Wednesday, May 1, 2019

Consult Rounds: Heavy Chain Deposition Disease

Heavy-chain deposition disease (HCDD) is the least common non-organized monoclonal immunoglobulin deposition disease (MIDD), with close to 50 documented cases in world literature to date. The existence of this entity was postulated for many years until the first case was reported by Tubbs et al. in 1982 followed by another report by Aucouturier et al. in 1993.
It is mostly characterized by γ-heavy chain(HC), and occasionally α-HC, μ--HC,  or δ-HC deposits. Nearly half of HCDD cases were in patients without a symptomatic B-cell disorder, a condition now referred to as monoclonal gammopathy  of renal significance (MGRS).  A constant biochemical characteristic of deposited HC is the deletion of the first constant domain (CH1), which is required for the secretion of an isolated free HC. Other pathologic and clinical features differ from those of LCDD, including the higher frequency of nodular glomerulosclerosis, hypertension, hematuria, and serum hypocomplementemia in g-HCDD.

Recent studies have confirmed that the heavy chain with complement components, mostly C3 and C1q, is frequent in γ 3- and γ 1-HCDD with hypocomplementemia. These findings have been attributed to the capacity of IgG3 and, to a lesser extent, IgG1, to activate the complement classic pathway through C1q binding to the CH2 domain. Whether local and/or systemic complement classic pathway activation is involved in the pathogenesis of γ -HCDD remains unclear.

So what really happens?

When there is the CH1 domain lacking in the heavy chain, this doesn’t allow for the heavy chain binding to it’s chaperone protein in the endoplasmic reticulum, resulting in a truncated heavy chain by the B cell or plasma cell clone. This then starts depositing as it has a higher affinity to tissue- mainly the kidney! Even a small amount of it can cause damage. Hence, most of these cases didn’t have full blown myeloma but bone marrow showed in most as MGUS or smoldering myeloma.  Interestingly, in this latest study by Bridoux et al in 2017, they showed that in over 60% of the cases they reported, there was an abnormal serum free light chain ratio and a positive free light chain immunofixation as well. Interestingly, free light-chain assay levels correlated with disease response in the majority of patients. This suggests that the underlying B- or plasma cell clone produces a monoclonal light chain in addition to the pathogenic heavy chain, and thus the serum-free light-chain assay can be useful in HCDD diagnosis and monitoring after treatment.

Earlier studies had shown that there is a grim prognosis for HCDD. I think this might have been before MGRS was defined and many of them never got treated with anti-plasma cell agents. In the post bortezomib era, the newer data suggests otherwise. Bridoux et al from France data suggests that the outcomes were not that grim and the response to proteasome inhibitors were excellent. Recent mouse models have shown that this efficient response to proteasome inhibitors mostly relies on the presence of the isolated truncated heavy chain that sensitizes plasma cells to bortezomib through an elevated unfolded protein response.

So in summary

HCDD is rare but is a form of MIDD
Most commonly associated with MGUS or smoldering myeloma
The most common HC involved is γ and IgG3 specific
It is not unusual to see hypocomplementemia with this entity
Nodular sclerosis is the pathology finding on light microscopy
Response to proteasome inhibitors appears promising

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