Renal Tubular Acidosis and Fanconi Syndrome

Today is my last post here on Horses and Zebras. Thanks for the good times. The banner will be picked up again by the next CMR come January.


This morning we discussed Fanconi Syndrome and touched briefly on Renal Tubular Acidosis (RTA).

Here are two links to review articles, one from the Journal of the American Society of Nephrology and one from the Archives of Internal Medicine.

Some points about RTA:

1) In the setting of an acidosis, the kidneys maintain acid/base homeostasis by increasing resorption of HCO3 and increasing H+ excretion. HCO3 resorption occurs predominantly in the proximal convoluted tubule (85-95%) with the remainder occurring in the distal convoluted tubule (10%). The secretion of H+ typically occurs in the DCT as ammonium.


2) In RTA, the kidney loses the ability to perform one of these functions and a non-anion gap (hyperchloremic) metabolic acidosis develops.


3) There are 3 types of RTA:
a) Type 1 (distal)
b) Type 2 (proximal)
c) Type 4 (hypoaldosteronism)

(Type 3 RTA is a mix between types 1 and 2 and is seen in a rare genetic disorder)


4) Type 1 (distal) RTA:
a) Results in decreased ammonium secretion in the DCT causing systemic acidosis (HCO3 less than 10).
b) Most common adult causes include: autoimmune diseases (Sjogren's, RA, SLE), hyperglobulinemia, meds (lithium, amphotericin B), hypercalciuria, liver disease and sickle cell disease.
c) Often presents with NAG metabolic acidosis, hypokalemia, hypercalciuria and an elevated urine pH (greater than 5.5).

5) Type 2 (proximal) RTA:
a) Can occur in isolation, but is most commonly seen in the setting of diffuse proximal tubular dysfunction (Fanconi syndrome - as discussed today).
b) The typical findings in Fanconi syndrome include: bicarbonaturia, glucosuria, phosphaturia, uricosuria, aminoaciduria and tubular range proteinuria.
c) Isolated Type 2 RTA presents with bicarbonaturia due to impairment in bicarbonate resorption in the PCT.
d) While the bulk of HCO3 resorption occurs in the proximal tubule, some occurs in the DCT. In Type II RTA, there is a threshold level of serum HCO3 above which filtered the HCO3 overwhelms the resorptive capacity of the DCT and HCO3 loss in the urine occurs. The borderline is generally around 16mmol/L.
e) The most common cause of Fanconi syndrome in adults is multiple myeloma (due to light chains), acetazolamide use and some chemotherapeutic agents.

6) Type 4 (hypoaldosteronism) RTA:
a) Characterized by a deficiency in, or tubular resistance to, the action of aldosterone.
b) Typically presents with hyperkalemia and a mild acidosis.
c) Most common causes include: diabetic nephropathy, CKD, primary adrenal pathologies and medications that inhibit the RAAS.

7) Differentiating Type I from Type II:
a) Consider calculating the urine anion gap (Na + K - Cl) on a random sample. The Cl- is an indirect marker for NH4+ secretion and thus a positive value supports a dx of Type I RTA (reduced H+ secretion) whereas a negative value may suggest Type II.
b) An increased urine osmole gap can also suggest Type I RTA.
c) The metabolic effects of Fanconi syndrome are only found in Type II RTA.
d) Urine pH will always be elevated in Type I RTA but will be variable and increase in Type II RTA if the serum HCO3 is raised beyond the reabsorbing threshold of the DCT (since the PCT is dysfunctional).

8) Management of Type I and II RTA typically involves reversing any causative conditions and providing oral alkali either as sodium bicarbonate or citrate. Type IV RTA is managed again by addressing the underlying etiology and providing aldosterone replacement in the form of fludrocortisone.

Streptococcus Anginosus Empyema

Today we discussed a patient with a chronic empyema ultimately proven to be secondary to streptococcus anginosus.

Please follow the link to a recent review on parapneumonic effusions and empyema.

Some take-home points about S.anginosus and empyema:

1) The Streptococcus milleri group of organisms is made up of S. intermedius, S. anginosus and S. constellatus which are considered a sub-group of Viridans streptococci. These gram positive cocci are normal flora in the respiratory and GI tract and are known to cause abscesses in the brain, liver, lungs and oropharynx.

2) S.milleri are generally susceptible to beta-lactam antibiotics.

3) In general, lung abscesses related to S. milleri are thought to occur from aspiration of oropharyngeal contents.

4) Don't forget to look for the caramel of butterscotch smell associated with S. anginosus infections! Actually no, please don't.

5) The management includes prompt drainage of any collections and IV antibiotic therapy, usually with a beta-lactam. Duration of treatment is dependent on symptoms, but often a minimum 4 week duration of IV antibiotics is required. Specific antibiotic selection should be based on sensitivity testing.

6) Regarding complicated parapneumonic effusions and empyema:

a) These effusions typically occur in the context of pneumonia and represent a spectrum from an uncomplicated parapneumonic (UPPE) effusion to a complicated parapneumonic effusion (CPPE)to an empyema.

b) The signs and symptoms of an empyema are often indistinguishable from a typical pneumonia. All patients with pneumonia should be assessed for a pleural effusion.

c) In the setting of pneumonia with a pleural effusion, the phrase "never let the sun set on a parapneumonic effusion" is used to emphasize the importance of prompt investigation and drainage if necessary. Effusions greater than 10mm on the lateral decubitus CXR should be sampled.

d) More chronic presentations of an empyema can occur with less virulent organisms such as S.anginosus (as in our patient).

e) In general, a PPE should be drained if the pH of the fluid is less than 7.2, there is a positive gram stain/culture, a glucose less than 40-60 (U.S. units), an LDH greater than 1000 (U.S. units) or the effusion is greater than 50% of the volume of the hemi-thorax.

f) Drainage of a CPPE or empyema typically involves a large bore chest tube +/- adjunctive therapies such as fibrinolytics, VATS or decortication.

Antibiotics and Pneumonia

Today we talked today about a patient with community acquired pneumonia (CAP) and the appropriate antibiotics and investigations for CAP.


Here's a link to the 2007 IDSA/ATS CAP Guidelines (scroll down to CAP). The BTS also released guidelines in 2009.

In brief:


1) While it seems obvious, an infiltrate on CXR (in the right clinical context) is required for the diagnosis of pneumonia.

2) Generally, all patients with pneumonia admitted to hospital should have blood and sputum cultures drawn.

3) In patients with severe pneumonia, urinary antigens for Legionella pneumophila and Streptococcus pneumoniae should be sent.

4) Options for outpatient treatment:
a) If previously healthy, can use a macrolide or doxycyline.
b) In patients with comorbidities or recent Abx use, give a respiratory FQ or a (beta- lactam + a macrolide).
c) Remember, if the presence of macrolide resistant S.pneumo is greater than 25% in your practice area, macrolides should be avoided.

5) Inpatient, non-ICU treatment:
a) (Respiratory FQ) or a (beta-lactam + a macrolide).

6) Inpatient, ICU treatment:
a) A beta-lactam plus either a macrolide or a FQ (better evidence for FQ over macrolide).
b) If concerned re: pseudomonas, give an anti-pseudomonal beta-lactam that has anti-pneumococcal activity (PipTazo, Cefepime, Imipenem or Meropenem) plus either (Cipro of Levo) or (an aminoglycoside + azithromycin) or (an aminoglycoside + an anti-pseudomonal FQ).
c) Add Vano or Linezolid if MRSA risk factors present.

7) The beta-lactam in the outpatient and in-patient not ICU treatment arms can be high dose amoxicillin/ampicillin.

Fever of Unknown Origin

Last week Friday at Rheumatology Morning Report we discussed a patient with a fever of unknown origin (FUO).

This is a challenging Internal Medicine presentation with limited high quality evidence and a wide differential diagnosis.

A number of reviews have been published in recent years offering varied approaches to making a diagnosis. Take a look at our own Toronto approach published by Drs. Mourad, Detsky and Palda in the Archives of Internal Medicine. Two other reviews include one from AFP and another from Postgraduate Medicine.

A few points about FUO:

1) The classical definition of FUO is a temperature greater than 38.3C on multiple occasions over a period of 3 weeks with no diagnosis found after 1 week of inpatient investigations.

While this definition is likely outdated in the era of expanded outpatient management, the bottom line is that there must be a documented fever for a prolonged period of time. This is done in an attempt to exclude any transient viral infections. One modern definition suggests that the fever should persist for more than 3 weeks despite 3 outpatient visits and/or 3 days of in-hospital investigations to be considered an FUO.

The classic definition and approach to FUO typically excludes patients with HIV, immunosuppression or neutropenia.

2) The incidence of FUO has been estimated in one series to be less than 3% of admitted medical patients. The frequency of FUO continues to decline with the advent of increasingly sophisticated investigative modalities (cultures, serology, radiology).

3) The etiologies of FUO can be grouped into 5 categories: infection (16%), inflammation (22%), malignancy (7%), miscellaneous (4%) and undetermined (51%).

4) As always, the investigation should start with a focused history and physical examination. Remember to pay special attention to recent travel, medication use (including anti-pyretics), possible immunosuppression, the pattern of fever and any localizing symptoms.

5) A number of initial investigations have been suggested. One approach is to ensure the patient has a minimum set of investigations before proceeding down a FUO algorithm.

These might include:
i) CBC and differential
ii) Blood film
iii) 3 set of blood cultures (separated in space and time)
iv) Lytes, Cr, HCO3, LDH, liver enzymes and function tests
v) Urinalysis and culture
vi) CXR

From here if a source of fever has not be elucidated, further minimum investigations might include:

i) ANA and RF
ii) HIV testing
iii) CMV IgM or heterophile testing (if suggested clinically)
iv) Hepatitis serologies (if liver enzymes elevated)
v) ESR or CRP
vi) One article suggests Q-fever serology (if suspected clinically)
vii) One article suggests an SPEP (if MM suspected clinically)
viii) CK
ix) A TB skin test has been suggested in some articles

If this second set of investigations fails to yield of a diagnosis, all non-essential medications should be discontinued had imaging should be pursued:

i) CT chest/abdomen - assess for lymphadenopathy or collections
ii) One article suggests a technetium scan in addition to the above CTs.

Following these investigations, if no etiology is apparent, then further testing should increasingly be focused towards the most likely diagnosis. This may include:

i) Echocardiography - assess for valvular vegetations
ii) Leg dopplers - assess for a silent DVT
iii) Temporal artery biopsy - in patients greater than 50 years old to assess for TA
iv) Liver biopsy - if clinically deteriorating
v) Bone marrow biopsy - if abnormalities are seen in the CBC and blood film

6) Therapeutic Trials
In general, therapeutic trials of antibiotics or corticosteroids are discouraged unless a thorough hunt for an etiology has been completed. This is out of concern of exacerbating an undiagnosed infection (steroids), sterilizing cultures (antibiotics) or suppressing a fever while the etiology remains.

7) Prognosis
If no diagnosis is found after an extensive evaluation, the prognosis of these patients is generally good.

Pulmonary Embolism and IVC Filters

Today we discussed the diagnosis and management of a pulmonary embolism (PE) and the role of Inferior Vena Cava (IVC) filters.

The role of IVC filters in PE remains controversial and there is significant variability in clinical practice. Guidelines from the ACCP exist, however recent evidence suggests that up 25% of IVC filter insertions are done for indications that do not follow the guidelines.

As mentioned today, IVC filters can be associated with catastrophic consequences in the event of filter fracture and embolism as discussed in this 2010 study.

Here's an excellent recent review on acute PE from the NEJM this year and a link to the PIOPED II Trial we discussed today.

A few points on the diagnosis and management of a PE with a focus on IVC filters:

1) The diagnosis or exclusion of a PE is heavily influenced by the pre-test probability before objective testing begins. The Well's criteria is a well validated scoring system to estimate the pre-test probability of a PE:

i) Clinical symptoms of a DVT - (3 points)
ii) Other dx less likely than PE - (3 points)
iii) HR greater than 100 - (1.5 points)
iv) Immobilization for more than 3 days or
surgery within the past 4 weeks - (1.5 points)
v) Previous DVT/PE - (1.5 points)
vi) Hemoptysis - (1 point)
vii) Malignancy - (1 point)

A score of greater than 4 is considered "PE likely" whereas a score of 4 or less is considered "PE unlikely". A reasonable approach is to pursue CTA in the "PE likely" group and consider d-dimer (ELISA) testing in the "PE unlikely" group. One caveat is that most of these studies were done in outpatients and the approach of using d-dimer testing may not be generalizable to admitted GIM patients. Often this means going directly to CTA.

Remember, PIOPED II demonstrated that if the results of CTA are discordant with your clinical assessment (i.e. CTA negative in a high pre-test probability patient or positive in a low risk patient), this should promote additional testing.

2) After the diagnosis is made, anticoagulation should be initiated with heparin first (preferably LMWH over IV heparin) or Fondaparinux. The patient can then be bridged onto warfarin for a minimum of 3-6 months of anticoagulation. The exception to this is in patients with an active malignancy or receiving chemo where the CLOT Trial showed that anticoagulation with LMWH is superior to warfarin in preventing recurrent VTE and may reduce mortality in patients with solid tumors (sub-group analysis).

3) Consider thrombolysis in patients with hemodynamic instability from an acute PE.

4) The only indication for IVC filter insertion recommended in the 2008 ACCP Guidelines is for patients with a PE and a contraindication to anticoagulation. Furthermore, if an IVC filter is inserted, anticoagulation should be re-instituted as soon as is deemed safe.

5) Some authorities suggest inserting an IVC filter in the context of a recurrent pulmonary embolism while on anti-coagulation.

6) Controversy exists regarding the role of IVC filter placement in patients with poor cardiopulmonary reserve or a large clot burden.

7) "Prophylactic" IVC filters should be avoided.

8) The largest trials to date have shown that in hemodynamically stable patients, IVC filters reduce the incidence of recurrent symptomatic PEs, but do not change mortality and cause an increased rate of DVTs (when left in). The benefits may be greater in hemodynamically unstable patients.

9) Most IVC filters are retrievable! Talk to Interventional Radiology and arrange to have them removed. Do not leave your patient with a long term IVC filter unless they still need it!

Portal Vein Thrombosis

Today we discussed a patient with a portal vein thrombosis (PVT) in the setting of acute cholecystitis. Following the management of acute cholecystitis, the discussion turned to the management of a PVT.

Here's an excellent review article on an approach to managing a PVT.

A few things to keep in mind:

1) The causes of a PVT include inflammatory, malignant, infectious and hypercoaguable states, however the most common cause is cirrhosis (25%).

2) An incidentally found PVT should trigger a search for cirrhosis, a hypercoaguable state or occult malignancy (including a myeloproliferative disorder).

3) An acute PVT is usually asymptomatic.

4) The rationale for treating a PVT is to prevent clot extension and compromise of intestinal perfusion and to prevent portal HTN.

5) It's estimated that 85-90% of patients with a chronic PVT thrombosis have esophageal varices.

6) There is very limited evidence to inform the decision to anticoagulate or not. Management is often extrapolated from the lower extremity DVT literature.

7) In the context of cirrhosis, anticoagulation is generally NOT recommended due to the increased risk of bleeding.

8) In a chronic PVT with portal HTN and NO cirrhosis, it may be reasonable to anticoagulate if there is a history of a hypercoaguable state or previous thrombosis. Otherwise, the risk of bleeding in the context of portal HTN (varices) may outweigh the benefits.

10) In an acute PVT and NO cirrhosis, it is reasonable to investigate for and treat any underlying etiology (including a hypercoaguable state) and consider anticoagulating for a minimum of 3-6 months or longer if there is a persistent risk factor.

11) If anticoagulating, the same medications (warfarin, LMWH, IV heparin) and targets (i.e. INR 2-3) can be used as for lower extremity DVTs.

12) The management of a PVT is highly variable, clinician dependent and must be tailored to the individual patient and clinical scenario.

ASA Overdose

This morning we talked about the approach to an aspirin (ASA) overdose. This is an important topic to review since we don't see it very frequently on GIM yet its management requires time sensitive interventions to prevent morbidity and mortality.

Here's a flow chart from the BMJ. If you have access, here's a review article from Postgraduate Medicine. The Merck Manual also has a short review as does Harrison's. The Uptodate article on "Aspirin Poisoning in Adults" is also a nice summary.

We talked about urine alkalinization quite a bit today. Here's a link to a position paper published in the Journal of Toxicology that supports urinary alkalinization.

Some key points:

1) Salicylates are found not only in aspirin (acetylsalicylic acid), but also in a number of OTC/herbal products including Bismuth subsalicylate (Pepto Bismol), salicylic acid and Oil of Wintergreen.

2) In general (watch your units):
i) Therapeutic Range: 0.7-2.2mmol/L
ii) Toxic Range: >greater than 2.9mmol/L
iii) Consider dialysis when level is greater than 7.2mmol/L

3) In usual doses, aspirin is rapidly absorbed and reaches a peak concentration in 1 hour. However, in the setting of an overdose, this can be significantly delayed (5-6 hours from ingestion) due to slowed gastric emptying or enteric coated/slow-release preparations.

4) Pathophysiology of Toxicity:
i) Uncoupling of oxidative phosphorylation at the cellular level
ii) Stimulation of the respiratory centre in the medulla
iii) Metabolic acidosis (primary from salicyltes, secondary from mitochondrial poisoning)
iv) Central hypoglycemia despite normal peripheral blood glucose levels

5) Signs and Symptoms of overdose: nausea, vomiting, tinnitus, hyperventilation. More severe symptoms include: fever, decreased LOC, non-cardiogenic pulmonary edema, rhabdomyolysis, hypotension, seizures and AKI.

6) When suspecting any overdose, always check a Tylenol and ASA level.

7) Important investigations: ASA level (check q2h until two values show decreasing levels), ABG (or venous blood gas), CBC, lytes, creatinine, liver enzymes, INR, plasma glucose, extended electrolytes, urinalysis, urine pH and CXR. The blood work and urine tests should be repeated frequently during the initial period of management.

8) ASA intoxication is one of the prototypical causes of a mixed repiratory alkalosis with an anion gap metabolic acidosis (although an isolated anion gap metabolic acidosis can be seen).

9) Remember the common causes of an anion gap metabolic acidosis: methanol, uremia, diabetic/starvation/alcoholic ketoacidosis, lactic acidosis, ethylene glycol, salicylates.

10) Management:

i) Stabilize ABCs.

ii) If tolerated, activated charcoal should be given (1g/Kg up to 50g) and can be repeated q4h x 2 after the first dose. This works best if given within 1 hour of toxic ingestion. Contraindicated if level of consciousness is depressed unless the patient is intubated.

iii) Supplemental glucose should be given in patients with altered LOC due to the risk of neuroglycopenia despite normal peripheral blood glucose.

iv) Potassium must be aggressively replaced. Hypokalemia can impair urine alkalinization, and any initial hypokalemia will be exacerabted by alkalinization.

v) Urine alkalinization: This is a critical step. Here's a position paper published in the Journal of Toxicology on the topic.

Salicylic acid is a weak acid. The non-ionic form can diffuse across membranes, while the ionic form cannot. Increasing the serum pH will result in diffucion of the non-ionic form out of cells and trap it in the blood/urine in the ionic form.

Pre-existing alkalosis is not a contraindication to urinary alkalinization.

A rise in the urine pH of 1 unit can theoretically increase salicylate excretion by a factor of 10.

Start with a bolus of 1-2mEq/Kg of NaHCO3 followed by an infusion of 3amps of NaHCO3 mixed in 850cc D5W (NOT normal saline) run at 1.5-2 times maintenance. Urine pH should be checked frequently with a target of > 7.5 - 8. Failure to achieve this within 1-2 hours may be an indication for dialysis.

11) Avoid acetazolamide and any medication that depresses respiratory drive.

12) Indications for dialysis:
i) Renal failure impairing salicylate clearance
ii) Inability to alkalinize the urine
iii) Fluid overload limiting sodium bicarbonate treatment
iv) Plasma salicylate level greater than 7.2 mmol/L
v) Coma
vi) Failure of medical management

13) Always call your local poison centre for advice when managing an overdose.

Hemorrhage

Yesterday we talked about a patient presenting with a Hg of 42 and an MCV of 50 with no signs of bleeding. During our discussion, a number of topics related to anemia, hemorrhage and transfusions came up.

We talked briefly about the TRICC trial published in the NEJM. This study looked at 838 ICU patients with a Hg of less than 90 and randomized them to a liberal (transfuse if Hg less than 100) vs. a conservative (transfuse if Hg less than 70) transfusion strategy.

The study showed that at 30 days there was no between arm difference in mortality but there was reduced in-hospital mortality in the restrictive transfusion arm. In sub-group analysis, this arm also demonstrated reduced mortality in younger patients (less than 55 years old) and less acutely ill patients (APACHE-II score less than 20). No difference in outcome was seen between the arms in patients with an ACS.

TRICC Bottom Line:

1) These were ICU patients so be cautious with generalizing to GIM patients, but we generally follow the results from TRICC.

2) Consider a RBC transfusion in patients with a Hg of less than 70, especially if symptomatic. This is not a hard and fast rule - you may not transfuse a patient with a Hg of 65 who is well and asymptomatic, especially if it is chronic.

3) Consider not transfusing RBCs in a patient with a Hg greater than 100. However, it may be reasonable to aim for a higher Hg (i.e. greater than 100) in patients with an acute coronary syndrome.

4) A significant gray zone exists inbetween 70 and 100.

Sources of Blood Loss:

1) When presented with a very low Hg, you need to rule out immediate life theatening causes right away - bleeding and hemolysis.

2) A reasonable initial screen for hemolysis includes an LDH, haptolgobin, blood film and bilirubin. The combination of an elevated LDH and low haptoglobin are 90% specific and 92% sensitive for hemolysis.

3) Looks for obvious sources of bleeding: GI tract (BRBPR, melena, hematemesis), GU tract, trauma (laceration, hemo-thorax/peritoneum, etc.) or Gyne.

4) If no obvious source, consider hemolysis and/or a retroperitoneal bleed.

5) Large hemodynamically significant blood loss will not occur from an intracranial hemorrhage due to the limited space in which there is to bleed. Additionally, in a pulmonary hemorrhage, hypoxia will be a greater threat to life before anemia is.

A few points on microcytic anemias:

1) We talked briefly about differentiating iron deficiency anemia from thalassemia. Thank you to Lauren for pointing out that the RDW may be useful in this case. In thalassemia, the RDW is generally low or normal whereas in iron deficiency anemia it may be elevated as the bone marrow pushes out RBC precursors.

2) In a patient over the age of 50 with iron deficiency anemia, remember to look for occult bleeding from a GI malignancy.

3) A ferritin of less than 10-15 is virtually diagnostic of iron deficiency anemia (99% specific, 59% sensitive). Using a value of 41 increases the sensitivity to 98% and the specificity to 99%. The challenge is that ferritin is an acute phase reactant and is increased in inflammation. One possible approach is to divide the ferritin value by three in these patients, if it's less than 20, this is highly suggestive of co-existing iron deficiency anemia.

4) Don't forget celiac disease as a not uncommon cause of iron deficiency anemia.

5) Many other tests including iron saturation, TIBC, Hg electrophoresis, reticulocyte count, soluble transferrin receptor and blood film examination can help in the assessment of a microcytic anemia.

Atrial Fibrillation

Today we talked about atrial fibrillation in a patient with a history of rheumatic fever. On GIM, atrial fibrillation is a diagnosis we see very commonly.

One of the best atrial fibrillation resources is the 2006 ACC/AHA Guidelines which you can find here. As a side note, the ACC/AHA have guidelines on a huge variety of cardiovascular topics that provide an evidence base for cardiac decision making on the wards. Here's the list.

Briefly about atrial fibrillation:

1. Afib is a very common arrhythmia. Seen in ~10% of patients greater than 85 years old.

2. While afib can cause distressing symptoms (palpitations, SOB, etc.), the biggest concern is thromboembolism and the impact of afib on cardiac function.

3. Generally we classify afib as:

a) paroxysmal (less than 7 days duration)

b) persistent (lasting greater than 7 days and terminating spontaneously or with cardioversion)

c) permanent (afib lasting greater than 1year and failed cardioversion/not attempted).

Regardless of the classification,

they all portend the same yearly risk of stroke.

A fourth classification is "lone atrial fibrillation" which applies to atrial fibrillation in a patient with no structural heart disease (and often less than 60 years old). These patients are generally felt to be at a low risk of stroke.

4. Most common causes of afib: HTN, valvular disease, hyperthyroidism, heart failure and alcohol.

Usually afib is not associated with stable coronary artery disease unless it results in an MI or heart failure. Afib can also be seen in the context of surgery or a pulmonary embolism.

5. Minimum set of investigations for new onset atrial fibrillation: ECG (confirm diagnosis, assess for other complicating disease), CBC, lytes, TSH and 2D Echo (to assess for structural heart disease).

6. Management consists of rate vs. rhythm control and thromboembolism risk reduction.

a) Rate vs. rhythm control:

Often a trial of cardioversion is given for the first episode of atrial fibrillation. In the long term, most patients with recurrent atrial fibrillation are managed with rate control rather than rhythm control (unless they have significant symptoms or cardiovascular compromise when in afib).

The AFFIRM Trial demonstrated that there was no survival or stroke risk advantage to a rhythm control strategy and that rhythm control more frequently resulted in medication side effects and hospitalization.

Rate control is usually accomplished with B-blockers, non-dihydropyridine calcium channel blockers (Dilt, Verapamil) or Digoxin. The guidelines suggest a HR target of less than 80bpm at rest and less than 110bpm with exercise. However, the recently published RACE-II Trial suggests that strict rate control may confer no additional benefit over lenient rate control.

b) Thromboembolism risk reduction:

The yearly risk of stroke depends on a variety of factors. Several risk scores exist, but one of the easiest to use is the CHADS2 Score. This only applies for patients with non-valvular atrial fibrillation:

Chronic Heart Failure - 1 point

HTN - 1 point

Age greater than 75 - 1 point

Diabetes - 1 point

Stroke/TIA - 2 points

If the CHADS2 score is 0 then no therapy or ASA is reasonable. With a CHADS2 score of 1 then ASA or Warfarin (INR 2-3) is acceptable and with a CHADS2 score greater than 1 warfarin is recommended.

The reason for this is that the benefit you obtain from ASA or warfarin is determined by your yearly risk of stroke. ASA provides a RRR of ~25% while warfarin gives a RRR of ~66%. The risk of a significant bleeding complication from ASA is small, while with warfarin is ~1%/year (depending on the patient).

Remember, for patients with valvular atrial fibrillation, their stroke risk is much higher (as in our patient this morning) so they should be managed with warfarin.

Interestingly, the recently published RE-LY trial showed that Dabigatran, a direct thrombin inhibitor that does not require monitoring may be superior to warfarin in terms of stroke prevention or bleeding risk (depending on the dose). This could revolutionize the way atrial fibrillation in managed.

Acute Hepatitis

Today we discussed a case of acute hepatitis NYD with moderate-severe liver enzyme elevation. This is not an uncommon referral to Internal Medicine.

Here's a very useful review from CMAJ in 2005 on elevated liver enzymes.

Some points about marked liver enzyme elevation (>5x the upper limit of normal):

1. Remember that the "liver function tests" are bilirubin, INR, albumin +/- glucose and can reflect the synthetic function of the liver. Conversely, the "liver enzymes" - AST, ALT, ALP and GGT are NOT liver function tests as they offer no information on the liver's synthetic function but merely are a marker of hepatocyte integrity and/or cholestasis.

2. The differential diagnosis of moderate to severe transaminitis includes: viral hepatitis, toxic hepatitis, ischemic hepatitis, severe obstruction, autoimmune and alcoholic hepatitis.

3. Decide what the predominant pattern is to help you guide investigations:
a) Hepatic (increased AST, ALT > ALP)
b) Cholestatic (increased ALP > AST, ALT)

4. How elevated are the enzymes? 5x vs. 5-10x vs. >10x of normal? What is the trend? Is there synthetic dysfunction (increased INR, bilirubin, decreased albumin)? Typically liver enzyme values at this level represent acute liver injury.

5. In acute viral hepatitis, the liver enzymes often peak before the bilirubin and the patient may have non-specific symptoms such as fatigue, arthralgias and a low grade fever (as in our patient) .

6. Consider ischemic hepatitis in the right clinical context and an ALT/LDH ratio of less than 1.

7. Hepatitis screen: Hep A IgM Ab, Hep B core Ab (IgM), Hep B surface Ag and Ab, Hep C Ab.

8. Always ask about Tylenol use, herbal and over the counter medications, periods of illness (hypotension), autoimmune symptoms and alcohol.

9. Some form of abdominal imaging (usually ultrasound) is often appropriate to assess for evidence of hepatitis and/or obstruction.

10. Once the common causes of moderate to severe transaminitis have been ruled out, consider testing for auto-immune hepatitis and other viral causes such as EBV and CMV.

Knee Pain

Yesterday we talked about the diagnostic dilemma of a painful knee that ultimately was presumed to be secondary to osteoarthritis.

This a good opportunity to review the approach to an acute monoarthritis and to osteoarthritis.

Let's start with some Canadian content. Here's a recent review published in the CMAJ looking at the management of a patient with an acute monoarthritis.

The NEJM published a very thorough review article on OA of the knee in 2006.

There are many causes of knee pain outside of a monoarthritis or osteoarthritis, many of which we do not see very often as internists (i.e. orthopedic problems in younger patients).

To summarize, here are some key points on evaluating a patient with acute knee pain:

1. Determine if there is a recent history of trauma. This raises the pre-test probability of a fracture, hemarthrosis, meniscal tear or ligamentous injury.

2. Decide whether this is an intra-articular, peri-articular or referred process (there is significant overlap in some of these signs/symptoms):

a) Intra-articular: pain localized to the knee without radiation, knee effusion, mechanical symptoms (clicking, locking, giving way), abnormal structural physical exam, reduced range of motion.

b) Peri-articular: focal area of pain or abnormalities on exam, pain only during parts of the range of motion, +/- mechanical symptoms.

c) Referred pain: vague location of pain, back or hip pain, pain not exacerbated by knee movement, lack of an effusion, normal knee exam.

3. If the pain is articular, you need to decide if it is inflammatory (i.e. arthritis - pain, redness, swelling, warmth) or non-inflammatory (structural). Any acute effusion should be drained and analyzed.

4. Remember if an effusion is present -> rule out INFECTION. Missing a septic joint can have catastrophic consequences for the joint, and very quickly.

5. Arthrocentesis fluid should be sent for cell count and differential, gram stain, C&S, microscopy for crystals at a minimum.

6. Imaging: Start with x-rays. If there is any history of trauma, lack of localizing symptoms to the knee or a question of pain origin, image the ipsilateral joints above and below the knee.

7. Consider MRI as the next imaging test of choice after x-ray if no diagnosis can be found or if a soft tissue etiology is being considered.

8. An effusion can be present in an acute exacerbation of osteoarthritis.

Renal Cell Carcinoma

Today we talked about renal cell carcinoma presenting with anorexia, abdominal distension, hematuria, ascites and renal failure.

Here are links to two review articles, the first is from the Lancet in 2009 and the second is from NEJM in 2005.

Some key points about RCC:

1) RCC is the 7th most common cancer in men and the 9th most common in women. The peak incidence is in the 6th and 7th decades of life (mean age of 60). Men are affected twice as frequently as women.

2) Risk factors include: HTN, obesity, smoking, acquired cystic diseases of the kidney, ESRD and certain inherited conditions (e.g. von Hippel-Lindau). Regardless, most patients with RCC do not have an identifiable risk factor. Fruit and vegetable consumption may be protective!

3) This tumor was classically known as "The Internist's Tumor" due to its varied presentation, however with the widespread use of abdominal imaging and incidental diagnosis, some argue that RCC is now "The Radiologist's Tumor".

4) Signs and Symptoms at Presentation:
a) Local: The classic triad of abdominal pain, a palpable mass and hematuria is uncommonly seen today.
b) Systemic: Anorexia, fatigue, wasting and a variety of paraneoplastic phenomena including hypercalcemia (PTHrp), HTN (renin) and erythrocytosis (EPO).

5) Any patient over the age of 40 with hematuria should be assessed for RCC since prognosis is determined by stage.

6) Imaging: CT abdomen is the investigation of choice. However, abdominal U/S while less sensitive can help differentiate a simple cyst from a more complex structure. MRI can be useful if the U/S is non-diagnostic or contrast dye is contraindicated.

7) If a solid renal mass is identified with radiologic features consistent with RCC, biopsy is usually not performed due to low specificty and concern with seeding the peritoneum. Good surgical candidates often go directly for a partial or radical nephrectomy.

8) Surgical resection is the cornerstone of therapy as chemotherapy is minimally effective. Surgery can be curative in the majority of patients with Stage I, II and III disease. Resection of the primary tumor is recommended even in the setting of metastatic disease (in patients with good functional status).

9) Significant interest is currently focused on biologic agents including VEGF and mTOR inhibitors given the limited benefit and significant toxicity of Interleukin-2 immunotherapy.

The Art of Pimping

Hi folks,

Usually we keep things pretty formal and academic here on Horses and Zebras, but today we're going to talk about something different - the art of pimping.

For those unfamiliar with the term as it applies to Medicine, this is when a staff "poses a series of very difficult questions to an intern or student." Often this is done to further learning or highlight gaps in knowledge, but at times it can make the learner feel self-conscious or even uncomfortable.

We've all experienced this and part of going through your training is knowing how to handle it.

Check out the very humorous, but all too true article that started it all. Some excellent defensive tips are offered.

Our own Dr. Detsky furthered the discussion on this topic with his article from JAMA in 2009.

In all seriousness, "pimping" will continue to be a part of medical education for the foreseeable future. Here are some things (from one trainee to another) that have helped get me though the 10,000 times I've been put on the spot:

1) Remember that your staff is trying to help you learn, not hurt your feelings. You will never forget something you got wrong when pimped (i.e. the Toronto clinical prediction rule for aortic stenosis).

2) It's OK to stop, take a deep breath and think about the answer rather than blurting out the first thing that comes to mind.

3) If you don't know the answer or are never going to remember it, just be honest and say, "I don't know." This is better than squirming for 5 minutes during which time it'll be obvious you didn't know the answer.

4) If you think you know the answer, then answer with confidence. Not arrogance, but confidence. If you're right, you'll get credit for being right! If you're wrong - you were going to be wrong anyway, so you've lost nothing. However, if you're right but you answered in a sheepish, high pitched and uncertain voice, you'll only get credit for guessing.

Finally, when it's your turn to be the teacher, remember what it felt like to get "pimped".