Whipple's disease
Encyclopedia
Whipple's disease is a rare
, systemic
infectious disease caused by the bacterium Tropheryma whipplei
. First described by George Hoyt Whipple in 1907 and commonly considered a gastrointestinal disorder, Whipple's disease primarily causes malabsorption
but may affect any part of the body including the heart, lungs, brain, joints, skin, and the eyes. Weight loss, diarrhea, joint pain, and arthritis are common presenting symptoms, but the presentation can be highly variable and approximately 15% of patients do not have these classic signs and symptoms. Whipple's disease is significantly more common in men, with 87% of the patients being male. When recognized and treated, Whipple's disease can usually be cured with long-term antibiotic therapy; untreated the disease is ultimately fatal.
, abdominal pain
, weight loss
and joint pains
. Sometimes, the joint pains occur many years before any digestive tract symptoms develop; they tend to involve the large joints but can occur in any pattern and tend not to damage the joint surface to the point that the joint becomes deformed. Fever and chills occur in a small proportion of people.
In its more advanced form, malabsorption
(insufficient absorption of nutrients from the diet) leads to wasting
and the enlargement of lymph nodes in the abdomen. Neurological symptoms (discussed below) are more common in those with severe abdominal disease. The poor absorption of fat means that many develop steatorrhea
(fatty, offensive stool). Depletion of albumin
, a blood protein, causes swelling of the skin.
Darkening of the skin occurs in almost half; some also have skin nodules. Various eye problems, such as uveitis
, may occur; this is typically associated with deteriorating vision and pain in the affected eye. Endocarditis
(infection of the heart valve
) has been reported in a small number of cases, sometimes in people with no other symptoms of Whipple's disease; this is typically noticed as breathlessness and leg swelling due to fluid accumulation as the heart is unable to pump fluid through the body.
10–40% of people with Whipple's disease have problems related to involvement of the brain
; the symptoms relate to the part of the brain that is affected. The most common problems are dementia
, memory loss
, confusion
and decreased level of consciousness. Eye movement disturbances and myorhythmia (rapidly repetitive movements of the muscles) of the face, together referred to as oculomasticatory myorrhythmia, are highly characteristic
for Whipple's disease. Weakness and poor coordination of part of the body, headache
s, seizures, as well as a number of more uncommon neurological features, are present in some cases.
s and those exposed to soil and animals, suggesting that the infection is acquired from these sources.
Individuals who are most susceptible to the disease are those with decreased ability to perform intracellular degradation of ingested pathogens or particles, particularly in the macrophages. Several studies indicate that defective T-lymphocyte (particularly TH1 population) function may be an important predisposing factor for the disease. In particular circulating cells that are CD11b (also known as Integrin Alpha) expressive, are reduced in susceptible individuals. CD11b has a vital role in activation of macrophages to destroy intracellularly ingested T. whipplei bacteria.
Diagnosis is made by biopsy
, usually by duodenal
endoscopy
, which reveals presence of the organism as PAS
-positive, non-acid-fast
macrophage
inclusions. Immunohistochemical staining for antibodies against T. whipplei has been used to detect the organism in a variety of tissues, and a PCR
-based assay is also available. PCR can be confirmatory if performed on blood, vitreous
fluid, synovial
fluid, heart valves, or cerebrospinal fluid
. PCR of saliva, gastric or intestinal fluid, and stool specimens is highly sensitive, but not specific enough, indicating that healthy individuals can also harbor the causative bacterium without the manifestation of Whipple's disease, but that a negative PCR is most likely indicative of a healthy individual.
Endoscopy
of the duodenum
and jejunum
can reveal pale yellow shaggy mucosa with erythematous eroded patches in patients with classic intestinal Whipple's disease, and small bowel X-ray
s may show some thickened folds. Other pathological findings may include enlarged mesentric lymph nodes, hypercellularity of lamina propria
with "foamy macrophages", and a concurrent decreased number of lymphocytes and plasma cells, per high power field view of the biopsy.
, ampicillin
, tetracycline or co-trimoxazole
for one to two years. Any treatment lasting less than a year has an approximate relapse rate of 40%. Recent expert opinion is that Whipple's disease should be treated with doxycycline
with hydroxychloroquine
for 12 to 18 months. Sulfonamides (sulfadiazine
or sulfamethoxazole
) may be added for treatment of neurological symptoms.
(new number of cases per year) of one case per million people. The patients are predominantly male (86% in a survey of American patients), although in some countries the rate of women receiving a diagnosis of Whipple's disease has increased in recent years. It occurs predominantly in those of Caucasian ethnicity
, suggesting a genetic predisposition
in that population.
T. whipplei appears to be an environmental organism that is commonly present in the gasterointestinal tract but remains asymptomatic. Several lines of evidence suggest that some defect - inherited or acquired - in immunity is required for it to become pathogenic. The possible immunological defect may be specific for T. whipplei, since the disease is not associated with a substantially increased risk of other infections.
The disease is usually diagnosed in middle age
(median 49 years). Studies from Germany
have shown that age at diagnosis has been rising since the 1960s.
, together with a French expert in the disease, applied novel diagnostic methods to stored tissue samples from Whipple's original patient, and demonstrated T. whipplei in these tissues.
Rare disease
A rare disease, also referred to as an orphan disease, is any disease that affects a small percentage of the population.Most rare diseases are genetic, and thus are present throughout the person's entire life, even if symptoms do not immediately appear...
, systemic
Systemic disease
Life-threatening disease redirects here.A systemic disease is one that affects a number of organs and tissues, or affects the body as a whole. Although most medical conditions will eventually involve multiple organs in advanced stage Life-threatening disease redirects here.A systemic disease is one...
infectious disease caused by the bacterium Tropheryma whipplei
Tropheryma whipplei
Tropheryma whipplei, formerly called Tropheryma whippelii, is a bacterium and the causative organism of Whipple's disease.While T. whipplei is categorized with the Gram-positive Actinobacteria, the organism is commonly found to be Gram-negative or Gram-indeterminate when stained in the laboratory...
. First described by George Hoyt Whipple in 1907 and commonly considered a gastrointestinal disorder, Whipple's disease primarily causes malabsorption
Malabsorption
Malabsorption is a state arising from abnormality in absorption of food nutrients across the gastrointestinal tract.Impairment can be of single or multiple nutrients depending on the abnormality...
but may affect any part of the body including the heart, lungs, brain, joints, skin, and the eyes. Weight loss, diarrhea, joint pain, and arthritis are common presenting symptoms, but the presentation can be highly variable and approximately 15% of patients do not have these classic signs and symptoms. Whipple's disease is significantly more common in men, with 87% of the patients being male. When recognized and treated, Whipple's disease can usually be cured with long-term antibiotic therapy; untreated the disease is ultimately fatal.
Signs and symptoms
The most common symptoms are diarrheaDiarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
, abdominal pain
Abdominal pain
Abdominal pain can be one of the symptoms associated with transient disorders or serious disease. Making a definitive diagnosis of the cause of abdominal pain can be difficult, because many diseases can result in this symptom. Abdominal pain is a common problem...
, weight loss
Weight loss
Weight loss, in the context of medicine, health or physical fitness, is a reduction of the total body mass, due to a mean loss of fluid, body fat or adipose tissue and/or lean mass, namely bone mineral deposits, muscle, tendon and other connective tissue...
and joint pains
Arthralgia
Arthralgia literally means joint pain; it is a symptom of injury, infection, illnesses or an allergic reaction to medication....
. Sometimes, the joint pains occur many years before any digestive tract symptoms develop; they tend to involve the large joints but can occur in any pattern and tend not to damage the joint surface to the point that the joint becomes deformed. Fever and chills occur in a small proportion of people.
In its more advanced form, malabsorption
Malabsorption
Malabsorption is a state arising from abnormality in absorption of food nutrients across the gastrointestinal tract.Impairment can be of single or multiple nutrients depending on the abnormality...
(insufficient absorption of nutrients from the diet) leads to wasting
Cachexia
Cachexia or wasting syndrome is loss of weight, muscle atrophy, fatigue, weakness, and significant loss of appetite in someone who is not actively trying to lose weight...
and the enlargement of lymph nodes in the abdomen. Neurological symptoms (discussed below) are more common in those with severe abdominal disease. The poor absorption of fat means that many develop steatorrhea
Steatorrhea
Steatorrhea is the presence of excess fat in feces. Stools may also float due to excess lipid, have an oily appearance and be especially foul-smelling. An oily anal leakage or some level of fecal incontinence may occur. There is increased fat excretion, which can be measured by determining the...
(fatty, offensive stool). Depletion of albumin
Albumin
Albumin refers generally to any protein that is water soluble, which is moderately soluble in concentrated salt solutions, and experiences heat denaturation. They are commonly found in blood plasma, and are unique to other blood proteins in that they are not glycosylated...
, a blood protein, causes swelling of the skin.
Darkening of the skin occurs in almost half; some also have skin nodules. Various eye problems, such as uveitis
Uveitis
Uveitis specifically refers to inflammation of the middle layer of the eye, termed the "uvea" but in common usage may refer to any inflammatory process involving the interior of the eye....
, may occur; this is typically associated with deteriorating vision and pain in the affected eye. Endocarditis
Endocarditis
Endocarditis is an inflammation of the inner layer of the heart, the endocardium. It usually involves the heart valves . Other structures that may be involved include the interventricular septum, the chordae tendineae, the mural endocardium, or even on intracardiac devices...
(infection of the heart valve
Heart valve
A heart valve normally allows blood flow in only one direction through the heart. The four valves commonly represented in a mammalian heart determine the pathway of blood flow through the heart...
) has been reported in a small number of cases, sometimes in people with no other symptoms of Whipple's disease; this is typically noticed as breathlessness and leg swelling due to fluid accumulation as the heart is unable to pump fluid through the body.
10–40% of people with Whipple's disease have problems related to involvement of the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
; the symptoms relate to the part of the brain that is affected. The most common problems are dementia
Dementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
, memory loss
Memory loss
Memory loss can be partial or total and it is normal when it comes with aging. Sudden memory loss is usually a result of brain trauma and it may be permanent or temporary. When it is caused by medical conditions such as Alzheimers, the memory loss is gradual and tends to be permanent.Brain trauma...
, confusion
Mental confusion
Confusion of a pathological degree usually refers to loss of orientation sometimes accompanied by disordered consciousness and often memory Confusion (from Latin confusĭo, -ōnis, noun of action from confundere "to pour together", also "to confuse") of a pathological degree usually refers to loss...
and decreased level of consciousness. Eye movement disturbances and myorhythmia (rapidly repetitive movements of the muscles) of the face, together referred to as oculomasticatory myorrhythmia, are highly characteristic
Pathognomonic
Pathognomonic is a term, often used in medicine, that means characteristic for a particular disease. A pathognomonic sign is a particular sign whose presence means that a particular disease is present beyond any doubt...
for Whipple's disease. Weakness and poor coordination of part of the body, headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
s, seizures, as well as a number of more uncommon neurological features, are present in some cases.
Mechanism
T. whipplei is one of the actinomycetes, and is a distant relative of Mycobacterium avium-intracellulare, and Mycobacterium paratuberculosis explaining in part why Whipple's disease is similar to the diseases caused by these bacteria. The disease is common in farmerFarmer
A farmer is a person engaged in agriculture, who raises living organisms for food or raw materials, generally including livestock husbandry and growing crops, such as produce and grain...
s and those exposed to soil and animals, suggesting that the infection is acquired from these sources.
Individuals who are most susceptible to the disease are those with decreased ability to perform intracellular degradation of ingested pathogens or particles, particularly in the macrophages. Several studies indicate that defective T-lymphocyte (particularly TH1 population) function may be an important predisposing factor for the disease. In particular circulating cells that are CD11b (also known as Integrin Alpha) expressive, are reduced in susceptible individuals. CD11b has a vital role in activation of macrophages to destroy intracellularly ingested T. whipplei bacteria.
Diagnosis
Common clinical signs and symptoms of Whipple's disease include weight loss, joint pain or arthritis, diarrhea, skin rashes, fever, and adenopathy. Weight loss and diarrhea are the most common symptoms that lead to identification of the process, but may be preceeded by chronic, unexplained, relapsing episodes of non-destructive seronegative arthritis, often of large joints.Diagnosis is made by biopsy
Biopsy
A biopsy is a medical test involving sampling of cells or tissues for examination. It is the medical removal of tissue from a living subject to determine the presence or extent of a disease. The tissue is generally examined under a microscope by a pathologist, and can also be analyzed chemically...
, usually by duodenal
Duodenum
The duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms anterior intestine or proximal intestine may be used instead of duodenum...
endoscopy
Endoscopy
Endoscopy means looking inside and typically refers to looking inside the body for medical reasons using an endoscope , an instrument used to examine the interior of a hollow organ or cavity of the body. Unlike most other medical imaging devices, endoscopes are inserted directly into the organ...
, which reveals presence of the organism as PAS
Periodic acid-Schiff
Periodic acid-Schiff is a staining method used to detect glycogen and other polysaccharides in tissues. The reaction of periodic acid oxidizes the diol functional groups in glucose and other sugars, creating aldehydes that react with the Schiff reagent to give a purple-magenta color...
-positive, non-acid-fast
Acid-fast
Acid-fastness is a physical property of certain bacteria, specifically their resistance to decolorization by acids during staining procedures.Acid-fast organisms are difficult to characterize using standard microbiological techniques Acid-fastness is a physical property of certain bacteria,...
macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
inclusions. Immunohistochemical staining for antibodies against T. whipplei has been used to detect the organism in a variety of tissues, and a PCR
Polymerase chain reaction
The polymerase chain reaction is a scientific technique in molecular biology to amplify a single or a few copies of a piece of DNA across several orders of magnitude, generating thousands to millions of copies of a particular DNA sequence....
-based assay is also available. PCR can be confirmatory if performed on blood, vitreous
Vitreous humour
The vitreous humour or vitreous humor is the clear gel that fills the space between the lens and the retina of the eyeball of humans and other vertebrates...
fluid, synovial
Synovium
Synovial membrane is the soft tissue found between the articular capsule and the joint cavity of synovial joints....
fluid, heart valves, or cerebrospinal fluid
Cerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...
. PCR of saliva, gastric or intestinal fluid, and stool specimens is highly sensitive, but not specific enough, indicating that healthy individuals can also harbor the causative bacterium without the manifestation of Whipple's disease, but that a negative PCR is most likely indicative of a healthy individual.
Endoscopy
Endoscopy
Endoscopy means looking inside and typically refers to looking inside the body for medical reasons using an endoscope , an instrument used to examine the interior of a hollow organ or cavity of the body. Unlike most other medical imaging devices, endoscopes are inserted directly into the organ...
of the duodenum
Duodenum
The duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms anterior intestine or proximal intestine may be used instead of duodenum...
and jejunum
Jejunum
The jejunum is the middle section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms middle intestine or mid-gut may be used instead of jejunum.The jejunum lies between the duodenum...
can reveal pale yellow shaggy mucosa with erythematous eroded patches in patients with classic intestinal Whipple's disease, and small bowel X-ray
X-ray
X-radiation is a form of electromagnetic radiation. X-rays have a wavelength in the range of 0.01 to 10 nanometers, corresponding to frequencies in the range 30 petahertz to 30 exahertz and energies in the range 120 eV to 120 keV. They are shorter in wavelength than UV rays and longer than gamma...
s may show some thickened folds. Other pathological findings may include enlarged mesentric lymph nodes, hypercellularity of lamina propria
Lamina propria
The lamina propria is a constituent of the moist linings known as mucous membranes or mucosa, which line various tubes in the body ....
with "foamy macrophages", and a concurrent decreased number of lymphocytes and plasma cells, per high power field view of the biopsy.
Treatment
Treatment is with penicillinPenicillin
Penicillin is a group of antibiotics derived from Penicillium fungi. They include penicillin G, procaine penicillin, benzathine penicillin, and penicillin V....
, ampicillin
Ampicillin
Ampicillin is a beta-lactam antibiotic that has been used extensively to treat bacterial infections since 1961. Until the introduction of ampicillin by the British company Beecham, penicillin therapies had only been effective against Gram-positive organisms such as staphylococci and streptococci...
, tetracycline or co-trimoxazole
Co-trimoxazole
Trimethoprim/sulfamethoxazole or co-trimoxazole is a sulfonamide antibiotic combination of trimethoprim and sulfamethoxazole, in the ratio of 1 to 5, used in the treatment of a variety of bacterial infections.The name co-trimoxazole is the British Approved Name, and has been marketed worldwide...
for one to two years. Any treatment lasting less than a year has an approximate relapse rate of 40%. Recent expert opinion is that Whipple's disease should be treated with doxycycline
Doxycycline
Doxycycline INN is a member of the tetracycline antibiotics group, and is commonly used to treat a variety of infections. Doxycycline is a semisynthetic tetracycline invented and clinically developed in the early 1960s by Pfizer Inc. and marketed under the brand name Vibramycin. Vibramycin...
with hydroxychloroquine
Hydroxychloroquine
Hydroxychloroquine is an antimalarial drug, sold under the trade names Plaquenil,Axemal, Dolquine, and Quensyl, also used to reduce inflammation in the treatment of rheumatoid arthritis and lupus...
for 12 to 18 months. Sulfonamides (sulfadiazine
Sulfadiazine
Sulfadiazine is a sulfonamide antibiotic.-Uses:It eliminates bacteria that cause infections by stopping the production of folic acid inside the bacterial cell, and is commonly used to treat urinary tract infections ....
or sulfamethoxazole
Sulfamethoxazole
Sulfamethoxazole is a sulfonamide bacteriostatic antibiotic.It is most often used as part of a synergistic combination with trimethoprim in a 5:1 ratio in co-trimoxazole , also known under trade names such as Bactrim, Septrin, or Septra; in Eastern Europe it is marketed as Biseptol...
) may be added for treatment of neurological symptoms.
Epidemiology
The disease is regarded as extremely rare, with an incidenceIncidence (epidemiology)
Incidence is a measure of the risk of developing some new condition within a specified period of time. Although sometimes loosely expressed simply as the number of new cases during some time period, it is better expressed as a proportion or a rate with a denominator.Incidence proportion is the...
(new number of cases per year) of one case per million people. The patients are predominantly male (86% in a survey of American patients), although in some countries the rate of women receiving a diagnosis of Whipple's disease has increased in recent years. It occurs predominantly in those of Caucasian ethnicity
Caucasian race
The term Caucasian race has been used to denote the general physical type of some or all of the populations of Europe, North Africa, the Horn of Africa, Western Asia , Central Asia and South Asia...
, suggesting a genetic predisposition
Genetic predisposition
A genetic predisposition is a genetic affectation which influences the phenotype of an individual organism within a species or population but by definition that phenotype can also be modified by the environmental conditions. In the rest of the population, conditions cannot have that effect...
in that population.
T. whipplei appears to be an environmental organism that is commonly present in the gasterointestinal tract but remains asymptomatic. Several lines of evidence suggest that some defect - inherited or acquired - in immunity is required for it to become pathogenic. The possible immunological defect may be specific for T. whipplei, since the disease is not associated with a substantially increased risk of other infections.
The disease is usually diagnosed in middle age
Middle age
Middle age is the period of age beyond young adulthood but before the onset of old age. Various attempts have been made to define this age, which is around the third quarter of the average life span of human beings....
(median 49 years). Studies from Germany
Germany
Germany , officially the Federal Republic of Germany , is a federal parliamentary republic in Europe. The country consists of 16 states while the capital and largest city is Berlin. Germany covers an area of 357,021 km2 and has a largely temperate seasonal climate...
have shown that age at diagnosis has been rising since the 1960s.
History
Whipple described the disease in 1907 in a paper in the now-defunct Bulletin of Johns Hopkins Hospital. The patient was a 36-year old medical missionary. Whipple referred to the disease as "intestinal lipodystrophy". It was long presumed to be an infectious disease, but the causative organism was only fully identified in 1992. In 2003, doctors from Johns Hopkins HospitalJohns Hopkins Hospital
The Johns Hopkins Hospital is the teaching hospital and biomedical research facility of Johns Hopkins University School of Medicine, located in Baltimore, Maryland . It was founded using money from a bequest by philanthropist Johns Hopkins...
, together with a French expert in the disease, applied novel diagnostic methods to stored tissue samples from Whipple's original patient, and demonstrated T. whipplei in these tissues.