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Lei et al. HLH presenting as ACS

a case series reviewing the diseases associated with to HLH-2004 for adult HLH are summarized as follows.
[5]
gallbladder wall thickening, HLH accounted for 6.0%. First of all, unilineage cytopenia is emphasized as an
Though hepatosplenomegaly noted on CT next day is absolutely required criterion, in contrast to bilineage
a common finding in HLH, rapid progression to ACS is involvement as a dispensable criterion in HLH-2004.
unusual. To the best of the authors’ knowledge, this has Secondly, a known predisposing underlying disease
never been reported in the PubMed listed literature. is considered of major importance in diagnosing
adult HLH, but not mentioned in HLH-2004. Thirdly,
With our single case report of ACS associated with HLH, high LDH is included, which is not part of HLH-2004
it is difficult to ascertain the underlying mechanism(s) either. Fourthly, NK cell activity and soluble CD25 are
responsible for ACS in this clinical setting. However, considered of limited use due to the poor availability
the fulminant course of hepatosplenomegaly seen of these tests. Molecular diagnosis, which is adequate
in our case would not allow compensative stretch of by itself to diagnose primary HLH, is disregarded in
the abdominal wall, and is therefore expected to the consensus survey for the adult HLH. Lastly, the
cause rapid elevation of intra-abdominal pressure value of hypertriglyceridemia and hypofibrinogeneima
and consequent ACS. In addition, prominent for diagnosing adult HLH fails to reach consensus
lymphadenopathy, gallbladder and duodenal wall among experts.
edema, large uterine fibroid may also contribute more
or less to the development of ACS in our patient. We A scoring system, available online at http://saintantoine.
postulate that, ACS is less likely to be encountered aphp.fr/score/, has recently been proposed to
[10]
in HLH cases of relatively chronic clinical course; estimate an individual’s risk of having reactive HLH.
at the other extreme of HLH, ACS may not be fully Additional differences reflected in this system include
developed or recognized promptly before the patients hepatomegaly and elevated AST. Degree of fever also
expire. Raising awareness of ACS as an unusual contributes to the final score (HScore). An HScore ≥
presentation of HLH would facilitate timely treatment 169 has been chosen as the cut-off value for confirming
and improve survival rate. the diagnosis of HLH, with a reported sensitivity of
93%, specificity of 86% and correct classification rate
of 90%. [10,11] Using the scoring system, our patient has
The HLH-2004 diagnostic guidelines proposed by
the Histiocyte Society include a molecular diagnosis an HScore of 203, and her probability of having HLH is
consistent with HLH or fulfillment of five out of the estimated to be 90%.
following eight criteria: fever, splenomegaly, cytopenia Though hemophagocytosis documented in bone
affecting two or more lineages (hemoglobin < 9 g/dL, marrow, spleen or lymph nodes is one of the diagnostic
9
platelets < 100 × 10 /L and/or neutrophils < 1.0 × criteria and a hallmark of HLH, it should be noted
9
10 /L), hypertriglyceridemia (≥ 265 mg/dL) and/or that hemophagocytosis per se is neither sensitive
hypofibrinogenemia (≤ 150 mg/dL), hemophagocytosis nor specific for HLH. The reported incidence of
in bone marrow, spleen or lymph node, impaired hemophagocytosis on bone marrow examination of
natural killer (NK) cell function, hyperferritinemia patients with HLH ranges from 25% to 100%. [1,8,12] On
(≥ 500 µg/L), and elevated soluble CD25/sIL-2R the other hand, hemophagocytosis may be encountered
(≥ 2,400 U/mL). [6,7] Our patient met the HLH-2004 in conditions other than HLH, including sepsis, post
diagnostic criteria based on fever, splenomegaly, transfusion or cytotoxic therapies, and critically ill
pancytopenia, hyperferritinemia, hypertriglyceridemia patients who fall short of diagnostic criteria of HLH. [8,13]
and hypofibrinogeneima. Other features that have Because hemophagocytosis is a systemic event, it can
been documented in adult HLH cases but not listed be observed in many other organs, such as liver and
in the HLH-2004 guideline include hyponatremia, brain. [14,15] However, on liver biopsy, hemophagocytic
hyperbilirubinemia, elevated AST, LDH and CRP. [8] histiocytes are present in variable numbers, and
Except elevated CRP, all other ancillary features were therefore not always seen. [16] A more common but less
observed in the present case. specific finding is portal, periportal and intrasinusoidal
infiltrates of T lymphocytes and histiocytes, [17-19] as
Because HLH-2004 guidelines were established for seen in the present case. Interestingly, destruction
primary HLH in pediatric patients, whether or not it of interlobular bile ducts has been described as an
can be readily applied to secondary HLH in adults has important feature of hepatic involvement by primary
been questioned. For instance, significantly elevated HLH, [18] but not in cases of secondary HLH for reasons
ferritin is considered specific for HLH in the pediatric that are poorly understood.
population but not in adults. [3,7] To define the diagnostic
guidelines for secondary HLH, an international consensus The trigger of HLH in our patient is most likely EBV
survey was recently conducted. Major revisions made infection, as evidenced by the dramatic increase of EBV
[9]
290 Hepatoma Research ¦ Volume 2 ¦ October 21, 2016