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Heavy metals, Outdated tetracycline, Gentamicin, Ifosfamide, Cyclosporine, tacrolimus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
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