart failure. Signs of pulmonary hypertension include right parasternal heave, fixed splitting of S2 with accentuated pulmonic component (P2), right ventricular fourth heart sound gallop, tricuspid regurgitation, and/or pulmonary insufficiency murmur. As the disease progresses and if left untreated, right ventricular dysfunction and right heart failure occur; significant findings at this time include pedal edema, elevated jugular venous pressure, and hepatomegaly.

Dyspnea is a common presenting symptom with many potential causes. Most cases of dyspnea are caused by cardiac or pulmonary disease. CTEPH has been misdiagnosed as being more common causes of dyspnea, such as coronary artery disease, chronic obstructive pulmonary disease, or interstitial lung disease. Some patients have been further improperly labeled with psychogenic dyspnea or physical deconditioning when the dyspnea persists.

All clinicians evaluating patients with unexplained dyspnea must have a high index of suspicion for abnormalities of the pulmonary vascular system and should rule out pulmonary vascular etiologies such as pulmonary embolism and pulmonary hypertension. Not considering this diagnosis under these circumstances is a breach in the standard of care.

The diagnosis of CTEPH requires a high index of suspicion because the presenting symptoms and signs are nonspecific. The chest radiograph (which may be normal in early stages) can reveal dilatation of the central pulmonary arteries (suggestive of pulmonary hypertension) and oligemic lung fields or parenchymal opacities from prior infarcts. The electrocardiogram may show changes of right heart disease (right ventricular hypertrophy, right atrial enlargement, or strain with T-wave inversions in anterior, precordial and inferior limb leads), depending on the severity of CTEPH, but are not specific to this disease. Transthoracic Doppler echocardiography is a useful screening test for suspected pulmonary hypertension. Echocardiography can help estimate the level of systolic pulmonary arterial pressure (PAP) and assess the presence of associated abnormalities, such as right atrial enlargement, right ventricular dilation or hypertrophy, right or left ventricular dysfunction, valvular heart disease, interventricular septal motion abnormalities, and pericardial effusion. A diagnosis of CTEPH is supported by an echocardiographic finding of a mean PAP exceeding 40 mm Hg in a patient with a history of pulmonary emboli. Pulmonary function testing will identify coexisting parenchymal disease and exclude other causes of pulmonary hypertension, such as interstitial lung disease. Patients with CTEPH may show a mild-to-moderate restrictive ventilatory defect secondary to parenchymal scarring from prior parenchymal infarcts.

Any patient with unexplained dyspnea should have the pulmonary vascular system evaluated. Chest CT angiography can provide pertinent clues to both the presence of thromboembolic disease and pulmonary hypertension in patients with CTEPH. Direct CT signs of chronic thromboembolic disease include the presence of organized thrombus lining the pulmonary vessels in a concentric or eccentric pattern that may cause pouch defects, intimal irregularities, bands/webs, or abrupt vessel narrowing. (These signs differ from the intraluminal filling defect and complete vessel cutoff of acute thromboembolism). Indirect signs of chronic thromboembolic disease on CT include poststenotic dilatation, tortuous vessels, asymmetric dilatation of the central pulmonary arteries, enlargement of the bronchial arteries and/or presence of collaterals and parenchymal abnormalities of mosaic attenuation (from irregular perfusion), and peripheral densities (scars from prior pulmonary infarct). A CT sign of pulmonary hypertension is enlargement of the main pulmonary artery, with a ratio between the CT diameter of the main pulmonary artery to the diameter of the aorta greater than 1:1. Other CT signs of pulmonary hypertension, resulting from right heart disease secondary to the pulmonary hypertension, include right ventricular dilatation, leftward septal bowing, thickening of the free right ventricular wall, and right atrial dilatation. It should be noted that CT angiography of the chest may appear normal in the presence of CTEPH, and should not be considered the diagnostic study of choice to rule out this disorder.

Ventilation/perfusion (V/Q) scanning is another imaging technique that is important in the diagnosis of CTEPH. A normal V/Q scan rules out the diagnosis of CTEPH. In patients with chronic thromboembolic disease, the V/Q invariably shows multiple segmental or larger perfusion defects in lung regions with normal ventilation. In contrast, patients with primary pulmonary hypertension show normal or subsegmental mottled perfusion patterns. Since V/Q mismatch defects are not specific to CTEPH, further imaging studies should be done to define the vascular abnormality with a view to establishing the diagnosis. Pulmonary angiography is the gold standard test to diagnose chronic thromboembolic disease. The five angiographic patterns seen in CTEPH include pouch defects, intimal irregularities, pulmonary artery webs or band-like narrowings, abrupt and often angular narrowing of major pulmonary arteries, and proximal obstruction of the pulmonary vessels.  Right heart catheterization, which can be performed at the time of pulmonary angiography, defines the severity of pulmonary hypertension and degree of cardiac dysfunction; it measures mean pulmonary artery pressure, pulmonary vascular resistance, right atrial pressure, cardiac output, and cardiac index.

The definitive treatment of patients with CTEPH is pulmonary thromboendarterectomy (PTE). Survival without surgical treatment is based on the degree of pulmonary hypertension. With mean pulmonary artery pressures of 30-50 mm Hg, five-year survival is 30%, whereas among patients with mean pulmonary artery pressures of greater than 50 mm Hg, five-year survival is only 10%. However, survival remains approximately 90-95% (5-10% mortality rate) after pulmonary thromboendarterectomy. The decision to opt for surgery is based on the patient’s symptom severity and comorbidities. The criteria for surgical selection in patients with CTEPH include accessibility of the thrombi (more proximal thrombi are more amendable to surgery than distal ones), hemodynamic/ventilatory compromise, and the patient’s comorbid conditions and associated risks of the procedure. Moser and colleagues pointed out that there are three major areas to consider when evaluating a patient for thromboendarterectomy: hemodynamic, alveolorespiratory, and prophylactic considerations. The hemodynamic goal is to prevent or ameliorate right ventricular compromise caused by pulmonary hypertension. The respiratory objective is to improve respiratory function by the removal of a large ventilated but nonperfused physiologic dead space, regardless of the severity of pulmonary hypertension. The prophylactic goal is to prevent progressive right ventricular dysfunction or retrograde extension of the obstruction, which may result in further cardiorespiratory deterioration or death.

Surgical treatment and endarterectomy must be bilateral because this is a bilateral disease in the vast majority of patients. The procedure is conducted with the aid of cardiopulmonary bypass, and the patient is cooled to allow for hypothermic circulatory arrest. A Greenfield filter is usually inserted before surgery to minimize recurrent pulmonary embolism after pulmonary endarterectomy. However, if this is not possible, it can also be placed at the time of operation. Meticulous postoperative management is essential to the success of this surgical procedure.

All patients are mechanically ventilated for at least 24 hours, and all patients are subjected to maintained diuresis. Patients are subject to all complications associated with open-heart and major lung surgery (eg, arrhythmias, atelectasis, wound infection, pneumonia, renal failure, stroke, and mediastinal bleeding, but also may develop complications specific to this operation. These include persistent pulmonary hypertension, reperfusion injuries, and neurologic disorders related to hypothermic arrest and deep hypothermia. Reduction in pulmonary pressures, resistance to normal levels, and corresponding improvements in pulmonary blood flow and cardiac output are generally immediate and sustained. In general, these changes can be assumed to be permanent.

This case emphasizes the need for clinicians to be aware of CTEPH since its diagnosis is commonly delayed or missed because of the nonspecific nature of its presentation and, sometimes, because of a lack of prior history of acute symptomatic PE or deep vein thrombosis. All clinicians should have a high index of suspicion and consider pulmonary vascular disease (thromboembolic disease/pulmonary hypertension) in the differential diagnosis of any patient complaining of unexplained persistent dyspnea.


The delay in diagnosis and treatment in this patient ultimately led to his demise.  A lawsuit was filed by the family against the emergency physician, the hospital, and the primary care physician.  The case was settled out of court by all three parties for a six figure amount after all expert depositions were taken.



  1. Dartevelle P, Fadel E, Mussot S, et al. Chronic thromboembolic pulmonary hypertension. Eur Respir J. 2004;23:637-648.
  2. Pengo V, Lensing AW, Prins MH, et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med. 2004;350:2257-2264.
  3. Wolf M, Boyer-Neumann C, Parent F, et al. Thrombotic risk factors in pulmonary hypertension. Eur Respir J. 2000;15:395-399.
  4. Ribeiro A, Lindmarker P, Johnsson H, Juhlin-Dannfelt A, Jorfeldt L. Pulmonary embolism: one-year follow-up with echocardiography Doppler and five-year survival analysis. Circulation. 1999;99:1325-1330.
  5. Bonderman D, Jakowitsch J, Adlbrecht C, et al. Medical conditions increasing the risk of chronic thromboembolic pulmonary hypertension. Thromb Haemost. 2005;93:512-516.
  6. Lang IM. Chronic thromboembolic pulmonary hypertension--not so rare after all. N Engl J Med. 2004;350:2236-2238.
  7. Wittram C, Kalra MK, Maher MM, Greenfield A, McLoud TC, Shepard JA. Acute and chronic pulmonary emboli: angiography-CT correlation. AJR Am J Roentgenol. 2006;186:S421-S429.
  8. Dunning J, McNeil K. Pulmonary thromboendarterectomy for chronic thromboembolic pulmonary hypertension. Thorax. 1999;54:755-756.
  9. Subias PE, Cano MJ, Flox A. [Medical treatment in patients with chronic thromboembolic pulmonary hypertension]. Arch Bronconeumol. 2009;45:35-39.
  10. Bresser P, Pepke-Zaba J, Jaïs X, Humbert M, Hoeper MM. Medical therapies for chronic thromboembolic pulmonary hypertension: an evolving treatment paradigm. Proc Am Thorac Soc. 2006;3:594-600.


61 Year Old Man With Severe Abdominal Pain


A 61-year-old white man presents to the emergency department with a 1-week history of diffuse "crampy" abdominal pain. For the past 2 months, he has had diarrhea and has been passing blood with every bowel movement, either on the stool surface or separately from the stool. Recently, he has had 10-15 loose stools per day, with associated urgency and tenesmus. He has lost 4 lb in the past week. He feels lightheaded upon standing and is experiencing fatigue and mild shortness of breath. He takes atorvastatin for hypercholesteremia and acetaminophen for intermittent back and knee pain. He is allergic to penicillin. He has no history of gastrointestinal tract disease; screening colonoscopy performed 2 years ago was unremarkable. His father died of myocardial infarction when he was in his 60s, and his mother died of breast cancer when she was in her 40s. He has no siblings. He is retired from his work as an accountant and lives with his wife. He has not travelled recently. He has a 25-pack-year smoking history but has not smoked for approximately 10 years. He drinks alcohol on social occasions and on weekends, and he denies illicit drug abuse.

On physical examination, the patient is a pale, diaphoretic man in some distress due to abdominal pain. His oral temperature is 101.5°F (38.6°C), blood pressure is 110/62 mm Hg, pulse is 107 beats/min, and respiratory rate is 24 breaths/min. His body mass index is 29.7 kg/m2. Examination of his head and neck is unremarkable aside from pale mucosal membranes. Lung auscultation reveals normal breath sounds, with no crackles or rhonchi. His heart rate is tachycardic, and his heart rhythm is regular. There are no murmurs or extra heart sounds. His abdomen is distended and firm, with diffuse rebound tenderness that seems worse in the lower left quadrant. Bowel sounds are diminished. No hepatosplenomegaly, ascites, or palpable masses are appreciated. Digital rectal examination demonstrates normal rectal tone, "velvety" rectal mucosa, and bright red blood on withdrawal of the examining finger. There is pitting edema of the legs and feet.

Laboratory analysis includes a complete blood count (CBC), which demonstrates anemia (hemoglobin concentration of 6.7 g/dL [67 g/L]), leukocytosis (leukocyte count of 14.2 x 103 cells/μL [14.2 x 109 cells/L]), and thrombocytosis (platelet count of 540 x 103 cells/µL [540 x 109 cells/L]). Additional findings include elevations in the erythrocyte sedimentation rate (78 mm/h) and C-reactive protein level (114 mg/L). His albumin level is low, at 2.0 g/dL (20 g/L). The basic metabolic panel is unremarkable. Repeat stool cultures and samples for ova and parasites are negative. Flexible sigmoidoscopy shows diffusely erythematous and friable colonic mucosa with large ulcerated patches, abundant yellow-white exudate, and oozing blood. These findings extend in a proximal and continuous fashion from the rectum to at least the middle of the sigmoid colon. Tissue biopsy samples sent for histopathologic examination reveal lymphoplasmacytic inflammation along the base of the crypts; neutrophils that infiltrate the crypt epithelium and collect in the depths of the colonic crypts to form "crypt abscesses"; and focal chronic reactive changes, including crypt branching, gland atrophy, and goblet-cell mucin depletion. No granulomas are identified.



The diagnosis of fulminant inflammatory bowel disease was initially suspected on the basis of the patient's history, physical examination, and laboratory test results; endoscopic and biopsy findings confirmed the diagnosis. The rectal bleeding was bright red, indicating that the source of the bleeding was most likely the lower gastrointestinal tract. The concurrent presence of crampy abdominal pain, diarrhea, tenesmus, and fever suggested that an inflammatory process had damaged the colonic mucosa. The unremarkable colonoscopy findings 2 years before presentation rendered a neoplasm unlikely. Although not impossible, it is rare for colon cancer to present with diarrhea. Most compelling was the continuity and character of the mucosal damage identified on endoscopy and the histopathologic findings, which were diagnostic of ulcerative colitis. Symptom duration suggested a chronic inflammatory process and infectious causes of colitis had been ruled out.

Ulcerative colitis is estimated to respectively have an incidence of 7.3 and prevalence of 116 per 100,000 people in the United States.[1] The peak age at onset is 15-25 years, with a second peak at 40-60 years.[2] Individuals of Ashkenazi Jewish or Scandinavian descent are more often affected, with men and women experiencing a similar disease incidence. Smoking seems to play a protective role against the development of ulcerative colitis, and it has been proposed that the second incidence peak in part represents patients who stopped smoking at a later age.[3] Most research suggests that the etiology and pathogenesis of ulcerative colitis are multifactorial, with a combination of genetic susceptibility, bacterial antigens, and alteration of mucosal immunity responsible for the development of the disease.[4]

The diagnosis of fulminant inflammatory bowel disease was initially suspected on the basis of the patient's history, physical examination, and laboratory test results; endoscopic and biopsy findings confirmed the diagnosis. The rectal bleeding was bright red, indicating that the source of the bleeding was most likely the lower gastrointestinal tract. The concurrent presence of crampy abdominal pain, diarrhea, tenesmus, and fever suggested that an inflammatory process had damaged the colonic mucosa. The unremarkable colonoscopy findings 2 years before presentation rendered a neoplasm unlikely. Although not impossible, it is rare for colon cancer to present with diarrhea. Most compelling was the continuity and character of the mucosal damage identified on endoscopy and the histopathologic findings, which were diagnostic of ulcerative colitis. Symptom duration suggested a chronic inflammatory process and infectious causes of colitis had been ruled out.

Ulcerative colitis is estimated to respectively have an incidence of 7.3 and prevalence of 116 per 100,000 people in the United States.[1] The peak age at onset is 15-25 years, with a second peak at 40-60 years.[2] Individuals of Ashkenazi Jewish or Scandinavian descent are more often affected, with men and women experiencing a similar disease incidence. Smoking seems to play a protective role against the development of ulcerative colitis, and it has been proposed that the second incidence peak in part represents patients who stopped smoking at a later age.[3] Most research suggests that the etiology and pathogenesis of ulcerative colitis are multifactorial, with a combination of genetic susceptibility, bacterial antigens, and alteration of mucosal immunity responsible for the development of the disease.[4]

Histopathologically, ulcerative colitis is characterized by lymphoplasmacytic inflammation of the mucosa and submucosa, with scattered neutrophils in the lamina propria (Figure 1). The neutrophils typically injure the crypt epithelium and may collect in the base of the crypts, forming crypt abscesses (Figure 2). Within weeks of disease onset, features of crypt architectural distortion (such as crypt branching and shortening) develop; these chronic changes are a nonspecific regenerative response to previous injury. Deep granulomas and transmural inflammation, 2 hallmarks of Crohn's disease, do not occur.[5]

Classically, ulcerative colitis is insidious in onset. Affected patients present with frequent passage of bloody, loose stools and tenesmus. The intensity of the symptoms generally correlates with the extent of anatomic involvement, allowing classification of disease as mild, moderate, or severe/fulminant. The majority of patients have mild, indolent disease limited to the rectum and sigmoid colon that is characterized by diarrhea, intermittent rectal bleeding, and tenesmus. The physical examination is often normal aside from bright red blood within the rectum. Other patients present with systemic symptoms, including more frequent bowel movements, crampy abdominal pain, decreased bowel sounds, high-grade fever, tachycardia, anemia, orthostatic hypotension, and weight loss. Extraintestinal manifestations, such as acute arthropathy, episcleritis, erythema nodosum, and pyoderma gangrenosum may also arise. Fewer than 10% of patients with ulcerative colitis initially present with fulminant disease, with older individuals represented in greater numbers. Fulminant ulcerative colitis is more abrupt in onset and is usually characterized by extensive colonic involvement ("pancolitis"), with rectal bleeding that may be extensive enough to necessitate blood transfusion. Abdominal distention and tenderness to palpation with signs of peritoneal inflammation (eg, rebound tenderness) may be observed in these patients. Of greatest concern in patients with fulminant disease is the prospect of massive hemorrhage, toxic megacolon, or bowel perforation. Immediate hospitalization is often necessary in these patients.

The differential diagnosis of bright red blood in the rectum associated with diarrhea includes infectious colitis, ischemic colitis, and nonsteroidal anti-inflammatory drug enteropathy. Other causes of colonic bleeding, such as diverticular disease, can present with loose stools, because blood is a cathartic. Stool studies (eg, fecal leukocytes, culture, ova, and parasites) and a Clostridium difficile toxin screen should be considered to eliminate the possibility of infectious colitis. A complete blood cell count should be obtained to evaluate for anemia or leukocytosis. Low albumin levels signify poor nutritional status and protein-losing enteropathy. A basic metabolic panel may demonstrate electrolyte abnormalities in the setting of severe prolonged diarrhea. Inflammatory markers, such as the erythrocyte sedimentation rate and C-reactive protein level, are typically elevated in patients with inflammatory bowel disease. Radiographic studies may be used as an adjunct in diagnosing complications of ulcerative colitis (eg, plain films can establish the presence of toxic megacolon). In the setting of acute flares, other radiologic studies, such as computed tomography (CT), may be done to evaluate for an alternative diagnosis. Common CT findings in ulcerative colitis include thickening of the colonic wall, pericolonic fat stranding, and a "target" appearance of the rectum. Most important in confirming the diagnosis of ulcerative colitis is flexible sigmoidoscopy with biopsy; colonoscopy may also be used in some settings, but it is associated with a higher risk for perforation and is contraindicated in cases of suspected toxic megacolon. Typical endoscopic findings in ulcerative colitis patients include diffuse erythema; edema; friability; and granularity of the mucosa, with loss of the normal vascular pattern. Ulceration with exudate and pseudopolyps are frequently identified as well. These findings invariably begin in the rectum and extend proximally in a continuous manner, up to and including the cecum, in cases of pancolitis.[6]

In most cases, ulcerative colitis can be managed in the outpatient setting. Treatment is designed to achieve and maintain disease remission. Topical therapy and 5-aminosalicylic acid (ASA) agents are the first-line means of treating ulcerative colitis, with steroids for acute flares and immunomodulators as maintenance therapy in severe refractory disease. Fulminant ulcerative colitis requires careful attention to the development of toxic megacolon. Parenteral corticosteroids; rehydration; bowel rest; nutritional supplementation; anticoagulation with low-dose heparin to prevent venous thrombosis, which is common in patients with ulcerative colitis; and monitoring of hemoglobin values (with transfusion sometimes required) are recommended. If remission is achieved, a maintenance regimen consisting of immunomodulators (such as cyclosporine, 6-mercaptopurine, or azathioprine) and/or 5-ASA should be initiated. In patients with fulminant ulcerative colitis that is refractory to first-line therapy, infusion of a biologic agent (such as infliximab) or colectomy may be necessary.[7]

The patient in this case was immediately admitted to the hospital because of concerns that he was at risk for massive hemorrhage, toxic megacolon, or bowel perforation. Three units of cross-matched blood were transfused, and he was prescribed bowel rest, peripheral hyperalimentation, and prednisolone. Shortly thereafter, 5-ASA was added to his therapeutic regimen. His symptoms resolved gradually, and he was discharged to home. Over the next few years, he experienced several disease flares, and the benefits and risks of immunomodulators and biologic agents versus colectomy were reviewed with him during a particularly severe flare. After considerable reflection, he decided in favor of colectomy; the patient tolerated the operation well. Gross examination of the colectomy specimen demonstrated involvement of the entire colon from cecum to anus. Multiple irregular ulcers with an associated yellow-white exudate were scattered throughout the colon, and diffuse pseudopolyps (Figure 3) were present. Findings consistent with Crohn's disease (eg, fissures, fistulas, perianal involvement, "creeping fat," and segmental disease) were not identified. As expected, the procedure resulted in complete remission of the patient's symptoms. After ileal pouch anal anastomosis surgery, most patients can expect to have 4-6 loose bowel movements per day.


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