Immune Conference

By NTUH Ped.R2 鄭嘉琪 /VS. 楊曜旭/P 江伯倫 , 周正成

C.C

Abnormal liver function for 2+ years

Brief Hx

1. Birth history: G1P1, GA: 42wks, NSD, BW: 3780gm, PROM (-), DOIC (-), perinatal insult (-), neonatal hyperbilirubinemia (-) 2. Vaccination: As scheduled, Hibx3. 3. G & D: BW: 43kg ( 25-50 th percentile) BH: 144cm ( 3-10 th percentile) DMS: WNL 4. Maternal history: n.p 5. Previous history: n.p 6. Family history: no contributory

P.I.• 1993 (4y/o) in 高醫 hospital ‧Several episodes of GTC ‧Hypocalcemia Hypoparathyroidism(PTH<8pg/ml) -Ca. carbonate 5# qd and calcitriol 5# qd • 1997 (8y/o) ‧Frequent infections (HSV, oral thrush, submandibular cellulitis); pneumonia r/o sepsis -> admitted 高醫 hospital• T-cell immune deficiency was found

P.I.• 2000 ( 11 Y/O) -> Admitted to 高醫 hospital

• Hypoparathyroidism & hypocalcemia

• T3,T4, TSH, ACTH and cortisol: WNL

• T cell & B cell number: WNL

• T cell & B cell function: WNL

• Total T cell:74.2; Active T cell:27.29

• Total B cell: 20.42

• CD4 36.13; CD8:28.79

P.I.• 2000 ( 11 Y/O)• Impaired liver function GOT/GPT: 97/104; Bil(T/D): 1.53/0.49

‧ Gallstone and medullary nephrocalcinosis• Anemia: IDA or chronic dx related• 2002.4(13y/o) -> 小港 hospital • Abnormal liver function• Amnonia:195;GOT/GPT:403/411; Bil(T/D):6.7

9/5.63;• ALP:1464; γ-GT:67

Brief hx Summary

13 y/o 7 m/o boy :

(1) GTC-> Hypocalcemia-Hypoparathyroidism since 4

y/o,1993, s/p Ca and Vit D3 supplement

(2) Chronic mucocutaneous candidiasis (oral thrush,

onychomycosis), viral infection

(3) Vitiligo, enamel hypoplasia, nail dystrophy

(4) Anemia, cause to be determined since 8y/o, 1997

(5) Impaired liver function since 11y/o, 2000

(6) Gallstones and nephrocalcinosis since 11y/o, 2000

Our Work Up

Hypocalcemia

• 24hr Ca2+ excretion: 1.75mg/kg/day• 24hr CCR: 145.2 cc/min/1.73m2• Urinary Ca/Cr ratio: 0.09• 24hr Mg2+excretion: 0.05mmol/kg/day • % TRP: 98.2% • iPTH < 1 pg/ml

2002.7.2 Ca P Mg Cre

Serum 1.54 9.5 0.73 0.5

Urine 3.59 51.6 4.14 152.2

D/D of Hypocalcemia

• Parathyroid hormone (PTH) deficiency

• PTH receptor defects (pseudohypoparathyroidism)

• Ca2+ -sensing receptor activating mutation

•  Magnesium deficiency

• Exogenous inorganic phosphate excess

• Vitamin D deficiency

D/D of PTH deficiency

* Aplasia or hypoplasia of parathyroids

 & DiGeorge syndrome ; Velocardiofacial syndrome

* Surgery

* Autoimmune parathyroiditis

     & Autoimmune Polyendocrinopathy-Candidiasis-

Ectodermal Dystrophy (APECED)(APS type I)

      & Wilson disease

*  Idiopathic hypoparathyroidism

R/O DiGeorge syndrome

• Parathyroid glands aplasia/ hypoplasia

→ hypoparathyroidism (+)

• Thymus aplasia/ hypoplasia (?)

→ T-cell immunity deficiency (+)

‧Congenital heart disease (atrial and ventricular septal defects) (-)

‧Anomalies of the great vessels (-)

‧Facial anomalies: (-)

‧Chromosome: normal

Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED)(APS type I)

• Chronic mucocutaneous candidiasis (CMC)

• Hypoparathyroidism

• Addison’s disease

• Other associated disorders

CMC- Immunodeficiency ?• T.B cell amount( 07/05 ): WNL IgG, IgA, IgM: WNL T cell: 82; B cell: 9, NK cell:7; CD8:32, CD4:44; Nativ

e23; Memory:21.• Mitogen stimulation test (proliferation ): normal • Candida delayed skin test: (-) Induration< 1 cm at 48 hour & 72 hour• T cell function to candida: decreased• B-cell function: blood type: O ; Anti-A Titer, Anti-B Tite

r: WNL

APECED Other associated disorders

Endocrine components

Prevalence

%

Non-endocrine components

Prevalence%

Ovarian failure 60 Enamel hypoplasia 77

IDDM 18 Nail dystrophy 52

Testicular atrophy 14 T.M calcification 33

Parietal cell atrophy 13 Alopecia 27

Hypothyroidism 6 Keratopathy 22

Non- endocrine Vitiligo 13

Cholelithiasis rare Autoimmune Hepatitis

13

Asplenism rare Intestinal malabsorption

10

APECED-Other Endocrinopathy w/u

• Cortisol, ACTH: WNL

• Anti-microsomal Ab, thyroglobulin Ab: (-)

T3, T4, free T4, hs TSH:WNL

• FSH, LH, and testosterone: WNL

• HbA1C, AC sugar: WNL

• Gastric parietal cell Ab (-)

• Anti-parathyroid Ab: (-)

D/D of chronic hepatitis

• Chronic viral hepatitis HAV, HBV, HCV, EBV, CMV infection evidenc

e• Drug induced hepatitis• Metabolic disorder associated with chronic liver d

x• Autoimmune hepatitis elevated liver enzyme, ANA(+), biopsy: chronic h

epatitis, negative viral infection

Chronic Hepatitis w/u • Liver span: 2fb below RCM• Anti-HAV; HbsAg, AntiHbs-Ag;Anti-HCV(-) • EBV: no recent infection • CMV IgM, IgG: (-) • Ceruloplasmin : WNL• Elevated liver enzyme• Autoimmune hepatitis: anti-smooth muscle Ab

(-) and ANA (+)• Liver echo: increased echogenicity, gallstone.

Chronic hepatitis

Piece-meal necrosis

Limiting plate disruption

Enlarged portal area

Work up Summary at NTUH• Definite diagnosis * Hypoparathyroidism * Nephrocalcinosis * Chronic mucocutaneous candidiasis (CMC) * T cell immunodeficiency * Ectodermal dystrophy: vitiligo, enamel hypoplasia, nail dystrophy * Chronic hepatitis (autoimmune hepatitis) * Anemia• Combined hypoparathyroidism,CMC,and chronic hepatitis in

OMIM -> Tentative Dx: APECED

Discussion

Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED)(APS type I)

• Chronic mucocutaneous candidiasis (70%, <5 y/o)

• Hypoparathyroidism (90%, >3 y/o)

• Addison’s disease (90%, > 6 y/o)

• Other associated disorders

• AIRE(autoimmune regulator) gene mutation

Chronic mucocutaneous candidiasis

Oral thrush, onychomycosis without disseminated candidiasis (cause ?)

In our patient

• Autoimmune hepatitis: Steroid full dose for autoimmune process -> f/u liver function and immune profile at OPD

• CMC: Give topical anti-candida drug • Hypoparathyroidism: Keep Ca and vit D3, nutritio

n education of Ca & P balance for prevention of nephrocalcinosis progression -> check level and f/u renal echo per year

• Educate the patient about possible disorders in the future, like Addison’s disease and adequate mx

OPD f/u GOT GPT ALP LDH Ca P Am-m

oniaANA medication

7/2 89 64 1397 599 1.54 9.5 86 1:640 nil

7/15 18 29 1657 553 1.63 4.8 67 1:40- Predonine Sandimmun

Oral thrush

7/22 88 89 1738 581 1.38 0.4 Predonine, Sandimmun, Imuran

8/1 24 29 1.42 6.8

8/3 30 32 862 1.01 10.

8/5 32 35 1073 614 1.38 7.5 Imuran, Predonine