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New season. M EDICAL G RANDROUNDS. Michelle Anne Rosales Ozaeta , MD Department of Internal Medicine FIRST YEAR RESIDENT Fellow In-Charge: Maria Princess M. Landicho , M.D. Moderator : Maria Jocelyn C. Isidro, M.D Resource Speaker: Marysia T. Recto, M.D. Objectives. GENERAL : - PowerPoint PPT Presentation
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Michelle Anne Rosales Ozaeta, MD
Department of Internal MedicineFIRST YEAR RESIDENT
Fellow In-Charge: Maria Princess M. Landicho, M.D.
Moderator: Maria Jocelyn C. Isidro, M.D
Resource Speaker: Marysia T. Recto, M.D.
New seasonNew seasonNew seasonNew season
1
Objectives
1. GENERAL :• Discuss multiple autoimmune disorders in a 19 year
old male with alopecia universalis.
2. Specific :• Discuss a patient with newly diagnosed diabetes mellitus
with diabetic ketoacidosis at presentation.• Determine other possible autoimmune diseases that may
accompany diabetes mellitus and alopecia universalis.• Explore immunodeficiency as a possible cause of recurrent
infections since childhood.
2
What we theoretically read in books is someone else’s
reality.
3
JMC, 19 year old maleadmitted on Oct. 10, 2010
Chief complaint:
FEVER and CHILLS
4
HISTORY OF PRESENT ILLNESS
CHILDHOOD
CHILDHOOD
Bouts of flu-like symptoms every 4-5 months; Pneumonia 1x/year
Patchy hair loss when he was 10
Diagnosed to have alopecia universalis at 11 of unknown etiology.
5
HISTORY OF PRESENT ILLNESS
CHILDHOODCHILDHOOD
2 months2 monthsHe was admitted at MMC for 8 days and treated as a case of pneumonia
Negative AFB smear and culture
6
HISTORY OF PRESENT ILLNESS
CHILDHOODCHILDHOOD
2 months2 months
2 weeks2 weeks Polyphagia, polydipsia, polyuria, nocturia
AdmissionAdmission 12
(+) Generalized weakness, anorexia, undocumented weight loss(+) thirst, nausea, dizziness
5 days5 days
Few hoursFew hours (+) Fever and chills, vomiting
REVIEW OF SYSTEMS
SYSTEM POSITIVE NEGATIVERespiratory Occasional
nonproductive cough and colds
Hemoptysis, shortness of breath
Cardiac Chest pain, orthopnea, exertional dyspnea, paroxysmal nocturnal dyspnea, palpitations, edema
Gastrointestinal
Abdominal pain, abdominal distension, diarrhea, constipation, steatorrhea
Genitourinary Dysuria, hematuria, intermittency, feeling of incomplete voiding, incontinence 13
REVIEW OF SYSTEMSSYSTEM POSITIVE NEGATIVEEndocrine Headache, diplopia,
numbness/tingling sensation, heat/cold intolerance, tremors, changes in bowel movement, experiences morning erection
Dermatologic Generalized absence of hair
Active dermatoses, rashes, photosensitivity
Musculoskeletal
Joint pains/swelling/stiffness, limitation of motion, myalgia
Neurologic Unilateral extremity weakness/numbness, slurring of speech, behavioral changes
Ophthalmologic
Occasional blurred vision when looking at objects at a distance
Eye pain, redness, swelling, or discharge
14
Brief Pediatric History
• Birth/Maternal History: Born to a then 38 year old G2P1 (1001) via Caesarian Section, no complications. No maternal illnesses during pregnancy.
• Immunization History: Completely immunized child. (BCG, DPTx3, OPVx3, HepBx3, Measles, MMR)
• Nutritional History: Initially breastfed then shifted to formula milk. No food preferences.
• Developmental History: At par with age
15
PAST MEDICAL HISTORY
• Bronchial asthma: (last attack in past year) on as needed salbutamol inhaler, no oral/inhaled steroid use
• Not known diabetic, non-hypertensive, no thyroid/liver/kidney disease
• No cancer• No surgeries/blood transfusion• No history of trauma
16
FAMILY MEDICAL HISTORY
• Hypertension and stroke: father• Endometrial carcinoma, stage 1: mother• Cancer (unrecalled type): paternal
grandfather
(-) Alopecia(-) Diabetes, asthma, thyroid disease(-) Autoimmune or connective tissue disease(-) Fetal death in-utero or recurrent abortion in the
mother17
PERSONAL / SOCIAL HISTORY
• Second of 2 siblings• Had an active childhood• 2nd year philosophy student • Non smoker, occasional alcoholic drinker• Had ear piercing done 2 years ago• Tattoo on chest painted in August 2010.• Denies illicit drug use, denies sexual contact
18
PHYSICAL EXAM
19
Awake, weak-looking, slender, ambulatory,
tachypneic, speaks with an adult male voice
Awake, weak-looking, slender, ambulatory,
tachypneic, speaks with an adult male voice
PHYSICAL EXAM
BP 110/80HR 104 Weight 45kgRR 22 Height 173cmTemp 37.5 BMI 15.1O2sats 99%Pain 0/10 20
Generalized absence of hair: head, face,
axilla, trunk, extremities. Dry skin especially on lower extremities, no
hypo-/hyperpigmented skin lesions.
Generalized absence of hair: head, face,
axilla, trunk, extremities. Dry skin especially on lower extremities, no
hypo-/hyperpigmented skin lesions.
PHYSICAL EXAM
21
Anicteric sclerae, pink palpebral conjunctivae, with dry lips, and buccal mucosa, no oral thrush, non hyperemic posterior pharyngeal wall and tonsils, no neck mass, flat neck veins.
Equal chest expansion, no retractions, no use of accessory muscles of respiration, clear lungs, no wheezes nor rales
Quiet precordium, distinct heart sounds, tachycardic, regular rhythm, no murmurs
PHYSICAL EXAM
22
PHYSICAL EXAMINATION
Flat abdomen, normoactive bowel sounds, soft, nontender, no palpable masses, no CVA tenderness
Sparse pubic hair: Tanner stage 2
Size of penis adequate for age
No edema, no cyanosis, pulses full and equal
PUBIC HAIR12-13 yo
13-14 yo
14-15 yo
PENIS15-16yo
PHYSICAL EXAM
23
PHYSICAL EXAMINATION
Alert, GCS 15, oriented to 3 spheresPupils 2mm ERTLVisual acuity 20/25, both eyesFull range of extraocular muscle motionsMuscle strength 5/5 all extremitiesNo sensory deficitsNormoreflexiveNo nystagmus, dysmetria, dysdiadochokinesiaNo Babinsky
NEURO EXAMNEURO EXAM
24
19 year old male19 year old male
FEVER, CHILLS, VOMITINGFEVER, CHILLS, VOMITING
Polydipsia, polyuria, polyphagia, nocturia, urinary frequency
Polydipsia, polyuria, polyphagia, nocturia, urinary frequency
Anorexia, weight loss, generalized weakness, nausea,
dizziness
Anorexia, weight loss, generalized weakness, nausea,
dizziness
Underweight, tachycardic, tachypneic,
weak-looking, dehydrated
Underweight, tachycardic, tachypneic,
weak-looking, dehydrated
Recurrent respiratory infectionsRecurrent respiratory infections
Generalized absence of hair, Sparse pubic hair
(tanner 2)
Generalized absence of hair, Sparse pubic hair
(tanner 2)
25
COURSE IN THE WARDS
26
FEVER & CHILLSPROBLEM #1
S> fever, chills, urinary frequency occasional nonproductive cough and colds no abdominal pain, no BM changesO> normotensive, tachycardic at 104, RR 22, temp 37.5 no tonsillopharyngeal congestion Clear lungs, nontender abdomen, no CVA tenderness
URINALYSIS: Significant pyuria and few-many bacteria, RBCCBC: leukocytosis 14,430, segmenter predominanceCHEST XRAY: no infiltrates, no effusion
27
28
FEVER & CHILLSPROBLEM #1
Complicated urinary tract infection
IMPRESSION
Antibiotic coverage: Cefuroxime 750 mg IV q8
Hydration: PNSS 100ml/hour
Antiemetic: Metoclopromide 10 mg IV now; Ondansetron drip
BLOOD CS: No growth after 5 daysURINE CS: No growth after 2 days
30
POLYPHAGIA, POLYDIPSIA, POLYURIA
PROBLEM #2
S> Progressing to loss of appetite, malaise, weight loss, vomiting
O> BMI 15 CBG = 588 mg/dl URINALYSIS: Sugars 2+, Ketones +2, negative protein SERUM KETONES: 6.6mmol/L HbA1C: 8.5%
31
DKA HHSMILD MODERATE SEVERE
Plasma glucose588
> 250 > 250 > 250 > 600
Arterial pH7.2
7.25 – 7.30
7.00 -7.24
<7.00 >7.30
Serum Bicarbonate
8
15-18 10 - <15 < 10 >18
Ketones (serum/urine)
++
+ + + Small
Serum osm311
300 - 320 300 - 320 300 - 320 > 320 mOsm/kg
Anion gap > 10 > 12 > 12 Variable
Mental statusAlert
Alert Alert/Drowsy
Stupor/Coma
Stupor/Coma
Diabetic Ketoacidosis
OR
Hyperglycemic Hyperosmolar State
Kitabachi, A., et. Al. 2009. Hyperglycemic crises in adult patients with diabetes. Diabetes Care, 32: 7 (1335-43).32
HYPERGLYCEMIAPROBLEM #2
Diabetic Ketoacidosis, moderate
IMPRESSION
Control of hyperglycemia: Hydration, insulin
Monitoring: CBGs, Hydration status (Central line inserted: CVP;
accurate I/O), K+
Acidosis: Sodium bicarbonate
33
GLUCOSE MONITORING DKA acute phase
(nth) hour of admission
CBG
34
Input – output monitoring
CVPinitial=5-6 CVP =8-10
35
Day 1 2 3 4 5
Serum Sodium
Corrected Na = (RBS - 100) x 0.016 + actual Na36
432Day 1
Serum Potassium
5 6
37
SERUM CHEMISTRIES
N.V. 10/10 10/11 10/12 10/13 10/14 10/15BUN 7 – 18 mg/dl 18.4 9.20Crea 0.6 – 1.0
mg/dl1.19 0.58 0.5
Mg 1.7 - 2.55 mg/dl
2.02 1.6 1.77
Phos 2.7-4.5 mg/dl
4.41
iCa 1.12-1.32 meq/L
1.30
38
39
Usually develops over a long period of time (months to years)
Associated with metabolic syndrome, insulin resistance
40Harrison’s Internal Medicine 17th ed.
Latent Autoimmune Diabetes of Adults•Slow-onset diabetes or type 1.5
•Form of type 1 diabetes, similar to juvenile diabetes, however, occurs in adults typically over the age of 25.
•Destruction of the pancreas occurring slowly, usually over years.
Latent Autoimmune Diabetes in Adults: Symptoms, Diagnosis, Treatment, and Prognosis (http://www.isletsofhope.com/diabetes/symptoms/latent_autoimmune_diabetes_lada_1. html).
41
Maturity Onset Diabetes of the Young•Age of onset before 25 with an autosomal dominant mode of inheritance (“monogenic diabetes”) with variable penetrance.
•Confirmed by specific gene testing
•Ineffective insulin production or release by pancreatic β-cells; Mild to moderate hyperglycemia
"What is maturity-onset diabetes of the young (MODY)?" (http://www.diabetes.niddk.nih.gov/dm/pubs/mody/#3).42
•Classic: polyuria, polydipsia, polyphagia, tiredness, and weight loss. Commonly with DKA as presenting symptom
•Polygenic disease, environmental influence, immunologic factors
•Autoimmune destruction of pancreatic beta cells, regardless of causative entity.
http://www.ncbi.nlm.nih.gov/omim/22210043
44
45
T1DM SPECIAL TESTS
Shivam Champaneri, M.D. and Christopher Saudek, M.D. Autoantibodies in Type 1 Diabetes. 02-03-2011 46
TESTS Description PATIENT
Insulin Connecting Peptide (C-peptide)
Measures residual beta cell function by determining the level of insulin secretion
0.26ng/ml (VERY LOW)Normal 1.1-4.4
Insulin autoantibodies Diverse, high-affinity, more predictive of T1D; appearance at a young age, subsequent progression to multiple autoantibody positivity
49-92% sensitivity
Glutamic acid decarboxylase (GAD); autoantibodies
Particularly important in late onset autoimmunity (LADA)
84% sensitivity
Phosphatase-related IA-2 autoantibodies
Often appear after other autoantibodies; have a higher positive-predictive value for T1DM than GAD.
54-75% sensitivity
• Rapid loss of all hair, including eyebrows and eyelashes. It is the most severe form of alopecia areata
*Alopecia Totalis = loss of all scalp hair only
• Most cases linked to underlying autoimmune disease, but some cases may be inherited as an autosomal recessive trait (gene HR in 8p21.2).
ALOPECIA UNIVERSALIS
PERSON IN THE PHOTO IS NOT THE PATIENT47
WHAT WE ALREADY KNOW…
Type 1 diabetes : 0.1 to 37 in 100,000 5-10% of all diabetes cases
Alopecia universalis: 1 in 100,000
RULE OUT OTHER POSSIBLE AUTOIMMUNE DISEASES
PROBLEM #3
49
RULE OUT OTHER POSSIBLE AUTOIMMUNE DISEASES
PROBLEM #3
LUPUS PANEL PATIENTANA negativeantiSmith negativeantiRNP negativeantiJJO negativeantiSSA/SSB negativeantidsDNA negative
50
RULE OUT OTHER POSSIBLE AUTOIMMUNE DISEASES
PROBLEM #3
51
Van den Driessche, A,, et al. 2009. Type 1 diabetes and autoimmune polyglandular syndrome: a clinical review. Netherlands J of medicine 67(11): 376-384.52
• Different clusters of autoimmune disorders and are rare endocrinopathies characterized by the coexistence of at least two glandular autoimmune mediated diseases
• The definition of the syndrome depends on the fact that if one of the component disorders is present, an associated disorder occurs more commonly than in the general population.
Kahali. 2010. Polyglandular autoimmune syndromes. European J or Endocrinology 116:11-20. 53
PAS I PAS II & PAS IIIPrevalence Rare Relatively common
Incidence <1 : 100,000/year 1– 2 : 10,000/year
M/F ratio 3:4 1:3
Onset Childhood Childhood through adulthood
Inheritance Monogenic (AIRE/APECED Gene)
PolygenicSusceptibility: HLA DR3 and DR4
54
PAS I
– Alopecia– Hypogonadism– Type 1 diabetes– Hypothyroidism– Dental enamel hypoplasia– Malabsorption– Chronic active hepatitis– Vitiligo– Pernicious anemia– Interstitial nephritis– Keratoconjunctivitis
Harrison’s Internal Medicine 17th ed.55
PAS II: Schmidt's syndrome
– Alopecia – Primary hypogonadism – Hypophysitis– Myasthenia gravis– Vitiligo– Pernicious anemia– Celiac disease– Seronegative arthritis– Parkinson’s disease
Majeroni, B. 2007. Autoimmune Polyglandular Syndrome Type II. American Family Physician 75(5): 667-670.
Carpenter's syndrome
56
PAS II: Schmidt's syndrome
Majeroni, B. 2007. Autoimmune Polyglandular Syndrome Type II. American Family Physician 75(5): 667-670.
Carpenter's syndrome
vomiting, anorexia, unexplained weight loss, and malaise
hyperpigmentation of the skin and mucosal surfaces
hypotension, hypoglycemia, and craving for salt
57
Autoimmune Thyroid disease
Anti TPO Up to 100 8.201Anti TG Up to 100 0.0238
ACTH 8 am : 2.196; 9 am : 4.038
normal
ACTH Stimulation test normalAnti21-hydroxylase n/a
n.v. In-patient Out-patientTSH 0.27–
3.756.71 high
2.030
FT3 4.2 – 12 3.995 low
5.243
FT4 8.8 – 33 16.66 19.533
Prolactin 86 – 324 217.8 mIU/mLLH 1.7 - 8.6 1.89 mIU/mLFSH 1.5 - 12.4 3.35 mIU/mLTestosterone 2.8 - 8.0 4.16 ng/mL
58
PAS II: Schmidt's syndrome
– Alopecia – Primary hypogonadism – Hypophysitis– Myasthenia gravis– Vitiligo– Pernicious anemia– Celiac disease– Seronegative arthritis– Parkinson’s disease
Majeroni, B. 2007. Autoimmune Polyglandular Syndrome Type II. American Family Physician 75(5): 667-670.
Carpenter's syndrome
59
PAS III
Absence of Addison’s disease
Vitamin B12Assay Normal
Kahali. 2010. Polyglandular autoimmune syndromes. European J or Endocrinology 116:11-20. 60
RECURRENT RESPIRATORY INFECTIONS
PROBLEM #4
61
n.v. PATIENTSerum IgM 0.4-2.3 0.55g/L Serum IgA 0.7-4.0 0.19g/L LOWSerum IgG 7-16.0 1.99g/L LOW
62
Immunoglobulin deficiency syndromesSevere combined immunodeficiency (SCID) After 6 months of age,
Both T and B cellsX
Transient hypogammaglobulinemia of infancy
X-linked agammaglobulinemia
IgG subclass deficiency
Selective IgA deficiency
X-linked immunodeficiency deficiency with hyper-IgM
Common variable immunodeficiency (CVID) 63
Immunoglobulin deficiency syndromesSevere combined immunodeficiency (SCID) After 6 months of age,
Both T and B cellsX
Transient hypogammaglobulinemia of infancy Between 3 and 6 months of age
X
X-linked agammaglobulinemia
IgG subclass deficiency
Selective IgA deficiency
X-linked immunodeficiency deficiency with hyper-IgM
Common variable immunodeficiency (CVID) 64
Immunoglobulin deficiency syndromesSevere combined immunodeficiency (SCID) After 6 months of age,
Both T and B cellsX
Transient hypogammaglobulinemia of infancy Between 3 and 6 months of age
X
X-linked agammaglobulinemia all Classes decreased XIgG subclass deficiency Only IgG decreased XSelective IgA deficiency Only IgA decreased XX-linked immunodeficiency deficiency with hyper-IgM
Elevated IgM X
Common variable immunodeficiency (CVID) 65
COMMON VARIABLE IMMUNEDEFICIENCY
• Most commonly encountered primary immunodeficiency.
(aka Acquired hypogammaglobulinemia) 1:50,000 – Defective antibody production: low levels of serum
immunoglobulins (both IgG and IgA, and in others also IgM) – Increased susceptibility to infection
• The intrinsic dysregulation of the immune system leads to defective T-cell activation and proliferation, as well as dendritic cell and cytokine defects.
Filipovic, et al. 2009. Common Variable Immunodeficiency Associated with Inflammatory Bowel Disease and Type I Diabetes. Clinical Medicine: Case Reports 2009:2 67–71
66
COMMON VARIABLE IMMUNEDEFICIENCY
• The primary cause of common variable immunodeficiency (CVID) remains unknown despite 40 years of research.
• MOST ARE SPORADIC
• Different modes of inheritance such as autosomal dominant with variable penetrance, autosomal recessive, and X-linked forms
Chapel, H., et al. 2008. Common variable immunodeficiency disorders: division into distinct clinical phenotypes. Blood. 112:277-286c67
CD Tests Normal Values Result (mm3)CD 3 (mature T cells)
1600 (73%) (960-2600)
1133 (74.02%)
CD 4 (helper T cells)
940 (46%) (540-1660)
665 (43.42%)
CD 8 (suppressor T cells)
520 (27%) (270-930)
528 (34.5%)
CD4/CD8 ratio 1.7(0.9-4.5)
1.3%
CD3-/CD16/CD56 (natural killer cell)
0-530 49
CD19 (B lymphocyte)
246 (13%) (122-632)
57 (3.7%)
LOW
CD 20 (B lymphocyte)
246 (13%) (122-632)
146 (9.54%)
68
COMMON VARIABLE IMMUNEDEFICIENCY
DISTINCT CLINICAL
PHENOTYPES
Chapel, H., et al. 2008. Common variable immunodeficiency disorders: division into distinct clinical phenotypes. Blood. 112:277-286c
Recurrent infections +RR 4.0 (P<.001)
RR 2.5 (P =.03)
RR 2.5 (P<.001)
RR 5.5 (P = .002)
69
COMMON VARIABLE IMMUNEDEFICIENCY
• MAINSTAY OF TREATMENT: Ig replacement therapy
70
72
THE END
73
Common variable immunodeficiencyAlopecia universalisDiabetes Mellitus Type 1Diabetic Ketoacidosis, RESOLVEDComplicated urinary tract infection, RESOLVEDAcute Kidney Injury from volume depletion, RESOLVEDHypokalemia, RESOLVEDThoracic dextroscoliosis
74
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