management conference 18 year old man with chronic diarrhea raika jamali md digestive disease...

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.