Introduction to Thalassemia

Today we had a few special guests at Presby – Alex filled in for Hari, and (more importantly) Dr. Farzana Sayani gave us a awesome case study of Thalassemia.  Here is the summary of the high points of the talk:

Definitions and Diseases

(note: I will use small letters (ex: a, b) in place of corresponding Greek letters)

HbA = a2b2 (normally 96-98% of adult hgb)

HbA2 = a2d2 (normally 2-3.5% of adult hgb)

HbF = a2g2 (normally < 1% adult hgb)

 

A-Thalassemia:

  • Underproduction of a chains, thus relative over-abundance of b chains.
  • There are 2 a alleles (a1 and a2), and there are 2 of each chromosome, so a total of 4 a alleles

Silent Carrier = One alleles deleted (-a/aa)

  • Most Common, typically seen in African Americans (25% of all AAs are silent carriers)
  • CBC findings: Normal hgb, low-normal MCV (high 70’s)
  • Hgb electrophoresis: normal
  • DNA analysis: uncovers single a gene deletion

 

Double Deletion = 2a alleles deleted (aa/– or a-/a-), can be both on the same chromosome or on opposite chromosomes which only matters for prenatal counselling not phenotype

  • Typically seen in SE Asians
  • CBC findings: Hgb slightly low or normal (11-13), MCV low (~70)
  • Hgb electrophoresis: normal
  • DNA analysis: uncovers 2 a gene deletions

 

Hemoglobin H Disease = 3a alleles deleted (-a/–), but the real story is that all of the excess b globulin makes its own tetramers called HgH, but it’s not as good at its job as normal hgb

  • HgH hemolyzes more and doesn’t bind O2 very well, HgH inclusion bodies can even be seen on smear. Patients are often transfusion dependent
  • CBC findgins: hgb low (think 7’s), MCV low (think < 70)
  • Hgb electrophoresis: Can see many different patters of HgA vs. HgA2, but the big point is there is HgH

 

Hemoglobin Barts = all 4 a’s are deleted (–/–) which leads to Hydrops Fetalis, there is no a chains so g chains make tetramers that are called HbBarts.  But wait, why don’t we just get HgH again?!  It’s because the b globulin isn’t made until the baby is a bit older, at this stage the baby makes g chains instead.  All babies die within the first few days of birth (from heart failure from high output 2/2 severe anemia), but if they somehow lived long enough, yes they would make HgH instead of HgBarts.  Oh, and of course CHOP is doing some crazy stuff with in-utero transfusions, so maybe babies will start living long enough for exactly this scenario…

B-Thalassemia

  • Similar story to above. Underproduction of b chains, thus relative over-abundance of a chains.
  • There are 2 b alleles, some mutations reduce production and some stop production all together

Minor/Trait = One normal b, and one abnormal

  • CBC findings: slightly low hgb (10-13), low MCV (60’s)
  • Hgb electrophoresis: presence of HbA2 (remember, that’s a2d2 so doesn’t require b), maybe some HbF but < 5%

Major = many possible genetic possibilities, but classically is a loss of function of both B genes

  • CBC Findings: Severe anemia usually transfusion dependent, MCV low (60’s)
  • Hgb electrophoresis: the point is there is ZERO HbA (remember, the one that’s a2b2) because there are no b to put in. Should have a lot of HbF and some HbA2

Intermedia = Essentially any combination of genotypes that has any CBC findings, but the point is that the don’t have absent HbA so can’t be called Major.  They may or may not require intermittent transfusions depending on the actual gene alterations.

 

Taking Care of Thalassemia Patients

  • Big issue is frequent transfusions leading to iron overload (usually goal hgb 9-10)
  • Many patients also need genetic counseling

 

Iron Overload

  • Most common complication is hypogonadism
  • High mortality is actually driven by heart failure 2/2 iron deposition (not high output 2/2 anemia)
  • Patient’s get frequent MRIs of heart and liver to monitor therapy, and see a ton of specialists to mitigate a number of complications
  • Treatment works, and patients can meet targets that adequately manage iron overload and leads to very long lives
  • Here is an outline of the common iron chelators:
    Property Desferoxamine Deferiprone Deferasirox
    Route of administration Subcutaneous, intravenous Oral tablets Oral suspension/Film coated tablet
    Remove liver iron +++ ++ +++
    Remove cardiac iron ++ +++ ++
    Reverse iron related cardiac dysfunction ++ +++
    Adverse effects Skin reaction

    Allergy

    Opthalmology

    Bone changes

    Gastrointestinal

    Neutropenia

    Agranulocytosis

    Arthralgias

    Gastrointestinal

    Rash

    Rise in creatinine

    Elevated liver enzymes

    GI bleeding

    Laboratory Monitoring Weekly: CBC

    Monthly: CBC, liver enzymes

    Monthly: CBC, liver enzymes, creatinine, urinalysis
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11/28 HUP Report: Hemoptysis due to ABPA

Thank you Dr. Dine for coming to report to discuss a case of Allergic BronchoPulmonary Aspergillosis (ABPA for short!). The patient we talked about today was a young female who had a history of asthma diagnosed in childhood who presented with a subacute history of cough and subjective fevers, with recent recurrent non-massive hemoptysis.

We discussed important characteristics of hemoptysis to gather information about during a history, including volume, appearance, color, rate and any associated symptoms or triggers. The lungs receive a dual blood supply – the bronchial artery usually arises from the aorta and has a relatively small circulating blood volume at high pressure, while the pulmonary circulation is at lower pressure and involves almost the entire blood volume. Usually, massive hemoptysis arises from bronchial arteries due to their higher pressure and the fact that they supply the airways and airway lesions. It is important to remember that in a minority of patients a spinal artery can originate from the bronchial artery, so a potential rare but serious complication of embolizing the bronchial artery can be paralysis in these patients. Diagram below is from Netter’s Anatomy.

ABPA1.pngThis patient’s imaging was notable for bronchiectasis and mucus plugging, and her workup showed elevated total IgE, eosinophilia, and positive aspergillus skin test. She was diagnosed with ABPA. In this disease, the airways are colonized with aspergillus and a hypersensitivity reaction causes inflammation –it is important to realize that the pathology here is not due to fungal infection, but rather an inflammatory response to fungal colonization. There are differing guidelines for diagnostic criteria; below is the set proposed by the International Society for Human and Animal Mycology (patient must have predisposing condition and both obligatory criteria plus two other criteria; non-CF bronchiectasis patients can also get ABPA).

ABPA2Glucocorticoids are the cornerstone of therapy for ABPA. There are differing perspectives on antifungal therapy – some physicians use antifungal therapy only if patients fail glucocorticoid therapy, and some physicians use antifungal therapy in all patients with this diagnosis. There are studies looking into use of monoclonal antibodies for treatment (omalizumab) – stay tuned for more data!

 

 

11/21 Presby report: pulmonary complications of cocaine, cavitary lung lesions

Thanks to Robin Mansour for presenting a great case of a middle aged woman who presented with a cough, chest pain and a 90 lb (!) weight loss, who was found to have several cavitary chest masses

We talked about some of the pulmonary complications of cocaine use:

Screen Shot 2017-11-21 at 10.19.35 AM.png

Restrepo et al. RSNA Radiographics 2007

 

Crack lung is a specific term for an acute hemorrhagic alveolitis after crack inhalation, characterized by cough, SOB, hypoxia, fever, bronchospasm and even hemoptysis and focal infiltrates (and diffuse alveolar damage, microscopically)

Remember that cocaine can be adulterated with substances that can cause a variety of toxic effects in and of themselves:

  • Levamisole (a veterinary antihelminthic): can cause P- and C-ANCA+ leukocytoclastic vasculitis
  • Clenbuterol (beta agonist) that can cause hyperglycemia, hypokalemia, tachycardia (which cocaine can also cause)
  • Other ‘cutting’ agents like talc or baking soda can lodge in the pulmonary microcirculation and cause a local granulomatous reaction

What’s the difference between a cavity and a cyst?

  • Cavities tend to be thicker walled: generally we call something with a wall >5mm a cavity, while <5mm is called a cyst
  • Cavity wall thickness can help with figuring out etiology
    • in one study, cavities w/ max wall thickness >15mm were 90% malignant while those <4mm were 95% nonmalignant

Here’s a framework for thinking about cavitary lung lesions:

Screen Shot 2017-11-21 at 11.32.10 AM.png

Derived from Gadkowski et al, Clin Microbio Rev 2008

Lastly, a differential for skin lesions involving tattoos:

  • Sarcoidosis
  • Nontuberculous mycobacteria
  • Discoid lupus
  • Local foreign-body granulomatous skin reaction

References

  1. Restrepo et al. Pulmonary Complications from Cocaine and Cocaine-based Substances: Imaging Manifestations. RSNA 2007.
  2. Gadkowski et al. Cavitary Pulmonary Disease. Clin Microbio Rev 2008.

11/21 HUP Report: Pembrolizumab-Induced Myocarditis

Today we discussed a case that demonstrates an interesting side effect of immunomodulatory chemotherapy. Thank you to Dr. O’Quinn for joining us! The case we discussed today was a young female patient being treated for ovarian cancer with pembrolizumab, who presented with positional chest pain and was found to be in ventricular tachycardia with elevated cardiac enzymes. Her workup included a left heart catheterization that was negative for coronary artery disease, and a CT chest that was negative for pulmonary embolus.

One point that we discussed was the role for contrast to enhance echocardiograms. The use of contrast can be helpful to allow the cardiologists to get a more accurate estimate of LV ejection fraction and assess for presence of regional wall motion abnormalities; in this case the patient had a TTE without contrast that was difficult to interpret, and the addition of contrast provided a study consistent with reduced LV ejection fraction and moderately decreased RV systolic function.

Ultimately this patient’s presentation was thought to be myocarditis secondary to pembrolizumab toxicity. Pembrolizumab is a PD1 inhibitor, and many side effects of this therapy are related to activation of the immune system.

CM1.png

Cardiac side effects of this therapy are relatively rare, but have been reported in case series with presentations similar to our patient. Histologic studies show that pathology involves a lymphocytic infiltrate causing inflammation in cardiac tissue, which can manifest with arrhythmias and heart failure.

The primary treatment for autoimmune side effects of PD1 inhibitors is usually steroids. This patient was treated with corticosteroids and improved initially, but was unable to wean. Next steps in management were discussed with multiple institutions and departments within our own institution, as this is a newly described entity with limited experience. Ultimately, she was given infliximab and did really well!

 

References:

Varracchi et al. Cardiotoxicity of immune checkpoint inhibitors. ESMO Open. 2017 Oct 26;2(4):e000247. doi: 10.1136/esmoopen-2017-000247.

 

11/15 HUP Report: Infectious Endocarditis

Thank you to Dr. Amorosa for teaching us about advanced management of infectious endocarditis! Today we discussed the case of a young male IV drug user who presented with fever, new cardiac murmur, and evidence of embolic phenomena on his skin exam who was found to have MRSA endocarditis.

When dealing with a case of suspected endocarditis, make sure you get cultures!! This is really important – in the majority of cases cultures will identify an organism and allow for targeted treatment. Ideally, at least two sets of cultures separated in space and time (at least thirty minutes) should be collected. While waiting for this data, if empiric treatment is necessary clinically, consider covering strep, staph (MRSA and MSSA), and enterococcus species.

In cases of MSSA endocarditis, a bacteriocidal agent such as nafcillin or oxacillin is usually recommended; addition of aminoglycoside has not shown clinical benefit and confers the downside of lots of potentially permanent and serious side effects, so their synergistic use has fallen out of favor. In cases of MRSA endocarditis, vancomycin is usually a good first line agent. Coagulase negative staph should be treated like MRSA.

We also discussed surgical interventions in patients with endocarditis. There has been a recent trend toward increased discussion of early surgery (performed before the completion of the initial antibiotic course), especially in cases where the infection has been demonstrated to be causing valvular disease and subsequent heart failure (as in our patient), perivalvular abscess or extension, and other difficult-to-treat situations. Here is some data to support early surgery in cases similar to ours:

  1. This study published in JAMA (full reference below) was a prospective, multicenter study of n= 4166 patients with infective endocarditis. The researchers looked to see which factors were associated with mortality among the patients. Of patients with heart failure symptoms (classified into NYHA classes), those who underwent early surgery had improved in-hospital mortality rates. (Of course, there are confounding factors to consider here).

IE1.png

2. This study from the Journal of Thoracic Cardiovascular Surgery (full reference below) retrospectively reviewed n=212 patients with left-sided native valve infective endocarditis. Early surgery was defined as occurring within 2 weeks of initial diagnosis. They found that in patients who received early surgery, there was statistically significant reduction in IE-related death and major adverse cardiac event (again, there are caveats here too!)

IE2.png

Infectious endocarditis can be difficult to treat. Always get infectious disease colleagues involved! And consider early surgical intervention if clinically indicated. Sadly, this disease is one of the many health hazards that accompanies the opioid epidemic.
References:

Kiefer et al. Association between valvular surgery and mortality among patients with infective endocarditis complicated by heart failure. JAMA 2011; 306(20):2239-2247.

Funakoshi et al. Impact of early surgery in the active phase on long-term outcomes in left-sided native valve endocarditis. J Thorac Cardiovasc Surg 2011;142:836-42.

 

 

11/9 Presby report: a moste curious case of metformin-associated lactic acidosis

Late post because I’m on service (sorry!).

A huge thanks to recent Penn IM alum Geoff Bass for giving a great talk on a middle-aged diabetic man who came in with abdominal pain and was found to have metformin-associated lactic acidosis (MALA).

Screen Shot 2017-11-13 at 2.18.09 PM.png

Lactate metabolism is intertwined with that of glucose and pyruvate

Hyperlactatemia occurs via one of four mechanisms:

  • Tissue hypoxia
  • Aerobic glycosis (aka glycolysis that depends on factors other than tissue hypoxia (think high-epinephrine states)
    • Sepsis
    • Severe asthma + beta-agonist use
    • Cardiogenic or hemorrhagic shock
    • Pheochromocytoma, cocaine
  • Impaired oxidative phosphorylation
    • Drugs: ARVs, propofol (PRIS), metformin, toxic alcohols, salicylates, cyanide
  • Liver dysfunction
    • the liver normally clears ~70% of whole body lactate, so acute liver dysfunction can lead to elevated serum lactate; but chronic liver disease (ie cirrhosis) usually doesn’t (in the absence of sepsis or some other driver)

Metformin toxicity is generally rare, and usually only occurs in the context of other predisposing conditions: AKI/CKD, liver disease, alcohol use, concurrent critical illness, heart failure

It is a clinical diagnosis, as there is no one test that confirms the diagnosis; you can send off a metformin level, but it takes a while to come back and is generally unhelpful unless it’s totally negative (in which case you should look for other causes)

MALA is mostly treated with conservative measures:

  • Gastric decontamination
  • Supportive care
  • Hemodialysis
    • Consider if lactate >15-20, pH <7.1, or other conditions such as shock, renal failure, etc

References

  1. DeFonzo R, Fleming GA, Chen K, et al. Metformin-associated lactic acidosis: Current perspectives on causes and risk. Metabolism, 2016 Feb; 65(2): 20-29.

  2. Kraut JA, Madias NE. Lactic Acidosis. NEJM,  2014 Dec 11;371(24):2309-19.

11/13 Presby report: sulfonylurea toxicity, loop diuretics

Thanks to Dan Kim for giving a great talk (and to the audience of contributing lots of great learning points!) on a middle aged woman who presented with hypoglycemia after taking a dose of her sulfonylurea.

Recall that sulfonylureas work by inhibiting the ATP-sensitive potassium channel in pancreatic beta cells; this leads to increased endogenous insulin release. Long acting sulfonylureas (ie glyburide) are more likely than short-acting agents (glipizide, glimepiride) to cause hypoglycemia.

Screen Shot 2017-11-13 at 1.19.18 PM.png

Symptoms of hypoglycemia; remember that it can mimic virtually any neurologic condition

When thinking about hypoglycemia, it helps to think in terms of whether the patient is ill-looking or not

Ill-appearing

  • drugs (insulin or insulin secretagogue, alcohol, ?others)
  • Sepsis/critical illness
  • Hormone deficiency (cortisol, glucagon or epinephrine)

Seemingly well-appearing

  • Endogenous hyperinsulinism
    • insulinoma
    • post-gastric bypass hypoglycemia
    • antibodies to insulin or insulin receptor
  • Surreptitious/factitious hypoglycemia

Diagnosis

Sulfonylurea toxicity is generally a clinical diagnosis based on history. There are sulfonylurea assays that can be sent, but they generally take too long to result and are thus of limited use

Management of sulfonylurea toxicity

  • D50
  • D5 or D10 gtt
    • should not be used as monotherapy for sulfonylurea toxicity, as it will cause transient hyperglycemia that triggers insulin release and further episodes of hypoglycemia
  • Octreotide
    • works by decreasing insulin release from beta cells
    • Give for the first 24h, and then stop; can restart if hypoglycemia recurs
  • Glucagon
    • NB: very short acting, so should only be used as a temporizing measure while getting IV access or some other longer-acting source of glucose

Activated charcoal can be used within 2-3h of the ingestion, but hemodialysis has not been shown to be effective. Diazoxide, an older drug which also inhibits pancreatic insulin release, used to be used, but is less effective than octreotide and can cause hypotension.


 

We talked briefly about the threshold effect with loop diuretics:

Screen Shot 2017-11-13 at 1.55.05 PM.png

The inflection point where the blue line takes off is the ‘threshold’, and is largely determined by the rate at which the diuretic gets to its site of action. HF patients show resistance at any given diuretic dose due to Na reabsorption at other segments of the nephron. Brater 1983.

Lastly, this study compared bolus vs continuous infusion of lasix in patients with ADHF, and found that there was no real difference between the two dosing strategies. However, keep in mind that this was part of a research setting, where even bolus doses were probably timed perfectly. In real life, doses may be given late (ie beyond the point that the previous dose is effective), so continuous diuretic infusion may still have a role in clinical practice.

References

  1. Oh S et al. Loop Diuretics In Clinical Practice. Electrolyte Blood Press 2015.
  2. Felker et al. Diuretic Strategies in Patients with Acute Decompensated Heart Failure. NEJM 2011.
  3. Brater DC, Day B, Burdette A, et al. Kidney Int 1984; 26:183.