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Heavy Chain Disease

HCD

Heavy chain diseases (HCDs) belong to the larger group of plasma cell (or B cell proliferative) disorders. The diseases are characterized by the presence of structurally defective monoclonal immunoglobulin heavy chains carrying various mutations, usually large deletions. Three main groups, which are classified according to the class of the aberrant heavy chain proteins, constitute the HCDs: alpha-HCD, gamma-HCD, and mu-HCD.


Presentation

The three groups of HCDs (alpha-HCD, gamma-HCD, and mu-HCD) are regarded as variants of non-Hodgkin lymphoma; all have abnormal heavy chains, usually with parts of the constant region deleted, but otherwise have diverse features [1]. The abnormal heavy chains, which have lost the ability to bind light chains or chaperone molecules, are also parts of the B cell receptor, and therefore, possibly through spontaneous aggregation of the receptors, may be responsible for the uncontrolled division of the neoplastic B cells [2].

Alpha-HCD has the least diversified presentation and the highest prevalence within the HCDs [1], though still a rare disease. It typically affects young people of Mediterranean origin [3]. This disease most often damages the gastrointestinal system and causes a malabsorption syndrome with weight loss, diarrhea, nausea and other digestive symptoms. Rarely, a respiratory form is also encountered.

The presentation of gamma-HCDs, which affect middle-aged and older people, is very heterogeneous [4]. The majority (two-thirds) of the patients have disseminated disease, whereas about a quarter have the disease localized to the bone marrow or other locations, most frequently the skin. About ten percent of the patients show only gammopathy. Gamma-HCD is associated with autoimmune diseases in about a quarter of the patients.

People suffering from the disseminated form of the disease present with the general symptoms of lymphoproliferative conditions, such as fever, weight loss, mild anemia and other general complaints. Lymphadenopathy and splenomegaly are common; hepatomegaly is less frequent [5]. Lymphadenopathy may eventually lead to edema of the soft palate.

Mu-HCD occurs mainly in late middle-aged adults. In the early examples of Mu-HCD, a strong association with chronic lymphocytic leukemia was suspected, but by now the two diseases seem more distinct [6], with only about a third of mu-HCD patients also diagnosed with chronic lymphocytic leukemia. The presentation of Mu-HCD is variable, as is its association with other conditions such as multiple myelomas, plasmacytoma, and other diseases, such as amyloidosis [7]. Splenomegaly is observed in almost all cases, and hepatomegaly is frequent. Lymphadenopathy is present in almost half the cases. Bone lesions and fractures are also fairly common and may be ascribed to lymphocytic infiltration of the bone [8].

Anemia
  • Some of these are general, such as mild anemia, leukopenia, thrombocytopenia, hypoalbuminemia, hypocalcemia, hypokalemia, and hypomagnesemia.[symptoma.com]
  • He had direct Coombs' test positive auto-immune hemolytic anemia associted with subacute bacterial endocarditis (SBE).[ncbi.nlm.nih.gov]
  • Up to one third of patients with γ-HCD have an associated autoimmune disorder (eg, rheumatoid arthritis, Sjogren syndrome, lupus erythematosus, and autoimmune hemolytic anemia ). [5, 6] Watchful observation is warranted in asymptomatic patients who have[emedicine.com]
  • Autoimmune disorders, notably rheumatoid arthritis and autoimmune hemolytic anemia or thrombocytopenic purpura, are frequent (26% of cases). There is no specific histological pattern.[ncbi.nlm.nih.gov]
  • It is characterized by lymphadenopathy, fever, anemia, malaise, hepatosplenomegaly, and weakness. The most distinctive symptom is palatal edema, caused by nodal involvement of Waldeyer's ring.[en.wikipedia.org]
Constitutional Symptom
  • Gamma heavy chain disease most often presents as a lymphoproliferative disorder featured by lymphadenopathies, splenomegaly, and constitutional symptoms.[ncbi.nlm.nih.gov]
  • Lymphadenopathy and constitutional symptoms are the usual features. Localized proliferative disease is found in approximately 25% of γHCD patients.[en.wikipedia.org]
  • The patient had originally presented with two months of constitutional symptoms and cough refractory to antibiotics and prednisone.[bloodjournal.org]
  • (Wahner-Roedler et al., 2003) Patients with systemic disease typically present with constitutional symptoms such as fever, unintentional weight loss, and malaise.[atlasgeneticsoncology.org]
Splenectomy
  • Sixteen patients were treated for lymphoplasma cell proliferative disorder or autoimmune disorder (14 with chemotherapy, 1 splenectomy, and 1 thyroidectomy followed by radiation therapy).[doi.org]
Intermittent Fever
  • Patients with Franklin disease usually have a history of progressive weakness, fatigue, intermittent fever, night sweats and weight loss and may present with lymphadenopathy (62%), splenomegaly (52%) or hepatomegaly (37%).[en.wikipedia.org]

Workup

Alpha-HCD is accompanied by some abnormal laboratory results. Some of these are general, such as mild anemia, leukopenia, thrombocytopenia, hypoalbuminemia, hypocalcemia, hypokalemia, and hypomagnesemia. Plasma alkaline phosphatase levels are often high, owing to an increase in the intestinal isoform of the enzyme [3]. Serum electrophoresis can be normal, and the electrophoretic pattern is not revealing [9]. Thus, the diagnosis of the disease, that is the identification of the abnormal heavy chain, has to rely on immunological methods [9]. The mutated protein is also present in intestinal secretions, but absent, or only in very small concentrations, in urine. If otherwise undetected, the defective heavy chain has to be identified by an intestinal biopsy.

Alpha-HCD primarily affects the duodenum and jejunum, and these parts of the small bowel are heavily infiltrated by plasma cells mixed with small lymphocytes. Endoscopy of the upper part of the gastrointestinal tract has been used to identify mucosal abnormalities. Of the several types of anomaly identified, the patterns of infiltration are the most sensitive predictors of the disease [10]. The disease has been classified as the immunoproliferative small intestinal disease (IPSID); an association with Campylobacter jejuni infection has been proposed for this and other lymphomas of the small intestine.

Diagnosis of gamma-HCDs is challenging because this disease presents as a spectrum of disorders. The difficulty in differentiating the gamma-HCDs from other lymphoproliferative diseases is reflected by the fact that the 2008 World Health Organization classification places this condition as a separate disease within the heavy chain disease group, but then also discusses gamma-HCD as a variant of lymphoplasmacytic lymphoma [11]. It may also be difficult to distinguish gamma-HCD from inflammation or infections.

The disease is accompanied by general symptoms, such as anemia. The complete blood cell count often reveals eosinophilia and thrombocytopenia. Serum protein electrophoresis shows the monoclonal gamma heavy chain in about three-quarter of the patients. The defective gamma chain is often present in the urine. Diagnosis is by immunological detection of the abnormal heavy chain in the serum or urine, with no immunologically observable light chains. The sites affected are mainly the bone marrow, spleen, and lymph nodes, but extranodal sites are also involved [11]. The histology is variable. Hyperuricemia frequently occurs in advanced stages.

For diagnosing Mu-HCDs, exploration of the bone marrow is often necessary. The marrow contains multivacuolated plasma cells, observed in the majority (two-thirds) of the patients; thus, this is a characteristic but not universal feature of the disease. Almost half of the patients present with osteolytic lesions, necessitating the evaluation of the state of the skeleton.

Serum or urine protein electrophoresis and immunofixation are indispensable for diagnosis. The mu heavy chains are shown by these methods to be present in the form of heterogeneous polymers without associated light chains [12] [13]. However, light chains are produced, and being unbound to the heavy chains, are often excreted in the urine.

Enlargement of the Liver
  • It may cause enlargement of the liver and spleen as well as enlargement of the lymph nodes in the abdomen. Fractures may also occur. Bone marrow examination is usually needed for diagnosis.[merck.com]
Hyperviscosity
  • Hyperviscosity. Nephrotic syndrome, cardiac failure, malabsorption. Peripheral neuropathies, carpal tunnel syndrome. Incidental persistent elevated erythrocyte sedimentation rate (ESR).[patient.info]
Penicillium
  • Weng et al. described the first case of Penicillium sp. infection in a patient with Franklin disease and emphasized the importance of proper preparation for biopsy, complete hematologic investigation, culture preparation and early antifungal coverage[en.wikipedia.org]

Treatment

  • This review focuses on current knowledge and novel insight regarding its pathogenesis, outcome, and treatment, with an emphasis on future directions.[ncbi.nlm.nih.gov]
  • Treatment usually includes chemotherapy drugs and corticosteroids. Length of survival and response to treatment vary widely. Generic Name Select Brand Names cyclophosphamide CYTOXAN (LYOPHILIZED) prednisone RAYOS NOTE: This is the Consumer Version.[merck.com]
  • Management of symptomatic disease focuses on palliative care, as disease treatment has been disappointing. (See Treatment, Medication, and Follow-up )[emedicine.com]
  • For 5 patients, treatment was not felt to be necessary; 2 patients were thought to be too sick for treatment.[doi.org]

Prognosis

  • Overall prognosis is poor but the recent use of doxorubicin-based chemotherapy offers some hope for the future.[ncbi.nlm.nih.gov]
  • Prognosis is variable, and no standardized effective treatment programs are available except for alpha-HCD, which in its early stage may respond to antibiotics.[ncbi.nlm.nih.gov]
  • Prognosis The clinical course is variable, depending on subtype. Outcome is very good in patients without lymphoma, in whom prognosis is related to underlying autoimmune disease.[atlasgeneticsoncology.org]
  • Prognosis The course of mu-HCD is variable.[emedicine.com]

Etiology

  • Etiology Deletions, insertions or point mutations in the constant 1 (CH1) domain of the IgH are acquired during the process of somatic hypermutation.[atlasgeneticsoncology.org]

Epidemiology

  • Kyle Springer Science & Business Media , 31.07.2012 - 1431 Seiten Neoplastic Diseases of the Blood integrates the history, epidemiology, pathology, pathophysiology, and therapeutics of modern neoplastic hematopathology.[books.google.de]
  • The heavy chain thus bypasses degradation and is instead secreted into the serum, where it can be detected. [2, 5, 6] Epidemiology Frequency United States Mu-HCD is the least common of the HCDs.[emedicine.com]
  • October 01, 2015) Signs and Symptoms Fever (alpha & gamma) Hypocalcemia (alpha) Malabsorption (alpha) Wasting (alpha) Weakness (gamma) Weight loss (gamma) Diagnostic Exams Immunophenotyping Peripheral blood smear Progression and Transformation None Epidemiology[seer.cancer.gov]
  • Plasma cell disorders can be considered as a spectrum of conditions ranging from monoclonal gammopathy of undetermined significance (MGUS), through asymptomatic, to symptomatic myeloma. [ 1 ] Epidemiology The incidence of a paraprotein is 3.2% in people[patient.info]
Sex distribution
Age distribution

Pathophysiology

  • Kyle Springer Science & Business Media , 31.07.2012 - 1431 Seiten Neoplastic Diseases of the Blood integrates the history, epidemiology, pathology, pathophysiology, and therapeutics of modern neoplastic hematopathology.[books.google.de]
  • Pathophysiology The pathogenesis of mu-HCD is not completely understood.[emedicine.com]

Prevention

  • Infiltration of the intestinal tract wall by cancerous plasma cells often prevents proper absorption of nutrients from food ( malabsorption ), resulting in severe diarrhea and weight loss. A rare form affects the respiratory tract.[merck.com]
  • . : Immunoproliferative small intestinal disease: portrait of a potentially preventable cancer from the Third World. Am J Med 1990, 89:483–490. PubMed CrossRef Google Scholar 36.[link.springer.com]
  • The malignant B lymphocytes replace the normal marrow cells and may cause anemia and other blood cell deficiencies by preventing the normal marrow cells from making blood cells efficiently.[lls.org]
  • George Carlone (Centers for Disease Control and Prevention, Atlanta) and Margaret Goodall (Recognition Sciences, Birmingham, United Kingdom) for the gift of monoclonal antibodies, to Mrs.[nejm.org]

References

Article

  1. Wahner-Roedler DL, Kyle RA. Heavy chain diseases. Best Pract Res Clin Haematol. 2005;18:729-746.
  2. Corcos D, Osborn MJ, Matheson LS. B-cell receptors and heavy chain diseases: guilty by association? Blood. 2011;117:6991-8.
  3. Doe WF, Henry K, Hobbs JR, et al. Five cases of alpha chain disease. Gut. 1972;13:947-57.
  4. Wester SM, Banks PM, Li CY. The histopathology of gamma heavy-chain disease. Am J Clin Pathol. 1982 Oct. 78(4):427-36.
  5. Wahner-Roedler DL, Witzig TE, Loehrer LL, Kyle RA. Gamma-heavy chain disease: review of 23 cases. Medicine (Baltimore). 2003;82:236-50.
  6. Bonhomme J, Seligmann M, Mihaesco C, et al. MU-chain disease in an African patient. Blood. 1974 Apr. 43(4):485-92.
  7. Kinoshita K, Yamagata T, Nozaki Y, et al. Mu-heavy chain disease associated with systemic amyloidosis. Hematology. 2004 Apr. 9(2):135-7.
  8. Forte FA, Prelli F, Yount WJ, et al. Heavy chain disease of the gamma (gamma M) type: report of the first case. Blood. 1970;36:137-44.
  9. Seligmann M. Alpha chain disease: immunoglobulin abnormalities, pathogenesis and current concepts. Br J Cancer Suppl. 1975;2:356-61.
  10. Halphen M, Najjar T, Jaafoura H, et al. Diagnostic value of upper intestinal fiber endoscopy in primary small intestinal lymphoma. A prospective study by the Tunisian-French Intestinal Lymphoma Group. Cancer. 1986;58:2140-5.
  11. Bieliauskas S, Tubbs RR, Bacon CM, et al. Gamma heavy-chain disease: defining the spectrum of associated lymphoproliferative disorders through analysis of 13 cases. Am J Surg Pathol. 2012;36:534-43.
  12. Witzens M, Egerer G, Stahl D, et al. A case of mu heavy-chain disease associated with hyperglobulinemia, anemia, and a positive Coombs test. Ann Hematol. 1998;77:231-4.
  13. Iwasaki T, Hamano T, Kobayashi K, Kakishita E. A case of mu-heavy chain disease: combined features of mu-chain disease and macroglobulinemia. Int J Hematol. 1997;66:359-65.

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Last updated: 2018-06-22 04:45