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LITERATURE REVIEW
CHRONIC DIARRHEA
2.1. Definition
Diarrhea is defined when the stool weight is more than 200 gram per 24
hours containing more than 200 ml fluid per 24 hours, or greater than 3 loose
stools in 24 hours. Some experts emphasize the diarrhea definition on frequency
of loose stools over the stool weight.1 Diarrhea may be further classified as acute
if the duration is less than 2 weeks, persistent if the duration varies from 2 to 4
weeks, and chronic if it lasts more than 4 weeks in duration. 2
2.2. Epidemiology
The Centers for Disease Control and Prevention (CDC) estimates that 76
million food borne illnesses occur annually in the United States, resulting in
325,000 hospitalizations and 5200 deaths. In a report by the American Academy
of Microbiology on the global burden of gastrointestinal diseases in 2002, it was
estimated that 660 billion cases of gastrointestinal illness occur annually
throughout the world.2.
Chronic diarrhea is a common complaint in pediatric medicine and can
pose a complex situation for practitioners and families. This complaint is both a
symptom and a sign.3 Results from basic health research (RISKESDAS) of
Indonesian Ministry of Health in 2007 shows the prevalence of diarrhea in
Indonesia of 9% and it is the 13th cause of death with 3.5% proportion based on
pattern of death at all ages. Data of one study in Cipto Mangunkusumo Hospital
that reviewed 207 patients with chronic diarrhea within period of 1999 2000
reported that the diarrhea was due to infectious cause in 100 patients (48.3%),
non-infectious cause in 69 patients (33.3%) and mixed causes in 38 patients
(18.4%).1
It is estimated that diarrheal illnesses are responsible for about 2 to 4
million childhood deaths worldwide each year. In 2002, the World Health
Organization estimated that 13.2% of all childhood deaths worldwide were caused

by diarrheal diseases, 50% of which were chronic diarrheal illnesses. Large-scale


studies indicate that the prevalence of chronic diarrheal illnesses worldwide
ranges from 3% to 20%, and the incidence is about 3.2 episodes per childyear. 3
2.3 Etiology
Overall, most chronic diarrhea is caused by non-infectious disease;
however, in developing countries, it is mostly due to infectious disease. A 5-year
study at Cipto Mangunkusumo Hospital in Jakarta reported similar data that
infectious causes were greater than non-infectious causes.1 The common cause of
chronic diarrhea we can see at (Tabel 1).4
In the other hand, Diarrhea is an even more common manifestation of HIV
disease in third-world countries. The cause of AIDS-relate diarrhea is complex
and probably multifactorial, with both common and atypical pathogens noted
among patients with diarrhea. many enteric pathogens have been identified in
stools or mucosa from patients with chronic HIV-related diarrhea, the major
pathogens

identified

today

are

cryptosporidia,

isospora,

cyclospora,

mycobacterium avium complex (MAC), microsporidia, and cytomegalovirus. As


mentioned previously, the accurate identification of one or more pathogens
depends on the thoroughness of the enteric evaluation in patients with HIV-related
diarrhea. Thus stool analyses should be the initial step in evaluating these
patients.5

Tabel 1. Common Cause of chronic diarrhea. 4

Clearly the most common cause of chronic debilitating diarrhea among


patients with AIDS is Cryptosporidium parvum. Patients with cryptosporidiosis
have profuse watery diarrhea, weight loss, paraumbilical abdominal pain, nausea,
and vomiting. The diagnosis of cryptosporidiosis is usually easily made with use
of an acidfast stain of concentrated stool. Cryptosporidium is confined to the
brush border of enterocyte and is not tissue invasive. Microsporidiosis was
identified in the last 5 years as a major cause of chronic diarrhea among patients
with HIV disease. Microsporidiosis is responsible for 15% to 20% of all chronic
diarrheal illnesses in patients with AIDS. Clinically, patients with microsporidiosis

have profuse watery diarrhea, weight loss, and abdominal pain, but no fever or
loss of appetite. The diagnosis of microsporidiosis has traditionally been made by
enteric biopsies, whether studied by electron microscopy or light microscopy. 5
Then, Cytomegalovirus is an extremely common agent among patients
with HIV disease and may be responsible for 10% to 20% of debilitating chronic
diarrheal illness. Enteric cytomegalovirus is extremely variable in its clinical
presentation, with some patients manifesting only cytomegalovirus esophageal
ulcerations, whereas in others debilitating large- and/or small-bowel diarrhea
develops. Abdominal pain is a common component of cytomegalovirus disease in
the gut, and not infrequently patients have significant bleeding or even an acute
abdomen. MAC involves the entire reticulo-endothelial system. In the gut, MAC
is associated with diarrhea, weight loss, fever, and generalized abdominal pain,
particularly right upper quadrant pain related to hepatic infiltration. Profound
norexia is also noted in these patients. The diagnosis of MAC can be suggested by
blood or faecal cultures, while endoscopic biopsies of thickened folds easily
demonstrate foamy macrophages in the lamina propria, containing numerous acidfast-positive organisms.5
2.4 Pathophysiology
`

The many causes of chronic diarrhea can be divided into four principle

pathophysiologic mechanisms: osmotic, secretory, dysmotility associated, and


inflammatory. Often, a single disorder will involve multiple overlapping
mechanisms.3
1. Osmotic diarrhea
Osmotic diarrhea is caused by a failure to absorb a luminal solute, resulting in
secretion of fluids and net water retention across an osmotic gradient. This
outcome can result from either congenital or acquired disease and is best
exemplified by the common disorder of lactose malabsorption. Other
carbohydrates may be malabsorbed, either because of dissacharidase deficiencies
or because the absorptive capacity of the intestine for that sugar may be
overwhelmed by excessive consumption, eg, fructose and sorbitol. Such excessive

intake may be seen in young children drinking fruit juices. Dissacharidase


deficiencies, such as lactase deficiency, are rarely congenital but more often are a
result of gut mucosal injury secondary to some process later in infancy, such as an
enteritis. Pure osmotic diarrhea should cease when the offending dietary nutrients
are removed. 3
2.

Secretory diarrhea

Secretory diarrhea occurs when there is a net secretion of electrolyte and fluid
from the intestine without compensatory absorption. Endogenous substances,
often called secretagogues, induce fluid and electrolyte secretion into the lumen
even in the absence of an osmotic gradient. Children with a pure secretory
diarrhea will therefore continue to experience diarrhea even while fasting.
Typically, secretagogues affect ion transport in the large and small bowel both by
inhibiting sodium and chloride absorption and by stimulating chloride secretion
via cystic fibrosis (CF) transmembrane regulator activation. Examples of
secretory diarrhea include multiple congenital diarrheal disorders associated with
identified genetic mutations that affect gut epithelial ion transport. Congenital
chloride diarrhea (CCD) is one such disorder. 3
3. Dysmotility associated diarrhea
Chronic diarrhea associated with intestinal dysmotility typically occurs in the
setting of intact absorptive abilities. Intestinal transit time is decreased, the time
allowed for absorption is minimized, and fluid is retained within the lumen. Highamplitude propagated contractions play a key role in motility disorders of the gut
and have been found to be more frequent in patients with diarrhea predominant
irritable bowel syndrome (IBS). Although diarrhea-predominant IBS may be
diagnosed in older adolescents, toddlers commonly present with chronic
nonspecific diarrhea (CNSD). Changes in small intestinal motility also have been
implicated in causing CNSD. 3
4. Inflammatory diarrhea

Inflammatory diarrhea may encompass all of the pathophysiologic


mechanisms. Inflammation with resultant injury to the intestine may lead to
malabsorption of dietary macronutrients which, in turn, creates a luminal osmotic
gradient. Additionally, particular infectious agents may induce secretion of fluid
into the lumen, and blood in the gut may alter intestinal motility. Diseases such as
inflammatory bowel disease (IBD) and celiac disease exemplify this inflammatory
mechanism. 3
Beside

the

above

statement,

In

situation

where

immunodeficiency develops in HIV-infected individuals, one of the


hardest-hit organs is the intestine. First, the enterocytes can undergo
atrophy, as a result of the HIV virus infecting the enterocytes and
damaging their function. Second, as the intestine is the largest
immunological organ in the body, destruction of immunocompetent
cells in the intestine will cause intestinal dysfunction, which is among
several symptoms observed in diarrhea. 7 However, diarrhea may affect
patients at all stages of HIV infection and may have multiple causes,
including noninfectious causes such as HAART, effects of HIV on the GI
tract

(ie,HIV

pancreatitis.

enteropathy),

HIV-associated

malignancies,

and

HIV enteropathy is an idiopathic form of diarrhea that can occur


during the acute phase of HIV infection through advanced AIDS and for
which there is no identified pathogen. Histologically, villous atrophy,
crypt hyperplasia, and villous blunting exemplify damage to the GI
tract, and inflammatory infiltrates of lymphocytes in the lamina propria
may be observed. Notably, HIV enteropathy may improve with HAART,
but it may also occur in patients receiving HAART. The pathogenic
mechanisms leading to HIV enteropathy remain unclear but may
involve effects of HIV infection on the GI tract and the gut-associated
lymphoid tissue (GALT). 8

2.5. Diagnosis

History Taking
History taking is the first important step in making diagnosis of chronic
diarrhea. It is important for us to have precise understanding on what is being
perceived as diarrhea by the patient who seeks treatment from us. (Murdani
Abdullah). A detailed history is essential in the assessment of patients with chronic

diarrhoea. This should attempt (a) to establish the likelihood that the symptoms
are organic (as opposed to functional), (b) to distinguish malabsorptive from
colonic/ inflammatory forms of diarrhoea, and (c) to assess for specific causes of
diarrhoea.6
In taking history, we should find out whether the symptom is organic or
functional problem; we should also distinguish the type of diarrhea, i.e.
malabsorption from inflammatory or watery diarrhea; and try to evaluate the
probable specific causes of diarrhea. Symptom of diarrhea that lasts for three
months with nocturnal pattern and significant weight loss may suggest to organic
disease.1
The presence of malabsorption is usually evident by steatorrhea and the
passage of bulky malodorous pale stool. However, milder forms of malabsorption
may not result in any reported stool abnormality. Colonic, inflammatory, or
secretory forms of diarrhoea typically present with liquid loose stools with blood
or mucous discharge.6 For bloody diarrhea, symptoms depend on the cause.
Moreover, symptoms of diarrhea with no bleeding and no fat also usually depend
on each cause. If the diarrhea stop after 72-hour of fasting, then it is suggestive for
osmotic diarrhea. 1
Physical Examination
Usually clinical manifestation of chronic diarrhea cases is more associated
with vitamin and electrolytes deficiencies and nutrient malabsorption. The
presence of significant weight loss or lymphadenopathy may result from chronic
infection or malignancy. Episcleritis may suggest to inflammatory bowel disease
and exophtalmus is suggestive for hyperthyroid causes. 1 An abdominal
examination for scars (surgical causes of diarrhea), bowel sounds (hypermotility),

tenderness (infection and inflammation), and masses (neoplasia) should be


followed by rectal examination, including fecal occult blood testing. Anal fistulae
suggest Crohn disease. 4
Evaluation Using Laboratory Work-up
To assist physicians establishing diagnosis and the etiology of chronic
diarrhea, Microbiologic examination of feces should be performed, including
culture for enteric pathogens; microscopic examination for ova, cysts, and
parasites; and testing for the Clostridium difficile toxin when appropriate. In
addition to microscopic examination, diagnosis of stool protozoa may be
accomplished using polymerase chain reaction analysis or a variety of antigen
detection tests, including direct fluorescent antibody, enzyme immunoassay, or
rapid, dipstick-like tests. Fecal examination will yield a diagnosis approximately
half of the time. If no pathogen is identified during fecal examination and the
diarrhea is severe (eg, 10 viscous, liquid, or watery stools in a 24-hour period)
and persistent, further examination by upper endoscopy and flexible
sigmoidoscopy or colonoscopy may be performed to obtain biopsy samples and
rule out other potential causes of diarrhea, such as inflammatory bowel disease.
Upper endoscopy and colonoscopy should be strongly considered for patients with
CD4+ cell counts <100 cells/L. Microsporidial or mycobacterial infections of the
small intestine, cytomegalovirus infections, and giardiasis may be identified using
these procedures. 8
Radiologic assessments or direct visualization (eg, colonoscopy) may be
warranted for patients with Kaposis sarcoma or non-Hodgkins lymphoma to
identify lesions in the GI tract. For patients in whom diagnostic testing has yielded
negative results and in whom diarrhea has persisted for >1 month, a diagnosis of
HIV enteropathy or HAART-associated diarrhea may be made or considered.
Other idiopathic forms of diarrhea such as irritable bowel syndrome or functional
diarrhea may also be considered, depending on the signs and symptoms the
patient is experiencing. 8

2.6.

Management
In general, the management of chronic diarrhea can be divided into two

groups, i.e. supportive and pharmacological treatment, both for infectious and
non-infectious causes. Pharmacological treatment is also subdivided into two
classes including symptomatic and causal treatment. Causal treatment can be done
through empirical therapy. 1
Empirical therapy for chronic diarrhea, according to American
Gastroenterological Association (AGA) guidelines is used in three conditions: (1)
as an initial or temporary therapy prior to diagnostic testing; (2) when the
diagnostic testing has failed to confirm a diagnosis; and (3) when a diagnosis has
been established, but no specific treatment is available or it fails to provide any
therapeutic effect. Empirical antibiotic treatment may be justified if the prevalence
of bacterial infection is high in a specific location and it can be customized to the
pattern of bacterial resistance. However, other empirical therapy of bile acidbinding resin such as cholestyramine (rarely used in Indonesia) can be used for
bile acid-induced diarrhea. 1
Patients in whom a pathogenic cause for diarrhea has been identified
should be treated accordingly. Specific treatment recommendations for pathogenic
diarrhea are beyond the scope of this review and have been reviewed elsewhere.
Briefly, treatment of pathogenic diarrhea typically targets the specific pathogen
causing the condition. Some therapies that may be used include antibacterial
agents, such as ciprofloxacin (for bacterial pathogens) or clarithromycin plus
ethambutol with or without rifabutin (for Mycobacterium avium complex
infection); antiviral therapies, such as ganciclovir or valganciclovir (for
cytomegalovirus infection); and antifungal or antiprotozoal agents, such as
metronidazole (for Giardia infection) or albendazole (for Encephalitozoon
intestinalis). 8
In chronic diarrhea in HIV-positive patients, the mainstay of therapy in
countries where it is economically and socially feasible, is treatment with highly
active ART (HAART). The risk of chronic diarrhea in HIV-positive patients has
been reduced dramatically where HAART is accessible, and the decision to

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introduce HAART is now taken at higher CD4+ levels. However, HAART is


associated with lipodystrophy, which in turn is related to insulin resistance and its
metabolic complications, such as impaired glucose tolerance, diabetes and
hypertriglyceridimia.7. Furthermore, there are statement that diarrhea may be
associated with several of the therapies used in HAART regimens, including
nucleoside reverse-transcriptase inhibitors (NRTIs) and nonnucleoside reversetranscriptase inhibitors, protease inhibitors (PIs), and integrase inhibitors. 8
Adverse effects, especially metabolic, of ART, including HAART, means that their
introduction should be delayed as long as possible. 7
However, for noninfectious forms of HIV-associated diarrhea, currently
no FDA-approved treatment options. For patients with HAART-associated
diarrhea, modification of HAART regimen may be attempted. Otherwise,
pharmacologic options for treatment of HAART-associated diarrhea and HIV
enteropathy are primarily supportive.8
Table 2. Pharmacologic Treatments for Noninfectious HIV-Associated Diarrhea8

Adequate fluid (hydration) is still anessential part in the management of


chronic diarrhea, for example by administering oral rehydration solutions.
Intravenous fluid administration is provided when oral rehydration is not possible.
Supportive treatment can be useful including providing education, avoid
unnecessary medication or food intake that may cause chronic diarrhea, good

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nutrition which is not irritative to gastrointestinal tract, either by oral or parenteral


route. It should be noted that the nutrition issupposed to be customized with the
possible etiology of chronic diarrhea, for example oral nutrition of fat restriction
(e.g. milk containing short-chain peptides) for diarrhea cases with steatorrhea. 1
Pharmacological therapy can also be addressed for symptomatic treatment,
e.g. by giving symptomatic antidiarrheal drugs. These drugs are aimed to reduce
fluid loss due to diarrhea. Symptomatic anti-diarrheal drugs include: (1) inhibitor
of intestinal motility and secretion such as diphenoxylate, loperamide, codeine
HCl/phosphate, atropine sulfate; (2) stool bulking agents such as kaolin-morphine
and toxic absorber such as activated charcoal, kaolin-pectin, atapulgite and
smectite; (3) antisecretory drugs such as ocreotide (somatostatin analogues) or
natural somatostatin.
Other symptomatic treatment are antiemetic drugs, vitamin and mineral,
extract of pancreatic enzymes, aluminium hydroxide, phenotiazine, nicotinic acid.
In addition, causative treatment is customized with possible causes, both for
infectious

(by

administering

antibiotics,

antifungal,

antiprotozoal,

and

antihelminthics) and non-infectious causes (e.g. in IBD, radiation colitis, etc). 1

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REFERENCES
1. Abdullah,M. and Firmansyah M.A. Clinical Approach and Management of
Chronic Diarrhea. Indo Journ of Internal Med. April 2013;2 : 157-165.
2. Guandalini, S. Diarrhea : Diagnostic and therapeutic advances. 2011.
Springer New York Dordrecht Heidelberg London.
3. Zella, G.C. and Israel, E.J. Chronic Diarrhea in Children. Pediatrics in
Review 2012;33;207.
4. Juckett, G. and Trivedi, R. Evaluation of Chronic Diarrhea. Am Fam
Physician. 2011;84(10):1119-1126
5. Zacharof, A.K. AIDS-Related diarrhea: pathogenesis, evaluation and
treatment. Annals of GastroEntero 2001, 14(1):22-26.
6. Thomas, P.D. et al. Guidelines for the investigation of chronic diarrhoea,
2nd edition. Gut 2003;52: v1v15

7. Elfstrand, L. and Florn, C.H. Management of chronic diarrhea in HIVinfected patients: current treatment options, challenges and future
directions. HIV/AIDS -Research and Palliative Care : 2010:2: 219224.

8. MacArthur, R. D.

and DuPont H.,L. Etiology and Pharmacologic

Management of Noninfectious Diarrhea in HIV-Infected Individuals in the


Highly Active Antiretroviral Therapy Era. Clinical Infectious Diseases
2012;55(6):8607