All posts by alp37

VA AM Report 5.21.18: Hypoglycemia and adrenal insufficiency

Case summary: Thanks to our favorite R3/intern centaur Daniel Kwon, who presented the case of a 60M with PMH HIV on ARVs who presented with dyspnea due to a viral pneumonia and was found to have adrenal insufficiency due to ritonavir potentiation of inhaled nasal steroids!

Top pearls:

  1. In evaluating a patient with hypoglycemia, ensure you confirm Whipple’s triad: 1)  hypoglycemia is not a lab error (repeat FSBG and ensure it correlates with serum glucose on a Chem panel), 2) the patient has symptoms of hypoglycemia while hypoglycemic, 3) the patient’s symptoms are relieved with reversal. Finally, if you’re entertaining the diagnosis of insulinoma, ensure you draw the labs for work-up (e.g. C peptide) while the patient is hypoglycemic.
  2. VA hospitalist and medical educator extraordinaire Denise Connor wrote up a fantastic case in JAMA IM reviewing causes of false FSBG readings, which range from shock and PVD to Waldenstrom’s macroglobinemia.
  3. Ritonavir and other CYP450 inhibitors can potentiate the action of steroids that are not typically systemically active (topical, inhaled, nasal) and lead to adrenal insufficiency and iatrogenic Cushing’s syndrome.
  4. Urine studies in hyponatremia due to adrenal insufficiency mimic SIADH (see mechanism below, and thanks to Renal attending Naomi Anker for the teaching!).

“Pseudohypoglycemia”: When FSBG readings don’t reflect serum [glucose]

  • Type 1: FSBGs accurately reflect glucose levels in the microcirculation, but are considerably lower than the systemic plasma glucose owing to sluggish capillary blood flow.
    • shock
    • peripheral vascular disease
    • cyanotic heart disease
    • acrocyanosis
    • Raynaud phenomenon
    • scleroderma
  • Type 2: in vitro glycolysis in the collection tube
    • leukemia
    • polycythemia
    • Waldenström macroglobulinemia

Here is the fantastic Teachable Moment case on pseudohypoglycemia from Denise Connor et al.: Wang EY, Patrick L, Connor D. Blind Obedience and an Unnecessary Workup for Hypoglycemia: A Teachable Moment. JAMA Intern Med. 2018 Feb 01; 178(2):279-280.

Here is a review of protease inhibitor-mediated potentiation of nasal/inhaled steroids:

What causes hyponatremia in adrenal insufficiency?

  • Big picture: low cortisol–> CRH–> ADH–> hyponatremia
  • Urine studies therefore are indistinguishable from SIADH


We like the Endocrine society breakdown for classifying causes of hypoglycemia: ill/medicated or well


  • Drugs (insulin, secretagogues, adulterated illicit drugs, alcohol, lots of prescription meds)
  • Critical illness (hepatic, renal, cardiac failure; sepsis)
  • Hormone deficiency (adrenal insufficiency)


  • Insulinoma
  • Other rare disorders (functional beta cell disorders from other pancreatic tumors or post-gastric bypass, insulin autoimmune hypoglycemia)
  • Accidental or surreptitious insulin/secretagogue ingestion

VA ICU report 5.11.18: Group B strep necrotizing cellulitis

Case summary: Thanks to Serge for presenting the case of a 46M with uncontrolled DMT2 presenting with R buttock SSTI, with profound tachycardia, DKA and necrotizing cellulitis.

Top pearls:

1. When evaluating a patient with SSTI who appears ill, be sure to run through the list of SSTI “plus” syndromes that can cause systemic disease and often require additional interventions or consultations: abscess, osteomyelitis, bacteremia, septic joint, tenosynovitis, necrotizing soft tissue infection, pyomyositis, toxic shock syndrome.

2. A shorter mnemonic for AG metabolic acidosis is KULT, which stands for ketones, uremia, lactate and toxins. We like this because it allows you to focus on the most common etiologies and then look up the various toxins included in the lengthy MUDPILERS.

3. The term necrotizing soft tissue infection encompasses not only necrotizing fasciitis (infection of the deep fascia) but also necrotizing myositis (infection of the muscle), and necrotizing cellulitis (infection of the skin that spares the fascia and muscle). Necrotizing cellulitis is typically more indolent and less severe than fasciitis and myositis.

Group B Strep

  • Most often associated with bacteruria/UTI in pregnant women and neonatal sepsis.
  • Incidence of infection in non-pregnant adults is increasing (3.6 cases per 100,000 persons during 1990 to 7.3 cases per 100,000 persons during 2007 (P<.001))
  • Older age, black race, and underlying medical conditions are associated with higher rates of invasive GBS disease.
  • Common presentations of GBS disease in adults include skin and/or soft-tissue infection (including necrotizing soft tissue infection), bacteremia without focus, pneumonia, and osteomyelitis
  • Serious clinical syndromes, such as meningitis, streptococcal toxic shock syndrome, and endocarditis, are rare but are often associated with considerable morbidity and mortality (5% of patients die).
  • Treatment is with penicillin, and necrotizing SSTIs require surgery.

Reference: Clinical Infectious Diseases, Volume 49, Issue 1, 1 July 2009, Pages 85–92

See Grant Smith’s great summary post for ALLLLLL you could want to know about necrotizing fasciitis:

VA Intern report pearls 5.3.18: Paraneoplatic puffy hands and feet

Case summary: Thanks to Jake and Taylor for presenting the case of an 88M with new diagnosis of metastatic likely pancreatic adenocarcinoma, who presented with orthostasis 1 day after CT-guided liver mass biopsy, and was found to have bilateral foot and hand edema and obstructive LFTs.

Top pearls:

1. Goop’s differential for a unilateral puffy hand or foot: DVT, cellulitis, trauma, gout, synovitis.

2. Pancreatic cancer has one of the highest risks of VTE of any malignancy (4-7x that of other adenocarcinomas); risk is highest in the 3 months after diagnosis and increases with treatment.

3. Consider paraneoplastic phenomenon when dealing with a patient with cancer + a neurologic, dermatologic or musculoskeletal complaint, as these are the most common systems affected (endocrine and hematologic phenomenon are also possible but less common).

4. RS3PE (remitting seronegative symmetrical synovitis with pitting edema) is a benign, seronegative syndrome of acute onset of pitting edema of the dorsum of both hands and feet and can be idiopathic or paraneoplastic.

5. Malignant biliary obstruction is most often incomplete and intermittent and thus less likely to cause cholangitis than choledocholithiasis.

Paraneoplastic phenomenon


  • Limbic encephalitis
  • Cerebellar degeneration
  • Lambert-Eaton
  • Myasthenia gravis
  • Autonomic neuropathy
  • Sensory polyneuropathy


  • Dermatomyositis
  • Acanthosis nigricans
  • Erythroderma
  • Sweet syndrome
  • Hypertrophic osteoarthropathy
  • Paraneoplastic pemphigus
  • Polymyalgia rheumatica
  • Rheumatoid arthritis

Reference:  Mayo Clinic Proceedings 2010;85(9): 838-854.

Trosseau’s syndrome

  • Defined as unexplained thrombotic events that precede the diagnosis of an occult visceral tumor or occur concomitantly with the tumor.
  • Sometimes incorrectly used to refer to any hypercoagulability of malignancy (e.g. from DVT to chronic DIC).
  • In reality, even this restricted definition encompasses a many disorders with multiple overlapping mechanisms.
  • Probably best understood as a spectrum of disorders ranging from thrombosis induced by tissue factor produced by the tumor to platelet-rich microthrombi triggered by carcinoma mucins and P- and L-selectins



VA AM Report 4.24.18: Lung cancer– what the internist should know

Case summary: Thanks to our stellar sub-I Ryan Chang with back-up from superb senior Izzy Marshall for presenting a 77M with PMH tobacco use and homelessness who was admitted with scant hemoptysis and L flank pain and found to have metastatic lung adenocarcinoma.

Top pearls:

  1. For non-small cell lung cancer (NSCLC), molecular testing is the key for treatment, with the main prognostic determinants: 1) EGFR mutation (which can be treated with erlotinib), 2) ALK mutation, 3) PDL1 staining
  2. We are moving away from using immunotherapy only in those whose tumors stain positive for PDL1, as some patients who stain negative will still respond to immunotherapy (see 4. below).
  3. All patients with newly diagnosed, later-stage NSCLC should undergo brain MRI given the high incidence of clinically silent brain metastases.
  4. Check out this recent NEJM trial that showed improved overall survival with COMBINATION immunotherapy (regardless of PDL1 staining) and chemotherapy in metastatic lung adenocarcinoma that is EGFR/ALK negative.

NSCLC molecular testing + treatment algorithm

Thanks to Gerald Hsu for these fantastic teaching slides!

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See this great NEJM review on NSCLC for more details: Reck M, Rabe KF. N Engl J Med 2017;377:849-861.

Pembrolizumab + chemotherapy has better OS than chemotherapy alone

  • Double-blind, placebo controlled RCT of ~600 patients with metastatic non-squamous NSCLC (EGFR/ALK negative) who had never been previously treated
  • Assigned to chemotherapy (pemetrexed and platinum-based drug) + placebo versus chemotherapy (pemetrexed and platinum-based drug) + pembolizumab (PDL1 inhibitor)
  • Overall survival at 12 months: 69% in chemo+pembro group versus 49% in chemo+placebo group (HR 0.49, 95% CI 0.38-0.64, p<0.001)
  • Improvement regardless of PDL1 staining (e.g. no difference between 0% versus 100%)
  • No difference in adverse events between the two groups

VA AM report 4.17.18: Small bowel obstruction from abdominal tuberculosis

Case summary: Thanks to Nick for presenting the fascinating case of a 27F with no PMH who emigrated from India 4 years ago and presented with 1 month of intermittent abdominal pain, 1 week of nausea vomiting, found to have omental nodularity, ascites and partial SBO from abdominal tuberculosis.

Top pearls:

  1. Adenosine deaminase has great test characteristics for ascitic fluid for diagnosing tuberculous peritonitis (+LR=26.8, -LR=0.038)
  2. Abdominal TB takes 3 classic forms: peritoneal (e.g. ascites, omental caking), intestinal (e.g. terminal ileum involvement, SBO) and hepatic (e.g. hepatomegaly).
  3. Abdominal TB can result from: reactivation of abdominal latent TB, ingestion of tuberculous mycobacteria, hematogenous or contiguous spread from active pulmonary or miliary TB.
  4. In a patient with SBO, in addition to acute decompressive management, also consider the underlying diagnosis; adhesions, cancer and hernia are the 3 most common.

Ascitic adenosine deaminase (ADA) for diagnosing tuberculous peritonitis

  • Thanks to Jake Mayfield for pointing us in the direction of a systematic review from 2006 that established ADA as having both high sensitivity (99%) and specificity (97%) for diagnosing tuberculous peritonitis
    • Cutoff point= 39
    • +LR= 26.8
    • -LR= 0.038
    • FNs can occur in HIV; Fps can occur in malignancy

Gastrointestinal tuberculosis

  • Approx 5% of all cases of TB
  • Risk factors: cirrhosis, HIV, DM, malignancy, anti-TNF agents, peritoneal HD
  • Most common sites:
    • Peritoneum
    • Intestines
    • Liver
    • Can also include: upper GI tract, pancreas, perianal area, LNs
  • Diagnosis:
    • Signs/symptoms:
      • Peritoneal- subacute-to-chronic ascites, abdominal pain, fever
        • 10% of cases can have a “doughy” abdomen, which is fibroadhesive form
        • SAAG< 1.1, TP>3, lymphocytic-predominant, elevated ADA, <3% have +smear and <20% have +culture. GeneXprt still being validated
      • Intestinal- ileocecal involvement (75%), stricture/inflammation leads to abdominal pain and ultimately bowel obstruction, diarrhea, LGIB, constipation, constitutional symptoms
      • Hepatic- hepatomegaly, fever, abdominal pain, constitutional symptoms
    • Imaging w/ CT A/P and either AFB smear/culture in peritoneal fluid or biopsy
      • Can also get AFB sputum if concurrent symptoms of pulmonary TB, but should have diagnostic evaluation of abdominal involvement as well

Debi U, Ravisankar V, Prasad KK, Sinha SK, Sharma AK. Abdominal tuberculosis of the gastrointestinal tract: Revisited. World Journal of Gastroenterology : WJG. 2014;20(40):14831-14840.

Causes of small bowel obstruction

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VA AM Report 4.11.18 and 4.12.18: When two become one!

We had two doozies yesterday and today. In this rapid-fire pearls, two become one as we pick out the top learning points from each case!

4.11.18 AM Report

Case summary: Thanks to Karen for presenting the case of a 30F with PMH thyroiditis and celiac disease, who presented with several months of dyspnea and acute hypoxia and was found to have hypersensitivity pneumonitis from marijuana inhalational exposure.

Top pearls:

  1. Keep in mind that in addition to hypoxia causing dyspnea, patients may also have additional features (e.g. elevated lactate) contributing to their sensation of dyspnea.
  2. Recall that CXR can lack sensitivity for significant pathology. The classic cases are interstitial lung disease (as in this patient), immunocompromise and PCP (where up to 30% of patients have a normal CXR).
  3. Inhaled marijuana, synthetic cannabinoids, and their associated smoking devices are emerging triggers for hypersensitivity pneumonitis, either directly or via drug or device contaminants.

4.12.18 Intern Report

Case summary: Alex cared for a 63M with PMH decompensated cirrhosis, ESRD on iHD, and microscopic polyangiitis on steroids, who developed a new leukocytosis and ultimately had ESBL bacteremia and DIC.

Top pearls:

  1. We would not expect chronic steroids to yield a new leukocytosis, as we see this with steroid initiation leading to abrupt (e.g. in <15 min) leukocyte demargination from vessel walls and increased measurement in the serum.
  2. Gerald Hsu gave us some great pointers for distinguishing the coagulopathy of liver disease from DIC:
    • Always measure a fibrinogen (although this reflects hepatic synthetic dysfunction, baseline levels are usually not low)
    • See if the patient is bleeding (suggests DIC and also directs therapy)
    • Tempo of thrombocytopenia (new drop more concerning than stably low)
    • Measure fibrin degradation products like D-dimer (elevated in DIC but not in cirrhosis)
  3. Yes, Jake Mayfield, like the Jarisch-Herxheimer reaction from penicillin in syphilis, lipopolysaccharide (LPS) released from GNR cell walls after treatment with antibiotics can provoke an inflammatory surge and worsening signs of sepsis. Beta-lactam antibiotics appear to liberate a greater amount of endotoxin compared to other antibiotics.
  4. The major branch points in treating DIC are: 1) Is the patient bleeding? (transfuse), 2) Does the patient have thrombosis? (therapeutic anticoagulation), 3) Neither (prophylactic anticoagulation). See this algorithm based on this breakdown.
    Screen Shot 2018-04-12 at 11.14.19 AM


  1. Hemenerd article on how WBC demargination is related to changes in WBC biomechanics (e.g. the WBCs get “softer” and thus release from the vessel wall): Myers, D. R., Kumar, A., Byler, R., Sulchek, T. A., & Graham, M. D. (2013).White Blood Cell Mechanics Mediate Glucocorticoid- and Catecholamine-Induced DemarginationBlood, 122(21)3459.
  2. GNRs, antibiotics, and the Jarisch-Herxheimer-like reaction: Lepper PM, Held TK, Schneider EM, Bolke E, Gerlach H, Trautmann M. Clinical implications of antibiotic-induced endotoxin release in septic shock. Intensive Care Medicine 2002;28:824-833.
  3. Fantastic recent DIC review (see Patient 2 for how to distinguish coagulopathy from cirrhosis from DIC): Levi, M., & Scully, M. (2018)How I treat disseminated intravascular coagulationBlood, 131(8)845-854.

VA AM Report 4.10.18: Isolated prolonged aPTT

Case summary: AJ, Colette and Anne presented a doozy of a case this morning– a 64F with DMT2, HTN and hemorrhoids, who presented with acute R calf pain, R forearm hematoma and hemorrhoidal bleeding and was found to have an isolated prolonged aPTT due to an acquired factor VIII inhibitor (acquired hemophilia A).

Top pearls:

  1. A thorough bleeding history includes questions to distinguish between platelet-associated (e.g. petechiae, mucosal bleeding) and coagluation-associated (e.g. post-traumatic or post-procedural bleeding) symptoms, as well as personal (e.g. prolonged bleeding after surgeries, pregnancy) and family history of bleeding diatheses.
  2. The differential diagnosis for isolated prolonged aPTT is limited: Acquired causes include anticoagulants (heparin, direct-thrombin inhibitors), DIC, acquired vWD, APLS and acquired factor inhibitors. Inherited causes include hereditary hemophilia A/B and hereditary vWD.
  3. Patients with acquired factor inhibitors (of which inhibitors to 8 are most common) can present with dramatic life- and limb-threatening bleeding and have high morbidity and mortality.
  4. Treatment of acquired factor VIII inhibitor includes immunosuppression with steroids and activated prothrombin complex concentrate (FEIBA) in the presence of major bleeding, which bypasses factor VIII in the coagulation cascade.

Mixing study 101

The first step in work-up of an isolated prolonged aPTT is a mixing study, which Colette explained brilliantly to us.

  • Step 1: “Mixing study,” which is an inhibitor screen.
    • If adding normal plasma to a patient’s plasma corrects the aPTT, this suggests a factor deficiency (classically, this would be clear based on history [e.g. consistently prolonged aPTT and history of bleeding diatheses])
    • If adding normal plasma to a patient’s plasma does not correct the aPTT, this suggests factor inhibitor (factor VIII inhibitors can initially correct and then prolong again, so they require more prolonged incubation)
  • Step 2: Factor activity assays (8, 9, 11, 12 from the intrinsic pathway) tell you the level of the specific factor (from normal to undetectably low)
  • Step 3: At the VA, the test also includes a DRVVT to test for lupus anticoagulant
  • Step 4: Finally, the Bethesda Factor VIII Inhibitor Titering Assay tells you the titer of the inhibitor (a confirmatory test for a factor inhibitor that does not correlate with severity and isn’t used to guide intervention)

The skinny on acquired factor VIII inhibitors

  • This is is an autoantibody against factor VIII in the coagulation cascade.
  • Can have inherited and acquired inhibitors; of acquired, factor VIII is the most common.
  • 1.3-1.5 cases/million/year and bimodal age distribution (peri-partum in younger women and then in patients >65yo)
  • Predisposing conditions: ~50% are idiopathic, while the remainder are associated with chronic inflammation–> antibody generation
    • pregnancy
    • autoimmune disease (SLE, RA)
    • MGUS/MM or amyloid
    • Solid and heme malignancies
    • IBD
    • Dermatologic disorders (pemphigus, psoriasis)
    • chronic respiratory disease (COPD)
    • Diabetes
    • acute HBV/HCV infection
    • Drug-associated (penicillins, sulfa drugs)
  • Bleeding symptoms are more severe than hereditary hemophilia (usually trauma-related muscle and joint bleeding)
    • severe, spontaneous subcutaneous, muscle and retroperitoneal bleeds are most common
    • mucosal (GI, lung, urogenital) and brain can also occur
    • mortality is between 7-22%
  • Treatment:
    • 1) bleeding control with therapies that “bypass” factor VIII in the coagulation cascade (“bypassing therapies”) for patients
      • FEIBA- activated prothrombin complex concentrate
      • NovoSeven- recombinant active factor VII
      • Both carry a high risk of thrombosis (MI, DIC, DVT/PE, acute limb ischemia, CVA)
      • Remember to avoid procedures or interventions (e.g. subQ injections) and discontinue exacerbating meds (anticoagulants, anti platelet agents)
      • Supportive care with transfusions, fluids, holding pressure, etc.
      • New kid on the block: Obizur (porcine factor 8)
    • 2) inhibitor eradication with immunosuppresion
      • prednisone and cyclophosphamide (alone or in combination)
    • 3) treatment of underlying provoking disease

Reference: How I Treat Acquired Factor VIII Inhibitors, Frachini, Blood, 2008