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__NOTOC__
'''For patient information click [[{{PAGENAME}} (patient information)|here]]'''
{{Infobox_Disease |
{{Infobox_Disease |
   Name          = Multiple myeloma |
   Name          = Multiple myeloma |
   Image          = Bone marrow aspiration in multiple myeloma 0001.jpg|
   Image          = Bone marrow aspiration in multiple myeloma 0001.jpg|
   Caption        = Bone marrow aspiration in multiple myeloma. <br> (Image courtesy of Melih Aktan M.D.)|
   Caption        = Bone marrow aspiration in multiple myeloma. <br> (Image courtesy of Melih Aktan M.D.)|
  DiseasesDB    = 8628 |
   
  ICD10          = {{ICD10|C|90|0|c|90}} |
  ICD9          = {{ICD9|203.0}} |
  ICDO          = {{ICDO|9732|3}} |
  OMIM          = 254500 |
  MedlinePlus    = 000583 |
  eMedicineSubj = med |
  eMedicineTopic = 1521 |
  MeshID        = D009101 |
}}
}}
{{SI}}
{{Multiple myeloma}}
{{CMG}}
{{CMG}} {{AE}}{{HL}} {{SN}} {{shyam}}


{{Editor Help}}
{{SK}}Kahler disease; Kahler's disease; MM; Myeloma; Myelomatosis; Medullary plasmacytoma; Plasmacytoma
==[[Multiple myeloma overview|Overview]]==


'''Multiple myeloma''' (also known as '''MM''', '''myeloma''', '''plasma cell myeloma''', or as '''Kahler's disease''' after [[Otto Kahler]]) is a type of [[cancer]] of [[plasma cell]]s which are [[immune system]] cells in bone marrow that produce [[antibody|antibodies]]. Its [[prognosis]], despite therapy, is generally poor, and treatment may involve [[chemotherapy]] and [[stem cell transplant]]. It is part of the broad group of diseases called [[Hematological malignancy|hematological malignancies]].
==[[Multiple myeloma historical perspective|Historical Perspective]]==


==Clinical features==
==[[Multiple myeloma Classification|Classification]]==
Because many organs can be affected by myeloma, the symptoms and signs vary greatly. A [[mnemonic]] sometimes used to remember the common tetrad of multiple myeloma is ''CRAB'' - C = Calcium (elevated), R =Renal failure, A = Anemia, B = Bone lesions.<ref name="IMWG">International Myeloma Working Group. ''Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group.'' Br J Haematol 2003;121:749-57. PMID 12780789.</ref> Myeloma has many possible symptoms, and all symptoms may be due to other causes. They are presented here in decreasing order of incidence.


;Bone pain
==[[Multiple myeloma pathophysiology|Pathophysiology]]==
Myeloma bone pain usually involves the spine and ribs, and worsens with activity. Persistent localized pain may indicate a pathological [[bone fracture]]. Involvement of the vertebrae may lead to [[spinal cord compression]]. Myeloma bone disease is due to proliferation of tumor cells and release of [[Interleukin 6|IL-6]], also known as osteoclast activating factor (OAF), which stimulates [[osteoclast]]s to break down bone. These bone lesions are lytic in nature and are best seen in plain radiographs, which may show a "punched-out" resorptive lesions. The breakdown of bone also leads to release of [[calcium]] into the blood, leading to [[hypercalcemia]] and its associated symptoms.


;Infection
==[[Multiple myeloma causes|Causes]]==
The most common infections are [[pneumonia]]s and [[pyelonephritis]]. Common pneumonia pathogens include ''[[streptococcus pneumoniae|S pneumoniae]]'', ''[[staphylococcus aureus|S aureus]]'', and ''[[klebsiella pneumoniae|K pneumoniae]]'', while common pathogens causing pyelonephritis include ''[[escherichia coli|E coli]]'' and other [[gram-negative]] organisms. The increased risk of infection is due to immune deficiency resulting from diffuse [[hypogammaglobulinemia]], which is due to decreased production and increased destruction of normal [[antibody|antibodies]].


;Renal failure
==[[Multiple myeloma differential diagnosis|Differentiating Multiple Myeloma from other Diseases]]==
[[Renal failure]] may develop both [[acute renal failure|acutely]] and [[chronic renal failure|chronically]]. It is commonly due to [[hypercalcemia]] (see above). It may also be due to tubular damage from excretion of [[light chain]]s, also called [[Bence Jones protein]]s, which can manifest as the [[Fanconi syndrome]] (type II [[renal tubular acidosis]]). Other causes include glomerular deposition of [[amyloid]], [[hyperuricemia]], recurrent infections ([[pyelonephritis]]), and local infiltration of tumor cells.


;Anemia
==[[Multiple myeloma epidemiology and demographics|Epidemiology and Demographics]]==
The [[anemia]] found in myeloma is usually normocytic and normochromic. It results from the replacement of normal bone marrow by infiltrating tumor cells and inhibition of normal red blood cell production ([[hematopoiesis]]) by [[cytokines]].


;Neurological symptoms
==[[Multiple myeloma risk factors|Risk Factors]]==
Common problems are weakness, confusion and fatigue due to [[hypercalcemia]]. [[Headache]], visual changes and [[retinopathy]] may be the result of hyperviscosity of the blood depending on the properties of the [[paraprotein]]. Finally, there may be [[radicular pain]], loss of bowel or bladder control (due to involvement of [[spinal cord]] leading to cord compression) or [[carpal tunnel syndrome]] and other [[neuropathies]] (due to infiltration of [[peripheral nerves]] by [[amyloid]]).  It may give rise to [[paraplegia]] in late presenting cases.


==Diagnosis==
==[[Multiple myeloma risk factors|Screening]]==
===Investigations===


The presence of unexplained [[anemia]], [[kidney]] dysfunction, a high [[erythrocyte sedimentation rate]] (ESR) and a high serum [[protein]] (especially raised [[immunoglobulin]]) may prompt further testing. A [[medical doctor|doctor]] will request [[protein electrophoresis]] of the blood and urine, which might show the presence of a [[paraprotein]] (monoclonal protein, or M protein) band, with or without reduction of the other (normal) immunoglobulins (known as immune paresis). One type of paraprotein is the [[Bence Jones protein]] which is a urinary paraprotein composed of free light chains (see below).  Quantitative  measurements of the paraprotein are necessary to establish a diagnosis and to monitor the disease. The paraprotein is an abnormal [[immunoglobulin]] produced by the tumor clone. Very rarely, the myeloma is ''nonsecretory'' (not producing immunoglobulins).
==[[Multiple myeloma natural history|Natural History, Complications and Prognosis]]==


In theory, multiple myeloma can produce all classes of immunoglobulin, but IgG paraproteins are most common, followed by IgA and IgM.  IgD and IgE myeloma are very rare. In addition, light and or heavy chains (the building blocks of antibodies) may be secreted in isolation: κ- or λ-light chains or any of the five types of heavy chains (α-, γ-, δ-, ε- or μ-heavy chains).
==Diagnosis==
 
[[Multiple myeloma diagnostic criteria|Diagnostic Criteria]] | [[Multiple myeloma staging|Staging]] | [[Multiple myeloma history and symptoms|History and Symptoms]] | [[Multiple myeloma physical examination|Physical Examination]] | [[Multiple myeloma laboratory tests|Laboratory Findings]] | [[Multiple myeloma x ray|X Ray]] | [[Multiple myeloma CT|CT]] | [[Multiple myeloma MRI|MRI]] | [[Multiple myeloma other imaging findings|Other Imaging Findings]] | [[Multiple myeloma other diagnostic studies|Other Diagnostic Studies]]
Additional findings include: a raised [[calcium]] (when [[osteoclasts]] are breaking down bone, releasing calcium into the bloodstream), raised serum creatinine due to reduced [[renal function]], which may be due to paraprotein deposition in the [[kidney]].
 
==Diagnostic Findings==
 
===MRI===
 
([http://www.radswiki.net Images courtesy of RadsWiki])
 
<gallery>
Image:Multiple_myeloma_MRI101.jpg
Image:Multiple_myeloma_MRI102.jpg
Image:Multiple_myeloma_MRI103.jpg
</gallery>
 
===Pathology===
 
 
<gallery>
Image:Multiple Myeloma.jpg|thumb|left|Multiple Myeloma <ref>http://picasaweb.google.com/mcmumbi/USMLEIIImages</ref>
Image:Vertebras in multiple myeloma 0001.jpg|thumb|left|Vertebras in multiple myeloma <br> (Image courtesy of Melih Aktan M.D.)
Image:Calvarium in multiple myeloma.jpg|thumb|left|Calvarium in multiple myeloma. <br>  (Image courtesy of Melih Aktan M.D.)
Image:Bone marrow aspiration in multiple myeloma 0001.jpg|thumb|left|Bone marrow aspiration in multiple myeloma. <br> (Image courtesy of Melih Aktan M.D.)
Image:Bone marrow biopsy in multiple myeloma 0001.jpg|thumb|left|Bone marrow biopsy in multiple myeloma.  <br> (Image courtesy of Melih Aktan M.D.)
Image:Bone marrow in multiple myeloma 0001.jpg|thumb|left|Bone marrow in multiple myeloma.  <br> (Image courtesy of Melih Aktan M.D.)
Image:Bone marrow in multiple myeloma 0002.jpg|thumb|left|Bone marrow in multiple myeloma.  <br> (Image courtesy of Melih Aktan M.D.)
</gallery>
 
===Workup===
The workup of suspected multiple myeloma includes a [[skeletal survey]]. This is a series of [[X-ray]]s of the skull, axial skeleton and proximal long bones. Myeloma activity sometimes appear as "lytic lesions" (with local disappearance of normal bone due to resorption), and on the skull X-ray as "punched-out lesions" (pepper pot skull).  [[Magnetic resonance imaging]] (MRI) is more sensitive than simple X-ray in the detection of lytic lesions, and may supersede skeletal survey, especially when vertebral disease is suspected.  Occasionally a [[CT scan]] is performed to measure the size of soft tissue plasmacytomas.
 
A [[bone marrow biopsy]] is usually performed to estimate the percentage of bone marrow occupied by plasma cells. This percentage is used in the diagnostic criteria for myeloma.  [[Immunohistochemistry]] (staining particular cell types using antibodies against surface proteins) can detect plasma cells which express immunoglobulin in the cytoplasm but usually not on the surface; myeloma cells are typically [[CD56]], [[CD38]], [[CD138]] positive and [[CD19]] and [[CD45]] negative.<ref name=IMWG /> [[Cytogenetics]] may also be performed in myeloma for prognostic purposes.
 
Other useful laboratory tests include quantitative measurement of [[IgA]], [[IgG]], [[IgM]] ([[immunoglobulin]]s) to look for immune paresis, and β2-microglobulin which provides prognostic information.  On peripheral blood smear the rouleaux formation of red blood cells is commonly seen.
 
The recent introduction of a commercial immunoassay for measurement of free light chains potentially offers an improvement in monitoring disease progression and response to treatment, particularly where the paraprotein is difficult to measure accurately by electrophoresis (for example in light chain myeloma, or where the paraprotein level is very low). Initial research also suggests that measurement of free light chains may also be used, in conjunction with other markers, for assessment of the risk of progression from [[monoclonal gammopathy of undetermined significance]] (MGUS) to multiple myeloma.
 
===Diagnostic criteria===
In 2003, the International Myeloma Working Group<ref name=IMWG /> agreed on diagnostic criteria for symptomatic myeloma, asymptomatic myeloma and [[monoclonal gammopathy of undetermined significance|MGUS]] (monoclonal gammopathy of undetermined significance):
 
* Symptomatic myeloma:
*# Clonal plasma cells >10% on [[bone marrow]] [[biopsy]] or (in any quantity) in a biopsy from other tissues ([[plasmacytoma]])
*# A [[monoclonal]] protein ([[paraprotein]]) in either [[blood plasma|serum]] or [[urine]]
*# Evidence of end-organ damage (''related organ or tissue impairment'', ROTI):
*#* [[Hypercalcemia]] (corrected calcium >2.75 mmol/L)
*#* [[Renal insufficiency]] attributable to myeloma
*#* [[Anemia]] (hemoglobin <10 g/dL)
*#* Bone [[lesions]] (lytic lesions or [[osteoporosis]] with compression fractures)
*#* Frequent severe [[infections]] (>2 a year)
*#* [[Amyloidosis]] of other organs
*#* [[Hyperviscosity syndrome]]
* Asymptomatic myeloma:
*# Serum paraprotein >30 g/L AND/OR
*# Clonal plasma cells >10% on bone marrow biopsy AND
*# NO myeloma-related organ or tissue impairment
* Monoclonal gammopathy of undetermined significance (MGUS):
*# Serum paraprotein <30 g/L AND/OR
*# Clonal plasma cells <10% on bone marrow biopsy AND
*# NO myeloma-related organ or tissue impairment
 
Related conditions include ''solitary [[plasmacytoma]]'' (a single tumor of plasma cells, typically treated with irradiation), ''plasma cell [[dyscrasia]]'' (where only the antibodies produce symptoms, e.g. AL [[amyloid|amyloidosis]]), and [[POEMS syndrome]] (peripheral neuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes).
 
===Staging===
;International Staging System
The International Staging System (ISS) for myeloma was published by the International Myeloma Working Group in 2003 <ref name="ISS">Greipp PR, San Miguel J, Fonseca R, Avet-Loiseau H, Jacobson JL, Rasmussen E, Crowley J, Durie BMG. Development of an international prognostic index (IPI) for myeloma: report of the international myeloma working group. ''Hematology Journal'' 2003;4:S42. NLM ID 100965523.</ref>:
* Stage I: [[beta-2-microglobulin|β<sub>2</sub>-microglobulin]] (β2M) < 3.5 mg/L, [[serum albumin|albumin]] >= 3.5 g/dL
* Stage II: β2M < 3.5 and albumin < 3.5; or β2M between 3.5 and 5.5
* Stage III: β2M > 5.5
 
;Durie-Salmon staging system
First published in 1975, the Durie-Salmon staging system <ref name="Salmon">Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment and survival. ''Cancer'' 1975;36:842–854. PMID 1182674.</ref> is still in use, but has largely been superseded by the simpler ISS:
* stage 1: all of
** Hb > 10g/dL
** normal calcium
** Skeletal survey: normal or single plasmacytoma or osteoporosis
** Serum paraprotein level < 5 g/dL if IgG, < 3 g/dL if IgA
** Urinary light chain excretion < 4 g/24h
* stage 2: fulfilling the criteria of neither 1 nor 3
* stage 3: one or more of
** Hb < 8.5g/dL
** high calcium > 12mg/dL
** Skeletal survey: 3 or more lytic bone lesions
** Serum paraprotein >7g/dL if IgG, > 5 g/dL if IgA
** Urinary light chain excretion > 12g/24h
 
Stages 1, 2 and 3 of the Durie-Salmon staging system can be divided into A or B depending on serum creatinine:
* A: serum creatinine < 2mg/dL (< 177 umol/L)
* B: serum creatinine > 2mg/dL (> 177 umol/L)
 
==Pathophysiology==
Multiple myeloma develops in post-germinal center [[B lymphocytes]].
 
A [[chromosomal translocation]] between the immunoglobulin heavy chain gene (on the fourteenth [[chromosome]], locus 14q32) and an [[oncogene]] (often 11q13, 4p16.3, 6p21, 16q23 and 20q11<ref name="Kyle">Kyle RA, Rajkumar SV. ''Multiple myeloma.'' [[N Engl J Med]] 2004;351:1860-73. PMID 15509819.</ref>) is frequently observed in patients with multiple myeloma.  This mutation results in dysregulation of the oncogene which is thought to be an important initiating event in the pathogenesis of myeloma. The result is proliferation of a plasma cell clone and genomic instability that leads to further mutations and translocations. The chromosome 14 abnormality is observed in about 50% of all cases of myeloma. Deletion of (parts of) the thirteenth chromosome is also observed in about 50% of cases.
 
Production of [[cytokine]]s (especially [[Interleukin 6|IL-6]]) by the plasma cells causes much of their localised damage, such as [[osteoporosis]], and creates a microenvironment in which the malignant cells thrive. [[Angiogenesis]] (the attraction of new blood vessels) is increased.
 
The produced antibodies are deposited in various organs, leading to renal failure, polyneuropathy and various other myeloma-associated symptoms.
 
==Epidemiology==
There are approximately 45,000 people in the United States living with multiple myeloma, and the [[American Cancer Society]] estimates that approximately 14,600 new cases of myeloma are diagnosed each year in the United States. It follows from here that the average survival at diagnosis is about three years.
 
Multiple myeloma is the second most prevalent blood cancer (10%) after [[non-Hodgkin's lymphoma]]. It represents approximately 1% of all cancers and 2% of all cancer deaths. Although the peak age of onset of multiple myeloma is 65 to 70 years of age, recent statistics indicate both increasing incidence and earlier age of onset. 
 
Multiple myeloma affects slightly more men than women. African Americans and Native Pacific Islanders have the highest reported incidence of this disease in the United States and Asians the lowest. Results of a recent study found the incidence of myeloma to be 9.5 cases per 100,000 African Americans and 4.1 cases per 100,000 Caucasian Americans. Among African Americans, myeloma is one of the top 10 leading causes of cancer death.


==Treatment==
==Treatment==
Treatment for multiple myeloma is focused on disease containment and suppression. If the disease is completely asymptomatic (i.e. there is a paraprotein and an abnormal bone marrow population but no end-organ damage), treatment may be deferred.
[[Multiple myeloma medical therapy|Medical Therapy]] | [[Multiple myeloma surgery|Surgery]] | [[Multiple myeloma primary prevention|Primary Prevention]] | [[Multiple myeloma secondary prevention|Secondary Prevention]] | [[Multiple myeloma future or investigational therapies|Future or Investigational Therapies]]
 
Although [[bone marrow transplant|allogeneic stem cell transplant]] might cure the cancer, it is considered investigational given the high treatment-related mortality of 5-10% associated with the procedure. In addition to direct treatment of the plasma cell proliferation, [[bisphosphonate]]s (e.g. [[pamidronate]] or [[zoledronic acid]]) are routinely administered to prevent fractures and [[erythropoietin]] to treat anemia.
 
===Initial therapy===
Initial treatment is aimed at treating symptoms and reducing disease burden. Commonly used induction regimens include [[dexamethasone]] with or without [[thalidomide]] and [[cyclophosphamide]], and ''VAD'' ([[vincristine]], [[doxorubicin|adriamycin]], and dexamethasone). Low-dose therapy with [[melphalan]] combined with prednisone can be used to palliate symptoms in patients who cannot tolerate aggressive therapy.  [[Plasmapheresis]] can be used to treat symptomatic protein proliferation ([[hyperviscosity syndrome]]).
 
In younger patients, therapy may include high-dose [[chemotherapy]], [[melphalan]], and ''[[bone marrow transplant|autologous stem cell transplantation]]''.  This can be given in ''tandem'' fashion, i.e. an autologous transplant followed by a second transplant. 
[[Bone marrow transplant#Conditioning Regimens|Nonmyeloablative (or "mini") allogeneic stem cell transplantation]] is being investigated as an alternative to autologous stem cell transplant, or as part of a tandem transplant following an autologous transplant (also known as an "auto-mini" tandem transplant).
 
A 2007 trial indicated that the addition of thalidomide to reduced-intensity chemotherapy (melphalan and prednisone, MP) in patients between 65-75 led to a marked prolongation (median 51 versus 33 months) in survival. Reduced intensity melphalan followed by a stem cell transplant was inferior to the MP-thalidomide regimen (median survival 38 months).<ref>{{cite journal |author=Facon T, Mary JY, Hulin C ''et al'' |year=2007 |month= |title=Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99–06): a randomised trial |journal= Lancet|volume=370 |issue= |pages=1209-1218 |id=| url=http://www.thelancet.com/journals/lancet/article/PIIS0140673607615372/abstract | DOI=10.1016/S0140-6736(07)61537-2}}</ref>
 
===Relapse===
The natural history of myeloma is of relapse following treatment.  Depending on the patient's condition, the prior treatment modalities used and the duration of remission, options for relapsed disease include re-treatment with the original agent, use of other agents (such as melphalan, cyclophosphamide, thalidomide or dexamethasone, alone or in combination), and a second autologous stem cell transplant.
 
Later in the course of the disease, "treatment resistance" occurs.  This may be a reversible effect,<ref name=Kyle /> and some new treatment modalities may re-sensitize the tumor to standard therapy.  For patients with ''relapsed disease'', [[bortezomib]] (or Velcade®) is a recent addition to the therapeutic arsenal, especially as second line therapy.  Bortezomib is a [[proteasome]] inhibitor.  Finally, [[lenalidomide]] (or Revlimid®), a less toxic thalidomide analog, is showing promise for treating myeloma.
 
Renal failure in multiple myeloma can be [[acute renal failure|acute]] (reversible) or [[chronic renal failure|chronic]] (irreversible). Acute renal failure typically resolves when the calcium and paraprotein levels are brought under control. Treatment of chronic renal failure is dependent on the type of renal failure and may involve [[dialysis]].
 
==Prognosis==
The [[#Staging|International Staging System]] can help to predict survival, with a median survival of 62 months for stage 1 disease, 45 months for stage 2 disease, and 29 months for stage 3 disease.<ref name=ISS />
 
[[Cytogenetic]] analysis of myeloma cells may be of [[prognosis|prognostic value]], with deletion of chromosome 13, non-hyperdiploidy and the balanced translocations t(4;14) and t(14;16) conferring a poorer prognosis.  The 11q13 and 6p21 cytogenetic abnormalities are associated with a better prognosis.


Prognostic markers such as these are always generated by retrospective analyses, and it is likely that new treatment developments will improve the outlook for those with traditionally 'poor-risk' disease.
==Case Studies==
 
[[Multiple myeloma case study one|Case #1]]
==See also==
* [[Waldenström macroglobulinemia]]
* [[Multiple Myeloma Research Consortium]]
* [[Multiple Myeloma Research Foundation]]
* MM Support Network
 
==References==
{{Reflist|2}}
 
==External links==
* [http://www.myeloma.org.uk Myeloma UK]
* [http://www.myeloma.org International Myeloma Foundation]
* [http://www.multiplemyeloma.org Multiple Myeloma Research Foundation]
* [http://www.mmsupport.net/ MM Support Network]
* [http://www.myeloma-euronet.org Myeloma Euronet] - European Network of Myeloma Patient Groups
* [http://www.leukemia-lymphoma.org/all_page?item_id=7032 The Leukemia & Lymphoma Society's Myeloma Page]
 
 
{{Hematological malignancy histology}}
{{SIB}}


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Latest revision as of 22:46, 29 July 2020

For patient information click here

Multiple myeloma
Bone marrow aspiration in multiple myeloma.
(Image courtesy of Melih Aktan M.D.)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Haytham Allaham, M.D. [2] "sandbox:SN"

Template:Pernicious Anemia

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3]; Associate Editor(s)-in-Chief:

Overview

Pernicious anemia (also called Addison's anemia) is a type of red blood cell disorder caused by impaired vitamin B12 metabolism. Vitamin B12 is primarily absorbed by the small intestine, after being bound to intrinsic factor secreted by parietal cells of gastric mucosa. When this process is disrupted by conditions like atrophic gastritis, celiac disease, small bowel resection etc, B12 deficiency ensues.

Historical perspective

  • Pernicious anemia was first discovered by Thomas Addison, hence it is also known as addison's anemia.
  • Loss of life from large volume blood loss in the people fighting in the first world war inspired George Whipple to investigate blood forming components such as arsenic, iron pills etc, but found liver to be the most effective. He bled dogs until they had clinical anemia and fed them cooked liver which showed an improvement in symptoms and hematopoeisis. [1]
  • In 1948, Smith, Rickles et al., isolated the anti-pernicious factor from liver extract and named it Vitamin B12. They showed that even small amounts of this factor can be used to treat and to prevent pernicious anemia. [2]

Pathophysiology

Vitamin B12 is an essential vitamin for humans and animals because we cannot synthesise it on our own. B12 is a cofactor in DNA synthesis and other important biochemical reactions. Vitamin B12 deficiency manifests as anemia because hematopoetic stem cells in the bone marrow which are rapidly dividing need B12 for division and DNA production. This process is impaired leading to ineffective hematopoeisis. Vitamin B12 is also necessary for production of myelin which is an important component in the covering sheath of nerves. Deficiency results in improper nerve conduction due to nerve destabilisation. [3]

Physiology

  • Vitamin B12 is also called cobalamin because it contains cobalt at the core of its structure. Dietary sources of vitamin B12 include meat, fish and eggs.[4]
  • When consumed through its dietary source, B12 is bound to protein till it enters the stomach.
  • In the stomach, B12 is uncoupled from its carrier protein due to the presence of gastric acid, which is why vitamin B12 deficiency is so commonly seen among those on chronic antacid medication. [5]
  • Once in the stomach, it is then bound to gastric R binder, a glycoprotein secreted by the salivary glands till it reaches the duodenum.[6]
  • In the duodenum and jejunum, the pancreatic enzymes digest the gastric R binder and cobalamin is bound to intrinsic factor (IF).
  • Intrinsic factor is secreted by the gastric parietal cells. Once bound to IF, vitamin B12 travels up to the ileum where IF is removed and B12 binds with carrier proteins called transcobalamins and this complex is taken up by the liver and bone marrow, among other tissues.
  • Inside the cells, the transcobalamin-B12 complex is dissolved and cobalamin is reduced to methylcobalamin which serves as a cofactor and coenzyme in many important biochemical reactions[7].

The two major reactions involving B12 in the human body are:

  • Vitamin B12 in the from of cyanocobalamin is required in the synthesis of methionine. Methionine is produced from homocysteine and is catalysed by the enzyme methionine synthase. This enzyme utilises cyanocobalamin as a cofactor. Deficiency of vitamin B12 causes a decreased production of methionine and buildup of homocysteine. Hyperhomocysteinemia is implicated as a risk factor in cardiovascular disease.[8]
  • The Kreb's cycle utilises vitamin B12 in the reaction converting methylmalonyl-CoA to succinyl-CoA. Thus vitamin B12 deficiency causes a buildup of methylmalonic acid, the substrate for the enzyme methylmalonyl coenzyme A mutase. Methylmalonic acid levels are elevated in the urine of people affected with pernicious anemia and other forms of B12 deficiency.

Storage

The human body can store anywhere from 2-5mg of vitamin B12. Most of this is stored in the liver and is recycled via enterohepatic circulation.

Pathogenesis

Pernicious anemia is a type of megaloblastic anemia caused due to improper vitamin B12 absorption by the body. Impaired absorption occurs because of deficiency of intrinsic factor which is produced by the parietal cells of the stomach. The etiology of pernicious anemia can be due to autoimmune causes or genetic disease. In autoimmune disease, the antibodies attack most of the gastric mucosa, but the antrum is spared.

Autoimmune causes of pernicious anemia

This is the most common cause of pernicious anemia. In autoimmune pernicious anemia, the body produces antibodies against parietal cells or intrinsic factor.

  • Antibodies against parietal cells of the gastric mucosa work to inhibit the H+/K(+)-ATPase which is the proton pump present in the parietal cells. The proton pump serves as an auto antigen and activates the cytotoxic CD4+ T cells which proceed to destroy gastric mucosal cells.[9][10]
  • Intrinsic factor antibodies are present in fewer cases of pernicious anaemia but are highly specific. There are 2 types of IF antibodies. They prevent the binding and absorption of cobalamin in the ileum via its receptor.[11]

Clinical features

  • The symptoms of pernicious anemia take months, and often years to manifest. Patients most commonly present with symptoms of anemia like lightheadedness, dizziness, shortness of breath etc. The population affected with pernicious anemia is usually the elderly (>60 years) owing to its insidious onset.
  • Pernicious anemia has hematological, gastrointestinal and neurological manifestations.
  • Hematological signs are the earliest manifestation of the disease while neurological signs are seen much later.
  • Patients with pernicious anemia usually have very low levels of hydrochloric acid in the stomach (achlorhydria) and high levels on gastrin (hypergastrinemia).

Differentiating pernicious anemia from other diseases

Pernicious anemia shares many similarities with other forms of megaloblastic anemia like B12 and folate deficiency.

  • Vitamin B12 deficiency due to insufficient intake (eg veganism) has all the features of pernicious anemia like megaloblasts, hypersegmented neutrophils, neuropsychiatric manifestations. But atrophic gastritis is absent, so achlorhydria, parietal cell antibodies or IF antibodies are absent. Intrinsic factor levels are also normal.[6]
  • Folic acid deficiency also results in megaloblastic anemia and similar hematological changes as pernicious anemia, but urinary excretion of methylmalonic acid is absent, so are features of pernicious anemia like achlorhydria, antibodies and normal IF levels.
  • Ileal resection causes B12 deficiency due to decreased absorption.
  • Certain drugs such as methotrexate, azathioprine cause folate deficiency and result in megaloblastic anemia. This is usually seen in patients taking chemotherapy or other chronic conditions such as rheumatoid arthritis. [12]
  • Chronic proton pump inhibitor therapy also results in B12 deficiency as vitamin B12 cannot dissociate from its carrier protein in the absence of an acidic environment.[13]
  • Long term use of metformin, such as in diabetics, is linked to vitamin B12 deficiency and symptoms similar to pernicious anemia, but this can be differentiated from pernicious anemia as it is seen in diabetics on chronic therapy.[14]

Associated Conditions

People affected with pernicious anemia might have other coexisting autoimmune conditions such as autoimmune thyroiditis, autoimmune diabetes, vitiligo etc. Autoimmune thyroiditis is most commonly seen in patients with pernicious anemia, particularly females. HLA DR3 has been implicated in the development of autoimmune diseases such as pernicious anemia[15].

Epidemiology and demographics

  • Pernicious anemia is a disease of the elderly. The mean age of patients who are symptomatic is >60.[16]
  • An exception is the genetic form of the disease which is a congenital deficiency of intrinsic factor and is seen in children <10 years of age.
  • Men and women are equally affected
  • Prevalence of pernicious anemia is estimated at 0.1% of the population.[17]

Genetics

  • Some forms of pernicious anemia are congenital and a genetic link has been postulated because of a higher incidence in certain populations.
  • Affected people have a complete or near total absence of intrinsic factor and the presence of antibodies against intrinsic factor.
  • The genetic variant is transmitted through an autosomal recessive pattern.[18]

Risk factors

  • People who have autoimmune conditions like diabetes mellitus, autoimmune thyroiditis are at higher risk of developing pernicious anemia.

Natural History, Complications and Prognosis

  • In most cases, patients affected with pernicious anemia remain asymptomatic for many years.
  • Early manifestations include fatigue, shortness of breath, pallor and weakness.
  • Long standing untreated pernicious anemia results in irreversible neurological damage such as subacute combined degeneration of the spinal cord.
  • Neurological changes are irreversible once they set in and do not resolve with cobalamin supplementation.

Diagnosis

A diagnosis of pernicious anemia is made by a history and physical examination, along with hematological and neurological examination.

Diagnostic criteria

  • The only specific criteria to diagnose pernicious anemia is an intrinsic factor output of less than 200U/h after pentagastrin stimulation, where normal levels would be >2000U/h. [19]

Symptoms

Symptoms of pernicious anemia are summarised below

Hematological symptoms Gastrointestinal symptoms Neurological symptoms
Fatigue Loss of appetite Parasthesias
Weakness Weight loss


Depression
Shortness of breath Nausea Gait problems
Dizziness Burning sensation on tongue Weakness
Tachycardia Diarrhea Loss of balance
Lightheadedness Vomiting Confusion

Physical examination findings

Most important physical examination findings are the neurological findings of long standing B12 deficiency which leads to subacute combined degeneration of the spinal cord.

  • Hematological signs include pallor and icterus.[20]
  • Neurological signs: Vitamin B12 deficiency causes nerve demyelination. B12 deficiency also causes a buildup of methylmalonic acid which is toxic to neuronal cells and causes apoptosis.[21].

The main neurological manifestation of pernicious anemia and vitamin B12 deficiency is subacute combined degeneration. The posterior and lateral columns of the spinal cord are affected. Lateral column demyelination manifests as hyperreflexia and spasticity, while posterior column defects are loss of proprioception and vibration sense. Ataxia and loss of tandem gait are also manifestations of posterior column demyelination. Recreational or accidental inhalation of nitrous oxide gas (laughing gas) can precipitate subacute combined degeneration in people with low levels of vitamin B12.[22]

  • Gastrointestinal signs: Upto 25% of people affected with pernicious anemia develop glossitis. The tongue appears red, "beefy" and smooth due to atrophy and blunting of the lingual papillae.[23]

Subacute combined degeneration


Laboratory findings

  • The first step in diagnosis is a blood vitamin B12 level. Blood levels less than 200 pg/ml are seen in pernicious anemia.
  • Intrinsic factor antibodies and Parietal cell antibodies.
  • Low intrinsic factor level.[24]
  • Gastric mucosal sampling shows parietal cell atrophy with antral sparing.[25]
  • Increased level of gastrin.
  • Increased levels of homocysteine and methylmalonyl-CoA.
  • Decreased folate levels are seen due to "folate trapping" in the form of methyltetrahydrofolate.

Shilling Test

The Shilling test is no longer done to detect an IF deficiency but has historical importance. After a vitamin B12 deficiency is noted, the patient is given radioactively tagged cobalamin to take orally. Soon after this step, the patient is injected with unlabelled cobalamin intramuscularly. Urine is checked for radioactive cobalamin for the next 24 hours. In pernicious anemia, there is an intrinsic factor deficiency, therefore the orally consumed radioactive cobalamin will not be absorbed and can be detected in the urine. In the next step, the patient is given radioactive cobalamin along with intrinsic factor and their urine is checked for traces of radioactive cobalamin. Absence of radioactive cobalamin in the urine points to the deficiency of intrinsic factor in the patients stomach which is the cause of vitamin B12 deficiency[26]. If the cobalamin absorption does not increase even with intrinsic factor supplementation, patient can be given a course of antibiotics as bacterial overgrowth may hinder absorption.

Peripheral smear findings

  1. The most obvious peripheral smear finding is megaloblasts and macrocytes.

Megaloblastic anemia results due to the lagging behind of nuclear development when compared to cytoplasmic development. This is known as nuclear-cytoplasmic asynchrony. Such defective cells are destroyed in the bone marrow (intramedullary hemolysis).

  1. Decreased number of RBCs (erythopenia)
  2. Macrocytosis- the RBCs in pernicious anemia are very large. Macrocytosis is defined as cells that have an MCV >100 femtolitres (normal :80-100fL)
  3. Hypersegmented neutrophils : Neutrophils containing ≥ 6 lobes. [27]
  4. Poikilocytosis and anisocytosis
  5. Low reticulocyte count (reticulopenia)
  6. Howell-Jolly bodies


Treatment

  • Standard treatment for pernicious anemia is replacement of cobalamin via intramuscular injection. [28]
  • 1000 mcg IM everyday for one week, followed by weekly injections the next month and then monthly once injections.
  • Response to treatment is measured by an increase in reticulocyte count within 5 days of starting therapy.
  • Patient also experience a sense of wellbeing shortly after beginning therapy.
  • If reticulocytosis is not observed within the first week of therapy, other factors such as hypothyroidism, folate deficiency should be considered.
  • Intramuscular therapy can be replaced by high dose oral therapy.[17]
  • Neurological disease always warrants parenteral treatment.
  • Within the first 3-4 weeks of treatment, marrow changes revert and there is resolution in macrocytosis.
  • Most patients require lifelong monthly therapy.
  • Routine follow up should be done with a CBC every few months.
  • A small percentage of patients develop gastric carcinoma, particularly in the elderly. Regular surveillance helps in early detection and treatment. [29]

Prevention

  • There is no primary preventive measure for pernicious anemia.
  • Once sucessfully diagnosed and treated, patients with pernicious anemia are followed up every year for development of stomach cancer[30], or symptoms of anemia.

==References== Shyam Patel [4]

Synonyms and keywords:Kahler disease; Kahler's disease; MM; Myeloma; Myelomatosis; Medullary plasmacytoma; Plasmacytoma

Overview

Historical Perspective

Classification

Pathophysiology

Causes

Differentiating Multiple Myeloma from other Diseases

Epidemiology and Demographics

Risk Factors

Screening

Natural History, Complications and Prognosis

Diagnosis

Diagnostic Criteria | Staging | History and Symptoms | Physical Examination | Laboratory Findings | X Ray | CT | MRI | Other Imaging Findings | Other Diagnostic Studies

Treatment

Medical Therapy | Surgery | Primary Prevention | Secondary Prevention | Future or Investigational Therapies

Case Studies

Case #1

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  2. SMITH EL (1948). "Purification of anti-pernicious anaemia factors from liver". Nature. 161 (4095): 638. doi:10.1038/161638a0. PMID 18856623.
  3. Miles LM, Allen E, Clarke R, Mills K, Uauy R, Dangour AD (2017). "Impact of baseline vitamin B12 status on the effect of vitamin B12 supplementation on neurologic function in older people: secondary analysis of data from the OPEN randomised controlled trial". Eur J Clin Nutr. 71 (10): 1166–1172. doi:10.1038/ejcn.2017.7. PMID 28225050.
  4. Watanabe F (2007). "Vitamin B12 sources and bioavailability". Exp Biol Med (Maywood). 232 (10): 1266–74. doi:10.3181/0703-MR-67. PMID 17959839.
  5. Jung SB, Nagaraja V, Kapur A, Eslick GD (2015). "Association between vitamin B12 deficiency and long-term use of acid-lowering agents: a systematic review and meta-analysis". Intern Med J. 45 (4): 409–16. doi:10.1111/imj.12697. PMID 25583062.
  6. 6.0 6.1 Del Corral A, Carmel R (1990). "Transfer of cobalamin from the cobalamin-binding protein of egg yolk to R binder of human saliva and gastric juice". Gastroenterology. 98 (6): 1460–6. doi:10.1016/0016-5085(90)91076-i. PMID 2110915.
  7. Harrington DJ (2017). "Laboratory assessment of vitamin B12 status". J Clin Pathol. 70 (2): 168–173. doi:10.1136/jclinpath-2015-203502. PMID 27169753.
  8. Tinelli C, Di Pino A, Ficulle E, Marcelli S, Feligioni M (2019). "Hyperhomocysteinemia as a Risk Factor and Potential Nutraceutical Target for Certain Pathologies". Front Nutr. 6: 49. doi:10.3389/fnut.2019.00049. PMC 6491750. PMID 31069230.
  9. Callaghan JM, Khan MA, Alderuccio F, van Driel IR, Gleeson PA, Toh BH (1993). "Alpha and beta subunits of the gastric H+/K(+)-ATPase are concordantly targeted by parietal cell autoantibodies associated with autoimmune gastritis". Autoimmunity. 16 (4): 289–95. doi:10.3109/08916939309014648. PMID 7517707.
  10. Toh BH, Sentry JW, Alderuccio F (2000). "The causative H+/K+ ATPase antigen in the pathogenesis of autoimmune gastritis". Immunol Today. 21 (7): 348–54. doi:10.1016/s0167-5699(00)01653-4. PMID 10871877.
  11. Schade SG, Abels J, Schilling RF (1967). "Studies on antibody to intrinsic factor". J Clin Invest. 46 (4): 615–20. doi:10.1172/JCI105563. PMC 442045. PMID 6021209.
  12. Green R, Datta Mitra A (2017). "Megaloblastic Anemias: Nutritional and Other Causes". Med Clin North Am. 101 (2): 297–317. doi:10.1016/j.mcna.2016.09.013. PMID 28189172.
  13. Heidelbaugh JJ (2013). "Proton pump inhibitors and risk of vitamin and mineral deficiency: evidence and clinical implications". Ther Adv Drug Saf. 4 (3): 125–33. doi:10.1177/2042098613482484. PMC 4110863. PMID 25083257.
  14. Aroda VR, Edelstein SL, Goldberg RB, Knowler WC, Marcovina SM, Orchard TJ; et al. (2016). "Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study". J Clin Endocrinol Metab. 101 (4): 1754–61. doi:10.1210/jc.2015-3754. PMC 4880159. PMID 26900641.
  15. Zulfiqar AA, Andres E (2017). "Association pernicious anemia and autoimmune polyendocrinopathy: a retrospective study". J Med Life. 10 (4): 250–253. PMC 5771255. PMID 29362601.
  16. Carmel R (1996). "Prevalence of undiagnosed pernicious anemia in the elderly". Arch Intern Med. 156 (10): 1097–100. PMID 8638997.
  17. 17.0 17.1 Andres E, Serraj K (2012). "Optimal management of pernicious anemia". J Blood Med. 3: 97–103. doi:10.2147/JBM.S25620. PMC 3441227. PMID 23028239.
  18. Gordon MM, Brada N, Remacha A, Badell I, del Río E, Baiget M; et al. (2004). "A genetic polymorphism in the coding region of the gastric intrinsic factor gene (GIF) is associated with congenital intrinsic factor deficiency". Hum Mutat. 23 (1): 85–91. doi:10.1002/humu.10297. PMID 14695536.
  19. Cattan D (2011). "Pernicious anemia: what are the actual diagnosis criteria?". World J Gastroenterol. 17 (4): 543–4. doi:10.3748/wjg.v17.i4.543. PMC 3027024. PMID 21274387.
  20. Seynabou F, Fatou Samba Diago N, Oulimata Diop D, Abibatou Fall S, Nafissatou D (2016). "Biermer anemia: Hematologic characteristics of 66 patients in a Clinical Hematology Unit at Senegal". Med Sante Trop. 26 (4): 402–407. doi:10.1684/mst.2016.0625. PMID 28073728.
  21. Han L, Wu S, Han F, Gu X (2015). "Insights into the molecular mechanisms of methylmalonic acidemia using microarray technology". Int J Clin Exp Med. 8 (6): 8866–79. PMC 4538064. PMID https://www.ncbi.nlm.nih.gov/pubmed/26309541 Check |pmid= value (help).
  22. Choi C, Kim T, Park KD, Lim OK, Lee JK (2019). "Subacute Combined Degeneration Caused by Nitrous Oxide Intoxication: A Report of Two Cases". Ann Rehabil Med. 43 (4): 530–534. doi:10.5535/arm.2019.43.4.530. PMC 6734019 Check |pmc= value (help). PMID 31499607.
  23. Stoopler ET, Kuperstein AS (2013). "Glossitis secondary to vitamin B12 deficiency anemia". CMAJ. 185 (12): E582. doi:10.1503/cmaj.120970. PMC 3761039. PMID 23359038.
  24. Lahner E, Annibale B (2009). "Pernicious anemia: new insights from a gastroenterological point of view". World J Gastroenterol. 15 (41): 5121–8. doi:10.3748/wjg.15.5121. PMC 2773890. PMID 19891010.
  25. Korman MG, Strickland RG, Hansky J (1972). "The functional 'G' cell mass in atrophic gastritis". Gut. 13 (5): 349–51. doi:10.1136/gut.13.5.349. PMC 1412218. PMID 5036089.
  26. "StatPearls". 2020. PMID 29939561.
  27. Farrelly SJ, O'Connor KA (2017). "Hypersegmented neutrophils and oval macrocytes in the setting of B12 deficiency and pancytopaenia". BMJ Case Rep. 2017. doi:10.1136/bcr-2016-218508. PMC 5612428. PMID 28821482.
  28. Annibale B, Lahner E, Fave GD (2011). "Diagnosis and management of pernicious anemia". Curr Gastroenterol Rep. 13 (6): 518–24. doi:10.1007/s11894-011-0225-5. PMID 21947876.
  29. Murphy G, Dawsey SM, Engels EA, Ricker W, Parsons R, Etemadi A; et al. (2015). "Cancer Risk After Pernicious Anemia in the US Elderly Population". Clin Gastroenterol Hepatol. 13 (13): 2282-9.e1-4. doi:10.1016/j.cgh.2015.05.040. PMC 4655146. PMID 26079040.
  30. Venerito M, Link A, Rokkas T, Malfertheiner P (2016). "Gastric cancer - clinical and epidemiological aspects". Helicobacter. 21 Suppl 1: 39–44. doi:10.1111/hel.12339. PMID 27531538.