Post on 23-Jan-2016
description
Management conference
18 year old man with chronic diarrhea
Raika Jamali MDDigestive 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 AST=39
• Cr=0.7 ALT=41
• Ca=7.5 ALP=406
• P=4 Bili direct =0.8
• Na=142 Bili direct=0.3
• K=3.8 Total protein=3.6
• Mg=1.3 Albumin=1.8
• ESR=6 PT=16
• FBS=108
• TG=62 ABG: metabolic Alkalosis
• Cholesterol=94
S/E (3 times):
Consistency=loose
Ova & parasite=neg
O.B=neg
U/A:
Normal. (without proteinuria)
T4=4.9 TSH=2.5
T3=88 T3RU=36
• Ig M=39 (40-200)
• Ig G=200 (700-1400)
• Ig A=37 (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, high-protein, medium-chain triglyceride diet .
• Some patients require additional supplementation with calcium salts and water-soluble 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-1-antitrypsin 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-1-antitrypsin 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 alpha-1-antitrypsin clearance.
• Increased clearance of alpha-l antitrypsin from plasma should be interpreted cautiously in patients with diarrhea, since diarrhea itself (without underlying protein-losing 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
withCommon 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.