Gout

Gout (also known as podagra when it involves the big toe[1]) is a medical

condition usually characterized by recurrent attacks of acute inflammatory arthritis—a
red, tender, hot, swollen joint. The metatarsal-phalangeal joint at the base of the big
toe is the most commonly affected, in around half of all cases. However, it may also
present as tophi, kidney stones, or urate nephropathy. It is caused by elevated levels
of uric acid in the blood which crystallize and are deposited in joints, tendons, and
surrounding tissues.
Diagnosis is confirmed clinically by the visualization of the characteristic crystals in joint
fluid. Treatment with non-steroidal anti-inflammatory drugs(NSAIDs), steroids,
or colchicine improves symptoms. Once the acute attack has subsided, levels of uric
acid are usually lowered via lifestyle changes, and in those with frequent
attacks allopurinol or probenicid provide long-term prevention.
Affecting around 1–2% of the Western population at some point in their lives, gout has
increased in frequency in recent decades. This is believed to be due to increasing risk
factors in the population such as metabolic syndrome, longer life expectancy, and
changes in diet. Gout was historically known as "the disease of kings" or "rich man's
disease".
Signs and symptoms
Gout can present in a number of ways, although the most usual is a recurrent attack of
acute inflammatory arthritis (a red, tender, hot, swollen joint).[2] Themetatarsal-
phalangeal joint at the base of the big toe is affected most often, accounting for half of
cases.[3] Other joints such as the heels, knees, wrists and fingers may also be affected.
[3]
 Joint pain usually begins over 2–4 hours and during the night.[3] The reason for onset
at night is due to the lower body temperature during this time.[1] Other symptoms that
may occur along with the joint pain include fatigue and a high fever.[3][1]
Long-standing elevated uric acid levels (hyperuricemia) may result in other
symptomatology including hard, non-painful deposits of uric acid crystal known astophi.
Extensive tophi may lead to chronic arthritis due to bone erosion.[4] Elevated levels of
uric acid may also lead to crystals precipitating in the kidneysresulting
in stone formation. This may result in urate nephropathy.[5]
Cause
Hyperuricemia is the underlying cause of gout. This can occur for a number of reasons
including dietary, genetic, or underexcretion of urate, the salts of uric acid.[2] Renal
underexcreation of uric acid is the primary cause of hyperuricaemia in about 90% of
cases while overproduction is the cause in less than 10%.[6] About 10% of people with
hyperuricemia develop gout at some point in their lifetime.[7] The risk however varies
depending on the degree of hyperuricemia. When levels are between 415 and
530 μmol/L (7 and 8.9 mg/dL) the risk is 0.5% per year; while in those with a level
greater than 535 μmol/L (9 mg/dL) the risk is 4.5% per year.[1]

1
Lifestyle
Dietary causes account for about 12% of gout,[2] and include a strong association with
the consumption of alcohol, fructose sweetened drinks, meat, and seafood.[4] Other
triggers include physical trauma and surgery.[6] Recent studies have found that dietary
factors once believed to be associated are in fact not, including the intake of purine rich
vegetables and total protein.[8][9] Coffeeconsumption, vitamin C, dairy products and
physical fitness appear to decrease the risk.[10][11][12] This is believed to be partly due to
their effect in reducing insulin resistance.[12]
Genetics
The occurrence of gout is partly genetic contributing to about 60% of variability in uric
acid level.[6] A few rare genetic disorders including familial juvenile hyperuricaemic
nephropathy, medullary cystic kidney disease, phosphoribosylpyrophosphate
synthetase superactivity, and hypoxanthine-guanine
phosphoribosyltransferase deficiency as seen in Lesch-Nyhan syndrome are
complicated by gout.[6]
Medical conditions
Gout frequently occurs in combination with other medical problems. Metabolic
syndrome, a combination of abdominal obesity, hypertension, insulin
resistance and abnormal lipid levels occurs in nearly 75% of cases.[3] Other conditions
which are commonly complicated by gout include: polycythaemia, lead poisoning, renal
failure, hemolytic anemia, psoriasis, and solid organ transplants.[6][13] A body mass
index greater than or equal to 35 increases a male's risk of gout three-fold.[9] Chronic
lead exposure and lead contaminated alcohol are risk factors for gout due to the harmful
effect of lead on kidney function.[14]
Medication
Diuretics have been associated with attacks of gout however a low dose
of hydrochlorothiazide (HCTZ) does not seem to increase the risk.[15] Other medicines
that have been associated include niacinand aspirin (acetylsalicylic acid).
[4]
 Cyclosporine is also associated with gout, particularly when used in combination
with hydrochlorothiazide[16] as are the immunosuppressive
drugs ciclosporin andtacrolimus.[6]
Pathophysiology
Gout is a disorder of purine metabolism[6] and occurs when its final metabolite uric
acid crystallizes in the form of monosodium urate, precipitating in joints, on tendons,
and in the surrounding tissues.[4] These crystals then trigger a
local immune mediated inflammatory reaction[4] with one of the key proteins in the
inflammatory cascade being interleukin 1β.[6] An evolutionary loss of uricase, which
breaks down uric acid, in humans and higher primates is what has made this condition
so common.[6]
The triggers for precipitation of uric acid are not well understood. While it may crystallize
at normal levels, it is more likely to do so as levels increase.[4][17]Other factors believed to
be important in triggering an acute episode of arthritis include: cool temperatures, rapid

2
changes in uric acid levels, acidosis[18][19], articular hydration, and extracellular
matrix proteins such as proteoglycans, collagens, and chondroitin sulphate.[6] The
increased precipitation at low temperatures partly explains why the joints in the feet are
most commonly affected.[2] Rapid changes in uric acid may occur due to a number of
factors including: trauma, surgery, chemotherapy, diuretics, and stopping or
starting allopurinol.[1]
Diagnosis
Gout may be diagnosed and treated without further investigations in someone with
hyperuricemia and the classic podagra. Synovial fluid analysis should be done however
if the diagnosis is in doubt.[1]X-rays while useful for identifying chronic gout have little
utility in acute attacks.[6]
Synovial fluid
Spiked rods of uric acid (MSU) crystals photographed under a microscope withpolarized
light from a synovial fluid sample. Formation of uric acid crystals in the joints are
associated with gout.
A definitive diagnosis of gout is based upon the identification of monosodium urate
(MSU) crystals in synovial fluid or a tophus.[3] All synovial fluid samples obtained from
an undiagnosed inflamed joints should be examined for these crystals.
[6]
 Under polarized light microscopy they have a needle-like morphology and strong
negative birefringence. This test is difficult to perform and often requires a trained
observer.[20] The fluid must also be examined relatively quickly after aspiration as
temperature and PH affect their solubility.[6]
Blood tests
Hyperuricemia is a classic feature of gout, however gout occurs nearly half of the time
without hyperuricemia and most people with raised uric acid levels never develop gout.
[3][21]
 Thus the diagnostic utility of measuring a uric acid level is limited.[3] Hyperuricemia
is defined as a plasma urate level greater than 420 μmol/L (7.0 mg/dL) in males and
360 μmol/L (6.0 mg/dL) in females.[22] Other blood tests commonly performed are white
blood cell count, electrolytes,renal function, and erythrocyte sedimentation rate (ESR).
However both the white blood cells and ESR may be elevated due to gout in the
absence of infection.[23][24] A white blood cell count as high as 40×109/L (40,000/mm3)
has been documented.[1]
Differential diagnosis
The most important differential diagnosis in gout is septic arthritis.[3][6] This should be
considered in those with signs of infection or those who do not improve with treatment.
[3]
 To help with diagnosis a synovial fluid gram stain and culture may be performed.
[3]
 Other conditions which present similarly includepseudogout and rheumatoid arthritis.
[3]
 Gouty tophi, in particular when not located in a joint, can be mistaken for basal cell
carcinoma,[25] or other neoplasms.[26]

3
Prevention
Both lifestyle changes and medication can decrease uric acid levels. Dietary and
lifestyle choices that are effective include reducing intake of food high in purines such
as meat and seafood, consuming adequate vitamin C,
limiting alcohol and fructose consumption and avoiding obesity.[2] A low-calorie diet in
obese men decreased uric acid levels by 100 µmol/L (1.7 mg/dL).[15] Vitamin C intake of
1,500 mg per day decreases the risk of gout by 45% compared to 250 mg per day.
[27]
 Coffee but not tea consumption is associated with a lower risk of gout.[28] Gout may
be secondary to sleep apneavia the release of purines from oxygen-starved cells.
Treatment of apnea can lessen the occurrence of attacks.[29]
Treatment
The initial aim of treatment is to settle the symptoms of an acute attack.[30] Repeated
attacks can be prevented by different drugs used to reduce the serum uric acid levels.
[30]
 Ice applied for 20 to 30 minutes several times a day decreases pain.[2][31] Options for
acute treatment include nonsteroidal anti-inflammatory
drugs (NSAIDs), colchicine and steroids[2] while options for prevention
includeallopurinol, probenecid and febuxostat. Lowering uric acid levels can cure the
disease.[6] Treatment of co-morbidities is also important.[6]
NSAIDs
NSAIDs are the usual first-line treatment for gout, and no specific agent is significantly
more or less effective than any other.[2] Improvement may be seen within 4 hours and
treatment is recommended for 1-2 weeks.[2][6] They however are not recommended in
those with certain other health problems such as gastrointestinal bleeding, renal failure,
or heart failure.[32] While indomethacin has historically been the most commonly used
NSAID, an alternative like ibuprofen may be preferred due to its better side-effect profile
in the absence of superior effectiveness.[15] For those at risk of gastric side effects from
NSAIDs, an additional proton pump inhibitor may be given.[33]
Colchicine
Colchicine is an alternative for those unable to tolerate NSAIDs.[2] Its side-effects
(primarily gastrointestinal upset) limit its usage.[34][35] Gastrointestinal upset, however,
depends on the dose and the risk can be decreased by using smaller yet still effective
doses.[15] Colchicine may interact with other commonly prescribed drugs such
as atorvastatin and erythromycin among others.[35]
Steroids
Glucocorticoids have been found to be as effective as NSAIDs[36] and may be used if
contraindications exist for NSAIDs.[2] They also lead to improvement when injected into
the joint, however the risk of a joint infection must be excluded as they worsen this
condition.[2]
Prophylaxis
A number of medications are useful for preventing further episodes of gout,
including allopurinol, probenecid, and febuxostat. They are not usually commenced until

4
one to two weeks after an acute attack has resolved, due to theoretical concerns of
worsening the attack,[2] and are often used in combination with either an NSAID or
colchicine for the first 3-6 months.[6] They are not recommended until a person has
suffered two attacks of gout,[2] unless destructive joint changes, tophi, or urate
nephropathy exist,[5] as it is not until this point that medications have been found to be
cost effective.[2]Urate lowering measures should be increased until serum uric acid
levels are below 300-360 µmol/L (5.0-6.0 mg/dL) and are continued indefinitely.[2][6] If
these medications are being used chronically at the time of an attack, it is
recommended that they be continued.[3]
Allopurinol blocks uric acid production, and is the most commonly used hypourecemic
agent.[2] Long term therapy is safe and well tolerated, and can be used in people with
renal impairment or urate stones, although hypersensitivity occurs in a small number of
individuals.[2] Probenecid is effective for treating hyperuricemia but has been found to be
less effective than allopurinol.[2] Febuxostat, a non-purine inhibitor of xanthine oxidase,
is now available as an alternative to allopurinol. It is approved in both Europe and the
United States.[37][38]
Prognosis
Without treatment an acute attack of gout will usually resolve in 5 to 7 days however
60% of people will have a second attack within one year.[1] Those with gout are at
increased risk of hypertension,diabetes mellitus, metabolic syndrome, renal
and cardiovascular disease and thus at increased risk of death.[6][39] This may be partly
due to its association with insulin resistance, obesity but some of the increased risk
appears to be independent.[39]
Without treatment episodes of acute gout may develop into chronic gout with
destruction of joint surfaces, joint deformity, and painless tophi.[6] These tophi occur in
30% of those who are untreated for 5 years often in the helix of the ear, over
the olecranon processes, or on the Achilles tendons.[6] With aggressive treatment they
may dissolve. Kidney stones also frequently complicate gout affecting between 10-40%
of people and occur due to the low urine pH promoting precipitation of uric acid.[6] Other
forms of chronic renal dysfunction may occur.[6]
Epidemiology
Gout affects around 1–2% of the Western population at some point in their lifetime and
is becoming more common.[2][6] Rates of gout have approximately doubled between
1990 and 2010.[4] This rise is believed to be due to increasing life expectancy, changes
in diet, and an increase in diseases associated with gout such as metabolic
syndrome and high blood pressure.[9] A number of factors have been found to influence
rates of gout including: age, race, and the season of the year. In men over the age of 30
and women over the age of 50 prevalence is 2%.[32]
In the United States, gout is twice as likely in African American males as it is in
European-Americans.[40] Rates are high among the peoples of the Pacific Islands and
the Māori of New Zealand, but rare in Australian aborigines despite a higher mean
concentration of serum uric acid in the latter group.[41] It has become common in China,
Polynesia, and urban sub-Saharan Africa.[6] Some studies have found that attacks of

5
gout occur more frequently in the spring. This has been attributed to seasonal changes
in diet, alcohol consumption, physical activity, and temperature.[42]
History
The word gout was initially used by Randolphus of Bocking, around 1200 AD. It is
derived from the Latin word gutta, meaning "a drop" (of liquid).[43]
Gout has however been known since antiquity. Historically it has been referred to as
"the king of diseases and the disease of kings"[6][44] or "rich man's disease".[45] The first
documentation of the disease is from Egypt in 2,600 BC in a description of arthritis of
the big toe. The Greek physician Hippocratesaround 400 BC commented on it in
his Aphorisms noting its absence in eunuchs and premenopausal women.[43][46] Aulus
Cornelius Celsus (30 AD) described the linkage with alcohol, later onset in women, and
associated kidney problems:
Again thick urine, the sediment from which is white, indicates that pain and disease are
to be apprehended in the region of joints or viscera... Joint troubles in the hands and
feet are very frequent and persistent, such as occur in cases of podagra and cheiragra.
These seldom attack eunuchs or boys before coition with a woman, or women except
those in whom the menses have become suppressed... some have obtained lifelong
security by refraining from wine, mead and venery.[47]
While in 1683 Thomas Sydenham, an English physician, described it occurrence in the
early hours of the morning, and its predilection for older males:
Gouty patients are, generally, either old men, or men who have so worn themselves out
in youth as to have brought on a premature old age - of such dissolute habits none
being more common than the premature and excessive indulgence in venery, and the
like exhausting passions. The victim goes to bed and sleeps in good health. About two
o'clock in the morning he is awakened by a severe pain in the great toe; more rarely in
the heel, ankle or instep. The pain is like that of a dislocation, and yet parts feel as if
cold water were poured over them. Then follows chills and shivers, and a little fever...
The night is passed in torture, sleeplessness, turning the part affected, and perpetual
change of posture; the tossing about of body being as incessant as the pain of the
tortured joint, and being worse as the fit comes on.[48]
The Dutch scientist Antonie van Leeuwenhoek first described the microscopic
appearance of urate crystals in 1679.[43] In 1848 English physician Alfred Baring
Garrod realized that this excess uric acid in the blood was the cause of gout.[49]
Research
A number of new medications are under study for treating gout
including: anakinra, canakinumab, and rilonacept.[50] A recombinant uricase enzyme
(rasburicase) is available however its use is limited as it triggers
an autoimmune response. Less antigenic versions are in development.[1] Pegloticase is
a medication being investigated to determine if it is useful in the prevention of acute
gouty attacks. Proper trials as of 2010 however have not yet been done.[51]

6
In other animals
Gout is rare in most other animals due to their ability to produce
the enzyme uricase which breaks down uric acid.[52] Humans and the great apes have
lost this ability and thus gout is common.[52][1]The Tyrannosaurus rex specimen known as
"Sue" however is believed to have suffered from gout.[53]
What is gout? What is hyperuricemia?
Gout is a disease that results from an overload of uric acid in the body. This overload of
uric acid leads to the formation of tiny crystals of urate that deposit in tissues of the
body, especially the joints. When crystals form in the joints, it causes recurring attacks
of joint inflammation (arthritis). Gout is considered a chronic and progressive disease.
Chronic gout can also lead to deposits of hard lumps of uric acid in the tissues,
particularly in and around the joints and may cause joint destruction, decreased kidney
function, and kidney stones.
Gout has the unique distinction of being one of the most frequently recorded medical
illnesses throughout history. It is often related to an inherited abnormality in the body's
ability to process uric acid. Uric acid is a breakdown product of purines that are part of
many foods we eat. An abnormality in handling uric acid can cause attacks of painful
arthritis (gout attack), kidney stones, and blockage of the kidney-filtering tubules with
uric acid crystals, leading to kidney failure. On the other hand, some people may only
develop elevated blood uric acid levels (hyperuricemia) without having manifestations of
gout, such as arthritis or kidney problems. The state of elevated levels of uric acid in the
blood without symptoms is referred to as asymptomatic hyperuricemia. Asymptomatic
hyperuricemia is considered a precursor state to the development of gout. The
term goutrefers the disease that is caused by an overload of uric acid in the body,
resulting in painful arthritic attacks and deposits of lumps of uric acid crystals in body
tissues.
Gouty arthritis is typically an extremely painful attack with a rapid onset of joint
inflammation. The joint inflammation is precipitated by deposits of uric acid crystals in
the joint fluid (synovial fluid) and joint lining (synovial lining). Intense joint inflammation
occurs as the immune system reacts, causing white blood cells to engulf the uric acid
crystals and chemical messengers of inflammation to be released, leading to pain, heat,
and redness of the joint tissues. As gout progresses, the attacks of gouty arthritis
typically occur more frequently and often in additional joints.
Who is affected by gout?
Approximately 5 million people in the United States suffer from gout. (Did you know that
none other than Benjamin Franklin had terribly painful gouty arthritis?) Gout is nine
times more common in men than in women. It predominantly attacks males
after puberty, with a peak age of 75. In women, gout attacks usually occur
after menopause.

7
While an elevated blood level of uric acid may indicate an increased risk of gout, the
relationship between hyperuricemia and gout is unclear. Many patients with
hyperuricemia do not develop gout (asymptomatic hyperuricemia), while some patients
with repeated gout attacks have normal or low blood uric acid levels. In fact, the blood
level of uric acid often lowers during an acute attack of gout. Among the male
population in the United States, approximately 10% have hyperuricemia. However, only
a small portion of those with hyperuricemia will actually develop gout. What are gout
causes and risk factors?
In addition to an inherited abnormality in handling uric acid, other risk factors for
developing gout include obesity, excessiveweight gain (especially in youth), moderate to
heavy alcohol intake, high blood pressure, and abnormal kidney function. Certain drugs,
such as thiazide diuretics (hydrochlorothiazide [Dyazide]), low-
doseaspirin, niacin, cyclosporine, tuberculosismedications
(pyrazinamide and ethambutol), and others can also cause elevated uric acid levels in
the blood and lead to gout. Furthermore, certain diseases lead to excessive production
of uric acid in the body. Examples of these diseases includeleukemias, lymphomas,
and hemoglobindisorders.
Interestingly, a recent study demonstrated an increased prevalence of abnormally low
thyroid hormone levels (hypothyroidism) in patients with gout.
In patients at risk of developing gout, certain conditions can precipitate acute attacks of
gout. These conditions include dehydration, injury to the joint, fever, excessive eating,
heavy alcohol intake, and recent surgery. Gout attacks triggered by recent surgery are
probably related to changes in the body-fluid balance as patients temporarily
discontinue normal oral fluid intake in preparation for and after their operation.
What are gout symptoms and signs?
The small joint at the base of the big toe is the most common site of an acute gout
attack of arthritis. An acute attack of gouty arthritis at the base of the big toe is medically
referred to as podagra. Other joints that are commonly affected include the ankles,
knees, wrists, fingers, and elbows. Acute gout attacks are characterized by a rapid
onset of pain in the affected joint followed by warmth, swelling, reddish discoloration,
and marked tenderness. Tenderness can be intense so that even a blanket touching the
skin over the affected joint can be unbearable. Patients can develop fever with the acute
gout attacks. These painful attacks usually subside in hours to days, with or without
medication. In rare instances, an attack can last for weeks. Most patients with gout will
experience repeated attacks of arthritis over the years.
Uric acid crystals can deposit in tiny fluid-filled sacs (bursae) around the joints. These
urate crystals can incite inflammation in the bursae, leading to pain and swelling around
the joints (a condition called bursitis). In rare instances, gout leads to a more chronic
type of joint inflammation that mimics rheumatoid arthritis.In chronic (tophaceous) gout,
nodular masses of uric acid crystals (tophi) deposit in different soft-tissue areas of the
body. Even though they are most commonly found as hard nodules around the fingers,
at the tips of the elbows, in the ears, and around the big toe, tophi nodules can appear
anywhere in the body. They have been reported in unexpected areas such as in the

8
vocal cords or (rarely) even around the spinal cord. When tophi appear in the tissues,
the gout condition is felt to represent a substantial overload of uric acid within the body.
How is gouty arthritis diagnosed?
Gout is suspected when a patient reports a history of attacks of painful arthritis,
particularly at the base of the toes. Ankles and knees are the next most commonly
involved joints in gout. Gout usually attacks one joint at a time, while other arthritis
conditions, such as systemic lupus and rheumatoid arthritis, usually attack multiple
joints simultaneously.
The most reliable test for gout is finding uric acid crystals in a sample of the joint fluid
obtained by joint aspiration (arthrocentesis). Arthrocentesis is a common office
procedure performed under local anesthesia. Using sterile technique, fluid is withdrawn
(aspirated) from the inflamed joint using a syringe and needle. The joint fluid is then
analyzed for uric acid crystals and for infection. Shiny, needle-like uric acid crystals are
best viewed with a special polarizing microscope. The diagnosis of gout can also be
made by finding these urate crystals from material aspirated from tophi nodules and
bursitis fluid. Although many doctors can do the procedure, rheumatologists are
specialists who are particularly trained in this evaluation.
Sometimes patients with a classic history and symptoms of gout can be successfully
treated and presumed to have gout without undergoing arthrocentesis. However,
establishing a firm diagnosis is still preferable since other conditions can mimic gout.
These include another crystal-induced arthritis called pseudogout, psoriatic arthritis,
rheumatoid arthritis, and even infection in the joint.
X-rays can sometimes be helpful and may show tophi-crystal deposits and bone
damage as a result of repeated bouts of inflammation. X-rays can also be helpful for
monitoring the effects of chronic gout on the joints. What is the treatment for gout?
There are two key concepts essential to treating gout. First, it is critical to stop the acute
inflammation of joints affected by gouty arthritis. Second, it is important to address the
long-term management of the disease in order to prevent future gouty arthritis attacks
and shrink gouty tophi crystal deposits in the tissues.
The treatment of an acute attack of gouty arthritis involves measures and medications
that reduce inflammation. Preventing future acute gout attacks is equally as important
as treating the acute arthritis. Prevention of acute gout involves maintaining adequate
fluid intake, weight reduction, dietary changes, reduction in alcohol consumption, and
medications to lower the uric acid level in the blood (reduce hyperuricemia).
Maintaining adequate fluid intake helps prevent acute gout attacks. Adequate fluid
intake also decreases the risk of kidney stone formation in patients with gout. Alcohol is
known to have diuretic effects that can contribute to dehydration and precipitate acute
gout attacks. Alcohol can also affect uric acid metabolism to cause hyperuricemia.
Therefore, alcohol has two major effects that worsen gout by impeding (slowing down)
the excretion of uric acid from the kidneys as well as by causing dehydration, both of
which contribute to the precipitation of uric acid crystals in the joints.

9
Foods to eat and foods to avoid with gout
Dietary changes can help reduce uric acid levels in the blood. Since purine chemicals
are converted by the body into uric acid, purine-rich foods are avoided. Examples of
foods rich in purines include shellfish and organ meats such as liver, brains, kidneys,
and sweetbreads. Researchers have reported, in general, that meat or seafood
consumption increases the risk of gout attacks, while dairy food consumption seemed to
reduce the risk. Protein intake or purine-rich vegetable consumption was not associated
with an increased risk of gout. Total alcohol intake was strongly associated with an
increased risk of gout (beer and liquor were particularly strong factors). Fructose from
the corn syrup in soft drinks also increases the risk of gout.
Weight reduction can be helpful in lowering the risk of recurrent attacks of gout. This is
best accomplished by reducing dietary fat and calorie intake, combined with a
regularaerobic exercise program.
Gout medications
There are three aspects to the treatment of gout with medications. First, pain relievers
such as acetaminophen (Tylenol) or other more potent analgesics are used to manage
pain. Secondly, anti-inflammatory agents such as nonsteroidal anti-inflammatory
drugs (NSAIDS), colchicine, and corticosteroids are used to decrease joint
inflammation. Finally, medications are considered for managing the chronic underlying
metabolic derangement that causes hyperuricemia and gout. This means treating the
elevated levels of uric acid in the blood with medications that reduce these levels.
NSAIDS such as indomethacin (Indocin) andnaproxen (Naprosyn) are effective anti-
inflammatory medications for acute gout. These medications are tapered after the
arthritis resolves. Common side effects of NSAIDS include irritation of the
gastrointestinal system, ulceration of the stomach and intestines, and even intestinal
bleeding. People who have a history ofallergy to aspirin or nasal polyps should avoid
NSAIDS because of the risk of an intense allergic (anaphylactic) reaction. Colchicine for
acute gout is administered by mouth to reduce inflammation as well as to prevent gouty
arthritis attacks while correcting hyperuricemia with medications such
asallopurinol (Zyloprim) or febuxostat (Uloric). For acute attacks, it is given hourly or
every two hours until there is significant improvement in pain or the patient develops
gastrointestinal side effects such as severe diarrhea. For prevention, it is given once or
twice daily. Other common side effects of colchicine include nausea and vomiting.
Corticosteroids such as prednisone, given in short courses, are powerful anti-
inflammatory agents for treating acute gout. They can be administered orally or injected
directly into the inflamed joint. Corticosteroids can be prescribed to patients who have
accompanying kidney, liver, or gastrointestinal problems. Long-term chronic use of
corticosteroids is discouraged because of serious long-term side effects.
In addition to medications for acute gout attacks, other drugs can be taken over
prolonged periods to lower blood uric acid levels. Lowering blood uric acid levels
reduces the risk of recurrent attacks of arthritis, kidney stones, and kidney disease, and
also slowly dissolves hard tophi deposits. Medicines used to lower blood uric acid level
work either by increasing the kidney's excretion of uric acid or by decreasing the body's
production of uric acid from the purines in foods. These medicines are generally not
10
started until after the inflammation from acute gouty arthritis has subsided because they
can worsen the attack. If they are already being taken prior to the attack, they are
continued and only adjusted after the attack has resolved.
Probenecid (Benemid) and sulfinpyrazone (Anturane) are medications that are
commonly used to decrease uric acid blood levels by increasing the excretion of uric
acid into the urine. Since these drugs can, in rare instances, cause kidney stones, they
should be avoided by those patients with a history of kidney stones. These medications
should be taken with plenty of fluid so as to promote the rapid passage of uric acid out
of the urinary system in order to prevent kidney stone formation.
Allopurinol  lowers the blood uric acid level by preventing uric acid production. It actually
blocks the metabolic conversion from purines in foods to uric acid. This medication is
used with caution in patients with poor kidney function, as they are at a particular risk of
developing side effects, including severe rash and liver damage.
Febuxostat was approved by the U.S. Food and Drug Administration (FDA) for the
chronic management of hyperuricemia from gout in 2009. Febuxostat has been shown
to be more effective than allopurinol in preventing acute attacks of gouty arthritis and is
effective in shrinking tophi deposits of uric acid in the tissues such as the fingers,
elbows, and ears. Because febuxostat is not significantly metabolized by the kidneys, it
may have advantages over allopurinol in patients with underlying kidney disease. While
taking febuxostat, patients have uric acid and liver function blood tests monitored
regularly.
Again, uric acid-lowering medications such as allopurinol and febuxostat are generally
not started in patients who are having acute attacks of gout. These medications, when
started during an acute attack, actually can worsen the acute inflammation. Therefore,
uric acid-lowering drugs are usually instituted only after complete resolution of the acute
arthritis attacks, but if patients are already taking these medications, they are
maintained at the same doses during the acute attacks. In some patients, increasing the
dose of uric acid-lowering medications can precipitate gout attacks. In these patients,
low doses of colchicine can be given to prevent the precipitation of acute gout.
It is essential to monitor the blood level of uric acid regularly once uric acid-lowering
medications are used for optimal maintenance, as the uric acid metabolism can change
over time.
Home remedies which can alleviate the symptoms of acute gout include resting and
elevating the inflamed joint. Ice-pack applications can be helpful to reduce pain and
decrease inflammation. Patients should avoid aspirin-containing medications, when
possible, because aspirin prevents kidney excretion of uric acid
What does the future hold for patients with gout and hyperuricemia?
Active research is ongoing in a variety of fields related to gout and hyperuricemia. The
management of the chronic gouty disease and its relationship to improving blood
pressure and kidney function is becoming better defined.

11
 Scientists recently reported that high animal protein intake slightly increased the risk for
gout. Others found that dietary calcium intake may protect patients from getting gout
attacks. Vitamin C may also lower blood uric acid levels.
New medications to increase the elimination of uric acid in the urine (such as
benzbromarone) and lower uric acid blood levels (such as PEG-uricase) are being
evaluated in clinical trials. Researchers are also reporting on experimental drugs that
can affect the chemical messengers involved in gouty inflammation.
The optimal regimens for the treatment of acute gout attacks and chronic gout
conditions still require further long-term studies. Research scientists will continue to
develop less toxic and more effective medications to battle this "scourge of the ages."
Gout and Hyperuricemia At A Glance

 Painful gouty arthritis is caused by uric acid crystal deposits in joint tissue.
 Gout is a chronic, progressive disease.
 The tendency to develop gout and elevated blood uric acid level (hyperuricemia)
is often inherited.
 Gout and hyperuricemia are aggravated by obesity, weight gain, alcohol intake,
high blood pressure, fructose in corn syrup found in soft drinks, abnormal kidney
function, and certain medications.
 Gouty arthritis attacks can be precipitated by dehydration, injury, fever, heavy
eating, heavy alcohol consumption, and recent trauma or surgery.
 The most reliable diagnostic test for gout is the identification of crystals in joints,
body fluids, and tissues.
 The treatment of an attack of gouty arthritis is different than the treatment of
hyperuricemia. There are two key concepts essential to treating gout. First, it is critical
to stop acute inflammation of joints affected by gouty arthritis. Second, it is important
to address the long-term management of the gout disease in order to prevent future
gout arthritis attacks and shrink gouty tophi crystal deposits.

1. Typically, gout patients are about 95% men, 5% women. An initial attack of gout (50%
of initial attacks involve the big toe) may last several days and disappear even if untreated.
Subsequent attacks may not occur for weeks, months, years, or not at all. In severe cases,
repeated attacks occurring over a long period may cause damage to the joints and loss of
mobility. The big toe is eventually affected in 90% of cases. Knowing how to treat gout is
important for preventing attacks.
2. Gout is often related to an inherited abnormality in the body to process uric acid. Uric
acid levels can become elevated by eating a lot of purine-rich foods such as meats, by the
overproduction of uric acid by the body, or if the kidneys do not eliminate excess uric acid.
3. Treatment goals include terminating acute gout attacks, rapid and safe relief of pain and
inflammation, preventing future attacks, and avoiding complications (formation of tophi,
kidney stones, and joint destruction).

12
4. Though gout treatment is most often treated successfully and without complications, it
becomes more of a challenge if other conditions exist along with gout or if there is poor
patient compliance to recommended lifestyle changes or a medication regimen.

5. Dietary alterations are recommended, such as avoiding a purine-rich diet. Other

preventive measures include maintaining adequate fluid intake, weight reduction, reduction
in alcohol consumption, and medications to reduce hyperuricemia.
6. Medications for gout include:
 non-steroidal anti-inflammatory drugs (NSAIDS)
 colchicine
 corticosteroids
 adrenocorticotropic hormone (ACTH)
 allopurinol
 probenecid
 sulfinpyrazone
. NSAIDS, specifically indomethacin, are commonly the first medication prescribed to
treat acute gout. Other NSAIDS may be equally effective. NSAIDS are initially prescribed
at maximum dosage and reduced as symptoms subside. The medication should be continued
until pain and inflammation are non-existent for at least 48 hours. NSAIDS which are COX-
2 inhibitors may be useful for patients with gastrointestinal concerns but their use for acute
gout has not been specifically reported yet.
. Colchicine is used to treat acute flares of gouty arthritis and to prevent recurrent acute
attacks. Colchicine does not cure gout or take the place of other medicines that lower the
amount of uric acid in the body. It prevents or relieves gout attacks by reducing
inflammation. Colchicine may be used in 2 ways: some people take small amounts of it
regularly for months or years, while others take large amounts of colchicine during a short
period of time (several hours).
. Corticosteroids or adrenocorticotropic hormone can be used for patients who cannot take
NSAIDS or colchicine. Patients with acute gout typically receive daily doses of prednisone
(20-40mg) or its equivalent for 3 to 4 days, then it is tapered gradually over one to two
weeks. ACTH is administered as an intramuscular injection (an initial dose and subsequent
doses over several days as needed).
. Allopurinol (brand name - Zyloprim) is prescribed for chronic gout or gouty arthritis and
works by affecting the system that manufactures uric acid in the body. It is used to prevent
gout attacks, not to treat them once they occur.
. Probenecid (brand names - Benemid, Probalan) is prescribed for chronic gout and gouty
arthritis. It is used to prevent attacks related to gout, not treat them once they occur. It acts
on the kidneys to help the body eliminate uric acid. Probenecid is known as a uricosuric
agent.
. ColBenemid (other brand names are Col-Probenecid and Proben-C) is a gout medication
that contains Probenecid, which is a uricosuric agent, and Colchicine, which has anti-gout
properties.
. Sulfinpyrazone (brand name - Anturane) is also known as a uricosuric agent and is used
to treat gouty arthritis. It works by lowering the amount of uric acid in your blood,
preventing gout attacks. The drug helps prevent attacks but is not used to treat an attack
once it has started. Sulfinpyrazone is not currently available in the U.S.
13
 . Losartan, (brand names - Cozaar and Hyzaar), is not specifically a gout medication but is
an angiotensin II receptor antagonist, antihypertensive drug that may help control uric acid
levels. Fenofibrate, (brand name - Tricor), is not a specific gout medication but it a lipid-
lowering drug that may help uric acid levels.
. Analgesic painkillers are also used to relieve the intense pain of gout. All of the
aforementioned drugs can be used in combination, to control symptoms, prevent future
attacks, and maintain healthy uric acid levels.

Crohn's disease
Crohn's disease, also known as granulomatous enteritis and colitis, is an inflammatory
disease of the intestines that may affect any part of thegastrointestinal tract from mouth to anus,
causing a wide variety of symptoms. It primarily causes abdominal pain, diarrhea (which may be
bloody if inflammation is at its worst), vomiting, or weight loss,[1][2][3] but may also cause
complications outside of the gastrointestinal tract such as skin rashes,arthritis, inflammation of
the eye, tiredness, and lack of concentration.[1]
Crohn's disease is thought to be an autoimmune disease, in which the body's immune
system attacks the gastrointestinal tract, causing inflammation; it is classified as a type
of inflammatory bowel disease. There has been evidence of a genetic link to Crohn's disease,
putting individuals with siblings afflicted with the disease at higher risk.[4] It is understood to have
a large environmental component as evidenced by the higher number of cases in western
industrialized nations. Males and females are equally affected. Smokers are three times more
likely to develop Crohn's disease.[5] Crohn's disease affects between 400,000 and 600,000
people in North America.[6] Prevalence estimates for Northern Europe have ranged from 27–48
per 100,000.[7] Crohn's disease tends to present initially in the teens and twenties, with another
peak incidence in the fifties to seventies, although the disease can occur at any age.[1][8]
There is no known pharmaceutical or surgical cure for Crohn's disease.[9] Treatment options are
restricted to controlling symptoms, maintaining remission, and preventing relapse.
The disease was named for American gastroenterologist Burrill Bernard Crohn, who in 1932,
along with two colleagues, described a series of patients with inflammation of the terminal ileum,
the area most commonly affected by the illness.[10] For this reason, the disease has also been
called regional ileitis[10] or regional enteritis. The condition, however, has been independently
identified by others in the literature prior, most notably in 1904 by Polish surgeon Antoni
Leśniowski for whom the condition is additionally named (Leśniowski-Crohn's disease) in the
Polish literature.
Classification

Crohn's disease is one type of inflammatory bowel disease (IBD). It affects the gastrointestinal
tract and can be categorized by the area of the gastrointestinal tract which it
affects. Ileocolic Crohn's disease, which affects both the ileum (the last part of the small
intestine that connects to the large intestine) and the large intestine, accounts for fifty percent of
cases. Crohn's ileitis, affecting the ileum only, accounts for thirty percent of cases, and Crohn's
colitis, affecting the large intestine, accounts for the remaining twenty percent of cases and may
be particularly difficult to distinguish from ulcerative colitis. Gastroduodenal Crohn's disease
causes inflammation in the stomach and first part of the small intestine, called the duodenum.
Jejunoileitis causes spotty patches of inflammation in the top half of the small intestine, called
the jejunum (MedlinePlus 2010). The disease can attack any part of the digestive tract, from
mouth to anus. However, individuals affected by the disease rarely fall outside these three

14
classifications, being affected in other parts of the gastrointestinal tract such as
the stomach and esophagus.[1]

Crohn's disease may also be categorized by the behavior of disease as it progresses. This was
formalized in the Vienna classification of Crohn's disease.[11]There are three categories of
disease presentation in Crohn's disease: stricturing, penetrating, and inflammatory. Stricturing
disease causes narrowing of the bowel that may lead to bowel obstruction or changes in the
caliber of the feces. Penetrating disease creates abnormal passageways (fistulae) between the
bowel and other structures such as the skin. Inflammatory disease (or non-stricturing, non-
penetrating disease) causes inflammation without causing strictures or fistulae.[11][12]
Gastrointestinal symptoms
Many people with Crohn's disease have symptoms for years prior to the diagnosis.[13] The usual
onset is between 15 and 30 years of age but can occur at any age.[14] Because of the 'patchy'
nature of the gastrointestinal disease and the depth of tissue involvement, initial symptoms can
be more vague than with ulcerative colitis. People with Crohn's disease will go through periods
of flare-ups and remission. [15]
Abdominal pain may be the initial symptom of Crohn's disease. It is often accompanied by
diarrhea, especially in those who have had surgery. The diarrhea may or may not be bloody.
People who have had surgery or multiple surgeries often end up with short bowel syndrome of
the gastrointestinal tract. The nature of the diarrhea in Crohn's disease depends on the part of
the small intestine or colon that is involved. Ileitis typically results in large-volume watery feces.
Colitis may result in a smaller volume of feces of higher frequency. Fecal consistency may
range from solid to watery. In severe cases, an individual may have more than 20 bowel
movements per day and may need to awaken at night to defecate.[1][8][16][17] Visible bleeding in the
feces is less common in Crohn's disease than in ulcerative colitis, but may be seen in the
setting of Crohn's colitis.[1] Bloody bowel movements are typically intermittent, and may be bright
or dark red in colour. In the setting of severe Crohn's colitis, bleeding may be copious.
[8]
 Flatulence and bloating may also add to the intestinal discomfort.[8]
Symptoms caused by intestinal stenosis are also common in Crohn's disease. Abdominal pain
is often most severe in areas of the bowel with stenoses. In the setting of severe stenosis,
vomiting and nausea may indicate the beginnings of small bowel obstruction.[8] Although the
association is greater in the context of ulcerative colitis, Crohn's disease may also be associated
with primary sclerosing cholangitis, a type of inflammation of the bile ducts.[18]
Perianal discomfort may also be prominent in Crohn's disease. Itchiness or pain around
the anus may be suggestive of inflammation, fistulization or abscess around the anal
area[1] or anal fissure. Perianal skin tags are also common in Crohn's disease.[19] Fecal
incontinence may accompany peri-anal Crohn's disease. At the opposite end of the
gastrointestinal tract, the mouth may be affected by non-healing sores (aphthous ulcers).
Rarely, the esophagus, and stomach may be involved in Crohn's disease. These can cause
symptoms including difficulty swallowing (dysphagia), upper abdominal pain, and vomiting.[20]
[edit]Systemic symptoms
Crohn's disease, like many other chronic, inflammatory diseases, can cause a variety
of systemic symptoms.[1] Among children, growth failure is common. Many children are first
diagnosed with Crohn's disease based on inability to maintain growth.[21] As Crohn's disease
may manifest at the time of the growth spurt in puberty, up to 30% of children with Crohn's
disease may have retardation of growth.[22] Fever may also be present, though fevers greater
than 38.5 ˚C (101.3 ˚F) are uncommon unless there is a complication such as an abscess.
[1]
 Among older individuals, Crohn's disease may manifest as weight loss. This is usually related

15
to decreased food intake, since individuals with intestinal symptoms from Crohn's disease often
feel better when they do not eat and might lose their appetite.[21] People with extensive small
intestine disease may also have malabsorption of carbohydrates or lipids, which can further
exacerbate weight loss.[23]
Extraintestinal symptoms
In addition to systemic and gastrointestinal involvement, Crohn's disease can affect many other
organ systems.[24]Inflammation of the interior portion of the eye, known as uveitis, can cause eye
pain, especially when exposed to light (photophobia). Inflammation may also involve the white
part of the eye (sclera), a condition called episcleritis. Both episcleritis and uveitis can lead to
loss of vision if untreated.
Crohn's disease is associated with a type of rheumatologic disease known as seronegative
spondyloarthropathy. This group of diseases is characterized by inflammation of one or
more joints (arthritis) or muscle insertions (enthesitis). The arthritis can affect larger joints such
as the knee or shoulder or may exclusively involve the small joints of the hand and feet. The
arthritis may also involve the spine, leading to ankylosing spondylitis if the entire spine is
involved or simply sacroiliitis if only the lower spine is involved. The symptoms of arthritis
include painful, warm, swollen, stiff joints and loss of joint mobility or function. [15]
Crohn's disease may also involve the skin, blood, and endocrine system. One type of skin
manifestation, erythema nodosum, presents as red nodules usually appearing on the shins.
Erythema nodosum is due to inflammation of the underlying subcutaneous tissue and is
characterized by septal panniculitis. Another skin lesion, pyoderma gangrenosum, is typically a
painful ulcerating nodule. Crohn's disease also increases the risk of blood clots; painful swelling
of the lower legs can be a sign of deep venous thrombosis, while difficulty breathing may be a
result of pulmonary embolism. Autoimmune hemolytic anemia, a condition in which the immune
system attacks the red blood cells, is also more common in Crohn's disease and may cause
fatigue, pallor, and other symptoms common in anemia. Clubbing, a deformity of the ends of the
fingers, may also be a result of Crohn's disease. Finally, Crohn's disease may
cause osteoporosis, or thinning of the bones. Individuals with osteoporosis are at increased risk
of bone fractures.[7]
Crohn's disease can also cause neurological complications (reportedly in up to 15% of patients).
[25]
 The most common of these are seizures, stroke, myopathy, peripheral
neuropathy, headache anddepression.[25]
Crohn's patients often also have issues with small bowel bacterial overgrowth syndrome, which
has similar symptoms.[26]
Complications
Crohn's disease can lead to several mechanical complications within the intestines,
including obstruction, fistulae, and abscesses. Obstruction typically occurs
from strictures or adhesions which narrow the lumen, blocking the passage of the intestinal
contents. Fistulae can develop between two loops of bowel, between the bowel and bladder,
between the bowel and vagina, and between the bowel and skin. Abscesses are walled off
collections of infection, which can occur in the abdomen or in the perianal area in Crohn's
disease sufferers.
Crohn's disease also increases the risk of cancer in the area of inflammation. For example,
individuals with Crohn's disease involving the small bowel are at higher risk for small intestinal
cancer. Similarly, people with Crohn's colitis have a relative risk of 5.6 for developing colon
cancer.[27] Screening for colon cancer with colonoscopy is recommended for anyone who has
had Crohn's colitis for at least eight years.[28] Some studies suggest that there is a role for

16
chemoprotection in the prevention of colorectal cancer in Crohn's involving the colon; two
agents have been suggested, folate and mesalaminepreparations.[29]
Individuals with Crohn's disease are at risk of malnutrition for many reasons, including
decreased food intake and malabsorption. The risk increases following resection of the small
bowel. Such individuals may require oral supplements to increase their caloric intake, or in
severe cases, total parenteral nutrition(TPN). Most people with moderate or severe Crohn's
disease are referred to a dietitian for assistance in nutrition.[30]
Crohn's disease can cause significant complications including bowel obstruction, abscesses,
free perforation and hemorrhage.[31]
Crohn's disease can be problematic during pregnancy, and some medications can cause
adverse outcomes for the fetus or mother. Consultation with an obstetrician and
gastroenterologist about Crohn's disease and all medications allows preventative measures to
be taken. In some cases, remission can occur during pregnancy. Certain medications can also
impact sperm count or may otherwise adversely affect a man's ability to conceive.[32]
Cause

Although the exact cause of Crohn's disease is still unknown, a combination of environmental
factors and genetic predisposition seems to cause the disease.[33] The genetic risk factors have
now more or less been comprehensively elucidated, making Crohn's disease the first genetically
complex disease of which the genetic background has been resolved.[34] The relative risks of
contracting the disease when one has a mutation in one of the risk genes, however, are actually
very low (approximately 1:200). Broadly speaking, the genetic data indicate that innate immune
systems in patients with Crohn's disease malfunction, and direct assessment of patient
immunity confirms this notion.[35] This had led to the notion that Crohn's disease should be
viewed as innate immune deficiency, chronic inflammation being caused by adaptive immunity
trying to compensate for the reduced function of the innate immune system.[36]
Genetics
Some research has indicated that Crohn's disease may have a genetic link.[37] The disease runs
in families and those with a sibling with the disease are 30 times more likely to develop it than
the general population.
Mutations in the CARD15 gene (also known as the NOD2 gene) are associated with Crohn's
disease[38] and with susceptibility to certain phenotypes of disease location and activity.[39] In
earlier studies, only two genes were linked to Crohn's, but scientists now believe there are over
thirty genes that show genetics play a role in the disease, either directly through causation or
indirectly as with a mediator variable. Anomalies in the XBP1 gene have recently been identified
as a factor, pointing towards a role for the unfolded protein response pathway of
the endoplasmatic reticulum in inflammatory bowel diseases.[40][41]
Environmental factors
Diet is believed to be linked to its higher prevalence in industrialized parts of the world. A
positive correlation has been found between the incidence of the disease and an increased
intake of animal protein, milk protein and an increased ratio of n-6 to n-3 polyunsaturated fatty
acids.[42] Negative correlation of the disease incidence was found to the increased consumption
of vegetable protein, and no correlation to fish protein.[42] Smoking has been shown to increase
the risk of the return of active disease, or "flares".[5] The introduction of hormonal
contraception in the United States in the 1960s is linked with a dramatic increase in the
incidence rate of Crohn's disease. Although a causal linkage has not been effectively shown,
there remain fears that these drugs work on the digestive system in ways similar to smoking.[43]

17
Immune system
Abnormalities in the immune system have often been invoked as being causes of Crohn's
disease. Crohn's disease is thought to be an autoimmune disease, with inflammation stimulated
by an over-active Th1 cytokine response.[44] However, more recent evidence has shown
that Th17 is of greater importance in the disease.[45] The most recent gene to be implicated in
Crohn's disease is ATG16L1, which may induce autophagy and hinder the body's ability to
attack invasive bacteria.[46]
Contrary to the prevailing view that Crohn's disease is a primary T cell autoimmune disorder,
there is an increasing body of evidence in favor of the hypothesis that Crohn's disease results
from an impaired innate immunity.[47] The immunodeficiency, which has been shown to be due to
(at least in part) impaired cytokine secretion by macrophages, is thought to lead to a sustained
microbial-induced inflammatory response, particularly in the colon where the bacterial load is
especially high.[35][48]
Microbes
A variety of pathogenic bacteria were initially suspected of being causative agents of Crohn's
disease.[49] However, most health care professionals now believe that a variety of
microorganisms are taking advantage of their host's weakened mucosal layer and inability to
clear bacteria from the intestinal walls, both symptoms of the disease.[50] Some studies have
suggested that Mycobacterium avium subspecies paratuberculosis (MAP) plays a role in
Crohn's disease, in part because it causes a very similar disease, Johne's disease, in cattle.
[51]
 The mannose bearing antigens (mannins) from yeast may also elicit an antibody response.
[52]
 Other studies have linked specific strains of enteroadherent E. coli to the disease.[53] Still, this
relationship between specific types of bacteria and Crohn's disease remains unclear.[54][55]
Some studies have suggested that some symptoms of Crohn's disease, ulcerative colitis
and irritable bowel syndrome have the same underlying cause. Biopsy samples taken from the
colons of all three patient groups were found to produce elevated levels of a serine protease.
[56]
 Experimental introduction of the serine protease into mice has been found to produce
widespread pain associated with irritable bowel syndrome as well as colitis, which is associated
with all three diseases.[57] The authors of that study were unable to identify the source of the
protease, but a separate review noted that regional and temporal variations in those illnesses
follow those associated with infection with a poorly understood protozoan, Blastocystis.[58]
A study in 2003 put forth the "cold-chain" hypothesis, that psychrotrophic bacteria such as
Yersinia spp and Listeria spp contribute to the disease. A statistical correlation was found
between the advent of the use of refrigeration in the United States and various parts of Europe
and the rise of the disease.[59][60] Later studies have provided support for this hypothesis.[61]
Studies done at the University of Liverpool have offered ideas that would explain the apparent
connection between Crohn's disease, Mycobacterium, other pathogenic bacteria, and genetic
markers.[62][63] In many individuals genetic factors predispose individuals to Mycobacterium
avium subsp. paratuberculosis infection. This bacteria then produce mannins which protect both
itself and various bacteria from phagocytosis, which causes a variety of secondary infections.
[64]
 Other mycobacterial diseases, such as leprosy and Tuberculosis could be considered similar
in that they have strong genetic components, but are not genetic per se.
Pathophysiology

During a colonoscopy, biopsies of the colon are often taken in order to confirm the diagnosis.
There are certain characteristic features of the pathology seen that point toward Crohn's
disease. Crohn's disease shows a transmural pattern of inflammation, meaning that the

18
inflammation may span the entire depth of the intestinal wall.[1] Grossly, ulcerationis an outcome
seen in highly active disease. There is usually an abrupt transition between unaffected tissue
and the ulcer. Under a microscope, biopsies of the affected colon may
show mucosal inflammation. This inflammation is characterized by focal infiltration
of neutrophils, a type of inflammatory cell, into the epithelium. This typically occurs in the area
overlying lymphoid aggregates. These neutrophils, along with mononuclear cells, may infiltrate
into the crypts leading to inflammation (crypititis) or abscess (crypt abscess).Granulomas,
aggregates of macrophage derivatives known as giant cells, are found in 50% of cases and are
most specific for Crohn's disease. The granulomas of Crohn's disease do not show "caseation",
a cheese-like appearance on microscopic examination that is characteristic of granulomas
associated with infections such as tuberculosis. Biopsies may also show chronic mucosal
damage as evidenced by blunting of the intestinal villi, atypical branching of the crypts, and
change in the tissue type (metaplasia). One example of such metaplasia, Paneth cell
metaplasia, involves development of Paneth cells (typically found in the small intestine) in other
parts of the gastrointestinal system.
Diagnosis
The diagnosis of Crohn's disease can sometimes be challenging,[13] and a number of tests are
often required to assist the physician in making the diagnosis.[8] Even with a full battery of tests it
may not be possible to diagnose Crohn's with complete certainty; a colonoscopy is
approximately 70% effective in diagnosing the disease with further tests being less effective.
Disease in the small bowel is particularly difficult to diagnose as a traditional colonoscopy only
allows access to the colon and lower portions of the small intestines; introduction of the capsule
endoscopy[66] aids in endoscopic diagnosis. Multinucleated giant cells, a common finding in the
lesions of Crohn's disease, are less common in the lesions of lichen nitidus.[67]

Endoscopy
A colonoscopy is the best test for making the diagnosis of Crohn's disease as it allows direct
visualization of the colon and the terminal ileum, identifying the pattern of disease involvement.
Occasionally, the colonoscope can travel past the terminal ileum but it varies from patient to
patient. During the procedure, thegastroenterologist can also perform a biopsy, taking small
samples of tissue for laboratory analysis which may help confirm a diagnosis. As 30% of
Crohn's disease involves only the ileum,[1] cannulation of the terminal ileum is required in
making the diagnosis. Finding a patchy distribution of disease, with involvement of the colon or
ileum but not the rectum, is suggestive of Crohn's disease, as are other endoscopic stigmata.
[68]
 The utility of capsule endoscopy for this, however, is still uncertain. [69]
Radiologic tests
A small bowel follow-through may suggest the diagnosis of Crohn's disease and is useful when
the disease involves only the small intestine. Because colonoscopy and gastroscopy allow
direct visualization of only the terminal ileum and beginning of the duodenum, they cannot be
used to evaluate the remainder of the small intestine. As a result, a barium follow-through x-ray,
wherein barium sulfate suspension is ingested and fluoroscopic images of the bowel are taken
over time, is useful for looking for inflammation and narrowing of the small bowel.[68][70] Barium
enemas, in which barium is inserted into the rectum and fluoroscopy used to image the bowel,
are rarely used in the work-up of Crohn's disease due to the advent of colonoscopy. They
remain useful for identifying anatomical abnormalities when strictures of the colon are too small
for a colonoscope to pass through, or in the detection of colonic fistulae.[71]
CT and MRI scans are useful for evaluating the small bowel with enteroclysis protocols.[72]They
are additionally useful for looking for intra-abdominal complications of Crohn's disease such

19
as abscesses, small bowel obstruction, or fistulae.[73] Magnetic resonance imaging (MRI) is
another option for imaging the small bowel as well as looking for complications, though it is
more expensive and less readily available[74]
Blood tests
A complete blood count may reveal anemia, which may be caused either by blood loss or vitamin
B12 deficiency. The latter may be seen with ileitis because vitamin B12 is absorbed in the ileum.
[75]
 Erythrocyte sedimentation rate, or ESR, and C-reactive protein measurements can also be
useful to gauge the degree of inflammation.[76] It is also true in patients with ilectomy done in
response to the complication. Another cause of anaemia is anaemia of chronic disease,
characterized by its microcytic and hypochromic anaemia. There can be various reasons for
anaemia, including medication used in treatment of inflammatory bowel disease like
azathioprine which can lead to cytopenia and sulfasalazine which can also result in folate
malabsorption, etc. Testing for anti-Saccharomyces cerevisiae antibodies (ASCA) and anti-
neutrophil cytoplasmic antibodies (ANCA) has been evaluated to identify inflammatory diseases
of the intestine[77] and to differentiate Crohn's disease from ulcerative colitis.[78] Furthermore,
increasing amounts and levels of serological antibodies such as ASCA, anti-laminaribioside
[Glc(β1,3)Glb(β); ALCA], anti-chitobioside (GlcNAc(β1,4)GlcNAc(β); ACCA], anti-mannobioside
[Man(α1,3)Man(α)AMCA], anti-Laminarin [Glc(β1,3))3n(Glc(β1,6))n; anti-L] and anti-Chitin
[(GlcNAc(β1,4)n; anti-C] associate with disease behavior and surgery, and may aid in the
prognosis of Crohn's disease.[79][80][81][82]
Comparison with ulcerative colitis
The most common disease that mimics the symptoms of Crohn's disease is ulcerative colitis, as
both are inflammatory bowel diseases that can affect thecolon with similar symptoms. It is
important to differentiate these diseases, since the course of the diseases and treatments may
be different. In some cases, however, it may not be possible to tell the difference, in which case
the disease is classified as indeterminate colitis.[1][8][16]

Comparisons of various factors in Crohn's disease and ulcerative colitis

Crohn's disease Ulcerative colitis

Terminal
Commonly Seldom
ileum involvement

Colon involvement Usually Always

Rectum involvement Seldom Usually[83]

Involvement around
Common[84] Seldom
the anus

20
 No increase in rate of primary sclerosing
Bile duct involvement Higher rate[85]
cholangitis

Continuous area of
Distribution of Disease Patchy areas of inflammation (Skip lesions)
inflammation[83]

Deep geographic and serpiginous (snake-

Endoscopy Continuous ulcer
like) ulcers

Depth of inflammation May be transmural, deep into tissues[1][84] Shallow, mucosal

Fistulae Common[84] Seldom

Stenosis Common Seldom

Autoimmune disease Widely regarded as an autoimmune disease No consensus

Cytokine response Associated with Th17 [45] Vaguely associated with Th2

May have non-necrotizing non-peri-intestinal Non-peri-intestinal

Granulomas on biopsy
crypt granulomas[84][86][87] crypt granulomas not seen[83]

Often returns following removal of affected Usually cured by removal of

Surgical cure
part colon

Smoking Higher risk for smokers Lower risk for smokers[83]

Treatment

Main articles: Treatment of Crohn's disease and Biological therapy for inflammatory bowel

disease

Currently there is no cure for Crohn's disease and remission may not be possible or prolonged if
achieved.[88] In cases where remission is possible, relapse can be prevented
and symptoms controlled with medication, lifestyle changes and in some cases, surgery.

21
Adequately controlled, Crohn's disease may not significantly restrict daily living.[89] Treatment for
Crohn's disease is only when symptoms are active and involve first treating the acute problem,
then maintaining remission.
Medication
Acute treatment uses medications to treat any infection (normally antibiotics) and to reduce
inflammation (normally aminosalicylate anti-inflammatory drugs and corticosteroids). When
symptoms are in remission, treatment enters maintenance with a goal of avoiding the
recurrence of symptoms. Prolonged use of corticosteroids has significant side-effects; as a
result they are generally not used for long-term treatment. Alternatives include aminosalicylates
alone, though only a minority are able to maintain the treatment, and many require
immunosuppressive drugs.[84] It has been also suggested that antibiotics change the enteric flora
and their continuous use may pose the risk of overgrowth with pathogens such as Clostridium
difficile.[90]
Medications used to treat the symptoms of Crohn's disease include 5-aminosalicylic acid (5-
ASA) formulations, prednisone, immunomodulators such
as azathioprine, mercaptopurine, methotrexate,infliximab, adalimumab,[16] certolizumab[91] and n
atalizumab.[92][93] Hydrocortisone should be used in severe attacks of Crohn's disease.[94]
Low doses of the opiate receptor antagonist Naltrexone (also Low dose naltrexone) have been
found to be effective in inducing remission in 67% of patients with Crohn's disease in a small
study conducted at Pennsylvania State University. Dr. Jill Smith, Professor of Gastroenterology
at Pennsylvania State University's College of Medicine concluded that "LDN therapy appears
effective and safe in subjects with active Crohn’s disease."[95] Smith and her colleagues have
since received a NIH grant and are proceeding with a definitive Phase II placebo-
controlled clinical trial.
Since late 1990s, biological medications are available (see Infliximab).
Lifestyle changes
Certain lifestyle changes can reduce symptoms, including dietary adjustments, proper hydration,
and smoking cessation. Smoking may increase Crohn's disease; stopping is recommended.
Eating small meals frequently instead of big meals may also help with a low appetite. To
manage symptoms have a balanced diet with proper portion control. Fatigue can be helped with
regular exercise, a healthy diet, and enough sleep. A food diary may help with identifying foods
that trigger symptoms. Some patients should follow a low dietary fiber diet to control symptoms
especially if fibrous foods cause symptoms.[89]
Surgery
Crohn's cannot be cured by surgery, though it is used when partial or a full blockage of the
intestine occurs. Surgery may also be required for complications such as obstructions, fistulas
and/or abscesses, or if the disease does not respond to drugs. After the first surgery, Crohn's
usually shows up at the site of the resection though it can appear in other locations. After a
resection, scar tissue builds up which can cause strictures. A stricture is when the intestines
become too small to allow excrement to pass through easily which can lead to a blockage. After
the first resection, another resection may be necessary within five years.[96] For patients with an
obstruction due to a stricture, two options for treatment are strictureplasty and resection of that
portion of bowel. There is nostatistical significance between strictureplasty alone versus
strictureplasty and resection in cases of duodenal involvement. In these cases, re-operation
rates were 31% and 27%, respectively, indicating that strictureplasty is a safe and effective
treatment for selected patients with duodenal involvement.[97]

22
Short bowel syndrome (SBS, also short gut syndrome or simply short gut) can be caused by the
surgical removal of the small intestines. It usually develops if a person has had half or more of
their small intestines removed.[98] Diarrhea is the main symptom of short bowel syndrome though
other symptoms may include cramping, bloating and heartburn. Short bowel syndrome is
treated with changes in diet, intravenous feeding, vitamin and mineral supplements and
treatment with medications. Another complication following surgery for Crohn's disease where
the terminal ileum has been removed is the development of excessive watery diarrhea. This is
due to an inability to reabsorb bile acids after resection of the terminal ileum.[citation needed]
In some cases of SBS, intestinal transplant surgery may be considered; though the number of
transplant centres offering this procedure is quite small and it comes with a high risk due to the
chance of infection and rejection of the transplanted intestine.[99]
Prospective treatments
Researchers at University College London have questioned the wisdom of suppressing the
immune system in Crohn's, as the problem may be an under-active rather than an over-active
immune system: their study found that Crohn's patients showed an abnormally low response to
an introduced infection, marked by a poor flow of blood to the wound, and the response
improved when the patients were given sildenafil citrate.[35]
Recent studies using helminthic therapy or hookworms to treat Crohn's Disease and other (non-
viral) auto-immune diseases seem to yield promising results.[100]
Complementary and alternative medicine
More than half of Crohn's disease sufferers have tried complementary or alternative therapy.
[101]
 These include diets, probiotics, fish oil and other herbal and nutritional supplements. The
benefit of these medications is uncertain.

 Acupuncture is used to treat inflammatory bowel disease in China, and is being used
more frequently in Western society.[102] However, there is no evidence that acupuncture has
benefits beyond the placebo effect.[102]
 Methotrexate is a folate anti-metabolite drug which is also used for chemotherapy. It is
useful in maintenance of remission for those no longer taking corticosteroids.[103]
 Metronidazole and ciprofloxacin are antibiotics which are used to treat Crohn's that have
colonic or perianal involvement, although, in the United States, this use has not been
approved by the Food and Drug Administration.[104] They are also used for treatment of
complications, including abscesses and other infections accompanying Crohn's disease.[8]
 Thalidomide has shown response in reversing endoscopic evidence of disease.[105]
 Cannabis-derived drugs may be used to treat Crohn's Disease with their anti-
inflammatory properties. Cannabis-derived drugs may also help to heal the gut lining.[106]
 Soluble Fiber has been used by some to treat symptoms.^ a b c Tungland BC, Meyer D,
Nondigestible oligo- and polysaccharides (dietary fiber): their physiology and role in human
health and food, Comp Rev Food Sci Food Safety, 3:73-92, 2002 (Table 3)[1]
 Probiotics include Sacchromyces boulardii[107] and E. coli Nissle 1917.[108]
 Boswellia is an ayurvedic (Indian traditional medicine) herb, used as a natural drug. One
study has found that the effectiveness of "Boswellia serrata extract H 15" is not inferior
to mesalazine, and concludes that the Boswellia extract's safety and efficacy make it
superior to mesalazine in benefit-risk evaluations.Prognosis
Crohn's disease is a chronic condition for which there is currently no cure. It is characterised by
periods of improvement followed by episodes when symptoms flare up. With treatment, most
people achieve a healthy height and weight, and the mortality rate for the disease is relatively

23
low. However, Crohn's disease is associated with an increased risk of small bowel and
colorectal carcinoma, including bowel cancer.[110]
Epidemiology

The incidence of Crohn's disease has been ascertained from population studies in Norway and
the United States and is similar at 6 to 7.1:100,000.[111][112] Crohn's disease is more common in
northern countries, and shows a higher preponderance in northern areas of the same country.
[113]
 The incidence of Crohn's disease is thought to be similar in Europe but lower
in Asia and Africa.[111] It also has a higher incidence in Ashkenazi Jews.[16]
Crohn's disease has a bimodal distribution in incidence as a function of age: the disease tends
to strike people in their teens and 20s, and people in their 50s through to their 70s, and ages in
between due to not being diagnosed with Crohn's and being diagnosed instead with irritable
bowel syndrome (IBS).[1][8] It is rarely diagnosed in early childhood. It usually strikes females who
are pediatric patients more severely than males.[114] However, only slightly more women than
men have Crohn's disease.[115] Parents, siblings or children of people with Crohn's disease are 3
to 20 times more likely to develop the disease.[116] Twin studies show a concordance of greater
than 55% for Crohn's disease.[117]
History

Inflammatory bowel diseases were described by Giovanni Battista Morgagni (1682–1771) and

by Scottish physician T. Kennedy Dalziel in 1913.[118]
Ileitis terminalis was first described by Polish surgeon Antoni Leśniowski in 1904, however, due
to the precedence of Crohn's name in the alphabet, it became later to be known in the
worldwide literature as Crohn’s disease.[citation needed] Only in Poland it continues to be
named Leśniowski-Crohn’s disease. Burrill Bernard Crohn, an American gastroenterologist
at New York City's Mount Sinai Hospital, described fourteen cases in 1932, and submitted them
to the American Medical Association under the rubric of "Terminal ileitis: A new clinical entity".
Later that year, he, along with colleagues Leon Ginzburg and Gordon Oppenheimer published
the case series as "Regional ileitis: a pathologic and clinical entity".[10]

What is Crohn’s disease?

Crohn’s disease is an ongoing disorder that causes inflammation of the digestive tract,
also referred to as the gastrointestinal (GI) tract. Crohn’s disease can affect any area of
the GI tract, from the mouth to the anus, but it most commonly affects the lower part of
the small intestine, called the ileum. The swelling extends deep into the lining of the
affected organ. The swelling can cause pain and can make the intestines empty
frequently, resulting in diarrhea.

Crohn’s disease is an inflammatory bowel disease, the general name for diseases that
cause swelling in the intestines. Because the symptoms of Crohn’s disease are similar
to other intestinal disorders, such as irritable bowel syndrome and ulcerative colitis, it
can be difficult to diagnose. Ulcerative colitis causes inflammation and ulcers in the top
layer of the lining of the large intestine. In Crohn’s disease, all layers of the intestine
may be involved, and normal healthy bowel can be found between sections of diseased
bowel.

24
Crohn’s disease affects men and women equally and seems to run in some families.
About 20 percent of people with Crohn’s disease have a blood relative with some form
of inflammatory bowel disease, most often a brother or sister and sometimes a parent or
child. Crohn’s disease can occur in people of all age groups, but it is more often
diagnosed in people between the ages of 20 and 30. People of Jewish heritage have an
increased risk of developing Crohn’s disease, and African Americans are at decreased
risk for developing Crohn’s disease.

Crohn’s disease may also be called ileitis or enteritis.

What causes Crohn’s disease?

Several theories exist about what causes Crohn’s disease, but none have been proven.
The human immune system is made from cells and different proteins that protect people
from infection. The most popular theory is that the body’s immune system reacts
abnormally in people with Crohn’s disease, mistaking bacteria, foods, and other
substances for being foreign. The immune system’s response is to attack these
“invaders.” During this process, white blood cells accumulate in the lining of the
intestines, producing chronic inflammation, which leads to ulcerations and bowel injury.

Scientists do not know if the abnormality in the functioning of the immune system in
people with Crohn’s disease is a cause, or a result, of the disease. Research shows that
the inflammation seen in the GI tract of people with Crohn’s disease involves several
factors: the genes the patient has inherited, the immune system itself, and the
environment. Foreign substances, also referred to as antigens, are found in the
environment. One possible cause for inflammation may be the body’s reaction to these
antigens, or that the antigens themselves are the cause for the inflammation. Scientists
have found that high levels of a protein produced by the immune system, called tumor
necrosis factor (TNF), are present in people with Crohn’s disease.

What are the symptoms?

The most common symptoms of Crohn’s disease are abdominal pain, often in the lower
right area, and diarrhea. Rectal bleeding, weight loss, arthritis, skin problems, and fever
may also occur. Bleeding may be serious and persistent, leading to anemia. Children
with Crohn’s disease may suffer delayed development and stunted growth. The range
and severity of symptoms varies.

How is Crohn’s disease diagnosed?

A thorough physical exam and a series of tests may be required to diagnose Crohn’s
disease.

Blood tests may be done to check for anemia, which could indicate bleeding in the
intestines. Blood tests may also uncover a high white blood cell count, which is a sign of

25
inflammation somewhere in the body. By testing a stool sample, the doctor can tell if
there is bleeding or infection in the intestines.

The doctor may do an upper GI series to look at the small intestine. For this test, the
person drinks barium, a chalky solution that coats the lining of the small intestine, before
x rays are taken. The barium shows up white on x-ray film, revealing inflammation or
other abnormalities in the intestine. If these tests show Crohn’s disease, more x rays of
both the upper and lower digestive tract may be necessary to see how much of the GI
tract is affected by the disease.

The doctor may also do a visual exam of the colon by performing either a
sigmoidoscopy or a colonoscopy. For both of these tests, the doctor inserts a long,
flexible, lighted tube linked to a computer and TV monitor into the anus. A
sigmoidoscopy allows the doctor to examine the lining of the lower part of the large
intestine, while a colonoscopy allows the doctor to examine the lining of the entire large
intestine. The doctor will be able to see any inflammation or bleeding during either of
these exams, although a colonoscopy is usually a better test because the doctor can
see the entire large intestine. The doctor may also do a biopsy, which involves taking a
sample of tissue from the lining of the intestine to view with a microscope.

What are the complications of Crohn’s disease?

The most common complication is blockage of the intestine. Blockage occurs because
the disease tends to thicken the intestinal wall with swelling and scar tissue, narrowing
the passage. Crohn’s disease may also cause sores, or ulcers, that tunnel through the
affected area into surrounding tissues, such as the bladder, vagina, or skin. The areas
around the anus and rectum are often involved. The tunnels, called fistulas, are a
common complication and often become infected. Sometimes fistulas can be treated
with medicine, but in some cases they may require surgery. In addition to fistulas, small
tears called fissures may develop in the lining of the mucus membrane of the anus.

Nutritional complications are common in Crohn’s disease. Deficiencies of proteins,

calories, and vitamins are well documented. These deficiencies may be caused by
inadequate dietary intake, intestinal loss of protein, or poor absorption, also referred to
as malabsorption.

Other complications associated with Crohn’s disease include arthritis, skin problems,
inflammation in the eyes or mouth, kidney stones, gallstones, or other diseases of the
liver and biliary system. Some of these problems resolve during treatment for disease in
the digestive system, but some must be treated separately.

26
What is the treatment for Crohn’s disease?

Treatment may include drugs, nutrition supplements, surgery, or a combination of these

options. The goals of treatment are to control inflammation, correct nutritional
deficiencies, and relieve symptoms like abdominal pain, diarrhea, and rectal bleeding.
At this time, treatment can help control the disease by lowering the number of times a
person experiences a recurrence, but there is no cure. Treatment for Crohn’s disease
depends on the location and severity of disease, complications, and the person’s
response to previous medical treatments when treated for recurring symptoms.

Some people have long periods of remission, sometimes years, when they are free of
symptoms. However, the disease usually recurs at various times over a person’s
lifetime. This changing pattern of the disease means one cannot always tell when a
treatment has helped. Predicting when a remission may occur or when symptoms will
return is not possible.

Someone with Crohn’s disease may need medical care for a long time, with regular
doctor visits to monitor the condition.

Drug Therapy

Anti-Inflammation Drugs. Most people are first treated with drugs containing

mesalamine, a substance that helps control inflammation. Sulfasalazine is the most
commonly used of these drugs. Patients who do not benefit from it or who cannot
tolerate it may be put on other mesalamine-containing drugs, generally known as 5-ASA
agents, such as Asacol, Dipentum, or Pentasa. Possible side effects of mesalamine-
containing drugs include nausea, vomiting, heartburn, diarrhea, and headache.

Cortisone or Steroids. Cortisone drugs and steroids—called corticosteriods—provide

very effective results. Prednisone is a common generic name of one of the drugs in this
group of medications. In the beginning, when the disease it at its worst, prednisone is
usually prescribed in a large dose. The dosage is then lowered once symptoms have
been controlled. These drugs can cause serious side effects, including greater
susceptibility to infection.

Immune System Suppressors. Drugs that suppress the immune system are also used
to treat Crohn’s disease. Most commonly prescribed are 6-mercaptopurine or a related
drug, azathioprine. Immunosuppressive agents work by blocking the immune reaction
that contributes to inflammation. These drugs may cause side effects like nausea,
vomiting, and diarrhea and may lower a person’s resistance to infection. When patients
are treated with a combination of corticosteroids and immunosuppressive drugs, the
dose of corticosteroids may eventually be lowered. Some studies suggest that
immunosuppressive drugs may enhance the effectiveness of corticosteroids.

Infliximab (Remicade). This drug is the first of a group of medications that blocks the
body’s inflammation response. The U.S. Food and Drug Administration approved the

27
drug for the treatment of moderate to severe Crohn’s disease that does not respond to
standard therapies (mesalamine substances, corticosteroids, immunosuppressive
agents) and for the treatment of open, draining fistulas. Infliximab, the first treatment
approved specifically for Crohn’s disease is an anti-TNF substance. Additional research
will need to be done in order to fully understand the range of treatments Remicade may
offer to help people with Crohn’s disease.

Antibiotics. Antibiotics are used to treat bacterial overgrowth in the small intestine

caused by stricture, fistulas, or prior surgery. For this common problem, the doctor may
prescribe one or more of the following antibiotics: ampicillin, sulfonamide,
cephalosporin, tetracycline, or metronidazole.

Anti-Diarrheal and Fluid Replacements. Diarrhea and crampy abdominal pain are

often relieved when the inflammation subsides, but additional medication may also be
necessary. Several antidiarrheal agents could be used, including diphenoxylate,
loperamide, and codeine. Patients who are dehydrated because of diarrhea will be
treated with fluids and electrolytes.

Nutrition Supplementation

The doctor may recommend nutritional supplements, especially for children whose
growth has been slowed. Special high-calorie liquid formulas are sometimes used for
this purpose. A small number of patients may need to be fed intravenously for a brief
time through a small tube inserted into the vein of the arm. This procedure can help
patients who need extra nutrition temporarily, those whose intestines need to rest, or
those whose intestines cannot absorb enough nutrition from food. There are no known
foods that cause Crohn’s disease. However, when people are suffering a flare in
disease, foods such as bulky grains, hot spices, alcohol, and milk products may
increase diarrhea and cramping.

Surgery

Two-thirds to three-quarters of patients with Crohn’s disease will require surgery at

some point in their lives. Surgery becomes necessary when medications can no longer
control symptoms. Surgery is used either to relieve symptoms that do not respond to
medical therapy or to correct complications such as blockage, perforation, abscess, or
bleeding in the intestine. Surgery to remove part of the intestine can help people with
Crohn’s disease, but it is not a cure. Surgery does not eliminate the disease, and it is
not uncommon for people with Crohn’s Disease to have more than one operation, as
inflammation tends to return to the area next to where the diseased intestine was
removed.

Some people who have Crohn’s disease in the large intestine need to have their entire
colon removed in an operation called a colectomy. A small opening is made in the front
of the abdominal wall, and the tip of the ileum, which is located at the end of the small
intestine, is brought to the skin’s surface. This opening, called a stoma, is where waste

28
exits the body. The stoma is about the size of a quarter and is usually located in the
right lower part of the abdomen near the beltline. A pouch is worn over the opening to
collect waste, and the patient empties the pouch as needed. The majority of colectomy
patients go on to live normal, active lives.

Sometimes only the diseased section of intestine is removed and no stoma is needed.
In this operation, the intestine is cut above and below the diseased area and
reconnected.

Because Crohn’s disease often recurs after surgery, people considering it should
carefully weigh its benefits and risks compared with other treatments. Surgery may not
be appropriate for everyone. People faced with this decision should get as much
information as possible from doctors, nurses who work with colon surgery patients
(enterostomal therapists), and other patients. Patient advocacy organizations can
suggest support groups and other information resources. (See For More Information for
the names of such organizations.)

People with Crohn’s disease may feel well and be free of symptoms for substantial
spans of time when their disease is not active. Despite the need to take medication for
long periods of time and occasional hospitalizations, most people with Crohn’s disease
are able to hold jobs, raise families, and function successfully at home and in society.

Can diet control Crohn’s disease?

People with Crohn’s disease often experience a decrease in appetite, which can affect
their ability to receive the daily nutrition needed for good health and healing. In addition,
Crohn’s disease is associated with diarrhea and poor absorption of necessary nutrients.
No special diet has been proven effective for preventing or treating Crohn’s disease, but
it is very important that people who have Crohn’s disease follow a nutritious diet and
avoid any foods that seem to worsen symptoms. There are no consistent dietary rules
to follow that will improve a person’s symptoms.

People should take vitamin supplements only on their doctor’s advice.

Can stress make Crohn’s disease worse?

There is no evidence showing that stress causes Crohn’s disease. However, people
with Crohn’s disease sometimes feel increased stress in their lives from having to live
with a chronic illness. Some people with Crohn’s disease also report that they
experience a flare in disease when they are experiencing a stressful event or situation.
There is no type of person that is more likely to experience a flare in disease than
another when under stress. For people who find there is a connection between their
stress level and a worsening of their symptoms, using relaxation techniques, such as
slow breathing, and taking special care to eat well and get enough sleep, may help
them feel better.

29
Is pregnancy safe for women with Crohn’s disease?

Research has shown that the course of pregnancy and delivery is usually not impaired
in women with Crohn’s disease. Even so, women with Crohn’s disease should discuss
the matter with their doctors before pregnancy. Most children born to women with
Crohn’s disease are unaffected. Children who do get the disease are sometimes more
severely affected than adults, with slowed growth and delayed sexual development in
some cases.

Hope through Research

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
conducts and supports research into many kinds of digestive disorders, including
Crohn’s disease. Several clinical trials are currently evaluating the efficacy and safety of
different therapies for the treatment of Crohn’s disease. For a complete listing of trials
being conducted, visit www.ClinicalTrials.gov.

What is Crohn's disease?

Crohn's disease is a chronic inflammatory disease of the intestines. It primarily causes ulcerations (breaks in the
lining) of the small and large intestines, but can affect the digestive system anywhere from the mouth to the anus. It is
named after the physician who described the disease in 1932. It also is called granulomatous enteritis or colitis,
regional enteritis, ileitis, or terminal ileitis.

Crohn's disease is related closely to another chronic inflammatory condition that involves only the colon called
ulcerative colitis. Together, Crohn's disease and ulcerative colitis are frequently referred to as inflammatory bowel
disease (IBD). Ulcerative colitisand Crohn's disease have no medical cure. Once the diseases begin, they tend to
fluctuate between periods of inactivity (remission) and activity (relapse). They affect approximately 500,000 to two
million people in the United States. Men and women are equally affected. IBD most commonly begins during
adolescence and early adulthood, but it also can begin during childhood and later in life.

Crohn's disease tends to be more common in relatives of patients with Crohn's disease. It also is more common
among relatives of patients with ulcerative colitis.

What causes Crohn's disease?

The cause of Crohn's disease is unknown. Some scientists suspect that infection by certain bacteria, such as strains
of mycobacterium, may be the cause of Crohn's disease. To date, however, there has been no convincing evidence
that the disease is caused by infection. Crohn's disease is not contagious. Although diet may affect the symptoms in
patients with Crohn's disease, it is unlikely that diet is responsible for the disease.

Activation of the immune system in the intestines appears to be important in IBD. The immune system is composed
of immune cells and the proteins that these immune cells produce. Normally, these cells and proteins defend the
body against harmful bacteria, viruses, fungi, and other foreign invaders. Activation of the immune system causes
inflammation within the tissues where the activation occurs. (Inflammation is an important mechanism of defense
used by the immune system.)

Normally, the immune system is activated only when the body is exposed to harmful invaders. In patients with IBD,
however, the immune system is abnormally and chronically activated in the absence of any known invader. The
continued abnormal activation of the immune system results in chronic inflammation and ulceration. The susceptibility
to abnormal activation of the immune system is genetically inherited. Thus, first degree relatives (brothers, sisters,

30
children, and parents) of patients with IBD are more likely to develop these diseases. Recently a gene called NOD2
has been identified as being associated with Crohn's disease. This gene is important in determining how the body
responds to some bacterial products. Individuals with mutations in this gene are more susceptible to developing
Crohn's disease

How does Crohn's disease affect the intestines?

In the early stages, Crohn's disease causes small, scattered, shallow, crater-like areas (erosions) on the inner
surface of the bowel. These erosions are called aphthous ulcers. With time, the erosions become deeper and larger,
ultimately becoming true ulcers (which are deeper than erosions) and causing scarring and stiffness of the bowel. As
the disease progresses, the bowel becomes increasingly narrowed, and ultimately can become obstructed. Deep
ulcers can puncture holes in the wall of the bowel, and bacteria from within the bowel can spread to infect adjacent
organs and the surrounding abdominal cavity.

When Crohn's disease narrows the small intestine to the point of obstruction, the flow of the contents through the
intestine ceases. Sometimes, the obstruction can be caused suddenly by poorly-digestible fruit or vegetables that
plug the already-narrowed segment of the intestine. When the intestine is obstructed, digesting food, fluid and gas
from the stomach and the small intestine cannot pass into the colon. The symptoms of small intestinal obstruction
then appear, including severe abdominal cramps,nausea, vomiting, and abdominal distention. Obstruction of the
small intestine is much more likely since the small intestine is much narrower than the colon to begin with.

Deep ulcers can puncture holes in the walls of the small intestine and the colon, and create a tunnel between the
intestine and adjacent organs. If the ulcer tunnel reaches an adjacent empty space inside the abdominal cavity, a
collection of infected pus (an abdominal abscess) is formed. Patients with abdominal abscesses can develop tender
abdominal masses, high fevers, andabdominal pain.

When the ulcer tunnels into an adjacent organ, a channel (fistula) is formed. The formation of a fistula between the
intestine and the bladder (enteric-vesicular fistula) can cause frequent urinary tract infections and the passage
of gas and feces during urination. When a fistula develops between the intestine and the skin (enteric-cutaneous
fistula), pus and mucous emerge from a small painful opening on the skin of the abdomen. The development of a
fistula between the colon and the vagina (colonic-vaginal fistula) causes gas and feces to emerge through the vagina.
The presence of a fistula from the intestines to the anus (anal fistula) leads to a discharge of mucous and pus from
the fistula's opening around the anus.

How is Crohn's disease different from ulcerative colitis?

While ulcerative colitis causes inflammation only in the colon (colitis) and/or the rectum (proctitis), Crohn's disease
may cause inflammation in the colon, rectum, small intestine (jejunum and ileum), and, occasionally, even the
stomach, mouth, and esophagus.

The patterns of inflammation in Crohn's disease are different from ulcerative colitis. Except in the most severe cases,
the inflammation of ulcerative colitis tends to involve the superficial layers of the inner lining of the bowel. The
inflammation also tends to be diffuse and uniform. (All of the lining in the affected segment of the intestine is
inflamed.) Unlike ulcerative colitis, the inflammation of Crohn's disease is concentrated in some areas more than
others and involves layers of the bowel that are deeper than the superficial inner layers. Therefore, the affected
segment(s) of bowel in Crohn's disease often is studded with deeper ulcers with normal lining between these ulcers.

What are the symptoms of Crohn's disease?

Common symptoms of Crohn's disease include abdominal pain, diarrhea, and weight loss. Less common symptoms
include poor appetite, fever, night sweats, rectal pain, andrectal bleeding. The symptoms of Crohn's disease are
dependent on the location, the extent, and the severity of the inflammation. The different subtypes of Crohn's disease
and their symptoms are:

31
 1. Crohn's colitis is inflammation that is confined to the colon. Abdominal pain and bloody diarrhea are the
common symptoms. Anal fistulae and peri-rectal abscesses also can occur.
2. Crohn's enteritis refers to inflammation confined to the small intestine (the first part, called the jejunum or
the second part, called the ileum). Involvement of the ileum alone is referred to as Crohn's ileitis. Abdominal
pain and diarrhea are the common symptoms. Obstruction of the small intestine also can occur.
3. Crohn's terminal ileitis is inflammation that affects only the very end of the small intestine (terminal ileum),
the part of the small intestine closest to the colon. Abdominal pain and diarrhea are the common symptoms.
Small intestinal obstruction also can occur.
4. Crohn's entero-colitis and ileo-colitisare terms to describe inflammation that involve both the small
intestine and the colon. Bloody diarrhea and abdominal pain are the common symptoms. Small intestinal
obstruction also can occur.

Crohn's terminal ileitis and ileo-colitis are the most common types of Crohn's disease. (Ulcerative colitis frequently
involves only the rectum or rectum and sigmoid colon at the distal end of the colon. These are called ulcerative
proctitis and procto-sigmoiditis, respectively.)

Up to one third of patients with Crohn's disease may have one or more of the following conditions involving the anal
area:

1. Swelling of the tissue of the anal sphincter, the muscle at the end of the colon that controls defecation.
2. Development of ulcers and fissures (long ulcers) within the anal sphincter. These ulcers and fissures can
cause bleeding and pain with defecation.
3. Development of anal fistulae (abnormal tunnels) between the anus or rectum and the skin surrounding the
anus). Mucous and pus may drain from the openings of the fistulae on the skin.

Development of peri-rectal abscesses (collections of pus in the anal and rectal area). Peri-rectal abscesses
can cause fever, pain and tenderness around the anus.

What are the complications of Crohn's disease?

Complications of Crohn's disease may be related or unrelated to the inflammation within the intestine (such as
intestinal or extra-intestinal). Intestinal complications of Crohn's disease include obstruction and perforation of the
small intestine, abscesses (collections of pus), fistulae, and intestinal bleeding. Massive distention or dilatation of the
colon (megacolon), and rupture (perforation) of the intestine are potentially life-threatening complications. Both
generally require surgery, but, fortunately, these two complications are rare. Recent data suggest that there is an
increased risk of cancer of the small intestine and colon in patients with long-standing Crohn's disease.Extra-
intestinal complications involve the skin, joints, spine, eyes, liver, and bile ducts. Skin involvement includes painful
red raised spots on the legs (erythema nodosum) and an ulcerating skin condition generally found around the ankles
called pyoderma gangrenosum. Painful eye conditions (uveitis, episcleritis) can cause visual difficulties. Arthritis can
cause pain, swelling, and stiffness of the joints of the extremities. Inflammation of the low back (sacroiliac joint
arthritis) and of the spine (ankylosing spondylitis) can cause pain and stiffness of the spine. Inflammation of the liver
(hepatitis) or bile ducts (primary sclerosing cholangitis) also can occur. Sclerosing cholangitis causes narrowing and
obstruction of the ducts draining the liver and can lead to yellow skin (jaundice), recurrent bacterial infections,
and liver cirrhosis with liver failure. Sclerosing cholangitis with liver failure is one of the reasons for performing liver
transplantation. Sclerosing cholangitis frequently is complicated by the development of cancer of the bile ducts.

How is Crohn's disease diagnosed?

The diagnosis of Crohn's disease is suspected in patients with fever, abdominal pain and tenderness, diarrhea with or
without bleeding, and anal diseases. Laboratory blood tests may show elevated white cell counts and sedimentation

32
rates, both of which suggest infection or inflammation. Other blood tests may show low red blood cell counts
(anemia), low blood proteins, and low body minerals, reflecting loss of these elements due to chronic diarrhea.

Barium x-ray studies can be used to define the distribution, nature, and severity of the disease. Barium is a chalky
material that is visible by x-ray and appears white on x-ray films. When barium is ingested orally (upper GI series) it
fills the intestine and pictures (x-rays) can be taken of the stomach and the small intestines. When barium is
administered through the rectum (barium enema), pictures of the colon and the terminal ileum can be obtained.
Barium x-rays can show ulcerations, narrowing, and, sometimes, fistulae of the bowel.

Direct visualization of the rectum and the large intestine can be accomplished with flexible viewing tubes
(colonoscopes).Colonoscopy is more accurate than barium x-rays in detecting small ulcers or small areas of
inflammation of the colon and terminal ileum. Colonoscopy also allows for small tissue samples (biopsies) to be taken
and sent for examination under the microscope to confirm the diagnosis of Crohn's disease. Colonoscopy also is
more accurate than barium x-rays in assessing the degree (activity) of inflammation.

Computerized axial tomography (CAT or CT) scanning is a computerized x-ray technique that allows imaging of the
entire abdomen and pelvis. It can be especially helpful in detecting abscesses.

Most recently, video capsule endoscopy has been added to the list of diagnostic tests for diagnosing Crohn's
disease. For video capsule endoscopy, a capsule containing a miniature video camera is swallowed. As the capsule
travels through the small intestine, it sends video images of the lining of the small intestine to a receiver carried on a
belt at the waist. The images are downloaded and then reviewed on a computer. The value of video capsule
endoscopy is that it can identify the early, mild abnormalities of Crohn's disease. Video capsule endoscopy may be
particularly useful when there is a strong suspicion of Crohn's disease but the barium x-rays are normal. (Barium x-
rays are not as good at identifying early, mild Crohn's disease.)

Video capsule endoscopy should not be performed in patients who have obstruction of the small intestine. The
capsule may get stuck behind the obstruction and make the obstruction worse. Doctors usually also are reluctant to
perform video-capsule endoscopy for the same reason in patients who they suspect of having small intestinal
strictures (narrowed segments of small intestine that can result from prior surgery, prior radiation, or chronic
ulceration, for example, from Crohn's disease). There is also a theoretical concern for electrical interference between
the capsule and implanted cardiac pacemakers and defibrillators; however, so far in a small number of patients with
pacemakers or defibrillators who have undergone video capsule endoscopy there have been no problems.

How is Crohn's disease treated?

The symptoms and severity of Crohn's disease vary among patients. Patients with mild or no symptoms may not
need treatment. Patients whose disease is in remission (where symptoms are absent) also may not need treatment.

There is no medication that can cure Crohn's disease. Patients with Crohn's disease typically will experience periods
of relapse (worsening of inflammation) followed by periods of remission (reduced inflammation) lasting months to
years. During relapses, symptoms of abdominal pain, diarrhea, andrectal bleeding worsen. During remissions, these
symptoms improve. Remissions usually occur because of treatment with medications or surgery, but occasionally
they occur spontaneously without any treatment.

Since there is no cure for Crohn's disease, the goals of treatment are to 1) induce remissions, 2) maintain remissions,
3) minimize side effects of treatment, and 4) improve the quality of life. Treatment of Crohn's disease and ulcerative
colitis with medications is similar though not always identical.

Medications for treating Crohn's disease include 1) antiinflammatory agents such as 5-ASA compounds,
corticosteroids, topical antibiotics, 2) immuno-modulators, 3) other medications.

33
 Antiinflammatory medications
Antiinflammatory medications that decrease intestinal inflammation are analogous toarthritis medications that
decrease joint inflammation. Different types of antiinflammatory medications used in the treatment of Crohn's disease
are:

 5-ASA compounds such assulfasalazine (Azulfidine) andmesalamine (Pentasa, Asacol, Dipentum, Colazal,

Rowasa enema, Canasa suppository) that act via direct contact (topically) with the inflamed tissue in order to be
effective.

 Corticosteroids that act systemically (without the need for direct contact with the inflamed tissue) to
decrease inflammation throughout the body. Systemic corticosteroids have important and predictable side effects if
used long-term.

 A new class of topical corticosteroid (for example, budesonide) that acts via direct contact (topically) with the
inflamed tissue. This class of corticosteroids has fewer side effects than systemic corticosteroids which are
absorbed into the body.

Antibiotics such as metronidazole (Flagyl) and ciprofloxacin (Cipro) that decrease inflammation by an

unknown mechanism5-ASA (mesalamine) oral medications
5-aminosalicylic acid (5-ASA), also calledmesalamine, is similar chemically to aspirin. Aspirin has been used for
many years for treating arthritis, bursitis, and tendonitis (conditions of tissue inflammation). Aspirin, however, is not
effective in treating Crohn's disease and ulcerative colitis, and even may worsen the inflammation. On the other hand,
5-ASA can be effective in treating Crohn's disease and ulcerative colitis if the drug can be delivered topically onto the
inflamed intestinal lining. For example, mesalamine (Rowasa) is an enema containing 5-ASA that is effective in
treating inflammation in the rectum. However, the enema solution cannot reach high enough to treat inflammation in
the upper colon and the small intestine. Therefore, for most patients with Crohn's disease involving both the ileum
(distal small intestine) and colon, 5-ASA must be taken orally.

If pure 5-ASA is taken orally, however, most of the 5-ASA would be absorbed in the stomach and the upper small
intestine, and very little 5-ASA would reach the ileum and colon. To be effective as an oral agent in treating Crohn's
disease, 5-ASA has to be modified chemically to escape absorption by the stomach and the upper intestines.

Sulfasalazine (Azulfidine)

Sulfasalazine (Azulfidine) was the first modified 5-ASA compound used in the treatment of Crohn's colitis and
ulcerative colitis. It has been used successfully for many years to induce remissions among patients with mild to
moderate ulcerative colitis. Sulfasalazine also has been used for prolonged periods for maintaining remissions.

Sulfasalazine consists of a 5-ASA molecule linked chemically to a sulfapyridine molecule. (Sulfapyridine is a sulfa
antibiotic.) Connecting the two molecules together prevents absorption by the stomach and the upper intestines.
When sulfasalazine reaches the ileum and the colon, the bacteria that normally are present break the link between
the two molecules. After breaking away from 5-ASA, sulfapyridine is absorbed into the body and later eliminated in
the urine. Most of the active 5-ASA, however, is available within the terminal ileum and colon to treat the colitis.

Most of the side effects of sulfasalazine are due to the sulfapyridine molecule. These side effects include nausea,
heartburn, headache, anemia, skin rashes, and, in rare instances, hepatitis and kidney inflammation. In men,
sulfasalazine can reduce the sperm count. The reduction in sperm count is reversible, and the count usually becomes
normal after the sulfasalazine is discontinued or changed to a different 5- ASA compound.

Because the newer 5-ASA compounds [for example, mesalamine (Asacol and Pentasa)] do not have the
sulfapyridine component and have fewer side effects than sulfasalazine, they are being used more frequently in
treating Crohn's disease and ulcerative colitis.

Asacol

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Asacol is a tablet consisting of the 5-ASA compound surrounded by an acrylic resin coating. Asacol is sulfa-free. The
resin coating prevents the 5-ASA from being absorbed as it passes through the stomach and the small intestine.
When the tablet reaches the terminal ileum and the colon, the resin coating dissolves, and the active 5-ASA drug is
released.

Asacol is effective in inducing remissions in patients with mild to moderate ulcerative colitis. It also is effective when
used in the longer term to maintain remissions. Some studies have shown that Asacol also is effective in treating
Crohn's ileitis and ileo-colitis, as well as in maintaining remission in patients with Crohn's disease.

The recommended dose of Asacol for inducing remissions is two 400 mg tablets three times daily (a total of 2.4
grams a day). At least two tablets of Asacol twice daily (1.6 grams a day) is recommended for maintaining remission.
Occasionally, the maintenance dose is higher.

As with Azulfidine, the benefits of Asacol are dose-related. If patients do not respond to 2.4 grams a day of Asacol,
the dose frequently is increased to 3.6 - 4.8 grams a day to induce remission. If patients fail to respond to the higher
doses of Asacol, then other alternatives such as corticosteroids are considered.

Pentasa

Pentasa is a capsule consisting of small spheres containing 5-ASA. Pentasa is sulfa-free. As the capsule travels
down the intestines, the 5-ASA inside the spheres is released slowly into the intestine. Unlike Asacol, the active drug
5-ASA in Pentasa is released into the small intestine as well as the colon. Therefore, Pentasa can be effective in
treating inflammation in the small intestine and is currently the most commonly used 5-ASA compound for treating
mild to moderate Crohn's disease in the small intestine.

Patients with Crohn's disease occasionally undergo surgery to relieve small intestinal obstruction, drain abscesses, or
remove fistulae. Usually, the diseased portions of the intestines are removed during surgery. After successful
surgery, patients can be free of disease and symptoms (in remission) for a while. In many patients, however, Crohn's
disease eventually returns. Pentasa helps maintain remissions and reduces the chances of the recurrence of Crohn's
disease after surgery.

In the treatment of Crohn's ileitis or ileocolitis, the dose of Pentasa usually is four 250 mg capsules four times daily (a
total of 4 grams a day). For maintenance of remission in patients after surgery, the dose of Pentasa is between 3-4
grams daily.

Olsalazine (Dipentum)

Olsalazine (Dipentum) is a capsule in which two molecules of 5-ASA are joined together by a chemical bond. In this
form, the 5-ASA cannot be absorbed from the stomach and intestine. Intestinal bacteria are able to break apart the
two molecules releasing the active individual 5-ASA molecules into the intestine. Since intestinal bacteria are more
abundant in the ileum and colon, most of the active 5-ASA is released in these areas. Therefore, olsalazine is most
effective for disease that is limited to the ileum or colon. Although clinical studies have shown that olsalazine is
effective for maintenance of remission in ulcerative colitis, up to 11% of patients experience diarrhea when taking
olsalazine. Because of this, olsalazine is not often used. The recommended dose of olsalazine is 500 mg twice a day.

Balsalazide (Colazal)

Balsalazide (Colazal) is a capsule in which the 5-ASA is linked by a chemical bond to another molecule that is inert
(without effect on the intestine) and prevents the 5-ASA from being absorbed. This drug is able to travel through the
intestine unchanged until it reaches the end of the small bowel (terminal ileum) and colon. There, intestinal bacteria
break apart the 5-ASA and the inert molecule releasing the 5-ASA. Because intestinal bacteria are most abundant in

35
the terminal ileum and colon, balsalazide is used to treat inflammatory bowel disease predominantly localized to the
colon.

Side effects of oral 5-ASA compounds

The 5-ASA compounds have fewer side effects than Azulfidine and also do not reduce sperm counts. They are safe
medications for long-term use and are well-tolerated.

Patients allergic to aspirin should avoid 5-ASA compounds because they are similar chemically to aspirin.

Rare kidney and lung inflammation has been reported with the use of 5-ASA compounds. Therefore, 5-ASA should
be used with caution in patients with kidney disease. It also is recommended that blood tests of kidney function be
done before starting and periodically during treatment.

Rare instances of worsening of diarrhea, cramps, and abdominal pain, at times accompanied by fever, rash, and
malaise, may occur. This reaction is believed to represent an allergy to the 5-ASA compound.

5-ASA rectal medications (Rowasa Canasa)

Rowasa is 5-ASA in enema form. 5-ASA by enema is most useful for treating ulcerative colitis involving only the distal
colon since the enema easily can reach the inflamed tissues of the distal colon. Rowasa also is used in treating
Crohn's disease in which there is inflammation in and near the rectum. Each Rowasa enema contains 4 grams of 5-
ASA. The enema usually is administered at bedtime, and patients are encouraged to retain the enema through the
night. The enema contains sulfite and should not be used by patients with sulfite allergy. Otherwise, Rowasa enemas
are safe and well-tolerated.

Canasa is 5-ASA in suppository form. It is used for treating ulcerative proctitis. Each suppository contains 500 mg of
5-ASA and usually is administered twice daily.

Both enemas and suppositories have been shown to be effective in maintaining remission in patients with ulcerative
colitis limited to the distal colon and rectum.

Corticosteroids
Corticosteroids (for example, prednisone,prednisolone, hydrocortisone, etc.) have been used for many years to treat
patients with moderate to severe Crohn's disease and ulcerative colitis and to treat patients who fail to respond to 5-
ASA. Unlike 5-ASA, corticosteroids do not require direct contact with the inflamed intestinal tissues to be effective.

Oral corticosteroids are potent antiinflammatory medications. After absorption, corticosteroids exert prompt
antiinflammatory actions throughout the body, including the intestines. Consequently, they are used in treating
Crohn's disease anywhere in the small intestine, as well as ulcerative and Crohn's colitis. In critically ill patients,
intravenous corticosteroids (such as hydrocortisone) can be given in the hospital. For patients with proctitis,
hydrocortisone enemas (Cortenema) can be used to deliver the corticosteroid directly to the inflamed tissue. By using
the corticosteroid topically, less of it is absorbed into the body and the frequency and severity of side effects are
lessened (but not eliminated) as compared with systemic corticosteroids.

Corticosteroids are faster-acting than 5-ASA, and patients frequently experience improvement in their symptoms
within days of beginning them. Corticosteroids, however, do not appear to be useful in maintaining remission in
Crohn's disease and ulcerative colitis or in preventing the return of Crohn's disease after surgery.

Side effects of corticosteroids

The frequency and severity of side effects of corticosteroids depend on the dose and duration of their use. Short
courses of corticosteroids, for example, usually are well-tolerated with few and mild side effects. Long-term use of

36
 high doses of corticosteroids usually produces predictable and potentially serious side effects. Common side effects
include:

 rounding of the face (moon face),

 acne, 

 increased body hair, 

 diabetes, 

 weight gain, 

 high blood pressure,

 cataracts, 

 glaucoma, 

 increased susceptibility to infections, 

 muscle weakness,

 depression,

 insomnia,

 mood swings,

 personality changes,

 irritability, and

 thinning of the bones (osteoporosis) with fractures of the spine. 

Children receiving corticosteroids experience stunted growth.

The most serious complication from long term corticosteroid use is aseptic necrosis of the hip joints. Aseptic
necrosis is a condition in which there is death and degeneration of the hip bone. It is a painful condition that can
ultimately lead to the need for surgical replacement of the hip. Aseptic necrosis also has been reported in the knee
joints. It is not known how corticosteroids cause aseptic necrosis. The estimated incidence of aseptic necrosis among
corticosteroid users is 3%-4%. Patients on corticosteroids who develop pain in the hips or knees should report the
pain to their doctors promptly. Early diagnosis of aseptic necrosis with cessation of corticosteroids might decrease the
severity of the aseptic necrosis and the need for hip replacement surgery.

Prolonged use of corticosteroids can depress the ability of the body's adrenal glands to produce cortisol (a natural
corticosteroid necessary for proper functioning of the body). Therefore, abruptly discontinuing corticosteroids can
cause symptoms due to a lack of natural cortisol (a condition called adrenal insufficiency). Symptoms of adrenal
insufficiency include nausea, vomiting, and even shock. Withdrawing corticosteroids too quickly also can produce
symptoms of joint pain, fever, and malaise. Therefore, when corticosteroids are discontinued, the dose usually is
tapered gradually rather than stopped abruptly.

37
 Even after corticosteroids are discontinued, the adrenal glands' ability to produce cortisol can remain depressed from
months up to two years. The depressed adrenal glands may not be able to produce increased amounts of cortisol to
help the body handle thestress of accidents, surgery, and infections. Therefore, patients need additional
corticosteroids during stressful situations to avoid developing adrenal insufficiency. Because corticosteroids are not
useful in maintaining remission in ulcerative colitis and Crohn's disease, and because they have predictable and
potentially serious side effects, they should be used for the shortest possible length of time.

Proper use of corticosteroids

Once the decision is made to use systemic corticosteroids, treatment usually is initiated with prednisone, 40-60 mg
daily. The majority of patients with Crohn's disease respond with an improvement in symptoms within a few weeks.
Once symptoms have improved, prednisone is reduced by 5-10 mg per week until a dose of 20 mg per day is
reached. The dose then is reduced at a slower rate until the corticosteroid is discontinued. Gradually reducing
corticosteroids not only minimizes the symptoms of adrenal insufficiency, it also reduces the chances of an abrupt
recurrence of inflammation.

Many doctors use 5-ASA compounds and corticosteroids together. In patients who achieve remission with
corticosteroids, 5-ASA compounds often are continued alone to maintain remission.

In patients whose symptoms return corticosteroids are slowly being reduced, the dose of corticosteroids is increased
slightly to control the symptoms. Once the symptoms are under control, the reduction of corticosteroids can resume
at a slower pace. Unfortunately, many patients who require corticosteroids to induce remissions become
corticosteroid dependent. These patients consistently develop symptoms whenever the corticosteroid dose falls
below a certain level. In such patients who are corticosteroid dependent as well as in patients who are unresponsive
to corticosteroids and other antiinflammatory medications, immuno-modulator medications or surgery must be
considered. The management of patients who are corticosteroid dependent or patients with severe disease that
responds poorly to medications is complex. Doctors who are experienced in treating ulcerative colitis and Crohn's
disease and in using immuno-modulators should evaluate these patients.

Prevention of osteoporosis

Long-term use of corticosteroids can cause osteoporosis. Calcium is very important in the formation and maintenance
of healthy bones. Corticosteroids decrease the absorption of calcium from the intestine and increase the loss of
calcium from the kidneys. Increasing dietary calcium intake is important but alone cannot halt corticosteroid-induced
osteoporosis. To prevent or minimize osteoporosis, management of patients on long-term corticosteroids should
include:

 Adequate intake of calcium (1000 mg daily in premenopausal women, 1,500 mg daily in postmenopausal
women) and vitamin D (800 units daily).

 Periodic review with the doctor of the need for continued corticosteroid treatment and use of the lowest
effective dose if continued treatment is necessary.

 For patients taking corticosteroids for more than three months, a bone density study may be helpful in
determining the extent of bone loss and the need for more aggressive treatment. 

 Regular weight-bearing exercise and stopping smoking (cigarettes). 

 Discussion with the doctor regarding the use of alendronate (Fosamax),risedronate (Actonel),

or etidronate (Didronel) to prevent or treat corticosteroid-induced osteoporosis

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Budesonide (Entocort EC)
Budesonide (Entocort EC) is a new type of corticosteroid for treating Crohn's disease. Like other corticosteroids,
budesonide is a potent antiinflammatory medication. Unlike other corticosteroids, however, budesonide acts only via
direct contact with the inflamed tissues (topically) and not systemically. As soon as budesonide is absorbed into the
body, the liver converts it into inactive chemicals. Therefore, for effective treatment of Crohn's disease, budesonide,
like topical 5-ASA, must be brought into direct contact with the inflamed intestinal tissue.

Budesonide capsules contain granules that allow a slow release of the drug into the ileum and the colon. In a double-
blind multicenter study (published in 1998), 182 patients with Crohn's ileitis and/or Crohn's disease of the right colon
were treated with either budesonide (9 mg daily) or Pentasa (2 grams twice daily). Budesonide was more effective
than Pentasa in inducing remissions while the side effects were similar to Pentasa. In another study comparing the
effectiveness of budesonide with corticosteroids, budesonide was not better than corticosteroids in treating Crohn's
disease but had fewer side effects.

Because budesonide is broken down by the liver into inactive chemicals, it has fewer side effects than systemic
corticosteroids. It also suppresses the adrenal glands less than systemic corticosteroids. Budesonide will be available
as an enema for the treatment of proctitis.

Budesonide has not been shown to be effective in maintaining remission in patients with Crohn's disease. If used
long-term, budesonide also may cause some of the same side effects as corticosteroids. Because of this, the use of
budesonide should be limited to short-term treatment for inducing remission. Most budesonide is released in the
terminal ileum, it will have its best results in Crohn's disease limited to the terminal ileum.

It is not known whether budesonide is effective in treating patients with ulcerative colitis, and it is currently not
recommended for the treatment of ulcerative colitis.

Antibiotics for Crohn's disease

Antibiotics such as metronidazole (Flagyl) and ciprofloxacin (Cipro) have been used for treating Crohn's colitis. Flagyl
also has been useful in treating anal fistulae in patients with Crohn's disease. The mechanism of action of these
antibiotics in Crohn's disease is not well understood.

Metronidazole (Flagyl)

Metronidazole (Flagyl) is an antibiotic that is used for treating several infections caused by parasites (for example,
giardia) and bacteria (for example, infections caused by anaerobic bacteria, and vaginal infections). It is effective in
treating Crohn's colitis and is particularly useful in treating patients with anal fistulae. Chronic use of metronidazole in
doses higher than 1 gram daily can be associated with permanent nerve damage (peripheral neuropathy). The early
symptoms of peripheral neuropathy are numbness and tingling in the fingertips, toes, and other parts of the
extremities. Metronidazole should be stopped promptly if these symptoms appear. Metronidazole and alcohol
together can cause severe nausea, vomiting, cramps, flushing, and headache. Patients taking metronidazole should
avoid alcohol. Other side effects of metronidazole include nausea, headaches, loss of appetite, a metallic taste, and,
rarely, a rash.

Ciprofloxacin (Cipro)

Ciprofloxacin (Cipro) is another antibiotic used in the treatment of Crohn's disease. It can be used in combination with
metronidazole.

39
 Summary of antiinflammatory medications

 Azulfidine, Asacol, Pentasa, Dipentum, Colazal and Rowasa all contain 5-ASA which is the active topical
antiinflammatory ingredient. Azulfidine was the first 5-ASA medication used in treating ulcerative colitis and
Crohn's disease, but the newer 5-ASA medications have fewer side effects.

 Pentasa and Asacol have been found to be effective in treating patients with Crohn's ileitis and ileo-colitis.
Rowasa enemas and Canasa suppositories are safe and effective for treating patients with proctitis. For mild to
moderate Crohn's ileitis or ileo-colitis, doctors usually start with Pentasa or Asacol. If Pentasa or Asacol is
ineffective, doctors may try antibiotics such as Cipro or Flagyl for prolonged periods (often months).

 In patients with moderate to severe disease and in patients who fail to respond to 5-ASA compounds and/or
antibiotics, systemic corticosteroids can be used. Systemic corticosteroids are potent and fast-acting
antiinflammatory agents for treating Crohn's enteritis and colitis as well as ulcerative colitis.

 Systemic corticosteroids are not effective in maintaining remission in patients with Crohn's disease. Serious
side effects can result from prolonged corticosteroid treatment.

 To minimize side effects, corticosteroids should be gradually tapered as soon as a remission is achieved. In
patients who become corticosteroid dependent or are unresponsive to corticosteroid treatment, surgery or
immuno-modulator treatment are considered.

 A new class of topical corticosteroids (budesonide) may have fewer side effects than systemic
corticosteroids.

Immuno-modulator medications
Immuno-modulators are medications that affect the body's immune system. The immune system is composed of
immune cells and the proteins that they produce. These cells and proteins serve to protect the body against harmful
bacteria, viruses, fungi, and other foreign invaders. Activation of the immune system causes inflammation within the
tissues where the activation occurs. (Inflammation is, in fact, an important mechanism used by the immune system to
defend the body.) Normally, the immune system is activated only when the body is exposed to foreign invaders. In
patients with Crohn's disease and ulcerative colitis, however, the immune system is abnormally and chronically
activated in the absence of any known invader.

Immuno-modulators decrease tissue inflammation by reducing the population of immune cells and/or by interfering
with their production of proteins. Decreasing the activity of the immune system with immuno-modulators increases the
risk of infections; however, the benefits of controlling moderate to severe Crohn's disease usually outweigh the risks
of infection due to weakened immunity. Examples of immuno-modulators are 6-mercaptopurine (6-
MP),azathioprine (Imuran), methotrexate (Rheumatrex, Trexall), infliximab (Remicade), adalimumab(Humira).

Azathioprine (Imuran) and 6-mercaptopurine (6-MP, Purinethol)

Azathioprine (Imuran) and 6-mercaptopurine (6-MP, Purinethol) are medications that weaken the body's immune
system by reducing the population of a class of immune cells called lymphocytes. Azathioprine and 6-MP are related
chemically. (Actually, azathioprine is converted into 6-MP within the body.) In high doses, these two drugs have been
useful in preventing rejection of transplanted organs and in treating leukemia. In low doses, they have been used for
many years to treat patients with moderate to severe Crohn's disease and ulcerative colitis.

Azathioprine and 6-MP are increasingly recognized by doctors as valuable drugs in treating Crohn's disease and
ulcerative colitis. Some 70% of patients with moderate to severe disease will benefit from these drugs. Azathioprine
and 6-MP are used primarily in the following situations:

1. Severe Crohn's disease and ulcerative colitis not responding to corticosteroids.

40
 2. The presence of undesirable corticosteroid-related side effects.
3. Corticosteroid dependency, a condition in which patients are unable to discontinue corticosteroids without
developing relapses of their disease.
4. Maintenance of remission.

When azathioprine and 6-MP are added to corticosteroids in the treatment of Crohn's disease not responding to
corticosteroids alone, there may be an improved response. Also, smaller doses and shorter courses of corticosteroids
may be able to be used. Some patients can discontinue corticosteroids altogether without experiencing relapses of
their disease. This corticosteroid-lowering effect has earned azathioprine and 6-MP their reputation as "steroid-
sparing" medications.

In Crohn's disease patients with severe disease who suffer frequent relapses, 5-ASA may not be sufficient, and the
more potent azathioprine and 6-MP will be necessary to maintain remissions. In the lower doses used to treat
Crohn's disease, the long-term side effects of azathioprine or 6- MP are less serious than those of long-term
corticosteroids or repeated courses of corticosteroids.

Patients with Crohn's disease may undergo surgery to remove a segment of the intestine that is obstructed or
contains a fistula. After surgical removal of the diseased segments, the patients often will be free of disease and
symptoms for a while, but many eventually will have their disease recur. During these recurrences, previously healthy
intestine can become inflamed. Long-term 5-ASA (such as Pentasa) and 6-MP both are effective in reducing the
chances of recurrence after surgery.

Anal fistulae can develop in some patients with Crohn's disease. Anal fistulae are abnormal tracts (tunnels) that form
between the small intestine or colon and the skin around the anus. Drainage of fluid and mucous from the opening of
the fistula is a troublesome problem. These fistulae are difficult to treat and do not heal readily. Metronidazole (Flagyl)
has been used with some success in promoting healing of these fistulae. In difficult cases, azathioprine and 6-MP
may be successful in promoting healing.

Side effects of azathioprine and 6-MP

Side effects of azathioprine and 6-MP include increased vulnerability to infections, inflammation of the liver (hepatitis)
and the pancreas (pancreatitis), and bone marrow toxicity (interference with the formation of cells that circulate in the
blood).

The goal of treatment with azathioprine and 6-MP is to lower the body's production of certain types of white blood
cells (lymphocytes) in order to decrease the inflammation in the intestines; however, lowering the number of
lymphocytes may increase vulnerability to infections. For example, in a group of patients with severe Crohn's disease
unresponsive to standard doses of azathioprine, raising the dose of azathioprine helped to control the disease, but
two patients developed cytomegalovirus (CMV) infection. (CMV typically infects individuals with weakened immune
systems such as patients with AIDS and cancer patients receiving chemotherapy).

Azathioprine and 6-MP can induce inflammation of the liver (hepatitis) and pancreas (pancreatitis). Pancreatitis
typically causes severe abdominal pain and sometimes vomiting. Pancreatitis due to azathioprine or 6-MP occurs in
3%-5% of patients, usually during the first several weeks of treatment. Patients who develop pancreatitis should not
receive either of these two medications again.

Azathioprine and 6-MP also suppress the bone marrow. The bone marrow is where the red blood cells, white blood
cells, and platelets are made. Actually, a slight reduction in the white cell count during treatment is desirable since it
suggests that the dose of azathioprine or 6-MP is high enough to have an effect; however, excessively low red or

41
white blood cell counts indicates bone marrow toxicity. Therefore, patients on azathioprine or 6-MP should have
periodic blood counts (usually every two weeks initially and then every three months during maintenance) to monitor
the effect of the drugs on the bone marrow.

Patients on long-term, high dose azathioprine to prevent rejection of the kidney after kidney transplantation have an
increased risk of developing lymphoma, a malignant disease of lymph cells. There is no evidence at present that long
term use of azathioprine or 6-MP, in the lower doses used in Crohn's disease, increases the risk of lymphoma,
leukemia or other malignancies.

The use of azathioprine and 6-MP in pregnant women must be carefully considered. There are reports suggesting
that the use of azathioprine or 6-MP in pregnancy is safer than once thought. The risk of continuing azathioprine or 6-
MP during conception and pregnancy must be weighed against the risk of worsening disease if they are stopped. On
the other hand, worsening disease has been shown clearly to be a significant risk to the fetus.

Other issues with azathioprine and 6-MP

One problem with 6-MP and azathioprine is their slow onset of action. Typically, full benefit of these drugs is not
realized for three months or longer. During this time, corticosteroids frequently have to be maintained at high levels to
control inflammation.

The reason for this slow onset of action is partly due to the way doctors prescribe these drugs. For example, 6-MP is
typically started at a dose of 50 mg daily. The blood count is then checked two weeks later. If the lymphocytes are not
reduced, the dose of 6-MP is increased. This cautious, stepwise approach helps reduce bone marrow and liver
toxicity but also delays benefit from the drug.

Studies have shown that giving higher doses of 6-MP early can hasten the benefit of 6-MP without increasing the
toxicity in most patients, but some patients do develop severe bone marrow toxicity. Scientists now believe that an
individual's vulnerability to 6-MP toxicity is genetically inherited. Blood tests can be performed to identify those
individuals with increased vulnerability to 6-MP toxicity. Blood tests also can be performed to measure the levels of
certain by-products of 6-MP. The levels of these by-products in the blood help doctors more quickly determine
whether the dose of 6-MP is right for the patient.

TPMT genetics and safety of azathioprine and 6-MP

Azathioprine is converted into 6-MP in the body and 6-MP then is partially converted in the body into inactive and
non-toxic chemicals by an enzyme called thiopurine methyltransferase (TPMT). These chemicals then are eliminated
from the body. The activity of TPMT enzyme (the ability of the enzyme to convert 6-MP into inactive and non-toxic
chemicals) is genetically determined, and approximately 10% of the population in the Untied States has a reduced or
absent TPMT activity. In this 10% of patients, 6-MP accumulates and is converted into chemicals that are toxic to the
bone marrow where blood cells are produced. Thus, when given normal doses of azathioprine or 6-MP, these
patients with reduced or absent TPMT activities can develop seriously low white blood cell counts for prolonged
periods of time, exposing them to serious life-threatening infections.

Doctors now can perform genetic testing for TPMT before starting azathioprine or 6-MP. Patients found to have
genes associated with reduced or absent TPMT activity are treated with alternative medications or are prescribed
substantially lower than normal doses of 6-MP or Azathioprine.

A word of caution is in order, however. Having normal TPMT genes is no guarantee against azathioprine or 6-MP
toxicity. Rarely, a patient with normal TPMT genes can develop severe toxicity in the bone marrow and a low white
blood cell count even with normal doses of 6-MP or azathioprine. Therefore, all patients taking 6-MP or azathioprine
(regardless of TPMT genetics) have to be closely monitored by a doctor who will order periodic blood counts for as
long as the medication is taken.

42
Another cautionary note; allopurinol (Zyloprim), used in treating high blood uric acids levels, can induce bone marrow
toxicity when used together with azathioprine or 6-MP. Zyloprim used together with azathioprine or 6-MP has similar
effect as having reduced TPMT activity, causing increased accumulation of the 6-MP metabolite that is toxic to the
bone marrow.

6-MP metabolite levels

In addition to monitoring blood cell counts and liver tests, doctors also may measure blood levels of the chemicals
that are formed from 6-MP (6-MP metabolites), which can be helpful in several situations such as:

1. If a patient's disease is not responding to standard doses of 6-MP or azathioprine and his/her 6-MP blood
metabolite levels are low, doctors may increase the 6-MP or azathioprine dose.
2. If a patient's disease is not responding to treatment and his/her 6-MP blood metabolite levels are zero,
he/she is not taking his/her medication. The lack of response in this case is due to patient non-compliance.

Duration of treatment with azathioprine and 6-MP

Patients have been maintained on 6-MP or azathioprine for years without important long-term side effects.
Patients on long-term azathioprine or 6-MP, however, should be closely monitored by their doctors. There
are data suggesting that patients on long-term maintenance fare better than those who stop these
medications. Thus, those who stop azathioprine or 6-MP are more likely to experience recurrence of their
disease and are more likely to need corticosteroids or undergo surgery.

Infliximab (Remicade)
Infliximab (Remicade) is an antibody that attaches to a protein called tumor necrosis factor-alpha (TNF-alpha). TNF-
alpha is one of the proteins produced by immune cells during activation of the immune system. TNF-alpha, in turn,
stimulates other cells of the immune system to produce and release other proteins that promote inflammation. In
Crohn's disease, there is continued production of TNF-alpha as part of the immune activation. Infliximab, by attaching
to TNF-alpha, blocks its activity and in so doing decreases the inflammation.

Infliximab, an antibody to TNF-alpha, is produced by the immune system of mice after the mice are injected with
human TNF-alpha. The mouse antibody then is modified to make it look more like a human antibody, and this
modified antibody is infliximab. Such modifications are necessary to decrease the likelihood of allergic reactions when
the antibody is administered to humans. Infliximab is given by intravenous infusion over two hours. Patients are
monitored throughout the infusion for adverse reactions.

In August 1998 the United States Food and Drug Administration approved the use of infliximab for the short-term
treatment of moderate to severe Crohn's disease patients who respond inadequately to corticosteroids, azathioprine,
or 6-MP.

Effectiveness of infliximab

Infliximab is an effective and fast-acting drug for the treatment of active Crohn's disease. In a study involving patients
with moderate to severe Crohn's disease who were not responding to corticosteroids or immuno-modulators, 65%
experienced improvement in their disease after one infusion of infliximab. Some patients noticed improvement in
symptoms within days of the infusion. Most patients experienced improvement within two weeks.

In patients who respond to infliximab, the improvements in symptoms can be dramatic. Moreover, there can be
impressively rapid healing of the ulcers and the inflammation in the intestines after just one infusion.

43
The anal fistulae of Crohn's disease are troublesome and often difficult to treat. Infliximab has been found to be
effective for treating fistulae.

Duration of benefits with infliximab

The majority of the patients who responded to a first infusion of infliximab developed recurrence of their disease
within three months. However, studies have shown that repeated infusions of infliximab every eight weeks are safe
and effective in maintaining remission in many patients over a one to two year period. Response to infliximab after
repeated infusions sometimes is lost if the patient starts to develop antibodies to the infliximab (which attach to the
infliximab and prevent it from working). Studies are now being done to determine the long-term safety and
effectiveness of repeated infusions of infliximab.

One potential use of infliximab is to quickly control active and severe disease. The use of infliximab then may be
followed by maintenance treatment with azathioprine, 6-MP or 5-ASA compounds. Azathioprine or 6-MP also may be
helpful in preventing the development of antibodies against infliximab.

Side effects of infliximab

Infliximab generally is well-tolerated. There have been rare reports of side effects during infusions, including chest
pain, shortness of breath, and nausea. These effects usually resolve spontaneously within minutes if the infusion is
stopped. Other commonly-reported side effects include headache and upper respiratory tract infection.

TNF-alpha is an important protein for defending the body against infections. Infliximab, like immuno-modulators,
increases the risk for infection. One case of salmonella colitis and several cases of pneumonia have been reported
with the use of infliximab. There also have been cases of tuberculosis (TB) reported after the use of infliximab.

Because infliximab is partly a mouse protein, it may induce an immune reaction when given to humans, especially
with repeated infusions. In addition to the side effects that occur while the infusion is being given, patients also may
develop a "delayed allergic reaction" that occurs 7-10 days after receiving the infliximab. This type of reaction may
cause flu-like symptoms with fever, joint pain and swelling, and a worsening of Crohn's disease symptoms. It can be
serious, and if it occurs, a physician should be contacted. Paradoxically, those patients who have more frequent
infusions of infliximab are less likely to develop this type of delayed reaction compared to those patients who receive
infusions separated by long intervals (6-12 months). Although infliximab is only FDA approved for a single infusion at
this time, patients should be aware that they are likely to require repeated infusions once Remicade therapy has been
initiated.

Rare cases of nerve inflammation such as optic neuritis (inflammation of the nerve of the eye) and mother neuropathy
has been reported with the use of infliximab.

Precautions with infliximab

Infliximab can aggravate and cause the spread of an existing infection. Therefore, it should not be given to patients
with pneumonia, urinary tract infection or abscess (localized collection of pus). It now is recommended that patients
be tested for TB prior to receiving infliximab. Patients who previously had TB should inform their physician of this
before they receive infliximab infliximab can cause the spread of cancer cells; therefore, it should not be given to
patients with cancer.

Infliximab can promote intestinal scarring (part of the process of healing) and, therefore, can worsen strictures
(narrowed areas of the intestine caused by inflammation and subsequent scaring) and lead to intestinal obstruction. It
also can cause partial healing (partial closure) of anal fistulae. Partial closure of fistulae impedes drainage of fluid
through the fistulae, and may result in collections of fluid in which bacteria multiply, which can result in abscesses.

The effects infliximab on the fetus are not known.

44
Because infliximab is partly a mouse protein, some patients can develop antibodies against infliximab with repeated
infusions. Such antibodies can decrease the effectiveness of the drug. The chance of developing such antibodies can
be decreased by the concomitant use of 6-MP and corticosteroids. There are some reports of worsening heart
disease in patients who have received Remicade. The precise mechanism and role of infliximab in the development
of this side effect is unclear. As a precaution, individuals with heart disease should inform their physician of this
condition before receiving infliximab.

While infliximab represents an exciting new class of medications in the fight against Crohn's disease, caution is
warranted in its use. The long-term safety and effectiveness is not yet known.

Adalimumab (Humira)
Adalimumab is an anti-TNF agent similar to infliximab and decreases inflammation by blocking tumor necrosis factor
(TNF-alpha). In contrast to infliximab, adalimumab is a fully humanized anti-TNF antibody (no mouse protein).
Adalimumab is administered subcutaneously (under the skin) instead of intravenously as in the case of infliximab.

Rheumatologists have been using adalimumab for treating inflammation of the joints in patients with rheumatoid
arthritis,psoriatic arthritis, and ankylosing spondylitis. Four recent clinical trials (involving almost 1,500 patients)
comparing adalimumab to placebo, have demonstrated that adalimumab is also effective in treating inflammation in
the intestines of patients with Crohn's disease and in reducing signs and symptoms of Crohn's disease.

Adalimumab is comparable to infliximab in effectiveness and safety for inducing and maintaining remission in patients
suffering from Crohn's disease. Adalimumab is also effective in healing Crohn's anal fistulas. Adalimumab has been
shown to be effective for patients who either failed or cannot tolerate infliximab.

The Food and Drug Administration in February 2007, approved Humira (adalimumab) to treat adult patients with
moderately to severely active Crohn's disease. Adalimumab (Humira) is administered subcutaneously every two
weeks.

The side effects of Adalimumab

Adalimumab generally is well-tolerated. The most common side effect is skin reactions at the site of injection with
swelling, itching, or redness. Other common side effects include upper respiratory infections, sinusitis, and nausea.

TNF-alpha is an important protein for defending the body against infections. Adalimumab, like infliximab, increases
the risk of infection. There have been cases of tuberculosis (TB) reported after the use of infliximab and adalimumab.
It now is recommended that patients be tested for TB prior to receiving these agents. Patients who previously had TB
should inform their physician of this before they receive these agents. Adalimumab, like infliximab, can aggravate and
cause the spread of an existing infection. Therefore, it should not be given to patients with pneumonia, urinary tract
infection or abscess (localized collection of pus).

Rare cases of lymphoma (cancer of the lymphatic system) have been reported with the use of adalimumab. Rare
cases of nervous system inflammation have been reported with the use of adalimumab. The symptoms may include
numbness and tingling, vision disturbances, weakness in legs. Some patients receiving adalimumab may rarely
develop symptoms that mimic systemic lupus; these symptoms include skin rash, arthritis, chest pain, or shortness of
breath. These lupus-like symptoms resolve after stopping the drug.

There are some reports of worsening heart disease such as heart failure in patients who have received infliximab or
adalimumab. The precise mechanism and role of these agents in the development of this side effect is unclear. As a
precaution, individuals with heart disease should inform their physician of this condition before receiving infliximab or
adalimumab.

45
Severe allergic reactions with rash, difficulty breathing, and severe low blood pressure or shock are rare, but serious
allergic reactions can occur either after the fist injection or after many injections. Patients experiencing symptoms
of serious allergic reactionsshould seek emergency care are immediately

Methotrexate (Rheumatrex, Trexall)

Methotrexate (Rheumatrex, Trexall) is both an immuno-modulator and antiinflammatory medication. Methotrexate has
been used for many years in the treatment of severe rheumatoid arthritis and psoriasis. It has been helpful in treating
patients with moderate to severe Crohn's disease who are either not responding to azathioprine and 6- MP or are
intolerant of them. Methotrexate also may be effective in patients with moderate to severe ulcerative colitis who are
not responding to corticosteroids, azathioprine, or 6-MP. It can be given orally or by weekly injections under the skin
or into the muscles, but it is more reliably absorbed with the injections.

One major complication of methotrexate is the development of liver cirrhosis when the medication is given over a
prolonged period of time (years). The risk of liver damage is higher in patients who also abuse alcohol or are severely
obese. Although it has been recommended that a liver biopsy should be obtained in patients who have received a
cumulative (total) methotrexate dose of 1.5 grams or higher, the need for such biopsies is controversial.

Other side effects of methotrexate include low white blood cell counts and inflammation of the lungs.

Methotrexate should not be used in pregnant women because of toxic effects on the fetus.

Surgery in Crohn's disease

There is no surgical cure for Crohn's disease. Even when all of the diseased parts of the intestines are removed,
inflammation frequently recurs in previously healthy intestines months to years after the surgery. Therefore, surgery
in Crohn's disease is used primarily for:

1. Removal of a diseased segment of the small intestine that is causing obstruction.

2. Drainage of pus from abdominal and peri-rectal abscesses.
3. Treatment of severe anal fistulae that do not respond to drugs.
4. Resection of internal fistulae (such as a fistula between the colon and bladder) that are causing infections.

Usually, after the diseased portions of the intestines are removed surgically, patients can be free of disease and
symptoms for some time, often years. Surgery, when successfully performed, can lead to a marked improvement in a
patient's quality of life. In many patients, however, Crohn's disease eventually returns, affecting previously healthy
intestines. The recurrent disease usually is located at or near the previous site of surgery. In fact, 50% of patients can
expect to have a recurrence of symptoms within four years of surgery. Drugs such as Pentasa or 6-MP have been
useful in some patients to reduce the chances of relapse of Crohn's disease after surgery.

General measures
General measures which may help control Crohn's disease include dietary changes and supplementation. Since fiber
is poorly digestible, it can worsen the symptoms of intestinal obstruction. Hence, a low fiber diet may be
recommended, especially in those patients with small intestinal disease. A liquid diet may be of benefit when
symptoms are more severe. Intravenous nutrition or TPN (total peripheral nutrition) may be utilized when it is felt that
the intestine needs to "rest." Supplementation of calcium, folate andvitamin B12 is helpful when malabsorption of
these nutrients is apparent. The use of anti-diarrheal agents [diphenoxylate and atropine (Lomotil), loperamide
(Imodium)] and anti-spasmotics also can help relieve symptoms of cramps and diarrhea.

Conclusions
Crohn's disease is a chronic inflammatory disease involving predominantly the small intestine and colon. The
symptoms and the activity of the disease can come and go. Even though many effective medications are available to

46
control the activity of the disease, there is as yet no cure for Crohn's disease. Surgery can significantly improve the
quality of life in selected individuals, but recurrence of the disease after surgery is common. The disease can have
complications, both within and outside of the intestine. Newer treatments are actively being evaluated. A better
understanding of the role of genetics and environmental factors in the cause of Crohn's disease may lead to
improved treatments and prevention of the disease.

Postpartum psychosis
Postpartum (or puerperal) psychosis is a term that covers a group of mental illnesses with the sudden onset
of psychotic symptoms following childbirth. In this group there are at least a dozen organic psychoses, which
are described under another heading "organic pre- and postpartum psychoses".[1] The relatively common non-
organic form, still prevalent in Europe, North America and throughout the world, is sometimes called puerperal
bipolar disorder, because of its close link with manic depressive (bipolar) disorder;[2] but some of these mothers
have atypical symptoms (see below), which come under the heading of acute polymorphic (cycloid) psychosis
(schizophreniform in the US).[3] Puerperal mania was first clearly described by the German obstetrician
Osiander in 1797,[4] and a literature of over 2,000 works has accumulated since then. These psychoses are
endogenous, heritable illnesses with acute onset, benign episodic course and response to mood-normalizing
and mood-stabilizing treatments. The inclusion of severe postpartum depression under postpartum psychosis is
controversial: many clinicians would allow this only if depression was accompanied by psychotic features (see
below).

The onset is abrupt, and symptoms rapidly reach a climax of severity. Manic and acute polymorphic forms
almost always start within the first 14 days, but depressive psychosis may develop somewhat later.

[edit]Symptoms

Some patients have typical manic symptoms, such as euphoria, overactivity, decreased sleep requirement,
loquaciousness, flight of ideas, increased sociability, disinhibition, irritability, violence and delusions, which are
usually grandiose or religious in content; on the whole these symptoms are more severe than in mania
occurring at other times, with highly disorganized speech and extreme excitement. Others have severe
depression with delusions, verbal hallucinations, mutism, stupor or transient swings into hypomania. Some
switch from mania to depression (or vice versa) within the same episode. Atypical features include perplexity,
confusion, emotions like extreme fear and ecstasy, catatonia or rapid changes of mental state with transient
delusional ideas; these are so striking that some authors have regarded them as a distinct, specific disease,
but they are the defining features of acute polymorphic (cycloid) psychoses, and are seen in other contexts (for
example, menstrual psychosis) and in men.

[edit]Course and treatment

Without treatment, these psychoses can last many months; but with modern therapy they usually resolve within
a few weeks. A small minority follow a relapsing pattern, usually related to the menstrual cycle. Mothers who

47
suffer a puerperal episode are liable to other manic depressive or acute polymorphic episodes, some of which
occur after other children are born, some during pregnancy or after an abortion, and some unrelated to
childbearing. Puerperal recurrences occur after at least 20% of subsequent deliveries, or over 50% if
depressive episodes are included.[5]

Severe overactivity and delusions may require rapid tranquilization by neuroleptic (antipsychotic) drugs, but
they should be used with caution because of the danger of severe side effects including the neuroleptic
malignant syndrome.[6] Electro-convulsive (electroshock) treatment is highly effective.[7] Mood stabilizing drugs
such as lithium are also useful in treatment and possibly the prevention of episodes in women at high risk (i.e.,
women who have already experienced manic or puerperal episodes). The location of treatment is an issue:
hospitalization is disruptive to the family, and it is possible to treat moderately severe cases at home, where the
sufferer can maintain her role as a mother and build up her relationship with the newborn. This requires the
presence, round the clock, of competent adults (such as the baby's maternal grandmother), and frequent visits
by professional staff.[8] If hospital admission is necessary, there are advantages in conjoint mother and baby
admission. Yet multiple factors must be considered in the subsequent discharge plan to ensure the safety and
healthy development of both the baby and its mother.[9] This plan often involves a multidisciplinary team
structure to follow-up on mother, baby, their relationship and the entire family.

Suicide is rare, and infanticide extremely rare, during these episodes. It does occur, as illustrated by the
famous cases summarized below. Infanticide after childbirth is usually due to profound postpartum depression
(melancholic filicide) when it is often accompanied by suicide.[10]

[edit]Causes

These are world-wide disorders. Their incidence has been carefully measured by state-of-the-art
epidemiological studies, and is somewhat less than 1/1,000 deliveries.[11] They are more common in first time
mothers. As recognized by Marcé (1962), the link to menstruation, and especially menstrual psychosis, is an
important clue to the cause.[12][13] Molecular genetic studies suggest that there is a specific heritable factor.
[14]
 There is evidence of linkage to chromosome 16.[15]

[edit]Famous cases
[edit]Melanie Blocker-Stokes
Melanie Blocker-Stokes, of Chicago, IL, committed suicide by jumping from a building on June 11, 2001. In
February 2001 she gave birth to a healthy baby girl. In the weeks following the birth of her daughter, she
developed severe depression, in which (4 weeks after the birth) she stopped eating and drinking and could no
longer swallow. She thought her neighbors had all closed their blinds because they thought she was a bad
mother (a postpartum depressive psychosis).[16] She was in and out of Chicago area hospitals several times

48
over period of a few months. Her death led to the proposal of the Melanie Blocker-Stokes Postpartum
Depression Research and Care Act (H.R. 846 and S. 450), intended to expand research into the condition.[17]

[edit]Andrea Yates
Main article:  Andrea Yates

Andrea Yates methodically drowned her 5 children in a bathtub in her Clear Lake City, Houston, Texas house

on June 20, 2001. Her mental health began to deteriorate with the birth of each of her children, combined with
other external stressors. She attempted suicide twice and was hospitalized twice in a psychiatric facility in 1999
after delivering her fourth child. Yates was warned against having any more children, but conceived
approximately 7 weeks later. 3 months after the birth of her fifth child and shortly after the death of her father,
she began to rapidly degenerate. She was hospitalized twice more, and eventually released with orders that
she should not be left alone. During an hour when her husband had left for work and her mother-in-law was
scheduled to arrive, she killed all five of her children. She was consequently committed to a high-security
psychiatric hospital. Her case attracted a great deal of media attention, particularly to the concept of serious
mental illness following (and also caused by) childbirth. Some of this coverage proved to be problematic and
misleading. For example, the National Organization for Women (NOW) initially incorrectly noted on their
website that Yates had suffered from postpartum depression. The Individualist Feminists quickly pointed out
that Yates suffered from postpartum psychosis, a more serious and much less common disorder, and that the
clinical definition of postpartum depression does not list infanticide as a symptom.[18][19] This misrepresentation
of Yates' illness stigmatized a large number of mothers and made them less likely to seek professional help for
fear of being seen as a threat to their children and consequently being committed. NOW promptly revised their
statement to indicate postpartum psychosis.[20][21]

[edit]Legal status

Several nations including Canada, Great Britain, Australia and Italy recognize post partum mental illness as a
mitigating factor in cases where mothers kill their children.[22] In the United States, such a legal distinction is not
currently made.[22] Britain has had the Infanticide Act since 1922.

In 2009, Texas legislator Jessica Farrar proposed a bill that would recognize postpartum psychosis as a
defense for mothers who kill their infants.[23] Under the terms of the proposed legislation, if jurors concluded that
a mother's "judgment was impaired as a result of the effects of giving birth or the effects of lactation following
the birth", they would be allowed to convict her of the crime of infanticide, rather than murder.[22] The maximum
penalty for infanticide would be two years in prison.
Post partum psychosis

First recognized as a disorder in 1850, postpartum psychosis is a very serious mental condition that
requires immediate medical attention. Interestingly, studies on the rates of the disorder have shown that
the number of women experiencing postpartum psychosis haven’t changed since the mid 1800s.

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 What Is Postpartum Psychosis?
While it is the most extreme form of postpartum mood disorders, postpartum psychosis is also one of
the rarest. Usually described as a period when a woman loses touch with reality, the disorder occurs in
women who have recently given birth. It affects between one and two women per 1,000 women who have
given birth.

Unfortunately, though many women with the disorder realize something is wrong with them, fewer than
20% actually speak to their healthcare provider. Sadder still is the fact that often postpartum psychosis is
misdiagnosed or thought to be postpartum depression, thereby preventing a woman from receiving the
appropriate medical attention that she needs.

Women who do receive proper treatment often respond well but usually experience postpartum
depression before completely recovering. However, without treatment, the psychosis can lead to tragic
consequences. Postpartum psychosis has a 5% suicide rate and a 4% infanticide rate.

Postpartum Psychosis Signs

Although the onset of symptoms can occur at anytime within the first three months after giving birth,
women who have postpartum psychosis usually develop symptoms within the first two to three weeks
after delivery. Postpartum psychosis symptoms usually appear quite suddenly; in 80% of cases, the
psychosis occurs three to 14 days after a symptom-free period.

Signs of postpartum psychosis include:

 Hallucinations
 Delusions
 Illogical thoughts
 Insomnia
 Refusing to eat
 Extreme feelings of anxiety and agitation
 Periods of delirium or mania
 Suicidal or homicidal thoughts

Who Is At Risk?
Women with a personal history of psychosis, bipolar disorder or schizophrenia have an increased risk of
developing postpartum psychosis. Likewise, women who have a family history of psychosis, bipolar
disorder or schizophrenia have a greater chance of developing the disorder. Additonally, women who
have had had a past incidence of postpartum psychosis are between 20% and 50% more likely of
experiencing it again in a future pregnancy.

Causes of Postpartum Psychosis

Experts aren’t exactly sure why postpartum psychosis happens. However, they do offer a variety of
explanations for the disorder, with a woman’s changing hormones being at the top of their list. Other
possible reasons or contributing factors include a lack of social and emotional support; a low sense of
self-esteem due to a woman’s postpartum appearance; feeling inadequate as a mother; feeling isolated
and alone; having financial problems; and undergoing a major life change such as moving or starting a
new job.

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Treating Postpartum Psychosis
Postpartum psychosis is considered to be a mental health emergency and therefore requires immediate
attention. Because women who suffer from the psychosis are not always able or willing to speak with
someone about their disorder, it is sometimes necessary that their partner or another family member help
them get the medical attention they need. The condition is usually treated with medications, typically
antipsychotic drugs and sometimes antidepressants and/or antianxiety drugs. If a woman is thought to
pose a threat to herself or others, she will likely be hospitalized for a short time. Many women can also
benefit from psychological counseling and support group therapy. With proper care, most women are able
to recover from their disorder.

Postpartum Psychiatric Disorders

General Information
The Postpartum Period

During the postpartum period, about 85% of women experience some type of mood disturbance. For most
the symptoms are mild and short-lived; however, 10 to 15% of women develop more significant
symptoms of depression or anxiety. Postpartum psychiatric illness is typically divided into three
categories: (1) postpartum blues (2) postpartum depression and (3) postpartum psychosis. It may be useful
to conceptualize these disorders as existing along a continuum, where postpartum blues is the mildest and
postpartum psychosis the most severe form of postpartum psychiatric illness.

Postpartum Blues

It appears that about 50 to 85% of women experience postpartum blues during the first few weeks after
delivery. Given how common this type of mood disturbance is, it may be more accurate to consider the
blues as a normal experience following childbirth rather than a psychiatric illness. Rather than feelings of
sadness, women with the blues more commonly report mood lability, tearfulness, anxiety or irritability.
These symptoms typically peak on the fourth or fifth day after delivery and may last for a few hours or a
few days, remitting spontaneously within two weeks of delivery. While these symptoms are unpredictable
and often unsettling, they do not interfere with a woman’s ability to function. No specific treatment is
required; however, it should be noted that sometimes the blues heralds the development of a more
significant mood disorder, particularly in women who have a history of depression. If symptoms of
depression persist for longer than two weeks, the patient should be evaluated to rule out a more serious
mood disorder.

Postpartum Depression

PPD typically emerges over the first two to three postpartum months but may occur at any point after
delivery. Some women actually note the onset of milder depressive symptoms during pregnancy.
Postpartum depression is clinically indistinguishable from depression occurring at other times during a
woman’s life. The symptoms of postpartum depression include:

 Depressed or sad mood

 Tearfulness
 Loss of interest in usual activities
 Feelings of guilt
 Feelings of worthlessness or incompetence
 Fatigue

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  Sleep disturbance
 Change in appetite
 Poor concentration
 Suicidal thoughts
Significant anxiety symptoms may also occur. Generalized anxiety is common, but some women also
develop panic attacks or hypochondriasis. Postpartum obsessive-compulsive disorder has also been
reported, where women report disturbing and intrusive thoughts of harming their infant. Especially with
milder cases, it may be difficult to detect postpartum depression because many of the symptoms used to
diagnose depression (i.e., sleep and appetite disturbance, fatigue) also occur in postpartum women in the
absence of depression. The Edinburgh Postnatal Depression Scale is a 10-item questionnaire that may be
used to identify women who have PPD. On this scale, a score of 12 or greater or an affirmative answer on
question 10 (presence of suicidal thoughts) raise concern and indicate a need for more thorough
evaluation.
Postpartum Psychosis

Postpartum psychosis is the most severe form of postpartum psychiatric illness. It is a rare event that
occurs in approximately 1 to 2 per 1000 women after childbirth. Its presentation is often dramatic, with
onset of symptoms as early as the first 48 to 72 hours after delivery. The majority of women with
puerperal psychosis develop symptoms within the first two postpartum weeks.

It appears that in most cases, postpartum psychosis represents an episode of bipolar illness; the symptoms
of puerperal psychosis most closely resemble those of a rapidly evolving manic (or mixed) episode. The
earliest signs are restlessness, irritability, and insomnia. Women with this disorder exhibit a rapidly
shifting depressed or elated mood, disorientation or confusion, and erratic or disorganized behavior.
Delusional beliefs are common and often center on the infant. Auditory hallucinations that instruct the
mother to harm herself or her infant may also occur. Risk for infanticide, as well as suicide, is significant
in this population.

What Causes Postpartum Depression?

The postpartum period is characterized by a rapid shift in the hormonal environment. Within the first 48
hours after delivery, estrogen and progesterone concentrations fall dramatically. As these gonadal steroids
modulate neurotransmitter systems involved in the regulation of mood, many investigators have proposed
a role for these hormonal shirts in the emergence of postpartum affective illness. While it appears that
there is no consistent correlation between serum levels of estrogen, progesterone, cortisol, or thyroid
hormones and the occurrence of postpartum mood disturbance, some investigators hypothesize that there
is a subgroup of women who are particularly sensitive to the hormonal changes that take place after
delivery. This population of women may be more vulnerable to PPD and to other hormonally driven
mood disturbances, such as those occurring during the premenstrual phase of the menstrual cycle or
during the perimenopause.

Other factors may play a role in the etiology of PPD. One of the most consistent findings is that among
women who report marital dissatisfaction and/or inadequate social supports, postpartum depressive illness
is more common. Several investigators have also demonstrated that stressful life events occurring either
during pregnancy or near the time of delivery appear to increase the likelihood of postpartum depression.

While all of these factors may act together to cause PPD, the emergence of this disorder probably reflects
an underlying vulnerability to affective illness. Women with histories of major depression or bipolar
disorder are more vulnerable to PPD, and women who develop PPD will often go on to have recurrent
episodes of depression unrelated to pregnancy or childbirth.

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Who is at Risk for Postpartum Depression?

All women are vulnerable to postpartum depression, regardless of age, marital status, education level, or
socioeconomic status. While it is impossible to predict who will develop PPD, certain risk factors for
PPD have been identified, including:

 Previous episode of PPD

 Depression during pregnancy
 History of depression or bipolar disorder
 Recent stressful life events
 Inadequate social supports
 Marital problem
Do you think you may be suffering from Postpartum Depression? Take this quiz.
Click here to read a 2005 blog post on risk factors for PPD.
Click here to read about obesity linked to postpartum risk.
Treatment for Postpartum Illness

Postpartum depression presents along a continuum, and the type of treatment selected is based on the
severity and type of symptoms present. However, before initiating psychiatric treatment, medical causes
for mood disturbance (e.g., thyroid dysfunction, anemia) must be excluded. Initial evaluation should
include a thorough history, physical examination, and routine laboratory tests.

Non-pharmacological therapies are useful in the treatment of postpartum depression. In a randomized

study it was demonstrated that short-term cognitive-behavioral therapy (CBT) was as effective as
treatment with fluoxetine in women with postpartum depression. Interpersonal therapy (IPT) has also
been shown to be effective for the treatment of women with mild to moderate postpartum depression. Not
only is IPT effective for treating the symptoms of depression, women who receive IPT also benefit from
significant improvements in the quality of their interpersonal relationships. Read this 2004 blog
post and this 2007 post to learn more about CBT as a treatment option.
These non-pharmacological interventions may be particularly attractive to those patients who are
reluctant to use psychotropic medications (e.g., women who are breast-feeding) or for patients with
milder forms of depressive illness. Women with more severe postpartum depression may choose to
receive pharmacological treatment, either in addition to or instead of these non-pharmacological
therapies.

To date, only a few studies have systematically assessed the pharmacological treatment of postpartum
depression. Conventional antidepressant medications (fluoxetine, sertraline, fluvoxamine, and
venlafaxine) have shown efficacy in the treatment of postpartum depression. In all of these studies,
standard antidepressant doses were effective and well tolerated. The choice of an antidepressant should be
guided by the patient’s prior response to antidepressant medication and a given medication’s side effect
profile. Specific serotonin reuptake inhibitors (SSRIs) are ideal first-line agents, as they are anxiolytic,
non-sedating, and well tolerated. For women who cannot tolerate SSRIs, bupropion (Wellbutrin) may be
an alternative; although one pilot study suggests bupropion may not be as effective as SSRIs. Tricyclic
antidepressants (TCAs) are frequently used and, because they tend to be more sedating, may be more
appropriate for women who present with prominent sleep disturbance. Given the prevalence of anxiety
symptoms in this population, adjunctive use of a benzodiazepine (e.g., clonazepam, lorazepam) may be
very helpful.

Puerperal psychosis is considered a psychiatric emergency that typically requires inpatient treatment.
Acute treatment with either typical or atypical anti-psychotic medications is indicated. Given the well-
established relationship between puerperal psychosis and bipolar disorder, postpartum psychosis should

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be treated as an affective psychosis and a mood stabilizer is indicated. Electroconvulsive therapy (ECT) is
well tolerated and rapidly effective for severe postpartum depression and psychosis.

Using Medications While Breastfeeding

The nutritional, immunologic and psychological benefits of breastfeeding have been well documented.
Women who plan to breastfeed must be informed that all psychotropic medications, including
antidepressants, are secreted into the breast milk. Concentrations in the breast milk appear to vary widely.
The amount of medication to which an infant is exposed depends on several factors, including dosage of
medication, rate of maternal drug metabolism, and frequency and timing of feedings (Llewelyn and
Stowe).

Over the past five years, data have accumulated regarding the use of various antidepressants during
breastfeeding (reviewed in Newport et al 2002). Available data on the tricyclic antidepressants,
fluoxetine, paroxetine, and sertraline during breastfeeding have been encouraging and suggest that
significant complications related to neonatal exposure to psychotropic drugs in breast milk appear to be
rare. While less information is available on other antidepressants, there have been no reports of serious
adverse events related to exposure to these medications.

For women with bipolar disorder, breastfeeding may be more problematic. First is the concern that on-
demand breastfeeding may significantly disrupt the mother’s sleep and thus may increase her
vulnerability to relapse during the acute postpartum period. Second, there have been reports of toxicity in
nursing infants related to exposure to various mood stabilizers, including lithium and carbamazepine, in
breast milk. Lithium is excreted at high levels in the mother’s milk, and infant serum levels are relatively
high, about one-third to one-half of the mother’s serum levels, increasing the risk of neonatal toxicity.
Exposure to carbamazepine and valproic acid in the breast milk has been associated with hepatotoxicity in
the nursing infant.

Learn more in our Breastfeeding and Psychiatric Medication specialty area.

How to Prevent PPD

Although it is difficult to reliably predict which women in the general population will experience
postpartum mood disturbance, it is possible to identify certain subgroups of women (i.e., women with a
history of mood disorder) who are more vulnerable to postpartum affective illness. Current research
indicates that prophylactic interventions may be instituted near or at the time of delivery to decrease the
risk of postpartum illness. Several studies demonstrate that women with histories of bipolar disorder or
puerperal psychosis benefit from prophylactic treatment with lithium instituted either prior to delivery (at
36 weeks gestation) or no later than the first 48 hours postpartum. For women with histories of
postpartum depression, several studies have described a beneficial effect of prophylactic antidepressant
(either TCAs or SSRIs) administered after delivery. Patients with postpartum psychiatric illness are
offered a variety of services by clinicians with particular expertise in this area:

 Clinical evaluation for postpartum mood and anxiety disorders

 Medication management
 Consultation regarding breastfeeding and psychotropic medications
 Recommendations regarding non-pharmacological treatments
 Referral to support services within the community

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