Transcript Management conference 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.