Bri presented a case of a gentleman with multiple medical comorbidities with a recent lap chole presenting with confusion. His labs were significant for anemia, thrombocytopenia, elevated indirect bilirubin, elevated LDH, and undetectable haptoglobin. A smear revealed numerous schistocytes concerning for MAHA. ADAMTS13 levels were found to be very low, and the presence of an ADAMTS13 inhibitor was detected as well. This presentation is consistent with thrombotic thrombocytopenic purpura (TTP)!
Common differential for microangiopathic hemolytic anemia (MAHA):
- TTP/HUS, atypical HUS
- Mechanical heart valves
- Severe B12 deficiency
- Rare, most often > 40 in adults, congenital ADAMTS13 deficiencies can be seen in kids (Upshaw-Schulman Syndrome, autosomal recessive)
- 2:1 female to male predominance
- Non-immune mediated platelet and RBC destruction due to mechanical shearing of platelets and RBC when they pass through platelet/fibrin deposits on small vessel walls in absence of ADAMTS13 activity.
- Further consumption of plts via formation of microthrombi in small arterioles/capillaries, brain/heart/kidneys are especially affected.
- ADAMTS13 cleaves VWF, preventing large multimer formation on vessel walls
J Evan Saldler. Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura. Blood 2008 112:11-18; doi: https://doi.org/10.1182/blood-2008-02-078170
- Drug-induced (Immunosuppressants, chemo)
- Pregnancy (preeclampsia/eclampsia)
- Hemorrhagic colitis
- HUS: more likely in kids, more commonly presents with AKI and in higher severity. Associated with E.coli O157:H7 infection and some strains of Shigella
- Atypical HUS: very similar to TTP but differnet pathophys (congenital complementary activation defect)
- Pentad of FATRN: < 1/3, can be indolent (days to weeks of malaise)
- Fever( 10%)
- Anemia (100%)
- Thrombocytopenia (100%)
- Renal dysfunction, more common in HUS
- Neuro (encephalopathy): More common in TTP (53%), less in HUS
- Triad that’s almost always present:
- LDH elevation
- Sx: Non-specific, encephalopathy, abd pain, N/V, diarrhea, arrhythmia.
- Exam: SICK compared to pts with ITP.
- E/O hemolysis: Anemia, polychromasia, elevated retic, reduced hepato, elevated LDH, elevated indirect bilirubin
- Fibrinogen is normal (although early DIC can also be relatively normal)
- PT/PTT are normal (vs elevated in DIC!)
- Low ADAMTS13 level (<10%) is highly specific for TTP
- ADAMTS13 inhibitor usually seen in adults, suggestive of autoimmune related deficiency of ADAMTS13. Generally responsive to immune suppression.
- Emergent consultation with specialists, coordinate with MICU, Heme/Onc, and Renal!
- FFP can be given to temporize things, fastest treatment option
- DO NOT TRANSFUSE PLATELETS
- 90% mortality without tx
- Emergent PLEX: reduces mortality to 20-30%, but those who survive the initial episode can have relapses 20-50% of the time.
- Low ADAMTS13 activity and higher titers of ADAMTS13 inhibitor are associated with worse prognosis.
- Plasma exchange usually continued until e/o dz activity has decreased (nrl plt, nrl LDH)
- Immune suppression with corticosteroids, rituximab can be considered in refractory cases.
- For HUS, tx is mainly supportive +/- dialysis but Eculizumab can be used.
Yonglu presented a middle age man with no medical history presenting with syncope. In the preceding months, he has been having non-specific fatigue, decreased exercise tolerance, dizziness, and diaphoresis. He was found to be hypoglycemic after this syncopal episode, and in the hospital his labs were consistent with hyperinsulinism when he was in a hypoglycemic state. CT revealed diffuse liver masses concerning for HCC, as well as a lesion on his left iliac crest appearing to be an osteosarcoma. He was also found to have a pancreatic mass as well…
Three malignant processes? Octreotide scan revealed increased uptake at these regions, and biopsy of the liver revealed a diagnosis of a neuroendocrine tumor!
When we think about hypoglycemia, its pattern can actually give us a clue.
- Fasting: Most common
- Post-prandial: non-insulinoma pancreatogenous hypoglycemia syndrome (NIPHS), post-bariatric surgery hyperinsulinemic hypoglycemia
- Both: Insulin autoantibody, insulinoma
- Rare, not enough data
- Small cohort: median age 48 years, 77% men
- MEN Type 1: Younger presentation, 20s
- Pancreatic islet cell origin
- Generally benign, single vs multiple
- Rare to be malignant (10%)
- Pattern: fasting hypoglycemia mainly but can be both
- May have some sympathoadrenal sx i.e. palpitations, diaphoresis (seen in this patient), tremulousness
- Likes to spread to liver, rarely can have bony mets (~13%)
Whipple’s Triad: Presence of all three demonstrates “true” hypoglycemia
- Symptoms of hypoglycemia
- Low plasma glucose at time of symptoms
- Relief of symptoms when glucose is back to normal
- Evidence of inappropriately high serum insulin during episode of hypoglycemia
- 72 hour fasting plasma glucose test: Supervised fast in order to bring on hypoglycemia in order to evaluate etiology. If pt has underlying hyperinsulinism, 95-99% of the time they will be hypoglycemia within 48 hours of fasting.
- Blood test is drawn when pt has sx of hypoglycemia
- Test: Glucose, insulin, proinsulin, and c-peptide level.
- Normal: suppression of endogenous insulin
- Abnormal: Inappropriately elevated insulin, pro-insulin, and c-peptide in setting of hypoglycemia.
- Octreotide scan: Increased uptake seen in tumors of neuroendocrine etiology, more sensitive than US, CT, or MRI for detection of somatostatin receptor positive tumors
- Evidence of hyperinsulinism
- Low BHB
- High insulin level
- High C-peptide
- High pro-insulin
- Chromogranin A: used to help diagnose carcinoid tumors (NET of the digestive tract and lungs). Nowadays carcinoid is generally used to refer to well differentiated NETs originating in the lungs. GI tract tumors are now termed NET.
- Localized lesion: Surgical resection is curative
- Somatostatin analogy
- Octreotide: Inhibits growth hormone secretion, can switch to Q-monthly formulation
- Diazoxide: Diminishes insulin secretion, side effects include hirsutism and edema
- Radiation therapy: Data also limited in utility but can be consider if evidence of bony mets (which is also rare for NET)
- Minority of NET, namely high-grade, well differentiated with Ki67 index > 20%, are rare and there is no consensus on how to treat these patients. These patients generally respond poorly to platinum/etoposide based regimens used to treat most NETs.
- Other options: Temozolomide, Sunitinib (RTK inhibitor), Everolimus (mTOR inhibitor)
Helpful table for hypoglycemia work up.
Beta-hydroxybutyrate (BHB) is by product of alternate metabolism (more specifically ketone bodies) in a fasting state, so it can be elevated in setting of prolonged fasting (not just DKA).
Also thanks to Arathi for pointing out that insulin has a negative feedback on this process, hence in a hyperinsulinemic state (despite concurrent hypoglycemia), beta hydroxybutyrate would be very low!
Insulinomas can appear like hypoglycemia secondary to oral glycemic agents, but the key is the oral glycemic agent screen would be positive in the latter case!
IGF-omas can cause s/sx hypoglycemia due to similarity with insulin. Expect IGF2 levels to be elevated in such cases and elevated BHB.
Please refer to this helpful review article if you want to know more about NETs!
Also please refer to this paper for a case report on AFP-producing pancreatic NET (AFP elevated in this patient!)
Thanks to Barnie for presenting the case of a middle-aged woman who was admitted with acute onset of SOB, found to have submassive PE.
- Risk stratification tools are helpful in estimating the pre-test probability of PE. The best and most validated is Wells criteria.
- YEARS items is a newer tool that was studied in an RCT in the Netherlands and found to lower the number of CTPA scans ordered by 14% without a significant impact on rates of missed PE diagnoses.
- For patients at low risk of PE according to Wells, PERC is useful in ED or outpatient setting to rule out PE without ordering a d-dimer (see graphic below).
- Age-adjusted d-dimer is age x 10 for patients older than 50 years. This accounts for the increase in d-dimer baseline related to aging. ADJUST-PE trial showed that age-adjusted d-dimer leads to higher specificity without subsequent VTE.
- Studies have shown an 11.6% reduction in CTPA scans with the use of this correction factor without an appreciable increase in missed diagnoses of PE.
- Think of PE in three broad categories:
- Massive PE = hemodynamically unstable ⇒ anticoagulation + thrombolysis
- Submassive PE = hemodynamically stable + RV strain ⇒ anticoagulation + thrombolysis
- Low risk PE = hemodynamically stable, no RV strain ⇒ anticoagulation. Use the PESI score to determine if your patient can be treated outpatient.
- Remember that the most common EKG finding in PE is normal sinus rhythm! The most common abnormal EKG finding is sinus tachycardia. S1Q3T3 pattern is only seen in 10% of patients with PE.
Suggested algorithm for diagnostic work up of suspected PE:
Remember that the scoring tools above are only there to add to your clinical judgment, not replace it!
Recent study in the Lancet looked at the utility of a different diagnostic algorithm, using the three most predictive items on Wells together with d-dimer. Compared to Wells, this diagnostic tool led to a 14% reduction in unnecessary CTPA!
- Remember that clot burden does not factor into the treatment categories of PE. Low clot burden in a patient with baseline cardiopulmonary disease can still lead to hemodynamic compromise and would be considered massive PE.
- Submassive PE treatment is an area of much debate. A famous trial (PEITHO trial) in 2014 randomized 1006 patients to receive heparin + placebo vs heparin + tenecteplase (European version), and found a >50% reduction in combined death and cardiovascular collapse at 7 days but a > four-fold increase in risk of major bleed including intracranial hemorrhage. Subsequent meta-analyses (and this one) found that the risk of major bleeding was highest in people >65 years of age. So treatment decisions here are tricky and require consulting multiple services!
Signs of RV strain:
- EKG findings:
- S1Q3T3: this is a sign of cor pulmonale and can be seen in a number of conditions in addition to PE
- Bronchospasm (really bad asthma)
- Echo findings:
- Elevated RVSP
- Septal bowing
- McConnell’s sign (regional wall motion abnormality sparing the RV apex)
- Not sensitive but helpful in distinguishing RV strain due to chronic pulmonary HTN from RV strain due to acute PE
- Increased RV size
- Decreased RV function
- Tricuspid regurgitation
- Elevated troponin
- Elevated BNP
Thank you Charles for presenting this really interesting case. A 18 year old woman with a history of asymptomatic thrombocytopenia who presents with several days of non-specific fever, chills, malaise, mild shortness of breath and she was found to have acute anemia, thrombocytopenia, elevated transaminitis, and patchy bilateral pulmonary infiltrates on CXR during initial presentation. She became acutely ill with submassive hemoptysis and went into respiratory failure in 24-48 hours. She was found to have DAH on BAL. Her autoimmune and infectious work up came back negative, but her ferritin came back at 75776. Base on this and her constellation of symptoms, further work up revealed a 6/8 criteria for diagnosis of hemophagocytic lymphohistiocytosis!
- Dyspnea, cough fever, respiratory failure, acute anemia
- Hemoptysis only in 2/3 of cases
- Definition: Hemoptysis, diffuse alveolar infiltrates, acute anemia, and hypoxemic respiratory failure
- Widespread damage to pulmonary small vessels, leading to blood within the alveoli eventually causing impaired gas exchange.
- Causes: Autoimmune/connective tissue disease leading to pulmonary vasculitis (ANCA, anti-GBM), certain pulmonary infections, toxins, drug reactions, mitral stenosis in some cases
- 3 distinct histologic subtypes that can give hints to underlying pathology
- Most common: Pulmonary capillaritis: ANCA vasculitis, GPA, EPGA, pauci-immune, Goodpasture, HSP, SLE, RA, APLS, MCTD, Behcet, drug-induced, lung transplant rejection, etc.
- Systemic vasculitis manifestation
- Bland pulmonary hemorrhage: Coagulopathy, mitral stenosis, toxin/inhalation, SLE, drugs, Goodpasture
- Anti-GBM, SLE, no inflammation or destruction of capillaries but RBC leakage
- Diffuse alveolar damage: BM transplantation, radiation, ARDS, cytotoxic drugs, other causes
- CXR: Diffuse bilateral alveolar infiltrates, no pathognomonic findings
- BAL: serial bloody aspirate with sequential sampling
- CT: Non-specific GGO
- Biopsy: Tissue biopsy of the lung is definitive in confirmation of DAH but underlying cause might not be revealed.
- Treat underlying cause
- Respiratory support, most patients die from respiratory failure
- High dose corticosteroids, i.e. methylprednisolone up to 500mg Q6H (up to 2g daily)
- Other agents: Cyclophosphamide, azathioprine, MTX, mycophenolate, etanercept.
- Plasmapheresis for Goodpasture or vasculitidies.
- Key: Early identification and treatment
- Worldwide incidence is unknown, not enough data available, thought to be rare AND underrecognized but growing recognitive leads to higher incidence.
- Familial types: more common to occur in pts < 18yo
- Secondary HLH: any age
- Uncontrolled hyperinflammatory response with dysregulated macrophage activity leading to excessive cytokine production
- Primary: HLH due to an underlying genetic abnormality or without clear cause
- Autosomal recessive familial HLH
- Secondary: Due to something else
- Retrospective study at Mayo in 2014:
- Infection (34%), most commonly EBV
- Autoimmune (8%), Macrophage activation syndrome (MAS), most often associated with AOSD, systemic juvenile idiopathic arthritis, or SLE.
- Malignancy (52%) NHL, HL, acute leukemia
- Idiopathic/Immune deficiency/other (6%)
- Fever, splenomegaly, cytopenias are most common
- + manifestation of the trigger
- Complications: Infection, DIC, bleeding complications (reports of intracranial hemorrhage, GIB, DAH), end organ damage.
Diagnosis: Per the Histiocyte Society: 5/8 criteria for diagnosis. In case you cannot remember all 8, please refer here for the famous HLH Song by Dr. Eric Lau:
- Peripheral cytopenia (> 2 cell lines)
- Hypertriglyceridemia or Hypofibrinogenemia
- Elevated ferritin > 500 (> 10000 = 90% sensitive and 96% specific for HLH)
- Low NK cell activity
- Elevated soluble CD25 (soluble IL2-R)
- Hemophagocytosis in BM, spleen, or LN: Only seen in later course of the diseases and not required for the diagnosis, neither sensitive nor specific, can be seen in severe sepsis/critical illness)
- Like all things in medicine, treat the underlying cause
- Current treatment is based on the HLH-94 study on pediatric population
- Induction: 8 weeks dexamethasone and etoposide.
- Maintenance: Cyclosporine, tacrolimus, dex pulses
- If MAS: Steroids alone, usually responsive.
- Hematopoietic stem cell transplant is refractory/relapsing.
For more information on HLH, please refer to this article by Dr. Schram and Dr. Berliner published in Blood (as in the journal) in 2015.
Thanks to Naina for presenting the case of an elderly man presenting with acute onset of n/v, and abdominal pain, found to have anemia and AKI, with work up revealing small cell cancer of the bladder causing ureteral obstruction with mets to the lymph nodes, liver, lung, and bone, hospitalization complicated by TLS prior to onset of chemo and contrast induced nephropathy.
- Bladder cancer is the most common malignancy of the urinary system and urothelial (transitional cell) carcinoma is the culprit >90% of the time. Less common subtypes include squamous, adeno, small cell (our patient), and sarcoma.
- Unexplained hematuria in anyone >40 years is bladder cancer until proven otherwise!
- CT urography is the diagnostic imaging of choice in the work up of hematuria.
- Diagnosis of bladder cancer is often delayed due to similarity of symptoms with other benign disorders. However, majority of cases are still caught in stage 0-1 (muscle non-invasive disease) with overall good prognosis.
- Most common malignancy of the urinary system, 3-4 x more common in men but women are usually diagnosed with more advanced disease and have a higher mortality rate.
- Median age at diagnosis is ~70
- Incidence has increased by more than 50% during the past 20-30 years.
- Urothelial (transitional cell) carcinoma is the predominant histologic subtype in the US and Europe (>90% of all bladder cancers) and can arise in renal pelvis, ureter, or urethra
- Other: squamous, adeno, small cell, sarcoma
- Degree of invasion:
- Superficial (non-muscle-invasive)
- Clinical presentation
- Painless hematuria
- Irritative voiding symptoms (frequency, urgency, dysuria) – only in 30% of patients
- Sometimes metastases cause the initial symptoms that lead to diagnosis (as in our patient)
- Most cancers eventually become symptomatic
- Diagnosis: often delayed due to similarity of symptoms to other benign d/o
- Urine cytology >98% specific, 12-64% sensitive based on grade of tumor
- TURBT done for diagnosis and staging
- Hematuria from enlarged prostate
- Passage of renal calculi
Source: Nature Outlook.
- Over 50% of people diagnosed with non-invasive disease develop recurrence
- Assess performance status with Karnofsky or Eastern Cooperative Oncology Group scales for older patients before deciding on chemotherapy
- Chemo regimens are often cisplatin-based which carry the side effects of nephrotoxicity, ototoxicity, and neuropathy
Source: Nature Outlook
Refer to this thorough algorithm on UpToDate.
- Incidence of malignancy in microscopic hematuria is ~2-5%
- Incidence of malignancy in macroscopic hematuria is ~20%
Extra pearls on onset of hematuria during voiding:
- Occurs at the beginning? Urethral source
- Discharge noted between voidings or stain on undergarment? Urethral meatus or anterior urethra
- Terminal hematuria? Bladder neck or prostatic urethra
- Throughout voiding? Anywhere in the GU tract
Thanks to Sahar for presenting the interesting case of a middle-aged woman with metastatic melanoma recently started on ipilimumab who presented with a headache and fatigue, found to have hypothyroidism and adrenal insufficiency with work up consistent with hypopituitarism related to an adverse effect of ipilimumab: lymphocytic hypophysitis!
- Remember that adrenal insufficiency and hypothyroidism are causes of elevated ADH levels.
- Red flags for obtaining head imaging for headache include age >55, sudden onset, positional, onset after trauma or exercise, fever, focal neuro findings, and immunosuppression.
- Pituitary adenomas can have three manifestations: mass effect, hormonal hypersecretion, and hypopituitarism. When imaging shows a pituitary mass, your work up should address each of these categories.
- The most sensitive test to assess hypothalamic-pituitary access function is LH/FSH!
- Immunotherapies are commonly associated with a flare of autoimmune diseases. A more rare side effect of CTLA-4 inhibitors (like ipilimumab) is lymphocytic hypophysitis (inflammation of the pituitary gland)
- This condition commonly presents with headache out of proportion to neurologic findings and preferential decline in ACTH and TSH though other hormones can also be impacted.
- For hypopituitarism, remember to always treat adrenal insufficiency first before replacing thyroid hormone. Failure to do so can precipitate adrenal crisis!
Indications for imaging a patient with headache:
- Age >55
- Sudden onset
- Worse with lying down or wakes patient from sleep
- Rapid onset after trauma or exercise
- Focal neurologic findings
- New headache in immunosuppressed patient
- Evaluate for the following
- Mass effect: visual field deficit, headache
- Hormonal hypersecretion
- Prolactin ⇒ galactorrhea, amenorrhea, infertility
- GH ⇒ Acromegaly
- TSH ⇒ hyperthyroidism
- ACTH ⇒ Cushing disease
- ADH ⇒ SIADH
- Inflammation of the pituitary
- Four categories based on histologic findings:
- Most common form
- Seen in late pregnancy and post-partum period
- Also associated with ipilimumab as our patient here!
- Idiopathic or secondary to GPA, sarcoid, TB
- Plasmacytic (IgG4-related)
- Xanthomatous (most rare)
- Clinical presentation
- Headache out of proportion to exam findings
- Preferential decrease in ACTH and TSH ⇒ adrenal insufficiency and hypothyroidism
- Pituitary size eventually normalizes but pituitary loss of function is often permanent.
Lastly, refer to this algorithm from our recent morning report to help you think through hyponatremia.
Sarah presented a middle age woman with a history of schizophrenia, HFpEF, possibly COPD, who presented from her Board and Care facility due to inability to ambulate. She was able to provide much of a history but her exam was normal. Her labs were notable for alk phos in the 700-1000 range, and mildly elevated AST/ALT in the 60-70s. An abdominal US revealed hepatic steatosis but really nothing else… Her medical history was also obscure since she receives her care from multiple institutions.
She was incidentally found to have a breast mass on exam, and subsequent work up for her elevated alk phos unfortunately revealed metastatic breast cancer.
Elevated Alk Phos
Background: Alk Phos is derived from mainly bone and liver, higher in men, varies with age (higher in kids, thought to be due to physiologic osteoblastic activity)
GGT (gamma glutamyl transpeptidase): liver specific, can be used to verify if alk phos elevation is due to biliary disease if GGT is also elevated.
Most common tumor in women
- > 50
- Personal Hx
- Strong family Hx of pre-menopausal breast cancer
- Genetic BRCA 1 & 21
- Personal hx or ovarian or endometrial cancer
- Dense breasts
- OCP use for > 15 years
- Late menopause
- Screen F > 50 or < 5-10 yrs prior to age in 1st degree relative with breast cancer, and then Q2yr
- More frequent screening recommended for specific mutations, i.e. BRCA, TP53, then MRI Q year
- How about F with breast implants? MRI, CT, or mammogram? The recommendation is still mammogram but with multiple views
|Local disease in situ
||No malignancy beyond basement membrane
||Lumpectomy + RT, or mastectomy. If ER +, use tamoxifen/aromatase inhibitors
|Lobular carcinoma in situ (LCIS)
||Isolated to lobule, within basement membrane, not exactly cancer yet but high risk
||ER+ use tamoxifen/AI to dec risk of development into invasive breast cancer.
NSABP-P1 trial: Pt with LCIS tx with tamoxifen dec risk of invasive breast cancer, but inc risk of endometrial cancer esp in > 50yo
|Infiltrating ductal carcinoma, LN negative
||Spread beyond BM, need to sample sentinel LN, if negative, no further need for dissection.
||Wide excision of mass with free margins + RT, adjuvant chemo for size > 1cm. Tamoxifen/AI if ER +
|Infiltrating ductal carcinoma with LN positive
||Same as above but LN +, warrants further LN dissection, automatic adjuvant chemo
||Wide excision (modified radical mastectomy), RT + adjuvant chemo + Tamoxifen/AI if ER+.
|Local invasive dz involving skin or chest wall
||Chemo followed by mastectomy, + tamox/AI if ER+
Lymph node positivity is the most important prognostic factor, followed by tumor size, then receptors, and then grade.
For diagnosis, always get excision biopsy for dx, FNA has low sensitivity, hence even if negative, always follow by excisional bx.
Receptors and Management
||Chemo + tamoxifen
||Aromatase inhibitors + chemo
Tamoxifen: Use for 10 years if ER/PR+. Dec risk of new breast cancer and effective for metastatic dz of receptor positive.
Down side: inc risk of endometrial cancer 3x, inc thromboembolic risk.
Aromatase inhibitors: Watch out for osteoporosis