12/5 HUP Report: An unusual case of TTP

Today we discussed an unusual case of TTP, and along the way we reviewed the differential for hemolytic anemia and Evans Syndrome in particular. Thank you to our faculty expert, Dr. Cuker, for some amazing teaching! Our patient was a young female previously treated for melanoma who developed thrombocytopenia and hemolytic anemia. There are different frameworks in which to classify hemolytic anemias. Today we thought about immune vs. non-immune mediated processes (which is not perfect, and some etiologies can fall within both categories!). Here is some of the differential that we discussed:

TTP1

Direct antibody test can be used to determine if there is antibody or complement bound to the patient’s RBCs. In this test, the patient’s RBCs are separated out from the serum and incubated with anti-human IgG; if there is antibody or C3 bound to the patient’s RBCs, then agglutination will occur, resulting in a positive test result. Indirect antibody testing looks at the patient’s serum to test for antibodies to RBCs – the serum is incubated with other RBCs (ie not from the patient), and then anti-human IgG  is added. If the serum contains anti-RBC antibodies, they will bind the cells and then agglutination will occur when anti-human IgG is added. (Figure adapted from Wikipedia.org)

TTP2.png

Our patient was initially thought to have Evans Syndrome, which is a condition that involves at least two immune-mediated cytopenias, most commonly thrombocytopenia and hemolytic anemia. Corticosteroids are usually the first line of treatment, especially if the patient is presenting with anemia. If the patient is presenting with thrombocytopenia as the primary concern, then IVIg can be considered. These patients typically have relapsing courses, and this can be really difficult to treat.

Our patient initially did really well with steroids, but then had recurrence of thrombocytopenia and hemolytic anemia, this time accompanied by abdominal pain and a peripheral smear with many schistocytes, which had not previously been seen. She was ultimately diagnosed with TTP, which is a form of thrombotic microangiopathy caused by low ADAMTS13 level. In healthy patients, ADAMTS13 cleaves ultralarge Von Willebrand Factor multimers, so when activity is low these multimers can persist. This causes platelet activation and aggregation, which can lead to thrombosis and ischemia to end-organs, and a hemolytic anemia from shearing.

TTP3.png

Treatment for TTP has made a dramatic change in mortality of this condition. Patients with suspected TTP should be treated immediately! Plasma exchange should be initiated as soon as possible, along with corticosteroids. There is also growing evidence to support use of rituximab in all patients without contraindications; this can be removed by plasma exchange, so should be dosed following sessions when possible.

References: please see citations underneath figures

 

 

 

 

 

 

 

 

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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

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.

 

11/1 Presby report: pancreatic masses, with a helping of chronic diarrhea

Today we discussed the interesting case of a middle aged man with chronic diarrhea who was found to have a pancreatic mass, ultimately found to be a gastrinoma. We spent some time discussing pancreatic masses, as the differential doesn’t just start and end with pancreatic cancer!

Pancreatic masses are not a trivial problem: 2-20% of patients who get MRIs for other reasons will have a pancreatic cysts or other solid lesions!

Screen Shot 2017-10-31 at 8.21.13 PM.png

Mets to the pancreas are usually from RCC or melanoma, or occasionally ovarian cancer.

Pancreatic cysts vary in their malignant potential

Screen Shot 2017-11-01 at 9.17.43 AM.png

JAMA 2016

 


WORKUP OF CHRONIC DIARRHEA

There are 5 questions that will help you work-up chronic diarrhea:

  1. Is it really diarrhea? Make sure it’s not fecal incontinence due to chronic constipation or stool impaction/overflow
  2. Is it medication-induced? Beware of metformin, NSAIDs, PPIs, SSRIs, antibiotics, Mg-containing meds, mycophenolate mofetil; also sorbitol- or xylitol-containing gums, and herbal teas/supplements which contain sennosides or other compounds
  3. Is it factitious? (consider if stool osm <290 or >600, female healthcare worker age ~45)
  4. How long? acute (<2 weeks) vs chronic (>4 weeks) diarrhea
  5. What’s the diarrhea like? inflammatory (frequent/bloody BMs, fever) vs fatty (greasy, hard to flush, weight loss) vs watery diarrhea
Screen Shot 2017-11-01 at 9.51.58 AM.png

Mayo Clinic Proceedings 2012

The majority of people with chronic diarrhea do not need stool cultures! In patients with chronic diarrhea, the highest yield would be in immunosuppressed patients (AIDS, organ transplant, etc), as they are more likely to have prolonged infection with a pathogenic organism like Salmonella or Shigella; this type of prolonged infection just doesn’t happen in immunocompetent individuals.

Other pearls

  • CA 19-9 can be elevated in pancreatic cancer but ALSO in any cause of pancreatic inflammation; so it is very NONSPECIFIC, meaning you shouldn’t jump to order it on anyone with a pancreatic mass
  • Gastrinomas generally don’t require adjuvant chemo after resection since they’re so slow growing
  • Carcinoid tumors will only produce symptoms (flushing etc) once they’ve metastasized to the liver, even if they’re radiographically invisible by CT or MRI
  • Blastocystis hominis is a commonly seen fecal protozoan, but it’s not clear that it truly causes diarrhea; for most people, it’s probably just a bystander to some other cause of diarrhea
  • Fecal calprotectin is secreted by neutrophils, and is a sign of inflammation; it’s most commonly used in IBD, but any cause of inflammatory diarrhea would cause it to be elevated

A lot of this is pulled from Becca’s excellent post from the summer. Take a look at hers for more re: the workup of chronic diarrhea!

References

  1. AGA Guideline on Diagnosis/Management of Asymptomatic Neoplastic Pancreatic Cysts. 2015.
  2. Stark et al. Pancreatic cystic disease: a review. JAMA 2016.
  3. Sweester S. Evaluating the Patient with Diarrhea: A Case Based Approach. Mayo Clin Proc.June 2012;87(6):596-602.

10/18 HUP Report – Thalassemia

Thank you to Dr. Sayani for joining us to discuss thalassemia! She has provided the images in this post.

Thalassemia arises from a defect in the globin chains that make up the hemoglobin molecule. Alpha globin is encoded by two genes, and beta globin is encoded by one gene. In healthy adults, the majority of hemoglobin molecules is comprised of 2 alpha and 2 beta globin chains.

thal1

In thalassemia, there is a defect (or absence) of production of either the alpha or beta globin in alpha and beta thalassemia, respectively. Severity of disease manifestations depends on number and severity of mutations. Problems arise from imbalance in alpha and beta globins. In thalassemia, the major causes of end-organ damage are chronic anemia, ineffective erythropoiesis with chronic hemolysis and extramedullary hematopoiesis, and iron overload. Transfusion support can be used to treat the consequences of anemia and to suppress extramedullary hematopoiesis.

thal2.png

Iron overload can happen in thalassemia due to the body’s response to ineffective erythropoiesis causing upregulation in dietary iron absorption and from iron delivered with transfusions. Iron deposition can impact the function of many endocrine organs, the liver, and the heart. This is a major cause of morbidity and mortality in thalassemia patients.

thal3.png

The advent of iron chelator therapy has made a huge impact on survival. Below is a table outlining characteristics of the three main iron chelators:thal4

Always remember to STOP the iron chelator if the patient presents with concern for sepsis, as “iron loving” bacteria can thrive with iron chelators making iron more available in the bloodstream.

 

10/10 HUP Report – Small Bowel Mass

Today we discussed an interesting case of a patient with longstanding Crohn’s disease, well-managed off immunosuppression, who presented with an enterovesicular fistula. This is actually a really RARE complication of Crohn’s disease (approximately 3%), and almost always requires surgical intervention. Aside from being secondary to active inflammation from his IBD, this new clinical finding could be secondary to a small bowel neoplasm (small bowel cancer is also really rare, but the rate is increased in Crohn’s disease patients).

Here is our basic differential for a small bowel mass:

Malignant

  • Neuroendocrine tumor
  • Adenocarcinoma
  • Sarcoma
  • Lymphoma
  • Metastatic disease (hematogenous spread or direct spread from peritoneal carcinomatosis)

Benign

  • Lipoma
  • Fibroma
  • Leiomyoma
  • Adenoma
  • Desmoid tumor

Infectious

  • Tuberculosis
  • Abscess
  • Histoplasma

This patient’s biopsy was consistent with neuroendocrine tumor, and he had numerous metastases — this is a common finding at the time of diagnosis due to indolent and asymptomatic growth in many patients. First line treatment for neuroendocrine tumors is usually somatostatin receptor analogues. Symptomatic surgical debulking or curative surgical resection can be considered in appropriate candidates, but is less common. Prominent symptomatic liver mets can be managed with ablation techniques. Systemic chemotherapy can be attempted for refractory disease — everolimus, bevacizumab, and sunitinib have been used.

 

 

10/4 Presby report: diagnosis of NSCLC, new targeted agents

Today we discussed the case of a middle aged man with newly diagnosed metastatic non-small cell lung cancer; this is a hot area because there have been a lot of exciting new developments in this area over the past few years– particularly the development of several new targeted agents and immune therapy.

Here’s a diagram showing the approach for a patient with newly diagnosed NSCLC:

Screen Shot 2017-10-05 at 4.39.55 PM.png

NEJM 2017

Takeaways

  • There are a growing list of targeted therapies based on driver mutations for NSCLC, noted in the table below
  • PD1 or PDL1 expression is important in determining the patient’s eligibility for immune therapy; 50% is the usual cut-off
    • Note that metastatic lesions may have different PD1 or PDL1 expression than the primary tumor; the reason for this is unclear, but basically means that they may still be a candidate for immune therapy even if the originally biopsied tumor had low PD expression
  • For EGFR positive patients that have disease progression on a 1st line agent like afatinib, you can get more tumor tissue and look for the T790M mutation which would make them a candidate for osimertinib (which per recent data is increasingly being used as a first line therapy for patients with EGFR exon 19 or 21 mutations)
  • It is exceedingly rare for more than one driver mutation to occur in one patient; if that happens, it may mean there are two primary cancers which would also be unusual
  • These targeted therapies don’t have the same adverse effects as standard chemo, so oncologists may have a lower threshold for giving them to patients with low performance status
Screen Shot 2017-10-04 at 9.59.31 AM

NEJM 2017

 

Lastly, remember that there is a trial showing the survival benefit of early palliative care in NSCLC. Obviously this finding can be extended to other types of malignancies, but at least here at Penn is mostly limited by the availability of access to palliative care.

References

  1. Precision Diagnosis and Treatment for Advanced Non–Small-Cell Lung Cancer. NEJM 2017.
  2. Temel J et al. Early Palliative Care for Patients with Metastatic Non-Small Cell Lung Cancer. NEJM 2010.