Does Acetazolamide Prevent Altitude Sickness?

May 7, 2009

alaskamtnSeema Pursnani MD

Because your parents have designated you as the family doctor, your Uncle Joe calls to ask you if he should take this medication called Diamox before going trekking in the Himalayas. You work at Bellevue in New York City: who climbs mountains here? What do you say?

Why do illnesses develop from changes in altitude?

The essential culprit is the fall in atmospheric pressure with an increase in altitude. While at sea level, barometric pressure (Pb) is ~760mm Hg (1atm), whereas at the summit of Mount Everest (~8800 meters high), this pressure drops to ~250mm Hg. The fraction of inspired oxygen remains constant (21% of air is made of oxygen molecules), so the net result is a decrease in the pressure of inspired oxygen. Remember that the pressure of oxygen in our alveoli is determined by the alveolar gas equation: PAO2 = ( FiO2 * (Pb – 47)) – (PaCO2 / 0.8). For example, the pressure of oxygen at sea level is roughly 100mm Hg, whereas at Mount Everest, this pressure would be <50 mm Hg.

How do our bodies respond to this lack of oxygen?

Normal responses to hypoxemia acutely include hypoxic pulmonary vasoconstriction to shunt blood away from poorly oxygenated areas, and vasodilation in other organs, namely in the brain, to improve delivery of oxygen. The body compensates with an increase in minute ventilation. In cases of altitude related illness it is not well understood what goes wrong but, essentially, these normal adaptations are inadequate or maladaptive.

The term mountain sickness includes a spectrum of illnesses, namely the following entities: acute mountain sickness (AMS), high altitude cerebral edema (HACE), and high altitude pulmonary edema (HAPE). AMS is a clinical syndrome that occurs in someone who has ascended >2500 meters. Clinical features are the presence of a headache AND at least one of the following: GI symptoms, insomnia, fatigue, or dizziness. HACE is considered an end-stage form of AMS; ataxia and change in mental status are the key features of this syndrome. HAPE is a type of noncardiogenic pulmonary edema that results from acute pulmonary hypertension and manifests with typical symptoms of pulmonary edema-dyspnea, cough, decreased exercise tolerance, etc.

Treatment of all forms of mountain sickness includes immediate descent and oxygen supplementation. Vasodilators (calcium channel blockers, phosphodiesterase 5 inhibitors) and long acting beta agonists have been studied in the prevention of HAPE. In addition, steroids, diuretics, and vasodilators have also been studied for the treatment of HACE and HAPE. Treatment and prevention of AMS includes primarily the use of acetazolamide (diamox).

Slow ascent to allow acclimatization is the key to preventing AMS; avoiding a direct ascent of 2750 meters is considered a standard recommendation. Acetazolamide is a carbonic anhydrase inhibitor and works by stimulating renal bicarbonate excretion. The increased blood acidity serves as a central stimulus to increase ventilation, thus facilitating adaptation to hypoxic conditions.

Show me the data! Here are a few trials:

Basnyat et al, looked at the efficacy of low-dose acetazolamide for the prophylaxis of AMS.1 In this prospective, double-blind, randomized, placebo-controlled trial, acetazolamide at 125mg bid or placebo was given to approximately 200 healthy trekkers to Mount Everest. In the treatment group, only 9 out of 74 (12.2%) developed AMS versus 20 out of 81 (24.7%) in the placebo group; the number needed to treat (NNT) in this trial was 8. Another randomized, double-blind, placebo-controlled trial, compared ginkgo biloba and acetazolamide for the prevention of acute mountain sickness among Himalayan trekkers.2 In this trial, acetazolamide 250 mg bid, gingko biloba, both, or placebo were given to more than 600 western trekkers to Mount Everest. In the acetazolamide group, 12% developed AMS versus 14%, 34%, and 35% for combined group, placebo, and gingko groups, respectively. The NNT in this trial was only about 4.

So regarding our family member, unless Uncle Joe is allergic to sulfonamides, I would recommend acetazolamide at the 250 mg twice-daily dose. Other contraindications to taking acetazolamide include hepatic disease, hyponatremia or hypokalemia; adrenocortical insufficiency, hyperchloremic acidosis, severe renal dysfunction, and severe pulmonary obstruction. Addressing any underlying cardiac, pulmonary function prior to climbing to such a great height would be of utmost importance. In addition, if Uncle Joe is diabetic, acetazolamide should be used with caution as it can cause a change in glucose control. Assuming Uncle Joe has none of the above medical conditions to cause concern in recommending acetazolamide, he should begin taking it 24-48 hours before ascending and continue it for at least 48 hours after arrival at his high altitude.

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

1. Basnyat B et al. Efficacy of low-dose acetazolamide (125 mg BID) for the prophylaxis of acute mountain sickness: a prospective, double-blind, randomized, placebo-controlled trial. High Alt med Biol. 2003; 4(1): 45-52.

2. Gertsch JH et al. Randomised, double blind, placebo-controlled comparison of ginkgo biloba and acetazolamide for prevention of acute mountain sickness among Himalayan trekkers: the prevention of high altitude illness trial (PHAIT). BMJ. 2004; 328(7443):797. Epub 2004 Mar 11.

Faculty peer reviewed and commentary by Nishay Chitkara MD, Instructor of Clinical Medicine, Division of Pulmonary and Critical Care Medicine:

The hypoxic ventilatory response (HVR) is an increase in alveolar ventilation initiated by the carotid body upon ascent. When one remains at the same altitude, this peripheral chemosensor increases its sensitivity to hypoxemia, and an even greater increase in ventilation ensues. The result is a rise in arterial oxygen content and a respiratory alkalosis which is only partially compensated by kidneys. Acetazolamide effectively mimics this normal acclimatization response, by inducing a respiratory acidosis (impaired cellular delivery of CO2 to the lungs) and a metabolic acidosis (enhanced renal bicarbonate excretion), thus stimulating alveolar ventilation. It also prevents two commonly encountered phenomena in acclimatizing individuals: periodic breathing and accentuated hypoxemia during sleep.

The mechanisms of disease for both HACE and HAPE have undergone much investigation. The HVR protects against hypoxia-induced stresses which lie at the root of their development. Much evidence supports the formation of HACE as a consequence of vasogenic edema and hypoxia-induced increased permeability of the endothelium. In HAPE, exaggerated pulmonary vascular responses to hypoxia can lead to high intravascular pressures and stress injury of the pulmonary microvasculature. Acetazolamide can be effective in the prevention of HAPE, by reducing pulmonary vascular resistance. It does not however substitute for more established HAPE treatments such as calcium channel blockers, PDE-5 inhibitors, glucocorticoids, or beta-agonists.

You may want to warn your Uncle Joe about carbonated beverages during his trek to the Himalayas – acetazolamide tends to make them distasteful!

1. Schoene, Robert B. Illness at High Altitude. Chest. 2008; 134:402-416.

Grand Rounds: The Role of Omega-3 fatty Acids in Rheumatoid Arthritis

May 6, 2009

Grand Rounds ImageMichael Owen MD

Please also see the clinical vignette presented before Grand Rounds on the 15th of April.

Grand rounds on April 15th was presented by Dr. Joel Kremer, Pfaff Family Professor of Medicine at Albany Medical College and Director of Research at the Center for Rheumatology. Dr. Kremer informed the NYU community about the role of omega-3 fatty acid supplementation in rheumatoid arthritis.

Dr. Kremer began with an overview of fatty acid biochemistry including saturated, mono-unsaturated, and polyunsaturated fatty acids. Omega-3 fatty acids are in the polyunsaturated group and include alpha-linolenic acid, EPA, and DHA. Alpha-linolenic acid was the highest omega-3 in the diet of pre-industrial humans. It is found in some plants and in livestock that are grass-fed. It is less common in modern diets because most livestock are grain-fed. Alpha-linolenic acid is the predominant omega-3 in flax seed oil supplements. On the other hand, EPA and DHA mostly come from cold water fish, such as wild salmon, tuna, and mackerel. Similar to the difference between grass-fed vs. grain-fed livestock, farm-raised salmon contains less EPA and DHA than wild salmon.

Dr. Kremer reviewed data that the amount of omega-3 fatty acids in the average diet since the advent of industrial agriculture has declined, while the content of omega-6 and saturated fats has dramatically increased. Alterations in the ratio of omega-3 to omega-6 can change the metabolism of these fatty acids and increase or decrease the ratio of the final metabolic products including thromboxane and prostaglandins and thereby alter the inflammatory cascade. Dr. Kremer reviewed evidence and hypotheses that increasing the proportion of omega-3 relative to omega-6 can increase red blood cell deformability, decrease platelet adhesion and aggregation, decrease blood pressure, decrease the incidence of arrhythmias, decrease the size and density of lipoproteins, and decrease the production of interleukin 1. These findings correlate with epidemiological studies that have shown decreased rates of cardiovascular mortality in populations with increased dietary intake of omega-3, such as in Crete and Greenland.

Next, Dr. Kremer discussed evidence of benefit from omega-3 in clinical and basic science research. One study showed an increased time to induction of symptoms from cold exposure in patients with Raynauld’s after 6 weeks of supplementation with 3 g/day of fish oil. Also, omega-3 was shown to decrease proteinuria and mortality in a mouse model of SLE. Finally, Dr Kremer commented on the implications of the Jupiter study with regard to the role of inflammation in cardiovascular disease.

The core of the presentation was Dr. Kremer’s review of the literature on omega-3 supplementation in rheumatoid arthritis. In all, he said that there have been 20 published clinical trials testing the hypothesis that omega-3 could be beneficial in rheumatoid arthritis. Most of these studies were published in the 1980’s and 1990’s. All 20 showed a reduction in the number of painful joints after supplementation with at least 3 g/day of fish oil for at least 12 weeks. Some also showed a reduction in morning stiffness and reduced levels of leukotriene B4. Several of the studies were limited by small numbers and flawed study design, including a crossover study with a washout period that was too short.

Dr. Kremer ended by saying that the potential role of omega-3 fatty acids in decreasing cardiovascular morbidity and mortality in patients with rheumatoid arthritis deserves further study.

Dr. Owen is a second year resident in internal medicine at NYU Medical Center.

Mystery Quiz- The Answer

May 1, 2009

Posted by Vivian Hayashi MD and Robert Smith MD, Mystery Quiz Section Editors

The answer to the mystery quiz is sarcoidosis. The CXR shows diffuse, bilateral infiltration with a predominantly nodular pattern. The pulmonary hila are also prominent. The CT image shows innumerable 2-3mm nodules, many of which have a perilymphatic distribution. The lymphatics, in parallel with the pulmonary vasculature, course through the interstitium. Hence, the perilymphatic nodularity has an interstitial distribution and appears as “studding” along the interstitium which is enhanced by vascular contrast (Image 2, short arrows). Additional nodules, however, have a random distribution (Image 2, arrowhead), while others appear to be centrilobular (Image 2, long arrow). As a granulomatous disease that involves activated CD4 lymphocytes, it is not surprising to find pathological involvement of perilymphatic tissue along with lymph nodes (Image 3, arrows). That said, sarcoidosis may involve any anatomical lung site: airways, interstitium or alveoli.

Perilymphatic nodularity also appears in the fissures and along the pleura where lymphatics are found (not shown). Other lung diseases included in the differential are also characterized by small nodules on chest imaging. Depending on their origin, the nodules have different distributions. Hematogenous spread of disease, such as miliary TB, will appear as interstitial disease because it is perivascular. Interstitial nodules due to miliary TB or metastatic disease, for example, appear to have sharp borders because they are enveloped by the interstitium which gives them a smooth edge on imaging. Nodules that arise from endobronchial spread of disease, such as aspiration or aerogenous spread of infection, often appear in a centrilobular distribution. The centrilobular location is where a bronchiole, filled with material conferring the appearance of a radiographic nodule, enters the lobule. The lobule appears as a polygonal structure (distal interstitium) on CT imaging. Beyond the bronchiole, nodules will manifest with a fuzzy border because they occupy airspace. Such nodules may also appear larger depending on how much neighboring airspace is involved.

Our patient was treated with prednisone to alleviate his cough. His cough improved after a few weeks and repeat imaging showed regression of the pulmonary nodules (Image 4) and mediastinal lymphadenopathy (Image 5). Our case illustrates how patients with sarcoidosis often have imaging that is worse than would be expected from their clinical presentation.



Should we treat asymptomatic autoimmune hepatitis?

April 30, 2009

120px-gray1086-liverBani Chander MD

Faculty Peer Reviewed

Autoimmune hepatitis (AIH) is a progressive, inflammatory disease of the liver of unknown etiology and may progress to cirrhosis. While it is does have a predilection for women, this disease entity crosses genders and ethnic groups, and may occur in both adults and children. AIH is characterized by a fluctuating course and is often associated with autoimmune features including hypergammaglobulinemia, circulating serum autoantibodies, and hepatitis with lymphoplasmacytic infiltration on liver biopsy . Autoimmune hepatitis is a heterogeneous disease with a broad spectrum of clinical manifestations ranging from mild, non-specific symptoms to fulminant hepatic failure. The physical findings range from a normal examination to the presence of hepatomegaly, jaundice and all other stigmata of cirrhosis. It is important to be aware that long periods of subclinical disease may occur for years before or even after the time of diagnosis.

Autoimmune hepatitis is most likely the result of a cell-mediated immunologic attack against hepatocytes that have an aberrant display of human leukocyte antigen (HLA) class II on the surface. These activated liver cells stimulate the clonal expansion of sensitized cytotoxic T cells. Cytotoxic T cells, in turn, invade liver tissue where they release cytokines, and destroy the liver cells. Although the etiology for aberrant HLA display in AIH remains uncertain, environmental agents are postulated to play a role; evidence points to, among other things, a viral trigger. Viruses that have been postulated to elicit disease include hepatitis viruses, EBV, measles, and CMV and disease induction may occur many years before clinical symptoms manifest. Most recently, two medications have also been implicated in inducing AIH; Minocycline and statins, both of which have been known to induce other autoimmune syndromes, have now been identified as possible triggers of AIH. Although the majority of cases of medication-associated AIH have been shown to improve with discontinuation of offending drugs, a smaller number of cases will progress into chronic AIH.

Type 1, the most common and also considered to be the classic form of autoimmune hepatitis, is characterized by circulating serum antibodies to nuclei (ANA) and/or smooth muscle (ASMA) and/or antiactin antibodies (AAA). Other autoantibodies may also occur less commonly in this type. Type 2 AIH is instead characterized by the presence of antibodies to liver/kidney microsomes (ALKM-1), which are directed towards an epitope of CYP2D6 (cytochrome P450IID6), and/or antibodies to a liver cytosol antigen (ALC-1 or LC1). Type 1 may affect people of all ages while type 2 typically affects young women.

Much is known about the disease history of symptomatic AIH, including its prognosis as well as treatment. In fact, large clinical trials have demonstrated a mortality benefit in treating those with moderate to severe disease with immunosuppressive therapy including glucocorticoids with and without azathioprine (AZA) or 6-mercaptopurine (6-MP). AZA and 6-MP may be administered as steroid-sparing agents to avoid long-term use of steroids, with their attendant long-term complications. Unfortunately, the natural history and treatment options for asymptomatic AIH remains poorly understood. While there is data to suggest that asymptomatic patients clearly have the potential to progress to cirrhosis, for the most part, the prognosis remains unclear. Given that corticosteroids have numerous toxicities, it would be helpful to know if there is a clear mortality benefit with immunosupression in those patients who remain asymptomatic.

Feld et al , in a recent retrospective study of autoimmune hepatitis, compared survival in symptomatic patients with AIH to those who were asymptomatic. The authors reviewed the charts of all patients given a clinical diagnosis of type 1 AIH at a single medical center between the years of 1970 to 2002. They found that asymptomatic patients (who made up 25% of the total cohort) tended to have overall lower serum aminotransferases, bilirubin, and immunoglobulin levels at baseline. The asymptomatic patient group was primarily composed of patients with an inflammation-induced transaminitis, but without cirrhosis on liver biopsy and with patients with inactive “burned out” cirrhosis with near normal liver enzymes and no signs of portal hypertension or hepatic decompensation.
Ten-year survival was similar in both groups (80% vs 84%) although only half of the asymptomatic group received immunosuppressive therapy.

Survival was significantly worse in patients who had cirrhosis at the time of diagnosis in this study, regardless of presence of symptoms or receipt of therapy, although prior studies have shown that elderly patients with cirrhosis actually have a better response to treatment . The authors ultimately concluded that the prognosis is good in patients with AIH who are asymptomatic at presentation and that these patients may not require any immunosuppressive therapy. However, 25% of the study group that was asymptomatic ultimately did ultimately have progression of disease and became symptomatic during follow up.

In 2002, the American Association for the Study of Liver Diseases (AASLD) published clinical guidelines for the treatment of autoimmune hepatitis. These guidelines were based on a review of the 914 previous published global studies and recommended treatment in all patients with serum aminotransferase levels greater than 10 fold the upper limit of normal or with serum aminotransferases that are five fold the upper limit of normal in conjunction with a serum gamma globulin level at least two times the upper limit of normal. However, in patients with mild to moderate AIH, these guidelines suggested that treatment “must be individualized….and should be based on clinical judgment.” While Field et al sought to clarify these guidelines, the question of treatment in an asymptomatic patient so far remains unanswered. It is clear that further studies are needed to determine which asymptomatic patients are at highest risk of progressing to cirrhosis and which may benefit from early steroid therapy.

 Bani Chander is a third year resident in internal medicine at NYU Medical Center.

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

1) Czaja AJ. Natural history, clinical features, and treatment of autoimmune hepatitis. Semin Liver Dis 1980; 4:1-11
2) Gough A et al. “Minocycline induced autoimmune hepatitis and SLE-like syndrome,” BMJ 1996; 312: 169-72.
3) Alla V et al, “Autoimmune hepatitis triggered by statins,” J Clin Gastroenterol. 2006 Sep;40(8):757-61
4) Vento S, Cainelli F. Is there a role for viruses in triggering autoimmune hepatitis?. Autoimmun Rev. Jan 2004;3(1):61-9.
5) Liu ZX, Kaplowitz N. Immune-mediated drug-induced liver disease. Clin Liver Dis. Aug 2002;6(3):755-74
6) Field J et al, “Autoimmune Hepatitis: Effects of Symptoms and Cirrhosis on Natural History and Outcome,” Hepatology 2005; 42: 53-62
7) Czaja AJ; Carpenter HA, “Distinctive clinical phenotype and treatment outcome of type 1 autoimmune hepatitis in the elderly,” Hepatology. 2006 Feb 22;43(3):532-538
8 ) Czaja et al, “AASLD practice guidelines: Diagnosis and Treatment of Autoimmune Hepatitis, Hepatology. 2002 Aug; 36(2):479-497.


Mystery Quiz

April 28, 2009

Vivian Hayashi MD and Robert Smith MD, Mystery Quiz Section Editors

The patient is a 42 year old man with a history of non-productive cough for several weeks. Three weeks prior to evaluation by the pulmonary service, the patient presented to the ER with a presumed vasovagal syncopal event that occurred on a subway platform. The patient’s prior medical history included allergic sinusitis and nasal polypectomy. Other than cough, the patient denied constitutional symptoms. The patient was not taking any medications. His social history was negative for smoking, intravenous drug abuse, risk factors for HIV infection, significant occupational exposures and travel. The patient did not own any pets. PPD placed by the pulmonary service was negative. Physical exam revealed a thin man with normal vital signs including normal resting pulse oximetry, clear chest, and otherwise no focal findings.


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Breaking News: Swine Flu Reaches New York

April 26, 2009

pigEunice Kang, MD

The Centers for Disease Control (CDC) has confirmed eight cases of swine influenza A (A/H1N1) virus infection in New York City, in addition to a dozen cases caused by the same strain scattered throughout California, Texas, Ohio, and Kansas. The eight confirmed cases in New York are in students who just returned from a trip to Mexico, where officials began reporting three separate outbreaks of influenza-like illness beginning March 18th. According to the New York Times there have been 81 deaths and approximately 1,300 illnesses caused by the swine flu in Mexico, the apparent epicenter of the outbreak, prompting President Felipe Calderón to announce that the government would “take all the necessary measures to deal with this epidemic.” While the swine influenza virus has been confirmed in only 20 of the 81 deaths in Mexico, many of the affected were adults who were previously healthy, an epidemiologic trait that distinguishes the swine flu virus from other flu viruses of prior pandemics.
Swine influenza virus, like other animal flu viruses, usually causes a respiratory illness confined to the animal population that serves as its source. The swine flu virus can be spread to humans who are in close contact with pig populations. Modes of human-to-human transmission are similar to those of seasonal flu viruses. Collecting a respiratory specimen and sending it to the CDC can confirm a suspected diagnosis of swine flu.
The virus that has been isolated in Mexico and the US is being described as a new subtype of A/H1N1 not previously detected in pigs or humans. While the cases in the United States have been mild with only one requiring hospitalization, the CDC earlier today declared a public health emergency over concern of a potential swine flu pandemic. Symptoms of swine flu are similar to those of seasonal flu and include fever, malaise, lethargy, cough, anorexia, and in many cases nausea, vomiting, and diarrhea. Prevention of transmission is also similar to seasonal flu. The CDC is recommending oseltamivir (Tamiflu) and zanamavir (Relenza) as treatments for the current swine flu strain given findings of resistance to amantadine and rimantadine.
The New York City Department of Health and Mental Hygiene is currently recommending routine treatment of severe flu-like illness in people associated with the Queens high school (St. Francis Preparatory School) that is at the center of the New York outbreak. Otherwise, treatment of mild cases of flu-like symptoms, in both persons affiliated with the school and the general population, should be given to individuals who are susceptible to severe illness due to an underlying condition. For updated information on the swine flu outbreak as it evolves go to

Eunice Kang is a Third Year Internal Medicine Resident at NYU Medical Center 

Picture Courtesy Wikimedia Commons

The Skinny on Cachexia…Can it be Treated?

April 22, 2009

megace-2Michael T. Tees, MD, MPH

On the wards and in the clinic, the physician is frequently presented with a patient with a decreased appetite and alarming weight loss. The patient is likely frustrated with their own fraility, the family is upset at the poor nutritional state of their loved one, but the healthcare provider should be the most concerned. This clinical presentation without a prior diagnosis is worrisome, and if the patient does have an underlying etiology, this likely represents progression.

Caring for the cachectic patient presents a frustrating and recurring dilemma. Cachexia is defined as ongoing weight loss, often with muscle wasting, associated with a long-standing disease. In cachexia, refeeding often does not induce weight gain. Anorexia, excluding the willful avoidance of eating, usually occurs in conjunction cachexia (1).


The causes of cachexia and anorexia are only now beginning to be elucidated. Research has shown the important role of cytokines causing metabolic abnormalities in chronic illnesses, such as cancer, chronic obstructive pulmonary disease (COPD), HIV-associated wasting syndrome, cardiac disease, and some rheumatologic diseases (1). Cytokines are elevated in pro-inflammatory states and have been found to cause an activation of proteolysis and lipolysis (2, 3). Many tumors are known to produce their own cytokines, which were found to cause a decreased appetite and weight loss in animal models (4). The activity of the various cytokines involved produces a net negative energy balance in the patient suffering from a chronic disease.

There are several other implicated hormonal factors that may induce cachexia. Decreased testosterone levels, seen in the aging and those with disease may lead to cachexia. Testosterone normally inhibits macrophage release of pro-inflammatory cytokines, and low levels of the hormones is associated with lipolysis and anorexia (5, 6). Studies have also found alterations in insulin-like growth factor (IGF)-1, which normally works to increase muscle protein synthesis (4). However, low concentrations are found in malnourished individuals. Elevated glucocorticoid levels are also seen in cachectic patients; these hormones are known to suppress cell transporters involved in amino acid and glucose uptake (6).


The prognostic sign of cachexia is alarming. In cancer patients, weight loss documented prior to initiating chemotherapy predicts a shortened survival than those who had maintained weight (7). In nursing home residents, long-term patients losing 5% or more of his or her body weight have a 10-fold increase in mortality over 6 months compared to those who gain weight over a 1 month period (8). This indicates that if any intervention can be effective to reverse or stop weight loss, the physician should employ them early. Unfortunately however, a meta-analysis found that nutritional supplementation alone does little to decrease mortality or complications (1).


Megestrol acetate (Megace) is the most studied progestational agent, and its efficacy likely stems from its suppression of cytokines or cytokine receptors. Megestrol can improve appetite and induce weight gain in patients with cancer, HIV-associated wasting syndrome, end-stage renal disease on dialysis, and those requiring long-term care. Studies have shown appetite increased in 50-75% of patients, and modest weight gains in 50-70%, varying by disease and study. Typically, single digit kg gains were seen in those who responded to the medication, and cancer patients gained just over 1 kg on average (1). Importantly however, Megestrol has been associated with venous thromboembolism, deep venous thrombosis, hypertension, impotence, edema, and suppression of the pituitary-adrenal axis. In cancer patients, who already have an increased risk of thrombosis, the physician must prescribe judiciously.

Dronabinol (Marinol) and nabilone (Cesamet) are cannabinoids that are often used to treat chemotherapy related nausea and vomiting. Cannabinoids work on central CNS receptors, and have also been found to improve appetite in cancer and AIDS patients. However, this class was found to induce weight gain only in long-term care patients (1). The cannabinoids may induce dependence, but more commonly side effects of tachycardia, dizziness, somnolence, anxiety, paranoia, hallucinations, or confusion cause the medication to be discontinued. In a direct comparison study, appetite improvement was reported in 75% of patients taking megestrol compared to 49% of those receiving dronabinol (9).

Corticosteroids, such as dexamethasone, have been studied and used to treat anorexia and cachexia. The corticosteroid decreases the inflammatory state, and has efficacy with preventing chemotherapy related nausea/vomiting. This therapy is effective at improving appetite in patients with cancer or HIV-associated wasting syndrome. This therapy has been shown to induce weight gain comparable to megestrol, however, the side effects of steroid therapy caused discontinuation more frequently than with megestrol (10). Corticosteroids can potentially cause gastritis, hyperglycemia, immune suppression, and weakness. These side effects are so significant, that in cancer, it is recommended to use only near the end-of-life. However, if treatment is indicated and the patient has a history of DVT, corticosteroid use can be considered as an alternative to megestrol (7).

Another anti-inflammatory, thalidomide, works by suppressing TNF-a. Thalidomide therapy has been proven effective at inducing weight gain in those with HIV-associated wasting, but only one small study showed weight gain in cancer patients (11). Thalidomide use has been associated with fevers, sensory neuropathy, neutropenia, thromboembolism, rash and sedation.

Oxandrolone, an androgen that inhibits IL-1, IL-6, and TNF-a, can produce weight gain in HIV-associated wasting syndrome, but has not yet been proven efficacious in other cachectic states (1). Oxandolone and other androgens may cause hypertension, fluid retention, sexual organ alterations, masculinization, hepatic disease, and dyslipidemia, among other effects.

Cyproheptadine, an anti-histamine, has been shown to help with anorexia in cancer patients, but not with weight gain. Cyproheptadine may cause agranulocytosis or thrombocytopenia, but more commonly dry mouth, dizziness, and fatigue are side effects.

Sadly, reviewing all available therapies shows that even the “best” medication, megestrol, rarely leads to significant weight gain. Furthermore, combination therapy has not been proven to be more effective than a single agent. Of the many potential interventions being assessed, researchers have been studying anti-cytokine and anti-inflammatory agents. Researchers are also focusing on blocking the proteolytic system, while others are looking at inducing protein synthesis. Some trials are ongoing, such as the use of oxandrolone in cancer patients (12). With multiple biological pathways and cellular signals involved in cachexia and anorexia, research will continue and hopefully yield favorable results in the near future. Until better therapies are developed, treating the patient with a poor nutritional state will continue to be a difficult problem.

Peer Review/Commentary by Theresa Ryan, MD Assistant Professor of Medicine, NYU Division of Medical Oncology:

Anorexia-Cachexia Syndrome, or ACS, affects up to 80% of patients with advanced solid tumor malignancies. Although definitions vary, ACS is typically  defined as a weight loss of  > 5% of a patient’s pre-illness weight over a 2-6month period. ACS causes both physical and psychological distress and is associated with early mortality independent of staging, functional status or tumor histology. ACS can be categorized as primary or secondary. Primary ACS results from a hypermetabolic state caused directly by cancer while secondary ACS results from cancer-related barriers that reduce dietary intake, such as nausea/vomiting, mucositis, intestinal obstruction etc. For primary ACS, therapies have primarily been directed at appetite stimulation with newer therapies targeting the proinflammatory/hypermetabolic state while the role for nutritional support such as TPN is predominantly in secondary ACS.

The above reviewed some of the available drugs to combat ACS as well as some the possible future agents. But drugs are just one part of the treatment of ACS. Nutritional, psychological, and behavioral therapies are important components and should be incorporated into a multidisciplinary approach to this complex medical problem. Physicians, nurses, and dietitians, along with patients and families, can identify specific needs and plan individualized treatment. The first attempt should be to maximize oral intake by allowing the patient flexibility in type, quantity, and timing of meals. Interventions to should also be aimed at minimizing the secondary factors of nausea, vomiting, diarrhea, pain, fatigue, changes in taste, or food preferences that may influence appetite. Encouraging patient and family interactions and providing emotional and educational support may be helpful. For example, when family members are able to provide the patient’s favorite foods, food intake usually improves.

In addition, psychiatric disorders are common among cancer patients. ACS may result in a secondary depression, or depression may be a prime contributor to the anorexia and subsequent weight loss. Evaluations of relaxation, hypnosis, and short-term group psychotherapy have suggested some benefit with regard to anorexia and fatigue

Ultimately, the best way to treat cancer related ACS is to cure the cancer, but unfortunately this remains an elusive goal for most patients with advanced solid tumors. That being said, if cure is not possible, chemotherapy does have an important role in palliation including demonstrated ability to ameliorate ACS.  One example is in the treatment of advanced pancreatic cancer. In this pivotal trial of 1st line chemotherapy for advanced pancreatic cancer the novel endpoint of clinical benefit response (CBR) was used. CBR was defined as improvement in quality of life factors such as amount of pain medication used (decrease of >50% as positive) performance status (improvement of >20points in KPS) and weight gain (of >7%). To be classified as having a positive response, a patient had to have exhibited sustained (4 wks) improvement in at least one of the CBR components, without deterioration in any of the others. The number of patients experiencing a CBR was significantly greater in the group randomized to Gemcitabine (23.8%) vs. control arm (4.8%; p = 0.0022). It was this improvement in CBR that was one of the critical endpoints that led to the FDA “approval” of Gemcitabine and its subsequent establishment as standard of care for metastatic pancreatic cancer.  Better future cancer treatment will also hopefully also continue to lead to improvements in the treatment of cancer related ACS.

References for Part 1:

1. Thomas DR. Guidelines for the use of orexigenic drugs in long-term care. Nutr Clin Pract 2006; 21:82-7.  

2. Kotler DP. Cachexia. Ann Intern Med 2000; 1333:622-34.

3. Mitch WE, Goldberg AL. Mechanisms of muscle wasting. The role of the ubiquitin-proteasome pathway. N Engl J Med 1996; 335:1897-1905.

4. Jatoi A. Weight loss in patients with advanced cancer: effects, causes, and potential management. Curr Opin Support Palliat Care 2008; 2:45-8.

5. D’Agostino P, Milano S, Barbera C, et al. Sex horome modulate inflammatory mediators produced by macrophages. Ann NY Acad Sci 1999; 876:426-9.

6. Morley JE, Thomas DR, Wilson MG. Cachexia: pathophysiology and clinical relevance. Am J Clin Nutr 2006; 83:735-43.

7. Jatoi A. Pharmacologic therapy for the cancer cachexia/weight loss syndrome: a data-driven, practical approach. J Support Oncol 2006; 4:499-502.

8. Ryan C, Bryant E, Eleazer P, Rhodes A, Guest K. Unintentional weight loss in long-term care: predictor of mortality in the elderly. South Med J 1995; 88:721-4.

9. Jatoi A, Windschitl HE, Loprinzi CL, et al. Dronabinol versus megestrol acetate versus combination therapy for cancer-associated anorexia: a North Central Cancer Treatment Group Study. J Clin Oncol 2002; 20:567-73.

10. Loprinzi CL, Kugler JW, Sloan JA, et al. Randomized comparison of megestrol acetate versus dexamethasone versus fluoxymesterone for the treatment of cancer anorexia/cachexia. J Clin Oncol 1999; 17:3299-3306.

11. Bruera E, Neumann CM, Pituskin E, et al. Thalidomide in patients with cachexia due to terminal cancer: preliminary report. Ann Oncol 1999; 10:857-9.

12. Strasser F. Appraisal of current and experimental approaches to the treatment of cachexia. Curr Opin Support Palliat Care 2007; 1:312-6.

References for Commentary:

HA Burris, 3rd, MJ Moore, J Andersen, MR Green, ML Rothenberg, MR Modiano, MC Cripps, RK Portenoy, AM Storniolo, P Tarassoff, R Nelson, FA Dorr, CD Stephens, and DD Von Hof     Improvements in survival and clinical benefit with gemcitabine as first- line therapy for patients with advanced pancreas cancer: a randomized trial.  Journal of Clinical Oncology 1997;15(6):2403-2413

Michael Tees is a first year resident in Internal Medicine at NYU Medical Center

Clinical Questions: How do you dose argatroban?

April 16, 2009


Frederick Gandolfo, MD

Case: An 85 year-old woman admitted to the hospital with pneumonia and after a prolonged hospital course developed heparin-induced thrombocytopenia (HIT). She is currently being treated with argatroban and her platelet counts are recovering. You are the covering physician and are called by the lab for an INR of 12 on her routine labs. The patient shows no signs of bleeding and she is not on warfarin. The PTT at the time is 160 seconds. What is the appropriate course of action?

A few questions immediately come to mind:
• How are the INR and PTT interpreted while on direct thrombin inhibitors?
• Is there a co-existing coagulopathy and can that be determined from the numbers provided?
• How can this patient be safely transitioned to warfarin for long term therapy?

The direct thrombin inhibitor argatroban is widely used in the treatment of HIT to prevent thrombotic complications of the disease. The usual course of therapy conshists of discontinuing all sources of heparin, starting an alternative injectable anticoagulant, and then initiating warfarin when the platelet count recovers to above 150, 000/mL. Warfarin and the non-heparin anticoagulant should then overlap for 5 days. The INR on warfarin should be therapeutic (between 2-3) for at least 48 hours before discontinuing the injectable anticoagulant.

Converting patients from agratroban to warfarin is problematic, since argatroban elevates the PT/INR making the actual PT/INR difficult to interpret while the patient is still receiving argatroban. GlaxoSmithKline, the manufacturer provides a curve to estimate the actual INR from the measured INR while receiving ( Using the curve, to obtain an actual INR of 2-3 with warfarin alone, the measured INR while on argatroban and warfarin can be between 3-6 depending on the specific reagent used by the lab. Thus, one way of successfully transitioning patients from argatroban to warfarin is to aim for an INR goal of approximately 4 measured at a time when the PTT is in the therapeutic range. It can then be predicted that the INR once off argatroban will be approximately 2-3, which solely reflects the influence of warfarin. However, the manufacturer warns that this linear relationship becomes unpredictable at argatroban doses exceeding 2 mcg/kg/min.

Is there a way to predict the actual INR from the measured INR at higher argatroban doses? In the case above, was the elevation in INR solely due to the supratherapeutic dose of argatroban or was it too high to be explained by argatroban alone and may instead be a result of a concomitant coagulopathy? A brief review of the literature revealed a study by Warkentin et al.that measured the PTT and INR elevations obtained y spiking plasma samples with several direct thrombin inhibitors including argatroban. The therapeutic concentration of argatroban in humans (defined as increasing the PTT twofold) is approximately 1 micromole/L. The highest concentration of argatroban tested in this study, 8 micromoles/L (eight times the therapeutic concentration), resulted in a PTT of approximately 150 seconds and an INR range of approximately 8-14, depending on the reagent used by the lab. Thus, the INR prolongation obtained by extreme supratherapeutic concentrations of argatroban does indeed appear unpredictable, resulting in a wide range of the measured INR. It also appears that the INR increase observed at supratherapeutic concentrations of argatroban rises out of proportion to the 1-2 INR units expected when argatroban is used at therapeutic concentrations. Thus, caution should be used when dosing argatroban, as the effect on INR prolongation is variable at supratherapeutic doses.

To monitor coumadin anitcoagulation in these patients, it is recommended to hold argatroban until the PTT is elevated to approximately two times the upper limit of normal and to recheck the INR at that time, using the adjustment curve provided by the manufacturer. An alternative to the INR would be to measure factor X activity by chromogenic assay.

Thus, in the case above, the proper course of action in the non-bleeding patient it to hold the argatroban and recheck the INR and PTT in approximately 2 hours. If the PTT decreases to normal but the INR remains elevated then there is evidence for a concomitant coagulopathy that cannot be explained by argatroban or alternatively the patient is highly sensitive to Coumadin AC.

Bottom line:
• The goal PTT for argatroban therapy is two-times the upper limit of normal for the lab.
• In HIT, warfarin should be started after both the platelet count recovers above 150,000 and the patient has been therapeutic on argatroban.
• After a minimum of five days of argatroban therapy and warfarin overlap, it is safe to stop the argatroban when BOTH the PTT is in the therapeutic range AND the INR has been approximately 4 for a minimum of 48 hours.
• The INR should be rechecked 2-4 hours after discontinuing argatroban. This should be the “true” INR reflective of warfarin alone, and should now be between 2-3.
• In patients on argatroban, the INR should not be monitored until the patient is ready to be transitioned to warfarin therapy.
• In patients on argatroban, the INR should not be interpreted when the PTT is greater that twice the upper limit of normal.

Faculty Peer Reviewed and Commentary by David Green PhD, MD NYU Division of Hematology and Oncology

HIT is said to be the most hypercoagulable state known. There is now widespread recognition of this rare but potentially devastating complication. HIT is much less common with low-molecular-weight heparin and to my knowledge there is only a single published case report of HIT with fondaparinox.

Fortunately, we have three direct thrombin inhibitors (DTIs) available as alternative anticoagulants for the treatment of HIT. HIT laboratory testing is highly sensitive but suffers from poor specificity and we are consequently over-diagnosing HIT. In the above clinical vignette, the INR on DTI therapy is significantly elevated. But why was it ordered to begin with? After all, the calculation of INR is heavily influenced by the ISI assignment of the thromboplastin, which is calibrated by its sensitivity to the relative depletion of vitamin K dependent factors by warfarin. The use and interpretation of INR in other clinical settings is controversial. The INR alone should not be used to guide clinical decision-making of patients on DTIs unless they are being transitioned to warfarin, since the known interference of the INR by DTIs values makes it difficult to interpret. One must consider the basis and limitations of clinical laboratory testing. Adding to the uncertainty, PTT reagents are not standardized for sensitivity to DTIs, although there is no practical alternative at the moment. Fortunately in practice the transition from DTIs to warfarin anticoagulant is fairly seamless, even if the tools for monitoring anticoagulation intensity in this setting are far from optimal.

Further reading:

N Engl J Med. 2006 Aug 24;355(8):809-17. PMID: 16928996

Walenga JM, Fasanella AR, Iqbal O, Hoppenstaedt D, Sarfraz A, Wallis D, Bakhos M. Coagulation laboratory testing in patients treated with argatroban. Semin Thromb Hemost 1999;25:61-66. PMID: 10357154

Warkentin TE, Greinacher A, Craven S, Dewar L, Sheppard JI, Ofosu FA. Differences in the clinically effective molar concentrations of four direct thrombin inhibitors explain their variable prothrombin time prolongation. Thromb Haemost 2005;94:958-64. PMID: 16363236

Fenyvesi T, Joerg I, Harenberg J. Influence of lepirudin, argatroban, and melagatran on prothrombin time and additional effect of oral anticoagulation. Clin Chem 2002; 48:1791-1794. PMID: 12324500

Siegmund R, Boer K, Poeschel K, Wolf G, Deufel T, Kiehntopf M. Influence of direct thrombin inhibitor argatroban on coagulation assays in healthy individuals, patients under oral anticoagulation therapy and patients with liver dysfunction. Blood Coagul Fibrinolysis 2008;19(4):288-93. PMID: 18469550

Fred Gandolfo is a third year resident in Internal Medicine at NYU Medical Center

Grand Rounds: Gastroesophageal Reflux Disease (GERD)

April 15, 2009

Grand Rounds ImageSummary by Daniel Frenkel MD

Please also see the clinical vignette presented before grand rounds on the 1st of April.

In his grand rounds lecture on April 1st 2009, Dr. Fritz Francois enlightened us to some novel aspects of gastroesophageal reflux disease (GERD). Despite simple and effective treatment approaches such as acid suppression medication, Dr. Francois explored “why the issues are still burning?” by discussing the changing face of GERD, the connection to obesity, and it’s association with Helicobacter Pylori.

What is GERD? As Dr. Francois explains, it is traditionally the reflux of gastric contents into the esophagus leading to symptoms and/or mucosal damage. However, it took a lot of debate from leading experts to arrive at a globally accepted definition for “GERD” and interestingly, some languages don’t have words to describe heartburn or refux, which has provided difficulty in identifying this disorder. From observational studies, GERD appears to be most common in North America with an increase in prevalence from 12% to >20% over the past decade. There haven’t been any studies looking at GERD or its complications in Africa, however, Dr. Francois points out that looking at racial and geographic differences may help elucidate some of the mystery of GERD.

The concern for the development of GERD is progression to adenocarcinoma since data from the National Cancer Institute’s Surveillance Epidemiology and End Results (SEER) program has shown a 5-fold increase in esophageal adenocarcinoma over the past 25 years while squamous cell carcinoma is on the decline. An proposed paradigm for progression is movement from: normal epithelium à esophagitis à Barrett’s à Dysplasia à adenocarcinoma. According to cross-sectional surveys, there are no significant differences in weekly GERD symptoms among races, however, whites have a significant increase in esophagitis (2 times more likely) and Barrett’s esophagus (3-5 times more likely). Given this racial/ethnic discrepancy in reflux-associated pathology one is left asking is this paradigm correct and what predicts progression to esophagitis and beyond? Studies have identified several independent predictors of progression in GERD: male gender (RR4.3), smoking (RR 1.2), acid suppression (RR 0.54), and interestingly metabolic syndrome (RR 1.75). Therefore energy homeostasis shoud be evaluated as part of the pathophysiology of GERD.

Obesity is increasing throughout the world in both the developing and developed world. Increases in both BMI and abdominal diameter have been shown to correlate with increases in GERD, regardless of gender. In a meta-analysis, it was estimated that a BMI>25 was associated with GERD (OR 1.43), esophagitis (OR 1.76), Barrett’s esophagus (OR 2.46), and adenocarcinoma (OR 1.52). How can one connect obesity to GERD? Mechanisms include effects on esophageal motility, lower esophageal sphincter pressure, increased hiatal hernias, increased intragastric pressure, and physiologic factors.

The physiologic mechanism of swallowing involves decreased pressure of the lower esophageal sphincter at the initiation of the swallow, ahead of the transit of the bolus. Although this can expose the esophagus to gastric contents and reduce the pH, it is short-lived (less than 5 seconds) and the contents are cleared by the physiologic swallow mechanism. Transient lower esophageal sphincter relaxations (TLESRs), which is the physiologic mechanism of belching, are not initiated by a swallow mechanism, can last upwards of 30 seconds, and as a result gives greater occasion for the esophagus to be exposed to gastric contents for a longer period of time until the next swallow mechanism clears the esophagus. Studies have shown that increased BMI and waist circumference results in an increased number of TLESRs.

In addition to physical effects on the LES, adipose tissue is metabolically active and releases numerous molecules including leptin which may have a role in GERD. Leptin’s role is to decrease food intake while it’s counterpart Ghrelin, which is secreted by the stomach, promotes food intake. Grehlin significantly fluctuates with each meal while leptin although fluctuates with meals has a gradual increase throughout the day. Leptin receptors are present throughout the GI tract and in the stomach it has been shown to reduce acid secretion. However, leptin has been shown to induce proliferation of two esophageal adenocarcinoma lines. Could leptin be the link to the progression of GERD to adenocarcinoma, i.e. more receptors in the esophagus versus more leptin secreted? Dr. Francois presented some of his own data that demonstrated the number of leptin receptors was the same in the esophagus regardless of it’s mucosal state, however, in patient’s with Barrett’s there is an increase in leptin production in the stomach fundus (for every 2 fold increase in leptin there was a 3.4 fold increase in Barrett’s). Leptin may provide an alternative metabolic mechanism for the pathophysiology of GERD.

The final topic discussed by Dr. Francois is the role of H. Pylori in GERD. Studies have linked H. Pylori eradication with the development of esophagitis and those patient were also found to have weight gain. There are conflicting results on whether H. Pylori has any association with obesity but some studies have shown that patients with H. Pylori have higher levels of leptin and lower levels of grehlin. Dr. Francois’ own research, as well as other studies, have demonstrated that the eradication of H. Pylori reversed the levels of these adipokines and is associated with an increase in BMI.

Despite what we do know regarding GERD and its treatment, there are still questions that remain regarding its pathophysiology. Dr. Francois has highlighted a pathophysiologic difference amongst races as well as some novel associations between the eradication of H. Pylori, obesity, and GERD. These interesting connections may lead to a clearer understanding of the progression of GERD to adenocarcinoma and new targets for therapy.

Daniel Frenkel is a third year resident in Internal Medicine at NYU Medical Center

Grand Rounds: Purines, Alcohol, and Fatty Liver Disease

April 8, 2009

Grand Rounds Image

Commentary by Peter Shue MD, PGY-3

The medical grand rounds presentation on March 4, 2009 was delivered by a distinguished NYU faculty member and research investigator, Dr. Bruce Cronstein.  Although his training and research is primarily in rheumatology, he breathed new insight into mechanisms of fatty liver disease.  In his talk, he reviewed his own published experiments showing that fatty liver disease, similar to gout, is potentiated by elevations in adenosine.  In gout, excess adenosine is ultimately metabolized to uric acid which is then deposited into joint spaces, causing inflammation. However, the development of fatty liver disease is mediated by cell signaling from adenosine and its receptors. He showed that excess ethanol ingestion or high fructose consumption increases adenosine levels within hepatocytes and can result in fatty liver disease.

Dr. Cronstein began his talk by introducing adenosine as an endogenous purine nucleoside which plays an important role in cellular metabolism. It is the basic substrate for the production of ATP, which is the chemical fuel for virtually all metabolic processes in the cell. Cellular stresses such as hypoxia, exposure to oxygen free radicals, direct injury and certain toxins, upregulate production of adenosine. This ultimately increases production of ATP, which alters cellular metabolism to react to the stress. Besides being a substrate for ATP production, adenosine has an important role in signal transduction. The adenosine receptor includes several subtypes: A1, A2A, A2B, and A3. They are all seven transmembrane G-protein coupled receptors. These receptors are found in multiple cell types and have a wide range of function.

The A1 receptor is responsible for AV nodal blockade and endothelial dependent vasodilation. Adminstration of intravenous adenosine has been used to terminate certain supraventricular tachycardias that require the AV node for re-entry. The A2A receptor appears to mediate an anti-inflammatory effect and is important in wound healing. The A2B receptor induces mass cell degranulation and bronchospasm. The A3 receptor currently has an unknown function. Whereas the A1,A2A,A2B receptors are well conserved among different species, the A3 is the only adenosine receptor that is poorly conserved. This makes it difficult to elucidate its function in animal models.

Heavy ethanol ingestion has been well described to result in the development of fatty liver disease. The pathophysiology is not well understood, but recent studies suggest that adenosine and its receptors may play a role in the progression of hepatic steatosis. Ethanol is metabolized to acetaldehyde by alcohol dehydrogenase, which is further metabolized to acetate by aldehyde dehydrogenase. Acetate is subsequently metabolized to acetyl-CoA, which generate adenosine from the catabolism of ATP to ADP. Ethanol is also well known to stimulate increased extracellular adenosine concentration in vitro through its action on the nucleoside transporter.

Dr. Cronstein reviewed his own experimental data that was recently published in the Journal of Clinical Investigation. In his elegant mice experiments, he demonstrated that ethanol-induced hepatic steatosis is mediated by the A1 and A2B adenosine receptors by two distinct signaling pathways in hepatocytes. The A1 receptor upregulates expression of transcription factors, SREBP1 and PPARg. The end result is the upregulation of lipogenesis in the hepatocyte. The A2B adenosine receptor activates PPARa and AMP-activated kinase that downregulate fatty oxidation and reduce ultilization of lipid stores in the hepatocyte. In animal knock-out models, mice that lack either the A1 or A2B adenosine receptor have significantly diminished fatty liver changes as compared to wildtype mice when fed ethanol. These differences were reproduced in wildtype mice that were given A1 or A2B receptor antagonists.

Non-alcoholic fatty liver disease (NAFLD) is an increasing prevalent disease process in the United States and may lead to cirrhosis. It is often associated with metabolic syndrome and/or obesity. Similar to ethanol-induced hepatic steatosis, NAFLD may also be mediated by adenosine and its receptors. High fructose ingestion is associated with NAFLD and epidemical data reveals a strong correlation in the rising incidence of NAFLD and fructose consumption (high fructose corn-syrup being an ingredient in many processed foods). Mice fed a high fructose diet develop NAFLD, which further supports this association. The mechanism may be due to the excess generation of adenosine during the metabolism of fructose. A1 adenosine receptor knock-out mice have significantly reduced fatty liver changes when compare to wildtype mice that are fed a high fructose diet.

Dr. Cronstein concluded his talk with a discussion of caffeine, a weak non-selective adenosine receptor antagonist, and its ability to reduce fatty liver changes in mice. In human epidemiological studies, Dr. Arthur Klatsky and colleagues at the Kaiser Permanente Medical Care Program studied more than 125,000 people over a 20-year period and found that drinking coffee reduced the risk of cirrhosis, particularly from alcoholic cirrhosis.

Dr. Bruce Cronstein presented an insightful grand rounds lecture on the key role of adenosine and its receptors in the development of fatty liver disease, both in alcohol and non-alcohol induced. Agents that block this pathway may have great clinical application in the future.

Bedside to Bench: Clubbing Revisited

April 3, 2009

Commentary by Judith Brenner MD, Associate Editor, Clinical Correlations 

Faculty Peer Reviewed 

For an internist, discovering a patient with clubbing is so rewarding since it appeals to the core of our profession, a profession which can often be very similar to that of a detective. The physical finding of clubbing was first described by the ancient Greeks, who recognized it to be a clue to much more.

When a clinician discovers clubbing of the fingers, he must consider that hypoxemia may be present, whether secondary to a cardiac or pulmonary process. In fact, more than 90% of clubbing is pathologic, with the remainder being a benign familial condition.

How do we recognize clubbing on physical exam?

Let’s begin at the bedside. One can judge finger clubbing in many ways. The simplest way is to think of the clubbed finger is as a “drumstick digit”. There is an increase in the curvature of the nail and a general rounding at the tip. However, curvature is difficult to measure at the bedside. Most physicians look for the “Shamroth Sign”. This sign, named for the doctor who first described it in 1976, is performed by looking for loss of the diamond that is usually formed in non-clubbed fingers when the dorsal surfaces of the distal phalanx of the right and left fingers are apposed. Unfortunately, though commonly considered to be a “standard” in terms of diagnosis, this sign has never been rigorously studied.

Another way to determine if clubbing is present involves use of the “phalangeal depth ratio.” This ratio compares the “distal phalangeal depth” with the “interphalangeal depth”. In normal individuals, the DPD:IPD ratio is <1. However, in clubbed fingers, the distal portion is thicker and thus, the ratio of DPD:IPD is >1.

The last finding to consider is the hyponychial angle. The normal angle is 180 degrees. With clubbing the curvature of the nail increases and the angle thus increases. An angle greater than 190 degrees is considered consistent with clubbing.

Unfortunately determining the evidence for these findings is difficult.  No sensitivities, specificities or likelihood ratios are available.  Why? Simply because there is no gold standard.   Here’s where experience counts.  A clinician can look at a finger, observe that its appearance is not “normal” and then start to ask the appropriate questions.

Is clubbing really a marker of hypoxic disease?

The answer is: yes.  In one study of 350 patients with clubbed fingers, 80% had underlying respiratory disorders, including tumors, abscesses, cystic fibrosis, and interstitial fibrosis.  An additional 10-15% had cyanotic heart disease, endocarditis, and even thyroid disease and inflammatory bowel disease.  Only 5% were found to be either idiopathic or hereditary.

What is the unifying pathology in all of these disorders?

On a molecular level, the pathophysiology has been studied by investigating rare individuals with familial hypertrophic osteoarthropathy.  In these patients, mutations of HPGD, a prostaglandin E2 catabolizing enzyme, has been identified.  This mutation results in elevated prostaglandin levels.  Although the familial form is rare, the secondary forms of hypertrophic osteoarthropathy (HO) are more common and clubbing is often the first clue.  The clinical commonality in many patients with secondary HO is right to left shunting.  Ordinarily, prostaglandin E2 (PGE2) is metabolized in the lung.  The hypotheseis is that, with shunting, the proper metabolism is prevented.  As a result, PGE2 levels are elevated and elevated prostaglandin levels result in platelet activation. 

Activated platelets are returned to the systemic circulation and are thought to lodge in the distal phalanges, releasing their growth factors.  While trapped, the platelets release growth factors, which leads to fibrovascular proliferation, ultimately manifesting in what we clinically call clubbing.

Though compelling, these explanations are all still just hypotheses.  While many diseases associated with clubbing have shunting in common, several do not, such as Graves’ Disease and inflammatory bowel disease.  The pathophysiology in these cases remains unclear.

The Bottom line:

Clubbing is indeed a clinical clue to an underlying disorder and thus must be taken seriously when recognized.  It is diagnosed at the bedside where simple observations are made.  When present, a search for diseases of the lungs or heart that cause right to left shunting is warranted.  If cardiac and pulmonary etiologies are ruled out, one can consider other diseases that are marked by platelet excess, such as inflammatory bowel disease.  Inheritance (<5%), since it is so rare, should be accepted as the etiology only as a diagnosis of exclusion.

Coggins, KG et al. The hippocratic finger points the blame at PGE.   Nature Genetics 2008;40:691-2.

Meyers, KA et al. Does this Patient Have Clubbing? JAMA 2001;286:341-347.

Uppal, S, et al.  Mutations in 15-hydroxyprostaglandin dehydrogenase cause
Primary Hypertrophic Osteoarthropathy.  Nature Genetics 2008;40:789-93.

McGee, S.  Evidence Based Physical Diagnosis (2nd edition).

Reviewed by Nishay Chitkara MD, NYU Division of Pulmonary and Critical Care Medicine

BREAKING NEWS: Another Nut that You’d Rather Not…

March 31, 2009


Commentary by Rebecca Hall MD, PGY-1

Growing concerns over Salmonella  contamination of pistachio products sold by Setton Pistachio of Terra Bella Inc in California have lead the manufacturer to voluntarily recall about a million pounds of its pistachio containing products. 1  The recall involves bulk lots o f roasted shelled pistachios and roasted inshell pistachios shipped on or after September 1st 2008. 2 Because pistachios are a component of numerous other products including many baked goods and nut mixes, many additional products may be affected and could be recalled in the near future.Already, nut containing products from Kroger, the “Georgia Nut Company” and  “Back to Nature Foods Company” have been recalled.

Multiple strains of Salmonella have been implicated.  Thus far, several illnesses in consumers which may be related to pistachio consumption have been reported but it has not yet been verified whether these illnesses have been caused by the Salmonella strains found on the implicated pistachio products.   Salmonellosis most often occurs in those most susceptible to food borne illness including the elderly, infants, and those with compromised immune systems.  Twelve to seventy two hours after exposure, persons infected with Salmonella may experience as diarrhea, fever, abdominal cramps.  It occasionally causes life-threatening diarrhea.3

Diagnosis is based on isolation of Salmonellae from stool cultures which takes a minimum of 48-72 hours. 4  However, given the lack of a rapid diagnostic test, symptomatic patients should be treated empirically with fluids and electrolyte replacement.  For mild to moderate illness, antibiotic treatment is not recommended for immunocompetent children over 12 months of age and adults.4  However, treatment with a fluroquinolone, TMP-SMX, or amoxicillin should be considered in immunocompetent patients with severe diarrhea (>9 stools/day), a high fever, or those patients requiring hospitalization.4


1.U.S. Food and Drug Administration, “Pistachio Product Recalls: Salmonella“. Updated 3/31/09.

2.U.S. Food and Drug Administration, “Recall- Firm Press Release, Setton Pistachio of Terra Bella”

3. CDC, Division of Foodborne, Bacterial and Mycotic Diseases.  “Salmonellosis.”  

4. “Approach to the patient with nontyphoidal Salmonella in a stool culture”, accessed 3/31/09.