Management of TTP

This week at morning report, we discussed TTP. Here is how you should think about the management of TTP:

Plasma Exchange: cornerstone of treatment. Perform daily until there is a complete response (see below).

Rituximab: beneficial to start early, there is data that suggests better remission rates when added to plasma exchange upfront.

Steroids: adjunctive because there is minimal data to back this up, but generally recommended if there is no contraindication.

These treatment modalities are initiated early and urgently in a patient with presumptive TTP. Treatment is continued until there is a complete response, which is defined by a platelet count above 150,000 for two consecutive days, together with normal or normalizing LDH and clinical recovery (ie end organ damage has resolved). After treatment, patients are most vulnerable to a recurrence within the first week after tapering of therapy. Patients are followed closely to assess for symptoms and for CBC/ADAMTS13 monitoring. What is unclear is what to do with patients who are asymptomatic but have a down trending/low ADAMTS13. In this situation, data suggests that treatment with rituximab can reduce the possibility of relapse, likely through decreasing the production of the antibodies inhibiting ADAMTS13.

 

Who needs HCC screening?

Guidelines differ slightly between the different liver societies (AASLD & EASL & APASL) but most agree that we should screen the following high-risk groups:

  • Patients with Child Pugh A or B cirrhosis
  • Patients with Child Pugh C cirrhosis, only if awaiting liver transplant
  • Non-cirrhotic patients with HBV infection & any of the following characteristics:
    • Active hepatitis (ALT and/or high viral load)
    • Family history of HCC
    • Africans & African Americans (age does not matter)
    • Asian males > 40
    • Asian females > 50
  • +/- Chronic HCV & advanced fibrosis (stage F3), rather than strict cirrhosis

Keep these in mind when you’re seeing your PCIM & PRIME patients!

MEN Syndromes

Last week at the VA, we discussed a case of MEN1 in morning report! Here are some pearls about MEN syndromes:

MEN1: The 3 Ps”

  • Primary hyperparathyroidism – 90%
  • (Anterior) Pituitary tumor – 40%
    • MC prolactinoma à GH + prolactin à GH  à non functioning
    • ACTH / TSH secreting tumors are rare
  • Pancreatic islet cell tumor
    • Gastrinoma (ZES) – 30-40%
    • Insulinoma – 10%
    • Non-functioning – 20-55%

Caused by autosomal dominant mutation in MEN1 tumor suppressor gene

Clinical dx: 2+ MEN1 tumor types OR occurrence of 1 MEN tumor in a family member of a patient with diagnosis of MEN1

Who gets genetic testing? Any index patient with clinical MEN1, 1st degree relative of known MEN1 carrier regardless of symptoms, individuals with “suspicious or atypical MEN1”; if asymptomatic, offer genetic testing first to avoid extensive imaging / lab work-up

Who to screen: index patients & 1st degree relatives.

How to screen: Follow clinically for amenorrhea, galactorrhea, ED, growth abnormalities, nephrolithiasis, cushingoid changes, PUD / diarrhea, hypoglycemia, HA, visual changes. Labwork:  annual Ca, PTH, gastrin (fasting), glucagon, VIP, pancreatic polypeptide, chromogranin A, insulin, fasting glucose, prolactin, IGF-1. Radiology: There is no consensus on radiologic screening guidelines – suggest annual pancreatic imaging with EUS/MRI/CT and MR pituitary q3-5 years

MEN2A & B:

  • caused by autosomal dominant mutation in RET proto-oncogene
  • MEN2A – has 4 variants, 60-90% of MEN2 syndromes
  • MEN2B –  5% of all MEN variants
  • Manifestations:
    • Medullary thyroid carcinoma – typically earliest manifestation & almost all patients with MEN2 have it
    • Pheochromocytoma – 50%
    • Primary hyperparathyroidism – 10-50% of only MEN2A patients
    • cutaneous lesions / mucosal neuromas, Hirschsprung’s disease
  • thyroid, parathyroid, adrenal glands are at risk of developing tumors that reduce life expectancy –> importance of early diagnosis because of the excellent prognosis of medullary thyroid cancer if diagnosed early
  • Who to screen: as a result, you screen first and second degree relatives of an index case.
  • How to screen: plasma metanephrines, calcium / PTH, calcitonin and thyroid / neck US

Infective endocarditis

Today at morning report, we discussed a case of tricuspid valve  endocarditis in IVDU. Here are some points to keep in mind about endocarditis:

Subacute bacterial endocarditis – often due to strep species of low virulence (mainly viridans strep); clinical course is slowly progressive, indolent over weeks to months, has low propensity to embolize

Acute bacterial endocarditis –  fulminant disease over days to weeks, more likely staph aureus, and frequently causes metastatic infection

 

Microbiology: based on a large cohort 2700+ patients with infective endocarditis:

  • ​Staph aureus – 31%
  • Viridans group strep (oral flora) – 17%
  • CoNS – 11%
  • Strep bovis – 7%
  • Other strep – 5%
  • Enterococcus – 11%
  • Then, atypical organisms: HACEK – 2% / Fungi – 2% / non-HACEK gram negative organisms – 2%; 8% are culture-negative
In IVDU, staph aureus is still the most common – especially MRSA – followed by strep species and enterococcus; though we classically think of gram negative endocarditis (pseudomonas, E coli) in association with IVDU, these are rarer.
Indications for surgery: The class I indications (ACC / AHA guidelines) can be categorized as such:
  • ​heart failure – valvular dysfunction causing refractory pulmonary edema or cardiogenic shock
  • Prevention of embolization – vegetation > 10 mm with prior embolization (class I) or isolated vegetation > 15 mm and feasible valve repair (class IIb); recurrent emboli despite appropriate antibiotic therapy (class II)
  • uncontrolled infection – resistant organism – S. aureus (in many cases), fungi (candida, aspergillus) – (class I), persistent cultures after 7-10 days appropriate therapy (class I); enlarging vegetation despite 7-10 days appropriate therapy (class I), other evidence of uncontrolled infection defined as abscess / fistula / pseudoaneurysm (class I)
  • prosthetic valve endocarditis
  • neurologic complications – TIA / ischemic stroke without hemorrhagic conversion, cerebral abscess, silent microembolism
The indications for surgery in endocarditis associated with IVDU are generally the same though in general, surgery is not advised unless the patient agrees to enter drug rehabilitation program post-operatively. In IVDU, there is a risk of co-infection with HIV/Hepatitis B/C, but the presence of HIV infection is not a contraindication though it is considered higher-risk by CT surgery in advanced AIDS. Unfortunately, outcomes after surgery for patients with IE and IVDU are often poor: though they have similar short-term mortality, they have a substantially higher long-term mortality (noted at 60% in 13 months in 1 study; 45% at 20 months in another study) though these outcomes are related to risk of reinfection rather than operative mortality. Larger vegetations (> 2 cm) are a/w worse mortality.
Timing of surgery: no strict consensus on optimal timing but emergent = within 24 hours / urgent = within a few days / elective = after 1-2 weeks of antibiotic therapy. In general, early surgery is warranted for indications above and there is no advantage to delaying surgery

Left Ventricular Non-compaction

Today at morning report at the VA, we talked about left ventricular non-compaction:
– defined by prominent LV trabeculae (2:1 ratio of trabeculae to myocardial wall); deep intertrabecular recesses, and thin compacted layer.
Here are some echo images:
 
Here is a schematic to help you visualize what’s going on:
it is debated whether LVNC in adults is a distinct cardiomyopathy or an anatomic variant / morphologic trait shared by different types of cardiomyopathies. AHA classifies it as a genetic cardiomyopathy and it is associated with mutations in genes implicated in other genetic cardiomyopathies (ie HOCM). However, there is emerging evidence that pathogenic mechanisms leading to non-compaction or increased trabeculation may occur in adult life (found de novo in pregnant women, athletes, patients with sickle cell anemia).
– An important thing to note is that there are no genome-wide association studies because the challenge is that there are many phenotypic variants; so, a limitation of genetic studies is that most only screened genes associated with other cardiomyopathies (sarcomere mutations of HOCM).
– There is no gold standard for the diagnosis of LVNC, but TTE and cMRI with contrast are the best tools; if trabecula are biopsied, myocytes are histologically normal so biopsy is not part of the diagnostic work-up. Of note, it is common for either LV dilation or hypertrophy to be present and this does not influence the diagnosis but hypokinesis of non-trabeculated segments can strengthen the diagnosis of cardiomyopathy 2/2 LVNC. An important part of imaging is to distinguish true LVNC meeting criteria from hyper-trabeculation that is considered not pathologic.
Management
    – guidelines suggest that familial LVNC should be diagnosed by screening family members with TTE; genetic testing is not recommended routinely because does not change management
​- Patients are treated based on presence of cardiac dysfunction (ie GDMT for HFrEF) / arrhythmias
    ​- oral anticoagulation is administered to patients with LV dysfunction, proven thrombi, arrhythmias (atrial fibrillation is common) but debated in their absence
    – sudden cardiac death is a complication but not clear if this is related to the functional phenotype (reduced EF, HOCM) rather than LVNC itself. Clinical predictors for appropriate ICD therapy are not available
Find out more in this great review article: https://www.ncbi.nlm.nih.gov/pubmed/25443708 

Cox’s Conference: Thrombotic Thrombocytopenic Purpura

In this week’s Ambulatory Cox’s Conference, Dr. Esther de Boer presented a case of a young female who presented with altered mental status in the setting of severe thrombocytopenia. Our expert discussant, Dr. Nagalla guided us through the differential diagnosis of microangiopathic hemolytic anemia (MAHA).

The differential diagnosis for our patient with altered mental status and severe thrombocytopenia included intracranial hemorrhage in the setting of immune thrombocytopenia (ITP), cerebral vascular accident in the setting of heparin-immune thrombocytopenia (HIT), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulation (DIC) in the setting of sepsis, paroxysmal nocturnal hemoglobinuria (PNH), HELLP syndrome in the setting of pregnancy, acute liver failure, and tick-born illnesses such as ehrlichiosis. In addition to severe thrombocytopenia, the patient was also found to have severe anemia and evidence of hemolysis on laboratory evaluation. A peripheral smear revealed numerous schistocytes consistent with MAHA. The patient was started on plasma exchange and an ADAMTS13 activity level was sent off which later returned as < 5% and a high ADAMTS13 inhibitor titer consistent with acquired TTP.

Thrombotic Thrombocytopenic Purpura Pearls:

  • TTP is defined as a severe deficiency in ADAMTS13 (less than 10%). It can be hereditary due to inherited mutations (Upshaw-Shulman Syndrome) or acquired by formation of an autoantibody against ADAMTS13.
  • ADAMTS13 is a protein that cleaves von Willebrand factor (vWF). Deficiency in this protein leads to formation of platelet microthrombi in the microvasculature.1

Clinical Presentation:

  • Patients can present with non-specific symptoms such as fatigue, generalized weakness, GI symptoms (nausea, vomiting, abdominal pain), dyspnea, petechiae (or other bleeding), headaches and altered mental status.
  • The classic “pentad” of TTP which includes thrombocytopenia, fever, acute renal failure, and severe neurologic findings is rare and occurs in <5% of patients.2
  • Laboratory evaluation will show severe thrombocytopenia, anemia, and evidence of hemolysis with elevated LDH, low haptoglobin, and increased unconjugated bilirubin. Hemolysis can also elevate the AST, but not the ALT.

Diagnosis:

  • When TTP is suspected, urgent review of the peripheral blood smear is needed.
  • Schistocytes and thrombocytopenia on a peripheral smear is concerning for TTP.
  • ADAMTS13 activity and inhibitor testing should be sent before starting treatment.
  • The diagnosis is confirmed with ADAMTS13 activity < 10%. Acquired TTP will show the presence of ADAMTS13 inhibitor.

Treatment:

  • The mainstay of treatment for TTP is therapeutic plasma exchange. If TTP is suspected, plasma exchange should be initiated while ADAMTS13 testing is pending.
  • The addition of glucocorticoids to plasma exchange and use of rituximab have been shown to improve outcomes and decrease the need for plasma exchange sessions.3
  • Plasma exchange should be continued daily until platelet count recovery.

References:

  1. George JN, Nester CM. Syndromes of thrombotic microangiopathy. N Engl J Med 2014; 371:654.
  2. Griffin D, Al-Nouri ZL, Muthurajah D, et al. First symptoms in patients with thrombotic thrombocytopenic purpura: what are they and when do they occur? Transfusion 2013; 53:235.
  3. Som S, Deford CC, Kaiser ML, et al. Decreasing frequency of plasma exchange complications in patients treated for thrombotic thrombocytopenic purpura-hemolytic uremic syndrome, 1996 to 2011. Transfusion 2012; 52:2525.

Cox’s Conference: Mucormycosis

In this week’s Ambulatory Cox’s Conference, Dr. Jasmine Sukumar presented a case of a 50 year old man with history of alcohol cirrhosis, uncontrolled diabetes, and rectal cancer on chemotherapy who presented with right sided vision loss for 1 day. Our expert discussant, Dr. Pearlie Chong guided us through infectious complications to consider in an immunocompromised host.

The differential diagnosis for our patient with acute persistent vision loss included diabetic retinopathy with vitreous hemorrhage, retinal detachment, glaucoma, retinal artery or vein occlusion, optic neuritis, and giant cell arteritis. On exam the patient was found to have swelling and redness of the right eye with associated cranial nerve deficits. Based on the exam and the patient’s past medical history, we had to consider potentially less common etiologies of vision loss including intracranial malignancy (or metastasis), CMV retinitis, or invasive fungal infection. Imaging of the head and sinuses revealed thickening of the right ethmoid and maxillary sinus as well as a large soft-tissue mass in the retroorbital area. Surgical biopsies were performed that showed broad, irregularly branched hyphae with rare septations consistent with Rhizopus oryzae.

Mucormycosis Pearls:

·     Mucormycosis is a life-threatening fungal infection that typically affects immunocompromised patients as well as those with diabetes mellitus.

·     Infections in humans are most commonly caused by Rhizopus, Mucor, and Rhizomucor. These organisms are ubiquitous in nature and commonly found in soil and decaying vegetation.

·     In addition to immunocompromised patients, those with hemochromatosis (particularly those receiving deferoxamine therapy) and burn/trauma patients are also at risk of mucormysosis.

Clinical Presentation:

·     Most common clinical presentation in rhino-orbital-cerebral infection caused by inhalation of spores into the paranasal sinuses.

o     Common presenting complaints are fever, headache, nasal congestion, purulent nasal discharge, and sinus pain.

o     If the infection spreads beyond the sinuses, nearby structures can be involved resulting in perinasal swelling, palate eschars, and erythema or necrosis of the skin overlying the sinuses or orbit.

o     Signs of orbital involvement include periorbital edema, proptosis, and blindness as in our patient. Spread to the nearby cavernous sinus can result in cranial nerve palsies.1

·     Mucormycosis can also present with pulmonary, gastrointestinal, cutaneous, renal, or isolated CNS involvement. Disseminated disease occurs in severely immunocompromised patients.

·     Interestingly, many diabetic patients had ketoacidosis at the time of presentation.2

Diagnosis:

·     As Mucormycosis is a rapidly progressive, fatal disease, prompt diagnosis and empiric treatment is crucial.

·     Diagnosis relies on identification of the organism in tissue by histopathology, which requires a tissue biopsy. Cultures often yield no growth.

·     The 1,3-beta-D-glucan assay and the Aspergillus galactomannan assay will be negative in these patients.

Treatment:

·     Treatment requires both surgical deridement of involved tissues as well as antifungal therapy.

·     It is also important to eliminate any potential predisposing factors for this infection including hyperglycemia, deferoxamine administration, immunosuppressive medications, and neutropenia.

·     First line therapy is intravenous amphotericin B at 5-10mg/kg daily. After a patient has shown clinical improvement, the patient can be transitioned to posaconazole.3

·     Some data suggests improved patient outcomes with addition of caspofungin to amphotericin B compared to amphotericin B monotherapy. However larger studies are needed to establish whether combination therapy is truly beneficial.4

·     Despite appropriate antifungal therapy, aggressive surgical debridement is required for adequate disease control.

References:

1.     Yohai RA, Bullock JD, Aziz AA, Markert RJ. Survival factors in rhino-orbital-cerebral mucormycosis. Surv Ophthalmol 1994; 39:3.

2.     McNulty JS. Rhinocerebral mucormycosis: predisposing factors. Laryngoscope 1982; 92:1140.

3.     McCarthy M, Rosengart A, Schuetz AN, et al. Mold infections of the central nervous system. N Engl J Med 2014; 371:150.

4.     Reed C, Bryant R, Ibrahim AS, et al. Combination polyene-caspofungin treatment of rhino-orbital-cerebral mucormycosis. Clin Infect Dis 2008; 47:364.

Cox Conference: Ipilimumab-Induced Hypophysitis

In this week’s Ambulatory Cox’s Conference, Dr. Namrah Siddiq presented a case of a man with history of malignant melanoma on ipilimumab who presented with nausea, vomiting, and altered mentation. Further evaluation discovered that the patient had severe hyponatremia. Our expert discussant, Dr. Jessica Abramowitz guided us through immune checkpoint inhibitor related endocrinopathies.

Our differential diagnosis for an elderly patient with nausea, vomiting, and altered mental status initially included commonly encountered illnesses including viral gastroenteritis, urinary tract infection, dehydration, small bowel obstruction, malignancy (gastrointestinal tract tumor or metastatic disease), medication side effects, and metabolic disturbances. After we discovered the patient had a history of melanoma and was on ipilimumab, an immune checkpoint inhibitor that targets CTLA-4, our differential broadened to include ipilimumab-related enterocolitis, hepatitis, and hypophysitis. In the setting of severe hyponatremia, the patient was found to have an AM cortisol of 1 mcg/dL, undetectable TSH, and low free T4. Findings were consistent with hypophysitis, a known adverse effect of immune checkpoint inhibitors.

Immune Checkpoint Inhibitor Induced Hypophysitis Pearls:

  • Immune checkpoint inhibitors are a type of immunotherapy that use a patient’s immune system to fight their disease. They have provided significant benefit for a range of different cancer types and in patients who may not have had good treatment options in the past.
  • A number of immune-mediated adverse reactions have been described including enterocolitis, hepatitis, dermatitis, pneumonitis, nephritis, encephalitis/aseptic meningitis, myocarditis, and endocrinopathies (thyroid disease, diabetes, hypophysitis, and adrenal insufficiency). – NEJM paper.1
  • Hypophysitis is an inflammation of the pituitary gland with varying effects on pituitary hormone function. Most commonly presents with central adrenal insufficiency but may have central hypothyroidism, diabetes insipidus, or hypogonadism.
  • Hypophysitis has been described in 11-17% patients on ipilimumab. Ipilimumab in particular appears to most commonly be associated with hypophysitis.2

Clinical Presentation:

  • Patients will typically present with a constellation of symptoms including headache and vision changes along with symptoms of the various hormone deficiencies:
    • ACTH Deficiency – More mild symptoms ranging from fatigue, anorexia, weight loss, nausea/vomiting, postural hypotension, and tachycardia to severe symptoms including vascular collapse or death. Patients may have hyponatremia due to inappropriate secretion of antidiuretic hormone.
    • TSH Deficiency – Fatigue, cold intolerance, decreased appetite, constipation, dry skin, bradycardia, menstrual irregularies, and anemia.
    • FSH/LH Deficiency – Amenorrhea, infertility, hot flashes, and low libido.

Diagnosis:

  • Tests to order include electrolytes (BMP), morning cortisol, TSH and free T4, and ACTH.
  • Can consider ordering LH, FSH, and testosterone levels in males or premenopausal females with complaints of fatigue, loss of libido, and mood changes.
  • Consider MRI of brain with pituitary/sellar cuts in patients with multiple endocrine abnormalities.3
  • Patients with hypophysitis will have low ACTH and low cortisol, low or normal TSH with a low free T4, and low testosterone or estradiol with low LH and FSH.
  • Metabolic abnormalities can occur. In the case of central adrenal insufficiency and hypothyroidism, will have hyponatremia. With central diabetes insipidus, patients can have hypernatremia and volume depletion.

Treatment:

  • Temporarily withhold ipilimumab for symptomatic endocrinopathies.
  • Initiate appropriate hormone replacement therapy. In this case, the patient was started on stress dose steroids, hydrocortisone 150mg per day divided into 3-4 doses. He was also started on IV levothyroxine for thyroid hormone replacement.
  • It is important to use steroids with both glucocorticoid and mineralocorticoid effects such as hydrocortisone.
  • When a patient has hypophysitis with adrenal insufficiency and hypothyroidism, it is important to give the corticosteroids prior to thyroid hormone to prevent precipitating adrenal crisis.
  • After the endocrinopathies are stabilized on replacement hormones, patients can be restarted on ipilimumab with close monitoring by an endocrinologist.
  • Educate patients on increasing steroids during times of illness or surgery. They should also be told to get a medical alert bracelet for adrenal insufficiency. 3

References:

  1. Postow MA, Sidlow R, Hellman MD. Immune-Related Adverse Events Associated with Immune Checkpoint Blockade. NEJM 2018.
  2. Faje A. Immunotherapy and hypophysitis: clinical presentation, treatment, and biologic insights. Pituitary 2016; 19:82.
  3. Brahmer JR, et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2018.

UTSW Internal Medicine

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