Metabolic Acidosis and Congenital Diarrhea

1. Metabolic Acidosis and Congenital Diarrhea Dr. Amir Bar, Bnei-Zion Medical Center, Haifa

2. תיאור מקרה : • היריון תקין • ניתוח קיסרי, חוסר התקדמות לידה, במועד (38+ 4) • מים מקוניאלים • מ.ל. – 3.310 • אפגר 10\10 • בדיקה גופנית תקינה • הורים צעירים ממוצא מוסלמי, קרובי משפחה - דרגה1 • לידה ראשונה לאחר מספר הפלות טיבעיות (בשלבים מוקדמים) • האם סובלת מחסר פקטור 5 ליידן, טופלה בקלקסן בהיריון • אב סובל מאי-סבילות לחלב פרה

3. תיאור מקרה -המשך • מועמדת לשחרור, ביום הרביעי לחייה: • שלשולים מרובים, צהבהבים, מימיים, בחלקם עם תוכן, ללא הקאות, בטן רכה, לא תפוחה ולא רגישה • סימנים חיוניים תקינים, ללא חום סיסטמי, עירנית וחיונית, ללא נשמת, סטורציה תקינה • סימני דהידרציה קלינית, טורגור שמור

4. ע.ג - מעבדה: (3)

5. שלשול וחמצת מטבולית • שלשול– זיהומי ?? • העדר חום סיסטמי, עירנית וחיונית, לא "ספטית" • ללא לוקוציטוזיס, CRP תקין • תרביות שליליות (דם וצואה כולל וירוסים) • חמצת מטבולית - מישנית לשלשול או הפרעה מטבולית ראשונית ?? • שיפור הדהידרציה וההפרעה האלקטרוליטרית, ללא שיפור משמעותי בחמצת המטבולית >> הפרעה מטבולית ראשונית • הורים קרובי משפחה דרגה 1 • אין סיפור משפחתי של מחלות מטבוליות

6. Metabolic Acidosis • Normal AG Bicarbonate loss • Renal – RTA • GI – diarrhea • Increased AG Additional anion • Sepsis – lactate • Diabetes – ketones • Inborn errors of metab. (AG = 16) (Normal WBC & CRP, Normal lactate) (Normal glucose levels, No ketonuria) (No hyperammonemia, Negative organic & amino Ac)

7. Renal tubular Acidosis (RTA) • Normal AG, hyperchloremic metabolic acidosis resulting from either impaired HCO3 reabsorption or impaired H+ excretion • Type 1 (Distal) • Type 2 (Proximal) • Type 3 (Mixed of type 1 and 2) • Primarily in Pt with inherited carbonic anhydrase def • Type 4 • Hyperkalemic, deficiency/resistance to Aldosteron

8. Proximal RTA: dd • Isolated (Rare) • Sporadic • Hereditary (AD, AR) • Fanconi syn (more common) glycosuria, aminoaciduria, proteinuria (LMW), phosphaturia • Primary • Sporadic • Hereditary (AD, AR) • Cystinosis, Lowe syndrome, Galactosemia, Tyrosenemia, Fructosemia, Fanconi-Bickel syndrome, Wilson disease, Mitochondrial diseases • Secodary: • Heavy metals, Outdated tetracycline, Gentamicin, Ifosfamide, Cyclosporine, tacrolimus

9. Peritubular fluid Na+ Na+ H+ H+ K+ H2CO3 H2O Na+ Carb. Anhyd. 85% HCO3- H2O+CO2 CO2+HO- HCO3- Carb. Anhyd. Proximal Tubule HCO3- Na+ HCO3-

10. Proximal RTA: Dx (A) Serum HCO3 levels were in the range of 7-12 • Hyperchloremic/Hypokalemic metabolic acidosis • The serum HCO3 level falls until it reaches the PT-HCO3 threshold (15-16) >> urine excretion stops • Urine is acidified (pH < 5.5) when serum HCO3 < 16 (Normal distal H+ secretion) >> RTA-2, while alkaline urine implies RTA-1 • HCO3 provision – serum HCO3 will be increased but not to the normal range, and Ur-pH will increase gradually (C) Proximal RTA is rarely isolated !!! (B) HCO3=23

11. Distal RTA: dd • Primary • Sporadic • Hereditary (AD, AR) • Secondary • Interstitial nephritis • Obstructive uropathy • Vesicoureteral reflux • Pyelonephritis • Transplant rejection • Sickle cell nephropathy • Ehlers-Danlos syndrome • Lupus nephritis • Nephrocalcinosis • Medullary sponge kidney • Hepatic cirrhosis • Toxins/Medications • Amphotericin B • Lithium • Toluene • Cisplatin

12. Distal Tubule Collecting duct Peritubular fluid Na+ H+ H+ H2O Cl- 15% HCO3- CO2+HO- HCO3- + NH3 H+ NH3 Cl-/NH4+

13. Distal RTA: Dx • Ur: Na-20, K-8.8, Cl-50.6 >> Ur-AG = ( - 21.8) • Hyperchloremic/Hypokalemic M.A. • “Urine AG” (Na+ + K+ - Cl-): • Normal subjects: Met. Ac. >> acidification of the urine via NH4/Cl excretion (only the Cl is presence in the equation) >> • Negative “Urine AG” • Low urine pH • Abnormal urine acidification, low NH4/Cl excretion >> zero or positive Urine AG and high urine pH (B) Urine pH=5.0

14. Metabolic Acidosis • Increased AG • Additional anion • Sepsis – lactate • Diabetes – ketones • Inborn errors of metab. • Normal AG • Bicarbonate loss • Renal – RTA • GI – diarrhea (Normal WBC & CRP, Normal lactate) (Normal glucose levels) (No hyperammonemia, Negative organic & amino Ac) (AG = 16)

15. Diarrhea: Pathophysiology • Secretory diarrhea • Osmotic diarrhea • Ion transport defects • Reduced surface area • Abnormal motility

16. Hypochloremia/Hyponatremia/Alkalosis HCO3- H+ Villus Epithelial cell Na+ Cl- - • cAMP • cGMP • Ca+2 + Secretory diarrhea GI Lumen Cl- K+ Na+ Crypt Epithelial cell K- Na+-K+/Cl

17. Osmotic diarrhea • Diarrhea under Neocate (lactase def) • Carbohydrate free diet (glucose-Galactose malabs.) • Diarrhea during NPO

18. Hyponatremia Hyponatremia Amino Ac Na+ Glu Na+ Bile Ac Na+ Ions Transport Defects H+ Na+ Cl- HCO3- Hyponatremia Alkalosis

19. Diarrhea: Pathophysiology • Secretory diarrhea • Osmotic diarrhea • Ion transport defects • Reduced surface area • Abnormal motility

20. Intractable Diarrhea of Infancy (IDI) • 1968 - 1st described by the following features: • Diarrhea in an infant <3m • Lasting > 2 w • 3 or more negative stool cultures

21. IDI / PDI: Causes • The list of causes can be divided into: • Normal villus-crypt axis • Villus atrophy

22. IDI / PDI: CausesA. Normal Villus • Ion transport defects • Chloride-bicarbonate exchanger (chloride-losing d.) • Sodium-hydrogen exchanger (congenital sodium d.) • Ileal bile acid receptor defect • Sodium-glucose cotransporter (glucose-galactose mal) • Micronutrient deficiency • Acrodermatitis enteropathica (zinc def) • Enzyme deficiency • Enterokinase def • Congenital short bowel

23. IDI / PDI: CausesB.Villus Atrophy • Microvillus inclusion disease (MVID) • Tufting enteropathy • Autoimmune enteropathy • IPEX syndrome • Infectious enteropathy • Post-infectious enteropathy • Allergic enteropathy • Idiopathic

24. Microvillus Inclusion Disease • The 2nd most common identified cause of IDI/PDI beginning in the 1st week of life (After infection) • Various names: • Microvillus inclusion disease • (microvillus inclusions in enterocytes/colonocytes - the characteristic diagnostic feature on EM) • Congenital microvillus atrophy • Familial microvillous atrophy • Davidson’s syndrome

25. Davidson’s syndrome • 1978, Davidson et al - 5 newborns with severe, persistent diarrhea • LM: thin mucosa, villous atrophy • EM: intra-cytoplasmic cysts made up of brush border and increased secretory granules • From this 1st clinical and histologic description, MVID has been established as a distinct disease within the syndrome of IDI

26. MVID • Typical form - 1st days of life, a severe watery diarrhea (>250-300mL/kg/d), which can be mistaken for urine • Massive diarrhea >> Life-threatening >> dehydration, electrolyte imbalance, and metabolic acidosis within hours, persists despite GI rest • Atypical clinical presentation - predominant occlusive syndrome • “Late-onset” (>1m), less severe diarrhea, secretory granules and microvillous inclusions are present, but distributed differently

27. MVID • Crypt cells – increase in secretory granules, otherwise appear near normal on EM, well-developed brush border • In contrast, in mid- to upper villous – rare/absent microvilli, the diagnostic presence of microvillous inclusions • The colon is involved, and although it may be easier to Bx the rectum, Dx features are not easily recognized

28. MVID: Histology • Variable degree of villous atrophy, generally w/o any inflammatory infiltrate • Staining: • Periodic Acid Schiff (PAS) - positive secretory granules and abnormal brush border pattern • CD10

29. PAS-Control PAS-MVID CD10 - control CD10 - MVID

32. MVID: Pathogenesis • A defect in the membrane trafficking of immature / differentiating enterocytes • Enterocyte cytoskeleton • Autosomal recessive • Affected siblings • Consanguinity • No candidate genes have been identified

33. MVID: Tx • It is recommended that once the diagnosis of typical MVID has been made, transplant should be considered • Conversely, Pt with a late-onset or atypical MVID should not be automatically scheduled for transplant

34. Tufting Enteropathy/Intestinal epithelial Dysplasia • Chronic watery diarrhea on the 1st few months • Dysmorphic features - in some affected infants • The long-term prognosis is variable

35. Tufting Enteropathy:Morphology – LM • The characteristic feature is the epithelial “tufts” (80-90% of epithelial surface, in contrast to other known enteropathies <15%) + other typical findings: • Total or partial villus atrophy • Crypt hyperplasia • Normal or slightly increased density of inflammatory cells in the lamina propria • No colonic involvement

36. Tufting Enteropathy

37. Tufting Enteropathy: Pathogenesis • The molecular basis for TE is unknown • Defect in adhesion molecules ? • A genetic defect ?? • Cluster of patients in Malta • Involved families can have many affected infants

38. Autoimmune Enteropathy • Villus atrophy, infiltration of activated T cells into the lamina propria • In contrast to MVID and Tufting E.: • Extra-intestinal manifestations of autoimmunity (arthritis, Membranous GN, IDDM, hepatitis, hypothyroidism, hemolytic anemia, thronbocytopenia • Rarely had a family history of unexplained infantile diarrhea • Onset frequently > 2 m life • Responsive to immune suppression Tx

39. Autoimmune Enteropathy:Morphology • The histopathology is similar to celiac disease, except that there is a relative paucity of intraepithelial lymphocytes • Most of the affected infants have no history of gluten ingestion before the onset of diarrhea

40. Autoimmune Enteropathy:Morphology (Cont’) • Bx: total villus atrophy, crypt hyperplasia, crypt abscesses are identified in severely affected cases • The lesions are not confined to the small bowel; can be seen in the stomach and colon • Immunohistochemistry: increase in CD3-positive lymphocytes within the epithelium and lamina propria

41. Autoimmune Enteropathy:Pathogenesis • Circulating systemic antibody against enterocytes • The villus atrophy and crypt hyperplasia are both considered 2nd features of an autoimmune-induced injury to the gut • Immune suppression Tx: • Antibody levels decline/disappear • The titer may correlate with the volume of stool output

42. IPEX Syndrome • IPEX is characterized by: • Immune dysregulation • Polyendocrinopathy • Enteropathy • X-linkage • The syndrome has many intestinal manifestations in common with autoimmune enteropathy, including villus atrophy with a marked infiltration into the lamina propria of activated T cells

43. IPEX Syndrome • The genetic basis is a mutation of the FOXP3 gene, a transcription factor involved in the proliferation of CD4+ T cells • Autoimmune enteropathy • IDDM, thyroid disease, eczematous ichthyosis hemolytic anemia

44. IDI / PDI: CausesB.Villus Atrophy • Microvillus inclusion disease (MVID) • Tufting enteropathy • Autoimmune enteropathy • IPEX syndrome • Infectious enteropathy • Post-infectious enteropathy • Allergic enteropathy • Idiopathic

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