HEAVY CHAIN DISEASES (HCDs)

Rare, proliferative disorders affecting lymphoplasma B cells. They are characterized by the
presence of immunoglobulin heavy-chain fragments in the absence of free light chains.

α HEAVY CHAIN DISEASES

Features

Geographically, patients affected by HCDs (approximately 400 by the end of the 70s) mainly reside in countries stretching from the Mediterranean area to the Middle Eastern countries

Prevalence is slightly higher in men than in women.

α-HCD mainly affects younger subjects, with ages ranging from 20 to 30 years.

STRUCTURES OF α-HCD PROTEINS

Most α-HCD proteins consist of multiple polymers.

  The basic monomeric unit ranges from 29 to 34 kDa

Characteristics of a defective α chain:

missing V regions,

loss of CH1domains

absence of free light chains.

Most α-HCD proteins contain unusual N-terminus sequences.

Nonetheless, all α-HCD proteins analyzed fall under the α1 subclass group.

GENE SEQUENCES ENCODING FOR α-HCD PROTEINS

Show non-contiguous deletions in the V/J as well as in the S/CH1 regions.

Genomic structures with unusual coding regions display unusual sequences of different length, with coding and non-coding nucleotides.

The inserted regions show no homology with any known sequence!

CLINICAL FEATURES

Patients mainly present with digestive discomfort

The condition is characterized by malabsorption, manifested by:

    diarrhea

    weight loss

    abdominal pain

·Amenorrhea, alopecia and growth retardation in children correlate with the extent and severity of disease progression

· Upon physical examination, these patients present with oedema, ascites and tetanus

LABORATORY INVESTIGATIONS

METABOLIC AND HEMATOLOGIC ABNORMALITIES

Anemia is often present.

Hypocalcemia, hypomagnesemia and hypoalbuminemia

Possible increase in alkaline phosphatase levels as a result of increased intestinal isoenzyme fractions.

Malabsorption detecting tests usually yield positive results.

PROTEIN ANALYSIS

· 50% of all cases show a detectable abnormal band in the β-globulin or in the α2 regions due to the polymerization of α-chains.

· The remaining 50% show normal serum protein electrophoretic patterns, without evidences of abnormal protein.

If the serum concentration is low, the pathological protein may escape detection by means of immunofixation!

THERAPY

Therapeutical schemes require:

· nutritional improvement

· reduction of exposure to intestinal pathogens

In the absence of hyper-growth of intestinal bacteria, the use of tetracyclines is deemed appropriate.

Good results have been achieved by means of cyclophosphamide, doxorubicin and prednisone treatment, as well as with vincristine, prednisolone, metatrexate, and dexamethasone.

Advanced stage disease should not exclude surgical treatment!!

DIAGNOSIS AND PROGNOSIS

The diagnosis of α-HCDs requires

the detection of an incomplete immunoglobulin heavy chain fragment in either serum or urine, unaccompanied by light chains.

The prognosis is variable and no specifically standardized treatment options are available.

Early stage α-HCD may respond to antibiotic treatment.

γ-HEAVY CHAIN DISEASES

Since the mid-60s, only 120 patients affected by γ-HCD have been reported worldwide in the literature.

Although γ-HCD affects all genders,

    there is a clear predominance of female patients

The underlying causes of this disease are still unknown!

STRUCTURAL ABNORMALITIES OF THE PROTEINS

· Most γ-HCD proteins consist of incomplete heavy chain dimers, unbound to light chains

· The molecular weight of the monomeric unit ranges from 27 to 49 kDa

· Variable in length. They usually correspond to approximately 3/8 of the length of normal γ chains.

STRUCTURAL FEATURES

Structural analysis of defective monoclonal γ heavy chains revealed the following characteristics:

· All proteins generally begin with a variable region.

· The short sequence is interrupted by a long deletion that includes the remaining portion of the V region.

· All γ-HCD proteins lack the entire CH1 domain. Thus, the normal sequence either begins with the hinge region H, or at the level of the CH2 domain.

γ-HCDs

γ-HCDs fall into three main categories:

1) Disseminated lymphoproliferative diseases

    Account for 60% of all cases

2) Localized proliferative diseases

     Localized lymphoproliferative processes (25% of all cases)

3) Non-visible proliferative diseases

    Patients with autoimmune disorders with or without lymphoproliferative processes.

LABORATORY INVESTIGATIONS

HAEMATOLOGICAL ABNORMALITIES

· Anemia is frequent

· Autoimmune hemolytic anemia has often been reported in association with thrombocytopenic purpura

· Lymphocytosis with chronic lymphocytic leukemia (CLL) may occur

· Circulating plasma cells or plasmacytoid lymphocytes have sometimes been observed

PROGNOSIS

The clinical course of a γ-HCD is extremely variable, ranging from totally asymptomatic and benign affections to rapidly progressing tumors, leading to death within weeks.

The total amount of serum γ-HCD protein correlates with the severity of the related maligancy.

The disappearance of the monoclonal component from serum and urine is associated with a complete apparent regression, induced by chemotherapy, radiation therapy or surgical removal of localized processes.

μ HEAVY CHAIN DISEASES

EPIDEMIOLOGY AND PATHOGENESIS

· μ-HCDs are extremely rare

· Since the first case was detected in 1969, only 33 other cases have been reported worldwide

· The average age at diagnosis is approximately 60 years (ranging between 15-80 years)

· The causes underlying μ-HCD are still unknown

STRUCTURAL ABNORMALITIES OF μ PROTEINS

· The molecular weight of μ-HCD proteins varies from 26.5 to 15.8 kDa, depending on the polymerization of μ chain fragments.

· As for other HCD types, the incomplete heavy chains of patients with μ-HCD  contain long deletions of variable regions.

· Moreover, as opposed to other HCD proteins, μ-HCD proteins retain normal constant regions.

CLINICAL FEATURES

Common symptoms of μ-HCD are typically related to the lymphoproliferative  malignancy associated to lymphoplasmacytic cell proliferation, including chronic lymphocytic leukemia (CLL)

μ-HCD proteins have been reported in association with:

· SLE,

· liver cirrhosis

· hepatosplenomegaly with ascites

· lung infections

· splenomegaly

· myelodysplasia

LABORATORY INVESTIGATIONS

HEMATOLOGIC ABNORMALITIES

Frequent anemia. Rare lymphocytosis and thrombocytopenia.

Bone marrow examination typically shows increased amounts of lymphocytes as well as plasma cells and plasmacytoid lymphocytes.

PROGNOSIS

The clinical course of μ-HCD is quite variable.

The average life expectancy from diagnosis is 24 months.

THERAPY

There is no specific therapy for μ-HCD.

· The detection of a μ-HCD protein in serum should be regarded as an MGUS.

· Multiple drugs are used in combination, such as cyclophosphamide, vincristine and prednisone

CONCLUSIONS

· HCDs are rare diseases, not readily detectable among the variety of immunofixation patterns.

· Through a series of simple steps, this protocol allows to confirm the presence of rare immunofixation patterns. These are difficult to interpret, and may include the presence of incomplete Igs.

· IFE of supernatant enabled the identification of IgG3 in two cases, by using specific anti-IgG-subclass specific antisera.

· The technique is reproducible, and can easily be employed by labs that occasionally perform MC detection.