Moffitt Morning Report: EBV-associated HLH!

Happy Monday, Moffitt!

Thank you to Dan Minter for presenting an awesome case of an elderly man who presented with weight loss and fevers, and was found to have liver injury in a cholestatic pattern, AKI, and pancytopenia. He was diagnosed with EBV, HLH (meeting all 8 criteria, see criteria below!), and ultimately thought to have NK cell leukemia. See the case report that Dan wrote up about this case here: https://www.ncbi.nlm.nih.gov/pubmed/30066116! So many teaching points and thanks for the awesome participation from all!

 TLC (Tim and Laura, your Chiefs)

 

Cholestatic liver injury (elevated AlkP/GGT, Tbili)

Can break down into intrahepatic and extrahepatic causes

Intrahepatic:

  • Primary sclerosing cholangitis (PSC)
  • Primary biliary cirrhosis (PBC)
  • Pregnancy: ICP
  • Medications (eg. antibiotics, contraceptives, TPN, anabolic steroids)
  • Infxn: Fungal, TB, echinococcocus

Extrahepatic

  • Gallstones
  • Malignancy
  • Primary Sclerosing cholangitis
  • Chronic pancreatitis
  • HIV cholangiopathy

To work up elevated LFTs in a cholestatic pattern:

  1. First check GGT to ensure biliary origin (elevated if biliary origin)
  2. Review medication list, stop possible offending meds
  3. Get a RUQ ultrasound
    1. If dilated ducts: Call hepatobiliary, consider MRCP/ERCP
    2. If normal ducts: Check anti-mitochondrial antibody (PBC) and consider liver biopsy to confirm dx if positive. Otherwise, consider broad work-up for other etiologies

 

Pancytopenia

  • In general, when all cell lines are down, the issue is likely in the bone marrow
  • Many causes, but one way to approach it is:
    • Aplastic (e.g. 2/2 viral infection, meds/toxins)
    • Infiltrative processes (e.g. infections, rheumatologic)
    • Fibrotic (e.g. myelofibrosis)

 

Short ddx for Ferritinemia

*of note, ferritin is an acute phase reactant so elevation is non-specific. But the higher it is (esp if >10K) the more you can think about this differential diagnosis).

  • Adult onset Still’s
  • HLH (hemophagocytic lymphohistiocytosis)
  • Disseminated histo
  • Lymphoma
  • Hemochromatosis

 

HLH (hemophagocytic lymphohistiocytosis) basics

  • Initial presentation: Often multiorgan involvement, cytopenias, hepatosplenomegaly with LFT abnormalities, neuro sxs
  • Pathophysiology: Disorder of excessive immune activation
  • Think about primary vs secondary HLH, and in adults always assume it’s secondary!
    • Primary HLH is often seen in kids and is related to an underlying genetic disorder
    • Secondary HLH: This is the case in almost all adult patients, so it is essential to look for the trigger! It is essentially an acquired disorder, with triggers including viral illness (esp EBV, CMV), lymphoma, as well as some rheumatologic disorders (most common association is juvenile idiopathic arthritis, but others as well). Always go hunting for the reason for HLH (eg. viral serologies, PET scan for lymphoma, BM biopsy) because affects treatment!
  • Diagnostic criteria (based on the HLH-2004 trial…): The patient must meet 5 of 8 of the below criteria!
  1. Fever >5
  2. Splenomegaly
  3. Cytopenias 9at least 2)
  4. Hypertriglyceridemia (fasting TG >265) and/or hypofibrinogenemia (<150)
  5. Hemophagocytosis in bone marrow, spleen, LN, o rliver
  6. Low or absent NK cell activity
  7. Ferritin >500 (though many people would say it needs to be higher)
    1. Elevated soluble CD25 (2 standard deviations above age-adjusted norm)
  • PEARL: As Rabih pointed out this morning, all relatively non-specific except very elevated ferritin, high TG, and low ESR can be helpful clues
  • Treatment:
    • High dose steroids + etoposide
      • PEARL: Typically as soon as you start steroids, fevers go away, as was the case here!
    • If EBV-induced, add rituximab. As Harry explained this morning, EBV assoc HLH can be particularly aggressive
    • If CMV-induced, add valgancyclovir
    • If +LP, add intrathecal treatment
  •  Prognosis:
    • Mortality is high without treatment
    • Poor prognostic signs: delayed diagnosis, neuro involvement, higher ferritin, slower rate of decline in ferritin, underlying malignancy
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