Download 18 year old man with chronic diarrhea

Management conference
18 year old man with
chronic diarrhea
Raika Jamali MD
Digestive Disease Research Center
Tehran University of Medical Sciences
A young man with watery large volume
diarrhea, 3-4 times a day from 4 months
ago .
Perioral paresthesia with hand & foot
cramps from 3 months ago.
Ulcerative lesion in the right middle & ring
fingers from the same time.
Physical exam
• A young man with stable vital sign & no
fever.
• Periorbital edema.
• No icterus or anemia. No LAP. Thyroid
was NL. BMI=20.
• Heart & lung were NL.
• There was no organomegaly or ascitis.
• Exophytic lesion in distal phalanxes of the
right middle & ring fingers .
• Edema of lower extremities.
• In the W/U for his cramps ,hypocalcemia
was detected and was treated with
calcium fort (4 gr/D) & rocaltrol(8000
IU/D).
• The vaccination was complete.
• There were no history of upper & lower
respiratory tract infection or diarrhea.
• Family history was negative for any
recurrent infections .
LAB DATA
• Giardia cyst was seen in the first S/E
(which had been treated with
metronidazole).
• Ca=6 mg/dl
24h urinary Ca=30 mg/dl
• P=3.1 mg/dl
• ALP=473
• PTH=171
• Mg=2.1 mg/dl
• K=3 mg/dl
NEW LAB DATA
•
•
•
•
•
•
WBC=4500 (NL Diff)
Hb=13.1
Ferritin=20
MCV=78
Serum Iron=115
MCH=26
TIBC=208
MCHC=33
Plt=249000
•
•
•
•
•
•
•
•
•
•
•
BUN=9
Cr=0.7
Ca=7.5
P=4
Na=142
K=3.8
Mg=1.3
ESR=6
FBS=108
TG=62
Cholesterol=94
AST=39
ALT=41
ALP=406
Bili direct =0.8
Bili direct=0.3
Total protein=3.6
Albumin=1.8
PT=16
ABG: metabolic Alkalosis
S/E (3 times):
Consistency=loose
Ova & parasite=neg
O.B=neg
U/A:
Normal. (without proteinuria)
T4=4.9
T3=88
TSH=2.5
T3RU=36
• Ig M=39
• Ig G=200
• Ig A=37
(40-200)
(700-1400)
(70-400)
HIV Ab=neg
• Anti TTG Ab=neg
• Anti Endomesial Ab=neg
• “25OH VIT D “ requested
• Stool fat droplets with sudan 3 requested
• Quantitative 72 h stool fat requested
• CXR: NL
• WATERS VIEW: NL
Hand Radiography
• Soft tissue swelling in distal part of the
right middle & ring fingers .
• No sign of osteomyelitis.
• Diffuse osteopenia without signs of
hyperparathyroidism.
Dermatology Consult
• Exophytic mass in middle finger and
nodular lesion in ring finger.
DDx:
•
•
•
•
•
SCC
TB
Atypical mycobacterium
Deep mycosis
Leshmaniosis?
Bx:Orf
Sonography
• Liver, spleen, gall bladder, kidneys,
pancreas were normal.
• No ascitis.
• No calcification.
Thickened nodular folds in the proximal small intestine.
Thickened regular folds
Diffuse mucosal edema
Small bowel transit
• Diffuse edema of mucosa.
• No stricture, polyp or mass.
• Ileum terminal was Nl.
UGI Endoscopy
Upper endoscopy Report
• Esophagus:
• Crico-pharyngeus , upper third, middle third and lower
third were normal.
• ____________________________
• Stomach:
• Fundus, body, incisura and antrum were normal.
• ____________________________
• Duodenum:
• Bulb was normal.
• ____________________________
• Additional procedures:
• Multiple biopsies were takenfrom D2.
Duodenal Pathology
•
•
•
•
No Giardia.
Normal mucosal pattern without atrophy.
Adequate plasma cells in submucosa.
Dilated lymphatic ducts are seen
suggesting intestinal lymphangiectasia
ABDOMINAL CT SCAN
• LIVER,SPLEEN,PANCREASE AND
KIDNYS WERE NORMAL.
• NO ABDOMINAL LAP DETECTED.
Rectosigmoidoscopy
• Anus was NL.
• Rectum was NL.
• Descending colon up to splenic flexure
was Nl.
• Bx was done.
Colon Pathology
• Rectal sample was NL.
• Sample of descending colon was NL.
Intestinal lymphangiectasia with
protein losing enteropathy, toxic
copper accumulation and
hypoparathyroidism.
• Aust N Z J Med. 1990 Apr;20(2):167-9
• A 13-year-old girl presented with malabsorption
which was ascribed to intestinal
lymphangiectasia.
• Three years later a generalised seizure resulted
from hypocalcaemia that was shown to be due
to hypoparathyroidism during investigation of
which toxic copper accumulation was
recognised.
• The chance occurrence of three rare conditions
is extremely remote making intestinal
lymphangiectasia likely as the primary
pathology.
• It is suggested that chronic intestinal loss
of the copper-carrying caeruloplasmin
resulted in toxic parathyroid deposition of
copper leading to hypoparathyroidism with
consequent hypocalcaemic seizure.
Protein-losing gastroenteropathy
• Protein-losing gastroenteropathies are
characterized by an excessive loss of
serum proteins into the gastrointestinal
tract, resulting in :
• hypoproteinemia (detected as
hypoalbuminemia),
• edema,
• and, in some cases, pleural and
pericardial effusions.
Diagnosis
• The diagnosis of protein-losing
gastroenteropathy should be considered in
patients with hypoproteinemia in whom
other causes, such as malnutrition, heavy
proteinuria, and impaired protein synthesis
due to liver diseases have been excluded.
PATHOGENESIS
• Once plasma proteins pass into the
gastrointestinal tract, they are degraded
rapidly to amino acids and reabsorbed into
the portal circulation.
• Other serum components (eg, iron, lipids,
trace elements) also may be lost in the
gut.
• The increase in intestinal leakage of
plasma proteins can occur via one of two
mechanisms:
• Mucosal injury
with or without erosions/ulcerations as in
inflammatory bowel disease (IBD) and
celiac disease.
• Increased Iymphatic pressure
in the gut due to granulomatous and
neoplastic involvement of the Iymphatic
system or after dilated lymph vessels leak
protein via the surface epithelium into the
gut.
• The latter mechanism can occur in :
• intestinal lymphangiectasia,
• congenital abnormalities of the lymphatic
system,
• or disorders of venous stasis such as
congestive heart failure or constrictive
pericarditis.
Causes of protein losing
enteropathy
DISEASES ASSOCIATED WITH
IMPAIRED LYMPHATIC
DRAINAGE
• Decreased absorption of chylomicrons
and fat-soluble vitamins (A, D, E, K)
• Reduced recirculation of intestinal
lymphocytes into the peripheral circulation
• Leakage of intestinal lymph into the
intestinal lumen
Intestinal lymphangiectasia
• Intestinal lymphangiectasia is abnormal
dilatation of intestinal mucosal lymphatic
channels leading to loss of lymph with
immunoglobulins and lymphocytes into the gut.
• The disorder may be congenital, or may arise
secondarily to processes which obstruct lymph
drainage of the gut or raise central venous
pressure.
• Congenital forms may also be associated with
pulmonary chylothorax and lymphedema.
• Hypogammaglobulinemia and lymphopenia are
not usually severe, but some patients have an
increased rate of infections.
• There is evidence for a functional T cell defect
as well, possibly related to nutritional losses .
• Somewhat selective loss of CD4 T cells with
inversion of the CD4/CD8 ratio has been
reported .
• Patients with recurrent infections and low
serum IgG may benefit from gamma
globulin infusions; however, relatively
large doses may be required due to
ongoing intestinal loss.
Primary intestinal
lymphangiectasia
• Primary intestinal lymphangiectasia is
characterized by diffuse or localized
ectasia of enteric lymphatics, which is
often associated with lymphatic
abnormalities elsewhere in the body.
• The ectatic lymphatics may be located in
the mucosa, submucosa, or subserosa.
• The disease primarily affects children and
young adults (the mean age of onset is
approximately 11 years), and exhibits no
gender specificity.
• Although most cases are sporadic, intestinal
lymphangiectasia has been reported in multiple
siblings of several families, suggesting that at
least in certain cases it may have a genetic
etiology.
• Protein-losing gastroenteropathy in association
with the yellow-nail syndrome (chronic
peripheral lymphedema accompanied by
yellowish-colored slow growing nails, recurrent
pleural and pericardial effusions, and chylous
ascites) has been described in a case report.
Clinical manifestations
primary intestinal lymphangiectasia
A- Intermittent diarrhea,
B- Nausea & vomiting.
C- Steatorrhea. (in some patients)
D- Edema is often present and may be
pitting if it results from
hypoalbuminemia,
or asymmetric and nonpitting if it
results from an underlying lymphatic
abnormality of the affected extremity
E-Reversible blindness can rarely occur
due to macular edema.
F-Chylothorax or chylous ascites may also
be present and should be differentiated
from pleural effusions or ascites resulting
from hypoproteinemia.
Diagnosis
• The diagnosis of primary intestinal
lymphangiectasia is established based
upon the clinical manifestations discussed
above, and laboratory and pathologic
findings.
• Laboratory findings are similar to those in
other forms of protein-losing enteropathy
and include:
• hypoproteinemia with
• decreased serum levels of albumin, IgG,
IgM, IgA, transferrin, and ceruloplasmin.
• Clotting factors are also frequently
decreased, but this rarely leads to clinical
consequences.
• Loss of lymphocytes into the gut can result
in significant lymphocytopenia, with
detectable alteration in cellular immunity.
• Patients who have steatorrhea may
develop fat-soluble vitamin deficiencies.
• Small bowel contrast studies may show
thickened, nodular mucosal folds that
simulate stacked coins.
• On endoscopy, scattered white spots,
which have been described as having a
snowflake-like appearance, may overly the
small intestinal mucosa .
• Consumption of a high-fat meal during the
evening before endoscopic evaluation may
make these findings more apparent.
• Histopathologic examination reveals
markedly dilated lymphatics, which are
most apparent in the tips of the villi.
• In addition, electron microscopy reveals
dilated lymphatic vessels filled with
chylomicrons and precipitated lymph
proteins.
• The abnormal intestinal lymphatics can also be
demonstrated by contrast lymphangiography,
nuclear scintigraphy, or magnetic resonance
lymphangiography .
• Contrast lymphangiography involves injection of
contrast material via the pedal vein. Dilated
lacteals in the bowel appear as punctuate
densities.
• Nuclear scintigraphy can also demonstrate the
abnormal intestinal lymphatics by using a
technetium labeled tracer (usually albumin or
dextran) and assessing intestinal leakage .
Treatment
• The principles of treatment of primary intestinal
lymphangiectasia are similar to the treatment of
other forms of protein-losing gastroenteropathy.
The mainstay of therapy is a low-fat, highprotein, medium-chain triglyceride diet .
• Some patients require additional
supplementation with calcium salts and watersoluble forms of fat-soluble vitamins.
• The need for dietary therapy is often permanent,
although occasional spontaneous remissions do
occur.
• Not all patients respond completely to this
dietary approach.
• Intestinal resection or anastomosis of
abnormal lymphatics to venous channels
may be beneficial for selected patients
who have refractory disease.
• However, these approaches are not
always feasible. Patients with primary
intestinal lymphangiectasia often have
extensive lymphatic involvement
precluding resection.
• Furthermore, focal lymphatic abnormalities
are often difficult to localize.
• A case report suggested that octreotide
(200 micrograms BID) was associated with
a decrease in enteral protein loss and
clinical improvement . The mechanism of
action is unclear.
Secondary intestinal
lymphangiectasia
• The most common causes are:
• A- cardiac diseases,
• B-chemotherapeutic, infectious, or toxic
substances that are associated with
inflammatory processes that cause
retroperitoneal lymph node enlargement
• C- Portal hypertension or hepatic venous
outflow obstruction after liver
transplantation, and in congenital hepatic
fibrosis due to phosphomannose
isomerase deficiency .
• Secondary intestinal lymphangiectasia due
to portal hypertension may be improved by
placement of a transjugular intrahepatic
portosystemic shunt .
• Alpha-l antitrypsin has a moderately higher
molecular weight than albumin (50,000)
and is excreted intact in the stool because
it is resistant to proteolysis and
degradation in the intestinal lumen .
• The normal rate of alpha-1 antitrypsin
excretion in the stool is less than 2.6 mg/g
stool, which reflects an intestinal clearance
of less than 13 mL/day .
• Possible drawbacks to measuring alpha-1antitrypsin clearance measurements are
that the test does not distinguish between
gastric and small intestinal protein loss
and that alpha-1-antitrypsin is apparently
degraded by the acidic gastric juice below
pH 3.5 .
• To improve the reliability of the test in disorders
characterized by gastric acid hypersecretion (eg,
secretory gastropathy), an additional refinement
has been introduced: measuring alpha-1antitrypsin clearance during cimetidine infusion ;
other acid blockade should be equally effective.
• This modification may be used in patients
suspected to have hypertrophic secretory
gastropathy or in those with apparent
gastrointestinal protein loss but a normal alpha1-antitrypsin clearance.
• Increased clearance of alpha-l antitrypsin
from plasma should be interpreted
cautiously in patients with diarrhea, since
diarrhea itself (without underlying proteinlosing gastroenteropathy) can produce this
finding .
• For this reason, values indicative of
enhanced enteral protein loss are an
alpha-l antitrypsin clearance greater than
24 mL/day in patients without diarrhea and
greater than 56 mL/day in patients with
diarrhea.
Further studies should be
performed as indicated:
• Measurement of stool fat can indicate small
bowel disease.
• Radiographic studies of the gastrointestinal tract
can help to localize anatomic lesions.
• Upper and lower gastrointestinal endoscopy with
biopsy should be performed if the diagnosis
remains uncertain.
• If all else is normal, consideration should be
given to lymphatic disorders and the use of CT
scan and lymphangiography (eg, to diagnose
intestinal lymphangiectasia).
• Echocardiography and, if necessary,
cardiac catheterization may be necessary
to determine the diagnosis, such as
constrictive pericarditis.
TREATMENT
• Maintenance of nutritional status
• Treatment of the underlying disease
CVID
• Number of B lymphocyte are normal.
• They recognize Ag and proliferate in
response to it, but can not change to
plasma cell and memory cells.
• There is hyperplasia of lymphocytes in
reticuloendothelial system especially in
spleen and intestine (intestinal lymphoid
hyperplasia).
Duodenal Lymphoid Hyperplasia
• Usual presentation is recurrent
sinopulmonary infections resulting in
bronchiectasia.
• Chronic diarrhea and malabsorbtion with
Giardiasis is common.
• Fever, weight loss, anemia,
thrombocytopenia, splenomegaly, LAP
and lymphocytosis can be seen at
presentation. So they can mimic lymphoid
malignancies.
• They are suseptible to auto immune
diseases and lymphoid malignancies.
• Pernicious anemia and atrophic gastritis
may be seen in CVID.
• Prevalence of lymphoma is also
increased.
• IgA deficiency can progress to CVID and
viceversa.
• For differentiating lymphoma from CVID,
detection of monoclonality of surface Ab
and light chain in peripheral and tissue B
cell is helpful. (it is seen in lymphoma)
Diagnosis of CVID
• At least 2 groups of immuneglobins must
be decreased
• Older than 2 years of age
• R/O of other immunodeficiency syndromes
• Normal number of B&T cell by
flowcytometry
TREATMENT
• IVIG every 4 weeks
Clinical and Immunological
Features of 65 Iranian Patients
with
Common Variable
Immunodeficiency
• CLINICAL AND DIAGNOSTIC
LABORATORY IMMUNOLOGY, July
2005, p. 825–832
• Asghar Aghamohammadi,et al
• All of the patients presented with
infectious diseases at the time of onset,
the most common of which were :
• otitis media,
• diarrhea,
• pneumonia,
• sinusitis.
• Acute and recurrent infections were
also found in almost all of the patients,
particularly involving respiratory and
gastrointestinal systems.
• The most common infections, before
diagnosis and during follow-up, were:
• pneumonia,
• acute diarrhea,
• acute sinusitis,
• otitis media.
• CVID should be considered in any
patient with a history of recurrent
infections and decreased levels of all
serum immunoglobulin isotypes.
• Six other patients had significant
malabsorption without any known
gastrointestinal disorder.
• Among 12 patients in whom upper
gastrointestinal tract endoscopy was done
villous atrophy was seen in eight patients
(66.6%) and nodular lymphoid hyperplasia
was seen in six (50%).
• Biopsies showed villous atrophy in five of
six patients whose endoscopy results were
normal.