Metabolic Acidosis and Congenital Diarrhea - Presentation

Metabolic Acidosis and Congenital Diarrhea Dr. Amir Bar, Bnei-Zion Medical Center, Haifa ‫תיאור מקרה :‬ ‫היריון תקין‬ ‫ניתוח קיסרי, חוסר התקדמות לידה, במועד (83+ 4)‬ ‫מים מקוניאלים‬ ‫מ.ל. – 013.3‬ ‫אפגר 01\01‬ ‫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 ‫‪‬‬ ‫‪‬‬ ‫‪‬‬ ‫‪‬‬ ‫‪‬‬ ‫‪‬‬ ‫‪‬‬ ‫‪‬‬ ‫‪‬‬ ‫‪‬‬ ‫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 )3( :‫ע.ג - מעבדה‬ Na+ 151 BE HCO3 PCO2 pH 06:43 18.12 144 147 139 137 -21.5 -19.4 -20.0 -17.5 8.2 8.6 8.2 9.5 25.7 21.0 20.7 20.3 7.11 7.21 7.20 7.27 20:11 22:07 01:45 09:57 18.12 18.12 19.12 19.12 ‫שלשול וחמצת מטבולית‬ ‫1. שלשול – זיהומי ??‬ ‫העדר חום סיסטמי, עירנית וחיונית, לא "ספטית"‬ ‫ללא לוקוציטוזיס, ‪ CRP‬תקין‬ ‫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 ‫‪‬‬ ‫‪‬‬ ‫‪‬‬ Metabolic Acidosis 1. Normal AG Bicarbonate loss  Renal – RTA  GI – diarrhea (AG = 16) 2. Increased AG Additional anion  Sepsis – lactate  Diabetes – ketones  Inborn errors of metab. (Normal WBC & CRP, Normal lactate) (Normal glucose levels, No ketonuria) (No hyperammonemia, Negative organic & amino Ac) 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 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Tyrosenemia, Fructosemia, Fanconi-Bickel syndrome, Wilson disease, Mitochondrial diseases  Secodary:  Heavy metals, Outdated tetracycline, Gentamicin, Ifosfamide, Cyclosporine, tacrolimus Proximal Tubule HCO3Na+ Peritubular fluid Na+ Na+ HCO3- H+ H+ K+ H2CO3 H2O 85% HCO3- Na+ Carb. Anhyd. H2O+CO2 CO2+HO- HCO3- Carb. Anhyd. 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 PTHCO3 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 Distal RTA: dd  Primary   Sporadic Hereditary (AD, AR) Interstitial nephritis            Secondary  Obstructive uropathy Vesicoureteral reflux Pyelonephritis Transplant rejection Sickle cell nephropathy Ehlers-Danlos syndrome Lupus nephritis Nephrocalcinosis Medullary sponge kidney Hepatic cirrhosis Amphotericin B Lithium Toluene Cisplatin  Toxins/Medications     Distal Tubule Collecting duct Na+ H+ H+ Peritubular fluid H2O Cl15% CO2+HOH+ + NH3 Cl-/NH4+ HCO3HCO3NH3 Distal RTA: Dx  Normal (A) Ur: Na-20, K-8.8, Cl-50.6 >> Ur-AG = ( - 21.8)  Hyperchloremic/Hypokalemic M.A.  “Urine AG” (Na+ + K+ - Cl-): 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 Metabolic Acidosis Increased AG  Additional anion Sepsis – lactate Diabetes – ketones Inborn errors of metab. (Normal WBC & CRP, Normal lactate) (Normal glucose levels) (No hyperammonemia, Negative organic & amino Ac) Normal AG  Bicarbonate loss Renal – RTA GI – diarrhea (AG = 16) Diarrhea: Pathophysiology 1. 2. 3. 4. 5. Secretory diarrhea Osmotic diarrhea Ion transport defects Reduced surface area Abnormal motility Hypochloremia/Hyponatremia/Alkalosis Secretory diarrhea H+ Villus Epithelial cell Na+ Cl- HCO3- GI Lumen + ClCrypt Na+ KNa+-K+/Cl •cAMP •cGMP •Ca+2 Epithelial cell K+ Osmotic diarrhea Osmotic Secretory Stool volume Fasting Stool Na+ Stool pH Red. Subs <200 ml/d D. stops <70mEq/L <5 Positive >200ml/d D. cont >70mEq/L >6 Negative Diarrhea under Neocate (lactase def) Carbohydrate free diet (glucose-Galactose malabs.) Diarrhea during NPO Ions Transport Defects Hyponatremia Hyponatremia Amino Ac Na+ Glu Na+ Bile Ac Na+ H+ Na+ Cl- HCO3- Hyponatremia Alkalosis Diarrhea: Pathophysiology 1. 2. 3. 4. 5. Secretory diarrhea Osmotic diarrhea Ion transport defects Reduced surface area Abnormal motility Intractable Diarrhea of Infancy (IDI)  1968 - 1st described by the following features: 1. 2. 3. Diarrhea in an infant <3m Lasting > 2 w 3 or more negative stool cultures IDI / PDI: Causes The list of causes can be divided into: Normal villus-crypt axis Villus atrophy IDI / PDI: Causes A. Normal Villus a) 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) b) Micronutrient deficiency  Acrodermatitis enteropathica (zinc def) c) Enzyme deficiency  Enterokinase def d) Congenital short bowel IDI / PDI: Causes B.Villus Atrophy  Microvillus inclusion disease (MVID)  Tufting enteropathy  Autoimmune enteropathy  IPEX syndrome  Infectious enteropathy  Post-infectious enteropathy  Allergic enteropathy  Idiopathic Microvillus Inclusion Disease  The 2nd most common identified cause of IDI/PDI beginning in the 1st week of life (After infection)  Various names: a) Microvillus inclusion disease  (microvillus inclusions in enterocytes/colonocytes - the characteristic diagnostic feature on EM) b) Congenital microvillus atrophy c) Familial microvillous atrophy d) Davidson’s syndrome 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 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 MVID Crypt cells – increase in secretory granules, otherwise appear near normal on EM, welldeveloped 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 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 PAS-Control PAS-MVID CD10 - control CD10 - MVID 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 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 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 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 Tufting Enteropathy 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 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 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 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 CD3positive lymphocytes within the epithelium and lamina propria 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  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 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 IDI / PDI: Causes B.Villus Atrophy  Microvillus inclusion disease (MVID)  Tufting enteropathy  Autoimmune enteropathy  IPEX syndrome  Infectious enteropathy  Post-infectious enteropathy  Allergic enteropathy  Idiopathic Thank You!