Today, we talked about the case of a middle aged woman with recent diagnosis of metastatic breast cancer on palliative Paclitaxel who was admitted with acute onset of bloody diarrhea found to have Shiga toxin and progression to HUS! She developed neurologic manifestations for which she underwent PLEX and is now recovering in rehab.
- TTP and HUS present very similarly and are difficult to distinguish clinically. HUS typically has worse renal failure than TTP and rarely has neurologic manifestations.
- Because they are tough to tease apart, start PLEX early if TTP is on your differential for HUS because TTP has a high mortality rate.
- Acute diarrhea requires work up in those with severe illness, inflammatory features, risk factors, persistent symptoms, or work in fields that are of public health related concern (food handlers, daycare workers, etc.)
- The most common cause of acute bloody diarrhea worldwide is shigella.
- Bloody diarrhea with a normal fecal leukocyte/lactoferrin count is highly suggestive of E. histolytica.
- Majority of shiga toxin produced in adults is by E coli.
- Avoid antibiotics if possible in a patient with bloody diarrhea due to shiga toxin as it can precipitate HUS.
Indications for work up of acute diarrhea:
- Age >65
- Significant volume depletion
- Blood in stool
- Severe abdominal pain
- Recent antibiotics
- Known or suspected IBD
- Food handler, daycare worker, healthcare worker
- Recent travel
DDx for acute bloody diarrhea:
- Ischemic colitis
- Invasive infections
- Shigella (most common)
- EHEC and EIEC (most commonly associated with shiga toxin)
- Nontyphoidal salmonella
- Entamoeba histolytica
- Schistosoma (more common in resource limited settings)
Work up for acute bloody diarrhea:
- Enteric pathogen panel (NAAT):
- Campylobacter, salmonella, shigella species, vibrio, yersinia, shiga toxins, norovirus, and rotavirus
- Stool culture
- Grows campylobacter, Shigella, Salmonella, and E coli strains. If suspecting other organism, must specifically request that culture from lab
- Stool leukocytes or lactoferrin
- More helpful if negative to rule in amebiasis.
Shiga toxin mediated hemolytic uremic syndrome
- Characterized by the triad of MAHA, thrombocytopenia, and acute renal failure. Rare neurologic manifestations can occur as in our patient.
- Other clinical symptoms ⇒ bloody stools, absence of fever, WBC>10k, and abdominal pain.
- 23-47% require hospitalization
- 6-9% of people infected with EHEC (O157:H7 and O104:H4) can go on to developing HUS and it is much more common in children.
- Ingestion of undercooked beef and E coli
- Shiga toxin produced by E coli binds to vascular endothelial cell surface, thereby inhibiting protein synthesis, generating lots of cytokines and chemokines, and causing end organ damage and thrombosis.
- Clinical course
- HUS develops 5-10 days after onset of diarrhea
- Up to 50% of patients require dialysis and 39% have long term renal injury.
- Mortality is 3-5%
- Supportive care is the mainstay
- Some data from an outbreak in Germany suggests there may be benefit to plasma exchange (PLEX) via removal of shiga toxin and prothrombotic factors from the body
- Eculizumab ⇒ beneficial in patients with complement-mediated HUS (not shiga-toxin mediated)
- Main distinguishing features from HUS
- Renal failure can often be mild
- Neurologic impairment is more common
- Mortality rates are much higher
- Confirmatory test is ADAMTS13
- Mainstay of treatment is PLEX!
Moral of this story: start PLEX while you’re waiting to decide if it’s HUS or TTP!
Thanks to Jen for presenting the case of a middle-aged lady with h/o HTN on hydralazine and PE noted to have progressively worsening glomerulonephritis and a discoid skin rash, with anti-MPO and anti-histone antibody positive serologies concerning for drug-induced ANCA associated vasculitis!
- Many cases of drug-induced lupus are actually drug-induced ANCA vasculitis!
- Medications associated with drug induced ANCA-vasculitis include hydralazine (most common and most severe presentation), followed by methimazole/PTU, and minocycline.
- Drug-induced vasculitis tends to present with anti-histone antibody positivity (sensitive but less specific). Drug-induced ANCA vasculitis can be anti-MPO positive especially in the case of hydralazine.
- Treatment involves witholding the offending agent. In the case of hydralazine induced ANCA-vasculitis, steroids and additional immunosuppressive therapy (cytoxan or rituxan) are also indicated to reduce progression to ESRD.
- >500 eos ⇒ eosinophilia
- > 1500 eos ⇒ severe eosinophilia
- > 5000 eos ⇒ severe eosinophilia at risk of end organ damage
- Etiology (NAACP-P)
- Monoclonal leukemias (eosinophil proliferation)
- Polyclonal: T cell lymphomas, Hodgkin lymphoma, some solid organ tumors (cervical, ovarian, gastric, colon, urotherlial, and squamous cell carcinomas)
- Adrenal insufficiency (super rare)
- Parasites: remember that only multicellular parasites can cause eosiniphilia
- Other bugs: ABPA, cocci, HIV
- Primary eosinophilic syndromes
- M:F is 1:1 but hydralazine induced lupus is more common in women
- Mechanism is poorly understood and genetic predisposition may play a role. More likely to happen in patients who are slow acetylators
- Anti-histone antibodies: 95% sensitive
- Other antibodies are uncommon
- Drugs: long list!
- Procainamide, hydralazine, chlorpromazine, quinidine, minocycline, PTU, statins, anti-TNF agents, IFN, methyldopa
- Weaker associations: AEDs, antimicrobials, beta blockers, lithium, HCTZ, amiodarone, cipro etc.
- Stop offending agent
- Joint symptoms: NSAIDs
- Skin symptoms: topical steroids
- Hydral-induced vasculitis: need cytotoxic or other immunosuppressive therapy. Treatment similar to ANCA positive vasculitis
- Resolution of symptoms weeks to months
Drug induced ANCA positive vasculitis:
- Patients typically present with constitutional symptoms, arthralgias/arthritis, and cutaneous vasculitis
- Strongest association with hyperthyroidism meds, hydralazine, and minocycline (hydral is the most common)
- Rare, but should be aware of this association because it impacts management and because it is often not diagnosed until too late in the disease course. In fact, many cases of drug induced lupus are actually drug induced ANCA-associated vasculitis
- In a small case series of hydral-induced ANCA-associated vasculitis of 10 patients, 90% had renal involvement of whom 7 recovered at 6 month follow up (though one required HD).
- Hydralazine-induced ANCA vasculitis is generally p-ANCA pattern with anti-MPO positivity (might also have anti-lactoferrin or anti-elastase)
- Treatment involves immunosuppression with steroids and cytoxan or rituxan.
- Non-hydralazine drug-induced ANCA vasculitis is typically treated with stopping the offending agent and has a better prognosis than its hydralazine-induced counterpart. In fact, ANCA positivity without clinical vasculitis is common especially in cases involving PTU.
Katie presented an elderly man presenting with few weeks of unintentional 40lbs weight loss and abdominal pain, found to be jaundiced on exam with notable hepatomegaly. Labs notable for mild hepatitis and mix conjugated and unconjugated hyperbilirubinemia with mild coagulopathy. He was ultimately diagnosed with cirrhosis and extremely likely HCC with “numerous” masses of varying size (largest one was 10 cm) with portal vein invasion.
Please refer to this previous post on etiology of hyperbilirubinemia.
Please refer to this other post on hepatitis serologies made ridiculously simple.
Hepatomegaly and jaundice: Think infiltrative/malignant process!
For patients with cirrhosis and abdominal distension, palpating and percussing the liver can be challenging.
A strategy we went over during the last physical exam round was the scratch test, which relies on the principle of the different of sound transmission through materials of various densities.
To perform the scratch test, place your stethoscope over the RUQ just above the costal margin or just below the xiphoid, and from the RLQ, lightly scratch the patient horizontally and then slowly move superiorly toward the costal margins until the sound intensities. The location of sound intensification marks the inferior edge of the liver.
Small study re: accuracy of using the scratch test.
- Most of the time a complication from liver cirrhosis
- Risk Factors
- Cirrhosis, any etiology
- Chronic HBV even without cirrhosis (oncogenic virus)
- HCV with cirrhosis
- Fungal aflatoxins
- Higher prevalence in East and SE Asia + Sub-Saharan African nations
- HBV inc risk by 100x
- Variable initial presentation
- Decompensated cirrhosis
- Jaundice, abd pain, B-sx, +/- palpable pass
- Variceal hemorrhage
- Tumor rupture leading to acute hemorrhagic shock
- Obstructive jaundice due to biliary tree invasion
- 10-15% with metastatic dz at time of dx.
- Most common sites: Lung, lymph nodes, adrenal glands.
- Paraneoplasic: Hypoglycemia (adv HCC), erythrocytosis, hypercalcemia, diarrhea
- Imaging: Sensitivity generally dec with small lesions, but imaging alone to establish dx of HCC without a biopsy in certain patient populations.
- Contrast enhanced CT (triphasic)
- Arterial phase hyperenhancement: Characteristic of HCC lesions but not specific, can be small hemangiomas, focal nodular hyperplasia, atypical focal fibrosis, non-HCC malignancy
- Venous phase Washout: Again characteristic of HCC but not specific, cirrhosis nodules can be similar.
- Capsular appearance: Pretty specific for HCC
- All 3 of the above = diagnostic of HCC, very specific not but as sensitive.
- Highest PPV for pts with cirrhosis with lesions > 2cm
- Contraindicated in GFR < 30, Nephrogenic systemic fibrosis
- More sensitive than CT, ~ specificity,
- US: Can be use as diagnosis but cannot evaluate disease burden, transplant candidacy, operator dependent. 90% sensitive and 97% specifc
- Should only be applied to pts with cirrhosis, chronic HBV, lesions identified on surveillance US for HCC, current or prior dx of HCC.
- Should NOT be applied to: no risk factors for HCC, < 18, cirrhosis secondary to congenital hepatic fibrosis or vascular etiology.
- LIRADS definitions for hepatocellular carcinoma based on ACR v2017:
- LR-1: Definitely benign
- LR-2: Probably benign
- LR-3: Intermediate probability for HCC
- LR-4: Probably HCC
- LR-5 – Definitely HCC
- LR-5V: Definitely HCC with tumor in vein
- LR-M: Probably malignancy, not specific for HCC
- LR-TR Viable: Treated, probably or definitely viable HCC
- LT-TR Nonviable: Treated, probably or definitely not viable
- LR-TR Equivocal: Treated, equivocally viable
- LR-TR Nonevaluable: TReated, response not evaluable
- Alpha-fetoprotein: Elevated in 40-65% of patients with HCC
- Normally produced during gestation, not during adulthood.
- Levels do not correlate well with degree of disease
- Sensitivity: 60%, spec: 80%, not good as a screening tool.
- Higher levels > 400 are very specific for HCC.
- May be seen in chronic liver disease so not very sensitive.
- Elevated levels are associated with advanced fibrosis, pregnancy
- Biopsy: Reserved for indeterminate nodules that do not meet radiologic criteria for HCC.
- Not recommended for LR1, LR2, LR3, or LR5 lesions
- Risk: spread of tumor along needle track, sampling error (false negative), usual surgical risk (bleeding, infection, etc)
- Barcelona Clinic Liver Cancer staging system
- Surveillance for at risk patients:
- Cirrhosis or HBV: Q6mo liver US
- Preferred therapy for localized disease
- Sufficient liver reserve, can’t be worse than Child Pugh A cirrhosis
- 5 year survival rate as high as 90%
- Stage IIIB, IVA, and IVB are incurable by resection (any invasion of a major portal or hepatic vein, other organs, visceral peritoneum, nodal mets)
- Recommended for those with active viral infection and HBV related HCC.
- Liver transplantation
- Milan criteria widely accepted, to be considered a candidate for transplant, pt must meet all criteria
- Solitary tumor < 5cm or up to 3 tumors all < 3cm
- No evidence of regional nodal or distant mets
- No evidence of vascular invasion
- Radiofrequency or microwave or localized ethanol/acetic acid/cryo localized ablation
- Best outcomes for tumor size < 4 cm
- Cirrhosis: Restricted to Child Class A or B
- Can be used to bridge to liver transplant
- Disruption of HCC supply, usually derived from the hepatic artery
- Leads to tumor necrosis from ischemia.
- Usually used for tx of large unresectable HCC not amenable to other tx i.e. resection or RFA.
- Best candidates: No vascular invasion or extrahepatic spread, Child Puph A or B
- Relative contraindication:
- bili > 2
- LDH > 425
- AST > 100
- Tumor > 50% of liver
- Untreated EV
- Significant medical comorbidities
- Localized external radiation vs radioembolization, HCC is radiation sensitive.
- Systemic chemo
- SHARP trial, prolongs survival over supportive care in pts with adv HCC)
- Might be more beneficial for HCC related to viral etiology
- Other agents: Regorafenib, Lenvatinib
- Complication during tx
- Reactivation of viral hepatitis
- 10-20% of cases are curable (resectable disease)
- 5-yr survival rates of about 5% or less if beyond stage III (portal vein invasion)
- Some evidence that sorafenib improves survival by around 3 months but it is a costly medication (60 tablets can cost up to $9000 after discount!)
Thanks to John for presenting the case of a middle-aged woman with metastatic renal cell carcinoma who presented with subacute diffuse weakness and constipation, found to have symptomatic hypercalcemia, treated with IV fluids and zoledronic acid.
- A third of patients with malignancy develop hypercalcemia in their disease course. Hypercalcemia of malignancy is associated with very poor prognosis (~50% 30 day mortality).
- Constipation plus polyuria is the most specific symptom combination for hypercalcemia
- Denosumab is superior to zoledronic acid in treating hypercalcemia of malignancy and is safe to use in renal failure.
- One way to quickly determine the etiology of hypercalcemia from your chemistry panel is to look at the chloride to phosphate ratio. A ratio > 33 is highly suggestive of a PTH or PTHrP mediated process.
** Primary hyperPTH is the most common cause of hypercalcemia in the outpatient setting. Malignancy is the most common cause of hypercalcemia in the inpatient setting.
Treatment of hypercalcemia:
- No treatment if asymptomatic
- Avoid exacerbating factors
- If chronic/asymptomatic ⇒ same tx as Ca <12
- If acute/symptomatic ⇒ same tx as Ca 14-18
- IVF – lots!
- Lasix only if concurrent renal/heart failure
- Bisphosphonate (zoledronic acid >>pamidronate if malignancy. Denosumab if refractory to ZA or severe renal impairment)
Thanks to Grace for presenting the case of a middle aged man who presented with chronic weight loss, acute SOB, and splenomegaly on exam, found to have a WBC of 188 on work up and chest imaging concerning for leukostasis.
- Most common cause of splenomegaly is portal HTN. But the ddx is broad (see schema below).
- Most common cause of a WBC 25k-75k is infection (C diff)
- WBC >100k is leukemia until proven otherwise.
- Leukostasis is symptomatic hyperleukocytosis, most commonly associated with AML.
- Management involves lowering the WBC by leukapharesis, hydrea, and TKIs (if CML) and preventing TLS.
- ↑ Water: portal HTN (most common cause)
- ↑ Cells:
- Hemolysis ⇒ Thalassemias, hereditary spherocytosis, malaria, babesia
- Mono ⇒ EBV, CMV, HIV
- Tick-borne ⇒ Rickettsia, anaplasmosis, ehrlichiosis
- Granuloma ⇒ TB, histo, leishmaniasis
- Myeloproliferative d/o
- Polycythemia vera
- Essential thrombocythemia
- ↑ Molecules:
- Other (lysosomal and glycogen storage diseases)
- Defined as symptomatic hyperleukocytosis and is a hematologic emergency!
- Mortality rate can be as high as 40% within the first week of presentation.
- Clinical manifestations of ischemia primarily in CNS, MI, lungs, and kidneys. Can also see limb ischemia and priapism.
- Malignancies at highest risk of leukostasis in order of prevalence:
- AML (WBC >50k)
- ALL (WBC >100k, though tends to present with TLS and DIC much more commonly than leukostasis)
- CML (WBC >100k), generally if in myeloid blast crisis
- CLL (WBC >400k)
- FLUIDS, lots and lots of fluids
- Cytoreduction: lowers the WBC
- Leukapharesis: not readily available as it requires a dialysis line and trained nursing staff
- Hydroxyurea: to lower the WBC
- Tyrosine kinase inhibitors (especially for CML related leukostasis)
- Induction chemo (for non-CML related leukostasis)
- Prevent tumor lysis syndrome:
- Uric acid lowering therapy
- In hemodynamically stable patients AVOID TRANSFUSION – it’s like adding fuel to the fire and can worsen ischemia. Platelet transfusion is less dangerous than RBCs and you may have to do it before trialysis line placement.
- ↑K, ↑Phos, ↑uric acid, ↑creatinine, ↓calcium
- Occurs in bulky or chemosensitive tumors with high proliferative rate (Burkitt’s lymphoma, acute leukemias, small cell lung cancer)
- Allopurinol takes 1-2 days to show effect and does not reduce preexisting elevated uric acid levels so use rasburicase if uric acid already high or preemptively if TLS risk is high or if there is kidney injury.
- HD if concern for renal damage
Causes of pseudohyperkalemia
- Technique of blood drawing (tourniquets and fist pumping)
- Leukocytosis (>120k)
We worked through a case from the Human Diagnosis Project with a 57 yo M originally form Guatemala (moved to US 25 years ago) with a history of pre-DM and recently diagnosed and treated Lyme disease presenting with 2 months of persistent fever, chills, malaise, and myalgias. He received extensive work up, and everything turned (including TEE, LP, SPEP, rheum, BM biopsy, HIV) were negative. He had splenomegaly on exam, and CT CAP revealed hilar LAD + LLL tree-in-bud along iwth a 20cm spleen. The patient was ultimately diagnosed with DLBCL, AND cryptococcal pneumonia secondary to immunosuppression from his lymphoma!
Credit: Dr. Ron Cho, New York Medical College, Internal Medicine.
Fever of Unknown Origin
- Classic Definition
- Fever > 38.3 °C on multiple occasions
- Duration > 3 weeks
- Uncertain diagnosis after 3 outpatient visits or 3 days in the hospital (revised, used to be 1 week inpatient investigation) or 1 week of “intelligent and invasive” ambulatory investigation
- TB is the single most common infection in most FUO series, can be extrapulmonary, military, or pulmonary. May occur concurrent in AIDS patient, leading to a more subtle presentation.
- Bacterial endocarditis (2-5% of these are culture negative bacterial endocarditis, i.e. from Coxiella brunetii and tropheryma whipplei).
- Super rare causes of endocarditis with difficult to grow culture: Mycoplasma, Legionella, Bartonella, Brucella, HACEK organisms
- TEE is positive in > 90% of cases of FUO from infective endocarditis.
- Viral i.e. EBV
- Malignancy: Most common are lymphoma and leukemia.
- NH Lymphoma
- Myelodysplastic syndromes
- Systemic Rheumatic disease
- Adult onset Still’s disease: young and middle age adults, daily fevers, arthritis, evanescent rash.
- GCA: Older patients
- Polyarteritis nodosa, Takayasu, GPA, cryoglobulinemia
- Drugs: Antibiotics, H1 & H2 blocking antihistamines, antiepileptic drugs, NSAIDS, hydralazine, antithyroid drugs, digoxin.
- Factitious fever: Psych, predominantly affects F and healthcare professionals
- Disordered heat homeostasis after a stroke or from hyperthyroidism
- Dental abscess
- Multiple concurrent infections
- Alcoholic hepatitis
- Hereditary periodic fever syndromes
- Unidentified: 19% of cases are unidentified.
- Management/Diagnostic Principles
- Get a detailed history, including fever pattern exposure history, sexual history, family history, medications.
- Do not start empiric therapy unless pt is neutropenic or unstable, or you have a high-suspicions for GCA or culture negative endocarditis.
- Most common type of NH Lymphoma, representing 25% of cases
- Median age: 64, 55% men. Also accounts for 25% of childhood NHL.
- Caucasians at higher risk and esp patients of Swedish and Danish ancestry
- Other risk factors: HIV, h/o radiation or chemotherapy
- Heterogenous group of tumors that arise from mature B cells in (90% of cases, the other 10% from T cells)
- Most common mutations found in DLBCL:
- BCL6 gene mutation
- BCL2 activation
- MYC overexpression
- Nodal and extra-nodal manifestation at time of diagnosis. Most common extra-nodal manifestation is bonemarrow or GI tract.
- Typically pts present with a mass, most commonly in the neck, abd, or mediastinum but it can manifest anywhere.
- Painless LAD might be present in 2/3 of cases.
- Less than 50% will have B-sx.
- Can present with pancytopenia. Might see elevated LDH, uric acid, and calcium.
- Excision LN or tissue biopsy, excisional LN is preferred
- Ann Arbor Criteria
- Stage I – disease in single lymph node or lymph node region.
- Stage II – disease in two or more lymph node regions on same side of diaphragm. Note: Stage II contiguous means two or more lymph nodes in close proximity (side by side).
- Stage III – disease in lymph node regions on both sides of the diaphragm are affected.
- Stage IV – disease is wide spread, including multiple involvement at one or more extranodal (beyond the lymph node) sites, such as the bone marrow (which is involved commonly), liver, pleura (thin lining of the lungs).
- Spleen is considered nodal
- 1st line is RCHOP (3 cycles) and local regional radiation, 6-8 cycles of R-CHOP is an acceptable alternative.
- Emerging data, DA-EPOCH is better for younger patients < 60 yo and with certain phenotypes
- Double Hit Lymphoma: Lymphoma resembling DLBCL but has MYC gene translocation AND rearrangement of BCL 2 or BCL 6. RCHOP still first line but overall prognosis is worse. DA-EPOCH-R might work better.
Thanks to Erica for presenting the case of a middle aged man who presented with acute back pain and B symptoms after trauma to his back, found to have stage 3B multiple myeloma.
- Remember that majority of cases of acute low back pain (<6 weeks) is due to musculoskeletal etiologies that spontaneously improve on their own. Imaging and further diagnostic work up is not indicated unless there are red flags (see below).
- A straight leg test is more useful when negative as it has a high negative predictive value for ruling out radiculopathy. False positive rates are quite high.
- Unexplained anemia and worsening renal function in the outpatient setting should trigger a work up for multiple myeloma.
- The most common presenting symptoms for MM are anemia (73%), bone pain (58%), and renal insufficiency (48%).
- In diagnosing MM, sensitivity increases with each added test: SPEP (82%) → IFE (93%) → FLC/UPEP (97%). The other 3% that would not be diagnosed with these tests have a non-secretory MM (monoclonal increase in plasma cells in bone marrow that do not produce immunoglobulins or light chains).
Red flags for acute low back pain:
- Focal neurologic complaints/deficits
- History of cancer
- Age >50 years
- Fever not explained by another cause
- History of recent bacteremia or IVDU
- Steroid use
- Weight loss
- Pain that is worse at night
- No relief with bed rest or pain lasting >1 month
Multiple Myeloma: refer to this prior blog post. Other info below:
- SPEP: picks up M protein or elevated immunoglobulins (heavy + light chain) in the serum. You can diagnose over 80% of patients with MM using an SPEP.
- IFE: identifies the specific type of immunoglobulin that is elevated with its light chain.
- Free light chains (FLC): measures the amount of free light chains not bound to a heavy chain floating around in the blood. Normally people have about a 2:1 ratio of kappa to lambda chains. In light chain only multiple myeloma, there is a disproportionate increase in one type over the other and the ratio will be off. If there is an increase in both light chains but the ratio is normal, think kidney disease!
- Keep in mind that the reason to check FLC when you suspect MM is to diagnose those people who are only producing light chains and not whole immunoglobulins that would have been picked up by SPEP/IFE.
- UPEP: measures light chains dumped in the urine (Bence Jones protein)