1. R3 case conference 報告者 : 楊仁星 指導老師 : 方基存醫師 報告日期 :2011-11-2

2. Index Case presentation Discussion Back to the case

3. Case Presentation

4. Patient ’ s Profiles Name: 陳 x 羽 Gender: female Age: 58 years Ethnic: Taiwanese Marriage: married Occupation: Waitress, School janitor, 有線電視服 務員 Chart number: 39037xxx Date of admission: 2011-9-26

5. Chief complaint General weakness for 4 days

6. Present Illness-I The patient had weakness of bilateral lower limbs for several days 4 days before admission, the weakness was progressed to general weakness. She received injection of unknown substance (may be analgestic) at LMD.

7. Present Illness-II After injection, the weakness became worsen and then the patient couldn’t walk and stand. The associated symptoms included palpitation. She came to our ER for help

8. Present Illness-III She denied fever, chest pain, chest tightness, cold sweating, dyspnea, dizzness, nausea, vomiting, diarrhea, anorexia, tarry or bloody stool, frequency, urgency and flank pain.

9. Past History: Diabetes mellitus for half year without control Denied hypertension, heart disease, HBV, HCV and operation history

10. Personal history: Allergy: no known allergy Alcohol: denied Smoking: denid Betelnut: denied Medication history: Chinese Medicine ( 大豆 類黃酮, 保護關節藥 )

11. Family History:

12. Physical Examination-I Vital sign: BT: 36 ℃, PR:62/min, RR: 18/min, BP: 121/80 mmHg General appearance: fair looking Consciousness: alert, E4V5M6 HEENT: sclera: not icteric, conjunctiva: not pale Neck: supple, JVE (-/-), LAP (-/-) Chest: bilateral symmetric expansion bilateral breathing sound: clear Heart: regular heart beat without murmur

13. Physical Examination-II Abdomen: flat no superficial vein engorgement no spider angioma normoactive bowel sound no tenderness, no rebound pain no Murphy’s sign liver and spleen not palpable no shifting dullness Back: no knocking pain over bilateral flank pain Extremities: no pitting edema at bilateral lower limbs Skin: no petechiae or ecchymoses no skin rash

14. EKG at ER

15. CXR at ER

16. Lab data-I 9/25 CBC/DC WBC (/uL)8400 RBC4.28 x 106 Hb (g/dL)12.6 Hct (%)36 MCV (fL)84.1 MCH (pg/Cell)29.4 MCHC (gHb/dL)35 Platelets (/uL)220 x 103 Seg (%)82 Lymphocyte (%)12 Monocyte (%)6 Eosinophil (%)0 Basophil (%)0 9/25 Biochemistry BUN (mg/dL)12.9 Cr. (mg/dL)0.74 Na (mEq/L)141 K (mEq/L)1.4 Ca (mEq/L)9.3 ALT (U/L)16

17. Lab data-II

18. Impression Hypokalemia periodic paralysis Diabetes mellitus

19. Clinical course-I

20. Clinical course-II Other blood tests during hospitalization

21. Clinical course-III Urine anion gap: 56+14.1-62 = 7.9

22. Clinical course-III kidney echo on 9/30

23. Clinical course-IV kidney echo on 9/30

24. Clinical course-V kidney echo on 9/30 Left Kidney Length: 10.7 cm Right Kidney Length: 11.8 cm Impression: 1. Right renal stone (0.7cm) 2. Bilateral renal calcification spots 3. Parenchymal renal disease

25. Clinical course-IV

26. Final diagnosis Type I renal tubular acidosis, suspect autoimmune disease related Renal stones Type II diabetes mellitus, under diet control

27. Discussion

28. Renal tubular acidosis

29. A systemic hyperchloremic and normal anion gap acidosis with relatively normal glomerular filtration rate Results from either the net retention of hydrogen chloride or net loss of sodium bicarbonate Three major subgroups of RTA Distal or type 1 RTA Proximal or type 2 RTA Hypoaldosteronism or type 4 RTA

30. Renal tubular acidosis-distal RTA (type 1) Failure of distal nephron and collecting duct to secret hydrogen ion Failure to reabsorb filtered bicarbonate that was not reabsorbed in proximal tubule Failure of titration of phosphate buffer and decreased exc retion of NH4+ Precise nature of defect is not known.

31. dRTA (Type I)

32. dRTA (Type I)- Etiology

33. dRTA (Type 1)- Clinical features muscle weakness Hyperventilation Acute acidosis Hypokalemia Inability to acidify the urine to a pH of less than 5.3 70% have either nephrocalcinosis (very rarely a feature of other types) or calcium containing renal calculi Rickets and growth stunting are frequent features in childhood cases. ± osteomalacia in adults

34. Renal tubular acidosis-proximal RTA (type 2) Proximal tubule reabsorption of approximaly 80~90% Type 2 RTA: an impariment of HCO 3 - reabsorption in the proximal tubule Decreased renal HCO 3 - threshold Distal acidifcation mechanisms are intact May lower urine pH below 5.5

35. pRTA ( Type 2)

36. pRTA ( Type 2): Etiology

37. pRTA ( Type 2): Clinical feature General weakness Metabolic acidosis Hypokalemia proximal myopathy, osteomalacia or rickets Normal urinary acidification Nephrocalcinosis and renal calculi are virtually never present

38. Renal tubular acidosis-type 4 Type 4 RTA is not actually a tubular disorder reduction in proximal tubular ammonium excretion, which is secondary to hypoaldosteronism or pseudohypoaldosteronism, and results in a decrease in urine buffering capacity. Presentation: hyperkalemia and normal urinary acidification Nephrocalcinosis and Urolithiasis are absent in type 4

39. Hyperkalemic RTA (Type 4): Etiology

40. Renal tubular acidosis

41. Sjogren ’ s syndrome

42. Sj ö gren's syndrome A chronic autoimmune disease, affecting mainly the exocrine glands. Prevalence: 0.3%~0.6% Female:male: 9:1 Can affect extraglandular, such as involvement of the musculoskeletal, pulmonary, GI, hepatobiliary, hematologic, vascular, dermatologic, renal and nervous systems.

43. Sj ö gren's syndrome- Classification Primary SS: occur alone Secondary SS: association with another defined autoimmune disease (eg, SLE, RA, or scleroderma)

44. Sj ö gren's syndrome-Symptoms Two main symptoms: dry eye and dry mouth Other: Joint pain, swelling and stiffness Swollen salivary gland Skin rashes or dry skin Vaginal dryness Persistent dry cough Prolonged fatigue

45. Diagnosis Criteria 2002 American-European consensus Classification Criteria, required four of the following

46. Renal involvement in primary Sjogren ’ s syndrome

47. Sjogren’s syndrome is an autoimmune disorder and the target organs are the exocrine glands, especialy the lacrimal and salivary Kidney involvement is a frequent extraglandular manifestation of primary Sjogren’s syndrome 30~40% of Sjogren’s syndrome patients have symptomatic and asymptomatic renal involvment. The understanding of the clinical presentation of renal involvement in primary Sjogren’s syndrome is based on case reports and small retrospective cohorts.

48. Clinical and laboratory features

49. Patient with Sjogren’s syndrome and RTA tend to present hypokalemic periodic paralysis (HPP)

50. 20 cases of SS-associated HPP reported between 1966~2008

51. Pathogenesis The pathogenesis of the RTA in Sjogren syndrome is unclear Interstitial infiltrate composed of lymphocytes and plasma cells, with secondary invasion of the tubular membrane and lining epithelium -> tubular cell architecture disrupt -> secretion of distal tubule defect Absence of intact H + -ATPase in intercalated cell -> H+ ion secretion defect Hypergammaglobulinemia cause distal renal tubular dysfunction Anti-carbonic anhydrase II antibiodies

52. Carbonic anhydrases (CAs) Key enzymes in the regulation of acid- base balance in both physiological and pathological status Autoantibodies to carbonic anhydrase II (CA II) are increased in renal tubular acidosis with Sjogren’s syndrome ( in the past study )

53. Several new CA isoenzymes (1~13) have been discovered in recent. Recent study, published in Rheumatogy 2011 revealed that none of the anti-CA antibiotics was associated with presence of RTA or proteinuria or urinary α 1 m excretion in patients with PSS. Carbonic anhydrases (CAs)

54. Title: Novel carbonic anhydrase autoantibodies and renal manifestations in patient with primary Sjogren ’ s syndrome Methods: examined anti-CA II antibodies as well as anti-CA I, VI, VII and XIII antibodies by ELISA test in 74 pSS patients (F:M : 70:2) and 56 patients with Sicca symptoms (F:M : 46:10)

55. Title: Novel carbonic anhydrase autoantibodies and renal manifestations in patient with primary Sjogren ’ s syndrome Result: The levels of anti-CA I, II, VI and VII antibiotics differed significantly between two groups

56. Title: Novel carbonic anhydrase autoantibodies and renal manifestations in patient with primary Sjogren ’ s syndrome Result: 33 patients (45%) of pSS had proteinuria and 31% pSS had overt or latent dRTA. None of the studied anti-CA antibodies ( anti- CA I, II, VI, VII and XIII antibodies) was associated with dRTA, presence of protienuria. Urinary pH was significantly associated with levels of anti-CA II, VI and XIII antibodies.

57. Title: Novel carbonic anhydrase autoantibodies and renal manifestations in patient with primary Sjogren ’ s syndrome

58. Histological The most presentation is tubulo-interstitial nephritis (71%)

59. Histological Patients had chronic glomerulonephritis is rare The most common types are membranoproliferative glomerulonephritis and global glomerulosclerosis

61. Histological

62. Proliferative glomerulonephritis with humps and monotypic IgG1-kappa deposits had reported ( NDT,2010/9: Non-Randall proliferative glomerulonephritis with humps and monotypic IgG deposits in primary Sjogren’s syndrome, first case report) 50-year-old female Has experienced asymmetric joint pain and swelling associated with relapsing episodes of fever Has mild proteinuria, intermittent microscopic hematuria, normal renal function Negative cryoglobulinemia, anti-DsDNA and ANCA Positive ANA, SSA, SSB, RF and anti-phospholipid antibodies Total serum protein elevated with hypergammaglobulinemia

63. Immunofluorescence showed abundant subepithelial and mesangial deposits staining brightly for IgG1, C3 and kappa light chain Absence of organization of the deposits appearing as humps by light microscopy.

65. Immunofluorescence showed abundant subepithelial and mesangial deposits staining brightly for IgG1, C3 and kappa light chain

66. Treatment: Potassium replacement therapy Consider steroids in case of RTA associated with SS

67. Back to the case

68. Our patient ’ s characteristics: Progressive weakness Hypokalemic Normal anion gap metabolic acidosis Positive urine anion gap Positive ANA, anti-SSA, anti-SSB Negative for dsDNA Normal RF, C3, C4

69. Suspect the patient presented with symptoms of hypokalemic periodic paralysis and distal RTA is due to autoimmune disease, especially like Sjogren’s syndrome

70. Thanks for your listening