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.