A rare case of gamma heavy-chain disease highlighting the need of a comprehensive evaluation of laboratory data

AUTORI

ABSTRACT

An 88-year old woman was admitted to the emergency room (ER) after a syncope and subsequent head trauma. A complete blood count and imaging studies showed cytopenia and bilateral cervical lymphadenopathy, respectively. After three months, the patient returned to ER with dyspnea and a large abdominal effusion. Cytopenia was progressed and protein electrophoresis revealed a monoclonal peak in the beta zone. Immunofixation showed the presence of gamma heavy-chains without associated light-chains. Capillary electrophoresis with immunosubtraction and immunophenotyping by flow cytometry returned the same results. Immunohistochemistry was apparently discordant, describing a monotypic kappa population. An important ascites with low total proteins in the ascitic fluid, a liver with lumpy margins and non-homogeneous structure, elevated GGT, and decreased albumin, suggested ascitogen liver cirrhosis in the context of a rare gamma heavy-chain disease.

CASE PRESENTATION
A caucasic 88-year old woman initially presented to the emergency room (ER) after a syncope, and subsequent head trauma. The patient had the following underlying diseases: well-managed type-2 diabetes, mild dyslipidemia, duodenal ulceration on chronic gastritis, and colic diverticulosis. Chronic therapy included statin, oral hypoglicemic, anticoagulant, antihistamine, and diuretic (furosemide).
Computed tomography (CT) showed bilateral cervical lymphadenopathy. Complete blood count showed mild leukopenia [3.73×109/L (r.i. 4.5-11.0)] and thrombocytopenia [63×109/L (r.i. 140-450)], normal erythrocytes [4.71×1012/L (r.i. 4.0-5.4)], and increased RDW [18.4%, (r.i.11.4-14.5)]. The most recent complete blood count was performed about 6 months earlier, showing normal values. The patient was discharged because the negative cranial CT scan.
After three months the patient returned to the ER with dyspnea and abdominal enlargement, mentioning also a recent oral mycosis. Arterial blood gas showed hypoxemia [62.8 mmHg (r.i. 80-100)] and hypocapnia [29.7 mmHg (r.i.35-45)]. Compared to the previous test, the complete blood count showed pancytopenia with stable thrombocytopenia, but worsened leukopenia (2.31×109/L, 38% decrease) and erythropenia (3.85×1012/L, 18% decrease). C-reactive protein was slightly elevated [15.8 mg/L, (r.v <5.0)]. Other notable findings were slightly elevated glucose compatible with known diabetes, hyperuricemia [7.8 mg/dL (r.i. 2.6-6.0)], elevated total amylase [132 U/L (r.i. 28-100)]; creatinine, ions, lactate dehydrogenase, alkaline phosphatase, and thyroid hormones were normal. A large abdominal effusion was observed at ultrasound examination (US), and the patient was hospitalized.
During hospitalization, abdominal CT revealed multiple abnormal lymph nodes and nodules in an enlarged spleen, in the thyroid, parotid gland and neck. The liver was described with lumpy margins and with dishomogeneous structure. Investigating possible hepatopathy, transaminase and bilirubin were normal, but gamma-glutamyl transferase (GGT) was elevated [105 U/L (r.v. <38)], and serum albumin decreased [2.3 g/dL (r.i. 3.5-5.2)]. Serological tests for A, B and C viral hepatitis were negative. Anti-nucleus antibodies (ANA), anti-neutrophil cytoplasmic antibody (ANCA), anti-mitochondrial antibodies (AMA), anti-smooth muscle antibodies (ASMA), liver kidney microsomal antibodies (LKM), and soluble liver antigen (SLA) were all negative. Coagulation tests (PT, aPTT, fibrinogen) were normal.
The abdominal effusion was drained multiple times, and ascitic fluid had low total proteins (1.6 mg/dL), a moderate immune monocytic infiltrate, no malignant cells, and it was negative for Mycobacterium tuberculosis (staining and culture).
Serum protein electrophoresis (SPE) (Sebia Italia, Firenze) showed hypoalbuminemia (23 g/L [35-52]) and hypogammaglobulinemia (4.5 g/L [r.i.7-16]), with a monoclonal peak (5.9 g/L) between beta-1 and beta-2 zones. Despite hypogammaglobulinemia on SPE, serum immunoglobulin levels were normal. Capillary electrophoresis immunosubtraction (CE-IS) (Sebia) showed the presence of a monoclonal IgG without associated light chains;immunofixation electrophoresis (IFE) on agarose gel (Sebia) returned the same results (Figure 1). The finding was further confirmed by immunophenotyping (IPT) using flow cytometry: an abnormal B-cell population was described, most of the cells (83%) did not express light chains. CD5 was not expressed. Immunohistochemistry (IHC) on a lymph node biopsy showed a mixed lymphoid proliferation with plasmacytic differentiation and monotypic kappa+, Multiple Myeloma 1+ (MUM1) population. (Figure 2)
The patient was discharged after a month with a diagnosis of B-cell lymphoproliferative disorder and ascitogen liver cirrhosis. Considering the overall status of the patient, the recommended therapy was only low-dose prednisone. One month later, the patient deceased.

DISCUSSION
Heavy-chain diseases (HCD) are rare and heterogeneous B-cell lymphoproliferative disorders characterized by the accumulation of truncated immunoglobulin heavy-chains (HC), without associated light-chains (LC). Truncation usually occurs at CH1 level. Normally, HC are not secreted, and rarely detected in serum or urine, because the abnormal HC are captured by heat-shock proteins (hsp-78) and digested by proteasome (1). In the rare case where mutations alter both the LC-binding site and the hsp-binding site, HC bypass protein degradation and can be secreted and detected in body fluids. HC are also part of the transmembrane B-cell receptor (BCR), which has an important role in activation and signaling of B-cells. Interestingly, Corcos et al. suggested that the presence of a truncated HC might cause a constitutive activation of BCR, leading to a ligand-independent receptor aggregation and activation. This may play a major pathogenic role in conferring a growth advantage to neoplastic cells (2).
There are three types of HCD, defined by the mutated HC: alpha (IgA-HC, most common), gamma (IgG-HC, intermediate), and mu (IgM-HC, least common) (1,3-5).
Gamma HCD, also called Franklin disease, typically affects adults in their 50-70s, with female predominance, on an underlying lymphoma (83-91% of patients), and it is commonly associated with autoimmune disease (reported in 25% of patients). There are approximately 130 cases reported in the literature (1,3-5). The underlying lymphoproliferative disease defines the type of clinical presentation. The most common is characterized by an aggressive disseminated lymphoproliferative disease (57-66%), followed by a localized lymphoproliferative disease (25%), and no evidence of lymphoproliferation (9-17%). Asymptomatic presentation is possible. Typical symptoms are fever, malaise, asthenia, and weight loss (6).
In this case, the patient presented atypically with a syncope, shortly followed by oral mycosis (suggesting immune dysfunction), dyspnea and ascites. Non-specific systemic symptoms such as fever, malaise or asthenia were absent.
The underlying lymphoproliferative disease was compatible with the most common aggressive disseminated presentation: generalized lymphadenopathy, spleen enlargement and extra-nodal involvement of thyroid gland and parotid, which are also reported in the literature (6).
Liver involvement in our case was peculiar. The hospital discharge diagnosis was ascitogen liver cirrhosis, which is described only in rare cases of mu HCD (7), and to the best of our knowledge in no cases of gamma HCD.
After reviewing and discussing the case with clinicians and radiologists, the final diagnosis was actually HCD with liver cirrhosis supported by the following evidence: history of hepatomegaly and elevated GGT in the past four years, decreased albumin, imaging pattern, and low total proteins in the ascitic fluid, mostly present in portal hypertension and cirrhotic effusions (8); lack of other compatible causes such as malignancy (excluded by negative cytology, low proteins in ascitic fluid), heart failure, and tuberculosis, which together account for more than 90% of cases of ascites in the western world (8), further support the diagnosis. Another possible cause to be excluded was malignancy-related lymph node fibrosis; malignancies, especially lymphomas, might obstruct lymph flow from the gut to the cysterna chyli, and cause ascites. However, this would result in chylous ascites, which was not the case.
Diagnosis of gamma HCD was based on IFE, and confirmed both by CE-IS and IPT, as commonly accepted (9). IHC was instead apparently discordant. However, we found that a minority of cases shows staining for monotypic LC by IHC or in situ hybridization, despite the absence of LC on IFE (10). The described histopathological pattern is the typical pattern of HCD (1,3,5).
Interestingly, SPE detected hypogammaglobulinemia, but serum IgG level was normal. This is most likely because the monoclonal HC peak, migrated in the beta zone of ELP, causing a decreased gamma zone. Serum IgG quantification is based on nephelometry, which, employing polyclonal antisera, cannot discriminate the structure of Ig and thus HC are detected together with normal IgG, resulting in a normal value of total IgG. This apparent disagreement between laboratory data (IFE/CE-IS/IPT versus IHC and SPE versus serum IgG) highlights the importance of an exhaustive evaluation of laboratory tests and knowledge of their strength and limitations. In specific situations, considering the single laboratory test on its one might lead to wrong conclusions.
SPE performed at hospital admission revealed a monoclonal peak in beta zone. The laboratory report included a comment with the suggestion to the clinicians for an IFE request. The laboratory did not autonomously perform IFE because of hospital administrative restrictions. IFE and CE-IS were performed autonomously when SPE was requested the second time, but this occurred only after three months. This highlights the importance to allow autonomous decisions of the laboratory, which in this case might have rapidly cast light on a complex case.
For completeness of information, it is worthy to add that other potentially more informative methods could be used to study and confirm the presence of truncated heavy chains. These are: the Hevylite immunoassay (Binding site, UK) (11) that can measure separately the immunoglobulin classes of different types (i.e. IgG kappa and IgG lambda) and the mass spectrometry methods like MASS-FIX, a very promising but rather complex and not yet routinely used method (12), nanobody enrichment and mass spectrometry.

CONFLICT OF INTEREST
None.

BIBLIOGRAFIA

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