M EDICAL G RANDROUNDS

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.

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CHILDHOODCHILDHOOD

2 months2 monthsHe was admitted at MMC for 8 days and treated as a case of pneumonia

Negative AFB smear and culture

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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

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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

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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

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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

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PHYSICAL EXAM

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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

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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

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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

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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

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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)

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COURSE IN THE WARDS

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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

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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

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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%

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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

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GLUCOSE MONITORING DKA acute phase

(nth) hour of admission

CBG

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Input – output monitoring

CVPinitial=5-6 CVP =8-10

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Day 1 2 3 4 5

Serum Sodium

Corrected Na = (RBS - 100) x 0.016 + actual Na36

432Day 1

Serum Potassium

5 6

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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

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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).

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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

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

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PROBLEM #3

LUPUS PANEL PATIENTANA negativeantiSmith negativeantiRNP negativeantiJJO negativeantiSSA/SSB negativeantidsDNA negative

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PROBLEM #3

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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

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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

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vomiting, anorexia, unexplained weight loss, and malaise

hyperpigmentation of the skin and mucosal surfaces

hypotension, hypoglycemia, and craving for salt

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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

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– Alopecia – Primary hypogonadism – Hypophysitis– Myasthenia gravis– Vitiligo– Pernicious anemia– Celiac disease– Seronegative arthritis– Parkinson’s disease



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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

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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

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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


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



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 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

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• 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%)

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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)

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• MAINSTAY OF TREATMENT: Ig replacement therapy

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THE END

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Common variable immunodeficiencyAlopecia universalisDiabetes Mellitus Type 1Diabetic Ketoacidosis, RESOLVEDComplicated urinary tract infection, RESOLVEDAcute Kidney Injury from volume depletion, RESOLVEDHypokalemia, RESOLVEDThoracic dextroscoliosis

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M EDICAL G RANDROUNDS

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