Cold Agglutinin Disease 2015-4-28

Cold Agglutinin Disease: Background, Pathophysiology, Etiology
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Cold Agglutinin Disease

Author: Salman Abdullah Aljubran, MD; Chief Editor: Michael A Kaliner, MD more...
Updated: Apr 28, 2015
Background
Cold agglutinin disease is a form of autoimmune hemolytic anemia caused by coldreacting autoantibodies. Autoantibodies that bind to the erythrocyte membrane
leading to premature erythrocyte destruction (hemolysis) characterize autoimmune
hemolytic anemia. (See Pathophysiology and Etiology.)
Autoimmune hemolytic anemia is classified as primary or secondary and is
subclassified according to autoantibody type. (See Pathophysiology, Etiology, and
Presentation.)
In primary autoimmune hemolytic anemia, no underlying systemic disease explains

the presence of autoantibodies, whereas secondary autoimmune hemolytic anemia
results from a systemic disease. The autoantibody may be immunoglobulin G (IgG),
immunoglobulin M (IgM), or, rarely, immunoglobulin A (IgA); it may be warm reacting
or cold reacting. (See the image below.)
Peripheral blood smear showing several clumps of RBCs with the largest in the center. These
are typical of aggregates seen in persons with cold agglutinin disease.
Autoimmune hemolytic anemia syndromes associated with cold-reacting

autoantibodies include cold agglutinin disease and, to a much lesser extent,
paroxysmal cold hemoglobinuria. (Most paroxysmal cold hemoglobinuria cases are
not caused by a cold agglutinin.) (See Presentation and DDx.)
IgM antibodies generally cause cold agglutinin disease. Donath-Landsteiner
hemolytic anemia (previously referred to as paroxysmal cold hemoglobinuria) is
caused by IgG antibodies.
Primary and secondary disease
Primary cold agglutinin disease is usually associated with monoclonal cold-reacting

autoantibodies. Primary cold agglutinin disease is chronic and occurs after the fifth
decade of life, with a peak incidence in the seventh and eighth decades. (See
Epidemiology.)
Secondary cold agglutinin disease may be associated with either monoclonal or
polyclonal cold-reacting autoantibodies. It predominantly is caused by infection and
lymphoproliferative disorders. Monoclonal secondary disease is usually chronic,
occurring in adults. Polyclonal secondary cold agglutinin disease, which occurs in
children and young adults, is usually transient. (See Etiology and Prognosis.)
Requirements for induction of active hemolytic anemia
Several factors play a role in determining the ability of a cold agglutinin to induce an
active hemolytic anemia.[1, 2] These include the following:
Ability to initiate
Extent of antibody-induced complement activation
Concentration of the antibody
Range of temperatures, including the highest temperature at which the
antibody interacts with the RBC (its thermal amplitude)
Qualitative binding of IgM to the RBC
http://emedicine.medscape.com/article/135327-overview
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Modification of the antibody's ability to fix complement components onto the

RBCs
Pathophysiology
Cold agglutinins, or cold autoantibodies, occur naturally in nearly all individuals.

These natural cold autoantibodies occur at low titers, less than 1:64 measured at 4
C, and have no activity at higher temperatures. Pathologic cold agglutinins occur at
titers over 1:1000 and react at 28-31C and sometimes at 37C.
Cold agglutinin disease usually results from the production of a specific IgM antibody
directed against the I/i antigens (precursors of the ABH and Lewis blood group
substances) on red blood cells (RBCs). Cold agglutinins commonly have variable
heavy-chain regions encoded by VH, with a distinct idiotype identified by the 9G4 rat
murine monoclonal antibody.[1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19]
Because the I antigen is not activated until after birth, anti-i autoantibodies
predominantly agglutinate neonatal RBCs, and anti-I autoantibodies predominantly
agglutinate adult RBCs.
VH genes
The 9G4 idiotope is localized to the V4-34 encoded portion of the variable region.[20]
It is found on cold agglutinin-producing malignant lymphoid cells in the bone marrow
in persons with lymphoproliferative disorders, on a small proportion of normal
lymphoid cells, and in the spleen of a 15-week-old fetus. In contrast, the cold
agglutinins found in healthy individuals, those with no clinical symptoms, are often
derived from a variable segment other than the V4-34 portion.[21, 22]
The VH genes appear to regulate not only the production of cold agglutinins, but also
the formation of normal antibodies to other carbohydrate antigens, both sharing the
same fundamental mechanism of production. The I/i antigen analogues are present
on human lymphocytes, neutrophils, and monocytes and in human saliva, milk, and
amniotic fluid. Thus, in disease states, the finding of a clone of B cells producing this
antibody may be the result of expansion of a normal clone that is specific for the
production of an immunoglobulin with these properties. Autoimmune and
lymphoproliferative disorders can also be associated with the production of cold
agglutinins.
In vitro studies have shown that human monoclonal antibodies encoded by the V434 gene segment not only have cold agglutinin properties but also exhibit
multireactivity. This is in contrast to the generally monospecific I/i reactivity of sera
from patients with cold agglutinin disease.[17]
Associated infections
The hemolytic anemia associated with monoclonal cold agglutinins is typically more
serious than that associated with polyclonal cold agglutinins. The monoclonal form is
usually chronic, whereas the polyclonal form is often limited.[23]
Some polyclonal IgM cold agglutinins arise in association with infections with
Mycoplasma pneumoniae, infectious mononucleosis, influenza B, and human
immunodeficiency virus (HIV), as well as with other infections. (Cold agglutinins
develop in more than 60% of patients with infectious mononucleosis, but hemolytic
anemia is rare.)
Cytomegalovirus (CMV), rubella virus, varicella-zoster virus (VZV), parvovirus B19,

and Chlamydia psittaci have also been implicated.[24]
In the case of infectious mononucleosis, hemolysis tends to develop 1-2 weeks after
the onset of illness, but it may occur simultaneously for up to 2 months after onset.[24]
Furthermore, increased expression of I/i antigens have been described on
hemoglobin SS (HbSS) erythrocytes, which suggests that such patients may have
increased susceptibility to cold-mediated hemolysis.[25]
Antigen specificity
In its classic presentation, with hemolytic anemia and Raynaud syndrome, cold
agglutinin disease is usually idiopathic. As with most autoimmune diseases of a
chronic nature, stimulated B lymphocytes begin to produce pathogenic antibodies
against an antigen that is normally present in human tissue. In cold agglutinin
disease, the antibody is an IgM, usually monoclonal, with kappa () or lambda ()
light chains. In chronic cold agglutinin disease, the antibody is usually directed
against the I antigen on the membrane of normal adult RBCs.
Uncommonly, the antibody may be directed against only the i antigen found on fetal
cord blood RBCs, which lack the mature I antigen; this has been reported in
association with infectious mononucleosis.[8]
In a study of 78 patients, light-chain specificity was found in the majority of patients

with chronic cold agglutinin disease or Waldenstrm macroglobulinemia, whereas
two thirds of cold agglutinins found in patients with lymphomas had light-chain
specificity. The type of light chain appears to correlate with the antigen specificity of
the cold agglutinin. Fifty-eight percent of IgM/ (usually III variable region subgroup)
was anti-I, but 75% of IgM/ had other antigen specificities.[10]
Antigen specificities of cold agglutinins other than the I/i system that have been
described include those against Pr, M, P, and Lud and anti-Gd, anti-Fl, and anti-Sa.
[5, 9, 12]
Exclusive occurrence of chains has also been shown with some cold
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agglutinins.[4] Thus, benign and malignant cold agglutinins exhibit differences in their
light chains and their specificities toward membrane antigens.
Association of complement fixation with temperature
In vivo, the IgM antibody attaches to RBCs and causes them to agglutinate at
temperatures below 37C and maximally at 0-5C, resulting in impaired blood flow to
the digits, nose, and ears (ie, areas more likely to have colder temperatures [in the
30C range]) when exposed to the cold.
Fixation of the C3 component of complement to the RBC by the cold agglutinin
usually occurs in vivo at higher temperatures than those required by the IgM cold
agglutinin to attach to the RBC, but it is generally less than 31C. When the
IgM/C3b-coated RBC circulates to warmer tissues, the IgM dissociates, leaving
complement C3b on the original RBC.
The dissociated IgM cold agglutinin can then bind to another RBC at lower
temperatures. Fixation of complement results in C3b and/or C4b components on the
RBC membrane, which may lead to phagocytosis by macrophages in the
reticuloendothelial system, particularly in the liver, where the macrophages have
specific complement receptors. With time, the C3b components are converted
enzymatically to C3dg, which is not recognized by macrophage receptors.
Complement levels in hemolysis
In chronic cold agglutinin disease, complement tends to be depleted. Thus, the

hemolysis is self-controlled, and anemia may be only mild or moderate, because
these C3dg-coated RBCs are no longer capable of reacting with the IgM antibody in
the cold, the C3dg-coated RBCs are not recognized by the macrophages, and low
complement levels become rate limiting.
Temporary increases in complement levels, as can occur with intercurrent febrile

illnesses, can increase hemolysis. Lytic components of complement C5-C9 generally
do not form on these cells, and intravascular hemolysis by complement is less likely
to occur.[14] Hemolysis develops acutely following M pneumoniae infections and lasts
approximately 1-3 weeks. Subclinical mild hemolysis with reticulocytosis may also
occur, and the results of a direct Coombs test may be weakly positive, especially
with M pneumoniae infections.
Idiopathic disease and lymphoma
Monoclonal cold agglutinin IgM antibodies found in patients with lymphoma are the
product of the abnormal clone. Progression of an idiopathic cold agglutinin disease
to malignant lymphoma may occur in some cases; thus, affected patients require
close, long-term follow-up, with obvious therapeutic implications.[8, 12] One study of
86 patients in Norway showed clonal light-chain predominance in 90% of patients,
evidence of lymphoplasmacytic lymphoma in 50% of patients, and lymphoma of any
type in 76% of patients overall.[2]
Warm-cold antibody combinations
Hemolysis due to cold agglutinins can sometimes be accompanied by a warm

antibody (IgG), resulting in a mixed autoimmune hemolytic anemia,[8, 11] that is, cold
agglutinin syndrome and warm antibody autoimmune hemolysis, with the direct
antiglobulin (direct Coombs) test results positive for the presence of IgG and
complement on the surface of the sensitized RBC.
In mixed antibody syndromes, the IgG and IgM antibody components can be
separated. The cold autoantibodies reactive at temperatures of 30C or higher often
show blood group specificity to the adult I antigen, whereas the warm autoantibodies
are not directed against this system. A combination of cold agglutinins and
cryoglobulins has also been reported with an IgM/ monoclonal antibody, with
specificity to the Pr2 antigen system.[18]
Biphasic hemolysins
The presence of biphasic hemolysins implicates more severe disease. Biphasic

hemolysins bind to RBCs at low temperatures and activate complement to produce
in vitro hemolysis at warmer temperatures (37C), whereas monophasic hemolysins
bind to RBCs and activate complement at the same temperature.[26]
Modulation of agglutinin production
Data have confirmed an immunomodulatory/immunosuppressive role of the naturally

occurring anti-F(ab')2 antibodies in the production of cold agglutinins, with an inverse
correlation between the titers of IgG-anti-F(ab')2 and cold agglutinins.[16] This inverse
correlation was found only in patients with anti-I/i and in the presence of a
monoclonal lymphocyte population.
Etiology
Cold agglutinins develop in more than 60% of patients with infectious

mononucleosis, but hemolytic anemia is rare.
Classic chronic cold agglutinin disease is idiopathic, associated with symptoms and
signs in relation to cold exposure. Causes of the monoclonal secondary disease
include the following:
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B-cell neoplasms - Waldenstrm macroglobulinemia, lymphoma, chronic

lymphoid leukemia, myeloma [27]
Nonhematologic neoplasms
Causes of polyclonal secondary cold agglutinin disease include the following:
Mycoplasma infections - M pneumoniae [28]

Viral infections - Infectious mononucleosis due to Epstein-Barr virus (EBV) or
CMV
Viral infections, other - Mumps, varicella, rubella, adenovirus, HIV, influenza,
hepatitis C
Bacterial infections - Legionnaire disease, syphilis, listeriosis, Escherichia coli
Parasitic infections - Malaria, trypanosomiasis
Bacterial and viral infections
Transient acute hemolysis may occur secondary to certain infectious diseases, such
as M pneumoniae infection and infectious mononucleosis (eg, EBV). Other viral
infections, such as influenza, HIV, CMV, rubella, varicella, and mumps, have also
been reported to be associated with a hemolytic anemia due to cold agglutinins.
Associated illnesses also include subacute bacterial endocarditis, syphilis, and
malaria. The development of a febrile illness in a patient with chronic cold agglutinin
disease may also accelerate hemolysis.
CANOMAD syndrome
Cold agglutinins are seen in CANOMAD syndrome (chronic ataxic neuropathy

ophthalmoplegia M-protein agglutination disialosyl antibodies). This syndrome is
described by gait and upper-limb ataxia; cranial nerve involvement with external
ophthalmoplegia; and the presence of cold agglutinins, IgM paraprotein, and antidisialosyl antibodies.[29] The neurologic and hematologic symptoms have been seen
to respond to rituximab.[30]
Malignancies
Lymphoproliferative and autoimmune diseases, myeloma, Kaposi sarcoma, and

angioimmunoblastic lymphoma may occasionally be associated with the production
of cold agglutinins. An idea of associated disease distribution was provided by a
study of 78 patients with persistent cold agglutinins. Among these patients, 31 had
lymphoma, 13 had Waldenstrm macroglobulinemia, 6 had chronic lymphoid
leukemia, and 28 had chronic idiopathic cold agglutinin disease.[10]
A case of cold agglutinininduced hemolytic anemia has been described in
association with an aggressive natural killer cell (NK-cell) leukemia.[31]
Nonhematologic malignancies can occasionally be associated with a high-titer cold
agglutinininduced hemolytic anemia.[7, 32]
Trisomy and translocation
Cytogenetic studies in patients with cold agglutinin disease have revealed the
presence of trisomy 3 and trisomy 12. Translocation (8;22) has also been reported in
association with cold agglutinin disease.[2, 33, 34]
Transplantation
Cold agglutininmediated hemolytic anemia has been described in patients after

living-donor liver transplantation treated with tacrolimus and after bone marrow
transplantation with cyclosporine treatments. It is postulated that such calcineurin
inhibitors, which selectively affect T-cell function and spare B-lymphocytes, may
interfere with the deletion of autoreactive T-cell clones, resulting in autoimmune
disease.[35, 36, 37]
Systemic sclerosis
Cold agglutinin disease has been described in patients with sclerodermic features,
with the degree of anemia being associated with increasing disease activity of the
patients systemic sclerosis. This may suggest a close association between systemic
rheumatic disease and autoimmune hematologic abnormalities.[38]
Hyperreactive malarial splenomegaly
Hyperreactive malarial splenomegaly (HMS) is an immunopathologic complication of

recurrent malarial infection. Patients with HMS develop splenomegaly, acquired
clinical immunity to malaria, high serum concentrations of anti-Plasmodium
antibodies, and high titers of IgM, with a complement-fixing IgM that acts as a cold
agglutinin.[39]
DPT vaccination
Diphtheria-pertussis-tetanus (DPT) vaccination has been implicated in the

development of autoimmune hemolytic anemia caused by IgM autoantibody with a
high thermal range. A total of 6 cases have been reported; 2 followed the initial
vaccination and 4 followed the second or third vaccinations.[22, 40, 41, 42, 43]
Other
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Equestrian perniosis is a rare cause of persistent elevated titers of cold agglutinins.

[19]
Also rarely, the first manifestations of cold agglutinin disease can develop when a
patient is subjected to hypothermia for cardiopulmonary bypass surgery.[13]
Epidemiology
Occurrence in the United States
The development of cold agglutinin syndrome is relatively uncommon, at least in the

classic chronic form. Various reports state that 7-25% of cases of autoimmune
hemolytic anemia are cold agglutinin mediated. Thus, while the incidence of cold and
warm autoimmune hemolytic anemia (combined) is approximately 1 in 80,000, the
incidence of cold agglutinin disease is approximately 1 in 300,000. Among
autoimmune hemolytic anemias, cold agglutinin disease is the second most common
cause, after warm autoantibodyinduced immune hemolysis.
International occurrence
Data regarding the incidence of cold agglutinin disease are lacking. Frequency
figures listed for the United States probably also apply to Canada and the United
Kingdom.
Sex- and age-related demographics
In general, no predilection for either sex is noted, although some report a female
predilection in older populations. Autoimmune hemolytic anemia appears to be more
common in male children and female adolescents.[3, 8]
Only rarely do Infants and children develop chronic cold agglutinin disease, although
M pneumoniae and infectious mononucleosis are diseases of young persons.
Chronic cold agglutinin disease appears to affect adults who are of middle age and
older, with an average age of older than 60 years and peaking in the seventh and
eighth decades of life. Although found in persons of all age groups, mixed
autoimmune hemolysis is also more frequent in later life.
Prognosis
Cold agglutinin disease may be associated with an excellent long-term prognosis if it

is secondary to M pneumonia or viral infections that are, in themselves, self-limited.
In children and young adults, acute hemolysis lasts 1-3 weeks; evidence of cold
agglutinins disappears within 6 months.
Patients with the mildly to moderately severe primary (idiopathic) variety of cold
agglutinin disease are expected to have a good long-term prognosis if excessive
exposure to cold is avoided and with close medical surveillance for complications or
progression to lymphoma.
The nature of the antigenic specificity of the cold agglutinin, as when it is directed
against the Pr antigen system, may be associated with greater severity of disease.
Cold agglutinin disease associated with HIV infection may have a relatively poor
prognosis due to the nature of the underlying disease. The same applies to cases
associated with lymphoma, with the prognosis dependent on remission of the
underlying malignancy.
Morbidity and mortality
Complications of cold agglutinin disease include the following:
Brisk hemolysis due to cold exposure

Ischemic complications at exposed sites due to prolonged cold exposure
Other symptoms related to severe anemia
Infrequently, development of malignant disease during follow-up care of a
patient with idiopathic chronic cold agglutinin disease
Shock or congestive heart failure, resulting from severe hemolysis and
anemia
Peripheral gangrene and, rarely, fatalities after inadvertent and perhaps
prolonged exposure to the cold
Transfusions for life-threatening symptoms due to severe anemia require

prewarming and the use of washed RBCs (not cold). In general, autoimmune
hemolytic anemia has a mortality rate of 10%.
A study by Kamesaki et al indicated that the clinical characteristics of patients with

autoimmune hemolytic anemia who have a positive direct Coombs test (direct
antiglobulin test [DAT]) differ from those of patients with this type of anemia and a
negative DAT. The report used data from 216 patients with autoimmune hemolytic
anemia, including 154 who were DAT negative and 62 who were DAT positive.[44]
The investigators found that patients who were DAT negative tended to have milder
anemia and hemolysis than did patients who were DAT positive and that they
needed significantly lower steroid doses during maintenance treatment. The 2
groups of patients were found to have an equally good response to steroids. Survival
at 1-year follow-up for each group was comparable to that of the other.
Patient Education
It is essential to educate patients with chronic cold agglutinin disease about the
importance of keeping all body parts warm at all times and avoiding cooling of body
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parts. Appropriate clothing is necessary in cold environments, and avoidance of cold

foods and working in cold storage areas is also important.
Patients must comprehend the importance of their daily folic acid intake, which
supplies a needed hematinic. Folic acid could easily become a rate-limiting
hematinic in a patient with a chronic hemolytic process.
Teach patients to watch for signs of anemia, such as dyspnea, palpitations, and
pallor, and to observe for signs of hemolysis, such as jaundice and dark urine.
For patient education information, see Anemia.
Clinical Presentation
Contributor Information and Disclosures
Author
Salman Abdullah Aljubran, MD Clinical Fellow, Division of Allergy and Immunology, University of South Florida
College of Medicine
Salman Abdullah Aljubran, MD is a member of the following medical societies: American Academy of Allergy
Asthma and Immunology, American College of Allergy, Asthma and Immunology, American Thoracic Society,
Massachusetts Medical Society
Disclosure: Nothing to disclose.
Coauthor(s)
Richard F Lockey, MD University Distinguished Health Professor, Professor of Medicine, Pediatrics and Public
Health, Joy McCann Culverhouse Chair in Allergy and Immunology, University of South Florida College of
Medicine; Director, Division of Allergy and Immunology, James A Haley Veterans Hospital
Richard F Lockey, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of
Allergy Asthma and Immunology, American Association for the Advancement of Science, American College of
Occupational and Environmental Medicine, American College of Chest Physicians, American College of
Physicians, American Medical Association, Florida Medical Association
Chief Editor
Michael A Kaliner, MD Clinical Professor of Medicine, George Washington University School of Medicine;
Medical Director, Institute for Asthma and Allergy
Michael A Kaliner, MD is a member of the following medical societies: American Academy of Allergy Asthma and
Immunology, American Association of Immunologists, American College of Allergy, Asthma and Immunology,
American Society for Clinical Investigation, American Thoracic Society, Association of American Physicians
Disclosure: Received honoraria from Meda for speaking and teaching; Received honoraria from genentech for
speaking and teaching.
Acknowledgements
Nicolas A Camilo, MD Consulting Staff, Mountain States Tumor Institute, Division of Pediatric HematologyOncology, St Luke's Regional Medical Center
Max J Coppes, MD, PhD, MBA Senior Vice President, Center for Cancer and Blood Disorders, Children's
National Medical Center; Professor of Medicine, Oncology, and Pediatrics, Georgetown University School of
Medicine; Clinical Professor of Pediatrics, George Washington University School of Medicine and Health Sciences
Max J Coppes, MD, PhD, MBA is a member of the following medical societies: American Association for Cancer
Research, American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research
Gary D Crouch, MD Program Director of Pediatric Hematology-Oncology Fellowship, Department of Pediatrics,

Associate Professor, Uniformed Services University of the Health Sciences
Gary D Crouch, MD is a member of the following medical societies: American Academy of Pediatrics and
American Society of Hematology
Sharon Georgy, MD Resident Physician, Department of Internal Medicine, University of South Florida College of
Medicine
Sharon Georgy, MD is a member of the following medical societies: Phi Beta Kappa
James L Harper, MD Associate Professor, Department of Pediatrics, Division of Hematology/Oncology and Bone
Marrow Transplantation, Associate Chairman for Education, Department of Pediatrics, University of Nebraska
Medical Center; Assistant Clinical Professor, Department of Pediatrics, Creighton University School of Medicine;
Director, Continuing Medical Education, Children's Memorial Hospital; Pediatric Director, Nebraska Regional
Hemophilia Treatment Center
James L Harper, MD is a member of the following medical societies: American Academy of Pediatrics, American
Association for Cancer Research, American Federation for Clinical Research, American Society of Hematology,
American Society of Pediatric Hematology/Oncology, Council on Medical Student Education in Pediatrics, and
Hemophilia and Thrombosis Research Society
Gary R Jones, MD Associate Medical Director, Clinical Development, Berlex Laboratories
07-Mar-16
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Gary R Jones, MD is a member of the following medical societies: American Academy of Pediatrics, American
Society of Pediatric Hematology/Oncology, and Western Society for Pediatric Research
Jeffrey Lee Kishiyama, MD Assistant Clinical Professor of Medicine, University of California, San Francisco,
School of Medicine; Consulting Staff, Allergy and Asthma Associates of Santa Clara Valley Research Center
Thomas W Loew, MD Director, Clinical Associate Professor of Pediatrics, Pediatric Hematology/Oncology

Subspecialty Training Program, University of Iowa Hospitals and Clinics
Rajalaxmi McKenna, MD, FACP Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan
Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical
Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Harry L Messmore, Jr, MD Professor, Department of Medicine, Division of Hematology/Oncology, Loyola

University Stritch School of Medicine
Harry L Messmore, Jr, MD is a member of the following medical societies: Alpha Omega Alpha, American College
of Angiology, American College of Physicians, American Heart Association, American Society of Hematology, and
Phi Beta Kappa
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College
of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of
Pharmacy; Editor-in-Chief, Medscape Drug Reference
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Cold Agglutinin Disease: Background, Pathophysiology, Etiology