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

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Presentation on theme: "Metabolic Acidosis and Congenital Diarrhea Dr. Amir Bar, Bnei-Zion Medical Center, Haifa."— Presentation transcript:

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 - דרגה 1  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) Na + BE HCO 3 PCO 2 pH 151 18.12 06:43 144-21.58.225.77.11 20:11 18.12 20:11 18.12 147-19.48.621.07.21 22:07 18.12 139-20.08.220.77.20 01:45 19.12 137-17.59.520.37.27 09:57 19.12

5 שלשול וחמצת מטבולית 1. שלשול – זיהומי ??  העדר חום סיסטמי, עירנית וחיונית, לא " ספטית "  ללא לוקוציטוזיס, CRP תקין  תרביות שליליות ( דם וצואה כולל וירוסים ) 2. 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 1.Normal AG Bicarbonate loss  Renal – RTA  GI – diarrhea 2.Increased AG Additional anion  Sepsis – lactate  Diabetes – ketones  Inborn errors of metab. (AG = 16) (Normal glucose levels, No ketonuria) (No hyperammonemia, Negative organic & amino Ac) (Normal WBC & CRP, Normal lactate)

7 Renal tubular Acidosis (RTA)  Normal AG, hyperchloremic metabolic acidosis resulting from either impaired HCO 3 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 Proximal Tubule HCO 3 - Na + K+K+K+K+ HCO 3 - Peritubular fluid H2OH2OH2OH2O Na + H+H+H+H+ H+H+H+H+ H 2 CO 3 H 2 O+CO 2 Carb. Anhyd. HCO 3 - CO 2 +HO - Carb. Anhyd. 85%

10 Proximal RTA: Dx  Hyperchloremic/Hypokalemic metabolic acidosis  The serum HCO 3 level falls until it reaches the PT- HCO 3 threshold ( 15-16 ) >> urine excretion stops  Urine is acidified (pH > RTA-2, while alkaline urine implies RTA-1  HCO 3 provision – serum HCO 3 will be increased but not to the normal range, and Ur-pH will increase gradually (A) Serum HCO 3 levels were in the range of 7-12 (B) HCO 3 =23 (C) Proximal RTA is rarely isolated !!!

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 Na + H+H+H+H+ CO 2 +HO - HCO 3 - H2OH2OH2OH2O H+H+H+H+ Cl - NH 3 HCO 3 - Peritubular fluid NH 3 H+H+H+H+ + Cl - /NH 4 + Collecting duct Distal Tubule 15%

13 Distal RTA: Dx  Hyperchloremic/Hypokalemic M.A.  “ Urine AG ” (Na + + K + - Cl - ) :  Normal subjects: Met. Ac. >> acidification of the urine via NH 4 /Cl excretion (only the Cl is presence in the equation) >>  Negative “ Urine AG ”  Low urine pH  Abnormal urine acidification, low NH 4 /Cl excretion >> zero or positive Urine AG and high urine pH (A)Ur: Na-20, K-8.8, Cl-50.6 >> Ur-AG = ( - 21.8) (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 (AG = 16) (Normal glucose levels) (No hyperammonemia, Negative organic & amino Ac) (Normal WBC & CRP, Normal lactate)

15 Diarrhea: Pathophysiology 1. Secretory diarrhea 2. Osmotic diarrhea 3. Ion transport defects 4. Reduced surface area 5. Abnormal motility

16 GI Lumen Villus H+H+H+H+ Na + Cl - HCO 3 - Epithelial cell Crypt Na + K-K-K-K- Na + -K + /Cl Cl- K+K+K+K+ Epithelial cell - cAMPcAMP cGMPcGMP Ca +2Ca +2 + Hypochloremia/Hyponatremia/Alkalosis Secretory diarrhea

17 Osmotic diarrhea OsmoticSecretory Stool volume <200 ml/d >200ml/d Fasting D. stops D. cont Stool Na + <70mEq/L>70mEq/L Stool pH <5>6 Red. Subs PositiveNegative  Diarrhea under Neocate (lactase def)  Carbohydrate free diet (glucose-Galactose malabs.)  Diarrhea during NPO

18 Ions Transport Defects Na + H+H+H+H+ HCO 3 - Cl - HyponatremiaAlkalosis Na + Glu Amino Ac Na + Bile Ac HyponatremiaHyponatremia

19 Diarrhea: Pathophysiology 1. Secretory diarrhea 2. Osmotic diarrhea 3. Ion transport defects 4. Reduced surface area 5. Abnormal motility

20 Intractable Diarrhea of Infancy (IDI)  1968 - 1 st 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: Causes A. 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: Causes B.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 2 nd most common identified cause of IDI/PDI beginning in the 1 st 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 1 st clinical and histologic description, MVID has been established as a distinct disease within the syndrome of IDI

26 MVID Typical form - 1 st 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 Periodic Acid Schiff (PAS) - positive secretory granules and abnormal brush border patternCD10

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

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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 1 st 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 2 nd 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: Causes B.Villus Atrophy  Microvillus inclusion disease (MVID)  Tufting enteropathy  Autoimmune enteropathy  IPEX syndrome  Infectious enteropathy  Post-infectious enteropathy  Allergic enteropathy  Idiopathic

45 Thank You!


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